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 non-aqueous liquid composition comprising:
bendamustine, or a pharmaceutically acceptable salt thereof;
a pharmaceutically acceptable fluid comprising a mixture of polyethylene glycol and propylene glycol, wherein the ratio of polyethylene glycol to propylene glycol in the pharmaceutically acceptable fluid is from about 95:5 to about 50:50; and
a stabilizing amount of an antioxidant;
wherein the composition has less than about 5% total impurities after 15 months of storage at about 5° C., as calculated on a normalized peak area response basis as determined by high performance liquid chromatography at a wavelength of 223 nm.
2. The non-aqueous liquid composition of claim 1 , wherein the bendamustine concentration is from about 10 mg/mL to about 100 mg/mL.
3. The non-aqueous liquid composition of claim 1 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL.
4. The non-aqueous liquid composition of claim 1 , wherein the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL.
5. The non-aqueous liquid composition of claim 1 , wherein the bendamustine concentration is about 25 mg/mL.
6. The non-aqueous liquid composition of claim 1 , wherein the concentration of the antioxidant is from about 2.5 mg/mL to about 35 mg/mL.
7. The non-aqueous liquid composition of claim 1 , wherein the concentration of the antioxidant is from about 5 mg/mL to about 20 mg/mL.
8. The non-aqueous liquid composition of claim 1 , wherein the concentration of the antioxidant is from about 10 mg/mL to about 15 mg/mL.
9. The non-aqueous liquid composition of claim 1 , comprising bendamustine hydrochloride.
10. A method of treating leukemia, Hodgkin's disease, or multiple myeloma in a mammal comprising administering to the mammal an effective amount of the composition of claim 1 .
11. The method of claim 10 , for the treatment of leukemia.
12. The method of claim 10 , for the treatment of Hodgkin's disease.
13. The method of claim 10 , for the treatment of multiple myeloma.
14. A non-aqueous liquid composition comprising:
bendamustine, or a pharmaceutically acceptable salt thereof;
a pharmaceutically acceptable fluid comprising a mixture of polyethylene glycol and propylene glycol, wherein the ratio of polyethylene glycol to propylene glycol in the pharmaceutically acceptable fluid is from about 95:5 to about 50:50; and
a stabilizing amount of an antioxidant;
wherein the composition has less than about 5% total impurities after storage for 15 days at 25° C., as calculated on a normalized peak area response basis as determined by high performance liquid chromatography at a wavelength of 223 nm.
15. The non-aqueous liquid composition of claim 14 , wherein the bendamustine concentration is from about 10 mg/mL to about 100 mg/mL.
16. The non-aqueous liquid composition of claim 14 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL.
17. The non-aqueous liquid composition of claim 14 , wherein the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL.
18. The non-aqueous liquid composition of claim 14 , wherein the bendamustine concentration is about 25 mg/mL.
19. The non-aqueous liquid composition of claim 14 , wherein the concentration of the antioxidant is from about 2.5 mg/mL to about 35 mg/mL.
20. The non-aqueous liquid composition of claim 14 , wherein the concentration of the antioxidant is from about 5 mg/mL to about 20 mg/mL.
21. The non-aqueous liquid composition of claim 14 , wherein the concentration of the antioxidant is from about 10 mg/mL to about 15 mg/mL.
22. The non-aqueous liquid composition of claim 14 , comprising bendamustine hydrochloride.
23. A method of treating leukemia, Hodgkin's disease, or multiple myeloma in a mammal comprising administering to the mammal an effective amount of the composition of claim 14 .
24. The method of claim 23 , for the treatment of leukemia.
25. The method of claim 23 , for the treatment of Hodgkin's disease.
26. The method of claim 23 , for the treatment of multiple myeloma.