MXPA00006459A - Biostatic coatings for the reduction and prevention of bacterial adhesion - Google Patents

Abstract

The present invention relates to biostatic compositions, as well as coatings and methods for preparing biostatic articles using the same. The compositions contain a hydrophilic polymer possessing a functional group which covalently bonds to an amine, thiol, carboxyl, or hydroxyl active group of an antimicrobial agent. The functional group is capable of reacting with and covalently bonding to an antimicrobial agent without effectively reducing antimicrobial property of the antimicrobial agent below its capability of acting as a biostatic agent and without releasing the antimicrobial agent into a solution.

Description

BIO-STATIC COATINGS FOR THE REDUCTION AND PREVENTION OF BACTERIAL ACCESSION BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to bio-static compositions, as well as to coatings and to methods for preparing bio-static articles that use them. 2. Description of the State of the Art There have been numerous attempts to concentrate anti-microbial, anti-septic or anti-biotic agents on the surface of bio-materials or medical devices as means to reduce the likelihood of bacterial adhesion and subsequent bacterial infection. . Various approaches have been followed, including (1) entrapment of active compounds or agents in surface coatings containing polymer layers or matrices, (2) coupling of active agents to polymers or surface coatings via ionic or other electrostatic forces , and (3) the covalent or chemical bond of active agents to the surface of polymers or materials. The first approach involves mechanical entrapment agents within a polymeric matrix. The agents are generally released by two mechanisms, including (a) the dissolution of the polymeric material or (b) the diffusion of the agent as a result of osmosis. The second approach involves the coupling of agents to polymeric materials as a result of an ionic bond or other intermolecular attractive forces. The intermolecular forces of attraction include dipole-dipole, London or dispersion forces, or hydrogen bonding. These attractive forces occur as a result of electro-negativity or charge differences between the polymer molecule and the active agent or agents. The release mechanism involves desorption of the agent or active agents from the polymer matrix. The third approach involves the covalent binding of agents to polymeric surfaces. This includes the joining of the two materials as a result of the formation of chemical bonds. The covalent binding of anti-microbial agents to polymer matrices results in systems that do not generally release the bound or bound agent under normal physiological conditions. If release of the agent occurs, it is usually as a result of the hydrolysis of a chemical bond. Attempts have been made to use the first approach by mechanically trapping agents in a polymer matrix. For example, U.S. Patent No. 4,603,152, issued to Laurin and Stupar, discloses anti-microbial compositions comprising 30 to 85% polymeric binder and 15 to 70% metal anti-microbial agents or mixtures. Anti-microbial agents form a chain-like structure that releases itself into solutions to create an initial dose and then provides the path for further release of the agents. U.S. Patent No. 5,019,096, issued to Fox et al., Relates to a method of preparing an infection resistant medical material or device comprised of bio-medical polymers and an effective amount of anti-microbial agents such as salts chlorhexidine and silver salts. The agents are released in a controlled manner when the material resistant to the infection is in contact with fluids. U.S. Patent No. 5,133,090, issued to Modak and Sampath, discloses an anti-viral glove that is composed of an elastomeric material with an internal coating composed of a chlorhexidine salt and a lubricating agent that delivers the anti-infective agent in a lapse of time within 10 minutes after exposure to an aqueous solution. U.S. Patent No. 4,853,978, issued to Stockum and Surgioms, is directed to an anti-microbial medical glove having an internal coating composed of a slow-release anti-microbial agent in a cross-linked starch. The coating provides slow release of the anti-microbial agent or agents in order to maintain a bacteria-free environment. The above patents are directed to dissolution or diffusion of the anti-microbial agent in solution. The aforementioned second approach involves the coupling of agents to polymeric materials as a result of the electrostatic interaction of compounds with polymeric materials. For example, U.S. Patent No. 4,769,013, issued to Lorenz and Creasy, refers to materials that contain an anti-microbial agent in complex with polyvinylpyrrolidone, which has been considered insoluble because it is complexed with polyurethane. The medical material is capable of releasing the anti-microbial agent upon contact with water. U.S. Patent No. 4,381,380, issued to LaVeen et al., Is directed to an article of thermoplastic polyurethane treated with iodine for antibacterial use. The polymer composition is composed of partially crosslinked polyurethane which has been complexed with iodine. Other attempts have been made to use the second approach. U.S. Patent No. 4,539,239, issued to Sakamoto and Takagi, discloses the use of chemically bonded ion exchange groups, which serve to ionically bind active agents to the surface of bio-materials. This patent also relates to a process for producing a urinary catheter having film-forming materials that possess functional groups capable of becoming ion exchange groups. The ion exchange groups, described as carboxylic acids, are then linked with anti-microbial agents. These materials serve to release the agent to the surrounding environment as a result of changes in external media. With this second approach, the active agents are loosely bound via Van der Waals or ionic forces and are easily released into the surrounding environments when in contact with solutions. Attempts have also been made to use the third approach mentioned above to achieve covalent binding of agents to polymeric surfaces. United States Patents Nos. 4,973,493; 5,263,992; and 5,002,582, assigned to Guire and Guire et al., disclose polymers, surfaces and devices that are modified with biocompatible agents, including anti-microbial compounds, whereby polymer is chemically bonded to a surface or a device via a fraction of chemical linkage that responds to a photochemical stimulus and whereby the anti-microbial agent is covalently bound to the surface via a different reactive group. The different reactive group does not respond to the photochemical stimulus. The anti-microbial agents