JP4526589B2 - Covered stent - Google Patents

Description

  The present invention relates to a covered stent that is placed in a stenosis or occlusion in a blood vessel and maintained in an open state. More specifically, the present invention relates to a stent covered with a polymer material film that easily follows expansion and contraction of the stent body.

In recent years, a medical device called a stent has been used in order to improve a narrowed portion generated in a blood vessel. In order to treat various diseases caused by stenosis or occlusion of blood vessels, stents are used to expand lesions that are stenosis or occlusions and maintain their lumens in an open state. It is a hollow tubular medical device that can be placed.
For example, the coronary artery of the heart is used for the purpose of preventing restenosis after percutaneous coronary angioplasty (PTCA).

  Although this hollow tubular medical device called a stent has been successfully placed in the blood vessel after surgery, it has succeeded in reducing the rate of acute vascular occlusion and restenosis. Due to follow-up and the like, restenosis is recognized at an average ratio of about 20% in the stent indwelling portion, and the problem of restenosis still remains as a major issue.

In addition, in the repair of damaged blood vessels such as arterial dissection and aneurysm, there is a problem that a stent formed only of metal or polymer wires cannot be used.
As a technique for solving such a problem, for example, Patent Document 1 and Patent Document 2 describe a technique in which a cover is sewn and attached to a stent body. Patent Document 3 describes a technique of forming a non-woven fabric cover on a stent, and Patent Document 4 discloses a technique of winding a sheet of a polymer material around a stent in a coil shape and bonding the ends. Are listed.

  However, a stent in which a cover is sewn to the stent body and a stent in which a non-woven cover is formed on the stent has one of the characteristics required for the stent because the diameter of the stent is considerably larger than that of the stent body alone. Delivery to the lesion is greatly impaired. In the case of a cover in the form of a nonwoven fabric, there are problems such as thin fibers being cut and fluffing when hindered, obstructing blood flow, and inducing blood clot adhesion. Furthermore, in the cover in the form of a nonwoven fabric having holes, when the film thickness is large, the positions of the holes from the inner surface side to the outer surface side are easily twisted and the material exchange between the inner surface side and the outer surface side cannot be sufficiently performed. Moreover, since it becomes easy to shift | deviate between blood vessel inner walls, there exists a possibility of inducing a strong inflammatory reaction and also the inflammatory reaction on the outer membrane side.

  In a stent in which a polymer material sheet described in Patent Document 4 is wound in a coil shape, one end portion of the polymer material sheet needs to be bonded or fixed to a part of the sheet and fixed. There is. When the stent is expanded, the fixing site is released and the polymer material sheet is unwound, and the stent needs to be in close contact with the stent and the inner wall of the blood vessel. However, there is a problem whether the stent can be stably performed in the blood vessel when performing the procedure. . In addition, this document describes that a plurality of holes are provided in a sheet of a polymer material. However, in this document, the interval between the holes in the sheet is wide and the number of holes is small, so the stent is placed in the blood vessel. After indwelling, it is unclear whether the material exchange between the inner surface side and the outer surface side can be performed sufficiently and the endothelialization of the inner surface of the blood vessel is sufficiently promoted. Further, since the thickness of the sheet is as thick as about 0.002 to 0.020 inches, there is a problem that there is a high possibility that the stent is not placed in a state where the stent is sufficiently expanded by recoil.

Japanese Patent Laid-Open No. 4-231954 JP-A-6-343703 JP-A-9-285550 JP-A-8-224297

  The covered stent of the present invention has a cover that is excellent in delivery to a lesion, has a cover that can be expanded and contracted following expansion and contraction of the stent body, and further has an effect of promoting endothelialization of the blood vessel inner surface. An object is to provide a stent.

  JP 2001-157574 A describes a polymer material film having a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure.

  As a result of intensive studies by the inventors of the present invention in order to achieve the above-mentioned problems, for example, a polymer material film having a honeycomb structure as described in JP-A-2001-157574 is used on the outer side of the stent body. When coated on at least part of the surface or the inner surface, the polymer material film has a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure. It has been found that when the stent body is expanded or contracted, the hole diameter expands or contracts to expand or contract following the stent body. Further, it has been found that the substance exchange between the inner surface side and the outer surface side of the stent can be sufficiently performed, the endothelialization of the blood vessel inner surface is promoted, and restenosis can be prevented. In addition, since the polymer material film can be made thinner than the conventional polymer material sheet, it has been found that even when the outer side of the stent body is coated, the delivery to the lesioned part can be maintained. Furthermore, with a polymer material film of 10 μm or less, the stent body and the polymer material film, and the polymer material film can be bonded to each other without using an adhesive or the like, and the covered stent can be easily manufactured because it is difficult to peel off. I found out. That is, this invention is made | formed based on the said knowledge, and provides the following (1)-(12).

(1) A covered stent for placement in a blood vessel comprising a stent body and a polymer material film provided on at least a part of the outer surface or the inner surface of the stent body,
The polymer material film is a covered stent having a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure at least in part.

(2) A covered stent for placement in a blood vessel comprising a stent body and a polymer material film provided on at least a part of the outer surface or the inner surface of the stent body,
The polymer material film has at least a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure, and the polymer material film has a biological physiology. A covered stent carrying an active substance.

  (3) The covered stent according to the above (1) or (2), wherein the polymer material film is composed of a biodegradable polymer.

  (4) The covered stent according to (1) or (2), wherein the polymer material film is made of a thermoplastic elastomer.

