Indwelling tool and manufacturing method of indwelling tool

Abstract

To provide an indwelling tool capable of securing a drug-sustained releasing property effective for a therapy, and a manufacturing method of the indwelling tool.SOLUTION: An indwelling tool has: a coil 10 having a rough surface part 20 having a surface roughness Ra of 0.010 μm or more and 0.50 μm or less; and a drug 40 arranged on a surface of the rough surface part 20. Here, the surface roughness Ra of the coil 10 is an arithmetic average roughness in a reference length of a roughness curve in a peripheral direction of the surface of the coil 10 and the reference length is a length of one-fourth of a peripheral length of the coil 10.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to an in-vivo indwelling device for embolizing a blood vessel in a vascular diseased area and a method for manufacturing the in-vivo indwelling device. [Background technology]

[0002] Endovascular therapy is one of the treatments for vascular lesions, such as head and neck aneurysms, arteriovenous malformations, arteriovenous fistulas, pulmonary vascular malformations, renal vascular malformations, and renal artery and abdominal aneurysms. In endovascular therapy, embolization is used, in which an in-vivo device containing embolization coils is placed at the target site to promote thrombosis and prevent aneurysm rupture, for example. Embolization involves a procedure to fill the aneurysm with coils, which consists of framing, filling, and finishing phases. In embolization, coils with different flexibility are generally selected for each phase. For example, in the framing phase, it is necessary to form a framework within the aneurysm by running coils along the inner surface of the aneurysm. On the other hand, in the filling and subsequent phases, coils are filled into the framework formed during framing, so coils with greater flexibility than the framing coils are selected. Several to several dozen coils are used in a single embolization procedure. Patent Documents 1 to 4 disclose in-vivo devices in which the coils carry drugs. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] US Patent Application Publication No. 2007 / 0299461 [Patent Document 2] Special Publication No. 2005-513081 [Patent Document 3] Special Publication No. 2013-537046 [Patent Document 4] Japanese Patent Application Laid-Open No. 2015-195978 Summary of the Invention [Problem to be solved by the invention]

[0004] In the coils described in Patent Documents 1 to 4, the drug may fall out of the coil due to blood flow immediately after the coil is placed in the aneurysm. Therefore, an object of the present invention is to provide an in-vivo indwelling device that can ensure sustained drug release that is effective for treatment, and a method for manufacturing the in-vivo indwelling device. [Means for solving the problem]

[0005] The in-vivo indwelling device according to the embodiment of the present invention that can solve the above problems is as follows. [1] A coil having a rough surface portion with a surface roughness Ra of 0.010 μm or more and 0.50 μm or less; and a drug disposed on the surface of the rough surface portion. Here, the surface roughness Ra of the coil is the arithmetic mean roughness over a reference length of the roughness curve in the circumferential direction of the surface of the coil, and the reference length is one-fourth the circumferential length of the coil.

[0006] Furthermore, the in-vivo indwelling device according to the embodiment is preferably any one of the following [2] to [8]. [2] The in-vivo indwelling device according to [1], wherein the rough surface portion is disposed over the entire length of the coil in the longitudinal axis direction. [3] The coil has the rough surface portion on each of its outer and inner surfaces, The in-vivo indwelling device according to [1] or [2], wherein the surface roughness Ra of the rough surface portion of the outer circumferential surface is greater than the surface roughness Ra of the rough surface portion of the inner circumferential surface. [4] The in-vivo indwelling device according to [3], wherein the amount of the drug disposed on the rough surface portion of the outer circumferential surface is greater than the amount of the drug disposed on the rough surface portion of the inner circumferential surface. [5] The in-vivo indwelling device according to any one of [1] to [4], wherein the drug is distributed over the entire rough surface portion. [6] The in-vivo indwelling device according to any one of [1] to [5], wherein the rough surface portion has a recess, and the drug is disposed in the recess. [7] The in-vivo indwelling device according to any one of [1] to [6], wherein the drug is encapsulated in a capsule containing a biodegradable material. [8] The in-vivo indwelling device according to any one of [1] to [7], wherein the drug has at least one of an anti-inflammatory effect, an antioxidant effect, a hypotensive effect, and an inhibitory effect on shear stress sensing.

[0007] The manufacturing method of an in-vivo indwelling device according to an embodiment of the present invention, which has been able to solve the above problems, is as follows. [9] providing a coil; forming a roughened surface portion having a surface roughness Ra of 0.010 μm or more and 0.50 μm or less on the surface of the prepared coil; and applying a drug to the rough surface portion. Here, the surface roughness Ra is the arithmetic mean roughness over a reference length of the roughness curve in the circumferential direction of the surface of the coil on which the rough surface portion is formed, and the reference length is one-fourth the circumferential length of the coil.

[0008] Furthermore, the method for producing the in-vivo indwelling device according to the embodiment is preferably any one of the following

[10] to

[13] .

[0009]

[10] The method for manufacturing an in-vivo indwelling device according to [9], wherein in the step of forming the rough surface portion, the surface of the prepared coil is irradiated with at least one of plasma and laser light.

[11] The method for producing an in-vivo indwelling device according to [9] or

[10] , further comprising the step of imparting a three-dimensional shape to the coil to which the drug has been applied.

[12] The method for manufacturing an in-vivo indwelling device according to [9] or

[10] , further comprising a step of imparting a three-dimensional shape to the coil on which the rough surface portion has been formed, between the step of forming the rough surface portion and the step of applying a drug to the rough surface portion.

[13] The method for manufacturing an in-vivo indwelling device according to [9] or

[10] , wherein in the step of preparing a coil, a coil having a three-dimensional shape is prepared. [Effects of the Invention]

[0010] According to the in-vivo indwelling device, the roughened surface of the coil increases the bonding strength between the roughened surface and the drug applied to the roughened surface, which prevents the drug from falling off the coil immediately after placing the coil in the affected area during the procedure, ensuring effective sustained drug release for treatment.

[0011] Furthermore, according to the manufacturing method of the in-vivo indwelling device, the strength of adhesion to the drug can be increased by forming a roughened surface on the coil, which prevents the drug from falling off the coil immediately after placing the coil in the affected area during the procedure, ensuring effective sustained drug release for treatment. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a schematic diagram of an in-vivo indwelling device according to one embodiment of the present invention. [Figure 2] FIG. 2 is a cross-sectional view (partial side view) taken along the longitudinal axis of the in-vivo indwelling device shown in FIG. [Figure 3] FIG. 3 is an enlarged cross-sectional view of a portion of the in-vivo indwelling device shown in FIG. 2. [Figure 4] FIG. 4 is a cross-sectional view showing a modified example of the in-vivo indwelling device shown in FIG. [Figure 5] FIG. 4 is a cross-sectional view showing a modified example of the in-vivo indwelling device shown in FIG. [Figure 6] FIG. 4 is a cross-sectional view showing a modified example of the in-vivo indwelling device shown in FIG. [Figure 7] FIG. 4 is a cross-sectional view showing a modified example of the in-vivo indwelling device shown in FIG. [Figure 8] FIG. 2 is a cross-sectional view taken along the longitudinal axis direction of the in-vivo indwelling device according to one embodiment of the present invention, showing an enlarged cross-sectional view of a rough surface portion. [Figure 9] 9 is a cross-sectional view showing a modified example of the rough surface portion shown in FIG. 8. FIG. [Figure 10] 3 is a cross-sectional view perpendicular to the longitudinal axis of the extension resistance member shown in FIG. 2. [Figure 11]11 is a cross-sectional view showing a modified example of the extension resistance member shown in FIG. [Figure 12] 1 is a flowchart showing a method for manufacturing an in-vivo indwelling device according to one embodiment of the present invention. [Figure 13] 13 is a flowchart showing a modified example of the method for manufacturing the in-vivo indwelling device shown in FIG. [Figure 14] 14 is a flowchart showing a modified example of the method for manufacturing the in-vivo indwelling device shown in FIG. [Figure 15] 13 is a flowchart showing yet another modified example of the method for manufacturing the in-vivo indwelling device shown in FIG. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention will be described in more detail below based on the following embodiments. However, the present invention is not limited to the following embodiments, and can be implemented with appropriate modifications within the scope of the above and below-described purposes, and all such modifications are included within the technical scope of the present invention. For convenience, hatching and component symbols may be omitted in the drawings. In such cases, reference should be made to the specification or other drawings. The dimensions of various components in the drawings may differ from actual dimensions, as priority is given to helping understand the features of the present invention.

[0014] 1. Intravital device Hereinafter, an in-vivo indwelling device may be simply referred to as an indwelling device. Examples of uses for an indwelling device include embolization, which promotes thrombosis at target sites such as cerebral aneurysms, head and neck aneurysms, arteriovenous malformations, arteriovenous fistulas, pulmonary vascular malformations, renal vascular malformations, renal arteries, and abdominal aneurysms. Of these, an indwelling device for cerebral aneurysms is preferred. Examples of the shape of the aneurysm include fusiform and saccular.

[0015] One embodiment of the present invention relates to an in-vivo indwelling device, which includes a coil having a rough surface portion with a surface roughness Ra of 0.010 μm or more and 0.50 μm or less, and a drug disposed on the surface of the rough surface portion. Here, the surface roughness Ra of the coil is the arithmetic mean roughness over a reference length of the roughness curve in the circumferential direction of the coil surface, and the reference length is one-fourth the circumferential length of the coil. According to this in-vivo indwelling device, the roughened surface portion of the coil increases the bonding strength between the rough surface portion and the drug disposed on the surface of the rough surface portion. This prevents the drug from falling off the coil immediately after placing the coil on the affected area during the procedure, ensuring effective sustained drug release for treatment.

[0016] Embolization has three phases: framing, filling, and finishing. An indwelling device can be used in any one of the phases, or across any two or three of the phases. The indwelling device may be used for finishing, but is preferably used for framing and / or filling.

[0017] An in-vivo indwelling device according to one embodiment of the present invention will be described with reference to FIGS. 1 to 11. FIG. 1 is a schematic diagram of an in-vivo indwelling device according to one embodiment of the present invention. FIG. 2 is a cross-sectional view (partial side view) taken along the longitudinal axis of the in-vivo indwelling device shown in FIG. 1. FIG. 3 is an enlarged cross-sectional view of a portion of the in-vivo indwelling device shown in FIG. 2. FIGS. 4 to 7 are cross-sectional views showing modifications of the in-vivo indwelling device shown in FIG. 3. FIG. 8 is a cross-sectional view taken along the longitudinal axis of an in-vivo indwelling device according to one embodiment of the present invention, showing an enlarged cross-sectional view of the roughened surface portion. FIG. 9 is a cross-sectional view showing a modification of the roughened surface portion shown in FIG. 8. FIG. 10 is a cross-sectional view perpendicular to the longitudinal axis of the stretch resistance member shown in FIG. 2. FIG. 11 is a cross-sectional view showing a modification of the stretch resistance member shown in FIG. 10. Note that the stretch resistance member is omitted from FIGS. 3 to 7. As shown in FIGS. 1 to 3, indwelling device 1 includes coil 10 and drug 40.

[0018] As can be seen from FIG. 2, the coil 10 preferably has a longitudinal axis direction x, a circumferential direction, and a radial direction. The coil 10 preferably has a distal end and a proximal end in the longitudinal axis direction x. The proximal side of the coil 10 refers to the direction toward the user or surgeon with respect to the longitudinal axis 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 FIG. 2, the right side of the drawing is the proximal side, and the left side of the drawing is the distal side. The radial direction of the coil 10 refers to the radial direction of the coil 10, and the inward radial direction of the coil 10 refers to the direction toward the center of the longitudinal axis of the coil 10, and the outward radial direction refers to the direction extending radially from the center of the longitudinal axis opposite to the inward direction. The circumferential direction of the coil 10 refers to the direction around the longitudinal axis.

[0019] The coil 10 is formed by spirally winding one or more wires 31. Examples of the wires 31 include solid wires, twisted wires, and coiled wires, among which solid wires are preferred. It is also preferred that the wires 31 are not coil wires.

[0020] A coil formed by winding wire 31 in a spiral shape is sometimes called a primary coil. A primary coil that is further formed into a spiral or three-dimensional shape is sometimes called a secondary coil. Unless otherwise specified, the coil 10 in this specification shows the configuration in the state of a primary coil. Preferably, the coil 10 of the primary coil shown in Figures 2 to 9 is formed into a secondary coil as shown in Figure 1. In Figure 1, a three-dimensional secondary coil shape is formed by winding the primary coil 10.

[0021] The wire 31 is preferably biocompatible and flexible. Examples of materials that can be used for the wire 31 include metal materials such as platinum, gold, titanium, tungsten, alloys thereof, and stainless steel, as well as combinations of these metals. Of these, the wire 31 is more preferably made of a platinum-tungsten alloy.

[0022] The wire 31 has a longitudinal axis direction and a distal end and a proximal end in the longitudinal axis direction of the wire 31. The wire 31 may be composed of a single linear member from the distal end to the proximal end, or may be composed of multiple linear members connected to each other in the longitudinal axis direction. The cross-sectional shape of the wire 31 perpendicular to the longitudinal axis direction may be circular, elliptical, polygonal, or a combination thereof. The cross-sectional shape of the wire 31 perpendicular to the longitudinal axis direction may be the same throughout the entire longitudinal axis direction of the wire 31, or may vary depending on the position in the longitudinal axis direction.

[0023] The outer diameter of the wire 31 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.

[0024] The outer diameter of the wire 31 may be the same in the longitudinal direction of the wire 31, or may be different depending on the position in the longitudinal direction of the wire 31. When the cross section of the wire 31 is not circular, the outer diameter of the wire 31 refers to the diameter equivalent to a circle.

[0025] As shown in Figures 2 and 3, coil 10 preferably has a lumen 11 extending in its longitudinal axis direction x. Coil 10 preferably has an outer circumferential surface 12 and an inner circumferential surface 13. Outer circumferential surface 12 of coil 10 faces the outside of coil 10, i.e., the outside in the radial direction, and inner circumferential surface 13 of coil 10 faces lumen 11. A stretch-resisting member 35, which will be described later, is preferably disposed in lumen 11.

[0026] 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 axis direction x may be single-layered, and the remaining portion may be multi-layered.

[0027] The density of the coil 10, i.e., the winding spacing, is not particularly limited, and can be close winding, pitch winding, or a combination of these. In the coil 10, adjacent wire rods 31 may be in contact with each other in the longitudinal axis direction x. In the coil 10, adjacent wire rods 31 may be in contact with each other only in a portion of the longitudinal axis direction x, or adjacent wire rods 31 may be in contact with each other over the entire longitudinal axis direction x. Furthermore, in the coil 10, adjacent wire rods 31 may not be in contact with each other in the longitudinal axis direction x. A non-contact state refers to a state in which adjacent wire rods 31 in the longitudinal axis direction x of the coil 10 are spaced apart from each other.

[0028] The cross-sectional shape of the coil 10 perpendicular to the longitudinal axis direction x may be circular, oval, polygonal, or a combination thereof. The oval shape includes an ellipse, an egg, and a rounded rectangle. The same applies to the following description.

[0029] The maximum and minimum outer diameters of the coil 10 are not particularly limited and can be selected appropriately depending on the phase of the procedure, but may be, for example, 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.

