Drug-eluting medical devices and methods for manufacturing the same

Abstract

[Problem] To provide: a drug-eluting medical device that provides sustained drug release and has high peeling durability for coating layers; and a production method therefor. [Solution] A drug-eluting medical device that has: a base material 20; a first coating layer 31 that has a first polymer wherein dopamine molecules or an analog thereof has self-oxidized and polymerized on the base material 20; a second coating layer 32 that has a second polymer that forms a covalent bond with the first polymer on the first coating layer 31; and a third coating layer 33 that has a drug and a third polymer that that is loaded with the drug, on the second coating layer 32. The second polymer and the third polymer form an interpenetrating polymer network.

Description

[Technical Field]

[0001] The present invention relates to a drug-eluting medical device and a method for manufacturing the same. [Background Art]

[0002] A drug-eluting stent (hereinafter also referred to as "DES") is known as a drug-eluting medical device. DES is a device in which a drug such as an immunosuppressant is coated on the surface of a stent, which is a tubular structure capable of radially expanding and contracting. When treating a lesion such as stenosis occurring in a biological lumen such as a blood vessel using DES, an operator percutaneously introduces a catheter with DES mounted thereon into the biological lumen, delivers it to the lesion, and expands the DES. The drug coated on the DES infiltrates the lesion, and the medicinal effect is exerted locally at the lesion.

[0003] Properties required for DES include high peeling durability between the drug and the stent, and sustained release of the drug.

[0004] Regarding peeling durability, the drug may peel off from the stent surface during mounting, delivery, and expansion, which reduces the drug loading amount. In particular, if drug peeling occurs when DES is in a living body during processes such as delivery and expansion, the peeled drug and thrombus formation starting from the peeled drug may occlude the peripheral biological lumen, leading to serious damage. Therefore, high peeling durability between the drug and the stent is required.

[0005] Regarding sustained release, long-term duration of medicinal effect is often required for treating lesions. For example, when expanding a stent at a stenotic lesion in a blood vessel, physical stimulation caused by stent expansion induces biological reactions such as excessive proliferation of smooth muscle cells, which causes restenosis. Such a biological reaction starts immediately after stent placement and is said to reach a peak in about several months to half a year. In this case, drug elution from DES needs to be sustained for at least several months or longer. Therefore, sustained release of the drug is required.

[0006] From this perspective, various techniques have been disclosed for supporting drugs using polymers and coating the stent surface with them.

[0007] Patent Document 1 discloses a technique for forming a medical device having a hydrophilic coating with excellent peel resistance, comprising a first coating layer coated on a substrate with polydopamine, known as an ideal primer applicable to a wide range of substrates such as metals, ceramics, and polymers, and a second coating layer coated on the first coating layer with a crosslinked copolymer having hydrophilic function. Patent Document 1 discloses that the second coating layer may be in the form of a crosslinked copolymer formed via a crosslinking agent, in which the functional groups in the crosslinked copolymer are covalently bonded to polydopamine, and that the second coating layer may contain chemical substances (drugs) having pharmacological activity such as antithrombotic agents, hemostatic agents, angiogenesis inhibitors, angiogenic agents, antibacterial agents, antiproliferative agents, growth agents, and anti-inflammatory drugs. Patent Document 1 gives a stent as an example of a medical device to which this technique is applied. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Special Publication No. 2016-508776 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] However, when the technology described in Patent Document 1 is applied to a stent, it becomes difficult to satisfy the characteristic of sustained drug release required for DES. In "Example 5 - Formation of a hydrophilic coating containing beneficial chemical substances" of Patent Document 1, various drugs are introduced into the hydrophilic coating (second coating layer) by the following methods: coating with an aqueous solution containing heparin and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) after forming a hydrophilic coating which is the second coating layer; alternately coating with a heparin layer and a polyamine layer; coating with an aqueous solution containing heparin and NaCl; coating with an aqueous solution containing doxorubidin; or coating with an ethanol solution of silver carbonate and chlorhexidine. In this case, the drug adheres to the surface of the second coating layer. If the structure of the second coating layer is porous and there are gaps into which the drug can enter, the drug may enter those gaps. However, generally speaking, the binding force of the drug to the polymer is weak, and in all of the above cases, the drug is released early. In order to release the drug slowly, it is preferable that it be incorporated into the interior of a non-porous coating layer. Even if the hydrophilic polymer of the second coating layer in Patent Document 1 is replaced with a polymer such as polylactic acid, which is well known as a polymer that supports DES drugs, the situation in which sustained drug release is difficult remains unchanged.

[0010] On the other hand, it is possible to incorporate a drug into a non-porous coating layer by forming a covalent bond between the second and first coating layers while the drug is already present. However, in this case, the heat and light required to form the covalent bond may break chemical bonds within the drug, or radicals from polymerization initiators generated during the reaction process may cause oxidation reactions at the cleavage sites, resulting in the production of related substances with altered structures of the original drug. Consequently, the drug's efficacy is lost, and if the related substances cause side effects, they become harmful.

[0011] This invention was made to solve the above-mentioned problems, and aims to provide a drug-eluting medical device and a method for manufacturing the same, which exhibits sustained drug release and high durability of the coating layer peeling. [Means for solving the problem]

[0012] A drug-eluting medical device that achieves the above objective comprises a substrate, a first coating layer having a first polymer formed by the auto-oxidative polymerization of dopamine molecules or their analogs 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.

[0013] Furthermore, a method for manufacturing a drug-eluting medical device that achieves the above objective is characterized by comprising: a first step of applying a first solution containing a dopamine molecule or its analogue, which is a first coating material, onto a substrate to form a first coating layer having a first polymer by polymerization of the first coating material; a second step of applying a second solution containing a polymer and / or monomer, which is a second coating material, onto the first coating layer, and then heating or irradiating with light 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, which is a third coating material, onto the second coating layer, and then drying to form a third coating layer having a third polymer supporting the drug. [Effects of the Invention]

[0014] The drug-eluting medical device configured as described above, and the drug-eluting medical device manufactured by the above manufacturing method, have the following characteristics: the drug is supported on the third polymer in its original structure, the drug has the intended therapeutic effect, the drug is released in a sustained manner, and the third polymer forms an interpenetrating polymer network structure with the second polymer, resulting in high durability of the coating layer's peeling resistance. [Brief explanation of the drawing]

[0015] [Figure 1]This is a cross-sectional view of the substrate and coating layer of a drug-eluting medical device according to an embodiment. [Figure 2] This is a TEM image of a cross-section of the coating layer (interface between the second and third coating layers) in the example. [Figure 3] This is a TEM image of a cross-section of the coating layer (interface between the second and third coating layers) in the example. [Figure 4] This is a TEM image of the cross-section of the coating layer of the comparative example (the interface between the second and third coating layers). [Modes for carrying out the invention]

[0016] Embodiments of the present invention will be described below with reference to the drawings. Note that the dimensional ratios in the drawings may be exaggerated for illustrative purposes and may differ from the actual ratios.

[0017] As shown in Figure 1, the drug-eluting medical device 10 according to this embodiment has a substrate 20 and a coating layer 30. The coating layer 30 has a first coating layer 31 that coats the substrate 20, a second coating layer 32 that coats the first coating layer 31, and a third coating layer 33 that coats the second coating layer 32. The first coating layer 31 may coat the entire substrate 20, or it may coat at least a part of it. The second coating layer 32 may coat the entire first coating layer 31, or it may coat at least a part of it. The third coating layer 33 may coat the entire second coating layer 32, or it may coat at least a part of it. If the drug-eluting medical device 10 has a cylindrical shape such as a DES, the coating layer 30 may coat all of the surfaces of the stent substrate 20, including the outer surface on the tissue side of the biological lumen, the inner surface on the lumen side of the biological lumen, and the sides located between the outer and inner surfaces, or it may coat only one or two of these surfaces. Furthermore, the coating layer 30 coats all or at least part of each surface, and the coating layer 30 on each surface may be formed integrally or separately.

[0018] In at least a part of the coating layer 30, such as an end portion of the coating layer 30 in a direction parallel to the surface of the base material 20, the contact relationship between the base material 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 does not necessarily have to be satisfied. For example, the base material 20 and the second coating layer 32 may be in contact with each other, and the third coating layer 33 may not be provided on the second coating layer 32. The contact relationship between the base material 20 and the first coating layer 31, between the first coating layer 31 and the second coating layer 32, and between the second coating layer 32 and the third coating layer 33 only needs to be satisfied in at least a part of the coating layer 30.

[0019] <Medical device 10> The drug-eluting medical device 10 according to the present embodiment is a medical device that is used to come into contact with a body tissue and transfer a drug to the body tissue. Since the drug elution has sustained-release properties, the medical device 10 is suitable for use in medical devices that are in contact with body tissues for a long time, and is more suitable for use in implantable medical devices that can be embedded in the body. Examples of medical devices used for coming into contact with body tissues and transferring drugs to body tissues include catheters such as balloon catheters, contrast catheters, ablation catheters, suction catheters, perfusion catheters, imaging catheters, and microcatheters; sheathes such as sheath introducers and guiding sheathes; guide wires; and medical patches such as anti-inflammatory analgesic patches. Examples of implantable medical devices that can be embedded in the body include stents, stent grafts, artificial blood vessels, artificial bones, artificial heart valves, pacemakers, artificial joints, auxiliary artificial hearts, indwelling catheters, embolization coils, aneurysm clips, thrombus filters, and implantable insulin pumps.

[0020] Furthermore, due to the high peeling durability of the coating layer, medical devices to which a force that peels the coating layer 30 is easily applied before and after introducing the drug-eluting medical device 10 according to the present embodiment to a target position in the body are suitable as the drug-eluting medical device 10 according to the present embodiment. The above-mentioned implantable medical device that can be implanted in the body is easily applied with a force that peels the coating layer 30 before and after being introduced to a target position in the body.

[0021] During mounting, delivery, and expansion, a force that peels the coating layer 30 is easily applied to DES, and it is necessary that the elution of the drug that suppresses biological reactions causing restenosis persists for at least several months or more. Therefore, DES is particularly suitable as the drug-eluting medical device 10 according to the present embodiment. However, the drug-eluting medical device 10 according to the present embodiment is not limited to DES, and can also be applied to the above-mentioned medical devices.

[0022] <Base material 20> The base material 20 of the drug-eluting medical device 10 according to the present embodiment is made of metal, polymer, ceramic, or fibrous protein such as silk or wool. At least a part of the base material 20 may be composed of one or more of these materials.

[0023] Examples of metals applicable to the base material 20 include, but are not limited to, stainless steel, cobalt-chromium alloy, platinum, platinum alloy, nickel-titanium alloy, titanium alloy, tantalum, tantalum alloy, gold, silver, iron, zinc, magnesium, niobium alloy, and mixtures thereof.

[0024] Examples of polymers applicable to the base material 20 include, but are not limited to, polyglycolic acid, polylactic acid, polycaprolactone, polydioxanone, polytetrafluoroethylene, trimethylene carbonate, polyethylene terephthalate, polybutylene terephthalate, polybutylene 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 covinyl acetate, polyethylene elastomer, polyvinyl chloride, rubber, silicone rubber, polyhydroxy acid, polyallylamine, polyallyl alcohol, polyacrylamide, polyacryllonitrile, acrylic oxide, polyacrylic acid, polymethacrylic acid, polystyrene, polyoxymethylene, phenolic resin, amino epoxy resin, cellulose-based plastics, and copolymers, derivatives, and mixtures thereof. A copolymer refers to any polymer formed from two or more monomers. These polymers may or may not be crosslinked. Furthermore, these polymers may be blended with fillers or colorants.

[0025] Examples of ceramics that can be applied to the substrate 20 include, but are not limited to, silicone oxide, aluminum oxide, silica, hydroxyapatite, glass, calcium oxide, polysilanol, and phosphorus oxide.

[0026] The surface of the substrate 20 of the drug-eluting medical device 10 according to this embodiment may be smooth or rough. Furthermore, in order to improve adhesion with the first coating layer 31, known surface treatment techniques such as cleaning or plasma treatment may be applied to the surface of the substrate 20.

[0027] <First coat layer 31> The first coating layer 31 of the drug-eluting medical device 10 according to this embodiment has a first polymer formed by the autooxidative polymerization of dopamine molecules or their analogs. The first polymer is preferably polydopamine, which is a polymer formed by the autooxidative polymerization of dopamine molecules, which are catecholamines. In 2007, Lee and Messersmith et al. discovered that polydopamine can be coated on the surface of a wide range of substrate materials, has high peel resistance through hydrogen bonding and coordination bonding to hydrophilic substrates, and hydrophobic interactions such as π-π interactions to hydrophobic substrates, and is also easily modified (Science, 2007, pp. 318, 426-430), and since then, polydopamine has attracted attention as a highly versatile coating material. Its structure has been proposed to include a structure in which 5,6-dihydroxyindole and non-cyclized dopamine produced by the oxidation of dopamine molecules are continuously bonded by covalent bonds, as exemplified in Figure 3 of Patent Document 1, and a structure in which supramolecular aggregates are formed by bonding through physical interactions other than covalent bonds. The structure of the first polymer obtained by the autooxidative polymerization of a dopamine molecule or its analogues in the present invention is not limited to a specific structure, but represents all possible structures that a dopamine molecule or its analogues can take when undergoing autooxidative polymerization.

[0028] Furthermore, the first coating layer 31 has the structure of the first polymer in at least a portion of it. That is, the first coating layer 31 may contain structures derived from substances other than dopamine molecules or their analogues. As an example of the presence of the first polymer structure in a portion of the coating layer, Japanese Patent Publication No. 2016-513545 discloses a coating layer polymerized by mixing dopamine molecules and molecules that covalently bond to dopamine molecules in order to improve the adhesion between the substrate and polydopamine. In this case, a portion of the coating layer has the structure of polydopamine, and structures derived from molecules that covalently bond to dopamine molecules are included in the coating layer as structures derived from substances other than dopamine molecules or their analogues. As another example, the first coating layer 31 may contain substances that do not covalently bond to dopamine molecules or their analogues. In this case as well, the first coating layer 31 has the structure of the first polymer in at least a portion of it and is within the technical scope of the present invention.

[0029] The first coating layer 31 may have a first polymer formed by the autooxidative polymerization of dopamine analogs, which are analogs of the dopamine molecule. Alternatively, the first coating layer 31 may have a first polymer formed by the autooxidative polymerization of multiple dopamine analogs. Alternatively, the first coating layer 31 may have a first polymer formed by the autooxidative polymerization of a dopamine molecule and one or more dopamine analogs. The chemical formulas of the dopamine analogs are, for example, the chemical formulas described in paragraphs "0189" to "0193" and "0228" to "0230" of Patent Document 1.

[0030] The thickness of the first coating layer 31 is not particularly limited, but is, for example, 1 to 200 nm, preferably 5 to 150 nm, more preferably 10 to 100 nm, and even more preferably 15 to 80 nm. The thickness of the first coating layer 31 may be uniform or non-uniform. The surface of the first coating layer 31 may be smooth or rough. The thickness of the first coating layer is measured, for example, by an atomic force microscope (AFM).

[0031] <Second coating layer 32> The second coating layer 32 of the drug-eluting medical device 10 according to this embodiment has a second polymer that is covalently bonded to a first polymer formed by the autooxidative polymerization of dopamine molecules or their analogues. The second coating layer 32 is formed, for example, by placing the material of the second polymer on the first coating layer 31 and applying energy such as heat or light. The second coating layer 32 may 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.

[0032] The covalent bond between the first polymer and the second polymer is formed, for example, by a functional group of the first polymer from which an abstractable hydrogen atom has been abstracted on the surface of the first coating layer 31, and by a functional group of the second polymer in the second coating layer 32 in contact with the surface of the first coating layer 31. In another example, it is formed by a polymerizable functional group of the first polymer on the surface of the first coating layer 31, and by a functional group of the second polymer in the second coating layer 32 in contact with the surface of the first coating layer 31. The functional groups that form the covalent bond are determined by the materials and structures of the first and second polymers. Patent Document 1 suggests that the functional group that forms the covalent bond on the substrate side is a functional group from which an abstractable hydrogen atom has been abstracted on the substrate surface when the radical initiator, which is the polymerization initiator, is Norrish type II, and is a polymerizable functional group on the substrate surface when the radical initiator is Norrish type I. In the present invention, the mechanism of covalent bonding between the first polymer and the second polymer is not particularly limited.

[0033] The second polymer of the second coating layer 32 is preferably a crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer. This configuration allows for the formation of covalent bonds between the functional groups of the crosslinkable monomer and the first polymer on the surface of the first coating layer 31, improving the bonding strength between the first coating layer 31 and the second coating layer 32 and enhancing the peel resistance of the coating layer 30. In this case, the functional groups of the base polymer do not necessarily need to covalently bond with the first polymer on the surface of the first coating layer 31, allowing for the selection of a wide range of polymers as the base polymer. Furthermore, covalent bonds may also be formed between the functional groups of the base polymer and the first polymer on the surface of the first coating layer.

[0034] When the second polymer of the second coating layer 32 is a crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer, the base polymer can be, for example, polyester, aliphatic polyester, polyacid anhydride, polyorthoester, polycarbonate, polyphosphazene, polyphosphate ester, polyvinyl alcohol, polypeptide, polysaccharide, protein, cellulose, and copolymers, derivatives, or 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. The copolymer can be, but is not limited to, alternating copolymers, random copolymers, block copolymers, or graft copolymers.

[0035] While optical isomers may exist for the monomers that make up these polymers, the polymers are not limited to those composed of specific optical isomers. For example, lactic acid (LA), a constituent monomer of polylactic acid (PLA), exists in the form of L-lactic acid and D-lactic acid, which have different optical activities. Therefore, polylactic acid can be poly-L-lactic acid (PLLA), which is polymerized from L-lactic acid; poly-D-lactic acid (PDLA), which is polymerized from D-lactic acid; and poly-D,L-lactic acid (PDLLA), which is a random copolymer of L-lactic acid and D-lactic acid. However, the polymers are not limited to any of these.

[0036] In this invention, polymers polymerized using lactic acid as a monomer are referred to as polymers having lactic acid monomer units, regardless of the optical activity of the lactic acid used. Lactic acid monomer units refer to the form in which lactic acid reacts within the polymer. Polymers polymerized using not only polylactic acid but also lactic acid and other monomers are included in polymers having lactic acid monomer units.

[0037] Furthermore, natural polymer materials such as collagen, fibrin, elastin, proteins, extracellular matrix components, other biologically active substances, and their derivatives or mixtures may be used as the base polymer.

[0038] In the present invention, in preferred embodiments, the base polymer has lactic acid monomer units. That is, the second polymer preferably has lactic acid monomer units. The content of lactic acid monomer units in the base polymer is preferably 50 mol% or more (up to 100 mol%), and more preferably 70 mol% or more (up to 100 mol%), relative to the total monomers constituting the base polymer. Furthermore, the second polymer is preferably hydrophobic from the viewpoint of being able to better exhibit the intended effects of the present invention. Therefore, the base polymer is also preferably hydrophobic.

[0039] Furthermore, 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 viewpoint of peel durability and other factors. In this specification, the weight-average molecular weight is the value measured by gel permeation chromatography (GPC) using polystyrene as the standard substance under the following measurement conditions.

[0040] (Measurement conditions for molecular weight) Equipment: Semi-micro GPC system LC-VP system (manufactured by Shimadzu Corporation) Detector: Shodex® RI-104 (manufactured by Showa Denko K.K.) Columns: Two Shodex® GPC LF-804 columns (manufactured by Showa Denko Corporation) were used. Guard column: Shodex® LF-G (manufactured by Showa Denko Corporation) Column temperature: 40℃ Mobile phase solvent: CHCl3 Flow rate: 1.00mL / min Injection volume: 200μL.

[0041] When the second polymer of the second coating layer 32 is a crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer, it is preferable that the crosslinkable monomer has high affinity with the base polymer and strong bonding with the first polymer on the surface of the first coating layer 31.

[0042] Examples of crosslinkable monomers include those having functional groups such as vinyl (CH2=CH-), allyl (CH2=CH-CH2-), acryloyl (CH2=CH-CO-), methacryloyl (CH2=C(CH3)-CO-), and acrylamide (CH2=CH-CO-NH-), which are types of vinyl groups. Generally, the greater the polarity of the chemical structure connected to the terminal structure with an unsaturated bond of the functional group (CH2=CH- or CH2=C(CH3)- in the above example), the greater the reactivity of the crosslinkable monomer. The relationship between the magnitudes of these polarities is (allyl group) < (acryloyl group) ≈ (methacryloyl group) < (acrylamide group). Therefore, the reactivity of crosslinkable monomers having an allyl group is often less than that of crosslinkable monomers having an acryloyl or methacryloyl group, and the reactivity of crosslinkable monomers having an acrylamide group is often greater than that of crosslinkable monomers having an acryloyl or methacryloyl group. The reactivity of crosslinkable monomers containing a methacryloyl group is slightly lower than that of crosslinkable monomers containing an acryloyl group, due to the steric hindrance of the CH3 group within the methacryloyl group, but is equivalent to that of crosslinkable monomers containing an acryloyl group. Furthermore, among crosslinkable monomers with the same type of functional group, the reactivity increases as the number of functional groups increases. Hereafter, when (meth)acrylate is used, it refers to both acrylate, which is a crosslinkable monomer containing an acryloyl group, and methacrylate, which is a crosslinkable monomer containing a methacryloyl (methacryloyl) group.

[0043] Examples of difunctional (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 di(meth)acrylate, neopentyl glycol 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 1,10-decanediol di(meth)acrylate. Examples of trifunctional (meth)acrylates include trimethylolpropane tri(meth)acrylate, pentaerythritol tri(meth)acrylate, and tetramethylolmethane(meth)acrylate. Examples of tetrafunctional or more (meth)acrylates include pentaerythritol tetra(meth)acrylate, ditrimethylolpropane tetra(meth)acrylate, dipentaerythritol penta / hexa(meth)acrylate, dipentaerythritol hexa(meth)acrylate, and dipentaerythritol monohydroxypenta(meth)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)acrylamidemethylene)urea, N-[tris(3-(meth)acrylamidepropoxymethyl)methyl](meth)acrylamide (e.g., FOM-03006; N-[tris(3-acrylamidepropoxymethyl)methyl]acrylamide), N,N-bis(2-(meth)acrylamideethyl)(meth)acrylamide Examples include FOM-03007 (N,N-bis(2-acryloylamideethyl)acrylamide), N,N'-[oxybis(2,1-ethanediyloxy-3,1-propanediyl)]bis(meth)acrylamide (e.g., FOM-03008; N,N'-[oxybis(2,1-ethanediyloxy-3,1-propanediyl)]bisacrylamide), and N,N'-1,2-ethanediylbis{N-[2-(meth)acryloylamino)ethyl](meth)acrylamide} (e.g., FOM-03009; N,N'-1,2-ethanediylbis{N-[2-(acryloylamino)ethyl]acrylamide}). Examples of crosslinkable monomers having an allyl group include triallyl trimellitic acid ester, triallyl pyromellitic acid ester, diallyl oxalate, triallyl cyanurate, and triallyl isocyanurate (TAIC). Of these, from the viewpoint of having high bonding affinity with the first polymer on the surface of the first coating layer 31, the crosslinkable monomer is preferably a (meth)acrylate, and more preferably a (meth)acrylate with four or more functions.

[0044] In the present invention, from the viewpoint of high affinity between the base polymer and the crosslinkable monomer, it is preferable that the base polymer has lactic acid monomer units and the crosslinkable monomer is (meth)acrylate.

[0045] When the second polymer is a crosslinkable polymer formed by crosslinking a crosslinkable monomer and a base polymer, the content ratio (weight ratio) of the crosslinkable monomer to the base polymer is not particularly limited, however, the crosslinkable monomer is preferably contained in an amount of 1% to 95% by weight, more preferably 5% to 90% by weight, even more preferably 10% to 90% by weight, even more preferably 30% to 90% by weight, and particularly preferably 30% to 70% by weight, based on the weight (100% by weight) of the base polymer. In one embodiment, the crosslinkable monomer is preferably contained in an amount of 20% to 80% by weight, and more preferably 30% to 75% by weight, based on the weight (100% by weight) of the base polymer. When the crosslinkable monomer is contained within the above range, the interpenetrating polymer network structure described later can be efficiently formed, and the intended effects of the present invention can be more fully realized.

[0046] Furthermore, the crosslinkable monomers in the present invention are not limited to those having a vinyl group, allyl group, acryloyl group, methacryloyl group, or acrylamide group as a functional group. Examples of other crosslinkable monomers having functional groups include maleimide compounds such as N-phenylmaleimide and N,N'-m-phenylenebismaleimide, compounds having two or more triple bonds such as dipropagyl phthalate and dipropagyl maleate, and divinylbenzene.

[0047] A crosslinked polymer may be formed by crosslinking a base polymer with a crosslinkable monomer, or by crosslinking a base polymer's constituent monomer with a crosslinkable monomer. The structure of a crosslinked polymer formed by crosslinking a base polymer's constituent monomer with a crosslinkable monomer also has the structure of a crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer. A crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer is a polymer that has constituent monomer units of the base polymer and crosslinkable monomer units in its molecular structure. Here, the constituent monomer units of the base polymer refer to the form obtained when the constituent monomers of the base polymer react in the crosslinked polymer, and the crosslinkable monomer units refer to the form obtained when the crosslinkable monomer reacts in the crosslinked polymer.

[0048] A crosslinked polymer may be composed of one type of base polymer or one type of constituent monomer of a base polymer and one type of crosslinkable monomer, but it may also be composed of multiple base polymers or multiple constituent monomers of base polymers and multiple crosslinkable monomers.

[0049] The second polymer of the second coating layer 32 does not have to be a structure in which the base polymer and a crosslinkable monomer are crosslinked. For example, if a polymer having one or more functional groups selected from vinyl, allyl, acryloyl, methacryloyl, or acrylamide groups is used as the second polymer, and this 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 be formed between the first polymer and the second polymer. The number and position of these functional groups in the second polymer are not limited. Furthermore, in this case, the types of functional groups that the second polymer has are not limited to vinyl, allyl, acryloyl, methacryloyl, and acrylamide groups, but include all functional groups that can form a covalent bond with the first polymer.

[0050] The second coating layer 32 only needs to contain a second polymer that is covalently bonded to the first polymer in at least a portion of it, and may contain additives other than the second polymer. Additives that are intentionally added or unintentionally included during the formation of the second coating layer 32 may form part of the second polymer in a covalently bonded form.

[0051] The second coating layer 32 may contain a polymerization initiator. While thermal polymerization initiators and photopolymerization initiators are known, the process is not limited to either. Multiple polymerization initiators may also be used. Examples of photopolymerization initiators include alkylphenone-based ones such as benzyldimethylketal, α-hydroxyalkylphenone, α-aminoalkylphenone, and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone, as well as acylphosphine oxide-based ones such as MAPO and BAPO, and oxime ester-based ones. Commercially available polymerization initiators may also be used. Examples of commercially available photopolymerization initiators include Irgacure 2959, 184, 1173, 907, 369E, 379EG, TPO, and 819 from BASF. The form of the polymerization initiator may change after energy is applied, but the form of the polymerization initiator present in the second coating layer 32 may be the changed form.

[0052] The crosslinking and polymerization mechanisms of the second polymer are not limited. Furthermore, the primary, secondary, and higher-order structures of the second polymer are not limited.

[0053] The thickness of the second coating layer 32 is not particularly limited, but is 1 to 500 nm, preferably 5 to 400 nm, more preferably 10 to 350 nm, and even more preferably 30 to 250 nm. The thickness of the second coating layer 32 may be uniform or non-uniform. The surface of the second coating layer 32 may be smooth or rough. The thickness of the second coating layer is measured, for example, by AFM.

[0054] <Third coat layer 33> The third coating layer 33 of the drug-eluting medical device 10 according to this embodiment has a drug and a third polymer that supports the drug on 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.

[0055] An interpenetrating polymer network (IPN) structure, also known as an Interpenetrating Polymer Network (IPN), refers to a structure in which one polymer network and another polymer network are intertwined without covalent bonds. When an interpenetrating polymer network structure is formed, the bonding strength within each polymer network is improved. Therefore, it is difficult to separate the entire polymer network after formation into the individual polymer networks that existed before formation. In this 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 improving the bonding strength between the third coating layer 33 and the second coating layer 32, and improving the peeling durability of the coating layer 30.

[0056] The formation of an interpenetrating polymer network structure can be confirmed, for example, by observing a cross-section including the interface of each layer using a transmission electron microscope (TEM). For example, the coating layer 30 of the present invention can be embedded in resin, and the resin-embedded sample can be thinly sliced ​​using an ultramicrotome (Leica EM UC7) to obtain a sample in which the cross-section of the coating layer 30 is exposed. By observing this sample with a TEM, the interpenetrating polymer network structure formed between the second coating layer 32 and the third coating layer 33 can be confirmed. Known resins can be used for embedding, but for example, epoxy resin (Epon812), caprolactone (EVONIK C212), etc., can be preferably used. TEM observation can be specifically performed by the method described in the examples. When an interpenetrating polymer network structure is formed, the interface between the coating layer 32 and the coating layer 33 may become unclear in the TEM image of the cross-section of the coating layer 30, resulting in uneven brightness at the interface, or the brightness at the interface may differ from the brightness of the coating layer 32 and the coating layer 33. Therefore, if the above findings are obtained at the interface between the coating layer 32 and the coating layer 33 in the TEM image, it can be determined that an interpenetrating polymer network structure has been formed.

[0057] Alternatively, the formation of an interpenetrating polymer network structure can be determined by analyzing the layer structure using an optical analysis instrument such as Nano-FTIR. Furthermore, in medical devices having a coating layer, to confirm whether an interpenetrating polymer network structure is formed in the coating layer, one may directly examine the cross-section of the coating layer of the medical device, or one may identify the components contained in the coating layer and examine the cross-section of a sample of the coating layer prepared with the identified components.

[0058] In this invention, when the second polymer and the third polymer form an interpenetrating polymer network structure, the interface between the second coating layer and the third coating layer becomes indistinct. For example, the cross-section of the coating layer may be observed as a four-layer structure consisting of "first coating layer + second coating layer + interpenetrating polymer network structure + third coating layer," or a two-layer structure consisting of "first coating layer + interpenetrating polymer network structure." The present invention can be in either of these forms as long as the interpenetrating polymer network structure is present, and the effects of the present invention are achieved in either form.

[0059] Here, when preparing the coating layer 30, whether or not the third polymer and the second polymer form an interpenetrating polymer network structure can be confirmed, for example, by visual inspection. Specifically, in this embodiment, when the third solution containing the third polymer is applied to the second coating layer 32 containing the second polymer, the third solution containing the third polymer penetrates into the second coating layer, causing the second coating layer to swell. At this time, the thickness of the second coating layer changes, and the color tone derived from the interference color of the coating film changes. This allows us to determine that the third polymer and the second polymer have formed an interpenetrating polymer network structure. Furthermore, whether or not an interpenetrating polymer network structure has been formed can also be confirmed in the peel durability test performed in the embodiments described later.

[0060] Furthermore, the peeling durability of the coating layer 30 improves as the formation of the interpenetrating polymer network is promoted, but the degree of such promotion is not limited in the present invention.

[0061] In the present invention, the third polymer is preferably hydrophobic. The hydrophobic nature of the third polymer allows it to dissolve 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 second coating layer swells as the third solution penetrates it. This forms an interpenetrating polymer network structure between the third polymer and the second polymer. Since the third solution also contains a drug, when the third polymer and the second polymer form the interpenetrating polymer network structure, the drug supported on the third polymer may be incorporated into the network structure. In the present invention, if the third polymer is non-porous, longer-term sustained release of the drug becomes possible. Furthermore, since swelling of the second coating layer by the solvent is necessary, the second polymer is also preferably hydrophobic.

[0062] Furthermore, it is believed that the medical device of the present invention exhibits peel resistance under usage conditions because the third polymer is hydrophobic. For example, if the third polymer is hydrophilic (e.g., polyethylene glycol), the third and second coating layers will swell under usage conditions, making it impossible to maintain the peel resistance of the coating layers and preventing the sustained release of the drug. On the other hand, in the medical device of the present invention, because the third and second polymers are hydrophobic, the third and second coating layers do not swell under usage conditions, and the peel resistance of the coating layers can be maintained.

