Stable bortezomib formulations

• US 9,061,037 B2
• Filed: 03/18/2011
• Issued: 06/23/2015
• Est. Priority Date: 03/18/2010
• Status: Expired due to Fees

• 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): MCMILLIAN, KARA RENITA
• Application Number:
  US13/051,102
• Publication Number:
  US 20110230441A1
• Time in Patent Office: 1,558 Days
• US Class Current: 1/1
• 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 ready to inject pharmaceutical parenteral composition, comprising:

a liquid formulation comprising Bortezomib and an acidic buffer;

wherein the liquid formulation is a substantially non-aqueous solvent system suitable for injection, and present in a container in a quantity suitable for at least two independent administrations;

wherein the solvent system comprises at least 50 vol % 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 ready to inject pharmaceutical parenteral composition in the multi-use container of claim 1 wherein the Bortezomib is present in an amount of at least 10 mg.

3. The ready to inject pharmaceutical parenteral composition in the multi-use container of claim 1 wherein the substantially non-aqueous solvent system comprises at least 90 vol % propylene glycol.

4. The ready to inject pharmaceutical parenteral composition in the multi-use container of claim 1 wherein the multi-use container comprises at least one of an ampoule, a vial, a pre-filled syringe, and an intravenous bag, and wherein the liquid formulation has not undergone lyophilization before being stored over the at least three months at ambient conditions.

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

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

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

8. The ready to inject pharmaceutical parenteral composition in the multi-use container of claim 1 wherein the Bortezomib is present in an amount of at least 25 mg.

9. The ready to inject pharmaceutical parenteral composition in the multi-use container of claim 1 wherein the solvent system is formulated to maintain degradation of the Bortezomib at a level of less than 2 wt % when the liquid formulation is stored over at least three months at ambient conditions.

10. The ready to inject pharmaceutical composition in the multi-use container of claim 1, wherein the Bortezomib is present in an amount suitable to allow at least ten independent administrations.

11. A storage stable pharmaceutical parenteral composition comprising:

a liquid formulation comprising Bortezomib and an acidic buffer;

wherein the liquid formulation is a substantially non-aqueous solvent system for injection;

wherein the solvent system comprises at least 50 vol % propylene glycol;

wherein the Bortezomib is present at a pharmaceutically effective concentration;

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.

12. The storage stable pharmaceutical parenteral composition of claim 11 wherein the solvent system is formulated to maintain degradation of the Bortezomib at a level of less than 2 wt % when the liquid formulation is stored over at least three months at ambient conditions.