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 sterile container containing a ready for dilution, liquid, bendamustine-containing solution comprising:
bendamustine, or a pharmaceutically acceptable salt thereof, wherein the bendamustine concentration in the solution is from about 20 mg/mL to about 60 mg/mL; and
a stabilizing amount of an antioxidant;
a solvent, wherein the solvent is a pharmaceutically acceptable fluid consisting of polyethylene glycol and optionally one or more of propylene glycol, ethanol, benzyl alcohol and glycofurol; and
wherein the total impurities 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.
2 . The sterile container of claim 1 , comprising 100 mg of bendamustine or a pharmaceutically acceptable salt thereof.
3 . The sterile container of claim 1 , wherein the bendamustine concentration in the solution is about 25 mg/mL.
4 . The sterile container of claim 1 , wherein the antioxidant is monothioglycerol.
5 . The sterile container of claim 1 , wherein the antioxidant is monothioglycerol in a concentration of about 5 mg/mL.
6 . The sterile container of claim 1 , wherein the solution is stable for at least about 15 months at 5° C. or for at least about 15 months at 25° C.
7 . The sterile container of claim 1 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and one or more of propylene glycol, ethanol, benzyl alcohol, and glycofurol.
8 . The sterile container of claim 7 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and propylene glycol.
9 . The sterile container of claim 7 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and ethanol.
10 . The sterile container of claim 7 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and benzyl alcohol.
11 . The sterile container of claim 7 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and glycofurol.
12 . The sterile container of claim 1 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol.
13 . The sterile container of claim 1 , further comprising ethanol.
14 . The sterile container of claim 1 , wherein the bendamustine has not been reconstituted from a lyophilized powder.
15 . A ready for dilution, liquid, bendamustine-containing solution comprising:
bendamustine, or a pharmaceutically acceptable salt thereof, wherein the bendamustine concentration in the solution is from about 20 mg/mL to about 60 mg/mL; and
a stabilizing amount of an antioxidant;
a solvent, wherein the solvent is a pharmaceutically acceptable fluid consisting of polyethylene glycol and optionally one or more of propylene glycol, ethanol, benzyl alcohol and glycofurol; and
wherein the total impurities 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.
16 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , comprising 100 mg of bendamustine or a pharmaceutically acceptable salt thereof.
17 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , wherein the bendamustine concentration in the composition is about 25 mg/mL.
18 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , wherein the antioxidant is monothioglycerol.
19 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , wherein the antioxidant is monothioglycerol in a concentration of about 5 mg/mL.
20 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , wherein the composition is stable for at least about 15 months at 5° C. or for at least about 15 months at 25° C.
21 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and one or more of propylene glycol, ethanol, benzyl alcohol, and glycofurol.
22 . The ready for dilution, liquid, bendamustine-containing solution of claim 21 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and propylene glycol.
23 . The ready for dilution, liquid, bendamustine-containing solution of claim 21 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and ethanol.
24 . The ready for dilution, liquid, bendamustine-containing solution of claim 21 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and benzyl alcohol.
25 . The ready for dilution, liquid, bendamustine-containing solution of claim 21 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol and glycofurol.
26 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , wherein the pharmaceutically acceptable fluid consists of polyethylene glycol.
27 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , further comprising ethanol.
28 . The ready for dilution, liquid, bendamustine-containing solution of claim 15 , wherein the bendamustine has not been reconstituted from a lyophilized powder.
29 . A method of treating leukemia in a patient in need thereof comprising providing a ready for dilution, liquid, bendamustine-containing solution according to claim 15 , diluting the solution, and administering the diluted solution to the human.