JPWO2007116646A1 - In vivo indwelling - Google Patents

Abstract

An in-vivo indwelling material having a layer that releases a drug containing a biodegradable polymer on its surface, and the biodegradable polymer has a necessary strength in the living body and is easily stretched during an expansion operation using a balloon or the like. Further, the in vivo indwelling body having a drug release layer on the surface of the main body part, which is less prone to cracking and can adjust the decomposition rate in the living body to a desired rate, the drug release layer, In vivo, comprising a polylactic acid complex in which a D-form polylactic acid and an L-form polylactic acid form a stereocomplex complex with a mass ratio of 45:55 to 55:45, and a biological physiologically active substance Detainment.

Description

  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 generated in the living body, is expanded, and is retained in the site to maintain the state. The present invention relates to an in-vivo indwelling material such as a stent graft.

  Examples of the in-vivo indwelling material of the present invention include various types such as a stent, a catheter, an artificial blood vessel, and a stent graft. In the following, a description will be given by taking a stent as an example.

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

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

  Stents have been studied and used to some extent as a method for preventing such restenosis. The term stent is used to treat various diseases caused by stenosis or occlusion of blood vessels and other lumens, and expand the stenosis or occlusion site and place it there to secure the lumen. A tubular medical device that can be used. And 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 metal wire or a polymer material fiber Various shapes have been proposed, such as those obtained by knitting and forming a cylindrical shape. The purpose of stent placement is to prevent and reduce restenosis that occurs after procedures such as PTCA, but such stent placement alone has not been able to significantly suppress stenosis. The actual situation was.

Therefore, in recent years, a method has been proposed in which a drug such as an immunosuppressive agent or an anticancer drug is carried on this stent so that the drug is locally released over a long period of time at the placement site of the lumen, thereby reducing the restenosis rate. ing.
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 substance for treatment. And it is described that poly L lactic acid and polycaprolactone 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), polyglycolic acid, polylactic acid / polyglycolic acid copolymer can be used.
JP-A-8-33718 JP-A-9-56807

However, poly-L lactic acid described in Patent Document 1, and poly-DL lactic acid (copolymer of D-form and L-form) described in Patent Document 2, polyglycolic acid, polylactic acid / polyglycolic acid copolymer Since the polymer polymer is low in strength, when a stent coated on the surface thereof is placed in a living body, it may be damaged by an external force. In addition, since these polymers are difficult to stretch and have a low elongation of several percent, they cannot follow the expansion operation when placed in a living body with a balloon or the like, and sometimes peel from the stent body. Furthermore, cracks may occur due to the expansion operation.
Thus, when the polymer on the surface of the stent body is broken, the fragments may block the lumen in the living body. For example, when applied to blood vessels, there is a risk of blocking peripheral blood flow. In addition, when a crack occurs, the surface is in a state of rolling, so that, for example, when used in a blood vessel, turbulence may occur in the blood flow, possibly causing thrombosis. Further, when the polymer is damaged or cracked, it may be difficult to keep the drug release rate constant.

In addition, the polycaprolactone 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 may be damaged by an external force. .
Moreover, this polycaprolactone 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, thrombosis tends to occur on the surface of this polymer, so it is necessary to apply antiplatelet therapy for a long period until polycaprolactone disappears. Is done.

  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 a living body and extends during an expansion operation using a balloon or the like. No cracks were easily generated, and there was no one capable of adjusting the degradation rate in vivo to a desired rate.

  In the above, a stent is taken as an example. However, such a problem is not limited to a stent. In order to expand a stenosis or occlusion in a living body, This is a problem common to an in-vivo indwelling object that is indwelled at the site in order to maintain the state.

  Therefore, an object of the present invention is an in-vivo indwelling material having a layer that releases a drug containing a biodegradable polymer on the surface, and the biodegradable polymer has a necessary strength in vivo, It is an object of the present invention to provide an in-vivo indwelling material that is easily stretched during expansion operation using a balloon or the like, hardly cracks, and can be adjusted to a desired decomposition speed in the living body.

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

That is, the present invention includes the following (1) to (18).
(1) An in-vivo indwelling body having a drug release layer on the surface of the main body, wherein the drug release layer is stereo in a mass ratio of D: polylactic acid and L: polylactic acid of 45:55 to 55:45. An in-vivo indwelling comprising a polylactic acid complex forming a complex structure complex and a biological physiologically active substance.
(2) The in-vivo indwelling product according to (1), wherein the main body is made of a metal material and / or a polymer material.
(3) In the above (1) or (2), 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. The in-vivo indwelling object described.
(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 release layer is composed of two or more layers, and these layers include the layer containing the biological and physiologically active substance and the layer containing the polylactic acid complex. In vivo indwelling material.

