Intravivo stents and stent delivery systems

Abstract

To provide an in vivo stent and stent delivery system that have a low probability of peeling off the drug coating formed on the curved portion. [Solution] The in vivo stent 1 comprises a stent body and a drug-containing covering portion 3 provided on the outer surface of the stent body. The stent body has a linear first strut portion 23 and a linear second strut portion 24, and bent portions 21 and 22 connecting the strut portions 23 and 24. The bent portion comprises bent tip portions 21a and 22a including the apex and bent leg portions 21b and 22b. The stent 1 comprises a first drug-containing covering portion 30 covering the strut portion, a second drug-containing covering portion 35 covering the bent tip portion, and a third drug-containing covering portion 36 that covers the upper surface of the bent leg portions 21b and 22b and is more flexible than the first drug-containing covering portion 30.

Description

Technical Field

[0001] The present invention relates to an intravascular stent for treating stenotic or occlusive portions formed in the lumens of blood vessels, bile ducts, tracheas, esophaguses, urethras, and other organs. In particular, it relates to a drug eluting stent (DES).

Background Art

[0002] A stent is a medical device composed of a cylindrical body having an opening on its side surface, in which a plurality of annular bodies each composed of wavy struts having curved portions are arranged in the axial direction, and adjacent annular bodies are integrated via connecting portions. For example, it is applied for preventing restenosis after percutaneous coronary angioplasty used for myocardial infarction or angina pectoris. The application of a so-called bare metal stent without drug coating has a lower restenosis rate compared to the case of only PTCA or PCI without using a stent at all, but restenosis occurs at a rate of about 20 to 30% in the stent implantation site. The main cause of restenosis is intimal hyperplasia due to the migration and proliferation of vascular smooth muscle cells. Therefore, a drug eluting stent has been proposed, in which a drug capable of suppressing the migration and proliferation of vascular smooth muscle cells is coated on the outer surface of the stent, and the drug is eluted at the stent implantation site to prevent restenosis. As the drug, paclitaxel, mitomycin C, adriamycin, genistein, tilorone, cytochalasin, sirolimus (rapamycin), etc. are used. For coating, a coating solution in which these drugs and a biocompatible polymer are dissolved in a solvent is used, and 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, a stent is expanded and deformed when it reaches the target site in the lumen and is implanted. Therefore, due to stress concentration and distortion occurring in the drug coating layer formed on the outer surface of the curved portion of the strut with the expansion and deformation, there arises a problem that the drug coating layer peels off or falls off. To address these problems, the stent described in Patent Document 1 prevents peeling or detachment of the coating layer by making the curved portion an uncoated layer where the drug is not applied. Furthermore, as a method for forming the uncoated layer, when the nozzle that dispenses the drug reaches the curved portion, the nozzle is moved away from the curved portion (jumps), thereby preventing the drug from being applied to the curved portion. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Patent No. 6352279 [Overview of the project] [Problems that the invention aims to solve]

[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. In particular, the inventors of this application investigated and found that strain during stent expansion deformation occurs more frequently on the outer surface of the bent portion of the stent than on the inner surface. Furthermore, the strain also affects the chemical coating layer formed on the outer surface of the bent portion, resulting in the occurrence of cracks, delamination, and detachment that appears to be caused by these factors. The object of the present invention is to provide an in vivo stent and stent delivery system that has 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 that has a low possibility of peeling off the drug-coated portion formed on the bent portion. [Means for solving the problem]

[0005] The following will achieve the above objectives. (1) 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 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 bent portion comprises a bent tip portion including the apex, and two bent leg portions formed between the bent tip portion and the first and second strut portions. The in vivo stent comprises a first drug-containing covering portion that covers the linear first strut portion and the linear second strut portion, and a second drug-containing covering portion that covers the bent tip portion, and further, the two bent leg portions have a third drug-containing covering portion that is more flexible than the first drug-containing covering portion.

[0006] (2) The in vivo stent described in (1) above, wherein the bent leg portion is a part that deforms when the in vivo stent expands or compresses in the radial direction. (3) The in vivo stent according to (1) or (2) above, wherein the stent body is made up of multiple annular bodies arranged in the axial direction and adjacent annular bodies connected to each other. (4) The drug-containing coating portion is a drug-eluting coating portion, which is the in vivo stent according to any one of (1) to (3) above. (5) The in vivo stent according to any one of (1) to (3) above, wherein the first drug-containing coating portion has the same drug content as the second drug-containing coating portion. (6) The in vivo stent according to any one of (1) to (5) above, wherein the glass transition temperature of the first drug-containing coating is 50 to 60°C, and the glass transition temperature of the third drug-containing coating is 35 to 45°C. (7) The in vivo stent according to any one of (1) to (6) above, wherein the third drug-containing coating contains a polymer with a smaller molecular weight than the first drug-containing coating, and the first drug-containing coating contains a polymer with a molecular weight of 100,000 to 1,000,000, and the third drug-containing coating contains a polymer with a molecular weight of 10,000 to 100,000. (8) The in vivo stent according to any one of (1) to (7) above, wherein the second drug-containing covering portion is more flexible than the first drug-containing covering portion. (9) The drug-containing covering portion is flexible or elastic, and is an in vivo stent according to any one of (1) to (8) above. (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 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 (10) above, 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 described in any 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 a body, and expands outward to return to its pre-compression shape when placed in a body.

[0007] Furthermore, the following items will achieve the above objectives. (13) A stent delivery system comprising a sheath, an in vivo stent according to any one of (1) to (12) above housed in the tip of the sheath, and an inner tube slidably inserted through the sheath for pushing the in vivo stent out from the tip of the sheath. [Effects of the Invention]

[0008] 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 with vertices on one or the other end in the axial direction, and a drug-containing covering 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 bent portion has a bent tip portion including a vertex and two bent leg portions formed between the bent tip portion and the first and second strut portions. The in vivo stent comprises a first drug-containing covering portion covering the linear first strut portion and the linear second strut portion, and a second drug-containing covering portion covering the bent tip portion. Furthermore, the two bent leg portions have a third drug-containing covering portion that is more flexible than the first drug-containing covering portion. The stent of the present invention includes not only a linear covering portion that covers the linear first strut portion and the linear second strut portion, but also a second drug-containing covering portion that covers the bent tip portion. Furthermore, the two bent leg portions have a third drug-containing covering portion that is more flexible than the first drug-containing covering portion. Therefore, even when the stent is placed in a stenosis caused by calcification in the lower limb artery, drug administration can be performed at the bent tip portion and the bent leg portion. Moreover, since the third drug-containing covering portion provided on the bent leg portion is more flexible than the first drug-containing covering portion, it effectively suppresses the occurrence of peeling of the covering portion when the bent leg portion deforms. [Brief explanation of the drawing]

