WO2016015055A1 - Colon cleansing compositions - Google Patents

Abstract

The present invention relates to compositions comprising guanylate cyclase C agonist peptides, and dosage forms, methods, and kits thereof. The compositions, dosage forms, methods and kits may be used for colon cleansing prior to colonoscopy, or in preparation for other medical, radiologic and/or surgical procedures.

Description

COLON CLEANSING COMPOSITIONS

Field

The present invention relates to compositions, dosage forms, methods, and kits for colon cleansing prior to colonoscopy, or in preparation for other medical, radiologic and/or surgical procedures.

Claim of Priority

This application also claims priority to U.S. Provisional Patent Application Serial No.

62/028,963 filed July 25, 2014. The entire contents of the aforementioned applications are incorporated herein by reference.

Background

In 2006, an estimated 55,170 people in the United States died from colorectal cancer and 148,650 new cases were diagnosed. According to the National Cancer Institute, colon cancer is the second most deadly cancer in the United States. Of great importance in each case is early and accurate diagnosis, in which case colonoscopy is the standard tool for examination. Colonoscopy screening has been shown to reduce the expected morbidity and mortality of colorectal carcinoma by 76% to 90%.

Colon cleansing is a required prerequisite for successful colonoscopy as well as most other medical or surgical colorectal procedures. Given the requirement to identify flat or recessed lesions (nonpolypoid colorectal neoplasms), which are more likely to be cancerous than polyps, there is now an even greater need for proper colon preparation. Flat or recessed lesions are much more difficult to spot than raised polyps with traditional colonoscopy, because their appearance is similar to normal tissue.

Colonoscopy preparation is commonly achieved by orally administering purgative solutions that lavage the colon to rid it of fecal matter. Many of these solutions comprise various phosphate or sulfate salts often in combination with polyethylene glycol (PEG). A major disadvantage of this method is that patients are required to ingest large volume of liquid within a short period of time for purgation. For instance, patients may have to ingest four liters of solution within a period of two to three hours. A large number of patients experience significant volume-related discomfort and adverse side effects such as nausea, abdominal discomfort, cramping, and vomiting. Some preparations can also cause fluid and electrolyte disturbances in subjects with certain medical conditions, including diabetes or renal insufficiency. Another drawback of many of these preparations is their salty and unpleasant taste, which may also lead to patient noncompliance. Poor bowel preparation, due to lack of patient compliance or insufficient cleansing, decreases the diagnostic efficacy and increases the cost of these procedures, especially if a procedure must be repeated. Further, patients may elect to forego routine colon cancer screening because it is uncomfortable and unpleasant.

Thus, there is need for compositions, methods and kits to be used for colon cleansing that are safe, easy to use, and well tolerated by the patient, while also providing quality preparation of the colon.

Summary

The compositions, methods, dosage forms and kits disclosed herein address the need for safe, well tolerated and effective colon cleansing.

In some embodiments, a GCCA peptide or a pharmaceutically acceptable salt thereof is provided in a composition suitable for administration to a subject in need of colon cleansing. In some embodiments, the composition comprising the GCCA peptide or salt thereof further comprises one or more purgative agents. In some embodiments, the composition comprising the GCCA peptide or salt thereof, and optionally one or more purgative agents, further comprises an electrolyte solution.

In some embodiments, dosage forms are provided comprising a composition comprising a GCCA peptide or pharmaceutically acceptable salt thereof in an amount effective to cleanse the colon in a single dose, either alone or in conjunction with one or more purgative agents. In some embodiments, the dosage form comprises a GCCA peptide or salt thereof in an amount effective to cleanse the colon in two doses, either alone or in conjunction with one or more purgative agents. In some embodiments, the dosage form comprises a GCCA peptide or salt thereof in an amount effective to cleanse the colon in three, four, five or six doses, either alone or in conjunction with one or more purgative agents. In some embodiments, the dosage form comprises one or more purgative agents. In some embodiments, the dosage form comprising the GCCA peptide or salt thereof, and optionally one or more purgative agents, further comprises a ready to drink electrolyte solution, or a dry, powdered, or concentrated dosage form of electrolytes that can be reconstituted to form an electrolyte solution.

In some embodiments, methods are provided for cleansing the colon of a patient in need thereof by administering a GCCA peptide or a pharmaceutically acceptable salt thereof. In some embodiments, the GCCA peptide or a pharmaceutically acceptable salt thereof is administered without a purgative agent to a patient in need of colon cleansing. In some embodiments, the GCCA peptide is administered in conjunction with effective amounts of one or more purgative agents to a patient in need of colon cleansing. In some embodiments, the GCCA peptide is administered to a patient at the same time as one or more purgative agents. When the GCCA peptide is administered to a patient at the same time as one or more purgative agents, the purgative agents may be administered as a separate dosage form or as part of a single composition. In some embodiments, the GCCA peptide is administered to a patient before administration of one or more purgative agents. In some embodiments, the GCCA peptide is administered to a patient after administration of one or more purgative agents.

In some embodiments, methods are provided for cleansing the colon of a patient in need thereof comprising administering a GCCA peptide or salt thereof, and optionally one or more purgative agents, and further administering an electrolyte solution. In some embodiments, the GCCA peptide, and optionally one or more purgative agents, is administered to a patient at the same time as the electrolyte solution. When the GCCA peptide is administered to a patient at the same time as the electrolyte solution, the electrolyte solution may be administered as a separate dosage form or as part of a single composition. In some embodiments, the GCCA peptide, and optionally one or more purgative agents, is administered to a patient before administration of the electrolyte solution. In some embodiments, the GCCA peptide, and optionally one or more purgative agents, is administered to a patient after administration of the electrolyte solution. In some embodiments, the GCCA peptide or pharmaceutically acceptable salt thereof is administered to a patient in need of colon cleansing once before a diagnostic or therapeutic procedure requiring a cleansed colon. In some embodiments the GCCA peptide is administered to a patient in need of colon cleansing twice before the diagnostic or therapeutic procedure. In some embodiments, the GCCA peptide is administered to a patient in need of colon cleansing three or four times before the diagnostic or therapeutic procedure. In some embodiments, an effective amount of the GCCA peptide is administered to a patient in need of colon cleansing five, six, seven or eight times before the diagnostic or therapeutic procedure. In some embodiments, effective amounts of one or more purgative agents are administered at the same time, before, or after each administration of the GCCA peptide. In some embodiments, effective amounts of one or more purgative agents are administered at the same time, before, or after at least one administration of the GCCA peptide. In some embodiments, effective amounts of an electrolyte component are administered at the same time, before, or after each administration of the GCCA peptide. In some embodiments, effective amounts of an electrolyte component are administered at the same time, before, or after at least one administration of the GCCA peptide. In some embodiments, the electrolyte component is administered as an electrolyte solution.

In some embodiments, kits are provided comprising one or more dosage forms comprising a composition comprising a GCCA peptide or pharmaceutically acceptable salt thereof. In some embodiments, the kit further provides dosage forms of one or more purgative agents. In some embodiments, the kit further provides dosage forms of an electrolyte component. In some embodiments, the dosage form of an electrolyte component is a ready to drink electrolyte solution. In some embodiments, the dosage form of the electrolyte component is dry, powdered, or concentrated, which can be reconstituted to form an electrolyte solution.

In some embodiments, the kit provides sufficient dosage forms comprising the GCCA peptide or pharmaceutically acceptable salt thereof, and optionally including dosage forms of one or more purgative agents and/or dosage forms of an electrolyte component, to effectuate the colon cleansing. In some embodiments, the kits may further comprise instructions for use, containers for mixing and administering dosage forms of the GCCA peptide or pharmaceutically acceptable salt thereof, or one or more purgative agents, and/or electrolyte solutions.

In some embodiments, pharmaceutical compositions, dosage forms, kits and methods are provided comprising a GCCA peptide or pharmaceutically acceptable salt thereof that comprises or consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82), wherein the GCCA peptide includes disulfide bonds between Cys_! and Cys₆, between Cys₂ and Cys and between Cys_s and Cysi₃. In some embodiments, the pharmaceutical compositions, dosage forms, kits and methods further comprise one or more purgative agents. In some embodiments, the pharmaceutical compositions, dosage forms, kits and methods further comprise a PDE5 inhibitor.

Description of the Drawings

FIGURE 1 presents an example showing that Peptide 2 (SEQ ID NO:82), Peptide 4 (SEQ ID NO:5) and Peptide 1 (SEQ ID NO:81) promote duodenal fluid secretion.

FIGURE 2 presents an example showing that Peptide 2, dephosphorylated Peptide 2, and Peptide 4 promote gastrointestinal transit in mice.

Detailed Description

GCCA peptides may be advantageously used in compositions and methods for colon cleansing because these peptides bind to and activate guanylate cyclase C (GCC), a transmembrane receptor found on the apical epithelial surface of the gastrointestinal tract. Activation of GCC by a GCCA peptide causes an influx of fluid into the lumen of the small intestine and colon. This fluid influx effectuates the emptying of fecal matter from the colon. GCC activation also slows fluid reabsorption from the colon, further amplifying this effect.

Using GCCA peptides in colon cleansing preparations may provide further advantages for patients and physicians. First, smaller volumes of liquids and smaller amounts of purgative agents can be used and still achieve good colon cleansing effects. This may increase patient compliance and lead to fewer adverse effects such as electrolyte shifts. Second, it has been shown in animal models that GCCA peptides have anti-nociceptive effects, which may mitigate the abdominal discomfort caused by administration of purgative agents. Finally, since the fluid influx begins in the small intestine with GCCA administration, the ascending colon will be more adequately cleansed. This will be advantageous to physicians since many colon cleansing routines currently do not completely cleanse the ascending colon.

As used herein, cleansing the colon or colon cleansing means completely emptying or nearly completely emptying the colon of fecal matter. In certain embodiments, colon cleansing can be assessed by volume or weight of fecal matter that is emptied from the colon. In other

embodiments, the degree of colon cleansing can be assessed by a colonoscopy or similar procedure to determine that most or all fecal matter has been emptied from the colon.

In some embodiments, a gastroenterologist experienced in performing colonoscopies can assess the degree of colon cleansing (i.e., the quality of the bowel preparation) to determine that a sufficient amount of fecal matter has been emptied from the colon to permit good visualization of the colon. In some embodiments, an effective amount of a GCCA peptide is the amount necessary to cleanse the colon by itself or in combination with one or more purgative agents in at least 70% of patients undergoing the procedure. In some embodiments, an effective amount of a GCCA peptide is the amount necessary to cleanse the colon by itself or in combination with one or more purgative agents in at least 75% of patients. In some embodiments, an effective amount of a GCCA peptide is the amount necessary to cleanse the colonby itself or in combination with one or more purgative agents in at least 80% of patients. In some embodiments, an effective amount of a GCCA peptide is the amount necessary to cleanse the colon by itself or in combination with one or more purgative agents in at least 85% of patients. In some embodiments, an effective amount of a GCCA peptide is the amount necessary to cleanse the colonby itself or in combination with one or more purgative agents in at least 90% of patients.

As used herein, the colon includes the ascending colon, transverse colon, descending colon and rectum.

As used herein, a patient means one or more patients.

As used herein, an effective amount of a GCCA peptide is the amount necessary to cleanse the colon by itself or in combination with one or more purgative agents. An effective amount of a GCCA peptide may be in a single dosage form or in multiple dosage forms. An effective amount of a purgative agent is the amount necessary to cleanse the colonin combination with a GCCA peptide and, optionally, one or more other purgative agents. An effective amount of a purgative may be in a single dosage form or in multiple dosage forms. Guanylate Cyclase C Agonist Peptides

As used herein, a guanylate cyclase C agonist (GCCA) peptide is a peptide consists of less than 50 amino acids that binds to and activates guanylate cyclase C in a mammal. In some embodiments, a GCCA peptide consists of less than 40 amino acids. In further embodiments, a GCCA peptide consists of less than 30 amino acids. In still further embodiments, a GCCA peptide consists of 21 or fewer amino acids.

In some embodiments, the GCCA peptide comprises or consists of an amino acid sequence of:

Xaa₁ Xaa₂ Xaa₃ Xaa_i) Xaas Xaa6 Cys₇ Xaa_s Xaa₉ Xaa₁₀ Cys_n Asn₁₂ Pro₁₃ Ala₁₄ Cys₁₅ Xaa₁₆ Gly₁₇ Xaa₁₈ Xaa₁₉ Xaa₂₀ Xaa₂i (SEQ ID NO:l) or a pharmaceutically acceptable salt thereof;

wherein

Xaaj Xaa₂ Xaa₃ Xaa₄ Xaa₅ is Asn Ser Ser Asn Tyr (SEQ ID NO:2) or is missing or Xaai Xaa₂ Xaa₃ Xaa₄ is missing and Xaa₅ is Asn;

Xaa₆ is Cys or D-Cys;

Xaa_s is Glu or Asp;

Xaa₉ is Leu, lie, Val, Trp, Tyr or Phe;

Xaaio is Cys or D-Cys;

Xaaie is Thr, Ala, Trp;

Xaa₁₈ is Cys or D-Cys;

Xaa₁₉ is Trp, Tyr, Phe or Leu or is missing; and Xaa₂₀ Xaa₂₁ is AspPhe or is missing.

In various embodiments, Xaai Xaa₂ Xaa₃ Xaa₄ Xaa₅ is missing. In various embodiments, Xaa₉ is Trp, Tyr or Phe. In various embodiments, Xaaio is Cys. In various embodiments, Xaa₁₆ is Thr or Ala. In various embodiments, Xaa₁₉ is Tyr or is missing. In various embodiments, Xaa₂₀ Xaa₂₁ is missing.

The peptide includes disulfide bonds between Xaa₆ and Cys₁₁₍ between Cys₇ and Cysi₅ and between Xaa₁₀ and Cys_1B.