(6) The D-form polylactic acid and / or the L-form polylactic acid forming the polylactic acid complex has a weight average molecular weight of 1,000 to 1,000,000, and any one of the above (1) to (5) The in-vivo indwelling object described.
(7) The in-vivo indwelling material in any one of said (1)-(6) whose weight average molecular weights of the said polylactic acid complex are 1,000-1,000,000.
(8) The in-vivo indwelling thing in any one of said (1)-(7) whose said polylactic acid composite_body | complex is an expanded polylactic acid composite_body | complex.
(9) The polylactic acid complex is a polylactic acid complex having 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 thing in any one of said (1)-(8).
(10) The above 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 100 MPa or more (1 The in-vivo indwelling object in any one of (9)-(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 alternating lamination method is an alternating lamination method performed by forming a micro-order thin film and / or a nano-order ultra-thin film.
(13) The in-vivo indwelling product according to (12), wherein the thickness of the micro-order thin film and / or the nano-order ultra-thin film is 1 nm to 50 μm.
(14) The in-vivo indwelling product according to (12) or (13), wherein the biologically physiologically active substance is contained between the micro-order thin film and / or the nano-order ultra-thin thin film.

  (15) The biological physiologically active substance is an anticancer agent, immunosuppressant, antibiotic, antirheumatic agent, antithrombotic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemia Drugs, integrin inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, biological materials, The in-vivo indwelling material in any one of said (1)-(14) which is at least 1 chosen from the group which consists of an interferon and NO production promoter.

(16) The D-form polylactic acid or the L-form polylactic acid chemically bonded to the stenosis or restenosis inhibitor which is the biological physiologically active substance, and the anti-inflammatory drug and the chemistry which are the biological physiologically active substance The biological and physiological activity produced by the alternate lamination method in which the micro-order thin film and / or the nano-order ultra-thin film is formed using the combined L-form polylactic acid or the D-form polylactic acid. The in-vivo indwelling material in any one of said (12)-(15) which has a chemical | medical agent release layer containing the said polylactic acid complex containing a substance.
(17) The in-vivo indwelling material 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 object in any one of said (1)-(17) which is a stent.

  According to the present invention, an in-vivo indwelling material having a layer for releasing a drug containing a biodegradable polymer on the surface thereof, the biodegradable polymer has a necessary strength in vivo, and a balloon or the like. It is possible to provide an in-vivo indwelling material that is easily stretched during an expansion operation by the above-described method, hardly cracks, and that can be adjusted to a desired decomposition rate in vivo.

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 of FIG. 4 is an enlarged cross-sectional view taken along line BB in FIG. FIG. 5 is another enlarged cross-sectional view taken along the line BB of FIG. FIG. 6 is an enlarged photograph (800 times) after enlargement of the stent in Example 5. FIG. 7 is an enlarged photograph (800 times) 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 an angiogram (magnification) of the right and left iliac arteries of the rabbit according to the in vivo placement test of Example 7. FIG. 10 is a contrast photograph (magnification) of the right and left iliac arteries of a rabbit according to the in vivo placement test of Comparative Example 10.

The present invention is described in detail below.
The present invention is an in-vivo indwelling material having a drug release layer on the surface of a main body part, wherein the drug release layer has a mass ratio of D-form polylactic acid and L-form polylactic acid of 45:55 to 55:45. It is an in-vivo indwelling containing a polylactic acid complex forming a complex of a stereocomplex structure and a biological physiologically active substance.

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 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 force to produce structural fitting.

A stereocomplex structure can also be formed in a polymer having stereoregularity such as isotactic and syndiotactic.
Examples of forming a stereocomplex include poly-γ-benzyl glutamate, poly-γ-methyl glutamate, poly-tert-butylene oxide, poly-tert-butylethylene sulfide, poly-α-methylbenzyl in addition to polylactic acid. Methacrylate, poly-α-methyl-α-ethyl-β-propiolactone, β-1,1-dichloropropyl-β-propiolactone and the like are known.

In the polylactic acid composite, 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 composite having such a mass ratio and having the above-described stereocomplex structure has a remarkably high strength and elongation, and does not easily crack when expanded.
In addition, the mass ratio of D-form polylactic acid and L-form polylactic acid here means each mass ratio used when manufacturing the said polylactic acid composite_body | complex.

The weight average molecular weight of the D-form polylactic acid forming the polylactic acid complex is preferably 1,000 to 1,000,000, more preferably 2,000 to 700,000, More preferably, it is 000 to 400,000.
The weight average molecular weight of the L-form polylactic acid forming the polylactic acid complex is preferably 1,000 to 1,000,000, more preferably 2,000 to 700,000, More preferably, it is 000 to 400,000.
The polylactic acid complex preferably has a weight average molecular weight of 1,000 to 1,000,000, more preferably 2,000 to 700,000, and 5,000 to 400,000. More preferably.
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 (melting point) between 200 and 250 ° C. It is preferable that it has. Here, the differential scanning calorimetry is assumed to be performed at a rate of temperature increase of 5 ° C./min in a N ₂ gas stream. 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 polylactic acid The strength and elongation of the composite are further increased, and cracks during expansion are further less likely to occur.

