WO2020045611A1 - インプラント用の筒状体 - Google Patents
インプラント用の筒状体 Download PDFInfo
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- WO2020045611A1 WO2020045611A1 PCT/JP2019/034060 JP2019034060W WO2020045611A1 WO 2020045611 A1 WO2020045611 A1 WO 2020045611A1 JP 2019034060 W JP2019034060 W JP 2019034060W WO 2020045611 A1 WO2020045611 A1 WO 2020045611A1
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- block copolymer
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- tubular
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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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- 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
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
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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
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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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
- C09D167/00—Coating compositions based on polyesters obtained by reactions forming a carboxylic ester link in the main chain; Coating compositions based on derivatives of such polymers
- C09D167/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
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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
- C09D171/00—Coating compositions based on polyethers obtained by reactions forming an ether link in the main chain; Coating compositions based on derivatives of such polymers
- C09D171/02—Polyalkylene oxides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
- A61F2/06—Blood vessels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
- A61F2/06—Blood vessels
- A61F2/07—Stent-grafts
Definitions
- the present invention relates to a tubular body for an implant.
- Biodegradable polymers are widely used in medical applications such as medical coating materials, vascular embolization materials, sutures, and DDS carriers. Since the medical coating material embedded in the body is to be placed in the body, it must be non-toxic and eventually decomposed and discharged outside the body.
- a coating material that comes into contact with blood may lose its original function if it induces thrombus formation, and is therefore required to be biocompatible.
- a copolymer obtained by mixing a component selected from L-lactic acid, D, L-lactic acid, glycolic acid and ⁇ -caprolactone with a component selected from polyvinyl alcohol and polyethylene glycol is used as a biodegradable synthetic polymer.
- a component selected from L-lactic acid, D, L-lactic acid, glycolic acid and ⁇ -caprolactone is used as a biodegradable synthetic polymer.
- a component selected from L-lactic acid, D, L-lactic acid, glycolic acid and ⁇ -caprolactone a component selected from polyvinyl alcohol and polyethylene glycol
- the block copolymer described in Patent Document 1 has a large content of polyalkylene glycol, so that it swells when it comes into contact with blood, leading to the extension of an artificial blood vessel.
- the inner diameter may be reduced, and the shear rate of blood increases.
- the voids into which blood components enter increase due to a decrease in fiber density. In either case, platelet adhesion / aggregation is promoted, leading to thrombus formation.
- the block copolymer described in Patent Document 2 has a low polyalkylene glycol content, so that it does not elongate due to swelling, but has a high Young's modulus. Due to the high Young's modulus, the artificial blood vessel coated with the block copolymer has a reduced kink resistance, cannot follow the movement of the living body, and buckles, leading to occlusion of the artificial blood vessel.
- block copolymers of the prior art may not be able to maintain the required high patency even when applied to artificial blood vessels due to their high swelling properties and high Young's modulus.
- the artificial blood vessel described in Patent Document 3 has a high biodegradable polymer because polyethylene glycol is mixed with the biodegradable polymer to be coated, and polyethylene glycol is eluted in the early stage of transplantation, and the antithrombotic property is not maintained. Further improvement was needed for use as a sustainable implant.
- an object of the present invention is to provide a tubular body for an implant that can maintain a high patency rate by achieving antithrombotic properties, low swelling properties, and a low Young's modulus.
- a tubular base material having an elongation percentage in the long axis direction of 5 to 100% under a condition of applying a tensile load of 20 N, a block copolymer comprising a polyalkylene glycol block and a polyhydroxyalkanoic acid block, Wherein the ratio of the total mass of the alkylene glycol residue to the total mass of the block copolymer is 5 to 25%, and the block copolymer has a Young's modulus of 200 MPa or less when formed into a film.
- Tubular body for implant having an elongation percentage in the long axis direction of 5 to 100% under a condition of applying a tensile load of 20 N
- a block copolymer comprising a polyalkylene glycol block and a polyhydroxyalkanoic acid block, Wherein the ratio of the total mass of the alkylene glycol residue to the total mass of the block copolymer is 5 to 25%, and the block copolymer has a Young's modulus of 200 MP
- L1 At the outer diameter measured when no stress is applied to the cylindrical base material, a marked line is drawn on the outer periphery of the cylindrical base material at a distance five times the maximum value of the outer diameter, The distance between the marked lines when the base material is compressed with a stress of 0.01 cN / dtex in the major axis direction.
- L2 Distance between marked lines when elongated in the major axis direction with a stress of 0.01 cN / dtex.
- (6) The cylindrical body according to any one of (1) to (5), wherein the cylindrical base material satisfies the following formula 2.
- the tubular body for an implant of the present invention was coated with a block copolymer composed of a polyalkylene glycol block and a polyhydroxyalkanoic acid block in which the weight ratio of a monomer was controlled, with respect to a tubular substrate having a specific elongation.
- the use of the cylindrical body enables the maintenance of a high patency rate, which could not be achieved conventionally, and can be suitably used particularly as a material for medical devices for cardiovascular implants.
- the tubular body for an implant of the present invention comprises a tubular base material having an elongation percentage in the major axis direction of 5 to 100% under a tensile load of 20 N, a polyalkylene glycol block and a polyhydroxyalkanoic acid block.
- the mass ratio of the polyalkylene glycol to the total mass in the block copolymer is 5 to 25%
- the Young's modulus of the film comprising the block copolymer is 200 MPa or less. It is characterized by having.
- the tubular base material can easily follow the movement of the living body when implanted in the body, and the elongation rate is 100% or less. If this is the case, it is possible to prevent meandering during the operation and easily fit into the target site.
- the above-mentioned tubular base material preferably has an elongation ratio in the long axis direction of 5% to 100%, more preferably 7% to 75% under the condition of applying a tensile load of 20N, More preferably, it is 10% to 50%.
- the elongation percentage in the long axis direction under a condition of applying a tensile load of 20 N can be measured by Measurement Example 4 described later.
- the above tubular base material is suitable for an implant having excellent stretchability, flexibility and kink resistance (flexibility).
- a tubular body can be provided.
- L1 At the outer diameter of the woven fabric measured in a state where no stress is applied to the cylindrical substrate, a marked line is drawn on the outer periphery of the cylindrical substrate at a distance of 5 times the maximum value of the outer diameter of the woven fabric. The distance between the marked lines when the cylindrical base material was compressed with a stress of 0.01 cN / dtex in the major axis direction.
- L2 distance between marked lines when elongated with a stress of 0.01 cN / dtex in the major axis direction.
- the cylindrical base material When the cylindrical base material is bent, stress is applied in the compression direction on the bent inner peripheral side and stress is applied on the outer circumferential side in the elongation direction.
- the cylindrical base material has the following distances L1 and L2 between the marked lines.
- the elongating operation or the compressing operation with a stress of 0.01 cN / dtex usually corresponds to the stress when a person stretches and compresses the cylindrical base material lightly in the long axis direction by hand and is in the above range.
- the operability is good even when a person performs a bending operation by hand, which means that the elasticity and flexibility are excellent.
- the values of the distances L1 and L2 between the marked lines of the cylindrical base material can be measured by Measurement Example 6 described later. Further, the value of (L2-L1) / L1 is preferably 0.15 or more, more preferably 0.18 or more, from the viewpoint of further improving stretchability and flexibility. Further, the value of (L2 ⁇ L1) / L1 is preferably 1.0 or less.
- the values of the outer diameter a during compression, the outer diameter b during elongation b, and the value of (ab) / a of the cylindrical base material are determined by a measurement example 7 described below.
- b can be derived from the outer diameter of the cylindrical base material when elongated in the major axis direction with a stress of 0.01 cN / dtex.
- the value of (ab) / a is 0.03 from the viewpoint that the difference in the inner diameter of the tubular base material is reduced when bending, elongation, and compression occur at the same time and a flow path that does not change can be secured. As mentioned above, it is preferable that it is less than 0.2, and it is more preferable that it is 0.05 or more and less than 0.15.
- the inner surface roughness of the cylindrical substrate refers to an arbitrary point on the outer surface of the cylindrical substrate, a straight line from any point on the outer surface to the center of the cylindrical substrate, and an inner surface. the distance between the intersection of the set to D, the shortest D D s in the tubular base member, when the longest D was D l, the difference between D s and D l.
- the center of the tubular substrate refers to a point at which the variation in the shortest distance from the center of the tubular substrate to the inner surface is minimized.
- the inner surface roughness of the cylindrical substrate is preferably 100 ⁇ m or less, more preferably 80 ⁇ m or less, and even more preferably 60 ⁇ m or less.
- the lower limit is preferably 3 ⁇ m or more from the viewpoint of endothelial formation when used as an artificial blood vessel.
- the water permeability of the tubular substrate refers to the property of water flowing out from the outer surface when a certain pressure is applied to the inner surface of the tubular substrate.
- a pressure of 16 kPa is applied to the surface
- the amount (mL) of water flowing out from the outer surface is divided by a unit area (cm 2 ) and a unit time (min.).
- the method of measuring the water permeability is based on ISO 7198, and the amount of water (mL) flowing out of the cylindrical base material when a pressure of 16 kPa is applied to the inner surface of the cylindrical base material is defined as a unit area (cm 2 ).
- unit time (min.) The water permeability of the cylindrical substrate is 5 mL / cm 2 / min.
- the water permeability is 500 mL / cm 2 / min. If it is below, it becomes easy to prevent blood leakage. Therefore, the water permeability under the condition that a pressure of 16 kPa is applied to the inner surface is 5 mL / cm 2 / min. ⁇ 500 mL / cm 2 / min. Is preferred, and 50 mL / cm 2 / min. Up to 350 mL / cm 2 / min. Is more preferable, and 100 mL / cm 2 / min. ⁇ 250 mL / cm 2 / min. Is more preferred.
