Antimicrobial bioabsorbable materials

• US 20010055622A1
• Filed: 04/16/2001
• Published: 12/27/2001
• Est. Priority Date: 04/17/2000
• Status: Active Grant

• Current Assignee: NUCRYST Pharmaceuticals Corp. (The Westaim Corporation)
• Original Assignee: NUCRYST Pharmaceuticals Corp. (The Westaim Corporation)
• Inventors: Djokic, Stojan, Yin, Hua Qing, Burrell, Robert Edward, Langford, Rita Johanna Mary
• Granted Patent: US 6,719,987 B2
• Time in Patent Office: Days
• US Class Current: 424/600
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61L 15/18 containing inorganic materials
• CPC Class Codes: A61L 15/46 Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
• CPC Class Codes: A61L 17/005 containing a biologically active substance, e.g. a medicament or a biocide
• 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 2300/606 Coatings
• CPC Class Codes: A61L 2300/622 Microcapsules
• CPC Class Codes: A61L 2300/624 Nanocapsules
• CPC Class Codes: A61L 2300/63 Crystals
• CPC Class Codes: A61L 27/306 Other specific inorganic materials not covered by A61L27/303 - A61L27/32
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/088 Other specific inorganic materials not covered by A61L31/084 or A61L31/086
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Abstract

The invention provides bioabsorbable materials with antimicrobial coatings or powders which provide an effective and sustainable antimicrobial effect. Specifically, this invention provides bioabsorbable materials comprising a bioabsorbable substrate associated with one or more antimicrobial metals being in a crystalline form characterized by sufficient atomic disorder, such that the bioabsorbable material in contact with an alcohol or water based electrolyte, releases atoms, ion, molecules, or clusters of at least one antimicrobial metal at a concentration sufficient to provide an antimicrobial effect. The one or more antimicrobial metals do not interfere with the bioabsorption of the bioabsorbable material, and do not leave behind particulates larger than 2 μm, as measured 24 hours after. The bioabsorbable material has disappeared. Most preferably, the particulate sizing from the coating or powder is sub-micron that is less than about 1 μm, as measured 24 hours after the bioabsorbable material has disappeared. Particulates are thus sized to avoid deleterious immune responses or toxic effects. Such antimicrobial metals are in the form of a continuous or discontinuous coating, a powder, or a coating on a bioabsorbable powder. The antimicrobial coating is thin, preferably less than 900 nm or more preferably less than 500 nm, and very fine grained, with a grain size (crystallite size) of preferably less than 100 nm, more preferably less than 40 nm, and most preferably less than 20 nm. The antimicrobial coating is formed of an antimicrobial metal, which is overall crystalline, but which is created with atomic disorder, and preferably also having either or both of a) a high oxygen content, as evidenced by a rest potential greater than about 225 mV, more preferably greater than about 250 mV, in 0.15 M Na₂CO₃ against a SCE (standard calomel electrode), or b) discontinuity in the coating. The antimicrobial metal associated with the bioabsorbable substrate may also be in the form of a powder, having a particle size of less than 100 μm, or preferably less than 40 μm, and with a grain size (crystallite size) of preferably less than 100 nm, more preferably less than 40 nm, and most preferably less than 20 nm, Such powders may be prepared as a coating preferably of the above thickness, onto powdered biocompatible and bioabsorbable substrates; as a nanocrystalline coating and converted into a powder; or as a powder of the antimicrobial metal which is cold worked to impart atomic disorder. Methods of preparing the above antimicrobial bioabsorbable materials are thus also provided.

Claims

1. A bioabsorbable material comprising:

a bioabsorbable substrate; and

one or more antimicrobial metals associated with the bioabsorbable substrate, the one or more antimicrobial metals being in a crystalline form characterized by sufficient atomic disorder, such that the material 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 antimicrobial effect, and wherein the one or more antimicrobial metals are associated with the bioabsorbable substrate such that particulates of the one or more antimicrobial metals formed during dissociation are sized to avoid deleterious immune responses or toxic effects.

2. The material of

claim 1

, wherein the one or more antimicrobial metals associated with the bioabsorbable substrate are in the form of a continuous or discontinuous coating or a powder.

3. The material of

claim 1

, wherein the one or more antimicrobial metals associated with the bioabsorbable substrate are in the form of a coating on a powder.

4. The material of

claim 2

, wherein the one or more antimicrobial metals are formed as discontinuous coatings and/or with sufficient high oxygen content that the particulate of the one or more antimicrobial metals formed during dissociation has a size of less than 2 μ

m.

5. The material of

claim 4

, wherein the particulate has a size of less than 1 μ

m.

6. The material of

claim 2

, wherein the one or more antimicrobial metals are provided in the form of a coating, having a thickness of less than 900 nm.

7. The material of

claim 6

, wherein the one or more antimicrobial metals are provided in the form of a coating, having a thickness of less than 500 nm.

8. The material of

claim 2

, wherein the one or more antimicrobial metals are provided in the form of a powder, having a particle size of less than 100 μ

m.

9. The material of

claim 8

, wherein the one or more antimicrobial metals are provided in the form of a powder, having a particle size of less than 40 μ

m.

10. The material of

claim 2

, wherein the one or more antimicrobial metals are in the form of a nanocrystalline coating or powder, formed with sufficient atomic disorder to provide sustained release of atoms, ions, molecules, or clusters of the one or more antimicrobial metals.

11. The material of

claim 10

, wherein the nanocrystalline coating or powder has a crystallite size of less than 100 nm.

12. The material of

claim 10

, wherein the nanocrystalline coating or powder has a grain size less than 40 nm.

13. The material of

claim 10

, wherein the nanocrystalline coating or powder has a grain size less than 20 nm.

14. The material of

claim 13

, wherein the one or more antimicrobial metals are selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, Zn, or alloys or compounds thereof.

15. The material of

claim 11

, wherein at least one of the one or more antimicrobial metals is Ag or Au, or alloys or compounds thereof.

16. The material of

claim 11

, wherein the antimicrobial metal is silver, or an alloy or compound thereof.

17. The material of

claim 14

, wherein the coating or powder includes absorbed, trapped, or reacted atoms or molecules of oxygen.

18. The material of

claim 17

, wherein sufficient oxygen is incorporated in the coating or powder such that the particulate of the one or more antimicrobial metals during dissociation has a size less than 2 μ

m.

19. The material of

claim 17

, wherein sufficient oxygen is incorporated in the coating or powder such that the particulate of the one or more antimicrobial metals during dissociation has a size less than 1 μ

m.

20. The material of

claim 18

, wherein the one or more antimicrobial metals are silver, or an alloy or compound thereof, and wherein the coating or powder has a ratio of its temperature of recrystallization to its melting temperature, in degrees K (T_rec/T_m), less than 0.33.

21. The material of

claim 20

, wherein the ratio is less than 0.3.

22. The material of

claim 21

, wherein the temperature of recrystallization is less than about 140°

C.

23. The material of

claim 20

, wherein the coating has a positive rest potential, when measured against a standard calomel electrode, in 0.15 M Na₂CO₃ or 0.15 M KOH.

24. The material of

claim 23

, wherein the positive rest potential is greater than 225 mV in 0.15 M Na₂CO₃.

25. The material of

claim 23

, wherein the positive rest potential is greater than 250 mV in 0.15 M Na₂CO₃.

26. The material of

claim 23

, wherein the bioabsorbable substrate is formed from a bioabsorbable polymer selected from:

(a) polyester or polylactone selected from the group comprising polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate, polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers;

(b) protein, selected from the group comprising albumin, fibrin, collagen, or elastin;

(c) polysaccharide, selected from the group comprising chitosan, alginates, or hyaluronic acid;

or

(d) biosynthetic polymer, comprising 3-hydroxybutyrate polymers.

27. The material of

claim 23

, wherein the bioabsorbable substrate is a medical device or a part of a medical device selected from:

a wound closure, a suture, a staple, an adhesive;

a mesh;

a prosthetic device;

a controlled drug delivery system;

a wound covering; and

a filler.

28. The material of

claim 23

, wherein the bioabsorbable substrate is an alginate dressing coated with a coating of the one or more antimicrobial metals or impregnated with a powder of the one or more antimicrobial metals.

29. The material of

claim 23

, wherein the bioabsorbable substrate is a chitosan powder coated with a coating of the one or more antimicrobial metals.

30. A method of preparing a bioabsorbable material comprising:

providing a bioabsorbable substrate; and

contacting the bioabsorbable substrate with one or more antimicrobial metals, such that the one or more antimicrobial metals remain associated with the bioabsorbable substrate, the one of more antimicrobial metals being formed by creating atomic disorder under process conditions which limit diffusion for retaining atomic disorder therein, the atomic disorder being sufficient, such that the material in contact with an alcohol or water-based electrolyte, releases atoms, ions, molecules, or clusters of at least one anti-microbial metal at a concentration sufficient to provide a localized antimicrobial effect, and wherein the one or more antimicrobial metals are associated with the bioabsorbable substrate such that particulates of the one or more antimicrobial metals formed during dissociation are sized to avoid deleterious immune responses or toxic effects.

31. The method of

claim 30

, wherein the bioabsorbable substrate is contacted with the one or more antimicrobial metals by forming a coating on the bioabsorbable substrate, or by incorporating a powder into or onto the bioabsorbable substrate, and wherein the one or more antimicrobial metals associated with the bioabsorbable substrate are formed as a continuous or discontinuous coating or powder.

32. The method of

claim 30

, wherein the one or more antimicrobial metals associated with the bioabsorbable substrate are formed as a coating on a powder

33. The method of

claim 31

, wherein the one or more antimicrobial metals are formed as discontinuous coatings and/or with sufficient high oxygen content that the particulate of the one or more antimicrobial metals formed during dissociation has a size of less than 2 μ

m.

34. The method of

claim 33

, wherein the particulate has a size of less than 1 μ

m.

35. The method of

claim 31

, wherein the one or more antimicrobial metals are formed as a coating, having a thickness of less than 900 nm.

36. The method of

claim 35

, wherein the one or more antimicrobial metals are formed as a coating, having a thickness of less than 500 nm.

37. The method of

claim 31

, wherein the one or more antimicrobial metals are formed as a powder, having a particle size of less than 100 μ

m.

38. The method of

claim 37

, wherein the one or more antimicrobial metals are formed as a powder, having a particle size of less than 40 μ

m.

39. The method of

claim 31

, wherein the one or more antimicrobial metals are formed as a nanocrystalline coating or powder, formed with sufficient atomic disorder to provide sustained release on atoms, ions, molecules, or clusters of the one or more antimicrobial metals.

40. The method of

claim 39

, wherein the one or more antimicrobial metals are formed as a nanocrystalline coating or powder having a crystallite size of less than 100 nm.

41. The method of

claim 40

, wherein the one or more antimicrobial metals are formed as a nanocrystalline coating or powder having a grain size less than 40 nm.

42. The method of

claim 41

, wherein the one or more antimicrobial metals are formed as a nanocrysalline coating or powder having a grain size less than 20 nm.

43. The method of

claim 40

, wherein the one or more antimicrobial metals are selected from the group consisting of Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi, and Zn, or alloys or compounds thereof.

44. The method of

claim 40

, wherein at least one of the one or more antimicrobial metal is Ag or Au, or alloys or compounds thereof.

45. The method of

claim 40

, wherein the antimicrobial metal is silver, or an alloy or compound thereof.

46. The method of

claim 43

, wherein the coating or powder of the one or more antimicrobial metals is formed by either

A. physical vapor deposition selected from vacuum evaporation, sputtering, magnetron spattering, or ion plating, under one or more of the following conditions:

(a) maintaining the ratio of the temperature of the substrate being coated to the melting point of the one of more antimicrobial metals or metal compounds being deposited, in degrees Kelvin, at less than 0.5;

(b) maintaining the angle of incidence of the coating flux on the surface to be coated at less than 75°

; and

(c) maintaining ambient or working gas pressures, depending on the technique of vapour deposition, of;

(i) greater than 0.01 mT, if by e-beam or are evaporation;

(ii) greater than 20 mT, if by gas scattering or reactive are evaporation;

(iii) greater than 75 mT, if by sputtering;

(iv) greater than 10 mT, if by magnetron sputtering;

or

(v) greater than 200 mT, if by ion plating;

or

B. by forming the antimicrobial material as a composite material containing the one or more antimicrobial metals by co-, sequentially or reactively depositing by vapour deposition, an anti-microbial metal in a crystalline matrix with atoms or molecules of a material different from the antimicrobial metal, the atoms or molecules of the different material creating atomic disorder in the matrix;

or

C. cold working an antimicrobial material containing the one or more antimicrobial metals at a temperature below the recrystallization temperature for the material to retain the atomic disorder, wherein the antimicrobial metal is in the form of a powder.

47. The method of

claim 46

, wherein the antimicrobial metal is formed as a coating under the conditions set forth in step A and/or B, and includes absorbed trapped, or reacted atoms or molecules of oxygen which is included in the working gas atmosphere during deposition, said coating being either formed directly on the bioabsorbable substrate, or as a coating which is converted to a powder.

48. The method of

claim 47

, wherein a ratio of the working gas to oxygen is about 96:

4 or less.

49. The method of

claim 47

, wherein sufficient oxygen is incorporated in the coating or powder such that the particulate of the one or more antimicrobial metals during dissociation has a size less than 2 μ

m.

50. The method of

claim 49

, wherein the particulate of the one or more antimicrobial metals during dissociation has a size less than 1 μ

.

51. The method of

claim 49

, wherein the one or more antimicrobial metals is silver, or an alloy or compound thereof, and wherein the coating or powder has a ratio of its temperature of recrystallization to its malting temperature, in degrees K (T_rec/T_m), less than 0.33.

52. The method of

claim 51

, wherein the ratio is less than 0.3.

53. The method of

claim 52

, wherein the temperature of recrystallization is less than about 140°

C.

54. The method of

claim 51

, wherein the coating has a positive rest potential, when measured against a standard calomel electrode, in 0.15 M Na₂CO₃ or 0.15 M KOH.

55. The method of

claim 54

, wherein the positive rest potential is greater than 225 mV in 0.15 M Na₂CO₃.

56. The method of

claim 54

, wherein the positive rest potential is greater than 250 mV in 0.15 M Na₂CO₃.

57. The method of

claim 54

, wherein the bioabsorbable substrate is formed from a bioabsorbable polymer selected from:

(a) polyester or polylactone selected from the group comprising polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate, polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers;

(b) protein, selected from the group comprising albumin, fibrin, collagen, or elastin;

(c) polysaccharide, selected from the group comprising chitosan, alginates, or hyaluronic acid;

or

(d) biosynthetic polymer, comprising 3-hydroxybutyrate polymers.

58. The method of

claim 54

, wherein the bioabsorbable substrate is a medical device or a part of a medical device selected from:

a wound closure, a suture, a staple, an adhesive;

a mesh, a prosthetic device;

a controlled drug delivery system;

a wound covering; and

a filler.

59. The method of

claim 54

, wherein the bioabsorbable substrate is an alginate dressing coated with a coating of the one or more antimicrobial metals or impregnated with a powder of the one or more antimicrobial metals.

60. The material of

claim 54

, wherein the bioabsorbable substrate is a chitosan powder coated with a coating of the one or more antimicrobial metals.