Composition for inducing urination and defecation

Abstract

Synthetic neurokinin A peptide analogs are provided as therapeutic compounds for inducing voluntary "on-demand" excretion of urine and feces in mammals that are unable to excrete without external entry into the bladder and intestine or that excrete involuntarily (i.e., those with urinary and / or fecal incontinence). Controlling when and where an individual excretes can result in a dramatic improvement in quality of life.

Description

【Technical Field】 【0001】 Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 089,268, filed on October 8, 2020, the disclosure of which is incorporated herein in its entirety by reference. 【0002】 The subject matter of the present disclosure relates to compositions containing peptide - mimetic compounds for inducing urination and defecation. 【Background Art】 【0003】 The inability to excrete urine and / or feces is a life - threatening condition. Current standard care for severe urinary retention requires the passage of a clean catheter through the urethra and into the bladder to facilitate urine flow externally through a catheter. Current standard care for severe fecal impaction includes digital extraction of feces from the rectum combined with a diet that promotes fecal passage. Some patients may receive large - volume (1 L) warm water enemas or stimulant suppositories that require a waiting period of 30 minutes to 1 hour until fecal contents are excreted. Lack of control over urination and defecation substantially impairs the quality of life of both patients and caregivers and is a major cause of institutionalization (Lee et al., 2016). 【0004】 Urinary dysfunction is very widely recognized in patients with spinal cord injury, spina bifida, multiple sclerosis, and other conditions involving spinal cord pathology. Urinary dysfunction is also widely recognized in subjects with diabetic cystopathy and gastrointestinal disorders. Urinary dysfunction is also seen in various elderly subjects and is widely recognized among institutionalized individuals. 【0005】 Existing treatments for urinary retention include either clean intermittent or indwelling catheterization, which can lead to catheter-associated urinary tract infections (CAUTIs). CAUTIs account for over 15% of infections reported by emergency hospitals and, in men, can lead to complications such as cystitis, pyelonephritis, Gram-negative bacteremia, prostatitis, epididymitis, and orchitis, as well as, less commonly, endocarditis, spondylomyelitis, septic arthritis, endophthalmitis, and meningitis in all patients. Complications associated with CAUTIs cause discomfort to patients, prolong hospital stays, and increase costs and mortality. More than 13,000 deaths each year are associated with UTIs. Furthermore, individuals with SCIs (and other CNS injuries) often lack the physical ability to insert a catheter themselves. 【0006】 Cholinergic drugs such as bethanechol (a muscarinic receptor agonist) and distigmine (an acetylcholinesterase inhibitor) are used to treat urinary retention. However, the effectiveness of these compounds is limited, and their tolerability is low due to severe side effects such as sweating, spasms, bradycardia, convulsions, hypotension, and bronchoconstriction. Alternative methods have been developed to empty the bladder by preventing the sphincter from closing the urethra, but most of them, including sphincterotomy, sphincter paralysis, and urethral stenting, cause incontinence and lead to further complications. 【0007】 Lower urinary tract disorders, including underactive bladder and incontinence, significantly impact patients' quality of life. Voiding dysfunction, associated with the inability to completely empty the bladder during urination, is a condition affecting the elderly, diabetic patients, neurogenic patients (spinal cord injury, spina bifida, multiple sclerosis, stroke patients, traumatic brain injury, Parkinson's disease, Alzheimer's disease, ALS), and other patient populations. This condition can result from, for example, myogenic bladder smooth muscle contractility disorders in the elderly, for example, urethral smooth muscle relaxation disorders in the elderly, for example, peripheral nerve (afferent and / or efferent nerve) damage in diabetic neuropathy, for example, impaired neuronal control due to spinal cord or brain damage in, for example, spinal cord injury, multiple sclerosis, stroke patients, traumatic brain injury, Parkinson's disease, Alzheimer's disease, and other conditions and disorders. This condition is accompanied by increased residual urine volume after urination and Frequent urination This can lead to symptoms such as nocturia, incontinence, and urinary tract infections. 【0008】 Spinal cord injury is the most common injury that deeply affects urination and is usually caused by traffic accidents or sports injuries, but can also result from infections, vascular disorders, cancer, birth defects, polio, tuberculosis, and other conditions. The annual incidence of spinal cord injury (SCI), excluding those who died at the scene of an accident, is estimated to be about 40 cases per million people in the United States, or about 12,000 new cases per year. The number of Americans living with SCI in 2012 was approximately 270,000, estimated to be in the range of 236,000 to 327,000. 【0009】 For individuals with spinal cord injury (SCI), direct medical expenses related to urinary tract dysfunction can exceed $8,000 annually, representing a significant portion of the estimated $31,000–$75,000 in annual medical and living expenses for individuals with spinal cord injury. Furthermore, loss of control over urinary function can alter social relationships, cause personal distress, lead to depression, anger, poor self-image, confusion, and frustration, and hinder the achievement of personal goals. 【0010】 The urinary sphincter is also affected by spinal cord injury, sometimes resulting in a condition known as "dyscoordination." Dyscoordination involves the inability of the urinary sphincter to relax during bladder contraction, including active contractions in response to bladder contraction. This prevents urine from flowing through the urethra, leading to incomplete bladder emptying and "return" of urine to the kidneys. Traditional treatments for dyscoordination include medications, which have been somewhat inconsistent in their effectiveness or surgical intervention. 【0011】 Damage to the spinal cord and / or brain can lead to an inability to defecate spontaneously and subsequent constipation. Currently, patients use rectal finger stimulation and manual fecal extraction, or in some cases, large (1L) warm water enemas that require sitting on the toilet for 30 minutes to an hour while water and fecal contents are expelled. In some cases, stimulant laxatives are administered rectally, but their effects can last longer than necessary and they cannot be administered regularly. These methods are performed by the patient or caregiver, if feasible. They can lower the patient's self-esteem, cause personal distress and stigma, alter social relationships, and lead to depression, anger, poor self-image, embarrassment, frustration, etc. 【0012】 Incontinence, fecal impaction, and urinary retention require thorough personal care. Repeated catheterization to empty the bladder can lead to urinary tract infections and other complications requiring further intervention (Singh et al., 2011; Yilmaz et al., 2014). Relieving fecal impaction typically requires enemas and manual extraction (Hughes, 2014). Pharmacological therapies that can be used to facilitate urination and defecation on demand would significantly improve the quality of care. However, this remains a largely ignored and unmet medical need (van Koeveringe et al., 2011). 【0013】 Existing treatments and procedures for urinary dysfunction are associated with the limitations described above, and therefore new treatments and procedures are desirable. The subject matter of this disclosure provides such new treatments and procedures to address these limitations. [Overview of the project] 【0014】 In one embodiment of the subject matter of this disclosure, Asp-Ser-Phe-Val-gc-Met-NH2 (Compound A, SEQ ID NO: 1), Asp-Ser-Phe-Val-gc-Nle-NH2 (Compound B, SEQ ID NO: 2), Asp-Lys-Phe-Val-gc-Met-NH2 (Compound C, SEQ ID NO: 3), Asp-Lys-Phe-Val-gc-Nle-NH2 (Compound D, SEQ ID NO: 4), Asp-Arg-Phe-Val-gc-Met-NH2 (Compound A, SEQ ID NO: 1), A synthetic peptide analog is provided, selected from the group consisting of Compound E (SEQ ID NO: 5), Asp-Arg-Phe-Val-gc-Nle-NH2 (Compound F (SEQ ID NO: 6)), and Lys-Asp-Ser-Phe-Val-gc-Nle-NH2 (Compound G (SEQ ID NO: 7)), where "gc" represents the "gamma constraint" (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl moiety as shown below. In the following structure, "A" represents a string of amino acid residues at the amino terminus relative to the "gc" structure in the peptide compound, and "B" represents an amino acid at the carboxyl terminus relative to the "gc" structure. [ka] 【0015】 In one embodiment of the subject matter of this disclosure, the following general formula (I) and sequence number 11 [ka] (I) (Sequence ID 11) (In the formula, A is Xaa1-Asp-Xaa3-Phe-Val, where Xaa1 is absent or Lys, and Xaa3 is Ser, Lys, or Arg, There is provided a peptide compound having (B is Met-NH2 or Nle-NH2) or a pharmaceutically acceptable salt thereof. 【0016】 In one embodiment, there is provided a peptide compound of general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 1, Compound A), wherein Xaa1 is absent, Xaa3 is Ser, and B is Met-NH2. 【0017】 In one embodiment, there is provided a peptide compound of general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 2, Compound B), wherein Xaa1 is absent, Xaa3 is Ser, and B is Nle-NH2. 【0018】 In one embodiment, there is provided a peptide compound of general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 3, Compound C), wherein Xaa1 is absent, Xaa3 is Lys, and B is Met-NH2. 【0019】 In one embodiment, there is provided a peptide compound of general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 4, Compound D), wherein Xaa1 is absent, Xaa3 is Lys, and B is Nle-NH2. 【0020】 In one embodiment, there is provided a peptide compound of general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 5, Compound E), wherein Xaa1 is absent, Xaa3 is Arg, and B is Met-NH2. 【0021】 In one embodiment, there is provided a peptide compound of general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 6, Compound F), wherein Xaa1 is absent, Xaa3 is Arg, and B is Nle-NH2. 【0022】 In one embodiment, a peptide compound of general formula (I) wherein Xaa1 is Lys, Xaa3 is Ser, and B is Nle-NH2, or a pharmaceutically acceptable salt thereof (SEQ ID NO: 7, Compound G) is provided. 【0023】 In one embodiment, a pharmaceutical composition comprising any one of peptide compounds A - G or a pharmaceutically acceptable salt thereof for use in a method of inducing one or both of urination and defecation is provided. 【0024】 In one embodiment, a pharmaceutical composition comprising a peptide compound having general formula (I) and SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof for use in a method of inducing one or both of urination and defecation is provided, wherein the peptide compound has selectivity for activation of the human neurokinin 1 receptor (hNK1R) over the human neurokinin 2 receptor (hNK2R) of at least 20-fold, at least 50-fold, at least 100-fold, or at least 200-fold. 【0025】 In one embodiment, a method of inducing one or both of urination and defecation in a mammal, comprising administering to the mammal, as needed, a composition comprising a therapeutically effective amount of any one of peptide compounds A - G or a pharmaceutically acceptable salt thereof to induce one or both of urination and defecation as needed, is provided. 【0026】 In one embodiment, a method of inducing one or both of urination and defecation in a mammal, comprising administering to the mammal, as needed, a composition comprising a therapeutically effective amount of a peptide compound having general formula (I) and SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof to induce one or both of urination and defecation as needed, wherein the peptide compound has selectivity for activation of the human neurokinin 1 receptor (hNK1R) over the human neurokinin 2 receptor (hNK2R) of at least 20-fold, at least 50-fold, at least 100-fold, or at least 200-fold, is provided. 【0027】 The compositions of this disclosure may be formulated as immediate-release dosage forms. 【0028】 The composition may be administered parenterally, intravenously, topically, percutaneously, intramuscularly, subcutaneously, nasally, by inhalation, transrectally, lingually, sublingually, transmucosally, and transbuccally, or in combination thereof. Administration may be in the form of rapidly disintegrating tablets or films for the tongue. 【0029】 In one embodiment, one of the urinary and defecation disorders is a result of one of the following: spinal cord injury, traumatic brain injury, multiple sclerosis, spina bifida, degenerative brain disease, Alzheimer's disease, Parkinson's disease, dementia, diabetes, old age, postoperative condition, or a combination thereof. 【0030】 Mammals can include humans, animals, cats, dogs, horses, cattle, pigs, or sheep. 