N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide, preparation and uses thereof

Patent metadata

Field	Value
Publication number	US-9284276-B2
Application number	US-201313768919-A
Country	US
Kind code	B2
Filing date	Feb 15, 2013
Priority date	Feb 16, 2012
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

The subject invention provides a pharmaceutical composition containing laquinimod or a pharmaceutically acceptable salt thereof, and a compound of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide or a salt thereof.

First claim

What is claimed is:

1. A pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof, and 1) N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide or a salt thereof, wherein N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide is present in the composition in an amount greater than about 0.02% and less than about 0.50%, by weight, relative to the amount of laquinimod, based on a determination by an HPLC method; or 2) at least one pharmaceutically acceptable carrier, and a light-resistant coating wherein the coating is resistant to light with wavelength in the range of 310-400 nm.

2. The pharmaceutical composition of claim 1 , wherein the amount of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide in the composition is greater than about 0.02% and less than about 0.10% by weight relative to the amount of laquinimod.

3. The pharmaceutical composition of claim 1 , wherein the amount of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide in the composition is greater than about 0.02% and less than about 0.05% by weight relative to the amount of laquinimod.

4. A process for preparing a pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof, comprising: admixing laquinimod or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier in a low-light environment to form the pharmaceutical composition, wherein the pharmaceutical composition further comprises N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide in an amount of less than 0.5% by weight relative to the amount of laquinimod.

5. A process for preparing a validated pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, comprising:
a) obtaining a batch of laquinimod or a pharmaceutically acceptable salt thereof;
b) determining the amount of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide in the batch using a suitable apparatus; and
c) preparing the pharmaceutical composition from the batch only if the batch is determined to have less than about 0.50% N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide by weight relative to the amount of laquinimod.

6. The process of claim 5 , wherein in step c) the pharmaceutical composition is prepared from the batch only if the batch is determined to have less than about 0.02% N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide by weight relative to the amount of laquinimod.

7. A process for preparing a packaged pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof comprising:
a) obtaining a pharmaceutical composition of laquinimod or a pharmaceutically acceptable salt thereof;
b) analyzing the pharmaceutical composition for the presence of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide; and
c) packaging the pharmaceutical composition in a light-resistant packaging only if the content of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide is less than about 0.50% by weight relative to the amount of laquinimod.

8. The process of claim 7 , wherein in step c) packaging the pharmaceutical composition in a light-resistant packaging only if the content of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide is less than about 0.02% by weight relative to the amount of laquinimod.

9. A process of distributing a validated batch of a pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, comprising:
a) obtaining a batch of the pharmaceutical composition;
b) performing stability testing with a sample of the batch;
c) determining the total amount of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide in the sample of the batch by a suitable apparatus after stability testing;
d) validating the batch for distribution only if the sample of the batch after stability testing is determined to have less than about 0.50% by weight of N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide relative to the amount of laquinimod; and
e) distributing the validated batch.

10. The process of claim 9 , wherein in step d) the batch is validated only if the sample of the batch after stability testing is determined to have N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide present in an amount of less than about 0.02% by weight relative to the amount of laquinimod.

11. The pharmaceutical composition of claim 1 , comprising the pharmaceutically acceptable salt of laquinimod which is a sodium salt.

12. The pharmaceutical composition of claim 1 , further comprising at least one pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 , wherein the at least one pharmaceutically acceptable carrier is magnesium stearate.

14. The pharmaceutical composition of claim 1 , in the form of a capsule or a tablet.

15. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is a tablet coated with a light-resistant coating, and/or is in light-resistant packaging.

16. The pharmaceutical composition of claim 15 , wherein 1) the light-resistant coating is a coating comprising titanium dioxide, and/or 2) the light-resistant packaging is an opaque blister pack or an opaque high density polyethylene (HPDE) container.

17. The pharmaceutical composition of claim 1 , which is a solid pharmaceutical composition.

Assignees

• Ioffe Vladimir
• Ulanenko Konstantin
• Laxer Avital
• Safadi Muhammad
• Licht Danit
• Lovinger Ioana
• Fristedt Ulf Tomas
• Teva Pharma

Inventors

• Ioffe Vladimir
• Ulanenko Konstantin
• Laxer Avital
• Safadi Muhammad
• Licht Danit
• Lovinger Ioana
• Fristedt Ulf Tomas

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

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

• A61P29/00

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

• A61P25/28

  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 title

• A61K9/48

  Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)} · CPC title