Indwelling system for in vivo indwelling tool and method for manufacturing in vivo indwelling tool

Abstract

An indwelling system (1) for an in vivo indwelling device comprising a first coil (11) and a second coil (21) having a coil hardness less than that of the first coil (11), wherein: a drug is disposed on the surface of the first coil (11); and, on the surface of the second coil (21), either a drug is disposed so that the amount of the drug per unit length of the coil is less than that of the first coil (11), or no drug is disposed.

Description

In-vivo indwelling device placement system and method of manufacturing an in-vivo indwelling device

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

[0002] Endovascular treatment 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 treatment, 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 the procedure of filling 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, coils must be threaded along the inner surface of the aneurysm to form a framework within 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.

[0003] US Patent Application Publication No. 2007 / 0299461 JP 2005-513081 A JP 2013-537046 A JP 2015-195978 A

[0004] Although drugs may be applied to all of the multiple coils used in a single procedure, the application of drugs may cause the coils to become stiff, which may reduce operability. Therefore, an object of the present invention is to provide an in-vivo indwelling device placement system and a method for manufacturing an in-vivo indwelling device that can deliver the amount of drug required for treatment to the aneurysm while minimizing the impact of reduced operability.

[0005] The following are placement systems for in-vivo indwelling devices according to embodiments of the present invention that have been able to solve the above problems: [1] A placement system for an in-vivo indwelling device, comprising: a first coil; and a second coil having a coil hardness less than that of the first coil, wherein a drug is disposed on the surface of the first coil, and the drug is either disposed on the surface of the second coil in such a way that the amount of drug per unit length of the coil is less than that of the first coil, or no drug is disposed on the surface of the second coil.

[0006] Furthermore, the indwelling system for a biological indwelling device according to the embodiment is preferably any one of the following [2] to

[10] . [2] The indwelling system for a biological indwelling device according to [1], wherein the drug disposed on the first coil is distributed over the entire longitudinal axis of the first coil. [3] The indwelling system for a biological indwelling device according to [1] or [2], wherein the drug disposed on the first coil is distributed on the outer and inner circumferential surfaces of the first coil. [4] The indwelling system for a biological indwelling device according to any one of [1] to [3], wherein the drug disposed on the first coil is distributed on the outer circumferential surface of the first coil, but not on the inner circumferential surface of the first coil. [5] The indwelling system for a biological indwelling device according to any one of [1] to [4], further comprising a first stretch resistance member disposed in the lumen of the first coil, wherein a drug is disposed on the surface of the first stretch resistance member. [6] The coil hardness of the first coil is 5.0 x 10 －９ [7] The placement system for an in-vivo indwelling device according to any one of [1] to [5], further comprising a third coil having a coil hardness greater than that of the first coil, and a drug is disposed on the surface of the third coil so that the amount of drug per unit length of the coil is greater than that of the first coil. [8] The coil hardness of the third coil is 3.5 x 10 －８[9] The indwelling system for a biological indwelling device according to any one of [1] to [8], wherein at least one of the drugs disposed in the first coil and the second coil is encapsulated in a capsule containing a biodegradable material.

[10] The indwelling system for a biological indwelling device according to any one of [1] to [9], wherein at least one of the drugs disposed in the first coil and the second coil has at least one of an anti-inflammatory effect, an antioxidant effect, a hypotensive effect, a vasoconstrictor effect, an anticoagulant effect, and a shear stress sensing inhibitory effect.

[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:

[11] A manufacturing method of an in-vivo indwelling device, which includes the step of applying a drug if the hardness of the coil is equal to or greater than a first reference value, and not applying a drug if the hardness of the coil is less than the first reference value.

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

[12] to

[14] .

[0009]

[12] The first reference value is 5.0 × 10 －９ N / mm or more 1.5×10 －８

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

[11] , wherein the stiffness of the coil is equal to or greater than a first reference value, and the amount of the drug applied per unit length of the coil is increased when the stiffness of the coil is equal to or greater than a second reference value that is higher than the first reference value, compared to when the stiffness of the coil is less than the second reference value and equal to or greater than the first reference value.

[14] The second reference value is 3.5 x 10 －８ N / mm or more 4.5×10 －８ The method for producing an in-vivo indwelling device according to

[13] , wherein the strength is 0.1 N / mm or less.

[0010] According to the above-described placement system for an in-vivo indwelling device, the second coil, which is softer than the first coil, is loaded with a smaller amount of drug than the first coil or no drug at all, thereby maintaining the flexibility of the second coil and enabling the coil to be placed within the aneurysm while ensuring operability. Furthermore, because the first coil is harder than the second coil, the rate of change in coil hardness before and after drug application is smaller for the first coil than for the second coil. Therefore, even if the first coil becomes harder due to drug application, the first coil can be prevented from being affected by reduced operability. By combining the above-described first and second coils, a placement system for an in-vivo indwelling device can be provided that can apply the amount of drug required for treatment to the affected area and also ensures operability.

[0011] Furthermore, according to the above-described method for manufacturing an in-vivo indwelling device, a drug is applied to a coil with a small change in stiffness before and after application of the drug, so even if the coil becomes stiffer due to application of the drug, the effect of a decrease in coil operability can be suppressed. Furthermore, with such a coil, the amount of drug required for treatment can be applied to the affected area.

[0012] 1 is a schematic diagram of an indwelling system for a biological indwelling device according to an embodiment of the present invention. FIG. 1 is a cross-sectional view (partially a side view) taken along the longitudinal axis direction of the first coil shown in FIG. 1. FIG. 2 is a cross-sectional view (partially a side view) showing a modified example of the first coil shown in FIG. 2. FIG. 1 is a cross-sectional view (partially a side view) taken along the longitudinal axis direction of the second coil shown in FIG. 1. FIG. 4 is a cross-sectional view (partially a side view) showing a modified example of the second coil shown in FIG. 4. FIG. 4 is a cross-sectional view (partially a side view) showing another modified example of the second coil shown in FIG. 4. FIG. 15 is a schematic diagram of a modified example of the indwelling system for a biological indwelling device shown in FIG. 1. FIG. 7 is a cross-sectional view (partially a side view) taken along the longitudinal axis direction of the third coil shown in FIG. 7. FIG. 8 is a cross-sectional view (partially a side view) showing a modified example of the third coil shown in FIG. 8. FIG. 2 is a cross-sectional view perpendicular to the longitudinal axis direction of the first stretch resistance member shown in FIG. 2. FIG. 10 is a cross-sectional view showing a modified example of the first stretch resistance member shown in FIG. 10. FIG. 11 is a cross-sectional view perpendicular to the longitudinal axis direction of the second stretch resistance member shown in FIG. 4. FIG. 12 is a cross-sectional view showing a modified example of the second stretch resistance member shown in FIG. 12. Fig. 16 is a cross-sectional view perpendicular to the longitudinal axis direction of the third stretch resistance member shown in Fig. 8. Fig. 17 is a cross-sectional view showing a modified example of the third stretch resistance member shown in Fig. 14. Fig. 18 is a flowchart showing a method for manufacturing an in-vivo indwelling device according to one embodiment of the present invention. Fig. 19 is a flowchart showing a modified example of the method for manufacturing the in-vivo indwelling device shown in Fig. 16.

[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 and other drawings. The dimensions of various components in the drawings may differ from their actual dimensions, as priority is given to helping understand the features of the present invention.

[0014] 1. Placement System for Intracorporeal Device Hereinafter, an in-vivo placement system for an intracorporeal device may be simply referred to as an in-vivo placement system, and an intracorporeal device may simply be referred to as an in-vivo placement device. Examples of uses for placement systems 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 artery aneurysms, and abdominal aneurysms. Of these, a placement system for cerebral aneurysms is preferred. Examples of the shape of the aneurysm include fusiform and saccular.

[0015] The gist of one embodiment of the present invention is that the indwelling system includes a first coil and a second coil having a coil hardness less than that of the first coil, a drug disposed on the surface of the first coil, and a drug disposed on the surface of the second coil so that the amount of drug per unit length of the coil is less than that of the first coil, or no drug is disposed on the surface. According to the above-described indwelling device system, the second coil, which is softer than the first coil, is provided with a smaller amount of drug than the first coil, or no drug is disposed on the second coil, thereby maintaining the flexibility of the second coil and enabling the coil to be placed within the aneurysm while ensuring operability. Furthermore, because the first coil is harder than the second coil, the rate of change in the coil hardness before and after drug application is smaller than that of the second coil. Therefore, even if the first coil becomes harder due to drug application, the first coil can be prevented from being affected by reduced operability. By combining the first coil and second coil as described above, a system for an indwelling device for an indwelling device can be provided that can deliver the amount of drug required for treatment to the affected area while also ensuring operability.