【0031】 Administration as needed may occur approximately 1 to 5 minutes before urination and / or defecation is desired. Administration as needed may occur approximately 1 to 10 minutes before urination and / or defecation is desired. Administration as needed may be repeated multiple times a day. [Brief explanation of the drawing] 【0032】 [Figure 1] Figure 1 shows the mass spectrum of compound A. [Figure 2] Figure 2 shows the HPLC chromatogram of compound A. [Figure 3A] Figure 3A is a graph showing the stimulation of the [Ca2+] response in CHO cells expressing human NK2 or NK1 receptors with compound A. Data are expressed as the percentage of the maximum response to substance P for the NK1 receptor or to NKA for the NK2 receptor. Each data point is the mean ± SD from double repeated measures. [Figure 3B]Figure 3B is a graph showing the stimulation of the [Ca2+] response in CHO cells expressing human NK2 or NK1 receptors with compound B. Data are expressed as the percentage of the maximum response to substance P for the NK1 receptor or to NKA for the NK2 receptor. Each data point is the mean ± SD from double repeated measures. [Figure 3C] Figure 3C is a graph showing the stimulation of the [Ca2+] response in CHO cells expressing human NK2 or NK1 receptors with compound G. Data are expressed as the percentage of the maximum response to substance P for the NK1 receptor or to NKA for the NK2 receptor. Each data point is the mean ± SD from double repeated measures. [Modes for carrying out the invention] 【0033】 For the purpose of facilitating an understanding of the principles of this disclosure, preferred embodiments are referenced herein, and specific language is used to describe them. Nevertheless, it will be understood that no limitation of the scope of this disclosure is intended therein, and any such modifications and further alterations of this disclosure as shown herein are intended to be as commonly recalled by those skilled in the art. 【0034】 In accordance with long-standing patent law convention, the terms “a,” “an,” and “the,” when used in this application in connection with the claims, refer to “one or more.” Therefore, a reference to “subject matter,” for example, includes multiple subjects unless the context clearly indicates otherwise (e.g., multiple subjects). 【0035】 Throughout this specification and the claims, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense unless the context requires a different meaning. Similarly, the terms “include” and “have,” and their grammatical variations, are intended to be non-restrictive; therefore, the enumeration of items in a list does not exclude other similar items that may be substituted for or added to the enumerated items. 【0036】 For the purposes of this specification and the appended claims, the term “about” should be understood, when used in relation to one or more numbers or numerical ranges, to refer to all such numbers, including all numbers within the range, and modifying that range by extending the upper and lower boundaries of the numerical values ​​described. An enumeration of numerical ranges by endpoints includes all numbers within that range (for example, an enumeration of 1 to 5 includes 1, 2, 3, 4, and 5, as well as their fractions, e.g., 1.5, 2.25, 3.75, 4.1, etc.) and all numbers contained within any range within that range, e.g., all integers, their fractions. Furthermore, as used herein, the term “about” can refer to a value or amount of distance, diameter, mass, time, volume, concentration, and / or percentage, and may encompass variations of, in some embodiments, + / -20%, in some embodiments, + / -10%, in some embodiments, + / -5%, in some embodiments, + / -1%, in some embodiments, + / -0.5%, and in some embodiments, + / -0.1%, from a specified amount, such variations are appropriate in the disclosed compositions and methods. Alternatively, particularly with respect to biological systems or processes, the term may mean within one order of magnitude of a given value, preferably within five times, and more preferably within two times. Where a particular value is described in this application and claims, unless otherwise specified, the term “about” should be assumed to mean within an acceptable margin of error for that particular value. 【0037】 The terms “peptide analog,” “peptide,” “peptide compound,” “compound,” and “active agent” are used herein interchangeably for the purposes of this specification and the claims. 【0038】 The terms “human NK2R” and “human NK1R” are used herein interchangeably with the terms “hNK2R” and “hNK1R” for the purposes of this specification and the claims. 【0039】 For example, the “effective” dose or “therapeutic effective dose” of a drug or pharmacologically active agent in this disclosure, including peptide analogues (SEQ ID NOs. 1-10) or pharmaceutically acceptable salts thereof, means a non-toxic but sufficient amount of the drug or active agent to provide the desired effect, i.e., treatment of urinary and / or defecation disorders, such as causing spontaneous urination and / or defecation and / or reducing urinary and / or fecal incontinence. It is recognized that the effective dose of a drug or pharmacologically active agent will vary depending on the route of administration, the selected peptide analogue, and the species to which the drug or pharmacologically active agent is administered. Those skilled in the art will also recognize that an appropriate effective dose will be determined by considering factors such as metabolism, bioavailability, and other factors that affect the level of the drug or pharmacologically active agent after administration within the unit dose range further disclosed herein for different routes of administration. 【0040】 For example, "pharmaceutically acceptable" in the enumeration of "pharmaceutically acceptable excipients" or "pharmaceutically acceptable salts" means a material that is not biologically or otherwise undesirable; that is, the material can be incorporated into a pharmaceutical composition administered to a patient or subject without causing undesirable biological effects or interacting in a detrimental manner with any of the other components of the composition in which it is contained. "Pharmacologically active" (or simply "active"), as in "pharmaceutically active" derivatives or metabolites, refers to a derivative or metabolite that has the same type of pharmacological activity as the parent compound. When the term "pharmaceutically acceptable" is used to refer to a derivative (e.g., a salt) of an active agent, the derivative should also be understood to be pharmacologically active, i.e., therapeutically effective in treating urinary and / or defecation disorders. 【0041】 As-needed dosing, also known as pro re nata or prn dosing, and on-demand dosing or administration mean the administration of a single dose of an active drug at a point in time prior to the start of emptying the bladder or bowel. Depending on the formulation and route of administration, administration may be immediately before such time, including about 1 minute, about 1 to about 5 minutes, about 1 to about 10 minutes, about 1 to about 20 minutes, about 1 to about 30 minutes, or about 1 to about 40 minutes before such time. 【0042】 "Rapid onset" refers to any period of time from approximately 1 second to 1 hour, 1 second to 45 minutes, 1 second to 30 minutes, 1 second to 15 minutes, 1 second to 10 minutes, or 1 second to 5 minutes after administration of the active drug, including any period within these ranges. 【0043】 "Short duration of action" refers to durations of approximately 2 hours to 10 minutes, 1 hour to 10 minutes, 30 minutes to 10 minutes, and 20 minutes to 5 minutes after administration of the active drug. 【0044】 The term "immediate release" is used in its original sense to refer to a formulation that provides drug release immediately after administration. 【0045】 The term "transdermal" drug delivery refers to the delivery of drugs by passing them through the skin or mucous membrane tissue into the bloodstream. 【0046】 The term "topical administration," used in its traditional sense, refers to the delivery of a topical drug or pharmacologically active agent to the skin or mucous membrane. 【0047】 The term "inhalation administration" is used in its traditional sense to mean the delivery of an aerosolized form of a drug by passage through the nose or mouth during inhalation and by passage through the walls of the lungs. 【0048】 The term "parenteral" drug delivery refers to delivery of a drug by passage into the bloodstream, without the need to first pass through the intestines or gastrointestinal tract. Parenteral drug delivery can also be "subcutaneous," which refers to delivery of a drug by administration under the skin. Another form of parenteral drug delivery is "intramuscular," which refers to delivery of a drug by administration into muscle tissue. Another form of parenteral drug delivery is "intradermal," which refers to delivery of a drug by administration into the skin. Additional forms of parenteral drug delivery are "intravenous," or "iv," or "IV," which refers to delivery of a drug by administration into a vein. Additional forms of parenteral drug delivery are "intra-arterial," which refers to delivery of a drug by administration into an artery. Another form of parenteral drug delivery is "transdermal," which refers to delivery of a drug by passage through the skin into the bloodstream. 【0049】 Another form of parenteral drug delivery is “transmucosal,” which refers to the administration of a drug to the mucosal surface of an individual so that the drug passes through mucosal tissue and enters the individual's bloodstream. Transmucosal drug delivery can be “buccal” or “transbuccal,” which refers to the delivery of a drug by passage through the buccal mucosa of an individual into the bloodstream. Another form of transmucosal drug delivery as used herein is “lingual” drug delivery, which refers to the delivery of a drug by passage through the lingual mucosa of an individual into the bloodstream. Another form of transmucosal drug delivery as used herein is “sublingual” drug delivery, which refers to the delivery of a drug by passage through the sublingual mucosa of an individual into the bloodstream. Another form of transmucosal drug delivery as used herein is “transnasal” or “intranasal” drug delivery, which refers to the delivery of a drug by passage through the nasal mucosa of an individual into the bloodstream. An additional form of transmucosal drug delivery as used herein is “rectal” or “transrectal” drug delivery, which refers to the delivery of a drug by passage through the rectal mucosa of an individual into the bloodstream. Another form of transmucosal drug delivery is intravaginal drug delivery. 【0050】 Synthetic peptide analogs of the endogenous peptide neurokinin A (NKA) are provided as therapeutic agents to stimulate bladder and rectal excretion in patients as needed. The peptide analogs of this disclosure are agonists that act on the tachykinin NK2 receptor (NK2R). NK2R is expressed on the smooth muscle of urinary, gastrointestinal, and respiratory tissues. The endogenous peptide NKA has been shown to contract bladder and colonic smooth muscle preparations from various species (including humans) (see, for example, Mussap et al., 1996; Parlani et al., 1996; Warner et al., 2002, 2003; Burcher et al., 2008; Carini et al., 2001; Mule et al., 2000). However, since bladder and colon contractions must be accompanied by coordinated, synergistic relaxation of the urethral and anal sphincters, the ability to contract bladder and GI smooth muscle is not sufficient to suggest the clinical utility of NK2R agonists for drug-induced excretion. For example, Palea et al. (1996) found that NK2R agonists actually induce contraction of human prostatic urethral smooth muscle, suggesting that urethral obstruction can occur simultaneously with bladder contraction. Simultaneous, uncoordinated contraction of both urethral and bladder smooth muscle is highly undesirable and can lead to secondary obstructive excretion and increased bladder pressure, potentially causing renal damage. Furthermore, NK2R agonists must be safe for lifetime administration in once-daily or multiple doses. 【0051】 Ten peptide analogs (compounds A-J) were synthesized according to standard Fmoc-mediated solid-phase techniques and purified under typical C18 reversed-phase conditions (see Table 1 and Example 1 below). In Table 1, "gc" represents the "gamma-constrained" (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl moiety, and in SEQ ID NOs. 1-7, "A" in the gamma-constrained schematic diagram represents the amino-terminus amino acid string of the "gc" structure, and "B" represents the carboxyl-terminus amino acid of the "gc" structure. An exemplary mass spectrum of compound A is shown in Figure 1, and an exemplary HPLC chromatogram of compound A is shown in Figure 2. Table 2 of Example 1 shows the molecular weight, HPLC purity, and water solubility of compounds A-J, respectively. [Table 1] 【0052】 Experiments for measuring in vitro binding and functional efficacy in human NK2R and NK1R are described for compounds A-J in Examples 2 and 3, respectively. Example 3 describes intracellular calcium mobilization by in vitro activation of recombinant hNK2R or hNK1R expressed in CHO cells with 10 peptide analogues, and the data are provided in Table 3. Figures 3A-3C show the [Ca] mobilization in CHO cells expressing hNK2 or hNK1 receptors by compounds A, B, and G, respectively. 