Biostatic coatings for the reduction and prevention of bacterial adhesion
Abstract
A biostatic composition to reduce and prevent bacterial and microbial adhesion, comprising: (a) a hydrophilic polymer having a functional group that reacts with and covalently binds to an active group selected from the group consisting of amine, thiol, carboxyl, or hydroxyl, in which the hydrophilic polymer is selected from the group constituted by copolymers of poly (maleic anhydride-styrene), polyols, and polyurethane polymers derived from polyurethane polyurethane prepolymers, said functional group covalently bonded to an antimicrobial agent; (b) an antimicrobial agent covalently bonded to said functional group of said hydrophilic polymer, wherein said antimicrobial agent has a reactive group selected from the group consisting of thiol, carboxyl, and hydroxyl; (c) a compatible polymer selected from homopolymers or copolymers derived from pyrrolidones and vinyl pyrrolidones; and (d) a solvent selected from methyl ethyl ketones, tetrahydrofurans and alcohols.

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10 claims: 3 independent, 7 dependent
- 1ES 2 328 307 T3 REIVINDICACIONES 1. Una composición bioestática para reducir y prevenir la adherencia bacteriana y microbiana, que comprende:(a) un polímero hidrófilo que posee un grupo funcional que reacciona con y se une de manera covalente a un grupo activo seleccionado entre el grupo constituido por amina, tiol, carboxilo, o hidroxilo, en la que el polímero hidrófilo se selecciona entre el grupo constituido por copolímeros de poli(anhídrido maleico-estireno), polioles, y polímeros de poliuretano derivados de prepolímeros de poliuretano poliisocianato, dicho grupo funcional unido de manera covalente a un agente antimicrobianos;(b) un agente antimicrobiano unido de manera covalente a dicho grupo funcional de dicho polímero hidrófilo, en el que dicho agente antimicrobiano tiene un grupo reactivo seleccionado entre el grupo constituido por tiol, carboxilo, e hidroxilo;(c) un polímero compatible seleccionado entre homopolímeros o copolímeros derivados de pirrolidonas y vinilpirrolidonas;y (d) un disolvente seleccionado entre metil etil cetonas, tetrahidrofuranos y alcoholes.
- 2La composición bioestática de acuerdo con la reivindicación 1, en la que dicho grupo funcional de dicho polímero hidrófilo se selecciona entre el grupo constituido por isocianatos, isotiocianatos, aldehídos, ésteres de N-hidrosuccinimida, epóxidos, ésteres carboxílicos, tresilatos, anhídridos, ácidos carboxílicos, alquenos y alquinos.
- 3La composición bioestática de acuerdo con la reivindicación 1, en la que dicho polímero hidrófilo reacciona con y se une de manera covalente a dicho agente antimicrobiano para formar un resto antimicrobiano unido a polímero.
- 4La composición bioestática de acuerdo con la reivindicación 1, en la que dicho agente antimicrobiano se selecciona entre el grupo constituido por 1,3-bis(1-metil-3,5-dioxa-ciclohexil)-5-amino-5-metilhexahidropirimidina, 1,3bis(1-metil-3,5-dioxa-ciclohexil)-5-amino-5-propilhexahidropirimidina, 5-nitro-1,3-bis(1,3-diisopropil)-5-hidroximetilhexahidropirimidina, 5-amino-1,3-bis(1,3-diisopropil)-5-hidroximetilhexahidropirimidina, 5-amino-1,3-bis(1,3-diisopropil)-5-metilhexahidropirimidina, 5-amino-1,3-bis(1,3-diisopropil)-hexahidropirimidina, y 5-nitro-1,3-bis(metil)5-hidroximetilhexahidropirimidina.
- 5La composición bioestática de acuerdo con la reivindicación 1, en la que dicho agente antimicrobiano es 5amino-1,3-bis(2-etilhexil)-5-metil-hidroximetilhexahidropirimidina.
- 6La composición bioestática de acuerdo con la reivindicación 1, que comprende además al menos un aditivo seleccionado entre el grupo constituido por antibióticos químicamente no reactivos, antisépticos químicamente no reactivos, agentes antimicrobianos químicamente no reactivos, tensioactivos, complejos metálicos, agentes antiespumantes, pigmentos, adyuvantes de visualización, tintes, lubricantes, modificadores de reología, fragancias, plastificantes, agentes antitrombogénicos, agentes de efectividad biológica, y las mezclas de los mismos.
- 7Un revestimiento para reducir y prevenir la adherencia bacteriana y microbiana que comprende una composición bioestática de acuerdo con una cualquiera de las reivindicaciones 1-6.
- 8Un método para preparar un artículo bioestático, que comprende:(a) preparar una composición bioestática de acuerdo con una cualquiera de las reivindicaciones 1-6;(b) aplicar dicha composición a la superficie de dicho artículo;(c) permitir que dicho disolvente de la composición se seque;y (d) curar dicho artículo.
- 9El método de acuerdo con la reivindicación 8, en el que dicho artículo es un dispositivo médico.
- 10El método de acuerdo con la reivindicación 9, en el que dicho dispositivo médico se selecciona entre el grupo constituido por catéteres, guías de alambre, guantes, anticonceptivos, vendajes de heridas, tubos de drenaje, tubos de alimentación, tubos de miringotomía, grapas de heridas, implantes, suturas, espumas, lentes oftálmicas, prótesis, bolsas de sangre, ultrafiltración o membranas de diálisis, oxigenadores de sangre, e injertos vasculares.
Independent claims10
114 paragraphs in 8 sections, as filed
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DESCRIPTION
Biostatic coatings for the reduction and prevention of bacterial adherence.
1. Field of the invention
The present invention relates to biostatic compositions, as well as coatings and methods for preparing biostatic articles using the same.
2. Description of the prior art
There have been numerous attempts to concentrate antimicrobial, antiseptic, or antibiotic agents on the surface of biomaterials or medical devices as a means of reducing the likelihood of bacterial adherence and subsequent bacterial infection. Various approaches have been undertaken including (1) entrapment of active compounds or agents in surface coatings containing polymer layers or matrices (2), coupling of active agents to surface polymers or coatings by ionic or other electrostatic forces and ( 3) the covalent or chemical bonding of active agents to the surface of polymers or materials.
The first approach involves mechanically entrapment of agents within a polymer matrix. The agents are generally released by two mechanisms including (a) dissolution of the polymer material or (b) diffusion of the agents as a result of osmosis. The second approach involves the coupling of agents to polymer materials as a result of ionic bonding or other intermolecular forces of attraction. Intermolecular forces of attraction include dipole-dipole, London or scattering forces, or hydrogen bonding. These attractive forces occur as a result of electronegativity or charge differences between the polymer molecule and the active agent (s). The release mechanism involves the desertion of the active agent (s) from the polymer matrix. The third approach involves the covalent attachment of agents to polymer surfaces. This includes the coupling of the two materials as a result of chemical bond formation. Covalent attachment of antimicrobial agents to polymer matrices produces systems that generally do not release the bound or coupled agent under normal physiological conditions. If release of the agent occurs, it is generally as a result of hydrolysis of a chemical bond.
Attempts have been made to use the first approach by mechanically entrapment agents in a polymer matrix. For example, US Patent No. 4,603,152 to Laurin and Stupar describes antimicrobial compositions comprising 30 to 85% polymeric binder and 15 to 70% antimicrobial agents or metal mixtures. Antimicrobial agents form a chain-like structure that is released in solutions to create an initial dosage and then provides the route for further release of the agents.
US Patent No. 5,019,096 to Fox et al. Relates to a method of preparing an infection resistant material or medical device comprising biomedical polymers and an effective amount of antimicrobial agents such as chlorhexidine salts and salts. silver. The agents are released in a controlled manner when the infection resistant material is in fluids.
US Patent No. 5,133,090 to Modak and Sampath describes an antiviral glove comprising an elastomeric material with an internal coating comprising a chlorhexidine salt and a lubricating agent that delivers the anti-infective agent within 10 minutes of exposure to an aqueous solution.
US Patent No. 4,853,978 to Stockum and Surgicos relates to an antimicrobial medical glove having an inner liner comprising a slow release antimicrobial agent in a cross-linked starch. The coating produces the slow release of the antimicrobial agent (s) in order to maintain a bacteria-free environment.
The above patents refer to dissolution or diffusion of the antimicrobial agent in solution.
The second approach mentioned above involves the coupling of agents to polymer materials as a result of electrostatic interaction of the compounds with polymer materials. For example, US Patent No. 4,769,013 to Lorenz and Creasy relates to materials containing an antimicrobial agent that complexes with polyurethane. Medical material is capable of releasing the antimicrobial agent upon contact with water.
US Patent No. 4,381,380 to La Veen et al. Relates to a thermoplastic polyurethane article treated with iodine for antibacterial use. The polymer composition consists of a partially cross-linked polyurethane that has complexed with iodine.
Other attempts have been made to use the second approach. US Patent No. 4,539,239 to Sakamoto and Takagi describes the use of chemically bonded ion exchange groups that serve to ionically bond active agents to the surface of biomaterials. This patent also relates to a process for producing a urinary catheter having film-forming materials possessing functional groups capable of converting into ion exchange groups. Ion exchange groups, described as carboxylic acids,
ES 2 328 307 T3 are then ionically bound with antimicrobial agents. These materials serve to release the agent into the surrounding environment as a result of changes in the external environment.