[0016] The placement system preferably comprises a first in-vivo indwelling device having a first coil and a second in-vivo indwelling device having a second coil. The first in-vivo indwelling device preferably comprises a first coil and a first stretch resisting member disposed in the lumen of the first coil. The second in-vivo indwelling device preferably comprises a second coil and a second stretch resisting member disposed in the lumen of the second coil. The placement system preferably comprises a plurality of coils including a first coil, a second coil, and a third coil. The placement system preferably comprises a first in-vivo indwelling device having a first coil, a second in-vivo indwelling device having a second coil, and a third in-vivo indwelling device having a third coil. The third in-vivo indwelling device preferably comprises a third coil and a third stretch resisting member disposed in the lumen of the third coil.

[0017] Embolization has three phases: framing, filling, and finishing. The first coil and second coil of the placement system can each be used in one phase, or across two or three phases. Of these, the first coil is preferably used for framing and / or filling. The second coil is preferably used for finishing. The third coil, described below, is preferably used for framing and / or filling, and more preferably for framing.

[0018] An indwelling system for an in-vivo indwelling device according to one embodiment of the present invention will be described with reference to Figures 1 to 15. Figure 1 is a schematic diagram of an indwelling system for an in-vivo indwelling device according to one embodiment of the present invention. Figure 2 is a cross-sectional view (partially a side view) taken along the longitudinal axis of the first coil shown in Figure 1. Figure 3 is a cross-sectional view (partially a side view) showing a modified version of the first coil shown in Figure 2. Figure 4 is a cross-sectional view (partially a side view) taken along the longitudinal axis of the second coil shown in Figure 1. Figure 5 is a cross-sectional view (partially a side view) showing a modified version of the second coil shown in Figure 4. Figure 6 is a cross-sectional view (partially a side view) showing another modified version of the second coil shown in Figure 4. Figure 7 is a schematic diagram of a modified version of the indwelling system for an in-vivo indwelling device shown in Figure 1. Figure 8 is a cross-sectional view (partially a side view) taken along the longitudinal axis of the third coil shown in Figure 7. Figure 9 is a cross-sectional view (partially a side view) showing a modified version of the third coil shown in Figure 8. Figure 10 is a cross-sectional view perpendicular to the longitudinal axis of the first extension resistance member shown in Figure 2. Fig. 11 is a cross-sectional view showing a modified example of the first stretch resistance member shown in Fig. 10. Fig. 12 is a cross-sectional view perpendicular to the longitudinal axis direction of the second stretch resistance member shown in Fig. 4. Fig. 13 is a cross-sectional view showing a modified example of the second stretch resistance member shown in Fig. 12. Fig. 14 is a cross-sectional view perpendicular to the longitudinal axis direction of the third stretch resistance member shown in Fig. 8. Fig. 15 is a cross-sectional view showing a modified example of the third stretch resistance member shown in Fig. 14. As shown in Fig. 1, the placement system 1 has a first coil 11 and a second coil 21.

[0019] In the following, when describing the configuration common to the first coil 11 and the second coil 21, they may be referred to simply as "coils."

[0020] As can be seen from Figures 2 to 6, 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 x. The proximal side of the coil refers to the direction toward the user or surgeon with respect to the longitudinal axis direction x of the coil, and the distal side refers to the opposite direction from the proximal side, i.e., the direction toward the treatment target. Note that in Figures 2 to 6 and 8 to 9, the right side of the figure is the proximal side, and the left side of the figure is the distal side. 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.

[0021] In the longitudinal axis direction x, the first coil 11 and the second coil 21 may have the same length or different lengths. In the longitudinal axis direction x, the second coil 21 may be longer than the first coil 11. In the longitudinal axis direction x, the first coil 11 may be longer than the second coil 21.

[0022] As shown in Figures 1 to 3, the first coil 11 is preferably made of a first wire material 12. As shown in Figures 1 and 4 to 6, the second coil 21 is preferably made of a second wire material 22. Hereinafter, when describing the configuration common to the first wire material 12 and the second wire material 22, these or each of them may be simply referred to as a wire material.

[0023] The coil is formed by winding one or more wires in a spiral shape. Examples of the wires include solid wires, twisted wires, and coil-wound coil wires, among which solid wires are preferred. It is also preferred that the wires are not coil wires. It is preferred that the first wire 12 and the second wire 22 are each solid wires.

[0024] A wire wound in a spiral shape is sometimes called a primary coil. A primary coil that is further bent into a spiral or three-dimensional shape is sometimes called a secondary coil. Unless otherwise specified, the coil in this specification refers to the configuration of the primary coil. It is preferable that a primary coil such as that shown in FIGS. 2 to 6 and 8 to 9 be bent to form a secondary coil such as that shown in FIGS. 1 and 7.

[0025] The wire is preferably biocompatible and flexible. Examples of materials constituting the wire include platinum, gold, titanium, tungsten, alloys thereof, stainless steel, and other metal materials, or combinations thereof. Of these, the wire is more preferably made of a platinum-tungsten alloy.

[0026] The wire has a longitudinal axis direction and a distal end and a proximal end along the longitudinal axis direction of the wire. The wire 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 along the longitudinal axis direction. The cross-sectional shape of the wire perpendicular to the longitudinal axis direction may be circular, elliptical, polygonal, or a combination thereof. The cross-sectional shape of the wire perpendicular to the longitudinal axis direction may be the same throughout the entire longitudinal axis direction of the wire, or may vary depending on the position along the longitudinal axis.

[0027] The outer diameter of the wire 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.

[0028] Outer diameter D of the first wire 12 １１ and the outer diameter D of the second wire 22 ２１ The outer diameter D of the first wire 12 may be the same. １１ and the outer diameter D of the second wire 22 ２１ The outer diameter D of the first wire 12 may be different from that of the second coil 21 so that the first coil 11 is more likely to be hard than the second coil 21. １１ is the outer diameter D of the second wire 22 ２１ The outer diameter D of the first wire 12 may be larger than １１ is the outer diameter D of the second wire 22 ２１ It may be smaller than

[0029] The outer diameter of the wire may be the same along the longitudinal axis of the wire, or may vary depending on the position along the longitudinal axis of the wire. If the cross section of the wire is not circular, the outer diameter of the wire refers to the diameter equivalent to a circle.

[0030] 2 and 3, the first coil 11 preferably has a bore 111 extending in the longitudinal axis direction x. The first coil 11 preferably has an outer circumferential surface 112 and an inner circumferential surface 113. The outer circumferential surface 112 of the first coil 11 faces the outside of the first coil 11, i.e., the outer side in the radial direction, and the inner circumferential surface 113 of the first coil 11 faces the bore 111. A first extension resistance member 15, which will be described later, is preferably disposed in the bore 111.

[0031] 4 to 6, the second coil 21 preferably has a lumen 211 extending in the longitudinal axis direction x. The second coil 21 preferably has an outer circumferential surface 212 and an inner circumferential surface 213. The outer circumferential surface 212 of the second coil 21 faces the outside of the second coil 21, i.e., the outer side in the radial direction, and the inner circumferential surface 213 of the second coil 21 faces the lumen 211. A second extension resistance member 25, which will be described later, is preferably disposed in the lumen 211.

[0032] The coil may be a single-layer coil or a multi-layer coil having multiple layers. A portion of the coil in the longitudinal axis direction x may be single-layered, and the remaining portion may be multi-layered.

[0033] The coil density, i.e., the winding spacing, is not particularly limited, and can be close-wound, pitch-wound, or a combination of these. In the coil, adjacent wire rods may be in contact with each other over a portion of the longitudinal axis direction x, or adjacent wire rods may be in contact with each other over the entire longitudinal axis direction x. A state in which adjacent wire rods are in contact with each other in the longitudinal axis direction x of the coil is called close-wound, and a state in which they are not in contact is called pitch-wound. A state in which adjacent wire rods are not in contact with each other in the longitudinal axis direction x of the coil is called a space between them. It is preferable that the first coil 11 and the second coil 21 are each close-wound coils.

