Details for Patent: 9,572,797

Title:	Formulations of bendamustine
Abstract:	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.degree. C. to about 25.degree. C.
Inventor(s):	Palepu; Nagesh R. (Southampton, PA), Buxton; Philip Christopher (Great Dunmow, GB)
Assignee:	EAGLE PHARMACEUTICALS, INC. (Woodcliff Lake, NJ)
Filing Date:	Feb 02, 2016
Application Number:	15/013,436
Claims:	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.degree. 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.degree. 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.degree. 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.degree. 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.degree. 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.degree. 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.degree. 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.degree. 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.degree. 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.degree. 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.degree. C., has less than or equal to 0.43% total PG esters at about 3 months of storage at a temperature of about 25.degree. 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.degree. 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.