[0030] The outer diameter and / or inner diameter of coil 10 may be the same size in the longitudinal axis direction x of coil 10, or may be different sizes depending on the position in the longitudinal axis direction x of coil 10. Note that if the cross section of coil 10 is not circular, the outer diameter of coil 10 refers to the circle-equivalent diameter. Also, if the cross section of the lumen of coil 10 is not circular, the inner diameter of coil 10 refers to the circle-equivalent diameter.

[0031] The coil 10 may have a constant outer diameter in the longitudinal axis direction x. A constant outer diameter means that the outer diameter of the coil 10 is substantially constant throughout the entire longitudinal axis direction x of the coil 10, and includes cases where the change in the outer diameter of the coil 10 is within a range of ±5% throughout the entire longitudinal axis direction x.

[0032] Although not shown, the coil 10 may have a transition section in which the outer diameter decreases toward the distal side. This allows the flexibility of the coil 10 to be gradually increased from the distal side toward the proximal side. In the transition section, the outer diameter of the coil 10 may decrease in a tapered manner toward the distal side. Here, tapered includes a configuration in which the outer diameter of the wire material 31 constituting the coil 10 decreases with each turn, resulting in a tapered envelope of the outer diameter of the coil 10 in the transition section. In the transition section, the outer diameter of the coil 10 may decrease in a stepped manner toward the distal side. Here, stepped includes a configuration in which the outer diameter of the wire material 31 constituting the coil 10 decreases every two or more turns.

[0033] When the coil 10 is divided into two equal halves, a distal portion and a proximal portion, in the longitudinal axis direction x, the average outer diameter of the proximal portion of the coil 10 may be smaller than the average outer diameter of the distal portion. The smaller outer diameter of the proximal portion can increase the flexibility of the proximal portion of the coil 10, thereby ensuring operability.

[0034] The in-vivo indwelling device 1 includes a coil 10 (primary coil) having a rough surface portion 20 with a surface roughness Ra of 0.010 μm or more and 0.50 μm or less, and a drug 40 disposed on the surface of the rough surface portion 20. Here, the surface roughness Ra of the coil 10 (primary coil) is the arithmetic mean roughness over a reference length of a roughness curve in the circumferential direction of the surface of the coil 10 (primary coil), and the reference length is one-fourth the circumferential length of the coil 10. The roughened surface of the rough surface portion 20 of the coil 10 increases the bonding strength between the rough surface portion 20 and the drug 40 disposed on the surface of the rough surface portion 20. This prevents the drug 40 from falling off the coil 10 immediately after placing the coil 10 on the affected area during the procedure, ensuring effective sustained drug release for treatment.

[0035] The arithmetic mean roughness Ra of the coil 10 (primary coil) corresponds to the arithmetic mean roughness Ra specified in JIS B 0601 (2001) and is measured in accordance with JIS B 0633 (2001). A measuring device specified in JIS B 0651 (2001) (e.g., an ultra-precision non-contact three-dimensional measuring device, model NH-3SP, manufactured by Mitaka Koki Co., Ltd.) is used for the measurement. For the measurement, the wire 31 constituting the coil 10 (primary coil) is held at both ends, or at the distal end and a position several centimeters proximal to the distal end (e.g., a position 5 cm proximal to the distal end), and pulled to straighten the wire 31. The surface roughness of the straightened wire 31 may then be measured in accordance with JIS B 0633 (2001). Similarly, when the coil 10 (primary coil) is formed into a secondary coil by bending, the wire 31 constituting the secondary coil may be pulled while being held at both ends, or at the distal end of the wire 31 and a position several centimeters proximal to the distal end (for example, a position 5 cm proximal to the distal end), to straighten the wire 31, and then the surface roughness of the straightened wire 31 may 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 31 that corresponds to the outer surface of the coil 10 (primary coil). 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 31 that corresponds to the inner surface of the coil 10 (primary coil). Since the coil 10 is formed by winding the wire 31, the outer periphery of the straightened wire 31, for example, in a range of 0° to 180°, corresponds to the outer periphery of the coil 10, and the outer periphery of the straightened wire 31, for example, in a range of 180° to 360°, corresponds to the inner periphery of the coil 10. Therefore, the surface roughness Ra of the coil 10 can be measured by measuring the surface roughness Ra of the wire 31. When measuring the calculated average roughness Ra of a coil 10 (primary coil) that already has a drug 40 disposed therein, the drug 40 can be removed from the coil 10 before measurement. The drug 40 can be removed by dissolving it in a solvent such as physiological saline.

[0036] The surface roughness Ra of the rough surface portion 20 of the coil 10 may be 0.010 μm or more, may be 0.015 μm or more, or may be 0.020 μm or more, and may be 0.50 μm or less, preferably 0.30 μm or less, and more preferably 0.10 μm or less. As described below, the drug 40 is preferably placed on the rough surface portion 20 in a state where it is encapsulated in a capsule 41, and if the surface roughness Ra of the rough surface portion 20 is within the above range, the capsule encapsulating the drug 40 is easily fixed to the rough surface portion 20. The surface roughness of the entire rough surface portion 20 of the coil 10 is preferably 0.010 μm or more and 0.50 μm or less.

[0037] The surface roughness Ra of the rough surface portion 20 of the coil 10 being 0.010 μm or more and 0.50 μm or less means that the part of the surface of the coil 10 having a surface roughness Ra of 0.010 μm or more and 0.50 μm or less corresponds to the rough surface portion 20.

[0038] In this specification, portions of the surface of the coil 10 having a surface roughness Ra of less than 0.010 μm and more than 0.50 μm are not considered to be rough surface portions 20. Therefore, for example, when the primary coil 10 is formed by tightly winding wire rods 31 having a circular or elliptical cross section, the uneven structure 32 (see FIG. 3 ) formed between adjacent wire rods 31 of the coil 10 due to the wire rods 31 having a circular or elliptical cross section, and scratches having a size of more than 0.50 μm caused during the manufacturing process are not considered to be rough surface portions 20.

[0039] The surface roughness of the rough surface portion 20 of the coil 10 may be uniform or non-uniform.

[0040] The coil 10 having the rough surface portion 20 can be rephrased as the roughened surface of the wire 31 (strand) constituting the coil 10. Therefore, the surface roughness Ra of the wire 31 constituting the coil 10 is preferably 0.010 μm or more and 0.50 μm or less. The surface roughness Ra of the wire 31 is the arithmetic mean roughness over a reference length of a roughness curve in the circumferential direction of the surface of the wire 31, where the reference length is one-fourth the circumferential length of the wire 31. The surface roughness Ra of the wire 31 corresponds to the arithmetic mean roughness Ra defined in JIS B 0601 (2001) and can be measured in accordance with JIS B 0633 (2001). A measuring instrument defined in JIS B 0651 (2001) (e.g., an ultra-precision non-contact three-dimensional measuring instrument, model NH-3SP, manufactured by Mitaka Koki Co., Ltd.) is used for the measurement. Additionally, the surface roughness Ra of the surface of the wire 31 can be measured in the same manner as the measurement of the surface roughness Ra of the surface of the coil 10.

[0041] For a method of forming the rough surface portion 20 on the coil 10, please refer to the description in "2. Method of manufacturing an in-vivo indwelling device" below.

[0042] The rough surface portion 20 may be disposed on only a portion of the surface of the coil 10, or may be disposed on the entire surface of the coil 10. The rough surface portion 20 may be disposed on only a portion of the longitudinal axis direction x of the coil 10. As shown in FIG. 2, the rough surface portion 20 may be disposed over the entire longitudinal axis direction x of the coil 10. By disposing the rough surface portion 20 over a wide area of the coil 10, a large amount of the drug 40 can be distributed on the coil 10.