[0063] Preferably, the second polymer and the third polymer have the same monomer units. This configuration improves the affinity between the second polymer and the third polymer, promotes the formation of an interpenetrating polymer network between the second coating layer 32 and the third coating layer 33, increases the bonding force between the second coating layer 32 and the third coating layer 33, and improves the peel resistance of the coating layer 30. Here, the monomer units of the second polymer and the third polymer refer to the reacted forms of the constituent monomers of each polymer. If each polymer is synthesized using the same constituent monomers regardless of optical activity, the second polymer and the third polymer will have the same monomer units. In a preferred embodiment, the second polymer and the third polymer each have the same monomer units in at least a portion of their respective components.

[0064] The drug in the third coat layer 33 is, for example, at least one compound selected from the group consisting of immunosuppressants, anticancer agents, antibiotics, antirheumatic agents, antithrombotic agents, HMG-CoA reductase inhibitors, ACE inhibitors, calcium channel blockers, antihyperlipidemic agents, integrin inhibitors, antiallergic agents, antioxidants, GPIIb / IIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, anti-inflammatory agents, hemostatic agents, angiogenesis inhibitors, angiogenic agents, bio-derived materials, interferons, and NO production promoters.

[0065] Examples of immunosuppressants include sirolimus, everolimus, pimecrolimus, zotarolimus, biolimus, tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, and gusperimus. Examples of anticancer drugs include paclitaxel and docetaxel. Examples of antibiotics include mitomycin and adriamycin. 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 hifedipine. Examples of antihyperlipidemic drugs include probucol. Examples of integrin inhibitors include AJM300. Examples of antiallergic drugs include tranilast. Examples of antioxidants include α-tocopherol. Examples of GPIIb / IIIa antagonists include absiximab. Examples of retinoids include all-trans retinoic acid. Examples of lipid-lowering agents 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 angiogenesis inhibitors include sunitinib. Examples of angiogenic agents include RGD protein. However, the list is not limited to these.

[0066] The third polymer within the third coating layer 33 supports and slowly releases the drug. Generally, to release the drug slowly, it is preferable that the drug be dispersed within a non-porous polymer. Even if the drug is dispersed within a polymer, if the polymer is porous, the drug may be released prematurely through the polymer's pores. For this reason, it is preferable that the third polymer be non-porous. Also, generally, the release rate of the drug from a drug-supported polymer depends on the diffusion rate of the drug within the polymer in the case of a non-biodegradable polymer, and on the degradation rate of the polymer in addition to the diffusion rate of the drug within the polymer in the case of a biodegradable polymer. The diffusion rate of the drug within the polymer is correlated with the flexibility of the polymer. For this reason, it is known that the drug release rate can be controlled by adjusting the flexibility and degradation rate of the polymer. Furthermore, it is known that polymer surfaces can cause foreign body reactions in living organisms, and such foreign body reactions are known to be a contributing factor to inflammatory reactions. Biodegradable polymers, in which polymer-derived inflammatory reactions will disappear in the future, are preferred over non-biodegradable polymers, in which polymer-derived inflammatory reactions may persist chronically. Based on the above, it is preferable that the third polymer is a non-porous, biodegradable polymer having appropriate flexibility and decomposition rate. The non-porous nature of a polymer can be confirmed by scanning electron microscopy (SEM). In this invention, a polymer being non-porous refers to a polymer that does not have pores that can be confirmed by SEM. For example, a polymer in which gaps of about 0.1 μm can be confirmed by SEM observation is considered porous.

[0067] Examples of such third polymers include polylactic acid, polycaprolactone, polyglycolic acid, polydioxanone, polybutyrolactone, polyvalerolactone, polyhydroxybutyric acid, polytrimethylene carbonate, and copolymers, derivatives, or mixtures thereof. These polymers are hydrophobic and non-porous biodegradable polymers. Among these, polymers having lactic acid monomer units are preferred as third polymers because their degradation products are endogenous metabolites, thus possessing excellent biosafety and excellent drug release rates. Examples include PLLA, PDLA, PDLLA, poly(lactic acid-ε-caprolactone), a copolymer of lactic acid and ε-caprolactone, and poly(lactic acid-glycolic acid), a copolymer of lactic acid and glycolic acid. In particular, when lactic acid is copolymerized with another monomer, the flexibility can be changed by adjusting the ratio of lactic acid to the other monomer, and thus the release rate can be adjusted, which is why it is preferable for the third polymer to have lactic acid monomer units. However, the third polymer is not limited to these.

[0068] In one embodiment, the third polymer is poly(lactic acid-ε-caprolactone), which is a copolymer of lactic acid and ε-caprolactone. In this case, since caprolactone is softer than other polymers, the inclusion of caprolactone as the third polymer can impart flexibility to the third coating layer, thereby improving peel resistance.

[0069] In one embodiment of the present invention, the second polymer and the third polymer preferably have the same monomer units, and more preferably have lactic acid monomer units. With this configuration, the second polymer and the third polymer have the same monomer units, improving the affinity between the second polymer and the third polymer, promoting the formation of an interpenetrating polymer network structure between the second coating layer 32 and the third coating layer 33, increasing the bonding force between the second coating layer 32 and the third coating layer 33, and improving the peel durability of the coating layer 30. Furthermore, the presence of lactic acid monomer units in the third polymer improves biosafety and the sustained release of drug elution. The content of lactic acid monomer units in the third polymer is preferably 50 mol% or more (up to 100 mol%) and more preferably 70 mol% or more (up to 100 mol%) relative to the total monomers constituting the third polymer.

[0070] Furthermore, 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 viewpoint of peel durability and other factors.

[0071] Here, the third polymer forms a good interpenetrating polymer network structure with respect to the base polymer constituting the second polymer. Preferably, the third polymer is present in the same amount as the base polymer constituting the second polymer, and the content ratio (weight ratio) of the third polymer to the base polymer is preferably 2:1 to 1:2, and more preferably 1.5:1 to 1:1.5.

[0072] In one preferred embodiment of the present invention, the third polymer has lactic acid monomer units, and the crosslinkable monomer is contained in an amount of 5% to 90% by weight relative to 100% by weight of the base polymer. In one more preferred embodiment of the present invention, the third polymer has lactic acid monomer units, and the crosslinkable monomer is contained in an amount of 30% to 90% by weight relative to 100% by weight of the base polymer. In one yet another preferred embodiment of the present invention, the third polymer has lactic acid monomer units, and the crosslinkable monomer is contained in an amount of 30% to 70% by weight relative to 100% by weight of the base polymer.

[0073] The third coating layer 33 only needs to contain the drug and the third polymer in at least part of it, and may contain other additives. Examples of additives include elution aids that improve the diffusion rate of the drug within the polymer, such as dimethyl tartrate and diethyl tartrate, but the additives contained in the third coating layer 33 are not limited to these.

[0074] The primary, secondary, and higher-order structures of the third polymer are not limited.

[0075] The drug in the third coating layer 33 is preferably uniformly dispersed, but is not limited to that. Furthermore, the drug present in each dispersed region may form clusters of multiple drug molecules. The third coating layer 33 may also contain nanoparticles, and the drug may be encapsulated within these nanoparticles. The material of the nanoparticles is, for example, a copolymer of lactic acid and glycolic acid.

[0076] In the formation of the third coating layer 33, the drug is formed without applying heat or light energy to prevent the original structure of the drug from changing into a related substance and losing its efficacy. Therefore, the drug is supported on the third polymer in its original structure and does not form covalent bonds with the third polymer. In addition, during the formation process of the third coating layer 33, a portion of the drug may migrate into the second coating layer 32.

[0077] The thickness of the third coating layer 33 is not particularly limited, but is 0.1 to 200 μm, preferably 1 to 150 μm, more preferably 5 to 100 μm, and even more preferably 10 to 80 μm. The thickness of the third coating layer 33 may be uniform or non-uniform. The surface of the third coating layer 33 may be smooth or rough. The thickness of the third coating layer is measured, for example, by a laser microscope.

[0078] Herein, a combination of a second polymer and a 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 lactic acid monomer units, the crosslinkable monomer is a crosslinkable monomer having two or more (preferably four or more) (meth)acrylate groups; and the third polymer has lactic acid monomer units. In this case, the covalent bonds between the first and second coating layers, and the interpenetrating polymer network structure between the second and third coating layers are well formed, and the intended effects of the present invention can be further exhibited.

[0079] For example, if the base polymer of the second polymer is polylactic acid, the crosslinkable monomer is a crosslinkable monomer having two or more (preferably four or more) (meth)acrylate groups (e.g., 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, or dipentaerythritol hexaacrylate); the third polymer is preferably polylactic acid or poly(lactic acid-ε-caprolactone).

[0080] Furthermore, for example, if the base polymer of the second polymer is poly(lactic acid-ε-caprolactone), the crosslinkable monomer is a crosslinkable monomer having two or more (preferably four or more) (meth)acrylate groups (e.g., 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, or dipentaerythritol hexaacrylate); the third polymer is poly-L-lactic acid or poly(lactic acid-ε-caprolactone).

[0081] In one embodiment, when the base polymer of the second polymer has caprolactone units, the crosslinkable monomer is a crosslinkable monomer having two or more (preferably four or more) functional (meth)acrylate, allyl group, or acrylamide group; the third polymer has lactic acid monomer units or caprolactone units. In this case, a covalent bond between the first and second coat layers, and an interpenetrating polymer network structure between the second and third coat layers are well formed, and the effects intended by the present invention can be achieved.

[0082] For example, if the base polymer of the second polymer is polycaprolactone, the crosslinkable monomer is a crosslinkable monomer having two or more functional (preferably four or more functional) (meth)acrylate, allyl group, or acrylamide group; the third polymer is poly-L-lactic acid or poly(lactic acid-ε-caprolactone).

[0083] <Other coating layers> The third coating layer 33 may have an additional coating layer. The additional coating layer may, for example, have a function to suppress the release rate of the drug in the third coating layer 33, thereby providing sustained release, or it may contain a drug other than the drug in the third coating layer 33, thereby assisting the efficacy of the drug in the third coating layer 33. The material of the additional coating layer is not particularly limited.

[0084] <Method for manufacturing drug-eluting medical device 10> The following describes the method for manufacturing the drug-eluting medical device 10 according to this embodiment.

[0085] The method for manufacturing the drug-eluting medical device 10 according to this embodiment comprises: a first step of applying a first solution containing a dopamine molecule or its analogues (hereinafter also referred to as "containing the first coating material"), which is a first coating material, onto a substrate to form a first coating layer 31 formed by polymerization of the first coating material; a second step of applying a second solution containing a polymer and / or monomer (hereinafter also referred to as "containing the second coating material"), which is a second coating material, onto the first coating layer 31, and then forming a second coating layer 32 by heating or light irradiation; and a third step of applying a third solution containing a drug and a polymer (hereinafter also referred to as "containing the third coating material"), which is a third coating material, onto the second coating layer 32, and then drying to form a third coating layer 33. More specifically, the method for manufacturing the drug-eluting medical device 10 according to this embodiment comprises: a first step of applying a first solution containing a dopamine molecule or its analogue, which is a first coating material, onto a substrate to form a first coating layer having a first polymer by polymerization of the first coating material; a second step of applying a second solution containing a polymer and / or monomer, which is a second coating material, onto the first coating layer, and then heating or irradiating with light 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, which is a third coating material, onto the second coating layer, and then drying to form a third coating layer having a third polymer supporting the drug.

