JP2006262960A - Stent - Google Patents

Abstract

Provided is a stent having low cell adhesion compared to a conventional stent.
A stent having a polymer layer on the surface of a stent body, which is made of a composition containing a copolymer of a polysaccharide and a biodegradable polyester structural unit and can control cell adhesion.
[Selection figure] None

Description

  The present invention relates to a stent that maintains the patency of these lesions by being placed in a stenosis or occlusion in a lumen in a living body such as a blood vessel, bile duct, trachea, esophagus, or urethra.

As an example, the case of angioplasty applied to ischemic heart disease will be described.
The westernization of dietary habits in Japan is rapidly increasing the number of patients with ischemic heart disease (angina and myocardial infarction). In response to this, percutaneous transvascular coronary angioplasty (PTCA) has been performed as a method for reducing such coronary artery lesions, and it has become very popular.

  PTCA is a method for improving blood flow by expanding the vascular lumen of a lesion as shown below.

  First, a small incision is made in the artery of the patient's leg or arm, an introducer sheath (introducer) is placed, and a long hollow tube called a guide catheter is inserted into the blood vessel while leading the guide wire through the lumen. To do.

  For example, if the lesion is in the coronary artery, place a guide catheter at the entrance of the coronary artery, remove the guide wire, insert another guide wire and balloon catheter into the lumen of the guide catheter, and advance the guide wire. Then, the balloon catheter is advanced to the lesioned part of the patient's coronary artery under X-ray contrast, and the balloon is positioned in the lesioned part.

  Furthermore, if the doctor inflates the balloon at that position at a predetermined pressure for 30 to 60 seconds, once or a plurality of times, the blood vessel lumen of the lesion can be expanded.

  Currently, the number of cases in which PTCA is applied is increasing due to technical development, and at the initial application of PTCA, a single branch lesion (stenosis only in one site) is localized (one having a short lesion length). PTCA expands to more distal lesions that are eccentric and calcified, and multi-branch lesions (lesions with stenosis in more than one site) Has been.

  However, even if the vascular lumen of the lesion is expanded by PTCA, the intima proliferates and restenosis occurs at a rate of 30 to 40%.

  Therefore, a stent may be used as a countermeasure.

  This stent is used to treat various diseases caused by stenosis or occlusion of blood vessels or other lumens, to expand the stenosis or occlusion site, and to secure the lumen to the stenosis or occlusion site. It is a tubular medical device that can be placed.

  Many of them are medical devices made of a metal material or a polymer material. For example, a tubular body made of a metal material or a polymer material provided with pores, a metal material wire, or a polymer material made of fiber. Various shapes have been proposed, such as knitted into a cylindrical shape and formed into a cylindrical shape.

If such a stent is placed at a stenosis or occlusion site after PTCA as described above, the occurrence of restenosis can be suppressed to some extent.
However, it is not possible to exert a remarkable effect by itself.

  Therefore, in recent years, a biological physiologically active substance (hereinafter also referred to as “drug”) such as an anticancer agent is supported on the stent using a polymer, so that the stent can be locally applied over a long period of time. Attempts have been made to reduce the restenosis rate by releasing this drug from the stent.

The drug can be retained on the stent surface by containing the drug in the polymer and coating the stent surface, or coating the drug on the stent surface with the polymer. Furthermore, when the stent is expanded at a stenosis or the like, the polymer expands, so that the drug does not peel from the stent surface.
In this way, the restenosis rate can be reduced.

  Here, as the polymer used for supporting the drug on the surface of the stent, a biocompatible polymer or a biodegradable polymer is used, and a biodegradable polymer is more preferably used. This is because all or part of the polymer remains in the body even after the drug is released, and thus chronic inflammation or thrombosis caused by the polymer may occur at the site.

As such a stent carrying a drug on its surface by a biodegradable polymer, for example, Patent Document 1 states that restenosis is a natural therapeutic effect response to arterial wall damage by an angioplasty method. Probably, provide a stent with a substance to treat this, and a stent that is delivered to the selected blood vessel and expands within it without losing a therapeutically significant amount of the applied drug. For the purpose of manufacturing an endovascular stent characterized in that it includes the following steps: (a) a method of manufacturing a generally cylindrical stent; (b) a solvent and a solvent A method of manufacturing an intravascular stent is described in which a solution comprising a polymer and a therapeutic agent dispersed in a solvent is applied to the stent body; and (c) the solvent is evaporated. It has been.
The polymer may be a bioabsorbable polymer, and specific examples include poly (L-lactic acid), poly (lactide coglycolide) and the like.

In addition, for example, Patent Document 2 discloses that a biocompatible polymer or a biopolymer is used so that a drug having an effect of preventing or treating arterial intimal thickening can be firmly attached and the drug can be released in a body fluid. For the purpose of providing a stent coated with a degradable polymer, a stent having a drug attached and coated with a biocompatible polymer and / or a biodegradable polymer is described.
Examples of this biodegradable polymer include polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, collagen, gelatin, chitin, chitosan, hyaluronic acid, poly-L-glutamic acid, poly-L -Polyamino acids such as lysine, starch, poly-ε-caprolactone, polyethylene succinate, poly-β-hydroxyalkanoate are mentioned, and further, these polymers can be used alone or in appropriate combination. Has been.

  In the case of a stent having such a biodegradable polymer on its surface, the polymer disappears after a lapse of a certain time, so that no chronic inflammation or thrombosis caused by the polymer occurs.

As described above, the performance of the stent has been gradually improved. That is, the original stent was used for suppressing restenosis after PTCA application. And, to improve the suppression rate (decrease in restenosis rate), by using a polymer to carry a drug on the surface, and making the polymer biodegradable, chronic inflammation caused by the polymer Stents with reduced thrombosis have been proposed.
JP-A-8-33718 Japanese Patent No. 3476604

  However, the present inventors have found that the rate of restenosis may increase as a result of cells adhering to the stent and the cells adhering to the stent proliferating.

  Even if it is an original stent that does not have a drug or polymer on its surface (that is, a simple metal stent, etc.) or a stent that has a drug or biodegradable polymer on its surface, cell adhesion The present inventors have found that there is a need to further lower the cell adhesion on the stent surface.

  Accordingly, an object of the present invention is to provide a stent that has the performance of a conventional stent, and further has low cell adhesion on the stent surface and low restenosis rate.

  The present inventor has repeatedly studied and found that a stent having a specific type of biodegradable polymer layer on the surface of the stent body solves the problems of the present invention.

  That is, this invention is following (1)-(9).

  (1) A stent having a polymer layer on the surface of a stent body, which is made of a composition containing a copolymer of a polysaccharide and a biodegradable polyester structural unit and can control cell adhesion.

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

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

  (4) The stent according to any one of (1) to (3), wherein the composition further contains a biological physiologically active substance.

  (5) The stent according to any one of (1) to (4), further including a layer made of the biological physiologically active substance between the stent body and the polymer layer.

  (6) The biological physiologically active substance is an anticancer agent, immunosuppressant, antibiotic, antirheumatic agent, antithrombotic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemia Drugs, integrin inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, biological materials, The stent according to any one of the above (1) to (5), which is at least one selected from the group consisting of interferon and NO production promoter.

  (7) The stent according to any one of (1) to (6), wherein the biodegradable polyester structural unit is lactic acid.

  (8) The above (1) to (1), wherein the polysaccharide is at least one selected from the group consisting of hyaluronic acid, amylose, pullulan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, dermatan sulfate, keratan sulfate, and heparan sulfate. The stent according to any one of (7).

  (9) The stent according to any one of (1) to (8), wherein the content of the polysaccharide in the copolymer is 1 to 50% by mass.

  The stent of the present invention does not cause polymer-induced chronic inflammation or thrombosis like the conventional stent, and further has a lower cell adhesion than the conventional stent. For this reason, the restenosis rate is also low.

  In the stent of the present invention, it is preferable that the composition further contains a biological and physiologically active substance, so that the composition has high flexibility even when the stent is expanded. The biological physiologically active substance can be continuously carried on the surface, and the restenosis rate can be further reduced.

  Further, in the stent of the present invention, it is preferable that a layer made of the biological and physiologically active substance is further provided between the stent body and the polymer layer. Because of its high flexibility, the biological and physiologically active substance can be carried on the surface of the stent body, and the restenosis rate can be reduced. Further, by adjusting the thickness of the polymer layer, there is an effect that the sustained release period of the biological physiologically active substance can be adjusted.

The present invention is a stent comprising a composition containing a copolymer of a polysaccharide and a biodegradable polyester structural unit on the surface of a stent body, and having a polymer layer capable of controlling cell adhesion.
Hereinafter, this stent is also referred to as “the stent of the present invention”.
The “composition containing a copolymer of a polysaccharide and a biodegradable polyester structural unit” is also referred to as a “biodegradable composition”.

<Stent body>
If the stent body material used in the present invention has strength or the like that allows the stent of the present invention to be placed in a lesion in a living body lumen such as a blood vessel, bile duct, trachea, esophagus, urethra, etc. The material, shape, size, etc. are not particularly limited. Balloon expansion means can be used as the indwelling means, but if the material of the stent body is an elastic body, self-expanding means using this elastic force can be used.

  The material of the stent body used in the present invention is not particularly limited, and a metal material, a polymer material, ceramics, or the like can be used, but it is preferable to use a metal material. This is because the strength is excellent and the stent of the present invention can be surely placed in the lesion.

  Here, examples of the metal material include stainless steel, Ni—Ti alloy, tantalum, nickel, chromium, iridium, tungsten, cobalt-based alloy, and the like. Of these, stainless steel is preferable, and SUS316L is most preferable. This is because the corrosion resistance is high.

  Many stent bodies formed of metallic materials can be expanded using balloons. Also, it is made of a metal material called pseudoelasticity, for example, a metal material such as a Ni-Ti alloy that has a constant stress and a large change in strain, or a metal material that gradually increases and changes as the stress increases. The stent body is self-expandable. Therefore, the stent compressed and held in advance is expanded by its elastic force by releasing the compression at the lesion.

  The material of the stent body used in the present invention is preferably a polymer material. The reason is that it has excellent flexibility and does not apply excessive force to the blood vessel wall when expanded.

  Here, as the polymer material, for example, polyesters such as polyethylene terephthalate and polybutylene terephthalate, or polyester-based elastomers having the structural unit, polyamides such as nylon 6, nylon 12, nylon 66, nylon 610, or the like are used. Examples of the structural unit include polyamide-based elastomers, polyurethanes, polyethylene, polypropylene, and polyolefins such as polyolefin-based elastomers having these structural units, polycarbonates such as polyethylene carbonate and polypropylene carbonate, cellulose acetate, and cellulose nitrate.

  Among these, polyethylene, polypropylene, polyethylene terephthalate, cellulose acetate, and cellulose nitrate are preferable. The reason is that platelets are difficult to adhere, do not exhibit irritation to the biological composition, and can be eluted when a biological physiologically active substance is contained.

  The shape of the stent body used in the present invention is not particularly limited as long as it has a strength capable of being 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 used in the present invention may be either a balloon expansion type or a self-expansion type. The size of the stent body may be appropriately selected according to the application location.

<Polymer layer>
The stent of the present invention has a polymer layer on the surface of the stent body as described above. This polymer layer is made of a biodegradable composition and can control cell adhesion.

<Biodegradable composition>
This biodegradable composition is a composition containing a copolymer of a polysaccharide and a biodegradable polyester structural unit.

  Here, the polymerization form of the copolymer is not particularly limited as long as the polymer layer made of the composition containing the copolymer can control cell adhesion.

For example, a statistical copolymer, an alternating copolymer, a graft copolymer, a block copolymer, and a random copolymer of a polysaccharide and a biodegradable polyester structural unit may be used, but a graft copolymer is preferable. , Block copolymers and random copolymers, and more preferably graft copolymers.
Specifically, the graft copolymer is obtained by grafting a biodegradable polyester structural unit with a polysaccharide as a skeleton.

  More preferably, the content of the polysaccharide in the copolymer is 1 to 50 mass%, more preferably 1 to 30 mass%, and most preferably 5 to 20 mass%. Within such a range, when the biodegradable composition is placed in the living body, the biodegradation rate does not cause an inflammatory reaction or the like accompanying the decomposition, and the passage of a period required in the living body This is because the biodegradation rate disappearing from the living body can be adjusted later. The period required in the living body is preferably 2 weeks to 1 year, more preferably 1 month to 10 months, and most preferably 2 months to 6 months. Moreover, if it is such a range, since it is difficult for a cell to adhere to a biodegradable composition, the restenosis resulting from cell adhesion can be suppressed.

<Polysaccharide>
The polysaccharide is not particularly limited as long as it is stable in vivo, but is selected from the group consisting of hyaluronic acid, amylose, pullulan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, dermatan sulfate, keratan sulfate, and heparan sulfate. It is preferable that at least one of them is used. The reason is that it has ductility enough to follow the stent expansion operation.
Most preferably, the polysaccharide is only dextran. The reason is that it is the most stable in blood vessels and has a track record as a plasma expander.

  The weight average molecular weight of such a polysaccharide is not particularly limited, but is preferably 1000 to 100000 g / mol, more preferably 5000 to 50000 g / mol, and most preferably 15000 to 30000 g / mol. A polymer layer made of a biodegradable composition containing a polysaccharide-based copolymer with a weight average molecular weight in such a range has low cell adhesion and higher strength that can withstand expansion when the stent is expanded. And flexibility are preferable.

<Biodegradable polyester constitutional unit>
The biodegradable polyester structural unit is not particularly limited as long as it becomes a biodegradable polyester when polymerized and can form a copolymer with the polysaccharide. For example, lactic acid (L-lactic acid, D-lactic acid, DL-lactic acid), glycolic acid (hydroxyacetic acid), caprolactone (α-caprolactone, β-caprolactone, γ-caprolactone, δ-caprolactone, ε-caprolactone, etc.), succinic acid And at least one selected from the group consisting of ethylene glycol and / or butanediol (1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, etc.) Or oligomers thereof.

  Such a biodegradable polyester structural unit is preferably lactic acid, and more preferably DL lactic acid. The reason is that the strength for following the balloon expansion operation of the polymer layer becomes higher and the flexibility becomes higher.

  More preferably, it is polylactic acid grafted dextran in which lactic acid is grafted using dextran as a skeleton. The reason is that dextran has excellent stability in blood vessels, has a track record as a plasma expander, and lactic acid is a biological material.

  More preferably, the polylactic acid grafted dextran has 1-100 grafts per molecule of lactic acid, more preferably 1-50, most preferably 10-30. The reason is that the cell adhesion becomes lower.

  The weight average molecular weight of such a copolymer is not particularly limited, but is preferably 10,000 to 1,000,000 g / mol, more preferably 50,000 to 800,000 g / mol, and 100,000 to 500,000 g. / Mol is most preferred. A polymer layer made of a biodegradable composition containing a copolymer having a weight average molecular weight in such a range has low strength for cell adhesion and higher strength and flexibility that can withstand expansion. Therefore, it is preferable.

<Synthesis of copolymer>
A method for synthesizing a copolymer of such a polysaccharide and a biodegradable polyester structural unit is not particularly limited, and a usual method may be applied.
For example, in the case of a block copolymer, a method in which the monomers constituting each of the polysaccharide and the biodegradable polyester constituent unit are polymerized in order by living polymerization, and a polymer having an active group at the terminal is first synthesized and the terminal Examples thereof include a method of polymerizing another monomer from the above, a method of connecting different polymers, and the like.

  Further, for example, in the case of a graft copolymer, a method of chemically connecting a polysaccharide to a biodegradable polyester constituent unit, or a monomer molecule or an oligomer constituting a biodegradable polyester constituent unit is polymerized on the polysaccharide. And a method using a macromer.

  Further, as a preferred synthesis method, a method in which most of hydroxyl groups of a polysaccharide are protected with a trimethylsilyl (TMS) group solubilized in an organic solvent, and lactide (cyclic diester) is polymerized using the remaining unreacted hydroxyl group as an initiation point. (T.Ouchi, T. Kontani, Y. Ohya, “Modification of polylactide upon physical properties by solution-cast blends from polylactide and polylactide-grafted dextran”, Polymer, April 10, 2003 (: application approval date), No. 44, p3927).

  The copolymer can copolymerize other monomers in addition to the polysaccharide and the biodegradable polyester constituent unit.

  Examples of the copolymerizable monomer include hydroxycarboxylic acids such as 3-hydroxybutyric acid, 4-hydroxybutyric acid, 3-hydroxyvaleric acid, 4-hydroxyvaleric acid, and 6-hydroxycaproic acid; ethylene glycol, propylene glycol, Compounds containing multiple hydroxyl groups in the molecule such as butanediol, neopentyl glycol, polyethylene glycol, glycerin, pentaerythritol or their derivatives; succinic acid, adipic acid, sebacic acid, fumaric acid, terephthalic acid, isophthalic acid , 2,6-naphthalenedicarboxylic acid, 5-sodium sulfoisophthalic acid, 5-tetrabutylphosphonium sulfoisophthalic acid-containing compounds containing a plurality of carboxylic acid groups in the molecule, or derivatives thereof.

<Additives>
The biodegradable composition used in the present invention is a composition containing such a copolymer, but may contain other additives as long as the effects of the present invention are not impaired.
For example, pigments, dyes, reinforcing agents (glass fiber, carbon fiber, talc, mica, viscosity favorite, potassium titanate fiber, etc.) that do not harm the living body, fillers (carbon black, silica, alumina, titanium oxide, metal powder) , Wood powder, rice husk, etc.), heat stabilizer, oxidative degradation inhibitor, ultraviolet absorber, lubricant, mold release agent, crystal nucleating agent, plasticizer, flame retardant, antistatic agent, foaming agent, etc. . These may be contained within a range not inhibiting the effects of the present invention, for example, 20% by mass or less, preferably 15% by mass or less, and more preferably 10% by mass or less as a content ratio relative to the entire biodegradable composition.

  The biodegradable composition used in the present invention is a composition containing the above-mentioned copolymer, but preferably further contains a biological physiologically active substance. The reason is that the stent surface can suppress cell adhesion, and further, the surface of the stent body can continue to carry a biological physiologically active substance, so that the restenosis rate can be further reduced. In addition, since this copolymer does not peel off even when the stent is expanded, these effects are effectively exhibited.

Such a biological physiologically active substance is 10 to 500 parts by weight, preferably 20 to 300 parts by weight, and more preferably 30 to 200 parts by weight with respect to 100 parts by weight of the copolymer. It is contained in the biodegradable composition.
Such a ratio is preferable in that the biological and physiologically active substance of the present invention can be loaded as much as possible while taking into consideration the physical properties and degradability of the biodegradable composition.

  The biological and physiologically active substance is not particularly limited as long as it suppresses stenosis and occlusion of the vascular system that can occur when the stent of the present invention is placed in a lesion, and can be arbitrarily selected. For example, the biological physiologically active substance is an anticancer agent, immunosuppressant, antibiotic, antirheumatic agent, antithrombotic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemic agent , Integrin inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, anti-inflammatory agents, biological materials, interferon And at least one selected from the group consisting of NO production promoting substances is preferable because it reliably suppresses stenosis and occlusion of the vascular system that may occur when the stent of the present invention is placed in a lesion.

  Preferred examples of the anticancer agent include vincristine, vinblastine, vindesine, irinotecan, pirarubicin, paclitaxel, docetaxel, and methotrexate.

  As the immunosuppressive agent, for example, sirolimus, everolimus, biolimus, tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, gusperimus, mizoribine and the like are preferable.

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

  As the anti-rheumatic agent, for example, methotrexate, sodium thiomalate, penicillamine, lobenzalit and the like are preferable.

  As the antithrombotic agent, for example, heparin, aspirin, antithrombin preparation, ticlopidine, hirudin and the like are preferable.

  Preferred examples of the HMG-CoA reductase inhibitor include cerivastatin, cerivastatin sodium, atorvastatin, nisvastatin, itavastatin, fluvastatin, fluvastatin sodium, simvastatin, rosuvastatin, pravastatin and the like.

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

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

  As the antihyperlipidemic agent, for example, probucol is preferable.

  As the integrin inhibitor, for example, AJM300 is preferable.

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

  Preferred examples of the antioxidant include catechins, anthocyanins, proanthocyanidins, lycopene, and β-carotene. Of the catechins, epigallocatechin is particularly preferred.

  As the GPIIbIIIa antagonist, for example, abciximab is preferable.

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

  As the flavonoid, for example, epigallocatechin, anthocyanin, and proanthocyanidin are preferable.

  As the carotenoid, for example, β-carotene and lycopene are preferable.

  As the lipid improving agent, for example, eicosapentaenoic acid is preferable.

  As the DNA synthesis inhibitor, for example, 5-FU is preferable.

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

  As the antiplatelet drug, for example, ticlopidine, cilostazol, and clopidogrel are preferable.

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

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

  As the interferon, for example, interferon-γ1a is preferable.

  As the NO production promoting substance, for example, L-arginine is preferable.

  Whether these biological physiologically active substances are to be one kind of biological physiologically active substance or to combine two or more different biological physiologically active substances may be appropriately selected according to the case. .

  As described above, the stent of the present invention has a polymer layer made of such a biodegradable composition on the surface of the stent body, and the thickness (average thickness) of the polymer layer is the distance to the lesion. It should be determined in consideration of the reachability (delivery property), the strength required at the time of stent expansion, and the degradation rate that is completely degraded after a necessary period in vivo. Specifically, if the polymer layer is too thick, the delivery property is impaired, the polymer layer is damaged at the time of stent expansion, and further stays in the living body more than necessary. On the other hand, even if the polymer layer is too thin, the polymer layer is damaged when the stent is expanded, and the polymer layer cannot exist for a necessary period of time in the living body, resulting in restenosis.

  The period during which the polymer layer should be present in the living body is different depending on whether the polymer layer contains a biological physiologically active substance or not.

If the polymer layer contains a biological physiologically active substance, the period during which the polymer layer should be present in the living body is 2 weeks to 1 year, preferably 3 weeks to 10 months, most preferably 1 month to 6 Months.
If the polymer layer does not contain a biological physiologically active substance, the period during which the polymer layer should exist in the living body is 2 weeks to 1 year, preferably 1 month to 10 months, most preferably 2 months. ~ 6 months.

In this way, the thickness of the polymer layer (average thickness) is the degradation that is all decomposed after the reach to the lesion (delivery), the strength required during stent expansion, and the period required in vivo. However, if the polymer layer contains a biological physiologically active substance, it is preferably 1 to 100 μm, more preferably 1 to 50 μm, and most preferably 1. 10 μm.
Moreover, if a polymer layer does not contain a biological physiologically active substance, Preferably it is 1-75 micrometers, More preferably, it is 1-25 micrometers, Most preferably, it is 1-10 micrometers.

  In the stent of the present invention, it is preferable that a layer made of the biological and physiologically active substance is further provided between the stent body and the polymer layer. The reason is that even when the stent is expanded, the biological physiologically active substance can continue to be carried on the surface of the stent body, so that the restenosis rate can be prevented. Furthermore, by adjusting the thickness of the polymer layer, the sustained release rate of the biological physiologically active substance can be adjusted.

  Here, the biologically physiologically active substance is not particularly limited as long as it suppresses stenosis and occlusion of the vascular system that can occur when the stent of the present invention is placed in a lesioned part, and can be arbitrarily selected. The same biologically active substance that can be contained in the biodegradable composition described above can be used.

  Further, the thickness (average thickness) of the biological physiologically active substance layer is not particularly limited, but is preferably 1 to 100 μm, more preferably 1 to 50 μm, and most preferably 1 to 10 μm. is there. A layer with a thickness within this range does not impair the performance of the stent, such as reachability to the lesion (delivery) and irritation to the blood vessel wall, and the amount necessary for treatment of the lesion The biological and biologically active substance of the present invention can be mounted.

  In the stent of the present invention, a plurality of the polymer layer on the surface of the stent body and a layer made of the biological physiologically active substance may be provided.

  Examples of such a stent of the present invention include a coiled stent, a mesh stent, and a porous tubular stent.

Examples of the shape of the stent of the present invention include those shown in FIG.
In FIG. 1, a stent body 1 is a cylindrical body that is open at both ends and extends in the longitudinal direction between the ends. The side surface of the cylindrical body has a large number of notch portions that communicate with the outer side surface and the inner side surface. To maintain its shape.
In the embodiment shown in FIG. 1, the stent body 1 is composed of a linear member 2 and has a substantially rhombic element 3 having a notch therein as a basic unit. A plurality of substantially rhombic elements 3 form an annular unit 4 by arranging and coupling substantially rhombus shapes continuously in the minor axis direction. The annular unit 4 is connected to an adjacent annular unit via a linear connecting member 5. Thereby, the some annular unit 4 is continuously arrange | positioned in the axial direction in the state couple | bonded. With such a configuration, the stent body (stent) 1 has a cylindrical body that opens at both ends and extends in the longitudinal direction between the ends. The stent body (stent) 1 has a substantially diamond-shaped notch, and has a structure that can be expanded and contracted in the radial direction of the cylindrical body by deformation of the notch.

  A preferred embodiment of the stent of the present invention shown in FIG. 1 has a layer 6 made of a biological physiologically active substance on the surface of the stent body 1 and further has a layer 7 made of a biodegradable composition on the upper surface thereof. FIG. 2 shows a cross section taken along the line AA in FIG. 3, and FIG. 3 shows a cross section taken along the line BB in FIG.

  1 is a preferred embodiment in which the stent of the present invention shown in FIG. 1 has a layer comprising a biological physiologically active substance 9 and a biodegradable composition 8 on the surface of the stent body 1. FIG. 4 shows the cross section, and FIG. 5 shows the BB cross section of FIG.

  When the stent body 1 is composed of the linear member 2, the length in the width direction of the linear member 2 configured to have a large number of notches is preferably 0.01 to 0.5 mm. And more preferably 0.05 to 0.2 mm.

  As other specific examples of the shape of the stent body having such a radially expandable / contractible structure, an elastic wire as disclosed in Japanese Patent Laid-Open Nos. 9-215753 and 7-529 is coiled. The main body of the stent in which the gap between the elastic wires forms a notch in an example in which a plurality of them are bent and connected to form a cylindrical shape; Japanese Patent Publication No. 8-502428 and Japanese Patent Publication No. 7-5000027 A stent main body in which a gap between elastic wires forms a notch in an example in which a plurality of elastic wires are bent in a zigzag shape and formed into a cylindrical shape as disclosed in Japanese Patent Laid-Open No. 2000-501328 In an example in which an elastic wire is bent into a shape of a snake-like flat ribbon and wound into a helix around a mandrill to form a cylindrical shape as disclosed in Japanese Patent Laid-Open No. 11-212288. 1. Main body of stent in which gaps between wires form notches; as disclosed in Japanese Patent Publication No. 10-503676, the shape of the notches differs from the stent body of FIG. The main body of the stent having a mesh-shaped structure, such as disclosed in JP-A-8-507243, in which the plate-like member is bent into a coil shape and formed into a cylindrical shape between adjacent coil portions. The stent main body etc. in which the gap | interval forms a notch part are mentioned.

  Japanese Patent Publication No. 4-68939 discloses an example in which an elastic plate-like member is formed into a spiral shape to form a cylindrical shape, and a stent body in which a gap between adjacent spiral portions forms a notch and an elastic wire are braided. A cylindrical stent body having a plurality of different structures including a stent body in which a gap between elastic wires forms a notch in an example of a cylindrical shape. In addition, the main stent body may be a leaf spring coil shape, a multiple spiral shape, an atypical tubular shape, or the like.

  Further, FIGS. 2 (a) and 2 (b) of Japanese Patent Publication No. 4-68939 describe a stent body in which an elastic plate member is bent into a spiral shape to form a cylindrical shape. A cylindrical stent body that does not have a notch on the side surface but is configured to be capable of expanding and contracting in the radial direction of the cylindrical body can also be used as the stent body of the present invention. All of these above references and patent applications are hereby incorporated by reference.

  The magnitude | size of the stent of this invention can be suitably selected according to an application location. For example, when used for a coronary artery of the heart, the diameter of a circle (hereinafter, also simply referred to as an “outer diameter”) in a cross section perpendicular to the longitudinal direction (radial direction) before expansion is generally 1.0 to 3.0 mm, The length is preferably 5 to 50 mm and the thickness is preferably 0.01 to 0.5 mm.

  The stent main body 1 shown above is only one aspect, and both end portions are open, and are cylindrical bodies extending in the longitudinal direction between the both end portions. It has a large number of notches that communicate with the inner surface, and a wide range of structures that can expand and contract in the radial direction of the cylindrical body by deforming the notches.

<Stent manufacturing method>
1 illustrates a method for manufacturing a stent of the present invention.
First, the manufacturing method of a stent main body is shown.
The stent body can be produced by a known method such as injection molding, extrusion molding, press molding, vacuum molding, blow molding or the like. Details are illustrated below.

For example, when manufacturing a stent main body using a metal material, the following method can be mentioned.
First, the metal material is dissolved in an inert gas or a vacuum atmosphere.
Next, it is cooled to form an ingot, the ingot is mechanically polished, and then hot-pressed and extruded to obtain a large-diameter pipe. Then, the diameter of the pipe is reduced to a predetermined thickness and outer shape by sequentially repeating the die drawing process and the heat treatment process. And an opening pattern is affixed on the pipe surface, and pipe parts other than this opening pattern are melt | dissolved by etching techniques, such as laser etching and chemical etching, and an opening part is formed. Alternatively, the opening can be formed by cutting the pipe according to the pattern by a laser cutting technique based on the pattern information stored in the computer.
By such a method, a stent body made of metal and used in the present invention can be manufactured.

Moreover, when manufacturing a stent main body using a polymeric material, the following methods can be mentioned.
First, a pipe having a predetermined thickness and outer shape is formed from a polymer material using an extruder. And an opening pattern is affixed on the pipe surface, and pipe parts other than this opening pattern are melt | dissolved by etching techniques, such as laser etching and chemical etching, and an opening part is formed. Alternatively, the opening can be formed by cutting the pipe according to the pattern by a laser cutting technique based on the pattern information stored in the computer.

  In addition, for example, in the case of a coiled stent, a metal material or a polymer material is formed into a wire having a predetermined thickness and an outer shape using an extruder. Then, after the wire is bent to form a wave pattern or the like, the wire is spirally wound on the mandrel, and then the mandrel is extracted and the shaped wire is cut into a predetermined length. .

  The biodegradable composition, or the biodegradable composition and the biological organizing active substance are melted on the stent body manufactured by the above-described method, and applied or melted by a conventional method. Soak in.

  Alternatively, the biological physiologically active substance is melted and applied or immersed in a melt and then dried. And the said biodegradable composition is similarly melt | dissolved, and it is made to immerse in application | coating or a melt by the same method.

  Here, instead of melting the biologically physiologically active substance and / or the biodegradable composition, it is dissolved in a solvent such as acetone that can easily wet the surface of the stent body, and a spray, a dispenser, etc. A method of volatilizing the solvent after applying by the conventional method used or immersing in a solution can also be used. Such a method is preferable because it is the simplest. Further, such a method is preferable because a polymer layer in which the biological physiologically active substance is dispersed can be easily produced on the surface of the stent body.

  Here, before applying the biologically physiologically active substance, the biodegradable composition, and the mixture thereof to the stent body, the surface of the stent body is chemically treated or etched using plasma or the like. It is preferable to perform an operation for forming fine irregularities on such a surface. The reason is that adhesion between the stent body and the biological and physiologically active substance, the biodegradable composition, and a mixture thereof is improved.

For the same reason, an adhesive or the like may be applied to the surface of the stent body, and the stent body is thermally bonded to the biological physiologically active substance, the biodegradable composition, and a mixture thereof. May be.
By such a method, the stent of the present invention can be manufactured.

<How to use the stent>
The method of using the stent of the present invention is the same as usual. For example, when the stent of the present invention is placed in a stenosis that has occurred in a coronary artery, the stent of the present invention having a diameter smaller than the diameter of the coronary artery is attached to the distal balloon of the catheter so as to percutaneously reach the stenosis. Thereafter, the stent of the present invention is expanded by the action of an external force based on the expansion of the balloon to secure the inner diameter of the coronary artery.

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

Example 1
An electropolished SUS316L stainless steel plate (circular diameter of 20 mm, thickness 0.08 mm) was prepared, and one main surface thereof was ultrasonically cleaned in acetone with an ultrasonic cleaner (US-3, manufactured by ASONE). did.

Next, polylactic acid grafted dextran (PLA-Dex) was prepared.
First, dextran (number average molecular weight = 20000 g / mol, manufactured by Sigma Chemical Co.) was prepared.
Then, PLA-Dex was prepared by a method in which most of the hydroxyl groups of this dextran were protected with a trimethylsilyl (TMS) group and solubilized in an organic solvent, and lactic acid was polymerized using the remaining unreacted hydroxyl groups as starting points.

  And the solution which dissolved PLA-Dex produced in this way in tetrahydrofuran (henceforth THF) was produced. The concentration of PLA-Dex in this solution was 1.0% by mass.

  Then, this solution was sprayed onto a stainless steel plate using a spray (Micro Spray Gun-II, manufactured by NORDSON), and then THF as a solvent was evaporated under vacuum. As a result, it was confirmed that PLA-Dex having a thickness of about 10 μm was formed on one main surface of the stainless steel plate.

Next, a porcine vascular smooth muscle cell adhesion test was performed on this stainless steel plate. Specifically, after the PLA-Dex on the stainless steel plate was sterilized with ethylene oxide gas, it was placed in the center of a plastic dish having a diameter of 35 mm under aseptic operation, and porcine smooth muscle cells were 15000 cells / dish from above. Sowing.
Then, after culturing in an incubator for 3 days, the medium was removed, and porcine smooth muscle cells were immobilized on a stainless steel plate with a 10% by mass formalin solution.
Then, after 2 days, the plate was taken out from the incubator and sufficiently dried with a vacuum dryer.

  After such an operation, the number of porcine smooth muscle cells adhering onto the PLA-Dex on the stainless steel plate was measured using a scanning electron microscope.

The results are shown in FIG. The number of porcine smooth muscle cell adhesion on the stainless steel plate coated with PLA-Dex was 32/1 mm ² . In addition, this value is an average value after measuring 3 times.

(Comparative Example 1)
In place of PLA-Dex used in Example 1 above, L-polylactic acid (glass transition point 60 ° C. obtained by ring-opening polymerization of lactide of L-lactic acid, melting temperature (melting point) 168 ° C., weight average) A test was conducted using polylactic acid having a molecular weight of about 180,000 (PLLA) under the same conditions. The thickness of PLLA formed on the stainless steel plate was also the same.

The results are shown in FIG. The number of porcine smooth muscle cell adhesion on a stainless steel plate coated with PLLA was 121 cells / 1 mm ² . This value is similarly an average value.

(Example 2)
First, a solution was prepared by dissolving cerivastatin (CV), which is an antihyperlipidemic agent, and PLA-Dex in THF at a mass ratio of 1: 1. The concentration of the solute (CV + PLA-Dex) in this solution was 1.0% by mass.

  Next, this solution is sprayed on the outer surface of a stent body (outer diameter: 2.0 mm, length: 15 mm, manufactured by SUS316L) having the same shape as in FIG. 1 using a spray (Micro Spray Gun-II, manufactured by NORDSON). Thereafter, the solvent THF was evaporated under vacuum. As a result, it was confirmed that a layer of about 600 μg of CV and PLA-Dex was formed on the surface of the stent.

The stent was percutaneously inserted into the porcine coronary artery and left for 1 month for pathological evaluation.
The results are shown in FIG.
Thus, it was found that even after one month, no significant stenosis was observed, and the stenosis rate (AS%) was suppressed to about 25%.

(Comparative Example 2)
In place of the PLA-Dex used in Example 2 above, polylactic acid (trade name: poly-d, l-lactide, manufactured by API) (PLA) was used, and the test was performed with all other conditions being the same. went. The mass of the mixture layer of CV and PLA formed on the surface of the stent was also about 600 μg.

The results are shown in FIG.
Thus, no significant stenosis was observed even after one month, but the stenosis rate (AS%) was found to be about 38%.

(Example 3)
Without using cerivastatin (CV) used in Example 2 above, only PLA-Dex was used, the concentration of the solute (PLA-Dex only) in the solution was 1.0 mass%, and all other conditions were the same. The test was performed. The mass of the PLA-Dex layer formed on the surface of the stent was also about 600 μg.

The results are shown in FIG.
Thus, no significant stenosis was observed even after one month, and the stenosis rate (AS%) was 45%.

(Comparative Example 3)
Instead of the PLA-Dex used in Example 3 above, a test was performed using PLA in which all other conditions were the same. The mass of the PLA layer formed on the surface of the stent was also about 600 μg.

The results are shown in FIG.
Thus, after 1 month, remarkable stenosis was observed. The stenosis rate (AS%) was 58%.

(Comparative Example 4)
A test was conducted in which polycaprolactone (PCL) was used in place of the PLA-Dex used in Example 3 and all other conditions were the same. The mass of the PLA layer formed on the surface of the stent was also about 600 μg.

The results are shown in FIG.
Thus, after 1 month, remarkable stenosis was observed. The stenosis rate (AS%) was 78%.

Example 4
A stent having a layer of about 600 μg of a mixture of CV and PLA-Dex formed on the surface thereof was prepared in the same manner as in Example 2 above.
And it expanded until the final external shape became 3.0 mm using the balloon catheter.
As a result, as shown in FIG. 9, the destruction of the layer accompanying balloon expansion was not recognized.

(Comparative Example 5)
Instead of the PLA-Dex used in Example 4 above, a test was performed using PLA with all other conditions being the same. The mass of the PLA layer formed on the surface of the stent was also about 600 μg.
And it expanded until the final external shape became 3.0 mm using the balloon catheter.
As a result, as shown in FIG. 10, destruction of the layer accompanying balloon expansion was observed.

FIG. 1 is a side view showing an embodiment of the stent of the present invention. 2 is an enlarged cross-sectional view taken along line AA in FIG. FIG. 3 is an enlarged cross-sectional view taken along line BB in FIG. 4 is an enlarged cross-sectional view taken along line AA in FIG. FIG. 5 is an enlarged cross-sectional view taken along line BB in FIG. FIG. 6 is an enlarged photograph (50 times) of porcine smooth muscle cells on the stainless steel plate of Example 1 and Comparative Example 1. FIG. 7 is an enlarged photograph (20 ×) showing a pathological image after implantation of a porcine intracoronary stent in Example 2 and Comparative Example 2. FIG. 8 is an enlarged photograph (20 ×) showing a pathological image after implantation of a porcine intracoronary stent in Example 3, Comparative Example 3, and Comparative Example 4. FIG. 9 is an enlarged photograph (100 ×) after balloon expansion of the stent according to Example 4. FIG. 10 is an enlarged photograph (100 times) of the stent according to Comparative Example 5 after balloon expansion.

Explanation of symbols

1 Stent body 1
2 Linear member 3 Element of substantially rhombus 4 Ring unit 5 Connecting member 6 Layer made of biological physiologically active substance 7 Layer made of biodegradable composition 8 Biodegradable composition 9 Biologically physiologically active substance

Claims (9)

  A stent having a polymer layer on the surface of a stent body, which is made of a composition containing a copolymer of a polysaccharide and a biodegradable polyester structural unit and can control cell adhesion.   The stent according to claim 1, wherein the stent body is made of a metal material.   The stent according to claim 1, wherein the stent body is made of a polymer material.   The stent according to any one of claims 1 to 3, wherein the composition further contains a biological physiologically active substance.   The stent according to any one of claims 1 to 4, further comprising a layer made of the biological and physiologically active substance between the stent body and the polymer layer.   The biological and physiologically active substance is an anticancer agent, immunosuppressive agent, antibiotic, antirheumatic agent, antithrombotic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemic agent, integrin Inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, biomaterials, interferon and NO The stent according to any one of claims 1 to 5, wherein the stent is at least one selected from the group consisting of production promoting substances.   The stent according to any one of claims 1 to 6, wherein the biodegradable polyester structural unit is lactic acid.   8. The polysaccharide according to claim 1, wherein the polysaccharide is at least one selected from the group consisting of hyaluronic acid, amylose, pullulan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, dermatan sulfate, keratan sulfate, and heparan sulfate. The stent according to 1.   The stent according to any one of claims 1 to 8, wherein the content of the polysaccharide in the copolymer is 1 to 50% by mass.

Images