[0009] [Figure 1] Figure 1 is an unfolded view of an in-vivo stent according to an embodiment of the present invention when expanded. [Figure 2] Figure 2 is an unfolded view of the in-vivo stent shown in Figure 1 when its diameter is reduced. [Figure 3] Figure 3 is a magnified view of the area near the bend of the in-vivo stent shown in Figure 1. [Figure 4] Figure 4 is a cross-sectional view taken along line AA in Figure 3. [Figure 5]Figure 5 is an enlarged view of the vicinity of the bent portion of the in-vivo indwelling stent during the expansion of another embodiment of the present invention. [Figure 6] Figure 6 is a cross-sectional view taken along line B-B of Figure 5. [Figure 7] Figure 7 is a partially omitted front view of the stent delivery system of an embodiment of the present invention. [Figure 8] 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] Figure 9 is a partially omitted enlarged cross-sectional view of the vicinity of the base end portion of the stent delivery system shown in Figure 7. [Figure 10] Figure 10 is an explanatory diagram for explaining the operation of the stent delivery system of an embodiment of the present invention. [Figure 11] Figure 11 is an explanatory diagram for explaining the coating device used in the manufacture of the in-vivo indwelling stent of the present invention. [Figure 12] Figure 12 is an explanatory diagram for explaining the main part of the coating device shown in Figure 11. [Figure 13] Figure 13 is an explanatory diagram for explaining the coating path of the nozzle in the coating device used in the manufacture of the in-vivo indwelling stent of the present invention. [Figure 14] Figure 14 is a partially enlarged view of Figure 13. [Figure 15] Figure 15 is an explanatory diagram for explaining the coating path of the nozzle in the next coating when coating is performed along the coating path of the pattern shown in Figure 14. [Figure 16] Figure 16 is an explanatory diagram for explaining the coating path of the nozzle of another pattern in the coating device used in the manufacture of the in-vivo indwelling stent of the present invention. [Figure 17] Figure 17 is an explanatory diagram for explaining the coating path of the nozzle in the next coating when coating is performed along the coating path of the pattern shown in Figure 16. [Figure 18] Figure 18 is a flowchart for explaining the imaging process in the manufacturing method of the in-vivo indwelling stent of an embodiment of the present invention. [Figure 19]Figure 19 is a flowchart illustrating the coating path setting step in the method for manufacturing an in vivo stent according to an embodiment of the present invention. [Figure 20] Figure 20 is a flowchart illustrating the first coating solution application step and the second coating solution application step in the method for manufacturing an in-vivo stent according to an embodiment of the present invention. [Figure 21] Figure 21 is a flowchart illustrating the third coating solution application step in the method for manufacturing an in-vivo stent according to an embodiment of the present invention. [Figure 22] Figure 22 is a flowchart illustrating the fourth coating solution application step in the method for manufacturing an in vivo stent according to an embodiment of the present invention. [Modes for carrying out the invention]

[0010] The in vivo stent of the present invention will be described using the embodiments 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.

[0011] The bent portions 21 and 22 each include a bent tip portion 21a, 22a including the apex, and two bent leg portions 21b, 22b located between the bent tip portions 21a, 22a and the first and second strut portions 23, 24. The in vivo stent 1 comprises a first drug-containing covering portion 30 that covers the linear first strut portion 23 and the linear second strut portion 24, a second drug-containing covering portion 35 that covers the bent tip portions 21a and 22a, and a third drug-containing covering portion 36 that covers the upper surfaces of the two bent leg portions 21b and 22b. The third drug-containing covering portion 36 is more flexible than the first drug-containing covering portion. The drug-containing coating portion 3 covers the outer surface (top surface) of the stent body 10, but it may also cover the sides of the stent body 10.

[0012] The in vivo stent 1 of the present invention is particularly effective as a stent for the arteries of the lower extremities. The stent body 10 comprises a plurality of one-end bent portions 21 having a peak on one end in the axial direction, and a plurality of other-end bent portions 22 having a valley on the other end in the axial direction of the stent. The peaks of the one-end bent portions 21 and the other-end bent portions 22 are the parts that deform when the in vivo implantable stent 1 expands or contracts in the radial direction.

[0013] In this embodiment of the in vivo implantable stent, as shown in Figure 3, the drug-containing covering portion 3 comprises a first drug-containing covering portion (in other words, a linear covering portion) 30 covering the linear first strut portion 23 and the linear second strut portion 24, a second drug-containing covering portion (in other words, a bending tip upper surface covering portion) 35 located on the bending tip portions 21a and 22a of the bending portions 21 and 22, and a third drug-containing covering portion (in other words, a bending leg upper surface covering portion) 36 located on the bending leg portions 21b and 22b of the bending portions 21 and 22.

[0014] 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 and is self-expanding, compressing in the direction of the central axis when inserted into the body and expanding outward to return to its pre-compression shape when implanted in the body. The stent body 10 is formed by cutting a superelastic metal tube to create the basic shape of the stent body, then expanding its diameter, and subsequently heat-treating it, thereby having a stent body that is superelastic in its expanded state. The drug-containing coating portion 3 may be applied to the outer surface of the stent body 10 after expansion and before or after heat treatment.

[0015] 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.

[0016] The in vivo stent 1 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, 32 that connect the annular bodies when the plurality of annular bodies 2 are arranged in the axial direction of the stent body. As shown in Figure 3, a drug-containing coating portion 3 is provided on the outer surface of the stent body 10. The drug-containing coating portion 3 (drug-containing coating portions 30, 35, 36) is preferably a drug-eluting coating portion. Furthermore, the drug-containing coating portion 3 (drug-containing coating portions 30, 35, 36) is preferably flexible or elastic.

[0017] 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 is supported on a polymer in the drug-containing coating 3, 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 in 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.

[0018] 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.

[0019] The bent portions 21 and 22 each include a bent tip portion 21a, 22a including the apex, and two bent leg portions 21b, 22b located between the bent tip portions 21a, 22a and the first and second strut portions 23, 24. The drug-containing coating portion 3 includes a first drug-containing coating portion (linear coating portion) 30 that covers the linear first strut portion 23 and the linear second strut portion 24, a second drug-containing coating portion 35 that covers the bent tip portions 21a and 22a, and a third drug-containing coating portion 36 that covers the entire upper surface of the bent leg portions 21b and 22b.

[0020] In this embodiment of stent 1, due to the stent's shape, the bent leg portions 21b and 22b of the bent portions 21 and 22 deform to open outwards. This deformation causes strain in the bent portions, particularly the bent leg portions. However, in this embodiment of stent 1, the bent tip portions 21a and 22a of the bent portions 21 and 22 are provided with a second drug-containing coating portion 35. Furthermore, the upper surface (outer surface) of the bent leg portions 21b and 22b has a third drug-containing coating portion 36 that is more flexible than the first drug-containing coating portion (linear coating portion) 30 that covers the linear first strut portion 23 and the linear second strut portion 24. Therefore, even if the bent leg portions 21b and 22b deform in the direction of spreading, although a flexible drug-containing coating portion 36 exists on its outer surface, its flexibility minimizes distortion, and also minimizes distortion in the second drug-containing coating portion 35 provided on the outer surface of the bent tip portions 21a and 22a.

[0021] For lower limb DES stents, long-term sustained release of the drug is desirable. When the stent 1 of the present invention is applied to a lower limb DES stent, a third drug-containing covering portion 36 is provided on the upper surface of the flexed leg portions 21b and 22b, and a second drug-containing covering portion 35 (upper surface covering portion of the flexed tip portion) is provided on the flexed tip portions 21a and 22a. Therefore, since the drug-containing covering portion is formed over the entire upper surface of the flexed portions 21 and 22, the stent has a sufficient drug-containing covering portion over its entire upper surface.

[0022] In this embodiment of the stent 1, the second drug-containing coating portion 35 is formed from the same material as the first drug-containing coating portion 30. Therefore, the second drug-containing coating portion 35 has the same drug content and physical properties as the first drug-containing coating portion 30. Preferably, the second drug-containing coating portion 35 has the same drug content as the first drug-containing coating portion 30. Also, as shown in the examples described later, the second drug-containing coating portion 35 may be more flexible than the first drug-containing coating portion 30.

[0023] As in this embodiment, the drug-containing coating portion 3 (first drug-containing coating portion 30, second drug-containing coating portion 35, third drug-containing coating portion 36) has, as shown in Figure 4, a cross-sectional view of line AA in Figure 3, a first coating layer 3a (described later), a second coating layer 3b (described later) provided on the first coating layer 3a, and a third coating layer 3c (first drug-containing coating portion 30, second drug-containing coating portion 35) and a third coating layer 3d (third drug-containing coating portion 36) (described later) containing a drug, provided on the second coating layer 3b.

[0024] In this embodiment, it is preferable that the glass transition temperature of the third drug-containing coating 36 is lower than that of the first drug-containing coating 30 and that it has high flexibility. Specifically, it is preferable that the glass transition temperature of the first drug-containing coating 30 is 50 to 60°C, and the glass transition temperature of the third drug-containing coating 36 is 35 to 45°C. Furthermore, it is preferable that the glass transition temperature of the third drug-containing coating 36 is 5 to 25°C lower than that of the first drug-containing coating 30, and particularly preferably 10 to 20°C lower.

[0025] The in vivo stent of the present invention may be such as the in vivo stent 1a shown in Figures 5 and 6. In the embodiment of the in vivo stent 1a shown in Figure 6, which is a cross-sectional view of line BB in Figure 5, the second drug-containing covering portion 37 that covers the bent tip portions 21a and 22a, which are the second drug-containing covering portion, is different from the first drug-containing covering portion (linear covering portion) 30. Specifically, the second drug-containing coating portion (upper coating portion of the bent tip) 37 is more flexible than the first drug-containing coating portion (linear coating portion) 30. The other components of stent 1a are the same as those of stent 1 described above.

[0026] In this embodiment, it is preferable that the glass transition temperature of the second drug-containing coating 37 is lower than that of the first drug-containing coating 30 and that it has high flexibility. Specifically, it is preferable that the glass transition temperature of the first drug-containing coating 30 is 50 to 60°C, and the glass transition temperature of the second drug-containing coating 37 is 35 to 45°C. Furthermore, it is preferable that the glass transition temperature of the second drug-containing coating 37 is 5 to 25°C lower than that of the first drug-containing coating 30, and particularly preferably 10 to 20°C lower. Furthermore, it is preferable that the glass transition temperature of the third drug-containing coating portion 36 is lower than that of the second drug-containing coating portion 37, and that it has high flexibility. Specifically, it is preferable that the glass transition temperature of the third drug-containing coating portion 36 is 5 to 20°C lower than that of the second drug-containing coating portion 37, and in particular, it is preferable that it is 7 to 15°C lower.

[0027] As a method for making the third drug-containing coating portion (upper surface coating portion of the bent leg portion) 36 and the second drug-containing coating portion (upper surface coating portion of the bent tip portion) 37 more flexible than the first drug-containing coating portion (linear coating portion) 30, the third drug-containing coating portion (upper surface coating portion of the bent leg portion) 36 can be formed by making the third coating layer 3d that forms the third drug-containing coating portion (upper surface coating portion of the bent leg portion) 36 more flexible than the third coating layer 3c. Alternatively, the second drug-containing coating portion 37 can be formed by making the third coating layer 3e that forms the second drug-containing coating portion 37 more flexible than the third coating layer 3c. Furthermore, the third coating layer 3d may be made more flexible than the third coating layer 3e.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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 optionally 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.

[0032] Furthermore, the third drug-containing coating portion 36 in the stent 1 of the above-described embodiment shown in Figures 3 and 4, and in the stent 1a of the above-described embodiment shown in Figures 5 and 6, is preferably as follows. In these embodiments, the third drug-containing coating portion 36 is more flexible than the first drug-containing coating portion 30. Specifically, in these embodiments, the third coating layer 3d of the third drug-containing coating portion 36 preferably contains a polymer with a smaller molecular weight than the third coating layer 3c of the first drug-containing coating portion 30 and is flexible.

[0033] More specifically, it is preferable that the third coating layer 3c of the first drug-containing coating portion 30 contains a polymer with a molecular weight of 100,000 to 1,000,000, and the third coating layer 3d of the third drug-containing coating portion 36 contains a polymer with a molecular weight of 10,000 to 100,000. Furthermore, it is preferable that the third coating layer 3c of the first drug-containing coating portion 30 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.

[0034] Furthermore, as shown in Figures 5 and 6, the second drug-containing coating portion 37 in the stent 1a of the above-described embodiment is preferably as follows. In this embodiment, the second drug-containing coating portion 37 is preferably more flexible than the first drug-containing coating portion 30. Furthermore, in the stent 1a of this embodiment, the third drug-containing coating portion 36 is preferably more flexible than the second drug-containing coating portion 37.

[0035] Specifically, in these embodiments, the third coating layer 3e of the second drug-containing coating portion 37 preferably contains a polymer having a molecular weight between that of the polymer contained in the third coating layer 3c of the first drug-containing coating portion 30 and that of the polymer contained in the third coating layer 3d of the third drug-containing coating portion 36.

[0036] The drug-containing coating portion 3 (first drug-containing coating portion 30, second drug-containing coating portions 35, 37, third drug-containing coating portion 36) preferably has, as shown in Figure 4, 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.

[0037] <First coating layer 3a> The first coating layer 3a in 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.

[0038] 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.

[0039] 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. Alternatively, 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.

[0040] 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).

[0041] <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 dopamine molecules or their analogs. 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.

[0042] 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 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 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 groups that form the covalent bond on the substrate side are functional groups 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 polymerizable functional groups 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.

[0043] The second polymer of the second coating layer 3b is preferably a crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer. This configuration allows for the formation of covalent bonds between the functional groups of the crosslinkable monomer and the first polymer on the surface of the first coating layer 3a, improving the bonding strength between the first coating layer 3a and the second coating layer 3b, and thus improving the peel resistance of the drug-containing coating 3. Alternatively, covalent bonds may be formed between the functional groups of the base polymer and the first polymer on the surface of the first coating layer. Furthermore, covalent bonds may be formed between the functional groups of the crosslinkable monomer and the functional groups of the base polymer and the first polymer on the surface of the first coating layer.

[0044] When the second polymer of the second coating layer 3b is a crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer, the base polymer can be, for example, polyester, aliphatic polyester, polyacid anhydride, polyorthoester, polycarbonate, polyphosphazene, polyphosphate ester, polyvinyl alcohol, polypeptide, polysaccharide, protein, cellulose, and copolymers, derivatives, or mixtures thereof. Specific examples of aliphatic polyesters include polylactic acid, polycaprolactone, polyglycolic acid, polydioxanone, polybutyrolactone, polyvalerolactone, polyhydroxybutyric acid, polytrimethylene carbonate, and copolymers, derivatives, or mixtures thereof. The copolymer can be, but is not limited to, alternating copolymers, random copolymers, block copolymers, or graft copolymers.

[0045] In a preferred embodiment, the base polymer has lactic acid monomer units. That is, the second polymer preferably has lactic acid monomer units. The content of lactic acid monomer units in the base polymer is preferably 50 mol% or more (up to 100 mol%), and more preferably 70 mol% or more (up to 100 mol%), relative to the total monomers constituting the base polymer. Furthermore, the second polymer is preferably hydrophobic from the viewpoint of being able to better exhibit the intended effects of the present invention. Therefore, the base polymer is also preferably hydrophobic.

[0046] Furthermore, the weight-average molecular weight of the base polymer is preferably 100,000 to 1,000,000, and more preferably 150,000 to 800,000, from the viewpoint of peel durability and other factors. In this specification, the weight-average molecular weight is the value measured by gel permeation chromatography (GPC) using polystyrene as the standard substance under the following measurement conditions.

[0047] (Measurement conditions for molecular weight) Equipment: Semi-micro GPC system LC-VP system (manufactured by Shimadzu Corporation) Detector: Shodex® RI-104 (manufactured by Showa Denko K.K.) Columns: Two Shodex® GPC LF-804 columns (manufactured by Showa Denko Corporation) were used. Guard column: Shodex® LF-G (manufactured by Showa Denko Corporation) Column temperature: 40℃ Mobile phase solvent: CHCl3 Flow rate: 1.00mL / min Injection volume: 200μL

[0048] When the second polymer of the second coating layer 3b is a crosslinked polymer formed by crosslinking a base polymer with a crosslinkable monomer, it is preferable that the crosslinkable monomer has a high affinity for the base polymer and a strong bond with the first polymer on the surface of the first coating layer 3a.

[0049] Examples of crosslinkable monomers include those having functional groups such as vinyl (CH2=CH-), allyl (CH2=CH-CH2-), acryloyl (CH2=CH-CO-), methacryloyl (CH2=C(CH3)-CO-), and acrylamide (CH2=CH-CO-NH-), which are types of vinyl groups. Generally, the greater the polarity of the chemical structure connected to the terminal structure with an unsaturated bond of the functional group (CH2=CH- or CH2=C(CH3)- in the above example), the greater the reactivity of the crosslinkable monomer. The relationship between the magnitudes of these polarities is (allyl group) < (acryloyl group) ≈ (methacryloyl group) < (acrylamide group). Therefore, the reactivity of crosslinkable monomers having an allyl group is often less than that of crosslinkable monomers having an acryloyl or methacryloyl group, and the reactivity of crosslinkable monomers having an acrylamide group is often greater than that of crosslinkable monomers having an acryloyl or methacryloyl group.

[0050] The reactivity of crosslinkable monomers containing a methacryloyl group is slightly lower than that of crosslinkable monomers containing an acryloyl group, due to the steric hindrance of the CH3 group within the methacryloyl group, but is equivalent to that of crosslinkable monomers containing an acryloyl group. Furthermore, among crosslinkable monomers with the same type of functional group, the reactivity increases as the number of functional groups increases. Hereafter, when (meth)acrylate is used, it refers to both acrylate, which is a crosslinkable monomer containing an acryloyl group, and methacrylate, which is a crosslinkable monomer containing a methacryloyl (methacryloyl) group.

[0051] 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.

[0052] 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.

[0053] Examples of crosslinkable monomers having an acrylamide group include N,N'-methylenebis(meth)acrylamide, N,N'-ethylenebis(meth)acrylamide, N,N'-hexamethylenebis(meth)acrylamide, N,N'-benzylidenebis(meth)acrylamide, N,N'-bis((meth)acrylamidemethylene)urea, N-[tris(3-(meth)acrylamidepropoxymethyl)methyl](meth)acrylamide (e.g., FOM-03006; N-[tris(3-acrylamidepropoxymethyl)methyl]acrylamide), N,N-bis(2-(meth)acrylamideethyl)(meth)acrylamide Examples include FOM-03007 (N,N-bis(2-acryloylamideethyl)acrylamide), N,N'-[oxybis(2,1-ethanediyloxy-3,1-propanediyl)]bis(meth)acrylamide (e.g., FOM-03008 (N,N'-[oxybis(2,1-ethanediyloxy-3,1-propanediyl)]bisacrylamide), and N,N'-1,2-ethanediylbis{N-[2-(meth)acryloylamino)ethyl](meth)acrylamide} (e.g., FOM-03009 (N,N'-1,2-ethanediylbis{N-[2-(acryloylamino)ethyl]acrylamide}).

[0054] 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.

[0055] In the present invention, from the viewpoint of high affinity between the base polymer and the crosslinkable monomer, it is preferable that the base polymer has lactic acid monomer units and the crosslinkable monomer is (meth)acrylate.

[0056] When the second polymer is a crosslinkable polymer formed by crosslinking a crosslinkable monomer and a base polymer, the content ratio (weight ratio) of the crosslinkable monomer to the base polymer is not particularly limited, however, the crosslinkable monomer is preferably contained in an amount of 1% to 95% by weight, more preferably 5% to 90% by weight, even more preferably 10% to 90% by weight, even more preferably 30% to 90% by weight, and particularly preferably 30% to 70% by weight, based on the weight (100% by weight) of the base polymer. In one embodiment, the crosslinkable monomer is preferably contained in an amount of 20% to 80% by weight, and more preferably 30% to 75% by weight, based on the weight (100% by weight) of the base polymer. When the crosslinkable monomer is contained within the above range, the interpenetrating polymer network structure described later can be efficiently formed, and the intended effects of the present invention can be more fully realized.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] <Third coating layers 3c, 3d, 3e> The third coating layers 3c, 3d, and 3e in the drug-containing coating portion 3 are located on the second coating layer 3b and contain the drug and a third polymer that supports the drug. Preferably, the third polymer in the third coating layers 3c, 3d, and 3e forms an interpenetrating polymer network structure with the second polymer in the second coating layer 3b.

[0065] An interpenetrating polymer network (IPN) structure, also known as an Interpenetrating Polymer Network (IPN), refers to a structure in which one polymer network and another polymer network are intertwined without covalent bonds. When an interpenetrating polymer network structure is formed, the bonding strength within each polymer network is improved. Therefore, it is difficult to separate the entire polymer network after formation into the individual polymer networks that existed before formation. In this invention, the third polymer in the third coating layers 3c, 3d, and 3e 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 layers 3c, 3d, and 3e and the second coating layer 3b, and improving the peeling durability of the drug-containing coating portion 3.

[0066] 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 layers 3c, 3d, and 3e can be confirmed. Known resins can be used for embedding, but for example, epoxy resin (Epon812) and caprolactone (EVONIK C212) can be preferably used. TEM observation can be specifically performed by the method described in the examples. 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 layers 3c, 3d, and 3e becomes unclear in the cross-section of the drug-containing coating portion 3, resulting in uneven brightness at the interface, or the brightness of the interface may differ from that of the second coating layer 3b and the third coating layers 3c, 3d, and 3e. Therefore, if the above findings are obtained at the interface between the second coating layer 3b and the third coating layers 3c, 3d, and 3e in the TEM image, it can be determined that an interpenetrating polymer network structure has been formed.

[0067] The third polymer in the third coating layers 3c, 3d, and 3e is preferably hydrophobic. Being hydrophobic allows the third polymer to dissolve in a solvent. When the 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.

[0068] Furthermore, the hydrophobic nature of the third polymer in the third coating layers 3c, 3d, and 3e 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 hindering the sustained release of the chemical. On the other hand, the hydrophobic nature of the third and second polymers in the third coating layers 3c, 3d, and 3e prevents swelling of the third and second coating layers under usage conditions, thus maintaining the peel resistance of the coating layers.

[0069] 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 layers 3c, 3d, and 3e, increases the bonding force between the second coating layer 3b and the third coating layers 3c, 3d, and 3e, 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 reacted forms of the constituent monomers of each polymer. If each polymer is synthesized using the same constituent monomers regardless of optical activity, the second polymer and the third polymer will have the same monomer units. In a preferred embodiment, the second polymer and the third polymer have the same monomer units in at least a portion of each. The drugs within the third coating layers 3c, 3d, and 3e are as described above.

[0070] 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 portion 23 and a linear second strut portion 24, a wavy strut having a plurality of bent portions 21 with a peak on one end side in the axial direction of the stent body 10 that connects the linear first strut portion 23 and the linear second strut portion 24, and a plurality of bent portions 22 with a valley on the other end side of the stent body 10.

[0071] 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. 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 40-60% 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 40-60% 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.

[0072] 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. The connecting portions 31 and 32 extend diagonally with respect to the central axis of the stent body 10. The connecting portions 31 and 32 are generally straight, and the widths (line widths) of the connecting portions 31 and 32, the struts 23 and 24, and the bent portions are approximately the same. The widths (line widths) of the connecting portions 31 and 32, the struts 23 and 24, and the bent portions are preferably 0.08 mm to 0.120 mm, and particularly preferably 0.10 mm to 0.115 mm.

[0073] Furthermore, the annular body 2 is formed from a wavy linear component having multiple bent portions 21 and 22, each having a vertex at one end and the other end in the axial direction. Between adjacent annular bodies 2 in the axial direction of an in vivo implantable stent, the vertices of the adjacent bent portions 21 and 22 are offset by a predetermined length (specifically, about 0.040 to 0.042 mm) in the circumferential direction of the stent body.

[0074] Each connecting portion 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 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.

[0075] 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.

[0076] 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.

[0077] 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).

[0078] 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 (on 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 (on the drawing).

[0079] 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 40-60% 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 40-60% 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. It is preferable that the first diminished connection portion holders have 45-55% of the number of connection portions in the maximum connection portion holders. Furthermore, it is preferable that the second reduced connection holder has 45 to 55% of the number of connection parts in the first reduced connection holder.

[0080] 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 at a predetermined angle with respect to the central axis of the stent body (on the drawing).

[0081] 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 (in the drawing) with respect to the central axis of the stent body.

[0082] 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 connection portion 12a, which has 40-60% of the number of connection portions in the most connection portion 11a. 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 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 connection portion are arranged at equiangled angles with respect to the central axis of the stent body 10.

[0083] 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 connection portion 12b having 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 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 connection portion are arranged at equiangled angles with respect to the central axis of the stent body 10.

[0084] 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 40-60% of the number of connections in the first diminishing connection holder. In Figures 1 and 2, the number of connections in the first diminishing connection holders 12a and 12b is 8, and the number of connections in the second diminishing connection holders 13a and 13b is 4, which is 50% of the number of connections in the first diminishing connection holders 12a and 12b. The connections in the second diminishing connection holders 13a and 13b are arranged at equiangled angles with respect to the central axis of the stent body 10.

[0085] 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.

[0086] 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 also 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%).

[0087] 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.

[0088] 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. Furthermore, 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 by "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)".

[0089] 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%).

[0090] 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.

[0091] 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.

[0092] 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.

[0093] The material used to form the stent body 10 is preferably a metal with superelastic properties. Specific examples of alloys with 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).

[0094] 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, which has the highest corrosion resistance, is preferred as the stainless steel.

[0095] 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 in-vivo implantation 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 in-vivo implantation out from the tip of the sheath 52.

[0096] The in-vivo stent 1 is as described above. As shown in Figure 7, the stent delivery system 50 of this embodiment comprises a sheath 52, a self-expanding in vivo stent 1, and an inner tube 54.

[0097] As shown in Figures 7, 8, and 10, the sheath 52 is tubular and has openings at its tip and posterior 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 located proximal to the housing section 55. The sheath side hole 41 is for guiding the guide wire to the outside.

[0098] 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 has a side port 63 that branches diagonally rearward from near the center of the sheath hub body 61.

[0099] 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.

[0100] The operating member 64 comprises 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. In addition, as shown in Figure 9, the tip portion of the valve body pressing portion 64a extends into the recess for housing the valve body, allowing the valve body 62 to be compressed by moving the operating member to the tip.

[0101] 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 contacts 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] Furthermore, in the stent delivery system 50 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.

[0109] 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 guidewire 9 is inserted from the tip of the lumen 48 of the inner tube 54, and is led out 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 (e.g., a blood vessel) along the guidewire 9 to position the target in vivo stent 1 for placement in the stenotic area.

[0110] 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 stenosis, and is then placed within the stenosis. 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.

[0111] Next, a method for manufacturing the in-vivo stent of the present invention will be described. The present invention relates to a method for manufacturing an in vivo stent, comprising a tubular stent body 10 formed from a wavy linear component having a plurality of bent portions 2 with 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.

[0112] 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.

[0113] 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 process of forming the drug-containing coating portion, the drug and polymer are dissolved in a solvent, and a nozzle with discharge pressure applied to the viscous coating solution is positioned on the outer surface of the linear first strut portion. The nozzle is then moved along the outer surface of the linear first strut portion to coat the outer surface of the linear first strut portion with the coating solution.

[0114] Furthermore, in the process of forming the drug-containing coating, it is preferable to perform a second coating step after the first coating step. In the second coating step, the direction of the nozzle's movement may be the same as in the first coating step, or it may be in a different direction (reverse of the first coating step).

[0115] Furthermore, in the process of forming the drug-containing coating, a third coating step may be performed after the second coating step. In the third coating step, the direction of the nozzle's movement may be the same as in the first coating step, or it may be in a different direction (reverse of the first coating step). Furthermore, it is preferable that the coating solution contains a polymer with a molecular weight of 150,000 or more.

