Composition for colon lavage and treatment of gastrointestinal disorders

Abstract

To provide peptides and compositions useful for treatment of gastrointestinal disorders or for colon cleansing.SOLUTION: The present invention provides compositions and methods of treating gastrointestinal disorders as well as pharmaceutical compositions for accomplishing the same. In some embodiments, these pharmaceutical compositions include oral dosage forms. The present invention features peptides, compositions and related methods for colon cleansing treatment as well as other conditions and disorders described herein. In one embodiment, the peptides may be used to prepare subjects for colonoscopy treatment. In some embodiments, the peptides or pharmaceutically acceptable salts may be used to prepare subjects for surgery, such as bowel surgery.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Field of Invention The present invention relates to peptides, compositions, and methods for colon cleansing and the treatment of disorders of the gastrointestinal tract and other internal organs.

[0002] Claim of priority This application claims priority to U.S. Provisional Patent Application No. 62 / 156,077, filed on 1 May 2015 under Section 119(e) of the U.S. Patent Act, the entire contents of which are incorporated herein by reference.

[0003] Sequence List This application incorporates, by reference, the sequence listing titled "IW154PCT1Sequence_ST25.txt" (45.1 kilobytes), which was prepared on 28 April 2016 and submitted electronically with this specification. [Background technology]

[0004] background In the United States, approximately 15 million colonoscopies are performed annually, all of which require proper colon preparation. However, inadequate colon preparation is reported in about 20% of colonoscopies. Inadequate preparation can lead to lower adenoma detection, longer procedure times, and shorter intervals between examinations. Consequently, there is a need for safe, effective, and well-tolerated colon preparation to ensure that a broad population of patients can reliably and effectively undergo colonoscopies and reduce their risk of colon cancer. [Overview of the Initiative] [Means for solving the problem]

[0005] overview The present invention features peptides, compositions, and related methods for colon cleansing therapy and other medical conditions and disorders described herein. In one embodiment, a target for colonoscopy therapy can be prepared using a peptide. In some embodiments, a target for surgical procedures such as bowel surgery can be prepared using a peptide or a pharmaceutically acceptable salt. In other embodiments, a target for colon cancer, hereditary nonpolyposis colorectal cancer (HNPCC), i.e., Lynch syndrome, gastroparesis (GP), polyps, pain, generalized abdominal pain, postoperative ileus, opioid-induced constipation, functional dyspepsia, SUDD (symptomatic simple diverticular disease) and SCAD (segmental colitis associated with diverticular disease), diverticular diseases including but not limited to diverticulosis, diarrhea-predominant irritable bowel syndrome, and irritable bowel syndrome (IBS) It can treat pain, ulcerative colitis, ulcerative proctitis, Crohn's disease, inflammatory bowel disease (IBD), chronic or acute radiation-induced rectal pain, rectal pain, chronic rectal neuralgia, transient rectal neuralgia, anal pain, chronic anal fissure, postoperative anal pain, overactive bladder syndrome, stress urinary incontinence, interstitial cystitis, bladder pain syndrome, colorectal cancer, cancer-related pain, generalized pelvic pain, endometriosis, testicular pain, chronic prostatitis, prostatic pain, vvodynia, urethral syndrome, penile pain, perianal pain, and other gastrointestinal and visceral disorders.

[0006] One aspect of the present invention provides a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence: [ka] , or comprising a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK or absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa , 21 , 20 , , is Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 is Cys, Ag, or penicillamine (Pen); Xaa 12 is Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is Asn or Leu; Xaa 14 is Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 is Cys, Ag, Pen, or Cth; Xaa 17 is Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 is Cys, Ag, or Pen; Xaa 20 is Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methyl Tyr (Nme-Tyr) or absent; Xaa 21 [[ID=4​In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro; and The peptides are Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19 It contains a covalent bond between them.

[0007] A second aspect of the present invention provides a pharmaceutical composition comprising the peptide of the present invention.

[0008] A third aspect of the present invention provides a method for treating gastrointestinal disorders, comprising administering a pharmaceutical composition according to the present invention. The pharmaceutical composition according to the present invention may be used as a colonoscope or as a preparation for the treatment of gastrointestinal disorders and pain. In some embodiments, the composition is a solid oral composition.

[0009] Further details regarding one or more embodiments of the present invention are provided in the accompanying description. [Brief explanation of the drawing]

[0010] [Figure 1] This section explains the results regarding the activity and stability of representative peptides. [Figure 2] This paper explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO:3-7. [Figure 3] This paper explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO:8-10. [Figure 4] We present the results of cGMP accumulation in a T84 cell assay for the analysis of GC-C activity related to SEQ ID NOs: 12-13 and 23-27. [Figure 5] This paper explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO:28-34. [Figure 6] This section explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NOs: 35-37, 39, and 44. [Figure 7] This paper explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO:2 and 40-42. [Figure 8] This paper explains the results of cGMP accumulation in a T84 cell assay for the analysis of GC-C activity related to SEQ ID NO:43. [Figure 9] This paper explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO:44~47. [Figure 10] This section explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO: 45, 48, and 51-52. [Figure 11] This paper explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO: 12, 13, 27, 47, and 53. [Figure 12] This paper describes the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO:47, along with the original test, a repeat of the original test, and a second weighing. [Figure 13] This paper explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO: 54-59. [Figure 14] This paper explains the results of cGMP accumulation in the T84 cell assay for the analysis of GC-C activity related to SEQ ID NO:60-64. [Figure 15] This section explains the results of the in vivo rat duodenal loop assay for SEQ ID NO: 62 and 47. [Figure 16] This section explains the results of rat duodenal loop volume tests for SEQ ID NO: 62 and 47. [Figure 17]This paper explains the results of mouse gastrointestinal transport (mGIT) assays for SEQ ID NO:2 and 47 compared to ST core. [Figure 18] This paper explains the results of the in vivo ligated rat loop assay for SEQ ID NO: 67 and 69. [Figure 19] This paper explains the results of the in vivo ligated rat loop volume test for SEQ ID NO: 67 and 69. [Figure 20] We present the results of in vitro rat intestinal fluid (RIF) assays for SEQ ID NO: 2, 26, 43, 47, and 53. [Figure 21] We present the results of the in vitro RIF assay for SEQ ID NO: 60-66. [Figure 22] We present the results of in vivo RIF assays for SEQ ID NO: 47, 62, 67, and 69. [Figure 23] The results of various assays performed on representative peptides are presented. [Figure 24] We present the results of cGMP accumulation in the T84 cell assay for SEQ ID NO:14-22. [Figure 25] This section explains the results of mouse gastrointestinal transport assays for SEQ ID NO:2, 7, and 11. [Figure 26] This section explains the results of a mouse gastrointestinal transport assay for SEQ ID NO:47. [Figure 27] This section explains the results of mouse gastrointestinal transport assays for SEQ ID NO: 62, 67, and 69. [Modes for carrying out the invention]

[0011] These figures are provided as examples and are not intended to limit the scope of the present invention.

[0012] Detailed explanation Guanylate cyclase C (GC-C) is a transmembrane receptor located on the apical surface of epithelial cells in the stomach and intestines. The receptor has an extracellular ligand-binding domain, a single transmembrane domain, and a C-terminal guanylyl cyclase domain. When a ligand binds to the extracellular domain of GC-C, the intracellular catalytic domain catalyzes the production of cGMP from GTP. In vivo, this increase in intracellular cGMP initiates a cascade of events leading to increased secretion of chloride and bicarbonate into the intestinal lumen, increased luminal pH, decreased luminal sodium absorption, increased fluid secretion, and accelerated intestinal transport. cGMP, secreted bidirectionally from the epithelium into the mucosa and lumen, has also been shown to weaken the firing of afferent C fibers, suggesting a potential mechanism for the observed analgesic effect of GC-C agonists on visceral pain.

[0013] Linaclotide, a peptide GC-C agonist currently approved in the United States for oral administration for the treatment of irritable bowel syndrome (IBS-c) and chronic idiopathic constipation (CIC), has numerous effects on lower GI physiological functions, including (1) reduced visceral pain, (2) reduced bloating, and (3) increased GI transport, which can lead to increased bowel movement frequency and improved stool consistency. Orally administered linaclotide acts locally by activating GC-C receptors on the luminal surface. Therefore, results from clinical trials of linaclotide, as well as from preclinical studies using linaclotide and related peptides, suggest that GC-C peptide agonists may be therapeutically useful. Peptides described and claimed herein may be characterized as GC-C peptide agonists that can bind to and activate GC-C receptors.

[0014] definition When used herein, C12 is a C12 alkyl carboxylic acid, C14 is a C14 alkyl carboxylic acid, C16 is a C16 alkyl carboxylic acid, C18 is a C18 alkyl carboxylic acid, (4-F)Phe is 4-fluorophenylalanine, Cth is cystathionine, Ag is allylglycine, Hag is allylglycine with a reduced dicarba bond, Pent is pentenoic acid, Pen is penicillamine, Cha is cyclohexylalanine, Sar is sarcosine, OH-Pro is hydroxyproline, Nme-Tyr is N-methyltyrosine, 4-Mepip is 1-methyl-piperidine-4-carboxylic acid, Dpr is diaminopropionic acid, BE is glutamic acid whose side chain carboxylic acid forms a peptide linkage, and BK is lysine whose side chain amine forms a peptide linkage. An example of a BE-BK linkage pattern is: [ka] It is likely.

[0015] Further examples of peptide bonds include, without limitation, I. Dicardia [ka] II. Hag-Hag [ka] III.Cth-C [ka] IV.C-Cth [ka] VD-Dpr (lactam bond) [ka] VI. [ka] [ka] others [ka] VII. Ag-Ag(2, -10) [ka] VIII. Hag-Hag(2, -10) [ka] IX.Cth-C(2, -10) [ka] XC-Cth(2, -10) [ka] XI. (2, -10) [ka] [ka] others [ka] XII. Ag-Ag(5, -13) [ka] XIII.Hag-Hag(5, -13) [ka] XIV.Cth-C(5, -13) [ka] XV.C-Cth(5, -13) [ka] XVI. (5, -13) [ka] [ka] others [ka] It includes.

[0016] peptide In one embodiment, the present invention provides a peptide or a pharmaceutically acceptable salt thereof useful in the methods described herein, wherein the peptide has an amino acid sequence: [ka] , or comprising a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK, or is absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 This is Cys, Ag, or penicillamine (Pen); Xaa 12 These are Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is either Asn or Leu; Xaa 14 These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 These are Cys, Ag, Pen, or Cth; Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 It is Cys, Ag, or Pen; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro; and The peptides are Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19 It contains a covalent bond between them.

[0017] In some embodiments, the N-terminus of the peptide is acetylated or modified at the N-terminus to provide additional stability to the peptide. In other embodiments, the N-terminus is capped with pentenoic acid, biotin, 4-Mepip(1-methyl-4-carboxylic acid), C12 alkylcarboxylic acid, C14 alkylcarboxylic acid, C16 alkylcarboxylic acid, or C18 alkylcarboxylic acid. In some embodiments, the C=C double bond of pentenoic acid may be cyclized with another C=C double bond to form a dicarba bond.

[0018] In some embodiments, the C-terminus of the peptide is amidated or modified to provide additional stability to the peptide.

[0019] In yet another embodiment, the N-terminus of the peptide is acetylated or capped, and the C-terminus is amidated.

[0020] In some embodiments, dichard bonds (CH2-CH=CH-CH2) or other covalent bonds described herein between peptide residues may be useful in stabilizing the peptide. Dicarbal bonds and other covalent bonds described herein may, in some cases, provide greater peptide stability than disulfide bonds. In some embodiments, dichard bonds may be reduced (CH2-CH2-CH2-CH2).

[0021] In some embodiments, enhanced peptide stability allows for long-term storage at room temperature.

[0022] In some embodiments, Xaa7 and Xaa 12 Both are Ag, and the dicarba bond is Ag7 and Ag 12 It exists between Xaa7 and Xaa 12 Both are Cys, and the disulfide bond is between Cys7 and Cys 12 It exists between Xaa8 and Xaa 16 Both are Cys, and the disulfide bond is Cys8 and Cys 16 It exists between; Xaa 11 and Xaa 19 It is a BothCys and the disulfide bond is Cys 11 and Cys 19 It exists between; or any combination thereof.

[0023] In another embodiment, Xaa7 is Cth, and Xaa 12 It is Cys, and the bond is Cth7 and Cys 12 It exists between; Xaa8 is Cth, and Xaa 16 It is Cys, and the bond is Cth8 and Cys 16 It exists between; or any combination thereof.

[0024] In some embodiments, Xaa7 is allylglycine or Cys.

[0025] In some embodiments, Xaa8 is Cys or cystathionine.

[0026] In some embodiments, Xaa9 is Glu.

[0027] In some embodiments, Xaa 10 It is Leu.

[0028] In some embodiments, Xaa 12 It is Cys or allylglycine.

[0029] In some embodiments, Xaa 14 It is either Val or Pro.

[0030] In some embodiments, Xaa 17 It is either Tyr or Thr.

[0031] In some embodiments, Xaa 20 It is either Tyr or lacking.

[0032] In some embodiments, Xaa 21 It is lacking.

[0033] In some embodiments, Xaa1 is missing; Xaa2 is missing; Xaa3 is missing; Xaa4 is missing; Xaa5 is missing; Xaa6 is missing; Xaa7 is Ag, Cys, or Cth; Xaa8 is Cys or Cth; Xaa9 is Glu; Xaa 10 is Leu; Xaa 12 is Ag or Cys; Xaa 14 is Val or Pro; Xaa 17 is Tyr or Thr; and Xaa 20 It is either Tyr or lacking.

[0034] In some embodiments, Xaa 14 It's not Pro.

[0035] In some embodiments, Xaa 17 It is not Phe.