[0034] The cross-sectional shape of the coil perpendicular to the longitudinal axis direction x may be circular, elliptical, polygonal, or a combination thereof. The elliptical shape includes an elliptical shape, an oval shape, and a rounded rectangular shape. The same applies to the following description.

[0035] The maximum and minimum outer diameters of the coil 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 are also acceptable to be 400 μm or less, 380 μm or less, or 350 μm or less.

[0036] Outer diameter D of the first coil 11 １２ and the outer diameter D of the second coil 21 ２２ The outer diameter D of the first coil 11 may be the same. １２ and the outer diameter D of the second coil 21 ２２ The outer diameter D of the first coil 11 may be different from that of the second coil 21 so that the first coil 11 is more likely to be stiff than the second coil 21. １２ is the outer diameter D of the second coil 21 ２２ The outer diameter D of the first coil 11 may be smaller than １２ is the outer diameter D of the second coil 21 ２２ Here, the outer diameter D of the first coil 11 may be larger than １２ and the outer diameter D of the second coil 21 ２２ and respectively indicate the average value of the outer diameter in the longitudinal axis direction x of the coil.

[0037] The outer diameter and / or inner diameter of the coil may be the same in the longitudinal axis direction x of the coil, or may be different depending on the position in the longitudinal axis direction x of the coil. Note that if the cross section of the coil is not circular, the outer diameter of the coil refers to the circle-equivalent diameter. Also, if the cross section of the lumen of the coil is not circular, the inner diameter of the coil refers to the circle-equivalent diameter.

[0038] The coil may have a constant outer diameter in the longitudinal direction x. A constant outer diameter means that the outer diameter of the coil is substantially constant throughout the entire longitudinal direction x, and includes cases where the change in the outer diameter of the coil is within a range of ±5% throughout the entire longitudinal direction x.

[0039] Although not shown, the coil may have a transition section in which the outer diameter decreases toward the distal side. This allows the flexibility of the coil to be gradually increased from the distal side to the proximal side. In the transition section, the outer diameter of the coil may decrease in a tapered manner toward the distal side. Here, "tapered" includes an embodiment in which the outer diameter of the wire material constituting the coil decreases with each turn, resulting in a tapered envelope of the outer diameter of the coil in the transition section. In the transition section, the outer diameter of the coil may decrease in a stepped manner toward the distal side. Here, "stepped" includes an embodiment in which the outer diameter of the wire material constituting the coil decreases every two or more turns.

[0040] When the coil is divided into two equal parts, a distal part and a proximal part, along the longitudinal axis x, the average outer diameter of the coil at the proximal part may be smaller than the average outer diameter at the distal part. The smaller outer diameter at the proximal part can increase the flexibility of the proximal part of the coil, thereby ensuring operability.

[0041] In this specification, the coil hardness refers to the coil hardness in the state of the primary coil. １ (unit: N / mm) and the coil hardness S of the second coil 21 (primary coil) ２ (unit: N / mm) can be calculated using the following formula: １ =D １１ ４ ×G / (8D １２ ３ ×n １ ) S ２ =D ２１ ４ ×G / (8D ２２ ３ ×n ２ ) Here D １１ is the outer diameter of the first wire 12 (unit: mm), G is the shear modulus of elasticity (unit: Pa (N / mm ２ )) D １２ is the outer diameter of the first coil 11 (unit: mm), n １ is the number of turns of the first coil 11 (unitless), D ２１ is the outer diameter of the second wire 22 (unit: mm), D ２２ is the outer diameter of the second coil 21 (unit: mm), n２ is the number of turns (unitless) of the second coil 21. When the outer diameter of the first wire 12 is not constant in the longitudinal direction of the first wire 12, the outer diameter D １１ indicates the average value of the outer diameter of the first wire 12 in the longitudinal direction. ２１ , the outer diameter D of the third wire 32 described later ３１ If the outer diameter of the first coil 11 is not constant in the longitudinal direction of the first coil 11, the outer diameter D １２ indicates the average value of the outer diameter of the first coil 11 in the longitudinal direction. ２２ , the outer diameter D of the third coil 31 described later ３２ The same applies to the number of turns n of the first coil 11. １ The number of turns of the second coil 21 is n, which is the number of turns that can be counted when the first coil 11 is viewed from the side at an angle that gives the largest number of turns. ２ , the number of turns n of the third coil 31 described later ３ The same applies to the shear modulus G. The shear modulus G varies depending on the material that makes up the wire, and if the chemical components of the wire material are the same, the value of the shear modulus G will be the same. This also applies to the following explanation. It is preferable to calculate the hardness of the coil before applying a drug. For coils with drugs or coatings applied to the surface, the hardness of the coil is measured after removing these. There are no limitations on the method for removing the drug or coating, but methods such as dissolving the drug or coating in an organic solvent such as ethanol, methanol, or chloroform can be used.

[0042] When calculating the coil hardness, the outer diameter D of the first wire 12 １１ , the outer diameter D of the first coil 11 １２ , the outer diameter D of the second wire 22 ２１ , the outer diameter D of the second coil 21 ２２ The outer diameter D of the third wire 32 described later may be a value measured by a measuring means such as a vernier caliper, a micrometer, or an image dimension measuring instrument. ３１ , the outer diameter D of the third coil 31 ３２ The same is true for .

[0043] When calculating the coil hardness, the outer diameter D of the first wire 12１１ , the outer diameter D of the first coil 11 １２ , the number of turns n of the first coil 11 １ , the outer diameter D of the second wire 22 ２１ , the outer diameter D of the second coil 21 ２２ , the number of turns n of the second coil 21 ２ The number of turns n of the third coil 31 (described later) may be a value listed in the product catalog of the coil. ３ The same is true.

[0044] The coil hardness of the first coil 11 is 5.0×10 －９ The first coil having such hardness can suppress the influence of a decrease in operability even if the first coil becomes hard by applying a drug.

[0045] The coil hardness of the first coil 11 is 8.0×10 －９ N / mm or more, and more preferably 1.0×10 －８ It is more preferable that the coil hardness of the first coil 11 is 3.5×10 －８ N / mm, and preferably less than 3.0 × 10 －８ N / mm or less, 2.0×10 －８ By disposing the drug in a coil with such hardness, it is possible to apply the amount of drug required for treatment to the affected area while minimizing the impact of reduced operability.

[0046] The coil hardness of the second coil 21 is 5.0×10 －９ The second coil 21 preferably has a hardness of less than 1.0×10 N / mm. A second coil having such hardness maintains its flexibility even when a drug is applied, allowing the coil to be placed in the aneurysm while ensuring operability. －９ N / mm or more, 2.0×10 －９ N / mm or more, and －９ N / mm or less, 3.0×10 －９ It is also acceptable for the strength to be less than N / mm.

[0047] 7, the placement system 1 may further include a third coil 31 having a coil hardness greater than that of the first coil 11. By including the third coil 31 in addition to the first coil 11 and the second coil 21, the placement system 1 can use different coils depending on the phase of the procedure, thereby expanding the options for the procedure.

[0048] As shown in Figures 7 to 9, the third coil 31 is preferably composed of a third wire 32. The third coil 31 is preferably composed of a wound third wire 32. The third coil 31 preferably has an inner cavity 311 extending in the longitudinal axis direction x. The third coil 31 preferably has an outer peripheral surface 312 and an inner peripheral surface 313. The outer peripheral surface 312 of the third coil 31 faces the outside of the third coil 31, and the inner peripheral surface 313 of the third coil 31 faces the inner cavity 311. A third extension resistance member 35, which will be described later, is preferably disposed in the inner cavity 311.

[0049] Coil hardness S of the third coil 31 (primary coil) ３ (unit: N / mm) can be calculated using the following formula: ３ =D ３１ ４ ×G / (8D ３２ ３ ×n ３ ) Here D ３１ is the outer diameter of the third wire 32 (unit: mm), G is the shear modulus of elasticity (unit: Pa (N / mm ２ )) D ３２ is the outer diameter of the third coil 31 (unit: mm), n ３ is the number of turns of the third coil 31 (unitless).

[0050] In the longitudinal axis direction x, the first coil 11 and the third coil 31 may have the same length or may be different from each other. In the longitudinal axis direction x, the third coil 31 may be longer than the first coil 11. In the longitudinal axis direction x, the first coil 11 may be longer than the third coil 31. In the longitudinal axis direction x, the second coil 21 and the third coil 31 may have the same length or may be different from each other. In the longitudinal axis direction x, the third coil 31 may be longer than the second coil 21. In the longitudinal axis direction x, the second coil 21 may be longer than the third coil 31.