In some embodiments, the GCCA peptide comprises or consists of an amino acid sequence of:

Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:3);

Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:4);

Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:5);

Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:6);

Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7); or

Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:8).

In some embodiments, the GCCA peptide comprises or consists of an amino acid sequence of: Xaai Xaa₂ Xaa₃ Xaa,i Cyss Xaa₆ Xaa₇ Xaa₈ Cys₉ Asn₁₀ Prou Ala_i2 Cys₁₃ Xaa_M Gly₁₅ Xaa_i6 Xaa₁₇ (SEQ ID NO:9) or a pharmaceutically acceptable salt thereof; wherein

Xaai is Asn, D-Asn, Gin, D-GIn, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, β-carboxylated Asp, Glu, D-Glu, y-carboxylated Glu, a-aminosuberic acid (Asu), a-aminoadipic acid (Aad), or a-aminopimelic acid (Apm);

Xaa₂ is Asp, β-carboxylated Asp, Glu, y-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa₃ is Asp, β-carboxylated Asp, Glu, y-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa₄ is Cys or D-Cys;

Xaa₆ is Asp or Glu;

Xaa₇ is Tyr, Leu, Phe or lie;

Xaa₈ is Cys or D-Cys;

Xaa_w is Thr, Ala or Phe;

Xaais is Cys or D-Cys; and

Xaa_i7 is Tyr, D-Tyr, or is absent;

wherein:

aai may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; and if both Xaa₂ and Xaa₃ are absent, then aai rnust be β-carboxylated Asp or y-carboxylated Glu, or Xaai must be Asp, D-Asp, Glu, D-Glu, Asu, Aad, or Apm and must be modified on its amino group by ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.

In several embodiments, Xaai is modified on its amino group at either or both hydrogen atoms by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.

In several embodiments, Xaa_x is not modified on its amino group when either or both of Xaa₂ and Xaa₃ are present.

In several embodiments, Xaa₂ is Asp or Glu. In others, Xaa₂ is Asp.

In several embodiments, Xaa₂ and Xaa₃ are both present. In several embodiments, Xaa₂ is present and Xaa₃ is absent. In several embodiments, Xaa₂ and Xaa₃ are both absent

In several embodiments, Xaa₃ is Asp or Glu. In others, Xaa₃ is Asp.

In several embodiments, either or both of Xaa₂ and Xaa₃ are present and Xaa_! is Asn, D- Asn, Gin, D-GIn, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, β-carboxylated Asp, Glu, D-Glu, y-carboxylated Glu, Asu, Aad or Apm. In further embodiments, Xaai is Asn, D-Asn, Gin, D-GIn, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu. In yet further embodiments, Xaai is Asp, D-Asp, Glu or D-Glu. In several embodiments, Xaa is Cys.

In several embodiments, Xaa₆ is Glu.

In several embodiments, Xaa₇ is Tyr or Leu.

In several embodiments, Xaa₈ is Cys.

In several embodiments, Xaa_w is Thr.

In several embodiments, Xaa₁₆ is Cys.

In several embodiments, Xaa₁₇ is Tyr.

In several embodiments, Xaai₇ is absent. The peptide includes disulfide bonds between Xaa₄ and Cys₉, between Cys_s and Cysi₃ and between Xaa_s and Xaa_a6.

In some embodiments, the present invention provides a peptide or pharmaceutically acceptable salt thereof, wherein said peptide comprises the amino acid sequence Xaai Xaa₂ Xaa₃ Cys₄ Cys₅ Glu₆ Xaa₇ Cys₈ Cys₉ Asn₁₀ Pro_n Ala₁₂ Cysis Thr₁₄ Gly_ls Cys₁₆ Xaa_i7 (SEQ ID NO:10); wherein

Xaai is Asn, D-Asn, Gin, D-GIn, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu;

Xaa₂ is Asp or Glu;

Xaa₃ is Asp, Glu, or is absent;

Xaa₇ is Tyr or Leu; and

Xaa_i7 is Tyr or is absent.

The peptide includes disulfide bonds between Cys and Cys₉, between Cys₅ and Cys_i3 and between Cys₈ and Cys₁₆

In some embodiments, the GCCA peptide comprises or consists of an amino acid sequence of:

Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:ll);

Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:12);

Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:13);

Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID N0:14);

Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:15);

Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:16);

Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:17);

Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:18);

Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:19);

Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:20);

β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:21);

β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:22);

Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:23);

Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:24); β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:25); β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:26); Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:27); Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:28); Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:29); Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:30); Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:31); Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:32); Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:33); Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:34); Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID N0.35); Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:36); Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:37); Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:38); Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:39); Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:40); Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:41); Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:42); Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:43);

Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:44);

Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:45);

Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:46);

Glu Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:47); Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:48);

Glu Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:49); Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:50); Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:51);

Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:52);

Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:53); Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:54);

D-Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:55); D-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:56); D-Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:57); D-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:58); Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys D-Tyr (SEQ ID NO:59); D-Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:60);

Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:61);

Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:62);

Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:63);

Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:64);

Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:65);

Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:66);

Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:67);

Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:68);

β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:69); Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:70);

Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:71);

Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:72);

Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:73);

Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:74); or Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:75).

In some embodiments, the GCCA peptide comprises or consists of an amino acid sequence of:

Xaa₁ aa₂ aa3 Xaa4 Cys5 Xaa₆ Xaa₇ Xaa8 Cys₉ Asn_i0 Pron Ala₁₂ Cys₁₃ Xaa₁ Gl ^ Xaa_i6 Xaa_i7 (SEQ ID NO:76), or a pharmaceutically acceptable salt thereof; wherein

Xaaj is Asn, D-Asn, Gin, D-GIn, Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, y-carboxylated Asp, Glu, D-Glu, y-carboxylated Glu, a-aminosuberic acid (Asu), a-aminoadipic acid (Aad), a-aminopimelic acid (Apm), or is absent;

Xaa₂ is Asp, y-carboxylated Asp, Glu, y-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa₃ is Asp, y-carboxylated Asp, Glu, y-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa₄ is Cys or D-Cys;

Xaa₆ is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-Tyr;

Xaa₇ is Tyr, Leu, Phe or lie;

Xaa_g is Cys or D-Cys;

Xaa₁₄ is Thr, Ala or Phe;

Xaa₁₆ is Cys or D-Cys; and

Xaaiy is Tyr, D-Tyr, or is absent;

wherein: if Xaai is present, Xaai may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid;

if aai is absent and Xaa₂ is present, then Xaa₂ may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; or

if both Xaaj and Xaa₂ are absent, then Xaa₃ may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.

As used herein, the P- prefix before an amino acid indicates that the amino acid is phosphorylated. For example, P-Ser is phosphoserine, P-Thr is phosphothreonine, P-homo-Ser is phosphohomoserine, P-homo-Thr is phosphohomothreonine, P-Cys is phosphocysteine and P-Tyr is phosphotyrosine.

In some embodiments, both Xaa₂ and Xaa₃ are absent. In other embodiments, Xaa₂ is Asp or Glu and Xaa₃ is absent. In yet other embodiments, Xaa₂ is Asp or Glu and Xaa₃ is Asp or Glu.

In some embodiments, Xaa₇ is Tyr or Leu.

In some embodiments, Xaa_w is Thr.

In some embodiments, Xaa₁₇ is Tyr or is absent.

In some embodiments, Xaai is Asn, D-Asn, Gin, D-Gln, Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu. In further embodiments, Xaa_a is Asp, D-Asp, Glu or D-Glu. In some embodiments, Xaa₆ is P-Ser or P-Thr. In further embodiments, Xaa₆ is P-Ser.

In some embodiments, Xaai, Xaa₂ and Xaa₃ are absent and Xaa₄ is D-Cys or Cys. In further embodiments, Xaa₇ is Tyr or Leu. In further embodiments, Xaa_M is Thr. In further embodiments, Xaa₁₇ is Tyr or is absent. In further embodiments, Xaa₆ is P-Ser.

In some embodiments, at least one of Xaa₄, Xaa₈ or Xaai₆ is Cys. In some embodiments, at least two of Xaa₄, Xaa₈ or Xaa₁₆ are Cys. In some embodiments, all of Xaa₄, Xaa₈ and Xaa₁₆ are Cys. In some embodiments, at least one of Xaa , Xaa_g or Xaa₁₆ is D-Cys. In some embodiments, at least two of Xaa₄, Xaa₈ or Xaai6 are D-Cys. In some embodiments, all of Xaa , Xaa₈ and Xaaie are D-Cys.

The peptide includes disulfide bonds between Xaa₄ and Cys₉, between Cys₅ and Cys₁₃ and between Xaa₈ and Xaa₁₆

In some embodiments, a peptide or pharmaceutically acceptable salt thereof is provided, wherein the peptide comprises or consists of the amino acid sequence

Cys₄ Cys₅ P-Ser₆ Xaa₇ Cys₈ Cys₉ Asn₁₀ ΡΓΟ_χ1 Ala₁₂ Cys₁₃ Thr_i4 Glyi₅ Cys₁₆ Xaa₁₇, wherein Xaa₇ is Tyr or Leu. The peptide includes disulfide bonds between Cys₄ and Cys₉, between Cys₅ and Cys₁₃ and between Cys₈ and Cys₁₆.

In some embodiments, the GCCA peptide comprises or consists of the amino acid sequence

Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:77);

Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ. ID NO:78);

Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:79);

Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:80);

Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:81);

Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82);

Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:83); or

Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:84).

In some embodiments, the GCCA peptide may be a peptide described in WO 2011/156453.

As used herein, a GCCA peptide may comprise other chemical moieties conjugated to or otherwise attached to the GCCA peptide to form a "conjugated GCCA peptide." A conjugated GCCA peptide may be used for detection opportunities or colon cancer treatment. In the case of using the conjugated GCCA peptide for detection, a linker may be conjugated to the N-terminus. The linker may then be conjugated to a dye or the linker may be conjugated to a dye prior to conjugation to the GCCA peptide . The dye-conjugated GCCA peptide would be useful in detection of peptide binding interactions. In another embodiment, the GCCA peptide may be conjugated to a toxin for treatment of, inter alia, colon cancer or metastatic colon cancer. A linker may be conjugated to the N-terminus. The linker may then be conjugated to a toxin or the linker may be conjugated to a toxin prior to conjugated to the GCCA peptide.

Purgative Agents

As used herein, a purgative agent is a drug that facilitates or increases bowel movements in a manner that by itself, or in combination with other purgative agents or active compounds, effectuates the production of copious amounts of diarrhea or colonic cleansing. The purgative agents may be organic or inorganic in nature and may function via various mechanisms, including but not limited to increase in motility, increase in fluid secretion in either or both the small and large intestines, decrease in fluid reuptake, increase in bulk of stool, and enhancement of lubrication.

Examples of purgative agents include, but are not limited to, surfactants or stool softeners, such as ducosate salts (e.g., Colace, Diocto, Gibs-Eze); bulking agents, such as bran and other insoluble fibers, gum karaya, sterculia (e.g., Normacol), psyllium husk and other soluble fibers ( e.g.,Metamucil), methylcellulose (e.g.,Citrucel),and polycarbophil; lubricants or emollients, such as mineral oil; hydrating agents or osmotics, such as sodium phosphate (and variants), potassium sodium tartrate, magnesium citrate, magnesium hydroxide (Milk of magnesia or Cream of magnesia), and magnesium sulfate (a.k.a. Epsom salt); hyperosmotic agents, such as sorbitol, lactulose, and polyethylene glycols (PEGs); stimulant or contact laxatives, such as sodium picosulfate, anthraquinones, e.g., dantron, emodin, aloe emodin, and senna glycosides, phenolphthalein, bisacodyl, and castor oil or ricinoleic acid; serotonin agonist or 5-HT₄ receptor agonists, such as tegaserod, cisapride, and rucalopride; and chloride channel activators, such as lubiprostone.

Effective doses of stimulant laxatives include: Aloe, 250-1000 mg.; Bisacodyl, about 5-80 mg.; Casanthranol, 30 to 360 mg.; Cascara aromatic fluid extract, 2-24 ml.; Cascara sagrada bark, 300-4000 mg.; Cascada sagrada extract, 300 to 2000 mg.; Cascara sagrada fliuid extract, 0.5 to 5 ml.; Castor oil, 15-240 ml.; Danthron, 75-300 mg.; Dehydrocholic Acid, 250-2000 mg; Phenolphthalein, 30-1000 mg.; Sennosides A and B, 12-200 mg.; and Picosulfate, 1-100 mg. Of course, larger or smaller doses may be used, as necessary, to produce a bowel movement within less than about 12 hours, while avoiding unnecessary discomfort.

In some embodiments, the polyethylene glycol (PEG) used has an average molecular weight of 2000 or greater. In some embodiments, the PEG has an average molecular weight of 2500 or greater. In some embodiments, the PEG has an average molecular weight of 4500 or lower. For example the PEG may be PEG 3350 or PEG 4000. Optionally, the PEG may comprise two or more different PEG species. In some embodiments, a composition of the invention comprises 90 g or more of PEG per liter; in further embodiments, 100 g or more of PEG per liter. In some embodiments, a composition of the invention comprises 250 g or less of PEG per liter; in further embodiments, 150 g or less of PEG per liter, in still further embodiments, 140 g or less of PEG per liter, in yet further embodiments, 125 g or less of PEG per liter. For example, a composition may comprise PEG at a concentration within a range wherein the lower limit is 90 or 100 g per liter and the upper limit is, independently, 350, 250, 150 or 125 g per liter. For example, a composition of the invention may comprise 100 or 125 g per liter. In further embodiments, a composition of the invention comprises 100 g of PEG per liter.

