WO2009027971A2 - Polymeres antimicrobiens - Google Patents

Polymeres antimicrobiens Download PDF

Info

Publication number
WO2009027971A2
WO2009027971A2 PCT/IL2008/001160 IL2008001160W WO2009027971A2 WO 2009027971 A2 WO2009027971 A2 WO 2009027971A2 IL 2008001160 W IL2008001160 W IL 2008001160W WO 2009027971 A2 WO2009027971 A2 WO 2009027971A2
Authority
WO
WIPO (PCT)
Prior art keywords
process according
polymer
article
particles
particle
Prior art date
Application number
PCT/IL2008/001160
Other languages
English (en)
Other versions
WO2009027971A3 (fr
Inventor
Abraham J. Domb
Haim Wilder
Stanislaw Ratner
Original Assignee
H2Q Water Industries Ltd.
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 H2Q Water Industries Ltd. filed Critical H2Q Water Industries Ltd.
Publication of WO2009027971A2 publication Critical patent/WO2009027971A2/fr
Publication of WO2009027971A3 publication Critical patent/WO2009027971A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/20—Compounding polymers with additives, e.g. colouring
    • C08J3/203—Solid polymers with solid and/or liquid additives
    • 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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L29/126—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/128—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing other specific inorganic fillers not covered by A61L31/126 or A61L31/127
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/20—Compounding polymers with additives, e.g. colouring
    • C08J3/201—Pre-melted polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/21—Acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/04—Coatings containing a composite material such as inorganic/organic, i.e. material comprising different phases
    • 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
    • C08K9/00—Use of pretreated ingredients
    • C08K9/08—Ingredients agglomerated by treatment with a binding agent

