Pharmaceutical Compositions for the Treatment of Visceral Pain

Abstract

The present disclosure provides peptides, pharmaceutical compositions, liquid pharmaceutical compositions; pharmaceutical rectal foam compositions; and methods of making and using same that can be used for the treatment of visceral pain conditions, such as bladder pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS). There are few approved therapies available for IC / BPS. Patients often begin treatment with non-pharmacological treatments (general relaxation, stress management, behavioral modification, and physical therapy techniques). Due to the marginally effective therapies available for IC / BPS, many patients utilize off-label therapies, including intravesical infusions (i.e., a mixture of medications delivered directly to the bladder through a catheter) to relieve their symptoms. There is a need for more effective and well-tolerated treatments for IC / BPS. The present invention solves this problem.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 283,731, filed November 29, 2021, and U.S. Provisional Application No. 63 / 382,612, filed November 7, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] Sequence Listing This application incorporates by reference in its entirety the Sequence Listing XML (3,810 bytes) entitled "223355-513525.xml", created on August 26, 2022 at 3:09 PM and submitted electronically herewith.

[0003] Technical Field Described and claimed are new pharmaceutical compositions, liquid pharmaceutical compositions; pharmaceutical rectal foam compositions; enemas; new processes, production techniques, new peptides, new formulations, and new combinations thereof for the treatment of bladder pain associated with one or more visceral pain conditions, e.g., interstitial cystitis / bladder pain syndrome (IC / BPS). [Background technology]

[0004] background Abdominal visceral pain conditions include, for example, bladder pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS), which affects more than 20% of the world's population; abdominal pain; bladder hypersensitivity; colonic pain; extraintestinal chronic pelvic pain; endometriosis; pain from excessive menstrual cramps; pain during intercourse; radiation proctopathy; pain associated with vaginal irritation; allodynia; and hypersensitivity of bladder afferents in the absence of bladder pathology. See Grundy et al., Visceral Pain. Annu Rev Physiol. 2019 Feb 10;81:261-284. However, despite its prevalence, visceral pain remains poorly understood.

[0005] Interstitial cystitis / bladder pain syndrome (IC / BPS) is a chronic condition that typically involves bladder pain accompanied by urinary urgency, increased frequency, and / or nocturia. IC / BPS is often misdiagnosed as a urinary tract infection, and antibiotics are generally ineffective. It is estimated that 3-7% of women and 3-4% of men meet the definition of IC / BPS. There may be several contributing factors to the cause of IC / BPS, and it is not known whether IC / BPS is a primary disorder or a secondary result of another disorder. See Hanno et al., Diagnosis and treatment of interstitial cystitis / bladder pain syndrome: AUA guideline amendment. Urol. 2015 May;193(5):1545-53.

[0006] There is no diagnostic test for IC / BPS, and diagnosis is generally based on urinary symptoms of urgency and frequency accompanied by bladder-related pain. Diagnosis is generally withheld until other conditions that may be causing these symptoms have been ruled out.

[0007] There are few approved therapies available for IC / BPS. Patients often begin treatment with non-pharmacological measures (general relaxation, stress management, behavioral modification, and physical therapy techniques). Due to the limited effectiveness of therapies available for IC / BPS, many patients utilize off-label therapies, including intravesical infusions (i.e., a cocktail of medications delivered directly to the bladder through a catheter), to relieve their symptoms. There is a need for more effective, well-tolerated treatments for IC / BPS.

[0008] A 13-amino acid guanylate cyclase C (GC-C) agonist synthetic peptide is under development for the treatment of bladder pain associated with IC / BPS, and potentially other abdominal visceral pain conditions.

[0009] Guanylate cyclase C (GC-C) is primarily expressed on the luminal surface of the small and large intestine. Upon stimulation of the GC-C receptor, extracellular cyclic guanosine monophosphate (cGMP) is secreted across the basolateral membrane of colonic epithelial cells in the submucosa by the multidrug resistance proteins MRP4 and MRP5, reducing the activity of afferent nerve fibers located in the colon wall and resulting in a reduction of visceral pain. This ultimately produces an analgesic effect in other abdominopelvic organs via actions mediated through common afferent pathways. See Castro et al., Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic GMP. Gastroenterology. 2013;145(6):1334-46; and Grundy et al., Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction. JCI Insight. 2018;3(19):e121841. Experiments performed in animals show that chronic linaclotide treatment induces persistent hypersensitivity of bladder afferents in the absence of bladder pathology. See Grundy et al., Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction. JCI Insight. 2018;3(19). Hypersensitivity of bladder afferents resembles symptoms observed in patients with IC / BPS. Afferent nerves are known to have peripheral terminals in both the colon and bladder, and the axons of colonic and bladder neurons travel through the same splanchnic and pelvic nerves. These sensory afferents have cell bodies located within the dorsal root ganglia (DRG) in the thoracic (TL) and lumbosacral (LS) regions, as well as central projections in the dorsal horn of the corresponding regions of the spinal cord. See Grundy et al., Cross-organ sensitization between the colon and bladder: to pee or not to pee? Am J Physiol Gastrointest Liver Physiol. 2018;314:G301-G8. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Grundy et al., Visceral Pain. Annu Rev Physiol. 2019 Feb 10;81:261-284 [Non-patent document 2] Hanno et al., Diagnosis and treatment of interstitial cystitis / bladder pain syndrome: AUA guideline amendment. Urol. 2015 May;193(5):1545-53 [Non-patent document 3] Castro et al., Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic GMP. Gastroenterology. 2013;145(6):1334-46 [Non-patent document 4] Grundy et al., Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction. JCI Insight. 2018;3(19):e121841 [Non-patent document 5] Grundy et al., Cross-organ sensitization between the colon and bladder: to pee or not to pee? Am J Physiol Gastrointest Liver Physiol. 2018;314:G301-G8 Summary of the Invention [Problem to be solved by the invention]

[0011] Thus, there is a need for new pharmaceutical compositions and methods for treating and / or reducing symptoms associated with visceral pain conditions, such as IC / BPS. [Means for solving the problem]

[0012] overview The present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide has the formula (I): [ka] where Cth is cystathionine; cysteines at positions 1 and 6 (Cys1 and Cys6), and cysteines at positions 5 and 13 (Cys5 and Cys6) 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in ) connected by a thioether bond; pharmaceutical compositions are described.

[0013] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide is in an amount ranging from about 0.000498% w / w to about 0.335% w / w of the total weight of the pharmaceutical composition; the excipient comprises a sodium phosphate buffer; the pharmaceutical composition has a pH ranging from about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or a rectal foam.

[0014] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount ranging from about 0.000498% w / w to about 0.0335% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH ranging from about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0015] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.000498% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0016] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00149% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0017] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00299% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0018] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00448% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0019] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00870% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0020] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00896% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0021] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00961% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0022] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0124% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0023] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0261% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0024] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0288% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0025] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.301% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0026] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.335% w / w of the total weight of the pharmaceutical composition; the excipient comprises sodium phosphate buffer; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema or rectal foam.

[0027] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) describes a pharmaceutical composition in which the following are connected by a thioether bond:

[0028] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide is in an amount ranging from about 0.000498% to about 0.335% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w of the total weight of the composition; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0029] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount ranging from about 0.000498% to about 0.335% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w of the total weight of the composition; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0030] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.000498% of the total weight of the composition; the one or more excipients comprise: sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0031] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00149% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0032] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00299% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0033] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00448% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0034] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00870% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0035] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00896% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0036] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00961% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0037] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond); the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0124% w / w of the total weight of the composition; the one or more excipients comprise: monobasic sodium phosphate monohydrate in an amount that is about 0.116% w / w; dibasic sodium phosphate heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0038] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0261% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0039] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0288% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0040] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.301% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0041] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.335% w / w of the total weight of the composition; the one or more excipients comprise sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; sodium phosphate dibasic heptahydrate in an amount that is about 0.308% w / w; and water in an amount that is about 99.6% w / w of the total weight of the composition; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as an enema.

[0042] Additionally, the present disclosure provides a liquid pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and a plurality of excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the plurality of excipients comprises 1.165 mg / mL of monobasic sodium phosphate monohydrate; 3.095 mg / mL of dibasic sodium phosphate heptahydrate; and an amount of water that brings the total volume of the liquid pharmaceutical composition to 20 mL; the liquid pharmaceutical composition comprises an amount of peptide in the range of about 5 μg / mL to about 125 μg / mL; and the liquid composition has a pH in the range of about 6.9 to about 7.2.

[0043] Additionally, the present disclosure provides a unit dosage form comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; and the unit dosage form describes a unit dosage form containing an amount of peptide ranging from about 100 μg to about 2500 μg.

[0044] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I), wherein Cth is cystathionine, and the cysteines at positions 1 and 6 (Cys1 and Cys6), and 5 and 13 (Cys5 and Cys6) are cysteines. 13 ) are connected by disulfide bonds, and cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 a pharmaceutical composition, wherein the peptide or a pharmaceutically acceptable salt thereof is linked by a thioether bond; a liquid composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in formula (I), wherein Cth is cystathionine, and the cysteines at positions 1 and 6 (Cys1 and Cys6), and the cysteines at positions 5 and 13 (Cys5 and Cys6) are linked by a thioether bond; 13 ) are connected by disulfide bonds, and cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 or a unit dosage form comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients, wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in formula (I), wherein Cth is cystathionine and the cysteines at positions 1 and 6 (Cys1 and Cys6), and the cysteines at positions 5 and 13 (Cys5 and Cys6) are linked by a thioether bond. 13 ) are connected by disulfide bonds, and cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; a syringe; and an enema kit including an enema applicator.

[0045] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; wherein the peptide has the formula (I): [ka] where Cth is cystathionine; cysteines at positions 1 and 6 (Cys1 and Cys6), and cysteines at positions 5 and 13 (Cys5 and Cys6) 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) is connected by a thioether bond; the peptide is in an amount ranging from about 0.000498% to about 0.335% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium phosphate dibasic monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount of about 0.1% w / w; methylparaben in an amount of about 0.1% w / w; light mineral oil in an amount of about 6% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as a rectal foam.

[0046] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; wherein the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I): wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount ranging from about 0.000498% to about 0.335% w / w of the total weight of the composition; the one or more excipients are water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0047] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.000498% w / w of the total weight of the composition; the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0048] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00149% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0049] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6).13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00299% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0050] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00448% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0051] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00870% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0052] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00896% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0053] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.00961% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0054] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0124% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0055] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0261% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0056] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.0288% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; wherein the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and wherein the pharmaceutical composition is formulated as a rectal foam.

[0057] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.301% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as a rectal foam.

[0058] Additionally, the present disclosure provides a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; the peptide comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in Formula (I); wherein Cth is cystathionine; and wherein Cth is a cysteine ​​at positions 1 and 6 (Cys1 and Cys6), and a cysteine ​​at positions 5 and 13 (Cys5 and Cys6). 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) are connected by a thioether bond; the peptide has an acetylated N-terminus; the peptide is in an amount that is about 0.335% w / w of the total weight of the composition; and the one or more excipients are: water in an amount that is about 77.5495% w / w of the total weight of the composition; propylene glycol in an amount that is about 10% w / w; sodium phosphate dibasic in an amount that is about 0.1640% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1165% w / w; disodium EDTA in an amount that is about 0.05% w / w; isopropyl myristate in an amount of about 0.5% w / w; white petrolatum in an amount of about 1% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.5% w / w; cetyl alcohol in an amount of about 1% w / w; stearyl alcohol in an amount of about 1% w / w; and propylparaben in an amount of about 0.02% w / w; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; and the pharmaceutical composition is formulated as a rectal foam.

[0059] Additionally, the present disclosure provides a pharmaceutical rectal foam composition comprising a peptide or a pharmaceutically acceptable salt thereof; one or more excipients; and a propellant; wherein the peptide is a compound represented by formula (I): [ka] where Cth is cystathionine; cysteines at positions 1 and 6 (Cys1 and Cys6), and cysteines at positions 5 and 13 (Cys5 and Cys6) 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) is connected by a thioether bond; a pharmaceutical rectal foam composition is described.

[0060] Additionally, the present disclosure provides a pharmaceutical rectal foam composition comprising a peptide or a pharmaceutically acceptable salt thereof; one or more excipients; and a propellant; wherein the peptide is a compound represented by formula (I): [ka] where Cth is cystathionine; cysteines at positions 1 and 6 (Cys1 and Cys6), and cysteines at positions 5 and 13 (Cys5 and Cys6) 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in ) connected by a thioether bond; the peptide is in an amount that is about 0.0087% w / w of the total weight of the composition; and the one or more excipients are water in an amount that is about 69.8847% w / w of the total weight of the composition; propylene glycol in an amount that is about 9.0116% w / w; sodium phosphate dibasic in an amount that is about 0.1478% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1050% w / w; EDT in an amount that is about 0.0451% w / w of the total weight of the composition. disodium A; methylparaben in an amount of about 0.0901% w / w; light mineral oil in an amount of about 5.4070% w / w; isopropyl myristate in an amount of about 0.4506% w / w; white petrolatum in an amount of about 0.9012% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.2529% w / w; cetyl alcohol in an amount of about 0.9012% w / w; stearyl alcohol in an amount of about 0.9012% w / w; propylparaben in an amount of about 0.0180% w / w; and the propellant is AP35 in an amount of about 9.8837% w / w.

[0061] Additionally, the present disclosure provides a pharmaceutical rectal foam composition comprising a peptide or a pharmaceutically acceptable salt thereof; one or more excipients; and a propellant; wherein the peptide is a compound represented by formula (I): [ka] where Cth is cystathionine; cysteines at positions 1 and 6 (Cys1 and Cys6), and cysteines at positions 5 and 13 (Cys5 and Cys6) 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in ) connected by a thioether bond; the peptide is in an amount that is about 0.0260% w / w of the total weight of the composition; and the one or more excipients are water in an amount that is about 69.8587% w / w of the total weight of the composition; propylene glycol in an amount that is about 9.0116% w / w; sodium phosphate dibasic in an amount that is about 0.1478% w / w; sodium dihydrogen phosphate monohydrate in an amount that is about 0.1050% w / w; EDT in an amount that is about 0.0451% w / w of the total weight of the composition. disodium A; methylparaben in an amount of about 0.0901% w / w; light mineral oil in an amount of about 5.4070% w / w; isopropyl myristate in an amount of about 0.4506% w / w; white petrolatum in an amount of about 0.9012% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.2529% w / w; cetyl alcohol in an amount of about 0.9012% w / w; stearyl alcohol in an amount of about 0.9012% w / w; propylparaben in an amount of about 0.0180% w / w; and the propellant is AP35 in an amount of about 9.8837% w / w.

[0062] Additionally, the present disclosure provides a pharmaceutical rectal foam composition comprising a peptide or a pharmaceutically acceptable salt thereof; one or more excipients; and a propellant; wherein the peptide is a compound represented by formula (I): [ka] where Cth is cystathionine; cysteines at positions 1 and 6 (Cys1 and Cys6), and cysteines at positions 5 and 13 (Cys5 and Cys6) 13) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10 ) comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in ) connected by a thioether bond; the peptide has an N-terminus that is acetylated; the peptide is in an amount that is about 0.0087% w / w of the total weight of the composition; and the one or more excipients are water in an amount that is about 69.8847% w / w of the total weight of the composition; propylene glycol in an amount that is about 9.0116% w / w; sodium phosphate dibasic in an amount that is about 0.1478% w / w; sodium phosphate dibasic monohydrate in an amount that is about 0.1050% w / w; A pharmaceutical rectal foam composition is described comprising disodium EDTA in an amount of about 0.0901% w / w; methylparaben in an amount of about 0.0901% w / w; light mineral oil in an amount of about 5.4070% w / w; isopropyl myristate in an amount of about 0.4506% w / w; white petrolatum in an amount of about 0.9012% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.2529% w / w; cetyl alcohol in an amount of about 0.9012% w / w; stearyl alcohol in an amount of about 0.9012% w / w; propylparaben in an amount of about 0.0180% w / w; and the propellant is AP35 in an amount of about 9.8837% w / w.

[0063] Additionally, the present disclosure provides a pharmaceutical rectal foam composition comprising a peptide or a pharmaceutically acceptable salt thereof; one or more excipients; and a propellant; wherein the peptide is a compound represented by formula (I): [ka] where Cth is cystathionine; cysteines at positions 1 and 6 (Cys1 and Cys6), and cysteines at positions 5 and 13 (Cys5 and Cys6) 13 ) are connected by disulfide bonds; cystathionine at position 2 (Cth2) and cysteine ​​at position 10 (Cys 10) is connected by a thioether bond; the peptide has an N-terminus that is acetylated; the peptide is in an amount that is about 0.0260% w / w of the total weight of the composition; and the one or more excipients are water in an amount that is about 69.8587% w / w of the total weight of the composition; propylene glycol in an amount that is about 9.0116% w / w; sodium phosphate dibasic in an amount that is about 0.1478% w / w; sodium phosphate dibasic monohydrate in an amount that is about 0.1050% w / w; A pharmaceutical rectal foam composition is described comprising disodium EDTA in an amount of about 0.0901% w / w; methylparaben in an amount of about 0.0901% w / w; light mineral oil in an amount of about 5.4070% w / w; isopropyl myristate in an amount of about 0.4506% w / w; white petrolatum in an amount of about 0.9012% w / w; polyoxyl 20 cetostearyl ether in an amount of about 2.2529% w / w; cetyl alcohol in an amount of about 0.9012% w / w; stearyl alcohol in an amount of about 0.9012% w / w; propylparaben in an amount of about 0.0180% w / w; and the propellant is AP35 in an amount of about 9.8837% w / w.

[0064] Additionally, the present disclosure describes a canister containing the pharmaceutical rectal foam composition described herein.

[0065] Additionally, the present disclosure describes kits that include the pharmaceutical rectal foam compositions described herein, or canisters containing the pharmaceutical rectal foam compositions.

[0066] Additionally, the present disclosure describes a method of treating a visceral pain condition in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein; a liquid pharmaceutical composition described herein; a unit dosage form described herein; or a pharmaceutical rectal foam composition described herein. [Brief explanation of the drawings]

[0067] [Figure 1] FIG. 1 shows a flow diagram illustrating the manufacturing process for a pharmaceutical composition of the present disclosure formulated as a low-dose enema.

[0068] [Figure 2] FIG. 2 shows a flow diagram illustrating the manufacturing process for a pharmaceutical composition of the present disclosure formulated as a rectal foam.

[0069] [Figure 3] Figure 3 shows how the foam height of pharmaceutical rectal foam compositions was evaluated. Three separate actuations were performed using the apparatus shown. Visual observations of the actuated foam were made and the foam heights were averaged.

[0070] [Figure 4] Figure 4 shows an illustration of a pharmaceutical rectal foam composition, in which the liquid and vapor phases of the propellant within the canister are depicted in opposite directions.

[0071] [Figure 5] FIG. 5 shows a flow diagram of the manufacturing process for the 100 μg and 300 μg pharmaceutical rectal foam compositions.

[0072] [Figure 6] Figure 6 shows the packaging integrity for 30 μg and 3000 μg Prototype A and placebo after 1, 3, and 6 months at 5°C (left panel) and 25°C (right panel).

[0073] [Figure 7] Figure 7 shows the packaging integrity for 30 μg and 3000 μg Prototype A and placebo after 1, 3, and 6 months at 5°C (left panel) and 25°C (right panel).

[0074] [Figure 8] Figure 8 shows the results of the foam collapse study, showing foams for placebo, 30 μg / mL Prototype A, and 3000 μg / mL Prototype A at early time points.

[0075] [Figure 9] Figure 9 shows the results of the foam collapse study, showing foam for placebo, 30 μg / mL Prototype A, and 3000 μg / mL Prototype A after 15 minutes at 40°C.

[0076] [Figure 10] Figure 10 shows the results of the foam collapse study, showing foam for placebo, 30 μg / mL Prototype A, and 3000 μg / mL Prototype A after 30 minutes at 40°C.

[0077] [Figure 11] Figure 11 shows the results of the foam collapse study, showing foam for placebo, 30 μg / mL Prototype A, and 3000 μg / mL Prototype A after 45 minutes at 40°C.

[0078] [Figure 12] Figure 12 shows the results of the foam collapse study, showing foam for placebo, 30 μg / mL Prototype A, and 3000 μg / mL Prototype A after 60 minutes at 40°C.

