Formulations comprising chelators, permeation enhancers and hydroxyethyl cellulose for treating ophthalmic disorders

Abstract

To provide compositions for treatment of ophthalmic disorders including adverse ocular conditions associated with aging.SOLUTION: An ophthalmic formulation, comprising a chelator (such as EDTA and its salts), and a transport enhancer (such as Methyl Sulfonyl Methane; MSM) and an effective amount of a viscoelastic polymer (such as hydroxymethyl cellulose; HEC) is provided. Together, the combination of the two substances unexpectedly and beneficially reduces discomfort associated with and increases efficacy of chelator / transport enhancers as compared to formulations without the viscoelastic polymers.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention generally relates to the field of treatment of ophthalmic diseases, including adverse eye conditions often associated with aging. More specifically, the present invention relates to the treatment of conditions associated with the presence of polymeric aggregates, such as may be present in the eye. In particular, the present invention relates to antimicrobial compositions containing a transport enhancer, a chelating agent, and hydroxyethylcellulose (HEC). In one exemplary embodiment, such compositions contain MSM, a chelating agent, and HEC. [Background technology]

[0002] Progressive age-related changes in the eye, including normal and pathological changes, are an inevitable part of life in humans and other mammals. Many of these changes have serious effects on both the function and cosmetic appearance of the eye. These changes include: development of cataracts; hardening, clouding, loss of flexibility, and yellowing of the crystalline lens; yellowing and opacification of the cornea; presbyopia; clogging of the trabeculum leading to increased intraocular pressure and glaucoma; increased floaters in the vitreous humor; hardening of the iris and its narrowing of its dilated range; age-related macular degeneration (AMD); formation of atherosclerotic deposits in the retinal arteries; dry eye syndrome; and a decrease in the sensitivity and ability of the rods and cones of the retina to adapt to light levels. Age-related loss of vision includes loss of visual acuity, visual contrast, color and depth perception, lens accommodation, light sensitivity, and dark adaptation. Age-related changes also include changes in the coloration of the iris and the formation of arcus senilis.

[0003] The present inventors have previously disclosed a formulation for treating ophthalmic diseases, comprising a chelating agent and a penetration enhancer. International application PCT / US2006 / 027686 (International Publication No. 2007011875) discloses a formulation for reducing macromolecular aggregates in the eye using a formulation comprising a metal chelating agent and a charge masking agent such as MSM and EDTA. US Patent Application No. 20060177430 discloses a formulation for treating adverse ocular conditions, comprising a biocompatible chelating agent, an effective penetration enhancing amount of an ocular penetration enhancer such as methylsulfonylmethane (MSM), and an anti-AGE (advanced glycation endproducts) agent.

[0004] However, it has been observed that administration of formulations containing chelating agents and MSM (or similar penetration enhancers), while effective in treating polymeric aggregation, results in discomfort for patients who exhibit significant stinging in the eyes, thus causing patients to discontinue treatment. This may be caused, in part, by the higher concentrations of chelating agents and / or penetrating agents in the formulation.

[0005] Artificial tears are used to relieve ocular discomfort by using one or more demulcents, including carboxymethylcellulose, dextran, glycerin, hypromellose, polyethylene glycol 400 (PEG400), polysorbate, polyvinyl alcohol, povidone, or propylene glycol, among others. The FDA has approved the use of artificial tears in the treatment of ocular discomfort specifying the ingredients and concentrations for such use. (Food and Drug Administration: “Ophthalmic Drug Products for Over-the-counter Human use; Final Monograph” 21 CFR Parts 349 and 369. Federal Register 1988, 53(43):7076-7093, available at www.fda.gov / downloads / Drugs / DevelopmentApprovalProcess / DevelopmentResources / Over-the-CounterOTCDrugs / StatusofOTCRulemakings / ucm094081.pdf). Other ingredients used in artificial tears include emollients, which are oil- or fat-based agents used to soften and protect tissues and prevent them from cracking and drying.

[0006] Efforts to solve the problem by using viscoelastic polymers (e.g., hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, and polyvinyl alcohol) in standard concentrations (approximately 0.2%) as used in artificial tears. These polymers and concentrations used always resulted in more stinging for a longer period of time than without the use of the polymers. Summary of the Invention

[0007] The present invention is based on the surprising observation that there was a significant reduction in stinging by using hydroxyethyl cellulose (HEC) in significantly higher concentrations (0.5-5.0%).

[0008] Without being bound by theory, it is hypothesized that at very high HEC concentrations, the release rate of EDTA / MSM is dramatically reduced, resulting in a significant reduction in stinging: the ocular mucosa no longer experiences the levels of chelating agent / MSM that caused stinging at lower levels of the viscoelastic compound, especially at the edge of the eye near the nose where most of the stinging occurs.

[0009] In several embodiments, the invention relates to methods of using a formulation comprising a transport enhancer (e.g., MSM) and a chelating agent (e.g., EDTA) and HEC at a concentration of 0.5% to 5% and an ophthalmically acceptable inert carrier to reduce adverse ocular conditions caused by macromolecular aggregation.

[0010] The concentration of HEC may be selected from 0.5%, 0.6%, 0.7%, 0.8%, 0.85%, 0.9%, 1.0%, 1.5%, 2.0%, 5.0%, or ranges encompassed by these values. In certain embodiments, HEC is 0.8%-1.0%. In one embodiment, the concentrations are EDTA 1.3%, MSM 2.7% and HEC 0.85%.

[0011] The method comprises administering to the subject a therapeutically effective amount of a chelating agent and a compound of formula (I): [ka] [In the formula, R 1 and R 2 are independently optionally substituted, C2-C6 alkyl, C1-C6 heteroalkyl, C6-C 14 Aralkyl and C2-C 12 heteroaralkyl, and Q is S or P. The method includes administering an effective amount of a formulation comprising an effective transport-enhancing amount of a transport-enhancing agent having the formula:

[0012] The transport enhancer can be, for example, methylsulfonylmethane (MSM; also known as methylsulfone, dimethylsulfone, and DMSO2), and the chelating agent can be ethylenediaminetetraacetic acid (EDTA), and the like.

[0013] The formulations may be administered in any form suitable for ophthalmic administration, including liquid and gel-based compositions. Additionally, in preferred embodiments, the formulations are entirely composed of naturally occurring ingredients and / or GRAS ("Generally Regarded as Safe") ingredients according to the U.S. Food and Drug Administration.

[0014] In another embodiment, the invention provides a method of inhibiting ocular biofilm formation comprising contacting bacteria with an effective amount of a formulation comprising a transport enhancer (e.g., MSM), a chelating agent (e.g., EDTA) and 0.5%-5.0% HEC, thereby inhibiting ocular biofilm formation.

[0015] A further embodiment of the present invention provides an ocular insert for inhibiting biofilm formation, wherein the ocular formulation comprises a formulation comprising a transport enhancer (e.g., MSM), a chelating agent (e.g., EDTA) and 0.5% to 5% HEC and a pharma- ceutically acceptable vehicle.

[0016] The present invention also relates to a method for preventing and treating adverse eye conditions, including those related to oxidative and / or free radical damage in the eye, and some related to the formation or deposition of macromolecular aggregates.The formulation contains a therapeutically effective amount of an ophthalmologically active agent, a sequestrant for metal cations, such as a chelating agent as described above, and a transport enhancer as described above.These adverse eye conditions include, by way of example, conditions, diseases or disorders of the cornea, retina, lens, sclera, and anterior and posterior eye segments.As used herein, adverse eye conditions may be "normal" conditions (e.g., decreased visual acuity and contrast sensitivity) that are frequently seen in aging individuals, or pathological conditions that may or may not be related to the aging process.The latter adverse eye conditions include a wide variety of eye disorders and diseases. Age-related eye problems that can be prevented and / or treated using the formulation of the present invention include, but are not limited to, opacification (both corneal and crystalline), cataract formation (including secondary cataract formation), and other problems associated with lipid deposition, reduced visual acuity, reduced contrast sensitivity, photophobia, glare, dry eye, loss of night vision, constriction of the pupil, presbyopia, age-related macular degeneration, elevated intraocular pressure, glaucoma, and arcus senilis. By "age-related" is meant conditions that are generally recognized to occur much more frequently in older patients, but may also occur in younger people. The formulation can also be used to treat ocular surface proliferations such as pinguecula and pterygium, which are typically caused by dust, wind or ultraviolet light, but may also be symptoms of degenerative diseases associated with presbyopia. Another adverse condition that is not generally considered to be age-related but can be treated using the formulation includes keratoconus. It should also be emphasized that the formulation can generally be advantageously used to improve vision in any mammalian individual. That is, intraocular administration of the formulation can improve visual acuity and contrast sensitivity, as well as color and depth perception, regardless of the patient's age or the presence of an adverse ocular condition. The formulations are useful for treating adverse ocular conditions in both humans and animals.

