Sustained release formulation of methotrexate as a disease-modifying antirheumatic drug (DMARD) and an anti-cancer agent

Patent metadata

Field	Value
Publication number	US-9770414-B2
Application number	US-91494410-A
Country	US
Kind code	B2
Filing date	Oct 28, 2010
Priority date	May 13, 2010
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

Disclosed is are formulations comprising a multivesicular liposome and MTX, the administration of which results in a C max of MTX between 5% and 50% of the C max of an immediate release dosage form of MTX, the duration of which lasts from about 1 to about 30 days. Also disclosed are methods of treating autoimmune diseases and cancer by administering these formulations of MTX.

First claim

What is claimed is:

1. A method for treating autoimmune diseases, comprising administering a formulation to a subject in need thereof by injection, wherein said formulation comprises multivesicular liposomes, said multivesicular liposomes comprise an amount of a basic addition salt of methotrexate, one or more amphipathic lipids or salts thereof, one or more neutral lipids, and optionally cholesterol or plant sterols, wherein the formulation is substantially cyclodextrin free, wherein administration of a single dose of said formulation to the subject in need thereof results in a plasma C max of said methotrexate of from 5% to 50% of the plasma C max of immediate release dosage forms of methotrexate, and wherein a duration of said methotrexate in the subject is from about 1 to about 30 days.

2. The method of claim 1 , wherein the autoimmune disease is rheumatoid arthritis.

3. The method of claim 1 , wherein the autoimmune disease is psoriasis.

4. The method of claim 1 , wherein the autoimmune disease is lupus.

5. The method if claim 1 wherein the autoimmune disease is scleroderma.

6. The method of claim 1 , wherein the autoimmune disease is Sjogren's syndrome.

7. The method of claim 1 , wherein the autoimmune disease is Goodpasture's syndrome.

8. The method of claim 1 , wherein the autoimmune disease is Wegener's granulomatosis.

9. The method of claim 1 , wherein the autoimmune disease is polymyalgia rheumatica.

10. The method of claim 1 , wherein the autoimmune disease is Guillain-Barre syndrome.

11. The method of claim 1 , wherein the autoimmune disease is Crohn's disease.

12. The method of claim 1 , wherein the basic addition salt of methotrexate is a sodium or potassium salt.

13. The method of claim 1 , wherein the multivesicular liposome further comprises a Folate to decrease C max -related side effects.

14. The method of claim 1 , further comprising administering a Folate to decrease C max -related side effects.

15. The method of claim 1 , further comprising administering a Folate encapsulated in multivesicular liposomes that do not contain methotrexate to decrease C max -related side effects.

16. The method of claim 1 , wherein the multivesicular liposome further comprises lysine.

17. The method of claim 1 , wherein the multivesicular liposome comprises cholesterol, one or more amphipathic lipids or salts thereof, and tricaprylin.

18. The method of claim 1 , wherein the amphipathic lipid comprises one or more phosphatidylcholines, one or more phosphatidylglycerols or salts thereof, and the neutral lipid comprises triolein.

19. The method of claim 18 , wherein the phosphatidylcholine comprises DOPC or DEPC.

20. The method of claim 1 , wherein the duration of the methotrexate plasma levels is about 1 to 7 days.

21. The method of claim 1 , wherein the injection is subcutaneous.

22. The method of claim 1 , wherein the injection is intramuscular.

23. The method of claim 1 , wherein the injection is intradermal.

24. The method of claim 1 , wherein the injection is administered every 5 to 7 days.

25. The method of claim 24 , wherein the injection is administered once a week.

26. A method for treating rheumatoid arthritis, comprising administering a formulation to a subject in need thereof by injection, wherein said formulation comprises multivesicular liposomes, said multivesicular liposomes comprise an amount of a basic addition salt of methotrexate, one or more amphipathic lipids or salts thereof, one or more neutral lipids, and optionally cholesterol or plant sterols, wherein the formulation is substantially cyclodextrin free, wherein administration of a single dose of said formulation to the subject in need thereof results in a plasma C max of said methotrexate of from 5% to 50% of the plasma C max of immediate release dosage forms of methotrexate, and wherein a duration of said methotrexate in the subject is from about 1 to about 30 days.

27. The method of claim 26 , wherein the basic addition salt of methotrexate is a sodium or potassium salt.

28. The method of claim 26 , wherein the multivesicular liposome further comprises a Folate to decrease C max -related side effects.

29. The method of claim 26 , further comprising administering a Folate to decrease C max -related side effects.

30. The method of claim 26 , further comprising administering a Folate encapsulated in multivesicular liposomes that do not contain methotrexate to decrease C max -related side effects.

31. The method of claim 26 , wherein the multivesicular liposome further comprises lysine.

32. The method of claim 26 , wherein the multivesicular liposome comprises cholesterol, one or more amphipathic lipids or salts thereof, and tricaprylin.

33. The method of claim 32 , wherein the amphipathic lipid comprises one or more phosphatidylcholines, one or more phosphatidylglycerols or salts thereof and the neutral lipid is triolein.

34. The method of claim 26 , wherein the phosphatidylcholine comprises DOPC or DEPC.

35. The method of claim 26 , wherein the duration of the methotrexate plasma levels is about 1 to 7 days.

36. The method of claim 26 , wherein the injection is subcutaneous.

37. The method of claim 26 , wherein the injection is intramuscular.

38. The method of claim 26 , wherein the injection is intradermal.

39. The method of claim 26 , wherein the injection is administered every 5 to 7 days.

40. The method of claim 39 , wherein the injection is administered once a week.

41. A method for treating rheumatoid arthritis, comprising administering a formulation to a subject in need thereof by injection, wherein said formulation comprises multivesicular liposomes, said multivesicular liposomes comprise an amount of a basic addition salt of methotrexate, one or more amphipathic lipids or salts thereof, one or more neutral lipids, cholesterol, and optionally lysine, wherein the formulation is substantially cyclodextrin free, wherein administration of a single dose of said formulation to the subject in need thereof results in a plasma C max of said methotrexate of from 5% to 50% of the plasma C max of immediate release dosage forms of methotrexate, and wherein a duration of said methotrexate in the subject is from about 1 to about 30 days.

42. The method of claim 41 , wherein the amphipathic lipids or salts thereof are selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, phosphatidic acid and cardiolipins, and combinations thereof.

43. The method of claim 42 , wherein the amphipathic lipids or salts thereof are selected from phosphatidylcholines or phosphatidylglycerols, or combinations thereof.

44. The method of claim 43 , wherein the amphipathic lipids or salts thereof are selected from DOPC, DEPC, DPPG or a salt thereof, or combinations thereof.

45. The method of claim 41 , wherein the neutral lipids are selected from the group consisting of triglycerides, propylene glycol esters, et

Assignees

• Garcia Louie Daniel
• Gibson Lois
• Lambert William
• Li Benjamin W
• Zhu Liangjin
• Pacira Pharmaceuticals Inc

Inventors

• Garcia Louie Daniel
• Gibson Lois
• Lambert William
• Li Benjamin W
• Zhu Liangjin

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title