Liquid pharmaceutical composition comprising pemetrexed

Abstract

The present invention relates to a liquid pharmaceutical composition suitable for parenteral administration comprising: a) pemetrexed diacid; b) at least one organic amine; c) at least one antioxidant; d) 10-200 mg/ml of propylene glycol; and e) one or more parenteral solvents, wherein the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1 The invention further relates to the use of said liquid pharmaceutical composition as medicament in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.

1 . A liquid pharmaceutical composition suitable for parenteral administration comprising:
 a. pemetrexed diacid;   b. at least one organic amine;   c. at least one antioxidant;   d. 10-200 mg/ml of propylene glycol, and   e. one or more parenteral solvents,   wherein the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1.   
     
     
         2 . The composition according to  claim 1 , wherein the antioxidant is a monothiol compound. 
     
     
         3 . The composition according to  claim 1 , wherein the antioxidant is L-cysteine. 
     
     
         4 . The composition according to  claim 3 , wherein L-cysteine is present in a concentration of 0.5-4 mg/ml. 
     
     
         5 . The composition according to  claim 1 , wherein the concentration of propylene glycol is in the range of 20-50 mg/ml. 
     
     
         6 . The composition according to  claim 1 , wherein the parenteralsolvent is selected from: ethanol, isopropanol, dimethylsulfoxide, dimethylformamide, dimethylacetamide, glycerol and water (for injection) or mixtures thereof. 
     
     
         7 . The composition according to  claim 1 , wherein the parenteral solvent is water (for injection). 
     
     
         8 . The composition according to  claim 1 , wherein the organic amine is arginine. 
     
     
         9 . The composition according to  claim 1 , wherein arginine is present in at least 2.5 equivalents (mole/mole) with respect to pemetrexed diacid. 
     
     
         10 . The composition according to  claim 1  comprising optionally at least one chelating agent. 
     
     
         11 . The composition according to  claim 10 , wherein the chelating agent is citric acid. 
     
     
         12 . The composition according to  claim 1 , wherein the pemetrexed diacid concentration is 25-50 mg/ml. 
     
     
         13 . A process for preparing the composition according to  claim 1  comprising dissolving the organic amine(s), pemetrexed diacid, the antioxidant(s), optionally the chelating agent(s) and propylene glycol in the solvent(s), making up the volume using water (for injection), filtrating and filling the glass vials. 
     
     
         14 . The process according to  claim 13  comprising the step of terminal sterilization. 
     
     
         15 . The composition according to  claim 1  for use in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.