WO2007116646A1

WO2007116646A1 - In vivo indwelling object

Info

Publication number: WO2007116646A1
Application number: PCT/JP2007/055979
Authority: WO
Inventors: Keiko Yamashita; Yotaro Fujita
Original assignee: Terumo Kabushiki Kaisha
Priority date: 2006-04-04
Filing date: 2007-03-23
Publication date: 2007-10-18
Also published as: JPWO2007116646A1

Abstract

An in vivo indwelling object has a layer containing a biodegradable polymer and releasing a drug on a surface. Because of the biodegradable polymer, the in vivo indwelling object having a drug-releasing layer on a surface of a main body portion has a necessary strength in vivo, is easily stretched upon an expansion operation with a balloon or the like, is difficult to cause a crack, and is capable of adjusting a degradation rate in vivo to a desired rate. The drug-releasing layer contains a polylactic acid complex in which a complex with a stereocomplex structure of D-polylactic acid and L-polylactic acid at a mass ratio of 45:55 to 55:45 is formed and a biologically physiologically active substance.

Description

Specification

In vivo indwelling

Technical field

[0001] The present invention relates to an in-vivo indwelling object. More specifically, a stent, a catheter, an artificial blood vessel, which is inserted into the site in order to expand a stenosis or occlusion in the living body, is expanded, and is placed in the site to maintain the state. The present invention relates to in-vivo articles such as stent grafts. 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 However, when the blood vessel wall is damaged by a catheter, the intima proliferates, which is a healing reaction of the blood vessel wall, and restenosis has been reported at a rate of about 30 to 40%.

[0005] Stents have been studied for use as a method for preventing such restenosis, and have 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 reduce stenosis. The actual situation was.

[0006] Therefore, in recent years, by carrying a drug such as an immunosuppressive agent or an anticancer drug on this stent, this drug is locally released over a long period of time at the indwelling site of the lumen, thereby reducing the restenosis rate. A method for achieving this is proposed.

For example, Patent Document 1 describes a stent in which the surface of a stent body is coated with a mixture of a bioabsorbable polymer or a biostable polymer and a therapeutic substance. It is described that poly-L lactic acid and poly-strength prolatatone can be used as the polymer.

Patent Document 2 describes a stent in which a drug is attached and coated using a biocompatible polymer or the like. As this biocompatible polymer, it is described that poly DL lactic acid (copolymer of D-form and L-form), polydaricholic acid, polylactic acid Z polyglycolic acid copolymer can be used.

Patent Document 1: JP-A-8-33718

Patent Document 2: JP-A-9-56807

Disclosure of the invention

Problems to be solved by the invention

[0007] However, the poly L lactic acid described in Patent Document 1 and Poly DL lactic acid (copolymer of D-form and L-form), polydaricholic acid, and polylactic acid Z-polydalicolic acid copolymer are low in strength, so stents coated with these on the surface When indwelled, it could be damaged by external force. In addition, since these polymers have a low elongation of only a few percent, they cannot follow the expansion operation when placed in a living body with a balloon or the like, and the stent body force may be peeled off. In addition, cracks may occur due to the expansion operation.

Thus, when the polymer on the surface of the stent body is damaged, the fragments may block the lumen in the living body. For example, when applied to blood vessels, there was a risk of blocking peripheral blood flow. In addition, when a crack occurs, the surface is turned upside down. For example, when used in a blood vessel, blood flow may be turbulent and may cause thrombosis. Furthermore, when the polymer is damaged or cracked, it may be difficult to keep the drug release rate constant.

[0008] In addition, the poly-force prolataton described in Patent Document 1 has a high elongation of several hundred%, but the strength is low. When a stent coated on the surface thereof is placed in a living body, it is damaged by an external force. There was a case.

In addition, this poly force prolatatone has a slow degradation rate in vivo. For this reason, for example, when a stent having this polymer on the surface is used in a blood vessel, a blood plug is likely to be attached to the surface of this polymer. Therefore, antiplatelet therapy is applied for a long period until poly force prolatatone disappears. Will be forced.

[0009] As described above, the stent has a layer that releases a drug containing a biodegradable polymer on the surface, and the biodegradable polymer has a necessary strength in vivo, and is expanded by a balloon or the like. In addition, cracks that are easy to stretch during operation are less likely to occur, and there is no such thing that can adjust the degradation rate in vivo to a desired rate.

[0010] It should be noted that in the above, the force exemplified in the stent, such a problem is not limited to the stent, but is inserted into the site to expand the stenosis or occlusion in the living body, and then expanded. This is a problem common to in-vivo indwelling objects that are indwelled at the site in order to maintain the state.

[0011] Accordingly, an object of the present invention is to surface a drug releasing layer comprising a biodegradable polymer. The biodegradable polymer possesses the necessary strength in vivo, and it is difficult for cracks to easily extend during expansion operations using a balloon or the like. An object of the present invention is to provide an in-vivo indwelling object capable of adjusting the speed to a desired speed.

Means for solving the problem

[0012] The present inventor has intensively studied for the purpose of solving the above-mentioned problems, and on the surface of the main body, a biologically physiologically active substance and a polylactic acid having a specific structure which is a biodegradable polymer. It has been found that an in-vivo indwelling material having a drug release layer containing a complex solves the above problems.

That is, the present invention includes the following (1) to (18).

(1) An in-vivo indwelling material having a drug release layer on the surface of a main body, wherein the drug release layer strength is 0-polylactic acid and 1 ^ -polylactic acid and a stereocompressor at a mass ratio of 5:55 to 55:45. An in-vivo indwelling material comprising a polylactic acid complex that forms and forms a complex with a skeleton structure and a biological physiologically active substance.

(2) The in-vivo indwelling according to (1), wherein the main body is made of a metal material and Z or a polymer material.

(3) 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 drug release layer! In vivo indwelling object as described in 2).

(4) The in-vivo indwelling product according to any one of (1) to (3), wherein at least a part of the biological physiologically active substance is chemically bonded to the polylactic acid complex!

(5) The drug-releasing layer is composed of two or more layers, and the layers include the layer containing the biologically bioactive substance and the layer containing the polylactic acid complex. In vivo indwelling.

[0014] (6) The above (1) to (5), wherein the weight average molecular weight of D-form polylactic acid and Z-form L-form polylactic acid forming the polylactic acid complex is 1,000 to 1,000,000 The in-vivo indwelling object in any one of.

(7) The above polylactic acid complex having a weight average molecular weight of 1,000-1,000,000 ( The in-vivo indwelling object according to any one of 1) to (6).

(8) The in-vivo indwelling product according to any one of (1) to (7), wherein the polylactic acid complex is a stretched polylactic acid complex.

(9) 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 (8), which is a body.

(10) 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 The in-vivo indwelling object according to any of (9) to (9).

(11) The in-vivo indwelling product according to any one of (1) to (10), wherein the polylactic acid complex is a polylactic acid complex produced by an alternating lamination method.

(12) The in-vivo indwelling product according to (11), wherein the alternate lamination method is an alternate lamination method performed by forming a micro-order thin film and a Z- or nano-order ultrathin film.

(13) The thickness of the micro-order thin film and the Z or nano-order ultra-thin film is Inn! The in-vivo indwelling thing as described in said (12) which is -50 m.

(14) The in-vivo indwelling product according to (12) or (13), wherein the biological physiologically active substance is contained between the micro-order thin film and the Z- or nano-order ultra-thin film.

[0016] (15) The biological physiologically active substance is an anticancer agent, immunosuppressive agent, antibiotic, antirheumatic agent, antithrombotic agent, HMG—CoA reductase inhibitor, ACE inhibitor, calcium antagonist, anti-high Lipemia, integrin inhibitor, antiallergic agent, antioxidant, GPIIbllla antagonist, retinoid, flavonoid, carotenoid, lipid improver, DNA synthesis inhibitor, tyrosine kinase inhibitor, antiplatelet drug, anti-inflammatory drug In vivo indwelling material in any one of said (1)-(14) which is at least one selected from the group force which is a biomaterial, an interferon, and NO production promotion substance power.

(16) The D-form polylactic acid or the L-form polylactic acid chemically bonded to the stenosis or restenosis inhibitor which is the biologically physiologically active substance, and the antimicrobial agent which is the biologically physiologically active substance Using the L-form polylactic acid or the D-form polylactic acid chemically bonded to an inflammatory drug, The above (12) having a drug release layer comprising the polylactic acid complex containing the biologically bioactive substance, produced by an alternating lamination method performed by forming a black order thin film and a thin z-order nanothin film. The in-vivo indwelling object in any one of-(15).

(17) The in-vivo indwelling product according to any one of (1) to (16), 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.

(18) The in-vivo indwelling material according to any one of (1) to (17), which is a stent. The invention's effect

[0018] According to the present invention, an in-vivo indwelling material having a layer that releases a drug containing a biodegradable polymer on its surface, the biodegradable polymer has a necessary strength in vivo. In addition, it is difficult to generate a crack that easily expands during an expansion operation using a balloon or the like, and further, it is possible to provide an in-vivo indwelling product that can adjust the decomposition rate in a living body to a desired speed.

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

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

FIG. 6 is an enlarged photograph (800 ×) after expansion of the stent in Example 5.

FIG. 7 is an enlarged photograph (800 ×) after expansion of the stent in Comparative Example 8.

FIG. 8 is an enlarged photograph (800 ×) after expansion of the stent in Comparative Example 9.

FIG. 9 is a contrast-enhanced photograph (magnification of the right and left iliac arteries) of a rabbit according to the in vivo placement test of Example 7.

FIG. 10 is a contrast-enhanced photograph (same magnification) of the right and left iliac arteries of a rabbit according to the in vivo placement test of Comparative Example 10. BEST MODE FOR CARRYING OUT THE INVENTION

[0020] The present invention is described in detail below.

The present invention is an in-vivo indwelling product having a drug release layer on the surface of a main body part, the drug The agent release layer forms a complex of stereocomplex structure with D-form polylactic acid and L-form polylactic acid at a mass ratio of 5:55 to 55:45! In vivo indwelling material containing a physiologically active substance.

[0021] First, the polylactic acid complex contained in the drug release layer of the in-vivo indwelling material of the present invention will be described.

The polylactic acid complex contained in the drug release layer of the in-vivo indwelling material of the present invention is a complex of D-form polylactic acid and L-form polylactic acid. In this composite, 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.

[0022] 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 -Methylbenzyl metatalylate, poly-α-methyl-α-ethyl-j8-propiolatathone, j8-1, 1-dichloropropyl-j8-propiolatathone, etc. are known.

[0023] The mass ratio of D-form polylactic acid to L-form polylactic acid in the polylactic acid complex is 45:55 to 55:45. This mass ratio is preferably 50: 50! /.

A polylactic acid composite having such a mass ratio and having the above-described stereocomplex structure is unlikely to crack during expansion when the strength and elongation are significantly high.

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.

[0024] The weight average molecular weight of D-form polylactic acid forming the polylactic acid complex is a force S of 1,000 to 1,000,000, preferably 2,000 to 700,000. More preferably, the power of 5,000 to 400,000 is even more preferred! /.

The weight average molecular weight of the L-form polylactic acid forming the polylactic acid complex is 1,000 to A force that is 1,000,000 S, preferably a force that is 2,000 to 700,000, more preferably a force that is S, more preferably a force that is 5,000 to 400,000! /.