In some embodiments, the alkali metal or alkaline earth metal sulphate or the mixture of alkali metal or alkaline earth metal sulphates is present in a quantity of 2 g or more per liter; in further embodiments, in a quantity of 3 g or more per liter; in further embodiments, in a quantity of 5 g or more per liter. In some embodiments, the alkali metal or alkaline earth metal sulphate or the mixture of alkali metal or alkaline earth metal sulphates is present in a quantity of 10 g or less per liter; in further embodiments, in a quantity of 9 g or less per liter; in yet further embodiments, in a quantity of 7.5 g or less per liter. For example, the alkali metal or alkaline earth metal sulphate or the mixture of alkali metal or alkaline earth metal sulphates may be present in a quantity within a range in which the lower limit is selected from any of 2, 3 and 5 g per liter and the upper limit is selected, independently, from any of 10, 9 and 7.5 g per liter. For example the alkali metal or alkaline earth metal sulphate or the mixture of alkali metal or alkaline earth metal sulphates is present in a quantity of 5 g or 7.5 g per liter, for example 7.5 g per liter. The alkali earth metal or alkaline earth metal may be, for example, sodium, magnesium or calcium.

In some embodiments, a purgative agent may be sodium chloride. Sodium chloride may be present in a quantity of 0.5 g or more per liter, may be present at 1 g or more per liter or a quantity of 2 g or more per liter. Sodium chloride may be present in a quantity of 7 g or less per liter, may be present at 5 g or less per liter, may be present at a quantity of 4 g or less per liter. For example, sodium chloride may be present in at a concentration within a range in which the lower limit is selected from any of 0.5, 1 and 2 g per liter and the upper limit is selected, independently, from any of 7, 5 and 4 g per liter.

In some embodiments, the purgative agent may be potassium chloride. In some embodiments, potassium chloride is present in a quantity of 0.2 g or more per liter; in some embodiments, in a quantity of 0.5 g or more per liter, in some embodiments, in a quantity of 0.7 g or more per liter. In some embodiments, potassium chloride is present in a quantity of 4 g or less per liter; in some embodiments, in a quantity of 2 g or less per liter; in some embodiments, in a quantity of 1.3 g or less per liter. For example, potassium chloride may be present In at a concentration within a range in which the lower limit is selected from any of 0.2, 0.5 and 0.7 g per liter and the upper limit is selected, independently, from any of 4, 2, and 1.3 g per liter.

In some embodiments, the purgative agent may also be sodium bicarbonate. Because of the reaction between sodium bicarbonate and acids, bicarbonate ions are generally destroyed, with accompanying effervescence as C0₂ is produced, on addition of water to a composition comprising ascorbic acid and a bicarbonate. The same reaction may occur in a dry powder composition if small amounts of moisture, for example atmospheric moisture, are present. The reaction between bicarbonate and ascorbic acid in the dry powder composition may be avoided if coated ascorbic acid is used. The reaction may also be avoided by packaging the dry composition in two separate individual units such that the bicarbonate and the ascorbic acid are not in contact.

In some embodiments, a purgative agent may be an ascorbate component. The term "ascorbate component" is used herein to denote the ascorbic acid, one or more salts thereof, such as sodium ascorbate, or a mixture of ascorbic acid that is used in a composition of the present invention. In some embodiments, the ascorbate component is present in a composition of the invention in a quantity of from 3-20 g per liter of solution. In some embodiments, the ascorbate component is present in a quantity of 4 g or more per liter; in some embodiments, in a quantity of 5 g or more per liter. In some embodiments, the ascorbate component is present in a quantity of 15 g or less per liter; in some embodiments, in a quantity of 10 g or less per liter. For example, the ascorbate component may be present in a quantity within a range in which the lower limit is 4 or 5 g per liter and the upper limit is, independently, 15 or 10 g per liter. For example, the ascorbate component is present in a quantity of 5 to 10 g per liter, for example, 5 or 10 g per liter.

Salts of ascorbic acid include alkali metal and alkaline earth metal salts, for example sodium ascorbate, potassium ascorbate, magnesium ascorbate and calcium ascorbate. In some

embodiments, a salt of ascorbic acid is sodium ascorbate. In some embodiments, the ascorbate component comprises both ascorbic acid and one or more salts thereof. In some embodiments, the ascorbic acid and the salt(s) thereof are present in a weight ratio within the range of from 1:9 to 9:1. Ascorbic acid and salts thereof may, in practice, be provided as hydrates. If a hydrate is used, the weight and/or weight ratio mentioned here is the weight and/or weight ratio of ascorbic acid or salt(s) thereof without water of hydration. In some embodiments, the ascorbic acid and the salt(s) thereof are present in a weight ratio within the range of from 2:8 to 8:2, more preferably 3:7 to 7:3, still more preferably 4:6 to 6:4, for example 4.7 to 5.9.

Oral administration of about 5 to about 40 mg. of bisacodyl is usually effective to produce a bowel movement within about 3 to about 6 hours after administration. About 5 to about 80 mg. of bisacodyl may be administered to a patient to produce a bowel movement. In some embodiments, a dose of from about 10 to about 20 mg of bisacodyl can be used . It has been shown that a 20 mg dose of bisacodyl is effective to produce a bowel movement within reasonable time.

In some embodiments, a combination of purgative agents may be used. For example, administering an effective amount of bisacodyl and allowing it to produce a bowel movement, followed by administering an amount of PEG solution can comfortably purge the colon in patients within from about 3 hours to overnight. Volumes from about 0.5 L to about 4L are believed to be effective. In some embodiments, the effective volume of PEG solution is between about 1.5 L and about 2.5 L.

In some embodiments, mixtures of sulfate salts that omit phosphates (which are avidly absorbed) can be effective purgative agents. In particular, formulations comprising effective amounts of one or more of the following sulfate salts Na₂S0₄, MgS0₄, and K₂S0₄ are effective. Dosage amounts of Na₂S0₄ from about 0.01 g to about 40.0 g can be effective to produce purgation. Doses of from about 0.1 g to about 20.0 g may be used. Dosages of 1.0 to 10.0 g may be used. Dosage amounts of MgS0₄ from about 0.01 g to about 40.0 g can be effective to produce purgation. Doses of from about 0.1 g to about 20.0 g may be used. Dosages of 1.0 to 10.0 g may be used. Dosage amounts of K₂S0 from about 0.01 g to about 20.0 g can be effective to produce purgation. Doses of from about 0.1 g to about 10.0 g may be used. Dosages of about 0.5 to about 5.0 g may be used. The formulation is advantageously a mixture of the foregoing salts.

In some embodiments, addition of an osmotic laxative agent, such as polyethylene glycol (PEG) improves the effectiveness of the above salt mixtures. Doses of PEG from about 1.0 to about 100 g are effective to produce purgation. Doses from about 10.0 g to about 50 g of PEG have been shown to be effective. A dose of about 34 g of PEG has been used.

The purgative component of the compositions of the current invention may contain magnesium oxide coated granules which have a layer of magnesium oxide coated on a core of citric acid; and sodium picosulphate coated granules having a spray-coated layer of sodium picosulphate coating a potassium bicarbonate core. The thickness of the layer of magnesium oxide may be 2 to 15 μπι. The thickness of the layer of magnesium oxide may be 5 to 10 μπι. The magnesium oxide coated granules may be between 450 and 800 μιη broad at their broadest point. The magnesium oxide coated granules may be between 100 and 900 μιτι broad at their broadest point. In addition, more than 85% of the magnesium oxide coated granules may have a size between about 100 μιη and about 900 μιτι. It is possible that the magnesium oxide and citric acid form magnesium citrate in solution. The purgative agent may comprise less than 5% of the magnesium oxide coated granules having a size greater than about 900 μηι; or wherein less than 5% of the magnesium oxide coated granules have a size less than about 100 μιη.

The purgative agents useful in the present application may include Lubiprostone (formerly known as SPI-0211; Sucampo Pharmaceuticals, Inc.; Bethesda, MD), a laxative (eg. a bulk-forming laxative (e.g. nonstarch polysaccharides, Colonel Tablet (polycarbophil calcium), Plantago Ovata, Equalactin (Calcium Polycarbophil)), fiber (e.g. FIBERCON (Calcium Polycarbophil), an osmotic laxative, a stimulant laxative (such as diphenylmethanes (e.g. bisacodyl), anthraquinones (e.g.

cascara, senna), and surfactant laxatives (e.g. castor oil, docusates), an emollient/lubricating agent (such as mineral oil, glycerine, and docusates), MiraLax (Braintree Laboratories, Braintree MA), dexloxiglumide (Forest Laboratories, also known as CR 2017 Rottapharm (Rotta Research

Laboratorium SpA)), saline laxatives, and CR 3700 (Rottapharm (Rotta Resea rch Laboratorium SpA). They also include purgatives that draw fluids to the intestine (e.g., VISICOL^®, a combination of sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydrate).

In some embodiments, phosphodiesterase inhibitors may be used to slow the degradation of cyclic GMP (cGMP) by phosphodiesterases, thus potentiating the activity of the GCCA peptide. In some embodiments, phosphodiesterase 5 (PDE5) inhibitors may be used, including vesnarinone, zaprinast, SKF-96231, ER-21355, BF/GP-385, NM-702 and sildenafil (Viagra^®), vinpocetin, papaverine, enprofylline, cilomilast, fenoximone, pentoxifylline, roflumilast, tadalafil(Cialis^®)₍ theophylline, and vardenafil(Levitra^e). Electrolyte Components and Solutions

In some embodiments, the present invention provides an electrolyte component. In some embodiments, the electrolyte component comprises or consists of one or more salts. In some embodiments, the electrolyte component is provided in a solid form suitable for oral administration in solid form. In some embodiments, the electrolyte component is provided in solid or liquid concentrated form that can be reconstituted for oral administration as a liquid solution. In some embodiments, the electrolyte component is provided in ready to administer liquid oral solution. In some embodiments, the electrolyte component of the present invention comprises one or more cations (e.g., sodium, potassium, magnesium, calcium, etc.). In some embodiments,

the electrolyte component comprises the anions (e.g., bicarbonate, chloride, phosphate, sulfate, etc.). In some embodiments, the electrolyte component comprises or consists of sodium bicarbonate, sodium chloride, and potassium chloride. In some embodiments,

the electrolyte component comprises or consists of sodium sulfate, sodium bicarbonate, sodium chloride, and potassium chloride. In some embodiments, the electrolyte component of the present invention comprises or consists of sodium sulfate, sodium bicarbonate, sodium chloride, sodium phosphate (e.g. monosodium phosphate, disodium phosphate, trisodium phosphate, etc.), potassium bicarbonate, potassium chloride, potassium phosphate, potassium sulfate, magnesium sulfate, magnesium bicarbonate, magnesium chloride, magnesium phosphates, calcium bicarbonate, calcium chloride, calcium phosphate, calcium sulfate, etc. In some embodiments,

the electrolyte component is configured to maintain proper electrolyte levels in a subject undergoing colon cleansing.

In some embodiments, the electrolyte component is a commercially available electrolyte solution that helps to maintain plasma isotonicity). Examples of such solutions include, without limitation, Gatorade^®, Overtime^®, Pedialyte^®, Equalyte^®, Electrolyte Gastro^®, Cytomax^®, Allsport^®, and Accelerade^®.

Compositions and Formulations

In some embodiments, compositions or formulations may be prepared by mixing a GCCA peptide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, one or more purgative agents may be prepared in a similar fashion. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS-Generally Regarded as Safe) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g. enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an attractove presentation of the drug or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

The compositions may be prepared using conventional dissolution and mixing procedures. For example, the GCCA peptide or purgative agent is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The GCCA peptide or purgative agent is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. When the purgative agent described herein is a solid amorphous dispersion formed by a solvent process, additives may be added directly to the spray-drying solution when forming the mixture such as the additive is dissolved or suspended in the solution as a slurry which can then be spray dried. Alternatively, the additives may be added following spray-drying process to aid in the forming of the final formulated product.

The GCCA peptide or a pharmaceutically acceptable salt thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen. Similarly, the purgative agent may be formulated into a convenient dosage form. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. For example, an oral formulation may contain approximately 0.05 to 50 mg of GCCA peptide compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight: weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. An example of an oral formulation for a GCCA peptide is described in US 8,748,573.

Illustrative commercial compositions of purgative agents are summarized below in Table 1. The indicated quantities are the quantities present per liter of aqueous solution. The calculated osmolarity of the solutions (in mOsmol/kg) is also given in the table together with the recommended dose (in liters).

TABLE 1

Compositions of the invention are preferably flavored. Flavoring for use in compositions of the invention should preferably mask saltiness, be relatively sweet but not excessively so, and be stable in the composition. Flavoring makes the solutions more palatable and thus aids patient compliance. Preferred flavorings include lemon e.g. Ungerer Lemon (available from Ungerer Limited, Sealand Road, Chester, England CHI 4LP) strawberry e.g. Ungerer Strawberry, grapefruit e.g.

Ungerer Grapefruit flavoring powder, blackcurrant e.g. Ungerer Blackcurrant, pineapple e.g. IFF (International Flavours and Fragrances) Pineapple flavoring powder and vanilla/lemon and lime e.g. IFF Vanilla and Givaudin Roure Lemon and Lime Flav-o-lok. Those and further suitable flavorings are available from International Flavors and Fragrances Inc. (Duddery Hill, Haverhill, Suffolk, CB9 8LG, England), Ungerer & Company (Sealand Road, Chester, England CHI 4LP) or Firmenich (Firmenich UK Ltd., Hayes Road, Southall, Middlesex UB2 5NN). More preferred flavorings are lemon, kiwi, strawberry and grapefruit. The most preferred flavoring is lemon.

Preferably compositions of the invention comprise a sweetener. Sugar-based sweeteners are not suitable because delivery of unabsorbed sugars to the colon provides a substrate for bacteria. Such sugars may be metabolized by the bacteria to form explosive gases such as hydrogen and methane. The presence of explosive gases in the colon can be highly dangerous when electrical apparatus is to be used during colonoscopy or other procedures. Preferred sweeteners include aspartame, acesulfame K and saccharine or combinations thereof. Citric acid may also be present as a taste enhancer.

