In-vivo indwelling device and method for manufacturing in-vivo indwelling device

Abstract

This in-vivo indwelling device (1) comprises a coil (10) having a longitudinal direction, and a fiber layer (30) disposed on an outer peripheral surface (12) of the coil (10) and containing a fiber (40), wherein: the fiber (40) contains a polymer material and a medicine; and when the coil (10) is viewed from a direction perpendicular to the longitudinal direction, the fiber layer (30) is present in a circular virtual region (70) centered on the centroid (C) of the coil (10) and having a diameter (D2) that has a size corresponding to 1.1 times the outer diameter (D1) of the coil (10), and is not present outside the virtual region (70).

Description

Intravascular Implant and Method for Manufacturing the Same

[0001] The present disclosure relates to an intravascular implant for forming an embolism in a blood vessel in a vascular disease site and a method for manufacturing the same.

[0002] As one of the treatment methods for vascular lesions such as aneurysms, arteriovenous malformations, arteriovenous fistulas, pulmonary vascular malformations, renal vascular malformations, renal arteries, and abdominal aneurysms in the head and neck region, endovascular treatment can be mentioned. In endovascular treatment, an embolization procedure is used in which an intravascular implant having a coil for embolization is placed at the target site to promote thrombosis, thereby preventing, for example, the rupture of an aneurysm. Several to dozens of coils are used in a single embolization procedure. Patent Document 1 discloses a medical device that can be implanted for occluding a lumen, cavity, blood vessel, or organ of the body. Patent Document 1 discloses that an implantable occlusion device is functionally enhanced by including a membranous substance that increases the cross-sectional size of the occlusion device to enhance thrombus-inducing properties, and that the membranous substance on the occlusion device is formed as a number of elongated fringe materials that increase the cross-sectional size to enhance thrombus-inducing properties.

[0003] Japanese Patent Application Laid-Open No. 2022-2781

[0004] The fringe or membranous tube attached to the coiled wire of the occlusion device described in Patent Document 1 protrudes radially outward of the coil, so there is a problem that it is difficult to insert the occlusion device into the body. Therefore, the present disclosure aims to solve the problem of providing an intravascular implant and a method for manufacturing the same that can improve the ease of inserting the coil into the body.

[0005] The intravascular implant according to an embodiment that has solved the above problems is as follows. [1] A coil having a longitudinal direction, and a fiber layer disposed on the outer peripheral surface of the coil and containing fibers, the fibers containing a polymer material and a drug, and when the coil is viewed from a direction perpendicular to the longitudinal direction, the fiber layer exists within a circular virtual region centered on the centroid of the coil with a diameter equal to 1.1 times the outer diameter of the coil and does not exist outside the virtual region.

[0006] Furthermore, the in-vivo implantation device according to the embodiment is preferably any of the following [2] to [6]. [2] The in-vivo implantation device according to [1], wherein the fiber includes a core-sheath type fiber having a core and a sheath, the core contains the drug and the sheath contains the polymer material. [3] The in-vivo implantation device according to [1] or [2], wherein the fiber layer is located within the virtual region and not outside the virtual region over the entire longitudinal direction of the coil. [4] The in-vivo implantation device according to any one of [1] to [3], wherein the average fiber diameter of the fiber is 3.0 μm or more and 10 μm or less. [5] The in-vivo implantation device according to any one of [1] to [4], wherein the coil is constructed by winding a long wire, and the fiber extends in the longitudinal axis direction of the wire. [6] The in-vivo implantation device according to any one of [1] to [5], wherein the polymer material is a biodegradable polymer material.

[0007] A method for manufacturing an in-vivo implantable device according to an embodiment that has been able to solve the above problems is as follows: [7] A method for manufacturing an in-vivo implantable device comprising the steps of: preparing a coil on which a fiber layer is arranged on its outer surface and a first cylinder having an inner diameter no more than 1.1 times the outer diameter of the coil; applying an unsolidified resin agent to the inner surface of the first cylinder; inserting the coil into the lumen of the first cylinder and sliding the coil within the first cylinder; and removing the slid coil from the first cylinder and solidifying the resin agent.

[0008] Furthermore, the method for manufacturing an in-vivo implantable device according to the embodiment is preferably any of the following [8] to [9]. [8] The method for manufacturing an in-vivo implantable device according to [7], further comprising the steps of: preparing a second cylinder having an inner diameter no more than 1.1 times the outer diameter of a coil on which a fiber layer is arranged on the outer surface; and inserting a coil on which the resin agent has been solidified into the lumen of the second cylinder and shaping it. [9] The method for manufacturing an in-vivo implantable device according to [7] or [8], wherein the resin agent comprises a biodegradable resin.

[0009] In the above-mentioned in-vivo implantation device, since the fibers of the fibrous layer contain the drug, it prevents the drug from detaching from the coil early in the procedure and enhances the sustained release of the drug, compared to cases where the drug is coated on the coil surface. Furthermore, by setting the thickness of the fibrous layer within the above range, the ease of inserting the coil into the body can be improved.

[0010] According to the above-described method for manufacturing an in-vivo implantable device, when the coil is viewed from a direction perpendicular to its longitudinal direction, the fiber layer exists within a circular virtual region centered on the centroid of the coil, with a diameter 1.1 times the outer diameter of the coil, and does not exist outside this virtual region. This makes it easier to obtain an in-vivo implantable device, and such an in-vivo implantable device can enhance the ease of inserting the coil into the body.

[0011] These are schematic diagrams of an in-vivo implantation device according to an embodiment of the present disclosure. This is a side view (partially a cross-sectional view) of the coil of the in-vivo implantation device shown in Figure 1, along the longitudinal direction, showing the coil extended in a straight line. This is a cross-sectional view (partially a side view) of the coil of the in-vivo implantation device shown in Figure 1, along the longitudinal direction, showing the coil extended in a straight line. This is an end view of the cut section of the IV-IV line of the in-vivo implantation device shown in Figure 3. This is a cross-sectional view showing the fiber layer of the in-vivo implantation device shown in Figures 2 and 3. This is an end view of the cut section showing a modified example of the in-vivo implantation device shown in Figure 4. This is a schematic diagram showing the fiber structure of the fiber layer. This is a schematic diagram showing a modified example of the fiber structure shown in Figure 7. This is a schematic diagram of an enlarged view of the fiber layer. This is a schematic diagram of a fiber having a branched portion. This is a schematic diagram showing a modified example of the fiber layer shown in Figure 9. This is a side view (partially a cross-sectional view) showing a modified example of the in-vivo implantation device shown in Figure 2. This is a side view (partially a cross-sectional view) showing another modified example of the in-vivo implantation device shown in Figure 2. This is a side view (partially cross-sectional view) showing yet another modified example of the in-vivo implantation device shown in Figure 2. This is a side view (partially cross-sectional view) showing yet another modified example of the in-vivo implantation device shown in Figure 2. This is a side view (partially cross-sectional view) showing yet another modified example of the in-vivo implantation device shown in Figure 2. This is a side view (partially cross-sectional view) showing yet another modified example of the in-vivo implantation device shown in Figure 2. This is a side view (partially cross-sectional view) showing yet another modified example of the in-vivo implantation device shown in Figure 3. This is a side view (partially cross-sectional view) showing yet another modified example of the in-vivo implantation device shown in Figure 3. This is a flowchart of a method for manufacturing an in-vivo implantation device according to an embodiment of the present disclosure. This is a schematic diagram showing step S11 of the manufacturing method shown in Figure 20. This is a schematic diagram showing step S11 of the manufacturing method shown in Figure 20. This is a schematic diagram showing step S12 of the manufacturing method shown in Figure 20. This is a schematic diagram showing the first half of step S13 of the manufacturing method shown in Figure 20. This is a schematic diagram showing the second half of step S13 of the manufacturing method shown in Figure 20. This is a schematic diagram showing step S14 of the manufacturing method shown in Figure 20. This is a flowchart showing a modified version of the manufacturing method shown in Figure 20. This is a schematic diagram showing step S16 of the manufacturing method shown in Figure 27. This is a flowchart showing another modified version of the manufacturing method shown in Figure 20. This is a schematic diagram showing step S23 of the manufacturing method shown in Figure 29.

[0012] The contents of this disclosure will be described in more detail below based on the embodiments described below. However, the contents of this disclosure are not limited by the embodiments described below, and it is certainly possible to implement the disclosure with appropriate modifications within the scope that is consistent with the spirit of the preceding and following descriptions, and all such modifications are included within the technical scope of this disclosure. In addition, hatching and component reference numerals may be omitted in the drawings for convenience, in which case refer to the specification or other drawings. Furthermore, the dimensions of various components in the drawings may differ from the actual dimensions, as priority is given to helping to understand the features of this disclosure.

[0013] 1. Intra-vivo implantation device The intra-vivo implantation device according to the embodiment of this disclosure comprises a coil having a longitudinal direction and a fiber layer disposed on the outer circumferential surface of the coil, the fiber layer comprising a polymer material and a drug, and the gist of the device is that when the coil is viewed from a direction perpendicular to the longitudinal direction, the fiber layer exists within a circular virtual region centered on the centroid of the coil, with a diameter 1.1 times the outer diameter of the coil, and does not exist outside the virtual region. Hereinafter, the intra-vivo implantation device may be simply referred to as the implantation device.

[0014] An implantable device is placed inside the body in minimally invasive treatments for lesions or abnormalities in blood vessels or the digestive tract, such as aneurysms, thrombi, stenosis, or occlusion. Preferably, the implantable device is for cerebral aneurysms. A cerebral aneurysm implantable device can be used in one of the framing, filling, or finishing phases, or it can be used across two or three of these phases.

[0015] An in-vivo implantation device according to an embodiment will be described with reference to Figures 1 to 19. Figure 1 is a schematic diagram of an in-vivo implantation device according to an embodiment of the present disclosure. Figure 2 is a side view (partially a cross-sectional view) along the longitudinal direction of the coil of the in-vivo implantation device shown in Figure 1, showing the coil extended in a straight line. Figure 3 is a cross-sectional view (partially a side view) along the longitudinal direction of the coil of the in-vivo implantation device shown in Figure 1, showing the coil extended in a straight line. Figure 4 is a cross-sectional view of the section of the IV-IV line of the in-vivo implantation device shown in Figure 3. Figure 5 is a cross-sectional view showing the fiber layer of the in-vivo implantation device shown in Figures 2 to 3. Figure 6 is a cross-sectional view showing a modified example of the in-vivo implantation device shown in Figure 4. Figure 7 is a schematic diagram showing the fiber structure of the fiber layer. Figure 8 is a schematic diagram showing a modified example of the fiber structure shown in Figure 7. Figure 9 is a schematic diagram of an enlarged view of the fiber layer. Figure 10 is a schematic diagram of a fiber having a branched portion. Figure 11 is a schematic diagram showing a modified example of the fiber layer shown in Figure 9. Figures 12 to 17 are side views (partially cross-sectional views) showing modified examples of the in-vivo implant shown in Figure 2. Figures 18 to 19 are side views (partially cross-sectional views) showing modified examples of the in-vivo implant shown in Figure 3. In Figure 1, the fiber layer 30 is omitted to facilitate understanding of the shape of the secondary coil. In Figures 12 to 18, only the coil 10 and the fiber layer 30 are shown, but it is preferable that other components are arranged as in Figures 2 to 3. As shown in Figures 2, 3, etc., the implant 1 has a coil 10 and a fiber layer 30.

[0016] As can be seen from Figures 2 and 3, the coil 10 preferably has a longitudinal direction x, a radial direction y, and a circumferential direction z. The longitudinal direction x can also be called the longitudinal axis direction. The coil 10 preferably has a distal end and a proximal end in the longitudinal direction x. The proximal side of the coil 10 refers to the direction toward the user or operator's hand with respect to the longitudinal direction x of the coil 10, and the distal side refers to the opposite direction from the proximal side, i.e., the direction toward the treatment target. In Figures 2 and 3, the right side of the figure is the proximal side, and the left side of the figure is the distal side. The radial direction y of the coil 10 refers to the radial direction of the coil 10, and in the radial direction y, inward refers to the direction toward the center of the longitudinal axis of the coil 10, and outward refers to the direction extending radially from the center of the longitudinal axis on the opposite side from the inward direction. The circumferential direction z of the coil 10 refers to the direction around the longitudinal axis. In the following, when the length of each component of the coil 10 is divided into two equal parts in the longitudinal direction x, the proximal side may be referred to as the proximal portion, and the distal side as the distal portion.

[0017] As shown in Figure 3, the coil 10 has an outer circumferential surface 12. Preferably, the coil 10 has an inner circumferential surface 13. The surface of the coil 10 includes the outer circumferential surface 12 and the inner circumferential surface 13. Preferably, the coil 10 has a lumen 11 that extends in the longitudinal direction x. The outer circumferential surface 12 of the coil 10 faces the outside of the coil 10, i.e., the outside in the radial direction y, and the inner circumferential surface 13 of the coil 10 faces the lumen 11. Preferably, a stretch resistance member 50, which will be described later, is placed in the lumen 11.

[0018] As shown in Figures 1 to 3, the coil 10 is constructed by winding a wire 21. Preferably, the coil 10 is constructed by winding a long wire 21. Preferably, the coil 10 is constructed by winding one or more wires 21 in a spiral shape. Examples of wires 21 include single wires, stranded wires, and coiled wires, with single wires being preferred. Furthermore, it is preferable that the wire 21 is not a coiled wire.

[0019] The wire 21 is preferably biocompatible and flexible. Examples of materials constituting the wire 21 include platinum, gold, titanium, tungsten and their alloys, stainless steel, and other metallic materials or combinations thereof. Among these, it is more preferable that the wire 21 is composed of a platinum-tungsten alloy.

[0020] As shown in Figure 2, the wire 21 has a longitudinal axis direction p, and has a distal end and a proximal end in the longitudinal axis direction p. The wire 21 may be composed of a single wire from the distal end to the proximal end, or it may be composed of multiple wires connected to each other in the longitudinal axis direction p. The shape of the cross section perpendicular to the longitudinal axis direction p of the wire 21 may be circular, oval, polygonal, or a combination thereof. The shape of the cross section perpendicular to the longitudinal axis direction p of the wire 21 may be the same throughout the entire longitudinal axis direction p of the wire 21, or it may differ depending on the position in the longitudinal axis direction p.

[0021] The outer diameter of the wire 21 is not particularly limited, but may be, for example, 25 μm or more, 30 μm or more, or 35 μm or more, and may be 75 μm or less, or 70 μm or less.

[0022] The outer diameter of the wire 21 may be the same in the longitudinal axis direction p of the wire 21, or it may be different depending on the position in the longitudinal axis direction p of the wire 21. If the cross-section of the wire 21 is not circular, the outer diameter of the wire 21 shall refer to the diameter equivalent to a circle.

[0023] The coil 10 may be a single-layer coil or a multi-layer coil having multiple layers. A portion of the coil 10 in the longitudinal direction x may be a single layer, and the remaining portion may be multi-layer.

[0024] The density of the coil 10, i.e., the winding spacing, is not particularly limited and can be tightly wound, pitched, or a combination of these. The coil 10 may have adjacent wires 21 in contact with each other in the longitudinal direction x. The coil 10 may have adjacent wires 21 in contact with each other in only a part of the longitudinal direction x, or adjacent wires 21 in contact with each other throughout the entire longitudinal direction x. Furthermore, the coil 10 may not have adjacent wires 21 in contact with each other in the longitudinal direction x. The state of not being in contact means that there is a gap between adjacent wires 21 in the longitudinal direction x of the coil 10.

[0025] The outer edge shape of the cross-section perpendicular to the longitudinal direction x of the coil 10 may be circular, oval, polygonal, or a combination thereof. The oval shape includes elliptical, egg-shaped, and rounded rectangular shapes. The same applies in the following description.

[0026] The surface of the coil 10 may have an uneven surface structure if the cross-sections of adjacent wires 21 in the longitudinal direction x of the coil 10 are circular, elliptical, or the like.

[0027] The maximum and minimum outer diameters of the coil 10 are not particularly limited and can be appropriately selected according to the phase of the procedure. For example, they may be 150 μm or more, 180 μm or more, or 200 μm or more, and may also be 400 μm or less, 380 μm or less, or 350 μm or less.

[0028] The outer diameter and / or inner diameter of the coil 10 may be the same size in the longitudinal direction x of the coil 10, or they may be different sizes depending on the position in the longitudinal direction x of the coil 10. If the cross-section of the coil 10 is not circular, the outer diameter of the coil 10 shall refer to the equivalent diameter of a circle. Similarly, if the inner lumen cross-section of the coil 10 is not circular, the inner diameter of the coil 10 shall refer to the equivalent diameter of a circle.

[0029] The coil 10 may have a constant outer diameter in the longitudinal direction x. A constant outer diameter means that the outer diameter of the coil 10 is substantially constant over the entire longitudinal direction x, and includes cases where the change in the outer diameter of the coil 10 over the entire longitudinal direction x is within ±5%.

[0030] As shown in Figures 2 and 3, the retaining device 1 is positioned on the outer circumferential surface 12 of the coil 10 and has a fiber layer 30 containing fibers 40.

[0031] The fiber layer 30 may be arranged on only a part of the outer surface 12 of the coil 10, or it may be arranged on the entire outer surface 12 of the coil 10. The fiber layer 30 may be arranged on the inner surface 13 of the coil 10. The fiber layer 30 may be arranged on only a part of the inner surface 13 of the coil 10, or it may be arranged on the entire inner surface 13 of the coil 10.

[0032] As shown in Figures 2 and 3, it is preferable that the fiber layer 30 has a cylindrical shape arranged along the peripheral wall of the coil 10. As shown in Figure 4, it is preferable that the fiber layer 30 has a cylindrical shape with only one lumen 31. As can be seen from Figure 3, it is preferable that the axis center in the longitudinal direction x of the coil 10 coincides with the axis center in the longitudinal direction of the cylindrical fiber layer 30.

[0033] If the fiber layer 30 has a cylindrical shape, it is preferable that the fiber layer 30 has an outer peripheral surface 32 facing outward from the retaining device 1 and an inner peripheral surface 33 facing outward from the outer peripheral surface 12 of the coil 10. It is preferable that the fiber layer 30 has a distal end 34 and a proximal end 35 in the longitudinal direction x.

[0034] As can be seen from Figures 2 and 3, it is preferable that the inner circumferential surface 33 of the fiber layer 30 is in contact with the outer circumferential surface 12 of the coil 10. It is preferable that no other members are disposed between the coil 10 and the fiber layer 30 in the radial direction y. For example, it is preferable that no drug is applied to the outer circumferential surface 12 of the coil 10 in any form other than the fiber layer 30.

[0035] The fiber layer 30 may consist of a single layer or multiple layers.

[0036] The fiber layer 30 may be fixed to the coil 10. The method of fixation is not particularly limited and can include suturing, bonding, welding, clamping, etc. The fiber layer 30 may be fixed to the coil 10 by a part of the fiber layer 30 being sandwiched between two wires 21 that make up the coil 10. The fiber layer 30 may be fixed by bonding or welding its inner circumferential surface 33 to the outer circumferential surface 12 of the coil 10.

[0037] In the fiber layer 30, the fibers 40 may be wound around the outer surface 12 of the coil 10. That is, in the fiber layer 30, the fibers 40 may be wound around an axis in the longitudinal direction x of the coil 10.

[0038] The coil 10 may have only one fiber layer 30, or it may have multiple fiber layers 30. In the latter case, for example, a first fiber layer may be located at the distal end of the coil 10, and a second fiber layer may be located at the proximal end of the coil 10. It is preferable that the multiple fiber layers 30 are arranged in the longitudinal direction x. The multiple fiber layers 30 may be spaced apart from each other in the longitudinal direction x, or they may be in contact with each other. It is preferable that all of the multiple fiber layers 30 have a cylindrical shape.

[0039] As shown in image 60 in Figure 9, the fiber layer 30 contains fibers 40. Generally, fibers are thin, thread-like substances, but in this specification, fibers 40 refer to those with an average fiber diameter of 100 μm or less, and those with an average fiber diameter exceeding 100 μm are excluded. The average fiber diameter of fibers 40 can be measured by the following method: Obtain an image of the fibers at a magnification of 1000x using a scanning electron microscope or laser microscope (for example, a scanning transmission electron microscope (STEM-EDX / EELS) HD-2700 manufactured by Hitachi High-Technologies Corporation). The arithmetic mean of the diameters of at least 20 fibers measured in the obtained image is taken as the average fiber diameter of fibers 40. When measuring the fiber diameter, if the cross-sectional shape of the fiber is not circular, the average of the diameters of the circumcircle and incircle of the irregular cross-section is taken as the fiber diameter.

[0040] As shown in FIGS. 7 to 8, in the indwelling device 1, since the fiber layer 30 contains the fibers 40 containing the polymer material 41 and the drug 42, compared with the case where the drug is applied to the coil surface, it is possible to prevent the drug from falling off the coil at an early stage of the procedure and to enhance the drug sustained release property.

[0041] As the fiber layer 30, a sheet-like or tubular fiber aggregate composed of the fibers 40 can be used. The fiber aggregate may be a knitted fabric, a woven fabric, a non-woven fabric, etc. formed of the fibers 40, and the non-woven fabric may be a dry non-woven fabric or a wet non-woven fabric. In the fiber aggregate, the fibers 40 may be joined physically, chemically or mechanically. In the fiber layer 30, the fibers 40 may be joined by being intertwined with each other, or may be joined by heat fusion.

[0042] The fiber layer 30 can be composed of one or a plurality of fibers 40. The fiber 40 may be composed of a fiber bundle of a plurality of fibers. The form of the fiber bundle is not particularly limited, and it may be twisted, untwisted or non-twisted. The number of fibers in the fiber bundle may be, for example, 2 or more and 10 or less.

[0043] The fiber layer 30 may be composed of one type of fiber 40. For example, the fiber layer 30 may be composed only of fibers containing a biodegradable polymer material and a drug, or may be composed only of fibers containing a non-biodegradable polymer material and a drug.

