Use of glycosaminoglycan sulfated polysaccharides such as sodium pentosan polysulfate in combination with permeation agents to treat alzheimer's disease

Abstract

The present invention is directed to methods and compositions for the administration of sodium pentosan polysulfate and related glycosaminoglycans, particularly by oral administration, particularly in combination with administration of an intestinal penetration agent. The methods and compositions are suitable for treatment of neurodegenerative diseases such as, but not limited to, Alzheimer's disease. Methods and compositions according to the present invention can be used together with other agents suitable for treatment of neurodegenerative diseases such as, but not limited to, Alzheimer's disease.

Description

PATENT PARSON-58748 USE OF GLYCOSAMINOGLYCAN / SULFATED POLYSACCHARIDES SUCH AS SODIUM PENTOSAN POLYSULFATE IN COMBINATION WITH PERMEATION AGENTS TO TREAT ALZHEIMER’S DISEASE by C. Lowell Parsons CROSS-REFERENCE TO RELATED APPLICATION

[0001] This PCT application claims the benefit of United States Patent Application Serial No. 63 / 620,278 by C. Lowell Parsons, entitled “Use of Glycosaminoglycan / Sulfated Polysaccharides such as Sodium Pentosan Polysulfate in Combination with Permeation Agents to Treat Alzheimer’s Disease,” and filed on January 12, 2024, the contents of which are hereby incorporated in their entirety by this reference. FIELD OF THE INVENTION

[0002] The present invention is directed to methods and compositions for treatment of Alzheimer’s disease and other degenerative conditions of the central nervous system by administration of a sulfated polysaccharide or glycosaminoglycan (also known as a heparinoid) such as sodium pentosan polysulfate in combination with an intestinal permeation agent. BACKGROUND OF THE INVENTION

[0003] Degenerative diseases and conditions of the central nervous system, particularly Alzheimer’s disease, are becoming increasingly common, particularly in Western countries whose populations have longer lifespans. As of 2020, there were about 50 million people worldwide with Alzheimer’s disease. Alzheimer’s disease most frequently begins in people over 65 years of age, although up to 10% of cases are early-onset Alzheimer’s disease, which impacts patients in their 30s to their mid-60s. Alzheimer’s disease affects about 6% of people 65 years or older, with the risk increasing with age, and affects women more than men. The financial burden of Alzheimer’s disease on society is extremely great, with an estimated global annual cost of about $1 trillion. It is the seventh leading cause of death in the United States.PATENT PARSON-58748

[0004] Alzheimer’s disease is a neurodegenerative disease that typically starts slowly and then progressively worsens. The disease is the cause of about 60% to about 70% of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, further symptoms experienced by patients can include problems with language, disorientation with respect to place, mood swings, loss of motivation, self-neglect, and behavioral issues. As an Alzheimer’s disease patient declines, they frequently withdraw from family and society. In many cases, bodily functions are lost, eventually resulting in death. Although the speed of progression of the disease can vary from patient to patient, the typical life expectancy following diagnosis is three to nine years.

[0005] The causes of Alzheimer’s disease are poorly understood. However, it is now recognized that there are many environmental and genetic risk factors associated with the development of Alzheimer’s disease. The strongest genetic risk factor is from a particular allele of APOE, the gene that encodes Apolipoprotein E. Other risk factors include a history of head injury, hypertension, and clinical depression. The disease process is largely associated with amyloid plaques, neurofibrillary tangles, and loss of normal neuronal connections in the brain. A probable diagnosis is based on the history of the illness and cognitive testing, with medical imaging and blood tests to rule out other possible causes by differential diagnosis. Initial symptoms are often mistaken for normal brain aging. Examination of brain tissue is needed for a definite diagnosis, but this is only possible as a post-mortem. Good nutrition, physical activity, and social engagement are considered to be of general benefit in aging, and may help in reducing the risk of cognitive decline and the occurrence of Alzheimer’s disease.

[0006] No known treatments can stop or reverse the progression of Alzheimer’s disease, though some treatments may temporarily improve symptoms. Affected people typically become reliant on others for assistance, placing an increasing burden on family and caregivers, which can lead to social, psychological, physical, and economic stresses.

[0007] The course of Alzheimer’s disease is generally described in three stages, with a progressive pattern of cognitive and functional impairment. These three stages are typically described as: early or mild; middle or moderate; and late or severe. Alzheimer’s disease is known to target the hippocampus which is associated with memory. This is responsible for the first symptoms of memory impairment, the degree of which progresses as the disease progresses.PATENT PARSON-58748

[0008] Alzheimer’s disease is believed to occur when abnormal amounts of amyloid beta, accumulating extracellularly as amyloid plaques or tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neural functioning and connectivity. The specific cause for most cases is still mostly unknown, except for a relatively small percentage of cases where deterministic genetic differences have been identified. The hypotheses that have been advanced include the cholinergic hypothesis, which postulates that the disease is caused by reduced synthesis of the neurotransmitter acetylcholine, and the amyloid hypothesis, which postulates that extracellular amyloid beta deposits are the fundamental cause of the disease, as well as the tau hypothesis. At least one other mutation in the APP gene has been shown to increase the risk of Alzheimer’s disease; however, this mutation is recessive and the increased risk is only apparent in homozygotes. The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell’s cytoskeleton which collapses the neuron’s transport system. A number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of Alzheimer’s disease as bringing about oxidative stress that leads to chronic inflammation.

[0009] Various medications and lifestyle interventions have been employed to reduce the risk of Alzheimer’s disease. As cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with an increased risk of onset and a worsened course of Alzheimer’s disease, so medications such as statins or other medications to treat hypertension or diabetes may reduce the risk of development of Alzheimer’s disease. Depression is also associated with an increased risk of Alzheimer’s disease, so that antidepressants may prove useful as a preventative measure if warranted by the occurrence of depression.

[0010] Current medications used for the treatment of Alzheimer’s disease are essentially palliative in nature. Medications used to treat the cognitive symptoms of Alzheimer’s disease rather than the underlying disease process include: four acetylcholinesterase inhibitors, tacrine, rivastigmine, galantamine, and donepezil; and one NMDA antagonist, memantine.

[0011] Therefore, there is a need for new methods and pharmaceutical compositions that can prevent the development or progression of Alzheimer’s disease. Preferably, such methodsPATENT PARSON-58748 and pharmaceutical compositions can be used together with current therapies or lifestyle interventions that may assist in preventing the development of Alzheimer’s disease or in slowing its progression.

[0012] The use of a glycosaminoglycan, such as a heparinoid or sulfated polysaccharide, optionally together with a penetration agent, typically administered orally, is proposed to resolve epithelial dysfunction present in the blood vessels of the brain and thus prevent or treat Alzheimer’s disease or other neurodegenerative diseases and conditions.

[0013] The blood-brain barrier is a highly selective semipermeable border of endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system, and functions to protect the brain from harmful or undesirable substances that may be present in the blood. The blood-brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillaries, and pericytes embedded in the capillary basement membrane. The blood-brain barrier allows the passage of some small molecules by passive diffusion, as well as allowing selective and active transport of various nutrients, ions, organic anions, glucose, amino acids, and certain macromolecules that are crucial to neural function. The blood-brain barrier restricts the passage of pathogens and some large or hydrophilic molecules into the cerebrospinal fluid, while allowing the diffusion of oxygen, carbon dioxide, hormones, and many small non-polar molecules. The blood-brain barrier also restricts the passage of peripheral immune factors such as signaling molecules, antibodies, and immune cells into the central nervous system, which can serve to insulate the brain from damage due to peripheral immune events. The blood-brain barrier results from the selectivity of the tight junctions between the endothelial cells of brain capillaries. The blood-brain barrier can become damaged in a number of neurological diseases, including, but not limited to, Alzheimer’s disease. This may allow an increased permeability of the blood-brain barrier to proinflammatory factors.

[0014] The blood-urine barrier has an analogous function. The blood-urine barrier, which is formed during differentiation of superficial urothelial cells, is also one of the tightest and most impermeable barriers in the body. Tight junctions and unique apical plasma membrane of superficial urothelial cells play a role in the barrier maintenance. But the most important component of the barrier is the superficial mucus layer which is composed of highly negatively charged proteogylcans and glycoproteins. Alterations in the blood-urine barrier function cause most of the urinary diseases.PATENT PARSON-58748

[0015] The urinary bladder is lined by a surface mucus layer that is relatively impermeable and is also responsible for the “blood-urine barrier”1. This layer, also known as the glycosaminoglycans (GAG) layer is strongly anionic due to its sulfate and sialic acid content.1This highly negatively charged mucus will avidly bind water to the transitional cell surface and block movement of urinary solutes into the bladder wall. This bound water is sometimes referred to as an “unstirred water layer” and is also present on bowel mucosa where it also regulates permeability18. Highly positively charged amines such as protamine sulfate can injure this layer and cause it to leak in both rodents and humans1,2. If this layer becomes dysfunctional it will leak and allow potassium to diffuse into the bladder wall and cause symptoms, bladder disease and interstitial cystitis (IC) which is the most common cause of bladder symptoms in females4,5,6. The leaking potassium causes nerve depolarization, inflammation, cell death, mast cell stimulation (histamine release), eosinophilic infiltration and, in some people, deposition of amyloid. As stated above, deposition of amyloid is believed to be associated with the etiology of Alzheimer’s disease as well as of other neurodegenerative diseases.

[0016] It has therefore been hypothesized that the blood-urine barrier and the blood- brain barrier perform similar functions, namely to protect the bladder wall and brain from either urine or blood compounds. The role of surface mucus in the urinary bladder has been extensively investigated in regard to how it accomplishes its purpose of controlling epithelial permeability. Furthermore, as stated below, what happens when the blood-urine barrier that is primarily due to the function of the surface mucus layer becomes dysfunctional will be used herein as a model for the role of the barrier function of the blood vessels in the brain, including the consequences of disruption of the barrier function.

[0017] Blood vessels in general are lined by a mucus layer that is a glycocalyx and highly negatively charged, similarly to bladder mucus that also acts as a barrier protecting the inner walls of the vasculature from compounds in the bloodstream. It is this mucus layer in the brain blood vessels that is responsible for the “blood-brain barrier”12. The blood-brain barrier performs an important function in preserving the functionality and integrity of the central nervous system. To demonstrate this function, rabbit carotid arteries were infused with protamine sulfate to injure the mucus layer of brain vessels and this resulted in brain edema confirming the importance of this critical barrier11. Additional data supports the function of the endothelial mucus. When investigators infused one carotid artery of rabbits with protaminePATENT PARSON-58748 sulfate and the other with a saline solution it resulted in a marked increase of albumin leaking into the brain and cerebral spinal fluid in the protamine-infused side of the brain but not in the control side infused with saline16.

[0018] Dysfunction of the mucus layer of arteries is a real potential for vessel disease that results in a greater risk of atherosclerosis10and Alzheimer’s disease. When patients develop Alzheimer’s disease, they accumulate beta-amyloid in the brain tissue, similar to what can happen to some patients with interstitial cystitis, the heart, the kidney, and in other organs17. Amyloid deposition in organs may well represent a protective mechanism that results from the underlying disease process and not a cause of disease. Patients with interstitial cystitis may have eosinophils and amyloid accumulate in the bladder interstitium because of the epithelial leak of potassium that injures and kills tissue. In some cases of interstitial cystitis, it is believed that the bladder produces amyloid as a protective mechanism and its presence in the bladder wall is hence a result and not the cause of the disease. In support of this hypothesis, one patient who had severe interstitial cystitis and massive amyloid deposition was placed on sodium pentosan polysulfate and was eventually cured of her bladder symptoms. After the resolution of her symptoms, a repeat exam of the bladder by cystoscopy showed that the amyloid had completely disappeared. In the brain, it might well be that the accumulation of beta-amyloid is a reaction to the disease process associated with an epithelial leak and not the actual cause of Alzheimer’s disease. This hypothesis is supported by experience with the FDA-approved drug lecanemab, which is a beta-amyloid-directed humanized monoclonal antibody; administration of lecanemab reduces the number of plaques in Alzheimer’s patients but clinically only showed moderate effectiveness with respect to the prevention of decline of cognitive function in patients with mild cognitive impairment or mild dementia. If accumulation of beta-amyloid plaques were the cause of Alzheimer’s disease, plaque removal would be expected to drastically improve the clinical outcome of the disease, but this does not appear to be the case.

[0019] In both rodent and human studies, the cation protamine sulfate has been shown to injure the bladder surface mucus layer, and treatment with heparinoids, specifically, heparin and pentosan polysulfate (PPS), has been shown to restore the permeability barrier by coating the bladder wall1,2. Pentosan polysulfate is available in an oral form and was evaluated in interstitial cystitis patients to determine if it could successfully treat interstitial cystitis and it was found to be effective in two multi-center randomized placebo controlled trials13,14that were the basis forPATENT PARSON-58748 FDA approval of PPS to treat interstitial cystitis. Pentosan polysulfate also reduces the epithelial leak of potassium in interstitial cystitis patients15. The mechanism of action was believed in part to be from its ability to coat the abnormal bladder surface and help restore the permeability barrier. Subsequently data showed that it may also sequester the urinary amines that damage the bladder mucus initiating disease. The evidence for this statement is as follows. It was hypothesized that the bladder mucus was damaged by urinary amines that could bind to the negatively charged mucus, displace the bound water (critical to the barrier activity) and allow potassium to leak into the bladder interstitium as described. The only cations in urine besides minerals are amino-containing molecules. The cations that were found to damage the bladder cells (and hence initiated the epithelial leak) were primarily nucleic acid metabolites that were found to be increased in urine from 2 to 5.5 times compared to normal human controls.8,9These cations are sequestered by PPS and heparin and are part of the reason for the successful therapy of IC by PPS and heparin.8,9

[0020] The following references are cited above by superscripts and are stated below. The recitation of these references is not an admission that they are to be considered to be prior art. (1) C.L. Parsons et al., “Bladder Surface Glycosaminoglycans: An Epithelial Permeability Barrier,” J. Urol. 143: 139-142 (1990). (2) J.D. Lilly & C.L. Parsons, “Bladder Surface Glycosaminoglycans Is a Human Epithelial Permeability Barrier,” Surg. Gynecol. Obstet. 171: 493-496 (1990). (3) C.L. Parsons et al., “Epithelial Dysfunction in Nonbacterial Cystitis (Interstitial Cystitis,” J. Urol. 145: 732-735 (1991). (4) C.L. Parsons et al., “The Role of Urinary Potassium in the Pathogenesis and Diagnosis of Interstitial Cystitis,” J. Urol. 159: 1862-1867 (1998). (5) C.L. Parsons et al., “Increased Prevalence of Interstitial Cystitis: Previously Unrecognized Urologic and Gynecologic Cases Identified Using a New Symptom Questionnaire and Intravesical Potassium Sensitivity,” Urology 60: 573-578 (2002) (6) C.L. Parsons, “The Role of a Leaky Epithelium and Potassium in the Generation of Bladder Symptoms in Interstitial Cystitis / Overactive Bladder, Urethral Syndrome, Prostatitis and Gynaecological Chronic Pelvic Pain,” BJU Int’l 107: 370-375 (2011).PATENT PARSON-58748 (7) T.C. Theoharides, “Hydroxyzine in the Treatment of Interstitial Cystitis,” Urol. Clin. North Am. 21: 113-119 (1994). (8) C.L. Parsons et al., “Role of Urinary Cations in the Aetiology of Bladder Symptoms and Interstitial Cystitis,” BJU Int’l 114: 286-293 (2014). (9) C.L. Parsons et al., “Role of Urinary Cations in the Etiology of Interstitial Cystitis: A Multisite Study,” Int. J. Urol. 27: 731-735 (2020). (10) E. Lupia et al., “Pentosan Polysulfate Inhibits Atherosclerosis in Watanabe Heritable Hyperlipidemic Rabbits: Differential Modulation of Metalloproteinase-2 and -9,” Lab. Invest. 92: 236-245 (2012). (11) L.J. Strausbaugh, “Intracarotid Infusions of Protamine Sulfate Disrupt the Blood- Brain Barrier of Rabbits,” Brain Res. 409: 221-226 (1987). (12) J.E. Hardebo & J. Kåhrström, “Endothelial Negative Surface Charge Areas and Blood-Brain Barrier Function,” Acta Physiol. 125: 485-489 (1985). (13) C.L. Parsons et al., “A Quantitatively Controlled Method to Study Prospectively Interstitial Cystitis and Demonstrate the Efficacy of Pentosanpolysulfate,” J. Urol. 150: 845-848 (1993). (14) S.G. Mulholland et al., “Pentosan Polysulfate Sodium for Therapy of Interstitial Cystitis: A Double-Blind Placebo-Controlled Clinical Study,” Urology 35: 552-558 (1990). (15) C.L. Parsons et al., “Effect of Pentosan Polysulfate Therapy on Intravesical Potassium Sensitivity,” 59: 329-333 (2002). (16) J. Westergren & B.B. Johansson, “Albumin Content in Brain and CSF After Intracarotid Infusion of Protamine Sulfate: A Longitudinal Study,” Exp. Neurol. 107: 192-196 (1990). (17) H.E. Adrogue, “Amyloidosis of the Heart and Kidney,” Methodist Debakey Cardiovasc. J. 18: 27-33 (2022). (18) F.A. Wilson et al., “Unstirred Water Layers in Intestine: Rate Determinant of Fatty Acid Absorption from Micellar Solutions,” Science 174: 1031-1033 (1971). (19) S. Argade et al., “Increased Toxic Urinary Cations in Males with Interstitial Cystitis: A Possible Cause of Bladder Symptoms,” World J. Urol. 34: 1685-1691 (2016). SUMMARY OF THE INVENTIONPATENT PARSON-58748

[0021] The use of a glycosaminoglycan, sulfated polysaccharide (pentosanpolysulfate) or heparinoid, optionally together with a penetration agent, typically administered orally, is proposed to resolve epithelial dysfunction present in the blood vessels of the brain and thus prevent or treat Alzheimer’s disease or other neurodegenerative diseases or conditions.

[0022] One aspect of the present invention is a method for treating a neurodegenerative disease comprising the step of administering a therapeutically effective quantity of a sulfated polysaccharide (pentosanpolysulfate) or glycosaminoglycan to a patient with a neurodegenerative disease or at risk of developing a neurodegenerative disease to treat or prevent the neurodegenerative disease.

[0023] Typically, the sulfated polysaccharide is a salt of pentosan polysulfate. Preferably, the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate and calcium pentosan polysulfate. More preferably, the salt of pentosan polysulfate is sodium pentosan polysulfate. Alternatively, the salt of pentosan polysulfate can be, but is not limited to, a salt of pentosan polysulfate selected from the group consisting of lithium pentosan polysulfate, rubidium pentosan polysulfate, cesium pentosan polysulfate, magnesium pentosan polysulfate, strontium pentosan polysulfate, and barium pentosan polysulfate. In another alternative, the drug utilized is a glycosaminoglycan selected from the group consisting of chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and keratan sulfate.

[0024] Typically, the neurodegenerative disease is Alzheimer’s disease. Alternatively, the neurodegenerative disease can be selected from the group consisting of Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis.

[0025] Typically, the method further comprises the step of administering a pharmacologically effective quantity of a pharmacologically compatible intestinal penetration agent.

[0026] Typically, the sulfated polysaccharide selected, which, as stated above, is preferably sodium pentosan polysulfate, is administered orally. Preferably, when a glycosaminoglycan is administered orally, the glycosaminoglycan is administered with a pharmacologically effective quantity of a pharmacologically compatible intestinal penetration agent.PATENT PARSON-58748

[0027] In other alternatives, the glycosaminoglycan or sulfated polysaccharide can be administered subcutaneously or intravenously.

[0028] Typically, when the polysaccharide selected is sodium pentosan polysulfate, the sodium pentosan polysulfate is administered orally, and the sodium pentosan polysulfate is administered with an intestinal penetration agent, the quantity of sodium pentosan polysulfate originally administered is from about 40 mg to about 300 mg per unit dose. Preferably, the quantity of sodium pentosan polysulfate originally administered is from about 50 mg to about 200 mg per unit dose based on approximately 5% to 15% absorbed drug. In one alternative, typically, the salt of pentosan polysulfate is administered orally and is administered twice daily or three times daily; preferably, in this alternative, the salt of pentosan polysulfate is sodium pentosan polysulfate. In another alternative, typically, the salt of pentosan polysulfate is administered intravenously or subcutaneously and is administered once daily or twice daily; preferably, in this alternative, the salt of pentosan polysulfate is sodium pentosan polysulfate. In yet another alternative, typically, the salt of pentosan polysulfate is administered intravenously or subcutaneously and is administered once daily, twice daily, or three times daily, and a lower dose of the salt of pentosan polysulfate is administered; preferably, in this alternative, the salt of pentosan polysulfate is sodium pentosan polysulfate.

[0029] Typically, when the medication is sodium pentosan polysulfate, the therapeutically effective quantity of sodium pentosan polysulfate actually absorbed is from about 2.5 mg to about 20 mg per unit dose. Preferably, the therapeutically effective quantity of sodium pentosan polysulfate actually absorbed is from about 10 mg to about 20 mg per unit dose.

[0030] Typically, when a pharmaceutical composition according to the present invention comprises a pentosan polysulfate salt, preferably sodium pentosan polysulfate, the quantity of intestinal penetration agent is from about 50 mg to about 800 mg per unit dose. Preferably, the quantity of intestinal penetration agent is from about 100 mg to about 500 mg per unit dose. More preferably, the quantity of intestinal penetration agent is from about 150 mg to about 400 mg per unit dose.

[0031] Typically, the ratio, by weight, of the intestinal penetration agent to the pentosan polysulfate salt, in particular, sodium pentosan polysulfate, is from about 0.167:1 to about 8:1. Preferably, the ratio, by weight, of the intestinal penetration agent to the pentosan polysulfate salt, in particular, sodium pentosan polysulfate, is from about 0.50:1 to about 3:1. MorePATENT PARSON-58748 preferably, the ratio, by weight, of the intestinal penetration agent to the pentosan polysulfate salt, in particular, sodium pentosan polysulfate, is from about 0.75:1 to about 2:1.

[0032] When the pentosan polysulfate salt is sodium pentosan polysulfate, typically, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 5%. Preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 10%. More preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 20%. Still more preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least 30%.

[0033] In one alternative, the administration of the pentosan polysulfate salt, preferably sodium pentosan polysulfate, reduces permeability of the mucus-containing layer of arteries of the central nervous system to amino-containing cations and thus stabilizes the blood-brain barrier, reducing penetration of the blood-brain barrier by amino-containing cations such as, but not necessarily limited to, protamine sulfate, 1-methyladenine, 5 methylcytosine, 1- methylguanine, N2,N2-dimethylguanosine, and L-tryptophan.

[0034] When the pentosan polysulfate salt is sodium pentosan polysulfate, typically, the administration of the sodium pentosan polysulfate provides a peak plasma concentration of sodium pentosan polysulfate from about 0.1 hour to about 3 hours after administration. Preferably, the administration of the sodium pentosan polysulfate provides a peak plasma concentration of sodium pentosan polysulfate from about 0.2 hour to about 0.6 hour after administration. In another alternative, the administration of the sodium pentosan polysulfate provides a first peak plasma concentration of sodium pentosan polysulfate at about 0.3 hours after the administration of the composition and a second peak plasma concentration of sodium pentosan polysulfate at about 1.1 hours after administration.

[0035] Typically, the intestinal penetration enhancer is selected from the group consisting of Alternatives (1)-(114) and analogs or derivatives of Alternatives (1)-(114).

[0036] Preferred intestinal penetration agents include, but are not necessarily limited to: (1) compounds of Formula (VII) wherein n is 7, 8, or 9, particularly sodium N-[8-(2- hydroxybenzoyl)amino]caprylate (“SNAC”); (2) N-(5-chlorosalicyloyl)-8-aminocaprylic acid (“5-CNAC”); (3) N-(10-[2-hydroxybenzoyl]amino)decanoic acid (“SNAD”); (4) 8-(N-2-PATENT PARSON-58748 hydroxy-4-methoxybenzoyl)aminocaprylic acid; (5) N-(9-(2-hydroxybenzoyl)aminononanoic acid; (6) a compound of Formula (XXIV); (7) 8-(N-2-hydroxy-4-methoxybenzoyl)- aminocaprylic acid (“4-MOAC”); (8) N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (“NAC”); (9) N-(8-[2-hydroxybenzoyl]-amino)decanoic acid (“NAD”); (10) N-(8-[2-hydroxy-5- chlorobenzoyl]-amino)octanoic acid (“5-CNAC”); (11) 4-[(2-hydroxy-4- chlorobenzoyl)amino]butanoate (“4-CNAB”); (12) 5-(2-hydroxy-4-chlorobenzoyl) aminovaleric acid; (13) lauroyl-L-carnitine; and (14) (4-[(4-chloro, 2-hydroxybenzoyl)amino] butanoic acid. Particularly preferred intestinal penetration enhancers include, but are not necessarily limited to, SNAC, 5-CNAC, SNAD, 4-MOAC, NAC, NAD, 5-CNAC, and 4-CNAB.

[0037] In some alternatives of a method according to the present invention, the glycosaminoglycan or sulfated polysaccharide such as pentosan polysulfate salt, preferably sodium pentosan polysulfate, or the intestinal penetration agent, if used, is administered together with a pharmaceutically acceptable carrier in a pharmaceutical composition. In one alternative, the pentosan polysulfate salt is administered in a pharmaceutical composition together with a suitable quantity of a pharmaceutically acceptable carrier and the intestinal penetration agent is administered separately. In another alternative, the intestinal penetration agent is administered in a pharmaceutical composition together with a suitable quantity of a pharmaceutically acceptable carrier and the pentosan polysulfate salt is administered separately. In yet another alternative, the pentosan polysulfate salt is administered in a first pharmaceutical composition together with a suitable quantity of a pharmaceutically acceptable carrier and the intestinal penetration agent is administered in a second pharmaceutical composition together with a suitable quantity of a pharmaceutically acceptable carrier; in this alternative, the pharmaceutically acceptable carrier in the first pharmaceutical composition and the pharmaceutically acceptable carrier in the second pharmaceutical composition can be the same or different. In still another alternative, the pentosan polysulfate salt and the intestinal penetration agent are administered in a single pharmaceutical composition together with a suitable quantity of a pharmaceutically acceptable carrier.

[0038] In some alternatives, more than one pharmaceutically acceptable carrier can be included in a pharmaceutical composition employed in a method according to the present invention.PATENT PARSON-58748

[0039] The type of pharmaceutically acceptable carrier and the quantity of pharmaceutically acceptable carrier used in a pharmaceutical composition employed in a method according to the present invention can be determined by one of ordinary skill in the art taking into account such factors as the quantity of pentosan polysulfate salt or intestinal penetration agent to be included in the pharmaceutical composition, the molecular weight, chemical structure including the presence of particular functional groups, molecular weight, physical form, and degree of hydrophobicity of the intestinal penetration agent if included in the pharmaceutical composition, possible interactions between the pentosan polysulfate salt and the intestinal penetration agent if both are included in a single composition, and other similar factors understood in the art.

[0040] In general, pharmaceutically acceptable carriers include, but are not necessarily limited to, carriers in the following categories: acidifying agents; aerosol propellants; air displacements; alcohol denaturants; alkalizing agents; anticaking agents; antifoaming agents; antimicrobial preservatives; antioxidants; buffering agents; capsule lubricants; chelating agents; coating agents; colorants; complexing agents; desiccants; emulsifying and / or solubilizing agents; filtering aids; flavors and perfumes; glidants and / or anticaking agents; humectants; plasticizers; polymers; solvents; sorbents; carbon dioxide sorbents; stiffening agents; suspending and / or viscosity-increasing agents; sweetening agents; tablet binders; tablet and / or capsule diluents; tablet disintegrants; tablet and / or capsule lubricants; tonicity agents; vehicles (flavored and / or sweetened); vehicles (oleaginous); vehicles (solid carrier); vehicles (sterile); water-repelling agents; and wetting and / or solubilizing agents.

[0041] Methods according to the present invention can also be used to treat other neurodegenerative diseases, including, but not limited to, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and multiple sclerosis.

[0042] The administration of the glycosaminoglycan to treat the neurodegenerative disease can be combined with administration of another agent to treat the neurodegenerative disease. Therefore, another aspect of the present invention is a method for treating a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and multiple sclerosis. Typically, the neurodegenerative disease is Alzheimer’s disease. When the neurodegenerative disease is Alzheimer’s disease, the method comprises administering: a therapeutically effectivePATENT PARSON-58748 quantity of the glycosaminoglycan; typically, a pharmacologically effective quantity of a pharmacologically compatible intestinal penetration agent as described above; and a therapeutically effective quantity of an additional agent to treat Alzheimer’s disease. Typically, in this method, the glycosaminoglycan is sodium pentosan polysulfate. Alternatively, the glycosaminoglycan can be another pentosan polysulfate salt or chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, or keratan sulfate as described above.

[0043] In one alternative, the additional agent to treat Alzheimer’s disease includes, but is not necessarily limited to, an agent selected from the group consisting of tacrine, rivastigmine, galantamine, donepezil, memantine, CPHPC ((R)-1-{6-[(R)-2-carboxypyrrolidin-1-yl]-6- oxohexanoyl}pyrrolidine-2-carboxylic acid), and lecanemab.

[0044] In another alternative, the additional agent to treat Alzheimer’s disease is an antidepressant. One category of antidepressants that can be used is the selective serotonin reuptake inhibitors (SSRIs). Selective serotonin reuptake inhibitors include, but are not necessarily limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, zimelidine, cericlamine, and panuramine. Another category of antidepressants that can be used is the serotonin-norepinephrine reuptake inhibitors. Serotonin-norepinephrine reuptake inhibitors include, but are not necessarily limited to, venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran. Yet another category of antidepressants that can be used is the serotonin modulators. Serotonin modulators include, but are not necessarily limited to, vortioxetine and vilazodone. Still another category of antidepressants is the serotonin antagonists and reuptake inhibitors. Serotonin antagonists and reuptake inhibitors include, but are not necessarily limited to, etoperidone, lorpiprazole, lubazodone, mepiprazole, nefazodone, and trazodone. Yet another category of antidepressants that can be used is the norepinephrine reuptake inhibitors. Norepinephrine reuptake inhibitors include, but are not necessarily limited to, amedalin, CP-39,332 (1,2,3,4-tetrahydro-N-methyl-4- phenyl-2-naphthalenamine), daledalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, viloxazine, buproprion, ciclazindole, manifaxine, maprotiline, radafaxine, tapentadol, and teniloxazine. Still another category of antidepressants that can be used is the tricyclic antidepressants. Tricyclic antidepressants include, but are not necessarily limited to, amitriptyline, butriptyline, clomipramine, desipramine, dolesupin, doxepin, imipramine, iprindole, lofepramine, nortriptyline, protriptyline, and trimipramine. YetPATENT PARSON-58748 another category of antidepressants that can be used is the tetracyclic antidepressants. Tetracyclic antidepressants include, but are not necessarily limited to, mianserin, mirtazapine, pirlindole, setiptiline, aptazapine, esmirtazapine, metralindole, and oxprotiline. Still another category of antidepressants that can be used is the monoamine oxidase inhibitors. Monoamine oxidase inhibitors include, but are not necessarily limited to, isocarboxazid, nialamide, phenelzine, hydracarbazide, tranylcypromine, bifemelane, moclobemide, toloxatone, rasagline, selegiline, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, and minaprine. Yet another category of antidepressants that can be used is the atypical antidepressants. Atypical antipsychotics include, but are not necessarily limited to, amisulpride, lurasidone, and quetiapine. Still another category of antidepressants that can be used is the antidepressants that act by one or more other mechanisms. Antidepressants that act by one or more other mechanisms include, but are not necessarily limited to, agomelatine, tandospirone, α-methyltryptamine, etryptamine, indeloxazine, medifoxamine, nomifensine, oxaflozane, and pivagabine.

[0045] When the neurodegenerative disease is Parkinson’s disease, the additional agent can be, but is not necessarily limited to, an agent selected from the group consisting of: levodopa; monoamine oxidase inhibitors selected from the group consisting of isocarboxazid, nialamide, phenelzine, hydracarbazide, tranylcypromine, bifemelane, moclobemide, toloxatone, rasagline, selegiline, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, and minaprine; and dopamine agonists selected from the group consisting of bromocriptine, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, cabergoline, ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine, lisuride, propylnorapomorphine, roxindole, sumanirole, and fenaldopam.

[0046] When the neurodegenerative disease is amyotrophic lateral sclerosis, the additional agent can be, but is not necessarily limited to, an agent selected from the group consisting of riluzole, edaravone, sodium phenylbutyrate / taurursodiol, toferse, gabapentin, and pregabalin.

[0047] When the neurodegenerative disease is multiple sclerosis, the additional agent can be, but is not limited to, an agent selected from the group consisting of methylprednisolone, interferon beta-1a, interferon beta-1b, glatiramer acetate, fingolimod, teriflunomide, dimethylPATENT PARSON-58748 fumarate, alemtuzumab, natalizumab, mitoxantrone, ocrelizumab, siponimod, cladribine, ozanimod, and ponesimod.

[0048] When an additional agent is used to treat a neurodegenerative disease such as, but not necessarily limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, or multiple sclerosis, the dosage, dose frequency, route of administration, and duration of administration can be determined by one of ordinary skill in the art by evaluation of factors including, but not limited to: the age, sex, and weight of the patient; the overall health of the patient; the stage or severity of the neurodegenerative disease; the particular tissues and cell types of the brain or other portions of the central or peripheral nervous system affected by the neurodegenerative disease; other diseases affecting the patient; other therapeutic agents being administered to the patient; and pharmacokinetic factors affecting metabolism and excretion of the agent.

[0049] Although, in some alternatives, the additional agent can be administered in a pharmaceutical composition that includes the glycosaminoglycan or sulfated polysaccharide and, typically, an intestinal penetration agent; typically, the additional agent is administered in a separate pharmaceutical composition that is formulated for administration of the additional agent by a route that would be preferred for administration of the additional agent.

[0050] Another aspect of the present invention is a composition comprising: (1) a therapeutically effective quantity of a glycosaminoglycan or sulfated polysaccharde; and (2) a pharmacologically effective quantity of an intestinal penetration agent.

[0051] Suitable glycosaminoglycans or sulfated polysaccharide are as described above. Typically, the compound is a pentosan polysulfide salt; preferably, the pentosan polysulfide salt is sodium pentosan polysulfate. Other salts of pentosan polysulfate or glycosaminoglycans that can be included in compositions according to the present invention are described above.

[0052] Suitable intestinal penetration agents are as described above. Typically, the intestinal penetration enhancer is selected from the group consisting of Alternatives (1)-(114) and analogs or derivatives of Alternatives (1)-(114). Preferred intestinal penetration agents include, but are not necessarily limited to: (1) compounds of Formula (VII) wherein n is 7, 8, or 9, particularly sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (“SNAC”); (2) N-(5- chlorosalicyloyl)-8-aminocaprylic acid (“5-CNAC”); (3) N-(10-[2-PATENT PARSON-58748 hydroxybenzoyl]amino)decanoic acid (“SNAD”); (4) 8-(N-2-hydroxy-4- methoxybenzoyl)aminocaprylic acid; (5) N-(9-(2-hydroxybenzoyl)aminononanoic acid; (6) a compound of Formula (XXIV); (7) 8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid (“4- MOAC”); (8) N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (“NAC”); (9) N-(8-[2- hydroxybenzoyl]-amino)decanoic acid (“NAD”); (10) N-(8-[2-hydroxy-5-chlorobenzoyl]- amino)octanoic acid (“5-CNAC”); (11) 4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate (“4- CNAB”); (12) 5-(2-hydroxy-4-chlorobenzoyl) aminovaleric acid; (13) lauroyl-L-carnitine; and (14) (4-[(4-chloro, 2-hydroxybenzoyl)amino] butanoic acid. Particularly preferred intestinal penetration agents include, but are not necessarily limited to, SNAC, 5-CNAC, SNAD, 4- MOAC, NAC, NAD, 5-CNAC, and 4-CNAB.

[0053] Typically, the pharmaceutical composition further comprises a suitable quantity of a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers are as described above.

[0054] In a pharmaceutical composition as described above, the quantities of the glycosaminoglycan / sulfated polysaccharide and the intestinal penetration enhancer in the pharmaceutical composition can be determined by one of ordinary skill in the art so that there is no negative interaction between the glycosaminoglycan / sulfated polysaccharide and the intestinal penetration enhancer. Additionally, the pharmaceutically acceptable carrier is chosen to avoid negative interactions between the pharmaceutically acceptable carrier, the glycosaminoglycan / sulfated polysaccharide, and the intestinal penetration enhancer.

[0055] Typically, the pharmaceutical composition is formulated to treat a neurodegenerative disease. The neurodegenerative disease can be, but is not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and multiple sclerosis; typically, the neurodegenerative disease is Alzheimer’s disease.

[0056] In some alternatives, the pharmaceutical composition also further comprises an additional agent to treat a neurodegenerative disease, such as, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and multiple sclerosis; typically, the neurodegenerative disease is Alzheimer’s disease. Suitable additional agents are described above.

[0057] When the composition comprises the additional agent to treat a neurodegenerative disease, the quantities of the glycosaminoglycan / sulfated polysaccharide, thePATENT PARSON-58748 intestinal penetration enhancer, and the additional agent to treat the neurodegenerative disease in the pharmaceutical composition can be determined by one of ordinary skill in the art so that there is no negative interaction between the glycosaminoglycan / sulfated polysaccharide, the additional agent, and the intestinal penetration enhancer. Additionally, the pharmaceutically acceptable carrier is chosen to avoid negative interactions between the pharmaceutically acceptable carrier and any of the glycosaminoglycan / sulfated polysaccharide, the additional agent, and the intestinal penetration enhancer. DEFINITIONS

[0058] Although any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of embodiments described herein or other embodiments within the scope of the invention, some preferred methods, compositions, materials, and devices are described herein. However, in this context, it must be understood that this invention is not limited to the particular molecules, compositions, methodologies, or protocols described herein, as these aspects of the invention may vary in accordance with routine experimentation and optimization as is generally known in the art. It is also to be understood that the terminology used in the description and the claims is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the embodiments as described herein as understood by one of skill in the art.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. However, in case of any conflict of meanings, the present specification and claims, including definitions therein, shall control. Accordingly, in the context of the embodiments described herein, the following definitions apply.

[0060] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include references to the plural unless the context clearly dictates otherwise. Thus, for example, a reference to “an intestinal penetration agent” is a reference to one or more intestinal penetration agents or equivalents thereof known to those skilled in the art.

[0061] As used herein, the terms “comprise,” “include,” and linguistic variations thereof denote the presence of recited features, elements, method steps, or other components of the invention without the exclusion of the presence of additional / recited features, elements, methodPATENT PARSON-58748 steps, or other components. Conversely, the terms “consisting of” and linguistic variations thereof denote the presence of recited features, elements, method steps, or other components of the invention and exclude any unrecited recited features, elements, method steps, or other components of the invention except for ordinarily-associated impurities. The phrase “consisting essentially of” and linguistic variations thereof denote the presence of recited features, elements, method steps, or other components of the invention and any additional features, elements, method steps, or other components of the invention that do not materially affect the basic nature of the composition, system, or method. Many embodiments herein are described using open “comprising” language; such embodiments also encompass embodiments described in terms of “consisting essentially of” or “consisting of” language, which may be alternatively claimed or described using such language, unless the context clearly excludes “consisting essentially of” or “consisting of” language.

[0062] All chemical names used herein, including names of substituents, should be interpreted in light of the chemical nomenclature conventions of IUPAC and / or a modified format in which functional groups within a substituent are read in the order in which they branch from the scaffold or main structure. For example, in the modified nomenclature, methylsulfonylpropanol refers to CH2SO2CH2CH2CH2OH or. As another example, according to the modified nomenclature, a methylamine substituent iswhile an aminomethyl substituent is.PATENT PARSON-58748

[0063] As used herein, the term “subject” broadly refers to any animal, including, but not limited to, humans and non-human mammals. The reference to non-human mammals includes, but is not limited to, socially or economically important animals or animals used for research including cattle, sheep, goats, horses, pigs, llamas, alpacas, dogs, cats, rabbits, guinea pigs, rats, and mice. Unless specified, methods and compositions according to the present invention are not limited to treatment of humans. In general, when treatment of humans is intended, the term “patient” can used in place of “subject.”

[0064] As used herein, the terms “effective amount,” “therapeutically effective amount,” or other equivalent terminology refer to the amount of a compound or compounds or to the amount of a composition sufficient to effect beneficial or desired results. The beneficial or desired results are typically a reduction in severity, symptoms, or duration of a disease or condition being treated and can generally be characterized as an amount of a therapeutic agent or composition effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect. The use of such terminology cannot, unless specifically indicated, be interpreted as implying a complete cure for any disease or condition as recited herein. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or administration route unless a particular formulation or administration route is specified. The effect induced by the administration of a therapeutically effective amount can be detected by, for example, chemical markers, antigen levels, or changes in pathological indicators such as, in the case of diseases or conditions such as Alzheimer’s disease, assessable reductions in cognitive functioning or memory. The precise therapeutically effective amount for a subject will depend upon the subject’s size, weight, and health, the nature and extent of the condition affecting the subject, the administration of other therapeutics administered to treat the particular disease or condition being treated or other diseases or conditions affecting the subject, as well as variables such as liver and kidney function that affect the pharmacokinetics of administered therapeutics. Thus, it is not useful to specify an exact effective amount in advance. However, the therapeutically effective amount for a given situation can be determined by routine experimentation and is within the judgment of the clinician.

[0065] As used herein, the terms “administration,” “administering,” or other equivalent terminology, refer to the act of giving a drug, prodrug, pharmaceutical composition, or otherPATENT PARSON-58748 therapeutic agent intended to provide therapeutic treatment to a subject or in vivo, in vitro, or ex vivo to cells, tissues, or organs. Exemplary routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs or other portions of the respiratory tract (inhalant), oral mucosa (buccal), ear, rectal, vaginal, by injection (such as, but not limited to, intravenously, subcutaneously, intraperitoneally, or by other injection routes as known in the art). Further details on administration of therapeutic agents are described herein.

[0066] As used herein, the terms “co-administration” and “co-administering” refer to the administration of at least two agents or therapies to a subject. In some embodiments, the co- administration of two or more agents or therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the formulations and / or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co- administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of an agent for which a higher dosage may produce one or more potentially deleterious side effects, and / or when co-administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent. As used herein, the term “concurrent administration” refers to the administration of two or more active agents sufficiently close in time to achieve a combined therapeutic effect that is preferably greater than that which would be achieved by the administration of either agent alone. Such concurrent administration can be carried out simultaneously, e.g., by administering the active agents together in a common pharmaceutically acceptable carrier, thereby forming a pharmaceutical composition with two or more active agents, in one or more doses of the pharmaceutical composition. When methods according to the present invention recite steps of administering two or more therapeutic agents, the two agents can be either administered simultaneously or can be administered at different times unless it is specifically recited either that the two or more agents need to be administered simultaneously or need to be administered at different times. If the two or more agents are to be administered simultaneously, they can either be administered in a singlePATENT PARSON-58748 pharmaceutical composition incorporating two or more of the agents or can be administered in multiple pharmaceutical compositions, each including either one of the agents, or, in the case where three or more agents are to be administered, fewer than all of the agents. When the two or more agents are to be administered at different times, one of ordinary skill in the art can determine the optimal times for administration of the agents based on factors such as pharmacokinetics or pharmacodynamics of the agents, the optimal routes of administration of the agents, the possibility of interactions of the agents, the particular cytochrome P450 enzymes that metabolize the agents, or other factors known in the art.

[0067] As used herein, the term “pharmaceutical composition” refers to the combination of one or more therapeutically active agents with at least one pharmaceutically acceptable carrier, making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.

[0068] As used herein, the terms “pharmaceutically acceptable” or “pharmacologically acceptable,” as used herein, refer to compositions, or components within compositions, that do not substantially produce adverse reactions, such as, but not limited to, toxic, allergic, or unwanted immunological reactions, when administered to a subject.

[0069] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions, such as oil / water or water / oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants such as potato starch or sodium starch glycolate), and the like. The carriers also can include stabilizers and preservatives. A number of categories of carriers with various functions are described below. In some alternatives, a particular carrier can fulfill one or more functions.

[0070] As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound that is used in a method of the present invention or is a component of a composition of the present invention, which, upon administration to a subject, is capable of providing a compound of the present invention or an active metabolite or residue thereof. As is known to those of skill in the art, salts of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric,PATENT PARSON-58748 perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfonic, benzenesulfonic acid, and other acids known in the art as suitable for formation of pharmaceutically acceptable salts. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metals (such as sodium or potassium) hydroxides, alkaline earth metals (such as calcium or magnesium), hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-C4alkyl, and the like. Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, NH4+, and NW4+, wherein W is a C1-C4alkyl group), and the like. For therapeutic use, salts of the compounds herein are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0071] As used herein, the term “instructions for administering a compound to a subject,” and grammatical equivalents thereof, includes instructions for using the compositions contained in a kit according to the present invention for the treatment of conditions; typically, the conditions are specified in the instructions; the conditions may encompass a single condition or a range of conditions. Such instructions, for example, provide dosing, routes of administration, or decision trees for treating physicians for correlating patient-specific characteristics with therapeutic courses of action. Such instructions may be part of a kit according to the present invention.PATENT PARSON-58748

[0072] The following applies to analogs and derivatives of the compounds described in further detail below, including, but not necessarily limited to, intestinal penetration agents as well as other therapeutic agents described herein. As used herein, “analog” refers to a chemical compound that is structurally similar to a parent compound, but differs slightly in composition (e.g., one atom or functional group is different, added, or removed). The analogue may or may not have different chemical or physical properties than the original compound and may or may not have improved biological and / or chemical activity. For example, the analogue may be more hydrophilic or hydrophobic or it may have altered reactivity as compared to the parent compound. The analogue may mimic the chemical and / or biological activity of the parent compound (i.e., it may have similar or identical activity), or, in some cases, may have increased or decreased activity. The analogue may be a naturally or non-naturally occurring variant of the original compound. Other types of analogues include isomers (enantiomers, diastereomers, and the like) and other types of chiral variants of a compound, as well as structural isomers. As used herein, “derivative” refers to a chemically or biologically modified version of a chemical compound that is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound. A “derivative” differs from an “analog” in that a parent compound may be the starting material to generate a “derivative,” whereas the parent compound may not necessarily be used as the starting material to generate an “analog.” A derivative may or may not have different chemical or physical properties than the parent compound. For example, the derivative may be more hydrophilic or hydrophobic or it may have altered reactivity as compared to the parent compound. Derivatization (i.e., modification) may involve substitution of one or more moieties within the molecule (e.g., a change in functional group). The term “derivative” also includes conjugates and prodrugs of a parent compound (i.e., chemically modified derivatives which can be converted into the original compound under physiological conditions), where such conjugates or prodrugs would have equivalent or substantially equivalent therapeutic or pharmacological activity or other properties.

[0073] As used herein, the term “alkyl” refers to an unbranched, branched, or cyclic saturated hydrocarbyl residue, or a combination thereof, of from 1 to 12 carbon atoms, or in some cases up to 50 or more carbon atoms, that can be optionally substituted; the alkyl residues contain only C and H when unsubstituted. Typically, the unbranched or branched saturated hydrocarbyl residue is from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferablyPATENT PARSON-58748 1 to 3 carbon atoms, which is referred to herein as “lower alkyl.” When the alkyl residue is cyclic and includes a ring, it is understood that the hydrocarbyl residue includes at least three carbon atoms, which is the minimum number to form a ring. An alkyl group can be linear, branched, cyclic, or a combination thereof, and may contain from 1 to 50 or more carbon atoms, such as a straight chain or branched C1-C20alkane. Examples of alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl isomers (e.g. n-butyl, isobutyl, and tert-butyl), cyclobutyl isomers (e.g. cyclobutyl, methylcyclopropyl, or other isomers), pentyl isomers, cyclopentane isomers, hexyl isomers, cyclohexane isomers, and the like. Unless specified otherwise (e.g., substituted alkyl group, heteroalkyl, alkoxy group, haloalkyl, alkylamine, thioalkyl, or other possible groups), an alkyl group contains carbon and hydrogen atoms only. As used herein, the term “linear alkyl” refers to a chain of carbon and hydrogen atoms (e.g., ethane, propane, butane, pentane, hexane, or other examples). A linear alkyl group may be referred to by the designation --(CH2)qCH3, where q is 0-49. The designation “C1-C12 alkyl” or a similar designation refers to alkyl having from 1 to 12 carbon atoms such as methyl, ethyl, propyl isomers (e.g. n-propyl or isopropyl), butyl isomers, cyclobutyl isomers (e.g. cyclobutyl or methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, heptyl isomers, cycloheptyl isomers, octyl isomers, cyclooctyl isomers, nonyl isomers, cyclononyl isomers, decyl isomers, cyclodecyl isomers, or other alternatives known in the art. Similar designations refer to alkyl with a number of carbon atoms in a different range. As used herein, the term “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, alkynyl, or carbocycle is meant to include groups that contain from x to y carbons in the chain or ring. For example, the term “Cx-Cyalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, or other alternatives. The terms “Cx-Cyalkenyl” and “Cx-Cy alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. As used herein, the term “carbocycle,” “carbocyclyl,” or “carbocyclic” refers to a cyclic ring containing only carbon atoms in the ring, whereas the term “heterocycle” or “heterocyclic” refers to a ring comprising a heteroatom. The carbocyclyl can be fully saturated or partially saturated, but non-aromatic. For example, the general termPATENT PARSON-58748 “carbocyclyl” encompasses cycloalkyl. The carbocyclic and heterocyclic structures encompass compounds having monocyclic, bicyclic or multiple ring systems; and such systems may mix aromatic, heterocyclic, and carbocyclic rings. Mixed ring systems are described according to the ring that is attached to the rest of the compound being described. The term “Cx-Cy carbocycle” refers to a substituted or unsubstituted carbocycle, that contain from x to y ring carbons. As used herein, the term “branched alkyl” refers to a chain of carbon and hydrogen atoms, without double or triple bonds, that contains a fork, branch, and / or split in the chain (e.g., 3,5-dimethyl-2- ethylhexane, 2-methyl-pentane, 1-methyl-cyclobutane, ortho-diethyl-cyclohexane, or other alternatives). “Branching” refers to the divergence of a carbon chain, whereas “substitution” refers to the presence of non-carbon / non-hydrogen atoms in a moiety. Unless specified otherwise (e.g., substituted branched alkyl group, branched heteroalkyl, branched alkoxy group, branched haloalkyl, branched alkylamine, branched thioalkyl, or other alternatives), a branched alkyl group contains carbon and hydrogen atoms only.

[0074] As used herein, the term “carbocycle,” “carbocyclyl,” or “carbocyclic” refers to a cyclic ring containing only carbon atoms in the ring, whereas the term “heterocycle” or “heterocyclic” refers to a ring comprising a heteroatom. The carbocycle can be fully saturated or partially saturated, but non-aromatic. For example, the general term “carbocyclyl” encompasses cycloalkyl. The carbocyclic and heterocyclic structures encompass compounds having monocyclic, bicyclic or multiple (polycyclic) ring systems; and such systems may mix aromatic, heterocyclic, and carbocyclic rings. Mixed ring systems are described according to the ring that is attached to the rest of the compound being described. Bicyclic or polycyclic rings may include fused or spiro rings. Carbocycles may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic carbocycle, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. In some embodiments, the carbocycle is an aromatic carbocycle . In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. An alkenyl group can be optionally substituted by one or more substituents such as those substituents described herein. A “non-aromatic carbocycle” includes rings and ring systems that arePATENT PARSON-58748 saturated, unsaturated, substituted or unsubstituted, but not aromatic or aryl rings or ring systems.

[0075] As used herein, the term “cycloalkyl” refers to a completely saturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups of the present application may range from three to ten carbons (C3 to C10). A cycloalkyl group may be unsubstituted, substituted, branched, and / or unbranched. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or can be selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated. While “alkyl” as used herein includes cycloalkyl and cycloalkylalkyl groups, the term “cycloalkyl” may be used herein to describe a carbocyclic non-aromatic group that is connected via a ring carbon atom, and “cycloalkylalkyl” may be used to describe a carbocyclic non-aromatic group that is connected to the molecule through an alkyl linker.

[0076] As used herein, the term “heteroalkyl” refers to an alkyl group, as defined herein, wherein one or more carbon atoms are independently replaced by one or more heteroatoms (e.g., oxygen, sulfur, nitrogen, phosphorus, selenium, silicon, or combinations thereof). The alkyl group containing the non-carbon substitution(s) may be a linear alkyl, branched alkyl, cycloalkyl (e.g., cycloheteroalkyl), or combinations thereof. Non-carbons may be at terminal locations (e.g., 2-hexanol) or integral to an alkyl group (e.g., diethyl ether). In general, the “hetero” terms refer to groups that typically contain 1 to 3 O, S or N heteroatoms or combinations thereof within the backbone residue; thus at least one carbon atom of a corresponding alkyl, alkenyl, or alkynyl group is replaced by one of the specified heteroatoms to form, respectively, a heteroalkyl, heteroalkenyl, or heteroalkynyl group. In some cases, more than three heteroatoms may be present. Unless stated otherwise specifically in the specification, the heteroalkyl group may be optionally substituted as described herein. Representative heteroalkyl groups include, but are not limited to --OCH2OMe, --OCH2CH2OMe, or --OCH2CH2OCH2CH2NH2. For reasons of chemical stability, it is also understood that, unless otherwise specified, such groups do not include more than two contiguous heteroatoms except where an oxo group is present on N or S as in a nitro or sulfonyl group.PATENT PARSON-58748

[0077] As used herein, the term “heteroalkylene” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a heteroatom, e.g., O, N or S, or another heteroatom as described above. “Heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkylene group may be optionally substituted as described herein. Representative heteroalkylene groups include, but are not limited to --OCH2CH2O--, --OCH2CH2OCH2CH2O--, or --OCH2CH2OCH2CH2OCH2CH2O-- .

[0078] As used herein, the term “optionally substituted” indicates that the particular group or groups referred to as optionally substituted may have no non-hydrogen substituents, or the group or groups may have one or more non-hydrogen substituents consistent with the chemistry and pharmacological activity of the resulting molecule and such that a stable compound is formed thereby, i.e., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, hydrolysis, lactone or lactam formation, or other reaction. If not otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present on the unsubstituted form of the group being described; fewer than the maximum number of such substituents may be present. Where an optional substituent is attached via a double bond, such as a carbonyl oxygen (C=O), the group takes up two available valences on the carbon atom to which the optional substituent is attached, so the total number of substituents that may be included is reduced according to the number of available valences. As used herein, the term “substituted,” whether used as part of “optionally substituted” or otherwise, when used to modify a specific group, moiety, or radical, means that one or more hydrogen atoms are, each, independently of each other, replaced with the same or different substituent or substituents. Substitution of a structure depicted herein may result in removal or moving of a double bond or other bond, as will be understood by one in the field. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds that do not significantly alter the pharmacological activity of the compound in the context of the present invention. In a broad aspect, the permissible substituents include acyclic and cyclic,PATENT PARSON-58748 branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. The heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0079] As used herein, the term “haloalkyl” or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include, but are not limited to, halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1- haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2- dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, or I). When an alkyl group is substituted with more than one halogen radical, each halogen may be independently selected e.g., 1-chloro, 2-fluoroethane.