The ascorbic acid and/or salt(s) of ascorbic acid in a dry composition of the present invention may be coated. A coating helps to maintain the stability of the ascorbic acid and/or the salt(s) thereof. As stated above, ascorbic acid and salts thereof are otherwise poorly stable in the presence of moisture.

Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, tretralose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURON ICS™ or polyethylene glycol (PEG). The active pharmaceuti cal ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively; in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's: The Science and Practice of Pharmacy, 21^st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter

"Remington's").

"Controlled drug delivery systems" supply the drug to the body in a manner precisely controlled to suit the drug and the conditions being treated. The primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time. The term "controlled release" is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release", "delayed release", "modified release" or "sustained release". In general, one can provide for controlled release of the agents described herein through the use of a wide variety of polymeric carriers and controlled release systems including erodible and non-erodible matrices, osmotic control devices, various reservoir devices, enteric coatings and multiparticulate control devices.

"Sustained-release preparations" are the most common applications of controlled release. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene- vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.

"Immediate-release preparations" may also be prepared. The objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent deaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.

Agents described herein can be incorporated into an erodible or non-erodible polymeric matrix controlled release device. By an erodible matrix is meant aqueous-erodible or water- swellable or aqueous-soluble in the sense of being either erodible or swellable or dissolvable in pure water or requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution. When contacted with the aqueous environment of use, the erodible polymeric matrix imbibes water and forms an aqueous-swollen gel or matrix that entraps the agent described herein. The aqueous-swollen matrix gradually erodes, swells, disintegrates or dissolves in the environment of use, thereby controlling the release of a compound described herein to the environment of use. One ingredient of this water-swollen matrix is the water-swellable, erodible, or soluble polymer, which may generally be described as an osmopolymer, hydrogel or water-swellable polymer. Such polymers may be linear, branched, or cross linked. The polymers may be

homopolymers or copolymers. In certain embodiments, they may be synthetic polymers derived from vinyl, acrylate, methacrylate, urethane, ester and oxide monomers. In other embodiments, they can be derivatives of naturally occurring polymers such as polysaccharides (e.g. chitin, chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum and scleroglucan), starches (e.g. dextrin and maltodextrin), hydrophilic colloids (e.g. pectin), phosphatides (e.g. lecithin), alginates (e.g.

ammonium alginate, sodium, potassium or calcium alginate, propylene glycol alginate), gelatin, collagen, and cellulosics. Cellulosics are cellulose polymer that has been modified by reaction of at least a portion of the hydroxyl groups on the saccharide repeat units with a compound to form an ester-linked or an ether-linked substituent. For example, the cellulosic ethyl cellulose has an ether linked ethyl substituent attached to the saccharide repeat unit, while the cellulosic cellulose acetate has an ester linked acetate substituent. In certain embodiments, the cellulosics for the erodible matrix comprises aqueous-soluble and aqueous-erodible cellulosics can include, for example, ethyl cellulose (EC), methylethyl cellul ose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC). In certain embodiments, the cellulosics comprises various grades of low viscosity (MW less than or equal to 50,000 daltons, for example, the Dow Methocef series E5, E15LV, E50LV and K100LY) and high viscosity (MW greater than 50,000 daltons, for example, E4MCR, EIOMCR, K4M, K15M and K100M and the Methocef K series) HPMC. Other commercially available types of HPMC include the Shin Etsu Metolose 90SH series. Other materials useful as the erodible matrix material include, but are not limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT^®, Rohm America, Inc., Piscataway, New Jersey) and other acrylic acid derivatives such as

homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

Alternatively, the agents of the present invention may be administered by or incorporated into a non-erodible matrix device. In such devices, an agent described herein is distributed in an inert matrix. The agent is released by diffusion through the inert matrix. Examples of materials suitable for the inert matrix include insoluble plastics (e.g methyl acrylate-methyl methacrylate copolymers, polyvinyl chloride, polyethylene), hydrophilic polymers (e.g. ethyl cellulose, cellulose acetate, cross linked polyvinylpyrrolidone (also known as crospovidone)), and fatty compounds (e.g. carnauba wax, microcrystalline wax, and triglycerides). Such devices are described further in Remington: The Science and Practice of Pharmacy, 20th edition (2000).

As further noted above, the agents described herein may be provided in the form of microparticulates, generally ranging in size from about ΙΟμηη to about 2mm (including, for example, from about ΙΟΟμιη to 1mm in diameter) . Such multiparticulates may be packaged, for example, in a capsule such as a gelatin capsule or a capsule formed from an aqueous-soluble polymer such as HPMCAS, HPMC or starch; dosed as a suspension or slurry in a liquid ; or they may be formed into a tablet, caplet, or pill by compression or other processes known in the art. Such multiparticulates may be made by any known process, such as wet- and dry-granulation processes,

extrusion/spheronization, roller-compaction, melt-congealing, or by spray-coating seed cores. For example, in wet-and dry- granulation processes, the agent described herein and optional excipients may be granulated to form multiparticulates of the desired size.

The agents can be incorporated into microemulsions, which generally are

thermodynamically stable, isotropically clear dispersions of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology, New York: Marcel Dekker, 1992, volume 9). For the preparation of microemulsions, surfactant (emulsifier), co-surfactant (co-emulsifier), an oil phase and a water phase are necessary. Suitable surfactants include any surfactants that are useful in the preparation of emulsions, e.g., emulsifiers that are typically used in the preparation of creams. The co-surfactant (or "co- emulsifier") is generally selected from the group of polyglycerol derivatives, glycerol derivatives and fatty alcohols. Preferred emulsifier/co-emulsifier combinations are generally although not necessarily selected from the group consisting of: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; and caprilic and capric triglycerides and oleoyl macrogolglycerides. The water phase includes not only water but also, typically, buffers, glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phase will generally comprise, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono- di- and triglycerides, mono- and di-esters of PEG (e.g., oleoyl macrogol glycerides), etc.

The agents described herein can be incorporated into pharmaceutically-acceptable nanoparticle, nanosphere, and nanocapsule formulations (Delie and Blanco-Prieto, 2005, Molecule 10:65-80). Nanocapsules can generally entrap compounds in a stable and reproducible way. To avoid side effects due to intracellular polymeric overloading, ultrafine particles (sized around 0.1 μητι) can be designed using polymers able to be degraded in vivo (e.g. biodegradable polyalkyl- cyanoacrylate nanoparticles). Such particles are described in the prior art.

In some embodiments, there is provided a pharmaceutical composition comprising a GCCA peptide described herein and one or more stabilizing agents selected from Mg²⁺, Ca²⁺, Zn²⁺, Mn²*, K*, Na⁺ or Al³⁺, a combination thereof, and/or a sterically hindered primary amine. In further embodiments, the agent is Mg²⁺, Ca * or Zn²* or a combination thereof In some embodiments, the cation is provided, without limitation, as 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.

In another embodiment, the stabilizing agent is a sterically hindered primary amine. In a further embodiment, the sterically hindered primary amine is an amino acid. In yet a further embodiment, the amino acid is a naturally-occurring amino acid. In a still further 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; yet further, the naturally-occurring amino acid is leucine, isoleucine, alanine or methionine. In another embodiment, the sterically hindered primary amine is a non-naturally occurring amino acid (e.g., 1-aminocyclohexane carboxylic acid). In a further embodiment, the sterically hindered primary amine is cyclohexylamine, 2-methylbutylamine or a polymeric amine such as chitosan. In another embodiment, one or more sterically hindered primary amines may be used in a composition.

In some cases, the sterically hindered primary amine has the formula:

_/ wherein R_lt R₂ and R₃ are independently selected from: H, C(0)OH, C C₆ alkyl, C_rC₆ alkylether, C₁-Ce alkylthioether, Cj-Cg alkyl carboxylic acid, Ci-C₃ alkyl carboxylamide and alkylaryl, wherein any group can be singly or multiply substituted with: halogen or amino, and provided that no more than two of R R₂ and R₃ are H. In another embodiment, no more than one of R₁₍ R₂ and R₃ is H.

In other embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier, peptide, a cation selected from Mg²*, Ca²*, Zn²*, Mn²*, K*, Na* or Al³*, or a mixture thereof, and a sterically hindered primary amine. In one embodiment, the cation is Mg²*, Ca²* or Zn²* or a mixture thereof.. In a further embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable binder and/or a pharmaceutically acceptable glidant, lubricant or additive that acts as both a glidant and lubricant and/or an antioxidant. In some embodiments, the pharmaceutical composition is applied to a carrier. In some embodiments, the carrier is a filler.

In some cases the molar ratio of cation:sterically hindered primary amine: peptide in the aqueous solution applied to the carrier is 5-100:5-50:1. In some cases, the molar ratio of cation :sterically hindered primary amine may be equal to or greater than 2:1 (e.g., between 5:1 and 2:1). Thus, in some cases the molar ratio of cation:sterically hindered primary amine: peptide applied to the 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. When binder, e.g., methylcellulose, is present in the GC-C agonist peptide solution applied to the carrier it can be present at 0.5% - 2.5% by weight (e.g., 0.7%-1.7% or 0.7% - 1% or 1.5% or 0.7%).

A cation selected from Mg²*, Ca²*, Zn²*, Mn²*, K*, Na* and Al³*may be useful for suppressing the formation of an oxidation product of the GCCA peptide during storage. A sterically hindered primary amine may be useful for suppressing the formation of a formaldehyde imine adduct ("formaldehyde imine product") of the GCCA peptide during storage. Thus, the GCCA peptide formulations comprising a cation selected from Mg²*, Ca²*, Zn²*, Mn²*, K*, Na* or Al³*— for example, a divalent cation selected from Zn²*, Mg²* and Ca²*— and/or a sterically hindered primary amine, such as an amino acid, have a sufficient shelf life (as measured by chromatographic purity and/or by a weight/weight assay) for manufacturing, storing and distributing the drug. Further, while the presence of a sterically hindered amine alone may increase the formation of a hydrolysis product of GCCA peptide during storage, the combination of a sterically hindered primary amine and a cation, e.g., but not limited to, the combination of leucine and Caⁱ⁺, may suppress the formation of the hydrolysis product of the GCCA peptide as well as the oxidation product of GCCA peptide during storage, leading to an even greater overall stability as determined by a weight/weight assay and/or by chromatographic purity.

In a further embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable binder or additive, and/or a pharmaceutically acceptable glidant, lubricant or additive that acts as both a glidant and lubricant and/or an antioxidant.

In some embodiments, the peptides described herein may be administered orally, e.g., as a tablet, capsule, sachet containing a predetermined amount of the active ingredient pellet, gel, paste, syrup, bolus, electuary, slurry, powder, lyophilized powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a liposomal formulation (see, e.g., EP 736299) or in some other form. Orally administered compositions can include binders, lubricants, inert diluents, lubricating, surface active or dispersing agents, flavoring agents, and humectants. Orally administered formulations such as tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein. The peptides can be co-administered with other agents used to treat gastrointestinal disorders including but not limited to the agents described herein.

In some embodiments, the peptides described herein may be administered non-orally. In some embodiments, the peptides described herein may be administered intranas

ally, e.g., as a gel, paste, syrup, bolus, electuary, slurry, powder, lyophilized powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion, via a liposomal formulation (see, e.g., EP 736299) or in some other form. Intranasally administered compositions can include binders, lubricants, inert diluents, lubricating, surface active or dispersing agents, flavoring agents, and humectants. Intranasal compositions can be administered by any device designed to administer the above compositions into the nasal cavity, including but not limited to intranasal pumps, cartridges, nebulizers and atomizers. Nasally administered formulations such as solutions or powders may optionally include agents that provide sustained, delayed or controlled release of the active ingredient therein. The peptides can be co-administered with other agents used to treat gastrointestinal disorders including but not limited to the agents described herein.

The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Dosage Forms

In some embodiments, the GCCA peptide composition may be in capsule, tablet, or powder or granular unit dosage form. In some embodiments, the GCCA peptide composition may be in a capsule, tablet or single use container (e.g., a sachet) containing a powder or granular form of the GCCA peptide formulation. In some embodiments, the GCCA peptide composition may be a powder, suspension or solution dosage form adapted for intranasal use, i.e., a cartridge filled with the dosage form. The cartridge may contain one or more dosage forms.

In some embodiments, a purgative agent may be in powder, granular or any other suitable physical form. A dry composition of the invention may be provided in unit dosage form, for example, in a sachet. A dry composition may be provided in two or more component form, in which the one component is packaged separately from another other component. For example, a first component may be in a unit dose form, such as a sachet containing polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride, sweeten ing and flavoring agents, and a second component may be in a separate unit dose form, such as a sachet containing ascorbic acid and sodium ascorbate.

In some embodiments, the GCCA peptide or a purgative agent may be provided as a solution in water, for example, in one or more containers, each containing, for example, 0.1 to 1 liter of solution. The preparations may optionally include an anti-gas compound, such as simethicone.

Dosage forms for oral administration include capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,

tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeten ing, flavoring, and perfuming agents.

Liquid dosage forms may be prepared by the patient or physician by dissolving or suspending a GCCA peptide and/or one or more purgative agents in water or other aqueous solution prior to administration. In some embodiments, the GCCA peptide and/or purgative agents are provided as a capsule, tablet, pre-measured powder or sachet that is added to water or other aqueous solution and then dissolved or suspended.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or may be coated by known techniques including microencapsulation to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestina l tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. A water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.

Formulations suitable for oral administration may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, sachets, emulsions, hard or soft capsules, e.g. gelatin capsules, syrups or elixirs. Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.

Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil. The active compounds can also be in microencapsulated form with one or more excipients as noted above.

