Claims for Patent: 10,174,073

Summary for Patent: 10,174,073

Title:	Preparation and uses of obeticholic acid
Abstract:	The present invention relates to obeticholic acid: ##STR00001## or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof. Obeticholic acid is useful for the treatment or prevention of a FXR mediated disease or condition, cardiovascular disease or cholestatic liver disease, and for reducing HDL cholesterol, for lowering triglycerides in a mammal, or for inhibition of fibrosis. The present invention also relates to processes for the synthesis of obeticholic acid.
Inventor(s):	Steiner; Andre (Raubling, DE), Waenerlund Poulsen; Heidi (Koge, DK), Jolibois; Emilie (Cambridge, GB), Rewolinski; Melissa (San Diego, CA), Gross; Ralf (Raubling, DE), Sharp; Emma (Cambridge, GB), Dubas-Fisher; Fiona (Cambridge, GB), Eberlin; Alex (Cambridge, GB)
Assignee:	Intercept Pharmaceuticals, Inc. (New York, NY)
Application Number:	15/496,398
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,174,073
Patent Claims:	1. A pharmaceutical composition comprising non-crystalline obeticholic acid (OCA) comprising less than 1% by weight of chenodeoxycholic acid (CDCA), wherein the non-crystalline OCA is prepared by a process comprising at least one step of crystallizing crude OCA using at least one organic solvent. 2. The pharmaceutical composition of claim 1, wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate. 3. The pharmaceutical composition of claim 1, wherein the at least one organic solvent comprises n-butyl acetate. 4. The pharmaceutical composition of claim 1, wherein the process further comprises the step of converting a crystalline form of OCA to the non-crystalline OCA by dissolving the crystalline form in an aqueous NaOH solution and adding HCl. 5. The pharmaceutical composition of claim 1, wherein the process further comprises the step of reacting 3.alpha.-hydroxy-6.alpha.-ethyl-7-keto-5.beta.-cholan-24-oic acid with NaBH.sub.4 to form the crude OCA. 6. The pharmaceutical composition of claim 1, wherein the non-crystalline OCA comprises a total of not more than 0.15% by weight of 6-ethylursodeoxycholic acid and 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid. 7. The pharmaceutical composition of claim 6, wherein the non-crystalline OCA comprises a total of less than about 0.07% by weight of 6-ethylursodeoxycholic acid and 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid. 8. The pharmaceutical composition of claim 7, wherein the non-crystalline OCA comprises a total of less than about 0.06% by weight of 6-ethylursodeoxycholic acid and 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid. 9. The pharmaceutical composition of claim 8, wherein the non-crystalline OCA comprises a total of less than about 0.05% by weight of 6-ethylursodeoxycholic acid and 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid. 10. The pharmaceutical composition of claim 1, wherein the non-crystalline OCA comprises not more than 0.15% by weight of 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid. 11. The pharmaceutical composition of claim 10, wherein the non-crystalline OCA comprises less than 0.07% by weight of 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid. 12. The pharmaceutical composition of claim 11, wherein the non-crystalline OCA comprises less than 0.06% by weight of 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid. 13. The pharmaceutical composition of claim 12, wherein the non-crystalline OCA comprises less than 0.05% by weight of 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid. 14. The pharmaceutical composition of claim 1, wherein the non-crystalline OCA comprises not more than 0.15% by weight of 6.beta.-ethylchenodeoxycholic acid. 15. The pharmaceutical composition of claim 14, wherein the non-crystalline OCA comprises less than about 0.07% by weight of 6.beta.-ethylchenodeoxycholic acid. 16. The pharmaceutical composition of claim 15, wherein the non-crystalline OCA comprises less than about 0.06% by weight of 6.beta.-ethylchenodeoxycholic acid. 17. The pharmaceutical composition of claim 16, wherein the non-crystalline OCA comprises less than about 0.05% by weight of 6.beta.-ethylchenodeoxycholic acid. 18. The pharmaceutical composition of claim 1, wherein the non-crystalline OCA comprises less than about 0.5% by weight of CDCA. 19. The pharmaceutical composition of claim 18, wherein the non-crystalline OCA comprises less than about 0.3% by weight of CDCA. 20. The pharmaceutical composition of claim 19, wherein the non-crystalline OCA comprises less than about 0.2% by weight of CDCA. 21. The pharmaceutical composition of claim 1, wherein the non-crystalline OCA comprises from 0.01% by weight to less than 1% by weight of CDCA. 22. The pharmaceutical composition of claim 21, wherein the non-crystalline OCA further comprises not more than 0.15% by weight of 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 23. The pharmaceutical composition of claim 22, wherein the non-crystalline OCA comprises less than about 0.07% by weight of 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 24. The pharmaceutical composition of claim 23, wherein the non-crystalline OCA comprises less than about 0.06% by weight of 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 25. The pharmaceutical composition of claim 24, wherein the non-crystalline OCA comprises less than about 0.05% by weight of 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 26. The pharmaceutical composition of claim 1, wherein the non-crystalline OCA further comprises less than about 3% by weight of water. 27. A pharmaceutical composition comprising non-crystalline obeticholic acid (OCA) and not more than 1% by weight of chenodeoxycholic acid (CDCA), wherein the OCA is prepared by a process comprising at least one step of crystallizing crude OCA using an organic solvent selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate. 28. The pharmaceutical composition of claim 27, wherein the solvent comprises n-butyl acetate. 