In-vivo indwelling stent, stent delivery system, and method for manufacturing in-vivo indwelling stent

Abstract

An in-vivo indwelling stent 1 comprises a stent body 10 and a drug-containing coating part 3 provided on the outer surface of the stent body 10. The stent body includes: a linear first strut part 23 and a linear second strut part 24; and bent parts 21, 22 connecting the linear first strut part and the linear second strut part. The drug-containing coating part 3 comprises: linear part coating parts 34 for coating the linear first strut part and the linear second strut part; bent part thin coating parts 35 positioned on the bent parts and having a smaller coating thickness than the other portion of the drug-containing coating part; and thick coating parts 36 formed at both ends of each of the bent part thin coating parts.

Description

Intravivo stent, stent delivery system, and method for manufacturing an intravivo stent

[0001] This invention relates to an in vivo indwelling stent used for treating narrowing or obstruction in the lumen of blood vessels, bile ducts, trachea, esophagus, urethra, and other organs. In particular, it relates to a drug-eluting stent (DES).

[0002] A stent is a medical device consisting of a cylindrical body with an opening on its side, composed of multiple annular bodies arranged axially, each annular body made up of a wavy strut with a curved section, with adjacent annular bodies integrated via connecting sections. For example, it is used to prevent restenosis after percutaneous coronary angioplasty for myocardial infarction or angina pectoris. While the restenosis rate is lower with so-called bare-metal stents (which are not coated with a drug) compared to PTCA or PCI without any stents, restenosis still occurs in approximately 20-30% of cases at the stent placement site. The main cause of restenosis is intima thickening due to the migration and proliferation of vascular smooth muscle cells. Therefore, drug-eluting stents have been proposed, which are coated on the outer surface of the stent with a drug that can suppress the migration and proliferation of vascular smooth muscle cells, and the drug is released at the stent placement site to prevent restenosis. Examples of drugs used include Taxol (paclitaxel), mitomycin C, adriamycin, genistein, tylfostine, cytochalasin, and sirolimus (rapamycin). For coating, a coating solution is used in which these drugs and a biocompatible polymer are dissolved in a solvent, and the solution is applied to part or all of the stent so that a predetermined amount of the drug is present on the outer surface of the stent. Generally, stents expand and deform when they reach the target site in the lumen and are placed. As a result of this expansion and deformation, stress concentrates on the drug coating layer formed on the outer surface of the curved portion of the strut, causing strain and leading to the problem of the drug coating layer peeling off or falling off. To address this problem, the stent described in Patent Document 1 prevents peeling or falling off of the coating layer by making the curved portion an uncoated layer without the drug coating. Furthermore, as a method for forming the uncoated layer, when the nozzle that discharges the drug arrives at the curved portion, the nozzle is moved away from the curved portion (jumped), thereby preventing the drug from being applied to the curved portion.

[0003] Patent No. 6352279 (US2016-235565A, EP3034048A, WO2015-046168)

[0004] In recent years, there has been an increase in cases of stenosis due to calcification in the arteries of the lower extremities. To improve stenosis caused by calcification in the arteries of the lower extremities, such as the superficial femoral artery (SFA), and to prevent restenosis after improvement, it is desirable that the entire outer surface of the stent, including the curved portion, be covered with a drug coating, and that the drug coating formed on the curved portion does not peel off.

[0005] The object of the present invention is to provide an in vivo stent, a stent delivery system, and a method for manufacturing an in vivo stent, which have a linear covering portion covering a linear first strut portion and a linear second strut portion, as well as a drug-coated portion on the bent portion, and which have a low possibility of peeling off the drug-coated portion formed on the curved portion.

[0006] The following invention achieves the above objective: A stent for implantation in a living body comprising a tubular stent body formed of a wavy linear component having a plurality of bent portions having vertices on one or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body, wherein the stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion, and the drug-containing coating portion comprises a linear portion coating portion covering the linear first strut portion and the linear second strut portion, a bent portion thin layer coating portion located on the bent portion and having a thinner coating thickness than the linear portion coating portion, and a thick coating portion formed at both ends of the bent portion thin layer coating portion.

[0007] Furthermore, the following is a device that achieves the above objective: a stent delivery system comprising a sheath, the above-mentioned in vivo implantable stent housed within the tip of the sheath, and an inner tube slidably inserted through the sheath for pushing the in vivo implantable stent out from the tip of the sheath.

[0008] Furthermore, the following is a method for manufacturing an in vivo stent, comprising a tubular stent body formed of a wavy linear component having a plurality of bent portions having vertices on one end or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body, wherein the stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion, and the method for manufacturing the in vivo stent is as follows: A first coating step is performed by applying the coating liquid to the outer surface of the linear first strut portion, by positioning a nozzle, which has been in a state of discharging pressure to a coating liquid in which the drug and polymer have been dissolved in a solvent, on the outer surface of the linear first strut portion and moving the nozzle on the outer surface of the linear first strut portion to coat the outer surface of the linear first strut portion, and when the nozzle arrives at one end of the bent portion, moving the nozzle from the end of the bent portion outward from the outer edge of the bent portion, and further, after the nozzle has been detouring outside the outer edge of the bent portion, when the nozzle approaches the other end of the bent portion, positioning the nozzle on the other end of the bent portion and moving the nozzle on the outer surface of the linear second strut portion to coat the outer surface of the linear second strut portion, A method for manufacturing an in-vivo stent, comprising: a second coating step, after the first coating step, the direction of travel of the nozzle is changed to a direction different from that of the first coating step, the nozzle is positioned on the outer surface of the linear second strut portion with discharge pressure applied to the coating liquid, and the nozzle is moved on the outer surface of the linear second strut portion to coat the outer surface of the linear second strut portion with the coating liquid; when the nozzle arrives at the other end of the bent portion, the nozzle is moved from the other end of the bent portion to the outside of the outer edge of the bent portion, and further, after the nozzle is detoured outside the outer edge of the bent portion, when the nozzle approaches one end of the bent portion, the nozzle is positioned on one end of the bent portion and moved on the outer surface of the linear first strut portion to coat the outer surface of the linear first strut portion with the coating liquid;

[0009] The in vivo stent of the present invention comprises a tubular stent body formed of a wavy linear component having a plurality of bent portions having vertices on one end or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body. The stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion. The drug-containing coating portion comprises a linear portion coating portion covering the linear first strut portion and the linear second strut portion, a bent portion thin layer coating portion located on the bent portion and having a thinner coating thickness than the linear portion coating portion, and a thick coating portion formed at both ends of the bent portion thin layer coating portion.

[0010] The stent of the present invention is equipped not only with a linear covering portion that covers the linear first strut portion and the linear second strut portion, but also with a bent portion thin-layer covering portion located on the bent portion and having a thinner covering thickness than the linear covering portion, and thick covering portions formed at both ends of the bent portion thin-layer covering portion. Therefore, even when placed in a stenosis caused by calcification in the lower limb artery, effective drug administration is possible, and it is effective in suppressing restenosis of the stenosis. Furthermore, since the stent has a drug covering portion in the bent portion and thick covering portions formed at both ends of the bent portion thin-layer covering portion, the amount of drug that can be loaded can be improved and the peeling of the covering portion can be reduced.

[0011] Figure 1 is an unfolded view of an in-vivo stent according to an embodiment of the present invention when expanded. Figure 2 is an unfolded view of the in-vivo stent shown in Figure 1 when reduced in diameter. Figure 3 is a partially enlarged view of the in-vivo stent shown in Figure 1. Figure 4 is an enlarged cross-sectional view of the vicinity of one of the bends of the in-vivo stent shown in Figure 3. Figure 5 is an explanatory diagram for illustrating the structure of the drug-containing coating portion in the in-vivo stent according to an embodiment of the present invention. Figure 6 is a partially enlarged view of an in-vivo stent according to another embodiment of the present invention when expanded. Figure 7 is a partially omitted front view of a stent delivery system according to an embodiment of the present invention. Figure 8 is an enlarged longitudinal cross-sectional view of the vicinity of the tip of the stent delivery system shown in Figure 7. Figure 9 is a partially omitted enlarged cross-sectional view of the vicinity of the proximal end of the stent delivery system shown in Figure 7. Figure 10 is an explanatory diagram for illustrating the operation of a stent delivery system according to an embodiment of the present invention. Figure 11 is an explanatory diagram for illustrating a coating device used in the manufacture of the in-vivo stent according to the present invention. Figure 12 is an explanatory diagram for illustrating the main parts of the coating device shown in Figure 11. Figure 13 is an explanatory diagram illustrating the nozzle coating path. Figure 14 is an explanatory diagram illustrating the nozzle coating path. Figure 15 is a flowchart illustrating the imaging step in the manufacturing method of an in-vivo stent according to an embodiment of the present invention. Figure 16 is a flowchart illustrating the coating path setting step in the manufacturing method of an in-vivo stent according to an embodiment of the present invention. Figure 17 is a flowchart illustrating the first coating solution coating step and the second coating solution coating step in the manufacturing method of an in-vivo stent according to an embodiment of the present invention. Figure 18 is a flowchart illustrating the third coating solution coating step in the manufacturing method of an in-vivo stent according to an embodiment of the present invention.

[0012] The in vivo stent of the present invention will be described using the embodiment shown in the drawings. The in vivo stent 1 of the present invention comprises a tubular stent body 10 formed of a wavy linear component having a plurality of bent portions 21, 22 having vertices on one end or the other end in the axial direction, and a drug-containing coating portion 3 provided on the outer surface of the stent body 10. The stent body 10 has an annular body 2 composed of a wavy strut having a linear first strut portion 23, a linear second strut portion 24, and bent portions 21, 22 connecting the linear first strut portion 23 and the linear second strut portion 24.

[0013] The drug-containing coating portion 3 comprises a linear coating portion 34 that covers the linear first strut portion 23 and the linear second strut portion 24, a bent portion thin-layer coating portion 35 located on the bent portions 21 and 22 and having a thinner coating thickness than the linear coating portion 34, and a thick coating portion 36 formed at both ends of the bent portion thin-layer coating portion 35.

[0014] The in vivo stent of the present invention is particularly effective as a stent for lower limb arteries. The stent body 10 comprises a plurality of one-end bends 21 having a peak on one end in the axial direction, and a plurality of other-end bends 22 having a valley on the other end in the axial direction of the stent. The peaks of the one-end bends 21 and the other-end bends 22 are parts that deform when the in vivo stent 1 expands or contracts in the radial direction.

[0015] In this embodiment, the stent body 10 is made up of multiple annular bodies 2 arranged in the axial direction, with adjacent annular bodies connected by connecting parts. The in vivo stent 1 in this embodiment is formed in a tubular shape, is compressed in the axial direction when inserted into the body, and expands outward to return to its pre-compression shape when implanted in the body, thus being a self-expanding type. Furthermore, the stent body 10 is made by cutting a superelastic metal tube to form the basic shape of the stent body, then expanding its diameter, and subsequently heat-treating it, thereby making the stent body superelastic in the expanded state. The drug-containing coating part 3 may be applied to the outer surface of the stent body 10 after the diameter has been expanded and either before or after the heat treatment.

[0016] Furthermore, the in vivo stent of the present invention is not limited to a self-expanding type, but may also be a stent formed in a substantially tubular shape, having a diameter for insertion into a lumen in the body, and capable of expanding when a radially expanding force is applied from the inside of the tubular body, a so-called balloon-expanding type stent.

[0017] The in vivo stent of this embodiment comprises a stent body 10, the stent body 10 comprising a plurality of annular bodies 2 that can deform in a direction in which the outer diameter decreases when stress is applied, and connecting parts 31 and 32 that connect the annular bodies when the plurality of annular bodies 2 are arranged in the axial direction of the stent body.

[0018] As shown in Figure 3, a drug-containing coating portion 3 is provided on the outer surface of the stent body 10. Preferably, the drug-containing coating portion is a drug-eluting coating portion. Furthermore, it is preferable that the drug-containing coating portion is flexible or elastic.

[0019] The drug covering the outer surface of the stent body may be supported on a polymer to form the drug-containing coating 3. When the drug-containing coating 3 is supported on a polymer, the drug is gradually released after the stent is placed in the body, so the drug effect lasts for a long period of time and restenosis at the stent placement site is reliably prevented. When the drug of the drug-containing coating 3 is supported on a polymer, it can be formed by applying a coating solution prepared by dissolving the drug and polymer in a solvent to the stent body.

[0020] Furthermore, a primer coating layer may be placed between the stent body and the drug-containing coating to reduce variations in the ease of peeling of the drug-containing coating on the stent body. As the material for the primer coating layer, for example, a biodegradable polymer material can be used when the drug-containing coating is supported on a polymer.

[0021] The drug-containing coating portion 3 comprises a linear coating portion 34 that covers the linear first strut portion 23 and the linear second strut portion 24, a bent portion thin-layer coating portion 35 that covers the bent portions 21 and 22, and a thick coating portion 36 provided at both ends of the bent portions 21 and 22 (in other words, both ends of the bent portion thin-layer coating portion 35, and further in other words, the ends of the linear first strut portion 23 and the linear second strut portion 24). The bent portion thin-layer coating portion 35 has a thinner coating thickness than the linear coating portion 34. The thick coating portion 36 has a thicker coating thickness than the bent portion thin-layer coating portion 35 and the linear coating portion 34. In this embodiment, the thick coating portion 36 is a bulging portion.

