Drug elution medical device and method of production thereof

Abstract

[Problem] Provide: a drug-eluting medical device that provides sustained drug release and has high peel durability for the coating layers; and a method of production thereof. [Solution] A drug-eluting medical device having: a base material 20; a first coating layer 31 having a first polymer in which dopamine molecules or an analogue thereof have been auto-oxidized and polymerized in the base material 20; a second coating layer 32 having a second polymer covalently bonded to the first polymer in the first coating layer 31; and a third coating layer 33 having a drug and a third polymer loaded with the drug in the second coating layer 32. The second polymer and the third polymer form an interpenetrating polymer network.

Description

Drug elution medical device and method of production thereof Technical field The present invention relates to a drug-eluting medical device and a method for producing it. Background of the art A drug elution stent (hereafter referred to as "DES") is a medical device for drug elution. A DES is a device in which a surface of a stent, a tubular structure capable of expanding and contracting radially, is coated with a drug, such as an immunosuppressant. When treating a lesion, such as a stricture, in a body lumen, such as a blood vessel, using a DES, the operator percutaneously inserts a catheter with a DES mounted on it into the body lumen to deliver the drug to the lesion and expands the DES. The drug applied to the DES infiltrates the lesion, and the drug's efficacy is exerted locally. Required properties for a DES include high detachment durability between the drug and the stent and sustained drug elution. Regarding detachment durability, the drug can detach from the stent surface during assembly, administration, and expansion, thereby reducing the drug load. In particular, when the drug detaches while the DES is in the living body, such as during administration or expansion, the detached drug or thrombus formation originating from the detached drug can block the body lumen on the peripheral side, leading to serious complications. Therefore, high detachment durability between the drug and the stent is required. Regarding sustained release, it is often necessary to maintain drug efficacy over a long period in the treatment of the lesion. For example, when a stent expands into a stenotic lesion in a blood vessel, the physical stimulation from the stent expansion induces a biological reaction, such as excessive proliferation of smooth muscle cells, causing restenosis. This biological reaction begins immediately after stent implantation and peaks in approximately several months to six months. In this case, drug elution from the DES must last at least several months or longer. Therefore, drug elution is required for sustained release. From this point of view, various techniques have been described for supporting a drug using a polymer and coating it on the surface of a stent. Patent literature 1 describes, as a medical device having an excellent hydrophilic coating with peel durability, a technique for forming, on a substrate, a first coating layer coated with polydopamine, which is applicable to a wide variety of substrates made of metals, ceramics, polymers and the like, and is known as an ideal primer, and a second coating layer coated with a crosslinked copolymer having a hydrophilic function over the first coating layer.Patent literature 1 describes that the second coating layer can be configured as a crosslinked copolymer formed by a crosslinking agent, and that a functional group in the crosslinked copolymer and polydopamine are covalently linked. It also describes that the second coating layer can contain a chemical substance (drug) with pharmacological activity, such as an antithrombotic drug, a hemostatic agent, an angiogenic inhibitor, an angiogenic agent, an antimicrobial agent, an antiproliferative agent, a proliferative agent, or an anti-inflammatory drug. Patent document 1 discloses a stent as an example of a medical device to which this technology is applied. List of cited documents Patent document Patent Document 1: JP 2016-508776 A Summary of the invention Technical problem However, when the technique described in patent document 1 is applied to a stent, it is difficult to achieve sustained drug release, a required property for drug delivery. In "Example 5: Formation of a Hydrophilic Coating Containing Useful Chemicals" of patent literature 1, various drugs are introduced into a hydrophilic coating (second coating layer) by a method that includes, after forming a hydrophilic coating that is the second coating layer, applying an aqueous solution containing heparin and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC); alternatively forming a heparin layer and a polyamine layer; applying an aqueous solution containing heparin and NaCl; applying an aqueous solution containing doxorubicin; and applying an ethanol solution of silver carbonate and chlorhexidine. In this case, the drug adheres to the surface of the second coating layer.When the second coating layer has a porous structure and a space where the drug can enter, there is also the possibility that the drug will enter the space. However, in general, the drug has little binding force to act on the polymer, and in either of the above cases, the agent is released early. In order to sustainably release the drug, it is preferably incorporated into a coating layer with a non-porous structure. Even when the polymer with a hydrophilic function in the second coating layer of patent literature 1 is replaced with a polymer such as polylactic acid, which is well known as a drug-supporting polymer, the situation in which sustained drug release is difficult remains unchanged. On the other hand, by forming a covalent bond between the second coating layer and the first coating layer in a state where the drug already exists, the drug can be incorporated into the coating layer, which has a non-porous structure. However, in this case, the heat or light required to form a covalent bond cleaves a chemical bond in the drug, or a radical from a polymerization initiator generated in a reaction process causes an oxidation reaction at the cleavage site, thus generating an analogue in which the original drug structure has been altered. Therefore, when the drug's efficacy is lost and the analogue also causes side effects, the analogue becomes harmful. The present invention has been made to solve the problems described above, and an object of the present invention is to provide a medical drug elution device in which the drug elution is sustained release and the durability of peeling off a coating layer is high, and a method for producing the same. Solution to the problem A drug-elution medical device that achieves the above objective includes: a substrate; a first coating layer having a first polymer obtained by auto-oxidation polymerization of a dopamine molecule or an analogue thereof on the substrate; a second coating layer having a second polymer covalently bonded to the first polymer on the first coating layer; and a third coating layer having a drug and a third polymer that supports the drug on the second coating layer, wherein the second polymer and the third polymer are hydrophobic and form an interpenetrating polymer network structure. A method for producing a drug-elution medical device that achieves the above objective includes: a first step of applying a first solution containing a dopamine molecule or an analogue thereof as a first coating material onto a substrate and polymerizing the first coating material to form a first coating layer having a first polymer; a second step of applying a second solution containing a polymer and / or a monomer as a second coating material onto the first coating layer, and then performing heating or light irradiation to form a second coating layer having a second polymer;and a third step of applying a third solution containing a drug and a polymer as a third coating material over the second coating layer, and then performing drying to form a third coating layer having a third polymer that supports the drug, wherein the second and third polymers are hydrophobic. Advantageous effects of the invention The drug elution medical device configured as described above and the drug elution medical device produced by the production method described above are characterized in that the drug has a predicted drug efficacy and the drug elution is sustained release because the drug is supported by the third polymer while having its original structure; and the coating layer has a high peel durability because the third polymer forms an interpenetrating polymer network structure with the second polymer. Brief description of the drawings Figure 1 is a cross-sectional view of a substrate and coating layer of a drug elution medical device according to one embodiment. Figure 2 is a TEM image of a cross-section of a coating layer (interface between a second coating layer and a third coating layer) of the example. Figure 3 is a TEM image of a cross-section of a coating layer (interface between a second coating layer and a third coating layer) of the example. Figure 4 is a TEM image of a cross-section of a coating layer (interface between a second coating layer and a third coating layer) from the comparative example. Description of the achievements An embodiment of the present invention will now be described with reference to the drawings. Note that the dimensional relationships in the drawings may be exaggerated and differ from the actual relationships for the sake of clarity. As illustrated in Figure 1, a drug elution medical device 10 according to the present embodiment includes a substrate 20 and a coating layer 30. The coating layer 30 includes a first coating layer 31 coating the substrate 20, a second coating layer 32 coating the first coating layer 31, and a third coating layer 33 coating the second coating layer 32. The first coating layer 31 may coat the entire substrate 20, or may coat at least a portion thereof. The second coating layer 32 may coat the entire first coating layer 31, or may coat at least a portion thereof. The third coating layer 33 may coat the entire second coating layer 32, or may coat at least a portion thereof.When the drug elution medical device 10 has a cylindrical shape, such as the des, the coating layer 30 can coat all surfaces of the stent, which is the substrate 20, including the outer surface (the tissue side of the body lumen), the inner surface (the light side of the body lumen), and the lateral surface located between the outer and inner surfaces. However, it may only coat one or two surfaces. Furthermore, the coating layer 30 may cover all or at least part of each surface, and the coating layer 30 on each surface may be integrally formed or formed separately. At least a portion of the coating layer 30, such as an end of the coating layer 30 in a direction parallel to the surface of the substrate 20, does not necessarily satisfy the contact relationship between the substrate 20 and the first coating layer 31, between the first coating layer 31 and the second coating layer 32, or between the second coating layer 32 and the third coating layer 33. For example, the substrate 20 and the second coating layer 32 may be in contact with each other, or the third coating layer 33 is not necessarily provided on the second coating layer 32.The contact relationship between the substrate 20 and the first coating layer 31, the contact relationship between the first coating layer 31 and the second coating layer 32, and the contact relationship between the second coating layer 32 and the third coating layer 33 is only required to be satisfied by at least a part of the coating layer 30. Medical device 10 Drug elution medical device 10, according to the present embodiment, is a medical device used to transfer a drug to body tissue while in contact with that tissue. Furthermore, since the drug elution is sustained-release, it is suitable for use in a medical device that has prolonged contact time with body tissue, and is particularly suitable for use in an implantable medical device that can be implanted in the body. Examples of medical devices used to transfer a drug to body tissue while in contact with that tissue include catheters such as balloon catheters, contrast catheters, ablation catheters, suction catheters, perfusion catheters, imaging catheters, and microcatheters; sheaths such as introducers and guidewires; guidewires; and medical patches such as analgesic and anti-inflammatory patches.Examples of implantable medical devices that can be implanted in the body include stents, stent grafts, artificial blood vessels, artificial bones, artificial heart valves, pacemakers, artificial joints, auxiliary artificial hearts, permanent catheters, embolic coils, aneurysm clips, thrombus filters, and implantable insulin pumps. Furthermore, given the high durability of the coating layer's peelability, a medical device to which a force is likely to be applied to peel off the coating layer 30 before and after the drug elution medical device 10 according to the present embodiment is inserted into a target position in the body is suitable as the drug elution medical device 10 according to the present embodiment. In the implantable medical device that can be implanted in the body described above, a force is likely to be applied to peel off the coating layer 30 before and after the medical device is inserted into a target position in the body. The DES is particularly suitable as the drug-elution medical device 10 according to the present embodiment because a force is likely to be applied to peel off the coating layer 30 during assembly, delivery, and expansion, and the elution of a drug that suppresses a biological reaction causing restenosis needs to last at least several months or longer. However, the drug-elution medical device 10 according to the present embodiment is not limited to the DES and can also be applied to the medical devices described above. Substrate 20 The substrate 20 of the drug elution medical device 10 according to the present embodiment is metal, polymer, ceramic, or a fibrous protein such as silk or wool. At least a portion of the substrate 20 may be composed of one or more of these materials. Examples of metal that can be applied to substrate 20 include, but are not limited to, stainless steel, a cobalt-chromium alloy, platinum, a platinum alloy, a nickel-titanium alloy, a titanium alloy, tantalum, a tantalum alloy, gold, silver, iron, zinc, magnesium, a niobium alloy, and mixtures thereof. Examples of polymers that can be applied to substrate 20 include, but are not limited to, polyglycolic acid, polylactic acid, polycaprolactone, polydioxanone, polytetrafluoroethylene, trimethylene carbonate, polyethylene terephthalate, polybutylene terephthalate, polybutyl methacrylate, polycarbonate urethane, polyether ether ketone, polyolefin, polyester, polyurethane, polyamide, polyether block amide, polyimide, polycarbonate, polyphenylene sulfide, polyphenylene oxide, polyether, silicone, polycarbonate, polymethacrylate, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyethylene acetate, and vinyl acetate.Polyethylene elastomer, polyvinyl chloride, rubber, silicone rubber, polyhydroxy acid, polyallylamine, polyallyl alcohol, polyacrylamide, polyacrylonitrile, acrylic