used in these patents include penicillin and lysozyme. The solid surface and the anti-microbial agent are chemically bonded in U.S. Patent No. 5,263,992, as in the following formula: AXB, where A is a photochemically responsive group, such as a nitrophenylazide derivative or a derivative benzylbenzoyl, X is a linking moiety such as a Cx-C ^ alkyl group, and B is a thermo-chemically reactive group, such as nitrophenylhalides, alkylamines, alkylcarboxyls, alkylthiols, alkylaldehydes, alkylmethylimidates, alkyl isocyanates, alkylisothiocyanates and alkylhalides. Lysozyme is an enzyme (protein) that dissolves the mucopolysaccharides of the bacterial cell wall by hydrolysing the ß (l? 4) links between N-acetyl-D-muramic acid residues and 2-acetylamino-2-deoxy-D-glucose. Penicillin is a broad-spectrum β-lactam anti-biotic that inhibits the synthesis of bacterial cell wall. However, the above patents require the use of photochemically reactive groups. In contrast, the present invention provides a polymer-bound anti-microbial fraction that, when applied to a surface of an article, reduces the likelihood of adherence of microorganisms and thus the possibility of infection without the use of photochemical stimuli. . The polymer-bound antimicrobial fraction does not release the anti-microbial agent to solution and does not reduce the anti-microbial properties of the anti-microbial agent below its ability to act as a bio-static agent. For a better understanding of the present invention, together with other and further objectives, reference will be made to the following description, taken in conjunction with the examples, the scope of which is set forth in the appended claims. SUMMARY OF THE INVENTION The present invention is a bio-static composition for reducing and preventing bacterial or microbial adhesion. The composition contains (a) a hydrophilic polymer having a functional group that is covalently linked to an amine, thiol, carboxyl or hydroxyl active group of anti-microbial agents; (b) an anti-microbial agent covalently linked to the hydrophilic polymer; (c) a compatible polymer; and (d) a solvent. The functional group is capable of covalently binding to an anti-microbial agent without effectively reducing the anti-microbial property of the anti-microbial agent below its ability to act as a bio-static agent and without releasing the anti-microbial agent to a solution. The hydrophilic polymer can be, but is not limited to, a polyurethane polymer or prepolymer, a maleic anhydride polymer, a maleic anhydride copolymer, a polyol polymer, a polyamine polymer, an acrylate polymer, a copolymer of acrylate, a modified polymer of ethylene oxide, and a modified copolymer of ethylene oxide. The anti-microbial agent can be any antimicrobial or anti-microbial derivative having an amine, thiol, carboxyl or hydroxyl reactive group. The compatible polymer includes homopolymers or copolymers that are chemically compatible with the present composition and do not interfere with bio-static performance. The function of the compatible polymer is to provide increased lubricity as a result of water absorption or to improve the adhesion of the polymers or coatings to the surface of an article. The solvent can be, but not limited to, methyl ethyl ketones, N-methylpyrrolidinones, tetrahydrofurans, ethyl lactates, dichloromethanes, chloroforms, ethyl acetates, propylene glycol methyl ethers, propylene glycol methyl ether acetates, alcohols, ethers, esters, aromatics, chlorinated hydrocarbons, hydrocarbons, water and their mixtures. In a preferred embodiment, the present composition also contains at least one additive. The additive may be, but is not limited to, non-chemically reactive, anti-septic, non-chemically reactive, non-chemically reactive antimicrobial agents, surfactants, metal complexes, plasticizers, colorants, lubricants, stabilizers, rheology modifiers, pigments. , visualization adjuvants, anti-foam agents, lubricants, anti-thrombogenic agents, bio-effect agents, and their mixtures. In another preferred embodiment, the invention includes a polymer-bound anti-microbial fraction formed by reacting a hydrophilic polymer with an antimicrobial agent to form a covalent bond therebetween.

The present invention is also a coating for reducing and preventing bacterial adhesion. The coating is formed from a composition containing (a) a hydrophilic polymer having a functional group that reacts with and is covalently linked to an amine, thiol, carboxyl or hydroxyl active group of anti-microbial agents; (b) an antimicrobial agent that is covalently linked to the hydrophilic polymer; (c) a compatible polymer; (d) a solvent; and (e) optionally, at least one additive. The solvent in the composition is then evaporated, thereby leaving behind a bio-static coating. The present invention is also a method for preparing a bio-static article by preparing a composition containing a hydrophilic polymer having a functional group which reacts with and is covalently linked to an amine, thiol, carboxyl or hydroxyl active group of agents anti-microbial; an anti-microbial agent that is covalently linked to the hydrophilic polymer; a compatible polymer; a solvent; and at least one additive; (b) applying the composition to the surface of the article; (c) allowing the solvent of the composition to dry; and (d) curing the article. As a result, the present invention advantageously provides a polymer system that possesses a covalently or chemically bound antimicrobial agent that does not release itself into solutions and at the same time does not effectively reduce its anti-microbial property below its ability to act as a bio agent. -static ~. The present invention also advantageously provides a polymer system which, when applied to a surface, reduces and prevents adhesion of microorganisms and thus reduces the likelihood of microbial and bacterial infection. The present invention also advantageously reduces the coefficient of friction of the surface of medical articles. The present invention also advantageously provides a polymer system that exhibits reduced bacterial adhesion in a bacterial adhesion assay without exhibiting a zone of inhibition. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a polymer-bound anti-microbial fraction produced by reacting polyurethane polyisocyanate with hexetidine to form a covalent bond via a urea linkage. Figure 2 illustrates a polymer-bound anti-microbial fraction produced by reacting maleic anhydride with hexetidine to form a covalent bond via an amide linkage. Figure 3 illustrates a polymer-bound anti-microbial fraction produced by reacting a polymer having an epoxy group with hexetidine to form a covalent bond via an alkylamine linkage.

