WO2015125890A1 - 医療材料、および該医療材料を利用した医療用具 - Google Patents
医療材料、および該医療材料を利用した医療用具 Download PDFInfo
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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
- C08F220/00—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
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
- C08F220/281—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing only one oxygen, e.g. furfuryl (meth)acrylate or 2-methoxyethyl (meth)acrylate
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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
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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
- 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
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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
- 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
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
- A61L33/0041—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate characterised by the choice of an antithrombatic agent other than heparin
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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
- 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
- A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L33/00—Compositions of homopolymers or 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 of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- C08L33/04—Homopolymers or copolymers of esters
- C08L33/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical
- C08L33/08—Homopolymers or copolymers of acrylic acid esters
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L33/00—Compositions of homopolymers or 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 of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- C08L33/04—Homopolymers or copolymers of esters
- C08L33/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical
- C08L33/10—Homopolymers or copolymers of methacrylic acid esters
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L33/00—Compositions of homopolymers or 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 of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- C08L33/24—Homopolymers or copolymers of amides or imides
- C08L33/26—Homopolymers or copolymers of acrylamide or methacrylamide
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- 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
- C09D133/14—Homopolymers or copolymers of esters of esters containing halogen, nitrogen, sulfur or oxygen atoms in addition to the carboxy oxygen
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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
- 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
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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
- A61L2420/00—Materials or methods for coatings medical devices
Definitions
- the present invention relates to a medical material and a medical device using the medical material. More specifically, the present invention relates to a medical material including a copolymer having a specific repeating unit, and a medical device using the medical material.
- imparting antithrombogenicity to a medical device is performed by a method of coating a base material constituting the medical device with an antithrombotic material or a method of fixing an antithrombotic material on the surface of the base material.
- Japanese Patent Application Laid-Open No. 4-152955 discloses on the surface a synthetic polymer that simultaneously satisfies biocompatibility such as suppression of platelet adhesion / activation, inhibitory effect of complement system activation, and affinity with tissue in vivo.
- An artificial organ membrane or medical device is disclosed.
- US Patent Application Publication No. 2008/0262181 (corresponding to International Publication No. 2005/113620) is a homopolymer that exhibits excellent biocompatibility with reduced interaction with biological components such as proteins and blood cells.
- a biocompatible material comprising a copolymer is disclosed.
- a thrombus tends to be formed around the stepped portion.
- a throttle portion such as a joint portion of a tube used in the medical device
- a thrombus is relatively easily formed.
- Japanese Patent Application Laid-Open No. 4-152952 and US Patent Application Publication No. 2008/0262181 corresponding to International Publication No. 2005/113620.
- the material according to the invention may not have sufficient antithrombogenic properties.
- the present invention has been made in view of the above circumstances, and particularly provides a medical material and a medical device that exhibit excellent antithrombogenicity even when used under severe conditions where thrombus is easily formed.
- the purpose is to do.
- the present invention has the following contents.
- R 11 is a hydrogen atom or a methyl group
- Z is an oxygen atom or —NH—
- R 12 is an alkylene group having 1 to 6 carbon atoms
- R 13 and R 14 are each independently An alkyl group having 1 to 4 carbon atoms
- R 15 is an alkylene group having 1 to 6 carbon atoms.
- R 21 is a hydrogen atom or a methyl group
- R 22 is an alkylene group having 1 to 6 carbon atoms
- R 23 is an alkyl group having 1 to 4 carbon atoms.
- R 21 is a hydrogen atom or a methyl group
- R 22 is an alkylene group having 1 to 3 carbon atoms
- R 23 is an alkyl group having 1 or 2 carbon atoms. 1 above. Medical materials as described in; 3.
- R 11 is a methyl group
- Z is an oxygen atom or —NH—
- R 12 is an alkylene group having 1 to 4 carbon atoms
- R 13 and R 14 are each independently
- R 15 is an alkylene group having 1 to 4 carbon atoms; 4).
- the copolymer comprises 0.6 to 7 mol% of the repeating unit (A) and 99.4 to 93 mol% of the repeating unit (B) (of the repeating unit (A) and the repeating unit (B). The total amount is 100 mol%).
- a medical material according to any of the above; 5. A substrate; The above 1.
- FIG. 1 shows a tube (stepped tube) used in the example and having both ends connected by connectors.
- a portion surrounded by a circle indicates a joint portion between the tube 1 and the tube 2.
- FIG. 2 is an enlarged view schematically showing a cross section in the major axis direction at the joint between the tube 1 and the tube 2 in FIG.
- FIG. 3 is an enlarged photograph of the joint immediately after the antithrombogenicity test for the stepped tube to which the medical material containing the copolymer manufactured in Example 1 is applied.
- FIG. 4 is an enlarged photograph of the joint immediately after the antithrombogenicity test on the stepped tube to which the medical material containing the copolymer manufactured in Comparative Example 7 is applied.
- the present invention relates to a medical material containing a copolymer having a specific repeating unit, and a medical device using the medical material.
- X to Y indicating a range means “X or more and Y or less”, “weight” and “mass”, “weight%” and “mass%”, “part by weight” and “weight part”. “Part by mass” is treated as a synonym. Unless otherwise specified, measurement of operation and physical properties is performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.
- R 11 is a hydrogen atom or a methyl group
- Z is an oxygen atom or —NH—
- R 12 is an alkylene group having 1 to 6 carbon atoms
- R 13 and R 14 are each independently An alkyl group having 1 to 4 carbon atoms
- R 15 is an alkylene group having 1 to 6 carbon atoms.
- R 21 is a hydrogen atom or a methyl group
- R 22 is an alkylene group having 1 to 6 carbon atoms
- R 23 is an alkyl group having 1 to 4 carbon atoms.
- the medical material of the present invention comprises a repeating unit (A) represented by the above formula (1) (hereinafter also simply referred to as “repeating unit (A)”) and a repeating unit (B) represented by the above formula (2) (
- the copolymer simply having “repeating unit (B)” is essential, and the copolymer contains 0.6 to 7 mol% of the repeating unit (A) in all the structural units. It is characterized by including.
- the present inventors combined a repeating unit (A) with a repeating unit (B), and formed a coat layer using a copolymer containing these repeating units, whereby a medical material (anti-antithrombogenic property) It was found that a thrombotic material) can be obtained.
- Japanese Patent Application Laid-Open No. 4-152955 discloses a biocompatible medical material using a homopolymer of the repeating unit (B) or a copolymer containing the same, but as described above, thrombus is very formed.
- the present inventors examined the structural unit contained in the copolymer together with the repeating unit (B). In the process, it was surprisingly found that the anti-thrombogenicity of the copolymer can be improved by having as a repeating unit a skeleton containing a zwitterion that is apparently nonionic, such as a sulfobetaine skeleton.
