ORAL FORMULATIONS OF CYTIDINE ANALOGS AND METHODS OF USE THEREOF

• US 20090286752A1
• Filed: 05/14/2009
• Published: 11/19/2009
• Est. Priority Date: 05/15/2008
• Status: Active Grant

• Current Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Original Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Inventors: Lai, Mei, Etter, Jeffrey B., Backstrom, Jay Thomas
• Granted Patent: US 8,846,628 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• 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 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present disclosure provides pharmaceutical compositions comprising cytidine analogs for oral administration, wherein the compositions release the cytidine analog substantially in the stomach. Also provided are methods of treating diseases and disorders using the oral formulations provided herein.

Claims

1. A pharmaceutical composition for oral administration comprising a therapeutically effective amount of 5-azacytidine, wherein the composition releases the 5-azacytidine substantially in the stomach following oral administration to a subject.

2. The composition of claim 1, which is an immediate release composition.

3. The composition of claim 1, which is non-enteric-coated.

4. The composition of claim 1, which is a tablet.

5. The composition of claim 1, which is a capsule.

6. The composition of claim 1, which further comprises an excipient selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

7. The composition of claim 1, which further comprises a permeation enhancer.

8. The composition of claim 7, wherein the permeation enhancer is d-alpha-tocopheryl polyethylene glycol 1000 succinate.

9. The composition of claim 8, wherein the d-alpha-tocopheryl polyethylene glycol 1000 succinate is present in the formulation at about 2% by weight relative to the total weight of the formulation.

10. The composition of claim 1, which is essentially free of a cytidine deaminase inhibitor.

11. The composition of claim 1, which is essentially free of tetrahydrouridine.

12. The composition of claim 1, which further comprises an additional therapeutic agent.

13. The composition of claim 1, wherein the amount of 5-azacytidine is at least about 40 mg.

14. The composition of claim 1, wherein the amount of 5-azacytidine is at least about 400 mg.

15. The composition of claim 1, wherein the amount of 5-azacytidine is at least about 1000 mg.

16. The composition of claim 1, which achieves an area-under-the-curve value of at least about 200 ng-hr/mL following oral administration to a subject.

17. The composition of claim 1, which achieves an area-under-the-curve value of at least about 400 ng-hr/mL following oral administration to a subject.

18. The composition of claim 1, which achieves a maximum plasma concentration of at least about 100 ng/mL following oral administration to a subject.

19. The composition of claim 1, which achieves a maximum plasma concentration of at least about 200 ng/mL following oral administration to a subject.

20. The composition of claim 1, which achieves a time to maximum plasma concentration of less than about 180 minutes following oral administration to a subject.

21. The composition of claim 1, which achieves a time to maximum plasma concentration of less than about 90 minutes following oral administration to a subject.

22. The composition of claim 1, which achieves a time to maximum plasma concentration of less than about 60 minutes following oral administration to a subject.

23. A method for treating a subject having a disease associated with abnormal cell proliferation, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of 5-azacytidine, wherein the composition releases the 5-azacytidine substantially in the stomach following oral administration to the subject.

24. The method of claim 23, wherein the disease is myelodysplastic syndrome.

25. The method of claim 23, wherein the disease is acute myelogenous leukemia.

26. The method of claim 23, wherein the disease is non-small-cell lung cancer.

27. The method of claim 23, wherein the disease is ovarian cancer.

28. The method of claim 23, wherein the disease is pancreatic cancer.

29. The method of claim 23, wherein the disease is colorectal cancer.

30. The method of claim 23, which results in improved overall survival.

31. The method of claim 23, wherein the method further comprises co-administering to the subject in need thereof an additional therapeutic agent.

32. The method of claim 23, wherein the composition is an immediate release composition.

33. The method of claim 23, wherein the composition further comprises a permeation enhancer.

34. The method of claim 33, wherein the permeation enhancer is d-alpha-tocopheryl polyethylene glycol 1000 succinate.

35. The method of claim 34, wherein the d-alpha-tocopheryl polyethylene glycol 1000 succinate is present in the formulation at about 2% by weight relative to the total weight of the formulation.