2+ This is an exemplary graph showing the stimulus response. Data are expressed as the percentage of the maximum response to substance P for the hNK1 receptor or to NKA for the hNK2 receptor. Each data point is the mean ± SD from double repeated measures. Compounds A-G (SEQ ID NOs: 1-7) and J (SEQ ID NO: 10) elicit a concentration-dependent calcium response and are complete agonists in hNK2R (≥85% maximum response compared to neurokinin A). Of these, in hNK2R, compounds A (SEQ ID NO: 1), C (SEQ ID NO: 3), and E (SEQ ID NO: 5) are the most potent, and compound J (SEQ ID NO: 10) is the least potent (see Table 3). Compounds H (SEQ ID NO: 8) and I (SEQ ID NO: 9) do not elicit a significant calcium response when tested at concentrations up to 10 μM. 【0053】 Compounds A (SEQ ID NO: 1), C-F (SEQ ID NOs: 3-6), and J (SEQ ID NO: 10) elicit a concentration-dependent calcium response and are full agonists in hNK1R (maximum response ≥85% compared to substance P). Compounds B (SEQ ID NO: 2) and G (SEQ ID NO: 7) are partial agonists in hNK1R (maximum response ≤73% compared to substance P). In hNK1R, compounds C (SEQ ID NO: 3) and E (SEQ ID NO: 5) are the most potent, while compounds B (SEQ ID NO: 2) and G (SEQ ID NO: 7) are the least potent (see Table 3). Compounds H (SEQ ID NO: 8) and I (SEQ ID NO: 9) do not elicit a significant calcium response when tested at concentrations up to 10 μM. 【0054】 The EC50 ratio for hNK2R / hNK1R reveals the selectivity of various compounds for the activation of hNK2R versus hNK1R (see Table 3). Table 3 shows that compound A (SEQ ID NO: 1) exhibits remarkably high selectivity for hNK2R (>700 times). Compounds B-G (SEQ ID NOs: 2-7) and J (SEQ ID NO: 10) are all >20 times selectivity for hNK2R. Compounds H (SEQ ID NO: 8) and I (SEQ ID NO: 9) show no selectivity for hNK2R. 【0055】 In one embodiment, a compound having NK2R agonist activity and selectivity for NK2R than for NK1R is provided for use as a pharmaceutical composition to improve the quality of life of patients by promoting on-demand urination and defecation and address this unmet medical need. The peptide compound may have at least 20-fold, at least 50-fold, at least 100-fold, or at least 200-fold selectivity for activation of the human neurokinin 2 receptor (hNK2R) compared to the human neurokinin 1 receptor (hNK1R). 【0056】 In one embodiment, compounds A to G are provided for use as pharmaceutical compositions to improve the quality of life of patients by promoting on-demand urination and defecation, and to address this unmet medical need. 【0057】 In one embodiment, the following general formula (I) and sequence number 11 are used: [ka] (I) (Sequence ID 11) (In the formula, A is Xaa1-Asp-Xaa3-Phe-Val, where Xaa1 is either nonexistent or Lys, and Xaa3 is Ser, Lys, or Arg. The following are provided: a peptide compound having (B being Met-NH2 or Nle-NH2) or a pharmaceutically acceptable salt thereof. 【0058】 In one embodiment, a peptide compound according to general formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein Xaa1 is absent, Xaa3 is Ser, and B is Met-NH2. 【0059】 In one embodiment, a peptide compound according to general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 2, compound B) is provided, wherein Xaa1 is absent, Xaa3 is Ser, and B is Nle-NH2. 【0060】 In one embodiment, a peptide compound according to general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 3, Compound C) is provided, wherein Xaa1 is absent, Xaa3 is Lys, and B is Met-NH2. 【0061】 In one embodiment, a peptide compound according to general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 4, compound D) is provided, wherein Xaa1 is absent, Xaa3 is Lys, and B is Nle-NH2. 【0062】 In one embodiment, a peptide compound according to general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 5, Compound E) is provided, in which Xaa1 is absent, Xaa3 is Arg, and B is Met-NH2. 【0063】 In one embodiment, a peptide compound according to general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 6, compound F) is provided, wherein Xaa1 is absent, Xaa3 is Arg, and B is Nle-NH2. 【0064】 In one embodiment, a peptide compound according to general formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 7, compound G) is provided, wherein Xaa1 is Lys, Xaa3 is Ser, and B is Nle-NH2. 【0065】 In one embodiment, a pharmaceutical composition is provided comprising any of peptide compounds A to G or a pharmaceutically acceptable salt thereof for use in a method of inducing either or both urination and / or defecation. 【0066】 In one embodiment, a pharmaceutical composition is provided comprising a peptide compound having general formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of inducing either or both urination and / or defecation, wherein the peptide compound has at least 20-fold, at least 50-fold, at least 100-fold, or at least 200-fold selectivity for activation of the human neurokinin 2 receptor (hNK2R) compared to the human neurokinin 1 receptor (hNK1R). 【0067】 In one embodiment, any of peptide compounds A to G, or the peptide compound of general structure (I) and SEQ ID NO: 11, or a pharmaceutically acceptable salt or solvated compound thereof, is provided for use in a method for inducing either or both urination and / or defecation. 【0068】 In one embodiment, a method is provided for inducing either or both urination and defecation in a mammal, comprising administering to the mammal, as needed, a composition containing a therapeutically effective amount of any of peptide compounds A to G or a pharmaceutically acceptable salt thereof, to induce either or both urination and defecation as needed. 【0069】 In one embodiment, a method is provided for inducing either or both urination and defecation in a mammal, comprising administering to the mammal, as needed, a composition comprising a therapeutically effective amount of a peptide compound having general formula (I) and sequence number 11, or a pharmaceutically acceptable salt thereof, to induce either or both of urination and defecation as needed, wherein the peptide compound has at least 20-fold, at least 50-fold, at least 100-fold, or at least 200-fold selectivity for activation of the human neurokinin 2 receptor (hNK2R) compared to the human neurokinin 1 receptor (hNK1R). 【0070】 In one embodiment, the following general formula (II): [ka] (II) (In the formula, R1 comprises two or more amino acid residues, at least one of which has an ionizable side chain selected from the amino acids Asp, Glu, Lys, and Arg. R2 is a lipophilic amino acid selected from Nle and Met. A peptide compound having the following is provided. 【0071】 In one embodiment, a pharmaceutical composition is provided comprising a peptide compound having general formula (II), or a pharmaceutically acceptable salt thereof, for use in a method of inducing either or both urination and / or defecation, wherein the peptide compound has at least 20-fold, at least 50-fold, at least 100-fold, or at least 200-fold selectivity for activation of the human neurokinin 2 receptor (hNK2R) compared to the human neurokinin 1 receptor (hNK1R). 【0072】 In one embodiment, a method is provided for inducing either or both urination and defecation in a mammal, comprising administering to the mammal, as needed, a composition comprising a therapeutically effective amount of a peptide compound having general formula (II) or a pharmaceutically acceptable salt thereof, to induce either or both urination and defecation as needed, wherein the peptide compound has at least 20-fold, at least 50-fold, at least 100-fold, or at least 200-fold selectivity for activation of the human neurokinin 2 receptor (hNK2R) compared to the human neurokinin 1 receptor (hNK1R). 【0073】 In one embodiment, any of i) peptide compounds A to G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, or iii) peptide compounds having general formula (II), or a pharmaceutically acceptable salt or solvated compound thereof, is provided for use in a method of inducing either or both urination and defecation. 【0074】 In one embodiment, a method for providing "on-demand, rapidly initiated, short-duration, drug-induced excretion" is provided herein using a peptide analog selected from the group consisting of i) compounds A-G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II), or a pharmaceutically acceptable salt thereof. The peptide compounds may have at least 20-fold, at least 50-fold, at least 100-fold, or at least 200-fold selectivity for activation of the human neurokinin 2 receptor (hNK2R) compared to the human neurokinin 1 receptor (hNK1R). Peptide-induced excretion may be useful for persons with urinary dysfunction or other mammals for whom excretion induction is otherwise desirable. The compositions and methods of the present disclosure provide pharmaceutical formulations and methods of administration of smooth muscle motility-promoting peptides for providing a duration of motility-promoting effect that can induce excretion, then subsequently relax the bladder and rectum to allow storage of newly formed urine and feces, and prevent subsequent incontinence. The formulations and methods of administration of the present disclosure can minimize the duration of side effects in other organ systems. The exercise-promoting peptide formulation and method of administration described herein can be administered multiple times a day to initiate excretion. 【0075】 One advantage of the subject matter described herein is the provision of smooth muscle motility enhancers having rapid onset and short duration of action for administration to mammals to achieve rapid onset and short duration of action of the rectum and bladder, peptide compounds A-G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II). In one embodiment, the majority of the effect of the peptide is completed within about 20 minutes. In one embodiment, the majority of the effect of the peptide is completed within about 10 minutes. In one embodiment, the majority of the effect of the peptide is completed within about 5 minutes. 【0076】 Another advantage of the subject matter described herein is that peptide-induced excretion can be achieved without unbearable gastric and intestinal contractions that cause vomiting and painful spasms. 【0077】 Another advantage of the subject matter described herein is that peptide-induced excretion can be achieved without the adverse effects of respiratory smooth muscle contraction and dyspnea. This is an unexpected advantage, given that NK2 receptors are present in the airways, where stimulation of NK2 receptors can be expected to cause contraction of tracheal and bronchial smooth muscles, closing the airways. 【0078】 One advantage of the peptides provided herein for excretion as needed, or "on-demand," is that they are rapidly inactivated in vivo. Therefore, excretion can be completed within approximately 5–20 minutes of administration, without leaving any contractile activity until the next on-demand dose. 【0079】 Despite the allure of approaches using compounds with rapid onset and short duration of action, they are not without complications. A significant disadvantage of peptide NK2 agonists is their limited selectivity to activate the NK2 receptor rather than the NK1 receptor. For example, NKA is a potent NK1 receptor agonist in functional assays, despite its weak ability to replace recombinant NK1 receptors with radiolabeled substance P, binding to the “septide-sensitive” site on the NK1 receptor with sub-nM affinity (Sagan et al., 1996; Hasrup & Schwartz, 1996; Torrens et al., 2000). Since cutaneous vasodilation is a well-recognized response to intra-arterial injection of substance P (Newby et al., 1997), activation of the NK1 receptor is most likely to explain the cutaneous flushing observed after NKA injection in human studies. Because NK1 receptors are widely distributed throughout the body and involved in many physiological systems, including cardiovascular, respiratory, inflammatory, and immune responses, the ability of NKAs to activate NK1 receptors via the ceptide site can confer adverse effects and limit the safety margin. Examples of physiological systems that can be activated by NKAs via NK1 receptors include NKA-induced hypotension in rats that may disappear after blockade of NK1 (but not NK2) receptors (Kaczynska et al., 2016), and NKA-induced bronchoconstriction in guinea pigs with NK1 receptor-mediated components (Ricciardolo et al., 2000). Since such activation is associated with toxin-induced liver damage (Bang et al., 2003; Yang et al., 2013) and hypertension-induced kidney damage (Wang and Wang, 2012), there is also the possibility of widespread organ toxicity from chronic exposure to compounds that activate NK1 receptors. Therefore, NK2 agonists that have selectivity for NK2 receptor activation rather than for ceptide-sensitive sites on NK1 receptors may be useful in minimizing NK1 receptor-mediated adverse effects and toxicity. Selectivity for NK2 receptors rather than NK1 receptors is provided for the 10 NKA analogs disclosed herein. 