JP4588986B2 - Implantable medical device - Google Patents

Description

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

  A stent is a tubular device for maintaining a stenosis that has occurred in a blood vessel or other in-vivo lumen in an expanded state, for example, for improving the stenosis after percutaneous coronary angioplasty (PTCA). It is used. PTCA is a very effective treatment for ischemic heart disease, but there is a problem that restenosis occurs at a rate of 40 to 50% within several months after PTCA (Popma JJ, Topol EJ. Am J Med 88). : 1N-16N, 1990). Causes of restenosis after PTCA are mainly due to (1) thrombotic occlusion, (2) lumen narrowing by elastin recoil of the vascular wall after dilatation by balloon, and (3) coronary artery wall repair caused by PTCA The neointimal may be excessively thickened. Therefore, in order to prevent restenosis, stent therapy has been attempted in which the vessel stenosis is expanded with a balloon after PTCA and a stent made of a metal mesh structure is placed to minimize elastin recoil (Fischman). DL, Leon MB et al. N Engl J Med 331: 495-501, 1994). In addition, for thrombotic occlusions, there was a problem that more spread thrombi were formed when stents were used than when they were not used, and subacute thrombotic occlusions occurred 1 to 2 weeks after stent insertion. However, combined use of ticlopidine and aspirin made it possible to prevent thrombus formation. However, when the stent is used, the restenosis rate is lower than that of PTCA alone, but restenosis is observed at a rate of about 20-30% mainly due to intimal thickening, and this problem is still solved. Not done.

  Intimal thickening, which is the main cause of restenosis after stent placement, is thought to occur by the following mechanism. Due to intimal damage caused by PTCA or stent placement, platelets aggregate around the stent wire to form a thrombus, and from there, cytokines such as Platelet Derived Growth Factor (PDGF) and Transforming Growth Factor (TGF), and 12-hydroxyeticate (TGF) Such as 12-HETE) is released. On the other hand, inflammatory cells such as monocytes adhere to the blood vessel wall via adhesion molecules such as vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and selectin at the intimal lesion site. Then, various physiologically active substances such as PDGF are released while invading into the blood vessel wall at the same time as it accumulates around the stent wire. Furthermore, in addition to the endothelial cells that controlled the activation of vascular smooth muscle cells falling off or falling in function due to intimal damage, stimulation of various physiologically active substances such as PDGF or vascular wall machinery produced during vasodilation As a result of mechanical disruption, smooth muscle cells in the vascular media are activated and transformed from contracted to synthetic. Synthetic smooth muscle cells migrate to the vascular intima and proliferate, resulting in intimal thickening.

  Therefore, various studies have been conducted to prevent restenosis by mounting a drug that can inhibit the migration and proliferation of vascular smooth muscle cells, which is the direct cause of intimal thickening, on the stent and releasing it at the stent placement site. . As specific examples of such drugs, Patent Document 1 discloses Taxol (paclitaxel), Patent Document 2 discloses Mitocin C, Adriamycin, Genistein, Tylphostin, and Patent Document 3 discloses cytochalasin. ing. Recently, a stent loaded with sirolimus (rapamycin) has also been reported. However, since these drugs do not have the effect of improving or repairing injured or reduced function of the intima and only directly suppress the proliferation and migration of vascular smooth muscle cells, the drugs are released and drugs in the stent placement area Restenosis is a concern when the concentration of is reduced. In addition, these drugs may inhibit even the function of vascular endothelial cells, which is indispensable in the blood vessel healing process.

JP-T 9-503488 JP-A-9-56807 Japanese National Patent Publication No. 11-500355

  Therefore, an object of the present invention can be directly and locally applied to a lumen in a living body, and further suppresses the proliferation of vascular smooth muscle cells and improves the function of vascular endothelial cells to improve the vascular endothelium. An object of the present invention is to provide an in-vivo medical device that promotes the development and reliably suppresses restenosis.

  Such an object is achieved by the present inventions (1) to (14) below.

  (1) A device for indwelling in a living body characterized by comprising a medical device main body, 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 (1), wherein the vascular endothelial cell function improving drug is an HMG-CoA reductase inhibitor.

  (3) The body according to (2) above, wherein the HMG-CoA reductase inhibitor is any one of simvastatin, cerivastatin sodium, pitavastatin, lovastatin, atorvastatin, fluvastatin sodium, pravastatin sodium, and rosuvastatin Implanted medical device.

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

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

  (6) The implantable medical device as described in (5) above, wherein the NO donor is S-Nitroso-N-acetyl-DL-penicillamine (SNAP) or arginine.

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

  (8) The vascular smooth muscle cell proliferation inhibitor is sirolimus (rapamycin), tacrolimus hydrate, everolimus, everolimus plus, paclitaxel (taxol), docetaxel hydrate, actinomycin D, mitomycin C, or adriamycin. The implantable medical device described in (1) above, wherein

  (9) The medical device main body has 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 inside. The implantable medical device according to any one of (1) to (8) above.

  (10) The vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function-improving drug are provided on the surface of the medical device body, and biodegraded outside the vascular smooth muscle cell proliferation-suppressing drug and the vascular endothelial cell function-improving drug. The implantable medical device according to any one of (1) to (8) above, which has a polymer layer made of an adhesive polymer or a biocompatible polymer.

  (11) The biodegradable polymer is polylactic acid, polyglycolic acid, polylactic acid-polyglycolic acid copolymer, polyhydroxybutyric acid, polymalic acid, poly α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, Either chondroitin sulfate or hyaluronic acid, and the biocompatible polymer is any one of silicone, a blend of polyether-type polyurethane and dimethylsilicone or a block copolymer, polyurethane, polyacrylamide, polyethylene oxide, and polycarbonate. The implantable medical device described in (9) or (10) above,

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

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

  (14) The vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function-improving drug are directly mounted on the surface of the medical device main body, and outside the vascular smooth muscle cell proliferation-suppressing drug and the vascular endothelial cell function-improving drug. The implantable medical device according to any one of (1) to (8) above, which is coated with a polymer layer comprising a biodegradable polymer or a biocompatible polymer.

  As described above, the present invention is an implantable medical device for indwelling in a lumen in a living body, the medical device main body, a vascular smooth muscle cell proliferation inhibitor and a blood vessel mounted on the medical device main body. Since it is composed of an endothelial cell function improving drug, it can be directly applied locally to a lumen in a living body. Then, the growth of vascular smooth muscle cells is suppressed by releasing the vascular smooth muscle cell proliferation inhibitor, and the function of the vascular endothelial cells is improved by releasing the vascular endothelial cell function improving drug. Therefore, even after the release of the vascular smooth muscle cell proliferation inhibitor, the intimal thickening is suppressed by the endothelial cells whose function has been improved, so that restenosis can be reliably suppressed.

  Further, in the case where the medical device body is a stent, the narrowed portion generated in the lumen in the living body is expanded, and in order to secure the expanded lumen, the medical device body is placed therein for a long period of time. Is possible.

  Hereinafter, the implantable medical device of the present invention will be described in detail.

  The implantable medical device of the present invention includes a medical device 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.

  Examples of the medical device main body include a stent, a catheter, a balloon, a vascular prosthesis material, and an artificial blood vessel. Among them, there is a portion for expanding a stenosis portion generated in a lumen in a living body and securing the expanded lumen. A stent that can be placed in a long period of time is a preferred embodiment. Hereinafter, the 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.

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

  The stent is not particularly limited in its material, shape, size, and the like as long as it can expand and place a stenosis in a lumen in a living body such as a blood vessel, bile duct, trachea, esophagus, and urethra.

  The material for forming the stent may be appropriately selected depending on the application location, and examples thereof include metal materials, polymer materials, ceramics, and the like. When the stent is formed of a metal material, the metal material is excellent in strength, so that the stent can be reliably placed in the stenosis. In addition, when the stent is formed of a polymer material, the polymer material is excellent in flexibility, and thus exhibits an excellent effect in terms of reachability (delivery property) to the narrowed portion of the stent.

  Examples of the metal material include stainless steel, Ni—Ti alloy, tantalum, titanium, gold, platinum, inconel, iridium, tungsten, cobalt-based alloy, and the like. And among stainless steel, SUS316L with favorable corrosion resistance is suitable.

  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 has sufficient strength to be stably placed in a stenosis portion formed in a lumen in a living body. For example, a wire of a metal material or a fiber of a polymer material is formed in a net shape. Preferred examples include any shape body such as a cylindrical body constituted by the above, or a cylindrical body made of a metal material or a polymer material as shown in FIG.
In the embodiment shown in FIG. 1, the stent 10 is composed of a linear member 11 and has a substantially rhombic element 12 having a notch therein as a basic unit. A plurality of substantially rhombic elements 12 are continuously arranged in the minor axis direction and joined to form an annular unit 13. The annular unit 13 is connected to an adjacent annular unit via a linear connecting member 14. Thereby, the some annular unit 13 is continuously arrange | positioned in the axial direction in the state couple | bonded.

  The stent may be either a balloon expandable type or a self-expandable type. Further, the size of the stent may be appropriately selected according to the application location. For example, when used for the coronary artery of the heart, the outer diameter before expansion is usually 1.0 to 3.0 mm, and the length is preferably 5 to 50 mm.

  The surface of the stent is coated with a vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function-improving drug. When the stent is placed in a stenosis of a lumen in a living body, the vascular smooth muscle cell proliferation inhibitor and vascular The endothelial cell function improving drug is released into the stent placement site and the surrounding tissue.

  By coating both a vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function improver, the following effects are obtained. In general, a vascular smooth muscle cell proliferation inhibitor also inhibits the function and proliferation of vascular endothelial cells. Therefore, when only a vascular smooth muscle cell proliferation inhibitor is coated on a stent, the function / proliferation of vascular endothelial cells may be inhibited. However, vascular smooth muscle cell proliferation inhibitors inhibit the proliferation of vascular smooth muscle cells by coating the stent with both vascular smooth muscle cell proliferation drug and vascular endothelial cell function improving drug and releasing it locally. At the same time, the vascular endothelial cell function-improving drug improves the proliferation and function of vascular endothelial cells, so that the vascular intima is improved and repaired more completely. Therefore, even after the release of the vascular smooth muscle cell proliferation inhibitor, the intimal thickening is suppressed by the endothelial cells whose function has been improved, so that restenosis (rebound) after a long period of time hardly occurs.

  Examples of a method for evaluating the degree of improvement in the function of vascular endothelial cells include immunostaining with an anti-von Willebrand factor antibody (Dako, CA, USA). As a result, if the affected area is covered with von Willebrand factor positive vascular endothelial cells, intimal repair / function improvement is confirmed, while if von Willebrand factor positive vascular endothelial cells cannot be confirmed, intima repair Is not observed, so that intimal thickening occurs and the possibility of stenosis increases.

  Vascular smooth muscle cell growth inhibitors include, for example, immunosuppressants such as sirolimus (rapamycin), tacrolimus hydrate, everolimus, everolimus plus, anticancer agents such as paclitaxel (taxol), docetaxel hydrate, actinomycin D, mitocin C And antibiotics such as adriamycin, genistein, tyrphostin, and cytochalasin.

  The vascular endothelial cell function improving agent is preferably one that promotes NO production, and examples thereof include HMG-CoA reductase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, calcium antagonists, and NO donors.

  HMG-CoA reductase inhibitor has been used as a therapeutic agent for hyperlipidemia because it blocks cholesterol synthesis in the liver, but recently, it has been applied directly to the vascular wall. It has been reported that there is an effect related to suppression of thickening. Specifically, inhibition of oxidation of LDL (Massy Ziad A., et al., Biochem Biophys Res Commun 267 536-540 (2000)), suppression of inflammatory reaction (Sakai M., et al., Atherosclerosis 133 51-59) (1997)), suppression of foaming of smooth muscle cells / macrophagy (Bellosta S., et al., Atherocleosis 137 Suppl. S101-109 (1998)) has been reported.

  And recently, NO-producing effects of HMG-CoA reductase inhibitors (Laufs U et al, Circulation (97) 1129-1135 1998) have attracted attention. It is considered that vascular endothelialization is promoted by improving the function of vascular endothelial cells and promoting NO production. And, it is considered that migration and proliferation of smooth muscle cells to the intima side are suppressed by promoting endothelialization of blood vessels.

  The ACE inhibitor inhibits the production of angiotensin II from angiotensin I in the renin-angiotensin system, which is a powerful pressor system in the living body, thereby inhibiting vasoconstriction and suppressing sympathetic nerve enhancement. In addition to acting on the antihypertensive calclein-kinin-prostaglandin system to suppress the degradation of bradykinin and dilate the blood vessels, it promotes the production of prostaglandins to relax the blood vessels and reduce blood pressure. Has the function of lowering. In recent years, it has been reported that this ACE inhibitor also acts on endothelial cells and promotes NO production via bradykinin.

  An angiotensin II receptor antagonist has a function of lowering blood pressure by inhibiting angiotensin II produced in the renin-angiotensin system from binding to its main receptor, an angiotensin II-I type receptor. It has been reported that this angiotensin II receptor antagonist also acts on endothelial cells and upregulates the angiotensin II-II receptor to promote NO production.

  Calcium antagonists bind to and inhibit calcium channels on the cell membrane, thereby inhibiting the inflow of calcium ions into the cells, suppressing vasoconstriction and lowering blood pressure. Amlodipine besylate, a kind of calcium antagonist, has also been reported to act on endothelial cells and promote NO production (Kobayashi N, Yanaka H, Tojo A, Kobayashi K, Matsuoka H. J.). Cardiovasc Pharm 34: 173-181, 1999).

  From the above, HMG-CoA reductase inhibitors, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and some calcium antagonists have improved vascular endothelial cell function in addition to the conventionally known effects, It is expected that vascular endothelialization is promoted by promoting NO production.

  Examples of the HMG-CoA reductase inhibitor include simvastatin, cerivastatin sodium, pitavastatin, lovastatin, atorvastatin, fluvastatin sodium, pravastatin sodium, and rosuvastatin.

  Examples of the ACE inhibitor include ramipril, captopril, alacepril, enalapril maleate, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, and perindopril erbumine.

  Examples of the angiotensin II receptor antagonist include losartan potassium, candesartan cilexetil, and valsartan.

  Examples of calcium antagonists include amlodipine besylate.

  Examples of the NO donor include S-Nitroso-N-acetyl-DL-penicillamine (SNAP) and arginine.

  The amount of the vascular endothelial cell function-improving drug coated on the surface of the stent is not particularly limited as long as the vascular endothelial cells are not killed and NO production is promoted. 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 proliferation of vascular smooth muscle cells is inhibited.

The form of the stent coated with the vascular smooth muscle cell growth inhibitor and the vascular endothelial cell function improver is not particularly limited. For example, in the polymer layer 21 made of biodegradable polymer or biocompatible polymer as shown in FIG. Alternatively, the stent surface may be coated in a form containing (mixed) the vascular smooth muscle cell proliferation inhibitor 22 and the vascular endothelial cell function improver 23.
Further, as shown in FIG. 3, a vascular smooth muscle cell growth inhibitor 22 and a vascular endothelial cell function-improving drug 23 are directly coated on the surface of the stent to provide a drug layer (drug layer 31). You may cover with the polymer layer 32 which consists of a degradable polymer or a biocompatible polymer.

  Further, as shown in FIG. 4, a polymer layer 42 made of a biodegradable polymer or a biocompatible polymer containing one of a vascular smooth muscle cell proliferation inhibitor or a vascular endothelial cell function improving agent 41 is provided on the surface of the stent, A polymer layer 44 made of a biodegradable polymer or a biocompatible polymer containing the other 43 of a vascular smooth muscle cell proliferation inhibitor or a vascular endothelial cell function improving drug may be provided on the outer side, and the outer side may be biodegraded. It may be covered with a polymer layer 45 made of a conductive polymer or a biocompatible polymer. The polymer layers 42, 44, 45 made of these biodegradable polymers or biocompatible polymers may be the same or different.

  Further, as shown in FIG. 5, a drug layer 51 composed of one of a vascular smooth muscle cell proliferation inhibitor or a vascular endothelial cell function improving drug is provided on the surface of the stent, and further, a vascular smooth muscle cell proliferation inhibitor or vascular endothelial cell is provided on the outer side. A drug layer 52 made of the other of the function improving drugs may be provided, and the outside may be covered with a polymer layer 53 made of a biodegradable polymer or a biocompatible polymer.

  Further, as shown in FIG. 6, a drug layer 61 made of either a vascular smooth muscle cell growth inhibitor or a vascular endothelial cell function improving drug is provided on the surface of the stent, and further, it is made of a biodegradable polymer or a biocompatible polymer. A barrier layer 62 may be provided, and a drug layer 63 composed of the other of a vascular smooth muscle cell proliferation inhibitor or a vascular endothelial cell function-improving drug may be provided on the outside of the barrier layer 62, and a biodegradable polymer may be provided on the outside thereof. Alternatively, it may be covered with a polymer layer 64 made of a biocompatible polymer. The barrier layer 62 and the polymer layer 64 made of biodegradable polymer or biocompatible polymer 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 proliferation inhibitor and a vascular endothelial cell function improver (drug layer) Is covered with a polymer layer composed of a biodegradable polymer, the biodegradable polymer is decomposed, so that the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function-improving agent are placed on the stent placement site and the Released directly into the surrounding tissue.

  Biodegradable polymers are those that are enzymatically or non-enzymatically degraded in vivo, the degradation products do not exhibit toxicity, and can release the aforementioned vascular smooth muscle cell proliferation inhibitor and vascular endothelial cell function improving agent. Although not particularly limited, for example, polylactic acid, polyglycolic acid, polylactic acid-polyglycolic acid copolymer, polyhydroxybutyric acid, polymalic acid, poly α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate And hyaluronic acid. 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 improver are contained in a polymer layer made of a biocompatible polymer, or a vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function improver (drug layer) Vascular smooth muscle cell proliferation inhibitor and vascular endothelial cell function-improving agent are leached on the outer surface of the biocompatible polymer when the outside of the membrane is covered with a polymer layer made of a biocompatible polymer. Cytostatics and vascular endothelial cell function improvers are released directly to the stent placement site and surrounding tissue.

  The biocompatible polymer is essentially one that does not easily adhere to platelets, does not show irritation to tissues, and is capable of leaching the vascular smooth muscle cell proliferation inhibitor and vascular endothelial cell function improving agent. Although not particularly limited, for example, various synthetic polymers such as silicone, polyether type polyurethane and dimethyl silicone blend or block copolymer, polyurethane such as segmented polyurethane, polycarbonate such as polyacrylamide, polyethylene oxide, polyethylene carbonate, polypropylene carbonate, etc. Is mentioned.

  When the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function-improving drug are contained in a polymer layer composed of a biodegradable polymer or a biocompatible polymer, the mode of inclusion is not particularly limited, and vascular smooth muscle cell proliferation The inhibitor and the vascular endothelial cell function improving agent may be present uniformly or non-uniformly 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 using a stent as a medical device body, rapamycin as a vascular smooth muscle cell growth inhibitor, simvastatin as a vascular endothelial cell function improving drug, and polylactic acid as a biodegradable polymer, simvastatin and rapamycin are converted into dichloroethane. A method of providing a polylactic acid layer (polymer layer) containing simvastatin and rapamycin on the stent surface by mixing the dissolved solution and a solution of polylactic acid dissolved in dichloroethane and spraying the mixed solution onto the stent. Is mentioned.

  The implantable medical device of the present invention thus obtained can be used by being directly placed in a lumen in a living body. The vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function-improving drug are released into the indwelling site of the stent and the surrounding tissues, and the vascular smooth muscle cell proliferation inhibitor suppresses the proliferation of vascular smooth muscle cells and Endothelial cell function-improving drug improves vascular endothelial cell function. Therefore, even after the release of the vascular smooth muscle cell proliferation inhibitor, the intimal thickening is suppressed by the endothelial cells whose function has been improved, so that restenosis can be reliably suppressed.

Hereinafter, the present invention will be described more specifically with reference to examples. In addition, this invention is not limited to the following Example.
( Reference Example 1 )
A solution prepared by dissolving 20 mg of simvastatin and 20 mg of rapamycin in 1 ml of dichloroethane and a solution of 40 mg of polylactic acid dissolved in 4 ml of dichloroethane were mixed. Then, this mixed solution is sprayed onto a 15 mm long stent produced by processing a 2 mm diameter stainless steel pipe, thereby providing a polylactic acid layer (polymer layer) containing simvastatin and rapamycin on the surface of the stent. Thus, the implantable medical device of the present invention was produced.

(Comparative Example 1)
A solution in which 20 mg of rapamycin was dissolved in 1 ml of dichloroethane was mixed with a solution in which 40 mg of polylactic acid was dissolved in 4 ml of dichloroethane. Then, the mixed solution is sprayed onto a 15 mm long stent produced by processing a stainless steel pipe having a diameter of 2 mm, thereby providing a polylactic acid layer (polymer layer) containing rapamycin on the stent surface. An implantable medical device was made.

(Comparative Example 2)
A solution was prepared by dissolving 40 mg of polylactic acid in 4 ml of dichloroethane. Then, this solution was sprayed onto a 15 mm long stent produced by processing a stainless steel pipe having a diameter of 2 mm, thereby providing a polylactic acid layer (polymer layer) on the stent surface, thereby producing an implantable medical device. .

(Evaluation 1)
<Therapeutic effect comparison test using vascular injury model by rabbit iliac artery balloon abrasion>
Rabbit muscles were anesthetized with ketamine (30 mg / kg) and xylazine (3 mg / kg). The right common carotid artery was detached from the tissue. After introducing about 150 U / kg of heparin from the auricular vein, a sheath introducer was introduced by a predetermined method. A PTCA balloon preloaded with a guide wire was inserted into the blood vessel and carried to the distal portion of the iliac artery. With the balloon expanded to the specified pressure, the balloon was pulled to the proximal portion of the iliac artery and the blood vessels were scratched. This balloon rubbing was repeated three times. Subsequently, the implantable medical device produced in Reference Example 1, the implantable medical device produced in Comparative Example 1, and the implantable medical device produced in Comparative Example 2 were introduced into the right iliac artery, respectively. Indwelling at the specified pressure. After removing the balloon, the common carotid artery was ligated, sutured in three layers, and left for a predetermined period. The indwelling period was 4 weeks and 8 weeks.

After indwelling for a predetermined period (4 weeks and 8 weeks), approach the blood vessel from the left carotid artery in the same way as in the implantation of an implantable medical device. did. Perfusion with 2 U / ml heparinized physiological saline was started from the carotid artery sheath line, and at the same time, the abdominal vena cava was excised and killed by blood removal. After systemic perfusion with heparinized physiological saline, systemic perfusion was performed with 10% neutral buffered formalin solution to fix the target blood vessel. 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 inner film thickness was measured. Three measurements were performed on the implantable medical devices of Reference Example 1 , Comparative Example 1 and Comparative Example 2, respectively. Table 1 shows the average value of these measurement results.

In addition, immunostaining with anti-von Willebrand factor antibody (Dako, CA, USA) was performed on the cells left for 4 weeks to identify endothelial cells. As a result, the vascular intima of the right iliac artery indwelling the implantable medical device produced in Reference Example 1 was covered with von Willebrand factor-positive vascular endothelial cells, confirming intimal repair and functional improvement On the other hand, in the indwelling medical devices of Comparative Examples 1 and 2, almost no von Willebrand factor-positive vascular endothelial cells were confirmed, and intimal repair was hardly observed.

From Table 1, the reference example 1 was significantly (p <0.05: p is a judgment value of statistical processing), and the thickening inhibitory effect was confirmed after 4 weeks and 8 weeks compared with Comparative Example 2 for 4 weeks. No change was seen in the inner film thickness even after comparison with 8 weeks later. On the other hand, although the comparative example 1 showed the thickening inhibitory effect after 4 weeks, the inner film thickness after 8 weeks increased and the rebound of thickening was seen. This is because in Comparative Example 1 in which only rapamycin was mounted, intimal repair was hardly observed after 4 weeks as described above, and therefore, vascular smooth muscle was released after rapamycin was released from the implantable medical device. It is thought that the cell growth inhibitory effect disappeared and the inner film thickness increased. On the other hand, in Reference Example 1 in which simvastatin and rapamycin were loaded, the intima was repaired after 4 weeks. It is thought that intimal thickening was suppressed.

( Example 1 )
A solution in which 20 mg of arginine and 20 mg of paclitaxel were dissolved in 1 ml of ethanol and a solution in which 40 mg of polylactic acid were dissolved in 4 ml of acetone were mixed. Then, the mixed solution is sprayed onto a 15 mm long stent produced by processing a stainless steel pipe having a diameter of 2 mm, thereby providing a polylactic acid layer (polymer layer) containing arginine and paclitaxel on the stent surface. The implantable medical device of the present invention was produced.

(Comparative Example 3)
A solution in which 20 mg of paclitaxel was dissolved in 1 ml of ethanol and a solution in which 40 mg of polylactic acid were dissolved in 4 ml of acetone were mixed. Then, this mixed solution is sprayed on a 15 mm long stent produced by processing a stainless steel pipe having a diameter of 2 mm, thereby providing a polylactic acid layer (polymer layer) containing paclitaxel on the stent surface. An implantable medical device was made.

(Comparative Example 4)
A solution in which 40 mg of polylactic acid was dissolved in 4 ml of acetone was prepared. Then, this solution was sprayed onto a 15 mm long stent produced by processing a stainless steel pipe having a diameter of 2 mm, thereby providing a polylactic acid layer (polymer layer) on the stent surface, thereby producing an implantable medical device. .

(Evaluation 2)
<Therapeutic effect comparison test using porcine coronary artery vascular injury model>
Azaperone and atropine sulfate were intramuscularly administered to 8 pigs as a preanesthetic. Anesthesia was performed by intramuscular administration of ketamine hydrochloride, and anesthesia was maintained with a mixed gas of air: oxygen = 1: 1 and 2% sevoflurane.

The implantable medical device produced in Example 1 , the implantable medical device produced in Comparative Example 3, and the implantable medical device produced in Comparative Example 4 were placed in each of the three branches of the porcine coronary artery according to a conventional method. This was performed on 8 pigs. The indwelling period was 4 weeks and 12 weeks.
After indwelling for a predetermined period (4 weeks and 12 weeks), anesthesia was performed in the same manner as in the implantation of the implantable medical device. After angiography of the coronary artery, the blood was killed and the heart was taken out. The implantable medical device was removed from the heart and fixed with 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 intima cross-sectional area was measured. Table 2 shows the average values of the measurement results for the implantable medical devices of Example 1 , Comparative Example 3 and Comparative Example 4.

In addition, for those left for 4 weeks, immunostaining with an anti-von Willebrand factor antibody was performed to identify endothelial cells. As a result, the vascular intima of the right iliac artery where the implantable medical device produced in Example 1 was placed was entirely covered with von Willebrand factor-positive vascular endothelial cells, and intimal repair was confirmed. On the other hand, in the implantable medical devices of Comparative Examples 3 and 4, only a part of von Willebrand factor-positive vascular endothelial cells can be confirmed, and the intima repair has not progressed much. confirmed.

From Table 2, Example 1 showed a significant (p <0.05) thickening inhibitory effect compared to Comparative Example 4 after 4 weeks and after 12 weeks, comparing 4 weeks and 12 weeks later. There was no significant change in the intima cross section. On the other hand, in Comparative Example 3, although the thickening inhibitory effect was observed after 4 weeks, the intima cross-sectional area after 12 weeks was increased, and thickening rebound was observed. This is because in Comparative Example 3 in which only paclitaxel is mounted, intimal repair is not so much observed after 4 weeks as described above, and therefore, after the release of paclitaxel from the implantable medical device, vascular smooth muscle It is thought that the cell growth inhibitory effect disappeared and the intima cross-sectional area increased. On the other hand, in Example 1 loaded with arginine and paclitaxel, the intima was repaired after 4 weeks. It is thought that intimal thickening was suppressed.

FIG. 1 is a side view showing one embodiment of a stent. FIG. 2 is an enlarged cross-sectional view taken along line AA in FIG. FIG. 3 is a view similar to FIG. 2 and shows an embodiment in which the coat forms of the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent are different. FIG. 4 is a view similar to FIG. 2 and shows an embodiment in which the coat forms of the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent are different. FIG. 5 is a view similar to FIG. 2, and shows an embodiment in which the coat forms of the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent are different. FIG. 6 is a view similar to FIG. 2 and shows an embodiment in which the coat forms of the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function improving agent are different.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Stent 11 Linear member 12 Element of substantially rhombus 13 Ring unit 14 Connecting member 21 Polymer layer 22 Vascular smooth muscle cell proliferation inhibitor 23 Vascular endothelial cell function improving agent 31 Drug layer 32 Polymer layer 41 Vascular smooth muscle cell proliferation inhibitor or One of vascular endothelial cell function improving drug 42 polymer layer 43 Other of vascular smooth muscle cell proliferation inhibitor or vascular endothelial cell function improving drug 44 polymer layer 45 polymer layer 51 of vascular smooth muscle cell proliferation inhibitor or vascular endothelial cell function improving drug Drug layer made of one 52 Drug layer made of the other of vascular smooth muscle cell proliferation inhibitor or vascular endothelial cell function improving drug 53 Polymer layer 61 Drug layer made of one of vascular smooth muscle cell proliferation inhibitor or vascular endothelial cell function improving drug 62 Barrier layer 63 Vascular smooth muscle cell proliferation inhibitor or vascular endothelial cell function improving agent Drug layer 64 polymer layer made of the other

Claims (5)

A vascular smooth muscle cell proliferation inhibitor and a vascular endothelial cell function-improving drug mounted on the medical instrument body, wherein the vascular smooth muscle cell proliferation inhibitor is paclitaxel, and the vascular endothelial cell body for functional improvement agent Ri NO donor der, the NO donor is placed in a lumen in a living body, which is a S-nitroso-N-acetyl- DL-penicillamine (SNAP) or arginine Implanted medical device. The medical device main body has 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. 2. The implantable medical device according to 1. The surface of the medical device main body has the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function-improving agent, and a biodegradable polymer or the outer side of the vascular smooth muscle cell proliferation inhibitor and the vascular endothelial cell function-improving agent The implantable medical device according to claim 1, further comprising a polymer layer made of a biocompatible polymer. The biodegradable polymer is polylactic acid, polyglycolic acid, polylactic acid-polyglycolic acid copolymer, polyhydroxybutyric acid, polymalic acid, polyα-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, One of hyaluronic acid,
Wherein the biocompatible polymer is a silicone, blend or block copolymer of polyether type polyurethane and dimethyl silicon, polyurethane, polyacrylamide, polyethylene oxide, to claim 2 or 3, characterized in that either the polycarbonate The implantable medical device described. The medical device body, Implantable medical device according to any one of claims 1 to 4, characterized in that a stent.

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