WO2017150000A1 - コポリマー、これを利用する抗血栓コーティング剤及び医療用具 - Google Patents
コポリマー、これを利用する抗血栓コーティング剤及び医療用具 Download PDFInfo
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- WO2017150000A1 WO2017150000A1 PCT/JP2017/002199 JP2017002199W WO2017150000A1 WO 2017150000 A1 WO2017150000 A1 WO 2017150000A1 JP 2017002199 W JP2017002199 W JP 2017002199W WO 2017150000 A1 WO2017150000 A1 WO 2017150000A1
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- antithrombotic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/10—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
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/064—Use of macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- C08F216/00—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 an alcohol, ether, aldehydo, ketonic, acetal or ketal radical
- C08F216/12—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 an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by an ether radical
- C08F216/14—Monomers containing only one unsaturated aliphatic radical
- C08F216/16—Monomers containing no hetero atoms other than the ether oxygen
- C08F216/18—Acyclic compounds
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—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
- A61L2420/00—Materials or methods for coatings medical devices
-
- 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
- C08F216/00—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 an alcohol, ether, aldehydo, ketonic, acetal or ketal radical
- C08F216/12—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 an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by an ether radical
- C08F216/14—Monomers containing only one unsaturated aliphatic radical
- C08F216/1416—Monomers containing oxygen in addition to the ether oxygen, e.g. allyl glycidyl ether
- C08F216/1425—Monomers containing side chains of polyether groups
- C08F216/1433—Monomers containing side chains of polyethylene oxide groups
Definitions
- the present invention relates to a copolymer and an antithrombotic coating agent using the copolymer, and more particularly, a copolymer capable of imparting excellent antithrombogenicity, an antithrombotic coating agent containing the copolymer, and an anti-thrombus formed with the copolymer.
- the present invention relates to a thrombus film and a medical device provided with the film.
- biocompatible materials having antithrombogenicity examples include poly (2-methoxyethyl acrylate) (PMEA) (see Patent Document 1).
- PMEA poly (2-methoxyethyl acrylate)
- This PMEA is considered to be water that is weakly bound to the polymer chain due to the interaction with the polymer chain, so-called intermediate water (the exothermic peak derived from the low-temperature crystal formation of water in the temperature rising process from ⁇ 100 ° C. ⁇
- intermediate water the exothermic peak derived from the low-temperature crystal formation of water in the temperature rising process from ⁇ 100 ° C.
- Patent Document 2 a thin film by a polymer blend in which PMEA is mixed with polymethyl methacrylate (PMMA) has been reported (see Patent Document 2).
- PMMA polymethyl methacrylate
- hydrophobic components make it difficult for proteins, cells, other biological components, etc. to adhere, and cannot be used in applications that require anti-fouling properties (protein adsorption suppression and cell adhesion suppression).
- poly (2-methoxyethyl vinyl ether) (PMOVE) is known as a biocompatible material having an oxyethylene chain structure in the side chain as in PMEA and having intermediate water, and is superior in antithrombosis to PMEA. It has been reported to show sex (see Patent Document 3).
- Patent Document 3 only anti-thrombogenicity is specifically shown in Patent Document 3 as PMOVE, and the anti-thrombogenicity of a polymer obtained by extending an oxyethylene chain constituting a side chain of a vinyl ether polymer, or a copolymer with a hydrophobic comonomer. There is no indication of thrombosis. Furthermore, no investigation has been made on the anti-fouling properties of these vinyl ether polymers.
- PMOVE is a highly viscous oily substance, and in addition, it is water-soluble at the living body temperature, so that it is difficult to use as it is as an antithrombotic coating agent. For this reason, in Patent Document 3, the PMOVE applied to the substrate is irradiated with gamma rays and crosslinked to insolubilize.
- a film forming method is not a general one, and the coating target is There is a problem that the material, shape and form of the base material to be formed are limited.
