Stable bortezomib formulations

• US 9,107,821 B2
• Filed: 08/22/2012
• Issued: 08/18/2015
• 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): MCMILLIAN, KARA RENITA
• Application Number:
  US13/592,228
• Publication Number:
  US 20120322762A1
• Time in Patent Office: 1,091 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. An extended potency, ready to inject pharmaceutical parenteral composition in a vial, the composition comprising:

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

wherein the single-phase liquid formulation is formulated such that at least 95% of the bortezomib remain as active ingredient after storage at ambient conditions for at least three months;

wherein the substantially non-aqueous solvent system comprises more than 50 vol % propylene glycol; and

wherein the liquid formulation and bortezomib are present in the vial in a quantity suitable for at least two independent and distinct administrations.

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 75 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 buffer is an aqueous acetate buffer.

6. The composition of claim 1 wherein the buffer has a pH between 2.0 and 4.0.

7. The composition of claim 1 wherein the buffer has a pH that is equal or less than 4.0, and wherein the single-phase liquid formulation has not undergone lyophilization before storage at ambient conditions for at least three months.

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

9. A method of stabilizing bortezomib in a liquid pharmaceutical composition that includes bortezomib in a therapeutically effective amount, comprising:

formulating a ready to inject single-phase liquid formulation from a substantially non-aqueous solvent system suitable for injection, an aqueous buffer, and bortezomib;

wherein the solvent system comprises more than 50 vol % propylene glycol and wherein the bortezomib is present in the formulation at a therapeutically effective concentration;

adjusting the pH of the buffer such that the single-phase liquid formulation has a pH that is equal or less than 4.0; and

placing the single-phase liquid formulation in a vial, optionally in a quantity suitable for at least two independent and distinct administrations.

10. The method of claim 9 wherein the single-phase liquid formulation is formulated such that at least 98% of the bortezomib remain as active ingredient after storage at ambient conditions for at least three months.

11. The method of claim 10 wherein the single-phase liquid formulation comprises ethanol and propylene glycol, or exclusively propylene glycol.

12. The method of claim 9 wherein the single-phase liquid formulation includes the aqueous buffer and is formulated such that at least 98% of the bortezomib remain as active ingredient after storage at ambient conditions for at least three months.

13. The method of claim 12 wherein the single-phase liquid formulation comprises at least 75 vol % propylene glycol.

14. The method of claim 13 wherein the aqueous buffer is acetate buffer.

15. The method of claim 12 wherein the pH of the buffer is adjusted such that the single-phase liquid formulation has a pH that is between 2.7. and 3.3.

16. A method of maintaining potency of a liquid pharmaceutical composition that contains bortezomib by reducing degradation of bortezomib in a liquid formulation, the method comprising:

preparing a single-phase ready to inject liquid formulation from a substantially non-aqueous solvent system suitable for injection, and bortezomib;

wherein the substantially non-aqueous solvent system comprises more than 50 vol % propylene glycol;

including an aqueous buffer into the formulation and adjusting the pH of the buffer to a value between 2.0 and 4.0 to thereby reduce formation of at least one degradation product as compared to the formulation without buffer; and

wherein the at least one degradation product is selected form the group consisting of an amide degradation product, a carboxylic acid degradation product, a first carbinolamide degradation product, and a second carbinolamide degradation product; and

placing the single-phase liquid formulation in a multi-use vial, optionally in a quantity suitable for at least two independent and distinct administrations.

17. The method of claim 16 wherein the aqueous buffer is selected from the group consisting of an acetate buffer, a citrate buffer, and a potassium hydrogen phthalate/HCl buffer.

18. The method of claim 16 wherein the pH of the buffer is adjusted to a value between 2.7 and 3.3 to thereby reduce formation of the amide degradation product, the carboxylic acid degradation product, the first carbinolamide degradation product, and the second carbinolamide degradation product.

19. The method of claim 18 wherein the buffer is an acetate buffer.

20. The method of claim 16 wherein the bortezomib is present in the liquid pharmaceutical composition at a concentration of 1 mg/ml and 5 mg/ml.