Stabilized formulations of alpha adrenergic receptor antagonists and the uses thereof

• US 7,575,757 B2
• Filed: 03/18/2005
• Issued: 08/18/2009
• Est. Priority Date: 06/20/2002
• Status: Active Grant

• Current Assignee: Septodont Holding
• Original Assignee: Novalar Pharmaceuticals, Inc.
• Inventors: Knowles, Julius, Chen, Andrew X., Weber, Eckard
• Primary Examiner(s): Richter; Johann R
• Assistant Examiner(s): Kassa; Tigabu
• Application Number:
  US11/082,968
• Publication Number:
  US 20050203099A1
• Time in Patent Office: 1,614 Days
• Field of Search: None
• 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 about 0.02 mg to about 0.43 mg of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, a metal chelator, optionally a tonicity modifier, optionally an antioxidant, and optionally a complexing agent, wherein said composition has a pH of between about 2.0 and 6.0.

2. The stable liquid formulation according to claim 1, 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.

3. The stable liquid formulation according to claim 2, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

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

5. The stable liquid formulation according to claim 4, wherein said aqueous solvent is water.

6. The stable liquid formulation according to claim 1, wherein said metal chelator is selected from diammonium ethylenediamine triacetate, hydroxyethyl-ethylenediamine triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, citric acid, or EDTA.

7. The stable liquid formulation according to claim 6, wherein said metal chelator is EDTA present at a concentration of between about 0.5 and about 1.0 mg/mL.

8. The stable liquid formulation according to claim 7, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

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

10. The stable liquid formulation according to claim 9, wherein said pH is achieved with a 10 to 50 mM acetate buffer, or with methanesulfonic acid.

11. The stable liquid formulation according to claim 10, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

12. The stable liquid formulation according to claim 1 further containing a tonicity modifier.

13. The stable liquid formulation according to claim 12, wherein said tonicity modifier is selected from the group consisting of NaCl, d-mannitol and dextrose.

14. The stable liquid formulation according to claim 13, wherein said tonicity modifier is d-mannitol at 4-5%.

15. The stable liquid formulation according to claim 14, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

16. The stable liquid formulation according to claim 1, containing further an antioxidant in an amount sufficient to prevent oxidization of said alpha adrenergic receptor antagonist.

17. The stable liquid formulation according to claim 16, wherein said antioxidant is selected from the group consisting of ascorbic acid, sodium metabisulfite, butylated hydroxyanisole, and butylated hydroxytoluene.

18. The stable liquid formulation of claim 17, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

19. The stable liquid formulation according to claim 1, containing further a complexing agent.

20. The stable liquid formulation according to claim 19, wherein said complexing agent is selected from α

-cyclodextrin or niacinamide.

21. The stable liquid formulation of claim 20, wherein said alpha adrenergic receptor antagonist is phentolamine mesylate.

22. The stable liquid formulation of claim 1, containing further 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.

23. A container containing a single dosage form of a stable liquid formulation according to claim 1.

24. The container according to claim 23, selected from an ampule, a dental cartridge or a pre-filled sterile syringe.

25. The container according to claim 24, wherein said stable liquid formulation is present in a volume of between about 1.6 and 1.8 mL.

26. A stable liquid formulation consisting essentially of about 0.02 mg to about 0.43 mg of an alpha adrenergic receptor antagonist, a buffer for maintaining pH, an aqueous solvent, a metal chelator, optionally a tonicity modifier, optionally an antioxidant, and optionally a complexing agent.

27. The stable liquid formulation according to claim 26, wherein the pH of said composition is between about 2.0 and 7.0.