[0022] In the stent 1 of this embodiment, due to the shape of the stent, a force acts radially outward on the bent portions 21 and 22, which can cause a phenomenon called fraying, where the area near the apex curls radially outward. Therefore, when the stent is housed in the sheath of the stent delivery system, stronger friction may occur between the bent portions 21 and 22 of the stent and the inner surface of the stent sheath than between the linear first strut portion 23 and the linear second strut portion 24 and the inner surface of the sheath. As a result, when the stent is extruded from the sheath, peeling of the drug-containing coating portion on the bent portions 21 and 22 may occur. In the stent 1 of the present invention, the drug-containing coating portion on the bent portions 21 and 22 is a thin-walled bent portion thin-layer coating portion 35, so there is less contact between the bent portion thin-layer coating portion and the stent sheath, and peeling of the bent portion thin-layer coating portion is also reduced. For stents used in lower limb DES, long-term sustained release of the drug is desirable. When the stent 1 of the present invention is applied to a stent for lower limb DES, the amount of drug-containing coating layer can be increased overall, particularly in the linear first strut portion 23 and the linear second strut portion 24, thereby increasing the amount of drug carried. Furthermore, a thinner drug-containing coating layer can be provided on the bent portions 21 and 22 than that on the struts. In addition, thick coating portions 36 can be provided at both ends of the bent portions 21 and 22. This improves the amount of drug carried throughout the stent 1 and reduces peeling of the coating.

[0023] The thin layer coating portion 35 of the bent portion is preferably 2 / 7 to 1 / 2 of the coating thickness of the linear portion coating portion 34, and is particularly preferably 1 / 3 to 2 / 5.

[0024] Furthermore, the thickness of the thick coating portion 36 is preferably 1.1 to 2.3 times the coating thickness of the linear coating portion 34, and more preferably 1.2 to 2.0 times. Also, the thickness of the thick coating portion 36 is preferably 2 to 4 times the coating thickness of the bent thin coating portion 35, and more preferably 2.5 to 3.5 times.

[0025] Furthermore, as shown in Figure 6, in the in vivo stent 1b of another embodiment of the present invention, the thickened covering portions provided at both ends of the bent portions 21 and 22 (in other words, both ends of the thin-layer covering portion 35 of the bent portion) may be of different sizes. In this in vivo stent 1b, one thickened covering portion 36a is larger than the other thickened covering portion 36. Also, in this in vivo stent 1b, one thickened covering portion 36a is larger in both area and height than the other thickened covering portion 36, but it is also possible for only one of them to be larger.

[0026] The drug contained in the drug-containing coating portion 3 of the in vivo implantable stent of the present invention is, for example, at least one compound selected from the group consisting of anticancer agents, immunosuppressants (e.g., sirolimus, sirolimus derivatives), antibiotics, antirheumatic agents, antithrombotic agents, HMG-CoA reductase inhibitors, ACE inhibitors, calcium channel blockers, antihyperlipidemic agents, integrin inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid-improving agents, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, anti-inflammatory agents, bio-derived materials, interferon, and NO production-promoting substances.

[0027] The drug contained in the drug-containing coating of the in vivo implantable stent 1 is preferably sirolimus or a sirolimus derivative. Examples of sirolimus derivatives include everolimus, temsirolimus, ridafololimus, and zotarolimus.

[0028] The drug coating the outer surface of the stent body may be supported on a polymer to form a drug-containing coating. When the drug-containing coating is supported on a polymer, the drug is gradually released after the stent is placed in the body, so the drug effect lasts for a long period of time and restenosis at the stent site is reliably prevented. Furthermore, since residual polymer may cause an inflammatory reaction, it is preferable that the polymer be a biodegradable polymer.

[0029] Biodegradable polymers include, for example, at least one polymer selected from the group consisting of polyester, aliphatic polyester, polyacid anhydride, polyorthoester, polycarbonate, polyphosphazene, polyphosphate ester, polyvinyl alcohol, polypeptide, polysaccharide, protein, and cellulose; copolymers obtained by arbitrarily copolymerizing monomers constituting a polymer; and mixtures of polymers and / or copolymers. Aliphatic polyesters include, for example, polylactic acid (PLA), polyglycolic acid (PGA), lactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), and copolymers of lactic acid and caprolactone. Here, copolymers of lactic acid and caprolactone are preferred. The drug-containing coating portion preferably contains a polymer with a molecular weight of 150,000 or more, and in particular, the above-mentioned biodegradable polymer with a molecular weight of 150,000 or more is preferred.

[0030] The drug-containing coating portion 3 preferably has, as shown in Figure 5, a first coating layer 3a having a first polymer formed by the self-oxidative polymerization of dopamine molecules or their analogs on the outer surface of the stent body, a second coating layer 3b having a second polymer covalently bonded to the first polymer on the first coating layer 3a, and a third coating layer 3c having a drug and a third polymer supporting the drug on the second coating layer 3b. Furthermore, it is preferable that the second polymer and the third polymer in the drug-containing coating portion 3 form an interpenetrating polymer network structure.

[0031] <First Coating Layer 3a> The first coating layer 3a of the drug-containing coating portion 3 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. Furthermore, the first coating layer 3a has the structure of the first polymer in at least a portion of it.

[0032] In other words, the first coating layer 3a may contain structures derived from sources other than dopamine molecules or their analogues. As an example in which the structure of the first polymer is present in part 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. As another example, the first coating layer 3a may contain a substance that does not covalently bond to dopamine molecules or their analogues. In this case as well, the first coating layer 3a has the structure of the first polymer in at least part of it.

[0033] The first coating layer 3a 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 3a may have a first polymer formed by the autooxidative polymerization of multiple dopamine analogs. Furthermore, the first coating layer 3a may have a first polymer formed by the autooxidative polymerization of a dopamine molecule and one or more dopamine analogs. Examples of chemical formulas for dopamine analogs include those described in paragraph "0052" of Japanese Patent Publication No. 2016-513545.

[0034] The thickness of the first coating layer 3a 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 3a may be uniform or non-uniform. The surface of the first coating layer 3a may be smooth or rough. The thickness of the first coating layer is measured, for example, by an atomic force microscope (AFM).

[0035] <Second Coating Layer 3b> The second coating layer 3b in the drug-containing coating portion 3 has a second polymer that is covalently bonded to a first polymer formed by the self-oxidative polymerization of a dopamine molecule or its analogues. The second coating layer 3b is formed, for example, by placing the material of the second polymer on the first coating layer 3a and applying energy such as heat or light. The second coating layer 3b may contain a polymerization initiator. When the second coating layer 3b is formed, a covalent bond is formed between the first polymer and the second polymer.

[0036] 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 3a, and by a functional group of the second polymer in the second coating layer 3b that is in contact with the surface of the first coating layer 3a. In another example, it is formed by a polymerizable functional group of the first polymer on the surface of the first coating layer 3a and by a functional group of the second polymer in the second coating layer 3b that is in contact with the surface of the first coating layer 3a. The functional groups that form the covalent bond are determined by the materials and structures of the first and second polymers. Japanese Patent Publication No. 2016-513545 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 a polymerizable functional group on the substrate surface when the radical initiator is Norrish type I. Furthermore, the mechanism of covalent bonding between the first polymer and the second polymer is not particularly limited.

[0037] The second polymer of the second coat layer 3b is preferably a crosslinked polymer formed by crosslinking a base polymer and a crosslinkable monomer. By adopting such a configuration, a covalent bond is formed between the functional group of the crosslinkable monomer and the first polymer on the surface of the first coat layer 3a, the bonding force between the first coat layer 3a and the second coat layer 3b is improved, and the peeling durability of the drug-containing coating portion 3 is improved. Note that a covalent bond may be formed between the functional group of the base polymer and the first polymer on the surface of the first coat layer 3a. Further, a covalent bond may be formed between the functional group of the crosslinkable monomer and the functional group of the base polymer and the first polymer on the surface of the first coat layer

[0038] When the second polymer of the second coat layer 3b is a crosslinked polymer formed by crosslinking a base polymer and a crosslinkable monomer, examples of the base polymer include polyester, aliphatic polyester, polyanhydride, polyorthoester, polycarbonate, polyphosphazene, polyphosphoric acid ester, polyvinyl alcohol, polypeptide, polysaccharide, protein, cellulose, and copolymers, derivatives, mixtures, etc. thereof. Specific examples of the aliphatic polyester include polylactic acid, polycaprolactone, polyglycolic acid, polydioxanone, polybutyrolactone, polyvalerolactone, polyhydroxybutyric acid, polytrimethylene carbonate, and copolymers, derivatives, or mixtures thereof. Examples of the form of the copolymer include, but are not limited to, alternating copolymer, random copolymer, block copolymer, graft copolymer, etc.

[0039] In a preferred embodiment, the base polymer has lactic acid monomer units. That is, it is preferable that the second polymer has lactic acid monomer units. The content of the lactic acid monomer units in the base polymer is preferably 50 mol% or more (upper limit 100 mol%), more preferably 70 mol% or more (upper limit 100 mol%) with respect to all the monomers constituting the base polymer. Further, from the viewpoint that the second polymer can exhibit the intended effects of the present invention more effectively, it is preferable that the second polymer is hydrophobic. Therefore, it is also preferable that the base polymer is hydrophobic.

[0040] Also, from the viewpoint of peel durability and the like, the weight average molecular weight of the base polymer is preferably from 100,000 to 1,000,000, and more preferably from 150,000 to 800,000. In the present specification, the weight average molecular weight is a value measured under the following measurement conditions by gel permeation chromatography (Gel Permeation Chromatography, GPC) using polystyrene as a standard substance.

[0041] (Measurement conditions for molecular weight) Apparatus: Semi-micro GPC system LC-VP system (manufactured by Shimadzu Corporation) Detector: Shodex (registered trademark) RI-104 (manufactured by Showa Denko K.K.) Column: Two Shodex (registered trademark) GPC LF-804 (manufactured by Showa Denko K.K.) Guard column: Shodex (registered trademark) LF-G (manufactured by Showa Denko K.K.) Column temperature: 40 °C Mobile phase solvent: CHCl ３ Flow rate: 1.00 mL / min Injection volume: 200 μL

[0042] When the second polymer of the second coat layer 3b is a crosslinked polymer obtained by crosslinking a base polymer and a crosslinkable monomer, the crosslinkable monomer preferably has a high affinity with the base polymer and a strong bond with the first polymer on the surface of the first coat layer 3a.

[0043] Examples of the crosslinkable monomer include crosslinkable monomers having a functional group such as a vinyl group (CH ２ =CH-), an allyl group (CH ２ =CH-CH ２ -), an acryloyl group (CH ２ =CH-CO-), a methacryloyl group (CH ２ =C(CH ３ )-CO-), an acrylamide group (CH ２ =CH-CO-NH-). Generally, a terminal structure having an unsaturated bond of a functional group (in the above examples, CH ２ =CH- or CH ２ =C(CH ３The greater the polarity of the chemical structure connected to the )-) group, the more reactive the crosslinkable monomer becomes. The relationship of polarity is (allyl group) < (acryloyl group) ≈ (methacryloyl group) < (acrylamide group). Therefore, the reactivity of crosslinkable monomers with an allyl group is often less than that of crosslinkable monomers with an acryloyl group or methacryloyl group, and the reactivity of crosslinkable monomers with an acrylamide group is often greater than that of crosslinkable monomers with an acryloyl group or methacryloyl group. The reactivity of crosslinkable monomers with a methacryloyl group is due to the CH group within the methacryloyl group. ３ Because the steric hindrance can occur, the reactivity is slightly lower than that of crosslinkable monomers having an acryloyl group, but it is equivalent to that of crosslinkable monomers having an acryloyl group. Furthermore, among crosslinkable monomers having the same type of functional group, if the number of functional groups differs, the reactivity increases as the number of functional groups increases. Hereafter, when (meth)acrylate is written, it refers to both acrylate, which is a crosslinkable monomer having an acryloyl group, and methacrylate, which is a crosslinkable monomer having a methacryloyl (methacryloyl) group.

[0044] 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-acrylamidoethyl)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 trialyl trimellitic acid ester, trialyl pyromellitic acid ester, diallyl oxalate, trialyl cyanurate, and trialyl isocyanurate (TAIC). Of these, from the viewpoint of high bonding affinity with the first polymer on the surface of the first coating layer 3a, the crosslinkable monomer is preferably a (meth)acrylate, and more preferably a (meth)acrylate with four or more functions.

[0045] 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 a (meth)acrylate.

[0046] 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, but 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] The second polymer in the second coating layer 3b 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 3a, and energy such as heat or light is applied to form the second coating layer 3b, 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.

[0051] The second coating layer 3b 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 3b may form part of the second polymer in a covalently bonded form.

[0052] The second coating layer 3b may contain a polymerization initiator. While thermal polymerization initiators and photopolymerization initiators are known, the method 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 3b may be the changed form.

[0053] The thickness of the second coating layer 3b 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 3b may be uniform or non-uniform. The surface of the second coating layer 3b may be smooth or rough. The thickness of the second coating layer is measured, for example, by AFM.

[0054] <Third Coating Layer 3c> The third coating layer 3c in the drug-containing coating portion 3 is located on the second coating layer 3b and contains the drug and a third polymer that supports the drug. Preferably, the third polymer in the third coating layer 3c forms an interpenetrating polymer network structure with the second polymer in the second coating layer 3b.

[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 in 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 3c and the second polymer in the second coating layer 3b form an interpenetrating polymer network structure, thereby improving the bonding strength between the third coating layer 3c and the second coating layer 3b, and improving the peeling durability of the drug-containing coating portion 3.

[0056] The formation of an interpenetrating polymer network structure can be confirmed, for example, by observing a cross-section including the interfaces of each layer using a transmission electron microscope (TEM). For example, by embedding the drug-containing coating portion 3 in resin and thin-sectioning the resin-embedded sample using an ultramicrotome (Leica EM UC7), a sample with an exposed cross-section of the drug-containing coating portion 3 can be obtained. By observing this sample with TEM, the interpenetrating polymer network structure formed between the second coating layer 3b and the third coating layer 3c can be confirmed. Known resins can be used for embedding, but for example, epoxy resin (Epon812) and caprolactone (EVONIK C212) can be preferably used. Specifically, TEM observation can be carried out by the method described in the examples. In this case, if an interpenetrating polymer network structure is formed, the TEM image may show that the interface between the second coating layer 3b and the third coating layer 3c becomes unclear in the cross-section of the drug-containing coating portion 3, resulting in uneven brightness at the interface or a difference in brightness between the second coating layer 3b and the third coating layer 3c. Therefore, if the above findings are obtained at the interface between the second coating layer 3b and the third coating layer 3c in the TEM image, it can be determined that an interpenetrating polymer network structure has been formed.

[0057] The third polymer in the third coating layer 3c is preferably hydrophobic. Being hydrophobic allows the third polymer to dissolve in a solvent. A third solution, obtained by dissolving the third polymer in a solvent, is applied to the second coating layer. The third solution penetrates the second coating layer, causing it to swell. This forms an interpenetrating polymer network structure between the third polymer and the second polymer. Since the third solution also contains a drug, the drug supported on the third polymer may be incorporated into the network structure when the third polymer and the second polymer form the interpenetrating polymer network structure. If the third polymer is non-porous, a longer-term sustained release of the drug becomes possible. Furthermore, since the second coating layer needs to swell with the solvent, the second polymer is also preferably hydrophobic.

[0058] Furthermore, the hydrophobic nature of the third polymer in the third coating layer 3c is thought to enable peel resistance under usage conditions. For example, if the third polymer is hydrophilic (e.g., polyethylene glycol), the third and second coating layers will swell under usage conditions, preventing the peel resistance of the coating layers from being maintained and preventing the sustained release of the chemical agent. On the other hand, because the third and second polymers in the third coating layer 3c are hydrophobic, the third and second coating layers will not swell under usage conditions, and the peel resistance of the coating layers can be maintained.

[0059] 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 3b and the third coating layer 3c, increases the bonding force between the second coating layer 3b and the third coating layer 3c, and improves the peel resistance of the drug-containing coating portion 3. Here, the monomer units of the second polymer and the third polymer refer to the form obtained when the constituent monomers of each polymer react. 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 have the same monomer units in at least a portion of each. The drug in the third coating layer 3c is as described above.

[0060] The stent body 10 consists of multiple annular bodies 2 arranged in multiple axial directions, with adjacent annular bodies connected by connecting parts 31 and 32. The annular body 2 is composed of a linear first strut part 23 and a linear second strut part 24, and a wavy strut having multiple bent parts 21 with vertices (PEEK) on one end in the stent body 10 axial direction that connects the linear first strut part 23 and the linear second strut part 24, and multiple bent parts 22 with vertices (Valley) on the other end of the stent body 10.

[0061] The in vivo stent 1 in this embodiment is formed in a tubular shape, is compressed in the direction of the central axis when inserted into the body, and expands outward to return to its pre-compression shape when placed in the body, thus being a self-expanding type.

[0062] Furthermore, in the in vivo implantable stent 1 of this embodiment, the stent body 10 has two maximum connection portion holders 11 that have connection portions between all adjacent vertices of adjacent annular bodies 2 at both ends of the stent body, two first diminished connection portion holders 12 that have 40 to 60% of the number of connection portions in the maximum connection portion holder between the annular body 2 having the maximum connection portion holder and the annular body 2 located axially inward of the stent body, and a second diminished connection portion holder 13 that has 40 to 60% of the number of connection portions in the first diminished connection portion holder between a plurality of annular bodies 2 located between the two first diminished connection portion holders.

[0063] The number of bent portions 21 at one end and bent portions 22 at the other end of the annular body 2, and the number of vertices at one end and the other end of the annular body 2, are preferably 12 to 20, and particularly preferably 16.

[0064] Furthermore, the connecting portions 31 and 32 extend diagonally with respect to the central axis of the stent body 10, and the connecting portions 31 and 32 are generally straight, and the width (line width) of the connecting portions 31 and 32, the struts 23 and 24, and the bent portion is approximately the same. The width (line width) of the connecting portions 31 and 32, the struts 23 and 24, and the bent portion is preferably 0.08 mm to 0.120 mm, and particularly preferably 0.10 mm to 0.115 mm.

[0065] Furthermore, the annular body 2 is formed from a wavy linear component having a plurality of bent portions 21, 22 with vertices on one end and the other end in the axial direction. Between annular bodies 2 adjacent to each other in the axial direction of an in vivo implantable stent, the vertices of the adjacent bent portions 21, 22 are offset by a predetermined length (specifically, about 0.040 to 0.042 mm) in the circumferential direction of the stent body.

[0066] Each of the connecting portions 31 and 32 comprises a first pattern connecting portion 31 extending at a predetermined angle oblique to the central axis of the stent body, and a second pattern connecting portion 32 extending at a predetermined angle oblique to the central axis of the stent body and in a direction different from that of the first pattern connecting portion 31. The connecting portion between two opposing annular bodies 2 is either the first pattern connecting portion 31 or the second pattern connecting portion 32, and is the same pattern connecting portion. The connecting portions adjacent to each other in the axial direction of the stent body are arranged so that the first pattern connecting portion 31 and the second pattern connecting portion 32 alternate.

[0067] In particular, in the in vivo stent 1 of this embodiment, as shown in Figures 1 and 2, the group of connection parts 15a located at one end (between the annular body at one end and the adjacent annular body) are all composed of a first pattern connection part 31 that extends diagonally downward to the left (on the drawing) at a predetermined angle with respect to the central axis of the stent body. The group of connection parts 16a adjacent to the group of connection parts 15a in the axial direction of the stent body 10 are all composed of a second pattern connection part 32 that extends diagonally downward to the right (on the drawing) at a predetermined angle with respect to the central axis of the stent body.

[0068] Furthermore, all connection group 17a adjacent to connection group 16a in the axial direction of the stent body 10 are composed of a first pattern connection part 31 that extends diagonally downward and to the left (in the drawing) at a predetermined angle with respect to the central axis of the stent body. Similarly, all connection group 17b adjacent to connection group 17a in the axial direction of the stent body 10 are composed of a second pattern connection part 32 that extends diagonally downward and to the right (in the drawing) at a predetermined angle with respect to the central axis of the stent body. Thereafter, connection group 17a composed of the first pattern connection part 31 and connection group 17b composed of the second pattern connection part 32 are arranged alternately in the axial direction.

[0069] Furthermore, as shown in Figures 1 and 2, the connection portion 31 and the connection portion 32 are not continuous in the axial direction of the stent body 10 between the connection portion group 17a and the connection portion group 17b. Specifically, the connection portion 32 of the connection portion group 17b is not located in the direction of the other end of the axis of the connection portion 31 of the connection portion group 17a, in other words, downward (on the drawing), and the other end bent portion 22, which is a free end, is located below the connection portion 31 (on the drawing). Similarly, the connection portion 31 of the connection portion group 17a is not located in the direction of the other end of the axis of the connection portion 32 of the connection portion group 17b, in other words, downward (on the drawing), and the other end bent portion 22, which is a free end, is located below the connection portion 32 (on the drawing).

[0070] Furthermore, the group of connection parts 15b located at the other end (between the annular body at the other end and the adjacent annular body) are all composed of a second pattern connection part 32 that extends diagonally downward to the right at a predetermined angle with respect to the central axis of the stent body (in the drawing). Furthermore, the group of connection parts 16b adjacent to the group of connection parts 15b in the axial direction of the stent body 10 are all composed of a first pattern connection part 31 that extends diagonally downward to the left at a predetermined angle with respect to the central axis of the stent body (in the drawing).

[0071] Furthermore, in the in vivo implantable stent 1 of this embodiment, the stent body 10 has two maximum connection portion holders 11a, 11b that have connection portions between all adjacent vertices of adjacent annular bodies 2 at both ends of the stent body, two first diminished connection portion holders 12a, 12b that have 40 to 60% of the number of connection portions in the maximum connection portion holders between the annular bodies 2 having the maximum connection portion holders 11a, 11b and the annular bodies 2 located axially inward of the stent body, and second diminished connection portion holders 13a, 13b that have 40 to 60% of the number of connection portions in the first diminished connection portion holders between a plurality of annular bodies 2 located between the two first diminished connection portion holders 12a, 12b. Furthermore, it is preferable that the second reduction connection holder has 45 to 55% of the number of connection parts in the first reduction connection holder.

[0072] Specifically, as shown in Figures 1 and 2, one end (between the annular body at one end and the adjacent annular body) has a maximum connection portion 11a that connects all of the diagonally opposing bent portions 22 on the other end and the bent portion 21 on the one end. Therefore, the annular bodies 2 at one end do not have any bent portions 21 and 22 that become free ends. Furthermore, all the connection portions between the annular body at one end and the adjacent annular body, in other words, the connection portions in the maximum connection portion 11a, are first pattern connection portions 31 that extend diagonally downward to the left (in the drawing) at a predetermined angle with respect to the central axis of the stent body.

[0073] Furthermore, the stent body 10 has a maximum connection portion 11b at the other end (between the annular body at the other end and the adjacent annular body) that connects all of the diagonally opposing bent portions 22 on the other end side and the bent portion 21 on the one end side. For this reason, there are no free-end bent portions 21 and 22 between the annular bodies 2 at the other end. The connection portions between the annular body at the other end and the adjacent annular body, in other words, the connection portions in the maximum connection portion 11b, are all second pattern connection portions 32 that extend diagonally downward to the right at a predetermined angle with respect to the central axis of the stent body (in the drawing).

[0074] Furthermore, the space between the annular body 2 having the most connection portion 11a at one end and the annular body 2 located axially inward from the stent body is a first reduced number of connection portion 12a, which has 40 to 60% of the number of connection portions in the most connection portion 11a. In the examples shown in Figures 1 and 2, the number of connection portions in the most connection portion 11a is 16, and the number of connection portions in the first reduced number of connection portion 12a is 8, which is 50% of the number of connection portions in the most connection portion 11a. The connection portions in the first reduced number of connection portion 12a are arranged at equiangled angles with respect to the central axis of the stent body 10.

[0075] Similarly, the space between the annular body 2 having the most connection portion 11b at the other end and the annular body 2 located axially inward from the stent body is a first reduced number of connection portion 12b, which has 40-60% of the number of connection portions in the most connection portion 11b. In Figures 1 and 2, the number of connection portions in the most connection portion 11b is 16, and the number of connection portions in the first reduced number of connection portion 12b is 8, which is 50% of the number of connection portions in the most connection portion 11b. The connection portions in the first reduced number of connection portion 12b are arranged at equiangled angles with respect to the central axis of the stent body 10.

[0076] Furthermore, the space between the annular bodies 2 located between the first diminishing connection holders 12a and 12b is a second diminishing connection holder 13a and 13b, each having 40 to 60% of the number of connection parts in the first diminishing connection holder. In Figures 1 and 2, the number of connection parts in the first diminishing connection holders 12a and 12b is 8, and the number of connection parts in the second diminishing connection holders 13a and 13b is 4, which is 50% of the number of connection parts in the first diminishing connection holders 12a and 12b. The connection parts in the second diminishing connection holders 13a and 13b are arranged at equal angles with respect to the central axis of the stent body 10.

[0077] Furthermore, the axial length of the annular body 2 when it is self-expanding is preferably 1.3 to 1.7 mm, more preferably 1.4 to 1.6 mm, and even more preferably 1.45 to 1.55 mm. The lengths of the connecting parts 31 and 32 are preferably 0.35 to 0.50 mm, more preferably 0.40 to 0.45 mm. In addition, the total axial length of one annular body and the connecting parts connected thereto is preferably 1.5 to 2.5 mm, more preferably 2.0 to 2.2 mm.

[0078] Furthermore, the inclination angle of the connection portions 31 and 32 with respect to the central axis of the stent body during the self-expansion of the annular body 2 (the inclination angle with respect to the central axis of the stent body in the deployed state of the stent) is preferably 110 to 130 degrees, and particularly preferably 115 to 125 degrees. It is preferable that the inclination angle at connection portion 31 and the inclination angle at connection portion 32 are approximately the same (specifically, the difference is less than 5%).

[0079] In this embodiment, the stent body 10 has an outer diameter of 4.0 to 10.0 mm during self-expansion, and is particularly preferably 5.0 to 9.0 mm. The axial length of the stent during self-expansion is preferably 30 to 200 mm, particularly preferably 40 to 180 mm, and more preferably 40 to 150 mm. The number of annular bodies 2 in the stent body 10 is preferably 7 to 100, and more preferably 20 to 90.

[0080] In the in vivo stent 1 of the present invention, the ratio of the outer surface area of ​​the stent body 10 to the outer surface area of ​​the virtual cylindrical body of the in vivo stent 1 during self-expansion is preferably 15% to 20%, and particularly preferably 15% to 18%. The virtual cylindrical body of the in vivo stent 1 refers to the cylindrical body formed by the outer diameter and total length of the stent body 10 during expansion. The ratio of the outer surface area of ​​the stent body 10 to the outer surface area of ​​the virtual cylindrical body can be calculated as "total outer surface area of ​​the stent body 10 / outer surface area of ​​the virtual cylindrical body (outer surface area of ​​the cylindrical body formed by the outer diameter and total length of the stent body 10 during expansion)".

[0081] The in vivo stent has multiple lateral openings formed within adjacent annular bodies 2 during self-expansion. These multiple lateral openings formed within adjacent annular bodies 2 during self-expansion are formed by struts 23, struts 24, bent portions 21, 22, and connecting portions 31, 32. The radius of the maximum inscribed circle at each lateral opening is preferably 0.37 to 0.45 mm, and particularly preferably 0.37 to 0.40 mm. The size of the lateral openings is not uniform and varies depending on the location. The radius of the maximum inscribed circle at each lateral opening does not vary greatly, but it is not all the same. It is preferable that the radii of the maximum inscribed circle at each lateral opening are all approximately the same (specifically, the difference is less than 15%, preferably less than 10%).

[0082] Furthermore, it is preferable that the diameter retention rate at the center of the in-vivo stent 1, when the central part of the in-vivo stent is curved with a radius of curvature of R7.5 mm, is 85% or more, and particularly preferably 87% or more. The diameter retention rate at the center of the in-vivo stent when the central part of the in-vivo stent is curved with a radius of curvature of R7.5 mm is calculated by pressing the central part of the in-vivo stent against a cylindrical rod with a radius of curvature of R7.5 mm and pressing down on both sides of the in-vivo stent so that the in-vivo stent is aligned with the cylindrical rod with a radius of curvature of R7.5 mm. In this state, the central part of the in-vivo stent deforms into an elliptical cross-section, with a short-diameter portion. The diameter retention rate (%) is calculated by "length of the short-diameter portion of the central part when deformed / outer diameter of the in-vivo stent when not deformed" × 100.

[0083] Furthermore, the in-vivo stent 1 preferably has an expansion force of 9 to 11 N / cm. This expansion force can be measured using a commercially available radial force measuring device.

[0084] Furthermore, as in the stent 1 of this embodiment, it is preferable to provide markers 5 made of radiopaque material. It is preferable to provide the radiopaque material markers 5 at both ends of the stent body 10. In particular, as shown in Figures 1 and 2, it is preferable to provide multiple radiopaque material markers 5 at each end. The radiopaque material markers 5 are fixed to the stent so as to close the small opening formed in the stent. Such markers are preferably attached, for example, by placing a disc-shaped member of an X-ray contrast material having a portion slightly smaller and a portion larger than the small opening formed in the stent body 10, pressing it from both sides, and crimping it in a rivet-like manner.

[0085] The material used to form the stent body 10 is preferably a metal having superelastic properties. Specific examples of alloys having superelastic properties include Ni-Ti alloys (which may also contain Co, Fe, Zr, Hf, Pd, Au, Fe, Pt, and Mo), Cu alloys (which may also contain Al, Mn, Ni, and Zn), and Mg alloys (which may also contain Li, Al, Zn, Ca, Y, W, Zr, Gd, Mn, Sc, Cu, Ag, Nd, and other rare earth metals).

[0086] Furthermore, if the in vivo stent is formed in a substantially tubular shape, has a diameter for insertion into a lumen in the body, and is expandable when a radially expanding force is applied from the inside of the tubular body, a so-called balloon-expandable stent, then the forming material can be, for example, stainless steel, tantalum or tantalum alloy, platinum or platinum alloy, gold or gold alloy, cobalt-nickel alloy, cobalt-chromium alloy, etc. Alternatively, the stent may be plated with a precious metal (gold, platinum) after its shape is fabricated. SUS316L is preferred as the most corrosion-resistant stainless steel.

[0087] Next, the stent delivery system 50 of the present invention will be described with reference to Figures 7 to 10. The stent delivery system 50 of the present invention comprises a sheath 52, a stent 1 for implantation in a living body housed in the tip of the sheath 52, and an inner tube 54 that is slidably inserted inside the sheath 52 and pushes the stent 1 for implantation in a living body out from the tip of the sheath 52.

[0088] The in vivo stent 1 is as described above. The stent delivery system 50 of this embodiment comprises a sheath 52, a self-expanding in vivo stent 1, and an inner tube 54, as shown in Figure 7.

[0089] As shown in Figures 7, 8, and 10, the sheath 52 is tubular and has openings at its tip and rear end. The tip opening functions as a discharge port for the in vivo stent 1 when it is placed in a narrowed area within a body cavity. The in vivo stent 1 is pushed out through this tip opening, releasing the stress load and expanding to return to its pre-compression shape. The tip of the sheath 52 is a stent housing section 55 that houses the in vivo stent 1 inside. The sheath 52 also has a sheath side hole 41 provided on the proximal end side of the housing section 55. The sheath side hole 41 is for guiding the guide wire to the outside.

[0090] Furthermore, as shown in Figures 7 and 9, a sheath hub 56 is fixed to the base end of the sheath 52. As shown in Figure 9, the sheath hub 56 comprises a sheath hub body 61 and a valve body 62 housed within the sheath hub body 61, which slidably and liquid-tightly holds the inner tube 54. The sheath hub 56 also includes a side port 63 that branches diagonally rearward from near the center of the sheath hub body 61.

[0091] Furthermore, the sheath hub 56 is equipped with an inner tube locking mechanism that restricts the movement of the inner tube 54. In this embodiment, the locking mechanism consists of a valve body 62 that clamps the base end of the inner tube 54 in a liquid-tight manner by compression, an operating member 64 that compresses the valve body 62, and the sheath hub body 61. By providing this locking mechanism, the inner tube 54 can be fixed in any position relative to the sheath 52. The valve body 62 is installed in a valve body housing recess provided at the base end of the sheath hub body 61, and an inner tube insertion passage that forms part of the inner tube lumen is formed inside the valve body 62. In addition, the inner diameter of the valve body housing recess is made slightly larger than the outer diameter of the valve body 62, allowing the valve body 62 to expand radially when compressed by the operating member 64. The internal shape of the valve body 62 (in other words, the shape of the inner tube insertion passage) is made into a shape in which two substantially spherical shapes partially overlap in the axial direction, with both ends and the center part having a reduced diameter.

[0092] The operating member 64 has a cylindrical valve body pressing portion 64a protruding towards the tip in the central part, an inner cylindrical portion 64c formed to enclose the valve body pressing portion 64a and having a screw portion 64b that can be screwed into a screw portion 61a formed on the outer surface of the rear end of the sheath hub body 61, and a cylindrical gripping portion 64d formed to enclose the inner cylindrical portion 64c. The gripping portion 64d is the part used to grip the operating member 64 when it is rotated. Furthermore, an internal passage is formed inside the valve body pressing portion 64a, specifically inside the valve body pressing portion 64a, forming part of the lumen for the inner tube. Also, as shown in Figure 9, the tip portion of the valve body pressing portion 64a is inserted into the recess for housing the valve body, and the valve body 62 can be compressed by moving the operating member to the tip.

[0093] In this embodiment of the locking mechanism, when the operating member 64 is rotated to advance the screwing process so that it moves toward the tip of the sheath hub 56, the tip of the valve body pressing portion 64a comes into contact with the rear end of the valve body 62. Further rotation of the operating member 64 to advance the screwing process compresses the valve body 62 in the axial direction. As the compression of the valve body 62 progresses, the inner diameter of the internal passage decreases, and finally the inner tube 54 is gripped and fixed by the valve body 62. The locking mechanism is released by the reverse rotation operation described above.

[0094] Furthermore, a reinforcing tube 66 is provided between the base end of the sheath 52 and the sheath hub 56, extending from the tip of the sheath hub 56 toward the tip. This reinforcing tube 66 prevents kinking of the sheath 52 at the tip of the sheath hub 56. It is preferable to use a heat-shrinkable tube as the reinforcing tube.

[0095] As shown in Figures 7, 8, and 9, the inner tube 54 comprises a shaft-shaped inner tube body portion 40, a tip portion 47 provided at the tip of the inner tube body portion 40 and protruding from the tip of the sheath 52, and an inner tube hub 70 fixed to the base end of the inner tube body portion 40.

[0096] The tip portion 47 preferably protrudes from the tip of the sheath 52 and is tapered, gradually decreasing in diameter towards the tip, as shown in Figure 8. This configuration facilitates insertion into the stenosis. Furthermore, the inner tube 54 is preferably located on the tip side of the in-vivo stent 1 and is equipped with a stopper to prevent the sheath from moving toward the tip. The base end of the tip portion 47 is capable of contacting the tip of the sheath 52 and functions as the stopper described above.

[0097] Furthermore, as shown in Figure 8, the inner tube 54 is provided with two protrusions 43 and 45 for holding the in vivo stent 1. The protrusions 43 and 45 are preferably annular. A stent-holding protrusion 43 is provided on the proximal end side of the tip 47 of the inner tube 54. The in vivo stent 1 is positioned between the two protrusions 43 and 45. Therefore, the area between these two protrusions 43 and 45 in the stent delivery system 50 is the stent storage area 55. In other words, the inner tube 54 is provided with a stent extrusion protrusion 45 located on the proximal end side of the stent storage area 55, and a stent-holding protrusion 43 located on the tip side of the stent storage area 55. The outer diameters of these protrusions 43 and 45 are sized to be in contact with the compressed in vivo stent 1, which will be described later. Therefore, the in vivo stent 1 is restricted from moving toward the tip by the protruding portion 43 and from moving toward the proximal end by the protruding portion 45. Then, as shown in Figure 10, when the sheath 52 moves backward, the in vivo stent 1 is exposed by the sheath 52, expands, and is eventually discharged as a whole.

[0098] As shown in Figure 8, the inner tube 54 includes a lumen 48 that extends from its tip to at least the proximal end side of the stent housing portion 55 of the sheath 52, and an inner tube side hole 42 that communicates with the lumen 48 on the proximal end side of the stent housing portion. In this embodiment of the stent delivery system 50, the lumen 48 terminates at the portion where the side hole 42 is formed. The lumen 48 is for inserting one end of a guide wire from the tip of the stent delivery system 50, partially inserting it into the inner tube, and then leading it out to the outside from the side of the inner tube. The inner tube side hole 42 is located slightly towards the tip of the stent delivery system 50 from the sheath side hole 41.

[0099] The inner tube 54 penetrates the sheath 52 and protrudes from the rear end opening of the sheath 52. An inner tube hub 70 is fixed to the base end of the inner tube 54, as shown in Figures 7 and 10.

[0100] Furthermore, in the stent delivery system of this embodiment, a rigid pipe 72 is fitted over the base end of the inner tube 54. This rigid pipe 72 extends a predetermined distance toward the tip from the base end of the inner tube 54, and at least the tip of the pipe 72 penetrates into the sheath hub 56 and extends to a position that is toward the tip of the valve body 62. Furthermore, it is preferable that the base end of the inner tube 54 is provided with an insertion depth restricting portion that restricts the distance the sheath 52 moves toward the tip. The inner tube 54 is provided with an insertion depth restricting tube 73 at its base end. The outer diameter of this tube 73 is larger than the inner diameter of the passage of the operating member 64 of the sheath hub 56, and it is impossible for it to penetrate into the sheath hub 56.

[0101] Next, the method of using the stent delivery system 50 of the present invention will be explained with reference to the drawings. First, as shown in Figure 10, the rear end 9a of the guide wire 9 is inserted from the tip of the lumen 48 of the inner tube 54, and is led out to the outside by passing it through the side hole 42 of the inner tube 54 and the sheath side hole 41 of the sheath 52. Then, the sheath 52 is grasped and the stent delivery system 50 of the present invention is inserted into a body cavity (for example, a blood vessel) along the guide wire 9 to position the target in vivo stent 1 for placement in the stenotic area.

[0102] Next, the sheath 52 is moved axially towards the proximal end. At this time, the rear end face of the in vivo stent 1 abuts against the tip surface of the stent extrusion projection 45 and is locked in place, so it is released from the tip opening of the sheath 52 as the sheath 52 moves. As a result of this release, the in vivo stent 1 expands itself, as shown in Figure 10, and expands the stenotic area, and is then placed within the stenotic area. After that, the inner tube 54 is moved axially towards the proximal end and stored inside the sheath 52, and the procedure is completed by removing the sheath 52 together with the inner tube 54 from the body cavity.

[0103] Next, the method for manufacturing the in vivo stent of the present invention will be described. The method for manufacturing the in vivo stent of the present invention comprises a tubular stent body 10 formed of a wavy linear component having a plurality of bent portions 2 having vertices on one end or the other end in the axial direction, and a drug-containing coating portion 3 provided on the outer surface of the stent body 10.

[0104] The stent body 10 has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion.

[0105] The present invention provides a method for manufacturing an in-vivo stent, which includes a step of forming a drug-containing coating on the outer surface of the stent body 10. In the drug-containing coating formation step, a nozzle, which has discharge pressure applied to a viscous coating solution containing a drug and a polymer dissolved in a solvent, is positioned on the outer surface of the linear first strut portion and moved along the outer surface of the linear first strut portion to coat the outer surface of the linear first strut portion. When the nozzle reaches one end of the bent portion, the nozzle is moved from the end of the bent portion to the outside of the outer edge of the bent portion, and then the nozzle is detoured to the outside of the outer edge of the bent portion. When the nozzle approaches the other end of the bent portion, the nozzle is positioned on the other end of the bent portion and moved along the outer surface of the linear second strut portion to apply the coating to the outer surface of the linear second strut portion. Furthermore, it is preferable that the detour beyond the outer edge of the nozzle's bend passes through the side opening of the stent base, avoids the bend of the annular body adjacent in the axial direction, and passes between the bends of the annular body adjacent in the axial direction.

[0106] Then, in the drug-containing coating formation process, after the first coating process, the nozzle's direction of movement is changed to a different direction from that of the first coating process, and the nozzle, with discharge pressure applied to the coating liquid, is positioned on the outer surface of the linear second strut section. The nozzle is moved along the outer surface of the linear second strut section to coat the outer surface of the linear second strut section with the coating liquid. When the nozzle reaches the other end of the bent section, the nozzle is moved from the other end of the bent section to the outside of the outer edge of the bent section. Furthermore, the nozzle is detoured around the side opening outside the outer edge of the bent section. Then, when the nozzle approaches one end of the bent section, the nozzle is positioned on one end of the bent section and moved along the outer surface of the linear first strut section to coat the outer surface of the linear first strut section with the coating liquid. In this process as well, it is preferable that the detour of the nozzle outside the outer edge of the bent section is made to pass through the side opening of the stent base. Furthermore, it is preferable that the detour beyond the outer edge of the nozzle's bend passes through the side opening of the stent base, avoids the bend of the annular body adjacent in the axial direction, and passes between the bends of the annular body adjacent in the axial direction.

[0107] Furthermore, in the process of forming the drug-containing coating, a third coating step may be performed after the second coating step, in which the coating solution is applied in the same manner as in the first coating step. In addition, it is preferable that in the first, second, and third coating steps, pressure is continuously applied to the coating solution when bypassing the outer edge of the bent portion of the nozzle. It is also preferable that the coating solution contains a polymer with a molecular weight of 150,000 or more.

[0108] In the embodiment described, during the first coating step, when the nozzle bypasses the outside of the bent portion, by maintaining the discharge pressure applied to the coating liquid, a mass of coating liquid and a linear portion extending from the coating liquid mass are formed at the tip of the nozzle. When the nozzle is positioned on the other end of the bent portion, the mass of coating liquid is placed on the other end of the bent portion, and the linear portion is placed on the outer surface between one end and the other end of the bent portion (including the apex). During the second coating step, when the nozzle bypasses the outside of the bent portion, by maintaining the discharge pressure applied to the coating liquid, a mass of coating liquid and a linear portion extending from the coating liquid mass are formed at the tip of the nozzle. When the nozzle is positioned on one end of the bent portion, the mass of coating liquid is placed on one end of the bent portion, and the linear portion is placed between one end and the other end of the bent portion (including the apex).

[0109] As a result, the drug-containing coating portion 3 is formed with a linear coating portion 34 that covers the linear first strut portion 23 and the linear second strut portion 24, a bent portion thin-layer coating portion 35 that covers the bent portions 21 and 22, and a thick coating portion 36 provided at both ends of the bent portions 21 and 22 (in other words, at both ends of the bent portion thin-layer coating portion 35).

[0110] A method for manufacturing an in vivo stent according to an embodiment of the present invention will be described. In this embodiment, the method for manufacturing an in vivo stent includes a stent body preparation step, a coating solution preparation step, a drug-containing coating formation step, and a drying step.

[0111] In the manufacturing method of this embodiment, the prepared stent body is formed in a tubular shape, is compressed in the direction of the central axis when inserted into a body, and expands outward to return to its pre-compression shape when placed in a body, thus being a self-expanding type. Specifically, it is preferable that the stent body is made by cutting a superelastic metal tube to form the basic shape of the stent body, then expanding its diameter, and then heat-treating it, so that the stent body has superelasticity in the expanded state. Furthermore, it is preferable that the drug-containing coating is applied to the outer surface of the stent body 10 after the diameter has been expanded and before or after the heat treatment.

[0112] Each step will be explained. In the stent body preparation step, the stent base is formed first. In this stent base formation, for example, a substantially cylindrical metal pipe capable of imparting superelastic properties is prepared, having an outer diameter smaller than the inner diameter of the internal body site where it will be implanted. The metal pipe prepared may already possess superelastic properties, or it may be capable of being imparted superelastic properties by a step described later.

[0113] Then, the sides of the pipe are partially removed to form a stent base comprising multiple annular bodies 2 and connecting parts that connect the annular bodies in an axial position of the stent. This process can be carried out by cutting processes such as laser processing (e.g., YAG laser), electrical discharge machining, mechanical polishing, or chemical etching. Furthermore, a combination of these methods may also be used.

[0114] Next, the stent base fabricated as described above is expanded to an outer diameter that matches the internal location in the body where it will be implanted, and then heat-treated in the expanded state to form an expanded stent base shape that retains its shape in the expanded state and exhibits superelasticity. The outer diameter expansion process can be carried out, for example, by using a mandrel having a tapered portion at one end that is smaller in outer diameter than the stent base and can be inserted into the stent base, and a larger diameter portion continuous with this tapered portion that has the outer diameter of the expanded stent. The stent base is placed over the tapered end of the mandrel, and then the stent base is pushed into the larger diameter portion of the mandrel, thereby expanding the stent base. This expansion process may also be carried out in stages.

[0115] Then, the stent base is heat-treated in its expanded state to impart shape memory in the expanded state and superelastic properties. For example, with the stent base positioned on the large-diameter portion of the core metal, the stent base is heated using a heating means such as a heater to impart shape memory in the expanded state and superelasticity. The heating temperature and heating time in this process (heat treatment process) vary depending on the metal used, but it is preferable to maintain the expanded stent base at a temperature of 350 to 550°C for 5 to 20 minutes.

[0116] Next, a preparation step for the coating solution used in the drug-containing coating formation step is performed. In this embodiment, in the drug-containing coating formation step, a first coating solution is prepared for forming a first coat layer 3a having a first polymer formed by the self-oxidative polymerization of dopamine molecules or their analogs on the outer surface of the stent body described above; a second coating solution is prepared for forming a second coat layer 3b having a second polymer covalently bonded with the first polymer on the first coat layer 3a; and a third coating solution is prepared for forming a third coat layer 3c having a drug and a third polymer supporting the drug on the second coat layer 3b.

[0117] For forming the first coat layer 3a, a first coating solution containing the material for forming the first coat layer 3a described above is used. For forming the second coat layer 3b, a second coating solution containing the material for forming the second coat layer 3b described above is used. For forming the third coat layer 3c, a third coating solution containing the material for forming the third coat layer 3c described above is used.

[0118] The solvent for each coating solution is appropriately selected depending on the materials it contains. Preferably, the solvent is one that dissolves polymers, pharmaceuticals, etc., but one that can uniformly disperse them is also acceptable. Furthermore, a solvent with good stent wettability and a suitable evaporation rate is preferred, and the solvent should be selected to strike a balance between these factors. Examples of preferred solvents include acetone, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, methylene chloride, chloroform, Freon, dioxane, ethyl acetate, ethanol, tetrahydrofuran, dimethylformamide, dimethylacetamide, and mixtures thereof.

[0119] Furthermore, additives may be added for purposes such as adjusting the physical properties of the drug-containing coating, improving adhesion to the stent, adjusting the viscosity of the application solution, and preventing oxidation of the therapeutic substance. Examples of these additives include glycerol, triacetylglycerin, ethylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, propylene glycol, polyalkylene oxide, sebacate ester, citrate ester, and phthalate ester.

[0120] Then, the process involves applying the first coating solution to the outer surface of the stent body 10, applying the second coating solution to the outer surface of the stent body to which the first coating solution has been applied, and applying the third coating solution to the outer surface of the stent body to which the second coating solution has been applied. It is desirable to apply the third coating solution at least twice, and especially three times. It is also acceptable to omit either the application of the first coating solution or the application of the second coating solution, or to perform only one of the application of the first or second coating solution.

[0121] The application of the first coating solution to the stent body may be performed using a coating device described later. Alternatively, the application of the first coating solution to the stent body may be performed by immersing the mandrel to which the stent body is attached in the first coating solution and then lifting it out. When the application of the first coating solution to the stent body is performed by immersion as described above, the second and third coating solutions may be applied simultaneously using a coating device having two nozzles, as described later.

[0122] Furthermore, the first and second coating solutions may be applied using a coating device having two nozzles, as described later. In this case, the third coating solution can be applied independently using the coating device described later. Moreover, a coating device of the type described later, having three nozzles, may be prepared to apply the first coating solution, the second coating solution, and the third coating solution to the stent body.

[0123] Figures 11 and 12 are a front view and a side view of the main part of a coating apparatus applied to the process of forming a drug-containing coating, and Figures 13 and 14 are plan views illustrating the coating path of the nozzle of the coating head shown in Figure 12. The coating apparatus 200 includes a chamber 210, a holder 220, a moving device 230, a first coating head 240, a second coating head 245, a first position information acquisition device 270, a second position information acquisition device 280, and a control unit 290.

[0124] The chamber 210 comprises a base 212, a main frame 214 positioned on the base 212, and a duct 216 connected to the top. The main frame 214 is covered from the outside with a transparent synthetic resin plate, making the inside of the chamber 210 airtight. An air conditioning unit 218 is connected to the duct 216. The air conditioning unit 218 supplies air with adjusted temperature and humidity to the chamber 210. Therefore, it is possible to maintain a constant temperature and humidity inside the chamber 210 and keep the coating conditions constant. Reference numeral 215 indicates a support frame horizontally mounted on the main frame 214.

[0125] The retainer 220 is positioned at the bottom inside the chamber 210 and is used to hold the stent body 10. It has a base 222, a chuck 224, a motor 226, and a mandrel 228.

[0126] The base portion 222 is mounted on the moving device 230 and, as will be described later, is movable in the X-Y direction, and a chuck portion 224 and a motor 226 are arranged thereon. The chuck portion 224 is used to chucking the base end of the mandrel 228. The motor 226 is configured to allow the chuck portion 224 to rotate in forward and reverse directions. The mandrel 228 has an outer circumference on which the stent body 10 is detachably mounted. Therefore, the holder 220 can rotate the stent body 10 mounted on the mandrel 228 in forward and reverse directions, move it in the X direction, and move it in the Y direction.

[0127] The outer diameter of the mandrel 228 is preferably approximately the same as or slightly larger than the inner diameter of the stent body 10. The mandrel 228 is preferably painted with a light-absorbing black paint to increase the contrast ratio between the struts 30 of the stent body 10 and the gap. The outer surface of the mandrel 228 is preferably formed with recesses that create a gap between the outer surface of the mandrel 228 and the lower surface of the struts 30 of the stent body 10 when the stent body 10 is mounted on the mandrel 228.

[0128] The moving device (corresponding to the means of movement) 230 is used to move the holder 220 in the X-Y direction and has an X-direction moving mechanism 231 and a Y-direction moving mechanism 236.

[0129] The X-direction movement mechanism 231 includes a running rail 233 that extends in the X direction and has a linear motor drive source, and an X-direction movement table 234 that moves along the running rail 233. The Y-direction movement mechanism 236 includes a running rail 237 that extends in the Y direction, a Y-direction movement table 238 that moves along the running rail 237, and a motor 239 that drives the Y-direction movement table 238. The running rail 237 is placed on the X-direction movement table 234, and the base 222 of the holder 220 is placed on the Y-direction movement table 238. In the embodiment described here, the outer surface of the stent body 10 is sequentially coated with a first coating liquid, a second coating liquid, and a third coating liquid.

[0130] As shown in Figures 12 and 11, the first coating head 240 and the second coating head 245 are located in the middle of the chamber 210 and are used to apply the coating liquid, and have a dispenser 252, a vertical table 253, a bracket 258, and a nozzle section 262.

