Stable bortezomib formulations

• US 8,263,578 B2
• Filed: 03/27/2012
• Issued: 09/11/2012
• Est. Priority Date: 03/18/2010
• Status: Active Grant

• Current Assignee: InnoPharma, Inc. (Pfizer Inc.)
• Original Assignee: InnoPharma, Inc. (Pfizer Inc.)
• Inventors: Soppimath, Kumaresh, Pejaver, Satish, Patel, Kanaiyalal R., Dasaradhi, Lakkaraju, Sodum, Rama, Desu, Hari, Puri, Navneet
• Primary Examiner(s): Wang, Shengjun
• Assistant Examiner(s): MCMILLIAN, KARA RENITA
• Application Number:
  US13/431,313
• Publication Number:
  US 20120172808A1
• Time in Patent Office: 168 Days
• Field of Search: 514/64, 514/255.06, 544/229, 544/336
• 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: C07B 63/04 Use of additives anti-oxidant compositions or compositions inhibiting chemical change in general C09K15/00

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 storage-stable liquid pharmaceutical composition that includes bortezomib in a therapeutically effective amount, the composition comprising:

a single-phase liquid formulation comprising a substantially non-aqueous solvent system suitable for injection, an aqueous acetate buffer, and bortezomib, wherein the bortezomib is present in the formulation at a therapeutically effective concentration;

wherein the solvent system comprises as a predominant component propylene glycol, and wherein the buffer has a pH of 3; and

wherein the solvent system, the buffer, and the pH are selected such as to be effective to suppress formation of at least one of an amide degradation product, a first carbinolamide degradation product, and a second carbinolamide degradation product when the liquid formulation is stored under storage conditions.

2. The composition of claim 1 wherein the substantially non-aqueous solvent system consists essentially of propylene glycol.

3. The composition of claim 1 wherein the formulation comprises at least 70 vol % propylene glycol.

4. The composition of claim 1 wherein the formulation comprises at least 90 vol % propylene glycol.

5. The composition of claim 1 wherein the liquid formulation is stored for at least 15 days under storage conditions.

6. The composition of claim 5 wherein the storage conditions comprises storage at 50°

C.

7. The composition of claim 1 wherein the bortezomib is present at a concentration of between 1 mg/ml and 5 mg/ml.

8. The composition of claim 7 wherein the buffer is an aqueous acetate buffer at a concentration of between 0.05 and 0.25M.

9. The pharmaceutical composition of claim 1 in a container, 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.

10. The container of claim 9 comprising a quantity of the liquid formulation that is suitable for independent multiple administrations.

11. A method of suppressing formation of a plurality of degradation products of bortezomib in solution, comprising:

compounding a single-phase liquid formulation from a substantially non-aqueous solvent system suitable for injection, an aqueous acetate buffer, and bortezomib, wherein the bortezomib is present in the formulation at a pharmaceutically effective concentration;

wherein the solvent system comprises as a predominant component propylene glycol and wherein the buffer has a pH of 3; and

wherein the solvent system, the buffer, and the pH are selected such as to be effective to suppress formation of at least one of an amide degradation product, a first carbinolamide degradation product, and a second carbinolamide degradation product when the liquid formulation is stored under storage conditions.

12. The method of claim 11 wherein the substantially non-aqueous solvent system consists essentially of propylene glycol.

13. The method of claim 12 wherein the buffer is an acetate buffer at a concentration of between 0.05 and 0.25M.

14. The method of claim 11 wherein the bortezomib is present at a concentration of between 1 mg/ml and 5 mg/ml.

15. The method of claim 11 wherein the storage conditions comprise storage at 50°

C. over 15 days.