Intra-biological implantable devices

Abstract

To provide an in-vivo device that can release drugs at an appropriate rate. [Solution] An in-vivo implantation device 1 comprising a coil 10 and a fiber layer 30 disposed on the outer peripheral surface 12 of the coil 10, the fiber 40 comprising a polymer material and a drug, and the average fiber diameter of the fiber 40 being 3.0 μm or more.

Description

Technical Field

[0001] The present invention relates to an implant for forming an embolism in a blood vessel at a diseased part of a blood vessel.

Background Art

[0002] Endovascular treatment is one of the treatment methods for vascular lesions such as aneurysms, arteriovenous malformations, arteriovenous fistulas, pulmonary vascular malformations, renal vascular malformations, renal arteries, and abdominal aneurysms in the head and neck. In endovascular treatment, an embolization coil-containing implant is placed at the target site to promote thrombosis, and embolization is used to prevent, for example, the rupture of an aneurysm. Several to dozens of coils are used in a single embolization procedure. Patent Documents 1 to 3 disclose implants in which a coil holds a drug.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, the implants described in Patent Documents 1 to 3 had room for improvement in terms of the drug release rate. Therefore, an object of the present invention is to provide an implant that can release a drug at an appropriate rate.

Means for Solving the Problems

[0005] The implant according to an embodiment that has solved the above problems is as follows. [1] A coil, and Displaced on the outer surface of the coil, it has a fiber layer containing fibers, The aforementioned fiber contains a polymer material and a drug, An in-vivo implantation device having an average fiber diameter of 3.0 μm or more.

[0006] Furthermore, the in-vivo implantation device according to the embodiment is preferably one of the following [2] to [9]. [2] The in-vivo device according to [1], wherein the average fiber diameter is 10 μm or less. [3] The in-vivo device according to [1] or [2], wherein the fiber has an irregular cross-section. [4] The in vivo implantation device according to any one of the claims [1] to [3], wherein the fiber includes a core-sheath type fiber having a core and a sheath, the core containing the drug and the sheath containing the polymer material. [5] The intravascular device according to [4], wherein the core portion has an irregular cross-section. [6] The in-vivo implantation device according to any one of the following [1] to [5], wherein the average fiber diameter of the fiber layer located in the proximal part of the coil is smaller than the average fiber diameter of the fiber layer located in the distal part of the coil. [7] The in-vivo implantation device according to any one of [1] to [6], wherein the fiber layer comprises, as fibers, a first fiber and a second fiber having an average fiber diameter smaller than that of the first fiber. [8] The polymer material is a biodegradable polymer material, as described in any one of the claims [1] to [7]. [9] An in-vivo device according to any one of the claims [1] to [8], wherein a second drug is impregnated into the interfibrous spaces of the fiber layer. [Effects of the Invention]

[0007] In the above-mentioned in-vivo implantation device, since the fibers of the fiber layer contain the drug, it prevents the drug from detaching from the coil early in the procedure and enhances the sustained release of the drug, compared to cases where the drug is coated on the coil surface. Furthermore, because the average fiber diameter of the fibers in the fiber layer is 3.0 μm or more, the surface area per unit volume of the fibers can be made appropriately sized, making it easier to release the drug contained in the fibers at an appropriate rate. [Brief explanation of the drawing]

[0008] [Figure 1] This is a schematic diagram of an in-vivo implantable device according to an embodiment of the present invention. [Figure 2] Figure 1 shows a side view (partially a cross-sectional view) of the coil of the in-vivo implantation device along its longitudinal direction, illustrating the coil in a straight-lined state. [Figure 3] Figure 1 shows a cross-sectional view (partially a side view) of the coil of the in-vivo implantation device along its longitudinal direction, illustrating the coil in a straight-lined state. [Figure 4] Figures 2 and 3 show cross-sectional views of the fibrous layer of the in-vivo implantable device. [Figure 5] This is a schematic diagram showing the structure of the fibers in a fiber layer. [Figure 6] This is a schematic diagram showing a modified example of the fiber structure shown in Figure 5. [Figure 7] This is a schematic diagram showing an enlarged view of the fiber layer. [Figure 8] This is a schematic diagram of a fiber having branching points. [Figure 9] This is a schematic diagram showing an example of the shape of a fiber cross-section. [Figure 10] Figure 9 is a schematic diagram showing a modified cross-section of the fiber. [Figure 11] Figure 9 is a schematic diagram showing another modified example of the fiber cross-section. [Figure 12] Figure 9 is a schematic diagram showing yet another modified example of the fiber cross-section. [Figure 13] Figure 9 is a schematic diagram showing yet another modified example of the fiber cross-section. [Figure 14] It is a schematic diagram showing still another modification of the cross-section of the fiber shown in FIG. 9. [Figure 15] It is a schematic diagram showing still another modification of the cross-section of the fiber shown in FIG. 9. [Figure 16] It is a schematic diagram showing still another modification of the cross-section of the fiber shown in FIG. 9. [Figure 17] It is a schematic diagram showing still another modification of the cross-section of the fiber shown in FIG. 9. [Figure 18] It is a side view (partial cross-sectional view) showing a modification of the implantable device shown in FIG. 3. [Figure 19] It is a side view (partial cross-sectional view) showing another modification of the implantable device shown in FIG. 3. [Figure 20] It is a side view (partial cross-sectional view) showing still another modification of the implantable device shown in FIG. 3. [Figure 21] It is a side view (partial cross-sectional view) showing still another modification of the implantable device shown in FIG. 3. [Figure 22] It is a side view (partial cross-sectional view) showing still another modification of the implantable device shown in FIG. 3. [Figure 23] It is a side view (partial cross-sectional view) showing still another modification of the implantable device shown in FIG. 3. [Figure 24] It is a side view (partial cross-sectional view) showing still another modification of the implantable device shown in FIG. 3. [Figure 25] It is a schematic diagram showing a modification of the fiber layer shown in FIG. 7. [Figure 26] It is a schematic diagram showing another modification of the fiber layer shown in FIG. 7.

BEST MODE FOR CARRYING OUT THE INVENTION

[0009] The present invention will be described in more detail below based on the embodiments described below. However, the present invention is not limited by the embodiments described below, and it is certainly possible to implement it with appropriate modifications within the scope that is consistent with the spirit of the preceding and following descriptions, and all such modifications are included within the technical scope of the present invention. In addition, hatching and component reference numerals may be omitted in the drawings for convenience, in which case please refer to the specification or other drawings. Furthermore, the dimensions of various components in the drawings may differ from the actual dimensions, as priority has been given to helping to understand the features of the present invention.

[0010] The in-vivo implantation device according to this embodiment comprises a coil and a fiber layer containing fibers disposed on the outer surface of the coil, wherein the fibers contain a polymer material and a drug, and the average fiber diameter of the fibers is 3.0 μm or more. Hereinafter, the in-vivo implantation device may be simply referred to as the implantation device.

[0011] An implantable device is placed inside the body in minimally invasive treatments for lesions or abnormalities such as aneurysms, thrombi, stenosis, or occlusion in blood vessels or the digestive tract. Preferably, the implantable device is for cerebral aneurysms. A cerebral aneurysm implantable device can be used in one of the framing, filling, or finishing phases, or it can be used across two or three of these phases.

[0012] The in-vivo implantable device according to the embodiment will be described with reference to Figures 1 to 24. Figure 1 is a schematic diagram of an in-vivo implantable device according to an embodiment of the present invention. Figure 2 is a side view (partially a cross-sectional view) along the longitudinal direction of the coil of the in-vivo implantable device shown in Figure 1, showing the coil in a straight line. Figure 3 is a cross-sectional view (partially a side view) along the longitudinal direction of the coil of the in-vivo implantable device shown in Figure 1, showing the coil in a straight line. Figure 4 is a cross-sectional view showing the fiber layer of the in-vivo implantable device shown in Figures 2 to 3. Figure 5 is a schematic diagram showing the fiber structure of the fiber layer. Figure 6 is a schematic diagram showing a modified example of the fiber structure shown in Figure 5. Figure 7 is a schematic diagram of an enlarged view of the fiber layer. Figure 8 is a schematic diagram of a fiber having a branched portion. Figures 9 to 17 are schematic diagrams showing examples of the shape of the cross-sectional surface of the fiber. Figures 18 to 24 are side views (partially a cross-sectional view) showing modified examples of the in-vivo implantable device shown in Figure 3. Figures 25-26 are schematic diagrams showing modified examples of the fiber layer shown in Figure 7. In Figure 1, the fiber layer 30 is omitted to facilitate understanding of the shape of the secondary coil. In Figures 18-24, only the coil 10 and fiber layer 30 are shown, but it is preferable that other components are arranged as in Figures 2-3. As shown in Figures 2, 3, etc., the retaining device 1 has a coil 10 and a fiber layer 30.

