Pharmaceutical formulation of a platinum derivative

Abstract

The present invention relates to novel stable solution formulations comprising oxaliplatin, an effective stabilizing amount of malonic acid and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A method for manufacturing such formulations ready for administration and their use in the antitumor therapy are also within the scope of the invention.

1 . Stable oxaliplatin solution formulation comprising a formulation selected from the group consisting of: 
 (a) oxaliplatin, an effective stabilizing amount of malonic acid, and a pharmaceutically acceptable carrier;    (b) oxaliplatin, an effective stabilizing amount of a pharmaceutically acceptable salt of malonic acid, and a pharmaceutically acceptable carrier; and    (c) oxaliplatin, an effective stabilizing amount of malonic acid and a pharmaceutically acceptable salt of malonic acid, and a pharmaceutically acceptable carrier.    
     
     
         2 . Stable oxaliplatin solution formulation comprising oxaliplatin, an effective stabilizing amount of malonic acid and a pharmaceutically acceptable carrier.  
     
     
         3 . A formulation as claimed in  claim 1 , wherein the pharmaceutically acceptable salt of malonic acid is an alkali metal salt.  
     
     
         4 . A formulation as claimed in  claim 3  wherein the alkali metal salt of malonic acid is sodium malonate.  
     
     
         5 . A formulation according to  claim 1 , wherein the carrier is water.  
     
     
         6 . A formulation according to  claim 2  wherein the carrier is water.  
     
     
         7 . A formulation according to  claim 3  wherein the carrier is water.  
     
     
         8 . A formulation according to  claim 4 , wherein the carrier is water.  
     
     
         9 . A formulation as claimed in  claim 1 , wherein the effective stabilizing amount of malonic acid or a pharmaceutically acceptable salt thereof or both ranges from a molar concentration of 5.10 −7  M to 1 M.  
     
     
         10 . A formulation as claimed in  claim 9 , wherein the effective stabilizing amount of malonic acid or a pharmaceutically acceptable salt thereof or both ranges from a molar concentration of 5.10 −5  M to 5.10 −3  M.  
     
     
         11 . A formulation as claimed in  claim 2 , wherein the effective stabilizing amount of malonic acid ranges from a molar concentration of 5.10 −7  M to 1 M.  
     
     
         12 . A formulation as claimed in  claim 11 , wherein the effective stabilizing amount of malonic acid ranges from a molar concentration of 5.10 −5  M to 5.10 −3  M.  
     
     
         13 . A formulation as claimed in  claim 12 , wherein the effective stabilizing amount of malonic acid is 4.10 −4  M.  
     
     
         14 . A formulation as claimed in  claim 1 , wherein the pH of the solution ranges from 3 to 9.  
     
     
         15 . A formulation as claimed in  claim 14 , wherein the pH of the solution ranges from 3 to 7.  
     
     
         16 . A formulation as claimed in  claim 2 , wherein the pH of the solution ranges from 3 to 9.  
     
     
         17 . A formulation as claimed in  claim 16 , wherein the pH of the solution ranges from 3 to 7.  
     
     
         18 . A formulation as claimed in  claim 1 , wherein the amount of oxaliplatin ranges from 0.1 mg/ml to 10 mg/ml.  
     
     
         19 . A formulation as claimed in  claim 18 , wherein the amount of oxaliplatin ranges from 2 mg/ml to 5 mg/ml.  
     
     
         20 . A formulation as claimed in  claim 2 , wherein the amount of oxaliplatin ranges from 0.1 mg/ml to 10 mg/ml.  
     
     
         21 . A formulation as claimed in  claim 20 , wherein the amount of oxaliplatin ranges from 2 mg/ml to 5 mg/ml.  
     
     
         22 . A formulation as claimed in  claim 1 , for use in-the treatment of a cancer.  
     
     
         23 . A method for treating a cancer, which comprises administering a formulation as claimed in  claim 1  to a patient in need thereof.  
     
     
         24 . A method for stabilizing a formulation of oxaliplatin, which comprises adding an effective stabilizing amount of malonic acid or a pharmaceutically acceptable salt thereof or both to an aqueous carrier and then dissolving oxaliplatin in said carrier.  
     
     
         25 . A formulation as claimed in  claim 1 , wherein oxaliplatin is cis-oxalato(trans-l-1,2-diaminocyclohexane)platinum(II).  
     
     
         26 . A formulation as claimed in  claim 1 , wherein oxaliplatin is cis-oxalato(trans-l-1,2-diaminocyclohexane)platinum(II) having high optical purity.  
     
     
         27 . A formulation as claimed in  claim 26 , wherein the melting point of cis-oxalato(trans-l-1,2-diaminocyclohexane)platinum(II) is between 198° C. and 292° C.  
     
     
         28 . A formulation as claimed in  claim 26 , wherein the cis-oxalato(trans-l-1,2-diaminocyclohexane) platinum(II) possesses optical purity equal to or higher than 99.94%.  
     
     
         29 . A formulation as claimed in  claim 28 , wherein the melting point of the cis-oxalato(trans-l-1,2-diaminocyclohexane)platinum(II) is between 198.3° C. and 199.7° C.