Stable bortezomib formulations

• US 9,180,093 B2
• Filed: 08/22/2012
• Issued: 11/10/2015
• 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:
  US13/592,235
• Publication Number:
  US 20120322763A1
• Time in Patent Office: 1,175 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: 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 method of manufacturing a ready to inject bortezomib-containing pharmaceutical article comprising:

formulating a liquid parenteral formulation that contains bortezomib such that the formulation exhibits equal or less than 10% degradation of the bortezomib at accelerated conditions after 3 months;

wherein the liquid parenteral formulation is prepared as a single-phase liquid formulation that comprises a substantially non-aqueous solvent system suitable for injection and including at least 50 vol % propylene glycol, an aqueous buffer, and bortezomib, wherein the bortezomib is present in the formulation at a therapeutically effective concentration; and

packaging the liquid parenteral formulation in an amount sufficient for at least two distinct uses into a container, wherein the container is configured to allow providing multiple independent dosages of the liquid formulation.

2. The method of claim 1 wherein the liquid parenteral formulation is formulated such as to exhibit equal or less than 6% degradation of the bortezomib at ambient conditions after 3 months.

3. The method of claim 1 wherein the substantially non-aqueous solvent system includes at least 75 vol % propylene glycol.

4. The method of claim 1 wherein the liquid parenteral formulation has a pH that is equal or less than 4.0.

5. The method of claim 1 wherein the aqueous buffer has a buffer strength of between 0.05 and 0.25M.

6. The method of claim 1 wherein the bortezomib is present in the liquid parenteral formulation in an amount of between 0.5 mg/ml and 5.0 mg/ml.

7. The method of claim 1 wherein the amount is sufficient for at least ten distinct uses.

8. The method of claim 1 wherein the liquid parenteral formulation is formulated to allow storage at accelerated conditions over at least 1 month after first use without significant degradation of the bortezomib.

9. A bortezomib-containing pharmaceutical article, comprising:

a liquid parenteral formulation contained in a container suitable for providing multiple independent dosages of the liquid formulation;

wherein the liquid parenteral formulation is a single-phase liquid formulation and comprises a substantially non-aqueous solvent system suitable for injection that includes at least 50 vol % propylene glycol, an aqueous buffer, and bortezomib, wherein the bortezomib is present in the formulation at a therapeutically effective concentration;

wherein the liquid parenteral formulation is present in an amount sufficient for at least two distinct uses; and

wherein the liquid parenteral formulation is formulated such as to exhibit equal or less than 10% degradation of bortezomib at accelerated storage conditions after 3 months.

10. The pharmaceutical article of claim 9 wherein the container is a vial or a bag and contains the liquid formulation in an amount sufficient for at least five distinct uses.

11. The pharmaceutical article of claim 9 wherein the liquid parenteral formulation is sterile, and wherein the liquid formulation has not undergone lyophilization before accelerated storage for 3 months.

12. The pharmaceutical article of claim 9 wherein the substantially non-aqueous solvent system includes at least 75 vol % propylene glycol.

13. The pharmaceutical article of claim 12 wherein the liquid parenteral formulation has a pH that is equal or less than 4.0.

14. The pharmaceutical article of claim 13 wherein the aqueous buffer has a buffer strength of between 0.05 and 0.25M.

15. The pharmaceutical article of claim 13 wherein the aqueous buffer is an acetate buffer.

16. A method of using the bortezomib-containing parenteral formulation of claim 9, comprising:

withdrawing from a container a first dosage of a liquid bortezomib-containing pharmaceutical parenteral formulation for a first administration, wherein the container contains at least a second dosage of the liquid bortezomib-containing pharmaceutical parenteral formulation for a second administration;

storing the at least second dosage for at least one week;

withdrawing from the container the at least second dosage for the second administration.

17. The method of claim 16 further comprising a step of withdrawing from the container at least a third dosage.

18. The method of claim 16 wherein the step of storing comprises storage at 4°

C. or ambient condition.

19. The method of claim 16 wherein the container is configured to include the liquid bortezomib-containing pharmaceutical formulation in an amount sufficient for at least ten distinct uses.

20. The method of claim 16 wherein the substantially non-aqueous solvent system includes at least 75 vol % propylene glycol, a buffer having a pH of equal or less than 4.0, and bortezomib at a concentration of between 0.5 mg/ml and 5.0 mg/ml.