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 pharmaceutical composition comprising:
 a) pemetrexed;   b) a non-aqueous solvent present at less than 0.30 mL/mL; and   c) at least about 600 μL/mL of water;   wherein the composition is substantially free of an anti-oxidant and comprises no more than about 5% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.   
     
     
         32 . The pharmaceutical composition of claim  1  comprising 10 to 50 mg/mL pemetrexed. 
     
     
         33 . The pharmaceutical composition of claim  6  comprising 25 mg/mL pemetrexed. 
     
     
         34 . The pharmaceutical formulation of claim  1  wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof. 
     
     
         35 . The pharmaceutical formulation of claim  8  wherein the non-aqueous solvent is propylene glycol. 
     
     
         36 . The pharmaceutical formulation of claim  9  wherein propylene glycol is present at 250 μL/mL. 
     
     
         37 . The pharmaceutical composition of claim  1  wherein the pemetrexed is in the form of pemetrexed diacid. 
     
     
         38 . The pharmaceutical composition of claim  1  wherein the pemetrexed is in the form of pemetrexed disodium. 
     
     
         39 . A pharmaceutical composition comprising
 a) 25 mg/mL pemetrexed;   b) propylene glycol at 250 μL/mL; and   c) at least about 600 μL/mL water   wherein the composition is substantially free of an anti-oxidant and comprises no more than about 5% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.   
     
     
         40 . The pharmaceutical formulation of  claim 31  wherein the composition comprises no more than about 4% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen. 
     
     
         41 . The pharmaceutical formulation of  claim 31  wherein the composition comprises no more than about 3.5% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen. 
     
     
         42 . The pharmaceutical formulation of  claim 31  wherein the composition comprises no more than about 3% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen. 
     
     
         43 . The pharmaceutical formulation of  claim 39  wherein the composition comprises no more than about 4% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen. 
     
     
         44 . The pharmaceutical formulation of  claim 39  wherein the composition comprises no more than about 3.5% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen. 
     
     
         45 . The pharmaceutical formulation of  claim 39  wherein the composition comprises no more than about 3% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen. 
     
     
         46 . A pharmaceutical composition comprising:
 a) pemetrexed at an initial concentration of 10 to 50 mg/mL   b) a non-aqueous solvent present at less than 0.30 mL/mL; and   c) at least about 600 μL/mL water   wherein the composition is substantially free of an anti-oxidant and comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 12 months at about 20% head space oxygen.   
     
     
         47 . The pharmaceutical composition of  claim 46  having an initial pemetrexed concentration of 25 mg/mL. 
     
     
         48 . The pharmaceutical formulation of  claim 46  wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol; polyethylene glycol, or combinations thereof. 
     
     
         49 . The pharmaceutical formulation of  claim 48  wherein the non-aqueous solvent is propylene glycol. 
     
     
         50 . The pharmaceutical formulation of  claim 49  wherein propylene glycol is present at 250 μL/mL. 
     
     
         51 . The pharmaceutical composition of  claim 46  wherein the pemetrexed is in the form of pemetrexed di acid. 
     
     
         52 . The pharmaceutical composition of  claim 46  wherein the pemetrexed is in the form of pemetrexed disodium. 
     
     
         53 . A pharmaceutical composition comprising
 a) an initial pemetrexed concentration of 25 mg/mL,   b) propylene glycol at 250 μL/mL, and   c) at least about 600 μL/mL water;   wherein the composition is substantially free of an anti-oxidant and the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 12 months at about 20% head space oxygen.