Method of induction of apoptosis and inhibition of matrix metalloproteinases using antimicrobial metals

• US 7,001,617 B2
• Filed: 05/30/2002
• Issued: 02/21/2006
• Est. Priority Date: 04/23/2001
• Status: Expired due to Term

• Current Assignee: NUCRYST Pharmaceuticals Corp. (The Westaim Corporation)
• Original Assignee: Nueryst Pharmaceuticals Corporation
• Inventors: Lam, Kan, Burrell, Robert Edward, Wright, John Barrymore
• Primary Examiner(s): PAK, JOHN D
• Application Number:
  US10/159,587
• Publication Number:
  US 20030072810A1
• Time in Patent Office: 1,363 Days
• Field of Search: 424618-619, 424/487, 424/489, 424/400, 424/402, 424404-405, 424/490, 424/646, 424/649, 424/443, 424/445, 424/447, 514/492, 514/495, 514/825, 514/878, 514/951, 514/964
• US Class Current: 424/618
• 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 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/242 Gold; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 33/38 Silver; Compounds 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
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61L 15/46 Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
• CPC Class Codes: A61L 17/145 Coating
• CPC Class Codes: A61L 2300/102 Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
• CPC Class Codes: A61L 2300/104 Silver, e.g. silver sulfadiazine
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/434 of enzymes
• CPC Class Codes: A61L 2300/63 Crystals
• CPC Class Codes: A61L 27/30 Inorganic materials
• CPC Class Codes: A61L 29/10 Inorganic materials
• CPC Class Codes: A61L 31/082 Inorganic materials
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders

Abstract

The invention relates to a method to induce apoptosis and to inhibit matrix metalloproteinases in a disease condition in a human or animal by contacting hyperplastic tissue, tumor tissue, or a cancerous lesion with one or more antimicrobial metals, preferably formed with atomic disorder, and preferably in a nanocrystalline form. In another aspect of the invention, there is provided a method of preventing excessive release of matrix metalloproteinases from an inflammatory cell in a disease condition in a human or an animal by contacting the cell with a therapeutically effective amount of a noble metal in a crystalline form characterized by atomic disorder, or with a solution derived therefrom to provide a modulatory effect on one or more matrix metalloproteinases, wherein the one or more noble metals is formed with atomic disorder, and preferably in a nanocrystalline form. The nanocrystalline antimicrobial or noble metal of choice may be used in the form of a nanocrystalline coating of one or more antimicrobial or noble metals, a nanocrystalline powder of one or more antimicrobial or noble metals, or a solution containing dissolved species from a nanocrystalline powder or coating of one or more antimicrobial or noble metals.

Claims

1. A method of treating excessive release of one or more matrix metalloproteinases from an inflammatory cell in a disease condition in a human or an animal, which comprises:

contacting the cell with a therapeutically effective amount of a noble metal in a crystalline form characterized by atomic disorder, or with a solution derived therefrom, to provide a modulating effect on one or more matrix metalloproteinases, wherein the noble metal is formed with sufficient atomic disorder, such that the metal, in contact with an alcohol or water-based electrolyte, releases atoms, ions, molecules, or clusters of at least one noble metal at a concentration sufficient to provide a localized anti-MMP effect.

2. The method according to claim 1, further comprising providing a modulating effect on one or more cytokines.

3. The method as set forth in claim 2, wherein the noble metal is silver.

4. The method as set forth in claim 3, wherein the noble metal is nanocrystalline and is formed with sufficient atomic disorder such that, in contact with an alcohol or water based electrolyte, the noble metal releases ions, atoms, molecules or clusters of the noble metal on a sustainable basis.

5. The method as set forth in claim 4, wherein the one or more matrix metalloproteinases are selected from the group consisting of collagenases, gelatinases, stromelysins, and stromelysin-like matrix metalloproteinases.

6. The method as set forth in claim 5, wherein the one or more matrix metalloproteinases is a gelatinase.

7. The method as set forth in claim 6, wherein the gelatinase is MMP-9.

8. The method as set forth in claim 7, wherein the cytokine is TNF-α

.

9. The method as set forth in claim 8, wherein the noble metal is nanocrystalline silver.

10. The method as set forth in claim 8, wherein the noble metal is silver, formed as a composite with oxygen.

11. The method as set forth in claim 8, wherein the one or more noble metals are provided as a coating on, or filler in, a dressing or a hydrated dressing, or in a pharmaceutical composition with one or more pharmaceutically and dermatogically acceptable carriers, diluents, or excipients suitable for topical application.