[0013] As can be seen from Figures 2 and 3, the coil 10 preferably has a longitudinal direction x, a radial direction y, and a circumferential direction z. The longitudinal direction x can also be called the longitudinal axis direction. The coil 10 preferably has a distal end and a proximal end in the longitudinal direction x. The proximal side of the coil 10 refers to the direction toward the user or operator's hand with respect to the longitudinal direction x of the coil 10, and the distal side refers to the opposite direction from the proximal side, i.e., the direction toward the treatment target. In Figures 2 and 3, the right side of the figure is the proximal side, and the left side of the figure is the distal side. The radial direction y of the coil 10 refers to the radial direction of the coil 10, and in the radial direction y, inward refers to the direction toward the center of the longitudinal axis of the coil 10, and outward refers to the direction extending radially from the center of the longitudinal axis on the opposite side from the inward direction. The circumferential direction z of the coil 10 refers to the direction around the longitudinal axis. In the following, when the length of each component of the coil 10 is divided into two equal parts in the longitudinal direction x, the proximal side may be referred to as the proximal portion, and the distal side as the distal portion.

[0014] As shown in Figure 3, the coil 10 has an outer circumferential surface 12. Preferably, the coil 10 also has an inner circumferential surface 13. The surface of the coil 10 includes the outer circumferential surface 12 and the inner circumferential surface 13. Preferably, the coil 10 has a lumen 11 extending in the longitudinal direction x. The outer circumferential surface 12 of the coil 10 faces the outside of the coil 10, i.e., the outside in the radial direction y, and the inner circumferential surface 13 of the coil 10 faces the lumen 11. Preferably, a stretch resistance member 50, which will be described later, is placed in the lumen 11.

[0015] As shown in Figures 1 to 3, the coil 10 is constructed by winding a wire 21. Preferably, the coil 10 is constructed by winding a long wire 21. Preferably, the coil 10 is constructed by winding one or more wires 21 in a spiral shape. Examples of wires 21 include single wires, stranded wires, and coiled wires, with single wires being preferred. Furthermore, it is preferable that the wire 21 is not a coiled wire.

[0016] The wire 21 is preferably biocompatible and flexible. Examples of materials constituting the wire 21 include platinum, gold, titanium, tungsten and their alloys, stainless steel, and other metallic materials or combinations thereof. Among these, it is more preferable that the wire 21 is composed of a platinum-tungsten alloy.

[0017] As shown in Figure 2, the wire 21 has a longitudinal axis direction p, and has a distal end and a proximal end along the longitudinal axis direction p. The wire 21 may be composed of a single wire from the distal end to the proximal end, or it may be composed of multiple wires connected to each other along the longitudinal axis direction p. The shape of the cross section perpendicular to the longitudinal axis direction p of the wire 21 may be circular, oval, polygonal, or a combination thereof. The shape of the cross section perpendicular to the longitudinal axis direction p of the wire 21 may be the same along the entire longitudinal axis direction p of the wire 21, or it may differ depending on the position along the longitudinal axis direction p.

[0018] The outer diameter of the wire 21 is not particularly limited, but may be, for example, 25 μm or more, 30 μm or more, or 35 μm or more, and may be 75 μm or less, or 70 μm or less.

[0019] The outer diameter of the wire 21 may be the same in the longitudinal axis direction p of the wire 21, or it may be different depending on the position in the longitudinal axis direction p of the wire 21. If the cross-section of the wire 21 is not circular, the outer diameter of the wire 21 shall refer to the equivalent circular diameter.

[0020] The coil 10 may be a single-layer coil or a multi-layer coil having multiple layers. A portion of the coil 10 in the longitudinal direction x may be a single layer, and the remaining portion may be multi-layer.

[0021] The density of the coil 10, i.e., the winding spacing, is not particularly limited and can be tightly wound, pitched, or a combination of these. The coil 10 may have adjacent wires 21 in contact with each other in the longitudinal direction x. The coil 10 may have adjacent wires 21 in contact with each other in only a part of the longitudinal direction x, or adjacent wires 21 in contact with each other throughout the entire longitudinal direction x. Furthermore, the coil 10 may not have adjacent wires 21 in contact with each other in the longitudinal direction x. Non-contact means that there is a gap between adjacent wires 21 in the longitudinal direction x of the coil 10.

[0022] The outer edge shape of the cross-section perpendicular to the longitudinal direction x of the coil 10 may be circular, oval, polygonal, or a combination thereof. The oval shape includes elliptical, egg-shaped, and rounded rectangular shapes. The same applies in the following description.

[0023] The surface of the coil 10 may have an uneven surface if the cross-sections of adjacent wires 21 in the longitudinal direction x of the coil 10 are circular, elliptical, or the like.

[0024] The maximum and minimum outer diameters of coil 10 are not particularly limited and can be appropriately selected according to the phase of the procedure. For example, they may be 150 μm or more, 180 μm or more, or 200 μm or more, and may also be 400 μm or less, 380 μm or less, or 350 μm or less.

[0025] The outer diameter and / or inner diameter of the coil 10 may be the same size along the longitudinal direction x of the coil 10, or they may be different sizes depending on the position along the longitudinal direction x of the coil 10. If the cross-section of the coil 10 is not circular, the outer diameter of the coil 10 shall refer to the equivalent circular diameter. Similarly, if the inner lumen cross-section of the coil 10 is not circular, the inner diameter of the coil 10 shall refer to the equivalent circular diameter.

[0026] The coil 10 may have a constant outer diameter in the longitudinal direction x. A constant outer diameter means that the outer diameter of the coil 10 is substantially constant over the entire longitudinal direction x, and includes cases where the change in the outer diameter of the coil 10 over the entire longitudinal direction x is within ±5%.

[0027] As shown in Figures 2 and 3, the retaining device 1 is positioned on the outer circumferential surface 12 of the coil 10 and has a fiber layer 30 containing fibers 40.

[0028] The fiber layer 30 may be arranged on only a part of the outer surface 12 of the coil 10, or it may be arranged on the entire outer surface 12 of the coil 10. The fiber layer 30 may be arranged on the inner surface 13 of the coil 10. The fiber layer 30 may be arranged on only a part of the inner surface 13 of the coil 10, or it may be arranged on the entire inner surface 13 of the coil 10.

[0029] As shown in Figures 2 and 3, it is preferable that the fiber layer 30 has a cylindrical shape arranged along the peripheral wall of the coil 10. As shown in Figure 4, it is preferable that the fiber layer 30 has a cylindrical shape with only one lumen 31. As can be seen from Figure 3, it is preferable that the axis center in the longitudinal direction x of the coil 10 coincides with the axis center in the longitudinal direction of the cylindrical fiber layer 30.

[0030] If the fiber layer 30 has a cylindrical shape, it is preferable that the fiber layer 30 has an outer peripheral surface 32 facing outward from the retaining device 1 and an inner peripheral surface 33 facing outward from the coil 10. It is preferable that the fiber layer 30 has a distal end 34 and a proximal end 35 in the longitudinal direction x.

[0031] As can be seen from Figures 2 and 3, it is preferable that the inner circumferential surface 33 of the fiber layer 30 is in contact with the outer circumferential surface 12 of the coil 10. It is preferable that no other members are placed between the coil 10 and the fiber layer 30 in the radial direction y. For example, it is preferable that no drug is applied to the outer circumferential surface 12 of the coil 10 in any form other than the fiber layer 30.

[0032] The fiber layer 30 may consist of a single layer or multiple layers.

[0033] The fiber layer 30 may be fixed to the coil 10. The method of fixation is not particularly limited and can include suturing, bonding, welding, clamping, etc. The fiber layer 30 may be fixed to the coil 10 by a portion of the fiber layer 30 being sandwiched between two wires 21 that constitute the coil 10. The fiber layer 30 may be fixed by bonding or welding its inner circumferential surface 33 to the outer circumferential surface 12 of the coil 10.

[0034] In the fiber layer 30, the fibers 40 may be wound around the outer surface 12 of the coil 10. That is, in the fiber layer 30, the fibers 40 may be wound around the axis in the longitudinal direction x of the coil 10.

[0035] The coil 10 may have only one fiber layer 30, or it may have multiple fiber layers 30. In the latter case, for example, the first fiber layer may be located at the distal end of the coil 10, and the second fiber layer may be located at the proximal end of the coil 10. It is preferable that the multiple fiber layers 30 are arranged in the longitudinal direction x. The multiple fiber layers 30 may be spaced apart from each other in the longitudinal direction x, or they may be in contact with each other. It is preferable that all of the multiple fiber layers 30 have a cylindrical shape.