Definitions

  • This invention generally relates to a method for the manufacture of polymeric articles having antimicrobial properties and to antimicrobial polymers for use in the manufacture of such articles.
  • Adhesion of bacterial cells and infective agents to solid surfaces is caused by electrostatic interaction, hydrophobic interaction and other forces of interaction such as hydrogen bonding, van der Walls forces, etc.
  • a number of polymers that exhibit antibacterial properties have been developed for this purpose including soluble and insoluble pyridinium-type polymers for use in surface coating, azidated poly(vinyl chloride) which can be used to prevent bacterial adhesion of medical devices, PEG polymers that can be modified on polyurethane surfaces and also prevent initial adhesion bacteria to the biomaterial surfaces, and chitosans/polyethyleneimine that exhibit antibacterial and antifungal activity.
  • Antimicrobial surfaces have been a major challenge particularly in medicine where microbial agents tend to accumulate and propagate onto implantable devices made of various materials, particularly onto polymers.
  • indwelling catheters have to be removed sometimes shortly after administration due to accumulation of bacteria.
  • indwelling catheters For orthopedic implants such as artificial hips accumulation of bacteria may result in severe infection shortly or a few months after implant which in turn necessitates the removal of the implant and administration of high doses of antibacterial agents for healing before re-implantation.
  • Urinary catheters may also result in a bladder infection from bacteria tracking through the catheter.
  • Dental restoration material tend also to accumulate bacteria which results in the deterioration of the restoration material while infecting the neighboring soft and hard tissues including the gums and dentin.
  • the antibacterial activity associated with polycations has also been researched and is believed to result from an interaction which disrupts bacterial cell membranes.
  • a number of polymers that exhibit antibacterial properties were developed for this purpose including soluble and insoluble pyridinium-type polymers which are involved in surface coating, azidated poly(vinyl chloride) which can be used to prevent bacterial adhesion of medical devices, PEG polymers that can be modified on polyurethane surfaces and also prevent initial adhesion bacteria to the biomaterial surfaces, and chitosans- polyethyleneimine that exhibit antibacterial and antifungal activity.
  • One approach in the manufacturing plastics and polymeric products having antimicrobial properties involves the incorporation, in the manufacturing process of such plastics and polymeric products, antimicrobial additives.
  • antimicrobial additives In searching for such additives amongst the very many materials and composites known to have antimicrobial properties, quaternary ammonium derivatives appear not to be suitable candidates as they exhibit instability at temperatures above 130 0 C even for short periods of time. Under such conditions, which are typical to melt processing, the quaternary ammonium based materials tend to degrade and release alkyl amines and are thus considered by the industry useless for making plastics and other articles by melt processing. Other known antimicrobial materials have similarly exhibited instability under such processing conditions.
  • a second approach for obtaining antimicrobial surfaces involves the coating of surfaces having no antimicrobial activity with an antimicrobial agent or a coating.
  • the requirements for such effective coating in products having their surfaces in continuous contact with, e.g., an aqueous medium include antimicrobial activity over a predetermined time period and stability of the coating under the use conditions, so as to avoid delamination of the coatings or leachout of agents therefrom to the aqueous media.
  • antimicrobial plastics Despite the abundance of technologies for manufacturing antimicrobial plastics, there remains a need in the plastics industry, as well as in related industries such as the bottle industry needing such antimicrobial plastics, for antimicrobial agents that are stable under the application conditions, and possess antimicrobial activity under the conditions of use for a predetermined, yet substantially long time period.
  • antimicrobial agents added to the plastic during processing must, therefore, be heat stable, easy to disperse in a molten polymer and for some processing technologies should also be capable of incorporation into the plastic during the melt processing at temperatures above 130°C.
  • Antimicrobial agents that are applied onto surfaces from solution or other means should have the ability to strongly adhere to the surface they are applied to without exhibiting any leaching-out or surface- delamination.
  • quaternary ammonium derivatives may be employed in the manufacture of plastics having antimicrobial properties, with minimal or no loss in the antibacterial activity.
  • the quaternary ammonium derivatives have been shown to sustain high- temperature melt processing and be used in the preparation of antimicrobial polymer structures and compositions that may be easily applied onto common plastic or other surfaces and possess durability and antimicrobial activity when in contact with water.
  • an objective of the present invention to provide a method for the preparation of an antimicrobially effective article coated with or embedded with a polymeric host, with the antimicrobially effective article possessing:
  • a process for manufacturing of an article e.g., a polymeric article, having antimicrobial properties, said process comprising:
  • composite particles a composite (herein referred to as composite particles) of:
  • At least one negatively charged (anionic) material at least one polymer having at least one antimicrobially active quaternary ammonium group chemically bound thereto; bonded to the nitrogen atom of said ammonium group is one linear alkyl having between 4 and 18 methylene carbons and optionally one or two short alkyl groups, e.g., methyl groups, said nitrogen atom having at least one bond to said polymer. to thereby obtain a flowable host polymer comprising a plurality of composite particles; and
  • the process further comprises the step of drying said at least a portion of said article coated with the flowable host polymer to thereby obtain a solid polymeric coat of antimicrobial polymer on at least a portion of the surface of said article.
  • the "host polymer in a physical state allowing application” is a polymer in a flowable state or form, namely having the ability to flow as a liquid.
  • the host polymer used may thus be dissolved in a carrier to afford a solution, a suspension or a dispersion (such as nano- or micro-emulsion or dispersion), the host polymer may be used as a gel, neat or as a gel in one or more liquid carrier or the host polymer may be used as a melt.
  • the melt temperature of a polymer be it a low-melting or a high melting polymer, as known to a person skilled in the art, is the temperature at which the polymer melts and flows.
  • the melt temperature of various polymers varies depending on the physical characteristics of the polymer it self. Typically, at temperatures below the melt temperature the polymer may be molded to the desired shape or article.
  • the host polymer is, in some embodiments, different from the polymer bearing the antimicrobial active groups and the matrix polymer which are recited herein.
  • the host polymer is typically selected amongst thermoplastic and thermosetting polymers that either form the bulk product or being coated onto a surface.
  • Non-limiting examples of the host polymer which may be suitable in the manufacture of the antimicrobial articles are acetal, acrylic, acrylonitrile, butadiene styrene, cellulosic, chlorinated polyether, fluorocarbons, polyamides (nylons), polycarbonate, polyethylene, ethylene vinyl acetate, polypropylene, polystyrene, melamine, polyetherimide, polysulfone, polyketone, polyacetic acid, polyimide, urea- formaldehyde, phenol formaldehyde, some types of polyurethanes, epoxy, polyester and vinyl resins.
  • the host polymer is selected from polyethylene polymers, acrylic polymers, and copolymers thereof. In other embodiments, the host polymer is a quaternary ammonium bearing polymers based on polyethylene imine (PEI), N 5 N- dialkylaminoethylmethacrylate and chitosan.
  • PEI polyethylene imine
  • N 5 N- dialkylaminoethylmethacrylate N 5 N- dialkylaminoethylmethacrylate and chitosan.
  • the flowable form of the host polymer is a room- temperature solution thereof. In some other embodiments, the solution is at a temperature allowing dissolution of the host polymer or precursors thereof.
  • the flowable form of the host polymer is its melt form.
  • the temperature of the melt may be, in some embodiments, between about 120°C and 200 0 C. In other embodiments, the melt temperature is between about 130 0 C and 19O 0 C. In yet further embodiments, the melt temperature is between about 14O 0 C and 180 0 C and in still other embodiments, the melt temperature is between about 150 0 C and 170 0 C.
  • the mixing of the composite particles in the flowble host polymer can be achieved using equipment employed in the manufacturing of polymers and coating compositions.
  • High shear mixing may be used, for example, where the composite particles tend to agglomerate.
  • the composite particles may be added neat, as a mixture with an inert carrier or pre-blended in a polymeric matrix, namely a low-melting polymer.
  • the plurality of composite particles are pre-blended in a low-melting polymer (the so-called matrix) prior to the mixing into the host polymer melt or a solution.
  • the low-melting polymer is chosen so as to have a melting temperature at which the composite particles of the invention do not deteriorate nor their antimicrobial potency diminished upon addition to the melt.
  • the pre-blending may be achieved by heating the matrix, i.e., a low-melting polymer to its melting temperature, adding the particles thereto and allowing the mixture to cool down, e.g., while stirring.
  • the resulting cooled polymeric matrix having been embedded with the composite particles may be further processed to afford the matrix in a form suitable for addition into the melt of the high-melting host polymer.
  • the low melting polymer has a melt temperature between 60 and 120 0 C.
  • the low-melting polymer is selected from low melting polyethylene, polypropylene, poly(ethylene vinyl acetate), plasticized poly(viny chloride), polystyrene and other commercial polymers in a form having a melting temperature at temperatures below 120 0 C.
  • the invention provides a process for manufacturing an article, e.g., polymeric article, having antimicrobial properties, said method comprising:
  • At least one negatively charged (anionic) material e.g., clay nanoparticles
  • the process may further comprise drying of the coated article surface to obtain a solid coat having antimicrobial properties on at least a portion of the surface of the article.
  • the melt may be allowed to cool down to a temperature below its melting temperature to allow solidification and optionally further molding.
  • the solid host polymer that results, now embedded with a plurality of the composite particles may be used to coat at least a portion of the surface of an article, or may itself be used, as further discussed below, as an antimicrobial polymer for direct manufacture of such polymeric articles.
  • the application of the solution to at least a portion of the article's surface may be by any application method known in the art, including in a non-limiting fashion: brushing, spraying, dipping, spin-coating and elctrodeposition.
  • the solution to be applied onto the surface of the article may further comprise the neat antimicrobial polymer (as used in the composite particle), a mixture of composite particles embedded within another soluble bioactive polymer, and/or a mixture of particles in an inert polymer coating.
