WO2007119423A1 - Substance to be placed in the living body - Google Patents

Abstract

It is intended to provide a substance to be placed in the living body which is made of a biodegradable material, causes neither mechanical stress nor chronic inflammation in the living body after placing in the living body, sustains a required strength and elongation in the living body and scarcely suffers from breakage or cracking due to an external force. The above problem is solved by providing a substance to be placed in the living body which has the main body made of a biodegradable material comprising, as the main component, a polylactic acid complex wherein D-polylactic acid and L-polylactic acid form together a complex of a stereo complex structure at a ratio by mass of from 45:55 to 55:45.

Description

 Specification

 In vivo indwelling

 Technical field

 [0001] The present invention relates to an in-vivo indwelling object.

 Background art

 [0002] The in vivo indwelling material of the present invention includes various forces such as a stent, a catheter, an artificial blood vessel, and a stent graft. Hereinafter, a stent will be described as an example.

 [0003] First, angioplasty applied to ischemic heart disease will be described.

 The Westernization of dietary habits in Japan has led to a sudden increase in the number of patients with ischemic heart disease (anginal angina, myocardial infarction). Transvascular coronary angioplasty (PTCA) has been performed and has become very popular. At present, the number of applied cases has increased due to technological development. Whether it is localized at the time PTCA began (short lesion length) or single-branch lesion (lesion with stenosis only at one site)? Thus, PTCA has been extended to more distal, eccentric, calcified, and multi-branch lesions (lesions with stenosis in more than one site).

 [0004] PTCA is a guide catheter in which a small incision is made in the artery of a patient's leg or arm, an introducer system (introducer) is placed, and a guide wire is advanced through the lumen of the introducer sheath. After inserting a long hollow tube called a blood vessel 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 lead the guide wire ahead The balloon catheter is advanced to the lesion area of the patient's coronary artery under X-ray contrast, and the balloon is positioned in the lesion area. At that position, the doctor presses the balloon once at a predetermined pressure for 30 to 60 seconds. It is a technique to inflate.

 As a result, the vascular lumen of the lesion is expanded and the blood flow through the vascular lumen is increased. However, when the vessel wall is damaged by the catheter, the intima proliferates, which is a healing reaction of the vessel wall, and restenosis has been reported at a rate of about 30 to 40%.

[0005] Stents have been studied for use in methods of preventing such restenosis, Has achieved some results. The term stent refers to the expansion of the stenosis or occlusion site and the securing of the lumen in order to treat various diseases caused by stenosis or occlusion of blood vessels and other lumens. It is a tubular medical device that can be indwelled. Most 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 wire made of a metal material, or a polymer material. Various shapes have been proposed, such as those formed by knitting fibers into a cylindrical shape. The purpose of stent placement is the force that aims to prevent and reduce restenosis that occurs after procedures such as PTCA. Stent placement alone does not significantly suppress stenosis. The actual situation was.

[0006] Therefore, in recent years, this biological physiologically active substance is locally released over a long period of time at the indwelling site of the lumen by loading the biological physiologically active substance such as an immunosuppressive agent or an anticancer agent on this stent. A method to reduce the restenosis rate has been proposed! RU

 For example, Patent Document 1 discloses a biodegradable polymer and a therapeutic substance on the surface of a stent body that also has metal (tantalum or the like) or biostable or bioabsorbable polymer (polylattic acid or the like) force. And a stent coated with a mixture thereof.

 Patent Document 2 describes a stent in which a drug layer is provided on the surface of a stent body having a metal (such as stainless steel) or polymer force, and a biodegradable polymer layer is further provided on the surface of the drug layer. Yes.

 [0007] However, in the metal stents described in Patent Documents 1 and 2, the stent body is indwelled in the living body semipermanently. Therefore, after the biodegradable polymer on the surface is degraded in vivo and the drug is released, chronic inflammation due to mechanical stress on the vessel wall of the stent body may occur. This is patent document 1,

The present invention is not limited to the metal stents described in 2, but is a problem in all stents using metal materials such as tantalum and stainless steel and polymers that are difficult to biodegrade.

In this regard, Non-Patent Document 1 discloses that the polymer layer may be left in the living body semipermanently to cause chronic inflammation, and restenosis may occur due to degradation of the polymer. Reported to be provoked by thrombosis Has been.

 [0008] On the other hand, a stent made of a biostable or biodegradable polymer such as polylatatic acid described in Patent Document 1 or a bioabsorbable polymer described in Patent Document 3 A stent with a certain poly-L-lactic acid power degrades and disappears in the living body, so that it is left in the body for a long time and mechanical stress is applied to the blood vessel wall, so that chronic inflammation hardly occurs. In addition, blood vessels gradually meander with age, but if the stent disappears, the remaining endothelial cell layer can follow this meandering motion well. Therefore, it is possible to provide a stent with little or no invasion to a living body.

 Patent Document 1: JP-A-8-33718

 Patent Document 2: JP-A-9-56807

 Patent Document 3: WO01 / 067990 Pamphlet

 Special Reference 1: Renu Virmani ect., Mechanism of Late In— Stent Restenosis After Impl antation of a Paclitaxel Derivate- Eluting Polymer Stent System in Humans, “Circulation”, 2002, VOL106, p2649— 2651

 Disclosure of the invention

 Problems to be solved by the invention

[0009] However, the stent described in Patent Document 1 that has a polylatatic acid equivalent force and the stent described in Patent Document 3 that also has a poly L-lactic acid force have lesions with low strength and elongation. Even if left in place, it could be damaged by some external force. In addition, since the radial force is low, the stent may drop out of the lesion after placement. Furthermore, since the force for crimping the stent onto the stent (cribing force) is low, the stent may drop out of the balloon catheter during delivery of the lesion.

 [0010] In the above, the force given as an example of a stent. Problems such as strength reduction are not limited to stents.

It is a problem common to in vivo indwelling materials having biodegradability.

[0011] Therefore, the object of the present invention is to provide biodegradable material strength, does not cause mechanical stress and chronic inflammation in the living body after being placed in the living body, and has the necessary strength and elongation in the living body ( Elongation), damage and cracking due to external force are difficult to occur. There is to be.