[0116] 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.

[0117] 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 the 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 subsequently heat-treating it, so that the stent body is superelastic 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 either before or after the heat treatment.

[0118] Let's explain each step. In the stent body preparation process, the first step is to form the stent base. 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 biological site where the stent will be implanted. The metal pipe prepared may already possess superelastic properties, or it may be capable of being imparted superelastic properties by a process described later.

[0119] 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.

[0120] 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.

[0121] Then, the stent base is heat-treated in its expanded state to impart shape memory and superelastic properties to it. 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 and superelasticity to it. 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.

[0122] Next, the preparation of the coating solution used in the process of forming the drug-containing coating is carried out. In this embodiment, in the step of forming the drug-containing coating, a first coating solution is prepared for forming a first coating layer 3a having a first polymer formed by the auto-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 coating layer 3b having a second polymer covalently bonded to the first polymer on the first coating layer 3a; and a third coating solution is prepared for forming a third coating layer 3c having a drug and a third polymer supporting the drug on the second coating layer 3b.

[0123] 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. In addition, a fourth coating solution containing the material for forming the third coat layer 3d, and, if necessary, a fifth coating solution containing the material for forming the third coat layer 3e, are prepared in the same manner as the third coating solution.

[0124] 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.

[0125] 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.

[0126] Next, 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 and fourth coating solutions to the outer surface of the stent body to which the second coating solution has been applied. It is desirable that the application of the third and fourth coating solutions be performed at least twice, and especially three times. It is also acceptable to omit either the application of the first or second coating solution, or to perform only one of the application of the first or second coating solution.

[0127] 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.

[0128] Alternatively, the first and second coating liquids may be applied using a coating apparatus having two nozzles, as described later. In this case, the third coating liquid can be applied independently using the coating apparatus described later. Furthermore, 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.

[0129] 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. Figure 15 is an explanatory diagram illustrating the coating path of the nozzle in the next coating when coating is performed using the coating path pattern shown in Figure 14. Figure 16 is an explanatory diagram illustrating the coating path of the nozzle in another pattern in the coating apparatus used in the manufacture of the in-vivo stent of the present invention. Figure 17 is an explanatory diagram illustrating the coating path of the nozzle in the next coating when coating is performed using the coating path pattern shown in Figure 16.

[0130] 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.

[0131] 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.

[0132] The air conditioning unit 218 supplies air with controlled 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.

[0133] The retainer 220 is located at the bottom inside the chamber 210 and is used to hold the stent body 10, and has a base 222, a chuck 224, a motor 226 and a mandrel 228.

[0134] The base 222 is mounted on a moving device 230 and is movable in the XY direction, as will be described later, and the chuck portion 224 and motor 226 are located therein. The chuck portion 224 is used to chucking the base end of the mandrel 228. The motor 226 is configured to rotate the chuck portion 224 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.

[0135] 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.

[0136] The moving device (corresponding to the means of movement) 230 is used to move the holder 220 in the XY direction and has an X-direction moving mechanism 231 and a Y-direction moving mechanism 236.

[0137] 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 mounted on the X-direction movement table 234, and the base 222 of the holder 220 is mounted 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 solution, a second coating solution, and a third coating solution.

[0138] As shown in Figures 12 and 11, the first dispensing head 240 and the second dispensing head 245 are located in the middle of the chamber 210 and are used to dispense the coating liquid, and have a dispenser 252, a vertical table 253, a bracket 258, and a nozzle section 262.

[0139] 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.

[0140] The cylinder section 255 is a container for storing the coating liquid and is attached to the vertical table 253. The piston section 256 is slidably positioned within the cylinder section 255. The drive section 257 has, for example, a motor or a hydraulic mechanism and is configured to press the piston section 256 with a predetermined force.

[0141] The nozzle section 262 communicates with the cylinder section 255 and includes a mounting member 264 and a nozzle 266. The mounting member 264 is located at the lower end of the cylinder section 255 and is used to connect the nozzle 266 to the cylinder section 255. 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.

[0142] The viscosity of the third coating solution, the fourth coating solution, and the fifth coating solution is preferably 0.1 to 2000 cp, and more preferably 100 to 1000 cp. For example, if the viscosity of the coating solution is greater than the upper limit of the range, the discharge pressure of the coating solution may become excessively high or it may not be possible to discharge it from the nozzle 266. Also, if it is less than the lower limit of the range, a portion of the discharged coating solution may drip from the surface of the stent body 10 (strut 30), making it difficult to form a uniform coating layer.

[0143] 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).

[0144] 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.

[0145] The first position information acquisition device 270 is an imaging means provided for acquiring position information in the XY 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.

[0146] 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.

[0147] 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. The calculation processes include, for example, processes for obtaining position information in the X and Y directions, processes for obtaining position information in the Z direction, and processes for setting the coating path by the nozzle 266.

[0148] In the process for acquiring positional information in the XY 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 positional information acquisition device 270 is binarized with an appropriate brightness to separate the stent body 10 (strut) from the void, and converted into the XY coordinates of the stent body 10 (strut), that is, positional information in the XY direction in a Cartesian coordinate system, and stored in memory. The obtained positional information in the XY 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.

[0149] 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 quantitatively and precisely apply each coating liquid, 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.

[0150] In the process of setting the coating path for each coating liquid by the nozzle 266, the position information in the XY 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).

[0151] Next, the process for forming the drug-containing coating will be described in detail. Figures 18, 19, 20, 21, and 22 are flowcharts illustrating the process of forming the drug-containing coating. In this embodiment, the process of forming the drug-containing coating consists of a preparation step, an imaging step, a first 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, a second application step of the third coating solution, a first application step of the fourth coating solution, and a second application step of the fourth coating solution. Note that if the application of the first and second coating solutions 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.

[0152] 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.

[0153] Next, the imaging process will be explained with reference to Figure 18. First, the control unit 290 receives input imaging parameters and stores the input imaging parameters in memory (step S11). The imaging parameters are, for example, entered by the operator of the coating apparatus 200 using a keyboard and include the rotation speed of the mandrel 228, the number of imaging lines, the imaging line width, and the imaging speed, as measured by the line sensor unit of the first position information acquisition device 270.

[0154] 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).

[0155] 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. 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).

[0156] Next, the coating path setting process will be explained with reference to Figure 19. The control unit 290 sets a path based on the acquired shape data of the stent body 10 (strut) and the coordinate data of the trajectory passing through the center on the linear strut portions 23 and 24 of the stent body 10 (strut). When it reaches the bent leg portions 21b and 22b, it moves above the bent leg portions 21b and 22b and designs a trajectory passing through the center of the bent leg portions 21b and 22b (see Figures 13 and 14). When it reaches the bent tip portion 21a, it moves downward, approaches the bent tip portion 21a, and designs a path based on the coordinate data of the trajectory passing through the center of the bent tip portion 21a (see Figures 13 and 14), setting the application paths for the first and second coating liquids and the third coating liquid (step S21).

