Lyophilized pharmaceutical compositions

Abstract

The invention provides a method of preparing a lyophilized pharmaceutical composition containing a compound described herein or a pharmaceutically-acceptable salt thereof. The process comprises dissolving the compound in a solvent comprising dimethylsulfoxide and optionally one or more co-solvents to form a solution, and then removing the solvent and any co-solvents by a freeze-drying process. Also provided by the invention are lyophilized pharmaceutical compositions and their use in medicine and in particular in the treatment of cancer.

1 - 14 . (canceled) 
     
     
         15 . A method of preparing a pharmaceutical composition, the method comprising:
 a) dissolving a compound of formula (1):   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof, in a solvent comprising dimethyl sulfoxide (DMSO) to form a solution;
 b) removing the solvent by a freeze-drying process to give a lyophilized product; and 
 c) reconstituting the lyophilized product in a substantially anhydrous solvent to give the pharmaceutical composition, wherein a reconstitution time of the reconstituting of the lyophilization product is less than about 20 minutes. 
 
     
     
         16 . The method of  claim 15 , wherein the reconstitution time of the reconstituting of the lyophilization product is less than 15 minutes. 
     
     
         17 . The method of  claim 15 , wherein the reconstitution time of the reconstituting of the lyophilization product is less than 10 minutes. 
     
     
         18 . The method of  claim 15 , wherein the substantially anhydrous solvent comprises 45% to 85% (v/v) propylene glycol, 5% to 45% (v/v) glycerin, and 0% to 30% (v/v) ethanol. 
     
     
         19 . The method of  claim 15 , wherein the substantially anhydrous solvent comprises about 45% to about 85% (v/v) propylene glycol, about 5% to about 45% (v/v) glycerin, and about 0% to about 30% (v/v) ethanol. 
     
     
         20 . The method of  claim 15 , wherein the substantially anhydrous solvent comprises about 65% (v/v) propylene glycol, about 25% (v/v) glycerin, and about 10% (v/v) ethanol. 
     
     
         21 . The method of  claim 15 , wherein the compound of formula (1) is in the form of a sodium salt. 
     
     
         22 . The method of  claim 15 , wherein in an amount of the lyophilized pharmaceutical composition obtained from 1 gram of the solution, there is a residual DMSO content of no greater than about 20 mg. 
     
     
         23 . The method of  claim 15 , wherein any residual DMSO present in the lyophilized pharmaceutical composition is in an amount corresponding to no more than 35 mg per 100 mg equivalent of a free base of the compound of formula (1). 
     
     
         24 . The method of  claim 15 , the method further comprising packing the lyophilized product in a sealed pharmaceutical container. 
     
     
         25 . The method of  claim 15 , wherein the reconstituting occurs without mechanized stirring. 
     
     
         26 . The method of  claim 15 , wherein the pharmaceutical composition is an injectable liquid composition. 
     
     
         27 . The method of  claim 15 , wherein the lyophilized product has a purity of at least 80%. 
     
     
         28 . The method of  claim 15 , wherein the lyophilized product has a purity of at least 85%. 
     
     
         29 . The method of  claim 15 , wherein the lyophilized product has a purity of at least 90%. 
     
     
         30 . The method of  claim 27 , wherein the purity is as measured by high performance liquid chromatography (HPLC).