WO2004017939A1

WO2004017939A1 - Medical instrument to be implanted in the body

Info

Publication number: WO2004017939A1
Application number: PCT/JP2003/010510
Authority: WO
Inventors: Ichiro Hirahara; Ryota Sugimoto; Kenichi Yasuda
Original assignee: Terumo Kabushiki Kaisha
Priority date: 2002-08-20
Filing date: 2003-08-20
Publication date: 2004-03-04
Also published as: AU2003257624A1; JP2010155095A

Abstract

It is intended to provide a medical instrument to be implanted in the body which can be directly and topically applied to a hollow structure in the body, inhibits the proliferation of vascular smooth muscle cells, improves the functions of vascular endothelial cells to thereby promote the endothelialization of vessels and thus surely inhibits restenosis. Namely, a medical instrument to be implanted in the body which comprises the main unit, a vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function improving agent loaded on the main unit and from which the a vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent are released into a hollow structure in the body.

Description

Description Implantable medical device Technical field

The present invention relates to an implantable medical device used for improving a stenosis in a lumen in a living body such as a blood vessel, a bile duct, a trachea, an esophagus, and a urethra. Background art

Stents are tubular devices that maintain the stenosis of a blood vessel or other body lumen in a living body in an expanded state. For example, a stent is used to improve stenosis after percutaneous coronary angioplasty (PTCA). Used. PTC A is an extremely effective treatment for ischemic heart disease, but has the problem that within a few months after PTCA, restenosis occurs at a rate of 40% to 50% ( _popma JJ, To po 1 EJ. Am J Med 88: 1N-16N, 1990). The causes of restenosis after PTCA are mainly ① thrombotic occlusion, ② elastin of the blood vessel wall after balloon dilatation, narrowing of the lumen by recoil, and ③ neovascularization due to restoration of coronary artery wall injury caused by PTCA. Excessive thickening of the membrane is considered. In order to prevent restenosis, stent therapy has been attempted to minimize elastin rec 0 i 1 by expanding the vascular stenosis with a balloon and placing a metal mesh stent after PTCA. (Fischman DL, Leon MBeta 1.N Engl J Med 331: 496—501, 1994). In the case of thrombotic occlusion, there is a problem that more invasive thrombus is formed when a stent is used than when it is not used, and subacute thrombotic occlusion occurs one to two weeks after stent implantation. However, the combined use of ticlovidine and aspirin prevented thrombus formation. However, when using a stent, although the restenosis rate is lower than when using PTC A alone, restenosis is observed at a rate of about 20 to 30%, mainly due to intimal hyperplasia. Still not resolved. Intimal thickening, which is the main cause of restenosis after stent placement, is thought to occur by the following mechanisms. Platelet aggregates around the stent wire due to intimal damage caused during PTCA ゃ stent placement, forming a thrombus, from which P 1 atelet Derived d Growth h F ac tor (PDGF) or Tran Cytokines such as sfo rming Group F actor (TGF) are released. Substances such as 12-hydro xy eicosatetraenoic (12-HETE) are released. On the other hand, at sites of intimal injury, inflammatory cells such as monocytes are found to contain vascular cell adhesion on leucle-1 (VCAM-1) and intercellular adhesion on mo lecu 1 e-1 (ICAM-1) ゃ selectin. It adheres to the vascular wall via the adhesive molecule and accumulates around the stent wire, and at the same time penetrates into the vascular wall and releases various physiologically active substances such as PDGF. In addition, endothelial cells, which controlled the activation of vascular smooth muscle cells, are shed or deteriorated due to intimal damage, as well as stimulation of various physiologically active substances such as PDGF, or vascular The mechanical destruction of this triggers the activation of smooth muscle cells in the media of the vasculature, transforming them from contracted to molded. And the synthetic smooth muscle cells migrate to the vascular intima and Overgrowth results in intimal hyperplasia.

Therefore, various studies have been made to prevent restenosis by mounting a drug that can suppress the migration and proliferation of vascular smooth muscle cells, which is a direct cause of intimal hyperplasia, on a stent and releasing it at the stent placement site. . Specific examples of such a drug include Taxol (Pacli-Nixel) in Japanese Patent Application Laid-Open No. 9-503488, and Mite Machine in Japanese Patent Application Laid-Open No. 9-56807. C, adriamycin, genistein, and tilphosphin are disclosed, and cytochalasin is disclosed in Japanese Patent Application Laid-Open No. 11-500635. Recently, a stent loaded with sirolimus (rapamycin) has also been reported. However, these drugs have no effect on the repair or repair of damaged or degraded intima of the blood vessel, and only directly inhibit the proliferation and migration of vascular smooth muscle cells. When the drug concentration decreases, restenosis may occur. In addition, these drugs may inhibit the function of vascular endothelial cells, which is essential during the process of vascular healing. Disclosure of the invention

An object of the present invention is to apply directly and locally to a lumen in a living body, and to suppress endothelialization of blood vessels by suppressing the proliferation of vascular smooth muscle cells and improving the function of vascular endothelial cells. An object of the present invention is to provide an implantable medical device that promotes and reliably suppresses restenosis.