[0080] As used herein, the term “aryl” refers to a monocyclic or fused bicyclic moiety having the well-known characteristics of aromaticity; examples include phenyl and naphthyl, which can be optionally substituted. Additional examples of aromatic rings include furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo(c)thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzooxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, benzene, naphthalene, pyridine, quinolone, isoquinoline, pyrazine, quinoxaline, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine, triazine (e.g., 1,2,3-triazine; 1,2,4-triazine; 1,3,5 triazine), and thiadiazole. The term “aromatic carbocycle” refers to an aromatic ring without heteroatoms present within the ring structure, such as, but not limited to benzene or naphthalene. Other terms that can be used include “aromatic ring,” “aryl group,” or “aryl ring.”

[0081] As used herein, the term “heterocycle,” “heterocyclyl,” “heterocyclic ring” or “heterocyclic group” is intended to mean a stable 4-, 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic heterocyclic ring which is saturated, partiallyPATENT PARSON-58748 unsaturated, or fully unsaturated or aromatic, and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S; and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Other heteroatoms, such as P, Se, B, or Si, can be included in some alternatives. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. When the term “heterocycle,” “heterocyclyl,” “heterocyclic ring" or “heterocyclic group” is used, it is intended to include heteroaryl unless heteroaryl is excluded. Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,PATENT PARSON-58748 triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[0082] As used herein, the term “non-aromatic heterocycle” refers to a cycloalkyl or cycloalkenyl, as defined herein, wherein one or more of the ring carbons are replaced by a moiety selected from --O--, --N=, --NR--, --C(O)--, --S--, --S(O)-- or --S(O)2--, wherein R is hydrogen, C1-C8 alkyl or a nitrogen protecting group, with the proviso that the ring of such a group does not contain two adjacent O or S atoms. In some alternatives, other heteroatoms including P, Se, B, or Si can be included. Non-limiting examples of non-aromatic heterocycles, as used herein, include morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro(4.5)dec-8-yl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, 1,3- dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,4-dioxanyl, 1,4- dithianyl, thiomorpholinyl, azepanyl, hexahydro-1,4-diazepinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, oxepanyl, thiepanyl, 1,2,3,6-tetrahydropyridinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, imidazolinyl, imidazolidinyl, 3-azabicyclo(3.1.0)hexanyl, and 3- azabicyclo(4.1.0)heptanyl, 3,8-diazabicyclo(3.2.1)octanyl, and 2,5-diazabicyclo(2.2.1)heptanyl. In certain embodiments, a non-aromatic heterocyclic ring is aziridine, thiirane, oxirane, oxaziridine, dioxirane, azetidine, oxetan, thietane, diazetidine, dioxetane, dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperdine, oxane, thiane, piperazine, morpholine, thiomorpholine, dioxane, dithiane, trioxane, thithiane, azepane, oxepane, thiepane, homopiperazine, or azocane.

[0083] As used herein, the term “heteroatom” refers to any atom that is not carbon or hydrogen, such as nitrogen, oxygen or sulfur. When it is part of the backbone or skeleton of a chain or ring, a heteroatom must be at least divalent, and will typically be selected from N, O, P, and S.

[0084] As used herein, the terms “heteroaryl” or “heteroaromatic” refer to monocyclic, bicyclic, or polycyclic ring systems, wherein at least one ring in the system is aromatic and contains at least one heteroatom, for example, nitrogen, oxygen and sulfur. Each ring of the heteroaromatic ring systems may contain 3 to 7 ring atoms. Exemplary heteroaromaticPATENT PARSON-58748 monocyclic ring systems include 5- to 7-membered rings whose ring structures include one to four heteroatoms, for example, one or two heteroatoms. The inclusion of a heteroatom permits aromaticity in 5-membered rings as well as in 6-membered rings. Typical heteroaromatic systems include monocyclic C5-C6 heteroaromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, and imidazolyl, as well as the fused bicyclic moieties formed by fusing one of these monocyclic heteroaromatic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a C8-C10bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolylpyridyl, quinazolinyl, quinoxalinyl, cinnolinyl, and other ring systems known in the art. Any monocyclic or fused ring bicyclic system that has the characteristics of aromaticity in terms of delocalized electron distribution throughout the ring system is included in this definition. This definition also includes bicyclic groups where at least the ring that is directly attached to the remainder of the molecule has the characteristics of aromaticity, including the delocalized electron distribution that is characteristic of aromaticity. Typically the ring systems contain 5 to 12 ring member atoms and up to four heteroatoms, wherein the heteroatoms are selected from the group consisting of N, O, and S. Frequently, the monocyclic heteroaryls contain 5 to 6 ring members and up to three heteroatoms selected from the group consisting of N, O, and S; frequently, the bicyclic heteroaryls contain 8 to 10 ring members and up to four heteroatoms selected from the group consisting of N, O, and S. The number and placement of heteroatoms in heteroaryl ring structures is in accordance with the well-known limitations of aromaticity and stability, where stability requires the heteroaromatic group to be stable enough to be exposed to water at physiological temperatures without rapid degradation. As used herein, the term “hydroxyheteroaryl” refers to a heteroaryl group including one or more hydroxyl groups as substituents; as further detailed below, further substituents can be optionally included. As used herein, the terms “haloaryl” and “haloheteroaryl” refer to aryl and heteroaryl groups, respectively, substituted with at least one halo group, where “halo” refers to a halogen selected from the group consisting of fluorine, chlorine, bromine, and iodine, typically, the halogen is selected from the group consisting of chlorine, bromine, and iodine; as detailed below, further substituents can be optionally included. As used herein, the terms “haloalkyl,” “haloalkenyl,” and “haloalkynyl” refer to alkyl, alkenyl, and alkynyl groups, respectively, substituted with at least one halo group, where “halo” refers toPATENT PARSON-58748 a halogen selected from the group consisting of fluorine, chlorine, bromine, and iodine, typically, the halogen is selected from the group consisting of chlorine, bromine, and iodine; as detailed below, further substituents can be optionally included. When a range of values is listed, such as for the number of carbon atoms in an alkyl group, it is intended to encompass each value and subrange within the range. For example, “C1-C6alkyl” includes alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms and all possible subranges.

[0085] As used herein, the term “hydroxyaryl” refers to an aryl group including one or more hydroxyl groups as substituents; as further detailed below, further substituents can be optionally included.

[0086] As used herein, the term “solvate” means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute), or an aggregate that consists of a solute ion or molecule, i.e., a compound of the invention, with one or more solvent molecules. The term “solvate” typically means a physical association of a compound involving varying degrees of ionic and / or covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent atoms are incorporated into the crystal lattice of the crystalline solid. The term “solvate” encompasses both solution-phase and isolatable solvates. Suitable solvates in which the solvent is other than water include, but are not limited to, ethanolates or methanolates. When water is the solvent, the corresponding solvate is a “hydrate.” Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and other hydrated forms. It should be understood by one of ordinary skill in the art that the pharmaceutically acceptable salt and / or prodrug of compounds, where applicable, described herein for use in methods or compositions according to the present invention may also exist in a solvate form. When the solvate is a hydrate, the hydrate is typically formed via hydration which is either part of the preparation of the present compound or through natural absorption of moisture by the anhydrous compound of the present invention. Additionally, compounds may exist as clathrates or other complexes, which are therapeutic agent-host inclusion complexes wherein the therapeutic agent and the host are present in stoichiometric or non-stoichiometric amounts.

[0087] As used herein, the term “ester” means any ester of a present compound in which any of the --COOH functions of the molecule is replaced by a --COOR function, in which the R moiety of the ester is any carbon-containing group which forms a stable ester moiety, includingPATENT PARSON-58748 but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl and substituted derivatives thereof. The hydrolyzable esters of the present compounds are the compounds whose carboxyls are present in the form of hydrolyzable ester groups. That is, these esters are pharmaceutically acceptable and can be hydrolyzed to the corresponding carboxyl acid in vivo.

[0088] As used herein, the term “alkenyl” refers to an unbranched, branched or cyclic hydrocarbyl residue having one or more carbon-carbon double bonds. Typically, the hydrocarbyl residue has from 2 to 12 carbon atoms (C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (C2-C8alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1- enyl, pent-1-enyl, penta-1,4-dienyl, and the like. An alkenyl group can be optionally substituted by one or more substituents such as those substituents described herein. With respect to the use of “alkenyl,” the presence of multiple double bonds cannot produce an aromatic ring structure.

[0089] As used herein, the term “alkynyl” refers to an unbranched, branched, or cyclic hydrocarbyl residue having one or more carbon-carbon triple bonds; the residue can also include one or more double bonds. Typically, the hydrocarbyl residue has from 2 to 12 carbon atoms (C2-C12alkynyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (C2- C8 alkynyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. With respect to the use of “alkynyl,” the presence of multiple double bonds in addition to the one or more triple bonds cannot produce an aromatic ring structure.

[0090] As used herein, the term “alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to thePATENT PARSON-58748 rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C10alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises only one carbon atom (i.e., C1alkylene or a –CH2— group). An alkylene group can be optionally substituted by one or more substituents such as those substituents described herein.

[0091] As used herein, the term “alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). An alkenylene group can be optionally substituted by one or more substituents such as those substituents described herein.

[0092] As used herein, “alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may bePATENT PARSON-58748 through any two carbons within the chain. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). An alkenylene group can be optionally substituted by one or more substituents such as those substituents described herein.

[0093] As used herein, the term “amine” or “amino” includes primary, secondary, and tertiary amines wherein each non-hydrogen group on nitrogen may be selected from alkyl, aryl, and the like. Amines include but are not limited to --NH2, --NH-phenyl, --NH--CH3, --NH-- CH2CH3, and --N(CH3)benzyl. The amino group can be optionally substituted. For example, the term can include NR′R′′ wherein each R′ and R′′ is independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl groups is optionally substituted with the substituents described herein as suitable for the corresponding group; the R′ and R′′ groups and the nitrogen atom to which they are attached can optionally form a 3- to 8-membered ring which may be saturated, unsaturated or aromatic and which contains 1-3 heteroatoms independently selected from N, O and S as ring members, and which is optionally substituted with the substituents described as suitable for alkyl groups or, if NR′R′′ is an aromatic group, it is optionally substituted with the substituents described as typical for heteroaryl groups.

[0094] As used herein, the term “amide” or “amido” includes C- and N-amide groups, e.g., --C(O)NR2, and --NRC(O)R groups, respectively, where R can be H, alkyl, aryl, or other groups, which can be optionally substituted. Amide groups therefore include but are not limited to --C(O)NH2, --NHC(O)H, --C(O)NHCH2CH3, --NHC(O)CH3,or --C(O)N(CH2CH3)phenyl.

[0095] As used herein, “acyl” encompasses groups comprising an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical attached at one of the two available valence positions of a carbonyl carbon atom, and heteroacyl refers to the corresponding groups wherein at least one carbon other than the carbonyl carbon has been replaced by a heteroatom chosen from N, O and S.PATENT PARSON-58748

[0096] As used herein, similarly, “arylalkyl” and “heteroarylalkyl” refer to aromatic and heteroaromatic ring systems which are bonded to their attachment point through a linking group such as an alkylene, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linkers. Typically the linker is C1-C8 alkyl. These linkers may also include a carbonyl group, thus making them able to provide substituents as an acyl or heteroacyl moiety. An aryl or heteroaryl ring in an arylalkyl or heteroarylalkyl group may be substituted with the same substituents described above for aryl groups. Preferably, an arylalkyl group includes a phenyl ring optionally substituted with the groups defined above for aryl groups and a C1-C4alkylene that is unsubstituted or is substituted with one or two C1-C4alkyl groups or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane. Similarly, a heteroarylalkyl group preferably includes a C5-C6 monocyclic heteroaryl group that is optionally substituted with the groups described above as substituents typical on aryl groups and a C1-C4 alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, or it includes an optionally substituted phenyl ring or C5-C6monocyclic heteroaryl and a C1-C4heteroalkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.

[0097] As used herein, the term “heteroatom” refers to any atom that is not carbon or hydrogen, such as nitrogen, oxygen or sulfur. When it is part of the backbone or skeleton of a chain or ring, a heteroatom must be at least divalent, and will typically be selected from N, O, P, and S, more typically from N, O, and P. The term “heteroatom” can include, in some contexts, other atoms, including selenium, silicon, or boron, where such alternative heteroatoms do not interfere with the function of the molecule in which they are included.

[0098] As used herein, the term “alkanoyl” refers to an alkyl group covalently linked to a carbonyl (C=O) group. The term “lower alkanoyl” refers to an alkanoyl group in which the alkyl portion of the alkanoyl group is C1-C6. The alkyl portion of the alkanoyl group can be optionally substituted as described above. The term “alkylcarbonyl” can alternatively be used. Similarly, the terms “alkenylcarbonyl” and “alkynylcarbonyl” refer to an alkenyl or alkynyl group, respectively, linked to a carbonyl group.PATENT PARSON-58748

[0099] As used herein, the term “alkoxy” refers to an alkyl group covalently linked to an oxygen atom; the alkyl group can be considered as replacing the hydrogen atom of a hydroxyl group. The term “lower alkoxy” refers to an alkoxy group in which the alkyl portion of the alkoxy group is C1-C6. The alkyl portion of the alkoxy group can be optionally substituted as described above. As used herein, the term “haloalkoxy” refers to an alkoxy group in which the alkyl portion is substituted with one or more halo groups.

[0100] As used herein, the term “sulfo” refers to a sulfonic acid (—SO3H) substituent.

[0101] As used herein, the term “sulfamoyl” refers to a substituent with the structure — S(O2)NH2, wherein the nitrogen of the NH2portion of the group can be optionally substituted as described above; the optional substituents, if present, would replace one or both of the hydrogens of the NH2 portion of the group.

[0102] As used herein, the term “carboxyl” refers to a group of the structure —C(O2)H.

[0103] As used herein, the term “carbamyl” refers to a group of the structure — C(O2)NH2, wherein the nitrogen of the NH2 portion of the group can be optionally substituted as described above; the optional substituents, if present, would replace one or both of the hydrogens of the NH2 portion of the group.

[0104] As used herein, the terms “monoalkylaminoalkyl” and “dialkylaminoalkyl” refer to groups of the structure —Alk1-NH-Alk2and —Alk1-N(Alk2)(Alk3), wherein Alk1, Alk2, and Alk3refer to alkyl groups as described above. In some alternatives, each of Alk1, Alk2, and Alk3are C1-C6 alkyl.

[0105] As used herein, the term “alkylsulfonyl” refers to a group of the structure — S(O)2-Alk wherein Alk refers to an alkyl group as described above. The terms “alkenylsulfonyl” and “alkynylsulfonyl” refer analogously to sulfonyl groups covalently bound to alkenyl and alkynyl groups, respectively. The term “arylsulfonyl” refers to a group of the structure —S(O)2- Ar wherein Ar refers to an aryl group as described above. The term “aryloxyalkylsulfonyl” refers to a group of the structure —S(O)2-Alk-O-Ar , where Alk is an alkyl group as described above and Ar is an aryl group as described above. The term “arylalkylsulfonyl” refers to a group of the structure —S(O)2-AlkAr, where Alk is an alkyl group as described above and Ar is an aryl group as described above.

[0106] As used herein, the term “alkyloxycarbonyl” refers to an ester substituent including an alkyl group wherein the carbonyl carbon is the point of attachment to the remainderPATENT PARSON-58748 of the molecule. An example is ethoxycarbonyl, which is CH3CH2OC(O)—. Similarly, the terms “alkenyloxycarbonyl,” “alkynyloxycarbonyl,” and “cycloalkylcarbonyl” refer to similar ester substituents including an alkenyl group, alkenyl group, or cycloalkyl group respectively. Similarly, the term “aryloxycarbonyl” refers to an ester substituent including an aryl group wherein the carbonyl carbon is the point of attachment to the remainder of the molecule. Similarly, the term “aryloxyalkylcarbonyl” refers to an ester substituent including an alkyl group wherein the alkyl group is itself substituted by an aryloxy group.

[0107] As used herein, “heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” and the like are defined similarly to the corresponding hydrocarbyl (alkyl, alkenyl and alkynyl) groups, but the “hetero” terms refer to groups that contain 1 to 3 O, S or N heteroatoms or combinations thereof within the backbone residue; thus at least one carbon atom of a corresponding alkyl, alkenyl, or alkynyl group is replaced by one of the specified heteroatoms to form, respectively, a heteroalkyl, heteroalkenyl, or heteroalkynyl group. For reasons of chemical stability, it is also understood that, unless otherwise specified, such groups do not include more than two contiguous heteroatoms except where an oxo group is present on N or S as in a nitro or sulfonyl group.

[0108] While “alkyl” as used herein includes cycloalkyl and cycloalkylalkyl groups, the term “cycloalkyl” may be used herein to describe a carbocyclic non-aromatic group that is connected via a ring carbon atom, and “cycloalkylalkyl” may be used to describe a carbocyclic non-aromatic group that is connected to the molecule through an alkyl linker.

[0109] Similarly, “heterocyclyl” may be used to describe a non-aromatic cyclic group that contains at least one heteroatom (typically selected from N, O and S) as a ring member and that is connected to the molecule via a ring atom, which may be C (carbon-linked) or N (nitrogen-linked); and “heterocyclylalkyl” may be used to describe such a group that is connected to another molecule through a linker. The heterocyclyl can be fully saturated or partially saturated, but non-aromatic. The sizes and substituents that are suitable for the cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as those described above for alkyl groups. The heterocyclyl groups typically contain 1, 2 or 3 heteroatoms, selected from N, O and S as ring members; and the N or S can be substituted with the groups commonly found on these atoms in heterocyclic systems. As used herein, these terms also include rings that contain a double bond or two, as long as the ring that is attached is notPATENT PARSON-58748 aromatic. The substituted cycloalkyl and heterocyclyl groups also include cycloalkyl or heterocyclic rings fused to an aromatic ring or heteroaromatic ring, provided the point of attachment of the group is to the cycloalkyl or heterocyclyl ring rather than to the aromatic / heteroaromatic ring.

[0110] As used herein, “acyl” encompasses groups comprising an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical attached at one of the two available valence positions of a carbonyl carbon atom, and heteroacyl refers to the corresponding groups wherein at least one carbon other than the carbonyl carbon has been replaced by a heteroatom chosen from N, O and S.

[0111] Acyl and heteroacyl groups are bonded to any group or molecule to which they are attached through the open valence of the carbonyl carbon atom. Typically, they are C1-C8 acyl groups, which include formyl, acetyl, pivaloyl, and benzoyl, and C2-C8 heteroacyl groups, which include methoxyacetyl, ethoxycarbonyl, and 4-pyridinoyl.

[0112] Similarly, “arylalkyl” and “heteroarylalkyl” refer to aromatic and heteroaromatic ring systems which are bonded to their attachment point through a linking group such as an alkylene, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linkers. Typically the linker is C1-C8 alkyl. These linkers may also include a carbonyl group, thus making them able to provide substituents as an acyl or heteroacyl moiety. An aryl or heteroaryl ring in an arylalkyl or heteroarylalkyl group may be substituted with the same substituents described above for aryl groups. Preferably, an arylalkyl group includes a phenyl ring optionally substituted with the groups defined above for aryl groups and a C1-C4 alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane. Similarly, a heteroarylalkyl group preferably includes a C5-C6 monocyclic heteroaryl group that is optionally substituted with the groups described above as substituents typical on aryl groups and a C1-C4alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, or it includes an optionally substituted phenyl ring or C5-C6 monocyclic heteroaryl and a C1-C4 heteroalkylene that is unsubstituted or is substituted with one or two C1-C4alkyl or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.PATENT PARSON-58748

[0113] Where an arylalkyl or heteroarylalkyl group is described as optionally substituted, the substituents may be on either the alkyl or heteroalkyl portion or on the aryl or heteroaryl portion of the group. The substituents optionally present on the alkyl or heteroalkyl portion are the same as those described above for alkyl groups generally; the substituents optionally present on the aryl or heteroaryl portion are the same as those described above for aryl groups generally.

[0114] “Arylalkyl” groups as used herein are hydrocarbyl groups if they are unsubstituted, and are described by the total number of carbon atoms in the ring and alkylene or similar linker. Thus a benzyl group is a C7-arylalkyl group, and phenylethyl is a C8-arylalkyl group.

[0115] “Heteroarylalkyl” as described above refers to a moiety comprising an aryl group that is attached through a linking group, and differs from “arylalkyl” in that at least one ring atom of the aryl moiety or one atom in the linking group is a heteroatom selected from N, O and S. The heteroarylalkyl groups are described herein according to the total number of atoms in the ring and linker combined, and they include aryl groups linked through a heteroalkyl linker; heteroaryl groups linked through a hydrocarbyl linker such as an alkylene; and heteroaryl groups linked through a heteroalkyl linker. Thus, for example, C7-heteroarylalkyl would include pyridylmethyl, phenoxy, and N-pyrrolylmethoxy.

[0116] “Alkylene” as used herein refers to a divalent hydrocarbyl group; because it is divalent, it can link two other groups together. Typically it refers to —(CH2)n— where n is 1-8 and preferably n is 1-4, though where specified, an alkylene can also be substituted by other groups, and can be of other lengths, and the open valences need not be at opposite ends of a chain. The general term “alkylene” encompasses more specific examples such as “ethylene,” wherein n is 2, “propylene,” wherein n is 3, and “butylene,” wherein n is 4. The hydrocarbyl groups of the alkylene can be optionally substituted as described above.

[0117] In general, any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group that is contained in a substituent may itself optionally be substituted by additional substituents as long as the therapeutic or pharmacological activity of the compound that is optionally substituted is retained. The nature of these substituents is similar to those recited with regard to the primary substituents themselves if the substituents are not otherwise described.

[0118] As used herein, the term “absent” when used in reference to a functional group or substituent, particularly in reference to the chemical structure of a compound, means that thePATENT PARSON-58748 particular functional group or substituent is not present in the compound being described. When used in reference to a substituent, the absence of the substituent typically means that the bond to the substituent is absent and that absence of the bond is compensated for with a H atom. When used in reference to a position within a chain or ring, the absence of the position typically means that the two positions otherwise connected by the absent position are instead directly connected by a covalent bond.

[0119] Other combinations of substituents are known in the art and are described, for example, in United States Patent No. 8,344,162 to Jung et al. or in PCT Patent Application Publication No. WO 2019 / 204768 by Kobilka et al. For example, the term “thiocarbonyl” and combinations of substituents including “thiocarbonyl” include a carbonyl group in which a double-bonded sulfur replaces the normal double-bonded oxygen in the group. The term “alkylidene” and similar terminology refer to an alkyl group, alkenyl group, alkynyl group, or cycloalkyl group, as specified, that has two hydrogen atoms removed from a single carbon atom so that the group is double-bonded to the remainder of the structure.

[0120] Certain compounds described herein for use in methods and compositions according to the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, or stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention unless specific isomers are excluded. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. The term “tautomer,” as used herein, refers to one of two or more structural isomers that exist in equilibrium and that are readily converted from one form to another. Examples of tautomerism include, but are not limited to, keto-enol tautomerism, enamine-imine tautomerism, and lactam-lactim tautomerism. Unless one of the tautomeric alternatives is expressly excluded, all such tautomeric forms are intended to be within the scope of the invention.PATENT PARSON-58748

[0121] For a number of compounds and classes of compounds disclosed in methods and compositions according to the present invention, alternative structures are presented in terms of Markush groups; an example is a ring moiety in a structure that includes one or more substituents which are described in the alternative as, for example, ethyl, methyl, or propyl. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit. DETAILED DESCRIPTION OF THE INVENTION

[0122] The urinary bladder is lined by a surface mucus layer that is relatively impermeable and is responsible for the blood-urine barrier (C.L. Parsons et al., “Bladder Surface Glycosaminoglycan / sulfated polysaccharides: An Artificial Permeability Barrier,” J. Urol. 143: 139-142 (1990) (“Parsons et al. (1990)”). This layer (also known as the glycosaminoglycan / sulfated polysaccharide (GAG) layer is strongly anionic due to the sulfate and sialic acid content. Sialic acids include N- and O-substituted derivatives of neuraminic acid.

[0123] Highly-charged amines such as protamine sulfate can injure the glycosaminoglycan / sulfated polysaccharide layer and cause it to leak in both rodents and humans (Parsons et al. (1990), supra; J.D. Lilly & C.L. Parsons, “Bladder Surface Glycosaminoglycans Is a Human Epithelial Permeability Barrier,” Surg. Gynecol. Obstet. 17: 493-496 (1990)).

[0124] If this layer becomes dysfunctional, it will leak and allow potassium to leak into the bladder wall and cause symptoms such as bladder disease and interstitial cystitis, which is the most common cause of bladder symptoms in women (C.L. Parsons et al., “Epithelial Dysfunction in Nonbacterial Cystitis (Interstitial Cystitis),” J. Urol. 145: 732-735 (1991); C.L. Parsons et al., “The Role of Urinary Potassium in the Pathogenesis and Diagnosis of Interstitial Cystitis,” J. Urol. 159: 1862-1867 (1998); C.L. Parsons et al., “Increased Prevalence of Interstitial Cystitis: Previously Unrecognized Urologic and Gynecologic Cases Identified Using a New Symptom Questionnaire and Intravesical Potassium Symphony,” Urology 60: 573-578 (2002); C.L. Parsons, “The Role of a Leaky Epithelium and Potassium in the Generation of Bladder Symptoms in Interstitial Cystitis / Overactive Bladder, Urethral Syndrome, Prostatitis and Gynaecological Chronic Pelvic Pain,” BJU Int. 107: 370-375 (2011)).

[0125] The leaking potassium causes nerve depolarization, inflammation, mast cell stimulation (leading to histamine release), eosinophilic infiltration, and, at least in some patients,PATENT PARSON-58748 deposition of amyloid. The deposition of amyloid is particularly relevant to the development of Alzheimer’s disease (T.C. Theoharides, “Hydroxyzine in the Treatment of Interstitial Cystitis,” Urol. Clin. North Am. 21: 113-119 (1994)). It is now known that cationic urinary amines are markedly elevated in the urine of interstitial cystitis patients compared to normal subjects; it is these amines that damage the bladder epithelium just as protamine does. These cationic amines include 1-methyladenine, 1-methylguanine, N2,N2-dimethylguanosine, and L-tryptophan (C.L. Parsons et al., “Role of Urinary Cations in the Aetiology of Bladder Symptoms and Interstitial Cystitis,” BJU Int.114: 286-293 (2014); C.L. Parsons et al., “Role of Urinary Cations in the Etiology of Interstitial Cystitis: A Multisite Study,” Int. J. Urol. 731-735 (2020)). These toxic cations are primarily nucleic acid metabolites of DNA or RNA, althoughL-tryptophan is an amino acid that occurs as an amino acid residue in polypeptides and proteins, and are filtered by the kidneys so that their serum levels are likely to be high or else their urine levels would not be elevated.

[0126] Blood vessels are lined by a mucus layer that is a glycocalyx and is highly negatively charged, similar to bladder mucus, and that also acts as a barrier to protect the inner walls of the vasculature. It is this mucus layer that forms part of the blood-brain barrier.

[0127] The blood-brain barrier is a highly selective semipermeable border of endothelial cells that prevents solutes in circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system where neurons are located. The blood-brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. The blood-brain barrier allows the passage of some small molecules by passive diffusion, as well as the selective and active transport of various nutrients, ions including organic anions, and macromolecules; the molecules that can be transported include glucose and amino acids that are critical to neural function. The blood-brain barrier restricts the passage of pathogens, the diffusion of solutes in the blood, and the passage of large or hydrophilic molecules into the cerebrospinal fluid, while generally allowing the diffusion of hydrophobic molecules, such as many hormones, the diffusion of gases such as O2or CO2, and the diffusion of small nonpolar molecules. Cells that are part of the barrier actively transport metabolic products such as glucose across the barrier using specific transport proteins. The barrier also restricts the passage of peripheral immune factors, likePATENT PARSON-58748 signaling molecules, antibodies, and immune cells, into the CNS, thus insulating the brain from damage due to peripheral immune events.

[0128] The blood-brain barrier results from the selectivity of the tight junctions between the endothelial cells of brain capillaries, restricting the passage of certain solutes. At the interface between the blood and the brain, endothelial cells are adjoined continuously by these tight junctions, which are comprised of smaller subunits of transmembrane proteins, such as occludin, claudins such as claudin-5, and junctional adhesion molecules such as JAM-A. Each of these tight junction proteins is stabilized to the endothelial cell membrane by another protein complex that includes scaffolding proteins such as tight junction protein 1 and associated proteins.

[0129] The blood-brain barrier may become damaged in certain neurological diseases, including, but not necessarily limited to, Alzheimer’s disease and amyotrophic lateral sclerosis (B. Segura-Collar et al., “Blood-Brain Barrier Disruption: A Common Driver of Central Nervous System Diseases,” Neuroscientist 28: 222-237 (2021)).

[0130] Particularly when the blood-brain barrier is damaged or its function disrupted, the potential for injury to the mucus linings of blood vessels by high levels of nucleic acid metabolites, such as, but not limited to, 1-methyladenine, 1-methylguanine, or N2,N2- dimethylguanosine, as well as other amino-containing metabolites such as protamine, is significant, and can lead to the development or progression of diseases such as atherosclerosis (E. Lupia et al., “Pentosan Polysulfate Inhibits Atherosclerosis in Watanabe Heritable Hyperlipidemic Rabbits: Differential Modulation of Metalloproteinase-2 and -9,” Lab. Invest. 92: 236-245 (2012)) or Alzheimer’s disease or other central nervous system neurodegenerative diseases. It has been shown that protamine will damage the blood-brain barrier (similarly to what occurs in the urinary bladder) and when such damage occurs, the protamine leaks (L.J. Strausbaugh, “Intracarotid Infusions of Protamine Sulfate Disrupt the Blood-Brain Barrier of Rabbits,” Brain Res. 409: 221-226 (1987); J.E. Hardebo & J. Kåhrström, “Endothelial Negative Surface Charge Areas and Blood-Brain Barrier Function,” Acta Physiol. Scand. 125: 495-499 (1985)).

[0131] When patients develop Alzheimer’s disease they accumulate beta-amyloid in the brain tissue in a similar manner to what can happen in some patients with interstitial cystitis. ItPATENT PARSON-58748 may well be that the beta-amyloid accumulation is a reaction to the disease process of an epithelial leak and not the actual cause of Alzheimer’s disease.

[0132] The elevated nucleic acid metabolites and other amine-containing molecules in urine that cause interstitial cystitis are neutralized by pentosan polysulfate (PPS), typically in the form of sodium pentosan polysulfate, and this drug essentially cures interstitial cystitis by restoring a healthy urothelium. In patients administered pentosan polysulfate, the symptoms of interstitial cystitis resolve and the patients stay healthy if they remain on this treatment (C.L. Parsons et al., “A Quantitatively Controlled Method to Study Prospectively Interstitial Cystitis and Demonstrate the Efficacy of Pentosanpolysulfate,” J.Urol. 150: 845-848 (1993); S.G. Mulholland et al., “Pentosan Polysulfate Sodium for Therapy of Interstitial Cystitis. A Double- Blind Placebo-Controlled Clinical Study,” Urology 35: 552-558 (1990); C.L. Parsons et al., “Effect of Pentosan Polysulfate Therapy on Intravesical Potassium Sensitivity,” Urology 59: 329-333 (2002)).

[0133] Therefore, although Applicant is not bound by this hypothesis, Applicant proposes that pentosan polysulfate can successfully resolve the epithelial dysfunction seen in the blood vessels of the brain and thereby prevent the development or progression of neurodegenerative brain disease, particularly Alzheimer’s disease.

[0134] One embodiment of the present invention, therefore, is a method of preventing or treating a neurodegenerative disease by administering a therapeutically effective quantity of a glycosaminoglycan / sulfated polysaccharide to a subject with a neurodegenerative disease or at risk of developing a neurodegenerative disease.

[0135] Typically, the glycosaminoglycan / sulfated polysaccharide is pentosan polysulfate, preferably sodium pentosan polysulfate. However, other cations can be used in place of sodium, including lithium, rubidium, cesium, calcium, magnesium, strontium, or barium. Generally, however, potassium should not be used as it may exacerbate symptoms associated with the urinary tract as stated above. Preferably, therefore, the glycosaminoglycan / sulfated polysaccharide is selected from the group consisting of sodium pentosan polysulfate and calcium pentosan polysulfate. More preferably, the glycosaminoglycan / sulfated polysaccharide is sodium pentosan polysulfate.

[0136] Preferably, as stated above, the glycosaminoglycan / sulfated polysaccharide is pentosan polysulfate. However, other acidic glycosaminoglycans can be used. SuitablePATENT PARSON-58748 glycosaminoglycans include, but are not limited to, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and keratan sulfate.

[0137] In one alternative, the method typically further comprises administering a pharmacologically effective quantity of a pharmacologically compatible intestinal penetration agent, as detailed below.

[0138] The glycosaminoglycan / sulfated polysaccharide, preferably sodium pentosan polysulfate, can be administered orally, subcutaneously, or intravenously. In general, oral administration is preferred. However, as detailed below, if oral administration is used, it is preferable to administer the glycosaminoglycan / sulfated polysaccharide, preferably sodium pentosan polysulfate, with an intestinal penetration agent.

[0139] The structure of sodium pentosan polysulfate is shown below as Formula (I): .

[0140] The reasons for thethe presence of charged groups (sulfate moieties). It is well known that charged groups have great difficulty penetrating the lipid bilayer of the cell membrane, because such lipid bilayers are extremely hydrophobic and the passage of a compound with multiple charged groups such as sulfate moieties through a lipid bilayer is energetically unfavorable. The relatively large size of the molecule also contributes to its poor bioavailability.

[0141] Pentosan polysulfate (PPS) is a semi-synthetic, polysulfated oligosaccharide comprising a mixture of multiply charged anionic polysaccharides. PPS is produced by chemical sulfation of polysaccharides such as xylan obtained from woody plants such as beechwood trees. The resulting product typically contains approximately 15-17% sulfur in the form of approximately 1.5-1.9 covalently bound sulfate groups per sugar residue in a mixture of polydisperse polymeric molecules estimated to have a molecular weight of from about 4,000 toPATENT PARSON-58748 about 10,000 daltons. PPS consists of sulfated, linear polysaccharides of about 12 to 301-4 conjugated β-D-xylopyranose units (Mrof from about 4000 to about 10000) which has a D- gluconic acid at approximately every tenth unit. PPS can also be obtained from microorganisms.

[0142] United States Patent Application Publication No. 2011 / 0212914 by Ellinghuysen et al. discloses stabilized pentosan polysulfate formulations, including formulations that are stable without refrigeration in a solution with a pH from about 4 to about 8, or with a pH of from about 7 to about 8. In another alternative, the formulation is stable without refrigeration after terminal sterilization. The formulation may comprise pentosan polysulfate in a concentration of from about 25 mg / mL to about 500 mg / mL, preferably from about 100 mg / mL to about 250 mg / mL. The formulation can undergo terminal sterilization by moist heat with or without rapid cooling fluids, ethylene oxide, or radiation. Formulations can comprise additional components such as one or more buffers, such as sodium bisulfite, sodium citrate, or citric acid; one or more chelating agents, such as EDTA; one or more preservatives; one or more antimicrobial agents, such as methylparaben; one or more antioxidants; or other suitable excipients. Pentosan polysulfate preparations can also include an amino sugar and hyaluronic acid.

[0143] One study (M. Simon et al., “Metabolism of [3H]pentosan Polysulfate Sodium (PPS) in Healthy Human Volunteers,” Xenobiotica 35: 775-784 (2005)), reported that more than 94% of sodium pentosan polysulfate is excreted unchanged in feces without providing any beneficial effect and only 6% is excreted through urine. However, this study used tritiated pentosan polysulfate and did not directly measure pentosan polysulfate; the tritiated pentosan polysulfate spontaneously releases3H. The key point from this study is that oral absorption of pentosan polysulfate is low.

[0144] Therefore, because of the relatively poor bioavailability of sodium pentosan polysulfate, relatively large doses are required when sodium pentosan polysulfate is administered orally to treat interstitial cystitis and other diseases or conditions affecting the urinary tract, and would also be expected if sodium pentosan polysulfate were administered to treat or prevent Alzheimer’s disease or another neurodegenerative disease. The requirement for such large doses may lead to side effects. Patients who have taken sodium pentosan polysulfate orally have reported a variety of side effects, primarily gastrointestinal complaints such as diarrhea, heartburn, and stomach pain. Hair loss, headache, rash, and insomnia have also been reported.PATENT PARSON-58748

[0145] The importance of being able to improve the bioavailability of pentosan polysulfate is increased by the effect of pentosan polysulfate on the blood-brain barrier (M.A. Deli et al., “Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity,” J. Alzheimers Dis. 22: 777-794 (2010)).

[0146] The dosage range for sodium pentosan polysulfate is typically from about 100 mg to about 1200 mg daily. Sodium pentosan polysulfate is only about 2.5% bioavailable by mouth in the absence of an intestinal penetration agent, so that a dose of 100 mg administered orally results in about 2.5 mg being absorbed by the body. Therefore, if oral administration is employed in the absence of a penetration agent, the dosage range of about 100 mg to about 1200 mg yields about 2.5 mg to about 30 mg of absorbed drug. Sodium pentosan polysulfate acts as an anticoagulant if administered intravenously, and a 100-mg dose administered intravenously would cause anti-coagulation, which would be undesirable in most patients. Lower dosages of from about 20 mg to about 40 mg daily, administered intravenously, would be acceptable but would cause difficulties if administered on a once-daily or twice-daily basis, and patient compliance could be a problem for such a dosing schedule. As another alternative for the administration of sodium pentosan polysulfate to treat Alzheimer’s disease, subcutaneous administration could be employed, with administration of sodium pentosan polysulfate at doses of from about 10 mg to about 20 mg twice daily to minimize anticoagulant activity. However, in summary, oral administration would be the safest and most practical route to administer sodium pentosan polysulfate for most patients, particularly in combination with an intestinal penetration agent to minimize the quantity of sodium pentosan polysulfate required. Preferably, two divided doses are administered daily to ensure that there is always a blood level of sodium pentosan polysulfate that can inactivate serum nucleic acid metabolites and other amino-containing compounds causing injury to the blood-brain barrier. Using an intestinal penetration agent that can increase absorption of sodium pentosan polysulfate by a factor of about 5-fold would reduce the quantity of sodium pentosan polysulfate required to deliver a therapeutic dose and thus reduce potential gastrointestinal side effects as compared to such side effects that might occur with an oral dosage of from about 900 mg to about 1200 mg of sodium pentosan polysulfate (without use of an intestinal penetration agent), most of which would not be absorbed. These dosages are similar to those typically used for the treatment of interstitial cystitis with sodium pentosan polysulfate. When an intestinal penetration enhancer is administered together withPATENT PARSON-58748 sodium pentosan polysulfate, the dose of sodium pentosan polysulfate is typically much lower, varying from about 25 mg / day to about 500 mg / day, depending on which intestinal penetration enhancer is administered. Typically, the intestinal penetration enhancer increases the absorption of the drug about 5-fold compared with the absorption of the drug when an intestinal penetration enhancer is not used; however, the actual increase will vary to some extent depending on the intestinal penetration enhancer used. These dosages and considerations for the determination of suitable dosages are described herein for prevention and treatment of Alzheimer’s disease; however similar dosages and considerations for the determination of suitable dosages can be employed for prevention or treatment of other neurodegenerative diseases such as, but not necessarily limited to, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis.

[0147] For oral administration of sodium pentosan polysulfate, a preferred dose would be a dose that would deliver from about 15 mg / day to about 25 mg / day that is absorbed into the body. Typically, the required quantity of sodium pentosan polysulfate is administered in two divided doses to maintain a more continuous blood level of the drug. With use of an intestinal penetration agent yielding about a 5-fold increased absorption of sodium pentosan polysulfate, one would only need to administer from about 50 mg / day to about 100 mg / day of sodium pentosan polysulfate orally to achieve these levels. At these low dosage levels, virtually no gastrointestinal side effects would be seen but good protective activity with respect to the blood- brain barrier would occur. When the sodium pentosan polysulfate (or, alternatively, another salt such as calcium pentosan polysulfate as described below) is administered orally, typically, the frequency of administration is twice daily or three times daily. When the sodium pentosan polysulfate (or, alternatively, another salt such as calcium pentosan polysulfate as described below) is administered subcutaneously or intravenously, the frequency of administration is typically once daily or twice daily; however, for lower dosages of sodium pentosan polysulfate or another pentosan polysulfate salt that are administered subcutaneously or intravenously, the frequency of administration can be once daily, twice daily, or three times daily.

[0148] In describing the dosages of sodium pentosan polysulfate (or, alternatively, another salt such as calcium pentosan polysulfate as described below), it is important to distinguish the administered dose from the therapeutically effective quantity actually absorbed. When the reference is to the quantity of sodium pentosan polysulfate (or other salts) in a unit dose of the composition described herein or in a method described herein, it refers to thePATENT PARSON-58748 administered dose and not to the therapeutically effective quantity actually absorbed by the subject to whom the dose is administered; the therapeutically effective quantity actually absorbed is specifically referenced.

[0149] Typically, the ratio, by weight, of the intestinal penetration agent to the sodium pentosan polysulfate is from about 0.167:1 to about 8:1. Preferably, the ratio, by weight, of the intestinal penetration agent to the sodium pentosan polysulfate is from about 0.50:1 to about 3:1. More preferably, the ratio, by weight, of the intestinal penetration agent to the sodium pentosan polysulfate is from about 0.75:1 to about 2:1.

[0150] Typically, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least 5%. Preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least 10%. More preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least 20%. Still more preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least 30%. Typically, as stated above, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate by at least fivefold as compared with the bioavailability in the absence of intestinal penetration agent.

[0151] Typically, the administration of the pentosan polysulfate salt, preferably sodium pentosan polysulfate, reduces permeability of the mucus-containing layer of arteries of the central nervous system to amino-containing cations and thus stabilizes the blood-brain barrier, reducing penetration of the blood-brain barrier by amino-containing cations such as, but not necessarily limited to, protamine sulfate, 1-methyladenine, 1-methylguanine, N2,N2- dimethylguanosine, andL-tryptophan.

[0152] Suitable intestinal penetration agents and, where employed, pharmaceutically acceptable carriers, are described below.

[0153] Intestinal penetration agents suitable for use in methods or compositions according to the present invention can include, but are not limited to the intestinal penetration agents described below as Alternatives (1)-(114) or derivatives or analogs thereof.

[0154] These additional intestinal penetration agents are described below and can be used in methods or compositions according to the present invention.PATENT PARSON-58748

[0155] In the context of the present invention, while intestinal penetration agents enhance intestinal absorption of the glycosaminoglycan / sulfated polysaccharides included in methods and compositions according to the present invention, they substantially preserve integrity of the blood-brain barrier and do not function in a way that will increase the permeability of the blood-brain barrier to the nucleic acid metabolites and other amino- containing metabolites described above.

[0156] One group of intestinal penetration agents is: (1) N-benzoyl-α-amino acids of Formula (II) and salts, analogues, or bioisosteres thereof:(II), wherein the α-amino acid is selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tyrosine, aspartic acid, glutamic acid, lysine, ornithine, arginine, and serine, wherein X is selected from the group consisting of C(O) and SO2, and wherein Y is selected from the group consisting of phenyl and cyclohexyl.

[0157] Another group of intestinal penetration agents is: (2) derivatized leucines of Formula (III) and salts, analogues, or bioisosteres thereof:(III), wherein R is selected from the group consisting of cyclohexyl, 2-methylcyclohexyl, 3- methylcyclohexyl, 4-methylcyclohexyl, cycloheptyl, cyclopentyl, cyclopropyl, 2- carboxycyclohexyl, benzoyl, 3-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, and (CH2)2cyclohexyl.

[0158] Yet another group of intestinal penetration agents is: (3) N-cyclohexanoylamino acids of Formula (IV) and salts, analogues, or bioisosteres thereof:PATENT PARSON-58748 (IV),wherein R is selected from the group consisting of CH2Ph, (CH2)3NHC(NH)NH2, i-butyl, s- butyl, (CH2)4NH, CH2(4-C6H4OH), (CH2)3NHC(O)NH2, CH2(imidazole), and phenyl.

[0159] Yet another group of intestinal penetration agents is: (4) derivatized phenylglycines of Formula (V) and salts, analogues, or bioisosteres thereof:(V), wherein R is selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl, methylcyclohexyl, (CH2)2cyclohexyl, phenyl, and 2-hydroxyphenyl.

[0160] Still another group of intestinal penetration agents is (5): derivatives of 4- aminobenzoic acid, 2-(4-aminophenyl)acetic acid, 3-(4-aminophenyl)propionic acid, or 4-(4- aminophenyl)butyric acid of Formula (VI) and salts, analogues, or bioisosteres thereof:(VI), wherein: (a) Y is selected from the group consisting of H, F, 2-OH, 2,3-Ph, 4-Ph, 3,4-Ph, 4- OCH3, 4-F, 2-Cl, 2-F, 2,4-(OH)2, 3-CF3, 3-Cl, 2-CH3, 2,6-(OH)2, 3-N(CH3), 3,4-OCH2O, 2,6- diCH3, 2-COOH, 2-NO2, 2-OCH3, 3-NO2, 2-OCF3, 4-CH3, and 4-i-Bu; (b) n is 0, 1, 2, 3, 4, or a vinyl group; (c) m is 0, 1, or 2, a vinyl group, a CHMe group, a CHEt group; a (CH2)2O group, a (CH2)2C=O group, or a (CH2OH)2 group; (d) X is C=O, SO2, or CH2; and (e) Z is phenyl, cyclohexyl, or cycloheptyl.PATENT PARSON-58748

[0161] Yet another group of intestinal penetration agents is: (6) compounds of Formula (VII):(VII), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, and salts, analogues, or bioisosteres thereof. Preferred intestinal penetration agents are compounds or salts of Formula (VII) in which n is 7, 8, or 9.

[0162] A particularly preferred intestinal penetration agent is sodium N-[8-(2- hydroxybenzoyl)amino]caprylate, also known as salcaprozate sodium or SNAC (S.A. Mousa et al., “Pharmacokinetics and Pharmacodynamics of Oral Heparin Solid Dosage Form in Healthy Human Subjects,” J. Clin. Pharmacol. 47: 1508-1520 (2007)). This is the sodium salt of a compound of Formula (VI) with n equal to 7.

[0163] Other intestinal penetration agents are known in the art and can be used in methods and compositions according to the present invention. United States Patent No. 8,410,309 to Leone-Bay et al. describes phenoxycarboxylic acid compounds as intestinal penetration agents, specifically phenoxycarboxylic acid compounds of Formula (VIII):(VIII), wherein: (i) R1, R2, R3, and R4are each independently hydrogen, hydroxyl, halo, C1-C4 alkyl, C2- C4alkenyl, C1-C4alkoxy, -C(O)R8, -NO2, -NR9R10, or –N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, -NO2, halo, trifluoromethyl, -NR14R15, –N+R14R15R16(R13)-, amide, C1-C12 alkoxy, C1- C12 alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or -C(O)R18; (iii) R5is optionally substituted with halo, hydroxyl, sulfhydryl, or carboxyl; (iv) R5is optionally interrupted by O, N, S, or –C(O)-; (v) R6is a C1-C12 alkylene, C2-C12 alkenylene, or arylene; (vi) C6is optionally substituted with a C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, halo, amino, orPATENT PARSON-58748 –CO2R8; (vii) R6is optionally interrupted by O or N; (viii) R7is a bond or arylene; (ix) R7is optionally substituted with hydroxyl, halogen, -C(O)CH3, -NR10R11, or –N+R10R11R12(R13)-; (x) R8is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or amino; (xi) R9, R10, R11, and R12are each independently hydrogen or C1-C10 alkyl; (xii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiv) R14, R15, and R16are each independently hydrogen, C1-C10alkyl, C1-C10 alkyl substituted with carboxyl, C2-C12 alkenyl, C2-C12 alkenyl substituted with carboxyl, or C(O)R17; (xv) R17is hydroxyl, C1-C10 alkyl, or C2-C12 alkenyl; (xvi) R18is hydrogen, C1-C6alkyl, hydroxyl, -NR14R15, or –N+R14R15R16(R13)-; with the proviso that: (a) when R1, R2, R3, R4, and R5are hydrogen and R7is a bond, then R6is not a C1-C6, C9, or C10alkyl; (b) when R1, R2, R3, and R4are hydrogen, R5is hydroxyl, and R7is a bond, then R6is not a C1-C3 alkyl; (c) when at least one of R1, R2, R3, and R4is not hydrogen, R5is hydroxyl, and R7is a bond, then R6is not a C1-C4alkyl; (d) when R1, R2, and R3are hydrogen, R4is –OCH3, R5is C(O)CH3, and R6is a bond, then R7is not a C3 alkyl; and (e) when R1, R2, R4, and R5are hydrogen, R3is hydroxyl, and R7is a bond, then R6is not a methyl group.

[0164] United States Patent No. 8,383,852 to Tang et al. describes compounds having a cyclic moiety as intestinal penetration agents, specifically compounds of Formula (IX):(IX), wherein: m is 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, or 4, q and x are independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R may be the same or different and is selected from hydrogen, halogen, a substituted or non-substituted alkyl, substituted or non-substituted alkyloxyl, substituted or non-substituted alkenyloxyl, substituted or non-substituted alkynyloxyl and substituted or non-substituted aryloxyl; and R1, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, substituted or non-substituted alkyl, substituted or non-substituted alkenyl, substituted or non-substituted alkynyl, substituted or non-substituted alkyloxyl, substituted or non-substituted aryloxyl, substituted or non-substituted aryl groups, substituted or non-substituted heteroaryl, substituted or non-substituted cycloalkyl, and substituted or non- substituted heterocycloalkyl groups.PATENT PARSON-58748

[0165] United States Patent No. 8,273,794 to Gomez-Orellana et al. discloses intestinal penetration agents with an aromatic nucleus of Formula (X):(X), wherein: (i) R1 is –(CH2)m-R8, wherein m is 0 or 1; (ii) R2, R3, R4, R5, and R6 are each independently selected from hydrogen, hydroxyl, halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4alkoxy, and cyano; (iii) R7is selected from C1-C10alkyl, C2-C10alkenyl, and C2- C10alkynyl; (iv) R8is selected from cyclopentyl, cyclohexyl, and phenyl, wherein, when R8is phenyl, m is 1; and (v) R8 is optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo, hydroxyl, or a combination thereof.

[0166] United States Patent No. 8,207,227 to Bay et al. discloses disodium salts, monohydrates, and ethanol solvates as intestinal penetration agents. Specifically, the intestinal penetration agents are: (1) disodium salts of Formula (XI); (2) monohydrates of disodium salts of Formula (XI); and (3) alcohol solvates of disodium salts of Formula (XI), wherein the alcohol is methanol, ethanol, propanol, propylene glycol, or other monohydroxylic or dihydroxylic alcohols:(XI), wherein: (i) R1, R2, R3, and R4are each independently hydrogen, hydroxyl, -NR6R7, halo, C1-C4 alkyl, or C1-C4alkoxy; (ii) R5is a substituted or unsubstituted C2-C16alkylene, substituted or unsubstituted C1-C12 alkyl(arylene), or substituted or unsubstituted aryl(C1-C12 alkylene); and (iii) R6and R7are each independently hydrogen, oxygen, or C1-C4 alkyl. Preferred compounds of Formula (XI) include N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N-(10-[2- hydroxybenzoyl]amino)decanoic acid (SNAD), N-(8-[2-hydroxybenzoyl]amino)caprylic acidPATENT PARSON-58748 (SNAC), 8-(N-2-hydroxy-4-methoxybenzoyl)aminocaprylic acid, and N-(9-(2- hydroxybenzoyl)aminononanoic acid.

[0167] United States Patent No. 8,110,547 by Lee et al. discloses several intestinal penetration agents, including, but not limited to, 8-(N-2-hydroxy-4-methoxybenzoyl)- aminocaprylic acid (“4-MOAC”), N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (“NAC”), N- (8-[2-hydroxybenzoyl]-amino)decanoic acid (“NAD”), N-(8-[2-hydroxy-5-chlorobenzoyl]- amino)octanoic acid (“5-CNAC”), and 4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate (“4- CNAB”).

[0168] United States Patent No. 8,026,392 to Dhoot et al. discloses the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid as an intestinal penetration agent.

[0169] United States Patent No. 7,977,506 to Boyd et al. discloses intestinal penetration agents of Formula (XII):(XII), wherein: (i) R1, R2, R3, R4, and R5are each independently selected from hydrogen, halo, hydroxyl, -OCH3, C1-C4 alkyl, amino, methylamino, dimethylamino, or nitro; (ii) m is 0, 1, 2, 3, or 4; (iii) R6is phenyl substituted with –O-R7-COOH at the ortho, meta, or para position; (iv) R6is optionally substituted with one or more substituents selected from hydrogen, halo, hydroxyl, - OCH3, C1-C4 alkyl, amino, methylamino, dimethylamino, or nitro; and (iv) R7is C1-C12 alkyl.

[0170] United States Patent No. 7,947,841 to Jungheim et al. discloses intestinal penetration agents of Formula (XIII): ,PATENT PARSON-58748 wherein: (i) R1and R2are each independently hydrogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, CF3, halo, or NR4R4′; (ii) R3is H or C1-C6alkyl; (iii) X is a 5-membered aromatic heterocycle that is optionally substituted with C1-C4alkyl; wherein the heterocycle contains at least two or three heteroatoms selected from N, S, and O wherein at least one heteroatom is N; (iv) Y is S, CR5=N or N=CR5; (v) n is 2, 3, 4, 5, 6, or 7; (vi) R4is H, COR6, SO2R7, or C1-C6 alkyl; (vii) R4′is H or C1-C6alkyl; (viii) R5is H or forms a bond with X; (ix) R6is H or C1-C6alkyl; and (x) R7is H or C1-C6alkyl.

[0171] United States Patent No. 7,939,494 to Khan et al. discloses an intestinal penetration agent of Formula (XIV):(XIV).

[0172] United States Patent No. 7,893,297 to Bhandarkar et al. discloses An intestinal penetration agent that is sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate.

[0173] United States Patent No. 7,744,910 to Gschneidner et al. discloses intestinal penetration agents, including a penetration agent of Formula (XV): .

[0174] United Statesintestinal penetration agents of Formula (XVa): ,PATENT PARSON-58748 wherein: (i) R16is R3-R4; (ii) R3is -NHC(O)NH-, -C(O)NH-, -NHC(O) -, -OOC-, -COO, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -N HCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O) CH2O-, -OCH2C(O)NH-, -NH-, -O-, or a carbon-carbon bond; R4is Subformula (XVIa(1)):(XVIa(1)); R5, R6, R7, R8, and R9are each independently a bond to R3, or hydrogen, chloro, bromo, fluoro, hydroxyl, methyl, methoxy, or -(CH2)mCH3; R10is a bond to R3, carboxyl, or –C(O)NHR11R12; R11is a substituted or unsubstituted, linear or branched alkylene having a chain length of 1 to 11 carbon atoms or –R13R14-; R12is a bond to R3, carboxyl, amino, hydroxyl, –C(O)–R15, –COO– R15, –NHR15, –OR15, chloro, or bromo; R13is a substituted or unsubstituted phenylene; R14is a substituted or unsubstituted, linear or branched alkylene having a chain length of 1 to 5 carbon atoms; R15is a bond to R3; m is 1, 2, 3, or 4; R17is hydroxyl or methoxy; R23is hydrogen or methyl; and n is an integer from 3 to 200.

