Liquid Formulations of Bendamustine

Abstract

Stable liquid formulations of bendamustine, and pharmaceutically acceptable salts thereof, and polar aprotic solvents, are described.

1 . A stable, non-aqueous, liquid formulation comprising from about 5 mg/mL to about 200 mg/mL of bendamustine or a pharmaceutically acceptable salt thereof, and up to about 90% of a mixture of polyethylene glycol and propylene glycol wherein said formulation contains not less than 95% of the amount of bendamustine present prior to exposure to storage conditions that include a temperature of about 5° C. and a time period of about 180 days. 
     
     
         2 . The liquid formulation of  claim 1 , further comprising an antioxidant. 
     
     
         3 . The liquid formulation of  claim 1 , wherein said formulation comprises 1.5% or less of PG-1, PG-2, or a combination thereof 
       
         
           
           
               
               
           
         
         as determined by HPLC analysis, after about 1 year of storage at about 5° C. 
       
     
     
         4 . A method of treating cancer comprising:
 providing the stable, non-aqueous, liquid formulation of  claim 1 ;   diluting the stable, non-aqueous, liquid formulation with a pharmaceutically acceptable injectable diluent to form an injectable pharmaceutical preparation;   administering the injectable pharmaceutical preparation to a patient in need of treatment for cancer.   
     
     
         5 . The method of  claim 4 , wherein the cancer is chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, or breast cancer. 
     
     
         6 . The method of  claim 4 , wherein the cancer is chronic lymphocytic leukemia or non-Hodgkin's lymphoma. 
     
     
         7 . An anhydrous, sterile, liquid, pharmaceutical formulation of bendamustine, or a pharmaceutically acceptable salt thereof, comprising propylene glycol and 1.5% or less of PG-1, PG-2, or a combination thereof 
       
         
           
           
               
               
           
         
         as determined by HPLC analysis, wherein the analysis is performed after about 1 year of storage. 
       
     
     
         8 . The anhydrous, liquid, pharmaceutical formulation of  claim 7 , wherein the analysis is performed after about 1 year of storage at about 5° C. 
     
     
         9 . The anhydrous, liquid, pharmaceutical formulation of  claim 7 , comprising at least about 90% of the amount of bendamustine present prior to storage of about 1 year, as determined by HPLC analysis. 
     
     
         10 . The anhydrous, liquid, pharmaceutical formulation of  claim 9 , wherein the storage is at about 5° C. 
     
     
         11 . The anhydrous, liquid, pharmaceutical formulation of  claim 7 , comprising at least about 90% of the amount of bendamustine present prior to storage of about 180 days, as determined by HPLC analysis. 
     
     
         12 . The anhydrous, liquid, pharmaceutical formulation of  claim 11 , wherein the storage is at about 5° C. 
     
     
         13 . The anhydrous, liquid, pharmaceutical formulation of  claim 7 , comprising at least about 90% of the amount of bendamustine present prior to storage of about 90 days, as determined by HPLC analysis. 
     
     
         14 . The anhydrous, liquid, pharmaceutical formulation of  claim 13 , wherein the storage is at about 5° C. 
     
     
         15 . The anhydrous, liquid, pharmaceutical formulation of  claim 7 , comprising at least about 90% of the amount of bendamustine present prior to storage of about 30 days, as determined by HPLC analysis. 
     
     
         16 . The anhydrous, liquid, pharmaceutical formulation of  claim 15 , wherein the storage is at about 5° C. 
     
     
         17 . The anhydrous, liquid, pharmaceutical formulation of  claim 7 , comprising bendamustine at a concentration of about 5 mg/mL to about 200 mg/mL. 
     
     
         18 . A method of treating cancer comprising
 providing the anhydrous, liquid, pharmaceutical formulation of  claim 7 ;   diluting the anhydrous, liquid, pharmaceutical formulation with a pharmaceutically acceptable injectable diluent to form an injectable pharmaceutical preparation;   administering the injectable pharmaceutical preparation to a patient in need of treatment for cancer.   
     
     
         19 . The method of  claim 18 , wherein the cancer is chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, or breast cancer. 
     
     
         20 . The method of  claim 18 , wherein the cancer is chronic lymphocytic leukemia or non-Hodgkin's lymphoma.