[0131] The dispenser 252 has a cylinder section 255, a piston section 256, and a drive section 257, and is mounted on a vertical table 253. The vertical table 253 is mounted on a support frame 215 of the chamber 210 via a bracket 258, and is configured to allow the dispenser 252 to move in the Z direction by a screw feed mechanism driven by a motor 254.

[0132] The cylinder portion 255 is a container for storing the coating liquid and is attached to the vertical table 253. The piston portion 256 is slidably positioned within the cylinder portion 255. The drive unit 257 has, for example, a motor or a hydraulic mechanism and is configured to press the piston portion 256 with a predetermined force.

[0133] The nozzle portion 262 communicates with the cylinder portion 255 and includes a mounting member 264 and a nozzle 266. The mounting member 264 is positioned at the lower end of the cylinder portion 255 and is used to connect the nozzle 266 to the cylinder portion 255.

[0134] The outer diameter of the tip of the nozzle 266 is preferably 10 to 1000 μm. The inner diameter of the tip of the nozzle 266 (inner diameter of the opening 266a) is preferably 1 to 500 μm, and more preferably 5 to 250 μm.

[0135] The viscosity of the third coating liquid is preferably 0.1 to 2000 cp, and more preferably 100 to 1000 cp. For example, if the viscosity of the third coating liquid is greater than the upper limit of the range, the discharge pressure of the third coating liquid may become excessively high or it may not be possible to discharge it from the nozzle 266. Conversely, if it is less than the lower limit of the range, a portion of the discharged third coating liquid may drip from the surface of the stent body 10 (strut 30), making it difficult to form a uniform coating layer.

[0136] The distance G (Figure 12) between the nozzle 266 and the surface of the stent body 10 (strut) is preferably 0.1 to 200 μm, and more preferably 1 to 100 μm, in order to quantitatively discharge the third coating solution with good controllability (in order to accurately and reliably prepare the quantity of the drug solution). For example, if the distance G is greater than the upper limit of the range, there is a risk that the coating solution will be interrupted, and if it is smaller than the lower limit of the range, there is a risk that the third coating solution will drip from the surface of the stent body 10 (strut 30).

[0137] The second coating head 245 shown in Figure 11 is located in the middle of the chamber 210 and is used to apply the coating liquid. The second coating head 245 is substantially the same as the first coating head 240, except that a different coating liquid is stored in the cylinder portion 255, so its description is omitted.

[0138] The first position information acquisition device 270 is an imaging means provided for acquiring position information in the X-Y direction in a Cartesian coordinate system on the surface of the stent body 10 (strut), and is attached to the support frame 215 via a bracket 272. The first position information acquisition device 270 has a camera unit 274 and a line sensor unit arranged to extend in the axial direction of the stent body 10. The line sensor unit is used to scan the surface of the stent body 10 in synchronization with the rotation of the stent body 10 attached to the mandrel 228 of the holder 220, acquire image data of the surface of the stent body 10, and transmit it to the control unit 290.

[0139] The second position information acquisition device 280 is a Z-direction displacement measuring means provided to acquire position information in the Z-direction in a Cartesian coordinate system on the surface of the stent body 10 (strut). It is fixed to the lower end of a bracket 282 attached to the support frame 215 and has a laser displacement sensor 284. The laser displacement sensor 284 is a vertical sensor that measures the Z-direction displacement of the linear first strut portion 23 and the linear second strut portion 24. It is used to scan along a trajectory passing through the centers of the linear first strut portion 23, the linear second strut portion 24 and the bent portions 21 and 22 while rotating the stent body 10 in forward and reverse directions, acquire Z-direction displacement data for the entire stent body 10, and transmit it to the control unit 290. The measurement start point is not particularly limited, but for example, it may coincide with the application start position.

[0140] The control unit 290 is located outside the chamber 210 and includes, for example, a microprocessor that controls the above-mentioned parts and performs various calculations according to a program, a memory for storing various settings and data, a monitor for displaying various settings and data, a keyboard for inputting various settings and data, etc., and is used to control the holder 220, the moving device 230, the first coating head 240, the second coating head 245, the first position information acquisition device 270, and the second position information acquisition device 280.

[0141] The calculation processes include, for example, a process for acquiring position information in the X-Y direction, a process for acquiring position information in the Z direction, and a process for setting the coating path by the nozzle 266.

[0142] In the process for acquiring position information in the X-Y direction, based on the fact that the brightness of the stent body 10 (strut) is high and the brightness of the void is low, the image data of the surface of the stent body 10 acquired from the first position information acquisition device 270 is binarized with an appropriate brightness to separate the stent body 10 (strut) from the void, and converted into the X-Y coordinates of the stent body 10 (strut), that is, position information in the X-Y direction in a Cartesian coordinate system, and stored in memory. The obtained position information in the X-Y direction is used to calculate the coordinates of the trajectory passing through the center of the stent body 10 (strut), and the obtained trajectory coordinates are stored in memory.

[0143] In the process for acquiring position information in the Z direction, the Z-direction displacement data of the entire stent body 10 acquired from the second position information acquisition device 280 is converted into Z-direction position information in the Cartesian coordinate system of the surface of the stent body 10 (strut) and stored in memory. The stent body 10 (strut) is not strictly a smooth surface, but has irregularities. Therefore, in order to apply each coating liquid quantitatively and precisely, it is necessary to control the movement of the tip of the nozzle 266 based on the Z-direction position information so that it is strictly parallel to the surface of the stent body 10 (strut), and to apply a predetermined amount of each coating liquid.

[0144] In the process of setting the coating path for each coating liquid by the nozzle 266, the position information in the X-Y direction and the Z direction of the stent body 10 (linear strut sections 23, 24, bent sections 21, 22, and connecting sections 31, 32) in the Cartesian coordinate system is used to calculate the settings for continuous coating on the stent body 10 (struts).

[0145] The coating path of the third coating liquid is set to detour significantly outward at locations where stress concentration and / or strain occurs due to expansion deformation (bent portions 21, 22 and connecting portions 31, 32 of the stent body 10), passing through the side opening of the stent base, and passing over the linear first strut portion 23 and linear second strut portion 24 of the stent body 10, as shown in Figure 13. Furthermore, it is preferable that there are no overlapping sections in the coating path of the third coating liquid in a single coating. It is also preferable that the detour outward from the outer edge of the bent portion of the nozzle passes through the side opening of the stent base, avoids the bent portion of the annular body that is adjacent in the axial direction, and passes between the bent portions of the annular body that are adjacent in the axial direction.

[0146] Furthermore, the application routes for the first and second coating solutions may be continuous, without the detours described above, and may coat the entire stent body 10 (strut). Alternatively, they may be the same as the application route for the third coating solution described above. It is also preferable that there are no overlapping sections in the application routes for the first and second coating solutions in a single application.

[0147] In the present invention, the third coating liquid is applied at least twice, preferably three times. The first application of the third coating liquid is performed, for example, along the application path shown in Figure 13. Note that the illustrated application path shows only a portion, not the entire length. In the application path R1 of the first application of the third coating liquid, the nozzle moves diagonally forward (towards the tip) along the outer surface of the linear first strut portion 23 located at the leftmost part of the annular body at the top of Figure 13. When the nozzle reaches one end of the bent portion 21, it moves to the outside of that end, bypasses the outer edge of the bent portion 21, and moves along a deformed pentagon as shown in Figure 13. After approaching the other end of the bent portion 21 that it bypassed, the nozzle is positioned on the other end of the bent portion and moves diagonally backward (towards the base) along the outer surface of the linear second strut portion 24.

[0148] When the nozzle is moving along the outer edge of the bent portion, the third coating liquid is not applied to the outer surface of the stent body 10. However, when the nozzle bypasses the outer edge of the bent portion 21, maintaining the discharge pressure applied to the coating liquid causes a coating liquid mass and a linear portion extending from the coating liquid mass to form at the tip of the nozzle. The coating liquid mass, with the nozzle positioned at the other end of the bent portion 21, rests on the other end of the bent portion 21, and the linear portion rests on the outer surface between one end and the other end of the bent portion 21 (including the vertex). As a result, as shown in Figure 3, a linear portion covering 34 covering the linear first strut portion 23, a bent portion thin layer covering 35 covering the bent portion 21, and a thick covering portion 36 are formed at the other end of the bent portion 21.

[0149] Next, the nozzle moves diagonally backward (towards the base end) along the outer surface of the linear second strut portion 24. When the nozzle reaches one end of the bent portion 22, it moves to the outside of that end, makes a large detour around the outer edge of the bent portion 22, and moves along a deformed pentagon as shown in Figure 13. After approaching the other end of the bent portion 22, the nozzle is positioned on the other end of the bent portion and moves diagonally forward (towards the tip) along the outer surface of the linear first strut portion 23.

[0150] When the nozzle is moving along the outer edge of the bent portion, the third coating liquid is not applied to the outer surface of the stent body 10. However, when the nozzle bypasses the outer edge of the bent portion 22, maintaining the discharge pressure applied to the coating liquid causes a lump of coating liquid and a linear portion extending from the lump of coating liquid to form at the tip of the nozzle. When the nozzle is positioned at the other end of the bent portion 22, the lump of coating liquid rests on the other end of the bent portion 22, and the linear portion rests on the outer surface between one end and the other end of the bent portion 22 (including the vertex). As a result, a linear portion covering portion 34 covering the linear second strut portion 24, a bent portion thin layer covering portion 35 covering the bent portion 22, and a thick covering portion 36 are formed at the other end of the bent portion 22.

[0151] Then, after the nozzle has completed its movement along the entire length of one annular strut, the nozzle moves to the adjacent annular strut to the rear (towards the base end). As shown in Figure 13, the nozzle's direction of travel is reversed, but the third coating liquid is applied to the adjacent annular in the same manner. The first coating process is completed when the coating is applied to all annulars. In this embodiment of the manufacturing method, as shown in Figure 13, even in the bent section connected by connecting parts 31 and 32, the coating path (nozzle) deviates outward from one end of the bent section, passes through the side opening of the stent base, crosses the connecting part, and is positioned on the other end of the bent section. When the nozzle passes over the connecting part, droplets of the coating liquid fall onto the connecting part, forming a thin drug-containing coating layer on the connecting part. In the bent section connected by the connecting part, droplets do not fall on both ends, as in the bent section with a free end as described above, and a thick coating layer is not formed.

[0152] Next, the second coating process of the third coating solution is performed. In the second coating, the coating path R2 is the reverse of the first coating, or in other words, it travels in the reverse direction of the first coating path. Specifically, the nozzle moves diagonally backward (towards the base end) along the outer surface of the linear first strut portion 23 located at the far right of the annular body at the top of Figure 14. When the nozzle reaches the other end of the bent portion 22, it moves to the outside of the other end of the bent portion, bypasses the outer edge of the bent portion 22, and moves along a deformed pentagon as shown in Figure 14. After approaching one end of the bent portion 22 that it bypassed, the nozzle is positioned on that end of the bent portion and moves diagonally forward (towards the tip) along the outer surface of the linear second strut portion 24.

[0153] When the nozzle is moving outside the outer edge of the bent portion 22, the third coating liquid is not applied to the outer surface of the stent body 10. However, when the nozzle bypasses the outside of the bent portion 22, the discharge pressure applied to the coating liquid is maintained, forming a coating liquid mass and a linear portion extending from the coating liquid mass at the tip of the nozzle. When the nozzle is positioned at one end of the bent portion 22, the coating liquid mass rests on one end of the bent portion 22, and the linear portion rests on the outer surface between one end and the other end of the bent portion 22 (including the vertex). As a result, a linear portion covering 34 covering the linear first strut portion 23, a bent portion thin layer covering 35 covering the bent portion 22, and a thick covering portion 36 at one end of the bent portion 22 are formed.

[0154] Next, the nozzle moves diagonally forward (towards the tip) along the outer surface of the linear second strut portion 24. When the nozzle reaches the other end of the bent portion 21, it moves to the outside of the other end of the bent portion 21, bypasses the outer edge of the bent portion 21 by passing through the side opening of the stent base, and moves along a deformed pentagon as shown in Figure 14. After approaching one end of the bypassed bent portion 21, the nozzle is positioned on the other end of the bent portion and moves diagonally backward (towards the base) along the outer surface of the linear first strut portion 23. It is preferable that the bypass of the nozzle to the outside of the outer edge of the bent portion is performed by passing through the side opening of the stent base, avoiding the bent portion of the annular body that is axially close, and passing between the bent portions of the annular body that are axially close.

[0155] When the nozzle is moving outside the outer edge of the bent portion 21, the third coating liquid is not applied to the outer surface of the stent body 10. However, when the nozzle bypasses the outside of the bent portion 21, the discharge pressure applied to the coating liquid is maintained, forming a coating liquid mass and a linear portion extending from the coating liquid mass at the tip of the nozzle. When the nozzle is positioned at one end of the bent portion 21, the coating liquid mass is placed on the end of the bent portion 21, and the linear portion is placed on the outer surface between the end and the other end of the bent portion 21 (including the vertex). As a result, a linear portion covering portion 34 covering the linear second strut portion 24, a bent portion thin layer covering portion 35 covering the bent portion 21, and a thick covering portion 36 at one end of the bent portion 21 are formed.

