WO2023054500A1 - 医療用コーティング剤及び医療機器 - Google Patents

医療用コーティング剤及び医療機器 Download PDF

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WO2023054500A1
WO2023054500A1 PCT/JP2022/036237 JP2022036237W WO2023054500A1 WO 2023054500 A1 WO2023054500 A1 WO 2023054500A1 JP 2022036237 W JP2022036237 W JP 2022036237W WO 2023054500 A1 WO2023054500 A1 WO 2023054500A1
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polymer
water
mass
meth
coating agent
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French (fr)
Japanese (ja)
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賢 田中
将太 谷口
賢一 中村
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Kyushu University NUC
Toagosei Co Ltd
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Kyushu University NUC
Toagosei Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials

Definitions

  • Patent Document 1 discloses the use of a polymer having structural units derived from 2-methoxyethyl acrylate as a biocompatible medical material.
  • Platelets and fibrinogen are considered to be the main components in blood involved in thrombus formation. Therefore, the present inventors considered that it is important to prevent these components from recognizing a medical device inserted into the body as a foreign body. That is, if the property of suppressing the adsorption of platelets and fibrinogen (hereinafter also referred to as "anti-adsorption”) can be sufficiently imparted to the surface of the base material, excellent antithrombotic properties can be imparted to medical devices, and biocompatibility can be improved. It can be said.
  • the present disclosure has been made in view of such circumstances, and its purpose is to provide a medical coating agent that has high platelet and fibrinogen anti-adsorption properties and excellent anti-thrombotic properties.
  • [1] contains a polymer containing a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond, the polymer contains water, the differential scanning calorimeter (DSC ) in the DSC curve obtained by heating at a rate of 5 ° C./min, the water content state of the polymer when the endothermic peak top due to melting of ice appears at 0 ° C. is called a saturated water content state.
  • Condition (i): The amount of intermediate water contained in the saturated water-containing polymer is 2.0% by mass or more relative to the total amount of the saturated water-containing polymer.
  • the polymer satisfies the following condition (ii): Condition (ii): The amount of water of hydration contained in the saturated water-containing polymer is 6.0% by mass or more with respect to the total amount of the saturated water-containing polymer.
  • the polymer satisfies the following conditions (iii): Condition (iii): The ratio of the amount of intermediate water to the amount of antifreeze water contained in the polymer in a saturated water content state is 0.50 or more.
  • [4] contains a polymer containing a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond, the polymer contains water, the differential scanning calorimeter (DSC ) in the DSC curve obtained by heating at a rate of 5 ° C./min, the water content state of the polymer when the endothermic peak top due to melting of ice appears at 0 ° C. is called a saturated water content state.
  • Condition (ii): The amount of water of hydration contained in the saturated water-containing polymer is 6.0% by mass or more with respect to the total amount of the saturated water-containing polymer.
  • a medical coating agent that satisfies
  • [5] contains a polymer containing a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond, the polymer contains water, the differential scanning calorimeter (DSC ) in the DSC curve obtained by heating at a rate of 5 ° C./min, the water content state of the polymer when the endothermic peak top due to melting of ice appears at 0 ° C. is called a saturated water content state.
  • a medical coating agent that satisfies
  • the polymer contained in the medical coating agent of the present disclosure has high antiadsorption of platelets and fibrinogen, and excellent antithrombogenicity. Therefore, by coating the base material of a medical device with the medical coating agent of the present disclosure, it is possible to provide a medical device with excellent antithrombotic properties.
  • FIG. 1 is a diagram showing an example of a DSC curve in a saturated water content state of a polymer containing intermediate water upon hydration.
  • (meth)acryl means acryl and/or methacryl
  • (meth)acrylate means acrylate and/or methacrylate
  • the first medical coating agent in the present disclosure is a polymer (hereinafter referred to as "polymer (P )”).
  • the polymer (P) is obtained by adding water to the polymer (P) and using a differential scanning calorimeter (DSC) to raise the temperature at a rate of 5 ° C./min.
  • DSC differential scanning calorimeter
  • the second medical coating agent in the present disclosure contains a polymer (P) containing a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond.
  • the polymer (P) is obtained by soaking water in the polymer (P) and using a DSC to raise the temperature at a rate of 5° C./min.
  • the following condition (ii) is satisfied when the water content state of the polymer (P) when appears at 0° C. is defined as the “saturated water content state”.
  • a third medical coating agent in the present disclosure contains a polymer (P) containing a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond.
  • the polymer (P) is obtained by soaking water in the polymer (P) and using a DSC to raise the temperature at a rate of 5° C./min.
  • the water content state of the polymer (P) when appears at 0° C. is defined as the “saturated water content state”.