[0017] In some embodiments, the formulations are effective in relieving dry eye symptoms, particularly dry eye associated with inflammation.

[0018] These and other aspects will become apparent from the following description of the preferred embodiments taken in conjunction with the following drawings, in which changes and modifications can be effected without departing from the spirit and scope of the novel concepts of the present disclosure.

[0019] Detailed Description of the Invention The terms used herein generally have their ordinary meaning in the art, within the context of the present invention and in the specific context in which each term is used. Certain terms used to describe the present invention are discussed below or elsewhere herein to provide additional guidance to the practitioner regarding the description of the present invention. For convenience, certain terms may be highlighted, for example using italics and / or quotation marks. The use of highlighting does not affect the scope and meaning of a term; the scope and meaning of a term is the same in the same context whether or not it is highlighted. It will be understood that the same thing can be said in more than one way. Thus, alternative language or synonyms may be used for one or more of the terms described herein, with no special meaning as to whether the term is elaborated or explained. Synonyms for certain terms are provided. The remark of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of terms described herein, is merely illustrative and does not limit in any way the scope and meaning of the invention or the exemplified terms. Similarly, the invention is not limited to the various embodiments provided herein.

[0020] Where a range of values ​​is provided, it is understood that each intermediate value between the upper and lower limits of that range and any other value or intermediate value within that stated range, to the nearest tenth of the lower limit, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the scope of the invention, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0021] Throughout this application, various publications, patents, and published patent applications are cited. The inventions of these publications, patents, and published patent applications referenced in this application are hereby incorporated by reference. Citation of a publication, patent, or published patent application herein is not an admission that the publication, patent, or published patent application is prior art.

[0022] As used herein and in the claims that follow, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "a transport enhancer" includes a plurality of transport enhancers as well as a single transport enhancer. Reference to a "chelating agent" includes reference to two or more chelating agents as well as a single chelating agent, and the like. Throughout this specification and the claims that follow, reference will be made to a number of terms that are defined to have the following meanings.

[0023] When referring to a formulation component, the term used, e.g., "agent," is intended to encompass not only the specific molecular entity but also pharma- ceutically acceptable analogs thereof, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.

[0024] The terms "treat" and "treatment" as used herein refer to the administration of an agent or formulation to a clinically symptomatic individual suffering from an adverse condition, disorder or disease to result in a reduction in the severity and / or frequency of symptoms, to eliminate the symptoms and / or their underlying causes, and / or to promote the amelioration or repair of damage. The terms "prevent" and "prevention" refer to the administration of an agent or composition to a clinically asymptomatic individual susceptible to a particular adverse condition, disorder, or disease, and thus relate to the prevention of the occurrence of the symptoms and / or their underlying causes. Unless otherwise specified herein, either explicitly or implicitly, when the term "treatment" (or "treating") is used without reference to possible prevention, prevention is also intended to be included, and a "method of treating gingivitis" is interpreted as encompassing a "method of preventing gingivitis".

[0025] "Optional" or "optional," as in "optional substituent" or "optional additive," means that the subsequently described component (e.g., substituent or additive) may or may not be present, and thus the description includes the presence and absence of the component.

[0026] "Pharmaceutically acceptable" means a biologically or otherwise undesirable substance, e.g., the substance can be incorporated into the formulation of the present invention without causing undesirable biological effects or adversely interacting with any of the other components of the dosage form formulation. However, when the term "pharmaceutically acceptable" is used to refer to a pharmaceutical excipient, it means that the excipient has met the necessary standards of toxicological and manufacturing testing, and / or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. As explained in more detail below, "pharmacologically active" (or simply "active"), as in the case of "pharmacologically active" derivatives or analogs, refers to derivatives or analogs that have the same type of pharmacological activity as the parent drug. As used herein, the terms "treat" and "treatment" refer to reducing the severity and / or frequency of symptoms, eliminating symptoms and / or underlying causes, preventing the occurrence of symptoms and / or their underlying causes, and improving or treating an undesirable condition or injury. Thus, for example, "treating" a subject includes the prevention of an adverse condition in a susceptible individual, as well as the treatment of a clinically symptomatic individual by inhibiting or causing the regression of the condition. The term "chelating agent" (or "active agent") refers to a compound, complex, or composition that exhibits a desired effect in a biological context, i.e., when administered to a subject or introduced into a cell or tissue in vitro. The term includes pharma- ceutically acceptable derivatives of these active agents specifically described herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, analogs, crystals, and hydrates. When the term "chelating agent" is used, or when a particular chelating agent is specifically identified, it should be understood that not only the agent itself but also pharma-ceutically acceptable salts, esters, amides, prodrugs, active metabolites, isomers, analogs, and the like of the agent are intended.

[0027] An "effective" amount or a "therapeutically effective" amount of an active agent refers to an amount of the active agent that is sufficient to provide a non-toxic but beneficial effect. The amount of an "effective" active agent varies from subject to subject, depending on the age and general condition of the individual, as well as the specific active agent. Unless otherwise specified, a "therapeutically effective" amount as used herein is intended to include an amount effective for preventing an adverse condition and / or ameliorating an adverse condition, in addition to an amount effective for treating an adverse condition.

[0028] The term "controlled release" refers to a drug-containing formulation or fraction thereof in which the release of the drug is not immediate, i.e., administration of a "controlled release" formulation does not result in the immediate release of the drug into the absorption pool. The term is used interchangeably with "non-immediate release" as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). In general, the term "controlled release" as used herein refers to "sustained release" formulations rather than "delayed release" formulations. "Sustained release" (synonymous with "extended release") is used in its conventional sense to refer to a formulation that provides a sustained release of drug over an extended period of time.

[0029] By "pharmacologically acceptable" or "ophthalmically acceptable" is meant an ingredient that is not biologically or otherwise undesirable, i.e., the ingredient can be incorporated into the ophthalmic formulations of the present invention and administered topically to the eye of a patient without causing undesirable biological effects or adversely interacting with any of the other ingredients of the formulation composition in which it is contained. When the term "pharmacologically acceptable" is used to refer to an ingredient other than a pharmacologically active agent, it means that the ingredient has met the necessary standards of toxicological and manufacturing testing or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0030] The terms "peptide" and "peptidyl" are intended to include structures composed of two or more types of amino acids. The amino acids forming all or part of the peptide can be any of the 20 common natural amino acids, namely alanine (A), cysteine ​​(C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y). Any of the amino acids can be replaced with a non-conventional amino acid, such as an isomer or analog of a conventional amino acid (e.g., a D-amino acid), a non-protein amino acid, a post-translationally modified amino acid, an enzymatically modified amino acid, or a construct or structure designed to mimic an amino acid. Peptidyl compounds as used herein include proteins, oligopeptides, polypeptides, lipoproteins, glycosylated peptides and glycoproteins.

[0031] As will be apparent to one of ordinary skill in the art upon reading the present invention, each of the individual embodiments described and illustrated herein has distinct elements and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. A recited method may be carried out in the order of events recited or in any other order which is logically possible.

[0032] Unless otherwise specified, the present invention is not limited to particular formulation components, modes of administration, chelating agents, or methods of manufacture, etc., which as such can vary.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the present specification, including definitions, will control.