[0036] As shown in image 60 in Figure 7, the fiber layer 30 contains fibers 40. Generally, fibers are thin, thread-like substances, but in this specification, fibers 40 refer to those with an average fiber diameter of 100 μm or less, and those with an average fiber diameter exceeding 100 μm are excluded. The average fiber diameter of fibers 40 can be measured by the following method: Obtain an image of the fibers at a magnification of 1000x using a scanning electron microscope or laser microscope (for example, a scanning transmission electron microscope (STEM-EDX / EELS) HD-2700 manufactured by Hitachi High-Technologies Corporation). The arithmetic mean of the diameters of at least 20 fibers measured in the obtained image is taken as the average fiber diameter of fibers 40. When measuring the fiber diameter, if the cross-sectional shape of the fiber is not circular, the average of the diameters of the circumscribed and inscribed circles of the irregular cross-section is taken as the fiber diameter.

[0037] As shown in Figures 5 and 6, in the implantation device 1, the fiber layer 30 contains fibers 40 that include a polymer material 41 and a drug 42. Therefore, compared to the case where the drug is applied to the coil surface, it is possible to prevent the drug from falling off the coil at an early stage of the procedure and to improve the sustained release of the drug.

[0038] As the fiber layer 30, a sheet-like or tubular fiber assembly composed of fibers 40 can be used. The fiber assembly may be a knitted fabric, woven fabric, nonwoven fabric, etc., formed from the fibers 40, and the nonwoven fabric may be a dry-laid or wet-laid nonwoven fabric. In the fiber assembly, the fibers 40 may be joined to each other physically, chemically, or mechanically. In the fiber layer 30, the fibers 40 may be joined to each other by entanglement, or they may be joined by heat fusion.

[0039] The fiber layer 30 can be composed of one or more fibers 40. The fibers 40 may be composed of fiber bundles of multiple fibers. The form of the fiber bundle is not particularly limited and may be twisted, untwisted, or untwisted. The number of fibers in the fiber bundle may be, for example, two to ten.

[0040] The fiber layer 30 may be composed of only one type of fiber 40. For example, the fiber layer 30 may be composed only of fibers containing a biodegradable polymer material and a drug, or it may be composed only of fibers containing a non-biodegradable polymer material and a drug.

[0041] The fiber layer 30 may be composed of multiple types of fibers 40.

[0042] The fiber 40 may be a hollow fiber or a solid fiber. The fiber 40 may or may not have crimp. A crimped fiber is, for example, a solid fiber having a spiral-shaped three-dimensional crimp structure.

[0043] A single fiber 40 may have a straight, linear shape, or it may have a branched shape as shown in Figure 8. Figure 8 shows an example in which the fiber 40 has a branched portion 46, and the branched portion 46 has a first branch 46a and a second branch 46b.

[0044] The fiber layer 30 may stretch in the radial direction y. For example, as the coil 10 expands, the fiber layer 30 may stretch in the radial direction y.

[0045] The average fiber diameter of fiber 40 is 3.0 μm or more. An average fiber diameter of 3.0 μm or more allows for an appropriate surface area per unit volume of the fiber, thus facilitating the release of the chemicals contained in the fiber at an appropriate rate. The average fiber diameter of fiber 40 should be 3.0 μm or more, preferably 4.0 μm or more, and more preferably 5.0 μm or more. The average fiber diameter of fiber 40 can be measured using the method described above.

[0046] The average fiber diameter of fiber 40 is preferably 10 μm or less. Having an average fiber diameter of 10 μm or less prevents the surface area per unit volume of the fiber from becoming excessively small, making it easier to release the chemicals contained in the fiber at an appropriate rate. The average fiber diameter of fiber 40 is more preferably 9.0 μm or less, and even more preferably 8.0 μm or less.

[0047] It is preferable that the fiber layer 30 is arranged in the proximal portion 10P and the distal portion 10D of the coil 10. The proximal portion 10P and the distal portion 10D of the coil 10 are the proximal and distal portions, respectively, when the length of the coil 10 is divided into two equal parts in the longitudinal direction x of the coil 10. When the fiber layer 30 is arranged in the proximal portion 10P and the distal portion 10D of the coil 10, it is preferable that the average fiber diameter of the fiber layer 30 arranged in the proximal portion 10P of the coil 10 is smaller than the average fiber diameter of the fiber layer 30 arranged in the distal portion 10D of the coil 10. This makes it easier to release the drug contained in the fibers more quickly in the proximal portion 10P of the coil 10 compared to the distal portion 10D.

[0048] The average fiber diameter of the fiber layer 30 located in the proximal portion 10P of the coil 10 may be 0.1 times or more, 0.2 times or more, 0.3 times or more, and may be 0.9 times or less, 0.8 times or less, or 0.7 times or less, compared to the average fiber diameter of the fiber layer 30 located in the distal portion 10D of the coil 10.

[0049] Preferably, the average fiber diameter of the fiber layer 30 decreases from the distal end to the proximal end of the coil 10. The average fiber diameter of the fiber layer 30 may decrease in stages from the distal end to the proximal end of the coil 10, or it may decrease gradually.

[0050] Preferably, the thickness of the fiber layer 30 decreases from the distal end to the proximal end of the coil 10. The thickness of the fiber layer 30 may decrease in stages or gradually from the distal end to the proximal end of the coil 10.

[0051] The thickness of the fiber layer 30 located in the proximal portion 10P of the coil 10 may be the same as or different from the thickness of the fiber layer 30 located in the distal portion 10D of the coil 10. For example, it is preferable that the thickness of the fiber layer 30 located in the proximal portion 10P of the coil 10 is thinner than the thickness of the fiber layer 30 located in the distal portion 10D of the coil 10. The thickness of the fiber layer 30 located in the proximal portion 10P of the coil 10 is preferably 1 / 2 or less, more preferably 1 / 3 or less, and even more preferably 1 / 4 or less, of the thickness of the fiber layer 30 located in the distal portion 10D of the coil 10. The thickness of the fiber layer 30 located in the proximal portion 10P of the coil 10 per unit length of the coil may be 1 / 50 or more, 1 / 30 or more, or 1 / 10 or more, of the thickness of the fiber layer 30 located in the distal portion 10D of the coil 10 per unit length of the coil. With a fiber layer 30 of this thickness, even if it is applied to the proximal portion 10P of the coil 10, the flexibility of the coil 10 is maintained, allowing the coil 10 to be placed in the nodule while ensuring maneuverability.

[0052] The thickness of the fibrous layer 30 is not particularly limited, but may be, for example, 1 μm or more, 10 μm or more, 100 μm or less, 50 μm or less, or 20 μm or less. A thickness of 1 μm or more in the fibrous layer 30 makes it easier to hold the amount of drug necessary for treatment. Also, a thickness of 100 μm or less in the fibrous layer 30 ensures that the flexibility of the coil 10 is maintained even when the fibrous layer 30 is placed in the proximal part 10P of the coil 10, so that the coil 10 can be placed in the aneurysm while ensuring maneuverability.

[0053] (Method 1 for measuring the thickness of the fiber layer: Method for measuring the total thickness of the fiber layer) Under standard conditions (temperature 23±2℃, relative humidity 50±5%), the coil 10 with the fiber layer 30 attached is cut along the radial y direction using 1cm precision nippers (ESD Corporation, model EA535TA-1) to obtain three test specimens with a length of 1cm in the longitudinal x direction of the coil 10, from the portion including the center of the longitudinal x direction of the fiber layer 30, the distal end of the longitudinal x direction of the fiber layer 30, and the proximal end of the fiber layer 30. Here, the obtained test specimens are designated A1, A2, and A3. The distal cross-section of each test specimen is observed with a microscope (digital microscope) (Keyence Corporation, model VHX-X1), and the average thickness of the fiber layer 30 at each cross-section is measured. The average thickness is obtained by measuring the thickness of the fiber layer 30 at equally spaced points in the circumferential direction of the coil 10 and calculating the average of these thicknesses. Equally spaced points can be, for example, 12 points that are 30° apart within the 360° circumferential z direction of the coil 10. For example, the average thickness of the distal cross-section of test specimen A1 can be the average of the thicknesses of the fiber layer 30 at 12 points that are equally spaced in the circumferential direction on the distal cross-section of test specimen A1. The average of the average thicknesses of test specimens A1 to A3 can be used as the thickness T of the fiber layer 30 of the coil 10.

