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EP2231761A2 - Polymères d'ammonium quaternaire désinfectants solubles dans l'alcool - Google Patents

Polymères d'ammonium quaternaire désinfectants solubles dans l'alcool

Info

Publication number
EP2231761A2
EP2231761A2 EP09701395A EP09701395A EP2231761A2 EP 2231761 A2 EP2231761 A2 EP 2231761A2 EP 09701395 A EP09701395 A EP 09701395A EP 09701395 A EP09701395 A EP 09701395A EP 2231761 A2 EP2231761 A2 EP 2231761A2
Authority
EP
European Patent Office
Prior art keywords
antimicrobial
composition
polymer
glycol
substrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09701395A
Other languages
German (de)
English (en)
Other versions
EP2231761A4 (fr
Inventor
William Toreki
Gerald Olderman
Rustom S. Kanga
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Quick Med Technologies Inc
Original Assignee
Quick Med Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Quick Med Technologies Inc filed Critical Quick Med Technologies Inc
Publication of EP2231761A2 publication Critical patent/EP2231761A2/fr
Publication of EP2231761A4 publication Critical patent/EP2231761A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/0804—Manufacture of polymers containing ionic or ionogenic groups
    • C08G18/0809—Manufacture of polymers containing ionic or ionogenic groups containing cationic or cationogenic groups
    • C08G18/0814—Manufacture of polymers containing ionic or ionogenic groups containing cationic or cationogenic groups containing ammonium groups or groups forming them
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/12—Quaternary ammonium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/87—Polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
    • C08G18/3203—Polyhydroxy compounds
    • C08G18/3206—Polyhydroxy compounds aliphatic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
    • C08G18/3203—Polyhydroxy compounds
    • C08G18/3218—Polyhydroxy compounds containing cyclic groups having at least one oxygen atom in the ring
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/76—Polyisocyanates or polyisothiocyanates cyclic aromatic
    • C08G18/7614—Polyisocyanates or polyisothiocyanates cyclic aromatic containing only one aromatic ring
    • C08G18/7621—Polyisocyanates or polyisothiocyanates cyclic aromatic containing only one aromatic ring being toluene diisocyanate including isomer mixtures
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/04—Oxygen-containing compounds
    • C08K5/05—Alcohols; Metal alcoholates
    • C08K5/053—Polyhydroxylic alcohols
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D175/00—Coating compositions based on polyureas or polyurethanes; Coating compositions based on derivatives of such polymers
    • C09D175/04—Polyurethanes
    • C09D175/12—Polyurethanes from compounds containing nitrogen and active hydrogen, the nitrogen atom not being part of an isocyanate group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/524—Preservatives

Definitions

  • TECHNICAL FIELD This invention relates to disinfectants compositions for coating and adhesive applications.
  • the disinfectants provide sustained antimicrobial activity for prolonged periods following their application to the surface.
  • washing of hard surfaces e.g. food preparation surfaces and surgical room equipment
  • food e.g. fruits and vegetables
  • skin e.g. hands
  • washing with soap is effective at removing a substantial number of microorganisms already present, but has only a minimal, if any, lasting or persistent effect on microorganisms that subsequently come into contact with the already washed hands, it is often recommended that people wash their hands frequently in order to reduce the spread of viruses, bacteria, and other microorganisms. Compliance with this recommendation is important for an individual's personal health and hygiene, but is especially important for individuals working in the health and food industries.
  • Antimicrobial cleansing products for the removal of microorganisms from surfaces, including skin, are available in a variety of types.
  • Dial ® liquid soaps containing triclosan when used for hand washing, have been shown to reduce the number of bacteria present on the skin by about 2.0-2.5 orders of magnitude (99.0-99.7%) after one 30-second handwash, as measured by standard Health Care Personal Handwash Tests (HCPHWT). In other words, after washing, the washed skin is contaminated with only 0.3%-1.0% of the number of bacteria than was the unwashed skin before the 30-second handwash.
  • Alcohol-based disinfectants result in the immediate removal or inactivation of a substantial portion of microorganisms present on the treated surface.
  • Disinfectants based on alcohol typically ethanol, have an additional advantage as disinfectants because alcohol readily evaporates from the skin at body temperature.
  • Purell ® is one example of a skin disinfectant that uses alcohol as the active ingredient.
  • alcohol-based sanitizers with less than approximately 60% alcohol content may not be suitable to provide a desirable degree of antimicrobial activity, and alcohol contents above 95% are also less potent because proteins are not denatured easily in the absence of water ["Hand Hygiene Revisited: Another Look at Hand Sanitizers and Antibacterial Soap" SAFEFOOD NEWS - Spring 2004 - Vol. 8 No. 3, Colorado State University Cooperative Extension] .
  • 6,627,207 disclose a water-based, quick-drying, gel-type disinfecting composition having a low alcohol content ( ⁇ 30%).
  • Osborne et al. (U.S Pat. 5,776,430 and 5,906,808) describe a topical antimicrobial cleanser composition containing 0.65- 0.85% chlorhexidine gluconate, or a pharmaceutically acceptable salt, and 50- 60% denatured alcohol.
  • Kross (U.S. Pat. 5,597,561) discloses water -based, adherent disinfecting composition directed at the prevention of microbial infections, which contains protic acid, a metal chlorite, and a gelling agent.
  • Smyth et al. (U.S. Pat.
  • AEGIS Environments' product line includes products that utilize polymers of 3-(trimethoxysilyl)propyldimethyloctadecyl ammonium chloride, and are generally applied using alcohol-based solutions.
  • AEM 5700 is 43% 3-(trimethoxysilyl) propyldimethyloctadecyl ammonium chloride in methanol, which can be used to coat the surface of textiles and other objects. This method results in the formation of a permanent covalent bond between the quaternary ammonium antimicrobial compound and the surface being treated. Removal of the applied antimicrobial is thus nearly impossible, even using alcohol-based solvents.
  • the reactive trimethoxysilyl compounds are toxic and not suitable for use on skin.
  • Sawan U.S. Pat. 6264936 describes an antimicrobial material which can be used to form on the surface of a substrate an antimicrobial coating or layer which kills microorganisms on contact.
  • the antimicrobial coating or layer characterized in the reference as “non-leaching,” is a combination of an organic matrix immobilized on the surface of the substrate to having biocidal metallic materials associated with the matrix.
  • the biocidal metallic material is transferred to the microorganism in amounts sufficient to kill it.
  • the metallic antimicrobial agent used is silver.
  • the organic material comprises a polyhexamethylene biguanide polymer which is crosslinked with an epoxide, such as N,N-bismethylene diglycidylaniline, to form a crosslinked network or matrix.
  • This crosslinking step is necessary to prevent dissolution of the matrix.
  • the materials described by Sawan generally require a curing step, generally in the range of 80 ° to 12O 0 C, which is unsuitable for many substrates, particularly human skin.
  • the preferred organic matrix polymer polyhexamethylene biguanide
  • the use of silver as an antimicrobial agent also incurs some undesirable effects.
  • One disadvantage to this approach is that certain bacteria have been able to develop resistance to silver. (Silver S., "Bacterial silver resistance: molecular biology and uses and misuses of silver compounds:' FEMS Microbiology Reviews, 2003; 27:341-353).
  • microorganisms present a threat to the health and safety of patients whenever the skin is penetrated, broken, or breached. For example, such pathogens may be a hazard during surgical procedures. Without adequate disinfection of the incision site prior to surgery, microorganisms present on the skin gain access to the incision during or following surgery and cause infection. To prevent such infections, it is critical to disinfect the incision site prior to surgery with a disinfectant that possesses a high antimicrobial activity and a broad spectrum of action.
  • a pre-surgical skin disinfectant be capable of reducing the number of flora on dry skin areas, such as an abdomen, by at least 2.5 orders of magnitude or to levels that are too low for reliable quantification (less than about 25 cfu/cm 2 ).
  • the disinfectant On moist skin, such as inguinal areas, the disinfectant must reduce the initial bacterial population by a minimum of 3.2 logs (1.5 x 10 3 cfu/mL) and be able to maintain this level for at least four hours.
  • the need for an effective, persistent, and durable surface disinfectant is also felt in all aspects of the food industry, including food collection (e.g. sanitation of cow teats), food processing (e.g. slaughterhouses), food packaging (e.g. fish canneries), and food distribution (e.g. restaurants and food stores). It is an embodiment of the current invention that the composition would be useful wherever a person has food handling responsibilities and particularly useful wherever proper hygiene is made difficult because the same individual has both food handling and money handling responsibilities (e.g. deli shop cashiers and wait staff).
  • food collection e.g. sanitation of cow teats
  • food processing e.g. slaughterhouses
  • food packaging e.g. fish canneries
  • food distribution e.g. restaurants and food stores.
  • the composition would be useful wherever a person has food handling responsibilities and particularly useful wherever proper hygiene is made difficult because the same individual has both food handling and money handling responsibilities (e.g. deli shop cashiers and wait staff).
  • the current invention provides a disinfectant composition
  • a disinfectant composition comprising a glycol- or alcohol-soluble, water-insoluble, antimicrobial polymer suitable for disinfecting and for providing a prolonged antimicrobial property to a variety of surfaces, including skin.
  • the invention provides a disinfectant composition, comprising an antimicrobial polymer in a solvent consisting essentially of a glycol or, alternatively, a solvent consisting essentially of a mixture comprising a glycol and an alcohol, wherein the antimicrobial polymer is readily soluble in the alcohol, glycol or the mixture, but insoluble in water, and wherein the solvent serves as a carrier for applying said antimicrobial polymer to a surface, whereby said surface acquires a coating of the antimicrobial polymer.
  • the antimicrobial polymer imparts a lasting antimicrobial activity to said surface.
  • the antimicrobial polymer is selected so that its antimicrobial activity occurs by virtue of a contact-killing mechanism, which does not require leaching, elution, or releasing into contacting fluids at levels that would result in fluid disinfection. Moreover it is preferred that the antimicrobial polymer does not appreciably leach, elute or release from the surface to which the antimicrobial composition is applied.
  • the alcohol-containing solvent consists essentially of at least one glycol selected from the group consisting of glycerol, ethylene glycol, propylene glycol, butylene glycol, pentane glycol, isomers and derivatives thereof, and mixtures of any of the aforesaid. It is preferred that the glycol content of the disinfectant solution is between 60% and 95% by weight.
  • the alcohol-containing solvent consists essentially of a mixture of at least one alcohol and one glycol, wherein the alcohol is selected from the group consisting of ethanol, methanol, and isopropanol, and wherein the glycol is selected from the group consisting of glycerol, ethylene glycol, propylene glycol, butylene glycol, pentane glycol, isomers and derivatives thereof, and mixtures of any of the aforesaid. It is preferred that the alcohol- glycol mixture content of the disinfectant solution is between 60% and 95% by weight.
  • the antimicrobial polymer may consist essentially of molecules that are derived or produced from at least one allyl- or vinyl- containing monomeric moiety. In some embodiments of the invention, the antimicrobial polymer consists essentially of molecules that are comprised of at least one quaternary- ammonium- containing monomeric moiety.
  • quaternary ammonium moieties are covalently bonded to the antimicrobial polymer, or attached to the molecular structure of the antimicrobial polymer by covalent chemical bonds, and are part of the polymer molecular structure, and that said quaternary ammonium moieties are located either in the main-chain of the polymer, or in side-groups of the polymer.