[0044] The fiber layer 30 may be composed of a plurality of types of fibers 40. For example, the fiber layer 30 may be composed of a first fiber containing a biodegradable polymer material and a drug, and a second fiber containing a non-biodegradable polymer material and a drug.

[0045] The fiber 40 may be a hollow fiber, but is preferably a solid fiber. The fiber 40 may or may not have crimps. The fiber having crimps refers to, for example, a solid and spiral-shaped three-dimensional crimp structure fiber.

[0046] A single fiber 40 may have a straight shape extending straight, or may have a shape branched in the middle as shown in FIG. 10.

[0047] The fiber layer 30 may extend in the radial direction y. For example, as the coil 10 expands, the fiber layer 30 may extend in the radial direction y.

[0048] The average fiber diameter of the fiber 40 is preferably 3.0 μm or more. When the average fiber diameter is 3.0 μm or more, the surface area per unit volume of the fiber can be made an appropriate size, so that the drug contained in the fiber is likely to be released at an appropriate rate. The average fiber diameter of the fiber 40 only needs to be 3.0 μm or more, preferably 4.0 μm or more, and more preferably 5.0 μm or more. The average fiber diameter of the fiber 40 can be measured by the method described above.

[0049] The average fiber diameter of the fiber 40 is preferably 10 μm or less. When the average fiber diameter is 10 μm or less, it is possible to prevent the surface area per unit volume of the fiber from becoming excessively small, and it becomes easier to release the drug contained in the fiber at an appropriate rate. The average fiber diameter of the fiber 40 is more preferably 9.0 μm or less, and even more preferably 8.0 μm or less.

[0050] The fiber layer 30 is preferably disposed at the proximal portion 10P and the distal portion 10D of the coil 10. The proximal portion 10P and the distal portion 10D of the coil 10 are the proximal side portion and the distal side portion when the length of the coil 10 is bisected in the longitudinal direction x of the coil 10, respectively. When the fiber layer 30 is disposed at the proximal portion 10P and the distal portion 10D of the coil 10, the average fiber diameter of the fiber layer 30 disposed at the proximal portion 10P of the coil 10 is preferably smaller than the average fiber diameter of the fiber layer 30 disposed at the distal portion 10D of the coil 10. Thereby, in the proximal portion 10P of the coil 10, the drug contained in the fiber is more likely to be released earlier than in the distal portion 10D.

[0051] The average fiber diameter of the fiber layer 30 disposed at the proximal portion 10P of the coil 10 may be 0.1 times or more, 0.2 times or more, 0.3 times or more of the average fiber diameter of the fiber layer 30 disposed at the distal portion 10D of the coil 10, and may be 0.9 times or less, 0.8 times or less, 0.7 times or less.

[0052] Preferably, the average fiber diameter of the fiber layer 30 decreases from the distal end to the proximal end of the coil 10. The average fiber diameter of the fiber layer 30 may decrease in steps or gradually from the distal end to the proximal end of the coil 10.

[0053] As shown in Figure 4, when the coil 10 is viewed from a direction perpendicular to the longitudinal direction x, the fiber layer 30 exists within a circular virtual region 70 centered on the centroid C of the coil 10, with a diameter D2 that is 1.1 times the outer diameter D1 of the coil 10, and does not exist outside the virtual region 70. In Figure 4, the outer edge of the virtual region 70 is shown by a dashed line. By setting the thickness of the fiber layer 30 within the above range, the ease of inserting the coil 10 into the body can be improved. The virtual region 70 has a perfect circle shape. The outer diameter of the coil 10 refers to the diameter equivalent to a circle when the shape of the coil 10 in a cross-section perpendicular to the longitudinal direction x of the coil 10 is not circular, as described above. Furthermore, the outer diameter of the coil 10 used to define the virtual region 70 is the maximum outer diameter of the coil 10.

[0054] Whether or not the fiber layer 30 is located within the virtual region 70 can be determined by acquiring an image of the coil 10 on which the fiber layer 30 is located, viewed from the longitudinal direction x, and superimposing the virtual region 70 onto the image. The image can be acquired using a microscope (digital microscope) (Keyence Corporation, model number VHX-X1).

[0055] Preferably, the fiber layer 30 exists within the virtual region 70 along the entire longitudinal direction x of the coil 10, and does not exist outside the virtual region 70. This further enhances the ease of inserting the coil 10 into the body.

[0056] Preferably, the thickness of the fiber layer 30 decreases from the distal end to the proximal end of the coil 10. The thickness of the fiber layer 30 may decrease in stages from the distal end to the proximal end of the coil 10, or it may decrease gradually.

[0057] The thickness of the fiber layer 30 located at the proximal portion 10P of the coil 10 is preferably thinner than the thickness of the fiber layer 30 located at the distal portion 10D of the coil 10. The thickness of the fiber layer 30 located at the proximal portion 10P of the coil 10 is preferably 1 / 2 or less, more preferably 1 / 3 or less, and even more preferably 1 / 4 or less, of the thickness of the fiber layer 30 located at the distal portion 10D of the coil 10. The mass per unit length of the fiber layer 30 located at the proximal portion 10P of the coil 10 may be 1 / 50 or more, 1 / 30 or more, or 1 / 10 or more of the mass per unit length of the fiber layer 30 located at the distal portion 10D of the coil 10. With such an amount of fiber layer 30, the flexibility of the coil 10 is maintained even when applied to the proximal portion 10P of the coil 10, so that the coil 10 can be placed in the knot while ensuring maneuverability.

[0058] (Method 1 for measuring the thickness of the fiber layer: Method for measuring the total thickness of the fiber layer) Under standard conditions (temperature 23±2℃, relative humidity 50±5%), the coil 10 with the fiber layer 30 attached is cut along the radial direction y using 1 cm precision nippers (ESD Corporation, model EA535TA-13) to obtain three test pieces with a length of 1 cm in the longitudinal direction x of the coil 10, from the portion including the center of the longitudinal direction x of the fiber layer 30, the distal end of the longitudinal direction x of the fiber layer 30, and the proximal end of the fiber layer 30. Hereinafter, these test pieces will be referred to as A1, A2, and A3. The distal cross-section of each test piece is observed with a microscope (digital microscope) (Keyence Corporation, model VHX-X1), and the average thickness of the fiber layer 30 at each cross-section is measured. The average thickness is obtained by measuring the thickness of the fiber layer 30 at equally spaced points in the circumferential direction of the coil 10 and calculating the average value of these thicknesses. Equally spaced points can be, for example, 12 points within the 360° circumferential z direction of the coil 10, each 30° apart. For example, the average thickness of the distal cross-section of test specimen A1 can be the average of the thicknesses of the fiber layer 30 at 12 equally spaced points in the circumferential direction on the distal cross-section of test specimen A1. The average of the average thicknesses of test specimens A1 to A3 can be used as the thickness T of the fiber layer 30 of the coil 10.

[0059] (Method 2 for measuring the thickness of the fiber layer: Method for measuring the thickness of the proximal and distal parts of the fiber layer) Under standard conditions (temperature 23±2℃, relative humidity 50±5%), the coil 10 with the fiber layer 30 attached is cut along the radial direction y using 1 cm precision nippers (ESD Corporation, model EA535TA-13) to obtain three test pieces each from the proximal part 10P and the distal part 10D of the coil 10, with a length of 1 cm in the longitudinal direction x of the coil 10. Here, the test pieces obtained from the proximal part 10P of the coil 10 are described as B1, B2, and B3, and the test pieces obtained from the distal part 10D of the coil 10 are described as C1, C2, and C3. The distal cross-section of each test piece is observed with a microscope (digital microscope) (Keyence Corporation, model VHX-X1), and the average thickness of the fiber layer 30 in each cross-section is measured. The average thickness is obtained by measuring the thickness of the fiber layer 30 at equally spaced points in the circumferential direction of the coil 10 and calculating the average value of these thicknesses. The equally spaced points can be, for example, 12 points that are 30° apart within the 360° circumferential direction z of the coil 10. For example, the average thickness of the distal cross-section of test piece B1 can be the average value of the thickness of the fiber layer 30 at 12 equally spaced points in the circumferential direction on the distal cross-section of test piece B1. The average of the average thicknesses of test pieces B1 to B3 can be taken as the thickness Tp of the fiber layer 30 located in the proximal part 10P of the coil 10, and the average of the average thicknesses of test pieces C1 to C3 can be taken as the thickness Td of the fiber layer 30 located in the distal part 10D of the coil 10.

[0060] The thickness of the fiber layer 30 is not particularly limited, but may be, for example, 1 μm or more, 5 μm or more, 10 μm or more, or 100 μm or less, 50 μm or less, or 20 μm or less. A fiber layer thickness of 1 μm or more makes it easier to hold the amount of drug necessary for treatment. Also, a fiber layer thickness of 100 μm or less ensures that the flexibility of the coil 10 is maintained even when the fiber layer 30 is placed on the proximal part 10P of the coil 10, so that the coil 10 can be placed in the aneurysm while ensuring maneuverability.

[0061] The average fiber length of the fiber 40 may be, for example, 100 mm or more, 200 mm or more, 300 mm or more, or 1300 mm or less, 1200 mm or less, 1100 mm or less, or 1000 mm or less.

[0062] (Method for measuring the average fiber length of a fiber) Ten single fibers are taken from the fiber layer 30. Each fiber is straightened without stretching, and its fiber length (mm) is measured on a measuring scale. The average of the measured lengths of the ten fibers is taken as the average fiber length of fiber 40. If the number of fibers constituting the fiber layer is less than ten, the fiber length of all the fibers constituting the fiber layer is measured, and the average of the measured lengths of the multiple fibers is taken as the average fiber length of fiber 40. If the number of fibers constituting the fiber layer is one, the fiber length of that one fiber is taken as the average fiber length of fiber 40. As shown in Figure 10, if the fiber 61 to be measured has a branching portion 64, and for example the branching portion 64 has a first branch 61a and a second branch 61b, the longer of the first branch 61a and the second branch 61b (the first branch 61a in Figure 10) is used to calculate the fiber length.

[0063] The fibers 40 can be formed using, for example, electrospinning, melt spinning, wet spinning, or dry spinning, and among these, it is preferable to form them using electrospinning. When forming the fiber layer 30 by electrospinning, a coil 10 is used as a collector in the electrospinning system, and the fibers 40 can be wound around the outer surface of the coil 10 by spinning while rotating the coil 10.

[0064] Preferably, the fiber layer 30 does not contain any materials other than the fibers 40, such as thread-like materials with an average fiber diameter of more than 100 μm, resin wires, metal wires, etc.

[0065] Preferably, the fiber layer 30 is composed only of fibers 40 containing a polymer material 41 and a drug 42.

[0066] The polymer contained in the polymer material 41 may be a synthetic polymer or a natural polymer. The polymer material 41 also includes resins.

[0067] The polymer material 41 contained in the fiber 40 is preferably a biodegradable polymer material. As the biodegradable material decomposes, the surface area of ​​the fiber 40 tends to increase, making it easier to release the drug 42 contained in the fiber 40. In this specification, a biodegradable polymer material refers to a material that has the property of being hydrolyzed in the body environment and, after decomposition, becomes a non-toxic low-molecular-weight substance that is metabolized.

