Title:  Dual mode antimicrobial compositions

United States Patent:  6,579,539

Issued:  June 17, 2003

Inventors:  Lawson; Glenn (Oxford, GA); Terry; Richard (Conyers, GA)

Assignee:  C. R. Bard, Inc. (NJ)

Appl. No.:  469909

Filed:  December 22, 1999

The present invention provides compositions which reduce the possibility of inducing microbial resistance. The compositions comprise a fast-acting antimicrobial agent and a long-lasting antimicrobial agent. The combined effect of the antimicrobial agents reduces microbial infection and resistance. Articles comprising the compositions of the present invention and methods for their manufacture are also provided.

SUMMARY OF THE INVENTION

This invention provides durable and lubricious compositions and articles that have a relatively potent short-term microbial resistance in addition to a sustained long-term microbial resistance. In addition, this invention provides methods for making microbially resistant compositions and articles wherein the compositions and articles have a relatively potent short-term microbial resistance and a sustained long-term microbial resistance and wherein the articles and compositions have a durable and lubricious surface.

In accordance with an embodiment of the invention, a composition is provided that is a multi-layer coating. The coating comprises a layer of metallic silver overlaid with a polymer, preferably a hydrogel, which contains an antimicrobial agent. In accordance with an additional embodiment of the invention, an article having a layer of metallic silver applied thereto which is overlaid with a hydrogel containing an antimicrobial agent is provided. Preferred articles for use according to the invention are medical articles. In particular, medical articles such as catheters are preferred. These articles have affixed to their surfaces a metallic silver layer which is covered by a hydrogel containing an antimicrobial agent. In accordance with a further embodiment of the invention, methods for producing the articles and the compositions of the invention are provided. The method comprises:

a) providing a layer of metallic silver

b) preparing a coating solution by dissolving a polymer, preferably a hydrogel, or the components to produce a polymer or hydrogel in one or more solvents

c) incorporating at least one antimicrobial agent into the coating solution; and

d) coating the metallic silver layer with the coating solution containing the antimicrobial agent.

DETAILED DESCRIPTION OF THE INVENTION

Articles that embody the present invention generally can be any article that contacts patients or is used in health care. The articles may be for use either internally or externally, and include, for example, catheters, tubes, shunts, condoms, medical gloves, implants, sutures, grafts and the like. The articles can be made from a variety of natural or synthetic materials, such as, for example, latex, polystyrene, polyester, polyvinylchloride, polyurethane, ABS polymers, ceramics such as aluminum oxide, glass, polyamide, polimide, polycarbonate, synthetic rubber, stainless steel, silicone and polypropylene.

The metallic silver layer is formed by methods known in the art such as wet deposition, electroplating, sputter coating and vacuum deposition. A preferred method of forming the metallic silver layer is wet deposition as described in U.S. Pat. No. 5,395,651. The entire disclosure of U.S. Pat. No. 5,395,651 is incorporated herein by reference. Briefly, metallic silver is deposited upon the surface of an article using a multi-step wet deposition process. The surface is cleaned, and then activated in an aqueous solution containing tin. The silver is deposited from an aqueous solution of a silver-containing salt, a reduction agent that reduces the salt to form the metallic silver, and a deposition control agent that prevents the silver from nucleating throughout the solution. After the article is coated, the coating is stabilized as described in U.S. Pat. No. 5,395,651. The metallic silver layer can be between about 2 angstroms and about 10 microns. A preferred thickness is between about 2 angstroms and about 2,000 angstroms. Alternatively, the amount of silver deposited is determined by weight per unit area. The amount of silver deposited can be from about 0.1 .mu.g/cm² to about 100 .mu.g/cm². A preferred about of silver deposited per unit area is from about 0.5 .mu.g/cm² to about 20 .mu.g/cm².

Nearly any hydrophilic polymer can be used according to this invention. For example, a polyurethane coating which takes up about 10% by weight of water or less can be used. Polymer coatings which are water soluble can also be used. For example, polyvinylpyrrolidone (PVP), which dissolves off when wet, can be used. However, polymer coatings known as hydrogels are preferred. Hydrogels for use according to the invention are those polymers known in the art that exhibit about 25% by weight to about 500% by weight water uptake. Preferably, the hydrogels for use according to this invention exhibit about 50% by weight to about 200% by weight water uptake, and, more preferably, from about 75% by weight to about 150% by weight water uptake. The hydrogels may be derived from water-soluble polymers including, but not limited to, poly(ethylene oxide), poly(ethylene glycol), poly(vinyl alcohol), polyvinyl-pyrrolidone, poly(ethyloxazoline), polyamino acids, pseudopolyamino acids, as well as mixtures of these with each other or other water-soluble polymers. These water-soluble polymers are complexed with or covalently bound to a second polymer, for example, a polyurethane, a polyurea, a polyurethaneurea, as well as mixtures of these with each other or with other polymers. The second polymer can be added as a preformed polymer or it can result from the polymerization of monomers which are polymerized in the presence of the water-soluble polymer. The polymerization reaction can take place before or after coating the substrate. The second polymer may or may not be cross-linked. If the second polymer is cross-linked, a preferred amount of cross-linking is between about 50% to about 90% or greater. A preferred polymer for coating is a polyether polyurethaneurea block copolymer which is not cross-linked. For example, the polyether polyurethaneurea block copolymer known as D6/40 obtained from Tyndale Plains-Hunter, Ltd. is a preferred polymer.

