JP6068921B2 - Manufacturing method of drug eluting device - Google Patents

Description

  The present invention relates to a medical device such as a stent or an expandable catheter used by being placed in a living body, and particularly a drug coated with biocompatible nanoparticles in which a bioactive substance is encapsulated in a biocompatible polymer. The present invention relates to a method for manufacturing an elution device.

  In recent years, with lifestyles becoming western and aging, arteriosclerotic diseases such as myocardial infarction, angina pectoris, stroke and peripheral vascular disease are increasing more and more in Japan. As a reliable treatment method for such arteriosclerotic diseases, for example, a stenosis or occlusion of a blood vessel such as percutaneous coronary angioplasty (hereinafter referred to as PTCA) in the coronary artery of the heart is surgically treated. Percutaneous intervention that opens up is widespread.

  PTCA is a narrow tube (catheter) with a balloon at the tip inserted from the artery of the arm or thigh and passed through the stenosis of the heart coronary artery. It is a technique to restore blood flow by pushing the spread. This dilates the vascular lumen of the lesion, thereby increasing blood flow through the vascular lumen.

  In recent years, a medical device called a stent that is placed in a stenosis portion in a lumen such as a blood vessel, a trachea, an esophagus, or a urethra to maintain an open state has been used. This stent is inserted into the target site in a contracted state that is folded in a small size, then the stress that maintains the contraction is removed, and the stent expands in the radial direction by the restoring force of the stent itself, and is firmly fixed to the inner surface of the living organ. There are a self-expanding type and a balloon expansion type in which the stent is expanded by the expansion force of the balloon disposed in the stent. However, the present situation is that restenosis cannot be sufficiently suppressed only by placing a stent in the stenosis.

  In general, a blood vessel site subjected to PTCA or stent placement is damaged such as endothelial cell detachment or elastic plate damage, and the biological healing response to these is relatively long (about 2 months after stent placement). It is believed that. More specifically, the cause of restenosis in humans is mainly due to the inflammation process seen in the adhesion and infiltration of monocytes that occurs 1 to 3 days after PTCA or stent placement, and smoothness that peaks most proliferatively after about 45 days. The process of intimal thickening by muscle cells is considered.

  Therefore, by using a drug-eluting device in which an anti-inflammatory agent or smooth muscle cell growth inhibitor is supported on the surface of a stent or catheter formed of a metal or a polymer material, it can be used for a long time at an indwelling site in the lumen. There have been many attempts to reduce the restenosis rate by locally releasing the drug.

  Here, since smooth muscle cell proliferation is the main cause of restenosis, the smooth muscle cell proliferation inhibitory treatment is performed from the 30th day when smooth muscle cell proliferation is confirmed in the intima from the pathological findings to 45 days when the proliferation peak is reached. It is judged that it is the most effective to perform. Therefore, at least within 10 days for suppressing the inflammatory process and 30 to 60 days for suppressing smooth muscle cell proliferation, there is a peak in the amount of drug released, and the amount of drug necessary to show the drug efficacy in each period is 10,000. It is considered to be most effective to design it so that it can be released evenly.

  Therefore, a drug-eluting stent capable of efficiently reaching a physiologically active substance into cells and having excellent handleability and a simple and inexpensive manufacturing method thereof have been proposed. Patent Document 1 discloses a physiologically active substance. A method for producing a drug-eluting stent is disclosed in which a biocompatible nanoparticle encapsulated with a positive charge is electrically attached to a stent body to form a nanoparticle layer.

  The drug-eluting stent manufactured by the method of Patent Document 1 is coated with biocompatible nanoparticles that are encapsulated with a high entrapment rate and excellent in cell migration, thereby bringing the bioactive substance into the cell. It can be reached efficiently. However, the strength of the nanoparticle layer in practical use was slightly insufficient only by electrically attaching the nanoparticles to the stent body.

  Therefore, in Patent Document 1, after the nanoparticle layer is formed, an impregnation step of impregnating the biodegradable polymer solution is provided before the nanoparticle layer is completely dried, and then the nanoparticle layer is dried and biodegraded. The polymer is solidified. As a result, the individual nanoparticles forming the nanoparticle layer are held without being aggregated by the biodegradable polymer. After the stent is placed in the living body, the nanoparticle is decomposed by the decomposition of the biodegradable polymer layer. Is gradually eluting.

  However, even if the impregnation step is provided as described above, due to the external force applied to the stent such as friction with the inner wall of the blood vessel when moving the stent to the diseased site in the blood vessel and deformation when expanding after reaching the diseased site The biodegradable polymer layer cracks, and the nanoparticle layer is peeled off from the stent body.