[0068] The polymers contained in biodegradable polymer materials may be synthetic polymers or natural polymers, but synthetic polymers are preferred. Biodegradable polymer materials also include biodegradable resins. Examples of biodegradable polymer materials include polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), glycolic acid-lactide copolymer (PLGA), glycolic acid-ε-caprolactone copolymer, lactide-ε-caprolactone copolymer, glycolic acid-lactide-ε-caprolactone copolymer, poly(p-dioxanone) (PDO), poly(2-oxetanone), polymalic acid, polyhydroxyalkanoic acid (PHA), polyhydroxybutyrate (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHH Examples of these substances include, but are not limited to, BV, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBH), starches (carboxymethyl starch, dialdehyde starch), celluloses (CMC, MC, HEC, HPC), proteins (collagen, gelatin, glue, mixture of collagen and elastin), polysaccharides (glycosaminoglycans, chitin, chitosan, hyaluronic acid), gums (acacia gum, guar gum, tragacanth gum), fibroin, laminin, casein, polypeptides, tannins, lignin, alginic acid, etc. These may be used individually or in combination of two or more.

[0069] The polymer material 41 contained in the fiber 40 may be a non-biodegradable polymer material. This makes it less likely to decompose compared to the case of a biodegradable material, thus delaying the release timing of the drug 42 contained in the fiber 40. In this specification, a non-biodegradable polymer material refers to a material other than a biodegradable polymer material that is resistant to hydrolysis in the internal environment of the body.

[0070] The polymers contained in non-biodegradable polymer materials may be synthetic polymers or natural polymers, but synthetic polymers are preferred. Non-biodegradable polymer materials also include non-biodegradable resins. Examples of non-biodegradable polymer materials include, but are not limited to, vinyl acetate such as ethylene vinyl acetate, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, polyamides such as nylon, fluorine such as polyvinylidene fluoride and polytetrafluoroethylene, vinyl chloride such as acrylic and polyvinyl chloride, polycarbonate, epoxy, polyurethanes such as polyurethane elastomers, polyacrylonitrile, keratin, and silk fibroin. These may be used individually or in combination of two or more.

[0071] In addition to the materials described above, the polymer material 41 may also contain various additives such as plasticizers, pigments, flame retardants, antistatic agents, lubricants, softeners, surfactants, and antibacterial agents.

[0072] The drug 42 contained in the fiber 40 may be the active ingredient (API) alone, or it may be a mixture with other additives. Preferred additives include base materials, plasticizers, stabilizers, surfactants, and the like.

[0073] The type of drug 42 contained in the fiber 40 is not particularly limited as long as it is necessary for the prevention or treatment of the affected area. Preferably, the drug 42 has at least one of the following effects: anti-inflammatory effect, antioxidant effect, antihypertensive effect, vasoconstriction inhibitory effect, anticoagulant effect, and shear stress sensing inhibitory effect, and more preferably, it has at least one of the following effects: anti-inflammatory effect, antioxidant effect, antihypertensive effect, and vasoconstriction inhibitory effect. Examples of drugs include selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, etc.), DPP-4 inhibitors (sitagliptin, linagliptin, alogliptin, etc.), HMG-CoA reductase inhibitors (atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin, fluvastatin, lovastatin, mevastatin, cerivastatin, etc.), nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, naproxen, celecoxib, etc.), angiotensin II receptor blockers (ARBs) (losartan, valsartan, telmisartan, etc.), tocopherol acetate (vitamin E acetate, eviprostat, estrol, etc.), ascorbic acid (Asconal, Cinal, Cefylol), and edaravone (Radicut, Free Radical Scavenger). Examples include anticoagulants (such as Jar), ​​N-acetyl-L-cysteine ​​(NAC), calcium channel blockers (such as amlodipine, nifedipine, and diltiazem), diuretics (such as furosemide, trichlormethiazide, and spironolactone), angiotensin-converting enzyme inhibitors (ACEs) (such as enalapril, lisinopril, and perindopril), beta-blockers (such as metoprolol, atenolol, and bisoprolol), alpha-blockers (such as prazosin, terazosin, and doxazosin), alpha-beta-blockers (such as carvedilol, labetalol, and butoxamine), nitrates (such as nitroglycerin and isosorbide dinitrate), prostacyclin analogs (such as epoprostenol and treprostinil), anticoagulants (such as heparin, heparin derivatives, warfarin, antithrombin drugs such as dabigatran, and rivaroxaban), and antiplatelet agents (such as aspirin, clopidogrel, and ticagrelor).

[0074] The drug 42 may be encapsulated in a capsule. The size of the capsule is preferably 10 nm or larger, more preferably 50 nm or larger, even more preferably 100 nm or larger, and also preferably 500 nm or smaller, more preferably 400 nm or smaller, and even more preferably 200 nm or smaller. The capsule is preferably made of a biodegradable material. As the biodegradable material, bioabsorbable polymers, natural polymers, decellularized biological tissues or cells, or combinations thereof can be used. As bioabsorbable polymers, at least one of polylactic acid (PLA), poly-L-lactic acid (PLLA), polyglycolic acid (PGA), copolymer of lactic acid and glycolic acid (PLGA), polycaprolactone (PCL), and polydioxanone (PDS) is preferably used. As natural polymers, at least one of collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptide is preferably used.

[0075] The fiber layer 30 may contain biodegradable materials other than the polymer material 41. Examples of such materials include biodegradable alloys such as magnesium alloys and iron-manganese alloys. A portion of the fiber 40 may be composed of a biodegradable alloy.

[0076] The fiber 40 may contain an X-ray opaque material. For example, the X-ray opaque material may be coated on the surface of the fiber 40, embedded within the fiber 40, or retained within the fiber 40. Examples of X-ray opaque materials include lead, barium, iodine, tungsten, gold, silver, platinum, iridium, platinum-iridium alloy, stainless steel, titanium, cobalt-chromium alloy, palladium, tantalum, and the like.

[0077] In addition to the materials mentioned above, the fiber 40 may also contain various additives such as plasticizers, pigments, flame retardants, antistatic agents, lubricants, softeners, and surfactants.

[0078] As shown in Figure 6, the indwelling device 1 may have a coating 38 applied to the outer circumferential surface 32 of the fiber layer 30. The coating 38 suppresses the outward protrusion of the fibers 40 of the fiber layer 30 in the radial direction y. Furthermore, the coating 38 suppresses the delivery sliding load within the catheter used for transporting the indwelling device, enabling smooth placement of the coil.

[0079] As shown in Figure 6, when viewing the coil 10 from a direction perpendicular to the longitudinal direction x, it is preferable that the fiber layer 30 and the coating 38 exist within a circular virtual region 70 centered on the centroid C of the coil 10, with a diameter D2 that is 1.1 times the outer diameter D1 of the coil 10, and do not exist outside the virtual region 70.

[0080] A portion of the coating 38 may be impregnated into the interfiber gaps of the fiber layer 30.

[0081] In a cross-section perpendicular to the longitudinal direction x of the coil 10, it is preferable that the average thickness of the coating 38 is smaller than the average thickness of the fiber layer 30.

[0082] As the constituent material of the coating 38, the material described as the polymer material 41 which is preferably included in the fiber 40 can be used.

[0083] The coating can be hydrophilic or hydrophobic depending on the purpose. The coating can be applied by immersing the fiber layer 30 in a hydrophilic or hydrophobic coating agent, applying a hydrophilic or hydrophobic coating agent to the outer surface 32 of the fiber layer 30, or covering the outer surface 32 of the fiber layer 30 with a hydrophilic or hydrophobic coating agent. The coating agent may contain chemicals or additives.

[0084] As shown in Figure 7, it is preferable that the polymer material 41 and the drug 42 are mixed in the fiber 40. The drug 42 may be dispersed in the polymer material 41 in the fiber 40. The drug 42 may be uniformly dispersed in the polymer material 41 or dispersed locally. The drug 42 may be dispersed in the polymer material 41 in particulate form. The drug 42 may be exposed on the surface of the fiber 40 or may be present only inside the fiber 40. In the fiber 40, the polymer material 41 may function as a matrix. In the fiber 40, the drug 42 may be dissolved in the polymer material 41.

[0085] The fiber 40 shown in Figure 7 can be produced, for example, by mixing (preferably kneading) a polymer material and a chemical agent. For production, a spinning system equipped with an extruder and a spinneret may be used, for example. The polymer material and chemical agent are mixed (preferably kneaded) in the extruder, the mixture is melted, and the mixture is extruded from the spinneret to produce the fiber.

[0086] In the fiber 40, the mixing ratio of polymer material 41 to drug 42 is preferably 1 / 1 or more by mass, more preferably 2 / 1 or more, even more preferably 3 / 1 or more, and also preferably 100 / 1 or less, more preferably 80 / 1 or less, and even more preferably 50 / 1 or less.

[0087] In the fiber 40, the content of the polymer material 41 is preferably 20 wt% or more, more preferably 30 wt% or more, even more preferably 40 wt% or more, preferably 80 wt% or less, more preferably 70 wt% or less, and even more preferably 60 wt% or less.

[0088] In the fiber 40, the content of the agent 42 is preferably 20 wt% or more, more preferably 30 wt% or more, even more preferably 40 wt% or more, preferably 80 wt% or less, more preferably 70 wt% or less, and even more preferably 60 wt% or less.

[0089] In the fiber 40, when the drug 42 is dispersed in particulate form within the polymer material 41, the particle size is not particularly limited, but may be, for example, 10.0 nm or larger, 50.0 nm or larger, 100 nm or larger, or 200 nm or larger. Alternatively, the particle size may be 5.00 μm or smaller, 4.00 μm or smaller, 3.00 μm or smaller, 2.00 μm or smaller, or 1.00 μm or smaller. Having the particle size within the above range makes it easier to uniformly disperse the particulate drug 42 in the polymer material 41, and also facilitates the manufacture of the fiber 40. Here, "particle size" refers to the volume-average particle size (D50) at the median 50% diameter in the particle size distribution obtained by dynamic light scattering or the like. Commercially available particulate drugs may be used, in which case the particle size listed in the catalog can be adopted.

[0090] The fiber 40 may be a composite fiber having a core-sheath structure, a side-by-side structure, or a sea-island structure. The core-sheath structure includes a concentric core-sheath structure and an eccentric core-sheath structure. In order to slow down the release rate of the drug 42 from the fiber 40, it is preferable that the drug 42 is encapsulated in the polymer material 41 in the fiber 40. Encapsulating the drug 42 in the polymer material 41 means that the drug 42 is covered by the polymer material 41 and is not exposed to the outside. By covering the drug 42 with the polymer material 41, the occurrence of an initial burst of the drug 42 can be suppressed and the release rate of the drug 42 can be easily controlled.

[0091] As shown in Figure 8, the fiber 40 preferably includes a core-sheath type fiber having a core portion 44 and a sheath portion 45, and more preferably consists of a core-sheath type fiber. In that case, it is preferable that the core portion 44 contains the drug 42 and the sheath portion 45 contains a polymer material 41. By using a composite fiber of this shape, it becomes easier to suppress the occurrence of an initial burst of the drug 42 and to control the release rate of the drug 42.