[0034] Ophthalmic Disorders and Adverse Conditions All parts of the eye, including the cornea, sclera, trabecular meshwork, iris, lens, vitreous humor and retina, are affected by the aging process, as explained below.

[0035] The cornea is the outermost layer of the eye. It is a transparent, dome-shaped surface that covers the front of the eye. The cornea is made up of five layers. The epithelium is the layer of cells that form the surface. It is only about 5-6 cell layers thick and regenerates quickly if the cornea is damaged. If an injury penetrates the cornea more deeply, scarring can occur, leaving areas of opacity, causing the cornea to lose its clarity and luster. Just below the epithelium is Bowman's membrane, a protective layer that is very tough and difficult to penetrate. The stroma, the thickest layer of the cornea, is just below Bowman's membrane and is made up of tiny collagen fibers arranged in parallel, an arrangement that provides the cornea with transparency. Descemet's membrane lies below the stroma and just above the innermost corneal layer, the endothelium. The endothelium is only one cell layer thick and is responsible for channeling water from the cornea to the aqueous humor, keeping it clear. If damaged or diseased, these cells do not regenerate.

[0036] As the eye ages, the cornea can become cloudy. The clouding can take a variety of forms. The most common form of clouding affects the periphery of the cornea and is referred to as "arcus senilis" or "arcus senilis." This type of clouding initially involves lipid deposition in Descemet's membrane. Lipid then deposits in Bowman's membrane and possibly in the corneal stroma. Although arcus senilis is not usually visually significant, it is an outwardly noticeable sign of aging. There are other age-related corneal cloudings that can have several visual consequences. These include central cloudy dystrophy of Francois, which affects the mid-corneal stroma, and posterior crocodile shagreen, which is a central clouding of the posterior corneal stroma. The clouding by scattering light results in a progressive loss of visual contrast and visual acuity.

[0037] Corneal opacification occurs as a result of many causes, including, for example, degeneration of corneal structure; cross-linking of collagen and other proteins by metalloproteinases; ultraviolet (UV) damage; oxidative damage; and accumulation of substances such as calcium salts, protein waste products, and excess lipids.

[0038] There is no established treatment to slow or reverse corneal changes other than surgical intervention. For example, after first removing the epithelium, the opacified structures can be scraped away with a blunt instrument, followed by a laser beam to smooth and reshape the corneal surface. In severe cases of corneal scarring and opacification, corneal transplantation has been the only effective approach.

[0039] Another common eye disorder that adversely affects the cornea and other intraocular structures is keratoconjunctivitis sicca, commonly referred to as "dry eye syndrome" or "dry eye". Dry eye can result from many causes and is often a problem for the elderly. The disorder is associated with a tingling sensation, excess mucus secretion, burning sensation, increased light sensitivity, and pain. Dry eye is currently treated with "artificial tears", which are over-the-counter products that contain lubricants such as low molecular weight polyethylene glycol. Surgical treatment is also not uncommon and usually involves the insertion of punctal plugs into the eye so that lacrimal gland secretions are retained in the eye. However, both types of treatment are problematic: surgical treatment is invasive and potentially risky, while artificial tear products only provide very temporary and often inadequate relief.

[0040] The sclera is the white of the eye. In young individuals, the sclera is pale, but as people age, the sclera turns yellow as a result of age-related changes in the conjunctiva. Over time, UV and dust exposure can cause changes in the conjunctival tissue, leading to pinguecula and pterygium formation. These eye growths can further cause destruction of scleral and corneal tissue. Currently, surgery, including conjunctival grafts, is the only approved treatment for pinguecula and pterygium.

[0041] The trabecular meshwork, also called the trabecular meshwork, is a mesh-like structure at the iris-scleral border of the anterior chamber. The trabecular meshwork serves to filter aqueous humor and control its flow from the anterior chamber to Schlemm's canal. As the eye ages, debris and protein-lipid waste products can build up and clog the trabecular meshwork, a problem that results in increased pressure within the eye, which can then lead to glaucoma and damage to the retina, optic nerve, and other ocular structures. Glaucoma medications can help reduce this pressure, and surgery can create artificial openings to bypass the trabecular meshwork and re-establish the flow of fluid from the vitreous and aqueous humor. However, there are no known methods to prevent the accumulation of debris and protein-lipid waste products within the trabecular meshwork.

[0042] Iris and Pupil: With age, the dilation and contraction of the iris in response to changes in illumination slows and its range of motion decreases. The pupil also becomes progressively smaller with age, greatly limiting the amount of light entering the eye, especially in low light conditions. Narrowing of the pupil, as well as hardening, slow adaptation, and contraction of the iris over time, are the primary causes of the difficulty experienced by older adults in seeing at night and adapting to changes in illumination. Changes in the shape, stiffness, and adaptability of the iris are generally thought to result from fibrosis and cross-linking between structural proteins. Deposits of protein and lipid waste products on the iris over time can also lighten its color. Both light-colored deposits on the iris and narrowing of the pupil are very noticeable outward age markers that can have social consequences for individuals. There is no standard treatment for either of these changes, or for age-related changes in iris color.

[0043] With age, the crystalline lens becomes yellow, harder, stiffer, less flexible, and may become opaque, either diffusely or in specific locations. Thus, the lens transmits less light, reducing visual contrast and visual acuity. The yellowing also affects color vision. When the lens becomes stiff and the muscles are no longer able to accommodate it, a condition commonly known as presbyopia results. Presbyopia, which almost always occurs after middle age, is the inability of the eye to focus properly. This age-related eye pathology manifests itself as a loss of accommodation, i.e., the eye's ability to focus on near or distant objects through the crystalline lens by changing its shape to become more spherical (or convex). Both myopic and hyperopic individuals are affected by presbyopia. Age-related loss of accommodation amplitude is progressive, and presbyopia is perhaps the most common of all eye diseases, eventually affecting virtually all individuals during the normal human lifespan.

[0044] These changes in the lens are believed to be due to degenerative changes in the structure of the lens, including glycation cross-links between collagen fibers, accumulation of protein complexes, UV-induced structural deterioration, oxidative damage, and deposits of waste proteins, lipids, and calcium salts. The elastic and viscous properties of the lens depend on the properties of the fiber membrane and cytoskeleton crystallins. The lens fiber membrane is characterized by a very high cholesterol to phospholipid ratio. Changes in these components affect the deformability of the lens membrane. The loss of lens deformability is also due to increased binding of lens proteins to the cell membrane.

[0045] Compensatory options for mitigating presbyopia currently include bifocal reading glasses and / or contact lenses, monovision intraocular lenses (IOLs) and / or contact lenses, multifocal IOLs, monovision and anesthetic corneal surgery using radial keratotomy (RK), photorefractive keratomileusis (PRK), and laser in situ keratomileusis (LASIK).Currently, no widely accepted treatment or therapy is available for presbyopia.

[0046] Clouding of the crystalline lens results in an abnormal condition commonly known as cataract. Cataract is a progressive eye disease that subsequently leads to loss of vision. Most of this eye disease is age-related senile cataract. The incidence of cataract formation is thought to be 60-70% in people in their 60s and nearly 100% in people over 80 years of age. However, at present, there is no drug that has been clearly proven to inhibit the development of cataracts. Thus, the development of an effective therapeutic agent was desired. Currently, the treatment of cataract relies on vision correction using glasses, contact lenses, or surgical procedures such as the insertion of an intraocular lens into the lens capsule after extracapsular lens extraction surgery.

[0047] In cataract surgery, the occurrence of secondary cataract after surgery is a problem. Secondary cataract is the same as the opacity present on the surface of the remaining posterior capsule after extracapsular lens extraction surgery. The mechanism of secondary cataract is mainly as follows. After the removal of the lens epithelial cells (anterior capsule), secondary cataract occurs when the remaining lens epithelial cells that are not completely removed during the extraction of the lens cortex migrate and proliferate to the posterior capsule, causing posterior capsule opacification. In cataract surgery, it is impossible to completely remove the lens epithelial cells, and as a result, it is difficult to always prevent secondary cataract. The incidence of the above-mentioned posterior capsule opacification is said to be 40-50% in eyes that do not receive intracapsular posterior chamber lens implants and 7-20% in eyes that receive intracapsular lens implants. In addition, eye infections classified as endophthalmitis have also been observed after cataract surgery.