[0079] [Figure 13] Figure 13 shows the results of the foam collapse study, showing foams for placebo, 30 μg / mL Prototype B, and 3000 μg / mL Prototype B at early time points.

[0080] [Figure 14] Figure 14 shows the results of the foam collapse study, showing foam for placebo, 30 μg / mL Prototype B, and 3000 μg / mL Prototype B after 15 minutes at 40°C.

[0081] [Figure 15]Figure 15 shows the results of the foam collapse study, showing foam for placebo, 30 μg / mL Prototype B, and 3000 μg / mL Prototype B after 30 minutes at 40°C.

[0082] [Figure 16] Figure 16 shows the results of the foam collapse study, showing foam for placebo, 30 μg / mL Prototype B, and 3000 μg / mL Prototype B after 45 minutes at 40°C.

[0083] [Figure 17] Figure 17 shows the results of a foam collapse study, showing foam for placebo, 30 μg / mL Prototype B, and 3000 μg / mL Prototype B after 60 minutes at 40°C.

[0084] [Figure 18] Figure 18 depicts a schematic of the clinical study design. The study consists of four periods: a screening period, a pre-treatment period, a 12-week treatment period, and a 2-week follow-up period.

[0085] [Figure 19] Figure 19 shows the Genitourinary Pain Index (GUPI) questionnaire for men.

[0086] [Figure 20] Figure 20 shows the Urogenital Pain Index (GUPI) questionnaire for women.

[0087] [Figure 21] FIG. 21 shows the scoring guide for the Urogenital Pain Index (GUPI) in response to the questionnaire for men and women.

[0088] [Figure 22] FIG. 22 shows the Global Response Assessment (GRA) scoring guide.

[0089] [Figure 23]FIG. 23 shows the O'Leary / Sant Interstitial Cystitis Symptom Index (ICSI) questionnaire.

[0090] [Figure 24] FIG. 24 shows the Margolis Body Map Questionnaire for pain assessment.

[0091] [Figure 25] Figure 25 shows the Hospital Anxiety and Depression Scale (HADS) questionnaire.

[0092] [Figure 26] Figure 26 shows the EuroQoL group EQ-5D questionnaire.

[0093] [Figure 27] Figure 27 shows the EuroQoL group EQ-5D health scale questionnaire. DETAILED DESCRIPTION OF THE INVENTION

[0094] Detailed Description definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Accordingly, the following terms are intended to have the following meanings:

[0095] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0096] "Excipient" refers to any pharmaceutically acceptable excipient, including, but not limited to, disintegrants, dispersion additives, lubricants, glidants, antioxidants, coating additives, diluents, surfactants, flavor additives, humectants, absorption-enhancing additives, controlled-release additives, anti-caking additives, antimicrobial agents (e.g., preservatives), colorants, desiccants, plasticizers, and dyes.

[0097] "ADL" refers to activities of daily living.

[0098] "Administering" or "administration" or "administering" means and refers to administering, providing, and / or applying any route of administration. For example, administering can refer to administration to a subject, for example, via suppository, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or via a delayed-release device, such as the implantation of a mini-osmotic pump, or a rectal foam. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). In some embodiments, parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. By "co-administered" is meant that a compound or composition described herein is administered at the same time as, immediately before, or immediately after the administration of one or more additional agents or therapies, also referred to herein as "additional agents." The peptides of the present disclosure or pharmaceutical compositions thereof can be administered alone or co-administered to a patient. Co-administration is meant to include simultaneous or sequential administration of compounds (two or more compounds or agents) individually or in combination.

[0099] "AE" refers to adverse events.

[0100] "Alignment" refers to a method of comparing two or more sequences (e.g., nucleotide, polynucleotide, amino acid, peptide, polypeptide, or protein sequences) for the purpose of determining their relationship to each other. Alignment is typically performed by a computer program that applies various algorithms, although manual alignment is also possible. Alignment programs typically iterate through potential alignments of the sequences, score the alignments using substitution tables, and use various strategies to arrive at the optimal potential alignment score.Commonly used alignment algorithms include, but are not limited to, CLUSTALW (see Thompson JD, Higgins DG, Gibson TJ, CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice, Nucleic Acids Research 22: 4673-4680, 1994); CLUSTALV (see Larkin MA, et al., CLUSTALW2, ClustalW and ClustalX version 2, Bioinformatics 23(21): 2947-2948, 2007); Jotun-Hein, Muscle et al., MUSCLE: a multiple sequence alignment method with reduced time and space complexity, BMC Bioinformatics 5: 113, 2004; Mafft, Kalign, ProbCons, and T-Coffee (See Notredame et al., T-Coffee: A novel method for multiple (See, sequence alignments, Journal of Molecular Biology 302: 205-217, 2000).Exemplary programs implementing one or more of the above algorithms include, but are not limited to, MegAlign from DNAStar (DNAStar, Inc. 3801 Regent St. Madison, Wis. 53705), MUSCLE, T-Coffee, CLUSTALX, CLUSTALV, JalView, Phylip, and Discovery Studio from Accelrys (Accelrys, Inc., 10188 Telesis Ct, Suite 100, San Diego, Calif. 92121). In some embodiments, alignment introduces "phase shifts" and / or "gaps" into one or both of the sequences being compared to maximize the similarity between the two sequences, and scoring refers to a process that quantitatively expresses the relatedness of the aligned sequences.

[0101] "ALT" refers to alanine aminotransferase.

[0102] "Ameliorating" or "remission" includes the arrest, prevention, reduction, or improvement of one or more symptoms, signs, and characteristics of the disease being treated, both temporarily and long term.

[0103] "AST" refers to aspartate aminotransferase.

[0104] "Binder" refers to any pharmaceutically acceptable binder that can be used in the practice of the present invention. Examples of pharmaceutically acceptable binders include, but are not limited to, starches (e.g., corn starch, potato starch, and pregelatinized starches (e.g., STARCH 1500® and STARCH 1500 LM®, sold by Colorcon, Ltd.) and other starches), maltodextrin, gelatin, natural and synthetic gums, such as acacia, tragacanth powder, guar gum, cellulose and its derivatives (e.g., methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose (hypromellose), ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose, microcrystalline cellulose (e.g., AVICEL®, e.g., AVICEL-PH-101®, -103®, and -105®, FMC Corporation, Marcus Hook, PA, USA), polyvinyl alcohol, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K30), and mixtures thereof.

[0105] "BUN" refers to blood urea nitrogen.

[0106] "CFB" refers to change from baseline.

[0107] "CRP" refers to c-reactive protein.

[0108] "Combination" refers to simultaneous, separate, or sequential administration. For example, in some embodiments, "combination" refers to simultaneous administration. In other embodiments, "combination" refers to separate administration. In further embodiments of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such as to eliminate the beneficial effect of the combination.

[0109] "Cth" refers to cystathionine, which has two α-aminocarboxyl groups, designated "1" and "2" in Scheme 1 below, which are capable of forming peptide bonds. [ka]

[0110] To facilitate the use of three-letter amino acid codes in describing the peptides of the present disclosure, when a cyclic peptide sequence is created by forming a peptide bond with each of the α-aminocarboxyl groups (designated "1" and "2") at non-consecutive positions in the peptide sequence to create a cyclic thioether bridge, the peptide bond formed by the α-aminocarboxyl group at "1" in Scheme 1 is designated "Cth," while the peptide bond formed by the α-aminocarboxyl group at "2" in Scheme 1 is designated "Cys." For further details, see the section entitled "Synthetic Peptides." Homocysteine ​​(Hcy) is shown above in Scheme 1. Those skilled in the art will recognize that cystathionine can be considered a combination of homocysteine ​​and cysteine, where their side chains share a sulfur atom. Thus, an alternative way of designating a cyclic peptide sequence created by forming a peptide bond with each of the α-aminocarboxyl groups of cystathionines at non-consecutive positions in the peptide sequence is by designating the peptide linkage formed by the α-aminocarboxyl group at position 1 as "Hcy" and the peptide linkage formed by the α-aminocarboxyl group at position 2 as "Cys." Additional methods for designating the peptides of the present disclosure are provided in the sections below.

[0111] "Reducing" or "reducing" or "reduced" or "reducing" or "reduced" or "reduction" or "inhibiting," or any variation of these terms, refers to lessening the size, amount, intensity, or degree of something (e.g., the amount of pain). For example, in some embodiments, administering a therapeutically effective amount of a peptide of the present disclosure or a pharmaceutical composition thereof to a patient in need thereof results in the following effect: a decrease in the amount or level of pain in a patient administered a therapeutically effective amount of a peptide of the present disclosure or a pharmaceutical composition comprising same, compared to the amount or level of pain experienced by the patient before being administered a therapeutically effective amount of a peptide of the present disclosure or a pharmaceutical composition thereof. In some embodiments, reducing or decreasing includes any measurable decrease or complete inhibition to achieve the desired result. For example, there may be about a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or greater decrease in visceral pain compared to normal. About, as used herein, means within ±10%, preferably ±5% of a given value. Thus, in some embodiments, the term "pain reduction" refers to a reduction in pain of at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 1.25%, at least about 1.5%, at least about 1.7%, or at least about 1.8%, compared to the amount of pain experienced by the patient before administering a therapeutically effective amount of a peptide of the present disclosure or a pharmaceutical composition thereof. 5%, at least about 2%, at least about 2.25%, at least about 2.5%, at least about 2.75%, at least about 3%, at least about 3.25%, at least about 3.5%, at least about 3.75%, at least about 4%, at least about 4.25%, at least about 4.5%, at least about 4.75%, at least about 5%, at least about 5.25%, at least about 5.5%, at least about 5.75%, at least about 6%, at least about 6.25%, at least about 6.5%, at least about 6.75%, at least about 7%, at least about 7.25%, at least about 7.5%, at least about 7.75%, at least about 8%, at least about 8.25%, at least about 8.5%, at least about 8.75%, at least about 9%, at least about 9.25%, at least about 9.5%, at least about 9.75%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, This refers to a reduction or decrease in the amount of pain experienced by a patient receiving a therapeutically effective amount of a peptide of the present disclosure or a pharmaceutical composition thereof of at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or greater than 100%.

[0112] A "disulfide bond" or "disulfide bridge" refers to a covalent bond between two cysteine ​​residues induced by the coupling of two thiol groups on their side chains. In some embodiments, the disulfide bond is formed through oxidative folding of two different thiol groups (-SH) present in a polypeptide.

[0113] "eCRF" refers to electronic case report form.

[0114] "eDiary" refers to an electronic diary.

[0115] "EQ-5D-5L" refers to the EuroQol 5-dimension 5-level version.

[0116] "Excipient" refers to any pharmaceutically acceptable additive, carrier, surfactant, emulsifier, thickener, preservative, solvent, disintegrant, glidant, lubricant, diluent, filler, bulking agent, binder, emollient, stiffening agent, chelating agent, stabilizer, solubilizer, dispersant, suspending agent, antioxidant, preservative, humectant, humectant, flavoring, suspending agent, pigment, coloring agent, isotonicity agent, viscosity enhancing agent, mucoadhesive agent, and / or any combination thereof that may be added to a pharmaceutical composition, preparation, and / or formulation, which may be useful to achieve desired modifications of the characteristics of the pharmaceutical composition, preparation, and / or formulation. Such modifications include, but are not limited to, physical stability, chemical stability, therapeutic efficacy, and / or any combination thereof.

[0117] "Filler" refers to any pharmaceutically acceptable filler that can be used in the practice of the present invention. Examples of pharmaceutically acceptable fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate (e.g., granules or powder), microcrystalline cellulose (e.g., Avicel PH101 or Celphere CP-305), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch (e.g., Starch 1500), pregelatinized starch, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, isomalt, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, xylitol, myo-inositol, and mixtures thereof.

[0118] "Hcy" refers to homocysteine.

[0119] "Homologous" or "homology" refers to the sequence similarity or sequence identity between two polypeptides or two nucleic acid molecules. If a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, for example, if a position in each of the two DNA molecules is occupied by adenine, the molecules are homologous at that position. The percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences, divided by the number of positions compared, multiplied by 100. Homology refers to the sequence similarity between two polypeptide molecules or two nucleic acid molecules. The homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences. For example, if 6 out of 10 positions in two sequences are matching or homologous, the two sequences are 60% homologous. As an example, the DNA sequences ATTGCC and TATGGC share 50% homology.

[0120] There may be partial homology, or complete homology, and therefore identity. "Sequence identity" refers to a measure of relatedness between two or more nucleic acid or two or more polypeptide sequences, given as a percentage relative to the total length of comparison. The identity calculation takes into account those nucleotide residues that are identical and their same relative positions within their respective longer sequences.

[0121] "IBS-C" refers to irritable bowel syndrome with constipation.

[0122] "IBS-D" refers to irritable bowel syndrome with diarrhea.

[0123] "IC" refers to interstitial cystitis.

[0124] "IC / BPS" refers to interstitial cystitis / bladder pain syndrome.

[0125] "Identity" refers to a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. The term "identity" also means the degree of sequence relatedness between two polypeptide or polynucleotide sequences, as the case may be, as determined by matches between amino acids or bases at the same positions in the compared sequences. "Identity" and "similarity" include, but are not limited to, those used in Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., Stockton Press, New York, 1991; and Carillo, H., and Lipman, D., SIAM J. Applied Math., 48:1073. (1988), the disclosures of which are incorporated herein by reference in their entireties. Furthermore, methods to determine identity and similarity are codified in publicly available computer programs.For example, in some embodiments, methods for determining identity and similarity between two sequences include, but are not limited to, the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(1): 387 (1984)), BLASTP, BLASTN, and FASTA (Altschul, S. F. et al., J. Molec. Biol. 215: 403-410 (1990)). The BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol. 215: 403-410 (1990)), the disclosures of which are incorporated herein by reference in their entireties.

[0126] "Molecular weight (MW)" refers to the mass or weight of a molecule and, for proteins, is typically measured in daltons (Da) or kilodaltons (kDa). In some embodiments, MW can be calculated using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), gel chromatography, analytical ultracentrifugation, mass spectrometry, or light scattering. In some embodiments, the SDS-PAGE method is as follows: a sample of interest is separated on a gel using a set of molecular weight standards. The sample is then run, and the gel is then treated with the desired stain, followed by destaining for approximately 2-14 hours. The next step is to determine the relative migration distance (Rf) of the standard and the protein of interest. Migration distance can be determined using the following equation: Rf = (migration distance of protein) / (migration distance of dye front). The logarithm of MW can then be determined based on the value obtained for the standard band; for example, in some embodiments, the logarithm of the molecular weight of an SDS-denatured polypeptide and its relative migration distance (Rf) are plotted on a graph. After plotting the graph, interpolation of the derived values ​​provides the molecular weight of the unknown protein band.

[0127] "One-letter code" refers to the peptide sequences listed in that one-letter code to identify the various amino acids in the primary structure of a protein: alanine = A, arginine = R, asparagine = N, aspartic acid = D, asparagine or aspartic acid = B, cysteine ​​= C, glutamic acid = E, glutamine = Q, glutamine or glutamic acid = Z, glycine = G, histidine = H, isoleucine = I, leucine = L, lysine = K, methionine = M, phenylalanine = F, proline = P, serine = S, threonine = T, tryptophan = W, tyrosine = Y, and valine = V.

[0128] "Patient" and "subject" are used interchangeably herein and refer to any animal (e.g., a mammal, e.g., a human; an experimental animal, e.g., a mouse, rat, rabbit, guinea pig, or other animal model of visceral pain; or a domestic animal, e.g., a dog, cat, or a domestic animal, e.g., a sheep, horse, cow, pig, and goat). A patient in need of treatment, according to the methods described herein, is a patient suffering from a visceral pain condition (e.g., bladder pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS); abdominal pain; bladder hyperirritability; colonic pain; extraintestinal chronic pelvic pain; endometriosis; pain from excessive menstrual pain; pain during intercourse; radiation rectal injury; pain associated with vaginal irritation; allodynia; hyperirritability of bladder afferents in the absence of bladder pathology; pain from diverticulitis; pain associated with gastrointestinal disorders; pain associated with sexually transmitted diseases). The pain may be pain associated with urinary tract infections, pain associated with irritable bowel syndrome (IBS), rectal pain, chronic perianal pain, transient rectal pain, anal pain, chronic anal fissures, post-operative anal pain, pain associated with cancer, pain associated with gastrointestinal neoplasms, general pelvic pain, testicular pain, chronic prostatitis, prostatodynia, vulvodynia, urethral syndrome, penile pain, perianal pain, and pain associated with ulcerative colitis, ulcerative proctitis, or Crohn's disease, such as those diagnosed as described herein.

[0129] "Peptide" and "protein" and "polypeptide" are used interchangeably herein.

[0130] The "peptide of the present disclosure" has the amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys 10 Tyr 11 Gly 12 Cys 13 (SEQ ID NO: 1) (wherein Cth is a cystathionine residue; Cys1 and Cys6, and Cys5 and Cys 13 are connected by disulfide bonds and Cth2 and Cys 10 refers to a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to In some embodiments, a peptide of the present disclosure having the amino acid sequence set forth in SEQ ID NO: 1 can have an acetylated N-terminus, for example, in some embodiments, a peptide of the present disclosure can be represented as follows: Ac-Cys-Cth-Glu-Leu-Cys-Cys-Asn-Val-Ala-Cys 10 -Tyr 11 -Gly 12 -Cys 13 -OH (wherein Cth is cystathionine; Cys1 and Cys6, Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 are connected by a thioether bond; Ac- indicates an acetylated N-terminus; -OH indicates an unmodified C-terminus).

[0131] In some embodiments, a peptide of the disclosure having the amino acid sequence set forth in SEQ ID NO: 1 can be represented as having a homocysteine ​​moiety at position 2 and the associated des-sulfhydryl cysteine ​​(or alanine) at position 10. For example, in some embodiments, a peptide of the disclosure can be represented as follows: Ac-Cys-Hcy-Glu-Leu-Cys-Cys-Asn-Val-Ala-Ala 10 -Tyr 11 -Gly 12 -Cys 13 -OH[cyclo 1-6, 5-13; thioether 2-10] (wherein any of the above peptides may be Cys1-Cys6, Cys5-Cys 13 , Hcy2-Ala 10 where Hcy is a homocysteine ​​residue, Ac- indicates an acetylated N-terminus, and -OH indicates an unmodified C-terminus.) The peptides of the present disclosure are discussed in more detail below.

[0132] "Pharmaceutically acceptable salts" is meant to include salts of the peptides of the present disclosure, which are prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When the peptides of the present disclosure contain a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such peptide with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Non-limiting examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the peptides of the present disclosure contain a relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such peptide with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like, as well as those derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid (see, e.g., Berge, SM, et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0133] "Pharmaceutical composition" or "pharmaceutical composition of the present disclosure" refers to a pharmaceutical composition comprising a peptide of the present disclosure and one or more excipients. For example, a pharmaceutical composition of the present disclosure refers to a pharmaceutical composition comprising an excipient and a peptide of the present disclosure, wherein the peptide has the amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys 10 Tyr 11 Gly 12 Cys 13 (SEQ ID NO: 1) (wherein Cth is cystathionine; Cys1 and Cys6, Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 are connected by a thioether bond). In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated into an enteral form; a parenteral form; or a transmucosal form. In other embodiments, the pharmaceutical compositions of the present disclosure can be formulated into a suppository form, an enema form, a feeding tube form, or a solution for intraluminal use. In still other embodiments, the pharmaceutical compositions of the present disclosure can be formulated as an enema, a rectal gel, a rectal foam, a rectal aerosol, or a suppository. In those embodiments in which the pharmaceutical composition of the present disclosure is formulated as a rectal foam, the terms "pharmaceutical composition" and "pharmaceutical rectal foam composition" are used interchangeably.

[0134] "QoL" refers to quality of life.

[0135] "SoA" refers to the Schedule of Activities.

[0136] "Subject" or "patient" are used interchangeably herein and refer to any animal (e.g., a mammal, e.g., a human) for whom diagnosis, prognosis, and / or treatment is desired. For example, in some embodiments, the subject can be a mammal, e.g., a human or non-human primate (e.g., an ape, monkey, orangutan, or chimpanzee), dog, cat, guinea pig, rabbit, rat, mouse, horse, cattle, or dairy cow. In certain embodiments, a "subject in need thereof" refers to one or more of the following: a subject who has been diagnosed with a visceral pain condition and / or who is exhibiting one or more conditions or symptoms associated with a visceral pain condition; a subject who has previously been diagnosed with or has exhibited one or more conditions associated with a visceral pain condition; or a subject who has been determined to be at risk for developing a visceral pain condition or one or more conditions associated with a visceral pain condition in the future due to genetic, lifestyle, and / or environmental factors.