  • the host polymer itself, having, as defined above, at least one antimicrobially active quaternary ammonium group chemically bound thereto; wherein the nitrogen atom of said ammonium group is bonded to one linear alkyl having between 4 and 18 methylene carbons and optionally one or two short alkyl groups, e.g., methyl groups, said nitrogen atom having at least one bond to said aliphatic polymer, exhibits antimicrobial activity and thus may be used neat, not as part of a composite particle. In such embodiments, the host polymer is used neat to coat the surface of the article.
  • the host polymer comprises a plurality of composite particles of different polymers.
  • embedded or any lingual variation thereof, refers to a mixture of a first component, e.g., a polymer being the host polymer or the matrix polymer, and a second component, e.g., a plurality of particle composites in any form.
  • the term should be considered in its broadest definition.
  • the particle composites are "pre-blended", it is meant that they are first added to a low-melting polymer, the so-called matrix, and prior to the addition into the melt of the high melting polymer.
  • pre-blended should not be regarded as having any meaning vis-avis the homogeneity, dispersability or activity of the particle composite in the low- or high-melting polymer.
  • the flowable host polymer in its melt state or in a solution, is treated with at least one additional additive selected in a non-limiting manner from flame retardants, smoke suppressors, anti- dripping agents, anti-oxidants, curing agents, pigments, dyes, colorants, color stabilizers, IR reflectors, mold inhibiting agents, lubricants, coupling agents, sealants, friction modifiers, biocides, additives to improve surface feel and/or roughness, and additives to reduce abrasion resistance.
  • at least one additional additive selected in a non-limiting manner from flame retardants, smoke suppressors, anti- dripping agents, anti-oxidants, curing agents, pigments, dyes, colorants, color stabilizers, IR reflectors, mold inhibiting agents, lubricants, coupling agents, sealants, friction modifiers, biocides, additives to improve surface feel and/or roughness, and additives to reduce abrasion resistance.
  • polymer making up a composite particle and recited as bearing the antimicrobial active groups is characterized as being either aliphatic or aromatic having amine groups or aniline groups that may be substituted with various side groups, including, but not restricted to, aromatic side groups having a pyridine side group.
  • Aliphatic polymers that may be included in particles according to the present invention may also comprise heteroatoms such as N, O and S, as part of the polymeric backbone or as side groups.
  • Non-limiting examples of such polymers are polyethylene imine (PEI), polyvinyl amine (PVA), poly(allyl amine) (PAA), poly(aminoethyl acrylate), aminomethyl styrene polymers, poly(vinylpyridine) and its copolymers, poly(vinylaniline) and its copolymers, polymers possessing aniline or aromatic amine groups, polypeptides with pendent alkyl-amino groups, and chitosan.
  • PEI polyethylene imine
  • PVA polyvinyl amine
  • PAA poly(allyl amine)
  • PA poly(aminoethyl acrylate)
  • aminomethyl styrene polymers poly(vinylpyridine) and its copolymers
  • poly(vinylaniline) and its copolymers polymers possessing aniline or aromatic amine groups
  • polypeptides with pendent alkyl-amino groups and chitosan.
  • the polymer is PEI, poly(vinyl pyridine) or poly(vinyl aniline).
  • the term "quaternary ammonium group” refers to a group of atoms consisting of a nitrogen atom with alkyl groups attached thereto, wherein each of the alkyl groups is attached to the nitrogen atom through a carbon atom. Any number of the alkyl groups (0, 1, 2, 3, or 4) may be a portion(s) of the polymeric backbone.
  • the further substitutions on the nitrogen atoms are of an organic residue having at least 4 carbon atoms and optionally one or two short alkyl groups having between 1 and 4 carbon atoms, e.g., having 1, 2, 3, or 4 carbon atoms.
  • the short alkyl group is a methyl group.
  • the polymer possesses aniline, pyridines or other aromatic amine groups (one or more) or imidazoles or combinations thereof, e.g., poly(vinylpyridine) and its copolymers, poly(vinylaniline) and its copolymers.
  • the substitution on, e.g., the pyridine may not require the substitution of one or two short alkyl groups such as methyl groups, thus rendering the substitution by such short alkyls as optional.
  • substitution by one or more short alkyls may not be necessary as substitution by only one organic residue, as defined next, suffices to transform the pyridine into a quaternary pyridinium group having antimicrobial properties.
  • the organic residue may be selected from a linear alkyl chain of 4 to 18 methylene groups, optionally substituted; polyethyleneglycols (PEGs); block copolymers of ethylene glycol and propylene glycol; polyethylene glycole - lipid conjugates, steroid residues such as cholesterol or ergosterol residues and benzyl derivatives.
  • PEGs polyethyleneglycols
  • block copolymers of ethylene glycol and propylene glycol polyethylene glycole - lipid conjugates
  • steroid residues such as cholesterol or ergosterol residues and benzyl derivatives.
  • quaternary ammonium groups may be of the following forms:
  • each of the -CH 3 groups shown in the above drawings is shown as such for the sake of clarity and brevity and may be replaced by any other short alkyl group having between 1 and 4 carbon atoms.
  • the polymer is referred to as a polyamine or polyimine.
  • the substitution of the polyamine may be ranging from 0.01% of the amine groups to 100% of the amine groups. In one embodiment, the substitution ranges between 0.01% and 99% of the amine groups of the polyamine. In another embodiment, the substitution is between 0.1% and 80% of the amine groups. In another embodiment, the substitution is between 0.1% and 10% of the amine groups. In still another embodiment, the substitution is between 10% and 99% of the amine groups.
  • the amine groups of the polyamine may be further substituted with at least one antimicrobial drug or at least one antimicrobial bioactive agent, thereby increasing the overall effect of the particles or matrices of the invention.
  • drugs or bioactive agents are from the group of aminoglucosides, tetracyclines, macrolides, sulfonamides, cyclic polypeptides, penicillin and other antimicrobial agents.
  • Specific drugs include gentamicin, amphotericin B, grisfulvin, azol derivatives, and antiviral agents such as acyclovir.
  • Other non-selective antimicrobial agents such as benzoic acid and salicylic acid are considered.
  • substitution of the drug or active agent onto the polymer bearing the antimicrobial active groups may be via the amine group of the polymer and a native functional group of the active agent or via any other group on the polymer or the active agent.
  • the substitution may be via covalent bonding or via any other type of bonding.
  • substitution of the active agent onto the polymer requires functional group transformation, such may be achieved either via modification of the polymer chain or the active agent, provided that such modification does not diminish the potency of the active agent.
  • substitution may be of 0.01% to about 5% of the amine groups.
  • the resulting quaternary ammonium groups are positively charged, their charge is typically balanced with at least one anion.
  • an anion may be organic or inorganic, a single atom anion or a multiatom anion.
  • Non-limiting examples of such an anion are nitrate, chloride, fluoride, phosphate, acetate, fumarate, succinate, salicilate and sulfate.
  • complexation of the ammonium groups with antimicrobial agents such as iodine in the I 3 " form or iodofors and chlorofors is also possible.
  • antimicrobial agents such as iodine in the I 3 " form or iodofors and chlorofors
  • Mixtures of such particles that have either optional residues at high concentration per particle with particles containing quaternary ammonium groups can be used to obtain a synergistic effect.
  • the complexation is achieved by immersing the particles is an aqueous solution of I 2 and KI at a 1 :2 molar ratio for one hour.
  • the iodine content may be varied, e.g., by shorter or longer immersion periods.
  • the amine groups or ammonium groups may be an integral part of the polymer, i.e., having a polyamine structure, or may be associated with the backbone of the polymer chain, preferably via covalent bonds.
  • the aliphatic polymer is a polyamine or polyimine.
  • the polymer is substituted with one or more amine groups.
  • the polymer is bonded to a polyamine and in yet other embodiments, the polymer is bonded to a polyamine, both being substituted by one or more amine groups.
  • said at least one polymer is a cross-linked polymer, which may be either naturally crosslinked or modified according to procedures known in the art.
  • Crosslinking as may be known to a person skilled in the art of polymer science, may be affected by various agents and reactions that are per se known in the art. For example, crosslinking may be affected by alkylating the polymer chains with dihaloalkane such as dibromoethane, dibromocyclohexane, or bis- bromomethylbenzene.
  • crosslinking may be carried out with aromatic dicarboxylic acids or diisocyanates such as terephthalic acid, phenylene diisocyanates and phenylene dialdehyde.
  • crosslinking by reductive animation may be used.
  • a polyamine with primary amines is reacted with a diketone or with an alkanedialdehyde to form an imine which is then further hydro genated to the corresponding amine.
  • This amine may be further reacted to form an antimicrobial effective quaternary ammonium group.
  • dihaloalkanes or dialdehydes one may use a tri- or polyhaloalkanes, polyaldehydes or polyketones.
  • crosslinking may be affected by amidation with di- or multi-carboxylic acids.
  • Crosslinked polyamines may also be prepared from the monomers where a crosslinking agent is added to the polymerization mixture.
  • a crosslinking agent is added to the polymerization mixture.
  • crosslinked polyethylene imine (PEI) may be prepared by polymerization of aziridine in the presence of a low percentage of a bisaziridine that serves as crosslinking agent.
  • polyamines employed in the present invention include: crosslinking of aliphatic and aromatic polyamines such as polyethyleneimine and poly(4-vinyl pyridine) via a dihaloalkane; polyethylneimine and polyvinylamine; mixture of linear short chain and branched high molecular weight polyethyleneimines; interpenetrating combinations of polyamine within a polyamine scaffold such as polyethyleneimine embedded within crosslinked polyvinyl pyridine nanoparticles, or a polyamine into a low density non-amine scaffold such as polystyrene nanoparticles.
  • polyamine combinations for forming particles of the invention by either chemical crosslinking or physical crosslinking (interpenetrating networks) may afford materials of varying properties, e.g., the ability to better kill one type of bacteria versus another type of bacteria.
  • the preferred degree of cross-linking is from 1% to 20%, when crosslinking of from about 2% to about 5% is more preferred.
  • the crosslinking may prevent unfolding of the polymer and separation of the various polymeric chains that form the particle.
  • the polymers useful for making composite particles according to the invention are those having chains made of at least 1,000 monomer units, or 10,000 monomer units optionally being crosslinked using less than 10% of crosslinking agent. The longer the polymers are, the fewer crosslinking bonds are needed to afford a particle. Branched polymers are used for crosslinking as small amount of crosslinking is required to form insoluble particles. Aromatic crosslinkers may be used for improved thermal stability. Chemical crosslinking with polyhaloalkyl molecules are beneficial but amidation with benzene dicarboxylic acid diisocyanates and dialdehydes or other polycarboxylic acids are also useful. Physical crosslinking by salt formation with polyacids are also considered.
  • each of said plurality of composite particles is composed of a negatively charged core and a coating of at least one aliphatic polymer having antimicrobially active quaternary ammonium groups chemically bound thereto, as defined hereinbefore.
  • each of said plurality of composite particles is composed of a negatively charged material in the form of a particulate having negatively charged surface.