The polylactic acid composite has a breaking strength of 70 MPa or more, a breaking elongation of 15% or more, and a Young's modulus when a 1/5 scale No. 2 test piece defined in JIS K7113 is used. A polylactic acid complex having a pressure of 100 MPa or more is preferable.
Here, the breaking strength is more preferably 75 MPa or more, and further preferably 80 MPa or more. The upper limit is not particularly limited, but is preferably 500 MPa or less.
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.
Further, the Young's modulus is more preferably 500 MPa or more, and further preferably 1,000 MPa or more. The upper limit is not particularly limited, but is preferably 50,000 MPa or less.
An in-vivo indwelling material using a polylactic acid complex having such values in such a range is preferable because it has high strength and elongation in the living body and hardly causes cracks during expansion.
In the following description, “breaking strength”, “breaking elongation”, and “Young's modulus” are all measured by the method defined in JIS K7113 (using a 1/5 scale No. 2 test piece). Means.

The polylactic acid complex is preferably 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 part of the molecule is stretched in the stretching direction and the degree of crystallinity is increased, and the molecules are oriented in the stretching direction. This is because the tensile strength and tensile modulus in the stretching direction are increased.

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 / or a nano-order ultrathin film. Furthermore, the thickness of the micro-order thin film and / or the nano-order ultra-thin film is preferably 1 nm to 50 μm, more preferably 10 nm to 30 μm, and still more preferably 100 nm to 20 μm.
Since the polylactic acid composite produced by this alternate lamination method has particularly good strength and elongation, the 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 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 lamination method, a polylactic acid complex having a stereocomplex structure can be formed more efficiently than in the bulk (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 copolymerization) is prepared. For example, a method of alternately immersing and drying a substrate such as a 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 stereo complex 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. However, in the case of manufacturing by an alternating lamination method, the stereocomplex structure is usually about 90% or more. It can be formed in proportion.

  Moreover, the manufacturing method of the said polylactic acid composite_body | complex is not limited, For example, it can manufacture by such an alternate lamination method and the casting method.

  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 the D-form polylactic acid or L-form polylactic acid used.

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

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 contains the polylactic 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, it is released from the drug release layer in the process of being decomposed in the living body, and the desired effect, for example, the effect of suppressing stenosis and restenosis, Any material may be used as long as it has an effect of suppressing an inflammatory reaction accompanying biodegradation of the release layer.

  Examples of the biological physiologically active substance include anticancer agents, immunosuppressive agents, antibiotics, antirheumatic agents, antithrombotic agents, HMG-CoA reductase inhibitors, ACE inhibitors, calcium antagonists, antihyperlipidemia Drugs, integrin inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, biological materials, Preferred examples include interferon and NO production promoting substances. More preferably, the biological physiologically active substance is at least one selected from the group consisting of these.

Here, as the anticancer agent, for example, vincristine, vinblastine, vindesine, irinotecan, pirarubicin, paclitaxel, docetaxel, methotrexate and the like are preferable.
As the immunosuppressive agent, for example, sirolimus, everolimus, biolimus, tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, gusperimus, mizoribine and the like are preferable.
Moreover, as an antibiotic, for example, mitomycin, adriamycin, doxorubicin, actinomycin, daunorubicin, idarubicin, pirarubicin, aclarubicin, epirubicin, pepromycin, dinostatin styramer and the like are preferable.

Moreover, as an anti-rheumatic agent, for example, methotrexate, sodium thiomalate, penicillamine, lobenzalit and the like are preferable.
Moreover, as an antithrombotic, 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, nisvastatin, itavastatin, fluvastatin, fluvastatin sodium, simvastatin, lovastatin, pravastatin and the like are preferable.

As the ACE inhibitor, for example, quinapril, perindopril erbumine, trandolapril, cilazapril, temocapril, delapril, enalapril maleate, lisinopril, captopril and the like are preferable.
Further, as the calcium antagonist, for example, hifedipine, nilvadipine, diltiazem, benidipine, nisoldipine and the like are preferable.
Moreover, as an antihyperlipidemic agent, for example, probucol is preferable.
Moreover, as an antiallergic agent, tranilast is preferable, for example.

Further, as the antioxidant, for example, catechins, anthocyanins, proanthocyanidins, lycopene, β-carotene and the like are preferable. Among catechins, epigallocatechin gallate is particularly preferable.
Further, as the retinoid, for example, all-trans retinoic acid is preferable.
Moreover, as a tyrosine kinase inhibitor, for example, genistein, tyrphostin, arbustatin and the like are preferable.
As the anti-inflammatory agent, for example, steroids such as dexamethasone and prednisolone are preferable.

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

  In the in-vivo indwelling material of the present invention, the drug release layer may be composed of such a biological physiologically active substance and the polylactic acid complex. May also be included. 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.

