JP2008113827A - In-vivo indwelling material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stent which is designed to inhibit/prevent an inflammation of a blood vessel wall and inhibits an inflammatory response accompanying especially a degradation in a living body by anti-inflammatory ligand effects by having multi-branched polylactate where an anti-inflammatory ligand is introduced as a constituent element of an intraluminal indwelling material. <P>SOLUTION: An in-vivo indwelling material indwelled in a living body comprises a main body 2 of the stent containing a polylactate complex, a layer 3 which is formed on the surface of the main body 2 and contains a physiological active substance, and a layer 4 which contains biodegradable macromolecules and is formed on the surface of the layer 3 containing the physiological active substance. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an in-vivo indwelling material, and more particularly to an in-vivo indwelling material that is inserted into and placed in a living body such as a blood vessel, bile duct, trachea, esophagus, and urethra.

  As an example, angioplasty applied to ischemic heart disease will be described.

  Westernization of dietary habits in Japan has led to a rapid increase in the number of patients with ischemic heart disease (angina, myocardial infarction). Coronary angioplasty (PTCA) has been performed and has become widespread. At present, the number of applied cases has increased due to technological development. From the one that was localized (the length of the lesion was short) and one-branch lesion (the lesion that had stenosis only in one site) at the time when PTCA started, The application of PTCA has been extended to those that are more eccentric and calcified in the more distal parts, and multi-branch lesions (lesions with stenosis in more than one site). PTCA is a long hollow tube called a guide catheter with a small incision in the artery of the patient's leg or arm and placement of an introducer sheath (leader) through the lumen of the introducer sheath, with the guide wire leading. After inserting the tube into the blood vessel and placing it at the entrance of the coronary artery, withdraw the guide wire, insert another guide wire and balloon catheter into the lumen of the guide catheter, and X-ray contrast the balloon catheter with the guide wire leading The procedure is to advance to the lesioned part of the patient's coronary artery, position the balloon in the lesioned part, and at this position, the doctor inflates the balloon at a predetermined pressure for 30 to 60 seconds once or a plurality of times. This dilates the vascular lumen of the lesion, thereby increasing blood flow through the vascular lumen. However, when the blood vessel wall is injured by the catheter, the intima proliferation, which is a healing reaction of the blood vessel wall, occurs, and restenosis has been reported at a rate of about 30 to 40%.

  As a method for preventing this restenosis, a method using a device such as a stent or an atherectomy catheter has been studied, and some results have been achieved. A stent as used herein refers to a variety of diseases caused by stenosis or occlusion of blood vessels or other lumens. In order to treat various diseases, the stenosis or occlusion site is expanded and placed there to secure the lumen. A tubular medical device that can be used. Most stents are medical devices made of metallic or polymeric materials, such as those made of metallic materials or polymeric materials, with a tubular body with pores, metallic wires or polymeric materials Various shapes have been proposed, such as those obtained by knitting fibers and forming them into a cylindrical shape. The purpose of stent placement is to prevent and reduce restenosis that occurs after procedures such as PTCA, but the actual situation is that stenosis cannot be remarkably suppressed with only a stent. It was.

  And in recent years, this stent is loaded with physiologically active substances such as immunosuppressive agents and anticancer agents, so that these physiologically active substances can be locally released over a long period of time at the indwelling site of the lumen, thereby reducing restenosis. Many attempts have been made to achieve this.

  For example, Patent Document 1 discloses a stent in which the surface of a stent body made of tantalum is coated with a mixture of a therapeutic substance and a biodegradable polymer material.

  Patent Document 2 discloses a stent in which a drug layer is provided on the surface of a stainless steel stent body, and a biodegradable polymer layer for eluting the drug is provided on the drug layer.

In addition, when the stent body is formed of polylactic acid as disclosed in Patent Document 3, the polylactic acid can be decomposed and the stent body can be decomposed / disappeared. The possibility of chronic inflammation due to mechanical stress being applied to the blood vessel wall can be avoided. Therefore, it is suggested that the in-vivo indwelling object according to Patent Document 3 has no invasion to a living body or is an in-vessel indwelling that is extremely invasive.
JP-A-8-33718 JP-A-9-56807 Japanese Patent No. 2842943

  However, in the stent proposed in Patent Document 1 or 2, since the stent body is formed of a metal material such as stainless steel or tantalum, the stainless steel body is left in the living body semipermanently. Therefore, after the biodegradable polymer is decomposed in vivo and the physiologically active substance is released, there is a problem that chronic inflammation due to mechanical stress on the blood vessel wall of the stent body may occur. This is not limited to the stents proposed in Patent Documents 1 and 2, but is a problem in all stents using a metal material.

  Furthermore, with respect to Patent Document 3, when a stent body is formed of polylactic acid, an inflammatory reaction accompanied by degradation of polylactic acid in vivo is induced, which may induce restenosis. Raising is a problem that has not been solved yet.

  An object of the present invention is to suppress / prevent inflammation of a blood vessel wall, which is a problem of the inventions according to the above-mentioned Patent Documents 1 to 3, and a multibranched polylactic acid introduced with an anti-inflammatory ligand is used as a tube. It is an object of the present invention to provide a stent that can suppress an inflammatory reaction caused by degradation in vivo by an anti-inflammatory ligand effect by using it as a constituent element of an indwelling object.

