In-vivo indwelling device and method for manufacturing same

Abstract

This in-vivo indwelling device has a coil (10), wherein a drug layer (60) including a drug and a base material composed of a non-biodegradable resin is disposed on a section of or the entirety of a surface of the in-vivo indwelling tool, and the mass ratio of the base material is greater than that of the drug. The base material is composed of a biodegradable resin, and the drug accounts for 5-45 mass % of the drug layer (60).

Description

In-vivo indwelling device and method for manufacturing the same

[0001] The present disclosure relates to an in-vivo indwelling device for forming an embolus in a blood vessel at a vascular lesion site and a method for manufacturing the in-vivo indwelling device.

[0002] As a minimally invasive treatment for cerebral aneurysms, endovascular therapy using a catheter or the like is known. In endovascular therapy, for example, an in-vivo indwelling device for embolization is inserted into a cerebral aneurysm through a catheter, cut at a detachment portion, a part of the in-vivo indwelling device is indwelled in the aneurysm, and the aneurysm is embolized. A part of the in-vivo indwelling device indwelled in the aneurysm acts as a physical obstacle to blood flow, and the formation of a thrombus around the indwelled part of the in-vivo indwelling device can reduce the risk of aneurysm rupture.

[0003] Patent Documents 1 and 2 disclose an in-vivo indwelling device for embolization comprising a coil, an elongation resistance member disposed in the coil, and a tip disposed at a distal end of the coil. The in-vivo indwelling device is attached to a distal end portion of a pusher, and is pushed distally through a catheter or the like used for indwelling by the pusher, thereby being delivered to a target site in the body such as an aneurysm. Patent Document 3 discloses an in-vivo indwelling device in which a coil holds a drug to promote organization in an aneurysm.

[0004] Japanese National Publication of International Patent Application No. 2008-525113, International Publication No. WO 2019 / 026364, Japanese Patent Laid-Open No. 2015-195978

[0005] The aforementioned organization in an aneurysm progresses over a relatively long period of time, so it is desirable that the drug held by the coil dissolves out slowly over time, that is, has sustained-release properties. Accordingly, an object of the present disclosure is to provide an in-vivo indwelling device that reduces abrupt elution of a drug at an early stage after implantation of the coil and can improve the sustained-release property of the drug, and a method for manufacturing the in-vivo indwelling device.

[0006] The in-vivo implants according to this disclosure that have been able to solve the above problems are as follows: [1] An in-vivo implant having a coil, wherein a drug layer containing a drug and a base material is disposed on part or all of the surface of the in-vivo implant, the base material is made of a non-biodegradable resin and is in a mass ratio greater than the drug. [2] The in-vivo implant according to [1], wherein a drug release control layer is disposed on the radially outer side of part or all of the drug layer. [3] The in-vivo implant according to [2], wherein the drug release control layer contains at least a base material. [4] The in-vivo implant according to any one of [1] to [3], wherein it has an extension resistance member disposed in the lumen of the coil. [5] The in-vivo implant according to any one of [1] to [4], wherein the base material is an ethylene vinyl acetate resin. [6] The in-vivo implant according to any one of [1] to [5], wherein the drug accounts for 5% by mass or more and 45% by mass or less of the drug layer. [7] The in-vivo device according to any one of [1] to [5], wherein the drug comprises at least one of an anti-inflammatory agent, an antioxidant, an antihypertensive agent, and a vasoconstrictor. [8] The in-vivo device according to any one of [1] to [7], wherein the drug is a statin drug.

[0007] A method for manufacturing an in-vivo device according to the present disclosure that can solve the above problems is as follows: [9] A method for manufacturing an in-vivo device comprising: a step of preparing a coil, a drug, a substrate made of a non-biodegradable resin, and a solvent; a step of dissolving the drug and the substrate in the solvent such that the mass ratio of the substrate is greater than that of the drug to prepare a drug solution; and a step of applying the drug solution to the surface of the coil.

[10] A method for manufacturing an in-vivo device according to [9], further comprising: a step of dissolving at least the substrate in the solvent to prepare a drug release control solution; and a step of applying the drug release control solution to the surface of a drug consisting of the drug solution.

[0008] According to the aforementioned in-vivo implantation device, the rapid dissolution of the drug in the early period after coil implantation is reduced, and the sustained release of the drug is enhanced.

[0009] Furthermore, the method for manufacturing the in-vivo device described above provides an in-vivo device that can enhance the sustained release of drugs.

[0010] Figure 1 shows a schematic diagram of a catheter including an in-vivo device according to an embodiment of the present disclosure. Figure 2 shows a schematic cross-sectional view (partial side view) of the in-vivo device along the longitudinal axis of the coil. Figure 2 shows a schematic enlarged cross-sectional view of the structure of the drug layer. Figure 3 shows a graph illustrating the relationship between time and drug dissolution rate for a drug with an EVA (non-biodegradable resin) substrate. Figure 4 shows a schematic enlarged cross-sectional view of the structure of the drug layer according to an embodiment. Figure 5 shows a graph illustrating the relationship between time and drug dissolution rate (change in cumulative drug dissolution rate) with and without a drug release control layer for a drug with an EVA substrate.

[0011] The contents of this disclosure will be described in more detail below based on the embodiments described below. However, the contents of this disclosure are not limited by the embodiments described below, and it is certainly possible to implement the disclosure with appropriate modifications within the scope that is consistent with the spirit of the preceding and following descriptions, and all such modifications are included within the technical scope of this disclosure. In addition, hatching and component reference numerals may be omitted in the drawings for convenience, in which case refer to the specification or other drawings. Furthermore, the dimensions of various components in the drawings may differ from the actual dimensions, as priority is given to helping to understand the features of this disclosure.

[0012] [Intra-vivo implantable devices] Examples of the use of intra-vivo implantable devices include embolization to promote 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. Among these, intra-vivo implantable devices for cerebral aneurysms are preferred. The shape of the aneurysm can be fusiform or saccular.

[0013] Figure 1 is a schematic diagram of catheter A including the in-vivo implantation device 1 and pusher 55, and Figure 2 is a cross-sectional view (partially a side view) of the in-vivo implantation device 1 along the longitudinal axis direction of the coil. As shown in Figure 2, in the in-vivo implantation device 1, the coil 10 has a longitudinal axis direction x, a radial direction y, and a circumferential direction z. The coil 10 has a distal end 10a and a proximal end 10b along the longitudinal axis 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 axis direction x of the coil 10, and the distal side refers to the opposite direction from the proximal side, i.e., the direction toward the target of treatment. In Figure 2, 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 or inner refers to the direction toward the longitudinal axis center of the coil 10, and outward or outer refers to the direction extending radially from the longitudinal axis center on the opposite side from inward. The circumferential direction z of coil 10 refers to the direction around the longitudinal axis.

[0014] As shown in Figures 2 and 3, in the in-vivo implantation device 1, a drug layer 60 containing a drug m and a base material s is disposed on the surface of the coil 10, with the base material s being more abundant than the drug m by mass ratio. For example, the mass ratio "s:m" of base material s to drug m is preferably 51:49 to 99:1. Here, the substance containing the drug m and base material s is called the drug 6, and the substance on the surface of the coil 10 to which the drug 6 is applied is called the drug layer 60. The base material is made of a non-biodegradable resin, preferably an ethylene vinyl acetate resin, but may be made of other non-biodegradable resins. In addition to the drug m and base material s, the drug layer 60 may also contain additives, preferably stabilizers, activators, and surfactants. For example, examples of stabilizers include ascorbic acid, tocopherol, and ethylenediaminetetraacetic acid; examples of activators include nicotinamide, adenosine, retinol, hyaluronic acid, and coenzyme Q10; and examples of surfactants include polysorbate and lecithin. Note that the base material may also be a base agent.

[0015] Figure 3 is a partially enlarged view of the coil 10 in Figure 2, showing an example of the structure of the drug layer 60. For example, it shows a structure in which a drug layer 60 based on a substrate s is attached to the surface of the coil 10 (wire 31) like a coating film, and the drug layer 60 is formed in which the drug m is dispersed in the polymer film of the substrate s. In the drug layer 60, since the drug m is dispersed and mixed in the substrate s, the drug m is less likely to dissolve due to the substrate s covering the outside in the radial direction of the cross-section of the wire 31 that forms the coil 10. In other words, the substrate s exerts a blocking effect that suppresses the dissolution of the drug m.

[0016] As shown in Figure 3, since the mass ratio of the base material s to the drug layer 60 is greater than the mass ratio of the drug m to the drug layer 60, the aforementioned blocking effect can be strengthened compared to the case where the mass ratio is small or equal. This strengthened blocking effect allows the drug m to be slowly eluted after the coil 10 is placed in the nodule, thereby improving the sustained release of the drug. For example, if the drug m accounts for 5% to 45% by mass of the drug layer 60, it is possible to gradually dissolve the drug m over a long period of time after placement in the nodule, such as 1 to 2 weeks or 1 to 2 months, which is highly preferable. If the mass ratio is less than 5%, the aforementioned blocking effect becomes excessively strong, resulting in the dissolution of the drug m taking too long or the amount dissolved being too small. Also, if the mass ratio exceeds 45%, the aforementioned blocking effect weakens, causing the drug to dissolve prematurely, making it difficult to supply the drug m over the relatively long period actually required.

[0017] Figure 3 is an illustrative diagram showing the structure of a drug layer 60 in which drug m is uniformly dispersed within a layer of substrate s, as an example. In Figure 3, the black dots indicate drug m dispersed in the substrate s.

[0018] For example, a drug layer 60 in which a particulate drug m (such as encapsulated drug) is dispersed in a base material s is also preferred, and it is preferable that the drug m accounts for 5% by mass or more and 45% by mass or less of the drug layer 60. The drug layer 60 may be made of a particulate base material s, or the drug layer 60 in which both the base material s and the drug m are made of particulate material. In addition to circular shapes, the cross-sectional shape of the particles such as the particulate drug m can also be irregular shapes such as elliptical, cloud-shaped, or rectangular.

[0019] The thickness of the drug layer 60 formed on the outer circumferential surface 12 of the coil 10, more specifically the thickness in the radial direction of the coil 10 from the surface of the wire 31, is appropriately selected and set. More specifically, in Figure 3, the thickness t of the drug layer 60 from the maximum diameter portion of the wire 31 is preferably 100 nm or more and 2.5 μm or less, and also preferably 200 nm or more and 2.0 μm or less, or 300 nm or more and 1.5 μm or less, but it is not limited to these, such as 500 nm or more and 1.0 μm or less. Although not shown in the figure, the drug layer 60 may also be formed on the inner circumferential surface 13 of the coil 10. The thickness range of the drug layer 60 formed on the outer circumferential surface 12 can be similarly applied to the drug layer 60 formed on the inner circumferential surface 13. Furthermore, the thickness t of the drug layer 60 formed on the outer circumferential surface 12 and the drug layer 60 formed on the inner circumferential surface 13 of the coil 10 can be made the same or different. Preferably, the drug layer 60 is formed on the outer circumferential surface 12 and / or inner circumferential surface 13 of the coil 10.

[0020] In this specification, unless otherwise specified, coil 10 refers to the configuration in the state of a primary coil. A primary coil that has been further shaped into a helical or three-dimensional form is sometimes called a secondary coil. It is preferable that the coil 10 of the primary coil, as shown in Figure 2, is shaped to form the secondary coil shown in Figure 1. In Figure 1, the primary coil is wound to form a three-dimensional secondary coil shape. The coil 10 of the in-vivo implantation device 1 is inserted into the lumen of a transport catheter (not shown) in the state of a linear coil 10 as shown in Figure 2 and transported to the target site. When the coil 10 is pushed out of the transport catheter, it is placed in the aneurysm in a state that has unfolded into a three-dimensional shape as shown in Figure 1, or in a state that conforms to the shape of the aneurysm.

[0021] As shown in Figure 2, the coil 10 has an outer circumferential surface 12 and an inner circumferential surface 13. The surface of the coil 10 includes the outer circumferential surface 12 and the inner circumferential surface 13. Preferably, the coil 10 has a lumen 11 that extends in the longitudinal axis 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 40, which will be described later, is placed in the lumen 11.

[0022] As shown in Figures 1 and 2, the coil 10 is preferably constructed by winding one or more wires 31 in a helical shape. Examples of wires 31 include single wires, stranded wires, and coiled wires, with single wires being preferred.

[0023] The wire 31 is preferably biocompatible and flexible. Examples of materials constituting the wire 31 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 31 is composed of a platinum-tungsten alloy.

[0024] It is preferable that the outer diameter of the coil 10 is constant in the longitudinal axis direction x. A constant outer diameter means that the outer diameter of the coil 10 is substantially constant throughout the entire longitudinal axis direction x, and includes cases where the change in the outer diameter of the coil 10 is within ±5% over the entire longitudinal axis direction x.

[0025] As shown in Figure 2, it is preferable that the in-vivo implantation device 1 has an extension resistance member 40 disposed in the lumen 11 of the coil 10. The extension resistance member 40 suppresses the stretching of the coil 10 in the longitudinal axis direction x during operation. It is preferable that the extension resistance member 40 is formed from a long member consisting of a single wire or stranded wire. The extension resistance member 40 has a longitudinal axis direction and has a first end and a second end in that longitudinal axis direction. It is preferable that the extension resistance member 40 is composed of one or more layers in the radial direction perpendicular to the longitudinal axis direction. It is preferable that the extension resistance member 40 has an inner layer composed of stranded wire made of multiple wires and an outer layer provided outside the inner layer and containing a resin composition. It is preferable that one or more extension resistance members 40 are disposed in the lumen 11.

[0026] The stretch resistance member 40 is preferably made of resin or metal. Examples of resins that make up the stretch resistance member 40 include polyester resins such as polyethylene terephthalate, polyamide resins such as nylon, and polyolefin resins such as polyethylene and polypropylene. Being made of resin increases flexibility and improves the delivery performance of the in-vivo implantation device 1. Also, if the stretch resistance member 40 is made of resin, fracture due to metal fatigue during delivery can be eliminated. By making the length of the stretch resistance member 40 longer than the length of the coil 10, or by using a material that is easily stretched for the stretch resistance member 40, the tension caused by the end of the coil 10 stretching in a straight line due to insufficient length of the stretch resistance member 40 when the coil 10 is placed in the nodule can be alleviated. Examples of metals that make up the stretch resistance member 40 include platinum, gold, rhodium, palladium, rhenium, silver, nickel, titanium, tantalum, tungsten and their alloys, and stainless steel.

[0027] The extension resistance member 40 is made of a different material from or the same material as the wire 31 that constitutes the coil 10. For example, a combination in which the coil 10 is made of a platinum-tungsten alloy and the extension resistance member 40 is made of polypropylene resin is conceivable, but is not limited to this.

[0028] The shape of the extension resistance member 40 can be various, such as a circular shape, an oval shape, a polygonal shape, or a combination thereof, with the cross-sectional shape perpendicular to the longitudinal axis.

[0029] To facilitate the placement of the stretch resistance member 40 in the lumen 11, the outer diameter of the stretch resistance member 40 is preferably less than half the inner diameter of the coil 10, and more preferably one-third or less. To prevent the stretch resistance member 40 from breaking, the outer diameter of the stretch resistance member 40 is preferably one-fifteenth or more the inner diameter of the coil 10, and more preferably one-tenth or more. The stretch resistance member 40 can be linear, wavy, helical, or a combination thereof.

[0030] The first end of the extension resistance member 40 may be connected to the distal end of the coil 10, specifically to the distal end of the wire 31 that constitutes the coil 10. The second end of the extension resistance member 40 may be connected to the proximal end of the coil 10, specifically to the proximal end of the wire 31. The second end of the extension resistance member 40 may be connected to the connecting portion 50 (described later) that connects the coil 10 and the pusher 55. The extension resistance member 40 may be placed in the lumen 11 in a state where it is folded back in the middle of its longitudinal axis. In that case, it is preferable that the folded portion 41 of the extension resistance member 40 is connected to the distal or proximal end of the coil 10, and the first end and the second end are connected to the proximal or distal end of the coil 10, or to the distal end of the connecting portion 50. For example, in Figure 2, the extension resistance member 40 has a folded portion 41 that is folded back in the middle of the longitudinal axis direction, the folded portion 41 is connected to the distal end of the coil 10, and the first end and the second end are connected to the connection portion 50.

[0031] Methods for connecting the extension resistance member 40 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.

[0032] As shown in Figures 1 and 2, it is preferable that the coil 10 has a head portion 35 at its distal end. The head portion 35 covers a part of the wire 31 to prevent the distal end of the wire 31 from directly contacting the inner wall surface of the living body. The shape of the head portion 35 is not particularly limited, but examples include hemispherical, semi-elongated spherical, cylindrical, and polygonal prism shapes.

[0033] The head portion 35 is preferably joined to at least one of the outer or inner surfaces of the coil 10. To prevent the head portion 35 from falling off, it is preferable that a part of the head portion 35 is positioned in the lumen 11 at the distal end of the coil 10. In Figure 2, the proximal end of the head portion 35 is located proximal to the distal end of the wire 31, but a configuration in which the proximal end of the head portion 35 is located distal to the distal end of the wire 31 is also possible. Furthermore, it is preferable that a tail portion 36 is provided at the proximal end of the coil 10 to close the proximal end of the coil 10.

[0034] The head portion 35 is preferably made of a metal material or a resin. Examples of resins that make up the head portion 35 include thermoplastic resins and ultraviolet-curing resins. Examples of resins that make up the head portion 35 include ester resins such as epoxy acrylate resins, urethane acrylate resins, polyester acrylate resins, and polyethylene terephthalate resins, and olefin resins such as polypropylene. As the metal that makes up the head portion 35, the metals mentioned in the description of the wire 31 can be used. It is preferable that the material of the wire 31 and the material of the head portion 35 are the same, but this is not limited to the present invention.

[0035] As shown in Figures 2 and 3, in the in-vivo implantation device 1, a drug layer 60 containing drug m and base material s is arranged on the surface of the coil 10, with the base material s being more abundant than the drug m by mass ratio. The base material is made of a non-biodegradable resin. Non-biodegradable resins are made of polymer materials and include, in addition to the ethylene vinyl acetate resins mentioned above, PE (polyethylene), PP (polypropylene), PC (polycarbonate), PET (polyethylene terephthalate), polyamide resin, polyurethane, silicone, etc. Ethylene vinyl acetate is a copolymer of ethylene and vinyl acetate, and it is preferable that the mass content of vinyl acetate in ethylene vinyl acetate be 20% or more and 40% or less, and more preferably 25% or more and 30% or less. If the mass content of vinyl acetate is less than 20%, the solubility in organic solvents such as tetrahydrofuran decreases significantly, making it difficult to mount on the coil.

[0036] The drug m preferably contains at least one of the following: an anti-inflammatory agent, an antioxidant, an antihypertensive agent, and a vasoconstrictor, with statins being more preferred. Examples of statins include pravastatin, simvastatin, rosuvastatin, pitavastatin, atorvastatin, and fluvastatin. Among these, atorvastatin and pitavastatin are preferred. The drug preferably accounts for 5% to 45% by mass of the drug layer 60, but it is even more preferable if it accounts for 10% to 40% by mass or 15% to 35% by mass. In other words, the base material preferably accounts for 55% to 95% by mass of the drug layer 60, and it is also preferable if it accounts for 70% to 90% by mass or 75% to 85% by mass.

[0037] Because there is no unintended sustained release due to the placement of the coil 10 in the aneurysm or contact with the aneurysm wall, and planned sustained release performance can be maintained over a long period of time, the amount of drug layer 60 per unit length of coil on the outer surface 12 of the coil 10 can be 0.9 times or less, 0.8 times or less, or 0.7 times or less than the amount of drug per unit length of coil on the inner surface 13 of the coil 10, and it is also possible to set it to 0.1 times or more, 0.2 times or more, or 0.3 times or more, but it is not limited to these.

[0038] When the coil 10 is divided into a distal and proximal portion in the longitudinal axis x (for example, into two equal parts), the amount of drug placed in the distal portion of the coil 10 may be greater than the amount of drug placed in the proximal portion. This allows the amount of drug 6 necessary for treatment to be applied to the aneurysm, and the proximal portion is more flexible than the distal portion, resulting in better operability.

[0039] The drug layer 60 does not necessarily have to be placed in the proximal part of the coil 10. This increases the flexibility in the proximal part, resulting in better operability. It is preferable that the type of drug m placed in the distal part and the type of drug m placed in the proximal part are the same, but they may be different. In addition, it is preferable that the drug layer 60 is placed distal to the distal end 50a of the connection part 50 in the longitudinal axis x of the coil 10, but it is not limited to this.

[0040] It is preferable to apply the aforementioned drug 6 to the surface of the stretch-resistance member 40 by means of coating or immersion, thereby creating a stretch-resistance member 40 with a drug layer 60. It is also preferable to have an in-vivo implantation device 1 in which the drug layer 60 is provided on both the coil 10 and the stretch-resistance member 40. The coil 10 and the stretch-resistance member 40 are both "parts of the in-vivo implantation device," and it is preferable that the coil 10 and the stretch-resistance member 40 constitute "the entire in-vivo implantation device." Note that in Figure 2, the illustration and notation of the drug layer 60 applied to the stretch-resistance member 40 are omitted.

[0041] [Experiment on the sustained release of drugs] Figure 4 shows a graph of the correlation between time and dissolution rate for a drug using ethylene vinyl acetate (EVA), a non-biodegradable resin, as the base material, and atorvastatin as the drug. In Figure 4, time (unit: h) is plotted on the horizontal axis and dissolution rate (unit: %) on the vertical axis. Experiments were conducted with six different drug concentrations: 30%, 35%, 40%, 45%, 50%, and 55% by mass of the drug. Dissolution rate refers to the ratio (%) of the amount of drug dissolved to the amount of drug per unit length in the longitudinal axis direction of the coil of part or all of the in-vivo implantation device 1.

[0042] From FIG. 4, it can be seen that at any blending ratio, the elution amount of the drug increases over time, and the smaller (lower) the blending ratio is, the smaller (lower) the elution rate is. Even within the range of "5% by mass to 45% by mass of the drug", the smaller the blending ratio is, the smaller the elution rate becomes. For example, in the drug layer 60, it is also preferable that the drug m accounts for 10% by mass or more and 40% by mass or less, and 15% by mass or more and 35% by mass or less, and 20% by mass or more and 30% by mass or less are also preferable. In addition, when it is intended to keep the elution rate low (for example, 35% or less), the idea that the drug accounts for 1% by mass or more and 35% by mass or less in the drug layer 60 is also preferable.

[0043] The effects and other aspects of the in vivo indwelling device 1 of the present disclosure will be described.

[0044] For the purpose of reducing the recanalization rate of cerebral aneurysms, coils imparted with drugs have been studied. In this case, it is known that a phenomenon called "initial burst" occurs, in which the drug applied by means such as coating or immersion is eluted at an early stage, such as immediately after the coil is implanted into the affected area (such as a cerebral aneurysm).

[0045] It is known that after a coil is implanted into a cerebral aneurysm, organization in the aneurysm progresses after a certain period of time (see, for example, Patent Document 3).

[0046] However, it has been found that if the aforementioned initial burst occurs and the drug is eluted at an early stage, the amount of the drug remaining in the in vivo indwelling device at an appropriate time (when organization progresses) will decrease, and sufficient drug effects cannot be obtained.

[0047] Therefore, in the in vivo indwelling device 1 of the present disclosure, the inventors have conceived that the drug to be imparted to a coil or the like is prepared by mixing the drug and a base material to form a drug agent, and the ratio of the drug to the base material in the drug agent is set within a predetermined range. By applying the thus-created drug agent to the coil 10 and / or the elongation resistance member 40 to form the drug layer 60 (see FIGS. 2 and 3), the initial burst can be suppressed and the sustained release property of the drug can be improved.

[0048] [Method for manufacturing in-vivo indwelling device] The method for manufacturing the aforementioned in-vivo indwelling device is as follows. Namely, the manufacturing method is characterized by comprising: a first step of preparing a coil, a drug, a base material composed of a non-biodegradable resin, and a solvent; a second step of dissolving the drug and the base material in a solvent such that the mass ratio of the base material is higher than that of the drug to prepare a drug solution; and a third step of applying the drug solution to the surface of the coil.

[0049] The aforementioned "coil" may be replaced with an "elongation resistance member", and the method may be a method for manufacturing an in-vivo indwelling device in which a drug solution is applied to the elongation resistance member 40 (see Figure 2). A manufacturing method in which the drug solution is applied to both the coil 10 and the elongation resistance member 40 is also preferable.

[0050] The first step is, for example, a step of preparing a statin-based drug, a non-biodegradable base material such as ethylene-vinyl acetate resin, and a solvent. The type of the solvent is not particularly limited, and for example, ethanol, methanol, acetone, ethyl acetate, acetonitrile, N,N-dimethylacetamide, propanol, chloroform, and benzyl alcohol can be used. The second step is, for example, a step of preparing a drug solution by dissolving the drug in a solvent such that the drug accounts for 5 mass% or more and 45 mass% or less relative to the total mass of (drug + base material). The third step is a step of applying the drug solution prepared in the second step to the surface of the coil by coating, immersion or the like.

[0051] The in-vivo indwelling device having a coil (or elongation resistance member) manufactured by the manufacturing method of the present disclosure can achieve the aforementioned effects, and an in-vivo indwelling device capable of improving the sustained release property of the drug can be obtained.

[0052] [Another Embodiment] As shown in Figure 5, an in-vivo implantation device 1 is also preferred in which a drug release control layer 2 is disposed as a top coat on the radially outer side of part or all of the drug layer 60 of the coil. That is, an in-vivo implantation device 1 having a coil 10, a drug layer 60, and a drug release control layer 2 from the radially inner side to the radially outer side of the coil. The drug release control layer 2 preferably contains at least a base material s used in the drug layer 60, and preferably contains a base material made of a non-biodegradable resin such as EVA. The thickness h of the drug release control layer 2 is preferably 0.01 μM (micrometers) or more and 100 μM or less (0.01 μM ≤ h ≤ 100 μM), and more preferably 0.05 μM or more and 50 μM or less, or 0.1 μM or more and 10 μM or less.