Detailed Description of the Invention The present invention is a bio-static composition for reducing and preventing bacterial or microbial adhesion. The composition contains (a) a hydrophilic polymer having a functional group that reacts with and covalently bonds to an amine, thiol, carboxyl or hydroxyl reactive group of antimicrobial agents; (b) an anti-microbial agent bound to the hydrophilic polymer; (c) a compatible polymer; and (d) a solvent. The present compositions are also effective against fungi and yeasts. The functional group of the hydrophilic polymer is capable of reacting with and covalently binding to an antimicrobial agent without effectively reducing the anti-microbial property of the anti-microbial agent below its ability to act as a bio-static agent and without releasing the antimicrobial agent to a solution. Examples of the functional group include, but are not limited to, isocyanates, isothiocyanates, esters, aldehydes, N-hydroxysuccinimide esters, epoxides, carboxylic esters, tresylates, anhydrides, alkylhalides, carboxylic acids, haloketones, alkenes, alkynes, and acyl chlorides . The hydrophilic polymer can be, but is not limited to, a polyurethane polymer, a maleic anhydride polymer, a maleic anhydride copolymer, a polyol polymer, a polyamine polymer, an acrylate polymer, an acrylate copolymer, a modified polymer of ethylene oxide, and a modified copolymer of ethylene oxide. Polyurethane polymers are derivatives of polyurethane polyisocyanate pre-polymers. The polyurethane polyisocyanate prepolymers can be derived from reacting (i) an aromatic or aliphatic polyisocyanate and (ii) a polyether polyol or polyester polyol or a polyamine. The polyurethane polyisocyanate prepolymers can also be prepared by reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyether polyol or a polyester polyol or a polyamine that has been modified with an anti-microbial agent. Examples of polyether polyols are, but are not limited to, polytetramethylene ether glycol, poly (ethylene glycol), poly (1,2-butanediol), poly (1,2-butylene glycol) or poly (propylene glycol). Examples of polyester polyols are, but are not limited to, those derived from the condensation of polycarboxylic acids, preferably dicarboxylic acids, such as adipic, sebacic, phthalic, isophthalic, terephthalic, oxalic, malonic, succinic, maleic, cyclohexane-1 acids. , 2-dicarboxylic, cyclohexane-1,4-dicarboxylic, polyacrylyl naphthalene-1,2-dicarboxylic, fumaric, itaconic, and similar dicarboxylic acids with polyalcohols, preferably diols such as ethylene glycol, diethylene glycol, pentaglycol, glycerol, sorbitol, triethanolamine, di (beta-hydroxyethyl) ether, similar diols and / or amino-alcohols such as ethanolamine, 3-aminopropanol, 5-aminopentanol, 1,6-aminohexanol, 10-aminodecanol, 6-amino-5-methylhexanol-1, p-hydroxymethylbenzylamine, etc. Polyesters derived from the opening / condensation of lactone rings with polyfunctional compounds such as any of the aforementioned polyalcohols can also be used. Examples of polyamines include, but are not limited to, 1,2-diamino-2-methylpropane, hexamethylenediamine, 1,2-diamino-cyclohexane-1,7-heptane diamine, 1,8-diaminooctane, 1,9-nonanodia mine. , diaminonaphthalene, polyethyleneimine, poly (allylamine hydrochloride), poly (propylene glycol) bis (2-aminopropyl ether), and poly (propylene glycol) -poly (ethylene glycol) -poly (propylene glycol) -bis (2-aminopropyl ether). The polyether, polyester and polyamine polyols can be modified with an anti-microbial using standard organic chemistry reactions including nucleophilic, substitution or condensation reactions. Suitable examples of polyurethane polyisocyanate prepolymers are, but are not limited to, diphenylmethane diisocyanate ricinoleic acid glyceride (MDI), polytetramethylene glycol-diphenylmethane diisocyanate ether (MDI), polytetramethylene-non-ether glycol isophorone diisocyanate (IPDI). ), poly (1,4-oxybutylene) glycol-diphenylmethane diisocyanate (MDI), poly (1,4-oxybutylene) glycol-tolylene diisocyanate (TDI), poly (1,4-oxybutylene) glycol-isophorone diisocyanate (IPDI), polyethylene glycol diphenylmethane diisocyanate (MDI), polyethylene glycol toluene diisocyanate (TDI), polyethylene glycol isophorone diisocyanate (IPDI), polycaprolactone diphenylmethane diisocyanate (MDI), polycaprolactone-tolylene diisocyanate (TDI), polycapro-lactone-isophorone diisocyanate (IPDI), polyethylene adipate-diphenylmethane diisocyanate (MDI), polyethylene adipate-tolylene diisocyanate (TDI), polyethylene adipate-isophorone diisocyanate (IPDI), polytetramethylene diphenylmethane diisocyanate (MDI), polytetramethylene tolylene diisocyanate (TDI), polytetramethylene isophorone diisocyanate (IPDI), polyethylene polypropylene adipate-diphenylmethane diisocyanate (MDI), polyethylene polypropylene adipate-tolylene diisocyanate (TDI), and polyethylene polypropylene adipate-isophorone diisocyanate (IPDI). Preferred polyurethane polyisocyanates are the glyceride of ricinoleic acid of diphenylmethane diisocyanate (MDI) or prepolymers of polytetramethyl ether ether glycol diphenylmethane diisocyanate (MDI). The maleic anhydride polymer and a maleic anhydride copolymer can be poly (styrene-maleic anhydride), poly (methyl vinyl ether-maleic anhydride), poly (ethylene maleic anhydride), poly (maleic anhydride-octadecene), poly (butadiene-anhydride) maleic), poly (vinyl acetate-maleic anhydride), or poly (vinyl methyl ether maleic anhydride), preferably poly (styrene-maleic anhydride), and more preferably poly (vinyl acetate-maleic anhydride). The acrylate polymer and the acrylate copolymer can be poly (ethyl acrylate), poly (ethyl methacrylate), poly (butyl acrylate), poly (butyl methacrylate), poly (methacrylate methyl methacrylate methacrylic acid), poly (acrylic anhydride) , poly (methyl methacrylate), poly (methyl methacrylate butyl methacrylate), poly (methyl methacrylate ethyl methacrylate) or poly (trifluoroethyl methacrylate), preferably poly (ethyl acrylate), and more preferably poly (acrylic anhydride). The modified polymer of ethylene oxide and the modified copolymer of ethylene oxide can be poly- (propylene glycol) diglycidyl ether, poly (allyl glycidyl ether ethylene glycol), poly (ethylene glycidyl methacrylate), poly (ethylene-methyl acrylate glycidyl) methacrylate), polybutadiene functionalized with an epoxy / hydroxy group, and any polymer modified or end-capped with glycidyl ether, preferably polymers end-capped with glycidyl ether, and more preferably polymers modified with glycidyl ether. Polymers that possess an epoxide group can be prepared using a variety of standard chemical techniques including the oxidation of alkenes or the cyclization of halohdrins. The percentage of the hydrophilic polymer in the composition is from about 0.1 to 15% by weight, preferably from about 0.1 to about 6% by weight, and more preferably from about 0.1 to about 4% by weight. The anti-microbial agent can be any antimicrobial or anti-microbial derivative having an amine, thiol, carboxyl or hydroxyl reactive group.