  As a result of earnest research for solving the above-mentioned problems, the present inventors have found that an in-vivo indwelling material for indwelling in vivo, wherein the in-vivo indwelling material is a polylactic acid in which an anti-inflammatory ligand is introduced into polylactic acid. The object of the present invention is achieved by an in-vivo indwelling material characterized by containing a lactic acid complex.

  According to the present invention, an in-vivo indwelling material for in-vivo indwelling, wherein the in-vivo indwelling material includes a polylactic acid complex in which an anti-inflammatory ligand is introduced into polylactic acid. The in-vivo indwelling itself is absorbed in vivo by its own in vivo degradation, and the inflammatory reaction can be suppressed by the introduced anti-inflammatory ligand. Further, in the case where a physiologically active substance and / or a biodegradable polymer is further attached to at least a part of the in vivo indwelling material of the present invention, after the in vivo indwelling material is indwelled at a lesion site in the living body, A bioactive substance is released by degrading the degradable polymer in vivo, and vascular restenosis can be suppressed.

  The first of the present invention is an in-vivo indwelling material for in-vivo indwelling, wherein the in-vivo indwelling material comprises a polylactic acid complex in which an anti-inflammatory ligand is introduced into polylactic acid. It is an indwelling object. Thereby, the inflammatory reaction accompanying the decomposition | disassembly in a biological body can be suppressed by the anti-inflammatory ligand effect.

  Examples of the polylactic acid according to the present invention include linear polylactic acid having at least one terminal having a carboxyl group, multi-branched polylactic acid having at least one terminal having a carboxyl group, and the like. Branched polylactic acid, polylactic acid dendrimer, and polylactic acid star polymer are preferred. A hyperbranched polymer is a multi-branched polymer that is synthesized by self-condensation of so-called ABx-type molecules having a total of 3 or more of two types of substituents in one molecule. The star polymer has the most basic structure among branched polymers, and one end of every molecular chain is grafted to the small core part in the center, so the segment density near the center becomes very large. The polymer has a gradient structure with respect to the segment density toward the outermost shell layer. Therefore, a star polymer is different from a hyperbranched polymer in that it grows while repeating branching during polymerization. Dendrimers have the same structure as hyperbranched polymers, but differ in properties and physical properties. A hyperbranched polymer has a lower viscosity than a linear polymer having the same molecular weight, but a dendrimer having the same molecular weight tends to have a lower viscosity. Hyperbranched polymers corresponding to highly crystalline linear polymers are also characterized by improved solubility and non-crystalline properties, and are often useful for material design. However, when the polymer is a branched polymer and the intermolecular interaction of the terminal group is strong, the above tendency is different. In addition, hyperbranched polymers have many terminal functional groups like dendrimers, and thus are useful skeletons for molecular design in which many functional atomic groups are to be introduced. Thus, the hyperbranched polymer is a polymer having useful properties and can be synthesized easily. Hyperbranched polymers can be used for applications such as biofunctional materials, heat-resistant polymer materials, and liquid crystal materials. A star dendrimer obtained by growing a dendrimer into a tree shape is also useful in the present invention.

  The polylactic acid according to the present invention is a known method, for example, a polycondensation method in which lactic acid is directly dehydrated by heating under reduced pressure, or a cyclic dimer from lactic acid. A ring-opening polymerization method produced by ring-opening polymerization via a lactide, and a small amount of chain extender (for example, an isocyanate compound, (Epoxy compound, acid anhydride, organic peroxide)).

  The polylactic acid according to the present invention may be either poly (L-lactic acid) or poly (D-lactic acid), or may be blended with poly (L-lactic acid) and poly (D-lactic acid). Good.

  In the polylactic acid according to the present invention, the number of carboxylic acids in one chain of polylactic acid is preferably 1-20, more preferably 1-15, and particularly preferably 1-10.

  When the polylactic acid according to the present invention is composed of multi-branched polylactic acid (multi-branched polylactic acid) and has a functional group such as a carboxyl group at the end of each branch, an anti-inflammatory ligand that binds to this functional group Since it is possible to introduce a plurality, it is possible not only to sequentially suppress the inflammatory reaction caused by the degradation product generated by the decomposition, but also to suppress even restenosis.

  The weight average molecular weight of the polylactic acid according to the present invention is preferably 1,000 to 1,000,000, more preferably 2,000 to 500,000, and particularly preferably 3,000 to 400,000. Examples of the method for measuring the weight average molecular weight include GPC, light scattering method, viscosity measurement method, mass spectrometry (TOFMASS and the like), and the polylactic acid according to the present invention preferably measures the weight average molecular weight by GPC. .

  The anti-inflammatory ligand according to the present invention is the M3 polypeptide of SEQ ID NO: 2 or a polypeptide having anti-inflammatory properties and having a homology of 80% or more with the amino acid sequence of the M3 polypeptide of SEQ ID NO: 1. Are preferred, with M3 polypeptides being particularly preferred.

  When the anti-inflammatory ligand according to the present invention is a polypeptide having 80% or more homology with the amino acid sequence of the M3 polypeptide (derived from SEQ ID NO: 1) of SEQ ID NO: 1, an active site having an anti-inflammatory effect remains. However, an amino acid having a site capable of easily binding to polylactic acid and the original amino acid residue of the M3 polypeptide can be exchanged.

  Moreover, when M3 polypeptide of sequence number 2 is used, it is excellent in an anti-inflammatory action, and it becomes possible to suppress the inflammatory reaction produced by a decomposition product. The M3 polypeptide (see FIGS. 7 and 8) is as follows.