When aqueous suspensions are required for oral use, the active ingredient may be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a

condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g.,

heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p- hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

The pharmaceutical composition (or formulation) may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal or plastic cylinders, syringes, cartridges, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

Dosage

The dose range for adult humans may be generally from 1 μg to 100 mg per day of the GCCA peptide or pharmaceutically acceptable salts described herein. In some embodiments, the dose range for adult humans may be generally from 10 μ to 50 mg per day. In some embodiments, the dose range for adult humans may be generally from 100 g to 30 mg per day. In some embodiments, the dose for adult humans may be 150 μg_l 250 μg, 300 μg , 500 μ%, lOOO g (1 mg), 200(tyg (2 mg), 2.5 mg, 3000 g (3mg), 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg per day. For pediatric patients, the dose range may be lower.

The dose per day may be provided as a single dose or may be administered in multiple doses. If administered as multiple doses, then the total dose per day is divided by the number of doses to be administered to give the amount of a single dose. For example, if the dose per day is 2 mg and two doses are given per day, then each dose would be 1 mg. The precise amount of GCCA peptide prescribed to a patient will be the responsibility of the attendant physician. The dose employed will depend upon a number of factors, including the age and sex of the patient.

Methods of Use

The terms "administer", "administering" or "administration" in reference to a compound, composition or formulation of the invention means introducing the compound into the system of the animal. In some embodiments, the animal is a human. When a compound of the invention is provided in combination with one or more other active agents, "administration" and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.

The pharmaceutical compositions will be formulated, dosed, and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles, and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.

In some embodiments, a GCCA peptide or pharmaceutically acceptable salt thereof is administered to a patient to cleanse the colon. The GCCA peptide is administered along with sufficient fluid to cleans the colon. The fluid may be water or an electrolyte solution (e.g., a commercially available solution such as Gatorade^®, Overtime'⁸, Pedialyte^®, Equalyte^®, Electrolyte Gastro^®, Cytomax^®, Allsport^® or Accelerade^® that helps to maintain plasma isotonicity). The GCCA peptide may be administered as a tablet or capsule or may be a powder or granules dissolved in fluid, such as water or an electrolyte solution. In some embodiments, the GCCA peptide will be administered at least once to cleanse the colon. In one embodiment, the GCCA peptide will be administered the night before the medical or surgical procedure (e.g., the colonoscopy). In some embodiments, the GCCA peptide will be administered at least twice to cleanse the colon. In one embodiment, one dose of the GCCA peptide is administered the night before the medical or surgical procedure (e.g., the colonoscopy) and one dose of the GCCA peptide is administered the morning of the procedure. In some embodiments, the GCCA peptide will be administered at least three times to cleanse the colon. In one embodiment, two doses of the GCCA peptide are administered the night before the medical or surgical procedure (e.g., the colonoscopy) and one dose of the GCCA peptide is administered the morning of the procedure. In some embodiments, the GCCA peptide is dosed four, five, six, seven or eight times prior to the procedure. In some embodiments, the GCCA peptide is administered at least 12 hours, 18 hours, 24 hours, 36 hours or 48 hours prior to the procedure.

In some embodiments, one or more purgation agents are administered in conjunction with the GCCA peptide. In some embodiments, the GCCA peptide and the purgation agent(s) are administered at the same time. The GCCA peptide and purgation agent(s) may be administered together in a single solid dosage form (e.g., as a tablet or capsule). The GCCA peptide and purgation agent(s) may be administered together in a single liquid dosage form (e.g., as a premixed liquid dosage form or as sachet mixed with fluid before administration). The GCCA peptide and purgation agent(s) may be administered separately at the same time. The dosage forms for the GCCA peptide and purgation agent(s) may be the same or different. For example, the GCCA peptide may be administered as a tablet or capsule while the purgation agent(s) may be separately administered as a tablet, capsule, sachet or pre-mixed liquid dosage form. In one embodiment, one dose of the GCCA peptide and one dose of the purgation agent(s) are administered the night before the medical or surgical procedure (e.g., the colonoscopy) and one dose of the GCCA peptide and one dose of the purgation agent(s) are administered the morning of the procedure.

In some embodiments, the GCCA peptide and the purgation agent(s) are administered sequentially. In some embodiments, the GCCA peptide is administered first and the purgation agent(s) are administered afterward. In some embodiments, the purgation agent(s) are administered after a bowel movement following the GCCA peptide administration. In some embodiments, the purgation agent(s) are administered after a set time period (e.g., 1 hour, 2 hours, 4 hours, 8 hours after GCCA peptide administration). In some embodiments, the GCCA peptide is administered once and the purgation agent(s) are administered multiple times (e.g., twice, three times or four times). In other embodiments, the GCCA peptide is administered multiple times (e.g., twice, three times or four times) and the purgation agent(s) are administered once. In other embodiments, the GCCA peptide and the purgation agent(s) are administered multiple times. In one embodiment, one dose of the GCCA peptide and one subsequent dose of the purgation agent(s) are administered the night before the medical or surgical procedure (e.g., the colonoscopy) and one dose of the GCCA peptide and one subsequent dose of the purgation agent(s) are administered the morning of the procedure.

In some embodiments, methods are provided for cleansing the colon in a patient comprising administering a GCCA peptide or salt thereof, and optionally one or more purgative agents, and further administering an electrolyte component. The electrolyte component may be supplied as a solid form or concentrated liquid, either of which may be reconstituted to an isotonic solution, or may be supplied as a ready to drink oral solution. In some embodiments, the electrolyte component is administered as a solid form. In some embodiments, the GCCA peptide, and optionally one or more purgative agents, is administered to a patient at the same time as the electrolyte component (e.g., a commercially available electrolyte solution such as Gatorade^®, Overtime^®, Pedialyte^®, Equalyte^®, Electrolyte Gastro^®, Cytomax^®, Allsport^® or Accelerade^®). When the GCCA peptide, and optionally one or more purgative agents, is administered to a patient at the same time as the electrolyte component, the electrolyte component may be administered as a separate dosage form or as part of a single composition. In some embodiments, the GCCA peptide, and optionally one or more purgative agents, is administered to a patient before administration of the electrolyte component. In some embodiments, the GCCA peptide, and optionally one or more purgative agents, is administered to a patient after administration of the electrolyte component. In some

embodiments, the electrolyte component is given ad libitum.

In some embodiments, the GCCA peptide and/or the purgation agent(s) can be dissolved in a convenient volume of water or electrolyte solution. A volume of less than one liter of water or electrolyte solution is well tolerated by most patients. The mixture can be dissolved in any volume of water or electrolyte solution, and volumes of between 100 and 500 ml are often convenient. Any volume may be administered. Optimally, the effective dose may be divided and administered, to the patient in two, or more administrations over an appropriate time period. Generally, 2 doses administered of equal portions of the effective dose, separated by 6 to 24 hours produce satisfactory purgation.

Kits

In some embodiments, a kit is supplied containing a composition comprising a GCCA peptide or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve colon cleansing. In some embodiments, the kit will contain one or more unit dosage forms of the GCCA peptide composition. The GCCA peptide unit dosage form may be a pill, powder, capsule, or liquid. The kit may further comprise one or more purgation agents in an amount sufficient to achieve colon cleansing in combination with the GCCA peptide. In some embodiments, the kit will contain one or more unit dosage forms of the purgation agent(s). For example, the purgation agent unit dosage form may be a pill, powder, capsule or liquid. The purgation agent unit dosage form may be packaged separately from the GCCA peptide unit dosage form or they may be packaged together. In some embodiments, the kit may comprise an electrolyte component. In some embodiments, the kit will contain one or more unit dosage forms of the electrolyte component. The electrolyte component dosage form may be a pill, powder, capsule, concentrated liquid or ready to drink liquid. In some embodiments, the GCCA peptide and/or purgation agent and/or electrolyte component may be supplied as a powder in a sachet or package or as a concentrated liquid to which clear liquid, e.g., water, may be added to form a solution prior to oral administration. The kit may include two or more containers or dispensers.

The compositions included in the kit may be supplied in containers of any sort such that the integrity of the different components are preserved and they are not adsorbed or altered by the materials of the container or by other components. For example, suitable containers include simple bottles that may be fabricated from glass, organic polymers such as polycarbonate, polystyrene, etc., ceramic, metal or any other material typically employed to hold reagents or food; envelopes, that may include foil-lined interiors, such as aluminum foil or an alloy. Other containers include test tubes, vials, flasks, and syringes. The containers may have two compartments that are separated by a readily removable membrane that upon removal permits the components to mix. Removable membranes may be glass, plastic, rubber, or the like.

Kits may also include instruction materials. Instructions may be printed on paper or other substrates, and/or may be supplied as an electronic-readable medium, such as CD-ROM, DVD-ROM, etc. Detailed instructions may not be physically associated with the kit; instead, a user may be directed to an internet web site specified by the manufacturer or distributor of the kit, or supplied as electronic mail.

It is convenient for the patient for a kit to be provided in the form of, for example, a box. The kit may be provided in a package, or example an envelope (which may be addressed to the subject), for example a padded envelope. The box or other package containing the kit may, for example, be one that can be posted into a standard domestic mailbox, so that it can conveniently be sent to a subject in the mail.

Assays

The effectiveness of any of the preparations disclosed herein may be gauged by physician observation, e.g., by reference to the Boston Bowel Preparation Scale. The Boston Bowel

Preparation Scale was developed for evaluating the quality of bowel preparation during

colonoscopy. The preparation scale uses a number from 0 to 3 to rate each of three sections of the colon; the right colon, the transverse colon, and the left colon. Decimal point scores should not be used. The individual segment scores are then summed for a total score ranging from 0 to 9. The hepatic flexure and the splenic flexure are considered parts of the transverse colon using the scale. These scores are assigned to the colon segment based upon the appearance after any maneuvers; such as washing, suctioning, or movement of debris and are meant to be applied during the withdrawal phase of colonoscopy. A segment score of 0 (zero) describes an unprepared colon segment with mucosa not seen due to solid stool or thick liquid stool that cannot be cleared. A segment score of 1 describes a segment where a portion of mucosa of the colon segment seen, but other areas of the colon segment not well seen due to staining, residual stool and/or opaque liquid. A segment score of 2 describes a segment where in there is a minor amount of residual staining, small fragments of stool and/or opaque liquid, but mucosa of colon segment seen well. Finally, a segment score of 3 describes a segment wherein the entire mucosa of colon segment seen well with no residual staining, small fragments of stool or opaque liquid. Each segment of the colon (Right, Transverse (the Transverse Colon, and Left is should be rated based on the cleanliness of the colon from 0 to 3; then the entire score is added.

Treatment failures are patients with insufficient evacuation of the bowel with a Boston bowel prep score <5, and/or with any colon segment score of 0.

The effectiveness of the present preparations may also be ascertained by measurement of stool weight and volume as described in US Pat. No. 7,169,381. Effeciveness may also be measured by measurement of clarity of diahrreal fluid as discussed in, for example, Am J Gastroenterol 2009; 104:953-965. Colon cleanliness may be measured by use of the kits and methods disclosed in publication WO 2008102340 or by a breath test as described by Urita, et al. "Hydrogen Breath Test as an Indicator of Quality of Colonic Preparation for Colonoscopy" Gastrointestinal Endoscopy Vol. 57, No. 2, 2003.

The preparations of the instant invention can also be assayed for reduction in undesirable side effects, such as feelings of fullness, discomfort, cramping and pain, nausea and vomiting. These side effects can be measured by patient self-reporting as discussed in US Pat. No. 7,291,324.

The foregoing descriptions reveal the general nature of the methods and assays. Others of skill in the art will appreciate that applying ordinary skill may readily modify, or adapt, the method or assay disclosed without undue experimentation. These descriptions are illustrative, not limiting.

GCCA Peptide 2

In some embodiments, pharmaceutical compositions are provided comprising a GCCA peptide or pharmaceutically acceptable salt thereof that comprises or consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82; Peptide 2), wherein the GCCA peptide includes disulfide bonds between Cys_! and Cys₆, between Cys₂ and Cysio and between Cys_s and Cysi₃ (herein, Peptide 2). In some embodiments, the pharmaceutical compositions further comprise one or more purgative agents. In some embodiments, the pharmaceutical compositions, dosage forms, kits and methods further comprise a PDE5 inhibitor. In some embodiments, the purgative agent is selected from a surfactant or stool softener, a bulking agent, a lubricant or emollient, a hydrating agent or osmotic, a hyperosmotic agent, a stimulant or contact laxative, a serotonin agonist, a 5-HT receptor agonist, a chloride channel activator or a combination thereof. In some embodiments, the purgative agent is selected from a ducosate salt, bran, an insoluble fiber, gum karaya, sterculia, psyllium husk, a soluble fiber, methylcellulose, polycarbophil, mineral oil, sodium phosphate, potassium sodium tartrate, magnesium citrate, magnesium hydroxide, magnesium sulfate, sodium ascorbate, ascorbic acid, sorbitol, lactulose, polyethylene glycol (PEG), sodium picosulfate, anthraquinones, dantron, emodin, aloe emodin, senna, phenolphthalein, bisacodyl, castor oil, ricinoleic acid, tegaserod, cisapride, rucalopride, lubiprostone or a combination thereof. In some embodiments, the purgative agent is selected from bisacodyl, senna, magnesium citrate, sodium ascorbate, ascorbic acid, or a combination thereof.

In some embodiments, the PDE5 inhibitor is vesnarinone, zaprinast, SKF-96231, ER-21355, BF/GP-385, NM-702 and sildenafil (Viagra^®), vinpocetin, papaverine, enprofylline, cilomilast, fenoximone, pentoxifylline, roflumilast, tadalafil(Cialis^®), theophylline, or vardenafil(Levitra^e).

In some embodiments, a dosage form is provided comprising a pharmaceutical composition comprising a GCCA peptide or pharmaceutically acceptable salt thereof that comprises or consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82), wherein the GCCA peptide includes disulfide bonds between Cysj and Cys₆, between Cys₂ and Cys₁₀ and between Cys_s and Cysu, wherein the pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents. In some embodiments, the dosage form provides the pharmaceutical composition, either alone or in conjunction with one or more purgative agents, in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses. In some embodiments, the dosage form provides the pharmaceutical composition, either alone or in conjunction with one or more purgative agents, in a single dose, two doses or three doses.