[0043] The rough surface portion 20 may be disposed on only a portion of the circumference of the coil 10, or may be disposed over the entire circumference of the coil 10. By disposing the rough surface portion 20 over a wide area of the coil 10, a large amount of the drug 40 can be distributed on the coil 10.

[0044] The rough surface portion 20 may be arranged to extend in the longitudinal axis direction x and the circumferential direction of the coil 10. The rough surface portion 20 may have a ring or cylindrical shape, or may have a shape in which a portion of the ring or cylinder is cut out in the circumferential direction. The rough surface portion 20 may also have a spiral shape, a linear shape, a strip shape, or the like.

[0045] As shown in Figures 3 and 4, the coil 10 may have a rough surface portion 20 on the outer circumferential surface 12. As shown in Figures 5 and 6, the coil 10 may have a rough surface portion 20 on the inner circumferential surface 13. As shown in Figure 7, the coil 10 may have a rough surface portion 20 on each of the outer circumferential surface 12 and the inner circumferential surface 13. In this way, the coil 10 may have one or more rough surface portions 20. Here, the term "multiple rough surface portions 20" refers to portions that are arranged at intervals in at least one of the longitudinal axis direction x, the circumferential direction, and the radial direction of the coil 10.

[0046] When the coil 10 has multiple rough surface portions 20, including a first rough surface portion and a second rough surface portion, the surface roughness Ra of the first rough surface portion may be different from the surface roughness Ra of the second rough surface portion. The surface roughness Ra of the first rough surface portion may be greater than the surface roughness Ra of the second rough surface portion. By arranging rough surface portions 20 with different surface roughness Ra values in this manner, it becomes easier to control the amount of drug 40 placed on the coil 10 and the release speed of the drug 40.

[0047] 7, when the coil 10 has rough surface portions 20 on both the outer peripheral surface 12 and the inner peripheral surface 13, the surface roughness Ra of the rough surface portion 20 on the outer peripheral surface 12 is preferably greater than the surface roughness Ra of the rough surface portion 20 on the inner peripheral surface 13. This makes it easier for more drug 40 to be applied to the outer peripheral surface 12 than to the inner peripheral surface 13 of the coil 10. Although not shown, when the coil 10 has rough surface portions 20 on both the outer peripheral surface 12 and the inner peripheral surface 13, the surface roughness Ra of the rough surface portion 20 on the inner peripheral surface 13 may be greater than the surface roughness Ra of the rough surface portion 20 on the outer peripheral surface 12.

[0048] The rough surface portion 20 may be disposed on only a portion of the outer peripheral surface 12 of the coil 10, or may be disposed over the entire outer peripheral surface 12. Furthermore, the rough surface portion 20 may be disposed on only a portion of the inner peripheral surface 13 of the coil 10, or may be disposed over the entire inner peripheral surface 13.

[0049] When the coil 10 is divided into two equal parts, distal and proximal, along the longitudinal axis x, it is preferable that the surface roughness Ra of the distal part of the coil 10 is greater than the surface roughness Ra of the proximal part. By processing the coil 10 in this manner, the amount of drug disposed in the proximal part of the coil 10 is smaller than that in the distal part, and the distal part of the coil is easily bent and flexibility is ensured even when the volume of the coil occupies a large amount within the aneurysm. To compare the surface roughness Ra of the distal and proximal parts of the coil 10, the coil 10 is divided into two equal parts along the longitudinal axis x, and the surface roughness Ra of the distal and proximal parts is measured, respectively. In addition, if the surface roughness Ra values of the outer surface 12 and inner surface 13 of the coil 10 are different in the distal and proximal portions of the coil 10, (i) the surface roughness Ra of the outer surface 12 of the distal portion of the coil 10, (ii) the surface roughness of the inner surface 13 of the distal portion of the coil 10, (iii) the surface roughness Ra of the outer surface 12 of the proximal portion of the coil 10, and (iv) the surface roughness Ra of the inner surface 13 of the proximal portion of the coil 10 are measured, and the average value of the measurement results of (i) and (ii) is taken as the surface roughness Ra in the distal portion, and the average value of the measurement results of (iii) and (iv) is taken as the surface roughness Ra in the proximal portion.

[0050] When the coil 10 has rough surface portions 20 on both the outer peripheral surface 12 and the inner peripheral surface 13, it is preferable that the area of the rough surface portion 20 on the outer peripheral surface 12 is larger than the area of the rough surface portion 20 on the inner peripheral surface 13. This makes it easier to apply more drug 40 to the outer peripheral surface 12 than to the inner peripheral surface 13 of the coil 10.

[0051] As shown in Figures 1 to 9, a drug 40 is disposed on the surface of the coil 10. The drug 40 may be an active ingredient (drug substance) alone or a mixture with other additives. Preferred additives include base materials, plasticizers, stabilizers, surfactants, etc. In this specification, the amount of drug refers to the weight of the drug 40. When the drug 40 is a mixture containing additives, the amount of drug refers to the weight of the mixture.

[0052] The type of drug 40 is not particularly limited as long as it is necessary for the prevention and treatment of the affected area. Drug 40 may have at least one of an anti-inflammatory effect, an antioxidant effect, a hypotensive effect, and a shear stress sensing inhibitory effect. Examples of drug 40 include selective serotonin reuptake inhibitors (SSRIs), DPP-4 inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, angiotensin II receptor blockers, tocopherol acetate, ascorbic acid, edaravone, N-acetyl-L-cysteine, calcium channel blockers, diuretics, angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEs), beta-blockers, alpha-blockers, and alpha-beta-blockers.

[0053] The drug 40 may be attached to the surface of the coil 10, or may be attached indirectly to the surface of the coil 10 via a bioadhesive. The type of material for the bioadhesive is not particularly limited, but examples that can be used include polysaccharide adhesives such as collagen, chitosan, and gelatin, polyethylene glycol-based hydrogel adhesives, and protein adhesives such as fibrin and collagen.

[0054] The drug 40 may be held on the surface of the coil 10 as a drug layer. The drug 40 may be held on the surface of the coil 10 in the form of a drug encapsulated in a capsule such as a microcapsule. The drug 40 encapsulated in a capsule may be held on the surface of the coil 10 in the form of a layer.

[0055] As shown in Figures 8 and 9, the drug 40 is preferably encapsulated in a capsule 41. This allows the drug 40 to be released effectively when the coil 10 is delivered to an affected area in a living body. The drug 40 encapsulated in the capsule 41 may be attached to the surface of the coil 10, or may be attached indirectly to the surface of the coil 10 via a bioadhesive.

[0056] The size of the capsules 41 is preferably 10 nm or more, more preferably 50 nm or more, even more preferably 100 nm or more, and is preferably 500 nm or less, more preferably 400 nm or less, even more preferably 200 nm or less.

[0057] The drug 40 is preferably encapsulated in a capsule 41 containing a biodegradable material. Examples of biodegradable materials include bioabsorbable polymers, natural polymers, decellularized biological tissues and cells, and combinations thereof. Examples of bioabsorbable polymers include at least one of polylactic acid (PLA), poly-L-lactic acid (PLLA), polyglycolic acid (PGA), lactic acid / glycolic acid copolymer (PLGA), polycaprolactone (PCL), and polydioxanone (PDS). Examples of natural polymers include at least one of collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptide. Among these, PLGA is preferred as a biodegradable material.

[0058] Capsule 41 preferably has a structure in which a plurality of filamentous bioabsorbable polymers are condensed into a spherical shape. The number of filamentous bioabsorbable polymers is preferably 10,000 or more, more preferably 20,000 or more, and even more preferably 30,000 or more. The number of filamentous bioabsorbable polymers may be 100,000 or less, 90,000 or less, or 80,000 or less. In particular, capsule 41 preferably has a structure in which 10,000 to 100,000 PLGA filaments are condensed into a spherical shape.

