FORMULATIONS OF BENDAMUSTINE
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.
1 . A method of preparing a liquid bendamustine-containing composition:
combining bendamustine, or a pharmaceutically acceptable salt thereof, polyethylene glycol, and a stabilizing amount of an antioxidant to produce a liquid bendamustine-containing composition comprising a bendamustine concentration of about 25 mg/mL;
wherein the composition has less than about 5% peak response of total impurities resulting from the degradation of the bendamustine after storing the composition for at least 15 months at a temperature of from about 5° C. to about 25° C., as measured by HPLC at a wavelength of 223 nm, the peak area response of total impurities resulting from the degradation of the bendamustine after the storing.
2 . A liquid bendamustine-containing composition prepared according to the method of claim 1 .
3 . A method of treating leukemia in a mammal comprising administering to the mammal an effective amount of the liquid bendamustine-containing composition of claim 2 .
4 . The composition of claim 2 , wherein the antioxidant is monothioglycerol.
5 . The composition of claim 2 , wherein the antioxidant is monothioglycerol in a concentration of about 5 mg/mL.
6 . The composition of claim 2 , further comprising ethanol.
7 . A method of preparing a liquid bendamustine-containing composition having less than about 5% peak response of total impurities resulting from the degradation of the bendamustine, as determined by HPLC at a wavelength of 223 nm comprising:
combining bendamustine, or a pharmaceutically acceptable salt thereof, polyethylene glycol, and a stabilizing amount of an antioxidant to produce a liquid bendamustine-containing composition comprising a bendamustine concentration of about 25 mg/mL;
storing the liquid bendamustine-containing composition for at least 15 months at a temperature of from about 5° C. to about 25° C.; and
measuring, by HPLC at a wavelength of 223 nm, the peak area response of total impurities resulting from the degradation of the bendamustine after the storing; and
determining that the liquid bendamustine-containing composition has less than about 5% peak response of total impurities resulting from the degradation of the bendamustine after the storing.
8 . A liquid bendamustine-containing composition prepared according to the method of claim 7 .
9 . A method of treating leukemia in a mammal comprising administering to the mammal an effective amount of the liquid bendamustine-containing composition of claim 8 .
10 . The composition of claim 8 , wherein the antioxidant is monothioglycerol.
11 . The composition of claim 8 , wherein the antioxidant is monothioglycerol in a concentration of about 5 mg/mL.
12 . The composition of claim 8 , further comprising ethanol.