  The viral protein known as M3 according to the present invention was originally isolated from gammaherpesvirus 68 (γHV68). Based in part on the discovery that this M3 protein binds to various biologically relevant compounds in the human body and mediates an anti-inflammatory and / or immunomodulatory role when administered in vivo. Yes. One such protein within the γHV68 genome, the M3 protein, is encoded by the third open reading frame of γHV68 and consists of 406 amino acid residues (VirginH.W. et al., Complete Sequence and genomic analysis of murine gammaherpesvirus 68, J. Virol., 71 (8): 5894 to 904 (1997)). This gene is located between nucleotide positions 6060 and 7277 in the γHV68 genome.

  The M3 polypeptide is characterized by a method of immunomodulation in mammals by administration of a therapeutically effective amount of M3 polypeptide to the mammal, and the polypeptide has an immunomodulatory action in mammals. In another aspect, the invention also relates to a cell in which the M3 gene is expressed in a construct capable of delivering an amount of M3 protein effective to reduce inflammation or inhibit an autoimmune response, wherein M3 It features an immunomodulatory method associated with providing the M3 gene under the control of a promoter that provides controllable expression of the gene.

  M3 polypeptides are also characterized by methods for inhibiting hyperplasia in mammals. For example, in response to vascular injury, chemokines are upregulated upon restenosis, leading to recurrent atheroma growth. The method comprises administering to a mammal having intimal hyperplasia a therapeutically effective amount of M3 polypeptide so as to inhibit intimal hyperplasia.

As used herein, “chemokine” means a low molecular weight ligand that is a chemoattractant for leukocytes (eg, neutrophils, basophils, monocytes, and T cells), and It is important in the infiltration of lymphocytes and monocytes to the site of inflammation. The term “chemokine” all mediates the recruitment and infiltration of leukocytes into tissues. It is known as a chemotactic cytokine expressed in mammals. The term “chemokine” is classified based on the distribution of cysteine residues therein and includes all mammalian members of the C, CC, CXC, and CX ₃ C families of chemotactic cytokines. It is not limited to.

  The method for introducing the M3 polypeptide into polylactic acid is not particularly limited. For example, a method of chemically bonding the M3 polypeptide to a lactic acid monomer or dimer unit and growing the monomer or dimer, An example is a method of first synthesizing polylactic acid and then chemically bonding the M3 polypeptide. Specifically, a method in which polylactic acid in which at least one terminal is modified with a carboxyl group and an N-terminal amino group of M3 polypeptide are reacted and bonded via an amide bond, or the carboxy terminal of polylactic acid is hydroxylated. A method in which capping with succinimide and subsequent reaction with M3 polypeptide to remove the protecting group is preferably used.

  The rate of introduction of the M3 polypeptide into the polylactic acid in the polylactic acid complex according to the present invention (the number of carboxyl groups bonded to the M3 polypeptide relative to the total carboxyl groups of the terminal groups of polylactic acid) is 1 to 90% is preferable, 1 to 80% is more preferable, and 1 to 50% is particularly preferable.

  If the introduction rate is less than 1%, the effect (inhibition of inflammation) as an M3 polypeptide may not be sufficiently exerted, and if the introduction rate exceeds 90%, the original mechanical strength of polylactic acid cannot be maintained. there is a possibility.

The amount of polylactic acid in the polylactic acid complex according to the present invention is preferably 1 to 99% by mass, more preferably 5 to 80% by mass, and particularly preferably 10 to 70% by mass with respect to the total polylactic acid complex.
If the amount of polylactic acid is less than 1% by mass, the strength of the polylactic acid composite may not be sufficiently maintained. Further, if the amount of polylactic acid exceeds 99% by mass, the effect (inhibition of inflammation) as the M3 polypeptide may not be sufficiently exhibited.

  The polylactic acid composite according to the present invention is preferably deformed under pressure. This is because when polylactic acid is deformed under pressure or stretched, it has better mechanical strength than unstretched one, so it has a high radial force and can be reliably placed in the lesion. In addition, when the second component described later is contained in polylactic acid, it is possible not only to impart plasticity to polylactic acid, which is a hard and brittle material, but also to impart strain residual property that the applied strain remains as it is. it can. This makes it possible to produce a balloon expandable stent while being a polymer.

  The pressure deformation according to the present invention can be carried out, for example, by putting a pellet-like polylactic acid complex into a kneading apparatus and melting and kneading it in the range of 180 to 250 ° C.

  In the in vivo indwelling material according to the present invention, it is preferable that a physiologically active substance and / or a biodegradable polymer is attached to at least a part of the in vivo indwelling material. That is, the in-vivo indwelling material according to the present invention preferably has a structure in which a biologically-active substance and / or a biodegradable polymer is attached to at least a part of the in-vivo in-vivo body. .

  In this case, the physiologically active substance and / or the biodegradable polymer may be attached inside the in-vivo indwelling body or outside. That is, the term “attachment” as used in the present specification means that the physiologically active substance is embedded in the body of the in-vivo indwelling body or the physiologically active substance is dispersed in the body of the in-vivo indwelling body. In other words, the term includes a case where a layer containing a physiologically active substance and / or a biodegradable polymer is formed on the outer surface of the in-vivo indwelling body.

  Thereby, after the in-vivo indwelling object according to the present invention is placed in the lesioned part in the living body, the biodegradable polymer layer is decomposed in the living body to release the physiologically active substance, thereby suppressing vascular restenosis. Furthermore, since the in-vivo indwelling material according to the present invention includes a polylactic acid complex into which an anti-inflammatory ligand is introduced, the in-vivo indwelling material itself is viable due to the biodegradability of the polylactic acid complex itself. Inflammatory reactions can be suppressed by anti-inflammatory ligands that are absorbed and introduced in the body.