  (5) The covered stent according to any one of (1) to (4), wherein the polymer material film has a surface that promotes proliferation of endothelial cells.

  (6) The covered stent according to any one of (1) to (5), wherein the polymer material film is wound around the stent body by 1 to 3 turns.

  (7) The covered stent according to any one of (1) to (6), wherein the stent body is formed of a metal material.

  (8) The covered stent according to any one of (1) to (6), wherein the stent body is formed of a polymer material.

  (9) The covered stent according to any one of (1) to (8), wherein the polymer material film has a thickness of 0.1 to 50 μm.

  (10) The covered stent according to any one of the above (1) to (9), wherein a spherical diameter of a hole of the polymer material film is 0.1 to 100 μm.

  (11) The biological and physiologically active substance is an anticancer agent, immunosuppressive agent, antibiotic, antirheumatic agent, antithrombotic agent, antihyperlipidemic agent, ACE inhibitor, calcium antagonist, integrin inhibitor , An antiallergic agent, an antioxidant, a GPIIbIIIa antagonist, a retinoid, a flavonoid, a carotenoid, a lipid improving agent, a DNA synthesis inhibitor, a tyrosine kinase inhibitor, an anti-inflammatory agent, a biological material, and at least one selected from the group consisting of interferons The covered stent according to any one of (2) to (10), which is one.

  (12) The polymer material film has a hydrophobic organic solvent solution of a polymer comprising at least part of a biodegradable polymer of 50 to 99 w / w% and an amphiphilic polymer of 50 to 1 w / w%, A honeycomb structure obtained by casting on a base material in the atmosphere of humidity 50 to 95 RH%, gradually evaporating the organic solvent and condensing on the surface of the cast liquid, and evaporating minute water droplets generated by the condensation The covered stent according to any one of (1) to (11), wherein the covered stent is a polymer material film.

According to the covered stent of the first aspect of the present invention, the delivery to the lesion is excellent, the polymer material film can follow the expansion and contraction of the stent body without difficulty, and the inner surface side of the stent. Can be sufficiently exchanged between the outer surface and the outer surface, promote endothelialization of the inner surface of the blood vessel and prevent restenosis.
Further, according to the covered stent of the second aspect of the present invention, the delivery to the lesion is excellent, the polymer material film can follow the expansion of the stent body without difficulty, and the inner surface side of the stent. Can be sufficiently exchanged between the outer surface and the outer surface, promote endothelialization of the inner surface of the blood vessel and prevent restenosis. Furthermore, since the biological physiologically active substance is locally released to the lesioned part, the effect of preventing restenosis is excellent.

FIG. 1 is a schematic diagram showing hatching a plan view of an example of a polymer material film having a honeycomb structure of the present invention. FIG. 2 is a cross-sectional view in the thickness direction of an example of a polymer material film having a honeycomb structure of the present invention. FIG. 3 is a front view showing an example of the stent body of the present invention. FIG. 4 is a partially enlarged photograph (2500 times) after reduction of the covered stent of Example 1. FIG. 5 is a partially enlarged photograph (2500 times) after expansion of the covered stent of Example 1.

Hereinafter, the covered stent of the present invention will be described in detail.
A first aspect of the present invention is a covered stent for placement in a blood vessel comprising a stent body and a polymer material film provided on at least a part of the outer surface or the inner surface of the stent body, The polymer material film is a covered stent having a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure at least partially.
The polymer material film and stent main body according to the first aspect of the present invention will be described in detail below.

<Polymer material film>
The polymer material film of the present invention has a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure at least partially. Here, the hole does not need to be a perfect sphere, and may be a part of a sphere.
The honeycomb structure in the present specification is not particularly limited as long as spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure, but preferably a science (1999, volume 283, p. 373), a polyphenylquinoline-polystyrene block copolymer, which is a rod-coil diblock polymer composed of a hydrophilic block and a hydrophobic block, is dissolved in a hydrophobic organic solvent, and this solution is cast on a substrate. A diblock polymer composed of polystyrene and polyparaphenylene, which is a rigid block, described in Nature (1994, 369, p. 387), and dissolved in a hydrophobic organic solvent. Honeycomb structure obtained by casting on a base material; biodegradable polymer described in JP-A No. 2001-157574 A hydrophobic organic solvent solution of a polymer consisting of 50 to 99 w / w% of mer and 50 to 1 w / w% of an amphiphilic polymer is cast on a substrate under an atmosphere with a relative humidity of 50 to 95 RH% and the organic Examples include a honeycomb structure obtained by gradually evaporating the solvent and condensing on the surface of the cast liquid and evaporating fine water droplets generated by the condensation. Among these, in particular, the honeycomb structure described in Japanese Patent Application Laid-Open No. 2001-157574 has high stability of the honeycomb structure and high self-supporting property when water is used as a base material (an interface between an aqueous phase and a gas phase). This is preferable because a honeycomb structure can be formed and the honeycomb structure floating on the water surface can be easily transferred.
Hereinafter, a polymer material film having a honeycomb structure described in JP-A No. 2001-157574 will be described in detail as a suitable example of the polymer material film of the present invention.

The material used for the polymer material film of the present invention is selected from materials that have stretchability, can be easily stretched even with a slight stress, and do not hinder expansion of the stent body. Among these, biodegradable polymers are preferable because they do not remain permanently in the living body and are metabolized within a predetermined period.
The biodegradable polymer used in the present invention is not particularly limited as long as it is a material that is not toxic to the living body and can be decomposed in the living body, but is preferably a material that can be absorbed into the living body after being decomposed. Specifically, for example, biodegradable aliphatic polyesters such as polylactic acid, polyhydroxybutyric acid, polycaprolactone, polyethylene adipate and polybutylene adipate; aliphatic polycarbonates such as polybutylene carbonate and polyethylene carbonate; polyglycolic acid and chondroitin sulfate Of these, a crosslinked product of hyaluronic acid, a copolymer thereof, a blend of these polymers, or the like is preferable from the viewpoints of solubility in an organic solvent and stretchability of the polymer. Among these, polylactic acid and polycaprolactone are particularly preferable from the viewpoint of availability, price, and the like. Most preferred is a blend of a highly extensible and elastic polycaprolactone with polylactic acid, polyglycolic acid or poly (lactic acid-glycolic acid) copolymer, which easily controls the degradation rate, or two of them. It is a ternary or ternary copolymer.

Further, when a thermoplastic elastomer is used as the polymer material of the present invention, it is not particularly limited as long as the glass transition point is a polymer having a room temperature (25 ° C.) or lower, that is, an elastomer. Specifically, for example, natural rubber (NR), isoprene rubber (IR), butadiene rubber (BR), 1,2-butadiene rubber, styrene-butadiene rubber (SBR), acrylonitrile-butadiene rubber (NBR), chloroprene rubber. (CR), diene rubbers such as butyl rubber (IIR), ethylene-propylene-diene rubber (EPDM) and hydrogenated products thereof; ethylene-propylene rubber (EPM), ethylene-butene rubber (EBM), chlorosulfonated polyethylene, acrylic Examples thereof include olefin rubbers such as rubber, methacrylic rubber, fluorine rubber, polyethylene rubber and polypropylene rubber, epichlorohydrin rubber, polysulfide rubber, silicone rubber, urethane rubber and styrene rubber. Among these, silicone rubber, urethane rubber, acrylic rubber, methacrylic rubber, and styrene rubber are preferable because of high biocompatibility.
The weight average molecular weight of the thermoplastic elastomer is preferably 30,000 to 300,000, and more preferably 50,000 to 100,000 for styrene rubber, for example.

  In this example, an amphiphilic polymer is used in producing the polymer material film. The amphiphilic polymer used in the present invention is not particularly limited as long as it is not toxic to a living body. Specifically, a polyethylene glycol-polypropylene glycol block copolymer; an acrylamide polymer as a main chain skeleton, Amphiphilic polymer having both a dodecyl group as a hydrophobic side chain and a lactose group or a carboxy group as a hydrophilic side chain; ions of anionic polymers such as heparin, dextran sulfate, DNA and RNA nucleic acids, and long-chain alkyl ammonium salts Complex: Amphiphilic polymers having hydrophilic groups such as gelatin, collagen, albumin and the like as water-soluble proteins are preferable. Among these, dodecylacrylamide-ω-carboxyhexylacrylamide is particularly preferable in that it has an excellent ability to stabilize water droplets as a template.

  In this example, when manufacturing a polymer material film having a honeycomb structure, fine water droplet particles are formed on the polymer solution, so that the organic solvent to be used is water-insoluble and has a lower boiling point than water. Specific examples include, but are not limited to, halogen-based organic solvents such as chloroform and methylene chloride; aromatic hydrocarbons such as benzene; esters such as ethyl acetate and butyl acetate; water-insoluble ketones such as methyl isobutyl ketone Carbon disulfide and the like. These organic solvents may be used alone or as a mixed solvent in which these solvents are combined. Among these, chloroform and methylene chloride are preferable from the viewpoints of easiness of evaporation, polymer solubility, and the like.

  In the method for producing a polymer material film having a honeycomb structure of the present invention, first, a polymer solution obtained by mixing the biodegradable polymer and the amphiphilic polymer in the organic solvent is cast on a substrate. Next, high-humidity air is blown onto the polymer solution cast on the substrate to evaporate the solvent and water to obtain a polymer material film having a honeycomb structure.

  As a base material used in the method for producing a polymer material film having a honeycomb structure of the present invention, inorganic materials such as glass, metal and silicon wafer, and high resistance to organic solvents such as polypropylene, polyethylene and polyetherketone are excellent. Liquids such as molecules, water, liquid paraffin, and liquid polyether can be used. In particular, when water is used as the base material, a polymer material film having a honeycomb structure at the interface between the aqueous phase and the gas phase can be obtained by taking advantage of the self-supporting property of the polymer material film having the honeycomb structure. It is preferable because the polymer material film floating on the water surface can be easily transferred.

  The total polymer concentration of the biodegradable polymer and the amphiphilic polymer dissolved in the organic solvent is preferably 0.01 to 10% by mass, and more preferably 0.05 to 5% by mass. When the polymer concentration is lower than 0.01% by mass, the resulting film has insufficient mechanical strength, which is not preferable. When the content is 10% by mass or more, the polymer concentration becomes too high, and minute water droplets cannot be regularly arranged, and the obtained film does not have pores regularly (a uniform honeycomb structure cannot be obtained). Therefore, it is not preferable.

  The mass ratio of biodegradable polymer: amphiphilic polymer is preferably 99: 1 to 50:50. When the proportion of the amphiphilic polymer is 1 w / w% or less, a uniform honeycomb structure cannot be obtained. On the other hand, when the ratio is 50 w / w% or more, the stability of the obtained polymer material film having the honeycomb structure, particularly mechanical strength, is not obtained. It is not preferable because it is insufficient. A more preferable biodegradable polymer: amphiphilic polymer mass ratio is 97: 3-70: 30. More preferably, it is 95: 5-85: 15.

As an environment for manufacturing the polymer material film having the honeycomb structure, it is desirable that the relative humidity is in the range of 50 to 95 RH%. If it is 50 RH% or less, the condensation on the cast film is insufficient, and if it is 95 RH% or more, it is difficult to control the environment, which is not preferable. A more preferable relative humidity is 60 to 85 RH%.
The temperature for producing the polymer material film may be room temperature.

  The mechanism for forming the honeycomb structure of the present invention is considered as follows. When the hydrophobic organic solvent evaporates, heat is taken away, so that the temperature of the cast film surface decreases, and minute water droplets in the air aggregate and adhere to the polymer solution surface. The water droplets are stabilized by reducing the surface tension due to the action of the hydrophilic part in the polymer solution and becoming smaller water droplets, so that the water droplets aggregate as the organic solvent evaporates, They are arranged in a hexagonal close-packed three-dimensional structure. Then, the water droplets evaporate to form a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure.

FIG. 1 is a schematic diagram showing hatching a plan view of an example of a polymer material film having a honeycomb structure of the present invention. As described above, the holes 2 of the polymer material film are formed by casting a polymer solution on a substrate, regularly arranging fine water droplets on the surface, and evaporating the solvent and water droplets. Therefore, since the holes 2 of the polymer material film are formed by using all or part of the shape of minute water droplets as a mold, the shape of the holes 2 is also all or one of spherical (not necessarily accurate spherical). Part. The honeycomb structure of the present invention is such that the spherical holes 2 are arranged in a hexagonal close-packed three-dimensional structure, and the polymer material film 1 other than the holes is, for example, a portion hatched in FIG. The shape of is shown. Here, the portion indicated by the dotted line in FIG. 1 is the hole 2 of the polymer material film, which is a portion where minute water droplets are filled and removed in a hexagonal close-packed manner. The spherical holes 2 do not necessarily have to be overlapped in the thickness direction. As shown in FIG. 2, a single spherical shape may be a hexagonal closest packed in the XY plane direction, or a single step The hole 2 may be a part of a one-stage spherical shape with a thickness less than the spherical shape.
FIG. 2 is a cross-sectional view in the thickness direction of an example of a polymer material film having a honeycomb structure of the present invention. Since the holes 2 of the honeycomb structure of the present invention have a spherical shape (a part of a spherical shape) or a shape in which the spherical shapes are continuous, the diameter R of the spherical shape of the holes 2 is substantially the same, but the cross section in the thickness direction of the polymer material film 1 in terms of the diameter L of the direction perpendicular to the thickness of the hole 2 present therein varies in the thickness direction of the polymeric material film 1 is equal to the diameter R in diameter L ₁ of the diameter L is maximized . Therefore, since the stretchability of the polymer material film having the honeycomb structure is increased, it becomes easy to follow the expansion or contraction of the stent body without difficulty.

The hole of the polymer material film may be a through hole, a non-through hole (indentation), or a non-through hole before expansion of the stent, and may become a through hole when expanded.
As will be described later, when a biologically physiologically active substance is supported on the polymeric material film of the present invention, the biologically physiologically active substance of the biologically physiologically active substance can be used as long as the polymeric material film has a honeycomb structure having non-through holes. This is preferable because the loading amount can be increased.
If the polymer material film has a honeycomb structure with non-through holes before expansion of the stent and holes that become through holes when expanded, it is possible to increase the amount of biologically physiologically active substance supported. In addition, it is possible to follow the expansion of the stent body reasonably, and further, the substance exchange between the inner surface side and the outer surface side of the stent can be sufficiently performed, promoting the endothelialization of the inner surface of the blood vessel, and restenosis. Since it can prevent, it is preferable.

  The spherical diameter of the holes in the polymer material film is preferably 0.1 to 100 μm, more preferably the spherical diameter of the holes is 0.1 to 50 μm, and the most preferable spherical diameter of the holes is 5 to 25 μm. . The spherical diameter of the hole is the maximum diameter in the direction perpendicular to the thickness of the hole when the hole is part of a sphere. When the size is within this range, when the stent having the honeycomb structure polymer film wound around the stent body is placed in the blood vessel, the substance exchange between the inner surface side and the outer surface side can be sufficiently performed. It is preferable because it can promote endothelialization of the inner surface of the blood vessel and prevent restenosis.

  The ratio of the area occupied by pores to the surface area of the polymer material film before covering the stent (porosity) is preferably about 30 to 80%, more preferably about 60 to 75%. If it has a porosity in this range, the mechanical strength and stretchability of the polymer material film can be aligned with an excellent balance. In addition, when the stent is covered, the material exchange between the inner surface side and the outer surface side of the covered stent can be sufficiently performed, the endothelialization of the inner surface of the blood vessel is promoted, and restenosis can be prevented. The porosity is a value obtained by observing the surface of the polymer material film of the present invention with an electron microscope.

  The thickness of the polymer material film of the present invention is preferably 0.1 to 50 μm. More preferably, it is 1-20 micrometers, More preferably, it is 1-10 micrometers. When the thickness of the polymer film is within such a range, the stent body, the polymer material film, and the polymer material film can be bonded without using an adhesive or the like, and are difficult to peel off. Moreover, it is preferable because the delivery property to the lesioned part of the stent having the polymer material film is excellent.

  The polymer material film of the present invention preferably has a surface that promotes the proliferation of endothelial cells. Specifically, for example, if there is an amphiphilic polymer in the polymer material film, the hydrophilic group of the amphiphilic polymer and a vascular endothelial cell precursor are easily chemically bonded to promote the proliferation of endothelial cells. be able to. In addition, a film in which polyethylene glycol is introduced on the surface of the polymer material film is preferable because it can promote the proliferation of endothelial cells.

<Stent body>
The stent body of the present invention is a cylindrical body that is open at both end portions and extends in the longitudinal direction between the both end portions. The side surface of the cylindrical body has a large number of notches communicating with the outer side surface and the inner side surface, and is deformed so that the cylindrical body can expand and contract in the radial direction. Maintains its shape when indwelling.
FIG. 3 is a front view showing an example of the stent body of the present invention. In the example shown in FIG. 3, the stent main body 31 is composed of a linear member 32, and has a substantially rhomboid element 33 having a notch therein as a basic unit. A plurality of substantially rhombic elements 33 are continuously arranged in the minor axis direction and joined to form an annular unit 34. The annular unit 34 is connected to an adjacent annular unit via a linear coupling member 35. Thus, the plurality of annular units 34 are continuously arranged in the axial direction in a partially coupled state.

  In the present invention, the stent body is not limited to the illustrated embodiment, and is a cylindrical body that is open at both end portions and extends between the both end portions in the longitudinal direction. It has a large number of notches that communicate with the side surfaces, and includes a wide range of structures that can expand and contract in the radial direction of the cylindrical body by deforming the notches.

  The stent main body is a medical device made of a metal material or a polymer material. For example, a hollow tubular body made of a metal material or a polymer material provided with pores on the side surface, a metal wire or a polymer material fiber Various shapes have been proposed, such as those obtained by knitting and forming a cylindrical shape.

  As a specific example of the stent body having such a structure that can be expanded and contracted in the radial direction, for example, an elastic wire as disclosed in Japanese Patent Laid-Open Nos. 9-215753 and 7-529 is bent into a coil shape. In the example in which a plurality of them are connected to form a cylindrical shape, the stent main body in which the gap between the elastic wires forms a notch; disclosed in JP-T-8-502428 and JP-A-7-5000027 A stent body in which elastic wires are bent in a zigzag shape and connected to each other to form a cylindrical shape, and a gap between elastic wires forms a notch; JP 2000-501328 A and JP 11 No. -22288, an elastic wire is bent into a snake-like flat ribbon shape and wound in a helix around a mandrill to form a cylindrical shape. Stent body in which gaps between materials form notches; Stent body having a mesh-like structure as disclosed in JP-T-10-503676; disclosed in JP-A-8-507243 In this example, a plate member is bent into a coil shape to form a cylindrical shape, such as a stent body in which a gap between adjacent coil portions forms a notch. Japanese Patent Publication No. 4-68939 discloses an example in which an elastic plate-like member is formed into a spiral shape to form a cylindrical shape, and a stent body in which a gap between adjacent spiral portions forms a notch, and an elastic wire is braided. Examples of the cylindrical shape include a cylindrical stent body having a plurality of different structures including a stent body in which a gap between elastic wires forms a notch. In addition, the stent main body of the present invention may be a leaf spring coil shape, a multiple spiral shape, an atypical tubular shape, or the like. Further, FIGS. 2 (a) and 2 (b) of Japanese Patent Publication No. 4-68939 describe a stent body in which an elastic plate-like member is bent into a spiral shape to form a cylindrical shape. A cylindrical stent body that does not have a notch on the side surface but can be expanded and contracted in the radial direction of the cylindrical body can also be used as the stent body of the present invention. All of these above references and patent applications are hereby incorporated by reference.

The size of the stent body may be appropriately selected according to the application location. For example, when used for the coronary artery of the heart, the outer diameter before expansion is usually 1.0 to 3.0 mm, and the length is preferably 5 to 50 mm.
As described above, when the stent body is composed of a linear member, the length in the width direction of the linear member configured to have a large number of notches is preferably 0.01 to 0.5 mm. And more preferably 0.05 to 0.2 mm.
The manufacturing method of the stent body is not particularly limited, and may be appropriately selected from commonly used manufacturing methods according to the structure and material of the stent.

Examples of the material of the stent body include polymer materials, metal materials, carbon fibers, ceramics, and the like, and are not particularly limited as long as they have a certain degree of rigidity and elasticity, but are preferably biocompatible materials. .
Specifically, examples of the polymer material include polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, cellulose polymers such as cellulose acetate and cellulose nitrate, polytetrafluoroethylene, and tetrafluoroethylene-ethylene copolymers. And the like. Examples of the metal material include stainless steel, tantalum, titanium, nickel titanium alloy, tantalum titanium alloy, nickel aluminum alloy, inconel, gold, platinum, iridium, tungsten, cobalt-based alloy, and the like. Among stainless steels, SUS316L, which has the best corrosion resistance, is suitable.

The stent main body can be suitably formed from the above-exemplified materials by a material appropriately selected according to the application site or expansion means. For example, when the stent body is formed of a metal material, the metal material is excellent in strength, so that the stent can be surely placed in the lesion. When the stent body is formed of a polymer material, the polymer material is excellent in flexibility, and thus exhibits an excellent effect in terms of reachability (delivery property) to the lesioned portion of the stent.
In addition, when the stent is self-expanding, a restoring force to the original shape is required, so a superelastic alloy such as titanium nickel is preferable. When the stent is balloon-expandable, shape recovery after expansion is unlikely to occur. Therefore, stainless steel or the like is preferable.
In addition, when the stent body is made of carbon fiber, it has an excellent effect in that it has high strength and excellent flexibility and high safety in vivo.

  The expansion means of the stent body is not particularly limited, and may be of a self-expanding type, that is, a type that expands in the radial direction by its own restoring force by removing the force holding the stent body that is finely and smallly folded. Well, it may be of the balloon expandable type, that is, a type in which the balloon is expanded from the inside of the stent body and expanded radially by an external force.

  To place a balloon-expandable stent at the target site, the catheter is inserted into the target site, then the balloon is positioned in the stent and the balloon is expanded, and the stent is expanded by plastic expansion force (plastic deformation). ) And fix it in close contact with the inner surface of the target site.

  When the stent itself has contraction and expansion functions, the stent is contracted and inserted into the target site, and then the stress applied to maintain the contracted state is removed. For example, the stent is contracted and accommodated in a tube having an outer diameter smaller than the inner diameter of the target site, the tip of the tube reaches the target site, and then the stent is pushed out of the tube. The extruded stent is released from the tube to release the stress load, and restores and expands to the shape before contraction. Thereby, it adheres and fixes to the inner surface of the blood vessel of the target site.

Next, a method for providing the polymer material film having the honeycomb structure on the stent body will be described.
The method of providing the polymer material film on the stent body is not particularly limited, and the polymer material film may be coated on the entire outer periphery of the stent body or may be partially coated. Further, a polymer material film may be provided on the inner surface of the stent body.
For example, a method of winding the polymer material film in accordance with the size of the stent body and winding it in advance, and a method of winding the polymer material film around the stent body and then cutting both ends But you can.
Moreover, when winding this polymeric material film around a stent main body, the adhesion method of the both ends of this polymeric material film is not specifically limited, For example, it can be made to adhere by an adhesive agent or heat fusion. When the thickness of the polymer material film is 10 μm or less, the polymer material film, the stent body, and the polymer material film can be bonded without being peeled off without using an adhesive or the like.
In addition, by covering the stent body with the polymer material film stretched appropriately, the polymer material film can follow the stent body without difficulty even when the stent body shrinks.

  When the polymer material film is wound around the stent body, it is preferable that the polymer material film is wound 1-3 times along the outer periphery of the stent body, and more preferably 2-3 times. preferable. Within this range, delivery to the lesioned part of the stent is excellent, and since the stretchability of the polymer material film can be maintained, it is possible to follow the expansion or contraction of the stent body without difficulty. The material exchange between the inner surface side and the outer surface side can be sufficiently performed, the endothelialization of the inner surface of the blood vessel is promoted, and the mechanical strength of the polymer material film is also excellent.

  A covered stent manufactured by a method in which the above-described polymer material film is processed into a cylindrical shape in advance according to the size of the stent body and is put on the stent body is excellent in deliverability to a lesioned part. Since the elasticity can be maintained, it is possible to follow the expansion or contraction of the stent body without difficulty, and the material exchange between the inner surface side and the outer surface side of the stent can be sufficiently performed to promote endothelialization of the inner surface of the blood vessel. Furthermore, it is preferable because it is excellent in mechanical strength.

  According to the covered stent of the first aspect of the present invention, the delivery to the lesion is excellent, the polymer material film can follow the expansion and contraction of the stent body without difficulty, and the inner surface side of the stent. Can be sufficiently exchanged with the outer surface, promote endothelialization of the inner surface of the blood vessel, and prevent restenosis.

  A second aspect of the present invention is a covered stent for placement in a blood vessel comprising a stent body and a polymer material film provided on at least a part of the outer surface or the inner surface of the stent body, The polymer material film has at least a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure, and the biological material has a biological physiological activity. A covered stent carrying a substance.

  The stent body according to the second aspect of the present invention is the same as the stent body according to the first aspect. The polymer material film of the second aspect is the same as the polymer material film of the first aspect, but further carries a biological physiologically active substance.

  The biological physiologically active substance is not particularly limited, but preferably has an effect of suppressing restenosis when the stent of the present invention is placed in a lesioned part of a blood vessel. Specifically, anticancer agents, immunosuppressive agents, antibiotics, antirheumatic agents, antithrombotic agents, antihyperlipidemic agents, ACE inhibitors, calcium antagonists, integrin inhibitors, antiallergic agents, antioxidants Agents, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, anti-inflammatory agents, biomaterials, interferons, etc., but in terms of dosage and medicinal properties, paclitaxel Anticancer agents such as are most preferably used.

  More specifically, as the anticancer agent, for example, vincristine sulfate, vinblastine sulfate, vindesine sulfate, irinotecan hydrochloride, paclitaxel, docetaxel hydrate, methotrexate, cyclophosphamide and the like are preferable.

  More specifically, as an immunosuppressant, for example, sirolimus, tacrolimus hydrate, azathioprine, cyclosporine, mycophenolate mofetil, gusperimus hydrochloride, mizoribine and the like are preferable.

  More specifically, as the antibiotic, for example, mitomycin C, doxorubicin hydrochloride, actinomycin D, daunorubicin hydrochloride, idarubicin hydrochloride, pirarubicin hydrochloride, aclarubicin hydrochloride, epirubicin hydrochloride, pepromycin sulfate, dinostatin stimaramer and the like are preferable.

  More specifically, the antirheumatic agent is preferably, for example, sodium gold thiomalate, penicillamine, lobenzalit disodium or the like.