  • the quaternary ammonium moieties alternatively may be the only moieties of the polymer structure, may be incorporated within the polymer structure, or may be attached to the polymer structure.
  • "Main-chain” and “side- groups” are terms commonly used to describe polymer molecular structure and will be familiar to one skilled in the art.
  • Some of the antimicrobial polymeric molecules used in the present invention can be synthesized by step- growth polymerization, such as by the reaction of a difunctional alcohol with a diisocyanate to form a polyurethane polymer that contains at least one quaternary ammonium group in a monomeric moiety which is attached to the molecular structure of the polymer by covalent chemical bonding.
  • the number of quaternary ammonium groups in the polyurethane polymer will be at least one mole (6.02 x 10 23 ) per 650 grams of polyurethane polymer. More preferably, the number of quaternary ammonium groups in the polyurethane polymer will be at least one mole (6.02 x 10 23 ) per 350 grams of polyurethane polymer.
  • the antimicrobial polymeric molecules may have an average degree of polymerization of 5 to 25,000; preferably 50 to 10,000; and more preferably 100 to 5,000.
  • the disinfectant composition is applied to a surface, which surface may be the skin of an animal, the skin of a human, a nonliving porous surface, or a nonliving nonporous surface.
  • the disinfectant composition may be applied to skin before a medical procedure.
  • medical procedure includes, without limitation, surgery, injection, phlebotomy, and catheter insertion, and further includes other procedures that breach the skin.
  • the disinfectant composition may be applied to the skin of an animal before a veterinary procedure.
  • veterinary procedure includes, without limitation, surgery, injection, catheter insertion, and other procedures that breach the skin or hide of an animal.
  • the disinfectant composition may be applied to the hands of health care workers to minimize transmission of microbes between infected patients or between infected sites on a patient.
  • the disinfectant composition may be incorporated in cosmetic formulations to reduce or prevent microbial growth in the cosmetic.
  • An advantage of the invention is that many embodiments of antimicrobial polymer coating do not visibly stain the skin, and are colorless.
  • Another embodiment of the invention provides a disinfectant composition that contains a dye, enabling the coating to be visualized.
  • the dye is bonded to the antimicrobial polymer, thereby preventing migration of the dye from the coating.
  • An advantage of many embodiments of the invention is that, after the solvent has dissipated, the coating is generally odorless.
  • disinfectant composition has a pH between approximately 5 and approximately 9, preferably between 6.5 and 8.0.
  • Various embodiments of the disinfectant composition may be applied to the skin in a form selected from the group consisting of liquid, gel, foam, and aerosol.
  • the disinfectant composition additionally contains at least one additive selected from the group consisting of a drug, an antimicrobial, an antiseptic, a thickening agent, a moisturizer, an emollient, a vitamin, a temporary dye, a permanent dye, and a UV absorber.
  • an additive is an antimicrobial, it may be an alcohol, which also serves as a solvent for the antimicrobial polymer with persistent activity.
  • the antimicrobial or antiseptic additive may also be a quaternary ammonium salt, a biguanide, or a phenolic compound.
  • the added antimicrobial or antiseptic is a quaternary ammonium salt, such as benzalkonium chloride, benzethonium chloride, dimethyldidecyl ammonium chloride, or mixtures thereof.
  • the added antimicrobial or antiseptic is a biguanide, such as chlorhexidine or poly(hexamethylene biguanide).
  • the added antimicrobial or antiseptic is a phenolic compound, such as phenol or triclosan.
  • the emollient is glycerol, ethylene glycol, propylene glycol, butylene glycol, pentane glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol, mineral oil, a fatty alcohol, isopropyl palmitate, lanolin, derivatives of lanolin such as the ethoxylated acetylated alcohol and surface active alcohol derivatives of lanolin, squalane, fatty alcohols, glycerin, and silicones such as dimethicone, cyclomethicone, or simethicone, or mixtures thereof.
  • the drug is an antibiotic, antiinflammatory, an analgesic, or an anesthetic agent.
  • the antimicrobial polymer can be manufactured by mixing one species of monomer with at least one other different species of monomer, and copolymerizing the monomers, wherein at least one of the monomers bears at least one quaternary ammonium moiety, producing a copolymer that is readily soluble in alcohol and insoluble in water.
  • the antimicrobial polymer can be manufactured by polymerizing a monomer, wherein the monomer bears at least one quaternary ammonium moiety, producing a polymer that is readily soluble in alcohol and insoluble in water.
  • a polymer which contains both dye (e.g. fluorescein) and antimicrobial (e.g. quaternary ammonium) units both covalently bonded to the polymer molecular structure, or attached to the polymer molecular structure by covalent chemical bonds, and hence are part of the polymer molecular structure, and are located either in the main-chain of the polymer, or in side-groups of the polymer.
  • dye e.g. fluorescein
  • antimicrobial e.g. quaternary ammonium
  • the antimicrobial polymer may be removed from a substrate to which it has been applied by using alcohol, glycol, or a solvent having significant alcohol content.
  • metals or metallic salts are not used as antimicrobial agents.
  • a curing step is not required to impart insolubility to the antimicrobial polymer after it has been applied to a surface.
  • a portion, less than approximately 50% of the total polymer weight, of the antimicrobial polymer be soluble in water or aqueous fluids.
  • This embodiment enhances the durable and quick-acting properties of the antimicrobial polymer. Enhancement of this activity can be achieved with lower molecular weight polymers.
  • the water-insoluble and the alcohol- soluble or glycol-soluble antimicrobial polymers of this invention may be utilized as components of polymeric devices including medical devices and household goods.
  • the antimicrobial polymers of this invention may be utilized to produce films, fibers, gels, foams, adhesives, sealants, or caulks which may be incorporated in or used to form other articles, such as cosmetic formulations, sutures, or wound dressings.
  • Another embodiment of this invention is to provide a permanent antimicrobial treatment for synthetic sutures, such as medical sutures or multifilament polyester sutures.
  • Another embodiment of this invention is to provide an antimicrobial polymer which is water-insoluble and either alcohol- soluble or glycol- soluble which can be incorporated into hydrophilic polyurethane foam to be used as a non-leaching antimicrobial wound dressing.
  • It is an embodiment of this invention is to provide an antimicrobial polymer which is water-insoluble and either alcohol- soluble or glycol- soluble which can be incorporated into a UV-curable coating which can be applied to plastic films or sheets.
  • the coated films and sheets can be further thermo-formed or vacuum-formed into antimicrobial products having a desired shape.
  • It is an embodiment of this invention to provide a method of disinfecting a substrate comprising the steps of treating the substrate with a solution of a water-insoluble antimicrobial polymer comprising quaternary ammonium moieties, wherein, the solvent and/or the polymer solution is capable of wholly or partially dissolving, absorbing-into, or otherwise penetrating the surface of the substrate; and drying the substrate to remove the solvent and to impregnate, infuse, coat, adhere, attach, or interpenetrate the antimicrobial polymer to the substrate wherein antimicrobial properties are imparted to the substrate and are not removed by exposure to aqueous fluids.
  • the substrate with polymer impregnated therein may comprise an interpenetrating network (IPN).
  • IPN interpenetrating network
  • the substrate may be a polymer which may be in a final-use form such as a film or fiber, or may be a polymer intended for subsequent use in a molding or shaping operation, such as one for making a resin, pellet, extrusion, or powder.
  • the substrate may also be a textile, wood, or paper.
  • the substrate may be wholly or just partially infused with the polymer solution. In the case of partial infusion, the antimicrobial polymer will be deposited to a greater extent at, or just below, the surface of the substrate, as opposed to throughout the interior of the substrate.
  • the substrate may be insoluble in the solvent used to prepare the antimicrobial polymer solution; however it is necessary that the solvent be capable of penetrating into the substrate material. For instance, some particular combinations of polymers and solvents may result in absorption of the solvent and polymer solution into the substrate without causing the substrate to dissolve.
  • the solvent may also be capable of dissolving the substrate either entirely or partially.
  • a polymer solution capable of entirely dissolving the substrate may be applied to the substrate for a period of time sufficient to allow the surface of the substrate to be affected by the polymer solution, but not long enough for the substrate to be dissolved. In this manner, the surface of the substrate becomes modified with antimicrobial polymer.
  • An embodiment of this invention is to provide a solution comprising a water-insoluble antimicrobial polymer comprising quaternary ammonium moieties and at least one other polymer which are both dissolved in a solvent.
  • a solution of an antimicrobial polymer in alcohol or other solvent
  • Merobe or "microorganism” refers to any organism or combination of organisms such as bacteria, viruses, protozoa, yeasts, fungi, molds, or spores formed by any of these.
  • Antimicrobial refers to the microbicidal or microbistatic properties of a compound, composition, article, or material that enables it to kill, destroy, inactivate, or neutralize a microorganism; or to prevent or reduce the growth, ability to survive, or propagation of a microorganism.
  • a "disinfectant” is an agent that destroys, neutralizes, or otherwise interferes with the growth or survival of microorganisms.
  • Alcohol means a volatile liquid having the formula C n H2n+2-x(OH) x where n is an integer from 1 to 10, and x is an integer from 1 to 3; and preferably where n is from 1 to 5, and x is 1 or 2; and more preferably where n is 2 or 3, and x is 1.
  • Soluble means that the substance is capable of being dissolved in a quantity of a specified liquid, such as glycol, alcohol or water. Many polymers that are soluble in alcohol solvents are also soluble in glycol solvents.
  • Readily soluble means that the solute in question is virtually 100% soluble, capable of forming a solution at room temperature containing up to 20 wt % of the solute, in a specified solvent, e.g. a particular glycol, alcohol, or combinations of alcohols and glycols.
  • a specified solvent e.g. a particular glycol, alcohol, or combinations of alcohols and glycols.
  • “Insoluble” means that the substance will not significantly dissolve in a large excess (e.g. >100-fold) of a particular solvent, e.g. water. "Volatile” means that the solvent or liquid fully evaporates at room temperature.
  • “Durable” means insoluble in water, not easily removed by, for example, perspiration, incidental contact with aqueous fluids, or light washing with aqueous fluids.
  • To impart means to instill, to bestow upon, to transmit, to convey, or to otherwise incorporate a functional characteristic or property to a substrate.
  • a quaternary ammonium group may impart antimicrobial activity to a something.
  • To combine means to infuse, to coat, to adhere, to attach, to impregnate, to penetrate, to absorb, to mix, or to otherwise physically incorporate some substance into or onto a substrate.
  • non-hydrolyzable bond is a chemical bond that does not hydrolyze under standard conditions to which the bond is expected to be exposed under normal usage of the material containing the bond.
  • the non- hydrolyzable bonds of a wound dressing or a suture according to the present invention would not undergo a hydrolysis-type reaction that results in the fission of such bonds under normal storage conditions such as exposure to wound exudates, body fluids, microbes, enzymes, antiseptic salves, creams, ointments, and other aqueous media in the normal physiological pH range.
  • Contact-killing means a property of killing microorganisms which does not require leaching, elution, or releasing into contacting fluids at levels that would result in fluid disinfection.
  • Antimicrobial metallic material means a metal, such as colloidal silver, or a metal salt, in a form capable of imparting antimicrobial activity to a composition. This invention provides antimicrobial activity in the absence of an antimicrobial metallic material.