[0137] A "therapeutically effective amount" or "effective amount" or "pharmaceutically effective amount" refers to a non-toxic but sufficient amount of one or more peptides described herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, to provide a desired biological result, and / or an amount sufficient to carry out a specifically stated purpose.

[0138] In some embodiments, the term "therapeutically effective amount" refers to an amount of a peptide of the present disclosure, or a pharmaceutical composition comprising same, that is effective to "treat" a disease or condition (e.g., a visceral pain condition) in a subject (e.g., a mammal such as a human), and provides some improvement or benefit to a subject having the disease or condition (e.g., a visceral pain condition). Thus, a "therapeutically effective" amount is an amount that provides some relief, alleviation, and / or reduction of at least one clinical symptom of a visceral pain condition. Clinical symptoms associated with diseases or conditions that can be treated by the methods of the present disclosure are well known. Furthermore, the therapeutic effect need not be complete or curative, as long as some benefit is provided to the subject. In some embodiments, the term "therapeutically effective" refers to an amount of a therapeutic agent that is capable of alleviating or ameliorating, whether partially or fully, one or more symptoms or conditions; reducing the extent of a condition, disorder or disease; stabilizing the condition, disorder or disease state; preventing the occurrence of a condition, disorder or disease; preventing the spread of a condition, disorder or disease; delaying or slowing the progression of a condition, disorder or disease; delaying or slowing the onset of a condition, disorder or disease; ameliorating or palliating, and relieving, a condition, disorder or disease state; limiting the symptoms of a condition, disorder or disease state; reducing the severity of, and / or any one or more symptoms associated with, a condition, disorder or disease state; or alleviating pain associated with and / or caused by a condition, disorder or disease state in a subject in need thereof.

[0139] In some embodiments, a "therapeutically effective amount" can be determined empirically and routinely for the stated purpose. Additionally, an appropriate therapeutically effective amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. The actual amount administered, as well as the rate and time course of administration, will depend on the nature and severity of the condition being treated. Prescribing treatment, e.g., determining dosage, is within the responsibility of general practitioners and other physicians.

[0140] In some embodiments, a "therapeutically effective amount" can be an amount of a peptide of the present disclosure and / or a pharmaceutical composition comprising the same that is sufficient to achieve a stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzymatic activity, increase enzymatic activity, reduce a signal transduction pathway, and / or reduce one or more symptoms of a disease or condition) compared to the absence of the peptide of the present disclosure and / or a pharmaceutical composition comprising the same. In one embodiment, an example of a "therapeutically effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom(s) of a disease, condition, or a symptom associated therewith (e.g., a visceral pain condition). In some embodiments, "reduction" of a symptom(s) (and grammatical synonyms of this phrase) refers to a decrease in the severity or frequency of the symptom, or the elimination of the symptom, either in whole or in part.

[0141] In some embodiments, a "therapeutically effective amount" may be an amount having a prophylactic effect, e.g., an amount of a peptide of the present disclosure and / or a pharmaceutical composition comprising the same, which, when administered to a subject, has the intended prophylactic effect, e.g., preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or one or more symptoms associated therewith. A complete prophylactic effect does not necessarily occur by administration of one dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations.

[0142] In some embodiments, a "therapeutically effective amount" can be an amount that results in a decrease in activity (e.g., an "activity-reducing amount"). In some embodiments, an activity-reducing amount can be an amount of a peptide of the present disclosure and / or a pharmaceutical composition comprising the same that, when administered to a subject, reduces the activity of an enzyme compared to the absence of the peptide of the present disclosure and / or a pharmaceutical composition comprising the same.

[0143] In some embodiments, a "therapeutically effective amount" can be an amount that results in increased activity (e.g., an "activity-increasing amount"). In some embodiments, an activity-decreasing amount can be an amount of a peptide of the present disclosure and / or a pharmaceutical composition comprising the same that, when administered to a subject, increases the activity of an enzyme compared to the absence of the peptide of the present disclosure and / or a pharmaceutical composition comprising the same.

[0144] "Treatment" or "treating" or "treatment of" a condition, disease, or disorder, or a symptom associated with a condition, disease, or disorder, refers to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, partial or total relief or amelioration of one or more symptoms or conditions; reduction in the severity of a condition, disorder, or disease; stabilization of a condition, disorder, or disease state; prevention of the onset of a condition, disorder, or disease; prevention of the spread of a condition, disorder, or disease; delay or slowing of the progression of a condition, disorder, or disease; delay or slowing of the onset of a condition, disorder, or disease; remission or palliative care of a condition, disorder, or disease state; limiting the symptoms of a condition, disorder, or disease state; reducing the severity of a condition, disorder, or disease state and / or any one or more symptoms associated therewith; and alleviating pain associated with and / or caused by a condition, disorder, or disease state.

[0145] "Treating" or "reducing" or "inhibiting" or "limiting," or any variation of these terms, refers to lessening the size, amount, intensity, or extent of something (e.g., the number of symptoms, the severity of symptoms, and / or the frequency of symptoms, e.g., the degree / severity of pain, and / or the frequency of pain). For example, in some embodiments, administration of a therapeutically effective amount of a peptide of the present disclosure and / or a pharmaceutical composition of the present disclosure to a subject in need thereof results in the following effects: a decrease in the frequency and / or severity of bladder pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS); a decrease in the frequency and / or severity of urinary urgency associated with IC / BPS; a decrease in the frequency and / or severity of urination frequency associated with IC / BPS; a decrease in the frequency and / or severity of nighttime urination (nocturia) associated with IC / BPS; a decrease in the frequency and / or severity of bladder burning associated with IC / BPS; a decrease in the frequency and / or severity of burning during urination associated with IC / BPS; a decrease in the frequency and / or severity of bladder pressure sensation associated with IC / BPS; a decrease in the frequency and / or severity of bladder pain associated with IC / BPS compared to the number, frequency, and / or severity of these symptoms and / or pain in the subject prior to administration of a therapeutically effective amount of a peptide of the present disclosure and / or a pharmaceutical composition of the present disclosure. a reduction in the frequency and / or severity of bladder discomfort associated with IC / BPS; a reduction in the frequency and / or severity of bladder pain associated with IC / BPS; a reduction in the frequency and / or severity of painful urination associated with IC / BPS; a reduction in the frequency and / or severity of genital pain associated with IC / BPS; a reduction in the frequency and / or severity of urogenital pain associated with IC / BPS; a reduction in the frequency and / or severity of sleep difficulties associated with IC / BPS; a reduction in the frequency and / or severity of bodily pain associated with IC / BPS; an increase in quality of life associated with IC / BPS; a reduction in the frequency and / or severity of suicidal ideation resulting from IC / BPS; a reduction in the frequency and / or severity of depression resulting from IC / BPS; a reduction in the use of pain medications used by the subject to treat IC / BPS; a reduction in the frequency and / or severity of sexual dysfunction associated with IC / BPS; a reduction in the frequency and / or severity of loss of libido associated with IC / BPS;Increased ability to engage in sexual intercourse in subjects who were previously unable to do so due to one or more symptoms associated with IC / BPS; Decreased frequency and / or severity of bladder inflammation associated with IC / BPS; Decreased frequency and / or severity of Hanna lesions (mucosal lesions or ulcers seen with or without hydrodistention of the bladder) associated with IC / BPS; Decreased frequency and / or severity of abdominal pain; Decreased frequency and / or severity of bladder hypersensitivity; Decreased frequency and / or severity of colonic pain; Decreased frequency and / or severity of extraintestinal chronic pelvic pain a reduction in the frequency and / or severity of symptoms and / or pain associated with endometriosis; a reduction in the frequency and / or severity of pain from menstrual cramps; a reduction in the frequency and / or severity of pain associated with endometriosis; a reduction in the frequency and / or severity of pain associated with sexual intercourse; a reduction in the frequency and / or severity of pain during sexual intercourse; a reduction in the frequency and / or severity of symptoms and / or pain associated with radiation proctopathy; a reduction in the frequency and / or severity of pain associated with vaginal irritation; a reduction in the frequency and / or severity of symptoms and / or pain associated with allodynia; in the absence of bladder pathology Decreased frequency and / or severity of bladder afferent hypersensitivity; Decreased frequency and / or severity of pain associated with diverticulitis; Decreased frequency and / or severity of pain associated with gastrointestinal disorders; Decreased frequency and / or severity of pain associated with sexually transmitted diseases; Decreased frequency and / or severity of pain associated with irritable bowel syndrome (IBS); Decreased frequency and / or severity of rectal pain; Decreased frequency and / or severity of chronic perianal pain; Decreased frequency and / or severity of transient rectal pain; Decreased frequency and / or severity of anal pain; Decreased frequency and / or severity of chronic anal fissures Reduced frequency and / or severity of postoperative anal pain; reduced frequency and / or severity of pain associated with cancer; reduced frequency and / or severity of pain associated with gastrointestinal neoplasms; reduced frequency and / or severity of general pelvic pain; reduced frequency and / or severity of symptoms and / or pain associated with testicular pain; reduced frequency and / or severity of chronic prostatitis; reduced frequency and / or severity of prostatodynia; reduced frequency and / or severity of vulvodynia; reduced frequency and / or severity of urethral syndrome; reduced frequency and / or severity of penile pain;A reduction in the frequency and / or severity of perianal pain; a reduction in the frequency and / or severity of pain associated with ulcerative colitis; a reduction in the frequency and / or severity of ulcerative proctitis; a reduction in the frequency and / or severity of symptoms and / or pain associated with Crohn's disease; or any combination thereof.

[0146] In some embodiments, limiting the symptoms of, reducing the severity of, or treating a visceral pain condition includes any measurable reduction or complete inhibition that achieves the desired result. For example, there may be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more reduction in the number, severity, and / or frequency of symptoms (e.g., the number, severity, and / or frequency of symptoms and / or pain associated with a visceral pain condition). As used herein, about means within ±10%, preferably ±5%, of a given value.

[0147] Thus, in some embodiments, the terms "limiting the symptoms of" or "reducing the severity of" or "treating a visceral pain condition" refer to a condition in which, when a therapeutically effective amount of a peptide and / or pharmaceutical composition of the present disclosure is administered to a subject in need thereof, the frequency and / or severity of symptoms and / or pain associated with a visceral pain condition is reduced by at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 1.25%, at least about 1.5%, at least about 1.75%, at least about 2%, at least about 2.25%, at least about 2.5%, at least about 2.75%, at least about 3%, at least about 3.25%, at least about 3.5%, at least about 3.75%, at least about 4%, at least about 4.25%, at least about 4.5%, at least about 4.75%, at least about 5%, at least about 5.25%, at least about 5.5%, at least about 5.75%, at least about 6%, at least about 6.25%, at least about 6.5%, at least about 6.75%, at least about 7%, at least about 7.25%, at least about 7.5%, at least about 7.75%, at least about 8%, at least about 8.25%, at least about 8.5%, at least about 8.75%, at least about 9%, at least about 9.25%, at least about 9.5, at least about 9.75%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48 %, at least about 49%, at least about 50%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or greater than 100% reduction or decrease in the frequency and / or severity of symptoms and / or pain associated with a visceral pain condition.

[0148] In some embodiments, "treating" can also mean extending the survival of a subject beyond that expected in the absence of treatment. "Treating" can also mean inhibiting the progression of a condition, disorder, or disease, temporarily slowing the progression of a condition, disorder, or disease, but in some instances includes permanently halting the progression of a condition, disorder, or disease. As used herein, the terms treatment, treating, or treating refer to a method of reducing the effects of one or more symptoms of a disease or condition. Thus, in some embodiments, treatment can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of a disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject compared to a control. Thus, a reduction can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percentage reduction between 10% and 100% compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete elimination of a disease, condition, or symptoms of a disease or condition. Furthermore, as used herein, references to decreasing, reducing, or inhibiting include changes of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to control levels, and such terms can include, but do not necessarily include, complete elimination.

[0149] "Thioether bond" refers to a covalent bond between the side chains of homocysteine ​​and cysteine ​​residues, in which the homocysteine ​​and cysteine ​​side chains share a sulfur atom. "Thioether bridge" refers to a bridge formed when a homocysteine ​​side chain and a cysteine ​​side chain are connected by a thioether bond, and can be represented by -CH2-CH2-S-CH2-.

[0150] As used herein, a "unit dosage form" refers to a physically discrete unit suitable as a single dosage for a subject to be treated, each unit containing a predetermined amount, optionally with respect to a pharmaceutical carrier (excipient, diluent, vehicle, or filler), calculated to produce a desired effect (e.g., a prophylactic or therapeutic effect) when administered in one or more doses. Unit dosage forms may be, for example, in ampoules and vials, which may contain a liquid composition, or a freeze-dried or lyophilized composition; a sterile liquid carrier may be added, for example, prior to in vivo administration or delivery. Individual unit dosage forms may be included in multi-dose kits or containers. The peptides of the present disclosure and pharmaceutical compositions thereof may be packaged in single or multiple unit dosage forms for ease of administration and uniformity of dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0151] "Visceral pain conditions" refers to one or more of the following: abdominal pain; bladder hypersensitivity; colonic pain; extraintestinal chronic pelvic pain; endometriosis; pain from excessive menstrual cramps; pain during sexual intercourse; radiation rectal disorders; pain associated with vaginal irritation; allodynia; hypersensitivity of bladder afferents in the absence of bladder pathology; pain from diverticulitis; pain associated with gastrointestinal disorders; pain associated with sexually transmitted diseases; pain associated with irritable bowel syndrome (IBS); rectal pain; chronic perianal pain; transient rectal pain; anal pain; chronic anal fissure; postoperative anal pain; cancer pain associated with; pain associated with gastrointestinal neoplasms; general pelvic pain; testicular pain; chronic prostatitis; prostatodynia; vulvodynia; urethral syndrome; penile pain; perianal pain; and ulcerative colitis; ulcerative proctitis; pain associated with Crohn's disease; interstitial cystitis / bladder pain syndrome (IC / BPS) and / or any pain or symptoms associated with IC / BPS, including, but not limited to: bladder pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS); urinary urgency associated with IC / BPS; Increased urinary frequency associated with IC / BPS; nighttime urination (nocturia) associated with IC / BPS; burning sensation in the bladder associated with IC / BPS; burning sensation during urination associated with IC / BPS; bladder pressure associated with IC / BPS; bladder discomfort associated with IC / BPS; bladder pain associated with IC / BPS; painful urination associated with IC / BPS; genital pain associated with IC / BPS; genital pain associated with IC / BPS; difficulty sleeping associated with IC / BPS; body pain associated with IC / BPS; IC decreased quality of life associated with IC / BPS; suicidal ideation associated with IC / BPS; depression associated with IC / BPS; increased use of pain medications to treat IC / BPS; sexual dysfunction associated with IC / BPS; loss of libido associated with IC / BPS; impotence associated with IC / BPS; bladder inflammation associated with IC / BPS; Hanna lesions (mucosal lesions or ulcers seen with or without hydrodistention of the bladder) associated with IC / BPS; or any combination thereof.

[0152] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, references to a single step, composition of matter, group of steps or group of compositions of matter should be interpreted as encompassing one and more (i.e., one or more) of that step, composition of matter, group of steps or group of compositions of matter.

[0153] The present disclosure is made without undue experimentation using, unless otherwise indicated, conventional techniques of molecular biology, microbiology, virology, recombinant DNA techniques, solid phase and liquid nucleic acid synthesis, peptide synthesis in solution, solid phase peptide synthesis, immunology, cell culture, and formulations. Such procedures are described, for example, in Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, New York, Second Edition (1989), Vols. I, II, and III, in their entirety; DNA Cloning: A Practical Approach, Vols. I and II (D.N. Glover, ed., 1985), IRL Press, Oxford, in its entirety; Oligonucleotide Synthesis: A Practical Approach (M.J. Gait, ed., 1984), IRL Press, Oxford, in its entirety, in particular the articles therein by Gait, pp. 1-22; Atkinson et al., pp. 35-81; Sproat et al., pp. 83-115; and Wu et al., pp. 135-151; 4. Nucleic Acid Hybridization: A Practical Approach (B.D. Hames & S.J. Higgins, eds., 1985), IRL Press, Oxford, in its entirety; Immobilized Cells and Enzymes: A Practical Approach (1986) IRL Press, Oxford, entire text; Perbal, B., A Practical Guide to Molecular Cloning (1984); Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.), entire series; JFRamalho Ortigao, “The Chemistry of Peptide Synthesis” In: Knowledge database of Access to Virtual Laboratory website (Interactiva, Germany); Sakakibara, D., Teichman, J., Lien, E. Land Fenichel, R. L. (1976). Biochem. Biophys. Res. Commun. 73 336-342; Merrifield, R. B. (1963). J. Am. Chem. Soc. 85, 2149-2154; Barany, G. and Merrifield, R. B. (1979) in The Peptides (Gross, E. and Meienhofer, 3. eds.), vol. 2, pp. 1-284, Academic Press, New York. 12. Wiinsch, E., ed. (1974) Synthese von Peptiden in Houben-Weyls Metoden der Organischen Chemie (Muler, E., ed.), vol. 15, 4th edn., Parts 1 and 2, Thieme, Stuttgart; Bodanszky, M. (1984) Principles of Peptide Synthesis, Springer-Verlag, Heidelberg; Bodanszky, M. & Bodanszky, A. (1984) The Practice of Peptide Synthesis, Springer-Verlag, Heidelberg; Bodanszky, M. (1985) Int. J. Peptide Protein Res. 25, 449-474; Handbook of Experimental Immunology, Vols. I-IV (D. M. Weir and C. C. Blackwell, eds., 1986, Blackwell Scientific Publications); and Animal Cell Culture: Practical Approach, Third Edition (John R.W. Masters, ed., 2000) (each of these references is incorporated herein by reference in its entirety).

[0154] Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers.

[0155] All patent applications, patents, and printed publications mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Also, all patent applications, patents, and printed publications cited herein are incorporated by reference in their entirety, except for any definitions, disclaimers of subject matter, or disclaimers, and except to the extent the incorporated material contradicts an express disclosure herein, in which case the language of this disclosure will control.

[0156] Peptides of the present disclosure The present disclosure contemplates peptides and pharmaceutical compositions comprising same, which are useful in treating visceral pain conditions (e.g., bladder pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS); abdominal pain; bladder hyperirritability; colonic pain; extraintestinal chronic pelvic pain; endometriosis; pain from excessive menstrual cramps; pain during intercourse; radiation rectal injury; pain associated with vaginal irritation; allodynia; hyperirritability of bladder afferents in the absence of bladder pathology, pain from diverticulitis, pain associated with gastrointestinal disorders, pain associated with sexually transmitted diseases, and the like). The compositions can be used for the treatment of pain associated with urinary tract infections, pain associated with irritable bowel syndrome (IBS), rectal pain, chronic perianal pain, transient rectal pain, anal pain, chronic anal fissures, post-operative anal pain, pain associated with cancer, pain associated with gastrointestinal neoplasms, general pelvic pain, testicular pain, chronic prostatitis, prostatodynia, vulvodynia, urethral syndrome, penile pain, perianal pain, and pain associated with ulcerative colitis, ulcerative proctitis, or Crohn's disease, such as those described herein.

[0157] In some embodiments, the peptides of the present disclosure have the formula (1): [ka] (wherein Cth is cystathionine) and a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to the amino acid sequence set forth in

[0158] Cystathionine has two α-aminocarboxyl groups, designated "1" and "2" in Scheme 1, as shown below, which are capable of forming peptide bonds. [ka]

[0159] However, to facilitate the use of the three-letter amino acid code in writing peptide sequences, when a cyclic peptide sequence is created by forming a peptide bond with each of the α-aminocarboxyl groups at non-consecutive positions in the peptide sequence (designated "1" and "2") to create a cyclic thioether bridge, the peptide bond formed by the α-aminocarboxyl group at position 1 is designated "Cth," while the peptide bond formed by the α-aminocarboxyl group at position 2 is designated "Cys."