[0036] In some embodiments, a peptide or a pharmaceutically acceptable salt thereof is provided, wherein the peptide has the amino acid sequence: [ka] [ka] [ka] [ka] The formula includes, where Ac- indicates an acetylated N-terminus, Pent- indicates an N-terminus capped with pentenoic acid, biotin- indicates an N-terminus capped with biotin, 4-Mepip indicates an N-terminus capped with 4-Mepip(1-methyl-piperidine-4-carboxylic acid), C12- indicates an N-terminus capped with C12 alkylcarboxylic acid, C14- indicates an N-terminus capped with C14 alkylcarboxylic acid, C16- indicates an N-terminus capped with C16 alkylcarboxylic acid, C18- indicates an N-terminus capped with C18 alkylcarboxylic acid, H- indicates an unmodified N-terminus, -NH2 indicates an amidated C-terminus, and -COOH indicates an unmodified C-terminus.

[0037] In further embodiments, the dicarba bond between two Ag residues may be either a cis or trans isomer of the dicarba bond. As used herein, the cis isomer of the dicarba bond has both hydrogen atoms on the same side of the C=C double bond, and the trans isomer of the dicarba bond has the hydrogen atoms on opposite sides of the C=C double bond.

[0038] In some embodiments, a peptide or a pharmaceutically acceptable salt thereof is provided, the peptide containing no more than 50, 40, 30, or 20 amino acids. In further embodiments, the peptide contains no more than 19, 18, 17, 16, 15, or 14 amino acids.

[0039] In another embodiment, the present invention provides a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence [ka] , or a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK, or is absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 This is Cys, Ag, or penicillamine (Pen); Xaa 12These are Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is either Asn or Leu; Xaa 14 These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 These are Cys, Ag, Pen, or Cth; Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 It is Cys, Ag, or Pen; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro, and The peptides are Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19 It contains a covalent bond between them.

[0040] In some embodiments, the N-terminus of the peptide is acetylated to provide additional stability to the peptide. In other embodiments, the N-terminus is capped with pentenoic acid, biotin, 4-Mepip(1-methyl-piperidine-4-carboxylic acid), C12 alkyl carboxylic acid, C14 alkyl carboxylic acid, C16 alkyl carboxylic acid, or C18 alkyl carboxylic acid. In some embodiments, the C=C double bond of pentenoic acid may be cyclized with another C=C double bond to form a dicarba bond.

[0041] In some embodiments, the C-terminus of the peptide is amidated to provide additional stability to the peptide.

[0042] In some embodiments, Xaa7 and Xaa 12 Both are Ag, and the dicarba bond is Ag7 and Ag 12 It exists between Xaa7 and Xaa 12 Both are Cys, and the disulfide bond is between Cys7 and Cys 12 It exists between Xaa8 and Xaa 16 Both are Cys, and the disulfide bond is Cys8 and Cys 16 It exists between; Xaa 11 and Xaa 19 It is a BothCys and the disulfide bond is Cys 11 and Cys 19 It exists between; or any combination thereof.

[0043] In some embodiments, Xaa7 is allylglycine or Cys.

[0044] In some embodiments, Xaa8 is Cys or cystathionine.

[0045] In some embodiments, Xaa9 is Glu.

[0046] In some embodiments, Xaa 10 It is Leu.

[0047] In some embodiments, Xaa 12 It is Cys or allylglycine.

[0048] In some embodiments, Xaa 14 It is either Val or Pro.

[0049] In some embodiments, Xaa 17 It is either Tyr or Thr.

[0050] In some embodiments, Xaa 20 is Tyr or absent.

[0051] In some embodiments, Xaa 21 is absent.

[0052] In some embodiments, Xaa1 is absent; Xaa2 is absent; Xaa3 is absent; Xaa4 is absent; Xaa5 is absent; Xaa6 is absent; Xaa7 is Ag, Cys, or Cth; Xaa8 is Cys or Cth; Xaa9 is Glu; Xaa 10 is Leu; Xaa 12 is Ag or Cys; Xaa 14 is Val or Pro; Xaa 17 is Tyr or Thr; and Xaa 20 is Tyr or absent.

[0053] In some embodiments, a peptide or a pharmaceutically acceptable salt thereof is provided, the peptide having the amino acid sequence:

Chemical formula

Chemical formula

Chemical formula

[0054] In another embodiment, the present invention provides a peptide or a pharmaceutically acceptable salt thereof useful in the methods described herein, the peptide having the amino acid sequence:

Chemical formula

[0055] In a further embodiment, the peptide or a pharmaceutically acceptable salt thereof, the peptide has the amino acid sequence:

Chemical formula

[0056] In some embodiments, the peptide is isolated. In other embodiments, the peptide is purified.

[0057] In some embodiments, pharmaceutically acceptable salts of the peptide are provided. In some cases, the pharmaceutically acceptable salt is a chloride salt, acetate salt, phosphate salt, or sulfate salt.

[0058] In some embodiments, the N-terminus of the peptide described herein is acetylated or capped. This modification may provide enhanced stability to the peptide. In other embodiments, the N-terminus peptide is a cysteine ​​residue modified with an imidazolidinone derivative.

[0059] The peptides disclosed herein may also be used for detection or treatment of colon cancer. When the peptides are used in a detection context, a linker is conjugated to the N-terminus. The linker can then be conjugated to a dye, or conjugated to a dye before binding to the peptide. Those skilled in the art will recognize that a dye conjugated to a peptide would be useful in detecting peptide bond interactions.

[0060] Another embodiment involves conjugating the peptide disclosed herein to a toxin with a linker. Toxins conjugated and coated with the peptide or pharmaceutically acceptable salt described herein would be useful as a treatment for colon cancer. Such formulations would result in systemic circulation for a long-acting treatment. Those skilled in the art would recognize the use of the long-acting peptide or pharmaceutically acceptable salt thereof described herein in the treatment of colon cancer.

[0061] Peptide production In one embodiment, the peptide or precursor peptide of the present invention can be recombinantly produced in any known protein expression system including, but not limited to, bacteria (e.g., E. coli or Bacillus subtilis), insect cell lines (e.g., Drosophila Sf9 cell line), yeast cell lines (e.g., S. cerevisiae, S. saccharomyces), or filamentous fungal expression systems, or animal cell expression systems (e.g., mammalian cell expression systems). When the peptide or variant peptide is to be produced recombinantly, for example, in E. coli, the nucleic acid molecule encoding the peptide may also encode a leader sequence that enables secretion of the mature peptide from the cell. Thus, the sequence encoding the peptide may include, for example, the pre and pro sequences of a naturally occurring bacterial heat-stable enterotoxin (ST) peptide. The secreted mature peptide can be purified from the culture medium.

[0062] The sequences encoding the peptides described herein can be inserted into vectors that can deliver and maintain the nucleic acid molecule in bacterial cells. The DNA molecule can be inserted into an autonomously replicating vector (suitable vectors include, for example, pGEM3Z and pcDNA3, and their derivatives). The vector nucleic acid can be bacterial or bacteriophage DNA, such as bacteriophage λ or M13 and their derivatives. After construction of the vector containing the nucleic acid described herein, transformation of a host cell such as bacteria can follow. Suitable bacterial hosts include, but are not limited to, E. coli, B. subtilis, Pseudomonas, and Salmonella. The gene construct includes, in addition to the coding nucleic acid molecule, elements that enable expression, such as a promoter and regulatory sequences. The expression vector may contain transcriptional control sequences that control transcription initiation, such as promoters, enhancers, operators, and repressor sequences. A variety of transcriptional control sequences are well known to those skilled in the art. The expression vector may also include translational regulatory sequences (e.g., untranslated 5' sequences, untranslated 3' sequences, or internal ribosome entry sites). The vector can be capable of autonomous replication or it can be integrated into the host DNA to ensure stability during peptide production.

[0063] Protein coding sequences containing the peptides described herein may also be fused to nucleic acids encoding peptide affinity tags, such as glutathione S-transferase (GST), maltose E binding protein, protein A, FLAG tag, 6-histidine, myc tag, or influenza HA tag, to facilitate purification. Fusion of an affinity tag or reporter joins the reading frame of the peptide of interest with the reading frame of the gene encoding the affinity tag, thereby generating a translational fusion. Expression of the fusion gene results in the translation of a single peptide containing both the peptide of interest and the affinity tag. In some cases where an affinity tag is utilized, a DNA sequence encoding a protease recognition site is fused between the reading frames for the affinity tag and the peptide of interest.

[0064] Peptides can also be produced in biological systems using gene constructs and methods suitable for the production of immature and mature forms of the peptides and variants described herein in protein expression systems other than bacteria and well known to those skilled in the art.

[0065] In some embodiments, peptides can be produced chemically. Peptides can be synthesized by several different methods, including liquid-phase and solid-phase synthesis using traditional BOC or FMOC protection. For example, peptides can be synthesized on 2-chlorotrityl chloride or Wang resin using sequential amino acid coupling. A variety of protecting groups can be used, without limitation, including: fluorenylmethyloxycarbonyl or tert-butyloxycarbonyl (α-amino group, N-terminus); trityl or tert-butyl (thiol group of Cys); tert-butyl (γ-carboxyl group of glutamic acid and hydroxyl group of threonine, if present); trityl (β-amide functional group of asparagine side chain and phenol group of tyrosine, if present); trityl or tert-butyldimethylsilyl (hydroxyl group of serine, if present), and tert-butyloxycarbonyl (N-terminus before subsequent side chain modification). Coupling, deprotection, and cleavage can be achieved by various methods. In some embodiments, coupling is achieved using DIC and HOBt in the presence of a tertiary amine, and the peptide can be deprotected and cleaved from the solid support using cocktail K (81% trifluoroacetic acid, 5% phenol, 5% thioanisole, 2.5% 1,2-ethanediol, 3% water, 2% dimethyl sulfide, 1.5% ammonium iodide w / w). The peptide can be isolated by various methods. In one embodiment, after removal of trifluoroacetic acid and other volatile substances, the peptide can be precipitated using an organic solvent. Disulfide bonds between Cys residues can be formed by various methods. In one embodiment, disulfide bonds between Cys residues can be formed using dimethyl sulfoxide (Tam et al. (1991) J.Am. Chem. Soc. 113:6657-62) or by an air oxidation strategy. The resulting peptide can be purified and lyophilized by various methods, including, without limitation, reverse-phase chromatography.

[0066] Peptides can be prepared, isolated, or used in the form of free bases or as pharmaceutically acceptable salts thereof. Examples of salts include, but are not limited to, acetates, chlorides, sulfates, and phosphates of peptides.

[0067] Composition of peptides and GC-C receptor agonists In another embodiment, compositions are provided in which peptides, alone or in combination, can be combined with any pharmaceutically acceptable carrier or medium. In some embodiments, the peptide or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutically acceptable composition. In other embodiments, the peptide or a pharmaceutically acceptable salt thereof can be formulated into a non-pharmaceutically acceptable composition. The peptide can be combined with a material that does not produce harmful, allergic, or otherwise undesirable reactions when administered to a patient. The carrier or medium used may include solvents, dispersants, coatings, absorption enhancers, controlled release agents, and one or more inert excipients (including starch, polyols, granulators, microcrystalline cellulose (e.g., Celphere, Celphere beads®)), diluents, lubricants, binders, disintegrants, etc.). If desired, tablets of the disclosed compositions can be coated by standard aqueous or non-aqueous techniques.

[0068] Examples of pharmaceutically acceptable carriers and pharmaceutically acceptable inert carriers and excipients for use as the aforementioned additional components include, but are not limited to, binders, fillers, disintegrants, lubricants, antimicrobial agents, and coatings.

[0069] As used herein, the term “binder” refers to any pharmaceutically acceptable binder that may be used in 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 starch (e.g., STARCH 1500® and STARCH 1500 LM® sold by Colorcon, Ltd., and other starches), maltodextrin, gelatin; natural and synthetic gums such as acacia, powdered tragacanth, and guar gum; cellulose and its derivatives (e.g., methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose (hypromellose)), ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose, carboxymethylcellulose, powdered cellulose, ultrafine cellulose, microcrystalline cellulose (e.g., FMC Corporation, Marcus) This includes AVCEL® products such as AVCEL-PH-101®, -103®, and -105®, sold by Hook, PA, USA, polyvinyl alcohol, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K30), and mixtures thereof.

[0070] Examples of binders that may be particularly used in pharmaceutical compositions include polyvinyl alcohol, polyvinylpyrrolidone (povidone), starch, maltodextrin, or cellulose ethers (e.g., methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose).

[0071] As used herein, the term “filler” refers to any pharmaceutically acceptable filler that may be used in practice of the present invention. Examples of pharmaceutically acceptable fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), dicalcium phosphate, tricalcium phosphate, calcium sulfate (e.g., granules or powder), microcrystalline cellulose (e.g., Avicel PH101 or Celphere CP-305), ultrafine cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch (e.g., Starch 1500), pregelatinized starch, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, isomalt, raffinose, maltitol, melegitose, stachyose, lactitol, palatinite, xylitol, myo-inositol, and mixtures thereof.

[0072] Examples of pharmaceutically acceptable fillers that may be used in particular for coating peptides include, but are not limited to, talc, microcrystalline cellulose (e.g., Avicel PH101 or Celphere CP-305), powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, isomalt, dicalcium phosphate, raffinose, maltitol, melegitose, stachyose, lactitol, palatinite, xylitol, mannitol, myo-inositol, and mixtures thereof.

[0073] As used herein, the term “additive” refers to any pharmaceutically acceptable additive. Pharmacochemically acceptable additives include, but are not limited to, disintegrants, dispersion additives, lubricants, antioxidants, coating additives, diluents, surfactants, flavoring additives, humectants, absorption enhancers, controlled-release additives, anti-caking additives, antimicrobial agents (e.g., preservatives), colorants, desiccants, plasticizers, and dyes. As used herein, “excipient” refers to any pharmaceutically acceptable additive, filler, binder, or active ingredient.