[0092] If the fiber 40 is a core-sheath type fiber having a core portion 44 and a sheath portion 45, and the fiber 40 is branched into a first branch portion and a second branch portion, then in the first branch portion and / or the second branch portion, the core portion 44 may be exposed without being covered by the sheath portion 45.

[0093] In the core portion 44, the content of the polymer material 41 is preferably 20 wt% or less, more preferably 10 wt% or less, even more preferably 5 wt% or less, and it is even more preferable that the core portion 44 does not contain the polymer material 41.

[0094] In the sheath portion 45, the content of the drug 42 is preferably 20 wt% or less, more preferably 10 wt% or less, even more preferably 5 wt% or less, and it is even more preferable that the sheath portion 45 does not contain the drug 42.

[0095] The fiber layer 30 is preferably composed of one or more core-sheath type fibers.

[0096] To facilitate control of the release rate of the active ingredient in the drug, a concentric core sheath type structure is preferred for the composite fiber.

[0097] The core-sheath type fiber contained in fiber 40 can be manufactured in the same manner as general core-sheath type fibers. For manufacturing, for example, an electrospinning system equipped with a spinneret and collector having a multi-tube shape may be used. Preferably, the core material supplied to the system contains a drug 42, and the sheath material contains a polymer material 41. The core material may contain a solvent that is soluble in the drug 42. The sheath material may also contain a solvent that is soluble in the polymer material 41. The solvent is not particularly limited as long as it can dissolve the polymer material 41 and / or the drug 42 and can be sprayed from the spinneret. Examples of solvents include water, N,N-dimethylformamide (DMF), ethanol, acetone, tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, toluene, and the like.

[0098] The cross-section of the fiber 40 is the cross-section perpendicular to the longitudinal axis of the fiber 40, and is sometimes called the fiber cross-section. The cross-sectional shape of the fiber 40 may refer to the outline shape of the outer perimeter of the cross-sectional figure perpendicular to the longitudinal axis of the fiber 40, or it may refer to the shape of the cross-sectional figure perpendicular to the longitudinal axis of the fiber 40 itself. The outer outline is composed of one or more sides. The outer outline may have only straight sections, only curved sections, or both straight and curved sections, but it is preferable that it has only curved sections.

[0099] The fiber 40 may have a hollow cross-section or a solid cross-section. If the fiber 40 has a hollow cross-section, that is, if the fiber 40 is a hollow fiber, the fiber 40 may have one or more lumens extending in the longitudinal direction of the fiber 40. The multiple lumens of the fiber may be arranged at equal intervals or uneven intervals in the circumferential direction of the fiber 40. Furthermore, the multiple lumens of the fiber may have the same or different cross-sectional areas.

[0100] The fiber 40 may have a circular cross-section or an irregular cross-section. An irregular shape is a shape other than a perfect circle. The type of cross-sectional shape of the fiber 40 is not particularly limited and can be, for example, a circular shape; an elliptical shape, an egg shape, an oblong shape such as a rounded rectangle; a polygonal shape such as a triangle or a square; an alphabet shape such as a Y shape or a W shape; an asterisk shape or a fin shape with multiple protrusions extending radially; a multilobe shape such as a flower shape or a multi-leaf shape; or a combination of these; or an irregular shape. A multilobe shape is a shape in which multiple protrusions and recesses are arranged alternately. Polygonal shapes include polygonal shapes with rounded corners and trapezoidal shapes.

[0101] The cross-sectional shape of the fiber 40 may be flattened or non-flattened. A flattened shape is a shape that is flat and has a difference between the length in one direction of the cross-section perpendicular to the longitudinal axis and the length in another direction perpendicular to that direction. More specifically, a cross-sectional figure has a flattened shape if the flatness (aspect ratio), which is the value obtained by dividing the length of the major axis of the cross-section perpendicular to the longitudinal axis of the fiber 40 by the length of the minor axis, is greater than 1, and a cross-sectional figure has a non-flattened shape if the flatness is 1.

[0102] If the fiber 40 has a flattened cross-section, the degree of flatness should be greater than 1.0, preferably 1.2 or more, more preferably 1.5 or more, even more preferably 2.0 or more, and also preferably 10 or less, more preferably 8.0 or less, and even more preferably 5.0 or less.

[0103] The biodegradable material contained in the fibers 40 of the proximal portion 10P and the distal portion 10D may be the same type. In that case, it is preferable that the mass of the biodegradable material per unit length of coil contained in the fibers 40 of the proximal portion 10P is greater than the mass of the biodegradable material per unit length of coil contained in the fibers 40 of the distal portion 10D. This makes it easier to change the rate of drug release from the fiber layer 30 between the distal portion 10D and the proximal portion 10P, as the decomposition rate of the fibers 40 of the proximal portion 10P tends to be relatively higher than that of the distal portion 10D.

[0104] The non-biodegradable material contained in the fibers 40 of the proximal portion 10P and the distal portion 10D may be the same type. In that case, it is preferable that the mass of the non-biodegradable material per unit length of coil contained in the fibers 40 of the proximal portion 10P is less than the mass of the non-biodegradable material per unit length of coil contained in the fibers 40 of the distal portion 10D. This makes it easier to change the rate of drug release from the fiber layer 30 between the distal portion 10D and the proximal portion 10P, as the decomposition rate of the fibers 40 of the proximal portion 10P tends to be relatively higher than that of the distal portion 10D.

[0105] As shown in Figure 11, the coil 10 is constructed by winding a long wire 21, and it is preferable that the fibers 40 contained in the fiber layer 30 extend in the longitudinal axis direction p of the wire 21. More specifically, an image 60 of the coil 10 viewed from the side is obtained, as shown in Figures 9 and 11, and the extension direction m of 20 target fibers 61 selected in the image 60 is measured. It is preferable that 60% or more of the total 20 target fibers 61, i.e., 12 or more, are within a range of ±5° with respect to the longitudinal axis direction p of the wire 21. As a result, many fibers 40 extend along the longitudinal axis direction p, and the fibers 40 can easily enter the lumen 11 of the coil 10 by passing between adjacent wires 21 in the longitudinal direction x of the coil 10. The entry of fibers 40 into the lumen 11 can improve the sustained release of the drug 42. In addition, since the fibers 40 can easily follow the longitudinal axis direction p of the wire 21, it is easier to obtain a rigid coil 10. Furthermore, when we say that coil 10 is stiff, we mean that coil 10 has high bending rigidity.

[0106] The extension direction m of a total of 20 target fibers 61 in image 60 can be measured by the method described in steps S1 to S3 below.

[0107] (Step S1: Acquisition of evaluation image) An image 60 of the coil 10 viewed from the side is acquired, as shown in Figure 9. The image 60 is obtained by photographing the fiber layer 30 at a magnification of 1000x from a direction perpendicular to the longitudinal direction x of the coil 10 using a scanning electron microscope or laser microscope (for example, a scanning transmission electron microscope (STEM-EDX / EELS) HD-2700 manufactured by Hitachi High-Technologies Corporation). An example of the acquired image 60 is shown in Figure 8. The length of the image 60 in the vertical direction (parallel to the radial direction y) and the length of the image 60 in the horizontal direction (parallel to the longitudinal direction x) are made to be the same size. The size of the image 60 may be, for example, 100 μm vertically and 100 μm horizontally. If the size in the vertical and horizontal directions are different, the image 60 is cropped.

[0108] Image 60 may be an image of any part of the fiber layer 30. For example, Image 60 may be an image of the distal part of the fiber layer 30, or an image of the proximal part of the fiber layer 30, but it is preferable that the image passes through the central position 14 in the longitudinal direction x of the fiber layer 30 (see Figure 3), and it is more preferable that the lateral center position of Image 60 coincides with the central position 14 in the longitudinal direction x of the fiber layer 30.

[0109] (Step S2: Selection of Fibers to be Measured) The 20 fibers in image 60 are designated as the fibers to be measured 61. As shown in Figure 8, the extension direction m of the fibers to be measured 61 is defined by the extension direction of the line segment (straight line) connecting the start point 62 and the end point 63 of the fibers to be measured 61. The 20 fibers to be measured 61 are selected in order from the longest to the shortest in image 60. The fibers to be measured 61 only need to have their start point 62 and end point 63 visible in image 60, and in parts not shown in image 60, the start point 62 or end point 63 may be connected to other fibers, or the fiber may branch midway. If the fiber branches midway, the start point 62 and end point 63 may be defined using the branch with the longest fiber length among the multiple branches formed by the branching. For example, the fiber 61 shown in Figure 10 has a branching portion 64, which has a first branch 61a and a second branch 61b, with the first branch 61a being longer than the second branch 61b. Therefore, in the fiber 61 shown in Figure 10, the length of the starting point 62, the ending point 63, and the line segment connecting them are defined using the first branch 61a, which is longer than the second branch 61b.

[0110] (Step S3: Measurement of angle θ) For each of the 20 fibers 61 to be measured, the relative angle θ of the direction of extension m of the fiber 61 to be measured is measured with respect to the direction p1 parallel to the longitudinal axis p of the wire 21.

[0111] The gap between adjacent wires 21 in the longitudinal direction x may be an extremely narrow gap relative to the outer diameter of the wire 21, for example, 1 nm to 100 μm. Preferably, the gap between the wires 21 is narrow enough for the fibers 40 to pass through.

[0112] As shown in Figures 2 to 3, it is preferable that the fiber layer 30 is arranged over the entire length x of the coil 10. Since the flexibility of the coil 10 tends to decrease when the fiber layer 30 is provided, the fiber layer 30 may be arranged only in a part of the length x of the coil 10, as shown in Figures 12 to 16. For example, the fiber layer 30 may be arranged in a section of 30% or more of the total length x of the coil 10, or in a section of 40% or more of the total length, or in a section of 50% or more of the total length. Alternatively, the fiber layer 30 may be arranged in a section of 90% or less of the total length x of the coil 10, or in a section of 80% or less of the total length, or in a section of 70% or less of the total length.

[0113] The length of the fiber layer 30 in the longitudinal direction x is preferably the same as or shorter than the length of the coil 10 in the longitudinal direction x. It is preferable that the fiber layer 30 is not located distal to the distal end of the coil 10. Furthermore, it is preferable that the fiber layer 30 is not located proximal to the proximal end of the coil 10.

[0114] As shown in Figures 2 and 3, the entire length x of the coil 10 is covered by the fiber layer 30, and the wire 21 does not need to be exposed.

[0115] As shown in Figure 12, the fiber layer 30 is located only in the distal portion 10D of the coil 10 and does not need to be located in the proximal portion 10P of the coil 10. As shown in Figure 13, the fiber layer 30 is located only in the proximal portion 10P of the coil 10 and does not need to be located in the distal portion 10D of the coil 10.

[0116] As shown in Figure 14, when the length of the coil 10 is divided into three equal parts in the longitudinal direction x of the coil 10 into a distal section 10A, a central section 10B, and a proximal section 10C, the fiber layer 30 may be located only in the central section 10B, or as shown in Figure 15, it may be located in the distal section 10A and the central section 10B but not in the proximal section 10C, or, although not shown, it may be located in the proximal section 10C and the central section 10B but not in the distal section 10A.

