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 obeticholic acid Form 1 and a pharmaceutically acceptable carrier, wherein the obeticholic acid Form 1 comprises less than 1% of chenodeoxycholic acid.
2. The pharmaceutical composition of claim 1 , wherein the obeticholic acid Form 1 further comprises not more than 0.15% of 6β-ethylchenodeoxycholic acid.
3. The pharmaceutical composition of claim 2 , wherein the obeticholic acid Form 1 comprises less than about 0.07% of 6β-ethylchenodeoxycholic acid.
4. The pharmaceutical composition of claim 3 , wherein the obeticholic acid Form 1 comprises less than about 0.06% of 6β-ethylchenodeoxycholic acid.
5. The pharmaceutical composition of claim 4 , wherein the obeticholic acid Form 1 comprises less than about 0.05% of 6β-ethylchenodeoxycholic acid.
6. The pharmaceutical composition of claim 1 , wherein the obeticholic acid Form 1 comprises less than about 0.5% of chenodeoxycholic acid.
7. The pharmaceutical composition of claim 6 , wherein the obeticholic acid Form 1 comprises less than about 0.3% of chenodeoxycholic acid.
8. The pharmaceutical composition of claim 7 , wherein the obeticholic acid Form 1 comprises less than about 0.2% of chenodeoxycholic acid.
9. The pharmaceutical composition of claim 1 , wherein the obeticholic acid Form 1 further comprises not more than 0.15% of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.
10. The pharmaceutical composition of claim 9 , wherein the obeticholic acid Form 1 comprises less than about 0.07% of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.
11. The pharmaceutical composition of claim 10 , wherein the obeticholic acid Form 1 comprises less than about 0.06% of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.
12. The pharmaceutical composition of claim 11 , wherein the obeticholic acid Form 1 comprises less than about 0.05% of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.
13. The pharmaceutical composition of claim 1 , wherein the obeticholic acid Form 1 further comprises not more than 0.15% of 6β-ethylchenodeoxycholic acid and not more than 0.15% of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.
14. The pharmaceutical composition of claim 13 , wherein the obeticholic acid Form 1 comprises less than about 0.07% of 6β-ethylchenodeoxycholic acid.
15. The pharmaceutical composition of claim 13 , wherein the obeticholic acid Form 1 comprises less than about 0.05% of 6β-ethylchenodeoxycholic acid.
16. The pharmaceutical composition of claim 13 , wherein the obeticholic acid Form 1 comprises less than about 0.5% of chenodeoxycholic acid.
17. The pharmaceutical composition of claim 16 , wherein the obeticholic acid Form 1 comprises less than about 0.3% of chenodeoxycholic acid.
18. The pharmaceutical composition of claim 17 , wherein the obeticholic acid Form 1 comprises less than about 0.2% of chenodeoxycholic acid.
19. The pharmaceutical composition of claim 1 , wherein the obeticholic acid Form 1 comprises less than about 0.05% of 6β-ethylchenodeoxycholic acid, and less than about 0.05% of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.
20. The pharmaceutical composition of claim 19 , wherein the obeticholic acid Form 1 comprises less than about 0.3% of chenodeoxycholic acid.
21. The pharmaceutical composition of claim 20 , wherein the obeticholic acid Form 1 comprises less than about 0.2% of chenodeoxycholic acid.
22. The pharmaceutical composition of claim 1 , wherein the obeticholic acid Form 1 further comprises less than about 2% of water.
23. A pharmaceutical composition comprising obeticholic acid Form 1 and a pharmaceutically acceptable carrier, wherein the obeticholic acid Form 1 comprises one or more compound selected from 6β-ethylchenodeoxycholic acid, chenodeoxycholic acid, and 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid, wherein 6β-ethylchenodeoxycholic acid is present in an amount between about 0% and not more than 0.05%, chenodeoxycholic acid is present in an amount between about 0% and not more than 0.2%, and 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid is present in an amount between about 0% and not more than 0.05%.