[0157] The application paths for the first coating liquid, the second coating liquid, and the third coating liquid are generated so that the entire stent body 10 (strut) can be coated in a continuous manner, while minimizing overlapping sections. In this embodiment, the application paths for the first coating liquid, the second coating liquid, and the third coating liquid are the same as those in Figures 13 and 14. Alternatively, the application paths for the first and second coating liquids may be set based on coordinate data of a trajectory passing through the center on the linear strut sections 23, 24 and the bent sections 21, 22 (including the legs of the bent sections). In this case, the first and second coating liquids are applied to the entire upper surface of the linear strut sections 23, 24 and the bent sections 21, 22 (including the legs of the bent sections).

[0158] Furthermore, the control unit 290 sets the coating path for the fourth coating liquid (see Figure 15) so that when it reaches one end of the bent leg portions 21b, 22b of the bent portions 21, 22b, it approaches the upper surface of the bent leg portions 21b, 22b, and when it reaches one end of the bent tip portion 21a, it moves upward, and this short path proceeds for all bent leg portions 21b, 22b (step S21). 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, for example, entered 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. The control unit 290 also adjusts the discharge amount of the coating liquid based on the input displacement measurement parameters.

[0159] Specifically, in the embodiments shown in Figures 13 and 14, when the nozzle is moving along the central part of the outer surface of the struts 23 and 24 (R1), when the nozzle reaches one end of the bent leg portions 21b and 22b of the bent portions 21 and 22 of the stent body 10, the discharge of the coating liquid stops, the nozzle moves upward (R1a), and moves along the central part while separated from the bent leg portions 21b and 22b. Then, when the nozzle reaches the other end of the bent leg portions 21b and 22b (in other words, one end of the bent tip portions 21a and 22a), it descends and approaches the bent tip portions 21a and 22a, and the discharge of the coating liquid resumes, and the nozzle moves along the central part of the bent tip portions 21a and 22a (R1b). Next, when the nozzle reaches the other end of the bent tip portions 21a, 22a (in other words, one end of the bent leg portions 21b, 22b), the discharge of the coating liquid stops, and the nozzle moves upward (R1c), moving away from the bent leg portions 21b, 22b. Then, when the nozzle reaches the other end of the bent leg portions 21b, 22b (in other words, one end of the struts 23, 24), it descends, approaches the struts 23, 24, and the discharge of the coating liquid resumes, moving along the center of the struts 23, 24 (R1). Note that the discharge of the coating liquid from the nozzle in path R1b is performed at the same discharge rate as when moving in R1.

[0160] 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).

[0161] When the operator of the coating device 200 inputs "adjustment complete" for example 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).

[0162] 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.

[0163] Next, the coating process for the first and second coating solutions will be explained with reference to Figure 20. 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.

[0164] 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 entered, for example, 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, and the normal discharge rate per unit time and the decreasing discharge rate per unit time from the first coating head 240 and the second coating head 245 (nozzle portion 262). The discharge rate of the coating liquid per unit time is preferably about 0.13 to 0.15 μl / sec. 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.

[0165] 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).

[0166] 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. The control unit 290 uses the first coating parameters received during the coating process of the first coating liquid, and calculates the rotational speed and axial movement speed of the stent body 10, the selection of the second coating head 245, and the normal discharge rate per unit time and the decreasing discharge rate per unit time of the second coating head 245 (nozzle portion 262). As shown in Figure 20, 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.

[0167] 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).

[0168] Next, referring to Figure 21, the application process of the third coating solution for forming the drug coating layer will be explained. The first coating liquid is discharged from the cylinder section 255 of the first coating head 240 in the coating apparatus 200, and the third coating liquid is stored, after which the coating process of the third coating liquid 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 normal discharge rate per unit time and the decreasing discharge rate per unit time of the first coating head 240 (nozzle portion 262), and the number of coatings (number of layers).

[0169] 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. 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 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.

[0170] As a result, the first coating head 240 applies the third coating liquid while moving along a predetermined coating path (see Figures 13 and 14) in the coating process of the third coating liquid. In this embodiment, the coating path of the third coating liquid is shown in Figures 13 and 14 and is as described above. The application of the third coating liquid proceeds by discharging the third coating liquid from the central part of the outer surface of the struts 23 and 24, and discharging the third coating liquid at a normal discharge rate per unit time (R1) across the entire width of the struts 23 and 24, thereby coating the entire outer surface of the struts 23 and 24.

[0171] Then, when the nozzle reaches one end of the bent leg portions 21b and 22b of the bent portions 21 and 22 of the stent body 10, the discharge of the third coating liquid is stopped, the nozzle moves upward and moves (R1a) over the central part of the bent leg portions 21b and 22b while separated from them. Then, when the nozzle reaches the other end of the bent leg portions 21b, 22b (in other words, one end of the bent tip portions 21a, 22a), it descends and approaches the bent tip portions 21a, 22a, and the discharge of the third coating liquid is resumed, and the nozzle moves through the central part of the bent tip portions 21a, 22a (R1b). Then, when the nozzle reaches the other end of the bent tip portions 21a, 22a (in other words, one end of the bent leg portions 21b, 22b), the discharge of the coating liquid stops, and the nozzle moves upward and moves (R1c) over the central part of the bent leg portions 21b, 22b while separated from them.

[0172] Then, when the nozzle reaches the other end of the bent leg portions 21b and 22b (in other words, one end of the struts 23 and 24), it descends and approaches the struts 23 and 24, and the discharge of the third coating liquid resumes, moving through the central part of the struts 23 and 24 (R1). The discharge of the coating liquid from the nozzle in path R1b is performed at the same discharge rate as when moving through R1. As a result, the in vivo stent is coated with a third coating solution containing a drug on the linear first strut portion 23 and the linear second strut portion 24, and also coated with a third coating solution containing a drug on the bent tip portions 21a and 22a, while the bent leg portions 21b and 22b are not coated with the third coating solution containing a drug.

[0173] In this invention, the third coating solution is applied at least twice. The first application of the third coating solution is carried out, for example, via the application path shown in Figures 13 and 14. Note that the illustrated application path shows only a portion, not the entire length.

[0174] After the nozzle has completed its movement along the entire length of one annular strut, it moves to the adjacent annular strut to the rear (towards the base). Then, as shown in Figure 13, the nozzle moves in the opposite direction, but the third coating solution is applied to the adjacent annular in the same manner. The first coating process is completed when the coating is applied to all annulars. Next, the second application of the third coating solution is performed. The application route for the second application can be the same as the route shown in Figure 13 (first application). Alternatively, the application route for the second application may be the reverse of the route shown in Figure 13 (first application). In the second coating process, the amount of the third coating solution applied and the position of the nozzle are changed, just as in the first process described above. The second coating process is completed when coating is finished on all the annular bodies.

[0175] Furthermore, after the completion of the second application of the third coating solution, a third application of the third coating solution may be performed. The third application of the third coating solution is performed in the same manner as the first. Then, in the application process of the third coating solution, when the number of applications (layers) reaches a set value (step S45: Yes), the application is stopped (step S46). When the holder 220 is moved 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) with the primer coating layer and drug coating layer formed on it is removed from the mandrel 228.