Such an object is achieved by the present invention described in the following (1) to (14).

(1) An in vivo living body comprising: a medical device main body; and a vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function improving agent mounted on the medical device main body. Implantable medical device to be placed in the lumen of a patient.

(2) The implantable medical device according to the above (1), wherein the vascular endothelial cell function improving agent is an HMG-CoA reductase inhibitor.

(3) The aforementioned HMG-CoA reductase inhibitor is Simbus Yutin, Celivas Yutin Sodium, Pipa Pastin, Oral Bath Yutin, Atorbas Yutin, Full Bath Yutin Sodium, Prabas Yutin Sodium, Ross Bath The implantable medical device according to the above (2), which is any one of evening chin.

(4) The implantable medical device according to (1), wherein the vascular endothelial cell function improving agent is any one of an ACE inhibitor, an angiotensin II receptor antagonist, and a calcium antagonist.

(5) The implantable medical device according to the above (1), wherein the vascular endothelial cell function improving agent is a NO donor.

(6) The implantable medical device according to the above (5), wherein the NO donor is S_N i tros o-N-ac e ty 1 -DL-p e n c i 11 am i n e (SNAP) or arginine.

(7) The implant according to (1), wherein the vascular smooth muscle cell proliferation inhibitor is any one of an immunosuppressant, an anticancer agent, an antibiotic, genistein, tilphosphine, and cytochalasin. Medical instruments.

(8) The vascular smooth muscle cell proliferation inhibitor is sirolimus (rapamycin), evening crolimus hydrate, everolimus, everolimus plus, paclitaxel (evening sol), docetaxel hydrate, actinonomycin D, mitomycin C, Admriamycin. Medical instruments.

(9) On the surface of the medical device body, having a polymer layer made of a biodegradable polymer or a biocompatible polymer containing the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent therein. The implantable medical device according to any one of the above (1) to (8), which is characterized by the following.

(10) The vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent are provided on the surface of the medical device body, and the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent are formed outside the vascular smooth muscle cell growth inhibitor. The implantable medical device according to any one of the above (1) to (8), further comprising a polymer layer made of a degradable polymer or a biocompatible polymer.

(1 1) The biodegradable polymer is polylactic acid, polydalicholic acid, polylactic acid-polyglycolic acid copolymer, polyhydroxybutyric acid, polymalic acid, polyamino acid, collagen, laminin, heparan sulfate, fibronectin, vitronone Any of cutin, chondroitin sulfate, and hyaluronic acid, wherein the biocompatible polymer is silicone, a blend or block copolymer of polyether polyurethane and dimethyl silicon, polyurethane, polyacrylamide, polyethylene oxide, The implantable medical device according to the above (9) or (10), wherein the medical device is any one of poly-polyponate.

(12) The implantable medical device according to any one of the above (1) to (11), wherein the medical device main body is a stent.

(13) The vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent are contained in a polymer layer composed of a biodegradable polymer or a biocompatible polymer. The implantable medical device according to any one of the above (1) to (8), wherein the medical device is mounted on the medical device main body in a modified form.

(14) The vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent are directly mounted on the surface of the medical device body, and the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent are The implantable medical device according to any one of the above (1) to (8), wherein the outside is covered with a polymer layer made of a biodegradable polymer or a biocompatible polymer. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a side view showing one embodiment of a stent.

FIG. 2 is an enlarged cross-sectional view taken along line A_A in FIG.

FIG. 3 is a view similar to FIG. 2, showing an embodiment in which the form of the coat of the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent is different.

FIG. 4 is a view similar to FIG. 2, showing an embodiment in which the form of the coat of the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent is different.

FIG. 5 is a view similar to FIG. 2, showing an embodiment in which the form of the coat of the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent is different.

FIG. 6 is a view similar to FIG. 2, showing an embodiment in which the form of the coat of the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent is different. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the implantable medical device of the present invention will be described in detail. The implantable medical device of the present invention comprises a medical device main body, a vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function improving agent.

The vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent may be coated on the surface of the medical device body, or may be contained in the medical device body itself.

Medical device bodies include, for example, stents, catheters, balloons, vascular prostheses, and artificial blood vessels.Especially, in order to expand a stenosis in a lumen in a living body and secure the expanded lumen. A preferred embodiment is a stent that can be indwelled for a long period of time. Hereinafter, a case where the medical device body is a stent will be described in more detail based on a preferred embodiment shown in the accompanying drawings.

FIG. 1 is a side view showing one embodiment of a stent, FIG. 2 is an enlarged cross-sectional view taken along line A--A in FIG. 1, and FIGS. 3 to 6 are views similar to FIG. An aspect in which the form of the coat of the smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent is different will be described.

The material, shape, size, and the like of the stent are not particularly limited as long as the stent can expand a stenosis formed in a lumen in a living body such as a blood vessel, a bile duct, a trachea, an esophagus, and a urethra and can be placed there.

The material for forming the stent may be appropriately selected according to the application site, and examples thereof include metal materials, polymer materials, and ceramics. When the stent is formed of a metal material, the metal material has excellent strength, so that the stent can be securely placed in the stenosis. In addition, when the stent is formed of a polymer material, the polymer material is excellent in flexibility, and thus has an excellent effect in terms of reachability (delivery property) to the stenotic portion of the stent. Examples of the metal material include stainless steel, Ni—Ti alloy, tantalum, titanium, gold, platinum, inconel, iridium, tungsten, and cobalt alloy. And among stainless steels, SUS316L, which has good corrosion resistance, is preferable.

Examples of the polymer material include polytetrafluoroethylene, polyethylene, polypropylene, polyethylene terephthalate, cellulose acetate and cellulose nitrate.

The shape of the stent is not particularly limited as long as it is strong enough to be stably placed in a stenotic part formed in a lumen in a living body. For example, a wire made of a metal material or a fiber made of a polymer material is used as a net. An arbitrary shape such as a cylindrical body formed by shaping, or a cylindrical body made of a metal material or a polymer material provided with pores as shown in FIG. 1 is preferably used.

In the embodiment shown in FIG. 1, the stent 10 is composed of a linear member 11 and has, as a basic unit, a substantially rhombic element 12 having a notch therein. A plurality of substantially rhombic elements 12 are arranged continuously in the short axis direction and connected to form an annular unit 13. The annular unit 13 is connected to an adjacent annular unit via a linear connecting member 14. As a result, the plurality of annular units 13 are continuously arranged in the axial direction in a state where the annular units 13 are joined.

The stent may be any of a ball-expandable double type and a self-expandable double type. In addition, the size of the stent may be appropriately selected according to the application site. For example, when used for the coronary artery of the heart, the outer diameter before expansion is preferably 1.0 to 3.0 mm, and the length is preferably 5 to 5 Omm. The surface of the stent is coated with a vascular smooth muscle cell growth inhibitor and a vascular endothelial cell function improving agent. When the stent is placed in a stenosis of a lumen in a living body, the vascular smooth muscle cell growth inhibitor and The vascular endothelial cell function improving drug is released into the stent placement site and the surrounding tissue.

Coating both a vascular smooth muscle cell growth inhibitor and a vascular endothelial cell function improving agent has the following effects. Generally, a vascular smooth muscle cell proliferation inhibitor also inhibits the function and proliferation of vascular endothelial cells. Therefore, when a stent is coated with only a vascular smooth muscle cell proliferation inhibitor, the function and proliferation of vascular endothelial cells may be suppressed. However, by coating the stent with both a vascular smooth muscle cell proliferating agent and a vascular endothelial cell function improving agent so that they are released locally, the vascular smooth muscle cell proliferation inhibitor can increase the vascular smooth muscle cell proliferation. In addition to the suppression, vascular endothelial cell function-improving drugs improve the proliferation and function of vascular endothelial cells, so that the intima is improved and repaired more completely. Therefore, even after the release of the vascular smooth muscle cell growth inhibitor has been completed, intimal hyperplasia is suppressed by the endothelial cells with improved functions, so that restenosis (rebound) after a long period of time is unlikely to occur.

Methods for evaluating the degree of improvement in the function of vascular endothelial cells include, for example, immunostaining with anti-von Willebrand factor-1 antibody (Dako, CA, USA). As a result, when the affected area is covered with von Wille brand factor-positive vascular endothelial cells, intimal repair and function improvement are confirmed. On the other hand, when von Wille brand factor-positive vascular endothelial cells cannot be confirmed, intimal repair is performed. Not being recognized, intimal thickening occurs and the likelihood of stenosis increases.