The polylactic acid complex has a weight average molecular weight of 1,000 to 1,000,000, preferably S, more preferably 2,000 to 700,000, and more preferably 5,000 to 400,000. It is further preferable that

Further, the polylactic acid complex has a first melting peak (glass transition point) between 65 and 75 ° C. in differential scanning calorimetry, and a second melting peak between 200 and 250 ° C. ( A melting point). Here, differential scanning calorimetry is performed at 5 ° C under N gas flow.

2

It shall be measured at Zmin heating rate. DT-50 manufactured by Shimadzu Corporation can be preferably used.

When the D-form polylactic acid, the L-form polylactic acid, and the polylactic acid complex have a weight average molecular weight in such a range, or when the polylactic acid complex has such a melting peak, The strength and elongation of the polylactic acid composite are further increased, and cracks during expansion are less likely to occur.

In addition, the polylactic acid composite has a breaking strength of 70 MPa or more, a breaking elongation of 15% or more, and a hang rate of lOOMPa when a 1Z5 scale No. 2 test piece specified in JIS K7113 is used. The polylactic acid complex as described above is preferable.

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 material using a polylactic acid complex having such a value in such a range is preferable because the strength and elongation in the living body are high and cracks during expansion are unlikely to occur.

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

[0026] The polylactic acid composite is preferably a stretched polylactic acid composite.

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.

[0027] 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 and a Z or nano-order ultrathin film. Furthermore, the thickness of the micro-order thin film and Z or nano-order ultra-thin film is Inn! It is preferable that it is ˜50 μm, and it is more preferable that it is 10 nm to 30 m, and it is more preferable that it is 100 nm to 20 m.

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. Further, it is preferable because cracks during expansion are less likely to occur.

Here, the alternate 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 can also be produced by a conventional casting method or the like. 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. Percentage of Can be formed.

[0029] The method for producing the polylactic acid composite is not limited, and can be produced, for example, by such an alternate lamination method or a casting method.

[0030] In addition, the polylactic acid complex can adjust the degradation rate in vivo to a desired rate. Specifically, it can be prepared by changing the molecular weight of D-form polylactic acid or L-form polylactic acid to be used.

[0031] The drug release layer of the in-vivo indwelling material of the present invention contains such a polylactic acid complex.

[0032] Next, the drug release layer and the biological physiologically active substance contained therein will be described. The in-vivo indwelling material of the present invention has a drug release layer on the surface of the main body, and the drug release layer comprises It contains a lactic acid complex and a biological physiologically active substance.

Here, the type and properties of the biologically physiologically active substance are not particularly limited. After the in vivo indwelling material of the present invention is placed in the living body, the drug release layer force is also released in the process of being decomposed in the living body, and the desired effect, for example, the effect of suppressing stenosis and restenosis, and the drug Any material may be used as long as it has an effect of suppressing an inflammatory reaction associated with biodegradation of the release layer.

[0033] Examples of this biological and physiologically active substance include anticancer agents, immunosuppressive agents, antibiotics, antirheumatic agents, antithrombotic agents, HMG-CoA reductase inhibitors, ACE inhibitors, calcium antagonists, anticancer agents, Hyperlipidemic agent, integrin inhibitor, antiallergic agent, antioxidant, GPIIbllla antagonist, retinoid, flavonoid, carotenoid, lipid improver, DNA synthesis inhibitor, tyrosin kinase inhibitor, antiplatelet agent, anti-inflammatory agent Preferred examples include biological material, interferon and NO production promoting substance. More preferably, the biologically and physiologically active substance is at least one selected from the group force consisting of these.

[0034] 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.

Examples of antibiotics include mitomycin, adriamycin, doxorubicin, Actinomycin, daunorubicin, idarubicin, pirarubicin, aclarubicin, epilubicin, pepromycin, dinostatin styramer and the like are preferred.

[0035] 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.

As the HMG-CoA reductase inhibitor, for example, cerivastatin, cerivastatin sodium, atorvastatin, nispastatin, itapastatin, flupastatin, flupastatin sodium, simpastatin, oral pastatin, pravastatin and the like are preferable.

[0036] 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.

[0037] 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.

[0038] Further, examples of the biological material include EGF (epidermal growth factor), VE

jr (vascular endothelial growth factor), ir LjF (hepatocyte growth fac tor), PDGF (platelet derived growth factor), BFGF (basic nbroblast gr owth factor) and the like.

[0039] In the in vivo indwelling material of the present invention, the drug release layer may be composed of such a biological and physiologically active substance and the polylactic acid complex. , Also referred to as “remainder component”). The remaining component is not particularly limited as long as it is safe for the living body and biodegradable. For example, a biodegradable polymer can be used.

[0040] Examples of such biodegradable polymers include polylactic acid having no stereocomplex structure such as the polylactic acid complex (D-form polylactic acid alone, L-form polylactic acid alone, D-form And L-form polymers (copolymers, etc.), polydalicolic acid, polyhydroxybutyric acid, polyphosphonic acid, poly α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, Poly-force prolatatones and their co-polymer power are at least one selected from mixtures and composites (copolymers, etc.). Among these, polylactic acid and cocoon, or a copolymer of polylactic acid and polydaricholic acid can be preferably used. The reason is that it is easy to set the desired strength and decomposition rate.

[0041] When the drug release layer having such component power is composed of one layer, the ratio of the content ratio of the polylactic acid complex and the biologically physiologically active substance is 99: 1 to 1:99. 90: 10˜: L0: 90 is more preferable than force S, and 80: 20-20: 80 is more preferable. The reason is that it is easy to obtain the release rate of the desired biological and physiologically active substance.

Furthermore, in this drug release layer, the content of the remaining component (the biodegradable polymer, etc.) is not particularly limited! However, the total mass of the polylactic acid complex and the biological physiologically active substance is not limited. The content is preferably 40% by mass or less. This is because the strength of the drug release layer becomes higher when it is 40% by mass or less.