[0054] (Method 2 for measuring the thickness of the fiber layer: Method for measuring the thickness at the proximal and distal parts of the fiber layer) Under standard conditions (temperature 23±2℃, relative humidity 50±5%), the coil 10 with the fiber layer 30 attached is cut along the radial direction y using 1cm precision nippers (ESD Corporation, model EA535TA-13) to obtain three test specimens each with a length of 1cm in the longitudinal direction x from the proximal part 10P and the distal part 10D of the coil 10. Here, the test specimens obtained from the proximal part 10P of the coil 10 are referred to as B1, B2, and B3, and the test specimens obtained from the distal part 10D of the coil 10 are referred to as C1, C2, and C3. The distal cross-section of each test specimen is observed with a microscope (digital microscope) (Keyence Corporation, model VHX-X1), and the average thickness of the fiber layer 30 at each cross-section is measured. The average thickness is obtained by measuring the thickness of the fiber layer 30 at equally spaced points in the circumferential direction of the coil 10 and calculating the average of these thicknesses. Equally spaced points can be, for example, 12 points separated by 30° intervals within the 360° circumferential z direction of the coil 10. For example, the average thickness of the distal cross-section of test specimen B1 can be the average of the thicknesses of the fiber layer 30 at 12 points equally spaced in the circumferential direction on the distal cross-section of test specimen B1. The average of the average thicknesses of test specimens B1 to B3 can be taken as the thickness Tp of the fiber layer 30 located in the proximal part 10P of the coil 10, and the average of the average thicknesses of test specimens C1 to C3 can be taken as the thickness Td of the fiber layer 30 located in the distal part 10D of the coil 10.

[0055] The average fiber length of fiber 40 may be, for example, 100 mm or more, 200 mm or more, 300 mm or more, or 1300 mm or less, 1200 mm or less, 1100 mm or less, or 1000 mm or less.

[0056] (Method for measuring the average fiber length of a fiber) Ten individual fibers are taken from the fiber layer 30. Each fiber is straightened without stretching, and its length (mm) is measured on a measuring scale. The average of the measured lengths of the ten fibers is taken as the average fiber length of fiber 40. If the number of fibers constituting the fiber layer is less than ten, the length of all the fibers constituting the fiber layer is measured, and the average of the measured lengths of the multiple fibers is taken as the average fiber length of fiber 40. If the number of fibers constituting the fiber layer is one, the length of that one fiber is taken as the average fiber length of fiber 40. As shown in Figure 8, if the fiber 40 to be measured has a branching section 46, and for example the branching section 46 has a first branch 46a and a second branch 46b, the longer of the first branch 46a and the second branch 46b (first branch 46a in Figure 8) is used to calculate the fiber length.

[0057] The fibers 40 can be formed using, for example, electrospinning, melt spinning, wet spinning, or dry spinning, and among these, it is preferable to form them using electrospinning. When forming the fiber layer 30 by electrospinning, a coil 10 is used as a collector in the electrospinning system, and the fibers 40 can be wound around the outer surface of the coil 10 by spinning while rotating the coil 10.

[0058] Preferably, the fiber layer 30 does not contain any materials other than the fibers 40, such as thread-like materials with an average fiber diameter of more than 100 μm, resin wires, metal wires, etc.

[0059] Preferably, the fiber layer 30 is composed only of fibers 40 containing a polymer material 41 and a drug 42.

[0060] The polymer contained in polymer material 41 may be a synthetic polymer or a natural polymer. Polymer material 41 also includes resins.

[0061] The polymer material 41 contained in the fiber 40 is preferably a biodegradable polymer material. As the biodegradable material decomposes, the surface area of ​​the fiber 40 tends to increase, making it easier to release the drug 42 contained in the fiber 40. In this specification, a biodegradable polymer material refers to a material that has the property of being hydrolyzed in the body environment and, after decomposition, becomes a non-toxic low-molecular-weight substance that is metabolized.

[0062] The polymers contained in biodegradable polymer materials may be synthetic polymers or natural polymers, but synthetic polymers are preferred. Biodegradable polymer materials also include biodegradable resins. Examples of biodegradable polymer materials include polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), glycolic acid-lactide copolymer (PLGA), glycolic acid-ε-caprolactone copolymer, lactide-ε-caprolactone copolymer, glycolic acid-lactide-ε-caprolactone copolymer, poly(p-dioxanone) (PDO), poly(2-oxetanone), polymalic acid, polyhydroxyalkanoic acid (PHA), polyhydroxybutyrate (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PH Examples of these substances include, but are not limited to, BV, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBH), starches (carboxymethyl starch, dialdehyde starch), celluloses (CMC, MC, HEC, HPC), proteins (collagen, gelatin, glue, mixture of collagen and elastin), polysaccharides (glycosaminoglycans, chitin, chitosan, hyaluronic acid), gums (acacia gum, guar gum, tragacanth gum), fibroin, laminin, casein, polypeptides, tannins, lignin, alginic acid, etc. These may be used individually or in combination of two or more.

[0063] The polymer material 41 contained in the fiber 40 may be a non-biodegradable polymer material. This makes it less likely to decompose compared to the case of a biodegradable material, thus delaying the release timing of the drug 42 contained in the fiber 40. In this specification, a non-biodegradable polymer material refers to a material other than a biodegradable polymer material that is resistant to hydrolysis in the internal environment of the body.

[0064] The polymers contained in non-biodegradable polymer materials may be synthetic polymers or natural polymers, but synthetic polymers are preferred. Non-biodegradable polymer materials also include non-biodegradable resins. Examples of non-biodegradable polymer materials include, but are not limited to, vinyl acetate such as ethylene vinyl acetate, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, polyamides such as nylon, fluorine such as polyvinylidene fluoride and polytetrafluoroethylene, vinyl chloride such as acrylic and polyvinyl chloride, polycarbonate, epoxy, polyurethanes such as polyurethane elastomers, polyacrylonitrile, keratin, and silk fibroin. These may be used individually or in combination of two or more.

[0065] In addition to the materials mentioned above, the polymer material 41 may also contain various additives such as plasticizers, pigments, flame retardants, antistatic agents, lubricants, softeners, surfactants, and antibacterial agents.

[0066] The drug 42 contained in the fiber 40 may be the active ingredient (API) alone, or it may be a mixture with other additives. Preferred additives include base materials, plasticizers, stabilizers, surfactants, and the like.

[0067] The type of drug 42 contained in the fiber 40 is not particularly limited as long as it is necessary for the prevention or treatment of the affected area. Preferably, the drug 42 has at least one of the following effects: anti-inflammatory effect, antioxidant effect, antihypertensive effect, vasoconstriction inhibitory effect, anticoagulant effect, and shear stress sensing inhibitory effect, and more preferably, it has at least one of the following effects: anti-inflammatory effect, antioxidant effect, antihypertensive effect, and vasoconstriction inhibitory effect. Examples of drugs include selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, etc.), DPP-4 inhibitors (sitagliptin, linagliptin, alogliptin, etc.), HMG-CoA reductase inhibitors (atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin, fluvastatin, lovastatin, mevastatin, cerivastatin, etc.), nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, naproxen, celecoxib, etc.), angiotensin II receptor blockers (ARBs) (losartan, valsartan, telmisartan, etc.), tocopherol acetate (vitamin E acetate, eviprostat, estrol, etc.), ascorbic acid (Asconal, Cinal, Cefylol), and edaravone (Radicut, Free Radical Scavenger). (e.g., jaber), N-acetyl-L-cysteine ​​(NAC), calcium channel blockers (amlodipine, nifedipine, diltiazem, etc.), diuretics (furosemide, trichlormethiazide, spironolactone, etc.), angiotensin-converting enzyme inhibitors (ACE inhibitors) (enalapril, lisinopril, perindopril, etc.), beta-blockers (metoprolol, atenolol, bisoprolol, etc.), alpha-blockers (prazosin, terazosin, doxamylase). Examples include zosyn, 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.), and antiplatelet agents (aspirin, clopidogrel, ticagrelor, etc.).

[0068] The drug 42 may be encapsulated in a capsule. The size of the capsule is preferably 10 nm or larger, more preferably 50 nm or larger, even more preferably 100 nm or larger, and preferably 500 nm or smaller, more preferably 400 nm or smaller, and even more preferably 200 nm or smaller. The capsule is preferably made of a biodegradable material. As the biodegradable material, bioabsorbable polymers, natural polymers, decellularized biological tissues or cells, or combinations thereof can be used. As bioabsorbable polymers, at least one of polylactic acid (PLA), poly-L-lactic acid (PLLA), polyglycolic acid (PGA), copolymer of lactic acid and glycolic acid (PLGA), polycaprolactone (PCL), and polydioxanone (PDS) is preferably used. As natural polymers, at least one of collagen, laminin, fibroin, gelatin, glycosaminoglycan, chitin, chitosan, hyaluronic acid, and polypeptide is preferably used.

[0069] The fiber layer 30 may contain biodegradable materials other than the polymer material 41. Examples of such materials include biodegradable alloys such as magnesium alloys and iron-manganese alloys. A portion of the fiber 40 may be composed of a biodegradable alloy.

