JP2005312584A - Stent, method for producing the same, and drug delivery method using the stent - Google Patents

Abstract

A stent capable of forming a coating layer containing a physiologically active substance on the surface of a stent main body by crosslinking with visible light and a method for producing the stent are provided.
A plurality of expandable tubular stent bodies 10 and a flexible polymer perforated with a plurality of micropores attached to both the inner and outer peripheral surfaces of the stent body 10 A stent 1 having a coating layer 2 formed on a film layer. This coating layer 2 coats a gel containing collagen or the like modified with a photosensitive group, a compound having an N-alkylamino group and / or an N, N-dialkylamino group, and a physiologically active substance, so that visible light is emitted. Irradiated and photocrosslinked.
[Selection] Figure 4

Description

  The present invention relates to a stent (intraluminal graft) widely used as a minimally invasive therapy. Specifically, the present invention relates to a drug-releasing stent capable of continuously administering a drug diffused from a coating layer covering the stent to an indwelling site and / or a downstream side of the indwelling site.

  A stent is an intraluminal graft that is carried through a lumen such as a blood vessel and supported by an action from the inside by expanding its diameter at the treatment site of the lumen, and is a primary percutaneous with a balloon catheter alone. It was developed to solve acute coronary occlusion and re-stenosis (so-called restenosis) at the site of PTCA, which was a problem of transluminal coronary angioplasty (PTCA). With the widespread use of stents, restenosis can be drastically prevented, but metal stent bodies are foreign bodies in the body, so thrombosis develops within a few weeks after insertion of the stent body. Or promotes thickening of the intima and causes restenosis. Therefore, as a second-generation technology that further improved the stent, a technology for reducing restenosis by providing a function to allow the stent base material to carry a physiologically active substance and locally release it has been actively studied. ing.

  JP-A-8-33718 and JP-A-2001-190687 disclose stents coated with a mixture of a physiologically active substance and a polymer.

  Japanese Patent Application Laid-Open No. 9-99056 discloses a technique in which a stent coated with a physiologically active substance is further coated with a polymer porous layer, and a drug is released from the pores of the polymer porous layer.

  Although not limited to stent coating technology, as a technology for imparting sustained drug release to the surface of a medical device, JP-A-5-123394 discloses a photoreactive azide derivative as an adhesive layer and a drug-containing gel thereon. A technique for insolubilizing a drug-containing gel on a substrate surface by coating and crosslinking with ultraviolet rays is disclosed.

While stents are mainly used for blood vessels such as the above-mentioned coronary arteries, they are also applied to other luminal parts of the human body such as bile ducts, ureters, and fallopian tubes. It is also being considered as a device for delivery of anticancer drugs for the purpose of treating other cancers.
JP-A-8-33718 JP 2001-190687 A JP-A-9-99056 JP-A-5-123394

  As described above, the drug-releasing stent is mixed and fixed to some carrier material. The support material not only functions as an excipient for diluting the drug, but also has low or no solubility in body fluids and needs to be fixed to the stent. Therefore, a polymer or a cross-linked gel that is hardly soluble in water is used as the support material, but an organic solvent is required to dissolve the hardly soluble polymer in water. Biologically-derived physiologically active substances may be denatured and deactivated by the action of organic solvents. The difference in solvent affinity between the two greatly regulates the function of the drug release stent.

  For example, in the method of spraying a polymer solution containing a drug disclosed in JP-A-8-33718, a physiologically active substance is not always stable with respect to an organic solvent that dissolves the polymer. There is a drawback that the polymers and physiologically active substances that can be used are limited. In addition, drug elution from a drug layer dispersed in a polymer layer that forms such a robust solid layer is inefficient in both the amount and rate of elution, and as a technology to suppress the restenosis and thrombus generation in the acute phase. May be a problem. Although the release of the drug is expected to be improved by making the polymer layer porous as in JP-A-9-99056, the drug cannot be protected from the polymer solvent. Japanese Patent Application Laid-Open No. 8-33718 also discloses a technique in which polylactic acid is used as a polymer and a bioactive substance is released by decomposing the polymer layer. However, since polylactic acid is decomposed, an acidic substance is generated, so that the bioactive substance is produced. May be deactivated.

  A technique for diffusing a drug in a cross-linked gel (insolubilized gel) is also known as a technique that does not decompose the carrier layer and has good drug release properties. For example, in the technique in which a water-affinity drug is dispersed in a water-affinity gel disclosed in JP-A-5-123394, the drug easily diffuses in the gel, and the drug is stably released from the coating layer. Can do. However, it is necessary to irradiate the gel with high-energy ultraviolet rays, and it is difficult to crosslink a cylindrical structure having an inner wall portion where ultraviolet rays cannot reach, such as a stent. There is also a technology to insert an ultra-thin lamp to irradiate the inner wall, but a high energy light source such as ultraviolet rays is also a heat source, and the heat generated from the light source denatures the physiologically active substance or the drug carrying layer itself It can be melted and is difficult to apply. This is particularly noticeable with stents that have become smaller in diameter.

  An object of the present invention is to provide a stent that can be formed by crosslinking a physiologically active substance-containing coating layer on the surface of a stent body with visible light, and a method for producing the stent.

The stent according to claim 1 is a stent in which a coating layer containing a physiologically active substance is formed on the peripheral surface of a tubular stent body, and the coating layer comprises a gel-like substance containing the following (A) and (B): The stent body is formed by photocrosslinking after coating the peripheral surface of the stent body.
(A) Collagen, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, laminin, thrombospondin, hydronectin, osteonectin, entactin, gazein, polyvinyl alcohol into which a photosensitive group has been introduced At least one selected from the group consisting of a copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, a copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide, and polyvinylpyrrolidone.
(B) A compound having at least one N-alkylamino group and / or N, N-dialkylamino group in one molecule.

  The stent according to claim 2 is the stent according to claim 1, wherein the compound having at least one N-alkylamino group and / or N, N-dialkylamino group in one molecule has an N, N-dialkylamino group. It is an acid derivative.

The stent according to claim 3 is a stent in which a coating layer containing a physiologically active substance is formed on the peripheral surface of a tubular stent body, and the coating layer contains a gel-like substance containing the following (C) and (D): The stent body is formed by photocrosslinking after coating the peripheral surface of the stent body.
(C) Collagen, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, into which at least one N-alkylamino group and / or N, N-dialkylamino group is introduced in one molecule Heparan sulfate, laminin, thrombospondin, hydronectin, osteonectin, entactin, casein, copolymer of polyvinyl alcohol hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, At least one selected from the group consisting of polydimethylacrylamide and polyvinylpyrrolidone.
(D) A compound having at least one photosensitive group in one molecule.

  The stent according to claim 4 is the stent according to any one of claims 1 to 3, wherein the compound having a photosensitive group is eosin, benzophenone, camphorquinone, olefin, benzalacetophenone, cinnamylideneacetyl, cinnamoyl, styrylpyridine, α-Phenylmaleimide, phenylazide, sulfonyl azide, carbonyl azide, o-quinonediazide, furylacryloyl, coumarin, pyrone, anthracene, benzoyl, stilbene, dithiocarbamate, xanthate, cyclopropene, 1,2,3-thiadiazole, aza-di It is at least one selected from the group consisting of oxabicyclo, alkyl halide, ketone and diazo.

The stent according to claim 5 is the stent according to any one of claims 1 to 4, wherein the light for photocrosslinking is light having an intensity of 1 to 1000 mW / cm ² and a wavelength of 300 to 700 nm. is there.

  A stent according to claim 6 is the stent according to any one of claims 1 to 5, wherein the physiologically active substance is heparin, low molecular weight heparin, hirudin, argatropane, formacholine, bapiprost, prostamorin, prostaquilin homologue, dextran, Rhofepro-Arugchloromethylketone, dipyridamole, glycoprotein platelet membrane receptor antibody, recombinant hirudin, thrombin inhibitor, vascular peptin, vascular tensin convertase inhibitor, steroid, fibroblast growth factor antagonist, fish oil , Omega З-fatty acid, histamine, antagonist, HMG-CoA reductase inhibitor, ceramine, serotonin blocking antibody, thioprotein inhibitor, trimazole pyridimine, interferon, rapamycin, FK506, blood serum Derived growth factor, epidermal growth factor, transforming growth factor α, insulin-like growth factor, insulin-like growth factor binding protein, hepatocyte growth factor, vascular endothelial growth factor, angiopoietin, nerve growth factor, brain-derived neurotrophic factor, Ciliary neurotrophic factor, transforming growth factor β, latent transforming growth factor β, activin, osteoplasmic protein, fibroblast growth factor, tumor growth factor β, diploid fibroblast growth factor, heparin binding Epidermal growth factor-like growth factor, schwanoma-derived growth factor, amphiregulin, betacellulin, epigrelin, lymphotoxin, erythroepoetin, tumor necrosis factor α, interleukin-1β, interleukin-6, interleukin-8, interleukin -17, interferon, antiviral agent, antibacterial agent, antibiotic, anticancer agent, antagonist , Receptor blockers, antiparkinsonian drugs, vitamin drugs, flavonoids, antiarrhythmic agents, insulin, calcitonin, radioactive substances, reduced glutathione, nitroglycerin, prostaglandins, polyphenols, erythropoietin, RNA, DNA, and RNA and / Or at least one selected from the group consisting of vectors into which DNA has been introduced.

  The stent according to claim 7 is the stent according to claim 6, wherein the vector is a virus.

  The stent according to claim 8 is the stent according to claim 6, wherein the vector is made of a polymer having a branched chain.

  The stent of claim 9 is the stent according to claim 8, wherein the branched chain has an N-alkylamino group and / or an N, N-dialkylamino group.

  The stent according to claim 10 is the stent according to claim 9, wherein (B) the compound having at least one N-alkylamino group and / or N, N-dialkylamino group in one molecule is the N-alkylamino group and It is a vector comprising a polymer having a branched chain having an N / N-dialkylamino group.

  The stent according to claim 11 is the stent according to any one of claims 1 to 10, wherein the coating layer is formed on the tubular stent body through a covering layer made of a flexible polymer layer. It is.

  A stent according to a twelfth aspect is the stent according to the eleventh aspect, wherein a plurality of micropores are formed in the polymer layer.

  A stent according to a thirteenth aspect is the stent according to the twelfth aspect, wherein the micropores are arranged at substantially uniform intervals.

  The method for manufacturing a stent according to claim 14 is a method for manufacturing the stent according to any one of claims 1 to 13, wherein the gel-like substance is applied to a peripheral surface of the stent body, and then visible light is applied. Is applied to form a coating layer by crosslinking the gel-like substance.

  A drug delivery method according to a fifteenth aspect is characterized in that the stent according to any one of the first to thirteenth aspects is placed in a blood vessel to release the physiologically active substance.

  The stent of the present invention and the method for producing the same are obtained by photocrosslinking a substance (A) such as collagen modified with a photosensitive group with visible light in the presence of a compound (B) having a specific substituent, or a specific substituent. A substance (C) such as collagen into which is introduced is photocrosslinked with visible light in the presence of a compound (D) having a photosensitive group to form a coating layer containing a physiologically active substance.

  In the stent provided by the present invention, since the coating layer made of a crosslinked gel formed on the surface of the stent body is crosslinked by visible light, the heat generated from the light source for visible light emission is for ultraviolet light emission. Significantly less than the light source. Therefore, even when the coating layer is formed on the inner peripheral surface of the small-diameter stent, the physiologically active substance is not denatured. Also, when the stent is a stent coated with a flexible polymer film, The coating layer can be formed without melting the polymer film.

  According to such a drug delivery method using the stent of the present invention, the physiologically active substance can be supplied into the living body in a good state.

  Hereinafter, embodiments will be described with reference to the drawings. 1 and 2 are explanatory views of the stent body, and FIGS. 3 and 4 are explanatory views of the stent. 3 and 4 are schematic diagrams, and particularly the thickness is shown to be significantly thicker than actual.

  As illustrated in FIGS. 3 and 4, the stent 1 according to this embodiment is such that the stent body 10 is coated on the inner and outer peripheral surfaces with the coating layer 2.

  The stent body 10 constituting the stent 1 of the present invention is a tube having a length of about 2 to 40 mm and a diameter of about 10 to 100% of the length. The stent body 10 is preferably in the form of a mesh so that the diameter can be expanded flexibly. In particular, the stent body 10 is preferably in the form of an oblique lattice as shown in FIG.

  The stent body 10 is preferably made of a biocompatible metal. Examples of the biocompatible metal include stainless steel, titanium, tantalum, aluminum, tungsten, nickel / titanium alloy, and the like. In addition to metals, high-strength polymer materials such as aromatic polyamide and polyimide can also be used.

  The coating layer 2 is a gel-like substance (generally an aqueous dispersion having a solid content concentration of 1 to 50% by weight) containing the substance (A) and the compound (B), or the substance (C) A gel-like substance (generally an aqueous dispersion having a solid content of 1% to 50% by weight) containing the substance and the compound (D) is applied to the stent body and then crosslinked by irradiation with visible light. It is a thing. This application method includes dipping and applying a doctor knife from the outer peripheral surface with a precisely controlled clearance while attaching the stent body to the mantle and rotating it in the circumferential direction, and flowing a gel substance on the inner wall of the stent body. A method of extending and inserting a mantle and rotating or moving it in the long axis direction, a method of inserting the stent body into a cylinder rotating in the circumferential direction, and casting uniformly using centrifugal force, etc. are suitable Can be used.

  Methods known to those skilled in the art can be used to synthesize the substance (A). For example, to modify gelatin with a photosensitive group, a method of modifying the amino group of the gelatin side chain via an amide bond condensed with a carboxyl group in the presence of carbodiimide, a Schiff base by condensation with an aldehyde, For example, a modification via an N-carboxy bond by Amadori transfer. However, the modification method with these photosensitive groups is not limited to the above examples.

  In addition, methods known to those skilled in the art can be used to synthesize the substance (C). For example, in order to introduce a dimethylamino group into gelatin, there is a method of allowing 4- (dimethylamino) butyric acid or 4- (dimethylamino) phenylacetic acid to act on gelatin in the presence of carbodiimide. However, the method for introducing the N-alkylamino group and / or the N, N-dialkylamino group is not limited to the above examples.

  The photosensitive group introduced into the substance (A) and the photosensitive group possessed by the compound (A) include eosin, benzophenone, camphorquinone, olefin, benzalacetophenone, cinnamylideneacetyl, cinnamoyl, styrylpyridine. , Α-phenylmaleimide, phenylazide, sulfonyl azide, carbonyl azide, o-quinonediazide, furylacryloyl, coumarin, pyrone, anthracene, benzoyl, stilbene, dithiocarbamate, xanthate, cyclopropene, 1,2,3-thiadiazole, aza- It is preferably at least one selected from the group consisting of dioxabicyclo, alkyl halide, ketone and diazo.

  The compound (B) is preferably an acrylic acid derivative having an N, N-dialkylamino group, and examples thereof include poly N, N-dimethylaminopropyl acrylamide and poly N, N-dimethyl acrylamide.

  Examples of the compound (D) include eosin, benzophene, camphorquinone, and cinnamic acid.

  The use ratio of the substance (A) to the compound (B) is preferably 0.001 to 50% by weight of the compound (B) with respect to the substance (A). If the amount of the substance (A) is greater than this range, crosslinking may be insufficient, and if it is less, the physical properties of the gel may not be exhibited.

  The use ratio of the substance (C) and the compound (D) may be 0.001% to 50% by weight of the compound (D) with respect to the substance (C). preferable. If the amount of the substance (C) is larger than this range, crosslinking is insufficient, if it is less, crosslinking may be insufficient, and if it is less, the physical properties of the gel may not be expressed.

  In the present invention, the coating layer formed on the stent body contains a physiologically active substance. Bioactive substances include heparin, low molecular weight heparin, hirudin, argatropane, formacholine, bapiprost, prostamorin, prostakyrin congeners, dextran, lofepro-algchloromethyl ketone, dipyridamole, glycoprotein platelet membrane receptor antibody, group Reversible hirudin, thrombin inhibitor, vascular peptin, vascular tensin converting enzyme inhibitor, steroid, fibroblast growth factor antagonist, fish oil, omega З-fatty acid, histamine, antagonist, HMG-CoA reductase inhibitor, ceramine, Serotonin blocking antibody, thioprotein inhibitor, trimazole pyridimine, interferon, rapamycin, FK506, platelet derived growth factor, epidermal growth factor, transforming growth factor α, insulin-like Growth factor, insulin-like growth factor binding protein, hepatocyte growth factor, vascular endothelial growth factor, angiopoietin, nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, transforming growth factor β, latent trait Conversion growth factor β, activin, osteoplasmic protein, fibroblast growth factor, tumor growth factor β, diploid fibroblast growth factor, heparin-binding epidermal growth factor-like growth factor, schwanoma-derived growth factor, amphiregulin, Betacellulin, epigrelin, lymphotoxin, erythroepoetin, tumor necrosis factor α, interleukin-1β, interleukin-6, interleukin-8, interleukin-17, interferon, antiviral agent, antibacterial agent, antibiotic Cancer agent, antagonist, receptor blocker, antiparkinsonian, vitamin, flavono Selected from the group consisting of id, antiarrhythmic agent, insulin, calcitonin, radioactive substance, reduced glutathione, nitroglycerin, prostaglandin, polyphenol, erythropoietin, RNA, DNA and RNA and / or DNA-introduced vector There is at least one kind.

  This physiologically active substance is preferably added to the gel material for forming the coating layer, and the amount added is the solubility of each physiologically active substance in body fluid, the number of doses (concentration showing medicinal effect), and the risk of side effects. The concentration varies depending on a certain concentration, the weight of the patient to be applied, drug sensitivity, and the like, and is appropriately set by those skilled in the art in consideration of the diffusibility of each physiologically active substance in the gel and the required sustained release period.

  The physiologically active substance used in the present invention may be a vector as described above. This vector may be a virus. Any virus such as an adenovirus, a retrovirus, or an RNA virus can be used as the virus, but may be appropriately selected by those skilled in the art in consideration of safety, the type and size of the gene to be introduced, and the like. Further, as another embodiment of this vector, a polymer may be used, and particularly, a vector having a branched chain may be used. In this vector, a plurality of branched chains are preferably bonded to a polyfunctional compound, preferably a benzene ring, naphthalene, anthracene or pyrene. In the case of a benzene ring, the number of bonds is 2 to 6, particularly 2, 3, 4 or 6, and the higher the number of bonds, the more effective. In the case of naphthalene, the number of bonds can be up to 8, and anthracene and pyrene can be up to 10.

  A benzene ring is preferable as a nucleus for bonding the branched chain, and specific examples are as follows. That is, for three-branched chains, 2,4,6-tris (N, N) obtained by addition reaction of 2,4,6-tris (bromomethyl) mesitylene and sodium N, N-diethyldithiocarbamate in ethanol. N-diethyldithiocarbamylmethyl) mesitylene, and obtained as a 4-branched chain by addition reaction of 1,2,4,5-tetrakis (bromomethyl) benzene and sodium N, N-diethyldithiocarbamate in ethanol. 1,2,4,5-tetrakis (N, N-diethyldithiocarbamylmethyl) benzene, and six-branched chains are hexakis (bromomethyl) benzene and sodium N, N-diethyldithiocarbamate in ethanol. Hexakis (N, N-diethyldithiocarbamylmethyl) benzone obtained by addition reaction It is down.

As the branched chain, a vinyl monomer alone or a copolymer is preferable, and specifically, a polymer of 3-N, N-dimethylaminopropylacrylamide CH ₂ ═CHCONHC ₃ H ₆ N (CH ₃ ) ₂ is used. preferable.

By mixing this 3-N, N-dimethylaminopropylacrylamide and each of the above benzene derivatives as an alcohol solution such as methanol or a solution of a low-polarity solvent such as chloroform in consideration of solubility, a photopolymerization reaction is performed. A cationic polymer in which the polymer of the vinyl monomer is bonded to the benzene ring via —CH ₂ — derived from the benzene derivative is generated. The molecular weight of the vector comprising this polymer is preferably from 5,000 to 500,000, particularly from 5,000 to 50,000, especially from 10,000 to 20,000.

  The vector composed of the cationic polymer thus generated surrounds the nucleic acid as a nucleic acid-containing complex, thereby suppressing the inactivation and degradation of the nucleic acid by the enzyme in the living body. The nucleic acids include herpes simplex virus thymidine kinase gene (HSV1-TK gene), p53 tumor suppressor gene, BRCA1 tumor suppressor gene, TNF-α gene, IL-2 gene, IL-4 gene, HLA-B7 / IL- 2 genes, HLA-B7 / B2M gene, IL-7 gene, GM-CSF gene, IFN-γ gene, IL-12 gene, gp-100, MART-1 and MAGE-1, VEGF gene, HGF gene, FGF gene , C-myc antisense, c-myb antisense, cdc2 kinase antisense, PCNA antisense, E2F decoy and p21 (sdi-1) gene, but are not limited thereto.

This polymer may be an N-alkylamino group and / or N, N-dialkyl, such as a polymer of 3-N, N-dimethylaminopropylacrylamide CH ₂ = CHCONHC ₃ H ₆ N (CH ₃ ) ₂ as a branched chain. In the case of having an amino group, this polymer may be used as the compound (B).

In the present invention, the gel substance containing the substance (A) and the compound (B) or the gel substance containing the substance (C) and the compound (D) is applied to the peripheral surface of the stent body. The light for photocrosslinking is preferably visible light having an intensity of 1 to 1000 mW / cm ² and a wavelength of 300 to 700 nm. If the strength is larger than this range, the physiologically active substance in the coating layer may be deactivated or the flexible polymer layer may be melted. If the strength is smaller, crosslinking of the coating layer may be insufficient. If the wavelength is longer than this range, the coating layer may be insufficiently crosslinked, and if the wavelength is shorter, the physiologically active substance in the coating layer may be deactivated or the flexible polymer layer may be melted. In addition, although irradiation time changes also with the thickness of the coating layer to form, the kind of contained substance, and the intensity | strength and wavelength of the light to be used, it is about 1 second-300 second normally.

  In addition, the stent body used in the present invention can cover and cover the entire outer surface of the stent body with a flexible polymer layer before forming the coating layer.

  As a material used as a flexible polymer layer, a high-flexibility polymer elastomer is suitable, for example, polystyrene, polyolefin, polyester, polyamide, silicone, urethane, fluororesin, natural rubber, etc. Various elastomers and their copolymers or their polymer alloys can be used. Among them, segmented polyurethane, polyolefin-based elastomer, and silicone-based polymer are preferable. Particularly, segmented polyurethane having high flexibility and high strength is optimal.

  The flexible polymer layer is provided with a plurality 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 20 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.

  If the arrangement density of the micropores is too high, the strength of the polymer film is lowered and the intimal tissue penetrates too much. If the density is too low, the endothelial cells do not sufficiently grow inside the stent. Accordingly, the micropores are arranged on a plurality of straight lines at intervals of 50 to 500 μm, preferably 100 to 300 μm. 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.

  In addition, it is preferable that the thickness of a polymer film shall be about 10-300 micrometers.

  The micropores are preferably provided by forming a polymer layer on both the inner and outer peripheral surfaces of the stent body and then drilling with a laser or the like.

  The stent of the present invention can be used as a drug delivery technique, whereas conventional stents are exclusively used for expansion of a stenosis site or occlusion of an aneurysm. In particular, in the conventional technique, in a small-diameter blood vessel for which stable drug delivery is difficult for a long time, the physiologically active substance is gradually released not only to the indwelling site but also to the downstream side of the indwelling vessel by indwelling in the blood vessel. be able to. According to the present invention, unlike the conventional method in which a bioactive substance impregnated in a biodegradable resin or the like is sustainedly released, the bioactive substance is deactivated by a decomposition product of the biodegradable resin. And stable drug delivery over a long period of time.

Example 1 (Preparation of a flexible polymer-coated stent)
As the stent body, a mesh-shaped stent body 10 having a diameter of 2 mm, a length of 7 mm, and a thickness of 0.1 mm shown in FIG. 1 was employed.

  FIG. 2 is a side view of the metallic stent body 10 'after expansion. The metal stent body 10 'has a diameter of 5 mm, a length of 7 mm, and a thickness of 0.1 mm.

  A segmented polyurethane polymer film 19 was applied as follows so as to be in close contact with the entire outer surface of the metal stent body 10. A polymer solution was prepared by dissolving polyurethane pellets (Milactolan E980, manufactured by Nippon Milactone Co., Ltd.) in tetrahydrofuran (Kanto Chemical Co., Ltd., special grade reagent) to a concentration of 10% by weight. A mandrill made of SUS440 having a diameter of 1.98 mm was slowly dipped here and then vertically pulled out and dried to form a segmented polyurethane polymer film having a thickness of 50 μm. After attaching a slightly expanded metal stent body here, it is strongly caulked and then immersed in a polymer solution vertically, extracted vertically, and dried to cover the entire outer surface of the stent body. It was.

  In the formed polyurethane polymer layer, holes having a diameter of 50 μm were formed substantially uniformly at intervals of 125 μm by an excimer laser. After drilling a row of holes in the long axis direction, the stent body was rotated 15 ° in the circumferential direction to drill 24 rows of holes on the entire circumference. This was removed from the SUS440 mantle after 1 hour in ethanol.

Example 2 (Synthesis of eosin-modified gelatin)
0.40 g (5.8 × 10 ⁻⁴ mol) of eosin (Sodium Tetrabromofluorescein) was dissolved in 40 mL of water. 0.56 g (2.9 × 10 ⁻³ mol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was dissolved in 200 mL of water. These were mixed at 0 ° C. and the pH was adjusted to 2 with 1N HCl. A solution prepared by dissolving gelatin (5.0 g, amino group content 1.9 × 10 ⁻³ mol) in 60 mL of water was mixed at room temperature, and the pH was adjusted to 9 with 1N NaOH. The total volume was adjusted to 1000 mL, then placed in a dialysis tube and dialyzed against water for 3 days. After completion of dialysis, lyophilization was performed to obtain eosin-modified gelatin. The amount of eosin introduced into gelatin was calculated to be 14% based on the molar extinction coefficient ε (94755) at λmax (522 nm) of eosin.

Example 3 (Synthesis of dimethylamino group-introduced gelatin)
3.0 g gelatin (molecular weight 95,000, amino group content 1.2 × 10 ⁻³ mol), 0.1 g 4- (dimethylamino) phenylacetic acid and 0.1 g 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Was added to 40 mL of water to form an aqueous solution, and the mixture was stirred at room temperature for 72 hours. The reaction solution was put into a dialysis tube and dialyzed against water for 3 days to remove unreacted substances. By lyophilization, white cotton-like dimethylamino group-introduced gelatin was obtained. The absorbance at 245 nm was measured with a spectrophotometer, and the introduction rate of dimethylamino groups was calculated to be 2.5%.

Example 4 (Preparation of the stent of the present invention)
Eosin-modified gelatin synthesized in Example 2 5%, 1, 1, 4, 7, 10, 10-hexamethyltriethylenetetramine and LacZ expression adenovirus vector (Ad-LacZ) were mixed in water to prepare a coating solution. did. Eosin-modified gelatin has a final concentration of 5%, 1,1,4,7,10,10-hexamethyltriethylenetetramine has a final concentration of 0.1%, and Ad-LacZ has an active concentration adjusted to a titer (activity value) of 109pfu. (Plapue formation units) / mL. The stent prepared in Example 1 was allowed to stand horizontally, and an equivalent amount of 20 μL of the coating solution was dropped per 1 cm ^{2 of the} inner wall of the stent, and uniformly spread with a PTFE round bar to form a coating layer. Using Tokso Power Light (Tokuyama Co., Ltd., halogen lamp, 400 nm to 520 nm) as a light source, 200 mW / cm ² (illuminance 7700 Lux) light is irradiated for 60 seconds to solidify the coating layer to form a 100 μm thick coating layer Thereafter, the unreacted material was removed by washing with deionized water to obtain the stent of the present invention.

  When observed with a confocal laser microscope (manufactured by Keyence Corporation, VK-8510), the film surface was not melted and a coating layer was formed while maintaining smoothness (FIG. 5), and the polymer film was thermally loaded. It was confirmed that the coating layer could be insolubilized by irradiation with visible light that did not give any.

  A similar coating layer was also obtained when the coating solution prepared by mixing dimethylamino group-introduced gelatin synthesized in Example 3, eosin, and LacZ-expressing adenovirus vector (ad-LacZ) was used.

Example 5 (Drug delivery by stent of the present invention)
The stent of the present invention prepared in Example 4 was mounted on a balloon catheter, inserted from the groin and thigh according to a standard method, and expanded and placed in the carotid artery. After 1 week and 4 weeks, the sputum was sacrificed, the vascular tissue at the site of stent placement was removed, and a tissue specimen was prepared by a conventional method. Staining was made by staining with x-gal using 5-bromo-4-chloro-indolyl-β-galactosidase, and the expression level of β-galactosidase in the tissue was observed. The body was also dyed almost uniformly in dark blue, and it was confirmed that Ad-LacZ was infected to cells in the vascular tissue and sustained gene expression occurred over 4 weeks (FIGS. 6A and 6B). )).

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 typical perspective view of the stent which concerns on embodiment. It is the IV-IV sectional view taken on the line of FIG. It is a confocal laser scanning microscope image of the coating layer formed on the polymer film layer. It is a photograph which shows that Ad-LacZ was delivered to the vascular tissue which indwelled the stent of this invention.

Explanation of symbols

1 Stent 2 Coating layer 10 Stent body

Claims (15)

In a stent formed by forming a coating layer containing a physiologically active substance on the peripheral surface of a tubular stent body, the coating layer contains a gel-like substance containing the following (A) and (B) as a peripheral surface of the stent body. A stent formed by photocrosslinking after application.
(A) Collagen, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, laminin, thrombospondin, hydronectin, osteonectin, entactin, gazein, polyvinyl alcohol into which a photosensitive group has been introduced At least one selected from the group consisting of a copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, a copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide, and polyvinylpyrrolidone.
(B) A compound having at least one N-alkylamino group and / or N, N-dialkylamino group in one molecule.   2. The compound according to claim 1, wherein the compound having at least one N-alkylamino group and / or N, N-dialkylamino group in one molecule is an acrylic acid derivative having an N, N-dialkylamino group. And stent. In a stent formed by forming a coating layer containing a physiologically active substance on the peripheral surface of a tubular stent body, the coating layer contains a gel-like substance containing the following (C) and (D) as a peripheral surface of the stent body. A stent formed by photocrosslinking after application.
(C) Collagen, fibronectin, gelatin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, into which at least one N-alkylamino group and / or N, N-dialkylamino group is introduced in one molecule Heparan sulfate, laminin, thrombospondin, hydronectin, osteonectin, entactin, casein, copolymer of polyvinyl alcohol hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, At least one selected from the group consisting of polydimethylacrylamide and polyvinylpyrrolidone.
(D) A compound having at least one photosensitive group in one molecule.   The compound having a photosensitive group according to any one of claims 1 to 3, wherein eosin, benzophenone, camphorquinone, olefin, benzalacetophenone, cinnamylideneacetyl, cinnamoyl, styrylpyridine, α-phenylmaleimide, phenylazide , Sulfonyl azide, carbonyl azide, o-quinonediazide, furylacryloyl, coumarin, pyrone, anthracene, benzoyl, stilbene, dithiocarbamate, xanthate, cyclopropene, 1,2,3-thiadiazole, aza-dioxabicyclo, alkyl halide, A stent characterized by being at least one selected from the group consisting of ketones and diazos. The stent according to any one of claims 1 to 4, wherein the light for photocrosslinking is light having an intensity of 1 to 1000 mW / cm ² and a wavelength of 300 to 700 nm.   6. The physiologically active substance according to claim 1, wherein the physiologically active substance is heparin, low molecular weight heparin, hirudin, argatropane, formacholine, bapiprost, prostamorin, prostachyline homologue, dextran, lofepro-algchloromethylketone. , Dipyridamole, platelet protein receptor antibody of glycoprotein, recombinant hirudin, thrombin inhibitor, vascular peptin, vascular tensin converting enzyme inhibitor, steroid, fibroblast growth factor antagonist, fish oil, omega З-fatty acid, histamine , Antagonist, HMG-CoA reductase inhibitor, ceramine, serotonin blocking antibody, thioprotease inhibitor, trimazole pyridimine, interferon, rapamycin, FK506, platelet-derived growth factor, epithelial increase Factor, transforming growth factor alpha, insulin-like growth factor, insulin-like growth factor binding protein, hepatocyte growth factor, vascular endothelial growth factor, angiopoietin, nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor , Transforming growth factor β, latent transforming growth factor β, activin, osteoplasmic protein, fibroblast growth factor, tumor growth factor β, diploid fibroblast growth factor, heparin-binding epidermal growth factor-like growth factor , Schwanoma-derived growth factor, amphiregulin, betacellulin, epigrelin, lymphotoxin, erythroepoetin, tumor necrosis factor α, interleukin-1β, interleukin-6, interleukin-8, interleukin-17, interferon, anti Virus agent, antibacterial agent, antibiotic, anticancer agent, antagonist, receptor blocker, anti Parkinson's disease drug, vitamin drug, flavonoid, antiarrhythmic agent, insulin, calcitonin, radioactive substance, reduced glutathione, nitroglycerin, prostaglandin, polyphenol, erythropoietin, RNA, DNA, and RNA and / or DNA introduced A stent comprising at least one selected from the group consisting of vectors.   The stent according to claim 6, wherein the vector is a virus.   The stent according to claim 6, wherein the vector is made of a polymer having a branched chain.   The stent according to claim 8, wherein the branched chain has an N-alkylamino group and / or an N, N-dialkylamino group.   The compound according to claim 9, wherein (B) at least one N-alkylamino group and / or N, N-dialkylamino group in one molecule is the N-alkylamino group and / or N, N-dialkyl. A stent comprising a polymer having a branched chain having an amino group.   The stent according to any one of claims 1 to 10, wherein the coating layer is formed on the tubular stent body through a coating layer made of a flexible polymer layer.   The stent according to claim 11, wherein a plurality of micropores are formed in the polymer layer.   The stent according to claim 12, wherein the micropores are arranged at substantially uniform intervals.   The method for manufacturing the stent according to any one of claims 1 to 13, wherein the gel-like substance is applied to a peripheral surface of the stent body, and then the gel-like substance is crosslinked by irradiating visible light. And forming the coating layer.   A drug delivery method comprising placing the stent according to any one of claims 1 to 13 into a blood vessel and releasing the physiologically active substance.

Images