- the medical material of the present invention has further improved antithrombogenicity than the copolymer having a carboxybetaine skeleton disclosed in US Patent Application Publication No. 2008/0262181 (corresponding to International Publication No. 2005/113620). This is considered to be highly effective.
- the medical material exhibits excellent antithrombogenicity and moderately controlled water solubility. As a result, a medical device having excellent characteristics can be provided.
- a medical material and a medical device exhibiting excellent antithrombogenicity are provided even when used under severe conditions in which thrombus is easily formed.
- the copolymer contained in the medical material according to the present invention includes the above repeating units (A) and (B), and the content ratio of the repeating unit (A) is within a specific range among all the structural units. It is a polymer. Therefore, if it has the said composition, the terminal in particular of a copolymer will not be restrict
- the structure of the copolymer is not particularly limited, and may be any of a random copolymer, an alternating copolymer, a periodic copolymer, and a block copolymer.
- the weight average molecular weight of the copolymer is preferably 1,000 to 1,000,000. When included in the above range, it is preferable from the viewpoint of solubility.
- the weight average molecular weight of the copolymer is more preferably 50,000 to 500,000 from the viewpoint of easy coating of the coat layer.
- the value measured by gel permeation chromatography (Gel permeation chromatography) using polystyrene as a standard substance and tetrahydrofuran (THF) as a mobile phase is adopted as the “weight average molecular weight”.
- repeating unit (A) In the present invention, the copolymer contained in the medical material essentially contains the repeating unit (A) represented by the above formula (1).
- R 11 is a hydrogen atom or a methyl group, and preferably a methyl group from the viewpoint of improving antithrombogenicity.
- Z is an oxygen atom or —NH—.
- oxygen atom or —NH— is equivalent, but from the viewpoint of durability, Z is preferably —NH—.
- Z is —NH—, an amide structure is formed in the above formula (1). Therefore, it is excellent in hydrolysis resistance compared with the case where Z is an oxygen atom (that is, the case where the ester structure in the above formula (1) is formed), and is suitable for use in contact with biological components for a long period of time.
- R 12 is a linear or branched alkylene group having 1 to 6 carbon atoms, specifically, a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, A pentamethylene group, a hexamethylene group, etc. are mentioned.
- a linear or branched alkylene group having 1 to 4 carbon atoms is preferable, and a methylene group, ethylene group, or trimethylene group is more preferable, and an ethylene group, trimethylene group is preferable.
- Particularly preferred is a group.
- R 13 and R 14 are each independently an alkyl group having 1 to 4 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, Examples thereof include a linear or branched alkyl group such as an isobutyl group, a sec-butyl group, and a tert-butyl group. Among these, from the viewpoint of improving antithrombogenicity, a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, and an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group) is preferable. And more preferably a methyl group.
- R 15 is a linear or branched alkylene group having 1 to 6 carbon atoms, and specific examples thereof include the same groups as those described in the description of R 12 above. . Among these, from the viewpoint of improving antithrombogenicity, it is preferably a linear or branched alkylene group having 1 to 4 carbon atoms, more preferably a methylene group, ethylene group or trimethylene group, and a trimethylene group. And particularly preferred.
- R 11 is a methyl group
- Z is an oxygen atom or —NH—
- R 12 is an alkylene group having 1 to 4 carbon atoms.
- R 13 and R 14 are each independently an alkyl group having 1 or 2 carbon atoms
- R 15 is preferably an alkylene group having 1 to 4 carbon atoms.
- R 11 is a methyl group
- R 12 is an alkylene group having 2 or 3 carbon atoms
- Z is an oxygen atom or —NH—
- R 13 and R 14 are carbon atoms.
- Particularly preferred is an alkyl group having 1 atom (methyl group), and R 15 is an alkylene group having 3 carbon atoms.
- the copolymer contained in the medical material according to the present invention includes a monomer that forms the repeating unit (A) (hereinafter also referred to as “monomer a”) and a monomer that forms the repeating unit (B) described in detail below. (Hereinafter also referred to as “monomer b”).
- the monomer a for example, when Z is an oxygen atom or when Z is —NH—, the following compounds can be used. The following monomers may be used alone or in combination of two or more. Further, a compound in which Z is an oxygen atom and a compound in which Z is —NH— may be used in combination.
- examples of the monomer a include [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (compound of formula (ii) in Examples), [2 -(Acryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide, ⁇ 2-[(meth) acryloyloxy] ethyl ⁇ dimethyl- (2-sulfoethyl) ammonium hydroxide, ⁇ 2-[(meth) acryloyl Oxy] ethyl ⁇ diethyl- (2-sulfoethyl) ammonium hydroxide, ⁇ 2-[(meth) acryloyloxy] ethyl ⁇ diethyl- (3-sulfopropyl) ammonium hydroxide, ⁇ 3-[(meth) acryloyloxy] propyl ⁇ Di
- examples of the monomer a include [3- (methacryloylamino) propyl] dimethyl (3-sulfopropyl) ammonium hydroxide (compound of the chemical formula (i) in the examples), [3- (acryloylamino) propyl] dimethyl (3-sulfopropyl) ammonium hydroxide, ⁇ 2-[(meth) acryloylamino] ethyl ⁇ dimethyl (2-sulfoethyl) ammonium hydroxide, ⁇ 2-[(meth) acryloyl Amino] ethyl ⁇ dimethyl (3-sulfopropyl) ammonium hydroxide, ⁇ 2-[(meth) acryloylamino] ethyl ⁇ diethyl (2-sulfoethyl) ammonium hydroxide, ⁇ 2-[(meth) acryloylamino] ethyl ⁇ diethyl (3-sulfoethy
- (meth) acryl means “acryl” and / or “methacryl”
- (meth) acryloyl means “acryloyl” and / or “methacryloyl”.
- repeating unit (B) In the present invention, the copolymer contained in the medical material essentially contains the repeating unit (B) represented by the above formula (2).
- R 21 is a hydrogen atom or a methyl group, and is preferably a hydrogen atom from the viewpoint of improving antithrombogenicity.
- R 22 is a linear or branched alkylene group having 1 to 6 carbon atoms, and specifically includes a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, A pentamethylene group, a hexamethylene group, etc. are mentioned.
- a linear or branched alkylene group having 1 to 3 carbon atoms is preferable, a methylene group or an ethylene group is more preferable, and an ethylene group is particularly preferable.
- R 23 is a linear or branched alkyl group having 1 to 4 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl. And a linear or branched alkyl group of a group, a sec-butyl group, and a tert-butyl group.
- a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, and an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group) is preferable. And more preferably a methyl group.
- R 21 is a hydrogen atom or a methyl group
- R 22 is an alkylene group having 1 to 3 carbon atoms
- R 23 is a carbon atom.
- An alkyl group having 1 or 2 atoms is preferable.
- R 21 is a hydrogen atom or a methyl group
- R 22 is an alkylene group having 2 carbon atoms (ethylene group)
- R 23 is an alkyl group having 1 carbon atom. (Methyl group) is particularly preferred.
- Monomer b is preferably methoxymethyl acrylate, methoxyethyl acrylate (MEA), ethoxymethyl acrylate, ethoxyethyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate.
- MEA methoxyethyl acrylate
- the said monomer may be used individually by 1 type or in mixture of 2 or more types.
- the copolymer contains 0.6 to 7 mol% of the repeating unit (A) in all the constituent units (100 mol%) of the copolymer. Since the repeating unit (A) has high hydrophilicity, when the copolymer is contained in a large amount in the copolymer, the copolymer exhibits good antithrombogenicity. On the other hand, when there are too many repeating units (A), the water solubility of a copolymer will become high, and when a medical material is applied to a medical device, there exists a possibility that a medical material may peel.
- the repeating unit (A) is present in a proportion of less than 0.6 mol% in all the constituent units of the copolymer, sufficient antithrombotic improvement effect cannot be obtained, and it is used for a long time under conditions where thrombus is easily formed. Thrombus is formed in such a severe environment.
- the repeating unit (A) exceeds 7 mol%, the medical material coated on the medical device when the repeating unit (A) comes into contact with a body fluid (for example, blood) due to the water-solubility-imparting action of the repeating unit (A). There is a risk of peeling from the substrate and elution (mixing) into the body fluid.
- the repeating unit (A) is preferably 0.8 to 6 mol% in the total constituent units, and preferably 0.9 to 4.7. More preferably, it is mol%, and particularly preferably 1 to 4 mol%.
- the content ratio of the repeating unit (B) is not particularly limited as long as the repeating unit (A) is within the above range in all the structural units, but in the entire structural unit of the copolymer
- the repeating unit (B) is, for example, preferably 60 mol% or more, more preferably 80 mol% or more, and particularly preferably 90 mol% or more.
- the upper limit is 99.4 mol% from the relationship with the repeating unit (A).
- the copolymer contained in the medical material may contain constituent units other than the repeating units (A) and (B), but is preferably composed only of the repeating units (A) and (B). . That is, in the copolymer contained in the medical material, the total amount of the repeating unit (A) and the repeating unit (B) is preferably 100 mol%.
- the copolymer has a repeating unit (A) of 0.6 to 7 mol% and a repeating unit (B) of 99.4 to 93 mol% (total of the repeating unit (A) and the repeating unit (B).
- the amount is preferably 100 mol%).
- the copolymer contained in the medical material contains 0.8 to 6 mol% of the repeating unit (A) and 99.2 to 94 mol% of the repeating unit (B) (the repeating unit (A) and the repeating unit).
- the total amount of (B) is more preferably 100 mol%).
- the copolymer comprises 0.9 to 4.7 mol% of the repeating unit (A) and 99.1 to 95.3 mol% of the repeating unit (B) (the repeating unit (A) and the repeating unit). It is even more preferable that the total amount of the unit (B) is 100 mol%.
- the copolymer has a repeating unit (A) of 1 to 4 mol% and a repeating unit (B) of 99 to 96 mol% (the total amount of the repeating unit (A) and the repeating unit (B) is 100%). It is particularly preferable that it is composed of (mol%).
- the value determined by the NMR method is adopted as the ratio of the repeating unit (A), the repeating unit (B), or the repeating unit derived from another monomer in the copolymer.
- each of the repeating units (A) and (B) has a characteristic structure of an alkylene group on the nitrogen atom ( That is, the integrated value of 1 H-NMR of R 15 ) and the alkoxy group (that is, —OR 23 ) was determined, and based on the ratio of the integrated value, the repeating unit (A) and repeating unit ( B) can be analyzed. Further, in the measurement of 1 H-NMR, when the peaks overlap, it can be calculated using 13 C-NMR.
- the copolymer contained in the medical material according to the present invention is preferably composed only of the repeating units (A) and (B), but may contain other repeating units. Good. That is, in another embodiment of the present invention, the copolymer contained in the medical material is also referred to as “monomer a”, “monomer b”, and another monomer copolymerizable therewith (hereinafter simply referred to as “other monomer”). ) -Derived structural units (repeating units) may be included.
- Examples of other monomers copolymerizable with monomer a and monomer b include acrylamide, N, N-dimethylacrylamide, N, N-diethylacrylamide, aminomethyl acrylate, aminoethyl acrylate, aminoisopropyl acrylate, diaminomethyl acrylate, Diaminoethyl acrylate, diaminobutyl acrylate, methacrylamide, N, N-dimethylmethacrylamide, N, N-diethylmethacrylamide, aminomethyl methacrylate, aminoethyl methacrylate, diaminomethyl methacrylate, diaminoethyl methacrylate, methyl acrylate, ethyl acrylate, isopropyl Acrylate, butyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, Methacrylate, butyl methacrylate, hexyl acrylate, hexyl methacryl
- the ratio of the repeating unit derived from the other monomer is not particularly limited in the total constitutional unit of the copolymer, but is, for example, more than 0 mol% and less than 39 mol%, preferably more than 0 mol% and 33 It is less than mol%, more preferably more than 0 mol% and less than 9 mol%, and particularly preferably more than 0 mol% and less than 3 mol%.
- the ratio of the repeating unit derived from the repeating unit (A), the repeating unit (B), or another monomer in the copolymer can be arbitrarily adjusted by changing the ratio of the monomer used in the polymerization. More specifically, the monomer a for constituting the repeating unit (A) may be added at a ratio of 0.6 to 7 mol% with respect to the total number of moles of all monomers used in the polymerization. Furthermore, at this time, it is preferable to add the monomer b for constituting the repeating unit (B) in a ratio of 99.4 to 93 mol% with respect to the total number of moles of all monomers used.
- the charging ratio of the monomer used for the copolymerization Is the content ratio of each repeating unit in the copolymer obtained.
- the method for producing the copolymer contained in the medical material according to the present invention is not particularly limited.
- known polymerization methods such as radical polymerization, anionic polymerization, and cationic polymerization can be employed, and radical polymerization that is easy to produce is preferably used.
- plasma polymerization using radiation or ultraviolet rays may be employed, and a coat layer containing the copolymer may be formed on the substrate surface.
- the polymerization method of the monomer is usually the monomer a corresponding to the repeating unit (A) (for example, [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SBAC) or [3- ( Methacryloylamino) propyl] dimethyl (3-sulfopropyl) ammonium hydroxide (SBAA)) and the monomer b corresponding to the repeating unit (B) (for example, methoxyethyl acrylate (MEA))
- a method is used in which one or more of these and other monomers, if necessary, are copolymerized by stirring and heating together with a polymerization initiator in a polymerization solvent.
- the polymerization temperature is preferably 30 ° C. to 100 ° C. from the viewpoint of controlling the molecular weight.
- the polymerization reaction is usually performed for 30 minutes to 24 hours.