With this second approach, the active agents are bound somewhat loosely by Van der Waals forces or ionic forces and are easily released into the surrounding environments when they come into contact with solutions.
Attempts have also been made to use the third approach mentioned above to achieve covalent attachment of agents to polymeric surfaces. US patents n<sup>you</sup> 4,851,163, 4,973,493, 5,263,992 and 5,002,582 to Guire and Guire et al. Describe polymers, surfaces, and devices that are modified with biocompatible agents, including antimicrobial compounds, whereby the polymer is chemically attached to a surface or device via a chemical bonding moiety that is sensitive to a photochemical stimulus and whereby the antimicrobial agent is covalently attached to the surface through a different reactive group. The different reactive group is not sensitive to the photochemical stimulus. The antimicrobial agents used in these patents include penicillin and lysozyme.
The solid surface and the antimicrobial agent are chemically bonded in US Pat. No. 5,263,992 as in the following formula: AXB; wherein A is a photochemically sensitive group such as a nitrophenylazide derivative or a benzylbenzoyl derivative, X is a linking moiety such as the Ci-Cio alkyl group and B is a thermochemically reactive group such as nitrophenylhalides, alkylamines, alkylcarboxyl, alkylthiols, alkyl aldehydes, alkylmethylimidates, alkyl isocyanates, alkyl isothiocyanates and alkylhalides. Lysoenzyme is an enzyme (protein) that dissolves mucopolysaccharides in the bacterial cell wall by hydrolysis of the /> '(1-4) bonds between the N-acetyl-D-muramic acid residues and 2-acetylamino- 2-deoxy-D-glucose. Penicillin is a broad-spectrum β-lactam antibiotic that inhibits cell wall synthesis. However, the above patents require the use of photochemically active groups.
EP-A-040498 refers to a biocidal composition containing recurring units of maleic anhydride-styrene copolymers with amine and organotine compounds covalently bound on the polymeric matrix to avoid biological fouling in seawater.
In contrast, the present invention provides a polymer-bound antimicrobial moiety that when applied to a surface of an article reduces the likelihood of microorganism adherence and thus the possibility of infection without the use of photochemical stimulation. The polymer bound antimicrobial moiety does not release the antimicrobial agent in solution and does not reduce the antimicrobial properties of the antimicrobial agent below its ability to act as a biostatic agent.
For a better understanding of the present invention, together with different and additional objectives, reference is made to the following description taken in combination with the examples, the scope of which is set out in the appended claims.
Summary of the present invention
The present invention is a biostatic composition to reduce and prevent bacterial or microbial adherence. The composition contains (a) a hydrophilic polymer possessing a functional group that covalently binds to an active amine, thiol, carboxyl, or hydroxyl group of antimicrobial agents; (b) an antimicrobial agent covalently bound to the hydrophilic polymer; (c) a compatible polymer, and (d) a solvent.
The functional group is covalently attached to an antimicrobial agent whereby the antimicrobial property of the antimicrobial agent has no observed reduced efficacy below its ability to act as a biostatic agent through such attachment and cannot be released into solution.
The hydrophilic polymer is selected from poly (maleic anhydride-styrene) copolymers, polyols, and polyurethane polymers derived from polyurethane polyisocyanate prepolymers.
The antimicrobial agent can be any antimicrobial or antimicrobial derivative having a reactive amine, thiol, carboxyl, or hydroxyl group.
The compatible polymer includes homopolymers or copolymers that are chemically compatible with the present composition and do not interfere with biostatic behavior. The function of the compatible polymer is to provide increased lubrication as a result of water absorption or to improve adhesion of the polymer or coatings to the surface of an article.
The solvent is selected from methyl ethyl ketones, tetrahydrofurans, and alcohols.
In a preferred embodiment, the present composition further contains at least one additive. The additive can be chemically non-reactive antibiotics, chemically non-reactive antiseptics, chemically non-reactive antimicrobial agents, surfactants, metal complexes, plasticizers, dyes, lubricants, stabilizers, rheology modifiers, fragrances, pigments, display aids, antifoaming agents, lubricants, and antithrombogenic agents, biologically effective agents, and mixtures thereof.
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In another preferred embodiment, the invention includes a polymer-bound antimicrobial moiety formed by reacting a hydrophilic polymer with an antimicrobial agent to form a covalent bond between them.
The present invention is also a coating to reduce and prevent bacterial adherence. The coating is formed from a composition containing (a) a hydrophilic polymer possessing a functional group that reacts with and covalently binds to an active amine, thiol, carboxyl, or hydroxyl group of antimicrobial agents; (b) an antimicrobial agent that covalently binds to the hydrophilic polymer; (c) a compatible polymer; (d) a solvent; and (e) optionally at least one additive. The solvent in the composition then evaporates and therefore leaves behind a biostatic coating.