Vascular smooth muscle cell proliferation inhibitors include, for example, sirolimus (rapamycin), tacroli Immunosuppressants such as Mus hydrate, everolimus, everolimus plus, etc .; anti-cancer drugs such as paclitaxel (taxol) and docetaxel hydrate; antibiotics such as actinomycin D, mitomachine C, adriamycin; Can be

The vascular endothelial cell function improving agent preferably promotes NO production, and includes, for example, an HMG-CoA reductase inhibitor, an ACE inhibitor, an angiotensin II receptor antagonist, a calcium antagonist, and an NO donor.

HMG-CoA reductase inhibitors have traditionally been used as a therapeutic agent for hyperlipidemia because they block cholesterol synthesis in the liver. It has been reported that there is an effect related to suppression of membrane thickening. Specifically, inhibition of LDL oxidation (Massy Ziad A., eta 1., Biochem Biophys Res Comm Ren 26 7 536-540 (2000)), suppression of inflammatory response (Sakai M., etal., A therosclerosis 133 5 1-59 (1997)), suppression of foaming of smooth muscle cells and macrophagy (Be 1 1 osta S., eta 1., Atherosclerosis 137 S υ p 1 S 101-109 (1998)).

Recently, attention has been focused on the NO-producing effect of HMG-CoA reductase inhibitors (Laufs Ueta Circulation (97) 1129-1135 1998). It is thought that the endothelialization of blood vessels is promoted by improving the function of vascular endothelial cells and promoting NO production. It is thought that the promotion of endothelialization of blood vessels suppresses the migration and proliferation of smooth muscle cells to the intima side. I have.

ACE inhibitors inhibit vasoconstriction and suppress sympathetic nerve enhancement by inhibiting the production of angiotensin II from angiotensin I in the renin-angiotensin system, a powerful pressor system in vivo. In addition, it acts on the anti-hypertensive system of calclein-kinin-prostaglandin to suppress the degradation of bradykinin and dilate blood vessels, and also promotes the production of prostaglandin to relax the blood vessels and increase blood pressure. Has the function of lowering. Recently, it has been reported that this ACE inhibitor also acts on endothelial cells and promotes NO production via bradykinin. Angiotensin II receptor antagonists lower blood pressure by inhibiting the binding of angiotensin II, produced in the renin-angiotensin system, to its main receptor, angiotensin II-I type I receptor. Having. It has been reported that this angiotensin II receptor antagonist also acts on endothelial cells and upregulates angiotensin II type II receptor to promote NO production.

Calcium antagonists bind to and inhibit calcium channels on cell membranes, thereby inhibiting the influx of calcium ions into cells, suppressing vasoconstriction and lowering blood pressure. It has been reported that amlodipine besylate, a type of calcium antagonist, also acts on endothelial cells and promotes NO production (Kob ay ashi N, yanaka H, Tojo A, Kob ay ashi K , Matsuoka H. J Car r di ov asc Phar rm 34: 173-181, 1999).

Based on the above, HMG-CoA reductase inhibitor, angiotensin converting enzyme inhibitor Some of the harmful drugs, angiotensin II receptor antagonists, and calcium antagonists promote the endothelialization of blood vessels by improving the function of vascular endothelial cells and promoting NO production in addition to the previously known efficacy It is expected to be.

HMG-Co A reductase inhibitors include, for example, simpastatin, ceribas quintin sodium, pibus quintin, mouth bath chin, atorbas quintin, full bath quintin sodium, pravath quintin sodium and rosuvastin .

Examples of ACE inhibitors include ramiprilat, captopril, alacepril, enalapril maleate, delapril hydrochloride, cilazapril, ricinoburil, benazepril hydrochloride, imidabril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril and perindopril elpermine.

Angiotensin II receptor antagonists include, for example, oral sultanate potassium, candesalen cilexetil, and valsalen.

Potassium antagonists include, for example, amphidipine besylate.

NO donors include, for example, S_Nitr0so—N_accetyl—DL—penicini 11 amine (SNAP) and arginine.

The amount of the vascular endothelial cell function improving agent coated on the surface of the stent is not particularly limited as long as it is an amount that promotes NO production without killing vascular endothelial cells. In addition, the amount of the vascular smooth muscle cell proliferation inhibitor coated on the surface of the stent is not particularly limited as long as the amount of vascular smooth muscle cell proliferation is suppressed.