  • Substrate is sometimes synonymous with “surface” and means any material in need of antimicrobial protection with which the compositions described herein may be used.
  • the substrate may exist as an independent article separate from the composition and may comprise the skin of an animal, the skin of a human, a nonliving porous surface, or a nonliving nonporous surface.
  • the surface may comprise a polymer, resin, powder, textile, wood, paper, skin, and may be a component of pellets, clothing, sutures, wound dressings, and various other articles.
  • composition may be incorporated with the substrate to form polymeric devices or objects including, for instance, films, fibers, sheets, gels, foams, adhesives, sealants, caulks, moldings, rods, tubes, medical devices, cosmetic formulations, and household goods.
  • polymeric devices or objects including, for instance, films, fibers, sheets, gels, foams, adhesives, sealants, caulks, moldings, rods, tubes, medical devices, cosmetic formulations, and household goods.
  • One exemplary embodiment of the current invention utilizes an antimicrobial polymer having polymeric molecules that are composed of one type of monomeric moiety; alternatively, the polymeric molecules may be composed of more than one type of monomeric moiety.
  • the quaternary ammonium groups of the monomeric moieties impart antimicrobial activity to the polymeric molecules.
  • such monomeric moieties, which comprise quaternary ammonium groups constitute at least 2% by weight of the polymeric molecules, more preferably at least 10% of the polymeric molecules, and most preferably at least 25% of the polymeric molecules.
  • the number of quaternary ammonium moieties in the antimicrobial polymer will be at least one mole (6.02 x 10 23 ) per 650 grams of polymer. More preferably, the number of quaternary ammonium moieties in the antimicrobial polymer will be at least one mole (6.02 x 10 23 ) per 350 grams of polymer.
  • quaternary ammonium moieties are covalently bonded to the antimicrobial polymer, or attached to the molecular structure of the antimicrobial polymer by covalent chemical bonds, and are part of the polymer molecular structure, and that said quaternary ammonium moieties are located either in the main-chain, also described as the backbone, of the polymer, or in side-groups of the polymer.
  • the quaternary ammonium moieties alternatively may be the only moieties of the polymer structure, may be incorporated within the polymer structure, or may be attached to the polymer structure.
  • Main-chain and side-groups are terms commonly used to describe polymer molecular structure and will be familiar to one skilled in the art. Groups within the main-chain of the polymer are also described as being within the "backbone” of the polymer. Groups that are side groups are also described as being “pendant” to the backbone of the polymer chain.
  • the quaternary ammonium moieties of the antimicrobial polymer are contained in the main chain or backbone of the polymer backbone, rather than pendant to the polymer backbone.
  • the quaternary ammonium moieties of the antimicrobial polymer are connected to the polymer molecular structure by stable chemical structures and covalent bonds that are non- hydroylzable.
  • hydrolyzable bonds or structures include esters, amides, and anhydrides.
  • bonds and structures that are non- hydrolyzable include urethanes, ureas, ethers (C-O-C), carbon-carbon (C-C), and carbon-nitrogen (C-N) bonds.
  • the antimicrobial polymer is formulated to be insoluble in water and readily soluble in aqueous solutions of at least 75 wt % of an alcohol, glycol, or a mixture thereof. More preferably it is formulated to be insoluble in water and is readily soluble in solutions of at least 50 wt % of an alcohol, glycol, or mixture thereof, and most preferably it is formulated to be insoluble in water and readily soluble in solutions of at least 25 wt % of an alcohol, glycol, or mixture thereof. It is an embodiment of the current invention that the antimicrobial polymer can be applied to surfaces, including skin, dissolved in an alcohol-containing solvent.
  • the relative solubility of polymers in different solvents is not trivial.
  • This invention pertains to polymers that are soluble in alcohol and glycols, yet insoluble in water. This specific combination of properties is manifested in only a relatively small number of the many different types of known natural and synthetic polymers.
  • Polymers may generally be divided into two groups: water- soluble, and water-insoluble. Some water-insoluble polymers may be soluble in various organic solvents. Solubility generally depends on the properties of the particular polymer-solvent combination, with soluble combinations resulting when the chemical structures of the polymer and solvent are similar. Polarity of the solvent is perhaps the most important consideration.
  • Polarity of some common solvents in order of most polar to least polar are: water, ethanol, ether, toluene, and hexane.
  • Many water-soluble polymers are also soluble in alcohol. Among the alcohols, the polarity decreases in the order of methanol, ethanol, and isopropanol, with the polarity of methanol being closest to that of water. Thus, many water-soluble polymers are more soluble in methanol, than in ethanol or isopropanol.
  • Ethanol, isopropanol and non-toxic glycols are preferred solvents for the practice of this invention. Isopropanol is not generally a very good solvent for most polymers.
  • the alcohol- containing or glycol-containing solvent may serve a two-fold purpose, not only as a carrier, but also as an immediate disinfectant. After the alcohol- containing or glycol-containing solvent has evaporated, absorbed, or dissipated, a coating of the antimicrobial polymer remains on the skin or other substrate. This coating is durable, and because it is insoluble in water, it is not easily removed by, for example, perspiration, incidental contact with aqueous fluids, or light washing with aqueous fluids.
  • a glycol is used as solvent and carrier, including, but not limited to glycerol, ethylene glycol, propylene glycol, butylene glycol, or pentane glycol.
  • Various isomers and derivatives of glycerol, ethylene glycol, propylene glycol, butylene glycol, and pentane glycol are also suitable solvents for the invention.
  • the family of pentane glycols includes 1,4-pentanediol, 1,5-pentanediol, 2,4- pentanediol, and another isomers.
  • Other derivatives of glycols may be suitable solvents for the invention.
  • a halogenated glycol may be employed in an appropriate embodiment of the invention.
  • Glycols are generally not as volatile as lower alcohols (such as ethanol); however, may still have utility as a solvent/carrier for the antimicrobial polymers of the current invention.
  • propylene glycol may be used as a solvent/carrier when the antimicrobial polymer is incorporated into a cosmetic formulation for application to the skin.
  • the propylene glycol may absorb into the skin, rather than evaporating, thus leaving a persistent antimicrobial polymer coating. This approach avoids possible undesirable effects of using lower alcohols (such as skin irritation, drying of skin, or flammability).
  • a mixture comprising an alcohol and a glycol is used as solvent and carrier.
  • the alcohol component of the mixture may include, but is not limited to, ethanol, methanol, isopropanol, and mixtures thereof.
  • the alcohol component of a solvent mixture is denatured alcohol, specifically Denatured Alcohol SDA 3- C, which is a commercial, non-beverage grade, denatured alcohol defined by the Alcohol and Tobacco Tax Division of the Internal Revenue Service as ethanol with a 5% isopropanol denaturant (i.e., 95% ethanol / 5% isopropanol).
  • the glycol component of the mixture may, for example be glycerol, ethylene glycol, propylene glycol, butylene glycol, pentane glycol, or an isomer or derivative thereof, or mixture of any of the aforesaid. It is preferred that the combined alcohol- glycol content of the disinfectant solution mixture is between 60% and 95% by weight.
  • the antimicrobial polymer may also be soluble in other organic solvents such as acetone, methyl ethyl ketone, tetrahydrofuran, ethyl acetate, ethers, esters, benzene, toluene, carbonates, hydrocarbons, or chlorinated hydrocarbons, and solutions of the antimicrobial polymer in any of these solvents may be used to prepare the antimicrobial composition; however, these solvents may not necessarily provide the advantage of immediate disinfection such as provided by alcohols or glycols.
  • organic solvents such as acetone, methyl ethyl ketone, tetrahydrofuran, ethyl acetate, ethers, esters, benzene, toluene, carbonates, hydrocarbons, or chlorinated hydrocarbons
  • the antimicrobial properties are permanently locked into the polymer structure. This can be accomplished, for example, by incorporating chemical functionalities with antimicrobial properties directly into the molecular structure of the polymer. This provides not only durability and persistence of antimicrobial effect, but also prevents soluble antimicrobial components, e.g. those of low molecular weight, from leaching from the antimicrobial coating and entering the substrate, or migrating to areas where it is not desirable to have antimicrobial activity. For example, when applied to skin, the composition will provide persistent antimicrobial activity; however, antimicrobial activity will not migrate from the polymer and penetrate the skin surface or enter into cells where it may have undesirable effects, after evaporation of the alcohol-based carrier solvent.
  • composition would be useful to protect individuals at risk of contacting biological warfare agents (e.g. military personnel and postal workers), either by treating their skin or by treating the surfaces of equipment and materials that these individuals contact. It is an embodiment of the current invention that a composition of the present invention may be used on animal skin (e.g. sanitization of cow teats, surgical procedures, and veterinary procedures).
  • biological warfare agents e.g. military personnel and postal workers
  • animal skin e.g. sanitization of cow teats, surgical procedures, and veterinary procedures.
  • An advantage of this invention is that it utilizes quaternary ammonium compounds as the active antimicrobial agent, and quaternary ammonium compounds do not promote the development of resistant organisms such as MRSA or VRE. Examples are provided below to demonstrate the efficacy of the materials of the current invention against such organisms.
  • the disinfectant composition of the present invention may additionally contain other inert or active ingredients.
  • thickening agents may be included in order to increase viscosity or to provide a gel form of the product.
  • Additives such as moisturizers, emollients, vitamins, UV absorbers, drugs, antimicrobials, or other inert and active agents, may also be added.
  • Such additives do not need to be water-insoluble, as they may serve their purpose by acting transiently or otherwise may be entrapped in the polymeric coating and thereby stabilized against easy removal by aqueous fluids.
  • permanent or temporary dyes may be added to the composition, or alternatively applied to the polymeric coating after it has been applied to the surface, in order to serve as a visual indicator of the presence of the polymeric coating.
  • composition of the current invention provides a polymer film or coating with non-leaching antimicrobial properties
  • an additional antimicrobial or antiseptic agent is not covalently bonded to the polymer, and thus may be leachable. This does not alter the non-leachable nature of the previously- described antimicrobial polymer.
  • the antimicrobial polymer will still provide non-leachable antimicrobial activity.
  • the antimicrobial polymer matrix can serve to slow the leaching rate of the additional agent, thus prolonging the efficacy of the added agent.
  • useful antimicrobial or antiseptic additives include quaternary ammonium salts, biguanides, and phenolic compounds.
  • the added antimicrobial or antiseptic is a quaternary ammonium salt, such as benzalkonium chloride, benzethonium chloride, dimethyldidecylammonium chloride, or mixtures thereof.
  • the added antimicrobial or antiseptic is a biguanide, such as chlorhexidine or poly(hexamethylene biguanide).
  • the added antimicrobial or antiseptic is a phenolic compound, such as phenol or triclosan.
  • the composition may be formulated as a liquid, gel, foam, or aerosol spray and may be applied to a surface, including the skin of a human or other animal, in order to achieve a prolonged antimicrobial effect.
  • glycol- soluble, alcohol- soluble, water-insoluble, antimicrobial polymeric molecules can be synthesized by free radical vinyl polymerization of, generally, a mixture of two different monomers, a first monomer (A) and a second monomer (B), at least one of which contains quaternary ammonium groups.
  • the first monomer (A), and homopolymers of monomer A are generally water-soluble, while the second monomer (B) is generally water-insoluble.