- the tubular substrate has a structure other than the bellows structure.
- a structure other than the bellows structure there is no inner surface roughness, turbulence does not occur even when fluid flows in a narrow space, and turbulence does not occur in blood flow, especially when used for thin artificial blood vessels, There is an advantage that a thrombus is hardly generated.
- a mandrel having a structure in which a mandrel having a spiral or annular corrugated groove is inserted into a fibrous tubular article and heated and not subjected to corrugation setting processing is referred to as a non-pleated structure.
- the above-mentioned cylindrical substrate is a hollow substrate made of the following materials, and examples of the material of the cylindrical substrate include synthetic polymers and natural polymers.
- the above-mentioned synthetic polymer is, for example, polyethylene, polypropylene, polyvinyl chloride, polystyrene, polyvinyl acetate, polyvinyl pyrrolidone, polyvinyl alcohol, polyurethane, PTFE, ePTFE, acrylic resin, polyamide, polyacetal, polycarbonate, polyester, and polysiloxane or these. Mixtures and copolymers are exemplified.
- the natural polymer include a polysaccharide, a protein, and a natural rubber.
- the protein include a gelatin and a collagen.
- the material of the above-mentioned cylindrical base material can be of any shape, and examples of the shape of the material include a film, a porous sheet, and a fiber.
- polyester is preferred from the viewpoint of water absorption and deterioration resistance.
- the polyester include polyethylene terephthalate and polybutylene terephthalate.
- a copolymerized polyester obtained by copolymerizing polyethylene terephthalate and polybutylene terephthalate with an aliphatic dicarboxylic acid such as isophthalic acid, 5-sodium sulfoisophthalic acid or adipic acid as an acid component may be used.
- the biodegradable polymer refers to a polymer that has the property of being degraded in vivo. Terms that can be used interchangeably with biodegradability include bioabsorbability, biocompatibility, and the like.
- the block copolymer is characterized by comprising a polyalkylene glycol block and a polyhydroxyalkanoic acid block.
- the polyalkylene glycol is a polymer obtained by polymerizing one or more alkylene glycols.
- alkylene glycol examples include ethylene glycol, propylene glycol, oxyethylene glycol dimethyl ether, oxypropylene glycol monobutyl ether, and oxypropylene glycol diacetate 1.
- One or more polymers are included.
- the polyhydroxyalkanoic acid is obtained by polymerizing one or more kinds of hydroxyalkanoic acids.
- the hydroxyalkanoic acid include 2-hydroxypropionic acid (lactic acid), 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 3-hydroxybutanoic acid (3-hydroxybutyric acid), 3-hydroxypentanoic acid (3-hydroxyvaleric acid), 3-hydroxyhexanoic acid, 3-hydroxyheptanoic acid, 3-hydroxyoctanoic acid, -Hydroxynonanoic acid, 3-hydroxydecanoic acid, 4-hydroxypentanoic acid, 4-hydroxyhexanoic acid, 4-hydroxyheptanoic acid, 4-hydroxyoctanoic acid, 5-hydroxyhexanoic acid, 5-hydroxyheptanoic acid, 6-hydroxy Heptanoic acid, 6-hydroxyoctanoic acid, -Hydroxynonanoic acid, 8-hydroxydecanoic acid, 9-
- the ratio of the total mass of the alkylene glycol residues to the total mass in the block copolymer refers to the ratio of the total mass of the alkylene glycol residues to the mass of all the residues contained in the block copolymer, which will be described later. As described in Measurement Example 1, it is calculated from numerical values obtained by 1 H-NMR measurement. If the ratio of the total mass of the alkylene glycol residue to the total mass of the block copolymer is 5% or more, a suitable antithrombotic property is obtained, and if it is 25% or less, a suitable swelling property is obtained.
- the ratio of the total weight of the alkylene glycol residues to the total weight of the block copolymer is preferably 5 to 25%, and 8 to 25%. 22% is more preferable, and 10 to 20% is still more preferable.
- the ratio of the total mass of caprolactone residues to the total mass in the block copolymer refers to the ratio of the total mass of caprolactone residues to the mass of all the residues contained in the block copolymer, and is a measurement example described later. As described in No. 1, it is calculated from numerical values obtained by 1 H-NMR measurement. When the ratio of the total mass of the caprolactone residue to the total mass in the block copolymer is 15% or more, the Young's modulus becomes a suitable value, and when it is 80% or less, it has suitable degradability.
- the ratio of the total mass of caprolactone residues to the total mass in the block copolymer is preferably 15 to 80%, more preferably 20 to 70%. Is more preferable, and 25 to 60% is further preferable.
- the ratio of the total mass of glycolic acid residues to the total mass in the block copolymer refers to the ratio of the total mass of glycolic acid residues to the mass of all residues contained in the block copolymer, which will be described later. As described in Measurement Example 1, it is calculated from numerical values obtained by 1 H-NMR measurement.
- the ratio of the total mass of glycolic acid residues to the total mass of the block copolymer is preferably 10% or less, since the Young's modulus becomes a suitable value, more preferably 7% or less, and even more preferably 5% or less.
- the polyalkylene glycol block may be a single polyalkylene glycol molecule, or a plurality of polyalkylene glycol molecules may be connected via a linker.
- the weight average molecular weight of the polyalkylene glycol molecule constituting the polyalkylene glycol block is preferably 7,000 to 170,000, more preferably 8,000 to 100,000, and further preferably 10,000 to 50,000.
- the Young's modulus of the film composed of the block copolymer can be evaluated by the method described in Measurement Example 2 described later.
- the Young's modulus of the film composed of the block copolymer is preferably 200 MPa or less, and is preferably 100 MPa or less. Is more preferable, and it is more preferable that it is 10 MPa or less.
- the weight average molecular weight of the block copolymer is preferably 10,000 or more.
- the upper limit is not particularly limited, but is preferably 1,600,000 or less, more preferably 800,000 or less, and still more preferably 400,000 or less, in order to improve moldability.
- the weight average molecular weight can be determined by a gel permeation chromatography (GPC) method, for example, by the following method.
- the block copolymer was dissolved in chloroform and passed through a 0.45 ⁇ m syringe filter (DISMIC-13HP; manufactured by ADVANTEC) to remove impurities and the like, followed by measurement by GPC to determine the weight average molecular weight of the block copolymer. calculate.
- DISMIC-13HP 0.45 ⁇ m syringe filter
- the above-mentioned swelling property refers to a property that the polymer is hydrated and swells when immersed in water, and in this specification, the swelling index is the swelling rate.
- the swelling ratio of the film composed of the block copolymer can be evaluated by the method described in Measurement Example 3 described later.
- the swelling ratio of the film made of the block copolymer is -10% or more, it is possible to prevent the film made of the block copolymer from peeling off from the cylindrical substrate even when the film shrinks. Even when the polymer film expands, it is possible to prevent thrombus formation due to excessive expansion of the implant tubular body.
- the swelling ratio of the film made of the block copolymer is preferably from -10% to 20%, more preferably from -5% to 15%, and further preferably from 0% to 10%.
- the polyhydroxyalkanoic acid block and the block copolymer can be prepared, for example, by a method of ring-opening polymerization of a cyclic monomer in the presence of an initiator and a catalyst (ring-opening polymerization method), or a method of using a block copolymer in the presence of a catalyst or a condensing agent. It can be synthesized by a method in which the same or another block copolymer is bonded to the terminal one by one via each terminal (multiplication method) and a method combining the ring-opening polymerization method and the multiplication method.
- cyclic monomers include D, L-lactide, L-lactide, glycolide, D, L-lactide-co-glycolide, L-lactide-co-glycolide, ⁇ -caprolactone, ⁇ -butyrolactone, ⁇ -valerolactone, ⁇ -caprolactone-co-lactic acid and ⁇ -caprolactone-co-glycolic acid-co-lactic acid.
- polymerization catalysts such as ordinary germanium-based, titanium-based, antimony-based and tin-based catalysts can be used.
- Specific examples of such a polymerization catalyst include tin (II) octoate, antimony trifluoride, zinc powder, dibutyltin (IV) oxide and tin (II) oxalate.
- the method of adding the catalyst to the reaction system is not particularly limited, but is preferably a method in which the catalyst is added in a state of being dispersed in the raw material at the time of charging the raw material, or in a state of being subjected to a dispersion treatment at the start of pressure reduction.
- the amount of the catalyst used is 0.01 to 3% by weight, more preferably 0.05 to 1.5% by weight, in terms of metal atoms, based on the total amount of the monomers used.
- Examples of the metal catalyst for the production by the mulching method include metals such as tin, titanium, lead, zinc, cobalt, iron, lithium and rare earths, and their metal alkoxides, metal halides, organic carboxylates, carbonates, and sulfates. Or an oxide, but a tin compound is preferred from the viewpoint of polymerization reactivity.
- metals such as tin, titanium, lead, zinc, cobalt, iron, lithium and rare earths, and their metal alkoxides, metal halides, organic carboxylates, carbonates, and sulfates. Or an oxide, but a tin compound is preferred from the viewpoint of polymerization reactivity.
- tin compound examples include tin powder, tin (II) chloride, tin (IV) chloride, tin (II) bromide, tin (IV) bromide, ethoxy tin (II), t-butoxy tin (IV), and isopropoxy.
- nonmetallic catalyst and condensing agent used in the production by the mulching method examples include 4,4-dimethylaminopyridine, 4,4-dimethylaminopyridinium p-toluenesulfonate, and 1- [3- (dimethylamino) propyl].
