Compositions of obeticholic acid and methods of use

Patent metadata

Field	Value
Publication number	US-10751349-B2
Application number	US-201916248512-A
Country	US
Kind code	B2
Filing date	Jan 15, 2019
Priority date	Apr 27, 2015
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

Abstract

The disclosure relates to obeticholic acid formulations with improved stability, dissolution, and/or solubility, methods of preparing the same for use and methods of treating various diseases and conditions.

First claim

The invention claimed is:

1. A tablet comprising obeticholic acid in an amount of 1 mg to 50 mg and a pharmaceutically acceptable excipient, wherein said obeticholic acid is in the form of jet-milled particles having a diameter of less than about 100 μm when analyzed by laser diffraction, and wherein D 50 is not more than 50 μm, and
wherein the pharmaceutically acceptable excipient has a total primary alcohol impurity of less than about 6% (wt/wt).

2. The tablet of claim 1 , wherein D 50 is not more than 20 μm.

3. The tablet of claim 1 , wherein D 50 is not more than 10 μm.

4. The tablet of claim 1 , wherein the tablet comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises said obeticholic acid and a pharmaceutically acceptable excipient, and the extra-granular portion comprises a pharmaceutically acceptable excipient.

5. The tablet of claim 4 , wherein the extra-granular portion does not contain obeticholic acid.

6. The tablet of claim 1 , wherein said pharmaceutically acceptable excipient having a total primary alcohol impurity of less than about 6% (wt/wt) is sodium starch glycolate.

7. The tablet of claim 5 , wherein the intra-granular portion comprises a diluent selected from: starch, pregelatinized starch, microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, and sucrose, and/or a combination thereof.

8. The tablet of claim 5 , wherein the extra-granular portion comprises a diluent selected from: starch, pregelatinized starch, microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, and sucrose, and/or a combination thereof.

9. The tablet of claim 7 , wherein the diluent is microcrystalline cellulose.

10. The tablet of claim 9 , wherein a ratio of microcrystalline cellulose to obeticholic acid in the intra-granular portion is from about 20:1 to about 1:5.

11. The tablet of claim 10 , wherein the ratio is from about 20:1 to about 1:1.

12. The tablet of claim 11 , wherein the ratio is from 20:1 to about 5:1.

13. The tablet of claim 5 , wherein the tablet comprises 5 mg of obeticholic acid.

14. The tablet of claim 5 , wherein the tablet comprises 10 mg of obeticholic acid.

15. The tablet of claim 5 , wherein the tablet comprises 25 mg of obeticholic acid.

16. The tablet of claim 1 , wherein the pharmaceutically acceptable excipient has a total primary alcohol impurity of less than about 3% (wt/wt).

17. The tablet of claim 1 , wherein the pharmaceutically acceptable excipient has a total primary alcohol impurity of less than about 0.5% (wt/wt).

18. The tablet of claim 1 , wherein D 50 is not more than 5 μm.

19. A tablet comprising:
obeticholic acid in an amount of 1 mg to 50 mg; and
sodium starch glycolate,
wherein said obeticholic acid is in the form of jet-milled particles having a diameter of less than about 100 μm when analyzed by laser diffraction, wherein D 50 is not more than 50 μm, and
wherein the total alcohol impurity in said sodium starch glycolate is less than about 6% (wt/wt).

20. The tablet of claim 19 , wherein D 50 is not more than 5 μm.

21. The tablet of claim 19 , wherein the total alcohol impurity in said sodium starch glycolate is less than about 3% (wt/wt).

22. The tablet of claim 19 , wherein the total alcohol impurity in said sodium starch glycolate is less than about 0.5% (wt/wt).

Assignees

• Intercept Pharmaceuticals Inc
• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Lancaster Richard Gail
• Olmstead Kay K
• Kagihiro Masashi
• Matono Mitsuhiro
• Taoka Ikuko
• Pruzanski Mark
• Shapiro David
• Hooshmand-Rad Roya
• Pencek Richard
• Sciacca Cathi
• Eliot Lise
• Edwards Jeffrey
• Macconell Leigh A
• Marmon Tonya K

Classifications

• C07J9/005

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K47/50

  the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title