[0117] As shown in Figure 16, it is preferable that the fiber layer 30 is not provided at the distal end of the coil 10. For example, when the wire 21 that is not covered by the tip 25 of the coil 10 and is at the farthest end is counted as the first turn from the distal side of the coil 10, it is preferable that the fiber layer 30 is located proximal to the third turn of the coil 10, more preferably proximal to the fifth turn of the coil 10, and even more preferably proximal to the tenth turn of the coil 10. By not providing the fiber layer 30 at the distal end of the coil 10, the outer surface 12 of the coil 10 is more easily exposed at the distal end, which makes it easier for the coil 10 to firmly engage with other parts of the coil and other coils when placed in the knot, making it easier to form a framework.

[0118] As shown in Figure 16, it is preferable that the fiber layer 30 is not provided at the proximal end of the coil 10. For example, when the wire 21 that is not covered by the base tip 26 and is at the nearest end of the coil 10 is counted as the first turn from the proximal side of the coil 10, it is preferable that the fiber layer 30 is located distal to the third turn of the coil 10, more preferably distal to the fifth turn of the coil 10, and even more preferably distal to the tenth turn of the coil 10. By not providing the fiber layer 30 at the proximal end of the coil 10, the outer surface 12 of the coil 10 is more easily exposed at the proximal end, which helps to prevent a decrease in the flexibility of the coil 10.

[0119] As shown in Figure 16, it is preferable that the fiber layer 30 is arranged only in the portion of the coil 10 excluding the distal and proximal ends.

[0120] Although not shown in the diagram, the fiber layer 30 may not be provided at the distal end of the coil 10, nor at the proximal portion 10P of the coil 10, and the fiber layer 30 may be provided only in the portion of the coil 10 excluding the distal end and the proximal portion 10P. This makes it easier to engage the distal end of the coil 10 with other members while preventing a decrease in flexibility at the proximal portion 10P of the coil 10.

[0121] When the coil has a longitudinal direction x, as shown in Figures 17 to 18, it is preferable that the fibers 40 are sandwiched between two adjacent wires 21 in the longitudinal direction x when the coil 10 is viewed from a direction perpendicular to the longitudinal direction x. Because the fibers 40 are sandwiched between the wires 21, the drug 42 is less likely to be released from the fibers 40 in the sandwiched portion, thereby improving the sustained release of the drug.

[0122] As shown in Figures 17 and 18, if there is a gap 22 between adjacent wires 21 in the longitudinal direction x, some of the fibers of the fiber layer 30 may be placed in the gap 22. Here, the gap 22 is defined as having a length in the longitudinal direction x that is 1 / 10 or larger than the outer diameter of the wire 21.

[0123] Although not shown in the diagram, even if there is a gap 22 between adjacent wires 21 in the longitudinal direction x, the fiber layer 30 does not need to be placed in the gap 22.

[0124] As shown in Figure 3, the fiber layer 30 may be arranged only on the radially y-outside of the outermost position of the outer peripheral surface 12 of the coil 10.

[0125] As shown in Figure 19, the fiber layer 30 may be positioned radially y-outward from the innermost position of the outer circumferential surface 12 of the coil 10. That is, if the cross-sections of adjacent wires 21 in the longitudinal direction x of the coil 10 are circular or elliptical, the fiber layer 30 may be positioned in the recesses of the uneven structure provided on the surface of the coil 10.

[0126] As shown in Figures 17 to 19, the fiber layer 30 may be positioned radially y inward from the outermost position of the outer peripheral surface 12 of the coil 10.

[0127] As shown in Figure 18, the fiber layer 30 may be arranged on the inner circumferential surface 13 side of the coil 10. That is, the fibers 40 of the fiber layer 30 may be located in the lumen 11 of the coil 10. Since the drug 42 is less likely to be released from the fibers 40 located in the lumen 11 compared to the fibers 40 located on the outer circumferential surface 12, the sustained release of the drug can be improved.

[0128] As can be seen from Figure 18, if there is a gap 22 between adjacent wires 21 in the longitudinal direction x, the fiber layer 30 may enter the lumen 11 of the coil 10 through the gap 22.

[0129] The coil 10 shown in Figure 18 may be formed by providing a fiber layer 30 on the outer surface of a wire 21, and then winding the wire 21 with the fiber layer 30 to form a coil shape.

[0130] Although not shown in the diagram, the second agent may be impregnated into the interfiber gaps of the fiber layer 30. This allows the fiber layer 30 to hold a large amount of the agent while preventing an initial burst of the agent. For the composition of the second agent, please refer to the description of agent 42.

[0131] The second agent may be impregnated throughout the entire longitudinal direction x of the fiber layer 30, or it may be impregnated only in a part of the longitudinal direction x of the fiber layer 30.

[0132] When the thickness of the fiber layer 30 is divided into three equal parts in the thickness direction of the fiber layer 30, i.e., in the radial direction y of the coil 10, from the outside to the inside in the radial direction y, it is preferable that the second agent impregnates at least one of the outer part, the central part, and the inner part, more preferably impregnated in the inner part, and even more preferably impregnated in the central part and the inner part but not in the outer part.

[0133] The surface roughness Ra of the outer circumferential surface 12 of the coil 10 may be greater than the surface roughness Ra of the inner circumferential surface 13 of the coil 10. This increases the frictional force acting between the outer circumferential surface 12 of the coil 10 and the inner circumferential surface 33 of the fiber layer 30, making it easier for the fiber layer 30 to adhere tightly to the outer circumferential surface 12 of the coil 10. The surface roughness Ra of the outer circumferential surface 12 and the inner circumferential surface 13 of the coil 10 corresponds to the arithmetic mean roughness Ra specified in JIS B 0601 (2001) and is measured in accordance with JIS B 0633 (2001). For measurement, a measuring instrument specified in JIS B 0651 (2001) (for example, an ultra-precision non-contact three-dimensional measuring device, model: NH-3SP, manufactured by Mitaka Kohki Co., Ltd.) is used. When measuring the calculated mean roughness Ra of a coil 10 that already has the fiber layer 30 installed, the fiber layer 30 can be removed from the coil 10 before measurement. The fibrous layer 30 can be removed by dissolving it in a solvent such as physiological saline.

[0134] When measuring the surface roughness Ra, the wire 21 constituting the coil 10 (primary coil) may be straightened by pulling it while gripping both ends of the wire 21, or the distal end of the wire 21 and a position several centimeters proximal to the distal end (for example, 5 cm proximal to the distal end). The surface roughness of the straightened wire 21 may then be measured in accordance with JIS B 0633 (2001). Similarly, if the coil 10 (primary coil) has been shaped to become a secondary coil, the wire 21 constituting the secondary coil may be straightened by pulling it while gripping both ends of the wire 21, or the distal end of the wire 21 and a position several centimeters proximal to the distal end (for example, 5 cm proximal to the distal end). The surface roughness of the straightened wire 21 may then be measured in accordance with JIS B 0633 (2001). The surface roughness Ra of the outer surface of the coil 10 (primary coil) can be determined by measuring the surface roughness Ra of the portion of the straightened wire 21 that corresponds to the outer surface of the coil 10 (primary coil). Similarly, the surface roughness Ra of the inner surface of the coil 10 (primary coil) can be determined by measuring the surface roughness Ra of the portion of the straightened wire 21 that corresponds to the inner surface of the coil 10 (primary coil). Since the coil 10 is constructed by winding the wire 21, the area of ​​the outer circumference of the straightened wire 21, for example, between 0° and 180°, corresponds to the outer surface of the coil 10, and the area of ​​the outer circumference of the straightened wire 21, for example, between 180° and 360°, corresponds to the inner surface of the coil 10. Therefore, by measuring the surface roughness Ra of the wire 21, the surface roughness Ra of the coil 10 can be measured.

[0135] Although not shown in the figures, in addition to the fiber layer 30, a drug may be placed on the surface of the coil 10. In that case, the drug may be placed on the outer circumferential surface 12 or on the inner circumferential surface 13. The drug placed on the surface of the coil 10 may be held on the surface of the coil 10 as a drug layer. A drug layer may be placed on the outer circumferential surface 12 of the coil 10, and the fiber layer 30 may be placed outside the drug layer in the radial direction y.

[0136] In addition to the fiber layer 30, the agent applied to the coil 10 may be directly attached to the surface of the coil 10, or it may be attached indirectly to the surface of the coil 10 via a bioadhesive. The type of bioadhesive material is not particularly limited, but for example, polysaccharide adhesives such as collagen, chitosan, and gelatin, polyethylene glycol-based hydrogel adhesives, and protein adhesives such as fibrin and collagen can be used.

[0137] If the drug is directly attached to the surface of the coil 10, the drug may be covered by the fiber layer 30 in order to control the rate of drug release.

[0138] In addition to the fiber layer 30, the drug applied to the coil 10 is preferably encapsulated. The drug encapsulated in the capsule may be directly attached to the surface of the coil 10, or it may be attached indirectly to the surface of the coil 10 via a bioadhesive. The size of the capsule is preferably 10 nm or larger, more preferably 50 nm or larger, even more preferably 100 nm or larger, and preferably 500 nm or smaller, more preferably 400 nm or smaller, and even more preferably 200 nm or smaller. The capsule preferably contains a biodegradable material.

[0139] As shown in Figure 3, it is preferable that the retaining device 1 has a stretch resistance member 50 positioned in the lumen 11 of the coil 10. The stretch resistance member 50 suppresses the stretching of the coil 10 in the longitudinal direction x during operation.

[0140] The stretch resistance member 50 may be a long member made of a single wire or stranded wire. The stretch resistance member 50 can be linear, wavy, helical, or a combination thereof. Only one or more stretch resistance members 50 may be placed in the lumen 11. The stretch resistance member 50 may be made of resin or metal.

[0141] The first end of the stretch resistance member 50 may be connected to the distal end of the coil 10 (for example, the distal end of the wire 21). The second end of the stretch resistance member 50 may be connected to the proximal end of the coil 10 (for example, the proximal end of the wire 21) or to the connection part 53. The stretch resistance member 50 may be placed in the lumen 11 in a state where it is folded back in the middle of its longitudinal axis direction.

[0142] Methods for connecting the stretch resistance member 50 to other members include welding, crimping, adhesive bonding, engagement, linking, binding, ligation, and other physical fixing methods, or combinations thereof. Here, "connection" includes both forms in which the two elements are directly connected and forms in which the two elements are indirectly connected through one or more other elements.

[0143] As shown in Figures 1 and 3, the retaining device 1 is positioned proximal to the coil 10 in the longitudinal direction x of the coil 10, and may further include a pusher 55 that pushes the coil 10 distally, and a connecting portion 53 that connects the proximal portion 10P of the coil 10 and the distal portion of the pusher 55.

[0144] The pusher 55 is a rod-shaped or wire-shaped member used to hold the coil 10 and push it distally. The pusher 55 can consist of one or more members. The pusher 55 can consist of a wire member, a coil member, or a combination thereof. The pusher 55 can be made of a conductive material such as stainless steel.

