Treatments for gastrointestinal disorders
Inventors
Fretzen, Angelika • Zhao, Hong • Kessler, Marco
Assignees
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Publication Number
US-8933030-B2
Publication Date
2015-01-13
Expiration Date
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.
Core Innovation
The invention relates to a modified guanylate cyclase C-activating peptide or a pharmaceutically acceptable salt thereof for gastrointestinal disorders. GC-C activation increases intracellular cGMP, which drives chloride and bicarbonate secretion, luminal pH changes, fluid secretion, and accelerated intestinal transit.
The disclosed peptides include a defined amino acid structure, including Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr or the Cys1-IMD peptide comprising SEQ ID NO:1, Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr. The described peptides include carboxyl group modifications as alkyl esters and amine group modifications as imine or imidazolidinone derivatives, including formaldehyde-mediated cyclization at the N-terminus, together with disulfide bond patterns for the Cys1-IMD peptide.
The pharmaceutical compositions combine the peptide or the pharmaceutically acceptable salt with linaclotide, with the peptide and/or its salt present at specified weight-percent levels relative to linaclotide. The compositions include pharmaceutically acceptable carriers and optional formulation components such as selected cations, a sterically hindered primary amine, binders, fillers, disintegrants, lubricants, antioxidant components, anti-microbial preservatives, and coating additives.
Claims Coverage
The provided claim content includes one independent claim directed to a peptide or a pharmaceutically acceptable salt comprising a defined amino acid structure, with dependent claims refining the sequence, specifying guanylate cyclase C receptor activation, and defining pharmaceutical compositions containing linaclotide with weight-percent constraints and selected formulation components. The consolidated inventive features are those explicitly reflected across the inputs.
Modified guanylate cyclase C-activating peptide
A peptide or a pharmaceutically acceptable salt thereof comprising a defined amino acid structure, including the Cys1-IMD peptide framework.
Defined peptide amino acid structure
The peptide comprises the amino acid structure Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr or the Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr sequence.
Guanylate cyclase C receptor activation
The peptide activates the guanylate cyclase C receptor.
Peptide present below a weight-percent threshold relative to linaclotide
A pharmaceutical composition wherein the peptide or a pharmaceutically acceptable salt of the peptide is present at less than 5% by weight relative to the total weight of linaclotide.
Selected agents for pharmaceutical compositions
A pharmaceutical composition further includes one or more selected cations and/or a sterically hindered primary amine.
Specified binder, antioxidant, and filler components
A pharmaceutical composition including a pharmaceutically acceptable binder or additive, antioxidant, and/or filler selected from specified cellulose ethers, specified antioxidants, and specified filler materials.
Overall, the claims focus on a defined modified guanylate cyclase C-activating peptide, including the specified amino acid structures, together with pharmaceutical-composition constraints involving linaclotide and selectable excipient, cation, amine, antioxidant, and filler components.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating gastrointestinal disorders by administering GC-C receptor-targeting peptide therapeutics, including IBS, constipation, GERD, Crohn’s disease, ulcerative colitis, and visceral pain, gastroparesis, and pseudo-obstruction.
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