  • a mutually effective solvent such as alcohol or glycol
  • monomers A & B may be used to prepare a homogeneous solution suitable for copolymerization of the two monomers.
  • the copolymer of A + B is soluble in alcohol or glycol. It should be understood that this is just one possible illustrative method to formulate the composition and one skilled in the art will realize that there are numerous other methods that can be used to prepare the alcohol- soluble, water-insoluble, antimicrobial polymeric molecules. Mixtures of three or more monomers may also be used to prepare suitable antimicrobial copolymers. It is an embodiment of this invention that the polymeric molecules can be synthesized by step-growth polymerization, such as by the reaction of a difunctional alcohol with a diisocyanate to form a polyurethane polymer.
  • step-growth polymers may also be utilized including, but not limited to, polyamides (nylons), polyesters, and polyureas.
  • the incorporation of the antimicrobial moiety into the polymer may be accomplished by utilizing an antimicrobial compound with reactive functionality.
  • Akzo Nobel offers a range of compounds sold under the trade-name of Ethoquad.
  • Ethoquad C/12-75DK which is a methyl/Cl2 quaternary ammonium compound with two reactive hydroxyethyl substituents that can be reacted with a diisocyanate such as tolylene-2,4- diisocyanate (TDI) to form an antimicrobial polyurethane polymer which contains quaternary ammonium moieties in the polymer main-chain structure.
  • TDI tolylene-2,4- diisocyanate
  • a dye molecule may be incorporated into, or covalently bonded to, the antimicrobial polymer structure in order to provide a nonleaching visible marker for the composition.
  • the fluorescein dye molecule contains two hydroxyl groups which may be reacted with a diisocyanate to form part of a polyurethane structure.
  • the resulting polymer contains both dye (fluorescein) and antimicrobial (quaternary ammonium) units in the polymer main- chain structure.
  • the antimicrobial moieties may also be incorporated into the polymer after formation of the polymer. This can be achieved, for example, by transesterification or other substitution reactions, such as the reaction of Ethoquad with a polyacrylate.
  • the polymer molecules synthesized will have an average degree of polymerization of 5 to 25,000 (monomeric moieties per molecule), but more preferably 50 to 10,000, and most preferably 100 to 5000.
  • Suitable vinyl monomers for use in generating the polymer include, but are not limited to, allyl- containing monomers, vinyl- containing monomers, styrene derivatives, allyl amines, ammonium salts, acrylates, methacrylates, acrylamides, methacrylamides, dimethylaminoethyl methacrylate (methyl chloride quaternary), dimethylaminoethyl methacrylate (benzyl chloride quaternary), dimethylaminoethyl acrylate (methyl chloride quaternary), dimethylaminoethyl acrylate (benzyl chloride quaternary), dimethylaminoethyl acrylate (methyl chloride quaternary), dimethylaminoethyl acrylate (
  • X is either O, S, or NH
  • R', R", and R'" are independently selected from the group consisting of H, Cl to C16 alkyl, aryl, arylamine, alkaryl, and aralkyl, and
  • Y " is an anionic counterion to the positive charge of the quaternary nitrogen; diallyldimethylammonium salts; vinyl pyridine and salts thereof; and vinylbenzyltrimethylammonium salts) .
  • Suitable free radical initiators for use in generating the polymer include, but are not limited to, azo compounds, such as AIBN and related compounds, and peroxides, such as benzoyl peroxide, dicumyl peroxide, t-butyl hydroperoxide, sodium persulfate, hydrogen peroxide, sodium peroxide, and other peroxides and hydroperoxides commonly used as free radical polymerization initiators.
  • Photoinitiated polymerization may also be used wherein a suitable photoinitiator (e.g. a benzophenone derivative) is used which initiates polymerization upon exposure to light.
  • Radiation polymerization may also be used, wherein polymerization is initiated by exposure to ionizing radiation (e.g. gamma rays).
  • the “Carrier Persistence Test”, or CPT is described below.
  • the compositions and materials of this invention have been found to give excellent results when tested by the CPT. Reductions of bacterial populations generally exceed 6 logs (99.9999% reduction of viable organisms).
  • the materials described by this invention are capable of producing a 3-log reduction of bacteria when tested using the CPT method.
  • the materials described by this invention are capable of producing a 4-log reduction of bacteria when tested using the CPT method. More preferably, the materials described by this invention are capable of producing a 5-log reduction of bacteria when tested using the CPT method.
  • the materials described by this invention are capable of producing a 6-log reduction of bacteria when tested using the CPT method.
  • the CPT is a comparative test in which the antimicrobial materials are compared to control materials not treated with antimicrobial agent.
  • the maximum theoretical log reduction obtainable in a particular CPT test is limited by the growth of the bacterial population on the untreated control. Thus, it is possible to obtain virtually 100% elimination of viable organisms even though the actual log reduction is below a specified number.
  • a portion (less than approximately 50% of the total polymer by weight) of the antimicrobial polymer be soluble in water or aqueous fluids.
  • the combined benefits of quick-acting antimicrobial efficacy from a soluble antimicrobial component, and prolonged durable antimicrobial activity from the insoluble antimicrobial polymer may be realized. This may be accomplished, for instance, by incorporation of hydrophilic units in the polymer structure in order to provide a degree of water- solubility to a portion of the polymer.
  • hydrophilic -CH2-CH2-O-CH2-CH2- units may be incorporated into a polyurethane-based antimicrobial polymer by reacting 6is(2-hydroxyethyl)ether with TDI. Enhancement of water-soluble or leachable antimicrobial content may also be achieved by preparing an antimicrobial polymer with a reduced molecular weight (smaller average degree of polymerization). Methods to reduce polymer molecular weight or degree of polymerization will be familiar to one skilled in the art.
  • the alcohol-soluble/water-insoluble antimicrobial polymers of this invention may also be utilized as components of polymeric devices or objects including, for example, medical devices and household goods. This may be accomplished, for instance, by blending the antimicrobial polymer, or solutions thereof, with other polymers or solutions thereof, or polymerizable monomers or prepolymers, or solutions thereof.
  • the antimicrobial polymers of this invention may also be used to form films, fibers, gels, foams, adhesives, sealants, and caulks which may be used as components in medical devices, polymeric devices, or other objects.
  • One embodiment of this invention is to provide a permanent antimicrobial treatment for synthetic sutures that will remain in the body, such as multifilament polyester sutures like Mersilene (uncoated) and Ethibond Excel (polybutylate coated), both sold by Ethicon.
  • These sutures would help prevent significant threats, such as deep wound postoperative infection contributing to the complication after cardiac surgical procedures (Immer FF, Durrer M, Muhlemann KS, Erni D, Gahl B, Carrel TP. "Deep sternal wound infection after cardiac surgery: modality of treatment and outcome". Ann Thorac Surg. 2005 Sep;80(3):957-61). According to the literature, the incidence of deep sternal wound infection varies between 1% and 3%.
  • Another embodiment of this invention is to provide an alcohol- soluble/water-insoluble antimicrobial polymer which can be incorporated into hydrophilic polyurethane foam to be used as a wound dressing with non-leaching antimicrobial activity.
  • Another embodiment of this invention is to provide an alcohol- soluble/water-insoluble antimicrobial polymer which can be incorporated into a UV-curable coating system to impart non-leaching antimicrobial efficacy to the cured coating.
  • This UV curable coating can be applied to plastic film which can subsequently be thermo-formed or vacuum-formed to a product with a desired shape.
  • Another embodiment of this invention is to provide an alcohol- soluble/water-insoluble antimicrobial polymer which can used as a component of an adhesive, such as an adhesive used to secure medical devices to skin, thereby providing an antimicrobial property to said adhesive.
  • EXAMPLE Al Co-polymerization of (2-(methacryloyloxy) ethyl) trimethylammonium chloride and butyl methacrylate.
  • a solution was made by dissolving 2.5 grams of quaternary vinyl monomer (2-(methacryloyloxy)ethyl)trimethylammonium chloride 75% aqueous solution (Aldrich Chemical Co.)), 7.5 grams of butyl methacrylate (Aldrich Chemical Co.), and 0.1 gram or AIBN (2,2'-azobis(2-methylpropionitrile) (Aldrich Chemical Co.) in 10 grams of ethanol. The solution was sparged for 60 seconds with argon gas to expel dissolved oxygen and then sealed in a glass vial under an argon atmosphere. The vial was placed in a 7O 0 C oven for 24 hours. The copolymer containing solution was then diluted in ethanol (1:25).
  • EXAMPLE A2 Application of the composition to skin.
  • Example Al Approximately 1 mL of the solution generated in Example Al was placed on the skin on the back of the hand of a human volunteer, then spread and rubbed with a gloved finger until dry. After drying, an inconspicuous film remained, which was not sticky or tacky, and was virtually imperceptible to the volunteer.
  • Bromthymol blue (BTB) indicator dye is known to bind strongly to quaternary ammonium compounds.
  • BTB indicator dye is known to bind strongly to quaternary ammonium compounds.
  • To visualize the presence of the polymeric coating the area of the hand to which the polymer-containing solution was applied was rinsed with a 0.5% aqueous solution of BTB indicator dye adjusted to a pH 10. The hand was rinsed under tepid running tap water for 30 seconds with light digital manipulation to remove excess BTB indicator dye solution.
  • the area of skin treated with the copolymer solution exhibited a blue/green color, while the surrounding skin did not, indicating presence of the applied polymer. Only after vigorous scrubbing with a detergent solution, was the coating diminished to the extent that the BTB indicator dye assay no longer indicated the presence of the polymeric coating.
  • EXAMPLE A3 Co-polymerization of (vinylbenzyl)trimethylammonium chloride and butyl methacrylate (H-I).
  • a solution was made by dissolving 2.5 grams of quaternary vinyl monomer (vinylbenzyl)trimethylammonium chloride (Aldrich Chemical Co.), 7.5 grams of butyl methacrylate (Aldrich Chemical Co.), and 0.1 grams of AIBN (2,2'-azobis(2- methylpropionitrile) (Aldrich Chemical Co.), in 20 grams of methanol.
  • This solution was sparged for 60 seconds with argon gas to expel dissolved oxygen, and then sealed in a glass vial under an argon atmosphere. The vial was placed in a 7O 0 C oven for 24 hours.
  • the copolymer containing solution was then diluted in ethanol (1:2). This composition was designated as "H-I" and is referred to in subsequent examples.
  • EXAMPLE A4 Application of the composition to polypropylene.
  • Example A3 The solution generated in Example A3 was used to coat the interior surface of several 15 niL polypropylene centrifuge tubes by filling them with the solution and leaving them filled overnight. The solution was then poured off and the alcohol was evaporated completely in a low temperature oven set to 5O 0 C. To visualize the presence of polymeric coating on the inside of the tubes, approximately 5 mL of 0.5% aqueous solution of BTB indicator dye was added to one of the tubes and then shaken to coat the entire inside of the tube. After rinsing the tube several times with distilled water, the interior surface of the tube remained a deep blue color, indicating that the inner surface of the tube was coated with water-insoluble polymer.
  • EXAMPLE A5 Antimicrobial activity of polymeric composition.