  As a method for firmly forming a layer containing a physiologically active substance on the surface of a device body such as a stent or a catheter, for example, Patent Document 2 discloses a step of applying a polymer component and a solvent to the surface of an implantable medical device; And a step of heating to a temperature equal to or higher than the glass transition temperature of the implantable medical device. Patent Document 3 discloses a method for producing an intraluminal device in which a metal anchor substrate having a thickness of 500 mm or less is formed by plasma treatment of a metal substrate, and a polymer matrix containing a therapeutic agent is coated thereon. Is disclosed.

JP 2009-131672 A Special table 2008-500116 gazette Special table 2009-539431

  However, since the method of Patent Document 2 is heated to a temperature equal to or higher than the glass transition temperature of the polymer component, there is a possibility that bioactive substances and additives are decomposed, deactivated, and modified. In addition, the method of Patent Document 3 requires a process for plasma-treating a metal substrate, which complicates the manufacturing process, and further requires a plasma generator and the like, resulting in high equipment costs.

  In view of the above-mentioned problems, the present invention provides a simple and inexpensive method for producing a drug-eluting device that can be easily introduced into a diseased site without the nanoparticle layer formed by coating the nanoparticles being peeled off. The purpose is to provide.

In order to achieve the above object, the first configuration of the present invention is to add a mixed solution of at least a solution of a physiologically active substance and a solution obtained by dissolving a lactic acid / glycolic acid copolymer in an organic solvent to an aqueous solution, A nanoparticle forming step for producing a suspension of biocompatible nanoparticles in which a physiologically active substance is encapsulated in the lactic acid / glycolic acid copolymer, and the biocompatible nanoparticle is a device body made of a cobalt-chromium alloy. 5 to the nanoparticle deposition step of electrically deposited thereby forming the nanoparticle layer, the device body said nanoparticle layer has been formed, the vapor of acetone can dissolve the lactic acid-glycolic acid copolymer And a post-treatment step of exposing for at least minutes .

  According to a second configuration of the present invention, in the method for manufacturing a drug-eluting device having the above-described configuration, the nanoparticle formation step is performed by dissolving a cationic polymer in an aqueous solution, whereby the particle surface is positively modified. It is characterized by producing a suspension of the biocompatible nanoparticles.

  According to a third configuration of the present invention, in the method for manufacturing a drug eluting device having the above configuration, an anionic drug is further added to the suspension of biocompatible nanoparticles.

According to a fourth configuration of the present invention, in the method for manufacturing a drug eluting device of the above configuration, the nanoparticle adhesion step is performed by any one of an electrophoresis method, an ultrasonic mist method, a spray method, or an air brush method. It is characterized by that.

According to a fifth configuration of the present invention, in the method for manufacturing a drug-eluting device having the above-described configuration, in the nanoparticle adhesion step, a nanoparticle layer is further laminated on the nanoparticle layer formed on the device body. It has the 2nd adhesion process.

According to a sixth aspect of the present invention, in the method for producing a drug-eluting device having the above-described structure, the nanoparticle attachment step is repeated a plurality of times to form biocompatible nanoparticles encapsulating different physiologically active substances. The nanoparticle layer is formed in a laminated shape or a mosaic shape.

According to the first configuration of the present invention, since the uniform nanoparticle layer is firmly formed on the device body by electrically attaching the biocompatible nanoparticles to the device body, It is possible to easily and inexpensively manufacture a drug-eluting device that can be efficiently delivered to the eye and is excellent in handleability. In addition, by providing a post-processing step in which the device body with the nanoparticle layer formed is exposed to a vapor of a volatile organic solvent capable of dissolving the biocompatible polymer for a certain period of time, the nanoparticle layer is attached to the device body. Since it adheres extremely firmly, there is no possibility that the nanoparticle layer is peeled off from the device body due to friction or deformation when the drug eluting device is introduced into the living body, and the drug eluting device is excellent in handleability. Furthermore, since the post-treatment is completed by simply exposing the device body with the nanoparticle layer formed in an organic solvent vapor for a certain period of time, it is also applicable to the use of physiologically active substances that are easily deactivated or denatured by heat. Yes, the manufacturing process can be greatly simplified. In addition, the biocompatible polymer that forms the nanoparticles is a lactic acid / glycolic acid copolymer, and by using acetone as an organic solvent used in the post-treatment process, there is no adverse effect on the living body and a highly safe drug. It becomes an elution type device. Furthermore, the nanoparticle layer of the drug-eluting device is made to have a practically no problem strength by exposing the device body made of cobalt-chromium alloy in which the nanoparticle layer is formed in acetone vapor for 5 minutes or more. Can do.

