Treatments for Gastrointestinal Disorders

• US 20130190238A1
• Filed: 02/17/2011
• Published: 07/25/2013
• Est. Priority Date: 02/17/2010
• Status: Active Grant

• Current Assignee: Angelika Fretzen, Hong Zhao, Marco Kessler
• Original Assignee: Ironwood Pharmaceuticals, Inc.
• Inventors: Fretzen, Angelika, Zhao, Hong, Kessler, Marco
• Granted Patent: US 8,933,030 B2
• Time in Patent Office: Days
• 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

1-100. -100. (canceled)

101. A peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr, wherein

at least one carboxyl group of the peptide is an alkyl ester having the formula (—

COOR) in which R is a C_1-6 alkyl.

102. The peptide of claim 101, wherein the peptide comprises the amino acid structure of:

103. The peptide of claim 102, wherein at least one R′

is methyl, ethyl, or propyl.

104. The peptide of claim 102, wherein the peptide comprises the amino acid structure of:

105. The peptide of claim 104, wherein the peptide comprises the amino acid structure selected from:

106. The peptide of claim 102, wherein the peptide comprises the amino acid structure of:

107. The peptide of claim 106, wherein the peptide comprises the amino acid structure selected from:

108. The peptide of claim 101, wherein the peptide consists of the amino acid sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr, wherein

at least one carboxyl group of the peptide is an alkyl ester having the formula (—

COOR) in which R is a C_1-6 alkyl.

109. The peptide of claim 108, wherein the peptide consists of the amino acid structure of:

110. The peptide of claim 109, wherein at least one R′

is methyl, ethyl or propyl.

111. The peptide of claim 109, wherein the peptide consists of the amino acid structure of:

112. The peptide of claim 111, wherein the peptide consists of the amino acid structure selected from:

113. The peptide of claim 109, wherein the peptide consists of the amino acid structure of:

114. The peptide of claim 113, wherein the peptide consists of the amino acid structure selected from:

117. The peptide of claim 101, wherein the peptide activates the guanylate cyclase C receptor.

118. The peptide of claim 101, wherein the peptide comprises 30, 20, or fewer amino acids, wherein fewer than five amino acids precede the first Cys residue of the amino acid sequence.

119. The peptide of claim 101, wherein said peptide or pharmaceutically acceptable salt thereof is isolated or purified.

120. A pharmaceutical composition comprising at least a peptide or pharmaceutically acceptable salt thereof according to claim 101 or 115.

121. The pharmaceutical composition of claim 120 comprising two or more peptides selected from:

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

122. The pharmaceutical composition of claim 120 comprising linaclotide and a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure selected from:

123. The pharmaceutical composition of claim 120 comprising a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid structure of:

124. The pharmaceutical composition of claim 120 consisting essentially of a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:

125. The pharmaceutical composition of claim 120, 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.

126. The pharmaceutical composition of claim 125, 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.

127. The pharmaceutical composition of claim 125, 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.

128. The pharmaceutical composition of claim 125, wherein the sterically hindered primary amine has the formula:

129. The pharmaceutical composition of claim 128, wherein said pharmaceutical composition further comprises Mg²⁺, Ca²⁺, Zn²⁺, Mn²⁺, K⁺, Na⁺ or Al³⁺.

130. The pharmaceutical composition of claim 125, 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.

131. The pharmaceutical composition of claim 125, further comprising an additional therapeutic agent, wherein said additional therapeutic agent is selected from one or more of an analgesic agent, an antidepressant, a promotility or prokinetic agent, an antiemetic, an antibiotic, a proton pump inhibitor, an acid blocker, a PDE5 inhibitor, an acid pump antagonist, a GABA-B agonist, a bile acid sequestrant or a mucosal protecting agent.

132. A method for treating a gastrointestinal disorder comprising administering the pharmaceutical composition according to claim 120.

133. The method of claim 132, wherein the gastrointestinal disorder is selected from the group consisting of:

irritable bowel syndrome (IBS), wherein the irritable bowel syndrome is constipation-predominant irritable bowel syndrome (c-IBS), diarrhea-predominant irritable bowel syndrome (d-IBS) or alternating between the two irritable bowel syndromes (a-IBS);

constipation, wherein the constipation is chronic constipation, idiopathic constipation, due to post-operative ileus, or caused by opiate use;

a functional gastrointestinal disorder, gastroesophageal reflux disease;

functional heartburn;

dyspepsia;

visceral pain;

gastroparesis, wherein said gastroparesis is idiopathic, diabetic or post-surgical gastroparesis;

chronic intestinal pseudo-obstruction;

colonic pseudo-obstruction;

Crohn'"'"'s disease;

ulcerative colitis; and

inflammatory bowel disease.

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

116. The peptide of claim 115, wherein the peptide consists of the amino acid structure of: