Stable laquinimod preparations

• US 8,383,645 B2
• Filed: 08/07/2012
• Issued: 02/26/2013
• Est. Priority Date: 06/12/2006
• Status: Active Grant

• Current Assignee: Active Biotech AB
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Patashnik, Shulamit, Licht, Daniella, Gilbert, Adrian
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): KAROL, JODY LYNN
• Application Number:
  US13/568,940
• Publication Number:
  US 20120302600A1
• Time in Patent Office: 203 Days
• Field of Search: None
• 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 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, wherein the amount of N-methylglucamine is such that it reduces the degradation of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof in the composition relative to a corresponding formulation without N-methylglucamine.

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

3. 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.

4. 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.

5. The pharmaceutical composition of claim 1 in solid form.

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

7. The pharmaceutical composition of claim 6, wherein the lubricant is sodium stearyl fumarate.

8. The pharmaceutical composition of claim 7, 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.

9. 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.

10. 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.

11. 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.

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

13. The sealed package of claim 12, further comprising a desiccant.

14. The sealed package of claim 12, wherein the desiccant is silica gel.

15. The sealed package of claim 12, 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.

17. A method of treating a subject afflicted with a form of multiple sclerosis comprising administering to the subject the pharmaceutical composition of claim 1 so as to thereby treat the subject.

18. A method for alleviating a symptom of multiple sclerosis in a subject afflicted with a form of multiple sclerosis comprising administering to the subject the pharmaceutical composition of claim 1 thereby alleviating the symptom of multiple sclerosis in the subject.

19. The pharmaceutical composition of claim 1, wherein the amount of N-methylglucamine is such that it reduces the degradation of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof in the composition to less than 2.5% of the degradation in the corresponding formulation without N-methylglucamine.

20. The pharmaceutical composition of claim 1, wherein the degradation is oxidation-related degradation.

21. The pharmaceutical composition of claim 1, wherein the amount of degradation is calculated by measuring the percent decrease in the amount of sodium laquinimod in the composition.

16. A sealed package containing a pharmaceutical composition comprising N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, wherein the sealed package has a moisture permeability of not more than 15 mg/day per liter.