The form of the coating of the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent on the stent is not particularly limited. For example, as shown in FIG. 2, a polymer composed of a biodegradable polymer or a biocompatible polymer is used. In layer 21, vascular smooth muscle cell growth inhibitor 22 Alternatively, the surface of the stent may be coated in a form containing (mixed with) the vascular endothelial cell function improving agent 23.

In addition, as shown in Fig. 3, a vascular smooth muscle cell growth inhibitor 22 and a vascular endothelial cell function improving agent 23 are directly coated on the surface of the stent to form a drug layer (drug layer 31). The outside may be covered with a polymer layer 32 made of a biodegradable polymer or a biocompatible polymer.

In addition, as shown in Fig. 4, a polymer layer 42 composed of a biodegradable polymer or a biocompatible polymer containing either a vascular smooth muscle cell proliferation inhibitor or a vascular endothelial cell function improving agent 41 on the surface of the stent is provided. Further, a polymer layer 44 of a biodegradable polymer or a biocompatible polymer containing the other of a vascular smooth muscle cell proliferation inhibitor or a vascular endothelial cell function improving agent 43 may be provided on the outside thereof, The outside may be covered with a polymer layer 45 of a biodegradable or biocompatible polymer. The polymer layers 42, 44, 45 made of these biodegradable polymers or biocompatible polymers may be the same or different. Also, as shown in Fig. 5, a drug layer 51 comprising one of a vascular smooth muscle cell growth inhibitor or a vascular endothelial cell function improving agent is provided on the surface of the stent, and a vascular smooth muscle cell growth inhibitor or vascular A drug layer 52 composed of the other of the endothelial cell function improving drug may be provided, and the outside thereof may be covered with a polymer layer 53 composed of a biodegradable polymer or a biocompatible polymer.

In addition, as shown in Fig. 6, a drug layer 61 made of one of a vascular smooth muscle cell growth inhibitor or a vascular endothelial cell function improving agent is provided on the surface of the stent, and a biodegradable polymer or a biocompatible polymer is further provided outside the drug layer 61. A barrier layer 62 made of Outside the barrier layer 62 of the vascular smooth muscle cell growth inhibitor or the vascular endothelial cell function improving agent, and a biodegradable polymer or biocompatible May be covered with a polymer layer 64 made of a conductive polymer. The barrier layer 62 made of biodegradable polymer or biocompatible polymer and the polymer layer 64 may be the same or different.

When a vascular smooth muscle cell growth inhibitor and a vascular endothelial cell function improver are contained in a polymer layer composed of a biodegradable polymer, or a vascular smooth muscle cell growth inhibitor and a vascular endothelial cell function improver (drug layer) If the outside of the stent is covered with a polymer layer composed of a biodegradable polymer, the biodegradable polymer is degraded, and the vascular smooth muscle cell growth inhibitor and vascular endothelial cell function improver are placed on the stent placement site and its Released directly into surrounding tissues.

The biodegradable polymer is one that is degraded enzymatically or non-enzymatically in vivo, the degradation product does not show toxicity, and can release the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent. Although not particularly limited, for example, polylactic acid, polydalicholic acid, polylactic acid-polyglycolic acid copolymer, polyhydroxybutyric acid, polymalic acid, polyamino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, Chondroitin sulfate, hyaluronic acid and the like. Among them, polylactic acid capable of releasing a vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function improving agent over a long period of time is preferable.

When a vascular smooth muscle cell growth inhibitor and a vascular endothelial cell function improving agent are contained in a polymer layer composed of a biocompatible polymer, or a vascular smooth muscle cell growth inhibitor and a vascular endothelial cell function improving agent (drug layer) Outside is biocompatible When covered with a polymer layer composed of a polymer, the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent leach onto the outer surface of the biocompatible polymer, thereby causing the vascular smooth muscle cell growth inhibitor and The vascular endothelial cell function-improving drug is released directly to the stent placement site and the surrounding tissue.

The biocompatible polymer is essentially a substance to which platelets are hardly adhered, does not show irritation to tissues, and is capable of leaching the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent. Although not particularly limited, for example, silicones, blends or block copolymers of polyether-polyurethane and dimethylsilicon, polyurethanes such as segmented polyurethanes, polycarbonates such as polyacrylamide, polyethylene oxide, polyethylene carbonate, polypropylene carbonate, etc. Various synthetic polymers are included.

When the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent are contained in a polymer layer composed of a biodegradable polymer or a biocompatible polymer, the mode of inclusion is not particularly limited. The inhibitor and the vascular endothelial cell function improving agent may be present uniformly or heterogeneously in the polymer layer, or may be present locally.

The method for producing the implantable medical device of the present invention is not particularly limited. For example, when a stent is used as a medical device body, rapamycin is used as a vascular smooth muscle cell growth inhibitor, simvastatin is used as a vascular endothelial cell function improving agent, and polylactic acid is used as a biodegradable polymer. A solution in which rapamycin is dissolved in dichloromethane and a solution in which polylactic acid is dissolved in dichloroethane are mixed, and the mixed solution is sprayed on a stent to produce a solution of simvacin and rapamycin. A method in which a polylactic acid layer (polymer layer) containing mycin is provided on the surface of the stent.

The thus-obtained implantable medical device of the present invention can be used by directly placing it in a lumen in a living body. The vascular smooth muscle cell proliferation inhibitor and vascular endothelial cell function improver are released into the stent placement site and the surrounding tissue, and the vascular smooth muscle cell proliferation inhibitor suppresses the proliferation of vascular smooth muscle cells. The function of vascular endothelial cells improves the function of vascular endothelial cells. Therefore, even after the release of the vascular smooth muscle cell growth inhibitor has been completed, the intimal hyperplasia is suppressed by the improved endothelial cells, so that restenosis can be reliably suppressed.

Hereinafter, the present invention will be described more specifically with reference to examples. Note that the present invention is not limited to the following examples.

(Example 1)

A solution prepared by dissolving 2 O mg of Simvathine and 2 O mg of rapamycin in 1 ml of dichloromethane was mixed with a solution of 4 O mg of polylactic acid dissolved in 4 ml of dichloromethane. The mixed solution was sprayed onto a 15 mm long stent made by processing a 2 mm diameter stainless steel pipe to form a polylactic acid layer (polymer layer) containing simvastatin and rapamycin. ) Was provided on the surface of the stent to produce the implantable medical device of the present invention.

(Comparative Example 1)

A solution in which rapamycin 2 O mg was dissolved in dichloride 1 ml and a solution in which polylactic acid 4 O mg was dissolved in dichloride 4 ml were mixed. Then, the mixed solution was processed into a stainless steel pipe with a diameter of 2 mm and a length of 15 mm. By spraying the stent, a polylactic acid layer (layer of polymer) containing rapamycin was provided on the stent surface to produce an implantable medical device.

(Comparative Example 2)

A solution was prepared by dissolving 40 mg of polylactic acid in 4 ml of dichloride. This solution is sprayed onto a 15 mm long stent made by processing a stainless steel pipe with a diameter of 2 mm to provide a polylactic acid layer (polymer layer) on the surface of the stent to produce an implantable medical device. did.

(Evaluation 1)

Comparative study of therapeutic effects using a vascular injury model caused by rubbing the spider iliac artery balloon>

(4) Kanemin (30 mgZkg) and xylazine (SmgZkg) were intramuscularly administered to the heron muscle and anesthetized. The right common carotid artery was dissected from the tissue. After introducing about 150 U / kg of heparin from the pinna vein, a sheath introducer was introduced by a predetermined method. A PTCA balloon pre-loaded with a guidewire was inserted into the blood vessel and carried to the distal part of the iliac artery. With the balloon inflated to the specified pressure, the balloon was pulled to the proximal part of the iliac artery and the blood vessel was scraped. This balloon rub was repeated three times. Subsequently, the implantable medical device prepared in Example 1, the implantable medical device prepared in Comparative Example 1, and the implantable medical device prepared in Comparative Example 2 were respectively introduced into the right iliac artery. Then, it was expanded and detained at the specified pressure. After removing the balloon, the common carotid artery was ligated, sutured in three layers, and left in place for a predetermined period. The detention period was 4 weeks and 8 weeks.