- the polymerization solvent is preferably an aqueous solvent such as water; alcohols such as methanol, ethanol, propanol and n-butanol; polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol and dipropylene glycol; Methanol, ethanol or propanol is preferred. These may be used alone or in combination of two or more.
- the monomer concentration (solid content concentration) in the polymerization solvent is usually 10 to 90% by weight, preferably 15 to 80% by weight, based on the entire reaction solution.
- the monomer concentration with respect to the polymerization solvent is the monomer a, the monomer b, and other monomers copolymerizable with these (hereinafter referred to as “monomer a, monomer b, and optional copolymerized with these”). “Other possible monomers” are also referred to as “polymerization monomers”)).
- the polymerization solvent to which the polymerization monomer has been added may be subjected to a deaeration treatment before the addition of the polymerization initiator.
- a polymerization solvent added with a polymerization monomer may be bubbled with an inert gas such as nitrogen gas or argon gas for about 0.5 to 5 hours.
- the polymerization solvent to which the polymerization monomer is added may be heated to about 30 ° C. to 100 ° C.
- polymerization initiators can be used, and are not particularly limited.
- KPS potassium persulfate
- sodium persulfate sodium persulfate
- ammonium persulfate etc.
- Redox-based polymerization initiators that combine oxidizing agents such as peroxides such as persulfate, hydrogen peroxide, t-butyl peroxide, and methyl ethyl ketone peroxide with reducing agents such as sodium sulfite, sodium hydrogen sulfite, and ascorbic acid Can be used.
- oxidizing agents such as peroxides such as persulfate, hydrogen peroxide, t-butyl peroxide, and methyl ethyl ketone peroxide
- reducing agents such as sodium sulfite, sodium hydrogen sulfite, and ascorbic acid
- the blending amount of the polymerization initiator is, for example, 0.0001 to 1 mol with respect to all monomers (1 mol) used for the production of the copolymer.
- a chain transfer agent e.g., a polymerization rate adjusting agent, a surfactant, and other additives may be appropriately used during the polymerization.
- the atmosphere in which the polymerization reaction is performed is not particularly limited, and may be performed in an air atmosphere or an inert gas atmosphere such as nitrogen gas or argon gas. Further, during the polymerization reaction, the reaction solution may be stirred.
- the copolymer after polymerization can be purified by a general purification method such as a reprecipitation method, a dialysis method, an ultrafiltration method, or an extraction method.
- the purified copolymer can be dried by any method such as freeze-drying, reduced-pressure drying, spray drying, or heat drying. However, from the viewpoint of little influence on the physical properties of the polymer, freeze-drying or reduced pressure Drying is preferred.
- the medical material which concerns on this invention may contain other components other than the said copolymer.
- the other components include unreacted monomers that have not reacted in the polymerization, and various additives such as a crosslinking agent, a thickener, a preservative, and a pH adjuster.
- the unreacted polymerization monomer contained in the obtained copolymer is 0.01% by weight or less based on the entire copolymer.
- the content of the residual monomer can be measured by a method known to those skilled in the art, such as high performance liquid chromatography.
- the medical material in the present invention may be used in the form of the obtained copolymer, or may be used after being processed into a gel or solution.
- it can be used as a medical material in the form of a coating agent in which a copolymer is dissolved in a solvent.
- the solvent used is not particularly limited as long as it can dissolve the copolymer.
- alcohol solvents such as methanol, ethanol, isopropanol and butanol
- water chloroform, tetrahydrofuran, acetone
- Non-proton donating organic solvents such as dioxane and benzene
- the above solvents may be used alone or in combination of two or more.
- the mixed solvent a water-alcohol solvent is preferable, and a water-methanol mixed solvent is particularly preferable.
- the amount of the copolymer contained in the coating agent can be arbitrarily set, and can be used as a solution in which the copolymer is dissolved up to a saturated amount. For example, 0.01 to 50% by weight based on the entire coating agent Is preferable, and 0.1 to 50% by weight is more preferable.
- the coating agent may be composed of the copolymer and the solvent, but may optionally contain other components such as a crosslinking agent, a thickener, a preservative, and a pH adjuster.
- a cross-linking agent By including a cross-linking agent, the copolymer can be more firmly fixed to the substrate surface.
- the repeating unit (A) contained in the medical material according to the present invention easily reacts with the cross-linking agent, the medical material can be more firmly immobilized on the substrate surface.
- the medical device according to the second embodiment of the present invention will be described in detail.
- the medical device which has a base material and the coating layer containing the said medical material on the said base material surface is provided.
- the medical material of the present invention is excellent in antithrombotic properties. Therefore, the medical device excellent in antithrombogenicity can be provided by using the said medical material.
- the medical device of the present invention is obtained by coating the surface of a base material with the above-described medical material.
- the material of the base material that can be used is not particularly limited.
- polyolefins such as polyethylene, polypropylene, and ethylene- ⁇ -olefin copolymers, and modified polyolefins; polyamides; polyimides; polyurethanes; polyethylene terephthalate (PET)
- Polyesters such as polybutylene terephthalate (PBT), polycyclohexane terephthalate, polyethylene-2,6-naphthalate; polyvinyl chloride; polyvinylidene chloride (PVDC); polycarbonate; polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene
- PTFE polytetrafluoroethylene
- PTFE ethylene-tetrafluoroethylene
- examples thereof include various polymer materials such as a fluororesin such as a polymer (ETFE
- the shape of the base material is appropriately selected depending on the use of the medical device, and can be, for example, a tube shape, a sheet shape, a rod shape, or the like.
- the form of the substrate is not limited to a molded body using the above-mentioned material alone, and a blend molded product, an alloyed molded product, a multilayered molded product, and the like can also be used.
- the substrate may be a single layer or may be laminated. At this time, when the base material is laminated, the base material of each layer may be the same or different. However, when it is desired to firmly fix the copolymer by swelling the substrate with a solvent, at least the material present on the surface of the substrate is preferably a material that can be satisfactorily swollen by the solvent of the coating agent of the medical material.
- the “base material surface” is a base material surface for a body fluid such as a biological tissue or blood.
- a coat layer is formed on the surface of the base material with the medical material having a copolymer, the antithrombogenicity of the base material surface is improved.
- the substrate may be surface-treated before forming the coat layer on the substrate surface.
- the surface treatment method of the substrate include a method of irradiating active energy rays (electron beam, ultraviolet ray, X-ray, etc.), a method using plasma discharge such as arc discharge, corona discharge, glow discharge, etc., and a high electric field. Examples thereof include a method of applying, a method of applying ultrasonic vibration via a polar liquid (water or the like), a method of treating with ozone gas, and the like.
- the coat layer is formed by coating the medical material on the surface of the base material.
- the coating layer is formed on the surface of the base material by coating the base material surface by applying a coating solution containing the above medical material (for example, the above coating agent) or by using a polymerization monomer for obtaining a copolymer.
