WO2011058171A1 - Copolymère hydrophile - Google Patents

Copolymère hydrophile Download PDF

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Publication number
WO2011058171A1
WO2011058171A1 PCT/EP2010/067472 EP2010067472W WO2011058171A1 WO 2011058171 A1 WO2011058171 A1 WO 2011058171A1 EP 2010067472 W EP2010067472 W EP 2010067472W WO 2011058171 A1 WO2011058171 A1 WO 2011058171A1
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WO
WIPO (PCT)
Prior art keywords
coating
coating composition
hydrophilic
copolymer
monomer
Prior art date
Application number
PCT/EP2010/067472
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English (en)
Inventor
Olga Crespo Biel
Onko Jan Gelling
Van Den Edith Elisabeth M Bosch
Alessio Piermattei
Original Assignee
Dsm Ip Assets B.V.
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Publication date
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Publication of WO2011058171A1 publication Critical patent/WO2011058171A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F226/00—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 a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
    • C08F226/06—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 a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
    • C08F226/10—N-Vinyl-pyrrolidone
    • 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
    • A61L29/14—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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M25/0045—Catheters; Hollow probes characterised by structural features multi-layered, e.g. coated
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
    • 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
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A61L2300/206—Biguanides, e.g. chlorohexidine
    • 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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M2005/3117—Means preventing contamination of the medicament compartment of a syringe
    • A61M2005/3118—Means preventing contamination of the medicament compartment of a syringe via the distal end of a syringe, i.e. syringe end for mounting a needle cannula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/329—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles characterised by features of the needle shaft

Definitions

  • the invention is directed to a coating composition comprising a hydrophilic polymer and a copolymer comprising a hydrophilic monomer and a monomer according to the structure X, as defined hereunder, and medical devices comprising the coating.
  • Medical devices are required to be infection resistant.
  • the desirable feature of such medical device is prevention or control of infection that occurs during the application of the device when in contact with body tissue or fluid or when the device is in the body for a longer time.
  • the term medical device as used herein is intended to encompass the full range of devices for intimate contact with the human or other mammalian body, or with the corresponding body fluids, as implants, prostheses, interface devices, surgical equipment and the like.
  • Medical devices in relation to the present invention are in particular intravenous access devices. In the US, physicians insert more than 5 million intravenous access devices every year. Intravenous access devices are normally used in patients in intensive care units for medical administration, parental hyperalimentation as well as for blood sampling.
  • intravenous access devices Unfortunately, the use of intravenous access devices is associated with adverse events that are both hazardous to patients and expensive to treat. More than 15% of the patients who received these devices have had thrombotic and/or infectious complications. Patients who were treated with intravenous access devices are thus at high risk for device-related thrombosis. Bloodstream infections (BSI) related to intravenous access devices are common, costly and potentially lethal. Each year in the US, intravenous access devices may cause an estimated 80.000 device-related BSI and, as a result, up to 28.000 deaths among patients in intensive care units.
  • BSI Bloodstream infections
  • Infections related to intravenous access devices are thought to arise by several mechanisms: infection of the exit site, followed by migration of the pathogen along the external surface of the device; contamination of the device hub, leading to intraluminal colonization in the device and thus spreading infection along the bloodstream, and hematogeneous seeding of the device.
  • a thrombin layer or sheath covers the external and the internal surfaces of the intravascular segment. This layer, which is rich in proteins, promotes adherence of potential microbial pathogens to the surface.
  • Thrombosis related to intravenous access devices and infections related to intravenous access devices can thus not be seen as separate entities. There is thus a need for the development of a coating with antimicrobial properties as well as hemocompatible properties.
  • Biguanidines are compounds containing biguanidine group -HN- C(NH)-HN-C(NH)-NH- and these compounds have been identified as having good antimicrobial activity. Biguanidines have a broad spectrum of anti-bacterial activity. At relatively low concentrations the anti-bacterial action is bacteriostatic. At higher concentrations the action becomes rapidly bactericidal. Guanidine groups (-HN-C(NH)- NH-) also have antimicrobial activity. Although the antimicrobial activity of guanidine compounds is less than for biguanidine compounds, according to the present invention biguanidine compounds can be replaced by guanidine compounds.