oxide, poly(acrylic acid), polymethacrylic acid, polystyrene, polyoxymethylene, phenol resin, amino epoxy resin, cellulose-based plastic, and copolymers, derivatives, and mixtures thereof. A copolymer means any polymer formed from two or more types of monomers. These polymers may or may not be cross-linked. These polymers may be mixed with a filler or a colorant. Examples of ceramics that can be applied to substrate 20 include, but are not limited to, silicon oxide, aluminum oxide, silica, hydroxyapatite, glass, calcium oxide, polysilanol, and phosphate. The surface of the substrate 20 of the drug elution medical device 10 according to the present embodiment may be smooth or rough. Furthermore, in order to improve adhesion to the first coating layer 31, a known surface treatment technique, such as a cleaning treatment or a plasma treatment, may be applied to the surface of the substrate 20. First coating layer 31 The first coating layer 31 of the drug elution medical device 10 according to the present embodiment has a first polymer obtained by auto-oxidation polymerization of a dopamine molecule or an analogue thereof. The first polymer is preferably polydopamine, which is a polymer formed by auto-oxidation polymerization of a dopamine molecule, a catecholamine. In 2007, Lee and Messersmith et al. found that polydopamine can be coated onto the surface of a substrate made of a wide range of materials, has high peel durability through hydrogen bonding and coordinate bonding to a hydrophilic substrate and through a hydrophobic interaction such as a - interaction to a hydrophobic substrate, and is also easy to perform secondary modification (Science, 2007, 318, pages 426 to 430), and polydopamine has attracted attention as a versatile coating material since this finding.As illustrated in Figure 3 of Patent Bibliography 1, a structure is proposed in which 5,6-dihydroxyindole or acyclic dopamine generated by oxidation of a dopamine molecule is continuously linked by a covalent bond, and a structure in which a supramolecular assembly is formed by a bond due to a physical interaction other than a covalent bond. The structure of the first polymer obtained by auto-oxidation polymerization of a dopamine molecule or an analogue thereof in the present invention is not limited to a specific structure, and encompasses all structures that can be assumed when the dopamine molecule or analogue thereof is subjected to auto-oxidation polymerization. Furthermore, the first coating layer 31 has a structure of the first polymer in at least a portion thereof. That is, the first coating layer 31 may contain a structure derived from a dopamine molecule or an analogue thereof. As an example where the structure of the first polymer is present in a portion of the coating layer, JP 2016-513545 A describes a coating layer obtained by mixing and polymerizing a dopamine molecule and a molecule covalently bonded to the dopamine molecule in order to improve adhesion between a substrate and polydopamine, and similar applications. In this case, a portion of the coating layer has a polydopamine structure, and a structure derived from a molecule covalently bonded to a dopamine molecule is contained within the coating layer as a structure derived from a molecule other than a dopamine molecule or an analogue thereof.As another example, a substance that is not covalently bonded to a dopamine molecule or an analogue thereof may be contained in the first coating layer 31. In this case as well, the first coating layer 31 has at least partially a structure of the first polymer, and this case is included within the technical scope of the present invention. The first coating layer 31 may have a first polymer formed by auto-oxidation polymerization of a dopamine analogue, which is an analogue of a dopamine molecule. The first coating layer 31 may have a first polymer formed by auto-oxidation polymerization of a plurality of dopamine analogues. The first coating layer 31 may have a first polymer formed by auto-oxidation polymerization of a dopamine molecule and two or more dopamine analogues. The chemical formula of the dopamine analogue is, for example, the chemical formulas described in paragraphs "0189" to "0193" and "0228" to "0230" of patent bibliography 1. The thickness of the first coating layer 31 is not particularly limited, but is, for example, from 1 to 200 nm, preferably from 5 to 150 nm, more preferably from 10 to 100 nm, and even more preferably from 15 to 80 nm. The thickness of the first coating layer 31 can be uniform or non-uniform. The surface of the first coating layer 31 can be smooth or rough. The thickness of the first coating layer is measured, for example, using an atomic force microscope (AFM). Second coating layer 32 The second coating layer 32 of the drug elution medical device 10 according to the present embodiment has a second polymer that is covalently bonded to the first polymer obtained by auto-oxidation polymerization of a dopamine molecule or an analogue thereof. The second coating layer 32 is formed, for example, by placing a material of the second polymer onto the first coating layer 31 and applying energy, such as heat or light. The second coating layer 32 may also contain a polymerization initiator. When the second coating layer 32 is formed, a covalent bond is formed between the first polymer and the second polymer. The covalent bond between the first polymer and the second polymer is formed by, for example, a functional group of the first polymer from which an extractable hydrogen atom has been removed on the surface of the first coating layer 31, and a functional group of the second polymer on the second coating layer 32 in contact with the surface of the first coating layer 31. In another example, the covalent bond is formed by a functional group of the first polymerizable polymer on the surface of the first coating layer 31 and a functional group of the second polymer on the second coating layer 32 in contact with the surface of the first coating layer 31. The functional group that forms a covalent bond is determined, for example, by the materials and structures of the first polymer and the second polymer.Patent literature¹ suggests that when the radical initiator acting as a polymerization initiator is Norrish type II, the functional group forming a covalent bond on the substrate side is a functional group from which a hydrogen atom has been extracted from the substrate surface. Conversely, when the radical initiator is Norrish type I, the functional group forming a covalent bond on the substrate side is a functional group polymerizable on the substrate surface. In the present invention, the mechanism of the covalent bond between the first polymer and the second polymer is not particularly constrained. The second polymer of the second coating layer 32 is preferably a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer. With this configuration, a covalent bond is formed between the functional group of the crosslinkable monomer and the first polymer on the surface of the first coating layer 31, improving the bond strength between the first coating layer 31 and the second coating layer 32, thus enhancing the peel durability of the coating layer 30. In this case, the functional group of the base polymer does not necessarily need to be covalently bonded to the first polymer on the surface of the first coating layer 31, and therefore a wide variety of polymers can be selected as the base polymer. A covalent bond can form between the functional group of the base polymer and the first polymer on the surface of the first coating layer 31.Furthermore, a covalent bond can form between the functional group of the crosslinkable monomer and the functional group of the base polymer and the first polymer on the surface of the first coating layer. When the second polymer of the second coating layer 32 is a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer, examples of the base polymer include polyesters, aliphatic polyesters, polyacid anhydrides, polyorthoesters, polycarbonates, polyphosphazenes, polyphosphate esters, poly(vinyl alcohols), polypeptides, polysaccharides, proteins, cellulose, and copolymers, derivatives, and mixtures thereof. Specific examples of aliphatic polyesters include polylactic acid, polycaprolactone, polyglycolic acid, polydioxanone, polybutyrolactone, polyvalerolactone, polyhydroxybutyric acid, polytrimethylene carbonate, and copolymers, derivatives, or mixtures thereof. Examples of the copolymer form include, but are not limited to, a staggered copolymer, a random copolymer, a block copolymer, and a graft copolymer. The monomers that constitute these polymers may have optical isomers, but the polymer is not limited to polymers composed of specific optical isomers. For example, lactic acid (LA), a constituent monomer of polylactic acid (PLA), includes L-lactic acid and D-lactic acid, which have different optical activities. Therefore, polylactic acid includes poly-L-lactic acid (PLLA), obtained by polymerizing L-lactic acid; poly-D-lactic acid (PDLA), obtained by polymerizing D-lactic acid; and poly-D,L-lactic acid (PDLLA), which is a random polymer of L-lactic acid and D-lactic acid. However, the present invention is not limited to these. In the present invention, a polymer polymerized using lactic acid as a monomer is referred to as a polymer having a lactic acid monomeric unit, regardless of the optical activity of the lactic acid used.The lactic acid monomer unit refers to a form in which lactic acid is incorporated into the polymer. Polymers polymerized using not only polylactic acid but also lactic acid and other monomers are included in the polymer that has a lactic acid monomer unit. In addition, proteins such as collagen, fibrin, and elastin, which are natural polymeric materials and components of the extracellular matrix, can be used, along with other biological agents and their derivatives, or mixtures thereof, as a base polymer. In a preferred embodiment of the present invention, the base polymer has a lactic acid monomer unit. That is, the second polymer preferably has a lactic acid monomer unit. The content of the lactic acid monomer unit in the base polymer is preferably 50 mol% or more (upper limit: 100 mol%), and more preferably 70 mol% or more (upper limit: 100 mol) with respect to all the monomers constituting the base polymer. Furthermore, the second polymer is hydrophobic to further exhibit the desired effect of the present invention. Therefore, the base polymer is also preferably hydrophobic. The weight-average molecular weight of the base polymer is preferably 100,000 to 1,000,000, and more preferably 150,000 to 800,000 from the standpoint of peel durability and similar properties. In this specification, the weight-average molecular weight is a value measured under the following measurement conditions by gel permeation chromatography (GPC) using polystyrene as the reference material. Conditions for measuring molecular weight Apparatus: Semi-micro GPC LC-VP system (manufactured by Shimadzu Corporation) Detector: Shodex (registered trademark) RI-104 (manufactured by Showa Denko KK) Column: Shodex (registered trademark) GPC LF-804 (manufactured by Showa Denko KK), two columns used. Protective column: Shodex (registered trademark) LF-G (manufactured by Showa Denko KK) Column temperature: 40 °C Mobile phase solvent: CHCl3 Flow rate: 1.00 ml / min Injection volume: 200 µl. When the second polymer of the second coating layer 32 is a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer, the crosslinkable monomer is preferably one that has high affinity with the base polymer and has a strong bond with the first polymer on the surface of the first coating layer 31. Examples of crosslinkable monomers include those with a functional group such as a vinyl group (CH2=CH-), an allyl group (CH2=CH-CH2-), an acryloyl group (CH2=CH-CO-), a methacryloyl group (CH2=C(CH3)-CO-), or an acrylamide group (CH2=CH-CO-NH-), which is a type of vinyl group. In general, the reactivity of a crosslinkable monomer increases with increasing polarity of the chemical structure connected to the final structure containing an unsaturated bond of a functional group (in the example above, CH2=CH- or CH2=C(CH3)-).Since the magnitude of polarity is (allyl group) < (acryloyl group) (methacryloyl group) < (acrylamide group), the reactivity of a crosslinkable monomer with an allyl group is often less than that of a crosslinkable monomer with an acryloyl or methacryloyl group, and the reactivity of a crosslinkable monomer with an acrylamide group is often greater than that of a crosslinkable monomer with an acryloyl or methacryloyl group. The reactivity of a crosslinkable monomer with a methacryloyl group is slightly less than that of a crosslinkable monomer with an acryloyl group because the CH3 group in the methacryloyl group can be sterically hindered, but it is equivalent to the reactivity of the crosslinkable monomer with an acryloyl group.When the number of functional groups differs in a crosslinkable monomer that has the same type of functional group, reactivity increases as the number of functional groups increases. Hereafter, the term "(meth)acrylate" refers to both acrylate, which is a crosslinkable monomer having an acryloyl group, and methacrylate, which is a crosslinkable monomer having a methacryloyl group. Examples of bifunctional (meth)acrylates include diethylene glycol di(meth)acrylate, 1,4-butanediol di(meth)acrylate, 1,3-butylene glycol di(meth)acrylate, dicyclopentanyl di(meth)acrylate, glycerol di(meth)acrylate, 1, 6-hexanediol, neopentylglycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, ethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, 1,9-nonanediol di(meth)acrylate and say (meth)acrylate of 1, 10-decanediol. Examples of trifunctional (meth)acrylate include tri(meth)acrylate of trimethylolpropane, tri(meth)acrylate of pentaerythritol, and (meth)acrylate of tetramethylolmethane.Examples of the functional tetra or higher (meth) acrylate include tetra(meth)pentaerythritol acrylate, tetra(meth)ditrimethylolpropane acrylate, penta / hexa(meth)dipentaerythritol acrylate, hexa(meth)dipentaerythritol acrylate, and monohydroxypenta(meth)dipentaerythritol acrylate.Examples of crosslinkable monomers having an acrylamide group include N,N'-methylenebis(meth)acrylamide, N,N'-ethylenebis(meth)acrylamide, N,N'-hexamethylenebis(meth)acrylamide, N,N'-benzylidenebis(meth)acrylamide, N,N'-bis((meth)acrylamidomethylene)urea, N-[tris(3-(meth)acrylamidopropoxymethyl)methyl](meth)acrylamide (e.g., FOM-03006; N-[tris(3-acrylamidopropoxymethyl)methyl]acrylamide), N,N-bis(2-(meth)acrylamidoethyl)(meth)acrylamide (e.g., FOM-03007; N,N-bis(2-acrylamidoethyl)acrylamide), N,N'-[oxybis(2,1-ethanediyloxy-3, 1-propanediyl) ]bis (meth) acrylamide (for example, FOM-03008; N,N'-[oxybis (2,1-ethanediyloxy-3,1-propanediyl) ]bisacrylamide) and N,N'-1,2-ethanediylbis{N-[2- ( (meth) acrylamino) ethyl] (meth) acrylamide} (for example, FOM-03009; N,N'-1,2-ethanediylbis{N-[2- (acrylamino) ethyl] acrylamide}).Examples of crosslinkable monomers having an allyl group include trialyl trimellitate, trialyl pyromethylate, diallyl oxalate, trialyl cyanurate, and trialyl isocyanurate (TAIC). Among these, the crosslinkable monomer is preferably a (meth) acrylate and more preferably a tetra- or higher functional (meth) acrylate, from