[0042] Further, the drug release layer may have one layer force as described above, or may have two or more layer forces. Further, it is preferably composed of two or more layers, and these layers include a layer containing the biological physiologically active substance and a layer containing the polylactic acid complex. That is, the drug release layer is preferably composed of two layers, ie, a layer containing the biological physiologically active substance and a layer containing the polylactic acid complex, and another layer. Furthermore, the drug release layer is preferably composed of two layers: a layer containing the biological physiologically active substance and a layer containing the polylactic acid complex.

Furthermore, in the drug release layer, it is preferable that a layer containing the biological physiologically active substance is present on the main body side, and a layer containing the polylactic acid complex 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, the biological physiology is performed. The active substance is easily released at a constant rate!

Here, the layer containing the biological physiologically active substance is a layer composed of the biological physiologically active substance and the remaining component (the biodegradable polymer or the like). Here, the mass ratio of the biologically biologically active substance and the remaining component is not particularly limited, but is preferably 10:90 to 90:10.

The layer containing the polylactic acid complex is a layer composed of the polylactic acid complex and the remaining component. Here, the mass ratio between the polylactic acid complex and the remaining component is not particularly limited, but is preferably 99: 1 to 70: 30! /.

[0044] In addition, when the drug release layer has a layer other than the two layers of the layer containing the biological physiologically active substance and the layer containing the polylactic acid complex, the other layer is the remaining portion. It is a layer that also has component power.

[0045] In the drug release layer, a plurality of these layers may be present. Further, the order in which these layers are stacked is not limited. For example, it may have a layer made of the remaining component on the surface of the main body, and a layer containing the biological physiologically active substance or a layer containing the polylactic acid complex on the upper surface. Even such a case is within the scope of the present invention.

[0046] Further, the thickness of such a drug release layer is not particularly limited, and the amount and type of the biological and physiologically active substance that needs to be held on the surface of the main body and the type of in-vivo indwelling material. Furthermore, it can be determined as appropriate in consideration of the extracorporeal force, delivery to the lesion in the living body (easy reachability), and other various conditions. This thickness is preferably 1 to: LOO μm, more preferably 1 to 50 μm, and most preferably 1 to 20 μm.

[0047] When the drug release layer is composed of two or more layers, the total thickness of all the layers is A range such as force is preferred. 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. The layer containing the polylactic acid complex preferably has a thickness of 1 to 75 m, more preferably 1 to 25 / ζ πι, and more preferably 1 to 10 / ζ πι. preferable.

[0048] In such a drug release layer, it is preferable that at least a part of the biological physiologically active substance is contained as a powder. The biologically and biologically active substance in the powder is preferably dispersed in the drug release layer. Further, when the drug release layer has a layer containing the biological physiologically active substance, it is preferable that the biological physiologically active substance of the leverage powder is dispersed in this layer. This is because the biologically biologically active substance is easily released at a constant rate in the process of decomposing in vivo after the in vivo indwelling material of the present invention is indwelled.

[0049] Further, it is preferable that at least a part of the biological physiologically active substance is chemically bonded to the polylactic acid complex. After the in vivo indwelling material of the present invention is indwelled in the living body, in the process of being decomposed in the living body, the biological physiologically active substance is decomposed at a more constant rate simultaneously with the decomposition of the polylactic acid complex. This is because it is easily released. This can further suppress the inflammatory reaction.

[0050] In addition, at least a part of the biological and physiologically active substance is a micro-order thin film and an ultrathin or nano-order ultra-thin film (ultra-thin film) formed by the alternate lamination method in the polylactic acid complex. (Including thin film) is preferred! 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, the biological physiologically active substance is released at a more constant rate simultaneously with the decomposition of the polylactic acid complex. It is easy.

[0051] In addition, such a drug-releasing layer has the D-form polylactic acid chemically bonded to the stenosis or restenosis inhibitor, which is the biological physiologically active substance, and the biological physiologically active substance. The biological and physiological activity produced by the alternate lamination method in which the micro-order thin film and the cocoon or nano-order ultra-thin film are formed using the L-form polylactic acid chemically bonded to the anti-inflammatory agent. It is preferable to include the polylactic acid complex containing a substance. In addition, the drug-releasing layer has the L-form polylactic acid chemically bonded to the biological physiologically active substance stenosis or restenosis inhibitor and the anti-inflammation which is the biological physiologically active substance. Using the D-form polylactic acid chemically bonded to an agent, and producing the micro-order thin film and the Z- or nano-order ultra-thin thin film by the alternate lamination method, including the biological and physiologically active substance It is preferable to contain the polylactic acid complex. In such a polylactic acid complex, the stenosis or restenosis inhibitor and the anti-inflammatory agent are alternately laminated in the laminated structure of the thin film forming the polylactic acid complex. The release rate into the living body is preferable because it becomes more constant.

[0052] The in-vivo indwelling material of the present invention has such a drug release layer on the surface of the main body.

Next, the main body will be described.

Note that the in-vivo indwelling material of the present invention preferably has the drug release layer on the surface of the main body described below, but other substances are present between the drug release layer and the main body. Also good. In other words, even when the drug release layer is present on the surface of the main body not only on the surface of the main body, it is within the scope of the present invention.

[0053] In the in-vivo indwelling body of the present invention, the main body is the main part of the in-vivo in-vivo.

For example, when the in-vivo indwelling material of the present invention is a stent having the drug release layer on the surface of the stent body, it corresponds to the body portion referred to in the present invention.

[0054] 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.

[0055] Further, the material forming the main body has a strength that allows the in-vivo indwelling material of the present invention to be placed in a lesion part generated in a lumen in a living body such as a blood vessel, a bile duct, a trachea, an esophagus, or a urethra. There is no particular limitation as long as it has the like. For example, a metal material, a polymer material, ceramics, or the like can be used. Among these, it is preferable that the main body portion is also made of metal material and Z or polymer material. This is because the strength of the metal material is excellent, and the in vivo indwelling material of the present invention can be surely placed in the affected area. In addition, when it has high polymer material strength, it has excellent flexibility, and when expanded, the body (blood vessels) This is because excessive force is not applied to the wall.