  • biguanidine compounds derives from the strongly basic character of their biguanidine groups which form acid addition salts with a cationic charge delocalised over the five neighbouring secondary amine nitrogen atoms. This enables the biguanidine to be rapidly attracted to a negatively charged bacterial cell membrane. Thereafter the biguanidine interacts with the cytoplasmic membrane of the bacterial cell, upsetting the ionic balances and, ultimately, disrupting the membrane and causing irreversible damage to the cell contents.
  • EP-A-0460385 describes polymers containing a biguanidine functionality. These polymers have been used in adhesive compositions, fibers, fabrics, films, bulk polymers, coating systems and sealants among other products to give the products antimicrobial properties.
  • EP-A- 1 175148 polymeric materials are described incorporating an infection resistant biguanidine compound pendant to the polymer chain, being chemically bound thereto through some but not all of the amine nitrogen atoms of the biguanidine group.
  • a hydrophilic coating made by curing the coating compositions according to the invention possess not only hydrophilic and antimibrobial properties, but are hemocompatible as well.
  • a coating composition according to the invention is characterized in that it comprises a hydrophilic polymer and a copolymer comprising a hydrophilic monomer and a monomer according to the structure X
  • the copolymer comprises at least one monomer X and at least one hydrophilic comonomer.
  • the copolymer can contain more than one monomer X and/or more than one hydrophilic comonomer.
  • the monomer X contains a biguanidine moiety to provide
  • the amount of the monomer X in the copolymer can be between 1-99 wt%, preferably 1-60 wt%, more preferably 5-30 wt%.
  • the molecular weight (Mw) of the copolymer preferaby is higher than
  • a higher Mw improves the integrity of a coating containing the copolymer.
  • the R group is a substituted or not-substituted alkyl group or aryl group.
  • the aryl group is, for instance, a phenyl group, a benzyl group or a substituted phenyl or benzyl group.
  • the substituents can for instance be hydrogen, alkyl, aryl, halogen (CI, Br, I), alkoxy or amine substituents.
  • T -H or an unbranched or branched Ci -20 alkyl such as methyl, or t-butyl,
  • n, m, p and q 0 - 99 and m + n + p + q >1 , -CHR'COOH
  • the R group preferably contains a phenyl group.
  • the R 1 group acts as a spacer between the biguanidine group and the polymerizable group Z.
  • the R 1 group can be any kind of group, like an alkyl or aryl group, but generally contains a phenylene group with the polymerizable group Z attached to it.
  • polymerizable Z groups are a vinyl moiety such as (meth)acrylate, n-allyl amide or allyl alcohol; an isocyanate moiety; an epoxy moiety; an aziridine moiety; an amide; a reactive hydrogen carrying moiety such as hydrogen, an alcohol, an amide or an acid; and an aliphatic carbon moiety terminated with any of these reactive hydrogen containing groups.
  • Z is preferaby a (meth)acrylate group.
  • the monomers X can, for instance, be prepared as described by T. Ikeda et al. Antimicrobial Agents and Chemotherapy, Aug. 1984, p. 139-144 or as described in EP-A-0460385.
  • copolymer contains a hydrophilic monomer.
  • a hydrophilic monomer gives the copolymer and the coating comprising the copolymer the properties of swelling and becoming lubricious after wetting.
  • hydrophilic monomers include but are not limited to lactams, for example vinylpyrollidones, urethanes,
  • (meth)acrylates acrylamide, maleic acid, fumaric acid, monomers comprising sulfonic acid, vinyl alcohol, vinylethers, maleic anhydride, vinylamines, ethyleneimines, ethyleneoxides, carboxylic acids, amides, anhydrides, phosphazenes, peptides, sacharrides, esters, for example (meth)acrylates, (vinyl)pyridines, ethyleneimines, lysines, monomers comprising quarternary ammonium salts and mixtures and/or derivatives and/or salts thereof.
  • the hydrophilic monomer preferably is chosen from lactams and
  • (meth)acrylates more preferably the monomer is a vinylpyrollidone.
  • the copolymers can be prepared by methods known to a person skilled in the art. Normally the monomers are copolymerised in the presence of an initiator. The polymerisation conditions that are applied determine the Mw and other properties of the copolymer.
  • a hydrophilic polymer is understood to be a high molecular weight linear, branched or cross-linked polymer composed of macromolecules.
  • the hydrophilic polymer is capable of providing hydrophilicity to a coating and may be synthetic or bio-derived and can be blends or copolymers of both.