[0086] In the first step, a first solution containing a dopamine molecule or its analogues, which is a first coating material, is applied to the substrate, and the first coating material polymerizes to form a first coating layer 31. Since the first coating layer 31 formed by this process is a polymer of polydopamine or a polymer of polydopamine, it has high peel resistance between the substrate 20 and the first coating layer 31, and additional coating with another material is easily performed.

[0087] The base material and dopamine molecule analogs are not particularly limited, but materials such as those exemplified in the description of the embodiment of the first coating layer 31 can be used. The solvent of the solution containing the first coating material is not particularly limited as long as the first coating material is soluble in it. The solution containing the first coating material may also contain additives such as buffers. Furthermore, the first coating material may be in the form of a hydrate or hydrochloride salt of a dopamine molecule or its analogs.

[0088] In the first step, the method of applying the first solution containing the first coating material to the substrate is not particularly limited. A preferred application method is immersion coating. As the solvent for the first solution, for example, water, a buffer solution, or the solvent used in the third solution described later can be used. For example, when dopamine hydrochloride is used as the first coating material, water or a buffer solution is preferred as the solvent, and Tris-HCl buffer solution is more preferred. In the first solution, the content of the first coating material is preferably 0.01 to 30% by mass, more preferably 0.05 to 10% by mass, and even more preferably 0.01 to 5% by mass, based on the total weight of the first solution. Dopamine molecules or their analogs are known to undergo auto-oxidative polymerization, and when the substrate is immersed in a solution containing these, they undergo auto-oxidative polymerization on the substrate surface, forming a thin film on the substrate surface. Alternatively, the first coating layer 31 may be formed by applying the first solution containing the first coating material to the substrate by another method and then polymerizing it by applying energy.

[0089] In the first step, after a film is formed by polymerizing the first coating material, additional steps such as washing, drying, and annealing may be taken to form the first coating layer 31. Regarding the annealing step, adding this step can improve the peel resistance between the substrate and the first coating layer 31. The temperature and time during annealing are not particularly limited.

[0090] In the second step, a second solution containing a polymer and / or monomer, which is the second coating material, is applied onto the first coating layer 31, and then the second coating layer 32 is formed by heating or light irradiation. The second coating material can be any combination thereof: a combination of a base polymer and a crosslinkable monomer; a combination of constituent monomers of the base polymer and a crosslinkable monomer; or a polymer having functional groups that can be covalently bonded with the first coating layer 31. As the base polymer and crosslinkable monomer, the materials exemplified in the description of the embodiment of the second coating layer 32 can be applied. After applying the second solution containing these second coating materials onto the first coating layer 31, heating or light irradiation forms a second coating layer 32 in which the second coating material is crosslinked and / or polymerized, and a covalent bond is formed between the first coating layer 31 and the second coating layer 32, improving the peel resistance between the first coating layer 31 and the second coating layer 32. In other words, in one embodiment, the second step involves applying a second solution containing a polymer and / or monomer, which is a second coating material, onto the first coating layer, and then heating or irradiating with light to form a second coating layer having a second polymer that is covalently bonded to the first polymer.

[0091] The solvent in the second solution containing the second coating material is not particularly limited as long as the second coating material is soluble in it. For example, the solvent used in the third solution described later can be used in the second solution. The solution containing the second coating material may also contain additives such as polymerization initiators and buffers. The second coating material may also be in the form of a hydrate or hydrochloride salt. In the second solution, the ratio of solvent to second coating material is not particularly limited, but it is preferably 10 to 800 mL, more preferably 20 to 600 mL, and even more preferably 100 to 500 mL per 1 part by weight of the second coating material.

[0092] In the second step, the method of applying the second solution containing the second coating material is not particularly limited. Furthermore, steps such as washing, drying, and annealing may be added before or after heating or light irradiation. Preferably, the drying step is added before heating or light irradiation. If the drying step is added after heating or light irradiation, the second coating material is crosslinked and / or polymerized while containing the solvent, resulting in a porous second coating layer 32. This can reduce the mechanical strength of the second coating layer and the bonding strength with the first coating layer 31 and / or the third coating layer 33, potentially decreasing the peel durability of the coating layer 30. Therefore, by adding the drying step before heating or light irradiation, the second coating layer 32 becomes non-porous, improving the peel durability of the coating layer 30. The drying conditions are not particularly limited.

[0093] In the second step, the conditions for heating or light irradiation, such as heating temperature, heating time, wavelength of the irradiated light, and integrated light intensity, are not particularly limited. Furthermore, energy can be supplied by methods other than heating or light irradiation, as long as it can promote crosslinking and / or polymerization.

[0094] In the third step, a third solution containing a third coating material, which is a drug and a polymer, is applied onto the second coating layer 32, and then dried to form a third coating layer 33. The drug and polymer of the third coating material can be the materials exemplified in the description of the embodiment of the third coating layer 33. After applying the third solution containing these third coating materials onto the second coating layer 32 and then drying it, a third coating layer 33 is formed in which the drug is supported on the polymer in its original structure and released gradually. At the same time, an interpenetrating polymer network is formed between the second coating layer 32 and the third coating layer 33, improving the peel resistance between the second coating layer 32 and the third coating layer 33.

[0095] In the third step, a third solution containing the drug and polymer, which is the third coating material, is applied and then dried without heating or light irradiation. By avoiding heating or light irradiation, the risk of heat or light breaking chemical bonds in the drug is eliminated, and related substances with altered drug structures are not generated. Therefore, the drug's efficacy is not lost, and there is no risk of related substances causing side effects. However, heating or light irradiation does not necessarily fall outside the technical scope of the present invention. Heating or light irradiation at a weak level that does not cause alteration of the drug's original structure is also included within the technical scope of the present invention. That is, in the third step, a third solution containing the drug and polymer, which is the third coating material, is applied and then dried without heating or light irradiation at a level that would cause alteration of the drug's original structure.

[0096] In 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 step, when the third solution containing the third coating material is applied onto the second coating layer 32, the second coating layer 32 swells. With this configuration, the polymer, which is the third coating material, can easily penetrate 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, increasing the bonding force between the second coating layer 32 and the third coating layer 33, and improving the peeling durability of the coating layers.

[0097] The solvent of the third solution containing the third coating material is not particularly limited as long as the second and third coating materials 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, hexafluoroisopropanol (hexafluoro-2-propanol (HFIP)), 1,1,1-trifluoroethanol, hexamethylphosphoramide, and combinations thereof. From the viewpoint of compatibility between the second and third polymers, 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 preferred, and chloroform, methylene chloride, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, 1,1,1-trichloroethane, hexafluoroisopropanol, and 1,1,1-trifluoroethanol are more preferred. In the third solution, the content ratio of the solvent to the third coating material is preferably 10 to 100 mL, more preferably 20 to 80 mL, and even more preferably 30 to 70 mL per 1 part by weight of the third coating material.

[0098] Furthermore, the third solution containing the third coating material may contain additives such as buffers. The third coating material may also be in the form of a hydrate or hydrochloride salt.

[0099] In the third step, the method of applying the third solution containing the third coating material is not particularly limited. Furthermore, the drying conditions after applying the third solution containing the third coating material are not particularly limited.

[0100] While embodiments of the present invention have been described in detail, these are descriptive and illustrative, and not limiting, and it is clear that the scope of the present invention should be interpreted by the appended claims.

[0101] The present invention encompasses the following embodiments and forms.

[0102] [1] A drug-eluting medical device comprising a substrate, a first coating layer having a first polymer formed by the autooxidative polymerization of a dopamine molecule or its analogues 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. [2] The drug-eluting medical device according to [1] above, wherein the second polymer and the third polymer have the same monomer units. [3] The third polymer is a drug-eluting medical device according to [1] or [2] above, having lactic acid monomer units. [4] The drug-eluting medical device according to any one of [1] to [3] above, wherein the second polymer and the third polymer have lactic acid monomer units. [5] The drug-eluting medical device according to any one of [1] to [4] above, wherein the second polymer is a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer. [6] The drug-eluting medical device according to [5] above, wherein the base polymer has lactic acid monomer units and the crosslinkable monomer is (meth)acrylate. [7] The drug-eluting medical device according to [6] above, wherein the (meth)acrylate is tetrafunctional or more. [8] The drug-eluting medical device according to any one of [5] to [7] above, wherein the third polymer has lactic acid monomer units, and the crosslinkable monomer is contained in an amount of 5% by weight or more and 90% by weight or less based on 100% by weight of the base polymer. [9] The drug-eluting medical device according to any one of [5] to [7] above, wherein the third polymer has lactic acid monomer units, and the crosslinkable monomer is contained in an amount of 30% to 90% by weight with respect to 100% by weight of the base polymer.

[10] The drug-eluting medical device according to any one of [5] to [7] above, wherein the third polymer has lactic acid monomer units, and the crosslinkable monomer is contained in an amount of 30% to 70% by weight with respect to 100% by weight of the base polymer.

[11] A drug-eluting medical device as described in any of [1] to

[10] above, which is a drug-eluting stent.

[12] A method for manufacturing a drug-eluting medical device, comprising: a first step of applying a first solution containing a dopamine molecule or an analog thereof, which is a first coating material, onto a substrate to form a first coating layer having a first polymer by polymerization of the first coating material; a second step of applying a second solution containing a polymer and / or monomer, which is a second coating material, onto the first coating layer, and then heating or irradiating with light 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, which is a third coating material, onto the second coating layer, and then drying to form a third coating layer having a third polymer supporting the drug.

[13] The method for manufacturing a drug-eluting medical device according to

[12] , wherein at least a portion of the second coating material is soluble in the solvent of the third solution, and in the third step, when the third solution is applied onto the second coating layer, the second coating layer swells.

[14] The method for producing a drug-eluting medical device according to

[12] or

[13] above, wherein the second polymer and the third polymer have the same monomer units.

[15] The third polymer having lactic acid monomer units, a method for producing a drug-eluting medical device according to any one of

[12] to

[14] above.

[16] A method for producing a drug-eluting medical device according to any one of

[12] to

[15] above, wherein the second polymer and the third polymer have lactic acid monomer units.

[17] The method for producing a drug-eluting medical device according to any one of

[12] to

[16] above, wherein the second polymer is a crosslinked polymer obtained by crosslinking a base polymer with a crosslinkable monomer.

[18] The method for producing a drug-eluting medical device according to

[17] above, wherein the base polymer has lactic acid monomer units and the crosslinkable monomer is (meth)acrylate.

[19] The method for producing a drug-eluting medical device according to

[18] above, wherein the (meth)acrylate is tetrafunctional or more.

