Pemetrexed formulations

Abstract

The present invention is directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable after dilution for at least about 48 hours when stored at 2° C. to 8° C. The present invention is also directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable for at least about 24 months when stored at 2° C. to 8° C.

1 - 30 . (canceled) 
     
     
         31 . A liquid pharmaceutical composition comprising:
 pemetrexed at a concentration of about 20 mg/mL to about 30 mg/mL;   at least about 24 mg/mL of tromethamine;   citric acid;   methionine; and   water,   wherein the composition comprises at least 90% of said pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 12 months.   
     
     
         32 . The liquid pharmaceutical composition of  claim 31 , comprising pemetrexed at a concentration of about 25 mg/mL. 
     
     
         33 . The liquid pharmaceutical composition of  claim 31 , wherein the pemetrexed is pemetrexed diacid, pemetrexed monoacid, a pharmaceutically acceptable salt of pemetrexed, or a combination thereof. 
     
     
         34 . The liquid pharmaceutical composition of  claim 31 , wherein the pemetrexed is pemetrexed diacid. 
     
     
         35 . The liquid pharmaceutical composition of  claim 31 , wherein the concentration of the citric acid is about 13 mg/mL. 
     
     
         36 . The liquid pharmaceutical composition of  claim 31 , wherein the pH of the composition is from about 7.4 to about 7.6. 
     
     
         37 . The liquid pharmaceutical composition of  claim 31 , wherein the pH of the composition is 7.4. 
     
     
         38 . The liquid pharmaceutical composition of  claim 31 , wherein the pH of the composition is 7.5. 
     
     
         39 . The liquid pharmaceutical composition of  claim 31 , wherein the pH of the composition is 7.6. 
     
     
         40 . The liquid pharmaceutical composition of  claim 31 , wherein the composition is stored in a vial with a headspace oxygen concentration of about 20 v/v %. 
     
     
         41 . The liquid pharmaceutical composition of  claim 31 , wherein the composition comprises at least 90% of said pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 18 months. 
     
     
         42 . The liquid pharmaceutical composition of  claim 31 , wherein the composition comprises no more than about 8% w/w total impurities after storing the composition at a temperature of 2° C. to 8° C. for at least 12 months. 
     
     
         43 . A liquid pharmaceutical composition consisting essentially of:
 pemetrexed at a concentration of about 20 mg/mL to about 30 mg/mL;   at least about 24 mg/mL of tromethamine;   citric acid;   methionine; and   water,   wherein the composition comprises at least 90% of said pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 12 months.   
     
     
         44 . A liquid pharmaceutical composition consisting of:
 pemetrexed at a concentration of about 20 mg/mL to about 30 mg/mL;   at least about 24 mg/mL of tromethamine;   citric acid;   methionine; and   water,   wherein the composition comprises at least 90% of said pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 12 months.   
     
     
         45 . A method of treating pleural mesothelioma or non-squamous, non-small cell lung cancer in a patient in need thereof comprising:
 providing the liquid pharmaceutical composition of  claim 31 ;   diluting the liquid pharmaceutical composition with a pharmaceutically acceptable diluent to form a diluted liquid composition having a diluted pemetrexed concentration; and   intravenously administering the diluted liquid composition to the patient.   
     
     
         46 . The method of  claim 45 , wherein the pharmaceutically acceptable diluent is selected from the group consisting of saline, water for injection, 5% dextrose in water, Ringer's Injection, and Lactated Ringer's Injection. 
     
     
         47 . The method of  claim 45 , wherein the diluent is 5% dextrose in water. 
     
     
         48 . The method of  claim 45 , wherein the diluted liquid composition comprises at least 90% of said diluted pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 12 hours. 
     
     
         49 . The method of  claim 45 , wherein the diluted liquid composition comprises at least 90% of said diluted pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 24 hours. 
     
     
         50 . The method of  claim 45 , wherein the diluted liquid composition comprises at least 90% of said diluted pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 48 hours.