Bortezomib formulations

• US 8,962,572 B2
• Filed: 10/04/2011
• Issued: 02/24/2015
• Est. Priority Date: 10/05/2010
• Status: Active Grant

• Current Assignee: Fresenius KABI USA LLC (Fresenius SE & Co. KGaA)
• Original Assignee: Fresenius KABI USA LLC (Fresenius SE & Co. KGaA)
• Inventors: Usayapant, Arunya, Bowman, David
• Primary Examiner(s): AUDET, MAURY A
• Application Number:
  US13/252,421
• Publication Number:
  US 20120083457A1
• Time in Patent Office: 1,239 Days
• Field of Search: None
• US Class Current: 514/21.91
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 33/22 Boron compounds
• 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 9/19 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

Abstract

A bortezomib composition includes bortezomib and boric acid in a mass ratio of boric acid to bortezomib is from 1:1 to 10:1. The composition is a solid, and may be prepared by forming a liquid mixture including a solvent, bortezomib and boric acid, and lyophilizing the liquid mixture.

Claims

1. A composition, comprising:

bortezomib, and

boric acid;

where the composition is a solid, and

the mass ratio of boric acid to bortezomib is from 1;

1 to 10;

1.

2. The composition of claim 1, where the mass ratio of boric acid to bortezomib is from 1:

1 to 4;

1.

3. The composition of claim 1, where the mass ratio of boric acid to bortezomib is from 2:

1 to 3;

1.

4. The composition of claim 1, further comprising at least one other substance selected from the group consisting of an amino acid and a saccharide.

5. The composition of claim 1, further comprising glycine, where the mass ratio of glycine to bortezomib is from 1:

1 to 20;

1.

6. The composition of claim 5, where the mass ratio of glycine to bortezomib is from 5:

1 to 15;

1.

7. The composition of claim 5, where the mass ratio of glycine to bortezomib is from 7:

1 to 10;

1.

8. The composition of claim 5, where the mass ratio of boric acid to bortezomib is about 3:

1, and the mass ratio of glycine to bortezomib is about 7;

1.

9. The composition of claim 8, comprising about 3.5 mg bortezomib, about 10.5 mg boric acid, and about 25 mg glycine.

10. The composition of claim 1, further comprising mannitol, where the mass ratio of mannitol to bortezomib is from 1:

1 to 20;

1.

11. The composition of claim 1, where at least a portion of the bortezomib is present in an anhydride structure.

12. The composition of claim 1, where at least a portion of the bortezomib and boric acid are present together in an anhydride structure.

13. The composition of claim 1, where when the composition is stored at 55°

C., at most 5% of the bortezomib degrades after 3 weeks.

14. The composition of claim 1, where when the composition is stored at 55°

C., at most 2% of the bortezomib degrades after 3 weeks.

15. The composition of claim 1, where when the composition is stored at 55°

C., at most 1% of the bortezomib degrades after 3 weeks.

16. The composition of claim 1, where when the composition is stored at 55°

C., at most 0.5% of the bortezomib degrades after 3 weeks.

17. The composition of claim 1, where

when the composition is combined with a 0.9% NaCl saline solution at a bortezomib concentration of 1 mg/mL saline and manually shaken every 15 seconds,

the composition forms a solution or an emulsion within 4 minutes.

18. The composition of claim 17, where the composition forms the solution or the emulsion within 3 minutes.

19. A method of making a solid composition, comprising:

forming a liquid mixture comprising a solvent, bortezomib, and boric acid; and

lyophilizing the liquid mixture,

where the mass ratio of the boric acid to the bortezomib in the liquid mixture is from 1;

1 to 10;

1, and

where the solvent includes water and 1-20% by volume of a water-miscible organic solvent selected from the group consisting of ethanol, isopropanol, and tert-butanol.

20. A composition, formed by a method comprising:

forming a liquid mixture comprising a solvent, bortezomib, and boric acid,

where the solvent includes water and 1-20% by volume of a water-miscible organic solvent selected from the group consisting of ethanol, isopropanol, and tert-butanol,

where the mass ratio of boric acid to bortezomib in the liquid mixture is from 1;

1 to 10;

1; and

lyophilizing the liquid mixture to form a solid composition.