  Further, according to the second configuration of the present invention, in the method for producing the drug eluting device of the first configuration, the cationic polymer is dissolved in advance in the aqueous solution used in the nanoparticle formation step. Since the surface of the nanoparticle is modified with a positive charge, the biocompatible nanoparticle with high cell adhesiveness whose surface is modified with a positive charge can be electrically attached to the device body. As a result, the cell adhesion of the nanoparticles eluted in the living body is enhanced and the transferability into the cell is improved, so that the physiologically active substance can be delivered into the cell more efficiently.

  According to the third configuration of the present invention, in the method for manufacturing a drug eluting device of the second configuration, an anionic drug is further added to the suspension of biocompatible nanoparticles in the nanoparticle formation step. As a result, the anionic drug is attracted to and attached to the device body in a state where the anionic drug is electrostatically supported by the positive charge on the surface of the nanoparticles, and thus the anionic drug such as nucleic acid or gene that has been difficult to coat on the device body Can be produced.

Moreover, according to the fourth configuration of the present invention, in the method for manufacturing a drug eluting device having any one of the first to third configurations, the nanoparticle adhesion step is performed by electrophoresis, ultrasonic mist method, spray method. Alternatively, a uniform nanoparticle layer can be efficiently formed by a simple method by performing either of the air brush methods. Especially when using electrophoresis, it is easy to control the layer thickness by adjusting the voltage and energization time, and since the device body is a negative electrode, there is no elution of metal ions during energization and the metal material to which nanoparticles are attached The selection range of is also widened.

Further, according to the fifth configuration of the present invention, in the method for manufacturing a drug eluting device having any one of the first to fourth configurations, after the nanoparticle layer is formed on the device body, the second adhesion step is performed. By further laminating a nanoparticle layer thereon, the amount of nanoparticles to be coated can be increased and the entire nanoparticle layer on the device surface can be made uniform.

According to the sixth configuration of the present invention, in the method for producing a drug eluting device having any one of the first to fifth configurations, the nanoparticle adhesion step is repeated a plurality of times to enclose different physiologically active substances. By forming a nanoparticle layer consisting of the formed nanoparticles in a stacked or mosaic shape, nanoparticles encapsulating bioactive substances that are desired to be eluted in a short time after being placed in the living body will remain in the outer layer for a long time. If nanoparticles encapsulating a physiologically active substance to be eluted later are attached to the inner layer, the elution time of two or more kinds of physiologically active substances can be systematically controlled.

The schematic diagram which shows the structure of the nanoparticle by which the particle surface used for DES of this invention was positively charged-modified Schematic which shows an example of the electrophoresis apparatus used for manufacture of DES of this invention Cross-sectional schematic diagram showing a state in which a nanoparticle layer is formed on the metal fibers constituting the stent body Cross-sectional schematic diagram showing a state in which a biodegradable polymer layer containing nanoparticles is formed on the metal fibers constituting the stent body Schematic configuration diagram of the nanoparticle coating apparatus used in Example 2 The figure which shows the state which inserted the balloon 21a of the balloon catheter 21 in the lumen | bore of DES20 in Example 5. FIG. In Example 5, the figure which shows the state which inserted the balloon catheter 21 equipped with DES20 in the soft tube 23 The Example which shows the state which expanded the balloon 21a inserted in the lumen | bore of DES20 in the physiological saline in Example 5. FIG. Optical micrograph after the peel test of the metal plate (A) before the peel test and the metal plates (B to E) having a treatment time of 1 minute, 5 minutes, 10 minutes, and 30 minutes in Example 6.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. The method for producing a drug-eluting device of the present invention includes a step of encapsulating a lipid-soluble or hydrophilic bioactive substance and forming a surface-charged (charge-modified) biocompatible nanoparticle; A nanoparticle adhesion step in which a nanoparticle layer is formed by electrically attaching the device body to the device body, a post-treatment step in which the device body on which the nanoparticle layer is formed is exposed to a volatile organic solvent vapor for a certain period of time, Is included.

  In general, many particles dispersed in a liquid are positively or negatively charged, and a layer (fixed layer) in which ions having opposite charges are strongly attracted and fixed to the particle surface (a fixed layer) and a layer existing outside the layer A so-called diffusion electric double layer is formed with (diffusion layer), and it is presumed that a part of the inside of the diffusion layer and the fixed layer move together with the particles.