  The in-vivo indwelling material according to the present invention may be formed from the polylactic acid complex according to the present invention, or may be a biodegradable polymer, a physiologically active substance or other composition that does not degrade in vivo (hereinafter referred to as “the present invention”). A layer made of the polylactic acid complex may be formed on the surface of the non-degradable composition of the present invention). Examples of the non-degradable composition in vivo of the present invention include stainless steel (SUS316L), Metal materials such as Ni-Ti alloy, tantalum, nickel, chromium, iridium, tungsten, cobalt-based alloy, ceramics, etc. may be used and are appropriately selected depending on conditions such as the site where the in-vivo indwelling material is used. It is a polylactic acid complex according to the present invention. If formed using the biodegradable polymer of the present invention, the entire indwelling material of the present invention is degraded in vivo after a lapse of a certain period of time. There is an effect that it is possible to prevent an adverse effect on the patient without re-operation. For example, when the in-vivo indwelling object according to the present invention is used as a balloon-expandable stent, it is easily expanded because it is excellent in flexibility and plastically deforms at room temperature, and hardly recoils after balloon expansion. In addition, as a method of forming a layer made of the polylactic acid complex on the surface of the biodegradable polymer or other in vivo non-degradable composition of the present invention, the polylactic acid complex of the present invention is mixed with alcohol (methanol). , Ethanol, propanol, etc.), and then directly applied to the surface of the biodegradable polymer and other non-degradable in vivo compositions of the present invention or sprayed. It is done.

  The biodegradable polymer, physiologically active substance and in vivo non-degradable composition of the present invention can be used alone or in the form of a mixture of two or more, or one of these. The above may be used in combination.

  As the biodegradable polymer, for example, those having high biostability are preferable, for example, polylactic acid, polylactic acid stereocomplex, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid. It is preferably at least one selected from the group consisting of poly-α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, polycaprolactone, and decomposes in vivo Considering the above, a medically safe one is preferable. Of these, polylactic acid is most preferably used.

  The physiologically active substance according to the present invention is not particularly limited as long as it has an effect of suppressing restenosis when a living indwelling object is placed in a lesioned part of a lumen, for example, an anticancer agent, an immunosuppressive agent, Antibiotics, anti-rheumatic agents, antithrombotic agents, HMG-Co reductase inhibitors, ACE inhibitors, calcium antagonists, antihyperlipidemic agents, anti-inflammatory agents, integrin inhibitors, antiallergic agents, antioxidant agents, GPIIbIIIa antagonist, retinoid, flavonoid, carotenoid, lipid improver, DNA synthesis inhibitor, tyrosine kinase inhibitor, antiplatelet drug, vascular smooth muscle growth inhibitor, anti-inflammatory drug, bio-derived material, interferon and NO production promoter, etc. Is mentioned.

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

  Examples of the immunosuppressant include sirolimus, everolimus, pimecrolimus, sirolimus derivatives such as ABT-578, AP23573, and CCI-779, tacrolimus, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, gusperimus, mizoribine, and the like. preferable.

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

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

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

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

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

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

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

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

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

  As said antioxidant, (alpha) -tocopherol is preferable, for example.

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

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

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

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

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

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

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

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

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

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

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

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

  Whether the physiologically active substance is a single type of physiologically active substance or a combination of two or more different physiologically active substances should be appropriately selected according to the case.

  The in-vivo indwelling material according to the present invention may further include a melt-kneaded second component. Or it is preferable that the in-vivo indwelling object which concerns on this invention contains the 2nd component which consists of polyester.

  By including the second component composed of the above-mentioned melt-kneaded second component or polyester in the in vivo indwelling material according to the present invention, the toughness of the in vivo indwelling material, improvement in flexibility, glass transition temperature Can be improved or reduced, moisture permeability, hydrophilicity and water repellency can be improved, and degradation can be improved or suppressed.

  As used herein, the “second component” refers to components other than the polylactic acid complex (polylactic acid into which an anti-inflammatory ligand is introduced), a biodegradable polymer, and a physiologically active substance. The above-described polylactic acid complex (in which an anti-inflammatory ligand is introduced into polylactic acid), a biodegradable polymer, and a physiologically active substance are also referred to as a first component in the present specification.

  The material of the second component according to the present invention preferably has a mechanical property that breaks at an elongation of 200% or more. Since the material of the second component according to the present invention has a mechanical property of breaking at an elongation of 200% or more, the in-vivo indwelling material according to the present invention containing the second component constituting this material has high flexibility. Have

  The measurement of breaking at an elongation of 200% or more, which is the mechanical property of the material of the second component according to the present invention, can be performed by a known method. Specifically, based on JISK-7113, 1/5. A tensile test was performed by punching out a No. 2 test piece of the scale.

  Examples of the second component include at least one selected from the group consisting of polybutylene succinate, polypropylene succinate, polybutylene succinate adipate, and polycaprolactone.

  The apparatus for kneading the second component of the present invention is not particularly limited as long as it can shear-knead each of the above components. For example, an extruder, a Banbury mixer, a roller, and a kneader can be mentioned.