[0048] Vitreous Humor: Floaters are debris particles that interfere with clear vision by casting a shadow on the retina. Currently, there is no standard treatment for the reduction or elimination of floaters.

[0049] As we age, many changes can occur to the retina. Atherosclerotic buildup and leakage of the retinal arteries can cause macular degeneration and reduced peripheral vision. Rods and cones can become less sensitive over time as they slowly replenish pigment. Gradually, all these effects can reduce vision and eventually lead to partial or complete blindness. Retinal diseases such as age-related macular degeneration are difficult to treat. Current retinal treatments include laser surgery to stop leaking blood vessels in the eye.

[0050] As alluded to above, current therapeutic attempts to address many ocular disorders and eye diseases, including age-related eye problems, often involve surgical intervention. Of course, surgical procedures are invasive and, moreover, often do not achieve the desired therapeutic goal. Furthermore, surgery can be very costly and can result in significant undesirable sequelae. For example, secondary cataracts can develop and infections can occur after cataract surgery. Endophthalmitis has also been observed after cataract surgery. Furthermore, advanced surgical techniques require a very well-developed medical infrastructure and are therefore not universally available. It would therefore be of great advantage to provide a simple and effective pharmacological treatment that would eliminate the need for surgery.

[0051] There are products proposed to address specific individual age-related ocular conditions. For example, artificial tears and herbal preparations have been suggested to treat dry eye syndrome, and other eye drops are utilized to lower intraocular pressure, relieve discomfort, promote healing after injury, reduce inflammation, and prevent infection. However, self-administration of multiple products several times a day can be inconvenient, can reduce patient compliance (and therefore overall efficacy), and can involve adverse interactions of formulation ingredients. For example, benzalkonium chloride, a common preservative, can react with other desirable ingredients such as ethylenediaminetetraacetic acid (EDTA). Thus, there is a need in the art for comprehensive pharmaceutical formulations that can prevent, halt, and / or reverse a number of age-related vision problems and associated ocular disorders.

[0052] Many adverse ocular conditions are associated with the formation, presence and / or proliferation of polymeric aggregates in the eye. Indeed, many pathologies are caused by or associated with the deposition and / or aggregation of proteins, other peptidyl species, lipoproteins, lipids, polynucleotides and other macromolecules throughout the body. For example, advanced glycation end products (also called AGEs) are formed by the binding and subsequent cross-linking of glucose or other reducing sugars to proteins, lipoproteins and DNA by a process known as nonenzymatic glycation. These cross-linked macromolecules harden connective tissues and cause tissue damage in the kidney, retina, blood vessel walls and nerves. Indeed, AGEs are involved in the pathogenesis of various debilitating diseases such as diabetes, atherosclerosis, Alzheimer's arthritis and rheumatoid arthritis, as well as the normal aging process. Peptidyl deposits are also associated with Alzheimer's disease, sickle cell anemia, multiple myeloma and prion diseases. Lipids, particularly sterols and sterol esters, represent an additional class of biomolecules that form pathogenic deposits in vivo, including atherosclerotic plaques, gallstones, etc. To date, no single formulation has been identified that can treat multiple such disorders.

[0053] Chelating agent / chelator Chelation is the chemical combination with a metal in a complex where the metal is part of a ring. The organic ligand is called a chelator or chelating agent, and the chelate is a metal complex. The more rings closed to the metal atom, the more stable the compound. The stability of the chelate is also related to the number of atoms in the chelate ring. Monodentate ligands with one coordination atom, such as H2O and NH3, are easily decomposed by other chemical processes, while multidentate chelators, which offer multiple bonds to the metal ion, provide more stable complexes. Chlorophyll, a green plant pigment, is a chelate consisting of a central magnesium atom bound to four complex chelators (pyrrole rings). Heme is an iron chelate that contains an iron(II) ion in a porphyrin center. Chelators offer a wide range of trapping agents for controlling metal ions in aqueous systems. Chelators form stable water-soluble complexes with multivalent metal ions, thereby blocking the normal reactivity of the metal ion, thus preventing undesirable interactions. EDTA (ethylenediaminetetraacetic acid) is a good example of a common chelating agent with a nitrogen atom and a short-chain carboxyl group.

[0054] Examples of iron and calcium chelating agents include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,3-propylenediaminetetraacetic acid (PDTA), ethylenediaminedisuccinic acid (EDDS) and ethyleneglycoltetraacetic acid (EGTA). Any suitable chelating agent known in the art that is biologically safe and capable of chelating iron, calcium or other metals is suitable for the present invention.

[0055] Compounds useful as chelating agents herein include compounds that coordinate or complex with divalent or polyvalent metal cations and thus serve as scavengers for such cations. Thus, the term "chelating agent" herein includes not only divalent and polyvalent ligands (typically referred to as "chelating agents"), but also monovalent ligands that can coordinate or complex with metal cations.

[0056] Suitable biocompatible chelating agents useful in the context of the present invention include, but are not limited to, monomeric polyacids such as EDTA, cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), citric acid, pharma- ceutically acceptable salts thereof, and combinations of any of the foregoing.Other exemplary chelating agents include phosphates, such as pyrophosphates, tripolyphosphates, and hexametaphosphates.

[0057] EDTA and ophthalmically acceptable salts of EDTA are particularly preferred, with representative ophthalmically acceptable salts of EDTA typically selected from diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA and disodium calcium EDTA.

[0058] EDTA is widely used as an agent for chelating metals in biological tissues and blood, and its inclusion in various formulations has been suggested. For example, US Patent No. 6,348,508 to Denick Jr. et al. describes EDTA as a scavenger to bind metal ions. In addition to its use as a chelating agent, EDTA is also widely used as a preservative in place of benzalkonium chloride, as described, for example, in US Patent No. 6,211,238 to Castillo et al. US Patent No. 6,265,444 to Bowman et al. discloses the use of EDTA as a preservative and stabilizer. However, EDTA is not generally applied topically in formulations at significant concentrations due to its poor penetration into biological membranes and biofilms, including skin, cell membranes, and even biofilms such as dental plaque.

[0059] Among the chelating / sequestering materials that may be included in the compositions that may be described, biocompatible chelating agents include, but are not limited to, monomeric polyacids such as EDTA, cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), citric acid, pharma- ceutically acceptable salts thereof, and combinations of any of the above.

[0060] Other exemplary chelating agents include phosphates, such as pyrophosphate, tripolyphosphate, and hexametaphosphate; chelating antibiotics, such as chloroquine and tetracycline; nitrogen-containing chelating agents containing two or more chelating nitrogen atoms in the imino group or in the aromatic ring (e.g., diimines, 2,2'-bipyridine, etc.); and polyamines, such as cyclam (1,4,7,11-tetraazacyclotetradecane), N-(C1-C2H2O4). 30alkyl) substituted cyclams (e.g., hexadecyclam, tetramethylhexadecylcyclam), diethylenetriamine (DETA), Spermine, diethylnorspermine (DENSPM), diethylhomospermine (DEHOP), deferoxamine (N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide, or N'-[5-(acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-amino)pentyl]-N-hydroxysuccinamide) Di-carbamoyl)propanoylamino]pentyl]-N-hydroxy-butanediamide; also known as desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB or desferal), deferiprone, pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol).

[0061] Additional suitable biocompatible chelating agents that may be useful in the practice of the present disclosure include those described in Solomon et al., Med. Chem. 2: 133-138, 2006, ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester esters, ([2-(bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester and the like EDTA-4-aminoquinoline conjugates.

[0062] Additionally, natural chelating agents include, but are not limited to, citric acid, phytic acid, lactic acid, acetic acid and their salts. Other natural chelating agents such as, but not limited to, curcumin (turmeric).