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

[0057] The polymer material may be biodegradable or non-biodegradable. Any material can be used as long as it does not decompose in a living body for a desired period of time (for example, several weeks to several months), maintains its shape, and can be placed in a lesion or the like.

Examples of such a polymer material include polyesters such as polyethylene terephthalate and polybutylene terephthalate, or polyester elastomers having the structural unit thereof, polyamides such as nylon 6, nylon 12, nylon 66, nylon 610, and the like. Polyamide elastomers as structural units, polyolefins such as polyurethanes, polyethylene and polypropylene, or polyolefin elastomers containing these as structural units, polycarbonates such as polyethylene carbonate and polypropylene carbonate, sanolose acetate, cellulose nitrate Etc. Also, for example, the biodegradable polymer can be used.

[0058] The shape, size, etc. of the main body are not particularly limited. The in-vivo indwelling material of the present invention may be any material that can be indwelled in a lesion in a living body such as a blood vessel, a bile duct, a trachea, an esophagus, or a urethra! ,.

The in-vivo indwelling material of the present invention is an in-vivo indwelling material having the drug release layer on the surface of such a main body.

The in-vivo indwelling material of the present invention is inserted into the site to expand a stenosis part or occlusion part, etc. generated in the living body, expanded, and then placed in the site to maintain the state. If it is an indwelling thing, it will not specifically limit.

Examples include stents, covered stents, stent grafts, aneurysm treatment devices, and implantable medical devices that use a stent as a holder.

Also, for example, it has a hollow organ and a function of supporting the lumen in the Z or duct system (ureter, bile duct, urethra, uterus, esophagus, bronchi). Further, for example, the size of the closing member as a closing system for hollow space connection and pipe system may be appropriately selected according to the application location.

[0060] Among these, the in-vivo indwelling material of the present invention is preferably a stent. The reason is that it can be easily delivered and placed in the affected area.

[0061] When the in-vivo indwelling object of the present invention is a stent, the main stent body may be either a balloon expansion type or a self-expansion type. If the material of the stent body is an elastic body, self-expanding means using this elastic force can be used.

[0062] The size of the stent may be appropriately selected according to the application location. For example, when used for a coronary artery of the heart, the outer diameter before dilation is preferably 1.0 to 3. Omm and the length is preferably 5 to 50 mm. In addition, the thickness of the stent has a radial force necessary for placement in the lesion, and is not particularly limited as long as it does not inhibit blood flow when used in a blood vessel, for example. As 1-: LOOO μm range is preferred 10-500 μm range force is preferred, 40-200 μm range force ^ most preferred! / ヽ.

[0063] Further, the shape of the stent is not limited. An example is 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. [0064] 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.

[0065] 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.

[0066] Next, a method for producing the in-vivo indwelling material of the present invention will be described.

The in-vivo indwelling thing of this invention can be manufactured with the following method, for example.

For example, the polylactic acid complex produced by the alternating lamination method and the casting method as described above, the biological and physiologically active substance, and optionally the remaining component so as to have a preferable content as described above, for example. To prepare a mixture by applying a known method such as a mixing method using a mixer, a method of melting and kneading each component, a method of kneading each component into a paste, and the like. The drug release layer can be formed on the surface of the main body by a known method such as coating, spraying, brushing, or dipping the main body. The thickness of the drug release layer can be appropriately adjusted by a known method shown here, such as adjusting the coating amount by the concentration of the solution or the like.

[0067] Also, for example, if the drug release layer contains the biologically physiologically active substance of the powder, the polylactic acid composite produced by, for example, the alternating lamination method or the casting method as described above And the biological and biologically active substance of the powder and, if desired, the remaining component, for example, by applying a known method similar to the above so as to have a preferable content as described above, and mixing the mixture And a method of forming a drug release layer on the surface of the main body using the mixture by a known method similar to the above.

[0068] Further, for example, if the drug release layer is composed of a layer containing the biological physiologically active substance and a layer containing the polylactic acid complex, for example, the biological physiologically active substance and the The remaining component is mixed by applying a known method similar to the above so as to have a preferable content as described above, for example, to form a layer containing the biologically physiologically active substance. In addition, similarly, the polylactic acid composite produced by the alternate lamination method or the casting method as described above and the remaining component are preferably used, for example, as described above so as to have a content. The same known method as described above is applied and mixed to prepare a mixture for forming the layer containing the polylactic acid complex, and these mixtures are sequentially applied to the surface of the main body part in the same manner as described above. Examples thereof include a method of forming a drug release layer by coating or the like. When the drug release layer further has a layer other than the layer containing the biological physiologically active substance and the layer containing the polylactic acid complex, the upper and lower surfaces of these layers formed by such a method, For example, a layer made of the biodegradable polymer can be formed between these layers by the same method.

[0069] Also, for example, when at least a part of the biological physiologically active substance is chemically bonded to the polylactic acid complex, for example, D-form and L-form having a hydroxyl group or a carboxyl group at the terminal in advance. Examples include a method of preparing a polylactic acid complex having a stereocomplex structure such as a polylactic acid body, and using the terminal functional group as a microinitiator to form an ester bond or an amide bond with the biological physiologically active substance. In addition, a mixture is prepared by applying a method of growing lactide starting from a specific functional group of the biological biologically active substance to form a polylactic acid complex having the stereocomplex structure, Furthermore, a method of forming a drug release layer on the surface of the main body using the mixture by a known method similar to the above can be mentioned.

