FORMULATIONS OF BENDAMUSTINE

• US 20110184036A1
• Filed: 01/28/2011
• Published: 07/28/2011
• Est. Priority Date: 01/28/2010
• Status: Active Grant

• Current Assignee: Eagle Pharmaceuticals Incorporated
• Original Assignee: Eagle Pharmaceuticals Incorporated
• Inventors: Buxton, Philip Christopher, Palepu, Nagesh R.
• Granted Patent: US 8,609,707 B2
• Time in Patent Office: Days
• 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 long term storage stable bendamustine-containing composition, comprising:

a) bendamustine or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable fluid comprising

i) a member of the group consisting of polyethylene glycol, propylene glycol and mixtures thereof; and

ii) a stabilizing amount of an antioxidant;

said bendamustine-containing composition having 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.

2. The long term storage stable 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 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 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 bendamustine-containing composition of claim 4, wherein the bendamustine concentration is about 50 mg/mL.

6. The long term storage stable bendamustine-containing composition of claim 1, wherein the pharmaceutically acceptable fluid comprises propylene glycol.

7. The long term storage stable bendamustine-containing composition of claim 1, wherein the pharmaceutically acceptable fluid comprises polyethylene glycol.

8. The long term storage stable bendamustine-containing composition of claim 1, wherein the pharmaceutically acceptable fluid comprises polyethylene glycol and propylene glycol.

9. The long term storage stable bendamustine-containing composition of claim 8, wherein the pharmaceutically acceptable fluid comprises about 90% polyethylene glycol and about 10% propylene glycol.

10. The long term storage stable bendamustine-containing composition of claim 8, wherein the pharmaceutically acceptable fluid comprises about 85% polyethylene glycol and about 15% propylene glycol.

11. The long term storage stable 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.

12. The long term storage stable bendamustine-containing composition of claim 11, wherein the antioxidant is thioglycerol or monothioglycerol.

13. The long term storage stable bendamustine-containing composition of claim 11, wherein the antioxidant is lipoic acid.

14. The long term storage stable 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.

15. The long term storage stable bendamustine-containing composition of claim 14, wherein the stabilizing amount of the antioxidant is from about 5 mg/mL to about 20 mg/mL.

16. The long term storage stable bendamustine-containing composition of claim 15, wherein the stabilizing amount of the antioxidant is from about 10 mg/mL to about 15 mg/mL.

17. The long term storage stable bendamustine-containing composition of claim 15, wherein the stabilizing amount of the antioxidant is about 5 mg/mL.

18. The long term storage stable bendamustine-containing composition of claim 1, wherein said long term storage is at least about 2 years.

19. The long term storage stable bendamustine-containing composition of claim 1, wherein said bendamustine-containing composition having less than about 3% total impurities, PAR as determined by HPLC at a wavelength of 223 nm, after at least about 2 years of storage at a temperature of from about 5°

C. to about 25°

C.

23. A method of treating cancer in mammals, comprising administering an effective amount of a long term storage stable bendamustine-containing composition of claim 1 to a mammal in need thereof.

20. A long term storage stable bendamustine-containing composition, comprising:

a) bendamustine or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable fluid comprising

i) polyethylene glycol and propylene glycol; and

ii) a stabilizing amount of thioglycerol;

said bendamustine-containing composition having 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.

21. A long term storage stable bendamustine-containing composition, comprising:

a) bendamustine or a pharmaceutically acceptable salt thereof at a concentration of about 50 mg/mL; and

b) a pharmaceutically acceptable fluid comprising

i) 90% polyethylene glycol and 10% propylene glycol; and

ii) thioglycerol at a concentration of about 2.5 mg/mL;

said bendamustine-containing composition having 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.

22. A long term storage stable bendamustine-containing composition, comprising:

a) bendamustine or a pharmaceutically acceptable salt thereof at a concentration of about 50 mg/mL; and

b) a pharmaceutically acceptable fluid comprising DMSO;

said bendamustine-containing composition having 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.