- multiplexing may be performed using a linker molecule having two or more carboxyl groups, isocyanate groups, amino groups or hydroxyl groups.
- linker molecule having two or more carboxyl groups examples include, for example, dicarboxylic acid, citric acid, and multi-branched polymers having two or more carboxyl groups at branch terminals or acid halides of the above dicarboxylic acids, citric acid, and multi-branched polymers.
- Acid anhydrides or esters that is, the carboxylic acid group may be converted to an acid halide structure, an ester structure or an acid anhydride structure.
- examples of the dicarboxylic acid include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, malic acid, tartaric acid, and dodecane diacid.
- examples of the hyperbranched polymer include a hyperbranched polymer and a dendrimer.
- linker molecule having two or more isocyanate groups examples include hexamethylene diisocyanate (HDI), 4,4′-diphenylmethane diisocyanate (MDI), 4,4′-dicyclohexylmethane diisocyanate, cyclohexyl diisocyanate (CHDI) and 2,4 -Toluene diisocyanate (TDI) and the like.
- linker molecule having two or more amino groups include ethylenediamine, putrescine, cadaverine, hexamethylenediamine, and phenylenediamine.
- linker molecule having two or more hydroxyl groups examples include ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, 1,12-dodecanediol, 1,13-tridecanediol, 1,14-tetradecanediol, Examples include 1,15-pentadecanediol, 1,16-hexadecanediol, and oxaaliphatic diol.
- linker molecule having a plurality of carboxyl groups, isocyanate groups, amino groups, and hydroxyl groups in the same molecule When a linker molecule having a plurality of carboxyl groups, isocyanate groups, amino groups, and hydroxyl groups in the same molecule is used as the linker molecule, a branched copolymer having a linker as a branch point can be synthesized.
- the linker having a plurality of carboxyl groups, isocyanate groups, amino groups and hydroxyl groups in the same molecule include 2,2-bis (hydroxymethyl) propionic acid, malic acid, and diaminediol.
- polyalkylene glycol having a carboxyl group, isocyanate group, or amino group at both terminals polyalkylene glycol having a carboxyl group, isocyanate group, or amino group at both terminals and A polyalkylene glycol having a carboxyl group, an isocyanate group, or an amino group can be obtained, and a copolymer can be produced using these as a raw material.
- the polymerization reaction has a living property, that is, if the polymerization reaction can be continuously started from the end of the polymer, the operation of additionally adding the monomer to the block copolymer solution after the polymerization reaction is completed is repeated. Thus, it can be multiplied.
- “residue” means, in principle, a repetition of a chemical structure derived from a monomer in a chemical structure of a block copolymer obtained by polymerizing two or more monomers including the monomer. Say the unit.
- lactic acid CH 3 CH (OH) COOH
- caprolactone ⁇ -caprolactone
- the lactic acid residue is Has a structure represented by the following chemical formula (II)
- the caprolactone residue has a structure represented by the following chemical formula (III).
- the “residue” means one of two-time repeating structures derived from the dimer.
- dilactide ( L -(-)-lactide) represented by the following chemical formula (IV) is polymerized with caprolactone
- the chemical structure of the block copolymer is represented by the above-mentioned chemical formula (II) as a dilactide residue.
- one of them is regarded as a lactic acid residue and two lactic acid residues are formed from dilactide.
- the properties of the block copolymer coated on the cylindrical substrate can be analyzed as follows. For example, the solids obtained by immersing the copolymer coated on the cylindrical substrate in a solvent such as chloroform and drying the extract are subjected to measurements as described in Measurement Examples 1 to 3 described below.
- ⁇ ⁇ Kink radius is an index for evaluating kink resistance.
- the kink radius refers to a minimum loop radius that does not buckle when a loop is formed by a tubular body for an implant and the diameter of the loop is gradually reduced.
- the kink radius can be evaluated by a method described in Measurement Example 10 described later. If the kink radius is too large, after transplantation into the living body, it cannot follow the movement of the surrounding tissue or cannot be transplanted into the bent part. It is preferable because it can easily follow the movement of the tissue and can be easily transplanted to a bent portion, and more preferably 10 mm or less.
- the coating thickness of the block copolymer refers to the thickness of the layer of the block copolymer in the cross section of the tubular body for implant, and the coating thickness of the block copolymer is described in Measurement Example 11 described later. Can be evaluated by the following method.
- the coating thickness of the block copolymer is 1 ⁇ m or more, the pressure resistance is improved, and when the coating thickness of the block copolymer is 500 ⁇ m or less, the time required for decomposition is a suitable time.
- the coating thickness of the block copolymer is preferably 1 ⁇ m to 500 ⁇ m, more preferably 10 ⁇ m to 300 ⁇ m, and still more preferably 20 ⁇ m to 200 ⁇ m.
- the inner diameter of the tubular substrate is preferably from 1 to 10 mm, more preferably from 2 to 4 mm in consideration of the use as an artificial blood vessel or a stent graft.
- An artificial blood vessel is a medical device used to replace a pathological living blood vessel such as arteriosclerosis or to form a bypass or shunt.
- Examples of the material for the artificial blood vessel include cloth, polytetrafluoroethylene, a biomaterial, and a synthetic polymer material, but a cloth is preferable because it can easily provide an anticoagulant ability.
- Patency rate is an index for the evaluation of artificial blood vessels.
- patency using artificial blood vessels as substitute blood vessels in bypass surgery for atherosclerosis of the lower limbs is 60%, whereas that using autologous veins is 80%.
- autologous veins are selected instead of artificial blood vessels in consideration of postoperative occlusion and stenosis.
- an artificial blood vessel having a patency rate equal to or higher than that of an autologous vein that is, an artificial blood vessel having a patency rate of 80% or more is of great significance in clinical practice.
- the anticoagulant ability refers to the property of preventing blood coagulation and suppressing the formation of thrombus.
- Examples of the method of imparting the anticoagulant ability include a technique of applying heparin or a heparin derivative to the surface of a material.
- a stent graft is a medical device that combines a stent and an artificial blood vessel (graft), and is placed in a living blood vessel to be used for treating an aneurysm.
- Reference Example 5 Upon addition to 0.20 g of 4,4-dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.), the amount of polyhydroxyalkanoic acid A added was changed from 14.2 g to 10.1 g, and hydroxyl groups were added to both ends. The addition amount of polyethylene glycol having a weight average molecular weight of 10,000 (from Sigma-Aldrich) to 0.45 g to 2.45 g, and the addition amount of polyethylene glycol having a carboxyl group at both terminals (weight average molecular weight of 10,200) being 0 A block copolymer of Reference Example 5 was obtained in the same manner as in Reference Example 1, except that the respective amounts were changed from .42 g to 2.50 g.
- Reference Example 7 Upon addition to 0.20 g of 4,4-dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.), the amount of polyhydroxyalkanoic acid A added was changed from 14.2 g to 6.75 g, and hydroxyl groups were added to both ends. Of polyethylene glycol (weight average molecular weight 10,000; Sigma-Aldrich) from 0.41 g to 3.27 g, and the addition amount of polyethylene glycol having a carboxyl group at both terminals (weight average molecular weight 10,200) to 0. A block copolymer of Reference Example 7 was obtained in the same manner as in Reference Example 1, except that each was changed from .42 g to 3.33 g.
- Reference Example 9 0.56 g of 4,4-dimethylaminopyridinium p-toluenesulfonate (synthesized by the method described in Messmore, Benjamin W. et al., Journal of the American Chemical Society, 2004, 126, 14452.); When adding 20 g of 4,4-dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.), the addition amount of polyhydroxyalkanoic acid 2 was changed from 9.81 g to 0.33 g, and the addition amount of polyhydroxyalkanoic acid 1 was changed.
- a block copolymer of Reference Example 9 was obtained in the same manner as in Reference Example 8, except that the weight was changed from 5.22 g to 14.7 g.
- a hydrogen atom at the ⁇ -position as a methylene group (chemical shift value is about 2.3 ppm) is a characteristic peak, and this is integrated with all signals.
- the molar ratio is calculated based on the value, and in the case of glycolic acid residue, the hydrogen atom at the ⁇ -position (methylene group) (chemical shift value is about 4.8 ppm) is a characteristic peak.
- the molar ratio is calculated based on the integrated value with the signal.
- four hydrogen atoms of the ethylene group (chemical shift value: about 3.6 ppm) are characteristic peaks. Based on the integral of all signals There was calculated molar ratios.
- W PEG (%) (M EG ⁇ x EG ) / Mx total ⁇ 100 Equation 3
- W PLA (%) (M LA ⁇ x LA ) / Mx total ⁇ 100 Expression 4
- W PCL (%) (M CL ⁇ x CL ) / Mx total ⁇ 100 Equation 5
- W PGA (%) (M GA ⁇ x GA ) / Mx total ⁇ 100 Equation 6
- Mx total M EG ⁇ x EG + M LA ⁇ x LA + M CL ⁇ x CL + M GA ⁇ x GA ...
- W PEG ratio of the total mass of ethylene glycol residues M EG : molecular weight of ethylene glycol residues x EG : molar ratio of ethylene glycol residues
- PLA ratio of total mass of lactate residue
- PCL ratio of total mass of caprolactone residue
- CL molecular weight of caprolactone residue x
- W PGA ratio of total mass of glycolic acid residues
- GA molecular weight of glycolic acid residues x GA : molar ratio of glycolic acid residues
- the Young's modulus of the obtained films comprising the block copolymers of Reference Examples 1 to 9 is measured in order to observe the properties of the film. Specifically, the film made of the block copolymer of Reference Examples 1 to 9 was cut into a strip shape (50 mm ⁇ 5 mm ⁇ 0.1 mm), and the film was cut into a Tensilon Universal Tester RTM-100 (manufactured by Orientec Co., Ltd.).