[0156] Then, after the nozzle has completed its movement along the entire length of one annular strut, it moves to the adjacent annular strut towards the rear (towards the base end). As shown in Figure 14, the nozzle's direction of travel is reversed, but the third coating solution is applied to the adjacent annular in the same manner. The second coating process is completed when the coating is applied to all annulars.

[0157] Then, if necessary, a third application of the third coating solution is performed. The third application is performed in the same manner as the first application, and the application path is the same as the first application path R1 shown in Figure 13. After the third application of the third coating solution, as shown in Figure 6, one of the thick-walled coating portions formed at the end of the bent portion becomes an enlarged thick-walled coating portion 36a.

[0158] Next, the process for forming the drug-containing coating will be described in detail. Figures 15, 16, 17, and 18 are flowcharts illustrating the process for forming the drug-containing coating. In this embodiment, the process for forming the drug-containing coating consists of a preparation step, an imaging step, a first coating solution and second coating solution application path setting step, a third coating solution application path setting step, a first coating solution application step, a second coating solution application step, a first application step of the third coating solution, and a second application step of the third coating solution. Note that if the application of the first coating solution and the second coating solution is performed by immersion as described above, the first and second coating solution application path setting step and the first and second coating solution application steps using the set application paths will not be performed.

[0159] In the preparation process, the air conditioning unit 218 is activated to maintain a constant temperature and humidity inside the chamber 210 of the coating device 200. The first coating head 240 and the second coating head 245 are then attached to the support frame 215 of the chamber 210 via the vertical table 253 and bracket 258. After the stent body 10 is mounted on the mandrel 228, it is attached to the chuck portion 224 of the holder 220, which is in a standby position, and positioned in a predetermined location.

[0160] Next, the imaging process will be explained with reference to Figure 15. First, the control unit 290 receives input of imaging parameters and stores the input imaging parameters in memory (step S11). The imaging parameters are, for example, input by the operator of the coating apparatus 200 using a keyboard and include the rotation speed of the mandrel 228, the number of lines to be photographed by the line sensor unit of the first position information acquisition device 270, the width of the photographed lines, and the photographing speed.

[0161] The control unit 290 activates the X-direction movement mechanism 231 (step S12). As a result, the holder 220 moves along the travel rail 233 from the standby position to a predetermined position below the first position information acquisition device 270. The control unit 290 confirms that the holder 220 has reached the predetermined position (step S13: Yes) and activates the motor 226 of the holder 220 to rotate the mandrel 228 (stent body 10) (step S14).

[0162] The line sensor unit of the first position information acquisition device 270 scans the surface of the stent body 10 and captures the surface pattern (step S15). The captured images are combined based on the imaging parameters and stored in the memory of the control unit 290 as a planar unfolded image. The planar unfolded image can also be output to a monitor for visual confirmation as needed.

[0163] The control unit 290 converts the planar unfolded image of the stent body 10 into a grayscale binarized image using a predetermined threshold (step S16), extracts an image of the stent body 10 (strut), calculates the shape data of the stent body 10 (strut), and obtains coordinate data of the trajectory passing through the center of the stent body 10 (strut) by thinning the width of the stent body 10 (strut) (step S17).

[0164] Next, the coating path setting process will be explained with reference to Figure 16. Based on the acquired shape data of the stent body 10 (strut) and the coordinate data of the trajectory passing through the center of the stent body 10 (strut), the control unit 290 sets the coating paths for the first coating liquid and the second coating liquid, and the coating path for the third coating liquid (step S21). The coating paths for the first coating liquid and the second coating liquid are generated so that the entire stent body 10 (strut) can be coated continuously and overlapping sections are minimized. As described above, the coating path for the third coating liquid is generated so as to make a large detour around the outside of the outer edges of the bent portions 21 and 22 of the stent body 10 (strut) (see Figure 13).

[0165] The control unit 290 receives input of displacement measurement parameters and stores the input displacement measurement parameters in memory (step S22). The displacement measurement parameters are entered, for example, by the operator of the coating device 200 using a keyboard and include the measurement start position, measurement direction, measurement speed, and measurement interval from the second position information acquisition device 280.

[0166] The control unit 290 operates the motor 239 of the Y-direction movement mechanism 236 to move the holder 220 (mandrel 228) to the measurement position of the second position information acquisition device 280 (step S23). The operator adjusts the stent body 10 attached to the mandrel 228 and the measurement position of the second position information acquisition device 280, for example by visual inspection, so that the measurement position of the second position information acquisition device 280 matches the designated position on the trajectory (step S24).

[0167] When the operator of the coating device 200 inputs, for example, "adjustment complete" using a keyboard (step S25: Yes), the control unit 290 commands the second position information acquisition device 280 to start measuring the Z-direction displacement of the stent body 10 (strut) (step S26), and also causes the motor 226 to rotate in forward and reverse directions and the motor 239 to move in the axial direction repeatedly, thereby causing the stent body 10 to repeatedly rotate and move in the axial direction (step S27).

[0168] The second position information acquisition device 280 moves along a trajectory passing through the center of the stent body 10 (strut), acquires displacement data in the Z direction of the entire stent body 10 (strut), and transmits it to the control unit 290 (step S28). The displacement data in the Z direction is converted into position information in the Z direction in a Cartesian coordinate system of the surface of the stent body 10 (strut), and is stored in memory along with the coordinates of the central trajectory.

[0169] Next, with reference to Figure 17, the coating process for the first and second coating solutions will be described. In this coating process, for example, the first coating solution is applied from the first coating head 240, and the second coating solution is applied from the second coating head 245.

[0170] The control unit 290 receives input of the first coating parameters and stores the input first coating parameters in memory (step S31). The first coating parameters are, for example, entered by the operator of the coating device 200 using a keyboard and include the rotational speed and axial movement speed of the stent body 10, the selection of the first coating head 240 and the second coating head 245, the discharge speed of the first coating head 240 and the second coating head 245 (nozzle portion 262), and the discharge amount per unit time. The drug solution discharge amount per unit time is preferably about 0.13 to 0.15 μl / sec. In the embodiment of the present invention, the amount of drug loaded is increased to achieve long-term sustained release, and is greater than the amount of drug applied and the discharge amount per unit time performed on cardiac stents.

[0171] The control unit 290 commands the movement of the holder 220 using the X-direction movement mechanism 231 (step S32). As a result, the stent body 10, which is mounted on the mandrel 228 of the holder 220, moves to the coating start position below the first coating head 240.

[0172] When the stent body 10 reaches the coating start position (step S33: Yes), the stent body 10 is rotated and moved axially, and the first coating liquid is continuously discharged from the nozzle portion 262 of the first coating head 240 (step S34). At this time, the control unit 290 commands the motor 226 to rotate in forward and reverse directions and the motor 239 to move axially, and moves the stent body 10 in the X and Y directions according to the specified parameters, and also moves the first coating head 240 in the Z direction by the motor 254. When the coating of the entire stent body 10 (strut) by the first coating head 240 along the predetermined coating path is completed, the coating of the first coating liquid is stopped (step S35).

[0173] The control unit 290 commands the movement of the holder 220 using the X-direction movement mechanism 231 (step S32). As a result, the stent body 10, which is mounted on the mandrel 228 of the holder 220, moves to the coating start position below the second coating head 245.

[0174] The control unit 290 uses the first coating parameters received during the first coating liquid application process to calculate the rotational speed and axial movement speed of the stent body 10, the selection of the second coating head 245, and the discharge speed of the second coating head 245 (nozzle portion 262).

[0175] As shown in Figure 16, the control unit 290 commands the movement of the holder 220 using the X-direction movement mechanism 231 (step S32). As a result, the stent body 10, which is mounted on the mandrel 228 of the holder 220, moves to the coating start position below the second coating head 245.

[0176] When the stent body 10 reaches the coating start position (step S33: Yes), the stent body 10 is rotated and moved axially, and the second coating liquid is continuously discharged from the nozzle portion 262 of the second coating head 245 (step S34). At this time, the control unit 290 commands the motor 226 to rotate in forward and reverse directions and the motor 239 to move axially, and moves the stent body 10 in the X and Y directions according to the specified parameters, and also moves the second coating head 245 in the Z direction by the motor 254. When the coating of the entire stent body 10 (strut) by the second coating head 245 along the predetermined coating path is completed, the coating of the second coating liquid is stopped (step S35).

[0177] Next, with reference to Figure 17, the application process of the third coating solution for forming the drug coating layer will be described. After the first coating solution is discharged from the cylinder portion 255 of the first coating head 240 in the coating device 200 and the third coating solution is stored, the application process of the third coating solution is performed. The control unit 290 receives input of parameters for the application of the third coating solution and stores the input parameters in memory (step S41). The parameters for the application of the third coating solution are, for example, entered by the operator of the coating device 200 using a keyboard and include the rotational speed and axial movement speed of the stent body 10, the selection of the first coating head 240, the discharge speed of the first coating head 240 (nozzle portion 262), and the number of applications (number of layers).

[0178] The control unit 290 commands the movement of the holder 220 using the X-direction movement mechanism 231 (step S42). As a result, the stent body 10, which is mounted on the mandrel 228 of the holder 220, moves to the coating start position below the first coating head 240.

[0179] When the stent body 10 reaches the coating start position (step S43: Yes), the stent body 10 is rotated and moved axially, and the third coating liquid is continuously discharged from the nozzle portion 262 of the first coating head 240 (step S44). At this time, the control unit 290 commands the motor 226 to rotate in forward and reverse directions and the motor 239 to move in the axial direction, and moves the stent body 10 in the X-axis and Y-axis directions according to the specified parameters, and also moves the first coating head 240 in the Z-axis direction with the motor 254.

[0180] As a result, the first coating head 240 applies the third coating liquid while moving along a predetermined coating path (see Figure 13) in the coating process of the third coating liquid. The predetermined coating path in the coating process of the third coating liquid is as described above. In this coating path, the coating head makes a large detour to the outside at the bent portions 21 and 22 of the stent body 10 (strut), and moves over the linear first strut portion 23 and the linear second strut portion 24 of the stent body 10 (strut). As a result, as described above, the stent body 10 is given a linear portion covering portion 34 that covers the linear second strut portion 24, a bent portion thin layer covering portion 35 that covers the bent portion 21, and a thick covering portion 36 at either one end or the other end of the bent portion 21.

[0181] Then, after the first application of the third coating solution is completed, the second application of the third coating solution is performed. In the second application of the third coating solution, the nozzle is moved in the reverse direction of the first application path to perform the application.

[0182] The control unit 290 commands the movement of the holder 220 using the X-direction movement mechanism 231. As a result, the stent body 10, which is mounted on the mandrel 228 of the holder 220, moves to the coating start position below the first coating head 240. The first coating head 240 then applies the second coat of the third coating liquid while moving along a predetermined coating path (see Figure 14, the reverse of the coating path in Figure 13) for the second application of the third coating liquid. The predetermined coating path for the second application of the third coating liquid is as described above. Even along this coating path, the stent body 10 (strut) makes a large detour to the outside at the bent portions 21 and 22, and moves over the linear first strut portion 23 and the linear second strut portion 24 of the stent body 10 (strut). As described above, the stent body 10 is provided with a linear covering portion 34 that re-covers the linear second strut portion 24, a thin-layer covering portion 35 that re-covers the bent portion 21, and a thick covering portion 36 that was not formed at the other end or one end of the bent portion 21 during the first application of the third coating liquid.

[0183] Furthermore, after the second application of the third coating solution is completed, a third application of the third coating solution is performed. The second application of the third coating solution is performed by running the nozzle along the inputted first application path.

[0184] The control unit 290 commands the movement of the holder 220 using the X-direction movement mechanism 231. As a result, the stent body 10, which is mounted on the mandrel 228 of the holder 220, moves to the coating start position below the first coating head 240. The first coating head 240 then applies the third coating solution for the third time while moving along a predetermined coating path (see Figure 13) for the first application of the third coating solution. The predetermined coating path for the third application of the third coating solution is the same as the first time, as described above. Even in this coating path, the coating makes a large detour outward at the bent portions 21 and 22 of the stent body 10 (strut), and moves over the linear first strut portion 23 and the linear second strut portion 24 of the stent body 10 (strut). As described above, the stent body 10 has a linear portion covering 34 which is coated three times over the linear second strut portion 24, a bent portion thin layer covering 35 which is coated three times over the bent portion 21, and an enlarged thickness covering portion 36a which is formed by applying another coating over one or the other end of the bent portion 21 that was formed in the first application step of the third coating liquid.

[0185] Then, in the application process of the third coating solution, when the number of applications (number of layers) reaches a set value (step S45: Yes), the application is stopped (step S46). When the holder 220 moves to the standby position by the X-direction movement mechanism 231, the mandrel 228 is removed from the holder 220. Then, the stent body 10 (see Figure 12) on which the primer coating layer and drug coating layer have been formed is removed from the mandrel 228.