- the present invention has been made in view of the above circumstances, has excellent film-forming properties and water resistance, can be easily coated on various substrates, and is biocompatible with excellent antithrombotic properties. It is an object of the present invention to provide an antithrombogenic coating agent and an antithrombotic film using the same and to provide a medical device provided with the antithrombotic film. Furthermore, this invention makes it a subject to provide the biocompatible material excellent also in the antifouling property, and a medical device using the same.
- the present inventors have examined in detail a copolymer of a vinyl ether containing an oxyethylene chain structure and a hydrophobic vinyl ether.
- the copolymer of a vinyl ether having an oxyethylene chain repeating number of 2 or more and an aliphatic vinyl ether is used. It has been found that the coalescence has excellent film-forming properties and water resistance, and surprisingly exhibits excellent antithrombogenicity and antifouling properties, thus completing the present invention.
- the present invention has the following contents.
- At least one of the following formula (1) (Wherein R 1 represents a methyl group or an ethyl group, and n represents an integer of 2 to 10)
- the group R 2 in the repeating unit (B) is a linear or branched alkyl group or alkenyl group having 2 to 10 carbon atoms, or a monocyclic or polycyclic alkyl group having 5 to 15 carbon atoms, or The copolymer according to (1) or (2), which is an alkenyl group.
- An antithrombotic coating agent comprising the copolymer according to any one of (1) to (4) above and an organic solvent.
- the organic solvent is one or more selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, ketones and esters. Antithrombotic coating agent.
- a medical device provided with an antithrombotic film formed from the copolymer according to any one of (1) to (4).
- Implantable artificial organs or therapeutic devices extracorporeal circulation type artificial organs, catheters, artificial blood vessels, blood vessel bypass tubes, artificial valves, blood filters, plasma separation devices, blood transfusion devices, or extracorporeal circulation circuits of blood
- catheters artificial blood vessels, blood vessel bypass tubes, artificial valves, blood filters, plasma separation devices, blood transfusion devices, or extracorporeal circulation circuits of blood
- the copolymer of the present invention can be easily coated on various substrates, has excellent film forming properties, water resistance, and can form an antithrombogenic film. Can be suitably used.
- this copolymer is useful as a component of an antithrombotic coating agent, and an antithrombotic film formed from this copolymer exhibits excellent antithrombotic properties, and coagulation of blood even in prolonged blood contact. Is greatly advantageous as a coating for medical devices.
- the coating formed of the copolymer of the present invention can prevent adhesion of biological components such as cells, and can be suitably used for various medical devices as an anti-fouling material.
- the copolymer of the present invention comprises at least one repeating unit (A) represented by the formula (1) and at least one repeating unit (B) represented by the formula (2).
- A repeating unit represented by the formula (1)
- B repeating unit represented by the formula (2).
- R 1 is a methyl group or an ethyl group
- the repeating number n of the oxyethylene chain is an integer of 2 to 10, preferably an integer of 2 to 6, more preferably an integer of 2 to 4. Particularly preferably 2 or 3.
- hydrophilic vinyl ether represented by the formula (3) examples include 2- (2-methoxyethoxy) ethyl vinyl ether (also known as diethylene glycol monomethyl monovinyl ether) and 2- (2-ethoxyethoxy) ethyl vinyl ether (also known as : Diethylene glycol monoethyl monovinyl ether; hereinafter referred to as “EOEOVE”), 2- [2- (2-methoxyethoxy) ethoxy] ethyl vinyl ether (also known as: triethylene glycol monomethyl monovinyl ether; hereinafter referred to as “TEGVE”) ), 2- [2- (2-ethoxyethoxy) ethoxy] ethyl vinyl ether (also known as triethylene glycol monoethyl monovinyl ether).
- EOEOVE and TEGVE are preferable in terms of film forming properties and water resistance, and EOEOVE is particularly preferable because of its superior antithrombogenicity.
