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 treating leukemia in a human in need thereof comprising
providing a liquid bendamustine-containing composition comprising
bendamustine, or a pharmaceutically acceptable salt thereof, wherein the bendamustine concentration in the composition is from about 20 mg/mL to about 60 mg/mL,
a pharmaceutically acceptable fluid consisting of polyethylene glycol and optionally one or more of propylene glycol, ethanol, benzyl alcohol and glycofurol; and
a stabilizing amount of an antioxidant
wherein the total impurities in the liquid bendamustine-containing composition resulting from the degradation of the bendamustine is less than about 5% peak area response, as determined by HPLC at a wavelength of 223 nm after at least about 15 months at a temperature of about 5° C. to about 25° C.;
diluting the liquid bendamustine containing composition; and
intravenously administering the diluted composition to the human.
2. The method of claim 1 , wherein the liquid bendamustine containing composition is diluted with about 50 mL of a diluent.
3. The method of claim 1 , wherein the concentration of bendamustine in the liquid bendamustine-containing compositions is about 25 mg/ml.
4. The method of claim 1 , wherein the concentration of bendamustine in the liquid bendamustine-containing composition is 25 mg/ml.
5. The method of claim 1 , wherein the liquid bendamustine-containing composition includes 100 mg of bendamustine at a concentration of 25 mg/mL.
6. The method of claims 1 , wherein the antioxidant is monothioglycerol.
7. The method of claim 1 , wherein the antioxidant in the liquid bendamustine containing composition is monothioglycerol in a concentration of about 5 mg/mL.
8. The method of claim 1 , wherein the liquid bendamustine-containing composition is stable for at least about 15 months at 5° C. or for at least about 15 months at 25° C., prior to dilution.
9. The method of claim 1 , wherein the liquid bendamustine-containing composition further comprises ethanol.
10. The method of claims 1 , wherein the liquid bendamustine-containing composition is packages in a sterile vial.
11. A method of treating leukemia in a human in need thereof comprising providing a liquid bendamustine-containing composition packaged in a sterile vial and comprising
100 mg of bendamustine, or a pharmaceutically acceptable salt thereof, at a concentration of about 25 mg/mL;
a pharmaceutically acceptable fluid consisting of polyethylene glycol and optionally one or more of propylene glycol, ethanol, benzyl alcohol and glycofurol; and
a stabilizing amount of an antioxidant that is monothioglycerol;
wherein the total impurities in the liquid bendamustine-containing composition resulting from the degradation of the bendamustine is less than about 5% peak area response, as determined by HPLC at a wavelength of 223 nm after at least about 15 months at a temperature of about 5° C. or for at least about 15 months at 25° C.;
diluting the liquid bendamustine containing composition with about 50 mL of a diluent;
and intravenously administering the diluted composition to the human.
12. The method of claim 11 , wherein the liquid bendamustine-containing composition comprises100 mg of bendamustine, or a pharmaceutically acceptable salt thereof, at a concentration of 25 mg/mL.
13. The method of claim 12 , wherein the liquid bendamustine-containing composition further comprises ethanol.
14. The method of claim 12 , wherein the liquid bendamustine containing composition is diluted with about 50 mL of a diluent.