  • said particulate having negatively charged surface is selected from clay particles such as kaoline clay, bentonite clay, etc.; silicon-based particles; ceramic-based particles; mineral-based negatively charged particles; organic particles such as alginates, hyaluronic acid, sulfated polysaccharides and polystyrene (e.g., in the form of crosslinked beads), acrylic and methacrylic acid homopolymers and copolymers.
  • the particulate having negatively charged surface is a clay particle or silicon or alumina-based particle.
  • the clay particle is preferably selected amongst montmorillonite, sodium montmorillonite, magnesium montmorillonite, calcium montmorillonite, nontronite, beidellite, volkonskoite, hectorite, saponite, sauconite, sobockite, kaolinite, svinfordite, vermiculite, magadiite, kenyaite, mica, talc, phyllosilicate, and mixtures thereof.
  • said clay particle is sodium montmorillonite.
  • the negatively charged particulate is an insoluble polymer having negative surface-exposed charges.
  • the composite particle employed by any of the processes of the invention has a core-shell structure, wherein said core is negatively charged and said shell is positively charged.
  • the shell may or may not fully coat the core.
  • the negatively charged material is in the form of a negatively charged particulate and the positively charged polymer is in the form of a positively charged particulate.
  • the association between the negatively charged and positively charged particulates to form the particle composite of the invention may be an electrostatic interaction which may have dependency on the extent of charge and charge distribution of one charged particulate versus another (or opposing) charged particulate.
  • the negatively charged particulate is at least one clay particle associated with at least one aliphatic polymer having antimicrobially active quaternary ammonium groups chemically bound thereto, as defined hereinbefore.
  • said at least one aliphatic polymer having antimicrobially active quaternary ammonium groups chemically bound thereto is in the form of a particulate.
  • the association between such particulates may be of any ratio and may be controlled for example by such as varying the charge density on each of the particulates, by varying the concentration of the different particulates, by employing specific conditions which would favor one ratio over another, or by imposing a certain chemical association or distance between the particulates.
  • the percent ratios between the negatively charged and the positively charged particulates is such to impair the composite particle employed by the processes of the invention with the heat stability necessary to allow it to be incorporated, as some embodiments of the processes require, in a polymer matrix by e.g., melt processing while maintaining high antimicrobial activity against a wide range of pathogens. Such ratios may be determined by a person skilled in the art based on the specification of the product.
  • each of the plurality of the particles employed in the method of the invention composes between 1% (w/w) to 150% (w/w) of said negatively charged material, e.g., in a particulate form. Li other embodiments, the particle composes between 5% (w/w) to 50% (w/w) of said negatively charged material, and in another embodiment, the particle composes between 5% (w/w) to 30% (w/w) of said negatively charged material.
  • the association between the particulates may be via complexation, electrostatic interaction, van der Walls interactions, hydrogen bonding, etc.
  • the composite particle of the invention is of the nanoscale size, hi some embodiments, the composite particle is between 100 to 10,000 nm in size. In other embodiments, the composite particle is between 150 and 2,000 nm in size. In yet other embodiments, the composite particle is between 200 and 500 nm in size.
  • the size of a composite particle is given in terms of its diameter - if the particle is spherical, or in equivalent terms, in case the particle is not spherical. Equivalent terms may for example be the average of the length of the main axes of the particle, or the third root of its volume.
  • the composite particles employed by the processes of the invention may be one comprising, for example, at least one antimicrobially active quaternary ammonium group chemically bound thereto, as defined hereinabove.
  • a composite particle comprising a negatively charged particulate, as defined hereinbefore, and at least one polymer having at least one antimicrobially active quaternary ammonium group chemically bound thereto, the nitrogen atom of the ammonium group is bonded to one linear alkyl having between 4 and 18 methylene carbons and optionally to one or two short alkyls, e.g., methyl groups, said nitrogen atom having at least one bond to said aliphatic polymer.
  • a composite particle comprising at least one clay particle and at least one polymer having at least one antimicrobially active quaternary ammonium group chemically bound thereto, the nitrogen atom of the ammonium group is bonded to one linear alkyl having between 4 and 18 methylene carbons and optionally to one or two short alkyls, e.g., methyl groups, said nitrogen atom having at least one bond to said polymer.
  • an alkyl chain having between 4 and 18 carbon atoms should be considered to have specifically disclosed sub-ranges such as from 4 to 17, 4 to 16, 4 to 15, 4 to 14, 4 to 13, 4 to 12, 4 to 11, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 5 to 18, 5 to 17, 5 to 16, 5 to 15, 5 to 14, 5 to 13, 5 to 12, 5 to 11, 5 to 10, 5 to 9, 5 to 8,
  • the one linear alkyl group having between 4 and 18 methylene carbons is selected from butyl, pentyl, hexyl, heptyl, octyl, nonyl and undecyl. In other embodiments, the one linear alkyl group having between 4 and 18 methylene carbons which is selected from heptyl, octyl, nonyl or undecyl. In yet other embodiments, the one linear alkyl group having between 4 and 18 methylene carbons is octyl.
  • the one linear alkyl group having between 4 and 18 methylene carbons which is bonded to the nitrogen atom of the ammonium group varies along the polymer.
  • the polymer composes a plurality of ammonium groups having different linear alkyl groups of between 4 and 18 methylene carbons.
  • one of a plurality of ammonium groups may bear a butyl group, while another ammonium group on the aliphatic polymer may bear a dodecyl group.
  • the polymer may compose of, e.g., 10% of ammonium groups bearing alkyl groups having, e.g., 12 carbons and, e.g., 30% of the ammonium groups bearing alkyl groups having, e.g., 16 carbon atoms.
  • composite particle whether used in connection with any process of the invention or the particles of the invention, thus refers to, in its broadest definition, to a composite of one or more negatively charged particulates (or materials in any solid form) and one or more positively charged particulates (or materials in any solid form), as defined herein.
  • the composite particle has a negatively charged core and a positively charged shell.
  • the composite particle is composed of a plurality of negatively and positively charged particulates, associated through complexation. It should be clear to a person skilled in the art that such association may result in a charge balance or in a charged composite or a complex depending on the ratios between the charged particulates.
  • each such particulate is on average of the nanoscale size.
  • the composite particle of the invention is of the nanoscale size.
  • the particle composite is between 100 to 10,000 nm in size, between 150 and 2,000 nm in size, or between 200 and 500 nm in size.
  • the size of a particle composite is given in terms of its diameter - if the particle is spherical, or in equivalent terms, in case the particle is not spherical. Equivalent terms may for example be the average of the length of the main axes of the particle, or the third root of its volume.
  • a processes for the preparation of a composite particle (or a plurality of particles) of the invention comprising mixing a negatively charged (anionic) material with at least one polymer having antimicrobially active quaternary ammonium groups chemically bound thereto, as recited above, in a desired ratio, to obtain the particles of the invention.
  • the negatively charged material is clay particulates and the method comprises mixing said clay particulates with at least one polymer having antimicrobially active quaternary ammonium groups chemically bound thereto, in a desired ratio, to obtain the particle composites of the invention having clay core associated with at least one polymer having antimicrobially active quaternary ammonium groups chemically bound thereto.
  • the negatively charged material is clay particulates and the positively charged polymer is in the form of a positively charged particulate and the method comprising mixing said clay particulates with said positively charged particulates, in a desired ratio, to obtain the particle composites of the present invention.
  • the mixing of the two materials or particulate materials is typically performed at room temperature or at a higher temperature which is suitable for such association.
  • the amount of each material, which is used, will vary depending on the desired final characteristics of the particle composite. Such characteristics may for example be dependent on any one of the following considerations:
  • the thermal stability of the resulting particle composites of the invention is improved, e.g., by 15°C. Higher content improved the heat stability even more.
  • Mixing with silica particulates in place of clay particulates provided a similar effect.
  • the stability of the antimicrobial groups was tested vis-avis the replacement of counter ions.
  • iodide as a counter ion, was replaced with a phosphate group, heat absorption was observed at 23O 0 C. No change in the heat absorption at temperatures below 230°C.
  • the iodide complex showed heat absorption starting at 133°C with a peak at 15O 0 C and heat absorption of -38 1/Jg.
  • Salicilate salts showed heat absorption onset at 200 0 C with a small peak at 169°C and heat absorption of -71 1/Jg. Similar results were obtained for the acetate and sulfate derivatives.
  • the composite particles employed by the processes of the invention or the composite particles of the invention, prepared as detailed hereinbefore, may be further derivatized by conjugation, e.g., through the free amino groups (namely the primary, secondary or tertiary amino groups) or any other functional group on the surface of the particle composite with organic residues of choice.
  • the modification of the composite particle may also be achieved by associating the particle composites with organic residues, wherein such association is not via covalent bonding but rather via complexation, electrostatic interaction, hydrogen bonding and other chemical or physical interactions.
  • the organic residues may be selected, in a non-limiting manner, from long alkyl chains, long PEG residues, benzyl groups or steroid residues, as defined above.
  • the present invention also provides a process for the preparation of a modified composite particle, said method comprising obtaining a composite particle according to the invention and modifying it as described hereinbefore.
  • the so-modified composite particle is referred to herein as a modified composite particle.
  • modified composites particle of the invention are also heat stable and so can be thermal processed into common plastics without rendering the particles or modified particles inactive. Therefore, where the use of composite particles of the invention is mentioned, modified composite particles may be used instead or in a combination with the non-modified particle composites.
  • composite particles (modified or non-modified) of the invention suitable for a great variety of applications, particularly in the manufacture of plastic materials that possess antimicrobial surfaces.
  • the composite particles of the invention may be incorporated into a low melting polymer plastic, e.g., at temperatures below 125°C, at a high concentration, thereby obtaining a master batch which may be then incorporated into a polymeric host at a melt molding process temperature, e.g., of between 160° and 200°C.
