STABLE BORTEZOMIB FORMULATIONS

• US 20110230441A1
• Filed: 03/18/2011
• Published: 09/22/2011
• Est. Priority Date: 03/18/2010
• Status: Active Grant

• Current Assignee: InnoPharma, Inc. (Pfizer Inc.)
• Original Assignee: Innopharma LLC (Pfizer Inc.)
• Inventors: Dasaradhi, Lakkaraju, Soppimath, Kumaresh, Desu, Hari, Patel, Kanaiyalal R., Sodum, Rama, Pejaver, Satish, Puri, Navneet
• Granted Patent: US 9,061,037 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/69 Boron compounds
• 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 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: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Multi-dose formulations for bortezomib are presented in which bortezomib has significantly improved stability. Especially preferred formulations include those in which bortezomib is in a liquid form suitable for injection, wherein the solvent system predominantly comprises propylene glycol. In other preferred aspects, bortezomib is present as a Lewis donor-acceptor complex with a hetero-bifunctional Lewis base.

Claims

1. A pharmaceutical composition comprising:

a liquid formulation comprising bortezomib;

wherein the liquid formulation is a substantially non-aqueous solvent system suitable for injection, wherein the solvent system comprises as a main component propylene glycol;

wherein the bortezomib is present at a pharmaceutically effective concentration; and

wherein the solvent system is formulated to maintain degradation of the bortezomib at a level of less than 10 wt % when the liquid formulation is stored over at least three months at ambient conditions.

2. The pharmaceutical composition of claim 1 wherein the substantially non-aqueous solvent system comprises at least 50 vol % propylene glycol.

3. The pharmaceutical composition of claim 2 wherein the substantially non-aqueous solvent system comprises at least 75 vol % propylene glycol.

4. The pharmaceutical composition of claim 2 wherein the substantially non-aqueous solvent system comprises 100 vol % propylene glycol.

5. The pharmaceutical composition of claim 1 wherein the substantially non-aqueous solvent system further comprises a polar solvent in an amount of equal or less than 25 vol %.

6. The pharmaceutical composition of claim 5 wherein the substantially non-aqueous solvent system further comprises a polar solvent in an amount of equal or less than 20 vol %.

7. The pharmaceutical composition of claim 5 or claim 6 wherein the polar solvent is ethanol.

8. The pharmaceutical composition of claim 1 wherein the substantially non-aqueous solvent system further comprises a polar solvent in an amount of equal or less than 50 vol %.

9. The pharmaceutical composition of claim 1 wherein the substantially non-aqueous solvent system further comprises a polar solvent in an amount of equal or less than 10 vol %.

10. The pharmaceutical composition of claim 8 wherein the polar solvent is water.

21. A container comprising the pharmaceutical composition of claim 1 or claim 11, wherein the container is a vial, an ampoule, an intravenous bag, or a syringe, and wherein the container is optionally configured as a multi-use container.

11. A pharmaceutical composition comprising:

a formulation comprising bortezomib and a hetero-bifunctional Lewis base;

wherein the bortezomib and the hetero-bifunctional Lewis base together are present in form of a Lewis donor-acceptor complex;

wherein the hetero-bifunctional Lewis base has at least two distinct donor groups selected from the group consisting of —

NH₂, —

SH, COOH, and —

OH; and

wherein the formulation is lyophilized or in solution.

12. The pharmaceutical composition of claim 11 wherein bortezomib and the hetero-bifunctional Lewis base are present in a ratio of 1:

100 to 1;

200.

13. The pharmaceutical composition of claim 11 wherein bortezomib and the hetero-bifunctional Lewis base are present in a ratio of 1:

10 to 1;

100.

14. The pharmaceutical composition of claim 11 wherein bortezomib and the hetero-bifunctional Lewis base are present in a ratio of 1:

1 to 1;

10.

15. The pharmaceutical composition of claim 11 wherein the hetero-bifunctional Lewis base is selected from the group consisting of an amino acid, a peptide, and a substituted polyethylene glycol.

16. The pharmaceutical composition of claim 15 wherein the amino acid is a naturally occurring amino acid or an N-acetylated amino acid.

17. The pharmaceutical composition of claim 15 wherein the peptide is a dipeptide or tripeptide.

18. The pharmaceutical composition of claim 15 wherein the substituted polyethylene glycol has a structure according to Formula I

19. The pharmaceutical composition of claim 11 further comprising at least one of a buffering agent, a lyoprotectant, a cryoprotectant, a preservative, and an antioxidant.

20. The pharmaceutical composition of claim 11 wherein the formulation is lyophilized.