[0070] Further, for example, when at least a part of the biological physiologically active substance is contained between the micro-order thin film and the Z- or nano-order ultra-thin thin film formed by the alternate lamination method. For example, a solution in which D-form polylactic acid 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 (four Substrate such as fluorinated styrene (perfluoroalkoxy-ether ether resin) is soaked in each solution in order, and the mixture is prepared by applying drying repeatedly. And a method of forming a drug release layer on the surface of the part by a known method similar to the above. Here, for example, this substrate is first dipped in a solution in which D-form polylactic acid is dissolved and dried, and then dipped in a solution in which the biological physiologically active substance is dissolved and then dried. L-form polylactic acid After immersing in a solution in which is dissolved, and then drying, it is again immersed in a solution in which the biological and physiologically active substance is dissolved and dried. By repeating this operation, the biological and physiologically active substance is contained between all the thin films of the micro-order thin film and the Z- or nano-order ultra-thin film forming the polylactic acid complex. By applying such a method, the polylactic acid complex containing the biological organization active substance is prepared, and further, using this, the drug release layer is formed on the surface of the main body by the same known method as described above. The method of forming is mentioned.

[0071] Further, for example, the D-form polylactic acid or the L-form polylactic acid chemically combined with the stenosis or restenosis inhibitor, which is the biological physiologically active substance, and the biological physiologically active substance. Using the L-form polylactic acid or the D-form polylactic acid chemically bound to the anti-inflammatory agent, the micro-order thin film and the Z- or nano-order ultra-thin film are formed by an alternating lamination method. In the case of using the polylactic acid complex containing the biological physiologically active substance, for example, a substance obtained by esterifying or amide-bonding D-form polylactic acid and the stenosis or restenosis inhibitor to acetononitrile. A solution prepared by dissolving an L-form polylactic acid and the above-mentioned anti-inflammatory agent in an ester bond or amide bond in acetonitrile is prepared, and PFA (tetrafluoroethylene perfluoroalkyl) is prepared. The mixture is prepared by applying a method of repeatedly immersing a substrate such as millet-luite monoterpolymer resin (resin) alternately in each solution and drying, and further using this mixture on the surface of the main body. Examples thereof include a method for forming a drug release layer by a known method similar to the above.

[0072] The method of forming the main body is not particularly limited, and can be formed by a known method.

For example, when the in-vivo indwelling material of the present invention is a stent, the above-described material is made into a fiber and then knitted into a cylindrical shape, or this material is molded into a tubular body. The method of providing a pore is mentioned.

Thus, the present invention is an in-vivo indwelling having the drug release layer on the surface of the main body.

Therefore, when the cross section of the in-vivo indwelling object of this invention is shown, it will become like FIG. [0074] Next, the case where the in-vivo indwelling object of the present invention is the stent shown in Fig. 1 is taken as an example, and some aspects of the A-A line cross-sectional view and the BB line cross-sectional view are described. To do.

2 and 3 are enlarged cross-sectional views taken along line AA in FIG. FIG. 2 shows a stent in which the stent 1 shown in FIG. 1 has a drug release layer composed of a layer 32 containing a biological physiologically active substance and a layer 42 containing a polylactic acid complex on the surface of the stent body 10. It is sectional drawing in the case of a certain aspect.

Also, FIG. 3 shows that the stent 1 shown in FIG. 1 has a stent main body 10 on which a drug release layer comprising a polylactic acid complex 40 in which a biological bioactive substance 30 in powder form is dispersed. FIG. 3 is a cross-sectional view in the case of having a stent.

Next, FIGS. 4 and 5 are enlarged cross-sectional views taken along the line BB in FIG.

FIG. 4 shows a case similar to that shown in FIG. FIG. 5 shows a case similar to that shown in FIG.

Example

[0076] Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited thereto.

L-polylactic acid (API, 100L0105) pellets (hereinafter also referred to as “PLLA”) having a weight average molecular weight of about 150,000, and D—polylactic acid having a weight average molecular weight of about 50,000 synthesized by fermentation ( (Hereinafter also referred to as “PLDA”) were each dissolved in a acetonitrile solution previously adjusted to 50 ° C. (hereinafter, each solution was also referred to as “PLLA solution” and “PLDA solution”). Here, each concentration was adjusted to 30 mg / ml.

Next, the PFA plate was alternately immersed in these two solutions for 15 minutes and dried. Specifically, the PFA plate is immersed in the PLLA solution for 15 minutes, washed with pure water, dried, then immersed in the PLDA solution for 15 minutes, and then similarly washed with pure water and dried. This series of operations was taken as one step, and this was repeated 630 steps. A thin film of polylactic acid composite having a thickness of 50 μm was formed on the surface of the PFA plate.

Next, the film formed by such an alternate lamination method was immersed in an oil bath at 120 ° C, and then the oil bath was heated to 150 ° C to uniaxially stretch the film. Total of this time The draw ratio was 4 times. The thickness of the film obtained by stretching was 40 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 specimens and used.

The results are shown in Table 1.

PLLA and PLDA were dissolved separately in a acetonitrile solution adjusted beforehand to 50 ° C., and then mixed so that the ratio of PLLA: PLDA = 50: 50 was obtained. Here, the total concentration of PLLA and PLDA was set to 20 mg / ml.

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.

In Example 3, the same operation and measurement were performed in the same manner as in Example 2, except that the ratio of PLLA: PLDA, which was 50:50, was 45:55.

In Example 4, the same operation and measurement were performed in the same manner as in Example 2, except that the ratio of PLLA: PLDA, which was 50:50, was 55:45.

The results are shown in Table 1.

[0079] [Table 1] Difficult cases

[0080] <Comparative Example 1>

A copolymer of 50% L polylactic acid and 50% 0 polylactic acid (API 100 D065) pellets (hereinafter also referred to as “DL-PLA”) in acetone adjusted to 23 ° C in advance. It was dissolved in. 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 μm. 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 / zm. 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.

