JP2006333940A - Stent and its production method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing a covered stent having many fine holes at comparatively low cost, and the stent produced by this method. <P>SOLUTION: The stent has a tubular main body of the stent of which the diameter can be enlarged, a soft polymer layer which covers the main body of the stent and the micropores which penetrate the polymer layer, wherein the polymer layer is produced by plastering eosinophilic gelatin, hardening the portion other than the micropores by the exposure through a mask and melting the micropores portion with water to be the pores. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a stent (intraluminal graft) used in recent years for endovascular therapy and surgery, in particular, stenotic coronary artery, stenotic carotid artery, bile duct, esophageal dilatation, and aneurysm occlusion.

  Conventional treatment of ischemic heart disease is percutaneous transluminal coronary angioplasty (PTCA), that is, a balloon catheter is carried through a lumen in a blood vessel to, for example, a stenotic site, and then the balloon is expanded with a liquid such as physiological saline. Treatment methods were common. However, with this method, there is a high probability that coronary occlusion in the acute phase and re-stenosis (so-called restenosis) at the site where PTCA is performed occur. In order to solve these problems, an intraluminal graft called a stent has been developed and recently put into practical use and has become widespread. Recent data show that nearly 75% of balloon catheter surgery has already been replaced by stent surgery.

  A stent is an intraluminal graft that is carried through a lumen such as a blood vessel and supported by action from the inside by expanding its diameter at the treatment site of the lumen. Although it is mainly used in the above-mentioned coronary artery surgery, it will be explained mainly here, but the stent is a bile duct, esophagus, trachea, prostate, ureter, fallopian tube, aortic aneurysm, peripheral artery, kidney It can also be used for other luminal parts of the human body such as arteries, carotid arteries, and cerebral blood vessels.

  Restenosis can be drastically prevented by the spread of surgery using stents. However, since a metal stent is a foreign substance in the body, thrombosis develops within a few weeks after the stent is inserted. In other words, since the metal stent itself has thrombogenicity, when exposed to blood, it contacts with plasma proteins such as albumin and fibrinogen and aggregation occurs due to adhesion of platelets. It is also pointed out that the placement of metal stents promotes thickening of the vascular endothelium, which is one cause of restenosis. Japanese Patent Application Laid-Open No. 11-299901 describes a stent (covered stent) in which the outer peripheral surface of a metal stent body is covered with a flexible polymer film having fine holes.

  FIG. 2 is a perspective view showing a mesh-shaped metal stent main body 10 used for the covered stent, and FIG. 3 is a perspective view showing a state 10 'in which the diameter of the stent main body 10 of FIG. 2 is expanded. FIG. 4 is a perspective view showing a stent 20 in which the outer peripheral surface of such a stent body 10 is covered with a flexible polymer film 19 having fine holes, and FIG. 5 shows a state in which the stent 20 is expanded. It is a perspective view. As shown in FIG. 6, the film 19 is fixed at the contact portion to each of the stent struts 11 constituting the mesh stent body on the outer peripheral surface of the mesh stent body. The unity with the main body is low.

  Therefore, the present applicant has proposed a stent in which both inner and outer peripheral surfaces of a stent body are covered with a polymer layer in Japanese Patent Application Laid-Open No. 2004-261567.

  In living tissue, inner surfaces such as blood vessels, that is, portions that come into contact with blood are covered with a cell layer called endothelial cells. Since the surface of these endothelial cells is covered with sugar and the endothelial cells themselves secrete substances that suppress platelet activation such as prostaglandins, thrombus and the like are unlikely to occur in living tissues. As described in JP-A-11-299901 and JP-A-2004-261567, by covering the outer peripheral surface of a metal stent body with a polymer film, appropriate endothelialization of cells is promoted and thrombosis is reduced. be able to.

