The present invention provides pharmaceutical compositions and methods of treating lower gastrointestinal disorders, including irritable bowel syndrome and constipation.
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1. A method for treating a lower gastrointestinal (GI) disorder in a patient in need thereof: and/or a method for treating, preventing or reducing visceral or abdominal pain or discomfort associated with a lower GI disorder in a patient in need thereof,comprising administering a pharmaceutical compo
1. A method for treating a lower gastrointestinal (GI) disorder in a patient in need thereof: and/or a method for treating, preventing or reducing visceral or abdominal pain or discomfort associated with a lower GI disorder in a patient in need thereof,comprising administering a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequenceXaa1 Xaa2 Xaa3 Xaa4 Cys5 Xaa6 Xaa7 Xaa8 Cys9 Asn10 Pro11 Ala12 Cys13 Xaa14 Gly15 Xaa16 Xaa17 (SEQ ID NO:1), or a pharmaceutically acceptable salt thereof; whereinXaa1 is Asn, D-Asn, Gln, D-Gln, Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, γ-carboxylated Asp, Glu, D-Glu, γ-carboxylated Glu, α-aminosuberic acid (Asu), α-aminoadipic acid (Aad), α-aminopimelic acid (Apm), or is absent;Xaa2 is Asp, γ-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;Xaa3 is Asp, γ-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;Xaa4 is Cys or D-Cys;Xaa6 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-Tyr;Xaa7 is Tyr, Leu, Phe or Ile;Xaa8 is Cys or D-Cys;Xaa14 is Thr, Ala or Phe;Xaa16 is Cys or D-Cys; andXaa17 is Tyr, D-Tyr, or is absent;wherein:if Xaa1 is present, Xaa1 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid;if Xaa1 is absent and Xaa2 is present, then Xaa2 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; orif both Xaa1 and Xaa2 are absent, then Xaa3 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid. 2. The method according to claim 1, wherein Xaa2 is Asp, Glu, or absent;Xaa3 is Asp, Glu, or absent;Xaa7 is Tyr or Leu;Xaa14 is Thr; andXaa17 is Tyr or is absent. 3. The method according to claim 1, wherein Xaa1 is Asp, D-Asp, Glu, D-Glu, or absent; and Xaa6 is P-Ser or P-Thr. 4. The method according to claim 3, wherein Xaa6 is P-Ser. 5. The method according to claim 1, wherein Xaa1, Xaa2 and Xaa3 are absent. 6. The method according to claim 1, wherein said peptide comprises the amino acid sequence Cys4 Cys5 P-Ser6 Xaa7 Cys8 Cys9 Asn10 Pro11 Ala12 Cys13 Thr14 Gly15 Cys16 Xaa17 (SEQ ID NO: 15),wherein Xaa7 is Tyr or Leu, and Xaa17 is Tyr, D-Tyr, or is absent. 7. The method according to claim 1, wherein said peptide comprises the amino acid sequence: (SEQ ID NO: 2)Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala CysThr Gly Cys Tyr;(SEQ ID NO: 3)Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala CysThr Gly Cys;(SEQ ID NO: 4)Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala CysThr Gly Cys Tyr;(SEQ ID NO: 5)Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala CysThr Gly Cys;(SEQ ID NO: 6)Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr;(SEQ ID NO: 7)Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr GlyCys;(SEQ ID NO: 8)Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys Tyr;or(SEQ ID NO: 9)Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr GlyCys. 8. The method according to claim 1, wherein the peptide comprises the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7). 9. The method according to claim 1, wherein said peptide or pharmaceutically acceptable salt thereof is isolated. 10. The method according to claim 9, wherein said peptide or pharmaceutically acceptable salt thereof is purified. 11. The method according to claim 1, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and one or more agents selected from (i) a cation selected from Mg2+, Ca2+, Zn2+, Mn2+, K+, Na− and Al3+, and (ii) a sterically hindered primary amine. 12. The method according to claim 11, wherein said agent is Mg2+, Ca2+, Zn2+, Mn2+, K+, Na− or Al3+. 13. The method according to claim 11, wherein said agent is a sterically hindered primary amine. 14. The method according to claim 11, wherein the sterically hindered primary amine is an amino acid. 15. The method according to claim 11, wherein the pharmaceutical composition further comprises an antioxidant selected from BHA, vitamin E and propyl gallate. 16. The method according to claim 11, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable binder or additive selected from polyvinyl alcohol, Polyvinylpyrrolidone (povidone), a starch, maltodextrin and a cellulose ether. 17. The method according to claim 11, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable filler selected from cellulose, isomalt, mannitol, lactose and dibasic calcium phosphate. 18. The method according to claim 1, wherein said pharmaceutical composition further comprises an additional therapeutic agent. 19. The method according to claim 18, wherein said additional therapeutic agent is selected from one or more of an analgesic agent, an antidepressant, a promotility or prokinetic agent, an antispasmodic or an additional therapeutic agent to treat constipation. 20. The method according to claim 1, wherein said lower GI disorder is selected from impaired lower intestinal mobility, intestinal or colonic pseudo-obstruction, functional bloating, post-operative ileus, irritable bowel syndrome or constipation. 21. The method according to claim 20, wherein said lower GI disorder is intestinal or colonic pseudo-obstruction. 22. The method according to claim 20, wherein said lower GI disorder is functional bloating. 23. The method according to claim 20, wherein said lower GI disorder is post-operative ileus. 24. The method according to claim 20, wherein said lower GI disorder is irritable bowel syndrome. 25. The method according to claim 24, wherein said irritable bowel syndrome is IBS-C or IBS-M. 26. The method according to claim 1, wherein said constipation is chronic constipation, idiopathic constipation or constipation caused by opiate use. 27. The method according to claim 26, wherein said constipation is chronic constipation. 28. The method according to claim 1, comprising treating or reducing visceral or abdominal pain or discomfort associated with a GI disorder. 29. The method according to claim 28, wherein the GI disorder is irritable bowel syndrome or constipation. 30. The method according to claim 28, wherein the GI disorder is IBS-C or IBS-M. 31. The method according to claim 28, wherein the GI disorder is chronic constipation.
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