[0051] Outer diameter D of the third wire 32 ３１ and the outer diameter D of the first wire 12 １１ The outer diameter D of the third wire 32 may be the same. ３１ and the outer diameter D of the first wire 12 １１ The outer diameter D of the third wire 32 may be different from that of the first coil 11 so that the third coil 31 is likely to be harder than the first coil 11. ３１ is the outer diameter D of the first wire 12 １１ The outer diameter D of the third wire 32 may be larger than ３１ is the outer diameter D of the first wire 12 １１ It may be smaller than

[0052] Outer diameter D of the third wire 32 ３１ and the outer diameter D of the second wire 22 ２１ The outer diameter D of the third wire 32 may be the same. ３１ and the outer diameter D of the second wire 22 ２１ The outer diameter D of the third wire 32 may be different from that of the second coil 21 so that the third coil 31 is likely to be harder than the second coil 21. ３１ is the outer diameter D of the second wire 22 ２１ The outer diameter D of the third wire 32 may be larger than ３１ is the outer diameter D of the second wire 22 ２１ It may be smaller than

[0053] Outer diameter D of the first coil 11 １２ and the outer diameter D of the third coil 31 ３２ The outer diameter D of the first coil 11 may be the same. １２ and the outer diameter D of the third coil 31 ３２The outer diameter D of the third coil 31 may be different from that of the first coil 11 so that the third coil 31 is more likely to be stiff than the first coil 11. ３２ is the outer diameter D of the first coil 11 １２ The outer diameter D of the third coil 31 may be smaller than ３２ is the outer diameter D of the first coil 11 １２ It may be larger than

[0054] Outer diameter D of the second coil 11 ２２ and the outer diameter D of the third coil 31 ３２ The outer diameter D of the second coil 21 may be the same. ２２ and the outer diameter D of the third coil 31 ３２ The outer diameter D of the third coil 31 may be different from that of the second coil 21 so that the third coil 31 is more likely to be stiff than the second coil 21. ３２ is the outer diameter D of the second coil 21 ２２ The outer diameter D of the third coil 31 may be smaller than ３２ is the outer diameter D of the second coil 21 ２２ It may be larger than

[0055] The coil hardness of the third coil 31 is 3.5×10 －８ The third coil having such hardness can suppress the influence of a decrease in operability even if the third coil becomes hard by adding a drug.

[0056] The coil hardness of the third coil 31 is 4.0×10 －８ N / mm or more, 8.0×10 －８ N / mm or more, and －７ N / mm or less, 2.0×10 －７ N / mm or less, 1.0×10 －７ By disposing the drug in a coil with such hardness, it is possible to apply the amount of drug required for treatment to the affected area while minimizing the impact of reduced operability.

[0057] For other preferable configurations of the third coil 31, the above description of the configurations of the first coil 11 and the second coil 21 can be referred to.

[0058] In the procedure, it is preferable that the third coil 31, the first coil 11, and the second coil 21 are inserted into the body in this order. In the procedure, the first coil 11, the third coil 31, and the second coil 21 may also be inserted into the body in this order.

[0059] 2 and 3, in the placement system 1, a drug 40 is disposed on the surface of the first coil 11. Furthermore, as can be seen from FIGS. 4 and 5, the drug 40 is disposed on the surface of the second coil 21 so that the amount of drug per unit length (mg / mm) of the coil is less than that of the first coil 11, or as shown in FIG. 6, no drug is disposed. This maintains the flexibility of the second coil 21, allowing the coil to be placed within the aneurysm while ensuring operability.

[0060] The drug 40 may be an active ingredient (drug substance) alone or a mixture with other additives. Examples of the additives include base materials, plasticizers, stabilizers, surfactants, etc. In this specification, the term "amount of drug" refers to the mass (mg) of the drug. When the drug is a mixture containing additives, the term "amount of drug" refers to the mass of the mixture.

[0061] The amount of drug per unit length of the first coil 11 can be calculated by dividing the total amount of drug 40 (total drug amount) disposed on the surface of the first coil 11 by the length in the longitudinal axis direction x (total length) of the first coil 11. The amount of drug per unit length of the second coil 21 and the amount of drug per unit length of the third coil 31 (described later) can also be calculated in a similar manner.

[0062] The amount of drug per unit area of ​​the coil on the surface of the second coil 21 (mg / mm ２ ) is the amount of drug per unit area of ​​the coil on the surface of the first coil 11 (mg / mm ２). The amount of drug per unit area of ​​the coil on the surface of the first coil 11 can be calculated by dividing the total amount of drug 40 (total drug amount) disposed on the surface of the first coil 11 by the surface area of ​​the first coil 11. Although the first coil 11 may have wires in close contact with each other, the area of ​​the portions where the wires are in close contact with each other is not included in the surface area of ​​the first coil 11 when calculating the amount of drug per unit area of ​​the first coil 11. The amount of drug per unit area of ​​the coil on the surface of the second coil 21 and the amount of drug per unit area on the surface of the third coil 31, which will be described later, can also be calculated in a similar manner.

[0063] When comparing the amounts of drug placed on different components (for example, the amounts of drug placed on the surface of the first coil 11 and the surface of the second coil 21), the drug amounts should be measured using the same method for each.

[0064] The amount of drug per unit length of the coil (mg / mm) or per unit area of ​​the coil (mg / mm) on the surface of the first coil 11 and the surface of the second coil 21 ２ ) can be measured using various elemental analyzers, for example, spectrophotometers such as Raman spectrophotometers and near-infrared spectrophotometers, X-ray fluorescence analyzers, etc. The amount of drug per unit length of the coil or the amount of drug per unit area of ​​the coil on the surface of the first coil 11 and the surface of the second coil 21 may be determined by extracting the drug disposed on the coil with a solvent and analyzing its concentration. The type of solvent is not particularly limited, and examples that can be used include ethanol, methanol, acetone, ethyl acetate, acetonitrile, N,N-dimethylacetamide, propanol, chloroform, and benzyl alcohol.

[0065] In the placement system 1, it is preferable that the drug 40 is attached to the surface of the first coil 11. In addition, in the placement system 1, the drug 40 may be attached to the surface of the second coil 21 so that the amount of drug per unit length of the coil is smaller than that of the first coil 11. In addition, the drug does not have to be attached to the surface of the second coil 21.

[0066] The types of drug 40 (active ingredient) placed in the first coil 11 and the types of drug 40 (active ingredient) placed in the second coil 21 may be the same or different from each other.

[0067] The amount of drug per unit length disposed on the surface of the second coil 21 is preferably ½ or less, more preferably ⅓ or less, and even more preferably ¼ or less of the amount of drug per unit length disposed on the surface of the first coil 11. The amount of drug per unit length disposed on the surface of the second coil 21 may be 1 / 1000 or more, 1 / 500 or more, or 1 / 100 or more of the amount of drug per unit length disposed on the surface of the first coil 11. If the amount of drug falls within this range, the flexibility of the coil is maintained even when applied to the coil, allowing the coil to be placed within the aneurysm while ensuring operability.

[0068] 2 and 3, the drug 40 disposed in the first coil 11 is preferably disposed over the entire longitudinal axis direction x of the first coil 11. This allows a larger amount of drug to be disposed in the first coil 11, making it easier to obtain the desired therapeutic effect. Note that the drug may be disposed over only a portion of the first coil 11 in the longitudinal axis direction x.

[0069] 2, the drug 40 disposed on the first coil 11 is preferably disposed on the outer peripheral surface 112 and the inner peripheral surface 113 of the first coil 11. For example, the drug 40 is preferably attached to the outer peripheral surface 112 and the inner peripheral surface 113 of the first coil 11. This allows a larger amount of drug to be disposed on the first coil 11, making it easier to obtain the desired therapeutic effect.

[0070] As shown in FIG. 3 , the drug 40 disposed on the first coil 11 is preferably disposed on the outer peripheral surface 112 of the first coil 11, but not on the inner peripheral surface 113 of the first coil 11. That is, the drug 40 is preferably disposed only on the outer peripheral surface 112 of the first coil 11. For example, the drug 40 is preferably attached to the outer peripheral surface 112 of the first coil 11, but not to the inner peripheral surface 113 of the first coil 11. Because the inner peripheral surface 113 of the first coil 11 is located farther from the inner surface of the aneurysm than the outer peripheral surface 112, the drug 40 disposed on the inner peripheral surface 113 generally tends to be less likely to be released early than the drug disposed on the outer peripheral surface 112. Therefore, the required therapeutic effect can be obtained even if the drug 40 is not disposed on the inner peripheral surface 113 of the first coil 11.