[0145] The connection portion 53 connects the coil 10 and the pusher 55. Preferably, the connection portion 53 has a detachment mechanism that allows the coil 10 to detach from the pusher 55. Examples of detachment mechanisms include hydraulic, electric, and mechanical types, and among these, an electric detachment mechanism is preferred. In the detachment mechanism, it is preferable that the connection portion 53 is heated and disconnected by electrical or thermal energy supplied through the pusher 55, thereby detaching the coil 10 from the pusher 55. In this case, it is preferable that the connection portion 53 is heated by a high-frequency current supplied between the distal end of the pusher 55 and the counter electrode.

[0146] The connecting portion 53 preferably contains a material that melts or dissolves when heated. The connecting portion 53 can be cut by Joule heating. Examples of such materials include synthetic resin materials, and it is preferable to use hydrophilic resins of synthetic polymer substances such as polyvinyl alcohol (PVA), PVA crosslinked polymers, PVA water-absorbing gel freeze-thaw elastomers, and polyvinyl alcohol copolymers.

[0147] As shown in Figures 1 to 3, the coil 10 is constructed by winding a wire 21, and the implantation device 1 may further have a tip 25 positioned at the distal end of the coil 10. The tip 25 covers a portion of the wire 21 to prevent the distal end of the wire 21 from directly contacting the inner wall surface of the body. The tip 25 may be in contact with the outer circumferential surface 12 of the coil 10, or it may be in contact with the inner circumferential surface 13 of the coil 10. Preferably, the tip 25 closes the distal end of the coil 10.

[0148] As shown in Figures 1 to 3, the indwelling device 1 is positioned at the proximal end of the coil 10 and may have a base tip 26 for closing the proximal end of the coil 10. The base tip 26 may be in contact with the outer circumferential surface 12 of the coil 10, or it may be in contact with the inner circumferential surface 13 of the coil 10. The base tip 26 has a lumen, and a part of the connecting portion 53, for example, its distal end, may be inserted into the lumen.

[0149] The tip 25 and / or base tip 26 may be made of a metal material or a resin. Examples of resins include thermoplastic resins and UV-curing resins. For example, ester resins such as epoxy acrylate resins, urethane acrylate resins, polyester acrylate resins, and polyethylene terephthalate resins, and olefin resins such as polypropylene can be used. The metal that constitutes the tip 25 can be one of the metals mentioned in the description of the wire 21.

[0150] In the longitudinal direction x, it is preferable that the fiber layer 30 is positioned distal to the distal end of the connecting portion 53. In the longitudinal direction x, it is preferable that the fiber layer 30 is not positioned in the portion where the coil 10 and the connecting portion 53 overlap.

[0151] 2. Method for Manufacturing an Intra-Visible Device The method for manufacturing an intra-vivable device according to an embodiment of the present disclosure comprises the steps of: preparing a coil having a fiber layer arranged on its outer surface and a first cylinder having an inner diameter no larger than 1.1 times the outer diameter of the coil; applying an unsolidified resin to the inner surface of the first cylinder; inserting the coil into the lumen of the first cylinder and sliding the coil within the first cylinder; removing the slid coil from the first cylinder and solidifying the resin. According to this manufacturing method, an intra-vivable device can be easily obtained in which, when the coil is viewed from a direction perpendicular to its longitudinal direction, the fiber layer exists within a circular virtual region centered on the centroid of the coil, with a diameter of 1.1 times the outer diameter of the coil, and does not exist outside the virtual region, and such an intra-vivable device can enhance the ease of inserting the coil into the body.

[0152] A method for manufacturing an in-vivo implantable device according to an embodiment of the present disclosure will be described with reference to Figures 20 to 30. Figure 20 is a flowchart of a method for manufacturing an in-vivo implantable device according to an embodiment of the present disclosure. Figure 21 is a schematic diagram showing step S11 of the manufacturing method shown in Figure 20. Figure 22 is a schematic diagram showing step S11 of the manufacturing method shown in Figure 20. Figure 23 is a schematic diagram showing step S12 of the manufacturing method shown in Figure 20. Figure 24 is a schematic diagram showing the first half of step S13 of the manufacturing method shown in Figure 20. Figure 25 is a schematic diagram showing the second half of step S13 of the manufacturing method shown in Figure 20. Figure 26 is a schematic diagram showing step S14 of the manufacturing method shown in Figure 20. Figure 27 is a flowchart of a modified example of the manufacturing method shown in Figure 20. Figure 28 is a schematic diagram showing step S16 of the manufacturing method shown in Figure 27. Figure 29 is a flowchart of another modified example of the manufacturing method shown in Figure 20. Figure 30 is a schematic diagram showing step S23 of the manufacturing method shown in Figure 29.

[0153] As shown in Figures 20 to 22, a coil 100 with a fiber layer 300 arranged on its outer surface 102 and a first cylinder 500 having an inner diameter no more than 1.1 times the outer diameter of the coil 100 are prepared (step S11).

[0154] As shown in Figure 21, the coil 100 preferably has a longitudinal direction l, a radial direction m, and a circumferential direction n. The radial direction m of the coil 100 refers to the radial direction of the coil 100, where inward refers to the direction toward the longitudinal axis center of the coil 10, and outward refers to the direction extending radially from the longitudinal axis center on the opposite side from the inward direction. The circumferential direction n of the coil 100 refers to the direction around the longitudinal axis.

[0155] As shown in Figure 21, the coil 100 has an outer circumferential surface 102. A fiber layer 300 is arranged on the outer circumferential surface 102 of the coil 100. The coil 100 has a distal end 104 and a proximal end 105 in the longitudinal direction l. For the configuration of the coil 100 on which the fiber layer 300 is arranged, refer to the description of the coil 10 on which the fiber layer 30 is arranged in "1. Intravascular Implantation Devices".

[0156] The first cylinder 500 is a resin agent 600 carrier member for transferring and adhering the resin agent 600, which suppresses the outward protrusion of the fibers of the fiber layer 300 in the radial direction m, to the surface of the coil 100 on which the fiber layer 300 is arranged. When the resin agent 600 adheres to the surface of the coil 100 and solidifies, it functions as a coating for the fiber layer.

[0157] As shown in Figure 22, the first cylinder 500 has a longitudinal direction l and a lumen 501 extending in the longitudinal direction l. Preferably, the first cylinder 500 has a radial direction m perpendicular to the longitudinal direction l and a circumferential direction n which is the direction around the axis of the longitudinal direction l. Preferably, the first cylinder 500 has an outer circumferential surface 502 and an inner circumferential surface 503. The outer circumferential surface 502 faces the outside of the first cylinder 500, i.e., the outside in the radial direction m, and the inner circumferential surface 503 faces the lumen 501. Preferably, the first cylinder 500 has a first end 504 and a second end 505 in the longitudinal direction l.

[0158] The first cylinder 500 preferably has a single-tube shape with only one internal lumen 501.

[0159] In a cross-section perpendicular to the longitudinal direction l of the first cylinder 500, the cross-sectional shape of the lumen 501 may be circular, oval, polygonal, or a combination thereof. The oval shape includes ellipse, egg, and rounded rectangle. The first cylinder 500 preferably has a cylindrical shape.

[0160] In a cross-section perpendicular to the longitudinal direction l of the first cylinder 500, it is preferable that the cross-sectional shape of the lumen 501 is similar to the cross-sectional shape perpendicular to the longitudinal direction l of the coil 100. This makes it easier to uniformly apply the resin 600 in the circumferential direction n from the inner circumferential surface 503 of the first cylinder 500 to the fiber layer 300 on the outer circumferential surface 102 of the coil 100.

[0161] If the cross-sectional shape of the lumen 501 of the first cylinder 500 is other than circular, the inner diameter of the first cylinder 500 shall refer to the diameter equivalent to a circle.

[0162] The material constituting the first cylinder 500 is preferably a resin, a metal, or a combination of resin and metal. Examples of resins constituting the first cylinder 500 include polyamide resins such as polyamide and polyamide elastomer, polyester resins such as polyethylene terephthalate and polyester elastomer, polyurethane resins such as polyurethane and polyurethane elastomer, polyolefin resins such as polyethylene, polypropylene, and ethylene-propylene copolymer, polyphenylene sulfide resin, polystyrene resin, fluororesin, vinyl chloride resin, silicone resin, natural rubber, synthetic rubber, and polyimide. These may be used individually or in combination of two or more. Examples of polyamides include nylon 12 and nylon 11. Examples of polyamide elastomers include polyether ester amide elastomer and polyamide ether elastomer.

[0163] Examples of metals that make up the first cylinder 500 include stainless steel such as SUS304 and SUS316, platinum, nickel, cobalt, chromium, titanium, tungsten, gold, nickel-titanium alloy, cobalt-chromium alloy, or combinations thereof.

[0164] The inner diameter of the first cylinder 500 may be 1.1 times or less the outer diameter of the coil 100, and may be 1.08 times or less, 1.07 times or less, 1.05 times or less, or 1.01 times or more, 1.02 times or more, or 1.03 times or more.

[0165] The outer diameter of coil 100 and the inner diameter of the first cylinder 500 can be measured using an outer diameter measuring instrument (for example, a laser outer diameter measuring device manufactured by Keyence Corporation, model number: LS-9006M).

[0166] In step S11, the outer diameter of the fiber layer 300 in the state arranged on the coil 100 may be larger or smaller than the inner diameter of the first cylinder 500.

[0167] As shown in Figures 20 and 23, an unsolidified resin agent 600 is applied to the inner circumferential surface 503 of the first cylinder 500 (step S12).

[0168] The unsolidified resin agent 600 may be liquid, or it may be a fluid paste or sol.

[0169] The unsolidified resin agent 600 may consist of one or more liquid agents. The unsolidified resin agent 600 may contain a liquid resin and a liquid solidifying agent. The solidifying agent may be a curing agent. The unsolidified resin agent 600 may contain a catalyst, a solidification accelerator, a pigment, etc.

[0170] The resin agent 600 preferably contains a biodegradable polymer material, and more preferably contains a biodegradable resin. The types of resin agents 600 can be found in the description of coating 38 in "1. Intravascular Devices".

[0171] In step S12, it is preferable to coat the inner circumferential surface 503 of the first cylinder 500 with the unhardened resin agent 600. Examples of coating methods include brush coating, roll coating, dip coating, and spray coating.

[0172] The unhardened resin 600 may be applied only to a portion of the inner circumferential surface 503 of the first cylinder 500, but it is preferable that the unhardened resin 600 is applied to the entire inner circumferential surface 503 of the first cylinder 500.

[0173] As shown in Figure 24, the coil 100 is inserted into the lumen 501 of the first cylinder 500, and as shown in Figure 25, the coil 100 is slid within the first cylinder 500 (step S13). By sliding the coil 100 within the first cylinder 500, the fiber layer 300 arranged on the outer circumferential surface 102 of the coil 100 can be contained within an area 1.1 times the outer diameter of the coil 100.

[0174] The process of inserting the coil 100 into the lumen 501 of the first cylinder 500 can be performed by inserting the coil 100 into the lumen 501 of the first cylinder 500 from either the first end 504 or the second end 505 in the longitudinal direction l of the first cylinder 500. In Figure 24, the second end 105 of the coil 100 is inserted from the first end 504 of the first cylinder 500.

