WO2020213529A1 - 抗血栓性材料、抗血栓性材料の製造方法、人工臓器及び抗血栓性付与剤 - Google Patents

抗血栓性材料、抗血栓性材料の製造方法、人工臓器及び抗血栓性付与剤 Download PDF

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WO2020213529A1
WO2020213529A1 PCT/JP2020/016144 JP2020016144W WO2020213529A1 WO 2020213529 A1 WO2020213529 A1 WO 2020213529A1 JP 2020016144 W JP2020016144 W JP 2020016144W WO 2020213529 A1 WO2020213529 A1 WO 2020213529A1
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Prior art keywords
antithrombotic
base material
structural unit
average molecular
molecular weight
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English (en)
French (fr)
Japanese (ja)
Inventor
賢 田中
八尾　滋
翔 平井
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Kyushu University NUC
Fukuoka University
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Kyushu University NUC
Fukuoka University
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Priority to JP2021514925A priority Critical patent/JP7457308B2/ja
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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
    • 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
    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule

Definitions

  • the present disclosure relates to an antithrombotic material, a method for producing an antithrombotic material, an artificial organ, and an antithrombotic imparting agent.
  • Medical materials are often composed of in vitro materials and are recognized as foreign substances by biomolecules.
  • biocompatibility for example, antithrombotic property
  • Patent Document 2 shows that the polymer contains a repeating unit derived from (meth) acrylate having a polyethylene oxide chain in the side chain, and describes that the polymer may be a copolymer. ing. On the other hand, Patent Document 2 does not study the influence of the weight average molecular weight and the like of each unit constituting the copolymer.
  • Medical materials need to be relatively stable even in the living body, so they are often manufactured using chemically stable substrates. On the other hand, it is difficult to impart antithrombotic properties to these base materials due to their excellent chemical stability, and the choice of base material may be limited. Further, according to the study by the present inventors, when the polymer described in Patent Document 2 is used to impart antithrombotic properties on the substrate, the adhesion between the polymer and the substrate may not be sufficient. For example, exposure to a flow of blood, body fluid, or the like can cause the polymer to peel off from the substrate. In order to impart antithrombotic properties, it is conceivable to perform special processing such as plasma treatment on the surface of the base material, but the manufacturing process tends to be complicated.
  • An object of the present disclosure is to provide an antithrombotic material having excellent antithrombotic properties and which can be easily manufactured. It is also an object of the present disclosure to provide a method for producing an antithrombotic material having excellent antithrombotic properties. The present disclosure is also intended to provide an antithrombotic imparting agent useful for modifying a substrate.
  • One aspect of the present disclosure comprises a base material and a surface-modified layer provided on at least a part of the base material, and the surface-modified layer is composed of a group consisting of an alkylene chain and a halogenated alkylene chain.
  • a block copolymer having a first structural unit having at least one selected structural unit in a side chain and a second structural unit represented by the following general formula (1) is included, and the first structural unit is used.
  • an antithrombotic material having a weight average molecular weight of a unit containing 9000 to 15000 and a weight average molecular weight of a unit containing the second structural unit of 10,000 to 40,000.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a methyl group or an ethyl group
  • n represents an integer of 1 to 6
  • m represents an integer of 1 to 100
  • x Indicates an integer greater than or equal to 1.
  • the antithrombotic material is excellent in antithrombotic material because the surface modification layer contains a block copolymer having the second structural unit and the weight average molecular weight of each unit in the block copolymer is within the above range. It has thrombotic properties. Further, since the block copolymer having the first structural unit is contained and the weight average molecular weight of each unit in the block copolymer is within the above range, a surface modification layer may be provided on the base material. It is easy, and the antithrombotic substrate can be easily produced.
  • the alkylene chain may have 8 or more carbon atoms.
  • the carbon number of the alkylene chain and the halogenated alkylene chain is within the above range, the side chain crystallinity of the block copolymer can be further improved, and the adhesive force between the surface modified layer and the base material can be further improved. Can be improved.
  • the surface modification layer can be more easily formed on the base material.
  • the base material may be a hard-to-modify base material. Since the above-mentioned surface-modifying layer contains the above-mentioned specific block copolymer, the surface-modifying layer can be provided even if the base material is difficult to modify.
  • the base material may be at least one selected from the group consisting of polyolefins, polystyrenes, and fluoropolymers.
  • One aspect of the present disclosure comprises a base material and a surface-modified layer provided on at least a part of the base material, and the surface-modified layer is composed of a group consisting of an alkylene chain and a halogenated alkylene chain.