In some embodiments, a dosage form comprising a pharmaceutical composition comprising a GCCA peptide or pharmaceutically acceptable salt thereof that comprises or consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82), wherein the GCCA peptide includes disulfide bonds between Cys_x and Cys₆, between Cys₂ and Cysjo and between Cys₅ and Cysi₃, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 10 μg to 50 mg. In some embodiments, the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 100 μ to 30 mg. In some embodiments, the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 250 to 25 mg per day. In some embodiments, the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 250 ig, 300 μξ, 500 μ 750 μ 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 9 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg or 25 mg.

In some embodiments, a method is provided for cleansing the colon of a patient in need thereof, comprising administering a pharmaceutical composition in an amount effective to cleanse the colon, wherein the pharmaceutical composition comprises a GCCA peptide or pharmaceutically acceptable salt thereof, wherein the GCCA peptide comprises or consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ. ID NO:82), and wherein the GCCA peptide includes disulfide bonds between Cys_! and Cys₆, between Cys₂ and Cys₁₀ and between Cys_s and Cys^. In some embodiments, the pharmaceutical composition is provided in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

In some embodiments, the pharmaceutical composition is provided in a single dose. The single dose may be given 3 hours, 6 hours, 9 hours, 12 hours or 18 hours before a diagnostic or therapeutic procedure requiring a cleansed colon. In some embodiments, the single dose is given the night before a diagnostic or therapeutic procedure requiring a cleansed colon. In some embodiments, the single dose is administered with water, with an electrolyte component, or with both water and an electrolyte component. The electrolyte component may be administered as an electrolyte solution. In some embodiments, the pharmaceutical composition is provided with at least 8 ounces of water, electrolyte component, both water and an electrolyte component, or an electrolyte solution. In some embodiments, at least 1 liter or at least 2 liters of additional clear liquid (e.g., water, electrolyte component, both water and an electrolyte component, or an electrolyte solution) is administered subsequent to the pharmaceutical composition.

In some embodiments, the pharmaceutical composition is provided in two doses. The doses may be administered sequentially before a diagnostic or therapeutic procedure requiring a cleansed colon. In some embodiments, the first dose is administered 9 hours, 12 hours, 15 hours, 18 hours or 24 hours before the procedure. In some embodiments, the second dose is administered 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours or 18 hours after the first dose and at least 2 hours, 3 hours, 4 hours, 5 hours, 6 hours or 8 hours prior to the procedure. In some embodiments, the first dose is given the night before the procedure and the second dose is given the morning of procedure. In some embodiments, the second dose is administered 4-6 hours prior to the procedure and is completed at least 2 hours prior to the procedure.

In some embodiments in which two doses are administered, each dose of the

pharmaceutical composition is provided with at least 8 ounces of water, electrolyte component, both water and an electrolyte component, or an electrolyte solution. In some embodiments, at least 1 liter or at least 2 liters of additional clear liquid (e.g., water, electrolyte component, both water and an electrolyte com ponent, or an electrolyte solution) is administered subsequent to the first dose of the pharmaceutical composition. In some embodiments, at least 1 liter or at least 2 liters of additional clear liquid (e.g., water, electrolyte component, both water and an electrolyte component, or an electrolyte solution) is administered subsequent to the second dose of the pharmaceutical composition. In some embodiments, at least 1 liter or at least 2 liters of additional clear liquid (e.g., water, electrolyte component, both water and an electrolyte component, or an electrolyte solution) is administered subsequent to both the first dose and the second dose of the pharmaceutical composition.

In some embodiments, the pharmaceutical composition is provided in three doses. The doses may be administered sequentially before a diagnostic or therapeutic procedure requiring a cleansed colon. In some embodiments, the first dose is administered 9 hours, 12 hours, 15 hours, 18 hours, 24 hours or 30 hours before the procedure. In some embodiments, the second dose is administered 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours or 12 hours after the first dose. In some embodiments, the third dose is administered 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours or 12 hours after the first dose and at least 2 hours, 3 hours, 4 hours, 5 hours, 6 hours or 8 hours prior to the procedure. In some embodiments, the first two doses are given the day or evening before the procedure and the third dose is given the morning of procedure. In some embodiments, the third dose is administered 4-6 hours prior to the procedure and is completed at least 2 hours prior to the procedure.

In some embodiments in which three doses are administered, each dose of the

pharmaceutical composition is provided with at least 8 ounces of water, electrolyte component, both water and an electrolyte component, or an electrolyte solution. In some embodiments, at least 1 liter or at least 2 liters of additional clear liquid (e.g., water, electrolyte component, both water and an electrolyte component, or an electrolyte solution) is administered subsequent to the first and/or second dose of the pharmaceutical composition. In some embodiments, at least 1 liter or at least 2 liters of additional clea r liquid (e.g., water, electrolyte component, both water and an electrolyte component, or an electrolyte solution) is administered subsequent to the third dose of the pharmaceutical composition. In some embodiments, at least 1 liter or at least 2 liters of additional clear liquid (e.g., water, electrolyte component, both water and an electrolyte component, or an electrolyte solution) is administered subsequent to both the first or second dose and the third dose of the pharmaceutical composition.

In some embodiments of the method, the pharmaceutical composition comprising a GCCA peptide or pharmaceutically acceptable salt thereof is administered in an amount from 10 ig to 50 mg. In some embodiments, the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 100 μg to 30 mg. In some embodiments, the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 250 μg to 25 mg per day. In some embodiments, the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 250 μg, 500 μ , 750 μ , 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 9 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg or 25 mg.

In some embodiments of the method, a purgative agent is also administered to the patient. The purgative agent can be a surfactant or stool softener, a bulking agent, a lubricant or emollient, a hyd rating agent or osmotic, a hyperosmotic agent, a stimulant or contact laxative, a serotonin agonist, a 5-HT receptor agonist, a chloride channel activator or a combination thereof. In some embodiments, the purgative agent is a ducosate salt, bran, an insoluble fiber, gum karaya, sterculia, psyllium husk, a soluble fiber, methylcellulose, polycarbophil, mineral oil, sodium phosphate, potassium sodium tartrate, magnesium citrate, magnesium hydroxide, magnesium sulfate, sodium ascorbate, ascorbic acid, sorbitol, lactulose, polyethylene glycol (PEG), sodium picosulfate, anthraquinones, dantron, emodin, aloe emodin, senna, phenolphthalein, bisacodyl, castor oil, ricinoleic acid, tegaserod, cisapride, rucalopride, lubiprostone or a combination thereof. In some embodiments, the purgative agent is bisacodyl, senna, magnesium citrate, sodium ascorbate, ascorbic acid or a combination thereof. In some embodiments, the purgative agent is administered at the same time as the GCCA peptide in a single dosage form or as a separate dosage form. In some embodiments, the purgative agent is administered either before or after the GCCA peptide is administered.

In some embodiments, an electrolyte component is also administered to the patient. The electrolyte component may be a ready to drink electrolyte solution or a dry, powdered, or concentrated dosage form of electrolytes that can be reconstituted to form an electrolyte solution. In some embodiments, the electrolyte component may contain sodium sulfate, sodium bicarbonate, sodium chloride, sodium phosphate, potassium bicarbonate, potassium chloride, potassium phosphate, potassium sulfate, magnesium sulfate, magnesium bicarbonate, magnesium chloride, magnesium phosphate, calcium bicarbonate, calcium chloride, calcium phosphate, calcium sulfate, and mixtures thereof. In some embodiments, electrolyte component is administered as an electrolyte solution in an amount sufficient to effectuate colon cleansing when used in conjunction with the GCCA peptide or pharmaceutically acceptable salt thereof, and optionally in conjunction with a purgative agent.

In some embodiments, the method further comprises administering the pharmaceutical composition with sufficient fluid to effectuate colon cleansing. In some embodiments, the fluid is water, a ready to drink electrolyte solution, or a dry, powdered, or concentrated dosage form of electrolytes that is reconstituted to form an electrolyte solution. In some embodiments, the fluid is clear and/or uncolored. In some embodiments, a kit is provided comprising a pharmaceutical composition comprising a GCCA peptide or pharmaceutically acceptable salt thereof that comprises or consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82), wherein the GCCA peptide includes disulfide bonds between Cysi and Cys₆, between Cys₂ and Cysi₀ and between Cys₅ and Cys₁₃. In some embodiments, the kit provides sufficient dosage forms comprising the pharmaceutical composition to effectuate colon cleansing. The kit may further provide one or more purgative agents. The kit may further comprise instructions for use. The kit may further comprise containers for mixing and administering dosage forms. The kit may further comprise an electrolyte component. The electrolyte component may be a ready to drink electrolyte solution or a dry, powdered, or concentrated dosage form of electrolytes that can be reconstituted to form an electrolyte solution.

In some embodiments, the electrolyte component may contain sodium sulfate, sodium bicarbonate, sodium chloride, sodium phosphate, potassium bicarbonate, potassium chloride, potassium phosphate, potassium sulfate, magnesium sulfate, magnesium bicarbonate, magnesium chloride, magnesium phosphate, calcium bicarbonate, calcium chloride, calcium phosphate, calcium sulfate, and mixtures thereof.

Examples

Example 1: Fluid secretion in rat intestinal loops

The effect of GC-C agonist peptides on secretion were studied by injecting GC-C agonist peptides described herein directly into an isolated loop in wild-type rats.

Loops were isolated by surgically ligating three loops in the small intestine of the rat. The methodology for ligated loop formation was similar to that described in (London et al., 1997, Am J Physiol, P.G93-105). The loops were roughly centered and at lengths of 1-3 cm. The loops were injected with 200 μΙ of either peptide/GC-C agonist (O.l^g) or vehicle (20 mM Tris, pH 7.5 or Krebs Ringer, lOmM Glucose, HEPES buffer (KRGH)). Following a recovery time of up to 90 minutes the loops were excised. Weights were recorded for each loop before and after removal of the fluid contained therein. The length of each loop was also recorded. A weight to length ratio (W/L) for each loop was calculated to determine the effects of the GC-C agonist peptide described herein on secretion. Loop fluid volume was also determined.

Data showing increases in fluid secretion, pH increase and bicarbonate secretion in ligated duodenal loops in rats are shown in Figure 1 and Table 2. Figure 1 shows that Peptide 2, which has the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82), and Peptide 4, which has the amino acid sequence Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO: 5), have similar potencies with regard to induction of fluid accumulation in ligated rat duodenal loops. Table 2 provides results for Peptide 1, which has the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO: 81), Peptide 2 and Peptide 4 as well as dephosphorylated forms of Peptide 1 and Peptide 2 in ligated rat duodenal loops using 2.5 μg of peptide per loop.

Table 2: Fluid secretion, pH increase, and bicarbonate secretion

Example 2: Gastrointestinal Transit Assay

The purpose of the assay was to test the effect of the GCCA peptides on in vivo

gastrointestinal transit in mice. Orally-dosed guanylate cyclase C agonists have been demonstrated to increase the % Distance Travelled by a charcoal meal in mice.

For the assay, female CD-I mice (n=10 per group) weighing 25-30 g were fasted overnight and given access to water ad libitum. Activated charcoal (20g; 100 mesh; Sigma cat# 242276) was suspended in 200 mL gum arabic (100 mg/mL), and stirred for at least one hour. Test peptides were prepared in a 20 mM Tris pH 6.9 vehicle.

Test peptide and vehicle were administered in 200 μί doses by oral gavage. Seven minutes after dosing the test peptides, 200 μί of the charcoal/gum arabic suspension was dosed by oral gavage. After 15 minutes, mice were sacrificed by C02 overdose. The gastrointestinal tract was removed from the esophagus to the caecum. The total length of the small intestine was measured from the pyloric junction to the ileocaecal junction. The distance travelled by the charcoal was measured from the pyloric junction to the charcoal front. The Distance Travelled (%) was determined as (distance travelled by charcoal/total length of the small intestine) x 100. Data were entered into the GraphPad Prism software program and analyzed by ANOVA using a Bonferroni multiple comparison test post-hoc. Plots of data and ED50 were also determined using the GraphPad Prism software package. The dose-dependent effects of acute doses of Peptide 4, Peptide 2 and the

dephosphorylated form of Peptide 2 on Gl transit were determined in female CD mice. The distance traveled by the charcoal front after seven minutes, expressed as a percent of total length of small intestine was used to calculate ED50 values.

Example 3; Colon Cleansing Protocol in Healthy Individuals

The safety and tolerability of a GCCA peptide may be tested as described herein.

Study Design: Healthy female and male subjects will be randomly split in up to seven groups each consisting of eight subjects each. The study will be conducted over a two day period with dosing on the evening of day 1 and on the morning of day 2. There will be four dosing groups. The first group will be dosed in up to four different single ascending dose levels on the evening of day 1 (i.e,. utilizing four different dose levels (e.g. 300 ug, 1000 ug, 2000 ug, 3000 ug, etc.). The second group will be dosed with up to three split doses in the evening of day 1 and the morning of day 2. The third group will be dosed in a combination of doses from groups 1 and 2 along with other solid oral dose laxatives (e.g., OTC laxatives). Each dose of peptide described herein will be taken with 8 ounces of water. Additional clear liquid will also be given for a total volume of greater than or equal to 2L.

Evaluation

Safety and tolerability evaluations will include clinical laboratory evaluations for stool electrolytes and urine osmolality; physical examination and vital signs; electrocardiograms; adverse events; and a validated tolerability questionnaire. Pharmacokinetic and pharmacodynamics evaluations will begin on day 3 after dosing. For pharmacokinetic ("PK") evaluation plasma samples will be collected for PK analysis of a peptide described herein and for metabolite levels at the following timepoints: Oh (prior to dose), 0.25h, 0.5h, lh, 2h, 3h, 4h, 6h, 9h, 12h, 24h, 36h and 48h post-dose. PK evaluation will also include stool samples for analysis of a peptide described herein and for metabolite levels from each bowel movement. Pharmacodynamic evaluation will include an evaluation of bowel movement characteristics (e.g. stool frequency, Bristol Stool Form Scale, stool color and clarity). Stool weight and volume for each bowel movement will also be evaluated.