  The zeta potential is a potential of a surface (sliding surface) where the above movement occurs when the potential of an electrically neutral region sufficiently separated from the particle is used as a reference. If the absolute value of the zeta potential is increased, the repulsive force between the particles is increased and the stability of the particles is increased. Conversely, as the zeta potential approaches 0, the particles are likely to aggregate. Therefore, the zeta potential is used as an index of the dispersed state of particles.

  Therefore, in order to increase the adhesion to the negatively charged cell wall and efficiently transfer the nanoparticles into the cell, it is preferable to charge the nanoparticle surface so as to have a positive zeta potential. In the present invention, a cationic polymer is added to a poor solvent in the nanoparticle formation step (described later). Thereby, the surface of the formed nanoparticle is modified (coated) with the cationic polymer, and the zeta potential on the particle surface becomes positive. In addition, by charging the surface of the nanoparticles positively, the device main body is negatively charged, whereby the nanoparticles can be actively attached to the device main body, and the attachment efficiency of the nanoparticles can be increased.

  On the other hand, it is also possible to form nanoparticles having a negative zeta potential on the surface of the nanoparticles without adding the cationic polymer to the poor solvent. In this case, by charging the device body positively, the nanoparticles can be actively attached to the device body, and the attachment efficiency of the nanoparticles can be increased.

  Furthermore, by exposing the device body on which the nanoparticle layer has been formed in the vapor of a volatile organic solvent, the nanoparticles once attached are more firmly fixed to the device surface. In addition, it effectively prevents detachment of nanoparticles during expansion. Hereinafter, regarding a method for manufacturing a drug-eluting stent (hereinafter abbreviated as DES) as an example of the drug-eluting device of the present invention, the nanoparticle layer is formed from the step of encapsulating a physiologically active substance in the interior of the nanoparticle. The post-treatment process of the formed stent body will be described in order.

(Nanoparticle formation process)
The biocompatible nanoparticle used in the present invention is a spherical crystal that can process a physiologically active substance and a biocompatible polymer into particles having a mean particle size of less than 1,000 nm (nanosphere). It is manufactured by encapsulating a physiologically active substance inside the nanoparticles using an analysis method. Since the spherical crystallization method is a particle preparation method that does not generate a high shearing force, it can be suitably used particularly in the case where the physiologically active substance is a nucleic acid compound that is weak against external stress.

  Spherical crystallization is a method in which spherical crystal particles can be designed and processed by directly controlling their physical properties by controlling the crystal generation and growth process in the final process of compound synthesis. One of the spherical crystallization methods is an emulsion solvent diffusion method (ESD method).

  The ESD method is a technique for producing nanospheres based on the following principle. In this method, there are two types of solvents: a good solvent that can dissolve PLGA (lactic acid / glycolic acid copolymer) as a base polymer that encapsulates a physiologically active substance, and a poor solvent that does not dissolve PLGA. Is used. As this good solvent, an organic solvent such as acetone that dissolves PLGA and is mixed with the poor solvent is used. And a polyvinyl alcohol aqueous solution etc. are normally used for a poor solvent.

  As an operation procedure, first, after dissolving PLGA in a good solvent, a solution of a physiologically active substance is added and mixed in the good solvent so that the PLGA does not precipitate. When the mixed solution of PLGA and a physiologically active substance is dropped into a poor solvent while stirring, the good solvent (organic solvent) in the mixed solution rapidly diffuses and moves into the poor solvent. As a result, self-emulsification of the good solvent occurs in the poor solvent, and submicron sized good solvent emulsion droplets are formed. Furthermore, because the organic solvent continuously diffuses from the emulsion to the poor solvent due to the mutual diffusion of the good solvent and the poor solvent, the solubility of the PLGA and the physiologically active substance in the emulsion droplets decreases, and finally, PLGA nanospheres of spherical crystal particles including a physiologically active substance are generated.

  In the above spherical crystallization method, nanoparticles can be formed by a physicochemical method, and the resulting nanoparticles are substantially spherical. Therefore, it is necessary to consider the problem of catalyst and raw material compound residues from homogeneous nanoparticles. And can be easily formed. Furthermore, in the present invention, a cationic polymer is added to a poor solvent to coat the nanoparticle surface with the cationic polymer, thereby charging the particle surface positively. The structure of such nanoparticles is shown in FIG. The surface of the nanoparticles 1 is coated with polyvinyl alcohol 2 and the outside thereof is coated with a cationic polymer 4, and the cationic polymer 4 has a positive zeta potential.