[20] A method for producing a drug-eluting medical device according to any one of

[17] to

[19] above, wherein the third polymer has lactic acid monomer units, and the crosslinkable monomer is contained in an amount of 5% by weight or more and 90% by weight or less based on 100% by weight of the base polymer. [Examples]

[0103] The peeling resistance, which is an effect of drug-eluting medical devices that achieve the objectives of the present invention, will be explained below using the following examples. However, the following examples are merely illustrative of some of the configurations of drug-eluting medical devices that achieve the objectives of the present invention. The configuration of drug-eluting medical devices that achieve the objectives of the present invention is not limited to these examples.

[0104] In the following examples, the third solution contains only the third polymer, and therefore the coating layer does not contain any drug. However, since the third polymer is non-porous, long-term sustained release of the drug is possible, and it will be understood by those skilled in the art that the samples obtained in these examples have long-term sustained-release properties.

[0105] <Preparation of the solution containing the first coating material (first solution)> Dopamine hydrochloride was mixed with 10 mM Tris-HCl buffer (pH 8.5) to prepare the first solution. The concentration of dopamine hydrochloride in the first solution was 0.2% by weight.

[0106] <Preparation of the solution containing the second coating material (second solution)> The base polymer is poly-L-lactic acid (PLLA, manufactured by BMG Co., Ltd., BioDegmer® PLLA, weight-average molecular weight 510,000), and L-lactic acid:ε-caprolactone copolymer (LCL7525, BMG Co., Ltd., BioDegmer®) with a molar ratio of L-lactic acid:ε-caprolactone = 75:25. One of the following four polymers is used: LCL (75:25, molecular weight 570,000), poly-D,L-lactic acid (PDLLA, manufactured by DURECT, molecular weight 102,000), and polycaprolactone (PCL, manufactured by Evonik, intrinsic viscosity: 1.13-1.38 dL / g). The crosslinkable monomers are 1,4-butanediol diacrylate (1,4-BDDA), pentaerythritol tetraacrylate (PETA), dipentaerythritol hexaacrylate (DPEHA), and triallyl isocyanate (TA). One of five crosslinking agents, IC) and N-[tris(3-acrylamidopropoxymethyl)methyl]acrylamide (FOM-03006), was mixed with one of six weights (0.05g, 0.10g, 0.30g, 0.50g, 0.70g, 0.90g) of the crosslinking agent; 0.01g of 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (IRGACURE2959); and 300ml of chloroform to prepare a total of 74 second solutions as listed in Tables 3 to 6.

[0107] <Preparation of the solution containing the third coating material (third solution)> Four types of third solutions were prepared by mixing 1 g of one of four polymers—PLLA, LCL7525, DL-lactic acid / ε-caprolactone copolymer (DLCL9010) with a DL-lactic acid:ε-caprolactone ratio of 90:10 mol%, and polyvinyl alcohol (PVA) manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product code 160-11485)—with 40 ml of solvent. When PLLA, LCL7525, or DLCL9010 was 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 this invention, when PLLA, LCL7525, or DLCL9010 was used as the polymer in the third solution, the resulting coating layer structure was that of the example, and when PVA was used as the polymer in the third solution, the resulting coating layer structure was that of the comparative example.

[0108] <Preparation of the first coating layer> A SUS304 plate (size: 150mm long x 70mm wide x 0.8mm thick) was immersed in an aluminum tray filled with the first solution. After standing for 24 hours, the sample was removed and the surface was rinsed with distilled water. It was then dried at room temperature in the air for 2 hours. After that, it was annealed by standing on a hot plate heated to 200°C in the air for 5 minutes. The thickness of the resulting first coating layer was measured to be 40 nm using an AFM (measuring instrument: Bruker Nano Surfaces, Dimension Icon). Hereafter, the polymer formed on the first coating layer will be referred to as the first polymer.

[0109] <Preparation of the second coating layer> The sample with the first coating layer formed was immersed in an aluminum tray filled with the second solution and immediately removed. It was then dried at room temperature in air for 1 hour. Next, it was dried in a vacuum oven at 40°C for 24 hours. The dried sample was placed in a polyethylene bag, and under nitrogen purging, ultraviolet light with a wavelength of 365 nm was applied from outside the bag at an integrated intensity of 300 J / cm². 2 The samples were irradiated in such a manner. Afterwards, the samples were removed from the bags, immersed in aluminum trays filled with chloroform, and washed in an ultrasonic cleaner for 10 minutes to remove residual components such as unreacted monomers and photopolymerization initiators. A second coating layer was prepared for each of the 74 types of second solutions. The thickness of the obtained second coating layers was measured using an AFM (measuring instrument: Bruker Nano Surfaces, Dimension Icon). In Tables 3 to 6 below, samples with evaluations indicated as "( )" (samples with evaluations enclosed in parentheses) had a thickness of 50 nm to 100 nm, while samples without parentheses had a thickness of 150 nm. Hereafter, the polymer formed on the second coating layer will be referred to as the second polymer.

[0110] <Preparation of the third coating layer> Approximately 0.02 ml of the third solution was added dropwise to the sample that had been prepared up to the second coating layer using a Pasteur pipette. The sample was then dried at room temperature in air for 2 hours. Next, it was dried in a vacuum oven at 40°C for 72 hours. For each of the four types of third solutions, the third coating layer was prepared on the surface of each of the 74 samples that had been prepared up to the second coating layer. The thickness of the resulting third coating layer was measured using a laser microscope (VK-X200, KEYENCE) and was found to be 30 μm. The thickness of the third coating layer was calculated by comparing the thickness of the sample before and after the formation of the third coating layer. Hereafter, the polymer formed on the third coating layer will be referred to as the third polymer.

[0111] Furthermore, the third polymer (PLLA, LCL7525, DLCL9010, PVA) was examined by ion milling (IM4000Plus, Hitachi High-Tech) to expose the cross-section of the sample, and then observed using SEM (S-3400N, Hitachi High-Tech). The results showed that no observable pores were present, confirming that the third polymer is nonporous.

[0112] In this experiment, when PLLA, LCL7525, and DLCL9010 were used as the third polymer, interference colors of the coating film were visually observed on the surface where the third solution was dropped onto the second coating layer. This indicated that the second coating layer swelled due to the third solution. On the other hand, when PVA was used as the third polymer, no interference colors of the coating film were observed on the surface where the third solution was dropped onto the second coating layer. In this case, it is considered that the second coating layer did not swell.

[0113] As described above, a sample of a coated layer was obtained in which the entire SUS plate material was covered and the first to third coating layers were formed sequentially. In the following experiment, measurements were taken from one side of the coated layer.

[0114] <Method for testing peel resistance> For each of the 296 types of coating layers fabricated up to the third coating layer, the surface of the third coating layer was rubbed with brass tweezers in air to evaluate peeling durability and identify the location of the interface where peeling occurred. Each sample was also immersed in 37°C water, and the unrubbed areas were rubbed in the same manner to evaluate peeling durability and identify the location of the peeling interface. The interface was identified using a stereomicroscope (SMZ645, Nikon) at 50x magnification, based on the presence or absence of interference colors originating from the second coating layer on the peeled surface. Specifically, as an indicator of the location of the peeling interface, "A" was used if no interference colors originating from the second coating layer were observed on the peeled surface; "B" was used if the interference colors originating from the second coating layer changed or were partially observed on the peeled surface; and "C" was used if the interference colors originating from the second coating layer were observed on the peeled surface in the same way as during the formation of the second coating layer. Here, if the peel resistance index is "1" or higher, it can be determined that an interpenetrating polymer network structure has been formed. If the peel resistance index is "0", it is considered that an interpenetrating polymer network structure has not been formed. In other words, in the evaluations in Tables 3 to 6 below, a "0C" evaluation indicates that an interpenetrating polymer network structure has not been formed, and evaluations other than "0C" (for example, "1C") indicate that an interpenetrating polymer network structure has been formed.

[0115] <Results of peel resistance test> The peel durability was evaluated using the index shown in Table 1, and the location of the interface where peeling occurred was identified using the index shown in Table 2. The results of the peel durability tests for each sample are summarized in Tables 3 to 6. In Tables 3 to 6, "( )" (evaluation enclosed in parentheses) indicates the test results for samples in which a portion of the second coating layer disappeared during ultrasonic cleaning with chloroform during the preparation of the second coating layer, "Dry" indicates the test results in air, and "Wet" indicates the test results in water.

[0116] [Table 1]

[0117] [Table 2]

[0118] [Table 3]

[0119] [Table 4]

[0120] [Table 5]

[0121] [Table 6]

[0122] As shown in Tables 3 to 6, a coating layer formed from one of PLLA, LCL7525, PDLLA, and PCL as the base polymer of the second polymer; one of 1,4-BDDA, PETA, DPEHA, TAIC, and FOM-03006 as the crosslinkable monomer of the second polymer; and one of PLLA, LCL7525, and DLCL9010 as the third polymer; was shown to have good peel resistance. On the other hand, as shown in Tables 3 to 6, a coating layer formed from one of PLLA, LCL7525, PDLLA, and PCL as the base polymer of the second polymer; one of 1,4-BDDA, PETA, DPEHA, TAIC, and FOM-03006 as the crosslinkable monomer of the second polymer; and one of PVA as the third polymer; was found not to have sufficient peel resistance.

[0123] In other words, when PVA was used as the third polymer, the peel durability index was "0," indicating low peel durability. Considering this together with the index of the interface location where peeling occurred, the peel durability result of "0C" suggests that when PVA is used as the third polymer, an interpenetrating polymer network structure with the second polymer is not formed. This is presumed to be because, when the third polymer is PVA, the solvent of the third solution is water, and therefore, even when the third solution is dropped onto the second coat layer, which has the hydrophobic second polymer, the second coat layer does not swell. In fact, when the third coat layer was formed, no interference color was observed in the coating film when the third solution was dropped onto the second coat layer, suggesting that the second coat layer did not swell. From the above, it has been shown that PVA is not suitable as the third polymer in this invention.

[0124] In the coating layers of the examples, when the crosslinkable monomer was 1,4-BDDA, PETA, or DPEHA, the peel resistance was generally higher than when it was TAIC or FOM-03006. Therefore, in the embodiments of the present invention, it is more preferable that the crosslinkable monomer is acrylate. This is thought to be because the acryloyl group, which is a functional group of acrylate, has good reactivity, the covalent bond between the first and second coating layers is sufficient, and the compatibility between acrylate and the base polymer used in this case is good, so a sufficient crosslinked structure is formed between the crosslinkable monomer and the base polymer, and the polymer components are retained even during ultrasonic cleaning with chloroform, so a sufficient interpenetrating polymer network structure can be formed between it and the third coating layer. Furthermore, when the crosslinkable monomer is methacrylate, the reactivity of the methacryloyl group, which is a functional group, is equivalent to that of the acryloyl group, so it is presumed that the peel resistance is similarly high. Therefore, in the embodiments of the present invention, it is more preferable that the crosslinkable monomer is (meth)acrylate.

