Preparation and uses of obeticholic acid

Abstract

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 .- 20 . (canceled) 
     
     
         21 . A tablet comprising non-crystalline obeticholic acid in the amount of about 1 mg to about 25 mg wherein the non-crystalline obeticholic acid comprises less than 1% of chenodeoxycholic acid. 
     
     
         22 . The tablet of  claim 21 , wherein the non-crystalline obeticholic acid further comprises not more than 0.15% of 6β-ethylchenodeoxycholic acid. 
     
     
         23 . The tablet of  claim 21 , wherein the non-crystalline obeticholic acid comprises less than about 0.5% of chenodeoxycholic acid. 
     
     
         24 . The tablet of  claim 23 , wherein the non-crystalline obeticholic acid comprises less than about 0.3% of chenodeoxycholic acid. 
     
     
         25 . The tablet of  claim 24 , wherein the non-crystalline obeticholic acid comprises less than about 0.2% of chenodeoxycholic acid. 
     
     
         26 . The tablet of  claim 21 , wherein the non-crystalline obeticholic acid 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. 
     
     
         27 . The tablet of  claim 21 , wherein the non-crystalline obeticholic acid 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. 
     
     
         28 . The tablet of  claim 27 , wherein the non-crystalline obeticholic acid comprises less than about 0.5% of chenodeoxycholic acid. 
     
     
         29 . The tablet of  claim 28 , wherein the non-crystalline obeticholic acid comprises less than about 0.3% of chenodeoxycholic acid. 
     
     
         30 . The tablet of  claim 29 , wherein the non-crystalline obeticholic acid comprises less than about 0.2% of chenodeoxycholic acid. 
     
     
         31 . The tablet of  claim 21 , wherein the non-crystalline obeticholic acid 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. 
     
     
         32 . The tablet of  claim 31 , wherein the non-crystalline obeticholic acid comprises less than about 0.3% of chenodeoxycholic acid. 
     
     
         33 . The tablet of  claim 32 , wherein the non-crystalline obeticholic acid comprises less than about 0.2% of chenodeoxycholic acid. 
     
     
         34 . A tablet comprising non-crystalline obeticholic acid wherein the non-crystalline obeticholic acid 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%. 
     
     
         35 . The tablet of  claim 21 , wherein the non-crystalline obeticholic acid is in the amount of about 25 mg. 
     
     
         36 . The tablet of  claim 21 , wherein the non-crystalline obeticholic acid is in the amount of about 10 mg. 
     
     
         37 . A method for treating NASH comprising administering to a subject in need thereof a tablet comprising non-crystalline obeticholic acid in the amount of about 1 mg to about 25 mg wherein the non-crystalline obeticholic acid comprises less than 1% of chenodeoxycholic acid. 
     
     
         38 . The method of  claim 37 , wherein the non-crystalline obeticholic acid comprises less than about 0.2% of chenodeoxycholic acid. 
     
     
         39 . The method of  claim 37 , wherein the non-crystalline obeticholic acid is in the amount of about 25 mg. 
     
     
         40 . The method of  claim 37 , wherein the non-crystalline obeticholic acid is in the amount of about 10 mg.