  Examples of cationic polymers include chitosan and chitosan derivatives, cationized cellulose in which a plurality of cationic groups are bonded to cellulose, polyamino compounds such as polyethyleneimine, polyvinylamine, and polyallylamine, polyamino acids such as polyornithine and polylysine, and polyvinylimidazole. , Polyvinylpyridinium chloride, alkylaminomethacrylate quaternary salt polymer (DAM), alkylaminomethacrylate quaternary salt / acrylamide copolymer (DAA) and the like, and chitosan or derivatives thereof are particularly preferably used.

  Chitosan is a cationic natural polymer in which many glucosamines, one of the sugars with amino groups, contained in shrimp, crabs, and insect shells are bound. Emulsification stability, shape retention, biodegradability Since it has characteristics such as biocompatibility and antibacterial properties, it is widely used as a raw material for cosmetics, foods, clothing, pharmaceuticals and the like. By adding this chitosan into a poor solvent, highly safe nanoparticles can be produced without adverse effects on the living body.

  In addition, since the zeta potential becomes a larger positive value by using a more cationic polymer among the cationic polymers, the electric adsorption force in the nanoparticle adhesion process described later increases, The repulsive force increases and the stability of the particles in the suspension also increases. For example, a chitosan derivative such as N- [2-hydroxy-3- (trimethylammonio) propyl] chitosan having a higher cationic property by quaternizing a part of chitosan which is originally cationic ( Cationic chitosan) is preferably used.

In addition, when the physiologically active substance encapsulated in the nanoparticle is an anionic drug that exists as an anion molecule having a negative charge in an aqueous solution, the addition of a cationic polymer to the poor solvent causes the nanoparticle to enter the interior of the nanoparticle. The entrapment rate of the physiologically active substance can be increased. Normally, when the encapsulated bioactive substance is hydrophilic (water-soluble), the bioactive substance dispersed and mixed in the good solvent leaks and dissolves in the poor solvent, and only the polymer that forms the nanoparticles is deposited. to reason, the physiologically active substance is hardly sealed, the case of adding a cationic polymer in a poor solvent, an anionic drug cationic polymer adsorbed to the nanoparticle surface is present Emar di tio emission droplet surfaces It is thought that it can interact and suppress the leakage of the anionic drug into the poor solvent.

  Further, in order to improve the affinity and dispersion stability of an anionic drug in a good solvent, a cationic lipid such as DOTAP may be added to the good solvent to form a complex with the anionic drug. However, since the cationic lipid released in the cell may cause cytotoxicity, attention should be paid to the amount added.

  In the spherical crystallization method, it is also possible to form nanoparticles without adding a cationic polymer to the poor solvent. In this case, since the surface of the nanoparticle generally has a negative zeta potential, it is advantageous when the physiologically active substance encapsulated in the nanoparticle is cationic.

  The type of the good solvent and the poor solvent used in the spherical crystallization method is determined according to the type of the physiologically active substance encapsulated in the nanoparticles, and is not particularly limited. Since compatible nanoparticles are used as a material for DES placed in the human body, it is necessary to use those that are highly safe for the human body and have a low environmental impact.

  Examples of such a poor solvent include water or water to which a surfactant is added. For example, a polyvinyl alcohol aqueous solution to which polyvinyl alcohol is added as a surfactant is preferably used. Examples of surfactants other than polyvinyl alcohol include lecithin, hydroxymethylcellulose, hydroxypropylcellulose, and the like.

  Examples of good solvents include halogenated alkanes, which are low-boiling and poorly water-soluble organic solvents, acetone, methanol, ethanol, ethyl acetate, diethyl ether, cyclohexane, benzene, toluene, and the like, for example, adverse effects on the environment and the human body. Acetone, or a mixture of acetone and ethanol, is preferably used.

  The concentration of the polyvinyl alcohol aqueous solution, the mixing ratio of acetone and ethanol, and the conditions at the time of crystal precipitation are not particularly limited, and the type of target physiologically active substance, the particle size of the spherical granulated crystal (of the present invention) In the case of nano-order) etc., it may be appropriately determined, but the higher the concentration of the polyvinyl alcohol aqueous solution, the better the adhesion of polyvinyl alcohol to the nanoparticle surface, and the redispersibility in water after drying is improved, When the concentration of the polyvinyl alcohol aqueous solution exceeds a predetermined value, the viscosity of the poor solvent increases and adversely affects the diffusibility of the good solvent.

  Therefore, depending on the polymerization degree and saponification degree of polyvinyl alcohol, when the organic solvent is distilled off after nanoparticle formation and further pulverized once by freeze-drying or the like, the concentration of the polyvinyl alcohol aqueous solution is 0.1% by weight or more. It is preferably 10% by weight or less, and more preferably about 2%. In addition, when distilling an organic solvent from the suspension after nanoparticle formation and using it for a nanoparticle adhesion process as it is, it is preferable to set it as 0.5 weight% or less, and about 0.1 weight% is especially preferable.

  The biocompatible polymer used in the present invention is desirably a biocompatible polymer that has low irritation and toxicity to the living body, is biocompatible, and is decomposed and metabolized after administration. Moreover, it is preferable that it is the particle | grains which release the physiologically active substance to include continuously and gradually. In particular, PLGA can be suitably used as such a material.

  The molecular weight of PLGA is preferably in the range of 5,000 to 200,000, and more preferably in the range of 15,000 to 25,000. The composition ratio of lactic acid and glycolic acid may be 1:99 to 99: 1, but glycolic acid is preferably 0.333 with respect to lactic acid 1. PLGA having a lactic acid and glycolic acid content in the range of 25 wt% to 65 wt% is preferably used because it is amorphous and soluble in an organic solvent such as acetone.

  Other biodegradable biocompatible polymers include polyglycolic acid (PGA), polylactic acid (PLA), and the like. Moreover, you may have the group which can be charged or functionalized like an amino acid.

  When the physiologically active substance to be encapsulated is hydrophilic (water-soluble), when the surface of PLGA modified with polyethylene glycol (PEG) (hereinafter referred to as PEG-PLGA) is used, It is preferable because the affinity with PLGA is improved and encapsulation becomes easy.

  Other biocompatible polymers include cellulose and other polysaccharides, and peptides or proteins, or copolymers or mixtures thereof.

  Thereafter, the suspension of the obtained nanoparticles is used as it is, or if necessary, the organic solvent which is a good solvent is distilled off under reduced pressure (solvent distillation step), and if necessary, the nanoparticles are temporarily removed by lyophilization or the like. After being powdered, it is dispersed again in water and used in the next nanoparticle adhesion step. When the nanoparticles are used in the next step as a suspension, it is not necessary to perform lyophilization or the like, which is preferable because the production process can be simplified and the amount of polyvinyl alcohol added to the poor solvent can be reduced.

  In addition, when the nanoparticles are once powdered, if they are combined with a binder (for example, trehalose) and re-dispersed aggregated particles to form composite particles, the nanoparticles are collected before use and are easy to handle. It is preferable because the binder can be dissolved and restored to redispersible nanoparticles by touching moisture during use.

  The biocompatible nanoparticles used in the present invention are not particularly limited as long as they have an average particle diameter of less than 1,000 nm. However, in order to introduce a bioactive substance into a stenosis where a stent is placed, nanoparticles are used. It must be taken up into the cell. In order to enhance the penetration effect into the target cell, the average particle size is preferably 500 nm or less, and in particular, the nucleic acid compound is encapsulated and the nanoparticle delivered to the target site is subjected to endocytosis of the cell membrane. In order to realize a high gene expression rate by being incorporated into cells, 100 nm or less is more preferable.

  Examples of physiologically active substances encapsulated in biocompatible nanoparticles include aspirin, dipyrimidamol, heparin, antithrombin preparations, antiplatelet drugs such as fish oil, low molecular weight heparins, smooth muscle growth inhibitors such as angiotensin converting enzyme inhibitors, sulfate Vincristine, vinblastine sulfate, vindesine sulfate, irinotecan hydrochloride, paclitaxel, docetaxel hydrate, methotrexate, cyclophosphamide and other anticancer agents, mitomycin C and other anti-cancer agents, sirolimus, tacrolimus hydrate and other immunosuppressants, Anti-inflammatory drugs such as steroids, lipid-improving drugs such as cerivastatin sodium and lovastatin, plasmid DNA, genes, siRNA, vertical nucleic acid pharmaceuticals (decoy), polynucleotides, oligonucleotides, antisense oligonucleotides, ribozymes, apsetas , Interleukins, intercellular messengers (cytokines), such as the nucleic acid compound, such as Guripekku and receptor tyrosine kinase inhibitors such as PTK787 including but not limited to these materials. In addition, although any one of the above physiologically active substances may be encapsulated, if a plurality of components having different efficacy and mechanism of action are encapsulated, the synergistic effect of each component can be expected to promote drug efficacy. .

  In particular, when nanoparticles encapsulating a nucleic acid compound are attached to the stent body, the nucleic acid compound can be safely and efficiently introduced into the stenosis using the stent. It is an effective treatment with little possibility. As the nucleic acid compound, plasmid DNA, gene, decoy, siRNA, oligonucleotide, antisense oligonucleotide, ribozyme, and apter are particularly preferable. The amount of bioactive substance enclosed in the nanoparticle depends on the amount of bioactive substance added during nanoparticle formation, the type of cationic polymer, adjustment of the amount added, and the type of biocompatible polymer that forms the nanoparticle. It can be adjusted.