In JP-A-11-299901 and JP-A-2004-261567, fine holes are drilled by a laser in a polymer film covering the stent body. The micropores are mainly for encapsulating endothelial cells on the inner wall of the stent to suppress thrombus generation and intimal thickening.
JP 11-299901 A JP 2004-261567 A

  As described in Japanese Patent Application Laid-Open No. 11-299901 and Japanese Patent Application Laid-Open No. 2004-261567, in order to drill fine holes with a laser, a laser processing facility is required, and the equipment cost is high, and a large number of fine holes are drilled. Takes a long time.

  An object of the present invention is to provide a method capable of efficiently producing a covered stent having a large number of micropores at a relatively low cost, and a stent produced by this method.

  The method for producing a stent of the present invention produces a stent having a tubular stent body that can be expanded in diameter and a flexible polymer layer that covers the stent body, and in which the polymer layer is provided with a large number of micropores. In this method, a light non-transmissive portion is provided in the arrangement pattern of the micropores, and the other is a light-transmitting mask, a photosensitive material layer that overlaps the mask, has water solubility, and is insolubilized by exposure. To the stent body, irradiating the photosensitive material layer with light through the mask to insolubilize the exposed photosensitive material, and unexposed photosensitivity overlapping the non-transmissive portion The stent is manufactured by a step of removing material to form micropores.

The method for producing a stent according to claim 2 is the method according to claim 1, wherein the photosensitive material is an aqueous solution containing the following compound (A) and a hydrogen donor, and the exposure is performed with visible light. It is characterized by.
(A) collagen, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, laminin, thrombospondin, vitronectin, osteonectin, entactin, gazein, polyethylene glycol, modified with xanthene dye Polypropylene glycol, polyglycidol, side chain esterified product of polyglycidol, polyvinyl alcohol, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide And at least one selected from the group consisting of polyvinylpyrrolidone.

  The method for producing a stent according to claim 3 is the method according to claim 1, wherein the hydrogen donor has thiol, alcohol, reducing sugar, polyphenol, or at least one N-alkyl and / or N, N-dialkylamino group in one molecule. It is a compound.

  The stent manufacturing method according to claim 4 is characterized in that, in claim 2 or 3, the xanthene dye is eosin.

  The method for manufacturing a stent according to claim 5 is characterized in that (A) is gelatin in any one of claims 2 to 4.

  The method for producing a stent according to claim 6 is characterized in that, in claim 5, gelatin is one in which 1 to 10 xanthene dye molecules are introduced in one molecule.

  The stent manufacturing method according to claim 7 is characterized in that, in claim 6, gelatin is one in which 2 to 6 xanthene dye molecules are introduced in one molecule.

  The method for producing a stent according to claim 8 is characterized in that, in any one of claims 2 to 7, a therapeutic agent is contained in the aqueous solution.

  The method for producing a stent according to claim 9 is the method according to claim 8, wherein the therapeutic agent is heparin, low molecular weight heparin, hirudin, argatroban, formacholine, bapiprost, prostamorin, prostaquilin homologue, dextran, lofeproargolchloro. Methyl ketone, dipyridamole, glycoprotein platelet membrane receptor antibody, recombinant hirudin, thrombin inhibitor, vascular peptin, vascular tensin converting enzyme inhibitor, steroid, fibroblast growth factor antagonist, fish oil, omega-3 fatty acid Histamine, antagonists, HMG-CoA reductase inhibitors, ceramine, serotonin blocking antibodies, thioprotein inhibitors, trimazole pyridimine, interferon, vascular endothelial growth factor (VEGF), rapamycin, and It is characterized in that a member selected from the group consisting of K506.

  A stent according to a tenth aspect is manufactured by the manufacturing method according to any one of the first to ninth aspects.

  In the present invention, the photosensitive material layer and the mask are applied to the main stent body, and the photosensitive material other than the portion to be drilled with micropores is exposed and insolubilized through the mask. The material is dissolved and removed with water to form micropores. According to this method, since no laser processing equipment is used, the equipment cost is low, and a stent having a large number of micropores can be produced efficiently.

  The polymer layer prepared by applying a water-soluble photosensitive material in this way and dissolving and removing the unexposed part with water after exposure does not use any organic solvent for its preparation. No residue at all.

  In one aspect of the stent of the present invention and a method for producing the same, the polymer layer is irradiated with an aqueous solution of a biodegradable water-soluble polymer compound modified with a xanthene dye in the presence of a hydrogen donor. This is formed by cross-linking insolubilization. This aqueous solution gels upon irradiation with visible light. This gelled polymer compound is biodegraded and gradually absorbed into the living body.

  Since this gel-like sheet is flexible, it does not extremely compress living tissue.

  A therapeutic agent may be contained in an aqueous solution of a water-soluble polymer for forming the gel polymer layer. Since this gel polymer layer is formed by crosslinking with visible light, even if it is a therapeutic drug weak to light, its activity is not impaired. Further, when the mask aqueous solution is applied to the stent, a polymer material is preferable if the mask material requires flexibility, but the polymer material generally does not transmit ultraviolet rays. . In the present invention, since the polymer layer can be insolubilized by exposure with visible light, a flexible polymer material can be used for the mask.

  Hereinafter, embodiments will be described with reference to the drawings.

  The stent main body constituting the stent of the present invention is preferably a tube having a length of about 2 to 40 mm and a diameter of about 1/10 to 1/2 of the length. Further, the thickness of the stent body (thickness of the tubular portion) is preferably 11 to 2000 μm, more preferably 51 to 500 μm, and particularly preferably 101 to 300 μm. The stent body is preferably in a mesh shape so that the diameter of the stent can be expanded flexibly, and in particular, it is preferably an oblique lattice shape as shown in FIG. 2 and the extending direction of the lattice is a spiral direction.

  The stent body is preferably made of a biocompatible metal. Examples of the biocompatible metal include stainless steel, titanium, tantalum, aluminum, tungsten, nickel / titanium alloy, cobalt / chromium / nickel / iron alloy, and the like. The metal stent body is preferably subjected to heat treatment in order to memorize the shape. By this heat treatment, self-expandability can be imparted to the stent body.

  The flexible polymer layer is formed using a photosensitive material described later.

  The coating thickness of this polymer layer (d in FIG. 1) is preferably about 1 μm to 100 μm, and particularly preferably about 5 μm to 50 μm.

  This polymer layer is provided with a large number of micropores. The fine holes may be randomly arranged, but preferably the fine holes are perforated at substantially uniform intervals. The fact that the micropores are perforated at a substantially uniform interval does not mean that the intervals are the same, but that the micropores are arranged at a substantially constant interval by a controlled method. Accordingly, the substantially uniform interval includes diagonal, circular, and elliptical arrangements that appear to be randomly arranged at first glance. The micropore may have any size and shape as long as the endothelial cells can enter and exit. Preferably, it is a circle having a diameter of 5 to 500 μm, most preferably 10 to 100 μm. Needless to say, other shapes such as an ellipse, a square, and a rectangle are also included. These are the states before expansion, and when the stent body is expanded and placed in the lumen, the circle is deformed into an oval shape, and the diameter changes accordingly. Moreover, as an arrangement | positioning space | interval of a micropore, it arrange | positions on a some straight line by the space | interval of 51-10000 micrometers, Preferably 101-8000 micrometers, More preferably, 201-5000 micrometers. The plurality of straight lines include, for example, 10 to 50 straight lines arranged at a predetermined constant angular interval in the axial direction of the stent.

  However, the most preferable micropore diameter and arrangement interval are dependent on each other, and this relationship is easy to understand when considered as the pore density on the polymer layer. That is, for example, when substantially circular holes are arranged at substantially constant intervals as in the three patterns shown in FIG. 7, the density per unit area naturally depends on the diameter and arrangement interval of the fine holes.

  FIG. 8 shows the relationship between the pore density (unit:%) and the thickening thickness (unit: μm) of the intima formed when the stent is placed in the blood vessel.