[0175] United States Patent No. 7,662,771 to Herr et al. discloses intestinal penetration agents of Formula (XVI):(XVI), wherein: (i) R1and R2are each independently hydrogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, CF3, halo, or NR4R4′; (ii) R3is H or C1-C6 alkyl; (iii) R4is H, COR5, SO2R6, or C1-C6 alkyl; (iv) R4′is H or C1-C6 alkyl; (v) R5is H or C1-C6 alkyl; (vi) R6is H or C1-C6 alkyl; (vii) X is a 5-membered aromatic heterocycle that is optionally substituted with C1-C4 alkyl, wherein the heterocycle contains at least two or three heteroatoms selected from N, S, and O, wherein at least one heteroatom is N, and wherein the heterocycle is not 1,3,4-oxadiazole; and (ix) n is 2, 3, 4, 5, 6, or 7.PATENT PARSON-58748

[0176] United States Patent No. 7,553,872 to Sarubbi et al. discloses an intestinal penetration agent of Formula (XVII):(XVII).

[0177] United States Patent No. 7,495,030 to Gschneidner discloses (5-(2-hydroxy-4- chlorobenzoyl) aminovaleric acid as an intestinal penetration agent.

[0178] United States Patent No. 7,390,834 to Moye-Sherman et al. discloses intestinal penetration agents that are cyanophenoxy carboxylic acid compounds of Formula (XVIII):(XVIII), wherein: (i) R1, R2, R3, R4, and R5are each independently hydrogen, cyano, hydroxyl, -OCH3 or halogen, where at least one of R1, R2, R3, R4, and R5is cyano; (ii) R6is C1-C12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene); with the proviso that where R1is cyano, R4is hydrogen or cyano, and R2, R3, and R5is not methylene.

[0179] United States Patent No. 7,351,741 to Weidner et al. discloses an intestinal penetration agent of Formula (XIX):(XIX).

[0180] United States Patent No. 7,297,794 to Gschneidner et al. discloses phenoxyamine compounds as intestinal penetration agents, including 4-(8-(2-PATENT PARSON-58748 hydroxyphenoxy)octyl)morpholine, 8-(2-hydroxyphenoxy)octyldiethanolamine, 7-(4-2- hydroxyphenoxy)heptylmorpholine, 4-(6-(4-hydroxyphenoxy)hexyl)morpholine, 4-(6-(2- hydroxyphenoxy)hexyl)morpholine, 8-(4-hydroxyphenoxy)octanamine, 6-(2-acetylphenoxy)-1- dimethylaminohexane, 7-(2-hydroxyphenoxy)heptyl-2-isopropylimidazole, 6-(2- hydroxyphenoxy)hexyl-2-methylimidazole, and 5-chloro-4-methyl-2-(8-morpholin-4- yloctyloxy)acetophenone.

[0181] United States Patent No. 7,279,597 to Leone-Bay et al. discloses intestinal penetration agents of Formula (XX):(XX); including compounds with the following combinations of substituents: (1) R1, R2, R3, and R4are each hydrogen, R5is carboxyl, R6is (CH2)7, R7is a bond, and R8is hydrogen; (2) R1, R2, R3, and R4are each hydrogen, R5is C(O)NH2, R6is (CH2)7, R7is a bond, and R8is hydrogen; (3) R1, R2, R3, and R4are each hydrogen, R5is C(O)CH3, R6is (CH2)7, R7is a bond, and R8is hydrogen; (4) R1, R2, R3, and R4are each hydrogen, R5is C(O)NH2, R6is (CH2), R7is p-phenyl, and R8is hydrogen; and (5) R1, R2, R3, and R4are each hydrogen, R5is nitro, R6is (CH2)7, R7is a bond, and R8is hydrogen.

[0182] United States Patent No. 7,276,534 to Milstein discloses carbon-substituted diketopiperazine intestinal penetration agents of Formula (XXI):(XXI), wherein: (i) R and R1are C1-C24 alkyl having a functional group selected from halogen, oxygen, sulfur or nitrogen; (ii) R and R1are optionally interrupted with O, N, or S; (iii) R and R1are optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or CO2R2or any combination thereof; and (iv) R2is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl.PATENT PARSON-58748

[0183] United States Patent No. 7,186,414 to Gschneidner et al. discloses intestinal penetration agents, including the compound of Formula (XXII):(XXII).

[0184] United States Patent No. 7,138,546 to Tang discloses intestinal penetration agents of Formula (XXIII):(XXIII) wherein: (i) R1, R2, R3, and R4are each independently hydrogen, hydroxy, halo, C1-C4 alkoxy, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, and aryl; (ii) R1, R2, R3, and R4are optionally substituted with halo, hydroxyl, C1-C4 alkoxy, or C1-C4 alkyl; (iii) R5is C1-C4 alkyl; (iv) R6is hydrogen or C1-C4 alkyl; (v) R7is hydrogen, C1-C4 alkyl, or aryl; and R7is optionally substituted with halogen or hydroxyl.

[0185] United States Patent No. 7,125,910 to Leone-Bay et al. discloses amino- substituted carboxylic acids including one or more aromatic moieties therein as penetration agents; the aromatic moieties can include phenyl, pyrazinyl, pyrimidyl, chromonyl, or other aromatic groups.

[0186] United States Patent No. 7,067,119 to Leone-Bay et al. discloses modified amino acid compounds as intestinal penetration agents. The modified amino acid compounds may be peptides. A preferred penetration agent that is a modified amino acid compound has the structure of Formula (XXIV):PATENT PARSON-58748 (XXIV).

[0187] United States Patent No. 6,991,798 to Gschneidner et al. discloses intestinal penetration agents, including the compound of Formula (XXV):(XXV).

[0188] United States Patent No. 6,972,300 to Leone-Bay et al. discloses intestinal penetration agents, including the compound of Formula (XXVI):(XXVI).

[0189] United States Patent No. 6,960,355 to Leone-Bay et al. discloses penetration agents of Formula (XXVII): (XXVII), wherein: (i) Ar is a phenyl or naphthyl substituted with at least one of C1-C5alkyl, C2-C4alkenyl, fluoro, chloro, hydroxyl, -SO2, carboxyl, or –SO3H; (ii) R7is selected from the group consisting of C4-C20 alkyl, C4-C20 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10alkyl), phenyl(C1-C10alkenyl), naphthyl(C1-C10alkyl), and phenyl(C1-C10alkenyl); (iii) R7is optionally substituted with C1-C4PATENT PARSON-58748 alkyl, C1-C5 alkenyl, C1-C5 alkoxy, hydroxyl, sulfhydryl, and –CO2R9or any combination thereof; (iv) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (v) R8is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, hydroxyl, and C1-C4 alkoxy; (vi) R8is optionally substituted with C1-C4 alkyl, C1-C5 alkenyl, C1-C5 alkoxy, hydroxyl, sulfhydryl, and –CO2R9or any combination thereof; and (vii) R9is hydrogen, C1-C4alkyl, or C1-C4 alkenyl, with the proviso that the compounds are not substituted with an amino group in the position α to the acid group.

[0190] United States Patent No. 6,846,844 to Tang discloses penetration agents of Formula (XXVIII):(XXVIII), wherein: (i) R1, R2, R3, and R4are independently hydrogen, hydroxyl, halo, C1-C4alkoxy, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, or aryl; (ii) R1, R2, R3, and R4are optionally substituted with halo, hydroxyl, C1-C4 alkoxy, or C1-C4 alkyl; and (iii) R5is a C2-C16 branched alkylene, optionally substituted with halogen.

[0191] United States Patent No. 6,699,467 to Leone-Bay et al. discloses an intestinal penetration agent of Formula (XXIX):(XXIX).

[0192] United States Patent No. 6,693,208 to Gschneidner et al. discloses intestinal penetration agents of Formulas (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), and (XLI):PATENT PARSON-58748 ; ; ; ; ;;PATENT PARSON-58748 ; ; ; ;PATENT PARSON-58748 (XLI).

[0193] United States Patent No. 6,663,887 to Leone-Bay et al. discloses an intestinal penetration agent of Formula (XLII):(XLII).

[0194] United States Patent No. 6,646,162 to Tang et al. discloses intestinal penetration agents of Formula (XLIII):(XLIII), wherein: (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, C2-C4alkenyl, C2-C4alkynyl, aryl, aryloxy, a heterocyclic ring, a C5-C7carbocyclic ring, halo, hydroxyl, sulfhydryl, CO2R6, NR7R8, or N+R7R8R9Y; (iii) (a) R1is C1-C16 alkylene, C2-C16 alkenylene, C2-C16 alkynylene, C6-C16 arylene, (C1-C16 alkyl)arylene, or aryl(C1-C16 alkylene); R2is -NR3R4, -N+R3R4, or -N+R3R4R5Y; R3and R4are each independently hydrogen, oxygen, hydroxyl, substituted or unsubstituted C1-C16alkyl, substituted or unsubstituted C2-C16alkenyl, substituted or unsubstituted C2-C16 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; R5is hydrogen, substituted orPATENT PARSON-58748 unsubstituted C1-C16 alkyl, substituted or unsubstituted C2-C16 alkenyl, substituted or unsubstituted C2-C16alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; (b) R1, R2, and R5are as above under (a), and R3and R4are combined to form a 5-, 6-, or 7-membered heterocyclic ring or a aryloxycarbonyl; (b) R1, R2, and R5are as above under (a), and R3and R4are combined to form a 5-, 6-, or 7- membered heterocyclic ring or a 5-, 6-, or 7-membered heterocyclic ring substituted with C1-C6alkyl, C1-C6 alkoxy, aryl, aryloxy, oxo, or carbocyclic ring; or (c) R2and R5are as defined above under (a), and R1and R3are combined to form a 5-, 6-, or 7-membered heterocyclic ring or a 5-, 6-, or 7-membered heterocyclic ring substituted with C1-C6alkyl, C1-C6alkoxy, aryl, aryloxy, oxo, or carbocyclic ring; (iv) R4is hydrogen, oxygen, hydroxyl, substituted or unsubstituted C1- C16 alkyl, substituted or unsubstituted C2-C16 alkenyl, substituted or unsubstituted C2-C16 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; (v) R6is hydrogen, C1-C4alkyl, C1-C4alkyl substituted with halogen or with hydroxyl, C2-C4 alkenyl, or C2-C4 alkenyl substituted with halogen or with hydroxyl; (vi) R7, R8, and R9are each independently hydrogen, oxygen, C1-C4 alkyl, C1-C4 alkyl substituted with halogen or with hydroxyl, C2-C4alkenyl, or C2-C4alkenyl substituted with halogen or with hydroxyl; and (vii) Y is halogen, hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, or carboxylate.

[0195] United States Patent No. 6,642,411 to Leone-Bay et al. discloses an intestinal penetration agent of Formula (XLIV): .PATENT PARSON-58748

[0196] United States Patent No. 6,627,228 to Milstein et al. discloses polymeric delivery agents. The polymeric delivery agent comprises a polymer conjugated to modified amino acid or derivative thereof via a linkage group selected from the group consisting of -NHC(O)NH-, -- C(O)NH--, -NHC(O)-, -OOC-, -COO-, --NHC(O)O-, -OC(O)NH-, -CH2NH-, -NHCH2-, - CH2NHC(O)O-, -OC(O)NH2-, CH2NHCOCH2O-, --OCH2C(O)NHCH2-, --NHC(O)CH2O-, -- OCH2C(O)NH-, -NH-, -O-, and a carbon-carbon bond, with the proviso that the polymeric delivery agent is not a polypeptide or polyamino acid, wherein the modified amino acids are acylated or sulfonated amino acids, ketones or aldehydes of acylated or sulfonated amino acids, salts thereof, or polyamino acids or polypeptides of any of the foregoing, and the polymer is selected from the group consisting of polyethylene; polyacrylates; polymethacrylates; poly(oxyethylene); poly(propylene); polypropylene glycol; polyethylene glycol (PEG); PEG- maleic anhydride copolymers; and derivatives and combinations thereof. The polymeric delivery agents act as intestinal penetration agents.

[0197] United States Patent No. 6,623,731 to Leone-Bay et al. discloses intestinal penetration agents, including a penetration agent of Formula (XLV):(XLV).

[0198] United States Patent No. 6,525,020 to Leone-Bay et al. discloses intestinal penetration agents, including a penetration agent of Formula (XLVI):(XLVI).

[0199] United States Patent No. 6,428,780 to Leone-Bay et al. discloses intestinal penetration agents, including a penetration agent of Formula (XLVII):PATENT PARSON-58748(XLVII).

[0200] United States Patent No. 6,358,504 to Leone-Bay et al. discloses a number of intestinal penetration agents, including 6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid, 8-(2-aminobenzoylamino)caprylic acid, 8(2-trifluoromethoxy)benzoylaminocaprylic acid, N-(2- hydroxybenzoyl)isonipecotic acid, 4-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid, 4-(4-(pentafluorobenzoyl)aminophenyl)butyric acid, 4-(4-(3-anisoyl)aminophenyl)butyric acid, 8-(3-anisoyl)aminocaprylic acid, 4-(4-(phenoxyacetyl)aminophenyl)butyric acid, 4-(4-(2- nitrobenzenesulfonyl)aminophenyl)butyric acid, 8-(2-nitrobenzenesulfonyl)aminocaprylic acid, 6-(4-(salicyloyl)aminophenyl)hexanoic acid, 8-(2-methoxybenzoyl)aminocaprylic acid, 2- [4-salicyloylaminophenyl]ethyl methyl sulfone, 1-salicyloyl-2-succinyl-hydrazide, 3-(4-(2,5- dimethoxycinnamoyl)aminophenyl)propionic acid, 4-(4-(2,5- dimethoxycinnamoyl)aminophenyl)butyric acid, 1-salicyloyl-2-glutaryl hydrazide, succinyl- 4-aminosalicylic acid, 8-(phenoxyacetylamino)caprylic acid, 8-(2- pyrazinecarbonyl)aminocaprylic acid, 4-(4-(2 pyrazinecarbonyl)aminophenylbutyric acid, 6-(4- (N-2-nitrobenzoyl)aminophenyl)hexanoic acid, 6-(4-(N-2- aminobenzoyl)aminophenyl)hexanoic acid, 4-(4-(2-(3- carbonyl)pyrazinecarboxyl)aminophenyl)butyric acid, 4(2-nitrobenzoyl)aminophenylsuccinic acid, 8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid, 8-(benzylcarbonylamino)caprylic acid, 8-(phenylcarbonylamino)caprylic acid, 2-[4-(2-methoxybenzoylamino)phenyl]ethyl H2PO4, 1- salicyloyl-2-suberyl hydrazide, 4-(4-benzyloxycarbonylaminophenyl)butyric acid, 4-(4-)2- hydroxynicotinoyl)aminophenyl)butyric acid, 9-salicyloylaminonanoic acid, 4-(4- phenyloxycarbonylaminophenyl)butyric acid, 3-(2-methoxybenzoylamino)-1-propanol, 8-(2- hydroxynicotinoyl)aminocaprylic acid, 6-(2-methoxybenzoyl)amino nicotinic acid, salicyloylglycine, 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid, 8-(chromone-3- carbonyl)aminocaprylic acid, 8-(vinylbenzoyl)aminocaprylic acid, 4-(4-(chromone-3- carbonyl)aminophenyl)butyric acid, 8-cinnamoylaminocaprylic acid, 5-(N- salicyloylamino)valeric acid, N-(4-salicyloylamino)-6-caproic acid, 4′-flavonic acid, 11-PATENT PARSON-58748 cinnamoylaminoundecanoic acid, 4-octanoylamino-3-hydroxybenzoic acid, (3-phenyl-2,3- dihydroxypropanoyl)-8-aminocaprylic acid, 8-[N-(3-coumarincarbonyl)]aminocaprylic acid, 8- [N-(4-chlorobenzyl)]aminocaprylic acid, 8-[N-(3-fluorobenzyl)]aminocaprylic acid, 8-(N-2,5- dihydroxybenzoyl)aminocaprylic acid, 8-(N-3,5-diacetyloxybenzoyl)aminocaprylic acid, 8-(N- 4-hydroxybenzoyl)aminocaprylic acid (dimer), 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid, 1-(1-(N-2-methoxyanilino)sebacic acid, 10-(N-2-methoxyanilino)sebacic acid, 8-(N- benzoyl)aminocaprylic acid, 2-methoxybenzenaminodecanoic acid, 8-(N- benzoyl)aminocaprylic acid, 8-(N-2-hydroxy-4-methoxybenzoyl)aminocaprylic acid, 8-(N-4- fluorobenzoyl)aminocaprylic acid, 8-(N-3-bromobenzoyl)aminocaprylic acid, 8-(4-(1,2- dihydroxyethyl)benzoyl)aminocaprylic acid, 8-(N-4-bromobenzoyl)aminocaprylic acid, 8- (N-4-iodobenzoyl)aminocaprylic acid, 4-{4-[N-(2-iodobenzoyl)aminophenyl]}butyric acid, 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid, 4-(4-(2,4- dimethoxybenzoyl)aminophenyl)butyric acid, 4-(o-anisoyl)aminophenylacetic acid, 3-[4- (2,4-dimethoxybenzoyl)aminophenyl]propionic acid, 4-{4-[N-(4- iodobenzoyl)]aminophenyl}butyric acid, 3-[4-(2,3-dimethoxybenzoyl) aminophenyl] propionic acid, 4{4 [N-2-bromobenzoyl)] aminophenyl} butyric acid, 4{4-[N-3-[bromobenzoyl) aminophenyl]} butyric acid, 8-(N-3,5-dihydroxybenzoyl)aminocaprylic acid, 8-(N-3,5- dimethoxy 4-hydroxybenzoyl)aminocaprylic acid, 8-(N-2,6-dimethoxybenzoyl)aminocaprylic acid, 4-{4[N-(4 bromobenzoyl)aminophenyl]butyric acid, 8-(2-hydroxy-4- chlorobenzoyl)aminocaprylic acid, 8-(N-2,6-dihydroxybenzoyl)aminocaprylic acid, 8-(N-2- hydroxy-6-methoxybenzoyl)aminocaprylic acid, 8-(5-chloro-o-anisoyl)aminocaprylic acid, 4-(4- (2,3-dimethoxybenzoyl)aminophenyl)butyric acid, 4-(4-(5 chloro-o-anisoyl)aminophenyl)butyric acid, 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid, 8-(4-chloro-o-anisoyl)aminocaprylic acid, 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid, 4-{N-[4-(3 iodobenzoyl)aminophenyl]butyric acid, 7-cinnamoylaminoheptanoic acid, 8-N-(3 iodobenzoyl)aminocaprylic acid, 8-N-(4 methoxy-3-nitrobenzoyl)aminocaprylic acid, 8-N-(2 methoxy 4 nitrobenzoyl)aminocaprylic acid, 4-{N-[4-(2-methoxy-4- nitrobenzoyl)aminophenyl]}butyric acid, 4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid, 8-(N-2-hydroxy-5-bromobenzoyl)aminocaprylic acid, 3-indolebutryic acid, 4-(4-(2,6- dimethoxybenzoyl)aminophenylbutyric acid, 4-[4-N-(4 methoxy-3- nitrobenzoyl)aminophenyl]butyric acid, 8-(N-2-hydroxy-5 chlorobenzoyl)aminocaprylic acid, 8-(N-PATENT PARSON-58748 2-hydroxy-5-iodobenzoyl)aminocaprylic acid, 8-(3-hydroxy-2-naphthoyl)aminocaprylic acid, 8-(N-2- hydroxy-2-nitrobenzoyl)aminocaprylic acid, 8-(N-3-methylsalicyloyl)aminocaprylic acid, 8-(N-5- methylsalicyloyl)aminocaprylic acid, 4-[-N-(2 hydroxy-4-bromobenzoyl)aminophenyl]butyric acid, 8-(N-2,3-dihydroxybenzoyl)aminocaprylic acid, 9-(cinnamoylamino)nonanoic acid, 4-(4-(2- chloro-5-nitrobenzoyl)aminophenyl)butyric acid, 4-[N-(2-hydroxy-5- iodobenzoyl)]aminophenylbutyric acid, N-2-nitrophenyl-N′-(8 octanoic acid) urea, 8-[N-(2-acetoxy- 3,5-dibromobenzoyl)aminocaprylic acid, 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid, 8-N-(4- hydroxy-3-nitrobenzoyl)caprylic acid, 4-(4-salicyloylaminophenyl)-4-oxobutyric acid, 12- cinnamoyldodecanoic acid, 4-{4-[N-(3-hydroxy-2-naphthoyl)aminophenyl]}butyric acid, 8-(4- chloro-3-nitrobenzoyl)aminocaprylic acid, 8-(2-chloronicotinoyl)aminocaprylic acid, 8-(2- chloro-5-nitrobenzoyl)aminocaprylic acid, 4-(4-phthalimidophenyl)butyric acid, 4-{4-[N-(3- hydroxy-2-napthoyl)aminophenyl]}propanoic acid, 3-(4-(2,6- dimethoxybenzoyl)aminophenyl)propionic acid, 8-(N-2-hydroxy-3,5- diiodobenzoyl)aminocaprylic acid, 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid, 8 (N 1 hydroxy-2-naphthoyl)aminocaprylic acid, 8-(phthalimido)caprylic acid, 10-(4-chloro-2- hydroxyanilino)sebacic acid monoamide, 6-(anisoyl)aminocaproic acid, 4-(4-(4-chloro-3- nitrobenzoyl)aminophenyl)butyric acid, 11-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid, bis(N-2-carboxylphenyl-N-(N′-8-octanoic acid)ureal)oxalyl diamide, 2-[2-N-(2- chlorobenzoyl)aminoethoxy]ethanol), 2-[2-N-(4 chlorobenzoyl)aminoethoxy]ethanol, 4-(2- methybenzoyl)amino-3-carboxysulfoxide, 4-(2-methoxybenzoyl)amino 3-carboxypropylsulfone, 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid, 2-[2-N-(2 methoxybenzoyl)aminoethoxyl]ethanol, 2-[2-N-(3 chlorobenzoyl)aminoethoxy]ethanol, bis(N-2- carboxyphenyl)-N-(N′-3(4-aminophenyl)propionic acid)ureal)oxalyl diamide, trans-4-(2 aminobenzamidomethyl)cyclohexamecarboxylic acid, 11-N-(3,5-dichloro-2- hydroxybenzoyl)aminoundecanoic acid, 2-[N-(2-bromobenzoyl)aminoethoxy]ethanol, 7-N-(3,5- dichloro-2-hydroxybenzoyl)aminoheptanoic acid, N-[3,5-dichloro-2-hydroxybenzoyl-4(4- aminophenyl)]butyric acid, trans-4-(N salicyloylaminomethyl)cyclohexane carboxylic acid, N- [3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid, 12-N-(3,5-dichloro-2- hydroxybenzoyl)aminodecanoic acid, N-(2-hydroxy-4-carboxy)-6-heptenamide, N-(2- bromobenzoyl)morpholine, 8-N-cyclohexanoylaminocaprylic acid, 2-[N-(2- iodobenzoyl)aminoethoxy]ethanol, 5-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid, 8-(2-PATENT PARSON-58748 hydroxyphenoxy)-aminocaprylic acid, N-salicyloyl-5-(3-aminophenyl-valeric acid, 4-(4-(2- ethoxylbenzoyl)aminophenyl)butyric acid, 9-[2-(3-hydroxy)pyridylaminocarbonyl]nonanic acid, 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid, 2-[N-2-hydroxybenzoylamino)ethoxy]ethanol. 4-[N-(3,5-chloro-2-hydroxybenzoyl)]aminophenylacetic acid 8-(2-hydroxy-5- chloroanilinocarbonyl)octanoic acid, N-salicyloyl-5-(4-aminophenyl)valeric acid, 9-(2-hydroxy-5- methylanilinocarbonyl)nonanoic acid, 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid, 8- (pentafluorobenzoyl)aminocaprylic acid, 3-(3-(salicyloyl)aminophenyl)propionic acid, 8-(2- ethoxybenzoyl)aminocaprylic acid, 4-(4-(2-dimethylamino benzoic)aminophenyl)butyric acid, 8- (3-phenoxylpropionylamino)caprylic acid, 4-(salicyloyl)aminophenylethyltetrazole, 4-(4-(N-(2- fluorocinnamoyl))aminophenyl)butyric acid, 4-(4-(N-8- salicyloyl)aminocaprylic)aminophenyl)butyric acid, 8-(p-anisoyl)aminocaprylic acid, 8-(4- hydroxybenzoyl)aminocaprylic acid, 8-(3-hydroxybenzoyl)aminocaprylic acid, 8-(3,4,5- trimethoxybenzoyl)aminocaprylic acid, 8-(N-4-methylsalicyloyl)aminocaprylic acid, N-10-(2- hydroxy-5-nitroanilino)decanoic acid, and 4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid.

[0201] United States Patent No. 6,344,213 to Leone-Bay et al. discloses intestinal penetration agents, including an intestinal penetration agent of Formula (XLVIII):(XVLIII).

[0202] United States Patent No. 6,313,088 to Leone-Bay et al. discloses 8-[(2-hydroxy- 4-methoxy-benzoyl) amino]-octanoic acid as an intestinal penetration agent.

[0203] United States Patent No. 6,180,140 to Leone-Bay et al. discloses modified amino acids as intestinal penetration agents. The intestinal penetration agent comprises: (i) at least one acylated amino acid; (ii) at least one peptide comprising one acylated amino acid; or (iii) a combination of (i) and (ii), wherein the acylated amino acid is acylated by: (1) a C3-C10cycloalkyl acylating agent, the agent being optionally substituted with C1-C7 alkyl, C2-C7 alkenyl, C1-C7 alkoxy, hydroxyl, phenyl, phenoxy, or –CO2R, wherein R is hydrogen, C1-C4 alkyl, or C2-C4alkenyl; or (2) a C3-C10cycloalkyl substituted C1-C6alkyl acylating agent. Amino acids suitable for use in these penetration agents are typically of formula (XLIX):PATENT PARSON-58748(XLIX), wherein: R1is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; R2is C1-C24 alkyl, C2-C24 alkenyl, C3- C10cycloalkyl, C3-C10cycloalkenyl, phenyl, naphthyl, (C1-C10alkyl) phenyl (C2-C10alkenyl) phenyl, (C1-C10 alkyl) naphthyl (C2-C10 alkenyl) naphthyl, phenyl (C1-C10 alkyl), phenyl (C2-C10 alkenyl), naphthyl (C1-C10 alkyl) naphthyl (C2-C10 alkenyl); R2can be optionally substituted with C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, hydroxyl, sulfhydryl, -CO2R3, C3-C10cycloalkyl, C3- C10cycloalkenyl, heterocycle having 3-10 ring atoms wherein the heteroatom is one or more of N, O. or S, or any combination thereof, aryl, C1-C10 alkaryl, aryl(C1-C10 alkyl), or any combination thereof; R2can be optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R3is hydrogen, C1-C4alkyl, or C2-C4alkenyl. The amino acid can be one of the following naturally-occurring amino acids: alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxyproline, γ-carboxyglutamate, phenylglycine, or O-phosphoserine. Alternatively, the amino acid can be one of the following non-naturally-occurring amino acids: β-alanine, α-aminobutyric acid, γ- aminobutyric acid, γ-(aminophenyl)butyric acid, α-aminoisobutyric acid, ε-aminocaproic acid, 7- aminoheptanoic acid, β-aspartic acid, aminobenzoic acid, aminophenyl acetic acid, aminophenyl butyric acid, γ-glutamic acid, S-acetamidomethyl-L-cysteine, ε-lysine, ε-lysine (A-Fmoc), methionine sulfone, norleucine, norvaline, ornithine, D-ornithine, p-nitro-phenylalanine, 1,2,3,4,- tetrahydroisoquinoline-3-carboxylic acid and thioproline.

[0204] United States Patent No. 6,071,510 to Leone-Bay et al. discloses modified amino acids as intestinal penetration agents. The modified amino acids can be prepared by acylation or sulfonation of amino acids such as aminobutyric acid, aminocaproic acid, or aminocaprylic acid.

[0205] United States Patent No. 6,001,347 to Leone-Bay et al. discloses intestinal penetration agents, including the compound of Formula (L):PATENT PARSON-58748 .

[0206] Unitedpenetration agents, :(LI).

[0207] United States Patent No. 5,965,121 to Leone-Bay et al. discloses intestinal penetration agents, including the compound of Formula (LII):(LII).

[0208] United States Patent No. 5,955,103 to Leone-Bay et al. discloses intestinal penetration agents that are modified amino acids and are of either Formula (LIII) or Formula (LIV): orPATENT PARSON-58748 (LIV), wherein: (i) Ar is an unsubstituted or substituted phenyl or naphthyl; (ii) Y is –C(O)- or -S(O2)-; (iii) R1has the formula –N(R3)-R2-C(O)-; (iv) R2is C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl(C1-C10alkyl), phenyl(C1-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C1-C10 alkenyl); (v) R2is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, CO2R4, or any combination thereof; (vi) R4is hydrogen, C1-C4 alkyl, or C1-C4alkenyl; (vii) R2is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (viii) R3is hydrogen, C1-C4alkyl, or C1-C4alkenyl; (ix) R5is either: (A) C3-C10 cycloalkyl, optionally substituted with C1-C7 alkyl, C2-C7 alkenyl, C1-C7 alkoxy, hydroxyl, phenyl, phenoxy, or –CO2R8, wherein R8is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; or (B) C1-C6alkyl substituted with C3-C10cycloalkyl; (x) R6is C3-C10cycloalkyl; R7is C1-C24alkyl, C2-C24 alkenyl, C3-C10 cycloalkyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C2-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C2-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C2-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C2-C10alkenyl); (xi) R7is optionally substituted with C1-C4 alkyl, C2-C4 alkyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, -CO2R9, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, a heterocycle having 3-10 ring atoms wherein the heteroatom is one or more of N, O, or S or any combination thereof, aryl, (C1-C10)alkaryl, aryl(C1-C10alkyl), or any combination thereof; (xii) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and (xiii) R9is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.

[0209] United States Patent No. 5,939,381 to Leone-Bay et al. discloses intestinal penetration agents, including the penetration agent of Formula (LV):(LV).

[0210] United States Patent No. 5,879,681 to Leone-Bay et al. discloses intestinal penetration agents, including a penetration agent of Formula (LVI):PATENT PARSON-58748(LVI).

[0211] United States Patent No. 5,876,710 to Leone-Bay et al. discloses intestinal penetration agents, including the intestinal penetration agent of Formula (LVII):(LVII).

[0212] United States Patent No. 5,866,536 to Leone-Bay et al. discloses intestinal penetration agents, including the intestinal penetration agent of Formula (LVIII):(LVIII).

[0213] United States Patent No. 5,863,944 to Leone-Bay et al. discloses intestinal penetration agents, including intestinal penetration agents of Formulas (LVIX), (LX), and (LXI): ;PATENT PARSON-58748 .

[0214] United States Patent No. 5,804,688 to Leone-Bay et al. discloses intestinal penetration agents, including the penetration agent of Formula (LXII):(LXII).

[0215] United States Patent No. 5,792,451 to Sarubbi et al. discloses intestinal penetration agents suitable for oral administration, including: (1) (a) at least one acylated aldehyde of an amino acid, (b) at least one acylated ketone of an amino acid, (c) at least one acylated aldehyde of a peptide, (d) at least one acylated ketone of a peptide, (e) any combination of (1)(a), (1)(b), (1)(c), and (1)(d); (2) (a) carboxymethyl-phenylalanylleucine; (b) 2-carboxy-3- phenylpropionylleucine; (c) 2-benzylsuccinic acid; (d) (phenylsulfonamide)phenylbutyric acid; and (e) any combination of (2)(a), (2)(b), (2)(c) and (2)(d); or (3) a combination of (1) and (2).

[0216] United States Patent No. 5,776,888 to Leone-Bay et al. discloses intestinal penetration agents, including the penetration agent of Formula (LXIII):PATENT PARSON-58748 (LXIII).

[0217] United States Patent No. 5,773,647 to Leone-Bay et al. discloses penetration agents, including the penetration agent of Formula (LXIV):(LXIV).

[0218] United States Patent No. 5,766,633 to Milstein et al. discloses intestinal penetration agents suitable for oral administration, including: (1) (a) at least one acetylated aldehyde of an amino acid; (b) at least one acetylated ketone of an amino acid; (c) at least one acetylated aldehyde of a peptide; (d) at least one acetylated ketone of a peptide; or (e) any combination of (1)(a), (1)(b), (1)(c), and (1)(d); (2) (a) carboxymethyl-phenylalanylleucine; (b) 2-carboxy-3-phenylpropionylleucine; (c) 2-benzylsuccinic acid; (d) an actinonin; (e) a compound having the formula Ar-Y-(R1)n-OH, wherein: (i) Ar is a substituted or unsubstituted phenyl or naphthyl; (ii) Y is –C(O)- or –SO2-; (iii) R1is –N(R4)-R3-C(O)-, wherein: (A) R3is C1-C24 alkyl, C1-C24alkenyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, (C1-C10alkyl)naphthyl, (C1-C10alkenyl)phenyl, C1-C10 alkenyl(naphthyl), phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), or phenyl(C1-C10 alkenyl); (B) R3is optionally substituted with C1-C4 alkyl, C1-C4alkenyl, C1-C4alkoxy, hydroxyl, sulfhydryl, -CO2R5, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, alkaryl, heteroaryl, or heteroalkaryl or any combination thereof; (C) R5is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl; (D) R3is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (E) R4is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl; and (F) n is an integer from 1 to 5; or (f) any combination of (2)(a), (2)(b), (2)(c), (2)(d), and (2)(e); or (3) a combination of (1) and (2).

[0219] United States Patent No. 5,541,155 to Leone-Bay et al. discloses intestinal penetration agents that are acids or acid salts having the general formula RCO2H, wherein R is C1-C24 alkyl, C2-C24 alkenyl, C3-C10 cycloalkyl, C3-C4 cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C2-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C2-C10 alkenyl)naphthyl, phenyl(C1-C10alkyl), phenyl(C2-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C2-C10alkenyl), with R being optionally substituted with C1-C10alkyl, C2-C10alkenyl, C1-C4alkoxy,PATENT PARSON-58748 hydroxyl, sulfhydryl, CO2R1, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl having 3-10 ring atoms wherein the heteroatom is one or more atoms of N, O, S or any combination thereof, aryl, (C1-C10 alk)aryl, aryl(C1-C10 alkyl), or any combination thereof, R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R1is hydrogen, C1-C4 alkyl, or C2-C4alkenyl. The penetration agent can comprise: (i) an acid as described above; (ii) a salt of the acid; or (iii) a combination of (i) and (ii). The preferred carboxylic acids are cyclohexanecarboxylic acid, cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, hexanoic acid, 3-cyclohexanepropanoic acid, methylcyclohexanecarboxylic acid, 1,2- cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1-adamantanecarboxylic acid, phenylpropanoic acid, adipic acid, cyclohexanepentanoic acid, cyclohexanebutanoic acid, pentylcyclohexanoic acid, 2-cyclopentanehexanoic acid, cyclohexanebutanoic acid, and (4-methylphenyl) cyclohexane acetic acid.

[0220] United States Patent No. 7,429,564 to Arbit et al. discloses the use of 4-[(4- chloro-2-hydroxybenzoyl)amino]butanoic acid and its sodium salt, monosodium 4-[(4-chloro-2- hydroxybenzoyl)amino]butanoate (“4-CNAB”) as intestinal penetration agents. Additional intestinal penetration agents are disclosed, namely penetration agents of Formulas (LXV) and (LXVI):; wherein, in Formula (LXV), X is one or more of hydrogen, halo, hydroxyl, or C1-C3 alkoxy. In Formula (LXVI), X is halo and R is substituted or unsubstituted C1-C3alkylene or substituted or unsubstituted C1-C3 alkenylene.PATENT PARSON-58748

[0221] United States Patent Application Publication No. 2012 / 0258911, by Gschneidner et al. discloses phenylalkylcarboxylic acids as intestinal penetration agents, including, but not limited to, 4-(4-methoxyphenyl)butanoic acid, 5-(2-methoxyphenyl)pentanoic acid, 5-(3- fluorophenyl)pentanoic acid, 5-(3-methoxyphenyl)pentanoic acid, 6-(3-fluorophenyl)hexanoic acid, 3-(4-t-butylphenyl)propanoic acid, 3-(4-n-butylphenyl)propanoic acid, 3-(4-n- propylphenyl)propanoic acid, 3-(4-n-propoxyphenyl)propanoic acid, 3-(4- isopropoxyphenyl)propanoic acid, 3-(4-n-butoxyphenyl)propanoic acid, 3-(3- phenoxyphenyl)propanoic acid, 3-(3-ethoxyphenyl)propanoic acid, 3-(3- isopropoxyphenyl)propanoic acid, 3-(3-n-butoxyphenyl)propanoic acid, 3-(3-n- propoxyphenyl)propanoic acid, 3-(3-isobutoxyphenyl)propanoic acid, 3-(4- isobutoxyphenyl)propanoic acid, 4-(4-ethylphenyl)butanoic acid, 4-(4-isopropylphenyl)butanoic acid, and 5-(4-ethylphenyl)pentanoic acid.

[0222] United States Patent Application Publication No. 2011 / 0183898 by Dinh discloses intestinal penetration agents including intestinal penetration agents of Formulas (LXVII), (LXVIII), and (LXIX):(LXVII); (LXVIII); and (LXIX),PATENT PARSON-58748 wherein: in Formula (LXVII): (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with one or more of hydroxyl, halo, C1-C4alkyl, C1-C4alkenyl, C1-C4alkoxy, or C1-C4haloalkoxy; (iii) R7is selected from C4-C20 alkyl, C4-C20 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C1-C10alkenyl); (iv) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (v) R7optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl, sulfhydryl, -CO2R9, and combinations thereof; (vi) R8is selected from hydrogen, C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, and C1-C4haloalkoxy; and (vii) R9is hydrogen, C1-C4alkyl, or C2-C4alkenyl; in Formula (LXVIII): (i) R1, R2, R3, and R4are each independently hydrogen, hydroxy, halo, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, -C(O)R8, -NO2, -NR9R10, and -N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, nitro, halo, trifluoromethyl, -NR14R15, -N+R14R15R16(R13)-, amide, C1-C12alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or –C(O)R18; (iii) R5is optionally substituted with halo, hydroxyl, sulfhydryl, or –COOH; (iv) R5is optionally interrupted by oxygen, nitrogen, sulfur, or –C(O)-; (v) R6is a C1-C12alkylene, C1-C12alkenylene, or arylene; (vi) R6is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, halo, amino, or – CO2R8; (vii) R6is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, amino, or –CO2R8; (viii) R6is optionally interrupted by oxygen or nitrogen; (ix) R7is a bond or arylene; (x) R7is optionally substituted with hydroxyl, halogen, -C(O)CH3, -NR10R11, -N+R10R11R12(R13)-; (xi) R8is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or amino; (xii) R9, R10, R11, and R12are each independently hydrogen or C1-C10 alkyl; (xiii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiv) R14, R15, and R16are each independently hydrogen, C1-C10 alkyl, C1-C10 alkyl substituted with –COOH, C2-C12 alkenyl, C2-C12 alkenyl substituted with –COOH, or –C(O)R17; (xv) R17is hydroxyl, C1-C10 alkyl, or C2-C12alkenyl; and (xvi) R18is hydrogen, C1-C6alkyl, hydroxyl, -NR14R15, or N+R14R15R16(R13); and in Formula (LXIX): (i) R1, R2, R3, R4, and R5are independently hydrogen, cyano, hydroxyl, -OCH3, or halo, provided that at least one of R1, R2, R3, R4, and R5is cyano; and (ii) R6is C1-C12linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene).PATENT PARSON-58748

[0223] United States Patent Application Publication No. 2010 / 0105604 by Song discloses allyloxybenzoic acid and alkoxybenzoic acid intestinal penetration agents, including intestinal penetration agents of Formulas (LXX), (LXXI), and (LXXII):(LXX);(LXXI); and(LXXII), wherein: in Formula (LXX): (i) R1, R2, and R3 are independently hydrogen, methyl, or halo; (ii) R4 is hydrogen, methyl, methoxy, hydroxyl, halo, acetyl, or 2-hydroxy-ethoxy; and (iii) n is 1, 2, 3, or 4; in Formula (LXXI): R is C1-C6straight-chain or branched alkyl; and in Formula (LXXII): R is methyl, ethyl, isopropyl, propyl, butyl, allyl, 1-methylallyl, 2-methylallyl, or butenyl.

[0224] United States Patent Application Publication No. 2010 / 0074861 by Tang et al. discloses intestinal penetration agents with a cyclic moiety of Formula (LXXIII):PATENT PARSON-58748 (LXXIII), wherein: (i) m is 1, 2, 3, 4, 5, or 6; (ii) n is 0, 1, 2, 3, or 4; (iii) q and x are each independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; (iv) R in [R]n (where n may be 0, 1, 2, 3, or 4 as set forth above) may be the same or different (if n is 2, 3, or 4) and is hydrogen, halo, a substituted or non-substituted alkyl, a substituted or non-substituted alkoxy, a substituted or non-substituted alkenyloxy, or a substituted or non-substituted aryloxy; and (v) R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogen, substituted or non-substituted alkyl, substituted or non-substituted alkenyl, substituted or non-substituted alkynyl, substituted or non-substituted alkoxy, substituted or non-substituted aryloxy, substituted or non-substituted aryl, substituted or non-substituted heteroaryl, substituted or non-substituted cycloalkyl, and substituted or non- substituted heterocycloaryl.

[0225] United States Patent Application Publication No. 20100062970 by Song discloses propylphenoxy ethers as intestinal penetration agents, including compounds of Formula (LXXIV):(LXXIV), wherein: (i) R1, R2, R3. R4, and R5are independently selected from hydrogen, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, -C(O)R8, nitro, -NR9R10, -N+R9R10R11(R12), carbonate, ureido, CX3, and cyano; (ii) R8is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or amino; (iii) R9, R10, R11, and R12are each independently hydrogen or C1-C10alkyl; and (iv) X is halo.

[0226] United States Patent Application Publication No. 2009 / 0092580 by Song discloses dialkyl ether intestinal penetration agents, including dialkyl ether intestinal penetration agents of Formula (LXXV):PATENT PARSON-58748 (LXXV), wherein: (i) A is a C1-C6alkylene group that is straight-chain or branched-chain or substituted or unsubstituted; (ii) B is a C1-C2 alkylene group that is straight-chain or branched-chain or substituted or unsubstituted; (iii) R1, R2, R3, R4, and R5 are each independently hydrogen, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, -C(O)R8, nitro, -NR9R10, -N+R9R10R11(R12), carbonate, ureido, -CX3, or cyano, optionally interrupted by an O, N, S, or –C(O)- group, wherein A and R1may together form a cycloalkyl group; (iii) R8is hydrogen, C1-C4alkyl, C2-C4alkenyl, or amino; (iv) R9, R10, R11, and R12are each independently hydrogen or C1-C10 alkyl; and X is halo.

[0227] United States Patent Application Publication No. 2008 / 0167217 by Rath et al. discloses aryl ketone intestinal penetration agents, including aryl ketone intestinal penetration agents of Formula (LXXVI):(LXXVI), wherein: (i) n is 1, 2, 3, 4, 5, 6, 7, 8, or 9; and (ii) R1, R2, R3, R4, and R5 are each independently hydrogen, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, halo, hydroxyl, -NH-C(O)–CH3, or -O-C6H5. Preferred compounds include 4-oxo-4-phenyl-butyric acid; 10-(4-hydroxy-phenyl)- 10-oxodecanoic acid; 10-(2-hydroxy-phenyl)-10-oxo-decanoic acid; 4-(4-methoxy-phenyl)-4- oxo-butyric acid; 5-(4-methoxy-phenyl)-5-oxo-pentanoic acid; 4-(3,5-difluoro-phenyl)-4-oxo- butyric acid; 5-oxo-5-phenyl-pentanoic acid; 4-(2,4-dimethyl-phenyl)-4-oxo-butyric acid; 6-(4- methoxy-3,5-dimethyl-phenyl)-6-oxo-hexanoic acid; 5-(4-isopropyl-phenyl)-5-oxo-pentanoic acid; 4-(2-methoxy-phenyl)-4-oxo-butyric acid; 4-(4-fluoro-phenyl)-4-oxo-butyric acid; 6-(4- methoxy-phenyl)-6-oxo-hexanoic acid; 4-(3,5-dimethyl-phenyl)-4-oxo-butyric acid; 6-(3,4- dimethyl-phenyl)-6-oxo-hexanoic acid; 4-(3,4-dimethyl-phenyl)-4-oxo-butyric acid; 4-oxo-4-(4- phenoxy-phenyl)-butyric acid; 4-(2,5-dimethyl-phenyl)-4-oxo-butyric acid; 8-(3,5-dimethyl- phenyl)-8-oxo-octanoic acid; 6-(2,5-dichloro-phenyl)-6-oxo-hexanoic acid; 4-(2,5-dichloro- phenyl)-4-oxo-butyric acid; 6-(3,5-dimethyl-phenyl)-6-oxo-hexanoic acid; 10-(2,5-dihydroxy-PATENT PARSON-58748 phenyl)-10-oxo-decanoic acid; 8-oxo-8-phenyl-octanoic acid; 6-(2,5-difluoro-phenyl)-6-oxo- hexanoic acid; 7-oxo-7-phenyl-heptanoic acid; 4-(4-ethyl-phenyl)-4-oxo-butyric acid; 4-(2,4- difluoro-phenyl)-4-oxo-butyric acid; 4-(4-butoxy-phenyl)-4-oxo-butyric acid; 4-oxo-4-(4-propyl- phenyl)-butyric acid; 4-oxo-4-(4-pentyl-phenyl)-butyric acid; 4-(4-hexyloxy-phenyl)-4-oxo- butyric acid; 4-(2,5-difluoro-phenyl)-4-oxo-butyric acid; 5-(4-chloro-phenyl)-5-oxo-pentanoic acid; 6-(3,5-difluoro-phenyl)-6-oxo-hexanoic acid; 4-oxo-4-p-tolyl-butyric acid; 6-oxo-6-phenyl- hexanoic acid; 5-oxo-5-(4-phenoxy-phenyl)-pentanoic acid; 5-oxo-5-(3-phenoxy-phenyl)- pentanoic acid; and 7-oxo-7-(3-phenoxy-phenyl)-heptanoic acid.

[0228] United States Patent No. 8,575,123 to Manoharan et al. describes a range of intestinal penetration agents such as: (i) arachidonic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a C1-10 alkyl ester, monoglyceride, diglyceride, or a pharmaceutically acceptable salt thereof; (ii) bile salts such as cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate, or sodium glycodihydrofusidate; (iii) polyoxyethylene-9-lauryl ether; (iv) chelating agents such as EDTA or citric acid; (v) a salicylate; (vi) an N-acyl derivative of collagen; (vii) an N-amino acyl derivative of a beta-diketone; (viii) a surfactant, including an ionic or nonionic surfactant, such as sodium lauryl sulfate, polyoxyethylene-20-cetyl ether, a perfluorochemical emulsion; or (ix) other compounds that can act as intestinal penetration agents, such as unsaturated cyclic ureas, 1-alkyl- alkanones, 1-alkenylazacyclo-alkanones, glycols, pyrroles, azones, and terpenes.

[0229] United States Patent No. 8,569,320 to Melzer et al. discloses a range of intestinal penetration agents, including polyvalent aliphatic C2-C10 alcohols, polyalkylene glycols having C2-C4alkylene groups, nonalkoxylated ethers of polyvalent aliphatic C2-C10alcohols and polyalkylene glycols having C2-C4 alkylene groups, azones, terpenes, terpenoids, pyrrolidones, and sulfoxides.

[0230] United States Patent Application Publication No. 2012 / 0231069 by Nowotnik et al. discloses nanoparticles and micelles as intestinal penetration agents. The nanoparticles and micelles can be constructed from a polymer, such as, but not necessarily limited to, dextran, carboxymethyl dextran, chitosan, trimethylchitosan, poly(lactic-co-glycolic acid) (PLGA),PATENT PARSON-58748 polylactic acid (PLA), polyglycolic acid (PGA), polyvinylalcohol (PVA), polyanhydrides, polyacrylates, polymethacrylates, polyacylamides, dextran, chitosan, cellulose, hypromellose, starch, dendrimers, peptides, proteins, polyethyleneglycols and poly(ethyleneglycol-co- propyleneglycol), and synthetic derivatives of the aforementioned polymers. In some alternatives, the pentosan polyacrylate salt can be covalently attached to the polymer, possibly through a linker. The linker can be, for example, a short peptide chain (H-[NHCHR--CO]n--OH) where n is 1-20 and R is the same or different for each of the n amino acids, and is one of the 22 side groups known to be present in natural amino acids; a short alkyl chain (CH2)nwhere n = 2 to 10, terminated by two amino groups or two carboxyl groups or one amino group and one carboxyl group; an oligoethyleneoxy chain (CH2CH2O)n where n = 2 to 100, terminated by two amino groups or two carboxyl groups or one amino group and one carboxyl group; a poly(lactic- co-glycolic acid) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA) chain of average molecular weight of 2 kDa to 70 kDa terminated by two amino groups or two carboxyl groups or one amino group and one carboxyl group; and any combination of two or more of any of the aforementioned linkers. Micelles and liposomes are also described. The polymer can be a linear, branched, or cross-linked polysaccharide. When the carrier is a micelle or a liposome, the lipid can include, but is not limited to, straight or branched alkanes or alkene functionalized at one end by hydrophilic groups that may be charged or neutral. Other components such as cholesterol, fatty acids and other lipid soluble molecules which are known in the art to modify the properties of liposomes and micelles can also be used in the formation of nanocapsules. The nanocarriers can be modified, such as by the introduction of charged or ionizable groups, covalent attachment of the therapeutically active agent, and the introduction of functional groups (for example, hydrophobic or hydrophilic) which either enhance the nanocarrier formation and / or the pharmaceutical qualities of the resultant nanocarriers. Similarly, the lipids can be modified by various moieties, including, but not limited to, the introduction of charged or ionizable groups, attachment of the therapeutically active agent, and the introduction of functional groups (for example, hydrophobic or hydrophilic) which either enhance the nanocarrier formation and / or the pharmaceutical qualities of the resultant nanocarriers. The carriers can include additional components before, during or after nanocarrier formation in order to control the size of nanoparticles, control stability and / or the drug release profile. Possible additional components include, but are not limited to, polyethylene glycol (PEG) and PEG block copolymers,PATENT PARSON-58748 polyacrylic, polymethacrylic, and other synthetic polymers, starch, cellulose, and other polysaccharides, fatty acids and other surfactants, and metal ions, especially di- and trivalent ions such as zinc, magnesium, and calcium. Additional components can also include a crosslinking agent, for example epoxy compounds, dialdehyde starch, glutaraldehyde, formaldehyde, dimethyl suberimidate, carbodiimides, succinimidyls, diisocyanates, acyl azide, reuterin, and crosslinking effected by ultraviolet irradiation.

[0231] United States Patent No. 6,916,789 to O’Mahoney et al. discloses synthetic peptide ligands as intestinal penetration agents.

[0232] United States Patent No. 7,087,236 to Brayden discloses biodegradable polymers that are copolymers of lactic acid and glycolic acid or enantiomers thereof as intestinal penetration agents.

[0233] United States Patent No. 7,268,214 to O’Mahoney et al. discloses membrane translocating full-length peptide sequences, as well as fragments thereof, motifs derived therefrom, derivatives thereof, analogs thereof, and peptidomimetics based on the peptide sequences, as intestinal penetration agents.

[0234] United States Patent No. 7,491,796 to O’Mahoney et al. discloses D-form retro- inverted peptides as intestinal penetration agents; these peptides have the reverse sequence so that the original amino-terminus of the peptide comprising L-amino acids becomes the carboxyl- terminus of the peptide comprising D-amino acids; amino acid substitutions can be made and the peptides can be modified, such as by glycosylation, acetylation, phosphorylation, amidation, derivation by known protecting / blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, or other methods, as penetration agents.

[0235] United States Patent No. 7,658,938 to Cumming et al., discloses intestinal penetration agents each of which: (i) is a solid at room temperature; and (ii) is a salt of a medium-chain fatty acid having a carbon length of from 8 to 14 carbon atoms in particulate form, such as sodium caprylate, sodium caprate and sodium laurate. Compositions including the penetration agent can further comprise rate-controlling polymers or other rate-controlling agents such as cellulose such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose; poly(ethylene) oxide; alkyl cellulose such as ethyl cellulose and methyl cellulose; carboxymethyl cellulose, hydrophilic cellulose derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate;PATENT PARSON-58748 polyvinyl acetate phthalate; hydroxypropylmethyl cellulose phthalate; hydroxypropylmethyl cellulose acetate succinate; polyvinyl acetaldiethylamino acetate; poly(alkylmethacrylate) and poly (vinyl acetate), or other suitable hydrophobic polymers including polymers and / or copolymers derived from acrylic or methacrylic acid and their respective esters, zein, waxes, shellac and hydrogenated vegetable oils can be used.

[0236] United States Patent No. 7,670,626 to Clancy et al. discloses intestinal penetration agents such as mono-, di-, and triglyceride esters of medium-chain (more than about 6 carbon atoms in length) and long-chain (more than about 12 carbon atoms in length) fatty acids, esters of fatty acids and glycols and esters of mixed fatty acids and glycols and mixtures thereof; diesters of propylene glycol having from about 7 to about 55 carbon atoms, propylene glycol esters of capric and caprylic acids, and mixtures thereof, having from 19 to 23 carbon atoms.

[0237] United States Patent No. 7,704,977 to Leonard discloses intestinal penetration agents that are medium-chain fatty acids or medium-chain fatty acid derivatives having a carbon chain length of from 6 to 20 carbon atoms, with the provisos that (i) where the intestinal penetration agent is an ester of a medium-chain fatty acid, the chain length of from 6 to 20 carbon atoms relates to the chain length of the carboxylate moiety, and (ii) where the intestinal penetration agent is an ether of a medium-chain fatty acid, at least one alkoxy group has a carbon chain length of from 6 to 20 carbon atoms, and wherein the enhancer and the composition are solids at room temperature.

[0238] United States Patent No. 7,820,722 to Raoof et al. discloses intestinal penetration agents that are compounds of Formula (LXXVII): (LXXVII), wherein Q is: (1) a partially or completely neutralized --COOH, or (2) a partially or completely neutralized --SO3H, or (3) a mono- or di-substituted alkyl or alkenyl group having one to about twelve carbon atoms, the substituent(s) thereof being a partially or completely neutralized -- COOH or partially or completely neutralized --SO3H; and R1 and R2 are independently: (1) anPATENT PARSON-58748 unsubstituted alkyl or alkenyl group having one to about twelve carbon atoms, or (2) a substituted alkyl or alkenyl group having one to about twelve carbon atoms, the substituent thereof being selected from the group consisting of (i) partially or completely neutralized -- COOH, (ii) partially or completely neutralized --SO3H, (iii) --NH2, (iv) --CONH2; and (v) --OH.

[0239] United States Patent Application Publication No. 2010 / 0016549 by O’Mahoney et al. discloses intestinal penetration agents that are purified synthetic polypeptide ligands comprising aL-peptide or homologue thereof.

[0240] United States Patent No. 7,115,707 to Ben-Sasson et al. discloses intestinal penetration agents that include peptide sequences possessing both hydrophobic amino acids and charged amino acids; optionally, the peptide sequences can be modified by hydrophobic moieties.