the point of view of having a high binding capacity to the first polymer on the surface of the first coating layer. In the present invention, the base polymer preferably has a lactic acid monomer unit, and the crosslinkable monomer is preferably a (meth) acrylate from the point of view of the high affinity between the base polymer and the crosslinkable monomer. When the second polymer is a crosslinkable polymer obtained by crosslinking a crosslinkable monomer and a base polymer, the content ratio (weight ratio) between the crosslinkable monomer and the base polymer is not particularly restricted, but the crosslinkable monomer is preferably contained in an amount of 1% by weight or more and 95% by weight or less, more preferably in an amount of 5% by weight or more and 90% by weight or less, even more preferably in an amount of 10% by weight or more and 90% by weight or less, still more preferably in an amount of 30% by weight or more and 90% by weight or less, and particularly preferably in an amount of 30% by weight or more and 70% by weight or less with respect to the weight (100% by weight) of the base polymer.In one embodiment, the crosslinkable monomer is contained in an amount of preferably 20 wt% or more and 80 wt% or less, more preferably 30 wt% or more and 75 wt% or less, with respect to the weight (100 wt%) of the base polymer. When the crosslinkable monomer is contained within the above range, an interpenetrating polymer network structure described below can be effectively formed, and the desired effect of the present invention can be further exhibited. The crosslinkable monomer in the present invention is not limited to those having a vinyl group, an allyl group, an acryloyl group, a methacryloyl group, or an acrylamide group as a functional group. Examples of crosslinkable monomers having other functional groups include maleimide-based compounds such as N-phenylmaleimide and N,N'-m-phenylenebismaleimide, compounds having two or more triple bonds, such as dipropargyl phthalate and dipropargyl maleate, and divinylbenzene. A crosslinked polymer can be formed by crosslinking a base polymer and a crosslinkable monomer, or it can be formed by crosslinking a constituent monomer of a base polymer and a crosslinkable monomer. The structure of a crosslinked polymer formed by crosslinking a constituent monomer of a base polymer and a crosslinkable monomer is similar to that of a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer. A crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer is a polymer that has one constituent monomer unit of the base polymer and one crosslinkable monomer unit in its molecular structure.In this document, the constituent monomeric unit of the base polymer refers to a form in which the constituent monomer of the base polymer is reacted into the crosslinked polymer, and the crosslinkable monomeric unit refers to a form in which the crosslinkable monomer is reacted into the crosslinked polymer. The crosslinked polymer may be composed of one type of base polymer or one type of monomer constituting the base polymer, and one type of crosslinkable monomer, but it may be composed of a plurality of base polymers or a plurality of monomers constituting the base polymer, and a plurality of crosslinkable monomers. The second polymer of the second coating layer 32 need not have a structure in which a base polymer and a crosslinkable monomer are crosslinked. For example, when a polymer having any functional group from a vinyl group, an allyl group, an acryloyl group, a methacryloyl group, and an acrylamide group, or a plurality of functional groups selected from these, is used as the second polymer, it is placed on the first coating layer 31, and energy such as heat or light is applied to form the second coating layer 32, a covalent bond may form between the first polymer and the second polymer. The number and positions of these functional groups in the second polymer are not limited.In this case, the type of functional group of the second polymer is not limited to the vinyl group, the allyl group, the acryloyl group, the methacryloyl group and the acrylamide group, and includes all functional groups that can form a covalent bond with the first polymer. The second coating layer 32 is only required to contain the second polymer covalently bonded to the first polymer at least in part, and may contain an additive other than the second polymer. At the time of forming the second coating layer 32, an additive, whether intentionally added or unintentionally included, may be part of the second polymer in a covalently bonded form. The second coating layer 32 may contain a polymerization initiator. Polymerization initiators are known to include thermal polymerization initiators and photopolymerization initiators, but are not limited to either. Furthermore, a plurality of polymerization initiators may be used. Examples of photopolymerization initiators include alkylphenone-based photopolymerization initiators such as benzyldimethylketal, -hydroxyalkylphenone, -aminoalkylphenone, and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone; acylphosphine oxide-based photopolymerization initiators such as MAPO and BAPO; and oxime ester-based photopolymerization initiators. A commercially available polymerization initiator may also be used. Examples of commercially available photopolymerization initiators include Irgacure 2959, 184, 1173, 907, 369E, 379EG, TPO and 819 manufactured by BASF SE.Although the shape of the polymerization initiator can be changed after applying energy, the shape of the polymerization initiator present in the second coating layer 32 can be the changed shape. The crosslinking mechanism and the polymerization mechanism of the second polymer are not limited. Furthermore, the primary structure, secondary structure, and higher-order structure of the second polymer are not limited. The thickness of the second coating layer 32 is not particularly limited, but is from 1 to 500 nm, preferably from 5 to 400 nm, more preferably from 10 to 350 nm, and even more preferably from 30 to 250 nm. The thickness of the second coating layer 32 can be uniform or non-uniform. The surface of the second coating layer 32 can be smooth or rough. The thickness of the second coating layer is measured, for example, using an AFM (Automatic Material Frequency). Third coating layer 33 The third coating layer 33 of the drug elution medical device 10 according to the present embodiment has a drug and a third polymer that supports the drug in the second coating layer 32. The third polymer in the third coating layer 33 forms an interpenetrating polymer network structure with the second polymer in the second coating layer 32. The interpenetrating polymer network structure is also called an interpenetrating polymer network (IPN), and it refers to a structure in which one polymer network and another polymer network are entangled with each other without a covalent bond between them. When the interpenetrating polymer network structure forms, the bonding strength is enhanced in each polymer network. Therefore, it is difficult to separate the entire polymer network into the individual polymer networks that formed before its formation. In the present invention, the third polymer in the third coating layer 33 and the second polymer in the second coating layer 32 form an interpenetrating polymer network structure, thereby enhancing the bonding strength between the third coating layer 33 and the second coating layer 32, and improving the peel durability of the coating layer 30.The formation of the interpenetrating polymer network structure can be confirmed, for example, by observing a cross-section that includes an interface of each layer using a transmission electron microscope (TEM). For example, a sample in which a cross-section of the coating layer 30 is exposed can be obtained by embedding the coating layer 30 of the present invention in a resin and cutting the resin-embedded sample with an ultramicrotome (Leica EM UC7). The interpenetrating polymer network structure formed between the second coating layer 32 and the third coating layer 33 can be confirmed by TEM observation of this sample. A known resin can be used as the embedding resin, and, for example, preferably an epoxy resin (EPON812), caprolactone (EVONIK C212), or similar resins. Specifically, the TEM observation can be performed using the method described in the examples.In this case, when an interpenetrating polymer network structure forms, as shown in a TEM image, in the cross-section of coating layer 30, the interface between coating layer 32 and coating layer 33 may not be clear, the brightness of the interface may be uneven, and the brightness of the interface may be different from the brightness of coating layer 32 and coating layer 33. Therefore, when the above findings are obtained at the interface between coating layer 32 and coating layer 33 in the TEM image, it can be determined that an interpenetrating polymer network structure is formed. Alternatively, the formation of the interpenetrating polymer network structure can also be determined by analyzing the layer structure using an optical analysis device such as Nano-FTIR. Furthermore, in a medical device with a coating layer, to confirm whether an interpenetrating polymer network structure forms within the coating layer, a cross-section of the coating layer can be directly examined, or the components contained within the coating layer can be identified, and a cross-section of a sample of the coating layer prepared with those components can be examined. In the present invention, when the second polymer and the third polymer form an interpenetrating polymer network structure, the interface between the second and third coating layers becomes indistinct. Therefore, for example, the cross-section of the coating layer may be observed as a four-layer structure of "first coating layer + second coating layer + interpenetrating polymer network structure + third coating layer" or a two-layer structure of "first coating layer + interpenetrating polymer network structure." The present invention may have any form provided that the interpenetrating polymer network structure exists, and the effects of the present invention are exerted in any form. Here, during the preparation of coating layer 30, it can be visually confirmed whether the third polymer and the second polymer form an interpenetrating polymer network structure, for example. Specifically, in the present embodiment, when a third solution containing the third polymer is applied to the second coating layer 32 containing the second polymer, the solution penetrates the second coating layer, causing it to swell. Since the thickness of the second coating layer changes at this time, the color tone resulting from the interference color of the coating film also changes. Therefore, it can be determined that the third polymer and the second polymer form an interpenetrating polymer network structure.Furthermore, it is possible to confirm whether or not an interpenetrating polymer network structure is formed also in a peel durability test performed in the Examples described below. Although the peel durability of coating layer 30 improves as the formation of the interpenetrating polymer network is promoted, the degree of promotion is not limited in the present invention. In the present invention, the third polymer is hydrophobic. Since the third polymer is hydrophobic, it can be dissolved in a solvent. As will be described later, in the present invention, a third solution obtained by dissolving the third polymer in a solvent is applied to the second coating layer, and the third solution penetrates the second coating layer, causing it to swell. In this way, an interpenetrating polymer network structure is formed between the third polymer and the second polymer.Since the third solution also contains a drug at this stage, when the third polymer and the second polymer form an interpenetrating polymer network structure, the drug supported on the third polymer can be incorporated into the network structure. In the present invention, when the third polymer is non-porous, sustained drug release over a longer period is possible. Since the second coating layer needs to swell with a solvent, the second polymer is also hydrophobic. The hydrophobicity of the third polymer is considered to allow the medical device of the present invention to exhibit peel durability in a use environment. For example (but not part of the invention), when the third polymer is hydrophilic (e.g., polyethylene glycol or similar), the third and second coating layers swell in a use environment, the peel durability of the coating layer cannot be maintained, and sustained drug release is not exhibited. On the other hand, in the medical device of the present invention, since the third and second polymers are hydrophobic, the third and second coating layers do not swell in a use environment, and the peel durability of the coating layer can be maintained. Preferably, the second polymer and the third polymer have an identical monomeric unit. With such a configuration, the affinity between the second and third polymers is enhanced, the formation of the interpenetrating polymer network between the second coating layer 32 and the third coating layer 33 is promoted, and the bond strength between the second coating layer 32 and the third coating layer 33 is increased, thereby improving the peel durability of the coating layer 30. Here, the monomeric units of the second and third polymers refer to the ways in which the constituent monomers of the respective polymers are reacted. The second and third polymers have an identical monomeric unit if the respective polymers are synthesized using the same constituent monomers, regardless of optical activity.Furthermore, in a preferred embodiment, the second polymer and the third polymer have an identical monomeric unit in at least part of each polymer. The drug in the third coating layer 33 is, for example, at least one compound selected from group ue consisting of immunosuppressive agents, anticancer agents, antibiotics, antirheumatic agents, antithrombotic drugs, HMG-CoA reductase inhibitors, ACE inhibitors, calcium antagonists, antilipemic drugs, integrin inhibitors, antiallergic agents, antioxidants, GPIIb / IIIa antagonists, retinoids, flavonoids, carotenoids, lipid enhancers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, anti-inflammatory drugs, hemostatic agents, angiogenic inhibitors, angiogenic agents, biological materials, interferons, and NO production promoters. Examples of immunosuppressant agents include sirolimus, everolimus, pimecrolimus, zotarolimus, biolimus, tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, and gusperimus. Examples of anticancer agents include paclitaxel and docetaxel. Examples of antibiotics include mitomycin and doxorubicin. Examples of antithrombotic drugs include aspirin, ticlopidine, and argatroban. Examples of HMG-CoA reductase inhibitors include cerivastatin. Examples of ACE inhibitors include quinapril. Examples of calcium channel blockers include nifedipine. Examples of antilipemic drugs include probucol. Examples of integrin inhibitors include AJM300. Examples of antiallergic agents include tranilast. Examples of antioxidants include beta-tocopherol. Examples of GPIIb / IIIa antagonists include abciximab. Examples of retinoids include