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 tong term storage stable non-aqueous liquid bendamustine-containing composition, comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof, and
b) a pharmaceutically acceptable fluid comprising
i) about 90% polyethylene glycol and about 10% propylene glycol; and
ii) a stabilizing amount of an antioxidant.
2. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 1 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL.
3. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 2 , wherein the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL.
4. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 3 , wherein the bendamustine concentration is from about 30 mg/mL to about 50 mg/mL.
5. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 4 , wherein the bendamustine concentration is about 50 mg/mL.
6. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 1 , wherein the antioxidant is selected from the group consisting of thioglycerol, monothioglycerol, lipoic acid, propyl gallate, methionine, cysteine, metabisulfites, sodium formaldehyde sulfoxylate, phenol-containing aromatic and aliphatic compounds and dihydrolipoic acid.
7. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 6 , wherein the antioxidant is thioglycerol or monothioglycerol.
8. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 6 , wherein the antioxidant is lipoic acid.
9. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 1 , wherein the stabilizing amount of the antioxidant is from about 2.5 mg/mL to about 35 mg/mL.
10. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 9 , wherein the stabilizing amount of the antioxidant is from about 5 mg/mL to about 20 mg/mL.
11. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 10 , wherein the stabilizing amount of the antioxidant is from about 10 mg/mL to about 15 mg/mL.
12. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 10 , wherein the stabilizing amount of the antioxidant is about 5 mg/mL.
13. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 1 , wherein said long term storage is at least 2 years.
14. A tong term storage stable non-aqueous liquid bendamustine-containing composition, comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof, and
b) a pharmaceutically acceptable fluid comprising
i) about 90% polyethylene glycol and about 10% propylene glycol; and
ii) a stabilizing amount of thioglycerol.
15. A tong term storage stable non-aqueous liquid bendamustine-containing composition, comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof, and
b) a pharmaceutically acceptable fluid comprising
i) about 90% polyethylene glycol and about 10% propylene glycol; and
ii) a stabilizing amount of 2.5 mg/mL thioglycerol.
16. A method of treating cancer in mammals, comprising administering an effective amount of a long term storage stable non-aqueous liquid bendamustine-containing composition of claim 1 to a mammal in need thereof.
17. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 14 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL.
18. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 17 , wherein the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL.
19. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 18 , wherein the bendamustine concentration is about 50 mg/mL.
20. The long term storage stable non-aqueous liquid bendamustine-containing composition of claim 14 , wherein said long term storage is at least 2 years.
21. The method of treating cancer in mammals of claim 16 , wherein the cancer is leukemia.
22. The method of treating cancer in mammals of claim 16 , wherein the cancer is Hodgkin's disease.