  • the hydrophilic polymers include but are not limited to poly(lactams), for example polyvinylpyrollidone (PVP), polyurethanes, homo- and copolymers of acrylic and methacrylic acid, polyvinyl alcohol, polyvinylethers, maleic anhydride based
  • copolymers polyesters, vinylamines, polyethyleneimines, polyethyleneoxides, poly(carboxylic acids), polyamides, polyanhydrides, polyphosphazenes, cellulosics, for example methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, and hydroxypropylcellulose, heparin, dextran, polypeptides, for example collagens, fibrins, and elastin, polysacharrides, for example chitosan, hyaluronic acid, alginates, gelatin, and chitin, polyesters, for example polylactides, polyglycolides, and polycaprolactones, polypeptides, for example collagen, albumin, oligo peptides, polypeptides, short chain peptides, proteins, and oligonucleotides.
  • the hydrophilic polymer has a molecular weight in the range of about 8 to about 5,000 kg/mol, preferably in the range of about 20 to about 3,000 kg/mol and more preferably in the range of about 200 to about 2,000 kg/mol.
  • the hydrophilic polymer may be used in more than 1 wt%, for example more than 10 wt%, more than 25 wt%, or more than 50 wt %, based on the total weight of the dry coating.
  • the hydrophilic polymer can be present up to 95 wt%, however, more often the hydrophilic polymer will be used up to 50, 60, 70 or 80 wt%, based on the total weight of the dry coating.
  • the coating composition according to the invention normally comprises, next to the copolymer and the hydrophilic polymer, also a liquid medium.
  • the polymers form a solution or dispersion in the liquid medium.
  • any liquid medium that allows application of the coating composition on a surface would suffice.
  • liquid media are alcohols, like methanol, ethanol, propanol, butanol or respective isomers and aqueous mixtures thereof or acetone, methylethyl ketone, tetrahydrofuran, dichloromethane, toluene, and aqueous mixtures or emulsions thereof or water.
  • the coating composition also can comprise a supporting polymer comprising a backbone and at least 2 reactive moieties capable of undergoing polymerization reactions.
  • the supporting polymer may also contain hydrophilic functional groups.
  • a supporting network can be formed upon curing said supporting polymer.
  • the reactive moiety of the supporting polymer may be selected from the group consisting of radically reactive groups, such as alkenes, amino, amido, sulfhydryl (SH), unsaturated esters, such as acrylate and methacrylate, unsaturated ethers, unsaturated amides, and alkyd/dry resins.
  • the supporting polymer has a backbone and at least one of the above-mentioned reactive moieties.
  • the backbone of the supporting polymer may be selected from the group consisting of polyethers, polyurethanes, polyethylenes, polypropylenes, polyvinyl chlorides, polyepoxides, polyamides, polyacrylamides, poly(meth)acrylics, polyoxazolidones, polyvinyl alcohols, polyethylene imines, polyesters like polyorthoesters and alkyd copolymers,
  • polypeptides or polysaccharides such as cellulose and starch or any combination of the above.
  • polymers with unsaturated esters, amides or ethers, thiol or mercaptan groups may suitably be used in the invention.
  • the supporting polymer has a number average molecular weight in the range of about 750 to about 20,000 g/mol, preferably in the range of about 1 ,000 to about 15,000 g/mol, more preferably in the range of about 1 100 to about 10,000 g/mol, in particular in the range of about 1200 to about 7000 g/mol, more in particular in the range of about 1400 to about 5000 g/mol.
  • the advantage of using a relatively high molecular weight supporting polymer, i.e. having molecular weight of more than about 750 g/mol, preferably more than about 1000 g/mol, is that a relatively open supporting network will be formed. Such a relatively open supporting network will swell more easily and therewith provide the coating with a higher lubricity and a longer dry-out time.
  • the average number of reactive moieties per molecule of the supporting polymer is preferably in the range of about 1.2 to about 64, more preferably in the range of about 1 .2 to about 16, most preferably in the range of about 1.2 to about 8. This means that apart from supporting polymer molecules comprising at least 2 reactive moieties also supporting polymer molecules comprising 1 reactive moiety, i.e. monofunctional polymers, may be present.
  • the monofunctional supporting polymers may also be part of the formed supporting network.