- the films made of the block copolymers of Reference Examples 1 to 9 were attached so that the distance between the chucks in the longitudinal direction was 10 mm, and a tensile test was performed under the following condition A, and the tensile test was performed according to JIS K6251 (2010).
- the Young's modulus (MPa) of the films made of the block copolymers of Reference Examples 1 to 9 was determined. Obtained. However, there are cases where the Young's modulus is calculated as a slope between two points or a least squares method. Table 1 shows the results.
- Equipment name Tensilon universal tensile tester RTM-100 (made by Orientec Co., Ltd.)
- Initial length 10mm
- Tensile speed 500mm / min
- Load cell 50N Number of tests: 5
- the tension of the warp B was set to 0.9 cN / dtex
- the tension of the warp A was set to 0.1 cN / dtex
- the weaving density after the post-processing was A, 201 / inch (2.54 cm)
- the weft C A tubular woven fabric having an inner diameter of 3.3 mm and a weft yarn D of 121 yarns / inch (2.54 cm) and a weft yarn of 121 yarns / inch (2.54 cm) was woven.
- the warp A and the warp B were arranged at a ratio of one warp B to three warp A. Further, the warp B was disposed between the weft C located in the inner layer and the weft D located in the outer layer.
- the processing conditions were a concentration of 0.2% by mass, a temperature of 130 ° C., and a time of 30 minutes.
- C-2 Alkali treatment Sodium hydroxide was used as the alkali.
- the processing conditions were a concentration of 1% by mass, a temperature of 80 ° C., and a time of 90 minutes.
- D Heat setting (first time) A round bar having an outer diameter of 3.3 mm was inserted into the tubular woven fabric, and both ends were fixed with wires or the like in a state where the rod was maximally compressed so as not to cause wrinkles in the warp direction, and heat treatment was performed.
- the processing conditions were a temperature of 180 ° C. and a time of 5 minutes.
- the material of the round bar was SUS.
- a sea-island fiber (sea / sea) in which the sea component polymer is constituted by polyethylene terephthalate obtained by copolymerizing 5-sodium sulfoisophthalic acid, and the island component polymer is constituted by polyethylene terephthalate.
- This multifilament A ′ becomes the multifilament A by the ultra-fine processing. This was used as a warp and a weft at the time of weaving.
- a multi-tubular woven fabric having an inner diameter of 3.3 mm was woven in a shuttle room and scoured at 98 ° C.
- the sea component of the sea-island conjugate fiber is completely leached by treating with a 4% by mass aqueous solution of sodium hydroxide at 98 ° C. for 20 minutes, and the single filament fineness of the multifilament A ′ is 0.08 dtex (single yarn diameter 2. 9 ⁇ m) and the total fineness was 53 dtex.
- the rod-shaped jig is inserted into the tube, and heat-set in a cylindrical shape at 170 ° C., and the weft density of the outer layer is 21 / 2.54 cm and the weft density of the inner layer is 336. This / 2.54 cm cylindrical base material C was obtained.
- polyester fibers constituting the outer layer of the tubular base material As the polyester fibers constituting the outer layer of the tubular base material, a monofilament having a single yarn fineness of 108 dtex (0.11 mm in diameter) and a multifilament having a single yarn fineness of 2.33 dtex and a total fineness of 56 dtex are prepared and woven. At times, the multifilament was used for the warp and the monofilament was used for the weft. In addition, a multifilament having a single-fiber fineness of 0.23 dtex (single-fiber diameter of 4.7 ⁇ m) and a total fineness of 33 dtex was prepared as a polyester fiber constituting the inner layer of the tubular base material. This was used as a warp and a weft at the time of weaving.
- a multi-tubular woven fabric having an inner diameter of 3.3 mm was woven in a shuttle room and scoured at 98 ° C. Then, it is dried at a dry heat of 120 ° C., a rod-shaped jig is inserted into the tube, and heat-set in a cylindrical shape at 170 ° C., and the weft density of the outer layer is 76 / 2.54 cm and the weft density of the inner layer is 230. Book / 2.54 cm cylindrical substrate D was obtained.
- the cylindrical substrates A to D were subjected to the tests of the following measurement examples 4 to 9, and the 20N load elongation (%), the inner diameter (mm), and the outer diameter (mm) of the cylindrical substrates A to D were obtained. ),
- Tables 2 and 3 show the values of the outer diameter b and (ab) / a, the inner surface roughness ( ⁇ m), and the water permeability (mL / cm 2 / min.) Under a pressure of 16 kPa.
- the mass ratio of the block copolymers provided in the cylindrical substrates A to D to the mass of the cylindrical substrates A to D is less than 1%.
- the mass ratio of the block copolymer constituting the coated cylindrical body to the mass of the cylindrical base material can be measured by the following method.
- the coated cylindrical body is cut out so as to have a length of 0.5 cm in the major axis direction, and the cut-out coated cylindrical body is dissolved in an organic solvent. .
- the solution is subjected to 1 H-NMR measurement at room temperature using JNM-EX270 (manufactured by JEOL Ltd.). Based on the obtained 1 H-NMR peaks, the ratio of the mass of the block copolymer to the mass of the tubular substrate is calculated. Specifically, in the case of an ethylene terephthalate residue, a hydrogen atom of a benzene ring (chemical shift value: about 8.2 ppm) is a characteristic peak.
- the hydrogen atom at the ⁇ -position (chemical shift value: about 5.2 ppm), which is a methine group, is a characteristic peak.
- the molar ratio was calculated, and in the case of a caprolactone residue, the hydrogen atom at the ⁇ -position (methylene group) (chemical shift value is about 2.3 ppm) was a characteristic peak.
- a hydrogen atom at the ⁇ -position (methylene group) (chemical shift value is about 4.8 ppm) is a characteristic peak.
- Equation 7 W cop : mass ratio of the block copolymer provided in the cylindrical substrate to mass of the cylindrical substrate M ET : molecular weight of ethylene terephthalate residue x ET : molar ratio of ethylene terephthalate residue
- the organic solvent to be used is not particularly limited as long as it can dissolve both the tubular base material and the block copolymer, but 1,1,1,3,3,3-hexafluoroisopropanol-D2 is preferably used. .
- the cylindrical substrates A to D are cut so that the length in the long axis direction becomes 150 mm, and the distance between the chucks in the long axis direction becomes 100 mm on a dual column bench type tester INSTRON 5965 (manufactured by Instron Japan).
- the cylindrical substrates A to D were attached to the test pieces, and a tensile test was measured under the following condition B in accordance with ISO 7198 (2016).
- the elongation ratio (%) of the cylindrical substrates A to D when a load of 20 N was applied was determined from the following equation (10).
- FIG. 1 is an explanatory diagram for drawing a marking line on a tubular base material. As shown in FIG. 1, a first marking line 2 is placed on the outer periphery of the base material 5 mm from one end of the tubular base material.
- a second marked line 3 is drawn from the first marked line to the outer periphery of the tubular base material at a distance A five times the maximum value of the outer diameter of the tubular base material.
- the cylindrical substrate is cut in the radial direction at a position 5 mm from the second mark line.
- FIG. 2 is a conceptual diagram of an apparatus for measuring the distance (mm) between the marked lines of the cylindrical substrates A to D when compressed.
- a load measuring device force gauge
- HANDY DIGITAL FORCE GAUGE HF-1 rated capacity 10 N
- Japan Measurement System Co., Ltd. Is attached to the load measuring device 4
- a compression receiving jig 7 having a hole into which the core rod can be inserted is attached to the gantry 5.
- the core material of the compression chuck jig 6 was passed through the cylindrical base materials A to D and set in the above-described apparatus, and the mark line distance L1 (compression mark when compressed) with a stress of 0.01 cN / dtex in the long axis direction was applied. The distance between lines) was measured with a caliper.
- FIG. 3 is a conceptual diagram of an apparatus for measuring the distance between the marked lines at the time of elongation of the tubular base material. As shown in FIG. 3, the apparatus is a load measuring device (force gauge) 4. , HANDY DIGITAL FORCE GAUGE HF-1 (rated capacity 10N) manufactured by Nippon Keisoku System Co., Ltd.
- the extension chuck jig 8 is attached to the load measuring device 4, and the extension receiving jig 9 is attached to the base 5. It is attached to.
- the outside of the marked line of the tubular base material 1 is fixed with a fixed string 10, and the distance L2 between the marked lines when extended with a stress of 0.01 cN / dtex in the major axis direction (the distance between the marked lines when stretched) is measured with a caliper. It was measured. Table 3 shows the results.
- the core members of the compression chuck jig 6 shown in FIG. 2 are passed through the cylindrical base materials A to D and set in the apparatus shown in FIG. 2, and the cylindrical base materials A to D are set to 0.01 cN in the longitudinal direction.
- the outer diameter is measured at five points in the longitudinal direction at intervals of 50 mm with a vernier caliper in a state of being stretched by a stress of / dtex, and the average value of the obtained measurement results is calculated for each of the cylindrical substrates A to D under “Extended Diameter b ".
- Example 1 The block copolymer of Reference Example 1 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical substrate A made of polyethylene terephthalate fiber to form a coating layer. 1 was obtained.
- Example 2 A coated tubular body was prepared in the same manner as in Example 1, except that the block copolymer of Reference Example 2 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 2 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical substrate A made of polyethylene terephthalate fiber, and the coating layer was formed. The coated cylindrical body of Example 2 was obtained.
- Example 3 A coated cylindrical body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 3 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 3 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical substrate A made of polyethylene terephthalate fiber, and the coating layer was formed. Thus, a coated cylindrical body of Example 3 was obtained.
