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.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 a) pemetrexed and   b) a non-aqueous solvent present at less than 0.30 mL/mL;   
       wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2° C. to 8° C. for at least 12 hours. 
     
     
         2 . The pharmaceutical composition of  claim 1  wherein the composition retains at least 90% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:
 a) at least 24 hours, and 
 b) at least 48 hours. 
 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein the composition retains at least 95% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:
 a) at least 12 hours, 
 b) at least 24 hours, and 
 c) at least 48 hours. 
 
     
     
         4 . The pharmaceutical composition of  claim 1  wherein the composition retains at least 98% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:
 a) at least 12 hours, 
 b) at least 24 hours, and 
 c) at least 48 hours. 
 
     
     
         5 . The pharmaceutical composition of  claim 1  wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer's Injection, and Lactated Ringer's Injection. 
     
     
         6 . The pharmaceutical composition of  claim 1  comprising 10 to 50 mg/mL pemetrexed. The pharmaceutical composition of  claim 6  comprising 25 mg/mL pemetrexed. 
     
     
         8 . 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. 
     
     
         9 . The pharmaceutical formulation of  claim 8  wherein the non-aqueous solvent is propylene glycol. 
     
     
         10 . The pharmaceutical formulation of  claim 9  wherein propylene glycol is present at 250 μL/mL. 
     
     
         11 . The pharmaceutical composition of  claim 1  comprising at least 0.50mL/mL water. 
     
     
         12 . The pharmaceutical composition of  claim 1  wherein the pemetrexed is in the form of pemetrexed diacid. 
     
     
         13 . The pharmaceutical composition of  claim 1  wherein the pemetrexed is in the form of pemetrexed disodium. 
     
     
         14 . The pharmaceutical composition of  claim 1  substantially free of an anti-oxidant. 
     
     
         15 . A pharmaceutical composition comprising
 a) 25 mg/mL pemetrexed, and   b) propylene glycol at 250 μL/mL   c) water   
       wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2° C. to 8° C. for at least 24 hours. 
     
     
         16 . The pharmaceutical composition of  claim 15  wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2° C. to 8° C. for at least 48 hours. 
     
     
         17 . A pharmaceutical composition comprising:
 a) pemetrexed at an initial concentration of 10 to 50 mg/mL and   b) a non-aqueous solvent present at less than 0.30 mL/mL,   
       wherein 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. 
     
     
         18 . The pharmaceutical composition of  claim 17  wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage for a period selected from:
 a) at least 18 months, and 
 b) at least 24 months. 
 
     
     
         19 . The pharmaceutical composition of  claim 17  wherein the composition comprises at least 95% of the initial pemetrexed concentration after storage for a period selected from:
 a) at least 12 months, 
 b) at least 18 months, and 
 c) at least 24 months. 
 
     
     
         20 . The pharmaceutical composition of  claim 17  wherein the composition comprises at least 98% of the initial pemetrexed concentration after storage for a period selected from:
 a) at least 12 months, 
 b) at least 18 months, and 
 c) at least 24 months. 
 
     
     
         21 . The pharmaceutical composition of  claim 17  having an initial pemetrexed concentration of 25 mg/mL. 
     
     
         22 . The pharmaceutical formulation of  claim 17  wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof. 
     
     
         23 . The pharmaceutical formulation of  claim 22  wherein the non-aqueous solvent is propylene glycol. 
     
     
         24 . The pharmaceutical formulation of  claim 23  wherein propylene glycol is present at 250 μL/mL. 
     
     
         25 . The pharmaceutical composition of  claim 17  comprising at least 0.50 mL/mL water. 
     
     
         26 . The pharmaceutical composition of  claim 17  wherein the pemetrexed is in the form of pemetrexed diacid. 
     
     
         27 . The pharmaceutical composition of  claim 17  wherein the pemetrexed is in the form of pemetrexed disodium. 
     
     
         28 . The pharmaceutical composition of  claim 17  substantially free of an anti-oxidant. 
     
     
         29 . A pharmaceutical composition comprising
 a) an initial pemetrexed concentration of 25 mg/mL,   b) propylene glycol at 250 μL/mL, and   c) water;   
       wherein 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. 
     
     
         30 . The pharmaceutical composition of  claim 29  wherein 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 24 months.