[0070] The fiber 40 may contain an X-ray opaque material. For example, the X-ray opaque material may be coated on the surface of the fiber 40, embedded within the fiber 40, or retained within the fiber 40. Examples of X-ray opaque materials include lead, barium, iodine, tungsten, gold, silver, platinum, iridium, platinum-iridium alloy, stainless steel, titanium, cobalt-chromium alloy, palladium, and tantalum.

[0071] In addition to the materials mentioned above, the fiber 40 may also contain various additives such as plasticizers, pigments, flame retardants, antistatic agents, lubricants, softeners, and surfactants.

[0072] As shown in Figure 5, it is preferable that the polymer material 41 and the drug 42 are mixed in the fiber 40. In the fiber 40, the drug 42 may be dispersed in the polymer material 41. The drug 42 may be uniformly dispersed in the polymer material 41, or it may be locally dispersed. The drug 42 may be dispersed in the polymer material 41 in particulate form. The drug 42 may be exposed on the surface of the fiber 40, or it may be present only inside the fiber 40. In the fiber 40, the polymer material 41 may function as a matrix. In the fiber 40, the drug 42 may be dissolved in the polymer material 41.

[0073] The fiber 40 shown in Figure 5 can be produced, for example, by mixing (preferably kneading) a polymer material and a chemical agent. For production, a spinning system equipped with an extruder and a spinneret may be used, for example. The polymer material and chemical agent are mixed (preferably kneaded) in the extruder, the mixture is melted, and the mixture is extruded from the spinneret to produce the fiber.

[0074] In the fiber 40, the mixing ratio of polymer material 41 to drug 42 is preferably 1 / 1 or more by mass, more preferably 2 / 1 or more, even more preferably 3 / 1 or more, and also preferably 100 / 1 or less, more preferably 80 / 1 or less, and even more preferably 50 / 1 or less.

[0075] In the fiber 40, the content of the polymer material 41 is preferably 20 wt% or more, more preferably 30 wt% or more, even more preferably 40 wt% or more, and also preferably 80 wt% or less, more preferably 70 wt% or less, and even more preferably 60 wt% or less.

[0076] In the fiber 40, the content of the agent 42 is preferably 20 wt% or more, more preferably 30 wt% or more, even more preferably 40 wt% or more, and also preferably 80 wt% or less, more preferably 70 wt% or less, and even more preferably 60 wt% or less.

[0077] In the fiber 40, when the drug 42 is dispersed in particulate form within the polymer material 41, the particle size is not particularly limited, but may be, for example, 10.0 nm or larger, 50.0 nm or larger, 100 nm or larger, or 200 nm or larger. Alternatively, the particle size may be 5.00 μm or smaller, 4.00 μm or smaller, 3.00 μm or smaller, 2.00 μm or smaller, or 1.00 μm or smaller. Having the particle size within the above range makes it easier to uniformly disperse the particulate drug 42 in the polymer material 41, and also facilitates the manufacture of the fiber 40. Here, "particle size" refers to the volume-average particle size (D50) at the median 50% diameter in the particle size distribution obtained by dynamic light scattering or the like. Commercially available particulate drugs may be used, in which case the particle size listed in the catalog can be adopted.

[0078] The fiber 40 may be a composite fiber having a core-sheath structure, a side-by-side structure, or a sea-island structure. The core-sheath structure includes a concentric core-sheath structure and an eccentric core-sheath structure. In order to slow down the release rate of the drug 42 from the fiber 40, it is preferable that the drug 42 is encapsulated in the polymer material 41 in the fiber 40. Encapsulating the drug 42 in the polymer material 41 means that the drug 42 is covered by the polymer material 41 and is not exposed to the outside. Covering the drug 42 with the polymer material 41 can suppress the occurrence of an initial burst of the drug 42 and make it easier to control the release rate of the drug 42.

[0079] As shown in Figure 6, the fiber 40 preferably includes a core-sheath type fiber having a core portion 44 and a sheath portion 45, and more preferably consists of a core-sheath type fiber. In that case, it is preferable that the core portion 44 contains the drug 42 and the sheath portion 45 contains a polymer material 41. By using a composite fiber of this shape, it becomes easier to suppress the occurrence of an initial burst of the drug 42 and to control the release rate of the drug 42.

[0080] If the fiber 40 is a core-sheath type fiber having a core portion 44 and a sheath portion 45, and the fiber 40 is branched into a first branch portion 46a and a second branch portion 46b, then the core portion 44 may be exposed in the first branch portion 46a and / or the second branch portion 46b without being covered by the sheath portion 45.

[0081] In the core portion 44, the content of the polymer material 41 is preferably 20 wt% or less, more preferably 10 wt% or less, even more preferably 5 wt% or less, and it is even more preferable that the core portion 44 does not contain the polymer material 41.

[0082] In the sheath portion 45, the content of the drug 42 is preferably 20 wt% or less, more preferably 10 wt% or less, even more preferably 5 wt% or less, and it is even more preferable that the sheath portion 45 does not contain the drug 42.

[0083] The fiber layer 30 preferably consists of one or more core-sheath type fibers.

[0084] To facilitate control of the release rate of the active ingredient in the drug, a concentric core sheath type structure is preferred for the composite fiber.

[0085] The core-sheath type fiber contained in fiber 40 can be manufactured in the same manner as general core-sheath type fibers. For manufacturing, for example, an electrospinning system equipped with a spinneret and collector having a multi-tube shape may be used. Preferably, the core material supplied to the system contains a drug 42, and the sheath material contains a polymer material 41. The core material may contain a solvent that is soluble in the drug 42. The sheath material may also contain a solvent that is soluble in the polymer material 41. The solvent is not particularly limited as long as it can dissolve the polymer material 41 and / or the drug 42 and can be sprayed from the spinneret. Examples of solvents include water, N,N-dimethylformamide (DMF), ethanol, acetone, tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, toluene, and the like.

[0086] The cross-section of fiber 40 is the cross-section perpendicular to the longitudinal axis of fiber 40, and is sometimes called the fiber cross-section. The cross-sectional shape of fiber 40 may refer to the outer contour shape of the cross-sectional figure perpendicular to the longitudinal axis of fiber 40, or it may refer to the shape of the cross-sectional figure perpendicular to the longitudinal axis of fiber 40 itself. The outer contour is composed of one or more sides. The outer contour may have only straight sections, only curved sections, or both straight and curved sections, but it is preferable that it has only curved sections.

[0087] The fiber 40 may have a hollow cross-section, as shown in Figures 9 to 11, or a solid cross-section, as shown in Figures 12 to 17. If the fiber 40 has a hollow cross-section, i.e., if the fiber 40 is a hollow fiber, the fiber 40 may have one or more lumens extending in the longitudinal direction of the fiber 40. For example, in Figure 9, the fiber has one lumen extending in the longitudinal direction of the fiber, and in Figure 11, the fiber has three lumens extending in the longitudinal direction. The multiple lumens of the fiber may be arranged at equal intervals in the circumferential direction of the fiber 40, or they may be arranged at unequal intervals. Furthermore, the multiple lumens of the fiber may have the same or different cross-sectional areas.

[0088] The fiber 40 may have a circular cross-section or an irregular cross-section. An irregular shape is a shape other than a perfect circle. The type of cross-sectional shape of the fiber 40 is not particularly limited and can be, for example, a circular shape; an elliptical shape, an egg shape, an oblong shape such as a rounded rectangle; a polygonal shape such as a triangle or a square; an alphabet shape such as a Y shape or a W shape; an asterisk shape or a fin shape with multiple protrusions extending radially; a multilobe shape such as a flower shape or a multi-leaf shape; or a combination of these; or an irregular shape. A multilobe shape is a shape in which multiple protrusions and recesses are arranged alternately. Polygonal shapes include polygonal shapes with rounded corners and trapezoidal shapes.

[0089] The cross-sectional shape of the fiber 40 may be flattened or non-flattened. A flattened shape refers to a shape that is flat and has a difference between the length in one direction and the length in another direction perpendicular to the longitudinal axis of the cross-section perpendicular to the longitudinal axis. More specifically, a cross-sectional figure has a flattened shape if the flatness (aspect ratio), which is the value obtained by dividing the length of the major axis of the cross-section perpendicular to the longitudinal axis of the fiber 40 by the length of the minor axis, is greater than 1, and a cross-sectional figure has a non-flattened shape if the flatness is 1.

[0090] If the fiber 40 has a flattened cross-section, the degree of flatness should be greater than 1.0, preferably 1.2 or greater, more preferably 1.5 or greater, even more preferably 2.0 or greater, and also preferably 10 or less, more preferably 8.0 or less, and even more preferably 5.0 or less.

