Liquid Formulations Of Bendamustine

• US 20130041004A1
• Filed: 10/19/2012
• Published: 02/14/2013
• Est. Priority Date: 09/25/2008
• Status: Abandoned Application

• Current Assignee: Anthony S. Drager, Piyush R. Patel, Rachel Y. Labell
• Original Assignee: Anthony S. Drager, Piyush R. Patel, Rachel Y. Labell
• Inventors: Drager, Anthony S., LaBell, Rachel Y., Patel, Piyush R.
• Application Number:
  US13/655,498
• Publication Number:
  US 20130041004A1
• 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 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• 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 47/40 Cyclodextrins; Derivatives thereof
• 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
• CPC Class Codes: A61P 35/02 specific for leukemia

Abstract

Stable liquid formulations of bendamustine, and pharmaceutically acceptable salts thereof, and polar aprotic solvents, are described.

Claims

1. A stable, liquid, pharmaceutical formulation comprising bendamustine, or a pharmaceutically acceptable salt thereof, and a polar aprotic solvent, wherein said formulation is suitable for injection into a patient following dilution with a pharmaceutically acceptable diluent.

2. The formulation of claim 1, wherein the polar aprotic solvent is 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate, or a mixture thereof.

3. The formulation of claim 2, wherein the polar aprotic solvent is dimethylacetamide.

4. The formulation of claim 1, further comprising a non-aqueous polar protic solvent.

5. The formulation of claim 4, comprising between about 30% and about 70%, by volume of the formulation, of the nonaqueous polar protic solvent.

6. The formulation of claim 4, wherein the non-aqueous polar protic solvent is an alcohol, a polyalkylene glycol, an amide, or a mixture thereof.

7. The formulation of claim 4, wherein the non-aqueous polar protic solvent is an alcohol.

8. The formulation of claim 7, wherein the alcohol is a cyclodextrin.

9. The formulation of claim 4, wherein the non-aqueous polar protic solvent is propylene glycol.

10. The formulation of claim 4, wherein the polar aprotic solvent is dimethylacetamide.

11. The formulation of claim 10, wherein the nonaqueous polar protic solvent is propylene glycol.

12. The formulation of claim 11, comprising about 66% (v/v) of the dimethylacetamide and about 34% (v/v) of the propylene glycol.

13. The formulation of claim 12, comprising from about 5 mg/ml to about 120 mg/mL of bendamustine, or a pharmaceutically acceptable salt thereof.

14. The formulation of claim 13, comprising about 100 mg/mL of bendamustine, or a pharmaceutically acceptable salt thereof.

15. The formulation of claim 1, comprising from about 5 mg/ml to about 200 mg/mL of bendamustine, or a pharmaceutically acceptable salt thereof.

16. The formulation of claim 1, comprising from about 5 mg/ml to about 120 mg/mL of bendamustine, or a pharmaceutically acceptable salt thereof.

17. The formulation of claim 1, comprising about 100 mg/mL of bendamustine, or a pharmaceutically acceptable salt thereof.

18. The formulation of claim 1, wherein the bendamustine is bendamustine hydrochloride.

19. The formulation of claim 1, further comprising at least one pharmaceutically acceptable excipient or diluent.

20. The formulation of claim 4, further comprising at least one pharmaceutically acceptable excipient or diluent.

21. The formulation of claim 1, further comprising an antioxidant, a surfactant, a lipid, a filler, an organic acid, a hydrophilic polymer, a complexing agent, a preservative, or a combination thereof.

22. A method of treating cancer comprising

providing a liquid, pharmaceutical formulation of claim 1;

diluting the liquid pharmaceutical formulation with a pharmaceutically acceptable injectable diluent to form an injectable pharmaceutical preparation;

administering the injectable pharmaceutical preparation to a patient in need of treatment for cancer.

23. The method of claim 22, wherein the liquid pharmaceutical formulation comprises the polar aprotic solvent dimethylacetamide.

24. The method of claim 23, wherein the liquid pharmaceutical formulation comprises the polar aprotic solvent dimethylacetamide and further comprises the nonaqueous polar protic solvent propylene glycol

25. The method of claim 24, wherein the liquid pharmaceutical formulation comprises about 66% (v/v) of the dimethylacetamide and about 34% (v/v) of the propylene glycol.

26. The method of claim 25, wherein the liquid pharmaceutical formulation comprises from about 5 mg/ml to about 120 mg/mL of bendamustine, or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the liquid pharmaceutical formulation comprises about 100 mg/mL of bendamustine, or a pharmaceutically acceptable salt thereof.

28. The method of claim 22, wherein the pharmaceutically acceptable injectable diluent is 0.9% sodium chloride.

29. The method of claim 22, wherein the cancer is chronic lymphocytic leukemia, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphoma, multiple myeloma, or breast cancer.

30. The method of claim 29, wherein the cancer is chronic lymphocytic leukemia or non-Hodgkin'"'"'s lymphoma.