36. The method of claim 23, wherein the method further comprises not co-administering a cytidine deaminase inhibitor with the cytidine analog.

37. The method of claim 23, wherein the composition is a single unit dosage form.

38. The method of claim 23, wherein the composition is non-enteric-coated.

39. The method of claim 23, wherein the composition is a tablet.

40. The method of claim 23, wherein the composition is a capsule.

41. The method of claim 23, wherein the composition further comprises an excipient selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

42. The method of claim 23, wherein the amount of 5-azacytidine is at least about 40 mg.

43. The method of claim 23, wherein the amount of 5-azacytidine is at least about 400 mg.

44. The method of claim 23, wherein the amount of 5-azacytidine is at least about 1000 mg.

45. The method of claim 23, which achieves an area-under-the-curve value of at least about 200 ng-hr/mL following oral administration to the subject.

46. The method of claim 23, which achieves an area-under-the-curve value of at least about 400 ng-hr/mL following oral administration to the subject.

47. The method of claim 23, which achieves a maximum plasma concentration of at least about 100 ng/mL following oral administration to the subject.

48. The method of claim 23, which achieves a maximum plasma concentration of at least about 200 ng/mL following oral administration to the subject.

49. The method of claim 23, which achieves a time to maximum plasma concentration of less than about 180 minutes following oral administration to the subject.

50. The method of claim 23, which achieves a time to maximum plasma concentration of less than about 90 minutes following oral administration to the subject.

51. A pharmaceutical composition comprising a therapeutically effective amount of 5-azacytidine, wherein the composition is for treating a disease or disorder associated with abnormal cell proliferation, wherein the composition is prepared for oral administration, and wherein the composition is prepared for release of the 5-azacytidine substantially in the stomach.

52. The pharmaceutical composition of claim 51, wherein the amount of 5-azacytidine is about 40 mg, about 400 mg, or about 1000 mg.

53. The pharmaceutical composition of claim 51, wherein the composition is prepared to achieve an area-under-the-curve value of at least about 200 ng-hr/mL or 400 ng-hr/mL following oral administration.

54. The pharmaceutical composition of claim 51, wherein the composition is prepared to achieve a maximum plasma concentration of at least about 100 ng/mL or 200 ng/mL following oral administration.

55. The pharmaceutical composition of claim 51, wherein the composition is prepared to achieve a time to maximum plasma concentration of less than about 60 minutes or 90 minutes after being administered.

56. The pharmaceutical composition of any one of claims 51 to 55, wherein the composition is prepared in the form of an immediate release composition.

57. The pharmaceutical composition of any one of claims 51 to 55, wherein the composition is prepared for oral administration in combination with an additional therapeutic agent.

58. The pharmaceutical composition of any one of claims 51 to 55, wherein the disease or disorder is myelodysplastic syndrome or acute myelogenous leukemia.

59. The pharmaceutical composition of any one of claims 51 to 55, wherein the composition is a single unit dosage form.

60. The pharmaceutical composition of any one of claims 51 to 55, wherein the composition is a tablet or a capsule.

61. The pharmaceutical composition of any one of claims 51 to 55, wherein the composition further comprises an excipient selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

62. Use of 5-azacytidine for the preparation of a pharmaceutical composition for treating a disease associated with abnormal cell proliferation, wherein the composition is prepared for oral administration, and wherein the composition is prepared for release of the 5-azacytidine substantially in the stomach.

63. The use of claim 62, wherein the disease is myelodysplastic syndrome or acute myelogenous leukemia.

64. The use of claim 62, wherein the amount of 5-azacytidine is about 40 mg, about 400 mg, or about 1000 mg.

65. The use of any one of claims 62 to 64, wherein the composition is prepared for immediate release.