- R 2 is an aliphatic hydrocarbon group, specifically, a linear or branched alkyl group or alkenyl group, or a monocyclic or polycyclic alkyl group or alkenyl group.
- the linear or branched alkyl group or alkenyl group preferably has 2 to 10 carbon atoms, more preferably 2 to 8 carbon atoms, and further preferably 2 to 6 carbon atoms. preferable.
- linear or branched alkyl group or alkenyl group include, for example, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 1- (2-methyl) -butyl group, 2- (2-methyl) -butyl group, 1- (3-methyl) -butyl group, 2- (3-methyl) -Butyl group, (2,2-dimethyl) -propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 1-heptyl group, 2-heptyl group, 3-heptyl group, 4-heptyl group, Linear or branched alkyl group such as 1-octyl group, 1- (2-ethyl) -hexyl group; vinyl group, 1-propenyl group, allyl group, 2-but
- the monocyclic or polycyclic alkyl group or alkenyl group preferably has 3 to 25 carbon atoms, more preferably 4 to 20 carbon atoms, and still more preferably 5 to 15 carbon atoms.
- the monocyclic or polycyclic alkyl group or alkenyl group include, for example, a cyclopentyl group, a cyclopentylmethyl group, a methylcyclopentyl group, a dimethylcyclopentyl group, a cyclohexyl group, a cyclohexylmethyl group, a methylcyclohexyl group, and a dimethyl group.
- a monocyclic alkyl group or alkenyl group such as cycloicosyl group; bicyclohexyl group, decahydronaphthyl group, norbornyl group, methylnorbornyl group, isobornyl group, adamantyl group, tricyclodecanyl group, tri Kurodeseniru group, polycyclic alkyl or alkenyl, etc. such as tetracyclododecyl group.
- n-butyl group and tricyclodecanyl group are preferable from the viewpoint of film forming property, water resistance and antithrombotic property, and n-butyl group is particularly preferable because of superior antithrombogenicity. preferable.
- the copolymer of the present invention can be prepared by polymerizing the hydrophilic vinyl ether (3) and the hydrophobic vinyl ether (4) according to a conventional method.
- living cationic polymerization is particularly preferable in order to obtain a copolymer having a desired composition ratio and molecular weight with good reproducibility.
- the molecular weight of the copolymer is almost uniquely determined by the molar ratio of the monomer to the polymerization initiator, so the molecular weight of the copolymer can be arbitrarily controlled over a wide range by changing the amount of monomer and polymerization initiator used. Is possible.
- the polymerization initiator used in the living cationic polymerization is not particularly limited as long as it allows cationic polymerization to proceed in a living manner.
- a living cationic polymerization initiator for vinyl ethers an HI / I 2 initiator (for example, JP-A-60-228509), a polymerization initiator (for example, Japanese Patent No. 3096494, Japanese Patent Publication No. 7), which is a combination of a Lewis acid catalyst (such as organoaluminum compound) and an additive such as a base (such as ether or ester) No. -2805, JP-A-62-257910, JP-A-1-108202, and JP-A-1-108203) are preferably used.
- the amount of the polymerization initiator used is preferably from 0.001 to 20 mol%, more preferably from 0.01 to 10 mol%, particularly preferably 1 mol% or less, based on the total amount of raw material monomers.
- the living cationic polymerization reaction is preferably performed in the presence of an appropriate organic solvent, but may be performed in the absence.
- organic solvents include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; propane, n-butane, isobutane, n-pentane, isopentane, n-hexane, n-heptane, and n-octane.
- Isooctane, decane, hexadecane, cyclohexane and other aliphatic hydrocarbon solvents methylene chloride, ethylene chloride, carbon tetrachloride and other halogenated hydrocarbon solvents; diethyl ether, dibutyl ether, tetrahydrofuran (THF), dioxane, ethylene glycol
- ether solvents such as diethyl ether.
- organic solvents may be used alone or in combination of two or more as required.
