Formulations of bendamustine

Abstract

Long term storage stable bendamustine-containing compositions are disclosed. The compositions can include bendamustine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable fluid which can include in some embodiments PEG, PG or mixtures thereof and an antioxidant or chloride ion source. The bendamustine-containing compositions have less than about 5% total impurities, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 15 months of storage at a temperature of from about 5° C. to about 25° C.

We claim: 
     
         1 . A liquid bendamustine-containing composition comprising bendamustine, or a pharmaceutically acceptable salt thereof, wherein the bendamustine concentration in the composition is from about 10 mg/mL to about 100 mg/mL;
 polyethylene glycol; and   a stabilizing amount of an antioxidant;   
       the composition having less than about 5% peak area response of total impurities resulting from the degradation of the bendamustine, as determined by HPLC as a wavelength of 223 nm after at least 15 months at a temperature of from about 5° C. to about 25° C. 
     
     
         2 . The liquid bendamustine-containing composition of  claim 1 , wherein the antioxidant is lipoic acid, thioglycerol, propyl gallate, methionine, cysteine, a metabisulfite, sodium formaldehyde sulfoxylate, a phenol-containing aromatic compound, a phenol-containing aliphatic compound, dihydrolipoic acid, or a mixture thereof. 
     
     
         3 . The liquid bendamustine-containing composition of  claim 1 , having less than about 5% peak area response of total impurities resulting from the degradation of the bendamustine, as determined by HPLC as a wavelength of 223 nm after at least 15 months at a temperature of about 5° C. 
     
     
         4 . The liquid bendamustine-containing composition of  claim 1 , having less than about 5% peak area response of total impurities resulting from the degradation of the bendamustine, as determined by HPLC as a wavelength of 223 nm after at least 15 months at a temperature of about 25° C. 
     
     
         5 . The liquid bendamustine-containing composition of  claim 1 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL. 
     
     
         6 . The liquid bendamustine-containing composition of  claim 1 , wherein the bendamustine concentration is about 25 mg/mL. 
     
     
         7 . The liquid bendamustine-containing composition of  claim 1 , comprising bendamustine hydrochloride. 
     
     
         8 . A method of treating cancer in a mammal, comprising administering an effective amount of the liquid bendamustine-containing composition of  claim 1  to the mammal. 
     
     
         9 . The method of  claim 8 , wherein the cancer is leukemia. 
     
     
         10 . The method of  claim 8 , wherein the cancer is Hodgkin's disease. 
     
     
         11 . The method of  claim 8 , wherein the antioxidant is lipoic acid, thioglycerol, propyl gallate, methionine, cysteine, a metabisulfite, sodium formaldehyde sulfoxylate, a phenol-containing aromatic compound, a phenol-containing aliphatic compound, dihydrolipoic acid, or a mixture thereof. 
     
     
         12 . The method of  claim 8 , wherein the liquid bendamustine-containing composition has less than about 5% peak area response of total impurities resulting from the degradation of the bendamustine, as determined by HPLC as a wavelength of 223 nm after at least 15 months at a temperature of about 5° C. 
     
     
         13 . The method of  claim 8 , wherein the liquid bendamustine-containing composition has less than about 5% peak area response of total impurities resulting from the degradation of the bendamustine, as determined by HPLC as a wavelength of 223 nm after at least 15 months at a temperature of about 25° C. 
     
     
         14 . The method of  claim 8 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL. 
     
     
         15 . The method of  claim 8 , wherein the bendamustine concentration is about 25 mg/mL. 
     
     
         16 . The method of  claim 8 , wherein the liquid bendamustine-containing composition comprises bendamustine hydrochloride.