JP2007313009A - Stent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stent which can avoid a chronic inflammation resulting from a semi-permanent mechanical stress after being indwelt in a living body, and also, is excellent in a mechanical strength compared with a conventional stent consisting of a biodegradable polymer material, and has a high radial force. <P>SOLUTION: This stent has a stent body consisting of the melt molded body containing a polylactic acid and a calcium phosphate by a composition ratio (mass%) of 99:1 to 60:40. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a stent used by being inserted and placed in a living body such as a blood vessel, bile duct, trachea, esophagus, urethra and the like.

As an example, angioplasty applied to ischemic heart disease will be described.
In response to the rapid increase in the number of patients with ischemic heart disease (angina pectoris, myocardial infarction) as the Westernization of dietary habits in Japan, percutaneous transvascularization is a method for reducing these coronary artery lesions. Coronary angioplasty (PTCA) has been performed and has become widespread.
At present, the number of applied cases has increased due to technological development. From the one that was localized (the length of the lesion was short) and one-branch lesion (the lesion that had stenosis only in one site) at the time when PTCA started, The application of PTCA has been extended to those that are more eccentric and calcified in the more distal parts, and multi-branch lesions (lesions with stenosis in more than one site).

  PTCA is a long hollow tube called a guide catheter with a small incision in the artery of the patient's leg or arm and placement of an introducer sheath (leader) through the lumen of the introducer sheath, with the guide wire leading. After inserting the tube into the blood vessel and placing it at the entrance of the coronary artery, withdraw the guide wire, insert another guide wire and balloon catheter into the lumen of the guide catheter, and X-ray contrast the balloon catheter with the guide wire leading The procedure is to advance to the lesioned part of the patient's coronary artery and place the balloon in the lesioned part, where the doctor inflates the balloon at a predetermined pressure for 30 to 60 seconds once or a plurality of times. This dilates the vascular lumen of the lesion, thereby increasing blood flow through the vascular lumen. However, when the blood vessel wall is injured by the catheter, the intima proliferation, which is a healing reaction of the blood vessel wall, occurs, and restenosis has been reported at a rate of about 30 to 40%.

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

In recent years, the biological physiologically active substance such as an immunosuppressive agent or an anticancer agent is carried on the stent, and the biologically physiologically active substance is locally released over a long period of time at the indwelling site of the lumen. Many attempts have been made to reduce the rate.
For example, Patent Document 1 discloses a stent in which a surface of a tantalum stent body is coated with a mixture of a biodegradable polymer such as polylactic acid and a therapeutic substance, and Patent Document 2 discloses a stainless steel stent. Stents have been proposed in which a drug layer is provided on the surface of the main body and a biodegradable polymer layer such as polylactic acid is provided on the drug layer.
However, since the stent body proposed in Patent Documents 1 and 2 is formed of a metal material such as stainless steel or tantalum, the stent body is placed in the living body semipermanently. Therefore, after the biodegradable polymer is degraded in vivo and the biological physiologically active substance is released, there is a possibility that chronic inflammation may occur due to mechanical stress on the blood vessel wall of the stent body. There is. This is not limited to the stents proposed in Patent Documents 1 and 2, but is a problem in all stents using a metal material.

  Furthermore, in Non-Patent Document 1, there is a possibility that inflammation is sustained chronically when a polymer layer is placed in a living body semipermanently, and restenosis is induced by degradation of the polymer. It has been reported that not only there is a fear, but there is even a risk of thrombosis.

On the other hand, when the stent body is formed of a biodegradable polymer material such as poly-L lactic acid as disclosed in Patent Document 3, the biodegradable polymer material is decomposed and the stent body is decomposed in vivo. -Since it disappears, it is possible to avoid the possibility of chronic inflammation caused by being left in the living body for a long time and applying mechanical stress to the blood vessel wall. In addition, blood vessels gradually meander with aging, but if the stent disappears, the remaining endothelial cell layer can follow this meandering motion well. Therefore, it is possible to provide an intravascular indwelling object that does not invade a living body or is extremely invasive.
However, when a stent is formed from a biodegradable polymer material such as poly-L-lactic acid, the mechanical strength such as breaking strength and breaking elongation is low. was there. In addition, since the radial force is low, the stent may fall off from the lesion after placement.

JP-A-8-33718 JP-A-9-56807 International Publication No. 01/067990 Pamphlet Circulation 2002, VOL106, 2649-2651

  The object of the present invention is to avoid chronic inflammation caused by semi-permanent mechanical stress after indwelling in a living body, and compared to a conventional stent made of a biodegradable polymer material. An object of the present invention is to provide a stent having excellent strength and high radial force.