- hydrocarbon solvents such as aromatic hydrocarbon solvents and aliphatic hydrocarbon solvents are preferable, and toluene or cyclohexane is particularly preferable.
- the polymerization temperature in this polymerization reaction varies depending on the type of polymerization initiator, monomer, solvent, etc., but is usually -80 to 150 ° C, preferably -50 to 100 ° C, particularly preferably -20 to 80 ° C. is there.
- the polymerization time varies depending on the polymerization initiator, monomer, solvent, reaction temperature, etc. used, but is usually about 10 minutes to 100 hours.
- the polymerization reaction can be suitably performed by either a batch method or a continuous method. After the polymerization reaction, purification treatment may be performed by a known method in order to remove unreacted monomers as necessary.
- composition ratio (molar ratio) between the repeating unit (A) and the repeating unit (B) in the copolymer of the present invention can be arbitrarily selected as long as the film-forming property and the antithrombotic property are not impaired.
- the copolymer of the present invention exhibits high antithrombogenicity in a copolymer having a smaller proportion of repeating units (A) that become hydrophilic units. Therefore, the composition ratio (molar ratio) between the repeating unit (A) and the repeating unit (B) is preferably in the range of 90/10 to 1/99, more preferably in the range of 70/30 to 3/97, A range of 50 to 5/95 is particularly preferred.
- the molecular weight of the copolymer in the present invention is, for example, about 1,000 to 1,000,000 as a weight average molecular weight (Mw) determined from a standard polystyrene calibration curve by gel permeation chromatography (GPC) method, Preferably it is 2,000 to 500,000, more preferably 3,000 to 300,000.
- Mw weight average molecular weight
- the ratio (Mw / Mn) of the weight average molecular weight (Mw) to the number average molecular weight (Mn) of the copolymer of the present invention is preferably 1.0 to 5.0, more preferably 1.0 to 3.0. 1.0 to 1.5 is particularly preferred.
- Mw and Mw / Mn are in this range, the resulting copolymer exhibits excellent coating performance and excellent antithrombogenicity.
- the copolymer of the present invention can be obtained by copolymerizing the hydrophilic vinyl ether and the hydrophobic vinyl ether as described above, but the arrangement of the monomer units is not particularly limited, and random copolymerization and block copolymerization are possible. Any of polymers may be used. Examples of the block copolymer include diblock type (AB), triblock type (ABA or BAB), and multi-branched star ([BA] n , [A- B] Each block polymer such as n or A n B m ; n and m are the number of branches). From the viewpoint of uniformly dispersing the hydrophilic unit, a random copolymer is preferable.
- the copolymer of the present invention obtained as described above exhibits excellent biocompatibility such as antithrombogenicity and antifouling property, it can be suitably used as a biocompatible material. For example, it can be used as an active ingredient. It can be set as the antithrombotic coating agent.
- This antithrombotic coating agent can be prepared by blending an appropriate solvent with the copolymer.
- the type and concentration of the solvent in this antithrombotic coating agent can be appropriately selected according to the composition and molecular weight of the copolymer, the type of substrate to be coated, the surface properties, and the like.
- the organic solvents mentioned as polymerization solvents in living cationic polymerization can be used.
- alcohol solvents such as methanol, ethanol and isopropanol
- ketone solvents such as acetone, methyl ethyl ketone and methyl amyl ketone
- ester solvents such as methyl acetate, ethyl acetate, amyl acetate and ethyl lactate are also preferably used. it can.
- organic solvents such as aromatic hydrocarbon solvents and aliphatic hydrocarbon solvents, ether solvents and mixed solvents thereof are preferable, and toluene, cyclohexane, THF and mixed solvents thereof are particularly preferable. .
- organic solvents may be used alone or in combination of two or more as required.
- the concentration of the solvent in the antithrombotic coating agent is preferably 99.95 to 90 parts by mass of the solvent with respect to 0.05 to 10 parts by mass of the copolymer.