  • Example A4 A 2 mL aliquot of a ICM dilution of an overnight culture of S. aureus ( ⁇ 1 x 10 8 CFU/mL) was added to one polypropylene centrifuge tube treated as in Example A4 (sample) and to one untreated polypropylene centrifuge tube (control). During overnight incubation at 37 0 C, the tubes were slowly rolled to ensure contact between the bacteria culture and the interior surface of the tubes. The next day, serial dilutions of the bacteria cultures harvested from each tube were streaked onto bacteria culture plates. The culture harvested from the untreated control tube yielded 2.5 x 10 4 CFU, while zero colonies were observed on plates streaked with cultures harvested from the treated sample tubes. The difference in the number of colonies enumerated translates into at least a 4.4 log reduction in the bacterial population.
  • EXAMPLE A6 Synthesis of a quaternary ammonium polyurethane (H3- C) that is soluble in alcohol, but insoluble in water.
  • Ethoquad C/12-75DK (Akzo Nobel) was placed in a round- bottom flask on a rotary evaporator and evaporated to dryness. The residue ( ⁇ 37.5 grams) was redissolved in 70 mL tetrahydrofuran (THF) with agitation at approximately 5O 0 C. Forty grams of tolylene-2,4-diisocyanate (TDI) was added and the solution was mixed for one hour while immersed in a water bath held at -5O 0 C. The viscosity of the solution increased during this time, and the solution remained clear when cooled to room temperature. The solution was stored overnight at room temperature and some additional increase in viscosity was observed.
  • THF tetrahydrofuran
  • the polymer solution was subsequently diluted to various concentrations ranging from 1% to 10% solids, and these solutions were used to coat various objects such as glass slides and polypropylene test-tubes.
  • the coatings were clear to slightly opaque when dry, were non-tacky, and were adherent to the substrate. Furthermore, the coatings were not removed by rinsing in water or saline solution.
  • the product polymer is believed to comprise a linear polyurethane with quaternary ammonium units in the main-chain structure of the polymer.
  • the product of this example was coded as "H3-C", and is used as an antimicrobial coating in some of the following examples.
  • EXAMPLE A7 Synthesis of a quaternary ammonium polyurethane (H3- F) containing covalently-bonded fluorescein moieties, which is soluble in alcohol, but insoluble in water.
  • H3- F quaternary ammonium polyurethane
  • Fifty milligrams of fluorescein dye (neutral molecule) was dissolved in 3 niL of THF, and then mixed with eight grams of tolylene-2,4-diisocyanate (TDI). This solution was mixed for one hour at ⁇ 50°C, and then stored overnight at room temperature before being mixed with ten grams of Ethoquad C/12-75DK (Akzo Nobel), which had previously been vacuum stripped to remove the isopropanol solvent and redissolved in 14 grams tetrahydrofuran (THF) with agitation at approximately 5O 0 C. This mixture was then mixed for several hours at ⁇ 50°C, and then subjected to vacuum stripping. The mixture was redissolved in isopropanol and then vacuum stripped.
  • TDI tolylene-2,4-diisocyanate
  • the dissolution/stripping was repeated one additional time, and the product was dissolved in -50 mL isopropanol. The solution was found to have a solids content of 17.4 wt%.
  • the product of this reaction is expected to be fluorescein-labeled linear polyurethane containing quaternary ammonium moieties in the polymer main-chain structure. Additionally, the polymer is expected to contain fluorescein moieties in the polymer main-chain structure. The fluorescein moieties provide a useful diagnostic tool to measure the presence, dispersion, persistence, and migration of the polymer. Coatings were prepared on various substrates as described in the preceding example, and the coatings had similar properties to those described above.
  • Coated glass microscope slides were placed into 50 mL culture tubes containing either 15 mL of deionized water or 15 mL of phosphate buffered saline and place in a shaking incubator for several hours at 37 0 C. The solutions were then analyzed by visible spectroscopy (Spectronic 20) at 495 nm. No leaching of fluorescein could be detected, indicating complete incorporation of the dye into the polymer structure.
  • EXAMPLE A8 Preparation of an antimicrobial coating composition.
  • EXAMPLE A9 Preparation of an antimicrobial coating composition containing a skin emollient (SS-IC).
  • Example A9 The formulation of Example A9 (SS-IC) was diluted with isopropanol at ratios of one part SS-IC to one part isopropanol, and one part SS-IC to three parts isopropanol.
  • EXAMPLE All: Preparation of an antimicrobial coating composition containing a skin emollient and UV absorber.
  • Example A9 The formulation of Example A9 (SS-IC) is modified to include UV- absorbing or UV-blocking sunscreen ingredient in order to protect the skin from absorption of UV rays and to prevent sunburn.
  • the UV-absorbing or UV- blocking additive is selected from the list comprising: para-aminobenzoic acid (PABA), PABA esters, cinnamates, benzophenes, salicylates, octocrylene, dibenzoyl-methane, avobenzone, oxybenzone, zinc oxide, and titanium dioxide.
  • EXAMPLE A12 Preparation of an antimicrobial coating composition containing a skin emollient and Vitamin E.
  • Example A9 (SS-IC) is modified to include 1% vitamin E.
  • Vitamin E is practically insoluble in water, but freely soluble in alcohol.
  • EXAMPLE A13 Preparation of an antimicrobial coating composition containing an antimicrobial additive (SS1C-BAC3).
  • An antimicrobial coating composition (SS1C-BAC3) is prepared by mixing 1.1 grams of benzalkonium chloride with 35.5 grams of the formulation of Example A9 (SS-IC). The benzalkonium chloride fully dissolved and the solution was clear and colorless. This composition was tested for antimicrobial efficacy using a modified version of ASTM test method #E 1874-97 ("Standard Test Method for Evaluation of Antibacterial Washes by Cup Scrub Technique'), as described below. Variations included using harvested pig skin from a slaughterhouse rather than live human volunteers. In addition to the SSlC- BAC3 material, a placebo was formulated which consisted of 5% propylene glycol and 5% dipropylene glycol in isopropanol. Results are presented below.
  • the sample skins were wiped with a towel that was thoroughly saturated with 70% alcohol, and then placed under UV light in the BSC (biological safety cabinet) to dry for approx 10 minutes.
  • the lids of the Petri dishes were also placed (facing up) along side of the samples under the UV light.
  • test Product and Placebo 2.1 After drying under UV light, the BSC was switched to fluorescence with the blower on, and a 1x1 in square was drawn on to each of the skins with an ink marker. This is used as the site of application. The UV light was turned on again, with the lids still facing up, for a few minutes to insure that no contamination occurred while marking the skins.
  • Step 2.2 is repeated 3 times with the placebo, and the remaining 3 sample skins are left as negative controls.
  • the cup (about 1.5 cm diameter and 1.5 in tall) was centered onto the application site of the sample with firm pressure to form a cup/skin seal.
  • the cup was first sterilized in 95% alcohol and then flame dried. While one person maintained constant pressure on the cup to protect the cup/skin seal, another person dispensed .25 mL of inoculum into the cup. Once dispensed, the inoculum was left for a 5 minute exposure.
  • Results were quantified by making standard serial dilutions of the recovered scrub fluids and then plated using the spread plate technique. Plates were incubated over night and log reductions were calculated for both the negative control and the placebo
  • the placebo showed no effect on the test organism.
  • EXAMPLE A14 Synthesis of a quaternary ammonium polyurethane that is soluble in alcohol, but insoluble in water, and which has flexible hydrophobic units incorporated within the molecular structure (SS50H).
  • Example A6 The method of Example A6 was substantially followed; however, a equimolar (1:1) mixture of 1,6-hexanediol and Ethoquad was used instead of Ethoquad.
  • the resulting polymer was found to be water insoluble, and at least partially immiscible with isopropanol; however, it was completely soluble in ethanol.
  • a solution of this polymer in ethanol (40.6 wt% polymer) was added dropwise to a large excess of distilled water with vigorous stirring.
  • the precipitated polymer was collected by filtration and dried in a vacuum oven.
  • the resulting dry polymer constituted over 85% recovery of the original material, despite the observation of considerable loss of precipitated material during filtration, drying, and recovery.
  • Example Al 4 The method of Example Al 4 was substantially followed; however, a 3:1 molar ratio of Ethoquad to 1,6-hexanediol was utilized. In addition, a less than equimolar amount of TDI was used (-65%) in order to promote the formation of short chains with hydroxyl end groups. The material is thus expected to have a lower molecular weight, and contain a relatively higher proportion of leachable (water-soluble) antimicrobial components. The exact molecular weight of the polymer is unknown; however, comparison of the viscosity of solutions of this polymer and those described above indicate that this polymer has a lower molecular weight.
  • EXAMPLE A16 Comparison of the quick-action antimicrobial efficacy of various compositions described herein.
  • compositions described in Examples A6, A14, and A15 were tested for quick-acting (5 minute) antimicrobial efficacy using the following procedure:
  • Solutions of the polymers were prepared (10% in alcohol). 50 microliters of each solution was pipetted into individual wells of plastic 24-well cell culture plates. The plates were swirled under a hand-held blowdryer to facilitate evaporation of the alcohol. Working solutions of bacteria were prepared using standard methods. Two-hundred-fifty microliters of bacterial solution (10 4 cfu/mL) were added to each coated well. The 24-well culture plates were incubated /shaken (37°C/100 rpm) for a desired time interval (5 min, 15 min, 30 min, or 60 min), and then 250 ⁇ L of Letheen broth (neutralizer solution) was added.
  • the solution was removed from the wells and lOO ⁇ L was plated onto TSA and spread using standard spread plating technique, or used to make serial dilutions and then plated. Plates were incubated at 37 0 C overnight, colonies were then enumerated, and antimicrobial efficacy was calculated. Testing was performed against Staph, aureus and Serratia marcescens. The relative antimicrobial efficacy of the three polymers was determined to be A15 (SS25HL) > A14 (SS50H) > A6(H3C). Sample A15 exhibited a full-kill of SA and SM after only 5 minutes. Sample A14 exhibited a full kill of SA after only 5 minutes. Sample A6 showed a full kill of SA after 30 minutes.
  • EXAMPLE A17 Preparation of a suture material coated with an antimicrobial composition.
  • Example A6 The polymer prepared by the method of Example A6 was used to coat multifilament polyester sutures material (Mersilene (uncoated) and Ethibond Excel (polybutylate coated), both produced and sold by Ethicon. Sutures ( ⁇ 10cm length each) were washed in 70% isopropanol for 5 minutes followed by three rinses in deionized water to remove surface contamination. Sutures were allowed to dry fully before the application of the antimicrobial polymer. Samples were placed in the 50 ml conical centrifuge tubes and fully covered with the 20 ml of the appropriate treatment solution (polymer of Example A6 dissolved in isopropanol at a concentration of either 0.5, 2.0 or 10 weight %).
  • Tubes were sonicated for 3-5 minutes in order to remove air trapped on the highly hydrophilic polyester fibers.
  • the samples were removed from the treatment solution and allow to dry at 60-80 0 C.
  • the coating process was repeated two times to assure the even coverage (three coats total).
  • Sutures were tested against clinically relevant bacteria: S. aureus, SA (ATCC 6538); E. coli EC (ATCC 15597); Pseudomonas aeruginosa, PA (ATCC 15442); and Methicillin-resistant
  • Staphylococcus aureus MRSA (ATCC 33593). Bacterial suspensions were prepared according to standard methods. The concentrations of bacteria in the suspensions were measured by spectrophotometer (Milton Roy Spectronic 2OD Spectrophotometer) at 580 nm for all bacteria. The measurements for S. aureus yield ⁇ 10 8 titer. The concentration of the bacteria in the stock solution was adjusted to provide a standard inoculum for experimental studies (1 x 10 6 cfu/mL) with PBS. The final concentrations also were confirmed by the Colony Forming Unit (cfu) Method. The treated and control suture samples were cut aseptically into 4-5cm lengths and stored at room temperature until use.
