US2023340010A1PendingUtilityA1

Preparation and uses of obeticholic acid

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Assignee: INTERCEPT PHARMACEUTICALS INCPriority: Jun 19, 2012Filed: Mar 22, 2023Published: Oct 26, 2023
Est. expiryJun 19, 2032(~5.9 yrs left)· nominal 20-yr term from priority
Inventors:André SteinerHeidi Waenerlund PoulsenEmilie JoliboisMelissa RewolinskiRalf GrossEmma SharpFiona Dubas-FisherAlex Eberlin
C07J 9/005A61K 9/2054A61K 31/575C07J 51/00C07B 2200/13A61P 1/16C07J 9/00A61P 13/04A61P 31/14A61P 3/06A61P 43/00A61P 9/00A61P 9/10A61K 31/56
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Claims

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.

Claims

exact text as granted — not AI-modified
We claim: 
     
         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 . The oral formulation according to  claim 1 , wherein 6β-ethylchenodeoxycholic 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 6β-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 that is pharmaceutically acceptable for administration to a human 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%. 
 
     
     
         8 . The oral formulation according to  claim 1 , wherein the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human is prepared on a commercial scale. 
     
     
         9 . The oral formulation according to  claim 2 , wherein the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human is prepared on a commercial scale. 
     
     
         10 . The oral formulation according to  claim 3 , wherein the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human is prepared on a commercial scale. 
     
     
         11 . The oral formulation according to  claim 1 , comprising from about 1 mg to about 30 mg of the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human. 
     
     
         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 6β-ethylchenodeoxycholic acid is present as an impurity in the obeticholic acid Form 1 and the amount of the 6β-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 . The composition according to  claim 12 , wherein the potency of the obeticholic acid Form 1 is greater than about 98%. 
     
     
         19 . The composition according to  claim 12 , wherein the obeticholic acid Form 1 is produced on a commercial scale. 
     
     
         20 . A composition comprising:
 obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human obtained by converting crystalline obeticholic acid or by converting a pharmaceutically acceptable salt of crystalline obeticholic acid; 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 obtained by converting crystalline obeticholic acid or by converting a pharmaceutically acceptable salt of crystalline obeticholic acid and the amount of the chenodeoxycholic acid is less than 1%.   
     
     
         21 . The composition according to  claim 20 , wherein the amount of the chenodeoxycholic acid is no more than 0.2%. 
     
     
         22 . The composition according to  claim 20 , wherein 6β-ethylchenodeoxycholic acid is present as an impurity in the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human obtained by converting crystalline obeticholic acid or by converting a pharmaceutically acceptable salt of crystalline obeticholic acid and the amount of the 6β-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 that is pharmaceutically acceptable for administration to a human obtained by converting crystalline obeticholic acid or by converting a pharmaceutically acceptable salt of crystalline obeticholic acid 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%. 
 
     
     
         23 . The composition according to  claim 20 , wherein the purity of the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human obtained by converting crystalline obeticholic acid or by converting a pharmaceutically acceptable salt of crystalline obeticholic acid is greater than about 96%. 
     
     
         24 . The composition according to  claim 20 , wherein the potency of the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human obtained by converting crystalline obeticholic acid or by converting a pharmaceutically acceptable salt of crystalline obeticholic acid is greater than about 95%. 
     
     
         25 . The composition according to  claim 20 , wherein the potency of the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human obtained by converting crystalline obeticholic acid or by converting a pharmaceutically acceptable salt of crystalline obeticholic acid is greater than about 98%. 
     
     
         26 . The composition according to  claim 20 , wherein the obeticholic acid Form 1 that is pharmaceutically acceptable for administration to a human obtained by converting crystalline obeticholic acid or by converting a pharmaceutically acceptable salt of crystalline obeticholic acid is produced on a commercial scale. 
     
     
         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.

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