- the antithrombotic coating agent described above is used to form an antithrombotic film containing the copolymer on various substrates, particularly on a substrate that may come into contact with blood.
- a method for forming an antithrombotic film using an antithrombotic coating agent is not particularly limited, and may be, for example, a coating method, a spray method, a dip method, a spin coating method, etc., depending on the material, shape, and form of the substrate. These are appropriately selected from known methods.
- the antithrombotic film can be formed by a simple operation such as air-drying or heat-drying after immersing the substrate in the anti-thrombotic coating agent containing the copolymer and the organic solvent.
- the material, shape, and form of the base material on which the antithrombotic film is formed are not particularly limited, for example, a film, a sheet, It can be used for substrates of arbitrary shapes and forms such as plates, fibers, non-woven fabrics, porous bodies, tubes, hollow fibers and fibers, particles, and powders.
- the material of the base material is polyolefin such as polypropylene and polyethylene, nylon, polyester, polyacrylonitrile, halogenated polyolefin, polystyrene, polycarbonate, polyvinyl chloride, polyurethane, polyamide, polysulfone, polyethersulfone, poly (meth) acrylate, Synthetic resins such as ethylene-vinyl alcohol copolymer and butadiene-acrylonitrile copolymer and blended polymers thereof; natural polymers such as cotton and hemp; inorganic materials such as metals, ceramics and glass; and composite materials thereof These can be used.
- polyolefin such as polypropylene and polyethylene
- nylon polyester
- polyacrylonitrile halogenated polyolefin
- polystyrene polycarbonate
- polyvinyl chloride polyurethane
- polyamide polysulfone
- polyethersulfone poly (meth) acrylate
- Synthetic resins such as ethylene-
- an antithrombotic film formed from the antithrombotic coating agent of the present invention a medical device can be mentioned.
- Many medical devices come into contact with blood, and in that case, it is necessary to prevent blood coagulation due to adhesion and aggregation of platelets, and thus it is required to have an antithrombotic coating. Therefore, in the medical device, it is preferable that at least a part, preferably all, of the site in contact with blood is covered with the antithrombotic film.
- the medical device of the present invention treated with the antithrombotic coating agent is provided with the antithrombotic coating as described above, it can be suitably used particularly for applications used in direct contact with blood.
- implantable artificial organs and therapeutic instruments extracorporeal circulation type artificial organs, catheters (vascular catheters such as angiographic catheters, guide wires, PTCA catheters, gastrointestinal catheters, gastrointestinal catheters, Gastrointestinal catheters such as esophageal tubes, tubes, urinary catheters, urinary catheters such as ureteral catheters, etc.), artificial blood vessels, vascular bypass tubes, artificial valves, blood filters, plasma separation devices, blood transfusion devices, blood extracorporeal circulation It can be suitably used in various applications such as circuits, blood bags, hemostatic agents, and biological tissue adhesives. Moreover, it can be set as the prevention method of thrombus by forming an antithrombotic film in part or all of the site
- composition ratio of the copolymer was determined from the analysis result of 1 H NMR, and the weight average molecular weight (Mw) and the molecular weight distribution (Mw / Mn) were determined from the molecular weight analysis result of GPC (polystyrene conversion).
- Mw weight average molecular weight
- Mw / Mn molecular weight distribution
- Synthesis example 1 Synthesis of N-butyl vinyl ether / diethylene glycol monoethyl monovinyl ether random copolymer (NBVE-ran-EOOEOVE): In a 300 mL three-necked flask equipped with a three-way stopcock that was dehydrated by heating at 300 ° C.
- a 1% by mass aqueous solution of the obtained copolymer C was prepared, and the solubility in water at 25 ° C. was visually confirmed.
- the aqueous solution was phase-separated into an aqueous phase and a polymer phase, and insolubilization in water due to the introduction of hydrophobic units was confirmed.