[0160] As used herein, "Hcy" represents homocysteine, as shown in Scheme 1. As shown in Scheme 1, cystathionine can be considered a combination of homocysteine ​​and cysteine, where their side chains share a sulfur atom. Thus, an alternative way of designating a cyclic peptide sequence created by forming a peptide bond with each of the α-aminocarboxyl groups of cystathionine at non-consecutive positions in a peptide sequence is by designating the peptide linkage formed by the α-aminocarboxyl group at position "1" in Scheme 1 as "Hcy," and the peptide linkage formed by the α-aminocarboxyl group at position "2" in Scheme 1 as "Cys."

[0161] Thus, it will be readily apparent to those skilled in the art that a peptide having the amino acid sequence shown in formula (I) contains four cysteine ​​residues at positions 1, 5, 6, and 13 (i.e., Cys1; Cys5; Cys6; and Cys 13 ), and these four cysteine ​​residues form two disulfide bonds. Similarly, as shown in formula (I) above, it will be recognized by those skilled in the art that peptide bonds are formed between each of the α-aminocarboxyl groups (designated "1" and "2" in Scheme 1) at non-consecutive positions in the peptide sequence, creating a cyclic thioether bridge.

[0162] Thus, to facilitate the use of the three-letter amino acid code in writing peptide sequences, when a cyclic peptide sequence is created by forming a peptide bond with each of the α-aminocarboxyl groups at non-consecutive positions in the peptide sequence (designated "1" and "2") to create a cyclic thioether bridge, the peptide bond formed by the α-aminocarboxyl group at position 1 is designated "Cth," while the peptide bond formed by the α-aminocarboxyl group at position 2 is designated "Cys."

[0163] Thus, one of skill in the art will recognize that when describing the peptides of the present disclosure, either as a linear representation of the peptide or using structural formulas, the cystathionine residue at position 2 can alternatively be represented as a homocysteine ​​(Hcy) moiety at position 2 (Hcy2). As one of skill in the art will also recognize, the related des-sulfhydryl cysteine ​​(Cys) at position 10 can also be represented as a homocysteine ​​(Hcy) moiety at position 10 (Hcy2). 10 ) can alternatively be substituted with alanine (Ala) at position 10 due to its chemical structure. 10 ) Additional descriptions of linear representations of peptides of the present disclosure are provided herein.

[0164] The peptides of the present disclosure can be represented using a variety of alternative chemical structures known to those of skill in the art. For example, an alternative way of showing the chemical structure for a peptide of the present disclosure is provided below in formula (II): [ka]

[0165] where the cysteine ​​residues at positions 1 and 6, and 5 and 13 are linked by disulfide bonds; the cystathionine (Cth) unit at position 2, and the residue at position 10 are linked by an internal sulfide (or thioether) bond.

[0166] A further alternative way of representing the structural formula of the peptides of the present disclosure is shown below in formula (III), where the peptides are substituted with the defined connectivity shown in formula (III) (i.e., Cys1-Cys6, Cys5-Cys 13 , Cth2-Cys 10 ), four cysteine ​​residues that form two disulfide bonds, and a cystathionine (Cth) unit (combining a homocysteine ​​and a cysteine) that provides an internal sulfide (or thioether) bond. [ka]

[0167] Despite their different styles of representing the chemical structures of the peptides of the present disclosure, Formula (I), Formula (II), and Formula (III) can all be used interchangeably.

[0168] Acetylated N-terminus In some embodiments, the peptides of the present disclosure can have an acetylated N-terminus.

[0169] The chemical structure of a peptide of the present disclosure having an acetylated N-terminus can be represented using formula (IV). [ka]

[0170] where the cysteine ​​residues at positions 1, 5, 6, and 13 are linked by disulfide bonds; the cystathionine (Cth) unit at position 2, and the residue at position 10 are linked by an internal sulfide (or thioether) bond.

[0171] An alternative way of representing the structural formula of a peptide of the present disclosure having an acetylated N-terminus is shown below in formula (V), where the peptide has the defined connectivity (i.e., Cys1-Cys6, Cys5-Cys6) shown in formula (IV). 13 , Cth2-Cys 10), containing four cysteine ​​residues that form two disulfide bonds, and a cystathionine (Cth) unit (combining homocysteine ​​and cysteine) that provides an internal sulfide (or thioether) bond. [ka]

[0172] As noted above, one of skill in the art will recognize that there are alternative ways to describe the peptides of the present disclosure having an acetylated N-terminus.

[0173] For example, in addition to the chemical structure or linear representation, a peptide of the present disclosure having an acetylated N-terminus can be depicted as follows: α -acetyl-{L-hemicystinyl 1 -[L-homocysteinyl 2 -L-Glutamyl 3 -L-Leucyl 4 -(L-hemicystinyl 5 -L-hemicystinyl 6}-L-asparagyl 7 -L-Baryl 8 -L-alanyl 9 -L-alanyl 10 ]-L-Tyrosyl 11 -Glycyl 12 -L-hemicystine 13 ) acids, cyclic bis-disulfides 1-6, 5-13, thioethers 2-10.

[0174] Linear Representation of Peptides of the Disclosure Those skilled in the art will recognize that the compound of formula (I): [ka] (wherein Cth is cystathionine) It will be appreciated that the peptide shown in can be represented linearly in a variety of ways.

[0175] As described above, cystathionine (Cth) has two α-aminocarboxyl groups, designated as positions "1" and "2" in Scheme 1 below, which form a peptide bond. [ka]

[0176] However, to facilitate the use of the three-letter amino acid code in writing peptide sequences, when a cyclic peptide sequence is created by forming a peptide bond with each of the α-aminocarboxyl groups at non-consecutive positions in the peptide sequence (designated "1" and "2") to create a cyclic thioether bridge, the peptide bond formed by the α-aminocarboxyl group at position 1 is designated "Cth," while the peptide bond formed by the α-aminocarboxyl group at position 2 is designated "Cys."

[0177] Homocysteine ​​(Hcy) is shown above in Scheme 1, and cystathionine can be considered a combination of homocysteine ​​and cysteine, where their side chains share a sulfur atom. Thus, an alternative way of designating a cyclic peptide sequence created by forming a peptide bond with each of the α-aminocarboxyl groups of cystathionine at non-consecutive positions in a peptide sequence is by designating the peptide linkage formed by the α-aminocarboxyl group at position "1" in Scheme 1 as "Hcy," and the peptide linkage formed by the α-aminocarboxyl group at position "2" in Scheme 1 as "Cys."

[0178] Thus, it will be readily apparent to those skilled in the art that a peptide having the amino acid sequence shown in formula (I) contains four cysteine ​​residues at positions 1, 5, 6, and 13 (i.e., Cys1; Cys5; Cys6; and Cys 13), and these four cysteine ​​residues form two disulfide bonds. Similarly, as shown in formula (I) above, it will be recognized by those skilled in the art that peptide bonds are formed between each of the α-aminocarboxyl groups (designated "1" and "2" in Scheme 1) at non-consecutive positions in the peptide sequence, creating a cyclic thioether bridge.

[0179] Thus, when describing the peptides of the present disclosure, either as a linear representation of the peptide or using structural formulas, those skilled in the art will recognize that the use of Cth at position 2 of formula (I) can alternatively be represented as a homocysteine ​​(Hcy) moiety (Hcy2) at position 2. Those skilled in the art will also recognize the related des-sulfhydryl cysteine ​​(Cys) at position 10 of formula (I). 10 ) may alternatively be substituted with alanine (Ala) at position 10 due to its chemical structure. 10 )

[0180] A linear representation of a peptide of the present disclosure having the amino acid sequence shown in Formula (I), using the three letter amino acid code, is, for example, as follows: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys 10 Tyr 11 Gly 12 Cys 13 (SEQ ID NO: 1) (wherein Cth is a cystathionine residue; Cys1 and Cys6, and Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 are connected by a thioether bond), additional explanations of linear representations of the peptides of the present disclosure are provided herein.

[0181] For example, alternatively, in other embodiments, peptides of the present disclosure can be represented linearly using the single letter amino acid code, e.g., as follows: CXELCCNVACYGC (SEQ ID NO: 1), where X is a cystathionine (Cth) residue; the cysteines at positions 1 and 6, and 5 and 13, are connected by disulfide bonds; and the cystathionine at position 2 and the cysteine ​​at position 10 are connected by a thioether bond.

[0182] Thus, the peptides of the present disclosure can be represented linearly using the following three-letter or one-letter amino acid codes, all of which are used interchangeably:

[0183] Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys 10 Tyr 11 Gly 12 Cys 13 (wherein Cth is cystathionine; Cys1 and Cys6, Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 are connected by a thioether bond);

[0184] Cys1Hcy2Glu3Leu4Cys5Cys6Asn7Val8Ala9Ala 10 Tyr 11 Gly 12 Cys 13 (wherein Hcy is homocysteine; Cys1 and Cys6, Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 are connected by a thioether bond);

[0185] CXELCCNVACYGC (wherein X is cystathionine; residues at positions 1 and 6, and 5 and 13 are connected by disulfide bonds; residues at positions 2 and 10 are connected by a thioether bond); and

[0186] CXELCCNVACYGC (where X is homocysteine; residues at positions 1 and 6, and 5 and 13 are connected by disulfide bonds; residues at positions 2 and 10 are connected by a thioether bond).

[0187] Additionally, in some embodiments, any of the above-described linear representations of peptides of the disclosure can be written to indicate an N-terminal acetyl group (i.e., "Ac-") and / or an unmodified C-terminus (e.g., "-COOH" or "-OH"). Thus, in some embodiments, peptides of the disclosure having an acetylated N-terminus and an unmodified C-terminus can be linearly represented using the following three-letter or one-letter amino acid codes, all of which are used interchangeably:

[0188] Ac- Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys 10 Tyr 11 Gly 12 Cys 13 -OH (wherein Cth is cystathionine; Cys1 and Cys6, Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 are connected by a thioether bond; Ac- indicates an acetylated N-terminus; -OH indicates an unmodified C-terminus);

[0189] Ac- Cys1Hcy2Glu3Leu4Cys5Cys6Asn7Val8Ala9Ala 10 Tyr 11 Gly 12 Cys 13 -OH (wherein Cth is cystathionine; Cys1 and Cys6, Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 are connected by a thioether bond; Ac- indicates an acetylated N-terminus; -OH indicates an unmodified C-terminus);

[0190] Ac-CXELCCNVACYGC-OH (where X is cystathionine; residues at positions 1 and 6, and 5 and 13 are connected by disulfide bonds; residues at positions 2 and 10 are connected by a thioether bond; Ac- indicates an acetylated N-terminus; -OH indicates an unmodified C-terminus);

[0191] Ac-CXELCCNVACYGC-OH (where X is homocysteine; residues 1 and 6, and 5 and 13 are connected by disulfide bonds; residues 2 and 10 are connected by a thioether bond; Ac- indicates an acetylated N-terminus; -OH indicates an unmodified C-terminus).

[0192] In some embodiments, a peptide of the present disclosure has the amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys 10 Tyr 11 Gly 12 Cys 13 (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof (wherein Cth is cystathionine; Cys1 and Cys6, Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 is connected by a thioether bond).

[0193] In some embodiments, the peptides of the present disclosure can have an acetylated N-terminus.

[0194] Production of the peptides of the present disclosure Methods for producing proteins are well known in the art, and there are a variety of techniques available. For example, in some embodiments, proteins can be produced using recombinant methods (e.g., recombinant expression systems).

[0195] In other embodiments, the peptides of the present disclosure can be chemically synthesized.

[0196] Synthetic peptides and related methods can be performed by one of skill in the art and / or by using commercial suppliers (e.g., GenScript®; Piscataway, New Jersey). For example, in some embodiments, chemical peptide synthesis can be achieved using liquid phase peptide synthesis (LPPS) or solid phase peptide synthesis (SPPS).

[0197] In some embodiments, peptide synthesis can be achieved by using a strategy in which the coupling of the carboxyl group of a subsequent amino acid to the N-terminus of a preceding amino acid results in a nascent polypeptide chain, a process that is generally the reverse of the type of polypeptide synthesis that occurs in nature.

[0198] The synthesis of sulfur compounds has been discussed in detail in:Anderson GW and McGregor AC (1957) T-butyloxycarbonylamino acids and their use in peptide synthesis. Journal of the American Chemical Society. 79, 6180-3; Carpino LA (1957) Oxidative reactions of hydrazines. Iv. Elimination of nitrogen from 1,1-disubstituted-2-arenesulfonehydrazides1-4. Journal of the American Chemical Society. 79, 4427-31; McKay FC and Albertson NF (1957) New amine-masking groups for peptide synthesis. Journal of the American Chemical Society. 79, 4686-90; Merrifield RB (1963) Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. Journal of the American Chemical Society. 85, 2149–54; Carpino LA and Han GY (1972) 9-Fluorenylmethoxycarbonyl amino-protecting group. The Journal of Organic Chemistry. 37, 3404-9; and A Lloyd-Williams P. et al. (1997) Chemical approaches to the synthesis of peptides and proteins. Boca Raton: CRC Press.278; U.S. Patent No. 3,714,140, ​​filed March 16, 1971; U.S. Patent No. 4,411,994, filed June 8, 1978; U.S. Patent No. 7,785,832, filed January 20, 2006; U.S. Patent No. 8,314,208, filed February 10, 2006; and U.S. Patent No. 10,442,834, filed October 2, 2015; and U.S. Patent Application No. 2005 / 0165215, filed December 23, 2004, the disclosures of which are incorporated herein by reference in their entireties.

[0199] Methods for making peptides of Formulas IV can be found in US Pat. No. 10,618,938, the disclosure of which is incorporated by reference in its entirety.

[0200] pharmaceutically acceptable salts In some embodiments, pharmaceutically acceptable salts, hydrates, solvates, crystalline forms, as well as individual isomers, enantiomers, tautomers, diastereomers and prodrugs of the peptides described herein may be utilized.

[0201] In some embodiments, pharmaceutically acceptable salts of the present disclosure possess the desired pharmacological activity of the parent compound, including acid addition salts formed with inorganic acids, acid addition salts formed with organic acids, or salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an aluminum ion, or coordinated with an organic base such as ethanolamine.

[0202] In some embodiments, pharmaceutically acceptable salts include conventional toxic or non-toxic salts. For example, in some embodiments, conventional non-toxic salts include fumarates, phosphates, citrates, chlorydrates, and the like. In some embodiments, pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds by conventional chemical methods. In some embodiments, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or in a mixture of the two. In some embodiments, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is incorporated herein by reference in its entirety.

[0203] In some embodiments, the pharmaceutically acceptable salt may be one of the following: hydrochloride; sodium; sulfate; acetate; phosphate or diphosphate; chloride; potassium; maleate; calcium; citrate; mesylate; nitrate; tartrate; aluminum; or gluconate.

[0204] In some embodiments, the list of pharmaceutically acceptable acids that can be used to form salts is glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid acid);pyroglutamic acid (-L);salicylic acid;sebacic acid;stearic acid;succinic acid;sulfuric acid;tartaric acid (+L);thiocyanic acid;toluenesulfonic acid (p);undecylenic acid;1-hydroxy-2-naphthoic acid;2,2-dichloroacetic acid;2-hydroxyethanesulfonic acid;2-oxoglutaric acid;4-acetamidobenzoic acid;4-aminosalicylic acid;acetic acid;adipic acid;ascorbic acid (L);aspartic acid (L);benzenesulfonic acid; The acid may be benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; or glycerophosphate.

[0205] In some embodiments, the pharmaceutically acceptable salt can be any organic or inorganic addition salt.

[0206] In some embodiments, salts may use inorganic and organic acids as free acids. Inorganic acids may be hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc. Organic acids may be citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, malonic acid, etc.

[0207] In some embodiments, salts include alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as calcium salts and magnesium salts). For example, acid addition salts include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthalate, and 2-napsylate. , nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts and the like, of which the hydrochloride or trifluoroacetate salts may be used.

[0208] In still other embodiments, the pharmaceutically acceptable salt may be a salt with an acid such as acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, polyacrylates, or carboxyvinyl polymers.

[0209] In some embodiments, pharmaceutically acceptable salts can be prepared from either inorganic or organic bases.Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, manganese salts, etc.Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, and cyclic amines, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, etc. Preferred organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, and choline.

[0210] In some embodiments, a pharmaceutically acceptable salt refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), the disclosure of which is incorporated herein by reference in its entirety.

[0211] In some embodiments, salts of the present disclosure can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0212] An exemplary description of pharmaceutically acceptable salts is provided in P.H. Stahl and C.G. Wermuth, (editors), Handbook of Pharmaceutical Salts: Properties, Selection and Use, John Wiley & Sons, Aug. 23, (2002), the disclosure of which is incorporated herein by reference in its entirety.

[0213] Chromatographic Purity The chromatographic purity of the peptide of the present disclosure can be evaluated by carrying out HPLC under the conditions described herein.For example, in some embodiments, the area under peptide peak is measured and compared with the total area under all peaks, excluding solvent peak and any non-polypeptide-related peak (i.e., the peak associated with excipients that may be observed in placebo).

[0214] In some embodiments, a chromatographic purity value can be provided at a predetermined time point during storage under accelerated conditions (40°C / 75% RH), or after 12, 18, 24 months, or longer, during storage under room temperature conditions (25°C / 60% RH), by comparing the chromatographic purity of the peptide in the composition after storage at room temperature or accelerated conditions to the chromatographic purity of the peptide in the composition at an earlier time (e.g., when the pharmaceutical composition is released for clinical or patient use ("release date")).

[0215] For example, the chromatographic purity of the peptide in the composition is measured after storage for a specified period of time, e.g., at accelerated conditions (40°C / 75% RH), and compared to the chromatographic purity of the peptide in the composition on the day of release.

[0216] In some embodiments, the chromatographic purity of the peptide in the composition is measured after storage for a specified period of time at room temperature conditions (25°C / 60% RH) and compared to the chromatographic purity of the peptide in the composition on the day of release.

[0217] Pharmaceutical Composition As used herein, "v / v" or "% v / v" or "volume per volume" refers to the volumetric concentration of a solution ("v / v" stands for volume per volume). Here, v / v can be used when both components of the solution are liquid. For example, if 50 mL of component X is diluted with 50 mL of water, there is 50 mL of component X in a total volume of 100 mL, and therefore this can be expressed as "50% v / v of component X." Percent volume per volume (% v / v) is calculated as follows: (volume of solute (mL) / volume of solution (100 mL)); for example, % v / v = mL of solute / 100 mL of solution.

[0218] As used herein, "w / w" or "% w / w" or "weight per weight" or "% wt / wt" refers to the weight concentration of a solution, i.e., weight percent in weight ("w / w" stands for weight per weight). Here, w / w represents the number of grams (g) of a constituent in 100 g of a solution or mixture. For example, a mixture consisting of 30 g of component X and 70 g of water can be expressed as "30% w / w of component X." Weight percent per weight (% w / w) is calculated as follows: (weight (g) of solute / weight (g) of solution) x 100; or (mass (g) of solute / mass (g) of solution) x 100.

[0219] As used herein, "w / v" or "% w / v" or "weight per volume" refers to the mass concentration of a solution, i.e., weight percent per volume ("w / v" stands for weight per volume). Here, w / v represents the number of grams (g) of a constituent in 100 mL of solution. For example, if 1 g of component X is used to make a total volume of 100 mL, a "1% w / v solution of component X" is made. Weight percent per volume (% w / v) is calculated as follows: (mass of solute (g) / volume of solution (mL)) x 100.

[0220] The present disclosure contemplates combinations, mixtures, and compositions comprising, consisting essentially of, or consisting of any one or more of the peptides described herein. The preparation of pharmaceutical compositions containing the peptides of the present disclosure will be known to those skilled in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990. It will also be understood that for animal (e.g., human) administration, preparations should meet sterility, pyrogenicity, general safety, and purity standards.

[0221] The preparations may be used in combination with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances, suitable for parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration known in the art. Pharmaceutical preparations may be sterilized and, if desired, mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic buffers, colorants, flavorings, and / or aromatic substances. They may also be combined with other active agents, such as other analgesics, if desired.

[0222] In some embodiments, one or more of the peptides of the present disclosure may be administered as a pharmaceutical composition in which one or more peptides are admixed with a suitable pharmaceutically acceptable carrier, diluent, excipient, vehicle, or carrier.

[0223] In some embodiments, a pharmaceutical composition may comprise, consist essentially of, or consist of a peptide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0224] In some embodiments, the pharmaceutical compositions of the present disclosure may be administered parenterally or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. Methods of administration are described in more detail below.

