WO2023162926A1 - 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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WO2023162926A1
WO2023162926A1 PCT/JP2023/005991 JP2023005991W WO2023162926A1 WO 2023162926 A1 WO2023162926 A1 WO 2023162926A1 JP 2023005991 W JP2023005991 W JP 2023005991W WO 2023162926 A1 WO2023162926 A1 WO 2023162926A1
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polymer
water
coating agent
amount
meth
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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
    • 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
    • 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
    • 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
    • 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
    • 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
    • C08F20/00—Homopolymers and 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
    • C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
    • C08F20/10—Esters
    • C08F20/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate

Definitions

  • Patent Document 1 discloses the use of a polymer having structural units derived from 2-methoxyethyl acrylate as a biocompatible medical material.
  • Fibrinogen a type of blood coagulation factor, is considered one of the main components in blood involved in the formation of thrombi. Therefore, the present inventors considered that it is important to prevent fibrinogen from recognizing a medical device inserted into the body as a foreign body in order to suppress the formation of a thrombus that accompanies the insertion of a medical device. In other words, if the surface of a medical device can be sufficiently endowed with the property of suppressing the adsorption of fibrinogen (hereinafter also referred to as "anti-adsorption property"), the medical device can be endowed with excellent antithrombotic properties and improved biocompatibility. I can say.
  • the present disclosure has been made in view of such circumstances, and its purpose is to provide a medical coating agent that has high 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 urea 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 3.0% 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 8.0% by mass or more relative to the total amount of the saturated water-containing polymer.
  • the medical coating agent according to [1] above, which further satisfies [3] 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 the saturated water content state is 0.50 or more.
  • the polymer contained in the medical coating agent of the present disclosure has high fibrinogen anti-adsorption properties and excellent antithrombotic properties. 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
  • (Meth)acrylo means acrylo and/or methacrylo.
  • the first medical coating agent in the present disclosure is a polymer (hereinafter referred to as "polymer (P)”).
  • the polymer (P) contained in the first medical coating agent is soaked with water and heated at a rate of 5° C./min using a differential scanning calorimeter (DSC).
  • 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 urea bond.
  • the polymer (P) contained in the second medical coating agent is a DSC curve obtained by soaking the polymer (P) with water and using a DSC to raise the temperature at a rate of 5 ° C./min. , the following condition (ii) is satisfied when the hydrous state of the polymer (P) when the endothermic peak top due to the melting of ice appears at 0°C is defined as the "saturated hydrous state".
  • Condition (ii) The amount of water of hydration contained in the saturated water-containing polymer (P) is 8.0% by mass or more with respect to the total amount of the saturated water-containing polymer (P).
  • 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 urea bond.
  • the polymer (P) contained in the third medical coating agent is a DSC curve obtained by soaking the polymer (P) with water and raising the temperature using a DSC at a rate of 5 ° C./min. , the following condition (iii) is satisfied when the hydrous state of the polymer (P) when the endothermic peak top due to the melting of ice appears at 0°C is defined as the "saturated hydrous 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.
  • Antifreeze water refers to water that interacts strongly with polymers 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. In order for the polymer to acquire biocompatibility, it is believed 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, it is conceivable that a thrombus is formed due to the action of the body's defense function, impeding the function of the medical device and affecting 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.
  • This fibrinogen is one of the main components in blood that is involved in the formation of thrombi, and the fact that fibrinogen is difficult to adsorb onto polymers gives biocompatibility (more specifically, antithrombotic properties) to medical devices. considered important for
  • the polymer (P) contained in the first to third medical coating agents of the present disclosure easily retains intermediate water during hydration, and sufficiently allows fibrinogen to be adsorbed to the polymer (P). can be suppressed.
  • the first to third medical coating agents of the present disclosure can impart excellent antithrombotic properties to medical devices.
  • the polymer (P) contained in the first medical coating agent contains a structural unit derived from an ethylenically unsaturated monomer having a urea 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 polymer (P) has a ratio of structural units derived from a (meth)acrylic monomer to 50 mass of all structural units derived from the monomers constituting the polymer (P). %, more preferably 60% by mass or more, still more preferably 70% by mass or more, even more preferably 80% by mass or more, and even more preferably 90% by mass or more.
  • the monomer (M) is preferably a compound capable of introducing a structure having a urea bond into the side chain of the polymer, and is preferably a (meth)acrylic monomer having a urea 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.