 Further, such an in-vivo indwelling material further has a necessary crimping force or radial force, and it is difficult to drop off after placement from a balloon catheter during delivery to a lesion. In-vivo indwelling (stents, catheters, artificial prostheses that are inserted into the site to expand stenosis or occlusion in the living body, and then expanded to maintain the state. In vivo indwelling materials such as blood vessels and stent grafts).

 Means for solving the problem

 [0012] The present inventor has intensively studied for the purpose of solving the above-mentioned problems, and contains D-form polylactic acid and L-form polylactic acid in a specific range, and further, they form a specific structure. It has been found that an in-vivo indwelling body having a main body portion composed of a biodegradable substance mainly composed of a polylactic acid complex can solve the above-mentioned problems.

 [0013] That is, the present invention includes the following (1) to (21).

 (1) Biodegradability mainly composed of polylactic acid complex forming a complex structure of stereocomplex structure with mass ratio of D-form polylactic acid and L-form polylactic acid 5: 55 ~ 55: 45 An in-vivo indwelling having a main body made of a substance.

 (2) The in-vivo indwelling product according to (1), wherein the biodegradable substance contains a biological physiologically active substance.

 (3) The biological bioactive substance according to (2), wherein at least a part of the biological physiologically active substance is a powder, and the biological physiologically active substance of the powder is dispersed in the biodegradable substance. Indwelling in the body.

 (4) The in vivo indwelling product according to (2) or (3), wherein at least a part of the biological physiologically active substance is chemically bonded to the polylactic acid complex.

 [0014] (5) The in-vivo indwelling product according to any one of (1) to (4), wherein a drug releasing layer containing the biological physiologically active substance is provided on the surface of the main body.

 (6) The in-vivo indwelling product according to (5), wherein the drug release layer further contains a biodegradable polymer.

(7) The drug release layer is composed of two or more layers, and these layers are the biological and physiological activities. The in-vivo indwelling material according to (6) above, comprising a layer containing a substance and a layer containing the biodegradable polymer.

 [0015] (8) The in-vivo indwelling product according to any one of (1) to (7), wherein the polylactic acid complex has a weight average molecular weight of 1,000 to 1,000,000.

 (9) The in-vivo indwelling product according to any one of (1) to (8), wherein the polylactic acid complex is a stretched polylactic acid complex.

 (10) The polylactic acid complex has a first melting peak between 65 and 75 ° C. and a second melting peak between 200 and 250 ° C. in differential scanning calorimetry. The in-vivo indwelling product according to any one of (1) to (9), which is a body.

 (11) The polylactic acid composite is a polylactic acid composite having a breaking strength specified by JIS K7113 of 70 MPa or more, a breaking elongation of 15% or more, and a Young's modulus of lOOMPa or more (1 ) To (10).

 [0016] (12) The in-vivo indwelling product according to any one of (1) to (11) above, wherein the polylactic acid complex is a polylactic acid complex produced by an alternating lamination method.

 (13) The in-vivo indwelling product according to (12), wherein the alternating lamination method is an alternating lamination method performed by forming a micro-order thin film.

 (14) The in-vivo indwelling product according to the above (13), wherein the thickness of the micro-order thin film is 1πι to 500 / ζ m.

 (15) The in-vivo indwelling product according to (13) or (14), wherein the biological physiologically active substance is contained between the micro-order thin films.

 [0017] (16) The living body according to any one of (1) to (15), wherein the shape of the main body portion is a tube shape, a tubular shape, a net shape, a fiber shape, a nonwoven fabric shape, a woven fabric shape, or a filament shape. Detainment.

(17) The biologically bioactive 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, GPIIbllla antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, biological origin Any of the above (2) to (16), which is at least one selected from the group power of materials, interferon and NO production promoting substances The in-vivo indwelling object described.

 (18) Biodegradable polymer strength Polylactic acid, polydaricholic acid, polyhydroxybutyric acid, polymalic acid, polya-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, polystrength prolatathone And the in vivo indwelling material according to any one of the above (6) to (17), which is at least one selected from the group force consisting of the copolymer force.

 (19) The biodegradable polymer strength The in-vivo indwelling product according to the above (18), which is a copolymer of polylactic acid and polydaricholic acid.

 [0018] (20) The in-vivo indwelling product according to any one of (1) to (19), which is a stent.

 (21) The stent according to (20) above, wherein the radial face when expanded from 2.1 mm to 3. Omm and then compressed by 1 mm is 130 to 500 gf per 10 mm stent length. The invention's effect

 [0019] According to the present invention, it is made of a biodegradable material, does not cause mechanical stress and chronic inflammation in the living body after being placed in the living body, and has necessary strength and elongation in the living body. However, it is difficult to cause damage and cracks due to external force, and an in-vivo indwelling object can be provided.

 Further, such an in-vivo indwelling material further has a necessary crimping force or radial force, and it is difficult to drop off after placement from a balloon catheter during delivery to a lesion. In-vivo indwelling (stents, catheters, artificial prostheses that are inserted into the site to expand stenosis or occlusion in the living body, and then expanded to maintain the state. In vivo indwelling materials such as blood vessels and stent grafts) can be provided.

 Brief Description of Drawings

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 another enlarged cross-sectional view taken along the line AA in FIG.

 FIG. 4 is another enlarged cross-sectional view taken along the line AA in FIG.

 FIG. 5 is an enlarged cross-sectional view taken along line BB in FIG. 1.

[FIG. 6] FIG. 6 is another enlarged cross-sectional view taken along line BB in FIG. FIG. 7 is an enlarged photograph (40 ×) showing a pathological image after implantation of a porcine intracoronary stent in Example 5.

 [8] FIG. 8 is an enlarged photograph (40 × magnification) showing a pathological image after implantation of a porcine intracoronary stent in Comparative Example 9.

 [9] FIG. 9 is an enlarged photograph (40 ×) showing a pathological image after implantation of a porcine intracoronary stent in Comparative Example 11.

 Explanation of symbols

 1 Stent (Stent body)

 2 Linear members

 11 elements

 12 Ring unit

 13 Connecting member

 10 Stent body

 20 Polylactic acid composite

 30 Biologically bioactive substances in powder

 32 Layers containing biologically bioactive substances

 40 Biodegradable polymer

 42 Layer containing biodegradable polymer

 BEST MODE FOR CARRYING OUT THE INVENTION

 [0022] The present invention is described in detail below.

 The present invention provides a biodegradable composition mainly composed of a polylactic acid complex in which D-form polylactic acid and L-form polylactic acid form a complex having a stereocomplex structure in a mass ratio of 45:55 to 55:45. It is an in-vivo indwelling body having a body part with material force.

[0023] Here, the in-vivo indwelling body of the present invention may be a force main body itself having no main body and no other parts. That is, the in-vivo indwelling material of the present invention is a polylactic acid complex that forms a complex of stereocomplex structure with a D-form polylactic acid and an L-form polylactic acid at a mass ratio of 5:55 to 55:45. It may be an in-vivo indwelling made of a biodegradable substance containing as a main component. Even that case is within the scope of the present invention. Therefore, examples of the in-vivo indwelling material of the present invention include a stent made of the biodegradable substance and a stent in which a drug or the like is coated on the surface of the stent body (main body part) made of the biodegradable substance. . Other aspects of the in-vivo indwelling material of the present invention will be described later.

 [0024] First, the polylactic acid complex used in the present invention will be described.

 The polylactic acid complex used in the present invention is a complex of D-form polylactic acid and L-form polylactic acid. In this complex, these polylactic acids form a stereocomplex structure.

 Here, the stereocomplex structure is a three-dimensional structure in which enantiomeric macromolecules such as D-form and L-form interact with each other by van der Waals forces to produce structural fitting.

[0025] A stereocomplex structure can be formed even on a polymer having stereoregularity such as isotactic and syndiotactic.

As an example of forming a stereocomplex, in addition to polylactic acid, poly - gamma - Benjirugu Rutameto, poly - gamma - methyl Dal data formate, poly - tert butylene oxide, poly - tert Bed chill ethylene sulfates id, poly - _alpha -Methylbenzylmetatalylate, poly-α-methyl-α-ethyl-j8-propiolatatone, β-1,1-dichloropropyl-β-propiolataton, etc. are known.

 [0026] In the polylactic acid complex used in the present invention, the mass ratio of D-form polylactic acid to L-form polylactic acid is 45:55 to 55:45. This mass ratio is preferably 50: 50! /.

A polylactic acid complex having such a mass ratio and a stereocomplex structure as described above has significantly high strength and elongation, and an in-vivo indwelling material using such a polylactic acid complex is unlikely to break in vivo. . In addition, since such a polylactic acid composite retains strength even after being stretched by an external force, an in-vivo indwelling material such as a stent using the polylactic acid composite (a constricted portion formed in the living body). In-vivo indwelling materials such as stents, catheters, artificial blood vessels, and stent grafts that are inserted into the site to expand the obstruction, occlusion, etc. For example, even if it is inserted into a lesioned part using a catheter, etc., expanded and extended for placement at that site, its shape It has the radial force necessary to maintain the shape.

 The mass ratio of D-form polylactic acid and L-form polylactic acid here refers to the respective mass ratios used in producing the polylactic acid composite.

[0027] The polylactic acid complex has a weight average molecular weight of 1,000-1,000,000, preferably S, more preferably 2,000-700,000, more preferably S, More preferably, it is 400,000.

 In addition, the polylactic acid complex has a first melting peak (that is, a glass transition temperature) between 65 and 75 ° C. in differential scanning calorimetry, and a second melting peak between 200 and 250 ° C. (That is, having a melting point) is preferable. Where differential scanning calorimetry is N

 2 It shall be measured in a gas stream at a temperature increase rate of 5 ° CZmin. DT-50 manufactured by Shimadzu Corporation can be preferably used.

 When the polylactic acid complex has a weight average molecular weight in such a range or has such a melting peak, the strength and elongation of the polylactic acid complex are further increased, and this is used. The in-vivo indwelling material is more difficult to break in vivo. In addition, an in-vivo indwelling material such as a stent using such a polylactic acid composite has a higher radial force.

 [0028] Further, the polylactic acid composite is a polylactic acid composite having a breaking strength specified in JIS K7113 of 70 MPa or more, a breaking elongation of 15% or more, and a Young's modulus of lOOMPa or more. Is preferred.

 Here, the breaking strength is more preferably 75 MPa or more, more preferably 80 MPa or more. The upper limit is not particularly limited, but is preferably 500 MPa or less. Further, the elongation at break is more preferably 20% or more, and further preferably 30% or more. The upper limit is not particularly limited, but is preferably 200% or less.

 The Young's modulus is more preferably 500 MPa or more, and more preferably 1, OOOMPa or more. The upper limit is not particularly limited, but is preferably 50, OOOMPa or less.

An in-vivo indwelling product using a polylactic acid complex having such values in such a range is preferable because it is more difficult to break in vivo. Also, using such a polylactic acid composite An in-vivo indwelling material such as a stent is preferable because it has a higher radial force.

 In the following, “breaking strength”, “breaking elongation”, and “Young's modulus” all mean the values measured by the method specified in JIS K7113 (using No. 2 test piece of 1Z5 scale). To do.

 [0029] Further, it is preferable that the polylactic acid complex is a stretched polylactic acid complex.

 This is because when the polylactic acid complex is stretched at a temperature not lower than the glass transition temperature and not higher than the melting point, the amorphous portion of the molecules is stretched in the stretching direction and the degree of crystallinity increases, and the molecules are oriented in the stretching direction. This is because the tensile strength and tensile modulus in the stretching direction increase.

 [0030] The polylactic acid complex is preferably a polylactic acid complex produced by an alternating lamination method. Further, this alternate lamination method is preferably an alternate lamination method performed by forming a micro-order thin film. Further, the thickness of the micro-order thin film is preferably 1 m to 500 μm, more preferably 10 μm to 400 μm, and more preferably 50 μm to 300 μm. Is more preferable.

 Since the polylactic acid composite produced by this alternate lamination method has particularly good strength and elongation, an in-vivo indwelling body using this polylactic acid composite is more difficult to break in vivo. In addition, an in-vivo indwelling material such as a stent using such a polylactic acid composite is preferable because it has a higher radial force.

 Here, the alternating lamination method is a method for producing a thin film by alternately immersing a substrate in a D-form polylactic acid solution and an L-form polylactic acid solution. By applying such an alternate layering method, a polylactic acid complex having a stereocomplex structure can be formed more efficiently than in a balta (solution).

 Specifically, for example, a solution in which D-form polylactic acid is dissolved in acetonitrile and a solution in which L-form polylactic acid is dissolved in acetonitrile are prepared, and PFA (tetrafluoroethylene / perfluoroalkoxy vinyl ether copolymer) is prepared. For example, a method of repeatedly immersing and drying a substrate such as a polymerized resin in each solution.

In the present invention, the polylactic acid composite is produced by a conventional casting method or the like. You can also. However, in this case, the probability that a stereocomplex structure is formed is lower than that in the alternate lamination method. In the case of the casting method, a structure that is not a stereocomplex structure, for example, the probability that a single crystal is formed is relatively high, but in the case of manufacturing by an alternating lamination method, the stereocomplex structure is usually about 90% or more. Can be formed at a ratio of

[0032] In the present invention, the biodegradable substance has such a polylactic acid complex as a main component.

 Here, “main component” means containing 60% by mass or more by mass%. That is, in the present invention, the biodegradable substance contains 60% by mass or more of the polylactic acid complex. The biodegradable substance preferably contains 70% by mass or more of the polylactic acid complex.

It is more preferable to contain at least%.

[0033] The biodegradable substance preferably contains a biological physiologically active substance. In the process in which the in vivo indwelling material of the present invention is placed in the living body and then decomposed in the living body, a biologically physiologically active substance is released, and an inflammatory reaction and restenosis associated with the biodegradation are released. This is because it can be suppressed with a physiologically physiologically active substance.

[0034] The content of the biologically physiologically active substance in the biodegradable substance is not particularly limited, but it is preferably 1 to 40% by mass, and more preferably 10 to 30% by mass. preferable.

 [0035] Further, it is preferable that at least a part of the biological physiologically active substance is a powder. The biologically and biologically active substance in the powder is preferably dispersed in the biodegradable substance. After the in-vivo indwelling object of the present invention is placed in the living body, it is decomposed in the living body! In the process of sowing, the biologically active substance is easily released at a constant rate!

 [0036] Further, it is preferable that at least a part of the biologically physiologically active substance is chemically bonded to the polylactic acid complex. In the process in which the in-vivo indwelling material of the present invention is in-vivo and then decomposed in the living body, the biological physiologically active substance is released at a more constant rate simultaneously with the decomposition of the polylactic acid complex. By being easily treated, the inflammatory reaction can be further suppressed.

[0037] Further, at least a part of the biologically physiologically active substance is shaped by the alternating lamination method. It is preferably contained between the formed micro-order thin films. Furthermore, it is more preferable that at least a part of the biologically physiologically active substance is chemically bonded to the polylactic acid complex. In the process in which the in-vivo indwelling material of the present invention is in-vivo and then decomposed in the living body, the biological physiologically active substance is released at a more constant rate simultaneously with the decomposition of the polylactic acid complex. It is easy.

 [0038] Such a biological physiologically active substance exhibits a desired effect, for example, an effect of suppressing restenosis when the in-vivo indwelling material of the present invention is placed in a diseased part in a living body. There is no particular limitation as long as it exists.

 For example, anticancer agents, immunosuppressive agents, antibiotics, antirheumatic agents, antithrombotic agents, HMG-CoA reductase inhibitors, ACE inhibitors, calcium antagonists, antihyperlipidemic agents, integrin inhibitors, antiallergic agents , Antioxidants, GPIIbllla antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, bio-derived materials, interferon and NO production promoters are preferred It can be illustrated. More preferably, the biologically and physiologically active substance is at least one selected from the group force consisting of these! /.

 [0039] Here, as the anticancer agent, for example, vincristine, vinblastine, vindesine, irinotecan, pirarubicin, paclitaxel, docetaxel, methotrexate and the like are preferable. Moreover, as an immunosuppressant, for example, sirolimus, everolimus, biolimus, tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolic acid mofeethyl, dasperimus, mizoribine and the like are preferable.

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

[0040] As the anti-rheumatic agent, for example, methotrexate, sodium thiomalate, penicillamine, oral benzalit and the like are preferable.

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

HMG-CoA reductase inhibitors include, for example, cerivastatin and cerivasta. Chin sodium, atorvastatin, nispastatin, itapastatin, flupastatin, flupastatin sodium, simpastatin, oral pastatin, pravastatin, etc. are preferred.

 [0041] Further, as the ACE inhibitor, for example, quinapril, perindopril elpmin, trandolapril, cilazapril, temocapril, delapril, enalapril maleate, lisinopril, captopril and the like are preferable.

 In addition, as the calcium antagonist, for example, hifedipine, dirubadipine, diltiazem, vedipine, disoldipine and the like are preferable.

 Moreover, as an antihyperlipidemic agent, for example, probucol is preferable.

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

[0042] Examples of the antioxidant include catechins, anthocyanins, and proanthocyanins.

Lycopene, j8-carotene and the like are preferred. Of the catechins, epigallocatechin gallate is particularly preferred.

 Further, as the retinoid, for example, all-trans retinoic acid is preferable. In addition, as the tyrosine kinase inhibitor, for example, genistein, chinorephostin, albumin and the like are preferable.

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

 [0043] Furthermore, examples of biological materials include EGF (epidermal growth factor), VE

 Preferred are jr (vascular endothelial growth factor), ir LjF (hepatocyte growth factor), PDGF (platelet derived growth factor), BFGF (basic nbrolast growth factor) and the like.

 [0044] As described above, the biodegradable substance preferably contains the polylactic acid complex as a main component and contains the biological and physiologically active substance, but in addition to these, a biodegradable ingredient that is safe for the living body. (Hereinafter also referred to as “remainder component”).

Examples of such remaining components include polylactic acid having no stereocomplex structure such as the above-mentioned polylactic acid complex (a simple substance of D-form polylactic acid, a simple substance of L-form polylactic acid, and a combination of D-form and L-form. (Co) polymers, etc.), polydaricholic acid, polyhydroxybutyric acid, polymalic acid, poly α- Mixtures and compounds (co-copolymers) that are at least one selected from the group consisting of amino acids, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, polyprolacton and their copolymer power. Polymer, etc.). Among these, polylactic acid and a copolymer of Z or polylactic acid and polydaricolic acid can be preferably used.

 [0045] The method for preparing such a biodegradable substance is not particularly limited!

 For example, if the biodegradable substance contains a powdered biological physiologically active substance, the polylactic acid complex, the biologically biologically active substance of the powder, and the remaining component are mixed. The mixture can be prepared by applying a known method, for example, a mixing method using a mixer, a method of melting and kneading each component, a method of kneading each component in a paste, and the like.

 For example, if the biodegradable substance contains a biological physiologically active substance and at least a part of the biologically physiologically active substance is chemically bonded to the polylactic acid complex, For example, a polylactic acid complex having the stereocomplex structure such as a D-form and an L-form polylactic acid having a hydroxyl group or a carboxyl group at the terminal in advance is prepared, and the biological group is used with the functional group at the end as a microinitiator. For example, a method of converting a physiologically active substance into an ester or amide. In addition, it can be prepared by growing a lactide starting from a specific functional group of the biological physiologically active substance to form a polylactic acid complex having the stereocomplex structure.

[0046] Also, for example, if at least a part of the biologically physiologically active substance is contained between the micro-order thin films formed by the alternating lamination method, for example, D-form polylactic acid A solution in which L is dissolved in acetonitrile, a solution in which L-form polylactic acid is dissolved in acetonitrile, and a solution in which the biological physiologically active substance is dissolved are prepared, and PFA (tetrafluoroethylene / perfluorocarbon) is prepared. It can be prepared by a method in which a substrate such as an alcohol ether copolymer (resin) is immersed in each solution in turn and dried.

[0047] In addition, for example, at least a part of the biological physiologically active substance is contained between the micro-order thin films formed by the alternating lamination method, and at least the biological physiologically active substance is included. Partial strength The polylactic acid composite of this micro-order thin film For example, a solution in which D-form polylactic acid and the biological physiologically active substance are chemically bonded with an ester bond or an amide bond dissolved in acetonitrile. And a solution prepared by dissolving L-form polylactic acid and the above biological physiologically active substance chemically bonded with ester bond or amide bond in acetonitrile, and preparing PFA (tetrafluoroethylene perfluorocarbon). It can be prepared by a method of repeatedly dipping and drying a substrate such as a alkoxyvinyl ether copolymer resin) in each solution alternately.

[0048] The in-vivo indwelling material of the present invention has a main body portion made of such a biodegradable substance.

 This main body is a main part in the in-vivo indwelling material of the present invention described later. For example, when the in-vivo indwelling body of the present invention is a stent in which a drug or the like is applied to the surface of the stent body having the biodegradable material force, the hemorrhoid stent body is the body of the present invention. Equivalent to.

 The shape of the main body is preferably a tube shape, a tubular shape, a net shape, a fiber shape, a nonwoven fabric shape, a woven fabric shape, or a filament shape. The reason is that it can be easily placed in a lumen in a living body such as a blood vessel.

[0049] The method for manufacturing the main body is not particularly limited, and can be manufactured by, for example, a known method.

 For example, in the case of the main body force of the tent, the biodegradable substance is made into a fiber and then knitted into a cylindrical shape, or a tubular body is formed from the biodegradable substance. And a method of providing pores.

[0050] The in-vivo indwelling material of the present invention has a main body portion made of such a biodegradable substance, and further has a drug release layer containing the biological physiologically active substance on the surface of the main body portion. It is preferable to have it.

 The reason for this is that after the in-vivo indwelling material of the present invention is placed in the living body, the biological physiologically active substance is released in the process of decomposing the drug release layer in the living body. This is because an inflammatory reaction associated with biodegradation can be suppressed by this biologically physiologically active substance.

Here, the biological and physiologically active substance can be of the same type and properties as those which the biodegradable substance may contain. [0051] The drug release layer preferably further contains a biodegradable polymer. The reason for this is that after the in-vivo indwelling material of the present invention is placed in the living body, the rate at which the biological physiologically active substance is released is moderately adjusted in the process of decomposition of the drug release layer in the living body. This is because it becomes easy to adjust.

 Here, the biodegradable polymer may be the polylactic acid complex or other polylactic acid, and may be the remaining component that the biodegradable substance may contain. A little.

 In other words, this biodegradable polymer includes polylactic acid (including the above-mentioned polylactic acid complex, and other polylactic acid (a simple substance of D-form polylactic acid, a simple substance of L-form polylactic acid, a combination of D-form and L-form (co- ) Polymer)), polydaricholic acid, polyhydroxybutyric acid, polymalic acid, poly-a-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, polystrength prolatathone and these Preferred examples of the copolymer are as follows. It is preferable that the biodegradable polymer is at least one of the group forces selected as these forces. Further, the biodegradable polymer strength is preferably polylactic acid and a copolymer of Z or polylactic acid and polyglycolic acid. The reason is that the desired strength and decomposition rate can be set.

 [0052] Further, the drug release layer contains other components as the remainder other than the biodegradable polymer and the biological physiologically active substance as long as the performance of the in-vivo in-vivo of the present invention is not impaired. (Hereinafter also referred to as “other components”.) O Examples of such other components include polyethylene succinate, polybutylene succinate, polybutylene succinate 'adipate, polylactic acid-trimethylene carbonate Examples thereof include a copolymer and a polyglycolic acid trimethylene carbonate copolymer.

 [0053] In such a drug release layer, the content of the biologically physiologically active substance is not particularly limited, and may be adjusted in consideration of the state of the lesion, the type of the biologically physiologically active substance used, and the like. However, it is preferably 1 to 99% by mass, more preferably 30 to 70% by mass.

Further, when the drug release layer further contains the biodegradable polymer, the ratio of the content ratio of the biodegradable polymer and the biological physiologically active substance is 99: 1 to 1: It is preferable that it is 99. 70: 30-30: It is more preferable that it is 70! /.

 The content of the other components in the drug release layer is preferably 40% by mass or less, more preferably 30% by mass or less. Further, 0% by mass, that is, it may not be contained.

 [0054] Preferably, the drug release layer comprises two or more layers, and these layers include a layer containing the biological and physiologically active substance and a layer containing the biodegradable polymer. That is, it is preferable that the drug release layer has two layers of the layer containing the biological physiologically active substance and the layer containing the biodegradable polymer and other layer forces.

 Furthermore, it is preferable that the drug release layer also has two layer forces: a layer containing the biological physiologically active substance and a layer containing the biodegradable polymer.

 Furthermore, in the drug release layer, it is preferable that a layer containing the biologically physiologically active substance is present on the main body side, and a layer containing the biodegradable polymer is present on the upper surface thereof. In the case where the drug release layer is composed of two or more layers, after the in-vivo indwelling material of the present invention is placed in the living body, in the process in which the drug release layer is decomposed in the living body, biological physiological activity Substances are easily released at a constant rate! / ヽ.

Here, the layer containing the biological physiologically active substance is a layer comprising the biological physiologically active substance, the biodegradable polymer and Z or the other component. Here, the mass ratio of the biologically physiologically active substance to the biodegradable polymer and Z or the other component is preferably 10:90 to 90: 10! /.

 The layer containing the biodegradable polymer is a layer that also has the biodegradable polymer and the other component forces. Here, the content of the other components is preferably 30% by mass or less, more preferably 20% by mass or less.

[0056] When the drug release layer has a layer other than the layer containing the biological physiologically active substance and the layer containing the biodegradable polymer, these layers may be layers composed of the other components. Good.

 Note that the order of stacking these layers is not particularly limited.

 A plurality of these layers may exist.

[0057] Further, the thickness of the drug release layer is not particularly limited, and is held on the surface of the main body. The amount can be determined as appropriate in consideration of various conditions such as the amount and type of the biologically physiologically active substance to be added and the type of in-vivo indwelling material. For example, if the in-vivo indwelling material of the present invention is an in-vivo indwelling material that particularly requires an operation for delivering from outside the living body to a lesion site in the living body, such as a stent, an artificial blood vessel, or a stent graft. The thickness may be any as long as the reachability (delivery property) is good and the biological and physiologically active substance can be contained in a desired amount. The thickness is preferably 1 to 100 / ζ πι, more preferably 1 to 50 / ζ πι, more preferably 1 to 20 / ζ πι.

[0058] Further, when the drug release layer is composed of two or more layers, it is preferable to have a range such as the total thickness force of all the layers. The thickness of the layer containing the biological physiologically active substance is 1 to: LOO m is preferably 1 to 15 / ζ πι, and more preferably 3 to 7 m. Further preferred. Also, the thickness of the layer containing the biodegradable polymer is preferably 1 to 75 m, more preferably 1 to 25 / ζ πι, and 1 to: LO / zm. Further preferred.

 [0059] The method for forming such a drug release layer on the surface of the main body is not particularly limited, and for example, a known method can be applied.

 For example, the biological physiologically active substance and the biodegradable polymer are mixed in a solvent such as acetone, ethanol, chloroform, tetrahydrofuran, or the like at a ratio as described above, and the concentration of the solution is preferably 0.001 to 20% by mass. Is dissolved so as to be 0.01 to 10% by mass to make a solution. Next, this solution is applied to the surface of the main body by a conventional method using a spray, a dispenser or the like, or the main body is immersed in this solution, and then the solvent is volatilized.

 This method uses a solvent (for example, acetone, ethanol, chloroform, tetrahydrofuran) that easily dissolves the biodegradable polymer and the biological physiologically active substance. The surface of the main body can be easily wetted. In this case, it can be preferably applied.

 [0060] For example, the biological physiologically active substance is melted and applied to the surface of the main body.

[0061] The drug release layer can be formed on the surface of the main body by such a method. in front The same applies to the case of containing other components. The thickness of each layer can be adjusted as appropriate depending on the amount of solution applied by spraying the solution concentration.

 [0062] As described above, the in-vivo indwelling material of the present invention is an in-vivo indwelling material having the main body part also having the biodegradable substance force, and preferably having the drug release layer on the surface of the main body part.

[0063] The type of the in-vivo indwelling material of the present invention is not particularly limited. Any in-vivo indwelling material that needs to be strong enough to be extinguished after it has existed in the living body for a certain period of time or elongation may be used. For example, stents, covered stents, coils, microcoils, artificial blood vessels, artificial bones, shields, wire braids, clips, and plugs.

 Further, for example, it has a hollow organ and a function of supporting a lumen in the Z or duct system (ureter, bile duct, urethra, uterus, esophagus, bronchi).

 Also, for example, a closure member as a closure system for a hollow space connection, tubing, etc. Also, for example, a fixation or support device for temporarily fixing a tissue implant or tissue transplant.

 Also, for example, orthopedic implants (bolts, nails, wires, plates, joints, etc.).

 Examples thereof include a stent graft, a vascular anastomosis device, a vascular hemostasis device, a vascular aneurysm treatment device, and an implantable medical device using a stent as a holding body.

 These sizes and the like may be appropriately selected according to the application location.

[0064] Among these, a stent or the like that is inserted into the site in order to expand a stenosis or occlusion in the living body, expands, and is placed in the site to maintain the state. In vivo indwelling materials (stents, catheters, artificial blood vessels, stent grafts, etc.) are preferable. Furthermore, among these, a stent is preferable. The reason is that it can be easily delivered and placed in the affected area.

[0065] Further, the stent may be either a balloon expansion type or a self-expansion type, and the size may be appropriately selected according to the application site. For example, when used in the coronary artery of the heart, the outer diameter before dilation is preferably 1.0 to 3. Omm and the length is 5 to 50 mm. In addition, the thickness of the stent has the radial force necessary to place it in the affected area. The thickness of the stent body is preferably 1 to 1000 μm in range force S, more preferably 10 to 500 μm in range force S, and 40 to 200 μm in thickness. A range is more preferred.

 [0066] Further, examples of the shape of the stent include those shown in FIG.

 In FIG. 1, a stent body 1 is a cylindrical body that is open at both ends and extends between the ends in the longitudinal direction. 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 this notch portion is deformed to have a structure that can expand and contract in the radial direction of the cylindrical body. It is placed at the target site and maintains 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 11 having a notch inside as a basic unit. A plurality of substantially rhombic elements 11 are arranged in a continuous manner in the minor axis direction of the approximately rhombus shape to form an annular unit 12. The annular unit 12 is connected to an adjacent annular unit via a linear coupling member 13. As a result, the plurality of annular units 12 are continuously arranged in the axial direction in a state where the portions are joined. With such a configuration, the stent body (stent) 1 has a cylindrical body having both ends opened and extending between the ends in the longitudinal direction. 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.