The present invention is also a method of preparing a biostatic article by (a) preparing a composition containing a hydrophilic polymer that possesses a functional group that reacts with and covalently binds to an active amine, thiol, carboxyl, or hydroxyl group. antimicrobial agents; an antimicrobial agent that covalently binds 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 in the composition to dry; and (d) cure the article.
As a result, the present invention advantageously provides a polymer system possessing a covalently or chemically bound antimicrobial agent that is not released into solutions and at the same time does not effectively reduce its antimicrobial property below its ability to act as a biostatic agent.
The present invention also advantageously provides a polymer system which when applied to a surface reduces and prevents the adherence of microorganisms and thus reduces the likelihood of microbial and bacterial infection.
The present invention also advantageously reduces the friction coefficient of the surface of medical articles.
The present invention also advantageously provides a polymer system that exhibits reduced bacterial adherence in a bacterial adherence test without displaying a zone of inhibition.
Brief description of the drawings
Figure 1 illustrates a polymer-bound antimicrobial moiety produced by reacting polyurethane polyisocyanate with hexetidine to form a covalent bond via urea bond.
Figure 2 illustrates a polymer bound antimicrobial moiety produced by reacting maleic anhydride with hexetidine to form a covalent bond via amide bond.
Figure 3 illustrates a polymer bound antimicrobial moiety produced by reacting a polymer possessing an epoxy group with hexetidine to form a covalent bond via alkylamine bond.
Detailed description of the invention
The present invention is a biostatic composition to reduce and prevent bacterial or microbial adherence. The composition contains (a) a hydrophilic polymer possessing a functional group that reacts with and covalently binds to an active amine, thiol, carboxyl, or hydroxyl group of antimicrobial agents; (b) an antimicrobial agent that covalently binds 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 covalently attached to an antimicrobial agent whereby the antimicrobial property of the antimicrobial agent has no observed reduced efficacy below its ability to act as a biostatic agent through such attachment and cannot be released in a solution. Examples of the functional group include isocyanates, isothiocyanates, esters, aldehydes, N-hydrosuccinimide esters, epoxides, carboxylic esters, tresylates, anhydrides, alkyl halides, carboxylic acids, haloketones, alkenes, alkynes, and acyl chlorides.
The hydrophilic polymer is selected from poly (maleic anhydride-styrene) copolymers, polyols, and polyurethane polymers derived from polyurethane polyisocyanate prepolymers.
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. Polyurethane polyisocyanate prepolymers can also be prepared by reacting (i) an aromatic or aliphatic polyisocyanate with (ii) a polyether polyol or polyester polyol or a polyamine that has been modified with an antimicrobial agent.
Examples of polyether polyols are polytetramethylene ether glycol, poly (ethylene glycol), poly (1,2-butanediol), poly (1,2-butylene glycol), or poly (propylene glycol).
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Examples of polyester polyols are those derived from the condensation of polycarboxylic acids, preferably dicarboxylic acids, such as adipic, sebacic, phthalic, isophthalic, terephthalic, oxalic, malonic, succinic, maleic, cyclohexane-1,2-dicarboxylic, cyclohexane-1 , 4-dicarboxylic, polyacrylic 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, 4-aminopropanol, 5-aminopentanol, 1,6-aminohexanol, 10-aminodecanol, 6-amino-5-methylhexanol -1, p-hydroxymethylbenzylamine, etc. Derivative ring opening / condensation polyesters 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-diaminocyclohexane, 1,7-heptanediamine, 1,8-diaminooctane, 1,9-nonanediamine, 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).
Polyether, polyester, and polyamine polyols can be modified with an antimicrobial using conventional organic chemistry reactions including nucleophilic, substitution, or condensation reactions.
Suitable examples of polyurethane polyisocyanate prepolymers are diphenylmethane diisocyanate ricinoleic acid glyceride (MDI), polymethylene ether glycol-diphenylmethane diisocyanate (MDI), polytetramethylene ether glycoltolylene diisocyanate (TDI) polymethylene ether diisocyanate (TDI) polymethylene ether diisocyanate (TDI) polymethylene ether diisocyanate (TDI) 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-diphenyl methane diisocyanate (MDI), polyethylene glycol-tolylene diisocyanate (TDI), polyethylene glycol-isophorone diisocyanate (IPDI), polycaprolactone-diphenyl methane diisocyanate (MDI), polycaprolactone diisocyanateDI (TDI) polycaprolactonecyanato-diisocyanateDI , polyethylene adipate-diphenyl methane 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-diphenyl methane diisocyanate (MDI), polyethylene polypropylene adipatotolylene diisocyanate (TDI) ispropylene diisocyanate (TDI) -polyethylene diisocyanate (TDI), and polyethylene polypropylene diisocyanate (TDI). Preferred polyurethane polyisocyanates are ricinoleic acid glyceride prepolymers of diphenyl methane diisocyanate (MDI) or polytetramethylene ether glycol-diphenylmethane diisocyanate (MDI).
