Formulations of bendamustine

• US 8,609,707 B2
• Filed: 01/28/2011
• Issued: 12/17/2013
• Est. Priority Date: 01/28/2010
• Status: Active Grant

• Current Assignee: Eagle Pharmaceuticals Incorporated
• Original Assignee: Eagle Pharmaceuticals Incorporated
• Inventors: Palepu, Nagesh R., Buxton, Philip Christopher
• Primary Examiner(s): Fubara, Blessing M.
• Assistant Examiner(s): Akhoon, Kauser M
• Application Number:
  US13/016,473
• Publication Number:
  US 20110184036A1
• Time in Patent Office: 1,054 Days
• Field of Search: 514/300, 514/394, 514/127
• US Class Current: 514/394
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/186 Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents

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° C. to about 25° C.

Claims

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.

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.

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.

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.

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.

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.