  • suture segments were placed in isolated wells of the sterile large-well culture plate, and exposed to the 4mL of bacterial suspension for 3 hours. The standardized inoculate was verified by serial plate count. Sutures were freely floating in the incubation media while agitated with a shaker at 120 rpm for the duration of incubation step. After exposure to test strains, suture segments were gently washed (three times [3X]) in PBS to remove nonadherent cells. Then, the suture segments were placed in the PBS containing 0.25% of Triton-X, vortexed three times [3X], and sonicated in same solution at 20 kHz for 2-5 minutes.
  • suture sonicate was serially diluted in PBS before plating, and incubated for 24 hours at 37° C. Three suture segments were evaluated per inoculum challenge. Microbial recovery was expressed as loglO cfu/cm suture segment. The following results were obtained [log reduction is in comparison to as-received (uncoated) suture material].
  • EXAMPLE A18 Preparation of plastic films coated with an antimicrobial composition by UV curing.
  • Example A6 The polymer described in Example A6 was blended with a UV-curable coating composition, and the mixture was used to prepare coatings on various plastic substrates. Subsequent testing using the "Agar Slurry Method" (ASTM E 2180-01) determined that the coatings had significant antimicrobial activity against various bacterial organisms, including staph aureus and E. coli, when the content of antimicrobial polymer in the coatings was between 10 and 30 % by weight of the dry coating.
  • EXAMPLE A19 Preparation of a hydrophilic polyurethane foam with antimicrobial properties.
  • This example demonstrates the incorporation of the alcohol- soluble/water- insoluble antimicrobial polymer described by Example A6 into a formulation used to prepare a non-leaching antimicrobial hydrophilic polyurethane foam useful as a wound dressing material.
  • An "aqueous solution was prepared by dissolving 90 mg of tetrasodium EDTA in 12 grams of water, then adding 10 grams of a 0.25% solution of Pluronic F-88 surfactant (BASF), and then 3 grams of ZnO 50% suspension with nonionic dispersant ("NanoShield" ZN-3010, Alfa-Aesar), followed by thorough mixing.
  • BASF Pluronic F-88 surfactant
  • a straight-edge spreader bar was then moved across the top surface of the second sheet of paper in order to spread the mixture to a uniform thickness in-between the two sheets of release paper.
  • the material was allowed to cure at room temperature for several minutes.
  • the top sheet of release paper was then removed.
  • the resulting foam, still attached to the bottom release paper, was then placed into a drying oven at HO 0 C for 15 minutes. The resulting yellow foam could then be removed from the release paper for use or testing.
  • the cured foam was observed to quickly ( ⁇ 5 seconds) absorb droplets of water placed onto its surface.
  • the absorbent capacity (drip free) of the foam was determined to be approximately 15.9 times its own weight of 1% saline solution, after immersion for 5 minutes.
  • the foam was tested according to ATCC Method #100, and found to give a 5.99 log reduction of Candida albicans, a 7.81-log reduction of Staph, aureus, and a 6.36-log reduction of Pseudomonas auerginosa, when compared to a non- antimicrobial hydrophilic PU foam wound dressing (Tielle, a product of J&J).
  • the non-leaching character of the foam antimicrobial activity was demonstrated by testing extracts of the foam (24 hours @ 37 0 C, 60 sq-cm of foam per 20 mL of PBS) by placing 20 microliter droplets of the extracts onto marked areas of agar plates which had been spread-plated with 10 6 cfu/mL Staph, aureus bacteria. After overnight incubation at 37 0 C, and subsequent visual observation, no evidence of growth inhibition was observed in the marked areas.
  • EXAMPLE A20 Synthesis of a quaternary ammonium polyurethane that is soluble in alcohol, but insoluble in water, and which has flexible hydrophobic and/or hydrophilic units incorporated within the molecular structure.
  • Example Al 4 The procedure described in Example Al 4 is followed, except that diethylene glycol (6is-(2-hydroxyethyl)ether) is substituted for all or part of the 1,6-hexanediol.
  • the polymeric product will be more hydrophilic when the relative content of diethylene glycol is higher.
  • EXAMPLE A21 Preparation of a clear, gel-based antimicrobial (SSG2) with prolonged durable efficacy, for disinfection of skin, which also contains a leachable antimicrobial (CHG), and a stabilizer/preservative (EDTA).
  • SSG2 clear, gel-based antimicrobial
  • CHG leachable antimicrobial
  • EDTA stabilizer/preservative
  • the EDTA is added as a stabilizer, and/or preservative, and/or for enhanced antimicrobial efficacy.
  • the described composition was tested on human volunteers using ASTM E 1874-97 "Standard Test Method for evaluation of Antibacterial Washes by Cup Scrub Technique".
  • the test organism was Serratia marcescens, and a "full kill” was obtained, with an average reduction in bacterial load of greater than 3.5 logs, when compared to a non-durable control antiseptic composition (Purell Hand Sanitizer). Results were similar when antimicrobial efficacy was tested approximately five minutes after application of the formulation to the skin, and when tested four hours after application to the skin. Additionally, significant antimicrobial activity was again detected even after rinsing the treated skin with soap and water, or with alcohol.
  • EXAMPLE A22 Preparation of a medical adhesive with antimicrobial properties.
  • Example A14 The polymer described in Example A14 was blended with low-Tg acrylate copolymers to give a composition suitable for use as a medical adhesive. The mixture was used to prepare coatings on plastic substrates. These coatings were found to have useful adhesive properties. Subsequent testing using the "Agar Slurry Method" (ASTM E 2180-01) determined that the coatings had significant antimicrobial activity against various bacterial organisms, including staph aureus and E. coli, when the content of antimicrobial polymer in the coatings was between 10 and 30 % by weight of the dry coating.
  • Example A23 Formulation of an antimicrobial barrier film for application to human skin, which has flexible hydrophobic units incorporated within the molecular structure, and which has a low molecular weight (solution "GlI").
  • Example Al 4 The method of Example Al 4 was substantially followed; however, a ratio of 20 grams Ethoquad solution (75 wt%) to 7.5 grams of 1,6-hexanediol was utilized. In addition, a less than equimolar amount of TDI was used ( ⁇ 65%) in order to promote the formation of short chains with hydroxyl end groups. The material is thus expected to have a lower molecular weight, and contain a relatively higher proportion of leachable (water-soluble) antimicrobial components. The exact molecular weight of the polymer is unknown; however, comparison of the viscosity of solutions of this polymer and those described above indicated that this polymer has a lower molecular weight. The resulting polymer was formulated into a solution with the following composition:
  • Antimicrobial polymer (10% by weight); PEG 600K thickener (1%); Water (12%); Isopropanol (27%); and Ethanol (50%). This formulation is referred to as G-Il in the following discussion.
  • the cup scrub method was used to test antimicrobial efficacy of G-Il against Serratia marcescens on the skin of human volunteers according to ASTM E 1874-97, "Standard Test Method for Evaluation of Antibacterial Washes by Cup Scrub Technique". Additional experiments employing a rinsing step were also performed. The results show high antibacterial efficacy for G-Il, even after rinsing the dried film with water, and are presented in the table below.
  • Rinsing step was 20 pumps ( ⁇ 1 ml each) of deionized water applied from standard spray bottle.
  • Formulation G-Il was evaluated for efficacy against the fungal organism, Candida albicans as follows: Evaluation of GlI vs. Candida albicans by Lawn Spread
  • Formulation GlI was evaluated against Candida albicans by lawn spread technique. Cultures of C. albicans ATCC# MYA-905, and ATCC# 10231, were grown from glycerol stocks in yeast medium broth for forty-eight hours. The cultures were then diluted to a 1O 2 dilution to serve as a working inoculum. A sterile cotton swab was saturated in the inoculum and evenly spread across the entire surface of yeast medium agar. Three 30 ⁇ L quantities of GlI were then pipetted onto the agar, evenly spaced. The agar plates were moved into an incubator for forty-eight hours and then assessed for results.
  • C. albicans Two strains of C. albicans, ATCC# MYA-905, and ATCC# 10231, were grown from glycerol stocks in yeast medium broth for forty-eight hours. The cultures were then diluted to a 10 2 dilution to serve as a working inoculum. 250 ⁇ L of GlI was distributed onto each of the glass slide carriers. After application the slides were placed in a biological safety cabinet for a ten minute drying period. lOO ⁇ L of C. albicans inoculum was added to each of the slides and gently distributed with a sterile loop, followed by a 5 minute contact time. Three treated slides and three negative control slides were used for each strain of the organism.
  • Results showed an average log reduction of 0.78 for strain MYA-905, and a 1.71 average log reduction for strain 10231.
  • Antiviral efficacy analysis on the GlI skin sanitizer sample was conducted by an independent laboratory (BCS Laboratories, Inc., Gainesville, Florida). The analysis was conducted using bacteriophage MS-2 as a model for human viruses. Bacteriophage MS-2 has been used extensively in many published research studies as a model for the inactivation of human viruses for evaluation of the potential antiviral properties of physical and chemical disinfectants in the water and healthcare industry. Its inactivation/survival correlates well with many human viruses. The antiviral efficacy testing was conducted of GlI was conducted using the well-plate model.
  • bacteriophage MS-2 (ATCC 15597B1; 30 nm RNA virus specific for Escherichia coli C3000; ATCC 15597) was used as surrogate model for human viruses.
  • Bacteriophage stock solutions containing approximately 10 9 plaque forming units (pfu) /niL were assayed prior to the day of challenge as per standard methods (Snustad and Dean, 1971).
  • MS-2 stock solution was diluted to approximately 10 6 pfu/ml in Phosphate Buffered Saline (PBS; Fisher Scientific). This phage dilution was used to evaluate the anti-bacteriophage efficacy of the Skin Sanitizer Formulation.
  • Experimental analysis was conducted in triplicates. Analyses were conducted in 24-well cell culture plates (Corning Inc., NY).
  • Difco Neutralizing Buffer Becton Dickinson, MD
  • the plate was placed on an orbital shaker (Hoefer, Red Rotor, San Francisco) on low speed for 5 minutes. Following the specified contact time, Neutralizing buffer was added to each well plate. Control (initial) bacteriophage titers were determined by adding 100 ⁇ l of bacteriophage solution to empty wells and 2 ml of Neutralizing Buffer was then added. Following the addition of Neutralizing Buffer in all the above instances, it was repeatedly pipetted and then transferred to a sterile 15 ml tube. Dilutions of solutions containing the bacteriophage were performed in PBS prior to enumeration.
  • orbital shaker Hoefer, Red Rotor, San Francisco
  • the number of MS-2 bacteriophage in each of the samples was enumerated as Plaque Forming Units (pfu) by an agar plaque assay using the host E. coli C3000 and molten Tryptic Soy Agar (TSA; Becton Dickinson, MD). Plates were allowed to incubate overnight at 37 0 C and the plaques were then counted, and percent reductions as compared to the controls were determined. Each analysis was plated in duplicates. The results of repeated experiments were comparable and efficacy was reproduced in each of the time points. Results are presented in the table below, and represent the average numbers obtained from triplicate analyses.