- Plasma polymerization may be performed by applying a polymerization solvent to the substrate surface.
- the above-described method for preparing the coding agent is appropriately taken into consideration for the method for preparing the coating liquid containing the medical material.
- a known method can be adopted as a method for applying a coating solution containing a medical material to the substrate surface, and is not particularly limited.
- dip coating, spraying, spin coating, dripping, doctor blade, brush examples thereof include coating, roll coater, air knife coat, curtain coat, wire bar coat, and gravure coat.
- the thickness of the coating solution may be appropriately adjusted depending on the use of the medical device, and is not particularly limited, but is formed thinner than, for example, 0.1 ⁇ m.
- a coating layer is formed on the surface of the substrate by drying the surface of the substrate to which the coating liquid containing the copolymer is applied.
- the drying process may be appropriately set in consideration of the glass transition temperature of the base material, etc., and is, for example, 15 to 50 ° C.
- the atmosphere in the drying step is not particularly limited, and can also be performed in the atmosphere under an inert gas atmosphere such as nitrogen gas or argon gas.
- Examples of the medical device according to the present invention include an implantable artificial organ and a therapeutic instrument, an extracorporeal circulation type artificial organ, a catheter, a guide wire, and the like.
- an artificial blood vessel, an artificial trachea, a stent, or an implantable medical device such as an artificial skin or an artificial pericardium, or an artificial heart system, an artificial lung system, an artificial heart lung or the like inserted into or replaced into a blood vessel or a lumen.
- an artificial lung system or the like is used continuously for a long time, and has a plurality of step portions in a tube connection portion or the like. Therefore, it is suitably used as an oxygenator system or an oxygenator system that contacts a large amount of blood.
- Example 1 above except that during the preparation of the copolymer in Example 1, the amount of SBAA used was changed to 0.37 g (1.3 mmol) and the amount of methanol used was changed to 21 g.
- a polymer (2) was obtained.
- the content ratio of the repeating unit (A) in the polymer (2) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (96.8 mol%) as the value calculated from the charged amount.
- Example 1 above except that during the preparation of the copolymer in Example 1, the amount of SBAA used was changed to 0.1 g (0.3 mmol) and the amount of methanol used was changed to 20 g.
- a polymer (3) was obtained.
- the content ratio of the repeating unit (A) in the polymer (3) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (99.1 mol%) as the value calculated from the charged amount.
- SBAA styrene-maleic anhydride
- MEA methacryloyloxypropyl
- the polymer (4) was obtained in the same manner as in Example 1 except that the amount was changed to 0.37 g (1.3 mmol) and the amount of methanol used was changed to 20 g. It was.
- the content ratio of the repeating unit (A) in the polymer (4) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (96.7 mol%) as the value calculated from the charged amount.
- Example 4 above except that during the preparation of the copolymer in Example 4, the amount of SBAC used was changed to 0.18 g (0.6 mmol) and the amount of methanol used was changed to 20 g.
- a polymer (5) was obtained.
- the content ratio of the repeating unit (A) in the polymer (5) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (98.3 mol%) as the value calculated from the charged amount.
- Example 4 above except that during the preparation of the copolymer in Example 4, the amount of SBAC used was changed to 0.07 g (0.3 mmol) and the amount of methanol used was changed to 20 g.
- a polymer (6) was obtained.
- the content ratio of the repeating unit (A) in the polymer (6) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (99.3 mol%) as the value calculated from the charged amount.
- Example 1 above except that during the preparation of the copolymer in Example 1, the amount of SBAA used was changed to 1.1 g (3.8 mmol) and the amount of methanol used was changed to 24 g.
- a comparative polymer (2) was obtained.
- the content ratio of the repeating unit (A) in the comparative polymer (2) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (91.1 mol%) as the value calculated from the charged amount.
- Example 1 above except that during the preparation of the copolymer in Example 1, the amount of SBAA used was changed to 0.05 g (0.2 mmol) and the amount of methanol used was changed to 20 g.
- a comparative polymer (3) was obtained.
- the content ratio of the repeating unit (A) in the comparative polymer (3) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (99.6 mol%) as the value calculated from the charged amount.
- Example 4 except that the amount of SBAC used was changed to 1.2 g (4.3 mmol) and the amount of methanol used was changed to 20 g during preparation of the copolymer in Example 4.
- a comparative polymer (4) was obtained.
- the content ratio of the repeating unit (A) in the comparative polymer (4) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (89.9 mol%) as the value calculated from the charged amount.
- Example 4 above except that during the preparation of the copolymer in Example 4, the amount of SBAC used was changed to 0.04 g (0.1 mmol) and the amount of methanol used was changed to 20 g.
- a comparative polymer (5) was obtained.
- the content ratio of the repeating unit (A) in the comparative polymer (5) was measured by 1 H-NMR, it was the same ratio as the value calculated from the charged amount. Further, the content ratio of the repeating unit (B) was the same ratio (99.6 mol%) as the value calculated from the charged amount.
- Example 7 (Homo) polymer of MEA (Repeating unit (A): 0 mol%)]
- a comparative polymer (7) was obtained in the same manner as in Example 1 except that only 5 g (38.4 mmol) of MEA was used during the preparation of the copolymer in Example 1. That is, a homopolymer of MEA was obtained as a comparative polymer (7).
- the comparative polymer (7) had a weight average molecular weight of 130,000. The weight average molecular weight was measured by GPC as described above.
- the polymers (1) to (6) and the comparative polymers (1) to (7) obtained in the above examples or comparative examples were purified by a reprecipitation method in diethyl ether. Thereafter, these copolymers or polymers were dried by vacuum drying and subjected to the following tests.
- the medical material when the repeating unit (A) is 7 mol% or less in all the structural units of the copolymer, the medical material can be appropriately coated on the base material, and the medical material is coated from the base material to the coating layer. It can be seen that it can be more effectively prevented from peeling off and mixing into the blood.
- repeating unit (A) when the repeating unit (A) is 4.7 mol% or less in all the structural units of the copolymer, dissolution in physiological saline can be particularly suppressed. Therefore, if the repeating unit (A) is 4.7 mol% or less in all the structural units of the copolymer, it is more effective that the medical material peels off the coating layer from the base material and enters the blood. It is suggested that it can be prevented.
- a stepped tube was prepared by inserting a 1 cm end of a soft vinyl chloride tube (tube 2) having a total length of 5 cm, an inner diameter of 6 mm and an outer diameter of 9 mm into both ends of a soft vinyl chloride tube (tube 1) having a total length of 30 cm and an inner diameter of 8 mm. .
- FIG. 1 shows the manufactured step tube.
- a circled portion indicates a joint portion between the tube 1 and the tube 2.
