WO2022191271A1 - Instrument médical - Google Patents

Instrument médical Download PDF

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WO2022191271A1
WO2022191271A1 PCT/JP2022/010494 JP2022010494W WO2022191271A1 WO 2022191271 A1 WO2022191271 A1 WO 2022191271A1 JP 2022010494 W JP2022010494 W JP 2022010494W WO 2022191271 A1 WO2022191271 A1 WO 2022191271A1
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ion
group
polymerizable monomer
copolymer
medical device
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PCT/JP2022/010494
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Japanese (ja)
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弘昌 小濱
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テルモ株式会社
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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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/02—Inorganic 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
    • A61L29/04—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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials

Definitions

  • the present invention relates to a medical device having a surface lubricating layer containing a hydrophilic copolymer.
  • a base material such as a catheter
  • a low-toxic solvent such as water, alcohol, or a water/alcohol mixed solvent from the viewpoint of application to biomaterials and worker safety. be. Therefore, the constituent components of the coating are required to dissolve or disperse in such solvents (solvent solubility).
  • the lubricating layer containing the hydrophilic copolymer described in International Publication No. WO 2018/038063 exhibits excellent lubricity and durability (lubricity maintaining property). can.
  • the hydrophilic copolymer described in International Publication No. WO 2018/038063 is resistant to solvents such as water, alcohol, and water/alcohol mixed solvents. It exhibits excellent solubility.
  • the hydrophilic copolymer described in International Publication No. 2018/038063 contains structural units (A), (B) and (C) It is a ternary or higher copolymer.
  • the number of constitutional units constituting the hydrophilic copolymer is small.
  • an object of the present invention is to provide a hydrophilic copolymer with a small number of constitutional units capable of forming a surface lubricating layer exhibiting excellent lubricity and durability (lubricity maintaining property).
  • Another object of the present invention is to provide a hydrophilic copolymer having good solvent solubility and a small number of constitutional units.
  • the inventor of the present invention has made intensive studies to solve the above problems. As a result, the inventors have found that the above object can be achieved by using an alkali metal cation as a counter ion for the sulfonate ion in the structural unit derived from the polymerizable monomer (A) having a sulfobetaine structure.
  • the above object is a medical device comprising a substrate layer and a lubricating layer containing a hydrophilic copolymer formed on at least a part of the substrate layer, wherein the hydrophilic copolymer comprises: A structural unit derived from the polymerizable monomer (A) having a sulfobetaine structure in which the counterion of the sulfonate ion is an alkali metal cation, and a structural unit derived from the polymerizable monomer (B) having a photoreactive group and the content of structural units derived from the polymerizable monomer (A) is more than 80 mol% and less than 100 mol% with respect to the total of structural units derived from all monomers. .
  • FIG. 2 is a partial cross-sectional view schematically showing the layered structure of the surface of a representative embodiment of the medical device according to the present invention.
  • 1 indicates a substrate layer
  • 2 indicates a surface lubricating layer
  • 10 indicates a medical device.
  • FIG. 2 is a partial cross-sectional view schematically showing a configuration example with a different layered configuration on the surface as an application example of the embodiment of FIG. 1 ;
  • the range "X to Y” includes X and Y and means "X or more and Y or less”. Unless otherwise specified, measurements of operations and physical properties are performed under the conditions of room temperature (20 to 25° C.)/relative humidity of 40 to 60% RH.
  • the term “(meth)acryl” includes both acryl and methacryl.
  • the term “(meth)acrylic acid” includes both acrylic acid and methacrylic acid.
  • the term “(meth)acryloyl” includes both acryloyl and methacryloyl.
  • the term “(meth)acryloyl group” includes both acryloyl and methacryloyl groups.
  • a and/or B means both A and B or either A or B.
  • substituted means a C1-C30 alkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a C1-C30 alkoxy group, an alkoxycarbonyl group (-COOR, R is C1-C30 alkyl group), halogen atom (F, Cl, Br or I atom), C6-C30 aryl group, C6-C30 aryloxy group, amino group, C1-C30 alkylamino group, cyano group, nitro group, thiol group, a C1-C30 alkylthio group or a hydroxyl group.
  • a structural unit when a structural unit is defined as "derived from” a certain monomer, the structural unit is one of the polymerizable unsaturated double bonds of the corresponding monomer. It means a divalent constitutional unit generated by bond cleavage.
  • a medical device comprising a substrate layer and a lubricating layer containing a hydrophilic copolymer formed on at least a part of the substrate layer, wherein the hydrophilic copolymer
  • the polymer is a structural unit derived from a polymerizable monomer (A) having a sulfobetaine structure in which the counterion of the sulfonate ion is an alkali metal cation, and a polymerizable monomer (B) derived from a photoreactive group.
  • the content of the structural units derived from the polymerizable monomer (A) is more than 80 mol% and less than 100 mol% with respect to the total of structural units derived from all monomers.
  • Equipment provided. According to the present invention, it is possible to form a surface lubricating layer exhibiting excellent lubricity and durability (lubricity maintaining property), and to provide a hydrophilic copolymer having a small number of constitutional units. That is, according to the medical device of the present disclosure, even a surface lubricating layer containing a hydrophilic copolymer having a small number of structural units can exhibit excellent lubricity and durability (lubricity maintaining property).
  • polymerizable monomer (A) having a sulfobetaine structure in which the counterion of the sulfonate ion is an alkali metal cation is simply referred to as “polymerizable monomer (A)” or “monomer (A)”.
  • structural unit derived from the polymerizable monomer (A) having a sulfobetaine structure in which the counter ion of the sulfonate ion is an alkali metal cation is also simply referred to as “structural unit (A)”.
  • polymerizable monomer (B) having a photoreactive group is also simply referred to as “polymerizable monomer (B)” or “monomer (B)".
  • structural unit derived from the polymerizable monomer (B) having a photoreactive group is also simply referred to as “structural unit (B)”.
  • Hydrophilic copolymer is also simply referred to as “hydrophilic copolymer according to the present invention” or “hydrophilic copolymer”.
  • the present invention is characterized in that the surface lubricating layer contains the above specific hydrophilic copolymer.
  • the hydrophilic copolymer which is the characteristic part, will be described first, and then the medical device will be described in the following [preferred embodiment of the medical device].
  • the present invention is not limited to this form, and the configuration other than the features of the present invention can be applied in the same manner as or by appropriately modifying the configuration of known medical devices.
  • the hydrophilic copolymer according to the present invention comprises a polymerizable monomer (A)-derived structural unit having a sulfobetaine structure in which the counterion of the sulfonate ion is an alkali metal cation, and a photoreactive group. It contains structural units derived from the monomer (B).
  • the content of structural units derived from the polymerizable monomer (A) constituting the hydrophilic copolymer according to the present invention exceeds 80 mol% with respect to the total of structural units derived from all monomers. less than 100 mol %.
  • the hydrophilic copolymer can form a surface lubricating layer exhibiting excellent lubricity and durability (lubricity maintaining property).
  • the hydrophilic copolymer has good solvent solubility (in particular, solubility in water, alcohol, and water/alcohol mixed solvent).
  • the sulfobetaine structure contained in the structural unit derived from the monomer (A) has an excellent lubricity-imparting effect. Therefore, a surface lubricating layer containing a hydrophilic copolymer in which the content of structural units derived from the monomer (A) exceeds 80 mol % can exhibit excellent lubricity.
  • the homopolymer of the monomer (A) is soluble in an aqueous sodium chloride solution, but is insoluble or difficult to dissolve in water and lower alcohols.