  Examples of such biodegradable polymers 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, D-form and L-form) Polymers (copolymers, etc.)), polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, polycaprolactone and Examples thereof include mixtures and compounds (copolymers and the like) which are at least one selected from the group consisting of these copolymers. Among these, polylactic acid and / or a copolymer of polylactic acid and polyglycolic acid can be preferably used. The reason is that it is easy to set a desired strength and decomposition rate.

When the drug release layer composed of such components is composed of one layer, the ratio of the content ratio of the polylactic acid complex and the biological physiologically active substance is 99: 1 to 1:99. Is more preferable, 90:10 to 10:90 is more preferable, and 80:20 to 20:80 is still more preferable. The reason is that it is easy to obtain a desired release rate of the biological physiologically active substance.
Furthermore, in this drug release layer, the content of the remaining components (the biodegradable polymer and the like) is not particularly limited, but is based on the total mass of the polylactic acid complex and the biological physiologically active substance. 40% by mass or less is preferable. It is because the intensity | strength of a chemical | medical agent release layer becomes higher as it is 40 mass% or less.

Further, the drug release layer may be composed of one layer as described above, or may be composed of two or more layers. Moreover, it consists of two or more layers, It is preferable that those layers contain the layer containing the said biological bioactive substance and the layer containing the said 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. This is because 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 physiologically 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.

  Moreover, when this drug release layer has other layers other than two layers of the layer containing the biological physiologically active substance and the layer containing the polylactic acid complex, the other layer is composed of the remaining component. Is a layer.

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

  In addition, 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, the type of in-vivo indwelling material, and the like. It can be determined as appropriate in consideration of delivery from the outside to the lesioned part in the living body (easy reachability) and other various conditions. The thickness is preferably 1 to 100 μm, more preferably 1 to 50 μm, and most preferably 1 to 20 μm.

  Moreover, when the said chemical | medical agent release layer consists of two or more layers, it is preferable that the total thickness of all these layers is in such a range. The thickness of the layer containing the biological and physiologically active substance is preferably 1 to 100 μm, more preferably 1 to 15 μm, and still more preferably 3 to 7 μm. The layer containing the polylactic acid complex preferably has a thickness of 1 to 75 μm, more preferably 1 to 25 μm, and still more preferably 1 to 10 μm.

  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. And it is preferable that the biological physiologically active substance of this powder is disperse | distributed in the said chemical | medical agent 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 powder is dispersed in this layer. This is because the biological physiologically 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.

  Moreover, it is preferable that at least a part of the biological 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 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. This can further suppress the inflammatory reaction.

  Further, at least a part of the biological physiologically active substance is between the micro-order thin film and / or nano-order ultra-thin film (including ultra-thin film) formed by the alternate lamination method in the polylactic acid complex. It is preferable that it is contained. 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.

In addition, the drug-releasing layer includes the D-form polylactic acid chemically bonded to the biological physiologically active substance stenosis or restenosis inhibitor, and the anti-inflammatory agent that is the biological physiologically active substance. The poly-containing biophysiologically active substance produced by an alternate lamination method in which the micro-order thin film and / or the nano-order ultra-thin thin film is formed using the chemically bonded L-form polylactic acid. It is preferable to contain a lactic acid complex.
In addition, the drug-releasing layer is composed of the L-form polylactic acid chemically bonded to the stenosis or restenosis inhibitor as the biological physiologically active substance, and the anti-inflammatory agent as the biological physiologically active substance. The poly-containing biobiologically active substance produced by an alternate lamination method in which the micro-order thin film and / or the nano-order ultra-thin thin film is formed using the chemically bonded D-form polylactic acid. It is preferable to contain a lactic acid complex.
In such a polylactic acid composite, since 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, these inhibitor and anti-inflammatory agent The release rate into the living body is preferable because it becomes more constant.

The in-vivo indwelling material of this invention has such a chemical | medical agent release layer on the surface of a main-body part.
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. That is, the drug release layer is not only present on the surface of the main body, but also within the scope of the present invention even when it is present on the surface of the main body.

In the in-vivo indwelling material of the present invention, the main body is the main part of the in-vivo in-vivo material.
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, the stent body referred to here corresponds to the body portion referred to in the present invention.

  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.

  In addition, the material forming the main body has such strength that the in-vivo indwelling material of the present invention can be indwelled in a lesion part generated in a body lumen such as a blood vessel, bile duct, trachea, esophagus, and urethra. If it is a thing, it will not specifically limit. For example, a metal material, a polymer material, ceramics, or the like can be used. Among these, it is preferable that this main-body part consists of a metal material and / or a polymeric material. This is because the metal material is excellent in strength, and the in-vivo indwelling material of the present invention can be reliably placed in a lesioned part. Moreover, when it consists of polymeric materials, it is because it is excellent in a softness | flexibility and an excessive force is not added to a biological body (blood vessel wall etc.) when it expands.