- FIG. 2 is an enlarged view schematically showing a joint portion between the tube 1 and the tube 2 in FIG. Since the inner diameter of the tube 2 is thinner than the inner diameter of the tube 1, a step surface 3 is formed. When blood is passed through the step tube, a thrombus is very easily formed on the step surface 3.
- the prepared step tube was used as a substrate, the above coating agent was passed through the step tube, and the coating agent was applied to the substrate surface. Thereafter, the step tube was dried at room temperature (25 ° C.), and a coat layer containing a medical material was formed on the substrate surface (step tube lumen surface).
- the (co) polymers obtained in the above Examples and Comparative Examples were each dissolved in methanol to prepare a 0.5 wt% solution, and dip coated to form a coat layer.
- Anti-thrombogenicity test In order to evaluate the antithrombogenicity of a medical material under severe conditions in which a thrombus is easily formed, the following test system was constructed using the above-described stepped tube on which a coating layer was formed.
- the lumen of the stepped tube on which the coat layer was formed was filled with 6 ml of a solution (diluted blood) obtained by diluting human fresh blood twice with physiological saline. Both ends of the step tube were connected with connectors, fixed to a cylindrical rotating device, and rotated at 40 rpm for 2 hours. Thereafter, the circulating blood was removed from the stepped tube, and the adhesion state of the thrombus (shown by reference numeral “4” in FIG. 4) to the joint portion (stepped surface) between the tube 1 and the tube 2 was visually observed.
- the fresh blood refers to blood collected from a healthy donor by whole blood transfusion within 30 minutes. In addition, no anticoagulant is added to fresh blood.
- FIG. 3 shows the joint produced immediately after the anti-thrombogenicity test for the stepped tube to which the coating layer containing the copolymer produced in Example 1 and FIG. 4 shows the polymer produced in Comparative Example 7 respectively. It is an enlarged photo. Thrombus formation was not observed in the stepped tube to which the copolymer according to the present invention was applied (FIG. 3). On the other hand, in the stepped tube to which the polymer of Comparative Example 7 was applied, thrombus 4 was observed at the joint (FIG. 4).
- the medical device according to the present invention exhibits high antithrombogenicity.
- Example 3 and Comparative Example 6 are copolymers obtained by combining SBAA and MEA, CBA and MEA, respectively. When these are compared, the content (ratio) of the betaine skeleton (zwitter ion portion) in the copolymer is almost the same, but in Example 3, good antithrombogenicity is obtained, In Example 6, the antithrombogenicity was inferior. Therefore, the copolymer obtained in Example 3 and Comparative Example 6 is a copolymer containing a zwitterion moiety in the same manner, but when the zwitterion moiety has a structure derived from SBAA. It was revealed that the effect of improving antithrombogenicity is higher than that of CBA.
- the polymer (5) and the comparative polymer (7) were each dissolved in a water-alcohol (methanol) mixed solution at a concentration of 0.05% by weight to obtain a coating agent.
- FIG. 4 of Japanese Patent Application Laid-Open No. 2009-219936 An artificial lung having the structure disclosed in 1); as a base material constituting a blood circulation path, polypropylene, polyurethane, polycarbonate, and SUS are included) from the blood import side, and after leaving for 120 seconds, they are removed. The mixture was blown and dried at room temperature (25 ° C.) for 240 minutes.
- the blood circulation module was incorporated into an extracorporeal circuit by connecting to a blood reservoir using a connection tube (made of soft vinyl chloride, total length: about 100 cm ⁇ inner diameter: 8 mm). Subsequently, 200 ml of lactated Ringer's solution was filled into the extracorporeal circuit, and then 200 ml of heparinized human fresh blood was added. The heparin concentration in the circulating blood was 0.5 unit / ml. Circulation was performed at room temperature (25 ° C.) at 500 ml / min.
- TAT thrombin antithrombin complex