  • the monomer (M) is from the viewpoint of obtaining a water-insoluble polymer (P) and from the viewpoint of increasing the amount of water of hydration retained by the polymer (P) when the polymer (P) is brought into contact with water.
  • the following general formula (I): CH2 CR1 -COO- R2 -NH-CO-NH-( R3O ) nR4 ...
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is an alkylene group having 2 to 5 carbon atoms
  • R 3 is an alkylene group having 1 to 3 carbon atoms
  • R 4 is an alkyl group having 1 to 12 carbon atoms, where n is an integer of 0 to 2, provided that the total number of carbon atoms in "-( R3O )n-" (that is, the number of carbon atoms in R3 multiplied by
  • n in general formula (I) is preferably 1 or 2, more preferably 1, from the viewpoint of sufficiently enhancing the anti-adsorption of fibrinogen and ensuring excellent biocompatibility.
  • R 4 in general formula (I) is more preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 or 2 carbon atoms.
  • Specific examples of the compound represented by the general formula (I) include 2-(3-(2-ethoxyethyl)ureido)ethyl (meth)acrylate, 2-(3-(3-methoxypropyl)ureido)ethyl (Meth)acrylate, 2-(3-(3-ethoxypropyl)ureido)ethyl (meth)acrylate, 2-(3-(4-methoxybutyl)ureido)ethyl (meth)acrylate, 3-(3-(2 - ethoxyethyl)ureido)propyl (meth)acrylate, 3-(3-(3-methoxypropyl)ureido)propyl (meth)acrylate, 4-(3-(2-ethoxyethyl)ureido)butyl (meth)acrylate, 2-(3-(n-butyl)ureido)ethyl (meth)acrylate, 2-(3
  • the monomer (M) is preferably a compound in which n in the general formula (I) is 1 and R 4 is an alkyl group having 1 to 5 carbon atoms. is more preferably 1 and R 4 is an alkyl group having 1 or 2 carbon atoms.
  • the polymer (P) may be composed only of structural units derived from the monomer (M).
  • the polymer (P) is a monomer other than the monomer (M) (hereinafter referred to as "other may further contain a structural unit derived from (also referred to as "monomer of").
  • Examples of other monomers include monomers that do not have a urea bond and are copolymerizable with the monomer (M).
  • 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, and (meth)acrylic acid.
  • Examples include isobornyl 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-butoxyethyl (meth)acrylate.
  • 3-methoxypropyl (meth)acrylate 3-ethoxypropyl (meth)acrylate, n-propoxypropyl (meth)acrylate, n-butoxypropyl (meth)acrylate, methoxybutyl (meth)acrylate,
  • Examples include ethoxybutyl meth)acrylate, n-propoxybutyl (meth)acrylate and n-butoxybutyl (meth)acrylate.
  • (Meth)acrylic acid hydroxyalkyl esters include 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, and 2-hydroxybutyl (meth)acrylate. , 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-cyanopropyl (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.
  • 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 preferred, more preferably an alkoxyalkyl (meth)acrylate having an alkoxyalkyl group having 3 to 12 carbon atoms, and an alkoxyalkyl (meth)acrylate having an alkoxyalkyl group having 3 or 4 carbon atoms. Esters are more preferred, and 2-methoxyethyl (meth)acrylate is particularly preferred.
  • 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 substrate coated with the first medical coating agent can be sufficiently imparted with the effect of suppressing the adsorption of fibrinogen, and is antithrombotic. This is preferable in that a medical device having excellent properties can be obtained.
  • 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, even more preferably 60% by mass or more, and even more preferably 80% by mass or more.
  • the polymer (P) when the polymer (P) is a copolymer of the monomer (M) and other monomers, the polymer (P) may be a random copolymer, a block copolymer, a graft copolymer, or the like. may be either. From the viewpoint of uniformly introducing a structure having a urea bond into the entire polymer to enhance the effect of improving antithrombotic properties, a random copolymer is preferred among the above.
  • 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 these treatments can be carried out by employing known methods.
  • an aqueous solvent may be used to recover the water-insoluble polymer with high purity.
  • 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 melting of ice appears at 0 ° C.
  • the water content state of the polymer is defined as "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).
  • "when the endothermic peak top due to melting of ice appears at 0 ° C.” means that the polymer contains sufficient water and can be regarded as being in a saturated water content state. A slight error (for example, 0°C ⁇ 0.2°C) in which the peak top appears near 0°C is allowed.