[0225] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys 10 Tyr 11 Gly 12 Cys 13 (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof (wherein Cth is cystathionine; Cys1 and Cys6, Cys5 and Cys 13 are connected by disulfide bonds; Cth2 and Cys 10 is connected by a thioether bond); and one or more excipients.

[0226] excipients In some embodiments, pharmaceutical compositions of the present disclosure may comprise, consist essentially of, or consist of a peptide of the present disclosure and one or more excipients.

[0227] For example, in some embodiments, an excipient can be a pharmaceutically acceptable additive, carrier, surfactant, emulsifier, thickener, preservative, solvent, disintegrant, glidant, lubricant, diluent, filler, bulking agent, binder, emollient, hardener, chelating agent, emulsifier, stabilizer, dispersant, suspending agent, antioxidant, preservative, and / or any combination thereof that can be added to a pharmaceutical composition, preparation, and / or formulation, which can be useful to achieve desired modifications to the characteristics of the pharmaceutical composition, preparation, and / or formulation. Such modifications include, but are not limited to, physical stability, chemical stability, therapeutic efficacy, and / or any combination thereof.

[0228] In some embodiments, for example, the excipients can be independently selected from thickening agents, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhancers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifiers, preservatives, stabilizers, antioxidants, wetting agents or emulsifying agents, suspending agents, pigments, colorants, isotonicity agents, chelating agents, emulsifiers, and diagnostic agents.

[0229] In other embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, mucoadhesives, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers.

[0230] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickening agents, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffering agents, preservatives, and fillers.

[0231] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from a diluent, a binder, a lubricant, a glidant, and a disintegrant.

[0232] Carrier In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a carrier.

[0233] In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a liquid carrier vehicle.

[0234] In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a liquid carrier vehicle, where the liquid carrier vehicle is, by way of non-limiting example, purified water, propylene glycol, polyethylene glycol, ethanol, 1-propanol, 2-propanol, 1-propen-3-ol (allyl alcohol), propylene glycol, glycerol, 2-methyl-2-propanol, formamide, methylformamide, dimethylformamide, ethylformamide, diethylformamide, acetamide, methyl The solvent may be methyl acetamide, dimethyl acetamide, ethyl acetamide, diethyl acetamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethyl urea, 1,3-dimethyl-2-imidazolidinone, propylene carbonate, 1,2-butylene carbonate, 2,3-butylene carbonate, dimethyl sulfoxide, diethyl sulfoxide, hexamethylphosphoramide, pyruvic aldehyde dimethyl acetal, dimethyl isosorbide, and combinations thereof.

[0235] In some embodiments, pharmaceutical compositions of the present disclosure that include a liquid carrier may contain an amount of liquid carrier ranging from about 0.005 wt% to about 99 wt%.

[0236] surfactants and emulsifiers In some embodiments, pharmaceutical compositions comprise a peptide of the present disclosure and one or more surfactants and / or emulsifiers.

[0237] In some embodiments, pharmaceutical compositions comprise a peptide of the present disclosure and one or more surfactants and / or emulsifiers, where the one or more surfactants and / or emulsifiers may include, by non-limiting example, a mixture of cetostearyl alcohol with sorbitan esterified with polyoxyethylene fatty acids, polyoxyethylene fatty ethers, polyoxyethylene fatty acid esters, fatty acids, sulfated fatty acids, phosphorylated fatty acids, sulfosuccinates, amphoteric surfactants, nonionic poloxamers, nonionic meroxapol, petroleum derivatives, fatty amines, polysiloxane derivatives, sorbitan fatty acid esters, laureth-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, cocoamphopropionate, poloxamer 188, meroxapol 258, triethanolamine, dimethicone, polysorbate 60, sorbitan monostearate, pharmaceutically acceptable salts thereof, and combinations thereof.

[0238] In some embodiments, a pharmaceutical composition of the present disclosure comprises a peptide of the present disclosure and a non-ionic surfactant.

[0239] For example, in some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a non-ionic surfactant, where the non-ionic surfactant includes, by way of non-limiting example, phospholipids, polyoxyl 20 cetostearyl (cetomacrogol), polyoxyethylene 10 stearyl ether and other ceteareth ethers, alkyl poly(ethylene oxide), poloxamer, polysorbate, dioctyl sodium sulfosuccinate, Brij™-30 (laureth-4), Brij™-58 (ceteth-20) and Brij™-78 (steareth-20), Brij™-721 (steareth-21), Crillet-1 (polysorbate 20), Crillet-2 (polysorbate 40), Crillet-3 (polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40 Stearate), Myrj-53 (PEG-50 Stearate), Pluronic™ F77 (Poloxamer 217), Pluronic™ F87 (Poloxamer 237), Pluronic™ F98 (Poloxamer 288), Pluronic™ L62 (Poloxamer 182), Pluronic™ L64 (Poloxamer 184), Pluronic™ F68 (Poloxamer 188), Pluronic™ L81 (Poloxamer 231), Pluronic™ L92 (Poloxamer 282), Pluronic™ L101 (Poloxamer 331), Pluronic™ P103 (Poloxamer 333), Pluracare™ F 108 NF (Poloxamer 338) and Pluracare™ F 127 NF (Poloxamer 407), and combinations thereof.

[0240] In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a cationic surfactant.

[0241] For example, in some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a cationic surfactant, where the cationic surfactant can be, by way of non-limiting example, benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, other alkyltrimethylammonium salts, cetylpyridinium chloride, polyethoxylated tallow, and combinations thereof.

[0242] In some embodiments, pharmaceutical compositions of the present disclosure that include a surfactant may contain an amount of surfactant ranging from about 0.005 wt% to about 99 wt%.

[0243] Thickeners, etc. In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a viscosity enhancing agent.

[0244] In some embodiments, pharmaceutical compositions comprise a peptide of the present disclosure and a thickening agent, where the thickening agent can be one or more of the following: natural polysaccharides, semi-synthetic polymers, synthetic polymers, and combinations thereof. Natural polysaccharides include, but are not limited to, acacia, agar, alginate, carrageenan, guar, arabic, tragacanth gum, pectin, dextran, gellan, and xanthan gum.

[0245] In some embodiments, the pharmaceutical composition comprises a peptide of the present disclosure and a thickening agent, wherein the thickening agent can be one or more semi-synthetic polymers. Non-limiting examples of semi-synthetic polymers include cellulose esters, modified starch, modified cellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

[0246] In some embodiments, the pharmaceutical composition comprises a peptide of the present disclosure and a viscosity enhancer, wherein the viscosity enhancer can be one or more synthetic polymers. Examples of synthetic polymers include, but are not limited to, polyoxyalkylene, polyvinyl alcohol, polyacrylamide, polyacrylate, carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidone), polyvinyl acetate, polyethylene glycol, and poloxamer.

[0247] In some embodiments, pharmaceutical compositions comprise a peptide of the present disclosure and a thickening agent, where the thickening agent can be one or more of the following: polyoxyethylene glycol isostearate, cetyl alcohol, stearyl alcohol, polyglycol 300 isostearate, propylene glycol, collagen, gelatin, and fatty acids (e.g., lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, oleic acid, etc.).

[0248] Examples of additional thickening agents, viscosity enhancing agents, and mucoadhesive agents include, but are not limited to, gums such as xanthan gum, guar gum, locust bean gum, tragacanth gum, karaya gum, ghatti gum, choy gum, psyllium seed gum, and gum arabic; poly(carboxylic acid-containing) polymers such as poly(acrylic acid, maleic acid, itaconic acid, citraconic acid, hydroxyethyl methacrylic acid, or methacrylic acid) having strong hydrogen bonding groups, or derivatives thereof, such as salts and esters; cellulose derivatives such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, or cellulose esters or ethers, or derivatives or salts thereof; clays such as montmorillonite clays, e.g., Veegun, attapulgite clays; polysaccharides such as dextran, pectin, amylopectin, agar, mannan, or polysaccharides. Examples of suitable adhesives include galactonic acid, or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosans such as lactate or glutamate salts, or carboxymethylchitin; glycosaminoglycans such as hyaluronic acid; metal or water-soluble salts of alginic acid, such as sodium alginate or magnesium alginate; scleroglucan; adhesive substances containing bismuth oxide or aluminum oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetate, polyvinyl methyl ether, polyvinyl chloride, polyvinylidene, etc.; polycarboxylated vinyl polymers such as the polyacrylic acids mentioned above; polysiloxanes; polyethers; polyethylene oxide and polyethylene glycol; polyalkoxy and polyacrylamide, and derivatives and salts thereof.

[0249] In some embodiments, the thickening agent may be a cellulose derivative, such as methyl cellulose, ethyl cellulose, methyl ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose or a cellulose ester or ether, or a derivative or salt thereof (e.g., methyl cellulose); and a polyvinyl polymer, such as polyvinylpyrrolidone (povidone).

[0250] In some embodiments, pharmaceutical compositions of the present disclosure that include a thickening agent may contain an amount of thickening agent ranging from about 0.005 wt% to about 99 wt%.

[0251] preservatives In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and one or more preservatives.

[0252] In some embodiments, pharmaceutical compositions comprise a peptide of the present disclosure and one or more preservatives, where the one or more preservatives may include, by non-limiting example, parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben, methylparaben, butylparaben, propylparaben, monothioglycerol, phenol, phenylethyl alcohol, propylparaben, sodium benzoate, sodium propionate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid, propyl gallate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorbutanol, phenoxyethanol, cetylpyridinium chloride, phenylmercuric nitrate, thiomersal, and combinations thereof.

[0253] Examples of additional preservatives include, but are not limited to, benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®, Polyquart®, and sodium perborate tetrahydrate.

[0254] In some embodiments, the preservative is a paraben or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl-substituted 4-hydroxybenzoate, or a pharmaceutically acceptable salt or ester thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.

[0255] In some embodiments, the pharmaceutical compositions of the present disclosure may include a preservative, wherein the preservative is methylparaben or propylparaben.

[0256] In some embodiments, pharmaceutical compositions of the present disclosure that include a preservative may contain an amount of preservative ranging from about 0.005 wt% to about 99 wt%.

[0257] Buffers and pH Modifiers In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a buffering or pH adjusting agent.

[0258] In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a buffering agent or pH adjusting agent, wherein the buffering agent or pH adjusting agent can be phosphoric acid, monobasic sodium phosphate or monobasic potassium phosphate, triethanolamine (TRIS), BICINE, HEPES, Trizma, glycine, histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonate, bicarbonate, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, acetic acid, acetate, citric acid, sodium citrate anhydrous, sodium citrate dihydrate, and combinations thereof.

[0259] In some embodiments, an acid or base is added to adjust the pH. Suitable acids or bases include, by way of non-limiting example, HCl, NaOH, and KOH.

[0260] Examples of buffering agents include, but are not limited to, phosphate buffer systems (sodium dihydrogen phosphate didehydrate, disodium phosphate dodecahydrate, dibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer systems, and bisulfate buffer systems.

[0261] In some embodiments, pharmaceutical compositions of the present disclosure that include a buffering agent may contain an amount of buffering agent ranging from about 0.005 wt% to about 99 wt%.

[0262] In some embodiments, a pharmaceutical composition of the present disclosure comprises a peptide of the present disclosure and a sodium phosphate buffer.

[0263] In some embodiments, a pharmaceutical composition of the present disclosure comprises a peptide of the present disclosure and a sodium phosphate buffer, wherein the sodium phosphate buffer has a concentration of about 20 mM and a pH of about 7.0.

[0264] In some embodiments, a pharmaceutical composition of the present disclosure comprises a peptide of the present disclosure and one or more buffer salts.

[0265] In some embodiments, pharmaceutical compositions of the present disclosure comprise a peptide of the present disclosure and one or more buffer salts, wherein the one or more buffer salts are sodium phosphate monobasic monohydrate and sodium phosphate dibasic heptahydrate.

[0266] In some embodiments, the pharmaceutical composition comprises about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 1 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, 156%, 157%, 158%, and concentrations of monobasic sodium phosphate monohydrate in the range of 3%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%.

[0267] In some embodiments, the pharmaceutical compositions of the present disclosure comprise, by wt / wt of the total composition, between about 0.1% and about 99.9%; between about 1% and about 99.9%; between about 2% and about 99.9%; between about 3% and about 99.9%; between about 4% and about 99.9%; between about 5% and about 99.9%; between about 6% and about 99.9%; between about 7% and about 99.9%; between about 8% and about 99.9%; between about 9% and about 99.9%; between about 10% and about 99.9%; between about 11% and about 99.9%; between about 12% and about 99.9%; between about 13% and about 99.9%; between about 14% and about 99.9%; between about 15% and about 99.9%; between about 16% and about 99.9%; between about 17% and about 99.9%; between about 18% and about 99.9% 9.9%; Approx. 19% to 99.9%; Approx. 20% to 99.9%; Approx. 21% to 99.9%; Approx. 22% to 99.9%; Approx. 23% to 99.9%; Approx. 24% to 99.9%; Approx. 25% to 99.9%; Approx. 26% to 99.9%; Approx. 27% to 99.9%; Approx. 28% to 99.9% ;About 29% to about 99.9%;About 30% to about 99.9%;About 31% to about 99.9%;About 32% to about 99.9%;About 33% to about 99.9%;About 34% to about 99.9%;About 35% to about 99.9%;About 36% to about 99.9%;About 37% to about 99.9%;About 38% to about 99.9%;About 39% ~approx. 99.9%; approx. 40% ~ approx. 99.9%; approx. 41% ~ approx. 99.9%; approx. 42% ~ approx. 99.9%; approx. 43% ~ approx. 99.9%; approx. 44% ~ approx. 99.9%; approx. 45% ~ approx. 99.9%; approx. 46% ~ approx. 99.9%; approx. 47% ~ approx. 99.9%; approx. 48% ~ approx. 99.9%; approx. 49% ~ approx. 99 .9%; Approximately 50% to approximately 99.9%; Approximately 51% to approximately 99.9%; Approximately 52% to approximately 99.9%; Approximately 53% to approximately 99.9%; Approximately 54% to approximately 99.9%; Approximately 55% to approximately 99.9%; Approximately 56% to approximately 99.9%; Approximately 57% to approximately 99.9%; Approximately 58% to approximately 99.9%; Approximately 59% to approximately 99.9%; Approximately 60% to 99.9%; Approximately 61% to 99.9%; Approximately 62% to 99.9%; Approximately 63% to 99.9%; Approximately 64% to 99.9%; Approximately 65% ​​to 99.9%; Approximately 66% to 99.9%; Approximately 67% to 99.9%; Approximately 68% to 99.9%; Approximately 69% to 99.9%; Approximately 70% ~approximately 99.9%; approximately 71% to approximately 99.9%; approximately 72% to approximately 99.9%; approximately 73% to approximately 99.9%; approximately 74% to approximately 99.9%; approximately 75% to approximately 99.9%; approximately 76% to approximately 99.9%; approximately 77% to approximately 99.9%; approximately 78% to approximately 99.9%; approximately 79% to approximately 99.9%; approximately 80% to approximately 99.9%; about 81% to about 99.9%; about 82% to about 99.9%; about 83% to about 99.9%; about 84% to about 99.9%; about 85% to about 99.9%; about 86% to about 99.9%; about 87% to about 99.9%; about 88% to about 99.9%; about 89% to about 99.9%; about 90% to about 99.9%; about 91% to about 99.9%; about 92% to about 99.9%; about 93% to about 99.9%; about 94% to about 99.9%; about 95% to about 99.9%; about 96% to about 99.9%; about 97% to about 99.9%; about 98% to about 99.9%; or about 99% to about 99.9%. .

[0268] In some embodiments, the pharmaceutical compositions of the present disclosure comprise, by wt / wt of the total composition, about 0.1% to about 99%; about 0.1% to about 98%; about 0.1% to about 97%; about 0.1% to about 96%; about 0.1% to about 95%; about 0.1% to about 94%; about 0.1% to about 93%; about 0.1% to about 92%; about 0.1% to about 91%; about 0.1% to about 90%; about 0.1% to about 89%; about 0.1% to about 88%; about 0.1% to about 87%; about 0.1% to about 86%; about 0.1% to about 85%; about 0.1% to about 84%; about 0.1% to about 83%; about 0.1% to about 82%; about 0.1% to about 81 ... Approximately 80%; Approximately 0.1% to approximately 79%; Approximately 0.1% to approximately 78%; Approximately 0.1% to approximately 77%; Approximately 0.1% to approximately 76%; Approximately 0.1% to approximately 75%; Approximately 0.1% to approximately 74%; Approximately 0.1% to approximately 73%; Approximately 0.1% to approximately 72%; Approximately 0.1% to approximately 71%; Approximately 0.1% to approximately 70%; Approximately 0.1% to approximately 69 %;About 0.1% to about 68%;About 0.1% to about 67%;About 0.1% to about 66%;About 0.1% to about 65%;About 0.1% to about 64%;About 0.1% to about 63%;About 0.1% to about 62%;About 0.1% to about 61%;About 0.1% to about 60%;About 0.1% to about 59%;About 0.1% to about 58%;About 0.1% to about 57%; about 0.1% to about 56%; about 0.1% to about 55%; about 0.1% to about 54%; about 0.1% to about 53%; about 0.1% to about 52%; about 0.1% to about 51%; about 0.1% to about 50%; about 0.1% to about 49%; about 0.1% to about 48%; about 0.1% to about 47%; about 0.1 % to about 46%; about 0.1% to about 45%; about 0.1% to about 44%; about 0.1% to about 43%; about 0.1% to about 42%; about 0.1% to about 41%; about 0.1% to about 40%; about 0.1% to about 39%; about 0.1% to about 38%; about 0.1% to about 37%; about 0.1% to about 36%; about 0.1% to about 35%; Approximately 0.1% to approximately 34%; Approximately 0.1% to approximately 33%; Approximately 0.1% to approximately 32%; Approximately 0.1% to approximately 31%; Approximately 0.1% to approximately 30%; Approximately 0.1% to approximately 29%; Approximately 0.1% to approximately 28%; Approximately 0.1% to approximately 27%; Approximately 0.1% to approximately 26%; Approximately 0.1% to approximately 25%; Approximately 0.1% to approximately 24% ;About 0.1% to about 23%;About 0.1% to about 22%;About 0.1% to about 21%;About 0.1% to about 20%;About 0.1% to about 19%;About 0.1% to about 18%;About 0.1% to about 17%;About 0.1% to about 16%;About 0.1% to about 15%;About 0.1% to about 14%;About 0.1% to about 13%;About 0.The composition may contain a concentration of monobasic sodium phosphate monohydrate in the range of 1% to about 12%, about 0.1% to about 11%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, about 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, or about 0.1% to about 0.5%.

[0269] In some embodiments, the pharmaceutical compositions of the present disclosure comprise about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 10 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45% %,46%,47%,48%,49%,50%,51%,52%,53%,54%,55%,56%,57%,58%,59%,60%,61%,62%,63%,64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%, and concentrations of sodium phosphate dibasic heptahydrate in the range of 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%.