- Example 4 A coated cylindrical body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 4 was used instead of the block copolymer of Reference Example 1. A measurement was made. Specifically, the block copolymer of Reference Example 4 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material A made of polyethylene terephthalate fiber to form a coating layer. The coated cylindrical body of Example 4 was obtained.
- Example 5 A coated cylindrical body was prepared in the same manner as in Example 2, except that a cylindrical base material B made of polyethylene terephthalate fiber was used instead of the cylindrical base material A made of polyethylene terephthalate fiber. Specifically, the block copolymer of Reference Example 2 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to the tubular substrate B described above to form a coating layer. Thus, a coated cylindrical body of Example 5 was obtained.
- Example 1 A coated cylindrical body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 5 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 5 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material A made of polyethylene terephthalate fiber to form a coating layer. Thus, a coated cylindrical body of Comparative Example 1 was obtained.
- Comparative Example 2 A coated cylindrical body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 6 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 6 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical substrate A made of polyethylene terephthalate fiber, and the coating layer was formed. Thus, a coated tubular body of Comparative Example 2 was obtained.
- Example 3 A coated cylindrical body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 7 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 7 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical substrate A made of polyethylene terephthalate fiber, and the coating layer was formed. The coated cylindrical body of Comparative Example 3 was obtained.
- Example 4 A coated tubular body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 8 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 8 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical substrate A made of polyethylene terephthalate fiber, and the coating layer was formed. Thus, a coated cylindrical body of Comparative Example 4 was obtained.
- Example 5 A coated cylindrical body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 9 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 9 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material A made of polyethylene terephthalate fiber to form a coating layer. Thus, a coated cylindrical body of Comparative Example 5 was obtained.
- Comparative Example 6 Coating was performed in the same manner as in Example 1 except that the cylindrical base material A was changed to the cylindrical base material B, and the block copolymer of Reference Example 1 was used instead of the block copolymer of Reference Example 1.
- a cylindrical body was prepared. Specifically, the block copolymer of Reference Example 5 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material B made of polyethylene terephthalate fiber to form a coating layer. Thus, a coated cylindrical body of Comparative Example 6 was obtained.
- Example 7 A coated cylindrical body was prepared in the same manner as in Example 2 except that the cylindrical base material A was changed and the cylindrical base material C was used. Specifically, the block copolymer of Reference Example 2 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material C made of polyethylene terephthalate fiber to form a coating layer. The coated cylindrical body of Comparative Example 7 was obtained.
- Example 8 The tubular base material A was changed to the tubular base material C, and further coated in the same manner as in Example 1 except that the block copolymer of Reference Example 5 was used instead of the block copolymer of Reference Example 1.
- a cylindrical body was made. Specifically, the block copolymer of Reference Example 5 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material C made of polyethylene terephthalate fiber to form a coating layer. Thus, a coated cylindrical body of Comparative Example 8 was obtained.
- Example 9 A coated cylindrical body was prepared in the same manner as in Example 2 except that the cylindrical base material A was changed and the cylindrical base material D was used. Specifically, the block copolymer of Reference Example 2 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material D made of polyethylene terephthalate fiber to form a coating layer. Thus, a coated cylindrical body of Comparative Example 9 was obtained.
- Example 6 A coated cylindrical body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 14 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 14 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material A made of polyethylene terephthalate fiber to form a coating layer. The coated cylindrical body of Example 6 was obtained.
- Example 10 A coated cylindrical body was prepared in the same manner as in Example 1 except that the block copolymer of Reference Example 15 was used instead of the block copolymer of Reference Example 1. Specifically, the block copolymer of Reference Example 15 was dissolved in chloroform to prepare a solution having a concentration of 20% by weight, and this solution was applied to a cylindrical base material A made of polyethylene terephthalate fiber to form a coating layer. A coated cylindrical body of Comparative Example 10 was obtained.
- Table 4 below shows the ratio (%) of the total mass of glycolic acid residues to the total and Young's modulus (MPa) when the block copolymer was formed into a film.
- the test level and the pump were connected by a silicon tube, and the prepared circuit was filled with the diluted PRP and circulated at room temperature for 30 minutes. Then, the test level was taken out and the length was measured.
