JP2005168937A - Stent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To prevent a vascular smooth muscle cell from adhering by using a metal sheet surface when a biological physiologically active substance is released when needed and when a stent main body having the metal sheet surface is exposed caused by the degradation of a biodegradable polymer in a living body. <P>SOLUTION: A stent 1 has the stent body 2, a metal sheet layer 3 formed on the surface of the stent body 2, the biological physiologically active substance layer 4, and a biodegradable polymer film layer 5 entirely covering it or a biological physiologically active substance 7 dispersed in a biodegradable polymer film layer 6. After the stent 1 is detained in the lesion in the living body, the biological physiologically active substance is released caused by the degradation of the biodegradable polymer film layer, and the biodegradable polymer is completely degraded thereafter. The stent 1 detained in the lesion is characterized by preventing the vascular smooth muscle cell from adhering through the influence of the exposed metal sheet surface. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a stent used to improve a stenosis or occlusion occurring in a lumen in a living body such as a blood vessel, a bile duct, a trachea, an esophagus, or a urethra.

  As an example, angioplasty applied to ischemic heart disease will be described.

  In response to the rapid increase in the number of patients with ischemic heart disease (angina pectoris, myocardial infarction) as the Westernization of dietary habits in Japan, percutaneous transvascularization is a method for reducing these coronary artery lesions. Coronary angioplasty (PTCA) has been performed and has become widespread. At present, the number of applied cases has increased due to technological development. From the one that was localized (the length of the lesion was short) and one-branch lesion (the lesion that had stenosis only in one site) at the time when PTCA started, The application of PTCA has been extended to those that are more eccentric and calcified in the more distal parts, and multi-branch lesions (lesions with stenosis in more than one site). PTCA is a long, hollow hollow tube called a guide catheter with a small incision in the artery of the patient's leg or arm and placement of an introducer sheath (leader) through the lumen of the introducer sheath, with the guide wire leading. After inserting the tube into the blood vessel and placing it at the entrance of the coronary artery, withdraw the guide wire, insert another guide wire and balloon catheter into the lumen of the guide catheter, and X-ray contrast the balloon catheter with the guide wire leading The procedure is to advance to the lesioned part of the patient's coronary artery and place the balloon in the lesioned part, where the doctor inflates the balloon at a predetermined pressure for 30 to 60 seconds once or a plurality of times. This dilates the vascular lumen of the lesion, thereby increasing blood flow through the vascular lumen. However, when the blood vessel wall is injured by the catheter, the intima proliferation, which is a healing reaction of the blood vessel wall, occurs, and restenosis has been reported at a rate of about 30 to 40%.

  A method for preventing restenosis has not been established so far, but methods using a device such as a stent or an atherectomy catheter have been studied and some results have been achieved. A stent as used herein refers to a variety of diseases caused by stenosis or occlusion of blood vessels or other lumens. In order to treat various diseases, the stenosis or occlusion site is expanded and placed there to secure the lumen. A tubular medical device that can be used. Many of them are medical devices made of metal materials or polymer materials. For example, tubular materials made of metal materials or polymer materials with pores, metal wires or polymer material fibers are knitted. Various shapes such as those formed into a cylindrical shape have been proposed. The purpose of stent placement is to prevent and reduce restenosis that occurs after procedures such as PTCA, but so far, the stent alone has not been able to significantly suppress stenosis. This is the actual situation.

  In recent years, the biological physiologically active substance such as an anticancer agent is supported on this stent, and this biologically physiologically active substance is locally released for a long time at the indwelling site of the lumen, thereby reducing the restenosis rate. Many attempts have been made to achieve this. For example, Patent Document 1 is a stent in which a surface of a stent body is coated with a mixture of a therapeutic substance and a biodegradable polymer, and the therapeutic substance is released by the degradation of the biodegradable polymer. However, in Patent Document 2, a drug layer is provided on the surface of the stent body, and a biodegradable polymer layer is further provided on the surface of the drug layer. Each of the stents from which a drug is released has been proposed.

