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 .- 28 . (canceled) 
     
     
         29 . A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a T-cell activating agent and a therapeutically effective amount of a pharmaceutical composition prepared by a process, wherein the process comprises:
 (a) dissolving a compound of formula (1):   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically-acceptable salt thereof, in a solvent comprising dimethylsulfoxide (DMSO) to form a solution, wherein the solvent is then removed by a freeze-drying process to give the lyophilized pharmaceutical product, wherein the freeze-drying process comprises: 
           (i) a first freezing stage in which the solution is frozen by reducing the temperature thereof to a temperature of no greater than about −20° C.; 
           (ii) a first warming stage in which the temperature of the frozen solution is raised to a temperature in the range from about −15° C. to about 5° C., wherein the temperature in the range from about −15° C. to about 5° C. keeps the solution frozen; 
           (iii) a second freezing stage in which the temperature of the solution is lowered to a temperature of no greater than about −20° C.; 
           (iv) a primary drying stage, wherein the primary drying stage comprises a sublimation step in which the DMSO is removed by sublimation from the solution in its frozen state under reduced pressure to give a partially dried product, wherein the reduced pressure in the primary drying stage is from about 5 μBar to about 40 μBar; and 
           (v) a secondary drying stage in which the DMSO is removed by evaporation from the partially dried product in a non-frozen state under reduced pressure to give the lyophilized pharmaceutical product, and 
         
         (b) reconstituting the lyophilized pharmaceutical product in a substantially anhydrous solvent to give the pharmaceutical composition. 
       
     
     
         30 . The method of  claim 29 , wherein the substantially anhydrous solvent comprises about 65% (v/v) propylene glycol, about 25% (v/v) glycerin, and about 10% (v/v) ethanol. 
     
     
         31 . The method of  claim 29 , wherein the reconstituting occurs without mechanized stirring. 
     
     
         32 . The method of  claim 29 , wherein the pharmaceutical composition is an injectable liquid composition. 
     
     
         33 . The method of  claim 29 , wherein the compound of formula (1) is in the form of a sodium salt. 
     
     
         34 . The method of  claim 29 , wherein the T-cell activating agent is an anti-CTLA4 antibody. 
     
     
         35 . The method of  claim 29 , wherein the condition is a leukemia. 
     
     
         36 . The method of  claim 35 , wherein the leukemia is acute myelogenous leukemia, acute promyelocyte leukemia, acute lymphoblastic leukemia, or chronic myelogenous leukemia. 
     
     
         37 . 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 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. 
 
     
     
         38 . The method of  claim 37 , wherein the compound of formula (1) is in the form of a sodium salt. 
     
     
         39 . The method of  claim 37 , wherein the substantially anhydrous solvent comprises about 65% (v/v) propylene glycol, about 25% (v/v) glycerin, and about 10% (v/v) ethanol. 
     
     
         40 . The method of  claim 37 , wherein any residual DMSO present in the lyophilized product 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). 
     
     
         41 . The method of  claim 37 , the method further comprising packing the lyophilized product in a sealed pharmaceutical container. 
     
     
         42 . The method of  claim 37 , wherein the reconstituting occurs without mechanized stirring. 
     
     
         43 . The method of  claim 37 , wherein the pharmaceutical composition is an injectable liquid composition.