[0071] For the same reasons as for the first coil 11, the drug 40 may be disposed on the second coil 21 as follows. The drug 40 may be disposed over the entire longitudinal axis direction x of the second coil 21. The drug 40 may be disposed over only a portion of the longitudinal axis direction x of the second coil 21. As shown in FIG. 4 , the drug 40 may be disposed on the outer circumferential surface 212 and the inner circumferential surface 213 of the second coil 21. For example, the drug 40 may be attached to the outer circumferential surface 212 and the inner circumferential surface 213 of the second coil 21. As shown in FIG. 5 , the drug 40 may be disposed on the outer circumferential surface 212 of the second coil 21, but not on the inner circumferential surface 213 of the second coil 21. For example, the drug 40 may be attached to the outer circumferential surface 212 of the second coil 21, but not on the inner circumferential surface 213 of the second coil 21.

[0072] As shown in FIG. 6, the drug is preferably not distributed over the entire surface of the second coil 21, and is preferably not distributed over the entire second coil 21.

[0073] When the placement system 1 also includes a third coil 31 as shown in Fig. 7, it is preferable that a drug 40 be disposed on the surface of the third coil 31 as shown in Fig. 8. For example, it is preferable that the drug 40 be attached to the surface of the third coil 31. By disposing the drug on a coil of such hardness, it is possible to apply the amount of drug required for treatment to the affected area while minimizing the impact of reduced operability.

[0074] The types of drug 40 placed in the third coil 31 and the first coil 11 may be the same or different from each other. Also, the types of drug 40 placed in the third coil 31 and the second coil 21 may be the same or different from each other.

[0075] The drug 40 is preferably disposed over the entire longitudinal axis direction x of the third coil 31. The drug 40 may be disposed only on a portion of the longitudinal axis direction x of the third coil 31. As shown in FIG. 8 , the drug 40 is preferably disposed on the outer peripheral surface 312 and the inner peripheral surface 313 of the third coil 31. For example, the drug 40 is preferably attached to the outer peripheral surface 312 and the inner peripheral surface 313 of the third coil 31. As shown in FIG. 9 , the drug 40 is preferably disposed on the outer peripheral surface 312 of the third coil 31, but not on the inner peripheral surface 313 of the third coil 31. In other words, the drug 40 may be disposed only on the outer peripheral surface 312 of the third coil 31. For example, the drug 40 may be attached to the outer peripheral surface 312 of the third coil 31, but not on the inner peripheral surface 313 of the third coil 31.

[0076] It is preferable that the drug be disposed on the surface of the third coil 31 so that the amount of drug per unit length of the coil is greater than that of the first coil 11. In other words, it is preferable that the amount of drug per unit length of the coil disposed on the surface of the third coil 31 is greater than the amount of drug per unit length of the coil disposed on the surface of the first coil 11. A coil having such hardness can accommodate a greater amount of drug because even if the coil becomes harder due to the application of the drug, the effect of reducing operability is minimal.

[0077] The amount of drug per unit length of the coil arranged on the surface of first coil 11 is preferably 1 / 2 or less, more preferably 1 / 3 or less, and even more preferably 1 / 4 or less of the amount of drug per unit length of the coil arranged on the surface of third coil 31. The amount of drug per unit length of the coil arranged on the surface of first coil 11 may be 1 / 1000 or more, 1 / 500 or more, or 1 / 100 or more of the amount of drug per unit length of the coil arranged on the surface of third coil 31.

[0078] The amount of drug per unit area of ​​the coil on the surface of the third coil 31 (mg / mm ２ ) is the amount of drug per unit area of ​​the coil on the surface of the first coil 11 (mg / mm ２ ) may be more than

[0079] When the first coil 11 is divided into two equal parts, a distal portion and a proximal portion, in the longitudinal axis direction x, the amount of drug per unit length of the coil disposed in the distal portion of the first coil 11 may be greater than the amount of drug per unit length of the coil disposed in the proximal portion. Furthermore, when the second coil 21 is divided into two equal parts, a distal portion and a proximal portion, in the longitudinal axis direction x, the amount of drug per unit length of the coil disposed in the distal portion of the second coil 21 may be greater than the amount of drug per unit length of the coil disposed in the proximal portion. Furthermore, when the third coil 31 is divided into two equal parts, a distal portion and a proximal portion, in the longitudinal axis direction x, the amount of drug per unit length of the coil disposed in the distal portion of the third coil 31 may be greater than the amount of drug per unit length of the coil disposed in the proximal portion. This allows the amount of drug required for treatment to be applied to the aneurysm, and improves operability due to the increased flexibility of the proximal portion compared to the distal portion.

[0080] The amount of drug per unit length of the coil arranged at the distal portion of second coil 21 may be less than the amount of drug per unit length of the coil arranged at the proximal portion of first coil 11. The amount of drug per unit length of the coil arranged at the distal portion of second coil 21 may be less than the amount of drug per unit length of the coil arranged at the proximal portion of third coil 31. The amount of drug per unit length of the coil arranged at the distal portion of first coil 11 may be less than the amount of drug per unit length of the coil arranged at the proximal portion of third coil 31.

[0081] The amount of drug present in the distal or proximal portion of the coil may be measured by cutting the coil radially at a position that divides the coil in half along the longitudinal axis x to separate the distal and proximal portions.

[0082] The type of drug is not particularly limited as long as it is necessary for the prevention and treatment of the affected area. The drug may have at least one of an anti-inflammatory effect, an antioxidant effect, a hypotensive effect, a vasoconstriction suppression effect, an anticoagulation effect, and a shear stress sensing suppression effect. It is preferable that at least one of the drug 40 disposed in the first coil 11 and the drug 40 disposed in the second coil 21 has at least one of an anti-inflammatory effect, an antioxidant effect, a hypotensive effect, a vasoconstriction suppression effect, an anticoagulation effect, and a shear stress sensing suppression 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.), non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, naproxen, celecoxib, etc.), angiotensin II receptor blockers (ARBs) (losartan, valsartan, telmisartan, etc.), tocopherol acetate (vitamin E acetate, ebiprostat, esterol, etc.), ascorbic acid (Asconal, Cinal, Cefirol), edaravone (Radicut, free radical scavenger, etc.), jar, etc.), N-acetyl-L-cysteine ​​(NAC), calcium channel blockers (amlodipine, nifedipine, diltiazem, etc.), diuretics (furosemide, trichlormethiazide, spironolactone, etc.), angiotensin-converting enzyme inhibitors (ACE) (enalapril, lisinopril, perindopril, etc.), beta-blockers (metoprolol, atenolol, bisoprolol, etc.), alpha-blockers (prazosin, terazosin, doxazosin, etc.), alpha-beta-blockers (carvedilol, labetalol, butoxamine, etc.), nitrates (nitroglycerin, isosorbide dinitrate, etc.), prostacyclin analogs (epoprostenol, treprostinil, etc.), anticoagulants (heparin, heparin derivatives, warfarin, antithrombin drugs such as dabigatran, rivaroxaban, etc.), antiplatelet drugs (aspirin, clopidogrel, ticagrelor, etc.), etc.

[0083] The drug 40 may be attached to the surface of at least one of the first coil 11, the second coil 21, and the third coil 31, or may be attached indirectly to the surface of the coil 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.

[0084] The drug is preferably encapsulated in a capsule, so that the drug can be effectively released when the coil is delivered to the affected area in the living body. In at least one of the first coil 11, the second coil 21, and the third coil 31, the encapsulated drug may be attached to the surface of the coil, or may be attached indirectly to the surface of the coil via a bioadhesive.

[0085] The capsule size 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.

[0086] The drug is preferably encapsulated in a capsule containing a biodegradable material. More preferably, at least one of the drug 40 disposed in the first coil 11 and the drug 40 disposed in the second coil 21 is encapsulated in a capsule containing a biodegradable material. Examples of biodegradable materials include bioabsorbable polymers, natural polymers, decellularized biological tissues and cells, or combinations thereof. Preferred 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). Preferred 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.

