US2023272007A1PendingUtilityA1
Treatments for gastrointestinal disorders
Assignee: IRONWOOD PHARMACEUTICALS INCPriority: Aug 17, 2011Filed: May 5, 2023Published: Aug 31, 2023
Est. expiryAug 17, 2031(~5.1 yrs left)· nominal 20-yr term from priority
C07K 7/08C11D 3/3436C07K 7/54C07K 5/02A61K 38/10A61K 38/12A61K 45/06G01N 2800/065Y02A50/30A61P 1/04A61P 1/06A61P 1/10A61P 1/12A61P 1/14A61P 29/00A61P 43/00
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Claims
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
exact text as granted — not AI-modifiedWhat is claimed is:
1 . 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 Cys 1 amino acid of the peptide is deaminated.
2 . The peptide or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the peptide comprises the amino acid structure of:
3 . The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein the peptide comprises the amino acid structure of:
4 . A peptide or a pharmaceutically acceptable salt thereof, 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 Cys 1 amino acid of the peptide is deaminated.
5 . The peptide or a pharmaceutically acceptable salt thereof according to claim 4 , wherein the peptide consists of the amino acid structure of:
6 . The peptide or pharmaceutically acceptable salt thereof according to claim 4 , wherein the peptide consists of the amino acid structure of:
7 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 6 , wherein the peptide activates the guanylate cyclase C receptor.
8 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 3 , wherein the peptide comprises 30 or fewer amino acids.
9 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 3 , wherein the peptide comprises 20 or fewer amino acids.
10 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 3 , wherein fewer than five amino acids precede the first Cys residue of the amino acid sequence.
11 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 10 , wherein said peptide or pharmaceutically acceptable salt thereof is isolated.
12 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 11 , wherein said peptide or pharmaceutically acceptable salt thereof is purified.
13 . A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 12 .
14 . A pharmaceutical composition comprising two or more peptides or pharmaceutically acceptable salts thereof according to any one of claims 1 - 12 .
15 . A pharmaceutical composition 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:
ii. a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure of:
and
iii. a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:
16 . A pharmaceutical composition comprising linaclotide and a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure of:
and the peptide or pharmaceutically acceptable salt thereof comprises less than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% by weight compared to the weight of linaclotide.
17 . A pharmaceutical composition comprising linaclotide and a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure of:
and the peptide or pharmaceutically acceptable salt thereof comprises less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% by weight compared to the weight of linaclotide.
18 . A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid structure of:
and the peptide comprises at least 90% by weight compared to the weight of linaclotide or another guanylate cyclase C agonist.
19 . A pharmaceutical composition consisting essentially of a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:
and the peptide comprises at least 90% by weight compared to the weight of linaclotide or another guanylate cyclase C agonist.
20 . A pharmaceutical composition comprising linaclotide and a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure of:
and the peptide or pharmaceutically acceptable salt thereof comprises less than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% by weight compared to the weight of linaclotide.
21 . A pharmaceutical composition comprising linaclotide and a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid structure of:
and the peptide or pharmaceutically acceptable salt thereof comprises less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% by weight compared to the weight of linaclotide.
22 . A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid structure of:
and the peptide comprises at least 90% by weight compared to the weight of linaclotide or another guanylate cyclase C agonist.
23 . A pharmaceutical composition consisting essentially of a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:
and the peptide comprises at least 90% by weight compared to the weight of linaclotide or another guanylate cyclase C agonist.
24 . A pharmaceutical composition comprising linaclotide, a Cys 1 -α-Ketone peptide, and one or more peptides selected from:
i. a peptide (“Cys 1 -IMD”) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:
ii. a hydrolysis peptide (“Asp 7 ”) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:
iii. an acetylation peptide (“Cys 1 -N-Acetyl”) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:
iv. a linaclotide trisulfide peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence of Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr wherein an additional sulfur atom may be attached to any one of the six cysteinyl sulfurs; and
v. a peptide (“Des-Tyr 14 ”) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid structure of:
25 . The pharmaceutical composition according to claim 24 , wherein the peptide is a Cys 1 -IMD peptide.
26 . The pharmaceutical composition according to claim 24 , wherein the peptide is a hydrolysis Asp 7 peptide.
27 . The pharmaceutical composition according to claim 24 , wherein the peptide is an acetylation Cys 1 -N-Acetyl peptide.
28 . The pharmaceutical composition according to claim 24 , wherein the peptide is a linaclotide trisulfide peptide.
29 . The pharmaceutical composition according to claim 24 , wherein the peptide is a Des-Tyr 14 peptide.
30 . The pharmaceutical composition according to any one of claims 13 - 29 , further comprising one or more agents selected from (i) a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ , or (ii) a sterically hindered primary amine.
31 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a peptide according to any one of claims 1 - 12 and one or more agents selected from (i) a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ , or (ii) a sterically hindered primary amine.
32 . The pharmaceutical composition according to claim 30 or 31 , wherein said agent is Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ .
33 . The pharmaceutical composition according to claim 32 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ 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.
34 . The pharmaceutical composition according to claim 30 or 31 , wherein said agent is a sterically hindered primary amine.
35 . The pharmaceutical composition according to claim 34 , wherein the sterically hindered primary amine is an amino acid.
