Treatments for gastrointestinal disorders

• US 8,933,030 B2
• Filed: 02/17/2011
• Issued: 01/13/2015
• Est. Priority Date: 02/17/2010
• Status: Active Grant

• Current Assignee: Ironwood Pharmaceuticals, Inc.
• Original Assignee: Ironwood Pharmaceuticals, Inc.
• Inventors: Fretzen, Angelika, Zhao, Hong, Kessler, Marco
• Primary Examiner(s): Alstrum Acevedo, James H
• Assistant Examiner(s): Miknis, Zachary J
• Application Number:
  US13/579,685
• Publication Number:
  US 20130190238A1
• Time in Patent Office: 1,426 Days
• Field of Search: None
• US Class Current: 514/13.2
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The present invention features peptides, compositions, and related methods for treating gastrointestinal disorders and conditions, including but not limited to, irritable bowel syndrome (IBS), gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux, Crohn'"'"'s disease, ulcerative colitis, inflammatory bowel disease, functional heartburn, dyspepsia, visceral pain, gastroparesis, chronic intestinal pseudo-obstruction (or colonic pseudo-obstruction), disorders and conditions associated with constipation, and other conditions and disorders are described herein, using peptides and other agents that activate the guanylate cyclase C (GC-C) receptor.

Claims

1. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of

2. The peptide of claim 1, wherein the peptide consists of the amino acid structure of:

3. The peptide of claim 1, wherein the peptide activates the guanylate cyclase C receptor.

4. A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof according to claim 1.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition further comprises linaclotide.

6. The pharmaceutical composition of claim 4, wherein the pharmaceutical compositions further comprises a peptide comprising an amino acid structure selected from:

7. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises less than 5% by weight of the peptide or pharmaceutically acceptable salt thereof relative to the total weight of linaclotide.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises less than 4% by weight of the peptide or pharmaceutically acceptable salt thereof relative to the total weight of linaclotide.

9. The pharmaceutical composition of claim 7, further comprising one or more agents selected from (i) a cation selected from Mg²⁺, Ca²⁺, Zn²⁺, Mn²⁺, K⁺, Na or Al³⁺, or (ii) a sterically hindered primary amine.

10. The pharmaceutical composition of claim 9, wherein said agent is Mg²⁺, Ca²⁺, Zn²⁺, Mn²⁺, K⁺, Na⁺ or Al³⁺ is provided 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.

11. The pharmaceutical composition of claim 9, wherein said agent is a sterically hindered primary amine which is an amino acid selected from:

a naturally-occurring amino acid, wherein the naturally-occurring amino acid is histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan or valine;

or

a non-naturally occurring amino acid or an amino acid derivative, wherein the non-naturally occurring amino acid is 1-aminocyclohexane carboxylic acid, lanthanine or theanine.

12. The pharmaceutical composition of claim 9, wherein the sterically hindered primary amine has the formula:

13. The pharmaceutical composition of claim 12, wherein said pharmaceutical composition further comprises Mg²⁺, Ca²⁺, Zn²⁺, Mn²⁺, K⁺, Na⁺ or Al³⁺.

14. The pharmaceutical composition of claim 9, further comprising one or more of

a pharmaceutically acceptable binder or additive, wherein the pharmaceutically acceptable binder or additive is selected from polyvinyl alcohol, polyvinylpyrrolidone (povidone), a starch, maltodextrin or a cellulose ether, wherein the cellulose ether is selected from:

methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose;

an antioxidant, wherein said antioxidant is BHA, vitamin E or propyl gallate;

or

a pharmaceutically acceptable filler, wherein the pharmaceutically acceptable filler is cellulose, microfine cellulose, microcrystalline cellulose, isomalt, mannitol or dibasic calcium phosphate.

15. A method for treating a gastrointestinal disorder comprising administering the pharmaceutical composition according to claim 7, wherein the gastrointestinal disorder is selected from the group consisting of:

irritable bowel syndrome (IBS);

constipation-predominant irritable bowel syndrome (c-IBS);

constipation;

chronic constipation;

idiopathic constipation;

constipation due to post-operative ileus;

constipation caused by opiate use; and

visceral pain.

16. The pharmaceutical composition of claim 9 comprising:

i Ca²⁺;

ii leucine;

iii linaclotide; and

iv one or more peptides or pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure selected from;

17. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable binder is hydroxypropyl methylcellulose and the pharmaceutically acceptable filler is microcrystalline cellulose.

18. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition further comprises a peptide comprising an amino acid structure selected from:

19. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition further comprises a peptide comprising an amino acid structure selected from:

20. The pharmaceutical composition of claim 16, wherein Ca²⁺ is provided as calcium acetate, calcium chloride, calcium phosphate, or calcium sulfate.