The percentage of the hydrophilic polymer in the composition is between about 0.1 and about 15% by weight, preferably between about 0.1 and about 6% by weight, and more preferably between about 0.1 and about 4% by weight.
The antimicrobial agent can be antimicrobial or antimicrobial derivative having a reactive amine, thiol, carboxyl, or hydroxyl group.
Preferred antimicrobial agents are hexahydropyrimidine derivatives. The most preferred antimicrobial agent is hexetidine. Hexetidine is a broad spectrum antimicrobial 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 thiamine utilization is notable.
Hexahydropyrimidine derivatives can be prepared as described by Murria Senkans in Journal of the American Chemical Society (1946) 68, 1611-1613. Typical reactions involve the condensation of substituted amines with formaldehyde followed by reaction with a compound, which possesses an active hydrogen such as nitromethane by a Mannich type reaction. For example, the preparation of 1,3-bis (2-ethylexyl) -5-amino-5-methylhexahydropyrimidine (Hexetidine) is prepared by reacting 2-ethylhexylamine with formaldehyde followed by reaction with nitroethane. The 5-aminohexahydropyrimidine derivative can be prepared by catalytic hydrogenation using Raney Nickel.
Examples of hexahydropyrimidine derivatives include 1,3-bis (1-methyl-3,5-dioxa-cyclohexyl) -5-amino-5-methylhexahydropyrimidine, 1,3-bis (1-methyl-3,5-dioxa- cyclohexyl) -5-amino-5-propylhexahydropyrimidine, 5-nitro-1,3-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-1,3-bis (methyl) -5-hydroxymethylhexahydropyrimidine.
Derivatives or antimicrobial agents that have a reactive amine, thiol, carboxyl, or hydroxyl group combine 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. Reaction of an amine with an ester, a carboxylic ester, an N-hydroxysuccinimide ester, a carboxylic acid, or an acyl chloride produces an amide bond. The reaction of an amine with an epoxide, or alkylhalide produces an alkylamine bond. The reaction of a hydroxyl group with an isocyanate produces a hydroxyurea bond. Hydroxyl groups combine with esters, carboxylic esters, hydroxysuccinimide N-esters, carboxylic acids, or acyl chlorides to produce carboxylic esters.
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The percentage of antimicrobial agent in the composition is between 0.1 and 7% by weight, preferably between 0.1 and 1% by weight, and more preferably between 0.1 and 0.5% by weight.
The compatible polymer is selected from homopolymers or copolymers derived from pyrrolidones and vinyl pyrrolidones. The function of the compatible polymer is to improve the lubrication of the coated article as a result of the absorption of water and / or to improve the adhesion of the polymers or coatings on the surface of an article.
The solvent is selected from methyl ethyl ketones, tetrahydrofurans, and alcohols.
The present composition optionally contains at least one additive. The additive can be chemically non-reactive antibiotics, chemically non-reactive antiseptics, chemically non-reactive antimicrobial agents, surfactants, metal complexes, antifoaming agents, pigments, display aids, fragrances, dyes, stabilizers, lubricants, rheology modifiers, plasticizers, antithrombogenic agents. , biologically effective agents, or mixtures thereof. Examples of antithrombogenic agents include heparin, streptokinase, tissue plasminogen activator, and urokinase. Examples of surfactants and antifoaming agents include nonionic and ionic alkylphenol alkoxylates, glucosides or polyglucosides, alkylammonium sulfates or sulfosuccinates, silicone derivatives, or fluorinated alkyl alkoxylates.
The invention also includes a polymer-bound antimicrobial moiety formed by reacting a hydrophilic polymer with an antimicrobial agent to form a covalent bond between them.
When subjected to an extraction test, the polymer-bound antimicrobial moiety may not be extracted from solutions. Additionally, the polymer-bound antimicrobial moiety is compatible with numerous substrates, including polyurethane, polyvinyl chloride, silicon, latex, nylon, etc.
The ratio of the hydrophilic polymer to the antimicrobial agent is between 1: 1 and 150: 1, preferably between 1: 1 and 40: 1.
Figure 1 illustrates the reaction of a polyisocyanate polyurethane with hexetidine to form a polyurethane-bound hexetidine. The covalent bond formed in this case is a urea bond. Figure 2 shows the reaction of hexetidine with maleic anhydride. This produces polymer bound hexetidine. 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 alkylation of the hexetidine primary amine by the epoxide functionality.