[0053] The configuration of the drug release control layer 2 is as follows (1) to (5), but is not limited to these. <1> In addition to the base material, other additives may be included. Examples of other additives are the same as those for the drug layer 60. <2> The non-biodegradable resin of the base material may be the same as the non-biodegradable resin included in the drug layer 60. For example, refer to the examples of non-biodegradable resins for the drug layer 60, such as ethylene vinyl acetate. <3> The base material is preferably the same as the base material s used in the drug layer 60, but may be different. <4> It is preferable that no drug is included, but may be included. If a drug is included, it is preferable that the drug is the same as the drug m (such as atorvastatin) included in the drug layer 60, but may be different. <5> If a drug is included, it is preferable that the mass ratio of the drug in the drug release control layer 2 is lower than the mass ratio of the base material. The concentration of the drug, i.e., the mass percentage of the drug, is preferably such that drug m accounts for 0% to 15% by mass, more preferably 3% to 13% by mass, and even more preferably 5% to 11% by mass. From the viewpoint of improving the sustained release of the drug from the drug layer 60, a drug release control layer 2 in which drug m is 1% by mass or less is preferred, and even more preferably 5% by mass or less or 3% by mass or less.

[0054] <Tests on sustained release properties> Basically, multiple "levels" were set up, with the drug layer 60 as the first layer and the drug release control layer 2 as the second layer on its outer diameter, and tests (experiments) were conducted to investigate their sustained release properties. The configuration of each level was one of three types, 1) to 3) as shown in Table 1. Refer to Figure 3 for the structure of level 1), and Figure 5 for the structures of levels 2) and 3).

[0055] The test method involved releasing the drugs at levels 1) to 3) described above in PBS (phosphate-buffered saline) at 37°C. PBS samples were collected at each time point, and drug quantification was performed by HPLC (High Performance Liquid Chromatography) up to 120 hours. After that, the coil was removed, and any drugs remaining on the coil and not eluted in the PBS were dissolved in the organic solvent THF (tetrahydrofuran) and the "residue" was quantitatively analyzed by HPLC. With all values ​​set to 1, the elution rates shown in Figure 6 were calculated.

[0056] Figure 6 shows the cumulative drug dissolution rate for levels 1) to 3) mentioned above, i.e., a graph showing the relationship between the cumulative drug dissolution rate and time. Line ● represents level 1), line ◎ represents level 2), and line × represents level 3). Table 2 shows the dissolution rates for levels 1) to 3) at times 0, 4, 24, 48, and 120 in the graph in Figure 6.

[0057]

[0058] From Figure 6 and Table 2, it can be seen that levels 1) to 3) suppress the drug dissolution rate in the order of 2), 3), and 1), i.e., they enhance sustained release. In other words, by applying a low-content AV (atorvastatin) EVA or EVA alone as the second drug release control layer 2, the amount of drug released is reduced compared to the case where there is no drug release control layer in the second layer. Therefore, it is considered that by placing the drug release control layer 2 outside the drug layer 60, the effect of "excellent sustained release" that enables long-term drug release can be obtained.

[0059] [Other Embodiments] The drug layer 60, drug release control layer 2, or the configuration of the drug layer 60 and drug release control layer 2 may also be as described below in (1) to (5). (1) The proportion of drug m contained in the drug layer 60 may vary in the radial direction y (radial direction y of the coil 10).

[0060] (2) It is preferable that the proportion of drug m on the outer side of the drug layer 60 in the radial direction y is lower than the proportion of drug m on the inner side. For example, the drug layer 60 may have multiple layers, with a first layer having a higher proportion of drug m and a second layer having a lower concentration of drug m than the first layer superimposed on the radially outer side of the first layer. The proportion of drug m within the drug layer 60 may change in stages. By lowering the proportion of drug m on the outer side of the diameter of the drug layer 60, the sustained release can be controlled (the dissolution rate can be suppressed).

[0061] (3) A drug release control layer 2 may be provided on the outside of the drug layer 60. Preferably, the drug release control layer 2 does not contain drugs. The base material of the drug release control layer 2 may be the same as or different from the base material s that constitute the drug layer 60, but it is preferable that it be the same as the base material s of the drug layer 60. By providing the drug release control layer 2, it is easier to control drug release.

[0062] (4) Although not shown in the diagram, when the thickness of the drug layer 60 and the drug release control layer 2 is divided into three equal parts, an outer part, a central part, and an inner part, in the thickness direction of the drug layer 60 and the drug release control layer 2, 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 drug m is impregnated in 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. A configuration in which the concentration of drug m in each part divided in the radial direction y of the coil decreases from the inside to the outside in the radial direction y of the coil. The number of divisions may be four or more. Preferred examples of the above-mentioned configuration having three or more layers are given in (4-1) to (4-4) below, but are not limited to these.

[0063] (4-1) A three-layer structure having an inner layer: a drug layer 60 containing 20% ​​by mass of drug m, a central layer: a drug layer 60 containing 10% by mass of drug m, and an outer layer: a drug release control layer 2 consisting only of a substrate. (4-2) A three-layer structure having an inner layer: a drug layer 60 containing 20% ​​by mass of drug m, a central layer: a drug release control layer 2 containing 5% by mass of drug, and an outer layer: a drug release control layer 2 consisting only of a substrate. (4-3) A three-layer structure having an inner layer: a drug layer 60 containing 30% by mass of drug m, a central layer: a drug layer 60 containing 20% ​​by mass of drug m, and an outer layer: a drug layer 60 containing 10% by mass of drug m, or a four-layer structure in which a drug release control layer 2 containing a substrate and 0-5% by mass of drug is further arranged outside the outer layer. (4-4) A three-layer structure having an inner part: a drug release control layer 2 containing 10% by mass of the drug, a central part: a drug release control layer 2 containing 5% by mass of the drug, and an outer part: a drug release control layer 2 containing 1 to 3% by mass of the drug, or a four-layer structure in which a drug release control layer 2 consisting only of a substrate s is placed further outside the outer part.

[0064] (5) In the in-vivo implantation device 1, it is preferable that a drug layer 60 is applied to the outer surface of the coil 10, and that a drug release control layer 2 is arranged on the outer surface of the drug layer 60. By providing the drug layer 60 and the drug layer 60 and drug release control layer 2, the delivery sliding load within the catheter for transporting the in-vivo implantation device 1 can be suppressed, and the coil 10 can be smoothly placed. Non-biodegradable polymer materials can be used as the base material s and base material which are constituent materials of the drug layer 60 and drug release control layer 2.

[0065] This application claims the benefit of priority based on Japanese Patent Application No. 2025-056951, filed on 28 March 2025. The entire specification of Japanese Patent Application No. 2025-056951, filed on 28 March 2025, is incorporated herein by reference.

[0066] 1 Intra-vivo device 6 Drug 10 Coil 10a Distal end 10b Proximal end 11 Lumen 12 Outer surface 13 Inner surface 31 Wire 35 Head part 36 Tail part 40 Elongation resistance member 41 Folded part 50 Connection part 50a Distal end 55 Pusher 60 Drug layer A Catheter m Drug s Base material t Thickness x Longitudinal axis direction y Radial direction z Circumferential direction

Claims

1. An in-vivo implant having a coil, wherein a drug layer containing a drug and a base material is disposed on part or all of the surface of the in-vivo implant, the base material being made of a non-biodegradable resin and being in a mass ratio greater than the drug.

2. The in-vivo device according to claim 1, wherein a drug release control layer is disposed on the outer side of part or all of the drug layer in the coil radial direction.

3. The in-vivo device according to claim 2, wherein the drug release control layer comprises at least a substrate.

4. The in-vivo implantation device according to any one of claims 1 to 3, further comprising an extension resistance member disposed in the lumen of the coil.

5. The in-vivo implantation device according to any one of claims 1 to 3, wherein the base material is an ethylene vinyl acetate resin.

6. The in-vivo device according to any one of claims 1 to 3, wherein the drug in the drug layer constitutes 5% by mass or more and 45% by mass or less.

7. The in-vivo device according to any one of claims 1 to 3, wherein the drug comprises at least one of an anti-inflammatory agent, an antioxidant, an antihypertensive agent, and a vasoconstrictor inhibitor.

8. The in-vivo device according to claim 7, wherein the drug is a statin drug.

9. A method for manufacturing an in-vivo device, comprising the steps of: preparing a coil, a drug, a substrate made of a non-biodegradable resin, and a solvent; dissolving the drug and the substrate in the solvent such that the mass ratio of the substrate is greater than that of the drug to prepare a drug solution; and applying the drug solution to the surface of the coil.

10. A method for manufacturing an in-vivo device according to claim 9, further comprising the steps of: dissolving at least the substrate in the solvent to prepare a drug release control solution; and applying the drug release control solution to the surface of a drug comprising the drug solution.

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