[0074] The compositions of the present invention may optionally contain other therapeutic ingredients, anti-caking agents, preservatives, sweeteners, colorants, flavorings, desiccants, plasticizers, pigments, lubricants, anti-adhesion agents, antistatic agents, surfactants (wetting agents), antioxidants, film coating agents, etc. Any such optional ingredients must be compatible with the compounds described herein in order to ensure the stability of the formulation. The compositions may contain, for example, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melegitose, stachyose, lactitol, palatinose, starch, xylitol, mannitol, myo-inositol, etc., and their hydrates, as well as other necessary additives, including amino acids such as alanine, glycine, and betaine, and peptides and proteins such as egg white.

[0075] The composition may include, for example, various additional solvents, dispersants, coatings, absorption-enhancing additives, controlled-release additives, and one or more inert additives (including, for example, starch, polyols, granulation additives, microcrystalline cellulose, diluents, lubricants, binders, disintegrants, etc.). If desired, tablets of the disclosed composition may be coated by standard aqueous or non-aqueous techniques. The composition may also include, for example, anti-caking additives, preservatives, sweeteners, colorants, flavorings, desiccants, plasticizers, and pigments.

[0076] Suitable disintegrants include, for example, agar-agar, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone, potassium polaritrin, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums, and mixtures thereof.

[0077] Suitable lubricants include, for example, calcium stearate, magnesium stearate, mineral oil, diesel fuel, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel (AEROSIL 200, WRGrace Co., Baltimore, MD USA), synthetic silica solidification aerosol (Evonik Degussa Co., Plano, TX USA), calcined silicon dioxide (CAB-O-SIL, Cabot Co., Boston, MA USA), and mixtures thereof.

[0078] Suitable lubricants include, for example, leucine, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0079] Suitable anti-caking additives include, for example, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, and mixtures thereof.

[0080] For example, suitable antimicrobial additives that can be used as preservatives for peptide compositions include, for example, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenoxyethanol, phenylmercury acetate, phenylmercury nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimersol, thymo, and mixtures thereof.

[0081] Suitable antioxidants include, for example, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, propyl gallate, ascorbic acid and its salts or esters, tocopherol and its esters, alpha-lipoic acid, and beta-carotene.

[0082] Suitable coating additives include, for example, sodium carboxymethylcellulose, cellulose phthalate acetate, ethylcellulose, gelatin, pharmaceutical glazes, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, and mixtures thereof. Suitable protective coatings include Aquacoat (e.g., Aquacoat ethylcellulose aqueous dispersion, 15% w / w, FMC Biopolymer, ECD-30), Eudragit (e.g., Eudragit E PO PE-EL, Roehm Pharma Polymers), and Opadry (e.g., Opadry AMB dispersion, 20% w / w, Colorcon).

[0083] In a particular embodiment, suitable additives for the peptide composition include one or more of sucrose, talc, magnesium stearate, crospovidone, or BHA.

[0084] The compositions of the present invention include L-histidine, Pluronic®, poloxamer (Lutrol® and poloxamer 188, etc.), ascorbic acid, glutathione, permeability enhancers (e.g., lipids, sodium cholate, acylcarnitine, salicylate, mixed bile salts, fatty acid micelles, chelating agents, fatty acids, surfactants, medium-chain glycerides), protease inhibitors (e.g., soy trypsin inhibitors, organic acids), pH-lowering agents and absorption enhancers effective in promoting bioavailability (US 6086918 and US Materials for chewable tablets (including, but not limited to, those listed in 5912014), such as dextrose, fructose, lactose monohydrate, lactose and aspartame, lactose and cellulose, maltodextrin, maltose, mannitol, microcrystalline cellulose and guar gum, and sorbitol crystals); parenteral agents (such as mannitol and povidone); plasticizers (such as dibutyl sebacate, plasticizers for coating, and polyvinyl acetate phthalate); powdered lubricants (such as glyceryl behenate); soft gelatin capsules (such as sorbitol special solution); spheres for coating (such as sugar spheres); spheroidizing agents (such as glyceryl behenate and microcrystalline cellulose); suspending / gelling agents (such as carrageenan, gellan gum, mannitol, and microcrystalline cellulose). Sucrose (aspartame, aspartame and lactose, dextrose, fructose, honey, maltodextrin, maltose, mannitol, molasses, sorbitol crystals, sorbitol special solution, sucrose); wet granulating agent (calcium carbonate, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, microcrystalline cellulose, povidone, starch-like substance), caramel, sodium carboxymethylcellulose, cherry cream flavoring and cherry flavoring, anhydrous citric acid, citric acid, powdered sugar, D&C Red No. 33, D&C Yellow No. 10 aluminum lake, disodium edetate, 15% ethyl alcohol, FD&C Yellow No. 6 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C Blue No.1. FD&C Blue No. 2 Aluminum Lake, FD&C Green No. 3, FD&C Red No. 40, FD&C Yellow No. 6 Aluminum Lake, FD&C Yellow No. 6, FD&C Yellow No. 10, glyceryl palmitostearate, glyceryl monostearate, indigocarmine, lecithin, mannitol, methyl and propyl parabens, ammonium monoglycyrrhizinate, natural and artificial orange flavoring, pharmaceutical glaze, poloxamer 188, polydextrose, polysorbate 20, polysorbate 80, polyvidone, pregelatinized starch, pregelatinized starch, red iron oxide, sodium saccharin, sodium carboxymethyl ether, sodium chloride, sodium citrate, sodium phosphate, strawberry flavoring, synthetic black iron oxide, synthetic red iron oxide, titanium dioxide, and other excipients, active substances, and their classes including but not limited to white wax may also be included.

[0085] In some embodiments, a pharmaceutical composition is provided that includes one or more stabilizers selected from the peptides described herein, and Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + , or Al 3+ , their combinations, and / or sterically hindered primary amines. In further embodiments, the active substance is Mg 2+ , Ca 2+ , or Zn 2+, or a combination thereof. In some embodiments, the cation is provided as, without limitation, magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate, or aluminum sulfate. In further embodiments, the cation is provided as magnesium chloride, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, manganese chloride, potassium chloride, sodium chloride, or aluminum chloride. In other embodiments, the cation is provided as calcium chloride, magnesium chloride, or zinc acetate.

[0086] In another embodiment, the stabilizer is a sterically hindered primary amine. In yet another embodiment, the sterically hindered primary amine is an amino acid. In yet another embodiment, the amino acid is a naturally occurring amino acid. In yet another embodiment, the naturally occurring amino acid is selected from the group consisting of histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan, glycine, and valine; furthermore, the naturally occurring amino acid is leucine, isoleucine, alanine, or methionine. In another embodiment, the sterically hindered primary amine is a naturally occurring amino acid (e.g., 1-aminocyclohexanecarboxylic acid). In yet another embodiment, the sterically hindered primary amine is a high molecular weight amine such as cyclohexylamine, 2-methylbutylamine, or chitosan. In another embodiment, one or more sterically hindered primary amines may be used in the composition.

[0087] In some cases, sterically hindered primary amines are given by formula: [ka] The formula comprises, where R1, R2, and R3 are independently selected from H, C(O)OH, C1-C6 alkyl, C1-C6 alkyl ether, C1-C6 alkyl thioether, C1-C6 alkyl carboxylic acid, C1-C6 alkyl carboxylamide, and alkylaryl, where any group may be substituted alone or multiple times with a halogen or amino, and where no more than two of R1, R2, and R3 are H. In another embodiment, no more than one of R1, R2, and R3 is H.

[0088] In other embodiments, a pharmaceutically acceptable carrier, peptide, Mg 2+ Ca 2+ Zn 2+ Mn 2+ , K + kaNa + , or Al 3+ A pharmaceutical composition is provided comprising a more selected cation, or a mixture thereof, and a sterically hindered primary amine. In one embodiment, the cation is Mg 2+ Ca 2+ , or Zn 2+ , or a mixture thereof. In further embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable binder and / or a pharmaceutically acceptable lubricant, lubricant, or additive acting as both a lubricant and a lubricant, and / or an antioxidant. In some embodiments, the pharmaceutical composition is applied to a carrier. In some embodiments, the carrier is a filler.

[0089] In some cases, the molar ratio of cation:sterically hindered primary amine:peptide in aqueous solution applied to a carrier is 5-100:5-50:1. In other cases, the molar ratio of cation:sterically hindered primary amine can be equivalent to or greater than 2:1 (e.g., 5:1-2:1). Therefore, in some cases, the molar ratio of cation:sterically hindered primary amine:peptide applied to a carrier is 100:50:1, 100:30:1, 80:40:1, 80:30:1, 80:20:1, 60:30:1, 60:20:1, 50:30:1, 50:20:1, 40:20:1, 20:20:1, 10:10:1, 10:5:1, or 5:10:1. If a binder, such as methylcellulose, is present in the GC-C agonist peptide solution applied to the carrier, it may be present in an amount of 0.5% to 2.5% by weight (e.g., 0.7% to 1.7% or 0.7% to 1% or 1.5% or 0.7%).

[0090] Mg 2+ Ca 2+ Zn 2+ Mn 2+ , K + kaNa + , and Al 3+ More selective cations have been found to be useful in suppressing the formation of oxidation products of GC-C receptor agonist polypeptides during storage. Sterically hindered primary amines have also been found to be useful in suppressing the formation of formaldehydeimine adducts ("formaldehydeimine products") of GC-C receptor agonist polypeptides during storage. Therefore, Mg 2+ Ca 2+ Zn 2+ Mn 2+ , K + kaNa + , or Al 3+ More selective cations, for example, Zn 2+ Mg 2+ , and Ca 2+GC-C receptor agonist polypeptide formulations containing more selective divalent cations and / or sterically hindered primary amines such as amino acids have a sufficient shelf life (measured by chromatographic purity and / or gravimetric assay) for drug production, storage, and distribution. Furthermore, although the presence of sterically hindered amines alone may increase the formation of hydrolysis products of GC-C receptor agonist polypeptides during storage, for example, leucine and Ca 2+ Combinations with, but not limited to, sterically hindered primary amines and cations suppress the formation of hydrolysis products, as well as oxidation products, of GC-C receptor agonist polypeptides during storage, leading to greater overall stability as determined by gravimetric assay and / or chromatographic purity.

[0091] In further embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable binder or additive, and / or a pharmaceutically acceptable lubricant, lubricant, or additive acting as both a lubricant and a lubricant, and / or an antioxidant.

[0092] A suitable pharmaceutical composition according to the present invention generally contains a certain amount of the active compound together with an acceptable pharmaceutical diluent or excipient, such as a sterile aqueous solution, which gives a final concentration in a certain range, depending on the intended use. The techniques for preparation are generally well known in the art, as exemplified by Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Company, 1995).

[0093] For the treatment of gastrointestinal disorders, the peptides described herein may be administered orally or rectally, for example, as tablets, capsules, pouches containing a predetermined amount of active ingredient pellets, gels, pastes, syrups, boluses, licks, slurries, powders, lyophilized powders, or granules, as aqueous or non-aqueous liquid solutions or suspensions; as oil-in-water or water-in-oil liquid emulsions, by liposomal formulations (see, for example, EP 736299), or in any other form. Orally administered compositions may contain binders, lubricants, inert diluents, lubricants, surfactants, or dispersants, flavorings, and humectants. Orally administered formulations, such as tablets, may be optionally coated, slitted, and formulated to provide sustained, delayed, or controlled release of the active ingredient therein. The peptides may be co-administered with other active ingredients used to treat gastrointestinal disorders, including but not limited to the active ingredients described herein.

[0094] In another embodiment, a suitable pharmaceutical composition may include one or more other therapeutic agents. Such therapeutic agents include, but are not limited to, analgesics; antisecretory agents including proton pump inhibitors, acid pump antagonists, and H2 receptor antagonists; PDE5 inhibitors; ODC inhibitors; GABA-B antagonists; bile acid chelating agents; motility enhancers and functional modifiers; antidepressants; antibiotics; antiemetics; opioids; and mucosal protectants.

[0095] Treatment methods In various embodiments, peptides or pharmaceutically acceptable salts thereof may be useful in methods for colon lavage therapy or treatment of gastrointestinal disorders. In some embodiments, peptides or pharmaceutically acceptable salts thereof may be useful in methods for lavage the colon before colonoscopy or surgical procedures. In further embodiments, peptides may be used to prepare objects for colonoscopy therapy. In some embodiments, peptides or pharmaceutically acceptable salts may be used to prepare objects for surgical procedures such as bowel surgery. In other embodiments, peptides have been used to treat gastrointestinal disorders, visceral disorders, colon cancer, hereditary nonpolyposis colorectal cancer (HNPCC), i.e., Lynch syndrome, gastroparesis (GP), polyps, pain, generalized abdominal pain, postoperative ileus, opioid-induced constipation, functional dyspepsia, SUDD (symptomatic simple diverticular disease) and SCAD (segmental colitis associated with diverticular disease), diverticular diseases including but not limited to diverticular diseases, diarrhea-predominant irritable bowel syndrome, irritable bowel syndrome (I) The present invention can treat pain associated with BS, ulcerative colitis, ulcerative proctitis, Crohn's disease, inflammatory bowel disease (IBD), chronic or acute radiation-induced proctitis, rectal pain, chronic rectal neuralgia, transient rectal neuralgia, anal pain, chronic anal fissure, postoperative anal pain, overactive bladder syndrome, stress urinary incontinence, interstitial cystitis, bladder pain syndrome, colorectal cancer, cancer-related pain, generalized pelvic pain, endometriosis, testicular pain, chronic prostatitis, prostatic pain, vulvodinia, urethral syndrome, penile pain, perianal pain, and other gastrointestinal and visceral disorders. In some embodiments of the present invention, a method of treatment is provided for gastrointestinal disorders. In one embodiment, the gastrointestinal disorder is colon cancer or polyps. In another embodiment, the gastrointestinal disorder is hereditary nonpolyposis colorectal cancer (HNPCC), i.e., Lynch syndrome. In yet another embodiment, the gastrointestinal disorder is gastrointestinal pain. In further embodiments, the gastrointestinal disorder is visceral or abdominal pain, or pain associated with cancer. In another embodiment, the gastrointestinal disorder is rectal cancer. In yet another embodiment, the gastrointestinal disorder is functional dyspepsia.