  • *pfu/ml Plaque forming units of MS-2 in the Neutralizing Buffer recovered from each well.
  • EXAMPLE A24 Preparation of a solution of water-insoluble antimicrobial propylene glycol as solvent.
  • Example Al 4 The polymer described in Example Al 4 was dried at 5O 0 C under vacuum to remove the alcohol solvent, and subsequently redissolved in propylene glycol to give a 40% solution of polymer in propylene glycol. This solution was observed to be clear and stable when stored at room temperature.
  • EXAMPLE A25 Preparation of an antimicrobial barrier film for application to human skin, which has improved physical and aesthetic properties.
  • Example A23 While effective for antimicrobial purposes, was perceived by human volunteers to be "sticky”, “gooey”, “lumpy”, or “stringy” either during or after application of the solution to the skin. It was determined that these undesireable physical and/or aesthetic effects were caused primarily by the thickening agent used in that formulation (1% PEG 600K).
  • the thickening agent is used to promote high viscosity, which in turn prevents "runoff of the product during application. It is generally desirable to use the least amount of thickening agent possible that still provides the desired level of thickening effect. Additionally, the thickening agent must be compatible with the other components of the formulation, including the alcohol solvent, and the quaternary antimicrobial polymer.
  • Carbomer (a poly acrylate) is a common thickening agent used in skin preparations; however, it is incompatible with quaternary ammonium polymers (precipitate formation).
  • HEC hydroxyethyl cellulose
  • the grade of HEC is chosen to optimize the desired physical properties.
  • Cellulose ethers such as methylcellulose or Methocel (Dow) are also a suitable thickening agent for the practice of this invention. The order of addition of ingredients is important in order to obtain a useful formulation.
  • a formulation was prepared according to the following procedure: A solution of 1.07 grams of Hydroxyethyl Cellulose (“HEC”) (Cellosize #QP-100M-H, Dow) in 50 niL of water was prepared by dispersing the HEC in the water, and then swirling on a rotary mixer ate 7O 0 C for two hours. The solution was stored overnight, and appeared to have a smoother consistency after storage. A total of lOOg (126.5 niL) of absolute ethanol was then added to the HEC solution, followed by thorough mixing. Hence, a solution comprising approximately 0.65 wt% HEC and 70% ethanol was formed.
  • HEC Hydroxyethyl Cellulose
  • This solution (105 grams) was mixed with 10 grams of absolute ethanol and 15 grams of a 40% solution of antimicrobial quaternary ammonium polymer in ethanol to give an antimicrobial barrier film formulation for application to skin.
  • the antimicrobial quaternary ammonium polymer used was substantially similar to that described in Example A14.
  • the formulation dried nicely and was not sticky while, or after, drying.
  • Example A26 Preparation of a free-standing polymer film containing an alcohol-soluble antimicrobial polymer and a plasticizer.
  • the antimicrobial quaternary ammonium polymer used was substantially similar to that described in Example Al 4.
  • the solution was poured onto a flat non-stick frying pan, and allowed to dry overnight. The frying pan was placed on a leveled surface in order to promote uniform film thickness.
  • the dried film was peeled-away from the pan.
  • a control film was prepared in a similar manner; however, it did not contain the antimicrobial polymer.
  • Films were tested for antimicrobial efficacy using the ASTM "shaker flask method" (ASTM E2149 - Antimicrobial Surface Test, "Determining the Antimicrobial Activity of Immobilized Antimicrobial Agents Under Dynamic Contact Conditions”).
  • the test organism was MRSA (ATCC# BAA-44), and the contact time was 30 minutes.
  • the film with antimicrobial content showed a 5.4 log reduction of bacteria (full kill), relative to the untreated film. Both films were similar in appearance and physical properties.
  • Example A27 Infusion of a polyurethane pellet with a solution of antimicrobial polymer.
  • a solution was prepared containing 10 grams of an antimicrobial quaternary ammonium polymer substantially similar to that described in example A15, dissolved in a mixture of 350 mL of THF and 50 niL of ethanol. To this solution was added 100 grams of polyurethane resin in the form of pellets approximately 3 mm in diameter and 3 mm long. The suspension was mixed overnight on a rotary mixer. The pellets absorbed all of the solution during this time. The pellets were dried under reduced pressure with slight heating. The dried pellets were substantially similar in appearance to the untreated pellets, with the exception that the treated pellets had a slight yellow color. No visual evidence of residual antimicrobial polymer or a coating was apparent.
  • the pellets were tested for antimicrobial efficacy using the ASTM "shaker flask method" (ASTM E2149 - Antimicrobial Surface Test, "Determining the Antimicrobial Activity of Immobilized Antimicrobial Agents Under Dynamic Contact Conditions”).
  • the test organism was MRSA (ATCC# BAA-44), and the contact time was 30 minutes.
  • the pellets with antimicrobial content showed a 2.5 log reduction of bacteria, relative to the untreated pellets.
  • Example A28 Treatment of a substrate with a solution of antimicrobial polymer.
  • a substrate for instance a thermoplastic polymer film comprising, for example, poly(vinyl chloride), polycarbonate, polyacrylate, or polystyrene is treated with a solution of a water-insoluble quaternary ammonium antimicrobial polymer dissolved in a suitable solvent; wherein, the suitable solvent and/or the polymer solution is capable of either dissolving (wholly or partially) absorbing-into, or otherwise penetrating the surface of the substrate.
  • Said substrate may be treated with said solution by any suitable means, including for example, brushing, spraying, or dipping. After said treatment, the treated substrate may be dried to remove said suitable solvent, leaving said water-insoluble quaternary ammonium antimicrobial polymer infused, coated, adhered, attached, or interpenetrated to the substrate, rendering the substrate with antimicrobial properties.
  • TFET Thin Film Efficacy Test
  • the media plates used for this assay are selective media plates that are appropriate to the respective organisms. Sixty plates are used for each organism.
  • MSA MSA (Mannitol Salt Agar) is the selective media for S. aureus and MRSA.
  • EMB Eosin Methylene Blue Agar is the selective media for E. coli.
  • EA Enterococcosel Agar is the selective media for VRE.
  • Coating 100 ⁇ l of the antibacterial solution is applied to each plate and allowed to air dry for a minimum of 1 hour in the biological safety cabinet before inoculating.
  • Inoculating The test organism is grown in the appropriate growth media and incubated overnight unless otherwise specified. The inoculum is made to achieve a titer of 10 6 CFU/ml. The coated plates are then inoculated with 1000 ⁇ l bacterial solution and the inoculum is then homogenously applied by moving the plate in a circular motion.
  • Exposure The samples are incubated at 37 0 C in a high humidity chamber and the exposure time is overnight unless otherwise stated.
  • Results After incubation, each plate is inspected for bacteriostatic activity on the area of application. The results are read as Pass/Fail. If there is no growth, the plate is read as Pass and if there is growth on the area, the plate is read as Fail.
  • TFET - Results After incubation, each plate is inspected for bacteriostatic activity on the area of application. The results are read as Pass/Fail. If there is no growth, the plate is read as Pass and if there is growth on the area, the plate is read as Fail.
  • the Thin Film Efficacy Test was used to determine the bacteriostatic ability of the antimicrobial solution.
  • the procedural steps of the TFET consist of using growth media plates as carriers in which 100 ⁇ l of the chosen antimicrobial solution is applied in the center of the plate.
  • the antimicrobial solution was allowed to air dry for a minimum of 1 hour prior to inoculation.
  • the coated plates were inoculated with 1000 ⁇ l inoculum at a titer of 10 6 CFU/ml.
  • the inoculum was homogeneously applied by swirling the plate until the inoculum completely covered the entire surface area of the plate.
  • the inoculated plates were then allowed to dry and subsequently incubated overnight at 37 0 C.
  • Example T2 uses Methicillin-Resistant S. aureus (MRSA, ATCC #BAA-44) as the test organism and again MSA is used as the growth media.
  • MRSA Methicillin-Resistant S. aureus
  • the results for MRSA are as follows: Antimicrobial Solution 24 hr Results 48 hr Results
  • Example T3 used E. coli, ATCC #15597, as the test organism and additionally Eosin Methylene Blue Agar was used as the growth media.
  • Example T4 used Vancomycin-Resistant Enterococcus (VRE, ATCC # 700221) as the test organism and additionally used Enterococcosel Agar as the growth media.
  • VRE Vancomycin-Resistant Enterococcus
  • Example T5 used the H-I formulation (see Example A3) as the antimicrobial solution.
  • the results for S. aureus were as follows:
  • Example T6 also used the H-I formulation as the antimicrobial solution.
  • Example T7 used Zero brand hand sanitizer (Aquagen International, Inc.) as the antimicrobial solution.
  • Example T8 For comparison with compositions of the present invention, Example T8 also used Zero brand hand sanitizer as the antimicrobial solution.
  • the results for E. coli were as follows:
  • Example T9 used Purell brand hand sanitizer (GOJO Industries, Inc.) as the antimicrobial solution.
  • Purell brand hand sanitizer GOJO Industries, Inc.
  • Example TlO also used Purell brand hand sanitizer (GOJO Industries, Inc.) as the antimicrobial solution.
  • Purell brand hand sanitizer GOJO Industries, Inc.
  • CPT Carrier Persistence Test
  • This procedure is a modification of the EPA's Standard Operating Procedure: Testing of Spray Disinfectants against Staphylococcus aureus, Pseudomonas aeruginosa, and Mycobacterium bovis; which is an adaptation of the AOAC method to determine the efficacy of spray products as hard surface disinfectants against three test organisms, Mycobacterium bovis (BCG), Pseudomonas aeruginosa, and Staphylococcus aureus.
  • BCG Mycobacterium bovis
  • Pseudomonas aeruginosa Pseudomonas aeruginosa
  • Staphylococcus aureus Staphylococcus aureus
  • the procedural steps of the CPT consist of applying an antimicrobial test solution to chosen carriers and allowing the carriers to dry before they are inoculated with the appropriate test organism. After inoculation, the carriers are incubated for the prescribed exposure time, subsequently placed into neutralizing solution, then serial diluted and plated for efficacy quantification using standard methods.
  • Carriers The carriers are 25 cm 2 and can be comprised of a variety of materials. The carriers are sterilized by methods appropriate to the carrier's composition. The three carriers types used in these assays are borosilicate glass, Vitro-Skin, and pig skin; however, carriers suitable for use in this method are not limited to the aforementioned.
  • Borosilicate glass slides are washed with ethanol and allowed to air dry. After drying, the borosilicate glass slides are placed into Petri dishes and autoclaved for 15 minutes.
  • Vitro-Skin The Vitro-Skin is prepared according to manufacturer's specifications. If Vitro-Skin becomes unsterile, it needs to be sterilized with 70% alcohol, allowed to dry, and re-hydrated according to the manufacturer's specifications. Vitro-Skin was directly purchased from the manufacturer (IMS Inc., Orange, CT). VITRO-SKIN is an advanced testing substrate that effectively mimics the surface properties of human skin. It contains both optimized protein and lipid components and is designed to have topography, pH, critical surface tension and ionic strength similar to human skin.