  Examples of the extruder include a screw extruder such as a single screw extruder and a twin screw extruder, an elastic extruder, a hydrodynamic extruder, a ram type continuous extruder, a roll type extruder, a gear type extruder, and the like. Can be mentioned. Among these, a screw extruder, particularly a twin screw extruder is preferable, and a twin screw extruder having one or more vents (deaeration ports) with good deaeration efficiency is more preferable. The mixing order of the components is not particularly limited. The temperature at which the second component is kneaded is preferably equal to or higher than the glass transition temperature of the second component of the present invention, and is equal to or higher than the glass transition temperature of the second component of the present invention and lower than the melting temperature. More preferred. When the kneading temperature is in such a range, it is preferable because the load on the kneading apparatus can be reduced by softening the second component of the present invention. Here, the melting temperature refers to the end point temperature of the crystal melting endothermic peak that appears during temperature rise measurement by a differential scanning calorimeter (DSC). Moreover, a glass transition point means the transition temperature calculated | required from the thermograph in the measurement by the differential scanning calorimeter based on JIS-K7121.

  1-50 mass% is preferable with respect to the polylactic acid composite based on this invention, and, as for content of the 2nd component in the in-vivo indwelling material which concerns on this invention, 1-30 mass% is more preferable. If it is in the range of 1 to 50% by mass, desired mechanical properties can be obtained. The second component according to the present invention is preferably included in the in vivo indwelling body, but mixed with a biodegradable polymer or a physiologically active substance and included in the in vivo indwelling according to the present invention. Also good.

  Hereinafter, a stent as a representative example of an in-vivo indwelling object according to the present invention will be described in detail based on a preferred form shown in the accompanying drawings. Note that the range of the in-vivo indwelling device according to the present invention is not limited to the stent shown in the drawings, and it goes without saying that artificial blood vessels and artificial organs are included. When the in-vivo indwelling object according to the present invention is a stent, the in-vivo indwelling body corresponds to the stent body 2.

  1 is a front view showing an embodiment of a stent according to the present invention, FIGS. 2, 4 and 6 are enlarged cross-sectional views taken along line AA in FIG. 1, and FIGS. It is the partial expanded longitudinal cross-sectional view cut | disconnected along 1 line BB.

  In FIG. 1, a stent 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 1 is composed of a linear member C and has a substantially rhombic element D having a notch therein as a basic unit. A plurality of substantially diamond-shaped elements D form an annular unit E by arranging and combining substantially diamond-shaped elements continuously in the minor axis direction. The annular unit E is connected to an adjacent annular unit via a linear connecting member F. Accordingly, the plurality of annular units E are continuously arranged in the axial direction in a partially coupled state. With such a configuration, the stent body 2 (stent 1) has a cylindrical body that opens at both ends and extends in the longitudinal direction between the ends. The stent 1 (stent body 2) has a substantially diamond-shaped notch, and has a structure that can be expanded and contracted in the radial direction of the cylindrical body by deformation of the notch.

  The stent body 2 shown above is only one aspect, and both end portions are open, and are cylindrical bodies extending in the longitudinal direction between the both end portions. It has a large number of notches that communicate with the inner surface, and a wide range of structures that can expand and contract in the radial direction of the cylindrical body by deforming the notches.

  The shape of the in-vivo indwelling material according to the present invention is preferably tubular, net-like, fiber-like, coiled, non-woven fabric, woven fabric, or filament-shaped, and more specifically, in-vivo indwelling material according to the present invention. The shape is tubular, net-like, coiled, or the indwelling is manufactured from a non-woven fabric, woven fabric or filament containing polylactic acid composite. That is, the shape of the stent body 2 is not particularly limited as long as it has a degree sufficient to be stably placed in a lumen in a living body. For example, those obtained by knitting fibers of a polymer material into a cylindrical shape, and those obtained by providing pores in a tubular body made of these polymer materials are preferable.

  As described above, in the in vivo indwelling material according to the present invention, it is preferable that a physiologically active substance and / or a biodegradable polymer is attached to at least a part of the in vivo indwelling material. The same applies to the case where the indwelling material is a stent. In this case, the physiologically active substance and / or the biodegradable polymer may be attached inside or outside the stent body. An example in which the active substance and / or biodegradable polymer is attached to the outside of the stent body is shown in FIGS. 2 to 5, and the physiologically active substance and / or biodegradable polymer is attached to the inside of the stent body. An example is shown in FIG.

  The stent which is an example of the in-vivo indwelling body according to the present invention includes a stent shown in FIG. 6 having a stent body 2 and a physiologically active substance 6 dispersed in the stent body 2, and a stent body 2 shown in FIG. A stent having a bioactive substance layer 3 provided on the surface of the stent body 2 and a biodegradable polymer layer 4 covering the bioactive substance layer, the stent body 2 shown in FIG. Examples include a stent having a bioactive substance 6 dispersed in a biodegradable polymer layer 5 so as to cover the surface of the stent body 2.

  More specifically, as shown in FIG. 2, the stent according to the present invention includes a stent main body 2 (which may include the second component as necessary) including the polylactic acid composite of the present invention, and the stent main body 2. And a layer 3 containing a bioactive substance and containing a biodegradable polymer on the surface of the layer 3 containing the physiologically active substance (which may contain the second component as necessary). A stent in which the above-mentioned second component may be included if necessary) is preferable.

  Although the diameter of said stent main body 2 is suitably selected according to conditions, such as a usage method and an indwelling place of a stent, 1-10 micrometers is preferable, for example, and 1-5 micrometers is more preferable.