  • condition (iii) The ratio of the amount of intermediate water to the amount of antifreeze water contained in the saturated water-containing polymer (P) is 0.50 or more.
  • the water interacting with the polymer (P) is, depending on the strength of the interaction with the polymer, "free water", It can take the form of “non-freezing water” and “intermediate water”.
  • “free water” refers to water that has a weak interaction with the polymer and has a freezing point of 0°C
  • non-freezing water refers to water that has a strong interaction with the polymer and has no detectable freezing point.
  • "Intermediate water” refers to water that interacts with the polymer intermediately between free water and antifreeze water (ie, interacts relatively slowly with the polymer) and has a freezing point below 0°C. Acquiring biocompatibility of the polymer is believed to be related to the fact that the hydrated polymer contains a large amount of intermediate water (see, for example, paragraphs 0003 and 0004 of JP-A-2016-35000). .
  • cells recognize foreign substances, activating biological defense functions and causing rejection. Therefore, when a medical device comes into contact with a biological component or tissue during treatment or surgery, if the body recognizes the medical device as a foreign object, the body's defense function may act and interfere with treatment. be. For example, when a medical device comes into contact with blood, a thrombus is formed, which may hinder the function of the medical device or affect the living body. On the other hand, a polymer having intermediate water on its surface is unlikely to be recognized as a foreign substance by the living body, and is thought to exhibit excellent antithrombotic properties.
  • Platelets and fibrinogen are known components in blood that are involved in thrombus formation. Platelets are blood cells that are activated by foreign substances and aggregate on foreign substances to form thrombi (platelet thrombi), contributing to primary hemostasis in the process of hemostasis.
  • Fibrinogen, coagulation factor I is a protein that is converted to fibrin at the final stage of blood coagulation to form a coagulation clot and contributes to secondary hemostasis in the process of hemostasis. That is, platelets and fibrinogen are both major components that form thrombi, and it is considered important for biocompatibility (more specifically, antithrombotic properties) that these components are less likely to be adsorbed onto the polymer. .
  • the polymer (P) contained in the first to third medical coating agents of the present disclosure tends to retain intermediate water during hydration, and platelets and fibrinogen are adsorbed to the polymer (P). sufficiently suppressed. It is believed that this allows the development of excellent antithrombotic properties.
  • the polymer (P) contains a structural unit derived from an ethylenically unsaturated monomer having a urethane bond (hereinafter also referred to as "monomer (M)").
  • the polymer (P) is preferably a (meth)acrylic polymer in that the reaction rate of the monomers can be easily increased and that it is easy to manufacture industrially.
  • the ratio of the structural units derived from the (meth)acrylic monomer preferably exceeds 50% by mass. , 60 mass % or more is more preferable, 70 mass % or more is still more preferable, 80 mass % or more is still more preferable, and 90 mass % or more is still more preferable.
  • the monomer (M) is preferably a compound capable of introducing a structure having a urethane bond into the side chain of the polymer, and is preferably a (meth)acrylic monomer having a urethane bond.
  • the monomer (M) is a (meth)acrylic monomer, it is preferable in that the reaction rate of the monomer can be easily increased.
  • the monomer (M) one type may be used alone, or two or more types may be used.
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is an alkylene group having 1 to 5 carbon atoms or a group represented by "-(R 5 O) m -R 6 -" ( provided that R 5 is an alkylene group having 1 to 3 carbon atoms, R 6 is an alkylene group having 1 to 3 carbon atoms, m is an integer of 1 to 3)
  • R 3 is an alkylene group having 1 to 3 carbon atoms. 3, any hydrogen atom of the alkylene group may be substituted with an alkoxy
  • R 3 in the general formula (I) is such that any hydrogen atom of the alkylene group is substituted with an alkoxy group having 1 to 4 carbon atoms. is more preferred, and substitution with an alkoxy group having 1 to 2 carbon atoms is even more preferred.
  • R 4 in general formula (I) is more preferably an alkoxy group having 1 to 4 carbon atoms, still more preferably an alkoxy group having 1 to 2 carbon atoms.
  • (methoxycarbonyl) aminoalkyl (meth) acrylates include (methoxycarbonyl) aminomethyl (meth) acrylate, 2-((methoxycarbonyl) amino) ethyl (meth) acrylate, 3-((methoxycarbonyl) amino ) propyl (meth)acrylate and the like.
  • 2-((methoxycarbonyl)amino)ethyl acrylate is preferably used in that the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state can be sufficiently lowered.