[0087] The capsule 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, the capsule preferably has a structure in which 10,000 to 100,000 PLGA filaments are condensed into a spherical shape.

[0088] The glass transition temperature of the material constituting the capsule is not particularly limited, but may be, for example, 40°C or higher, 41°C or higher, or 42°C or higher, and is also acceptable to be 50°C or lower, 49°C or lower, or 48°C or lower.

[0089] The capsule surface is preferably covered with a coating material. The coating material can prevent the drug from eluting into the blood or falling off during delivery of the indwelling device into the body. The material constituting the coating material is preferably a water-soluble polymer from the viewpoint of preventing an initial burst of the drug. Examples of coating materials 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.

[0090] A surfactant may be applied to the surface of the capsule. The application of a surfactant increases the fluidity of the capsule's cell membrane, thereby improving the permeability of the drug through the cell membrane. The type of surfactant is not particularly limited, but a nonionic surfactant is preferred, such as polyoxyethylene sorbitan monolaurate, preferably Tween (registered trademark) 20 or Tween (registered trademark) 80.

[0091] 2 and 3, the first coil 11 may have a first head 14 at its distal end. The first head 14 covers a portion of the first wire 12 to prevent the distal end of the first wire 12 from directly contacting the inner wall surface of the living body. The first head 14 may or may not be in contact with the first extension resistance member 15.

[0092] 4 to 6, the second coil 21 may have a second head 24 at its distal end. The second head 24 covers a portion of the second wire 22 to prevent the distal end of the second wire 22 from directly contacting the inner wall surface of the living body. The second head 24 may or may not be in contact with the second extension resistance member 25.

[0093] 8 and 9, the third coil 31 may have a third head 34 at its distal end. The third head 34 covers a portion of the third wire 32 to prevent the distal end of the third wire 32 from directly contacting the inner wall surface of the living body. The third head 34 may or may not be in contact with the third extension resistance member 35.

[0094] In the following, when describing the configuration common to the first head unit 14 and the second head unit 24 (preferably the configuration common to the first head unit 14, the second head unit 24, and the third head unit 34), these or each of them may be simply referred to as the head unit.

[0095] The shape of each head is not particularly limited, and may be, for example, a hemisphere, an oval hemisphere, a cylinder, or a polygonal column. The shapes of the first head 14, the second head 24, and the third head 34 may be the same or different from each other.

[0096] The head portion may be joined to at least one of the outer surface and the inner surface of the coil. Furthermore, a portion of the head portion may be disposed within the lumen of the distal end of the coil to prevent the head portion from falling off. The proximal end of the head portion may be located distal to the distal end of the wire, or the proximal end of the head portion may be located proximal to the distal end of the wire.

[0097] The head portion may be made of a metal material or a resin. Examples of resins that can be used to make the head portion include thermoplastic resins and ultraviolet-curing resins. Examples of resins that can be used to make the head portion 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 the head portion include the metals listed in the description of the wire material. The wire material and the head portion may be made of the same or different materials. The first head portion 14 and the second head portion 24 may be made of the same or different materials. The first head portion 14, the second head portion 24, and the third head portion 34 may be made of the same or different materials.

[0098] As can be seen from Figures 1 to 3, the first in-vivo indwelling device 10 preferably comprises a first coil 11 and a first stretch resistance member 15 disposed in the lumen 111 of the first coil 11. As can be seen from Figures 1 and 4 to 6, the second in-vivo indwelling device 20 preferably comprises a second coil 21 and a second stretch resistance member 25 disposed in the lumen 211 of the second coil 21. As can be seen from Figures 7 to 9, the third in-vivo indwelling device 30 preferably comprises a third coil 31 and a third stretch resistance member 35 disposed in the lumen 311 of the third coil 31. Hereinafter, when describing components common to the first stretch resistance member 15 and the second stretch resistance member 25, or preferably the first stretch resistance member 15, the second stretch resistance member 25, and the third stretch resistance member 35, these or each of them may be referred to as a stretch resistance member.

[0099] The stretch resistance member prevents the coil from stretching in the longitudinal direction x during operation. The stretch resistance member is preferably disposed within the lumen of the coil. The stretch resistance member may be an elongated member made of a solid wire or a stranded wire. The stretch resistance member has a longitudinal direction and has a first end and a second end in the longitudinal direction. The stretch resistance member may be composed of a single layer or multiple layers in a radial direction perpendicular to the longitudinal direction. The stretch resistance member may have an inner layer made of a stranded wire made of multiple wires and an outer layer disposed outside the inner layer and containing a resin composition. Only one stretch resistance member may be disposed within the lumen of the coil, or multiple stretch resistance members may be disposed.

[0100] The stretch resisting member may be made of resin or metal. Examples of resins constituting the stretch resisting member include polyester resins such as polyethylene terephthalate, polyamide resins such as nylon, and polyolefin resins such as polyethylene and polypropylene. Using a resin increases flexibility and improves the delivery performance of the indwelling device. Furthermore, using a resin stretch resisting member can prevent breakage due to metal fatigue during delivery. By making the stretch resisting member longer than the length of the coil or using a stretchable material for the stretch resisting member, tension caused by the end of the coil being stretched linearly due to insufficient length of the stretch resisting member when the coil is placed within the aneurysm can be alleviated. Examples of metals constituting the stretch resisting member include platinum, gold, rhodium, palladium, rhenium, silver, nickel, titanium, tantalum, tungsten, alloys thereof, and stainless steel.

[0101] The stretch resisting member may be made of a material different from the wire that makes up the coil, for example, the coil may be made of a platinum-tungsten alloy and the stretch resisting member may be made of polypropylene resin.

[0102] The cross-sectional shape of the stretch-resisting member perpendicular to its longitudinal axis may be circular, elliptical, polygonal, or a combination thereof.

[0103] To facilitate placement of the stretch resisting member within the lumen of the coil, the outer diameter of the stretch resisting member is preferably less than half, and more preferably less than one-third, of the inner diameter of the coil.To prevent breakage of the stretch resisting member, the outer diameter of the stretch resisting member is preferably at least one-fifteenth, and more preferably at least one-tenth, of the inner diameter of the coil.

[0104] The stretch-resisting members can be straight, wavy, spiral, or a combination thereof.

[0105] The first end of the stretch resistance member may be connected to the distal end of the coil, specifically the distal end of the wire constituting the coil. The second end of the stretch resistance member may be connected to the proximal end of the coil, specifically the proximal end of the wire constituting the coil. The second end of the stretch resistance member may be connected to a connecting portion (described below) connecting the coil and the pusher. The stretch resistance member may be disposed within the lumen of the coil in a folded state midway along the longitudinal axis x of the coil. In this case, it is preferable that the folded portion of the stretch resistance member is connected to the distal or proximal end of the coil, and the first and second ends are connected to the proximal or distal end of the coil or the distal end of the connecting portion. In Figures 2 and 3, the first stretch resistance member 15 has a folded portion 151 folded midway along the longitudinal axis, the folded portion 151 is connected to the distal end of the first coil 11, and the first and second ends are connected to the first connecting portion 18 described below. 4 to 6, the folded portion 251 of the second extension resistance member 25 is connected to the distal end of the second coil 21, and the first and second ends are connected to the second connection portion 28 described below. Similarly, in Figures 8 and 9, the folded portion 351 of the third extension resistance member 35 is connected to the distal end of the third coil 31, and the first and second ends are connected to the third connection portion 38 described below.

[0106] Methods for connecting the stretch resistant member to another member include welding, crimping, adhesive bonding, physical fastening such as engagement, coupling, fastening, and ligation, or a combination thereof. Here, "connection" includes both a direct connection between two elements and an indirect connection between two elements via one or more other elements.

[0107] As shown in Fig. 10, a drug 40 may be applied to the surface of the first stretch resistance member 15. This allows a larger amount of drug to be applied to the first in-vivo indwelling device 10 including the first coil 11, making it easier to achieve the desired therapeutic effect. It also enhances the sustained release effect of the drug. For example, the drug 40 may be applied to part or all of the outer surface of the first stretch resistance member 15. Note that, as shown in Fig. 11, the drug does not have to be applied to the surface of the first stretch resistance member 15, and the drug does not have to be applied to the entire outer surface of the first stretch resistance member 15.