Preferred anti-microbial agents are hexahydropyrimidine derivatives. The most preferred anti-microbial agent is hexetidine. Hexetidine is a broad spectrum anti-microbial agent that has found use in topical preparations for infections of the skin and body cavities. The mode of activity of hexetidine is unknown; however, its ability to block the use of thiamine is observed. Derivatives of hexahydropyrimidine can be prepared as described by Murray Senkas in Journal of the American Chemical Society (1946) 68, 1611-1613. Typical reactions involve the condensation of amines substituted with formaldehyde, followed by reaction with a compound, which possesses an active hydrogen such as nitromethane via a Mannich-like reaction. For example, the preparation of 1,3-bis (2-ethylhexyl) -5-amino-5-methylhexahydropyrimidine (hexetidine) is carried out by the reaction of 2-ethylhexylamine with formaldehyde, followed by reaction with nitroethane. The 5-aminohexahydropyrimidine derivative can then be prepared by catalytic hydrogenation using Raney nickel. Examples of hexahydropyrimidine derivatives include, but not limited to, 1, 3-bis (l-methyl-3, 5-dioxa-cyclohexyl) -5-amino-5-methylhexahydropyrimidine, 1,3-bis (l-methyl-3, 5-dioxa- ci-clohexyl) -5-amino-propylhexahydropyrimidine, 5-nitro-l, 3-bis (1,3-diisopropyl) -5-hydroxymethylhexahydropyrimidine, 5-amino-l, 3-bis (1,3-diisopropyl) -5 -hydroxymethylhexahydropyrimidine, 5-amino-l, 3-bis (1,3-diisopropyl) -5-methylhexahydropyrimidine, 5-amino-l, 3-bis (1,3-diisopropyl) -hexahydropyrimidine, and 5-nitro-l, 3-bis (methyl) -5-hydroxymethylhexahydropyrimidine. Anti-microbial agents or derivatives having an amine, thiol, carboxyl or hydroxyl reactive group are combined with the functional group of the hydrophilic polymer to form covalent bonds. For example, the reaction of an amine with an isocyanate forms a urea bond. The reaction of an amine with an isothiocyanate forms a thiourea. The reaction of an amine with an ester, a carboxylic ester, an N-hydroxysuccinimide ester, a carboxylic acid or an acyl chloride provides an amide link. The reaction of an amine with an epoxide or alkylhalide produces an alkylamine link. The reaction of a hydroxyl group with an isocyanate provides a hydroxyurea link. The hydroxyl groups are combined with esters, carboxylic esters, N-hydroxysuccinimide esters, carboxylic acids or acyl chlorides to produce carboxylic esters. The percentage of the anti-microbial agent in the composition is from about 0.1 to about 7% by weight, preferably from about 0.1 to about 1% by weight, and more preferably from about 0.1 to about 0.5%. in weigh. Examples of the compatible polymer include, but are not limited to, homopolymers or copolymers derived from α-olefins, vinyl chlorides, vinylidene chlorides, ethylene oxides, propylene oxides, pyrrolidones, vinylpyrrolidones, hydroxyethylmethacrylates, methacrylates, polysaccharides, acrylamides. , methacrylamides, peptides, proteins, nylons, silicone derivatives, acrylic acids, methacrylic acids, vinyl acetates, vinyl alcohols, vinyl ethers, celluloses, aromatic diisocyanates, aliphatic diisocyanates, and mixtures thereof. The function of the compatible polymer is to improve the lubricity of the coated article as a result of water absorption and / or to improve the adhesion of the polymers or coatings to the surface of an article. The solvent may be, but is not limited to, methyl ethyl ketones, N-methylpyrrolidones, tetrahydrofurans, ethyl lactates, dichloromethanes, chloroforms, ethyl acetates, propylene glycol methyl ethers, propylene glycol methyl ether acetates, alcohols, ethers, esters, aromatics , chlorinated hydrocarbons, hydrocarbons, water, and their mixtures. The present composition optionally contains at least one additive. The additive can be, but is not limited to, chemically unreactive antibiotics, surfactants, metal complexes, anti-foaming agents, pigments, visualization aids, fragrances, dyes, stabilizers, lubricants, rheology modifiers, plasticizers, anti-aging agents. thrombogenic agents, bio-effect agents, or their mixtures. Examples of anti-thrombogenic agents include heparin, streptokinase, tissue plasminogen activator and urokinase. Examples of surfactants and anti-foam agents include alkylphenol alkoxylates, glycosides or nonionic and ionic polyglycosides, sulfates or alkylammonium sulfosuccinates, silicone derivatives or fluorinated alkyl alkoxylates. The invention also includes a polymer-bound antimicrobial fraction formed by reacting a hydrophilic polymer with an anti-microbial agent to form a covalent bond therebetween. When subjected to an extraction test, the anti-microbial fraction bound to polymer can not be extracted from solutions. Additionally, the polymer-bound anti-microbial fraction is compatible with various substrates, including polyurethane, polyvinyl chloride, silicone, latex, nylon, etc. The ratio of the hydrophilic polymer and the antimicrobial agent is from about 1: 1 to about 150: 1, preferably from about 1: 1 to about 40: 1. Figure 1 illustrates the reaction of a polyurethane polyisocyanate with hexetidine to form a hexetidine linked to polyurethane. The covalent bond formed in this case is a urea link. Figure 2 demonstrates the reaction of hexetidine with maleic anhydride. This produces hexetidine linked to polymer. The bond formed between the polymer and hexetidine is an amide bond. Figure 3 shows the reaction of a polymer having an epoxide group with hexetidine. In this case, the polymer-bound hexetidine is formed as a result of the alkylation of the primary amine of hexetidine via the epoxide functionality. The present invention is also a coating for reducing and preventing bacterial adhesion. The coating is formed from a composition containing (a) a coating material comprising a polymer having a functional group that reacts with and covalently bonds to an amine, thiol, carboxyl or hydroxyl active group of antimicrobial agents; (b) an anti-microbial agent covalently bonded to said coating material; (c) a hydrophilic polymer; (d) a solvent; and (e) optionally, at least one additive. The composition in solution is applied on a desired substrate to reduce and prevent bacterial adhesion. Once applied, the solvent in the composition evaporates, leaving behind a coating containing the hydrophilic polymer covalently bonded to the anti-microbial agent, the compatible polymer and the additives. The coating composition contains from about 0.3 to about 99% of the hydrophilic polymer; about 0.3 to about 95% of the anti-microbial agent; around 0.3 to about 98% of the compatible polymer; around 0.3 to about 25% of the additives. The present invention is also a method for preparing a bio-static article by (a) preparing a composition containing a coating material comprising a polymer having a functional group that reacts with and covalently bonds to an amine, thiol active group , carboxyl or hydroxyl; an anti-microbial agent covalently bonded to said coating material; a hydrophilic polymer; a solvent; and at least one additive; (b) applying the composition to the surface of the article; (c) allowing the solvent of the composition to dry; and (d) cure the article. The composition in solution is applied to the article in a manner known in the art, generally