Example 4: Colon Cleansing Clinical Protocol in Colonoscopy Group

The safety and tolerability and colon cleansing efficacy of a GCCA peptide may be tested as described herein will be explored in Example 2.

Study Design: Healthy female and male subjects between the ages of 50 and 75 willing to undergo a screening/surveillance colonoscopy will be evaluated. The subjects will be randomly split in up to three groups each consisting of 20 subjects each. The study will be conducted over a two day period with dosing on the evening of day 1 (i.e., the evening before the colonoscopy) and on the morning of day 2 (i.e., the morning of the colonoscopy). The first dosing group will be dosed with a single dose of a peptide described herein taken the evening before the colonoscopy with 8 ounces of water plus additional clear liquid for a total volume of greater than or equal to 2L. The second group will be dosed with a split oral dose of a peptide described herein with one dose the evening before the colonscopy and one dose the morning of the colonoscopy. Both doses will be taken with 8 ounces of water, plus additional clear liquid for a total colume of greater than or equal to 2L. The third group is a comparator group and will be dosed with 4L of PEG-ELS (2L taken the evening before the colonoscopy and 2L taken the morning of the colonoscopy). No group will be allowed fluid intake at least 2 hours prior to the colonoscopy.

Evaluation

Safety and tolerability evaluation will include clinical laboratory evaluations such as a stool electrolyte evaluation; physical examination and vital signs; electrocardiograms; adverse events; validated tolerability questionnaire and compliance and acceptability PRO. Pharmacodynamic evaluation will include evaluation of bowel movement characteristics including stool frequency, Bristol Stool Form Scale, stool color and clarity. An efficacy evaluation will include colon cleansing success during both insertion and withdrawal using a validated cleansing scale (overall and segmental); additional quality indicators (including cecal intubation rate, cecum visualization and photodocumentation of landmarks, duration of procedure, withdrawal time (minus polypectomy time), time and volume of cleaning), polyp and adenoma detection rate, and photo documentation and adjudication.

Other Embodiments

All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling.

Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments of the present invention. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.

The present invention has been described with reference to certain exemplary embodiments thereof. However, it will be readily apparent to those skilled in the art that it is possible to embody the invention in specific forms other than those of the exemplary embodiments described above. This may 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 invention is defined by the appended claims and their equivalents, rather than by the preceding description.

Claims

What is claimed is:

1. A pharmaceutical composition comprising a guanylate cyclase C agonist (GCCA) peptide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient, wherein said composition is suitable for administration to a subject in need of colon cleansing.

2. The pharmaceutical composition according to claim 1, wherein said GCCA agonist peptide comprises or consists of the amino acid sequence

Xaai Xaa₂ aa3 Xaa₄ Cys₅ Xaa6 Xaa₇ Xaa₈ Cys₉ Asn₁₀ Pro_u Ala_i2 Cysi₃ Xaa_w Glyi₅ Xaa_i6 Xaa₁₇ (SEQ ID NO:76)or a pharmaceutically acceptable salt thereof; wherein

Xaa_! is Asn, D-Asn, Gin, D-Gln, Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, y-carboxylated Asp, Glu, D-Glu, y-carboxylated Glu, a-aminosuberic acid (Asu), a-aminoadipic acid (Aad), a-aminopimelic acid (Apm), or is absent;

Xaa₂ is Asp, y-carboxylated Asp, Glu, y-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa₃ is Asp, y-carboxylated Asp, Glu, y-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa« is Cys or D-Cys;

Xaa₆ is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-Tyr;

Xaa₇ is Tyr, Leu, Phe or He;

Xaa₈ is Cys or D-Cys;

aa_lt is Thr, Ala or Phe;

Xaaie is Cys or D-Cys; and

Xaa_i7 is Tyr, D-Tyr, or is absent;

wherein:

if aai is present, Xaai may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid;

if Xaaj is absent and Xaa₂ is present, then Xaa₂ may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; or

if both Xaa_: and Xaa₂ are absent, then Xaa₃ may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.

3. The pharmaceutical composition according to claim 2, wherein said GCCA peptide comprises or consists of the amino acid sequence

Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82); Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:77);

Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:78);

Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:79);

Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:80);

Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:81);

Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:83); or

Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:84) .

4. The pharmaceutical composition according to claim 1, wherein said GCCA peptide comprises or consists of the amino acid sequence

Xaa₁ Xaa₂ Xaa3 Xaa Cys_s Xaa6 Xaa₇ Xaa₈ Cys₉ Asn₁₀ Pron Ala_i2 Cys₁₃ Xaa₁₄ Gly₁₅ Xaa₁₆ Xaa₁₇ (SEQ ID NO:9) wherein

Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, β-carboxylated Asp, Glu, D-Glu, y-carboxylated Glu, a-aminosuberic acid (Asu), a-aminoadipic acid (Aad), or -aminopimelic acid (Apm);

Xaa₂ is Asp, β-carboxylated Asp, Glu, y-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa_s is Asp, β-carboxylated Asp, Glu, y-carboxylated Glu, Asu, Aad, Apm, or is absent;

Xaa is Cys or D-Cys;

Xaa₆ is Asp or Glu;

Xaa₇ is Tyr, Leu, Phe or lie;

Xaa₈ is Cys or D-Cys;

Xaa₁₄ is Thr, Ala or Phe;

Xaa₁₆ is Cys or D-Cys; and

Xaai? is Tyr, D-Tyr, or is absent;

wherein:

Xaai may he modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; and if both Xaa. and Xaa₃ are absent, then aai must be β-carboxylated Asp or y-carboxylated Glu, or Xaai must be Asp, D-Asp, Glu, D-Glu, Asu, Aad, or Apm and must be modified on its amino group by ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.

5. The pharmaceutical composition according to claim 4, wherein said GCCA peptide comprises or consists of the amino acid seq uence Xaa₁ Xaa₂ aa₃ Cys4 Cys₅ Glu₆ Xaa₇ Cys₈ Cys₉ Asn₁₀ Pron Ala₁₂ Cys₁₃ Thr₁₄ Glyu Cys₁₆ Xaa₁₇ (SEQ ID NO: 10) wherein

Xaai is Asn, D-Asn, Gin, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D- Asp, Glu or D-Glu;

Xaa₂ is Asp or Glu;

Xaa₃ is Asp, Glu, or is absent;

Xaa₇ is Tyr or Leu; and

aaiy is Tyr or is absent.

6. The pharmaceutical composition according to claim 4, wherein said GCCA peptide comprises or consists of the amino acid sequence

Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:ll);

Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:12);

Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:13);

Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:14);

Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:15);

Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:16);

Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:17);

Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:18);

Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:19);

Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:20);

β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:21);

β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:22);

Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:23);

Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:24);

β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:25);

β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:26);

Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:27);

Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:28);

Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:29);

Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:30);

Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:31);

Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:32);

Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:33); Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:34); Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:35); Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:36);

Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:37); Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:38); Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:39); Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:40); Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:41); Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:42); Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:43);

Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:44);

Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:45);

Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:46);

Glu Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:47); Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:48);

Glu Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:49); Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:50); Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:51);

Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:52);

Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:53); Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:54);

D-Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:55); D-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:56); D-Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:57); D-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:58); Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys D-Tyr (SEQ ID NO:59); D-Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:60); Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:61); Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:62);

Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:63); Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:64); Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:65); Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:66); Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:67); Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:68); β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:69); Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:70);

Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:71);

Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:72);

Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:73);

Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:74); or Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:75).

7. The pharmaceutical composition according to claim 1, wherein said GCCA peptide comprises or consists of the amino acid sequence

Xaa_! Xaa₂ Xaa₃ Xaa„ Xaa₅ Xaa₆ Cys₇ Xaa₈ Xaa₉ Xaa₁₀ Cys_u Asn₁₂ Pro₁₃ Ala₁₄ Cys_is Xaa₁₆ Gly₁₇ Xaa₁₈ Xaa₁₉ Xaa₂₀Xaa₂₁ (SEQ ID NO:l) wherein

Xaai Xaa₂ Xaa₃ Xaa₄ Xaa₅ is Asn Ser Ser Asn Tyr (SEQ ID NO:2) or is missing or Xaai Xaa₂ Xaa₃ Xaa₄ is missing and Xaa₅ is Asn;

Xaa₆ is Cys or D-Cys;

Xaa₈ is Glu or Asp;

Xaa₉ is Leu, He, Val, Trp, Tyr or Phe;

Xaaio is Cys or D-Cys;

Xaaie is Thr, Ala, Trp;

Xaais is Cys or D-Cys;

Xaa^ is Trp, Tyr, Phe or Leu or is missing; and Xaa₂₀ Xaa_2i is AspPhe or is missing.

8. The pharmaceutical composition according to claim 7, wherein said GCCA peptide comprises or consists of the amino acid sequence

Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:4);

Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:5);

Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:6);

Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7); or

Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:8).

9. The pharmaceutical composition according to any one of claims 1-8, wherein said composition further comprises one or more purgative agents.

10. The pharmaceutical composition according to claim 9, wherein said purgative agent is selected from the group consisting of a surfactant or stool softener, a bulking agent, a lubricant or emollient, a hydrating agent or osmotic, a hyperosmotic agent, a stimulant or contact laxative, a serotonin agonist, a 5-HT₄ receptor agonist and a chloride channel activator.

11. The pharmaceutical composition according to claim 9, wherein said surfactant or stool softener is a ducosate salt.

12. The pharmaceutical composition according to claim 9, wherein said bulking agent is selected from the group consisting of bran, an insoluble fiber, gum karaya, sterculia, psyllium husk, a soluble fiber, methylcellulose and polycarbophil.

13. The pharmaceutical composition according to claim 9, wherein said lubricant or emollient is mineral oil.

14. The pharmaceutical composition according to claim 9, wherein said hydrating agent or osmotic is selected from the group consisting of sodium phosphate, potassium sodium tartrate, magnesium citrate, magnesium hydroxide, and magnesium sulfate.

15. The pharmaceutical composition according to claim 9, wherein said hyperosmotic agent is selected from the group consisting of sorbitol, lactulose, and polyethylene glycol (PEGs).

16. The pharmaceutical composition according to claim 9, wherein said stimulant or contact laxative is selected from the group consisting of sodium picosulfate, anthraquinones, dantron, emodin, aloe emodin, and senna glycosides, phenolphthalein, bisacodyl, castor oil and ricinoleic acid.

17. The pharmaceutical composition according to claim 9, wherein said serotonin agonist or 5- HT₄ receptor agonist is selected from the group consisting of tegaserod, cisapride and rucalopride.

18. The pharmaceutical composition according to claim 9, wherein said chloride channel activator is lubiprostone.

19. The pharmaceutical composition according to any one of claims 1-18, wherein said composition further comprises a PDE5 inhibitor.

20. The pharmaceutical composition according to claim 19, wherein said PDE5 inhibitor is selected from vesnarinone, zaprinast, SKF-96231, E -21355, BF/GP-385, NM-702 and sildenafil (Viagra^®), vinpocetin, papaverine, enprofylline, cilomilast, fenoximone, pentoxifylline, roflumilast, tadalafil(Cialis^e), theophylline, and vardenafil(Levitra^e).

21. A dosage form comprising a pharmaceutical composition according to any one of claims 1-8, wherein said dosage form is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents.

22. The dosage form according to claim 21, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

23. The dosage form according to claim 22, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in a single dose.

24. The dosage form according to claim 22, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in two doses.

25. A dosage form comprising a pharmaceutical composition according to claim 9, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon.

26. The dosage form according to claim 25, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

27. The dosage form according to claim 26, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon in a single dose.

28. The dosage form according to claim 26, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon in two doses.

29. The dosage form according to claim 19, wherein said dosage form is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents.

30. The dosage form according to claim 29, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

31. The dosage form according to claim 30, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in a single dose.

32. The dosage form according to claim 30, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in two doses.

33. A method for cleansing the colon of a patient in need thereof, comprising administering a pharmaceutical composition according to any one of claims 1-8 in an amount effective to cleanse the colon.

34. The method according to claim 33, wherein said amount is provided in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

35. The method according to claim 34, wherein said amount is provided in a single dose.

36. The method according to claim 34, wherein said amount is provided in two doses.

37. The method according to claim 36, wherein the first dose is given the night before a diagnostic or therapeutic procedure requiring a cleansed colon and the second dose is given the morning of the diagnostic or therapeutic procedure.

38. The method according to claim 33, further comprising administering a purgative agent to said patient.

39. The method according to claim 38, wherein said purgative agent is provided in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

40. The method according to claim 39, wherein said effective amount is provided in one dose or two doses.

41. The method according to claim 38, wherein said GCCA peptide or pharmaceutically acceptable salt thereof is administered at the same time as the purgative agent.

42. The method according to claim 41, wherein said GCCA peptide and said purgative agent are administered as separate dosage forms.

43. The method according to claim 41, wherein said GCCA peptide and said purgative agent are administered in a single dosage form.

44. The method according to claim 38, wherein said GCCA peptide or pharmaceutically acceptable salt thereof is administered before administration of the purgative agent.

45. The method according to claim 38, wherein said GCCA peptide or pharmaceutically acceptable salt thereof is administered after administration of the purgative agent.

46. A kit comprising a dosage form according to claim 21.

47. The kit according to claim 46, wherein the kit provides sufficient dosage forms comprising the GCCA peptide or pharmaceutically acceptable salt thereof to effectuate the colon cleansing.

48. The kit according to claim 46, wherein the kit further provides dosage forms of one or more purgative agents.

49. The kit according to claim 48, wherein the kit provides sufficient dosage forms comprising the GCCA peptide or pharmaceutically acceptable salt thereof and sufficient dosage forms comprising the purgative agents to effectuate the colon cleansing.