  • Pig Skin The pig skin is sterilized with 70% alcohol. This procedure includes thoroughly wetting the carriers with the 70% alcohol and allowing the carriers to thoroughly air dry in a Biological Safety Cabinet (BSC). As an alternative, the pig skin may be exposed to UV light for 10 minutes. Fresh pig skin is purchased from a local slaughterhouse.
  • the antimicrobial solution is applied to each carrier until it thoroughly wets the carriers.
  • the solution volume should not exceed 1000 ⁇ l and will not be less than 20 ⁇ l.
  • the antimicrobial solution is then allowed to air dry for a minimum of 1 hour in a BSC before inoculating.
  • Test organisms are grown in appropriate growth media and incubated overnight at 37 0 C unless otherwise specified.
  • the inoculum is modified to produce a titer of 10 8 CFU/ml.
  • the carriers carrying the antimicrobial solution is then inoculated with 10 ⁇ l-20 ⁇ l of inoculum.
  • the inoculum will be distributed with sterile swabs saturated with inoculum. Exposure time begins directly after inoculation.
  • Exposure The exposure time is overnight unless otherwise specified and samples are incubated at 37 0 C in a high humidity chamber.
  • Neutralization Inoculated carriers are neutralized before recovering the organisms to stop antimicrobial activity of the antimicrobial solution. All neutralizations are done with 20 ml aliquots of Letheen Broth in 50 ml conical centrifuge tubes at a minimum of 10 minutes unless otherwise specified.
  • Organism recovery is started within the neutralization tubes.
  • the neutralized carriers are vortexed for 1 minute and the organisms are subsequently recovered with standard serial dilution and plating methods. Plates are incubated overnight at 37 0 C and colony forming units are quantified the following day.
  • Controls Carrier substrates without any applied antimicrobial coating are used as negative controls to determine the baseline microbial growth. Control substrates were of the same composition as the test substrates within each sample set. Colony counts for the control substrates are reported. Calculations: Calculations will be computed using a Microsoft Excel spreadsheet. Electronic copies of the spreadsheet as well as hard copies will be retained.
  • H-I antimicrobial polymer See Example A3
  • borosilicate glass slide carriers Using the tip of a pipette, 250 ⁇ l of NimbuDerm H-I was homogenously applied over the 25 cm 2 surface of the glass slide carrier.
  • the glass slide carriers were allowed to dry for at least 1 hour prior to inoculation.
  • the carriers were inoculated with 10 ⁇ l of 10 8 CFU/ml inoculum of to ensure a target load of 10 6 CFU/ml.
  • the organism used was S. aureus ATCC #6538, and the allowed exposure time was 30 minutes.
  • the inoculated glass slide carriers were placed in neutralizing solution of 20 ml Letheen Broth for no less than 10 minutes to allow for proper neutralization-the Letheen broth was chilled to 4 0 C prior to use. Following neutralization, the carriers were vortexed in the neutralization broth for one minute to facilitate the recovery of the organism. The recovery of viable organisms was done by standard serial dilution and plating methods.
  • Example C2 is identical to Example Cl with the exception to the exposure time.
  • the exposure time used for Example C2 was 16 hours (overnight exposure).
  • S. aureus control carrier population 2.30E07 CFU/ml Carrier: Borosilicate glass slides Exposure time: 16 hours
  • Example C3 is identical to Example C2 with the exception of the organism.
  • the organism used was E. coli ATCC 15597.
  • E. coli control carrier population 1.06E05 CFU/ml
  • Carrier Borosilicate glass slides Exposure time: 16 hours
  • Example C4 is identical to Example C3 with the exception of the carrier.
  • the carrier used was Vitro-Skin.
  • E. coli control carrier population 2.87E06 CFU/ml
  • Carrier Vitro-Skin Exposure time: 16 hours Samples Solution Log Reduction
  • H-3 antimicrobial polymer (see Example A6) was applied to borosilicate glass slide carriers. Using the tip of a pipette, 250 ⁇ l of H-3 (10% polymer content) was homogenously applied over the 25 cm 2 surface of the glass slide carrier. The glass slide carriers were allowed to dry for at least 1 hour prior to inoculation. The carriers were inoculated with 10 ⁇ l of 10 8 CFU/ml inoculum to ensure a target load of 10 6 CFU/ml. The organism used was S. aureus ATCC #6538 the allowed exposure time was 30 minutes. Following the exposure, the inoculated glass slide carriers were placed in neutralizing solution of 20 ml Letheen Broth for no less than 10 minutes to allow for proper neutralization. The Letheen broth was chilled to 4 0 C prior to use. Following neutralization, the carriers were vortexed in the neutralization broth for one minute to facilitate the recovery of the organism. The recovery of viable organisms was performed by standard serial dilution and plating methods.
  • E. coli control carrier population 1.06E05 CFU/ml
  • Example C6 is identical to Example C5 with the exception of the carrier.
  • the carrier used was Vitro-Skin.
  • Example C 7 is identical to Example C 5 with the exception of the concentration of skin sanitizer solution.
  • the H 3- C skin sanitizer's concentration is now reduced to 7%.
  • E. coli control carrier population 2.50E06 CFU/ml
  • Example C8 is identical to Example C7 with the exception of the carrier.
  • the carrier used was Vitro-Skin. Results were as follows:
  • E. coli control carrier population 2.08E06 CFU/ml
  • Carrier Vitro-Skin Exposure time: 16 hours
  • Example C9 is identical to Example C 7 with the exception of the concentration of skin sanitizer solution.
  • the H 3- C skin sanitizer's concentration is now further reduced to 1%.
  • Example ClO is identical to Example C 9 with the exception of the organism.
  • the organism used was S. aureus ATCC #6538.
  • Example ClI is identical to Example ClO with the exception of the organism.
  • the organism used was P. aeruginosa ATCC #15442.
  • a 1% solution H3-C antimicrobial polymer was applied to borosilicate glass slide carriers.
  • the sanitizer solution was applied by passing over the 25 cm 2 slide surface two times using a nonwoven wipe material (polyester/cotton) saturated with sanitizer solution.
  • the now coated glass slide carriers were allowed to dry for at least 1 hour prior to inoculation.
  • the coated glass slides were then inoculated with an inoculum of 10 8 CFU/ml to ensure a target load of 10 6 CFU/ml.
  • the organism used was E. coli ATCC 15597 and the allowed exposure time was 16 hours.
  • the inoculated glass slide carriers were placed into a neutralizing solution of 20 ml Letheen Broth for no less than 10 minutes to allow for proper neutralization.
  • the Letheen broth was chilled to 4 0 C prior to use.
  • the carriers were vortexed in the neutralization broth for one minute to facilitate the recovery of the organism.
  • the recovery of viable organisms was performed by standard serial dilution and plating methods.
  • E. coli control carrier population 1.57E06 CFU/ml
  • Carrier Borosilicate glass slides Exposure time: 16 hours
  • Example C13 is identical to Example C 12 with the exception of the organism.
  • the organism used was P. aeruginosa ATCC #15442. Results were as follows:
  • Purell brand instant hand sanitizer solution (GOJO Industries, Inc.) was applied to borosilicate glass slide carriers. Using the tip of a pipette, 250 uL of Purell was homogenously applied over the 25 cm 2 surface of the glass slide carrier. The glass slide carriers were allowed to dry for at least 1 hour prior to inoculation. The carriers were inoculated with 10 uL of 10 8 CFU/ml inoculum to ensure a target load of 10 6 CFU/ml. The organism used was S. aureus ATCC #6538, and the allowed exposure time was 30 minutes. Following the exposure, the inoculated glass slide carriers were placed in neutralizing solution of 20 ml Letheen Broth for no less than 10 minutes to allow for proper neutralization. The Letheen broth was chilled to 4 0 C prior to use. Following neutralization, the carriers were vortexed in the neutralization broth for one minute to facilitate the recovery of the organism. The recovery of viable organisms was performed by standard serial dilution and plating methods.
  • S. aureus control carrier population 1.02E05 CFU/ml Carrier: Borosilicate glass slides Exposure time: 30 minutes Samples Solution Log Reduction
  • Example C15 is identical to Example C14 with the exception of the organism.
  • the organism used was E. coli ATCC #15597.
  • E. coli control carrier population 4.70E06 CFU/ml
  • Carrier Borosilicate glass slides Exposure time: 30 min
  • Example C16 is identical to Example C14 with the exception of the organism.
  • the organism used was P. aeruginosa ATCC #15442.
  • Example A9 The material of Example A9 (SS-IC) was applied to pig skin carriers. Using the tip of a pipette, 1000 ⁇ l of SS-IC was homogenously applied over the 25 cm 2 surface of the pig skin carrier. The pig skin carriers were allowed to dry for at least 1 hour prior to inoculation. The carriers were inoculated with 20 ⁇ l of 10 8 CFU/ml inoculum of to ensure a target load of 10 6 CFU/ml. The organism used was Serratia. marcescens, ATCC #13380. The allowed exposure time was 4 hours.
  • the inoculated pig skin carriers were placed in neutralizing solution of 20 ml Letheen Broth for no less than 10 minutes to allow for proper neutralization-the Letheen broth was chilled to 4 0 C prior to use. Following neutralization, the carriers were vortexed in the neutralization broth for one minute to facilitate the recovery of the organism. The recovery of viable organisms was done by standard serial dilution and plating methods.
  • Example C18 is identical to Example Cl 7 with the exception of the organism.
  • the organism used was E. coli ATCC 8739. Results were as follows:
  • E. coli control carrier population 1.54E07 CFU/ml
  • Carrier Pig Skin Exposure time: 4 hours
  • Example C19 is identical to Example Cl 7 with the exception of the organism.
  • the organism used was MRSA (Methacillin-resistant Staph, aureus)
  • MRSA control carrier population 2.63E07 CFU/ml Carrier: Pig Skin Exposure time: 4 hours
  • Example C20 is identical to Example Cl 7 with the exception of the organism.
  • the organism used was VRE, ( Vancomycin resistant Enterococus)
  • VRE control carrier population 3.23E06 CFU/ml Carrier: Pig Skin Exposure time: 4 hours Samples Solution Log Reduction

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Abstract

L'invention porte sur une composition désinfectante non soluble dans l'eau, soluble dans l'alcool ou dans le glycol, et sur un procédé d'utilisation de cette dernière pour désinfecter une variété de surfaces, y compris cutanées, et leur conférer une propriété antimicrobienne de longue durée. Ladite composition comprend: (1) au moins un glycol ou un mélange d'au moins un glycol et d'un alcool; et (2) un polymère antimicrobien capable de conférer une propriété antimicrobienne à une surface sans recours à un composé métallique ou contenant du métal. La composition est appliquée sur une surface où elle s'évapore, laissant un revêtement de polymère antimicrobien sur le substrat. Dans un autre mode de réalisation, la composition est incorporée au substrat.
EP09701395.7A 2008-01-08 2009-01-08 Polymères d'ammonium quaternaire désinfectants solubles dans l'alcool Withdrawn EP2231761A4 (fr)

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PCT/US2009/030437 WO2009089346A2 (fr) 2008-01-08 2009-01-08 Polymères d'ammonium quaternaire désinfectants solubles dans l'alcool

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EP2231761A4 (fr) 2013-08-14
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JP2011511103A (ja) 2011-04-07
AU2009204189B2 (en) 2014-01-16
WO2009089346A2 (fr) 2009-07-16
WO2009089346A3 (fr) 2009-09-24

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