[0096] In one embodiment, a method is provided for cleansing the colon of a subject in preparation for a colonoscopy procedure, comprising administering an effective dose of a colon cleansing composition to the subject, wherein the colon cleansing composition comprises a pharmaceutically acceptable excipient, diluent, or carrier, and a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide or pharmaceutically acceptable salt thereof has an amino acid sequence: [ka] , or comprising a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK, or is absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 This is Cys, Ag, or penicillamine (Pen); Xaa 12 These are Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is either Asn or Leu; Xaa 14These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 These are Cys, Ag, Pen, or Cth; Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 It is Cys, Ag, or Pen; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro, and the peptide is Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19 It contains a covalent bond between them.

[0097] In another embodiment, a method is provided for cleansing the colon of a subject in preparation for a colonoscopy procedure, comprising administering an effective dose of a colon cleansing composition to the subject, wherein the colon cleansing composition comprises a pharmaceutically acceptable excipient, diluent, or carrier, and a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide or pharmaceutically acceptable salt thereof has an amino acid sequence: [ka] [ka] [ka] [ka] Includes.

[0098] In one embodiment, the peptides and compositions described herein provide a treatment for preparing a patient before colonoscopy.

[0099] In some embodiments, the peptides and pharmaceutically acceptable salts described herein may be used as a method for colon lavage in preparation for colonoscopy. In some embodiments, the method for colon lavage includes administering an effective first dose, such as 5 μg to 100 mg of the peptide or pharmaceutically acceptable salt. The following morning, an effective second dose, such as 5 μg to 100 mg of the peptide or pharmaceutically acceptable salt, is administered to substantially lavage the colon. In other embodiments, the peptide or pharmaceutically acceptable salt thereof is administered in a single dose of 5 μg to 200 mg.

[0100] The peptides and pharmaceutically acceptable salts described herein may be used alone or in combination to treat, prevent or reduce pain associated with gastrointestinal disorders, cancer, generalized pelvic pain, bladder pain, overactive bladder, endometriosis, testicular pain, chronic prostatitis, prostatic pain, vravodynia, urethral syndrome, penile pain, and perianal pain, or other disorders described herein.

[0101] The peptides and pharmaceutically acceptable salts described herein may be administered in combination with other active agents. For example, the peptides may be administered with analgesic peptides, soluble guanylate cyclase (sGC) stimulating factors, or compounds. The analgesic peptide or compound may be covalently attached to the peptides described herein, or it may be a separate active agent administered together with or sequentially with the peptides described herein in combination therapy. The peptides and pharmaceutically acceptable salts described herein may also be administered in combination with other agents used to treat GI disorders, including but not limited to antidepressants, functional modifiers or motility enhancers, antiemetics, antibiotics, proton pump inhibitors, acid blockers (e.g., histamine H2 receptor antagonists), acid pump antagonists, PDE5 inhibitors, ODC inhibitors, GABA-B agonists, bile acid chelators, COX-2 inhibitors, NSAIDs, corticosteroids, opioids, β-3 adrenergic receptor agonists; muscarinic receptor antagonists, tricyclic antidepressants, and anticholinergic agents, including but not limited to mucoprotectants.

[0102] In other embodiments, therapeutic combinations of peptides include celecoxib, slidac and other nonsteroidal anti-inflammatory drugs (NSAIDS), as well as phosphodiesterase (PDE) inhibitors and ornithine decarboxylase (ODC) inhibitors (e.g., d,l-α-difluoromethylornithine DFMO) for colon polyps such as idiopathic and Lynch syndrome; mesalamine or 5-aminosalicylic acid (5-asa), or steroids, budesonides, for inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis); opioids, tramadol, and isomers and analogs of tramadol, for chronic pain, including cancer pain; or elxalodine.

[0103] In some embodiments, useful analgesics that may be used with the peptides described herein include Ca channel blockers (e.g., diconotides), 5HT receptor antagonists (e.g., 5HT3, 5HT4, and 5HT1 receptor antagonists), 5HT4 agonists (e.g., tegaserod (Zelnorm®), mosapride, metoclopramide, zacoprid, cisapride, lenzaprid, benzimidazolon derivatives such as BIMU1 and BIMU8, and rilexapride), 5HT 1 agonists (e.g., sumatriptan and buspirone), opioid receptor agonists (e.g., loperamide, fedotodin, enkephalin pentapeptide, morphine, diphenyloxylate, flacaefamide, trimebutine, and fentanyl), CCK receptor agonists (e.g., roxiglumide and dexroxiglumide), NK1 receptor antagonists (e.g., aprepitant, vofopitant, ezropitant, R-673 (Hoffmann-La) Roche Ltd., SR-48968 and SR-14033 (Sanofi Synthelabo), CP-122,721 (Pfizer, Inc.), GW679769 (Glaxo Smith Kline), and TAK-637 (Takeda / Abbot)), NK2 receptor antagonists (e.g., Nepadutant, Saledutant, GW597599 (Glaxo Smith Kline), SR-144190 (Sanofi-Synthelabo), and UK-290795 (Pfizer) This includes NK3 receptor antagonists (e.g., osanetant (SR-142801; Sanofi-Synthelabo), SR-241586, and tarnetant), norepinephrine-serotonin reuptake inhibitors (NSRIs) (e.g., milnacipran), vanilloid and cannabanoid receptor agonists, sialorphines, and sialorphine-related peptides. Various classes of analgesics are described in the literature.

[0104] In some embodiments, one or more other therapeutic agents may be used in combination with the peptides described herein. Such agents include antidepressants, functional modifiers or motility enhancers, antiemetics, antibiotics, proton pump inhibitors, acid blockers (e.g., histamine H2 receptor antagonists), acid pump antagonists, PDE5 inhibitors, ODC inhibitors, GABA-B agonists, bile acid chelating agents, opioids, and mucosal protective agents.

[0105] Examples of antidepressants include, but are not limited to, tricyclic antidepressants such as amitriptyline (Elavir®), desipramine (Norpramin®), imipramine (Tofranil®), amoxapine (Asendin®), and nortriptyline; selective serotonin reuptake inhibitors (SSRIs) such as paroxetine (Paxil®), fluoxetine (Prozac®), sertraline (Zoloft®), and citralopram (Celexa®); and others such as doxepin (Sinequan®) and trazodone (Desyrel®).

[0106] Examples of functional modifiers and exercise promoters include, but are not limited to, itopride, octreotide, betanazole, metoclopramide (Reglan®), domperidone (Motilium®), erythromycin (and its derivatives), and cisapride (Propulsid®). Examples of antiemetics include, but are not limited to, prochlorperazine.

[0107] Examples of antibiotics that may be used include amoxicillin, tetracycline, metronidazole, or clarithromycin, which may be used to treat Heliobacter pylori infection. Other antibiotics, such as erythromycin and its derivatives, may also be used in combination with the peptides described herein.

[0108] Examples of proton pump inhibitors include, but are not limited to, omeprazole (Prilosec®), esomeprazole (Nexium®), lansoprazole (Prevacid®), pantoprazole (Protonix®), and rabeprazole (Aciphex®). Examples of H2 receptor blockers include, but are not limited to, cimetidine, ranitidine, famotidine, and nizatidine. Examples of acid pump antagonists include, but are not limited to, levaprazan, CS-526 (J.Pharmacol.Exp.Ther.(2007)323:308-317), PF-03716556 (J.Pharmacol.Exp.Ther.(2009)328(2):671-9), and YH1885 (Drug Metab.Dispos.(2001)29(1):54-9).

[0109] Examples of PDE5 inhibitors include, but are not limited to, avanafil, rodenafil, mirodenafil, sildenafil citrate, tadalafil, vardenafil, and udenafil. Examples of GABA-B agonists include, but are not limited to, baclofen and XP19986 (CAS registry number 847353-30-4). Examples of bile acid chelating agents include, but are not limited to, GT102-279, cholestyramine, coleseveram, coleseveram hydrochloride, ursodeoxycholic acid, cholestipol, cholestylane, sevelamer, polydiallylamines crosslinked with epichlorohydrin, dialkylaminoalkyl derivatives of crosslinked dextran, and N-(cycloalkyl)alkylamines. Examples of mucosal protective agents include, but are not limited to, sucralfate (Carafate), teprenone, polaprezinc, cetraxate, and bismuth subsalicylate.

[0110] Combination therapy can be achieved by administering two or more types of activators, each formulated and administered separately, such as peptides or pharmaceutically acceptable salts described herein, and another therapeutic peptide or compound, or by administering two or more types of activators in a single formulation. Other combinations are also encompassed by combination therapy. For example, two activators may be formulated together and administered in combination with a separate formulation containing a third activator. While two or more types of activators in combination therapy may be administered simultaneously, they do not necessarily have to be. For example, the administration of the first activator (or combination of activators) may precede the administration of the second active agent (or combination of active agents) by several minutes, several hours, several days, or several weeks. Therefore, two or more types of activators may be administered within a few minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable, though not necessary, for two or more types of activators used in combination therapy to be present in the patient's body at the same time.

[0111] Dosage The dosage range for adults, with respect to the peptides and pharmaceutically acceptable salts described herein, may generally be 5 μg to 100 mg / day, orally or rectally. Tablets, capsules, or other forms of presentation provided in individual units may conveniently contain a certain amount of the compounds described herein, effective in such dosages or as multiple doses; for example, a unit may contain 25 μg to 2 mg or approximately 100 μg to 1 mg. The exact amount of the compound prescribed to a patient is the responsibility of the attending physician. However, the dosage adopted depends on several factors, including the patient's age and sex, the exact disorder being treated, and its severity.

[0112] In various embodiments, the medication unit is administered with food at any time of day, without food at any time of day, with food after an overnight fast (e.g., with breakfast), or before bedtime after a low-fat snack. In one particular embodiment, the medication unit is administered before or after food consumption (e.g., a meal). In further embodiments, the medication unit is administered approximately 15 minutes to 1 hour before food consumption. In various embodiments, the medication unit is administered once, twice, three, four, five, or six times a day. In one particular embodiment, the medication unit and daily dose are equivalent.

[0113] In some embodiments, compositions containing the peptides described herein are provided in divided doses. These divided doses are administered the night before and on the day of the colonoscopy. In other embodiments, the dosage is provided as a single dose the night before, the day before, or on the day of the colonoscopy.

[0114] In embodiments of the combination therapy of the present invention, the precise amount of each of the two or more active ingredients in a dosing unit depends on the desired dosage of each component. Therefore, it may be useful to create dosing units that, when administered according to a specific dosing schedule (e.g., a schedule specifying a certain number of units and specific timing of administration), deliver the same dosage of each component as the patient would receive if treated with a single component alone. In other situations, it may be desirable to create dosing units that deliver one or more components in a lower dosage than the patient would receive if treated with a single component alone. Finally, it may be desirable to create dosing units that deliver one or more components in a higher dosage than the patient would receive if treated with a single component alone.

[0115] The pharmaceutical composition may include, but is not limited to, the active ingredients and excipients described herein, as well as additional components. In certain embodiments, one or more therapeutic agents in a dosing unit may be present in a long-release or controlled-release formulation, while additional therapeutic agents may not be present in the long-release formulation. For example, a peptide or agonist described herein may be present in a controlled-release or long-release formulation in the same dosing unit, along with another agent that may or may not be present in either a controlled-release or long-release formulation. Therefore, in certain embodiments, it may be desirable to provide immediate release of one or more of the agents described herein, and controlled release of one or more other agents.

[0116] The present invention is described in relation to certain exemplary embodiments. However, it will be readily apparent to those skilled in the art that the present invention can be employed in specific forms other than those of the exemplary embodiments described above. This can be done without departing from the spirit of the invention. The exemplary embodiments are merely illustrative and should not be considered restrictive in any way. The scope of the present invention is defined more by the appended claims and their equivalents than by the prior description. [Examples]

[0117] Example 1: cGMP accumulation in T84 cells for analysis of GC-C activity. For cGMP assay, 2.0 × 10 5T84 cells at a concentration of cells / mL were grown overnight in 96-well tissue culture plates. The following day, the T84 cells were washed twice with 200 μL of DMEM + 20 mM MES (pH 5) or DMEM + 50 mM sodium bicarbonate (pH 8) or DMEM without additives for pH 7. These buffers were serum-free. After the second wash, the cells were incubated at 37°C for 10 minutes with 180 μL of 1 mM isobutylmethylxanthine (IBMX) in either a pH 5, 7, or 8 buffer to inhibit any phosphodiesterase activity. The peptides were then diluted to a 10× concentration in either a pH 5, 7, or 8 buffer. 20 μL of the peptide solution was diluted to a final volume of 200 μL with T84 cells, bringing each peptide concentration to 1×. An 11-point curve analysis was performed for each peptide using the final peptide concentrations tested in each assay, at nM levels of 10000, 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1.

[0118] No peptide control was used to determine endogenous levels of cGMP. The peptide was incubated at 37°C for 30 minutes. After 30 minutes, the supernatant was removed and the cells were lysed with 200 μL of 0.1 M HCl. The cells were lysed on ice for 30 minutes. After 30 minutes, the lysate was pipetted and placed in a 96-well HPLC plate and spun at 10,000 × G for 10 minutes to remove any cell debris. The supernatant from the previous spin was removed and placed in a fresh 96-well HPLC plate. The sample was neutralized for better chromatography by diluting it with an equal volume of 1 M ammonium acetate (pH 7). A 2 × cGMP standard curve was prepared with 0.1 M HCl and then diluted with an equal volume of 1 M ammonium acetate, resulting in the following final concentrations in ng / mL: 1000, 500, 250, 125, 50, 25, 5, 2.5, and 0.5. The ST core peptide (hereinafter, ST core) has the following amino acid sequence: [ka] It has.

