Stable laquinimod preparations

• US 8,178,127 B2
• Filed: 12/19/2008
• Issued: 05/15/2012
• 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): Barham, Bethany
• Application Number:
  US12/317,104
• Publication Number:
  US 20090162432A1
• Time in Patent Office: 1,243 Days
• Field of Search: None
• US Class Current: 424/465
• 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. A process for validating a batch of a pharmaceutical product containing N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a salt thereof and a pharmaceutically acceptable carrier for distribution comprising

a) subjecting a sample of the batch to stability testing;

b) determining the total amount of an oxidation decomposition product in the sample of the batch after stability testing; and

c) validating the batch for distribution only if the sample of the batch after stability testing contains not more than a total of 0.5% w/w relative to N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide of the oxidation decomposition products of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, wherein the oxidation decomposition product is 2-Chloro-6-(1-ethyl-N-methyl-2-oxoindoline-3-carboxamido) benzoic acid, 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide or 1H,3H-spiro[5-chloro-1-methylquinoline-2,4-dione-3,3′

-[1]ethylindolin-[2]-one], or a mixture thereof.

2. The process of claim 1, wherein in the step (b), the amount is determined using a measurement of mass, ultraviolet absorption, refractive index, ionization or voltammogram.

3. The process 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.

4. The process of claim 3, 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.

5. The process of claim 3, 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.

11. The process of claim 5, wherein the oxidation decomposition product is 2-Chloro-6-(1-ethyl-N-methyl-2-oxoindoline-3-carboxamido) benzoic acid.

12. The process 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.

13. The process of claim 5, wherein the oxidation decomposition product is 1H,3H-spiro[5-chloro-1-methylquinoline-2,4-dione-3,3′

-[1]ethylindolin-[2]-one].

6. A process for validating a batch of a pharmaceutical product containing N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a salt thereof and a pharmaceutically acceptable carrier for distribution comprising

a) subjecting a sample of the batch to stability testing;

b) determining the total amount of an oxidation decomposition product in the sample of the batch after stability testing; and

c) validating the batch for distribution only if the sample of the batch after stability testing contains not more than a total of 0.1% w/w relative to N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide of the oxidation decomposition products of N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, wherein the oxidation decomposition product is 2-Chloro-6-(1-ethyl-N-methyl-2-oxoindoline-3-carboxamido) benzoic acid, 5-Chloro-N-ethyl-3-hydroxy-1-methyl-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydro-quinoline-3-carboxamide or 1H,3H-spiro[5-chloro-1-methylquinoline-2,4-dione-3,3′

-[1]ethylindolin-[2]-one], or a mixture thereof.

7. The process of claim 6, wherein in the step (b), the amount is determined using a measurement of mass, ultraviolet absorption, refractive index, ionization or voltammogram.

8. The process of claim 6, 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.

9. The process of claim 8, 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.

10. The process of claim 8, 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.

14. The process of claim 10, wherein the oxidation decomposition product is 2-Chloro-6-(1-ethyl-N-methyl-2-oxoindoline-3-carboxamido) benzoic acid.

15. The process of claim 10, 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.

16. The process of claim 10, wherein the oxidation decomposition product is 1H,3H-spiro[5-chloro-1-methylquinoline-2,4-dione-3,3′

-[1]ethylindolin-[2]-one].