[0241] United States Patent No. 8,535,695 to Salama et al. discloses an intestinal penetration agent that is a medium-chain fatty acid salt associated with a substantially hydrophobic medium, preferably castor oil.

[0242] United States Patent No. 8,241,670 to Ben-Sasson discloses intestinal penetration agents comprising octanoate, sodium decanoate, sodium dodecanoate, and combinations thereof. The composition further includes a hydrophobic medium to produce a suspension, wherein the hydrophobic medium is selected from the group consisting of aliphatic molecules, cyclic molecules, aromatic molecules, lecithin, a bile salt, a non-ionic detergent, and combinations thereof.

[0243] United States Patent Application Publication No. 2007 / 0275055 by Ben-Sasson et al. discloses intestinal penetration agents including counterions; the counter-ion is a liquid- forming counterion, such as cationic amphipathic molecules, i.e., imidazolium derivatives, pyridinium derivatives, phosphonium compounds or tetraalkylammonium compounds; the action of the cation can be modified by addition of hydrophobic moieties; a hydrophobic agent can be a single molecule or a combination of hydrophobic molecules, like aliphatic or aromatic molecules; examples of aliphatic hydrophobic agents include fatty acids, mono-, di-, or tri- glycerides, ethers, or cholesterol esters of fatty acids.

[0244] United States Patent Application Publication No. 2006 / 0251713 by Ben-Sasson et al. discloses peptides derived from Escherichia coli as intestinal penetration agents; the peptides can be modified to make them more hydrophobic.PATENT PARSON-58748

[0245] United States Patent No. 7,651,694 to Lee discloses calcium phosphate nanoparticles as intestinal penetration agents.

[0246] United States Patent Application Publication No. 2011 / 0142889 by Lee et al. discloses intestinal penetration agents that include fatty acid, a medium-chain glyceride, a surfactant, a steroidal detergent, an acyl carnitine, an alkanoyl choline, an N-acetylated amino acid, esters, salts and derivatives thereof, or any combination thereof.

[0247] United States Patent Application Publication No. 2012 / 0301401 by Botti et al. discloses intestinal penetration agents that are orthoester derivatives of crown ethers. Typically, these intestinal penetration agents are compounds of Formula (LXXVIII):(LXXVIII), wherein: (i) m is 4, 5, 6, 7, or 8; (ii) i is independently for each occurrence, 1 or 2; (iii) each occurrence of R1and R2is independently selected from hydrogen; linear or branched and substituted or unsubstituted C1-C10alkyl, alkenyl, or alkynyl; and substituted or unsubstituted aryl with up to 10 ring atoms, or R1and R2form an oxo group; (iv) there is at least one occurrence in the crown ether of R1, R2, and the carbon to which R1and R2are bound, the carbon being bound directly to an ether oxygen of Formula (LXXVIII), form together a group of Subformula (LXXVIII(a)):(LXXVIII(a)), wherein L is a linker that is absent or is selected from a covalent bond and (CR5R6)n, each occurrence of R5and R6being independently selected from: hydrogen; linear or branched and substituted or unsubstituted C1-C10alkyl, alkenyl, or alkynyl; and substituted or unsubstitutedPATENT PARSON-58748 aryl with up to 10 ring atoms; n is 1, 2, or 3; X and Y, independently from each other, are selected from O and S; Z, independently for each occurrence, is absent or an electron- withdrawing group; R3and R4, independently for each occurrence, are selected from: hydrogen; linear or branched and substituted or unsubstituted C1-C10 alkyl, alkenyl, or alkynyl; and substituted or unsubstituted aryl with up to 10 ring atoms; H(OCH2CH2)k— H(OCH2CH2)kO—, wherein k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and wherein substituents, if present, are selected from hydroxyl, halogens, and O-CH3.

[0248] United States Patent Application Publication No. 2012 / 0302502 by Botti et al. discloses intestinal penetration agents that are crown compounds employed in a nonaqueous hydrophobic vehicle; the crown compound can be associated with a counterion. The crown compounds include, for example, cyclic polyethers (crown ethers, such as 18-crown-6) and cyclic polyesters (crown esters, e.g., polylactones such as nonactine and tetranactine, polyglycolic or lactic esters), and analogues / derivatives thereof. Of particular interest are crown compounds selected from (i) cyclic polyester; (ii) cyclic polyamide; (iii) cyclic polyether; (iv) cyclic polyoxime; (v) polythioester; (vi) polymer of aminoxy acids; (vii) polydisulfide; (viii) cyclic polydioxanones, and (ix) a cyclic compound belonging to more than one of (i) to (ix), where the crown compound is a cation-binding crown compound capable of forming a charge masking complex with a cation, such as protonated primary amino groups and / or protonated secondary amino groups, and / or protonated guanidinium groups. In some alternatives, the crown compounds are cyclic polyethers, cyclic polyesters, or cyclic depsipeptides. The crown compounds can include a biodegradable linkage. The crown ethers can be oxo-crown ethers comprising 4 to 8 coordinating oxygen ring atoms, 8 to 16 ring carbon atoms, and at least one oxo-substituted side chain, such as oxo-(18-crown-6) compounds and analogs or derivatives thereof, such as those comprising a structure selected from oxo-(18-crown-6), oxo-(18-crown-6) diethyl tartrate, and oxo-(18-crown-6) diglycerol tartrate.

[0249] United States Patents No. 5,912,014 and 6,086,918 to Stern et al. disclose intestinal penetration agents comprising acylcarnitines, phospholipids, and bile acids.

[0250] United States Patent No. 6,673,574 to Stern et al. discloses intestinal penetration agents that have a covalent linkage to a membrane translocator that is a peptide, fatty acid, or bile acid.PATENT PARSON-58748

[0251] United States Patent No. 7,316,819 to Crotts et al. discloses lauroyl-L-carnitine as an intestinal penetration agent. Other acyl-L-carnitines are disclosed in United States Patent Application Publication No. 2004 / 0197323 by Mehta.

[0252] United States Patent No. 8,088,734 to Mehta et al. discloses intestinal penetration agents comprising: (i) an anionic agent that is a cholesterol derivative, (ii) a mixture of a negative charge neutralizer and an anionic surface active agent, (iii) non-ionic surface active agents, and (iv) cationic surface active agents. The cationic surfactant and an anionic surfactant can be cholesterol derivatives. The anionic surface active agent can be a bile acid.

[0253] United States Patent No. 8,324,156 to Arbit et al. discloses 4-[(4-chloro, 2- hydroxybenzoyl)amino] butanoic acid as an intestinal penetration agent.

[0254] United States Patent No. 8,383,852 to Tang et al. discloses intestinal penetration agents that are compounds with a cyclic moiety, including: 3-[4- (cyclopropylmethoxy)phenyl]propanoic acid; 4-(cyclobutylmethoxy)benzoic acid; [4- (cyclobutylmethoxy)-3-methoxyphenyl]acetic acid; 4-(cyclopropylmethoxy)benzoic acid; [4- (cyclopropylmethoxy)phenyl]acetic acid; 2-(cyclobutylmethoxy)benzoic acid; [4- (cyclopentyloxy)-3-methoxyphenyl]acetic acid; [4-(cyclopropylmethoxy)-3- methoxyphenyl]acetic acid; 2-(cyclopropylmethoxy)benzoic acid; 2-(cyclopentyloxy)benzoic acid; 2-(cyclohexylmethoxy)benzoic acid; 3-(cyclopropylmethoxy)benzoic acid; 3- (cyclobutylmethoxy)benzoic acid; 3-(cyclopentyloxy)benzoic acid; 3- (cyclohexylmethoxy)benzoic acid; 4-(cyclopentyloxy)benzoic acid; 4-(cyclopentyloxy)benzoic acid; [4-(cyclobutylmethoxy)phenyl]acetic acid; 3-[4-(cyclobutylmethoxy)phenyl]propanoic acid; [4-(cyclohexylmethoxy)phenyl]acetic acid; 3-[4-(cyclohexylmethoxy)phenyl]propanoic acid; [4-(cyclohexylmethoxy)-3-methoxyphenyl]acetic acid; 3-[2- (cyclopropylmethoxy)phenyl]propanoic acid; [4-(cyclopentyloxy)phenyl]acetic acid; and 3-[4- (cyclopentyloxy)phenyl]propanoic acid.

[0255] United States Patent No. 8,207,227 to Bay et al. discloses disodium salts, ethanol solvates, and hydrates of a number of intestinal penetration agents including N-(5- chlorosalicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate.

[0256] United States Patent No. 8,431,736 to Dhoot et al. discloses crystalline forms of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid as intestinal penetration agents.PATENT PARSON-58748

[0257] United States Patent No. 8,513,300 to Abbas et al. discloses intestinal penetration agents of Formula (LXXIX): (LXXIX), wherein: (i) Y is carbonyl or SO2; (ii) R1 is C3-C24 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, cycloalkyl, or aromatic; (iii) R2 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; and (iv) R3is C1-C7alkyl, C3-C10cycloalkyl, aryl, thienyl, pyrrolo, or pyridyl, wherein R3is optionally substituted with one or more C1-C5 alkyl groups, C2-C4 alkenyl groups, halogen, SO2, CO2H, or SO3H.

[0258] United States Patent Application Publication No. 2012 / 0189666 by Dhoot et al. discloses intestinal penetration agents in the form of microparticles or nanoparticles. The particles can comprise an active agent, such as, in this case, a pentosan polysulfate salt, and an intestinal penetration agent. In one alternative, the particles comprising a delivery agent compound and an active agent have a median particle size less than about 900 or 1000 micrometers. According to another embodiment, the particles have a median particle size less than about 1 micrometer. In some embodiments, particles may be as small as about 1 nanometer and as large as about 999 micrometers. For example, the particles may have a median particle size of less than about 999 micrometers. Alternatively, the penetration agent itself can be in the form of particles. The particles can have a median particle size of less than about 999 micrometers. The particles can be in the form of fine granules or micro-beads, and can include a muco-adhesive. The penetration agent can be an intestinal penetration agent of Formula (LXXX), (LXXXI), (LXXXII), (LXXXIII), or (LXXXIV):PATENT PARSON-58748 (LXXX); ; ; or(LXXXIV).

[0259] In Formula (LXXX): (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with one or more of hydroxyl, halogen, C1-C4 alkyl, C1- C4 alkenyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; (iii) R1is C3-C20alkyl, C4-C20alkenyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, (C1-C10alkenyl)phenyl, (C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), or naphthyl(C1-C10 alkenyl); (iv) R1is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl, or sulfhydryl or any combination thereof;PATENT PARSON-58748 (v) R2is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; and (vi) R1is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; wherein the term “2-OH—Ar” refers to a phenyl or naphthyl group having a hydroxyl group at the 2-position.

[0260] In Formula (LXXXI): (i) R1, R2, R3, and R4are each independently hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, --C(O)R8, --NO2, --NR9R10, or –N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, --NO2, halogen, --CF3, --NR14R15, –N+R14R15R16(R13)-, amide, C1-C12alkoxy, C1-C12alkyl, C1-C12alkenyl, carbamate, carbonate, urea, or --C(O)R18; (iii) R5is optionally substituted with halogen, hydroxyl, sulfhydryl, or carboxyl; (iv) R5is optionally interrupted by O, N, S, or –C(O)--; (v) R6is a C1-C12alkylene, C1-C12alkenylene, or arylene; (vi) R6is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, halogen, amino, or –CO2R8; (vii) R6is optionally interrupted by O or N; (viii) R7is a bond or arylene; (ix) R7is optionally substituted with hydroxyl, halogen, --C(O)CH3, --NR10R11, or – N+R10R11R12(R13)-; (x) R8is hydrogen, C1-C4alkyl, C2-C4alkenyl, or amino; (xi) R9, R10, R11, and R12are independently hydrogen or C1-C10 alkyl; (xii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiii) R14, R15, and R16are each independently hydrogen, C1-C10alkyl, C1-C10alkyl substituted with carboxyl, C2-C12 alkenyl, C2-C12 alkenyl substituted with carboxyl, or –C(O)R17; (xiv) R17is hydroxyl, C1-C10 alkyl, or C2-C12 alkenyl; and (xv) R18is hydrogen, C1-C6alkyl, hydroxyl, --NR14R15, or –N+R14R15R16(R13)-.

[0261] In Formula (LXXXII): (i) R1, R2, R3, R4, and R5are each independently hydrogen, --CN, hydroxyl, --OCH3, or halogen, wherein at least one of R1, R2, R3, R4, and R5is –CN; and (ii) R6is a C1-C12linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene).

[0262] In Formula (LXXXIII):PATENT PARSON-58748 (i) each occurrence of X is hydrogen, halogen, hydroxyl, or C1-C3 alkoxy; (ii) R is substituted or unsubstituted C1-C3alkylene or substituted or unsubstituted C2-C3alkenylene; and (iii) n is 1, 2, 3, or 4.

[0263] In Formula (LXXXIV): (i) X is halogen; and (ii) R is substituted or unsubstituted C1-C3 alkylene or substituted or unsubstituted C2-C3 alkenylene.

[0264] United States Patent Application Publication No. 2012 / 0064147 by Eibl et al. discloses intestinal penetration agents including 3-(3-hexyloxy-2-hydroxy-propoxy)-propane- 1,2-diol and 3-[2-hydroxy-3-(2-hydroxy-2-octyloxy-propoxy)-propoxy]-propane-1,2-diol.

[0265] United States Patent Application Publication No. 2009 / 0143330 by Levchik et al. discloses intestinal penetration agents including polymorphic forms of SNAC.

[0266] United States Patent Application Publication No. 2009 / 0010882 by Bhandarkar et al. discloses intestinal penetration agents including polymorphic forms of sodium 4-[(4-chloro-2- hydroxybenzoyl)amino]butanoate (sodium 4-CNAB).

[0267] United States Patent Application Publication No. 2012 / 0258911 by Gschneidner et al. discloses intestinal penetration agents that are phenylalkylcarboxylic acids, including 4-(4- methoxyphenyl)butanoic acid, 5-(2-methoxyphenyl)pentanoic acid, 5-(3-fluorophenyl)pentanoic acid, 5-(3-methoxyphenyl)pentanoic acid, 6-(3-fluorophenyl)hexanoic acid, 3-(4-t- butylphenyl)propanoic acid, 3-(4-n-butylphenyl)propanoic acid, 3-(4-n-propylphenyl)propanoic acid, 3-(4-n-propoxyphenyl)propanoic acid, 3-(4-isopropoxyphenyl)propanoic acid, 3-(4-n- butoxyphenyl)propanoic acid, 3-(3-phenoxyphenyl)propanoic acid, 3-(3-ethoxyphenyl)propanoic acid, 3-(3-isopropoxyphenyl)propanoic acid, 3-(3-n-butoxyphenyl)propanoic acid, 3-(3-n- propoxyphenyl)propanoic acid, 3-(3-isobutoxyphenyl)propanoic acid, 3-(4- isobutoxyphenyl)propanoic acid, 4-(4-ethylphenyl)butanoic acid, 4-(4-isopropylphenyl)butanoic acid, and 5-(4-ethylphenyl)pentanoic acid or pharmaceutically acceptable salts thereof.

[0268] United States Patent No. 9,345,722 to Shevchuk et al. discloses the use of oral or transdermal delivery of the agent CPHPC ((R)-1-{6-[(R)-2-carboxypyrrolidin-1-yl]-6- oxohexanoyl}pyrrolidine-2-carboxylic acid) to treat Alzheimer’s disease or other diseases or conditions associated with amyloidosis. The reference describes oral or transdermal delivery ofPATENT PARSON-58748 CPHPC using N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC), pegylated SNAC, N-(8-[2- hydroxybenzoyl]amino)decanoic acid (SNAD), or 4-[(4-chloro-2- hydroxybenzoyl)amino]butanoic acid (4-CNAB) as a delivery agent. If transdermal delivery is used, a transdermal patch can be used with a solvent such as a buffer providing a pH of about 8, an alcohol, a fatty acid / fatty acid ester blend, isopropyl palmitate, isopropyl myristate, mineral oil, silicone fluids, organic amine blends, and a plasticizer such as triethyl citrate.

[0269] United States Patent No. 7,084,279 to Gscheidner discloses oxadiazoles as intestinal penetration agents of Formula (LXXXV):(LXXXV), wherein: (1) R1is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, phenyl, naphthyl, or aromatic heterocyclyl; (2) R1is optionally substituted with C1-C4alkyl or fluoroalkyl, C2-C4alkenyl, C1-C4alkoxy or fluoroalkoxy, halo, hydroxyl, sulfhydryl, phenyl, phenoxy, --CO2R3, --N(CH3)2, --NO2, or amino; (3) R2is C1-C24alkylene, C2-C24alkenylene, C3-C10cycloalkylene, C3-C10cycloalkenylene, phenylene, naphthalene, (C1-C10alkyl)phenylene, (C2-C10alkenyl)phenylene, (C1-C10 alkyl)naphthalene, (C2-C10 alkenyl)naphthalene, phenyl(C1-C10 alkylene), phenyl(C2-C10 alkenylene), naphthyl(C1-C10 alkylene), or naphthyl(C2-C10 alkenylene); (4) R2is optionally substituted with C1-C4alkyl or fluoroalkyl, C2-C4alkenyl, C1-C4alkoxy or fluoroalkoxy, halo, hydroxyl, sulfhydryl, phenyl, phenoxy, --CO2R3, --N(CH3)2, --NO2, amino, C3-C10 cycloalkenyl, aryl, (C1-C10 alkyl)aryl, heterocyclyl having 3-10 ring atoms wherein the heteroatom is one or more of N, O, S, or any combination thereof; (5) R2is optionally interrupted by N, O, S, or any combination thereof; and (6) R3is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl, with the provisos that: (i) R1is not 4- (piperidin-4-yl)phenyl when R2is –(CH2)4--; (ii) R1is not –CH3when R2is –(CH2)3--; and (iii) R1is not 4-carboxyphenyl when R2is –(CH2)3— or R2is –(CH2)4--.PATENT PARSON-58748

[0270] United States Patent No. 8,703,821 to Song discloses dialkyl ether penetration agents having the structure of Formula (LXXXVI):(LXXXVI), wherein: (1) A is a C1-C6 alkylene group (preferably a straight-chain unsubstituted and unbranched alkylene C1-C6 group); (2) B is a C1-C2alkylene group (preferably a straight-chain unsubstituted and unbranched alkylene C1-C2group); and (3) R1, R2, R3, R4, and R5 are independently hydrogen, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, --C(O), --NO2, NR9R10, N+R9R10R11(R12), carbonate, ureido, --CX3, or –CN, optionally interrupted by O, N, S, or –C(O)— group, where A and R1 may form a cycloalkyl group, wherein: (a) R8is independently H, C1-C4alkyl, C2-C6alkenyl, or an –NH2group; (b) R9, R10, R11, and R12are independently H or C1-C10 alkyl; and (c) X is halogen.

[0271] United States Patent No. 9,458,089 to Mustata et al. discloses phenoxyalkyl diethanolamine and phenoxyalkyl diisopropanolamine intestinal penetration agents.

[0272] United States Patent No. 5,693,338 to Milstein discloses a ketopiperazine intestinal penetration agent of Formula (LXXXVII):(LXXXVII), wherein:PATENT PARSON-58748 (1) R1, R2, or R1and R2independently are hydrogen, C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, C1-C10alkenyl)phenyl, (C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), and naphthyl(C1-C10 alkenyl); (2) R1, R2, or R1and R2, optionally, are independently substituted with C1-C4alkyl, C1- C4 alkenyl, C1-C4 alkoxy, hydroxy, sulfhydryl, and –CO2R3or any combination thereof, wherein R3is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl; (3) wherein the phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are independently substituted by C1-C6alkyl, C1-C6alkenyl, C1-C6alkoxy, hydroxy, sulfhydryl, or – CO2R4, wherein R4is hydrogen, C1-C6 alkyl, C1-C6 alkenyl; and (4) R1and R2are not both hydrogen.

[0273] United States Patent No. 5,990,166 to Leone-Bay et al. discloses the following intestinal penetration agents: 6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid; 8(2- aminobenzoylamino)caprylic acid; 8(2-trifluoromethoxy)benzoylamino caprylic acid; N-(2- hydroxybenzoyl)isonipecotic acid; 54-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid; 4-[4-(pentafluorobenzoyl)aminophenyl)butyric acid; 4-[4-(3-anisoyl)aminophenyl)butyric acid; 8-(3-anisoyl)aminocaprylic acid; 4-[4-(phenoxyacetyl)aminophenyl)butyric acid; 4-(4-(2- nitrobenzenesulfonyl)aminophenyl)butyric acid; 8-(2-nitrobenzenesulfonyl)aminocaprylic acid; 6-(4-(salicyloyl)aminophenyl)hexanoic acid; 8-(2-methoxylbenzoyl)aminocaprylic acid; 2-[4- salicyloylamino)phenyl]ethyl methylsulfone; 1-salicyloyl-2-succinyl hydrazide; 3-(4-(2,5- dimethoxycinnamoyl)aminophenyl)propionic acid; 4-(4-(2,5- dimethoxycinnamoyl)aminophenyl)butyric acid; 1-salicyloyl-2-glutaryl hydrazide; succinyl-4- aminosalicylic acid; 8-(phenoxyacetylamino)caprylic acid; 8-(2-pyrazinecarbonyl)aminocaprylic acid; 4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid; 6-(4-(N-2- nitrobenzoyl)aminophenyl)hexanoic acid; 6-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid; 4-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid; 4-(2- nitrobenzoyl)aminophenylsuccinic acid; 8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid; 8- (benzylcarbonylamino)caprylic acid; 8-(phenylcarbonylamino)caprylic acid; 2-[4-(2- methoxybenzoylamino)phenyl]ethyl phosphate; 1-salicyloyl-2-suberyl hydrazide; 4-(4- benzyloxycarbonylaminophenyl)butyric acid; 4-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid; 9-salicyloylaminononanoic acid; 4-(4-phenyloxycarbonylaminophenyl)butyric acid; 3-(2-PATENT PARSON-58748 methoxybenzoylamino)-1-propanol; 8-(2-hydroxynicotinoyl)aminocaprylic acid; 6-(2- methoxybenzoyl)aminonicotinic acid; salicyloylglycine; 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid; 8-(chromone-3-carbonyl)aminocaprylic acid; 8-(vinylbenzoyl)aminocaprylic acid; 4-(4- (chromone-3-carbonyl)aminophenyl)butyric acid; 8-cinnamoylaminocaprylic acid; 5-(N- salicyloylamino)valeric acid; 9-(2-hydroxybenzamido)nonanoic acid; N-(4-salicyloylamino)-6- caproic acid; 4′-flavonic acid; 11-cinnamoylaminoundecanoic acid; 4-octanoylamino-3- hydroxybenzoic acid; (3-phenyl-2,3-dihydroxypropanoyl)8-aminocaprylic acid; 8-[N-(3- coumarincarbonyl)]aminocaprylic acid; 8-[N-(4-chlorobenzoyl)]aminocaprylic acid; 8-[N-3- fluorobenzoyl)]aminocaprylic acid; 8-(N-2,5-dihydroxybenzoyl)aminocaprylic acid; 8-(N-2,3- dimethoxybenzoyl)aminocaprylic acid; 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid; 8-(N- 2,5-dimethoxybenzoyl)aminocaprylic acid; 8-(N-3,5-diacetyloxybenzoyl)aminocaprylic acid; 8- (N-4-hydroxybenzoyl)aminocaprylic acid (dimer); 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid; 10-(N-2-methoxyanilino)sebacic acid; 10-(N-2-hydroxyanilino)sebacic acid; 2- methoxybenzaminodecanoic acid; 8-(N-benzoyl)aminocaprylic acid; 8-(N-2-hydroxy-4- methoxybenzoyl)aminocaprylic acid; 8-[N-(4-fluorobenzoyl)]aminocaprylic acid; 8-[N-(3- bromobenzoyl)]aminocaprylic acid; 8-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid; 8-[N- (4-bromobenzoyl)]aminocaprylic acid; 8-[N-(4-iodobenzoyl)]aminocaprylic acid; 4-{4-[N-(2- iodobenzoyl)aminophenyl]}butyric acid; 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid; 4-(4-(2,4-dimethoxybenzoyl)aminophenyl)butyric acid; 4-(o-anisoyl)aminophenylacetic acid; 3-[4-(2,4-dimethoxybenzoyl) aminophenyl]propionic acid; 4-{4-[N-(4- iodobenzoyl)]aminophenyl}butyric acid; 3-[4-(2,3-dimethoxybenzoyl) aminophenyl]propionic acid; 4{4-[N-2-bromobenzoyl)]aminophenyl}butyric acid; 4{-[N-3-bromobenzoyl) aminophenyl}butyric acid; 8-(N-3,5-dihydroxybenzoyl)aminocaprylic acid; (N-3,5-dimethoxy 4- hydroxybenzoyl)aminocaprylic acid; 8-(N-2-6-dimethoxybenzoyl)aminocaprylic acid; 4-{4-[N- (4-bromobenzoyl)aminophenyl]}butyric acid; 8-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid; 8-(N-2,6-dihydroxybenzoyl)aminocaprylic acid; 8-(N-2-hydroxy-6- methoxybenzoyl)aminocaprylic acid; 8-(5-chloro-o-anisoyl)aminocaprylic acid; 4-(4-(2,3- dimethoxybenzoyl)aminophenyl)butyric acid; 4-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid; 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid; 8-(4-chloro-o-anisoyl)aminocaprylic acid; 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid; 4-{N-[4-(3- iodobenzoyl)aminophenyl]}butyric acid; 7-cinnamoylaminoheptanoic acid; 8-N-(3-PATENT PARSON-58748 iodobenzoyl)aminocaprylic acid; 8-N-(3-iodobenzoyl)aminocaprylic acid; 8-N-(2-methoxy-4- nitrobenzoyl)aminocaprylic acid; 4-{N-[4-(2-methoxy-4-nitrobenzoyl)aminophenyl]}butyric acid; 4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid; 8-(N-2-hydroxy-5- bromobenzoyl)aminocaprylic acid; 3-indolebutyric acid; 4-(4-(2,6- dimethoxybenzoyl)aminophenylbutyric acid; 4-[4-N-(4-methoxy-3- nitrobenzoyl)aminophenyl]butyric acid; 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid; 8- (N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid; 8-(3-hydroxy-3-naphthoyl)aminocaprylic acid; 8-(N-2-hydroxy-4-nitrobenzoyl)aminocaprylic acid; 4-[N-(2-hydroxy-4- bromobenzoyl)aminophenyl]butyric acid; 8-(N-2,3-dihydroxybenzoyl)aminocaprylic acid; 8-(N- 3-methylsalicyloyl)aminocaprylic acid; 8-(N-5-methylsalicyloyl)aminocaprylic acid; 9- (cinnamoylamino)nonanoic acid; 4-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid; 4-{- [N-(2-hydroxy-5-iodobenzoyl)]aminophenyl}butyric acid; N-2-nitrophenyl-N′-(8-octanoic acid) urea; N-(2-methoxy-5-nitrophenyl) sebacoyl amide acid; 8-[N-(2-acetoxy-3,5- dichlorobenzoyl)]aminocaprylic acid; 8-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid; 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid; 8-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid; 4-(4-salicyloylaminophenyl)-4-oxobutyric acid; 12-cinnamoyldodecanoic acid; 4-{4-[N-(3- hydroxy-2-napthoyl)aminophenyl]}butyric acid; 8-(4-chloro-3-nitrobenzoyl)aminocaprylic acid; 8-(2-chloronicotinoyl)aminocaprylic acid; 8-(2-chloro-5-nitrobenzoyl)aminocaprylic acid; 4-(4- phthalimidophenyl)butyric acid; 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}propanoic acid; 3-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid; 8-(N-2-hydroxy-3,5- diiodobenzoyl)aminocaprylic acid; 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid; 8-(2- (1,2-dihydroisoindole-1-one))octanoic acid; 8-(N-2-hydroxy-2-naphthoyl)aminocaprylic acid; 8- (phthalimido)caprylic acid; 10-(4-chloro-2-hydroxyanilino)sebacic acid monoamide; 6- (anisoyl)aminocaproic acid; 4-(4-(4-chloro-3-nitrobenzoyl)aminophenyl)butyric acid; 11-N-(1- hydroxy-2-naphthoyl)aminoundecanoic acid; bis(N-2-carboxylphenyl-N-(N′-8-octanoic acid)oxalyl diamide; 2-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol; 2-[2-N-(4- chlorobenzoyl)aminoethoxy]ethanol; 4-(2-methoxybenzoyl)amino 3-carboxysulfoxide; 4-(2- methoxybenzoyl)amino 3-carboxypropylsulfone; 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid; [2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol; 2-[2-N-(3- chlorobenzoyl)aminoethoxy)]ethanol; bis(N-2-carboxyphenyl-N-(N′-3(4-aminophenyl)propionic acid)urea)oxalyl diamide; trans-4-(2-aminobenzamidomethyl)cyclohexaminylcarboxylic acid;PATENT PARSON-58748 11-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid; 2-[N-(2- bromobenzoyl)aminoethoxyl]ethanol; 7-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid; N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid; trans-4-(N- salicyloylaminomethyl)cyclohexane carboxylic acid; N-[3,5-dichloro-2-hydroxybenzoyl-3-(4- aminophenyl)]propionic acid; 12-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid; N- (2-hydroxy-4-carboxy)-6-heptenamide; N-(2-bromobenzoyl)morpholine; N- cyclohexanoylaminocaprylic acid; 2-[N-(2-iodobenzoyl)aminoethoxyl]ethanol; 5-(4-chloro-2- hydroxyanilinocarbonyl)valeric acid; 8-(2-hydroxyphenoxy)-aminocaprylic acid; N-salicyloyl-5- (3-aminophenyl)valeric acid; 4-(4-(2-ethoxylbenzoyl)aminophenyl)butyric acid; 9-[2-(3- hydroxy)pyridylaminocarbonyl]nonanoic acid; 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid; 2-[N-(2-hydroxybenzoylamino)ethoxyl]ethanol; 4-[N-(3,5-dichloro-2- hydroxybenzoyl)]aminophenylacetic acid; 8-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid; N-salicyloyl-5-(4-aminophenyl)valeric acid; 9-(2-hydroxy-5-methylanilinocarbonyl)nonanoic acid; 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid; 8-(pentafluorobenzoyl)aminocaprylic acid; 3-(3-(salicyloyl)aminophenyl)propionic acid; 8-(2-ethoxybenzoyl)aminocaprylic acid; 4-(4- (2-dimethylaminobenzoic)aminophenyl)butyric acid; 8-(3-phenoxylpropionylamino)caprylic acid; 4-(salicyloyl)aminophenylethyltetrazole; 8(-(4-(N-salicyloyl- 4aminophenyl)butyric)aminocaprylic acid); 4-(4-(N-(2-fluorocinnamoyl))aminophenyl) butyric acid; 4-(4-(N-8(N-salicyloyl)aminocaprylic)aminophenyl)butyric acid; 8-(p- anisoyl)aminocaprylic acid; 8-(4-hydroxybenzoyl)aminocaprylic acid; 8-(3- hydroxybenzoyl)aminocaprylic acid; 8-(3,4,5-trimethoxybenzoyl)aminocaprylic acid; 8-(N-4- methylsalicyloyl)aminocaprylic acid; N-10-(2-hydroxy-5-nitroanilino)decanoic acid; and 4-(4- (2-chloronicotinoyl)aminophenyl)butyric acid.

[0274] Additional intestinal penetration agents disclosed in this reference include intestinal penetration agents of Formulas (LXXXVIII), (LXXXIX), (XC), and (XCI): ;PATENT PARSON-58748 ;.

[0275] United States Patent No. 7,115,663 to Moye-Sherman et al. discloses cyanophenoxy carboxylic acid intestinal penetration agents of Formula (XCII):; wherein: (1) R1, R2, R3, R4, and R5are independently hydrogen, cyano, hydroxy, --OCH3, or halogen, wherein at least one of R1, R2, R3, R4, and R5is cyano; (2) R6is C1-C12linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene); and (3) with the proviso that when R1is cyano, R4is hydrogen or cyano, and R2, R3, and R5are hydrogen, then R6is methylene.

[0276] United States Patent No. 7,129,274 to Leone-Bay et al. discloses phenoxycarboxylic acid intestinal penetration agents of Formula (XCIII):PATENT PARSON-58748, wherein: (1) R1, R2, R3, and R4are independently hydrogen, hydroxy, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, --C(O)R8, nitro, NR9R10, or N+R9R10R11(R12)-; (2) R5is hydrogen, hydroxy, nitro, halogen, --CF3, NR14R15, N+R14R15R16(R13)-, amide, C1-C12 alkoxy, C1-C12 alkyl, C1-C12 alkenyl, carbamate, carbonate, urea, or –C(O)R18; (3) R5is optionally substituted with halogen, sulfhydryl, or carboxy; (4) R5is optionally interrupted by O, N, S, or –C(O)--; (5) R6is a C1-C12 alkylene, C2-C12 alkenylene, or arylene; (6) R6is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxy, sulfhydryl, halogen, amino, or –CO2R8; (7) R6is optionally interrupted with O or N; (8) R7is a valence bond or arylene; (9) R7is optionally substituted with hydroxy, halogen, --C(O)CH3, --NR10R11, or – N+R10R11R12(R13)-; (10) R8is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or amino; (11) R9, R10, R11, and R12are independently hydrogen or C1-C10 alkyl; (12) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (13) R14, R15, and R16are independently hydrogen, C1-C10 alkyl, C1-C10 alkyl substituted with carboxy, C2-C12 alkenyl, C2-C12 alkenyl substituted with carboxy, or –C(O)R17; (14) R17is hydroxy, C1-C10alkyl, or C2-C12alkenyl; and (15) R18is hydrogen, C1-C6alkyl, hydroxyl, --NR14R15, or –N+R14R15R16(R13)-, with the following provisos: (a) when R1, R2, R3, R4, and R5are hydrogen and R7is a bond, then R6is a C1-C6, C9, or C10alkyl;PATENT PARSON-58748 (b) when R1, R2, R3and R4are hydrogen and R5is hydroxyl, and R7is a bond, then R6is not a C1-C3alkyl; (c) when at least of R1, R2, R3and R4is not hydrogen, R5is hydroxyl, and R7is a bond, then R6is not a C1-C4 alkyl; (d) when R1, R2, and R3are hydrogen, R4is –OCH3, R5is –C(O)CH3, and R6is a bond, then R7is not a C3 alkyl; and (e) when R1, R2, R4, and R5are hydrogen, R3is hydroxyl, and R7is a bond, then R6is not methyl.

[0277] United States Patent No. 7,151,191 to Boyd et al. discloses intestinal penetration agents of Formula (XCIV):, wherein: (1) R1, R2, R3, R4, and R5are independently selected from hydrogen, halogen, hydroxy, methoxy, C1-C4 alkyl, amino, methylamino, dimethylamino, or nitro; (2) m is an integer ranging from 0 to 4; (3) R6is a phenyl substituted with –O—R7-COOH at the ortho, meta, or para position; (4) R6is optionally substituted with one or more moieties selected from the group consisting of halogen, hydroxy, methoxy, C1-C4alkyl, amino, methylamino, dimethylamino, and nitro; and (5) R7is C1-C12 alkylene.

[0278] United States Patent No. 7,217,703 to Gschneidner discloses 8-(2- hydroxyphenoxy)octyldiethanolamine and salts thereof as intestinal penetration agents.

[0279] United States Patent No. 7,700,775 to Liao et al. discloses intestinal penetration agents including Compounds (1)-(18) shown below:PATENT PARSON-58748 ); ); ); ); ); ););PATENT PARSON-58748 ););); ); ); );PATENT PARSON-58748 (Compound (14)); ); );).

[0280] United States Patent Application Publication No. 2002 / 0065255 by Bay et al. discloses intestinal penetration agents that are disodium salts, monohydrates or ethanol solvates of compounds of Formula (XCV): ,PATENT PARSON-58748 wherein: (1) R1, R2, R3, and R4are independently hydrogen, halogen, C1-C4alkyl, or C1-C4alkoxy; and (2) R5is a substituted or unsubstituted C2-C16 alkylene, substituted or unsubstituted C2- C16alkenylene, substituted or unsubstituted C1-C12alkyl(arylene), or substituted or unsubstituted aryl(C1-C12 alkylene).

[0281] United States Patent Application Publication No. 2005 / 0147662 by Freeman, Jr. discloses intestinal penetration agents including Compounds (19)-(20) shown below:).

[0282] United States Patent Application Publication No. 2011 / 0046050 by Gschneidner et al. discloses phenylalkylcarboxylic acid intestinal penetration agents of Formula (XCVI):, wherein: (1) n is 1-12; and (2) R1-R5are each independently hydrogen, C1-C6 alkyl, C2-C4 alkenyl, halogen, C1-C4 alkoxy, hydroxy, C6-C14 aryloxy, or C1-C6 haloalkyl.PATENT PARSON-58748

[0283] Additional United States patents disclosing intestinal penetration agents include United States Patent No. 8,466,199 to Song, United States Patent No. 8,492,330 to Khan et al., United States Patent No. 8,541,362 to Tang et al., United States Patent No. 8,546,581 to Jungheim et al., and United States Patent No. 8,552,039 to Herr et al.

[0284] Additional United States published patent applications disclosing intestinal penetration agents include United States Patent Application Publication No. 2012 / 0264834 by Bay et al., United States Patent Application Publication No. 2011 / 0251125 by Bay et al., United States Patent Application Publication No. 2010 / 0009621 by Bay et al., United States Patent Application Publication No. 2011 / 0190205 by Jungheim et al., United States Patent Application Publication No. 2010 / 0048454 by Arbit et al., United States Patent Application Publication No. 2010 / 0016229 by Sarubbi, and United States Patent Application Publication No. 2009 / 0286735 by Khan et al.

[0285] Other penetration agents are known in the art. In general, such penetration agents are compounds having both hydrophobic and hydrophilic elements. The hydrophobic elements can be, for example, aromatic moieties or the aliphatic portions of medium and long-chain fatty acids. The hydrophilic elements can be, for example, carboxylic acids or their derivatives. Additionally, derivatives or isosteres of penetration agents described above can be used. Isosterism is defined as the presence of substituents or groups that have chemical or physical similarities and that produce broadly similar biological properties. Many isosteric substitutions or replacements are known for moieties such as methyl groups, chloro groups, bromo groups, iodo groups, methylene groups, esters, amides, aromatic moieties, carbonyl groups, carboxylic acid groups, hydroxyl groups, catechol moieties, thioether moieties, thiourea moieties, and spacer groups, and are described in R.B. Silverman, “The Organic Chemistry of Drug Design and Drug Action” (2nded., Elsevier, 2004), pp. 29-34.

[0286] In general, in compositions employing penetration agents such as those described above, absorption of the sodium pentosan polysulfate can be detected in subjects treated with the pharmaceutical compositions of the present invention by monitoring the plasma levels of sodium pentosan polysulfate after administration of the composition. The time it takes for an active agent to reach peak concentration in the bloodstream (tmax) may depend on many factors such as the following: the nature of the unit dose (i.e., solid, liquid, tablet, capsule, suspension); the possible use of agents that delay absorption of the active agent in the composition beingPATENT PARSON-58748 administered; the concentration of active agent and the penetration agent in the gastrointestinal (GI) tract, the state of nutrition of the subject, the diet of the subject, the health of the subject, and the ratio of the active agent to the penetration agent. In one alternative, using 4-CNAB as the penetration agent, the composition provides a peak plasma concentration of sodium pentosan polysulfate from about 0.1 hour to about 3 hours after the administration of the composition. Preferably, the composition provides a peak plasma concentration of sodium pentosan polysulfate from about 0.2 hour to about 0.6 hour after the administration of the composition. More preferably, the composition provides a peak plasma concentration of sodium pentosan polysulfate from about 0.3 hour to about 0.4 hour after the administration of the composition. In another alternative, the composition provides a first peak plasma concentration of sodium pentosan polysulfate at about 0.3 hours after the administration of the composition and a second peak plasma concentration of sodium pentosan polysulfate at about 1.1 hours after the administration of the composition. Similar considerations apply if a pentosan polysulfate salt other than sodium pentosan sulfate, such as calcium pentosan polysulfate, is used in a method or composition according to the present invention, or if a glycosaminoglycan / sulfated polysaccharide other than a pentosan polysulfate salt is used in a method or composition according to the present invention.

[0287] The time it takes an intestinal penetration agent to reach a peak in the bloodstream (tmax) may depend on many factors such as the following: the nature of the unit dose (i.e., solid, liquid, tablet, capsule, suspension); the concentration of the glycosaminoglycan / sulfated polysaccharide, such as the sodium pentosan polysulfate or other pentosan polysulfate salt and the intestinal penetration agent in the gastrointestinal (GI) tract, the state of nutrition of the subject, the diet of the subject, the health of the subject, and the ratio of the active agent to the intestinal penetration agent. The intestinal penetration agents used in compositions or methods according to the present invention are typically rapidly absorbed from the GI tract when orally administered in an immediate release dosage form, and preferably provide a peak plasma concentration at about 0.1 hour to about 8 hours after oral administration, and more preferably at about 0.1 hour to about 3 hours after oral administration. In one preferred embodiment, the tmaxof the intestinal penetration agent occurs at about 0.3 hour to about 1.5 hours after oral administration. In certain embodiments, the intestinal penetration agent achievesPATENT PARSON-58748 a tmax of about 2 hours after oral administration, or, alternatively, about 1 hour after oral administration.

[0288] The amount of an intestinal penetration agent necessary to adequately deliver an active agent such as, in the context of the present invention, sodium pentosan polysulfate, into the bloodstream of a subject needing the therapeutic effect of that active agent may vary depending on one or more of the following; the chemical nature of the active agent; the chemical structure of the particular intestinal penetration agent; the nature and extent of interaction between the active agent and the intestinal penetration agent, including noncovalent interactions such as hydrogen bonds, salt links, hydrophobic bonds, and van der Waals interactions; the nature of the unit dose, i.e., solid, liquid, tablet, capsule, suspension; the concentration of the intestinal penetration agent in the GI tract; the feeding state of the subject; the diet of the subject; the health of the subject and the ratio of the intestinal penetration agent to the active agent. In a certain preferred embodiment of the invention, the amount of the intestinal penetration agent preferred for the pharmaceutical composition is from about 1 mg to about 2000 mg of the intestinal penetration agent per unit dose, more preferably from about 1 mg to about 800 mg of the intestinal penetration agent per unit dose, more preferably from about 50 mg to about 700 mg of the intestinal penetration agent per unit dose, even more preferably from about 70 mg to about 700 mg of the intestinal penetration agent per unit dose, still more preferably from about 100 to about 600 mg of the intestinal penetration agent per unit dose, and even still more preferably from about 150 mg to about 400 mg of the intestinal penetration agent per unit dose.

[0289] The optimum ratio of sodium pentosan polysulfate or other pentosan polysulfate salt or glycosaminoglycan and intestinal penetration agent can be varied depending on the dose of sodium pentosan polysulfate or other pentosan polysulfate salt or glycosaminoglycan to be delivered, the presence or absence of other carriers or excipients, and the specific intestinal penetration agent employed. One of ordinary skill can readily determine this ratio by, for example, making use of pharmacokinetic parameters such as: (1) bioavailability, defined as the degree or ratio (%) to which a drug or agent is absorbed or otherwise available to the treatment site in the body; in the case of sodium pentosan polysulfate, the treatment site is the epithelium of the lower urinary tract; bioavailability is calculated by the formula:PATENT PARSON-58748; (2) biopotency, defined as the degree or ratio (%) to which the drug or agent is effective to the treatment site in the body, and calculated by the formula: ; (3) Frel, which means the relative bioavailability of sodium pentosan polysulfate calculated by comparing dose-corrected oral sodium pentosan polysulfate AUC (defined below with the dose- corrected sodium pentosan polysulfate as administered by instillation AUC; (4) Kel, the terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration versus time curve; (5) AUC(0-x), the area under the plasma concentration-time curve using linear trapezoidal summation from time 0 to time x hours post-dose; (6) AUC(0-t), the area under the plasma concentration-time curve using linear trapezoidal summation from time 0 to time t hours post-dose, where t is the time of the last measurable concentration (Ct); (7) AUC(0-∞), the area under the plasma concentration-time curve from time 0 to infinity; AUC(0-∞)= AUC(0-t)+ Ct / Kel;(8) AUC%Extrapmeans the percentage of the total AUC(0-∞)obtained by extrapolation; (9) AEUC(0-x)means the area under the effect-time curve calculated using the linear trapezoidal summation from time 0 to the concentration at time x hours post-dose; (10) AEUC(0-t) means the area under the effect-time curve calculated using the linear trapezoidal summation from time 0 to the concentration at time t post-dose, where t is the time of the last measurable effect (E); (11) AURC(0-x)means the area under the response-time curve calculated using the linear trapezoidal summation from time zero to the concentration at time x (Baseline Subtracted AUEC); (12) AURC(0-x) means the response-time curve calculated using the linearPATENT PARSON-58748 trapezoidal summation from time 0 to the concentration at time t (Baseline Subtracted AUEC), where t is the time of the last measurable response (R); (12) the term CL / F means the apparent total body clearance calculated as Dose / AUC(0-∞); (13) MRT means the mean residence time calculated as the ratio of the area under the first moment of the plasma concentration-time curve (AUMC) and the area under the plasma concentration-time curve (AUMC) / AUC(0-∞).

[0290] The intestinal penetration agent may be used directly by mixing one or more such agents with the active agent (such as sodium pentosan polysulfate or another pentosan polysulfate salt or glycosaminoglycan) prior to administration. The intestinal penetration agent may be mixed in dry powder form or wet granulated together. To this mixture, other pharmaceutically acceptable excipients may be added. The mixture may be then tableted or placed into gelatin capsules containing a unit dose of the active agent and the intestinal penetration agent. Alternatively, the intestinal penetration agent / active agent mixture may be prepared as an oral solution or suspension. The intestinal penetration agent and active agent do not need to be mixed together prior to administration, such that, in certain embodiments, the unit dose of active agent (with or without other pharmaceutically acceptable excipients) is orally administered without the intestinal penetration agent as described herein, and the intestinal penetration agent is separately orally administered (with or without other pharmaceutically acceptable excipients) before, after, or simultaneously with the active agent.

[0291] In certain preferred embodiments, the oral dosage forms for compositions according to the present invention or used in methods according to the present invention are solid. The unmodified sodium pentosan polysulfate (when sodium pentosan polysulfate is used as the glycosaminoglycan / sulfated polysaccharide in methods or compositions according to the present invention) in dry powder form is stable, and in certain preferred embodiments is simply mixed in a desirable ratio with the intestinal penetration agent. The dry powder mixture may then be filled into gelatin capsules, with or without optional pharmaceutical excipients. Alternatively, the unmodified sodium pentosan polysulfate in dry powder form may be mixed with the intestinal penetration agent together with optional pharmaceutical excipients, and the mixture may be tableted in accordance with standard tableting procedures known to those having ordinary skill in the art.

[0292] The dosage forms of the present invention may be produced by first dissolving the active agent and the intestinal penetration agent into one solution or separate solutions. ThePATENT PARSON-58748 solvent will preferably be an aqueous solution, but organic solvents or aqueous organic solvent mixtures may be used when necessary to solubilize the delivery agent. If two solutions are used, the proportions of each necessary to provide the correct amount of either active agent or intestinal penetration agent are combined and the resulting solution may be dried, by lyophilization or equivalent means. In one alternative of the invention, the oral dosage form may be dried and rehydrated prior to oral administration when an oral dosage form is used in a method of the present invention.

[0293] The administration mixtures may be prepared, e.g., by mixing an aqueous solution of the intestinal penetration agent with an aqueous solution of the active ingredient, such as sodium pentosan polysulfate, just prior to administration. Alternatively, the intestinal penetration agent and the active ingredient, such as sodium pentosan polysulfate, can be admixed during the manufacturing process. The solutions may optionally contain additives such as, but not necessarily limited to, phosphate buffer salts, citric acid, acetic acid, gelatin, and gum acacia. Other suitable additives can be included as long as they do not interfere with the activity of the active ingredient or the intestinal penetration agent.

[0294] Stabilizing additives may be incorporated into the intestinal penetration agent solution or a solid dosage form including the intestinal penetration agent. With some drugs, the presence of such additives promotes the stability and dispersibility of the agent in solution. The stabilizing additives may be employed at a concentration ranging from about 0.1% to about 5% (w / v), preferably about 0.5% (w / v). Suitable, but non-limiting, examples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. The preferred stabilizing additives are gum acacia, gelatin and methyl cellulose.

[0295] The amount of active agent, such as sodium pentosan polysulfate, another pentosan polysulfate salt, or another glycosaminoglycan as described above is an amount effective to accomplish the purpose of the particular active agent. The amount in the composition is a therapeutically effective dose, i.e., a pharmacologically or biologically effective amount. However, the amount can be less than a pharmacologically or biologically effective amount when the composition is used in a dosage unit form, such as a capsule, a tablet or a liquid, because the dosage unit form may contain a multiplicity of intestinal penetration agents / active agents or may contain a divided pharmacologically or biologically effectivePATENT PARSON-58748 amount. The total effective amounts can then be administered in cumulative units containing, in total, pharmacologically or biologically or chemically active amounts of active agent.

[0296] The oral dosage forms according to the present invention, containing a mixture of the active agent, such as sodium pentosan polysulfate, another pentosan polysulfate salt, or a glycosaminoglycan, and an intestinal penetration agent as described herein, or separately containing the active agent and the intestinal penetration agent, may include additional materials known to those skilled in the art as fillers, excipients, or carriers. These materials are also known generally as pharmaceutically acceptable carriers. Any excipient or ingredient, including pharmaceutical ingredients or excipients, can be used. Such pharmaceutical excipients include, for example, the following: acidifying agents (acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid, nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid, tartaric acid); aerosol propellants (butane, dichlorodifluoromethane, dichlorotetrafluoroethane, isobutane, propane, trichloromonofluoromethane); air displacements (carbon dioxide, nitrogen); alcohol denaturants (denatonium benzoate, methyl isobutyl ketone, sucrose octacetate); alkalizing agents (strong ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine); anticaking agents (see glidants); antifoaming agents (dimethicone, simethicone); antimicrobial preservatives (benzalkonium chloride, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol); antioxidants (ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherols); buffering agents (acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate, sodium lactate solution, dibasic sodium phosphate, monobasic sodium phosphate, bicarbonate, Tris (Tris(hydroxymethyl)aminomethane), MOPS (3-(N-PATENT PARSON-58748 morpholino)propanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid), ADA (N-(2-acetamido)2- iminodiacetic acid), AMPSO (3-[(1,1-dimethy1-2-hydroxyethylamino]-2-propanesulfonic acid), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, Bicine (N,N-bis(2- hydroxyethylglycine), Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) , CAPSO (3-(cyclohexylamino)-2-hydroxy-1- propanesulfonic acid), CHES (2-(N-cyclohexylamino)ethanesulfonic acid), DIPSO (3-[N,N- bis(2-hydroxyethylamino]-2-hydroxy-propanesulfonic acid), HEPPS (N-(2- hydroxyethylpiperazine)-N′-(3-propanesulfonic acid), HEPPSO (N-(2-hydroxyethyl)piperazine- N′-(2-hydroxypropanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), triethanolamine, imidazole, glycine, ethanolamine, phosphate, MOPSO (3-(N-morpholino)-2- hydroxypropanesulfonic acid), PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid), POPSO (piperazine-N,N′-bis(2-hydroxypropaneulfonic acid), TAPS (N-tris[hydroxymethyl)methyl-3- aminopropanesulfonic acid), TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy- propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), tricine (N-tris(hydroxymethyl)methylglycine), 2-amino-2-methyl-1,3-propanediol, and 2-amino-2- methyl-1-propanol); capsule lubricants (see tablet and capsule lubricants); chelating agents (edetate disodium, ethylenediaminetetraacetic acid and salts); coating agents (sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcystalline wax, zein); colorants (caramel, red, yellow, black or blends, ferric oxide); complexing agents (ethylenediaminetetraacetic acid and salts (EDTA), gentisic acid ethanolamide, oxyquinoline sulfate); desiccants (calcium chloride, calcium sulfate, silicon dioxide); emulsifying and / or solubilizing agents (acacia, cholesterol, diethanolamine (adjunct), glyceryl monostearate, lanolin alcohols, lecithin, mono- and di-glycerides, monoethanolamine (adjunct), oleic acid (adjunct), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitanPATENT PARSON-58748 monolaurate, soritan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, triethanolamine, emulsifying wax); filtering aids (powdered cellulose, purified siliceous earth); flavors and perfumes (anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, orange flower oil, peppermint, peppermint oil, peppermint spirit, rose oil, stronger rose water, thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin); glidants and / or anticaking agents (calcium silicate, magnesium silicate, colloidal silicon dioxide, talc); humectants (glycerin, hexylene glycol, propylene glycol, sorbitol); plasticizers (castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono- and di-acetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin, triethyl citrate); polymers (e.g., cellulose acetate, alkyl celluloses, hydroxyalkylcelluloses, acrylic polymers and copolymers); solvents (acetone, alcohol, diluted alcohol, amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, methyl alcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanut oil, polyethylene glycol, propylene carbonate, propylene glycol, sesame oil, water for injection, sterile water for injection, sterile water for irrigation, purified water); sorbents (powdered cellulose, charcoal, purified siliceous earth); carbon dioxide sorbents (barium hydroxide lime, soda lime); stiffening agents (hydrogenated castor oil, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat, paraffin, polyethylene excipient, stearyl alcohol, emulsifying wax, white wax, yellow wax); suspending and / or viscosity-increasing agents (acacia, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, magma bentonite, carbomer 934p, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethycellulose sodium 12, carrageenan, microcrystalline and carboxymethylcellulose sodium cellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, methylcellulose, pectin, polyethylene oxide, polyvinyl alcohol, povidone, propylene glycol alginate, silicon dioxide, colloidal silicon dioxide, sodium alginate, tragacanth, xanthan gum); sweetening agents (aspartame, dextrates, dextrose, excipient dextrose, fructose, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol, solution sorbitol, sucrose, compressible sugar, confectioner’s sugar, syrup); tablet binders (acacia, alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide, povidone, pregelatinized starch, syrup); tablet and / orPATENT PARSON-58748 capsule diluents (calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, confectioner's sugar); tablet disintegrants (alginic acid, microcrystalline cellulose, croscarmellose sodium, risperidone, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch); tablet and / or capsule lubricants (calcium stearate, glyceryl behenate, magnesium stearate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, purified stearic acid, talc, hydrogenated vegetable oil, zinc stearate); tonicity agents (dextrose, glycerin, mannitol, potassium chloride, sodium chloride); vehicles (flavored and / or sweetened) (aromatic elixir, compound benzaldehyde elixir, iso-alcoholic elixir, peppermint water, sorbitol solution, syrup, tolu balsam syrup); vehicles (oleaginous) (almond oil, corn oil, cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, mineral oil, light mineral oil, myristic alcohol, octyldodecanol, olive oil, peanut oil, persic oil, sesame oil, soybean oil, squalane); vehicles (solid carrier) (sugar spheres); vehicles (sterile) (bacteriostatic water for injection, bacteriostatic sodium chloride for injection); viscosity-increasing agents (see suspending agent); water-repelling agent (cyclomethicone, dimethicone, simethicone); and wetting and / or solubilizing agent (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamer, polyoxyl 35 castor oil, polyoxyl 40, hydrogenated castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether, polyoxyl 20, cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sorbitan monolaureate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, tyloxapol). This list is not meant to be exclusive, but instead merely representative of the classes of excipients and the particular excipients which may be used in oral dosage forms of the present invention. Some compounds listed above can be included in more than one category depending on factors such as the quantity of the compound used in the pharmaceutical composition, the physical form of the pharmaceutical composition, the particular pentosan polysulfate salt or intestinal penetration agent included in the pharmaceutical composition or the intended method of administration of the pharmaceutical composition. Other excipients are known in the art and can be used if they do not interact negatively with either the active agent or the intestinal penetration agent.PATENT PARSON-58748

[0297] Other penetration agents are known in the art. For example, and not by way of limitation, pharmaceutically acceptable salts of penetration agents described above in non- ionized form can be employed. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a penetration agent in ionized form. Suitable anions include chloride, bromide, iodide, carbonate, nitrate, sulfate, bisulfate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, formate, acetate, adipate, butyrate, propionate, succinate, glycolate, gluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, mesylate, 4′-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, ethanedisulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, p-toluenesulfonate, sulfanilate, cyclohexylaminosulfonate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfonate, glucoheptanoate, glycerophosphonate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, nicotinate, isonicotinate, 1- naphthalenesulfonate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfurate, 2- phenylpropionate, picrate, pivalate, thiocyanate, mesylate, undecanoate, stearate, algenate, β- hydroxybutyrate, salicylate, galactarate, galacturonate, caprylate, isobutyrate, malonate, suberate, sebacate, chlorobenzoate, methylbenzoa+te, dinitrobenzoate, phthalate, phenylacetate, isethionate, lactobionate, p-aminobenzoate, sulfamate, diethylacetate, pimelate, aminosulfonate, acrylate, γ-hydroxybutyrate, and methoxybenzoate. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on an agent. Suitable cations include sodium, aluminum, lithium, calcium, magnesium, zinc, ammonium, caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N- ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine, ethanolamine, diethanolamine, N-methylglucamine, and tris(hydroxymethyl)aminomethane. Potassium as a counterion is avoided in some applications because of its association with the etiology of interstitial cystitis and other lower urinary tract dysfunctions, but may be used in applications in which the intention is to treat diseases and conditions not exacerbated by the administration of potassium or in which administration is performed by a route in which the pentosan polysulfate salt does not significantly reach the urinary tract.

[0298] Other intestinal penetration agents that can be used in compositions or methods according to the present invention typically are compounds including both hydrophobic groups,PATENT PARSON-58748 such as phenyl groups, naphthyl groups, cyclohexyl groups, and long-chain aliphatic groups, and hydrophilic groups, such as carboxylic acid groups, carboxylic acid ester groups, amide groups, amino groups, and carbonyl groups. Multiple hydrophobic groups, such as multiple phenyl groups, can be included in intestinal penetration agents used in compositions or methods according to the present invention.

[0299] Intestinal penetration agents such as those described above, and other intestinal penetration agents known in the art or constructed according to the principles described above, can be optionally substituted with one or more groups that do not substantially affect the ability of the intestinal penetration agent to enhance the absorption or bioavailability of sodium pentosan polysulfate, another pentosan polysulfate salt, or a glycosaminoglycan when administered orally. Definitions for a number of common groups that can be used as optional substituents are provided below; however, the omission of any group from these definitions cannot be taken to mean that such a group cannot be used as an optional substituent as long as the chemical and pharmacological requirements for an optional substituent are satisfied within the context of the present invention.

[0300] As used herein, the term “optionally substituted” indicates that the particular group or groups referred to as optionally substituted may have no non-hydrogen substituents, or the group or groups may have one or more non-hydrogen substituents consistent with the chemistry and pharmacological activity of the resulting molecule. If not otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present on the unsubstituted form of the group being described; fewer than the maximum number of such substituents may be present. Where an optional substituent is attached via a double bond, such as a carbonyl oxygen (C=O), the group takes up two available valences on the carbon atom to which the optional substituent is attached, so the total number of substituents that may be included is reduced according to the number of available valences. As used herein, the term “substituted,” whether used as part of “optionally substituted” or otherwise, when used to modify a specific group, moiety, or radical, means that one or more hydrogen atoms are, each, independently of each other, replaced with the same or different substituent or substituents.

[0301] Substituent groups useful for substituting saturated carbon atoms in the specified group, moiety, or radical include, but are not limited to, —Za, =O, —OZb, —SZb, =S-, —NZcZc, =NZb, =N—OZb, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, =N2, —N3, —PATENT PARSON-58748 S(O)2Zb, —S(O)2NZb, —S(O2)O-, —S(O2)OZb, —OS(O2)OZb, —OS(O2)O-, —OS(O2)OZb, — P(O)(O-)2, —P(O)(OZb)(O-), —P(O)(OZb)(OZb), —C(O)Zb, —C(S)Zb, —C(NZb)Zb, —C(O)O-, —C(O)OZb, —C(S)OZb, —C(O)NZcZc, —C(NZb)NZcZc, —OC(O)Zb, —OC(S)Zb, —OC(O)O-, —OC(O)OZb, —OC(S)OZb, —NZbC(O)Zb, —NZbC(S)Zb, —NZbC(O)O-, —NZbC(O)OZb, — NZbC(S)OZb, —NZbC(O)NZcZc, —NZbC(NZb)Zb, —NZbC(NZb)NZcZc, wherein Zais selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each Zbis independently hydrogen or Za; and each Zcis independently Zbor, alternatively, the two Zc’s may be taken together with the nitrogen atom to which they are bonded to form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring structure which may optionally include from 1 to 4 of the same or different heteroatoms selected from the group consisting of N, O, and S. As specific examples, —NZcZcis meant to include —NH2, —NH- alkyl, —N-pyrrolidinyl, and —N-morpholinyl, but is not limited to those specific alternatives and includes other alternatives known in the art. Similarly, as another specific example, a substituted alkyl is meant to include —alkylene-O-alkyl, —alkylene-heteroaryl, —alkylene- cycloheteroaryl, —alkylene-C(O)OZb, —alkylene-C(O)NZbZb, and —CH2—CH2—C(O)-CH3, but is not limited to those specific alternatives and includes other alternatives known in the art. The one or more substituent groups, together with the atoms to which they are bonded, may form a cyclic ring, including, but not limited to, cycloalkyl and cycloheteroalkyl.

[0302] Similarly, substituent groups useful for substituting unsaturated carbon atoms in the specified group, moiety, or radical include, but are not limited to, —Za, halo, —O-, —OZb, — SZb, —S-, —NZcZc, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, — S(O)2Zb, —S(O2)O-, —S(O2)OZb, —OS(O2)OZb, —OS(O2)O-, —P(O)(O-)2, —P(O)(OZb)(O-), —P(O)(OZb)(OZb), —C(O)Zb, —C(S)Zb, —C(NZb)Zb, —C(O)O-, —C(O)OZb, —C(S)OZb, — C(O)NZcZc, —C(NZb)NZcZc, —OC(O)Zb, —OC(S)Zb, —OC(O)O-, —OC(O)OZb, — OC(S)OZb, —NZbC(O)OZb, —NZbC(S)OZb, —NZbC(O)NZcZc, —NZbC(NZb)Zb, and — NZbC(NZb)NZcZc, wherein Za, Zb, and Zcare as defined above.

[0303] Similarly, substituent groups useful for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, —Za, halo, —O-, —OZb, —SZb, —S- , —NZcZc, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —S(O)2Zb, —S(O2)O-, —S(O2)OZb, —OS(O2)OZb, —OS(O2)O-, —P(O)(O-)2, —P(O)(OZb)(O-), —P(O)(OZb)(OZb), — C(O)Zb, —C(S)Zb, —C(NZb)Zb, —C(O)OZb, —C(S)OZb, —C(O)NZcZc, —C(NZb)NZcZc, —PATENT PARSON-58748 OC(O)Zb, —OC(S)Zb, —OC(O)OZb, —OC(S)OZb, —NZbC(O)Zb, —NZbC(S)Zb, — NZbC(O)OZb, —NZbC(S)OZb, —NZbC(O)NZcZc, —NZbC(NZb)Zb, and —NZbC(NZb)NZcZc, wherein Za, Zb, and Zcare as defined above.

[0304] The compounds described herein, in particular the intestinal penetration agents, may contain one or more chiral centers and / or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers such as E and Z), enantiomers or diastereomers. The invention includes each of the isolated stereoisomeric forms (such as the enantiomerically pure isomers, the E and Z isomers, and other stereoisomeric forms) as well as mixtures of stereoisomers in varying degrees of chiral purity or percentage of E and Z, including racemic mixtures, mixtures of diastereomers, and mixtures of E and Z isomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the disclosed compounds, in particular the intestinal penetration agents, including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The invention includes each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures, for such compounds. It also encompasses the various diastereomers. Other structures may appear to depict a specific isomer, but that is merely for convenience, and is not intended to limit the invention to the depicted olefin isomer. When the chemical name does not specify the isomeric form of the compound, it denotes any one of the possible isomeric forms or mixtures of those isomeric forms of the compound.

[0305] The intestinal penetration agents may also exist in several tautomeric forms, and the depiction herein of one tautomer is for convenience only, and is also understood to encompass other tautomers of the form shown. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the compounds described herein, in particular the intestinal penetration agents. The term “tautomer” as used herein refers to isomers that change into one another with great ease so that they can exist together in equilibrium. For example, ketone and enol are two tautomeric forms of one compound.PATENT PARSON-58748

[0306] In addition to the substituents described above, alkyl, alkenyl and alkynyl groups can alternatively or in addition be substituted by C1-C8acyl, C2-C8heteroacyl, C6-C10aryl, C3-C8cycloalkyl, C3-C8 heterocyclyl, or C5-C10 heteroaryl, each of which can be optionally substituted. Also, in addition, when two groups capable of forming a ring having 5 to 8 ring members are present on the same or adjacent atoms, the two groups can optionally be taken together with the atom or atoms in the substituent groups to which they are attached to form such a ring. Still other substitutions can be made, including ring-forming substitutions.

[0307] The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (See e.g., Fingl et al., in The Pharmacological Basis of Therapeutics, 1975, Ch. 1, p. 1). It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity, or to organ dysfunctions, based on clinical observation or test results for relevant markers. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administered dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient, as well as factors such as pharmacokinetic factors such as liver and kidney function.

[0308] In methods according to the present invention, when the pentosan polysulfate salt is sodium pentosan polysulfate, the sodium pentosan polysulfate is typically administered in a dosage form that is palatable and acceptable to the patient when administered orally. Many suitable dosage forms are known in the art. Details with respect to the composition and use of pharmaceutical compositions and pharmaceutically acceptable carriers for use in methods according to the present invention are described below.

[0309] For example, in general, dosage forms for the oral administration of the sodium pentosan polysulfate can be in the form of tablets, dragees, capsules, or solutions, although, for reasons of palatability and acceptability, solid dosage forms are typically preferred. Suitable solid dosage forms for the oral administration of pentosan polysulfate salts can be prepared by combining the pentosan polysulfate, the cationic counterion (typically sodium, as describedPATENT PARSON-58748 above, but alternatively another cation such as calcium), the intestinal penetration agent, if present, and any other ingredients such as stabilizers, preservatives, or excipients, adding other inert ingredients as necessary to provide the correct volume of the mixture, and grinding the mixture to homogeneity. The resulting mixture can be pressed into tablets or dragees or incorporated into capsules, as described further below.

[0310] Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Other suitable fillers, carriers, and excipients are described above.

[0311] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures . Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses, different intestinal penetration agents, or different concentrations of penetration agents or sodium pentosan polysulfate, other salts of pentosan polysulfate, or glycosaminoglycan as described below.

[0312] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0313] In one particularly preferred dosage form for administration, sodium pentosan polysulfate and the intestinal penetration agent SNAC are incorporated into soft gelatin capsules. However, other dosage forms can be prepared using either other salts of pentosan polysulfate or a glycosaminoglycans and other intestinal penetration agents.PATENT PARSON-58748

[0314] Other suitable dosage forms are known in the art.

[0315] Methods according to the present invention for the treatment of Alzheimer’s disease can be combined with other methods for the treatment of Alzheimer’s disease known in the art. These methods include, but are not necessarily limited to, administration of a therapeutically effective quantity of a therapeutic agent selected from the group consisting of tacrine, rivastigmine, galantamine, donepezil, CPHPC ((R)-1-{6-[(R)-2-carboxypyrrolidin-1-yl]- 6-oxohexanoyl}pyrrolidine-2-carboxylic acid), lecanemab, and memantine. These methods can alternatively further include the administration of a therapeutically effective quantity of an antidepressant as described herein.

[0316] Additionally, compositions according to the present invention can further comprise, in addition to a glycosaminoglycan as described above, one or more agents selected from the group consisting of tacrine, rivastigmine, galantamine, donepezil, CPHPC ((R)-1-{6- [(R)-2-carboxypyrrolidin-1-yl]-6-oxohexanoyl}pyrrolidine-2-carboxylic acid), lecanemab, memantine, and an antidepressant. Compositions according to the present invention are described below.

[0317] One category of antidepressants is the selective serotonin reuptake inhibitors (SSRIs). Selective serotonin reuptake inhibitors include, but are not necessarily limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, zimelidine, cericlamine, and panuramine.

[0318] Another category of antidepressants is the serotonin-norepinephrine reuptake inhibitors. Serotonin-norepinephrine reuptake inhibitors include, but are not necessarily limited to, venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran.

[0319] Yet another category of antidepressants is the serotonin modulators. Serotonin modulators include, but are not necessarily limited to, vortioxetine and vilazodone.

[0320] Still another category of antidepressants is the serotonin antagonists and reuptake inhibitors. Serotonin antagonists and reuptake inhibitors include, but are not necessarily limited to, etoperidone, lorpiprazole, lubazodone, mepiprazole, nefazodone, and trazodone.

[0321] Yet another category of antidepressants is the norepinephrine reuptake inhibitors. Norepinephrine reuptake inhibitors include, but are not necessarily limited to, amedalin, CP- 39,332 (1,2,3,4-tetrahydro-N-methyl-4-phenyl-2-naphthalenamine), daledalin, edivoxetine,PATENT PARSON-58748 esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, viloxazine, buproprion, ciclazindole, manifaxine, maprotiline, radafaxine, tapentadol, and teniloxazine.

[0322] Still another category of antidepressants is the tricyclic antidepressants. Tricyclic antidepressants include, but are not necessarily limited to, amitriptyline, butriptyline, clomipramine, desipramine, dolesupin, doxepin, imipramine, iprindole, lofepramine, nortriptyline, protriptyline, and trimipramine.

[0323] Yet another category of antidepressants is the tetracyclic antidepressants. Tetracyclic antidepressants include, but are not necessarily limited to, mianserin, mirtazapine, pirlindole, setiptiline, aptazapine, esmirtazapine, metralindole, and oxprotiline.

[0324] Still another category of antidepressants is the monoamine oxidase inhibitors. Monoamine oxidase inhibitors include, but are not necessarily limited to, isocarboxazid, nialamide, phenelzine, hydracarbazide, tranylcypromine, bifemelane, moclobemide, toloxatone, rasagline, selegiline, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, and minaprine.

[0325] Yet another category of antidepressants is the atypical antidepressants. Atypical antipsychotics include, but are not necessarily limited to, amisulpride, lurasidone, and quetiapine.

[0326] Still another category of antidepressants is the antidepressants that act by one or more other mechanisms. Antidepressants that act by one or more other mechanisms include, but are not necessarily limited to, agomelatine, tandospirone, α-methyltryptamine, etryptamine, indeloxazine, medifoxamine, nomifensine, oxaflozane, and pivagabine.

[0327] As stated above, although a particularly preferred glycosaminoglycan / sulfated polysaccharide for use in methods and compositions according to the present invention is pentosan polysulfate, particularly its sodium salt sodium pentosan polysulfate, or an acidic glycosaminoglycans can be used in methods and compositions according to the present invention. Suitable glycosaminoglycans include, but are not limited to, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and keratan sulfate.

[0328] Chondroitin sulfate is comprised of a chain of alternating sugars, N- acetylglucosamine and glucuronic acid. There are several types of chondroitin sulfate, depending on the site or sites of sulfation of the N-acetylglucosamine sugar or the site of sulfation of the glucuronic acid. In chondroitin sulfate A, the site of sulfation is carbon 4 of the N-acetylglucosamine sugar. In chondroitin sulfate C, the site of sulfation is carbon 6 of the N-PATENT PARSON-58748 acetylglucosamine sugar. In chondroitin sulfate D, the sites of sulfation are carbon 2 of the glucuronic acid and carbon 6 of the N-acetylglucosamine sugar. In chondroitin E, the sites of sulfation are carbons 4 and 6 of the N-acetylglucosamine sugar. The chemical structure of one unit in a chondroitin sulfate chain is shown below: ,wherein, in chondroitin-4-sulfate, R1 is H, R2 is SO3H, and R3 is H; and, in chondroitin-6- sulfate, R1 is SO3H, R2 is H, and R3 is H.

[0329] The size of chondroitin sulfate macromolecules varies; for chondroitin sulfate obtained from marine animals such as sharks, the molecular weight ranges up to 70 kDa, while for chondroitin sulfate obtained from terrestrial animals, the molecular weight is typically below 45 kDa.

[0330] Dermatan sulfate is another glycosaminoglycan that is similar to chondroitin sulfate. Dermatan sulfate is a linear polymer of repeating disaccharide units of N- acetylglucosamine and iduronic acid. The repeating disaccharide units are sulfated at a variety of positions. The repeating unit of dermatan sulfate is shown below:.

[0331] Heparan sulfate is another glycosaminoglycan that can be used in methods and processes according to the present invention and that is closely related in structure to heparin. Heparan sulfate consists of a variably sulfated repeating disaccharide unit. The most common disaccharide unit within heparan sulfate is composed of a glucuronic acid monomer linked to anPATENT PARSON-58748 N-acetylglucosamine monomer. Heparan sulfate contains rare disaccharides with 3-O-sulfated glucosamines or with a free amine group. Under physiological conditions the ester-linked or amide-linked sulfate groups are deprotonated and are associated with positively charged counterions, typically sodium.

[0332] Heparin is another glycosaminoglycan that can be used in methods and processes according to the present invention. Heparin exists in a variety of forms characterized by different degrees of sulfation. Typically, heparin has a molecular weight of from about 2 kDa to about 40 kDa. Heparin and heparan sulfate are both characterized by repeating units of disaccharides containing a uronic acid (glucuronic acid or iduronic acid) and glucosamine, which is either N-sulfated or N-acetylated. The sugar residues can be further O-sulfated at the C-6 and C-3 positions and the C-2 position of the uronic acid. There are at least 32 potential unique disaccharide units in this class of compounds. Five examples of sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate; (2) 2-deoxy-2-sulfamino-α-D-glucose 6-sulfate; (3) β-D- glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose, and (5) α-L-iduronic acid. Heparin is measured by its specific anticoagulation activity in units. As used herein, the term “units” refers to specific activity in International Units (IU) and / or United States Pharmacopoeia (USP) units. As used herein, the term “USP unit” refers to the quantity of heparin that prevents 1.0 mL of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 mL of 1% CaCl2at 20° C when compared to a USP reference standard (defined as units / mL). As used herein, the term “International Unit” or “IU” refers to the quantity of heparin that is active in assays as established by the Fifth International standard for Unfractionated Heparin (WHO-5) (defined as International Units / ml) (Linhardt, R. J. & Gunay, N. S. (1999) Semin Thromb Hemost 25, 5-16.). Typically, the molecular weight of heparin ranges from about 2 kDa to about 40 kDa. As used herein, the term “low-molecular-weight heparin” refers to a lower molecular weight species of heparin with a molecular weight of from about 2 kDa to about 8 kDa. As used herein, the term “high-molecular-weight heparin” refers to a higher molecular weight species of heparin with a molecular weight of from about 8 kDa to about 40 kDa. Low-molecular-weight heparins can be prepared by enzymatic or chemical controlled hydrolysis of unfractionated heparin and have a chemical structure that is very similar to that of unfractionated heparin except for some changes that may have been introduced due to the enzymatic or chemical treatment. In some alternatives, low-molecular-weight heparin can be isolated from bulk heparin. Because heparin has aPATENT PARSON-58748 negative charge due to the presence of sulfate groups and / or carboxylic acid groups in the molecules of heparin, heparin is administered in the form of a salt, with an appropriate cation to neutralize the negative charges on the sulfate and carboxylic groups. Typically, the cation is sodium, although other physiologically tolerable cations can be used, including inorganic cations such as, but not necessarily limited to, lithium, rubidium, cesium, magnesium, calcium, strontium, barium, aluminum, or manganese, as well as organic cations prepared from physiologically compatible organic bases such as, but not necessarily limited to, of heparin trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2- hydroxyethyl)amine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine, can be used.

[0333] Hyaluronic acid, also known as hyaluronan, is an anionic, nonsulfated glycosaminoglycan. It is a polymer of disaccharides; the disaccharides comprising hyaluronic acid are D-glucuronic acid and N-acetyl-D-glucosamine that are linked by alternating β-(1→4) and β-(1→3) glycosidic bonds. The general structure of hyaluronic acid is shown below:.

[0334] Polymers of hyaluronic acid can range from about 5×103daltons to about 20×106daltons in molecular weight. The average molecular weight of hyaluronic acid in human synovial fluid is from about 3×106daltons to about 7×106daltons. As for heparin, hyaluronic acid is administered in the form of a salt, with an appropriate cation to neutralize the negative charges on the carboxylic groups. Typically, the cation is sodium, although other physiologically tolerable cations can be used, including inorganic cations such as, but not necessarily limited to, lithium, rubidium, cesium, magnesium, calcium, strontium, barium, aluminum, or manganese, as well as organic cations prepared from physiologically compatible organic bases such as, but notPATENT PARSON-58748 necessarily limited to, trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, dibenzylpiperidine, N-benzyl-β- phenethylamine, dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine, N- methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine, can be used.

[0335] Keratan sulfate is another linear polymer that consists of a repeating disaccharide unit. The basic repeating disaccharide unit in keratan sulfate is -3Galβ1-4GlcNAc6Sβ1; the two monosaccharide units are galactose and N-acetylglucosamine. These monosaccharides can be sulfated at position 6 of either or both of the galactose or the N-acetylglucosamine monosaccharides. In some keratan sulfate molecules, mannose is present, and some disaccharides can be fucosylated. Additionally, in some keratan sulfate molecules, the end of the chain can be capped with N-acetylneuraminic acid.

[0336] The general structure of keratan sulfate is shown below:.

[0337] Although methods and compositions according to the present invention are generally described with respect to treatment of Alzheimer’s disease, such methods and compositions can also be used to treat other neurodegenerative diseases such as, but not necessarily limited to, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and multiple sclerosis.

[0338] When methods according to the present invention are used to treat a neurodegenerative disease, other than Alzheimer’s disease, including, but not necessarily limited to, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and multiplePATENT PARSON-58748 sclerosis, the methods can further comprise administration of a therapeutically effective quantity of a therapeutic agent to treat Parkinson’s disease, amyotrophic lateral sclerosis, or multiple sclerosis.

[0339] When compositions according to the present invention are used to treat a neurodegenerative disease, including, but not necessarily limited to, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and multiple sclerosis, the compositions can further comprise, in addition to a glycosaminoglycan as described above, one or more agents for the treatment of the neurodegenerative disease such as Parkinson’s disease, amyotrophic lateral sclerosis, or multiple sclerosis.

[0340] Agents for the treatment of Parkinson’s disease include, but are not necessarily limited to: levodopa; monoamine oxidase inhibitors selected from the group consisting of isocarboxazid, nialamide, phenelzine, hydracarbazide, tranylcypromine, bifemelane, moclobemide, toloxatone, rasagline, selegiline, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, and minaprine; and dopamine agonists selected from the group consisting of bromocriptine, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, cabergoline, ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine, lisuride, propylnorapomorphine, roxindole, sumanirole, and fenaldopam.

[0341] Agents for the treatment of amyotrophic lateral sclerosis include, but are not necessarily limited to riluzole, edaravone, sodium phenylbutyrate / taurursodiol, toferse, gabapentin, and pregabalin.

[0342] Agents for the treatment of multiple sclerosis include, but are not necessarily limited to, methylprednisolone, interferon beta-1a, interferon beta-1b, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, natalizumab, mitoxantrone, ocrelizumab, siponimod, cladribine, ozanimod, and ponesimod.

[0343] Accordingly, one aspect of the present invention is a method for treating a neurodegenerative disease comprising the step of administering a therapeutically effective quantity of a glycosaminoglycan / sulfated polysaccharide to a patient with a neurodegenerative disease or at risk of developing a neurodegenerative disease to treat or prevent the neurodegenerative disease.PATENT PARSON-58748

[0344] Typically, the glycosaminoglycan / sulfated polysaccharide is a salt of pentosan polysulfate. Preferably, the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate and calcium pentosan polysulfate. More preferably, the salt of pentosan polysulfate is sodium pentosan polysulfate. Alternatively, the salt of pentosan polysulfate can be, but is not limited to, a salt of pentosan polysulfate selected from the group consisting of lithium pentosan polysulfate, rubidium pentosan polysulfate, cesium pentosan polysulfate, magnesium pentosan polysulfate, strontium pentosan polysulfate, and barium pentosan polysulfate. In another alternative, the glycosaminoglycan is selected from the group consisting of chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and keratan sulfate.

[0345] Typically, the neurodegenerative disease is Alzheimer’s disease. Alternatively, the neurodegenerative disease can be selected from the group consisting of Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis.

[0346] Typically, the method further comprises the step of administering a pharmacologically effective quantity of a pharmacologically compatible intestinal penetration agent.

[0347] Typically, the glycosaminoglycan / sulfated polysaccharide, which, as stated above, is preferably sodium pentosan polysulfate, is administered orally. Preferably, when the glycosaminoglycan / sulfated polysaccharide is administered orally, the glycosaminoglycan / sulfated polysaccharide is administered with a pharmacologically effective quantity of a pharmacologically compatible intestinal penetration agent.

[0348] In other alternatives of a method according to the present invention, the glycosaminoglycan / sulfated polysaccharide can be administered subcutaneously or intravenously. In these alternatives, administration of an intestinal penetration agent is not required.

[0349] Typically, when the glycosaminoglycan / sulfated polysaccharide is sodium pentosan polysulfate, the sodium pentosan polysulfate is administered orally, and the sodium pentosan polysulfate is administered with an intestinal penetration agent, the quantity of sodium pentosan polysulfate originally administered is from about 50 mg to about 300 mg per unit dose. Preferably, the quantity of sodium pentosan polysulfate originally administered is from about 50 mg to about 200 mg per unit dose.PATENT PARSON-58748

[0350] Typically, when the glycosaminoglycan / sulfated polysaccharide is sodium pentosan polysulfate, the therapeutically effective quantity of sodium pentosan polysulfate actually absorbed is from about 2.5 mg to about 20 mg per unit dose. Preferably, the therapeutically effective quantity of sodium pentosan polysulfate actually absorbed is from about 10 mg to about 20 mg per unit dose.

[0351] Typically, when a pharmaceutical composition according to the present invention comprises a pentosan polysulfate salt, preferably sodium pentosan polysulfate, the quantity of intestinal penetration agent is from about 50 mg to about 800 mg per unit dose. Preferably, the quantity of intestinal penetration agent is from about 100 mg to about 500 mg per unit dose. More preferably, the quantity of intestinal penetration agent is from about 150 mg to about 400 mg per unit dose.

[0352] Typically, the ratio, by weight, of the intestinal penetration agent to the pentosan polysulfate salt, in particular, sodium pentosan polysulfate, is from about 0.167:1 to about 8:1. Preferably, the ratio, by weight, of the intestinal penetration agent to the pentosan polysulfate salt, in particular, sodium pentosan polysulfate, is from about 0.50:1 to about 3:1. More preferably, the ratio, by weight, of the intestinal penetration agent to the pentosan polysulfate salt, in particular, sodium pentosan polysulfate, is from about 0.75:1 to about 2:1.

[0353] When the pentosan polysulfate salt is sodium pentosan polysulfate, typically, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 5%. Preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 10%. More preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 20%. Still more preferably, the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least 30%.

[0354] When the pentosan polysulfate salt is sodium pentosan polysulfate, typically, the administration of the sodium pentosan polysulfate provides a peak plasma concentration of sodium pentosan polysulfate from about 0.1 hour to about 3 hours after administration. Preferably, the administration of the sodium pentosan polysulfate provides a peak plasma concentration of sodium pentosan polysulfate from about 0.2 hour to about 0.6 hour after administration. In another alternative, the administration of the sodium pentosan polysulfatePATENT PARSON-58748 provides a first peak plasma concentration of sodium pentosan polysulfate at about 0.3 hours after the administration of the composition and a second peak plasma concentration of sodium pentosan polysulfate at about 1.1 hours after administration.

[0355] Typically, the administration of the pentosan polysulfate salt, preferably sodium pentosan polysulfate, reduces permeability of the mucus-containing layer of arteries of the central nervous system to amino-containing cations and thus stabilizes the blood-brain barrier, reducing penetration of the blood-brain barrier by amino-containing cations such as, but not necessarily limited to, protamine sulfate, 1-methyladenine, 1-methylguanine, 5-methylcytosine, N2,N2-dimethylguanosine, and L-tryptophan.

[0356] In a 1stalternative for the intestinal penetration agent, the intestinal penetration agent is selected from the group consisting of N-benzoyl-α-amino acids of Formula (II) and salts, analogues, or bioisosteres thereof, wherein the α-amino acid is selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tyrosine, aspartic acid, glutamic acid, lysine, ornithine, arginine, and serine, wherein X is selected from the group consisting of C(O) and SO2, and wherein Y is selected from the group consisting of phenyl and cyclohexyl (Alternative (1)).

[0357] In a 2ndalternative for the intestinal penetration agent, the intestinal penetration agent is selected from the group consisting of derivatized leucines of Formula (III) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cycloheptyl, cyclopentyl, cyclopropyl, 2-carboxycyclohexyl, benzoyl, 3-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4- nitrophenyl, and (CH2)2cyclohexyl (Alternative (2)).

[0358] In a 3rdalternative for the intestinal penetration agent, the intestinal penetration agent is selected from the group consisting of N-cyclohexanoylamino acids of Formula (IV) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl, methylcyclohexyl, (CH2)2cyclohexyl, phenyl, and 2- hydroxyphenyl (Alternative (3)).

[0359] In a 4thalternative for the intestinal penetration agent, the intestinal penetration agent is a derivatized phenylglycine of Formula (V) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, cyclopentyl, cyclohe...

Claims

PATENT PARSON-58748 What is claimed is:

1. A method for treating a neurodegenerative disease comprising the step of administering a therapeutically effective quantity of a glycosaminoglycan / sulfated polysaccharide to a patient with a neurodegenerative disease or at risk of developing a neurodegenerative disease to treat or prevent the neurodegenerative disease.

2. The method of claim 1 wherein the glycosaminoglycan / sulfated polysaccharide is a salt of pentosan polysulfate.

3. The method of claim 2 wherein the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate, calcium pentosan polysulfate, lithium pentosan polysulfate, rubidium pentosan polysulfate, cesium pentosan polysulfate, magnesium pentosan polysulfate, strontium pentosan polysulfate, and barium pentosan polysulfate.

4. The method of claim 3 wherein the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate and calcium pentosan polysulfate.

5. The method of claim 4 wherein the salt of pentosan polysulfate is sodium pentosan polysulfate.

6. The method of claim 1 wherein the glycosaminoglycan is selected from the group consisting of chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and keratan sulfate.

7. The method of claim 1 wherein the neurodegenerative disease is Alzheimer’s disease.

8. The method of claim 1 wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis.

9. The method of claim 1 wherein the method further comprises the step of administering a pharmacologically effective quantity of a pharmacologically compatible intestinal penetration agent.

10. The method of claim 1 wherein the glycosaminoglycan / sulfated polysaccharide is administered orally.

11. The method of claim 1 wherein the glycosaminoglycan / sulfated polysaccharide is administered by a route selected from the group consisting of subcutaneously and intravenously.PATENT PARSON-58748 12. The method of claim 10 further comprising administering an intestinal penetration agent.

13. The method of claim 12 wherein the agent is sodium pentosan polysulfate.

14. The method of claim 13 wherein the quantity of sodium pentosan polysulfate originally administered is from about 50 mg to about 300 mg per unit dose.

15. The method of claim 14 wherein the quantity of sodium pentosan polysulfate originally administered is from about 50 mg to about 200 mg per unit dose.

16. The method of claim 13 wherein the therapeutically effective quantity of sodium pentosan polysulfate actually absorbed is from about 2.5 mg to about 20 mg per unit dose.

17. The method of claim 16 wherein the therapeutically effective quantity of sodium pentosan polysulfate actually absorbed is from about 10 mg to about 20 mg per unit dose.

18. The method of claim 13 wherein the quantity of intestinal penetration agent is from about 1 mg to about 2000 mg per unit dose.

19. The method of claim 18 wherein the quantity of intestinal penetration agent is from about 1 mg to about 800 mg per unit dose.

20. The method of claim 19 wherein the quantity of intestinal penetration agent is from about 50 mg to about 700 mg per unit dose.

21. The method of claim 20 wherein the quantity of intestinal penetration agent is from about 70 mg to about 700 mg per unit dose.

22. The method of claim 21 wherein the quantity of intestinal penetration agent is from about 100 mg to about 600 mg per unit dose.

23. The method of claim 22 wherein the quantity of intestinal penetration agent is from about 150 mg to about 400 mg per unit dose.

24. The method of claim 13 wherein the ratio, by weight, of the intestinal penetration agent to the sodium pentosan polysulfate is from about 0.167:1 to about 8:

1.

25. The method of claim 24 wherein the ratio, by weight, of the intestinal penetration agent to the sodium pentosan polysulfate is from about 0.50:1 to about 3:

1.

26. The method of claim 25 wherein the ratio, by weight, of the intestinal penetration agent to the sodium pentosan polysulfate is from about 0.75:1 to about 2:1.PATENT PARSON-58748 27. The method of claim 13 wherein the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 5%.

28. The method of claim 27 wherein the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 10%.

29. The method of claim 28 wherein the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 20%.

30. The method of claim 29 wherein the quantity of intestinal penetration agent used is sufficient to increase the bioavailability of sodium pentosan polysulfate to at least about 30%.

31. The method of claim 13 wherein the administration of the sodium pentosan polysulfate provides a peak plasma concentration of sodium pentosan polysulfate from about 0.1 hour to about 3 hours after administration.

32. The method of claim 31 wherein the administration of the sodium pentosan polysulfate provides a peak plasma concentration of sodium pentosan polysulfate from about 0.2 hour to about 0.6 hour after administration.

33. The method of claim 13 wherein the administration of the sodium pentosan polysulfate provides a first peak plasma concentration of sodium pentosan polysulfate at about 0.3 hours after the administration of the composition and a second peak plasma concentration of sodium pentosan polysulfate at about 1.1 hours after administration.

34. The method of claim 13 wherein the intestinal penetration agent provides a peak plasma concentration at about 0.1 hour to about 8 hours after oral administration.

35. The method of claim 34 wherein the intestinal penetration agent provides a peak plasma concentration at about 0.1 hour to about 3 hours after oral administration.

36. The method of claim 13 wherein the intestinal penetration agent has a tmax of about 0.3 hour to about 1.5 hours after oral administration.

37. The method of claim 13 wherein the intestinal penetration agent has a tmaxof about 2 hours after oral administration.PATENT PARSON-58748 38. The method of claim 13 wherein the intestinal penetration agent has a tmax of about 1 hour after oral administration.

39. The method of claim 2 wherein the salt of pentosan polysulfate is administered orally and is administered twice daily or three times daily.

40. The method of claim 39 wherein the salt of pentosan polysulfate is sodium pentosan polysulfate.

41. The method of claim 2 wherein the salt of pentosan polysulfate is administered intravenously or subcutaneously and is administered once daily or twice daily.

42. The method of claim 41 wherein the salt of pentosan polysulfate is sodium pentosan polysulfate.

43. The method of claim 2 wherein the salt of pentosan polysulfate is administered intravenously or subcutaneously and is administered once daily, twice daily, or three times daily, and wherein a lower dose of the salt of pentosan polysulfate is administered.

44. The method of claim 43 wherein the salt of pentosan polysulfate is sodium pentosan polysulfate.

45. The method of claim 13 wherein the administration of the sodium pentosan polysulfate reduces permeability of the mucus-containing layer of arteries of the central nervous system to amino-containing cations and thus stabilizes the blood-brain barrier.

46. The method of claim 45 wherein the administration of the sodium pentosan polysulfate reduces penetration of the blood-brain barrier by an amino-containing cation selected from the group consisting of protamine sulfate, 1-methyladenine, 1- methylguanine, 5-methylcytosine, N2,N2-dimethylguanosine, and L-tryptophan.

47. The method of claim 13 wherein the intestinal penetration agent is selected from the group consisting of intestinal penetration agents of Alternatives (1)-(114) and derivatives or analogs thereof.

48. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of N-benzoyl-α-amino acids of Formula (II) and salts, analogues, or bioisosteres thereof, wherein the α-amino acid is selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tyrosine, aspartic acid, glutamic acid, lysine, ornithine, arginine, and serine, wherein X is selected from the group consisting of C(O) and SO2, and wherein Y is selected from the group consisting of phenyl and cyclohexyl.PATENT PARSON-58748 49. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of derivatized leucines of Formula (III) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, 2- methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cycloheptyl, cyclopentyl, cyclopropyl, 2-carboxycyclohexyl, benzoyl, 3-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4- nitrophenyl, and (CH2)2cyclohexyl.

50. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of N-cyclohexanoylamino acids of Formula (IV) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl, methylcyclohexyl, (CH2)2cyclohexyl, phenyl, and 2-hydroxyphenyl.

51. The method of claim 47 wherein the intestinal penetration agent is a derivatized phenylglycine of Formula (V) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl, methylcyclohexyl, (CH2)2cyclohexyl, phenyl, and 2-hydroxyphenyl.

52. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of derivatives of 4-aminobenzoic acid, 2-(4- aminophenyl)acetic acid, 3-(4-aminophenyl)propionic acid, or 4-(4-aminophenyl)butyric acid of Formula (VI) and salts, analogues, or bioisosteres thereof, wherein: (a) Y is selected from the group consisting of H, F, 2-OH, 2,3-Ph, 4-Ph, 3,4-Ph, 4-OCH3, 4-F, 2-Cl, 2-F, 2,4-(OH)2, 3-CF3, 3-Cl, 2-CH3, 2,6-(OH)2, 3-N(CH3), 3,4-OCH2O, 2,6-diCH3, 2-COOH, 2-NO2, 2-OCH3, 3-NO2, 2-OCF3, 4-CH3, and 4-i-Bu; (b) n is 0, 1, 2, 3, 4, or a vinyl group; (c) m is 0, 1, or 2, a vinyl group, a CHMe group, a CHEt group; a (CH2)2O group, a (CH2)2C=O group, or a (CH2OH)2group; (d) X is C=O, SO2, or CH2; and (e) Z is phenyl, cyclohexyl, or cycloheptyl.

53. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of compounds of Formula (VII), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, and salts, analogues, or bioisosteres thereof.

54. The method of claim 53 wherein n is 7, 8, or 9.

55. The method of claim 54 wherein the intestinal penetration agent is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate.

56. The method of claim 47 wherein the intestinal penetration agent is agent is selected from the group of phenoxycarboxylic acid compounds of Formula (VIII), wherein: (i)PATENT PARSON-58748 R1, R2, R3, and R4are each independently hydrogen, hydroxyl, halo, C1-C4 alkyl, C2-C4 alkenyl, C1-C4alkoxy, -C(O)R8, -NO2, -NR9R10, or –N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, - NO2, halo, trifluoromethyl, -NR14R15, –N+R14R15R16(R13)-, amide, C1-C12 alkoxy, C1-C12 alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or -C(O)R18; (iii) R5is optionally substituted with halo, hydroxyl, sulfhydryl, or carboxyl; (iv) R5is optionally interrupted by O, N, S, or –C(O)-; (v) R6is a C1-C12 alkylene, C2-C12 alkenylene, or arylene; (vi) C6is optionally substituted with a C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, halo, amino, or –CO2R8; (vii) R6is optionally interrupted by O or N; (viii) R7is a bond or arylene; (ix) R7is optionally substituted with hydroxyl, halogen, -C(O)CH3, -NR10R11, or –N+R10R11R12(R13)-; (x) R8is hydrogen, C1-C4alkyl, C2-C4 alkenyl, or amino; (xi) R9, R10, R11, and R12are each independently hydrogen or C1- C10 alkyl; (xii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiv) R14, R15, and R16are each independently hydrogen, C1-C10alkyl, C1-C10alkyl substituted with carboxyl, C2-C12 alkenyl, C2-C12 alkenyl substituted with carboxyl, or C(O)R17; (xv) R17is hydroxyl, C1- C10 alkyl, or C2-C12 alkenyl; (xvi) R18is hydrogen, C1-C6 alkyl, hydroxyl, -NR14R15, or – N+R14R15R16(R13)-; with the proviso that: (a) when R1, R2, R3, R4, and R5are hydrogen and R7is a bond, then R6is not a C1-C6, C9, or C10 alkyl; (b) when R1, R2, R3, and R4are hydrogen, R5is hydroxyl, and R7is a bond, then R6is not a C1-C3 alkyl; (c) when at least one of R1, R2, R3, and R4is not hydrogen, R5is hydroxyl, and R7is a bond, then R6is not a C1-C4alkyl; (d) when R1, R2, and R3are hydrogen, R4is –OCH3, R5is C(O)CH3, and R6is a bond, then R7is not a C3alkyl; and (e) when R1, R2, R4, and R5are hydrogen, R3is hydroxyl, and R7is a bond, then R6is not a methyl group.

57. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of compounds of Formula (IX), wherein: m is 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, or 4, q and x are independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R may be the same or different and is selected from hydrogen, halogen, a substituted or non- substituted alkyl, substituted or non-substituted alkyloxyl, substituted or non-substituted alkenyloxyl, substituted or non-substituted alkynyloxyl and substituted or non-substituted aryloxyl; and R1, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, substituted or non-substituted alkyl, substituted or non-substituted alkenyl, substituted or non- substituted alkynyl, substituted or non-substituted alkyloxyl, substituted or non-substituted aryloxyl, substituted or non-substituted aryl groups, substituted or non-substituted heteroaryl,PATENT PARSON-58748 substituted or non-substituted cycloalkyl, and substituted or non-substituted heterocycloalkyl groups.

58. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of compounds with an aromatic nucleus of Formula (X), wherein: (i) R1is –(CH2)m-R8, wherein m is 0 or 1; (ii) R2, R3, R4, R5, and R6are each independently selected from hydrogen, hydroxyl, halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, and cyano; (iii) R7 is selected from C1-C10 alkyl, C2-C10 alkenyl, and C2- C10alkynyl; (iv) R8is selected from cyclopentyl, cyclohexyl, and phenyl, wherein, when R8is phenyl, m is 1; and (v) R8is optionally substituted with C1-C4alkyl, C1-C4alkoxy, halo, hydroxyl, or a combination thereof.

59. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of: (1) disodium salts of Formula (XI); (2) monohydrates of disodium salts of Formula (XI); and (3) alcohol solvates of disodium salts of Formula (XI), wherein the alcohol is methanol, ethanol, propanol, propylene glycol, or other monohydroxylic or dihydroxylic alcohols, wherein: (i) R1, R2, R3, and R4are each independently hydrogen, hydroxyl, -NR6R7, halo, C1-C4 alkyl, or C1-C4 alkoxy; (ii) R5is a substituted or unsubstituted C2- C16 alkylene, substituted or unsubstituted C1-C12 alkyl(arylene), or substituted or unsubstituted aryl(C1-C12alkylene); and (iii) R6and R7are each independently hydrogen, oxygen, or C1-C4alkyl.

60. The method of claim 59 wherein the intestinal penetration agent is selected from the group consisting of N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N- (10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC), 8-(N-2-hydroxy-4-methoxybenzoyl)aminocaprylic acid, and N-(9-(2- hydroxybenzoyl)aminononanoic acid.

61. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of 8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid (“4-MOAC”), N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (“NAC”), N-(8-[2- hydroxybenzoyl]-amino)decanoic acid (“NAD”), N-(8-[2-hydroxy-5-chlorobenzoyl]- amino)octanoic acid (“5-CNAC”), and 4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate (“4- CNAB”).PATENT PARSON-58748 62. The method of claim 47 wherein the intestinal penetration agent is the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid.

63. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XII), wherein: (i) R1, R2, R3, R4, and R5are each independently selected from hydrogen, halo, hydroxyl, -OCH3, C1-C4alkyl, amino, methylamino, dimethylamino, or nitro; (ii) m is 0, 1, 2, 3, or 4; (iii) R6is phenyl substituted with –O-R7-COOH at the ortho, meta, or para position; (iv) R6is optionally substituted with one or more substituents selected from hydrogen, halo, hydroxyl, -OCH3, C1-C4alkyl, amino, methylamino, dimethylamino, or nitro; and (iv) R7is C1-C12alkyl.

64. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XIII), wherein: (i) R1and R2are each independently hydrogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, CF3, halo, or NR4R4′; (ii) R3is H or C1-C6alkyl; (iii) X is a 5-membered aromatic heterocycle that is optionally substituted with C1-C4alkyl; wherein the heterocycle contains at least two or three heteroatoms selected from N, S, and O wherein at least one heteroatom is N; (iv) Y is S, CR5=N or N=CR5; (v) n is 2, 3, 4, 5, 6, or 7; (vi) R4is H, COR6, SO2R7, or C1-C6alkyl; (vii) R4′is H or C1-C6alkyl; (viii) R5is H or forms a bond with X; (ix) R6is H or C1-C6alkyl; and (x) R7is H or C1-C6alkyl.

65. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XIV).

66. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XV).

67. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XVa), wherein (i) R16is R3-R4; (ii) R3is -NHC(O)NH-, -C(O)NH-, -NHC(O) -, -OOC-, -COO, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -N HCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O) CH2O-, -OCH2C(O)NH-, -NH-, -O-, or a carbon-carbon bond; R4is Formula (XVIa(1)); R5, R6, R7, R8, and R9are each independently a bond to R3, or hydrogen, chloro, bromo, fluoro, hydroxyl, methyl, methoxy, or -(CH2)mCH3; R10is a bond to R3, carboxyl, or –C(O)NHR11R12; R11is a substituted or unsubstituted, linear or branched alkylene having a chain length of 1 to 11 carbon atoms or –R13R14-; R12is a bond to R3, carboxyl, amino, hydroxyl, –C(O)–R15, –COO– R15, –NHR15, –OR15, chloro, or bromo; R13is a substituted or unsubstituted phenylene; R14is aPATENT PARSON-58748 substituted or unsubstituted, linear or branched alkylene having a chain length of 1 to 5 carbon atoms; R15is a bond to R3; m is 1, 2, 3, or 4; R17is hydroxyl or methoxy; R23is hydrogen or methyl; and n is an integer from 3 to 200.

68. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XVI), wherein: (i) R1and R2are each independently hydrogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, CF3, halo, or NR4R4′; (ii) R3is H or C1-C6 alkyl; (iii) R4is H, COR5, SO2R6, or C1-C6alkyl; (iv) R4′is H or C1-C6alkyl; (v) R5is H or C1- C6alkyl; (vi) R6is H or C1-C6alkyl; (vii) X is a 5-membered aromatic heterocycle that is optionally substituted with C1-C4 alkyl, wherein the heterocycle contains at least two or three heteroatoms selected from N, S, and O, wherein at least one heteroatom is N, and wherein the heterocycle is not 1,3,4-oxadiazole; and (ix) n is 2, 3, 4, 5, 6, or 7.

69. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XVII).

70. The method of claim 47 wherein the intestinal penetration agent is (5-(2- hydroxy-4-chlorobenzoyl) aminovaleric acid.

71. The method of claim 47 wherein the intestinal penetration agent is a cyanophenoxy carboxylic acid compound of Formula (XVIII), wherein: (i) R1, R2, R3, R4, and R5are each independently hydrogen, cyano, hydroxyl, -OCH3or halogen, where at least one of R1, R2, R3, R4, and R5is cyano; (ii) R6is C1-C12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene); with the proviso that where R1is cyano, R4is hydrogen or cyano, and R2, R3, and R5is not methylene.

72. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XIX).

73. The method of claim 47 wherein the intestinal penetration agent is a compound selected from the group consisting of 4-(8-(2-hydroxyphenoxy)octyl)morpholine, 8- (2-hydroxyphenoxy)octyldiethanolamine, 7-(4-2-hydroxyphenoxy)heptylmorpholine, 4-(6-(4- hydroxyphenoxy)hexyl)morpholine, 4-(6-(2-hydroxyphenoxy)hexyl)morpholine, 8-(4- hydroxyphenoxy)octanamine, 6-(2-acetylphenoxy)-1-dimethylaminohexane, 7-(2- hydroxyphenoxy)heptyl-2-isopropylimidazole, 6-(2-hydroxyphenoxy)hexyl-2-methylimidazole, and 5-chloro-4-methyl-2-(8-morpholin-4-yloctyloxy)acetophenone.PATENT PARSON-58748 74. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XX), including compounds with the following combinations of substituents: (1) R1, R2, R3, and R4are each hydrogen, R5is carboxyl, R6is (CH2)7, R7is a bond, and R8is hydrogen; (2) R1, R2, R3, and R4are each hydrogen, R5is C(O)NH2, R6is (CH2)7, R7is a bond, and R8is hydrogen; (3) R1, R2, R3, and R4are each hydrogen, R5is C(O)CH3, R6is (CH2)7, R7is a bond, and R8is hydrogen; (4) R1, R2, R3, and R4are each hydrogen, R5is C(O)NH2, R6is (CH2), R7is p-phenyl, and R8is hydrogen; and (5) R1, R2, R3, and R4are each hydrogen, R5is nitro, R6is (CH2)7, R7is a bond, and R8is hydrogen.

75. The method of claim 47 wherein the intestinal penetration agent is a carbon-substituted diketopiperazine intestinal penetration agent of Formula (XXI), wherein: (i) R and R1are C1-C24 alkyl having a functional group selected from halogen, oxygen, sulfur or nitrogen; (ii) R and R1are optionally interrupted with O, N, or S; (iii) R and R1are optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or CO2R2or any combination thereof; and (iv) R2is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl.

76. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XXII).

77. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XXIII), wherein: (i) R1, R2, R3, and R4are each independently hydrogen, hydroxy, halo, C1-C4alkoxy, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, and aryl; (ii) R1, R2, R3, and R4are optionally substituted with halo, hydroxyl, C1-C4 alkoxy, or C1-C4 alkyl; (iii) R5is C1- C4 alkyl; (iv) R6is hydrogen or C1-C4 alkyl; (v) R7is hydrogen, C1-C4 alkyl, or aryl; and R7is optionally substituted with halogen or hydroxyl.

78. The method of claim 47 wherein the intestinal penetration agent is an amino-substituted carboxylic acid including one or more aromatic moieties, wherein the aromatic moiety is selected from the group consisting of phenyl, pyrazinyl, pyrimidyl, and chromonyl.

79. The method of claim 47 wherein the intestinal penetration agent is a modified amino acid compound of Formula (XXIV).

80. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XXV).

81. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XXVI).PATENT PARSON-58748 82. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XXVII), wherein: (i) Ar is a phenyl or naphthyl substituted with at least one of C1-C5 alkyl, C2-C4 alkenyl, fluoro, chloro, hydroxyl, -SO2, carboxyl, or –SO3H; (ii) R7is selected from the group consisting of C4-C20 alkyl, C4-C20 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10alkenyl)phenyl, C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), and phenyl(C1-C10 alkenyl); (iii) R7is optionally substituted with C1-C4 alkyl, C1-C5 alkenyl, C1-C5 alkoxy, hydroxyl, sulfhydryl, and –CO2R9or any combination thereof; (iv) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (v) R8is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, hydroxyl, and C1-C4 alkoxy; (vi) R8is optionally substituted with C1-C4 alkyl, C1-C5 alkenyl, C1-C5 alkoxy, hydroxyl, sulfhydryl, and – CO2R9or any combination thereof; and (vii) R9is hydrogen, C1-C4alkyl, or C1-C4alkenyl, with the proviso that the compounds are not substituted with an amino group in the position α to the acid group.

83. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XXVIII) wherein: (i) R1, R2, R3, and R4are independently hydrogen, hydroxyl, halo, C1-C4alkoxy, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, or aryl; (ii) R1, R2, R3, and R4are optionally substituted with halo, hydroxyl, C1-C4 alkoxy, or C1-C4 alkyl; and (iii) R5is a C2-C16branched alkylene, optionally substituted with halogen.

84. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XXIX).

85. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of any one of Formulas (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), and (XLI).

86. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLII).

87. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLIII) wherein: (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with C1-C4alkyl, C1-C4alkoxy, C2-C4alkenyl, C2-C4alkynyl, aryl, aryloxy, a heterocyclic ring, a C5-C7carbocyclic ring, halo, hydroxyl, sulfhydryl, CO2R6, NR7R8, or N+R7R8R9Y; (iii) (a) R1is C1-C16 alkylene, C2-C16 alkenylene, C2-C16 alkynylene, C6-C16PATENT PARSON-58748 arylene, (C1-C16 alkyl)arylene, or aryl(C1-C16 alkylene); R2is -NR3R4, -N+R3R4, or -N+R3R4R5Y; R3and R4are each independently hydrogen, oxygen, hydroxyl, substituted or unsubstituted C1- C16 alkyl, substituted or unsubstituted C2-C16 alkenyl, substituted or unsubstituted C2-C16 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; R5is hydrogen, substituted or unsubstituted C1-C16alkyl, substituted or unsubstituted C2-C16alkenyl, substituted or unsubstituted C2-C16alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; (b) R1, R2, and R5are as above under (a), and R3and R4are combined to form a 5-, 6-, or 7-membered heterocyclic ring or a aryloxycarbonyl; (b) R1, R2, and R5are as above under (a), and R3and R4are combined to form a 5-, 6-, or 7-membered heterocyclic ring or a 5-, 6-, or 7-membered heterocyclic ring substituted with C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, oxo, or carbocyclic ring; or (c) R2and R5are as defined above under (a), and R1and R3are combined to form a 5-, 6- , or 7-membered heterocyclic ring or a 5-, 6-, or 7-membered heterocyclic ring substituted with C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, oxo, or carbocyclic ring; (iv) R4is hydrogen, oxygen, hydroxyl, substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C2-C16 alkenyl, substituted or unsubstituted C2-C16alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; (v) R6is hydrogen, C1-C4 alkyl, C1-C4 alkyl substituted with halogen or with hydroxyl, C2-C4 alkenyl, or C2-C4 alkenyl substituted with halogen or with hydroxyl; (vi) R7, R8, and R9are each independently hydrogen, oxygen, C1-C4alkyl, C1-C4alkyl substituted with halogen or with hydroxyl, C2-C4alkenyl, or C2-C4 alkenyl substituted with halogen or with hydroxyl; and (vii) Y is halogen, hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, or carboxylate.PATENT PARSON-58748 88. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLIV).

89. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLV).

90. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLVI).

91. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLVII).