  However, in all of the stents proposed in these patent documents, after the biodegradable polymer is decomposed in vivo, the stent is placed in the body semi-permanently, and the intravascular due to proliferation of vascular smooth muscle cells and the like. There is a problem that membrane thickening may occur. This is not limited to the stents proposed in these patent documents, but is a problem in all stents using a metal material such as stainless steel.

On the other hand, metals such as titanium and platinum are said to have high biocompatibility. Among them, metal titanium has particularly high biocompatibility. This is considered to be because a very thin titanium oxide film having a high surface activity and formed by being naturally oxidized in the atmosphere is formed on the surface. In general, there is a method of measuring the contact angle with water as a method for easily knowing the surface activity. There is a close relationship between the contact angle and the surface activity, and the adhesion of vascular smooth muscle cells is less likely to occur due to the titanium oxide film or the metal film having the same surface activity.
JP-A-8-33718 JP-A-9-56807

  Accordingly, an object of the present invention is to release a biological physiologically active substance at a required time, and further, the biodegradable polymer is decomposed in vivo to expose a stent body having a metal thin film surface in vivo. The present invention provides a stent characterized in that the metal thin film layer suppresses adhesion of vascular smooth muscle cells.

  Such an object is achieved by the present inventions (1) to (6) below.

  (1) A stent for placement in a lumen in a living body, wherein the stent is formed on a stent body having a strength capable of withstanding an expansion operation when placed in a lumen, and a surface of the stent body. A biological thin film layer capable of suppressing adhesion of vascular smooth muscle cells, and a biological biologically active substance release comprising a biological biologically active substance and a biodegradable polymer formed on the metallic thin film layer A stent having a layer.

  (2) The stent according to (1), wherein the stent body is made of a metal material.

  (3) The stent according to (1) or (2), wherein the metal thin film layer is composed of a thin film composed of at least one metal element.

  (4) The biological physiologically active substance releasing layer is a mixture of a biologically physiologically active substance layer and a biodegradable polymer film layer completely covering the biological physiologically active substance layer or a biological physiologically active substance and a biodegradable polymer. The stent according to any one of (1) to (3), wherein the stent is a layer formed.

  (5) 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 Agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, vascular smooth muscle growth inhibitors, anti-inflammatory agents, bio-derived materials, interferons And the stent according to any one of (1) to (4) above, wherein the stent is at least one selected from the group consisting of NO production promoting substances.

  (6) The biodegradable polymer is at least one selected from the group consisting of polylactic acid, polyglycolic acid, a copolymer of lactic acid and glycolic acid, and polycaprolactone. The stent according to any one of 1) to (5).

  The stent of the present invention is a stent for placement in a lumen in a living body, and the stent has a strength sufficient to withstand an expansion operation when placed in a lumen, and a surface of the stent body. Biological physiology comprising a metal thin film layer capable of suppressing adhesion of vascular smooth muscle cells formed on the surface, a biological physiologically active substance and a biodegradable polymer formed on the metal thin film layer Since it has an active substance release layer, it releases biological and biologically active substances when needed, and the biodegradable polymer is decomposed in vivo to have a metal thin film surface. When the stent body is exposed in vivo, the surface of the metal thin film suppresses the proliferation of vascular smooth muscle cells.

  When the stent body is made of a metal material, the metal material is excellent in strength, so that the stent can be surely placed in the lesion.

  Hereinafter, the stent of the present invention will be described in detail based on preferred embodiments shown in the accompanying drawings.

  1 is a front view showing an embodiment of the stent of the present invention, FIGS. 2 and 4 are enlarged cross-sectional views taken along line AA of FIG. 1, and FIGS. 3 and 5 are lines B of FIG. It is the partial expansion longitudinal cross-sectional view cut | disconnected along -B.

  The stent 1 of the present invention shown in FIG. 2 to FIG. 5 completely covers the stent body 2, the metal thin film layer 3 provided on the surface of the stent body 2, the biological physiologically active substance layer 4. It has a biodegradable polymer membrane layer 5 or a biological and physiologically active substance 7 dispersed in the biodegradable polymer membrane layer 6. After the stent 1 is placed in a lesioned part in a living body, the biodegradable polymer film layer is decomposed to release a biological physiologically active substance, and then the biodegradable polymer is completely dissipated in the living body. The stent 1 that is decomposed and placed in the lesioned part suppresses adhesion of vascular smooth muscle cells due to the effect of the exposed metal thin film surface.

  First, each component which comprises the stent 1 is demonstrated in detail.

  The stent body 2 can be placed in a lesioned part in a living body lumen such as a blood vessel, a bile duct, a trachea, an esophagus, or a urethra, and has sufficient strength to withstand an expansion operation when placed in the lumen. If it does, the material, shape, size, etc. will not be specifically limited. As the indwelling means, the balloon expanding means as described above can be used. However, if the stent body 2 is an elastic body, a self-expanding means using this elastic force can be used.

  The material for forming the stent body 2 having the strength that can withstand the expansion operation when placed in the lumen may be appropriately selected according to the application location, and examples thereof include metal materials and ceramics. When the stent body 2 is formed of a metal material, the metal material is excellent in strength, so that the stent 1 can be reliably placed in the lesioned part.

  Examples of the metal material include stainless steel, Ni—Ti alloy, tantalum, nickel, chromium, iridium, tungsten, cobalt-based alloy, and the like. And among stainless steel, SUS316L with the best corrosion resistance is suitable.

  Many of the stent bodies 2 formed of a metal material can be expanded using a balloon. Further, a stent body 2 made of a metal material called pseudoelasticity, such as a metal material such as a Ni-Ti alloy whose stress is constant and greatly changes in strain, or a metal material whose strain increases gradually and changes as the stress increases. Since the self-expanding is possible, the stent body 2 compressed and held in advance is expanded by the elastic force by releasing the compression at the lesioned part.

  The shape of the stent body 2 is not particularly limited as long as it has sufficient strength to be stably placed in a lumen in a living body. For example, a metal material wire or a polymer material fiber knitted into a cylindrical shape, or a tubular body made of a metal material or ceramics with pores is preferably mentioned.

  The stent body 2 may be either a balloon expansion type or a self-expansion type. In addition, 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 0.5 to 10.0 mm, preferably 1.0 to 3.0 mm, and the length is 1 to 100 mm, preferably 5 to 50 mm. .

  The surface of the stent body 2 is covered with a metal thin film layer 3.

  A method for covering the surface of the stent body 2 with the metal thin film layer 3 is not particularly limited. For example, a method of depositing, injecting, or plating metal ions on the stent body 2 can be mentioned.

  The element forming the metal thin film layer 3 is not particularly limited as long as it can suppress adhesion of vascular smooth muscle cells, but is preferably highly biostable, for example, titanium, chromium, nickel, palladium, silver Tantalum, niobium, zirconium, molybdenum, platinum, gold, or a mixture thereof. More preferred are platinum and titanium, and most preferred is titanium, but should be appropriately selected according to the required biocompatibility or desired cell adhesion ability.

  Since the thickness of the metal thin film layer 3 should be set to such an extent that the performance of the stent main body 2 is not significantly impaired, such as delivery to a lesioned part and irritation to a blood vessel wall, preferably 0.0001 to 75 μm. More preferably, it is in the range of 0.001 to 25 μm, most preferably 0.01 to 5 μm.

  When the metal thin film layer 3 is less than 0.00001 μm, there is a concern that the function as a blood vessel smooth cell adhesion suppressing film covering the stent body 2 cannot be performed. Moreover, when the metal thin film layer 3 exceeds 75 μm, the outer diameter of the stent 1 itself becomes too large, and it is easily expected that the delivery to the lesioned part will be hindered.

  On the surface of the metal thin film layer 3, the biological physiologically active substance layer 4 and the biodegradable polymer film layer 5 or the biodegradable polymer film layer 6 completely covering the biological physiologically active substance layer 4 are disposed. A dispersed layer is provided.