all-trans-retinoic acid.Examples of lipid enhancers include eicosapentaenoic acid. Examples of antiplatelet agents include clopidogrel. Examples of anti-inflammatory agents include dexamethasone and prednisolone. Examples of hemostatic agents include thrombin and collagen. Examples of angiogenic inhibitors include sunitinib. Examples of angiogenic agents include RGD protein. However, the present invention is not limited to these. The third polymer in the third coating layer 33 supports the drug and sustainably releases it. Generally, to sustainably release the drug, it is preferable for the drug to be dispersed in a non-porous polymer. Even if the drug is dispersed in the polymer, if the polymer is porous, the drug may be released prematurely through the polymer pores. Therefore, the third polymer is preferably non-porous. Furthermore, the rate of drug release from the supporting polymer generally depends on the drug diffusion rate in the polymer in the case of a non-biodegradable polymer, and on both the polymer degradation rate and the drug diffusion rate in the case of a biodegradable polymer. The drug diffusion rate in the polymer is correlated with the polymer's flexibility.Therefore, it is known that the rate of drug release can be controlled by adjusting the flexibility and degradation rate of the polymer. Furthermore, it is known that the polymer surface elicits a foreign body reaction in a living organism, and this foreign body reaction contributes to an inflammatory response. A biodegradable polymer in which the polymer-derived inflammatory reaction disappears over time is preferable to a non-biodegradable polymer in which the polymer-derived inflammatory reaction may persist chronically. Based on the foregoing, the third polymer is preferably a non-porous biodegradable polymer that has moderate flexibility and degradation rate. The non-porous state of the polymer can be confirmed by scanning electron microscopy (SEM) or similar means. In the present invention, the non-porous polymer refers to a polymer that has no pores that can be confirmed by SEM.For example, a polymer where a void of approximately 0.1 µm can be confirmed by SEM is considered porous. Examples of third polymers include polylactic acid, polycaprolactone, polyglycolic acid, polydioxanone, polybutyrolactone, polyvalerolactone, polyhydroxybutyric acid, polytrimethylene carbonate, and copolymers, derivatives, or mixtures thereof. These polymers are biodegradable, hydrophobic, and non-porous. Among them, a polymer containing a lactic acid monomer unit is preferred as a third polymer because its degradation product is an in vivo metabolite, and this polymer exhibits excellent biosafety and a high rate of drug release. For example, PLLA, PDLA, PDLLA, poly(lactic-caprolactone), a copolymer of lactic acid and β-caprolactone, and poly(lactic-glycolic acid), a copolymer of lactic acid and glycolic acid, are preferred.In particular, in the case of a copolymer of lactic acid and another monomer, the third polymer preferably has a lactic acid monomer unit because the flexibility is changed by adjusting the ratio between the lactic acid and the other monomer, and the release rate can be adjusted. However, the third polymer is not limited to this. In one embodiment, the third polymer is poly(lactic-caprolactone), which is a copolymer of lactic acid and caprolactone. In this case, the presence of caprolactone, which is softer than other polymers such as the third polymer, imparts flexibility to the third coating layer, thereby improving peel durability. In one embodiment of the present invention, the second polymer and the third polymer preferably have an identical monomer unit, and more preferably have a lactic acid monomer unit. With this configuration, the affinity between the second and third polymers is enhanced, the formation of an interpenetrating polymer network structure between the second coating layer 32 and the third coating layer 33 is promoted, and the bond strength between the second coating layer 32 and the third coating layer 33 is increased, thereby improving the peel durability of the coating layer 30. Furthermore, when the third polymer has a lactic acid monomer unit, the biosafety and sustained release of the drug are improved.The content of the lactic acid monomer unit in the third polymer is preferably 50 mol% or more (upper limit: 100 mol%), and more preferably 70 mol% or more (upper limit: 100 mol%) with respect to all the monomers that constitute the third polymer. The weight-average molecular weight of the third polymer is preferably 100,000 to 1,000,000, and more preferably 150,000 to 800,000 from the standpoint of peel durability and the like. Here, the third polymer favorably forms an interpenetrating polymer network structure with respect to the base polymer that constitutes the second polymer. The content of the third polymer is preferably the same as that of the base polymer constituting the second polymer, and the content ratio (weight ratio) between the third polymer and the base polymer is preferably 2:1 to 1:2, and more preferably 1.5:1 to 1:1.5. As a preferred embodiment of the present invention, the third polymer has a lactic acid monomer unit, and the crosslinkable monomer is contained in an amount of 5% by weight or more and 90% by weight or less with respect to 100% by weight of the base polymer.In a more preferred embodiment of the present invention, the third polymer has a lactic acid monomer unit, and the crosslinkable monomer is contained in an amount of 30% by weight or more and 90% by weight or less with respect to 100% by weight of the base polymer. In a further preferred embodiment of the present invention, the third polymer has a lactic acid monomer unit, and the crosslinkable monomer is contained in an amount of 30% by weight or more and 70% by weight or less with respect to 100% by weight of the base polymer. The third coating layer 33 contains the drug and the third polymer, at least in part, and may contain an additive other than the drug and the third polymer. Examples of additives include elution aids that improve the diffusion rate of the drug in the polymer, such as dimethyl tartrate and diethyl tartrate, but the additives to be included in the third coating layer 33 are not limited to these. The primary structure, secondary structure, and higher-order structure of the third polymer are not limited. The drug in the third coating layer 33 is preferably, but not limited to, uniformly dispersed. Furthermore, the drug present in each of the dispersed regions may form a cluster where a plurality of drug molecules are assembled. The third coating layer 33 may contain nanoparticles, and the drug may also be present in an encapsulated state within the nanoparticles. The nanoparticle material is, for example, a copolymer of lactic acid and glycolic acid. In the formation of the third coating layer 33, to prevent loss of drug efficacy due to changes in the drug's original structure into an analogous substance, the third coating layer is formed without the application of energy such as heat or light. Therefore, the drug is supported by the third polymer, which retains its original structure and does not form a covalent bond with the coating layer. Furthermore, during the formation of the third coating layer 33, some of the drug may migrate to the second coating layer 32. The thickness of the third coating layer 33 is not particularly limited, but is from 0.1 to 200 µm, preferably from 1 to 150 µm, more preferably from 5 to 100 µm, and even more preferably from 10 to 80 µm. The thickness of the third coating layer 33 can be uniform or non-uniform. The surface of the third coating layer 33 can be smooth or rough. The thickness of the third coating layer is measured, for example, using a laser microscope. Herein, a combination of the second polymer and the third polymer according to one embodiment of the present invention will be described. In one embodiment, when the base polymer of the second polymer has a lactic acid monomer unit, the crosslinkable monomer is a crosslinkable monomer having a (meth)acrylate di- or higher functional group (preferably tetra- or higher functional group); and the third polymer has a lactic acid monomer unit. In this case, a covalent bond is favorably formed between the first coating layer and the second coating layer, and an interpenetrating polymer network structure is formed between the second coating layer and the third coating layer, so that the desired effect of the present invention can be further exhibited. For example, when the base polymer of the second polymer is polylactic acid, the crosslinkable monomer is preferably a crosslinkable monomer having a (meth) acrylate group di or higher functional (preferably tetra or higher functional) (e.g., 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, or dipentaerythritol hexaacrylate); and the third polymer is preferably polylactic acid or poly(lactic--caprolactone). For example, when the base polymer of the second polymer is poly(lactic acid--caprolactone), the crosslinkable monomer is a crosslinkable monomer having a (meth) acrylate group di or higher functional (preferably tetra or higher functional) (e.g., 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, or dipentaerythritol hexaacrylate); and the third polymer is either poly-L-lactic acid or poly(lactic--caprolactone). In one embodiment, when the base polymer of the second polymer has a caprolactone unit, the crosslinkable monomer is a crosslinkable monomer having a (meth)acrylate di- or higher functional (preferably tetra- or higher functional), an allyl group, or an acrylamide group; and the third polymer has a lactic acid monomer unit or a caprolactone unit. In this case, a covalent bond is favorably formed between the first coating layer and the second coating layer, and an interpenetrating polymer network structure is formed between the second coating layer and the third coating layer, so that the desired effect of the present invention can be exhibited. For example, when the base polymer of the second polymer is polycaprolactone, the crosslinkable monomer is preferably a crosslinkable monomer having a (meth)acrylate di- or higher functional (preferably tetra- or higher functional), an allyl group or an acrylamide group; and the third polymer is poly-L-lactic acid or poly(lactic-caprolactone). Other coating layers Another coating layer may be provided in addition to the third coating layer 33. The other coating layer may have, for example, a function of suppressing the rate of drug release in the third coating layer 33 to further impart a sustained-release property, or a function of containing a drug different from the drug in the third coating layer 33 and aiding the efficacy of the drug in the third coating layer 33. The material of the other coating layer is not particularly limited. Method for producing a drug-releasing medical device 10 The following document will describe a method for producing the drug elution medical device 10 according to the present embodiment. A method for producing the drug elution medical device 10 according to the present embodiment includes: a first step of applying a first solution containing a dopamine molecule or an analogue thereof as a first coating material (hereinafter also referred to as "containing a first coating material") onto a substrate to form the first coating layer 31 in which the first coating material polymerizes; a second step of applying a second solution containing a polymer and / or a monomer as a second coating material (hereinafter also referred to as "containing a second coating material") onto the first coating layer 31, and then heating or light irradiating it to form the second coating layer 32;and a third step of applying a third solution containing a drug and a polymer as a third coating material (hereinafter also referred to as "containing a third coating material") onto the second coating layer 32, and then performing drying to form the third coating layer 33. More specifically, the method for producing the drug elution medical device 10 according to the present embodiment includes: a first step of applying a first solution containing a dopamine molecule or an analogue thereof as a first coating material onto a substrate and polymerizing the first coating material to form a first coating layer having a first polymer;a second stage of applying a second solution containing a polymer and / or a monomer as a second coating material over the first coating layer, and then performing heating or light irradiation to form a second coating layer having a second polymer;and a third step of applying a third solution containing a drug and a polymer as a third coating material onto the second coating layer, and then drying to form a third coating layer having a third polymer that supports the drug. In the first step, a first solution containing a dopamine molecule or an analogue thereof as a first coating material is applied to a substrate, and the first coating material polymerizes to form the first coating layer 31. Since the first coating layer 31 formed by this step is polydopamine or a polydopamine-like polymer, the peel durability between the substrate 20 and the first coating layer 31 is high, and further coating with another material is facilitated. The substrate material and the dopamine molecule analogue are not particularly restricted, but the materials exemplified in the description of the embodiment of the first coating layer 31 and similar materials may be used. The solvent of the solution containing the first coating material is not particularly restricted, provided that the first coating material is soluble in it. Furthermore, the solution containing the first coating material may contain an additive such as a buffer. The first coating material may be in the form of a hydrate, hydrochloride, or similar form of a dopamine molecule or an analogue thereof. In the first stage, the method for applying the first solution containing the first coating material to the substrate is not particularly restricted. A preferred application method is a dip coating method. The solvent for the first solution can be, for example, water, a buffer, a solvent used for a third solution described later, or similar solvents. For instance, when dopamine hydrochloride is used as the first coating material, water and a buffer are preferred as the solvent, with a Tris-HCl buffer being the most preferred. In the first solution, the content of the first coating material is preferably from 0.01 to 30% by mass, more preferably from 0.05 to 10% by mass, and even more preferably from 0.01 to 5% by mass with respect to the total weight of the first solution.It is known that a dopamine molecule or an analogue thereof undergoes auto-oxidation polymerization, and when a substrate is immersed in a solution containing it, the dopamine molecule or analogue undergoes auto-oxidation polymerization on the substrate surface to form a thin film. The first coating layer 31 can also be formed by applying the first solution containing the first coating material to the substrate using another method, and then applying energy to effect the polymerization. In the first stage, after a film forms in which the first coating material polymerizes, steps such as a cleaning stage, a drying stage, and an annealing stage can be added to form the first coating layer 31. Regarding