Treatments for Gastrointestinal Disorders

• US 20150094272A1
• Filed: 08/17/2012
• Published: 04/02/2015
• Est. Priority Date: 08/17/2011
• Status: Active Grant

• Current Assignee: Ironwood Pharmaceuticals, Inc.
• Original Assignee: Ironwood Pharmaceuticals, Inc.
• Inventors: Kessler, Marco, Fretzen, Angelika, Zhao, Hong, Solinga, Robert, Volchenok, Vladimir
• Granted Patent: US 9,708,371 B2
• Time in Patent Office: Days
• US Class Current: 514/21.1
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C 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: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/02 containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C07K 7/54 with at least one abnormal peptide link in the ring
• CPC Class Codes: C11D 3/3436 containing disulfide groups
• CPC Class Codes: G01N 2800/065 Bowel diseases, e.g. Crohn, ulcerative colitis, IBS
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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

1-81. -81. (canceled)

82. A peptide or a 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 the α

-amine of the Cys¹ amino acid of the peptide is deaminated.

83. The peptide or a pharmaceutically acceptable salt thereof according to claim 82, wherein the peptide comprises the amino acid structure of:

84. The peptide or pharmaceutically acceptable salt thereof according to claim 82, wherein the peptide comprises the amino acid structure of:

85. The peptide or a pharmaceutically acceptable salt thereof according to claim 82, wherein the peptide consists of the amino acid sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr, wherein the α

-amine of the Cys¹ amino acid of the peptide is deaminated.

86. The peptide or a pharmaceutically acceptable salt thereof according to claim 85, wherein the peptide consists of the amino acid structure of:

87. The peptide or pharmaceutically acceptable salt thereof according to claim 85, wherein the peptide consists of the amino acid structure of:

88. The peptide or pharmaceutically acceptable salt thereof according to claim 82, wherein the peptide activates the guanylate cyclase C receptor.

89. The peptide or pharmaceutically acceptable salt thereof according to claim 82, wherein the peptide comprises 30, 20 or fewer amino acids.

90. The peptide or pharmaceutically acceptable salt thereof according to claim 82, wherein said peptide or pharmaceutically acceptable salt thereof is isolated or purified.

91. A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof according to claim 82.

92. The pharmaceutical composition of claim 91 comprising one or more peptides selected from:

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

93. The pharmaceutical composition of claim 91 comprising linaclotide and a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure of:

94. The pharmaceutical composition of claim 91 comprising a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid structure of:

95. The pharmaceutical composition of claim 91 consisting essentially of a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:

96. The pharmaceutical composition of claim 91 comprising linaclotide and a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure of:

97. The pharmaceutical composition of claim 91 comprising a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid structure of:

98. The pharmaceutical composition of claim 91 consisting essentially of a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:

99. The pharmaceutical composition of claim 91 comprising linaclotide, a Cys′

-a-Ketone peptide, and one or more peptides selected from;

i. a peptide (“

Cys¹-IMD”

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

100. The pharmaceutical composition according to claim 91 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.

101. The pharmaceutical composition according to claim 100, wherein said 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.

102. The pharmaceutical composition according to claim 100, wherein said agent is a sterically hindered primary amine.

103. The pharmaceutical composition according to claim 102, wherein the sterically hindered primary amine is an amino acid, naturally-occurring amino acid, a non-naturally occurring amino acid or an amino acid derivative.

104. The pharmaceutical composition according to claim 103, 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 the non-naturally occurring amino acid is 1-aminocyclohexane carboxylic acid, lanthanine or theanine.

105. The pharmaceutical composition according to claim 102, wherein the sterically hindered primary amine has the formula:

wherein R₁, R₂ and R₃ are independently

106. The pharmaceutical composition according to claim 102, wherein the sterically hindered primary amine is polymeric amine, chitosan, cyclohexylamine or 2-methylbutylamine.

107. The pharmaceutical composition according to claim 102, wherein said pharmaceutical composition further comprises Mg²⁺, Ca²⁺, Zn²⁺, Mn²⁺, K⁺, Na⁺ or Al³⁺.

108. The pharmaceutical composition according to claim 100 further comprising an antioxidant, a pharmaceutically acceptable binder or additive, a pharmaceutically acceptable filler, or an additional therapeutic agent.

109. The pharmaceutical composition according to claim 108, wherein said antioxidant is BHA, vitamin E or propyl gallate.

110. The pharmaceutical composition according to claim 108, wherein the pharmaceutically acceptable binder or additive is selected from polyvinyl alcohol, polyvinyl pyrrolidone (povidone), a starch, maltodextrin or a cellulose ether.

111. The pharmaceutical composition of claim 110, wherein the cellulose ether is selected from:

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

112. The pharmaceutical composition according to claim 108, wherein the pharmaceutically acceptable filler is cellulose, isomalt, mannitol or dibasic calcium phosphate.

113. The pharmaceutical composition of claim 112, wherein the cellulose is selected from microfine cellulose and microcrystalline cellulose.

114. The pharmaceutical composition according to claim 108, 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.

115. A dosage unit comprising a pharmaceutical composition according to claim 91.

116. The dosage unit according to claim 115, wherein said dosage unit is a capsule or tablet.

117. The dosage unit according to claim 115, wherein each of said dosage units comprises 5 μ

g to 1 mg of linaclotide.

118. The dosage unit according to claim 115, wherein each of said dosage units comprises 290 μ

g or 145 μ

g of linaclotide.

119. A method for treating a gastrointestinal disorder comprising administering the pharmaceutical composition according to claim 91.

120. The method of claim 119, wherein the gastrointestinal disorder is selected from the group consisting of:

irritable bowel syndrome (IBS), constipation, a functional gastrointestinal disorder, gastroesophageal reflux disease, functional heartburn, dyspepsia, visceral pain, gastroparesis, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, Crohn'"'"'s disease, ulcerative colitis, and inflammatory bowel disease.

121. The method of claim 120, wherein the constipation is chronic constipation, idiopathic constipation, due to post-operative ileus, or caused by opiate use.

122. The method of claim 120, 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).

123. The method according to claim 120, wherein said gastroparesis is idiopathic, diabetic or post-surgical gastroparesis.

124. A method for increasing intestinal motility in a patient, the method comprising administering to the patient an effective amount of the pharmaceutical composition according to claim 91.