[0270] In some embodiments, the pharmaceutical compositions of the present disclosure comprise, by wt / wt of the total composition, between about 0.1% and about 99.9%; between about 1% and about 99.9%; between about 2% and about 99.9%; between about 3% and about 99.9%; between about 4% and about 99.9%; between about 5% and about 99.9%; between about 6% and about 99.9%; between about 7% and about 99.9%; between about 8% and about 99.9%; between about 9% and about 99.9%; between about 10% and about 99.9%; between about 11% and about 99.9%; between about 12% and about 99.9%; between about 13% and about 99.9%; between about 14% and about 99.9%; between about 15% and about 99.9%; between about 16% and about 99.9%; between about 17% and about 99.9%; between about 18% and about 99.9% 9.9%; Approx. 19% to 99.9%; Approx. 20% to 99.9%; Approx. 21% to 99.9%; Approx. 22% to 99.9%; Approx. 23% to 99.9%; Approx. 24% to 99.9%; Approx. 25% to 99.9%; Approx. 26% to 99.9%; Approx. 27% to 99.9%; Approx. 28% to 99.9% ;About 29% to about 99.9%;About 30% to about 99.9%;About 31% to about 99.9%;About 32% to about 99.9%;About 33% to about 99.9%;About 34% to about 99.9%;About 35% to about 99.9%;About 36% to about 99.9%;About 37% to about 99.9%;About 38% to about 99.9%;About 39% ~approx. 99.9%; approx. 40% ~ approx. 99.9%; approx. 41% ~ approx. 99.9%; approx. 42% ~ approx. 99.9%; approx. 43% ~ approx. 99.9%; approx. 44% ~ approx. 99.9%; approx. 45% ~ approx. 99.9%; approx. 46% ~ approx. 99.9%; approx. 47% ~ approx. 99.9%; approx. 48% ~ approx. 99.9%; approx. 49% ~ approx. 99 .9%; Approximately 50% to approximately 99.9%; Approximately 51% to approximately 99.9%; Approximately 52% to approximately 99.9%; Approximately 53% to approximately 99.9%; Approximately 54% to approximately 99.9%; Approximately 55% to approximately 99.9%; Approximately 56% to approximately 99.9%; Approximately 57% to approximately 99.9%; Approximately 58% to approximately 99.9%; Approximately 59% to approximately 99.9%; Approximately 60% to 99.9%; Approximately 61% to 99.9%; Approximately 62% to 99.9%; Approximately 63% to 99.9%; Approximately 64% to 99.9%; Approximately 65% ​​to 99.9%; Approximately 66% to 99.9%; Approximately 67% to 99.9%; Approximately 68% to 99.9%; Approximately 69% to 99.9%; Approximately 70% ~approximately 99.9%; approximately 71% to approximately 99.9%; approximately 72% to approximately 99.9%; approximately 73% to approximately 99.9%; approximately 74% to approximately 99.9%; approximately 75% to approximately 99.9%; approximately 76% to approximately 99.9%; approximately 77% to approximately 99.9%; approximately 78% to approximately 99.9%; approximately 79% to approximately 99.9%; approximately 80% to approximately 99.9%; about 81% to about 99.9%; about 82% to about 99.9%; about 83% to about 99.9%; about 84% to about 99.9%; about 85% to about 99.9%; about 86% to about 99.9%; about 87% to about 99.9%; about 88% to about 99.9%; about 89% to about 99.9%; about 90% to about 99.9%; about 91% to about 99.9%; about 92% to about 99.9%; about 93% to about 99.9%; about 94% to about 99.9%; about 95% to about 99.9%; about 96% to about 99.9%; about 97% to about 99.9%; about 98% to about 99.9%; or about 99% to about 99.9%. .

[0271] In some embodiments, the pharmaceutical compositions of the present disclosure comprise, by wt / wt of the total composition, about 0.1% to about 99%; about 0.1% to about 98%; about 0.1% to about 97%; about 0.1% to about 96%; about 0.1% to about 95%; about 0.1% to about 94%; about 0.1% to about 93%; about 0.1% to about 92%; about 0.1% to about 91%; about 0.1% to about 90%; about 0.1% to about 89%; about 0.1% to about 88%; about 0.1% to about 87%; about 0.1% to about 86%; about 0.1% to about 85%; about 0.1% to about 84%; about 0.1% to about 83%; about 0.1% to about 82%; about 0.1% to about 81 ... Approximately 80%; Approximately 0.1% to approximately 79%; Approximately 0.1% to approximately 78%; Approximately 0.1% to approximately 77%; Approximately 0.1% to approximately 76%; Approximately 0.1% to approximately 75%; Approximately 0.1% to approximately 74%; Approximately 0.1% to approximately 73%; Approximately 0.1% to approximately 72%; Approximately 0.1% to approximately 71%; Approximately 0.1% to approximately 70%; Approximately 0.1% to approximately 69 %;About 0.1% to about 68%;About 0.1% to about 67%;About 0.1% to about 66%;About 0.1% to about 65%;About 0.1% to about 64%;About 0.1% to about 63%;About 0.1% to about 62%;About 0.1% to about 61%;About 0.1% to about 60%;About 0.1% to about 59%;About 0.1% to about 58%;About 0.1% to about 57%; about 0.1% to about 56%; about 0.1% to about 55%; about 0.1% to about 54%; about 0.1% to about 53%; about 0.1% to about 52%; about 0.1% to about 51%; about 0.1% to about 50%; about 0.1% to about 49%; about 0.1% to about 48%; about 0.1% to about 47%; about 0.1 % to about 46%; about 0.1% to about 45%; about 0.1% to about 44%; about 0.1% to about 43%; about 0.1% to about 42%; about 0.1% to about 41%; about 0.1% to about 40%; about 0.1% to about 39%; about 0.1% to about 38%; about 0.1% to about 37%; about 0.1% to about 36%; about 0.1% to about 35%; Approximately 0.1% to approximately 34%; Approximately 0.1% to approximately 33%; Approximately 0.1% to approximately 32%; Approximately 0.1% to approximately 31%; Approximately 0.1% to approximately 30%; Approximately 0.1% to approximately 29%; Approximately 0.1% to approximately 28%; Approximately 0.1% to approximately 27%; Approximately 0.1% to approximately 26%; Approximately 0.1% to approximately 25%; Approximately 0.1% to approximately 24% ;About 0.1% to about 23%;About 0.1% to about 22%;About 0.1% to about 21%;About 0.1% to about 20%;About 0.1% to about 19%;About 0.1% to about 18%;About 0.1% to about 17%;About 0.1% to about 16%;About 0.1% to about 15%;About 0.1% to about 14%;About 0.1% to about 13%;About 0.The composition contains a concentration of dibasic sodium phosphate heptahydrate in the range of 1% to about 12%, about 0.1% to about 11%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, about 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, or about 0.1% to about 0.5%.

[0272] In some embodiments, a pharmaceutical composition of the present disclosure comprises a peptide of the present disclosure and one or more pH-modifying agents.

[0273] In some embodiments, a pharmaceutical composition of the present disclosure comprises a peptide of the present disclosure and one or more pH modifying agents, wherein the one or more pH modifying agents is sodium hydroxide or phosphoric acid.

[0274] In some embodiments, a pharmaceutical composition of the present disclosure comprises a peptide of the present disclosure and one or more pH modifying agents, wherein the one or more pH modifying agents is sodium hydroxide or phosphoric acid, and the sodium hydroxide or phosphoric acid has a concentration of about 1 N.

[0275] In some embodiments, the sodium hydroxide or phosphoric acid is in an amount necessary to adjust the pH of the pharmaceutical composition to about 6.8 to about 7.2.

[0276] solvent In some embodiments, the pharmaceutical composition comprises a peptide of the present disclosure and a solvent.

[0277] In some embodiments, the solvent can be selected from water, Ringer's solution, lactated Ringer's solution, and isotonic sodium chloride solution. Other examples of solvents include, but are not limited to, sterile fixed oils commonly used as solvents or suspending media, and various blended fixed oils, including, for example, synthetic mono- or diglycerides.

[0278] In some embodiments, the solvent can be a fatty acid, such as oleic acid, used in the preparation of injectables.

[0279] In some embodiments, the solvent can be selected from glycerol, ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol.

[0280] In some embodiments, the pharmaceutical composition comprises a peptide of the present disclosure and a solvent, wherein the solvent is water.

[0281] In some embodiments, the pharmaceutical compositions of the present disclosure comprise about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5% by weight of the total composition. ,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%,36%,37%,38%,39%,40%,41%,42%,43 %,44%,45%,46%,47%,48%,49%,50%,51%,52%,53%,54%,55%,56%,57%,58%,59%,60%,61%,62%,63%,64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,8 Including concentrations of water in the ranges of 0%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%.

[0282] In some embodiments, the pharmaceutical compositions of the present disclosure comprise, by wt / wt of the total composition, between about 0.1% and about 99.9%; between about 1% and about 99.9%; between about 2% and about 99.9%; between about 3% and about 99.9%; between about 4% and about 99.9%; between about 5% and about 99.9%; between about 6% and about 99.9%; between about 7% and about 99.9%; between about 8% and about 99.9%; between about 9% and about 99.9%; between about 10% and about 99.9%; between about 11% and about 99.9%; between about 12% and about 99.9%; between about 13% and about 99.9%; between about 14% and about 99.9%; between about 15% and about 99.9%; between about 16% and about 99.9%; between about 17% and about 99.9%; between about 18% and about 99.9% 9.9%; Approx. 19% to 99.9%; Approx. 20% to 99.9%; Approx. 21% to 99.9%; Approx. 22% to 99.9%; Approx. 23% to 99.9%; Approx. 24% to 99.9%; Approx. 25% to 99.9%; Approx. 26% to 99.9%; Approx. 27% to 99.9%; Approx. 28% to 99.9% ;About 29% to about 99.9%;About 30% to about 99.9%;About 31% to about 99.9%;About 32% to about 99.9%;About 33% to about 99.9%;About 34% to about 99.9%;About 35% to about 99.9%;About 36% to about 99.9%;About 37% to about 99.9%;About 38% to about 99.9%;About 39% ~approx. 99.9%; approx. 40% ~ approx. 99.9%; approx. 41% ~ approx. 99.9%; approx. 42% ~ approx. 99.9%; approx. 43% ~ approx. 99.9%; approx. 44% ~ approx. 99.9%; approx. 45% ~ approx. 99.9%; approx. 46% ~ approx. 99.9%; approx. 47% ~ approx. 99.9%; approx. 48% ~ approx. 99.9%; approx. 49% ~ approx. 99 .9%; Approximately 50% to approximately 99.9%; Approximately 51% to approximately 99.9%; Approximately 52% to approximately 99.9%; Approximately 53% to approximately 99.9%; Approximately 54% to approximately 99.9%; Approximately 55% to approximately 99.9%; Approximately 56% to approximately 99.9%; Approximately 57% to approximately 99.9%; Approximately 58% to approximately 99.9%; Approximately 59% to approximately 99.9%; Approximately 60% to 99.9%; Approximately 61% to 99.9%; Approximately 62% to 99.9%; Approximately 63% to 99.9%; Approximately 64% to 99.9%; Approximately 65% ​​to 99.9%; Approximately 66% to 99.9%; Approximately 67% to 99.9%; Approximately 68% to 99.9%; Approximately 69% to 99.9%; Approximately 70% ~approximately 99.9%; approximately 71% to approximately 99.9%; approximately 72% to approximately 99.9%; approximately 73% to approximately 99.9%; approximately 74% to approximately 99.9%; approximately 75% to approximately 99.9%; approximately 76% to approximately 99.9%; approximately 77% to approximately 99.9%; approximately 78% to approximately 99.9%; approximately 79% to approximately 99.9%; approximately 80% to approximately 99.9%; about 81% to about 99.9%; about 82% to about 99.9%; about 83% to about 99.9%; about 84% to about 99.9%; about 85% to about 99.9%; about 86% to about 99.9%; about 87% to about 99.9%; about 88% to about 99.9%; about 89% to about 99.9%; about 90% to about 99.9%; about 91% to about 99.9%; about 92% to about 99.9%; about 93% to about 99.9%; about 94% to about 99.9%; about 95% to about 99.9%; about 96% to about 99.9%; about 97% to about 99.9%; about 98% to about 99.9%; or about 99% to about 99.9% of water.

[0283] In some embodiments, the pharmaceutical compositions of the present disclosure comprise, by wt / wt of the total composition, about 0.1% to about 99%; about 0.1% to about 98%; about 0.1% to about 97%; about 0.1% to about 96%; about 0.1% to about 95%; about 0.1% to about 94%; about 0.1% to about 93%; about 0.1% to about 92%; about 0.1% to about 91%; about 0.1% to about 90%; about 0.1% to about 89%; about 0.1% to about 88%; about 0.1% to about 87%; about 0.1% to about 86%; about 0.1% to about 85%; about 0.1% to about 84%; about 0.1% to about 83%; about 0.1% to about 82%; about 0.1% to about 81 ... Approximately 80%; Approximately 0.1% to approximately 79%; Approximately 0.1% to approximately 78%; Approximately 0.1% to approximately 77%; Approximately 0.1% to approximately 76%; Approximately 0.1% to approximately 75%; Approximately 0.1% to approximately 74%; Approximately 0.1% to approximately 73%; Approximately 0.1% to approximately 72%; Approximately 0.1% to approximately 71%; Approximately 0.1% to approximately 70%; Approximately 0.1% to approximately 69 %;About 0.1% to about 68%;About 0.1% to about 67%;About 0.1% to about 66%;About 0.1% to about 65%;About 0.1% to about 64%;About 0.1% to about 63%;About 0.1% to about 62%;About 0.1% to about 61%;About 0.1% to about 60%;About 0.1% to about 59%;About 0.1% to about 58%;About 0.1% to about 57%; about 0.1% to about 56%; about 0.1% to about 55%; about 0.1% to about 54%; about 0.1% to about 53%; about 0.1% to about 52%; about 0.1% to about 51%; about 0.1% to about 50%; about 0.1% to about 49%; about 0.1% to about 48%; about 0.1% to about 47%; about 0.1 % to about 46%; about 0.1% to about 45%; about 0.1% to about 44%; about 0.1% to about 43%; about 0.1% to about 42%; about 0.1% to about 41%; about 0.1% to about 40%; about 0.1% to about 39%; about 0.1% to about 38%; about 0.1% to about 37%; about 0.1% to about 36%; about 0.1% to about 35%; Approximately 0.1% to approximately 34%; Approximately 0.1% to approximately 33%; Approximately 0.1% to approximately 32%; Approximately 0.1% to approximately 31%; Approximately 0.1% to approximately 30%; Approximately 0.1% to approximately 29%; Approximately 0.1% to approximately 28%; Approximately 0.1% to approximately 27%; Approximately 0.1% to approximately 26%; Approximately 0.1% to approximately 25%; Approximately 0.1% to approximately 24% ;About 0.1% to about 23%;About 0.1% to about 22%;About 0.1% to about 21%;About 0.1% to about 20%;About 0.1% to about 19%;About 0.1% to about 18%;About 0.1% to about 17%;About 0.1% to about 16%;About 0.1% to about 15%;About 0.1% to about 14%;About 0.1% to about 13%;About 0.Containing concentrations of water in the range of 1% to about 12%; about 0.1% to about 11%; about 0.1% to about 10%; about 0.1% to about 9%; about 0.1% to about 8%; about 0.1% to about 7%; about 0.1% to about 6%; about 0.1% to about 5%; about 0.1% to about 4%; about 0.1% to about 3%; about 0.1% to about 2%; about 0.1% to about 1%; or about 0.1% to about 0.5%.

[0284] Disintegrant In some embodiments, the pharmaceutical composition comprises a peptide of the present disclosure and a disintegrant.

[0285] Examples of disintegrants include, but are not limited to, carmellose calcium, low-substituted hydroxypropyl cellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, sodium carboxymethyl starch, crospovidone, polysorbate 80 (polyoxyethylene sorbitan oleate), starch, sodium starch glycolate, hydroxypropyl cellulose pregelatinized starch, clay, cellulose, alginate, gum, or cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp.) In certain embodiments, the disintegrant is crospovidone.

[0286] In some embodiments, pharmaceutical compositions of the present disclosure that include a disintegrant may contain an amount of disintegrant ranging from about 0.005 wt% to about 99 wt%.

[0287] Glidants and Lubricants In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a flux enhancer.

[0288] In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a lubricant.

[0289] In some embodiments, pharmaceutical compositions comprise a peptide of the present disclosure and a lubricant, where the lubricant can be, for example, a natural or synthetic fat or oil (e.g., tris-fatty acid glycerate, etc.).

[0290] In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a lubricant, where the lubricant can be glycerin (also called glycerine, glycerol, 1,2,3-propanetriol, and trihydroxypropane), polyethylene glycol (PEG), polypropylene glycol, polyisobutene, polyethylene oxide, behenic acid, behenyl alcohol, sorbitol, mannitol, lactose, polydimethylsiloxane, and combinations thereof.

[0291] Examples of additional glidants and lubricants (aggregation inhibitors) include, but are not limited to, talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, finely divided silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, wax, hydrogenated oil, polyethylene glycol, sodium benzoate, glycerol stearate behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant / lubricant is magnesium stearate, talc, and / or colloidal silica, such as magnesium stearate and / or talc.

[0292] In some embodiments, pharmaceutical compositions of the present disclosure that include a glidant may contain an amount of glidant ranging from about 0.005 wt% to about 99 wt%.

[0293] Diluents, Fillers, and Bulking Agents In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a diluent.

[0294] In some embodiments, the pharmaceutical composition comprises a peptide of the present disclosure and a filler.

[0295] In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a bulking agent.

[0296] Examples of diluents, also referred to as "fillers" or "bulking agents," include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate, and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).

[0297] In some embodiments, pharmaceutical compositions of the present disclosure that include a diluent may contain an amount of diluent ranging from about 0.005 wt% to about 99 wt%.

[0298] Binder In some embodiments, a pharmaceutical composition comprises a peptide of the present disclosure and a binding agent.

[0299] Examples of binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums, such as acacia tragacanth, sodium alginate, hydroxypropylmethylcellulose, hydroxypropylcellulose, celluloses including ethylcellulose, and veegum, and synthetic polymers, such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).

[0300] In some embodiments, pharmaceutical compositions of the present disclosure that include a binder may contain an amount of binder ranging from about 0.005 wt% to about 99 wt%.

[0301] Emollients In some embodiments, the pharmaceutical compositions of the present disclosure may include an emollient.

[0302] In some embodiments, pharmaceutical compositions of the present disclosure may include emollients such as lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, and mineral oil.

[0303] In some embodiments, the pharmaceutical compositions of the present disclosure may contain an emollient such as mineral oil, a mixture of mineral oil and lanolin alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, petrolatum, petrolatum and lanolin alcohol, cetyl esters wax, cholesterol, glycerin, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, lecithin, allyl caproate, althea officinalis extract, arachidyl alcohol, argobase EUC, butylene glycol dicaprylate / caprate, acacia, allantoin, carrageenan, cetyl dimethicone, cyclomethicone, diethyl succinate, dihydroabietyl behenate, dioctyl adipate, ethyl laurate, ethyl palmitate, ethyl stearate, isoamyl laurate, octanoate, PEG-75 lanolin, sorbitan laurate, walnut oil, wheat germ oil May contain ultra-refined almonds, ultra-refined sesame seeds, ultra-refined soybeans, octyl palmitate, caprylic / capric triglyceride, and glyceryl cocoate.

[0304] Examples of emollients are well known in the art. Additional examples of emollients include, but are not limited to, triglyceride esters, fatty acid esters and amides, waxes such as beeswax, spermaceti, or carnauba wax, phospholipids such as lecithin, and sterols and their fatty acid esters.

[0305] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise an emollient, wherein the emollient is white petrolatum or white wax.

[0306] In some embodiments, pharmaceutical compositions of the present disclosure that include an emollient may contain an amount of emollient ranging from about 0.005 wt% to about 99 wt%.

[0307] hardener In some embodiments, the pharmaceutical compositions of the present disclosure can include a hardening agent, e.g., an agent that can harden a formulation of the present invention by increasing the viscosity of the formulation.

[0308] In some embodiments, pharmaceutical compositions of the present disclosure may include a stiffening agent, for example, stearyl alcohol, cetostearyl alcohol, polyoxyethylene(10) stearyl ether, mono- or diglycerides, and / or cetyl alcohol.

[0309] In some embodiments, pharmaceutical compositions of the present disclosure that include a stiffening agent may contain an amount of stiffening agent ranging from about 0.005 wt% to about 99 wt%.

[0310] Chelating Agents In some embodiments, the pharmaceutical compositions of the present disclosure may include a chelating agent.

[0311] Exemplary chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates.

[0312] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise a chelating agent, wherein the chelating agent is disodium EDTA.

[0313] In some embodiments, pharmaceutical compositions of the present disclosure that include a chelating agent may contain an amount of chelating agent ranging from about 0.005 wt% to about 99 wt%.

[0314] emulsifier In some embodiments, the pharmaceutical compositions of the present disclosure may include an emulsifier.

[0315] In some embodiments, pharmaceutical compositions of the present disclosure may include an emulsifier, for example, a nonionic, anionic, cationic, amphoteric, polymeric, synthetic emulsifier, and / or mixtures thereof.

[0316] In some embodiments, the emulsifier can include a polysorbate, an alkyl sulfate, Lipowax® D, or a combination thereof. Suitable polysorbate compounds include polysorbate 20, 40, 60, 80, or a combination thereof, such as Tween® 20, 40, 60, 80, or a combination thereof.