- the TAT concentration was lower than that of the blood circulation module coated with the comparative polymer (7) of Comparative Example 7. That is, it was confirmed that the medical device according to the present invention has an excellent antithrombotic property with low activation of the blood coagulation system.
- the medical device according to the present invention is used under severe conditions in which a thrombus such as a step having a stepped portion on a surface in contact with blood is easily formed, such as a medical device having a throttle portion such as a joint portion of a tube. Even in the case where it is, it can be seen that it exhibits excellent antithrombogenicity.
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Abstract
Description
で示される繰り返し単位(A)と、
下記式(2):
で示される繰り返し単位(B)と、を有する共重合体を含み、
前記繰り返し単位(A)が、前記共重合体の全構成単位中、0.6~7モル%含まれる、医療材料;
2.前記式(2)中、R21は、水素原子またはメチル基であり、R22は、炭素原子数1~3のアルキレン基であり、R23は、炭素原子数1または2のアルキル基である、上記1.に記載の医療材料;
3.前記式(1)中、R11はメチル基であり、Zは酸素原子または-NH-であり、R12は炭素原子数1~4のアルキレン基であり、R13およびR14はそれぞれ独立して炭素原子数1または2のアルキル基であり、R15は炭素原子数1~4のアルキレン基である、上記1または2に記載の医療材料;
4.前記共重合体は、前記繰り返し単位(A)を0.6~7モル%、前記繰り返し単位(B)を99.4~93モル%(前記繰り返し単位(A)および前記繰り返し単位(B)の合計量は100モル%である)から構成される、上記1.~3.のいずれかに記載の医療材料;
5.基材と、
前記基材表面に、上記1.~4.のいずれかに記載の医療材料を含むコート層と、を有する医療用具。
で示される繰り返し単位(A)と、
下記式(2):
で示される繰り返し単位(B)と、を有する共重合体を含み、
前記繰り返し単位(A)が、前記共重合体の全構成単位中、0.6~7モル%含まれる、医療材料が提供される。
以下では、まず、本発明の第一形態に係る医療材料について詳細に説明する。
本発明に係る医療材料に含まれる共重合体は、上記繰り返し単位(A)および(B)を含み、かつ、全構成単位中、繰り返し単位(A)の含有比率が特定の範囲内である共重合体である。したがって、上記組成を有していれば、共重合体の末端は特に制限されず、使用される原料の種類によって適宜規定されるが、通常、水素原子である。共重合体の構造も特に制限されず、ランダム共重合体、交互共重合体、周期的共重合体、ブロック共重合体のいずれであってもよい。
本発明において、医療材料に含まれる共重合体は、上記式(1)で示される繰り返し単位(A)を必須に含む。
本発明において、医療材料に含まれる共重合体は、上記式(2)で示される繰り返し単位(B)を必須に含む。
本発明において、共重合体は、共重合体の全構成単位(100モル%)中、繰り返し単位(A)を、0.6~7モル%含む。繰り返し単位(A)は、親水性が高いため、共重合体に多く含まれる場合、当該共重合体は良好な抗血栓性を示す。一方で、繰り返し単位(A)が多すぎると、共重合体の水溶性が高くなり、医療用具に医療材料を適用した際、医療材料が剥離してしまう虞がある。
上記のように、本発明に係る医療材料に含まれる共重合体は、繰り返し単位(A)および(B)のみからなると好ましいが、その他の繰り返し単位を含んでいてもよい。すなわち、本発明の他の実施形態において、医療材料に含まれる共重合体は、モノマーa、モノマーb、および、これらと共重合可能な他のモノマー(以下、単に「他のモノマー」とも称する。)に由来する構成単位(繰り返し単位)を含んでいてもよい。
共重合体における繰り返し単位(A)、繰り返し単位(B)、または他のモノマーに由来する繰り返し単位の割合は、重合の際に用いるモノマーの割合を変更することで、任意に調整できる。より詳細には、重合の際、用いる全モノマーの総モル数に対して、繰り返し単位(A)を構成するためのモノマーaを、0.6~7モル%の割合で添加すればよい。さらにこのとき、繰り返し単位(B)を構成するためのモノマーbを、用いる全モノマーの総モル数に対して99.4~93モル%の割合で添加すると好ましい。基本的には、モノマーa、モノマーb、および任意で添加される他のモノマーの共重合により得られた共重合体について、分子量分画等を行わない場合、共重合に用いたモノマーの仕込み比率が、得られる共重合体中の各繰り返し単位の含有比率となる。
本発明に係る医療材料は、上記共重合体以外の、他の成分を含んでいてもよい。当該他の成分としては、例えば、重合において反応しなかった未反応のモノマーや、架橋剤、増粘剤、防腐剤、pH調整剤等の各種添加剤が挙げられる。
次に、本発明の第二形態に係る医療用具について詳細に説明する。本発明の第二形態によれば、基材と、前記基材表面に上記医療材料を含むコート層と、を有する医療用具が提供される。
本発明の医療用具は、上記の医療材料によって基材表面が被覆されてなる。このとき、使用可能な基材の材質としては、特に制限されず、例えば、ポリエチレン、ポリプロピレン、エチレン-α-オレフィン共重合体等のポリオレフィンや変性ポリオレフィン;ポリアミド;ポリイミド;ポリウレタン;ポリエチレンテレフタレート(PET)、ポリブチレンテレフタレート(PBT)、ポリシクロヘキサンテレフタレート、ポリエチレン-2,6-ナフタレート等のポリエステル;ポリ塩化ビニル;ポリ塩化ビニリデン(PVDC);ポリカーボネート;ポリテトラフルオロエチレン(PTFE)、エチレン-テトラフルオロエチレン共重合体(ETFE)等のフッ素樹脂等の各種高分子材料、SUS等の金属、セラミック、カーボン、およびこれらの複合材料等が例示できる。
本発明に係る医療用具においては、上記医療材料を基材表面に被覆することにより、コート層が形成される。
本発明に係る医療用具としては、例えば、体内埋入型の人工器官や治療器具、体外循環型の人工臓器類、カテーテル、ガイドワイヤー等を例示できる。具体的には、血管や管腔内へ挿入あるいは置換される人工血管、人工気管、ステントや、人工皮膚、人工心膜等の埋入型医療器具や、人工心臓システム、人工肺システム、人工心肺システム、人工腎臓システム、人工肝臓システム、免疫調節システム等の人工臓器システムや、留置針、IVHカテーテル、薬液投与用カテーテル、サーモダイリューションカテーテル、血管造影用カテーテル、血管拡張用カテーテルおよびダイレーターあるいはイントロデューサー等の血管内に挿入ないし留置されるカテーテルや、あるいは、これらのカテーテル用のガイドワイヤー、スタイレット等や、胃管カテーテル、栄養カテーテル、経管栄養用(ED)チューブ、尿道カテーテル、導尿カテーテル、バルーンカテーテル、気管内吸引カテーテルをはじめとする各種の吸引カテーテルや排液カテーテル等の血管以外の生体組織に挿入ないし留置されるカテーテル類が例示できる。特に、人工肺システム等は、長時間連続して使用され、かつ、チューブの連結部等において複数の段差部を有している。そのため、大量の血液と接する人工肺システム、または人工心肺システムとして好適に使用される。
アクリル酸メトキシエチル(MEA)5g(38.4mmol)と[3-(メタクリロイルアミノ)プロピル]ジメチル(3-スルホプロピル)アンモニウムヒドロキシド(SBAA、下記化学式(i)の化合物)0.55g(1.9mmol)とをメタノール22gに溶解し、四口フラスコに入れ、50℃でN2バブリングを1時間行った。
実施例1における共重合体の調製時、用いたSBAAの量を変更して0.37g(1.3mmol)とし、用いたメタノールの量を変更して21gとしたこと以外は、上記実施例1と同様にして重合体(2)を得た。当該重合体(2)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(96.8モル%)であった。
実施例1における共重合体の調製時、用いたSBAAの量を変更して0.1g(0.3mmol)とし、用いたメタノールの量を変更して20gとしたこと以外は、上記実施例1と同様にして重合体(3)を得た。当該重合体(3)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(99.1モル%)であった。
単位(A):3.3モル%)]
実施例1における共重合体の調製時、用いたSBAAを[2-(メタクリロイルオキシ)エチル]ジメチル-(3-スルホプロピル)アンモニウムヒドロキシド(SBAC、下記化学式(ii)の化合物)に変更し、さらに、その量を変更して、0.37g(1.3mmol)とし、用いたメタノールの量を変更して20gとしたこと以外は、上記実施例1と同様にして重合体(4)を得た。当該重合体(4)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(96.7モル%)であった。