[0063] In some embodiments, the chelator incorporated into the formulation is a prochelator. A prochelator is a molecule that is converted to a chelator upon exposure to appropriate chemical or physical conditions. For example, the BSIH (isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide) prochelator is converted by hydrogen peroxide to the SIH (salicylaldehyde isonicotinoyl hydrazone) iron-chelator, which inhibits iron-catalyzed hydroxyl radical production.

[0064] Inactivated metal ion sequestrants are sometimes referred to herein as "prochelators," although the sequestration of metal ions may involve sequestration and complexation processes beyond chelation itself. The term "prochelator" is similar to the term "prodrug" in that a prodrug is a therapeutically inactive agent until activated in vivo, and the prochelator is similarly incapable of sequestrating metals until activated in vivo.

[0065] Transport enhancer: A transport enhancer is selected to enhance the transport of a chelating agent through bodily tissues, extracellular matrix and / or cell membranes. An "effective amount" of a transport enhancer refers to an amount and concentration sufficient to provide a measurable increase in the penetration of a chelating agent in a formulation of the invention through one or more sites in a subject, compared to the absence of the transport enhancer in the formulation.

[0066] In certain instances, the transport enhancer may be present in the formulations of the invention in an amount ranging from about 0.01% or less by weight to about 30% or more by weight, typically in the range of about 0.1% to about 20% by weight, more typically in the range of about 1% to about 11% by weight, and most typically in the range of about 2% to about 8% by weight, e.g., 5% by weight.

[0067] The transport enhancer generally has the formula (I): [ka] As shown in the figure.

[0068] In the formula, R 1 and R 2 are independently optionally substituted, C2-C6 alkyl, C1-C6 heteroalkyl, C6-C 14 Aralkyl, and C2-C 12 heteroaralkyl, and Q is S or P. Q is S, and R 1 and R 2 Compounds in which C1-C3 alkyl is preferred, with methylsulfonylmethane (MSM) being the transport enhancer of choice.

[0069] The phrase "having the formula" or "having the structure" is not intended to be limiting, and is used in the same manner as the term "comprising" is commonly used. With respect to the above structure, the term "alkyl" refers to a saturated straight, branched, or cyclic hydrocarbon group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, and the like. Unless otherwise indicated, the term "alkyl" includes unsubstituted alkyl and substituted alkyl, where the substituents may be, for example, halo, hydroxyl, sulfhydryl, alkoxy, acyl, and the like. The term "alkoxy" contemplates an alkyl group attached through a single terminal ether bond; i.e., an "alkoxy" group can be represented as -O-alkyl, where alkyl is as defined above. The term "aryl" refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings fused together, directly bonded, or indirectly bonded (such as different aromatic rings bonded with a common group such as a methylene or ethylene moiety). Preferred aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or bonded aromatic rings, such as phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone, and the like. "Aryl" includes unsubstituted aryl and substituted aryl, where the substituents can be as described above for the optionally substituted "alkyl" groups. The term "aralkyl" refers to an alkyl group having an aryl substituent, where "aryl" and "alkyl" are as defined above. Preferred aralkyl groups contain 6 to 14 carbon atoms, and particularly preferred aralkyl groups contain 6 to 8 carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like.The term "acyl" refers to a substituent having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)-aralkyl, where "alkyl", "aryl" and "aralkyl" are defined above. The terms "heteroalkyl" and "heteroaralkyl" are used to refer to heteroatom-containing alkyl and heteroatom-containing aralkyl groups, respectively, i.e., alkyl and aralkyl groups in which one or more carbon atoms have been replaced with an atom other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur.

[0070] In one embodiment, then, a method for eliminating or reducing the size of macromolecular aggregates in the eye is provided. The method comprises administering to the eye of a patient a therapeutically effective amount of a sterile ophthalmic preparation that is composed of (a) a non-cytotoxic chelating agent that contains at least three negatively charged chelating atoms, (b) a charge masking agent that contains at least one polar group, and (c) HEC at a concentration of more than 0.5%, and an ophthalmologically acceptable inert carrier. The polar group of the charge masking agent contains at least one, preferably at least two heteroatoms with a Pauling electronegativity greater than about 3.00, where the heteroatom is preferably an oxygen atom. The molar ratio of the charge masking agent to the chelating agent is sufficient to ensure that substantially all of the negatively charged chelating atoms are associated with at least one of the heteroatoms on the charge masking agent. The formulations can be applied to the eye in a form suitable for ocular drug administration, for example, as a solution or suspension for administration as eye drops or eye washes, as an ointment, or in an ocular insert that can be implanted in the conjunctiva, sclera, pars plana, anterior or posterior segments of the eye, such inserts providing a controlled release of the formulation to the ocular surface, typically a sustained release over an extended period of time.

[0071] The formulation may also be applied to the skin around the eye for penetration therein, so long as the compound used as the charge masking agent, e.g., methylsulfonylmethane, also functions as a penetration enhancer to enable penetration of the formulation through the skin.

[0072] In another embodiment, the formulations are effective in alleviating dry eye symptoms, particularly dry eye associated with inflammation, and can be used in methods of treating dry eye. Subjects with extremely dry eye, such as those with Sjogren's syndrome, may still experience some stinging due to the extreme dryness of the eyes.

[0073] Thus, a chelating agent is multifunctional in the context of the present invention insofar as, in addition to functioning as a preservative and stabilizer, the agent also serves to reduce undesirable proteins or peptides, prevent the formation of mineral deposits, and / or reduce already formed mineral deposits, reducing calcification.

[0074] The formulation also comprises an effective amount of a transport enhancer that promotes the penetration of the formulation components through cell membranes, tissues and extracellular matrices.The "effective amount" of a transport enhancer refers to a concentration sufficient to provide a measurable increase in the penetration of one or more of the formulation components through membranes, tissues and extracellular matrices, as just described.Suitable transport enhancers include, by way of example, methylsulfonylmethane (MSM; also referred to as methylsulfone), a combination of MSM and dimethylsulfoxide (DMSO), or a combination of MSM and, in a less preferred embodiment, DMSO, with MSM being particularly preferred.

[0075] MSM is an odorless, highly water-soluble (34% w / v at 79°F), white crystalline compound with a melting point of 108-110°C and a molecular weight of 94.1 g / mol. MSM functions as a multifunctional agent herein insofar as it acts as a "transport enhancer" (TFA) that not only increases cell membrane permeability but also aids in the transport of one or more formulation components to the eye. Furthermore, MSM itself provides medicinal benefits, acting as an anti-inflammatory and analgesic agent. MSM also acts to improve oxidative metabolism in living tissues and is a source of organic sulfur that aids in scar reduction. MSM further has unique and beneficial solubilizing properties in that it is soluble in water as described above, but exhibits both hydrophilic and hydrophobic properties due to the presence of polar S=O groups and non-polar methyl groups. The molecular structure of MSM also allows for the formation of hydrogen bonds with other molecules, i.e., hydrogen bonds between the oxygen atoms of each S=O group and hydrogen atoms of other molecules, and van der Waals associations between the methyl groups and non-polar moieties (e.g., hydrocarbyls) of other molecules. Ideally, the concentration of MSM in the present formulations ranges from about 0.1% to 40% by weight, or from about 1% to about 4, 5, 6, 7, 8, 10, 15% by weight, and preferably from about 1.5% to 8.0% by weight.

[0076] Other optional additives in the formulation include secondary enhancers, i.e., one or more additional transport enhancers. For example, the formulations of the present invention may include added DMSO. Because MSM is a metabolic product of DMSO (i.e., DMSO is enzymatically converted to MSM), the incorporation of DMSO into the MSM-containing formulations of the present invention will tend to gradually increase the percentage of MSM in the formulation. DMSO also functions as a free radical scavenger, thereby reducing the potential for oxidative damage. When DMSO is added as a secondary enhancer, the amount is preferably in the range of about 1.0% to 2.0% by weight of the formulation, and the weight ratio of MSM to DMSO is typically in the range of about 1:50 to about 50:1.