  • a melt molding process temperature e.g., of between 160° and 200°C.
  • the dispersion of the composite particle in the host may be improved because the compatibility of the low-melting matrix with the host is selected as such to be higher than the compatibility of matrix with the particles.
  • the composite particles of the invention are sufficiently prevented from agglomerating and localizing in the host, so that they can be dispersed homogeneously therein. This leads to a sufficient improvement of antimicrobial activity and mechanical strength of the antimicrobial molded products.
  • the manufacturing cost may also reduce since the minimum amount of the antimicrobial particle composites in the host is required to show the certain level of desired antimicrobial activity. As such, since the particles are dispersed homogeneously in the polymer, the need for dispersing or slipping agents in the manufacturing process of the antimicrobial molded products may be diminished.
  • the distribution of the composite particles of the invention in the polymer away from the outer surface, that is, their bulk concentration, may be similar to that on the outer surface.
  • the particles occupy at most about 20% of the surface of the matrix, between 1% and 15%, between 1% and 5% or about between 1% and 3% of the surface of the matrix.
  • the polymeric matrix embedding particle composites of the invention should have the physical and optical characteristics that are comparable to those of the polymeric host. These characteristics are obtained by using particle composites or pre-blended composites of small enough size, and typically, which for the purpose of maintaining the desired optical properties of the host polymer, by using particles having size that is smaller than the wavelength of light. Particles of up to 300nm in size are preferable for these purposes.
  • Optical characteristics of the embedded matrix and the non-embedded host polymer are said to be comparable if the two have the same refraction index (n) within tolerance of up to 10%, preferably up to 5%, and/or the same absorption coefficient ( " ⁇ ) with tolerance of up to 10%, preferably up to 5%, all in a given range of wave-lengths, preferably, visible light at a range of 400-700 nm.
  • the matrix embedded with the composite particles of the invention may be prepared by adding the composite particles or modified composite particles or pre- blended particles of the invention into the processed polymer melt as detailed above.
  • the term "incorporated", or any lingual variation thereof, refers to combining the article with the particle composites of the invention by physical or chemical means.
  • the article is prepared from molding of the polymer embedded with the antimicrobial composite particle of the invention.
  • the article is incorporated with the particles of the invention by impregnating, dipping, soaking or coating it with an antimicrobial composition containing the particle composites, wherein the composition may be a solution comprising the host polymer and the composite particles, as disclosed above, or the melt of said host polymer, as disclosed above.
  • the article is coated with a polymer (the host polymer) having antimicrobial properties, as disclosed herein.
  • At least a portion of its surface should have antimicrobial, whether by having thereon a coating of an antimicrobial polymer or by having embedded with antimicrobial particles, as disclosed.
  • the expression "at least a portion of a surface” or any lingual variation thereof, refers to any part of a surface of an article.
  • the surface may be the inner surface of an article, e.g., a container and/or its outer surface.
  • the surface may be a two-dimensional surface or a three-dimensional surface of said article.
  • the at least a portion of an article's surface is its inner surface.
  • the at least a portion of an article's surface is the article's complete surface.
  • the surface coating of the article is with an antimixrobial polymer, as disclosed herein, comprising 1-50% (w/w) of PEI or methacrylate antimicrobial nanoparticles.
  • the articles of the invention may be manufactured by various processes, forming useful articles for a multitude of applications. Such manufacturing processes are well known to a person skilled in the art.
  • the articles are polymeric, namely made from a polymer or mixtures thereof.
  • the article may be wholly polymeric or have only a portion thereof made of a polymer.
  • the article may be selected amongst medical devices that may be fabricated from the polymeric matrix of the invention or coated or treated with a polymeric matrix of the invention and include, in a non-limiting manner, microcapsules, dressings, implants, wound closures, staples, meshes, controlled drug delivery systems, wound coverings, fillers, sutures, tissue adhesives, tissue sealants, absorbable and nonabsorbable hemostats, catheters including urinary catheters and vascular catheters, wound drainage tubes, arterial grafts, soft tissue patches, gloves, shunts, stents, tracheal catheters, wound dressings, sutures, guide wires, prosthetic devices, breast implants, cartilage repair devices, orthopedic joint implants, and orthopedic fracture repairs.
  • the articles may also be such that come in contact with aqueous systems, such as bodily fluids in order to prevent or minimize the collection of microorganisms.
  • the article is in a form of a liner, film or sheet which may be cut, further molded or structured, or used as such for a multitude of applications.
  • the article is a preform, closure, container or a reservoir, or any part thereof, for solids or liquids, such as beverage bottles, food containers, kitchen articles, and others which may be of any size or shape and may be adapted for industrial or large scale use or personal small scale use.
  • the article is part of a filtering system where decontamination or growth prevention of biological species is required, as, for example in water supply systems where the containers and delivery devices and tubing have the capability of self deactivate microbial agents.
  • a method for inhibition of "biological species” such as bacteria, parasites, fungi, yeast, protozoa and viruses, by contacting said biological species with a polymeric matrix according to the invention or with a composition comprising the composite particle of the invention.
  • biological species such as bacteria, parasites, fungi, yeast, protozoa and viruses.
  • the inhibition results from the antimicrobial nature of the polymer embedded with a plurality of composite particles or of the article manufactured therefrom.
  • inhibitor is used to denote at least one antimicrobial property, as disclosed herein, such as destruction, i.e., annihilation, of at least 95% of the species, 99% of the species, or 99.99% of the species; reduction in the growth rate of said biological species; reduction in the size of the population of said biological species; prevention of growth of said species; causing irreparable damage to such species; destruction of a biofilm of said biological species; inducing damage, short term or long term, to a part or a whole existing biofilm; preventing formation of such biofilm; inducing biofilm management; or bringing about any other type of consequence which may effect such population or biofilm and impose thereto an immediate or long term damage (partial or complete).
  • Methods of determining microbial stasis or microbicidal effect include, for example, measuring the minimum inhibitory concentrations, zone of inhibition testing, and bacterial adherence testing, using known pathogens for all tests.
  • biofilm refers to a population of biological species attached to a solid surface.
  • a biofilm population can include bacteria, fungi, yeasts, protozoa, and other microorganisms.
  • the inhibition is achieved by contacting the biological species with a matrix containing up to 50% w/w, or up to 1% polymeric particles.
  • a metal precursor or “at least one metal precursor” may independently include a plurality of metal precursors, including mixtures thereof.
  • Example A Antibacterial properties of QA-PEI (quaternary ammonium polyethyleneimine) nanoparticles
  • PEG chains were bound to primary amino groups on the crosslinkd particle at a 0.1 to about 3% of the amino groups by reacting activated PEG chains of molecular weight of 1000, 2000 and 5000, with either one chain end or both chain ends activated by an aldehyde, isocyanate or reactive carboxylate end groups that are easily bound to primary amino groups.
  • PEG chains with reactive carboxylate group were prepared by reacting PEG with maleic anhydride in toluene at 60 0 C for 3 hours and precipitating the PEG in methanol.
  • the carboxylate end groups were activated by DCC and NHS coupling agents.
  • PEG hydroxyl end groups were reacted with hexamethylene or toluene diisocyanate which was then bound to the amino groups of the PEI particles via a urea bond.
  • Aldehyde terminated PEGs were obtained either by direct oxidation or by binding of amino terminated PEG with glutaraldehyde.
  • N-alkylation was conducted as follows: bromooctane (9.8 ml) was added at a 1 :0.25 mole ratio (PEI unit to alkylation agent). Alkylation step was carried out under reflux conditions for 24 hours. Excess Of NaHCO 3 (1.25 equimolar, 0.065 mol, 5.5 g) was added to neutralize HBr released. Neutralization reaction was continued for 1 to 3 hours at the same conditions. Methylation was carried out with 43 ml of methyl iodide (0.68 mol) which was added at 1:3 mole ratio (PEI monomer unit to methyl iodide) at 6O 0 C for 48 hours.
  • N-alkylation was conducted as follows: iodooctane (9.8 ml) was added at a 1:0.25 mole ratio (PEI unit to alkylation agent). Alkylation step was carried out under reflux conditions for 24 hours. Excess Of NaHCO 3 (1.25 equimolar, 0.065 mol, 5.5 g) was added to neutralize the formed HI. Neutralization reaction was continued for 3 hours at the same conditions. Methylation was carried out with 43 ml of methyl iodide (0.68 mol) which was added at 1:3 mole ratio (PEI monomer unit to methyl iodide) at 60 0 C for 48 hours.
  • Samples were determined also by a Fischer melting point apparatus which showed change in the particles' color from white to yellowish at temperatures above 13O 0 C. At 15O 0 C the color of the particles turned light brown and at 17O 0 C the particles were fully brown in color.
  • the nanoparticles were placed at 14O 0 C at room air and the antimicrobial activity of particles removed after 5, 10, 15 20, 30 and 60 minutes was determined using the methods described below. A decrease of about 0, 10, 30 50, 60 and 100% of the original antimicrobial activity was monitored, respectively.
  • the purpose of further studies is to prepare polyethylene surfaces exhibiting strong antibacterial effect.
  • the formulation is prepared by mixing QA-PEI particles with previously melted polyethylene at its melting point.
  • One of the difficulties of this step is low thermal stability of the QA-PEI particles.
  • Thermal behavior of the QA-PEI particles was evaluated using differential scanning calorimetry (DSC) analysis. According to DSC, QA-PEI particles change their physical or chemical structure at temperatures between 135°C and 141 0 C, and decomposed at temperatures between 219 0 C and 232 0 C.
  • DSC differential scanning calorimetry
  • To evaluate heat resistance of the QA-PEI particles were exposed to heat of 12O 0 C to 15O 0 C for between 15 to 30 min under air and inert conditions. Their antibacterial effect was examined against S. aureus.
  • the bacteria S. aureus was incubated overnight at 37 0 C in a growth medium.
  • test bacteria suspension was prepared by using an appropriate dilution stock suspension with TBS. Bacterial suspension was adjusted to an optical density of 0.15 at 595 nm by a 1:5 dilution from the source stock. A working suspension was then prepared by further dilution of 1:125 with an appropriate medium.
  • Each antimicrobial agent-containing well (i.e. PEI active nanoparticles) and each agent-free control well was inoculated with 50 ⁇ l ( ⁇ 105 bacteria) of the working suspension of S. aureus. Bacteria were exposed to various concentrations (0-40 ⁇ g) of the PEI antimicrobial compound for 24 h at 37 0 C. The microti ter plate (96- wells flat bottom plate) was incubated at 37°C for 24 hours.