[0176] Next, referring to Figure 22, the application process of the fourth coating solution for forming the third drug-containing coating portion (flexible leg coating portion) will be explained. The fourth coating step forms the third drug-containing coating portion (bent leg coating portion) 36 shown in Figures 3 and 4. Figure 15 shows the nozzle's path during the fourth coating step, or in other words, the step of forming the third drug-containing coating portion (bent leg coating portion) 36 on the bent leg portions 21b and 22b. During the fourth coating step, the fourth coating step is discharged only when the nozzle is moving along path R2 shown in Figure 15.

[0177] Before the application of the fourth coating solution, the fourth coating solution is prepared. The fourth coating solution is preferably one with the same composition as the third coating solution, and is prepared to produce a cured product that is more flexible than the cured product of the third coating solution after curing. In the fourth coating step, for example, the second coating liquid is discharged from the cylinder of the second coating head 245 in the coating apparatus 200, the fourth coating liquid is stored, and then the fourth coating step is performed.

[0178] The control unit 290 receives input for parameters for applying the fourth coating solution and stores the input parameters in memory (step S51). The parameters for applying the fourth coating solution (third coating parameters) are entered by the operator of the coating device 200 using a keyboard, for example, and include the rotational speed and axial movement speed of the stent body 10, the selection of the first coating head 240, the normal discharge rate per unit time and the decreasing discharge rate per unit time of the coating head (nozzle part), and the number of coatings (number of layers).

[0179] The control unit 290 commands the movement of the holder 220 using the X-direction movement mechanism 231 (step S52). 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. When the stent body 10 reaches the coating start position (step S53: Yes), the stent body 10 is rotated and moved axially, and the fourth coating liquid is discharged from the nozzle portion 262 of the second coating head 245 (step S54). 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.

[0180] In the fourth coating step, when the nozzle reaches the center of one end of the bent leg portions 21b and 22b, it proceeds along the center (R2) of the bent leg portions 21b and 22b, discharging the fourth coating at the normal discharge rate per unit time, thereby coating the entire outer surface of the bent leg portions 21b and 22b. When the nozzle reaches the other end of the bent leg portions 21b and 22b of the stent body 10 (in other words, when it reaches one end of the bent tip portions 21a and 22a), the discharge of the coating is stopped. By repeating this process, the first coating step is completed when the fourth coating is applied to all the bent leg portions 21b and 22b.

[0181] Next, the second application of the fourth coating solution is performed. The application route for the second application can be the same as the route shown in Figure 15 (first application). Alternatively, the application route for the second application may be the reverse of the route shown in Figure 15 (first application).

[0182] Furthermore, the second drug-containing coating portion (bent tip coating portion) 37 in the stent 1a of the embodiment shown in Figures 5 and 6 can be formed as follows. Figure 16 shows the path of the nozzle for forming the first drug-containing coating portion 30 on the struts 23 and 24 of the stent 1a of the embodiment. Specifically, the application of the third coating solution proceeds by discharging the third coating solution at a normal discharge rate per unit time across the entire width of the struts 23 and 24, through the central part of the outer surface of the struts 23 and 24 (R2), thereby coating the entire outer surface of the struts 23 and 24. After the nozzle reaches one end of the bent leg portions 21b and 22b of the stent body 10, the discharge of the coating solution is interrupted and the nozzle moves to the other end of the adjacent bent leg portions 21b and 22b (R2a). Then, the discharge of the coating solution is resumed and proceeds through the central part of the struts 23 and 24 (R2), coating the entire outer surface of the struts 23 and 24.

[0183] Next, the second application of the third coating solution is performed. The application route for the second application can be the same as the route shown in Figure 16 (first application). Alternatively, the application route for the second application may be the reverse of the route shown in Figure 16 (first application).

[0184] Next, in this embodiment, a fifth coating solution is prepared and applied. The fifth coating solution used contains a material for forming the third coating layer 3e. Then, the second drug-containing coating portion 37 is formed on the bent tip portions 21a and 22a using the fifth coating solution.

[0185] Figure 17 shows the nozzle's path for forming the second drug-containing coating portion 37 on the bent tip portions 21a and 22a of the stent 1a in the embodiment. Specifically, when applying the fifth coating solution to the bent tip portions 21a and 22a, the nozzle moves along the center (R3) of the bent tip portions 21a and 22a, discharging the fifth coating solution at the normal discharge rate per unit time, covering the entire width of the bent tip portions 21a and 22a, thereby coating the entire outer surface of the bent tip portions 21a and 22a. After the nozzle reaches the other end of the bent tip portions 21a and 22a of the stent body 10, the discharge of the coating solution is stopped. By repeating this process, the fifth coating solution is applied to all of the bent tip portions 21a and 22a.

[0186] Next, the second application of the fifth coating solution is performed. The application route for the second application can be the same as the route shown in Figure 17 (first application). Alternatively, the application route for the second application may be the reverse of the route shown in Figure 17 (first application). Next, in this embodiment, a fourth coating solution is prepared and applied. The application of the fourth coating solution is for forming the third drug-containing coating portion (bent leg coating portion) 36, and can be carried out in the same manner as the application process of the fourth coating solution described above. [Explanation of Symbols]

[0187] 1. Intravivo stent 2 Ring bodies 10 Stent Body 21, 22 Bending section 31,32 Connection part 34 First drug-containing coating 35 Second drug-containing coating 36 Part without drug-containing coating 50 Stent Delivery System 200 coating device 240 First coating head 245 Second dispensing head

Claims

1. An in vivo stent comprising 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 bent portion comprises a bent tip portion including the apex, and two bent leg portions formed between the bent tip portion and the first and second strut portions. The in vivo stent comprises a first drug-containing covering portion that covers the linear first strut portion and the linear second strut portion, and a second drug-containing covering portion that covers the bent tip portion, and further, the two bent leg portions have a third drug-containing covering portion that is more flexible than the first drug-containing covering portion.

2. The in vivo stent according to claim 1, wherein the bent leg portion is a part that deforms 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 first drug-containing coating portion has the same drug content as the second drug-containing coating portion.

6. The in vivo stent according to claim 1 or 2, wherein the glass transition temperature of the first drug-containing coating is 50 to 60°C, and the glass transition temperature of the third drug-containing coating is 35 to 45°C.

7. The in vivo stent according to claim 1 or 2, wherein the third drug-containing coating portion contains a polymer with a smaller molecular weight than the first drug-containing coating portion, and the first drug-containing coating portion contains a polymer with a molecular weight of 100,000 to 1,000,000, and the third drug-containing coating portion contains a polymer with a molecular weight of 10,000 to 100,000.

8. The in vivo stent according to claim 1 or 2, wherein the second drug-containing coating is more flexible than the first drug-containing coating.

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

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 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 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. A stent delivery system comprising a sheath, a stent for in-vivo implantation according to claim 1 or 2 housed within the tip of the sheath, and an inner tube slidably inserted through the sheath for pushing the stent for in-vivo implantation out from the tip of the sheath.

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