- test level after circulation was punched out with a biopsy trepan ( ⁇ 6 mm), and washed three times with PBS ( ⁇ ).
- the number of platelets adhering to the test level after washing was calculated by using LDH Cytotoxicity Detection Kit (manufactured by Takara Bio Inc.). At this time, the number of platelets adhered to the coated cylindrical body of Example 1 was set to 100%, and relative comparison was performed for the other Examples and Comparative Examples. Table 5 shows the results.
- male beagle dogs were administered aspirin and dipyridamole from 2 days before transplantation to the date of removal. Isoflurane inhalation anesthesia was performed. After incising the cervix to expose the carotid artery, 100 IU / kg of heparin was intravenously administered for systemic heparinization. The blood flow was blocked and the coated cylinder (3 cm) was implanted into the carotid artery by end-to-end anastomosis. Blood flow was resumed, closed, and awakened from anesthesia.
- Table 6 shows the patency (%) of the coated tubular bodies for implants of Examples 1, 2, 4, 5, and 6 and Comparative Examples 1, 6, 7, 8, 9, and 10.
- the present invention can be suitably used for medical applications relating to implants such as artificial blood vessels or stent grafts.
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Abstract
Description
(1) 20Nの引っ張り荷重をかけた条件下で長軸方向の伸長率が5~100%である筒状基材と、ポリアルキレングリコールブロック及びポリヒドロキシアルカン酸ブロックからなるブロック共重合体と、を備え、上記ブロック共重合体の全質量に対するアルキレングリコール残基の全質量の比率は、5~25%であり、上記ブロック共重合体は、フィルムにした際のヤング率が200MPa以下である、インプラント用の筒状体。
(2) 上記ポリヒドロキシアルカン酸ブロックは、乳酸、グリコール酸及びカプロラクトンからなる群から選択される残基を含む、(1)記載の筒状体。
(3) 上記ポリヒドロキシアルカン酸ブロックは、カプロラクトン残基を含み、上記ブロック共重合体の全質量に対するカプロラクトン残基の全質量の比率は、15~80%である、(2)記載の筒状体。
(4) 上記ポリヒドロキシアルカン酸ブロックは、グリコール酸残基を含み、上記ブロック共重合体の全質量に対するグリコール酸残基の全質量の比率は、10%以下である、(2)又は(3)記載の筒状体。
(5) 上記筒状基材は、下記式1を満たす、(1)~(4)のいずれか記載の筒状体。
(L2-L1)/L1≧0.1 ・・・式1
L1: 上記筒状基材に応力を加えない状態で測定したときの外径において、該外径の最大値の5倍の距離で筒状基材の外周上に標線を引き、該筒状基材の長軸方向に0.01cN/dtexの応力で圧縮した時の標線間距離。
L2: 長軸方向に0.01cN/dtexの応力で伸長した時の標線間距離。
(6) 上記筒状基材は、以下の式2を満たす、(1)~(5)のいずれか記載の筒状体。
0.03≦(a-b)/a<0.2 ・・・式2
a: 長軸方向に0.01cN/dtexの応力で圧縮したときの該筒状基材の外径
b: 長軸方向に0.01cN/dtexの応力で伸長したときの該筒状基材の外径
(7) 上記筒状基材の内表面粗さは、100μm以下である、(1)~(6)のいずれか記載の筒状体。
(8) (1)~(7)のいずれか記載の筒状体を備える、人工血管。
(9) (1)~(7)のいずれか記載の筒状体を備える、ステントグラフト。
(L2-L1)/L1≧0.1 ・・・式1
L1:上記筒状基材に応力を加えない状態で測定したときの織物外径において、その織物外径の最大値の5倍の距離で筒状基材の外周上に標線を引き、該筒状基材の長軸方向に0.01cN/dtexの応力で圧縮した時の標線間距離。
L2:長軸方向に0.01cN/dtexの応力で伸長した時の標線間距離。
0.03≦(a-b)/a<0.2 ・・・式2
a:長軸方向に0.01cN/dtexの応力で圧縮したときの該筒状基材の外径
b:長軸方向に0.01cN/dtexの応力で伸長したときの該筒状基材の外径
機器名:Prominence(株式会社島津製作所製)
移動相:クロロホルム(HPLC用)(和光純薬工業株式会社製)
流速:1mL/min
カラム:TSKgel GMHHR-M(φ7.8mm×300mm;東ソー株式会社製)
検出器:UV(254nm)、RI
カラム、検出器温度:35℃
標準物質:ポリスチレン
アミノ基を2以上有するリンカー分子としては、エチレンジアミン、プトレシン、カダベリン、ヘキサメチレンジアミン及びフェニレンジアミン等が挙げられる。
50.0gのL-ラクチド(PURASORB(登録商標) L;PURAC社製)と、38.5mLのεーカプロラクトン(和光純薬工業株式会社製)とを、モノマーとしてセパラブルフラスコに採取した。これらをアルゴン雰囲気下とし、14.5mLのトルエン(超脱水)(和光純薬工業株式会社製)に溶解した触媒である0.29gのオクチル酸スズ(II)(和光純薬工業株式会社製)、開始剤として90μLのイオン交換水を添加し、90℃で1時間、助触媒反応を行った。その後、150℃で6時間、共重合反応させて、粗ポリヒドロキシアルカン酸Aを得た。
0.20gの4,4-ジメチルアミノピリジン(和光純薬工業株式会社製)への添加の際、ポリヒドロキシアルカン酸Aの添加量を14.2gから13.4gに、両末端にヒドロキシ基を有するポリエチレングリコール(重量平均分子量10,000;シグマアルドリッチ社製)の添加量を0.41gから0.82gに、両末端カルボキシル基を有するポリエチレングリコール(重量平均分子量10,200)の添加量を0.42gから0.83gにそれぞれ変更した以外は、参考例1と同様の方法を用い、参考例2のブロック共重合体を得た。
0.20gの4,4-ジメチルアミノピリジン(和光純薬工業株式会社製)への添加の際、ポリヒドロキシアルカン酸Aの添加量を14.2gから11.7gに、両末端にヒドロキシ基を有するポリエチレングリコール(重量平均分子量10,000;シグマアルドリッチ社製)の添加量を0.41gから1.63gに、両末端カルボキシル基を有するポリエチレングリコール(重量平均分子量10,200)の添加量を0.42gから1.67gにそれぞれ変更した以外は、参考例1と同様の方法を用い、参考例3のブロック共重合体を得た。
0.20gの4,4-ジメチルアミノピリジン(和光純薬工業株式会社製)への添加の際、ポリヒドロキシアルカン酸Aの添加量を14.2gから10.9gに、両末端にヒドロキシ基を有するポリエチレングリコール(重量平均分子量10,000;シグマアルドリッチ社製)の添加量を0.41gから2.04gに、両末端カルボキシル基を有するポリエチレングリコール(重量平均分子量10,200)の添加量を0.42gから2.08gにそれぞれ変更した以外は、参考例1と同様の方法を用い、参考例4のブロック共重合体を得た。
0.20gの4,4-ジメチルアミノピリジン(和光純薬工業株式会社製)への添加の際、ポリヒドロキシアルカン酸Aの添加量を14.2gから10.1gに、両末端にヒドロキシ基を有するポリエチレングリコール(重量平均分子量10,000;シグマアルドリッチ社製)の添加量を0.41gから2.45gに、両末端カルボキシル基を有するポリエチレングリコール(重量平均分子量10,200)の添加量を0.42gから2.50gにそれぞれ変更した以外は、参考例1と同様の方法を用い、参考例5のブロック共重合体を得た。
0.20gの4,4-ジメチルアミノピリジン(和光純薬工業株式会社製)への添加の際、ポリヒドロキシアルカン酸Aの添加量を14.2gから8.40gに、両末端にヒドロキシ基を有するポリエチレングリコール(重量平均分子量10,000;シグマアルドリッチ社製)の添加量を0.41gから3.27gに、両末端カルボキシル基を有するポリエチレングリコール(重量平均分子量10,200)の添加量を0.42gから3.33gにそれぞれ変更した以外は、参考例1と同様の方法を用い、参考例6のブロック共重合体を得た。
0.20gの4,4-ジメチルアミノピリジン(和光純薬工業株式会社製)への添加の際、ポリヒドロキシアルカン酸Aの添加量を14.2gから6.75gに、両末端にヒドロキシ基を有するポリエチレングリコール(重量平均分子量10,000;シグマアルドリッチ社製)の添加量を0.41gから3.27gに、両末端カルボキシル基を有するポリエチレングリコール(重量平均分子量10,200)の添加量を0.42gから3.33gにそれぞれ変更した以外は、参考例1と同様の方法で作成し、参考例7のブロック共重合体を得た。
70.7gのL-ラクチド(PURASORB(登録商標) L;PURAC社製)と、19.0gのグリコリド(PURAC社製)とを、モノマーとしてセパラブルフラスコに採取した。これらをアルゴン雰囲気下とし、14.5mLのトルエン(超脱水)(和光純薬工業株式会社製)に溶解した触媒である0.29gのオクチル酸スズ(II)(和光純薬工業株式会社製)、開始剤として388μLのイオン交換水を添加し、90℃で1時間、助触媒反応を行った。その後、130℃で6時間、共重合反応させて、粗ポリヒドロキシアルカン酸2を得た。
0.56gのp-トルエンスルホン酸4,4-ジメチルアミノピリジニウム(Messmore,Benjamin W. et al.,Journal of the American Chemical Society,2004,126,14452.に記載の方法で合成)と、0.20gの4,4-ジメチルアミノピリジン(和光純薬工業株式会社製)の添加の際、ポリヒドロキシアルカン酸2の添加量を9.81gから0.33gに、ポリヒドロキシアルカン酸1の添加量を5.22gから14.7gに変更した以外は、参考例8と同様の方法で作成し、参考例9のブロック共重合体を得た。
参考例1~9のブロック共重合体を重クロロホルムに溶解し、JNM-EX270(日本電子株式会社製)を用いて室温で、1H-NMRで測定した。得られた1H-NMRの各ピークを元に、参考例1~9のブロック共重合体中の乳酸残基及びカプロラクトン残基及びエチレングリコール残基のモル比率をそれぞれ算出した。具体的には、乳酸残基であれば、メチン基であるα位の水素原子(化学シフト値:約5.2ppm)が特徴的なピークであるため、これを全シグナルとの積分値に基づいてモル比率を算出し、カプロラクトン残基の場合には、メチレン基であるα位の水素原子(化学シフト値が約2.3ppm)が特徴的なピークであるため、これを全シグナルとの積分値に基づいてモル比率を算出し、グリコール酸残基の場合には、メチレン基であるα位の水素原子(化学シフト値が約4.8ppm)が特徴的なピークであるため、これを全シグナルとの積分値に基づいてモル比率を算出し、エチレングリコール残基の場合には、エチレン基の4つの水素原子(化学シフト値:約3.6ppm)が特徴的なピークであるため、これを全シグナルとの積分値に基づいてモル比率を算出した。
WPEG(%)=(MEG×xEG)/Mxtotal×100 ・・・式3
WPLA(%)=(MLA×xLA)/Mxtotal×100 ・・・式4
WPCL(%)=(MCL×xCL)/Mxtotal×100 ・・・式5
WPGA(%)=(MGA×xGA)/Mxtotal×100 ・・・式6
Mxtotal=MEG×xEG+MLA×xLA+MCL×xCL+MGA×xGA ・・・式7
WPEG:エチレングリコール残基の全質量の比率
MEG:エチレングリコール残基の分子量
xEG:エチレングリコール残基のモル比
WPLA:乳酸残基の全質量の比率
MLA:乳酸残基の分子量
xLA:乳酸残基のモル比
WPCL:カプロラクトン残基の全質量の比率
MCL:カプロラクトン残基の分子量
xCL:カプロラクトン残基のモル比
WPGA:グリコール酸残基の全質量の比率
MGA:グリコール酸残基の分子量
xGA:グリコール酸残基のモル比