  • the supporting polymer may be used in more than 1 wt% based on the total weight of the dry coating, for example more than 10 %, more than 20 wt%, more than 30 wt% or more than 40 wt%.
  • the supporting polymer can be present in the coating composition up to 90 wt%, however, more often the supporting polymer will be used up to 50 or 60 wt%, based on the total weight of the dry coating.
  • the weight ratio of hydrophilic (co)polymer to supporting polymer may for example vary between 10 : 90 and 90 : 10, such as between 25 : 75 and 75: 25 or such as between 60 : 40 and 40 : 60.
  • the coating composition according to the invention can be cured in the presence of an initiator.
  • the term "to cure” includes any way of treating the composition such that it forms a firm or solid coating. In particular “curing” is
  • all or part of the components in the coating composition may be cross-linked forming covalent linkages between all or part of the components, for example by using UV or electron beam radiation.
  • all or part of the components may also be ionically bonded, bonded by dipole-dipole type interactions, via Van der Waals forces or hydrogen bonds.
  • the coating composition according to the invention can for example be cured using electromagnetic radiation, for example visible or UV light, electro-beam, plasma, gamma or IR radiation, in the presence of an initiator, for example a photo- initiator or thermal initiator, to form the medical coating.
  • electromagnetic radiation for example visible or UV light, electro-beam, plasma, gamma or IR radiation
  • an initiator for example a photo- initiator or thermal initiator
  • photo-initiators that can be used in the medical coating are free-radical photo-initiators, which are generally divided into two classes according to the process by which the initiating radicals are formed. Compounds that undergo unimolecular bond cleavage upon irradiation are termed Norrish Type I or homolytic photo-initiators.
  • a Norrish Type II photo-initiator interacts with a second molecule, i.e.
  • a synergist which may be a low molecular weight compound of a polymer, in the excited state to generate radicals in a bimolecular reaction.
  • the two main reaction pathways for Norrish Type II photo-initiators are hydrogen abstraction by the excited initiator or photo-induced electron transfer. The mechanisms are further explained in WO06/056482.
  • Polymeric photo-initiators may also be used.
  • the coating composition according to the invention further comprises at least one surfactant, which can improve the surface properties of the coating.
  • Surfactants constitute the most important group of detergent components. Generally, these are water-soluble surface-active agents comprised of a hydrophobic portion, usually a long alkyl chain, attached to hydrophilic or water solubility enhancing functional groups. Surfactants can be categorized according to the charge present in the hydrophilic portion of the molecule (after dissociation in aqueous solution): ionic surfactants, for example anionic or cationic surfactants, and non-ionic surfactants.
  • ionic surfactants include Sodium dodecylsulfate (SDS), Sodium cholate, Bis(2-ethylhexyl)sulfosuccinate Sodium salt, Cetyltrimethylammoniumbromide (CTAB), Lauryldimethylamine-oxide (LDAO), N- Laurylsarcosine Sodium salt and Sodium deoxycholate (DOC).
  • SDS sodium dodecylsulfate
  • cholate Bis(2-ethylhexyl)sulfosuccinate Sodium salt
  • CAB Cetyltrimethylammoniumbromide
  • LDAO Lauryldimethylamine-oxide
  • N- Laurylsarcosine Sodium salt Sodium deoxycholate
  • non-ionic surfactants include Alkyl Polyglucosides such as TRITONTM BG-10 Surfactant and TRITON CG-1 10 Surfactant, Branched Secondary Alcohol Ethoxylates such as TERGITOLTM TMN Series, Ethylene Oxide / Propylene Oxide Copolymers, such as TERGITOL L Series, and TERGITOL XD, XH, and XJ Surfactants, Nonylphenol
  • Ethoxylates such as TERGITOL NP Series, Octylphenol Ethoxylates, such as TRITON X Series, Secondary Alcohol Ethoxylates, such as TERGITOL 15-S Series and Specialty Alkoxylates, such as TRITON CA Surfactant, TRITON N-57 Surfactant, TRITON X-207 Surfactant, Tween 80 and Tween 20.