(Nanoparticle adhesion process)
Next, a method for forming a nanoparticle layer by attaching biocompatible nanoparticles encapsulating a physiologically active substance to a stent body will be described. As a method of attaching the nanoparticles, a method of physically attaching the nanoparticles to the stent main body by immersion in a nanoparticle suspension or mist coating may be used, but as described above, it is used in the present invention. Since the surface of the nanoparticle is positively or negatively charged, the stent body can be coated firmly and uniformly by electrically attaching the nanoparticle. Here, an electrophoretic method in which a stent body is used as a negative electrode in a suspension of biocompatible nanoparticles positively modified with a cationic compound, and a biocompatible nanoparticle-containing liquid on a negatively charged stent surface A spraying method for attaching droplets will be described as an example.

  FIG. 2 is a schematic diagram showing the configuration of an electrophoresis apparatus used for manufacturing the DES of the present invention. The electrophoretic device 5 is filled with a suspension 7 of nanoparticles 1 in a bathtub 6, and is connected to the negative electrode side of the electric circuit to become a negative electrode stent body 8, and the positive electrode 9 connected to the positive electrode side of the electric circuit; It is composed by dipping. Here, the stent body 8 formed into a cylindrical net shape using metal fibers is used.

As described above, the nanoparticle 1 obtained in the nanoparticle formation step is modified (coated) with a cationic polymer so that the zeta potential on the particle surface is positive. Therefore, since a negative potential is generated on the surface of the stent body 8 by energizing the electric circuit in the state of FIG. 2, the positively charged nanoparticles 1 are attracted and actively attached. Water molecules in the suspension 7 are also electrolyzed, and hydrogen ions (H ⁺ ) are attracted to the stent body 8 side, receiving electrons from the surface of the stent body 8 and generating hydrogen. On the other hand, hydroxide ions (OH ⁻ ) are attracted to the positive electrode 9 side, and electrons are released to the positive electrode 9 to generate oxygen and water.

  As the chemical reaction proceeds, the nanoparticles near the cathode (stent body) are aggregated to form a coating (nanoparticle layer) on the surface of the stent body 8. And since the part in which the nanoparticle layer was completed loses electrical conductivity and no further film formation is performed, a uniform nanoparticle layer can be formed. In addition, the nanoparticle adhesion process can be easily automated, and the layer thickness can be easily controlled by adjusting the voltage and energization time, which is suitable for industrialization. Furthermore, since the object to be coated (stent body) is used as a cathode, there is no elution of metal ions, and nanoparticles can be adhered to iron, magnesium and the like.

  FIG. 3 is an enlarged cross-sectional view showing a state in which nanoparticles are attached to the metal fibers constituting the stent body by electrophoresis. The surface of the negatively charged metal fiber 10 is completely covered with the positively charged nanoparticles 1 to form a nanoparticle layer 11. The nanoparticle layer 11 formed by this electrophoresis adheres significantly more strongly than the nanoparticle layer formed by, for example, immersing and lifting the nanoparticle suspension in the nanoparticle suspension without energizing the stent body. Good adhesion and excellent corrosion resistance.

  Therefore, it is possible to prevent the nanoparticle layer 11 from being peeled off from the stent body at the time of subsequent manufacturing steps, insertion into a living organ, and stent expansion. The reason why the adhesion force of the nanoparticle layer 11 to the stent body is increased by the electrophoresis method is considered to be due to van der Waals force acting between the nanoparticles 1.

  As the shape of the stent body, in addition to the one formed by knitting using a fiber material as shown in FIG. 2, a metal pipe cut by a laser or the like may be used, and a crown shape, a cylindrical shape may be used. For example, various conventionally known shapes can be used. The stent body may be either a balloon expansion type or a self-expansion type, and the size of the stent body may be appropriately selected according to the application location. For example, when used for a coronary artery of the heart, it is usually preferable that the outer diameter before expansion is 1.0 to 3.0 mm and the length is about 5.0 to 50 mm.

  Moreover, when attaching nanoparticles by electrophoresis, the stent body needs to use a conductive material such as metal. Examples of the metal used for the stent body include stainless steel, magnesium, tantalum, titanium, nickel-titanium alloy, inconel, gold, platinum, iridium, tungsten, cobalt-based alloy, and the like. When the stent is a self-expanding type, a superelastic alloy such as nickel titanium is preferable because it needs to be restored to its original shape. On the other hand, in the case of the balloon expansion type, stainless steel or the like that does not easily return to its shape after expansion is preferable, and among them, SUS316L having the highest corrosion resistance is preferably used.