Antimicrobial agents useful according to this invention include the biquanides, especially chlorhexidine, polymyxins, tetracyclines, aminoglycosides, rifampicin, bacitracin, neomycin, chloramphenicol, miconazole, quinolones, penicillins, nonoxynol 9, fusidic acid, cephalosporins, mupirocin, metronidazole, cecropins, protegrins, bacteriocins, defensins, nitrofurazone, mafenide, acyclovir (U.S. Pat. No. 5,744,151), vancomycins, clindamycins, lincomycins, sufonamides (U.S. Pat. No. 5,869,127), norfloxacin, pefloxacin, nalidixic acid, oxolinic acid (quinalone), enoxacin, ciprofloxacin, and fusidic acid (U.S. Pat. No. 5,019,096) and combinations thereof. A preferred antimicrobial agent is chlorhexidine, as it exhibits a synergistic effect with silver.

The antimicrobial agent is incorporated in the compositions of this invention in an amount that is effective at inducing microbial stasis or killing to produce microbial resistant compositions. Methods for determining microbial stasis or killing are know in the art and include, for example, measuring the minimum inhibitory concentration (MIC) of coated catheter extracts, zone of inhibition (ZOI) testing, and bacterial adherence testing, using known clinical pathogens for all tests.

A coating solution is prepared by dissolving a polymer or polymer components in a solvent. The solvent may be any organic solvent or combination of solvents that preferably includes a polar organic solvent. In addition, water may be used as a solvent either alone or as a mixture with organic solvents. An antimicrobial agent, preferably dissolved in a solvent, is then added to make the antimicrobial coating solution. For example, a hydrogel forming polymer such as a polyether polyurethaneurea is dissolved in a mixture of tetrahydrofuran (THF) and an alcohol to form a 3% weight/polymer solution. The ratio of THF to alcohol typically ranges from about 50% to about 100% THF. Chlorhexidine is dissolved in the same alcohol used to make the coating solution or in dimethylacetamide to form about a 5% solution by weight. The chlorhexidine solution is then added to the coating solution in an amount that produces a coating that contains about 1% to about 10%, preferably about 1% to about 5%, chlorhexidine based on the dry weight of the coating. The coating solution is then applied to a silver coated article by dip or spray coating techniques.

The superior and unexpected results obtained from the compositions, articles and methods of the present invention result from the dual modes of action resulting from two distinct antimicrobial layers. For example, when a catheter is inserted into a patient, there is a likelihood that microorganisms will be introduced along with the catheter. This sudden introduction of a relatively large number of microorganisms is suppressed by the chlorhexidine diffusing from the coating of the catheter. Once indwelling, the catheter continues to release chlorhexidine and prevent infection in the surrounding tissue. As the chlorhexidine becomes depleted, the surface of the catheter continues to be antimicrobial due to the metallic silver coating. Silver ions released from the metallic silver layer prevent microbial migration along the shaft of the catheter into the body. The continued presence of silver on the catheter surface and the slow release of silver ions not only prevents the attachment of bacteria, it also inhibits the development of biofilm. In fact, silver catheters with a polymer coating have been reported to delay the onset of urinary tract infections, in spite of their limited ability to kill bacteria on contact, as evidenced by the lack of zones in the ZOI test described below. In addition, the presence of silver ions weakens bacteria by a different mechanism from chlorhexidine, reducing the potential for the development of a resistant infection. Thus, the coatings of the present invention offer resistance to bacterial migration and growth resulting from the silver coating plus they offer additional resistance due to a rapid release of an antimicrobial agent which kills bacteria introduced upon insertion of the catheter.

Claim 1 of 34 Claims

We claim:

1. An article that resists microbial infection, the article having interior and exterior surfaces, the article comprising:

a metallic silver layer on at least one of the surfaces of the article;

a polyether polyurethaneurea block copolymer layer; and

an effective amount of an antimicrobial agent incorporated into the polymer layer and being capable of diffusing from the polymer layer.
 

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