  More specifically, as an antithrombotic agent, for example, heparin, ticlopidine hydrochloride, hirudin and the like are preferable.

  More specifically, the antihyperlipidemic agent is preferably an HMG-CoA reductase inhibitor or probucol. As the HMG-CoA reductase inhibitor, more specifically, for example, cerivastatin sodium, atorvastatin, nisvastatin, pitavastatin, fluvastatin sodium, simvastatin, lovastatin, pravastatin sodium and the like are preferable.

  More specific examples of the ACE inhibitor include quinapril hydrochloride, perindopril erbumine, trandolapril, cilazapril, temocapril hydrochloride, delapril hydrochloride, enalapril maleate, lisinopril, captopril and the like.

  More specifically, as the calcium antagonist, for example, nifedipine, nilvadipine, diltiazem hydrochloride, benidipine hydrochloride, nisoldipine and the like are preferable.

  More specifically, for example, tranilast is preferable as the antiallergic agent.

  More specifically, for example, all-trans retinoic acid is preferable as the retinoid.

  More specifically, as an antioxidant, for example, catechins, anthocyanins, proanthocyanidins, lycopene, β-carotene and the like are preferable. Among catechins, epigallocatechin gallate is particularly preferable.

  More specifically, as a tyrosine kinase inhibitor, for example, genistein, tyrphostin, arbustatin and the like are preferable.

  More specifically, as an anti-inflammatory agent, for example, steroids such as dexamethasone and prednisolone and aspirin are preferable.

  More specifically, examples of the bio-derived material include EGF (epidermal growth factor), VEGF (basic endorthous growth factor), HGF (hepatocyte growth factor), PDGF (platelet growth factor), PDGF (platelet growth factor), and PDGF (platelet growth factor). Etc.) are preferred.

  The method for supporting the biologically physiologically active substance on the polymer material film is not particularly limited. Specifically, a method of spraying a solution of the biologically physiologically active substance on the surface of the polymer material film, or bulk by heat. Examples include a method of welding, or a method of mixing a biological physiologically active substance in a polymer solution and containing the biologically physiologically active substance in the polymer material film when producing a polymer material film. The Among them, a method of spraying a solution of a biologically physiologically active substance on the surface of the polymer material film is preferred because of its simplicity of treatment.

  According to the covered stent of the second aspect of the present invention, the delivery to the lesion is excellent, the polymer material film can follow the expansion and contraction of the stent body without difficulty, and the inner surface side of the stent. Can be sufficiently exchanged with the outer surface, promote endothelialization of the inner surface of the blood vessel, and prevent restenosis. Furthermore, since the biological physiologically active substance is locally released to the lesioned part of the blood vessel, the effect of preventing restenosis is high.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated more concretely, this invention is not limited to the following Example.

Example 1
Poly (ε-caprolactone) having a weight average molecular weight of 100,000 (hereinafter abbreviated as “PCL”) and dodecylacrylamide-ω-carboxyhexylacrylamide having a weight average molecular weight of 32,000 in chloroform at a mass ratio of 10: 1. By dissolving, a polymer solution (1.5 mg / L as the total concentration of the above polymers) was prepared. Next, 6 ml of the above polymer solution is cast on a circular glass petri dish having a diameter of 10 cm, high-humidity air having a relative humidity of 70 RH% is blown at a flow rate of 2 L / min, and the spherical diameter (average) of the holes is 5 μm and the thickness is 3 μm. A polymer material film having a honeycomb structure was prepared.
Next, the polymer material film is immersed in ethanol and wound around a stainless steel (SUS316L) stent body while being peeled off from the petri dish, and then bonded without using an adhesive or the like, and then both ends are cut. A covered stent of Example 1 was obtained.

(Example 2)
PCL having a weight average molecular weight of 200,000 and poly (L-lactic acid) having a weight average molecular weight of 380,000 (hereinafter abbreviated as “PLLA”) were weighed at a mass ratio of PCL: PLLA = 8: 2 to obtain a weight average molecular weight. 32000 dodecylacrylamide-ω-carboxyhexylacrylamide was dissolved in chloroform at a mass ratio of 10: 1 with respect to the total mass of the biodegradable polymer, and a polymer solution (1.5 mg as the total concentration of the polymer) was dissolved. / L) was prepared. Next, 6 ml of the polymer solution prepared above was cast on a circular glass petri dish having a diameter of 10 cm, high-humidity air having a relative humidity of 70 RH% was blown at a flow rate of 2 L / min, and the spherical diameter (average) of the holes was 5 μm. A polymer material film having a honeycomb structure with a thickness of 3 μm was produced.
Next, the polymer material film is immersed in ethanol and wound around a stainless steel (SUS316L) stent body while being peeled off from the petri dish, and then bonded to each other without using an adhesive, and then both ends are cut. Thus, a covered stent of Example 2 was obtained.

(Example 3)
PCL having a weight average molecular weight of 100,000, dodecylacrylamide-ω-carboxyhexylacrylamide having a weight average molecular weight of 32,000, and paclitaxel were mixed at a mass ratio of PCL: dodecylacrylamide-ω-carboxyhexylacrylamide: paclitaxel = 10: 1: 1. A polymer solution (1.5 mg / L as the total concentration of the above polymers) was prepared by dissolving in chloroform. Next, 6 ml of the polymer solution prepared above was cast on a circular glass petri dish having a diameter of 10 cm, high-humidity air having a relative humidity of 70 RH% was blown at a flow rate of 2 L / min, and the spherical diameter (average) of the holes was 5 μm. A polymer material film having a honeycomb structure with a thickness of 3 μm was produced.
Next, the polymer material film is immersed in ethanol and wound around a stainless steel (SUS316L) stent body while being peeled off from the petri dish, and then bonded without using an adhesive or the like, and then both ends are cut. The covered stent of Example 3 was obtained.