[0119] The cGMP concentration was determined from each sample using the LC / MS conditions and calculated standard curves shown in Table 4. The EC was determined from the concentration response curve generated using GraphPad Prism software. 50 The values ​​were calculated. The results for the selected peptides can be found in Figures 1-14, 23, and 24. [Table 1]

[0120] Example 2: GC-C binding assay All GC-C bonding was performed at pH 5, 7, or 8 in a final volume of 200 μL of medium. A pH 5 medium was prepared using DMEM, 0.5% BSA, and 20 mM 2-(N-morpholino)ethanesulfonic acid (MES). A pH 7 medium was prepared using DMEM and 0.5% BSA. A pH 8 medium was prepared using DMEM and 0.5% BSA together with 20 mM sodium bicarbonate.

[0121] T84 cells were used at a rate of 250,000 cells per reaction. Cells were grown to confluence in T-150 flasks using DMEM-F12 50 / 50 medium, 5 mM L-glutamine, and 5% FBS. Cells were scraped and counted using DMEM and 0.5% BSA to determine how much volume to add to give 250,000 cells per reaction in a final volume of 200 μL. Next, 200,000 CPM of I125-STp, a cold peptide competitor, and then T84 cells were added per reaction to initiate the reaction. The sample was then incubated at 37°C for 1 hour. After 1 hour, the entire sample was added to a pre-blocked GF-C plate and aspirated. Each well was then washed twice with 200 μL of chilled PBS. The bottom of the filter plate was removed, and the 96-well plate was dried at 50°C. After drying, 100 μL of scintillation solution was added to each well, and the mixture was gently vortexed before counting. The results for the selected peptides can be found in Figures 1 and 23.

[0122] Example 3: In vitro metabolic incubation of rat intestinal fluid (RIF) Rat intestinal fluid was obtained by adding PBS to ligated rat jejunal loops for 30 minutes. The fluid was then collected, pooled, and kept on ice before centrifugation at 4°C. The supernatant was removed and rapidly frozen. 60 μM peptide (100 μg / mL) was then added to the rat intestinal fluid along with PBS and 0.5% BSA. A control incubation was performed in PBS. Subsequently, 50 μL aliquots from all samples were taken in pairs at 0, 10, 30, and 60 minutes and stopped with 12% trichloroacetic acid containing an internal standard.

[0123] The samples were spun, and the supernatant was extracted for LC-MS analysis using the calculated precise mass of each peptide (or predicted metabolite) to produce extracted ion chromatograms. The residual percentage compared to time = 0 was constructed using the relative response coefficient (analyte peak area / internal standard peak area) for each sample. Results for selected peptides can be found in Figures 1, 20, 21, and 23.

[0124] Example 4: In vivo ligated rat loop First, a 60 μM peptide was prepared in 200 μL of PBS. This solution was injected into ligated rat duodenal loops approximately 3–5 cm in length. Three animals were used per peptide at each time point. The loops were excised, measured, and weighed at 30 and 60 minutes. The body fluids were then collected in Eppendorf tubes and rapidly frozen, and the loops were re-weighed to determine their empty weights. The samples were then thawed and spun, and the supernatant was taken from each sample. A 50 μL aliquot was then taken and added to 12% trichloroacetic acid containing an internal standard.

[0125] The extracted ion chromatograms were generated by analyzing each peptide (or predicted metabolite) using the calculated precise mass by LC-MS. The residual percentage compared to time = 0 was constructed using the relative response coefficient (analyte peak area / internal standard peak area) for each sample. The amount of fluid secretion during incubation was determined by the formula (fluid secretion = (total loop - empty loop) / length). This formula was used to calculate how much fluid entered the loop at each time point. Results for the selected peptides can be found in Figures 15, 16, 18, 19, 22, and 23.

[0126] Example 5: Preparation of dicarbapeptides Dicarbapeptides were prepared using standard Fmoc- / Trt / Otbu protected amino acids. Dicarbapeptides were synthesized using Protein Technologies Symphony X® with amino acids dissolved in dimethylformamide (DMF) at a concentration of 0.5 M. Fmoc-Cys(Trt)-OH was dissolved in a solution containing 0.5 M oxyma pure in DMF. Next, HCTU was dissolved in 0.5 M NMP, and 1.0 M DIPEA in NMP was also used. DIC was dissolved in 0.5 M NMP. Fmoc deprotection was performed using a solution containing 20% ​​piperidine in DMF.

[0127] Fmoc-Cys(Trt)-O-Wang resin (0.2 mmol, 0.29 mmol / g) was treated with 20% piperidine in DMF (3 × 6 mL, 3 minutes, 1 × 6 mL, 10 minutes). The resulting resin was washed with DMF (6 × 10 mL, 30 seconds). A pre-mixed solution containing Fmoc-Xaa-OH, HCTU, and DIPEA in NMP was added for 30 seconds, and the mixture was stirred for 30 minutes. The resin was filtered and washed once with DMF. A second pre-mixed solution containing Fmoc-Xaa-OH, HCTU, and DIPEA in NMP was added for 30 seconds, and the mixture was stirred again for 30 minutes. In the case of Fmoc-Cys(Trt)-OH, the amino acid / oxyma solution was mixed with DIC in NMP for 5 minutes, added to the resin, and stirred for 45 minutes. The resin was filtered and washed once with DMF. The resulting resin was filtered and washed with DMF (6 × 10 mL). The material was subjected to the protocol described above, and the peptide was extended to its entire sequence. To dry the resin before metathesis, the resin was washed with CH2Cl2 (3 × 10 mL) and hexane (3 × 10 mL), and dried overnight under reduced pressure. The material was subjected to the protocol described above, and the peptide was extended to macrocyclic form.

[0128] The following procedure was used to perform metathesis on the peptide. 500 mg (0.1 mmol) of protected resin-bound peptide was added to 5 mL of a 4:1 DMA solution containing 6 mg / mL of HGII in 1,2-dichloroethane-0.4 M LiCl. The resulting suspension was heated to 160°C for 5 minutes in a 200 W microwave oven. The suspension was cooled, filtered, and washed with dichloromethane (3 × 10 mL) and NMP (3 × 10 mL). A small portion was cut to determine if metathesis was complete. The resin was immersed overnight in 10% DMSO (10 mL) in NMP solution to remove excess HGII catalyst. The resulting resin was washed with NMP (3 × 10 mL) and treated with 20% piperidine in DMF (3 × 15 mL, 10 minutes). The resin was washed with DMF (5 × 10 mL), CH2Cl2 (3 × 10 mL), and hexane (3 × 10 mL), and then dried under reduced pressure.

[0129] To cleave the peptide from the resin, the resin was treated with a solution (20 mL) containing 90:5:5 TFA-TIPS-H2O. After 2 hours, the resin was filtered, washed with TFA (3 mL), and concentrated to 50%. Cold (-78°C) ether was added to the solution (50 mL), and the resulting mixture was centrifuged at 3500 rpm for 10 minutes. The ether was decanted, and the solid was subjected to two further washes with cold (-78°C) ether and centrifuged. The resulting solid was dried under reduced pressure, dissolved in 1:1 H2O-ACN, frozen, and freeze-dried.

[0130] Peptides were purified using a Waters Autopure® system with 0.1% TFA in water and 0.1% TFA in acetonitrile on a Waters PST C18 RP column (250 × 30 mm, 10 μm, 130 Å) at a flow rate of 40 mL / min. A linear gradient with 5–45% acetonitrile was used for 40 or 60 minutes. Fractions containing the desired product were pooled and oxidized.

[0131] To oxidize the cysteine ​​residue for disulfide bond formation, the following procedure was used: 5 mL of DMSO was added to a solution containing 100 mL of 0.05 N NH4HCO3 (pH approximately 8) in a 9:1 water-acetonitrile mixture. After 72 hours, oxidation appeared complete by HPLC, and the material was acidified with acetic acid, frozen, and lyophilized. The peptide was purified using a Waters Autopure system with 0.1% TFA in water and acetonitrile on a Waters PST C18 RP column (250 × 30 mm, 10 μm, 130 Å) at a flow rate of 40 mL / min. A linear gradient was used over 60 minutes from 5–40% acetonitrile. The fraction containing the desired product was pooled and lyophilized.

[0132] Example 6: Preparation of cystathionine-containing peptide Materials were synthesized using Protein Technologies Symphony X® with amino acids dissolved in 0.5 M DMF. Fmoc-Cys(Trt)-OH was dissolved in a solution containing 0.5 M oxyma pure in DMF. HCTU was dissolved in 0.5 M NMP, and 1.0 M DIPEA in NMP was also used. DIC was dissolved in 0.5 M NMP. Fmoc deprotection was performed using a solution containing 20% ​​piperidine in DMF.

[0133] To couple the peptide to the resin, Rink amide resin (0.2 mmol, 0.24 mmol / g) was treated with 20% piperidine in DMF (3 × 6 mL, 3 minutes, 1 × 6 mL, 10 minutes). The resulting resin was washed with DMF (6 × 10 mL, 30 seconds). A pre-mixed solution containing Fmoc-Xaa-OH, HCTU, and DIPEA in NMP was added for 30 seconds, and the mixture was stirred for 30 minutes. The resin was filtered and washed once with NMP. A second pre-mixed solution containing Fmoc-Xaa-OH, HCTU, and DIPEA in NMP was added for 30 seconds, and the mixture was stirred again for 30 minutes. In the case of Fmoc-Cys(Trt)-OH, the amino acid / oxyma pure solution was mixed with DIC in NMP for 5 minutes, added to the resin, and stirred for 45 minutes. The resin was filtered and washed once with DMF. The resulting resin was filtered and washed with DMF (6 × 10 mL). The material was subjected to the protocol described above, and the peptide was extended to macrocyclic form.

[0134] To couple the diamino acids, the resin was treated with 20% piperidine in DMF (3 × 6 mL, 3 minutes, 1 × 6 mL, 10 minutes). The resulting resin was washed with DMF (6 × 10 mL, 30 seconds). A solution containing alloc-HCys((Fmoc-Ala-OH)-3-yl)-all (227 mg, 0.4 mmol), PyAOP (209 mg, 0.4 mmol), and DIPEA (139 μl, 125 mg, 0.8 mmol) in 5 mL of NMP was added to the resin. After 90 minutes, the resin was filtered and washed with DMF (6 × 10 mL). The peptide was then extended using the protocol described above.

[0135] To perform allyl-Alloc deprotection, the resin (0.2 mmol) was suspended in 10 mL of DMF, and a solution containing Pd(PPh3)4 (300 mg, 0.26 mmol) in 10 mL of CH2Cl2 was added, followed by 0.25 mL (2 mmol) of phenylsilane. The resulting mixture was shaken in the dark for 2 hours. A small sample was cut to ensure complete deprotection. The resulting resin was filtered and washed with CH2Cl2 (3 × 10 mL) and DMF (3 × 10 mL). The resin was treated with a solution containing 0.5% sodium diethyldithiocarbamate in DMF (10 mL, 4 × 15 minutes) and washed with DMF (3 × 10 mL).

[0136] To perform macrocyclic synthesis, the resin was treated with 20% piperidine in DMF solution (2 × 5 minutes, 1 × 10 minutes, 15 mL) and washed with DMF (6 × 15 mL). A solution containing 521 mg (1 mmol) of PyAOP was added to 15 mL of DMF, and after 1 minute, 0.35 mL (2 mmol) of DIPEA was added and shaken for 60 minutes. A small sample was taken for analysis. The resulting resin was washed with DMF (3 × 15 mL) and returned to SymphonyX to complete the synthesis.

[0137] To cleave the peptide from the resin, the resin was treated with a solution (20 mL) containing 90:5:3:2 TFA-TIPS-DODT-H2O. After 2 hours, the resin was filtered, washed with TFA (3 mL), and concentrated to 50%. Cold (-78°C) ether was added to the solution (50 mL), and the resulting mixture was centrifuged at 3500 rpm for 10 minutes. The ether was decanted, and the solid was subjected to two further washes with cold (-78°C) ether and centrifuged. The resulting solid was dried under reduced pressure, dissolved in 1:1 H2O-ACN, frozen, and freeze-dried. The peptide was then purified using a Waters autopure system with 0.1% TFA in water and 0.1% TFA in acetonitrile on a Waters PST C18 RP column (250 × 30 mm, 10 μm, 130 Å) at a flow rate of 40 mL / min. A linear gradient of 5–45% acetonitrile was used for 40 or 60 minutes. The fractions containing the desired product were pooled and oxidized.

[0138] Oxidation was carried out by adding 5 mL of DMSO to a solution containing 100 mL of 0.05 N NH4HCO3 (pH approximately 8) in a 9:1 water-acetonitrile mixture. After 72 hours, oxidation appeared complete by HPLC, and the material was acidified with acetic acid, frozen, and lyophilized. The peptide was purified using a Waters Autopure® system with 0.1% TFA in water and 0.1% TFA in acetonitrile at a flow rate of 40 mL / min on a Waters PST C18 RP column (250 × 30 mm, 10 μm, 130 Å). A linear gradient was used over 60 minutes from 5–40% acetonitrile. The fraction containing the desired product was pooled and lyophilized.

[0139] Example 7: Production of lactam-binding-containing peptide Peptides were synthesized using standard Fmoc- / Trt / Otbu protected amino acids. Materials were synthesized using Protein Technologies Symphony X® with amino acids dissolved in 0.5 M DMF. Fmoc-Cys(Trt)-OH was dissolved in a solution containing 0.5 M oxyma pure in DMF. HCTU was dissolved in 0.5 M NMP, and 1.0 M DIPEA in NMP was also used. DIC was dissolved in 0.5 M NMP. Fmoc deprotection was performed using a solution containing 20% ​​piperidine in DMF. Unusual amino acids were manually coupled as described below.

[0140] To incorporate Fmoc-Dpr(ivDde)-OH, a solution containing 533 mg (1.0 mmol) of Fmoc-Dpr(ivDde)-OH, 521 mg (1.0 mmol) of PyAOP, and 348 μL (258 mg, 2.0 mmol) of DIPEA in 6 mL of DMF was added to a deprotected resin (0.2 mmol). After 90 minutes, the resin was filtered and washed with DMF (3 × 10 mL), CH2Cl2 (3 × 10 mL), and again with DMF (3 × 10 mL). The resin was returned to the synthesizer and synthesis was continued.

[0141] To incorporate Fmoc-Asp(ODmab)-OH, a solution containing 667 mg (1.0 mmol) of Fmoc-Asp(Odmab)-OH, 521 mg (1.0 mmol) of PyAOP, and 348 μL (258 mg, 2.0 mmol) of DIPEA in 6 mL of DMF was added to a deprotected resin (0.2 mmol). After 90 minutes, the resin was filtered and washed with DMF (3 × 10 mL), CH2Cl2 (3 × 10 mL), and again with DMF (3 × 10 mL). For final deprotection, the resin was returned to the synthesizer.

[0142] To protect the N-terminus with Boc, the resin was treated with 218 mg (1.0 mmol) of di-tert-butyl dicarbonate in 5 mL of DMF. After 4 hours, a small sample (approximately 10 mg) was taken out and checked for completion by acetylation with 10 μL of acetic anhydride and 30 μL of DIPEA in DMF. The resulting resin was washed with DMF (5 × 10 mL) and treated with 100 μL of acetic anhydride and 300 μL of DIPEA in DMF for 50 minutes. The resulting resin was washed with DMF (6 × 10 mL).

[0143] To remove ivDDE and Dmab, the protected resin was treated with a solution containing 2% hydrazine monohydrate in DMF (5 × 5 mL, 5 minutes). The resulting resin was washed with DMF (6 × 10 mL).

[0144] To form a lactam, the resin was treated with 521 mg (1.0 mmol) of PyAOP and 348 μL (258 mg, 2.0 mmol) of DIPEA in 5 mL of DMF. The resulting mixture was heated in a microwave oven (200 W) to 100°C for 10 minutes. The resulting resin was cooled, filtered, washed with DMF (6 × 10 mL) and CH2Cl2 (6 × 10 mL), and dried under reduced pressure.

[0145] To cleave the peptide from the resin, the resin was treated with a solution (20 mL) containing 90:5:3:2 TFA-TIPS-DODT-H2O. After 2 hours, the resin was filtered, washed with TFA (3 mL), and concentrated to 50%. Cold (-78°C) ether was added to the solution (50 mL), and the resulting mixture was centrifuged at 3500 rpm for 10 minutes. The ether was decanted, and the solid was subjected to two further washes / centrifugations using cold (-78°C) ether. The resulting solid was dried under reduced pressure, dissolved in 1:1 H2O-ACN, frozen, and freeze-dried.

[0146] To oxidize the peptide, crude peptide (280 mg) was dissolved in water, and the mixture was treated with solid NH4HCO3 to adjust the pH to >7. Then, 20 mL of acetonitrile was added, followed by 10 mL of DMSO. After 24 hours, oxidation appeared complete by HPLC, and the material was acidified to approximately pH 2 with trifluoroacetic acid, filtered, frozen, and lyophilized.

[0147] Peptides were purified using a Waters Autopure® system with 0.1% TFA in water and 0.1% TFA in acetonitrile on a Waters PST C18 RP column (250 × 30 mm, 5 μm, 130 Å) at a flow rate of 40 mL / min. A linear gradient from 5% 0.1% TFA in acetonitrile to 25% 0.1% TFA in acetonitrile was used over 40 minutes. Fractions containing the desired product were pooled, frozen, and freeze-dried. The material was subjected to a second pass of purification.

[0148] Peptides were purified using a Waters Autopure® system with 0.1% TFA in water and 0.1% TFA in acetonitrile on a Waters PST C18 RP column (250 × 19 mm, 5u, 130A) at a flow rate of 20 mL / min. A linear gradient from 15% 0.1% TFA in acetonitrile to 25% 0.1% TFA in acetonitrile was used over 60 minutes. Fractions containing the desired product were pooled, frozen, and lyophilized to obtain a colorless solid.

[0149] Example 8: Gastrointestinal transport in mice The objective of the assay was to test the effect of guanylate cyclase C agonist peptides on in vivo gastrointestinal transport in mice. Orally administered guanylate cyclase C agonists were shown to increase the circulating distance of charcoal diets in mice.

[0150] For the assay, female CD-1 mice weighing 25-30 g (n=10 per group) were fasted overnight and given free access to water. Activated carbon (20 g; 100 mesh; Sigma catalog #242276) was suspended in 200 mL of gum arabic (100 mg / mL) and stirred for at least 1 hour. The test peptide was prepared in a 20 mM Tris pH 6.9 vehicle.

[0151] The test peptide and vehicle were administered orally in 200 μL doses via force-feeding. Seven minutes after administration of the test peptide, 200 μL of charcoal / gum arabic suspension was administered orally via force-feeding. Fifteen minutes later, the mice were sacrificed by CO2 overdose. The gastrointestinal tract was removed from the esophagus to the cecum. The total length of the small intestine was measured from the pyloric junction to the ileocecal junction. The distance traveled by the charcoal from the pyloric junction to the front of the charcoal was measured. The circulating distance (%) was determined as (distance traveled by charcoal / total length of the small intestine) × 100. The data were input into the GraphPad Prism software program and analyzed by ANOVA with Bonferroni multiple comparison post-hoc tests. Data plotting and ED were performed using the GraphPad Prism software package. 50 The results for the selected peptides can be found in Figures 17, 25, 26, and 27.

