Stabilized formulations of alpha adrenergic receptor antagonists and the uses thereof

• US 7,229,630 B2
• Filed: 06/20/2003
• Issued: 06/12/2007
• Est. Priority Date: 06/20/2002
• Status: Expired due to Term

• Current Assignee: Septodont Holding
• Original Assignee: Novalar Pharmaceuticals, Inc.
• Inventors: Weber, Eckard, Knowles, Julius, Chen, Andrew X.
• Primary Examiner(s): Webman; Edward J.
• Application Number:
  US10/465,810
• Publication Number:
  US 20040044019A1
• Time in Patent Office: 1,453 Days
• Field of Search: 424/400, 424/451, 424/422, 424/423, 514817-818, 514/784, 514/788
• US Class Current: 424/400
• 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 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48

Abstract

The present invention provides compositions and stable liquid formulations comprising alpha adrenergic receptor antagonists and use thereof for increasing blood flow. In one embodiment, the stable liquid formulations of this invention are useful for reversing the effects of an anesthetic agent, preferably a long-lasting local anesthetic agent administered in conjunction with an alpha adrenergic receptor agonist.

Claims

1. A stable liquid formulation consisting essentially of a low dose of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, and a metal chelator selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA, wherein said formulation has a pH of from about 2.0 and 6.0.

3. The stable liquid formulation according to claim 1 or 2, wherein said alpha adrenergic receptor antagonist is selected from phentolamine, phentolamine hydrochloride, phentolamine mesylate, tolazoline, yohimbine, rauwolscine, doxazosine, labetalol, prazosine, tetrazosine or trimazosine or a pharmaceutically acceptable salt of any of the above.

4. The stable liquid formulation of claim 3, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

5. The stable liquid formulation according to claim 1 or 2, wherein said alpha adrenergic receptor antagonist is present at a concentration of between about 0.01 mg/ml and about 10 mg/ml.

6. The stable liquid formulation according to claim 5, wherein said alpha adrenergic receptor antagonist is present at a concentration of between about 0.1 mg/ml and about 0.25 mg/ml.

7. The stable liquid formulation of claim 6, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

8. The stable liquid formulation according to claim 1 or 2, wherein said aqueous solvent is water.

9. The stable liquid formulation according to claim 1 or 2, wherein said metal chelator is EDTA present at a concentration of between about 0.5 and about 1.0 mg/ml.

10. The stable liquid formulation of claim 9, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

11. The stable liquid formulation according to claim 1 or 2, wherein the pH of said formulation is between about 3.5 and about 4.5.

12. The stable liquid formulation according to claim 1 or 2, wherein said pH is achieved with a 10 to 50 mM acetate buffer, or with methanesulfonic acid.

13. The stable liquid formulation of claim 12, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

29. A container comprising a single dosage form of a stable liquid formulation according to any one of claims 1, 2, 14, 15, 16, 17, 18, 19, 20, or 21.

30. The container according to claim 29, selected from an ampule, a dental cartridge or a pre-filled sterile syringe.

31. The container according to claim 30, wherein said stable liquid formulation is present in a volume of between about 1.6 and 1.8 mL.

32. A kit comprising a carrier having in close confinement therein two or more containers, wherein a first container contains an anesthetic agent and optionally an alpha adrenergic receptor agonist and a second container contains the stable liquid formulation according to any one of claims 1, 2, 14, 15, 16, 17, 18, 19, 20, or 21.

33. The kit according to claim 32, wherein said second container comprises a single dosage form of said stable liquid formulation.

2. A stable liquid formulation consisting essentially of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent and a metal chelator selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA, wherein said formulation has a pH of from about 2.0 and about 6.0, and wherein said stable liquid formulation is present in a dental cartridge or a pre-filled sterile syringe.

14. A stable liquid formulation consisting essentially of a low dose of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, a tonicity modifier, and a metal chelator selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA, wherein said formulation has a pH of from about 2.0 and 6.0.

22. The stable liquid formulation according to claim 14 or 19, wherein said tonicity modifier is selected from NaCl, d-mannitol or dextrose.

23. The stable liquid formulation according to claim 22, wherein said tonicity modifier is d-mannitol present at a concentration of between about 4 and about 5% (w/v).

24. The stable liquid formulation of claim 23, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

15. A stable liquid formulation consisting essentially of a low dose of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, an antioxidant in an amount sufficient to prevent oxidization of said alpha adrenergic receptor antagonist, and a metal chelator selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA, wherein said formulation has a pH of from about 2.0 and 6.0.

25. The stable liquid formulation according to claim 15 or 20, wherein said antioxidant is selected from ascorbic acid, sodium metabisulfite, butylated hydroxyanisole, and butylated hydroxytoluene.

26. The stable liquid formulation of claim 25, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

16. A stable liquid formulation consisting essentially of a low dose of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, a complexing agent, and a metal chelator selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA, wherein said formulation has a pH of from about 2.0 and 6.0.

27. The stable liquid formulation according to claim 16 or 21, wherein said complexing agent is selected from α

-cyclodextrin or niacinamide.

28. The stable liquid formulation of claim 27, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

17. A stable liquid formulation comprising 0.235 mg/ml phentolamine mesylate, 0.5 mg/ml EDTA, 5% d-mannitol, and 16.6 mM acetate buffer, wherein said formulation has a pH of 3.8 to 4.2.

18. A stable liquid formulation selected from:

19. A stable liquid formulation consisting essentially of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, a tonicity modifier, and a metal chelator selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA, wherein said formulation has a pH of from about 2.0 to about 6.0, and wherein said stable liquid formulation is present in a dental cartridge or a pre-filled sterile syringe.

20. A stable liquid formulation consisting essentially of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, an antioxidant in an amount sufficient to prevent oxidization of said alpha adrenergic receptor antagonist, and a metal chelator selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA, wherein said formulation has a pH of from about 2.0 to about 6.0, and wherein said stable liquid formulation is present in a dental cartridge or a pre-filled sterile syringe.

21. A stable liquid formulation consisting essentially of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, a complexing agent, and a metal chelator selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA, wherein said formulation has a pH of from about 2.0 to about 6.0, and wherein said stable liquid formulation is present in a dental cartridge or a pre-filled sterile syringe.