Antimicrobial medical devices

• US 7,537,779 B2
• Filed: 06/20/2003
• Issued: 05/26/2009
• Est. Priority Date: 12/22/2000
• Status: Expired due to Fees

• 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: Sampath, Lester A., Modak, Shanta M.
• Primary Examiner(s): Azpuru; Carlos A
• Application Number:
  US10/600,257
• Publication Number:
  US 20040052831A1
• Time in Patent Office: 2,167 Days
• Field of Search: 424/423
• US Class Current: 424/423
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: A61L 15/44 Medicaments
• 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 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C09D 175/04 Polyurethanes

Abstract

The present invention provides for antimicrobial medical articles prepared by a method comprising treating a surface of the medical article with a solution consisting essentially of one or more solvents and a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, at a weight/weight ratio of between about 1:1 to about 1:5, wherein the combined concentration of chlorhexidine free base and a water-soluble salt of chlorhexidine is about 2% (w/v) or greater. In alternative embodiments, the antimicrobial medical articles may be treated with a similar solution in which the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v). Other embodiments include those in which the solvent comprises methanol, or the treatment solution further comprises a silver salt, one or more organic acids, an anti-inflammatory agent, and a hydrogel.

Claims

1. An antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution comprising one or more solvents and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:

1 and 1;

5, and wherein the combined concentration of chlorhexidine free base and a water-soluble salt of chlorhexidine is about 2.00 percent (w/v) or greater.

2. The antimicrobial medical article of claim 1, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.00 percent (w/v).

3. The antimicrobial medical article of claim 1, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.20 percent (w/v).

4. The antimicrobial medical article of claim 1, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are about 0.625 percent (w/v) and about 1.375 percent (w/v), respectively.

5. The antimicrobial medical article of claim 1, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 2.00 percent (w/v).

6. The antimicrobial medical article of claim 1, wherein the one or more solvents comprise methanol.

7. The antimicrobial medical article of claim 6, wherein the solvent is a mixture of between 75 and 95 percent (volume/volume) tetrahydrofuran and 5 and 25 percent (volume/volume) methanol.

8. The antimicrobial medical article of claim 1, wherein the one or more solvents comprise ethanol.

9. The antimicrobial medical article of claim 8, wherein the solvent is a mixture of between 10 and 30 percent (volume/volume) tetrahydrofuran and 70 and 90 percent (volume/volume) ethanol.

10. The antimicrobial medical article of claim 1, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

31. The antimicrobial medical article of any one of claims 1, 11, 17, 19 or 25, wherein the article is a hydrophilic polymeric medical article.

32. The antimicrobial medical article of claim 31, wherein the article is a catheter.

33. The catheter of claim 32, wherein the catheter has a lumen which is treated, for an effective period of time, with the solution consisting essentially of one or more solvents and the mixture of chlorhexidine free base and water-soluble chlorhexidine salt.

34. The medical article of claim 31, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

35. The catheter of claim 32, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

36. The catheter of claim 33, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

11. An antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution comprising one or more solvents and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v).

12. The antimicrobial medical article of claim 11, wherein the one or more solvents comprise methanol.

13. The antimicrobial medical article of claim 12, wherein the solvent is a mixture of between 75 and 95 percent (volume/volume) tetrahydrofuran and 5 and 25 percent (volume/volume) methanol.

14. The antimicrobial medical article of claim 11, wherein the one or more solvents comprise ethanol.

15. The antimicrobial medical article of claim 14, wherein the solvent is a mixture of between 10 and 30 percent (volume/volume) tetrahydrofuran and 70 and 90 percent (volume/volume) ethanol.

16. The antimicrobial medical article of claim 11, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

17. An antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution comprising a solvent of methanol and an antimicrobial mixture consisting essentially of a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:

1 and 1;

5.

18. The antimicrobial medical article of claim 17, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

19. An antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution comprising one or more solvents, a silver compound, and a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:

1 and 1;

5.

20. The antimicrobial medical article of claim 19, wherein the one or more solvents comprise methanol.

21. The antimicrobial medical article of claim 20, wherein the solvent is a mixture of between 75 and 95 percent (volume/volume) tetrahydrofuran and 5 and 25 percent (volume/volume) methanol.

22. The antimicrobial medical article of claim 19, wherein the one or more solvents comprise ethanol.

23. The antimicrobial medical article of claim 22, wherein the solvent is a mixture of between 10 and 30 percent (volume/volume) tetrahydrofuran and 70 and 90 percent (volume/volume) ethanol.

24. The antimicrobial medical article of claim 19, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

25. An antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution comprising one or more solvents and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is greater than 1:

1.

26. The antimicrobial medical article of claim 25, wherein the one or more solvents comprise methanol.

27. The antimicrobial medical article of claim 26, wherein the solvent is a mixture of between 75 and 95 percent (volume/volume) tetrahydrofuran and 5 and 25 percent (volume/volume) methanol.