  • Specific examples of the compound represented by the general formula (I) include 2-(((2-methoxyethoxy)carbonyl)amino)ethyl (meth)acrylate, 2-(((2-ethoxyethoxy)carbonyl)amino ) ethyl (meth)acrylate, 2-(((2-propoxyethoxy)carbonyl)amino)ethyl (meth)acrylate, 2-((((1,3-dimethoxypropan-2-yl)oxy)carbonyl)amino) Ethyl (meth)acrylate, 2-((((1,3-diethoxypropan-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 2-((((1-methoxy-3-ethoxypropane -2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 6-oxo-2,5,10-trioxa-7-azadodecane-12
  • the polymer (P) is at least one compound selected from the group consisting of (methoxycarbonyl)aminoalkyl (meth)acrylates and compounds represented by the general formula (I).
  • Structural units derived from a compound hereinafter also referred to as "monomer (m-1)" are contained in an amount of 10% by mass or more of all structural units derived from monomers constituting the polymer (P).
  • the polymer (P) may have only one type of structural unit derived from the monomer (m-1), or may have two or more types.
  • the polymer (P) may be composed only of structural units derived from the monomer (m-1), but for the purpose of adjusting the glass transition temperature of the polymer, etc., the effect of the present disclosure is obtained. It may further have a structural unit derived from a monomer other than the monomer (m ⁇ 1) (hereinafter also referred to as “other monomer”) within a range that does not impair it.
  • Examples of other monomers include monomers that do not have a urethane bond and are copolymerizable with the monomer (m-1).
  • Examples of such monomers include unsaturated carboxylic acids, unsaturated acid anhydrides, (meth)acrylic acid alkyl esters, aliphatic cyclic esters of (meth)acrylic acid, and aromatic (meth)acrylic acid.
  • Esters (meth)acrylic acid alkoxyalkyl esters, (meth)acrylic acid hydroxyalkyl esters, polyalkylene glycol mono(meth)acrylates, vinyl compounds having a heterocyclic structure, amino group-containing vinyl compounds, amide group-containing vinyl compounds, nitriles Examples include group-containing vinyl compounds, aromatic vinyl compounds, maleimide compounds, and the like.
  • unsaturated carboxylic acids such as (meth)acrylic acid, itaconic acid, crotonic acid, maleic acid, fumaric acid, citraconic acid, cinnamic acid, monohydroxyethyl succinate (meth)acrylate, ⁇ -carboxy -caprolactone mono(meth)acrylate, ⁇ -carboxyethyl(meth)acrylate, 4-carboxystyrene and the like.
  • unsaturated acid anhydrides include maleic anhydride, itaconic anhydride, and citraconic anhydride.
  • Examples of (meth)acrylic acid alkyl esters include methyl (meth)acrylate, ethyl (meth)acrylate, isopropyl (meth)acrylate, n-propyl (meth)acrylate, n-butyl (meth)acrylate, ( meth)isobutyl acrylate, tert-butyl (meth)acrylate, hexyl (meth)acrylate and 2-ethylhexyl (meth)acrylate.
  • aliphatic cyclic esters of (meth)acrylic acid include cyclohexyl (meth)acrylate, methylcyclohexyl (meth)acrylate, tert-butylcyclohexyl (meth)acrylate, cyclododecyl (meth)acrylate, Examples include isobornyl (meth)acrylate, adamantyl (meth)acrylate, dicyclopentenyl (meth)acrylate and dicyclopentanyl (meth)acrylate.
  • aromatic esters of (meth)acrylic acid include phenyl (meth)acrylate, benzyl (meth)acrylate, phenoxymethyl (meth)acrylate, 2-phenoxyethyl (meth)acrylate and (meth)acrylate. and 3-phenoxypropyl acrylate.
  • (meth)acrylate alkoxyalkyl esters include 2-methoxyethyl (meth)acrylate, 2-ethoxyethyl (meth)acrylate, n-propoxyethyl (meth)acrylate, and n-(meth)acrylate.
  • (meth)acrylic acid hydroxyalkyl esters include 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, and 2-hydroxypropyl (meth)acrylate. -hydroxybutyl, 3-hydroxybutyl (meth)acrylate, and 4-hydroxybutyl (meth)acrylate.
  • Polyalkylene glycol mono(meth)acrylates include polyethylene glycol mono(meth)acrylate, polypropylene glycol mono(meth)acrylate and polyethylene glycol-polypropylene glycol mono(meth)acrylate.
  • Vinyl compounds having a heterocyclic structure include glycidyl (meth)acrylate, (3,4-epoxycyclohexyl)methyl (meth)acrylate, and tetrahydrofurfuryl (meth)acrylate.