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

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 predetermined period (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, for example, polyesters such as polyethylene terephthalate and polybutylene terephthalate, polyester elastomers having the same as structural units, polyamides such as nylon 6, nylon 12, nylon 66, and nylon 610, or the like. Examples of the structural unit include polyamide-based elastomers, polyurethanes, polyolefins such as polyethylene and polypropylene, or polyolefin-based elastomers including these structural units, polycarbonates such as polyethylene carbonate and polypropylene carbonate, cellulose acetate, and cellulose nitrate. In addition, for example, the biodegradable polymer can be used.

  Further, the shape, size, etc. of the main body are not particularly limited. Any indwelling object of the present invention may be used as long as the indwelling object can be indwelled in a lesion in a lumen 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 in-vivo product having the drug release layer on the surface of the main body.
The in-vivo indwelling material of the present invention is inserted into the site in order to expand a stenosis part or occlusion part, etc. generated in the living body, expanded, and then placed in the body in order to maintain the state. If it is an indwelling thing, it will not specifically limit.
For example, a stent, a covered stent, a stent graft, an aneurysm treatment device, and an implantable medical device using a stent as a holding body.
For example, it has a lumen supporting function in a hollow organ and / or a duct system (ureter, bile duct, urethra, uterus, esophagus, bronchi).
Also, for example, a closure member as a closure system for hollow space connections and tubing.
These sizes and the like may be appropriately selected according to the application location.

  Among these, the in-vivo indwelling material of the present invention is preferably a stent. The reason is that it can be easily delivered to and placed in the lesion.

  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.

  Further, 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 expansion is preferably 1.0 to 3.0 mm, and the length is preferably 5 to 50 mm. The thickness of the stent is not particularly limited as long as it has a radial force necessary for placement in a lesion, and is not particularly limited as long as it does not inhibit blood flow when used in a blood vessel, for example. Is preferably in the range of 1 to 1000 μm, more preferably in the range of 10 to 500 μm, and most preferably in the range of 40 to 200 μm.

Further, the shape of the stent is not limited. For example, what is shown in FIG. 1 is mentioned.
In FIG. 1, the 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 the notched portions are deformed to have a structure that can be expanded and contracted in the radial direction of the cylindrical body. To maintain its shape.
In the embodiment shown in FIG. 1, the stent body 1 is composed of a linear member 2, and has a substantially rhombic element 11 having a notch therein as a basic unit. A plurality of substantially diamond-shaped elements 11 are arranged in an annular unit 12 by connecting and arranging substantially diamond-shaped elements continuously in the minor axis direction. The annular unit 12 is connected to an adjacent annular unit via a linear connecting member 13. Thus, the plurality of annular units 12 are continuously arranged in the axial direction in a partially coupled state. With such a configuration, the stent body (stent) 1 has a cylindrical body that is open at both ends and extends 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.

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

  The stent 1 described above is only one aspect, and is a cylindrical body that is composed of a linear member 2, has both end portions opened, and extends between the both end portions in the longitudinal direction. It has a large number of notches that communicate with the outer surface and the inner surface, and includes a wide range of structures that can be expanded and contracted in the radial direction of the cylindrical body by deforming the notches.

Next, the manufacturing method of the in-vivo indwelling material of this invention is demonstrated.
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 or the casting method as described above, the biological and physiologically active substance, and, if desired, the remaining component may have a preferable content as described above, for example. To prepare a mixture 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, The drug release layer can be formed on the surface of the main body by a known method such as coating, spraying, brushing, dipping the main body, or the like. The thickness of the drug release layer can be appropriately adjusted by a known method shown here, such as adjusting the concentration of the solution or the amount of application by spraying.

  Also, for example, if the drug release layer contains the biological biologically active substance of the powder, for example, the polylactic acid complex produced by the alternating lamination method and the casting method as described above, A mixture is prepared by mixing the biological and biologically active substance of the powder and, if necessary, the remaining component by applying a known method similar to the above so as to achieve the preferable content as described above, for example. 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 is mentioned.

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 remaining component In order to obtain a preferable content as described above, for example, a known method similar to the above is applied and mixed to prepare a mixture for forming a layer containing the biologically physiologically active substance. Similarly, a known method similar to the above is applied so that the polylactic acid complex produced by the alternate lamination method or the casting method as described above and the remaining component have a preferable content as described above, for example. To prepare a mixture containing the polylactic acid complex, and sequentially apply these mixtures to the surface of the main body by a known method similar to the above to form a drug release layer. How to form .
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, Between these layers, for example, a layer made of the biodegradable polymer can be formed by the same method.

  In addition, for example, if 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 polylactic acid having a hydroxyl group or a carboxyl group at the terminal in advance. From the above, a method of preparing a polylactic acid complex having the stereocomplex structure and using the functional group at the end as a microinitiator to form an ester bond or an amide bond with the biological physiologically active substance can be mentioned. In addition, a mixture is prepared by applying a method of growing lactide starting from a specific functional group of the biological physiologically active substance and forming a polylactic acid complex having the stereocomplex structure, The method of forming a chemical | medical agent release layer by the well-known method similar to the above on the surface of the said main-body part using this mixture is mentioned.

