Oral formulations of cytidine analogs and methods of use thereof

• US 8,846,628 B2
• Filed: 05/14/2009
• Issued: 09/30/2014
• 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: Etter, Jeffrey B., Lai, Mei, Backstrom, Jay Thomas
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US12/466,213
• Publication Number:
  US 20090286752A1
• Time in Patent Office: 1,965 Days
• Field of Search: None
• 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 example, 5-azacytidine or decitabine, for oral administration, wherein the compositions release the cytidine analog, for example, 5-azacytidine or decitabine, 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 and at least one pharmaceutically acceptable excipient, wherein the composition is a non-enteric coated tablet.

2. The composition of claim 1, wherein the at least one pharmaceutically acceptable excipient is selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

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

4. The composition of claim 3, wherein the permeation enhancer is D-alpha-tocopheryl polyethylene glycol 1000 succinate.

5. The composition of claim 4, wherein the D-alpha-tocopheryl polyethylene glycol 1000 succinate is present in the composition at about 2% by weight relative to the total weight of the composition.

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

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

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

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

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

11. The composition of claim 1, which has been shown to achieve an area-under-the-curve value of at least about 200 ng-hr/mL following oral administration to a test subject.

12. The composition of claim 1, which has been shown to achieve an area-under-the-curve value of at least about 400 ng-hr/mL following oral administration to a test subject.

13. The composition of claim 1, wherein the tablet comprises a sugar coating, a film coating, or a compression coating.

14. The composition of claim 13, wherein the film coating is a cellulose ether polymer.

15. The composition of claim 14, wherein the cellulose ether polymer is hydroxypropyl methyl-cellulose, hydroxypropyl cellulose, or methyl-cellulose.

16. The composition of claim 1, wherein the amount of 5-azacytidine is 40 to 480 mg.

17. The composition of claim 1, wherein the amount of 5-azacytidine is 80 to 480 mg.

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

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

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

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

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

23. The composition of claim 1, wherein the amount of 5-azacytidine is 120 to 480 mg.

24. The composition of claim 1, wherein the amount of 5-azacytidine is at least about 300 mg.

25. The composition of claim 1, wherein the amount of 5-azacytidine is at least about 360 mg.

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

27. The composition of claim 1, wherein the amount of 5-azacytidine is at least about 480 mg.

28. A method for treating one or more symptoms of a disease associated with abnormal cell proliferation, comprising orally administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of 5-azacytidine and at least one pharmaceutically acceptable excipient, wherein the composition is a non-enteric coated tablet, and wherein the disease associated with abnormal cell proliferation is myelodysplastic syndrome or acute myelogenous leukemia.

29. The method of claim 28, wherein the composition further comprises a permeation enhancer.

30. The method of claim 29, wherein the permeation enhancer is D-alpha-tocopheryl polyethylene glycol 1000 succinate.

31. The method of claim 30, 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.

32. The method of claim 28, wherein the method further comprises not co-administering a cytidine deaminase inhibitor with the 5-azacytidine.

33. The method of claim 28, wherein the composition is a single unit dosage form.

34. The method of claim 28, wherein the at least one pharmaceutically acceptable excipient is selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

35. The method of claim 28, wherein the amount of 5-azacytidine is at least about 40 mg.

36. The method of claim 28, wherein the amount of 5-azacytidine is at least about 400 mg.

37. The method of claim 28, wherein the amount of 5-azacytidine is at least about 1000 mg.

38. The method of claim 28, which has been shown to achieve an area-under-the-curve value of at least about 200 ng-hr/mL following oral administration to a test subject.

39. The method of claim 28, which has been shown to achieve an area-under-the-curve value of at least about 400 ng-hr/mL following oral administration to a test subject.

40. The method of claim 28, which has been shown to achieve a maximum plasma concentration of at least about 100 ng/mL following oral administration to a test subject.

41. The method of claim 28, which has been shown to achieve a maximum plasma concentration of at least about 200 ng/mL following oral administration to a test subject.

42. The method of claim 28, which has been shown to achieve a time to maximum plasma concentration of less than about 180 minutes following oral administration to a test subject.

43. The method of claim 28, which has been shown to achieve a time to maximum plasma concentration of less than about 90 minutes following oral administration to a test subject.