  • amino group-containing vinyl compounds include dimethylaminomethyl (meth)acrylate, diethylaminomethyl (meth)acrylate, 2-dimethylaminoethyl (meth)acrylate, 2-diethylaminoethyl (meth)acrylate, (meth)acryl 2-(di-n-propylamino)ethyl acid, 2-dimethylaminopropyl (meth)acrylate, 2-diethylaminopropyl (meth)acrylate, 2-(di-n-propylamino)propyl (meth)acrylate , 3-dimethylaminopropyl (meth)acrylate, 3-diethylaminopropyl (meth)acrylate, 3-(di-n-propylamino)propyl (meth)acrylate and the like.
  • Amide group-containing vinyl compounds include (meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-dimethylaminopropyl(meth)acrylamide, N-methylol(meth)acrylamide, and the like.
  • nitrile group-containing vinyl compounds include cyanomethyl (meth)acrylate, 1-cyanoethyl (meth)acrylate, 2-cyanoethyl (meth)acrylate, 1-cyanopropyl (meth)acrylate, and 2-(meth)acrylate.
  • aromatic vinyl compounds include styrene, ⁇ -methylstyrene, ⁇ -methylstyrene, vinylxylene, methylstyrene, ethylstyrene, butylstyrene, methoxystyrene, hydroxystyrene, isopropenylphenol, vinylbenzoic acid and vinylnaphthalene. be done.
  • Maleimide compounds include maleimide and N-substituted maleimide compounds.
  • N-substituted maleimide compounds include N-methylmaleimide, N-ethylmaleimide, Nn-propylmaleimide, N-isopropylmaleimide, Nn-butylmaleimide, N-isobutylmaleimide, N-tert-butylmaleimide and the like.
  • N-alkyl-substituted maleimides N-cycloalkyl-substituted maleimides such as N-cyclopentylmaleimide and N-cyclohexylmaleimide; N-aralkyl-substituted maleimides such as N-benzylmaleimide; N-phenylmaleimide, N-(4-hydroxyphenyl)maleimide , N-(4-acetylphenyl)maleimide and N-(4-methoxyphenyl)maleimide.
  • monomers that have a urethane bond and can be copolymerized with the monomer (m-1) can also be used.
  • examples of such monomers include 2-((ethoxycarbonyl)amino)ethyl(meth)acrylate and 2-((isopropoxycarbonyl)amino)ethylacrylate.
  • other monomers include (meth)acrylic acid alkyl esters, (meth)acrylic acid aliphatic cyclic esters, (meth) It is preferably at least one selected from the group consisting of aromatic esters of acrylic acid, alkoxyalkyl (meth)acrylates, amino group-containing vinyl compounds, and amide group-containing vinyl compounds, and alkyl (meth)acrylates. At least one selected from the group consisting of esters and (meth)acrylic acid alkoxyalkyl esters is more preferred.
  • Other monomers are, among others, from the group consisting of (meth)acrylic acid alkyl esters having an alkyl group having 1 to 12 carbon atoms and (meth)acrylic acid alkoxyalkyl esters having an alkoxyalkyl group having 3 to 12 carbon atoms. At least one selected is preferable, and an alkoxyalkyl (meth)acrylate having an alkoxyalkyl group having 3 to 12 carbon atoms is more preferable, and an alkoxyalkyl (meth)acrylate having an alkoxyalkyl group having 3 to 4 carbon atoms. Esters are more preferred, and 2-methoxyethyl (meth)acrylate is particularly preferred.
  • the polymer (P) is selected from the group consisting of an alkyl (meth)acrylate having an alkyl group of 1 to 12 carbon atoms and an alkoxyalkyl (meth)acrylate having an alkoxyalkyl group of 3 to 12 carbon atoms.
  • the proportion of structural units derived from the monomer (N) is the polymer (P ) is preferably 5% by mass or more, more preferably 10% by mass or more, and even more preferably 20% by mass or more, relative to all structural units derived from the monomers constituting ).
  • the unit constituting the polymer (P) 90% by mass or less is preferable, 80% by mass or less is more preferable, 70% by mass or less is still more preferable, 50% by mass or less is even more preferable, and 40% by mass or less is even more preferable, based on the total structural units derived from the polymer. preferable.
  • the polymer (P) preferably contains 10% by mass or more of the structural unit (A) relative to the total structural units of the polymer (P).
  • the ratio of the structural unit (A) in the polymer (P) is within the above range, the effect of suppressing the adsorption of platelets and fibrinogen can be sufficiently imparted to the substrate coated with the first medical coating agent.
  • the proportion of the structural unit (A) in the polymer (P) is more preferably 20% by mass or more, more preferably 30% by mass or more, relative to the total structural units of the polymer (P). , more preferably 50% by mass or more, and even more preferably 60% by mass or more.
  • the polymer (P) is a copolymer of the monomer (M) and another monomer having no urethane bond
  • the polymer (P) is a random copolymer or a block copolymer. and graft copolymers.