The present invention is further a coating to reduce and prevent bacterial adherence. The coating is formed from a composition containing (a) a coating material comprising a polymer possessing a functional group that reacts with and covalently to an active amine, thiol, carboxyl, or hydroxyl group of antimicrobial agents ; (b) an antimicrobial agent covalently attached to said coating material; (c) a hydrophilic polymer, (d) a solvent; and (e) optionally at least one additive. The solution composition is applied to a desired substrate to reduce and prevent bacterial adherence. Once applied, the solvent in the composition evaporates leaving behind a coating containing the hydrophilic polymer covalently bonded to the antimicrobial agent, the compatible polymer, and additives.
The coating composition contains 0.3 to 99% of the hydrophilic polymer, 0.3 to 95% of the antimicrobial agent; 0.3 to 98% of the compatible polymer; 0.3 to 25% of the additives.
The present invention is also a method of preparing a biostatic article by (a) preparing a composition containing a coating material comprising a polymer possessing a functional group that reacts with and covalently binds to an active group amine, thiol , carboxyl, or hydroxyl; an antimicrobial agent covalently bound 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 in 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 the article in the composition. Once applied, the solvent in the composition is allowed to dry at room temperature between about 5 and about 60 minutes, or at temperatures between about 40 and about 120 ° C for about 5 and 60 minutes. After the solvent has dried, the solvent is cured in a manner known in the art, typically by placing in an oven for about 5 to about 60 minutes at between about 40 and about 120 ° C.
The article has a substrate that is compatible with the polymer-bound antimicrobial agent. Suitable examples of the substrate are polyurethane, polyvinyl chloride, silicon, latex, nylon, etc.
Preferably the article is a medical device. Examples of the medical device include catheters, wire guides, gloves, contraceptives, wound dressings, drainage tubes, feeding tubes, myringotomy tubes, wound staples, implants, sutures, foams, ophthalmic lenses, prostheses, blood bags , ultrafiltration or dialysis membranes, blood oxygenators, and vascular grafts.
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Examples
In the following examples, biostatic compositions containing polymer-bound antimicrobial agents were subjected to analysis of biostatic efficacy (zone of inhibition and bacterial adherence), gas chromatography, infrared, and coefficient of friction. The methodology for such analyzes is outlined below.
Biostatic efficacy test procedures
The biostatic efficacy of the polymeric systems was determined using two test procedures: zone of inhibition and bacterial adherence analysis. The zone of inhibition is a method that determines the efficacy and degree of antimicrobial agents that can be released. An unreleased chemically bound agent does not show a zone of inhibition, as this method relies on the release of the active agent. Adhesion analysis is a method that relies on the adherence of microorganisms to a surface that can result in the formation of a biofilm on the surface. A surface having a covalently bound antimicrobial agent demonstrates reduced bacterial adherence in an adherence assay. A polymeric system that releases an active agent shows a zone of inhibition as well as a reduction in bacterial adherence.
Analysis of the zone of inhibition
The zone of inhibition analysis employed involves a modification of the US Pharmacopoeia Procedure for Antibiotic-Microbial Assays. The procedure involved placing the test article (film, tubing, etc.) on an appropriate growth 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 showed no zone of inhibition against Staphylococcus aureus and a substrate coated 1% ampicillin showed a zone of 18 mm.
Bacterial adherence analysis
The bacterial adherence test used involves the incubation of the test article in 100 ml of Staphylococcus aureus (10<sup>3</sup> 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 tryptone soy broth at 37 ° C for 24 hours. The number of adherence organisms is then determined by the Total Aerobic Microbial Count of the US Pharmacopeia Procedure. An aliquot of the phosphate buffer wash is also seeded to determine the number of viable organisms and to ensure complete removal of non-adherent organisms. An uncoated substrate and a 1% ampicillin coated substrate served as control samples. The uncoated substrate showed a bacterial adherence of> 3 x 10<sup>7</sup> cfu / ml; the 1% ampicillin sample showed a bacterial adherence of <100 cfu / ml.
Gas Chromatography (GC) Analysis of Polymeric Coatings
GC analysis was performed using a Perkin Elmer AutoSystem Gas Chromatograph equipped with a J & W Scientific DBI capillary column (30 mx 0.32 mm; 0.25 μιη) and Software PE, Nelson Model 1022 GC Plus. The system operated with temperature programming between 40-160 ° for 18 minutes. The injector temperature was 210 ° C; the flame ionization detector operated at 250 ° C. The carrier gas was helium, operating at a pressure of 6.2 psi (42.747 kPa).