[0317] In some embodiments, the emulsifier is selected from natural emulsifiers such as acacia, gelatin, lecithin, and cholesterol; finely dispersed solids such as colloidal clays, bentonite, veegum (magnesium aluminum silicate); and synthetic emulsifiers such as salts of fatty acids, sulfates such as sorbitan trioleate, sorbitan tristearate, sucrose distearate, propylene glycol monostearate, glycerol monostearate, propylene glycol monolaurate, sorbitan monostearate, sorbitan monolaurate, polyoxyethylene-4-lauryl ether, sodium lauryl sulfate, sulfonates such as sodium dioctyl sulfosuccinate, glyceryl esters, polyoxyethylene glycol esters and ethers, diethylene glycol monostearate, PEG distearate. 200, and sorbitan fatty acid esters, such as sorbitan monopalmitate, and their polyoxyethylene derivatives, polyoxyethylene glycol esters, such as monostearate, polysorbate 80 (ethoxylated sorbitan monooleate) (supplied by Spectrum, etc.); and combinations thereof.

[0318] In some embodiments, the pharmaceutical compositions of the present disclosure may include stearyl alcohol.

[0319] In some embodiments, the pharmaceutical compositions of the present disclosure may include an emulsifying wax.

[0320] In some embodiments, pharmaceutical compositions of the present disclosure that include an emulsifier may contain an amount of emulsifier ranging from about 0.005 wt% to about 99 wt%.

[0321] Formulation and route of administration In some embodiments, the peptides described herein or pharmaceutical compositions thereof can be formulated into various forms for delivery to a subject in need thereof by any acceptable route of administration.

[0322] Rectal administration: General In some embodiments, the peptides of the present disclosure or pharmaceutical compositions thereof are suitable for local administration, e.g., by administering the peptides of the present disclosure or pharmaceutical compositions thereof locally at a particular treatment site (e.g., the digestive tract, the gastrointestinal ("GI") tract) to provide local administration of a chemical to the area in need of treatment (e.g., the gastrointestinal (GI) tract). Examples of such compositions include, but are not limited to, compositions for rectal administration.

[0323] In some embodiments, the peptides of the present disclosure or pharmaceutical compositions thereof are suitable for local administration to the GI tract.

[0324] In some embodiments, the peptides of the present disclosure or pharmaceutical compositions thereof are suitable for local administration to one or more specific locations within the digestive or GI tract. For example, in some embodiments, at least a portion of the peptides of the present disclosure or pharmaceutical compositions thereof is present in the lower GI tract (e.g., the large intestine, e.g., the colon, e.g., the ascending colon and / or transverse colon and / or distal colon; or the small intestine).

[0325] In some embodiments, at least a portion of the peptide of the present disclosure or a pharmaceutical composition thereof is present in the ascending colon and / or the transverse colon and / or the distal colon. The method of local administration can include, but is not limited to, rectal administration.

[0326] In certain embodiments, the peptides of the present disclosure or pharmaceutical compositions thereof are suitable for local, topical administration to the digestive or GI tract, e.g., rectal administration. Rectal compositions include, but are not limited to, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).

[0327] Pharmaceutically acceptable excipients useful in pharmaceutical compositions of the present disclosure formulated for rectal administration, such as gels, creams, enemas, rectal foams, or rectal suppositories, include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, petrolatum, which is a mixture of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide. SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0328] suppositories In certain embodiments, the pharmaceutical compositions of the present disclosure may be formulated as suppositories.

[0329] In some embodiments, suppositories can be prepared by mixing a peptide of the present disclosure or a pharmaceutical composition thereof with a suitable non-irritating excipient or carrier.

[0330] For example, in some embodiments, suppositories can be prepared by mixing a peptide of the present disclosure or a pharmaceutical composition thereof with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum and releases the active compound.

[0331] In some embodiments, the suppository formulation may contain an amount of the peptide of the present disclosure or a pharmaceutically acceptable salt thereof ranging from about 0.001 wt% to about 5.00 wt%.

[0332] Enema preparations and enema kits In some embodiments, the peptides of the present disclosure or pharmaceutical compositions thereof can be formulated as enemas.

[0333] In some embodiments, the enema formulation may contain an amount of a peptide of the present disclosure or a pharmaceutically acceptable salt thereof ranging from about 0.001 wt% to about 5.00 wt%.

[0334] In some embodiments, enema formulations containing the peptides of the present disclosure or pharmaceutical compositions thereof can be provided in a "ready to use" form.

[0335] In some embodiments, enema formulations containing the peptides of the present disclosure or pharmaceutical compositions thereof are provided in one or more kits or packs.

[0336] In certain embodiments, the kit or pack includes two or more separately contained / packaged components, e.g., two components that, when mixed together, provide the desired formulation (e.g., as a suspension).

[0337] In some embodiments, the present disclosure provides a two-component system comprising a first component and a second component, wherein (i) the first component (e.g., contained in a sachet) comprises a peptide of the present disclosure (as described elsewhere herein) and, optionally, one or more pharmaceutically acceptable excipients (e.g., formulated together as a solid preparation, e.g., formulated together as a wet-granulated solid preparation), and (ii) the second component (e.g., contained in a vial or bottle) comprises one or more liquids and, optionally, one or more other pharmaceutically acceptable excipients that together form a liquid carrier. Prior to use (e.g., immediately before use), the contents of (i) and (ii) are combined to form the desired enema formulation, e.g., as a suspension. In other embodiments, each of components (i) and (ii) is provided in its own separate kit or pack.

[0338] In some embodiments, each of the one or more liquids is water, or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents.Typical such solvents include, but are not limited to, water, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol.In other embodiments, each of the one or more liquids is water.In other embodiments, each of the one or more liquids is oil, for example, natural and / or synthetic oils commonly used in pharmaceutical preparations.

[0339] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickening agents, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhancers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifiers, preservatives, stabilizers, antioxidants, wetting or emulsifying agents, suspending agents, pigments, colorants, isotonicity agents, chelating agents, emulsifiers, and diagnostic agents.

[0340] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, mucoadhesives, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers.

[0341] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickening agents, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffering agents, preservatives, and fillers.

[0342] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from a diluent, a binder, a lubricant, a glidant, and a disintegrant.

[0343] Exemplary thickening, viscosity enhancing, and mucoadhesive agents for enema formulations include, but are not limited to, gums such as xanthan gum, guar gum, locust bean gum, tragacanth gum, karaya gum, ghatti gum, choya gum, psyllium seed gum, and gum arabic; poly(carboxylic acid-containing) polymers such as poly(acrylic acid, maleic acid, itaconic acid, citraconic acid, hydroxyethyl methacrylic acid, or methacrylic acid) having strong hydrogen bonding groups, or derivatives thereof, such as salts and esters; cellulose derivatives such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, or cellulose esters or ethers, or derivatives or salts thereof; clays such as montmorillonite clays, e.g., Veegun, attapulgite clays; polysaccharides such as dextran, pectin, amylopectin, agar, mannan, or Examples of adhesives include polygalactonic acid, or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosans such as lactate or glutamate, or carboxymethylchitin; glycosaminoglycans such as hyaluronic acid; metal or water-soluble salts of alginic acid, such as sodium or magnesium alginate; scleroglucan; adhesive substances containing bismuth oxide or aluminum oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetate, polyvinyl methyl ether, polyvinyl chloride, polyvinylidene, etc.; polycarboxylated vinyl polymers such as the polyacrylic acids mentioned above; polysiloxanes; polyethers; polyethylene oxide and polyethylene glycol; polyalkoxy and polyacrylamide, and derivatives and salts thereof.In some embodiments, examples may include cellulose derivatives, such as methyl cellulose, ethyl cellulose, methyl ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose or cellulose esters or ethers, or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers, such as polyvinylpyrrolidone (povidone).

[0344] Exemplary preservatives for enema formulations include, but are not limited to, benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®, Polyquart®, and sodium perborate tetrahydrate.

[0345] In some embodiments, the preservative for the enema formulation is a paraben or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl-substituted 4-hydroxybenzoate, or a pharmaceutically acceptable salt or ester thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.

[0346] Exemplary buffering agents for enema formulations include, but are not limited to, phosphate buffer systems (sodium dihydrogen phosphate dehydrate, disodium phosphate dodecahydrate, dibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer systems, and bisulfate buffer systems.

[0347] Exemplary disintegrants for enema formulations include, but are not limited to, carmellose calcium, low-substituted hydroxypropyl cellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, sodium carboxymethyl starch, crospovidone, polysorbate 80 (polyoxyethylene sorbitan oleate), starch, sodium starch glycolate, hydroxypropyl cellulose pregelatinized starch, clay, cellulose, alginate, gum, or crosslinked polymers such as crosslinked PVP (Polyplasdone XL from GAF Chemical Corp).

[0348] Exemplary glidants and lubricants (aggregation inhibitors) for enema formulations include, but are not limited to, talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, particulate silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, wax, hydrogenated oil, polyethylene glycol, sodium benzoate, glycerol stearate behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant / lubricant is magnesium stearate, talc, and / or colloidal silica, such as magnesium stearate and / or talc.

[0349] Exemplary diluents, also referred to as "fillers" or "bulking agents," for enema formulations include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate, and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).

[0350] Exemplary binders for enema preparations include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia tragacanth, sodium alginate, celluloses including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, as well as synthetic polymers such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).

[0351] rectal gel In some embodiments, the pharmaceutical compositions described herein are formulated as rectal gels.

[0352] In some embodiments, the rectal gel is suitable for local or topical non-systemic administration of one or more peptides of the present disclosure to the rectum and / or colon.

[0353] In some embodiments, the rectal gel formulation comprises a peptide of the present disclosure dissolved or suspended in a solvent / liquid carrier vehicle.

[0354] In some embodiments, the rectal gel formulation comprises a peptide of the present disclosure and at least one thickening agent dissolved or suspended in a solvent / liquid carrier vehicle.

[0355] In certain embodiments, the rectal gel formulation may further comprise one or more of the following: a buffering agent, a preservative, and an antioxidant.

[0356] In certain embodiments, the rectal gel has a gel-like consistency but is sufficiently fluid to allow for local or topical administration through a catheter, needle, syringe, or other equivalent means of local or topical administration.

[0357] In some embodiments, the rectal gel formulation may contain an amount of the peptide of the present disclosure or a pharmaceutically acceptable salt thereof ranging from about 0.001 wt% to about 5.00 wt%.

[0358] Foaming agent In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated as a foam or mousse (e.g., a pharmaceutical rectal foam composition).

[0359] As used herein, "foam" refers to a loose dispersion of gas in a liquid in which the volume of the gas is significantly greater than that of the liquid. Foams are thus aggregates of tightly packed gas bubbles separated from each other by thin films (lamellae) of liquid. The existence and stability of foams depend on a surface layer of solute molecules. At the surface of a liquid, the molecules are in a state of dynamic equilibrium, where the net attractive force exerted by the bulk of the fluid moves the molecules away from the surface, and this movement is counterbalanced by normal diffusion back to the diluted surface layer. Equilibrium results in a surface layer that is always less dense than the bulk fluid, which creates a state of tension at the surface. Tension can be somewhat relieved by adsorption of foreign molecules either from the bulk solution or from the gas phase.

[0360] In some embodiments, the pharmaceutical compositions of the present disclosure (e.g., pharmaceutical rectal foam compositions) can be formulated as a foam, where the foam may or may not be propellant-based (i.e., substantially propellant-free or propellant-free).

[0361] In some embodiments, the pharmaceutical compositions (e.g., pharmaceutical rectal foam compositions) of the present disclosure may further comprise one or more propellants described herein.

[0362] In some embodiments, adding propellant to pharmaceutical compositions of the present disclosure produces effervescent formulations through manual ventilation.In some embodiments, adding one or more propellants to pharmaceutical compositions of the present disclosure can provide more consistent delivery of active agent.For example, adding propellant to effervescent formulations can be useful for producing metered dosage of compositions.

[0363] Various properties of pharmaceutical compositions formulated as foams (e.g., pharmaceutical rectal foam compositions) described herein can be evaluated by methods known in the art, such as one or more of bubble expansion, bubble stickiness, bubble inversion, bubble density, and bubble collapse.

[0364] In some embodiments, pharmaceutical compositions formulated as foams (e.g., pharmaceutical rectal foam compositions) expand gradually and to a large volume so as to be evenly distributed within the body over the intended area of ​​treatment.

[0365] In some embodiments, pharmaceutical compositions formulated as foams (eg, pharmaceutical rectal foam compositions) exhibit good retention ("foam stickiness").

[0366] In some embodiments, pharmaceutical compositions formulated as foams (e.g., pharmaceutical rectal foam compositions) exhibit excellent foam reversibility. Foam reversal is another measure of foam retention, e.g., cohesion and / or adhesion, of a foam formulation.

[0367] In some embodiments, pharmaceutical compositions formulated as foams (e.g., pharmaceutical rectal foam compositions) exhibit good foam density, which can be measured as the weight of foam per unit volume.

[0368] In some embodiments, pharmaceutical compositions formulated as foams (e.g., pharmaceutical rectal foam compositions) exhibit good foam collapse, which in some embodiments is a measure of how quickly and for how long the active components of a foam formulation contact the site to be treated or administered (e.g., mucosa).

[0369] Exemplary descriptions of foaming agents and their properties are set forth in US Pat. Nos. 10,092,588 and 11,103,454, the disclosures of which are incorporated herein by reference in their entireties.

[0370] In some embodiments, the pharmaceutical composition is formulated as a rectal foam (eg, a pharmaceutical rectal foam composition).

[0371] In some embodiments, rectal foams are used for rectal administration of peptides of the present disclosure and for local or non-systemic delivery of peptides of the present disclosure to the rectum and / or colon.

[0372] In some embodiments, pharmaceutical rectal foam compositions comprise a peptide of the present disclosure dissolved or suspended in a liquid carrier vehicle.

[0373] In some embodiments, pharmaceutical rectal foam compositions comprise a peptide of the present disclosure dissolved or suspended in a liquid carrier vehicle and a surfactant / emulsifier having foaming properties.

[0374] In some embodiments, pharmaceutical rectal foam compositions comprise a peptide of the present disclosure dissolved or suspended in a liquid carrier vehicle, and a surfactant / emulsifier having effervescent properties, and a propellant (e.g., a propellant gas).

[0375] In certain embodiments, the pharmaceutical rectal foam composition may include one or more of the following: suspending / solubilizing agents, thickening agents, preservatives, chelating agents, buffering agents, antioxidants, tonicity modifying agents, and / or diffusing agents.

[0376] In some embodiments, surfactants / emulsifiers include, by way of non-limiting example, nonionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof.

[0377] In some embodiments, the rectal foam formulation may contain an amount of a peptide of the present disclosure or a pharmaceutically acceptable salt thereof ranging from about 0.001 wt% to about 5.00 wt%.

[0378] In some embodiments, the pharmaceutical compositions of the present disclosure may include methylparaben.

[0379] In some embodiments, the pharmaceutical compositions of the present disclosure may include propylparaben.

[0380] In some embodiments, the pharmaceutical compositions of the present disclosure may include propylparaben in an amount that is about 0.02% w / w of the total composition.

[0381] In some embodiments, pharmaceutical compositions of the present disclosure may include methylparaben in an amount that is about 0.18% w / w of the total composition.

[0382] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise propylene glycol in an amount that is about 0.164% w / w of the total composition.

[0383] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise purified water in an amount that is about 77.5495% w / w of the total composition.

[0384] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise propylene glycol in an amount that is about 10.0000% w / w of the total composition.

[0385] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise sodium phosphate dibasic in an amount that is about 0.1640% w / w of the total composition.

[0386] In some embodiments, pharmaceutical compositions of the present disclosure may comprise sodium phosphate dibasic monohydrate in an amount that is about 0.1165% w / w of the total composition.

[0387] In some embodiments, pharmaceutical compositions of the present disclosure may include disodium EDTA in an amount that is about 0.0500% w / w of the total composition.

[0388] In some embodiments, pharmaceutical compositions of the present disclosure may include methylparaben in an amount that is about 0.1000% w / w of the total composition.

[0389] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise light mineral oil in an amount that is about 6.0000% w / w of the total composition.

[0390] In some embodiments, pharmaceutical compositions of the present disclosure may comprise isopropyl myristate in an amount that is about 0.5000% w / w of the total composition.

[0391] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise white petrolatum in an amount that is about 1.0000% w / w of the total composition.

[0392] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise polyoxyl 20 cetostearyl ether in an amount that is about 2.5000% w / w of the total composition.

[0393] In some embodiments, pharmaceutical compositions of the present disclosure may include cetyl alcohol in an amount that is about 1.0000% w / w of the total composition.

[0394] In some embodiments, pharmaceutical compositions of the present disclosure may include stearyl alcohol in an amount that is about 1.0000% w / w of the total composition.

[0395] In some embodiments, pharmaceutical compositions of the present disclosure may include propylparaben in an amount that is about 0.0200% w / w of the total composition.

[0396] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise an amount of emulsifying wax that is about 1.4% w / w of the total composition.

[0397] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise polyoxyethylene(10) cetostearyl ether in an amount that is about 1.4% w / w of the total composition.

[0398] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise purified water in an amount that is about 77.5495% w / w of the total composition.

[0399] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise propylene glycol in an amount that is about 10.0000% w / w of the total composition.

[0400] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise sodium phosphate dibasic in an amount that is about 0.1640% w / w of the total composition.

[0401] In some embodiments, pharmaceutical compositions of the present disclosure may comprise sodium phosphate dibasic monohydrate in an amount that is about 0.1165% w / w of the total composition.

[0402] In some embodiments, pharmaceutical compositions of the present disclosure may include disodium EDTA in an amount that is about 0.0500% w / w of the total composition.

[0403] In some embodiments, pharmaceutical compositions of the present disclosure may include methylparaben in an amount that is about 0.1000% w / w of the total composition.

[0404] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise light mineral oil in an amount that is about 7.0000% w / w of the total composition.

[0405] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise white wax in an amount that is about 0.5000% w / w of the total composition.

[0406] In some embodiments, the pharmaceutical compositions of the present disclosure may comprise mono- and / or diglycerides in an amount that is about 2.5000% w / w of the total composition.

[0407] In some embodiments, pharmaceutical compositions of the present disclosure may include cetyl alcohol in an amount that is about 1.0000% w / w of the total composition.

[0408] In some embodiments, pharmaceutical compositions of the present disclosure may include stearyl alcohol in an amount that is about 1.0000% w / w of the total composition.

[0409] In some embodiments, pharmaceutical compositions of the present disclosure may include propylparaben in an amount that is about 0.0200% w / w of the total composition.

[0410] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of purified water ranges from about 99.93 to about 0.07%, about 99.94 to about 0.06%, about 99.95 to about 0.05%, about 99.96 to about 0.04%, about 99.97 to about 0.03%, about 99.98 to about 0.02%, or about 99.99 to about 0.01%.

[0411] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of propylene glycol ranges from about 99.93 to about 0.07%, from about 99.94 to about 0.06%, from about 99.95 to about 0.05%, from about 99.96 to about 0.04%, from about 99.97 to about 0.03%, from about 99.98 to about 0.02%, or from about 99.99 to about 0.01%.

[0412] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of dibasic sodium phosphate ranges from about 99.93 to about 0.07%, from about 99.94 to about 0.06%, from about 99.95 to about 0.05%, from about 99.96 to about 0.04%, from about 99.97 to about 0.03%, from about 99.98 to about 0.02%, or from about 99.99 to about 0.01%.

[0413] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of sodium dihydrogen phosphate monohydrate ranges from about 99.93 to about 0.07%, from about 99.94 to about 0.06%, from about 99.95 to about 0.05%, from about 99.96 to about 0.04%, from about 99.97 to about 0.03%, from about 99.98 to about 0.02%, or from about 99.99 to about 0.01%.

[0414] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of disodium EDTA ranges from about 99.93 to about 0.07%, about 99.94 to about 0.06%, about 99.95 to about 0.05%, about 99.96 to about 0.04%, about 99.97 to about 0.03%, about 99.98 to about 0.02%, or about 99.99 to about 0.01%.

[0415] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of methylparaben ranges from about 99.93 to about 0.07%, about 99.94 to about 0.06%, about 99.95 to about 0.05%, about 99.96 to about 0.04%, about 99.97 to about 0.03%, about 99.98 to about 0.02%, or about 99.99 to about 0.01%.

[0416] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of light mineral oil ranges from about 99.93 to about 0.07%, from about 99.94 to about 0.06%, from about 99.95 to about 0.05%, from about 99.96 to about 0.04%, from about 99.97 to about 0.03%, from about 99.98 to about 0.02%, or from about 99.99 to about 0.01%.

