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, Hodgkin's disease, or multiple myeloma in a mammal, comprising administering to the mammal, a liquid bendamustine-containing composition comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof; and
b) a non-aqueous pharmaceutically acceptable fluid comprising
about 5% to about 10%, based on the volume of the pharmaceutically acceptable fluid, of propylene glycol,
polyethylene glycol,
and a stabilizing amount of an antioxidant 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;
the bendamustine-containing composition having less than or equal to 0.11% total PG esters at about 1 month of storage at a temperature of about 5° C.;
wherein the ratio of polyethylene glycol to propylene glycol is selected from the group consisting of: about 95:5, about 90:10, about 85:15, about 80:20, and about 75:25.
2. The method of claim 1 , wherein the bendamustine-containing composition has less than or equal to 0.18% total PG esters at about 12 months of storage at a temperature of about 5° C.
3. The method of claim 1 , wherein the amount of propylene glycol in the pharmaceutically acceptable fluid is about 10%.
4. The method of claim 1 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL.
5. The method of claim 4 , wherein the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL.
6. The method of claim 5 , wherein the bendamustine concentration is about 50 mg/mL.
7. The method of claim 1 , wherein said bendamustine-containing composition has less than or equal to 0.12% total PG esters at about 15 days of storage at a temperature of about 25° C.
8. The method of claim 1 , wherein said bendamustine-containing composition has less than or equal to 0.25% total PG esters at about 1 month of storage at a temperature of about 25° C.
9. The method of claim 1 , wherein said bendamustine-containing composition has less than or equal to 0.43% total PG esters at about 3 months of storage at a temperature of about 25° C.
10. The method of claim 1 , wherein said bendamustine-containing composition has less than or equal to 0.77% total PG esters at about 6 months of storage at a temperature of about 25° C.
11. The method of claim 1 , wherein the antioxidant is thioglycerol or monothioglycerol.
12. The method of claim 1 , wherein the antioxidant concentration is from about 2.5 mg/mL to about 35 mg/mL.
13. The method of claim 1 , for the treatment of leukemia.
14. The method of claim 1 , for the treatment of Hodgkin's disease.
15. The method of claim 1 , for the treatment of multiple myeloma.
16. A method of treating leukemia, Hodgkin's disease, or multiple myeloma in a mammal, comprising administering to the mammal, a liquid bendamustine-containing composition, comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof; and
b) a non-aqueous pharmaceutically acceptable fluid comprising propylene glycol, polyethylene glycol, and a stabilizing amount of an antioxidant 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;
the bendamustine-containing composition having less than or equal to 0.12% total PG esters at about 15 days of storage at a temperature of about 25° C.;
wherein the ratio of polyethylene glycol to propylene glycol is selected from the group consisting of: about 95:5, about 90:10, about 85:15, about 80:20, and about 75:25.
17. The method of claim 16 , wherein said bendamustine-containing composition has less than or equal to 0.25% total PG esters at about 1 month of storage at a temperature of about 25° C.
18. The method of claim 16 , wherein said bendamustine-containing composition has less than or equal to 0.43% total PG esters at about 3 months of storage at a temperature of about 25° C.
19. The method of claim 16 , wherein said bendamustine-containing composition has less than or equal to 0.77% total PG esters at about 6 months of storage at a temperature of about 25° C.
20. The method of claim 16 , wherein the bendamustine-containing composition has less than or equal to 0.25% total PG esters at about 1 month of storage at a temperature of about 25° C., has less than or equal to 0.43% total PG esters at about 3 months of storage at a temperature of about 25° C., and has less than or equal to 0.77% total PG esters at about 6 months of storage at a temperature of about 25° C.
21. The method of claim 16 , wherein the amount of propylene glycol in the pharmaceutically acceptable fluid is about 10%.
22. The method of claim 16 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL.
23. The method of claim 16 , wherein the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL.
24. The method of claim 23 , wherein the bendamustine concentration is about 50 mg/mL.
25. The method of claim 16 , for the treatment of leukemia.
26. The method of claim 16 , for the treatment of Hodgkin's disease.
27. The method of claim 16 , for the treatment of multiple myeloma.