Pharmaceutical compositions of cytidine analogs and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9393255-B2
Application number	US-201213363008-A
Country	US
Kind code	B2
Filing date	Jan 31, 2012
Priority date	Jan 31, 2011
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

The present disclosure provides pharmaceutical compositions comprising cytidine analogs for parenteral administration. Also provided are methods of preparing the compositions and methods of treating diseases and disorders using the compositions provided herein.

First claim

What is claimed is:

1. A liquid pharmaceutical composition comprising 5-azacytidine prepared by reconstituting with cold sterile water, which is substantially free of impurities, wherein the liquid pharmaceutical composition is a suspension, wherein the cold sterile water is at a temperature of less than about 8° C.

2. The pharmaceutical composition of claim 1 , which is prepared by contacting the cold sterile water with a sterile lyophilized powder comprising 5-azacytidine.

3. The pharmaceutical composition of claim 1 , which is a single unit dosage form.

4. The pharmaceutical composition of claim 2 , wherein the cold sterile water is at a temperature of between about 2° C. and about 8° C.

5. The pharmaceutical composition of claim 2 , wherein the sterile lyophilized powder comprises 5-azacytidine and mannitol.

6. The pharmaceutical composition of claim 5 , wherein the weight ratio of 5-azacytidine and mannitol in the sterile lyophilized powder is about 1:1.

7. The pharmaceutical composition of claim 6 , wherein the sterile lyophilized powder comprises about 100 mg of 5-azacytidine and about 100 mg of mannitol.

8. The pharmaceutical composition of claim 2 , wherein the composition is stored at a temperature of less than about 8° C., or at a temperature of between about 2° C. and about 8° C., or at a temperature of about 5° C., or at a temperature of about 0° C.

9. The pharmaceutical composition of claim 8 , wherein the composition is stored for up to 16 hr, up to 18 hr, up to 20 hr, up to 22 hr, or up to 24 hr.

10. The pharmaceutical composition of claim 9 , wherein the composition is warmed to about 12° C., about 14° C., about 16° C., about 18° C., about 20° C., about 22° C., about 24° C., about 25° C., about 26° C., about 28° C., or about 30° C., prior to parenteral use.

11. The pharmaceutical composition of claim 10 , which is substantially free of impurities.

12. The pharmaceutical composition of claim 2 , wherein the composition is stored frozen at a temperature of less than 0° C., or at a temperature of about −20° C.

13. The pharmaceutical composition of claim 12 , wherein the composition is stored for about 1, 2, 3, 4, 5, 6, or 7 days.

14. The pharmaceutical composition of claim 13 , wherein the composition is warmed to about 12° C., about 14° C., about 16° C., about 18° C., about 20° C., about 22° C., about 24° C., about 25° C., about 26° C., about 28° C., or about 30° C., prior to parenteral use.

15. The pharmaceutical composition of claim 14 , which is substantially free of impurities.

16. A method for treating a disease associated with abnormal cell proliferation, comprising parenterally administering to a subject in need thereof a pharmaceutical composition of claim 2 .

17. The method of claim 16 , wherein the disease is myelodysplastic syndrome.

18. The method of claim 16 , wherein the disease is acute myelogenous leukemia.

19. The method of claim 16 , wherein the disease is non-small cell lung cancer, ovarian cancer, pancreatic cancer, or colorectal cancer.

20. The method of claim 16 , wherein the method further comprises co-administering to the subject an additional therapeutic agent.

21. The method of claim 20 , wherein the additional therapeutic agent is thalidomide, lenalidomide, or pomalidomide.

22. The method of claim 16 , wherein the amount of 5-azacytidine is about 10 mg/m 2 , about 15 mg/m 2 , about 20 mg/m 2 , about 25 mg/m 2 , about 30 mg/m 2 , about 45 mg/m 2 , about 50 mg/m 2 , about 75 mg/m 2 , or about 100 mg/m 2 .

23. A method of preparing a liquid pharmaceutical composition comprising 5-azacytidine, comprising the step of contacting cold sterile water with a sterile lyophilized powder comprising 5-azacytidine, wherein the cold sterile water is at a temperature of less than about 8° C.

24. The method of claim 23 , wherein the cold sterile water is at a temperature of between about 2° C. and about 8° C.

25. The method of claim 23 , wherein the sterile lyophilized powder further comprises mannitol.

26. The method of claim 25 , wherein the sterile lyophilized powder comprises about 100 mg of 5-azacytidine and about 100 mg of mannitol.

27. The method of claim 23 , further comprising the step of storing the liquid pharmaceutical composition at a temperature of less than about 8° C., or at a temperature of between about 2° C. and about 8° C., or at a temperature of about 5° C., or at a temperature of about 0° C.

28. The method of claim 27 , wherein the composition is stored for up to 16 hr, up to 18 hr, up to 20 hr, up to 22 hr, or up to 24 hr.

29. The method of claim 28 , further comprising the subsequent step of warming the pharmaceutical composition to about 12° C., about 14° C., about 16° C., about 18° C., about 20° C., about 22° C., about 24° C., about 25° C., about 26° C., about 28° C., or about 30° C., prior to parenteral use.

30. The method of claim 29 , wherein the pharmaceutical composition is substantially free of impurities.

31. The method of claim 29 , wherein the pharmaceutical composition remains sterile.

32. The method of claim 23 , further comprising the step of storing the liquid pharmaceutical composition frozen at a temperature of less than 0° C., or at a temperature of about −20° C.

33. The method of claim 32 , wherein the composition is stored for about 1, 2, 3, 4, 5, 6, or 7 days.

34. The method of claim 33 , further comprising the subsequent step of warming the pharmaceutical composition to about 12° C., about 14° C., about 16° C., about 18° C., about 20° C., about 22° C., about 24° C., about 25° C., about 26° C., about 28° C., or about 30° C., prior to parenteral use.

35. The method of claim 34 , wherein the pharmaceutical composition is substantially free of impurities.

36. The method of claim 35 , wherein the pharmaceutical composition remains sterile.

Assignees

• Tutino Anthony
• Lai Mei
• Etter Jeffrey B
• Celgene Corp

Inventors

• Tutino Anthony
• Lai Mei
• Etter Jeffrey B

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title

• A61K31/706 Primary

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title