[0077] Hydroxyethyl cellulose (HEC, also known and available as HESPAN; TYLOSE P; NATROSOL; HETASTARCH) is a non-ionic cellulose ether made through a series of chemical processes using the natural polymer cellulose as a raw material. It is in the form of a white to off-white powder or granules, and is odorless, tasteless, and non-toxic. It can be dissolved in water to form a clear viscous solution. The solubility of HEC in water is ≤5% by weight at 20°C. The CAS database reference for HEC is 9004-62-0. [ka]

[0078] Hydroxyethylcellulose is soluble in hot or cold water, does not precipitate by heating or boiling, and allows for a wide range of solubility and viscosity characteristics, as well as non-thermal gelation. It is non-ionic and can coexist with a wide range of other water-soluble polymers, surfactants and salts, and is a fine colloidal thickener for solutions containing high concentrations of electrolytes. Hydroxyethylcellulose can be dispersed in cold water without agglomeration, but the dissolution rate is slow, generally requiring about 30 minutes. It can be dissolved quickly by heating or adjusting the pH value to 8-10.

[0079] The formulation may also include a microcirculatory enhancer, i.e., an agent that helps to enhance blood flow in the capillaries. The microcirculatory enhancer may be a phosphodiesterase (PDE) inhibitor, e.g., a type I PDE inhibitor. Such compounds act to increase intracellular levels of cyclic AMP (cAMP), as will be appreciated by those skilled in the art. A preferred microcirculatory enhancer is vinpocetine, also referred to as apovincamine-22-oic acid ethyl. Vinpocetine, a synthetic derivative of the vinca alkaloid vincamine, is particularly preferred herein for its antioxidant properties and protection against excess calcium accumulation in cells. Vincamine is also useful as a microcirculatory enhancer herein, as are vinca alkaloids other than vinpocetine. Preferably, the microcirculatory enhancer present, e.g., vinpocetine, represents a range of about 0.01% to about 0.2% by weight of the formulation, preferably about 0.02% to about 0.1% by weight.

[0080] formulation A variety of means can be used to formulate the compositions of the present invention. Techniques for formulation and administration can be found in "Remington: The Science and Practice of Pharmacy," Twentieth Edition, Lippincott Williams & Wilkins, Philadelphia, PA (1995). For administration to humans or animals, the preparations must meet sterility, pyrogenicity, general safety and purity standards comparable to those required by the FDA. Administration of pharmaceutical preparations can be carried out in a variety of ways, as described herein.

[0081] Other possible additives for incorporation into at least partially aqueous formulations include, but are not limited to, thickening agents, isotonicity agents, buffering agents and preservatives, provided that such excipients do not adversely interact with any of the other components of the formulation.It should also be noted that preservatives are generally not necessary in light of the fact that the selected chelating agent itself functions as a preservative.Suitable thickening agents are known to those skilled in the art of formulation, and examples include cellulose-based polymers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl-methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC), as well as other swellable hydrophilic polymers (polyvinyl alcohol (PVA), hyaluronic acid or its salts (e.g., sodium hyaluronate)), and cross-linked acrylic acid polymers commonly referred to as "carbomers" (and available from BF Goodrich as Carbopol® polymers).

[0082] A gel with a viscosity of more than 10,000 cps is generally considered optimal for both comfort and retention of the formulation on the eye, so the preferred amount of thickening agent is that which provides a viscosity of more than 10,000 cps. Suitable isotonicity agents and buffering agents commonly used in ophthalmic formulations can be used, provided that the pH of the formulation is maintained in the range of about 4.5 to about 9.0, preferably in the range of about 6.8 to about 7.8, and optimally at about 7.4 pH. Preferred buffering agents include carbonates such as sodium bicarbonate and potassium bicarbonate.

[0083] However, an effective thickening agent must be used in an amount that also exhibits the important property of allowing the use of low concentrations of the chelating agent / MSM combination to achieve significant efficacy without causing severe stinging or other ocular discomfort.

[0084] The formulation of the present invention also includes a pharma- ceutically acceptable ophthalmic carrier or vehicle, depending on the particular type of formulation. For example, the formulation of the present invention can be provided as an ophthalmic solution or suspension, in which case the carrier is at least partially aqueous. Ideally, the ophthalmic solution that can be administered as eye drops is an aqueous solution. The formulation can also be an ointment, in which case the pharma-ceutically acceptable carrier is composed of an ointment base. The preferred ointment base herein has a melting or softening point close to body temperature, and can advantageously be used with ointment bases that are commonly used in ophthalmic formulations. Common ointment bases include petrolatum and mixtures of petrolatum and mineral oil. Suitable pharmaceutical formulations and dosage forms are known to those in the field of pharmaceutical formulations and can be prepared using conventional methods described in related texts and literature, such as Remington: The Science and Practice of Pharmacy, cited hereinabove.

[0085] The formulations of the present invention may also be prepared as hydrogels, dispersions, or colloidal suspensions. Hydrogels are formed by incorporating swellable gel-forming polymers, such as those listed above as suitable thickening agents (i.e., MC, HEC, HPC, HPMC, NaCMC, PVA, or hyaluronic acid or its salts, e.g., sodium hyaluronate), except that formulations referred to in the art as "hydrogels" are typically more viscous than those referred to as "thickened" solutions or suspensions. In contrast to such preformed hydrogels, formulations can also be prepared to form hydrogels in situ after application to the eye. Such gels are liquid at room temperature, but gel at elevated temperatures, such as when placed in contact with body fluids (hence, they are called "thermoreversible" hydrogels). Biocompatible polymers that confer this property include acrylic acid polymers and copolymers, N-isopropylacrylamide derivatives, and ABA block copolymers of ethylene oxide and propylene oxide (commonly referred to as "poloxamers" and available under the trade name Pluronic® from BASF-Wyandotte). The formulations can also be prepared in the form of dispersions or colloidal suspensions. A preferred dispersion is a liposome, in which the formulation is encapsulated within a "liposome," a microscopic vesicle composed of alternating aqueous compartments and lipid bilayers. Colloidal suspensions are generally formed from microparticles, i.e., microspheres, nanospheres, microcapsules, or nanocapsules, where microspheres and nanospheres are generally monolithic particles of polymer matrix that entrap, adsorb, or otherwise contain the formulation, and with respect to microcapsules and nanocapsules, the formulation is actually encapsulated. The upper size limit for these microparticles is about 5μ to about 10μ.

[0086] The formulation may also be incorporated into a sterile ocular insert, which provides controlled release of the formulation over an extended period of time, typically ranging from about 12 hours to 60 days, and possibly up to 12 months or more, after implantation of the insert into the conjunctiva, sclera or pars plana, or into the anterior or posterior segments of the eye. One type of ocular insert is an implant in the form of a monolithic polymer matrix that slowly releases the formulation into the eye via diffusion and / or matrix degradation. For such inserts, it is preferred that the polymer is completely soluble and / or biodegradable (i.e., physically or enzymatically damaged within the eye) so that removal of the insert is unnecessary. These types of inserts are well known in the art and are typically composed of water-swellable gel-forming polymers such as collagen, polyvinyl alcohol or cellulosic polymers. Another type of insert that can be used to deliver the formulation is a diffusion implant, in which the formulation is contained in a central reservoir enclosed within a permeable polymeric membrane that allows the formulation to slowly diffuse out of the implant. Osmotic inserts may also be used, ie, implants that release the formulation as a result of an increase in osmotic pressure within the implant following application to the eye and subsequent absorption by tear fluid.

[0087] The chelating agent may be administered, if necessary, in the form of a salt, ester, crystalline form, hydrate, etc., provided that it is pharma- ceutically acceptable. Salts, esters, etc. are known to those skilled in the art of organic synthetic chemistry and may be prepared using standard procedures, for example, as described in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992).

[0088] The amount of chelating agent administered depends on many factors, varies from subject to subject, and depends on the specific chelating agent, the specific disorder or condition being treated, the severity of symptoms, the age, weight and general condition of the subject, and the judgment of the prescribing physician. The term "dosage form" refers to a form of a pharmaceutical composition that contains a sufficient amount of chelating agent and transport enhancer to achieve a therapeutic effect in a single or multiple doses. The frequency of administration that provides the most effective results in an efficient manner without overdosing depends on the characteristics of the specific active agent, including both pharmacological properties and physical properties such as hydrophilicity.

