Living body indwelling object

Abstract

[Problem] To provide a living body indwelling object with which it is possible to effectively suppress the onset of inflammations derived from a porous structure composed of a biodegradable polymer while preventing the scattering of plaque and / or thrombus during stent expansion. [Solution] A living body indwelling object 100 comprises an expandable cylindrical stent 10 and a porous structure 20 that is composed of a first biodegradable polymer and that is arranged so as to cover the stent. The stent has a drug-carrying part 18 containing a second biodegradable polymer and a drug. The decomposition time of the porous structure is substantially the same as the decomposition time of the drug-carrying part or shorter than the decomposition time of the drug-carrying part.

Description

Living body incarceration

[0001] The present invention relates to a living body indwelling device.

[0002] A stent is a medical device that is used to treat various diseases caused by stenosis or occlusion of a biological lumen, such as a blood vessel. The stent is delivered to a lesion in the biological lumen by a stent delivery system and then placed there to expand the lesion, such as a stenosis or occlusion, and secure the lumen. A typical stent has linear struts that form the outer periphery of a cylindrical shape with gaps formed therein. After being delivered to the lesion, the stent applies tensile strength (expansion force) to the lesion when expanded (expanded) within the biological lumen. By maintaining this tensile strength for a predetermined period of time, the stent maintains the lesion in an expanded state and secures the lumen of the biological lumen.

[0003] For example, Patent Document 1 discloses a mesh-covered stent in which a mesh is arranged to cover the outer periphery of a stent in order to prevent peripheral embolism during stent placement. In a mesh-covered stent, the mesh, which has an expandable knitted structure, expands in response to the expansion of the stent, thereby preventing the scattering of plaque or thrombus when the stent is expanded.

[0004] WO 2006 / 126182

[0005] Mesh-covered stents sometimes use a polymer mesh to improve the mesh's ability to follow the stent when it expands, improve delivery to the lesion, and reduce the potential impact on the biological lumen after treatment. However, the use of a polymer mesh raises the following concerns:

[0006] In general, polymer materials are more likely to cause inflammation in tissues than metallic materials. For this reason, when known drug-eluting stents use polymers as drug carriers, biodegradable or bioinert polymers are often selected. However, it is believed that polymer-induced inflammation can be suppressed by the drug released (eluted) from the stent. Therefore, when using biodegradable polymers as stent construction materials, it is believed that the effects of polymer-induced inflammation can be reduced by using polymers that quickly disappear after drug release is complete.

[0007] Based on the above findings, the inventors of the present invention have discovered that in a mesh-covered stent (living device) comprising a polymer mesh (porous structure), by adjusting the time from placement of the mesh-covered stent until the polymer mesh decomposes and disappears, and the time from placement of the mesh-covered stent until drug release is completed, it is possible to prevent the scattering of plaque and thrombus during stent expansion while effectively suppressing the onset of inflammation caused by the polymer mesh.

[0008] The present invention aims to provide an indwelling device that can effectively suppress the onset of inflammation caused by a porous structure made of a biodegradable polymer while preventing the scattering of plaque and thrombus during stent expansion.

[0009] The above object of the present invention can be achieved by any one of the following means (1) to (15).

[0010] (1) A living body indwelling device comprising an expandable cylindrical stent and a porous structure made of a first biodegradable polymer arranged to cover the stent, wherein the stent has a drug-carrying portion containing a second biodegradable polymer and a drug, and the degradation time of the porous structure is substantially the same as or shorter than the degradation time of the drug-carrying portion.

[0011] (2) The indwelling device according to (1) above, wherein the stent is made of a non-biodegradable material, and the drug-carrying portion is disposed only on the portion of the surface of the ring that forms the stent that faces the porous structure.

[0012] (3) The indwelling device according to (1) above, wherein the stent is made of a non-biodegradable material, and the drug-carrying portion is arranged so as to cover the entire surface of the ring that forms the stent.

[0013] (4) The indwelling device according to (1) above, wherein the entire stent is constituted by the drug-carrying portion.

[0014] (5) The indwelling device according to any one of (1) to (4) above, wherein the first biodegradable polymer and the second biodegradable polymer are the same polymer, and the first biodegradable polymer and the second biodegradable polymer are selected from the group consisting of a homopolymer of one type of monomer or a copolymer of two or more types of monomers selected from the group consisting of lactic acid, caprolactone, glycolic acid, dioxanone, butyrolactone, valerolactone, hydroxybutyric acid, and trimethylene carbonate.

[0015] (6) The indwelling device according to any one of (1) to (4) above, wherein the first biodegradable polymer and the second biodegradable polymer are different polymers, the first biodegradable polymer is at least one selected from the group consisting of polyglycolic acid, polycaprolactone, glycolic acid-lactic acid copolymer, ε-caprolactone-lactic acid copolymer, and glycolic acid-ε-caprolactone copolymer, and the second biodegradable polymer is at least one selected from the group consisting of polylactic acid, lactic acid-ε-caprolactone copolymer, lactic acid-glycolic acid copolymer, and polydioxanone.

[0016] (7) The indwelling device according to (6) above, wherein the molecular weight of the first biodegradable polymer is 120,000 or more and 180,000 or less, and the molecular weight of the second biodegradable polymer is 100,000 or more and 200,000 or less.

[0017] (8) The indwelling device according to (6) or (7), wherein the first biodegradable polymer is at least one selected from the group consisting of polyglycolic acid or polyglycolic acid-polylactic acid copolymer, and the second biodegradable polymer is at least one selected from the group consisting of polylactic acid, lactic acid-ε-caprolactone copolymer, and polydioxanone.

[0018] (9) The living body indwelling device according to any one of (6) to (8), wherein the molecular weight of the first biodegradable polymer is 140,000 or more and 180,000 or less, and the molecular weight of the second biodegradable polymer is 100,000 or more and 120,000 or less.

[0019] (10) The living body indwelling device according to any one of (1) to (9) above, wherein the decomposition time of the porous structure is within four months.

[0020] (11) The living body indwelling device according to any one of (1) to (10) above, wherein the decomposition time of the drug-carrying part exceeds 4 months.

[0021] (12) The indwelling device according to any one of (1) to (11) above, wherein the number average molecular weight of the porous structure and the drug-carrying portion in a decomposed state is 50 to less than 800.

[0022] (13) The indwelling device according to (2) or (3) above, wherein the non-biodegradable material is a metal material or a polymer material.

[0023] (14) The living body indwelling device according to any one of (1) to (13) above, wherein the drug includes an anti-inflammatory agent.

[0024] (15) The living body indwelling device according to any one of (1) to (14) above, wherein the proportion of the drug in the drug-carrying portion is 40% by mass or more and 55% by mass or less relative to the total amount of the second biodegradable polymer and the drug.

[0025] According to the above-mentioned implantable device, the porous structure decomposes and disappears after a certain period of time has elapsed since placement, and the drug continues to be released from the drug-carrying portion disposed in the stent until the porous structure decomposes and disappears. Therefore, the above-mentioned implantable device can effectively suppress the onset of inflammation caused by the porous structure made of a biodegradable polymer while preventing the scattering of plaque and thrombus during stent expansion.

[0026] Fig. 4 is a schematic plan view showing a stent delivery system including a living body indwelling device according to an embodiment. Fig. 5 is a schematic plan view showing a reduced diameter state of the living body indwelling device according to an embodiment. Fig. 6 is a schematic plan view showing an expanded state (expanded diameter state) of the living body indwelling device according to an embodiment. Fig. 7 is a partially enlarged view showing an enlarged portion of the living body indwelling device in the state shown in Fig. 3. Fig. 4 is an enlarged cross-sectional view showing an enlarged cross-section of a portion of a stent and a porous structure, and is a diagram showing an example of the arrangement of a drug-carrying part. Fig. 5 is an enlarged cross-sectional view showing an enlarged cross-section of a portion of a stent and a porous structure, and is a diagram showing an example of the arrangement of a drug-carrying part. Fig. 6 is an enlarged cross-sectional view showing an enlarged cross-section of a portion of a stent and a porous structure, and is a diagram showing an example of the arrangement of a drug-carrying part.

[0027] Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings. Note that the following description does not limit the technical scope or meaning of terms described in the claims. Also, the dimensional proportions in the drawings are exaggerated for the convenience of explanation and may differ from the actual proportions.