[0152] Other Embodiments All publications and patents referenced herein are incorporated herein by reference to the same extent as each individual publication or patent application is specifically and individually indicated as being incorporated by reference. If the meaning of any term in any of the incorporated patents or publications conflicts with the meaning of any term used herein, the meaning in this disclosure is intended to prevail. Furthermore, the foregoing descriptions merely disclose and describe exemplary embodiments of the invention. Those skilled in the art will readily recognize from such descriptions, as well as from the accompanying drawings and claims, that various changes, modifications, and variations can be made within the spirit and scope of the invention as defined in the following claims. The present invention provides, for example, the following items: (Item 1) A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence [ka] , or comprising a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK, or is absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 This is Cys, Ag, or penicillamine (Pen); Xaa 12 These are Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is either Asn or Leu; Xaa 14 These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 These are Cys, Ag, Pen, or Cth; Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 It is Cys, Ag, or Pen; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro; and The peptides are Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19 The peptide or a pharmaceutically acceptable salt thereof, comprising a covalent bond between them. (Item 2) The N-terminus is capped with acetic acid, pentenoic acid, biotin, 4-Mepip, C12 alkyl carboxylic acid, C14 alkyl carboxylic acid, C16 alkyl carboxylic acid, or C18 alkyl carboxylic acid, as described in item 1 or a pharmaceutically acceptable salt thereof. (Item 3) A peptide or pharmaceutically acceptable salt thereof as described in either item 1 or 2, wherein the C-terminus is amidated. (Item 4) Xaa7 and Xaa 12 Both are Ag, and the dicarba bond is Ag7 and Ag 12 It exists between; Xaa7 and Xaa 12 Both are Cys, and the disulfide bond is between Cys7 and Cys 12 It exists between; Xaa8 and Xaa 16 Both are Cys, and the disulfide bond is Cys8 and Cys 16 It exists between; Xaa7 is Cth, and Xaa 12 It is Cys, and the bond is Cth7 and Cys 12 It exists between; Xaa8 is Cth, and Xaa 16 It is Cys, and the bond is Cth8 and Cys 16 It exists between; Xaa 11 and Xaa 19 It is Cys, and the disulfide bond is Cys 11 and Cys 19 It exists between; or Any combination of those A peptide or a pharmaceutically acceptable salt thereof as described in any one of items 1-3. (Item 5) Xaa7 is allylglycine, Cth, or Cys, a peptide or pharmaceutically acceptable salt thereof as described in any one of items 1-3. (Item 6) Xaa8 is Cys or cystathionine, a peptide or pharmaceutically acceptable salt thereof as described in any one of items 1-3. (Item 7) Xaa9 is Glu, a peptide or pharmaceutically acceptable salt thereof as described in any one of items 1-6. (Item 8) Xaa 10 Leu is a peptide or pharmaceutically acceptable salt thereof as described in any one of items 1-7. (Item 9) Xaa 12 The peptide is Cys or allylglycine, as described in any one of items 1-8, or a pharmaceutically acceptable salt thereof. (Item 10) Xaa 14 The peptide or pharmaceutically acceptable salt thereof described in any one of items 1-9 is Val or Pro. (Item 11) Xaa 17 The peptide or pharmaceutically acceptable salt thereof described in any one of items 1-10, which is Tyr or Thr. (Item 12) Xaa 20 Tyr is or is lacking in any one of items 1-11, the peptide or pharmaceutically acceptable salt thereof. (Item 13) Xaa 21 The peptide or pharmaceutically acceptable salt thereof described in any one of items 1 through 12 is lacking. (Item 14) Xaa1 is missing; Xaa2 is missing; Xaa3 is missing; Xaa4 is missing; Xaa5 is missing; Xaa6 is missing; Xaa7 is Ag, Cys, or Cth; Xaa8 is either Cys or Cth; Xaa9 is Glu; Xaa10 is Leu; Xaa 12 is Ag or Cys; Xaa 14 is either Val or Pro; Xaa 17 is Tyr or Thr; and Xaa 20 is Tyr or lacking The peptides listed in item 1 or pharmaceutically acceptable salts thereof. (Item 15) The aforementioned peptide has the following amino acid sequence: [ka] Peptides or pharmaceutically acceptable salts thereof, including those listed in item 13. (Item 16) The aforementioned peptide has the following amino acid sequence: [ka] [ka] [ka] [ka] Peptides or pharmaceutically acceptable salts thereof, including those listed in item 1. (Item 17) A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence [ka] , or a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK, or is absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 This is Cys, Ag, or penicillamine (Pen); Xaa 12 These are Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is either Asn or Leu; Xaa 14 These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 These are Cys, Ag, Pen, or Cth; Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 It is Cys, Ag, or Pen; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro; and The peptides are Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19 The peptide or a pharmaceutically acceptable salt thereof, comprising a covalent bond between them. (Item 18) The N-terminus is capped with acetic acid, pentenoic acid, biotin, 4-Mepip, C12 alkyl carboxylic acid, C14 alkyl carboxylic acid, C16 alkyl carboxylic acid, or C18 alkyl carboxylic acid, as described in item 17, or a pharmaceutically acceptable salt thereof. (Item 19) The C-terminus is amidated, and the peptide or pharmaceutically acceptable salt thereof as described in either item 17 or 18. (Item 20) Xaa7 and Xaa 12 Both are Ag, and the dicarba bond is Ag7 and Ag 12 It exists between; Xaa7 and Xaa 12 Both are Cys, and the disulfide bond is between Cys7 and Cys 12 It exists between; Xaa8 and Xaa 16 Both are Cys, and the disulfide bond is Cys8 and Cys 16 It exists between; Xaa7 is Cth, and Xaa 12 It is Cys, and the bond is Cth7 and Cys 12 It exists between; Xaa8 is Cth, and Xaa 16 It is Cys, and the bond is Cth8 and Cys 16 It exists between; Xaa 11 and Xaa 19 It is Cys, and the disulfide bond is Cys 11 and Cys 19 It exists between; or Any combination of those A peptide or a pharmaceutically acceptable salt thereof as described in any one of items 17-19. (Item 21) Xaa7 is allylglycine or Cys, the peptide described in any one of items 17-19 or a pharmaceutically acceptable salt thereof. (Item 22) Xaa8 is Cys or cystathionine, a peptide or pharmaceutically acceptable salt thereof as described in any one of items 17-19. (Item 23) Xaa9 is Glu, a peptide or pharmaceutically acceptable salt thereof as described in any one of items 17-22. (Item 24) Xaa 10 Leu is a peptide or pharmaceutically acceptable salt thereof as described in any one of items 17-23. (Item 25) Xaa 12 The peptide is Cys or allylglycine, as described in any one of items 17-24, or a pharmaceutically acceptable salt thereof. (Item 26) Xaa 14 The peptide or pharmaceutically acceptable salt thereof described in any one of items 17-25 is Val or Pro. (Item 27) Xaa 17 The peptide or pharmaceutically acceptable salt thereof described in any one of items 17-26, which is Tyr or Thr. (Item 28) Xaa 20is a peptide or pharmaceutically acceptable salt thereof as described in any one of items 17-27, which is either Tyr or lacking Tyr. (Item 29) Xaa 21 The peptide or pharmaceutically acceptable salt thereof described in any one of items 17-28 is lacking. (Item 30) Xaa1 is missing; Xaa2 is missing; Xaa3 is missing; Xaa4 is missing; Xaa5 is missing; Xaa6 is missing; Xaa7 is Ag, Cys, or Cth; Xaa8 is either Cys or Cth; Xaa9 is Glu; Xaa 10 is Leu; Xaa 12 is Ag or Cys; Xaa 14 is either Val or Pro; Xaa 17 is Tyr or Thr; and Xaa 20 is Tyr or lacking The peptides or pharmaceutically acceptable salts thereof listed in item 17. (Item 31) The peptide has an amino acid sequence [ka] A peptide or pharmaceutically acceptable salt thereof, as described in item 30. (Item 32) The aforementioned peptide has the following amino acid sequence: [ka] [ka] [ka] [ka] A peptide or pharmaceutically acceptable salt thereof, as described in item 17, comprising the above. (Item 33) A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence: [ka] , or comprising a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is either BK or missing; Xaa3 is either an Asn or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile or is missing; Xaa6 is or is absent as Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe); Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 12These are Cys, allylglycine (Ag), Hag, or Val; Xaa 14 These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, or Ala; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, or OH-Pro; and The peptides are Xaa7 and Xaa 12 , Xaa8 and Cys 16 , and Cys 11 and Cys 19 The peptide or a pharmaceutically acceptable salt thereof, comprising a covalent bond between them. (Item 34) The N-terminus is capped with acetic acid, pentenoic acid, 4-Mepip, C12 alkyl carboxylic acid, C14 alkyl carboxylic acid, C16 alkyl carboxylic acid, or C18 alkyl carboxylic acid, as described in item 33, or a pharmaceutically acceptable salt thereof. (Item 35) The C-terminus is amidated, and the peptide or pharmaceutically acceptable salt thereof as described in item 33 is used. (Item 36) A pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, wherein the peptide or pharmaceutically acceptable salt thereof has an amino acid sequence: [ka] , or comprising a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK, or is absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), 4-pentenoic acid (Pent), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 This is Cys, Ag, or penicillamine (Pen); Xaa 12 These are Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is either Asn or Leu; Xaa 14 These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 These are Cys, Ag, Pen, or Cth; Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 It is Cys, Ag, or Pen; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro; and The peptides are Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19 The pharmaceutical composition comprising a covalent bond between them. (Item 37) The peptide or pharmaceutically acceptable salt thereof has the amino acid sequence: [ka] [ka] [ka] [ka] A pharmaceutical composition consisting of the above, as described in item 36. (Item 38) The peptide or pharmaceutically acceptable salt thereof has the amino acid sequence: [ka] A pharmaceutical composition consisting of the above, as described in item 36. (Item 39) The pharmaceutical composition according to any one of items 36 to 38, wherein the N-terminus of the peptide is capped with acetic acid, pentenoic acid, 4-Mepip, C12 alkyl carboxylic acid, C14 alkyl carboxylic acid, C16 alkyl carboxylic acid, or C18 alkyl carboxylic acid; the C-terminus of the peptide is amidated; or any combination thereof. (Item 40) The pharmaceutical composition described above is in solid dosage form, as described in any one of items 36 to 39. (Item 41) The pharmaceutical composition described above is formulated as an oral solid dosage form, as described in item 40. (Item 42) A method for lavaging the colon of a subject in preparation for a colonoscopy procedure, comprising administering an effective dose of a colon lavage composition to the subject, wherein the colon lavage composition comprises a pharmaceutically acceptable excipient, diluent, or carrier, and a peptide or a pharmaceutically acceptable salt thereof, the peptide or pharmaceutically acceptable salt thereof having an amino acid sequence: [ka] , or comprising a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK, or is absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), 4-pentenoic acid (Pent), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 This is Cys, Ag, or penicillamine (Pen); Xaa 12 These are Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is either Asn or Leu; Xaa 14 These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 These are Cys, Ag, Pen, or Cth; Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 It is Cys, Ag, or Pen; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro; and The peptides are Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19The method comprising a covalent bond between the two. (Item 43) The aforementioned method, a. Administering a first dose of the colon cleansing composition effective to the subject orally or rectally; and b. Administering a second dose of the colon cleansing composition effective to the subject to substantially cleanse the subject's colon. The method described in item 42, further including the method described in item 42. (Item 44) The method described in item 43, wherein an effective first dose is administered, and an effective second dose is administered the morning after that. (Item 45) The colon cleansing composition has the following amino acid sequence: [ka] [ka] [ka] [ka] The method described in item 42, comprising a peptide containing or a pharmaceutically acceptable salt thereof. (Item 46) The colon cleansing composition has the following amino acid sequence: [ka] The method described in item 42, comprising a peptide containing or a pharmaceutically acceptable salt thereof. (Item 47) A method for producing the peptide according to any one of items 1 to 35, comprising providing cells having a nucleic acid molecule encoding the polypeptide, culturing the cells under conditions in which the peptide is expressed, and isolating the expressed peptide. (Item 48) A method for producing the peptide described in any one of items 1 to 35, comprising chemically synthesizing the peptide and purifying the synthesized peptide. (Item 49) A method for treating gastrointestinal or visceral disorders, comprising administering a peptide described in any one of items 1 to 35 to the subject. (Item 50) This includes administering a peptide listed in any one of items 1 to 35 to the target patient, and is used for the treatment of colon cancer, hereditary nonpolyposis colorectal cancer (HNPCC), Lynch syndrome, gastroparesis (GP), polyps, pain, generalized abdominal pain, postoperative ileus, opioid-induced constipation, functional dyspepsia, SUDD (symptomatic simple diverticular disease) and SCAD (segmental colitis associated with diverticular disease), diverticular diseases including but not limited to diverticular disease, diarrhea-predominant irritable bowel syndrome, and irritable bowel syndrome (IBS). Methods for treating selected disorders from among pain, ulcerative colitis, ulcerative proctitis, Crohn's disease, inflammatory bowel disease (IBD), chronic or acute radiation-induced rectal pain, rectal pain, chronic rectal neuralgia, transient rectal neuralgia, anal pain, chronic anal fissure, postoperative anal pain, overactive bladder syndrome, stress urinary incontinence, interstitial cystitis, bladder pain syndrome, colorectal cancer, cancer-related pain, generalized pelvic pain, endometriosis, testicular pain, chronic prostatitis, prostatic pain, vvodynia, urethral syndrome, penile pain, perianal pain, and other gastrointestinal and visceral disorders. (Item 51) The method according to item 51, further comprising administering to a subject a pharmaceutical composition containing an active ingredient selected from opioids, tramadol, β-3 adrenergic receptor agonists, anticholinergics, and tricyclic antidepressants. (Item 52) A pharmaceutical composition for use in lavaging the colon of a subject in preparation for colonoscopy, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient, diluent, or carrier, and a peptide or a pharmaceutically acceptable salt thereof, the peptide or pharmaceutically acceptable salt thereof having an amino acid sequence: [ka] , or comprising a pharmaceutically acceptable salt thereof; in the formula, Xaa1 is either BE or missing; Xaa2 is BK, Asn, or missing; Xaa3 is Asn, Ser, or missing; Xaa4 is either Ser or missing; Xaa5 is Ser, Asn, Ile, BE or is missing; Xaa6 is Tyr, Asp, 4-fluorophenylalanine ((4-F)Phe), BK, or is absent; Xaa7 is Cys, cystathionine (Cth), allylglycine (Ag), 4-pentenoic acid (Pent), Hag, or Asp; Xaa8 is Cys, cystathionine (Cth), penicillamine (Pen), or allylglycine (Ag); Xaa9 is Glu, Asp, Ser, Thr, or Gln; Xaa 10 These are Leu, cyclohexylalanine (Cha), Phe, or 4-fluorophenylalanine ((4-F)Phe); Xaa 11 This is Cys, Ag, or penicillamine (Pen); Xaa 12 These are Cys, allylglycine (Ag), Hag, Cth, Dpr, or Val; Xaa 13 is either Asn or Leu; Xaa 14These are Pro, Val, sarcosine (Sar), Leu, or hydroxyproline (OH-Pro); Xaa 16 These are Cys, Ag, Pen, or Cth; Xaa 17 These are Tyr, Thr, cyclohexylalanine (Cha), 4-fluorophenylalanine ((4-F)Phe), Phe, Ser, or Ala; Xaa 19 It is Cys, Ag, or Pen; Xaa 20 It is either Tyr, Leu, 4-fluorophenylalanine ((4-F)Phe), cyclohexylalanine (Cha), D-Tyr, N-methylTyr (Nme-Tyr), or is absent; Xaa 21 is missing or Asn; In the formula, at least one Xaa is BE, BK, (4-F)Phe, Cth, Ag, Hag, Pen, Cha, Sar, Dpr, or OH-Pro; and The peptides are Xaa7 and Xaa 12 , Xaa8 and Xaa 16 , and Xaa 11 and Xaa 19 The pharmaceutical composition comprising a covalent bond between them. (Item 53) Colon cancer, hereditary nonpolyposis colorectal cancer (HNPCC), Lynch syndrome, gastroparesis (GP), polyps, pain, generalized abdominal pain, postoperative ileus, opioid-induced constipation, functional dyspepsia, SUDD (symptomatic simple diverticular disease) and SCAD (segmental colitis associated with diverticular disease), diverticular diseases including but not limited to diverticulosis, diarrhea-predominant irritable bowel syndrome, pain associated with irritable bowel syndrome (IBS), ulcerative colitis, ulcerative proctitis, Crohn's disease, inflammatory bowel disease (IBD), chronic or acute radiation rectal injury. A pharmaceutical composition for use in treating a disorder selected from among disorders, rectal pain, chronic rectal neuralgia, transient rectal neuralgia, anal pain, chronic anal fissure, postoperative anal pain, overactive bladder syndrome, stress urinary incontinence, interstitial cystitis, bladder pain syndrome, colorectal cancer, cancer-related pain, generalized pelvic pain, endometriosis, testicular pain, chronic prostatitis, prostatic pain, vvodinia, urethral syndrome, penile pain, perianal pain, and other gastrointestinal and visceral disorders, wherein the pharmaceutical composition comprises a peptide described in any one of items 1 to 35.

Claims

1. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence: Xaa １４ , １５ , １３ Xaa ２ Xaa ３ Xaa ４ Xaa ５ Xaa ６ Xaa ７ Xaa ８ Xaa ９ Xaa １０ Xaa １１ Xaa １２ Xaa １３ Xaa １４ Ala １５ Xaaa １６ Xaaa １７ Gly １８ Xaaa １９ Xaaa ２０ Xaaa ２１ (SSEQ) ID NO: 1) is included in the formula, Xaa １ It is lacking; Xaa ２ It is lacking; Xaa ３ It is lacking; Xaa ４ It is lacking; Xaa ５ It is lacking; Xaa ６ It is lacking; Xaa ７ This is Cys, cystathionine (Cth), allylglycine (Ag), or allylglycine with a reduced dicarba bond (Hag); Xaa ８ These are Cys, Cth, or penicillamine (Pen); Xaa ９ is Glu; Xaa １０ is Leu; Xaa １１ is Cys, Ag, or Pen; Xaa １２ is Cys, Ag, or Hag; Xaa １３ is either Asn or Leu; Xaa １４ is Pro, Val, or hydroxyproline (OH-Pro); Xaa １６ is Cys, Ag, Pen, or Cth; Xaa １７ is Tyr or Thr; Xaa １９ is Cys, Ag, or Pen; Xaa ２０ is Tyr, or N-methylTyr (Nme-Tyr), or is absent; Xaa ２１ is either an Asn or missing; The peptide is Xaa ７ and Xaa １２ Xaa ８ and Xaa １６ , and Xaa １１ and Xaa １９ The peptide contains a covalent bond between the amino acids, and the amino acid sequence is: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 The peptide or a pharmaceutically acceptable salt thereof, comprising the above.

2. The peptide is amidated C-terminus (-NH ２ The peptide according to claim 1 or a pharmaceutically acceptable salt thereof, having a C-terminus (-COOH) or an unmodified C-terminus (-COOH).

3. Xaa ７ and Xaa １２ Both are Ag, and the dicarba bond is Ag ７ and Ag １２ It exists between; Xaa ７ and Xaa １２ Both are Cys, and the disulfide bond is Cys ７ and Cys １２ It exists between; Xaa ８ and Xaa １６ Both are Cys, and the disulfide bond is Cys ８ and Cys １６ It exists between; Xaa ７ is Cth and Xaa １２ It is Cys and the combination is Cth ７ and Cys １２ It exists between; Xaa ８ is Cth and Xaa １６ It is Cys and the combination is Cth ８ and Cys １６ It exists between; Xaa １１ and Xaa １９ It is Cys, and the disulfide bond is Cys １１ and Cys １９ It exists between; or Any combination of those The peptide or a pharmaceutically acceptable salt thereof according to claim 2.

4. The aforementioned peptide has the following amino acid sequence: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53)H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, comprising the above.

5. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence: Xaa １ Xaa ２ Xaa ３ Xaa ４ Xaa ５ Xaa ６ Xaa ７ Xaa ８ Xaa ９ Xaa １０ Xaa １１ Xaa １２ Xaa １３ Xaa １４ Ala １５ Xaaa １６ Xaaa １７ Gly １８ Xaaa １９ Xaaa ２０ Xaaa ２１ (SEQ ID NO:1)からなり; During the ceremony, Xaa １ It is lacking; Xaa ２ It is lacking; Xaa ３ It is lacking; Xaa ４ It is lacking; Xaa ５ It is lacking; Xaa ６ It is lacking; Xaa ７ This is Cys, cystathionine (Cth), allylglycine (Ag), or allylglycine with a reduced dicarba bond (Hag); Xaa ８ These are Cys, Cth, or penicillamine (Pen); Xaa ９ is Glu; Xaa １０ is Leu; Xaa １１ is Cys, Ag, or Pen; Xaa １２ is Cys, Ag, or Hag; Xaa １３ is either Asn or Leu; Xaa １４ is Pro, Val, or hydroxyproline (OH-Pro); Xaa １６ is Cys, Ag, Pen, or Cth; Xaa １７ is Tyr or Thr; Xaa １９ is Cys, Ag, or Pen; Xaa ２０ is Tyr, or N-methylTyr (Nme-Tyr), or is absent; Xaa ２１ is either an Asn or missing; and The peptide is Xaa ７ and Xaa １２ Xaa ８ and Xaa １６ , and Xaa １１ and Xaa １９ The peptide contains a covalent bond between the amino acids, and the amino acid sequence is: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53)H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 The peptide or a pharmaceutically acceptable salt thereof, comprising the above.

6. The peptide according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the peptide has an N-terminus modified with 1-methyl-piperidine-4-carboxylic acid (4-Mepip) or an unmodified N-terminus (H-).