[0417] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of isopropyl myristate is in the range of about 99.93 to about 0.07%, about 99.94 to about 0.06%, about 99.95 to about 0.05%, about 99.96 to about 0.04%, about 99.97 to about 0.03%, about 99.98 to about 0.02%, or about 99.99 to about 0.01%.

[0418] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of white petrolatum is in the range of about 99.93 to about 0.07%, about 99.94 to about 0.06%, about 99.95 to about 0.05%, about 99.96 to about 0.04%, about 99.97 to about 0.03%, about 99.98 to about 0.02%, or about 99.99 to about 0.01%.

[0419] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of polyoxyl 20 cetostearyl ether is in the range of about 99.93 to about 0.07%, about 99.94 to about 0.06%, about 99.95 to about 0.05%, about 99.96 to about 0.04%, about 99.97 to about 0.03%, about 99.98 to about 0.02%, or about 99.99 to about 0.01%.

[0420] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; Approximately 1% to approximately 99%; Approximately 2% to approximately 98%; Approximately 3% to approximately 97%; Approximately 4% to approximately 96%; Approximately 5% to approximately 95%; Approximately 6% to approximately 94%; Approximately 7% to approximately 93%; Approximately 8% to approximately 92%; Approximately 9% to approximately 91%; Approximately 10% to approximately 90%; Approximately 11% to approximately 89%; Approximately 12% to approximately 88%; Approximately 13% to approximately 87%; Approximately 14% to approximately 86%; Approximately 15% to approximately 85%; Approximately 16% to approximately 84%; Approximately 17% to approximately 83%; Approximately 18% to approximately 82%; Approximately 19% to approximately 81%; Approximately 20% to approximately 80%; Approximately 21% to approximately 79%; Approximately 22% to approximately 78%; Approximately 23% to approximately 77%; Approximately 24% to approximately 76%; Approximately 25% to approximately 75%; Approximately 26% to Approximately 74%; Approximately 27% to approximately 73%; Approximately 28% to approximately 72%; Approximately 29% to approximately 71%; Approximately 30% to approximately 70%; Approximately 31% to approximately 69%; Approximately 32% to approximately 68%; Approximately 33% to approximately 67%; Approximately 34% to approximately 66%; Approximately 35% to approximately 65%; Approximately 36% to approximately 64%; Approximately 37% to approximately 63%; Approximately 38% to approximately 62%; Approximately 39% to 61%; Approximately 40% to 60%; Approximately 41% to 59%; Approximately 42% to 58%; Approximately 43% to 57%; Approximately 44% to 56%; Approximately 45% to 55%; Approximately 46% to 54%; Approximately 47% to 53%; Approximately 48% to 52%; Approximately 49% to 51%; Approximately 50% to 50%; Approximately 51% to Approximately 49%; Approximately 52% to approximately 48%; Approximately 53% to approximately 47%; Approximately 54% to approximately 46%; Approximately 55% to approximately 45%; Approximately 56% to approximately 44%; Approximately 57% to approximately 43%; Approximately 58% to approximately 42%; Approximately 59% to approximately 41%; Approximately 60% to approximately 40%; Approximately 61% to approximately 39%; Approximately 62% to approximately 38%; Approximately 63% to approximately 37%; Approximately 64% to approximately 36%; Approximately 65% ​​to approximately 35%; Approximately 66% to approximately 34%; Approximately 67% to approximately 33%; Approximately 68% to approximately 32%; Approximately 69% to approximately 31%; Approximately 70% to approximately 30%; Approximately 71% to approximately 29%; Approximately 72% to approximately 28%; Approximately 73% to approximately 27%; Approximately 74% to approximately 26%; Approximately 75% to approximately 25%; Approximately 76% to Approximately 24%; Approximately 77% to approximately 23%; Approximately 78% to approximately 22%; Approximately 79% to approximately 21%; Approximately 80% to approximately 20%; Approximately 81% to approximately 19%; Approximately 82% to approximately 18%; Approximately 83% to approximately 17%; Approximately 84% to approximately 16%; Approximately 85% to approximately 15%; Approximately 86% to approximately 14%; Approximately 87% to approximately 13%; Approximately 88% to approximately 12%; Approximately 89% to approximately 11%; approximately 90% to approximately 10%; approximately 91% to approximately 9%; approximately 92% to approximately 8%; approximately 93% to approximately 7%; approximately 94% to approximately 6%; approximately 95% to approximately 5%; approximately 96% to approximately 4%; approximately 97% to approximately 3%; approximately 98% to approximately 2%; approximately 99% to approximately 1%; approximately 99.91 to approximately 0.09%; approximately 99.92 to approximately 0.The amount of cetyl alcohol ranges from about 99.93 to about 0.07%, from about 99.94 to about 0.06%, from about 99.95 to about 0.05%, from about 99.96 to about 0.04%, from about 99.97 to about 0.03%, from about 99.98 to about 0.02%, or from about 99.99 to about 0.01%.

[0421] In some embodiments, pharmaceutical compositions of the present disclosure can include a peptide of the present disclosure, purified water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, and propylparaben. from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99% w / w of the total composition; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95%; from about 0.06% to about 99.94%; from about 0.07% to about 99...

Claims

1. A pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and an excipient; The peptide has the formula (I): 【Transformation 73】 wherein Cth is cystathionine; Cysteine ​​at positions 1 and 6 (Cys １ and Cys ６ ) and cysteines at positions 5 and 13 (Cys ５ and Cys １３ ) are connected by a disulfide bond; Cystathionine (Cth) ２ ) and cysteine ​​at position 10 (Cys １０ ) are connected by a thioether bond) 10. A pharmaceutical composition comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in claim 1.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a pH of about 6 to about 8.

3. The pharmaceutical composition of claim 1, wherein the peptide or the pharmaceutically acceptable salt thereof has an acetylated N-terminus.

4. The pharmaceutical composition of claim 1, wherein the excipient is a buffer, a solvent, a pH modifier, or any combination thereof.

5. The pharmaceutical composition of claim 4, wherein the excipient is water, propylene glycol, dibasic sodium phosphate, sodium dihydrogen phosphate monohydrate, dibasic sodium phosphate heptahydrate, disodium EDTA, methylparaben, light mineral oil, isopropyl myristate, white petrolatum, polyoxyl 20 cetostearyl ether, cetyl alcohol, stearyl alcohol, propylparaben, emulsifying wax, polyoxyethylene (10) stearyl ether, white wax, monoglyceride, diglyceride, sodium hydroxide, phosphoric acid, or any combination thereof.

6. The pharmaceutical composition of claim 4, wherein the buffer is sodium phosphate buffer; the solvent is water; and the pH modifier is sodium hydroxide or phosphoric acid.

7. The pharmaceutical composition of claim 6, wherein the sodium phosphate buffer comprises monobasic sodium phosphate monohydrate and dibasic sodium phosphate heptahydrate.

8. The pharmaceutical composition of claim 7, wherein the monobasic sodium phosphate monohydrate is present in an amount ranging from about 0.05% w / w to about 0.2% w / w of the total weight of the composition, and / or the dibasic sodium phosphate heptahydrate is present in an amount ranging from about 0.2% w / w to about 0.4% w / w of the total weight of the composition.

9. The pharmaceutical composition of claim 6, wherein the water is present in an amount ranging from about 98% w / w to about 99.8% w / w of the total weight of the composition.

10. The composition of claim 1, wherein the excipient comprises: purified water in an amount ranging from about 50% w / w to about 90% w / w; propylene glycol in an amount ranging from about 5% w / w to about 20% w / w; dibasic sodium phosphate in an amount ranging from about 0.08% w / w to about 0.25% w / w; Sodium dihydrogen phosphate monohydrate in an amount ranging from about 0.05% w / w to about 0.2% w / w; Disodium EDTA in an amount ranging from about 0.02% w / w to about 0.1% w / w; methylparaben in an amount ranging from about 0.05% w / w to about 0.2% w / w; light mineral oil in an amount ranging from about 3% w / w to about 12% w / w; isopropyl myristate in an amount ranging from about 0.2% w / w to about 1% w / w; White petrolatum in an amount ranging from about 0.5% w / w to about 2% w / w; Polyoxyl 20 cetostearyl ether in an amount ranging from about 1% w / w to about 5% w / w; Cetyl alcohol in an amount ranging from about 0.5% w / w to about 2% w / w; stearyl alcohol in an amount ranging from about 0.5% w / w to about 2% w / w; and Propylparaben in an amount ranging from about 0.01% w / w to about 0.05% w / w The pharmaceutical composition according to claim 5, wherein 11. The composition of claim 1, wherein the excipient comprises: purified water in an amount ranging from about 50% w / w to about 90% w / w; propylene glycol in an amount ranging from about 8% w / w to about 30% w / w; dibasic sodium phosphate in an amount ranging from about 0.08% w / w to about 0.30% w / w; Sodium dihydrogen phosphate monohydrate in an amount ranging from about 0.05% w / w to about 0.2% w / w; Disodium EDTA in an amount ranging from about 0.02% w / w to about 0.1% w / w; methylparaben in an amount ranging from about 0.05% w / w to about 0.2% w / w; emulsifying wax in an amount ranging from about 0.7% w / w to about 3% w / w; Polyoxyethylene (10) stearyl ether in an amount ranging from about 0.7% w / w to about 3% w / w; Cetyl alcohol in an amount ranging from about 0.4% w / w to about 1.4% w / w; and Propylparaben in an amount ranging from about 0.01% w / w to about 0.04% w / w The pharmaceutical composition according to claim 5, wherein 12. The composition of claim 1, wherein the excipient comprises: purified water in an amount ranging from about 50% w / w to about 90% w / w; propylene glycol in an amount ranging from about 5% w / w to about 20% w / w; dibasic sodium phosphate in an amount ranging from about 0.08% w / w to about 0.30% w / w; Sodium dihydrogen phosphate monohydrate in an amount ranging from about 0.05% w / w to about 0.2% w / w; Disodium EDTA in an amount ranging from about 0.02% w / w to about 0.1% w / w; methylparaben in an amount ranging from about 0.05% w / w to about 0.2% w / w; light mineral oil in an amount ranging from about 3% w / w to about 14% w / w; White wax in an amount ranging from about 0.2% w / w to about 1% w / w; mono- and di-glycerides in an amount ranging from about 1% w / w to about 5% w / w; Cetyl alcohol in an amount ranging from about 0.5% w / w to about 2% w / w; stearyl alcohol in an amount ranging from about 0.5% w / w to about 2% w / w; and Propylparaben in an amount ranging from about 0.01% w / w to about 0.04% w / w The pharmaceutical composition according to claim 5, wherein 13. The pharmaceutical composition of claim 5, wherein the peptide is present in an amount ranging from about 0.0003% w / w to about 0.5% w / w of the total weight of the pharmaceutical composition, for example, the peptide is present in an amount of about 0.000498% w / w, about 0.00149% w / w, about 0.00299% w / w, about 0.00448% w / w, about 0.00870% w / w, about 0.00896% w / w, about 0.00961% w / w, about 0.0124% w / w, about 0.0261% w / w, about 0.0288% w / w, about 0.301% w / w, or about 0.335% w / w of the total weight of the pharmaceutical composition.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as a parenteral form; a transmucosal form; a suppository; an enema; a feeding tube form; a solution for intraluminal use; a rectal gel; a rectal foam; or a rectal aerosol.

15. A liquid composition comprising the pharmaceutical composition of claim 1.

16. The liquid composition of claim 15, wherein the peptide or the pharmaceutically acceptable salt thereof is present in an amount ranging from about 5 μg / mL to about 125 μg / mL.

17. A rectal foam comprising the pharmaceutical composition of claim 1 and a spray.

18. The rectal foam of claim 17, wherein the propellant is DME, A17, A31, AP35, A46, A48, A70, or AP70, for example, the propellant is AP35, and the AP35 is in an amount ranging from about 8% w / w to about 10% w / w of the total weight of the composition.

19. A unit dosage form comprising the pharmaceutical composition of claim 1.

20. The unit dosage form of claim 19, wherein the peptide or the pharmaceutically acceptable salt thereof is present in an amount ranging from about 50 μg to about 3 mg.

21. An enema kit comprising a pharmaceutical composition described in any one of claims 1 to 14, a liquid composition described in claim 15 or 16, or a unit dosage form described in claim 19 or 20; a syringe; and an enema applicator.

22. A canister containing the pharmaceutical rectal foam composition of any one of claims 14, 17 or 18.

23. A kit comprising the pharmaceutical composition of any one of claims 1 to 14, the liquid composition of claim 15 or 16, the rectal foam of claim 17 or 18, or the unit dosage form of claim 19 or 20.

24. A pharmaceutical composition according to any one of claims 1 to 14, a liquid composition according to claim 15 or 16, a rectal foam according to claim 17 or 18, or a unit dosage form according to claim 19 or 20 for use in treating a visceral pain condition.

25. The visceral pain condition is selected from the group consisting of interstitial cystitis / bladder pain syndrome (IC / BPS); bladder pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS); urinary urgency associated with IC / BPS; increased urination frequency associated with IC / BPS; nighttime urination (nocturia) associated with IC / BPS; bladder burning associated with IC / BPS; burning during urination associated with IC / BPS; bladder pressure associated with IC / BPS; bladder discomfort associated with IC / BPS; bladder pain associated with IC / BPS; Painful urination associated with IC / BPS; genital pain associated with IC / BPS; urogenital pain associated with IC / BPS; difficulty sleeping associated with IC / BPS; body pain associated with IC / BPS; decreased quality of life associated with IC / BPS; suicidal ideation associated with IC / BPS; depression associated with IC / BPS; increased use of pain medications to treat IC / BPS; sexual dysfunction associated with IC / BPS; loss of libido associated with IC / BPS; sexual dysfunction associated with IC / BPS impotence; bladder inflammation associated with IC / BPS; Hanna lesions (mucosal lesions or ulcers seen with or without hydrodistention of the bladder) associated with IC / BPS; abdominal pain; bladder hyperirritability; colonic pain; extraintestinal chronic pelvic pain; endometriosis; pain from excessive menstrual cramps; pain during intercourse; radiation rectal injury; pain associated with vaginal irritation; allodynia; hyperirritability of bladder afferents in the absence of bladder pathology; pain from diverticulitis; pain associated with gastrointestinal disorders; pain associated with sexually transmitted diseases; irritable bowel syndrome (IBS) 25. The pharmaceutical composition, liquid composition, rectal foam, or unit dosage form for use according to claim 24, wherein the therapeutic agent is selected from pain associated with rectal pain, chronic anal pain, transient rectal pain, anal pain, chronic anal fissure, post-operative anal pain, pain associated with cancer, pain associated with gastrointestinal neoplasms, general pelvic pain, testicular pain, chronic prostatitis, prostatodynia, vulvodynia, urethral syndrome, penile pain, perianal pain, and pain associated with ulcerative colitis, ulcerative proctitis, Crohn's disease; or any combination thereof.

26. A pharmaceutical composition, liquid composition, rectal foam or unit dosage form for use according to claim 25, wherein the visceral pain condition is interstitial cystitis / bladder pain syndrome (IC / BPS).

27. A pharmaceutical composition according to any one of claims 1 to 14, a liquid composition according to claim 15 or 16, a rectal foam according to claim 17 or 18, or a unit dosage form according to claim 19 or 20, for use in treating interstitial cystitis / bladder pain syndrome (IC / BPS).

28. A pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof and one or more excipients; The peptide has the formula (I): 【Chemistry 90】 wherein Cth is cystathionine; Cysteine ​​at positions 1 and 6 (Cys １ and Cys ６ ) and cysteines at positions 5 and 13 (Cys ５ and Cys １３ ) are connected by a disulfide bond; Cystathionine (Cth) ２ ) and cysteine ​​at position 10 (Cys １０ ) are connected by a thioether bond) an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in the peptide has an acetylated N-terminus; the peptide in an amount ranging from about 0.000498% to about 0.335% w / w of the total weight of the composition; The one or more excipients comprise, by total weight of the composition: Sodium phosphate monobasic monohydrate in an amount that is about 0.116% w / w; dibasic sodium phosphate heptahydrate in an amount that is about 0.308% w / w; and Water in an amount of about 99.6% w / w; Including; the pharmaceutical composition has a pH in the range of about 6.9 to about 7.2; Pharmaceutical compositions.

29. A liquid pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof; and one or more excipients; The peptide has the formula (I): 【Chemistry 103】 wherein Cth is cystathionine; Cysteine ​​at positions 1 and 6 (Cys １ and Cys ６ ) and cysteines at positions 5 and 13 (Cys ５ and Cys １３ ) are connected by a disulfide bond; Cystathionine (Cth) ２ ) and cysteine ​​at position 10 (Cys １０ ) are connected by a thioether bond) an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in the peptide has an acetylated N-terminus; the one or more excipients 1.165 mg / mL monobasic sodium phosphate monohydrate; 3.095 mg / mL dibasic sodium phosphate heptahydrate; and water in an amount that results in a total volume of the liquid pharmaceutical composition of 20 mL; Including; the liquid pharmaceutical composition comprising the peptide in an amount ranging from about 5 μg / mL to about 125 μg / mL; the liquid composition has a pH in the range of about 6.9 to about 7.2; Liquid pharmaceutical compositions.

30. A rectal foam comprising a peptide or a pharmaceutically acceptable salt thereof; one or more excipients; and a propellant; The peptide has the formula (I): 【Chemical 123】 wherein Cth is cystathionine; Cysteine ​​at positions 1 and 6 (Cys １ and Cys ６ ) and cysteines at positions 5 and 13 (Cys ５ and Cys １３ ) are connected by a disulfide bond; Cystathionine (Cth) ２ ) and cysteine ​​at position 10 (Cys １０ ) are connected by a thioether bond) an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in the peptide has an acetylated N-terminus; the peptide in an amount that is about 0.0087% w / w of the total weight of the composition; The one or more excipients comprise, by total weight of the composition: Water in an amount of about 69.8847% w / w; Propylene glycol in an amount of about 9.0116% w / w; dibasic sodium phosphate in an amount that is about 0.1478% w / w; Sodium dihydrogen phosphate monohydrate in an amount that is about 0.1050% w / w; Disodium EDTA in an amount of about 0.0451% w / w; methylparaben in an amount of about 0.0901% w / w; light mineral oil in an amount of about 5.4070% w / w; isopropyl myristate in an amount that is about 0.4506% w / w; White petrolatum in an amount of about 0.9012% w / w; Polyoxyl 20 cetostearyl ether in an amount of about 2.2529% w / w; cetyl alcohol in an amount of about 0.9012% w / w; stearyl alcohol in an amount of about 0.9012% w / w; Propylparaben in an amount that is about 0.0180% w / w; Including; The propellant is AP35 in an amount that is about 9.8837% w / w. Rectal foam.

31. A pharmaceutical rectal foam composition comprising a peptide or a pharmaceutically acceptable salt thereof; one or more excipients; and a propellant; The peptide has the formula (I): 【Chemistry 124】 wherein Cth is cystathionine; Cysteine ​​at positions 1 and 6 (Cys １ and Cys ６ ) and cysteines at positions 5 and 13 (Cys ５ and Cys １３ ) are connected by a disulfide bond; Cystathionine (Cth) ２ ) and cysteine ​​at position 10 (Cys １０ ) are connected by a thioether bond) an amino acid sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to the amino acid sequence set forth in the peptide has an acetylated N-terminus; the peptide in an amount that is about 0.0260% w / w of the total weight of the composition; The one or more excipients comprise, by total weight of the composition: Water in an amount of about 69.8587% w / w; Propylene glycol in an amount of about 9.0116% w / w; dibasic sodium phosphate in an amount that is about 0.1478% w / w; Sodium dihydrogen phosphate monohydrate in an amount that is about 0.1050% w / w; Disodium EDTA in an amount of about 0.0451% w / w; methylparaben in an amount of about 0.0901% w / w; light mineral oil in an amount of about 5.4070% w / w; isopropyl myristate in an amount that is about 0.4506% w / w; White petrolatum in an amount of about 0.9012% w / w; Polyoxyl 20 cetostearyl ether in an amount of about 2.2529% w / w; cetyl alcohol in an amount of about 0.9012% w / w; stearyl alcohol in an amount of about 0.9012% w / w; Propylparaben in an amount that is about 0.0180% w / w; Including; The propellant is AP35 in an amount that is about 9.8837% w / w. Pharmaceutical rectal foam composition.

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