Compositions, methods and devices for preparing less painful Botulinum toxin formulations

• US 8,192,979 B2
• Filed: 02/01/2005
• Issued: 06/05/2012
• Est. Priority Date: 01/03/2005
• Status: Active Grant

• Current Assignee: Revance Therapeutics, Inc.
• Original Assignee: Botulinum Toxin Research Associates, Inc.
• Inventors: Acquadro, Martin A., Borodic, Gary E.
• Primary Examiner(s): Ford, Vanessa L.
• Application Number:
  US11/046,721
• Publication Number:
  US 20060147471A1
• Time in Patent Office: 2,681 Days
• Field of Search: 424/184.1, 424/234.1, 424/236.1, 424/247.1, 530/300, 530/324
• US Class Current: 435/283.1
• CPC Class Codes: A61K 38/4893 Botulinum neurotoxin (3.4.24.69)
• CPC Class Codes: A61K 47/02 Inorganic 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: A61M 5/422 Desensitising skin

Abstract

Devices, methods and kits are disclosed for preparing and administering less-painful formulations of Botulinum toxin. The devices, methods and kits of the present invention are comprised of or use an acidic formulation of Botulinum toxin, or, in certain embodiments, a freeze- or flash-dried composition of Botulinum toxin, having a long shelf-life which is subsequently mixed with an acid-neutralizing solution and, optionally a sequestration agent prior to administration to a patient in need thereof. The pH-neutralized formulation of Botulinum toxin is pharmaceutically acceptable for administration to a patient and is significantly less painful than acidic formulations of Botulinum toxin or formulations of Botulinum toxin having unnecessary antigens.

Claims

1. A device comprising at least two chambers, wherein a first chamber comprises an acidic solution of Botulinum toxin, and a second chamber comprises an acid-neutralizing solution, wherein the acid-neutralizing solution is present in an amount sufficient to raise the pH of the acidic botulinum toxin solution to from about pH 7.0 to about pH 7.5 after mixing.

2. The device of claim 1, wherein said device comprises at least three chambers.

3. The device of claim 2, wherein a third chamber comprises a solution comprising one or more sequestering agents.

4. The device of claim 1, wherein said chambers comprise one or more barriers or seals separating the chambers.

5. The device of claim 4, wherein said one or more barriers or seals may be broken or breached or ruptured or punctured or rendered ineffective in preventing mixing of said solutions, to allow the contents of each chamber to mix.

6. The device of claim 1, wherein the pH of said acidic solution of Botulinum toxin is about 1.0 to about 6.9.

7. The device of claim 6, wherein the pH of said acidic solution of Botulinum toxin is about 2.0 to about 6.9.

8. The device of claim 7, wherein the pH of said acidic solution of Botulinum toxin is about 2.5 to about 6.8.

9. The device of claim 8, wherein the pH of said acidic solution of Botulinum toxin is about 2.5 to about 6.7.

10. The device of claim 1, wherein said acidic solution of Botulinum toxin comprises any combination of one or all of immunotypes A-G.

11. The device of claim 1, wherein said acidic solution of Botulinum toxin comprises about 1 to about 2000 LD 50 units of Botulinum toxin.

12. The device of claim 1, wherein said acid-neutralizing solution comprises one or more bases selected from the group consisting of weak bases, strong bases, inorganic bases, and organic bases.

13. The device of claim 1, wherein said acid-neutralizing solution comprises a buffering agent.

14. The device of claim 13, wherein said buffering agent is an organic buffer or an inorganic buffer or any combination of organic and inorganic buffers.

15. The device of claim 1, wherein said acid-neutralizing solution is present in an amount sufficient to raise the pH of said Botulinum toxin solution to from about pH 7.0 to about pH 7.4 after mixing.

16. The device of claim 1, wherein said acid-neutralizing solution is selected from the group consisting of a bicarbonate solution, a phosphate solution, a carbonate solution, a sodium hydroxide solution, a potassium hydroxide solution, a calcium hydroxide solution, an aluminum hydroxide solution, and any combination of these solutions.

17. A method of preparing a pharmaceutical formulation of Botulinum toxin comprising combining an acidic solution of Botulinum toxin and an acid-neutralizing solution in a device of claim 1, wherein the pH of said botulinum toxin formulation after mixing is from about pH 7.0 to about pH 7.5.

18. A method of claim 17, further comprising mixing a measured volume of said acid-neutralizing solution with said acidic formulation of Botulinum toxin, wherein the pH of said botulinum toxin formulation after mixing is from about pH 7.0 to about pH 7.5.

19. A method of preparing a pharmaceutical formulation of Botulinum toxin comprising withdrawing a measured volume of an acid-neutralizing solution from the device of claim 1 and mixing said measured volume with said acidic Botulinum toxin formulation in the device of claim 1, wherein the pH of said botulinum toxin formulation after mixing is from about pH 7.0 to about pH 7.5.

20. A kit comprising a device for preparing a pharmaceutical formulation of Botulinum toxin, wherein said kit comprises the device of claim 1.

21. A kit of claim 20, wherein said kit further comprises a solution of a sequestering agent.