[0059] The glass transition temperature of the material constituting capsule 41 is not particularly limited, but may be, for example, 40°C or higher, 41°C or higher, or 42°C or higher, or 50°C or lower, 49°C or lower, or 48°C or lower.

[0060] The surface of the capsule 41 is preferably covered with a coating material. The coating material can prevent the drug 40 from eluting into the blood or falling off during delivery of the indwelling device 1 into the body. The material constituting the coating material is preferably a water-soluble polymer in order to prevent an initial burst of the drug 40. Examples of materials for the coating material include carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, alginic acid, pectin, gum arabic, gellan gum, guar gum, xanthan gum, carrageenan, and gelatin.

[0061] A surfactant may be applied to the surface of the capsule 41. By applying a surfactant, the fluidity of the cell membrane of the capsule 41 is increased, and the permeability of the drug through the cell membrane can be improved. The type of surfactant is not particularly limited, but a nonionic surfactant is preferred, for example, polyoxyethylene sorbitan monolaurate, preferably Tween (registered trademark) 20, Tween (registered trademark) 80, etc.

[0062] An example of the location of the drug 40 will be described. The drug 40 may be disposed on only a portion of the rough surface portion 20. For example, the drug 40 may be disposed on only a portion of the rough surface portion 20 in the longitudinal axis direction x of the coil 10, or may be disposed on only a portion of the rough surface portion 20 in the circumferential direction of the coil 10. By disposing the drug 40 on only a portion of the rough surface portion 20 in this manner, the amount of drug disposed on the coil 10 can be adjusted.

[0063] 2, it is preferable that the drug 40 be distributed over the entire rough surface portion 20. This allows a larger amount of drug to be distributed in the coil 10, making it easier to obtain the required therapeutic effect and enhancing the sustained release effect of the drug 40.

[0064] As shown in FIG. 7 , when the coil 10 has rough surface portions 20 on both the outer peripheral surface 12 and the inner peripheral surface 13, it is preferable that the amount of drug 40 disposed on the rough surface portion 20 of the outer peripheral surface 12 is greater than the amount of drug 40 disposed on the rough surface portion 20 of the inner peripheral surface 13. This makes it easier to apply the amount of drug necessary for treatment to the affected area. Note that when the coil 10 has rough surface portions 20 on both the outer peripheral surface 12 and the inner peripheral surface 13, it is more preferable that the surface roughness Ra of the rough surface portion 20 of the outer peripheral surface 12 is greater than the surface roughness Ra of the rough surface portion 20 of the inner peripheral surface 13, and that the amount of drug 40 disposed on the rough surface portion 20 of the outer peripheral surface 12 is greater than the amount of drug 40 disposed on the rough surface portion 20 of the inner peripheral surface 13.

[0065] As shown in Figure 7, when coil 10 has rough surface portions 20 on both outer peripheral surface 12 and inner peripheral surface 13, and a drug layer is disposed on rough surface portion 20 on outer peripheral surface 12 and rough surface portion 20 on inner peripheral surface 13, the average thickness of the drug layer on rough surface portion 20 on outer peripheral surface 12 may be greater than the average thickness of the drug layer on rough surface portion 20 on inner peripheral surface 13. This makes it easier to deliver the amount of drug required for treatment to the affected area. The thickness of the drug layer refers to the length of the layer of drug 40 in the radial direction of coil 10.

[0066] Rough surface portion 20 may have an uneven structure. As shown in Figures 8 and 9, rough surface portion 20 preferably has recesses 21. In this case, it is preferable that drug 40 be disposed in recesses 21. By disposing drug 40 in such recesses, drug 40 can be prevented from falling off immediately after coil 10 is placed on the affected area during the procedure, and sustained drug release that is effective in treatment can be ensured.

[0067] 8 and 9, the length of recess 21 in the radial direction of coil 10 may be referred to as depth D of recess 21. The maximum value of depth D of recess 21 in rough surface portion 20 is preferably 0.010 μm or more and 0.50 μm or less.

[0068] 8 and 9, the rough surface portion 20 preferably has a plurality of recesses 21. When the rough surface portion 20 has a plurality of recesses 21, the drug 40 may be placed in one recess 21, and the drug 40 may not be placed in the other recesses 21.

[0069] As shown in Figures 8 to 9, capsules 41 containing a drug 40 are preferably disposed in the recesses 21 of the rough surface portion 20. It is preferable that one or more capsules 41 containing a drug 40 are fitted in one recess 21 of the rough surface portion 20. Figures 8 and 9 show an example in which one capsule 41 is disposed in one recess 21 of the rough surface portion 20. One capsule 41 may be entirely fitted in one recess 21 of the rough surface portion 20, or only a part of one capsule 41 may be fitted in one recess 21 of the rough surface portion 20. Multiple capsules 41 may be entirely fitted in one recess 21 of the rough surface portion 20. One recess 21 of the rough surface portion 20 may have a part of one capsule 41 and a part of another capsule 41 fitted in it.

[0070] The depth D of the recess 21 of the rough surface portion 20 may be greater than the outer diameter of the drug 40. This allows the entire capsule 41 to fit into the recess 21. The depth D of the recess 21 of the rough surface portion 20 may be smaller than the outer diameter of the drug 40 or the outer diameter of the capsule 41 containing the drug 40. However, to prevent the drug 40 from falling off the surface of the rough surface portion 20, the depth D of the recess 21 is preferably at least one-fourth the outer diameter of the drug 40 or one-fourth the outer diameter of the capsule 41. Note that if the drug 40 or capsule 41 has a shape other than a sphere, the outer diameter of the drug 40 or capsule 41 refers to the spherical equivalent diameter, i.e., the diameter of a sphere having the same volume as the drug 40 or capsule 41.

[0071] 2, the coil 10 may have a head portion 33 at its distal end. The head portion 33 covers a portion of the wire 31 to prevent the distal end of the wire 31 from directly contacting the inner wall surface of the living body. The head portion 33 may or may not be in contact with the stretch resistance member 35.

[0072] The shape of the head portion 33 is not particularly limited, but may be, for example, a hemisphere, an oval hemisphere, a cylinder, or a polygonal pillar.

[0073] The head portion 33 may be joined to at least one of the outer surface and the inner surface of the coil 10. Furthermore, to prevent the head portion 33 from falling off, a portion of the head portion 33 may be disposed in the lumen 11 at the distal end of the coil 10. The proximal end of the head portion 33 may be located distal to the distal end of the wire 31, or the proximal end of the head portion 33 may be located proximal to the distal end of the wire 31.

[0074] The head portion 33 may be made of a metal material or a resin. Examples of resins that make up the head portion 33 include thermoplastic resins and ultraviolet-curing resins. Examples of resins that can be used to make up the head portion 33 include ester resins such as epoxy acrylate resins, urethane acrylate resins, polyester acrylate resins, and polyethylene terephthalate resins, and olefin resins such as polypropylene. Examples of metals that can be used to make up the head portion 33 include the metals listed in the description of the wire material 31. The wire material 31 and the head portion 33 may be made of the same material or different materials.

[0075] The in-vivo indwelling device 1 preferably includes a stretch resistance member 35 disposed in the lumen 11 of the coil 10. The stretch resistance member 35 prevents the coil 10 from stretching in the longitudinal axis direction x during operation. The stretch resistance member 35 may be a long member made of a solid wire or a stranded wire. The stretch resistance member 35 has a longitudinal axis direction and has a first end and a second end in the longitudinal axis direction. The stretch resistance member 35 may be composed of a single layer in the radial direction perpendicular to the longitudinal axis direction, or may be composed of multiple layers. The stretch resistance member 35 may have an inner layer made of a stranded wire composed of multiple wires and an outer layer containing a resin composition disposed outside the inner layer. Only one stretch resistance member 35 may be disposed in the lumen 11 of the coil 10, or multiple stretch resistance members 35 may be disposed.