92. The method of claim 47 wherein the intestinal penetration agent is a carboxylic acid derivative selected from the group consisting of 6-N-(3,5-dichloro-2- hydroxybenzoyl)aminocaproic acid, 8-(2-aminobenzoylamino)caprylic acid, 8(2- trifluoromethoxy)benzoylaminocaprylic acid, N-(2-hydroxybenzoyl)isonipecotic acid, 4-[4-(2- aminobenzoylamino)phenyl]butyrylhydroxamic acid, 4-(4- (pentafluorobenzoyl)aminophenyl)butyric acid, 4-(4-(3-anisoyl)aminophenyl)butyric acid, 8-(3- anisoyl)aminocaprylic acid, 4-(4-(phenoxyacetyl)aminophenyl)butyric acid, 4-(4-(2- nitrobenzenesulfonyl)aminophenyl)butyric acid, 8-(2-nitrobenzenesulfonyl)aminocaprylic acid, 6-(4-(salicyloyl)aminophenyl)hexanoic acid, 8-(2-methoxybenzoyl)aminocaprylic acid, 2- [4-salicyloylaminophenyl]ethyl methyl sulfone, 1-salicyloyl-2-succinyl-hydrazide, 3-(4-(2,5- dimethoxycinnamoyl)aminophenyl)propionic acid, 4-(4-(2,5- dimethoxycinnamoyl)aminophenyl)butyric acid, 1-salicyloyl-2-glutaryl hydrazide, succinyl- 4-aminosalicylic acid, 8-(phenoxyacetylamino)caprylic acid, 8-(2- pyrazinecarbonyl)aminocaprylic acid, 4-(4-(2 pyrazinecarbonyl)aminophenylbutyric acid, 6-(4- (N-2-nitrobenzoyl)aminophenyl)hexanoic acid, 6-(4-(N-2- aminobenzoyl)aminophenyl)hexanoic acid, 4-(4-(2-(3- carbonyl)pyrazinecarboxyl)aminophenyl)butyric acid, 4(2-nitrobenzoyl)aminophenylsuccinic acid, 8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid, 8-(benzylcarbonylamino)caprylic acid, 8-(phenylcarbonylamino)caprylic acid, 2-[4-(2-methoxybenzoylamino)phenyl]ethyl H2PO4, 1- salicyloyl-2-suberyl hydrazide, 4-(4-benzyloxycarbonylaminophenyl)butyric acid, 4-(4-)2- hydroxynicotinoyl)aminophenyl)butyric acid, 9-salicyloylaminonanoic acid, 4-(4- phenyloxycarbonylaminophenyl)butyric acid, 3-(2-methoxybenzoylamino)-1-propanol, 8-(2- hydroxynicotinoyl)aminocaprylic acid, 6-(2-methoxybenzoyl)amino nicotinic acid,PATENT PARSON-58748 salicyloylglycine, 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid, 8-(chromone-3- carbonyl)aminocaprylic acid, 8-(vinylbenzoyl)aminocaprylic acid, 4-(4-(chromone-3- carbonyl)aminophenyl)butyric acid, 8-cinnamoylaminocaprylic acid, 5-(N- salicyloylamino)valeric acid, N-(4-salicyloylamino)-6-caproic acid, 4′-flavonic acid, 11- cinnamoylaminoundecanoic acid, 4-octanoylamino-3-hydroxybenzoic acid, (3-phenyl-2,3- dihydroxypropanoyl)-8-aminocaprylic acid, 8-[N-(3-coumarincarbonyl)]aminocaprylic acid, 8- [N-(4-chlorobenzyl)]aminocaprylic acid, 8-[N-(3-fluorobenzyl)]aminocaprylic acid, 8-(N-2,5- dihydroxybenzoyl)aminocaprylic acid, 8-(N-3,5-diacetyloxybenzoyl)aminocaprylic acid, 8-(N- 4-hydroxybenzoyl)aminocaprylic acid (dimer), 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid, 1-(1-(N-2-methoxyanilino)sebacic acid, 10-(N-2-methoxyanilino)sebacic acid, 8-(N- benzoyl)aminocaprylic acid, 2-methoxybenzenaminodecanoic acid, 8-(N- benzoyl)aminocaprylic acid, 8-(N-2-hydroxy-4-methoxybenzoyl)aminocaprylic acid, 8-(N-4- fluorobenzoyl)aminocaprylic acid, 8-(N-3-bromobenzoyl)aminocaprylic acid, 8-(4-(1,2- dihydroxyethyl)benzoyl)aminocaprylic acid, 8-(N-4-bromobenzoyl)aminocaprylic acid, 8- (N-4-iodobenzoyl)aminocaprylic acid, 4-{4-[N-(2-iodobenzoyl)aminophenyl]}butyric acid, 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid, 4-(4-(2,4- dimethoxybenzoyl)aminophenyl)butyric acid, 4-(o-anisoyl)aminophenylacetic acid, 3-[4- (2,4-dimethoxybenzoyl)aminophenyl]propionic acid, 4-{4-[N-(4- iodobenzoyl)]aminophenyl}butyric acid, 3-[4-(2,3-dimethoxybenzoyl) aminophenyl] propionic acid, 4{4 [N-2-bromobenzoyl)] aminophenyl} butyric acid, 4{4-[N-3-[bromobenzoyl) aminophenyl]} butyric acid, 8-(N-3,5-dihydroxybenzoyl)aminocaprylic acid, 8-(N-3,5- dimethoxy 4-hydroxybenzoyl)aminocaprylic acid, 8-(N-2,6-dimethoxybenzoyl)aminocaprylic acid, 4-{4[N-(4 bromobenzoyl)aminophenyl]butyric acid, 8-(2-hydroxy-4- chlorobenzoyl)aminocaprylic acid, 8-(N-2,6-dihydroxybenzoyl)aminocaprylic acid, 8-(N-2- hydroxy-6-methoxybenzoyl)aminocaprylic acid, 8-(5-chloro-o-anisoyl)aminocaprylic acid, 4-(4- (2,3-dimethoxybenzoyl)aminophenyl)butyric acid, 4-(4-(5 chloro-o-anisoyl)aminophenyl)butyric acid, 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid, 8-(4-chloro-o-anisoyl)aminocaprylic acid, 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid, 4-{N-[4-(3 iodobenzoyl)aminophenyl]butyric acid, 7-cinnamoylaminoheptanoic acid, 8-N-(3 iodobenzoyl)aminocaprylic acid, 8-N-(4 methoxy-3-nitrobenzoyl)aminocaprylic acid, 8-N-(2 methoxy 4 nitrobenzoyl)aminocaprylic acid, 4-{N-[4-(2-methoxy-4-PATENT PARSON-58748 nitrobenzoyl)aminophenyl]}butyric acid, 4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid, 8-(N-2-hydroxy-5-bromobenzoyl)aminocaprylic acid, 3-indolebutryic acid, 4-(4-(2,6- dimethoxybenzoyl)aminophenylbutyric acid, 4-[4-N-(4 methoxy-3- nitrobenzoyl)aminophenyl]butyric acid, 8-(N-2-hydroxy-5 chlorobenzoyl)aminocaprylic acid, 8-(N- 2-hydroxy-5-iodobenzoyl)aminocaprylic acid, 8-(3-hydroxy-2-naphthoyl)aminocaprylic acid, 8-(N-2- hydroxy-2-nitrobenzoyl)aminocaprylic acid, 8-(N-3-methylsalicyloyl)aminocaprylic acid, 8-(N-5- methylsalicyloyl)aminocaprylic acid, 4-[-N-(2 hydroxy-4-bromobenzoyl)aminophenyl]butyric acid, 8-(N-2,3-dihydroxybenzoyl)aminocaprylic acid, 9-(cinnamoylamino)nonanoic acid, 4-(4-(2- chloro-5-nitrobenzoyl)aminophenyl)butyric acid, 4-[N-(2-hydroxy-5- iodobenzoyl)]aminophenylbutyric acid, N-2-nitrophenyl-N′-(8 octanoic acid) urea, 8-[N-(2-acetoxy- 3,5-dibromobenzoyl)aminocaprylic acid, 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid, 8-N-(4- hydroxy-3-nitrobenzoyl)caprylic acid, 4-(4-salicyloylaminophenyl)-4-oxobutyric acid, 12- cinnamoyldodecanoic acid, 4-{4-[N-(3-hydroxy-2-naphthoyl)aminophenyl]}butyric acid, 8-(4- chloro-3-nitrobenzoyl)aminocaprylic acid, 8-(2-chloronicotinoyl)aminocaprylic acid, 8-(2- chloro-5-nitrobenzoyl)aminocaprylic acid, 4-(4-phthalimidophenyl)butyric acid, 4-{4-[N-(3- hydroxy-2-napthoyl)aminophenyl]}propanoic acid, 3-(4-(2,6- dimethoxybenzoyl)aminophenyl)propionic acid, 8-(N-2-hydroxy-3,5- diiodobenzoyl)aminocaprylic acid, 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid, 8 (N 1 hydroxy-2-naphthoyl)aminocaprylic acid, 8-(phthalimido)caprylic acid, 10-(4-chloro-2- hydroxyanilino)sebacic acid monoamide, 6-(anisoyl)aminocaproic acid, 4-(4-(4-chloro-3- nitrobenzoyl)aminophenyl)butyric acid, 11-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid, bis(N-2-carboxylphenyl-N-(N′-8-octanoic acid)ureal)oxalyl diamide, 2-[2-N-(2- chlorobenzoyl)aminoethoxy]ethanol), 2-[2-N-(4 chlorobenzoyl)aminoethoxy]ethanol, 4-(2- methybenzoyl)amino-3-carboxysulfoxide, 4-(2-methoxybenzoyl)amino 3-carboxypropylsulfone, 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid, 2-[2-N-(2 methoxybenzoyl)aminoethoxyl]ethanol, 2-[2-N-(3 chlorobenzoyl)aminoethoxy]ethanol, bis(N-2- carboxyphenyl)-N-(N′-3(4-aminophenyl)propionic acid)ureal)oxalyl diamide, trans-4-(2 aminobenzamidomethyl)cyclohexamecarboxylic acid, 11-N-(3,5-dichloro-2- hydroxybenzoyl)aminoundecanoic acid, 2-[N-(2-bromobenzoyl)aminoethoxy]ethanol, 7-N-(3,5- dichloro-2-hydroxybenzoyl)aminoheptanoic acid, N-[3,5-dichloro-2-hydroxybenzoyl-4(4- aminophenyl)]butyric acid, trans-4-(N salicyloylaminomethyl)cyclohexane carboxylic acid, N-PATENT PARSON-58748 [3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid, 12-N-(3,5-dichloro-2- hydroxybenzoyl)aminodecanoic acid, N-(2-hydroxy-4-carboxy)-6-heptenamide, N-(2- bromobenzoyl)morpholine, 8-N-cyclohexanoylaminocaprylic acid, 2-[N-(2- iodobenzoyl)aminoethoxy]ethanol, 5-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid, 8-(2- hydroxyphenoxy)-aminocaprylic acid, N-salicyloyl-5-(3-aminophenyl-valeric acid, 4-(4-(2- ethoxylbenzoyl)aminophenyl)butyric acid, 9-[2-(3-hydroxy)pyridylaminocarbonyl]nonanic acid, 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid, 2-[N-2-hydroxybenzoylamino)ethoxy]ethanol. 4-[N-(3,5-chloro-2-hydroxybenzoyl)]aminophenylacetic acid 8-(2-hydroxy-5- chloroanilinocarbonyl)octanoic acid, N-salicyloyl-5-(4-aminophenyl)valeric acid, 9-(2-hydroxy-5- methylanilinocarbonyl)nonanoic acid, 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid, 8- (pentafluorobenzoyl)aminocaprylic acid, 3-(3-(salicyloyl)aminophenyl)propionic acid, 8-(2- ethoxybenzoyl)aminocaprylic acid, 4-(4-(2-dimethylamino benzoic)aminophenyl)butyric acid, 8- (3-phenoxylpropionylamino)caprylic acid, 4-(salicyloyl)aminophenylethyltetrazole, 4-(4-(N-(2- fluorocinnamoyl))aminophenyl)butyric acid, 4-(4-(N-8- salicyloyl)aminocaprylic)aminophenyl)butyric acid, 8-(p-anisoyl)aminocaprylic acid, 8-(4- hydroxybenzoyl)aminocaprylic acid, 8-(3-hydroxybenzoyl)aminocaprylic acid, 8-(3,4,5- trimethoxybenzoyl)aminocaprylic acid, 8-(N-4-methylsalicyloyl)aminocaprylic acid, N-10-(2- hydroxy-5-nitroanilino)decanoic acid, and 4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid.

93. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLVII).

94. The method of claim 47 wherein the intestinal penetration agent is a modified amino acid or peptide comprising: (i) at least one acylated amino acid; (ii) at least one peptide comprising one acylated amino acid; or (iii) a combination of (i) and (ii), wherein the acylated amino acid is acylated by: (1) a C3-C10 cycloalkyl acylating agent, the agent being optionally substituted with C1-C7alkyl, C2-C7alkenyl, C1-C7alkoxy, hydroxyl, phenyl, phenoxy, or –CO2R, wherein R is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; or (2) a C3-C10 cycloalkyl substituted C1-C6 alkyl acylating agent, wherein the amino acids are of Formula (XLIX), wherein: R1is hydrogen, C1-C4alkyl, or C2-C4alkenyl; R2is C1-C24alkyl, C2-C24alkenyl, C3- C10cycloalkyl, C3-C10cycloalkenyl, phenyl, naphthyl, (C1-C10alkyl) phenyl (C2-C10alkenyl) phenyl, (C1-C10 alkyl) naphthyl (C2-C10 alkenyl) naphthyl, phenyl (C1-C10 alkyl), phenyl (C2-C10 alkenyl), naphthyl (C1-C10 alkyl) naphthyl (C2-C10 alkenyl); R2can be optionally substituted withPATENT PARSON-58748 C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, -CO2R3, C3-C10 cycloalkyl, C3- C10cycloalkenyl, heterocycle having 3-10 ring atoms wherein the heteroatom is one or more of N, O. or S, or any combination thereof, aryl, C1-C10 alkaryl, aryl(C1-C10 alkyl), or any combination thereof; R2can be optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R3is hydrogen, C1-C4alkyl, or C2-C4alkenyl.

95. The method of claim 47 wherein the intestinal penetration agent is a modified amino acid prepared by acylation or sulfonation of an amino acid selected from the group consisting of aminobutyric acid, aminocaproic acid, and aminocaprylic acid.

96. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (L).

97. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LI).

98. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LII).

99. The method of claim 47 wherein the intestinal penetration agent is a modified amino acid of either Formula (LIII) or Formula (LIV), wherein: (i) Ar is an unsubstituted or substituted phenyl or naphthyl; (ii) Y is –C(O)- or -S(O2)-; (iii) R1has the formula –N(R3)-R2-C(O)-; (iv) R2is C1-C24alkyl, C1-C24alkenyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, (C1-C10alkenyl)phenyl, (C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), or naphthyl(C1-C10 alkenyl); (v) R2is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, CO2R4, or any combination thereof; (vi) R4is hydrogen, C1-C4alkyl, or C1- C4 alkenyl; (vii) R2is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (viii) R3is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl; (ix) R5is either: (A) C3-C10 cycloalkyl, optionally substituted with C1-C7alkyl, C2-C7alkenyl, C1-C7alkoxy, hydroxyl, phenyl, phenoxy, or –CO2R8, wherein R8is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; or (B) C1- C6 alkyl substituted with C3-C10 cycloalkyl; (x) R6is C3-C10 cycloalkyl; R7is C1-C24 alkyl, C2- C24alkenyl, C3-C10cycloalkyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, (C2-C10alkenyl)phenyl, (C1-C10alkyl)naphthyl, (C2-C10alkenyl)naphthyl, phenyl(C1-C10alkyl), phenyl(C2-C10alkenyl), naphthyl(C1-C10 alkyl), or naphthyl(C2-C10 alkenyl); (xi) R7is optionally substituted with C1-C4 alkyl, C2-C4 alkyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, -CO2R9, C3-C10 cycloalkyl, C3-C10PATENT PARSON-58748 cycloalkenyl, a heterocycle having 3-10 ring atoms wherein the heteroatom is one or more of N, O, or S or any combination thereof, aryl, (C1-C10)alkaryl, aryl(C1-C10alkyl), or any combination thereof; (xii) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and (xiii) R9is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.

100. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LV).

101. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LVI).

102. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LVII).

103. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LVIII).

104. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXIV), (LX), or (LXI).

105. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXII).

106. The method of claim 47 wherein the intestinal penetration agent is a compound that includes: (a) at least one acylated aldehyde of an amino acid, (b) at least one acylated ketone of an amino acid, (c) at least one acylated aldehyde of a peptide, (d) at least one acylated ketone of a peptide, (e) any combination of (1)(a), (1)(b), (1)(c), and (1)(d); (2) (a) carboxymethyl-phenylalanylleucine; (b) 2-carboxy-3-phenylpropionylleucine; (c) 2- benzylsuccinic acid; (d) (phenylsulfonamide)phenylbutyric acid; and (e) any combination of (2)(a), (2)(b), (2)(c) and (2)(d); or (3) a combination of (1) and (2).

107. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXIII).

108. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXIV).

109. The method of claim 47 wherein the intestinal penetration agent is a compound selected from the group consisting of: (1) (a) at least one acetylated aldehyde of an amino acid; (b) at least one acetylated ketone of an amino acid; (c) at least one acetylated aldehyde of a peptide; (d) at least one acetylated ketone of a peptide; or (e) any combination ofPATENT PARSON-58748 (1)(a), (1)(b), (1)(c), and (1)(d); (2) (a) carboxymethyl-phenylalanylleucine; (b) 2-carboxy-3- phenylpropionylleucine; (c) 2-benzylsuccinic acid; (d) an actinonin; (e) a compound having the formula Ar-Y-(R1)n-OH, wherein: (i) Ar is a substituted or unsubstituted phenyl or naphthyl; (ii) Y is –C(O)- or –SO2-; (iii) R1is –N(R4)-R3-C(O)-, wherein: (A) R3is C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, (C1-C10alkyl)naphthyl, (C1-C10alkenyl)phenyl, C1-C10 alkenyl(naphthyl), phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), or phenyl(C1-C10 alkenyl); (B) R3is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, -CO2R5, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, alkaryl, heteroaryl, or heteroalkaryl or any combination thereof; (C) R5is hydrogen, C1-C4alkyl, or C1- C4 alkenyl; (D) R3is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (E) R4is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl; and (F) n is an integer from 1 to 5; or (f) any combination of (2)(a), (2)(b), (2)(c), (2)(d), and (2)(e); or (3) a combination of (1) and (2).

110. The method of claim 47 wherein the intestinal penetration agent is an acid or acid salt wherein the acid has the general formula RCO2H, wherein R is C1-C24alkyl, C2-C24alkenyl, C3-C10 cycloalkyl, C3-C4 cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C2-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C2-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C2-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C2-C10alkenyl), with R being optionally substituted with C1-C10alkyl, C2-C10alkenyl, C1-C4alkoxy, hydroxyl, sulfhydryl, CO2R1, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl having 3-10 ring atoms wherein the heteroatom is one or more atoms of N, O, S or any combination thereof, aryl, (C1-C10 alk)aryl, aryl(C1-C10alkyl), or any combination thereof, R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R1is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl, and wherein the intestinal penetration agent comprises: (i) the acid; (ii) a salt of the acid; or (iii) a combination of (i) and (ii).

111. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoic acid, monosodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate (“4-CNAB”), a compound of Formula (LXV), and a compound of Formula (LXVI), wherein, in Formula (LXV), X is one or more of hydrogen, halo, hydroxyl, or C1-C3 alkoxy, and in Formula (LXVI), X is halo and R is substituted or unsubstituted C1-C3 alkylene or substituted or unsubstituted C1-C3 alkenylene.PATENT PARSON-58748 112. The method of claim 47 wherein the intestinal penetration agent is a phenylalkylcarboxylic acid selected from the group consisting of 4-(4-methoxyphenyl)butanoic acid, 5-(2-methoxyphenyl)pentanoic acid, 5-(3-fluorophenyl)pentanoic acid, 5-(3- methoxyphenyl)pentanoic acid, 6-(3-fluorophenyl)hexanoic acid, 3-(4-t-butylphenyl)propanoic acid, 3-(4-n-butylphenyl)propanoic acid, 3-(4-n-propylphenyl)propanoic acid, 3-(4-n- propoxyphenyl)propanoic acid, 3-(4-isopropoxyphenyl)propanoic acid, 3-(4-n- butoxyphenyl)propanoic acid, 3-(3-phenoxyphenyl)propanoic acid, 3-(3-ethoxyphenyl)propanoic acid, 3-(3-isopropoxyphenyl)propanoic acid, 3-(3-n-butoxyphenyl)propanoic acid, 3-(3-n- propoxyphenyl)propanoic acid, 3-(3-isobutoxyphenyl)propanoic acid, 3-(4- isobutoxyphenyl)propanoic acid, 4-(4-ethylphenyl)butanoic acid, 4-(4-isopropylphenyl)butanoic acid, and 5-(4-ethylphenyl)pentanoic acid.

113. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXVII), (LXVIII), or (LXIX), wherein: in Formula (LXVII): (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with one or more of hydroxyl, halo, C1-C4alkyl, C1-C4alkenyl, C1-C4alkoxy, or C1-C4haloalkoxy; (iii) R7is selected from C4-C20 alkyl, C4-C20 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C1-C10alkenyl); (iv) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (v) R7optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl, sulfhydryl, -CO2R9, and combinations thereof; (vi) R8is selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, and C1-C4haloalkoxy; and (vii) R9is hydrogen, C1-C4alkyl, or C2-C4alkenyl; in Formula (LXVIII): (i) R1, R2, R3, and R4are each independently hydrogen, hydroxy, halo, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, -C(O)R8, -NO2, -NR9R10, and -N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, nitro, halo, trifluoromethyl, -NR14R15, -N+R14R15R16(R13)-, amide, C1-C12alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or –C(O)R18; (iii) R5is optionally substituted with halo, hydroxyl, sulfhydryl, or –COOH; (iv) R5is optionally interrupted by oxygen, nitrogen, sulfur, or –C(O)-; (v) R6is a C1-C12alkylene, C1-C12alkenylene, or arylene; (vi) R6is optionally substituted with C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, hydroxyl, sulfhydryl, halo, amino, or – CO2R8; (vii) R6is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, amino, or –CO2R8; (viii) R6is optionally interrupted by oxygen orPATENT PARSON-58748 nitrogen; (ix) R7is a bond or arylene; (x) R7is optionally substituted with hydroxyl, halogen, -C(O)CH3, -NR10R11, -N+R10R11R12(R13)-; (xi) R8is hydrogen, C1-C4alkyl, C2-C4alkenyl, or amino; (xii) R9, R10, R11, and R12are each independently hydrogen or C1-C10 alkyl; (xiii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiv) R14, R15, and R16are each independently hydrogen, C1-C10alkyl, C1-C10alkyl substituted with –COOH, C2-C12alkenyl, C2-C12 alkenyl substituted with –COOH, or –C(O)R17; (xv) R17is hydroxyl, C1-C10 alkyl, or C2-C12 alkenyl; and (xvi) R18is hydrogen, C1-C6 alkyl, hydroxyl, -NR14R15, or N+R14R15R16(R13); and in Formula (LXIX): (i) R1, R2, R3, R4, and R5are independently hydrogen, cyano, hydroxyl, -OCH3, or halo, provided that at least one of R1, R2, R3, R4, and R5is cyano; and (ii) R6is C1-C12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene).

114. The method of claim 47 wherein the intestinal penetration agent is an allyloxybenzoic acid or an alkoxybenzoic acid of Formula (LXX), (LXXI), or (LXXII), wherein: in Formula (LXX): (i) R1, R2, and R3 are independently hydrogen, methyl, or halo; (ii) R4 is hydrogen, methyl, methoxy, hydroxyl, halo, acetyl, or 2-hydroxy-ethoxy; and (iii) n is 1, 2, 3, or 4; in Formula (LXXI): R is C1-C6 straight-chain or branched alkyl; and in Formula (LXXII): R is methyl, ethyl, isopropyl, propyl, butyl, allyl, 1-methylallyl, 2-methylallyl, or butenyl.

115. The method of claim 47 wherein the intestinal penetration agent is a propylphenoxy ether of Formula (LXXIV) wherein: (i) R1, R2, R3. R4, and R5are independently selected from hydrogen, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, -C(O)R8, nitro, -NR9R10, -N+R9R10R11(R12), carbonate, ureido, CX3, and cyano; (ii) R8is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or amino; (iii) R9, R10, R11, and R12are each independently hydrogen or C1-C10 alkyl; and (iv) X is halo.

116. The method of claim 47 wherein the intestinal penetration agent is a dialkyl ether of Formula (LXXV) wherein: (i) A is a C1-C6 alkylene group that is straight-chain or branched-chain or substituted or unsubstituted; (ii) B is a C1-C2 alkylene group that is straight- chain or branched-chain or substituted or unsubstituted; (iii) R1, R2, R3, R4, and R5are each independently hydrogen, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, -C(O)R8, nitro, -NR9R10, -N+R9R10R11(R12), carbonate, ureido, -CX3, or cyano,PATENT PARSON-58748 optionally interrupted by an O, N, S, or –C(O)- group, wherein A and R1 may together form a cycloalkyl group; (iii) R8is hydrogen, C1-C4alkyl, C2-C4alkenyl, or amino; (iv) R9, R10, R11, and R12are each independently hydrogen or C1-C10 alkyl; and X is halo.

117. The method of claim 47 wherein the intestinal penetration agent is an aryl ketone selected from the group consisting of 4-oxo-4-phenyl-butyric acid; 10-(4-hydroxy- phenyl)-10-oxodecanoic acid; 10-(2-hydroxy-phenyl)-10-oxo-decanoic acid; 4-(4-methoxy- phenyl)-4-oxo-butyric acid; 5-(4-methoxy-phenyl)-5-oxo-pentanoic acid; 4-(3,5-difluoro- phenyl)-4-oxo-butyric acid; 5-oxo-5-phenyl-pentanoic acid; 4-(2,4-dimethyl-phenyl)-4-oxo- butyric acid; 6-(4-methoxy-3,5-dimethyl-phenyl)-6-oxo-hexanoic acid; 5-(4-isopropyl-phenyl)- 5-oxo-pentanoic acid; 4-(2-methoxy-phenyl)-4-oxo-butyric acid; 4-(4-fluoro-phenyl)-4-oxo- butyric acid; 6-(4-methoxy-phenyl)-6-oxo-hexanoic acid; 4-(3,5-dimethyl-phenyl)-4-oxo-butyric acid; 6-(3,4-dimethyl-phenyl)-6-oxo-hexanoic acid; 4-(3,4-dimethyl-phenyl)-4-oxo-butyric acid; 4-oxo-4-(4-phenoxy-phenyl)-butyric acid; 4-(2,5-dimethyl-phenyl)-4-oxo-butyric acid; 8-(3,5- dimethyl-phenyl)-8-oxo-octanoic acid; 6-(2,5-dichloro-phenyl)-6-oxo-hexanoic acid; 4-(2,5- dichloro-phenyl)-4-oxo-butyric acid; 6-(3,5-dimethyl-phenyl)-6-oxo-hexanoic acid; 10-(2,5- dihydroxy-phenyl)-10-oxo-decanoic acid; 8-oxo-8-phenyl-octanoic acid; 6-(2,5-difluoro- phenyl)-6-oxo-hexanoic acid; 7-oxo-7-phenyl-heptanoic acid; 4-(4-ethyl-phenyl)-4-oxo-butyric acid; 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid; 4-(4-butoxy-phenyl)-4-oxo-butyric acid; 4-oxo- 4-(4-propyl-phenyl)-butyric acid; 4-oxo-4-(4-pentyl-phenyl)-butyric acid; 4-(4-hexyloxy- phenyl)-4-oxo-butyric acid; 4-(2,5-difluoro-phenyl)-4-oxo-butyric acid; 5-(4-chloro-phenyl)-5- oxo-pentanoic acid; 6-(3,5-difluoro-phenyl)-6-oxo-hexanoic acid; 4-oxo-4-p-tolyl-butyric acid; 6-oxo-6-phenyl-hexanoic acid; 5-oxo-5-(4-phenoxy-phenyl)-pentanoic acid; 5-oxo-5-(3- phenoxy-phenyl)-pentanoic acid; and 7-oxo-7-(3-phenoxy-phenyl)-heptanoic acid.

118. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of: (i) a compound selected from the group consisting of arachidonic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monolein, dilaurin, glyceryl 1-monocaprate, 1- dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, and a C1-10alkyl ester, monoglyceride, diglyceride, or a pharmaceutically acceptable salt thereof; (ii) a bile salt selected from the group consisting of cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid,PATENT PARSON-58748 chenodeoxycholic acid, ursodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate, and sodium glycodihydrofusidate; (iii) polyoxyethylene-9-lauryl ether; (iv) a chelating agent selected from the group consisting of EDTA and citric acid; (v) a salicylate; (vi) an N-acyl derivative of collagen; (vii) an N-amino acyl derivative of a beta-diketone; (viii) a surfactant selected from the group consisting of sodium lauryl sulfate, polyoxyethylene-20-cetyl ether, and a perfluorochemical emulsion; and (ix) a compound selected from the group consisting of unsaturated cyclic ureas, 1-alkyl-alkanones, 1-alkenylazacyclo-alkanones, glycols, pyrroles, azones, and terpenes.

119. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of polyvalent aliphatic C2-C10 alcohols, polyalkylene glycols having C2-C4 alkylene groups, nonalkoxylated ethers of polyvalent aliphatic C2-C10 alcohols and polyalkylene glycols having C2-C4alkylene groups, azones, terpenes, terpenoids, pyrrolidones, and sulfoxides.

120. The method of claim 47 wherein the intestinal penetration agent is a nanoparticle or micelle that is constructed from a polymer that is selected from the group consisting of: dextran, carboxymethyl dextran, chitosan, trimethylchitosan, poly(lactic-co- glycolic acid) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyvinylalcohol (PVA), polyanhydrides, polyacrylates, polymethacrylates, polyacylamides, dextran, chitosan, cellulose, hypromellose, starch, dendrimers, peptides, proteins, polyethyleneglycols, and poly(ethyleneglycol-co-propyleneglycol), and synthetic derivatives thereof.

121. The method of claim 47 wherein the intestinal penetration agent is a synthetic peptide ligand.

122. The method of claim 47 wherein the intestinal penetration agent is a biodegradable polymer that is a copolymer of lactic acid and glycolic acid or enantiomers thereof.

123. The method of claim 47 wherein the intestinal penetration agent is a membrane translocating full-length peptide sequence or an analog or derivative thereof, wherein the analog or derivative is selected from the group consisting of: fragments thereof, motifs derived therefrom, derivatives thereof, analogs thereof, and peptidomimetics based on the peptide sequences.PATENT PARSON-58748 124. The method of claim 47 wherein the intestinal penetration agent is aD- form retro-inverted peptide.

125. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent that is: (i) a solid at room temperature; and (ii) a salt of a medium chain fatty acid having a carbon length of from 8 to 14 carbon atoms in particulate form, optionally further comprising a rate-controlling polymer or other rate-controlling agent.

126. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of: (i) a mono-, di-, or triglyceride ester of a medium-chain or long-chain fatty acid; (ii) an ester of a fatty acid and a glycol; (iii) an ester of a mixed fatty acid and a glycol; (iv) a diester of propylene glycol having from about 7 to about 55 carbon atoms; and (v) a propylene glycol ester of capric and caprylic acids and mixtures thereof, having from 19 to 23 carbon atoms.

127. The method of claim 47 wherein the intestinal penetration agent is a medium-chain fatty acid or a medium-chain fatty acid derivative having a carbon chain length of from 6 to 20 carbon atoms, with the provisos that (i) where the intestinal penetration agent is an ester of a medium-chain fatty acid, the chain length of from 6 to 20 carbon atoms relates to the chain length of the carboxylate moiety, and (ii) where the intestinal penetration agent is an ether of a medium-chain fatty acid, at least one alkoxy group has a carbon chain length of from 6 to 20 carbon atoms.

128. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (LXXVII) wherein Q is: (1) a partially or completely neutralized -- COOH, or (2) a partially or completely neutralized --SO3H, or (3) a mono- or di-substituted alkyl or alkenyl group having one to about twelve carbon atoms, the substituent(s) thereof being a partially or completely neutralized --COOH or partially or completely neutralized --SO3H; and R1and R2are independently: (1) an unsubstituted alkyl or alkenyl group having one to about twelve carbon atoms, or (2) a substituted alkyl or alkenyl group having one to about twelve carbon atoms, the substituent thereof being selected from the group consisting of (i) partially or completely neutralized --COOH, (ii) partially or completely neutralized --SO3H, (iii) --NH2, (iv) --CONH2; and (v) –OH.

129. The method of claim 47 wherein the intestinal penetration agent is a purified synthetic polypeptide ligand comprising aL-peptide or homologue thereof.PATENT PARSON-58748 130. The method of claim 47 wherein the intestinal penetration agent is a compound including a peptide sequence that possesses both hydrophobic amino acids and charged amino acids, wherein, optionally, the peptide sequences are modified by hydrophobic moieties.

131. The method of claim 47 wherein the intestinal penetration agent is a medium-chain fatty acid salt associated with a substantially hydrophobic medium.

132. The method of claim 47 wherein the intestinal penetration agent is a composition comprising: (i) octanoate, sodium decanoate, sodium dodecanoate, and combinations thereof; and (ii) a hydrophobic medium to produce a suspension, wherein the hydrophobic medium is selected from the group consisting of aliphatic molecules, cyclic molecules, aromatic molecules, lecithin, a bile salt, a non-ionic detergent, and combinations thereof.

133. The method of claim 47 wherein the intestinal penetration agent is a liquid-forming counterion that is a cationic amphipathic molecule selected from the group consisting of imidazolium derivatives, pyridinium derivatives, phosphonium compounds and tetraalkylammonium compounds.

134. The method of claim 47 wherein the intestinal penetration agent is a peptide derived from Escherichia coli that is optionally modified to increase its hydrophobicity.

135. The method of claim 47 wherein the intestinal penetration agent is a calcium phosphate nanoparticle.

136. The method of claim 47 wherein the intestinal penetration agent is a fatty acid, a medium-chain glyceride, a surfactant, a steroidal detergent, an acyl carnitine, an alkanoyl choline, an N-acetylated amino acid, esters, salts and derivatives thereof, or any combination thereof.

137. The method of claim 47 wherein the intestinal penetration agent is an orthoester derivative of a crown ether of Formula (LXXVIII) wherein: m is 4, 5, 6, 7, or 8; (ii) i is independently for each occurrence, 1 or 2; (iii) each occurrence of R1and R2is independently selected from hydrogen; linear or branched and substituted or unsubstituted C1-C10alkyl, alkenyl, or alkynyl; and substituted or unsubstituted aryl with up to 10 ring atoms, or R1and R2form an oxo group; and (iv) there is at least one occurrence in the crown ether of R1, R2, and the carbon to which R1and R2are bound, the carbon being bound directly to an ether oxygen ofPATENT PARSON-58748 Formula (LXXVIII), form together a group of Subformula (LXXVIII(a)), wherein, in Subformula (LXXVIII(a)), L is a linker that is absent or is selected from a covalent bond and (CR5R6)n, each occurrence of R5and R6being independently selected from: hydrogen; linear or branched and substituted or unsubstituted C1-C10 alkyl, alkenyl, or alkynyl; and substituted or unsubstituted aryl with up to 10 ring atoms; n is 1, 2, or 3; X and Y, independently from each other, are selected from O and S; Z, independently for each occurrence, is absent or an electron- withdrawing group; R3and R4, independently for each occurrence, are selected from: hydrogen; linear or branched and substituted or unsubstituted C1-C10alkyl, alkenyl, or alkynyl; and substituted or unsubstituted aryl with up to 10 ring atoms; H(OCH2CH2)k— H(OCH2CH2)kO—, wherein k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and wherein substituents, if present, are selected from hydroxyl, halogens, and O-CH3.

138. The method of claim 47 wherein the intestinal penetration agent is a crown compound selected from the group consisting of a cyclic polyester, a cyclic polyamide, a cyclic polyether, a cyclic polyoxime, a polythioester, a polymer of aminoxy acids, a polydisulfide, a cyclic depsipeptide, and a cyclic polydioxanone, wherein the crown compound is a cation- binding crown compound capable of forming a charge masking complex with a cation.

139. The method of claim 47 wherein the intestinal penetration agent comprises acylcarnitines, phospholipids, and bile acids.

140. The method of claim 47 wherein the intestinal penetration agent has a covalent linkage to a membrane translocator that is a peptide, fatty acid, or bile acid.

141. The method of claim 47 wherein the intestinal penetration agent is an acyl- L-carnitine.

142. The method of claim 47 wherein the intestinal penetration agent includes: (i) an anionic agent that is a cholesterol derivative, (ii) a mixture of a negative charge neutralizer and an anionic surface active agent, (iii) a non-ionic surface active agent, and (iv) a cationic surface active agent.

143. The method of claim 47 wherein the intestinal penetration agent is 4-[(4- chloro, 2-hydroxybenzoyl)amino] butanoic acid.

144. The method of claim 47 wherein the intestinal penetration agent is a compound with a cyclic moiety selected from the group consisting of: 3-[4- (cyclopropylmethoxy)phenyl]propanoic acid; 4-(cyclobutylmethoxy)benzoic acid; [4-PATENT PARSON-58748 (cyclobutylmethoxy)-3-methoxyphenyl]acetic acid; 4-(cyclopropylmethoxy)benzoic acid; [4- (cyclopropylmethoxy)phenyl]acetic acid; 2-(cyclobutylmethoxy)benzoic acid; [4- (cyclopentyloxy)-3-methoxyphenyl]acetic acid; [4-(cyclopropylmethoxy)-3- methoxyphenyl]acetic acid; 2-(cyclopropylmethoxy)benzoic acid; 2-(cyclopentyloxy)benzoic acid; 2-(cyclohexylmethoxy)benzoic acid; 3-(cyclopropylmethoxy)benzoic acid; 3- (cyclobutylmethoxy)benzoic acid; 3-(cyclopentyloxy)benzoic acid; 3- (cyclohexylmethoxy)benzoic acid; 4-(cyclopentyloxy)benzoic acid; 4-(cyclopentyloxy)benzoic acid; [4-(cyclobutylmethoxy)phenyl]acetic acid; 3-[4-(cyclobutylmethoxy)phenyl]propanoic acid; [4-(cyclohexylmethoxy)phenyl]acetic acid; 3-[4-(cyclohexylmethoxy)phenyl]propanoic acid; [4-(cyclohexylmethoxy)-3-methoxyphenyl]acetic acid; 3-[2- (cyclopropylmethoxy)phenyl]propanoic acid; [4-(cyclopentyloxy)phenyl]acetic acid; and 3-[4- (cyclopentyloxy)phenyl]propanoic acid.

145. The method of claim 47 wherein the intestinal penetration agent is a disodium salt, an ethanol solvate, or a hydrate of a compound selected from the group consisting of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate.

146. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (LXXIX) wherein: (i) Y is carbonyl or SO2; (ii) R1is C3-C24alkyl, C2- C20alkenyl, C2-C20alkynyl, cycloalkyl, or aromatic; (iii) R2is hydrogen, C1-C4alkyl, or C2-C4alkenyl; and (iv) R3 is C1-C7 alkyl, C3-C10 cycloalkyl, aryl, thienyl, pyrrolo, or pyridyl, wherein R3 is optionally substituted with one or more C1-C5 alkyl groups, C2-C4 alkenyl groups, halogen, SO2, CO2H, or SO3H.

147. The method of claim 47 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXXX), (LXXXI), (LXXXII), (LXXXIII), or (LXXXIV), wherein: in Formula (LXXX), (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with one or more of hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; (iii) R1is C3-C20 alkyl, C4-C20 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10alkenyl)phenyl, (C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10alkyl), phenyl(C1-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C1-C10alkenyl); (iv) R1is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl, or sulfhydryl or any combination thereof; (v) R2is hydrogen, C1-C4 alkyl,PATENT PARSON-58748 or C2-C4 alkenyl; and (vi) R1is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; wherein the term “2-OH—Ar” refers to a phenyl or naphthyl group having a hydroxyl group at the 2-position; in Formula (LXXXI), (i) R1, R2, R3, and R4are each independently hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, --C(O)R8, --NO2, --NR9R10, or –N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, --NO2, halogen, --CF3, -- NR14R15, –N+R14R15R16(R13)-, amide, C1-C12 alkoxy, C1-C12 alkyl, C1-C12 alkenyl, carbamate, carbonate, urea, or --C(O)R18; (iii) R5is optionally substituted with halogen, hydroxyl, sulfhydryl, or carboxyl; (iv) R5is optionally interrupted by O, N, S, or –C(O)--; (v) R6is a C1- C12alkylene, C1-C12alkenylene, or arylene; (vi) R6is optionally substituted with C1-C4alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, halogen, amino, or –CO2R8; (vii) R6is optionally interrupted by O or N; (viii) R7is a bond or arylene; (ix) R7is optionally substituted with hydroxyl, halogen, --C(O)CH3, --NR10R11, or –N+R10R11R12(R13)-; (x) R8is hydrogen, C1- C4 alkyl, C2-C4 alkenyl, or amino; (xi) R9, R10, R11, and R12are independently hydrogen or C1- C10 alkyl; (xii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiii) R14, R15, and R16are each independently hydrogen, C1-C10alkyl, C1-C10alkyl substituted with carboxyl, C2-C12 alkenyl, C2-C12 alkenyl substituted with carboxyl, or –C(O)R17; (xiv) R17is hydroxyl, C1- C10 alkyl, or C2-C12 alkenyl; and (xv) R18is hydrogen, C1-C6 alkyl, hydroxyl, --NR14R15, or – N+R14R15R16(R13)-; in Formula (LXXXII), (i) R1, R2, R3, R4, and R5are each independently hydrogen, --CN, hydroxyl, --OCH3, or halogen, wherein at least one of R1, R2, R3, R4, and R5is – CN; and (ii) R6is a C1-C12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene); in Formula (LXXXIII), (i) each occurrence of X is hydrogen, halogen, hydroxyl, or C1-C3alkoxy; (ii) R is substituted or unsubstituted C1-C3alkylene or substituted or unsubstituted C2-C3 alkenylene; and (iii) n is 1, 2, 3, or 4; and in Formula (LXXXIV), (i) X is halogen; and (ii) R is substituted or unsubstituted C1-C3 alkylene or substituted or unsubstituted C2-C3alkenylene.

148. The method of claim 47 wherein the intestinal penetration agent is selected from the group consisting of 3-(3-hexyloxy-2-hydroxy-propoxy)-propane-1,2-diol and 3-[2-hydroxy-3-(2-hydroxy-2-octyloxy-propoxy)-propoxy]-propane-1,2-diol.

149. The method of claim 47 wherein the intestinal penetration agent is a phenylalkylcarboxylic acid selected from the group consisting of 4-(4-methoxyphenyl)butanoic acid, 5-(2-methoxyphenyl)pentanoic acid, 5-(3-fluorophenyl)pentanoic acid, 5-(3-PATENT PARSON-58748 methoxyphenyl)pentanoic acid, 6-(3-fluorophenyl)hexanoic acid, 3-(4-t-butylphenyl)propanoic acid, 3-(4-n-butylphenyl)propanoic acid, 3-(4-n-propylphenyl)propanoic acid, 3-(4-n- propoxyphenyl)propanoic acid, 3-(4-isopropoxyphenyl)propanoic acid, 3-(4-n- butoxyphenyl)propanoic acid, 3-(3-phenoxyphenyl)propanoic acid, 3-(3-ethoxyphenyl)propanoic acid, 3-(3-isopropoxyphenyl)propanoic acid, 3-(3-n-butoxyphenyl)propanoic acid, 3-(3-n- propoxyphenyl)propanoic acid, 3-(3-isobutoxyphenyl)propanoic acid, 3-(4- isobutoxyphenyl)propanoic acid, 4-(4-ethylphenyl)butanoic acid, 4-(4-isopropylphenyl)butanoic acid, and 5-(4-ethylphenyl)pentanoic acid, and pharmaceutically acceptable salts thereof.

150. The method of claim 47 wherein the intestinal penetration agent is an oxadiazole of Formula (LXXXV) wherein: (1) R1is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, phenyl, naphthyl, or aromatic heterocyclyl; (2) R1is optionally substituted with C1-C4alkyl or fluoroalkyl, C2-C4alkenyl, C1-C4alkoxy or fluoroalkoxy, halo, hydroxyl, sulfhydryl, phenyl, phenoxy, --CO2R3, --N(CH3)2, --NO2, or amino; (3) R2is C1-C24 alkylene, C2-C24 alkenylene, C3-C10 cycloalkylene, C3-C10 cycloalkenylene, phenylene, naphthalene, (C1-C10alkyl)phenylene, (C2-C10alkenyl)phenylene, (C1-C10alkyl)naphthalene, (C2-C10 alkenyl)naphthalene, phenyl(C1-C10 alkylene), phenyl(C2-C10 alkenylene), naphthyl(C1- C10 alkylene), or naphthyl(C2-C10 alkenylene); (4) R2is optionally substituted with C1-C4 alkyl or fluoroalkyl, C2-C4alkenyl, C1-C4alkoxy or fluoroalkoxy, halo, hydroxyl, sulfhydryl, phenyl, phenoxy, --CO2R3, --N(CH3)2, --NO2, amino, C3-C10cycloalkenyl, aryl, (C1-C10alkyl)aryl, heterocyclyl having 3-10 ring atoms wherein the heteroatom is one or more of N, O, S, or any combination thereof; (5) R2is optionally interrupted by N, O, S, or any combination thereof; and (6) R3is hydrogen, C1-C4alkyl, or C2-C4alkenyl, with the provisos that: (i) R1is not 4- (piperidin-4-yl)phenyl when R2is –(CH2)4--; (ii) R1is not –CH3 when R2is –(CH2)3--; and (iii) R1is not 4-carboxyphenyl when R2is –(CH2)3— or R2is –(CH2)4—.

151. The method of claim 47 wherein the intestinal penetration agent is a dialkyl ether of Formula (LXXXVI) wherein: (1) A is a C1-C6 alkylene group; (2) B is a C1-C2 alkylene group; and (3) R1, R2, R3, R4, and R5 are independently hydrogen, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, --C(O), --NO2, NR9R10, N+R9R10R11(R12), carbonate, ureido, --CX3, or –CN, optionally interrupted by O, N, S, or – C(O)— group, where A and R1 may form a cycloalkyl group, wherein: (a) R8is independentlyPATENT PARSON-58748 H, C1-C4 alkyl, C2-C6 alkenyl, or an –NH2 group; (b) R9, R10, R11, and R12are independently H or C1-C10alkyl; and (c) X is halogen.

152. The method of claim 47 wherein the intestinal penetration agent is a phenoxyalkyl diethanolamine or phenoxyalkyl diisopropanolamine intestinal penetration agent.

153. The method of claim 47 wherein the intestinal penetration agent is a ketopiperazine intestinal penetration agent of Formula (LXXXVII), wherein: (1) R1, R2, or R1and R2independently are hydrogen, C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, C1-C10alkenyl)phenyl, (C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10alkyl), phenyl(C1-C10alkenyl), naphthyl(C1-C10alkyl), and naphthyl(C1-C10alkenyl); (2) R1, R2, or R1and R2, optionally, are independently substituted with C1-C4 alkyl, C1- C4 alkenyl, C1-C4 alkoxy, hydroxy, sulfhydryl, and –CO2R3or any combination thereof, wherein R3is hydrogen, C1-C4alkyl, or C1-C4alkenyl; (3) wherein the phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are independently substituted by C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, hydroxy, sulfhydryl, or –CO2R4, wherein R4is hydrogen, C1-C6 alkyl, C1-C6 alkenyl; and (4) R1and R2are not both hydrogen.

154. The method of claim 47 wherein the penetration agent is selected from the group consisting of: 6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid; 8(2- aminobenzoylamino)caprylic acid; 8(2-trifluoromethoxy)benzoylamino caprylic acid; N-(2- hydroxybenzoyl)isonipecotic acid; 54-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid; 4-[4-(pentafluorobenzoyl)aminophenyl)butyric acid; 4-[4-(3-anisoyl)aminophenyl)butyric acid; 8-(3-anisoyl)aminocapryic acid; 4-[4-(phenoxyacetyl)aminophenyl)butyric acid; 4-(4-(2- nitrobenzenesulfonyl)aminophenyl)butyric acid; 8-(2-nitrobenzenesulfonyl)aminocaprylic acid; 6-(4-(salicyloyl)aminophenyl)hexanoic acid; 8-(2-methoxylbenzoyl)aminocaprylic acid; 2-[4- salicyloylamino)phenyl]ethyl methylsulfone; 1-salicyloyl-2-succinyl hydrazide; 3-(4-(2,5- dimethoxycinnamoyl)aminophenyl)propionic acid; 4-(4-(2,5- dimethoxycinnamoyl)aminophenyl)butyric acid; 1-salicyloyl-2-glutaryl hydrazide; succinyl-4- aminosalicylic acid; 8-(phenoxyacetylamino)caprylic acid; 8-(2-pyrazinecarbonyl)aminocaprylic acid; 4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid; 6-(4-(N-2- nitrobenzoyl)aminophenyl)hexanoic acid; 6-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid; 4-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid; 4-(2- nitrobenzoyl)aminophenylsuccinic acid; 8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid; 8-PATENT PARSON-58748 (benzylcarbonylamino)caprylic acid; 8-(phenylcarbonylamino)caprylic acid; 2-[4-(2- methoxybenzoylamino)phenyl]ethyl phosphate; 1-salicyloyl-2-suberyl hydrazide; 4-(4- benzyloxycarbonylaminophenyl)butyric acid; 4-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid; 9-salicyloylaminononanoic acid; 4-(4-phenyloxycarbonylaminophenyl)butyric acid; 3-(2- methoxybenzoylamino)-1-propanol; 8-(2-hydroxynicotinoyl)aminocaprylic acid; 6-(2- methoxybenzoyl)aminonicotinic acid; salicyloylglycine; 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid; 8-(chromone-3-carbonyl)aminocaprylic acid; 8-(vinylbenzoyl)aminocaprylic acid; 4-(4- (chromone-3-carbonyl)aminophenyl)butyric acid; 8-cinnamoylaminocaprylic acid; 5-(N- salicyloylamino)valeric acid; 9-(2-hydroxybenzamido)nonanoic acid; N-(4-salicyloylamino)-6- caproic acid; 4′-flavonic acid; 11-cinnamoylaminoundecanoic acid; 4-octanoylamino-3- hydroxybenzoic acid; (3-phenyl-2,3-dihydroxypropanoyl)8-aminocaprylic acid; 8-[N-(3- coumarincarbonyl)]aminocaprylic acid; 8-[N-(4-chlorobenzoyl)]aminocaprylic acid; 8-[N-3- fluorobenzoyl)]aminocaprylic acid; 8-(N-2,5-dihydroxybenzoyl)aminocaprylic acid; 8-(N-2,3- dimethoxybenzoyl)aminocaprylic acid; 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid; 8-(N- 2,5-dimethoxybenzoyl)aminocaprylic acid; 8-(N-3,5-diacetyloxybenzoyl)aminocaprylic acid; 8- (N-4-hydroxybenzoyl)aminocaprylic acid (dimer); 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid; 10-(N-2-methoxyanilino)sebacic acid; 10-(N-2-hydroxyanilino)sebacic acid; 2- methoxybenzaminodecanoic acid; 8-(N-benzoyl)aminocaprylic acid; 8-(N-2-hydroxy-4- methoxybenzoyl)aminocaprylic acid; 8-[N-(4-fluorobenzoyl)]aminocaprylic acid; 8-[N-(3- bromobenzoyl)]aminocaprylic acid; 8-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid; 8-[N- (4-bromobenzoyl)]aminocaprylic acid; 8-[N-(4-iodobenzoyl)]aminocaprylic acid; 4-{4-[N-(2- iodobenzoyl)aminophenyl]}butyric acid; 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid; 4-(4-(2,4-dimethoxybenzoyl)aminophenyl)butyric acid; 4-(o-anisoyl)aminophenylacetic acid; 3-[4-(2,4-dimethoxybenzoyl) aminophenyl]propionic acid; 4-{4-[N-(4- iodobenzoyl)]aminophenyl}butyric acid; 3-[4-(2,3-dimethoxybenzoyl) aminophenyl]propionic acid; 4{4-[N-2-bromobenzoyl)]aminophenyl}butyric acid; 4{-[N-3-bromobenzoyl) aminophenyl}butyric acid; 8-(N-3,5-dihydroxybenzoyl)aminocaprylic acid; (N-3,5-dimethoxy 4- hydroxybenzoyl)aminocaprylic acid; 8-(N-2-6-dimethoxybenzoyl)aminocaprylic acid; 4-{4-[N- (4-bromobenzoyl)aminophenyl]}butyric acid; 8-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid; 8-(N-2,6-dihydroxybenzoyl)aminocaprylic acid; 8-(N-2-hydroxy-6- methoxybenzoyl)aminocaprylic acid; 8-(5-chloro-o-anisoyl)aminocaprylic acid; 4-(4-(2,3-PATENT PARSON-58748 dimethoxybenzoyl)aminophenyl)butyric acid; 4-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid; 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid; 8-(4-chloro-o-anisoyl)aminocaprylic acid; 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid; 4-{N-[4-(3- iodobenzoyl)aminophenyl]}butyric acid; 7-cinnamoylaminoheptanoic acid; 8-N-(3- iodobenzoyl)aminocaprylic acid; 8-N-(3-iodobenzoyl)aminocaprylic acid; 8-N-(2-methoxy-4- nitrobenzoyl)aminocaprylic acid; 4-{N-[4-(2-methoxy-4-nitrobenzoyl)aminophenyl]}butyric acid; 4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid; 8-(N-2-hydroxy-5- bromobenzoyl)aminocaprylic acid; 3-indolebutyric acid; 4-(4-(2,6- dimethoxybenzoyl)aminophenylbutyric acid; 4-[4-N-(4-methoxy-3- nitrobenzoyl)aminophenyl]butyric acid; 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid; 8- (N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid; 8-(3-hydroxy-3-naphthoyl)aminocaprylic acid; 8-(N-2-hydroxy-4-nitrobenzoyl)aminocaprylic acid; 4-[N-(2-hydroxy-4- bromobenzoyl)aminophenyl]butyric acid; 8-(N-2,3-dihydroxybenzoyl)aminocaprylic acid; 8-(N- 3-methylsalicyloyl)aminocaprylic acid; 8-(N-5-methylsalicyloyl)aminocaprylic acid; 9- (cinnamoylamino)nonanoic acid; 4-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid; 4-{- [N-(2-hydroxy-5-iodobenzoyl)]aminophenyl}butyric acid; N-2-nitrophenyl-N′-(8-octanoic acid) urea; N-(2-methoxy-5-nitrophenyl) sebacoyl amide acid; 8-[N-(2-acetoxy-3,5- dichlorobenzoyl)]aminocaprylic acid; 8-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid; 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid; 8-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid; 4-(4-salicyloylaminophenyl)-4-oxobutyric acid; 12-cinnamoyldodecanoic acid; 4-{4-[N-(3- hydroxy-2-napthoyl)aminophenyl]}butyric acid; 8-(4-chloro-3-nitrobenzoyl)aminocaprylic acid; 8-(2-chloronicotinoyl)aminocaprylic acid; 8-(2-chloro-5-nitrobenzoyl)aminocaprylic acid; 4-(4- phthalimidophenyl)butyric acid; 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}propanoic acid; 3-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid; 8-(N-2-hydroxy-3,5- diiodobenzoyl)aminocaprylic acid; 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid; 8-(2- (1,2-dihydroisoindole-1-one))octanoic acid; 8-(N-2-hydroxy-2-naphthoyl)aminocaprylic acid; 8- (phthalimido)caprylic acid; 10-(4-chloro-2-hydroxyanilino)sebacic acid monoamide; 6- (anisoyl)aminocaproic acid; 4-(4-(4-chloro-3-nitrobenzoyl)aminophenyl)butyric acid; 11-N-(1- hydroxy-2-naphthoyl)aminoundecanoic acid; bis(N-2-carboxylphenyl-N-(N′-8-acid)oxalyl diamide; 2-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol; 2-[2-N-(4- chlorobenzoyl)aminoethoxy]ethanol; 4-(2-methoxybenzoyl)amino 3-carboxysulfoxide; 4-(2-PATENT PARSON-58748 methoxybenzoyl)amino 3-carboxypropylsulfone; 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid; [2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol; 2-[2-N-(3- chlorobenzoyl)aminoethoxy)]ethanol; bis(N-2-carboxyphenyl-N-(N′-3(4-aminophenyl)propionic acid)urea)oxalyl diamide; trans-4-(2-aminobenzamidomethyl)cyclohexaminylcarboxylic acid; 11-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid; 2-[N-(2- bromobenzoyl)aminoethoxyl]ethanol; 7-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid; N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid; trans-4-(N- salicyloylaminomethyl)cyclohexane carboxylic acid; N-[3,5-dichloro-2-hydroxybenzoyl-3-(4- aminophenyl)]propionic acid; 12-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid; N- (2-hydroxy-4-carboxy)-6-heptenamide; N-(2-bromobenzoyl)morpholine; N- cyclohexanoylaminocaprylic acid; 2-[N-(2-iodobenzoyl)aminoethoxyl]ethanol; 5-(4-chloro-2- hydroxyanilinocarbonyl)valeric acid; 8-(2-hydroxyphenoxy)-aminocaprylic acid; N-salicyloyl-5- (3-aminophenyl)valeric acid; 4-(4-(2-ethoxylbenzoyl)aminophenyl)butyric acid; 9-[2-(3- hydroxy)pyridylaminocarbonyl]nonanoic acid; 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid; 2-[N-(2-hydroxybenzoylamino)ethoxyl]ethanol; 4-[N-(3,5-dichloro-2- hydroxybenzoyl)]aminophenylacetic acid; 8-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid; N-salicyloyl-5-(4-aminophenyl)valeric acid; 9-(2-hydroxy-5-methylanilinocarbonyl)nonanoic acid; 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid; 8-(pentafluorobenzoyl)aminocaprylic acid; 3-(3-(salicyloyl)aminophenyl)propionic acid; 8-(2-ethoxybenzoyl)aminocaprylic acid; 4-(4-(2-dimethylaminobenzoic)aminophenyl)butyric acid; 8-(3-phenoxylpropionylamino)caprylic acid; 4-(salicyloyl)aminophenylethyltetrazole; 8(- (4-(N-salicyloyl-4aminophenyl)butyric)aminocaprylic acid); 4-(4-(N-(2- fluorocinnamoyl))aminophenyl) butyric acid; 4-(4-(N-8(N- salicyloyl)aminocaprylic)aminophenyl)butyric acid; 8-(p-anisoyl)aminocaprylic acid; 8-(4- hydroxybenzoyl)aminocaprylic acid; 8-(3-hydroxybenzoyl)aminocaprylic acid; 8-(3,4,5- trimethoxybenzoyl)aminocaprylic acid; 8-(N-4-methylsalicyloyl)aminocaprylic acid; N-10-(2- hydroxy-5-nitroanilino)decanoic acid; and 4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid.