[0125] In the coating layers of the examples, when the crosslinkable monomer was PETA or DPEHA, a greater force was required to peel them off compared to when the crosslinkable monomer was 1,4-BDDA. This is likely because the number of covalent bonds formed between the first and second coating layers was greater when there were four or more functionalities than when there were fewer than four functionalities, resulting in a stronger bond between the first and second coating layers.

[0126] In the coating layers of the examples, when the base polymer had lactic acid monomer units, the peel resistance was generally higher than when the base polymer was PCL. Therefore, in the embodiments of the present invention, it is more preferable that the third polymer and the base polymer have lactic acid monomer units. One possible reason for this is that because the third polymer in the third coating layer has lactic acid monomer units, the base polymer having lactic acid monomer units has better affinity with the third polymer than the base polymer not having lactic acid monomer units, and the formation of an interpenetrating polymer network structure between the second and third coating layers is promoted. Furthermore, even when the base polymer was PCL, when the third polymer was LCL7525 or DLCL9010, the peel resistance was generally higher than when the third polymer was PLLA. One possible reason for this is that the presence of caprolactone monomer units in both the base polymer and the third polymer resulted in good affinity between them, promoting the formation of an interpenetrating polymer network structure between the second and third coating layers. Based on the above, it is suggested that when the second and third polymers have the same monomer units, not limited to lactic acid monomer units and / or caprolactone monomer units, the affinity between the second and third polymers is improved, promoting the formation of an interpenetrating polymer network structure between the second and third coating layers, thereby increasing the bonding force between the second and third coating layers and improving the peeling durability of the coating layers.

[0127] In the coating layers of the examples, when the crosslinkable monomer was PETA or DPEHA, the base polymer had lactic acid monomer units, and the crosslinkable monomer was contained in an amount of 5% to 90% by weight relative to the weight (100% by weight) of the base polymer, the peel resistance was generally high.Therefore, in the embodiments of the present invention, it is more preferable that the third polymer and the base polymer have lactic acid monomer units, the crosslinkable monomer is a tetrafunctional or more acrylate, and is contained in an amount of 5% to 90% by weight relative to the weight (100% by weight) of the base polymer.It is suggested that such a configuration allows for sufficient covalent bonding between the first and second coating layers, and promotes the formation of an interpenetrating polymer network between the second and third coating layers.

[0128] In the coating layers of the examples, when the crosslinkable monomer was PETA or DPEHA, the base polymer had lactic acid monomer units, and the crosslinkable monomer was contained in an amount of 30% to 90% by weight relative to the weight (100% by weight) of the base polymer, the peel resistance was generally high.Therefore, in the embodiments of the present invention, it is more preferable that the third polymer and the base polymer have lactic acid monomer units, the crosslinkable monomer is a tetrafunctional or more acrylate, and is contained in an amount of 30% to 90% by weight relative to the weight (100% by weight) of the base polymer.It is suggested that such a configuration allows for sufficient covalent bonding between the first and second coating layers, and promotes the formation of an interpenetrating polymer network structure between the second and third coating layers. Furthermore, even when the third polymer and base polymer have lactic acid monomer units, the crosslinkable monomer is a tetrafunctional acrylate, the base polymer further has caprolactone monomer units, and the crosslinkable monomer is contained in an amount of 10% to 30% by weight relative to the weight (100% by weight) of the base polymer, or when the third polymer and base polymer have lactic acid monomer units, the crosslinkable monomer is a pentafunctional or more acrylate, the base polymer further has caprolactone monomer units, and the crosslinkable monomer is contained in an amount of 5% to 30% by weight relative to the weight (100% by weight) of the base polymer, the peel resistance is high and is preferred in the embodiments of the present invention.

[0129] In the coating layers of the examples, when the crosslinkable monomer was PETA or DPEHA, the base polymer had lactic acid monomer units, and the crosslinkable monomer was contained in an amount of 30% to 70% by weight relative to the weight (100% by weight) of the base polymer, the peel resistance was generally high.Therefore, in the embodiments of the present invention, it is more preferable that the third polymer and the base polymer have lactic acid monomer units, the crosslinkable monomer is a tetrafunctional or more acrylate, and is contained in an amount of 30% to 70% by weight relative to the weight (100% by weight) of the base polymer.It is suggested that such a configuration allows for sufficient covalent bonding between the first and second coating layers, and promotes the formation of an interpenetrating polymer network structure between the second and third coating layers. When the crosslinkable monomer is PETA or DPEHA, the base polymer has lactic acid monomer units, and the crosslinkable monomer is present in an amount of 90% by weight relative to the weight (100% by weight) of the base polymer, the peeling interface is located between the second and third coat layers. The reason why the peeling durability is generally lower than when the crosslinkable monomer is present in an amount of 30% to 70% by weight relative to the weight (100% by weight) of the base polymer is thought to be that the higher proportion of the crosslinkable monomer in the second coat layer reduces the swelling of the second coat layer when the third solution is applied to it, and the formation of an interpenetrating polymer network structure between the second and third coat layers is not promoted as much. In fact, it has been confirmed that when the crosslinkable monomer is DPEHA and is present in an amount of 90% by weight relative to the weight (100% by weight) of the base polymer, the swelling of the second coat layer when the third solution is applied to it is lower than when it is present in an amount of 70% or less by weight. The reason why the peeling resistance was generally lower when the interface where peeling occurred was located inside the second coat layer, compared to when the crosslinkable monomer was contained in an amount of 30% to 70% by weight relative to the weight (100% by weight) of the base polymer, is thought to be that the second coat layer became more brittle due to the increased proportion of crosslinkable monomer in the second coat layer.Furthermore, since the interface where delamination occurred was not between the first and second coat layers, it is considered that sufficient covalent bonding was formed between the first and second coat layers. It should be noted that when the third polymer and base polymer have lactic acid monomer units, the crosslinkable monomer is a tetrafunctional acrylate, and the crosslinkable monomer is present in an amount of 70% to 90% by weight relative to the weight (100% by weight) of the base polymer, the delamination durability is generally higher than when the third polymer and base polymer have lactic acid monomer units, the crosslinkable monomer is a pentafunctional or more acrylate, and the crosslinkable monomer is present in an amount of 70% to 90% by weight relative to the weight (100% by weight) of the base polymer, and this is preferred in the embodiments of the present invention.

[0130] <TEM observation of interpenetrating polymer network structures> Next, a scanning electron microscope (TEM) was used to observe the interface between the second and third coating layers to confirm whether or not an interpenetrating polymer network structure was formed. Samples 1 and 2 of the coating layer having the configuration of the example, and sample 3 of the coating layer having the configuration of the comparative example were prepared according to the method described below.

[0131] [Preparation of Samples 1-3]

[0132] <Preparation of the solution containing the second coating material (second solution)> A second solution was prepared by mixing 1 g of an L-lactic acid / ε-caprolactone copolymer (LCL7525, BMG Co., Ltd., BioDegmer® LCL(75:25), molecular weight 570,000) with an L-lactic acid:ε-caprolactone molar ratio of 75:25 as the base polymer; 0.05 g of dipentaerythritol hexaacrylate (DPEHA) as the crosslinkable monomer; 0.01 g of 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (IRGACURE2959); and 20 ml of chloroform.

[0133] <Preparation of the solution containing the third coating material (third solution)> A third solution was prepared by mixing 1 g of DL-lactic acid / ε-caprolactone copolymer (DLCL9010), where DL-lactic acid:ε-caprolactone = 90:10 mol%, or polyvinyl alcohol (Fujifilm Wako Pure Chemical Industries, Ltd., product code 160-11485) (PVA) with 80 ml of solvent. In Sample 1, DLCL9010 was used as the polymer and 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 and 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 and water was used as the solvent, and the polymer was dissolved in water at 80°C.

[0134] <Preparation of a film sheet made from a second coating material> The second solution was poured into a φ75 mm PFA petri dish, taking care not to include any air bubbles, and air-dried at room temperature overnight to obtain a cast film. Next, the obtained film was placed in a polyethylene bag, and with the inside of the bag purged with nitrogen, ultraviolet light with a wavelength of 365 nm was applied from outside the bag to an integrated light intensity of 3000 mJ / cm². 2 The film formed by irradiation was peeled off the petri dish to obtain a film sheet made of a second coating material.

[0135] <Preparation of the third coating layer> Approximately 0.02 ml of the third solution was added dropwise to a film sheet made of the second coating material using a Pasteur pipette. It was then dried at room temperature in air for 2 hours. Finally, it was dried in a vacuum oven at 40°C for 72 hours.

[0136] In samples 1 to 3, the thickness of the film sheet made of the second coating material was measured using a thickness gauge (model: 547-360, manufactured by Mitutoyo Corporation) and was found to be 200 to 300 μm, while the thickness of the third coating layer was measured using a laser microscope (VK-X200, KEYENCE) and was found to be 3 to 6 μm. The composition of each coating layer in samples 1 to 3 is shown in Table 7 below.

[0137] [Table 7]

[0138] Samples 1 to 3, each having a coating layer with the composition shown in Table 7 above, were embedded in resin. For Samples 1 and 2, which are examples, epoxy resin (Epon812) was used as the embedding resin, while for Sample 3, which is a comparative example, caprolactone (EVONIK C212) was used as the embedding resin. Caprolactone, a hydrophobic polymer, was selected as the embedding resin for Sample 3 to avoid the dissolution of PVA, which was used as the third polymer, in the epoxy resin (Epon812).

[0139] The resin-embedded samples were sectioned using an ultramicrotome (Leica EM UC7), and magnified images of the resulting sections were taken using a transmission electron microscope (H-7100 model, Hitachi, Ltd., acceleration voltage 100kV). Figures 2 to 4 show the obtained TEM images (unstained, 25,000x magnification). Figure 2 is the TEM image of sample 1, Figure 3 is the TEM image of sample 2, and Figure 4 is the TEM image of sample 3.

[0140] As shown in Figures 2 and 3, in samples 1 and 2, a region of non-uniform brightness 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 identified, and no region of non-uniform brightness was observed between the second and third coating layers. Since the brightness of TEM images of polymer materials reflects density, average atomic number, etc., the region of non-uniform brightness observed at the interface between the second and third coating layers in samples 1 and 2 suggests that the polymer structure is more non-uniform than that of the second and third coating layers. Therefore, it can be concluded 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 the region where the interpenetrating polymer network structure is thought to be formed.

[0141] The results of the peel durability tests conducted on Samples 1 and 2 are shown in Table 8 below. The method for the peel durability tests is the same as described above. Sample 2 is the same system as described in Table 4, using the base polymer LCL7525 and the crosslinkable monomer DPEHA as the second polymer, and DLCL9010 (solvent species of the third solution: CHCl3) as the third polymer.

[0142] [Table 8]

[0143] As shown in Table 8, the peel durability tests for samples 1 and 2 yielded similar results. Therefore, it was confirmed that regardless of whether CHCl3 or HFIP solvent was used as the solvent for the third solution used to create the third coating layer, a similar interpenetrating polymer network structure was formed between the second and third coating layers.