[0108] As shown in FIG. 12 , a drug 40 may be applied to the surface of the second stretch resistance member 25. This allows a larger amount of drug to be applied to the second in-vivo indwelling device 20 including the second coil 21, thereby making it easier to achieve the desired therapeutic effect. This also enhances the sustained release of the drug. For example, the drug 40 may be applied to part or all of the outer surface of the second stretch resistance member 25. Alternatively, the drug may be applied to the surface of the second stretch resistance member 25 so that the amount of drug per unit length of the stretch resistance member is less than that of the first stretch resistance member 15. Alternatively, as shown in FIG. 13 , it is preferable that no drug be applied to the surface of the second stretch resistance member 25, and more preferably, no drug be applied to the entire outer surface of the second stretch resistance member 25. This prevents the second stretch resistance member 25 from becoming hard due to the application of the drug.

[0109] As shown in Figure 14, a drug 40 is preferably applied to the surface of the third stretch resistance member 35. This allows a larger amount of drug to be applied to the third in-vivo indwelling device 30 including the third coil 31, making it easier to achieve the desired therapeutic effect. It also enhances the sustained release effect of the drug. For example, the drug 40 can be applied to part or all of the outer surface of the third stretch resistance member 35. Note that, as shown in Figure 15, the drug does not necessarily have to be applied to the surface of the third stretch resistance member 35, and the drug does not necessarily have to be applied to the entire outer surface of the third stretch resistance member 35.

[0110] The amount of drug per unit length of the stretch resistance member disposed on the surface of the third stretch resistance member 35 may be greater than the amount of drug per unit length of the stretch resistance member disposed on the surface of the first stretch resistance member 15. The amount of drug per unit length of the stretch resistance member disposed on the surface of the third stretch resistance member 35 may be the same as the amount of drug per unit length of the stretch resistance member disposed on the surface of the first stretch resistance member 15.

[0111] As with the coil, in at least one of the first stretch resistance member 15, the second stretch resistance member 25, and the third stretch resistance member 35, the drug 40 may be attached to the surface of the stretch resistance member or indirectly attached to the surface of the stretch resistance member via a bioadhesive. Also, as with the coil, in at least one of the first stretch resistance member 15, the second stretch resistance member 25, and the third stretch resistance member 35, the drug 40 encapsulated in a capsule may be attached to the surface of the stretch resistance member or indirectly attached to the surface of the stretch resistance member via a bioadhesive. For the type of bioadhesive, please refer to the description of the type of bioadhesive attached to the coil. For the structure of the capsule, please refer to the description of the structure of the capsule attached to the coil.

[0112] As shown in Fig. 1 , in the placement system 1, the first in-vivo indwelling device 10 may include a first coil 11, a first connection part 18 connected to the proximal end of the first coil, and a first pusher 17 connected to the first coil 11 via the first connection part 18. The second in-vivo indwelling device 20 may include a second coil 21, a second connection part 28 connected to the proximal end of the second coil 21, and a second pusher 27 connected to the second coil 21 via the second connection part 28. As shown in Fig. 7 , in the placement system 1, the third in-vivo indwelling device 30 may include a third coil 31, a third connection part 38 connected to the proximal end of the third coil 31, and a third pusher 37 connected to the third coil 31 via the third connection part 38.

[0113] Hereinafter, when describing a configuration common to the first pusher 17 and the second pusher 27 (preferably a configuration common to the first pusher 17, the second pusher 27, and the third pusher 37), these or each of them may be simply referred to as a pusher. Also, when describing a configuration common to the first connecting portion 18 and the second connecting portion 28 (preferably a configuration common to the first connecting portion 18, the second connecting portion 28, and the third connecting portion 38), these or each of them may be simply referred to as a connecting portion.

[0114] The in-vivo indwelling device preferably has a detachment mechanism for detaching the coil from the pusher. Examples of detachment mechanisms include hydraulic, electrical, and mechanical mechanisms, with an electrical detachment mechanism being preferred. In the detachment mechanism, the connection portion is preferably heated and severed by electrical or thermal energy supplied via the pusher, thereby detaching the coil from the pusher. In this case, the connection portion is preferably heated by high-frequency current supplied between the coil and the counter electrode, thereby detaching the coil from the pusher.

[0115] The shape of the connection part 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.

[0116] The connecting portion preferably contains a material that melts or dissolves when heated, allowing the connecting portion to be fused by Joule heat. Examples of such a material include synthetic resin materials, and it is preferable to use a hydrophilic resin, such as a synthetic polymeric substance, for example, polyvinyl alcohol (PVA), a PVA cross-linked polymer, a PVA water-absorbing gel freeze-thaw elastomer, or a polyvinyl alcohol-based polymer such as an ethylene-vinyl alcohol copolymer.

[0117] The pusher is a rod-like or wire-like member used to hold the indwelling device and push it distally. The pusher can be composed of one or more members. The pusher can be composed of a wire member, a coil member, or a combination thereof. The pusher can be composed of a conductive material such as stainless steel.

[0118] 2. Manufacturing Method of Intracorporeal Indwelling Device A manufacturing method of an intracorporeal indwelling device according to one embodiment of the present invention includes a step of applying a drug if the coil's hardness is equal to or greater than a first reference value, and not applying the drug if the coil's hardness is less than the first reference value. By including such a step, the drug is applied to a coil whose hardness changes little before and after drug application, so that even if the coil becomes hard due to drug application, the impact of reduced coil operability can be minimized. Furthermore, such a coil also allows the drug to be applied to the affected area in the amount necessary for treatment. Furthermore, because a coil with a good balance between coil hardness and drug amount can be manufactured, an appropriate coil can be obtained for each of the Framing, Filling, and Finishing phases.

[0119] A method for manufacturing an in-vivo indwelling device according to one embodiment of the present invention will be described with reference to Figures 16 and 17. Figures 16 and 17 are flow charts showing a method for manufacturing an in-vivo indwelling device according to one embodiment of the present invention.

[0120] By carrying out the manufacturing method described in this specification, the first coil 11, the second coil 21, or the third coil 31 to which a drug has been applied can be obtained.

[0121] First, as shown in Figure 16, it is preferable to perform a step of preparing a coil and a drug (step S1). The coil preferably has a longitudinal axis direction, 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 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 the inward radial direction of the coil refers to the direction toward the center of the longitudinal axis of the coil, 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 refers to the direction around the longitudinal axis.

[0122] 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.

[0123] 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. The coil prepared in step S1 may be a primary coil or a secondary coil.

[0124] For details of the configuration of the coil prepared in step S1, the above description of the configuration of the first coil 11, second coil 21, or third coil 31 before drug administration described in "1. Placement system for in-vivo indwelling device" can be referred to.

[0125] After step S1, a step (step S2) of calculating the hardness of the prepared coil may be performed. In step S2, the hardness S (unit: N / mm) of the prepared coil (primary coil) can be calculated by the following formula: S=D １ ４ ×G / (8D ２ ３ ×n) where D １ is the outer diameter of the wire (unit: mm), G is the shear modulus of elasticity (unit: Pa (N / mm ２ )) D ２is the outer diameter of the coil (unit: mm), and n is the number of turns of the coil (unitless). If the outer diameter of the wire is not constant in the longitudinal direction of the wire, the outer diameter D １ indicates the average value of the outer diameter in the longitudinal direction of the wire. If the outer diameter of the coil is not constant in the longitudinal direction of the coil, the outer diameter D ２ indicates the average value of the outer diameter of the coil in the longitudinal direction. The number of turns n indicates the number of turns counted when the coil is viewed from the side at an angle that results in the largest number of turns. Note that if the hardness of the coil is known from a coil product catalog or the like, step S2 may be omitted.

[0126] As shown in Figure 16, it is preferable to perform a step (step S3) of determining whether the stiffness of the coil is equal to or greater than a first reference value. If the stiffness of the coil is equal to or greater than the first reference value, a drug is administered (step S4), and if the stiffness of the coil is less than the first reference value, a drug is not administered (step S5).

[0127] The determination in step S3 may be made by a person or by a processing device such as a CPU or a microprocessor.

[0128] In steps S3 to S5, the first reference value is 5.0×10 －９ N / mm or more 1.5×10 －８ It is preferable that the hardness of the coil is 1 / N / mm or less. A coil with such hardness can suppress the impact of reduced operability even if it becomes hardened by adding a drug. Note that a coil with a hardness equal to or greater than the first reference value can be preferably used in at least one of the framing and filling phases.