【0080】 In one embodiment, the subject of this disclosure provides a functional assay for NK1 receptor activation in toxic target organs. Given that in the cardiovascular system, activation of NK1 receptors located in the brainstem, vagal sensory nerves, and / or vascular endothelial cells can alter vascular tone and blood pressure (Feldman, 1995; Bowden et al., 1996; Jafri and Weinreich, 1996; Miike et al., 2009), it is unclear which physiological system or target tissue best predicts undesirable NK1 agonist-mediated effects in humans. Specifically, it is unclear which of these is the primary site responsible for NK1 agonist-mediated hypotension in vivo. Furthermore, even when examining a single tissue, differences in the receptor reserve of G protein-coupled receptors exist between species (and within different tissues of a species) that alter the efficacy of agonists (Oriowo et al., 1989; Drury et al., 1998). These complications, along with the possibility of crosstalk with other receptors expressed in native tissues, made it impractical to develop a functional assay that reliably predicts the potential NK1R-mediated toxicity of NK2R agonists in humans. Instead, intracellular calcium mobilization is used as a functional assay of relative agonist efficacy and potency using human recombinant NK2 and NK1 receptors expressed in CHO cells. These single-receptor systems allow for the independent investigation of the effects of compounds on NK2 and NK1 receptors. 【0081】 In one embodiment of the subject matter of this disclosure, synthetic peptide analogs are provided selected from the group consisting of i) compounds A to G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II). 【0082】 In one embodiment, a method is provided for preparing peptides selected from the group consisting of i) compounds A to G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II). The method comprises chemically synthesizing peptide analogs that contain, are essentially, or consist of one of the amino acid sequences of compounds A to G having SEQ ID NOs: 1 to 7, compounds having general formula (I) and SEQ ID NO: 11, and compounds having general formula (II), respectively, and purifying the peptides. The chemical synthesis step may include solid-phase chemical synthesis. The purification step may include reverse-phase chromatography. 【0083】 In one embodiment, a pharmaceutical composition is provided comprising, as an active agent, a peptide selected from i) compounds A to G, ii) a peptide compound having general formula (I) and SEQ ID NO: 11, and iii) a peptide compound having general formula (II), or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may be useful in inducing urinary and / or defecation on demand or "on-demand" in mammals. The pharmaceutical composition may further comprise pharmaceutically acceptable excipients. 【0084】 A pharmaceutical composition having, as an active agent, a peptide analog selected from i) compounds A to G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II), or a pharmaceutically acceptable salt thereof, may be provided in formulations useful for hydrophilic or hydrophobic active agents, depending on the properties of the particular peptide analog. Pharmaceutical formulations useful for the administration of hydrophilic and hydrophobic active agents, such as the peptide analogs of this disclosure, are known in the art. 【0085】 In one embodiment, the hydrophilic peptide analogs of this disclosure may be formulated and administered in an isotonic aqueous solution according to procedures known in the art, such as those described in Strickley (2004) Pharmaceutical Research, 21(2):201-230. Ionizable hydrophilic peptides can be solubilized for dose administration by adjusting the formulation pH to an acceptable range of pH 2 to 12. The formulation pH can be controlled, but is not limited, by the addition of an acid / base such as hydrochloric acid or sodium hydroxide, or by the addition of a buffer such as glycine, citrate, acetate, histidine, phosphate, tris(hydroxymethyl)aminomethane (TRIS), or carbonate. 【0086】 In one embodiment, hydrophilic peptide analog compounds C, D, E, F, and G are formulated for compatibility with hydrophilic peptide compounds in aqueous solutions. These peptide compounds may be formulated for administration in isotonic aqueous solutions. 【0087】 In one embodiment, the hydrophobic peptide analogs of the present disclosure may be formulated and administered according to procedures known in the art, such as using a combination of aqueous solution and a water-soluble biocompatible organic solvent / surfactant, as disclosed, for example, in Strickley (Pharmaceutical Research, 21(2):201-230, 2004). In particular, a variety of cosolvents can be used, including propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP, Pharmasolve), dimethyl sulfoxide (DMSO), Solutol HS15, Cremofor EL, Cremofor RH60, and polysorbate 80. 【0088】 In one embodiment, hydrophobic peptide analog compounds A and B are formulated for compatibility with hydrophobic peptide compounds. These peptide compounds may be formulated for compatibility with hydrophobic peptide compounds by including a water-soluble and biocompatible organic solvent or organic surfactant in the formulation. 【0089】 In one embodiment, parenteral formulations of the peptide analogs of the present disclosure may include, for example, permeabilis enhancers such as sodium lauryl sulfate, lysophosphatidylcholine and phosphatidylcholine, polyoxyethylene 23-lauryl ether (Brij35), quillaja saponins, alkyl glycoside derivatives, sodium glycocholate, sodium cholate, sodium deoxycholate, sodium glycodeoxycholate, sodium taurocholate, chitosan, and EDTA, as disclosed by Morales and McConville (Drug Dev Ind Pharm, 40(5):579-590, 2014). 【0090】 The pharmaceutical composition may further contain a therapeutically effective amount of an NK2R antagonist or a pharmaceutically acceptable salt thereof, wherein the onset of action of the NK2R antagonist is longer than that of the peptide analogue, terminating most of the effect of the peptide analogue within about 15 minutes after the occurrence of one or both urination and / or defecation, and the NK2R antagonist has a duration of action of less than about 4 hours. The NK2R antagonist may have a duration of action of less than about 3 hours. The NK2R antagonist may have a duration of action of less than about 2 hours. The onset of action of the NK2R antagonist is longer than that of the peptide analogue, and can terminate most of the effect of the peptide analogue within about 10 minutes after the occurrence of one or both urination and / or defecation. The onset of action of the NK2R antagonist is longer than that of the peptide analogue, and can terminate most of the effect of the NK2R agonist within about 5 minutes after the occurrence of one or both urination and / or defecation. 【0091】 In one embodiment, a pharmaceutical composition is provided comprising a peptide analog selected from i) compounds A to G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II), which exhibit high selectivity for NK2R over NK1R. The phrase "high selectivity for NK2R over NK1R" means that the binding affinity ratio (i.e., NK1 binding Ki / NK2 binding Ki) is at least about 100, at least about 150, or at least about 170. In one example, the binding affinity ratio (i.e., hNK1 binding Ki / hNK2 binding Ki) is at least about 170. 【0092】 In one embodiment, a method is provided for inducing either or both urination and defecation in a mammal, comprising administering to the mammal, if necessary, a composition comprising a therapeutically effective amount of i) compounds A to G, ii) a peptide compound having general formula (I) and sequence number 11, and iii) a peptide compound having general formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, to induce either or both urination and defecation as needed or "on demand". The mammal may be a human or a companion animal (e.g., a cat or a dog), or a livestock animal (e.g., a horse, a cow, a pig, or a sheep). 【0093】 The compositions and methods of this disclosure satisfy the existing need for new treatments for urinary and defecation disorders, including, for example, the inability to urinate or defecate spontaneously. Therefore, administration as needed may be repeated multiple times a day. Administration as needed may be by one or a combination of parenteral, intravenous, topical, transdermal, intramuscular, subcutaneous, transnasal, inhalation, transrectal, lingual, sublingual, transmucosal, buccal, and transbuccal administration. Urinary retention and defecation disorders may result from a wide range of injuries, conditions, diseases, or impairments, including one or more of the following, and combinations thereof: spinal cord injury, traumatic brain injury, multiple sclerosis, spina bifida, degenerative brain disease, Alzheimer's disease, Parkinson's disease, dementia, diabetes, old age, and postoperative conditions. The compositions and methods may be useful, for example, to induce urination and defecation in a person in a comatose state, causing defecation before the person unconsciously defecates. Another advantage of the methods and compositions of this disclosure is for pet owners who may want to induce urination in their dogs at a specific, convenient location or time. 【0094】 A method for inducing one or both of urination and / or defecation in a mammal as needed, the method may further include administering a therapeutically effective amount of an NK2R antagonist or a pharmaceutically acceptable salt thereof to terminate at least the majority of the effects of a peptide analog selected from i) compounds A to G, ii) a peptide compound having general formula (I) and SEQ ID NO: 11, and iii) a peptide compound having general formula (II), wherein the NK2R antagonist has a duration of action of less than about 4 hours. The NK2R antagonist may have a duration of action of less than about 3 hours. The NK2R antagonist may have a duration of action of less than about 2 hours. 【0095】 In a method for inducing either urination or defecation in a mammal as needed, further comprising the administration of an NK2R antagonist, the peptide analogues selected from i) compounds A-G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II), and the NK2R antagonist can be administered simultaneously in single or separate formulations, the onset of action of the NK2R antagonist is longer than that of the peptide analogues, and the majority of the effect of the peptide analogues can be terminated within approximately 15 minutes. The onset of action of the NK2R antagonist is longer than that of the peptide analogues, and the majority of the effect of the peptide analogues can be terminated within approximately 10 minutes. The onset of action of the NK2R antagonist is longer than that of the peptide analogues, and the majority of the effect of the peptide analogues can be terminated within approximately 5 minutes. 【0096】 In one embodiment, the NK2R antagonist can be administered after administration of the peptide analogue and after either or both urination and / or defecation, with the onset of action of the NK2R antagonist lasting approximately 1 to 15 minutes, and the majority of the effect of the peptide analogue being terminated within approximately 10 minutes. The onset of action of the NK2R antagonist lasting approximately 1 to 10 minutes, and the majority of the effect of the peptide analogue being terminated within approximately 10 minutes. The onset of action of the NK2R antagonist lasting approximately 1 to 5 minutes, and the majority of the effect of the peptide analogue being terminated within approximately 5 minutes. 【0097】 It will be understood by those skilled in the art that the timing of administration of an NK2R antagonist in response to the administration of a peptide analog may vary depending on the respective onset and duration of action of each individual peptide analog and antagonist selected to induce urination and reverse undesirable effects. A key characteristic of the timing of the method is that the NK2R antagonist must reach an effective plasma concentration during the time when urination is desired, but not during the undesirable effect of the peptide analog. 【0098】 In one embodiment, the administration of peptide analogs by the methods and formulations of the present disclosure may be combined with, but are not limited to, one or more urethral relaxants such as alpha-adrenergic receptor blockers, nitric oxide (NO) donors, PDE5 inhibitors, prostaglandin E receptor (EP1, 2, 3) agonists, and pharmacological or electrical blockade of the pudendal nerve. 【0099】 The compositions and formulations of active agents of this disclosure are provided in dosage forms as needed and may include immediate-release formulations to achieve the required dose of the active agent. 【0100】 Peptide analogs selected from i) compounds A to G, ii) peptide compounds having general formula (I) and sequence number 11, and iii) peptide compounds having general formula (II), or pharmaceutically acceptable salts thereof, can be formulated as immediate-release dosage forms, and administration as needed may occur approximately 1 to 40 minutes before urination and / or defecation is desired, approximately 1 to 20 minutes before urination and / or defecation is desired, approximately 1 to 10 minutes before urination and / or defecation is desired, or approximately 1 to 5 minutes before urination and / or defecation is desired. 