[0076] The stretch resisting member 35 may be made of resin or metal. Examples of resins that make up the stretch resisting member 35 include polyester resins such as polyethylene terephthalate, polyamide resins such as nylon, and polyolefin resins such as polyethylene and polypropylene. Using resin increases flexibility, improving the delivery performance of the indwelling device 1. Furthermore, using a resin for the stretch resisting member 35 can prevent breakage due to metal fatigue during delivery. By making the length of the stretch resisting member 35 longer than the length of the coil 10 or using a stretchable material for the stretch resisting member 35, tension caused by the end of the coil 10 being stretched linearly due to insufficient length of the stretch resisting member 35 when the coil 10 is placed within the aneurysm can be alleviated. Examples of metals that make up the stretch resisting member 35 include platinum, gold, rhodium, palladium, rhenium, silver, nickel, titanium, tantalum, tungsten, alloys thereof, and stainless steel.

[0077] The stretch resistance member 35 may be made of a material different from that of the wire 31 that makes up the coil 10. For example, the coil 10 may be made of a platinum-tungsten alloy, and the stretch resistance member 35 may be made of polypropylene resin.

[0078] The cross-sectional shape of the stretch resistance member 35 perpendicular to its longitudinal axis may be circular, elliptical, polygonal, or a combination thereof.

[0079] To facilitate placement of the stretch resistance member 35 in the lumen 11 of the coil 10, the outer diameter of the stretch resistance member 35 is preferably smaller than half, and more preferably one-third or less, of the inner diameter of the coil 10. To prevent breakage of the stretch resistance member 35, the outer diameter of the stretch resistance member 35 is preferably at least one-fifteenth, and more preferably at least one-tenth, of the inner diameter of the coil 10.

[0080] The stretch resistant member 35 can be straight, wavy, spiral, or a combination thereof.

[0081] The first end of the stretch resistance member 35 may be connected to the distal end of the coil 10, specifically the distal end of the wire 31 that constitutes the coil 10. The second end of the stretch resistance member 35 may be connected to the proximal end of the coil 10, specifically the proximal end of the wire 31 that constitutes the coil 10. The second end of the stretch resistance member 35 may be connected to a connecting portion 39 (described below) that connects the coil 10 and the pusher 37. The stretch resistance member 35 may be disposed in the lumen 11 of the coil 10 in a state where it is folded back midway along the longitudinal axis of the stretch resistance member 35. In this case, it is preferable that the folded portion of the stretch resistance member 35 is connected to the distal or proximal end of the coil 10, and that the first and second ends are connected to the proximal or distal end of the coil 10 or the distal end of the connecting portion 39. For example, in Figure 2, the elongation resistance member 35 has a folded portion 36 folded back halfway in the longitudinal axis direction, and the folded portion 36 is connected to the distal end of the coil 10, and the first end side and the second end side are connected to the connection portion 39 described later.

[0082] The stretch-resistant member 35 can be connected to another member by welding, crimping, or other crimping methods, or by physical fastening, such as by engaging, connecting, fastening, or ligating, or by any combination thereof. Here, "connection" includes both direct connection between two elements and indirect connection between two elements via one or more other elements.

[0083] As shown in FIG. 10, a drug 40 may be applied to the surface of the stretch resistance member 35. This allows a larger amount of drug to be applied to the in-vivo indwelling device 1 including the coil 10, making it easier to achieve the desired therapeutic effect. It also enhances the sustained release effect of the drug 40. For example, the drug 40 may be applied to part or all of the outer surface of the stretch resistance member 35. Note that, as shown in FIG. 11, the drug 40 does not have to be applied to the surface of the stretch resistance member 35, and the drug 40 does not have to be applied to the entire outer surface of the stretch resistance member 35.

[0084] As with coil 10, drug 40 may be attached to the surface of stretch resisting member 35, or may be indirectly attached to the surface of stretch resisting member 35 via a bioadhesive. Also, as with coil 10, drug 40 encapsulated in capsule 41 may be attached to the surface of stretch resisting member 35, or may be indirectly attached to the surface of stretch resisting member 35 via a bioadhesive. For types of bioadhesive, please refer to the description of the types of bioadhesive attached to coil 10. For the structure of capsule 41, please refer to the description of the structure of capsule 41 attached to coil 10.

[0085] As shown in FIG. 1, the in-vivo indwelling device 1 may include a coil 10, a connecting part 39 connected to the proximal end of the coil 10, and a pusher 37 connected to the coil 10 via the connecting part 39.

[0086] The in-vivo indwelling device 1 preferably has a detachment mechanism that detaches the coil 10 from the pusher 37. Examples of detachment mechanisms include hydraulic, electrical, and mechanical mechanisms, and among these, an electrical detachment mechanism is preferably used. In the detachment mechanism, the connection part 39 is preferably heated and cut by electrical or thermal energy supplied via the pusher 37, thereby detaching the coil 10 from the pusher 37. In this case, the connection part 39 is preferably heated by a high-frequency current supplied between the distal end of the pusher 37 and the counter electrode.

[0087] The shape of the connection portion 39 is not particularly limited, and may be a line, a rod, a column, a polygonal column, a cylinder, a polygonal tube, a truncated cone, a truncated polygonal pyramid, or a combination thereof.

[0088] The connecting portion 39 preferably contains a material that melts or dissolves when heated. The connecting portion 39 can be cut by Joule heat. Such a material includes a synthetic resin material, and it is preferable to use a hydrophilic resin of a synthetic polymer substance such as polyvinyl alcohol (PVA), PVA cross-linked polymer, PVA water-absorbing gel freeze-thaw elastomer, or polyvinyl alcohol-based polymer such as ethylene-vinyl alcohol copolymer.

[0089] The pusher 37 is a rod-like or wire-like member used to hold the indwelling device 1 and push it distally. The pusher 37 can be composed of one or more members. The pusher 37 can be composed of a wire member, a coil member, or a combination thereof. The pusher 37 can be composed of a conductive material such as stainless steel.

[0090] 2. Manufacturing method of in-vivo indwelling device A method for manufacturing an in-vivo indwelling device according to one embodiment of the present invention includes the steps of: preparing a coil; forming a roughened surface portion on the surface of the prepared coil, the roughened surface portion having a surface roughness Ra of 0.010 μm or more and 0.50 μm or less; and applying a drug to the roughened surface portion. Here, the surface roughness Ra is the arithmetic mean roughness over a reference length of a roughness curve in the circumferential direction of the surface of the coil on which the roughened surface portion is formed, and the reference length is one-fourth the circumferential length of the coil. According to the above method for manufacturing an in-vivo indwelling device, forming a roughened surface portion on the coil can increase the bonding strength with the drug. Therefore, it is possible to prevent the drug from falling off the coil immediately after placing the coil in the affected area during the procedure, ensuring effective sustained drug release for treatment.

[0091] A method for manufacturing the in-vivo indwelling device 1 according to one embodiment of the present invention will be described with reference to Figures 12 to 15. Figure 12 is a flowchart showing a method for manufacturing the in-vivo indwelling device 1 according to one embodiment of the present invention. Figures 13 and 15 are flowcharts showing modified examples of the method for manufacturing the in-vivo indwelling device 1 shown in Figure 12. Figure 14 is a flowchart showing a modified example of the method for manufacturing the in-vivo indwelling device 1 shown in Figure 13.

[0092] By carrying out the manufacturing method described in this specification, it is possible to obtain an in-vivo indwelling device 1 having a coil 10 to which a drug 40 is applied, as shown in FIGS.