  • surfactant Typically 0.001 to 1 wt% of surfactant is applied, preferably 0.05-
  • One or more other additives which may be present in the coating composition according to the invention are for example amine compounds, for example diallylamine, diisopropylamine, diethylamine, and diethylhexylamine; antioxidants; water-soluble radical stabilizers; UV absorbers; light stabilizers; (silane) coupling agents; coating surface improvers; heat polymerization inhibitors; leveling agents; surfactants; colorants, for example a pigment or a dye; discolorants; preservatives; dispersing agents; plasticizers; lubricants; solvents; fillers; wettability improvers; urea; and chain transfer agents.
  • the colorant can be a pigment or dye.
  • the coating composition according to the invention preferably contains 1-50 wt% of the copolymer, preferably 1 -30 wt% of the copolymer, based on the total weight of the dry coating.
  • the coating composition according to the invention can be coated on an article.
  • the coating composition can be coated on a substrate which may be selected from a range of geometries and materials.
  • the substrate may have a texture, such as porous, non-porous, smooth, rough, even or uneven.
  • the substrate supports the coating composition on its surface.
  • the coating composition can be on all areas of the substrate or on selected areas.
  • the coating composition can be applied to a variety of physical forms, including films, sheets, rods, tubes, molded parts (regular or irregular shape), fibers, fabrics, and particulates.
  • Suitable surfaces for use in the invention are surfaces that provide the desired properties such as porosity, hydrophobicity, hydrophilicity, colorisability, strength, flexibility, permeability, elongation abrasion resistance and tear resistance.
  • suitable surfaces are for instance surfaces that consist of or comprise metals, plastics, ceramics, glass and/or composites.
  • the coating composition may be applied directly to the said surfaces or may be applied to a pretreated or coated surface where the pretreatment or coating is designed to aid adhesion of the coating composition to the substrate.
  • the coating composition according to the invention is coated on a biomedical substrate.
  • a biomedical substrate refers, in part, to the fields of medicine, and the study of living cells and systems.
  • biomedical also relates to chemicals and compositions of chemicals, regardless of their source, that (i) mediate a biological response in vivo, (ii) are active in an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro assay or other model, e.g., an in vitro
  • biomedical also refers to the separation sciences, such as those involving processes of chromatography, osmosis, reverse osmosis, and filtration. Examples of biomedical articles include research tools, industrial, and consumer applications.
  • Biomedical articles include separation articles, implantable articles, and ophthalmic articles. Separation articles include filters, osmosis and reverse osmosis membranes, and dialysis membranes, as well as bio-surfaces such as artificial skins or other membranes. Implantable articles include catheters, and segments of artificial bone, joints, or cartilage. An article may be in more than one category, for example, an artificial skin is a porous, biomedical article. This invention may also be applied in the food industry, the paper printing industry, hospital supplies, diapers and other liners, and other areas where hydrophilic, wettable, or wicking articles are desired.
  • the medical device can be an implantable device or an
  • the devices can be of short-term temporary use or of long-term permanent implantation.
  • suitable devices are those that are typically used to provide for medical therapy and/or diagnostics in heart rhythm disorders, heart failure, valve disease, vascular disease, diabetes, neurological diseases and disorders, orthopedics, neurosurgery, oncology, ophthalmology, and ear, nose and throat (ENT) surgery.
  • Suitable examples of medical devices include, but are not limited to, a stent, stent graft, anastomotic connector, synthetic patch, lead, electrode, needle, guide wire, catheter, sensor, surgical instrument, angioplasty balloon, wound drain, shunt, tubing, infusion sleeve, urethral insert, pellet, implant, blood oxygenator, pump, vascular graft, vascular access port, heart valve, annuloplasty ring, suture, surgical clip, surgical staple, pacemaker, implantable defibrillator, neurostimulator, orthopedic device, cerebrospinal fluid shunt, implantable drug pump, spinal cage, artificial disc, replacement device for nucleus pulposus, ear tube, intraocular lens and any tubing used in minimally invasive surgery.
  • Articles that are particularly suited to be used in the present invention include medical devices or components such as intermittent catheters, balloon catheters, intravenous access devices, for example central venous (CVC) catheters, PTCA catheters, PIC catheters and stent delivery catheters, guide wires, stents, syringes, metal and plastic implants, contact lenses and medical tubing.
  • medical devices or components such as intermittent catheters, balloon catheters, intravenous access devices, for example central venous (CVC) catheters, PTCA catheters, PIC catheters and stent delivery catheters, guide wires, stents, syringes, metal and plastic implants, contact lenses and medical tubing.
