Tricolosan-containing medical devices

• US 6,626,873 B1
• Filed: 07/18/2000
• Issued: 09/30/2003
• Est. Priority Date: 01/05/1996
• 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: Sampath, Lester, Modak, Shanta
• Primary Examiner(s): KENNEDY, SHARON E
• Application Number:
  US09/618,432
• Time in Patent Office: 1,169 Days
• Field of Search: 604/264, 604/265, 428/35.7, 428/36.9, 606/76, 424/422, 623/1.1, 623/1.42, 623/1.43, 623/1.45
• US Class Current: 604/265
• CPC Class Codes: A61L 2300/104 Silver, e.g. silver sulfadiazine
• CPC Class Codes: A61L 2300/202 with halogen atoms, e.g. triclosan, povidone-iodine
• 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 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• 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: C08L 75/04 Polyurethanes
• CPC Class Codes: C08L 83/04 Polysiloxanes
• CPC Class Codes: Y10T 428/1331 Single layer [continuous layer]
• CPC Class Codes: Y10T 428/1352 Polymer or resin containing [i.e., natural or synthetic]

Abstract

The present invention relates to polymeric medical articles comprising the anti-infective agents chlorhexidine and triclosan. It is based, at least in part, on the discovery that the synergistic relationship between these compounds permits the use of relatively low levels of both agents, and on the discovery that effective antimicrobial activity may be achieved when these compounds are comprised in either hydrophilic or hydrophobic polymers. It is also based on the discovery that chlorhexidine free base and triclosan, used together, are incorporated into polymeric medical articles more efficiently. Medical articles prepared according to the invention offer the advantage of preventing or inhibiting infection while avoiding undesirably high release of anti-infective agent, for example into the bloodstream of a subject.

Claims

1. A hydrophilic polymeric medical article which has been impregnated with a treatment solution comprising (i) between about 1 and 10 percent of a hydrophilic polymer;

(ii) between 1 and 5 percent of chlorhexidine, wherein the chlorhexidine consists essentially of a mixture of chlorhexidine free base and a chlorhexidine salt; and

(iii) between 0.5 and 5 percent of triclosan.

2. The medical article of claim 1 which is fabricated from a hydrophilic polymer selected from the group consisting of natural rubber latex and biomedical polyurethane.

3. The medical article of claim 1 wherein the hydrophilic polymer in the treatment solution is a biomedical polyurethane.

4. The medical article of claim 2 wherein the hydrophilic polymer in the treatment solution is a biomedical polyurethane.

5. A hydrophilic polymeric medical article which has been impregnated with a treatment solution comprising (i) between about 1 and 10 percent of a hydrophobic polymer;

(ii) between 1 and 5 percent of chlorhexidine, wherein the chlorhexidine consists essentially of a mixture of chlorhexidine free base and a chlorhexidine salt; and

(iii) between 0.5 and 5 percent of triclosan.

6. The medical article of claim 5 which is fabricated from a hydrophilic polymer selected from the group consisting of natural rubber latex and biomedical polyurethane.

7. The medical article of claim 5 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

8. The medical article of claim 6 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

9. The medical article of claim 5 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

10. The medical article of claim 6 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

11. A hydrophobic polymeric medical article which has been impregnated with a treatment solution comprising (i) between about 1 and 10 percent of a hydrophobic polymer;

between 1 and 5 percent of chlorhexidine, wherein the chlorhexidine consists essentially of a mixture of chlorhexidine free base and a chlorhexidine salt; and

(iii) between 0.5 and 5 percent of triclosan.

12. The medical article of claim 11 which is fabricated from a hydrophobic polymer selected from the group consisting of polytetrafluoroethylene, Dacron, polyvinylchloride, biomedical silicone polymer, and silicone polyurethane copolymer.

13. The medical article of claim 11 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

14. The medical article of claim 12 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

15. The medical article of claim 11 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

16. The medical article of claim 12 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

17. A hydrophobic polymeric medical article which has been impregnated with a treatment solution comprising (i) between about 1 and 10 percent of a hydrophilic polymer;

(ii) between 1 and 5 percent of chlorhexidine, wherein the chlorhexidine consists essentially of a mixture of chlorhexidine free base and a chlorhexidine salt; and

(iii) between 0.5 and 5 percent of triclosan.

18. The medical article of claim 17 which is fabricated from a hydrophobic polymer selected from the group consisting of polytetratluoroethylene, Dacron, polyvinylchloride, biomedical silicone polymer, and silicone polyurethane copolymer.

19. The medical article of claim 17 wherein the hydrophilic polymer is a biomedical polyurethane.

20. A method of preparing an infection resistant medical article comprising:

(i) placing the medical article in an impregnating solution comprising (a) a solvent selected from the group consisting of water, reagent alcohol, tetrahydrofuran, and mixtures thereof; and

(b) chlorhexidine and triclosan in a molar ratio of between 1;

1 and 1;

3, wherein the total weight of chlorhexidine and triclosan is between 1 and 10 percent of the weight of the impregnating solution and wherein the chlorhexidine consists essentially of a mixture of chlorhexidine free base and a chlorhexidine salt;

(ii) soaking the medical article in the impregnating solution for a period of time sufficient to allow the medical article to swell and to incorporate the chlorhexidine and triclosan;

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

(iv) drying the medical article.

21. The method of claim 20, wherein the solvent in step (1)(a) is a mixture of reagent alcohol and tetrahydrofuran.

22. The method of claim 20, wherein the ratio of chlorhexidine free base and triclosan in step (1)(b) is about 1:

2.

23. The method of claim 20, wherein the total weight percent of chlorhexidine free base and triclosan in step (1)(b) is about 2-10.

24. The method of claim 20, which has further been coated with a coating solution comprising a biomedical polymer.

25. The method of claim 24, wherein the biomedical polymer in the coating solution comprises an antimicrobial agent.

26. The method of claim 20 which is fabricated from polyurethane.

27. The method of claim 26 which is a polyurethane catheter.

28. The method of claim 27 in which both the external and internal surfaces of the catheter are brought into contact with the impregnating solution.

29. The method of claim 27 in which only the external surface of the catheter is brought into contact with the impregnating solution.

30. The method of claim 27, in which only the internal surface of the catheter is brought into contact with the impregnating solution.