[0093] First, as shown in Figure 12, a coil preparation step (step S1) is performed. The coil preferably has a longitudinal axis direction x, a circumferential direction, and a radial direction. The coil preferably has a distal end and a proximal end in the longitudinal axis direction. The proximal side of the coil refers to the direction toward the user or surgeon's hand relative to the longitudinal axis direction of the coil, and the distal side refers to the opposite side of the proximal side, i.e., the direction toward the treatment target. The radial direction of the coil refers to the radial direction of the coil, and inward in the radial direction of the coil refers to the direction toward the center of the longitudinal axis of the coil, and outward in the radial direction refers to the direction extending radially from the center of the longitudinal axis opposite to the inward side. The circumferential direction of the coil refers to the direction around the longitudinal axis.

[0094] The coil is formed by winding one or more wires in a spiral shape. Examples of the wires include solid wires, twisted wires, and coiled wires, among which solid wires are preferred. It is also preferred that the wires are not coil wires.

[0095] A wire wound in a spiral shape is sometimes called a primary coil. A primary coil that is further formed into a spiral or three-dimensional shape is sometimes called a secondary coil. In the manufacturing method shown in Figure 12, the coil prepared in step S1 is a primary coil.

[0096] As shown in Figure 12, a step (step S2) is performed on the surface of the prepared coil to form a roughened surface portion with a surface roughness Ra of 0.010 μm or more and 0.50 μm or less. Here, the surface roughness Ra is the arithmetic mean roughness over a reference length of the roughness curve in the circumferential direction of the surface of the coil on which the roughened surface portion has been formed, and the reference length is one-fourth the circumferential length of the coil. The method described in "1. In-vivo indwelling device" can be referenced for measuring the surface roughness Ra.

[0097] In step S2, one or more rough surface portions may be formed on the prepared coil. When multiple rough surface portions are formed, the surface roughness Ra of one rough surface portion may be larger than the surface roughness Ra of the other rough surface portions.

[0098] In step S2, a rough surface portion may be formed only on the outer peripheral surface of the prepared coil. In step S2, a rough surface portion may be formed only on the inner peripheral surface of the prepared coil. In step S2, a rough surface portion may be formed on both the outer peripheral surface and the inner peripheral surface of the prepared coil.

[0099] In step S2, when rough surface portions are formed on the outer and inner surfaces of the prepared coil, the surface roughness Ra of the rough surface portion 20 of the outer surface 12 may be larger than the surface roughness Ra of the rough surface portion 20 of the inner surface 13.

[0100] In step S2, the rough surface portion formed may have one or more recesses.

[0101] In the step of forming the rough surface portion (step S2), a dry process or a wet process may be performed. For example, in the step of forming the rough surface portion (step S2), it is preferable to irradiate the surface of the prepared coil with at least one of plasma and laser light. By irradiating at least one of plasma and laser light, a highly accurate roughening process can be achieved. Furthermore, by changing the type and parameters of the plasma or laser light, the surface shape and size of the rough surface portion can be changed.

[0102] In step S2, the plasma can be irradiated using a known plasma generator capable of generating plasma in which molecules constituting a gas are ionized into positive ions and electrons. In step S2, it is preferable to irradiate the coil surface with a plasma flow ejected from the plasma generator. In step S2, atmospheric pressure plasma generated under atmospheric pressure may be used, or vacuum plasma generated under vacuum, i.e., at a pressure lower than atmospheric pressure, may be used. In step S2, high-temperature plasma (thermal plasma) or low-temperature plasma may be used. The method for generating plasma is not particularly limited, and it can be generated using, for example, high frequency or microwave. Gas species that can be used to form plasma include, for example, rare gases such as argon and helium, carbon dioxide, carbon monoxide, oxygen, nitrogen, methane, ethane, and tetrafluoromethane.

[0103] In step S2, the laser light to be irradiated may be visible light, ultraviolet light, infrared light, etc. Known types of lasers may be used, such as YAG lasers, fiber lasers, semiconductor lasers, carbon dioxide lasers, helium-neon lasers, excimer lasers, and argon lasers. In step S2, the laser light to be irradiated may be of either continuous wave or pulsed wave type.

[0104] In the step of forming the rough surface portion (step S2), the surface of the prepared coil may be subjected to at least one of corona discharge treatment, blast treatment, polishing treatment, etching treatment, and sandpaper treatment.

[0105] As shown in FIG. 12, a step (step S3) of applying a medicinal agent to the rough surface portion is performed. Step S3 is preferably performed after step S2. If a rough surface portion is formed on the outer peripheral surface of the prepared coil in step S2, it is preferable to apply a medicinal agent to the rough surface portion on the outer peripheral surface in step S3. By this method, a coil 10 as shown in FIGS. 3 and 4 can be obtained. If a rough surface portion is formed on the inner peripheral surface of the prepared coil in step S2, it is preferable to apply a medicinal agent to the rough surface portion on the inner peripheral surface in step S3. By this method, a coil 10 as shown in FIGS. 5 and 6 can be obtained. If a rough surface portion is formed on both the outer peripheral surface and the inner peripheral surface of the prepared coil in step S2, it is preferable to apply a medicinal agent to the rough surface portion on the outer peripheral surface and the rough surface portion on the inner peripheral surface, respectively. By this method, a coil 10 as shown in FIG. 7 can be obtained.

[0106] In step S3, it is preferable not to apply a drug to any portion of the coil surface other than the roughened portion. This is because there is a risk that the drug will fall off from any portion of the coil surface other than the roughened portion immediately after the coil is placed on the affected area during the procedure. For example, if a roughened portion is formed only on the outer circumferential surface of the prepared coil in step S2, it is preferable not to apply a drug to the inner circumferential surface of the prepared coil in step S3. This method can obtain a coil 10 as shown in FIG. 3. Similarly, if a roughened portion is formed only on the inner circumferential surface of the prepared coil in step S2, it is preferable not to apply a drug to the outer circumferential surface of the prepared coil in step S3. This method can obtain a coil 10 as shown in FIG. 5.

[0107] In step S3, a drug may be applied to the portion of the coil surface other than the roughened portion. By applying a drug to the portion of the coil surface other than the roughened portion, the drug elution rate can be made different between the portion other than the roughened portion and the roughened portion, thereby increasing the options for treatment methods. For example, if a roughened portion is formed only on the outer surface of the prepared coil in step S2, a drug may be applied to the roughened portion on the outer surface and the inner surface in step S3. This method can obtain a coil 10 as shown in FIG. 4. Similarly, if a roughened portion is formed only on the inner surface of the prepared coil in step S2, a drug may be applied to the roughened portion on the inner surface and the outer surface in step S3. This method can obtain a coil 10 as shown in FIG. 6.

[0108] In the step of applying a drug to the rough surface portion (step S3), the amount of drug applied per unit length of the coil may be different between the outer peripheral surface and the inner peripheral surface of the coil. For example, in step S3, it is preferable that the amount of drug applied per unit length of the coil is greater on the outer peripheral surface than on the inner peripheral surface of the coil. In step S3, the amount of drug applied per unit length of the coil may be different between the rough surface portion of the outer peripheral surface of the coil and the rough surface portion of the inner peripheral surface of the coil. For example, in step S3, the amount of drug applied per unit length of the coil may be different between the rough surface portion of the outer peripheral surface of the coil and the rough surface portion of the inner peripheral surface of the coil.

[0109] In step S3, the method for applying the drug to the coil is not particularly limited. Examples of methods for applying the drug include brush coating, roll coating, dip coating, and spray coating. In any of these methods, the drug applied to the surface of the coil can be a liquid drug, or a solution in which capsules 41 containing the drug are present in a solvent.