  • a block copolymer having a first structural unit having at least one selected structural unit in a side chain and a second structural unit represented by the following general formula (1) is included, and the first structural unit is used.
  • an artificial organ having a weight average molecular weight of a unit containing 9000 to 15000 and a weight average molecular weight of a unit containing the second structural unit of 10,000 to 40,000.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a methyl group or an ethyl group
  • n represents an integer of 1 to 6
  • m represents an integer of 1 to 100
  • x Indicates an integer greater than or equal to 1.
  • the artificial organ has an excellent antithrombotic property because it has a surface modification layer containing the above-mentioned specific block copolymer. Further, since the surface modification layer contains the above-mentioned specific block copolymer, it can be easily produced.
  • One aspect of the present disclosure is a method for producing an antithrombotic material, in which the block copolymer is applied to at least a part of the base material by contacting the base material with a solution containing the block copolymer.
  • the block copolymer comprises a first structural unit having at least one selected from the group consisting of an alkylene chain and a halogenated alkylene chain in a side chain, which comprises a step of forming a surface modified layer containing the above.
  • Provided is a method for producing an antithrombotic material having a weight average molecular weight of 10,000 to 40,000.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a methyl group or an ethyl group
  • n represents an integer of 1 to 6
  • m represents an integer of 1 to 100
  • x Indicates an integer greater than or equal to 1.
  • the method for producing the antithrombotic material uses a solution containing a block copolymer having the first structural unit and having a weight average molecular weight of each unit within the above range, the surface is modified on the substrate.
  • the polymer layer can be easily formed.
  • the method for producing the antithrombotic material has a surface modification layer containing a block copolymer having the second structural unit and a weight average molecular weight of each unit within the above range on the substrate. ,
  • the obtained antithrombotic material is excellent in antithrombotic property.
  • the temperature of the above solution may be room temperature or higher. By setting the temperature of the solution to room temperature or higher, a surface modification layer can be more easily formed on the base material. By setting the temperature of the solution to room temperature or higher, the stability of the obtained antithrombotic material against heat can be further improved.
  • the base material and the solution may be brought into contact with each other in a state where at least one of the base material and the solution is heated to 60 ° C. or higher.
  • the block copolymer in the solution can be more firmly adhered to the surface of the base material.
  • the alkylene chain may have 8 or more carbon atoms.
  • the base material may be a hard-to-modify base material. Since the above-mentioned method for producing an antithrombotic material uses a solution containing the above-mentioned specific block copolymer, the antithrombotic material can be produced even when a poorly modifying base material is used. be able to. When producing an antithrombotic material, it is not always necessary to pretreat the substrate.
  • the base material may be at least one selected from the group consisting of polyolefins, polystyrenes, and fluoropolymers.
  • One aspect of the present disclosure is a first structural unit having at least one selected from the group consisting of an alkylene chain and a halogenated alkylene chain in a side chain, and a second structure represented by the following general formula (1).
  • a unit containing a block copolymer having a unit and containing the first structural unit has a weight average molecular weight of 9000 to 15000, and a unit containing the second structural unit has a weight average molecular weight of 10000 to 40,000.
  • an antithrombotic imparting agent is provided.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a methyl group or an ethyl group
  • n represents an integer of 1 to 6
  • m represents an integer of 1 to 100
  • x Indicates an integer greater than or equal to 1.
  • the antithrombotic agent has a first structural unit and a second structural unit, and contains a block copolymer having a weight average molecular weight of each unit within the above range. It is suitable for imparting antithrombotic properties.
  • an antithrombotic material having excellent antithrombotic properties it is possible to provide an antithrombotic material having excellent antithrombotic properties and which can be easily manufactured. According to the present disclosure, it is also possible to provide a method for producing an antithrombotic material having excellent antithrombotic properties. According to the present disclosure, it is also possible to provide an antithrombotic imparting agent useful for modifying a base material.
  • FIG. 1 is a schematic cross-sectional view showing an example of an antithrombotic material.
  • FIG. 2 is a graph showing the evaluation results of the antithrombotic property of the antithrombotic material in the examples.
  • FIG. 1 is a schematic cross-sectional view showing an example of an antithrombotic material.
  • the antithrombotic material 10 includes a base material 2 and a surface modification layer 4 provided on the base material 2.
  • the surface modification layer 4 is provided on all the surfaces of the base material 2, but may be provided only on a part of the surface of the base material 2.
  • the base material 2 may contain, for example, polyolefin, polyester, polyamide, polystyrene, polyimide, polyurethane, a fluoropolymer, and the like, and is at least one selected from the group consisting of polyolefin, polystyrene, and fluoropolymer. May be good.
  • the polyolefin include polyethylene and polypropylene.
  • the polyester include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polycyclohexane terephthalate and the like.
  • the polyamide include nylon and the like.
  • the fluorine-based polymer include polytetrafluoroethylene and the like.
  • the base material 2 may be a hard-to-modify base material, and may contain at least one selected from the group consisting of polyolefins, polyesters and fluoropolymers.
  • the term "difficult-to-modify” means various functions on the surface due to its low solubility in organic solvents and polar solvents, or its high crystallinity and high resistance to physical treatment such as plasma. It means a property in which it is extremely difficult to introduce a group.
  • the shape of the base material 2 may be, for example, a sheet shape, a tube shape, a rod shape, or the like.
  • the base material 2 may also have irregularities, may be a porous body, a woven fabric, a non-woven fabric, or the like, and may have a complicated shape such as an artificial organ. Since the antithrombotic material can be produced by a method of contacting with a solution as described later, the surface modification layer 4 can be provided on the surface regardless of the shape.
  • the surface-modified layer 4 has a first structural unit having at least one selected from the group consisting of an alkylene chain and a halogenated alkylene chain in a side chain, and a second structure represented by the following general formula (1). Includes block copolymers with units.
  • the surface modification layer 4 may be composed of only the block copolymer.
  • the halogen constituting the halogenated alkylene chain may contain, for example, fluorine, chlorine, bromine, or the like, or may contain fluorine.
  • the number of carbon atoms in the alkylene chain may be 8 or more.
  • the carbon number of the alkylene chain may be, for example, 10 or more, 12 or more, 14 or more, 16 or more, or 17 or more.
  • the surface modification layer can be more easily formed on the base material.
  • the carbon number of the alkylene chain may be, for example, 30 or less, 28 or less, 26 or less, 24 or less, 22 or less, 20 or less, or 18 or less.
  • the carbon number of the alkylene chain can be adjusted within the above range, and may be, for example, 8 to 30 or 8 to 16.
  • the carbon number of the alkylene chain can be adjusted within the above range, the adhesive strength between the surface modification layer and the base material and the antithrombotic property are compatible at a higher level, and the platelets attached to the antithrombotic material. From the viewpoint of further suppressing the progress of the stage, for example, it may be 8 to 30, 16 to 30, or 17 to 22.
  • the alkylene chain may be linear.
  • the halogenated alkylene chain may have 3 or more carbon atoms or 4 or more carbon atoms.
  • the halogenated alkylene chain may have, for example, less than 6 carbon atoms and 5 or less carbon atoms.
  • the carbon number of the halogenated alkylene chain can be adjusted within the above range, and may be, for example, 3 to 6 or 3 to 5.
  • the halogenated alkylene chain may be linear.
  • R 1 represents a hydrogen atom or a methyl group.
  • R 2 represents a methyl group or an ethyl group.
  • n represents an integer of 1 to 6, and may be, for example, an integer of 1 to 5 or an integer of 1 to 3.
  • m represents an integer of 1 to 100, and may be, for example, an integer of 1 to 30 or an integer of 1 to 9.
  • x indicates an integer of 1 or more.
  • the weight average molecular weight of the block copolymer may be 19000 or more, or 20000 or more. When the weight average molecular weight of the block copolymer is within the above range, the solution viscosity of the block copolymer can be made appropriate, and the surface modification layer can be more easily formed on the substrate. be able to.
  • the weight average molecular weight of the block copolymer may also be, for example, 150,000 or less, 100,000 or less, 50,000 or less, or 30,000 or less. When the weight average molecular weight of the block copolymer is within the above range, it is possible to suppress an increase in the solution viscosity of the block copolymer and further improve workability when forming the surface-modified layer on the substrate. Can be done.
  • the weight average molecular weight of the block copolymer may be adjusted within the above range, and may be, for example, 19000 to 150,000 or 19000 to 30,000.
  • the weight average molecular weight in the present specification means a value measured by gel permeation chromatography and is a polystyrene-equivalent molecular weight.
  • the polymer constituting the surface modification layer in the antithrombotic substrate is to be measured, for example, nuclear magnetic resonance ( 1 H-NMR and 13 C-NMR) and mass spectrometry (MS) are used. It can be used to determine the weight average molecular weight of the copolymer.
  • the polymer is a block copolymer
  • the weight average molecular weight of the units constituting the block copolymer can be specified by performing elemental analysis in addition to the above method.
  • the unit may include, for example, a first structural unit and a second structural unit, and may be composed of only the first structural unit or the second structural unit.
  • the weight average molecular weight of the unit including the first structural unit is 9000 or more, but may be 10,000 or more, for example.
  • the adhesion stability between the base material 2 and the surface modification layer 4 is more excellent.
  • the weight average molecular weight of the unit containing the first structural unit is within the above range, it becomes easier to provide the surface modification layer 4 on the base material 2 when producing the antithrombotic material 10.
  • the weight average molecular weight of the unit including the first structural unit is 15,000 or less, but may be 14,000 or less, for example.
  • the solution viscosity of the block copolymer when producing the antithrombotic material 10 can be made appropriate, and the base material can be used. It becomes easier to provide the surface modification layer 4 on the 2.
  • the weight average molecular weight of the unit containing the second structural unit is 10,000 or more, but may be, for example, 11,500 or more, or 12,000 or more. When the weight average molecular weight of the unit containing the second structural unit is within the above range, the antithrombotic property of the antithrombotic material 10 is more excellent.
  • the weight average molecular weight of the unit containing the second structural unit is 40,000 or less, but may be, for example, 30,000 or less, 15,000 or less, or 13,000 or less.
  • the weight average molecular weight of the unit containing the second structural unit is within the above range, it is possible to maintain appropriate hydrophilicity and suppress a decrease in solubility.
  • the base material is sufficiently soluble in a solvent such as water when the antithrombotic material 10 is produced. It becomes easier to provide the surface modification layer 4 on the 2.
  • the weight average molecular weight of the unit including the first structural unit is 9000 to 15000
  • the weight average molecular weight of the unit including the second structural unit is 10,000 to 40,000.
  • the weight average molecular weight of the containing unit and the weight average molecular weight of the unit containing the second structural unit may be adjusted within the above ranges.
  • the weight average molecular weight of the unit including the first structural unit may be 9000 to 14000
  • the weight average molecular weight of the unit including the second structural unit may be 10,000 to 12000.
  • the solution viscosity of the block copolymer can be made appropriate, and A surface-modified layer can be more easily formed on the substrate.
  • the weight average molecular weight of the unit containing the second structural unit may be larger than the weight average molecular weight of the unit containing the first structural unit.
  • the antithrombotic property is further improved by designing the block copolymer so that the weight average molecular weight of the unit containing the second structural unit is larger than the weight average molecular weight of the unit containing the first structural unit. Moreover, the progress of the stage of platelets attached to the antithrombotic material can be further suppressed.
  • the antithrombotic material 10 is excellent in antithrombotic property.
  • Adhesive number of platelets to antithrombotic material 10 for example, less than 3 ⁇ 10 5 cells / cm 2 , 2 ⁇ 10 than 5 cells / cm 2, 1 ⁇ 10 than 5 cells / cm 2, 0.5 ⁇ 10 5 It can be less than cells / cm 2, less than 0.3 ⁇ 10 5 cells / cm 2 , or less than 0.1 ⁇ 10 5 cells / cm 2 .
  • the number of platelets adhered to the antithrombotic material 10 means a value observed by the platelet adhesion test described in Examples described later.
  • the antithrombotic material 10 has excellent hydrophilicity on the surface of the base material.
  • the contact angle on the surface of the antithrombotic material 10 can be, for example, less than 100 °, less than 90 °, or less than 80 °.
  • the contact angle on the surface of the antithrombotic material 10 means a value measured by the method described in Examples described later.
  • the antithrombotic material 10 can be suitably used for, for example, an artificial organ having a site in contact with a biological substance such as blood, a medical device, or the like.
  • the antithrombotic material 10 includes, for example, a blood filter, a blood storage bag, a platelet storage bag, an artificial lung device, a blood circuit, an artificial blood vessel, an artificial heart, an indwelling needle, a catheter, a guide wire, a stent, an artificial joint, and the like. It can be suitably used for endoscopes, dialysis machines and the like.
  • the above-mentioned antithrombotic material can be produced, for example, by the following method.
  • One embodiment of the method for producing an antithrombotic material is a step of preparing a block copolymer (step S1) and contacting the base material with a solution containing the block copolymer to bring the base material into contact with each other.
  • a step (step S2) of forming a surface modification layer containing the block copolymer is included in at least a part of the above.
  • the block copolymer may be the block copolymer described above.
  • the block copolymer has a first structural unit having at least one selected from the group consisting of an alkylene chain and a halogenated alkylene chain in a side chain, and a second structural unit represented by the general formula (1). It may be a block copolymer having the structural unit of.
  • Step S1 may be, for example, a step of preparing a ready-made block copolymer or a step of polymerizing a predetermined monomer to prepare a block copolymer.
  • the polymerization in step S1 may be, for example, living radical polymerization.
  • a second monomer After polymerizing the first monomer to prepare a unit containing the first structural unit, a second monomer may be added and polymerized to prepare a unit containing the second structural unit.
  • the type of living radical polymerization may be, for example, a nitroxide medium polymerization (NMP) method.
  • NMP nitroxide medium polymerization
  • As the polymerization solvent for example, butyl acetate, toluene, xylene and the like may be used.
  • the first monomer is a polymerizable compound that gives the first structural unit.
  • the first monomer for example, an ester of (meth) acrylic acid and an alcohol having at least one of an alkylene chain and a halogenated alkylene chain can be used.
  • the first monomer may be, for example, an alkyl (meth) acrylate, a fluoroalkyl (meth) acrylate or the like.
  • the type and blending amount of the first monomer can be adjusted depending on the type of the base material to which the solution containing the obtained block copolymer is brought into contact.
  • an alkyl (meth) acrylate may be used
  • a base material containing a fluorine-based polymer when used, a fluoroalkyl (meth) acrylate may be used.
  • alkyl (meth) acrylate examples include octyl (meth) acrylate, dodecyl (meth) acrylate, tetradecyl (meth) acrylate, hexadecyl (meth) acrylate, octadecyl (meth) acrylate (also referred to as stearyl (meth) acrylate), and Examples thereof include docosyl (meth) acrylate (also referred to as behenyl (meth) acrylate).
  • fluoroalkyl (meth) acrylate examples include 1H, 1H, 7H-dodecafluoroheptyl (meth) acrylate, 1H, 1H, 2H, 2H-tridecafluoro-n-octyl (meth) acrylate, and 1H, 1H, Examples thereof include 2H and 2H-heptadecafluoro-n-decyl (meth) acrylate.
  • the above compounds may be used alone or in combination of two or more.
  • the second monomer is a polymerizable compound that gives a second structural unit.
  • the type and blending amount of the second monomer can be adjusted according to the properties such as antithrombotic property required for the antithrombotic material to be produced.
  • the second monomer for example, a polymerizable compound having an oxyalkylene group or the like can be used.
  • the second monomer include poly (2-methoxyethyl acrylate), polytetrahydrofurfuryl acrylate, 2- (2-methoxyethoxy) ethyl (meth) acrylate, and 2- (2-ethoxyethoxy) ethyl (meth).
  • an alkoxyamine-based initiator such as 2-[[tert-butyl [1- (diethoxyphosphinyl) -2,2-dimethylpropyl] amino] oxy] isobutyric acid can be used. it can.
  • an alkoxyamine-based initiator such as 2-[[tert-butyl [1- (diethoxyphosphinyl) -2,2-dimethylpropyl] amino] oxy] isobutyric acid
  • RAFT polymerization method reversible addition cleavage chain transfer polymerization method
  • ATRP method atom transfer radical polymerization method
  • NMP method nitroxide radical polymerization method
  • the polymerization initiator May be used in combination with a chain transfer agent, a metal complex, or the like.
  • the polymerization initiator is, for example, a RAFT agent such as trithiocarbonate, an organic halide such as ⁇ -chloroketone, and an NMP initiation such as a (2,2,6,6-tetramethylpiperidinooxy) radical. Agents and the like can be used.
  • RAFT agent such as trithiocarbonate
  • organic halide such as ⁇ -chloroketone
  • NMP initiation such as a (2,2,6,6-tetramethylpiperidinooxy) radical.
  • Agents and the like can be used.
  • the above compounds may be used alone or in combination of two or more.
  • step S1 is an arbitrary step.
  • a method for producing the antithrombotic material for example, a solution containing the block copolymer described above (for example, an antithrombotic agent) may be directly obtained and step S2 may be carried out.
  • Step S2 is a step of performing a coating treatment for forming a surface modification layer on at least a part of the base material.
  • step S2 as a method of bringing the base material into contact with the solution containing the block copolymer, for example, a method of applying the above solution to the base material, a method of immersing the base material in the above solution, and the like can be used. .. From the viewpoint of reducing the influence of the shape of the base material and more easily producing the antithrombotic material, as a method of bringing the base material into contact with the solution containing the block copolymer, the base material is immersed in the above solution. It may be a method.
  • the above solution may consist of only the block copolymer, or may contain a solvent in addition to the block copolymer.
  • the above solution preferably contains a solvent and dissolves the block copolymer.
  • the solvent is preferably one that can dissolve the block copolymer.
  • the solvent may be, for example, ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO) or the like.
  • the temperature of the solution may be adjusted to room temperature or higher.
  • the temperature of the solution may be, for example, 30 ° C. or higher, 60 ° C. or higher, or 80 ° C. or higher.
  • the temperature of the solution may be, for example, 120 ° C. or lower, or 100 ° C. or lower.
  • the inventors raise the activity of the molecules constituting the surface of the base material by raising the temperature of the solution, and at the same time, the block copolymer in the solution is released. It is presumed that it is possible to penetrate the surface layer of the base material.
  • step S2 by setting the temperature of the solution to 60 ° C. or higher, the adhesion between the base material and the block copolymer can be further strengthened, and the flow of blood, body fluid, or the like causes the base material to come off. It is possible to more sufficiently suppress the peeling of the surface modified layer.
  • the above-mentioned effect can be obtained by performing the coating treatment on the base material forming the surface modification layer under the condition of 60 ° C. or higher.
  • the effect of suppressing peeling of the surface modification layer from the above-mentioned base material can be further improved by setting the temperature of the above-mentioned solution to 80 ° C. or higher.
  • Step S2 is preferably carried out by bringing the base material and the solution into contact with each other in a state where at least one of the base material and the solution is heated to 60 ° C. or higher.
  • the coating treatment method may be a method in which a solution containing the block copolymer is heated to 60 ° C. or higher and the base material is immersed in the heated solution. It may be a method of heating to °C or more and bringing a solution containing a block copolymer into contact with the heated base material, after heating both the solution containing the block copolymer and the base material to 60 °C or more. , The method may be a method in which both are brought into contact with each other.
  • the temperature in the coating treatment is preferably 80 ° C. or higher.
  • the means for bringing the solution containing the block copolymer into contact with the substrate may be, for example, a spray or the like.
  • poly (stearyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl acrylate) (indicated by SCCBC in the reaction formula) was obtained.
  • the weight average molecular weight of SCCBC obtained by the repolymerization was 21000. That is, the weight average molecular weight of the unit portion of poly (2- (2-ethoxyethoxy) ethyl acrylate) was 12000.
  • the molecular weight dispersion (Mw / Mn) of the obtained SCCBC was 1.41.
  • Stearyl acrylate and 2- (2-ethoxyethoxy) ethyl acrylate were used after removing the stabilizer before use.
  • the stearyl acrylate was made into a liquid under the condition of 60 ° C., a stabilizer removing agent was added thereto, and the stabilizer was removed by stirring under the condition of 60 ° C. for 10 minutes.
  • 2- (2-ethoxyethoxy) ethyl acrylate the stabilizer was added, and the stabilizer was removed by stirring at room temperature for 10 minutes.
  • An antithrombotic material was prepared using the SCCBC synthesized as described above.
  • the antithrombotic property was evaluated using the antithrombotic material (the base material having a plate shape) prepared as described above as a test piece.
  • the antithrombotic property was evaluated by the platelet adhesion test described later.
  • a platelet solution was prepared from human blood. Specifically, human blood was centrifuged at a rotation speed of 1500 rpm for 5 minutes, and the supernatant was collected as platelet-rich plasma (PRP). After collecting the supernatant, the remaining human blood components were centrifuged at a rotation speed of 4000 rpm for 10 minutes, and the supernatant was collected as platelet pore plasma (PPP). The above PPP was diluted 800-fold with a phosphate buffered saline (PBS) solution to prepare a diluted solution. The diluted solution was added to the above PRP and diluted until the platelet concentration reached 4 ⁇ 10 7 cell / mL to prepare a platelet solution. The concentration of the platelet solution was determined by confirming the number of platelets observed with a microscope.
  • PBS phosphate buffered saline
  • test piece to be measured was fixed on a sample table for a scanning electron microscope (SEM). 200 ⁇ L of the above platelet solution was added dropwise onto the test piece, and the mixture was allowed to stand for 1 hour under the condition of 37 ° C. The test piece was then washed twice with PBS. The test piece after washing with PBS was immersed in a 1% glutaraldehyde solution and allowed to stand for 2 hours under the condition of 37 ° C. to fix the surface condition. The fixed test piece was immersed in a mixture of PBS, PBS and water (a solution in which PBS and water were mixed so as to have a volume ratio of 1: 1) and water in this order for 10 minutes, 8 minutes and 8 minutes, respectively. The mixture was washed, immersed in water, washed for 8 minutes, and then air-dried at room temperature.
  • SEM scanning electron microscope
  • the number of platelets adhered to the test piece after air drying was measured using a scanning microscope.
  • the number of platelets adhered depends on the stage of platelets, from type I (normal type: platelets adhering to the material surface in a spherical form similar to that in blood) and type II (artificial limb formation type: spherical platelets).
  • type I normal type: platelets adhering to the material surface in a spherical form similar to that in blood
  • type II artificial limb formation type: spherical platelets
  • Activated platelets with artificial limbs formed and type III (extended type: platelets with greatly expanded cell body and more activated than type II).
  • the measurement was performed in three visual fields on the test piece, and the average value was taken as the platelet adhesion number. The results are shown in Table 1 and FIG. In addition, in Table 1 and FIG.
  • hydrophilicity of antithrombotic material The hydrophilicity was evaluated using the antithrombotic material (the base material having a plate shape) prepared as described above as a test piece. The hydrophilicity was evaluated by the contact angle measurement test described later. The results are shown in Table 1.
  • the contact angle was measured using an automatic contact angle meter for the dropped water droplets.
  • the contact angle of the water droplet is determined by the contact point between the surface (test surface X) provided with the surface modification layer of the antithrombotic material and the water droplet W as the origin O, and the tangent line L between the test surface X and the water droplet W.
  • the angle formed was ⁇ .
  • Example 2 The weight average molecular weight of the unit portion of poly (2- (2-ethoxyethoxy) ethyl acrylate) is such that the weight average molecular weight of poly (stearyl acrylate) is 14,000 and the weight average molecular weight of SCCBC obtained by additional polymerization is 24,000.
  • the antithrombotic agent and the antithrombotic material were prepared in the same manner as in Example 1 except that the amounts of stearyl acrylate and 2- (2-ethoxyethoxy) ethyl acrylate used were adjusted to 10000). Prepared.
  • the obtained antithrombotic material was evaluated for antithrombotic property in the same manner as in Example 1. The results are shown in Table 1 and FIG.
  • the weight average molecular weight of the unit portion of poly (2- (2-ethoxyethoxy) ethyl acrylate) is such that the weight average molecular weight of poly (stearyl acrylate) is 8000 and the weight average molecular weight of SCCBC obtained by the additional polymerization is 13000.
  • the antithrombotic agent and the antithrombotic material were prepared in the same manner as in Example 1 except that the amounts of stearyl acrylate and 2- (2-ethoxyethoxy) ethyl acrylate used were adjusted to be 5000). Prepared.
  • the obtained antithrombotic material was evaluated for antithrombotic property in the same manner as in Example 1. The results are shown in Table 1 and FIG.
  • the weight average molecular weight of the unit portion of poly (2- (2-ethoxyethoxy) ethyl acrylate) is such that the weight average molecular weight of poly (stearyl acrylate) is 9000 and the weight average molecular weight of SCCBC obtained by the additional polymerization is 9300.
  • the antithrombotic agent and the antithrombotic material were prepared in the same manner as in Example 1 except that the amounts of stearyl acrylate and 2- (2-ethoxyethoxy) ethyl acrylate used were adjusted to be 300). Prepared.
  • the antithrombotic property was evaluated in the same manner as in Example 1 except that the obtained antithrombotic material was used and a polyethylene terephthalate base material was used instead of the high-density polyethylene base material. went. The results are shown in Table 1 and FIG.
  • the product of the radical polymerization reaction was purified using ethanol to obtain poly (stearyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl vinyl ether).
  • the weight average molecular weight of the poly (stearyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl vinyl ether) obtained by the repolymerization was 7000. That is, the weight average molecular weight of the unit portion of poly (2- (2-ethoxyethoxy) ethyl vinyl ether) was 1000.
  • the molecular weight dispersion (Mw / Mn) of the obtained poly (stearyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl vinyl ether) was 1.23.
  • an antithrombotic material was prepared in the same manner as in Example 1.
  • the obtained antithrombotic material was evaluated for antithrombotic property in the same manner as in Example 1. The results are shown in Table 1 and FIG.
  • Example 3 Instead of stearyl acrylate, behenyl acrylate (shown by BHA in Table 1) was used to prepare an antithrombotic imparting agent.
  • the product of the radical polymerization reaction was purified using ethanol to obtain poly (behenyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl acrylate).
  • the weight average molecular weight of the poly (behenyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl acrylate) obtained by the repolymerization was 19000. That is, the weight average molecular weight of the unit portion of poly (2- (2-ethoxyethoxy) ethyl acrylate) was 10,000.
  • the molecular weight dispersion (Mw / Mn) of the obtained poly (behenyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl acrylate) was 1.51.
  • an antithrombotic material was prepared in the same manner as in Example 1.
  • the obtained antithrombotic material was evaluated for antithrombotic property in the same manner as in Example 1. The results are shown in Table 1 and FIG.
  • Example 4 Hexadecyl acrylate (indicated by HAD in Table 1) was used instead of stearyl acrylate to prepare an antithrombotic imparting agent.
  • the product of the radical polymerization reaction was purified using ethanol to obtain poly (hexadecyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl acrylate).
  • the weight average molecular weight of the poly (hexadecyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl acrylate) obtained by the repolymerization was 19000. That is, the weight average molecular weight of the unit portion of poly (2- (2-ethoxyethoxy) ethyl acrylate) was 10,000.
  • the molecular weight dispersion (Mw / Mn) of the obtained poly (hexadecyl acrylate) -block-poly (2- (2-ethoxyethoxy) ethyl acrylate) was 1.91.
  • an antithrombotic material was prepared in the same manner as in Example 1.
  • the obtained antithrombotic material was evaluated for antithrombotic property in the same manner as in Example 1. The results are shown in Table 1 and FIG.
  • An antithrombotic material was prepared using 2-methacryloyloxyethyl phosphorylcholine polymer (a polymer of MPC, hereinafter referred to as PMPC), which is well known as a biocompatible material.
  • PMPC 2-methacryloyloxyethyl phosphorylcholine polymer
  • the obtained antithrombotic material was evaluated for its antithrombotic property and contact angle in the same manner as in Example 1. The results are shown in Table 1 and FIG.
  • An antithrombotic material was prepared using poly (2-methoxyethyl acrylate) (a polymer of MEA, hereinafter referred to as PMEA) known as a biocompatible material.
  • the obtained antithrombotic material was evaluated for its antithrombotic property and contact angle in the same manner as in Example 1. The results are shown in Table 1 and FIG.
  • an antithrombotic material having excellent antithrombotic properties and which can be easily manufactured.
  • a surface-modified layer capable of exhibiting antithrombotic properties can be easily provided even on a base material that is difficult to modify.
  • the base material is modified by using the solution containing the antithrombotic agent as described above, the surface is modified regardless of the shape of the base material. It is possible to carry out the above, and it is suitable for modifying artificial organs having a complicated shape.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115260354A (zh) * 2022-08-19 2022-11-01 安徽农业大学 一种两亲性温敏材料、合成方法及其在绿僵菌野外防治害虫中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100063570A1 (en) * 2008-09-05 2010-03-11 Pacetti Stephen D Coating on a balloon comprising a polymer and a drug
JP2015074633A (ja) * 2013-10-09 2015-04-20 国立大学法人滋賀医科大学 血管塞栓剤
WO2016143787A1 (ja) * 2015-03-10 2016-09-15 国立大学法人山形大学 抗血栓性ブロック共重合体
WO2017150000A1 (ja) * 2016-02-29 2017-09-08 丸善石油化学株式会社 コポリマー、これを利用する抗血栓コーティング剤及び医療用具

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100063570A1 (en) * 2008-09-05 2010-03-11 Pacetti Stephen D Coating on a balloon comprising a polymer and a drug
JP2015074633A (ja) * 2013-10-09 2015-04-20 国立大学法人滋賀医科大学 血管塞栓剤
WO2016143787A1 (ja) * 2015-03-10 2016-09-15 国立大学法人山形大学 抗血栓性ブロック共重合体
WO2017150000A1 (ja) * 2016-02-29 2017-09-08 丸善石油化学株式会社 コポリマー、これを利用する抗血栓コーティング剤及び医療用具

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAO, SHIGERU: "Crystalline Supramolecular Interaction of Side Chain Crystalline Polymer and their Future", KOBUNSHI RONBUNSHU, vol. 73, no. 2, 2016, pages 139 - 146, XP055751073, ISSN: 0386-2186, DOI: 10.1295/koron.2015-0048 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115260354A (zh) * 2022-08-19 2022-11-01 安徽农业大学 一种两亲性温敏材料、合成方法及其在绿僵菌野外防治害虫中的应用

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