Stable laquinimod preparations

• US 9,340,307 B2
• Filed: 09/20/2013
• Issued: 05/17/2016
• Est. Priority Date: 12/20/2007
• Status: Active Grant

• Current Assignee: Active Biotech AB
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Safadi, Muhammad, Licht, Daniella, Lovinger, Ioana, Eyal, Aharon M., Fristedt, Tomas, Jansson, Karl
• Primary Examiner(s): Park, H. Sarah
• Application Number:
  US14/032,425
• Publication Number:
  US 20140024678A1
• Time in Patent Office: 970 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/2004 Excipients; Inactive ingredients
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: B65B 25/00 Packaging other articles presenting special problems bundling B65B27/00
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: Y10T 436/145555 Hetero-N

Abstract

The subject invention provides a pharmaceutical composition comprising N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or the salt thereof; a pharmaceutically acceptable carrier; and not more than 0.5% w/w relative to N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide of 2-Chloro-6-(1-ethyl-N-methyl-2-oxoindoline-3-carboxamido)benzoic acid, 1H,3H-spiro[5-chloro-1-methylquinoline-2,4-dione-3,3′-[1]ethylindolin-[2]-one], or 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide.

Claims

1. An isolated compound having the structure:

2. A composition comprising a compound having the structure:

3. A pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide or a salt thereof, wherein 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide is present in the composition in an amount greater than 0.1% w/w relative to laquinimod.

4. The pharmaceutical composition of claim 3 comprising 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide present in the composition in an amount less than 1.5% w/w relative to laquinimod.

9. The pharmaceutical composition of claim 3 comprising 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide present in the composition in an amount less than 1% w/w relative to laquinimod.

10. The pharmaceutical composition of claim 3 comprising 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide present in the composition in an amount not more than 0.5-% w/w relative to laquinimod.

11. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable salt of laquinimod is a lithium salt, a sodium salt or a calcium salt.

12. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is in solid form.

5. A pharmaceutical composition comprising

a) an amount of laquinimod or a pharmaceutically acceptable salt thereof,

b) an amount of a pharmaceutically acceptable carrier, and

c) an amount of an oxidation decomposition product of laquinimod,

wherein the oxidation decomposition product is 2-Chloro-6-(1-ethyl-N-methyl-2-oxoindoline-3-carboxamido)benzoic acid, 1H,3H-spiro[5-chloro-1-methylquinoline-2,4-dione-3,3′

-[1]ethylindolin-[2]-one], or 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide, a salt thereof or a mixture thereof, and the amount of the oxidation decomposition product present in the composition is not more than 0.5% w/w relative to laquinimod.

6. The pharmaceutical composition of claim 5 wherein the oxidation decomposition product is 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide or a salt thereof.

7. The pharmaceutical composition of claim 5 wherein the amount of oxidation decomposition product present in the composition is not more than 0.1% w/w relative to laquinimod or is undetectable.

8. The pharmaceutical composition of claim 6 wherein the amount of oxidation decomposition product present in the composition is not more than 0.1% w/w relative to laquinimod or is undetectable.

13. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable salt of laquinimod is a lithium salt, a sodium salt or a calcium salt.

14. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in solid form.

15. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is free of 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide.