Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same

• US 5,019,096 A
• Filed: 10/14/1988
• Issued: 05/28/1991
• Est. Priority Date: 02/11/1988
• Status: Expired due to Term

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Modak, Shanta M., Sampath, Lester A., Fox, Charles L. Jr.
• Primary Examiner(s): LUSIGNAN, MICHAEL R
• Application Number:
  US07/258,189
• Time in Patent Office: 956 Days
• Field of Search: 2/167, 2/168, 128/334 R, 128/335.5, 427/2, 427/387, 427/393.5, 427/385.5, 427/407.1, 523/113, 523/115, 523/122, 604/265, 623/2, 623/11, 623/1, 623/10, 623/18, 606/151
• US Class Current: 600/36
• CPC Class Codes: A01N 2300/00 Combinations or mixtures of active ingredients covered by classes A01N27/00 - A01N65/48 with other active or formulation relevant ingredients, e.g. specific carrier materials or surfactants, covered by classes A01N25/00 - A01N65/48
• CPC Class Codes: A01N 25/10 Macromolecular compounds
• CPC Class Codes: A01N 25/24 containing ingredients to enhance the sticking of the active ingredients
• CPC Class Codes: A01N 25/34 Shaped forms, e.g. sheets, not provided for in any other sub-group of this main group
• CPC Class Codes: A01N 47/44 Guanidine; Derivatives thereof
• CPC Class Codes: A01N 59/16 Heavy metals; Compounds thereof
• CPC Class Codes: A41D 19/0055 Plastic or rubber gloves
• CPC Class Codes: A41D 31/305 using layered materials
• CPC Class Codes: A61B 42/00 Surgical gloves; Finger-stalls specially adapted for surgery; Devices for handling or treatment thereof
• CPC Class Codes: A61B 42/10 Surgical gloves
• 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 2/16 using chemical substances
• CPC Class Codes: A61L 2300/104 Silver, e.g. silver sulfadiazine
• CPC Class Codes: A61L 2300/206 Biguanides, e.g. chlorohexidine
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/16 : Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/10 : Macromolecular materials
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61M 2025/0056 : provided with an antibacterial agent, e.g. by coating, residing in the polymer matrix or releasing an agent out of a reservoir
• CPC Class Codes: A61M 25/0009 : Making of catheters or other medical or surgical tubes
• CPC Class Codes: Y10S 623/921 : Blood vessel

Abstract

A method of preparing an infection-resistant medical device comprising one or more matrix-forming polymers selected from the group consisting of biomedical polyurethane, biomedical silicones and biodegradable polymers, and antimicrobial agents, especially a synergistic combination of a silver salt and chlorhexidine (or its salts); also disclosed are medical devices having the synergistic composition therein or compositions thereon.

Claims

1. A method for making an infection-resistant material comprising incorporating an effective amount of an antimicrobial agent in a matrix comprising a polymeric component selected from the group consisting of biomedical polyurethanes, biomedical silicones, biodegradable polymers and combinations thereof, wherein the matrix is effective to provide controlled release of the antimicrobial agent at a level sufficient to suppress infection when in contact with fluids, and wherein the antimicrobial agent includes synergistically effective amounts of a silver salt and a biguanide.

2. A method according to claim 1, wherein the silver salt is selected from the group consisting of silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein and silver sulfadiazine.

3. A method according to claim 1, wherein the biguanide is selected from the group consisting of chlorhexidine, and salts thereof.

4. A method according to claim 2, the biguanide is selected from the group consisting of chlorhexidine, and salts thereof.

5. A method according to claim 4, wherein the silver salt is silver sulfadiazine.

6. A method according to claim 1, wherein the matrix comprises a mixture of biomedical silicone and a biodegradable polymer.

7. A method according to claim 6, wherein the biodegradable polymer is poly(lactic acid).

8. A method according to claim 5, wherein the silver salt is selected from the group consisting of silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein and silver sulfadiazine.

9. A method according to claim 8, the biguanide is selected from the group consisting of chlorhexidine, and salts thereof.

10. A method according to claim 8, wherein the silver salt is silver sulfadiazine.

11. A method of preparing an infection-resistant article comprising the steps of

(a) dispersing an effective amount of an antimicrobial agent and a matrix forming polymeric material selected from the group consisting of biomedical polyurethanes, biomedical silicones, biodegradable polymers and combinations thereof in a solvent to form a first coating vehicle;

(b) applying the first coating vehicle to the article to form a first coating and;

(c) preparing a second coating vehicle and applying said second coating vehicle to the coated article to form a second coating thereon.

12. A method according to claim 11, wherein the antimicrobial agent is selected from the group consisting of silver and its salts, biguanides, polymyxin, tetracycline, aminoglycosides, rifampicin, bactitracin, neomycin, chloramphenicol, miconazole, quinolones, penicillins, nonoxynol 9, fusidic acid, cephalosporins and combinations thereof.

13. A method according to claim 12, wherein the antimicrobial agent includes a silver salt selected from the group consisting of silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein and silver sulfadiazine.

14. A method according to claim 12, wherein the antimicrobial agent includes a biguanide selected from the group consisting of chlorhexidine and salts thereof.

15. A method according to claim 14, wherein the antimicrobial agent includes a salt of chlorhexidine selected from the group consisting of chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride and chlorhexidine sulfate.

16. A method according to claim 11, wherein the matrix forming polymeric material includes poly(lactic acid).

17. A method according to claim 11, wherein the infection-resistant article is a medical device.

18. A method according to claim 17, wherein the medical device is selected from the group consisting of catheters, gloves, contraceptives, wound dressings, drainage tubes, wound clips, implants, sutures, vascular grafts and hernia patches.

19. A method according to claim 18, wherein the antimicrobial agent includes a biguanide.

20. A method according to claim 19, wherein the biguanide is chlorhexidine or a salt thereof.

21. A method according to claim 18, wherein the antimicrobial agent includes a silver salt.

22. A method according to claim 21, wherein the antimicrobial agent further includes a biguanide.

23. A method according to claim 22, wherein the biguanide is chlorhexidine or a salt thereof.

24. A method according to claim 18, wherein the device is formed from expanded PTFE having interstices therein, and wherein the said matrix is incorporated by applying a coating comprising the antimicrobial agent and matrix polymers in a solvent thereof to a preformed device causing the coating material to enter into the interstices and drying the treated device.

25. A method according to claim 24, wherein the matrix comprises poly(lactic acid).

26. A method according to claim 24, wherein the antimicrobial agent includes pipracil and chlorhexidine or a salt thereof.

27. A method according to claim 26, wherein the chlorhexidine is included as chlorhexidine acetate.

28. A method according to claim 24, wherein the matrix comprises a biodegradable polymer and the antimicrobial agent comprises a silver salt and a biguanide.

37. A method according to claim 14, wherein the antimicrobial agent includes silver or a salt thereof.

38. A method according to claim 37, wherein the antimicrobial agent includes a silver salt selected from the group consisting of silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein and silver sulfadiazine.

55. The method according to claim 11, wherein the silicone in said second coating solution has a concentration in the range of 0.5 to 5%.

56. The method according to claim 16, wherein the first coating solution additionally contains a polylactic acid at a concentration in the range of 0.2 to 2%.

57. The method according to claim 27, wherein the coating contains 0.25 to 1% biomedical polyurethane, 0.25 to 1% poly (lactic acid), 1% chlorhexidine acetate and 3% pipracil in a solvent comprising 25% N-ethyl-2-pyrrolidone and 75% tetrahydrofuran.

64. A method according to claim 11, wherein the second coating vehicle comprises a biomedical silicone.

65. A method according to claim 64, wherein the article is a catheter.

66. A method according to claim 65, wherein the second coating includes heparin.

67. A method according to claim 11, wherein the second coating vehicle includes a second antimicrobial agent different from the antimicrobial agent in the first coating.

29. A method of preparing an infection-resistant article comprising incorporating into the article an effective amount of an infection-resistant material in a matrix, the matrix comprising a polymeric component selected from the group consisting of biomedical polyurethanes, biomedical silicones, biodegradable polymers and combinations thereof and an antimicrobial agent, wherein the matrix is effective to provide controlled release of the antimicrobial agent at a level sufficient to suppress infection when in contact with fluids, and wherein the antimicrobial agent includes synergistically effective amounts of a silver salt and a biguanide.

30. A method according to claim 29, wherein the silver salt is selected from the group consisting of silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein and silver sulfadiazine.

31. A method according to claim 29, wherein the biguanide is selected from the group consisting of chlorhexidine and salts thereof.

32. A method according to claim 30, wherein the biguanide is selected from the group consisting of chlorhexidine and salts thereof.

33. A method according to claim 32, wherein the silver salt is silver sulfadiazine.

34. A method according to claim 29, wherein the polymer is a biomedical polyurethane.

35. A method according to claim 29, wherein the polymer is a mixture of biomedical silicone and a biodegradable polymer.

36. A method according to claim 35, wherein the biodegradable polymer is poly(lactic acid).

39. A method according to claim 29, wherein the infection-resistant material is incorporated as a coating on the article, and wherein the coating is formed by dispersing the matrix forming polymeric material in a solvent to form a coating vehicle, incorporating the antimicrobial agent in the coating vehicle to form a coating composition, coating a preformed article with the coating composition, and drying the coating.

40. A method according to claim 39, wherein the silver salt is selected from the group consisting of silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein and silver sulfadiazine.

41. A method according to claim 39, wherein the biguanide is selected from the group consisting of chlorhexidine, and salts thereof.

42. A method according to claim 40, the biguanide is selected from the group consisting of chlorhexidine, and salts thereof.

43. A method according to claim 42, wherein the silver salt is silver sulfadiazine.

44. A method of preparing an infection-resistant medical device which comprises:

(a) preparing a mixture of silver or a silver salt and a biguanide in effective amounts; and

(b) applying said mixture as a coating to a surface of the medical device, such that upon exposure to a fluid, the silver or its salt and the biguanide are released in synergistic infection-resistant amounts.

45. The method of claim 44, wherein the mixture is affixed to the surface of the device.

46. The method of claim 44, wherein the mixture is applied to the surface as a powder.

47. The method of claim 44, wherein the mixture is applied as an ingredient of a polymeric coating.

48. The method of claim 44, wherein the silver salt is silver sulfadiazine.

49. The method of claim 44, wherein the silver salt is silver carbonate.

50. A method according to claim 44, which comprises:

(a) preparing the mixture of

(i) a substance selected from the group consisting of chlorhexidine and its salts, and

(ii) a silver salt selected from the group consisting of silver sulfadiazine, silver acetate, silver benzoate, silver iodate, silver laurate, silver protein, silver chloride, silver palmitate, silver oxide, silver carbonate and silver nitrate; and

(b) applying a mixture to the surface of a medical device.

51. A method according to claim 45, further comprising the step of treating the surface of the device to render it at least slightly adhesive.

52. A method according to claim 44, wherein the medical device is a glove.

53. A method according to claim 52, wherein the glove is a latex and the mixture is applied as a powder to the surface of the glove at a point during the manufacture of the glove when the glove surface is soft, whereby the powder adheres to the glove surface.

54. A method according to claim 52, wherein the mixture is applied to the surface in a solvent-mediated dispersion.

58. An infection-resistant medical device comprising an effective amount of an antimicrobial agent comprising silver or a salt thereof and a biguanide in synergistically effective amounts.

59. A device according to claim 58, wherein the medical device is selected from the group consisting of catheters, gloves, contraceptives, wound dressings, drainage tubes, wound clips, implants, sutures, vascular grafts and hernia patches.

60. A device according to claim 58, wherein the antimicrobial agent comprises a silver salt selected from the group consisting of silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein and silver sulfadiazine.

61. A device according to claim 58, wherein the biguanide is selected from the group consisting of chlorhexidine, and salts thereof.

62. A device according to claim 61, wherein the medical device is selected from the group consisting of catheters, gloves, contraceptives, wound dressings, drainage tubes, wound clips, implants, sutures, vascular grafts and hernia patches.

63. An expanded PTFE vascular graft, a substantial proportion of the interstices of which contains a coating composition comprising, by weight, one part biomedical polyurethane, one part poly(lactic acid), one part chlorhexidine acetate, and three parts pipracil.