  The thickness of the layer 3 formed on the surface of the stent body 2 and containing the physiologically active substance significantly improves the performance of the stent body 2 such as reachability to the lesion (delivery property) and irritation to the blood vessel wall. Since it should be set at a thickness that does not impair and the effect of the physiologically active substance is confirmed, it is preferably in the range of 1 to 100 μm, more preferably 1 to 50 μm, and most preferably 1 to 20 μm. .

  The thickness of the layer 4 containing the biodegradable polymer on the surface of the layer 3 containing the physiologically active substance is the same as that of the physiologically active substance layer 3 such as delivery to the lesioned part and irritation to the blood vessel wall. Since it should be set to such an extent that the performance of the main body 2 is not significantly impaired, it is preferably 1 to 75 μm, more preferably 1 to 25 μm, and most preferably 1 to 10 μm.

  Moreover, as shown in FIG. 4, the stent according to the present invention is provided on the surface of a stent main body (which may include the second component as necessary) containing the polylactic acid composite of the present invention and the in-vivo indwelling body. A stent which is formed and has a layer containing a physiologically active substance and a biodegradable polymer (which may contain the second component as necessary) is preferable.

  Although the diameter of said stent main body 2 is suitably selected according to conditions, such as a usage method and an indwelling place of a stent, 1-10 mm is preferable, for example, and 1-5 mm is more preferable.

  The thickness of the layer 5 formed on the surface of the stent body 2 and containing a physiologically active substance and a biodegradable polymer is appropriately selected depending on the method of using the stent, and is, for example, 1 to 100 μm. Is preferable, and 1 to 40 μm is more preferable.

  As shown in FIG. 6, in the stent according to the present invention, it is preferable that a physiologically active substance is embedded or dispersed in the stent body.

  Although the diameter of said stent main body 2 is suitably selected according to conditions, such as a usage method and an indwelling place of a stent, 1-10 mm is preferable, for example, and 1-5 mm is more preferable.

  The stent body 2 according to the present invention may be either a balloon expansion type or a self-expansion type. Further, the size of the stent body may be appropriately selected according to the application location.

  The thickness of the stent according to the present invention (herein, the thickness of the stent refers to the thickness of the linear member itself constituting the stent) has a radial force necessary for placement in the lesioned part. Although it will not specifically limit if it is a grade which does not inhibit a blood flow, The range of 1-1000 micrometers is preferable, The range of 10-500 micrometers is more preferable, The range of 40-200 micrometers is the most preferable.

  The method for providing the layer 3 containing a physiologically active substance on the surface of the stent body 2 is not particularly limited. For example, the method of melting the physiologically active substance and coating the surface of the stent body 2 or dissolving the physiologically active substance in a solvent The stent body 2 is immersed in this solution and then pulled up, and then the solvent is evaporated or otherwise removed, or the solution is sprayed onto the stent body 2 using a spray, For example, a method of removing the water by transpiration or other methods.

  In addition, when the solvent for easily dissolving the physiologically active substance according to the present invention can easily wet the surface of the stent body 2, the stent body is added to the solution in which only the physiologically active substance is dissolved in the solvent. The method of immersing and drying 2 or the method of spraying the solution onto the stent body 2 by spraying and drying is the simplest and most preferably applied.

  Examples of the solvent include acetone and THF. However, the solvent is not necessarily limited thereto, and any solvent that can dissolve the physiologically active substance of the present invention can be applied to the present invention.

  The method for providing the biodegradable polymer film layer 4 on the surface of the stent body 2 is not particularly limited. For example, a method of melting the biodegradable polymer and coating the surface of the stent body 2 is also possible. A polymer is dissolved in a solvent to prepare a solution, and the stent body 2 is immersed in this solution, and then pulled up, and the solvent is evaporated or otherwise removed, or the solution is removed by using a spray. And a method of removing the solvent by transpiration or other methods.

  Further, when the solvent that easily dissolves the biodegradable polymer can easily wet the surface of the stent body 2, the stent body is added to the solution in which only the biodegradable polymer is dissolved in the solvent. The method of immersing and drying 2 or the method of spraying the solution onto the stent body 2 using a spray and drying is the simplest and most preferably applied.

  The polymer forming the biodegradable polymer layer 5 is not particularly limited as long as it is polylactic acid, but is preferably highly biostable, and is preferably medically safe in view of degrading in vivo. Among them, D, L-polylactic acid is optimally used as the most preferable copolymer, but it is appropriately determined according to the required mechanical property value or the release rate or biodegradation rate of the desired physiologically active substance. Is to be done.

  The method for embedding or dispersing the physiologically active substance 6 in the stent bodies 2 to 5 is not particularly limited, but a method that can be easily produced is preferable, for example, a method of kneading together at the time of melt molding, And a method of mixing a physiologically active substance. Thereby, the bioactive substance can be released together with the biodegradation, and the inflammatory reaction accompanying the biodegradation of the stent body can be suppressed by the bioactive substance.

  Eventually, the physiologically active substance is dissolved in and diffused into the biodegradable polymer film layer 4 by the bioactive substance 3 or the biodegradable polymer film layer 5 is decomposed in vivo. It is preferable that the active substance 6 is released into the living body, and further, all the indwelling objects disappear due to the decomposition of the stent body 2 in the living body.

Hereinafter, although one form of the manufacturing method of the stent which concerns on this invention is described, the scope of the present invention is not limited to this.
(Synthesis of polylactic acid complex)
First, polylactic acid whose terminal is carboxylated in advance is dissolved in a methylene chloride solvent. Then, hydroxysuccinimide is reacted at room temperature in the presence of dicyclohexylcarboimide. By this reaction, the terminal of polylactic acid is substituted (capped) with hydroxysuccinimide. And after changing a solvent to THF, M3 polypeptide is made to react at room temperature. By this reaction, hydroxysuccinimide is substituted with M3 polypeptide, and an amide bond is formed between polylactic acid and M3 polypeptide to obtain a polylactic acid complex according to the present invention.
(Stent body manufacturing method)
First, the polylactic acid composite of the present invention prepared by the above method, if necessary, the second component of the present invention, the biodegradable polymer of the present invention, and the physiologically active substance of the present invention are injected into an injection molding machine, an extrusion molding machine, a press Using a molding machine, a vacuum molding machine, a blow molding machine or the like, a pipe having a predetermined thickness and outer shape is formed. And an opening pattern is affixed on the pipe surface, and pipe parts other than this opening pattern are melted by etching techniques such as laser etching and chemical etching to form openings. Alternatively, the opening can be formed by cutting the pipe according to the pattern by a laser cutting technique based on the pattern information stored in the computer.

  In addition, for example, in the case of a coiled stent, the polylactic acid composite of the present invention, if necessary, the second component of the present invention, the biodegradable polymer of the present invention, and the physiologically active substance of the present invention are extruded. It is used as a wire having a predetermined thickness and outer shape. Then, after the wire is bent to form a wave pattern or the like, the wire is spirally wound on the mandrel, and then the mandrel is extracted and the shaped wire is cut into a predetermined length. .

When a physiologically active substance and / or biodegradable polymer is attached to the inside of the stent body, the polylactic acid complex of the present invention, the biodegradable polymer of the present invention, and the physiologically active substance of the present invention (necessary After kneading or melting the second component of the present invention, a pipe having a predetermined thickness and outer shape is formed using an extruder or the like, but the other methods are the same as described above.
(Method of attaching physiologically active substance and / or biodegradable polymer to the stent body)
<When bioactive substances and / or biodegradable polymers are attached to the outside of the stent body>
First, in the stent body produced by the method shown above, the physiologically active substance of the present invention, the biodegradable polymer of the present invention, and if necessary, the second component of the present invention are dissolved in a solvent such as acetone, It is applied or sprayed by a conventional method using a spray, a dispenser or the like, or the stent body is immersed. Then, the solvent is volatilized.

  Alternatively, the physiologically active substance of the present invention is dissolved in a solvent such as acetone and applied by a conventional method using a spray, a dispenser or the like, and then the solvent is volatilized. And the biodegradable polymer of this invention is similarly melt | dissolved in acetone etc., it apply | coated by the same method, and a solvent is volatilized.

Here, before applying the physiologically active substance of the present invention, the biodegradable polymer of the present invention, and a mixture thereof to the stent body, the surface of the stent body of the present invention is chemically treated or plasma is used. It is preferable to perform an operation such as etching to form fine irregularities on the surface. This is because adhesion between the stent body of the present invention and the physiologically active substance of the present invention, the biodegradable composition of the present invention, and a mixture thereof is improved.
For the same reason, an adhesive or the like may be applied to the surface of the stent body of the present invention, the stent body of the present invention, the bioactive substance of the present invention, the biodegradable polymer of the present invention, and a mixture thereof. May be thermally bonded. By such a method, the stent of the present invention can be manufactured. In addition, when attaching a physiologically active substance and / or biodegradable polymer to the exterior of a stent main body, since it has described with the manufacturing method of said stent main body, it abbreviate | omits here.

  Hereinafter, the present invention will be specifically described based on examples. The following example shows only one preferred embodiment of the present invention, and it goes without saying that the present invention is not limited thereto.

  Mouse 3T12 fibroblasts were infected with a WUMS strain in DMEM supplemented with γHV68 virus for 1 hour at a multiplicity of infection of 5, then the monolayer was washed with PBS and DMEM containing fresh 10% FCS was added. Further, the cells were infected at 37 ° C for 8 hours. Then, it was washed with monolayer PBS, and fresh FCS-free DMEM was added to infect at 37 ° C. for 20 hours. The culture supernatant was passed through a 0.2 μM filter, concentrated 120 times at 4 ° C., and centrifuged at 150,000 × g for 3 hours to remove the virus-free residue to obtain an M3 polypeptide. This M3 polypeptide concentrate was measured by silver-stained 12.5% acrylamide concentration using a known amount of M3 protein expressed in purified bacteria as a standard.

  Polylactic acid having a carboxylated terminal (100D040A manufactured by API) is dissolved in a methylene chloride solvent, and hydroxysuccinimide is reacted at room temperature in the presence of dicyclohexylcarbodiimide, and then the above M3 polypeptide is converted to room temperature using THF as a solvent. To synthesize M3 polypeptide grafted polylactic acid. The polymer was press-molded at 200 ° C. to obtain a sheet having a thickness of 150 μm. The sheet was cut into a size of 50 mm × 7 mm, and rolled and inserted into a PTFE shrink tube having a diameter of 2.4 mm and a length of 60 mm. Furthermore, when a 70 mm long PTFE tube (AWG-17 manufactured by Chukoh) is inserted into the tube and heated in an oven preheated to 200 ° C. for 1 hour, a pipe having a diameter of 2.1 mm and a wall thickness of 150 μm is obtained. At the same time, annealing was performed. The pipe was processed into a stent shape by an excimer laser (Sumitomo Heavy Industries SPL400H).