  • the polymer (P) is preferably a random copolymer from the viewpoint of uniformly introducing a structure having a urethane bond into the entire polymer to enhance the effect of improving the antithrombotic property.
  • the weight average molecular weight (Mw) of the polymer (P) is preferably in the range of 2,000 to 2,000,000. When the Mw is 2,000 or more, it is possible to sufficiently secure the mechanical strength of the coating layer formed using the medical coating agent. Moreover, when Mw is 2,000,000 or less, it is possible to prevent the viscosity of the medical coating agent from becoming too high, and to ensure coatability and handleability.
  • the Mw of the polymer (P) is more preferably 5,000 or more, still more preferably 10,000 or more, still more preferably 30,000 or more, still more preferably 50,000 or more.
  • the upper limit of Mw of the polymer (P) is more preferably 1,500,000 or less, still more preferably 1,000,000 or less.
  • Mw of a polymer is a standard polystyrene conversion value obtained using a gel permeation chromatography (GPC).
  • the polymerization method for producing the polymer (P) is not particularly limited.
  • the polymer (P) can be obtained by polymerizing monomers by employing known radical polymerization methods such as solution polymerization, suspension polymerization, emulsion polymerization and bulk polymerization.
  • a polymerization initiator eg, an azo compound
  • a polymer can be obtained.
  • isolating and/or purifying the polymer obtained by the polymerization reaction known methods can be employed for these treatments.
  • the water interacting with the polymer (P) can be classified into free water, antifreeze water and intermediate water.
  • the presence of intermediate water in the polymer (P) in the water-containing state, and the amount of hydration water, the amount of intermediate water, the amount of non-freezing water, and the amount of free water contained in the polymer (P) in the water-containing state are determined by the polymer (P) in the water-containing state. It can be calculated by performing differential scanning calorimetry on a sample.
  • Fig. 1 shows an example of a DSC curve in a saturated water content state of a polymer containing intermediate water during hydration.
  • Water that melts at around 0°C in the heating process is defined as "free water", and unlike free water, the crystallization temperature is lower than that of free water, and crystals are formed at a temperature lower than 0°C in the heating process.
  • intermediate water we define “intermediate water” as water that melts at a low temperature.
  • FIG. 1 shows the temperature of a polymer sufficiently saturated with water using a differential scanning calorimeter (DSC), and the The DSC curve when temperature is raised is shown.
  • DSC differential scanning calorimeter
  • the low-temperature crystallization peak during the cooling process is due to the formation of low-temperature crystals in intermediate water that is close to free water, and the low-temperature crystallization peak during the heating process is due to intermediate water that could not be frozen during the cooling process. Both are classified as intermediate water.
  • the relationship between the amount of hydration water, the amount of free water, the amount of antifreeze water, and the amount of intermediate water (unit: g) contained in the hydrated polymer is represented by the following formula (1).
  • Hydration water volume Free water volume + Non-freezing water volume + Intermediate water volume (1)
  • the amount of free water and the amount of intermediate water contained in the hydrated polymer can be calculated from the amount of transfer of latent heat (that is, the amount of enthalpy change) caused by phase transition.
  • the amount of hydrated water of the polymer can be calculated by subtracting the mass of the polymer before hydration (that is, the polymer in a dry state) from the total amount of the hydrated polymer.
  • the antifreeze water can be calculated by subtracting the amount of free water and the amount of intermediate water from the amount of hydration water according to the above formula (1).
  • the details of the method for measuring and calculating the amount of hydrated water, free water, antifreeze water and intermediate water in the hydrated polymer follow the methods described in Examples below.
  • the endothermic peak top due to the melting of ice appeared at 0°C.
  • the water content state of the polymer at that time is referred to as the “saturated water content state”. This is because the endothermic peak top due to the melting of ice appears at 0°C in a polymer that forms intermediate water when hydrated, in a state containing a sufficient amount of water, that is, in a state of saturated water content ( See P3 in FIG. 1).
  • the polymer (P) contained in the first medical coating agent is a polymer that satisfies the above condition (i). That is, the amount of intermediate water contained in the saturated water-containing polymer (P) is 2.0% by mass or more with respect to the total amount of the saturated water-containing polymer (P). When the intermediate water content is 2.0% by mass or more, when a coating layer is formed on the substrate surface using the first medical coating agent, the substrate surface exhibits high anti-adsorption to platelets and fibrinogen. can be given. From this point of view, the amount of intermediate water contained in the polymer (P) in a saturated water content state is preferably 2.5% by mass or more with respect to the total amount of the polymer (P) in a saturated water content state. It is more preferably 0.5% by mass or more, still more preferably 4.5% by mass or more, even more preferably 7.5% by mass or more, and still more preferably 10% by mass or more.
