Apixaban formulations

• US 9,326,945 B2
• Filed: 02/24/2011
• Issued: 05/03/2016
• Est. Priority Date: 02/25/2010
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company, Pfizer Inc.
• Original Assignee: Bristol-Myers Squibb Company, Pfizer Inc.
• Inventors: Patel, Jatin, Frost, Charles, Jia, Jingpin, Vemavarapu, Chandra
• Primary Examiner(s): Barham, Bethany
• Assistant Examiner(s): FRAZIER, BARBARA S
• Application Number:
  US13/579,796
• Publication Number:
  US 20130045245A1
• Time in Patent Office: 1,895 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4162 condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

Compositions comprising crystalline apixaban particles having a D₉₀ equal to or less than 89 μm, and a pharmaceutically acceptable carrier, are substantially bioequivalent and can be used to for the treatment and/or prophylaxis of thromboembolic disorders.

Claims

1. A solid pharmaceutical composition comprising a therapeutically effective amount of crystalline apixaban particles and a pharmaceutically acceptable diluent or carrier,

wherein the crystalline apixaban particles have a D₉₀ equal to or less than about 89 μ

m, and

wherein at least 77 wt % of apixaban dissolves within 30 minutes in a pH 6.8 phosphate buffer containing 0.05% sodium lauryl sulfate.

2. The composition as defined in claim 1, wherein said composition comprises Form N-1 of apixaban.

3. The composition as defined in claim 1, wherein the D₉₀ is equal to or less than 85 μ

m.

4. The composition as defined in claim 1, wherein the D₉₀ is equal to or less than 50 μ

m.

5. The composition as defined in claim 1, wherein the D₉₀ is equal to or less than 30 μ

m.

6. The composition as defined in claim 1, wherein the D₉₀ is equal to or less than 25 μ

m.

7. The composition as defined in claim 1, further comprising:

from 1% to 2% by weight of a surfactant.

8. The composition as defined in claim 7, wherein the surfactant is sodium lauryl sulfate.

9. The composition as defined in claim 1, wherein the pharmaceutical composition comprises from about 2.5 mg to about 5 mg of apixaban.

10. The composition as defined in claim 1, wherein the pharmaceutical composition comprises 2.5 mg of apixaban.

11. The composition as defined in claim 1, wherein the pharmaceutical composition comprises 5 mg of apixaban.

23. The composition as defined in claim 1, which is a tablet.

24. The composition as defined in claim 1, which is a capsule.

25. The composition as defined in claim 9, which is a tablet.

26. The composition as defined in claim 9, which is a capsule.

27. The composition as defined in claim 10, which is a tablet.

28. The composition as defined in claim 10, which is a capsule.

29. The composition as defined in claim 11, which is a tablet.

30. The composition as defined in claim 11, which is a capsule.

12. A solid pharmaceutical composition comprising a therapeutically effective amount of apixaban and a pharmaceutically acceptable diluent or carrier,

wherein apixaban comprises crystalline apixaban particles,

wherein the crystalline apixaban particles have a D₉₀ equal to or less than about 89 μ

m, and

wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL, of a dissolution medium at 37°

C., at least 77 wt % of apixaban in the pharmaceutical composition dissolves within 30 minutes in the dissolution medium, and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.

13. The composition as defined in claim 12, wherein said composition comprises Form N-1 of apixaban.

14. The composition as defined in claim 12, wherein the D₉₀ is equal to or less than 85 μ

m.

15. The composition as defined in claim 12, wherein the D₉₀ is equal to or less than 50 μ

m.

16. The composition as defined in claim 12, wherein the D₉₀ is equal to or less than 30 μ

m.

17. The composition as defined in claim 12, wherein the D₉₀ is equal to or less than 25 μ

m.

18. The composition as defined in claim 12, further comprising:

from 1% to 2% by weight of a surfactant.

19. The composition as defined in claim 18, wherein the surfactant is sodium lauryl sulfate.

20. The composition as defined in claim 12, wherein the pharmaceutical composition comprises from about 2.5 mg to about 5 mg of apixaban.

21. The composition as defined in claim 12, wherein the pharmaceutical composition comprises 2.5 mg of apixaban.

22. The composition as defined in claim 12, wherein the pharmaceutical composition comprises 5 mg of apixaban.

31. The composition as defined in claim 12, which is a tablet.

32. The composition as defined in claim 12, which is a capsule.

33. The composition as defined in claim 20, which is a tablet.

34. The composition as defined in claim 20, which is a capsule.

35. The composition as defined in claim 21, which is a tablet.

36. The composition as defined in claim 21, which is a capsule.

37. The composition as defined in claim 22, which is a tablet.

38. The composition as defined in claim 22, which is a capsule.