[0089] In further embodiments, the formulation may comprise additional ophthalmically active agents, such as selected from anti-infective or antibiotic agents including, for example, fluoroquinolones, such as ciprofloxacin, levofloxacin, gentafloxacin, ofloxacin, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamicin, and erythromycin; anti-inflammatory agents such as hydrocortisone, dexamethasone, fluocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone, and triamcinolone; anti-angiogenic agents such as thalidomide, VEGF inhibitors, and matrix metalloproteinase (MMP) inhibitors; antineoplastic agents; and dry eye medications such as cyclosporine and mitomycin. Further examples of ophthalmologically active agents that can be incorporated into the formulation include anesthetics, analgesics, and cell trafficking / migration inhibitors; antiglaucoma agents, including beta-blockers such as timolol, betaxolol, and atenolol; carbonic anhydrase inhibitors, such as acetazolamide, methazolamide, dichlorphenamide, and diamox; neuroprotectants, such as nimodipine and related compounds; antibacterial agents, such as sulfonamides, sulfacetamide, sulfamethizole, and sulfisoxazole; antimicrobial agents, such as fluconazole, nitrofurazone, amphotericin B, ketoconazole, and related compounds. anti-viral agents such as trifluorothymidine, acyclovir, ganciclovir, dideoxyinosine (DDI), zidovudine (AZT), foscamet, vidarabine, trifluorouridine, idoxuridine and ribavirin; protease inhibitors and anti-cytomegalovirus agents; anti-allergy drugs such as methapyriline, chlorpheniramine, pyrilamine and profenpyridamine; and decongestants such as phenylephrine, naphazoline, and tetrahydrazoline.

[0090] Exemplary ophthalmologically active agents that may be incorporated into the formulation include aceclidine, acetazolamide, anecortave, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befunolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbachol, carteolol, celecoxib, chloramphenicol, chlortetracycline, ciprofloxacin, cromoglycate, cromolyn, cyclopentolate, cyclosporine, dapiprazole, demeclovir, and the like. Potassium, dexamethasone, diclofenac, dichlorphenamide, dipivefrin, dorzolamide, echothiophate, emedastine, epinastine, epinephrine, erythromycin, ethoxyzolamide, eucatropine, fludrocortisone, fluorometholone, flurbiprofen, fomivirsen, framycetin, ganciclovir, gatifloxacin, gentamicin, homatropine, hydrocortisone, idoxuridine, indomethacin, isoflurophate, ketorolac, ketotifen, latanoprost, levothyroxine ... Bobetaxolol, levobunolol, levocabastine, levofloxacin, lodoxamide, loteprednol, medrysone, methazolamide, metipranolol, moxifloxacin, naphazoline, natamycin, nedocromil, neomycin, norfloxacin, ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pirenoxine, polymyxin B, prednisolone, proparacaine, ranibizumab, rimexolone, sucralose These include, but are not limited to, coporamine, sezolamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracycline, tetrahydrozoline, tetrizoline, timolol, tobramycin, travoprost, triamcinulone, trifluoromethazolamide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarbine, xylometazoline, a pharma- ceutically acceptable salt thereof, or a combination of any of the above.

[0091] The formulations of the present invention may also be prepared as hydrogels, dispersions, or colloidal suspensions. Hydrogels are formed by incorporating swellable gel-forming polymers, such as those listed above as suitable thickening agents (i.e., MC, HEC, HPC, HPMC, NaCMC, PVA, or hyaluronic acid or its salts, e.g., sodium hyaluronate), except that formulations referred to in the art as "hydrogels" are typically more viscous than those referred to as "thickened" solutions or suspensions. In contrast to such preformed hydrogels, formulations can also be prepared to form hydrogels in situ after application to the eye. Such gels are liquid at room temperature, but gel at elevated temperatures, such as when placed in contact with body fluids (hence, they are called "thermoreversible" hydrogels). Biocompatible polymers that confer this property include acrylic acid polymers and copolymers, N-isopropylacrylamide derivatives, and ABA block copolymers of ethylene oxide and propylene oxide (commonly referred to as "poloxamers" and available under the trade name Pluronic® from BASF-Wyandotte). The formulations can also be prepared in the form of dispersions or colloidal suspensions. A preferred dispersion is a liposome, in which the formulation is encapsulated within a "liposome," a microscopic vesicle composed of alternating aqueous compartments and lipid bilayers. Colloidal suspensions are generally formed from microparticles, i.e., microspheres, nanospheres, microcapsules, or nanocapsules, where microspheres and nanospheres are generally monolithic particles of polymer matrix that entrap, adsorb, or otherwise contain the formulation, and with respect to microcapsules and nanocapsules, the formulation is actually encapsulated. The upper size limit for these microparticles is about 5 μm to about 10 μm.

[0092] Methods of using the formulations of the present invention are also contemplated.The formulations of the present invention are useful for treating a wide variety of conditions associated with the formation and / or deposition of macromolecular aggregates.Many medical conditions are caused or aggravated by the in vivo formation or deposition of macromolecular aggregates, including crystalline aggregates, fibrillar aggregates and amorphous aggregates.Certain peptidyl compounds, including selected oligopeptides, polypeptides and proteins, are known to form crystals and fibrils associated with various conditions, disorders and diseases.For example, amyloid peptides, particularly β-amyloid, are known to form ordered fibrillar aggregates, including extracellular and cerebrovascular senile plaques associated with Alzheimer's disease.Han et al. (1995), “The Core Alzheimer's Peptide NAC Forms Amyloid Fibrils which Seed and are Seeded by .beta.-Amyloid: is NAC a Common Trigger or Target in Neurodegenerative Disease?” Chemistry and Biology 2:163-169;Serpell et al. (2000), “Molecular Structure of a Fibrillar Alzheimer's A.beta.,” Biochemistry 39:13269-13275; Jarrett and Lansbury (1992), “Amyloid Fibril Formation Requires a Chemically Discriminating Nucleation Event: Studies of an Amyloidogenic Sequence from the Bacterial Protein OsmB,” Biochemistry 31(49):12345-12352; and Jarrett et al. (1993), “The Carboxy Terminus of the See, Beta Amyloid Protein is Critical for the Seeding of Amyloid Formation: Implications for the Pathogenesis of Alzheimer's Disease," Biochemistry 32:4693-4697. Prion diseases, such as the class of diseases known as transmissible spongiform encephalopathies, are also characterized by abnormal protein deposits in brain tissue, which are primarily composed of fibrillar amyloid plaques formed from prion protein (PrP).Such diseases include scrapie-transmissible mink encephalopathy, chronic wasting disease in mule deer and elk, feline and bovine spongiform encephalopathy ("mad cow disease") in animals, and kuru, Creutzfeldt-Jakob disease, Gerstmann-Struessler-Scheinker disease, and fatal familial insomnia in humans. It has been proposed that a 15-mer amino acid sequence, PrP96-111, is responsible for initiating prion formation in vivo by providing the seed for amyloid fibril formation. See Come et al. (1993), "A Kinetic Model for Amyloid Formation in the Prion Diseases: Importance of Seeding," Proc Natl Acad Sc. USA 90:5959-5963. Fibrillin, which is associated with Martin's disease, is another example of a protein that forms ordered fibrillar structures that cause harmful pathologies.Fibrillar plaques formed from various collagens are also associated with certain medical pathologies, such as heart disease and collagenofibrotic glomerulopathy; see Rossi et al. (2001), "Connective Tissue Skeleton in the Normal Left Ventricle and in Hypertensive Left Ventricle Hypertrophy and Chronic Chagasic Monocarditis," Med Sci Mon 7:820-832;Yasuda et al. (1999), "Collagenofibrotic Glomerulopathy: A Systemic Disease," Am J Kidney Dis 33:123-127.