 [0067] When the stent main 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- It is 0.5 mm, more preferably 0.05 to 0.2 mm.

 [0068] It should be noted that the stent 1 shown above is only one embodiment, and is a cylindrical body that is composed of a linear member 2, has both end portions open, and extends between the both end portions in the longitudinal direction. In addition, a large number of notches that communicate the outer side surface and the inner side surface are provided on the side surface, and a structure that can be expanded and contracted in the radial direction of the cylindrical body by deforming the notch portion is widely included.

 [0069] Also, when the in-vivo indwelling body of the present invention is a stent, the radial force force when the outer diameter is expanded from 2.1 mm to 3. Omm and then compressed by 1 mm is 1 30 to 500 gf per 10 mm stent length. Preferable to be a stent!

Stents with such radial forces can be securely placed in the lesion. Then, I like it because it has a positive effect.

 Normally, the radial force is almost directly proportional to the stent length.

 [0070] Thus, the present invention is an in-vivo indwelling body having the main body part having the biodegradable material force, and preferably having the drug release layer on the surface of the main body part.

 Therefore, when the cross section of the in-vivo indwelling object of this invention is shown, it will become like FIG.

 [0071] Taking the case where the in-vivo indwelling object of the present invention is the stent shown in Fig. 1, several modes will be described with reference to the AA line cross-sectional view and the BB line cross-sectional view.

 2 to 4 are enlarged cross-sectional views taken along line AA in FIG. FIG. 2 shows a state in which the stent 1 shown in FIG. 1 is an in-vivo indwelling material having a biodegradable material force composed of a polylactic acid complex 20 containing a powdered biological physiologically active substance 30 in a dispersed state. It is sectional drawing in such a case.

 Further, FIG. 3 shows that the stent 1 shown in FIG. 1 has a stent body 10 that also has the biodegradable material force, and the surface thereof includes a layer 32 containing a biological bioactive substance and a biodegradable polymer. 4 is a cross-sectional view in the case of an in-vivo indwelling material having a drug release layer comprising a layer 42. FIG.

 FIG. 4 shows a biodegradable polymer in which the stent 1 shown in FIG. 1 has a stent body 10 that also has the biodegradable substance force, and a powdered biological bioactive substance 30 is dispersed on this surface. FIG. 4 is a cross-sectional view in the case of an in-vivo indwelling body having a drug release layer comprising 40.

Next, FIGS. 5 and 6 are enlarged cross-sectional views taken along the line BB in FIG.

 FIG. 5 shows a case similar to that shown in FIG.

 FIG. 6 shows a case similar to that shown in FIG. Example

 [0073] Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

 <Example 1>

L-polylactic acid (API, 100L0105) pellet (hereinafter also referred to as “PLLA”) and D-polylactic acid (hereinafter also referred to as “PLDA”) synthesized by fermentation are adjusted to 50 ° C. in advance. The case They were dissolved separately in the tonitrile solution and then mixed so that the ratio of 1 ^ 1 ^ \ :? 1 ^ 8 = 50: 50. Here, the total concentration of PLLA and PLDA was set to 20 mg / m 1.

 Next, the solution was put into a PFA petri dish to prepare a cast film having a thickness of 150 m. Thereafter, the film was uniaxially stretched in a warm bath at 80 ° C. The draw ratio at this time was 4 times. The thickness of the film obtained by stretching was 100 m. The stretched film was subjected to a tensile test based on JIS K7113 (plastic tensile test method) to determine the breaking strength and breaking elongation. Here, the film was punched into 1/5 scale type 2 test piece.

 The results are shown in Table 1.

<Examples 2 and 3>

 In Example 2, the test was carried out in the same manner as in Example 1, except that the ratio of! ^ 1 ^ \ :?] ^^ was 45:55, and everything else was the same.

 In Example 3, the test was carried out in the same manner as in Example 1, except that the ratio of! ^ 1 ^ \ :?] ^^ was 55:45, and everything else was the same.

 The results are shown in Table 1.

[0075] [Table 1] Table 1 Example tensile test values

<Comparative Example 1>

Copolymer (100 D065, API 100 D065) pellets of 50% polylactic acid and 0% polylactic acid (hereinafter also referred to as “DL-PLA”) in acetone adjusted to 23 ° C in advance. Dissolved. Here, the copolymer concentration in acetone was set to 5%. Next, the solution was put into a PFA petri dish to prepare a cast film having a thickness of 150 m. Thereafter, the film was uniaxially stretched in a warm bath at 80 ° C. The draw ratio at this time was 4 times. The thickness of the film obtained by stretching was 100 m. The stretched film was subjected to a tensile test based on JIS K7113 (plastic tensile test method) to determine the breaking strength and breaking elongation. Here, the film was punched into 1/5 scale type 2 test piece.

 The results are shown in Table 2.

[0077] <Comparative Examples 2 to 7>

 In Comparative Examples 2-7, the ratio of PLLA: PLDA in Example 1 to 50:50 was 70:30 (Comparative Example 2), 30:70 (Comparative Example 3), 60:40 ( Comparative Examples 4), 40:60 (Comparative Example 5), 100: 0 (Comparative Example 6), and 0: 100 (Comparative Example 7) were used.

 The results are shown in Table 2.

[0078] [Table 2] Table 2 Tensile test values of comparative examples

<Example 4>

 The cast film produced and stretched in the same manner as in Example 1 was cut into a rectangle having a size of 50 mm × 7 mm, and this was rolled into a cylindrical shape having a diameter of about 2 mm and a length of 50 mm. This was then inserted into a polytetrafluoroethylene shrink tube having a diameter of 2.4 mm and a length of 60 mm. Next, a PTFE tube (chukoh, AWG-17) having a diameter of 1.5 mm and a length of 70 mm was further inserted into the cast film cylinder.

A three-layer tube made in this way (with an internal force of PTFE tube and cast fiber) Cylinders and shrink tubes, which are also Lumka, were heated in an oven preheated to 200 ° C for 1 hour to obtain a pipe with a diameter of 2. lmm and a wall thickness of 100 m. The pipe was annealed.