  • the polymer in a dry state is immersed in a large excess of water (specifically, water in an amount of 100 times or more with respect to the mass of the polymer). and allowed to stand while being immersed in water at room temperature (25° C.) for several days (for example, 3 days), and then the polymer taken out of the water is used.
  • a large excess of water specifically, water in an amount of 100 times or more with respect to the mass of the polymer.
  • the polymer is water-insoluble if it can be taken out of water by pinching the polymer in a water-containing state with tweezers or the like.
  • the polymer dissolves in water under the above immersion conditions and cannot be taken out of water by pinching the polymer with tweezers or the like, the polymer is water-soluble.
  • the polymer (P) contained in the first medical coating agent is water-insoluble.
  • 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 3.0% by mass or more with respect to the total amount of the saturated water-containing polymer (P). Since the intermediate water content is 3.0% by mass or more, when a coating layer is formed on the substrate surface using the first medical coating agent, the substrate surface has high anti-adsorption to fibrinogen. be able to. From this point of view, the amount of intermediate water contained in the saturated water-containing polymer (P) is preferably 3.5% by mass or more with respect to the total amount of the saturated water-containing polymer (P).
  • the upper limit of the amount of intermediate water contained in the saturated water-containing polymer (P) is not particularly limited. Since the water-soluble polymer dissolves in water, it does not become saturated with water, and therefore does not satisfy the condition (i).
  • the polymer (P) contained in the first medical coating agent sufficiently suppresses the adsorption of fibrinogen to the polymer (P), and from the viewpoint of imparting excellent antithrombotic properties to the substrate surface, the conditions In addition to (i), one or both of the following conditions (ii) and (iii) are 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 8.0% 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 high anti-adsorption to fibrinogen It is suitable in that properties can be imparted to the substrate surface.
  • the saturated water content of the polymer (P) is more preferably 10.0% by mass or more, more preferably 15.0% by mass, relative to the total amount of the polymer (P) in a saturated water content state. more preferably 17.0% by mass or more, and still more preferably 20.0% by mass or more.
  • the upper limit of the saturated water content of the polymer (P) relative to the total amount of the polymer (P) in a saturated water content state is not particularly limited, and is, for example, 60.0% by mass or less.
  • the polymer (P) when the ratio of the amount of intermediate water to the amount of antifreeze water contained in the polymer (P) in the saturated water content state is within the above range, the polymer (P) has a ratio of intermediate water to antifreeze water. By including a large amount, it is preferable in that it can sufficiently impart anti-adsorption properties of fibrinogen to the base material surface-treated with the first medical coating agent.
  • the ratio of the amount of intermediate water to the amount of antifreeze water is more preferably 0.70 or more, still more preferably 0.85 or more, and still more preferably 0.85 or more, with respect to hydration water retained by the polymer (P) in a saturated water content state. is greater than or equal to 0.90.
  • the upper limit of the ratio of the intermediate water amount to the antifreeze water amount is not particularly limited, and is, for example, 2.0 or less. It should be noted that water-soluble polymers do not become saturated with water and therefore do not satisfy conditions (ii) and (iii).
  • the preferred numerical ranges for the intermediate water content, the saturated water content, and the ratio of the intermediate water content to the antifreeze water content in the saturated water-containing polymer (P) can be set by appropriately combining the respective preferred numerical ranges described above.
  • the hydration water property of the polymer (P) in a saturated water content state is such that the intermediate water content is 3.5% 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 10.0% 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 0.70 or more
  • the intermediate water content is in a saturated water content state is 5.0% by mass or more based on the total amount of the polymer (P)
  • the saturated water content is 15.0% by mass or more based on the total amount of the polymer (P) in a saturated water-containing state
  • the glass transition temperature (Tg1) of the polymer (P) in a dry state is, for example, 80°C or lower, preferably 65°C or lower.
  • the lower limit of the glass transition temperature (Tg1) of the polymer (P) in a dry state is, for example, ⁇ 50° C. or higher.
  • the glass transition temperature (Tg1) of the polymer (P) in a dry state is not particularly limited, but is preferably ⁇ 35° C. or higher, more preferably ⁇ 30° C. or higher.
  • the glass transition temperature of the polymer (P) is a value measured by a differential scanning calorimeter (DSC) under the condition of a heating rate of 5° C./min.
  • DSC differential scanning calorimeter
  • the polymer (P) preferably has a glass transition temperature (Tg2) of -35°C or lower in a saturated water content state.
  • Tg2 of the polymer (P) in a saturated water-containing state is -35°C or lower, the anti-adsorption property of fibrinogen to the substrate surface can be sufficiently imparted, and the anti-thrombotic property can be enhanced.
  • the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state is preferably ⁇ 40° C. or less, more preferably ⁇ 50° C. or less, and ⁇ 55° C. or less. More preferred.
  • the lower limit of the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state is, for example, ⁇ 100° C. or higher.
  • the glass transition temperature (Tg2) of the polymer (P) in a saturated water content state is adjusted to a value within the desired temperature range by adjusting the type and amount of the monomers constituting the polymer (P). be able to.
  • the glass transition temperature of the homopolymer composed of the monomer (M) used in the production of the polymer (P) in a saturated water-containing state is higher than the desired temperature, the saturation of the homopolymer
  • the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state can be adjusted.
  • the difference ⁇ Tg is preferably 30° C. or higher, more preferably 35° C. or higher, still more preferably 50° C. or higher, still more preferably 55° C. or higher, and still more preferably 60° C. or higher.
  • 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 thereof 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; ethylene glycol.
  • esters such as monomethyl 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; dimethyl sulfoxide etc.
  • amide solvents such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide
  • hydrocarbons such as n-hexane, cyclohexane, toluene and xylene
  • dimethyl sulfoxide etc.
  • 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 of the medical coating agent (here, the amount of the solvent other than the solvent in the medical coating agent relative to the volume of the solvent used to prepare the medical coating agent
  • the mass ratio of the components is preferably 0.001 to 30 (w/v)%.
  • the solid content concentration of the medical coating agent is more 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 hydrated water content of 8.0% by mass with respect to the total amount of the saturated water-containing polymer. That's it.
  • the amount of hydration water contained in the polymer in the saturated water content state is 8.0% by mass or more with respect to the total amount of the polymer (P) in the saturated water content state, so that intermediate water is formed on the surface of the polymer (P). It can be present in a sufficient amount, and can impart a high anti-adsorption property to fibrinogen to the substrate surface.
  • the type and amount of the monomers constituting the polymer (P) contained in the second medical coating agent, the properties of the polymer (P), the preferable range of the condition (ii), the second medical coating agent The description of the first medical coating agent can be used for details of other components that may be contained.
  • the polymer (P) contained in the second medical coating agent sufficiently suppresses the adsorption of fibrinogen to the polymer (P), and from the viewpoint of imparting excellent antithrombotic properties to the substrate surface, the conditions In addition to (ii), it is preferable to satisfy the above condition (iii).
  • 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 polymer (P) contains a relatively large amount of intermediate water relative to the amount of antifreeze water, A high anti-adsorption property to fibrinogen can be imparted to the substrate surface.
  • the type and amount of the monomers constituting the polymer (P) contained in the third medical coating agent, the properties of the polymer (P), the preferable range of the condition (iii), the third medical coating agent The description of the first medical coating agent can be used for details of other components that may be contained.
  • 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 fibrinogen is high, and the antithrombotic 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 constituting the base material of the medical device to which the medical coating agent is applied may be
  • 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 medical devices for various uses.
  • 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.
  • 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 internal liquid was transferred to a 200 mL 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) was added to the aqueous layer and shaken to extract the aqueous layer, and this operation was successively performed twice.
  • 30 mL of saturated saline was added to the recovered organic layer, and the organic layer was shaken and washed, and this operation was successively performed twice.
  • 30 mg of anhydrous sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) was added to the organic layer after washing, and the mixture was stirred for 1 hour to dehydrate.
  • ⁇ 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 "XA (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 (XA (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.
  • Tg2 glass transition temperature
  • 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 ethyl acetate as an organic solvent for reprecipitation purification, the reaction solution was purified by reprecipitation twice.
  • the recovered polymer was purified by reprecipitation using pure water as a water-based solvent for reprecipitation purification, and a polymer A was obtained.
  • the saturated water content of the saturated water-containing polymer A was 34.5% by mass
  • the intermediate water content was 19.1% by mass
  • the antifreeze water content was 14.2% by mass.
  • the glass transition temperature (Tg1) of the polymer A in a dry state was 23°C
  • the glass transition temperature (Tg2) in a saturated water-containing state was -64°C.
  • Table 1 shows the values of saturated water content, intermediate water content, non-freezing water content, glass transition temperature in a dry state (Tg1) and glass transition temperature in a saturated water content state (Tg2).
  • the ratio of the intermediate water content and the difference ⁇ Tg between Tg2 and Tg1 are shown (the same applies to the following production examples and comparative production examples).
  • Polymer B was obtained in the same manner as in Production Example 1 except that 3 g of EEA-UMA as a monomer, 0.044 g of V-65 initiator as a radical initiator, and 7 g of dimethylformamide as a solvent were used.
  • Ta The saturated water content of polymer B in a saturated water content state was 29.8% by mass, the intermediate water content was 12.1% by mass, and the antifreeze water content was 17.3% by mass.
  • the glass transition temperature (Tg1) of polymer B in a dry state was 52°C
  • the glass transition temperature (Tg2) in a saturated water-containing state was -61°C.
  • ⁇ Fibrinogen adsorption amount test (MicroBCA assay)> A 0.2 (w/v)% polymer solution (methanol solution) was prepared and used as a medical coating agent. 15 ⁇ L of each medical coating agent is dropped into each well of a 96-well plate (Corning, General Assay Plate Polypropylene 96-well Perfect Plate Flat Bottom Non-Sterilized) and left to dry for 3 days to obtain a coating substrate for evaluation. Ta. After that, 50 ⁇ L of a solution prepared by dissolving fibrinogen to 1 mg/mL in PBS( ⁇ ) (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) was added to each well. Then, it was incubated at 37°C for 10 minutes.
  • the absorbance at 540 nm was measured using a plate reader (Vmax KINETIC MICROPLATE READER manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). Based on the fibrinogen concentration of the obtained extract, the amount of fibrinogen adsorbed per unit area on the coating substrate for evaluation (hereinafter also referred to as "FIB adsorption amount”) was calculated. It can be judged that the smaller this value (unit: ⁇ g/cm 2 ), the better the antithrombotic property.
  • a marked line for concentration calculation was prepared using bovine serum albumin attached to the Micro BCA Protein Assay Kit (manufactured by Thermo Scientific) according to the instructions.
  • Comparative Example 1 A medical coating agent containing polymer G was examined to conduct a fibrinogen adsorption amount test.
  • the polymer G is water-soluble, and even if the surface of the base material of the medical device is coated with the polymer G, when the medical device is inserted into the blood, the coating layer on the base surface The polymer G of is eluted into the blood. Therefore, in Comparative Example 1, the fibrinogen adsorption amount test was discontinued.
  • Table 1 shows the properties of the polymers used in Examples 1 to 6 and Comparative Examples 1 and 2, the evaluation results of the medical coating agents, and the evaluation results of Comparative Example 3.
  • "-" indicates that the measurement was not possible or the measurement was not performed.
  • the medical coating agents of Examples 1 to 6 had a small fibrinogen adsorption amount (FIB adsorption amount) and were excellent in antithrombotic properties. This is because the polymers A to F contained in the medical coating agents of Examples 1 to 6 have a large amount of intermediate water on the surface of the polymer, making it difficult for them to be recognized as foreign substances by biological components, and they can exhibit excellent antithrombotic properties. This is thought to be due to
  • the medical coating agent of Comparative Example 1 containing the polymer G consisting of MEA-UA units the polymer G is water-soluble and the coating layer is easily peeled off in vivo. It is difficult to use as a coating agent.
  • the medical coating agent of Comparative Example 2 using the polymer H consisting of MEA units had a larger FIB adsorption amount than the medical coating agents of Examples 1 to 6, and was inferior in antithrombotic properties. .

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JP2017082174A (ja) * 2015-10-30 2017-05-18 国立大学法人山形大学 ポリマー、ポリマー溶液及びポリマー被覆基板

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KOBAYASHI SHINGO, WAKUI MIYUKI, IWATA YUKIHISA, TANAKA MASARU: "Poly(ω-methoxyalkyl acrylate)s: Nonthrombogenic Polymer Family with Tunable Protein Adsorption", BIOMACROMOLECULES, AMERICAN CHEMICAL SOCIETY, US, vol. 18, no. 12, 11 December 2017 (2017-12-11), US , pages 4214 - 4223, XP055773539, ISSN: 1525-7797, DOI: 10.1021/acs.biomac.7b01247 *

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