[0081] <Comparative Examples 2 to 7>

In Comparative Examples 2 to 7, the ratio of PLLA: PLDA, which was 50:50 in Example 1, was 70:30 (Comparative Example 2), 30:70 (Comparative Example 3), 60:40 (Comparative Example) 4), 40:60 (Comparative Example 5), 100: 0 (Comparative Example 6), 0: 100 (Comparative Example 7), and the other operations were the same. The results are shown in Table 2.

[0082] [Table 2] Specific tension value

[0083] <Example 5>

PLLA and PLDA are dissolved separately in the acetonitrile solution adjusted to 50 ° C in advance, and then they are mixed in a ratio of! ^ 1 ^:? 1 ^> 8 = 50: 50 The Here, the total concentration of PLLA and PLDA was set to 20 mg / ml.

Next, rabamycin (hereinafter also referred to as “RM”), which is an anticancer agent, was mixed with this solution. Here, the mixing amount of RM was set to 1: 1 by mass ratio with respect to the total mass of PLLA and PLDA. And these PLLA, Ka卩E the PLDA and RM further to Asetonitoriru the Asetonitoriru solution of the, PLLA, the total concentration of PLDA and RM was adjusted to 1 mass ^_0/0.

Next, spray this micro solution on the surface of the stent body (Tsunami (outer diameter 2. lmm, length 10mm, thickness 80 / zm), made of Thermonet), and apply this acetonitrile solution (Micro spray gun 11, NORD SON). Sprayed. Then, after drying, it was confirmed by a scanning electron microscope (SEM) that a polylactic acid complex of about 600 / g and a drug release layer having RM force were formed on the surface of the stent body.

Next, this stent was expanded to an outer diameter of 3. Omm with a balloon catheter (made by Alashi, Terumone Earth), and the degree of destruction of the drug release layer on the surface was observed with a microscope.

As a result, it was confirmed that no peeling or cracking was observed in the drug release layer (Fig. 6), and that the balloon expanded well.

PLLA and RM were dissolved in tetrahydrofuran (THF) at a mass ratio of 1: 1. Here, the total concentration force of PLLA and RM was set to be mass%. Next, this THF was sprayed onto the surface of the stent body (Tsunami (outer diameter 2. lmm, length 10mm, thickness 80m), made of Thermonet) using a spray (Micro Spray Gun I II NORDSON). . After drying, it was confirmed by a scanning electron microscope (SEM) that a drug release layer having PLLA and RM force of about 600 / zg was formed on the surface of the stent body.

As a result, peeling and cracking were observed in the drug release layer (Fig. 7), and it was confirmed that the balloon could not follow the balloon expansion well.

[0085] <Comparative Example 9>

Instead of PLLA used in Comparative Example 8, poly force prolatathon (PCL) was used, and the other conditions were the same.

Then, as in Comparative Example 8, it was confirmed by a scanning electron microscope (SEM) that after drying, a drug release layer having a PCL and RM force of about 600 / zg was formed on the surface of the stent body.

As a result, it was confirmed that cracking was observed (Fig. 8), and the drug release layer could not follow well, although the drug release layer did not peel.

A PLLA solution in which PLLA was dissolved in acetonitrile at 30 mg / ml was prepared in a beaker. Similarly, a PLDA solution in which PLDA was dissolved in acetonitrile to give 30 mg / ml was prepared in a beaker. Then, the beaker containing the PLLA solution and the beaker containing the PLDA solution were immersed in a hot water bath adjusted to 50 ° C., and the PLLA solution and the PLDA solution were maintained at 50 ° C. Here, PLLA and PLDA were completely dissolved in each solution. Separately, Aspirin is an anti-inflammatory agent (hereinafter, also referred to as "AP") solution in THF at 5 mass ^_0/0 (hereinafter also "AP solution", U) was prepared in a beaker.

Separately, PLLA: PLDA: RM = 1: 1: 0.5, and a beaker with a methylene chloride solution (hereinafter also referred to as “RM solution”) adjusted to a total concentration of 10 mgZ ml. Squeeze 7 o

[0087] Next, the stent (Tsunami (outer diameter 2. lmm, length 10mm, thickness 80μm), made of Thermonet) was immersed in the above PLLA solution adjusted to 50 ° C for 15 minutes. And from the PLLA solution After removal, the stent was washed and dried to form a PLLA thin film on the stent surface. Here, the washing and drying operation is specifically an operation in which the stent taken out from the PLLA solution is washed with acetonitrile for about 15 seconds, then washed with ultrapure water for about 10 seconds, and further dried with nitrogen gas. .

Next, the resulting stent with the PLLA thin film formed on it was immersed in the above-mentioned PLDA solution adjusted to 50 ° C for 15 minutes, and subjected to the same cleaning and drying operation on the stent surface. Furthermore, a thin film of PLD A was formed.

The process of forming a thin film of PLLA in this way and then forming a thin film of PLDA on the upper surface is one step. Then, this operation is further performed in 5 steps (that is, a total of 6 steps are performed, and 6 thin films of PLLA and 6 thin films of PLDA are alternately formed on the surface of the stent), and PLLA is formed on the surface of the stent. A layer (polylactic acid composite layer) in which a thin film of PLDA and a thin film of PLDA were laminated was formed. Here, the thickness of the polylactic acid composite layer was about 0.45 m.

A series of operations having a 6-step force for forming such a polylactic acid composite layer is also referred to as “operation 1” below.

[0088] Next, an AP solution was coated on the upper surface of the polylactic acid composite layer using a microsyringe to form a layer (AP layer) of about Lm.

Hereinafter, the operation for forming the AP layer of about 1 μm is also referred to as “operation 2”.

