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 . An oral formulation comprising:
obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human; and
a pharmaceutically acceptable excipient,
wherein chenodeoxycholic acid is present as an impurity in the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human and the amount of the chenodeoxycholic acid is less than 1%.
2 . The oral formulation according to claim 1 , wherein the amount of the chenodeoxycholic acid is less than 0.5%.
3 . The oral formulation according to claim 1 , wherein the amount of the chenodeoxycholic acid is no more than 0.2%.
4 . The oral formulation according to claim 1 , wherein the purity of the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human is greater than about 96%.
5 . The oral formulation according to claim 1 , wherein the potency of the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human is greater than about 95%.
6 . The oral formulation according to claim 1 , wherein the potency of the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human is greater than about 98%.
7 - 11 . (canceled)
12 . A composition comprising:
obeticholic acid Form 1; and
a pharmaceutically acceptable excipient,
wherein chenodeoxycholic acid is present as an impurity in the obeticholic acid Form 1 and the amount of the chenodeoxycholic acid is less than 1%,
wherein obeticholic acid Form 1 is pharmaceutically acceptable for administration to a human, and
wherein the obeticholic acid Form 1 contains an organic solvent at a residual level suitable for human pharmaceutical use.
13 . The composition according to claim 12 , wherein the amount of the chenodeoxycholic acid is less than 0.5%.
14 . The composition according to claim 12 , wherein the amount of the chenodeoxycholic acid is no more than 0.2%.
15 . The composition according to claim 12 , wherein 60-ethylchenodeoxycholic acid is present as an impurity in the obeticholic acid Form 1 and the amount of the 60-ethylchenodeoxycholic acid is no more than 0.15%, and
wherein 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid is present as an impurity in the obeticholic acid Form 1 and the amount of the 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid is no more than 0.15%.
16 . The composition according to claim 12 , wherein the purity of the obeticholic acid Form 1 is greater than about 96%.
17 . The composition according to claim 12 , wherein the potency of the obeticholic acid Form 1 is greater than about 95%.
18 - 26 . (canceled)
27 . A method of treating an FXR mediated disease or condition in a human subject, the method comprising:
orally administering to the human subject a composition comprising:
an effective amount of obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human; and
a pharmaceutically acceptable excipient,
wherein chenodeoxycholic acid is present as an impurity in the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human and the amount of the chenodeoxycholic acid is less than 1%.
28 . The method according to claim 27 , wherein the FXR mediated disease is nonalcoholic steatohepatitis.
29 . The method according to claim 27 , wherein the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human is prepared on a commercial scale.