[0110] After completion of step S3, the drug may be held on the surface of the coil as a drug layer, or may be held on the surface of the coil in the form of microcapsules or the like.

[0111] For other details regarding the type and structure of the drug applied to the coil in step S3 and the type of bioadhesive, please refer to the explanation given in "1. Intra-body indwelling device."

[0112] With reference to Figure 13, a modified example of the manufacturing method for the in-vivo indwelling device shown in Figure 12 will be described. The manufacturing method shown in Figure 13 differs from the manufacturing method shown in Figure 12 in that a three-dimensional shape is given to the coil to which the drug has been applied.

[0113] 12, the manufacturing method shown in Fig. 13 includes a step of preparing a coil (step S11), a step of forming a rough surface portion having a surface roughness Ra of 0.010 μm or more and 0.50 μm or less on the surface of the prepared coil (step S12), and a step of applying a drug to the rough surface portion (step S13). Steps S11, S12, and S13 are similar to steps S1, S2, and S3, respectively, and therefore will not be described here.

[0114] As shown in FIG. 13, the above manufacturing method preferably further includes a step (step S14) of imparting a three-dimensional shape to the coil to which the drug has been applied. Step S14 is preferably performed after step S13. Here, the coil to which the drug has been applied is a primary coil, and therefore a secondary coil can be formed by imparting a three-dimensional shape to this primary coil. In step S14, the three-dimensional shape can be imparted, for example, by winding the coil (primary coil) around a mandrel. In step S14, the three-dimensional shape refers to a three-dimensional shape.

[0115] With reference to Figure 14, a modified example of the method for manufacturing the in-vivo indwelling device shown in Figure 13 will be described. The manufacturing method shown in Figure 14 differs from the manufacturing method shown in Figure 13 in that a three-dimensional shape is imparted to a coil with a roughened surface portion formed thereon, and a drug is applied to the coil with the three-dimensional shape imparted. In detail, the manufacturing method shown in Figure 14 further includes a step of imparting a three-dimensional shape to the coil with a roughened surface portion formed thereon, between the step of forming the roughened surface portion and the step of applying a drug to the roughened surface portion. In this way, the three-dimensional shape is imparted after the roughened surface portion is formed and before the drug is applied, i.e., before the coil hardens due to the application of the drug, so that it is easy to process into a complex three-dimensional shape.

[0116] The manufacturing method shown in Fig. 14 includes a step of preparing a coil (step S21), a step of forming a roughened surface portion having a surface roughness Ra of 0.010 μm or more and 0.50 μm or less on the surface of the prepared coil (step S22), a step of imparting a three-dimensional shape to the coil with the roughened surface portion formed thereon (step S23), and a step of applying a drug to the roughened surface portion (step S24). As shown in Fig. 14, it is preferable to perform steps S21, S22, and S23 in this order.

[0117] Steps S21, S22, and S24 can be performed in the same manner as steps S1 and S11, steps S2 and S12, and steps S3 and S13, respectively. Step S23 can be performed in the same manner as step S14.

[0118] With reference to Figure 15, a modified example of the manufacturing method for the in-vivo indwelling device shown in Figure 12 will be described. The manufacturing method shown in Figure 15 differs from the manufacturing method shown in Figure 12 in that a coil having a three-dimensional shape is prepared in the coil preparation step. In detail, the coil prepared in step S1 in the manufacturing method shown in Figure 12 is a primary coil, whereas the coil prepared in step S31 in the manufacturing method shown in Figure 15 is a secondary coil.

[0119] 15 includes the steps of preparing a coil having a three-dimensional shape (step S31), forming a roughened surface portion having a surface roughness Ra of 0.010 μm or more and 0.50 μm or less on the surface of the prepared coil (secondary coil) (step S32), and applying a drug to the roughened surface portion (step S33). By preparing a secondary coil having a three-dimensional shape in advance in this way, forming a roughened surface portion on the prepared secondary coil, and applying a drug, it is possible to obtain an in-vivo indwelling device having a complex three-dimensional shape, because the three-dimensional shape is imparted to the coil before it hardens due to the application of the drug.

[0120] As shown in FIG. 15, it is preferable to perform the steps S31, S32, and S33 in this order.

[0121] In step S31, a coil (primary coil) that has not been given a three-dimensional shape may be wound around a mandrel to prepare a coil (secondary coil). Step S31 can be performed in the same manner as steps S14 and S23. Steps S32 and S33 can be performed in the same manner as steps S2, S12, and S22, and steps S3, S13, and S24, respectively.

[0122] When carrying out the above manufacturing method, the configurations and methods described in "1. In-vivo indwelling device" can be referred to as appropriate. [Explanation of symbols]

[0123] 1: Intravital device 10: Coil 11:Lumen 12: Outer surface 13: Inner surface 20: Rough surface area 21: Recess 31: Wire rod 33: Head 35: Tensile resistance member 36: Folded section 37: Pusher 39: Connection 40: Drugs 41: Capsule x: longitudinal axis direction D: Depth of recess

Claims

1. a coil having a rough surface portion with a surface roughness Ra of 0.010 μm or more and 0.50 μm or less; and a drug disposed on the surface of the rough surface portion. Here, the surface roughness Ra of the coil is the arithmetic mean roughness over a reference length of the roughness curve in the circumferential direction of the surface of the coil, and the reference length is one-fourth the circumferential length of the coil.

2. 2. The in-vivo indwelling device according to claim 1, wherein the rough surface portion is disposed over the entire length of the coil in the longitudinal direction.

3. the coil has the rough surface portions on both its outer and inner peripheral surfaces, 3. The in-vivo indwelling device according to claim 1, wherein the rough surface portion of the outer circumferential surface has a surface roughness Ra greater than the surface roughness Ra of the rough surface portion of the inner circumferential surface.

4. 4. The in-vivo indwelling device according to claim 3, wherein the amount of the drug applied to the rough surface portion of the outer circumferential surface is greater than the amount of the drug applied to the rough surface portion of the inner circumferential surface.

5. 3. The in-vivo indwelling device according to claim 1, wherein the drug is distributed over the entire rough surface portion.

6. 3. The in-vivo indwelling device according to claim 1, wherein the rough surface portion has a recess, and the drug is disposed in the recess.

7. 3. The in-vivo indwelling device according to claim 1, wherein the drug is encapsulated in a capsule containing a biodegradable material.

8. 3. The in-vivo indwelling device according to claim 1, wherein the drug has at least one of an anti-inflammatory effect, an antioxidant effect, a hypotensive effect, and an inhibitory effect on shear stress sensing.

9. providing a coil; forming a roughened surface portion having a surface roughness Ra of 0.010 μm or more and 0.50 μm or less on the surface of the prepared coil; and applying a drug to the rough surface portion. Here, the surface roughness Ra is the arithmetic mean roughness over a reference length of the roughness curve in the circumferential direction of the surface of the coil on which the rough surface portion is formed, and the reference length is one-fourth the circumferential length of the coil.

10. The method for manufacturing an in-vivo indwelling device according to claim 9, wherein in the step of forming the rough surface portion, the surface of the prepared coil is irradiated with at least one of plasma and laser light.

11. 11. The method for manufacturing an in-vivo indwelling device according to claim 9, further comprising the step of imparting a three-dimensional shape to the coil to which the drug has been applied.

12. 11. The method for manufacturing an in-vivo indwelling device according to claim 9 or 10, further comprising a step of imparting a three-dimensional shape to the coil on which the rough surface portion has been formed, between the step of forming the rough surface portion and the step of applying a drug to the rough surface portion.

13. The method for manufacturing an in-vivo indwelling device according to claim 9 or 10, wherein in the step of preparing a coil, a coil having a three-dimensional shape is prepared.

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