Example 4
A carboxy group derived from dodecylacrylamide-ω-carboxyhexylacrylamide on the surface of the polymer material film prepared in the same manner as in Example 1 was reacted with a hydroxyl group of polyethylene glycol (PEG) having a weight average molecular weight of 20,000 to form an ester bond. Formed.
Next, the polymer material film having PEG on the obtained surface was wound around the main stent body in the same manner as in Example 1 to obtain a covered stent of Example 4.

<Expansion experiment>
In order to mount each of the covered stents of Examples 1 to 4 on a balloon, the inner diameter of the covered stent was caulked from 2 mm to 1 mm, and the state of the covered stent was observed using an electron microscope. The polymer film was firmly attached to the stent and did not peel off, tear or float.
In addition, when the covered stent was expanded to an inner diameter of 3 mm with a balloon, it was confirmed that the polymer material film followed the expansion of the stent body by expanding the holes of the polymer material film. The polymer material film after the stent expansion was firmly fixed to the stent, and there was no portion damaged by the expansion.
FIG. 4 is a partially enlarged photograph (2500 times) after reduction of the covered stent of Example 1, and FIG. 5 is a partially enlarged photograph (2500 times) after expansion of the covered stent of Example 1.

(Comparative Example 1)
A nonwoven fabric covered stent was produced using a hot melt applicator system (CST-2, discharge nozzle, manufactured by Nordson). While rotating a stent body made of stainless steel (SUS316L) fixed to a pin gauge having a diameter of 1.86 mm at a rotation speed of 115 rpm, a PCL having a weight average molecular weight of 100,000 was applied at a nozzle temperature of 150 ° C., a discharge amount of 0.10 g / 5 min, a nozzle − Spraying was performed at an interstent distance of 50 mm. The nozzle was moved at an XY moving speed of 150 mm / min, and moved 1.5 reciprocating times on the stent body.
The thickness of the nonwoven fabric produced on the stent body was measured with a thickness gauge while being fixed to the pin gauge, and was 25 μm.

<Expansion experiment>
In order to mount the covered stent of Comparative Example 1 on a balloon, if the crimped operation is performed from 2 mm to 1 mm inside the covered stent, it is difficult to reduce the thickness to about 10 μm in the case of the nonwoven fabric cover, so that it rises from the stent. , Confirmed that the profile is getting bigger.
In addition, when the stent was expanded with a balloon, several damages at the welded portion between the nonwoven fabrics were confirmed. Furthermore, the positions of the holes were also different, and it was confirmed that the variation in the hole diameter was large.

DESCRIPTION OF SYMBOLS 1 Polymer material film 2 Hole R The spherical diameter of the hole L The maximum diameter in the direction perpendicular to the thickness of _one hole L The diameter in the direction perpendicular to the thickness of _two holes 31 Stent body 32 Linear member 33 Substantially diamond-shaped element 34 Annular unit 35 Connecting member

Claims (11)

A covered stent for placement in a blood vessel comprising a stent body and a polymer material film provided on at least a part of the outer surface or the inner surface of the stent body,
The polymer material film has at least a part of a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure by overlapping a plurality of spherical holes in the thickness direction of the polymer material film. A covered stent in which the diameter of the hole in a direction perpendicular to the thickness of the polymer material film changes in the thickness direction of the polymer material film. A covered stent for placement in a blood vessel comprising a stent body and a polymer material film provided on at least a part of the outer surface or the inner surface of the stent body,
The polymer material film has at least a part of a honeycomb structure in which spherical holes having a substantially constant diameter are arranged in a hexagonal close-packed three-dimensional structure by overlapping a plurality of spherical holes in the thickness direction of the polymer material film. The diameter of the hole in the direction perpendicular to the thickness of the polymer material film is changed in the thickness direction of the polymer material film, and the biological and physiologically active substance is present in the polymer material film. Supported covered stent.   The covered stent according to claim 1, wherein the polymer material film is composed of a biodegradable polymer.   The covered stent according to claim 1, wherein the polymer material film is made of a thermoplastic elastomer.   The covered stent according to any one of claims 1 to 4, wherein the polymer material film has a surface that promotes proliferation of endothelial cells.   The covered stent according to any one of claims 1 to 5, wherein the polymer material film is wound around the stent body by 1 to 3 turns.   The covered stent according to any one of claims 1 to 6, wherein the stent body is made of a metal material.   The covered stent according to any one of claims 1 to 6, wherein the stent body is formed of a polymer material.   The covered stent according to any one of claims 1 to 8, wherein the polymer material film has a thickness of 0.1 to 50 µm.   The covered stent according to any one of claims 1 to 9, wherein a spherical diameter of the hole of the polymer material film is 0.1 to 100 µm.   The biological and physiologically active substance is an anticancer agent, immunosuppressive agent, antibiotic, antirheumatic agent, antithrombotic agent, antihyperlipidemic agent, ACE inhibitor, calcium antagonist, integrin inhibitor, antiallergy At least one selected from the group consisting of agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, anti-inflammatory agents, biological materials, and interferons The covered stent according to any one of claims 2 to 10.

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