155. The method of claim 47 wherein the penetration agent is a compound of Formula (LXXXVIII), (LXXXIX), (XC), or (XCI).

156. The method of claim 47 wherein the penetration agent is a compound of Formula (XCII) wherein: (1) R1, R2, R3, R4, and R5are independently hydrogen, cyano,PATENT PARSON-58748 hydroxy, --OCH3, or halogen, wherein at least one of R1, R2, R3, R4, and R5is cyano; (2) R6is C1-C12linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene); and (3) with the proviso that when R1is cyano, R4is hydrogen or cyano, and R2, R3, and R5are hydrogen, then R6is methylene.

157. The method of claim 47 wherein the intestinal penetration agent is a phenoxycarboxylic acid of Formula (XCIII) wherein: (1) R1, R2, R3, and R4are independently hydrogen, hydroxy, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, --C(O)R8, nitro, NR9R10, or N+R9R10R11(R12)-; (2) R5is hydrogen, hydroxy, nitro, halogen, --CF3, NR14R15, N+R14R15R16(R13)-, amide, C1-C12alkoxy, C1-C12alkyl, C1-C12alkenyl, carbamate, carbonate, urea, or – C(O)R18; (3) R5is optionally substituted with halogen, sulfhydryl, or carboxy; (4) R5is optionally interrupted by O, N, S, or –C(O)--; (5) R6is a C1-C12 alkylene, C2-C12 alkenylene, or arylene; (6) R6is optionally substituted with C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, hydroxy, sulfhydryl, halogen, amino, or –CO2R8; (7) R6is optionally interrupted with O or N; (8) R7is a valence bond or arylene; (9) R7is optionally substituted with hydroxy, halogen, --C(O)CH3, -- NR10R11, or –N+R10R11R12(R13)-; (10) R8is hydrogen, C1-C4alkyl, C2-C4alkenyl, or amino; (11) R9, R10, R11, and R12are independently hydrogen or C1-C10 alkyl; (12) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (13) R14, R15, and R16are independently hydrogen, C1- C10alkyl, C1-C10alkyl substituted with carboxy, C2-C12alkenyl, C2-C12alkenyl substituted with carboxy, or –C(O)R17; (14) R17is hydroxy, C1-C10alkyl, or C2-C12alkenyl; and (15) R18is hydrogen, C1-C6 alkyl, hydroxyl, --NR14R15, or –N+R14R15R16(R13)-,with the following provisos: (a) when R1, R2, R3, R4, and R5are hydrogen and R7is a bond, then R6is a C1-C6, C9, or C10 alkyl; (b) when R1, R2, R3and R4are hydrogen and R5is hydroxyl, and R7is a bond, then R6is not a C1-C3 alkyl; (c) when at least of R1, R2, R3and R4is not hydrogen, R5is hydroxyl, and R7is a bond, then R6is not a C1-C4 alkyl; (d) when R1, R2, and R3are hydrogen, R4is –OCH3, R5is –C(O)CH3, and R6is a bond, then R7is not a C3alkyl; and (e) when R1, R2, R4, and R5are hydrogen, R3is hydroxyl, and R7is a bond, then R6is not methyl.

158. The method of claim 47 wherein the intestinal penetration agent is a compound of Formula (XCIV) wherein: (1) R1, R2, R3, R4, and R5are independently selected from hydrogen, halogen, hydroxy, methoxy, C1-C4alkyl, amino, methylamino, dimethylamino, or nitro; (2) m is an integer ranging from 0 to 4; (3) R6is a phenyl substituted with –O—R7- COOH at the ortho, meta, or para position; (4) R6is optionally substituted with one or morePATENT PARSON-58748 moieties selected from the group consisting of halogen, hydroxy, methoxy, C1-C4 alkyl, amino, methylamino, dimethylamino, and nitro; and (5) R7is C1-C12alkylene.

159. The method of claim 47 wherein the intestinal penetration agent is 8-(2- hydroxyphenoxy)octyldiethanolamine or a salt thereof.

160. The method of claim 47 wherein the intestinal penetration agent is a compound selected from the group consisting of Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), Compound (12), Compound (13), Compound (14), Compound (15), Compound (16), Compound (17), Compound (18), Compound (19), and Compound (20).

161. The method of claim 47 wherein the intestinal penetration agent is a disodium salt, a monohydrate, or an ethanol solvate of a compound of Formula (XCV) wherein: (1) R1, R2, R3, and R4are independently hydrogen, halogen, C1-C4alkyl, or C1-C4alkoxy; and (2) R5is a substituted or unsubstituted C2-C16 alkylene, substituted or unsubstituted C2-C16 alkenylene, substituted or unsubstituted C1-C12 alkyl(arylene), or substituted or unsubstituted aryl(C1-C12alkylene).

162. The method of claim 47 wherein the intestinal penetration agent is a phenylalkylcarboxylic acid of Formula (XCVI) wherein: (1) n is 1-12; and (2) R1-R5are each independently hydrogen, C1-C6alkyl, C2-C4alkenyl, halogen, C1-C4alkoxy, hydroxy, C6-C14aryloxy, or C1-C6haloalkyl.

163. The method of claim 47 wherein the intestinal penetration agent is a compound possessing both at least one hydrophobic group and at least one hydrophilic group.

164. The method of claim 163 wherein the at least one hydrophobic group is selected from the group consisting of phenyl groups, naphthyl groups, cyclohexyl groups, and long-chain aliphatic groups.

165. The method of claim 163 wherein the at least one hydrophilic group is selected from the group consisting of carboxylic acid groups, carboxylic acid ester groups, amide groups, amino groups, and carbonyl groups.

166. The method of claim 1 wherein the method comprises the administration of a pharmaceutically acceptable carrier in a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective quantity of thePATENT PARSON-58748 glycosaminoglycan / sulfated polysaccharide and a suitable quantity of the pharmaceutically acceptable carrier.

167. The method of claim 166 wherein the agent is a salt of pentosan polysulfate.

168. The method of claim 167 wherein the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate, calcium pentosan polysulfate, lithium pentosan polysulfate, rubidium pentosan polysulfate, cesium pentosan polysulfate, magnesium pentosan polysulfate, strontium pentosan polysulfate, and barium pentosan polysulfate.

169. The method of claim 168 wherein the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate and calcium pentosan polysulfate.

170. The method of claim 169 wherein the salt of pentosan polysulfate is sodium pentosan polysulfate.

171. The method of claim 166 wherein the glycosaminoglycan is selected from the group consisting of chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and keratan sulfate.

172. The method of claim 166 wherein the pharmaceutically acceptable carrier is selected from the group consisting of: acidifying agents; aerosol propellants; air displacements; alcohol denaturants; alkalizing agents; anticaking agents; antifoaming agents; antimicrobial preservatives; antioxidants; buffering agents; capsule lubricants; chelating agents; coating agents; colorants; complexing agents; desiccants; emulsifying and / or solubilizing agents; filtering aids; flavors and perfumes; glidants and / or anticaking agents; humectants; plasticizers; polymers; solvents; sorbents; carbon dioxide sorbents; stiffening agents; suspending and / or viscosity-increasing agents; sweetening agents; tablet binders; tablet and / or capsule diluents; tablet disintegrants; tablet and / or capsule lubricants; tonicity agents; vehicles (flavored and / or sweetened); vehicles (oleaginous); vehicles (solid carrier); vehicles (sterile); water-repelling agents; and wetting and / or solubilizing agents.

173. The method of claim 9 wherein the method comprises the administration of a pharmaceutically acceptable carrier in a pharmaceutical composition, wherein thePATENT PARSON-58748 pharmaceutical composition comprises a pharmacologically effective quantity of the intestinal penetration agent and a suitable quantity of the pharmaceutically acceptable carrier.

174. The method of claim 173 wherein the intestinal penetration agent is selected from the group consisting of intestinal penetration agents of Alternatives (1)-(114) and derivatives or analogs thereof.

175. The method of claim 173 wherein the pharmaceutically acceptable carrier is selected from the group consisting of: acidifying agents; aerosol propellants; air displacements; alcohol denaturants; alkalizing agents; anticaking agents; antifoaming agents; antimicrobial preservatives; antioxidants; buffering agents; capsule lubricants; chelating agents; coating agents; colorants; complexing agents; desiccants; emulsifying and / or solubilizing agents; filtering aids; flavors and perfumes; glidants and / or anticaking agents; humectants; plasticizers; polymers; solvents; sorbents; carbon dioxide sorbents; stiffening agents; suspending and / or viscosity-increasing agents; sweetening agents; tablet binders; tablet and / or capsule diluents; tablet disintegrants; tablet and / or capsule lubricants; tonicity agents; vehicles (flavored and / or sweetened); vehicles (oleaginous); vehicles (solid carrier); vehicles (sterile); water-repelling agents; and wetting and / or solubilizing agents.

176. The method of claim 9 wherein the method comprises the administration of the glycosaminoglycan / sulfated polysaccharide in a first pharmaceutical composition, wherein the first pharmaceutical composition comprises a therapeutically effective quantity of the glycosaminoglycan / sulfated polysaccharide and a suitable quantity of a pharmaceutically acceptable carrier, and comprises the administration of the intestinal penetration enhancer in a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a pharmacologically effective quantity of the intestinal penetration enhancer and a suitable quantity of a pharmaceutically acceptable carrier.

177. The method of claim 9 wherein the method comprises the administration of the glycosaminoglycan / sulfated polysaccharide and the intestinal penetration enhancer in a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective quantity of the glycosaminoglycan / sulfated polysaccharide, a pharmacologically effective quantity of the intestinal penetration agent, and a suitable quantity of a pharmaceutically acceptable carrier.PATENT PARSON-58748 178. The method of claim 177 wherein the agent is a salt of pentosan polysulfate.

179. The method of claim 178 wherein the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate, calcium pentosan polysulfate, lithium pentosan polysulfate, rubidium pentosan polysulfate, cesium pentosan polysulfate, magnesium pentosan polysulfate, strontium pentosan polysulfate, and barium pentosan polysulfate.

180. The method of claim 179 wherein the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate and calcium pentosan polysulfate.

181. The method of claim 180 wherein the salt of pentosan polysulfate is sodium pentosan polysulfate.

182. The method of claim 176 wherein the glycosaminoglycan is selected from the group consisting of chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and keratan sulfate.

183. The method of claim 176 wherein the intestinal penetration agent is selected from the group consisting of intestinal penetration agents of Alternatives (1)-(114) and derivatives or analogs thereof.

184. The method of claim 176 wherein the pharmaceutically acceptable carrier is selected from the group consisting of: acidifying agents; aerosol propellants; air displacements; alcohol denaturants; alkalizing agents; anticaking agents; antifoaming agents; antimicrobial preservatives; antioxidants; buffering agents; capsule lubricants; chelating agents; coating agents; colorants; complexing agents; desiccants; emulsifying and / or solubilizing agents; filtering aids; flavors and perfumes; glidants and / or anticaking agents; humectants; plasticizers; polymers; solvents; sorbents; carbon dioxide sorbents; stiffening agents; suspending and / or viscosity-increasing agents; sweetening agents; tablet binders; tablet and / or capsule diluents; tablet disintegrants; tablet and / or capsule lubricants; tonicity agents; vehicles (flavored and / or sweetened); vehicles (oleaginous); vehicles (solid carrier); vehicles (sterile); water-repelling agents; and wetting and / or solubilizing agents.PATENT PARSON-58748 185. The method of claim 7 wherein the method further comprises administering a therapeutically effective quantity of an additional agent to treat Alzheimer’s disease.

186. The method of claim 185 wherein the additional agent to treat Alzheimer’s disease is selected from the group consisting of tacrine, rivastigmine, galantamine, donepezil, memantine, CPHPC ((R)-1-{6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxohexanoyl}pyrrolidine-2- carboxylic acid), and lecanemab.

187. The method of claim 185 wherein the additional agent to treat Alzheimer’s disease is an antidepressant.

188. The method of claim 187 wherein the antidepressant is a selective serotonin reuptake inhibitor selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, zimelidine, cericlamine, and panuramine.

189. The method of claim 187 wherein the antidepressant is a serotonin- norepinephrine reuptake inhibitor selected from the group consisting of venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran.

190. The method of claim 187 wherein the antidepressant is a serotonin modulator selected from the group consisting of vortioxetine and vilazodone.

191. The method of claim 187 wherein the antidepressant is a serotonin antagonist and reuptake inhibitor selected from the group consisting of etoperidone, lorpiprazole, lubazodone, mepiprazole, nefazodone, and trazodone.

192. The method of claim 187 wherein the antidepressant is a norepinephrine reuptake inhibitor selected from the group consisting of amedalin, CP-39,332 (1,2,3,4- tetrahydro-N-methyl-4-phenyl-2-naphthalenamine), daledalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, viloxazine, buproprion, ciclazindole, manifaxine, maprotiline, radafaxine, tapentadol, and teniloxazine.

193. The method of claim 187 wherein the antidepressant is a tricyclic antidepressant selected from the group consisting of amitriptyline, butriptyline, clomipramine, desipramine, dolesupin, doxepin, imipramine, iprindole, lofepramine, nortriptyline, protriptyline, and trimipramine.PATENT PARSON-58748 194. The method of claim 187 wherein the antidepressant is a tetracyclic antidepressant selected from the group consisting of mianserin, mirtazapine, pirlindole, setiptiline, aptazapine, esmirtazapine, metralindole, and oxprotiline.

195. The method of claim 187 wherein the antidepressant is a monoamine oxidase inhibitor selected from the group consisting of isocarboxazid, nialamide, phenelzine, hydracarbazide, tranylcypromine, bifemelane, moclobemide, toloxatone, rasagline, selegiline, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, and minaprine.

196. The method of claim 187 wherein the antidepressant is an atypical antidepressant selected from the group consisting of amisulpride, lurasidone, and quetiapine.

197. The method of claim 188 wherein the antidepressant is an antidepressant that acts by one or more other mechanisms selected from the group consisting of agomelatine, tandospirone, α-methyltryptamine, etryptamine, indeloxazine, medifoxamine, nomifensine, oxaflozane, and pivagabine.

198. The method of claim 8 wherein the neurodegenerative disease is Parkinson’s disease.

199. The method of claim 198 wherein the method further comprises administering a therapeutically effective quantity of an additional agent to treat Parkinson’s disease.

200. The method of claim 199 wherein the additional agent to treat Parkinson’s disease is levodopa.

201. The method of claim 199 wherein the additional agent to treat Parkinson’s disease is a monoamine oxidase inhibitor selected from the group consisting of isocarboxazid, nialamide, phenelzine, hydracarbazide, tranylcypromine, bifemelane, moclobemide, toloxatone, rasagline, selegiline, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, and minaprine.

202. The method of claim 199 wherein the additional agent to treat Parkinson’s disease is a dopamine agonist selected from the group consisting of bromocriptine, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, cabergoline, ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine, lisuride, propylnorapomorphine, roxindole, sumanirole, and fenaldopam.PATENT PARSON-58748 203. The method of claim 8 wherein the neurodegenerative disease is amyotrophic lateral sclerosis.

204. The method of claim 203 wherein the method further comprises administering a therapeutically effective quantity of an additional agent to treat amyotrophic lateral sclerosis.

205. The method of claim 204 wherein the additional agent to treat amyotrophic lateral sclerosis is selected from the group consisting of riluzole, edaravone, sodium phenylbutyrate / taurursodiol, toferse, gabapentin, and pregabalin.

206. The method of claim 8 wherein the neurodegenerative disease is multiple sclerosis.

207. The method of claim 206 wherein the method further comprises administering a therapeutically effective quantity of an additional agent to treat multiple sclerosis.

208. The method of claim 207 wherein the additional agent to treat multiple sclerosis is selected from the group consisting of interferon beta-1a, interferon beta-1b, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, natalizumab, mitoxantrone, ocrelizumab, siponimod, cladribine, ozanimod, and ponesimod.

209. A composition comprising: (a) a therapeutically effective quantity of a glycosaminoglycan / sulfated polysaccharide; and (b) a pharmacologically effective quantity of an intestinal penetration agent; wherein the composition is formulated to treat a neurodegenerative disease.

210. The composition of claim 209 wherein the agent is a salt of pentosan polysulfate.

211. The composition of claim 210 wherein the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate, calcium pentosan polysulfate, lithium pentosan polysulfate, rubidium pentosan polysulfate, cesium pentosan polysulfate, magnesium pentosan polysulfate, strontium pentosan polysulfate, and barium pentosan polysulfate.PATENT PARSON-58748 212. The composition of claim 211 wherein the salt of pentosan polysulfate is selected from the group consisting of sodium pentosan polysulfate and calcium pentosan polysulfate.

213. The composition of claim 212 wherein the salt of pentosan polysulfate is sodium pentosan polysulfate.

214. The composition of claim 209 wherein the glycosaminoglycan is selected from the group consisting of chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and keratan sulfate.

215. The composition of claim 209 wherein the composition further comprises a suitable quantity of a pharmaceutically acceptable carrier.

216. The composition of claim 215 wherein the pharmaceutically acceptable carrier is selected from the group consisting of: acidifying agents; aerosol propellants; air displacements; alcohol denaturants; alkalizing agents; anticaking agents; antifoaming agents; antimicrobial preservatives; antioxidants; buffering agents; capsule lubricants; chelating agents; coating agents; colorants; complexing agents; desiccants; emulsifying and / or solubilizing agents; filtering aids; flavors and perfumes; glidants and / or anticaking agents; humectants; plasticizers; polymers; solvents; sorbents; carbon dioxide sorbents; stiffening agents; suspending and / or viscosity-increasing agents; sweetening agents; tablet binders; tablet and / or capsule diluents; tablet disintegrants; tablet and / or capsule lubricants; tonicity agents; vehicles (flavored and / or sweetened); vehicles (oleaginous); vehicles (solid carrier); vehicles (sterile); water-repelling agents; and wetting and / or solubilizing agents.

217. The composition of claim 209 wherein the composition is formulated to treat Alzheimer’s disease.

218. The composition of claim 209 wherein the composition is formulated to treat a neurodegenerative disease selected from the group consisting of Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and multiple sclerosis.

219. The composition of claim 209 wherein the composition comprises sodium pentosan polysulfate and wherein the composition is formulated to reduce permeability of the mucus-containing layer of arteries of the central nervous system to amino-containing cations and thus stabilize the blood-brain barrier.PATENT PARSON-58748 220. The composition of claim 219 wherein the composition is formulated to reduce penetration of the blood-brain barrier by an amino-containing cation selected from the group consisting of protamine sulfate, 1-methyladenine, 1-methylguanine, 5-metrhylcytosine, N2,N2-dimethylguanosine, andL-tryptophan.

221. The composition of claim 209 wherein the intestinal penetration agent is selected from the group consisting of intestinal penetration agents of Alternatives (1)-(114) and derivatives or analogs thereof.

222. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of N-benzoyl-α-amino acids of Formula (II) and salts, analogues, or bioisosteres thereof, wherein the α-amino acid is selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tyrosine, aspartic acid, glutamic acid, lysine, ornithine, arginine, and serine, wherein X is selected from the group consisting of C(O) and SO2, and wherein Y is selected from the group consisting of phenyl and cyclohexyl.

223. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of derivatized leucines of Formula (III) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, 2- methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cycloheptyl, cyclopentyl, cyclopropyl, 2-carboxycyclohexyl, benzoyl, 3-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4- nitrophenyl, and (CH2)2cyclohexyl.

224. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of N-cyclohexanoylamino acids of Formula (IV) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl, methylcyclohexyl, (CH2)2cyclohexyl, phenyl, and 2-hydroxyphenyl.

225. The composition of claim 221 wherein the intestinal penetration agent is a derivatized phenylglycine of Formula (V) and salts, analogues, or bioisosteres thereof, wherein R is selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl, methylcyclohexyl, (CH2)2cyclohexyl, phenyl, and 2-hydroxyphenyl.

226. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of derivatives of 4-aminobenzoic acid, 2-(4- aminophenyl)acetic acid, 3-(4-aminophenyl)propionic acid, or 4-(4-aminophenyl)butyric acid of Formula (VI) and salts, analogues, or bioisosteres thereof, wherein: (a) Y is selected from thePATENT PARSON-58748 group consisting of H, F, 2-OH, 2,3-Ph, 4-Ph, 3,4-Ph, 4-OCH3, 4-F, 2-Cl, 2-F, 2,4-(OH)2, 3-CF3, 3-Cl, 2-CH3, 2,6-(OH)2, 3-N(CH3), 3,4-OCH2O, 2,6-diCH3, 2-COOH, 2-NO2, 2-OCH3, 3-NO2, 2-OCF3, 4-CH3, and 4-i-Bu; (b) n is 0, 1, 2, 3, 4, or a vinyl group; (c) m is 0, 1, or 2, a vinyl group, a CHMe group, a CHEt group; a (CH2)2O group, a (CH2)2C=O group, or a (CH2OH)2 group; (d) X is C=O, SO2, or CH2; and (e) Z is phenyl, cyclohexyl, or cycloheptyl.

227. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of compounds of Formula (VII), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, and salts, analogues, or bioisosteres thereof.

228. The composition of claim 227 wherein n is 7, 8, or 9.

229. The composition of claim 228 wherein the intestinal penetration agent is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate.

230. The composition of claim 221 wherein the intestinal penetration agent is agent is selected from the group of phenoxycarboxylic acid compounds of Formula (VIII), wherein: (i) R1, R2, R3, and R4are each independently hydrogen, hydroxyl, halo, C1-C4 alkyl, C2- C4alkenyl, C1-C4alkoxy, -C(O)R8, -NO2, -NR9R10, or –N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, -NO2, halo, trifluoromethyl, -NR14R15, –N+R14R15R16(R13)-, amide, C1-C12 alkoxy, C1- C12 alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or -C(O)R18; (iii) R5is optionally substituted with halo, hydroxyl, sulfhydryl, or carboxyl; (iv) R5is optionally interrupted by O, N, S, or –C(O)-; (v) R6is a C1-C12alkylene, C2-C12alkenylene, or arylene; (vi) C6is optionally substituted with a C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, halo, amino, or –CO2R8; (vii) R6is optionally interrupted by O or N; (viii) R7is a bond or arylene; (ix) R7is optionally substituted with hydroxyl, halogen, -C(O)CH3, -NR10R11, or –N+R10R11R12(R13)-; (x) R8is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or amino; (xi) R9, R10, R11, and R12are each independently hydrogen or C1-C10 alkyl; (xii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiv) R14, R15, and R16are each independently hydrogen, C1-C10alkyl, C1-C10 alkyl substituted with carboxyl, C2-C12 alkenyl, C2-C12 alkenyl substituted with carboxyl, or C(O)R17; (xv) R17is hydroxyl, C1-C10 alkyl, or C2-C12 alkenyl; (xvi) R18is hydrogen, C1-C6alkyl, hydroxyl, -NR14R15, or –N+R14R15R16(R13)-; with the proviso that: (a) when R1, R2, R3, R4, and R5are hydrogen and R7is a bond, then R6is not a C1-C6, C9, or C10alkyl; (b) when R1, R2, R3, and R4are hydrogen, R5is hydroxyl, and R7is a bond, then R6is not a C1-C3 alkyl; (c) when at least one of R1, R2, R3, and R4is not hydrogen, R5is hydroxyl, and R7isPATENT PARSON-58748 a bond, then R6is not a C1-C4 alkyl; (d) when R1, R2, and R3are hydrogen, R4is –OCH3, R5is C(O)CH3, and R6is a bond, then R7is not a C3alkyl; and (e) when R1, R2, R4, and R5are hydrogen, R3is hydroxyl, and R7is a bond, then R6is not a methyl group.

231. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of compounds of Formula (IX), wherein: m is 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, or 4, q and x are independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R may be the same or different and is selected from hydrogen, halogen, a substituted or non- substituted alkyl, substituted or non-substituted alkyloxyl, substituted or non-substituted alkenyloxyl, substituted or non-substituted alkynyloxyl and substituted or non-substituted aryloxyl; and R1, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, substituted or non-substituted alkyl, substituted or non-substituted alkenyl, substituted or non- substituted alkynyl, substituted or non-substituted alkyloxyl, substituted or non-substituted aryloxyl, substituted or non-substituted aryl groups, substituted or non-substituted heteroaryl, substituted or non-substituted cycloalkyl, and substituted or non-substituted heterocycloalkyl groups.

232. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of compounds with an aromatic nucleus of Formula (X), wherein: (i) R1is –(CH2)m-R8, wherein m is 0 or 1; (ii) R2, R3, R4, R5, and R6are each independently selected from hydrogen, hydroxyl, halo, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4 alkoxy, and cyano; (iii) R7 is selected from C1-C10 alkyl, C2-C10 alkenyl, and C2- C10 alkynyl; (iv) R8 is selected from cyclopentyl, cyclohexyl, and phenyl, wherein, when R8 is phenyl, m is 1; and (v) R8is optionally substituted with C1-C4alkyl, C1-C4alkoxy, halo, hydroxyl, or a combination thereof.

233. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of: (1) disodium salts of Formula (XI); (2) monohydrates of disodium salts of Formula (XI); and (3) alcohol solvates of disodium salts of Formula (XI), wherein the alcohol is methanol, ethanol, propanol, propylene glycol, or other monohydroxylic or dihydroxylic alcohols, wherein: : (i) R1, R2, R3, and R4are each independently hydrogen, hydroxyl, -NR6R7, halo, C1-C4alkyl, or C1-C4alkoxy; (ii) R5is a substituted or unsubstituted C2- C16 alkylene, substituted or unsubstituted C1-C12 alkyl(arylene), or substituted or unsubstitutedPATENT PARSON-58748 aryl(C1-C12 alkylene); and (iii) R6and R7are each independently hydrogen, oxygen, or C1-C4 alkyl.

234. The composition of claim 233 wherein the intestinal penetration agent is selected from the group consisting of N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N- (10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC), 8-(N-2-hydroxy-4-methoxybenzoyl)aminocaprylic acid, and N-(9-(2- hydroxybenzoyl)aminononanoic acid.

235. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of 8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid (“4-MOAC”), N-(8-[2-hydroxybenzoyl]-amino) caprylic acid (“NAC”), N-(8-[2- hydroxybenzoyl]-amino)decanoic acid (“NAD”), N-(8-[2-hydroxy-5-chlorobenzoyl]- amino)octanoic acid (“5-CNAC”), and 4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate (“4- CNAB”).

236. The composition of claim 221 wherein the intestinal penetration agent is the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid.

237. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XII), wherein: (i) R1, R2, R3, R4, and R5are each independently selected from hydrogen, halo, hydroxyl, -OCH3, C1-C4alkyl, amino, methylamino, dimethylamino, or nitro; (ii) m is 0, 1, 2, 3, or 4; (iii) R6is phenyl substituted with –O-R7-COOH at the ortho, meta, or para position; (iv) R6is optionally substituted with one or more substituents selected from hydrogen, halo, hydroxyl, -OCH3, C1-C4 alkyl, amino, methylamino, dimethylamino, or nitro; and (iv) R7is C1-C12alkyl.

238. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XIII), wherein: (i) R1and R2are each independently hydrogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, CF3, halo, or NR4R4′; (ii) R3is H or C1-C6alkyl; (iii) X is a 5-membered aromatic heterocycle that is optionally substituted with C1-C4alkyl; wherein the heterocycle contains at least two or three heteroatoms selected from N, S, and O wherein at least one heteroatom is N; (iv) Y is S, CR5=N or N=CR5; (v) n is 2, 3, 4, 5, 6, or 7; (vi) R4is H, COR6, SO2R7, or C1-C6alkyl; (vii) R4′is H or C1-C6alkyl; (viii) R5is H or forms a bond with X; (ix) R6is H or C1-C6 alkyl; and (x) R7is H or C1-C6 alkyl.PATENT PARSON-58748 239. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XIV).

240. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XV).

241. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XVa), wherein (i) R16is R3-R4; (ii) R3is -NHC(O)NH-, -C(O)NH-, -NHC(O) -, -OOC-, -COO, -NHC(O)O-, -OC(O)NH-, -CH2NH-, -N HCH2-, -CH2NHC(O)O-, -OC(O)NHCH2-, -CH2NHCOCH2O-, -OCH2C(O)NHCH2-, -NHC(O) CH2O-, -OCH2C(O)NH-, -NH-, -O-, or a carbon-carbon bond; R4is Formula (XVIa(1)); R5, R6, R7, R8, and R9are each independently a bond to R3, or hydrogen, chloro, bromo, fluoro, hydroxyl, methyl, methoxy, or -(CH2)mCH3; R10is a bond to R3, carboxyl, or –C(O)NHR11R12; R11is a substituted or unsubstituted, linear or branched alkylene having a chain length of 1 to 11 carbon atoms or –R13R14-; R12is a bond to R3, carboxyl, amino, hydroxyl, –C(O)–R15, –COO– R15, –NHR15, –OR15, chloro, or bromo; R13is a substituted or unsubstituted phenylene; R14is a substituted or unsubstituted, linear or branched alkylene having a chain length of 1 to 5 carbon atoms; R15is a bond to R3; m is 1, 2, 3, or 4; R17is hydroxyl or methoxy; R23is hydrogen or methyl; and n is an integer from 3 to 200.

242. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XVI), wherein: (i) R1and R2are each independently hydrogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, CF3, halo, or NR4R4′; (ii) R3is H or C1-C6 alkyl; (iii) R4is H, COR5, SO2R6, or C1-C6 alkyl; (iv) R4′is H or C1-C6 alkyl; (v) R5is H or C1- C6 alkyl; (vi) R6is H or C1-C6 alkyl; (vii) X is a 5-membered aromatic heterocycle that is optionally substituted with C1-C4 alkyl, wherein the heterocycle contains at least two or three heteroatoms selected from N, S, and O, wherein at least one heteroatom is N, and wherein the heterocycle is not 1,3,4-oxadiazole; and (ix) n is 2, 3, 4, 5, 6, or 7.

243. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XVII).

244. The composition of claim 221 wherein the intestinal penetration agent is (5-(2-hydroxy-4-chlorobenzoyl) aminovaleric acid.

245. The composition of claim 221 wherein the intestinal penetration agent is a cyanophenoxy carboxylic acid compound of Formula (XVIII), wherein: (i) R1, R2, R3, R4, and R5PATENT PARSON-58748 are each independently hydrogen, cyano, hydroxyl, -OCH3 or halogen, where at least one of R1, R2, R3, R4, and R5is cyano; (ii) R6is C1-C12linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene); with the proviso that where R1is cyano, R4is hydrogen or cyano, and R2, R3, and R5is not methylene.

246. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XIX).

247. The composition of claim 221 wherein the intestinal penetration agent is a compound selected from the group consisting of 4-(8-(2-hydroxyphenoxy)octyl)morpholine, 8- (2-hydroxyphenoxy)octyldiethanolamine, 7-(4-2-hydroxyphenoxy)heptylmorpholine, 4-(6-(4- hydroxyphenoxy)hexyl)morpholine, 4-(6-(2-hydroxyphenoxy)hexyl)morpholine, 8-(4- hydroxyphenoxy)octanamine, 6-(2-acetylphenoxy)-1-dimethylaminohexane, 7-(2- hydroxyphenoxy)heptyl-2-isopropylimidazole, 6-(2-hydroxyphenoxy)hexyl-2-methylimidazole, and 5-chloro-4-methyl-2-(8-morpholin-4-yloctyloxy)acetophenone.

248. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XX), including compounds with the following combinations of substituents: (1) R1, R2, R3, and R4are each hydrogen, R5is carboxyl, R6is (CH2)7, R7is a bond, and R8is hydrogen; (2) R1, R2, R3, and R4are each hydrogen, R5is C(O)NH2, R6is (CH2)7, R7is a bond, and R8is hydrogen; (3) R1, R2, R3, and R4are each hydrogen, R5is C(O)CH3, R6is (CH2)7, R7is a bond, and R8is hydrogen; (4) R1, R2, R3, and R4are each hydrogen, R5is C(O)NH2, R6is (CH2), R7is p-phenyl, and R8is hydrogen; and (5) R1, R2, R3, and R4are each hydrogen, R5is nitro, R6is (CH2)7, R7is a bond, and R8is hydrogen.

249. The composition of claim 221 wherein the intestinal penetration agent is a carbon-substituted diketopiperazine intestinal penetration agent of Formula (XXI), wherein: (i) R and R1are C1-C24 alkyl having a functional group selected from halogen, oxygen, sulfur or nitrogen; (ii) R and R1are optionally interrupted with O, N, or S; (iii) R and R1are optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or CO2R2or any combination thereof; and (iv) R2is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl.

250. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XXII).

251. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XXIII), wherein: (i) R1, R2, R3, and R4are each independently hydrogen,PATENT PARSON-58748 hydroxy, halo, C1-C4 alkoxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and aryl; (ii) R1, R2, R3, and R4are optionally substituted with halo, hydroxyl, C1-C4alkoxy, or C1-C4alkyl; (iii) R5is C1- C4 alkyl; (iv) R6is hydrogen or C1-C4 alkyl; (v) R7is hydrogen, C1-C4 alkyl, or aryl; and R7is optionally substituted with halogen or hydroxyl.

252. The composition of claim 221 wherein the intestinal penetration agent is an amino-substituted carboxylic acid including one or more aromatic moieties, wherein the aromatic moiety is selected from the group consisting of phenyl, pyrazinyl, pyrimidyl, and chromonyl.

253. The composition of claim 221 wherein the intestinal penetration agent is a modified amino acid compound of Formula (XXIV).

254. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XXV).

255. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XXVI).

256. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XXVII), wherein: (i) Ar is a phenyl or naphthyl substituted with at least one of C1-C5 alkyl, C2-C4 alkenyl, fluoro, chloro, hydroxyl, -SO2, carboxyl, or –SO3H; (ii) R7is selected from the group consisting of C4-C20alkyl, C4-C20alkenyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, (C1-C10alkenyl)phenyl, C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), and phenyl(C1-C10 alkenyl); (iii) R7is optionally substituted with C1-C4 alkyl, C1-C5 alkenyl, C1-C5 alkoxy, hydroxyl, sulfhydryl, and –CO2R9or any combination thereof; (iv) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (v) R8is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, hydroxyl, and C1-C4 alkoxy; (vi) R8is optionally substituted with C1-C4alkyl, C1-C5alkenyl, C1-C5alkoxy, hydroxyl, sulfhydryl, and – CO2R9or any combination thereof; and (vii) R9is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl, with the proviso that the compounds are not substituted with an amino group in the position α to the acid group.

257. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XXVIII) wherein: (i) R1, R2, R3, and R4are independently hydrogen, hydroxyl, halo, C1-C4 alkoxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or aryl; (ii) R1, R2, R3,PATENT PARSON-58748 and R4are optionally substituted with halo, hydroxyl, C1-C4 alkoxy, or C1-C4 alkyl; and (iii) R5is a C2-C16branched alkylene, optionally substituted with halogen.

258. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XXIX).

259. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of any one of Formulas (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), and (XLI).

260. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLII).

261. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLIII) wherein: (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with C1-C4alkyl, C1-C4alkoxy, C2-C4alkenyl, C2-C4alkynyl, aryl, aryloxy, a heterocyclic ring, a C5-C7 carbocyclic ring, halo, hydroxyl, sulfhydryl, CO2R6, NR7R8, or N+R7R8R9Y; (iii) (a) R1is C1-C16 alkylene, C2-C16 alkenylene, C2-C16 alkynylene, C6-C16 arylene, (C1-C16alkyl)arylene, or aryl(C1-C16alkylene); R2is -NR3R4, -N+R3R4, or -N+R3R4R5Y; R3and R4are each independently hydrogen, oxygen, hydroxyl, substituted or unsubstituted C1- C16 alkyl, substituted or unsubstituted C2-C16 alkenyl, substituted or unsubstituted C2-C16 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; R5is hydrogen, substituted or unsubstituted C1-C16alkyl, substituted or unsubstituted C2-C16 alkenyl, substituted or unsubstituted C2-C16 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; (b) R1, R2, and R5are as above under (a), and R3and R4are combined to form a 5-, 6-, or 7-membered heterocyclic ring or a aryloxycarbonyl; (b) R1, R2, and R5are as above under (a), and R3and R4are combined to form a 5-, 6-, or 7-membered heterocyclic ring or a 5-, 6-, or 7-membered heterocyclic ring substituted with C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, oxo, or carbocyclicPATENT PARSON-58748 ring; or (c) R2and R5are as defined above under (a), and R1and R3are combined to form a 5-, 6- , or 7-membered heterocyclic ring or a 5-, 6-, or 7-membered heterocyclic ring substituted with C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, oxo, or carbocyclic ring; (iv) R4is hydrogen, oxygen, hydroxyl, substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C2-C16 alkenyl, substituted or unsubstituted C2-C16alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted aryloxycarbonyl; (v) R6is hydrogen, C1-C4alkyl, C1-C4 alkyl substituted with halogen or with hydroxyl, C2-C4 alkenyl, or C2-C4 alkenyl substituted with halogen or with hydroxyl; (vi) R7, R8, and R9are each independently hydrogen, oxygen, C1-C4alkyl, C1-C4alkyl substituted with halogen or with hydroxyl, C2-C4alkenyl, or C2-C4 alkenyl substituted with halogen or with hydroxyl; and (vii) Y is halogen, hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, or carboxylate.

262. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLIV).

263. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLV).

264. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLVI).

265. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLVII).

266. The composition of claim 221 wherein the intestinal penetration agent is a carboxylic acid derivative selected from the group consisting of 6-N-(3,5-dichloro-2- hydroxybenzoyl)aminocaproic acid, 8-(2-aminobenzoylamino)caprylic acid, 8(2- trifluoromethoxy)benzoylaminocaprylic acid, N-(2-hydroxybenzoyl)isonipecotic acid, 4-[4-(2- aminobenzoylamino)phenyl]butyrylhydroxamic acid, 4-(4- (pentafluorobenzoyl)aminophenyl)butyric acid, 4-(4-(3-anisoyl)aminophenyl)butyric acid, 8-(3- anisoyl)aminocaprylic acid, 4-(4-(phenoxyacetyl)aminophenyl)butyric acid, 4-(4-(2- nitrobenzenesulfonyl)aminophenyl)butyric acid, 8-(2-nitrobenzenesulfonyl)aminocaprylic acid, 6-(4-(salicyloyl)aminophenyl)hexanoic acid, 8-(2-methoxybenzoyl)aminocaprylic acid, 2-PATENT PARSON-58748 [4-salicyloylaminophenyl]ethyl methyl sulfone, 1-salicyloyl-2-succinyl-hydrazide, 3-(4-(2,5- dimethoxycinnamoyl)aminophenyl)propionic acid, 4-(4-(2,5- dimethoxycinnamoyl)aminophenyl)butyric acid, 1-salicyloyl-2-glutaryl hydrazide, succinyl- 4-aminosalicylic acid, 8-(phenoxyacetylamino)caprylic acid, 8-(2- pyrazinecarbonyl)aminocaprylic acid, 4-(4-(2 pyrazinecarbonyl)aminophenylbutyric acid, 6-(4- (N-2-nitrobenzoyl)aminophenyl)hexanoic acid, 6-(4-(N-2- aminobenzoyl)aminophenyl)hexanoic acid, 4-(4-(2-(3- carbonyl)pyrazinecarboxyl)aminophenyl)butyric acid, 4(2-nitrobenzoyl)aminophenylsuccinic acid, 8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid, 8-(benzylcarbonylamino)caprylic acid, 8-(phenylcarbonylamino)caprylic acid, 2-[4-(2-methoxybenzoylamino)phenyl]ethyl H2PO4, 1- salicyloyl-2-suberyl hydrazide, 4-(4-benzyloxycarbonylaminophenyl)butyric acid, 4-(4-)2- hydroxynicotinoyl)aminophenyl)butyric acid, 9-salicyloylaminonanoic acid, 4-(4- phenyloxycarbonylaminophenyl)butyric acid, 3-(2-methoxybenzoylamino)-1-propanol, 8-(2- hydroxynicotinoyl)aminocaprylic acid, 6-(2-methoxybenzoyl)amino nicotinic acid, salicyloylglycine, 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid, 8-(chromone-3- carbonyl)aminocaprylic acid, 8-(vinylbenzoyl)aminocaprylic acid, 4-(4-(chromone-3- carbonyl)aminophenyl)butyric acid, 8-cinnamoylaminocaprylic acid, 5-(N- salicyloylamino)valeric acid, N-(4-salicyloylamino)-6-caproic acid, 4′-flavonic acid, 11- cinnamoylaminoundecanoic acid, 4-octanoylamino-3-hydroxybenzoic acid, (3-phenyl-2,3- dihydroxypropanoyl)-8-aminocaprylic acid, 8-[N-(3-coumarincarbonyl)]aminocaprylic acid, 8- [N-(4-chlorobenzyl)]aminocaprylic acid, 8-[N-(3-fluorobenzyl)]aminocaprylic acid, 8-(N-2,5- dihydroxybenzoyl)aminocaprylic acid, 8-(N-3,5-diacetyloxybenzoyl)aminocaprylic acid, 8-(N- 4-hydroxybenzoyl)aminocaprylic acid (dimer), 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid, 1-(1-(N-2-methoxyanilino)sebacic acid, 10-(N-2-methoxyanilino)sebacic acid, 8-(N- benzoyl)aminocaprylic acid, 2-methoxybenzenaminodecanoic acid, 8-(N- benzoyl)aminocaprylic acid, 8-(N-2-hydroxy-4-methoxybenzoyl)aminocaprylic acid, 8-(N-4- fluorobenzoyl)aminocaprylic acid, 8-(N-3-bromobenzoyl)aminocaprylic acid, 8-(4-(1,2- dihydroxyethyl)benzoyl)aminocaprylic acid, 8-(N-4-bromobenzoyl)aminocaprylic acid, 8- (N-4-iodobenzoyl)aminocaprylic acid, 4-{4-[N-(2-iodobenzoyl)aminophenyl]}butyric acid, 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid, 4-(4-(2,4- dimethoxybenzoyl)aminophenyl)butyric acid, 4-(o-anisoyl)aminophenylacetic acid, 3-[4-PATENT PARSON-58748 (2,4-dimethoxybenzoyl)aminophenyl]propionic acid, 4-{4-[N-(4- iodobenzoyl)]aminophenyl}butyric acid, 3-[4-(2,3-dimethoxybenzoyl) aminophenyl] propionic acid, 4{4 [N-2-bromobenzoyl)] aminophenyl} butyric acid, 4{4-[N-3-[bromobenzoyl) aminophenyl]} butyric acid, 8-(N-3,5-dihydroxybenzoyl)aminocaprylic acid, 8-(N-3,5- dimethoxy 4-hydroxybenzoyl)aminocaprylic acid, 8-(N-2,6-dimethoxybenzoyl)aminocaprylic acid, 4-{4[N-(4 bromobenzoyl)aminophenyl]butyric acid, 8-(2-hydroxy-4- chlorobenzoyl)aminocaprylic acid, 8-(N-2,6-dihydroxybenzoyl)aminocaprylic acid, 8-(N-2- hydroxy-6-methoxybenzoyl)aminocaprylic acid, 8-(5-chloro-o-anisoyl)aminocaprylic acid, 4-(4- (2,3-dimethoxybenzoyl)aminophenyl)butyric acid, 4-(4-(5 chloro-o-anisoyl)aminophenyl)butyric acid, 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid, 8-(4-chloro-o-anisoyl)aminocaprylic acid, 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid, 4-{N-[4-(3 iodobenzoyl)aminophenyl]butyric acid, 7-cinnamoylaminoheptanoic acid, 8-N-(3 iodobenzoyl)aminocaprylic acid, 8-N-(4 methoxy-3-nitrobenzoyl)aminocaprylic acid, 8-N-(2 methoxy 4 nitrobenzoyl)aminocaprylic acid, 4-{N-[4-(2-methoxy-4- nitrobenzoyl)aminophenyl]}butyric acid, 4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid, 8-(N-2-hydroxy-5-bromobenzoyl)aminocaprylic acid, 3-indolebutryic acid, 4-(4-(2,6- dimethoxybenzoyl)aminophenylbutyric acid, 4-[4-N-(4 methoxy-3- nitrobenzoyl)aminophenyl]butyric acid, 8-(N-2-hydroxy-5 chlorobenzoyl)aminocaprylic acid, 8-(N- 2-hydroxy-5-iodobenzoyl)aminocaprylic acid, 8-(3-hydroxy-2-naphthoyl)aminocaprylic acid, 8-(N-2- hydroxy-2-nitrobenzoyl)aminocaprylic acid, 8-(N-3-methylsalicyloyl)aminocaprylic acid, 8-(N-5- methylsalicyloyl)aminocaprylic acid, 4-[-N-(2 hydroxy-4-bromobenzoyl)aminophenyl]butyric acid, 8-(N-2,3-dihydroxybenzoyl)aminocaprylic acid, 9-(cinnamoylamino)nonanoic acid, 4-(4-(2- chloro-5-nitrobenzoyl)aminophenyl)butyric acid, 4-[N-(2-hydroxy-5- iodobenzoyl)]aminophenylbutyric acid, N-2-nitrophenyl-N′-(8 octanoic acid) urea, 8-[N-(2-acetoxy- 3,5-dibromobenzoyl)aminocaprylic acid, 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid, 8-N-(4- hydroxy-3-nitrobenzoyl)caprylic acid, 4-(4-salicyloylaminophenyl)-4-oxobutyric acid, 12- cinnamoyldodecanoic acid, 4-{4-[N-(3-hydroxy-2-naphthoyl)aminophenyl]}butyric acid, 8-(4- chloro-3-nitrobenzoyl)aminocaprylic acid, 8-(2-chloronicotinoyl)aminocaprylic acid, 8-(2- chloro-5-nitrobenzoyl)aminocaprylic acid, 4-(4-phthalimidophenyl)butyric acid, 4-{4-[N-(3- hydroxy-2-napthoyl)aminophenyl]}propanoic acid, 3-(4-(2,6- dimethoxybenzoyl)aminophenyl)propionic acid, 8-(N-2-hydroxy-3,5-PATENT PARSON-58748 diiodobenzoyl)aminocaprylic acid, 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid, 8 (N 1 hydroxy-2-naphthoyl)aminocaprylic acid, 8-(phthalimido)caprylic acid, 10-(4-chloro-2- hydroxyanilino)sebacic acid monoamide, 6-(anisoyl)aminocaproic acid, 4-(4-(4-chloro-3- nitrobenzoyl)aminophenyl)butyric acid, 11-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid, bis(N-2-carboxylphenyl-N-(N′-8-octanoic acid)ureal)oxalyl diamide, 2-[2-N-(2- chlorobenzoyl)aminoethoxy]ethanol), 2-[2-N-(4 chlorobenzoyl)aminoethoxy]ethanol, 4-(2- methybenzoyl)amino-3-carboxysulfoxide, 4-(2-methoxybenzoyl)amino 3-carboxypropylsulfone, 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid, 2-[2-N-(2 methoxybenzoyl)aminoethoxyl]ethanol, 2-[2-N-(3 chlorobenzoyl)aminoethoxy]ethanol, bis(N-2- carboxyphenyl)-N-(N′-3(4-aminophenyl)propionic acid)ureal)oxalyl diamide, trans 4 (2 aminobenzamidomethyl)cyclohexamecarboxylic acid, 11-N-(3,5-dichloro-2- hydroxybenzoyl)aminoundecanoic acid, 2-[N-(2-bromobenzoyl)aminoethoxy]ethanol, 7-N-(3,5- dichloro-2-hydroxybenzoyl)aminoheptanoic acid, N-[3,5-dichloro-2-hydroxybenzoyl-4(4- aminophenyl)]butyric acid, trans-4-(N salicyloylaminomethyl)cyclohexane carboxylic acid, N- [3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid, 12-N-(3,5-dichloro-2- hydroxybenzoyl)aminodecanoic acid, N-(2-hydroxy-4-carboxy)-6-heptenamide, N-(2- bromobenzoyl)morpholine, 8-N-cyclohexanoylaminocaprylic acid, 2-[N-(2- iodobenzoyl)aminoethoxy]ethanol, 5-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid, 8-(2- hydroxyphenoxy)-aminocaprylic acid, N-salicyloyl-5-(3-aminophenyl-valeric acid, 4-(4-(2- ethoxylbenzoyl)aminophenyl)butyric acid, 9-[2-(3-hydroxy)pyridylaminocarbonyl]nonanic acid, 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid, 2-[N-2-hydroxybenzoylamino)ethoxy]ethanol. 4-[N-(3,5-chloro-2-hydroxybenzoyl)]aminophenylacetic acid 8-(2-hydroxy-5- chloroanilinocarbonyl)octanoic acid, N-salicyloyl-5-(4-aminophenyl)valeric acid, 9-(2-hydroxy-5- methylanilinocarbonyl)nonanoic acid, 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid, 8- (pentafluorobenzoyl)aminocaprylic acid, 3-(3-(salicyloyl)aminophenyl)propionic acid, 8-(2- ethoxybenzoyl)aminocaprylic acid, 4-(4-(2-dimethylamino benzoic)aminophenyl)butyric acid, 8- (3-phenoxylpropionylamino)caprylic acid, 4-(salicyloyl)aminophenylethyltetrazole, 4-(4-(N-(2- fluorocinnamoyl))aminophenyl)butyric acid, 4-(4-(N-8- salicyloyl)aminocaprylic)aminophenyl)butyric acid, 8-(p-anisoyl)aminocaprylic acid, 8-(4- hydroxybenzoyl)aminocaprylic acid, 8-(3-hydroxybenzoyl)aminocaprylic acid, 8-(3,4,5-PATENT PARSON-58748 trimethoxybenzoyl)aminocaprylic acid, 8-(N-4-methylsalicyloyl)aminocaprylic acid, N-10-(2- hydroxy-5-nitroanilino)decanoic acid, and 4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid.

267. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (XLVII).

268. The composition of claim 221 wherein the intestinal penetration agent is a modified amino acid or peptide comprising: (i) at least one acylated amino acid; (ii) at least one peptide comprising one acylated amino acid; or (iii) a combination of (i) and (ii), wherein the acylated amino acid is acylated by: (1) a C3-C10cycloalkyl acylating agent, the agent being optionally substituted with C1-C7alkyl, C2-C7alkenyl, C1-C7alkoxy, hydroxyl, phenyl, phenoxy, or –CO2R, wherein R is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; or (2) a C3-C10 cycloalkyl substituted C1-C6 alkyl acylating agent, wherein the amino acids are of Formula (XLIX), wherein: R1is hydrogen, C1-C4alkyl, or C2-C4alkenyl; R2is C1-C24alkyl, C2-C24alkenyl, C3- C10 cycloalkyl, C3-C10 cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl) phenyl (C2-C10 alkenyl) phenyl, (C1-C10 alkyl) naphthyl (C2-C10 alkenyl) naphthyl, phenyl (C1-C10 alkyl), phenyl (C2-C10 alkenyl), naphthyl (C1-C10alkyl) naphthyl (C2-C10alkenyl); R2can be optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, -CO2R3, C3-C10 cycloalkyl, C3- C10 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the heteroatom is one or more of N, O. or S, or any combination thereof, aryl, C1-C10alkaryl, aryl(C1-C10alkyl), or any combination thereof; R2can be optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R3is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.

269. The composition of claim 221 wherein the intestinal penetration agent is a modified amino acid prepared by acylation or sulfonation of an amino acid selected from the group consisting of aminobutyric acid, aminocaproic acid, and aminocaprylic acid.

270. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (L).

271. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LI).

272. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LII).