- Synthesis examples 2-14 By using EOEOVE or TEGVE as the hydrophilic vinyl ether and NBVE or tricyclodecanyl vinyl ether (TCDVE) as the hydrophobic vinyl ether based on Synthesis Example 1, respectively, by changing the starting species amount and composition ratio, Copolymers A, B, D to N described in Table 1 were obtained. About the obtained copolymer, the solubility in water was evaluated by the same operation as in Synthesis Example 1. The composition ratio, molecular weight (Mw), molecular weight distribution (Mw / Mn), and water solubility evaluation results of each copolymer are shown in Table 1 below.
- Synthesis examples 15-17 Homopolymers O, P, and Q listed in Table 1 were obtained by polymerizing EOEOVE, NBVE, and TCDVE each independently based on Synthesis Example 1. About the obtained homopolymer, the solubility in water was evaluated by the same operation as in Synthesis Example 1. The evaluation results of the molecular weight (Mw), molecular weight distribution (Mw / Mn) and water solubility of each homopolymer are shown in Table 1 below.
- PET polyethylene terephthalate
- Examples 1 to 14 surface-coated with the copolymers A to N according to the synthesis examples described above, and surface coating with homopolymers O to Q as comparative examples.
- a platelet adhesion test was performed on the PET plates (Comparative Examples 1 to 3).
- the surface coating of the PET plate with the polymers according to the examples and comparative examples is performed by applying a 0.2 wt / vol% toluene solution of the polymer obtained in the above synthesis example to the surface of the PET plate and evaporating the solvent to dryness. It was.
- 0.2 mL of human fresh platelet-rich plasma anticoagulated with sodium citrate was dropped with a pipette onto the PET surface coated with each polymer and a non-coated PET plate (blank), and allowed to stand at 37 ° C. for 60 minutes. Subsequently, after rinsing with a phosphate buffer solution and fixing with glutaraldehyde, the surface of the sample was observed with a scanning electron microscope, and the number of platelets adhered to an area of 1 ⁇ 10 4 ⁇ m 2 was counted. In addition, although peeling of the coating layer was confirmed in the polymer O (EOOEOVE homopolymer), the evaluation was performed as it was.
- Table 2 shows the results of the blood compatibility test. It was shown that the PET plate whose surface was coated with the copolymers A to N had a smaller platelet adhesion number than each of the comparative examples and the blank PET plate.
- Examples 15 to 18 Cancer cell adhesion test In the same manner as in Examples 1 to 3, PET plates coated with copolymers A, B, and C were prepared, and a cancer cell suspension (serum) was applied to the PET surface coated with each copolymer and a PET plate (blank) that was not coated. 1.0 mL was adjusted with a pipette, and the mixture was allowed to stand at 37 ° C. for 60 minutes. The human fibrosarcoma cell line HT-1080 was used as the cancer cell. Subsequently, rinsing was performed using physiological buffered saline, and the number of cells adhered to the sample surface was counted.
- a cancer cell suspension serum
- 1.0 mL was adjusted with a pipette, and the mixture was allowed to stand at 37 ° C. for 60 minutes.
- the human fibrosarcoma cell line HT-1080 was used as the cancer cell. Subsequently, rinsing was performed using physiological buffered sa
- cells were fixed with formaldehyde, stained with 4 ′, 6-diamino-2-phenylindole (DAPI), and nuclei using a confocal laser microscope (Olympus FV-1000). The number of cells was counted as the number of cells.
- DAPI 6-diamino-2-phenylindole
- Table 3 shows the results of the cell adhesion test. Copolymers A, B and C showed very little cell adhesion despite the inclusion of 90 mol% hydrophobic units.
- the film formed of the copolymer of the present invention is excellent in film forming property and water resistance, can prevent adhesion of platelets, and can prevent the subsequent thrombus formation.