[0093] Other similarly problematic biomolecules may be treated, such as cystine, which forms crystalline deposits in the bone marrow (associated with rickets and synovitis), the renal tubules and gastrointestinal tract (associated with cystinuria), and various other body tissues such as the kidneys, eyes and thyroid gland (associated with cystinosis, including nephropathic cystinosis and Fanconi syndrome, which are severe forms of cystinosis).

[0094] In some compositions, the ratio of EDTA to MSM ranges from about 1:100 to 100:1, with the percentage of EDTA and MSM in the composition being about 0.1% to 15% and about 0.1% to 40% by weight, respectively.

[0095] The formulation also contains an effective thickening agent used in an amount that also exhibits the primary property of allowing the use of low concentrations of the chelating agent / MSM combination to achieve significant efficacy without causing severe ocular discomfort such as stinging. Swellable viscoelastic cellulosic polymers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl-methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) are preferred. HEC at a concentration of 0.5% to 1.5%, specifically 0.8% to 1.0%, is preferred.

[0096] One major improvement of the formulations disclosed herein over previously tested ophthalmic formulations is the significant reduction in discomfort associated with the use of conventional formulations.Attempts to reduce discomfort such as stinging by using viscoelastic polymers (such as hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxyethylcellulose and polyvinyl alcohol) at standard concentrations (about 0.2%) as used in artificial tears have failed.These polymers and concentrations used always caused more stinging for a longer period of time than when no polymer was used.In the case of HEC, stinging occurred at lower concentrations (e.g., 0.3%).

[0097] Surprisingly, when the concentration of HEC was significantly increased from 0.8-1%, the stinging was significantly reduced. Virtually in the presence of such high concentrations of HEC, the ocular mucosa was not experiencing the levels of chelating agent / MSM that caused stinging at lower levels of the viscoelastic compound, especially at the edge of the eye near the nose where most of the stinging occurs.

[0098] The concentrations previously used, EDTA 2.6% and MSM 5.4%, caused severe discomfort upon initial application manifested as a severe stinging sensation. The stinging sensation dissipated over time, suggesting that the stinging sensation did not occur at the lower concentrations of this slowly dissipating chelator / MSM combination.

[0099] The second surprising effect was the significant reduction in the chelator / MSM levels required for efficacy. The slow release of EDTA / MSM from the highly viscous HEC solution significantly increases the amount of EDTA / MSM that enters the aqueous and vitreous humor of the eye. In the presence of higher HEC concentrations, only half the concentration of EDTA / MSM was needed to achieve the same clinical effect as without HEC. 1.3% EDTA, 2.7% MSM and 0.8% HEC are as effective as 2.6% EDTA and 5.4% MSM. EXAMPLES

[0100] The following examples are presented to provide one of ordinary skill in the art with a complete invention and description of how to make and use embodiments according to the invention, but are not intended to limit the scope of what the inventors regard as their discovery. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0101] Example 1: Increasing Residence Time of MSM / EDTA Solutions with Increasing Concentration of HEC MSM / EDTA eye drops were prepared with various concentrations of HEC and tested in human eyes to estimate their residence time. To assess residence time, the eye drops allow the subject to feel the presence of EDTA in the nasal cavity within a few seconds of applying the eye drop. The time interval between application of the eye drop and the perception of the presence of EDTA was considered to be equivalent to the residence time in the eye. The results for five eye drop concentrations of HEC are shown in the table below. [Table 1]

[0102] At low concentrations, the subject is aware of the presence of the eye drop due to a stinging sensation, which stings even more at low concentrations. At higher concentrations (0.75 and 1%), the stinging sensation is significantly reduced.

[0103] This showed that as the viscosity of the eye drops increased, the time it took for the eye drops to travel nonlinearly through the lacrimal punctum into the nasal cavity increased. The actual residence time in the eye may be shorter than these values.

[0104] Example 2: Permeation enhancement of porcine intestinal membranes by sodium EDTA iron with the use of hydroxyethylcellulose in aqueous media The following experimental solutions were prepared: Control: 1% Sodium Iron EDTA prepared in distilled water. Test Solutions: 1% Sodium Iron EDTA prepared in distilled water and 1%, 3% and 5% Hydroxyethylcellulose (HEC). [Table 2]

[0105] Example 3: Exemplary eye drop formulations according to the present invention Formulation A was prepared as follows: High purity deionized (DI) water (500ml) was filtered through a 0.2 micrometer filter. MSM, EDTA and HEC were added to the filtered DI water and mixed until visual clarity was achieved, indicating dissolution. The mixture was poured into a 10mL bottle with a dropper cap. On a weight percent basis, the eye drops had the following composition: MSM 2.7% w / w; Disodium EDTA 1.3% w / w; HEC 0.85% w / w.

[0106] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference herein.

[0107] Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of this invention that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

Claims

1. An ophthalmic formulation for treating an adverse ocular condition while reducing side effects, comprising: (a) a chelating agent or a salt thereof; (b) a transport enhancer which is methylsulfonylmethane (MSM); (c) a viscoelastic polymer selected from hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxyethylcellulose (HEC) and polyvinyl alcohol, at a concentration of 0.25% w / w to 5.0% w / w, which increases the penetration and residence time of the applied ocular agent into the eye; and (d) a pharma- ceutically acceptable inert vehicle A formulation comprising: The percentage of the chelating agent in the formulation is about 0.1% to 15% by weight, and the percentage of the transport enhancer is about 0.1% to 40% by weight. formulation.

2. The formulation described in claim 1, wherein the viscoelastic polymer is HEC.

3. 3. The formulation of Claim 1 or 2, wherein the amount of MSM is less than 5% w / w.

4. 4. The formulation of any one of claims 1-3, wherein the ratio of chelating agent to MSM ranges from about 10:1 to 1:

20.

5. 5. The formulation of any one of claims 1 to 4, wherein the concentration of HEC is from 0.25% w / w to 1.0% w / w.

6. 6. The formulation of any one of claims 1 to 5, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ArPA), citric acid, acetic acid and acceptable salts thereof, and combinations thereof.

7. 7. The formulation of claim 6, wherein the EDTA salt is selected from diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA, tetrasodium EDTA, tetrapotassium EDTA, disodium calcium EDTA, and combinations thereof.

8. The chelating agent is ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ester, 6. The formulation according to claim 1, wherein the EDTA-4-aminoquinoline conjugate is selected from the group consisting of ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester.

9. The formulation according to any one of claims 1 to 8, wherein the vehicle is aqueous.

10. The formulation of any one of claims 1 to 9, wherein administration of the formulation reduces macromolecular aggregates in the eye.

11. 11. The formulation of claim 10, wherein the polymeric aggregate is selected from a peptidyl compound, a protein, and a lipoprotein.

12. The formulation according to any one of claims 1 to 11, wherein the formulation comprises an ocular insert.

13. The formulation according to any one of claims 1 to 12, wherein the formulation is for timed release.

14. 2. The formulation of Claim 1, wherein the formulation comprises MSM 2.7% w / w; disodium EDTA 1.3% w / w; and HEC 0.85% w / w.

15. A formulation for treating an adverse ocular condition while reducing a stinging sensation in the eye, comprising: (a) a chelating agent or a salt thereof; (b) a charge masking agent which is methylsulfonylmethane (MSM); (c) a viscoelastic polymer, which is hydroxyethyl cellulose (HEC), at a concentration of 0.25% w / w to 1.0% w / w to increase the ocular penetration and residence and retention time of the applied eye; and (d) a pharma- ceutically acceptable inert vehicle A formulation comprising: the percentage of chelating agent is about 0.1% to 3.0% by weight and the percentage of MSM is about 0.1% to 6.0% by weight in the formulation; formulation.

16. The formulation of any one of claims 1 to 15, wherein the adverse ocular condition is caused by macromolecular aggregation.

17. The formulation according to any one of claims 1 to 15, wherein the adverse ocular condition is caused by dry eye syndrome.

18. 18. The formulation of claim 17, wherein the dry eye syndrome is caused by inflammation.

19. The formulation of any one of claims 1 to 15, wherein the adverse ocular condition is caused by cataracts.