by immersing the article in the composition. Once applied, the solvent in the composition is allowed to dry at room temperature for about 5 to about 60 minutes, or at temperatures of about 40 to about 120 'C for about 5 to about 60 minutes. After the solvent is dried, the article is cured in a manner known in the art, typically by clocking in an oven for about 5 to about 60 minutes at a temperature of about 40 to about 120 ° C. The article has a substrate that is compatible with the polymer-bound anti-microbial agent. Suitable examples of the substrate are polyurethane, polyvinyl chloride, silicone, latex, nylon, etc. Preferably, the article is a medical device. Examples of the medical device include, but are not limited to, catheters, guide wires, gloves, contraceptives, wound dressings, drainage tubes, feeding tubes, iringotomy tubes, wound pins, implants, sutures, foams, ophthalmic lenses, prostheses, blood bags, ultrafiltration or dialysis membranes, blood oxygenators, and vascular grafts. EXAMPLES The following examples have been established, below, as a guide for the person skilled in the art, and are not intended in any way to limit the scope of the present invention. In the following examples, bio-static compositions containing polymer-bound anti-microbial agents were subjected to analysis of bio-static efficacy (zone of bacterial inhibition and adhesion), gas chromatography, infrared, and coefficient of friction. The methodology for such analyzes is detailed below. Bio-Static Efficacy Testing Procedures The bio-static efficacy of the polymer systems was determined using two test procedures: analysis of zone of inhibition and bacterial adhesion. The zone of inhibition is a method that determines the efficacy and extent of releasable anti-microbials. A chemically bound agent, without releasing, does not exhibit a zone of inhibition, since this method is based on the release of the active agent. Adhesion analysis is a method that is based on the adherence of microorganisms to a surface, which can result in the formation of a bio-film on the surface. A surface possessing a covalently linked anti-microbial agent demonstrates reduced bacterial adhesion in an adhesion analysis. A polymer system that releases an active agent exhibits a zone of inhibition as well as reduced bacterial adhesion. Inhibition Zone Analysis The zone of inhibition analysis employed involves a modification of the US pharmacopoeia procedure for assays of microbial anti-biotics. The procedure involves placing the test article (film, tube, etc.) in an appropriate growing medium that has been seeded with microorganisms. The medium was then incubated for 24 hours at 37 ° C. The diameter of the area was then measured and recorded. An uncoated substrate exhibited no zone of inhibition versus Staphylococcus aureus and a substrate coated with 1% ampicillin exhibited a zone of 18 mm. Bacterial Adhesion Analysis The bacterial adherence assay employed involves incubating the test article in 100 ml of Staphylococcus aureus (103 organisms / ml) in phosphate buffer solution for 24 hours at 37 ° C, with shaking. The test article is removed, washed up to six times in 100 ml of phosphate buffer solution and then incubated in 100 ml of tryptic soy broth at 37"C for 24 hours, then the number of organisms that adhere is determined by the total aerobic microbial count by the United States pharmacopoeia procedure.An aliquot of the wash with phosphate buffer is also available on a plate to determine the number of viable organisms and ensure complete removal of non-adherent organisms. and a substrate coated with 1% ampicillin served as control samples.The uncoated substrate exhibited a bacterial adhesion of more than 3 x 107 cfu / ml; the sample with 1% ampicillin exhibited a bacterial adherence of less than 100 cfu / ml. Gas Chromatographic Analysis (GC) of Polymer Coatings GC analyzes were carried out using an AutoSystem gas chromatograph from Perkin Elmer, equipped with a J & W Scientific DBl capillary column (30 mx 0.32 mm, 0.25 μm) and Nelson model PE software 1022 GC Plus. The system operated with temperature programming from 40 to 160 ° C for 18 minutes. The temperature of the injector operated at 210 ° C, the flame ionization detector operated at 250 ° C. The carrier gas was helium, operating at a pressure of 6.2 psi.Extraction Test of Polymer Coatings The extraction test employed involved incubating the test article (films, tubes, etc.) in distilled water or saline (1 g of article per ml of solution) for 24 hours, with agitation, and determine the presence or absence of the active agent in the extraction medium using the GC analysis described above Infrared Analysis of Polymer Compositions Infrared analysis was carried out using a Nicolet Impact 400D Fourier transform infrared spectrometer, equipped with deuterated triglycine sulfate detector, OMNIC software and operating at a resolution of 4-16 cm "1 with Happ-Genzel apodization. Friction Coefficient of Bio-Static Surfaces The friction coefficient of polyvinyl chloride pipe was determined using a materials tester from Kayeness, Inc. equipped with Chatillon DFGS strength gauge and Forcedat data collection software from Johnson Scale Co. Example 1 Comparative Example A clean, uncoated polyvinyl chloride tube was air dried for 30 minutes and cured at 80 ° C. for 30 minutes.The coefficient of friction for the uncoated tube was determined using the method described above. coefficient of friction was approximately 0.3 Example 2 Bio-Static Composition of the Present Invention 2 g of the polyurethane polyisocyanate pre-polymer (Nordot 34D-2 adhesive, Synthetic Surfaces, Inc.), prepared by reaction of a 2 molar excess of diphenylmethane diisocyanate (MDI) with ricinoleate polyol were combined with 250 mg of hexetidine (Angus Chemical) in 35 g of methyl ethyl ketone.The reaction was monitored by gas chromatography.The depletion of hexetidine was evident within 8 hours. hours Infrared analysis showed the disappearance of the isocyanate peak at approximately 2,400 cm-1 With the solution 10 g of tetrahydrofuran, 10 g of N-methylpyrrolidinone, 30 g of diacetone alcohol, 3 g of polyvinyl pyrrolidone (Kollidone 90 F, Basf). A clean tube of polyvinyl chloride was immersed in the solution for 15 seconds, dried in air for 30 minutes and cured at 80 ° C. for 30 minutes.The tube was examined for bacterial adhesion of S. aureus using the method described above. Aliquots of both Tryptic Soy Broth (TSB) and washing with final phosphate buffer solution (PBS) were plated and showed no detectable colony formation (less than 100 cfu / ml) No zone of inhibition was detected using the analysis method outlined above, the coefficient of friction for the coated tube was determined to be about 0.075. The presence of hexetidine was not observed in the extraction medium Example 3 Hydrophilic Composition of the Present Invention 2 g of the pre-polymer of polyurethane polyisocyanate (Nordot 34D-2 adhesive, Synthetic Surfaces, Inc.), prepared by reacting a 2 molar excess of diphenylmethane diisocyanate (MDI) with ricinoleate polyol, fu They were combined with 35 g of methyl ethyl ketone, 10 g of tetrahydrofuran, 10 g of N-methylpyrrolidinone, 30 g of diacetone alcohol, 3 g of polyvinylpyrrolidinone.

