Preparation and uses of obeticholic acid
The present invention relates to obeticholic acid: 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.
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 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH 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 3α,7α-dihydroxy-6-ethyliden-5β-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 3α,7α-dihydroxy-6-ethyliden-5β-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 3α,7α-dihydroxy-6-ethyliden-5β-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 3α,7α-dihydroxy-6-ethyliden-5β-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 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.
11. The pharmaceutical composition of claim 10 , wherein the non-crystalline OCA comprises less than 0.07% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.
12. The pharmaceutical composition of claim 11 , wherein the non-crystalline OCA comprises less than 0.06% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.
13. The pharmaceutical composition of claim 12 , wherein the non-crystalline OCA comprises less than 0.05% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-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 6β-ethylchenodeoxycholic acid.
15. The pharmaceutical composition of claim 14 , wherein the non-crystalline OCA comprises less than about 0.07% by weight of 6β-ethylchenodeoxycholic acid.
16. The pharmaceutical composition of claim 15 , wherein the non-crystalline OCA comprises less than about 0.06% by weight of 6β-ethylchenodeoxycholic acid.
17. The pharmaceutical composition of claim 16 , wherein the non-crystalline OCA comprises less than about 0.05% by weight of 6β-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 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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, 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid, 6β-ethylchenodeoxycholic acid, 3α,7α-dihydroxy-6-ethyliden-5β-cholan-24-oic acid, chenodeoxycholic acid (CDCA), and 3a (3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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 6β-ethylursodeoxycholic acid, 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid, 6β-ethylchenodeoxycholic acid, 3α,7α-dihydroxy-6-ethyliden-5β-cholan-24-oic acid, chenodeoxycholic acid (CDCA), and 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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 3α,7α-dihydroxy-6-ethyliden-5β-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 3α,7α-dihydroxy-6-ethyliden-5β-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 3α,7α-dihydroxy-6-ethyliden-5β-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 3α,7α-dihydroxy-6-ethyliden-5β-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 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.
51. The pharmaceutical composition of claim 50 , wherein the non-crystalline OCA comprises less than 0.07% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.
52. The pharmaceutical composition of claim 51 , wherein the non-crystalline OCA comprises less than 0.06% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.
53. The pharmaceutical composition of claim 52 , wherein the non-crystalline OCA comprises less than 0.05% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-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 6β-ethylchenodeoxycholic acid.
55. The pharmaceutical composition of claim 54 , wherein the non-crystalline OCA comprises less than about 0.07% by weight of 6β-ethylchenodeoxycholic acid.
56. The pharmaceutical composition of claim 55 , wherein the non-crystalline OCA comprises less than about 0.06% by weight of 6β-ethylchenodeoxycholic acid.
57. The pharmaceutical composition of claim 56 , wherein the non-crystalline OCA comprises less than about 0.05% by weight of 6β-ethylchenodeoxycholic acid.
58. The pharmaceutical composition of claim 41 , wherein the non-crystalline OCA comprises not more than 0.15% by weight of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-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 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.