  A method for providing the biological physiologically active substance layer 4 on the surface of the metal thin film layer 3 is not particularly limited. For example, a method of melting the biological physiologically active substance and coating the surface of the metal thin film layer 3; A solution is prepared by dissolving a biological physiologically active substance in a solvent, the metal thin film layer 3 is immersed in the solution, and then lifted to remove the solvent by evaporation or other methods, or by using a spray. Examples thereof include a method of spraying the solution onto the metal thin film layer 3 and removing the solvent by evaporation or other methods.

  The thickness of the biological physiologically active substance layer 3 is such that it does not significantly impair the performance of the stent body 2 such as reachability to the lesioned portion (delivery property) and irritation to the blood vessel wall, and biological biological activity. Since the thickness should be set so that the effect of the substance is confirmed, the thickness is preferably 1 to 100 μm, more preferably 1 to 50 μm, and most preferably 1 to 10 μm.

  The biological physiologically active substance forming the biological physiologically active substance layer 3 is not particularly limited as long as it has an effect of suppressing restenosis when the stent 1 is placed in a lesioned part of a lumen. Anticancer agent, immunosuppressant, antibiotic, antirheumatic agent, antithrombotic agent, antihyperlipidemic agent, ACE inhibitor, calcium antagonist, integrin inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid, Examples include flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, vascular smooth muscle growth inhibitors, anti-inflammatory agents, biological materials, interferons, and NO production promoters.

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

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

  As the antibiotic, for example, mitomycin C, doxorubicin hydrochloride, actinomycin D, daunorubicin hydrochloride, idarubicin hydrochloride, pirarubicin hydrochloride, aclarubicin hydrochloride, epirubicin hydrochloride, pepromycin hydrochloride, dinostatin styramer and the like are preferable.

  As the antirheumatic agent, for example, sodium gold thiomalate, penicillamine, lobenzarit sodium, and the like are preferable.

  As the antithrombotic agent, for example, heparin, ticlopidine hydrochloride, hirudin and the like are preferable.

  As the antihyperlipidemic agent, an HMG-CoA reductase inhibitor and probucol are preferable. And as a HMG-CoA reductase inhibitor, cerivastatin sodium, atorvastatin, nisvastatin, pitavastatin, fluvastatin sodium, simvastatin, lovastatin, pravastatin sodium etc. are preferable, for example.

  As the ACE inhibitor, for example, quinapril hydrochloride, perindopril erbumine, trandolapril cilazapril, temocapril hydrochloride, delapril hydrochloride, enalapril maleate, lisinopril, captopril and the like are preferable.

  As the calcium antagonist, for example, hifedipine, nilvadipine, diltiazem hydrochloride, benidipine hydrochloride, nisoldipine and the like are preferable.

  As the antiallergic agent, for example, tranilast is preferable.

  As the retinoid, for example, all-trans retinoic acid is preferable.

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

  As the tyrosine kinase inhibitor, for example, genistein, tyrphostin, arbustatin and the like are preferable.

  As the anti-inflammatory agent, for example, steroids such as dexamethasone and prednisolone and aspirin are preferable.

  Examples of the biological material include EGF (epidemal growth factor), VEGF (basic endowment growth factor), HGF (hepatocyte growth factor), PDGF (platelet growth factor), PDGF (platelet growth factor).

  The biological physiologically active substance forming the biologically physiologically active substance layer 4 preferably contains at least one of the above substances in consideration of reliably suppressing restenosis. Whether the biological physiologically active substance forming the biological physiologically active substance layer 4 is a single kind of biological physiologically active substance or whether two or more different biological physiologically active substances are combined Should be appropriately selected according to the case.

  A biodegradable polymer film layer 5 made of at least one biodegradable polymer is provided on the surface of the biological physiologically active substance layer 4.

  The method for providing the biodegradable polymer film layer 5 on the surface of the biological physiologically active substance layer 4 is not particularly limited. For example, the biodegradable polymer is melted to form the biological physiologically active substance layer 4. A method of coating the surface, a biodegradable polymer is dissolved in a solvent to prepare a solution, the biological physiologically active substance layer 4 is immersed in this solution, and then lifted to evaporate the solvent or otherwise. Examples thereof include a method of removing, or a method of spraying the solution onto the biological physiologically active substance layer 4 using a spray to remove the solvent by evaporation or other methods.