  • the polymer (P) contained in the first medical coating agent sufficiently suppresses adsorption of platelets and fibrinogen to the polymer (P), and provides excellent antithrombotic properties to the substrate surface.
  • at least one of the following conditions (ii) and (iii) is preferably satisfied, and both conditions (ii) and (iii) are more preferably satisfied.
  • the amount of hydration water contained in the polymer (P) in the saturated water content state (hereinafter also referred to as "saturated water content”) is represented by the total amount of free water, antifreeze water and intermediate water. .
  • saturated water content is 6.0% by mass or more with respect to the total amount of the polymer (P) in the saturated water content state, a sufficient amount of intermediate water exists on the surface of the polymer (P), and it is effective against platelets and fibrinogen. It is suitable in that it can impart high anti-adsorption properties to the substrate surface.
  • the saturated water content of the polymer (P) is more preferably 7.0% by mass or more, more preferably 10.0% by mass, relative to the total amount of the polymer (P) in a saturated water content state. more preferably 15.0% by mass or more, and still more preferably 20.0% by mass or more.
  • the polymer (P) will compare the intermediate water to the antifreeze water.
  • the ratio of the amount of intermediate water to the amount of antifreeze water is more preferably 0.60 or more, still more preferably 0.80 or more, and still more preferably 0.80 or more, with respect to hydration water retained by the polymer (P) in a saturated water content state. is 0.90 or more, more preferably 1.00 or more.
  • the preferred numerical ranges for the intermediate water content, the saturated water content, and the ratio of the intermediate water content to the non-freezing water content in the polymer (P) in the saturated water content state can be set by appropriately combining the respective preferred numerical ranges described above.
  • the hydration water characteristic of the polymer (P) in a saturated water content state is such that the intermediate water content is 2.5% by mass or more with respect to the total amount of the polymer (P) in a saturated water content state, and the saturated water content is is 7.0% by mass or more with respect to the total amount of the polymer (P) in a saturated water content state
  • the ratio of the intermediate water content to the antifreeze water content is preferably 0.60 or more
  • the intermediate water content is in a saturated water content state is 3.5% by mass or more with respect to the total amount of the polymer (P)
  • the saturated water content is 10.0% by mass or more with respect to the total amount of the polymer (P) in a saturated water-containing state, and antifreeze More preferably, the ratio of
  • the first medical coating agent may further contain components different from the polymer (P) (hereinafter also referred to as “other components”) depending on the purpose of use.
  • the first medical coating agent is liquid
  • one aspect of the medical coating agent is a polymer composition in which the polymer (P) is optionally dissolved or dispersed in a solvent.
  • a solvent capable of dissolving the polymer (P) is preferably used as the solvent.
  • the solvent contained in the first medical coating agent is preferably an organic solvent. Specific examples include alcohols such as methanol, ethanol, n-propanol and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as ethylene glycol monomethyl ether, propylene glycol monomethyl ether, tetrahydrofuran and dioxane; esters such as ether acetate and ethyl acetate; amide solvents such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; hydrocarbons such as n-hexane, cyclohexane, toluene and xylene; is mentioned.
  • a solvent you may use individually by 1 type and may use it in combination of 2 or more type.
  • ingredients that may be incorporated into the first medical coating agent include solvents, as well as various agents such as antibacterial agents, anti-inflammatory agents, and antioxidants. 1 type or multiple types can be used for other components. The content of other components can be appropriately selected according to each component within a range that does not impair the effects of the present disclosure.
  • the content of the polymer (P) is based on 100 parts by mass of the total amount of solids contained in the medical coating agent (that is, components other than the solvent in the medical coating agent). , preferably 50 parts by mass or more, more preferably 70 parts by mass or more, still more preferably 80 parts by mass or more, even more preferably 90 parts by mass or more, and even more preferably 95 parts by mass or more.
  • the solid content concentration in the medical coating agent (here, the volume of the solvent used to prepare the medical coating agent, The mass ratio of the components) is not particularly limited, but is preferably 0.001 to 30 (w/v)%.
  • the solid content concentration is preferably 0.01 to 25 (w/v)%, still more preferably 0.05 to 20 (w/v)%.
  • the second medical coating agent of the present disclosure will be described.
  • the description of the first medical coating agent is used for the same configuration as that of the first medical coating agent, and the description thereof is omitted.
  • the polymer (P) contained in the second medical coating agent satisfies the above condition (ii). That is, the polymer (P) contained in the second medical coating agent has a hydration water content of 6.0% by mass relative to the total amount of the saturated water-containing polymer. That's it.
  • the type and amount of the monomer constituting the polymer (P) contained in the second medical coating agent, the molecular weight characteristics of the polymer (P), the preferable range of the condition (ii), the second medical coating agent For details such as other components that may be contained in the coating agent, the description of the first medical coating agent can be used.