実施例4における共重合体の調製時、用いたSBACの量を変更して0.18g(0.6mmol)とし、用いたメタノールの量を変更して20gとしたこと以外は、上記実施例4と同様にして重合体(5)を得た。当該重合体(5)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(98.3モル%)であった。
実施例4における共重合体の調製時、用いたSBACの量を変更して0.07g(0.3mmol)とし、用いたメタノールの量を変更して20gとしたこと以外は、上記実施例4と同様にして重合体(6)を得た。当該重合体(6)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(99.3モル%)であった。
実施例1における共重合体の調製時、用いたSBAAの量を変更して3.0g(10.3mmol)とし、用いたメタノールの量を変更して32gとしたこと以外は、上記実施例1と同様にして比較重合体(1)を得た。当該比較重合体(1)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(78.9モル%)であった。
実施例1における共重合体の調製時、用いたSBAAの量を変更して1.1g(3.8mmol)とし、用いたメタノールの量を変更して24gとしたこと以外は、上記実施例1と同様にして比較重合体(2)を得た。当該比較重合体(2)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(91.1モル%)であった。
実施例1における共重合体の調製時、用いたSBAAの量を変更して0.05g(0.2mmol)とし、用いたメタノールの量を変更して20gとしたこと以外は、上記実施例1と同様にして比較重合体(3)を得た。当該比較重合体(3)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(99.6モル%)であった。
実施例4における共重合体の調製時、用いたSBACの量を変更して1.2g(4.3mmol)とし、用いたメタノールの量を変更して20gとしたこと以外は、上記実施例4と同様にして比較重合体(4)を得た。当該比較重合体(4)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(89.9モル%)であった。
実施例4における共重合体の調製時、用いたSBACの量を変更して0.04g(0.1mmol)とし、用いたメタノールの量を変更して20gとしたこと以外は、上記実施例4と同様にして比較重合体(5)を得た。当該比較重合体(5)における繰り返し単位(A)の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(99.6モル%)であった。
実施例1における共重合体の調製時、SBAAの代わりにN-メタクリロイルオキシエチル-N,N-ジメチルアンモニウム-α-N-メチルカルボキシベタイン(CBA、下記化学式(iii)の化合物)0.07g(0.33mmol)とし、用いたメタノールの量を変更して25.5gとしたこと以外は、上記実施例1と同様にして比較重合体(6)を得た。当該比較重合体(6)におけるCBA由来の構成単位の含有比率を1H-NMRにより測定したところ、上記の仕込み量から計算される値と同様の比率であった。また、繰り返し単位(B)の含有比率も仕込み量から計算される値と同様の比率(99.16モル%)であった。
実施例1における共重合体の調製時、MEA 5g(38.4mmol)のみを使用したこと以外は、上記実施例1と同様にして比較重合体(7)を得た。すなわち、MEAの単独重合体を比較重合体(7)として得た。また、当該比較重合体(7)の重量平均分子量は130000であった。なお、重量平均分子量の測定は、上記のとおり、GPCにより測定した。
実施例または比較例で得られた、重合体(1)~(6)および比較重合体(1)~(2)および(4)をそれぞれ0.1gずつ量り採り、それぞれ別のガラス製試験管に入れた。
(コーティング剤の調製)
実施例または比較例で得られた、上記重合体(1)~(6)および比較重合体(3)および(5)~(7)のそれぞれについて、0.5重量%のメタノール溶液を調製し、コーティング剤とした。
全長30cm×内径8mmの軟質塩化ビニルチューブ(チューブ1)の両端にそれぞれ、全長5cm×内径6mm×外径9mmの軟質塩化ビニルチューブ(チューブ2)の端部1cmを挿入し、段差チューブを作製した。
血栓が形成されやすい過酷な条件における医療材料の抗血栓性を評価するため、コート層を形成した上記段差チューブを用いて、以下のような試験系を構築した。
上記実施例5で得られた重合体(5)および比較例7で得られた比較重合体(7)をコートした基材について、下記方法に従って、抗血栓性を評価した。
重合体(5)および比較重合体(7)をそれぞれ、0.05重量%の濃度で、水-アルコール(メタノール)混合溶液に溶解させ、コーティング剤とした。
上記コーティング剤を、模擬製品形態(血液循環モジュール:特開平11-114056号公報に開示された実施例1に係る血液外部灌流型中空糸膜人工肺を、特開2009-219936号公報の図4に開示された構造を有する人工肺としたもの;血液循環経路を構成する基材として、ポリプロピレン、ポリウレタン、ポリカーボネート、SUSを含む)に血液インポート側から充填し、120秒間静置した後に除去し、室温(25℃)で240分間、送風乾燥した。
上記血液循環モジュールを接続チューブ(軟質塩化ビニル製、全長約100cm×内径8mm)を用いて貯血槽と接続することによって体外循環回路中に組み込んだ。続いて、乳酸リンゲル液200mlを上記体外循環回路に充填し、その後、ヘパリン添加ヒト新鮮血200mlを添加した。循環血液中のへパリン濃度は、0.5単位/mlとした。室温(25℃)、500ml/minで循環させた。循環開始から120分後に、それぞれの血液循環回路から血液をサンプリングし、血液凝固系の活性化指標であるトロンビンアンチトロンビン複合体(TAT)の濃度を測定した。TAT濃度は、EIA法による測定キットを用いた。高いTAT濃度は、凝固活性化状態にあることを示し、血栓が生じやすいといえる。
2 チューブ2、
3 段差面、
4 血栓。
Claims (5)
- 下記式(1):
で示される繰り返し単位(A)と、
下記式(2):
で示される繰り返し単位(B)と、を有する共重合体を含み、
前記繰り返し単位(A)が、前記共重合体の全構成単位中、0.6~7モル%含まれる、医療材料。 - 前記式(2)中、R21は、水素原子またはメチル基であり、R22は、炭素原子数1~3のアルキレン基であり、R23は、炭素原子数1または2のアルキル基である、請求項1に記載の医療材料。
- 前記式(1)中、R11はメチル基であり、Zは酸素原子または-NH-であり、R12は炭素原子数1~4のアルキレン基であり、R13およびR14はそれぞれ独立して炭素原子数1または2のアルキル基であり、R15は炭素原子数1~4のアルキレン基である、請求項1または2に記載の医療材料。
- 前記共重合体は、前記繰り返し単位(A)を0.6~7モル%、前記繰り返し単位(B)を99.4~93モル%(前記繰り返し単位(A)および前記繰り返し単位(B)の合計量は100モル%である)から構成される、請求項1~3のいずれか1項に記載の医療材料。
- 基材と、
前記基材表面に、請求項1~4のいずれか1項に記載の医療材料を含むコート層と、を有する医療用具。
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WO2020203923A1 (ja) | 2019-03-29 | 2020-10-08 | 旭化成メディカル株式会社 | 血液浄化器 |
WO2020203927A1 (ja) | 2019-03-29 | 2020-10-08 | 旭化成メディカル株式会社 | 血液浄化器 |
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WO2020009008A1 (ja) | 2018-07-02 | 2020-01-09 | 旭化成メディカル株式会社 | 血液処理用ビーズ |
CN112827478A (zh) * | 2018-07-02 | 2021-05-25 | 旭化成医疗株式会社 | 血液处理用珠 |
EP3824921A1 (en) | 2018-07-02 | 2021-05-26 | Asahi Kasei Medical Co., Ltd. | Beads for blood processing |
CN112827478B (zh) * | 2018-07-02 | 2023-06-30 | 旭化成医疗株式会社 | 血液处理用珠 |
WO2020203923A1 (ja) | 2019-03-29 | 2020-10-08 | 旭化成メディカル株式会社 | 血液浄化器 |
WO2020203927A1 (ja) | 2019-03-29 | 2020-10-08 | 旭化成メディカル株式会社 | 血液浄化器 |
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JP6397889B2 (ja) | 2018-09-26 |
US9956324B2 (en) | 2018-05-01 |
EP3111969A4 (en) | 2017-10-18 |
JPWO2015125890A1 (ja) | 2017-03-30 |
EP3111969A1 (en) | 2017-01-04 |
US20170128636A1 (en) | 2017-05-11 |
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