  • bacterial outgrowth was estimated by changes in optical density (OD) which measured at 595 nm every several hours for 24 h. All the experiments were performed in triplicate and the mean values were calculated. According to OD results, no bacteria growth was detected with compounds heated to 12O 0 C for up to 30 min and with compounds exposed to 15O 0 C for 5 min, while prolong exposure to 15O 0 C resulted in a loss of the antibacterial activity. In addition, thermal degradation of QA-PEI particles at 13O 0 C and 140 0 C for 30 min under inert conditions did not significantly decrease their antibacterial properties.
  • Example B Stabilization of nanoparticles by Incorporation of Na-motmorillonite into QA-PEI
  • Thermal stability of the QA-PEI particles can be improved using adsorbed QA-
  • QA-PEI dispersed in 8 ml of DDW was mixed with 6 mg of Na- montmorillonite dispersed in 2 ml of DDW and the obtained suspension was lyophilized to dryness. Yield: 99 % (w/w).
  • QA-PEI as well as QA-PEI-motmorillonite showed complete decay of the bacteria within several hours at 10 ⁇ g per well. Samples of QA-PEI Na-montmorillonite particles heated at 15O 0 C for 15 minutes were significantly more active than QA-PEI.
  • mixtures containing 20% and 50% w/w of the clay nanoparticles were prepared.
  • low melting point PE containing 1% QA-PEI and with clay nanoparticles where heat mixed with high melting PE (17O 0 C).
  • the mixing time for all samples was set at 10 minutes.
  • QA-PEI loaded in high melting PE lost their antimicrobial activity while high meting PE loaded with 6, 20 and 50% clay nanoparticles show antimicrobial effect which was higher for the 20% clay content. All samples prepared from pre- compounding with low melting point PE (125 0 C) showed antibacterial activity close to the expected activity.
  • silica gel 60 (40-63 ⁇ m particle size), silica gel 45 (4.4-5.4 ⁇ m) and silica gel 100 (200-500 ⁇ m). Particles loaded with antibacterially active particles that are in the size of the silica particles.
  • Polystyrene beads (0.5% crosslinked with divinylbenzene, 200 micron average particle size) loaded with PEI were prepared in a similar way where the silica particles were replaced with polystyrene beads.
  • N-alkylation was conducted as follows: bromooctane (9.8 ml) was added at 1:0.25 mole ratio (PEI unit to alkylation agent). Alkylation was carried out under reflux conditions for 24 hours. Excess Of NaHCO 3 (1.25 equimolar, 0.065 mol, 5.5 g) was added to neutralize released HBr. Neutralization was continued for 1 to 3 hours at the same conditions. Methylation was carried out with 43 ml of methyl iodide (0.68 mol) which added at 1:3 mole ratio (PEI monomer unit to methyl iodide) at 6O 0 C for 48 hours.
  • Example C QA-PEI particles with PEG chains antimicrobial activity
  • the goal of this study was to evaluate antibacterial properties of QA-PEI against gram-negative and gram-positive bacteria including E. coli and S. aureus, respectively.
  • Bacteria were exposed to various concentrations (0-80 ⁇ g) of the QA-PEI for 24 h at 37 0 C. Decrease in the growth of the bacteria was demonstrated by the reduction in optical density (OD) measured at 595 nm every several hours during experiment.
  • Example D Preparation of QA-PEI particles with cholesterol and ergosterol side groups
  • Cholesteric acid bromoalkyl ester was prepare from the esterification or amination of cholesteric acid with bromo octanol or bromooctanamine and alkylated onto preferably the primary amino groups on polyethyleneimine.
  • Ergosterol was also modified by attaching an alkyl spacer through its hydroxyl group by esterification with bromooctanoic acid.
  • Particles containing 1 to 20% cholesteryl or ergosteryl residues showed a much higher antifingal activity than particles containing octyl or other linear chain alkyl groups.
  • This antifungal activity was related to the specific affinity of the ergosterol or cholesterol to the fungi cell membrane. The antifungal activity was determined against Candida albicans using common methods.
  • Example E Preparation of QA-PEI particles with antibacterial or antifungal drugs
  • Conjugation of amphotericin B to PEI via a reactive alkyl spacer- Conjugation is conducted in DMSO.
  • PEI is added to a solution of amphotericin B and the coupling agent glutaraldehyde or hexamethylene diisocyanate is added dropwise to achieve conjugation of the drug to PEL
  • the particles are separated by decantation and precipitation in water.
  • Aqueous solutions of the sodium or potassium salts of the above anions (10% w/v or IM solutions, 10 ml) were reacted with Ig of quaternary ammonium particles over night at room temperature. The particles were isolated by centrifugation and washed twice with deionized water and dried. The particles were white or off-white. The particles remained with their original particle size and possessed similar antimicrobial activity to the original nanoparticles.
  • the most sensitive to heat was the iodide salt which showed a large peak with onset at 133°C and a peak at 150°C and heat absorption of -38 1/Jg. Another two peaks at 257°C with onset starting at 220°C and at 330°C were noted.
  • Phosphate salt powder showed heat absorption only at 260 0 C with onset starting at 230 0 C and a large peak at 332°C, a flat line in the absorption heat at temperature below 230 0 C.
  • the salicilate salts showed heat absorption peak at 169°C with heat absorption of only -71 1/Jg and peaks at 250 and 336°C. Similar results were obtained for the other salts.
  • Example G Preparation of alkylated poMvinyl pyridine) nanoparticles
  • Nanoparticles of poly(4-vinyl pyridine) copolymer with PEG acrylate and divinyl benzene (DVB) were prepared by emulsion polymerization using benzoyl peroxide (BP) as initiator.
  • BP benzoyl peroxide
  • mixtures of 4-vinyl pyridine (VP) : DVB : PEGlOOO acrylate at a 100:1:0.1-5 w/w ratio and 0.5% BP were added to an aqueous solution of 0.1% polyvinyl alcohol at a 1:20 v/v. The mixture was homogenized to form a uniform thin emulsion.
  • the emulsion was heated to about 60 0 C over night to form a uniform dispersion of the polymer with particle size in the range of 400 nm.
  • the particles were separated by centrifugation and washed twice with ethanol.
  • the particles were dispersed in ethanol (1 :10 w/v) and octyl bromide was added at a 1.2 mole ratio to the pyridine groups and heated to reflux over night.
  • the quaternary pyridinium nanoparticles were separated by centrifugation and washed with ethanol and dried.
  • Different counter ions including: acetate, fumarate, fluoride, phosphate, sulfate and chloride were prepared as described above for the PEI particles.
  • the particles were heated at 180°C for 30 minutes and the antimicrobial activity thereof before and after heating was determined using the procedures described above for PEL No difference in antimicrobial activity between the heated particles and the original particles was found.
  • the particles were found effective after incorporating 1% w/w and 3% w/w in PE by melt process at 180 0 C.
  • Nanoparticles made from 2-vinyl pyridine showed also antimicrobial activity.
  • Other copolymers with hydroxyethyl methacrylate, styrene, and methacrylate derivatives were found effective and suitable for addition to melt plastics with suitable distribution to form a uniform distribution of particles in the plastic surface.
  • pyridinium based nanoparticles were found highly heat stable and did not release any odorous amine derivatives as had been the case with the PEI nanoparticles.
  • Example H Preparation of quaternary alkylated polyvinyl aniline) particles
  • Polymers possessing aniline based quaternary ammonium groups were prepared from polystyrene (PS) nanoparticles as starting material.
  • PS polystyrene
  • Commercially available crosslinked PS were nitrated using common methods for nitration, employing HNO 3 /H 2 SO 4 or other nitration agents.
  • the nitro groups on the polystyrene were reduced by a reducing agent such as Sn or Zinc in an HCl solution or using NaBH 4 as a reducing agent.
  • aniline side groups in the polystyrene beads were reacted with octyl iodide followed by methylation with methyl iodide to form the anilinic quaternary ammonium derivatives.
  • These nanoparticles were heat stable at 180 0 C for at least 30 minutes. No release of amines or change in particles properties were observed. The particles possessed antimicrobial activity as free particles and incorporated in PE.
  • poly(vinyl aniline) copolymers with imidazole or other vinyl monomers were converted into quaternary ammonium derivatives and served as heat stable antimicrobial agents.
  • Example I Preparation of OA- polydiethylaminoethyl methacrylate (TDEAEM) Polymerization of diethylaminoethyl methacrylate was carried out at 70°C in ethanol (4Og monomers per 100ml ethanol) with recrystallized AIBN as initiator (20mg) and with nitrogen continuously bubbled through the reaction medium. The reaction was quenched in cold water and the precipitate was recovered by decantation and vacuum- dried over NaOH pellets.
  • TDEAEM OA- polydiethylaminoethyl methacrylate
  • the dried polymer (1Og) was dissolved in ethanol (10ml) and N-alkylation was conducted using iodooctane at a 1:1.5 mole ratio (monomer to alkylation agent). Alkylation step was carried out under reflux conditions for 24 hours. Excess of NaHCO 3 (1.25 equimolar, 0.065 mol, 5.5 g) was added to neutralize HI released. Neutralization reaction was continued for 1 to 3 hours at the same conditions.
  • Example J Hydrophobic quaternary ammonium PEI and PDEAEM non- particulate polymers
  • Non-crosslinked QA-PEI and QA-PDEAEM were hydrophobized by partially alkylation (10-30%) with octadecyliodide (C 18 I) or partly amidation (5-30%) with oleoyl chloride for increasing hydrophobic properties of the polymer. This step was carried out before quaternarization by alkylation step with iodooctane.
  • the process of making soluble QA-polymers suitable for continuous coating of surfaces is as described above for making particles but without or with low amount of dibromopentane or crosslinking agent when acrylic polymers are used.
  • Another way of increasing solubility in organic solvents is by copolymerization of diethylaminoethyl methacrylate and methylmethacrylate (10%) or ethylmethacrylate (5%), carried out at the same conditions and procedure as described for the QA- PDEAEM.
  • Example K Polymer-coating of a surface of plastic trays for antimicrobial testing
  • QA-PDEAEM was dissolved in chloroform (10mg/ml) and each well was filled with 0.2ml of the polymer solution. The well plate was evaporated in the hood in a few minutes to form a stable film of polymer.
  • the QA-PEI particles and the QA-PEI on silica particles were suspended in 1%EVA in ethyl acetate solution or in 1% QA- PDEAEM in chloroform solution using 5min sonication. Each well was filled with 0.2ml of the polymer suspension and left for a few minutes to evaporate in the hood to form a stable film.
  • the film contains 30%w/w PEI in EVA or QA-PDEAEM. Each film can be repeated to form a multiple layers of polymer in the film for increase polymer concentration.
  • Staphylococcus aureus was incubated overnight at 37°C in a growth medium TSB.
  • the upper volume was centrifuged for lOmin at 5000 rpm and medium was replaced with fresh 5ml of TSB medium. After a short vortex the bacterial suspension was adjusted to an optical density of 0.2 at 650 nm.
  • Serial dilutions were prepared from stock solution (xl ⁇ ⁇ 5 , 5xl0 "6 , xlO "6 ) and seeded on agar plates for incubation (37 0 C) and bacterial count.
  • Each polymer-containing well was filled with ImI of the diluted bacterial suspensions (at duplicates) containing 100-lOOOcfu/ml and left at room temperature for 24 h. After 24h, the bacterial suspensions at each well were seeded on agar plates and incubated (37°C) for bacterial count.
  • QA-PEI nanoparticles, QA-PDEAEM and QA-PEI on silica gel (60 and 45) were found to have bactericidic activity when exposed to 100-lOOOcfu/ml of Staphylococcus aureus bacteria. These results where maintained even after 12 days of water exposure of the wells in the case of QA-PEI nanoparticels and after more than 20 days in the case of QA-PEI on silica gel 60.