  This stent was percutaneously placed in the left and right iliac arteries of a rabbit for 9 months and imaged. As a result,% DS (stent inner diameter stenosis ratio) was 36.2, and no significant stenosis was observed.

(Comparative Example 1)
Polylactic acid having a terminal carboxylated (100D040A manufactured by API) was press-molded by the same method as in Example 1 to obtain a pipe having a diameter of 2.1 mm and a wall thickness of 150 μm, and simultaneously annealed. The pipe was processed into a stent shape with an excimer laser (SPL400H, manufactured by Sumitomo Heavy Industries).

This stent was percutaneously placed in the right and left intestinal arteries of a rabbit for 9 months, and the imaging results were obtained.
As a result,% DS (stent inner diameter stenosis ratio) was 73.8, and stenosis that was thought to be caused by the inflammatory reaction of polylactic acid was observed.

It is a front view which shows the one aspect | mode of the stent of this invention. FIG. 2 is an enlarged view of an enlarged cross-sectional view taken along line AA in FIG. 1. It is the one aspect | mode of the expanded cross-sectional view cut | disconnected along line BB of FIG. FIG. 2 is an enlarged view of an enlarged cross-sectional view taken along line AA in FIG. 1. It is the one aspect | mode of the expanded cross-sectional view cut | disconnected along line BB of FIG. FIG. 2 is an enlarged view of an enlarged cross-sectional view taken along line AA in FIG. 1. The base sequence of M3 polypeptide based on this invention. The amino acid sequence of the M3 polypeptide according to the present invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Stent 2 Stent body 3 Layer containing bioactive substance 4 Layer containing biodegradable polymer 5 Biodegradable polymer 6 Bioactive substance C Linear member D Element of substantially rhombus E Ring unit F Connecting member

Claims (16)

  An in-vivo indwelling material for in-vivo indwelling, wherein the in-vivo indwelling material includes a polylactic acid complex in which an anti-inflammatory ligand is introduced into polylactic acid.   The in vivo indwelling material according to claim 1, wherein the polylactic acid is at least one selected from the group consisting of linear polylactic acid, hyperbranched polylactic acid, polylactic acid dendrimer, and polylactic acid star polymer.   The anti-inflammatory ligand is the M3 polypeptide of SEQ ID NO: 2 or a polypeptide having anti-inflammatory properties and having 80% or more homology with the amino acid sequence of the M3 polypeptide of SEQ ID NO: 1. 2. The in-vivo indwelling material according to 2.   The in-vivo indwelling product according to any one of claims 1 to 3, wherein the polylactic acid complex into which the anti-inflammatory ligand is introduced is pressure-deformed.   The in vivo indwelling material according to any one of claims 1 to 4, wherein a physiologically active substance and / or a biodegradable polymer is further attached to at least a part of the in vivo indwelling material. A layer containing a physiologically active substance formed on the surface of the in-vivo indwelling object,
The in vivo indwelling material of any one of Claims 1-5 which further has a layer containing the biodegradable polymer formed in the surface of the layer containing the said bioactive substance.   The in vivo indwelling material according to any one of claims 1 to 6, wherein a physiologically active substance is embedded or dispersed in the in vivo indwelling material. The in-vivo indwelling material according to any one of claims 5 to 7, further comprising a layer formed on a surface of the in-vivo indwelling material and including a physiologically active substance and a biodegradable polymer.   The shape of the in-vivo indwelling device according to any one of claims 1 to 8 is tubular, net-like, coiled, fibrous, non-woven fabric, woven fabric, or filament shape. The in-vivo indwelling article of 1 item | term.   The physiologically active substances include anticancer agents, immunosuppressive agents, antibiotics, anti-rheumatic agents, antithrombotic agents, HMG-Co reductase inhibitors, ACE inhibitors, calcium antagonists, antihyperlipidemic agents, anti-hyperlipidemic agents, Inflammatory agent, integrin inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid, flavonoid, carotenoid, lipid improver, DNA synthesis inhibitor, tyrosine kinase inhibitor, antiplatelet agent, vascular smooth muscle growth inhibitor, The in vivo indwelling material according to any one of claims 5 to 9, which is at least one selected from the group consisting of an anti-inflammatory drug, a biological material, an interferon, and a NO production promoting substance.   The biodegradable polymer is polylactic acid, polylactic acid stereocomplex, polyglycolic acid, polylactic acid and polyglycolic acid copolymer, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin, heparan sulfate. The in vivo according to any one of claims 5 to 10, which is at least one selected from the group consisting of fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, and polycaprolactone, or a copolymer thereof. Detainment.   The in vivo indwelling material according to any one of claims 1 to 11, wherein the in vivo indwelling material according to any one of claims 1 to 11 contains a melt-kneaded second component.   The in-vivo indwelling material of Claims 1-12 contains the 2nd component which consists of polyester, The in-vivo indwelling material of any one of Claims 1-12.   The in-vivo indwelling object according to claim 12 or 13 in which the material of said 2nd ingredient has the mechanical characteristic which fractures by 200% or more of elongation.   15. The second component according to any one of claims 12 to 14, wherein the second component is at least one selected from the group consisting of polybutylene succinate, polypropylene succinate, polybutylene succinate adipate, and polycaprolactone. In vivo indwelling material.   The in-vivo indwelling object of Claims 1-15 is a in-vivo indwelling object which is a stent.

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