【0101】 In one embodiment, one or more additional active agents or pudendal nerve blockades may be administered simultaneously with or sequentially with the peptide analog activator, either in separate formulations or as a single formulation. The additional active agents may be effective in treating bladder and / or bowel dysfunction associated with retention, such as overactive bladder or benign prostatic hyperplasia. The additional active agents may enhance the effect of the peptide analog activator on treating bladder and / or bowel retention. Suitable additional active agents include, but are not limited to, antimuscarinic agents (e.g., oxybutynin, solifenacin succinate, tolterodine), β-3 adrenergic agonists (e.g., mirabegron), α-adrenergic antagonists (e.g., silodosin, terazosin, tamsulosin, doxazosin, prazosin, alfuzosin), 5-α-reductase inhibitors (e.g., finasteride, dutasteride), phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil), and / or any agent that does not inhibit the action of the primary active agent. Pudendal nerve blockade can be achieved pharmacologically through drugs that suppress the pudendal nerve reflex, such as ethyl ketocyclazosine, or block the pudendal nerve action potential, such as local anesthetics (e.g., lidocaine). Pudendal nerve activity can also be blocked by high-frequency electrical stimulation of the pudendal nerve (e.g., a >5 kHz square wave pulse with an equal on-off duty cycle and sufficient current to activate pudendal motor neurons). 【0102】 Additional active agents may include, for example, alpha-adrenergic receptor blockers, nitric oxide (NO) donors, PDE5 inhibitors, or urethral relaxants such as prostaglandin E receptor (EP1, 2, 3) agonists. Alpha-adrenergic receptor blockers may include, for example, tamsulosin, silodosin, alfuzosin, or naphtopidil, or any other suitable alpha-adrenergic receptor blocker. NO donors may include, for example, sodium nitroprusside, glyceryl trinitrate, or the S-nitrosothiol class of NO donors, or any other suitable NO donor. PDE5 inhibitors may include, for example, sildenafil, tadalafil, vardenafil, avanafil, udenafil, dipyridamole, or vardenafil hydrochloride, or any other suitable PDE5 inhibitor. 【0103】 The additional active agent may be a compound capable of inducing either colonic contraction and / or sphincter relaxation in the subject. The anal sphincter relaxant may be, for example, a vasoactive intestinal polypeptide (VIP), an NO donor, amyl nitrate, butyl nitrate, glyceryl trinitrate, an α-adrenergic receptor blocker, tamsulosin, silodosin, alfuzosin, or naphtopidil, or one of the other suitable anal sphincter relaxants. 【0104】 Any active agent may be administered in the form of a salt, ester, amide, prodrug, active metabolite, derivative, etc., provided that the salt, ester, amide, prodrug, or derivative is pharmacologically suitable, i.e., effective in this method. Salts, esters, amides, prodrugs, and other derivatives of active agents are known to those skilled in synthetic organic chemistry and can be prepared using standard procedures, for example, those described by J. March (1992). For example, acid addition salts are prepared from free bases using conventional methodologies and involve reaction with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, as well as inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Acid addition salts can be converted back to free bases by treatment with a suitable base. Particularly preferred acid addition salts of active agents in this specification are salts prepared using organic acids. Conversely, preparations of basic salts of acidic moieties that may be present on active agents are prepared in a similar manner using pharmaceutically acceptable bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, and trimethylamine. 【0105】 The preparation of esters involves the functionalization of hydroxyl and / or carboxyl groups that may be present in the molecular structure of the drug. Esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties derived from carboxylic acids of the formula RCOOH (wherein R is alkyl, preferably a lower alkyl). Esters can be converted back to free acids by conventional hydrolysis or hydrolysis procedures, if necessary. Amides and prodrugs can also be prepared using techniques known to those skilled in the art or techniques described in the relevant literature. For example, amides can be prepared from esters using suitable amine reactants, or from anhydrides or acid chlorides by reaction with ammonia or lower alkylamines. Prodrugs are typically prepared by covalent bonding of moieties that result in a therapeutically inactive compound until modified by the metabolic system of the organism. 【0106】 Other salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives of the active agent can be prepared using standard techniques known to those skilled in the art of organic synthesis chemistry, or can be inferred by referring to relevant literature. Furthermore, the chiral active agent may be in isomerically pure form or administered as a racemic mixture of isomers. 【0107】 The active agents of this disclosure may be contained in pharmaceutical formulations. Pharmaceutical formulations may be in unit dosage forms. Pharmaceutical formulations may be selected from the group consisting of tablets, capsules, caplets, granules, beads, powders, pellets, liquid formulations, solutions, suspensions, syrups, suppositories, creams, ointments, pastes, gels, foams, and sprays. 【0108】 The pharmaceutical preparation may be in the form of a tablet. The pharmaceutical preparation may be in the form of a rapidly disintegrating tablet. The tablet may be a rapidly disintegrating open matrix network tablet. Administration may be transmucosal, and the rapidly disintegrating open matrix network tablet may contain a biodegradable polymer or ATRIX BEMA biodegradable polymer. The rapidly disintegrating open matrix network tablet may contain a biodegradable polymer or ATRIX BEMA biodegradable polymer. 【0109】 The pharmaceutical preparation may be in the form of a film. The pharmaceutical preparation may be a rapidly disintegrating film. The film may be a rapidly disintegrating mucosal adhesive film. Administration may be transmucosal, and the rapidly disintegrating mucosal adhesive film may contain a hydrophilic polymer. 【0110】 Pharmaceutical formulations may be selected from the group consisting of suppositories, creams, ointments, liquid formulations, pastes, gels, foams, and sprays. Pharmaceutical formulations may be delivered by the use of iontophoresis, electroporation, or phonophoresis delivery mechanisms. Pharmaceutical formulations may contain permeation enhancers. 【0111】 Pharmaceutical preparations may be administered through a transdermal patch. The transdermal patch may contain a permeation enhancer. The transdermal patch may include a needle-free transdermal patch containing electrical energy. The transdermal patch may include a needle-free transdermal patch containing microprotrusions. 【0112】 The administration of pharmaceutical preparations may be parenteral, or it may include injection using an injection device. 【0113】 Suitable compositions and dosage forms include tablets, capsules, caplets, pills, gel caps, lozenges, dispersions, suspensions, solutions, syrups, transdermal patches, gels, powders, magmas, lozenges, creams, pastes, bandages, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosolized formulations for inhalation, rapidly disintegrating tablets including effervescent tablets or wafers, ointments, liquid formulations, foams, and the like. Furthermore, those skilled in the art can readily deduce suitable formulations including these compositions and dosage forms, including formulations described elsewhere in this specification. 【0114】 The composition may be administered orally or placed in the oral cavity and absorbed from there. For example, transmucosal administration may be advantageous. Transmucosal administration is carried out using any type of formulation or dosage unit suitable for application to mucosal tissue. For example, the selected active agent may be administered to the buccal mucosa as an adhesive tablet, film or patch; administered sublingually by placing a solid dosage form under the tongue; administered lingually by placing a solid dosage form on the tongue; administered nasally as a droplet or nasal spray; administered by inhalation of an aerosol formulation, a non-aerosol liquid formulation or a dry powder; placed rectally or near the rectum ("transrectal" formulation); or administered urethra as a suppository, ointment, etc. 【0115】 The dosage form can also be effervescent tablets or rapidly disintegrating tablets, including wafers. Examples of effervescent tablets can be found in the literature and, for example, in U.S. Patent No. 5,211,957 by Hagemann et al. Generally, effervescent tablets contain the active agent in combination with sodium bicarbonate and additives such as organic acids, e.g., tartaric acid or citric acid. In the presence of water, these additives react to release carbon dioxide, thereby promoting the disintegration of the tablet. Once the tablet has substantially disintegrated, the active agent is absorbed through the oral mucosa, thereby resulting in systemic adsorption of the active agent. 【0116】 Another version of rapidly disintegrating tablets includes "open matrix network" tablets. These tablets can disintegrate within a few seconds, i.e., within 5 to 10 seconds, after being placed on the tongue of an individual. The contents of the tablet can then be swallowed with or without water. An example of such a tablet can be found in U.S. Patent No. 4,371,516 by Gregory et al., where the carrier is a low-density network, e.g., about 10 to about 200 mg / cm³. 3 The present invention provides water-soluble or water-dispersible materials. The tablets are manufactured by sublimating a solution containing both the drug and a carrier, which is then directed into a mold having a tablet-shaped cavity. The carrier can be any suitable material, but is preferably gelatin, with partially hydrolyzed gelatin being most preferred. Other examples of rapidly disintegrating tablets that can be adapted to contain the active agent disclosed herein are well known in the art. See, for example, U.S. Patent No. 5,776,492 by Betzing et al. 【0117】 A preferred buccal dosage form typically comprises a therapeutically effective amount of the active agent and a bioerosive (hydrolyzable) polymer carrier, which can also help adhere the dosage form to the buccal mucosa. The buccal administration unit is constructed to erode over a predetermined period, and drug delivery is essentially provided throughout. The time can range from about 1 minute to about 40 minutes, about 1 minute to about 30 minutes, and about 1 minute to about 10 minutes. As will be understood by those skilled in the art, buccal drug delivery avoids the drawbacks encountered with oral drug administration, such as the absorption of the active agent by fluids present in the gastrointestinal tract, delayed degradation, and / or first-pass inactivation in the liver. 【0118】 The "therapeutic effective dose" of the active agent in a buccal administration unit naturally depends on the potency of the drug and the intended dose, which in turn depends on the specific individual being treated, the specific indication, etc. A buccal administration unit generally contains about 1.0% to 60% by weight of the active agent, preferably about 1% to 30% by weight. Regarding bio-erosive (hydrolyzable) polymer carriers, it will be understood that substantially any such carrier can be used, as long as the desired drug release profile is not impaired and the carrier is compatible with the administered active agent and any other components of the buccal administration unit. Generally, polymer carriers include hydrophilic (water-soluble and water-swellable) polymers that adhere to the moist surface of the buccal mucosa. Examples of polymer carriers useful herein include acrylic polymers and co polymer These include, for example, those known as "carbomers" (CARBOPOL, which can be obtained from BFGoodrich, is one such polymer). Other suitable polymers include, but are not limited to, hydrolyzed polyvinyl alcohol, polyethylene oxide (e.g., SENTRY POLYOX water-soluble resin available from Union Carbide), polyacrylates (e.g., GANTREZ, which can be obtained from GAF), vinyl polymers and copolymers, polyvinylpyrrolidone, dextran, guar gum, pectin, starch, and cellulose polymers such as hydroxypropyl methylcellulose (e.g., METHOCEL, which can be obtained from Dow Chemical Company), hydroxypropyl cellulose (e.g., KLUCEL, which can also be obtained from Dow), hydroxypropyl cellulose ether (e.g., U.S. Patent No. 4,704,285 by Alderman), hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, cellulose phthalate acetate, and cellulose butyrate acetate. 【0119】 Other components may also be incorporated into the buccal dosage forms described herein. Additional components include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, colorants, and preservatives. Examples of disintegrants that may be used include, but are not limited to, cross-linked polyvinylpyrrolidone such as crospovidone (e.g., POLYPLASDONEXL, which can be obtained from GAF), croscarmellose (e.g., AC-DI-SOL, which can be obtained from FMC), alginic acid, cross-linked carboxymethylcellulose such as sodium starch glycolate (e.g., EXPLOTAB, which can be obtained from Edward Medell Co., Inc.), methylcellulose, and agar. 