  • the photoreactive group contained in the structural unit (structural unit (B)) derived from the monomer (B) generates a reactive species upon irradiation with an active energy ray and reacts with the substrate layer surface to chemically form a bond. Therefore, the surface lubricating layer containing the hydrophilic copolymer according to the present invention is firmly immobilized on the base material layer, and thus has excellent durability (lubricity maintaining property).
  • the homopolymer of monomer (B) does not dissolve or hardly dissolves in water or lower alcohols, and does not dissolve in aqueous sodium chloride solution.
  • the copolymer of the monomer (A) and the monomer (B) (especially the monomer having a benzophenone group) is resistant to water, aqueous sodium chloride solution, lower alcohol, water/lower alcohol mixed solvent, etc. There is a problem that it is difficult to apply to coatings because it hardly dissolves or disperses in water (that is, its solubility in solvents is extremely low).
  • the sulfobetaine structure of the polymerizable monomer (A) has a cation (quaternary ammonium ion (-N + (R) 4 )) and an anion (sulfonate ion (-SO 3 - )) in the molecule.
  • a cation quaternary ammonium ion (-N + (R) 4 )
  • an anion sulfonate ion (-SO 3 - )
  • the counter ion of the sulfonate ion is an alkali metal cation
  • the anion (sulfonate ion (-SO 3 - )) in one molecule is an alkali metal cation and the cation (quaternary ammonium ion ( ⁇ N + (R) 4 )) preferentially interact (form an ion pair) with the anion, which is the counterion of the alkali metal cation.
  • the interaction between the structural units (A) (sulfobetaine structure) between the polymers is reduced, and the hydrophilic polymer is easily dissolved or dispersed in water or an aqueous solvent such as a lower alcohol. Therefore, the hydrophilic copolymer according to the present invention has excellent solvent solubility (in particular, solubility in water, alcohol, and water/alcohol mixed solvent). Such an effect of improving solvent solubility is particularly remarkable when the monomer (A) is represented by the following formula (1).
  • the polymerizable monomer (A) is a polymerizable monomer having a sulfobetaine structure in which the counterion of the sulfonate ion is an alkali metal cation.
  • sulfobetaine structure means that a positive charge and a negative charge containing a sulfur element are present at positions that are not adjacent to each other, and a dissociable hydrogen atom is not bound to an atom having a positive charge, and a charge refers to a structure in which the sum of is zero.
  • Examples of the monomer (A) include, but are not particularly limited to, compounds having the following structures.
  • R a and R d may each independently be an optionally substituted alkylene group having 1 to 30 carbon atoms or an optionally substituted arylene group having 6 to 30 carbon atoms.
  • R b and R c may each independently be an optionally substituted alkyl group having 1 to 30 carbon atoms or an optionally substituted aryl group having 6 to 30 carbon atoms
  • the sum of positive charges and negative charges is zero.
  • alkylene groups having 1 to 30 carbon atoms examples include methylene group, ethylene group, triethylene group, propylene group, isopropylene group, butylene group, isobutylene group, sec-butylene group, tert-butylene group, pentylene group and the like. is mentioned.
  • arylene groups having 6 to 30 carbon atoms include phenylene groups, naphthylene groups, anthracenylene groups, phenanthrenylene groups, pyrenylene groups, perylenylene groups, fluorenylene groups, and biphenylene groups.
  • alkyl groups having 1 to 30 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and n-pentyl group. , iso-pentyl group, tert-pentyl group, neopentyl group, n-hexyl group and the like.
  • aryl groups having 6 to 30 carbon atoms include phenyl, biphenyl, terphenyl, pentalenyl, indenyl, naphthyl, azulenyl and biphenylenyl groups.
  • M + is an alkali metal cation.
  • X - is an anion moiety.
  • the monomer (A) is preferably a compound represented by the following formula (1) from the viewpoint of further improving lubricity and durability (lubricity maintaining property). That is, according to a preferred embodiment of the present invention, the polymerizable monomer (A) is represented by the following formula (1):
  • R 11 is a hydrogen atom or a methyl group.
  • Z 1 is an oxygen atom (--O--) or --NH--, preferably an oxygen atom (--O--).
  • R 12 and R 15 each independently represent a linear or branched chain having 1 to 20 carbon atoms, from the viewpoint of further improving lubricity and durability (lubricity maintaining property).
  • is an alkylene group preferably a linear or branched alkylene group having 1 to 12 carbon atoms, more preferably a linear or branched alkylene group having 1 to 8 carbon atoms, still more preferably carbon
  • R 12 and R 15 may be the same or different, preferably R 12 and R 15 are different.
  • R 13 and R 14 each independently represent a linear or branched alkyl having 1 to 20 carbon atoms, from the viewpoint of further improving lubricity and durability (lubrication maintenance property).
  • group preferably a linear or branched alkyl group having 1 to 12 carbon atoms, more preferably a linear or branched alkyl group having 1 to 8 carbon atoms, still more preferably 1 carbon atom
  • a linear or branched alkyl group of ⁇ 4 more preferably a methyl group or an ethyl group, particularly preferably a methyl group.
  • R 13 and R 14 may be the same or different, but are preferably the same, more preferably both are methyl groups.
  • M + is an alkali metal cation.
  • the alkali metal cation (M + ) is preferably sodium ion (Na + ) or potassium ion (K + ), more preferably sodium ion (Na + ), from the viewpoint of further improving solvent solubility. That is, in a preferred embodiment of the present invention, M + is sodium ion (Na + ) or potassium ion (K + ) in formula (1) above. In a more preferred form of the present invention, M + is a sodium ion (Na + ) in the above formula (1).
  • X - is an anion moiety.
  • the anion portion (X ⁇ ) is preferably fluoride ion (F ⁇ ), chloride ion (Cl ⁇ ), bromide ion (Br ⁇ ), iodide ion (I ⁇ ), hydrogen sulfate ion (HSO 4 ⁇ ), sulfate ion (SO 4 2- ), nitrate ion (NO 3 - ), dihydrogen phosphate ion (H 2 PO 4 - ), hydrogen phosphate ion (HPO 4 2- ), or phosphate ion (PO 4 3- ).
  • the anion portion (X ⁇ ) is more preferably fluoride ion (F ⁇ ), chloride ion (Cl ⁇ ), bromide ion (Br ⁇ ), iodide ion (I ⁇ ). , hydrogen sulfate (HSO 4 ⁇ ), sulfate (SO 4 2 ⁇ ), nitrate (NO 3 ⁇ ) or phosphate (PO 4 3 ⁇ ).
  • the anion portion (X ⁇ ) is even more preferably chloride ion (Cl ⁇ ), bromide ions (Br ⁇ ), hydrogen sulfate ions (HSO 4 ⁇ ) or sulfate ions (SO 4 2 ⁇ ), particularly preferably chloride ions (Cl ⁇ ) and sulfate ions (SO 4 2 ⁇ ).
  • X ⁇ is fluoride ion (F ⁇ ), chloride ion (Cl ⁇ ), bromide ion (Br ⁇ ), iodide ion (I ⁇ ). , hydrogen sulfate ion (HSO 4 ⁇ ), sulfate ion (SO 4 2 ⁇ ), nitrate ion (NO 3 ⁇ ), dihydrogen phosphate ion (H 2 PO 4 ⁇ ), hydrogen phosphate ion (HPO 4 2 ⁇ ) , and phosphate ions (PO 4 3 ⁇ ).
