Systems and methods for topical treatment with nitric oxide

• US 7,048,951 B1
• Filed: 05/24/2000
• Issued: 05/23/2006
• Est. Priority Date: 06/10/1998
• Status: Expired due to Fees

• Current Assignee: Nitric Solutions Inc
• Original Assignee: Nioxx LLC
• Inventors: Seitz, William A., Balaban, Alexandru T., Garfield, Robert E., Stewart, Randall J.
• Primary Examiner(s): Reamer, James H
• Application Number:
  US10/296,110
• Time in Patent Office: 2,190 Days
• Field of Search: 424/718, 514/474, 514/458, 514/578
• US Class Current: 424/718
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00

Abstract

A simple, biocompatible system and procedure for generating nitric oxide (NO) is described. A mixture of powdered sodium nitrite, ascorbic acid, and maleic acid (or another organic acid of adequate strength) immediately generates nitric oxide (NO) on treatment with water. To slow down the NO generation, one may prepare an ointment from a nonaqueous medium (petrolatum, Vaseline™) and the three powdered ingredients, which on being applied topically on the skin will release NO as water permeates through this medium; alternatively, one may convert the aqueous sodium nitrite solution into a gel with hydroxyethylcellulose (or other gel-forming compound) and combine this gel with another gel obtained from aqueous ascorbic and maleic acids with hydroxyethylcellulose for topical application (on intact skin, burns intra-cavity, burns, intra-cavity, etc.). The two gels may be admixed immediately before use (possibly from a single container with separate chambers and dual nozzle, via pushing or squeezing the two gels through the nozzle), or may be applied in sandwich-like fashion (possibly as a transdermal patch) for further slowing down the delivery of NO.

Claims

1. A method for therapeutically applying NO, the method comprising combining a nitrite salt, a biocompatible reductant and an acid with a pKa between about 1 and about 4 in a medium and topically applying said combination to a body site.

3. The method of claim 1 or 2 where the reductant is an ascorbate salt, an erythrobate or α

-tocopherol.

4. The method of claim 1 or 2 where the reductant is ascorbic acid.

5. The method of claim 1 or 2 where the acid is an organic acid.

6. The method of claim 1 or 2 where the acid is maleic acid.

7. The method of claim 1 or 2 where the acid is an inorganic acid.

8. The method of claim 1 or 2 where the nitrite salt is an inorganic salt.

9. The method of claim 1 or 2 where the nitrite salt is sodium nitrite.

10. The method of claim 1 or 2 where the medium is an aqueous gel.

11. The method of claim 1 or 2 where the medium comprises hydroxyethyl cellulose or poloxama.

12. The method of claim 1 or 2 where the medium is an organic salve.

2. A method for topical delivery of nitric oxide (NO) comprising mixing a powdered nitrite salt with a powdered reductant and an acid having a pKa between about 1 and about 4 in a diffusion-inhibiting topically applicable medium and topically applying an effective amount of said mixture to a body site.

13. A topically applicable ointment for controlled NO delivery comprising a nitrite salt, a reductant and an acid with a pKa between about 1 and about 4 in a medium sufficiently viscous to inhibit diffusion, permit slow NO release and facilitate topical application.

14. The ointment of claim 13 where the reductant is ascorbic acid, an ascorbate salt, an erythrobate or α

-tocopherol.

15. The ointment of claim 13 where the reductant is ascorbic acid.

16. The ointment of claim 13 where the acid is an organic acid.

17. The ointment of claim 13 where the acid is maleic acid.

18. The ointment of claim 13 where the acid is an inorganic acid.

19. The ointment of claim 13 where the nitrite salt is an inorganic salt.

20. The ointment of claim 13 where the nitrite salt is sodium nitrite.

21. The ointment of claim 13 where the medium is an aqueous gel.

22. The ointment of claim 13 where the medium is an organic salve.

33. A method in which the ointment of claim 13 or the two gels of the composition of claim 23 are applied on the skin through an interposed gas-permeable membrane for lessening any skin irritation.

23. A composition for generating and controlling the release rate of NO for topical applications comprising a first aqueous gel and a second aqueous gel, the first gel comprising a nitrite salt, and the second gel comprising an acid having a pKa between about 1 and about 4 and at least one of the first and second gel comprising a reductant.

24. The composition of claim 23 where the reductant is ascorbic acid, an ascorbate salt, an erythrobate or α

-tocopherol.

25. The composition of claim 23 where the reductant is ascorbic acid.

26. The composition of claim 23 where the acid is an organic acid.

27. The composition of claim 23 where the acid is maleic acid.

28. The composition of claim 23 where the acid is an inorganic acid.

29. The composition of claim 23 where the nitrite salt is an inorganic salt.

30. The composition of claim 23 where the nitrite salt is sodium nitrite.

31. A method for delivering the two gels of the composition of claim 23 from a single container with two separate chambers by forcing them through a nozzle with a hole for each chamber.

32. A method for topical application of the gels of the composition of claim 23 in layers, with the nitrite-containing gel layer being in contact with the skin, the second gel layer being separated from the first by an impermeable plastic or metal foil until just before use, when the plastic or foil is removed, and the gel layers are topically applied.

34. A gel comprising a nitrite salt, an acid with a pKa between 1 and 4, and a reductant, for medical use.

35. A kit containing a first gel comprising a nitrite salt, a second gel comprising an acid with a pKa between 1 and 4, and a reductant in at least one of the first and second gels.