  Further, for example, if at least a part of the biological physiologically active substance is contained between the micro-order thin film and / or the nano-order ultra-thin film formed by the alternate lamination method, 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 (ethylene tetrafluoride) is prepared. -A substrate such as a perfluoroalkoxy vinyl ether copolymer resin) is immersed in each solution in order, and a mixture is prepared by applying a method of repeating drying. Further, using this mixture, the surface of the main body is the same as described above. And a known method for forming a drug release layer. Here, for example, this substrate is first immersed in a solution in which D-form polylactic acid is dissolved and dried, and then is immersed in a solution in which the biological physiologically active substance is dissolved and dried. After immersing in a solution in which L-form polylactic acid is dissolved and drying, it is again immersed in a solution in which the biological 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 / or the 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, a drug release layer is formed on the surface of the main body by a known method similar to the above. The method of forming is mentioned.

  Further, for example, the D-form polylactic acid or the L-form polylactic acid chemically bonded to the stenosis or restenosis inhibitor which is the biological physiologically active substance, and the anti-inflammatory agent which is the biological physiologically active substance, The biological physiology produced by the alternate lamination method in which the micro-order thin film and / or the nano-order ultra-thin thin film is formed using the chemically bonded L-form polylactic acid or the D-form polylactic acid. If the polylactic acid complex containing an active substance is used, for example, a solution obtained by dissolving D-form polylactic acid and the stenosis or restenosis inhibitor in an ester bond or amide bond in acetonitrile, A solution prepared by dissolving L-form polylactic acid and the anti-inflammatory agent in an ester bond or amide bond in acetonitrile was prepared, and PFA (ethylene tetrafluoride / perfluoroalcohol) was prepared. A mixture of a substrate such as a vinyl ether copolymer resin) is alternately applied to each solution and dried to prepare a mixture, and the mixture is used to apply the mixture to the surface of the main body as described above. A method of forming a drug release layer by a known method may be mentioned.

The method for 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 fibrous shape and then knitted into a cylindrical shape, or this material is formed into a tubular body, and is then thinned into this. The method of providing a hole is mentioned.

Thus, this invention is an in-vivo indwelling which has the said chemical | medical agent release layer on the surface of the said main-body part.
Therefore, when the cross section of the in-vivo indwelling object of this invention is shown, it will become like FIG.

Next, the case where the in-vivo indwelling object of the present invention is the stent shown in FIG. 1 will be described as an example, and some aspects will be described with respect to the AA line sectional view and the BB line sectional view.
2 and 3 are enlarged cross-sectional views taken along line AA in FIG.
FIG. 2 is 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 an aspect.
3 shows that the stent 1 shown in FIG. 1 has a stent body 10 on which a drug release layer made of a polylactic acid complex 40 in which a biological bioactive substance 30 in powder form is dispersed. It is sectional drawing in the case of having a stent.

Next, FIGS. 4 and 5 are enlarged cross-sectional views when cut 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.

Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited thereto.
<Example 1>
L-polylactic acid having a weight average molecular weight of about 150,000 (API, 100L0105) pellet (hereinafter also referred to as “PLLA”), and D-polylactic acid having a weight average molecular weight of about 50,000 synthesized by fermentation (hereinafter referred to as “PLA”) , And also referred to as “PLDA”) were each dissolved in an acetonitrile solution previously adjusted to 50 ° C. (hereinafter, each solution is also referred to as “PLLA solution” and “PLDA solution”). Here, each concentration was adjusted to 30 mg / ml.
Next, the operation of dipping the PFA plate in these two solutions alternately for 15 minutes and drying was repeated. Specifically, the PFA plate is immersed in a PLLA solution for 15 minutes, washed with pure water, dried, then immersed in a PLDA solution for 15 minutes, and then similarly washed with pure water and dried. Such a series of operations is defined as one step, and this is repeated 630 steps. Then, 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 stretch the film uniaxially. The draw ratio at this time was 4 times. The thickness of the film obtained by stretching was 40 μm. 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 a 1/5 scale type 2 test piece.
The results are shown in Table 1.

<Example 2>
PLLA and PLDA were separately dissolved in an acetonitrile solution adjusted to 50 ° C. in advance, and then mixed so that the ratio of PLLA: PLDA was 50:50. 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 μm. Then, this 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 μm. 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 a 1/5 scale type 2 test piece.
The results are shown in Table 1.

<Examples 3 and 4>
In Example 3, the 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 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.

<Comparative Example 1>
Copolymer (100D065 manufactured by API Co.) pellets of 50% by mass of L-polylactic acid and 50% by mass of D-polylactic acid (hereinafter also referred to as “DL-PLA”) in acetone previously adjusted to 23 ° C. 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. Then, this 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 μm. 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 a 1/5 scale type 2 test piece.
The results are shown in Table 2.

<Comparative Examples 2-7>
In Comparative Examples 2 to 7, the ratio of PLLA: PLDA set to 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 and measurements were performed in the same manner.
The results are shown in Table 2.

<Example 5>
PLLA and PLDA were dissolved separately in an acetonitrile solution adjusted to 50 ° C. in advance, and then mixed so that the ratio of PLLA: PLDA was 50:50. Here, the total concentration of PLLA and PLDA was set to 20 mg / ml.
Next, rapamycin (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. Then, acetonitrile was further added to the acetonitrile solution in which PLLA, PLDA and RM were dissolved, and the total concentration of PLLA, PLDA and RM was adjusted to 1% by mass.
Next, this acetonitrile solution is sprayed on the surface of the stent body (Tsunami (outer diameter 2.1 mm, length 10 mm, thickness 80 μm), Terumo) using a spray (Micro Spray Gun-II, manufactured by NORDSON). Sprayed. After drying, it was confirmed by a scanning electron microscope (SEM) that a drug release layer composed of about 600 μg of polylactic acid complex and RM was formed on the surface of the stent body.
Next, this stent was expanded to an outer diameter of 3.0 mm with a balloon catheter (Arashi, manufactured by Terumo Corporation), 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.

<Comparative Example 8>
PLLA and RM were dissolved in tetrahydrofuran (THF) at a mass ratio of 1: 1. Here, the total concentration of PLLA and RM was set to 1% by mass.
Next, the THF is sprayed on the surface of the stent body (Tsunami (outside diameter 2.1 mm, length 10 mm, thickness 80 μm), Terumo) using a spray (Microspray Gun-II, NORDSON). did. Then, after drying, it was confirmed by a scanning electron microscope (SEM) that a drug release layer composed of about 600 μg of PLLA and RM was formed on the surface of the stent body.
As a result, peeling and cracks were observed in the drug release layer (FIG. 7), and it was confirmed that balloon expansion could not be followed well.

<Comparative Example 9>
The operation was performed under the same conditions except that polycaprolactone (PCL) was used instead of PLLA used in Comparative Example 8.
Then, similarly to Comparative Example 8, it was confirmed by a scanning electron microscope (SEM) that a drug release layer composed of about 600 μg of PCL and RM was formed on the surface of the stent body after drying.
As a result, although no peeling was observed in the drug release layer, cracks were observed (FIG. 8), and it was confirmed that the balloon expansion could not be followed well.

<Examples 6 and 7>
A PLLA solution in which PLLA was dissolved in acetonitrile so as to be 30 mg / ml was prepared in a beaker. Similarly, a PLDA solution prepared by dissolving PLDA in acetonitrile so as to be 30 mg / ml was prepared in a beaker. Then, the beaker containing these PLLA solutions and the beaker containing the PLDA solutions 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, a solution (hereinafter also referred to as “AP solution”) in which 5% by mass of aspirin (hereinafter also referred to as “AP”), which is an anti-inflammatory agent, was prepared in a beaker.
Separately, PLLA: PLDA: RM = 1: 1: 0.5, and a methylene chloride solution (hereinafter also referred to as “RM solution”) adjusted so that the total concentration thereof is 10 mg / ml is used as a beaker. Prepared.

Next, a stent (Tsunami (outside diameter 2.1 mm, length 10 mm, thickness 80 μm), Terumo) was immersed in the PLLA solution adjusted to 50 ° C. for 15 minutes. And after taking out from the PLLA solution, washing | cleaning and drying operation were given to this stent, and the thin film of PLLA was formed in the stent surface. Here, the washing / 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 stent on which the PLLA thin film obtained here is formed is immersed in the above-mentioned PLDA solution adjusted to 50 ° C. for 15 minutes, and subjected to the same washing and drying operation. A thin film of PLDA was formed.
An operation of forming a PLLA thin film in this way and further forming a PLDA thin film on the upper surface thereof is taken as one step. Then, this operation is further performed in 5 steps (that is, 6 steps in total are performed, and 6 thin films of PLLA and 6 thin films of PLDA are alternately formed on the surface of the stent), and the thin film of PLLA is formed on the surface of the stent. And a layer (polylactic acid composite layer) in which thin films of PLDA were laminated was formed. Here, the thickness of the polylactic acid composite layer was about 0.45 μm.
A series of operations comprising 6 steps for forming such a polylactic acid composite layer is also referred to as “operation 1” below.

Next, an AP solution was coated on the upper surface of the polylactic acid composite layer using a microsyringe to form an approximately 1 μm layer (AP layer).
Such an operation for forming an AP layer of about 1 μm is also referred to as “operation 2” below.

  Next, operation 1 is further applied to the stent on which this AP layer is formed, and then operation 2 and operation 1 are further applied to the surface of the stent from PLLA, PLDA and AP having a thickness of about 3.4 μm. A layer was formed.

  Next, an RM solution was coated on the upper surface of this layer using a microsyringe to form an approximately 4 μm layer (RM layer).

