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

Claims

We claim:

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.

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).

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.

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.

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.

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.

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.

BACKGROUND OF THE INVENTION

The present invention relates to infection-resistant compositions, medical devices and surfaces and to methods for using and preparing the same.

Medical devices for use externally or internally with humans or animals can serve to introduce bacterial, viral, fungal or other undesirable infections. Certain prior art devices become unworkable after a short period of time, and must be replaced. In the case of urinary catheters, for example, frequent replacement can cause excessive discomfort to the patient and prolonged hospitalization. In the case of intravenous catheters used for critical care patients, infections can themselves prove life threatening. Additionally, there is always a threat of exposure to infectious contamination from surfaces that contact patients, from surgical gloves, and from other medical gear and apparatus.

To prevent such contamination, medical devices can be treated with an antimicrobial agent. Known methods of preparing an infection-resistant medical device have been proposed in U.S. Pat. Nos. 3,566,874, 3,674,901, 3,695,921, 3,705,938, 3,987,797, 4,024,871, 4,318,947, 4,381,380, 4,539,234, and 4,612,337.

In addition, antimicrobial compositions useful as coatings for medical devices or for forming the device itself are disclosed in U.S. Pat. Nos. 3,699,956, 4,054,139, 4,592,920, 4,603,152, and 4,667,143. However, such known methods are somewhat complicated or deficient in the results obtained. The art has great need for medical devices which are able to resist microbial infection when placed in the area of the body to which it is applied and which provide this resistance over the period of time which it remains in place. At the same time, these desirable characteristics must be achieved without sacrifice of other well recognized desirable characteristics. In the case of catheters, for example, it is important that any coating thereon leave a surface which provides a minimum of resistance to insertion of the catheter and which does not release a toxic substance to be adsorbed by the body.

Furthermore, some uses of antimicrobial metal compounds including silver salts in antimicrobial coatings for medical devices are known. Also, chlorhexidine and its salts are known to be powerful antiseptics, but the combination of chlorhexidine with silver nitrate has been shown to have prophylactic properties in burn therapy. In addition, the combination of chlorhexidine and sulfadiazine is known in topical applications to exhibit synergism against strains of Pseudomonas, Proteus, and Staphylococcus, as disclosed in Quesnel et al, Synergism between Chlorhexidine and Sulphadiazine, Journal of Applied Bacteriology, 1978, 45, 397-405.

SUMMARY OF THE INVENTION

A principal object of the present invention is to provide an improved method of preparing an infection-resistant medical device which will impart antimicrobial activity to the medical device through a sustained and controlled activity rate over an appreciable period of time, without hampering the biocompatibility of the surface and other intended functions of the device. A further object of the present invention is to provide an infection-resistant medical device having superior antimicrobial properties.

Still another object of the present invention is to provide an antimicrobial composition useful in providing an antimicrobial coating on medical devices.

In accordance with the first embodiment of the present invention, there is provided a method of preparing an infection-resistant medical device which comprises

(a) preparing a coating vehicle by dissolving a matrix-forming polymer selected from the group consisting of biomedical polyurethane, biomedical silicones, biodegradable polymers and combinations thereof in at least one solvent therefor;

(b) incorporating at least one antimicrobial agent in the coating vehicle to form a coating composition;

(c) coating a medical device with the coating composition; and

(d) drying the coated medical device.

It is preferred in the first embodiment that the antimicrobial agent be a combination of a silver salt and a biguanide and further preferred that the antimicrobial agent be a combination of a silver salt and a member of the group consisting of chlorhexidine and its salts. Also useful are chlorhexidine alone or in combination with nonoxynol 9, or pipracil as well as silver sulfadiazine in combination with nonoxynol 9.

In accordance with a second embodiment of the present invention, there is provided an antimicrobial composition comprising a mixture of (a) chlorhexidine and its salts, and (b) a silver salt.

Further, in accordance with a second embodiment of the present invention there is provided a method of preparing an infection-resistant medical device which comprises incorporating thereon or therein an antimicrobial agent comprising (a) a member of the group consisting of chlorhexidine and its salts, and (b) a member of the group consisting of silver and its salts.

The second embodiment of the present invention further provides an infection-resistant medical device having a coating thereon comprising (a) a member of the group consisting of chlorhexidine and its salts, and (b) a member of the group consisting of silver and its salts.

Another embodiment of the present invention still further provides a method for coating a medical device to provide an infection-resistant coating thereon which comprises the steps of:

(a) dissolving a matrix-forming polymer in a solvent therefor;

(b) dissolving an antimicrobial agent selected from the group consisting of chlorhexidine and its salts in a solvent which is miscible with the solvent polymer mixture prepared in step (a);

(c) dispersing a silver salt in one of the solutions prepared in (a) or (b);

(d) combining the solvent solutions and dispersions prepared in steps (a), (b) and (c) to provide a coating vehicle;

(e) applying the coating vehicle to the surface of the medical device; and

(f) drying the coated medical device.

In addition, the present invention provides an antimicrobial composition useful in applying an infection-resistant coating to medical devices which, in use, will exhibit a sustained activity rate over an appreciable time period.

