Stable laquinimod preparations

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.

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, a lubricant and a pharmaceutically acceptable carrier, wherein the lubricant is magnesium stearate or sodium stearyl fumarate and the weight ratio of the lubricant to the N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof is between 2.0 to 1 and 5.5 to 1. 
     
     
         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 - 9 . (canceled) 
     
     
         10 . 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. 
     
     
         11 . (canceled) 
     
     
         12 . 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% H 2 O 2  solution for 40 minutes. 
     
     
         13 . 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. 
     
     
         14 . A sealed package comprising the pharmaceutical composition of  claim 1 . 
     
     
         15 . The sealed package of  claim 14 , further comprising a desiccant. 
     
     
         16 . The sealed package of  claim 14 , wherein the desiccant is silica gel. 
     
     
         17 . The sealed package of  claim 14 , 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. 
     
     
         18 . 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. 
     
     
         19 - 29 . (canceled) 
     
     
         30 . 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. 
     
     
         31 . 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. 
     
     
         32 - 33 . (canceled) 
     
     
         34 . The pharmaceutical composition of  claim 1 , wherein the weight ratio of the lubricant to the N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof is between 4 to 1 and 6 to 1. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the weight ratio of the lubricant to the N-ethyl-N-phenyl-1,2,-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof is between 4.5 to 1 and 5.5 to 1.