36 . The pharmaceutical composition according to claim 35 , wherein the amino acid is a naturally-occurring amino acid, a non-naturally occurring amino acid or an amino acid derivative.
37 . The pharmaceutical composition according to claim 36 , 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.
38 . The pharmaceutical composition according to claim 34 , wherein the sterically hindered primary amine has the formula:
wherein R 1 , R 2 and R 3 are independently selected from: H, C(O)OH, C1-C6 alkyl, C1-C6 alkylether, C1-C6 alkylthioether, C1-C6 alkyl carboxylic acid, C1-C6 alkyl carboxylamide and alkylaryl, wherein any group can be singly or multiply substituted with: halogen or amino, and provided that no more than one of R 1 , R 2 and R 3 is H.
39 . The pharmaceutical composition according to claim 38 , wherein the sterically hindered primary amine is cyclohexylamine or 2-methylbutylamine.
40 . The pharmaceutical composition according to claim 34 , wherein the sterically hindered primary amine is a polymeric amine.
41 . The pharmaceutical composition according to claim 40 , wherein the polymeric amine is chitosan.
42 . The pharmaceutical composition according to any one of claims 34 - 41 , wherein said pharmaceutical composition further comprises Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ .
43 . The pharmaceutical composition according to claim 42 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ 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.
44 . The pharmaceutical composition according to any one of claims 13 - 43 , further comprising an antioxidant.
45 . The pharmaceutical composition according to claim 44 , wherein said antioxidant is BHA, vitamin E or propyl gallate.
46 . The pharmaceutical composition according to any one of claims 13 - 39 , further comprising a pharmaceutically acceptable binder or additive.
47 . The pharmaceutical composition according to claim 46 , wherein the pharmaceutically acceptable binder or additive is selected from polyvinyl alcohol, polyvinyl pyrrolidone (povidone), a starch, maltodextrin or a cellulose ether.
48 . The pharmaceutical composition according to claim 47 , wherein the pharmaceutically acceptable binder or additive is polyvinyl alcohol.
49 . The pharmaceutical composition of claim 47 , wherein the pharmaceutically acceptable binder or additive is a cellulose ether.
50 . The pharmaceutical composition of claim 49 , wherein the cellulose ether is selected from: methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
51 . The pharmaceutical composition of any of claims 13 - 50 , further comprising a pharmaceutically acceptable filler.
52 . The pharmaceutical composition according to claim 51 , wherein the pharmaceutically acceptable filler is cellulose, isomalt, mannitol or dibasic calcium phosphate.
53 . The pharmaceutical composition of claim 52 , wherein the cellulose is selected from microfine cellulose and microcrystalline cellulose.
54 . The pharmaceutical composition according to any one of claims 13 - 53 , further comprising an additional therapeutic agent.
55 . The pharmaceutical composition according to claim 54 , 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.
56 . A dosage unit comprising a pharmaceutical composition according to any one of claims 13 - 23 .
57 . The dosage unit according to claim 56 , wherein said dosage unit is a capsule or tablet.
58 . The dosage unit according to claim 57 , wherein said dosage unit is a capsule.
59 . The dosage unit according to claim 57 , wherein each of said dosage units comprises 5 μg to 1 mg of linaclotide.
60 . A dosage unit comprising a pharmaceutical composition according to any one of claims 24 - 55 .
61 . The dosage unit according to claim 60 , wherein said dosage unit is a capsule or tablet.
62 . The dosage unit according to claim 61 , wherein said dosage unit is a capsule.
63 . The dosage unit according to claim 61 , wherein each of said dosage units comprises 5 μg to 1 mg of linaclotide.
64 . The dosage unit according to claim 63 , wherein each of said dosage units comprises 290 μg of linaclotide.
65 . The dosage unit according to claim 63 , wherein each of said dosage units comprises 145 μg of linaclotide.
66 . A method for treating a gastrointestinal disorder comprising administering the pharmaceutical composition according to any one of claims 13 - 55 .
67 . The method of claim 66 , 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.
68 . The method of claim 67 , wherein the gastrointestinal disorder is constipation.
69 . The method of claim 68 , wherein the constipation is chronic constipation, idiopathic constipation, due to post-operative ileus, or caused by opiate use.
70 . The method of claim 67 , wherein the gastrointestinal disorder is irritable bowel syndrome (IBS).
71 . The method of claim 70 , 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).
72 . The method of claim 67 , wherein the gastrointestinal disorder is dyspepsia.
73 . The method of claim 67 , wherein the gastrointestinal disorder is gastroparesis.
74 . The method according to claim 73 , wherein said gastroparesis is idiopathic, diabetic or post-surgical gastroparesis.
75 . The method of claim 67 , wherein the gastrointestinal disorder is chronic intestinal pseudo obstruction.
76 . The method of claim 67 , wherein the gastrointestinal disorder is Crohn's disease.
77 . The method of claim 67 , wherein the gastrointestinal disorder is ulcerative colitis.
78 . The method of claim 67 , wherein the gastrointestinal disorder is inflammatory bowel disease.
79 . The method of claim 67 , wherein the gastrointestinal disorder is visceral pain.
80 . 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 any one of claims 13 - 55 .
81 . A method of increasing guanylate cyclase C (GC-C) receptor activity in a biological sample or organism, comprising contacting said biological sample or organism with a peptide according to any one of claims 1 - 12 .Cited by (0)
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