  • X - is fluoride ion (F - ), chloride ion (Cl - ), bromide ion (Br - ), iodide ion (I - ), It is selected from the group consisting of hydrogen sulfate (HSO 4 ⁇ ), sulfate (SO 4 2 ⁇ ), nitrate (NO 3 ⁇ ) and phosphate (PO 4 3 ⁇ ).
  • X ⁇ is chloride ion (Cl ⁇ ), bromide ion (Br ⁇ ), hydrogen sulfate ion (HSO 4 ⁇ ) or sulfate ion (SO 4 2 - ) is selected from the group consisting of
  • X ⁇ in formula (1) above is chloride ion (Cl ⁇ ) or sulfate ion (SO 4 2 ⁇ ).
  • the anion moiety When the anion moiety has a valence of 2 or more, it interacts (ionic bond) with the sulfobetaine structure (quaternary ammonium ion, (-N + (R) 4 )) of two or more structural units (A). do.
  • the anion portion is a sulfate ion (SO 4 2 ⁇ )
  • the sulfate ion interacts with the quaternary ammonium ions of two adjacent structural units (A).
  • R 11 is a hydrogen atom or a methyl group
  • Z 1 is an oxygen atom (—O—) or —NH—
  • R 15 are each independently a linear or branched alkylene group having 1 to 8 carbon atoms
  • R 13 and R 14 are each independently a linear or branched chain having 1 to 8 carbon atoms
  • M + is sodium ion (Na + ) or potassium ion (K + );
  • X ⁇ is fluoride ion (F ⁇ ), chloride ion (Cl ⁇ ), bromide ion (Br ⁇ ), iodide ion (I ⁇ ), hydrogen sulfate ion (HSO 4 ⁇ ), sulfate ion (SO 4 2 ⁇ ), nitrate ion (NO 3 ⁇ ), dihydrogen phosphate ion (H 2 PO 4 ⁇ ), It is represented by the above formula (1) selected from
  • R 11 is a hydrogen atom or a methyl group
  • Z 1 is an oxygen atom (—O—) or —NH—
  • R 15 are each independently a linear or branched alkylene group having 1 to 6 carbon atoms
  • R 13 and R 14 are each independently a linear or branched chain having 1 to 4 carbon atoms
  • M + is sodium ion (Na + ) or potassium ion (K + );
  • X ⁇ is fluoride ion (F ⁇ ), chloride ion (Cl ⁇ ), bromide ion (Br ⁇ ), iodide (I ⁇ ), hydrogen sulfate (HSO 4 ⁇ ), sulfate (SO 4 2 ⁇ ), nitrate (NO 3 ⁇ ) and phosphate (PO 4 3 ⁇ ) is selected, represented by the above formula (1).
  • R 11 is a hydrogen atom or a methyl group
  • Z 1 is an oxygen atom (-O-)
  • R 12 and R 15 are Each independently is a methylene group, an ethylene group or a trimethylene group
  • R 13 and R 14 are each independently a methyl group or an ethyl group
  • M + is a sodium ion (Na + ) or a potassium ion ( K + )
  • X ⁇ is selected from the group consisting of chloride (Cl ⁇ ), bromide (Br ⁇ ), hydrogen sulfate (HSO 4 ⁇ ) or sulfate (SO 4 2 ⁇ ); It is represented by the above formula (1).
  • R 11 is a hydrogen atom or a methyl group
  • Z 1 is an oxygen atom (--O--)
  • R 12 is an ethylene group
  • R 15 is a trimethylene group
  • R 13 and R 14 are methyl groups
  • M + is a sodium ion (Na + )
  • X ⁇ is a chloride ion (Cl ⁇ ) or a sulfate ion (SO 4 2- ), represented by the above formula (1).
  • the content of the structural units derived from the polymerizable monomer (A) is based on the total of the structural units derived from all the monomers (of the structural units derived from all the monomers When the total is 100 mol %), it is more than 80 mol % and less than 100 mol %.
  • the content of the constituent units derived from the polymerizable monomer (A) is 80 mol % or less, there is a possibility that sufficient durability cannot be exhibited. Alternatively, there is a possibility that sufficient lubricity cannot be exhibited.
  • the content of structural units derived from the polymerizable monomer (A) is the sum of structural units derived from all monomers. On the other hand, it is preferably 85 mol % or more and less than 99.9 mol %, more preferably 90 mol % or more and 99.5 mol % or less. That is, in a preferred embodiment of the present invention, the content of structural units derived from the polymerizable monomer (A) is 85 mol% or more and less than 99.9 mol% with respect to the total of structural units derived from all monomers. be.
  • the content of structural units derived from the polymerizable monomer (A) is 90 mol% or more and 99.5 mol% or less with respect to the total of structural units derived from all monomers. .
  • the mol % is substantially equivalent to the ratio of the charged amount (mol) of the monomer (A) to the total charged amount (mol) of all the monomers when producing the polymer.
  • the hydrophilic copolymer contains two or more kinds of structural units derived from the monomer (A)
  • the content of the structural units derived from the monomer (A) is It is the total content of structural units derived from (A).
  • the polymerizable monomer (B) (monomer (B)) is a polymerizable monomer having a photoreactive group.
  • photoreactive group refers to a group capable of forming a chemical bond by generating reactive species such as radicals, nitrenes, and carbenes upon irradiation with an active energy ray and reacting with the substrate layer. .
  • the surface lubricating layer containing the hydrophilic copolymer according to the present invention can be firmly immobilized on the surface of the substrate layer (substrate). Therefore, the surface lubricating layer can exhibit excellent durability (lubricity maintaining property).
  • photoreactive groups include an azide group, a diazo group, a diazirine group, a ketone group, and a quinone group.
  • the azide group includes, for example, arylazide groups such as phenylazide and 4-fluoro-3-nitrophenylazide; acylazide groups such as benzoylazide and p-methylbenzoylazide; and azidoformates such as ethylazidoformate and phenylazidoformate. groups; sulfonyl azide groups such as benzenesulfonyl azide; phosphoryl azide groups such as diphenylphosphoryl azide and diethyl phosphoryl azide;
  • diazo group examples include diazoalkanes such as diazomethane and diphenyldiazomethane; diazoketones such as diazoacetophenone and 1-trifluoromethyl-1-diazo-2-pentanone; diazoacetates such as t-butyldiazoacetate and phenyldiazoacetate; ⁇ -keto- ⁇ -diazoacetoacetate such as t-butyl- ⁇ -diazoacetoacetate;
  • diazirine groups examples include groups derived from 3-trifluoromethyl-3-phenyldiazirine and the like.
  • ketone groups include groups having structures such as acetophenone, benzophenone, anthrone, xanthine, and thioxanthone.
  • the quinone group includes, for example, groups derived from anthraquinone and the like.
  • photoreactive groups are appropriately selected according to the type of base layer of the medical device.
  • the base material layer is formed from a polyolefin resin such as polyethylene resin, a polyamide resin, a polyurethane resin, a polyester resin, or the like
  • a ketone group or a phenylazide group is preferable because the monomer is easily available.
  • a group having a benzophenone structure is more preferable.
  • Examples of monomer (B) include 2-azidoethyl (meth)acrylate, 2-azidopropyl (meth)acrylate, 3-azidopropyl (meth)acrylate, 4-azidobutyl (meth)acrylate, 4-(meth) Acryloyloxybenzophenone, 4-(meth)acryloyloxyethoxybenzophenone, 4-(meth)acryloyloxy-4'-methoxybenzophenone, 4-(meth)acryloyloxyethoxy-4'-methoxybenzophenone, 4-(meth)acryloyloxy -4'-bromobenzophenone, 4-(meth)acryloyloxyethoxy-4'-bromobenzophenone, 4-styrylmethoxybenzophenone, 4-(meth)acryloyloxythioxanthone and the like.
  • Either a synthetic product or a commercial product may be used for the monomer (B), and the commercial product can be obtained from MRC Unitech Co., Ltd., etc.
  • the content of the structural units derived from the polymerizable monomer (B) is based on the total of the structural units derived from all the monomers (of the structural units derived from all the monomers When the total is 100 mol%), preferably more than 0 mol% and less than 20 mol%, more preferably more than 0.1 mol% and 15 mol% or less, particularly preferably 0.5 mol% It is more than 10 mol% or less.
  • the hydrophilic copolymer can sufficiently bond with the substrate layer, so that the surface lubricating layer containing the hydrophilic copolymer can be firmly immobilized by the substrate layer.
  • the hydrophilic copolymer has sufficient lubricity and Durability can be improved more effectively.
  • the mol % is substantially equivalent to the ratio of the charged amount (mol) of the monomer (B) to the total charged amount (mol) of all the monomers when producing the polymer.
  • the hydrophilic copolymer contains two or more kinds of structural units derived from the monomer (B)
  • the content of the structural units derived from the monomer (B) is It is the total content of structural units derived from (B).
  • the hydrophilic copolymer according to the present invention contains polymerizable monomers other than the above-described monomers (A) and (B) (hereinafter referred to as "other monomers (also referred to as "mer").
  • other monomers also referred to as "mer”
  • examples of other monomers include methyl vinyl ether, ethyl vinyl ether, propyl vinyl ether, acrylic acid, methacrylic acid, and N-methylacrylamide.
  • the content of structural units derived from other monomers is preferably less than 10 mol%, more preferably 5 mol, relative to 100 mol% of the total amount of structural units derived from all monomers.
  • the terminal of the hydrophilic copolymer according to the present invention is not particularly limited, and is appropriately defined depending on the type of raw material used, but is usually a hydrogen atom.
  • the structure of the copolymer is also not particularly limited, and may be any of random copolymer, alternating copolymer, periodic copolymer and block copolymer.
  • the hydrophilic copolymer according to the present invention has excellent solvent solubility, particularly excellent solubility in water, a lower alcohol, or a mixed solvent of water and a lower alcohol.
  • lower alcohol refers to alcohols having 1 to 3 carbon atoms, ie methanol, ethanol, n-propanol or isopropanol.
  • solvent having low toxicity can be applied to the coating liquid, so that the safety of the operator can be ensured.
  • solvents containing lower alcohols have a high evaporation rate and are quickly removed from the coating film. Therefore, the drying process can be simplified in the coating of medical devices, and the coating work can be performed quickly.
  • excellent in solvent solubility means that it dissolves or disperses in the above solvent preferably in an amount of 1% by weight or more (more preferably 3% by weight or more, particularly preferably 5% by weight or more). At this time, the time required for dissolution or dispersion is preferably within 2 hours.
  • the weight average molecular weight of the copolymer is preferably several thousand to several million.
  • the "weight average molecular weight” is a value measured by gel permeation chromatography (GPC) using polyethylene glycol as a standard substance.
  • FIG. 1 is a partial cross-sectional view schematically showing the layered structure of the surface of a representative embodiment of the medical device (hereinafter also simply referred to as “medical device") according to the present invention.
  • FIG. 2 is a partial cross-sectional view schematically showing a configuration example with a different layered structure on the surface as an application example of the present embodiment. 1 and 2, 1 represents a substrate layer, 1a a core portion of the substrate layer, 1b a surface layer of the substrate, 2 a lubricating layer on the surface, and 10 a medical device.
  • the base layer 1 and at least a part of the base layer 1 are immobilized (in the drawings, the base layer in the drawing 1 and a surface lubricating layer 2 containing a hydrophilic copolymer immobilized on the entire surface (entire surface).
  • the surface lubricating layer 2 is bonded to the substrate layer 1 via photoreactive groups of the hydrophilic copolymer.
  • the substrate layer used in the present embodiment may be composed of any material as long as it can react with the photoreactive groups contained in the hydrophilic copolymer to form chemical bonds.
  • the material that constitutes (forms) the base material layer 1 includes metal materials, polymer materials, ceramics, and the like.
  • the base layer 1 may be entirely (whole) composed (formed) of any of the above materials, or as shown in FIG.
  • the surface of the base layer core portion 1a composed (formed) of any of the above materials is covered (coated) with any other material by an appropriate method to constitute (form) the base material surface layer 1b.
  • the surface of the base material layer core portion 1a made of a resin material or the like is coated with a metal material by an appropriate method (plating, metal vapor deposition, sputtering, or other conventionally known method).
  • a base material surface layer 1b formed; a high-strength material, which is flexible compared to a reinforcing material such as a metal material, is formed on the surface of the base material layer core part 1a formed of a hard reinforcing material such as a metal material or a ceramic material;
  • the molecular material is coated by an appropriate method (a conventionally known method such as immersion (dipping), spraying (spraying), application/printing, etc.), or the reinforcing material of the base material layer core part 1a and the base material surface layer 1b are coated.
  • a base material surface layer 1b is formed by combining with a molecular material (appropriate reaction treatment).
  • the base material layer core portion 1a is a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which members formed of different materials for each part of the medical device are joined together. good too.
  • another middle layer (not shown) may be formed between the substrate layer core portion 1a and the substrate surface layer 1b.
  • the substrate surface layer 1b may be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which members formed of different materials for each part of the medical device are joined together. good.
  • the metal material is not particularly limited, and metal materials that are commonly used for medical devices such as catheters, stents, and guidewires are used. be.
  • various stainless steels such as SUS304, SUS316, SUS316L, SUS420J2, SUS630, gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin or nickel-titanium (Ni-Ti ) alloy, nickel-cobalt (Ni-Co) alloy, cobalt-chromium (Co-Cr) alloy, zinc-tungsten (Zn-W) alloy, and various other alloys.
  • SUS stainless steels
  • SUS stainless steels
  • SUS such as SUS304, SUS316, SUS316L, SUS420J2, SUS630, gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin or nickel-titanium (Ni-Ti ) alloy, nickel-cobalt (Ni-Co) alloy, cobalt-chrom
  • the polymer material is not particularly limited, and is a polymer commonly used for medical devices such as catheters, stents, and guide wires. material is used.
  • polyethylene such as polyamide resin, linear low density polyethylene (LLDPE), low density polyethylene (LDPE), high density polyethylene (HDPE), polyolefin resin such as polypropylene, polyester resin such as polyethylene terephthalate, polystyrene, etc.
  • styrene resin cyclic polyolefin resin, modified polyolefin resin, epoxy resin, urethane resin, diallyl phthalate resin (allyl resin), polycarbonate resin, fluorine resin, amino resin (urea resin, melamine resin, benzoguanamine resin), acrylic resin, polyacetal resin , vinyl acetate resin, phenol resin, vinyl chloride resin, silicone resin (silicon resin), polyether resin, polyimide resin, and the like.
  • the polymer material a polymer material suitable for use as a base layer for catheters, stents, guide wires, and the like may be appropriately selected.
  • the shape of the base material layer is not particularly limited, and may be appropriately selected from a sheet shape, a linear (wire) shape, a tubular shape, or the like, depending on the mode of use.
  • the lubricating layer (surface lubricating layer) is carried on at least a part of the substrate layer (substrate) 1 .
  • the reason why the lubricating layer 2 is carried on at least a part of the surface of the base material layer 1 is that medical devices such as catheters, guide wires, and indwelling needles, which are intended for use, are not necessarily used for these medical devices.
  • a lubricating layer not necessarily on all surfaces (entire surface) when wet, but only on parts (some or all) of the surface where the surface is required to be lubricious when wet is carried.
  • the lubricating layer is formed so as to cover both sides of the substrate layer as shown in FIGS. 1 and 2; forms formed; forms formed so as to partially cover both sides of the substrate layer in the same or different forms; forms formed so as to partially cover one side of the substrate layer.
  • the lubricating layer (surface lubricating layer) essentially contains a hydrophilic copolymer.
  • the lubricating layer may contain other components in addition to the hydrophilic copolymer.
  • other components are not particularly limited.
  • anticancer agents immunosuppressive agents, antibiotics, antirheumatic agents, antithrombotic agents, HMG-CoA reductase inhibitors, ACE inhibitors, calcium antagonists, antihyperlipidemic agents, integrin inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improving agents, DNA synthesis inhibitors, tyrosine kinase inhibitors
  • Drugs physiologically active substances
  • antiplatelet drugs such as antiplatelet drugs, vascular smooth muscle proliferation inhibitors, anti-inflammatory drugs, bio-derived materials, interferons, and substances promoting NO production, and the like.
  • the amount of other components to be added is not particularly limited, and the amounts normally used are applied in the same manner. Ultimately, the amount of other ingredients to be added is appropriately selected in consideration of the severity of the disease to be applied, the weight of the patient, and the like.
  • the lubricating layer does not contain other components (consisting only of the hydrophilic copolymer). That is, in a preferred embodiment of the present invention, the lubricating layer is composed of the hydrophilic copolymer.
  • the method for manufacturing the medical device according to the present invention is not particularly limited, and a known method can be applied in the same manner or by appropriately modifying it.
  • a structural unit (structural unit (A′)) derived from a polymerizable monomer having a sulfobetaine structure in which the counter ion of the sulfonate ion is a quaternary ammonium ion in the same molecule and the structural unit (B) are combined.
  • the content of the structural unit (A′) is more than 80 mol% and less than 100 mol% with respect to all structural units, is mixed with an alkali metal salt and a solvent to prepare a coating liquid, A method of applying a coating liquid to the substrate layer is used.
  • a method for manufacturing a medical device comprising a base layer and a lubricating layer carried on at least a part of the base layer, comprising: Containing a structural unit derived from a polymerizable monomer (A') represented by the following formula (2), and a structural unit derived from a polymerizable monomer (B) having a photoreactive group, the polymerizable monomer a copolymer containing more than 80 mol% and less than 100 mol% of the total amount of structural units derived from all monomers, an alkali metal salt, and a solvent
  • a method for manufacturing a medical device comprising preparing a coating liquid containing and applying the coating liquid onto the base layer:
  • R 11 is a hydrogen atom or a methyl group
  • Z 1 is an oxygen atom or -NH-
  • R 12 and R 15 are each independently a linear or branched alkylene group having 1 to 20 carbon atoms
  • R 13 and R 14 are each independently a straight or branched chain alkyl group having 1 to 20 carbon atoms.
  • the copolymer is easily dissolved or dispersed in the solvent. Therefore, a uniform coating liquid can be prepared. Therefore, by applying such a coating liquid to the base material layer, it is possible to impart lubricity and durability (lubricity maintaining ability) to the surface of the medical device.
  • polymerizable monomer (A') represented by formula (2) is also simply referred to as “polymerizable monomer (A')” or “monomer (A')”.
  • structural unit derived from the polymerizable monomer (A') represented by formula (2) is also simply referred to as “structural unit (A')”.
  • the copolymer is a structural unit derived from the polymerizable monomer (A') represented by the following formula (2) (structural unit (A')), and a polymerizable monomer having a photoreactive group containing a structural unit derived from the body (B) (structural unit (B)), the content of the structural unit derived from the polymerizable monomer (A') with respect to the total of structural units derived from all monomers, It is more than 80 mol % and less than 100 mol %.
  • the structural unit (A') constituting the copolymer according to the present invention is a quaternary ammonium ion (-N + (R 13 ) ( R 14 ) It is the same as the structural unit (A) derived from the polymerizable monomer (A) of formula (1) above, except that it is (R 15 )-). Therefore, in formula (2) above, R 11 , Z 1 , R 12 and R 15 , and R 13 and R 14 are the same as defined in formula (1) above.
  • Examples of the compound represented by the formula (2) include ⁇ 2-[(meth)acryloyloxy]ethyl ⁇ dimethyl-(3-sulfopropyl)ammonium hydroxide, ⁇ 2-[(meth)acryloyloxy]ethyl ⁇ dimethyl-(2-sulfoethyl) ammonium hydroxide, ⁇ 2-[(meth)acryloyloxy]ethyl ⁇ diethyl-(2-sulfoethyl)ammonium hydroxide, ⁇ 2-[(meth)acryloyloxy]ethyl ⁇ diethyl-( 3-sulfopropyl)ammonium hydroxide, ⁇ 3-[(meth)acryloyloxy]propyl ⁇ dimethyl-(2-sulfoethyl)ammonium hydroxide, ⁇ 3-[(meth)acryloyloxy]propyl ⁇ dimethyl-(3-sulfo Propyl) ammonium hydro
  • Either a synthetic product or a commercially available product may be used for the monomer (A').
  • a commercial product it can be obtained from Sigma-Aldrich and the like.
  • synthesizing A.I. Laschewsky, Polymers, 6, 1544-1601 (2014), etc. can be referred to.
  • the content of the structural unit (A') is more than 80 mol% and less than 100 mol% with respect to the total of structural units derived from all monomers.
  • the content of the structural unit (A') is the same as the content of the structural unit (A).
  • the structural unit (B) constituting the copolymer according to the present invention is derived from the same polymerizable monomer (B) as described above (polymerizable monomer (B)).
  • the content of the structural unit (B) is the same as described above (polymerizable monomer (B)).
  • the copolymer according to the present invention may contain structural units derived from other monomers in addition to the structural units (A') and (B). Other monomers and their contents in the form are the same as described above (other monomers).
  • the method for producing the copolymer according to the present invention is not particularly limited, and known polymerization methods such as radical polymerization, anionic polymerization, and cationic polymerization can be employed, and radical polymerization, which is easy to produce, is preferably used.
  • the polymerization method is usually carried out by stirring and heating the above monomers (A′) and monomers (B) and, if necessary, other monomers together with a polymerization initiator in a polymerization solvent.
  • a method of polymerization is employed.
  • the polymerization temperature is not particularly limited, it is preferably 25 to 100°C, more preferably 30 to 80°C.
  • the polymerization time is also not particularly limited, but preferably 30 minutes to 24 hours, more preferably 1 to 5 hours.
  • polymerization solvent examples include water; alcohols such as methanol, ethanol, propanol, n-butanol and 2,2,2-trifluoroethanol; polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol and dipropylene glycol; is preferably an aqueous solvent of From the viewpoint of dissolving raw materials used for polymerization, these may be used alone or in combination of two or more.
  • the concentration of the polymerizable monomer is not particularly limited, but the total solid content (g) of each polymerizable monomer with respect to the polymerization solvent (mL) is preferably 0.05 to 1 g / mL, more preferably 0.1 to 0.5 g/mL. Moreover, the ratio of the preferred charged amount (mol) of each monomer to the total charged amount (mol) of all monomers is as described above.
  • the reaction solution containing the polymerizable monomer may be degassed before adding the polymerization initiator.
  • the degassing treatment may be performed, for example, by bubbling the reaction solution with an inert gas such as nitrogen gas or argon gas for about 0.5 to 5 hours. During the deaeration treatment, the reaction solution may be heated to about 30 to 100.degree.
  • polymerization initiators can be used for the production of the polymer, and are not particularly limited.
  • KPS persulfate Potassium
  • persulfates such as sodium persulfate and ammonium persulfate
  • oxidizing agents such as peroxides such as hydrogen peroxide, t-butyl peroxide, methyl ethyl ketone peroxid
  • the blending amount of the polymerization initiator is preferably 0.01 to 10 mol%, more preferably 0.1 to 5 mol%, relative to the total amount (mol) of the polymerizable monomers.
  • chain transfer agents may be used as appropriate during polymerization.
  • polymerization rate modifiers may be used as appropriate during polymerization.
  • surfactants may be used as appropriate during polymerization.
  • the atmosphere in which the polymerization reaction is carried out is not particularly limited, and it can be carried out in an air atmosphere, an inert gas atmosphere such as nitrogen gas or argon gas. Further, the reaction solution may be stirred during the polymerization reaction.
  • the copolymer may precipitate during the polymerization reaction.
  • the copolymer after polymerization can be purified by general purification methods such as reprecipitation, dialysis, ultrafiltration and extraction. Also, after the precipitation and/or purification, the copolymer may be washed if necessary.
  • the copolymer after purification can be dried by any method such as freeze drying, vacuum drying, spray drying, or heat drying. Drying is preferred.
  • the ratio of structural units derived from each polymerizable monomer in the obtained copolymer is confirmed by analyzing the peak intensity of the group contained in each structural unit using known means such as NMR and IR. can be done.
  • the unreacted monomer contained in the resulting copolymer is preferably 0.01% by weight or less with respect to the entire copolymer.
  • the content of residual monomers can be measured by known means such as high performance liquid chromatography.
  • the above copolymer is mixed with an alkali metal salt and a solvent to prepare a coating liquid.
  • the sulfonate ion (—SO 3 ⁇ ) of the sulfobetaine structure of the structural unit (A′) forms an ion pair with the alkali metal cation
  • the quaternary ammonium ion forms an ion pair with the anion forming a pair with the alkali metal cation. form (becomes the hydrophilic copolymer according to the present invention).
  • the alkali metal salt is preferably a salt of the alkali metal cation and anion defined in formula (1) above.
  • Sodium hydride, potassium sulfate, sodium sulfate, potassium nitrate, sodium nitrate, potassium phosphate and sodium phosphate are preferred.
  • Potassium chloride, sodium chloride, sodium bromide, sodium hydrogensulfate and sodium sulfate are more preferable from the viewpoint of further improvement of lubricity and durability (lubricity maintaining property), further improvement of solubility, and balance of these.
  • the alkali metal salt is at least one selected from the group consisting of potassium chloride, sodium chloride, sodium bromide, sodium hydrogensulfate and sodium sulfate.
  • the alkali metal salt is selected from the group consisting of potassium chloride, sodium chloride, sodium hydrogen sulphate and sodium sulphate.
  • the alkali metal salt is sodium chloride or sodium sulphate.
  • Solvents that can be used to prepare the coating liquid are those described in the above [Physical properties of hydrophilic copolymer] section from the viewpoint of the solubility of the hydrophilic copolymer and work safety (low toxicity). is preferred.
  • the solvent is at least one selected from the group consisting of water, methanol, and ethanol, and is water, methanol, or a mixed solvent of water and methanol (water/methanol mixed solvent).
  • the concentration of the copolymer in the coating liquid is not particularly limited, but is preferably 1 to 50% by weight, more preferably 3 to 40% by weight, even more preferably 5 to 30% by weight, particularly preferably 10 to 25% by weight.
  • the concentration of the copolymer is the total concentration of all copolymers.
  • the coatability of the coating liquid is good, and the obtained surface lubricating layer has excellent lubricity and durability (lubricity maintaining property).
  • it is possible to easily obtain a uniform surface lubricating layer having a desired thickness (for example, the film thickness of the lubricating layer after drying 0.5 to 5 ⁇ m) in one coating, which is preferable in terms of production efficiency.
  • the concentration of the copolymer is less than 1% by weight, it may not be possible to fix a sufficient amount of the hydrophilic copolymer on the surface of the substrate layer.
  • the concentration of the copolymer exceeds 50% by weight, the coating The viscosity of the liquid may become too high, and a surface lubricating layer having a uniform thickness may not be obtained.However, even if it is outside the above range, it is sufficient as long as it does not affect the effects of the present invention. available for
  • the concentration of the alkali metal salt in the coating liquid is not particularly limited, it is preferably 1 part by weight or more and 60 parts by weight or less, more preferably more than 2 parts by weight and 50 parts by weight with respect to 100 parts by weight of the copolymer. parts by weight or less, and more preferably 35 to 50 parts by weight.
  • the hydrophilic copolymer can be easily dissolved in a solvent (especially water, a lower alcohol, or a mixed solvent of water and a lower alcohol).
  • the concentration of the alkali metal salt is the total concentration of all alkali metal salts.
  • the order of addition of the copolymer, alkali metal salt and solvent is not particularly limited. Specifically, the copolymer, alkali metal salt and solvent are charged together; the copolymer and alkali metal salt are added together to the solvent; the copolymer and alkali metal salt are added in any order ( addition to the solvent in the order of the alkali metal salt after the addition of the copolymer, or in the order of the copolymer after the addition of the alkali metal salt.
  • the conditions for mixing the copolymer, alkali metal salt and solvent are not particularly limited.
  • the mixing temperature is, for example, 0-50°C, preferably 5-40°C.
  • the mixing time is not particularly limited as long as it can be dissolved or dispersed, and is, for example, within 2 hours.
  • the sulfonate ion (—SO 3 ⁇ ) of the sulfobetaine structure of the structural unit (A′) of the copolymer is an alkali metal cation
  • the quaternary ammonium ion is an anion that is the counterion of the alkali metal cation. and each form an ion pair (becomes a hydrophilic copolymer according to the present invention).
  • the configuration of the copolymer e.g., structures other than the ion pair of the structural unit (A) (e.g., formulas (1) and (2), R 11 to R 15 and Z 1 ), structural unit (B), structural units derived from other monomers, content of each structural unit) do not change before and after the addition of the alkali metal salt.
  • the coating liquid prepared above is applied (coated) onto the base layer of the medical device.
  • the substrate layer surface may be treated in advance by ultraviolet irradiation treatment, plasma treatment, corona discharge treatment, flame treatment, oxidation treatment, silane coupling treatment, phosphoric acid coupling treatment, or the like.
  • the solvent of the coating liquid is only water, it is difficult to apply it to the surface of the hydrophobic base material layer, but the surface of the base material layer is hydrophilized by plasma-treating the surface of the base material layer.
  • the wettability of the coating liquid to the surface of the substrate layer is improved, and a uniform surface lubricating layer can be formed.
  • the above-described treatment to the surface of the base material layer having no C—H bonds such as metals and fluororesins, it becomes possible to form covalent bonds with the photoreactive groups of the hydrophilic copolymer.
  • the method of applying the coating liquid to the surface of the substrate layer is not particularly limited, and may be a coating/printing method, an immersion method (dipping method, dip coating method), an atomization method (spray method), a spin coating method, or a mixing method.
  • a conventionally known method such as a solution impregnation sponge coating method can be applied.
  • the immersion method dipping method, dip coating method
  • the immersion method is preferable.
  • the base layer when forming a surface lubricating layer on the thin and narrow inner surface of a catheter, stent, guidewire, etc., the base layer may be immersed in a coating liquid to depressurize the inside of the system to degas. By depressurizing and defoaming, the solution can be quickly permeated into the thin and narrow inner surface, and the formation of the surface lubricating layer can be promoted.
  • a surface lubricating layer can be formed on a desired surface portion of the substrate layer.
  • a suitable member that can attach and detach the surface part of the base material layer that does not need to be formed with a surface lubricating layer in advance.
  • the base material layer After protecting (coating, etc.) with a material, the base material layer is immersed in the coating liquid, and after coating the base material layer with the coating liquid, the surface part of the base material layer that does not need to form a surface lubricating layer.
  • a surface lubricating layer can be formed on a desired surface portion of the substrate layer by removing the protective member (material) and then reacting it by a heating operation or the like.
  • the surface lubricating layer can be formed by appropriately utilizing conventionally known methods without being limited to these forming methods.
  • another coating method for example, a predetermined surface portion of the medical device, the coating liquid, A coating method using a coating device such as a spray device, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, doctor knife, etc.
  • a coating device such as a spray device, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, doctor knife, etc.
  • An immersion method (dipping method) is preferably used because it can be used.
  • Drying conditions are not particularly limited as long as the solvent can be removed from the film, and hot air treatment may be performed using a dryer or the like, or natural drying may be performed.
  • the pressure conditions during drying are not particularly limited, and drying can be performed under normal pressure (atmospheric pressure), or under increased pressure or reduced pressure.
  • a drying means for example, an oven, a vacuum dryer, or the like can be used, but in the case of natural drying, no particular drying means (apparatus) is necessary.
  • the coating after the drying step is irradiated with active energy rays. This activates the photoreactive groups of the hydrophilic copolymer in the coating, forming chemical bonds between the photoreactive groups and the substrate layer. More specifically, the case of a combination of a photoreactive group having a benzophenone structure and a polyethylene substrate layer will be described.
  • the hydrophilic copolymer contains a photoreactive group having a benzophenone structure, two radicals are generated in the photoreactive group by irradiation with ultraviolet rays. One of these radicals abstracts a hydrogen atom from the polyethylene base layer, and instead one radical is generated on the polyethylene base layer.
  • a covalent bond is then formed between the photoreactive group and the polyethylene substrate layer by combining the remaining radicals in the photoreactive group with the radicals on the polyethylene substrate layer.
  • active energy rays examples include ultraviolet rays (UV), electron rays, gamma rays, and the like, but ultraviolet rays or electron rays are preferred, and ultraviolet rays are more preferred in consideration of the effects on the human body.
  • the irradiation wavelength can be appropriately selected from a wavelength that can activate the photoreactive group.
  • the irradiation intensity of ultraviolet rays is not particularly limited, it is preferably 1 to 5000 mW/cm 2 .
  • the integrated amount of UV light is not particularly limited, but is preferably 50 to 5000 mJ/cm 2 , more preferably 100 to 1000 mJ/cm 2 .
  • a high-pressure mercury lamp, a low-pressure mercury lamp, a metal halide lamp, a xenon lamp, a halogen lamp, etc. can be exemplified as a device for irradiating ultraviolet rays.
  • the surface of the substrate layer may be washed with a solvent (for example, the solvent used for coating liquid preparation) to remove unreacted hydrophilic copolymer.
  • a solvent for example, the solvent used for coating liquid preparation
  • the immobilization of the film (surface lubricating layer) on the substrate layer can be confirmed using known analysis means such as FT-IR and XPS. For example, it can be confirmed by performing FT-IR measurement before and after irradiation with an active energy ray and comparing the ratio between the peak of the bond formed by the irradiation of the active energy ray and the peak of the unchanged bond.
  • known analysis means such as FT-IR and XPS.
  • the counter ion of the sulfonate ion in the sulfobetaine structure in the film (surface lubricating layer) is an alkali metal cation.
  • the structural unit (A) is derived from the polymerizable monomer (A) of the above formula (1)
  • the coating (surface lubricating layer) is measured with a Raman spectrometer (for example, Raman RXN1 manufactured by Kaiser).
  • the surface of the medical device according to the present invention is formed with a surface lubricating layer containing the hydrophilic copolymer of the present invention.
  • the medical device according to the present invention can exhibit excellent lubricity and durability (lubricity maintenance property).
  • the medical device according to the present invention is used in contact with body fluids, blood, etc., and has lubricity on the surface in body fluids and water-based liquids such as physiological saline, improving operability and reducing damage to tissue mucosa.
  • can do Specific examples include catheters, stents, and guidewires used in blood vessels. That is, the medical device according to one embodiment of the invention is a catheter, stent or guidewire. Also shown are the following medical devices:
  • Catheters that are orally or nasally inserted or left in the gastrointestinal tract such as gastric catheters, feeding catheters, tube feeding tubes;
  • Catheters that are orally or nasally inserted or placed in the airway or trachea such as oxygen catheters, oxygen cannulas, endotracheal tube tubes or cuffs, tracheostomy tube tubes or cuffs, endotracheal suction catheters;
  • Catheters to be inserted or left in the urethra or ureter such as urethral catheters, urinary catheters, urethral balloon catheters and balloons;
  • Catheters to be inserted or left in various body cavities, organs and tissues such as aspiration catheters, drainage catheters and rectal catheters;
  • this reaction solution is placed in a 30 mL eggplant-shaped flask, oxygen is removed by sufficient nitrogen bubbling, and 4,4-azobis (4-cyanovaleric acid) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) is used as a polymerization initiator.
  • V-501 28 mg (0.10 mmol) was added, and then the reactor was quickly closed and polymerized in a water bath at 80° C. for 2 hours.
  • the polymer solution was dropped into acetone to precipitate, and after removing the supernatant by decantation, the polymer was washed twice with methanol to obtain a copolymer A.
  • Table 1 shows the compositions of the copolymers A to E obtained in Production Examples 1 to 5 (constituent unit ratio of MSPB:MBP (mol%)).
  • Examples 1-1 to 8-1 in Table 2 the content of the structural unit (A) derived from MSPB (monomer (A)) exceeds 80 mol% of the total structural units.
  • Polymers A to D exhibit good solubility in water or water/methanol mixed solvents by adding alkali metal salts (sodium chloride or sodium sulfate or trisodium phosphate).
  • alkali metal salts sodium chloride or sodium sulfate or trisodium phosphate
  • copolymer E in which the content of structural units derived from MSPB (monomer A) is 80 mol% of the total structural units, contains a considerable amount of alkali metal Even with the addition of salt, it cannot be dissolved in both water and water/methanol mixed solvents. Further, as shown in Comparative Example 2-1, even in a copolymer in which the content of structural units derived from MSPB (monomer A) exceeds 80 mol% of the total structural units, alkali metal salt is not added, it can be seen that it cannot be dissolved in both water and water/methanol mixed solvent.
  • Example 1-2 (Production of covering tube 1)
  • Copolymer B was uniformly dissolved and dispersed in the coating liquid.
  • a polyethylene tube (Novatec (registered trademark) HB530 manufactured by Nippon Polyethylene Co., Ltd.) having an outer diameter of 0.84 mm was immersed in the coating solution and pulled up at a speed of 5 mm/sec.
  • a coating was formed on the tube by drying at room temperature (25° C.) for 10 minutes.
  • the coating film was irradiated with UV light having a wavelength of 365 nm and a lamp power of 1 kW under the conditions of an irradiation distance of 200 mm and a sample transport speed of 2 m/min (integrated light amount: 230 mJ/cm 2 ), and a hydrophilic copolymer was applied to the tube surface.
  • a coated tube 1 having a coating layer (lubricating layer) (thickness after drying 1 ⁇ m) was produced.
  • UVC-1212/1MNLC3-AA04 high-pressure mercury lamp manufactured by Ushio Inc. was used.
  • the coating layer of the coating tube 1 prepared above is measured with a Raman spectrometer (manufactured by Kaiser, Raman RXN1, measurement wavelength: 532 nm, resolution: 1 cm ⁇ 1 ), and the sulfone of the hydrophilic copolymer in the coating layer is measured.
  • the counterion of the acid ion was confirmed. As a result, no ammonium peak (975 cm ⁇ 1 ) was confirmed, but a sodium peak (992 cm ⁇ 1 ) was confirmed.
  • the counter ion of the sulfonate ion of the hydrophilic copolymer in the coating layer was not the ammonium cation but the sodium cation (that is, the hydrophilic copolymer according to the present invention).
  • the coated tube 1 was evaluated for slidability (initial slidability of the lubricating layer) according to the following method. Specifically, the coated tube 1 was immersed in physiological saline at 25° C., rubbed with a finger, and compared with an untreated tube (tube made of polyethylene (Novatec (registered trademark) HB530 manufactured by Japan Polyethylene Co., Ltd.)). As a result, it was confirmed that the coated tube 1 had a slippery, low-friction surface compared to the untreated tube.
  • the coated tube 1 was evaluated for sliding durability (lubricating layer durability) according to the following method. Specifically, the coated tube 1 was immersed in a physiological saline solution at 25° C., and the slidability was sensory evaluated by pinching the sample with hands and rubbing it in the longitudinal direction. Sliding durability was evaluated by measuring the number of times of rubbing until lubricity (slippery feeling) was lost. It is judged that the greater the number of times, the better the sliding durability.
  • Example 2-2 (Preparation of covering tube 2)
  • Example 1-2 according to the same method as in Example 1-2, except that the copolymer B was changed to the copolymer C obtained in Production Example 3, a coating containing a hydrophilic copolymer was formed on the tube surface.
  • a coated tube 2 having a layer (lubricating layer) (film thickness after drying 1 ⁇ m) was produced.
  • Copolymer C was uniformly dissolved and dispersed in the coating liquid.
  • the coated tube 2 was evaluated for slidability (initial slidability of the lubricating layer) according to the method described in Example 1-2. As a result, it was confirmed that the coated tube 2 had a slippery, low-friction surface compared to the untreated tube.
  • the coating tube 2 was evaluated for sliding durability (durability of the lubricating layer) according to the method described in Example 1-2. The results are shown in Table 3 below.
  • Example 3-2 (Preparation of covering tube 3)
  • Copolymer D was uniformly dissolved and dispersed in the coating liquid.
  • the coated tube 3 was evaluated for slidability (initial slidability of the lubricating layer) according to the method described in Example 1-2. As a result, it was confirmed that the coated tube 3 had a slippery, low-friction surface compared to the untreated tube.
  • the coating tube 3 was evaluated for sliding durability (durability of the lubricating layer) according to the method described in Example 1-2. The results are shown in Table 3 below.
  • Example 4-2 (Preparation of covering tube 4)
  • the tube surface was coated with a hydrophilic copolymer in the same manner as in Example 2-2, except that sodium chloride was added in a proportion of 50 parts by weight with respect to 100 parts by weight of the copolymer C.
  • Copolymer C was uniformly dissolved and dispersed in the coating liquid.
  • the coated tube 4 was evaluated for slidability (initial slidability of the lubricating layer) according to the method described in Example 1-2. As a result, it was confirmed that the coated tube 4 had a slippery, low-friction surface compared to the untreated tube.
  • Example 5-2 (Production of covering tube 5)
  • Example 2-2 according to the same method as in Example 2-2 except that sodium sulfate was added instead of sodium chloride, a coating layer (lubricating layer) containing a hydrophilic copolymer on the tube surface (after drying A coated tube 5 having a film thickness of 1 ⁇ m) was produced. Copolymer C was uniformly dissolved and dispersed in the coating liquid.
  • the coated tube 5 was evaluated for slidability (initial slidability of the lubricating layer) according to the method described in Example 1-2. As a result, it was confirmed that the coated tube 5 had a slippery, low-friction surface compared to the untreated tube.
  • Example 6-2 (Preparation of covering tube 6)
  • Copolymer A was uniformly dissolved and dispersed in the coating liquid.
  • the coated tube 6 was evaluated for slidability (initial slidability of the lubricating layer) according to the method described in Example 1-2. As a result, it was confirmed that the coated tube 6 had a slippery, low-friction surface compared to the untreated tube.
  • copolymers A to D and alkali metal salts As shown in Table 3, copolymers A to D and alkali metal salts (The lubricating layer formed using a coating liquid containing sodium chloride or sodium sulfate) and containing the hydrophilic copolymer according to the present invention has excellent slidability (initial slidability) and durability (sliding durability). I know it's good. In particular, from a comparison of Examples 1-2 to 5-2 and Example 6-2, the content of structural units (A) derived from MSPB (monomer (A)) is 99.9 relative to all structural units. It can be seen that the durability (sliding durability) can be further improved when it is less than mol % (especially 99.5 mol % or less).
  • the lubricating layer according to the present invention can exhibit excellent lubricity (initial slidability) and durability (lubrication maintenance property).

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

Le but de la présente invention est de fournir un copolymère hydrophile capable de former une couche de lubrification de surface qui présente un excellent pouvoir lubrifiant et une excellente durabilité (propriétés de maintien du pouvoir lubrifiant). La présente invention concerne un instrument médical comprenant une couche de matériau de base et une couche de lubrification qui contient un copolymère hydrophile et est formée sur au moins une partie de la couche de matériau de base, le copolymère hydrophile contenant une unité structurale dérivée d'un monomère polymérisable (A) ayant une structure de sulfobétaïne dans laquelle le contre-ion d'ion d'acide sulfonique est un cation de métal alcalin, et une unité structurale dérivée d'un monomère polymérisable (B) ayant un groupe photoréactif ; et la teneur en unité structurale dérivée du monomère polymérisable (A) est supérieure à 80 % en moles mais inférieure à 100 % en moles par rapport à la somme des unités structurales dérivées de tous les monomères.
PCT/JP2022/010494 2021-03-12 2022-03-10 Instrument médical WO2022191271A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021-039825 2021-03-12
JP2021039825A JP2024057623A (ja) 2021-03-12 2021-03-12 医療用具

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WO2022191271A1 true WO2022191271A1 (fr) 2022-09-15

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017030950A1 (fr) * 2015-08-14 2017-02-23 Arrow International, Inc. Copolymères résistant à l'encrassement photoactivables
WO2018038063A1 (fr) * 2016-08-25 2018-03-01 テルモ株式会社 Copolymère hydrophile et dispositif médical

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017030950A1 (fr) * 2015-08-14 2017-02-23 Arrow International, Inc. Copolymères résistant à l'encrassement photoactivables
WO2018038063A1 (fr) * 2016-08-25 2018-03-01 テルモ株式会社 Copolymère hydrophile et dispositif médical

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