Polymeric coatings extraction test
The extraction test used involved incubating the test article (films, tubes, etc.) in distilled water or saline solution (1 gram of article per ml of solution) for 24 hours with shaking and determining 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 performed using a Nicolet Impact Series 400D Fourier-Transform Infrared spectrometer equipped with a deuterated triglycine detector, OMNIC software and operating at 4-16 cm resolution.<sup>-1</sup> with Hap-Genzel apodization.
Coefficient of friction of biostatic surfaces
The coefficient of friction of polyvinyl chloride pipe was determined using a KAYENESS, Inc. Material Tester equipped with a CHATILLON DFGS Force Gauge and Johnson Scale Co.'s FORCEDAT data collection software.
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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. The coefficient of friction was approximately 0.3.
Example 2
Biostatic composition of the present invention
Two grams of the polyurethane polyisocyanate prepolymer (NORDOT 34 D-2 adhesive, Synthetic Surfaces, Inc) prepared by reacting a 2 molar excess of diphenylmethane diisocyanate (MDI) with ricinoleate polyol, was combined with 250 mg of hexetidine (ANGUS Chemical) in 35 g of methyl ethyl ketone. The reaction was monitored by gas chromatography. Depletion of hexetidine was evident within 8 hours. Infrared analysis showed the disappearance of the isocyanate peak at approximately 2400 cm '. 10 g of tetrahydrofuran, 10 g of N-methylpyrrolidinone, 30 g of diacetone alcohol, 3 g of polyvinylpyrrolidinone (KOLLIDONE 90 F, BASF) were added to the solution. A clean polyvinyl chloride tube was immersed in the solution for 15 seconds, air dried for 30 minutes, and cured at 80 ° C for 30 minutes.
The tube was examined for bacterial adherence of S. aureus using the method described above. An aliquot of both Tryptone Soy Broth (TSB) and Phosphate Buffer Final Solution Wash (PBS) was seeded and showed no detectable colony formation (<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 approximately 0.075. The presence of hexetidine was not observed in the extraction medium.
Example 3
Hydrophilic composition of the present invention
Two grams of the polyurethane polyisocyanate prepolymer (NORDO 34D-2 adhesive, Synthetic Surfaces, Inc) prepared by reacting a 2 molar excess of diphenylmethane diisocyanate (MDI) with ricinoleate polyol, was combined with 35 mg of methyl ethyl ketone 10 g of tetrahydrofuran , 10 g of N-methylpyrrolidinone, 30 g of diacetone alcohol, 3 g of polyvinylpyrrolidinone (KOLLIDON 90 F, BASF). A clean polyvinyl chloride slide was coated with the solution using a cotton swab. The slide was air dried for 30 minutes and cured at 80 ° C for 30 minutes.
The slide was examined for S. aureus bacterial adherence using the procedure described above. An aliquot of TSB was seeded and bacterial adherence was shown (> 3 x 10<sup>7</sup> cfu / ml). A wash aliquot of PBS was seeded and showed no detectable colony formation (<100 cfu / ml).
Example 4
Composition of the present invention
Vorite 3025 polyisocyanate prepolymer (2g) (CasChem. Inc) was combined with hexetidine (0.25g) in methyl ethyl ketone (30g). the mixture was vigorously stirred overnight. GC analysis indicated the disappearance of hexetidine. Infrared analysis showed the disappearance of the isocyanate band at 2269 cm<sup>-1</sup>. Tetrahydrofuran (10 g), diacetone alcohol (30 g), N-methylpyrrolidinone (10 g), polyvinylpyrrolidinone (3 g; Kollidon 90 F), fluorinated alkyl alkoxylate (0.1 g; Flourad FC-171) were added to the mixture and methyl ethyl ketone (14.65 g). The material was then stirred until homogeneous.
A polyvinyl chloride (PVC) slide was coated with the solution using a cotton swab saturated with the solution. No bacterial adherence of S. aureus was observed to the coated slide followed by bacterial adherence analysis. An aliquot of the PBS wash was seeded and it was shown that there was no bacterial adherence. The presence of hexetidine was not observed in the extraction medium.
Example 5
Composition of the present invention
A polyisocyanate prepolymer was prepared by reacting 4,4-methylenebis (phenylisocyanate) (59 g) with castor oil (72 g) in ethyl methyl ketone (56 g) at 55 ° C. Two grams of this material were combined with hexetidine (0.25 g) and stirred at room temperature for 8 hours. Tetrahydrofuran (10 g), diacetone alcohol (30 g), N-methylpyrrolidinone (10 g), polyvinylpyrrolidinone (3 g; Kollidon 90 F), Flourad FC-171 (0.1 g) and methyl ethyl ketone were added to the mixture. (14.65 g). The material was then stirred until homogeneous.