28. The antimicrobial medical article of claim 25, wherein the one or more solvents comprise ethanol.

29. The antimicrobial medical article of claim 28, wherein the solvent is a mixture of between 10 and 30 percent (volume/volume) tetrahydrofuran and 70 and 90 percent (volume/volume) ethanol.

30. The antimicrobial medical article of claim 25, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

37. An antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution comprising one or more solvents and an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:

1 and 1;

5, wherein the article is a hydrophobic polymeric medical article, optionally comprising expanded polytetrafluoroethylene.

38. An antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution comprising

(1) one or more solvents;

(2) an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt; and

(3) one or more of (i) an organic acid, at a concentration of between 0.1 and 5 percent;

(ii) an anti-inflammatory agent, at a concentration of between 0.1 and 5 percent;

or (iii) a hydrogel at a concentration of between 0.5 to 10 percent,

wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1;

1 to 1;

5.

39. The antimicrobial medical article of claim 38, wherein the concentration of organic acid in the solution is between 0.1 and 2 percent.

40. The antimicrobial medical article of claim 38, wherein the concentration of anti-inflammatory agent is between 0.1 and 1 percent.

41. The antimicrobial medical article of claim 38, wherein the concentration of hydrogel in the solution is between 1 and 5 percent.

42. The antimicrobial medical article of claim 38, wherein the combined concentration of the mixture of chlorhexidine free base and a water-soluble salt of chlorhexidine is about 2.00 percent (w/v) or greater.

43. The antimicrobial medical article of claim 42, wherein the concentration of organic acid in the solution is between 0.1 and 2 percent.

44. The antimicrobial medical article of claim 42, wherein the concentration of anti-inflammatory agent is between 0.1 and 1 percent.

45. The antimicrobial medical article of claim 42, wherein the concentration of hydrogel in the solution is between 1 and 5 percent.

46. The antimicrobial medical article of claim 42, and wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v).

47. The antimicrobial medical article of claim 46, wherein the concentration of organic acid in the solution is between 0.1 and 2 percent.

48. The antimicrobial medical article of claim 46, wherein the concentration of anti-inflammatory agent is between 0.1 and 1 percent.

49. The antimicrobial medical article of claim 46, wherein the concentration of hydrogel in the solution is between 1 and 5 percent.

50. A method of preparing a medical article comprising the steps of

(i) placing the medical article in a solution comprising

(a) a solvent comprising methanol;

and

(b) an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and water-soluble chlorhexidine salt in the solution is between 1;

1 to 1;

5;

(ii) soaking the medical article in the solution for an effective period of time to allow the medical article to swell;

(iii) removing the medical article from the solution; and

(iv) drying the medical article.

51. The method of claim 50, wherein the combined concentration of the mixture of chlorhexidine free base and a water-soluble salt of chlorhexidine is about 2.00 percent (w/v) or greater.

52. The method of claim 50, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v).

53. The method of claim 51, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.00 percent (w/v).

54. The method of claim 51, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.20 percent (w/v).

55. The method of claim 51, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are about 0.625 percent (w/v) and about 1.375 percent (w/v), respectively.

56. The method of claim 51, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 2.00 percent (w/v).

57. A method of preparing a catheter having a lumen comprising the steps of

(i) exposing the lumen of the catheter to a solution comprising

(a) a solvent comprising methanol;

and

(b) an antimicrobial mixture consisting essentially of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the weight/weight ratio of chlorhexidine free base and water-soluble chlorhexidine salt in the solution is between 1;

1 to 1;

5;

(ii) filling the lumen of the catheter with the solution for an effective period of time to allow the lumen of the catheter to swell;

(iii) removing the solution from the lumen of the catheter; and

(iv) drying the catheter.

58. The method of claim 57, wherein the combined concentration of the mixture of chlorhexidine free base and a water soluble salt of chlorhexidine is about 2.00 percent (w/v) or greater.

59. The method of claim 58, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.00 percent (w/v).

60. The method of claim 58, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.20 percent (w/v).

61. The method of claim 58, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are about 0.625 percent (w/v) and about 1.375 percent (w/v), respectively.

62. The method of claim 58, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 2.00 percent (w/v).

63. The method of claim 57, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v).

64. An antimicrobial medical article prepared by a method comprising treating a surface of a polymeric medical article, for an effective period of time, with a solution comprising one or more solvents, a silver compound, and a mixture of chlorhexidine free base and a water-soluble chlorhexidine salt, wherein the silver compound is selected from the group consisting of silver carbonate and silver sulfadiazine, and wherein the weight/weight ratio of chlorhexidine free base and the water-soluble chlorhexidine salt in the solution is between 1:

1 and 1;

5.