  It can be seen from FIG. 8 that there is a relationship in the hole density between the preferable diameter of the fine holes and the arrangement interval. However, no matter how preferred the density is, if the pore diameter is too small, the endothelial cells will not grow sufficiently inside the stent, whereas if the pore diameter is too large, the strength of the polymer layer decreases and the intimal tissue It goes without saying that the intrusion is too advanced.

  In the present invention, this photosensitive material has water solubility and becomes insoluble when exposed to light. As the photosensitive material, an aqueous solution of a substance that gels by generating radicals upon irradiation with visible light is preferable. In particular, the substance (A) is preferably used as the gelling substance.

  As the xanthene dye in the compound (A), eosin is preferable, and as the substance (A), eosinized gelatin is preferable. This eosinized gelatin will be described later.

  When gelatin is modified with a xanthene dye, the number of xanthene dye molecules introduced per molecule of gelatin is preferably 10 or less, and particularly preferably 2 to 6. When this introduction number is more than 10, gelatin becomes hardly soluble in water, and eventually the stent becomes hard.

  In the present invention, a hydrogen donor is preferably used as a proton donor which is a radical counter. As the hydrogen donor, thiol, alcohol, reducing sugar, polyphenol, a compound having at least one N-alkyl and / or N, N-dialkylamino group in one molecule, and the like are preferable, and particularly in one molecule. Compounds having at least one N-alkyl and / or N, N-dialkylamino group are preferred.

  A therapeutic agent may be contained in the aqueous solution of the substance (A).

  Examples of this therapeutic agent include antiplatelet agents, antithrombotic agents, growth promoters, growth inhibitory agents, immunosuppressive agents and the like.

  Specifically, heparin, low molecular weight heparin, hirudin, argatroban, formacholine, bapiprost, prostamorin, prostakirin congeners, dextran, lofepro-alguchloromethyl ketone, dipyridamole, glycoprotein platelets Membrane receptor antibody, recombinant hirudin, thrombin inhibitor, vascular peptin, vascular tensin converting enzyme inhibitor, steroid, fibroblast growth factor antagonist, fish oil, omega-3 fatty acid, histamine, antagonist, HMG-CoA reductase Examples include inhibitors, ceramine, serotonin blocking antibodies, thioprotein inhibitors, trimazole pyridimine, interferon, vascular endothelial growth factor (VEGF), rapamycin, FK506, and the like.

  This therapeutic agent is gradually released from the gel into the body, suppressing thrombus formation, preventing smooth muscle cell proliferation to prevent stenosis, inhibiting cancerous cell proliferation, endothelial cells It is effective in promoting the proliferation of the cells and obtaining endothelialization at an early stage.

  The concentration of the substance (A) in the aqueous solution is preferably about 0.1 to 50% by weight.

  The ratio of the above (A), hydrogen donor, and therapeutic agent in the aqueous solution is 0.01 to 150 parts by weight of the hydrogen donor and 150 parts by weight or less, for example, 0. It is preferable that it is 01-150 weight part.

  This aqueous solution is preferably applied to the stent body so as to have a thickness of about 10 μm to 500 μm, and then exposed to visible light through a mask to be photocrosslinked and insolubilized. This mask is made of a transmissive material, but is impermeable only at the positions where the micropores are to be drilled.

  Since the portion that overlaps with the non-permeable portion is not exposed, when the stent is brought into contact with water (for example, immersed) after exposure, it is dissolved and removed to form micropores.

  As a mask, a transparent resin film such as PMMA is provided with a light non-transmissive portion by screen printing a light shielding material such as silver paste or by depositing a metal such as aluminum using a negative pattern. Although it is suitable, it is not limited to this.

  In the present invention, it is preferable that the film-like mask is spread flat, the aqueous solution is cast thereon, the sheet-like mask is wound around the stent body, then exposed, and then the mask is peeled off.

  In this exposure, a columnar or cylindrical light absorber (for example, a black body) is preferably disposed in the stent body to prevent reflection of light and penetration in the diameter or chord direction.

  For example, as shown in FIG. 1, the stent manufactured in this way has a polymer layer 12 in close contact with the entire outer surface of the stent strut 11 constituting the mesh-shaped stent body. The outer peripheral surface A is a smooth surface by a film-like mask. With such a stent, since there is no exposed surface of the metal stent body, the problems of metal allergy, metal irritation, and rust generation are eliminated. Moreover, the generation of thrombus is prevented.

  Next, eosinized gelatin suitable for use in the present invention will be described.

  Here, the gelatin may be a normal gelatin having a molecular weight of 5,000 to 100,000 and an amino group of about 10 to 100 per molecule.

  Eosinized gelatin is prepared by introducing eosin into the side chain of gelatin according to the following reaction.

  The number of eosin introduced into the gelatin molecule can be calculated based on, for example, the absorbance of an aqueous solution of eosinized gelatin measured at the maximum absorption wavelength of eosin at 522 nm and the molar extinction coefficient of eosin (ε = 94755). The number is preferably 1 to 10, more preferably about 2 to 5, with respect to the molecule. If the number of compounds having a photosensitive group such as eosin is small, the gelation rate is lowered, and if it is more than necessary, the flexibility inherent to gelatin may be impaired, and it becomes hardly soluble in water. End up.

  This eosinized gelatin is a viscous liquid. When this is made into an aqueous solution having a concentration of 1 to 10% by weight, it can be cured in a gel state by irradiation with visible light of about 300 to 30,000 lx for about 0.1 to 30 minutes.

  The polymer layer on the outer peripheral surface side of the stent may be coated with a lubricious substance on the outer surface in order to make the movement in the fine blood vessels in the human body smooth. Such lubricating substances include low molecular weight hydrophilic substances such as glycerin, biocompatible substances such as hyaluronic acid and gelatin, synthetic hydrophilic polymers such as polyethylene glycol, polyacrylamide, polydimethylacrylamide, and polyvinylpyrrolidone. Can be mentioned.

  Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples.

Example 1
[Synthesis of eosinized gelatin]
In the presence of gelatin (molecular weight 95,000, amino group content approximately 37 / molecule) and water-soluble carbodiimide N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide (WSC), By attaching eosin to the amino group of the side chain, about 5 eosin was introduced per gelatin molecule to synthesize eosinized gelatin.

[Preparation of solution containing polymer modified with xanthene dye, hydrogen donor and therapeutic agent]
Synthesized eosinized gelatin at a final concentration of 10%, 1,1,4,7,10,10-hexamethyltriethylenetetramine as a hydrogen donor at a final concentration of 1.2% by weight, and heparin as a therapeutic agent at a final concentration of 5% %, And a solution containing a polymer compound modified with a xanthene dye, a hydrogen donor, and a therapeutic agent.

[Create mask]
A mask was prepared by printing a UV curable silver paste on a PMMA film having a thickness of 30 μm and fixing it by UV exposure. The diameter of the non-light-transmitting portion was 30 μm, and the arrangement was one per mesh opening of the mesh-shaped stent body.

[Stent body]
As the stent body, a mesh-shaped stent body 10 having a diameter of 2 mm, a length of 8 mm, and a thickness of 0.1 mm shown in FIG. 2 was employed. There are five mesh openings in the circumferential direction and five in the length direction (four and two half openings on one side correspond to a total of five openings).

  FIG. 3 is a side view of the metallic stent body 10 'after expansion. The metal stent body 10 'has a diameter of 3.5 mm, a length of 7.7 mm, and a thickness of 0.1 mm.

[Create stent]
The aqueous solution was cast on the film-like mask to a thickness of 100 μm to obtain a sheet. This sheet was wound around the outer periphery of the stent body with the aqueous solution directed toward the stent body. The stent body is attached to a black mandrel.

While rotating the mandrel, visible light was irradiated for 20 minutes with Tokso Power Light (product of Tokuyama, halogen lamp, wavelength 400 nm to 520 nm) to an irradiation intensity of 200 mW / cm ² to crosslink and insolubilize the aqueous solution. I let you.

  Subsequently, the mask was peeled off, the stent was removed from the mandrel, and washed with water to dissolve and remove the unexposed portion. As a result, fine holes were drilled in the polymer layer in the same arrangement pattern as the non-transparent portion of the mask. The average pore diameter of these fine holes was 25 μm.

It is typical sectional drawing which shows the covering state by the polymer layer of the stent of this invention. It is a perspective view of a stent main body. It is a perspective view of the stent main body expanded in diameter. It is a perspective view of a stent. It is a perspective view of the expanded stent. It is typical sectional drawing which shows the covering state by the polymer film of the stent of Unexamined-Japanese-Patent No. 11-299901. It is explanatory drawing which shows the pattern of the micropore of a polymer layer, and the relationship between the diameter and arrangement space | interval of a micropore, and a hole density. It is a graph which shows the relationship between the hole density of a polymer layer, and the thickening thickness of the vascular intima formed when stenting in a blood vessel.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Stent main body 11 Stent strut 12 Polymer layer 19 Polymer film 20 Stent

Claims (10)

In a method of manufacturing a stent having an expandable tubular stent body, and a flexible polymer layer covering the stent body, the polymer layer having a large number of micropores,
The stent is provided with a mask that is provided with a light non-transmission portion in the arrangement pattern of the micropores and the other is translucent, and a photosensitive material layer that overlaps the mask and is water-soluble and insolubilized by exposure. A process of attaching to the main body;
Irradiating the photosensitive material layer with light through the mask to insolubilize the exposed photosensitive material;
Removing the unexposed photosensitive material overlapping the non-transmissive portion to form micropores;
A method for manufacturing a stent, characterized by manufacturing the stent. The photosensitive material layer according to claim 1,
A compound of the following (A);
With hydrogen donors,
Comprising an aqueous solution containing
A method for producing a stent, wherein the exposure is performed with visible light.
(A) collagen, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, laminin, thrombospondin, vitronectin, osteonectin, entactin, gazein, polyethylene glycol, modified with xanthene dye Polypropylene glycol, polyglycidol, side chain esterified product of polyglycidol, polyvinyl alcohol, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide And at least one selected from the group consisting of polyvinylpyrrolidone.   2. The stent according to claim 1, wherein the hydrogen donor is a thiol, alcohol, reducing sugar, polyphenol or a compound having at least one N-alkyl and / or N, N-dialkylamino group in one molecule. Production method.   The method for producing a stent according to claim 2 or 3, wherein the xanthene dye is eosin.   The method for manufacturing a stent according to any one of claims 2 to 4, wherein (A) is gelatin.   6. The method for producing a stent according to claim 5, wherein the gelatin is one into which 1 to 10 xanthene dye molecules are introduced in one molecule.   7. The method for producing a stent according to claim 6, wherein the gelatin is one into which 2 to 6 xanthene dye molecules are introduced in one molecule.   The method for producing a stent according to any one of claims 2 to 7, wherein a therapeutic agent is contained in the aqueous solution.   9. The therapeutic agent according to claim 8, wherein the therapeutic agent is heparin, low molecular weight heparin, hirudin, argatroban, formacholine, bapiprost, prostamorin, prostaquilin homologue, dextran, lofepro-alguchloromethyl ketone, dipyridamole, glycoprotein platelet membrane Receptor antibody, recombinant hirudin, thrombin inhibitor, vascular peptin, vascular tensin converting enzyme inhibitor, steroid, fibroblast growth factor antagonist, fish oil, omega-3 fatty acid, histamine, antagonist, HMG-CoA reductase inhibition Agent, ceramine, serotonin blocking antibody, thioprotease inhibitor, trimazole pyridimine, interferon, vascular endothelial growth factor (VEGF), rapamycin, and FK506 Method of manufacturing a stent, characterized in that the at it.   A stent manufactured by the manufacturing method according to claim 1.

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