7. The peptide is amidated C-terminus (-NH ２ The peptide according to claim 6 or a pharmaceutically acceptable salt thereof, having a C-terminus (-COOH) or an unmodified C-terminus (-COOH).

8. Xaa ７ and Xaa １２ Both are Ag, and the dicarba bond is Ag ７ and Ag １２ It exists between; Xaa ７ and Xaa １２ Both are Cys, and the disulfide bond is Cys ７ and Cys １２ It exists between; Xaa ８ and Xaa １６ Both are Cys, and the disulfide bond is Cys ８ and Cys １６ It exists between; Xaa ７ is Cth and Xaa １２ It is Cys and the combination is Cth ７ and Cys １２ It exists between; Xaa ８ is Cth and Xaa １６ It is Cys and the combination is Cth ８ and Cys １６ It exists between; Xaa １１ and Xaa １９ It is Cys, and the disulfide bond is Cys １１ and Cys １９ It exists between; or Any combination of those The peptide or a pharmaceutically acceptable salt thereof according to claim 7.

9. The aforementioned peptide has the following amino acid sequence: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53)H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A peptide or pharmaceutically acceptable salt thereof according to any one of claims 5 to 8, comprising the above.

10. A pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, wherein the peptide has the amino acid sequence: Xaa １ Xaa ２ Xaa ３ Xaa ４ Xaa ５ Xaa ６ Xaa ７ Xaa ８ Xaa ９ Xaa １０ Xaa １１ Xaa １２ Xaa １３ Xaa １４ Ala １５ Xaa １６ Xaa １７ Gly １８ Xaa １９ Xaa ２０ Xaa ２１ (SEQ ID NO: 1) is included in the formula, Xaa １ It is lacking; Xaa ２ It is lacking; Xaa ３ It is lacking; Xaa ４ It is lacking; Xaa ５ It is lacking; Xaa ６ It is lacking; Xaa ７ This is Cys, cystathionine (Cth), allylglycine (Ag), or allylglycine with a reduced dicarba bond (Hag); Xaa ８ These are Cys, Cth, or penicillamine (Pen); Xaa ９ is Glu; Xaa １０ is Leu; Xaa １１ is Cys, Ag, or Pen; Xaa １２ is Cys, Ag, or Hag; Xaa １３ is either Asn or Leu; Xaa １４ is Pro, Val, or hydroxyproline (OH-Pro); Xaa １６ is Cys, Ag, Pen, or Cth; Xaa １７ is Tyr or Thr; Xaa １９ is Cys, Ag, or Pen; Xaa ２０ is Tyr, or N-methylTyr (Nme-Tyr), or is absent; Xaa ２１ is either an Asn or missing; The peptide is Xaa ７ and Xaa １２ Xaa ８ and Xaa １６ , and Xaa １１ and Xaa １９ The peptide contains a covalent bond between the amino acids, and the amino acid sequence is: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 The pharmaceutical composition comprising the above.

11. The peptide is amidated C-terminus (-NH ２ The pharmaceutical composition according to claim 10, having ) or an unmodified C-terminus (-COOH).

12. Xaa ７ and Xaa １２ Both are Ag, and the dicarba bond is Ag ７ and Ag １２ It exists between; Xaa ７ and Xaa １２ Both are Cys, and the disulfide bond is Cys ７ and Cys １２ It exists between; Xaa ８ and Xaa １６ Both are Cys, and the disulfide bond is Cys ８ and Cys １６ It exists between; Xaa ７ is Cth and Xaa １２ It is Cys and the combination is Cth ７ and Cys １２ It exists between; Xaa ８ is Cth and Xaa １６ It is Cys and the combination is Cth ８ and Cys １６ It exists between; Xaa １１ and Xaa １９ It is Cys, and the disulfide bond is Cys １１ and Cys １９ It exists between; or Any combination of those The pharmaceutical composition according to claim 11.

13. The peptide or a pharmaceutically acceptable salt thereof has the following amino acid sequence: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53)H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A pharmaceutical composition according to any one of claims 10 to 12, comprising:

14. The peptide or a pharmaceutically acceptable salt thereof has the following amino acid sequence: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53)H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A pharmaceutical composition according to any one of claims 10 to 12, comprising the above.

15. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is in the form of an oral solid dosage form.

16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is formulated as an oral solid dosage form.

17. A colon cleansing composition for cleansing the colon in preparation for colonoscopy, wherein the colon cleansing composition comprises a peptide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent, or carrier, wherein the peptide has the amino acid sequence: Xaa １ Xaa ２ Xaa ３ Xaa ４ Xaa ５ Xaa ６ Xaa ７ Xaa ８ Xaa ９ Xaa １０ Xaa １１ Xaa １２ Xaa １３ Xaa １４ Ala １５ Xaa １６ Xaa １７ Gly １８ Xaa １９ Xaa ２０ Xaa ２１ (SEQ ID NO: 1) is included in the formula, Xaa １ It is lacking; Xaa ２ It is lacking; Xaa ３ It is lacking; Xaa ４ It is lacking; Xaa ５ It is lacking; Xaa ６ It is lacking; Xaa ７ This is Cys, cystathionine (Cth), allylglycine (Ag), or allylglycine with a reduced dicarba bond (Hag); Xaa ８ These are Cys, Cth, or penicillamine (Pen); Xaa ９ is Glu; Xaa １０ is Leu; Xaa １１ is Cys, Ag, or Pen; Xaa １２ is Cys, Ag, or Hag; Xaa １３ is either Asn or Leu; Xaa １４ is Pro, Val, or hydroxyproline (OH-Pro); Xaa １６ is Cys, Ag, Pen, or Cth; Xaa １７ is Tyr or Thr; Xaa １９ is Cys, Ag, or Pen; Xaa ２０ is Tyr, or N-methylTyr (Nme-Tyr), or is absent; Xaa ２１ is either an Asn or missing; The peptide is Xaa ７ and Xaa １２ Xaa ８ and Xaa １６ , and Xaa １１ and Xaa １９ The peptide contains a covalent bond between the amino acids, and the amino acid sequence is: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 The colon cleansing composition comprising the above.

18. The peptide is amidated C-terminus (-NH ２ The colon cleansing composition according to claim 17, having ) or an unmodified C-terminus (-COOH).

19. Xaa ７ and Xaa １２ Both are Ag, and the dicarba bond is Ag ７ and Ag １２ It exists between; Xaa ７ and Xaa １２ Both are Cys, and the disulfide bond is Cys ７ and Cys １２ It exists between; Xaa ８ and Xaa １６ Both are Cys, and the disulfide bond is Cys ８ and Cys １６ It exists between; Xaa ７ is Cth and Xaa １２ It is Cys and the combination is Cth ７ and Cys １２ It exists between; Xaa ８ is Cth and Xaa １６ It is Cys and the combination is Cth ８ and Cys １６ It exists between; Xaa １１ and Xaa １９ It is Cys, and the disulfide bond is Cys １１ and Cys １９ It exists between; or Any combination of those The colon cleansing composition according to claim 18.

20. The peptide or pharmaceutically acceptable salt thereof has the amino acid sequence: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A colon cleansing composition according to any one of claims 17 to 19, comprising:

21. The peptide or pharmaceutically acceptable salt thereof has the amino acid sequence: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A colon cleansing composition according to any one of claims 17 to 19, comprising the above.

22. The colon cleansing composition according to claim 20, characterized in that, in order to substantially cleanse the colon of the subject, a first dose of the colon cleansing composition effective for the subject is administered orally or rectally, and a second dose of the colon cleansing composition effective for the subject is administered.

23. The colon cleansing composition according to claim 22, characterized in that the effective second dose is administered the morning following the administration of the effective first dose.

24. A method for producing the peptide according to any one of claims 1 to 9, comprising chemically synthesizing the peptide and purifying the synthesized peptide.

25. A composition comprising the peptide according to any one of claims 1 to 9 for treating gastrointestinal or visceral disorders in a subject.

26. The study included colon cancer, hereditary nonpolyposis colorectal cancer (HNPCC), Lynch syndrome, gastroparesis (GP), polyps, pain, generalized abdominal pain, postoperative ileus, opioid-induced constipation, functional dyspepsia, SUDD (symptomatic simple diverticular disease) and SCAD (segmental colitis associated with diverticular disease), diverticular diseases including but not limited to diverticular disease, diarrhea-predominant irritable bowel syndrome, pain associated with irritable bowel syndrome (IBS), ulcerative colitis, ulcerative proctitis, Crohn's disease, inflammatory bowel disease (IBD), and chronic or acute radioactive contamination. A composition comprising a peptide according to any one of claims 1 to 9 for treating disorders selected from irritant rectal disorders, rectal pain, chronic rectal neuralgia, transient rectal neuralgia, anal pain, chronic anal fissure, postoperative anal pain, overactive bladder syndrome, stress urinary incontinence, interstitial cystitis, bladder pain syndrome, colorectal cancer, cancer-related pain, generalized pelvic pain, endometriosis, testicular pain, chronic prostatitis, prostatic pain, vvodynia, urethral syndrome, penile pain, perianal pain, and other gastrointestinal and visceral disorders, characterized in that the composition is administered to the subject.

27. The composition according to claim 26, characterized in that the subject is further administered a pharmaceutical composition containing an active ingredient selected from opioids, tramadol, β-3 adrenergic receptor agonists, anticholinergics, and tricyclic antidepressants.

28. A pharmaceutical composition for use in lavaging the colon of a subject in preparation for colonoscopy, wherein the pharmaceutical composition comprises a peptide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent, or carrier, wherein the peptide has the amino acid sequence: Xaa １ Xaa ２ Xaa ３ Xaa ４ Xaa ５ Xaa ６ Xaa ７ Xaa ８ Xaa ９ Xaa １０ Xaa １１ Xaa １２ Xaa １３ Xaa １４ Ala １５ Xaa １６ Xaa １７ Gly １８ Xaa １９ Xaa ２０ Xaa ２１ (SEQ ID NO: 1) is included in the formula, Xaa １ It is lacking; Xaa ２ It is lacking; Xaa ３ It is lacking; Xaa ４ It is lacking; Xaa ５ It is lacking; Xaa ６ It is lacking; Xaa ７ This is Cys, cystathionine (Cth), allylglycine (Ag), or allylglycine with a reduced dicarba bond (Hag); Xaa ８ These are Cys, Cth, or penicillamine (Pen); Xaa ９ is Glu; Xaa １０ is Leu; Xaa １１ is Cys, Ag, or Pen; Xaa １２ is Cys, Ag, or Hag; Xaa １３ is either Asn or Leu; Xaa １４ is Pro, Val, or hydroxyproline (OH-Pro); Xaa １６ is Cys, Ag, Pen, or Cth; Xaa １７ is Tyr or Thr; Xaa １９ is Cys, Ag, or Pen; Xaa ２０ is Tyr, or N-methylTyr (Nme-Tyr), or is absent; Xaa ２１ is either an Asn or missing; The peptide is Xaa ７ and Xaa １２ Xaa ８ and Xaa １６ , and Xaa １１ and Xaa １９ The peptide contains a covalent bond between the amino acids, and the amino acid sequence is: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A pharmaceutical composition containing [the specified substance].

29. The peptide is amidated C-terminus (-NH ２ The pharmaceutical composition according to claim 28, having ) or an unmodified C-terminus (-COOH).

30. Xaa ７ and Xaa １２ Both are Ag, and the dicarba bond is Ag ７ and Ag １２ It exists between; Xaa ７ and Xaa １２ Both are Cys, and the disulfide bond is Cys ７ and Cys １２ It exists between; Xaa ８ and Xaa １６ Both are Cys, and the disulfide bond is Cys ８ and Cys １６ It exists between; Xaa ７ is Cth and Xaa １２ It is Cys and the combination is Cth ７ and Cys １２ It exists between; Xaa ８ is Cth and Xaa １６ It is Cys and the combination is Cth ８ and Cys １６ It exists between; Xaa １１ and Xaa １９ It is Cys, and the disulfide bond is Cys １１ and Cys １９ It exists between; or Any combination of those The pharmaceutical composition according to claim 29.

31. The peptide or a pharmaceutically acceptable salt thereof has the following amino acid sequence: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53)H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A pharmaceutical composition according to any one of claims 28 to 30, comprising the above.

32. The peptide or a pharmaceutically acceptable salt thereof has the following amino acid sequence: (SEQ ID NO:12)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:18)H-Cys Cys Glu Leu Ag Cys Asn Pro Ala Cys Thr Gly Ag Tyr-NH ２ ; (SEQ ID NO:32)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Thr Gly Cys D-Tyr-NH ２ ; (SEQ ID NO:33)H-Ag Pen Glu Leu Cys Ag Asn Pro Ala Pen Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:39)H-Ag Cys Glu Leu Cys Ag Asn OH-Pro Ala Cys Thr Gly Cys-NH ２ ; (SEQ ID NO:41)H-Ag Cys Glu Leu Pen Ag Asn Pro Ala Cys Thr Gly Pen Tyr-NH ２ ; (SEQ ID NO:42)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:48)H-Ag Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Cys Nme-Tyr-NH ２ ; (SEQ ID NO:53)H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Thr Gly Cys Tyr-NH ２ (SEQ ID NO:55)H-Ag Cys Glu Leu Cys Ag Leu Pro Ala Cys Thr Gly Cys Tyr-NH ２ ; (SEQ ID NO:57) H-Cys Cys Glu Leu Cys Ag Asn Pro Ala Cys Tyr Gly Ag-COOH; (SEQ ID NO:59) H-Hag Cys Glu Leu Cys Hag Asn Pro Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO: 78) 4-Mepip- Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Tyr Gly Cys-COOH; (SEQ ID NO:79) H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-COOH; or (SEQ ID NO:80)H-Cys Cth Glu Leu Cys Cys Asn Val Ala Cys Thr Gly Cys-NH2 A pharmaceutical composition according to any one of claims 28 to 30, comprising the above.

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