Stable laquinimod preparations

• US 7,989,473 B2
• Filed: 06/12/2007
• Issued: 08/02/2011
• Est. Priority Date: 06/12/2006
• Status: Active Grant

• Current Assignee: Active Biotech AB
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Gilbert, Adrian, Patashnik, Shulamit, Licht, Daniella
• Primary Examiner(s): Chong; Yong
• Assistant Examiner(s): KAROL, JODY LYNN
• Application Number:
  US11/811,810
• Publication Number:
  US 20070293537A1
• Time in Patent Office: 1,512 Days
• Field of Search: 514/312
• US Class Current: 514/312
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders

Abstract

The invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, N-methylglucamine, and a pharmaceutically acceptable carrier.

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, N-methylglucamine, and a pharmaceutically acceptable carrier, wherein the weight ratio of N-methylglucamine to the pharmaceutical salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide is between 13 to 1 and 18 to 1.

2. The pharmaceutical composition of claim 1, further comprising a lubricant.

3. The pharmaceutical composition of claim 2, wherein the lubricant is sodium stearyl fumarate.

4. The pharmaceutical composition of claim 3, wherein the weight ratio of sodium stearyl fumarate to the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide is between 9 to 1 and 7 to 1.

5. The pharmaceutical composition of claim 1, comprising a pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, mannitol, N-methylglucamine and sodium stearyl fumarate.

6. The pharmaceutical composition of claim 5, comprising, by total weight of the pharmaceutical composition, 0.2% of the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, 95.6% mannitol, 3.2% N-methylglucamine, and 1.0% sodium stearyl fumarate.

7. The pharmaceutical composition of claim 1 characterized in that 1.0% or less of the of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or of the pharmaceutically acceptable salt thereof degrades upon exposure to a 0.15% H₂O₂ solution for 40 minutes.

8. A process of making the pharmaceutical composition of claim 1, comprising obtaining N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, N-methylglucamine, and a pharmaceutically acceptable carrier, and granulating the N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, N-methylglucamine, and a pharmaceutically acceptable carrier by a wet granulation process.

9. A sealed package comprising the pharmaceutical composition of claim 1.

10. The sealed package of claim 9, further comprising a desiccant.

11. The sealed package of claim 9, wherein the desiccant is silica gel.

12. The sealed package of claim 9, which after storage at 40°

C. and at a relative humidity of 75% for 3 months contains less than 3% of a degradant of sodium stearyl fumarate.

13. The sealed package of claim 9, wherein the sealed package is a blister pack in which the maximum moisture permeability of the blister pack is no more than 0.005 mg/day.

14. The sealed package of claim 9, wherein the sealed package is a bottle.

15. The sealed package of claim 14, wherein the bottle is closed with a heat induction liner.

16. The sealed package of claim 9, wherein the pharmaceutically acceptable carrier is an alkaline agent.

17. The sealed package of claim 16, further comprising a lubricant.

18. The sealed package of claim 17, wherein the lubricant is sodium stearyl fumarate.

19. The sealed package of claim 18, which after exposure of the sealed package to a temperature of 40°

C. and a relative humidity of 75% for 3 months contains less than 3% of a degradant of sodium stearyl fumarate.

20. The sealed package of claim 19, which after exposure of the sealed package to a temperature of 40°

C. and a relative humidity of 75% for 3 months contains less than 1% of a degradant of sodium stearyl fumarate.

21. The sealed package of claim 9, wherein the sealed package comprises an HDPE bottle.

22. The sealed package of claim 9, wherein the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide is N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide sodium.

23. The sealed package of claim 22, wherein the pharmaceutical composition further comprises sodium stearyl fumarate.

24. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide is a lithium salt, a sodium salt or a calcium salt.

25. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide is N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide sodium.

26. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide is N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide sodium.

27. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide is N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide sodium.

28. The pharmaceutical composition of claim 24 in solid form.

29. The pharmaceutical composition of claim 27 in solid form.

30. The pharmaceutical composition of claim 1, comprising a pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, mannitol and N-methylglucamine.

31. The pharmaceutical composition of claim 30, comprising, by total weight of the pharmaceutical composition, 0.2% of the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, 95.6% mannitol, and 3.2% N-methylglucamine.

32. The pharmaceutical composition of claim 30, wherein the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoguinoline-3-carboxamide is N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoguinoline-3-carboxamide sodium.

33. The pharmaceutical composition of claim 31, wherein the pharmaceutically acceptable salt of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide is N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoguinoline-3-carboxamide sodium.

34. The pharmaceutical composition of claim 32 in solid form.

35. The pharmaceutical composition of claim 33 in solid form.

36. A sealed package comprising the pharmaceutical composition of claim 34.

37. A sealed package comprising the pharmaceutical composition of claim 35.