29. The pharmaceutical composition of claim 27, wherein the non-crystalline OCA comprises from 0.01% by weight to not more than 1% by weight of CDCA. 30. A crystalline form of obeticholic acid (OCA) produced by a process of crystallizing crude OCA using at least one organic solvent. 31. The crystalline form of OCA of claim 30, wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate. 32. The crystalline form of OCA of claim 31, wherein the at least one organic solvent comprises n-butyl acetate. 33. A composition comprising a crystalline form of obeticholic acid (OCA), wherein the crystalline form of OCA is produced by a process comprising at least one step of crystallizing crude OCA using at least one organic solvent. 34. The composition of claim 33, wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate. 35. The composition of claim 34, wherein the at least one organic solvent comprises n-butyl acetate. 36. A pharmaceutical composition comprising non-crystalline obeticholic acid (OCA), wherein the OCA is prepared by a process comprising at least one step of crystallizing crude OCA using at least one organic solvent, and wherein the OCA comprises a total of less than 2% by weight of one or more impurities selected from 6-ethylursodeoxycholic acid, 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid, 6.beta.-ethylchenodeoxycholic acid, 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid, chenodeoxycholic acid (CDCA), and 3a (3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyloxy)-7.a- lpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 37. The pharmaceutical composition of claim 36, wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate. 38. The pharmaceutical composition of claim 37, wherein the at least one organic solvent comprises n-butyl acetate. 39. The pharmaceutical composition of claim 36, wherein the non-crystalline OCA comprises less than 1% by weight of CDCA. 40. The pharmaceutical composition of claim 39, wherein the non-crystalline OCA comprises from 0.01% by weight to less than 1% by weight of CDCA. 41. A pharmaceutical composition comprising non-crystalline obeticholic acid (OCA) wherein the non-crystalline OCA is prepared by a process comprising a step of crystallizing crude OCA using at least one organic solvent, and wherein the OCA comprises a total of less than 2% by weight of one or more impurities selected from 6.beta.-ethylursodeoxycholic acid, 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid, 6.beta.-ethylchenodeoxycholic acid, 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid, chenodeoxycholic acid (CDCA), and 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 42. The pharmaceutical composition of claim 41, wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate. 43. The pharmaceutical composition of claim 42, wherein the at least one organic solvent comprises n-butyl acetate. 44. The pharmaceutical composition of claim 41, wherein the non-crystalline OCA comprises less than 1% by weight of CDCA. 45. The pharmaceutical composition of claim 44, wherein the non-crystalline OCA comprises from 0.01% by weight to less than 1% by weight of CDCA. 46. The pharmaceutical composition of claim 41, wherein the non-crystalline OCA comprises a total of not more than 0.15% by weight of 6-ethylursodeoxycholic acid and 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid. 47. The pharmaceutical composition of claim 46, wherein the non-crystalline OCA comprises a total of less than about 0.07% by weight of 6-ethylursodeoxycholic acid and 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid. 48. The pharmaceutical composition of claim 47, wherein the non-crystalline OCA comprises a total of less than about 0.06% by weight of 6-ethylursodeoxycholic acid and 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid. 49. The pharmaceutical composition of claim 48, wherein the non-crystalline OCA comprises a total of less than about 0.05% by weight of 6-ethylursodeoxycholic acid and 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic acid. 50. The pharmaceutical composition of claim 41, wherein the non-crystalline OCA comprises not more than 0.15% by weight of 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid. 51. The pharmaceutical composition of claim 50, wherein the non-crystalline OCA comprises less than 0.07% by weight of 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid. 52. The pharmaceutical composition of claim 51, wherein the non-crystalline OCA comprises less than 0.06% by weight of 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid. 53. The pharmaceutical composition of claim 52, wherein the non-crystalline OCA comprises less than 0.05% by weight of 3.alpha.-hydroxy-6.alpha.-ethyl-7-cheto-5.beta.-cholan-24-oic acid. 54. The pharmaceutical composition of claim 51, wherein the non-crystalline OCA comprises not more than 0.15% by weight of 6.beta.-ethylchenodeoxycholic acid. 55. The pharmaceutical composition of claim 54, wherein the non-crystalline OCA comprises less than about 0.07% by weight of 6.beta.-ethylchenodeoxycholic acid. 56. The pharmaceutical composition of claim 55, wherein the non-crystalline OCA comprises less than about 0.06% by weight of 6.beta.-ethylchenodeoxycholic acid. 57. The pharmaceutical composition of claim 56, wherein the non-crystalline OCA comprises less than about 0.05% by weight of 6.beta.-ethylchenodeoxycholic acid. 58. The pharmaceutical composition of claim 41, wherein the non-crystalline OCA comprises not more than 0.15% by weight of 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 59. The pharmaceutical composition of claim 58, wherein the non-crystalline OCA comprises less than about 0.07% by weight of 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 60. The pharmaceutical composition of claim 59, wherein the non-crystalline OCA comprises less than about 0.06% by weight of 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid. 61. The pharmaceutical composition of claim 60, wherein the non-crystalline OCA comprises less than about 0.05% by weight of 3.alpha.(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oyl- oxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid.