WO2023190383A1 - Composition polymère - Google Patents

Composition polymère Download PDF

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WO2023190383A1
WO2023190383A1 PCT/JP2023/012287 JP2023012287W WO2023190383A1 WO 2023190383 A1 WO2023190383 A1 WO 2023190383A1 JP 2023012287 W JP2023012287 W JP 2023012287W WO 2023190383 A1 WO2023190383 A1 WO 2023190383A1
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polymer
polymer composition
formula
composition according
present
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PCT/JP2023/012287
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Japanese (ja)
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賢 田中
慎吾 小林
政一 清水
修一 後藤
孝徳 高橋
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国立大学法人九州大学
綜研化学株式会社
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Publication of WO2023190383A1 publication Critical patent/WO2023190383A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
    • C08F20/04—Acids, Metal salts or ammonium salts thereof
    • C08F20/06—Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D133/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Coating compositions based on derivatives of such polymers
    • C09D133/04—Homopolymers or copolymers of esters

Definitions

  • the present invention relates to a novel polymer composition and a coating composition for surface treatment containing the polymer compound.
  • biocompatible materials include 2-methacryloyloxyethylphosphorylcholine (MPC) polymer, polyethylene glycol (PEG), poly(2-mexyethyl acrylate) (PMEA), and the like.
  • MPC 2-methacryloyloxyethylphosphorylcholine
  • PEG polyethylene glycol
  • PMEA poly(2-mexyethyl acrylate)
  • MPC polymer is a type of betaine that maintains electrical neutrality in the biological environment. This is a polymer that exhibits biocompatibility by introducing into a synthetic polymer a structure that mimics the substance that binds to the body. Since the MPC polymer itself exhibits good water solubility, it is made water-insoluble as a copolymer with a hydrophobic unit, and then coated on the surface of a medical device using a coating composition dissolved in an appropriate solvent. This makes it possible to form a surface with excellent biocompatibility, such as suppressing the adhesion of platelets.
  • PEG is a polymer whose repeating unit is -(C 2 H 4 -O)-, which is a chain ether structure, and although it has a structure that is not similar to substances that make up living organisms, it is extremely superior. It is known to have good biocompatibility. Since PEG itself is water-soluble, it is bonded to a polymer surface by a technique such as graft polymerization to make it water-insoluble and is used in environments where it comes into contact with blood and the like.
  • PMEA is known to exhibit biocompatibility because it has a structure in which a side chain whose main structure is (C 2 H 4 -O), which is the constituent unit of PEG, is bonded to an acrylic skeleton. For example, it is used as a material for the surfaces that come into contact with blood inside heart-lung machines.
  • Patent Document 1 compares the density at which side chains having a -(C 2 H 4 -O)- structure are introduced with respect to the main chain structure with PMEA. It has been described that a polymer obtained by reducing the amount of carbon dioxide exhibits biocompatibility.
  • Patent Document 2 describes that by changing the number of repeats of the (C 2 H 4 -O) structure in the side chain portion of PMEA, it has biocompatibility and is resistant to aqueous phase at a predetermined temperature. It is described that polymers whose solubility changes discontinuously are obtained.
  • polymers that exhibit biocompatibility as described above generally exhibit hydrophilicity, and that when equilibrated with an aqueous phase, they form a hydrated structure with a predetermined amount of water molecules and a predetermined form.
  • polymers exhibiting biocompatibility can contain water molecules in the form of so-called "freezing-bound water" (intermediate water) inside their hydration shells.
  • Intermediate water is characterized by the movement of latent heat associated with the ordering/disordering of water molecules in the sub-zero temperature range, and there are two types of intermediate water: antifreeze water, which is strongly bound to the material surface, and unfreeze water, which is hardly restrained by the material surface.
  • various polymer compositions that exhibit biocompatibility have been known, and in particular, those polymer compositions that exhibit water-insolubility when in contact with biological components such as blood. It is used to form the surfaces of medical devices used in On the other hand, it is generally difficult for the various polymer compositions exhibiting biocompatibility described above to independently constitute various members constituting medical equipment in terms of mechanical properties and the like. Usually, by coating the surfaces of various members made of other materials with the above-mentioned polymer composition, biocompatibility is imparted to the surfaces of structural members that exhibit the required mechanical properties, etc. A method to do this is used.
  • a laminate in which the structural member and the surface coating polymer are laminated via an adhesive interface is formed. It is formed.
  • a coating layer made of a biocompatible polymer is provided on the inner surface of the tube using this method for a flexible tube for circulating blood used in equipment such as a heart-lung machine. In this case, the tube hardens due to the mechanical strength of the coating layer, resulting in a decrease in flexibility and poor handling.
  • the increase in the bending strength of various members due to the provision of the coating layer and the generation of stress that causes the coating layer to peel off from the underlying surface are thought to be due to the elastic modulus inherent to the coating layer.
  • the increase in bending strength when a coating layer is provided is due to the need for new stress to bend the coating layer against its elastic force, which reduces the elastic modulus inherent to the coating layer.
  • the increase in the strength of the member as a whole is suppressed, and it is thought that ease of handling is unlikely to be impaired.
  • the stress that causes the coating layer to peel off from the structural member is suppressed, and it is thought that the degree of adhesion of the biocompatible polymer to the substrate required can be reduced.
  • an object of the present invention is to provide a novel polymer composition that exhibits biocompatibility and is capable of suppressing the elastic modulus, which is the cause of the elastic force generated when deformed. do.
  • a polymer composition in which n in the following formula (2) is an integer of 20 or less.
  • the above polymer composition which is characterized by being water-insoluble.
  • a polymer composition and the like that exhibits biocompatibility and has a suppressed elastic modulus, which is the cause of elastic force generated when deformed, is provided.
  • FIG. 2 is a diagram showing the viscoelastic properties (G') of the polymer composition according to the present invention.
  • FIG. 3 is a diagram showing the viscoelastic properties (tan ⁇ ) of the polymer composition according to the present invention.
  • FIG. 2 is a diagram showing the viscoelastic properties (G') of the polymer composition according to the present invention.
  • FIG. 3 is a diagram showing the viscoelastic properties (tan ⁇ ) of the polymer composition according to the present invention.
  • FIG. 2 is a diagram showing the platelet adhesion properties on the surface of the polymer composition according to the present invention.
  • biocompatible polymers that have been used for surface coating of various parts typically include structural units that exhibit biocompatibility, and the expression of the biocompatibility is not inhibited.
  • synthetic polymers in various forms, polymers that exhibit biocompatibility as a whole are constructed.
  • the structural unit that exhibits biocompatibility generally exhibits hydrophilicity, polymers into which the structural unit has been introduced tend to exhibit water solubility, and may not be suitable for surface coating applications of various parts. It is generally difficult to obtain polymer compositions that are both water-insoluble and usable in surface coating applications.
  • the polymer used for the coating has It is necessary to determine the material, shape, form, etc. of the various parts to be coated according to the characteristics, and it is necessary to add biocompatibility to the surface of existing parts by coating with biocompatible polymers. It wasn't always easy.
  • the present inventor has developed a method for coating the surface of a member used in contact with an aqueous phase such as blood by having predetermined mechanical properties, specifically by reducing the elastic modulus related to elastic deformation. We believe that it is possible to suppress the frequency of peeling of the coating layer from the surface of the coated member when the coated member is deformed, without impairing the flexibility etc. of the coated member.
  • the search for polymer compositions that exhibit a lower modulus of elasticity compared to affinity polymers led to the present invention.
  • the polymer composition according to the present invention contains a polymer containing a repeating unit represented by the following formula (2).
  • R 1 and R 2 are each independently a hydrogen atom or a methyl group
  • n is the repeating number of propylene glycol and is in the range of n ⁇ 4
  • x is the repeating number of the main chain. This is a symbol that indicates a unit.
  • the polymer containing the repeating unit shown in formula (2) corresponds to the polymer described in Patent Document 3 above, in which the number of repeats of propylene glycol contained in the side chain portion is increased.
  • the present inventor studied a homopolymer composed of repeating units shown in formula (2) above it was found that the propylene glycol exhibits good biocompatibility in a range where the repeating number (n value) is less than 4.
  • the same degree of elastic modulus is observed compared to PMEA used for coating the surfaces of members such as medical devices, but by setting the n value in the range of 4 or more, the n value It was found that the elastic modulus decreases with size.
  • the above homopolymer is water-insoluble regardless of the n value, and even when the above n value is in the range of 4 or more, it can be used in equilibrium with the aqueous phase. Shown.
  • a polymer when a polymer is described as water-insoluble, for example, when a solution of the polymer dissolved in an appropriate organic solvent at a temperature around room temperature is mixed with an excess amount of the aqueous phase, the aqueous phase acts as a poor solvent for the polymer, and means that the solubility of the polymer is so low that almost the entire amount of the polymer is precipitated from the aqueous phase.
  • the polymer according to the present invention inhibits the flexibility of various parts when coated on the surface of various parts with a predetermined thickness, especially in the form of a coating composition. By suppressing the degree of shear stress generated between the surface of the member and the coating layer, it is possible to effectively suppress peeling of the coating layer.
  • n value By setting the above n value in the range of 4 or more, it is possible to reduce the elastic modulus, and in particular, by setting the n value in the range of 6 or more, it is possible to significantly reduce the elastic modulus compared to PMEA etc. becomes.
  • the upper limit of the n value is not particularly limited, in particular, in a polymer composed only of repeating units shown in formula (2), an increase in the n value causes a decrease in the elastic modulus and expands the viscous behavior.
  • the value When the value is in the range of 20 or more, it behaves as a viscous body when used near room temperature, so it is preferable to set the n value in the range of 20 or less.
  • the polymer composition according to the present invention can also be used in the form of a copolymer obtained by using the repeating unit shown in formula (2) above and another repeating unit having a (meth)acrylic skeleton. It is. That is, for example, by introducing the repeating unit shown in formula (2) above into mexiethyl acrylate (MEA), etc., which is a repeating unit constituting PMEA, to form a copolymer, biocompatibility can be achieved. It has been found that it is possible to reduce the elastic modulus based on the PMEA, etc., while maintaining water-insolubility and the like.
  • MCA mexiethyl acrylate
  • the repeating unit can be used as an elastic modulus reducing agent for a polymer made of repeating units having another structure, etc., to improve its mechanical properties. It shows the function that improves the performance.
  • copolymers formed by introducing repeating units other than the repeating units shown in formula (2) may be used. It is also possible to make a polymer composition containing the following. At that time, as the repeating unit (monomer) introduced to the repeating unit shown in formula (2), one that does not easily inhibit the expression of biocompatibility is preferably used, for example, the polymer composition according to the present invention An alkyl (meth)acrylate such as butyl acrylate can be introduced for the purpose of imparting hydrophobicity to the material.
  • alkyl (meth)acrylate and the like for forming a copolymer with the repeating unit shown in formula (2) above for example, those having the structure shown in formula (3) below can be used.
  • R 3 represents an alkyl group or an aralkyl group.
  • the alkyl group represented by R 3 may be linear or branched, for example, an alkyl group having 1 to 18 carbon atoms (for example, methyl group, ethyl group, n-propyl group, isopropyl group).
  • n-butyl group isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 2-methylbutyl group, 1-methylbutyl group, n-hexyl group, isohexyl group, 3 -Methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, n-heptyl group, n-octyl group, isooctyl group, 2-ethylhexyl group, n-nonyl group, n-decyl group, isodecyl group, n- Undecyl group, n-dodecyl group (lauryl group), n-tridecyl group, n-tetradecyl group (myristyl group), isomyristyl group, n-hexa
  • the aralkyl group represented by R3 has a structure in which one of the hydrogen atoms of the alkyl group is substituted with an aryl group, and the aralkyl group has 1 to 18 carbon atoms (for example, a benzyl group). (phenylmethyl group) and phenethyl group (phenylethyl group).
  • examples of monomers containing a polar group used when forming a copolymer with the repeating unit shown in formula (2) above include 2-hydroxyethyl acrylate, 2-hydroxy Ethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 4-hydroxybutyl acrylate, 4-hydroxybutyl methacrylate, 2-hydroxy-3-chloropropyl acrylate, 2-hydroxy-3-chloropropyl methacrylate, 2-hydroxy Hydroxyl group-containing (meth)acrylic monomers such as -3-phenoxypropyl acrylate and 2-hydroxy-3-phenoxypropyl methacrylate, N,N-dimethylaminoethyl acrylate, N,N-dimethylaminoethyl methacrylate, and N,N-diethylamino Nitrogen-containing monomers such as ethyl methacrylate, acrylamide, N,N-dimethylaminopropylacrylamide, diace
  • polymers having the following structure polymers composed of repeating units shown in formula (2) in which R 1 , R 2 , n, etc. are different from each other in a single molecule, repeating units shown in formula (2) It is possible to include polymers containing repeating units other than the above.
  • a mixture obtained by using a polymer containing the repeating unit shown in formula (2) above and mixing it with a polymer composed of other repeating units in an appropriate ratio may also be used as the polymer composition according to the present invention. Included.
  • the polymer composition it is possible to construct a polymer composition that has both low elastic modulus and biocompatibility as a whole.
  • the polymer composition according to the present invention When the polymer composition according to the present invention is mixed with other polymers and used as a composition, it can be used at an appropriate mixing ratio depending on the intended use. In particular, by setting the proportion of the polymer composition according to the present invention to 90% by weight or more, a composition having strong characteristics of the present invention can be obtained. In addition, depending on the intended use, by adjusting the proportion of the polymer composition according to the present invention to 50 to 70% by weight, it is possible to obtain a composition that has various characteristics while taking advantage of the features of the present invention.
  • composition obtained by mixing the polymer composition according to the present invention with other polymers, etc. is not necessarily limited to one composed of a uniform phase, and for example, a composition containing a repeating unit shown in formula (2) above
  • a hydrophobic polymer By mixing a hydrophobic polymer, it is possible to obtain a composite material having a form in which the polymer containing the repeating unit shown in the above formula (2) is dispersed using the hydrophobic polymer as a matrix.
  • the proportion of the repeating unit represented by formula (2) contained in the polymer constituting the polymer composition according to the present invention is not particularly limited, and can be appropriately determined depending on the use thereof.
  • a flexible polymer composition with a reduced elastic modulus can be obtained by using a polymer composed only of repeating units represented by formula (2), particularly repeating units whose n value is large.
  • the proportion (mol%) occupied by the repeating unit shown in formula (2) is 1
  • the ratio in the range of % to 10%, or around 20%, 30%, 40%, 50%, 60%, etc., the expression of characteristics due to the repeating unit having the other structure can be suppressed. Its elastic modulus can be reduced while maintaining its elasticity.
  • polymer and polymer are used interchangeably, and the term polymer composition refers to different configurations within a polymer aggregate. It is used to clarify the possibility that polymers with
  • a polymer substantially composed only of the repeating units shown in formula (2) may be referred to as a homopolymer, even if its n value has a distribution, and in particular, (2) )
  • a copolymer is referred to as a copolymer when it is intended to contain repeating units other than the repeating units shown in the formula.
  • the weight average molecular weight (Mw) and number average molecular weight (Mn) of the polymer composition according to the present invention are not particularly limited, and it is possible to synthesize a polymer having an appropriate molecular weight depending on the purpose and use the composition. can.
  • the elastic modulus of a polymer composition is preferably 1,000,000 or less, more preferably 500,000 or less, or 200,000 or less.
  • the weight average molecular weight (Mw) to 5,000 or more, more preferably 10,000 or more, stable water insolubility can be exhibited.
  • the molecular weight distribution (weight average molecular weight (Mw)/number average molecular weight (Mn)) in the polymer composition according to the present invention is not particularly limited, and for example, Mw/Mn can be about 10. On the other hand, by setting Mw/Mn to 5 or less, particularly 3 or less, stable behavior can be imparted to the polymer composition.
  • the polymer molecules can be cross-linked in the coating film by using various cross-linking agents or by irradiating energy such as electron beams.
  • the resistance of the coating can be improved, and the elastic modulus of the coating can be adjusted.
  • the polymer composition according to the present invention can be bonded to the surfaces of various members by means such as graft polymerization. You can also do that.
  • the glass transition temperature (Tg) exhibited by the polymer composition according to the present invention is not particularly limited, but since a low elastic modulus is generally observed in a polymer composition having a low Tg, for example, if the Tg is -20°C or lower, or Polymer compositions having a temperature of -30°C or lower, more preferably -40°C or lower are preferably used.
  • the polymer composition according to the present invention can be obtained by polymerizing the monomers by, for example, a solution polymerization method using a mixture of monomers including a (meth)acrylic monomer having the structure shown in the following formula (4). 2) It can be produced by forming a polymer containing the repeating unit shown in the formula.
  • formula (4) the contents represented by R 1 , R 2 , and n are the same as in formula (2).
  • a polymerization solvent and predetermined monomer components are charged into a reaction vessel, a polymerization initiator is added under an inert gas atmosphere such as nitrogen gas, and the reaction initiation temperature is set to usually 40 to 100°C, preferably 50 to 50°C.
  • the polymer composition according to the present invention can be obtained by setting the temperature to 80°C, maintaining the reaction system at a temperature of usually 50 to 90°C, preferably 70 to 90°C, and allowing the reaction to proceed for 4 to 20 hours.
  • polymerization solvent used in solution polymerization examples include aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, and n-octane; cyclopentane, Alicyclic hydrocarbons such as cyclohexane, cycloheptane, and cyclooctane; Ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dibutyl ether, tetrahydrofuran, dioxane, anisole, phenylethyl ether, and diphenyl ether; chloroform, Halogenated hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane, chlorobenzene; Esters such as ethyl acetate, propyl acetate, butyl
  • ketones examples include ketones; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; nitriles such as acetonitrile and benzonitrile; and sulfoxides such as dimethylsulfoxide and sulfolane.
  • amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone
  • nitriles such as acetonitrile and benzonitrile
  • sulfoxides such as dimethylsulfoxide and sulfolane.
  • examples of the polymerization initiator used in solution polymerization include azo initiators and peroxide initiators.
  • Specific examples include azo compounds such as 2,2'-asobisisobutyronitrile, and peroxides such as benzoyl peroxide and laurium peroxide. Among these, azo compounds are preferred.
  • azo compounds examples include 2,2'-azobisisobutyronitrile, 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2-cyclopropyl propionitrile), 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(2-methylbutyronitrile), 1,1'-azobis(cyclohexane-1-carbonitrile) , 2-(carbamoylazo)isobutyronitrile, 2-phenylazo-4-methoxy-2,4-dimethylvaleronitrile, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis( N,N'-dimethyleneisobutyramidine), 2,2'-azobis[2-methyl-N-(2-hydroxyethyl)-propionamide], 2,2'-azobis(isobutyramide) dihydrate, 4,4 '-azobis(4-cyan
  • the polymerization initiator is generally used in an amount of 0.01 to 5 parts by weight, preferably 0.1 to 3 parts by weight, based on 100 parts by weight of the monomer components to be polymerized. Further, during the above polymerization reaction, a polymerization initiator, a chain transfer agent, a monomer component, and a polymerization solvent may be additionally added as appropriate. Furthermore, the polymer composition according to the present invention can be produced by a bulk polymerization method, and can be produced using a hot-melt adhesive that does not contain an organic solvent, or an energy ray-curable adhesive by diluting it with a (meth)acrylic monomer. It can be used as an adhesive, and the use of organic solvents harmful to living organisms can be avoided in the polymerization process.
  • a random copolymer may be made by the method described above, Alternatively, a block copolymer may be used.
  • the polymer composition according to the present invention can also be produced using general living radical polymerization, and among these methods, reversible addition-fragmentation chain transfer (RAFT) is preferred from the viewpoint of ease of controlling the polymerization reaction. ) It can be suitably produced by polymerization.
  • methods include sequentially adding monomer units, polymerizing the next polymer block using a pre-synthesized polymer as a polymer initiator, and combining separately polymerized polymer blocks by reaction. Block polymers can be produced.
  • the polymer composition according to the present invention can be produced by using a mixture containing the monomers shown in formula (4) above and causing a polymerization reaction between the monomers while applying the mixture to the surfaces of various members. , polymer production and coating can be performed simultaneously.
  • a polymer having three or more groups polymerizable with the monomer shown in formula (4) above is used.
  • a mixture of a functional monomer and a monomer represented by the above formula (4) crosslinking occurs simultaneously with the polymerization reaction, and a highly stable polymer film can be formed.
  • a substance sensitive to ultraviolet light as a polymerization initiator used to cause the polymerization reaction, it is possible to generate a coating film in a desired shape at a desired timing. It can be carried out.
  • the average molecular weight of the polymer according to the present invention can be measured according to a standard method using gel permeation chromatography (GPC). Furthermore, the hydrophilicity exhibited by the surface of the polymer according to the present invention can be evaluated by measuring the contact angle with ion-exchanged water or the like using a method based on JIS R 3257.
  • GPC gel permeation chromatography
  • the elastic modulus etc. exhibited by the polymer according to the present invention are evaluated as storage elastic modulus G', loss elastic modulus G'', and loss tangent (tan ⁇ ) by dynamic mechanical analysis (DMA) in accordance with JIS K7244.
  • DMA dynamic mechanical analysis
  • the storage modulus G' is a coefficient that indicates the magnitude of the repulsive force generated on the sample in the same phase as the strain applied to the sample, and is the elastic modulus (
  • the loss modulus G'' is a coefficient that indicates the degree to which the deformation is compensated for by viscous distortion when a sample is deformed, and the loss modulus
  • the ratio (G''/G') is defined as the loss tangent (tan ⁇ ), which indicates the degree of contribution of viscous strain to the deformation of the sample.
  • the glass transition temperature (Tg) of a polymer can be defined as the temperature at which the above-mentioned tan ⁇ reaches the maximum, and can also be measured by a differential scanning calorimeter (DSC).
  • the degree of biocompatibility exhibited by the polymers and the like according to the present invention can be evaluated based on the properties related to the adhesion of platelets that occur as a result of activation of the platelet system on the surface of the polymer.
  • the degree of biocompatibility exhibited by a polymer, etc. when blood etc. containing platelets comes into contact with the surface of the polymer, the frequency of adhesion of platelets to the surface of the polymer changes, and the morphology of the adhered platelets changes. It is known that changes occur in
  • the polymer composition according to the present invention When forming a film on the surface of various materials using the polymer composition according to the present invention as a coating agent, the polymer composition according to the present invention is dissolved in a solvent capable of dissolving it at a predetermined concentration to form a coating composition.
  • the coating composition may be applied to the surface of a predetermined article by an appropriate coating method, and then the solvent may be dried and removed.
  • the coating composition containing the polymer composition according to the present invention can be applied by a known method, such as a spin coating method, a knife coating method, a roll coating method, a bar coating method, a blade coating method, and a die coating method.
  • the coating composition may be applied to the surface of the article to a predetermined thickness by a gravure coating method or a spray coating method, and then dried.
  • the polymer composition according to the present invention can also be produced by applying a monomer mixture that produces the polymer composition according to the present invention by polymerization to the surface of a member by the method described above, and then causing a polymerization reaction between the monomers. It is possible to form a coating film composed of substances.
  • the polymer composition according to the present invention can be applied to an article made of a plastic material such as a polyolefin film such as polyethylene terephthalate (PET), polyethylene, polypropylene, or ethylene-vinyl acetate copolymer. It exhibits good adhesion and can satisfactorily cover the surface of the member.
  • a plastic material such as a polyolefin film such as polyethylene terephthalate (PET), polyethylene, polypropylene, or ethylene-vinyl acetate copolymer. It exhibits good adhesion and can satisfactorily cover the surface of the member.
  • the thickness of the coating layer formed by the above method is not particularly limited, but since the polymer composition according to the present invention exhibits a low elastic modulus, it is possible to form a coating layer of a predetermined thickness even on the surface of a flexible member. It is.
  • the thickness of the coating layer can be, for example, about 10 to 1000 ⁇ m, and more preferably about 50 to 200 ⁇ m, so that the surface has good biocompatibility without inhibiting the deformation of the article. can be given.
  • the coating composition containing the polymer composition according to the present invention may contain antioxidants, light stabilizers, metal corrosion inhibitors, plasticizers, crosslinking agents, crosslinking accelerators, nano Particles, a silane coupling agent, and a drug exhibiting a certain medicinal effect may be contained as additives.
  • antioxidants light stabilizers, metal corrosion inhibitors, plasticizers, crosslinking agents, crosslinking accelerators, nano Particles, a silane coupling agent, and a drug exhibiting a certain medicinal effect.
  • One or more types of additives can be used.
  • the polymer composition according to the present invention is preferably used for medical purposes, and for example, a composition containing the polymer composition according to the present invention can be used as a coating agent etc. on the surface of an article constituting a medical device. . Furthermore, at least some members of a medical device can be made of the polymer composition according to the present invention.
  • the surface of the medical device etc. can be prevented from being recognized as a foreign substance. , it is possible to prevent foreign body reactions from occurring in biological components.
  • One embodiment of the present invention is a medical device comprising the biocompatible polymer composition of the present invention.
  • medical equipment refers to devices that are used outside the body in contact with biological components such as in-vivo tissues and blood, as well as devices that are implanted in the body such as artificial organs, catheters, etc. Including devices that come into contact with.
  • the surface of a medical device in the present invention refers to, for example, the surface of a material constituting the medical device with which blood or the like comes into contact when the medical device is used, the surface portion of a hole in the material, and the like.
  • used in contact with in-vivo tissue or blood means, for example, used in a state where it is placed in a living body or in a state where in-vivo tissue is exposed and used in contact with the tissue or blood. It naturally includes forms used in extracorporeal circulation medical materials in contact with blood, which is an in-vivo component taken out of the body. Furthermore, “used for medical purposes” includes the above-mentioned “used in contact with in-vivo tissue or blood” or intended use thereof.
  • the material and shape of the base material constituting the medical device are not particularly limited, and may be any of, for example, porous bodies, fibers, nonwoven fabrics, particles, films, sheets, tubes, hollow fibers, and powders.
  • Materials include natural polymers such as wood brocade and hemp, nylon, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyurethane, polyamide, polycarbonate, polysulfone, polyethersulfone, poly(meth)acrylate, and ethylene-vinyl alcohol.
  • Examples include synthetic polymers such as polymers, butadiene-acrylonitrile copolymers, and mixtures thereof.
  • metals, ceramics, composite materials thereof, etc. can be exemplified, and the present invention may be made of a plurality of base materials. It is desirable to provide a polymer composition according to the invention.
  • the polymer composition according to the present invention can be used for implantable prostheses and therapeutic instruments, extracorporeal circulation type artificial organs, surgical sutures, and catheters (angiographic catheters, guide wires, PTCA catheters, etc.).
  • catheters angiographic catheters, guide wires, PTCA catheters, etc.
  • the polymer composition according to the present invention is a type in which a large number of porous hollow fiber membranes for gas exchange are housed in a housing, blood flows on the outer surface side of the hollow fiber membranes, and oxygen-containing gas flows inside the hollow fiber membranes.
  • An artificial lung can be constructed by coating the outer surface or outer surface layer of the hollow fiber membrane of the hollow fiber membrane external blood perfusion type oxygenator.
  • a dialysate circuit including at least one dialysate container filled with dialysate and at least one drain container for collecting dialysate;
  • a dialysis device having a fluid delivery means for delivering a dialysate, at least a part of its blood-contacting surface may be coated with the polymer composition according to the present invention.
  • the polymer composition according to the present invention can be used as a hemostatic agent, an adhesive material for biological tissue, a repair material for tissue regeneration, a carrier for a sustained drug release system, a hybrid artificial organ such as an artificial pancreas or an artificial liver, an artificial blood vessel, and an embolic material. It can be used as a matrix material for scaffolds for cell engineering, etc.
  • the polymer composition of the present invention can be used by coating at least a portion of the surfaces that come into contact with blood, such as blood filters, blood storage containers, members constituting blood circuits, and tubes connecting them.
  • the surface made of the polymer composition according to the present invention can be used as a separation means for adsorbing and separating target protein components, cells, etc.
  • the polymer composition according to the present invention when using the polymer composition according to the present invention to coat a surface that comes into contact with biological components such as in-vivo tissues and blood, the polymer composition according to the present invention may be used in various ways. By coating the surface of the member of the medical device described above with a physiologically active substance supported thereon, the surface can exhibit various functions.
  • the elastic modulus of the polymer composition according to the present invention is suppressed, when coating the surfaces of various members as described above, the degree of inhibition of the flexibility of various members is low. , a coating film can be provided while maintaining its mechanical properties.
  • the surface of the member may be provided with lubricity for the purpose of facilitating insertion into a blood vessel or tissue and preventing damage to the tissue.
  • lubricity for the purpose of facilitating insertion into a blood vessel or tissue and preventing damage to the tissue.
  • a polymerization initiator is fixed on the inner surface of the tube, etc. in advance, and the polymer composition according to the present invention is produced by polymerization.
  • a uniform coating film can be formed by a method such as flowing a monomer mixture into the inner surface of the tube or the like.
  • Example 1 By the method shown below, a homopolymer having formula (2) in which R 1 and R 2 are both hydrogen atoms and the n value is about 6 was polymerized in a solution. Polymerization was carried out using a glass reactor equipped with a stirrer, reflux condenser, thermometer and nitrogen inlet tube, using polypropylene glycol-monoacrylate (NOF AP-400D; 6) 100 parts by weight and 80 parts by weight of methyl ethyl ketone (MEK) as a reaction medium, heated to 70°C while introducing nitrogen gas, and then dimethyl-2,2'-azobis as a polymerization initiator.
  • NOF AP-400D polypropylene glycol-monoacrylate
  • MEK methyl ethyl ketone
  • Example 2 In order to obtain a polymer having a different molecular weight, etc. from the polymer according to Example 1, the reaction medium was changed from MEK to ethyl acetate (EtOAc), and the polymerization initiator V-601 was changed to 0.3 parts by weight. A homopolymer in which R 1 and R 2 in formula (2) are both hydrogen atoms and the n value is about 6 was prepared in a solution in the same manner as in Example 1, except that the reaction temperature was changed to 65°C. Polymerized and purified. The weight average molecular weight (Mw) of the obtained polymer was 58,000, and the molecular weight distribution (Mw/Mn) was 1.6.
  • Mw weight average molecular weight
  • Example 3 The same method as in Example 1 was used, except that polypropylene glycol monoacrylate (NOF AP-1000D; the number of repeats of propylene glycol was approximately 17) was used as the monomer, and MEK as the reaction medium was changed to 50 parts by weight. Accordingly, in the formula (2), a homopolymer in which R 1 and R 2 are both hydrogen atoms and the n value is about 17 was polymerized in a solution. The weight average molecular weight (Mw) of the obtained polymer was 42,000, and the molecular weight distribution (Mw/Mn) was 1.3.
  • Mw weight average molecular weight
  • Example 4 In order to obtain a polymer having a different molecular weight, etc. from the polymer according to Example 3, the reaction medium was changed from MEK to ethyl acetate (EtOAc), 0.3 parts by weight of the polymerization initiator V-601, and the reaction temperature A homopolymer in which R 1 and R 2 in formula (2) are both hydrogen atoms and the n value is about 17 was polymerized in a solution in the same manner as in Example 3, except that the temperature was changed to 65 ° C. , purification was performed. The weight average molecular weight (Mw) of the obtained polymer was 51,000, and the molecular weight distribution (Mw/Mn) was 1.4.
  • Mw weight average molecular weight
  • PMEA Poly(2-mexyethyl acrylate)
  • Formula (5) shows the structure of PMEA.
  • Example 2 Same as Example 1 except that 100 parts by weight of 2-methoxyethyl acrylate as a monomer, 200 parts by weight of MEK as a reaction medium, 0.3 parts by weight of polymerization initiator V-601, and the reaction temperature was changed to 75°C.
  • PMEA was synthesized and purified in the same manner as in Example 1 using the method described above.
  • the weight average molecular weight (Mw) of the obtained polymer was 81,000, and the molecular weight distribution (Mw/Mn) was 3.2.
  • Example 5 By the method shown below, a repeating unit in which R 1 and R 2 are both hydrogen atoms in formula (2) and the n value is about 6 and a repeating unit constituting the above PMEA are mixed in a weight ratio of 1:1. The containing copolymers were polymerized in solution.
  • the polymerization was carried out using a mixture (100 parts by weight) containing polypropylene glycol monoacrylate (NOF AP-400D; the number of repeats of propylene glycol is approximately 6) and 2-methoxyethyl acrylate in a weight ratio of 1:1 as raw material monomers.
  • Formula (1) was prepared in the same manner as in Example 1 except that MEK as a reaction medium was changed to 140 parts by weight (however, R 1 and R 2 are both hydrogen atoms, and the n value is about 6).
  • a copolymer containing the repeating unit represented by formula (4) was polymerized in a solution and purified.
  • the weight average molecular weight (Mw) of the obtained polymer was 66,000, and the molecular weight distribution (Mw/Mn) was 2.4.
  • Example 6 Polypropylene glycol monoacrylate (AP-1000D manufactured by NOF; the number of repeating propylene glycol is approximately 17) was used as a monomer that provides the repeating unit shown in formula (2), and MEK as a reaction medium was changed to 125 parts by weight. Except for this, by the same method as in Example 5, a repeating unit containing the repeating unit shown in formula (2) (where R 1 and R 2 are both hydrogen atoms and the n value is about 17) and formula (4) was prepared. The polymer was polymerized in solution and purified. The weight average molecular weight (Mw) of the obtained polymer was 102,000, and the molecular weight distribution (Mw/Mn) was 2.8.
  • Mw weight average molecular weight
  • R 1 A homopolymer in which both R 2 are hydrogen atoms and an n value of about 3.5 was polymerized in solution.
  • the weight average molecular weight (Mw) of the obtained polymer was 126,000, and the molecular weight distribution (Mw/Mn) was 2.2.
  • Table 1 shows the glass transition temperature (Tg) of each polymer composition synthesized in Examples 1 to 6, Reference Example, and Comparative Example 1.
  • the glass transition temperature is determined by using a differential scanning calorimeter (DSC), using a sample of about 5 mg of each polymer composition, cooling the sample to -150°C in a nitrogen atmosphere, and then increasing the temperature to 100°C. After giving a thermal history, the inflection start point at which the baseline of the DSC curve, measured in the process of cooling down to -150°C and then raising the temperature to 100°C, changes to a sigmoid shape in the endothermic direction, is determined for each polymer composition. It was taken as the glass transition temperature. Note that the temperature of the sample was lowered and raised at a rate of 10° C./min.
  • the polymers of Examples 1 to 6 were expected to exhibit flexibility because they all had glass transition temperatures on the lower temperature side compared to PMEA, which is a reference example. Furthermore, when compared with the homopolymer (Comparative Example 1) in which the n value in formula (2) is approximately 3.5, the homopolymer (Examples 1 and 2) in which the n value in formula (2) is approximately 6 It was assumed that the homopolymers (Examples 3 and 4) with an n value of about 17 had a glass transition temperature on the lower temperature side, and that the glass transition temperature shifted to a lower temperature as the n value increased.
  • copolymers of the polymers according to Examples 1 and 2 and PMEA (Example 5) and the copolymers of the polymers and PMEA according to Examples 3 and 4 (Example 6) were both compared with PMEA. It was observed that the glass transition temperature shifted to lower temperatures. From this, it is possible to shift the glass transition temperature to a lower temperature by introducing the repeating unit shown in formula (2) into a polymer that exhibits a higher glass transition temperature, thereby increasing flexibility. It was assumed that it was possible.
  • Table 2 shows the surface contact angle of each of the above polymer compositions.
  • the surface contact angle was determined by applying a solution of each polymer composition diluted with MEK to a 10 w/w% solution to a glass plate using the bar coating method to a coating thickness of approximately 2 ⁇ m and drying it.
  • ion-exchanged water or glycerin filled in a syringe was dropped onto the surface of the coating layer at a flow rate of 1 ⁇ L/s in accordance with JIS R 3257, and contact was measured 33 seconds after dropping using a contact angle meter (OCA15EC manufactured by dataphysics). Obtained by measuring the angle.
  • Dynamic viscoelasticity measurement was performed for each polymer composition using a dynamic viscoelasticity measurement device (manufactured by TA Instruments Japan, HR-2) using a dynamic viscoelasticity measurement method (vibration measurement mode, This was done by measuring the viscoelastic spectrum under conditions of strain 0.1% (linear) and normal force 0N ⁇ 0.1N. Each sample was placed between an upper plate ( ⁇ 8 mm parallel plate) and a lower plate (25 mm plate) placed opposite each other so as not to contain air bubbles, and then heated from -69°C. During the process of increasing the temperature to 100°C at a temperature rate of 5°C/min, viscoelastic spectra were measured at each temperature of -50°C, 0°C, and 36°C.
  • FIGS. 3 and 4 show the storage modulus G' and loss tangent (tan ⁇ ) obtained by performing dynamic viscoelasticity measurements on the polymer compositions of Examples 5 and 6 and PMEA, respectively.
  • the storage modulus G' decreases and soft elastic deformation occurs. , it was observed that the extreme expression of viscous deformability was suppressed.
  • a platelet adhesion test was conducted on the polymer compositions according to Examples 1 and 3 by the following method, and the frequency of adhesion of platelets and the morphology of adhered platelets were evaluated.
  • a sample was spin-coated onto a PET substrate ( ⁇ 14 mm) using a polymer solution in which the polymers according to Examples 1 and 3 were added to 0.2 g per mL of THF and the entire amount was dissolved.
  • a piece cut into 8 mm squares was fixed on a sample stage for a scanning electron microscope (SEM).
  • a PET substrate coated with PMEA and MPC polymer and an uncoated PET substrate were fixed to a SEM sample stage in the same manner as above.
  • the platelet suspension used for evaluation was prepared by the following method. First, human blood was centrifuged at 1500 rpm (400 rcf) for 5 minutes, and the supernatant was collected as platelet rich plasma (PRP). The remaining blood was further centrifuged at 4000 rpm (2500 rcf) for 10 minutes, and the supernatant was collected as platelet poor plasma (PPP). The number of platelets in the PRP was confirmed using a hemocytometer, and the platelet concentration was adjusted to 3 to 4 x 10 cells/mL by mixing an appropriate amount of PPP with the PRP.
  • PRP platelet rich plasma
  • PPP platelet poor plasma
  • Figure 5 shows the results of the platelet adhesion test described above. As shown in FIG. 5, a large number of platelet adhesion was observed on the surface of the PET substrate, which does not exhibit biocompatibility. Furthermore, it was observed that approximately 40% of the adherent platelets had a high degree of activation and were classified as an extended adhesive form (type III). The evaluation results on the surface of the PET substrate indicate the adhesion behavior of platelets on a surface that does not exhibit biocompatibility.
  • the polymer composition according to the present invention is useful as a coating composition for imparting biocompatibility to the surfaces of various members, particularly for imparting biocompatibility to the surfaces of members that are required to be flexibly deformed. is useful as a coating composition.

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Abstract

L'invention concerne une composition polymère qui présente une biocompatibilité suffisante et est capable de supprimer le module élastique, qui est la source d'une force élastique qui est générée par déformation.　L'invention concerne une composition polymère contenant un polymère qui a un squelette de (méth)acrylate et qui contient, au niveau du segment de chaîne latérale par rapport à ce squelette, des unités de répétition ayant une structure de propylène glycol dans laquelle le nombre de répétitions est d'au moins quatre.
PCT/JP2023/012287 2022-03-30 2023-03-27 Composition polymère WO2023190383A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4787977A (en) * 1986-02-08 1988-11-29 Asahi Kasei Kogyo Kabushiki Kaisha Blood-purifying membrane
JPH10127755A (ja) * 1996-10-28 1998-05-19 Hitachi Cable Ltd 抗血栓性紫外線硬化樹脂組成物及びカテーテルチューブ
JP2017082174A (ja) * 2015-10-30 2017-05-18 国立大学法人山形大学 ポリマー、ポリマー溶液及びポリマー被覆基板
JP2018100350A (ja) * 2016-12-20 2018-06-28 東洋インキＳｃホールディングス株式会社 光学的立体造形用活性エネルギー線重合性樹脂組成物、及び立体造形物
JP2021147399A (ja) * 2020-03-16 2021-09-27 日油株式会社 防曇剤組成物、該組成物から形成される防曇膜を有する防曇性物品

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4787977A (en) * 1986-02-08 1988-11-29 Asahi Kasei Kogyo Kabushiki Kaisha Blood-purifying membrane
JPH10127755A (ja) * 1996-10-28 1998-05-19 Hitachi Cable Ltd 抗血栓性紫外線硬化樹脂組成物及びカテーテルチューブ
JP2017082174A (ja) * 2015-10-30 2017-05-18 国立大学法人山形大学 ポリマー、ポリマー溶液及びポリマー被覆基板
JP2018100350A (ja) * 2016-12-20 2018-06-28 東洋インキＳｃホールディングス株式会社 光学的立体造形用活性エネルギー線重合性樹脂組成物、及び立体造形物
JP2021147399A (ja) * 2020-03-16 2021-09-27 日油株式会社 防曇剤組成物、該組成物から形成される防曇膜を有する防曇性物品

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