得られた参考例1~9のブロック共重合体からなるフィルムについて、フィルム状態の特性を観察するため、ヤング率を測定する。具体的には、参考例1~9のブロック共重合体からなるフィルムを短冊状(50mm×5mm×0.1mm)に切りだし、テンシロン万能試験機RTM-100(株式会社オリエンテック製)に対し、参考例1~9のブロック共重合体からなるフィルムを長さ方向のチャック間距離が10mmになるよう取り付け、下記の条件Aで引張試験を行い、JIS K6251(2010)に従って測定し、ε1=0.2%及びε2=0.3%のひずみ2点間に対応する応力/ひずみ曲線の傾きを読み取ることで、参考例1~9のブロック共重合体からなるフィルムのヤング率(MPa)を得た。ただし、2点間又は最小二乗法による傾きとしてヤング率を計算する場合がある。結果を表1に示す。
(条件A)
機器名:テンシロン万能引張試験機RTM-100(株式会社オリエンテック製)
初期長:10mm
引張速度:500mm/min
ロードセル:50N
試験回数:5回
得られた参考例1~9のブロック共重合体からなるフィルムについて、さらにフィルム状態の特性を観察するため、膨潤率を測定する。具体的には、測定例2と同様の手順で。作成した短冊状(50mm×5mm×0.1mm)の参考例1~9のブロック共重合体からなるフィルムをプラスチックチューブに入れ、フィルム全体が浸るようにイオン交換水(15mL)を加えた。このプラスチックチューブを37℃に設定したインキュベーター内で3時間振盪させたあと、フィルムを取り出し、長辺長さを測定した。得られた長辺長さから、下記の式8を用いて、参考例1~9のブロック共重合体からなるフィルムの膨潤率(%)を算出した。結果を表1に示す。
膨潤率(%)=(Lw-Ld)/(Ld)×100 ・・・式8
Ld:乾燥時(イオン交換水浸漬前)の長辺長さ(cm)
Lw:湿潤時(イオン交換水浸漬後)の長辺長さ(cm)
製織工程において、下記の経糸(経糸A、経糸B)及び緯糸(緯糸C、緯糸D)を使用した。
・経糸A(海島複合繊維):ポリエチレンテレフタレート繊維、66dtex、9フィラメント(脱海処理後:52.8dtex、630フィラメント)
・経糸B(溶解糸):5-ナトリウムスルホイソフタル酸を共重合した易アルカリ溶解性のポリエステル繊維、84dtex、24フィラメント
・緯糸C(内層)(海島複合繊維):ポリエチレンテレフタレート繊維、66dtex、9フィラメント(脱海処理後:52.8dtex、630フィラメント)
・緯糸D(外層):ポリエチレンテレフタレート繊維、56dtex、18フィラメント
(a)湯洗
処理条件は、温度98℃、時間20分で行った。
(b)プレ熱セット
外径2.8mmの丸棒を筒状織物に挿入し、両端を針金で固定して、熱処理を行った。処理条件は、温度180℃、時間5分であった。なお、前記丸棒の材質は、SUSであった。
(c)脱海処理
前記の経糸A、緯糸Cの脱海処理を行うとともに、経糸Bの溶解除去を行った。
(c-1)酸処理
酸としては、マレイン酸を使用した。処理条件は、濃度0.2質量%、温度130℃、時間30分であった。
(c-2)アルカリ処理
アルカリとしては、水酸化ナトリウムを使用した。処理条件は、濃度1質量%、温度80℃、時間90分であった。
(d)熱セット(1回目)
外径3.3mmの丸棒を筒状織物に挿入し、経糸方向にシワが入らないよう最大限圧縮した状態で、両端を針金等で固定して、熱処理を行った。処理条件は、温度180℃、時間5分であった。なお、前記丸棒の材質は、SUSであった。
(e)熱セット(2回目)
外径3.3mmの丸棒を筒状織物に挿入し、経糸方向に30%伸長した状態で、両端を針金等で固定して、熱処理を行った。処理条件は、温度170℃、時間5分であった。なお、前記丸棒の材質は、SUSであった。
熱セット(1回目)及び熱セット(2回目)において、使用する丸棒の外径を外径3.3mmの丸棒から外径3.0mmの丸棒に変更し、さらに熱セット(2回目)において、経糸方向に30%伸長した状態で両端を固定することに変えて経糸方向に伸長せず針金で固定した以外は、参考例10と同様の方法で筒状基材を作成し、筒状基材Bを得た。
筒状基材の外層を構成するポリエステル繊維として、単糸繊度が180dtex(直径0.13mm)のモノフィラメントと、単糸繊度が2.33dtex、総繊度56dtexのマルチフィラメントとを準備し、これを製織時には、経糸に前記マルチフィラメントを使用し、緯糸に前記モノフィラメントを使用した。また、筒状基材の内層を構成するポリエステル繊維として、海成分ポリマーが5-ナトリウムスルホイソフタル酸を共重合したポリエチレンテレフタレートで構成され、島成分ポリマーがポリエチレンテレフタレートで構成される海島繊維(海/島(質量比)=20/80の比率にて、島成分の数70)で単糸繊度が7.3dtex、総繊度66dtexのマルチフィラメントA´を使用した。このマルチフィラメントA´は極細化処理によりマルチフィラメントAとなる。これを製織時には、経糸並びに緯糸として使用した。
筒状基材の外層を構成するポリエステル繊維として、単糸繊度が108dtex(直径0.11mm)のモノフィラメントと、単糸繊度が2.33dtex、総繊度56dtexのマルチフィラメントとを準備し、これを製織時には、経糸に前記マルチフィラメントを使用し、緯糸に前記モノフィラメントを使用した。また、筒状基材の内層を構成するポリエステル繊維として単糸繊度が0.23dtex(単糸直径4.7μm)、総繊度33dtexのマルチフィラメントを準備した。これを製織時には、経糸並びに緯糸として使用した。
Wcop(%)=Mxtotal/(MET×xET)×100 ・・・式9
Mxtotal=MEG×xEG+MLA×xLA+MCL×xCL+MGA×xGA ・・・式7
Wcop:筒状基材の質量に対する、筒状基材に備わるブロック共重合体の質量比率
MET:エチレンテレフタレート残基の分子量
xET:エチレンテレフタレート残基のモル比
用いる有機溶媒は筒状基材とブロック共重合体の両方を溶解させるものであれば特に限定はされないが、好ましくは1,1,1,3,3,3-ヘキサフルオロイソプロパノール-D2が用いられる。
筒状基材A~Dを長軸方向の長さが150mmとなるようにカットし、デュアルコラム卓上型試験機INSTRON5965(インストロンジャパン社製)に長軸方向のチャック間距離が100mmになるように筒状基材A~Dを取り付け、ISO7198(2016)に従い、下記の条件Bで引張試験を測定した。20Nの負荷がかかった際の筒状基材A~D筒状体の伸長率(%)を下記式10から求めた。
(条件B)
機器名:デュアルコラム卓上型試験機INSTRON5965(インストロンジャパン社製)
初期長:100mm
引張速度:50mm/min
ロードセル:1kN
試験回数:5回
伸長率(%)=20Nの負荷がかかった際の筒状基材の長さ(mm)/初期長(mm)×100 ・・・式10
筒状基材A~Dの内径については、ISO7198のガイダンスに則り測定した。具体的には、テーパー度1/10以下の円錐を垂直にたて、その上に筒状基材を径方向に切断した断面を被せるように垂直にそっと落とし、止まったサンプルの下端位置の円錐の径を測定した。長軸方向に50mm間隔で切断し、5箇所測定を行い、得られた測定結果の平均値を筒状基材A~Dのそれぞれの内径(mm)とした。また、筒状基材A~Dの外径については、筒状基材に応力を加えない状態で長軸方向に50mm間隔で5箇所、ノギスで外径を測定し、得られた測定結果の平均値を筒状基材A~Dのそれぞれの外径(mm)とした。結果を表2に示す。
測定例5で得られた筒状基材に応力を加えない状態における筒状基材A~Dの外径(mm)から、圧縮時標線間距離(mm)を測定した。図1は、筒状基材に標線を引くための説明図であるが、この図1に示す通り、筒状基材の一方端部から5mmの基材外周に1本目の標線2を引き、この1本目の標線から筒状基材の外径の最大値の5倍の距離Aで筒状基材の外周に2本目の標線3を引く。この2本目の標線から5mmの位置で、筒状基材を径方向に切断する。
筒状基材A~Dに、図2記載の圧縮用チャック治具6の芯棒部を通して図2記載の装置にセットし、筒状基材A~Dを長軸方向に0.01cN/dtexの応力で圧縮した状態で長軸方向に50mm間隔で5箇所、ノギスで外径を測定し、得られた測定結果の平均値を筒状基材A~Dのそれぞれの「圧縮時外径a」とした。
また、筒状基材A~Dに、図2記載の圧縮用チャック治具6の芯棒部を通して図2記載の装置にセットし、筒状基材A~Dを長軸方向に0.01cN/dtexの応力で伸長した状態で長軸方向に50mm間隔で5箇所、ノギスで外径を測定し、得られた測定結果の平均値を筒状基材A~Dのそれぞれの「伸長時外径b」とした。
筒状基材A~Dを長軸方向に切断した断面を電子顕微鏡にて150倍に拡大した写真をもとに、筒状基材A~Dの内表面のDsとDlを測定し、DsとDlの差から内表面粗さを求めた。図4はDsとDlの例である。視野を変えて5回測定を行い、平均値で評価した。平均値を「筒状基材の内表面粗さ」とした。結果を表3に示す。
筒状基材A~Dの両末端にジョイント(アイシス社製)を取り付け、シリコンチューブを繋いだ。筒状基材の内表面に16kPaの圧力がかかるように、片方のシリコンチューブから水を流す一方で、もう片方のシリコンチューブを鉗子で挟み、シリコンチューブから水が流れ出ないようにした。この状態で約1分間水を流し、筒状基材A~Dの外表面から流れ出てくる水の量(mL)を測定し、この値を、筒状基材A~Dの外表面の面積(cm2)及び水を流していた時間(min.)で除した値から、筒状基材A~Dの16kPa圧力下における透水性(mL/cm2/min.)を得た。結果を表3に示す。
参考例1のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて実施例1の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例2のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例2のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて実施例2の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例3のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例3のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて実施例3の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例4のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。測定を行った。具体的には、参考例4のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて実施例4の被覆された筒状体を得た。
ポリエチレンテレフタレート繊維からなる筒状基材Aに変えてポリエチレンテレフタレート繊維からなる筒状基材Bを用いた以外は実施例2と同様の方法で被覆された筒状体を作成した。具体的には、参考例2のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液を上記記載の筒状基材Bに塗布し、被覆層を形成させて実施例5の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例5のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例5のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて比較例1の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例6のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例6のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて比較例2の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例7のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例7のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて比較例3の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例8のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例8のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて比較例4の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例9のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例9のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて比較例5の被覆された筒状体を得た。
筒状基材Aを筒状基材Bに変え、さらに、参考例1のブロック共重合体に変えて参考例5のブロック共重合体を用いた以外は、実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例5のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Bに塗布し、被覆層を形成させて比較例6の被覆された筒状体を得た。
筒状基材Aを変えて、筒状基材Cを用いた以外は実施例2と同様の方法で被覆された筒状体を作成した。具体的には、参考例2のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Cに塗布し、被覆層を形成させて比較例7の被覆された筒状体を得た。