273. The composition of claim 221 wherein the intestinal penetration agent is a modified amino acid of either Formula (LIII) or Formula (LIV), wherein: (i) Ar is anPATENT PARSON-58748 unsubstituted or substituted phenyl or naphthyl; (ii) Y is –C(O)- or -S(O2)-; (iii) R1has the formula –N(R3)-R2-C(O)-; (iv) R2is C1-C24alkyl, C1-C24alkenyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, (C1-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), or naphthyl(C1-C10 alkenyl); (v) R2is optionally substituted with C1-C4alkyl, C1-C4alkenyl, C1-C4alkoxy, hydroxyl, sulfhydryl, CO2R4, or any combination thereof; (vi) R4is hydrogen, C1-C4 alkyl, or C1- C4 alkenyl; (vii) R2is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (viii) R3is hydrogen, C1-C4alkyl, or C1-C4alkenyl; (ix) R5is either: (A) C3-C10cycloalkyl, optionally substituted with C1-C7alkyl, C2-C7alkenyl, C1-C7alkoxy, hydroxyl, phenyl, phenoxy, or –CO2R8, wherein R8is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; or (B) C1- C6 alkyl substituted with C3-C10 cycloalkyl; (x) R6is C3-C10 cycloalkyl; R7is C1-C24 alkyl, C2- C24alkenyl, C3-C10cycloalkyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, (C2-C10alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C2-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C2-C10 alkenyl), naphthyl(C1-C10 alkyl), or naphthyl(C2-C10 alkenyl); (xi) R7is optionally substituted with C1-C4 alkyl, C2-C4alkyl, C1-C4alkoxy, hydroxyl, sulfhydryl, -CO2R9, C3-C10cycloalkyl, C3-C10cycloalkenyl, a heterocycle having 3-10 ring atoms wherein the heteroatom is one or more of N, O, or S or any combination thereof, aryl, (C1-C10)alkaryl, aryl(C1-C10 alkyl), or any combination thereof; (xii) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and (xiii) R9is hydrogen, C1-C4alkyl, or C2-C4alkenyl.

274. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LV).

275. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LVI).

276. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LVII).

277. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LVIII).

278. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXIV), (LX), or (LXI).

279. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXII).PATENT PARSON-58748 280. The composition of claim 221 wherein the intestinal penetration agent is a compound that includes: (a) at least one acylated aldehyde of an amino acid, (b) at least one acylated ketone of an amino acid, (c) at least one acylated aldehyde of a peptide, (d) at least one acylated ketone of a peptide, (e) any combination of (1)(a), (1)(b), (1)(c), and (1)(d); (2) (a) carboxymethyl-phenylalanylleucine; (b) 2-carboxy-3-phenylpropionylleucine; (c) 2- benzylsuccinic acid; (d) (phenylsulfonamide)phenylbutyric acid; and (e) any combination of (2)(a), (2)(b), (2)(c) and (2)(d); or (3) a combination of (1) and (2).

281. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXIII).

282. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXIV).

283. The composition of claim 221 wherein the intestinal penetration agent is a compound selected from the group consisting of: (1) (a) at least one acetylated aldehyde of an amino acid; (b) at least one acetylated ketone of an amino acid; (c) at least one acetylated aldehyde of a peptide; (d) at least one acetylated ketone of a peptide; or (e) any combination of (1)(a), (1)(b), (1)(c), and (1)(d); (2) (a) carboxymethyl-phenylalanylleucine; (b) 2-carboxy-3- phenylpropionylleucine; (c) 2-benzylsuccinic acid; (d) an actinonin; (e) a compound having the formula Ar-Y-(R1)n-OH, wherein: (i) Ar is a substituted or unsubstituted phenyl or naphthyl; (ii) Y is –C(O)- or –SO2-; (iii) R1is –N(R4)-R3-C(O)-, wherein: (A) R3is C1-C24alkyl, C1-C24alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)phenyl, C1-C10 alkenyl(naphthyl), phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), or phenyl(C1-C10alkenyl); (B) R3is optionally substituted with C1-C4alkyl, C1-C4alkenyl, C1-C4alkoxy, hydroxyl, sulfhydryl, -CO2R5, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, alkaryl, heteroaryl, or heteroalkaryl or any combination thereof; (C) R5is hydrogen, C1-C4 alkyl, or C1- C4alkenyl; (D) R3is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (E) R4is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl; and (F) n is an integer from 1 to 5; or (f) any combination of (2)(a), (2)(b), (2)(c), (2)(d), and (2)(e); or (3) a combination of (1) and (2).

284. The composition of claim 221 wherein the intestinal penetration agent is an acid or acid salt wherein the acid has the general formula RCO2H, wherein R is C1-C24 alkyl, C2-C24 alkenyl, C3-C10 cycloalkyl, C3-C4 cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl,PATENT PARSON-58748 (C2-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C2-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C2-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C2-C10alkenyl), with R being optionally substituted with C1-C10 alkyl, C2-C10 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, CO2R1, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl having 3-10 ring atoms wherein the heteroatom is one or more atoms of N, O, S or any combination thereof, aryl, (C1-C10alk)aryl, aryl(C1-C10 alkyl), or any combination thereof, R being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R1is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl, and wherein the intestinal penetration agent comprises: (i) the acid; (ii) a salt of the acid; or (iii) a combination of (i) and (ii).

285. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoic acid, monosodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate (“4-CNAB”), a compound of Formula (LXV), and a compound of Formula (LXVI), wherein, in Formula (LXV), X is one or more of hydrogen, halo, hydroxyl, or C1-C3 alkoxy, and in Formula (LXVI), X is halo and R is substituted or unsubstituted C1-C3alkylene or substituted or unsubstituted C1-C3alkenylene.

286. The composition of claim 221 wherein the intestinal penetration agent is a phenylalkylcarboxylic acid selected from the group consisting of 4-(4-methoxyphenyl)butanoic acid, 5-(2-methoxyphenyl)pentanoic acid, 5-(3-fluorophenyl)pentanoic acid, 5-(3- methoxyphenyl)pentanoic acid, 6-(3-fluorophenyl)hexanoic acid, 3-(4-t-butylphenyl)propanoic acid, 3-(4-n-butylphenyl)propanoic acid, 3-(4-n-propylphenyl)propanoic acid, 3-(4-n- propoxyphenyl)propanoic acid, 3-(4-isopropoxyphenyl)propanoic acid, 3-(4-n- butoxyphenyl)propanoic acid, 3-(3-phenoxyphenyl)propanoic acid, 3-(3-ethoxyphenyl)propanoic acid, 3-(3-isopropoxyphenyl)propanoic acid, 3-(3-n-butoxyphenyl)propanoic acid, 3-(3-n- propoxyphenyl)propanoic acid, 3-(3-isobutoxyphenyl)propanoic acid, 3-(4- isobutoxyphenyl)propanoic acid, 4-(4-ethylphenyl)butanoic acid, 4-(4-isopropylphenyl)butanoic acid, and 5-(4-ethylphenyl)pentanoic acid.

287. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXVII), (LXVIII), or (LXIX), wherein: in Formula (LXVII): (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with one or more of hydroxyl, halo, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; (iii) R7is selected from C4-C20 alkyl, C4-C20 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10PATENT PARSON-58748 alkenyl)phenyl, C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10alkenyl), naphthyl(C1-C10alkyl), or naphthyl(C1-C10alkenyl); (iv) R7is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; (v) R7optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl, sulfhydryl, -CO2R9, and combinations thereof; (vi) R8is selected from hydrogen, C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, and C1-C4 haloalkoxy; and (vii) R9is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; in Formula (LXVIII): (i) R1, R2, R3, and R4are each independently hydrogen, hydroxy, halo, C1-C4 alkyl, C2-C4alkenyl, C1-C4alkoxy, -C(O)R8, -NO2, -NR9R10, and -N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, nitro, halo, trifluoromethyl, -NR14R15, -N+R14R15R16(R13)-, amide, C1-C12alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or –C(O)R18; (iii) R5is optionally substituted with halo, hydroxyl, sulfhydryl, or –COOH; (iv) R5is optionally interrupted by oxygen, nitrogen, sulfur, or –C(O)-; (v) R6is a C1-C12alkylene, C1-C12alkenylene, or arylene; (vi) R6is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, halo, amino, or – CO2R8; (vii) R6is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, sulfhydryl, amino, or –CO2R8; (viii) R6is optionally interrupted by oxygen or nitrogen; (ix) R7is a bond or arylene; (x) R7is optionally substituted with hydroxyl, halogen, -C(O)CH3, -NR10R11, -N+R10R11R12(R13)-; (xi) R8is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or amino; (xii) R9, R10, R11, and R12are each independently hydrogen or C1-C10alkyl; (xiii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiv) R14, R15, and R16are each independently hydrogen, C1-C10 alkyl, C1-C10 alkyl substituted with –COOH, C2-C12 alkenyl, C2-C12 alkenyl substituted with –COOH, or –C(O)R17; (xv) R17is hydroxyl, C1-C10 alkyl, or C2-C12alkenyl; and (xvi) R18is hydrogen, C1-C6alkyl, hydroxyl, -NR14R15, or N+R14R15R16(R13); and in Formula (LXIX): (i) R1, R2, R3, R4, and R5are independently hydrogen, cyano, hydroxyl, -OCH3, or halo, provided that at least one of R1, R2, R3, R4, and R5is cyano; and (ii) R6is C1-C12linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene).

288. The composition of claim 221 wherein the intestinal penetration agent is an allyloxybenzoic acid or an alkoxybenzoic acid of Formula (LXX), (LXXI), or (LXXII), wherein: in Formula (LXX): (i) R1, R2, and R3 are independently hydrogen, methyl, or halo; (ii) R4 is hydrogen, methyl, methoxy, hydroxyl, halo, acetyl, or 2-hydroxy-ethoxy; and (iii) n is 1, 2, 3, or 4; in Formula (LXXI): R is C1-C6 straight-chain or branched alkyl; and in FormulaPATENT PARSON-58748 (LXXII): R is methyl, ethyl, isopropyl, propyl, butyl, allyl, 1-methylallyl, 2-methylallyl, or butenyl.

289. The composition of claim 221 wherein the intestinal penetration agent is a propylphenoxy ether of Formula (LXXIV) wherein: (i) R1, R2, R3. R4, and R5are independently selected from hydrogen, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, -C(O)R8, nitro, -NR9R10, -N+R9R10R11(R12), carbonate, ureido, CX3, and cyano; (ii) R8is hydrogen, C1-C4alkyl, C2-C4alkenyl, or amino; (iii) R9, R10, R11, and R12are each independently hydrogen or C1-C10alkyl; and (iv) X is halo.

290. The composition of claim 221 wherein the intestinal penetration agent is a dialkyl ether of Formula (LXXV) wherein: (i) A is a C1-C6 alkylene group that is straight-chain or branched-chain or substituted or unsubstituted; (ii) B is a C1-C2alkylene group that is straight- chain or branched-chain or substituted or unsubstituted; (iii) R1, R2, R3, R4, and R5 are each independently hydrogen, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, -C(O)R8, nitro, -NR9R10, -N+R9R10R11(R12), carbonate, ureido, -CX3, or cyano, optionally interrupted by an O, N, S, or –C(O)- group, wherein A and R1 may together form a cycloalkyl group; (iii) R8is hydrogen, C1-C4alkyl, C2-C4alkenyl, or amino; (iv) R9, R10, R11, and R12are each independently hydrogen or C1-C10alkyl; and X is halo.

291. The composition of claim 221 wherein the intestinal penetration agent is an aryl ketone selected from the group consisting of 4-oxo-4-phenyl-butyric acid; 10-(4- hydroxy-phenyl)-10-oxodecanoic acid; 10-(2-hydroxy-phenyl)-10-oxo-decanoic acid; 4-(4- methoxy-phenyl)-4-oxo-butyric acid; 5-(4-methoxy-phenyl)-5-oxo-pentanoic acid; 4-(3,5- difluoro-phenyl)-4-oxo-butyric acid; 5-oxo-5-phenyl-pentanoic acid; 4-(2,4-dimethyl-phenyl)-4- oxo-butyric acid; 6-(4-methoxy-3,5-dimethyl-phenyl)-6-oxo-hexanoic acid; 5-(4-isopropyl- phenyl)-5-oxo-pentanoic acid; 4-(2-methoxy-phenyl)-4-oxo-butyric acid; 4-(4-fluoro-phenyl)-4- oxo-butyric acid; 6-(4-methoxy-phenyl)-6-oxo-hexanoic acid; 4-(3,5-dimethyl-phenyl)-4-oxo- butyric acid; 6-(3,4-dimethyl-phenyl)-6-oxo-hexanoic acid; 4-(3,4-dimethyl-phenyl)-4-oxo- butyric acid; 4-oxo-4-(4-phenoxy-phenyl)-butyric acid; 4-(2,5-dimethyl-phenyl)-4-oxo-butyric acid; 8-(3,5-dimethyl-phenyl)-8-oxo-octanoic acid; 6-(2,5-dichloro-phenyl)-6-oxo-hexanoic acid; 4-(2,5-dichloro-phenyl)-4-oxo-butyric acid; 6-(3,5-dimethyl-phenyl)-6-oxo-hexanoic acid; 10-PATENT PARSON-58748 (2,5-dihydroxy-phenyl)-10-oxo-decanoic acid; 8-oxo-8-phenyl-octanoic acid; 6-(2,5-difluoro- phenyl)-6-oxo-hexanoic acid; 7-oxo-7-phenyl-heptanoic acid; 4-(4-ethyl-phenyl)-4-oxo-butyric acid; 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid; 4-(4-butoxy-phenyl)-4-oxo-butyric acid; 4-oxo- 4-(4-propyl-phenyl)-butyric acid; 4-oxo-4-(4-pentyl-phenyl)-butyric acid; 4-(4-hexyloxy- phenyl)-4-oxo-butyric acid; 4-(2,5-difluoro-phenyl)-4-oxo-butyric acid; 5-(4-chloro-phenyl)-5- oxo-pentanoic acid; 6-(3,5-difluoro-phenyl)-6-oxo-hexanoic acid; 4-oxo-4-p-tolyl-butyric acid; 6-oxo-6-phenyl-hexanoic acid; 5-oxo-5-(4-phenoxy-phenyl)-pentanoic acid; 5-oxo-5-(3- phenoxy-phenyl)-pentanoic acid; and 7-oxo-7-(3-phenoxy-phenyl)-heptanoic acid.

292. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of: (i) a compound selected from the group consisting of arachidonic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monolein, dilaurin, glyceryl 1-monocaprate, 1- dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, and a C1-10 alkyl ester, monoglyceride, diglyceride, or a pharmaceutically acceptable salt thereof; (ii) a bile salt selected from the group consisting of cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate, and sodium glycodihydrofusidate; (iii) polyoxyethylene-9-lauryl ether; (iv) a chelating agent selected from the group consisting of EDTA and citric acid; (v) a salicylate; (vi) an N-acyl derivative of collagen; (vii) an N-amino acyl derivative of a beta-diketone; (viii) a surfactant selected from the group consisting of sodium lauryl sulfate, polyoxyethylene-20-cetyl ether, and a perfluorochemical emulsion; and (ix) a compound selected from the group consisting of unsaturated cyclic ureas, 1-alkyl-alkanones, 1-alkenylazacyclo-alkanones, glycols, pyrroles, azones, and terpenes.

293. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of polyvalent aliphatic C2-C10 alcohols, polyalkylene glycols having C2-C4 alkylene groups, nonalkoxylated ethers of polyvalent aliphatic C2-C10 alcohols and polyalkylene glycols having C2-C4alkylene groups, azones, terpenes, terpenoids, pyrrolidones, and sulfoxides.

294. The composition of claim 221 wherein the intestinal penetration agent is a nanoparticle or micelle that is constructed from a polymer that is selected from the groupPATENT PARSON-58748 consisting of: dextran, carboxymethyl dextran, chitosan, trimethylchitosan, poly(lactic-co- glycolic acid) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyvinylalcohol (PVA), polyanhydrides, polyacrylates, polymethacrylates, polyacylamides, dextran, chitosan, cellulose, hypromellose, starch, dendrimers, peptides, proteins, polyethyleneglycols, and poly(ethyleneglycol-co-propyleneglycol), and synthetic derivatives thereof.

295. The composition of claim 221 wherein the intestinal penetration agent is a synthetic peptide ligand.

296. The composition of claim 221 wherein the intestinal penetration agent is a biodegradable polymer that is a copolymer of lactic acid and glycolic acid or enantiomers thereof.

297. The composition of claim 221 wherein the intestinal penetration agent is a membrane translocating full-length peptide sequence or an analog or derivative thereof, wherein the analog or derivative is selected from the group consisting of: fragments thereof, motifs derived therefrom, derivatives thereof, analogs thereof, and peptidomimetics based on the peptide sequences.

298. The composition of claim 221 wherein the intestinal penetration agent is aD-form retro-inverted peptide.

299. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent that is: (i) a solid at room temperature; and (ii) a salt of a medium chain fatty acid having a carbon length of from 8 to 14 carbon atoms in particulate form, optionally further comprising a rate-controlling polymer or other rate-controlling agent.

300. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of: (i) a mono-, di-, or triglyceride ester of a medium-chain or long-chain fatty acid; (ii) an ester of a fatty acid and a glycol; (iii) an ester of a mixed fatty acid and a glycol; (iv) a diester of propylene glycol having from about 7 to about 55 carbon atoms; and (v) a propylene glycol ester of capric and caprylic acids and mixtures thereof, having from 19 to 23 carbon atoms.

301. The composition of claim 221 wherein the intestinal penetration agent is a medium-chain fatty acid or a medium-chain fatty acid derivative having a carbon chain length of from 6 to 20 carbon atoms, with the provisos that (i) where the intestinal penetration agent is an ester of a medium-chain fatty acid, the chain length of from 6 to 20 carbon atoms relates to thePATENT PARSON-58748 chain length of the carboxylate moiety, and (ii) where the intestinal penetration agent is an ether of a medium-chain fatty acid, at least one alkoxy group has a carbon chain length of from 6 to 20 carbon atoms.

302. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (LXXVII) wherein Q is: (1) a partially or completely neutralized -- COOH, or (2) a partially or completely neutralized --SO3H, or (3) a mono- or di-substituted alkyl or alkenyl group having one to about twelve carbon atoms, the substituent(s) thereof being a partially or completely neutralized --COOH or partially or completely neutralized --SO3H; and R1and R2are independently: (1) an unsubstituted alkyl or alkenyl group having one to about twelve carbon atoms, or (2) a substituted alkyl or alkenyl group having one to about twelve carbon atoms, the substituent thereof being selected from the group consisting of (i) partially or completely neutralized --COOH, (ii) partially or completely neutralized --SO3H, (iii) --NH2, (iv) --CONH2; and (v) –OH.

303. The composition of claim 221 wherein the intestinal penetration agent is a purified synthetic polypeptide ligand comprising a L-peptide or homologue thereof.

304. The composition of claim 221 wherein the intestinal penetration agent is a compound including a peptide sequence that possesses both hydrophobic amino acids and charged amino acids, wherein, optionally, the peptide sequences are modified by hydrophobic moieties.

305. The composition of claim 221 wherein the intestinal penetration agent is a medium-chain fatty acid salt associated with a substantially hydrophobic medium.

306. The composition of claim 221 wherein the intestinal penetration agent is a composition comprising: (i) octanoate, sodium decanoate, sodium dodecanoate, and combinations thereof; and (ii) a hydrophobic medium to produce a suspension, wherein the hydrophobic medium is selected from the group consisting of aliphatic molecules, cyclic molecules, aromatic molecules, lecithin, a bile salt, a non-ionic detergent, and combinations thereof.

307. The composition of claim 221 wherein the intestinal penetration agent is a liquid-forming counterion that is a cationic amphipathic molecule selected from the group consisting of imidazolium derivatives, pyridinium derivatives, phosphonium compounds and tetraalkylammonium compounds.PATENT PARSON-58748 308. The composition of claim 221 wherein the intestinal penetration agent is a peptide derived from Escherichia coli that is optionally modified to increase its hydrophobicity.

309. The composition of claim 221 wherein the intestinal penetration agent is a calcium phosphate nanoparticle.

310. The composition of claim 221 wherein the intestinal penetration agent is a fatty acid, a medium-chain glyceride, a surfactant, a steroidal detergent, an acyl carnitine, an alkanoyl choline, an N-acetylated amino acid, esters, salts and derivatives thereof, or any combination thereof.

311. The composition of claim 221 wherein the intestinal penetration agent is an orthoester derivative of a crown ether of Formula (LXXVIII) wherein: m is 4, 5, 6, 7, or 8; (ii) i is independently for each occurrence, 1 or 2; (iii) each occurrence of R1and R2is independently selected from hydrogen; linear or branched and substituted or unsubstituted C1-C10alkyl, alkenyl, or alkynyl; and substituted or unsubstituted aryl with up to 10 ring atoms, or R1and R2form an oxo group; and (iv) there is at least one occurrence in the crown ether of R1, R2, and the carbon to which R1and R2are bound, the carbon being bound directly to an ether oxygen of Formula (LXXVIII), form together a group of Subformula (LXXVIII(a)), wherein, in Subformula (LXXVIII(a)), L is a linker that is absent or is selected from a covalent bond and (CR5R6)n, each occurrence of R5and R6being independently selected from: hydrogen; linear or branched and substituted or unsubstituted C1-C10alkyl, alkenyl, or alkynyl; and substituted or unsubstituted aryl with up to 10 ring atoms; n is 1, 2, or 3; X and Y, independently from each other, are selected from O and S; Z, independently for each occurrence, is absent or an electron- withdrawing group; R3and R4, independently for each occurrence, are selected from: hydrogen; linear or branched and substituted or unsubstituted C1-C10 alkyl, alkenyl, or alkynyl; and substituted or unsubstituted aryl with up to 10 ring atoms; H(OCH2CH2)k— H(OCH2CH2)kO—, wherein k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and wherein substituents, if present, are selected from hydroxyl, halogens, and O-CH3.

312. The composition of claim 221 wherein the intestinal penetration agent is a crown compound selected from the group consisting of a cyclic polyester, a cyclic polyamide, a cyclic polyether, a cyclic polyoxime, a polythioester, a polymer of aminoxy acids, a polydisulfide, a cyclic depsipeptide, and a cyclic polydioxanone, wherein the crown compound is a cation-binding crown compound capable of forming a charge masking complex with a cation.PATENT PARSON-58748 313. The composition of claim 221 wherein the intestinal penetration agent comprises acylcarnitines, phospholipids, and bile acids.

314. The composition of claim 221 wherein the intestinal penetration agent has a covalent linkage to a membrane translocator that is a peptide, fatty acid, or bile acid.

315. The composition of claim 221 wherein the intestinal penetration agent is an acyl-L-carnitine.

316. The composition of claim 221 wherein the intestinal penetration agent includes: (i) an anionic agent that is a cholesterol derivative, (ii) a mixture of a negative charge neutralizer and an anionic surface active agent, (iii) a non-ionic surface active agent, and (iv) a cationic surface active agent.

317. The composition of claim 221 wherein the intestinal penetration agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino] butanoic acid.

318. The composition of claim 221 wherein the intestinal penetration agent is a compound with a cyclic moiety selected from the group consisting of: 3-[4- (cyclopropylmethoxy)phenyl]propanoic acid; 4-(cyclobutylmethoxy)benzoic acid; [4- (cyclobutylmethoxy)-3-methoxyphenyl]acetic acid; 4-(cyclopropylmethoxy)benzoic acid; [4- (cyclopropylmethoxy)phenyl]acetic acid; 2-(cyclobutylmethoxy)benzoic acid; [4- (cyclopentyloxy)-3-methoxyphenyl]acetic acid; [4-(cyclopropylmethoxy)-3- methoxyphenyl]acetic acid; 2-(cyclopropylmethoxy)benzoic acid; 2-(cyclopentyloxy)benzoic acid; 2-(cyclohexylmethoxy)benzoic acid; 3-(cyclopropylmethoxy)benzoic acid; 3- (cyclobutylmethoxy)benzoic acid; 3-(cyclopentyloxy)benzoic acid; 3- (cyclohexylmethoxy)benzoic acid; 4-(cyclopentyloxy)benzoic acid; 4-(cyclopentyloxy)benzoic acid; [4-(cyclobutylmethoxy)phenyl]acetic acid; 3-[4-(cyclobutylmethoxy)phenyl]propanoic acid; [4-(cyclohexylmethoxy)phenyl]acetic acid; 3-[4-(cyclohexylmethoxy)phenyl]propanoic acid; [4-(cyclohexylmethoxy)-3-methoxyphenyl]acetic acid; 3-[2- (cyclopropylmethoxy)phenyl]propanoic acid; [4-(cyclopentyloxy)phenyl]acetic acid; and 3-[4- (cyclopentyloxy)phenyl]propanoic acid.

319. The composition of claim 221 wherein the intestinal penetration agent is a disodium salt, an ethanol solvate, or a hydrate of a compound selected from the group consisting of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate.PATENT PARSON-58748 320. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (LXXIX) wherein: (i) Y is carbonyl or SO2; (ii) R1is C3-C24alkyl, C2- C20 alkenyl, C2-C20 alkynyl, cycloalkyl, or aromatic; (iii) R2 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; and (iv) R3 is C1-C7 alkyl, C3-C10 cycloalkyl, aryl, thienyl, pyrrolo, or pyridyl, wherein R3is optionally substituted with one or more C1-C5alkyl groups, C2-C4alkenyl groups, halogen, SO2, CO2H, or SO3H.

321. The composition of claim 221 wherein the intestinal penetration agent is an intestinal penetration agent of Formula (LXXX), (LXXXI), (LXXXII), (LXXXIII), or (LXXXIV), wherein: in Formula (LXXX), (i) Ar is phenyl or naphthyl; (ii) Ar is optionally substituted with one or more of hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; (iii) R1is C3-C20 alkyl, C4-C20 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10alkenyl)phenyl, (C1-C10alkyl)naphthyl, (C1-C10alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), or naphthyl(C1-C10 alkenyl); (iv) R1is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl, or sulfhydryl or any combination thereof; (v) R2is hydrogen, C1-C4alkyl, or C2-C4 alkenyl; and (vi) R1is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; wherein the term “2-OH—Ar” refers to a phenyl or naphthyl group having a hydroxyl group at the 2-position; in Formula (LXXXI), (i) R1, R2, R3, and R4are each independently hydrogen, hydroxyl, halogen, C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, --C(O)R8, --NO2, --NR9R10, or –N+R9R10R11(R12)-; (ii) R5is hydrogen, hydroxyl, --NO2, halogen, --CF3, -- NR14R15, –N+R14R15R16(R13)-, amide, C1-C12 alkoxy, C1-C12 alkyl, C1-C12 alkenyl, carbamate, carbonate, urea, or --C(O)R18; (iii) R5is optionally substituted with halogen, hydroxyl, sulfhydryl, or carboxyl; (iv) R5is optionally interrupted by O, N, S, or –C(O)--; (v) R6is a C1- C12 alkylene, C1-C12 alkenylene, or arylene; (vi) R6is optionally substituted with C1-C4 alkyl, C2-C4alkenyl, C1-C4alkoxy, hydroxyl, sulfhydryl, halogen, amino, or –CO2R8; (vii) R6is optionally interrupted by O or N; (viii) R7is a bond or arylene; (ix) R7is optionally substituted with hydroxyl, halogen, --C(O)CH3, --NR10R11, or –N+R10R11R12(R13)-; (x) R8is hydrogen, C1- C4alkyl, C2-C4alkenyl, or amino; (xi) R9, R10, R11, and R12are independently hydrogen or C1- C10alkyl; (xii) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (xiii) R14, R15, and R16are each independently hydrogen, C1-C10 alkyl, C1-C10 alkyl substituted with carboxyl, C2-C12 alkenyl, C2-C12 alkenyl substituted with carboxyl, or –C(O)R17; (xiv) R17is hydroxyl, C1-PATENT PARSON-58748 C10 alkyl, or C2-C12 alkenyl; and (xv) R18is hydrogen, C1-C6 alkyl, hydroxyl, --NR14R15, or – N+R14R15R16(R13)-; in Formula (LXXXII), (i) R1, R2, R3, R4, and R5are each independently hydrogen, --CN, hydroxyl, --OCH3, or halogen, wherein at least one of R1, R2, R3, R4, and R5is – CN; and (ii) R6is a C1-C12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene); in Formula (LXXXIII), (i) each occurrence of X is hydrogen, halogen, hydroxyl, or C1-C3 alkoxy; (ii) R is substituted or unsubstituted C1-C3 alkylene or substituted or unsubstituted C2-C3 alkenylene; and (iii) n is 1, 2, 3, or 4; and in Formula (LXXXIV), (i) X is halogen; and (ii) R is substituted or unsubstituted C1-C3alkylene or substituted or unsubstituted C2-C3alkenylene.

322. The composition of claim 221 wherein the intestinal penetration agent is selected from the group consisting of 3-(3-hexyloxy-2-hydroxy-propoxy)-propane-1,2-diol and 3-[2-hydroxy-3-(2-hydroxy-2-octyloxy-propoxy)-propoxy]-propane-1,2-diol.

323. The composition of claim 221 wherein the intestinal penetration agent is a phenylalkylcarboxylic acid selected from the group consisting of 4-(4-methoxyphenyl)butanoic acid, 5-(2-methoxyphenyl)pentanoic acid, 5-(3-fluorophenyl)pentanoic acid, 5-(3- methoxyphenyl)pentanoic acid, 6-(3-fluorophenyl)hexanoic acid, 3-(4-t-butylphenyl)propanoic acid, 3-(4-n-butylphenyl)propanoic acid, 3-(4-n-propylphenyl)propanoic acid, 3-(4-n- propoxyphenyl)propanoic acid, 3-(4-isopropoxyphenyl)propanoic acid, 3-(4-n- butoxyphenyl)propanoic acid, 3-(3-phenoxyphenyl)propanoic acid, 3-(3-ethoxyphenyl)propanoic acid, 3-(3-isopropoxyphenyl)propanoic acid, 3-(3-n-butoxyphenyl)propanoic acid, 3-(3-n- propoxyphenyl)propanoic acid, 3-(3-isobutoxyphenyl)propanoic acid, 3-(4- isobutoxyphenyl)propanoic acid, 4-(4-ethylphenyl)butanoic acid, 4-(4-isopropylphenyl)butanoic acid, and 5-(4-ethylphenyl)pentanoic acid, and pharmaceutically acceptable salts thereof.

324. The composition of claim 221 wherein the intestinal penetration agent is an oxadiazole of Formula (LXXXV) wherein: (1) R1is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10 cycloalkyl, phenyl, naphthyl, or aromatic heterocyclyl; (2) R1is optionally substituted with C1-C4 alkyl or fluoroalkyl, C2-C4 alkenyl, C1-C4 alkoxy or fluoroalkoxy, halo, hydroxyl, sulfhydryl, phenyl, phenoxy, --CO2R3, --N(CH3)2, --NO2, or amino; (3) R2is C1-C24alkylene, C2-C24alkenylene, C3-C10cycloalkylene, C3-C10cycloalkenylene, phenylene, naphthalene, (C1-C10 alkyl)phenylene, (C2-C10 alkenyl)phenylene, (C1-C10 alkyl)naphthalene, (C2-C10 alkenyl)naphthalene, phenyl(C1-C10 alkylene), phenyl(C2-C10 alkenylene), naphthyl(C1-PATENT PARSON-58748 C10 alkylene), or naphthyl(C2-C10 alkenylene); (4) R2is optionally substituted with C1-C4 alkyl or fluoroalkyl, C2-C4alkenyl, C1-C4alkoxy or fluoroalkoxy, halo, hydroxyl, sulfhydryl, phenyl, phenoxy, --CO2R3, --N(CH3)2, --NO2, amino, C3-C10 cycloalkenyl, aryl, (C1-C10 alkyl)aryl, heterocyclyl having 3-10 ring atoms wherein the heteroatom is one or more of N, O, S, or any combination thereof; (5) R2is optionally interrupted by N, O, S, or any combination thereof; and (6) R3is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl, with the provisos that: (i) R1is not 4- (piperidin-4-yl)phenyl when R2is –(CH2)4--; (ii) R1is not –CH3 when R2is –(CH2)3--; and (iii) R1is not 4-carboxyphenyl when R2is –(CH2)3— or R2is –(CH2)4—.

325. The composition of claim 221 wherein the intestinal penetration agent is a dialkyl ether of Formula (LXXXVI) wherein: (1) A is a C1-C6 alkylene group; (2) B is a C1-C2 alkylene group; and (3) R1, R2, R3, R4, and R5 are independently hydrogen, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted haloalkoxy, hydroxy, --C(O), --NO2, NR9R10, N+R9R10R11(R12), carbonate, ureido, --CX3, or –CN, optionally interrupted by O, N, S, or – C(O)— group, where A and R1may form a cycloalkyl group, wherein: (a) R8is independently H, C1-C4 alkyl, C2-C6 alkenyl, or an –NH2 group; (b) R9, R10, R11, and R12are independently H or C1-C10 alkyl; and (c) X is halogen.

326. The composition of claim 221 wherein the intestinal penetration agent is a phenoxyalkyl diethanolamine or phenoxyalkyl diisopropanolamine intestinal penetration agent.

327. The composition of claim 221 wherein the intestinal penetration agent is a ketopiperazine intestinal penetration agent of Formula (LXXXVII), wherein: (1) R1, R2, or R1and R2independently are hydrogen, C1-C24alkyl, C1-C24alkenyl, phenyl, naphthyl, (C1-C10alkyl)phenyl, C1-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl(C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl(C1-C10 alkyl), and naphthyl(C1-C10 alkenyl); (2) R1, R2, or R1and R2, optionally, are independently substituted with C1-C4alkyl, C1- C4 alkenyl, C1-C4 alkoxy, hydroxy, sulfhydryl, and –CO2R3or any combination thereof, wherein R3is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl; (3) wherein the phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are independently substituted by C1-C6alkyl, C1-C6alkenyl, C1-C6alkoxy, hydroxy, sulfhydryl, or –CO2R4, wherein R4is hydrogen, C1-C6alkyl, C1-C6alkenyl; and (4) R1and R2are not both hydrogen.PATENT PARSON-58748 328. The composition of claim 221 wherein the penetration agent is selected from the group consisting of: 6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid; 8(2- aminobenzoylamino)caprylic acid; 8(2-trifluoromethoxy)benzoylamino caprylic acid; N-(2- hydroxybenzoyl)isonipecotic acid; 54-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid; 4-[4-(pentafluorobenzoyl)aminophenyl)butyric acid; 4-[4-(3-anisoyl)aminophenyl)butyric acid; 8-(3-anisoyl)aminocapryic acid; 4-[4-(phenoxyacetyl)aminophenyl)butyric acid; 4-(4-(2- nitrobenzenesulfonyl)aminophenyl)butyric acid; 8-(2-nitrobenzenesulfonyl)aminocaprylic acid; 6-(4-(salicyloyl)aminophenyl)hexanoic acid; 8-(2-methoxylbenzoyl)aminocaprylic acid; 2-[4- salicyloylamino)phenyl]ethyl methylsulfone; 1-salicyloyl-2-succinyl hydrazide; 3-(4-(2,5- dimethoxycinnamoyl)aminophenyl)propionic acid; 4-(4-(2,5- dimethoxycinnamoyl)aminophenyl)butyric acid; 1-salicyloyl-2-glutaryl hydrazide; succinyl-4- aminosalicylic acid; 8-(phenoxyacetylamino)caprylic acid; 8-(2-pyrazinecarbonyl)aminocaprylic acid; 4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid; 6-(4-(N-2- nitrobenzoyl)aminophenyl)hexanoic acid; 6-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid; 4-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid; 4-(2- nitrobenzoyl)aminophenylsuccinic acid; 8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid; 8- (benzylcarbonylamino)caprylic acid; 8-(phenylcarbonylamino)caprylic acid; 2-[4-(2- methoxybenzoylamino)phenyl]ethyl phosphate; 1-salicyloyl-2-suberyl hydrazide; 4-(4- benzyloxycarbonylaminophenyl)butyric acid; 4-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid; 9-salicyloylaminononanoic acid; 4-(4-phenyloxycarbonylaminophenyl)butyric acid; 3-(2- methoxybenzoylamino)-1-propanol; 8-(2-hydroxynicotinoyl)aminocaprylic acid; 6-(2- methoxybenzoyl)aminonicotinic acid; salicyloylglycine; 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid; 8-(chromone-3-carbonyl)aminocaprylic acid; 8-(vinylbenzoyl)aminocaprylic acid; 4-(4- (chromone-3-carbonyl)aminophenyl)butyric acid; 8-cinnamoylaminocaprylic acid; 5-(N- salicyloylamino)valeric acid; 9-(2-hydroxybenzamido)nonanoic acid; N-(4-salicyloylamino)-6- caproic acid; 4′-flavonic acid; 11-cinnamoylaminoundecanoic acid; 4-octanoylamino-3- hydroxybenzoic acid; (3-phenyl-2,3-dihydroxypropanoyl)8-aminocaprylic acid; 8-[N-(3- coumarincarbonyl)]aminocaprylic acid; 8-[N-(4-chlorobenzoyl)]aminocaprylic acid; 8-[N-3- fluorobenzoyl)]aminocaprylic acid; 8-(N-2,5-dihydroxybenzoyl)aminocaprylic acid; 8-(N-2,3- dimethoxybenzoyl)aminocaprylic acid; 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid; 8-(N- 2,5-dimethoxybenzoyl)aminocaprylic acid; 8-(N-3,5-diacetyloxybenzoyl)aminocaprylic acid; 8-PATENT PARSON-58748 (N-4-hydroxybenzoyl)aminocaprylic acid (dimer); 8-(N-2,4-dihydroxybenzoyl)aminocaprylic acid; 10-(N-2-methoxyanilino)sebacic acid; 10-(N-2-hydroxyanilino)sebacic acid; 2- methoxybenzaminodecanoic acid; 8-(N-benzoyl)aminocaprylic acid; 8-(N-2-hydroxy-4- methoxybenzoyl)aminocaprylic acid; 8-[N-(4-fluorobenzoyl)]aminocaprylic acid; 8-[N-(3- bromobenzoyl)]aminocaprylic acid; 8-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid; 8-[N- (4-bromobenzoyl)]aminocaprylic acid; 8-[N-(4-iodobenzoyl)]aminocaprylic acid; 4-{4-[N-(2- iodobenzoyl)aminophenyl]}butyric acid; 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid; 4-(4-(2,4-dimethoxybenzoyl)aminophenyl)butyric acid; 4-(o-anisoyl)aminophenylacetic acid; 3-[4-(2,4-dimethoxybenzoyl) aminophenyl]propionic acid; 4-{4-[N-(4- iodobenzoyl)]aminophenyl}butyric acid; 3-[4-(2,3-dimethoxybenzoyl) aminophenyl]propionic acid; 4{4-[N-2-bromobenzoyl)]aminophenyl}butyric acid; 4{-[N-3-bromobenzoyl) aminophenyl}butyric acid; 8-(N-3,5-dihydroxybenzoyl)aminocaprylic acid; (N-3,5-dimethoxy 4- hydroxybenzoyl)aminocaprylic acid; 8-(N-2-6-dimethoxybenzoyl)aminocaprylic acid; 4-{4-[N- (4-bromobenzoyl)aminophenyl]}butyric acid; 8-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid; 8-(N-2,6-dihydroxybenzoyl)aminocaprylic acid; 8-(N-2-hydroxy-6- methoxybenzoyl)aminocaprylic acid; 8-(5-chloro-o-anisoyl)aminocaprylic acid; 4-(4-(2,3- dimethoxybenzoyl)aminophenyl)butyric acid; 4-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid; 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid; 8-(4-chloro-o-anisoyl)aminocaprylic acid; 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid; 4-{N-[4-(3- iodobenzoyl)aminophenyl]}butyric acid; 7-cinnamoylaminoheptanoic acid; 8-N-(3- iodobenzoyl)aminocaprylic acid; 8-N-(3-iodobenzoyl)aminocaprylic acid; 8-N-(2-methoxy-4- nitrobenzoyl)aminocaprylic acid; 4-{N-[4-(2-methoxy-4-nitrobenzoyl)aminophenyl]}butyric acid; 4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid; 8-(N-2-hydroxy-5- bromobenzoyl)aminocaprylic acid; 3-indolebutyric acid; 4-(4-(2,6- dimethoxybenzoyl)aminophenylbutyric acid; 4-[4-N-(4-methoxy-3- nitrobenzoyl)aminophenyl]butyric acid; 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid; 8- (N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid; 8-(3-hydroxy-3-naphthoyl)aminocaprylic acid; 8-(N-2-hydroxy-4-nitrobenzoyl)aminocaprylic acid; 4-[N-(2-hydroxy-4- bromobenzoyl)aminophenyl]butyric acid; 8-(N-2,3-dihydroxybenzoyl)aminocaprylic acid; 8-(N- 3-methylsalicyloyl)aminocaprylic acid; 8-(N-5-methylsalicyloyl)aminocaprylic acid; 9- (cinnamoylamino)nonanoic acid; 4-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid; 4-{-PATENT PARSON-58748 [N-(2-hydroxy-5-iodobenzoyl)]aminophenyl}butyric acid; N-2-nitrophenyl-N′-(8-octanoic acid) urea; N-(2-methoxy-5-nitrophenyl) sebacoyl amide acid; 8-[N-(2-acetoxy-3,5- dichlorobenzoyl)]aminocaprylic acid; 8-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid; 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid; 8-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid; 4-(4-salicyloylaminophenyl)-4-oxobutyric acid; 12-cinnamoyldodecanoic acid; 4-{4-[N-(3- hydroxy-2-napthoyl)aminophenyl]}butyric acid; 8-(4-chloro-3-nitrobenzoyl)aminocaprylic acid; 8-(2-chloronicotinoyl)aminocaprylic acid; 8-(2-chloro-5-nitrobenzoyl)aminocaprylic acid; 4-(4- phthalimidophenyl)butyric acid; 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}propanoic acid; 3-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid; 8-(N-2-hydroxy-3,5- diiodobenzoyl)aminocaprylic acid; 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid; 8-(2- (1,2-dihydroisoindole-1-one))octanoic acid; 8-(N-2-hydroxy-2-naphthoyl)aminocaprylic acid; 8- (phthalimido)caprylic acid; 10-(4-chloro-2-hydroxyanilino)sebacic acid monoamide; 6- (anisoyl)aminocaproic acid; 4-(4-(4-chloro-3-nitrobenzoyl)aminophenyl)butyric acid; 11-N-(1- hydroxy-2-naphthoyl)aminoundecanoic acid; bis(N-2-carboxylphenyl-N-(N′-8-octanoic acid)oxalyl diamide; 2-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol; 2-[2-N-(4- chlorobenzoyl)aminoethoxy]ethanol; 4-(2-methoxybenzoyl)amino 3-carboxysulfoxide; 4-(2- methoxybenzoyl)amino 3-carboxypropylsulfone; 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid; [2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol; 2-[2-N-(3- chlorobenzoyl)aminoethoxy)]ethanol; bis(N-2-carboxyphenyl-N-(N′-3(4-aminophenyl)propionic acid)urea)oxalyl diamide; trans-4-(2-aminobenzamidomethyl)cyclohexaminylcarboxylic acid; 11-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid; 2-[N-(2- bromobenzoyl)aminoethoxyl]ethanol; 7-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid; N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid; trans-4-(N- salicyloylaminomethyl)cyclohexane carboxylic acid; N-[3,5-dichloro-2-hydroxybenzoyl-3-(4- aminophenyl)]propionic acid; 12-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid; N- (2-hydroxy-4-carboxy)-6-heptenamide; N-(2-bromobenzoyl)morpholine; N- cyclohexanoylaminocaprylic acid; 2-[N-(2-iodobenzoyl)aminoethoxyl]ethanol; 5-(4-chloro-2- hydroxyanilinocarbonyl)valeric acid; 8-(2-hydroxyphenoxy)-aminocaprylic acid; N-salicyloyl-5- (3-aminophenyl)valeric acid; 4-(4-(2-ethoxylbenzoyl)aminophenyl)butyric acid; 9-[2-(3- hydroxy)pyridylaminocarbonyl]nonanoic acid; 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid; 2-[N-(2-hydroxybenzoylamino)ethoxyl]ethanol; 4-[N-(3,5-dichloro-2-PATENT PARSON-58748 hydroxybenzoyl)]aminophenylacetic acid; 8-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid; N-salicyloyl-5-(4-aminophenyl)valeric acid; 9-(2-hydroxy-5-methylanilinocarbonyl)nonanoic acid; 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid; 8-(pentafluorobenzoyl)aminocaprylic acid; 3-(3-(salicyloyl)aminophenyl)propionic acid; 8-(2-ethoxybenzoyl)aminocaprylic acid; 4-(4-(2-dimethylaminobenzoic)aminophenyl)butyric acid; 8-(3-phenoxylpropionylamino)caprylic acid; 4-(salicyloyl)aminophenylethyltetrazole; 8(- (4-(N-salicyloyl-4aminophenyl)butyric)aminocaprylic acid); 4-(4-(N-(2- fluorocinnamoyl))aminophenyl) butyric acid; 4-(4-(N-8(N- salicyloyl)aminocaprylic)aminophenyl)butyric acid; 8-(p-anisoyl)aminocaprylic acid; 8-(4- hydroxybenzoyl)aminocaprylic acid; 8-(3-hydroxybenzoyl)aminocaprylic acid; 8-(3,4,5- trimethoxybenzoyl)aminocaprylic acid; 8-(N-4-methylsalicyloyl)aminocaprylic acid; N-10-(2- hydroxy-5-nitroanilino)decanoic acid; and 4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid.

329. The composition of claim 221 wherein the penetration agent is a compound of Formula (LXXXVIII), (LXXXIX), (XC), or (XCI).

330. The composition of claim 221 wherein the penetration agent is a compound of Formula (XCII) wherein: (1) R1, R2, R3, R4, and R5are independently hydrogen, cyano, hydroxy, --OCH3, or halogen, wherein at least one of R1, R2, R3, R4, and R5is cyano; (2) R6is C1-C12linear or branched alkylene, alkenylene, arylene, alkyl(arylene), or aryl(alkylene); and (3) with the proviso that when R1is cyano, R4is hydrogen or cyano, and R2, R3, and R5are hydrogen, then R6is methylene.

331. The composition of claim 221 wherein the intestinal penetration agent is a phenoxycarboxylic acid of Formula (XCIII) wherein: (1) R1, R2, R3, and R4are independently hydrogen, hydroxy, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, --C(O)R8, nitro, NR9R10, or N+R9R10R11(R12)-; (2) R5is hydrogen, hydroxy, nitro, halogen, --CF3, NR14R15, N+R14R15R16(R13)-, amide, C1-C12alkoxy, C1-C12alkyl, C1-C12alkenyl, carbamate, carbonate, urea, or – C(O)R18; (3) R5is optionally substituted with halogen, sulfhydryl, or carboxy; (4) R5is optionally interrupted by O, N, S, or –C(O)--; (5) R6is a C1-C12 alkylene, C2-C12 alkenylene, or arylene; (6) R6is optionally substituted with C1-C4alkyl, C2-C4alkenyl, C1-C4alkoxy, hydroxy, sulfhydryl, halogen, amino, or –CO2R8; (7) R6is optionally interrupted with O or N; (8) R7is a valence bond or arylene; (9) R7is optionally substituted with hydroxy, halogen, --C(O)CH3, -- NR10R11, or –N+R10R11R12(R13)-; (10) R8is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or amino; (11)PATENT PARSON-58748 R9, R10, R11, and R12are independently hydrogen or C1-C10 alkyl; (12) R13is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; (13) R14, R15, and R16are independently hydrogen, C1- C10 alkyl, C1-C10 alkyl substituted with carboxy, C2-C12 alkenyl, C2-C12 alkenyl substituted with carboxy, or –C(O)R17; (14) R17is hydroxy, C1-C10 alkyl, or C2-C12 alkenyl; and (15) R18is hydrogen, C1-C6alkyl, hydroxyl, --NR14R15, or –N+R14R15R16(R13)-,with the following provisos: (a) when R1, R2, R3, R4, and R5are hydrogen and R7is a bond, then R6is a C1-C6, C9, or C10 alkyl; (b) when R1, R2, R3and R4are hydrogen and R5is hydroxyl, and R7is a bond, then R6is not a C1-C3alkyl; (c) when at least of R1, R2, R3and R4is not hydrogen, R5is hydroxyl, and R7is a bond, then R6is not a C1-C4alkyl; (d) when R1, R2, and R3are hydrogen, R4is –OCH3, R5is –C(O)CH3, and R6is a bond, then R7is not a C3 alkyl; and (e) when R1, R2, R4, and R5are hydrogen, R3is hydroxyl, and R7is a bond, then R6is not methyl.

332. The composition of claim 221 wherein the intestinal penetration agent is a compound of Formula (XCIV) wherein: (1) R1, R2, R3, R4, and R5are independently selected from hydrogen, halogen, hydroxy, methoxy, C1-C4 alkyl, amino, methylamino, dimethylamino, or nitro; (2) m is an integer ranging from 0 to 4; (3) R6is a phenyl substituted with –O—R7- COOH at the ortho, meta, or para position; (4) R6is optionally substituted with one or more moieties selected from the group consisting of halogen, hydroxy, methoxy, C1-C4 alkyl, amino, methylamino, dimethylamino, and nitro; and (5) R7is C1-C12alkylene.

333. The composition of claim 221 wherein the intestinal penetration agent is 8-(2-hydroxyphenoxy)octyldiethanolamine or a salt thereof.

334. The composition of claim 221 wherein the intestinal penetration agent is a compound selected from the group consisting of Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), Compound (12), Compound (13), Compound (14), Compound (15), Compound (16), Compound (17), Compound (18), Compound (19), and Compound (20).

335. The composition of claim 221 wherein the intestinal penetration agent is a disodium salt, a monohydrate, or an ethanol solvate of a compound of Formula (XCV) wherein: (1) R1, R2, R3, and R4are independently hydrogen, halogen, C1-C4alkyl, or C1-C4alkoxy; and (2) R5is a substituted or unsubstituted C2-C16alkylene, substituted or unsubstituted C2-C16alkenylene, substituted or unsubstituted C1-C12 alkyl(arylene), or substituted or unsubstituted aryl(C1-C12 alkylene).PATENT PARSON-58748 336. The composition of claim 221 wherein the intestinal penetration agent is a phenylalkylcarboxylic acid of Formula (XCVI) wherein: (1) n is 1-12; and (2) R1-R5are each independently hydrogen, C1-C6 alkyl, C2-C4 alkenyl, halogen, C1-C4 alkoxy, hydroxy, C6-C14 aryloxy, or C1-C6 haloalkyl.

337. The composition of claim 221 wherein the intestinal penetration agent is a compound possessing both at least one hydrophobic group and at least one hydrophilic group.

338. The composition of claim 337 wherein the at least one hydrophobic group is selected from the group consisting of phenyl groups, naphthyl groups, cyclohexyl groups, and long-chain aliphatic groups.

339. The composition of claim 337 wherein the at least one hydrophilic group is selected from the group consisting of carboxylic acid groups, carboxylic acid ester groups, amide groups, amino groups, and carbonyl groups.

340. The composition of claim 217 wherein the composition further comprises a therapeutically effective quantity of an additional agent to treat Alzheimer’s disease.

341. The composition of claim 340 wherein the additional agent to treat Alzheimer’s disease is selected from the group consisting of tacrine, rivastigmine, galantamine, donepezil, memantine, CPHPC ((R)-1-{6-[(R)-2-carboxypyrrolidin-1-yl]-6- oxohexanoyl}pyrrolidine-2-carboxylic acid), and lecanemab.

342. The composition of claim 340 wherein the additional agent to treat Alzheimer’s disease is an antidepressant.

343. The composition of claim 342 wherein the antidepressant is a selective serotonin reuptake inhibitor selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, zimelidine, cericlamine, and panuramine.

344. The composition of claim 342 wherein the antidepressant is a serotonin- norepinephrine reuptake inhibitor selected from the group consisting of venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran.

345. The composition of claim 342 wherein the antidepressant is a serotonin modulator selected from the group consisting of vortioxetine and vilazodone.PATENT PARSON-58748 346. The composition of claim 342 wherein the antidepressant is a serotonin antagonist and reuptake inhibitor selected from the group consisting of etoperidone, lorpiprazole, lubazodone, mepiprazole, nefazodone, and trazodone.

347. The composition of claim 342 wherein the antidepressant is a norepinephrine reuptake inhibitor selected from the group consisting of amedalin, CP-39,332 (1,2,3,4-tetrahydro-N-methyl-4-phenyl-2-naphthalenamine), daledalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, viloxazine, buproprion, ciclazindole, manifaxine, maprotiline, radafaxine, tapentadol, and teniloxazine.

348. The composition of claim 342 wherein the antidepressant is a tricyclic antidepressant selected from the group consisting of amitriptyline, butriptyline, clomipramine, desipramine, dolesupin, doxepin, imipramine, iprindole, lofepramine, nortriptyline, protriptyline, and trimipramine.

349. The composition of claim 342 wherein the antidepressant is a tetracyclic antidepressant selected from the group consisting of mianserin, mirtazapine, pirlindole, setiptiline, aptazapine, esmirtazapine, metralindole, and oxprotiline.

350. The composition of claim 342 wherein the antidepressant is a monoamine oxidase inhibitor selected from the group consisting of isocarboxazid, nialamide, phenelzine, hydracarbazide, tranylcypromine, bifemelane, moclobemide, toloxatone, rasagline, selegiline, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, and minaprine.

351. The composition of claim 342 wherein the antidepressant is an atypical antidepressant selected from the group consisting of amisulpride, lurasidone, and quetiapine.

352. The composition of claim 342 wherein the antidepressant is an antidepressant that acts by one or more other mechanisms selected from the group consisting of agomelatine, tandospirone, α-methyltryptamine, etryptamine, indeloxazine, medifoxamine, nomifensine, oxaflozane, and pivagabine.

353. The composition of claim 218 wherein the composition is formulated to treat Parkinson’s disease and wherein the composition further comprises a therapeutically effective quantity of an additional agent to treat Parkinson’s disease.

354. The composition of claim 353 wherein the additional agent to treat Parkinson’s disease is levodopa.PATENT PARSON-58748 355. The composition of claim 353 wherein the additional agent to treat Parkinson’s disease is a monoamine oxidase inhibitor selected from the group consisting of isocarboxazid, nialamide, phenelzine, hydracarbazide, tranylcypromine, bifemelane, moclobemide, toloxatone, rasagline, selegiline, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, and minaprine.

356. The composition of claim 353 wherein the additional agent to treat Parkinson’s disease is a dopamine agonist selected from the group consisting of bromocriptine, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, cabergoline, ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine, lisuride, propylnorapomorphine, roxindole, sumanirole, and fenaldopam.

357. The composition of claim 218 wherein the composition is formulated to treat amyotrophic lateral sclerosis and wherein the composition further comprises a therapeutically effective quantity of an additional agent to treat amyotrophic lateral sclerosis.

358. The composition of claim 357 wherein the additional agent to treat amyotrophic lateral sclerosis is selected from the group consisting of riluzole, edaravone, sodium phenylbutyrate / taurursodiol, toferse, gabapentin, and pregabalin.

359. The composition of claim 218 wherein the composition is formulated to treat multiple sclerosis and wherein the composition further comprises a therapeutically effective quantity of an additional agent to treat multiple sclerosis.

360. The composition of claim 359 wherein the additional agent to treat multiple sclerosis is selected from the group consisting of interferon beta-1a, interferon beta-1b, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, natalizumab, mitoxantrone, ocrelizumab, siponimod, cladribine, ozanimod, and ponesimod.