  • the polymer (P) contained in the second medical coating agent sufficiently suppresses adsorption of platelets and fibrinogen to the polymer (P), and from the viewpoint of imparting excellent antithrombotic properties to the substrate surface. , in addition to condition (ii), it is preferable that the above condition (iii) is satisfied.
  • condition (iii) the description of the first medical coating agent can be used.
  • the third medical coating agent of the present disclosure will be described.
  • the description of the first medical coating agent is used for the same configuration as that of the first medical coating agent, and the description thereof is omitted.
  • the polymer (P) contained in the third medical coating agent satisfies the above condition (iii). That is, the polymer (P) contained in the third medical coating agent has a ratio of the intermediate water content to the antifreeze water content of the saturated water-containing polymer (P) of 0.50 or more.
  • the type and amount of the monomer constituting the polymer (P) contained in the third medical coating agent, the molecular weight characteristics of the polymer (P), the preferable range of the condition (iii), the third medical coating agent For details such as other components that may be contained in the coating agent, the description of the first medical coating agent can be used.
  • the medical device of the present disclosure is obtained by coating a base material with any one of the first to third medical coating agents of the present disclosure described above. A part or all of the surface of the medical device of the present disclosure is coated with the polymer (P) contained in the first to third medical coating agents of the present disclosure. Therefore, the anti-adsorption property of platelets and fibrinogen is high, and the anti-thrombotic property is excellent.
  • the base material of the medical device to which the first to third medical coating agents of the present disclosure are applied is not particularly limited.
  • materials that constitute the base material include various materials such as resins, rubbers, metals, glass, and ceramics.
  • resins for example, polycarbonate, polyethylene terephthalate, polyvinyl chloride, polyethylene, polypropylene, polymethylpentene, polyurethane, poly(meth)acrylate, polystyrene, polyacetal, polysulfone, polyethersulfone, fluorine resin (polyfluoride vinylidene, polyethylene tetrafluoride, etc.), acrylonitrile-butadiene-styrene (ABS) resin, polyamide, ethylene-vinyl acetate resin and the like.
  • rubber include silicone rubber and urethane rubber.
  • metals include various metal materials such as stainless steel, titanium, and aluminum.
  • the material that constitutes the base material of the medical device may be a mixture of two or more materials
  • the method of coating the substrate surface with the first to third medical coating agents of the present disclosure is not particularly limited.
  • the medical coating agent when the medical coating agent is in a solution state, at least a part of the substrate surface becomes a polymer (P ) can be obtained.
  • the coating method can be appropriately set according to the shape of the base material, purpose of use, etc.
  • coating methods include bar coaters, applicators, doctor blades, dip coaters, roll coaters, spin coaters, flow coaters, knife coaters, comma coaters, reverse coaters, die coaters, lip coaters, gravure coaters, micro gravure coaters, Various coating methods such as inkjet can be used.
  • the coating amount of the medical coating agent can be appropriately selected according to the application, material, etc. of the medical device so that the thickness of the coating layer formed by the medical coating agent is within the desired range.
  • the medical device whose substrate surface is coated with the first to third medical coating agents of the present disclosure is not particularly limited, and can be applied to various medical devices. Specifically, stents, catheters, blood bags, blood transfusion instruments, surgical instruments, dental instruments, blood circulation devices, blood purification devices, plasma separation devices, artificial blood vessels, artificial organs (e.g., artificial heart-lung, artificial kidney, etc.) ) can be exemplified.
  • the purpose and application are not particularly limited.
  • the first to third medical coating agents of the present disclosure may be used as antibacterial/antifouling coating agents.
  • the substrate of medical devices used in direct contact with blood As a material for coating the first to third medical coating agents of the present disclosure can be preferably applied.
  • AOI was added dropwise from the dropping funnel while maintaining the internal temperature at 10°C or lower.
  • the temperature was raised to room temperature (25° C.) and stirring was continued overnight.
  • 10 mL of saturated aqueous sodium bicarbonate solution was added dropwise to the flask to terminate the reaction.
  • 200 mL of the internal liquid was transferred to a separatory funnel to separate the organic layer and the aqueous layer.
  • 30 mL of ethyl acetate manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., special grade
  • ⁇ Quantification of hydration water Quantification of water of hydration contained in the polymer was performed using a differential scanning calorimeter (DSC). (Differential scanning calorimetry) Each of the obtained polymers was immersed in a large excess of pure water (10 g of pure water per 30 mg of polymer) and allowed to stand at room temperature (25° C.) for 3 days to retain water. The hydrated polymer was sandwiched between tweezers and taken out from the pure water. After removing the water adhering to each hydrated polymer using a medicine wrapping paper, 0.003 to 0.005 g of each hydrated polymer was added. Each was weighed in an aluminum pan. The weighed value at this time was defined as "X (unit: g)".