the annealing stage, the peel durability between the substrate and the first coating layer 31 can be improved by adding this step. The temperature and time for annealing are not particularly limited. In the second step, the second coating layer 32 is formed by applying a second solution containing a polymer and / or a monomer as a second coating material over the first coating layer 31, and then heating or light irradiation. The second coating material is any combination of a base polymer and a crosslinkable monomer; a combination of a constituent monomer of the base polymer and a crosslinkable monomer; and a polymer having a functional group capable of covalently bonding to the first coating layer 31; or a combination thereof. The materials exemplified in the description of the embodiment of the second coating layer 32 can be used as the base polymer and crosslinkable monomer.By applying the second solution containing the second coating material onto the first coating layer 31 and then heating or light irradiation, the second coating layer 32 is formed in which the second coating material is crosslinked and / or polymerized, a covalent bond is formed between the first coating layer 31 and the second coating layer 32, so that the peel durability between the first coating layer 31 and the second coating layer 32 is improved. That is, in one embodiment, in the second step, a second coating layer having a second polymer covalently bonded to the first polymer is formed by applying a second solution containing a polymer and / or a monomer as a second coating material onto the first coating layer, and then heating or light irradiation. The solvent for the second solution containing the second coating material is not particularly restricted, provided the second coating material is soluble in it. For example, a solvent used for a third solution, described later, can be used similarly as the solvent for the second solution. Furthermore, the solution containing the second coating material may contain additives such as a polymerization initiator and a buffer. The second coating material may also be in the form of a hydrate, a hydrochloride, or similar. In the second solution, the ratio of solvent to second coating material is not particularly restricted, but is preferably 10 to 800 ml, more preferably 20 to 600 ml, and even more preferably 100 to 500 ml to 1 part by weight of the second coating material. In the second step, the method for applying the second solution containing the second coating material is not particularly restricted. Furthermore, steps such as a cleaning step, a drying step, and an annealing step may be added before or after heating or light irradiation. Preferably, a drying step is added before heating or light irradiation. When the drying step is added after heating or light irradiation, the second coating material crosslinks and / or polymerizes in a solvent-containing state, so that the second coating layer 32 becomes porous, the mechanical strength of the second coating layer and the bond strength with the first coating layer 31 and / or the third coating layer 33 decrease, and the peel durability of the coating layer 30 may decrease.Therefore, by adding the drying stage before heating or light irradiation, the second coating layer 32 becomes non-porous and the peel durability of the coating layer 30 is improved. The drying conditions are not particularly limited. In the second stage, conditions such as heating temperature, heating time, wavelength of irradiation light, and the amount of light delivered during heating or irradiation are not particularly restricted. Furthermore, if crosslinking and / or polymerization can be promoted, energy can be applied using a method other than heating or light irradiation. In the third stage, the third coating layer 33 is formed by applying a third solution containing a drug and a polymer as a third coating material over the second coating layer 32, and then drying it. The materials exemplified in the description of the preparation of the third coating layer 33 can be used as the drug and polymer of the third coating material.By applying the third solution containing the third coating material onto the second coating layer 32, and then drying, the third coating layer 33 is formed in which the drug is supported in the polymer while having its original structure and is released sustainably, and an interpenetrating polymer network is formed between the second coating layer 32 and the third coating layer 33, so that the peel durability between the second coating layer 32 and the third coating layer 33 is improved. In the third stage, a third solution containing a drug and a polymer as a third coating material is applied, and then drying is carried out without heating or light irradiation. By avoiding heating or light irradiation, there is no risk of heat or light breaking a chemical bond in the drug, and no analogue substance is generated in which the original drug structure has been altered. Therefore, the drug's efficacy is not lost, and there is no risk of the analogue substance causing side effects. However, those obtained by heating or light irradiation are not necessarily outside the technical scope of the present invention. Those obtained by heating or light irradiation are also included within the technical scope of the present invention provided that the heating or light irradiation is carried out at a weak level that does not cause a change in the original drug structure.That is, in the third stage, after applying the third solution containing a drug and a polymer as a third coating material, drying is carried out without heating or light irradiation at a level that causes a change in the original structure of the drug. As a preferred embodiment of the present invention, at least a portion of the second coating material is soluble in the solvent of the third solution containing the third coating material, and in the third stage, the second coating layer 32 swells when the third solution containing the third coating material is applied over the second coating layer 32. With such a configuration, the polymer as the third coating material readily penetrates the second coating layer 32, promoting the formation of an interpenetrating polymer network structure between the second coating layer 32 and the third coating layer 33, and increasing the bond strength between the second coating layer 32 and the third coating layer 33, thereby improving the peel durability of the coating layer. The solvent of the third solution containing the third coating material is not particularly limited as long as the second coating material and the third coating material are soluble in it.Examples of solvents include, but are not limited to, dimethylacetamide, dimethylformamide, tetrahydrofuran, cyclohexanone, acetone, acetonitrile, propylene glycol monomethyl ether, methyl butyl ketone, methyl ethyl ketone, diethyl ketone, ethyl acetate, n-butyl acetate, dioxane, chloroform, dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, hexane, cyclohexane, pentane, heptane, octane, nonane, decane, decalin, isobutyl acetate, isopropyl acetate, diacetone alcohol, benzyl alcohol, 1-butanone, N-methylpyrrolidone, methylene chloride, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, 1,1,1-trichloroethane, formamide, and hexafluoroisopropanol. (hexafluoro-2-propanol (HFIP) ) , 1, 1, 1-trifluoroethanol, hexamethylphosphoramide, and combinations thereof.From the point of view of compatibility between the second polymer and the third polymer, solvents such as tetrahydrofuran, acetone, acetonitrile, methyl butyl ketone, methyl ethyl ketone, diethyl ketone, chloroform, methylene chloride, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, 1,1,1-trichloroethane, hexafluoroisopropanol and 1,1,1-trifluoroethanol are preferable, and chloroform, methylene chloride, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, 1,1,1-trichloroethane, hexafluoroisopropanol and 1,1,1-trifluoroethanol are more preferable. In the third solution, the content ratio between the solvent and the third coating material is preferably 10 to 100 ml, more preferably 20 to 80 ml, and even more preferably 30 to 70 ml with respect to 1 part by weight of the third coating material. Furthermore, the third solution containing the third coating material may contain an additive such as a buffer. The third coating material may also be in the form of a hydrate, a hydrochloride, or similar. In the third stage, the method for applying the third solution containing the third coating material is not particularly restricted. Furthermore, the drying conditions at the time of drying after applying the third solution containing the third coating material are not particularly restricted. Although embodiments of the present invention have been described in detail, this is illustrative and by way of example and not restrictive, and it is clear that the scope of the present invention should be interpreted by the appended claims. Examples The durability of drug release, which is an effect of the drug-elution medical device that achieves the object of the present invention, will be described in the following examples. However, these examples illustrate only a portion of the configuration of the drug-elution medical device that achieves the object of the present invention. The configuration of the drug-elution medical device that achieves the object of the present invention is not limited to these examples. In the following examples, since the third solution contains only the third polymer, the coating layer does not contain a drug. However, when the third polymer is non-porous, long-term sustained drug release is possible. Therefore, those skilled in the art can understand that the sample obtained in this example exhibits long-term sustained release. Preparation of the solution containing the first coating material (first solution) Dopamine hydrochloride was mixed in 10 mM Tris-HCl buffer (pH 8.5) to adjust the first solution. The concentration of dopamine hydrochloride in the first solution was 0.2% by weight. Preparation of the solution containing the second coating material (second solution) A total of 74 types of secondary solutions described in Tables 3 to 6 were prepared by mixing, as a base polymer, 1 g of any of the four types of poly-L-lactic acid (PLLA, BioDegmer (registered trademark) PLLA manufactured by BMG Inc., weight average molecular weight: 510.000), an L-lactic acid / caprolactone copolymer with a molar ratio of L-lactic acid to -caprolactone of 75:25 (LCL7525, BMG Inc., BioDegmer (registered trademark) LCL (75:25) , molecular weight: 570.000), poly-D, L-lactic acid (PDLLA, manufactured by DURECT Corporation, molecular weight: 102.000) and polycaprolactone (PCL, manufactured by Evonik Industries AG, intrinsic viscosity: 1.13 to 1.38 dL / g); as a crosslinkable monomer, any crosslinking agent of five types of 1,4-butanediol diacrylate (1,4-BDDA), pentaerythritol tetraacrylate (PETA), dipentaerythritol hexaacrylate (DPEHA), trialyl isocyanate (TAIC) and N-[tris(3-acrylamidopropoxymethyl)methyl]acrylamide (FOM-03006) in any of six weights of 0.05 g, 0.10 g, 0.30 g, 0.50 g, 0.70 g and 0.90 g; 0.01 g of 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (IRGACURE2959) ; and 300 ml of chloroform. Preparation of the solution containing the third coating material (third solution) A total of four types of third solutions were prepared by mixing 1 g of any one of the four polymer types: PLLA, LCL7525, a DL-lactic acid / β-caprolactone copolymer (DLCL9010) having a DL-lactic acid to β-caprolactone ratio of 90:10 (mole percent), and polyvinyl alcohol (manufactured by FUJIFILM Wako Pure Chemical Corporation, product code 160-11485) (PVA) with 40 mL of a solvent. When PLLA, LCL7525, and DLCL9010 were used as the polymer, chloroform was used as the solvent, and the polymer was dissolved in chloroform at room temperature. When PVA was used as the polymer, water was used as the solvent, and the polymer was dissolved in water at 80 °C.In the present invention, when PLLA, LCL7525 or DLCL9010 is used as the polymer in the third solution, the configuration of the resulting coating layer is the configuration of the examples, and when PVA is used as the polymer in the third solution, the configuration of the resulting coating layer is the configuration of the comparative examples. Preparation of the first coating layer A sheet of SUS304 material (size: 150 mm long × 70 mm wide × 0.8 mm thick) was immersed in an aluminum tray filled with the first solution. After standing for 24 hours, the sample was removed and its surface rinsed with distilled water. The sample was then air-dried at room temperature for 2 hours. Next, the sample was placed on a hot plate heated to 200 °C in air for 5 minutes for an annealing treatment. The thickness of the first coating layer obtained was 40 nm, as measured by an AFM (measuring instrument: Bruker Nano Surfaces, Dimension Icon). The polymer formed in the first coating layer will henceforth be referred to as the first polymer. Preparation of the second coating layer The sample on which the first coating layer had formed was immersed in an aluminum tray filled with the second solution and immediately removed. The sample was then air-dried at room temperature for 1 hour. Next, the sample was dried in a vacuum oven at 40 °C for 24 hours. The dried sample was placed in a polyethylene bag, and the inside of the bag was irradiated with ultraviolet light at a wavelength of 365 nm from the outside of the bag, resulting in an integrated light intensity of 300 J / cm², while the inside of the bag was purged with nitrogen. The sample was then removed from the bag, immersed in an aluminum tray filled with chloroform, and cleaned with an ultrasonic cleaner for 10 minutes to remove residual components such as unreacted monomers and a photopolymerization initiator.A second coating layer was prepared for each of the 74 types of second solutions. The thickness of the resulting second coating layer was measured using an AFM (measuring instrument: Bruker Nano Surfaces, Dimension Icon). The thickness of a sample whose evaluation is described as "( )" in Tables 3 to 6 below (a sample whose evaluation is enclosed in parentheses) ranged from 50 nm to 100 nm, and the thickness of a sample whose evaluation is not enclosed in parentheses was 150 nm. The polymer formed in the second coating layer is hereafter referred to as the second polymer. Preparation of the third coating layer Approximately 0.02 mL of the third solution was dripped onto the prepared sample up to the second coating layer using a Pasteur pipette. The sample was then air-dried at room temperature for 2 hours. Following this, the sample was dried in a vacuum oven at 40 °C for 72 hours. For each of the four types of third solutions, a third coating layer was applied to the surface of each of the 74 sample types prepared up to the second coating layer. The thickness of the resulting third coating layer was 30 µm, as measured using a laser microscope (VK-X200, KEYENCE Corporation). The thickness of the third coating layer was calculated by comparing the thickness of the sample before the third coating layer formed with the thickness of the sample after the third coating layer formed.From now on, the polymer formed in the third coating layer is referred to as a third polymer. In the third polymer (PLLA, LCL7525, DLCL9010, PVA), the cross-section of the sample was exposed by ion milling (IM4000Plus, Hitachi High-Tech Corporation) and then observed by a SEM (S-3400N, Hitachi High-Tech). As a result, no observable pores were found, confirming that the third polymer was non-porous. Here, when using PLLA, LCL7525, and DLCL9010 as the third polymer, the interference color of the coating film was visually observed on the surface when the third solution was applied to the second coating layer. This indicated that the second coating layer was swollen by the third solution. However, when using PVA as the third polymer, even when the third solution was applied to the second coating layer, no interference color was observed on the surface. In this case, the second coating layer was considered not to be swollen. As described above, samples of coating layers were obtained covering the entire SUS sheet material and including the first through third coating layers formed sequentially. In subsequent experiments, measurements are taken from one side of the coating layer surface. Peel durability test method Samples of the 296 coating types, prepared up to the third coating layer, were rubbed with brass tweezers from the surface side of the third coating layer in air. The durability of the peeling was assessed, and the interface location where the peeling occurred was identified. Additionally, each sample was immersed in water at 37°C, the unrubbed portion was rubbed in the same manner, and the durability of the peeling was assessed again, along with the interface location where the peeling occurred. The interface was identified based on the presence or absence of an interference color from the second coating layer on the peeling surface, observed at 50x magnification using a stereomicroscope (SMZ645, Nikon Corporation).Specifically, the "index of the interface position where detachment occurred" was defined as "A" when no interference color from the second coating layer was observed on the detachment surface, "B" when an interference color from the second coating layer was changed or partially observed on the detachment surface, and "C" when an interference color from the second coating layer was observed on the detachment surface in the same way as during the formation of the second coating layer. Here, when the detachment durability index is "1" or higher, it can be determined that an interpenetrating polymer network structure is formed.When the peel durability index is "0", it is considered that no interpenetrating polymer network structure forms. That is, in the evaluations in Tables 3 to 6 below, the "0C" rating indicates that no interpenetrating polymer network structure forms, and ratings other than "0C" (e.g., "1C" and similar) indicate that an interpenetrating polymer network structure forms. Peel durability test result The results of the peel durability test for each sample are shown collectively in Tables 3 to 6, using the indices shown in Table 1 for the peel durability assessment and the indices shown in Table 2 for the results of identifying the interface position where the peeling occurred. In Tables 3 to 6, "( )" (assessment in parentheses) represents a test result for a sample in which a portion of the second coating layer disappeared when ultrasonic cleaning with chloroform was performed during the preparation of the second coating layer, "Dry" represents a test result in air, and "Wet" represents a test result in water. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 As shown in Tables 3 through 6, coating layers formed from any of PLLA, LCL7525, PDLLA, and PCL as a base polymer of the second polymer; any of 1,4-BDDA, PETA, DPEHA, TAIC, and FOM-03006 as a crosslinkable monomer of the second polymer; and any of PLLA, LCL7525, and DLCL9010 as the third polymer were shown to have good peel durability. On the other hand, as shown in Tables 3 through 6, coating layers formed from any of PLLA, LCL7525, PDLLA, and PCL as a base polymer of the second polymer; any of 1,4-BDDA, PETA, DPEHA, TAIC, and FOM-03006 as a crosslinkable monomer of the second polymer; and PVA as the third polymer were found to have insufficient peel durability. In other words, when PVA was used as the third polymer, the peel durability index was "0," indicating low peel durability. When considered in conjunction with the index for the interface location where peeling occurred, the resulting peel durability was "0C," suggesting that when PVA was used as the third polymer, an interpenetrating polymer network structure did not form with the second polymer. This is presumed to be because the solvent in the third solution, when the third polymer is PVA, is water. Therefore, even when the third solution was applied to the second coating layer, which has a hydrophobic second polymer, the second coating layer did not swell.In fact, when forming the third coating layer, no interference color was observed from the coating film when the third solution was applied to the second coating layer, suggesting that the second coating layer did not swell. The above results showed that PVA is not suitable as the third polymer in the present invention. In the coating layers of the examples, when the crosslinkable monomer was 1,4-BDDA, PETA, or DPEHA, the peel durability was generally greater than that of TAIC or FOM-03006. Therefore, in the embodiment of the present invention, the crosslinkable monomer is more preferably an acrylate. This is because the following is considered: since the reactivity of the acryloyl group, a functional group of acrylate, is good, the covalent bond between the first and second coating layers is sufficient; and the compatibility between the acrylate and the base polymer used is good, a sufficient crosslinked structure forms between the crosslinkable monomer and the base polymer, and the polymer component is retained even during ultrasonic cleaning with chloroform, so that a sufficient interpenetrating polymer network structure can form between the third coating layer.When the crosslinkable monomer is methacrylate, since the reactivity of the methacryloyl group, which is a functional group, is equivalent to that of the acryloyl group, the detachment durability is assumed to be similarly high. Therefore, in the embodiment of the present invention, the crosslinkable monomer is more preferably (meth)acrylate. In the coating layers of the examples, when the crosslinkable monomer was PETA or DPEHA, a greater force was required for detachment compared to the case where the crosslinkable monomer was 1,4-BDDA. This is thought to be because the number of covalent bonds formed between the first and second coating layers is greater in the case of tetra or higher functionality than in the case of lower-than-tetra functionality, and therefore the bonding strength between the first and second coating layers was high. In the coating layers of the examples, when the base polymer had an actic acid monomer unit, the peel durability was generally greater than when the base polymer was PCL. Therefore, in the embodiment of the present invention, the third polymer and the base polymer more preferably have a lactic acid monomer unit. As a factor in this, the following is considered: since the third polymer in the third coating layer has a lactic acid monomer unit, the base polymer having a lactic acid monomer unit has a better affinity for the third polymer than the base polymer lacking a lactic acid monomer unit, thus promoting the formation of an interpenetrating polymer network structure between the second and third coating layers.Even when using PCL as the base polymer, when the third polymer was LCL7525 or DLCL9010, peel durability was generally higher than when the third polymer was PLLA. This is thought to be because the presence of the caprolactone monomeric unit in both the base and third polymers enhanced the affinity between them and promoted the formation of an interpenetrating polymer network structure between the second and third coating layers.Based on the above, it is suggested that when not only are the monomeric unit of lactic acid and / or the monomeric unit of caprolactone contained, but also the second polymer and the third polymer have an identical monomeric unit, the affinity between the second polymer and the third polymer is improved, the formation of an interpenetrating polymer network structure between the second coating layer and the third coating layer is promoted, and the bonding strength between the second coating layer and the third coating layer is increased, thus improving the peel durability of the coating layer. In the coating layers of the examples, when the crosslinkable monomer was PETA or DPEHA, the base polymer had a lactic acid monomer unit, and the crosslinkable monomer was contained in an amount of 5 wt% or more and 90 wt% or less with respect to the weight (100 wt%) of the base polymer, the peel durability was generally high. Therefore, in the embodiment of the present invention, it is preferable that the third polymer and the base polymer have a lactic acid monomer unit, the crosslinkable monomer is a tetrafunctional acrylate or higher, and the crosslinkable monomer is contained in an amount of 5 wt% or more and 90 wt% or less with respect to the weight (100 wt%) of the base polymer.It is suggested that by adopting this configuration, a sufficient covalent bond is formed between the first coating layer and the second coating layer, and the formation of an interpenetrating polymer network between the second coating layer and the third coating layer is promoted. In the coating layers of the examples, when the crosslinkable monomer was PETA or DPEHA, the base polymer had a lactic acid monomer unit, and the crosslinkable monomer was contained in an amount of 30 wt% or more and 90 wt% or less with respect to the weight (100 wt%) of the base polymer, the peel durability was generally high. Therefore, in the embodiment of the present invention, it is preferable that the third polymer and the base polymer have a lactic acid monomer unit, the crosslinkable monomer is a tetraacrylate or a higher-functionality acrylate, and the crosslinkable monomer is contained in an amount of 30 wt% or more and 90 wt% or less with respect to the weight (100 wt%) of the base polymer.It is suggested that by adopting this configuration, a sufficient covalent bond is formed between the first coating layer and the second coating layer, and the formation of an interpenetrating polymer network structure between the second coating layer and the third coating layer is promoted.Even when the third polymer and the base polymer have a monomeric unit of lactic acid, the crosslinkable monomer is a tetrafunctional acrylate, the base polymer also has a monomeric unit of caprolactone, and the crosslinkable monomer is contained in an amount of 10 wt% or more and 30 wt% or less with respect to the weight (100 wt%) of the base polymer, and even when the third polymer and the base polymer have a monomeric unit of lactic acid, the crosslinkable monomer is a pentafunctional or higher acrylate, the base polymer also has a monomeric unit of caprolactone, and the crosslinkable monomer is contained in an amount of 5 wt% or more and 30 wt% or less with respect to the weight (100 wt%) of the base polymer, the durability of the detachment is high, which is preferable in the embodiment of the present invention. In the coating layers of the examples, when the crosslinkable monomer was PETA or DPEHA, the base polymer had a lactic acid monomer unit, and the crosslinkable monomer was contained in an amount of 30 wt% or more and 70 wt% or less with respect to the weight (100 wt%) of the base polymer, the peel durability was generally high. Therefore, in the embodiment of the present invention, it is preferable that the third polymer and the base polymer have a lactic acid monomer unit, the crosslinkable monomer is a tetraacrylate or a higher-functionality acrylate, and the crosslinkable monomer is contained in an amount of 30 wt% or more and 70 wt% or less with respect to the weight (100 wt%) of the base polymer.It is suggested that by adopting this configuration, a sufficient covalent bond forms between the first and second coating layers, and the formation of an interpenetrating polymer network structure between the second and third coating layers is promoted. When the crosslinkable monomer was PETA or DPEHA, the base polymer had one lactic acid monomer unit, and the crosslinkable monomer was present at 90 wt% of the base polymer (100 wt%), the interface where delamination occurred was between the second and third coating layers, and the durability of the delamination was generally less than in the case where the crosslinkable monomer was present at 30 wt% or more and 70 wt% or less of the base polymer (100 wt).This is thought to be due to the swelling property of the second coating layer deteriorating when the third solution was applied over it. This deterioration is attributed to the increased proportion of crosslinkable monomer in the second coating layer, and the formation of an interpenetrating polymer network structure between the second and third coating layers was not significantly promoted. In fact, it has been confirmed that when the crosslinkable monomer was DPEHA, and its content was 90% by weight relative to the base polymer (100% by weight), the swelling property of the second coating layer upon application of the third solution was less than when the crosslinkable monomer was present at 70% by weight or less.The reason the interface where detachment occurred was within the second coating layer, and the durability of the detachment was generally less than in the case where the crosslinkable monomer was present at 30 wt% or more and 70 wt% or less relative to the weight (100 wt%) of the base polymer, is that the second coating layer became brittle due to the increased proportion of crosslinkable monomer in it. Furthermore, since the interface where detachment occurred was not between the first and second coating layers, the covalent bond between these layers is considered to have formed sufficiently.When the third polymer and the base polymer have a lactic acid monomer unit, the crosslinkable monomer is a tetrafunctional acrylate, and the crosslinkable monomer is contained in an amount of 70% by weight or more and 90% by weight or less with respect to the weight (100% by weight) of the base polymer, the peel durability is generally greater than in the case where the third polymer and the base polymer have a lactic acid monomer unit, the crosslinkable monomer is a pentafunctional or higher acrylate, and the crosslinkable monomer is contained in an amount of 70% by weight or more and 90% by weight or less with respect to the weight (100% by weight) of the base polymer, which is preferable in the embodiment of the present invention. TEM observation of the structure of the interpenetrating polymer network Next, an interface between the second and third coating layers was observed using a scanning electron microscope (TEM) to confirm whether or not an interpenetrating polymer network structure had formed. Samples 1 and 2 of the coating layer with the configuration of the examples, and sample 3 of the coating layer with the configuration of the comparative examples, were prepared according to the following method. Sample preparation 1 to 3 Preparation of the solution containing the