  • CVC central venous
  • the coating composition according to the invention is applied on a medical device; more preferably an intravenous access device.
  • the coating layer on the article preferably a medical device, can be one layer or several layers.
  • the coating composition according to the invention preferably forms the outer layer on the article.
  • a primer coating layer on the article generally contributes to the adherence of the outer coating layer(s), in particular if the surface of the article provided with the outer layer is more hydrophobic than the outer coating layer.
  • two coating layers are applied on the medical device, wherein the outer coating layer is formed from the coating composition according to the invention.
  • the coating composition can be applied to the substrate by for example dip-coating.
  • Other methods of application include spray, wash, vapor deposition, brush, roller and other methods known in the art.
  • HFT Harland FTS5000 Friction Tester
  • the desired test description was inserted when "run test” was activated.
  • the tube was attached in the holder.
  • the device was adjusted down to the desired position such that the tube was soaked in demineralized water for 1 min. After zero gauging in water the protocol was activated by pushing "start”. The data were saved after finishing.
  • the holder was removed from the force gauge and subsequently the catheter was removed from the holder.
  • the (meth)acrylate monomer with pendant biguanidine groups (5) was prepared from p-aminophenethylalcohol in a 4 steps synthesis. After introducing the (metha)acrylate group in the dicyandiamide derivative, the step for the biguanidine formation was followed. b. Purification N-vinyl pyrollidone
  • NVP N-vinyl pyrollidone
  • the tubes were then degassed by three freeze-pump-thaw cycles under high vacuum.
  • the polymerisation of NVP was started at 55°C and allowed to continue for 40 minutes, prior to the addition of the biguanidine monomer.
  • the biguanidine monomer was added dropwise over a period of 60 minutes.
  • the polymerisation was run for 24 h, until a viscous liquid was obtained.
  • the copolymer was purified by precipitation of the methanol solution into a large excess of cold ethylacetate. The precipitated polymer was filtered off, wash with cold ethylacetate and freeze dried.
  • the PVP-co-Biguanidine copolymer (PVP-co-Big) was collected as a white fine powder.
  • the degree of functionalization was determined as relative ratio between the CH 2 in the oposition of the acrylate moiety at 4.2 ppm compared with the 6H of the pyrollidone ring at 2.5-1.1 ppm.
  • the Mw of the copolymers was determined by size exclusion chromathography (SEC). It can be observed in Table 1 , that when copolymers with higher ratio of biguanidine were prepared the Mw of the copolymer decreases and the polydispersity index (PDI) increases .
  • SEC size exclusion chromathography
  • a Schlenk tube was charged with the desired amount of hydroxyethyl acrylate (HEA) and biguanidine monomer in different ratios, and desired amount of a stock solution of the initiator (from 1 .0 to 4.0% with respect to the solid content).
  • the reaction mixture was then degassed by three freeze-pump-thaw cycles under high vacuum.
  • the polymerization was run for 18 h at 60°C.
  • the copolymer was purified by precipitation of the methanol solution into a large excess of diethylether (Et 2 0).
  • the precipitated polymer was filtered off; washed with cold Et 2 0 and dried in a vacuum oven for 48h.
  • the copolymer was collected as a white fine powder.
  • the degree of functionalization was determined as relative ratio between the CH 2 in the a-position of the hydroxyl moiety of HEA at 3.5 ppm compared to the CH 2 in the ⁇ -position of acrylate moiety on the biguanidine monomer.
  • PTGL 10 oo(TDI-HEA) 2 was prepared as d escribed in WO2008/031595.
  • the above mentioned components were added to a brown colored glass flask and mixed overnight (-16 hours) at room temperature. The next morning the primer composition had become a homogeneous liquid with a viscosity of 6 mPa.s.
  • the viscosity was measured on a Brookfield CAP1000, v.1.2 in combination with cone nr. 1 at 25 ° C.
  • Coating composition for the top coat :
  • PEG1500 diacrylamide was prepared as described in WO2009/1 12548.
  • top coat (TC) compositions are prepared starting from the above- described composition which contains all the top coat components.
  • the PVP 1 .3M is partially substituted with the biguanidine copolymers.
  • Coatings were prepared on PET films (Toyobo) and the coating integrity was evaluated.
  • the coatings were applied on PET films at experimental condition of 20°C and 30% relative humidity. The following procedure was applied to prepare the films and to evaluate the coating integrity and adhesion.