(Kollidon 90F, Basf). A clean slide of polyvinyl chloride was coated with the solution using a cotton swab. The slide was dried in air for 30 minutes and cured at 80 ° C for 30 minutes.The slide was examined for bacterial adherence of S. aureus using the test procedure described above.An aliquot of TSB was placed on a plate and indicated bacterial adhesion (greater than 3 x 107 cfu / ml), an aliquot of the final wash with PBS was plated and showed no detectable colony formation (less than 100 cfu / ml) Example 4 Composition of the Present Pre-polymer Invention of polyisocyanate Vorite 3025 (2 g) (CasChem, Inc.), was combined with hexetidine (0.25 g) in methyl ethyl ketone (30 g). The mixture was vigorously stirred overnight. The GC analyzes indicated the disappearance of hexetidine. The infrared analysis showed the disappearance of the isocyanate band at 2,269 cm -1. Tetrahydrofuran (10 g), diacetone alcohol (30 g), N-methylpyrrolidinone (10 g), polyvinyl pyrrolidone (3 g, Kollidon 90F), fluorinated alkyl alkoxylate (0.1 g, Flourad FC-171) and methyl ethyl were added to the mixture. Ketone (14.65 g). The material was then agitated, until homogeneous.

A slide of polyvinyl chloride (PVC) was coated with the solution using a cotton swab saturated with the solution. No bacterial adherence of S was observed. aureus in the coated slide after analysis of bacterial adhesion. An aliquot of the PBS wash was plated and did not exhibit bacterial adherence. The presence of hexetidine in the extraction medium was not observed. Example 5 Composition of the Present Invention A polyisocyanate prepolymer was prepared by reaction of 4,4-methylenebis (phenylisocyanate) (59 g) with castor oil (72 g) in ethyl methyl ketone (56 g) at 55 * C . 2 g of this material were combined with hexetidine (0.25 g) and stirred at room temperature for 8 hours. To the mixture were added tetrahydrofuran (10 g), diacetone alcohol (30 g), N-methyl pyridinophthine (10 g), polyvinyl pyrrolidone (3 g) (Kollidon 90F), Flourad FC-171 (0.1 g) and methyl ethyl ketone. (14.65 g). The material was then stirred until homogeneous. A PVC slide was coated with a polymer derived from hexetidine using a cotton swab saturated with the solution, dried in air for 30 minutes, and cured at 80 ° C. for 30 minutes The slide was examined for bacterial adhesion of S Aureus using the test procedure described above Aliquots of TSB and the final wash with PBS were placed on a plate and did not indicate bacterial adherence The presence of hexetidine was not observed in the extraction medium Example 6 Composition of the Present Invention Polystyrene-co-maleic anhydride copolymer (10 g) was combined with hexetidine (2.2 ml) and triethylamine (0.5 g) in 250 ml acetone.The mixture was stirred at 40 ° C for 1 hour. The infrared analysis showed the appearance of new bands corresponding to an amide group (1,656 cm "1) and a carboxylic acid group (-3,500 cm-1, 1,712 cm-1 and 1,360 cm" 1). The GC analysis indicated the disappearance of hexetidine. A PVC slide was coated with the solution, using a cotton swab saturated with the solution. No bacterial adherence was observed to the coated slide after analysis of bacterial adhesion. The presence of microorganisms was not detected in the PBS wash. The presence of hexetidine in the extraction medium was not observed. Example 7 Composition of the Present Invention A polyol was chemically modified with hexetidine, combining glycidyl ether of castor oil (2.5 g) (Aldrich Chemical Co.) with triethylamine (0.1 g) (Aldrich Chemical Co.) and hexetidine (0.5 g) (Angus) The reaction was monitored by gas chromatography and was complete within 30 minutes. To the solution were added methyl ethyl ketone (10 g), a crystal of phosphoric acid, and, 4-methylenebis (phenylisocyanate) (3 g) (Aldrich Chemical Co.). The mixture was stirred for 24 hours, whereby infrared analysis showed the formation of the polyurethane polyisocyanate prepolymer (NCO -2,200 cm "1) To this solution (4.2 g) were added Nordot 34 D-2 adhesive (0.6 g), methyl ethyl ketone (42.1 g), tetrahydrofuran (10 g), N-methylpyrrolidinone (10 g), diacetone alcohol (30 g), polyvinyl pyrrolidone (Kollidon 90F) (3 g) and Fluorad FC-171 (0.1 g). was agitated for 24 hours.A PVC slide was coated with the solution, using a cotton swab saturated with the solution.Si.aureus bacterial adherence was not observed to the coated slide after the bacterial adhesion analysis. did not exhibit detectable microorganisms The presence of hexetidine was not observed in the extraction medium Thus, although those which are currently believed to be the preferred embodiments have been described, those skilled in the art will appreciate that Further and additional may be made without departing from the true spirit of the invention, and it is intended to include all such changes and modifications within the scope of the appended claims hereto.

Claims (49)

1. CLAIMS 1. A bio-static composition for reducing and preventing bacterial and microbial adhesion, comprising: (a) a hydrophilic polymer having a functional group that reacts with and is covalently linked to an active group selected from the group consisting of amine , thiol, carboxyl and hydroxyl, said functional group capable of reacting with and covalently binding to an anti-microbial agent without effectively reducing the anti-microbial property of said antimicrobial agent below its ability to act as a bio-static agent without releasing said anti-microbial agent to a solution; (b) an anti-microbial agent covalently linked to said functional group of said hydrophilic polymer; (c) a compatible polymer; and (d) a solvent.
2. 2. The bio-static composition according to claim 1, wherein said functional group of said hydrophilic polymer is selected from the group consisting of isocyanates, isothiocyanates, esters, aldehydes, esters of N-hydroxysuccinimide, epoxies, carboxylic esters, tresylates, anhydrides, alkyl halides, carboxylic acids, haloketones, alkenes, alkynes, and acyl chlorides.
3. 3. The bio-static composition according to claim 1, wherein said hydrophilic polymer reacts with and covalently bonds to said anti-microbial agent to form an anti-microbial fraction bound to polymer.
4. The bio-static composition according to claim 1, wherein said hydrophilic polymer is selected from the group consisting of a polyurethane polymer, a maleic anhydride polymer, a maleic anhydride copolymer, a polyol, a polyamine, a polymer of acrylate, an acrylate copolymer, a modified polymer of ethylene oxide, and a modified copolymer of ethylene oxide.