[0175] In Figure 24, the coil 100 is moved in the longitudinal direction l relative to the first cylinder 500. The direction of movement of the coil 100 relative to the first cylinder 500 may be parallel to the horizontal direction as shown in Figure 24, or it may be parallel to the vertical direction, although this is not shown.

[0176] In the step of sliding the coil 100 within the first cylinder 500, it is preferable to move the coil 100, the first cylinder 500, or both, parallel to the longitudinal direction l of the coil 100. The sliding direction of the coil 100 relative to the first cylinder 500 may be parallel to the horizontal direction as shown in Figure 25, or it may be parallel to the vertical direction, although this is not shown.

[0177] In the step of sliding the coil 100 within the first cylinder 500, it is preferable to alternately reciprocate the coil 100 between the first end 504 and the second end 505 of the first cylinder 500. For example, as shown in Figure 25, it is preferable to move it in the longitudinal direction l. This makes it possible to set the thickness of the fiber layer 300 arranged in the coil 100 within an appropriate range.

[0178] It is preferable that the resin agent 600 adheres to the fiber layer 300 by sliding the coil 100 within the first cylinder 500. At this time, a portion of the resin agent 600 may penetrate into the interfiber gaps of the fiber layer 300, or it may adhere to the outer surface of the fiber layer 300.

[0179] In the step of sliding the coil 100 within the first cylinder 500, it is preferable to either fix the coil 100 and move only the first cylinder 500, or to move both the coil 100 and the first cylinder 500. This makes it easier to make the thickness of the fiber layer 300 arranged in the coil 100 uniform in the circumferential direction n.

[0180] In the step of sliding the coil 100 within the first cylinder 500, the first cylinder 500 may be fixed while the coil 100 is moved. This makes it easier for the thickness of the fiber layer 300 arranged in the coil 100 to vary depending on the position n in the circumferential direction, and as a result, the release rate of the drug contained in the fiber layer 300 also varies depending on the position n in the circumferential direction, which is preferable from the viewpoint of sustained drug release.

[0181] The time for sliding the coil 100 within the first cylinder 500 is not particularly limited, but may be, for example, 5 seconds or more, 10 seconds or more, 30 seconds or more, or 5 minutes or less, 3 minutes or less, or 1 minute or less.

[0182] In step S13, when the coil 100 is inserted into the lumen 501 of the first cylinder 500 and / or when the coil 100 is slid within the first cylinder 500, it is preferable that the resin 600 penetrates into the interfiber gaps of the fiber layer 300.

[0183] As shown in Figures 20 and 26, the slid coil 100 is removed from the first cylinder 500 and the resin 600 is solidified (step S14). More specifically, in step S14, the resin 600 attached to the coil 100 is solidified.

[0184] After step S14 is completed, the resin 600 should be in a non-flowing solid state, for example, in a state where it does not fall off the fiber layer 300 on the outer surface 102 of the coil 100, but it is preferable that it is hardened.

[0185] The resin agent 600 may be solidified at room temperature (for example, 24°C), or it may be solidified at a temperature higher than room temperature.

[0186] The resin agent 600 may be solidified by heating, cooling, standing at room temperature, or irradiation with light.

[0187] In the process of solidifying the resin 600, it is preferable to dry the resin 600 by heating or by leaving it to stand at room temperature.

[0188] As shown in Figures 27 and 28, the above manufacturing method may further include a step (S15) of preparing a second cylinder 700 having an inner diameter no more than 1.1 times the outer diameter of a coil 100 on which a fiber layer 300 is arranged on the outer surface 102, and a step (S16) of inserting the coil 100, on which the resin agent 600 has been solidified, into the inner lumen 701 of the second cylinder 700 and shaping it.

[0189] The second cylinder 700 is a member for fixing the shape of the fiber layer 300 arranged on the outer circumferential surface 102 of the coil 100. Specifically, the second cylinder 700 has the role of fixing the shape by pressing the fiber layer 300 toward the coil 100, thereby keeping the outer diameter within a predetermined range, in order to prevent the fiber layer 300 from protruding outward or becoming bulky from the coil 100.

[0190] The inner diameter of the second cylinder 700 is preferably 1.1 times or less the outer diameter of the coil 100, and may be 1.08 times or less, 1.07 times or less, 1.05 times or less, or 1.01 times or more, 1.02 times or more, or 1.03 times or more.

[0191] For details regarding the configuration of the second cylinder 700, please refer to the explanation for the first cylinder 500.

[0192] Methods for shaping include heating, cooling, standing at room temperature, and light irradiation, but shaping by heating is preferred. By inserting the coil 100, which has been solidified with resin 600, into the lumen of the second cylinder 700 and heating it at a predetermined temperature for a predetermined time, it is possible to impart shape to the fiber layer 300 and to remove residual stress generated during the resin processing in step S14.

[0193] In step S16, it is preferable to shape the fiber layer 300 by leaving the second cylinder 700 and the coil 100 to stand at room temperature for 24 hours.

[0194] In step S16, the heating temperature of the second cylinder 700 and the coil 100 is preferably 35°C or higher, more preferably 38°C or higher, even more preferably 40°C or higher, and may also be 60°C or lower, 50°C or lower, or 45°C or lower.

[0195] In step S16, the heating time for the second cylinder 700 and the coil 100 may be, for example, 4 hours or more, 5 hours or more, 6 hours or more, or 10 hours or less, 9 hours or less, or 8 hours or less.

[0196] Figure 29 shows a modified example of the manufacturing method shown in Figure 27. Steps S21 and S22 in Figure 29 are the same as steps S11 and S12 in Figure 27. Steps S24 to S27 in Figure 29 are the same as steps S13 to S16 in Figure 27. As shown in Figures 29 to 30, it is preferable to insert the core material 800 into the lumen 101 of the coil 100 before the step (step S24) in which the coil 100 is inserted into the lumen 501 of the first cylinder 500 and the coil 100 is slid within the first cylinder 500 (step S23). This makes it easier to prevent misalignment between the coil 100 and the first cylinder 500.

[0197] The core material 800 may be inserted into the lumen 501 of the first cylinder 500 before inserting the coil 100 into the lumen 501 of the first cylinder 500. Alternatively, the core material 800 may be inserted into the lumen 100 after inserting the coil 100 into the lumen 501 of the first cylinder 500.

[0198] The core material 800 is preferably a long member. The core material 800 is preferably extending along the direction of extension of the lumen 101 of the coil 100. After the completion of step S23, the core material 800 is preferably extending along the longitudinal direction l of the coil 100 from the first end 104 to the second end 105 of the coil 100. After the completion of step S23, the core material 800 is preferably extending from at least one of the first end 104 and the second end 105 of the coil 100.

[0199] The core material 800 may be a hollow member having a lumen, such as a coil 100 or a tube. To make it easier to maintain the shape of the coil 100, the core material 800 is preferably a solid member, and more preferably a linear member or a rod-shaped member.

[0200] Although not shown in the figures, the method for manufacturing an in-vivo implantable device may include the steps of: placing a stretch resistance member in the lumen 101 of the coil 100 (step S17); and preparing a pusher and a connecting part, and connecting the coil 100 and the pusher at the connecting part (step S18).

[0201] The configuration of the stretch resistance member used in step S17 can be found by referring to the description of the stretch resistance member in "1. Intra-vivo implantation device".

[0202] For details on the structure of the pusher and connection parts, please refer to the description of the pusher 70 and connection part 75 in "1. Intravivo Devices".

[0203] In step S18, it is preferable to connect the proximal end of the coil 100 to the distal end of the connection part. In step S18, it is preferable to connect the proximal end of the connection part to the distal end of the pusher.

[0204] In step S18, methods for connecting the coil 100 to the connection part, or the connection part to the pusher, include methods such as welding, crimping, bonding with adhesive, engagement, linking, binding, ligation, or other physical fixing, or combinations thereof. Here, "connection" includes both forms in which the two elements are directly connected and forms in which the two elements are indirectly connected through one or more other elements.

[0205] When carrying out the above manufacturing method, the configuration and method described in "1. Intravivo Devices" can be referred to as appropriate.

[0206] This application claims the benefit of priority based on Japanese Patent Application No. 2025-17316, filed on February 5, 2025. The entire specification of Japanese Patent Application No. 2025-17316, filed on February 5, 2025, is incorporated herein by reference.

[0207] 1: Intravivo device 10: Coil 11: Lumen 12: Outer surface 13: Inner surface 21: Wire 22: Gap 25: Tip 26: Proximal tip 30: Fiber layer 31: Lumen 32: Outer surface 33: Inner surface 34: Distal end 35: Proximal end 38: Coating 40: Fiber 41: Polymer material 42: Drug 44: Core 45: Sheath 50: Stretch resistance member 53: Connection part 55: Pusher 60: Image 70: Virtual region 100: Coil 101: Lumen 102: Outer surface 103: Inner surface 104: First end 105: Second end 300: Fiber layer 301: Lumen 302: Outer surface 303: Inner surface 304: First end 305: Second end 500: First cylinder 501: Lumen 502: Outer surface 503: Inner surface 504: First end 505: Second end 600: Resin 700: Second cylinder 800: Core material p: Longitudinal axis direction of wire x, l: Longitudinal direction of coil y, m: Radial direction of coil z, n: Circumferential direction of coil

Claims

A coil having a longitudinal direction, Displaced on the outer surface of the coil, it has a fiber layer containing fibers, The aforementioned fiber comprises a polymer material and a drug. When the coil is viewed from a direction perpendicular to its longitudinal direction, the fiber layer exists within a circular virtual region centered on the centroid of the coil, with a diameter 1.1 times the outer diameter of the coil, and does not exist outside of the virtual region. 　 The in-vivo implantation device according to claim 1, wherein the fiber includes a core-sheath type fiber having a core portion and a sheath portion, the core portion containing the drug, and the sheath portion containing the polymer material. 　 The in-vivo implantation device according to claim 1 or 2, wherein the fiber layer is located within the virtual region and not outside the virtual region over the entire longitudinal direction of the coil. 　 The in-vivo implantation device according to claim 1 or 2, wherein the average fiber diameter of the aforementioned fibers is 3.0 μm or more and 10 μm or less. 　 The aforementioned coil is constructed by winding a long piece of wire, The in-vivo implantation device according to claim 1 or 2, wherein the fiber extends in the longitudinal direction of the wire. 　 The in-vivo implantation device according to claim 1 or 2, wherein the polymer material is a biodegradable polymer material. 　 A step of preparing a coil having a fiber layer arranged on its outer surface, and a first cylinder having an inner diameter no more than 1.1 times the outer diameter of the coil, A step of applying an unhardened resin agent to the inner circumferential surface of the first cylinder, The steps include inserting the coil into the lumen of the first cylinder and sliding the coil within the first cylinder, A method for manufacturing an in-vivo device, comprising the steps of removing the slid coil from the first cylinder and solidifying the resin agent. 　 A step of preparing a second cylinder having an inner diameter no more than 1.1 times the outer diameter of the coil on which a fiber layer is arranged on the outer surface, A method for manufacturing an in-vivo device according to claim 7, further comprising the step of inserting a coil solidified with the resin into the lumen of the second cylinder and shaping it. 　 The method for manufacturing an in-vivo device according to claim 7 or 8, wherein the resin agent comprises a biodegradable resin.

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