[0091] Figures 9 to 17 show fibers with irregular cross-sections. Figure 9 shows a fiber 40 with one lumen and a rounded rectangular outline around the outer circumference of the cross-sectional shape; Figure 10 shows a fiber 40 with eight fins around one lumen; Figure 11 shows a fiber 40 with three fan-shaped lumen and a circular outline around the outer circumference of the cross-sectional shape; Figure 12 shows a fiber 40 with a flower-shaped cross-section; Figure 13 shows a fiber 40 with a cross-shaped cross-section; Figure 14 shows a fiber 40 with a flattened cross-section and having a core portion 44 and a sheath portion 45; Figure 15 shows a fiber 40 with a flattened and multi-lobed cross-section; Figure 16 shows a fiber 40 with a flattened and W-shaped cross-section; and Figure 17 shows a fiber 40 with a Y-shaped cross-section.

[0092] If the fiber 40 includes a core-sheath type fiber having a core portion 44 and a sheath portion 45, the core portion 44 may have a circular cross-section, but it is preferable that it has an irregular cross-section, as shown in Figure 14. Having an irregular cross-section for the core portion 44 makes it easier to change the release rate of the drug 42 from the fiber 40.

[0093] As shown in Figure 14, in the cross-section of the fiber 40, it is preferable that the distance from the outer circumference of the core portion 44 to the outer circumference of the sheath portion 45 in the radial direction of the fiber 40 differs in the circumferential direction of the fiber 40. In Figure 14, the fiber 40 has a portion having a distance L1 from the outer circumference of the core portion 44 to the outer circumference of the sheath portion 45, and a portion having a distance L2 from the outer circumference of the core portion 44 to the outer circumference of the sheath portion 45, where distance L1 > distance L2. By having the core portion 44 have an irregular cross-section in this way, it is possible to form a portion of the fiber 40 in which the active ingredient of the drug 42 is easily released and a portion in which it is released with a delay.

[0094] When the fiber 40 includes a core-sheath type fiber having a core portion 44 and a sheath portion 45, the cross-sectional shape of the fiber 40 may be the same as the cross-sectional shape of the core portion 44, but it is preferable that it be different. This makes it easier to make the distance from the outer circumference of the core portion 44 to the outer circumference of the sheath portion 45 in the radial direction of the fiber 40 different in the circumferential direction of the fiber 40. When the cross-sectional shape of the fiber 40 is different from the cross-sectional shape of the core portion 44, it includes the case where the shapes are similar. It is preferable that the cross-sectional shape of the fiber 40 and the cross-sectional shape of the core portion 44 are not similar. The cross-sectional shape of the core portion 44 is the contour shape of the outer circumference of the core portion 44 in a cross section perpendicular to the longitudinal axis direction of the fiber 40.

[0095] The core portion 44 may be positioned eccentrically with respect to the fiber 40. That is, the centroid of the cross-sectional shape of the core portion 44 may be in a different position from the centroid of the cross-sectional shape of the fiber 40. By positioning the core portion 44 in this way, it becomes easier to make the distance from the outer circumference of the core portion 44 to the outer circumference of the sheath portion 45 in the radial direction of the fiber 40 different in the circumferential direction of the fiber 40.

[0096] For information on the types of cross-sectional shapes of the core portion 44, please refer to the description of the types of cross-sectional shapes of the fibers 40.

[0097] If the fiber 40 is a core-sheath type fiber, the ratio of the cross-sectional area of ​​the sheath portion 45 to the total cross-sectional area of ​​the cross section perpendicular to the longitudinal axis of the fiber 40 is defined as the sheath portion cross-sectional area ratio. If the entire fiber layer 30 is composed of core-sheath type fibers having a core portion 44 and a sheath portion 45, it is preferable that the sheath portion cross-sectional area ratio of the fiber 40 in the proximal portion 10P is smaller than that of the fiber 40 in the distal portion 10D. This makes it easier to differentiate the rate of drug release from the fiber layer 30 between the distal portion 10D and the proximal portion 10P, as the decomposition rate of the fiber 40 in the proximal portion 10P tends to be relatively higher than that of the distal portion 10D.

[0098] The sheath cross-sectional area ratio of the fibers 40 in the proximal portion 10P is obtained by measuring the sheath cross-sectional area ratio of each of 10 fibers 40, arbitrarily selected from the fiber layer 30 arranged in the proximal portion 10P, at the midpoint of their longitudinal axis, and then calculating the average value of the sheath cross-sectional area ratios of the 10 fibers 40. The cross-sectional image can be observed using a scanning electron microscope or a laser microscope (for example, a scanning transmission electron microscope (STEM-EDX / EELS) HD-2700 manufactured by Hitachi High-Technologies Corporation). The sheath cross-sectional area ratio of the fibers 40 in the distal portion 10D can be determined by the same method.

[0099] The biodegradable material contained in the fibers 40 of the proximal portion 10P and the distal portion 10D may be the same type. In that case, it is preferable that the mass of the biodegradable material per unit length of coil contained in the fibers 40 of the proximal portion 10P is greater than the mass of the biodegradable material per unit length of coil contained in the fibers 40 of the distal portion 10D. This configuration also makes it easier to relatively increase the decomposition rate of the fibers 40 of the proximal portion 10P compared to that of the distal portion 10D.

[0100] The non-biodegradable material contained in the fibers 40 of the proximal portion 10P and the distal portion 10D may be the same type. In that case, it is preferable that the mass of the non-biodegradable material per unit length of coil contained in the fibers 40 of the proximal portion 10P is less than the mass of the non-biodegradable material per unit length of coil contained in the fibers 40 of the distal portion 10D. This configuration also makes it easier to relatively increase the decomposition rate of the fibers 40 of the proximal portion 10P compared to that of the distal portion 10D.

[0101] As shown in Figures 2 and 3, it is preferable that the fiber layer 30 is arranged over the entire length x of the coil 10. Since the flexibility of the coil 10 tends to decrease when the fiber layer 30 is provided, the fiber layer 30 may be arranged only in a part of the length x of the coil 10, as shown in Figures 18 to 22. For example, the fiber layer 30 may be arranged in a section of 30% or more of the total length x of the coil 10, or in a section of 40% or more of the total length, or in a section of 50% or more of the total length. Alternatively, the fiber layer 30 may be arranged in a section of 90% or less of the total length x of the coil 10, or in a section of 80% or less of the total length, or in a section of 70% or less of the total length.

[0102] The length of the fiber layer 30 in the longitudinal direction x is preferably the same as or shorter than the length of the coil 10 in the longitudinal direction x. The fiber layer 30 is preferably not located distal to the distal end of the coil 10. Furthermore, the fiber layer 30 is preferably not located proximal to the proximal end of the coil 10.

[0103] As shown in Figures 2 and 3, the entire length x of the coil 10 is covered by the fiber layer 30, and the wire 21 does not need to be exposed.

[0104] As shown in Figure 18, the fiber layer 30 is located only in the distal portion 10D of the coil 10 and does not need to be located in the proximal portion 10P of the coil 10. As shown in Figure 19, the fiber layer 30 is located only in the proximal portion 10P of the coil 10 and does not need to be located in the distal portion 10D of the coil 10.

[0105] As shown in Figure 20, when the length of the coil 10 is divided into three equal parts in the longitudinal direction x of the coil 10 into a distal section 10A, a central section 10B, and a proximal section 10C, the fiber layer 30 may be located only in the central section 10B, or, as shown in Figure 21, it may be located in the distal section 10A and the central section 10B but not in the proximal section 10C, or, although not shown, it may be located in the proximal section 10C and the central section 10B but not in the distal section 10A.

[0106] As shown in Figure 22, it is preferable that the fiber layer 30 is not provided at the distal end of the coil 10. For example, when the wire 21 that is not covered by the tip 25 of the coil 10 and is at the farthest end is counted as the first turn from the distal side of the coil 10, it is preferable that the fiber layer 30 is located proximal to the third turn of the coil 10, more preferably proximal to the fifth turn of the coil 10, and even more preferably proximal to the tenth turn of the coil 10. By not providing the fiber layer 30 at the distal end of the coil 10, the outer surface 12 of the coil 10 is more easily exposed at the distal end, which makes it easier for the coil 10 to firmly engage with other parts of the coil and other coils when placed in the knot, and makes it easier to form a framework.

[0107] As shown in Figure 22, it is preferable that the fiber layer 30 is not provided at the proximal end of the coil 10. For example, when the wire 21 that is not covered by the base tip 26 and is at the nearest end of the coil 10 is counted as the first turn from the proximal side of the coil 10, it is preferable that the fiber layer 30 is located distal to the third turn of the coil 10, more preferably distal to the fifth turn of the coil 10, and even more preferably distal to the tenth turn of the coil 10. By not providing the fiber layer 30 at the proximal end of the coil 10, the outer surface 12 of the coil 10 is more easily exposed at the proximal end, which helps to prevent a decrease in the flexibility of the coil 10.