5. The bio-static composition according to claim 4, wherein said polyurethane polymer is a polyisocyanate polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyether polyol.
6. 6. The bio-static composition according to claim 4, wherein said polyurethane polymer is a polyisocyanate polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyester polyol.
7. The bio-static composition according to claim 4, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyamine.
8. The bio-static composition "according to claim 4, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyether polyol that has been modified with an anti-aging agent. -microbial 9.
9. The bio-static composition according to claim 4, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyester polyol that has been modified with a anti-microbial agent 10.
10. The bio-static composition according to claim 4, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyamine that has been modified with an anti-microbial agent 11.
11. The bio-static composition according to claim 1, wherein said anti-microbial agent has a A reactive selected from the group consisting of amine, thiol, carboxyl and hydroxyl.
12. The bio-static composition according to claim 1, wherein said anti-microbial is selected from the group consisting of 1,3-bis (l-methyl-3, 5-dioxa-cyclohexyl) -5-amino-5 -methylhexahydropyrimidine, 1,3-bis (l-methyl-3, 5-dioxa-ci-clohexyl) -5-amino-5-propylhexahydropyrimidine, 5-nitro-l, 3-bis (1,3-diisopropyl) -5-hydroxymethylhexahydropyrimidine, 5-amino-1, 3 bis (1, 3-diisopropyl) -5-hydroxymethylhexahydropyrimidine, 5-amino-1, 3 bis (1, 3-diisopropyl) -5-methylhexahydropyrimidine, 5-amino-l, 3bis (1, 3-diisopropyl) -hexahidropirimidina, and 5 -nitro-l, 3-bis (methyl) -5-hydroxymethylhexahydropyrimidine.
13. The bio-static composition according to claim 1, wherein said anti-microbial is 5-amino-l, 3-bis (2-ethylhexyl) -5-methyl-hexahydropyrimidine.
14. 14. The bio-static composition according to claim 1 wherein said compatibilizing polymer is a homopoly-mer or copolymer derived from the group consisting of a-olefins, vinyl chlorides, vinylidene chlorides, ethylene oxides, propylene oxides pyrrolidones, vinylpyrrolidone, hydroxy-etilmetacrilatos, methacrylates, polysaccharides, acrylamides, methacrylamides, peptides, proteins, nylons, derivatives of silicone, acrylic acids, methacrylic acids, vinyl acetates, vinyl alcohols, vinyl ethers, celluloses, aromatic diisocyanates, aliphatic diisocyanates , and its mixtures.
15. 15. The bio-static composition according to claim 1, wherein said solvent is selected from the group consisting of methyl ethyl ketone, N-metilpirrolidinonas, tetrahydrofurans, ethyl lactates, dichloromethanes, cloroformos, ethyl acetates, ethers propylene methyl glycol, propylene glycol methyl ether acetates, alcohols, ethers, esters, aromatics, chlorinated hydrocarbons, hydrocarbons, water, and mixtures thereof.
16. 16. The bio-static composition according to claim 1, further comprising at least one additive selected from the group consisting of anti-biotic chemically unreactive, anti-septic chemically unreactive, antimicrobial agents chemically nonreactive surfactants, metal complexes, anti-foam agents, pigments, visualization adjuvants, dyes, lubricants, rheology modifiers, fragrances, plasticizers, anti-thrombogenic agents, bio-effect agents, and mixtures thereof.
17. 17. A coating for reducing and preventing bacterial and microbial adhesion which comprises: (a) a hydrophilic polymer possessing a functional group which reacts with and covalently bonds to an active group selected from the group consisting of amine, thiol, carboxyl and hydroxyl, said functional group capable of reacting with and covalently binding to an anti-microbial agent without effectively reducing the anti-microbial property of said antimicrobial agent below its ability to act as a bio-static agent and without releasing said anti-microbial agent. microbial to a solution; (b) an anti-microbial agent covalently linked to said functional group of said hydrophilic polymer; (c) a compatible polymer; and (d) a solvent.
18. The coating according to claim 17, wherein said functional group of said hydrophilic polymer is selected from the group consisting of isocyanates, isothiocyanates, esters, aldehydes, N-hydroxysuccinimide esters, epoxides, carboxylic esters, tresylates, anhydrides, halides of alkyl, carboxylic acids, haloketones, alkenes, alkynes, and acyl chlorides.
19. 19. The coating according to claim 17, wherein said hydrophilic polymer reacts with and covalently bonds to said anti-microbial agent to form an anti-microbial fraction linked to polymer.
20. The coating according to claim 17, wherein said hydrophilic polymer is selected from the group consisting of a polyurethane polymer, a maleic anhydride polymer, a maleic anhydride copolymer, a polyol, a polyamine, an acrylate polymer, an acrylate copolymer, a polymer modified with ethylene oxide, and a modified copolymer with ethylene oxide.
21. The coating according to claim 20, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyether polyol.
22. 22. The coating according to claim 20, wherein said polyurethane polymer is a polyisocyanate polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyester polyol.
23. 23. The coating according to claim 20, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyamine.
24. The coating according to claim 20, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyether polyol that has been modified with an anti-microbial agent.
25. 25. The coating according to claim 20, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyester polyol that has been modified with an anti-microbial agent.
26. 26. The coating according to claim 20, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyamine that has been modified with an anti-microbial agent.
27. 27. The coating according to claim 17, wherein said anti-microbial agent has a reactive group selected from the group consisting of amine, thiol, carboxyl and hydroxyl.
28. The coating according to claim 17, wherein said anti-microbial is selected from the group consisting of 1,3-bis (l-methyl-3,5-dioxa-cyclohexyl) -5-amino-5-methylhexahydropyrimidine, 1, 3-bis (l-methyl-3,5-dioxacyclohexyl) -5-amino-5-propylhexahydropyrimidine, 5-nitro-l, 3-bis (1,3-diisopropyl) -5-hydroxymethylhexahydropyrimidine, 5- amino-1, 3 bis (1,3-diisopropyl) -5-hydroxymethylhexahydropyrimidine, 5-amino-1,3-bis (1,3-diisopropyl) -5-methylhexahydropyrimidine, 5-amino-1,3-bis (1, 3-diisopropyl) -hexahydropyrimidine, and 5-nitro-l, 3-bis (methyl) -5-hydroxymethylhexahydropyrimidine.