50. The kit according to any one of claims 46-49, further comprising instructions for use.

51. The kit according to any one of claims 46-50, further comprising containers for mixing and administering dosage forms.

52. The pharmaceutical composition according to any one of claims 1-9, further comprising an electrolyte component.

53. The dosage form according to claim 21, further comprising an electrolyte component.

54. The method according to either of claims 33 or 38, further comprising an electrolyte component.

55. The kit according to either of claims 46 or 48, further comprising an electrolyte component.

56. The pharmaceutical composition according to claim 3, wherein the GCCA peptide or pharmaceutically acceptable salt thereof consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:82), wherein the GCCA peptide includes disulfide bonds between Cyst and Cys₆, between Cys₂ and Cys₁₀ and between Cys₅ and Cys₁₃.

57. The pharmaceutical composition according to claim 56, wherein said composition further comprises one or more purgative agents.

58. The pharmaceutical composition according to claim 57, wherein said purgative agent is selected from the group consisting of a surfactant or stool softener, a bulking agent, a lubricant or emollient, a hydrating agent or osmotic, a hyperosmotic agent, a stimulant or contact laxative, a serotonin agonist, a 5-HT₄ receptor agonist and a chloride channel activator.

59. The pharmaceutical composition according to claim 58, wherein said purgative agent is selected from the group consisting of a ducosate salt, bran, an insoluble fiber, gum karaya, sterculia, psyllium husk, a soluble fiber, methylcellulose, polycarbophil, mineral oil, sodium phosphate, potassium sodium tartrate, magnesium citrate, magnesium hydroxide, magnesium sulfate, sodium ascorbate, ascorbic acid, sorbitol, lactulose, polyethylene glycol (PEG), sodium picosulfate, anthraquinones, dantron, emodin, aloe emodin, senna, phenolphthalein, bisacodyl, castor oil, ricinoleic acid, tegaserod, cisapride, rucalopride and lubiprostone.

60. The pharmaceutical composition according to claim 59, wherein said purgative agent is selected from the group consisting of bisacodyl, senna, magnesium citrate, sodium ascorbate and ascorbic acid.

61. The pharmaceutical composition according to either of claims 59 or 60, wherein said composition further comprises a PDE5 inhibitor.

62. The pharmaceutical composition according to claim 61, wherein said PDE5 inhibitor is selected from vesnarinone, zaprinast, SKF-96231, E -21355, BF/GP-385, NM-702 and sildenafil (Viagra^®), vinpocetin, papaverine, enprofylline, cilomilast, fenoximone, pentoxifylline, roflumilast, tadalafil(Cialis^®), theophylline, and vardenafil(Levitra^®).

63. A dosage form comprising a pharmaceutical composition according to claim 56, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents.

64. The dosage form according to claim 63, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

65. The dosage form according to claim 64, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in a single dose.

66. The dosage form according to claim 64, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in two doses.

67. The dosage form according to claim 64, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon, either alone or in conjunction with one or more purgative agents, in three doses.

68. A dosage form comprising a pharmaceutical composition according to any one of claims 57- 62, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon.

69. The dosage form according to claim 68, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

70. The dosage form according to claim 69, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon in a single dose.

71. The dosage form according to claim 69, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon in two doses.

72. The dosage form according to claim 69, wherein said pharmaceutical composition is provided in an amount effective to cleanse the colon in three doses.

73. A method for cleansing the colon of a patient in need thereof, comprising administering the pharmaceutical composition according to claim 56 in an amount effective to cleanse the colon.

74. The method according to claim 73, wherein said amount is provided in a single dose, two doses, three doses, four doses, five doses, six doses, seven doses or eight doses.

75. The method according to claim 74, wherein said amount is provided in a single dose.

76. The method according to claim 75, wherein the single dose is given the night before a diagnostic or therapeutic procedure requiring a cleansed colon.

77. The method according to claim 74, wherein said amount is provided in two doses.

78. The method according to claim 77, wherein the first dose is given the night before a diagnostic or therapeutic procedure requiring a cleansed colon and the second dose is given the morning of the diagnostic or therapeutic procedure.

79. The method according to claim 74, wherein said amount is provided in three doses.

80. The method according to claim 79, wherein the first two doses are given the night before a diagnostic or therapeutic procedure requiring a cleansed colon and the third dose is given the morning of the diagnostic or therapeutic procedure.

81. The method according to any one of claims 73-81, further comprising administering a purgative agent to said patient.

82. The method according to claim 81, wherein said purgative agent is selected from the group consisting of a surfactant or stool softener, a bulking agent, a lubricant or emollient, a hydrating agent or osmotic, a hyperosmotic agent, a stimulant or contact laxative, a serotonin agonist, a 5-HT₄ receptor agonist and a chloride channel activator.

83. The method according to claim 82, wherein said purgative agent is selected from the group consisting of a ducosate salt, bran, an insoluble fiber, gum karaya, sterculia, psyllium husk, a soluble fiber, methylcellulose, polycarbophil, mineral oil, sodium phosphate, potassium sodium tartrate, magnesium citrate, magnesium hydroxide, magnesium sulfate, sodium ascorbate, ascorbic acid, sorbitol, lactulose, polyethylene glycol (PEG), sodium picosulfate, anthraquinones, dantron, emodin, aloe emodin, senna, phenolphthalein, bisacodyl, castor oil, ricinoleic acid, tegaserod, cisapride, rucalopride and lubiprostone.

84. The method according to claim 82, wherein said purgative agent is selected from the group consisting of bisacodyl, senna, magnesium citrate, sodium ascorbate and ascorbic acid.

85. The method according to any one of claims 81-84, wherein said pharmaceutical composition is administered at the same time as the purgative agent.

86. The method according to claim 85, wherein said pharmaceutical composition and said purgative agent are administered as separate dosage forms.

87. The method according to claim 85, wherein said pharmaceutical composition and said purgative agent are administered in a single dosage form.

88. The method according to any one of claims 81-84, wherein said pharmaceutical composition is administered before administration of the purgative agent.

89. The method according to any one of claims 81-84, wherein said pharmaceutical composition is administered after administration of the purgative agent.

90. A kit comprising a dosage form according to any one of claims 63-67.

91. The kit according to claim 90, wherein the kit provides sufficient dosage forms comprising the pharmaceutical composition to effectuate the colon cleansing.

92. The kit according to claim 90, wherein the kit further provides dosage forms of one or more purgative agents.

93. The kit according to claim 92, wherein the kit provides sufficient dosage forms comprising the GCCA peptide or pharmaceutically acceptable salt thereof and sufficient dosage forms comprising the purgative agents to effectuate the colon cleansing.

94. The kit according to claim 92, wherein said purgative agent is selected from the group consisting of a surfactant or stool softener, a bulking agent, a lubricant or emollient, a hydrating agent or osmotic, a hyperosmotic agent, a stimulant or contact laxative, a serotonin agonist, a 5-HT, receptor agonist and a chloride channel activator.

95. The kit according to claim 94, wherein said purgative agent is selected from the group consisting of a ducosate salt, bran, an insoluble fiber, gum karaya, sterculia, psyllium husk, a soluble fiber, methylcellulose, polycarbophil, mineral oil, sodium phosphate, potassium sodium tartrate, magnesium citrate, magnesium hydroxide, magnesium sulfate, sodium ascorbate, ascorbic acid, sorbitol, lactulose, polyethylene glycol (PEG), sodium picosulfate, anthraquinones, dantron, emodin, aloe emodin, senna, phenolphthalein, bisacodyl, castor oil, ricinoleic acid, tegaserod, cisapride, rucalopride and lubiprostone.

96. The kit according to claim 95, wherein said purgative agent is selected from the group consisting of bisacodyl, senna, magnesium citrate, sodium ascorbate and ascorbic acid.

97. The kit according to any one of claims 90-96, further comprising instructions for use.

98. The kit according to any one of claims 90-97, further comprising containers for mixing and administering dosage forms.

99. The kit according to any one of claims 90-98, further comprising an electrolyte component.

100. The kit according to claim 99, wherein said electrolyte component is selected from a ready to drink electrolyte solution or a dry, powdered, or concentrated dosage form of electrolytes that can be reconstituted to form an electrolyte solution.

101. The kit according to either of claim 99 or claim 100, wherein said electrolyte component is selected from the group consisting of sodium sulfate, sodium bicarbonate, sodium chloride, sodium phosphate, potassium bicarbonate, potassium chloride, potassium phosphate, potassium sulfate, magnesium sulfate, magnesium bicarbonate, magnesium chloride, magnesium phosphate, calcium bicarbonate, calcium chloride, calcium phosphate, calcium sulfate, ascorbic acid, sodium ascorbate, and mixtures thereof.

102. The dosage form according to any one of claims 63-72, further comprising an electrolyte component.

103. The dosage form according to claim 102, wherein said electrolyte component is selected from the group consisting of sodium sulfate, sodium bicarbonate, sodium chloride, sodium phosphate, potassium bicarbonate, potassium chloride, potassium phosphate, potassium sulfate, magnesium sulfate, magnesium bicarbonate, magnesium chloride, magnesium phosphate, calcium bicarbonate, calcium chloride, calcium phosphate, calcium sulfate, ascorbic acid, sodium ascorbate, and mixtures thereof.

104. The method according to any one of claims 73-89, further comprising administering an electrolyte component.

105. The method according to claim 104, wherein said electrolyte component is selected from a ready to drink electrolyte solution or a dry, powdered, or concentrated dosage form of electrolytes that can be reconstituted to form an electrolyte solution.

106. The method according to either of claim 104 or claim 105, wherein said electrolyte component is selected from the group consisting of sodium sulfate, sodium bicarbonate, sodium chloride, sodium phosphate, potassium bicarbonate, potassium chloride, potassium phosphate, potassium sulfate, magnesi um sulfate, magnesium bicarbonate, magnesium chloride, magnesium phosphate, calcium bicarbonate, calcium chloride, calcium phosphate, calcium sulfate, ascorbic acid, sodium ascorbate, and mixtures thereof.

107. The method according to any one of claims 33-45, comprising administering the pharmaceutical composition with sufficient fluid to effectuate colon cleansing.

108. The method according to claim 107, wherein the fluid is water, a ready to drink electrolyte solution, or a dry, powdered, or concentrated dosage form of electrolytes that is reconstituted to form an electrolyte solution.

109. The method according to claim 108, wherein the fluid is clear.

110. The method according to either of claim 108 or claim 109, wherein the fluid is uncolored.

111. The method according to any one of claims 73-89, comprising administering the dosage form with sufficient fluid to effectuate colon cleansing.

112. The method according to claim 111, wherein the fluid is water, a ready to drink electrolyte solution, or a dry, powdered, or concentrated dosage form of electrolytes that is reconstituted to form an electrolyte solution.

113. The method according to claim 112, wherein the fluid is clear.

114. The method according to either of claim 112 or claim 113, wherein the fluid is uncolored.

115. The dosage form according to any one of claims 63-67, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 10 μ to 50 mg.

116. The dosage form according to claim 115, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 100 μg to 30 mg.

117. The dosage form according to claim 116, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 250 μ to 25 mg per day.

118. The dosage form according to claim 115, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is 250 μg, 500 g, 750 μ , 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 9 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg or 25 mg.

119. The dosage form according to any one of claims 68-72, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 10 μ¾ to 50 mg.

120. The dosage form according to claim 119, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 100 μg to 30 mg.

121. The dosage form according to claim 120, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 250 μg to 25 mg per day.

122. The dosage form according to claim 121, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is 250 μ , 500 μg, 750 μ , 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 9 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg or 25 mg.

123. The method according to any one of claims 73-80, wherein the amount of GCCA peptide or pharmaceutically acceptable salt thereof effective to cleanse the colon is from 10 μg to 50 mg.

124. The method according to claim 123, wherein the amount of GCCA peptide or

pharmaceutically acceptable salt thereof effective to cleanse the colon is from 100 μg to 30 mg.

125. The method according to claim 124, wherein the amount of GCCA peptide or

pharmaceutically acceptable salt thereof effective to cleanse the colon is from 250 μg to 25 mg per day.

126. The method according to claim 125, wherein the amount of GCCA peptide or

pharmaceutically acceptable salt thereof effective to cleanse the colon is 250 μg, 500 μg, 750 μg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 9 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg or 25 mg.

127. The method according to claim 81, wherein the amount of GCCA peptide or

pharmaceutically acceptable salt thereof effective to cleanse the colon is from 10 μg to 50 mg.

128. The method according to claim 127, wherein the amount of GCCA peptide or

pharmaceutically acceptable salt thereof effective to cleanse the colon is from 100 μg to 30 mg.

129. The method according to claim 128, wherein the amount of GCCA peptide or

pharmaceutically acceptable salt thereof effective to cleanse the colon is from 250 μg to 25 mg per day.

130. The method according to claim 129, wherein the amount of GCCA peptide or

pharmaceutically acceptable salt thereof effective to cleanse the colon is 250 pg, 500 μg, 750 μ , 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 9 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg or 25 mg.

131. The method according to any one of claims 123-130, further comprising administering at least 1 liter of clear liquid subsequent to administration of at least one dose of the pharmaceutical composition.

132. The method according to claim 131, comprising administering at least 2 liters of clear liquid subsequent to administration of at least one dose of the pharmaceutical composition.

133. The method according to any one of claims 123-130, further comprising administering at least 1 liter of clear liquid subsequent to administration of each dose of the pharmaceutical composition.

134. The method according to claim 133, comprising administering at least 2 liters of clear liquid subsequent to administration of each dose of the pharmaceutical composition.

135. The method according to any one of claims 123-130, further comprising administering at least 1 liter of clear fluid subsequent to administration of at least two doses of the pharmaceutical composition.

136. The method according to claim 135, comprising administering at least 2 liters of clear liquid subsequent to administration of at least two doses of the pharmaceutical composition.