[0129] The first reference value is 8.0×10 －９ N / mm or more, and more preferably 1.0×10 －８ It is more preferable that the first reference value is 3.5×10 －８ N / mm, and preferably less than 3.0 × 10 －８ N / mm or less, 2.0×10 －８A coil with such hardness can deliver the amount of drug required for treatment to the affected area while minimizing the impact of reduced operability even when a drug is applied.

[0130] In step S4, it is preferable to apply a drug to the surface of the coil. In step S4, the drug may be applied to the outer and inner surfaces of the coil. In step S4, the drug may be applied to the outer surface of the coil, but not to the inner surface of the coil.

[0131] In step S4, 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 S4, the amount of drug applied per unit length of the coil may be smaller on the inner peripheral surface than on the outer peripheral surface of the coil.

[0132] In step S4, the method for applying the agent to the coil is not particularly limited. Examples of methods for applying the agent include brush coating, roll coating, dip coating, and spray coating. In any of these methods, the agent applied to the surface of the coil can be a liquid agent, or a solution in which microcapsules containing the agent are present in a solvent.

[0133] After completion of step S4, 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.

[0134] For other details regarding the type and structure of the drug applied to the coil in step S4 and the type of bioadhesive, please refer to the explanation given in "1. Placement system for in-vivo indwelling device."

[0135] As can be seen from FIG. 17 , in or after step S3, a further determination may be made as to whether the coil's stiffness is equal to or greater than a second reference value higher than the first reference value (step S6). In steps S3 to S5, where a drug is applied if the coil's stiffness is equal to or greater than the first reference value and no drug is applied if the coil's stiffness is less than the first reference value, it is preferable to apply a larger amount of drug per unit length of the coil if the coil's stiffness is equal to or greater than the second reference value (step S7) than if the coil's stiffness is less than the second reference value but equal to or greater than the first reference value. A coil with such stiffness can minimize the impact of reduced operability even if the coil becomes stiffer due to the application of a drug.

[0136] In the flowchart shown in Figure 17, the amount of drug per unit length of the coil (unit: mg / mm) to be applied to a coil whose stiffness is less than the second reference value but equal to or greater than the first reference value is described as the first predetermined amount, and the amount of drug per unit length of the coil to be applied to a coil whose stiffness is equal to or greater than the second reference value is described as the second predetermined amount. That is, in steps S3 to S5, if the stiffness of the coil is equal to or greater than the second reference value (YES in step S6), it is preferable to apply the second predetermined amount of drug to the coil (step S7). Also, in steps S3 to S5, if the stiffness of the coil is less than the second reference value but equal to or greater than the first reference value (NO in step S6), it is preferable to apply the first predetermined amount of drug to the coil (step S8). Here, the second predetermined amount > the first predetermined amount > 0.

[0137] In steps S7 and S8, the first predetermined amount is preferably 1 / 2 or less of the second predetermined amount, more preferably 1 / 3 or less, and even more preferably 1 / 4 or less. The first predetermined amount may be 1 / 1000 or more, 1 / 500 or more, or 1 / 100 or more of the second predetermined amount.

[0138] In at least one of steps S7 and S8, it is preferable to apply a drug to the surface of the coil. In at least one of steps S7 and S8, a drug may be applied to the outer peripheral surface and the inner peripheral surface of the coil. In at least one of steps S7 and S8, a drug may be applied to the outer peripheral surface of the coil, but not to the inner peripheral surface of the coil.

[0139] In at least one of steps S7 and S8, 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 at least one of steps S7 and S8, it is preferable that the amount of drug applied per unit length of the coil be smaller on the inner peripheral surface than on the outer peripheral surface of the coil.

[0140] The second reference value is 3.5×10 －８ N / mm or more 4.5×10 －８ N / mm or less is preferable. A coil with such hardness can suppress the impact of reduced operability even if it hardens due to the addition of a drug. Note that a coil with a hardness equal to or greater than the second reference value can be preferably used in at least one of the framing and filling phases, and is more preferably used in the framing phase.

[0141] The second reference value is 4.0×10 －８ N / mm or more, 8.0×10 －８ N / mm or more, and －７ N / mm or less, 1.0×10 －７ A coil with such hardness can deliver the amount of drug required for treatment to the affected area while minimizing the impact of reduced operability even when a drug is applied.

[0142] This application claims the benefit of priority based on Japanese Patent Application No. 2023-208509, filed on December 11, 2023. The entire contents of the specification of Japanese Patent Application No. 2023-208509, filed on December 11, 2023, are incorporated herein by reference.

[0143] 1: In-vivo indwelling device placement system 10: First in-vivo indwelling device 11: First coil 111: Lumen 112: Outer circumferential surface 113: Inner circumferential surface 12: First wire 14: First head 15: First stretch resistance member 17: First pusher 18: First connecting portion 20: Second in-vivo indwelling device 21: Second coil 211: Lumen 212: Outer circumferential surface 213: Inner circumferential surface 22: Second wire 24: Second head 25: Second stretch resistance member 27: Second pusher 28: Second connecting portion 30: Third in-vivo indwelling device 31: Third coil 311: Lumen 312: Outer circumferential surface 313: Inner circumferential surface 32: Third wire 34: Third head 35: Third stretch resistance member 37: Third pusher 38: Third connection part 40: Drug x: Longitudinal axis direction

Claims

1. A placement system for an in-vivo placement device comprising: a first coil; and a second coil having a coil hardness less than that of the first coil, a drug being disposed on the surface of the first coil, and either a drug being disposed on the surface of the second coil such that the amount of drug per unit length of the coil is less than that of the first coil, or no drug is disposed on the surface of the second coil.

2. The in-vivo indwelling device placement system according to claim 1, wherein the drug placed in the first coil is placed over the entirety of the first coil in the longitudinal axial direction.

3. The in-vivo indwelling device placement system according to claim 1 or 2, wherein the drug placed in the first coil is placed on the outer and inner surfaces of the first coil.

4. A placement system for an in-vivo placement device as described in claim 1 or 2, wherein the drug placed on the first coil is placed on the outer peripheral surface of the first coil, and not placed on the inner peripheral surface of the first coil.

5. The in-vivo retention device retention system according to claim 1 or 2, further comprising a first elongation resistance member disposed in the inner cavity of the first coil, and a drug being disposed on the surface of the first elongation resistance member.

6. The coil hardness of the first coil is 5.0 x 10 －９ 3. The indwelling system of claim 1, wherein the tension is 0.01 N / mm or more.

7. The in-vivo retention device placement system according to claim 1 or 2, further comprising a third coil having a coil hardness greater than that of said first coil, and a drug being disposed on the surface of said third coil such that the amount of drug per unit length of the coil is greater than that of said first coil.

8. The coil hardness of the third coil is 3.5 x 10 －８ The indwelling system of claim 7, wherein the tension is 0.01 N / mm or more.

9. A placement system for an in-vivo placement device as described in claim 1 or 2, wherein at least one of the drug placed in the first coil and the drug placed in the second coil is encapsulated in a capsule containing a biodegradable material.

10. A placement system for an in-vivo placement device as described in claim 1 or 2, wherein at least one of the drugs disposed in the first coil and the second coil has at least one of an anti-inflammatory effect, an antioxidant effect, a hypotensive effect, a vasoconstriction inhibitory effect, an anticoagulant effect, and a shear stress sensing inhibitory effect.

11. A method for manufacturing an in-vivo indwelling device, comprising the steps of: applying a drug if the hardness of the coil is equal to or greater than a first reference value; and not applying a drug if the hardness of the coil is less than the first reference value.

12. The first reference value is 5.0×10 －９ N / mm or more 1.5×10 －８ The method for producing an in-vivo indwelling device according to claim 11, wherein the strength of the in-vivo indwelling device is 0.01 N / mm or less.

13. A method for manufacturing an in-vivo retention device as described in claim 11 or 12, wherein, in the step of applying a medicinal drug if the hardness of the coil is equal to or greater than a first reference value and not applying a medicinal drug if the hardness of the coil is less than the first reference value, the amount of medicinal drug applied per unit length of the coil is greater if the hardness of the coil is equal to or greater than a second reference value higher than the first reference value than if the hardness of the coil is less than the second reference value and equal to or greater than the first reference value.

14. The second reference value is 3.5×10 －８ N / mm or more 4.5×10 －８ The method for producing an in-vivo indwelling device according to claim 13, wherein the strength of the in-vivo indwelling device is 0.01 N / mm or less.

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