29. 29. The coating according to claim 17, wherein said anti-microbial is 5-amino-l, 3-bis (2-ethylhexyl) -5-methyl-hexahydropyrimidine.
30. The coating according to claim 17, wherein said compatible polymer is a homopolymer or copolymer derived from the group consisting of α-olefins, vinyl chlorides, vinylidene chlorides, ethylene oxides, propylene oxides, pyrrolidones, vinyl pyrrolidones, hydroxy-ethyl methacrylates, methacrylates, polysaccharides, acrylamides, methacrylamides, peptides, proteins, nylons, silicone derivatives, acrylic acids, methacrylic acids, vinyl acetates, vinyl alcohols, vinyl ethers, celluloses, aromatic diisocyanates, aliphatic diisocyanates, and mixtures thereof.
31. The coating according to claim 17, further comprising at least one additive selected from the group consisting of chemically non-reactive anti-biotics, chemically non-reactive anti-septic, chemically non-reactive anti-microbial agents, surfactants, metal complexes , anti-foam agents, pigments, visualization adjuvants, dyes, lubricants, rheology modifiers, fragrances, plasticizers, anti-thrombogenic agents, bio-effect agents, and their mixtures.
32. 32. A method for preparing a bio-static article, comprising: (a) preparing a composition comprising: (i) a hydrophilic polymer having a functional group that reacts with and is covalently linked to an active group selected from the group it consists of amine, thiol, carboxyl and hydroxyl, said functional group capable of reacting with and covalently binding to an anti-microbial agent without effectively reducing the anti-microbial property of said antimicrobial agent below its ability to act as a bio-static agent. and without releasing said anti-microbial agent to a solution; (ii) an anti-microbial agent covalently linked to said functional group of said hydrophilic polymer; (iii) a compatible polymer; and (iv) a solvent; (b) applying said composition to the surface of said article; (c) allowing said solvent to dry out of the composition; and (d) cure said article.
33. 33. The method according to claim 32, wherein said article is a medical device.
34. 34. The method according to claim 32, wherein said medical device is selected from a group consisting of catheters, guide wires, gloves, anti-concept, wounds, drainage tubes, feeding tubes, tubes. of myringotomy, pins for wounds, implants, sutures, foams, ophthalmic lenses, prostheses, blood bags, ultrafiltration or dialysis membranes, blood oxygenators, and vascular grafts.
35. 35. The method according to claim 32, wherein said functional group of said hydrophilic polymer is selected from the group consisting of isocyanates, isothiocyanates, esters, aldehydes, esters of N-hydroxysuccinimide, epoxides, carboxylic esters, tresylates, anhydrides, halides of alkyl, carboxylic acids, haloketones, alkenes, alkynes, and acyl chlorides.
36. 36. The method according to claim 32, wherein said hydrophilic polymer reacts with and covalently bonds to said anti-microbial agent to form an anti-microbial fraction bound to polymer.
37. 37. The method according to claim 32, wherein said hydrophilic polymer is selected from the group consisting of a polyurethane polymer, a maleic anhydride polymer, a maleic anhydride copolymer, a polyol, a polyamine, an acrylate polymer, an acrylate copolymer, a modified polymer of ethylene oxide, and a modified copolymer of ethylene oxide.
38. 38. The method according to claim 32, wherein said polyurethane polymer is a polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyether polyol.
39. 39. The method according to claim 37, wherein said polyurethane polymer is a polyisocyanate polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyester polyol.
40. 40. The method according to claim 37, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyamine.
41. 41. The method according to claim 37, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyether polyol that has been modified with an anti-microbial agent.
42. 42. The method according to claim 37, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyester polyol that has been modified with an anti-microbial agent.
43. 43. The method according to claim 37, wherein said polyurethane polymer is polyurethane polyisocyanate derived from reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyamine that has been modified with an anti-microbial agent.
44. 44. The method according to claim 32, wherein said anti-microbial agent has a reactive group selected from the group consisting of amine, thiol, carboxyl and hydroxyl.
45. 45. The method according to claim 32, wherein said anti-microbial is selected from the group consisting of 1,3-bis (l-methyl-3, 5-dioxa-cyclohexyl) -5-amino-5-methylhexahydropyrimidine, 1,3-bis (l-methyl-3,5-dioxacyclohexyl) -5-amino-5-propylhexahydropyrimidine, 5-nitro-l, 3-bis (1,3-diisopropyl) -5-hydroxymethylhexahydropyrimidine, 5- amino-l, 3a (1,3-diisopropyl) -5-hydroxymethylhexahydropyrimidine, 5-amino-1,3-bis (1,3-diisopropyl) -5-methylhexahydropyrimidine, 5-amino-1,3-bis (1,3-diisopropyl) -hexahydropyrimidine, and 5-nitro-l, 3-bis (methyl) -5-hydroxymethylhexahydropyrimidine.
46. 46. The method according to claim 32, wherein said anti-microbial is 5-amino-l, 3-bis (2-ethylhexyl) -5-methyl-hexahydropyrimidine.
47. 47. The method according to claim 32, wherein said compatible polymer is a homopolymer or copolymer derived from the group consisting of α-olefins, vinyl chlorides, vinylidene chlorides, ethylene oxides, propylene oxides, pyrrolidones, vinyl pyrrolidones, hydroxy- ethyl methacrylates, methacrylates, polysaccharides, acrylamides, methacrylamides, peptides, proteins, nylons, silicone derivatives, acrylic acids, methacrylic acids, vinyl acetates, vinyl alcohols, vinyl ethers, celluloses, aromatic diisocyanates, aliphatic diisocyanates, and mixtures thereof.
48. 48. The method according to claim 32, wherein said solvent is selected from the group consisting of methyl ethyl ketones, N-methylpyrrolidinones, tetrahydrofurans, ethyl lactates, dichloromethanes, chloroforms, ethyl acetates, propylene glycol methyl ethers, ether acetates. propylene glycol methyl, alcohols, ethers, esters, aromatics, chlorinated hydrocarbons, hydrocarbons, water, and mixtures thereof.
49. 49. The method according to claim 32, further comprising at least one additive selected from the group consisting of chemically non-reactive anti-biotics, chemically non-reactive antiseptics, chemically unreactive anti-microbial agents, surfactants, metal complexes, agents anti-foam, pigments, visualization adjuvants, dyes, lubricants, rheology modifiers, fragrances, plasticizers, anti-thrombogenic agents, bio-effect agents, and their mixtures.