[0144] <Means for solving the problem and the effects of the invention> Based on the above, the means for solving the problem and the effects of the invention are described below.

[0145] A drug-eluting medical device that achieves the objectives of the present invention comprises a substrate, a first coating layer having a first polymer formed by the auto-oxidative polymerization of dopamine molecules or their analogs 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.

[0146] This configuration allows the drug to be supported on the third polymer in its original structure, thus possessing the intended therapeutic effect, and the drug release is sustained. Furthermore, because the third polymer forms an interpenetrating polymer network structure with the second polymer, the coating layer has high durability against peeling.

[0147] Furthermore, the second polymer and the third polymer may be characterized by having the same monomer units.

[0148] This configuration improves the affinity between the second polymer and the third polymer, facilitates the formation of an interpenetrating polymer network structure between the second and third coating layers, increases the bonding strength between the second and third coating layers, and improves the peeling durability of the coating layers.

[0149] Furthermore, the second polymer may be characterized as a crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer.

[0150] This configuration allows for the formation of covalent bonds between the functional groups of the crosslinkable monomer and the first polymer, improving the bonding strength between the first and second coating layers and enhancing the peel resistance of the coating layers. Furthermore, the functional groups of the base polymer do not necessarily need to form covalent bonds with the first polymer, making it possible to select a wide range of polymers as the base polymer.

[0151] Furthermore, the third polymer may be characterized by having lactic acid monomer units.

[0152] This configuration improves both biosafety and the sustained release of the drug.

[0153] Furthermore, the second polymer and the third polymer may be characterized by having lactic acid monomer units.

[0154] This configuration improves the affinity between the second and third polymers, facilitates the formation of an interpenetrating polymer network structure between the second and third coating layers, increases the bonding strength between the second and third coating layers, and improves the peeling durability of the coating layers. Furthermore, it improves biosafety and the sustained release of drugs.

[0155] Furthermore, the base polymer may be characterized by having lactic acid monomer units, and the crosslinkable monomer may be characterized by being a (meth)acrylate.

[0156] This configuration facilitates the formation of covalent bonds between the first and second coating layers, as well as cross-linked structures between the base polymer and the cross-linkable monomer, thereby improving the peel resistance of the coating layers.

[0157] Furthermore, the (meth)acrylate may be characterized by having four or more functional properties.

[0158] This configuration facilitates the formation of covalent bonds between the first and second coating layers, improving the peeling resistance of the coating layers.

[0159] Furthermore, the third polymer and the base polymer may be characterized in that they have lactic acid monomer units, the crosslinkable monomer is a tetrafunctional or more acrylate, and the crosslinkable monomer is contained in an amount of 5% to 90% by weight relative to the weight (100% by weight) of the base polymer.

[0160] This configuration facilitates the formation of covalent bonds between the first and second coating layers, as well as interpenetrating polymer network structures between the second and third coating layers, thereby improving the peeling durability of the coating layers.

[0161] Furthermore, the third polymer and the base polymer may be characterized in that they have lactic acid monomer units, the crosslinkable monomer is a tetrafunctional or more acrylate, and the crosslinkable monomer is contained in an amount of 30% to 90% by weight relative to the weight (100% by weight) of the base polymer.

[0162] This configuration makes it easier for covalent bonds to form between the first and second coat layers compared to when the crosslinkable monomer is contained in an amount of 5% to less than 30% by weight relative to the weight (100% by weight) of the base polymer, thereby improving the peeling durability of the coat layers.

[0163] Furthermore, the third polymer and the base polymer may be characterized in that they have lactic acid monomer units, the crosslinkable monomer is a tetrafunctional or more acrylate, and the crosslinkable monomer is contained in an amount of 30% to 70% by weight relative to the weight (100% by weight) of the base polymer.

[0164] This configuration makes it easier for an interpenetrating polymer network structure to form between the second and third coat layers compared to when the crosslinkable monomer is contained in an amount greater than 70% by weight but less than or equal to 90% by weight relative to the weight (100% by weight) of the base polymer, thereby improving the peeling durability of the coat layers.

[0165] Furthermore, drug-eluting stents are particularly suitable as drug-eluting medical devices of the present invention because forces that peel off the coating layer are easily applied during mounting, delivery, and expansion, and the elution of drugs that suppress biological reactions that cause restenosis needs to continue for at least several months. For this reason, drug-eluting medical devices may be characterized as being drug-eluting stents.

[0166] A method for manufacturing a drug-eluting medical device that achieves the objectives of the present invention is characterized by comprising: a first step of applying a first solution containing a dopamine molecule or its analogue, which is a first coating material, onto a substrate to form a first coating layer having a first polymer by polymerization of the first coating material; a second step of applying a second solution containing a polymer and / or monomer, which is a second coating material, onto the first coating layer, and then heating or irradiating with light 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, which is a third coating material, onto the second coating layer, and then drying to form a third coating layer having a third polymer supporting the drug.

[0167] By manufacturing in this manner, in the first step, a first coating layer composed of polydopamine or a polymer similar to polydopamine is formed. In the second step, a second coating layer is formed by crosslinking and / or polymerization of the second coating material, and a covalent bond is formed between the first and second coating layers. In the third step, a third coating layer is formed on which the drug is supported and released slowly, and an interpenetrating polymer network structure is formed between the second and third coating layers. Furthermore, the drug, which is the third coating material, is supported on the polymer without losing its original efficacy. Therefore, it is possible to manufacture a drug-eluting medical device in which the original efficacy of the drug is not lost, drug elution is slow-release, and the coating layer has high durability against peeling.

[0168] Furthermore, at least a portion of the second coating material may be soluble in the solvent of the third solution, and the second coating layer may swell when the third solution is applied to the second coating layer in the third step.

[0169] These characteristics make it easier for the polymer, which is the third coating material, to penetrate the second coating layer, promoting the formation of an interpenetrating polymer network structure between the second and third coating layers. This increases the bonding strength between the second and third coating layers, improving the peeling durability of the coating layers.

[0170] Furthermore, the polymer constituting the second coating layer and the polymer constituting the third coating layer formed by the above-described manufacturing method may have the characteristics of the second and third polymers in a drug-eluting medical device that achieves the objectives of the present invention.

[0171] Specifically, a method for manufacturing a drug-eluting medical device may be characterized by the following: (1) The second polymer and the third polymer have the same monomer units; (2) The third polymer has lactic acid monomer units; (3) The second polymer and the third polymer have lactic acid monomer units; (4) The second polymer is a crosslinked polymer formed by crosslinking a base polymer and a crosslinkable monomer; (5) In (4), the base polymer has lactic acid monomer units and the crosslinkable monomer is (meth)acrylate; (6) In (5), the (meth)acrylate is tetrafunctional or more; and / or (7) In (4) to (6), the third polymer has lactic acid monomer units and the crosslinkable monomer is contained in an amount of 5% by weight or more and 90% by weight or less based on 100% by weight of the base polymer. The peeling durability of the coating layer is improved by the second polymer and the third polymer having the above characteristics.

[0172] Furthermore, the above-mentioned method for manufacturing drug-eluting medical devices may be characterized as a method for manufacturing drug-eluting stents.

[0173] Although the drug-eluting medical device according to the present invention has been described above, the present invention is not limited to the configurations described herein, and can be appropriately modified by those skilled in the art within the technical concept of the present invention, and such modifications should be considered to fall within the technical scope of the present invention. [Explanation of symbols]

[0174] 10. Drug-eluting medical devices 20 Base material 30 coat layers 31. First court layer 32. Second court layer 33. Third Court Layer

Claims

1. Substrate and A first coating layer having a first polymer formed by the auto-oxidative polymerization of dopamine molecules or their analogs on the substrate, A second coating layer having a second polymer covalently bonded to the first polymer on the first coating layer, A third coating layer having a drug and a third polymer supporting the drug on the second coating layer, It has, A drug-eluting medical device characterized in that the second polymer and the third polymer form an interpenetrating polymer network structure.

2. The drug-eluting medical device according to claim 1, wherein the second polymer and the third polymer have the same monomer units.

3. The drug-eluting medical device according to claim 1 or 2, wherein the third polymer has lactic acid monomer units.

4. The drug-eluting medical device according to claim 1 or 2, wherein the second polymer and the third polymer each have lactic acid monomer units.

5. The drug-eluting medical device according to claim 1, wherein the second polymer is a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer.

6. The base polymer has lactic acid monomer units, The drug-eluting medical device according to claim 5, wherein the crosslinkable monomer is (meth)acrylate.

7. The drug-eluting medical device according to claim 6, wherein the (meth)acrylate is tetrafunctional or more.

8. The third polymer has lactic acid monomer units, The drug-eluting medical device according to claim 5 or 6, wherein the crosslinkable monomer is contained in an amount of 5% by weight or more and 90% by weight or less based on 100% by weight of the base polymer.

9. The third polymer has lactic acid monomer units, The drug-eluting medical device according to claim 5 or 6, wherein the crosslinkable monomer is contained in an amount of 30% by weight or more and 90% by weight or less based on 100% by weight of the base polymer.

10. The third polymer has lactic acid monomer units, The drug-eluting medical device according to claim 5 or 6, wherein the crosslinkable monomer is contained in an amount of 30% by weight or more and 70% by weight or less based on 100% by weight of the base polymer.

11. A drug-eluting medical device according to claim 1 or 2, which is a drug-eluting stent.

12. A first step involves applying a first solution containing a dopamine molecule or its analogue, which is a first coating material, onto a substrate, thereby forming a first coating layer having a first polymer by polymerization of the first coating material. A second step involves applying a second solution containing a polymer and / or monomer, which is a second coating material, onto the first coating layer, and then heating or irradiating it with light to form a second coating layer having the second polymer. A third step is to apply a third solution containing a drug and a polymer, which are third coating materials, onto the second coating layer, and then dry it to form a third coating layer having a third polymer supporting the drug. It has, At least a portion of the second coating material is soluble in the solvent of the third solution. A method for manufacturing a drug-eluting medical device, wherein, in the third step, the second coating layer swells when the third solution is applied to the second coating layer.

13. The method for producing a drug-eluting medical device according to claim 12, wherein the second polymer and the third polymer have the same monomer units.

14. The method for producing a drug-eluting medical device according to claim 12 or 13, wherein the third polymer has lactic acid monomer units.

15. The method for producing a drug-eluting medical device according to claim 12 or 13, wherein the second polymer and the third polymer have lactic acid monomer units.

16. The method for producing a drug-eluting medical device according to claim 12, wherein the second polymer is a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer.

17. The base polymer has lactic acid monomer units, The method for producing a drug-eluting medical device according to claim 16, wherein the crosslinkable monomer is (meth)acrylate.

18. The method for producing a drug-eluting medical device according to claim 17, wherein the (meth)acrylate is tetrafunctional or more.

19. The third polymer has lactic acid monomer units, The method for producing a drug-eluting medical device according to claim 16 or 17, wherein the crosslinkable monomer is contained in an amount of 5% by weight or more and 90% by weight or less based on 100% by weight of the base polymer.

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