Abstract

L'invention concerne un procédé de fabrication d'articles présentant des caractéristiques antimicrobiennes.
PCT/IL2008/001160 2007-08-27 2008-08-27 Polymeres antimicrobiens WO2009027971A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US93569007P 2007-08-27 2007-08-27
US60/935,690 2007-08-27

Publications (2)

Publication Number Publication Date
WO2009027971A2 true WO2009027971A2 (fr) 2009-03-05
WO2009027971A3 WO2009027971A3 (fr) 2009-04-30

Family

ID=40342501

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2008/001160 WO2009027971A2 (fr) 2007-08-27 2008-08-27 Polymeres antimicrobiens

Country Status (1)

Country Link
WO (1) WO2009027971A2 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012025514A1 (fr) * 2010-08-23 2012-03-01 Matera Lda Conjugués nanoparticulaires antimicrobiens
KR20140040102A (ko) * 2011-02-11 2014-04-02 킴벌리-클라크 월드와이드, 인크. 살균 용액과 함께 사용하기 위한 와이프
US9066978B2 (en) 2010-05-26 2015-06-30 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
US9399044B2 (en) * 2014-05-28 2016-07-26 International Business Machines Corporation Antimicrobial cationic polyamines
WO2016146972A1 (fr) * 2015-03-13 2016-09-22 Sheffield Hallam University Matériau antimicrobien
CN107057288A (zh) * 2017-05-22 2017-08-18 安徽三义和能源科技有限公司 一种抗压防火板材的制备方法
EP3269771A1 (fr) * 2016-07-11 2018-01-17 Samsung Electronics Co., Ltd Composites modifiées de pyridinium, et article comprenant ladite composition
US9982121B2 (en) 2016-07-11 2018-05-29 Samsung Electronics Co., Ltd. Pyridinium modified composite, and article including same
US9994443B2 (en) 2010-11-05 2018-06-12 Selecta Biosciences, Inc. Modified nicotinic compounds and related methods
CN110372914A (zh) * 2019-06-27 2019-10-25 浙江中财管道科技股份有限公司 用于pvc管材的钙锌稳定剂及其制备方法
WO2021138144A1 (fr) * 2019-12-30 2021-07-08 Microban Products Company Composition et procédé de lutte antimicrobienne sur des surfaces de matériau
US11134676B2 (en) 2017-08-30 2021-10-05 Nobio Ltd. Anti-microbial particles and methods of use thereof
US11178867B2 (en) 2016-02-25 2021-11-23 Nobio Ltd. Micro and nanoparticulate compositions comprising anti-microbially active groups
CN114796485A (zh) * 2022-02-25 2022-07-29 中南大学湘雅医院 一种Sn纳米片及其复合材料的制备和在声动力抗菌中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006070376A1 (fr) * 2004-12-30 2006-07-06 Hadasit Medical Research Services & Development Ltd. Additifs nanoparticulaires antimicrobiens formant des compositions polymeres non lixiviables a activite antimicrobiennes soutenue
WO2008152417A2 (fr) * 2007-06-12 2008-12-18 Nottingham Trent University Nanocomposites polymères ayant des propriétés antimicrobiennes