 This pipe is then processed with an excimer laser (SPL400H, manufactured by Sumitomo Heavy Industries, Ltd.) to form a stent with the same shape as in Fig. 1, with an outer diameter of 2. lmm, a length of 10mm, and a thickness (wall thickness) of 100m. did.

 [0080] Next, rapamycin (hereinafter also referred to as “RM”) as an anticancer agent and polylactic acid-polyglycolic acid (composition ratio (mass ratio): 85-15) copolymer as a biodegradable polymer ( Hereinafter, a tetrahydrofuran solution (hereinafter referred to as “THF”) and a solution in which the mass ratio is 1: 1 (hereinafter referred to as “PLGA”) is prepared. The surface of the stent thus processed was sprayed with a spray (Micro Spray Gun 11, manufactured by NORDSON). After drying the solvent THF, a scanning electron microscope (SEM) indicates that about 600 μg of a mixture of RM and PLGA is applied to the surface of the stent with a thickness of 10 μm. Then, the stent was expanded to a diameter of 3. Omm with a balloon catheter (manufactured by Thermonet Earthenware, ARASI), and then the pushing force (radial force) when the stent was pushed inward by lmm was measured.

 As a result, the radial force was 198 kgf.

<Example 5>

 The stent of Example 4 was percutaneously placed in the porcine coronary artery for 1 month for pathological evaluation.

As shown in Fig. 7, no conspicuous stenosis was observed even after 1 month, and ⁰ / oArea Stenosis (% AS) calculated from the following formula was 35.5%.

[0082] <% Area Stenosis (% AS) calculation method>

 % AS = (Neointimal area) Z (Inner elastic plate area) X 100 (%)

[0083] <Comparative Example 8>

Using the cast film produced by the same method as Comparative Example 1, the same stent as Example 4 was produced and subjected to the same measurement. As a result, the radial force was 103 kgf.

<Comparative Example 9>

 The stent of Comparative Example 8 was percutaneously placed in the porcine coronary artery for 1 month for pathological evaluation.

As shown in FIG. 8, one month elapses when the value Gatineau yellowtail modeling seems to be due to a weak radial force is _{^{observed, 0/0 Area Stenosis (%}} AS) it was also 97.3%.

[0085] <Comparative Example 10>

 Using the cast film produced by the same method as in Comparative Example 4, the same stent as in Example 4 was produced and subjected to the same measurement.

 As a result, the radial force was 116 kgf.

[0086] <Comparative Example 11>

 The stent of Comparative Example 10 was percutaneously placed in the porcine coronary artery for 1 month for pathological evaluation.

As shown in FIG. 9, one month elapses when the value Gatineau yellowtail modeling seems to be due to a weak radial force is _{^{observed, 0/0 Area Stenosis (%}} AS) also 95. was 1%.

Claims

The scope of the claims

 [I] D-form polylactic acid and L-form polylactic acid from a biodegradable substance composed mainly of a polylactic acid complex that forms a complex with a stereocomplex structure at a mass ratio of 5:55 to 55:45 The in-vivo indwelling which has a main-body part.

 [2] The indwelling material according to claim 1, wherein the biodegradable substance contains a biological physiologically active substance.

 [3] The living body according to claim 2, wherein at least a part of the biological physiologically active substance is a powder, and the biological physiologically active substance of the powder is dispersed in the biodegradable substance. Detainment.

 [4] The in vivo indwelling product according to claim 2 or 3, wherein at least a part of the biological physiologically active substance is chemically bonded to the polylactic acid complex.

[5] The in-vivo indwelling product according to any one of [1] to [4], further comprising a drug release layer containing the biological physiologically active substance on the surface of the main body.

6. The in vivo indwelling product according to claim 5, wherein the drug release layer further contains a biodegradable polymer.

 7. The in-vivo indwelling product according to claim 6, wherein the drug release layer comprises two or more layers, and the layers include the layer containing the biologically bioactive substance and the layer containing the biodegradable polymer. .

 [8] The weight average molecular weight of the polylactic acid complex is 1,000 to 1,000,000.

The in-vivo indwelling object in any one of ~ 7.

[9] The in-vivo indwelling product according to any one of [1] to [8], wherein the polylactic acid complex is a stretched polylactic acid complex.

[10] The polylactic acid complex has a first melting peak between 65 and 75 ° C. and a second melting peak between 200 and 250 ° C. in differential scanning calorimetry. It is a body. The in-vivo indwelling object in any one of Claims 1-9.

[II] The polylactic acid composite is a polylactic acid composite having a breaking strength specified by JIS K7113 of 70 MPa or more, a breaking elongation of 15% or more, and a Young's modulus of lOOMPa or more. The in-vivo indwelling object in any one of 1-10.

[12] The in-vivo indwelling product according to any one of [1] to [1], wherein the polylactic acid complex is a polylactic acid complex produced by an alternating lamination method.

13. The in-vivo indwelling product according to claim 12, wherein the alternating lamination method is an alternating lamination method performed by forming a micro-order thin film.

14. The in-vivo indwelling object according to claim 13, wherein the thickness of the micro-order thin film is 1πι to 500 / ζ m.

 15. The in-vivo indwelling product according to claim 13 or 14, wherein the biological physiologically active substance is contained between the micro-order thin films.

 [16] The in-vivo indwelling product according to any one of [1] to [15], wherein the shape of the main body portion is a tube shape, a tubular shape, a net shape, a fiber shape, a nonwoven fabric shape, a woven fabric shape, or a filament shape.

 [17] 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, GPIIbllla antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, biological materials 17. The in-vivo indwelling product according to any one of claims 2 to 16, which is at least one selected from the group force that also has the ability to promote interferon and NO production.

 [18] The biodegradable polymer strength polylactic acid, polydaricholic acid, polyhydroxybutyric acid, polyphosphonic acid, poly α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, poly strength prolatathone and 18. The in-vivo indwelling product according to any one of claims 6 to 17, wherein at least one of the group forces that can be used as the copolymer force is selected.

 [19] The biodegradable polymer is a copolymer of polylactic acid and polydaricholic acid.

In vivo indwelling material of 8.

[20] The in-vivo indwelling product according to any one of [1] to [19], which is a stent.

21. The stent according to claim 20, wherein the radial force when the outer diameter is expanded from 2.1 mm to 3. Omm and then compressed by 1 mm is 130 to 500 gf per 10 mm of the stent length.