12. The method as set forth in claim 11, wherein the pharmaceutical composition includes a nanocrystalline powder of one or more noble metals, or a solution containing dissolved species from a nanocrystalline powder or coating of one or more noble metals.

13. The method as set forth in claim 12, wherein the pharmaceutical composition is a gel, cream, lotion, paste, or ointment containing the noble metal powder in an amount of 0.01–

10% by weight, or a liquid formulated as a topical solution, spray, mist, drops, infusion or instillation containing 0.001–

10% by weight of the noble metal.

14. The method as set forth in claim 12, wherein the noble metal is nanocrystalline silver.

15. The method as set forth in claim 12, wherein the noble metal is silver, formed as a composite with oxygen.

16. The method as set forth in claim 12, wherein the noble metal is in a powder form and is delivered directly to a locus of the disease condition.

17. The method of claim 16, wherein the powder is sized with particulates no larger than 2 μ

m.

18. The method of claim 16, wherein the powder is sized with particulates no larger than 1 μ

m.

19. The method of claim 18, wherein the noble metal is nanocrystalline silver.

20. The method of claim 18, wherein the noble metal is nanocrystalline silver, formed as a composite with oxygen.

21. A method of treating excessive release of one or more matrix metalloproteinases from an inflammatory cell in a disease condition in a human or an animal, which comprises:

contacting the cell with a therapeutically effective amount of an antimicrobial metal in a crystalline form characterized by atomic disorder, or with a solution derived therefrom, to provide a modulating effect on one or more matrix metalloproteinases, wherein the antimicrobial metal is formed with sufficient atomic disorder, such that the metal, in contact with an alcohol or water-based electrolyte, releases atoms, ions, molecules, or clusters of at least one antimicrobial metal at a concentration sufficient to provide a localized anti-MMP effect.

22. The method according to claim 21, further comprising providing a modulating effect on one or more cytokines.

23. The method as set forth in claim 22, wherein the antimicrobial metal is silver.

24. The method as set forth in claim 23, wherein the antimicrobial metal is nanocrystalline and is formed with sufficient atomic disorder such that, in contact with an alcohol or water based electrolyte, the antimicrobial metal releases ions, atoms, molecules or clusters of the antimicrobial metal on a sustainable basis.

25. The method as set forth in claim 24, wherein the one or more matrix metalloproteinases are selected from the group consisting of collagenases, gelatinases, stromelysins, and stromelysin-like matrix metalloproteinases.

26. The method as set forth in claim 25, wherein the one or more matrix metalloproteinases is a gelatinase.

27. The method as set forth in claim 26, wherein the gelatinase is MMP-9.

28. The method as set forth in claim 27, wherein the cytokine is TNF-α

.

29. The method as set forth in claim 28, wherein the antimicrobial metal is nanocrystalline silver.

30. The method as set forth in claim 28, wherein the antimicrobial metal is silver, formed as a composite with oxygen.

31. The method as set forth in claim 28, wherein the one or more antimicrobial metals are provided as a coating on, or filler in, a dressing or a hydrated dressing, or in a pharmaceutical composition with one or more pharmaceutically and dermatogically acceptable carriers, diluents, or excipients suitable for topical application.

32. The method as set forth in claim 31, wherein the pharmaceutical composition includes a nanocrystalline powder of one or more antimicrobial metals, or a solution containing dissolved species from a nanocrystalline powder or coating of one or more antimicrobial metals.

33. The method as set forth in claim 32, wherein the pharmaceutical composition is a gel, cream, lotion, paste, or ointment containing the antimicrobial metal powder in an amount of 0.01–

10% by weight, or a liquid formulated as a topical solution, spray, mist, drops, infusion or instillation containing 0.001–

10% by weight of the antimicrobial metal.

34. The method as set forth in claim 32, wherein the antimicrobial metal is nanocrystalline silver.

35. The method as set forth in claim 32, wherein the antimicrobial metal is silver, formed as a composite with oxygen.

36. The method as set forth in claim 32, wherein the antimicrobial metal is in a powder form and is delivered directly to a locus of the disease condition.

37. The method of claim 36, wherein the powder is sized with particulates no larger than 2 μ

m.

38. The method of claim 36, wherein the powder is sized with particulates no larger than 1 μ

m.

39. The method of claim 38, wherein the antimicrobial metal is nanocrystalline silver.

40. The method of claim 38, wherein the antimicrobial metal is nanocrystalline silver, formed as a composite with oxygen.