ES 2 328 307 T3
A PVC slide was coated with the hexetidine-derived polymer using a cotton swab saturated with the solution, air dried for 30 minutes and cured at 80 ° C for 30 minutes. The slide was examined for S. aureus bacterial adherence using the assay procedure described above. An aliquot of the TSB wash and the final PBS was seeded and it was shown that there was no bacterial adherence. The presence of hexetidine was not observed in the extraction medium.
Example 6
Composition of the present invention
A poly (maleic anhydride-styrene) copolymer (10 g) was combined with hexetidine (2.2 ml) and triethylamine (0.5 g) in 250 ml of acetone. The mixture was stirred at 40 ° C for 1 hour. Infrared analysis showed the appearance of new bands corresponding to an amide group (1656 cm<sup>-1</sup>) and a carboxylic acid group (about 3500 cm<sup>-1</sup>, 1712 cm<sup>-1</sup> and 1360 cm<sup>-1</sup>). GC analysis indicated disappearance of hexetidine.
A PVC slide was coated with the solution using a cotton swab with the solution. No bacterial adherence to the coated slide was observed after bacterial adherence analysis. The presence of microorganisms was not detected in the PBS wash. The presence of hexetidine was not observed in the extraction medium.
Example 7
Composition of the present invention
A polyol was chemically modified with hexetidine by combining glycidyl ether castor oil (2.5 g) (Aldrich Chemical Co.) with triethyl amine (0.1 g) (Aldrich Chemical Co.) and hexetidine (0.5 g) ( Angus). The reaction was monitored by Gas Chromatography and was completed in 30 minutes. Methyl ethyl ketone (10 g), a phosphoric acid crystal and 4,4-methylenebis (phenylisocyanate) (3 g) (Aldrich Chemical Co.) were added to the solution. The mixture was stirred for 24 hours whereby infrared analysis showed the formation of the polyurethane polyisocyanate prepolymer (NCO about 2200 cm<sup>-1</sup>).
To this solution (4.2 g) was 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), polyvinylpyrrolidinone; KOLLIDON 90 F) (3 g) and Flourad FC-171 (0.1 g). The mixture was stirred for 24 hours.
A PVC slide was coated with the solution using a cotton swab with the solution. Bacterial adherence of S. aureus to the coated slide was not observed after bacterial adherence analysis. The presence of microorganisms was not detected in the PBS wash. The presence of hexetidine was not observed in the extraction medium.
Contents8
3 sheets
Sheet 1 Sheet 2 Sheet 3
21 members in 15 offices
Priority claims5
| Document | Office | Kind | Date |
|---|---|---|---|
| 19970002220 | United States of America | – | |
| 222097 | United States of America | A | |
| 222097 | United States of America | A | |
| 989608222220 | – | – | – |
| US19970002220 | – | – | – |
Members21
| Document | Office | Kind | |
|---|---|---|---|
| CA2306106A1 | Canada | A1 | |
| WO9933344A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU1632899A | Australia | A | |
| US6054504A | United States of America | A | |
| BR9814570A | Brazil | A | |
| EP1043931A1 | European Patent Office (EPO) | A1 | |
| CN1282216A | China | A | |
| EA200000591A1 | Eurasian Patent Organization (EAPO) | A1 | |
| KR20010024621A | Republic of Korea | A | |
| JP2001527027A | Japan | A | |
| AU743620B2 | Australia | B2 | |
| OA11437A | African Intellectual Property Organization (OAPI) | A | |
| EP1043931A4 | European Patent Office (EPO) | A4 | |
| KR100542812B1 | Republic of Korea | B1 | |
| CA2306106C | Canada | C | |
| EP1043931B1 | European Patent Office (EPO) | B1 | |
| ATE433280T1 | Austria | T1 | |
| DE69840898D1 | Germany | D1 | |
| DK1043931T3 | Denmark | T3 | |
| ES2328307T3This record | Spain | T3 | |
| JP4585687B2 | Japan | B2 |
Numbers
- Publication
- 2328307
- Publication, DOCDB
- 2328307
- Publication, EPODOC
- ES2328307T
- Application
- 98960822
- Application, DOCDB
- 98960822
- Application, EPODOC
- ES19980960822T
Titles2
- Spanish
- REVESTIMIENTOS BIOESTATICOS PARA LA REDUCCION Y PREVENCION DE LA ADHERENCIA BACTERIANA.
- English
- Biostatic COATINGS FOR THE REDUCTION AND PREVENTION OF BACTERIAL ADHERENCE.
Classification
- CPC, 4
- A01N25/10
- A01N43/54
- A01N25/24
- C08G18/10
- IPC, 12
- A61L2 16
- A01N43 54
- A01N25 10
- A01N25 24
- A01N47 36
- A61L29 00
- C08G18 10
- C08G18 32
- C08L75 04
- C09D5 14
- C09D175 04
- C09D201 02