、 Bentonite and alginate are included. Suitable diluents are those generally useful in pharmaceutical formulations prepared using compression techniques, such as dicalcium phosphate dihydrate (e.g., DI-TAB, which can be obtained from Stauffer), sugars processed by co-crystallization with dextrin (e.g., co-crystallized sucrose and dextrin such as DI-PAK, which can be obtained from Amstar), calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Binders, when used, enhance adhesion. Examples of such binders, but are not limited to, starch, gelatin, and sugars such as sucrose, dextrose, molasses, and lactose. Particularly preferred lubricants are stearate and stearic acid, and the optimal lubricant is magnesium stearate. 【0120】 Sublingual and tongue-administered dosage forms include tablets, creams, ointments, lozenges, pastes, and any other solid dosage forms in which the active ingredient is mixed with a disintegrating matrix. Tablets, creams, ointments, or pastes for sublingual or tongue-administered delivery contain a therapeutically effective amount of a selected active agent and one or more conventional non-toxic carriers suitable for sublingual or tongue-administered drug delivery. The sublingual and tongue-administered dosage forms of the present invention can be manufactured using conventional methods. Sublingual and tongue-administered units are manufactured to disintegrate rapidly. The time for complete disintegration of an administration unit is typically in the range of about 10 seconds to about 30 minutes, and optimally less than 5 minutes. 【0121】 Other components may also be incorporated into the sublingual and tongue formulations described herein. Additional components include, but are not limited to, binders, disintegrants, wetting agents, and lubricants. Examples of binders that may be used include water, ethanol, polyvinylpyrrolidone, starch solutions, and gelatin solutions. Suitable disintegrants include dried starch, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Wetting agents, if used, include glycerin and starch. Particularly preferred lubricants are steart and polyethylene glycol. Additional components that may be incorporated into the sublingual and tongue formulations will be known or obvious to those skilled in the art. 【0122】 Preferred transrectal dosage forms include rectal suppositories, creams, ointments, and liquid formulations (enemas). Suppositories, creams, ointments, or liquid formulations for transrectal delivery contain a therapeutically effective amount of a selected active ingredient and one or more conventional non-toxic carriers suitable for transrectal drug administration. The transrectal dosage forms of the present invention can be manufactured using conventional methods. 【0123】 Active agents may also be administered intranasally or by inhalation. Compositions for intranasal administration are generally liquid formulations for administration as sprays or drops, but powder formulations for intranasal administration, e.g., blowing, are also known, as are nasal gels, creams, pastes, or ointments. In the case of liquid formulations, the active agent can be formulated into a solution, e.g., buffered or unbuffered water or isotonic saline, or a suspension. Preferably, such a solution or suspension is isotonic with respect to nasal secretions and has approximately the same pH, for example, in the range of about pH 4.0 to about pH 7.4 or about pH 6.0 to about pH 7.0. The buffer should be physiologically compatible and includes, simply as an example, phosphate buffer. Furthermore, a variety of devices for generating droplets, drops, and sprays, including droppers, squeeze bottles, and manual and electric intranasal pump dispensers, are available in the art. Active agents containing an intranasal carrier may also include nasal gels, creams, pastes, or ointments having a viscosity of, for example, about 10 to about 6500 cps or more, depending on the desired sustained contact with the nasal mucosal surface. Such carrier-viscosity formulations may be based, simply as an example, on alkylcellulose and / or other biocompatible carriers of high viscosity known in the art. Other components known in the art, such as preservatives, colorants, natural or synthetic plant extracts such as lubricating or viscous mineral or vegetable oils, fragrances, aromatic oils, and humectants and thickeners such as glycerol, may also be included in the formulation to provide additional viscosity, moisturizing properties, and a pleasant texture and odor. Formulations for inhalation may be prepared as either a solution aerosol in which the active agent is solubilized in a carrier (e.g., a spray) or a dispersion aerosol in which the active agent is suspended or dispersed throughout the carrier and an optional solvent. Non-aerosol formulations for inhalation may take the form of a liquid, typically an aqueous suspension, but aqueous solutions may also be used. In such cases, the carrier is typically a sodium chloride solution having a concentration such that the formulation is isotonic with respect to normal body fluids.In addition to the carrier, the liquid formulation may contain water and / or excipients containing antimicrobial preservatives (e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, thimerosal, and combinations thereof), buffers (e.g., citric acid, potassium metaphosphate, potassium phosphate, sodium acetate, sodium citrate, and combinations thereof), surfactants (e.g., polysorbate 80, sodium lauryl sulfate, sorbitan monopalmitate, and combinations thereof), and / or suspending agents (e.g., agar, bentonite, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, tragacanth, beegum, and combinations thereof). Non-aerosol formulations for inhalation may also include dry powder formulations, particularly blown powders having an average particle size of about 0.1 μm to about 50 μm and about 1 μm to about 25 μm. 【0124】 Topical formulations can be in any form suitable for application to the body surface, and may include, for example, ointments, creams, gels, lotions, solutions, pastes, and / or may be prepared to contain liposomes, micelles, and / or microspheres. Preferred topical formulations in this specification are ointments, creams, and gels. 【0125】 Ointments, as is well known in the field of pharmaceutical formulations, are typically semi-solid preparations based on petrolatum or other petroleum derivatives. As will be understood by those skilled in the art, the specific ointment base used will provide optimal drug delivery and, preferably, other desired characteristics, such as skin softening. Like other carriers or vehicles, ointment bases must be inert, stable, non-irritating, and non-sensitizing. Ointment bases can be classified into four classes: oily bases, emulsifying bases, emulsion bases, and water-soluble bases. Oily ointment bases include, for example, vegetable oils, fats derived from animals, and semi-solid hydrocarbons derived from petroleum. Emulsifying ointment bases, also known as absorbent ointment bases, contain little to no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsified ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of various molecular weights. 【0126】 As is well known in the art, creams are either oil-in-water or water-in-oil viscous liquids or semi-solid emulsions. The cream base is washable with water and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the “internal” phase, generally consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol. The aqueous phase, though not necessarily, usually exceeds the volume of the oil phase and generally contains a humectant. The emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. 【0127】 As those working in the field of pharmaceutical formulations will understand, a gel is a semi-solid suspension system. Single-phase gels typically contain organic polymers substantially uniformly distributed throughout a carrier liquid, which is usually aqueous, but preferably also contain alcohols and occasionally oils. Preferred “organic polymers,” i.e., gelling agents, are polymers of the “carbomer” family, such as cross-linked acrylic polymers like carboxypolyalkylenes, commercially available under the registered trademark CARBOPOL. Also preferred are hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, dispersants such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, and / or stirring. 【0128】 Various additives known to those skilled in the art may be included in topical formulations. For example, solubilizers can be used to solubilize certain active drugs. In the case of drugs that penetrate abnormally slowly through skin or mucous membrane tissue, it may be desirable to include a penetration enhancer in the formulation, suitable enhancers of which are described elsewhere in this specification. 【0129】 The compounds of the present invention may also be administered through skin or mucous membrane tissue using conventional transdermal drug delivery systems, where the drug is contained within a laminated structure “patch” that functions as a drug delivery device attached to the skin. Transdermal drug delivery may involve passive diffusion or may be facilitated using electrical transport, such as iontophoresis. In a typical transdermal “patch,” the drug composition is contained in a layer or “reservoir” beneath an upper backing layer. The laminated structure may contain a single reservoir or multiple reservoirs. In a certain type of patch, referred to as a “monolithic” system, the reservoir consists of a polymer matrix of a pharmaceutically acceptable contact adhesive material that helps adhere the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, and polyurethane. Alternatively, the drug-containing reservoir and the skin-contact adhesive are separate layers, with the adhesive located beneath the reservoir, and the reservoir may, in this case, be a polymer matrix as described above, or a liquid or hydrogel reservoir, or take any other form. 【0130】 The backing layer of these laminates, which serve as the top surface of the apparatus, functions as the main structural element of the laminate structure and provides much of the apparatus with its flexibility. The material selected for the backing material should be substantially impermeable to active agents and any other materials present, and the backing is preferably made from a sheet or film of flexible elastomer material. Examples of polymers suitable for the backing layer include polyethylene, polypropylene, polyester, and the like. 【0131】 During storage and before use, the laminated structure includes a release liner. Immediately before use, this layer is removed from the device to expose the base surface of either the drug reservoir or a separate contact adhesive layer, thereby allowing the system to be attached to the skin. The release liner should be made from a drug / vehicle impermeable material. 【0132】 Transdermal drug delivery systems may further contain skin permeability enhancers. That is, since the inherent permeability of the skin to some drugs may be too low to allow therapeutic levels of the drug to pass through a reasonably sized area of ​​skin without disruption, skin permeability enhancers need to be administered concurrently with such drugs. Suitable enhancers are well known in the art and include, for example, the enhancers listed above in transmucosal compositions. 【0133】 In one embodiment of the present disclosure, the active drug is administered transdermally. Transdermal administration may include the use of a transdermal patch. The transdermal patch may include a permeation enhancer. The transdermal patch may include a needle-free transdermal patch containing electrical energy. A needle-free transdermal patch containing electrical energy may be VYTERIS SMART PATCH DRUG DELIVERY. The transdermal patch may include a needle-free transdermal patch having microprotrusions. A needle-free transdermal patch having microprotrusions may be ZP PATCH TECHNOLOGY. A needle-free transdermal patch may be V-GO patch. 【0134】 Parenteral administration, when used, is generally characterized by injection, including intramuscular, intraperitoneal, intravenous (iv), and subcutaneous injections. Injectable formulations can be prepared in conventional forms, either as a liquid solution or suspension, a solid form suitable for dissolution or suspension in a liquid before injection, or as an emulsion. Preferably, sterile injection suspensions are formulated according to techniques known in the art, using suitable dispersants or wetting and suspending agents. Sterile injection formulations can also be sterile injection solutions or solvents in non-toxic, parenterally acceptable diluents or solvents. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils have conventionally been used as solvents or suspension media. 【0135】 Those skilled in the art will recognize that the concentration of the active agent in any of the aforementioned dosage forms and compositions can vary considerably and will depend on a variety of factors, including the type of composition or dosage form, the corresponding mode of administration, the properties and activity of the particular active agent, and the intended drug release profile. Preferred dosage forms contain a unit dose of the active agent, i.e., a single therapeutically effective dose. In the case of creams, ointments, etc., the "unit dose" requires an active agent concentration that provides a unit dose in a predetermined amount of the formulation applied. The unit dose of any particular active agent will, of course, depend on the active agent and the mode of administration. 