[0108] As shown in Figure 22, it is preferable that the fiber layer 30 is arranged only in the portion of the coil 10 excluding the distal and proximal ends.

[0109] Although not shown in the diagram, the fiber layer 30 may not be provided at the distal end of the coil 10, nor at the proximal portion 10P of the coil 10, and the fiber layer 30 may be provided only in the portion of the coil 10 excluding the distal end and the proximal portion 10P. This makes it easier to engage the distal end of the coil 10 with other members while preventing a decrease in flexibility at the proximal portion 10P of the coil 10.

[0110] If the coil 10 has a longitudinal direction x, as shown in Figures 23 to 24, when the coil 10 is viewed from a direction perpendicular to the longitudinal direction x, it is preferable that the fibers 40 are sandwiched between two adjacent wires 21 in the longitudinal direction x. By sandwiching the fibers 40 between the wires 21, the drug 42 is less likely to be released from the fibers 40 in the sandwiched portion, thereby improving the sustained release of the drug.

[0111] As shown in Figures 23 to 24, if there is a gap 22 between adjacent wires 21 in the longitudinal direction x, some of the fibers of the fiber layer 30 may be placed in the gap 22. Here, the gap 22 is defined as having a length in the longitudinal direction x that is at least 1 / 10 of the outer diameter of the wire 21.

[0112] Although not shown in the diagram, even if there is a gap 22 between adjacent wires 21 in the longitudinal direction x, the fiber layer 30 does not need to be placed in the gap 22.

[0113] As shown in Figure 3, the fiber layer 30 may be arranged only on the radially y-outside of the outermost position of the outer peripheral surface 12 of the coil 10.

[0114] Although not shown in the figures, the fiber layer 30 may be positioned radially y-outward from the innermost position of the outer circumferential surface 12 of the coil 10. That is, if the cross-sections of adjacent wires 21 in the longitudinal direction x of the coil 10 are circular, elliptical, etc., the fiber layer 30 may be positioned in the recesses of the uneven structure provided on the surface of the coil 10.

[0115] As shown in Figures 23 to 24, the fiber layer 30 may be positioned radially y-inward from the outermost position of the outer peripheral surface 12 of the coil 10.

[0116] As shown in Figure 24, the fiber layer 30 may be arranged on the inner circumferential surface 13 side of the coil 10. That is, the fibers 40 of the fiber layer 30 may be located in the lumen 11 of the coil 10. Since the drug 42 is less likely to be released from the fibers 40 located in the lumen 11 compared to the fibers 40 located on the outer circumferential surface 12, the sustained release of the drug can be improved.

[0117] As can be seen from Figure 24, if there is a gap 22 between adjacent wires 21 in the longitudinal direction x, the fiber layer 30 may enter the lumen 11 of the coil 10 through the gap 22.

[0118] The coil 10 shown in Figure 24 may be formed by providing a fiber layer 30 on the outer surface of a wire 21, and then winding the wire 21 with the fiber layer 30 to form a coil shape.

[0119] As shown in Figure 25, the second agent 48 may be impregnated into the interfiber gaps of the fiber layer 30. This allows the fiber layer 30 to hold a large amount of agent while preventing an initial burst of the agent. For the composition of the second agent 48, refer to the description of agent 42. When the second agent 48 is present in the fiber layer 30, agent 42 may also be referred to as the first agent 42 for distinction.

[0120] The second agent 48 may be impregnated throughout the entire longitudinal direction x of the fiber layer 30, or it may be impregnated only in a part of the longitudinal direction x of the fiber layer 30.

[0121] When the thickness of the fiber layer 30 is divided into three equal parts in the thickness direction of the fiber layer 30, i.e., in the radial direction y of the coil 10, from the outside to the inside in the radial direction y, it is preferable that the second agent 48 impregnates at least one of the outer part, the central part, and the inner part, more preferably impregnated in the inner part, and even more preferably impregnated in the central part and the inner part but not in the outer part.

[0122] The fiber layer 30 can be impregnated with the second agent 48 by applying the second agent 48 to the outer surface 12 of the coil 10 using a method such as electrospinning, and then applying the second agent 48 to the fiber layer 30. The method of applying the second agent 48 is not particularly limited, but for example, the chemical solution containing the second agent 48 may be applied to the fiber layer 30 by brush, spray, coater, etc., or the fiber layer 30 may be coated with the second agent 48 by immersing the fiber layer 30 in the chemical solution containing the second agent 48.

[0123] The surface roughness Ra of the outer circumferential surface 12 of the coil 10 may be greater than the surface roughness Ra of the inner circumferential surface 13 of the coil 10. This increases the frictional force acting between the outer circumferential surface 12 of the coil 10 and the inner circumferential surface 33 of the fiber layer 30, making it easier for the fiber layer 30 to adhere tightly to the outer circumferential surface 12 of the coil 10. The surface roughness Ra of the outer circumferential surface 12 and the inner circumferential surface 13 of the coil 10 corresponds to the arithmetic mean roughness Ra specified in JIS B 0601 (2001) and is measured in accordance with JIS B 0633 (2001). For measurement, a measuring instrument specified in JIS B 0651 (2001) (for example, an ultra-precision non-contact three-dimensional measuring device, model: NH-3SP, manufactured by Mitaka Kohki Co., Ltd.) is used. When measuring the calculated mean roughness Ra of a coil 10 that already has a fiber layer 30, the fiber layer 30 can be removed from the coil 10 before measurement. The fibrous layer 30 can be removed by dissolving it in a solvent such as physiological saline.

[0124] When measuring the surface roughness Ra, the wire 21 constituting the coil 10 (primary coil) may be straightened by pulling it while gripping both ends of the wire 21, or the distal end of the wire 21 and a position several centimeters proximal to the distal end (for example, 5 cm proximal to the distal end). The surface roughness of the straightened wire 21 may then be measured in accordance with JIS B 0633 (2001). Similarly, if the coil 10 (primary coil) has been bent to form a secondary coil, the wire 21 constituting the secondary coil may be straightened by pulling it while gripping both ends of the wire 21, or the distal end of the wire 21 and a position several centimeters proximal to the distal end (for example, 5 cm proximal to the distal end). The surface roughness of the straightened wire 21 may then be measured in accordance with JIS B 0633 (2001). The surface roughness Ra of the outer surface of coil 10 (primary coil) can be determined by measuring the surface roughness Ra of the portion of the straightened wire 21 that corresponds to the outer surface of coil 10 (primary coil). Similarly, the surface roughness Ra of the inner surface of coil 10 (primary coil) can be determined by measuring the surface roughness Ra of the portion of the straightened wire 21 that corresponds to the inner surface of coil 10 (primary coil). Since coil 10 is constructed by winding wire 21, the area of ​​the outer circumference of the straightened wire 21, for example, between 0° and 180°, corresponds to the outer surface of coil 10, and the area of ​​the outer circumference of the straightened wire 21, for example, between 180° and 360°, corresponds to the inner surface of coil 10. Therefore, by measuring the surface roughness Ra of wire 21, the surface roughness Ra of coil 10 can be measured.

[0125] Although not shown in the diagram, in addition to the fiber layer 30, a drug may be placed on the surface of the coil 10. In that case, the drug may be placed on the outer surface 12 or on the inner surface 13. The drug placed on the surface of the coil 10 may be held on the surface of the coil 10 as a drug layer. A drug layer may be placed on the outer surface 12 of the coil 10, and the fiber layer 30 may be placed outside the drug layer in the radial direction y.

[0126] In addition to the fiber layer 30, the agent applied to the coil 10 may be directly attached to the surface of the coil 10, or it may be attached indirectly to the surface of the coil 10 via a bioadhesive. The type of material of the bioadhesive is not particularly limited, but for example, polysaccharide adhesives such as collagen, chitosan, and gelatin, polyethylene glycol-based hydrogel adhesives, and protein adhesives such as fibrin and collagen can be used.

[0127] If the drug is directly attached to the surface of the coil 10, the drug may be covered by the fiber layer 30 to control the rate of drug release.

[0128] In addition to the fiber layer 30, the drug applied to the coil 10 is preferably encapsulated. The drug encapsulated in the capsule may be directly attached to the surface of the coil 10, or it may be attached indirectly to the surface of the coil 10 via a bioadhesive. The size of the capsule is preferably 10 nm or larger, more preferably 50 nm or larger, even more preferably 100 nm or larger, and preferably 500 nm or smaller, more preferably 400 nm or smaller, and even more preferably 200 nm or smaller. The capsule preferably contains a biodegradable material.

[0129] As shown in Figure 3, it is preferable that the implantation device 1 has a stretch resistance member 50 positioned in the lumen 11 of the coil 10. The stretch resistance member 50 suppresses the stretching of the coil 10 in the longitudinal direction x during operation.