- the copolymers of the present invention are useful as biocompatible materials that are compatible with ISO10993.
- the antithrombotic film formed by using the antithrombotic coating agent of the present invention containing the copolymer of the present invention has excellent antithrombotic properties, and in particular, by forming this antithrombotic film on a medical device in contact with blood. It becomes possible to prevent the formation of thrombus.
- the coating formed of the copolymer of the present invention can prevent adhesion of biological components such as cells, and can be suitably used for various medical devices as an anti-fouling material.
- the present invention is extremely useful in the medical field and medical device manufacturing field.
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Abstract
Description
(1)少なくとも1種の、下記式(1)
で表される繰り返し単位(A)と、少なくとも1種の、下記式(2)
で表される繰り返し単位(B)を含有するコポリマー。
本発明のコポリマーは、少なくとも1種の前記式(1)で表される繰り返し単位(A)と、少なくとも1種の前記式(2)で表される繰り返し単位(B)とを含むものであり、これにより、抗血栓性や抗ファウリング性などの優れた生体適合性を示すものである。
以上のようにして得られる本発明のコポリマーは、抗血栓性および抗ファウリング性などの優れた生体適合性を示すため、生体適合性材料として好適に用いることができ、例えば、これを有効成分とする抗血栓コーティング剤とすることができる。この抗血栓コーティング剤は、前記コポリマーに適当な溶媒を配合することで調製することができる。
・装 置:ブルカー製 AVANCE400
・溶 媒:重アセトン
・測定温度:30℃
・装 置:東ソー株式会社製、「HLC-8320GPC」
・検出器:RI検出器
・移動相:テトラヒドロフラン
・流 量:1mL/分
・カラム:昭和電工株式会社製「Shodex LF-804」×3本
・カラム温度:40℃
N-ブチルビニルエーテル/ジエチレングリコールモノエチルモノビニルエーテルランダム共重合体(NBVE-ran-EOEOVE)の合成:
乾燥窒素雰囲気下、300℃以上で10分間加熱脱水した三方活栓付きの300mL三ッ口フラスコに、溶媒としてトルエン181mL、添加塩基として酢酸エチル76.4mL、親水性ビニルエーテルとしてジエチレングリコールモノエチルモノビニルエーテル(EOEOVE)4.0mL、疎水性ビニルエーテルとしてN-ブチルビニルエーテル(NBVE)28.2mL、開始種としてイソブチルビニルエーテルの酢酸付加体4mM(0.45mL)を加え、よく撹拌した。
合成例1を基準に、親水性ビニルエーテルとしてEOEOVE又はTEGVEを、疎水性ビニルエーテルとしてNBVE又はトリシクロデカニルビニルエーテル(TCDVE)をそれぞれ用い、開始種量及び組成比を変更して合成を行うことで、表1記載のコポリマーA、B、D~Nを得た。得られたコポリマーについて、合成例1と同様の操作により水への溶解性を評価した。各コポリマーの組成比、分子量(Mw)、分子量分布(Mw/Mn)及び水への溶解性の評価結果を後記表1に示す。
合成例1を基準に、EOEOVE、NBVE、TCDVEをそれぞれ単独で重合させることにより、表1記載のホモポリマーO、P、Qを得た。得られたホモポリマーについて、合成例1と同様の操作により水への溶解性を評価した。各ホモポリマーの分子量(Mw)、分子量分布(Mw/Mn)及び水への溶解性の評価結果を後記表1に示す。
血液適合性試験:
血液適合性を調べるために、上記合成例に係るコポリマーA~Nで表面被覆したポリエチレンテレフタレート(PET)板(実施例1~14)、及び、比較例として、ホモポリマーO~Qで表面被覆したPET板(比較例1~3)について、血小板の粘着テストを行った。
がん細胞の接着性試験:
実施例1~3と同様にコポリマーA、B、Cで被覆したPET板を作製し、各コポリマーで被覆したPET表面及び被覆を行わないPET板(ブランク)に、がん細胞懸濁液(血清を10%添加した培地で10,000個/mLに調整)1.0mLをピペットで滴下し、37℃で60分間静置した。がん細胞として、ヒト線維肉腫細胞株HT-1080を使用した。続いて、生理緩衝食塩水を用いてリンスし、サンプル表面に接着した細胞の数をカウントした。カウントを容易にするために、ホルムアルデヒドで細胞を固定化後、4’,6-ジアミノ-2-フェニルインドール(DAPI)で細胞核を染色し、共焦点レーザー顕微鏡(オリンパスFV-1000)を用いて細胞核の数をカウントし、細胞の数とした。
Claims (12)
- 前記繰り返し単位(A)と繰り返し単位(B)の組成比(モル比)が90/10~1/99である請求項1記載のコポリマー。
- 繰り返し単位(B)における基R2が、炭素数2~10の直鎖状若しくは分岐鎖状のアルキル基又はアルケニル基、又は、炭素数5~15の単環状若しくは多環状のアルキル基又はアルケニル基である請求項1又は2記載のコポリマー。
- 繰り返し単位(B)における基R2が、炭素数2~10の直鎖状若しくは分岐鎖状のアルキル基又はアルケニル基である請求項1又は2記載のコポリマー。
- 請求項1ないし4の何れかの項記載のコポリマーを含有する生体適合性材料。
- 請求項1ないし4の何れかの項記載のコポリマーと、有機溶媒とを含む抗血栓コーティング剤。
- 前記有機溶媒が、芳香族炭化水素、脂肪族炭化水素、ハロゲン化炭化水素、エーテル、アルコール、ケトン及びエステルからなる群から選択される1種又は2種以上である請求項6記載の抗血栓コーティング剤。
- 前記コポリマーが、0.05~10質量部であり、前記有機溶媒が99.95~90質量部である請求項6又は7記載の抗血栓コーティング剤。
- 請求項1ないし4の何れかの項に記載のコポリマーから形成された抗血栓被膜。
- 請求項1ないし4の何れかの項に記載のコポリマーから形成された抗血栓被膜を備えた医療用具。
- 血液と接触する部位の一部又は全部が、前記抗血栓被膜で被覆された請求項10記載の医療用具。
- 体内埋め込み型の人工器官若しくは治療器具、体外循環型の人工臓器類、カテーテル類、人工血管、血管バイパスチューブ、人工弁、血液フィルター、血漿分離用装置、輸血用具又は血液の体外循環回路である請求項10又は11記載の医療用具。
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CN201780014104.XA CN108699191B (zh) | 2016-02-29 | 2017-01-24 | 共聚物、利用其的抗血栓涂布剂和医疗用具 |
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WO2020213529A1 (ja) * | 2019-04-15 | 2020-10-22 | 国立大学法人九州大学 | 抗血栓性材料、抗血栓性材料の製造方法、人工臓器及び抗血栓性付与剤 |
JP2021063160A (ja) * | 2019-10-11 | 2021-04-22 | 三菱瓦斯化学株式会社 | 抗血栓性材料、抗血栓性材料の使用方法、及び医療用器具 |
WO2022009968A1 (ja) | 2020-07-09 | 2022-01-13 | 丸善石油化学株式会社 | 癌細胞接着用組成物、癌細胞捕集フィルター、及び癌細胞の検出方法 |
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CN108699191B (zh) | 2021-08-31 |
EP3424964A1 (en) | 2019-01-09 |
EP3424964A4 (en) | 2019-10-09 |
CN108699191A (zh) | 2018-10-23 |
US20190091380A1 (en) | 2019-03-28 |
TW201800116A (zh) | 2018-01-01 |
JP6855440B2 (ja) | 2021-04-07 |
EP3424964B1 (en) | 2023-08-02 |
JPWO2017150000A1 (ja) | 2018-12-20 |
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