  The biodegradable biopolymer that forms the biodegradable polymer film layer 5 is not particularly limited, but is preferably one having high biostability and a relatively high rate of biodegradation, such as polylactic acid, polyglycolic acid, polyhydroxy Examples include butyric acid, polycaprolactone, collagen, gelatin, cellulose, chitin, chitosan, hyaluronic acid, and a covalently bonded polymer or a mixed polymer in which two or more of these are combined. More preferred are polylactic acid and polyglycolic acid, but they should be appropriately selected according to the required mechanical properties or the desired release rate or biodegradation rate of the biological physiologically active substance.

  The thickness of the biodegradable polymer film layer 5 is set to a level that does not significantly impair the performance of the stent body 2 such as delivery to the lesioned part and irritation to the blood vessel wall, as with the biological physiologically active substance layer 4. Therefore, it is preferably in the range of 1 to 75 μm, more preferably 1 to 25 μm, and most preferably 1 to 10 μm.

  When the biodegradable polymer film layer 5 is less than 1 μm, there is a concern that the biodegradable polymer film layer 5 cannot function as a coating film that completely covers the biological physiologically active substance layer 4. In addition, when the biodegradable polymer film layer 5 exceeds 75 μm, the outer diameter of the stent 1 itself becomes too large, and it is easily expected that the delivery to the lesioned part will be hindered.

  Further, on the surface of the metal thin film layer 3, a layer in which a biological bioactive substance 7 is dispersed in a biodegradable polymer film layer 6 is provided.

  The method for providing the biodegradable polymer film layer 6 with the layer in which the biological physiologically active substance 7 is dispersed is not particularly limited on the surface of the metal thin film layer 3. A method of melting the physiologically active substance and coating the surface of the metal thin film layer 3, or preparing a solution by dissolving the biodegradable polymer and the biological physiologically active substance in a solvent, and attaching the metal thin film layer 3 to this solution Examples include a method of immersing and then pulling up to remove the solvent by evaporation or other methods, or a method of spraying the solution onto the stent body 2 using a spray and removing the solvent by evaporation or other methods. .

  The thickness of the biodegradable polymer membrane layer 6 in which the biological physiologically active substance 7 is dispersed determines the performance of the stent body 2 such as reachability to the lesion (delivery) and irritation to the blood vessel wall. Since the thickness should not be significantly impaired and should be set at a thickness at which the effect of the biological physiologically active substance is confirmed, it is preferably 1 to 100 μm, more preferably 1 to 50 μm, most preferably 1 to 1 μm. The range is 10 μm.

  The biodegradable biopolymer forming the biodegradable polymer film layer 6 is not particularly limited, but is preferably a biostable one having a high biostability and a relatively high biodegradation rate, such as polylactic acid, polyglycolic acid, polyhydroxy Examples include butyric acid, polycaprolactone, collagen, gelatin, cellulose, chitin, chitosan, hyaluronic acid, and a covalently bonded polymer or a mixed polymer in which two or more of these are combined. More preferred are polylactic acid and polyglycolic acid, but they should be appropriately selected according to the required mechanical properties or the desired release rate or biodegradation rate of the biological physiologically active substance.

  The biological physiologically active substance forming the biologically physiologically active substance layer 7 is not particularly limited as long as it has an effect of suppressing restenosis when the stent 1 is placed in a lesioned portion of a lumen. Anticancer agent, immunosuppressant, antibiotic, antirheumatic agent, antithrombotic agent, antihyperlipidemic agent, ACE inhibitor, calcium antagonist, integrin inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid, Examples include flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, vascular smooth muscle growth inhibitors, anti-inflammatory agents, biological materials, interferons, and NO production promoters.

  Next, a process when the biological physiologically active substance forming the biological physiologically active substance layer 4 is released from the stent 1 will be described.

  After the stent 1 is placed in the lesioned part, the body fluid in the lumen comes into contact with the outer surface of the stent 1 (the outer surface of the biodegradable polymer layer 5). Thereafter, the biologically bioactive substance is released to the body fluid side, which is the outer surface of the stent, by degrading the biodegradable polymer film layer 5 in vivo.