[0028] Hereinafter, the living body indwelling device 100 according to this embodiment will be described with reference to FIGS.

[0029] Fig. 1 is a schematic plan view showing a stent delivery system 300 including a living body indwelling device 100 according to an embodiment of the present invention. Fig. 2 is a schematic plan view showing the living body indwelling device 100 according to an embodiment in a contracted state. Fig. 3 is a schematic plan view showing the living body indwelling device 100 according to an embodiment in an expanded state. Fig. 4 is a partially enlarged view showing the living body indwelling device 100 according to an embodiment. Figs. 5 to 7 are enlarged cross-sectional views schematically showing examples of the arrangement of a drug-carrying portion 18 in a stent 10.

[0030] In this specification, the direction in which the living body indwelling device 100 extends is referred to as the "axial direction." The axial direction is the direction from the distal end 10A to the proximal end 10B shown in Figure 2. The side inserted into the living body is referred to as the "distal side," and the side opposite the distal end where the surgeon operates the medical device is referred to as the "proximal side." The direction perpendicular to the "axial direction" is referred to as the "radial direction" of the living body indwelling device 100.

[0031] As shown in FIG. 1, the stent delivery system 300 includes an indwelling device 100 and a balloon catheter 200 .

[0032] <Balloon Catheter 200> The balloon catheter 200 is delivered in a deflated state to the lesion, and is used to expand and place the indwelling device 100 near the lesion.

[0033] The balloon catheter 200 has a long catheter body 210 , a balloon 220 provided at the tip of the catheter body 210 , and a hub 230 fixed to the base end of the catheter body 210 .

[0034] The catheter main body 210 includes an outer tube and an inner tube disposed inside the outer tube.

[0035] An inflation lumen is formed inside the outer tube, through which inflation fluid flows for inflating the balloon 220. The distal end of the outer tube is fixed to the proximal end of the balloon 220. The proximal end of the outer tube is fixed to the hub 230.

[0036] A guidewire lumen into which a guidewire is inserted is formed inside the inner tube. The distal end of the inner tube penetrates the interior of the balloon 220 and opens distally of the balloon 220. The proximal end of the inner tube penetrates the sidewall of the outer tube proximal to the balloon 220 and is fixed to the outer tube.

[0037] The catheter body 210 is preferably made of a material having a certain degree of flexibility, and examples thereof include polyolefins such as polyethylene, polypropylene, polybutene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, ionomer, or a mixture of two or more of these; thermoplastic resins such as polyvinyl chloride resin, polyamide, polyamide elastomer, polyester, polyester elastomer, polyurethane, and fluororesin; silicone rubber; and latex rubber.

[0038] The balloon 220 is a member that, for example, expands inside a stenotic portion (lesion portion) to widen the stenotic portion. The distal end side of the balloon 220 is fixed to the outer wall surface of the inner tube. The proximal end side of the balloon 220 is fixed to the outer wall surface of the distal portion of the outer tube. Therefore, the interior of the balloon 220 communicates with an expansion lumen formed in the outer tube. An expansion fluid can flow into the balloon 220 from a proximal end opening 231 via the expansion lumen. The balloon 220 expands when the expansion fluid flows in, and contracts and returns to a folded state when the inflowing expansion fluid is discharged.

[0039] The balloon 220 is preferably made of a flexible material that expands and contracts with the inflow and outflow of an inflation fluid. Examples of such materials include polymeric materials such as polyolefin, cross-linked polyolefin, polyester, polyester elastomer, polyvinyl chloride, polyurethane, polyurethane elastomer, polyphenylene sulfide, polyamide, polyamide elastomer, and fluororesin, as well as silicone rubber and latex rubber. The balloon 220 is not limited to a single polymeric material; a film formed by appropriately laminating multiple polymeric materials may also be used. The inflation fluid may be either a gas or a liquid, such as helium gas, CO2 gas, or O2 gas, or a liquid such as saline or an X-ray contrast medium.

[0040] The hub 230 has a proximal opening 231 that communicates with the inflation lumen of the outer tube. The proximal opening 231 functions as a port for the inflow and outflow of inflation fluid.

[0041] The material of which the hub 230 is made is not particularly limited, but examples include thermoplastic resins such as polyethylene, polyurethane, polyester, polypropylene, polycarbonate, polyamide, polysulfone, polyarylate, and methacrylate-butylene-styrene copolymer.

[0042] <Living body implant 100> The living body implant 100 according to this embodiment is used, for example, to treat strictures or obstructions occurring in blood vessels, bile ducts, tracheas, esophagus, urethra, or other living body lumens. The living body implant 100 is a so-called balloon-expandable stent that is attached to a balloon 220 in a crimped state, delivered to the lesion, and then expanded and placed at the lesion. The living body implant 100 can also be configured as a so-called self-expandable stent.

[0043] 2 to 7, the indwelling device 100 generally comprises an expandable cylindrical stent 10 and a porous structure 20 made of a first biodegradable polymer and disposed so as to cover the stent 10. The stent 10 also has a drug-carrying portion 18 containing a second biodegradable polymer and a drug.

[0044] The stent 10 has a generally cylindrical shape with an axially extending lumen formed therein. The stent 10 has a distal end 10A located at its distal end and a proximal end 10B located at its proximal end.

[0045] As shown in Figures 2 and 3, the stent 10 is formed so as to be capable of radial expansion (the state shown in Figure 3) and contraction (the state shown in Figure 2). As shown in Figures 3 and 4, the stent 10 has linear rings 11 that form the outer periphery of a cylindrical shape with gaps formed therein, and link portions 12 that connect the rings 11 with the gaps.

[0046] As shown in Figure 4, the wavy ring 11 has a plurality of straight or curved first strut portions 15, straight or curved second strut portions 16, and curved portions 17 formed between the first strut portions 15 and the second strut portions 16. As shown in Figure 4, the ring 11 also has a plurality of straight or curved third strut portions 14 that are adjacent to one side of the link portion 12 in the axial direction (for example, the left side in Figure 4) and that are arranged in pairs in the circumferential direction (up and down in Figure 4).

[0047] The rings 11 are arranged in a line in the axial direction, and adjacent rings 11 in the axial direction are integrated by links 12. Therefore, by increasing or decreasing the number of rings 11, it is possible to easily obtain a stent 10 of a desired length.

[0048] The porous structure 20 having a large number of voids passing therethrough is arranged so as to cover the outer periphery of the stent 10 (the portion of the surface 19 of the ring 11 facing outward), as shown in Figures 3, 4 and 5. The porous structure 20 is configured to be expandable in response to the expansion of the stent 10, as shown in Figures 2 and 3. By arranging the porous structure 20 on the outer periphery of the stent 10, when the stent 10 expands in a blood vessel, the stent 10 urges the porous structure 20 against the blood vessel, thereby reducing rupture of the porous structure 20 due to the pressure of the blood flowing in the blood vessel.

[0049] The porous structure 20 extends along the axial direction of the stent 10 and has a mesh structure. The gaps in the mesh structure of the porous structure 20 can be configured to be smaller than the gaps between adjacent rings 11. By making the mesh size of the porous structure 20 smaller than the gaps between the rings 11 in this way, it is possible to prevent plaque and thrombus from scattering when the stent 10 is expanded at the lesion site. This makes it possible to prevent peripheral embolism caused by plaque and thrombus.

[0050] The porous structure 20 includes, for example, a knitted fabric, a woven fabric (braided fabric), or a molded product. When the porous structure 20 is a knitted fabric, the porous structure 20 can be formed, for example, by stockinette stitching. By forming the porous structure 20 by stockinette stitching, it is possible to prevent the axial length of the porous structure 20 from shortening as the stent 10 expands. Since stockinette stitching is a known knitting method, a detailed description of this specification is omitted. When the porous structure 20 is a woven fabric, the woven fabric is formed by a known weaving method. When the porous structure 20 is a molded product, the porous structure 20 is formed by a cylindrical sheet having regularly arranged voids. The size, shape, and number of the knitted and woven stitches of the porous structure 20 are not particularly limited as long as they can prevent peripheral embolism during expansion of the stent 10.

[0051] The thread diameter of the porous structure 20 is not particularly limited, but can be, for example, 20 μm.

[0052] The porous structure 20 is not limited to those formed by knitting. The porous structure 20 can also be formed by, for example, knitting, woven (braided), etc. The size, shape, and number of stitches of the porous structure 20 are not particularly limited as long as they can prevent peripheral embolism due to plaque or thrombus when the stent 10 is expanded. The porous structure 20 can be fixed at any location of the stent 10, such as the distal end 10A, the proximal end 10B, or the link portion 12. There are no particular limitations on the method for fixing the porous structure 20 to the stent 10, and any method can be used, such as adhesive fixation using polymers or paraffin, or fixation using mechanical means such as cable ties, clips, or thread.

[0053] The following describes preferred materials and effects of the living body indwelling device 100, as well as preferred arrangements of the drug carrying portion 18, etc.

[0054] 5 , the drug-carrying portion 18 can be disposed only on at least a portion 19a (hereinafter referred to as the "facing portion 19a") of the surface 19 of the ring 11 that forms the stent 10, which faces the porous structure 20 in a cross-sectional view perpendicular to the axial direction. However, as will be described later, the drug-carrying portion 18 may have any form as long as it is present on at least a portion of the surface 19 of the ring 11 that forms the stent 10 or on at least a portion of the stent 10 itself. Furthermore, the drug-carrying portion 18 may be present on at least some or all of the multiple first strut portions 15, second strut portions 16, and third strut portions 14 of the ring 11, and may be present or absent in the multiple link portions 12 and / or curved portions 17. Preferably, the drug-carrying portion 18 is present on the multiple first strut portions 15, second strut portions 16, and third strut portions 14, and is not present in the link portions 12 and curved portions 17. This reduces the phenomenon in which the drug-carrying portion 18 peels off during expansion.

[0055] In the first embodiment, the drug-carrying portion 18 is formed only on the facing portion 19a of the ring 11. According to the first embodiment, the drug-carrying portion 18 is selectively disposed on the facing portion 19a, and therefore the drug contained in the drug-carrying portion 18 is selectively released only from the side where the porous structure 20 is disposed (the facing portion 19a side). Therefore, according to the first embodiment, an inflammatory reaction induced by the porous structure 20 can be more effectively suppressed or prevented with a smaller amount of drug than when the drug-carrying portion 18 is disposed so as to cover the entire surface 19 of the ring 11. In other words, the risk of inflammation caused by contact between the porous structure 20 and biological tissue near the facing portion 19a can be effectively reduced or eliminated.

[0056] In the first embodiment, the shape and size (cross-sectional shape, area provided on the opposing portion 19a, etc.) of the drug support portion 18 are not particularly limited and can be set appropriately depending on the cross-sectional shape and size of the ring 11. For example, if the cross-sectional shape of the ring 11 is square, approximately square, rectangular, or approximately rectangular, the drug support portion 18 can be formed over the entire area of ​​the surface of the ring 11 that can come into contact with the porous structure 20. The thickness of the drug support portion 18 is not particularly limited and can be appropriately selected depending on the desired decomposition time, drug content, etc. The thickness of the drug support portion 18 can be, for example, 1 to 20 μm.

[0057] In a second embodiment of the present invention, as shown in FIG. 6 , the stent 10 is made of a non-biodegradable material, and the drug-carrying portion 18 can be arranged to cover the entire area of ​​the surface 19 of the ring 11 forming the stent 10 in a cross section perpendicular to the axial direction. According to the second embodiment, the drug-carrying portion 18 is arranged in areas other than the contact area with the porous structure 20. Therefore, according to the second embodiment, the drug concentration can be maintained more sufficiently than when the drug-carrying portion 18 is arranged only on the opposing portion 19 a of the ring 11, and therefore, inflammatory reactions induced by the porous structure 20 can be sufficiently suppressed or prevented. Furthermore, in the in-vivo indwelling device 100, for example, an anti-inflammatory agent can be arranged on the side where the porous structure 20 comes into contact with biological tissue, and another drug that can be used to treat the target can be arranged in the other covered areas. Therefore, according to the second embodiment, inflammatory reactions induced by the porous structure 20 can be more effectively suppressed or prevented, while other necessary treatments can be performed simultaneously.

[0058] In the second embodiment, the thickness of the drug support portion 18 is not particularly limited and is appropriately selected depending on the decomposition time, drug content, etc. The thickness of the drug support portion 18 can be, for example, 0.5 to 10 μm.

[0059] In the third embodiment of the present invention, as shown in FIG. 7 , the entire stent 10 (all of the rings 11 forming the stent 10) is configured with the drug-carrying portion 18. In other words, the stent 10 itself can function as the drug-carrying portion 18. According to the third embodiment, since it is not necessary to separately form the drug-carrying portion 18 on the stent 10, the manufacturing process can be reduced, which is preferable from the viewpoint of mass production. Furthermore, as in the second embodiment, for example, a large amount of anti-inflammatory agent can be placed on the contact region side (the opposing portion 19 a side) of the stent 10 that comes into contact with the porous structure 20, and another drug that can be used for the treatment of the target can be placed in the remaining portion. Therefore, according to the third embodiment, it is possible to more effectively suppress or prevent an inflammatory response induced by the porous structure 20 and simultaneously perform other necessary treatments.

[0060] Of the first to third embodiments, the first and second embodiments are preferred, with the first embodiment being more preferred, from the viewpoints of further suppressing and preventing inflammatory reactions, higher tensile strength of the stent 10, and a longer period during which the tensile strength is maintained.

[0061] In the first and second embodiments, non-biodegradable materials that can be used for the stent 10 include carbon fiber, metal materials, and polymer materials. Preferably, the non-biodegradable material is a metal material or a polymer material. From the viewpoint of further reducing inflammation, it is particularly preferable that the non-biodegradable material be a metal material. When the stent 10 is made of a metal material, the metal material is not particularly limited, and metal materials commonly used in the stent manufacturing field can be used. Specific examples include stainless steels such as SUS304, SUS316, SUS316L, SUS420J2, and SUS630; tantalum; titanium; nickel-titanium alloys; tantalum-titanium alloys; nickel-aluminum alloys; Inconel; gold; platinum; iridium; tungsten; and cobalt-chromium (Co—Cr) alloys. Among stainless steels, SUS316L is preferred, as it has the best corrosion resistance. Among cobalt-based alloys, MP35N, L605, and the like are preferred. Furthermore, when the stent 10 is made of a polymer material, the polymer material to be used is not particularly limited, and may be any polymer material that is commonly used in the field of the product of the stent 10. Specific examples include polyolefins such as polyethylene and polypropylene, aromatic polyesters such as polyethylene terephthalate, cellulose-based polymers such as cellulose acetate and cellulose nitrate, and fluorine-containing polymers such as polytetrafluoroethylene and tetrafluoroethylene-ethylene copolymers.

[0062] The stent 10 can be suitably formed from a material appropriately selected from the materials exemplified above depending on the application site, etc. For example, when the stent 10 is formed from a metal material, the metal material has excellent strength, so the indwelling device 100 can be placed more reliably at the lesion site. When the stent 10 is formed from a polymer material, the polymer material has excellent flexibility, so the indwelling device 100 can be effectively delivered to the lesion site.

[0063] Furthermore, when the stent 10 is a self-expanding type, a superelastic alloy such as a nickel-titanium alloy is preferred because it requires the ability to return to its original shape. On the other hand, when the stent 10 is a balloon-expanding type, stainless steel is preferred because it is less likely to return to its original shape after expansion. Furthermore, when the stent 10 is made of carbon fiber, it exhibits excellent effects in that it is high in strength, has excellent flexibility, and is highly safe in vivo.

[0064] The stent 10 is not particularly limited in terms of material, shape, size, etc., as long as it can be placed at a lesion occurring in a lumen in a living body, such as a blood vessel, bile duct, trachea, esophagus, or urethra. For example, when used in a coronary artery of the heart, the outer diameter of the stent 10 before expansion is typically, for example, 1.0 to 3.0 mm. The wall thickness of the stent 10 (thickness in the cross-sectional views shown in Figures 5 to 7) is, for example, 0.05 to 0.25 mm. The length (axial length) of the stent 10 is, for example, 5 to 50 mm.

[0065] The method for manufacturing the stent 10 is not particularly limited, and may be appropriately selected from commonly used manufacturing methods depending on the structure and material of the stent 10. For example, a manufacturing method utilizing an etching technique such as laser etching or chemical etching, or a laser cutting technique may be selected.

[0066] In the living body indwelling device 100 of the present invention, the decomposition time of the porous structure 20 is substantially the same as or shorter than the decomposition time of the drug-carrying part 18. By employing such a configuration, the following effects can be achieved.

[0067] Research has been conducted into covering metal stents with porous structures to suppress or prevent peripheral embolism associated with the dispersal of plaque or thrombus during stent placement (e.g., International Publication No. 2008 / 062414). However, polymer materials generally have the problem of being more likely to induce inflammation in tissues that come into contact with them than metallic materials. In contrast, in the present invention, the porous structure 20 is made of a biodegradable polymer, and the degradation time of the porous structure 20 is equal to or shorter than the degradation time of the drug-carrying portion 18. That is, the drug continues to be released from the drug-carrying portion 18 until the porous structure 20 degrades or disappears, and inflammation in biological tissues in contact with the porous structure 20 (e.g., tissues located on the inner wall surface of a blood vessel) can be suppressed or prevented by the drug released from the drug-carrying portion 18. Therefore, the present invention can simultaneously suppress or prevent peripheral embolism and reduce or eliminate the risk of inflammation in tissues that come into contact with the porous structure 20.

[0068] The degradation time of the porous structure 20 and the degradation time of the drug-carrying portion 18 can be controlled by the type of the first biodegradable polymer that constitutes the porous structure 20 and the type of the second biodegradable polymer that constitutes the drug-carrying portion 18. Furthermore, the size of the first biodegradable polymer and the second biodegradable polymer that constitutes the drug-carrying portion 18 has little or no effect on the degradation time (degradation rate, solubility) (in a material that degrades evenly throughout), and therefore can be suitably controlled by the first biodegradable polymer that constitutes the porous structure 20 and the second biodegradable polymer that constitutes the drug-carrying portion 18. In other words, the degradation time of the first biodegradable polymer is substantially the same as or shorter than the degradation time of the second biodegradable polymer.

[0069] In this specification, the "degradation time" of the porous structure 20, the drug carrying portion 18, the first biodegradable polymer, and the second biodegradable polymer is a value measured, for example, according to the method described below.

[0070] [Method for Measuring Degradation Time] 0.3 mg of each of the first biodegradable polymer and the second biodegradable polymer (collectively referred to as "sample") was weighed into a screw-cap test tube. Next, phosphate-buffered saline (PBS) at pH 7.4 was poured into the test tube up to the 15 ml line. The phosphate-buffered saline (PBS) was used as a simulated body fluid. The test tube was then stored in a 37°C incubator for a predetermined period (0, 1, 3, 7, 14, and 30 days) to allow hydrolysis to occur. After the predetermined period had elapsed, the screw-cap test tube was removed from the incubator, and the PBS was removed from the screw-cap test tube with a Pasteur pipette. The water in the test tube was then completely evaporated by vacuum drying. A mobile phase solvent (hexafluoroisopropanol containing 5 mM sodium trifluoroacetate) was then added to the test tube to achieve a sample concentration of 1 mg / ml. The sample was then completely dissolved, and the weight-average molecular weight (Mw) and number-average molecular weight (Mn) were measured according to the following method.

[0071] (Method for measuring weight-average molecular weight (Mw) and number-average molecular weight (Mn)) The weight-average molecular weight (Mw) and number-average molecular weight (Mn) are values ​​measured by gel permeation chromatography (GPC) using polymethyl methacrylate as a standard substance under the following measurement conditions: (Measurement conditions) Apparatus: Semi-micro GPC system LC-VP (manufactured by Shimadzu Corporation) Detector: Shodex (registered trademark) RI-104 (manufactured by Showa Denko K.K.) Column: Shodex (registered trademark) GPC LF-404 (manufactured by Showa Denko K.K.) Column temperature: 40°C Mobile phase solvent: hexafluoroisopropanol (HFIP) containing 5 mM sodium trifluoroacetate Sample concentration: 1 mg / ml Flow rate: 0.30 mL / min Injection volume: 10 μL Sample preparation: 1 mL of mobile phase solvent is added to 1 mg of the sample to be measured, and the solution is dissolved, and then filtered through a 0.45 μm PTFE membrane filter.

[0072] Next, a logarithmic plot of the obtained number average molecular weight (Mn) was created, and the time when Mn reached 50 to 800 (preferably 50 to 150, more preferably 100) was determined from the linear regression equation of this plot, and this time was defined as the period during which the mesh disappeared after decomposition.

[0073] In the indwelling device 100, the period during which the first biodegradable polymer constituting the porous structure 20 and the second biodegradable polymer contained in the drug-carrying portion 18 are decomposed and eliminated, i.e., the period during which the number average molecular weight reaches 50 to 800 (preferably 50 to 150, more preferably 100), is preferably 1.9 months or more and 4.0 months or less.

[0074] The first biodegradable polymer and the second biodegradable polymer are not particularly limited, and known biodegradable polymers can be used, such as those described in JP-A Nos. 2011-528275, 2008-514719, WO 2008 / 1952, and 2004-509205. Specific examples include: (1) polymers selected from the group consisting of aliphatic polyesters, polyesters, polyacid anhydrides, polyorthoesters, polycarbonates, polyphosphazenes, polyphosphate esters, polyvinyl alcohols, polypeptides, polysaccharides, proteins, and cellulose; and (2) copolymers composed of two or more types of monomers constituting the above-mentioned (1). The aliphatic polyester is not particularly limited, and examples thereof include polylactic acids (PLA) such as poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), and poly-DL-lactic acid (PDLLA), polyglycolic acid (PGA), polyhydroxybutyric acid, polyhydroxyvaleric acid, polyhydroxypentanoic acid, polyhydroxyhexanoic acid, polyhydroxyheptanoic acid, poly(ε-caprolactone) (PCL), polytrimethylene carbonate, poly2,2-dimethyltrimethylene carbonate, polydioxanone, polybutyrolactone, polyvalerolactone, polymalic acid, polyethylene adipate, polyethylene succinate, polybutylene adipate, and polybutylene succinate. The polycarbonate is not particularly limited, and examples thereof include tyrosine-derived polycarbonate (Tyrosine-polycarbonate).

[0075] Alternatively, the first biodegradable polymer and the second biodegradable polymer may be copolymers obtained by arbitrarily copolymerizing the monomers that constitute the polymers. Here, the copolymer is not particularly limited. Specific examples include PDLLA-PCL, PLLA-r-PCL, PLLA-b-PCL, PLLA-r-PTMC (TMC = trimethylene carbonate), and PLLA-r-PDTC (DCT = 2,2-dimethyltrimethylene). carbonate), PLLA-b-PTMC, PLLA-b-PDTC, PLGA (poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(N-(2-hydroxypropyl)methacrylamide), DLPLA-poly(dl-lactide), LPLA-poly(l-lactide), PGA-polyglycolide, PDO-poly(dioxanone), PGA-TMC-poly(glycolide-co-trimethylene carbonate), PGA-LPLA-poly(l-lactide-co-glycolide), PGA-DLPLA-poly(dl-lactide-co-glycolide), LPLA-DLPLA-poly(l-lactide-co-dl-lactide), and PDO-PGA-TMC-poly(glycolide-co-trimethylene carbonate-co-dioxanone), and PAE (Polyanhydride esters)-Salicylate in which salicylic acid has been chemically introduced into the polymer main chain (for example, a polymer in which salicylic acid is bound to both ends of polylactide anhydride or polyadipic acid).

[0076] The above polymers and copolymers may be used alone or in combination of two or more types, or in combination of one or more polymers and one or more copolymers. Furthermore, the above polymers and copolymers may be synthesized or commercially available. The synthesis method is not particularly limited, and known methods can be used in the same manner or with appropriate modifications. For example, polylactic acid (PLA), polyglycolic acid (PGA), or lactic acid-glycolic acid copolymer (PLGA) can be obtained by dehydration polycondensation of L-lactic acid, D-lactic acid, or glycolic acid, whichever has the required structure. Alternatively, they can be obtained by ring-opening polymerization of lactide, a cyclic dimer of lactic acid, or glycolide, a cyclic dimer of glycolic acid, which has the required structure. Lactides include L-lactide, which is a cyclic dimer of L-lactic acid, D-lactide, which is a cyclic dimer of D-lactic acid, meso-lactide, which is a cyclic dimer of D-lactic acid and L-lactic acid, and DL-lactide, which is a racemic mixture of D-lactide and L-lactide. Any of these lactides can be used in the present disclosure.

[0077] Of these, the first biodegradable polymer and the second biodegradable polymer are preferably bulk erosion type polymers, and more preferably are selected from the group consisting of homopolymers of one monomer or copolymers of two or more monomers selected from the group consisting of lactic acid, caprolactone, glycolic acid, dioxanone, butyrolactone, valerolactone, hydroxybutyric acid, and trimethylene carbonate.

[0078] In an embodiment of the present invention, the decomposition time of the porous structure 20 can be substantially the same as the decomposition time of the drug-carrying portion 18 (such a configuration is referred to as the "fourth embodiment"). With this configuration, the drug-carrying portion 18 decomposes and disappears around the same time as the porous structure 20 decomposes and disappears. Therefore, for most of the time the porous structure 20 is present, the drug continues to be released from the drug-carrying portion 18 to the biological tissue with which the porous structure 20 is in contact. Therefore, with this configuration, it is possible to both suppress or prevent peripheral embolism and reduce or eliminate the risk of tissue inflammation due to contact with the porous structure 20. Here, "the decomposition time of the porous structure 20 is substantially the same as the decomposition time of the drug-carrying portion 18" means that the difference between the decomposition time of the porous structure 20 and the decomposition time of the drug-carrying portion 18 is within 24 hours, preferably within 10 hours, more preferably within 5 hours, and particularly preferably within 2 hours. Particularly preferably, the decomposition time of the porous structure 20 is the same as the decomposition time of the drug carrying portion 18 (the difference is 0 hours).

[0079] In the fourth embodiment, the degradation time of the porous structure 20 and the drug-carrying portion 18 is, for example, 2 to 6 months, preferably 3 to 5 months, and more preferably 3 to 4 months. With such a degradation time, the porous structure 20 can suppress the scattering of plaque and thrombus when the indwelling device 100 is placed, while an endothelial cell layer can be sufficiently formed on the stent 10. In this specification, one month is considered to be 30 days.

[0080] In the fourth embodiment, the porous structure 20 and the drug carrier 18 preferably contain the same biodegradable polymer. This facilitates adjusting the degradation times to be substantially the same. That is, the first biodegradable polymer and the second biodegradable polymer are preferably the same polymer. Specific examples of the first biodegradable polymer and the second biodegradable polymer include those similar to the biodegradable polymers exemplified above. Of these, the first biodegradable polymer and the second biodegradable polymer are preferably selected from the group consisting of a homopolymer of one monomer or a copolymer of two or more monomers selected from the group consisting of lactic acid, caprolactone, glycolic acid, dioxanone, butyrolactone, valerolactone, hydroxybutyric acid, and trimethylene carbonate. Furthermore, the first biodegradable polymer and the second biodegradable polymer are more preferably selected from the group consisting of a homopolymer of one monomer or a copolymer of two or more monomers selected from the group consisting of lactic acid, caprolactone, glycolic acid, and dioxanone.

[0081] That is, in a preferred embodiment of the present invention, the first biodegradable polymer and the second biodegradable polymer are the same polymer, and the first biodegradable polymer and the second biodegradable polymer are selected from the group consisting of a homopolymer of one monomer or a copolymer of two or more monomers selected from the group consisting of lactic acid, caprolactone, glycolic acid, dioxanone, butyrolactone, valerolactone, hydroxybutyric acid, and trimethylene carbonate. Also, in a more preferred embodiment of the present invention, the first biodegradable polymer and the second biodegradable polymer are the same polymer, and the first biodegradable polymer and the second biodegradable polymer are selected from the group consisting of a homopolymer of one monomer or a copolymer of two or more monomers selected from the group consisting of lactic acid, caprolactone, glycolic acid, and dioxanone.

[0082] The weight-average molecular weight of the biodegradable polymer used in the in-vivo indwelling device 100 is not particularly limited and can be appropriately selected depending on the desired degradation time (biodegradation rate). Specifically, the weight-average molecular weight of the biodegradable polymer is preferably 10,000 or more, more preferably 50,000 to 1,000,000, and even more preferably 100,000 to 500,000. The number-average molecular weight of the biodegradable polymer is preferably 5,000 or more, more preferably 20,000 to 800,000, and even more preferably 30,000 to 200,000. Methods for measuring molecular weight (weight-average molecular weight, number-average molecular weight) include gel permeation chromatography (GPC), light scattering, viscosity measurement, and mass spectrometry (such as TOF MASS). In this specification, the weight-average molecular weight is a value measured by GPC using polystyrene as a standard substance.

[0083] In another embodiment of the present invention, the decomposition time of the porous structure 20 is shorter than the decomposition time of the drug-carrying portion 18 (such a configuration is referred to as the "fifth embodiment"). With this configuration, the porous structure 20 decomposes and disappears, leaving only the stent 10, and then the drug-carrying portion 18 decomposes and disappears. Therefore, while the porous structure 20 is present, the drug continues to be released from the drug-carrying portion 18 into the biological tissue with which the porous structure 20 is in contact. Therefore, with this configuration, it is possible to simultaneously suppress or prevent peripheral embolism and reduce or eliminate the risk of inflammation of the biological tissue due to contact with the porous structure 20. Furthermore, in the above-described second embodiment (see FIG. 6) or third embodiment (see FIG. 7), when a drug other than an anti-inflammatory drug is used, the inflammatory response induced by the porous structure 20 can be more effectively suppressed or prevented, and other necessary treatments can be performed simultaneously and for a long period of time. Here, the difference between the decomposition time of the porous structure 20 and the decomposition time of the drug-carrying portion 18 is 2 hours or more, preferably 3 hours or more, and more preferably 1 month or more. The upper limit of the difference between the decomposition time of the porous structure 20 and the decomposition time of the drug-carrying portion 18 is not particularly limited, but is, for example, 22 months or less, preferably 12 months or less, and more preferably 5 months or less. Providing such a time difference allows a better balance between suppressing or preventing peripheral embolism and reducing or eliminating the risk of inflammation of tissues due to contact with the porous structure 20.

[0084] In the fifth embodiment, the degradation time of the porous structure 20 is preferably 5 months or less, more preferably 4 months or less, even more preferably 2 months or more and 4 months or less, and particularly preferably 3 months or more and 4 months or less. The degradation time of the drug-carrying portion 18 is preferably more than 5 months, more preferably more than 6 months, even more preferably more than 7 months and 12 months or less, and particularly preferably more than 8 months and 12 months or less. Within such a degradation time, the porous structure 20 can suppress the scattering of plaque and thrombus during placement of the indwelling device 100, while allowing a sufficient endothelial cell layer to be formed on the stent 10.

[0085] In the fifth embodiment, the first biodegradable polymer constituting the porous structure 20 and the second biodegradable polymer constituting the drug carrying portion 18 may be a combination of materials such that the degradation time of the porous structure 20 is shorter than the degradation time of the drug carrying portion 18. The same biodegradable polymers as those exemplified above may be used as the first biodegradable polymer and the second biodegradable polymer. For example, polyglycolic acid, glycolic acid-lactic acid copolymers (glycolic acid-L-lactic acid copolymer, glycolic acid-D-lactic acid copolymer, glycolic acid-DL-lactic acid copolymer, preferably glycolic acid-L-lactic acid copolymer, glycolic acid-D-lactic acid copolymer) containing glycolic acid at more than 10 mol% and less than 100 mol% of all monomers (preferably 25 mol% to 95 mol%, more preferably more than 50 mol% to 95 mol%), and caprolactone at 4 mol% or more of all monomers (preferably 5 mol% to 40 mol%, more preferably 10 mol% or more) may be used. It is preferable to use a biodegradable polymer with a relatively fast biodegradation rate for the porous structure 20, such as a glycolic acid-caprolactone copolymer containing more than 44 mol % and 50 mol % or less of caprolactone (preferably 5 mol % to 40 mol %, more preferably 8 mol % to 20 mol %) of caprolactone based on the total monomer content, or a caprolactone-lactic acid copolymer (ε-caprolactone-L-lactic acid copolymer, ε-caprolactone-D-lactic acid copolymer, ε-caprolactone-DL-lactic acid copolymer, and particularly ε-caprolactone-DL-lactic acid copolymer) containing more than 44 mol % and 50 mol % or less of caprolactone (preferably 5 mol % to 40 mol %, more preferably 8 mol % to 20 mol %) of caprolactone based on the total monomer content. That is, the first biodegradable polymer is preferably at least one selected from the group consisting of polyglycolic acid, polycaprolactone, glycolic acid-lactic acid copolymer, caprolactone-lactic acid copolymer, and glycolic acid-caprolactone copolymer. Furthermore, it is preferable to use biodegradable polymers containing many structural units derived from lactic acid, such as polylactic acid, lactic acid-glycolic acid copolymer containing lactic acid at 90 mol % or more of all monomers, or lactic acid-ε-caprolactone copolymer containing lactic acid at 96 mol % or more of all monomers, or polydioxanone, for the drug carrying portion 18. That is, the second biodegradable polymer is preferably at least one selected from the group consisting of polylactic acid, lactic acid-ε-caprolactone copolymer, lactic acid-glycolic acid copolymer, and polydioxanone.

[0086] That is, the first biodegradable polymer and the second biodegradable polymer are different polymers, and it is preferred that the first biodegradable polymer is at least one selected from the group consisting of polyglycolic acid, polycaprolactone, glycolic acid-lactic acid copolymer, caprolactone-lactic acid copolymer, and glycolic acid-caprolactone copolymer, and the second biodegradable polymer is at least one selected from the group consisting of polylactic acid, lactic acid-ε-caprolactone copolymer, lactic acid-glycolic acid copolymer, and polydioxanone.

[0087] It is more preferable that the first biodegradable polymer and the second biodegradable polymer are different polymers, the first biodegradable polymer is at least one selected from the group consisting of polyglycolic acid and glycolic acid-lactic acid copolymer, and the second biodegradable polymer is at least one selected from the group consisting of polylactic acid, lactic acid-ε-caprolactone copolymer, and polydioxanone.

[0088] In addition to the above-described combinations of materials, the following methods can also be used to adjust the degradation time of the porous structure 20 so that it is shorter than the degradation time of the drug-carrying portion 18. Examples of methods for controlling the degradation time of the porous structure 20 include controlling the composition (e.g., glass transition temperature), molecular weight (e.g., the length of the threads constituting the porous structure 20), and crystallinity (e.g., the spinning conditions for the porous structure 20, whether or not annealing is performed) of the first biodegradable polymer (e.g., a low crystallinity shortens the degradation time; for example, the crystallinity of the porous structure 20 is controlled to be 0% or more and 40% or less), appropriately selecting the presence or absence of terminal treatment (e.g., terminal treatment by esterification lengthens the degradation time), and using additives. Among these, controlling the molecular weight, composition (glass transition temperature), or crystallinity of the first biodegradable polymer is preferred from the viewpoint of ease of control of the degradation time. Methods for controlling the degradation time of the drug-carrying portion 18 include controlling the molecular weight, composition, or crystallinity of the second biodegradable polymer (e.g., a high degree of crystallinity increases the degradation time; for example, controlling the crystallinity of the second biodegradable polymer to greater than 40%), appropriately selecting whether or not to perform end treatment (e.g., terminal treatment by esterification increases the degradation time), controlling the compounding ratio of the drug, and the mixing ratio and mixing method of the second biodegradable polymer and the drug, using additives, and controlling the shape of the drug. Of these, from the perspective of ease of control of the degradation time of the drug-carrying portion 18 (second biodegradable polymer), methods of controlling the molecular weight, composition, or crystallinity of the second biodegradable polymer, and methods of controlling the compounding ratio of the drug, and the mixing ratio and mixing method of the second biodegradable polymer and the drug are preferred. Typically, the biodegradation rate slows as the molecular weight (weight-average molecular weight) of the biodegradable polymer increases. For this reason, a method can be used in which the molecular weight (weight average molecular weight) of the first biodegradable polymer used in the porous structure 20 is adjusted to be smaller than the molecular weight (weight average molecular weight) of the second biodegradable polymer used in the drug-carrying portion 18.

[0089] The molecular weight (weight average molecular weight) of the first biodegradable polymer is, for example, 250,000 or less, more preferably 100,000 to 200,000, more preferably 120,000 to 180,000, and more preferably 140,000 to 180,000. The molecular weight (weight average molecular weight) of the second biodegradable polymer is, for example, 50,000 or more, 100,000 to 500,000, more preferably 100,000 to 250,000, and particularly preferably 100,000 to 120,000. The molecular weight (number average molecular weight) of the first biodegradable polymer is, for example, 150,000 or less, more preferably 30,000 to 100,000. The molecular weight (number average molecular weight) of the second biodegradable polymer is, for example, 30,000 or more, and more preferably 40,000 or more and 150,000 or less.

[0090] The crystallinity of the first biodegradable polymer is, for example, 0% or more and 40% or less, more preferably 0% or 20% or more and 40% or less, and even more preferably 20% or more and 40% or less.

[0091] The crystallinity of the second biodegradable polymer is, for example, 0% or more and 50% or less, preferably 0% or more than 40% and 45% or less, and more preferably 0%.

[0092] Alternatively, the porous structure 20 may contain a biodegradable polymer that has been irradiated with an electron beam in advance. Generally, when a (co)polymer is irradiated with an electron beam, bonds within the (co)polymer are more likely to be broken, increasing the rate of biodegradation. Therefore, even when biodegradable polymers of the same composition are used, the decomposition time can be adjusted by irradiating the biodegradable polymer used in the porous structure 20 with an electron beam in advance.

[0093] For example, the degradation time and tensile strength retention period of polyglycolic acid (crystallinity = 38%, weight average molecular weight = 140,000, number average molecular weight = 70,000, terminally treated by esterification) (polyglycolic acid A) were 1.9 months and 15 days, respectively; and the degradation time and tensile strength retention period of glycolic acid-L-lactic acid copolymer (glycolic acid:L-lactic acid = 90:10 (molar ratio), crystallinity = 23%, weight average molecular weight = 180,000, number average molecular weight = 85,000, terminally treated by esterification) (glycolic acid-L-lactic acid copolymer B) were 2.1 months and 15 days, respectively; The degradation time and tensile strength retention period of a glycolic acid-caprolactone copolymer (glycolic acid:caprolactone=75:25 (molar ratio), crystallinity=22%, weight average molecular weight=120,000, number average molecular weight=60,000, terminally treated by esterification) (glycolic acid-caprolactone copolymer C) were 3.5 months and 9 days, respectively; and the degradation time and tensile strength retention period of a caprolactone-DL lactic acid copolymer (caprolactone:DL-lactic acid=10:90 (molar ratio), crystallinity=0%, weight average molecular weight=120,000, number average molecular weight=55,000, terminally treated by esterification) (caprolactone-DL lactic acid copolymer D) were 4 months and 7 days, respectively; The degradation time and tensile strength retention period of glycolic acid-DL-lactic acid copolymer (glycolic acid:DL-lactic acid = 25:75 (molar ratio), crystallinity = 0%, weight average molecular weight = 120,000, number average molecular weight = 45,000, terminally treated by esterification) (glycolic acid-DL-lactic acid copolymer E) were 1 month and 3 days, respectively; the degradation time and tensile strength retention period of poly-L-lactic acid (crystallinity = 48%, weight average molecular weight = 200,000, number average molecular weight = 120,000, terminally treated by esterification) (poly-L-lactic acid F) were 24 months and 7 months, respectively; and the degradation time and tensile strength retention period of polydioxanone (crystallinity = 45%, weight average molecular weight = 110,000, number average molecular weight = 45,000, terminally treated by esterification) (polydioxanone G) were 8 months and 1.5 months, respectively;The degradation time and tensile strength retention period of poly D,L lactic acid (crystallinity = 0%, weight average molecular weight = 100,000, number average molecular weight = 50,000) (poly DL lactic acid H) are 12 months, respectively.

[0094] Therefore, the combinations of the first biodegradable polymer and the second biodegradable polymer include polyglycolic acid A and poly-L-lactic acid F; glycolic acid-L-lactic acid copolymer B and poly-L-lactic acid F; glycolic acid-caprolactone copolymer C and poly-L-lactic acid F; caprolactone-DL-lactic acid copolymer D and poly-L-lactic acid F; glycolic acid-DL-lactic acid copolymer E and poly-L-lactic acid F; polyglycolic acid A and polydioxanone G; glycolic acid-L-lactic acid copolymer B and polydioxanone G; glycolic acid- The copolymer may be selected from caprolactone copolymer C and polydioxanone G; caprolactone-DL-lactic acid copolymer D and polydioxanone G; glycolic acid-DL-lactic acid copolymer E and polydioxanone G; polyglycolic acid A and polyDL-lactic acid H; glycolic acid-L-lactic acid copolymer B and polyDL-lactic acid H; glycolic acid-ε-caprolactone copolymer C and polyDL-lactic acid H; ε-caprolactone-DL-lactic acid copolymer D and polyDL-lactic acid H; glycolic acid-DL-lactic acid copolymer E and polyDL-lactic acid H.

[0095] In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer is selected from polyglycolic acid A and poly-L-lactic acid F; glycolic acid-L-lactic acid copolymer B and poly-L-lactic acid F; glycolic acid-caprolactone copolymer C and poly-L-lactic acid F; caprolactone-DL-lactic acid copolymer D and poly-L-lactic acid F; polyglycolic acid A and polydioxanone G; glycolic acid-L-lactic acid copolymer B and polydioxanone G; glycolic acid-caprolactone copolymer C and polydioxanone G; caprolactone-DL-lactic acid copolymer D and polydioxanone G; polyglycolic acid A and poly-DL-lactic acid H; glycolic acid-L-lactic acid copolymer B and poly-DL-lactic acid H; glycolic acid-ε-caprolactone copolymer C and poly-DL-lactic acid H; ε-caprolactone-DL-lactic acid copolymer D and poly-DL-lactic acid H.

[0096] In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer is selected from polyglycolic acid A and poly-L-lactic acid F; glycolic acid-L-lactic acid copolymer B and poly-L-lactic acid F; glycolic acid-caprolactone copolymer C and poly-L-lactic acid F; caprolactone-DL-lactic acid copolymer D and poly-L-lactic acid F. In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer is selected from polyglycolic acid A and poly-L-lactic acid F; glycolic acid-L-lactic acid copolymer B and poly-L-lactic acid F.

[0097] In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer is selected from polyglycolic acid A and polydioxanone G; glycolic acid-L-lactic acid copolymer B and polydioxanone G; glycolic acid-caprolactone copolymer C and polydioxanone G; caprolactone-DL-lactic acid copolymer D and polydioxanone G. In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer is selected from polyglycolic acid A and polydioxanone G; glycolic acid-L-lactic acid copolymer B and polydioxanone G.

[0098] In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer is selected from polyglycolic acid A and poly DL-lactic acid H; glycolic acid-L-lactic acid copolymer B and poly DL-lactic acid H; glycolic acid-ε-caprolactone copolymer C and poly DL-lactic acid H; ε-caprolactone-DL-lactic acid copolymer D and poly DL-lactic acid H. In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer is selected from polyglycolic acid A and poly DL-lactic acid H; glycolic acid-L-lactic acid copolymer B and poly DL-lactic acid H.

[0099] In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer may be selected from glycolic acid-L-lactic acid copolymer B and poly-L-lactic acid F; glycolic acid-caprolactone copolymer C and poly-L-lactic acid F; caprolactone-DL-lactic acid copolymer D and poly-L-lactic acid F; glycolic acid-L-lactic acid copolymer B and polydioxanone G; glycolic acid-caprolactone copolymer C and polydioxanone G; caprolactone-DL-lactic acid copolymer D and polydioxanone G; glycolic acid-L-lactic acid copolymer B and poly-DL-lactic acid H; glycolic acid-ε-caprolactone copolymer C and poly-DL-lactic acid H; ε-caprolactone-DL-lactic acid copolymer D and poly-DL-lactic acid H. The indwelling device 100 in this combination can be suitably used for cardiac diseases such as acute coronary syndrome (ACS), acute myocardial infarction (AMI), and ST-elevation myocardial infarction (STEMI).

[0100] In one embodiment of the present invention, the combination of the first biodegradable polymer and the second biodegradable polymer is polydioxanone G and poly-L-lactic acid F. The indwelling device 100 having this combination is particularly suitable for use in carotid artery stenosis.

[0101] The size of the porous structure 20 is not particularly limited and is set within a range that does not significantly impair the performance of the stent body, such as its deliverability to the lesion and its irritation to the blood vessel wall. Preferably, the porous structure 20 is disposed so as to cover the entire outer peripheral surface of the stent 10. The thickness of the porous structure 20 (outer diameter of the wire portion) is not particularly limited and is set within a range that does not significantly impair the performance of the stent 10, such as its deliverability to the lesion and its irritation to the blood vessel wall. Specifically, the thickness of the porous structure 20 (the radial thickness in the cross-sectional views perpendicular to the axial direction shown in Figures 5 to 7) is not particularly limited and is set within a range that does not significantly impair the performance of the stent 10, such as its deliverability to the lesion and its irritation to the blood vessel wall.

[0102] The thickness of the porous structure 20 is preferably 1 μm to 100 μm, more preferably 5 μm to 50 μm. This thickness can more effectively suppress and prevent peripheral embolism associated with the dispersal of plaque and thrombus during or after placement of the stent 10. Regarding the thickness-related functions of the porous structure 20, a thinner porous structure 20 is preferable as long as mechanical strength is maintained. A thinner porous structure 20 is advantageous in terms of preventing the foldability and device profile from becoming too large, thereby improving lesion penetration. In other words, an excessively thick porous structure 20 is disadvantageous in terms of foldability and device profile, and also reduces the stent inner diameter (expanded diameter) after placement in the lesion, reducing the effectiveness of blood flow improvement. As a result, thrombus adhesion is also likely to occur. The radial thickness of the stent 10 (the radial thickness in the cross-section perpendicular to the axial direction shown in FIGS. 5 to 7 ) can be configured to be greater than the thickness of the porous structure 20. When the thickness of the porous structure 20 is set to the above-mentioned dimensions, the thickness of the stent 10 can be set to, for example, 60 μm to 120 μm.

[0103] As for the method of producing the porous structure 20 and the method of coating the stent 10 with the porous structure 20, the methods described in, for example, WO 2008 / 062414 can be applied in the same manner or with appropriate modifications.

[0104] In the in-vivo indwelling device 100, the drug-carrying portion 18 contains a drug in addition to the second biodegradable polymer. The drug contained in the drug-carrying portion 18 is not particularly limited and can be appropriately selected depending on the desired application. Considering inflammation induced by the porous structure 20, the drug preferably contains an anti-inflammatory agent or an immunosuppressant. The anti-inflammatory agent is not particularly limited, and known anti-inflammatory agents can be used. The anti-inflammatory agent may be a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, or a combination thereof. Examples of anti-inflammatory agents include alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anilolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelain, broperamol, budesonide, and carprofen. , cycloprofen, synthasone, criprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormetasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, dif Talon, dimethyl sulfoxide, drocinonide, endrizone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamol, fenbufen, fenclofenac, fenclorac, fendosal, fenpiparone, fentiazac, flavazalon, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, flobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxol,Intrazol, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, romoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, mechlorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, prednisolone, methylprednisolone suleptanate, momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, Priferon Examples of the anti-inflammatory agent include prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, sarcorex, salnacedin, salsalate, sanguinarium chloride, seclazone, selmetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetridamine, thiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecollimus, prodrugs thereof, and co-drugs thereof. The above anti-inflammatory agents may be used alone or in combination of two or more.

[0105] The immunosuppressant is also not particularly limited, and known immunosuppressants can be used. Examples include sirolimus, everolimus, biolimus A9, pimecrolimus, zotarolimus, sirolimus derivatives such as ABT-578, biolimus (e.g., Biolimus A9 (registered trademark)), tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, and gusperimus. The above immunosuppressants may be used alone or in combination with two or more. Furthermore, the above immunosuppressants may be used in combination with an anti-inflammatory agent.

[0106] Here, the amount of drug contained in the drug-carrying portion 18 is not particularly limited as long as it is an amount that produces the desired medicinal effect, but from the viewpoint of further exerting an anti-inflammatory effect, it is preferable to contain a large amount of drug. Specifically, the drug content in the drug-carrying portion 18 is preferably 30% by mass or more and 60% by mass or less, and more preferably 45% by mass or more and 50% by mass or less, relative to the total amount (100% by mass) of the second biodegradable polymer and the drug. With this composition, an appropriate amount of drug can be effectively sustained-released for a predetermined period of time.

[0107] In one embodiment of the present invention, the drug-carrying portion 18 is a single layer composed of ε-caprolactone-DL-lactic acid copolymer D (ε-caprolactone:DL-lactic acid=10:90 (molar ratio), crystallinity=0%, weight-average molecular weight=120,000, number-average molecular weight=55,000, decomposition time=4 months) and sirolimus in a mixing ratio of ε-caprolactone-DL-lactic acid copolymer D and sirolimus of 50:50 (mass ratio) (additives: none, drug higher-order structure: amorphous state).

[0108] In one embodiment of the present invention, the drug-carrying portion 18 is a single layer composed of poly DL-lactic acid H (crystallinity = 0%, weight-average molecular weight = 100,000, number-average molecular weight = 50,000, decomposition time = 12 months) and Biolimus A9 (registered trademark) in a mixing ratio of poly DL-lactic acid H and Biolimus A9 (registered trademark) of 50:50 (mass ratio) (additives: none, drug higher-order structure: amorphous state).

[0109] Furthermore, the drug-carrying portion 18 may contain other drugs in addition to the anti-inflammatory drug. When the drug-carrying portion 18 further contains other drugs, the other drugs are not particularly limited, but are preferably drugs that suppress stenosis or occlusion of the vascular system that may occur when the stent is placed in the lesion. Specifically, anticancer drugs such as paclitaxel, docetaxel, vinblastine, vindesine, irinotecan, pirarubicin, etc.; immunosuppressants such as sirolimus, everolimus, pimecrolimus, sirolimus derivatives such as ABT-578, tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, gusperimus, etc.; antibiotics such as mitomycin, adriamycin, doxorubicin, actinomycin, daunorubicin, idarubicin, pirarubicin, aclarubicin, epirubicin, zinostatin stimalamer, etc.; antithrombotic drugs such as aspirin, ticlopidine, etc.; cerivastatin, cerivastatin sodium, atorvastatin, pitavastatin, fluvastatin, fluvastatin sodium, citravitis, thrombocytopenia ... Examples of suitable drugs include HMG-CoA reductase inhibitors such as ionvastatin and lovastatin; ACE inhibitors such as quinapril, trandolapril, temocapril, delapril, enalapril maleate, and captopril; calcium channel blockers such as hifedipine, nilvadipine, benidipine, and nisoldipine; antihyperlipidemic drugs such as probucol; integrin inhibitors such as AJM300; antiallergic agents such as tranilast; antioxidants such as α-tocopherol, catechin, dibutylhydroxytoluene, and butylhydroxyanisole; GPIIbIIIa antagonists such as abciximab; retinoids such as all-trans retinoic acid; lipid-improving drugs such as eicosapentaenoic acid; and antiplatelet drugs such as ticlopidine, cilostazol (500), and clopidogrel. These drugs are preferred because they can control the behavior of cells in the affected tissue and treat the affected area. The other drugs may be used alone or in combination of two or more.

[0110] The method for forming the drug-carrying portion 18 is not particularly limited, and examples that can be used include a method of mixing a second biodegradable polymer and a drug, and, if necessary, at least one of a solvent and other drugs, to obtain a mixture, and applying this mixture to a predetermined site on the stent 10 (the method for producing the indwelling device 100 of the first and second embodiments described above), a method of mixing a second biodegradable polymer and a drug, and, if necessary, at least one of a solvent and other drugs, to obtain a mixture, and using this mixture to mold the stent 10 (the method for producing the indwelling device 100 of the third embodiment described above), and the like.

[0111] As described above, the indwelling device 100 according to this embodiment comprises an expandable cylindrical stent 10 and a porous structure 20 made of a first biodegradable polymer arranged to cover the stent 10, the stent 10 having a drug-carrying portion 18 containing a second biodegradable polymer and a drug, and the degradation time of the porous structure 20 is substantially the same as or shorter than the degradation time of the drug-carrying portion 18.

[0112] According to the implantable stent 100 configured as described above, the porous structure 20 decomposes and disappears after a certain period of time has passed since implantation, and the drug continues to be released from the stent 10 until the porous structure 20 decomposes and disappears. Therefore, the implantable stent 100 can effectively suppress the onset of inflammation caused by the porous structure 20 made of a biodegradable polymer while preventing the scattering of plaque or thrombus when the stent 10 is expanded.

[0113] This application is based on Japanese Patent Application No. 2023-169879, filed on September 29, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0114] REFERENCE SIGNS LIST 10 Stent 11 Ring 12 Link portion 18 Drug-carrying portion 19 Surface of ring 19a Opposing portion 20 Porous structure 100 Living body indwelling device

Claims

1. A biological indwelling device comprising an expandable tubular stent and a porous structure made of a first biodegradable polymer arranged to cover the stent, the stent having a drug-carrying portion containing a second biodegradable polymer and a drug, the decomposition time of the porous structure being substantially the same as or shorter than the decomposition time of the drug-carrying portion.

2. The indwelling device according to claim 1, wherein the stent is made of a non-biodegradable material, and the drug-carrying portion is disposed only on the portion of the surface of the ring that forms the stent that faces the porous structure.

3. The indwelling device according to claim 1, wherein the stent is made of a non-biodegradable material, and the drug-carrying portion is disposed so as to cover the entire surface area of ​​the rings that form the stent.

4. The indwelling device according to claim 1, wherein the entire stent is constituted by the drug carrying portion.

5. The indwelling device according to any one of claims 1 to 4, wherein the first biodegradable polymer and the second biodegradable polymer are the same polymer, and the first biodegradable polymer and the second biodegradable polymer are selected from the group consisting of homopolymers of one type of monomer or copolymers of two or more types of monomers selected from the group consisting of lactic acid, caprolactone, glycolic acid, dioxanone, butyrolactone, valerolactone, hydroxybutyric acid, and trimethylene carbonate.

6. The indwelling device according to any one of claims 1 to 4, wherein the first biodegradable polymer and the second biodegradable polymer are different polymers, the first biodegradable polymer is at least one selected from the group consisting of polyglycolic acid, polycaprolactone, glycolic acid-lactic acid copolymer, ε-caprolactone-lactic acid copolymer, and glycolic acid-ε-caprolactone copolymer, and the second biodegradable polymer is at least one selected from the group consisting of polylactic acid, lactic acid-ε-caprolactone copolymer, lactic acid-glycolic acid copolymer, and polydioxanone.

7. The indwelling device according to claim 6, wherein the molecular weight of the first biodegradable polymer is 120,000 or more and 180,000 or less, and the molecular weight of the second biodegradable polymer is 100,000 or more and 200,000 or less.

8. The indwelling device according to claim 6, wherein the first biodegradable polymer is at least one selected from the group consisting of polyglycolic acid or polyglycolic acid-polylactic acid copolymer, and the second biodegradable polymer is at least one selected from the group consisting of polylactic acid, lactic acid-ε-caprolactone copolymer, and polydioxanone.

9. The indwelling device according to claim 6, wherein the molecular weight of the first biodegradable polymer is 140,000 or more and 180,000 or less, and the molecular weight of the second biodegradable polymer is 100,000 or more and 120,000 or less.

10. The indwelling device according to claim 1, wherein the decomposition time of the porous structure is within four months.

11. The indwelling device according to claim 1, wherein the decomposition time of the drug-carrying portion is more than four months.

12. The indwelling device according to claim 8, wherein the number average molecular weight of said porous structure and said drug-carrying portion in a decomposed state is 50 to 800.

13. The indwelling device according to claim 2 or 3, wherein the non-biodegradable material is a metal material or a polymer material.

14. The indwelling device according to claim 1, wherein the drug includes an anti-inflammatory agent.

15. The indwelling device according to claim 1, wherein the proportion of the drug in the drug-carrying portion is 40% by mass or more and 55% by mass or less relative to the total amount of the second biodegradable polymer and the drug.

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