Antimicrobial medical devices

• US 20040052831A1
• Filed: 06/20/2003
• Published: 03/18/2004
• Est. Priority Date: 12/22/2000
• Status: Active Grant

• 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.
• Granted Patent: US 7,537,779 B2
• Time in Patent Office: Days
• 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

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 consisting essentially of one or more solvents and a mixture 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 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, and comprising a solvent comprising methanol.

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. The antimicrobial medical article of claim 19, wherein the silver compound is selected from the group consisting of silver carbonate and silver sulfadiazine.

26. 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 consisting essentially of one or more solvents 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 greater than 1:

1.

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

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

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

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

31. The antimicrobial medical article of claim 26, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

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 consisting essentially of one or more solvents 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, wherein the article is a hydrophobic polymeric medical article, optionally comprising expanded polytetrafluoroethylene.

39. 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 consisting essentially of

(1) one or more solvents;

(2) a mixture 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.

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

41. The antimicrobial medical article of claim 39, wherein the concentration of anti-inflammatory agent is between 0.1 and 1 percent.

42. The antimicrobial medical article of claim 39, wherein the concentration of hydrogel in the solution is between 1 and 5 percent.

43. The antimicrobial medical article of claim 39, 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.

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

45. The antimicrobial medical article of claim 43, wherein the concentration of anti-inflammatory agent is between 0.1 and 1 percent.

46. The antimicrobial medical article of claim 43, wherein the concentration of hydrogel in the solution is between 1 and 5 percent.

47. The antimicrobial medical article of claim 43, and wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v).

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

49. The antimicrobial medical article of claim 47, wherein the concentration of anti-inflammatory agent is between 0.1 and 1 percent.

50. The antimicrobial medical article of claim 47, wherein the concentration of hydrogel in the solution is between 1 and 5 percent.

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

(i) placing the medical article in a solution consisting essentially of

(a) a solvent comprising methanol;

and

(b) a mixture 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.

52. The method of claim 51, 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.

53. The method of claim 51, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v).

54. The method of claim 52, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.00 percent (w/v).

55. The method of claim 52, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.20 percent (w/v).

56. The method of claim 52, 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.

57. The method of claim 52, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 2.00 percent (w/v).

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

(i) exposing the lumen of the catheter to a solution consisting essentially of

(a) a solvent comprising methanol;

and

(b) a mixture 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.

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 consisting essentially of one or more solvents 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, 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.

32. The antimicrobial medical article of any one of claims 1, 11, 17, 19 or 26, wherein the article is a hydrophilic polymeric medical article.

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

34. The catheter of claim 33, 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.

35. The medical article 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.

37. The catheter of claim 34, wherein the water-soluble chlorhexidine salt is chlorhexidine diacetate.

59. The method of claim 58, 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.

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

61. The method of claim 59, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 1.20 percent (w/v).

62. The method of claim 59, 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.

63. The method of claim 59, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 2.00 percent (w/v).

59-1. The method of claim 58, wherein the concentrations of chlorhexidine free base and a water-soluble salt of chlorhexidine are each about 0.20 percent (w/v).