The object is achieved by the present inventions (1) to (12) below.
(1) A stent having a stent body made of a melt-formed product containing polylactic acid and calcium phosphate in a composition ratio (mass%) 99: 1 to 60:40.
(2) The stent according to (1), wherein the calcium phosphate is treated with an alkaline inorganic compound.
(3) The above (1), wherein the alkaline inorganic compound is at least one selected from the group consisting of calcium hydroxide, potassium hydroxide, magnesium hydroxide, calcium chloride, potassium chloride, and magnesium chloride. Or the stent of (2).
(4) The stent according to any one of (1) to (3) above, wherein the stent body is produced by stretching the melt-molded body.
(5) The stent according to any one of (1) to (4) above, wherein the melt-formed product has a breaking strength of 100 to 350 MPa and a breaking elongation of 15 to 50%.
(6) The stent according to any one of (1) to (5) above, wherein a biological physiologically active substance is dispersed in the stent body.
(7) The biological physiologically active substance release layer comprising a biologically physiologically active substance formed on the stent body and a biodegradable polymer, (1) to (6) above ) One of the stents.
(8) The biological physiologically active substance release layer is composed of a biologically physiologically active substance layer and a biodegradable polymer layer formed on the biologically physiologically active substance layer. 7) Stent.
(9) The stent according to (7) above, wherein the biological physiologically active substance releasing layer comprises a layer containing a biological physiologically active substance and a biodegradable polymer.
(10) The biological physiologically active substance is an anticancer agent, immunosuppressive agent, 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 (6) to (9) above, which is at least one selected from the group consisting of interferon and NO production promoter.
(11) The biodegradable polymer is polylactic acid, polylactic acid stereocomplex, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin Any one of the above (6) to (10), which is at least one selected from the group consisting of heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid and polycaprolactone, or a copolymer thereof. Stent.
(12) Any of (1) to (11) above, wherein the radial force when the stent body is expanded to an outer diameter of 3.0 mm and compressed by 1 mm is 80 to 500 gf per 10 mm of the stent length. Stent.

The stent of the present invention consisting of a stent body made of a melt-molded body containing polylactic acid and calcium phosphate in a specific composition ratio can avoid chronic inflammation caused by semi-permanent mechanical stress after being placed in the living body. In addition to this, it is possible to provide a stent having excellent mechanical strength and high radial force as compared to a conventional stent made of a biodegradable polymer material.
Furthermore, the stent which can suppress the inflammatory reaction accompanying the decomposition | disassembly of polylactic acid with an alkaline inorganic substance by processing the said calcium phosphate with an alkaline inorganic substance is obtained.
Furthermore, restenosis can be appropriately suppressed by a stent including a biological physiologically active substance in the stent body.
Furthermore, restenosis can be appropriately suppressed in stages by using a stent having a biologically physiologically active substance releasing layer on the stent body.

Hereinafter, the stent having the above biological and physiologically active substance of the present invention will be described in detail with reference to the accompanying drawings, but the stent of the present invention is not limited thereto.
FIG. 1 is a side view showing an embodiment of the stent of the present invention. 2, 3, and 5 are enlarged cross-sectional views taken along line AA in FIG. 1, and FIGS. 4 and 6 are enlarged cross-sectional views taken along line BB in FIG. 1. .

The stent of the present invention has a stent main body formed of a cylindrical body having both ends opened and extending in the longitudinal direction between the ends. The side surface of the cylindrical body has a large number of notches communicating with the outer side surface and the inner side surface, and is deformed so that the cylindrical body can expand and contract in the radial direction. It is placed at the target site and maintains its shape.
For example, in the stent 1 of the present invention as shown in FIG. 1, the stent main body 2 is made of a linear member, and a substantially rhombic element 21 having a notch therein is a basic unit. A plurality of substantially rhombic elements 21 form an annular unit 23 by substantially arranging and connecting substantially rhombus shapes in the minor axis direction. The annular unit 23 is connected to an adjacent annular unit via a linear connecting member 22. Thereby, the some annular unit 23 is continuously arrange | positioned in the axial direction in the state couple | bonded. With such a configuration, the stent body 2 has a cylindrical body that is open at both ends and extends between the ends in the longitudinal direction. The stent body 2 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 deforming the notch.

  In the present specification, the “stent body” means a cylindrical body made of a linear member as shown in FIG. 1, and the “stent” means a biological body on the stent body or a stent body as described later. It means a stent having a biologically active substance releasing layer.

  The shape of the stent body 2 is not particularly limited as long as it has sufficient strength to be stably placed in a lumen in a living body. Specifically, for example, a fiber made of a melt-molded body described later is knitted. Suitable examples include those formed in a cylindrical shape and those in which pores are provided in a tubular body made of a melt-formed body described later.

  The length in the width direction of the linear member constituting the stent body 2 to have a large number of notches is preferably 0.01 to 0.5 mm, more preferably 0.05 to 0.2 mm. .

It is preferable that the radial force when the outer diameter of the stent body 2 is expanded from 2.1 mm to 3.0 mm and compressed by 1 mm is 80 to 500 gf per 10 mm of the stent length.
If the stent body 2 has a radial force in the above-described range, the stent body 2 can be surely placed in the lesion. Normally, the radial force is approximately proportional to the length of the stent.

Hereinafter, each component which comprises the stent 1 of this invention is demonstrated in detail.
The stent main body (linear member) 2 of the present invention is made of a melt-molded product containing polylactic acid and calcium phosphate in a specific composition ratio. Since the stent body (linear member) 2 made of a melt-molded product containing polylactic acid and calcium phosphate in a specific composition ratio is excellent in mechanical strength, when placed in a lumen in a living body, It is possible to prevent damage due to the influence of external force or the like.

The stent body (linear member) 2 is made of a melt-molded body containing polylactic acid and calcium phosphate in a composition ratio (mass%) of 99: 1 to 60:40, particularly preferably 90:10 to 70:30.
If it is the range of the said mass ratio, the stent main body (linear member) 2 which has desired mechanical strength (breaking strength, breaking elongation) will be obtained.

Lactic acid, which is a raw material for the polylactic acid, contains D-lactic acid and L-lactic acid as optical isomers. In addition, polylactic acid formed by polymerizing them has a D-lactic acid unit of about 10% or less and an L-lactic acid unit of about 90% or more, or an L-lactic acid unit of about 10% or less and a D-lactic acid unit of about 90% or more polylactic acid, crystalline polylactic acid having an optical purity of about 80% or more, and polylactic acid having 10-90% D-lactic acid units and 90-10% L-lactic acid units, and optical purity Is known to be about 80% or less of amorphous polylactic acid.
However, the polylactic acid resin used in the present invention is not particularly limited to the type of optical isomer, crystallinity, optical purity, and the like.

The mass average molecular weight of the polylactic acid is in the range of 1,000 to 500,000. Among these, 1,500 to 300,000 are preferable, and 2,000 to 200,000 are more preferable.
If it is the said range, it is possible to obtain a desired decomposition rate in the living body.

The polylactic acid can be produced according to a known method.
Examples thereof include a condensation polymerization method in which lactic acid is directly dehydrated under heating and reduced pressure to perform condensation polymerization, and a ring-opening polymerization method in which lactic acid is produced by ring-opening polymerization via lactide which is a cyclic dimer.

  The calcium phosphate is not particularly limited as long as it has high in vivo stability. For example, primary calcium phosphate, secondary calcium phosphate, anhydrous dibasic calcium phosphate, acidic calcium pyrophosphate, calcium pyrophosphate, tricalcium phosphate, tricalcium phosphate , Β-type tricalcium phosphate, α-type tricalcium phosphate, tetracalcium phosphate, and hydroxyapatite.

  The calcium phosphate is preferably treated with an alkaline inorganic compound. By treating calcium phosphate with alkali, it is possible not only to neutralize the area around the stent placement site due to the influence of lactic acid produced as polylactic acid decomposes in vivo, but also to an acidic environment. It is also possible to suppress the inflammatory reaction that occurs.

The alkaline inorganic compound is not particularly limited as long as it has high biocompatibility. For example, hydroxides such as calcium hydroxide, potassium hydroxide, and magnesium hydroxide, chlorides such as calcium chloride, potassium chloride, and magnesium chloride are used. Things.
Chlorides such as calcium chloride are originally neutral, but since commercially available chloride contains several percent of calcium hydroxide, the aqueous solution exhibits strong alkalinity. Therefore, they can also be used.

  Moreover, 99.9: 0.1-50: 50 is preferable and, as for the composition ratio (mass%) of the said calcium phosphate and an alkaline inorganic compound, 80: 20-60: 40 is especially suitable. Within this range, it is possible to more reliably neutralize the area around the stent placement site due to the influence of lactic acid produced as polylactic acid degrades in vivo, and to suppress the inflammatory reaction. Can do.

  Methods for preparing calcium phosphate treated with the alkaline inorganic compound include a method of mixing an alkaline inorganic compound with calcium phosphate in advance, and a method of coating the surface by immersing calcium phosphate in an aqueous alkaline inorganic compound solution, but are not limited thereto. There is nothing.

  In the case where calcium phosphate is treated with the alkaline inorganic compound, polylactic acid and calcium phosphate not treated with the alkaline inorganic compound have a composition ratio of 99: 1 to 60:40, particularly preferably 90:10 to 70:30. (Mass%) is preferably used. If the reason is within the range of this composition, a stent having a desired mechanical strength (breaking strength, breaking elongation) can be obtained.

The calcium phosphate melt-molded body treated with the polylactic acid and the alkaline inorganic compound has high mechanical properties (mechanical strength) in a tensile test based on JIS K7113.
Specifically, the breaking strength is preferably in the range of 70 to 500 MPa, more preferably 75 to 400 MPa, and most preferably 100 to 350 MPa. The breaking elongation is preferably in the range of 15 to 200%, more preferably 15 to 100%, and most preferably 15 to 50%. Within the above numerical range, the stent 1 can have sufficient mechanical strength.
Further, if the breaking elongation is 15% to 50%, it can be expanded using a balloon when it is placed in the body lumen. Further, since the stent body (linear member) 2 of the present invention is an elastic body, the stent body (linear member) 2 compressed and held in advance is compressed by using its own elastic force at the lesion. Self-expanding that opens is also possible.

In addition, another biodegradable polymer can be melt-kneaded in the stent body (linear member) 2 formed of the polylactic acid and the calcium phosphate. When a biodegradable polymer as described later is contained, a stent main body (linear member) 2 imparted with flexibility and strain persistence can be obtained. The strain survivability is a characteristic that the strain remains without recovering when the material is strained. The strain survivability is optimal for the balloon expandable stent.
The biodegradable polymer is not particularly limited. For example, polyethylene succinate, polybutylene succinate, polybutylene succinate adipate, polylactic acid-polycaprolactone copolymer, polyglycolic acid-polycaprolactone Examples include copolymers, polycaprolactone, polylactic acid-trimethylene carbonate copolymers, and polyglycolic acid-trimethylene carbonate copolymers. By melting and kneading such a biodegradable polymer, the stent body (linear member) 2 having improved mechanical strength (for example, elongation at break) by adding calcium phosphate treated with an alkaline inorganic compound is flexible. It is possible to impart residual strain.

The polylactic acid and the calcium phosphate may contain other additives as long as the effects of the present invention are not impaired.
Examples of the additive include pigments, dyes, X-ray contrast agents (barium sulfate, tungsten, bismuth oxide, etc.) that do not harm the living body, reinforcing agents (glass fiber, carbon fiber, talc, mica, viscosity favorite, titanium Potassium acid fiber, etc.), fillers (carbon black, silica, alumina, titanium oxide, metal powder, wood powder, rice husk, etc.), heat stabilizer, oxidative degradation inhibitor, UV absorber, lubricant, mold release agent, crystal nucleus Agents, plasticizers, flame retardants, antistatic agents, foaming agents and the like.

Further, as shown in FIG. 2, the stent 1 of the present invention is prepared by kneading the biological physiologically active substance 6 in the stent body (linear member) 2 to thereby mix the biologically physiologically active substance 6 with the stent body. (Linear member) 2 may be dispersed.
By dispersing the biological physiologically active substance in the stent body (linear member) 2, it becomes possible to release the biologically physiologically active substance 6 as the stent body (linear member) 2 is decomposed. It is also possible to appropriately suppress restenosis with the physiologically active substance 6.

  The biologically physiologically active substance 6 is not particularly limited as long as it has an effect of suppressing restenosis when a stent is placed in a luminal lesion, for example, an anticancer agent, an immunosuppressant, an antibiotic Substance, antirheumatic agent, antithrombotic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemic agent, integrin inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid Flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, biological materials, interferons, NO production promoters, and the like.

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

  As the immunosuppressant, for example, rapamycin (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, lovastatin, 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 (manufactured by Ajinomoto Co., Inc.) is preferable.

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

  Preferred examples of the antioxidant include catechins, anthocyanins, proanthocyanidins, lycopene, and β-carotene. Among catechins, epigallocatechin gallate is particularly preferable.

  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 proanthocyanin 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, fluorouracil (5-FU: manufactured by Kyowa Hakko) 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 agent, for example, steroids such as dexamethasone and prednisolone are preferable.

  Examples of the bio-derived material include EGF (epidemal growth factor), VEGF (basic endothelial 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.

  As the biological physiologically active substance 6, in view of the fact that restenosis is surely suppressed, at least one kind or two or more different biological physiologically active substances of the biological physiologically active substance are used. It is preferable to include. The biologically physiologically active substance is appropriately selected according to the case.

In the total mass of the stent body (linear member) 2 in which the polylactic acid, the calcium phosphate, and the biological physiologically active substance 6 are dispersed, the biological physiologically active substance 6 is 1 to 50% by mass, preferably 5-45 mass%, More preferably, it can contain in the range of 10-40 mass%.
If it is the said numerical range, when the stent main body (linear member) 2 decomposes | disassembles in_vivo | within_body, restenosis can be suppressed appropriately.

Furthermore, as shown in FIGS. 3 to 6, the stent 1 of the present invention includes a biological bioactive substance formed on the stent body (linear member) 2 and a biodegradable polymer. A physiologically active substance releasing layer can also be provided.
The biological physiologically active substance releasing layer is a layer containing a biologically physiologically active substance formed on the stent body (linear member) 2 and a biodegradable polymer. FIGS. 3 and 4 A layer composed of a biological bioactive substance layer 3 containing a biological bioactive substance and a biodegradable polymer layer formed on the biological bioactive substance layer (biodegradable polymer) Examples of the layer 4) or a layer (biodegradable polymer layer 5) containing a biological physiologically active substance 7 and a biodegradable polymer as shown in FIGS.

  The stent body (linear member) 2 having the biological physiologically active substance releasing layer can release the biologically physiologically active substance into the living body in stages, and can appropriately reduce restenosis in an appropriate biological manner. It can be suppressed with a physiologically active substance.

In the case of the stent 1 of FIGS. 3 and 4, the biological bioactive substance release layer is decomposed by the biodegradable polymer layer 4, so that all the biological bioactive substance layer 3 biological layers are disassembled. The physiologically active substance is released into the living body. Furthermore, due to the decomposition of the stent body (linear member) 2 in vivo, the biological and physiologically active substance 6 dispersed in the stent body 2 is released, and all the indwelling objects disappear and disappear.
In the case of the stent 1 shown in FIGS. 5 and 6, the biological bioactive substance release layer releases all the biological bioactive substance 7 into the living body when the biodegradable polymer layer 5 is decomposed. Is done. Furthermore, due to the decomposition of the stent body (linear member) 2 in vivo, the biological and physiologically active substance 6 dispersed in the stent body 2 is released, and all the indwelling objects disappear and disappear.

  3 and 4, the biological physiologically active substance forming the biologically physiologically active substance layer 3 is specifically described in the description of FIG. 2 in view of the fact that restenosis is surely suppressed. It is preferable that at least one of the biological physiologically active substances 6 or two or more different biological physiologically active substances are included. The biologically physiologically active substance is appropriately selected according to the case.

  The biological physiologically active substance layer 3 has a thickness that does not significantly impair the performance of the stent body (linear member) 2 such as reachability to the lesion (delivery) and irritation to the blood vessel wall, In addition, since it is necessary to set the thickness so that the effect of the biological physiologically active substance is confirmed, the thickness is preferably in the range of 1 to 100 μm, and more preferably 1 to 50 μm, and more preferably 1 to 20 μm. If it is the range, it is especially preferable.

Although it does not specifically limit as a biodegradable polymer which forms the biodegradable polymer layer 4, A thing with high biostability is preferable, for example, polylactic acid (A simple substance of D-form-polylactic acid, L-form-polylactic acid) Simple substance, (co) polymer of D-form and L-form), polylactic acid stereocomplex, polyglycolic acid, copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid It is preferably at least one selected from the group consisting of collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid and polycaprolactone, or a copolymer thereof, and decomposes in vivo Considering the above, a medically safe one is preferable. Of these, polylactic acid is most preferably used.
The polylactic acid stereocomplex refers to a three-dimensional structure in which D-lactic acid and L-lactic acid, which are in an enantiomeric relationship, interact with each other by van der Waals force to generate structural fitting. With this structure, a stent having higher mechanical strength and high radial force can be obtained.

  A biodegradable polymer layer 4 formed of at least one kind of the biodegradable polymer is provided on the surface of the biological physiologically active substance layer 3.

  The thickness of the biodegradable polymer layer 4 is such that it does not significantly impair the performance of the stent body (linear member) 2 such as reachability to the lesion (delivery) and irritation to the blood vessel wall, and Since it is necessary to set the thickness at which the effect of the biological physiologically active substance is confirmed, it is preferably in the range of 1 to 100 μm, but more preferably 1 to 50 μm, and more preferably 1 to 20 μm. If it is a range, it is especially preferable.

The total thickness of the biological physiologically active substance layer 3 and the biodegradable polymer layer 4 is preferably 2 to 200 μm, and more preferably 2 to 40 μm.
If it is in the above numerical range, the performance of the stent body 2 such as reachability to the lesioned part (delivery property) and irritation to the blood vessel wall will not be significantly impaired.

5 and 6, the biodegradable polymer forming the biodegradable polymer layer 5 is not particularly limited, but has high biostability and is medically safe in view of degrading in vivo. Is preferred.
Specifically, the same as the specific examples of the biodegradable polymer forming the biodegradable polymer layer 4 described above can be mentioned, and among them, polylactic acid is optimally used.
The biodegradable polymer should be appropriately selected in accordance with the required mechanical property value or the desired release rate or biodegradation rate of the biological physiologically active substance.

  As the biological physiologically active substance 7 dispersed in the biodegradable polymer layer 5, the biological physiologically active substance specifically described in the description of FIG. It is preferable that at least one or two or more different biological physiologically active substances of 6 are included. The biological physiologically active substance 7 is appropriately selected according to the case.

  In the biodegradable polymer layer 5 in which the biological physiologically active substance 7 is dispersed, the content of the biological physiologically active substance 7 is not particularly limited, and the state of the lesioned part and the biological physiology used are used. It can be prepared in consideration of the type of the active substance 7, etc., but in the total mass of the biological physiologically active substance release layer (the biodegradable polymer layer 5 in which the biological physiologically active substance 7 is dispersed), It is preferable that it is 1-60 mass%, and it is still more preferable that it is 10-50 mass%.

  The thickness of the layer in which the biological bioactive substance 7 is dispersed in the biodegradable polymer layer 5 is the stent body (linear member) such as reachability to the lesion (delivery property) and irritation to the blood vessel wall. ) Since it is necessary to set a thickness that does not significantly impair the performance of 2 and the effect of the biological physiologically active substance is confirmed, the thickness is preferably in the range of 1 to 100 μm, among which 1 to 50 μm If it is more preferable, it is especially preferable if it is the range of 1-20 micrometers.

The biological physiologically active substance release layer may contain other additives as long as the effects of the present invention are not impaired.
Examples of the additive include pigments, dyes, X-ray contrast agents (barium sulfate, tungsten, bismuth oxide, etc.) that do not harm the living body, reinforcing agents (glass fiber, carbon fiber, talc, mica, viscosity favorite, titanium Potassium acid fiber, etc.), fillers (carbon black, silica, alumina, titanium oxide, metal powder, wood powder, rice husk, etc.), heat stabilizer, oxidative degradation inhibitor, UV absorber, lubricant, mold release agent, crystal nucleus Agents, plasticizers, flame retardants, antistatic agents, foaming agents and the like.

As a method for producing the stent body (linear member) 2 of the present invention, a mixture of calcium phosphate and polylactic acid is formed into a desired shape such as a rod or a sheet using an extrusion molding machine or an injection molding machine.
When the stent 1 in which the biological physiologically active substance 6 is dispersed in the stent body (linear member) 2 as shown in FIG. 2 is produced, it is kneaded together with calcium phosphate and polylactic acid at the time of melt molding. Or a process of mixing the biological physiologically active substance 6 in a paste form. Moreover, when mixing materials, such as a calcium phosphate, an additive is mixed together as needed.
Next, in order to produce a pipe having a desired wall thickness and outer diameter, the molded body is produced by melt molding such as stretching (for example, uniaxial stretching), rolling, compression, or high pressure extrusion molding. A production method by stretching that can improve the strength and elastic modulus of the stent is preferable.

In addition, when the stent body is a tubular body (pipe) made of the melt-molded body provided with pores, after the melt-molded body is processed, an opening pattern is pasted on the pipe surface. The opening is formed by melting the pipe part by an etching technique such as laser etching or chemical etching. Alternatively, the opening is 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, when the stent body is formed into a cylindrical shape by knitting the fibers of the melt-formed body, a wire having a predetermined thickness and outer diameter is obtained by melt-kneading materials such as calcium phosphate and polylactic acid, followed by extrusion. Thereafter, the wire is bent to form a wave pattern or the like, and then the mandrel is wound in a spiral shape, and then the mandrel is extracted, and the shaped wire is cut into a predetermined length.

  As shown in FIGS. 3 and 4, a layer 3 (biological physiologically active substance layer 3) formed of a biological physiologically active substance on the surface of the stent body (linear member) 2, and further formed thereon. A method for manufacturing the stent 1 having the biodegradable polymer layer 4 will be described below.

The method for providing the biological physiologically active substance layer 3 on the surface of the stent body (linear member) 2 is not particularly limited. For example, the stent body (linear member) is obtained by melting the biological physiologically active substance. 2. A method of coating the surface of 2 and a biological physiologically active substance dissolved in a solvent to prepare a solution. The stent body (linear member) 2 is immersed in this solution and then pulled up to evaporate the solvent or otherwise. Or a method of spraying the solution onto the stent body (linear member) 2 using a spray to remove the solvent by evaporation or other methods.
When the above-mentioned solvent can easily dissolve the biologically physiologically active substance and can easily wet the surface of the stent body (linear member) 2, only the biologically physiologically active substance can be used. The simplest method is to immerse and dry the stent body (linear member) 2 in a solution dissolved in a solvent, or to spray and dry the solution onto the stent body (linear member) 2 by spraying. Yes, most preferably applied.
Examples of the solvent include acetone, ethanol, chloroform, tetrahydrofuran (THF) and the like. The biological physiologically active substance is used as the solvent, and the solution concentration is 0.0001 to 20% by mass, preferably 0.8. A solution dissolved so as to be 01 to 10% by mass is used.
The method for forming the biodegradable polymer layer 4 on the biological physiologically active substance layer 3 is not particularly limited. For example, a solution is prepared by dissolving the biodegradable polymer in a solvent. In this solution, the stent body (linear member) 2 coated with the biological physiologically active substance layer 3 is dipped, and then pulled up to remove the solvent by evaporation or other methods, or by using a spray. Examples thereof include a method of spraying the solution onto the biological physiologically active substance layer 3 and evaporating or removing the solvent by other methods.
Examples of the solvent include acetone, ethanol, chloroform, tetrahydrofuran and the like. The biodegradable polymer is used as the solvent, and the solution concentration is 0.0001 to 20% by mass, preferably 0.01 to 10% by mass. Use a solution that has been dissolved so that the concentration becomes 1%.

Next, as shown in FIGS. 5 and 6, a manufacturing method of the stent 1 in which the biodegradable polymer layer 5 in which the biological physiologically active substance 7 is dispersed is provided on the surface of the stent body (linear member) 2. This will be described below.
The method for providing the above-described layer on the surface of the stent body 2 is not particularly limited. For example, the biodegradable polymer and the biological body that form the biodegradable polymer layer 5 in which the biological physiologically active substance 7 is dispersed are used. A method in which the biologically physiologically active substance 7 is dissolved in a solvent to prepare a solution, and the stent body (linear member) 2 is immersed in the solution and then pulled up, and the solvent is removed by evaporation or other methods, or Examples include a method of spraying the solution onto the stent body (linear member) 2 using a spray and removing the solvent by evaporation or other methods.
Examples of the solvent include acetone, ethanol, chloroform, tetrohydrofuran (THF), and the like. The biological physiologically active substance 7 and the biodegradable polymer are used as the solvent, and the solution concentration is A solution dissolved so as to be 0.0001 to 20% by mass, preferably 0.01 to 10% by mass is used.

  Although the stent according to the present invention has been described with reference to the accompanying drawings, these are only examples of the stent according to the present invention. Accordingly, the stent according to the present invention has a shape, a size of its diameter, a length, and the like. Is not particularly limited, and can be appropriately selected depending on the purpose of use.

The stent 1 may be either a balloon expansion type or a self-expansion type.
In addition, the thickness of the stent 1 is not particularly limited as long as it has a radial force necessary for placement in a lesion and does not inhibit blood flow, but it is preferably in the range of 1 to 1000 μm, preferably 10 to 500 μm. The range is more preferable, and the range of 40 to 200 μm is most preferable.
The diameter of the stent 1 may be appropriately selected according to the application location. For example, when used for a coronary artery, the outer diameter (diameter of a cross-section in the direction perpendicular to the longitudinal direction (radial direction)) is usually 1.0 to 3.0 mm and the length is preferably 5 to 50 mm before expansion.

  The method of using the stent of the present invention is the same as a normal method. For example, when the stent of the present invention is placed in a stenosis that has occurred in the coronary artery, the stent of the present invention having a diameter smaller than that of the coronary artery is attached to the distal balloon of the catheter and percutaneously reached the stenosis. The stent of the present invention may be expanded by self-expanding means utilizing the action of an external force based on the expansion of the balloon or elastic force to secure the inner diameter of the coronary artery.

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

<Tensile test of melt-formed product: measurement of breaking strength and breaking elongation>
[Example 1]
Hydroxyapatite (Al-HA) prepared by immersing hydroxyapatite (manufactured by Taihei Chemical Sangyo Co., Ltd.) in a 30% calcium hydroxide aqueous solution and drying, and L-polylactic acid having a molecular weight of 150,000 (100L0105 manufactured by API) ) Pellets (PLLA) were melt-kneaded so as to have a ratio of PLLA: Al-HA = 70: 30, and then extruded at 190 ° C. to obtain a strand-like molded product. The obtained molded product was compression-molded into a film having a thickness of 150 μm at 140 ° C. using a hot press. Based on JIS standard K7113 (plastic tensile test method), a sample was punched into a 1/5 scale type 2 test piece and subjected to a tensile test to obtain the breaking strength and breaking elongation. The results are shown in Table 1.

[Example 2]
Hydroxyapatite powder (manufactured by Taihei Chemical Sangyo Co., Ltd.) was immersed in a 30% calcium hydroxide aqueous solution and dried, alkali-treated hydroxyapatite (Al-HA) and L-polylactic acid (API 100L0105) pellets (PLLA) All were carried out in the same manner as in Example 1 except that the mixture was mixed so that the ratio of PLLA: Al-HA = 80: 20. The results are shown in Table 1.

[Comparative Example 1]
Hydroxyapatite powder (manufactured by Taihei Chemical Sangyo Co., Ltd.) was immersed in a 30% calcium hydroxide aqueous solution and dried, alkali-treated hydroxyapatite (Al-HA) and L-polylactic acid (API 100L0105) pellets (PLLA) All were carried out in the same manner as in Example 1 except that they were mixed so that the ratio of PLLA: Al-HA = 50: 50. The results are shown in Table 1.

[Comparative Example 2]
Hydroxyapatite powder (manufactured by Taihei Chemical Sangyo Co., Ltd.) was immersed in a 30% calcium hydroxide aqueous solution and dried, alkali-treated hydroxyapatite (Al-HA) and L-polylactic acid (API 100L0105) pellets (PLLA) All were carried out in the same manner as in Example 1 except that they were mixed so that the ratio of PLLA: Al-HA = 30: 70. The results are shown in Table 1.

[Comparative Example 3]
L-polylactic acid (API 100L0105) pellets (PLLA) were compression molded to a thickness of 150 μm at 140 ° C. using a hot press. Based on JIS standard K7113 (plastic tensile test method), a sample was punched into a 1/5 scale type 2 test piece and subjected to a tensile test to obtain the breaking strength and breaking elongation. The results are shown in Table 1.