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000026212A (ja) * 1998-07-02 2000-01-25 Daicel Chem Ind Ltd 抗菌性粒子及びその製造方法
KR100679358B1 (ko) * 2005-05-25 2007-02-05 주식회사 한화건설 항균제가 결합되어 있는 고분자복합체의 구 및 그의제조방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006070376A1 (fr) * 2004-12-30 2006-07-06 Hadasit Medical Research Services & Development Ltd. Additifs nanoparticulaires antimicrobiens formant des compositions polymeres non lixiviables a activite antimicrobiennes soutenue
WO2008152417A2 (fr) * 2007-06-12 2008-12-18 Nottingham Trent University Nanocomposites polymères ayant des propriétés antimicrobiennes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 200016 Thomson Scientific, London, GB; AN 2000-176830 XP002515540 & JP 2000 026212 A (DAICEL CHEM IND LTD) 25 January 2000 (2000-01-25) *
DATABASE WPI Week 200850 Thomson Scientific, London, GB; AN 2007-706146 XP002515541 & KR 100 679 358 B1 (HANWHA E & C CORP) 5 February 2007 (2007-02-05) *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9764031B2 (en) 2010-05-26 2017-09-19 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
US9066978B2 (en) 2010-05-26 2015-06-30 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
EP2450058A1 (fr) * 2010-08-23 2012-05-09 Matera Lda Conjugués de nanoparticules antimicrobiennes
US20130216600A1 (en) * 2010-08-23 2013-08-22 Matera Lda Antimicrobial nanoparticle conjugates
WO2012025514A1 (fr) * 2010-08-23 2012-03-01 Matera Lda Conjugués nanoparticulaires antimicrobiens
US9994443B2 (en) 2010-11-05 2018-06-12 Selecta Biosciences, Inc. Modified nicotinic compounds and related methods
EP2672873A4 (fr) * 2011-02-11 2015-10-07 Kimberly Clark Co Chiffon à utiliser avec une solution germicide
KR20140040102A (ko) * 2011-02-11 2014-04-02 킴벌리-클라크 월드와이드, 인크. 살균 용액과 함께 사용하기 위한 와이프
AU2012215111B2 (en) * 2011-02-11 2017-05-25 Kimberly-Clark Worldwide, Inc. Wipe for use with a germicidal solution
KR101968771B1 (ko) * 2011-02-11 2019-04-12 킴벌리-클라크 월드와이드, 인크. 살균 용액과 함께 사용하기 위한 와이프
US9399044B2 (en) * 2014-05-28 2016-07-26 International Business Machines Corporation Antimicrobial cationic polyamines
WO2016146972A1 (fr) * 2015-03-13 2016-09-22 Sheffield Hallam University Matériau antimicrobien
US11178867B2 (en) 2016-02-25 2021-11-23 Nobio Ltd. Micro and nanoparticulate compositions comprising anti-microbially active groups
EP3269771A1 (fr) * 2016-07-11 2018-01-17 Samsung Electronics Co., Ltd Composites modifiées de pyridinium, et article comprenant ladite composition
US9982121B2 (en) 2016-07-11 2018-05-29 Samsung Electronics Co., Ltd. Pyridinium modified composite, and article including same
CN107057288A (zh) * 2017-05-22 2017-08-18 安徽三义和能源科技有限公司 一种抗压防火板材的制备方法
US11134676B2 (en) 2017-08-30 2021-10-05 Nobio Ltd. Anti-microbial particles and methods of use thereof
CN110372914A (zh) * 2019-06-27 2019-10-25 浙江中财管道科技股份有限公司 用于pvc管材的钙锌稳定剂及其制备方法
WO2021138144A1 (fr) * 2019-12-30 2021-07-08 Microban Products Company Composition et procédé de lutte antimicrobienne sur des surfaces de matériau
CN114828632A (zh) * 2019-12-30 2022-07-29 美可帮产品公司 用于材料表面上微生物控制的组合物和方法
EP4084615A4 (fr) * 2019-12-30 2024-04-10 Microban Products Composition et procédé de lutte antimicrobienne sur des surfaces de matériau
CN114796485A (zh) * 2022-02-25 2022-07-29 中南大学湘雅医院 一种Sn纳米片及其复合材料的制备和在声动力抗菌中的应用

Also Published As

Publication number Publication date
WO2009027971A3 (fr) 2009-04-30

Similar Documents

Publication Publication Date Title
WO2009027971A2 (fr) Polymeres antimicrobiens
Fazli et al. Controlled release of cefazolin sodium antibiotic drug from electrospun chitosan-polyethylene oxide nanofibrous Mats
Figueiredo et al. Antimicrobial bacterial cellulose nanocomposites prepared by in situ polymerization of 2-aminoethyl methacrylate
EP1984121B1 (fr) Compositions de film tensioactif non sujet à lixiviation pour empêcher une adhésion microbienne
AU2007245897B2 (en) Antiseptic-containing silicone elastomers
Druvari et al. Polymeric quaternary ammonium-containing coatings with potential dual contact-based and release-based antimicrobial activity
EP2454286B1 (fr) Dérivés d hydrogel de chitosane utilisés comme agent de revêtement à activité antimicrobienne à large spectre
AU2009255322B2 (en) Antimicrobial polymers and their uses
Fu et al. Recent advances in hydrogel-based anti-infective coatings
Wang et al. Characterization, antimicrobial activities, and biocompatibility of organically modified clays and their nanocomposites with polyurethane
US20130004586A1 (en) Biologically Efficacious Compositions, Articles of Manufacture and Processes for Producing and/or Using Same
EP2155825A2 (fr) Nanocomposites polymères ayant des propriétés antimicrobiennes
Corrales et al. In vitro biocompatibility and antimicrobial activity of poly (ε-caprolactone)/montmorillonite nanocomposites
KR20130133691A (ko) 접착특성을 갖는 항균 유기 공중합체, 그 유기 공중합체의 제조방법, 그 유기 공중합체가 코팅된 항균 코팅필름 및 그 코팅필름의 코팅방법
Kamaci et al. Biodegradable and antibacterial poly (azomethine‐urethane)‐chitosan hydrogels for potential drug delivery application
Wang et al. Quaternary tannic acid with improved leachability and biocompatibility for antibacterial medical thermoplastic polyurethane catheters
Liu et al. Nanocomposites of genipin‐crosslinked Chitosan/Silver nanoparticles‐structural reinforcement and antimicrobial properties
Arora et al. Polymer based antimicrobial coatings as potential biomaterial: A review
Chen et al. Intensifying the antimicrobial activity of poly [2-(tert-butylamino) ethyl methacrylate]/polylactide composites by tailoring their chemical and physical structures
Thomas et al. Breathing‐in/breathing‐out approach to preparing nanosilver‐loaded hydrogels: Highly efficient antibacterial nanocomposites
Irshad et al. Antimicrobial polymer coating
Guadarrama-Zempoalteca et al. Lysozyme immobilization onto PVC catheters grafted with NVCL and HEMA for reduction of bacterial adhesion
Domb et al. Quaternary ammonium antimicrobial polymers
Rennukka et al. Synthesis of poly (3‐hydroxybutyrate‐co‐4‐hydroxybutyrate)/chitosan/silver nanocomposite material with enhanced antimicrobial activity
WO2015106149A2 (fr) Gel thermique inverse antimicrobien et ses procédés de formation et d'utilisation

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08789832

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 08789832

Country of ref document: EP

Kind code of ref document: A2