DETAILED DESCRIPTION OF THE INVENTION

Surfaces which may embody the present invention can be generally any surfaces that contact patients or are important in health care, including table tops, hospital beds and various specific medical devices. Medical devices are those for use both externally and internally and include, for example, urinary, both internal and external, and intravenous catheters, contraceptives such as condoms, medical gloves, such as surgical and examination gloves, wound dressings, drainage tubes, orthopedic, penile and other implants, wound clips, sutures, hernia patches and arterial grafts. The devices or surfaces, sometimes generally together referred to as "surfaces" herein, can be made of a variety of natural or synthetic materials such as metals, plastics and polymers, and including Dacron.RTM., rubber, latex, collagenous substances, silicone, polyurethane, polyvinyl chloride, Teflon.RTM., polypropylene, polyethylene, poly(lactic acid), polyglycolic acid, cotton, silk, stainless steel, porous ceramics, and porcelain.

DEFINITIONS

The following specification refers to a number of microorganisms in describing the invention or its use. Unless otherwise stated, the following are the generally recognized names of the microorganisms, together with their source:

______________________________________ Organism Source ______________________________________ Staphylococcus aureus clinical isolate - Columbia Presbyterian Hosptial New York, New York Staphylococcus epidermidis clinical isolate - Columbia Presbyterian Hospital New York, New York Esherichia coli clinical isolate - Columbia Presbyterian Hospital New York, New York Candida albicans ATCC No. 11651 ______________________________________

It is also noted that unless otherwise stated, the concentrations and ranges expressed as percentages (%), indicates the respective value based on weight of solid per volume of solvent. As an example, a 1% polyurethane in a solvent coating vehicle comprising tetrahydrofuran (THF) represents 1 gram of polyurethane in 100 ml of THF. On the other hand, in expressing relative proportions of two or more solvents in a coating vehicle, the percentages given are on a vol/vol basis.

POLYMERIC COATING AGENT

The polymeric coating agent component of the coating vehicle of the present invention is selected from the group consisting of biomedical polyurethanes, biomedical silicones, biodegradable polymersand combinations thereof. It has been found that these particular polymeric materials enable the antimicrobial agent of the second embodiment of the invention to be retained and released in an active state on the coated medical device over an appreciable period of time, e.g., from about 12 to in excess of 21 days.

Selection of the coating vehicle depends upon the specific composition of the surface of the device to be coated, and the characteristics sought. For example, a polyurethane catheter is preferably coated with a formulation based on a biomedical polyurethane matrix-forming material. A silicone rubber catheter, on the other hand, preferably is provided with a coating having a silicone rubber as a matrix-forming material. It has also been discovered that a final thin coat of a silicone fluid after a first coating of biomedical polyurethane or of silicone rubber imparts surface glossiness and lubricity to the catheter. Thus, multiple, combined coatings, described in greater detail below, can also be achieved with improved characteristics.

In addition to polymeric coating compositions, the antimicrobial compositions of this invention may be applied to surfaces of medical devices in powder form, preferably under conditions which cause adherence of the powder to the surface of the device. For example, medical gloves, such as surgical or examination gloves fabricated from latex, polyurethane or polyvinyl acetate, may be coated with a powder containing the antimicrobial composition, as will be explained below in more detail.

A. Biomedical Polyurethane

In accordance with the first embodiment of the invention, the essential polymeric coating agent component of the coating vehicle is biomedical polyurethane, since it has been found unexpectedly that polymeric materials of this class enable the antimicrobial agent to be retained in an active state on the coated medical device and released over an appreciable period of time, e.g., from about 12 to in excess of 21 days, without altering the biocompatibility, lubricity and non-thrombogenicity of the surface. Suitable biomedical polyurethanes include both the ether-based polyurethanes and the ester-based polyurethanes described on pages 175-177 of Controlled Release of Biologically Active Agents, by Richard W. Baker, John Wiley and Sons, 1987; the ether-based compounds are preferred. A thorough discussion of a number of proprietary biomedical polyurethanes is found in Polyurethanes in Medicine, by Michael D. Lelah and Stuart L. Cooper, CRC Press, Inc., Fla. 1986, pp. 57-67.

The following is a listing of proprietary biomedical polyurethanes that are useful in accordance with the invention:

1. Biomer.RTM., which consists of 4,4-diphenylmethane-diisocyanate (MDI) and low molecular weight polytetramethyleneoxide (PTMO) segments with diamines as chain extenders. A proposed repeat unit chemical structure for Solution Grade Biomer.RTM. is: ##STR1##

2. Acuthane.RTM. is a block copolymer which contains 10% polymethylsiloxane and 90% polyetherurethane.

3. Pellethane.RTM. is an aromatic ether polyurethane. Pellethane.RTM. 2363 (80AE) is not crosslinked and is readily soluble in dimethylacetamide, tetrahydrofuran, or N-ethyl pyrrolidone. The 90A of the same series contains crosslinks due to the excess of isocyanates present during the polymerization process and is therefore more difficult to solubilize.

4. Rimplast.RTM. is a silicone urethane made with either aliphatic or aromatic ethers or esters of polyureth