[0089] Next, operation 1 is further performed on the stent on which the AP layer is formed, and then operations 2 and 1 are further performed, so that a PLLA having a thickness of about 3.4 μm is formed on the surface of the stent. A layer consisting of PLDA and AP was formed.

[0090] Next, the upper surface of this layer was coated with the RM solution using a microsyringe to form an approximately 4 m layer (RM layer).

[0091] In this way, a drug release layer (thickness: about 7 m) consisting of a layer consisting of PLLA, PLDA and AP (thickness: about 3.4 m) and an RM layer (thickness: about 4 m) on the surface. A stent with 4 m) was formed.

[0092] Three stents having such drug release layers were formed. Then, one was used for the “RM'AP release measurement test” described below, and the other two were used for the following “in vivo placement test”. [0093] <RM, AP release measurement test (Example 6)>

About the stent which has this chemical | medical agent release layer, the release amount of RM and AP was measured. Specifically, the stent having this drug release layer was immersed in 10 ml of 4% by mass urushi serum-added reverse osmosis water (hereinafter also referred to as “BSA”) adjusted to 50 ° C., and stirred with a diameter of 10 mm. The mass of RM and AP in BSA was measured after 7 days, 14 days, 28 days, 42 days, and 56 days after stirring with a magnetic stirrer using a magnetic stirrer. High performance liquid chromatography (HPLC) (manufactured by Shimadzu Corporation) was used for the measurement of RM and AP mass.

[0094] As a result, release of RM, relative RM weight of the drug release layer before immersion into the BSA, 14曰後ί or about 40 ^_0/0, 28曰後ί or about 100 ^_0/0 there were.

On the other hand, the amount of soot released after 14 days and 28 days was 0%. After that, the release of soot was started with the degradation of the polylactic acid complex in the drug release layer, and the amount of soot released after 42 days was compared to the soot mass in the drug release layer before being immersed in BSA. About 50%. Furthermore, it was about 100% after 56 days. After 56 days, all the polylactic acid complex in the drug release layer is degraded and disappears! /

[0095] <In vivo indwelling test (Example 7)>

For the stent having this drug release layer, a test was performed in which two stents were placed in the right and left iliac arteries of a rabbit for 3 months. Fig. 9 shows the contrast image.

As shown in Figure 9, 3 months after placement, stenosis did not appear.

[0096] <Comparative Example 10>

Two stents formed by the method shown in Comparative Example 8 were prepared. Then, the same test as in Example 7 was performed.

Fig. 10 shows the contrast photograph.

As shown in Fig. 10, stenosis was observed 3 months after placement.

Claims

The scope of the claims

[1] An in-vivo indwelling material having a drug release layer on the surface of the main body,

The drug release laminar force D-form polylactic acid and L-form polylactic acid form a complex of a stereocomplex structure at a mass ratio of 45:55 to 55:45, and the biological physiology An in vivo indwelling material containing an active substance.

[2] The indwelling object according to claim 1, wherein the main body portion is made of a metal material and Z or a polymer material.

[3] The biological bioactive substance according to claim 1 or 2, wherein at least a part of the biological bioactive substance is a powder, and the biological bioactive substance of the powder is dispersed in the drug release layer. Indwelling in the body.

[4] The in-vivo indwelling product according to any one of [1] to [3], wherein at least a part of the biological physiologically active substance is chemically bonded to the polylactic acid complex.

[5] The living body according to claim 1 or 2, wherein the drug release layer comprises two or more layers, and the layers include the layer containing the biologically physiologically active substance and the layer containing the polylactic acid complex. Detainment.

[6] The raw material according to any one of claims 1 to 5, wherein the D-form polylactic acid and the Z-form or L-form polylactic acid forming the polylactic acid complex have a weight average molecular weight of 1,000 to 1,000,000. In-vivo indwelling.

7. The weight average molecular weight of the polylactic acid complex is 1,000 to 1,000,000.

The in-vivo indwelling object of ~ 6!

[8] The in-vivo indwelling product according to any one of [1] to [7], wherein the polylactic acid complex is a stretched polylactic acid complex.

[9] 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 material according to any one of claims 1 to 8.

[10] The polylactic acid composite has a breaking strength specified in JIS K7113 of 70 MPa or more.

10. The in vivo indwelling product according to any one of claims 1 to 9, which is a polylactic acid composite having a breaking elongation of 15% or more and a Young's modulus of lOOMPa or more.

[11] The in-vivo indwelling product according to any one of [1] to [10], wherein the polylactic acid complex is a polylactic acid complex produced by an alternating lamination method.

12. The in-vivo indwelling product according to claim 11, wherein the alternating lamination method is an alternating lamination method performed by forming a micro-order thin film and a Z- or nano-order ultra-thin film.

[13] The thickness of the micro-order thin film and Z or nano-order ultra-thin film is Inn! The in-vivo indwelling thing of Claim 12 which is -50micrometer.

14. The in-vivo indwelling product according to claim 12 or 13, which contains the biologically physiologically active substance between the micro-order thin film and the Z- or nano-order ultra-thin film.

[15] The biologically 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 The in-vivo indwelling product according to any one of claims 1 to 14, which is at least one selected from the group force that also has the ability to promote interferon and NO production.

[16] The D-form polylactic acid or the L-form polylactic acid chemically bonded to the stenosis or restenosis inhibitor that is the biologically physiologically active substance, and the anti-inflammatory drug that is the biologically physiologically active substance and the chemistry The biological physiology produced by the alternate lamination method in which the micro-order thin film and the Z- or nano-order ultra-thin thin film are formed using the bound L-form polylactic acid or the D-form polylactic acid. The in-vivo indwelling material according to any one of claims 12 to 15, which has a drug release layer containing the polylactic acid complex containing an active substance.

[17] The in-vivo indwelling product according to any one of [1] to [16], wherein a 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.

18. The in-vivo indwelling product according to any one of claims 1 to 17, which is a stent.