  • the staining solution contained 0.2 wt%
  • the reference material (PVP) is marked in gray.
  • BactoTM Tryptone (7.5 g/l)
  • BactoTM Yeast Extract (3.75 g/l)
  • BactoTM Agar (1 1.25 g/l) (all obtained from Becton & Dickinson) and sodium chloride (3.75 g/l).
  • the obtained mixture was sterilized in an autoclave at 121 °C for 15 min.
  • the LB agar was poured into petri dishes after cooling down to approximately 60°C.
  • PPF buffer phosphate buffer solution
  • Escherichia col i AT CC 1 1 105 was cultured from frozen stock in sterile LB medium.
  • the bacterial suspension had a concentration of about 1x10 9 CFU/ml.
  • This suspension was diluted in sterile PBS buffer to obtain a final concentration of about 10 7 CFU/ml.
  • Modified- J IS test Japanese Industrial Standard Z 2801(2000)
  • the modified-JIS test JIS Z 2801 : 2000 was performed to check the AM activity of PET film coated with a basic primer and a TC containing different concentrations of biguanidine (in the form of PVP-co-Big).
  • Pieces of 5 x 5 cm of coated PET film were prepared. The coating was applied only on one side and the uncoated side was cleaned with 70% isopropanol. The film was washed in 20 ml sterile PBS for 24 h at 37°C without shaking. After that, the film was removed from the PBS and washed in fresh sterile PBS. The coated film was placed in a sterile Petri dish. Escherichia col ⁇ AT ' CC 1 1 105 was cultured from frozen stock in sterile LB medium. The bacterial
  • suspension had a concentration of about 1 x10 9 CFU/mL. This suspension was diluted in sterile PBS to obtain the desired final concentration (1 x10 5 and 1 x10 7 CFU/mL). 0.4 mL of the bacterial suspension was placed on the coated PET films and covered with a 4 x 4 cm parafilm, previously cleaned with 70% isopropanol. The coated film was placed in an exicator ⁇ 1) and incubated for 24 h at 37 0 C without shaking. 10 ml of STOP buffer (200 ml PBS + 1 ,4 g Tween 80) was added to the coated film. The petri dish was shaken for 1-2 min until the parafilm was to loosen up from the film. The suspension was subsequently serial diluted (to final
  • the coated film was washed in sterile PBS. Afterwards, the film was stamped onto a petri dish filled with LB agar (only the side that was in contact with the bacteria). It was allowed to be in contact with the agar for approx. 5 minutes. After incubation overnight at 37°C, photographs were made to compare the amount of colonies formed on the agar for different samples.
  • Table 5 Bactericidal activity of different coated films containing a biguanidine moiety (in the form of PVP-co-Big) against Escherichia coli A TCC 11105 after 24 h incubation at 37°C.
  • the purpose of the experiment was to position the coatings according to the invention against a commercial available AM coating for central venous catheters (CVC).
  • CVC central venous catheters
  • the PBS buffer showed elution of high contents of the active ingredient.
  • a bacterial suspension test was performed to check the AM activity of the commercial coating.
  • 3 cm catheter pieces of the commercial sample (coated intraluminal and extraluminal), was incubated in PBS buffer inoculated with Escherichia col 7 AT CC 1 1 105 at a final concentration of 10 5 and 10 7 CFU/mL, respectively. After incubation for 24 h at 37°C under shaking at 200 rpm the suspensions were serial diluted and plated out on petri dishes filled with LB agar. The experiments were performed in triple
  • Certofix Protect showed a log 2 reduction.
  • the coating was considered to be very effective even at a very high CFU/ml (10 7 CFU/ml).
  • 3 cm catheter pieces were incubated in the bacterial suspension for 24 h. Subsequently, the catheter pieces were washed with sterile PBS buffer. The catheter pieces were placed in between two layers of agar until they were completely surrounded by agar. The samples were incubated overnight at 37°C. At 10 5 CFU/ml, no living bacteria were found on the agar for Certofix Protect.
  • Coatings that successfully passed the adhesion test and the AM test were applied on PU tubing (7 fr.) (Raumedic; VWA20000750). The coating was applied only on the outside. These coatings were submitted for hemocompatibility testing.
  • the lubricity of the coating is inversely proportional to the measured friction force.