【0136】 The unit dose for oral administration of individual active agents can range from approximately 1 nanogram (ng) to approximately 10,000 mg, or from approximately 100 ng to approximately 5,000 mg, and for local administration, the appropriate unit dose may be lower. The unit dose for oral administration can be approximately 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 1,000 mg, 1,500 mg, 2,000 mg, 2,500 mg, 3,000 mg, 3,500 mg, 4,000 mg, 4,500 mg, 5,000 mg, 5,500 mg, 6,000 mg, 6,500 mg, 7,000 mg, 7,500 mg, 8,000 mg, 8,500 mg, 9,000 mg, or more than 9,500 mg. 【0137】 For each active agent, the unit dose for transmucosal, topical, transdermal, and parenteral administration can range from approximately 1 ng to approximately 10,000 mg, and from approximately 100 ng to approximately 5,000 mg. The unit dose for transmucosal, topical, transdermal, and parenteral administration can range from approximately 1 ng, approximately 5 ng, approximately 10 ng, approximately 20 ng, approximately 30 ng, approximately 40 ng, approximately 50 ng, approximately 100 ng, approximately 200 ng, approximately 300 ng, approximately 400 ng, approximately 500 ng, approximately 1 μg, approximately 5 μg, approximately 10 μg, approximately 20 μg, approximately 30 μg, approximately 40 μg, approximately 50 μg, approximately 100 μg, approximately 200 μg, approximately 300 μg, approximately 400 μg, approximately 500 μg, approximately 1 mg, approximately 5 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 5 The amount can be 0 mg, approximately 100 mg, approximately 200 mg, approximately 300 mg, approximately 400 mg, approximately 500 mg, approximately 1,000 mg, approximately 1,500 mg, approximately 2,000 mg, approximately 2,500 mg, approximately 3,000 mg, approximately 3,500 mg, approximately 4,000 mg, approximately 4,500 mg, approximately 5,000 mg, approximately 5,500 mg, approximately 6,000 mg, approximately 6,500 mg, approximately 7,000 mg, approximately 7,500 mg, approximately 8,000 mg, approximately 8,500 mg, approximately 9,000 mg, or more than approximately 9,500 mg. 【0138】 The therapeutically effective dose of a particular active agent administered to a given individual will, of course, depend on several factors, including the concentration, composition or dosage form of the particular active agent, the chosen mode of administration, the age and general condition of the individual being treated, the severity of the individual's condition, and other factors known to the prescribing physician. However, those skilled in the art will readily recognize that the therapeutically effective dose of a particular active agent must be selected to allow for administration as needed, as further defined herein. 【0139】 With immediate-release formulations, an additional dose may be administered as needed, immediately before the desired start of emptying the bladder or bowels. This additional dose may occur approximately 1 to 40 minutes, 1 to 20 minutes, 1 to 10 minutes, or 1 to 5 minutes before the desired emptying. 【0140】 In another embodiment, a packaged kit is provided which includes a pharmaceutical formulation to be administered, i.e., a pharmaceutical formulation containing a therapeutically effective amount of an individual active agent selected from i) compounds A-G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II), or pharmaceutically acceptable salts thereof, for the treatment of loss or reduction of spontaneous control of urination and / or defecation, or having urinary and / or fecal incontinence; a preferably sealed container for housing the formulation during storage and before use; and instructions for carrying out drug administration in a manner effective for treating loss or reduction of control and / or incontinence. The instructions are typically those found in a package insert and / or on a label. Depending on the type of formulation and the intended mode of administration, the kit may also include a device for administering the formulation. The formulation can be any suitable formulation described herein. A method for treating loss or reduction of spontaneous control of urination and / or defecation, or having urinary and / or fecal incontinence, can be an administration as needed for treating urinary and / or defecation dysfunction. If necessary, this may occur approximately 1 to 40 minutes before urination and / or defecation is desired, approximately 1 to 20 minutes before urination and / or defecation is desired, approximately 1 to 10 minutes before urination and / or defecation is desired, or approximately 1 to 5 minutes before urination and / or defecation is desired. 【0141】 The kit may contain multiple formulations of the same drug in different dosages. The kit may also contain multiple formulations of different active drugs. The kit may contain formulations suitable for sequential, separate, and / or concurrent use in the treatment of urinary and / or defecation disorders, and instructions for administering the formulations sequentially, separately, and / or concurrently in the treatment of urinary and / or defecation disorders. The components of the kit may be held independently in one or more containers, such as bottles, syringes, plates, wells, blister packs, or any other type of pharmaceutical packaging. 【0142】 The packaged kit may further contain a therapeutically effective dose of an NK2R antagonist or a pharmaceutically acceptable salt thereof to terminate the majority of the effects of peptide analogs selected from i) compounds A-G, ii) peptide compounds having general formula (I) and SEQ ID NO: 11, and iii) peptide compounds having general formula (II) within approximately 10 minutes, wherein the NK2R antagonist has a duration of action of less than approximately 4 hours. The NK2R antagonist may have a duration of action of less than approximately 3 hours. The NK2R antagonist may have a duration of action of less than approximately 2 hours. 【0143】 In packaged kits, the peptide analog and NK2R antagonist can be formulated together into a single pharmaceutical product, and the onset of action of the NK2R antagonist can be longer than that of the peptide analog. The onset of action of the NK2R antagonist is longer than that of the peptide analog, and can terminate most of the effect of the peptide analog within approximately 5 minutes. The onset of action of the NK2R antagonist is longer than that of the peptide analog, and can terminate most of the effect of the NK2R agonist within approximately 10 minutes. 【0144】 In the packaged kit, the peptide analog and the NK2R antagonist can be formulated separately into two distinct pharmaceutical formulations. The NK2R antagonist is administered after the peptide analog, and the onset of action of the NK2R antagonist may occur within approximately 1 to 10 minutes. The onset of action of the NK2R antagonist may occur within approximately 1 to 5 minutes. 【0145】 example The following examples are included to provide guidance to those skilled in the art for carrying out typical embodiments of the subject matter of this disclosure. In light of this disclosure and the general level of those skilled in the art, those skilled in the art will understand that the following examples are for illustrative purposes only and that numerous changes, modifications, and alterations may be adopted without departing from the scope of the subject matter of this disclosure. 【0146】 Example 1 NKA analogues: related purity and water solubility Peptide analog compounds A-J, shown in Table 2 below, were synthesized according to standard Fmoc-mediated solid-phase techniques by Genscript USA, INC of Piscataway, NJ, and purified under typical C18 reversed-phase conditions. Sequences containing the gamma-restricted moiety were synthesized using the N-Fmoc gamma-restricted residues C=fluorenylmethyloxycarbonyl protecting group and D=OH in the structures shown below. [ka] [Table 2] 【0147】 NKA peptide analogs were purified to a purity of ≥95%. Compounds C-G (SEQ ID NOs: 3-7) and I (SEQ ID NO: 9) were considered water-soluble and showed water solubility of at least 5 mg / mL, as 5 mg / mL was the maximum test concentration. Compounds A, B, H, and J (SEQ ID NOs: 1, 2, 8, and 10) were considered water-insoluble (<0.1 mg / mL). *The aqueous solubility of the lyophilized peptide analogs was determined based on the solubility observed in both Dulbecco's phosphate-buffered saline and water. gc = Gly-(R-γ-lactam)-Leu or (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl. 【0148】 Example 2 In vitro receptor binding selectivity A radioligand competitive binding assay was performed to determine the selectivity of compounds A-J (SEQ ID NOs: 1-10) shown in Table 1 for the human NK2 receptor (hNK2R) compared to a panel of potential drug targets including the human NK1 receptor. 【0149】 method This example is designed as a multi-well high-throughput screening (HTS) binding assay for 80 potential drug targets. Each well contains target proteins isolated from or expressed within human recombinant or mammalian cell lines expressing endogenous target proteins, in most cases. Cells are incubated with high-affinity radioligands pre-validated for each potential drug target. Human neurokinin 2 receptor (hNK2R) is included as a reference target for comparison. Other targets include ubiquitous GPCRs such as hNK1R, various transporters, and ion channels. A single concentration (1 or 10 μM) of each peptide analog is added to individual wells. This concentration is chosen because it is approximately 1000-fold higher than the predicted inhibitory binding constant (Ki) of hNK2R. The efficacy of the compound is expressed as the percentage of inhibition of control binding to each target. For each target, the validated reference ligand is run in parallel and compared with historical data to confirm the sensitivity and validity of the assay. Each assay is performed in a double series, and the result is expressed as the average inhibition percentage of binding of high-affinity radioactive ligands specific to each target. 【0150】 Example 3 In vitro functional activation In vitro binding assays provide affinity and binding selectivity information, but it is crucial to determine whether the compound provides functional activation of the receptor. Therefore, a series of experiments were performed to evaluate intracellular calcium mobilization produced during in vitro activation of hNK2R and hNK1R by compounds A-J. 【0151】 method Intracellular calcium mobilization: The agonist efficacy of compounds A-J in recombinant hNK2R or hNK1R expressed in CHO cells was evaluated by measuring intracellular calcium mobilization using the calcium-sensitive dye Fluo-4AM (MOLECULAR PROBES, EUGENE, OR, USA) and a Fluorometric Imaging Plate Reader (FLIPR, MOLECULAR DEVICES, CA, USA). CHO-hNK1 and CHO-hNK2 cells were cultured in 50 μL of culture medium at densities of 10,000 and 15,000 cells per well in a 384-well plate with black walls and clear bottoms. To The cells were seeded and grown overnight at 37°C in a humidified CO2 incubator. The cells were washed with washing buffer using a Microplate Washer BIOTEK 384 instrument, leaving 20 μL of buffer per well after final aspiration. The cells were then subjected to 2 μM cytoplasmic Ca in assay buffer containing 2.5 mM probenecid and 0.02% Pluronic® F-127. 2+ Cells were incubated with indicator Fluo-4 AM at 37°C for 45–60 minutes (cell load). The cells were then washed three times in wash buffer using a Microplate Washer BIOTEK 384 instrument, leaving 30 μL of buffer in each well after the final wash. The loaded cell plates were transferred to a FLIPR Tetra instrument, and the calcium response was monitored as described below. A dual-readout FLIPR protocol was used to allow characterization of both agonist and antagonist profiles. For quality control, the signal was monitored in each compound plate by evaluating the response to reference standards (NKA and substance P). 【0152】 The pEC50 values ​​were calculated for each of the 12 concentrations of compounds A-J, based on their ability to increase intracellular calcium levels relative to an agonist reference standard (NKA or substance P). The range of final concentrations tested was 0.169 nM to 100 nM. Concentration response curves of the compounds were run in two sequences for two different cases from the same stock solution. Test solutions were prepared from a 10 mM stock solution in DMSO, and 1 μL of each solution was imprinted onto a V-bottom assay plate containing 49 μL of assay buffer. The final concentration of DMSO was 0.5% in each well. 【0153】 As described above for the 10 peptide analogs A-J, the results of intracellular calcium mobilization by in vitro activation of recombinant hNK2R or hNK1R expressed in CHO cells are shown in Table 3 below. Furthermore, Figures 3A-3C show the results of [Ca] mobilization in CHO cells expressing human NK2 or NK1 receptors by compound A, compound B, and compound G, respectively. 2+ This is an exemplary graph showing the stimulus response. In Figures 3A-3C, the data are expressed as the percentage of the maximum response to substance P for the NK1 receptor or to NKA for the NK2 receptor. Each data point is the mean ± SD from double repeated measures. 