筒状基材Aを筒状基材Cに変え、さらに、参考例1のブロック共重合体に変えて参考例5のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例5のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Cに塗布し、被覆層を形成させて比較例8の被覆された筒状体を得た。
筒状基材Aを変えて、筒状基材Dを用いた以外は実施例2と同様の方法で被覆された筒状体を作成した。具体的には、参考例2のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Dに塗布し、被覆層を形成させて比較例9の被覆された筒状体を得た。
25.0gのL-ラクチド(PURASORB(登録商標) L;PURAC社製)と、57.8mLのεーカプロラクトン(和光純薬工業株式会社製)とを、モノマーとしてセパラブルフラスコに採取した。これらをアルゴン雰囲気下とし、14.5mLのトルエン(超脱水)(和光純薬工業株式会社製)に溶解した触媒である0.29gのオクチル酸スズ(II)(和光純薬工業株式会社製)、開始剤として90μLのイオン交換水を添加し、90℃で1時間、助触媒反応を行った。その後、150℃で6時間、共重合反応させて、粗ポリヒドロキシアルカン酸Bを得た。
得られたポリヒドロキシアルカン酸Bを10.1g、両末端にヒドロキシ基を有するポリエチレングリコール(重量平均分子量10,000;シグマアルドリッチ社製)を2.45g、両末端カルボキシル基を有するポリエチレングリコール(重量平均分子量10,200)を2.50g混合し、触媒として0.56gのp-トルエンスルホン酸4,4-ジメチルアミノピリジニウム(非特許文献1記載の方法で合成)と、0.20gの4,4-ジメチルアミノピリジン(和光純薬工業株式会社製)を添加した。これらをアルゴン雰囲気下とし、28mLのジクロロメタン(脱水)(和光純薬工業株式会社製)に溶解し、7mLのジクロロメタンに溶解した縮合剤である2.06gのジシクロヘキシルカルボジイミド(シグマアルドリッチ社製)を添加し、室温で2日間縮合重合させた。
参考例1のブロック共重合体に変えて、参考例14のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例14のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて実施例6の被覆された筒状体を得た。
参考例1のブロック共重合体に変えて、参考例15のブロック共重合体を用いた以外は実施例1と同様の方法で被覆された筒状体を作成した。具体的には、参考例15のブロック共重合体をクロロホルムに溶解し、濃度が20重量%の溶液を調製し、この溶液をポリエチレンテレフタレート繊維からなる筒状基材Aに塗布し、被覆層を形成させて比較例10の被覆された筒状体を得た。
実施例1~6並びに比較例4,5及び7~10の被覆された筒状体に対し非内圧下でループを形成し、ループに対して半径がR(mm)のチューブを挿入し、ループ径を徐々に小さくしていった。ループ径がチューブ径に達するまでに被覆された筒状体が座屈するかどうかを確認し、座屈しなかった場合、その被覆された筒状体のキンク半径をR(mm)以下であるとした。結果を表5に示す。
実施例1~6及び比較例1~10の被覆された筒状体を円周方向に切断し、断面におけるブロック共重合体層の厚みをSEMで測定した。視野を変えて5回測定し、得られたブロック共重合体層の厚みの平均値を被覆厚(μm)とした。結果を表5に示す。
クエン酸加ブタ血液を130gで15分間遠心し、上清を回収した。回収した上清に生理食塩水を加え、希釈PRPとした。
湿潤時伸長率(%)=(D2-D1)/(D1)×100 ・・・式11
D1:循環試験前の被覆された筒状体の長さ(cm)
D2:循環試験後の被覆された筒状体の長さ(cm)
実施例1、2、4、5及び6並びに比較例1、6、7、8、9及び10の被覆された筒状体を用いて、イヌ移植試験を行った。頸動脈に対し、端端吻合で被覆された筒状体(3cm)の移植を10例行い、移植3ヶ月後、エコー検査にて開存しているかどうかを確認した。
P=Np/Na×100 ・・・式12
P:開存率(%)
Np:移植3ヶ月後まで開存した被覆された筒状体の数(本)
Na:移植した被覆された筒状体の数(本)
Claims (9)
- 20Nの引っ張り荷重をかけた条件下で長軸方向の伸長率が5~100%である筒状基材と、
ポリアルキレングリコールブロック及びポリヒドロキシアルカン酸ブロックからなるブロック共重合体と、
を備え、
前記ブロック共重合体の全質量に対するアルキレングリコール残基の全質量の比率は、5~25%であり、
前記ブロック共重合体は、フィルムにした際のヤング率が200MPa以下である、インプラント用の筒状体。 - 前記ポリヒドロキシアルカン酸ブロックは、乳酸、グリコール酸及びカプロラクトンからなる群から選択される残基を含む、請求項1記載の筒状体。
- 前記ポリヒドロキシアルカン酸ブロックは、カプロラクトン残基を含み、
前記ブロック共重合体の全質量に対するカプロラクトン残基の全質量の比率は、15~80%である、請求項2記載の筒状体。 - 前記ポリヒドロキシアルカン酸ブロックは、グリコール酸残基を含み、
前記ブロック共重合体の全質量に対するグリコール酸残基の全質量の比率は、10%以下である、請求項2又は3記載の筒状体。 - 前記筒状基材は、下記式1を満たす、請求項1~4のいずれか一項記載の筒状体。
(L2-L1)/L1≧0.1 ・・・式1
L1: 前記筒状基材に応力を加えない状態で測定したときの外径において、該外径の最大値の5倍の距離で筒状基材の外周上に標線を引き、該筒状基材の長軸方向に0.01cN/dtexの応力で圧縮した時の標線間距離。
L2: 長軸方向に0.01cN/dtexの応力で伸長した時の標線間距離。 - 前記筒状基材は、以下の式2を満たす、請求項1~5のいずれか一項記載の筒状体。
0.03≦(a-b)/a<0.2 ・・・式2
a: 長軸方向に0.01cN/dtexの応力で圧縮したときの該筒状基材の外径
b: 長軸方向に0.01cN/dtexの応力で伸長したときの該筒状基材の外径 - 前記筒状基材の内表面粗さは、100μm以下である、請求項1~6のいずれか一項記載の筒状体。
- 請求項1~7のいずれか一項記載の筒状体を備える、人工血管。
- 請求項1~7のいずれか一項記載の筒状体を備える、ステントグラフト。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01195862A (ja) * | 1987-06-09 | 1989-08-07 | Yissum Res Dev Co Of Hebrew Univ Of Jerusalem | ポリエーテルグリコール系の生物分解性ポリマー材料,その製造法及びそれから作った外科用製品 |
WO1996021056A1 (fr) | 1995-01-04 | 1996-07-11 | Mitsubishi Chemical Corporation | Fibre, film, suture chirurgicale bioabsorbable et inhibiteur d'adhesion bioabsorbable comportant chacun un copolymere sequence biocompatible |
JPH09309947A (ja) | 1996-05-24 | 1997-12-02 | Naoyuki Koide | 側鎖にコレステロール基を有する脂肪族ポリエステル |
JP2004313310A (ja) | 2003-04-14 | 2004-11-11 | Ube Ind Ltd | 管状の人工器官 |
JP2008142534A (ja) * | 2006-11-17 | 2008-06-26 | National Cardiovascular Center | 血液凝固抑制材料並びにそれを用いたコーティング材料及び生体留置部材 |
JP2013524940A (ja) * | 2010-04-19 | 2013-06-20 | アボット カーディオヴァスキュラー システムズ インコーポレイテッド | 乳酸のポリマーを含む移植可能なデバイスのためのコーティング及びそれを製造する方法 |
WO2018066476A1 (ja) * | 2016-10-07 | 2018-04-12 | 東レ株式会社 | 筒状織物 |
WO2018181918A1 (ja) * | 2017-03-31 | 2018-10-04 | 東レ株式会社 | 筒状構造体 |
WO2019187569A1 (ja) * | 2018-03-30 | 2019-10-03 | 東レ株式会社 | 生分解性を有するブロック共重合体 |
-
2019
- 2019-08-30 TW TW108131199A patent/TW202031211A/zh unknown
- 2019-08-30 CA CA3105469A patent/CA3105469C/en active Active
- 2019-08-30 US US17/269,502 patent/US12115285B2/en active Active
- 2019-08-30 CN CN201980056346.4A patent/CN112584796B/zh active Active
- 2019-08-30 EP EP19853769.8A patent/EP3845202A4/en active Pending
- 2019-08-30 JP JP2019548083A patent/JP7290110B2/ja active Active
- 2019-08-30 WO PCT/JP2019/034060 patent/WO2020045611A1/ja unknown
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01195862A (ja) * | 1987-06-09 | 1989-08-07 | Yissum Res Dev Co Of Hebrew Univ Of Jerusalem | ポリエーテルグリコール系の生物分解性ポリマー材料,その製造法及びそれから作った外科用製品 |
WO1996021056A1 (fr) | 1995-01-04 | 1996-07-11 | Mitsubishi Chemical Corporation | Fibre, film, suture chirurgicale bioabsorbable et inhibiteur d'adhesion bioabsorbable comportant chacun un copolymere sequence biocompatible |
JPH09309947A (ja) | 1996-05-24 | 1997-12-02 | Naoyuki Koide | 側鎖にコレステロール基を有する脂肪族ポリエステル |
JP2004313310A (ja) | 2003-04-14 | 2004-11-11 | Ube Ind Ltd | 管状の人工器官 |
JP2008142534A (ja) * | 2006-11-17 | 2008-06-26 | National Cardiovascular Center | 血液凝固抑制材料並びにそれを用いたコーティング材料及び生体留置部材 |
JP2013524940A (ja) * | 2010-04-19 | 2013-06-20 | アボット カーディオヴァスキュラー システムズ インコーポレイテッド | 乳酸のポリマーを含む移植可能なデバイスのためのコーティング及びそれを製造する方法 |
WO2018066476A1 (ja) * | 2016-10-07 | 2018-04-12 | 東レ株式会社 | 筒状織物 |
WO2018181918A1 (ja) * | 2017-03-31 | 2018-10-04 | 東レ株式会社 | 筒状構造体 |
WO2019187569A1 (ja) * | 2018-03-30 | 2019-10-03 | 東レ株式会社 | 生分解性を有するブロック共重合体 |
Non-Patent Citations (2)
Title |
---|
MESSMORE, BENJAMIN W. ET AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 126, 2004, pages 14452 |
See also references of EP3845202A4 |
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EP3845202A4 (en) | 2022-05-18 |
US12115285B2 (en) | 2024-10-15 |
TW202031211A (zh) | 2020-09-01 |
JPWO2020045611A1 (ja) | 2021-08-12 |
CN112584796A (zh) | 2021-03-30 |
CA3105469A1 (en) | 2020-03-05 |
CN112584796B (zh) | 2024-05-28 |
US20210322650A1 (en) | 2021-10-21 |
EP3845202A1 (en) | 2021-07-07 |
CA3105469C (en) | 2022-08-30 |
JP7290110B2 (ja) | 2023-06-13 |
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