  In this way, a drug release layer (thickness: about 7.4 μm) composed of a layer (thickness: about 3.4 μm) made of PLLA, PLDA and AP and an RM layer (thickness: about 4 μm) is formed on the surface. A stent was formed.

  Three stents having such a drug release layer were formed. One was subjected to the “RM / AP release measurement test” described below, and the remaining two were subjected to the following “in vivo placement test”.

<RM / AP emission 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 weight bovine serum albimine-added reverse osmosis water (hereinafter also referred to as “BSA”) adjusted to 50 ° C., and a φ10 mm stirrer was used. 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. High-performance liquid chromatography (HPLC) (manufactured by Shimadzu Corporation) was used for measurement of RM and AP mass.

As a result, the amount of RM released was about 40% after 14 days and about 100% after 28 days with respect to the RM mass in the drug release layer before being immersed in BSA.
On the other hand, the amount of AP released after 14 days and 28 days was 0%. Thereafter, the release of AP is started with the degradation of the polylactic acid complex in the drug release layer, and the amount of AP released after 42 days is about the AP mass in the drug release layer before being immersed in BSA. 50%. Furthermore, it was about 100% after 56 days. Further, after 56 days, the entire amount of the polylactic acid complex in the drug release layer was decomposed and disappeared.

<In vivo indwelling test (Example 7)>
The stent having this drug release layer was subjected to a test in which two stents were placed in the right and left iliac arteries of a rabbit for 3 months. The contrast photograph is shown in FIG.
As shown in FIG. 9, no stenosis was observed 3 months after placement.

<Comparative Example 10>
Two stents formed by the method shown in Comparative Example 8 were prepared. And the test similar to Example 7 was done.
The contrast photograph is shown in FIG.
As shown in FIG. 10, stenosis was observed 3 months after placement.

Claims (18)

An in-vivo indwelling material having a drug release layer on the surface of the main body,
A biological physiological activity, wherein the drug release layer comprises a polylactic acid complex in which a D-form polylactic acid and an L-form polylactic acid form a stereocomplex complex with a mass ratio of 45:55 to 55:45 In-vivo indwelling material containing the substance.   The in-vivo indwelling object according to claim 1 in which said main part consists of metal material and / or polymer material.   The in-vivo indwelling product according to claim 1 or 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 drug release layer. .   The in vivo indwelling product according to any one of claims 1 to 3, wherein at least a part of the biological physiologically active substance is chemically bonded to the polylactic acid complex.   The in-vivo indwelling object according to claim 1 or 2 in which said medicine release layer consists of two or more layers, and those layers contain a layer containing said biological physiologically active substance, and a layer containing said polylactic acid complex.   The in-vivo indwelling product according to any one of claims 1 to 5, wherein the D-form polylactic acid and / or the L-form polylactic acid forming the polylactic acid complex has a weight average molecular weight of 1,000 to 1,000,000. .   The in vivo indwelling product according to any one of claims 1 to 6, wherein the polylactic acid complex has a weight average molecular weight of 1,000 to 1,000,000.   The in vivo indwelling product according to any one of claims 1 to 7, wherein the polylactic acid complex is a stretched polylactic acid complex.   The polylactic acid complex is a polylactic acid complex having 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 object in any one of 1-8.   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 100 MPa or more. The in-vivo indwelling material in any one.   The in-vivo indwelling product according to any one of claims 1 to 10, wherein the polylactic acid complex is a polylactic acid complex produced by an alternating lamination method.   The in-vivo indwelling material according to claim 11, wherein the alternating lamination method is an alternating lamination method performed by forming a micro order thin film and / or a nano order ultra thin film.   The in-vivo indwelling object according to claim 12, wherein the thickness of the micro-order thin film and / or the nano-order ultra-thin film is 1 nm to 50 µm.   The in-vivo indwelling thing of Claim 12 or 13 containing the said biological physiologically active substance between the thin films of the said micro order thin film and / or a nano order ultra thin film.   The biological and physiologically active substance is an anticancer agent, immunosuppressive agent, antibiotic, antirheumatic agent, antithrombotic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antihyperlipidemic agent, integrin Inhibitors, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improvers, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, anti-inflammatory drugs, biomaterials, interferon and NO The in-vivo indwelling material according to any one of claims 1 to 14, which is at least one selected from the group consisting of production promoting substances.   The D-form polylactic acid or the L-form polylactic acid chemically bonded to the biological physiologically active substance stenosis or restenosis inhibitor and the anti-inflammatory drug chemically bonded to the biological physiologically active substance Including the biological and physiologically active substance produced by an alternate lamination method in which the micro-order thin film and / or the nano-order ultra-thin thin film is formed using the 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 medicine release layer containing said polylactic acid complex.   The in-vivo indwelling product according to any one of claims 1 to 16, wherein the main body has a tube shape, a tubular shape, a net shape, a fiber shape, a nonwoven fabric shape, a woven fabric shape, or a filament shape.   It is a stent, The in-vivo indwelling thing in any one of Claims 1-17.

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