  Eventually, all biological and physiologically active substances are released into the living body due to the decomposition of the biodegradable polymer film layer 5 in the living body.

  The process when the biological physiologically active substance is released from the layer in which the biologically physiologically active substance 7 is dispersed in the biodegradable polymer membrane layer 6 will be described.

  After the stent 1 is placed in the lesioned part, the bodily fluid in the lumen comes into contact with the outer surface of the stent 1 (the outer surface of the layer in which the biological bioactive substance 7 is dispersed in the biodegradable polymer film layer 6). Thereafter, the biologically bioactive substance is released to the body fluid side, which is the outer surface of the stent, by degrading the biodegradable polymer film layer 6 in vivo.

  Eventually, all biological and physiologically active substances are released into the living body due to the decomposition of the biodegradable polymer film layer 6 in the living body.

  After all the biological and physiologically active substances are released from the stent body 2 and all the biodegradable polymers are decomposed, vascular smooth muscle cells are obtained by the effect of the metal thin film layer 3 covering the exposed stent body 2. Can be suppressed.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

(Example 1)
First, as shown in FIG. 4, titanium was vapor-deposited on the electropolished SUS316L stent body 2 using a vapor deposition apparatus (EBX-8C: ULVAC). In order to deposit titanium uniformly on the stent body 2, a stent rotating jig equipped with the stent body 2 is placed in the apparatus, and when the degree of vacuum becomes 2 × 10 ⁻⁵ Torr or less, the substrate is heated to 150 ° C. Deposition was started at a degree of 4 × 10 ⁻⁶ Torr or less, and a titanium thin film layer 3 having a thickness of 0.1 μm was deposited on the stent body 2. To this stent body 2, simvastatin (hereinafter SV) 7 which is an antihyperlipidemic agent and polylactic acid (hereinafter PLA) 6 which is a biodegradable polymer are tetrahydrofuran (hereinafter THF) so that the weight ratio becomes 1: 1. After spraying a solution having a concentration of 1% by weight of the mixture dissolved in the solution by spray (manufactured by Micro Spray Gun-II NORDSON) and drying the solvent THF, about 600 μg of the mixture of SV and PLA is placed on the stent. It was confirmed that it was applied (formation of biodegradable polymer film layer 6 in which biological physiologically active substance 7 was dispersed). The thickness of the biodegradable polymer film layer 6 coated on the stent body 2 was about 10 μm.

  And about the stent 1 obtained by doing in this way, the biological bioactive substance (SV) release amount was measured.

  In the measurement, the stent 1 was immersed in 30 ml of 4% BSA, stirred at 37 ° C., sampled every predetermined time, and the amount of SV released in 4% BSA was quantified by HPLC (manufactured by Hitachi). . Note that the amount of SV released is expressed as a ratio (%) to the amount of SV applied to the stent.

  As shown in Table 1, after immersion in 4% BSA, it was confirmed that about 100% of SV was released after 30 days as PLA was decomposed.

  Next, the stent was recovered and a porcine vascular smooth muscle cell adhesion test was performed. The recovered stent was thoroughly washed with pure water and dried, and then sterilized with ethylene oxide gas (EOG). Under aseptic operation, the stent 1 was placed in the center of a plastic dish having a diameter of 35 mm, and porcine smooth muscle cells were seeded on the stent 15000 cell / dish. After culturing in an incubator for 3 days, the medium was removed and immobilized with a 10% formalin solution. Two days later, the stent 1 was taken out and sufficiently dried in a vacuum dryer.

  The number of adherent porcine smooth muscle cells per area was measured with a scanning electron microscope (SEM).

As shown in Table 2, the number of porcine smooth muscle cell adhesion of the titanium vapor-deposited stent was 18/1 mm ^{2 on} average.