second coating material (second solution) A second solution was prepared by mixing, as the base polymer, 1 g of an L-lactic acid / caprolactone copolymer having a molar ratio of L-lactic acid to -caprolactone of 75:25 (LCL7525, BMG Inc., BioDegmer (registered trademark) LCL (75:25) , molecular weight: 570.000); as the crosslinkable monomer, 0.05 g of dipentaerythritol hexaacrylate (DPEHA); 0.01 g of 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (IRGACURE2959); and 20 ml of chloroform. Preparation of the solution containing the third coating material (third solution) A third solution was prepared by mixing 1 g of a DL-lactic acid / β-caprolactone copolymer (DLCL9010) having a DL-lactic acid to β-caprolactone ratio of 90:10 (mole percent) or polyvinyl alcohol (manufactured by FUJIFILM Wako Pure Chemical Corporation, product code 160-11485) (PVA), and 80 mL of a solvent. In sample 1, DLCL9010 was used as the polymer, hexafluoro-2-propanol (HFIP) was used as the solvent, and the polymer was dissolved in HFIP at room temperature. In sample 2, DLCL9010 was used as the polymer, chloroform was used as the solvent, and the polymer was dissolved in chloroform at room temperature. In sample 3, PVA was used as the polymer, water was used as the solvent, and the polymer was dissolved in water at 80 °C. Preparation of the film sheet made of second coating material The second solution was poured into a 75 mm PFA petri dish, ensuring no air bubbles were introduced, and air-dried overnight at room temperature to form a cast film. This film was then placed in a polyethylene bag, and a film formed by irradiation with ultraviolet light at a wavelength of 365 nm from outside the bag, resulting in an integrated light content of 3,000 mJ / cm², was peeled off the Petri dish after the bag's interior had been purged with nitrogen. This yielded a film sheet made of a second coating material. Preparation of the third coating layer Approximately 0.02 mL of the third solution was applied to the film sheet made of the second coating material using a Pasteur pipette. Drying was then carried out at room temperature in air for 2 hours. Subsequent drying was performed in a vacuum oven at 40 °C for 72 hours. In samples 1–3, the thickness of the film sheet made of the second coating material was 200–300 µm, as measured with a thickness gauge (model: 547-360, manufactured by Mitutoyo Corporation), and the thickness of the third coating layer was 3–6 µm, as measured with a laser microscope (VK-X200, KEYENCE Corporation). The composition of each coating layer in samples 1–3 is shown in Table 7 below. Table 7 Samples 1 to 3, which had a coating layer of the composition in Table 7, were embedded in a resin. In Samples 1 and 2, as examples, an epoxy resin (Epon812) was used as the embedding resin, and in Sample 3, as a comparative example, caprolactone (EVONIK C212) was used as the embedding resin. The hydrophobic polymer caprolactone was selected as the embedding resin for Sample 3 to avoid dissolving the PVA used as the third polymer in the epoxy resin (Epon812). The resin-embedded sample was sectioned using an ultramicrotome (Leica EM UC7), and a magnified image of the resulting thin section was photographed using a transmission electron microscope (H-7100 model, manufactured by Hitachi, Ltd., acceleration voltage: 100 kV). The TEM images obtained (unstained, 25,000x magnification) are shown in Figures 2 to 4. Figure 2 is a TEM image of sample 1, Figure 3 is a TEM image of sample 2, and Figure 4 is a TEM image of sample 3. As shown in Figures 2 and 3, in samples 1 and 2, a region of non-uniform luminosity was observed at the interface between the second and third coating layers. On the other hand, as shown in Figure 4, in sample 3, the interface between the second and third coating layers was clearly confirmed, and no region of non-uniform luminosity was observed between these layers. Since the TEM image luminosity of the polymeric material reflects density, average atomic number, and similar properties, it is suggested that the polymer structure is more uneven in the region where the luminosity is uneven at the interface between the second and third coating layers, confirmed in samples 1 and 2, than in the regions of the second and third coating layers themselves.Therefore, it can be determined that an interpenetrating polymer network structure is formed by the second and third polymers at the interface between the second and third coating layers, resulting in a non-uniform polymer structure. "IPN" in Figures 2 and 3 indicates a region where an interpenetrating polymer network structure is considered to form. Here, the results of the peel durability test for samples 1 and 2 are shown in Table 8 below. The peel durability test method is the same as the method described above. Sample 2 is the same as the system described in Table 4, in which LCL7525 was used as the base polymer and DPEHA as the crosslinkable monomer as the second polymer, and DLCL9010 (solvent species of the third solution: CHCl3) was used as the third polymer. Table 8 As shown in Table 8, the peel durability test results for samples 1 and 2 were the same. Therefore, in the third solution used to prepare the third coating layer, a similar interpenetrating polymer network structure was confirmed to form between the second and third coating layers, regardless of whether CHCl3 or HFIP was used as the solvent. Thus, a similar interpenetrating polymer network structure was confirmed to form between the second and third coating layers even when CHCl3 and HFIP were used as the solvent for the third solution used to prepare the third coating layer. Solution to the problem and advantageous effects of the invention Based on the above, the solution to the problem and the advantageous effects of the invention will be described again below. A medical drug elucidation device achieving an object of the present invention includes: a substrate; a first coating layer having a first polymer obtained by auto-oxidation polymerization of a dopamine molecule or an analogue thereof on the substrate; a second coating layer having a second polymer covalently bonded to the first polymer on the first coating layer; and a third coating layer having a drug and a third polymer supporting the drug on the second coating layer, wherein the second polymer and the third polymer form an interpenetrating polymer network structure. With this type of configuration, an effect is provided that the drug has a predicted pharmacological efficacy and the drug elution is sustained release because the drug is supported by the third polymer while having its original structure, and the coating layer has a high peel durability because the third polymer forms an interpenetrating polymer network structure with the second polymer. The second polymer and the third polymer can have an identical monomeric unit. With this configuration, the affinity between the second polymer and the third polymer is improved, an interpenetrating polymer network structure is easily formed between the second coating layer and the third coating layer, and the bonding strength between the second coating layer and the third coating layer is increased, thus improving the peel durability of the coating layer. The second polymer can be a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer. With this type of configuration, a covalent bond forms between the functional group of the crosslinkable monomer and the first polymer, enhancing the bond strength between the first and second coating layers and thus improving the peel durability of the coating layer. Furthermore, the functional group of the base polymer is not necessarily covalently bonded to the first polymer, and a wide variety of polymers can be selected as the base polymer. The third polymer may have a lactic acid monomer unit. With this type of configuration, biological safety and sustained release of the drug elution are improved. The second polymer and the third polymer may have a lactic acid monomer unit. This configuration enhances the affinity between the second and third polymers, facilitates the formation of an interpenetrating polymer network structure between the second and third coating layers, and increases the bond strength between them, thereby improving the coating layer's peel durability. Furthermore, it enhances biosafety and the sustained release of the drug during elution. The base polymer may have a lactic acid monomer unit and the crosslinkable monomer may be a (met) acrylate. With this configuration, a covalent bond is easily formed between the first coating layer and the second coating layer, and a crosslinked structure of the base polymer and the crosslinkable monomer is created, thus improving the peel durability of the coating layer. (Met) acrylate can be a tetra(met) acrylate or of higher functionality. With this type of configuration, a covalent bond is easily formed between the first coating layer and the second coating layer, thus improving the peel durability of the coating layer. The third polymer and the base polymer may have a lactic acid monomer unit, the crosslinkable monomer may be a tetra or higher functional acrylate, and the crosslinkable monomer may be contained in an amount of 5% by weight or more and 90% by weight or less with respect to the weight (100% by weight) of the base polymer. With this configuration, a covalent bond is easily formed between the first coating layer and the second coating layer, and an interpenetrating polymer network structure is formed between the second coating layer and the third coating layer, thus improving the durability against peeling of the coating layer. The third polymer and the base polymer may have a monomeric unit of lactic acid, the crosslinkable monomer may be a tetrafunctional acrylate or higher, and the crosslinkable monomer may be contained in an amount of 30% by weight or more and 90% by weight or less with respect to the weight (100% by weight) of the base polymer. With this configuration, a covalent bond is more easily formed between the first coating layer and the second coating layer than in the case where the crosslinkable monomer is contained in an amount of 5% by weight or more and less than 30% by weight with respect to the weight (100% by weight) of the base polymer, thus improving the durability against peeling of the coating layer. The third polymer and the base polymer may have a lactic acid monomer unit, the crosslinkable monomer may be a tetrafunctional or higher functionality acrylate, and the crosslinkable monomer may be contained in an amount of 30% by weight or more and 70% by weight or less with respect to the weight (100% by weight) of the base polymer. With this type of configuration, an interpenetrating polymer network structure between the second and third coating layers is more easily formed than in the case where the crosslinkable monomer is contained in an amount of more than 70% by weight and 90% by weight or less with respect to the weight (100% by weight) of the base polymer, thus improving the peel durability of the coating layer. Furthermore, the drug-eluting stent is particularly suitable as the drug-eluting medical device of the present invention because a force is likely to be applied to peel off the coating layer during assembly, delivery, and expansion, and the elution of a drug that suppresses a biological reaction causing restenosis needs to last at least several months or longer. Therefore, the drug-elution medical device can be a drug-elution stent. A method for producing a drug-elution medical device that achieves an object of the present invention includes: a first step of applying a first solution containing a dopamine molecule or an analogue thereof as a first coating material onto a substrate and polymerizing the first coating material to form a first coating layer having a first polymer; a second step of applying a second solution containing a polymer and / or a monomer as a second coating material onto the first coating layer, and then performing heating or light irradiation to form a second coating layer having a second polymer;and a third step of applying a third solution containing a drug and a polymer as a third coating material over the second coating layer, and then performing drying to form a third coating layer that has a third polymer that supports the drug. During production at this stage, a first coating layer composed of polydopamine or a polydopamine-like polymer is formed. In the second stage, a second coating layer is formed in which the second coating material is crosslinked and / or polymerized, and a covalent bond is formed between the first and second coating layers. Furthermore, in the third stage, a third coating layer is formed in which the drug is supported on the polymer and released sustainably. An interpenetrating polymer network structure is formed between the second and third coating layers, and the drug, as the third coating material, is supported on the polymer without losing its original pharmacological efficacy.Therefore, it is possible to produce a drug elution medical device where the drug elution is sustained release and the durability of the coating layer detachment is high without losing the original drug efficacy. At least part of the second coating material may be soluble in a solvent of the third solution, and in the third stage, the second coating layer may swell when the third solution is applied over the second coating layer. With such characteristics, the polymer as the third coating material easily penetrates the second coating layer, promoting the formation of the interpenetrating polymer network structure between the second and third coating layers, increasing the bonding strength between the second and third coating layers, thus improving the peel durability of the coating layer. The polymer that constitutes the second coating layer and the polymer that constitutes the third coating layer formed by the production method described above may have characteristics of the second polymer and the third polymer in the drug elution medical device that achieves an object of the present invention. Specifically, in the method for producing a drug elution medical device, (1) the second polymer and the third polymer may have an identical monomeric unit; (2) the third polymer may have a lactic acid monomeric unit; (3) the second polymer and the third polymer may have a lactic acid monomeric unit; (4) the second polymer may be a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer; (5) in the preceding (4), the base polymer may have a lactic acid monomeric unit, and the crosslinkable monomer may be a (meth) acrylate; (6) in the preceding (5), the (meth) acrylate may be a tetra-functional or higher (meth) acrylate;and / or (7) in the preceding (4) to (6), the third polymer may have a lactic acid monomeric unit, and the crosslinkable monomer may be contained in an amount of 5 wt% or more and 90 wt% or less with respect to 100 wt% of the base polymer. Since the second polymer and the third polymer have the above characteristics, the peel durability of the coating layer is improved. The method described above for producing a drug elution medical device may be a method for producing a drug elution stent. List of reference signs 10 Drug-releasing medical device 20 Substrate 30 Coating layer 31 First coating layer 32 Second coating layer 33 Third coating layer

Claims

1. A drug-elution medical device comprising: a substrate; a first coating layer having a first polymer obtained by auto-oxidation polymerization of a dopamine molecule or an analogue thereof on the substrate; a second coating layer having a second polymer covalently linked to the first polymer in the first coating layer; and a third coating layer having a drug and a third polymer supporting the drug on the second coating layer, wherein the second polymer and the third polymer are hydrophobic and form an interpenetrating polymer network structure.

2. A drug-elution medical device according to claim 1, wherein the second polymer and the third polymer have an identical monomeric unit.

3. A drug-elution medical device according to claim 1 or 2.wherein the third polymer has a lactic acid monomer unit.

4. Drug-eluting medical device according to any one of claims 1 to 3, wherein the second polymer and the third polymer have a lactic acid monomer unit.

5. Drug-elution medical device according to any one of claims 1 to 4, wherein the second polymer is a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer.

6. Drug-eluting medical device according to claim 5, wherein the base polymer has a lactic acid monomer unit, and the crosslinkable monomer is a (meth)acrylate.

7. Drug-eluting medical device according to claim 6, wherein the (meth)acrylate is a tetrafunctional or higher-functionality (meth)acrylate.

8. Drug-eluting medical device according to any one of claims 5 to 7,wherein the third polymer has a lactic acid monomer unit, and the crosslinkable monomer is contained in an amount of 5% by weight or more and 90% by weight or less with respect to 100% by weight of the base polymer.

9. A drug-releasing medical device according to any one of claims 5 to 7, wherein the third polymer has a lactic acid monomer unit, and the crosslinkable monomer is contained in an amount of 30% by weight or more and 90% by weight or less with respect to 100% by weight of the base polymer.

10. A drug-releasing medical device according to any one of claims 5 to 7, wherein the third polymer has a lactic acid monomer unit,and the crosslinkable monomer is contained in an amount of 30% by weight or more and 70% by weight or less with respect to 100% by weight of the base polymer.

11. A drug-eluting medical device according to any one of claims 1 to 10, which is a drug-eluting stent.

12. A method for producing a drug-elution medical device, the method comprising: a first step of applying a first solution containing a dopamine molecule or an analogue thereof as a first coating material onto a substrate and polymerizing the first coating material to form a first coating layer having a first polymer; a second step of applying a second solution containing a polymer and / or a monomer as a second coating material onto the first coating layer,and then performing heating or light irradiation to form a second coating layer having a second polymer; and a third step of applying a third solution containing a drug and a polymer as a third coating material onto the second coating layer, and then performing drying to form a third coating layer having a third polymer that supports the drug, wherein the second polymer and the third polymer are hydrophobic.

13. A method for producing a drug-eluting medical device according to claim 12, wherein at least a portion of the second coating material is soluble in a solvent of the third solution, and in the third step, the second coating layer swells when the third solution is applied onto the second coating layer.

14. A method for producing a drug-eluting medical device according to claim 12 or 13,wherein the second polymer and the third polymer have an identical monomer unit.

15. A method for producing a drug-elution medical device according to any one of claims 12 to 14, wherein the third polymer has a lactic acid monomer unit.

16. A method for producing a drug-elution medical device according to any one of claims 12 to 15, wherein the second polymer and the third polymer have a lactic acid monomer unit.

17. A method for producing a drug-elution medical device according to any one of claims 12 to 16, wherein the second polymer is a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer.

18. A method for producing a drug-elution medical device according to claim 17, wherein the base polymer has a lactic acid monomer unit.and the crosslinkable monomer is a (meth) acrylate.

19. A method for producing a drug-eluting medical device according to claim 18, wherein the (meth) acrylate is a tetra(meth) acrylate or of higher functionality.

20. A method for producing a drug-eluting medical device according to any one of claims 17 to 19, wherein the third polymer has a lactic acid monomer unit, and the crosslinkable monomer is contained in an amount of 5 wt% or more and 90 wt% or less with respect to 100 wt% of the base polymer.

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