  From the results shown in Table 1, it can be seen that the fracture strength and elongation at break of the melt-formed bodies of Examples 1 and 2 in which the composition ratio of PLLA: Al—HA is within 99: 1 to 60:40 mass%.

[Example 3]
The film obtained in [Example 1] was cut into a size of 50 mm × 7 mm, and was rolled and inserted into a PTFE shrink tube having a diameter of 2.4 mm and a length of 60 mm. Further, a 70 mm long PTFE tube (AWG-17, manufactured by Chuko Kasei Kogyo Co., Ltd.) is inserted into the tube and heated in an oven preheated to 200 ° C. for 1 hour to have a diameter of 2.1 mm and a wall thickness of 150 μm. At the same time, an annealing treatment was performed. The pipe was processed into a stent shape with an excimer laser (SPL400H manufactured by Sumitomo Heavy Industries, Ltd.).
The concentration of rapamycin (hereinafter referred to as RM) and polylactic acid (hereinafter referred to as DL-PLA), which are immunosuppressive agents, was dissolved in tetrahydrofuran (hereinafter referred to as THF) so that the mass ratio was 1: 1. After spraying a certain solution with a spray (manufactured by Micro Spray Gun-II NORDSON) and drying THF as a solvent, a scanning electron microscope (SEM) shows that about 600 μg of a mixture of RM and PLGA is applied on the stent. ).
The above-mentioned stent having an outer diameter of 2.1 mm, a length of 1.0 mm and a thickness of 160 μm is expanded to 3.0 mm with a balloon catheter (Arashi manufactured by Terumo Corporation), and the pushing force when the stent is pushed inward by 1 mm (radial force) ) Was measured by a compression test using an autograph (AG-IS type, manufactured by Shimadzu Corporation). As a result, the radial force was 201 gf.

[Comparative Example 4]
The film obtained in [Comparative Example 1] was processed into a stent by the same method as in [Example 3], and the radial force was measured by the same method. As a result, the radial force was 68 gf.

  As shown in the results of [Example 3] and [Comparative Example 4], a stent produced from a melt-molded molded product in which PLLA: Al-HA was mixed at a composition ratio of 99: 1 to 60: 40% by mass. The higher radial force value.

FIG. 1 is a side view showing an embodiment of the stent of the present invention. FIG. 2 is an enlarged cross-sectional view taken along line AA in FIG. FIG. 3 is an enlarged cross-sectional view taken along line AA in FIG. 4 is an enlarged cross-sectional view taken along line BB in FIG. FIG. 5 is an enlarged cross-sectional view taken along line AA in FIG. 6 is an enlarged cross-sectional view taken along the line BB in FIG.

Explanation of symbols

1 Stent 2 Stent body (linear member)
3 Biologically bioactive substance layer 4 Biodegradable polymer layer 5 Biodegradable polymer layer 6 Biologically bioactive substance 7 Biologically bioactive substance

Claims (12)

  A stent having a stent main body made of a melt-formed product containing polylactic acid and calcium phosphate in a composition ratio (mass%) of 99: 1 to 60:40.   The stent according to claim 1, wherein the calcium phosphate is treated with an alkaline inorganic compound.   3. The alkaline inorganic compound is at least one selected from the group consisting of calcium hydroxide, potassium hydroxide, magnesium hydroxide, calcium chloride, potassium chloride, and magnesium chloride. Stent.   The stent according to any one of claims 1 to 3, wherein the stent body is produced by stretching the melt-molded body.   The stent according to any one of claims 1 to 4, wherein the melt-formed product has a breaking strength of 100 to 350 MPa and a breaking elongation of 15 to 50%.   The stent according to any one of claims 1 to 5, wherein a biological physiologically active substance is dispersed in the stent body.   It has a biological bioactive substance release layer containing the biological bioactive substance formed on the said stent main body, and a biodegradable polymer, The any one of Claims 1-6 characterized by the above-mentioned. Stent.   8. The biological physiologically active substance release layer includes a biological physiologically active substance layer and a biodegradable polymer layer formed on the biological physiologically active substance layer. Stent.   The stent according to claim 7, wherein the biological physiologically active substance releasing layer comprises a layer containing a biological physiologically active substance and a biodegradable polymer.   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 6 to 9, wherein the stent is at least one selected from the group consisting of production promoting substances.   The biodegradable polymer is polylactic acid, polylactic acid stereocomplex, polyglycolic acid, copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin, heparan sulfate The stent according to any one of claims 6 to 10, which is at least one selected from the group consisting of, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid and polycaprolactone, or a copolymer thereof.   The stent according to any one of claims 1 to 11, wherein a radial force when the stent body is expanded to an outer diameter of 3.0 mm and compressed by 1 mm is 80 to 500 gf per 10 mm of the stent length.

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