  • the coating was considered to be lubricious if it was characterised by a friction force below 20 g under the given test conditions.
  • the maintenance of lubricity of the coating was considered to be good if the average friction force did not rise from cycle to cycle.
  • the coating showed wear resistance if no (part of the) coating was scraped off during the friction test.

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Abstract

L'invention porte sur une composition de revêtement comprenant un polymère hydrophile et un copolymère comprenant un monomère hydrophile et un monomère représenté par la structure X, dans laquelle R = un groupe terminal, R1 = un groupe de liaison, Z = un groupe polymérisable, et sur des dispositifs médicaux, de préférence un cathéter, comprenant le revêtement.
PCT/EP2010/067472 2009-11-16 2010-11-15 Copolymère hydrophile WO2011058171A1 (fr)

Applications Claiming Priority (2)

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EP09176127.0 2009-11-16
EP09176127 2009-11-16

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WO2011058171A1 true WO2011058171A1 (fr) 2011-05-19

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3219400A3 (fr) * 2016-03-17 2017-11-29 Tokyo Ohka Kogyo Co., Ltd. Procédé de traitement de surface, agent antistatique et agent de traitement d'hydrophilisation
CN112574376A (zh) * 2020-11-16 2021-03-30 万华化学集团股份有限公司 一种抗菌聚氨酯树脂及其制备方法
CN115779157A (zh) * 2022-11-17 2023-03-14 国科温州研究院(温州生物材料与工程研究所) 一种反应型生物医用涂层及其制备方法
WO2023232229A1 (fr) * 2022-05-31 2023-12-07 Ntt Research, Inc. Substrat pour microélectrodes implantables, élément d'électrode et système d'électrode, et son procédé de fabrication
US11896783B2 (en) 2016-12-27 2024-02-13 Vasonics, Inc. Catheter housing

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Publication number Priority date Publication date Assignee Title
EP0460385A2 (fr) 1990-05-10 1991-12-11 H.B. FULLER LICENSING & FINANCING, INC. Agents biocides polymères
EP1175148A1 (fr) 1999-05-01 2002-01-30 Biointeractions Ltd Polymeres resistant a l'infection, leur preparation et leurs utilisations
WO2006056482A1 (fr) 2004-11-29 2006-06-01 Dsm Ip Assets B.V. Methode permettant de reduire la quantite de composants extractibles des revetements polymeres

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0460385A2 (fr) 1990-05-10 1991-12-11 H.B. FULLER LICENSING & FINANCING, INC. Agents biocides polymères
EP1175148A1 (fr) 1999-05-01 2002-01-30 Biointeractions Ltd Polymeres resistant a l'infection, leur preparation et leurs utilisations
WO2006056482A1 (fr) 2004-11-29 2006-06-01 Dsm Ip Assets B.V. Methode permettant de reduire la quantite de composants extractibles des revetements polymeres

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Title
T. IKEDA ET AL., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, August 1984 (1984-08-01), pages 139 - 144
T. IKEDA ET AL., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, August 1984 (1984-08-01), pages 139 - 144, XP007913489 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3219400A3 (fr) * 2016-03-17 2017-11-29 Tokyo Ohka Kogyo Co., Ltd. Procédé de traitement de surface, agent antistatique et agent de traitement d'hydrophilisation
US10940504B2 (en) 2016-03-17 2021-03-09 Tokyo Ohka Kogyo Co., Ltd. Surface treatment method, anti-static agent, and hydrophilizing treatment agent
TWI802536B (zh) * 2016-03-17 2023-05-21 日商東京應化工業股份有限公司 表面處理方法、抗靜電劑及親水化處理劑
US11896783B2 (en) 2016-12-27 2024-02-13 Vasonics, Inc. Catheter housing
CN112574376A (zh) * 2020-11-16 2021-03-30 万华化学集团股份有限公司 一种抗菌聚氨酯树脂及其制备方法
WO2023232229A1 (fr) * 2022-05-31 2023-12-07 Ntt Research, Inc. Substrat pour microélectrodes implantables, élément d'électrode et système d'électrode, et son procédé de fabrication
CN115779157A (zh) * 2022-11-17 2023-03-14 国科温州研究院(温州生物材料与工程研究所) 一种反应型生物医用涂层及其制备方法

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