Prescribed period (4 weeks and 8 weeks) After implantation, approach the blood vessel from the left carotid artery in the same way as when placing an implantable medical device, and after imaging the left and right iliac arteries, open the abdomen and open the abdomen The vena cava was exposed. Perfusion with 2 UZm 1 of heparinized saline was started from the carotid sheath line, and at the same time the abdominal vena cava was excised and exsanguinated. After systemic perfusion with heparinized saline, systemic perfusion was performed with 10% neutral buffered formalin solution to fix the target blood vessel. The fixed sample was resin-embedded according to a standard method to prepare a pathological section, and hematoxylin and eosin staining was performed. This was subjected to observation with an optical microscope, and the intima thickness was measured. Example Three cases were measured for each of the implantable medical devices of Comparative Example 1 and Comparative Example 2. Table 1 shows the average of these measurement results. In addition, immunostaining with anti-vonville brand factor-1 antibody (Dako, CA, USA) was performed on the cells left in place for 4 weeks to identify endothelial cells. As a result, the intima of the right iliac artery in which the implantable medical device prepared in Example 1 was placed was covered with von Willebrand factor 1-positive vascular endothelial cells. In contrast, in the cases where the implantable medical devices of Comparative Example 1 and Comparative Example 2 were indwelled, von Willebrand factor-positive vascular endothelial cells could hardly be confirmed, and almost no intimal repair was observed. . table 1

From Table 1, it can be seen that Example 1 showed a significant (p <0.05: p is a criterion of statistical processing) thickening inhibitory effect of Comparative Example 2 after 4 weeks and 8 weeks. Weeks later and 8 weeks No change was found in the inner film thickness even after comparison. On the other hand, in Comparative Example 1, although the effect of suppressing thickening was observed after 4 weeks, the inner thickness was increased after 8 weeks, and rebound of thickening was observed. This is because, as described above, in Comparative Example 1 in which only rapamycin was loaded, almost no intimal repair was observed at the time point of 4 weeks later. It is considered that the cell growth inhibitory effect was lost and the inner layer thickness increased. On the other hand, in Example 1, which was equipped with simvastatin and ravamycin, the intima was repaired 4 weeks later, so the function was improved and repaired even after simpastatin and rapamycin were released from the implantable medical device. It is considered that the intimal hyperplasia was suppressed by the endothelial cells.

(Example 2)

A solution prepared by dissolving 2 mg of arginine and 2 mg of paclitaxel in 1 ml of ethanol and a solution obtained by dissolving 4 mg of polylactic acid in 4 ml of acetone were mixed. The mixed solution was sprayed onto a 15 mm long stent made by processing a 2 mm diameter stainless steel pipe to form a polylactic acid layer (polymer layer) containing arginine and paclitaxel. The medical device to be implanted in the body of the present invention was prepared on the surface of the stent.

(Comparative Example 3)

A solution prepared by dissolving 2 O mg of paclitaxel in ethanol lm 1 and a solution obtained by dissolving 4 O mg of polylactic acid in 4 ml of acetone were mixed. This mixed solution was sprayed onto a 15 mm long stent made by processing a 2 mm diameter stainless steel pipe to form a polylactic acid layer (polymer layer) containing paclitaxel. An implantable medical device was prepared on the surface. (Comparative Example 4)

A solution was prepared by dissolving 4 mg of polylactic acid in 4 ml of acetone. This solution was sprayed onto a 15 mm long stent made by processing a 2 mm diameter stainless steel pipe to provide a polylactic acid layer (polymer layer) on the surface of the stent. Was prepared.

(Evaluation 2)

As a pre-anesthetic, azaperone and atosulfate pin were intramuscularly administered to eight females. Anesthesia was performed by intramuscular administration of keyumin hydrochloride, and the anesthesia was maintained with a gas mixture of air: oxygen = 1: 1 and 2% sevoflurane.

The implantable medical device manufactured in Example 2, the implantable medical device manufactured in Comparative Example 3, and the implantable medical device manufactured in Comparative Example 4 were placed in the three branches of the porcine coronary artery, respectively, according to a standard method. . This was carried out on eight buses. The detention period was 4 weeks and 12 weeks.

After indwelling for a predetermined period (4 weeks and 12 weeks), anesthesia was performed as in the case of placing an implantable medical device, coronary angiography was performed, blood was killed, and the heart was removed. The implantable medical device was removed from the heart and fixed with a 10% neutral buffered formalin solution. The fixed sample was embedded in resin according to a standard method to prepare a pathological section and stained with hematoxylin and eosin. This was subjected to observation with an optical microscope, and the intimal cross-sectional area was measured. Table 2 shows the average values of the measurement results of the implantable medical devices of Example 2, Comparative Example 3 and Comparative Example 4.