[0186] The in vivo stent of the present invention comprises a tubular stent body formed of a wavy linear component having a plurality of bent portions having vertices on one end or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body. The stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion. The drug-containing coating portion comprises a linear portion coating portion covering the linear first strut portion and the linear second strut portion, a bent portion thin layer coating portion located on the bent portion and having a thinner coating thickness than the linear portion coating portion, and a thick coating portion formed at both ends of the bent portion thin layer coating portion. This stent not only has a linear covering portion that covers the linear first strut portion and the linear second strut portion, but also a thin-layer covering portion for the bent portion that is located on the bent portion and has a thinner covering thickness than the linear covering portion, and thick-walled covering portions formed at both ends of the thin-layer covering portion for the bent portion. Therefore, even when placed in a stenosis caused by calcification in the lower limb arteries, effective drug administration is possible, and it is effective in suppressing restenosis of the stenosis. Furthermore, because the stent has a drug covering portion in the bent portion and thick-walled covering portions formed at both ends of the thin-layer covering portion for the bent portion, the amount of drug that can be loaded can be improved and the peeling of the covering portion can be reduced.

[0187] Embodiments of the in vivo stent of the present invention are as follows: (1) An in vivo stent comprising a tubular stent body formed of a wavy linear component having a plurality of bent portions having vertices on one end or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body, wherein the stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion, and the drug-containing coating portion comprises a linear portion coating portion covering the linear first strut portion and the linear second strut portion, a bent portion thin layer coating portion located on the bent portion and having a thinner coating thickness than the linear portion coating portion, and a thick coating portion formed at both ends of the bent portion thin layer coating portion.

[0188] This in vivo implantable stent comprises a tubular stent body formed of a wavy linear component having multiple bent portions with vertices on one or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body. The stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion. The drug-containing coating portion comprises a linear portion coating portion covering the linear first strut portion and the linear second strut portion, a bent portion thin layer coating portion located on the bent portion and having a thinner coating thickness than the linear portion coating portion, and a thick coating portion formed at both ends of the bent portion thin layer coating portion. This stent not only has a linear covering portion that covers the linear first strut portion and the linear second strut portion, but also a thin-layer covering portion for the bent portion that is located on the bent portion and has a thinner covering thickness than the linear covering portion, and thick-walled covering portions formed at both ends of the thin-layer covering portion for the bent portion. Therefore, even when placed in a stenosis caused by calcification in the lower limb arteries, effective drug administration is possible, and it is effective in suppressing restenosis of the stenosis. Furthermore, because the stent has a drug covering portion in the bent portion and thick-walled covering portions formed at both ends of the thin-layer covering portion for the bent portion, the amount of drug that can be loaded can be improved and the peeling of the covering portion can be reduced.

[0189] Furthermore, the embodiments of the in vivo stent described above may also be as follows: (2) The in vivo stent according to (1) above, wherein the stent body comprises a plurality of one-end bent portions having a vertex on one end in the axial direction and a plurality of other-end bent portions having a vertex on the other end in the axial direction of the stent, and the vertices of the one-end bent portions and the other-end bent portions are parts that deform when the in vivo stent is expanded or compressed in the radial direction. (3) The in vivo stent according to (1) or (2) above, wherein the stent body comprises a plurality of annular bodies arranged in the axial direction and adjacent annular bodies connected to each other. (4) The in vivo stent according to any one of (1) to (3) above, wherein the drug-containing coating portion is a drug-eluting coating portion. (5) The in vivo stent according to any one of (1) to (4) above, wherein the thick coating portion is a bulging portion. (6) The in vivo stent according to any one of (1) to (5) above, wherein the thin-layer coating portion of the bent portion is 1 / 3 to 2 / 5 of the coating thickness of the linear portion coating portion. (7) The in vivo stent according to any one of (1) to (6) above, wherein the thick-walled coating portion is 1.2 to 2.0 times the coating thickness of the linear portion coating portion. (8) The in vivo stent according to any one of (1) to (7) above, wherein the drug-containing coating portion is flexible or elastic. (9) The in vivo stent according to any one of (1) to (8) above, wherein the drug-containing coating portion contains a polymer with a molecular weight of 150,000 or more. (10) The in vivo stent according to any one of (1) to (9) above, wherein the drug-containing coating portion comprises a first coating layer having a first polymer formed by the self-oxidative polymerization of dopamine molecules or their analogs on the outer surface of the stent body, 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. (11) The in vivo stent according to (10) above, wherein the drug-containing coating portion comprises a reciprocal polymer network structure formed by the second polymer and the third polymer.(12) The in vivo stent according to any one of (1) to (11) above, wherein the in vivo stent is formed in a tubular shape, is compressed in the direction of the central axis when inserted into the body, and expands outward to return to its pre-compression shape when implanted in the body. (13) The in vivo stent according to any one of (1) to (12) above, wherein the stent body is formed by cutting a superelastic metal tube to form the basic shape of the stent body, then expanding its diameter, and then heat-treating it to be a stent body that is superelastic in the expanded state, and the drug-containing coating is applied to the outer surface of the stent body after the expansion and before or after the heat treatment.

[0190] Embodiments of the stent delivery system of the present invention are as follows: (14) A stent delivery system comprising a sheath, a stent for implantation in a living body as described in (12) above housed in the tip of the sheath, and an inner tube that is slidably inserted through the sheath and for pushing the stent for implantation in a living body out from the tip of the sheath.

[0191] Embodiments of the present invention for manufacturing an in vivo stent are as follows: (15) A method for manufacturing an in vivo stent comprising a tubular stent body formed of a wavy linear component having a plurality of bent portions having vertices on one end or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body, wherein the stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion, and the method for manufacturing the in vivo stent is as follows: A first coating step is performed by applying the coating liquid to the outer surface of the linear first strut portion, by positioning a nozzle, which has been in a state of discharging pressure to a coating liquid in which the drug and polymer have been dissolved in a solvent, on the outer surface of the linear first strut portion and moving the nozzle on the outer surface of the linear first strut portion to coat the outer surface of the linear first strut portion, and when the nozzle arrives at one end of the bent portion, moving the nozzle from the end of the bent portion outward from the outer edge of the bent portion, and further, after the nozzle has been detouring outside the outer edge of the bent portion, when the nozzle approaches the other end of the bent portion, positioning the nozzle on the other end of the bent portion and moving the nozzle on the outer surface of the linear second strut portion to coat the outer surface of the linear second strut portion, A method for manufacturing an in-vivo stent, comprising: a second coating step, after the first coating step, the direction of travel of the nozzle is changed to a direction different from that of the first coating step, the nozzle is positioned on the outer surface of the linear second strut portion with discharge pressure applied to the coating liquid, and the nozzle is moved on the outer surface of the linear second strut portion to coat the outer surface of the linear second strut portion with the coating liquid; when the nozzle arrives at the other end of the bent portion, the nozzle is moved from the other end of the bent portion to the outside of the outer edge of the bent portion, and further, after the nozzle is detoured outside the outer edge of the bent portion, when the nozzle approaches one end of the bent portion, the nozzle is positioned on one end of the bent portion and moved on the outer surface of the linear first strut portion to coat the outer surface of the linear first strut portion with the coating liquid;

[0192] Furthermore, the following embodiments of the above-mentioned method for manufacturing an in-vivo stent may also be: (16) The method for manufacturing an in-vivo stent according to (15), wherein a third coating step is performed after the second coating step, in which the coating solution is applied in the same manner as the first coating step. (17) The method for manufacturing an in-vivo stent according to (16), wherein the discharge rate of the coating solution in the first coating step, the second coating step and / or the third coating step is 0.10 to 0.50 μl / sec. (18) The method for manufacturing an in-vivo stent according to any one of (15) to (17), wherein pressure is continuously applied to the coating solution when the nozzle bypasses outside the outer edge of the bent portion, and the coating solution is applied, and the coating solution contains a polymer with a molecular weight of 150,000 or more.

Claims

1. An in vivo stent comprising a tubular stent body formed of a wavy linear component having a plurality of bent portions having vertices on one or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body, wherein the stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion, and the drug-containing coating portion comprises a linear portion coating portion covering the linear first strut portion and the linear second strut portion, a bent portion thin layer coating portion located on the bent portion and having a thinner coating thickness than the linear portion coating portion, and a thick coating portion formed at both ends of the bent portion thin layer coating portion.

2. The in vivo stent according to claim 1, wherein the stent body comprises a plurality of one-end bent portions having a vertex on one end in the axial direction and a plurality of other-end bent portions having a vertex on the other end in the axial direction of the stent, and the vertices of the one-end bent portions and the other-end bent portions are portions that deform when the in vivo stent expands or compresses in the radial direction.

3. The in vivo stent according to claim 1 or 2, wherein the stent body is formed by arranging multiple annular bodies in the axial direction and connecting adjacent annular bodies.

4. The in vivo stent according to claim 1 or 2, wherein the drug-containing coating portion is a drug-eluting coating portion.

5. The in vivo stent according to claim 1 or 2, wherein the thickened covering portion is a bulging portion.

6. The in vivo stent according to claim 1 or 2, wherein the thin layer covering portion of the bent portion is 1 / 3 to 2 / 5 of the covering thickness of the linear portion covering portion.

7. The in vivo stent according to claim 1 or 2, wherein the thickened covering portion is 1.2 to 2.0 times the covering thickness of the linear covering portion.

8. The in vivo stent according to claim 1 or 2, wherein the drug-containing coating portion is flexible or elastic.

9. The in vivo stent according to claim 1 or 2, wherein the drug-containing coating portion comprises a polymer with a molecular weight of 150,000 or more.

10. The in vivo stent according to claim 1 or 2, wherein the drug-containing coating portion comprises a first coating layer having a first polymer formed by the autooxidative polymerization of dopamine molecules or their analogs on the outer surface of the stent body, 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.

11. The in vivo stent according to claim 10, wherein the drug-containing coating portion has an interpenetrating polymer network structure formed by the second polymer and the third polymer.

12. The in vivo stent according to claim 1 or 2, wherein the in vivo stent is formed in a tubular shape, is compressed in the direction of the central axis when inserted into the body, and expands outward to return to its pre-compression shape when implanted in the body.

13. The stent body is a stent body that is superelastic in the expanded state, obtained by cutting a superelastic metal tube to form the basic shape of the stent body, then expanding its diameter, and then heat-treating it, and the drug-containing coating portion is applied to the outer surface of the stent body after the diameter expansion and before or after the heat treatment, according to claim 1 or 2.

14. A stent delivery system comprising a sheath, a stent for in vivo placement according to claim 12 housed within the tip of the sheath, and an inner tube slidably inserted within the sheath for pushing the stent for in vivo placement out from the tip of the sheath.

15. A method for manufacturing an in vivo stent comprising a tubular stent body formed of a wavy linear component having a plurality of bent portions having vertices on one or the other end in the axial direction, and a drug-containing coating portion provided on the outer surface of the stent body, wherein the stent body has an annular body composed of a wavy strut having a linear first strut portion, a linear second strut portion, and a bent portion connecting the linear first strut portion and the linear second strut portion, and the method for manufacturing the in vivo stent is: A first coating step is performed by applying the coating liquid to the outer surface of the linear first strut portion, by positioning a nozzle, which has been in a state of discharging pressure to a coating liquid in which the drug and polymer have been dissolved in a solvent, on the outer surface of the linear first strut portion and moving the nozzle on the outer surface of the linear first strut portion to coat the outer surface of the linear first strut portion, and when the nozzle arrives at one end of the bent portion, moving the nozzle from the end of the bent portion outward from the outer edge of the bent portion, and further, after the nozzle has been detouring outside the outer edge of the bent portion, when the nozzle approaches the other end of the bent portion, positioning the nozzle on the other end of the bent portion and moving the nozzle on the outer surface of the linear second strut portion to coat the outer surface of the linear second strut portion, A method for manufacturing an in-vivo stent, characterized by performing a second coating step, after the first coating step, wherein the direction of travel of the nozzle is set to a different direction from that of the first coating step, the nozzle is positioned on the outer surface of the linear second strut portion with discharge pressure applied to the coating liquid, and the nozzle is moved on the outer surface of the linear second strut portion to coat the outer surface of the linear second strut portion with the coating liquid, and when the nozzle arrives at the other end of the bent portion, the nozzle is moved from the other end of the bent portion to the outside of the outer edge of the bent portion, and further, after the nozzle is detoured to the outside of the outer edge of the bent portion, when the nozzle approaches one end of the bent portion, the nozzle is positioned on one end of the bent portion and moved on the outer surface of the linear first strut portion to coat the outer surface of the linear first strut portion with the coating liquid.

16. The method for manufacturing an in-vivo stent, as described in claim 15, wherein a third coating step is performed after the second coating step, in which the coating solution is applied in the same manner as in the first coating step.

17. The method for manufacturing an in vivo stent according to claim 16, wherein the discharge rate of the coating solution in the first coating step, the second coating step, and / or the third coating step is 0.10 to 0.50 μl / sec.

18. A method for manufacturing an in-vivo stent according to claim 15 or claim 16, wherein pressure is continuously applied to the coating liquid when the nozzle bypasses the outer edge of the bent portion, and the coating liquid comprises a polymer with a molecular weight of 150,000 or more.

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