[0130] The stretch resistance member 50 may be a long member made of a single wire or stranded wire. The stretch resistance member 50 may be linear, wavy, helical, or a combination thereof. Only one or more stretch resistance members 50 may be placed in the lumen 11. The stretch resistance member 50 may be made of resin or metal. The stretch resistance member 50 may be linear, wavy, helical, or a combination thereof.

[0131] The first end of the stretch resistance member 50 may be connected to the distal end of the coil 10 (for example, the distal end of the wire 21). The second end of the stretch resistance member 50 may be connected to the proximal end of the coil 10 (for example, the proximal end of the wire 21) or to the connection part 53. The stretch resistance member 50 may be placed in the lumen 11 in a state where it is folded back midway along the longitudinal axis of the stretch resistance member 50.

[0132] Methods for connecting the stretch resistance member 50 to other members include physical fixing methods such as welding, crimping, adhesive bonding, engagement, linking, binding, ligation, or combinations thereof. Here, "connection" includes both forms in which the two elements are directly connected and forms in which the two elements are indirectly connected through one or more other elements.

[0133] As shown in Figures 1 to 3, the indwelling device 1 is positioned proximal to the coil 10 in the longitudinal direction x of the coil 10, and may further include a pusher 55 that pushes the coil 10 distally, and a connecting portion 53 that connects the proximal portion 10P of the coil 10 and the distal portion of the pusher 55.

[0134] The pusher 55 is a rod-shaped or wire-shaped member used to hold the coil 10 and push it distally. The pusher 55 can consist of one or more members. The pusher 55 can consist of a wire member, a coil member, or a combination thereof. The pusher 55 can be made of a conductive material such as stainless steel.

[0135] The connection portion 53 connects the coil 10 and the pusher 55. Preferably, the connection portion 53 has a detachment mechanism that allows the coil 10 to detach from the pusher 55. Examples of detachment mechanisms include hydraulic, electric, and mechanical types, and among these, an electric detachment mechanism is preferred. In the detachment mechanism, it is preferable that the connection portion 53 is heated and disconnected by electrical or thermal energy supplied through the pusher 55, thereby detaching the coil 10 from the pusher 55. In this case, it is preferable that the connection portion 53 is heated by a high-frequency current supplied between the distal end of the pusher 55 and the counter electrode.

[0136] The connecting portion 53 preferably contains a material that melts or dissolves upon heating. The connecting portion 53 can be cut by Joule heating. Examples of such materials include synthetic resin materials, and it is preferable to use hydrophilic resins of synthetic polymer substances such as polyvinyl alcohol (PVA), PVA crosslinked polymers, PVA water-absorbing gel freeze-thaw elastomers, and polyvinyl alcohol copolymers.

[0137] As shown in Figures 1 to 3, the coil 10 is constructed by winding a wire 21, and the implantation device 1 may further have a tip 25 positioned at the distal end of the coil 10. The tip 25 covers a portion of the wire 21 to prevent the distal end of the wire 21 from directly contacting the inner wall surface of the body. The tip 25 may be in contact with the outer circumferential surface 12 of the coil 10, or it may be in contact with the inner circumferential surface 13 of the coil 10. Preferably, the tip 25 closes the distal end of the coil 10.

[0138] As shown in Figures 1 to 3, the indwelling device 1 is positioned at the proximal end of the coil 10 and may have a proximal tip 26 for closing the proximal end of the coil 10. The proximal tip 26 may be in contact with the outer circumferential surface 12 of the coil 10 or with the inner circumferential surface 13 of the coil 10. The proximal tip 26 has a lumen, and a part of the connecting portion 53, for example, its distal end, may be inserted into the lumen.

[0139] The tip 25 and / or base tip 26 may be made of a metal material or a resin. Examples of resins include thermoplastic resins and UV-curing resins. For example, ester resins such as epoxy acrylate resins, urethane acrylate resins, polyester acrylate resins, and polyethylene terephthalate resins, and olefin resins such as polypropylene can be used. The metal that constitutes the tip 25 can be one of the metals mentioned in the description of the wire 21.

[0140] In the longitudinal direction x, it is preferable that the fiber layer 30 is positioned distal to the distal end of the connecting portion 53. In the longitudinal direction x, it is preferable that the fiber layer 30 is not positioned in the portion where the coil 10 and the connecting portion 53 overlap.

[0141] The fiber layer 40 may contain multiple types of fibers 40. For example, as shown in Figure 26, the fiber layer 40 may contain, as fibers 40, a first fiber 40A and a second fiber 40B having a smaller average fiber diameter than the first fiber 40A. This makes it easier for the drug to be released from the second fiber 40B before it is released from the first fiber 40A. This makes it easier to release the drug with a time difference, thereby improving the sustained release of the drug.

[0142] The average fiber diameter of the second fiber 40B may be 0.1 times or more, 0.2 times or more, 0.3 times or more, and may be 0.9 times or less, 0.8 times or less, or 0.7 times or less than the average fiber diameter of the first fiber 40A.

[0143] In the fiber layer 30, the first fiber 40A may be arranged in the proximal part 10P of the coil 10, and the second fiber 40B may be arranged in the distal part 10D of the coil 10.

[0144] The first fiber 40A and the second fiber 40B may have different cross-sectional shapes. By having different cross-sectional shapes in this way, it becomes easier to release the drug from the fiber layer 30 with a time difference. For example, the cross-section of the first fiber 40A may be hollow, and the cross-section of the second fiber 40B may be solid.

[0145] Either the first fiber 40A or the second fiber 40B may be a core-sheath type fiber having a core portion 44 and a sheath portion 45, where the core portion 44 contains a drug 42 and the sheath portion 45 contains a polymer material 41. In that case, the other of the first fiber 40A or the second fiber 40B may be a fiber in which the polymer material 41 and the drug 42 are mixed. By making the structures of the first fiber 40A and the second fiber 40B different in this way, it becomes easier to release the drug from the fiber layer 30 with a time difference.

[0146] Either the first fiber 40A or the second fiber 40B may be a fiber containing a biodegradable polymer material and a drug, but not a non-biodegradable polymer material, while the other fiber may contain a non-biodegradable polymer material and a drug, but not a biodegradable polymer material. In this way, by making the materials of the first fiber 40A and the second fiber 40B different, it becomes easier to release the drug from the fiber layer 30 with a time difference.

[0147] The first fiber 40A and the second fiber 40B may be fibers containing a biodegradable polymer material and a drug. Alternatively, the first fiber 40A and the second fiber 40B may be fibers containing a non-biodegradable polymer material and a drug.

[0148] For further details regarding the composition of the first fiber 40A and the second fiber 40B, please refer to the description of the fiber 40 composition described above. [Explanation of symbols]

[0149] 1: Intra-biological implantable device 10: Coil 11:Lumen 12: Outer surface 13: Inner surface 21: Wire rod 22: Gap 25: Tip 26: Base tip 30: Fiber layer 31: lumen 32: Outer surface 33: Inner surface 34: Distal end 35: Proximal end 40: Fibers 40A: First fiber 40B: Second fiber 41: Polymer materials 42: Medications 44: Core 45: Scabbard part 48: Second drug 50: Stretch resistance member 53: Connection part 55: Pusher 60: Image p: Long axis of the wire x: Longitudinal direction of the coil y: radial direction of the coil z: Circumferential direction of the coil

Claims

1. Coil and, Displaced on the outer surface of the coil, it has a fiber layer containing fibers, The aforementioned fiber contains a polymer material and a drug, An in-vivo implantation device having an average fiber diameter of 3.0 μm or more.

2. The in-vivo implantation device according to claim 1, wherein the average fiber diameter is 10 μm or less.

3. The in-vivo implantation device according to claim 1 or 2, wherein the fiber has an irregular cross-section.

4. The in-vivo implantation device according to claim 1 or 2, wherein the fiber includes a core-sheath type fiber having a core portion and a sheath portion, the core portion containing the drug, and the sheath portion containing the polymer material.

5. The in-vivo implantation device according to claim 4, wherein the core portion has an irregularly shaped cross-section.

6. The in-vivo implantation device according to claim 1 or 2, wherein the average fiber diameter of the fiber layer disposed in the proximal part of the coil is smaller than the average fiber diameter of the fiber layer disposed in the distal part of the coil.

7. The in-vivo implantation device according to claim 1 or 2, wherein the fiber layer comprises, as the fibers, a first fiber and a second fiber having a smaller average fiber diameter than the first fiber.

8. The in-vivo implantation device according to claim 1 or 2, wherein the polymer material is a biodegradable polymer material.

9. The in-vivo device according to claim 1 or 2, wherein a second drug is impregnated into the interfacial gaps of the fiber layer.

Images