For those indwelling for 4 weeks, anti-fonnville was used to identify endothelial cells. Immunostaining with a brand factor antibody was performed. As a result, the intima of the right iliac artery in which the implantable medical device prepared in Example 2 was indwelled was completely covered with von Wille brand factor 1-positive vascular endothelial cells, confirming intimal repair. In contrast, in the implanted medical devices of Comparative Examples 3 and 4, only a part of the von Willebrand factor-positive vascular endothelial cells could be confirmed, and the repair of the intima was not so advanced. Was confirmed. Table 2

From Table 2, it can be seen that Example 2 showed a significant (p <0.05) suppression effect on hyperplasia at 4 weeks and at 12 weeks compared to Comparative Example 4. No significant change was found in the intimal cross-sectional area in comparison. On the other hand, in Comparative Example 3, although the effect of suppressing thickening was observed after 4 weeks, the intimal cross-sectional area was increased after 12 weeks, and rebound of thickening was observed. This is because, in Comparative Example 3, in which only paclitaxel was mounted, pakurimixel was released from the implantable medical device because intimal repair was not recognized much after 4 weeks as described above. Later, the effect of inhibiting the growth of vascular smooth muscle cells was lost, and the intimal cross-sectional area seems to have increased. On the other hand, in Example 2 equipped with arginine and paclitaxel, the intima was repaired after 4 weeks, so the function was improved and repaired even after arginine and paclitaxel were released from the implantable medical device. It is considered that the intimal hyperplasia was suppressed by the endothelial cells. Industrial applicability

As described above, the present invention relates to an implantable medical device for indwelling in a lumen in a living body, comprising: a medical device main body; a vascular smooth muscle cell proliferation inhibitor mounted on the medical device main body; Since it is characterized by being composed of an endothelial cell function improving drug, it can be applied directly and locally to a lumen in a living body. The release of a vascular smooth muscle cell growth inhibitor suppresses the growth of vascular smooth muscle cells, and releases a vascular endothelial cell function improving agent to improve the function of vascular endothelial cells. Therefore, even after the release of the vascular smooth muscle cell proliferation inhibitor is terminated, the intimal hyperplasia is suppressed by the improved endothelial cells, so that restenosis can be surely suppressed.

When the medical device body is a stent, the stenosis formed in a lumen in a living body is expanded, and the stenosis is left there for a long time to secure the expanded lumen. Is possible.

Claims

The scope of the claims

1. A body for indwelling in a lumen in a living body, comprising: a medical device main body; and a vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function improving agent mounted on the medical device main body. Implantable medical device.

2. The implantable medical device according to claim 1, wherein the vascular endothelial cell function improving agent is an HMG-CoA reductase inhibitor.

3. The HMG-CoA reductase inhibitor is one of simvasin, ceribas sodium, pivasin, mouth bath, atorvastatin, fluvastatin sodium, pravastin, sodium and rosuvastin The implantable medical device according to claim 2, wherein:

4. The implantable medical device according to claim 1, wherein the vascular endothelial cell function improving agent is any of an ACE inhibitor, an angiotensin II receptor antagonist, and a calcium antagonist.

5. The implantable medical device according to claim 1, wherein the vascular endothelial cell function improving agent is a NO donor.

6. The implantable medical device according to claim 5, wherein the NO donor is S_Nitroso-N-acety1-DL-penici11amine (SNAP) or arginine.

7. The implantable medical device according to claim 1, wherein the vascular smooth muscle cell proliferation inhibitor is any one of an immunosuppressant, an anticancer agent, an antibiotic, genistein, tilphosphine, and cytochalasin.

8. The vascular smooth muscle cell proliferation inhibitor is sirolimus (rabamycin), tactose limus hydrate, everolimus, everolimus plus, paclitaxel (Taxo-1) V), docetaxel hydrate, actinomycin D, mitomycin C, 2. The implantable medical device according to claim 1, wherein the device is one of adriamycin.

9. On the surface of the medical device main body, there is provided a polymer layer made of a biodegradable polymer or a biocompatible polymer containing the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent therein. The implantable medical device according to claim 1.

10. The surface of the medical device main body has the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent, and is formed outside the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improving agent. The implantable medical device according to any one of claims 1 to 8, further comprising a polymer layer made of a degradable polymer or a biocompatible polymer.

1 1. The biodegradable polymer is polylactic acid, polydalicholic acid, polylactic acid-polyglycolic acid copolymer, polyhydroxybutyric acid, polymalic acid, polyhydroxyamino acid, collagen, laminin, heparan sulfate, fibronectin, One of vitronectin, chondroitin sulfate, or hyaluronic acid

The biocompatible polymer is any one of silicone, a blend or block copolymer of polyether polyurethane and dimethyl silicone, polyurethane, polyacrylamide, polyethylene oxide, and polycarbonate. The implantable medical device according to 0.

12. The medical device according to claim 1, wherein the medical device main body is a stent.