【0154】 Compounds A-G (SEQ ID NOs: 1-7) and J (SEQ ID NO: 10) elicited a concentration-dependent calcium response and were complete agonists in hNK2R (maximum response of ≥85% compared to neurokinin A). Among these, compounds A (SEQ ID NO: 1), C (SEQ ID NO: 3), and E (SEQ ID NO: 5) were the most potent in hNK2R, while compound J (SEQ ID NO: 10) was the least potent (see Table 3). Compounds H (SEQ ID NO: 8) and I (SEQ ID NO: 9) did not elicit a significant calcium response when tested at concentrations up to 10 μM. 【0155】 Compounds A (SEQ ID NO: 1), C-F (SEQ ID NOs: 3-6), and J (SEQ ID NO: 10) elicited a concentration-dependent calcium response and were complete agonists in hNK1R (maximum response ≥85% compared to substance P). Compounds B (SEQ ID NO: 2) and G (SEQ ID NO: 7) were partial agonists in hNK1R (maximum response ≤73% compared to substance P). In hNK1R, compounds C (SEQ ID NO: 3) and E (SEQ ID NO: 5) were the most potent, while compounds B (SEQ ID NO: 2) and G (SEQ ID NO: 7) were the least potent (see Table 3). Compounds H (SEQ ID NO: 8) and I (SEQ ID NO: 9) did not elicit a significant calcium response when tested at concentrations up to 10 μM. 【0156】 The EC50 ratio for hNK2R / hNK1R reveals the selectivity of various compounds for the activation of hNK2R versus hNK1R. Table 3 shows that compound A (SEQ ID NO: 1) showed remarkably high selectivity for hNK2R (>700-fold). Compounds B-G (SEQ ID NOs: 2-7) and J (SEQ ID NO: 10) were all >20-fold selective for hNK2R in this assay. Compounds H (SEQ ID NO: 8) and I (SEQ ID NO: 9) showed no selectivity for hNK2R. [Table 3] 【0157】 Example 4 In vivo pharmacodynamics in rats Individual peptide analogs selected from SEQ ID NOs: 1-10 will be administered to rats to evaluate their effects on bladder and intestinal activity and demonstrate efficacy after SC administration. 【0158】 Methods: The study was conducted in acute spinal cord transection rats under isovolumetric bladder pressure recording conditions. Acute spinal cord injury (aSCI) is an in vivo model of isolated bladder smooth muscle contraction without reinforcement from the micturition reflex (i.e., myogenic rather than neurogenic contraction). Therefore, it can be considered a model of severe bladder activity impairment. 【0159】 Animal preparation: In vivo studies will be conducted in anesthetized rats with acute spinal cord amputation (T8-10 level). Rats will be anesthetized with urethane (1.2-1.4 g / kg subcutaneous injection). Then, if necessary, isoflurane anesthesia (0.05-1.5% in O2) will be added before performing the surgical procedure. 【0160】 For aSCI, the dorsal skin and muscle are incised at the lower thoracic vertebral level, the spinal cord is carefully exposed by laminectomy, and then severed at the T8-T10 vertebral level. Gel foam is placed at the incision site, and the muscles and skin covering the vertebrae are closed with wound clips. The spinal cord is severed at least 60 minutes before starting the experimental protocol. Bladder pressure and colorectal pressure signals are amplified using LABCHART (AD Instruments, Colorado Springs, CO) and displayed on a computer. 【0161】 Bladder contractility: For isovolume recording of bladder pressure, a saline-filled polyethylene tube equipped with a flare-tip (PE50) catheter is inserted into the bladder and secured in place at the dome. This catheter is used to determine bladder capacity by slowly infusing saline (0.2-0.3 ml / min) using an infusion pump (PHD2000 INFUSION, HARVARD Apparatus, Holliston, MA). Bladder capacity is determined as the volume required to fill the bladder to the leak point pressure (i.e., the volume required to induce urination). The bladder is then emptied, the external urethra is occluded, and the bladder is filled to 70% of its capacity. This method provides a stable baseline pressure that allows for the measurement of drug-induced changes in bladder contractility. Peak pressure response, time to peak, and time to return to near baseline values ​​(within 5 mmHg of baseline, i.e., duration of action) are measured after vehicle and drug administration. 【0162】 Intestinal contractility: Colorectal pressure is measured via a latex balloon catheter (3-5 cm in length) inserted into the distal rectum / colon region (approximately 4 cm). The catheter is connected to a pressure monitoring system. The pressure in the balloon catheter is slowly increased to 15-20 mmHg by injecting saline solution (total volume 0.3-0.7 ml), and this pressure is maintained throughout the test. This allows for monitoring of drug-induced changes in colorectal pressure. Parameters measured include peak colorectal pressure response, duration above baseline activity, area under the curve, and the number of contraction events after vehicle and drug administration. 【0163】 Medication: Dissolve each compound in physiological saline solution and administer subcutaneously within a dose range of 1 to 300 μg / kg. 【0164】 References All publications, patent applications, patents, and other references referenced herein represent the level of skill of those skilled in the art to which the subject matter of this disclosure relates. All publications, patent applications, patents, and other references are incorporated herein by reference to the same extent as each individual publication, patent application, patent, and other reference is specifically and individually indicated to be incorporated by reference. JPEG0007873664000009.jpg159154 JPEG0007873664000010.jpg230152 JPEG0007873664000011.jpg29152 【0165】 Those skilled in the art will readily understand that the subject matter described herein is well suited to achieving the objectives and benefits mentioned, as well as those inherent thereto. The examples provided herein, along with the methods described herein, represent preferred embodiments and are illustrative, and do not limit the scope of the invention. Those skilled in the art will likely envision modifications and other uses therein that fall within the spirit of the invention as defined by the claims. [Sequence Listing Free Text] 【0166】 Sequence Listing 1 <223> Synthetic constructs Sequence Listing 1 <223> Xaa, ranked 1st, does not exist. Sequence Listing 1 <223> The gamma-bound moiety, (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl, is located between Val at position 5 and Met-NH2 at position 6. Sequence Listing 1 <223> The 6th position Met has an NH2 group at its carboxyl terminus. Sequence Listing 2 <223> Synthetic constructs Sequence Listing 2 <223> Xaa, ranked 1st, does not exist. Sequence Listing 2 <223> The gamma-bound moiety, (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl, is located between Val at position 5 and Nle-NH2 at position 6. Sequence Listing 2 <223> The 6th position, Xaa, is Nle, which has an NH2 group at the carboxyl terminus. Sequence Listing 3 <223> Synthetic constructs Sequence Listing 3 <223> Xaa, ranked 1st, does not exist. Sequence Listing 3 <223> The gamma-bound moiety, (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl, is located between Val at position 5 and Met-NH2 at position 6. Sequence Listing 3 <223> The Met at position 6 has an NH2 group at the carboxyl terminus. Sequence Listing 4 <223> Synthetic constructs Sequence Listing 4 <223> Xaa, ranked 1st, does not exist. Sequence Listing 4 <223> The gamma-bound moiety, (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl, is located between Val at position 5 and Nle-NH2 at position 6. Sequence Listing 4 <223> The 6th position, Xaa, is Nle, which has an NH2 group at the carboxyl terminus. Sequence Listing 5 <223> Synthetic constructs Sequence Listing 5 <223> Xaa, ranked 1st, does not exist. Sequence Listing 5 <223> The gamma-bound moiety, (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl, is located between Val at position 5 and Met-NH2 at position 6. Sequence Listing 5 <223> The Met at position 6 has an NH2 group at the carboxyl terminus. Sequence Listing 6 <223> Synthetic constructs Sequence Listing 6 <223> Xaa, ranked 1st, does not exist. Sequence Listing 6 <223> The gamma-bound moiety, (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl, is located between Val at position 5 and Nle-NH2 at position 6. Sequence Listing 6 <223> The 6th position, Xaa, is Nle, which has an NH2 group at the carboxyl terminus. Sequence Listing 7 <223> Synthetic constructs Sequence Listing 7 <223> The gamma-bound moiety, (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl, is located between Val at position 5 and Nle-NH2 at position 6. Sequence Listing 7 <223> The 6th position, Xaa, is Nle, which has an NH2 group at the carboxyl terminus. Sequence Listing 8 <223> Synthetic constructs Sequence Listing 8 <223> The fifth-ranked Xaa is βAla. Sequence Listing 8 <223> The 7th position, Xaa, is Nle, which has an NH2 group at the carboxyl terminus. Sequence Listing 9 <223> Synthetic constructs Sequence Listing 9 <223> Ranked 6th is Xaa, which is beta-alanine. Sequence Listing 9 <223> The Met at position 8 has an NH2 group at the carboxyl terminus. Sequence Listing 10 <223> Synthetic constructs Sequence Listing 10 <223> Ranked 6th is Xaa, which is beta-alanine. Sequence Listing 10 <223> The 8th position, Xaa, is Nle, which has an NH2 group at the carboxyl terminus. Sequence Listing 11 <223> Synthetic constructs Sequence Listing 11 <223> The first-place entry, Xaa, either does not exist or can be Lys. Sequence Listing 11 <223> The third-place entry, Xaa, can be Ser, Lys, or Arg. Sequence Listing 11 <223> The gamma-bound moiety, (S)-2-((R)-3-amino)-2-oxopyrrolidine-1-yl)-4-methylpantanoyl, is located between Val at position 5 and Xaa at position 6 (Group B). Sequence Listing 11 <223> Xaa, ranked 6th, is either Met-NH2 or Nle-NH2 (Group B).

Claims

[Claim 1] General formula (I): 【Chemistry 1】 (I) (In the formula, A is Xaa1-Asp-Xaa3-Phe-Val, where Xaa1 does not exist and Xaa3 is Ser. B is Met-NH ２ A peptide compound having ( ), or a pharmaceutically acceptable salt thereof (compound A, SEQ ID NO: 1). [Claim 2] The peptide compound according to claim 1, or a pharmaceutically acceptable salt thereof, having at least 20 times, at least 50 times, at least 100 times, or at least 200 times the selectivity for activating the human neurokinin 2 receptor (hNK2R) compared to the human neurokinin 1 receptor (hNK1R). [Claim 3] A pharmaceutical composition comprising the peptide compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for inducing either or both urination and / or defecation. [Claim 4] The pharmaceutical composition according to claim 3, wherein the need to induce one or both of the aforementioned urination and / or defecation is a result of one of the following: spinal cord injury, traumatic brain injury, multiple sclerosis, spina bifida, degenerative brain disease, Alzheimer's disease, Parkinson's disease, dementia, diabetes, old age, postoperative condition, and a combination thereof. [Claim 5] A pharmaceutical composition according to claim 3 or 4, comprising the peptide compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and formulated for compatibility with hydrophilic peptide compounds in aqueous solution. [Claim 6] A pharmaceutical composition according to any one of claims 3 to 5, comprising a peptide compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, formulated for administration in an isotonic aqueous solution. [Claim 7] A pharmaceutical composition according to any one of claims 3 to 6, comprising the peptide compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and formulated for compatibility with the hydrophobic peptide compound. [Claim 8] The pharmaceutical composition according to claim 7, comprising the peptide compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and formulated for compatibility with the hydrophobic peptide compound by comprising a water-soluble, biocompatible organic solvent or organic surfactant. [Claim 9] A pharmaceutical composition according to any one of claims 3 to 8, administered by parenteral, intravenous, topical, percutaneous, intramuscular, subcutaneous, nasal, inhalation, transrectal, lingual, sublingual, transmucosal, buccal, and transbuccal, or a combination thereof. [Claim 10] A pharmaceutical composition according to any one of claims 3 to 9, further comprising a pharmaceutically acceptable excipient. [Claim 11] The pharmaceutical composition according to claim 10, wherein the excipient comprises one or more antimicrobial preservatives, buffers, surfactants, or suspending agents. [Claim 12] A pharmaceutical composition according to any one of claims 3 to 11, formulated as an immediate-release dosage form. [Claim 13] The pharmaceutical composition according to claim 12, wherein the immediate-release dosage form is a rapidly disintegrating tablet or film. [Claim 14] The pharmaceutical composition according to claim 13, administered to the tongue in the form of a rapidly disintegrating tablet or film. [Claim 15] A pharmaceutical composition according to any one of claims 3 to 14, administered to humans, animals, cats, dogs, horses, cattle, pigs, or sheep. [Claim 16] The pharmaceutical composition according to any one of claims 3 to 15, which is administered approximately 1 to 5 minutes before urination and / or defecation is desired. [Claim 17] The pharmaceutical composition according to any one of claims 3 to 15, which is administered about 1 to 10 minutes before urination and / or defecation is desired. [Claim 18] A pharmaceutical composition according to any one of claims 3 to 17, which is administered multiple times a day.

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