  • Each weighed polymer was cooled from 40°C to -100°C at a temperature raising/lowering rate of 5°C/min using a differential scanning calorimeter (measurement equipment: DSC214Polyma manufactured by NETZSCH, measurement atmosphere: air atmosphere). , -100°C for 5 minutes, and then heated to 40°C.
  • the water contained in each hydrous polymer was classified into intermediate water, free water and non-freezing water according to the following method according to the observed exothermic transition during the low-temperature crystal formation of water, and was quantified.
  • each ratio of the amount of intermediate water (unit: g) and the amount of non-freezing water (unit: g) to the weighed value (X (unit: g)) was calculated.
  • a polymer that was immersed in a large excess of pure water (10 g of pure water for 30 mg of polymer) and allowed to stand at room temperature (25 ° C.) for 3 days was used, and the temperature was increased at a rate of 5 ° C./min.
  • a syringe needle was inserted through the three-way cock, and argon was blown into the solution at 100 mL/min for 30 minutes to deoxygenate it. After that, the three-way cock was closed to seal the test tube.
  • the test tube was inserted into a heat block set at 60°C to initiate polymerization. The temperature of the heat block was appropriately adjusted so that the internal temperature was 60°C. After 3 hours, the test tube was cooled in an ice bath to stop the polymerization. Using a mixed solvent of hexane and acetone at a mass ratio of 3:7 as a solvent for reprecipitation purification, reprecipitation purification of the reaction solution was performed twice.
  • the recovered polymer was purified by reprecipitation to obtain a polymer A.
  • the weight average molecular weight was 71,300.
  • the saturated water content of the saturated water-containing polymer A was 12.0% by mass, the intermediate water content was 4.1% by mass, and the antifreeze water content was 7.9% by mass.
  • the weight average molecular weight was 100,800.
  • the saturated water content of the saturated water-containing polymer B was 31.5% by mass, the intermediate water content was 12.5% by mass, and the antifreeze water content was 11.9% by mass.
  • ⁇ Fibrinogen adsorption amount test (MicroBCA assay)> 0.2 (w / v) % each polymer solution (Example 1: acetone solution, Comparative Examples 1 and 2: ethyl acetate solution, Examples 2 to 9 and Comparative Example 3: methanol solution) was prepared, was used as a medical coating agent. 15 ⁇ L of each medical coating agent is dropped into each well of a 96-well plate (manufactured by Corning, general assay plate polypropylene 96-well perfect plate flat bottom non-sterile), left to dry for 3 days, and a coating substrate 1 for evaluation is obtained. Obtained.
  • PET polyethylene terephthalate
  • the spin coating conditions were 500 rpm, 5 s ⁇ 1,500 rpm, 10 s ⁇ 1,500 to 4,000 rpm (slope), 5 s ⁇ 4,000 rpm, 10 s ⁇ 4,000 to 0 rpm (slope), 5 s.
  • a coating substrate 2 for evaluation was obtained for each medical coating agent.
  • the resulting coated base material 2 for evaluation was cut into an 8 mm square, and 200 ⁇ L of plasma solution adjusted to a platelet seeding density of 4 ⁇ 10 7 /cm 2 was placed on each of the cut coated base materials 2 for evaluation. After culturing at 37° C. for 1 hour, the coating substrate 2 for evaluation was washed twice with PBS( ⁇ ).
  • the evaluation coating substrate 2 was immersed in a 1% glutaraldehyde PBS(-) solution and allowed to stand overnight at 4°C.
  • the coating substrate 2 for evaluation was taken out, washed first with PBS(-), then washed with an aqueous solution obtained by mixing PBS(-) and water at a volume ratio of 1:1, and finally with pure water in this order. washed.
  • the coating substrate for evaluation 2 was immersed in the target cleaning liquid for 10 minutes.
  • Table 1 shows the properties of the polymers used in Examples 1-9 and Comparative Examples 1-3, the evaluation results of the medical coating agents, and the evaluation results of Comparative Example 4.
  • the medical coating agent of Comparative Example 3 using the polymer L having the MEA unit and not having the structural unit (A) has a higher fibrinogen adsorption amount (FIB adsorption) than the medical coating agents of Examples 1 to 9. amount) and platelet adsorption number were both high, and it was confirmed that the antithrombotic property was inferior.
  • FIB adsorption fibrinogen adsorption amount

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JP2018033846A (ja) * 2016-09-02 2018-03-08 国立大学法人山形大学 医療用具用重合体、医療用具用材料及びそれを用いた医療用具
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