(Comparative Example 1)
An electropolished SUS316L stent body is coated with tetrahydrofuran (hereinafter THF) with a weight ratio of simvastatin (hereinafter SV), an antihyperlipidemic agent, and polylactic acid (PLA), a biodegradable polymer, to a weight ratio of 1: 1. The solution in which the concentration of the mixture dissolved in 1) is 1% by weight is sprayed (by Micro Spray Gun-II NORDSON) and the solvent THF is dried, and then the mixture of about 600 μg of SV and PLA is the stent body. It was confirmed that it was applied on top (formation of a biological physiologically active substance release layer). The thickness of the polymer layer coated on the stent body was about 10 μm.

  Then, the biologically active substance (SV) release amount of the stent thus obtained was measured.

  In the measurement, the stent was immersed in 30 ml of 4% BSA, stirred at 37 ° C., sampled every predetermined time, and the amount of SV released in 4% BSA was quantified by HPLC (manufactured by Hitachi). Note that the amount of SV released is expressed as a ratio (%) to the amount of SV applied to the stent.

  As shown in Table 1, after immersion in 4% BSA, it was confirmed that about 100% of SV was released after 30 days as PLA was decomposed.

  Next, the stent was recovered, and a SUS316L porcine vascular smooth muscle cell adhesion test was performed. The collected plate was thoroughly washed with pure water and dried, and then EOG sterilization was performed. A plate was placed in the center of a plastic dish having a diameter of 35 mm under aseptic operation, and porcine smooth muscle cells were seeded from the plate at 15000 cells / dish. After culturing in an incubator for 3 days, the medium was removed and immobilized with a 10% formalin solution. Two days later, the stent was taken out and sufficiently dried in a vacuum dryer.

  The number of adherent porcine smooth muscle cells per area was measured with a scanning electron microscope (SEM).

As shown in Table 2, the number of porcine smooth muscle cell adhesion of the SUS316L stent was 40 / mm ^{2 on} average.

It is a front view which shows the one aspect | mode of the stent of this invention. FIG. 2 is an enlarged cross-sectional view of one embodiment taken along line AA in FIG. 1. It is the elements on larger scale of the one aspect | mode cut | disconnected along line BB of FIG. It is an expanded transverse cross section which shows the other aspect cut | disconnected along line AA of FIG. It is an expanded transverse cross section which shows the other aspect cut | disconnected along line BB of FIG.

Explanation of symbols

1 ... stent,
2 ... Stent body,
3 ... metal thin film layer,
4 ... biological and biologically active substance layer,
5, 6 ... biodegradable polymer membrane,
7: Biological physiologically active substance.

Claims (6)

  A stent for placement in a lumen in a living body, the stent having a strength sufficient to withstand an expansion operation when placed in the lumen, and a vascular smoothness formed on the surface of the stent body A metal thin film layer capable of suppressing adhesion of muscle cells, and a biological physiologically active substance release layer formed on the metal thin film layer and comprising a biological physiologically active substance and a biodegradable polymer. A stent characterized by   The stent according to claim 1, wherein the stent body is made of a metal material.   The stent according to claim 1 or 2, wherein the metal thin film layer is composed of a thin film made of at least one metal element.   The biological physiologically active substance releasing layer is a biologically physiologically active substance layer and a biodegradable polymer film layer completely covering the biological physiologically active substance layer or a layer in which a biological physiologically active substance and a biodegradable polymer are mixed. The stent according to any one of claims 1 to 3, wherein   The biological physiologically active substance is an anticancer agent, immunosuppressive agent, antibiotic, antirheumatic agent, antithrombotic agent, antihyperlipidemic agent, ACE inhibitor, calcium antagonist, integrin inhibitor, antiallergic agent, anti Oxidizing agent, GPIIbIIIa antagonist, retinoid, flavonoid, carotenoid, lipid improving agent, DNA synthesis inhibitor, tyrosine kinase inhibitor, antiplatelet agent, vascular smooth muscle growth inhibitor, anti-inflammatory agent, biomaterial, interferon and NO production The stent according to any one of claims 1 to 4, wherein the stent is at least one selected from the group consisting of accelerators.   6. The biodegradable polymer is at least one selected from the group consisting of polylactic acid, polyglycolic acid, a copolymer of lactic acid and glycolic acid, and polycaprolactone. The stent according to any one of the above.

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