  Examples of conductive materials other than metals include conductive polymers such as polyaniline, polypyrrole, polythiophene, polyisothianaphthene, and polyethylenedioxythiophene, and conductive ceramics. In addition, a conductive filler may be added, or a non-conductive resin provided with conductivity by conducting a conductive treatment on the surface by coating or the like may be used.

  If a material such as stainless steel that is not decomposed in vivo is used as the material of the stent body, inflammation may occur on the inner wall of the blood vessel due to long-term stent placement, which may cause restenosis. It was necessary to perform PTCA and to place the stent again, which caused a heavy burden on the patient. Therefore, if the stent body is made of magnesium, which is a biodegradable metal, the stent body is gradually degraded in vivo and disappears within a few months after placement. Can do.

  In particular, by attaching nanoparticles formed of biodegradable polymers such as PGA, PLA, and PLGA as biocompatible polymers to the magnesium stent body, it is completely in a predetermined period after being placed in the living body. The DES is less loaded on the living body. At this time, as the biodegradable polymer forming the nanoparticles, it is preferable to use a biodegradable polymer having a slower degradation rate in vivo than the biodegradable polymer impregnated in the nanoparticle layer in the impregnation step described later.

  In addition, when the physiologically active substance encapsulated in the nanoparticles is an anionic drug, when the nanoparticles are attached to the stent body by electrophoresis, an anionic drug can be further added to the suspension of the nanoparticles. The anionic drug is electrostatically supported by the positive charge on the surface of the nanoparticles, and is attracted to and attached to the stent body. Therefore, anionic drugs such as nucleic acids and genes that have been extremely difficult to coat on the stent body can be more efficiently attached.

  Here, as the voltage applied between the positive electrode and the negative electrode during electrophoresis increases, the amount of nanoparticles attracted to the stent surface per unit time increases, so the nanoparticle layer is formed on the stent surface in a short time. On the other hand, since a large amount of nanoparticles are attached at a time, it is difficult to form a uniform nanoparticle layer. Therefore, the voltage applied at the time of electrophoresis may be appropriately set according to the required uniformity of the nanoparticle layer and the formation efficiency of the nanoparticle layer.

  Next, the spray method will be described. The spraying method is a method in which fine suspension droplets of biocompatible nanoparticles with a positive charge are electrically attached to the surface of a stent body that is negatively charged by energization. Examples thereof include an ultrasonic mist method that mists by sound waves, a spray method in which a nanoparticle suspension is sprayed onto the stent surface using a spray device or an air brush, and an air brush method.

  Even in this spraying method, the stent body is energized and negatively charged, so as in the case of electrophoresis, the nanoparticle layer is modified with a positive charge compared to the case where the stent body is sprayed without being charged. It is possible to produce a DES that adheres remarkably firmly and has good adhesion between the stent body and the nanoparticles and excellent corrosion resistance. Furthermore, since the nanoparticles in the droplets are actively attached to the stent body, the efficiency of attaching the nanoparticles to the side and back surfaces of the stent where the mist or sprayed droplets are difficult to adhere directly can be increased. Note that the shape and material of the stent body used in the spraying method are the same as those in the electrophoresis method, and thus the description thereof is omitted.

  Further, in addition to the step of forming the nanoparticle layer on the stent surface by electrophoresis or spraying, a step of stacking the nanoparticle layer thereon (hereinafter referred to as a second attachment step) can also be provided. In the second attachment step, a new nanoparticle layer is laminated along the uniform nanoparticle layer formed on the stent surface, so that a desired layer thickness is obtained even if the amount of nanoparticle attachment per unit time is increased. A nanoparticle layer can be formed uniformly and efficiently. In the second attaching step, the above-described electrophoresis method, ultrasonic mist method, spray method, air brush method, or the like is used. When an ultrasonic mist method, a spray method, an air brush method, or the like is used in the second attachment step, it is preferable to negatively charge the stent body in order to stack the nanoparticle layer more efficiently and firmly.

  The method for attaching nanoparticles having a positively charged particle surface to the stent body has been described above, but nanoparticles having a negatively charged particle surface can also be attached to the stainless steel body by electrophoresis or spraying. In that case, it is only necessary to energize the stent body as the positive electrode when using the electrophoresis method, and when using the spray method, the nanoparticle is actively attached by energizing the stent body and positively charging it. Can do.

(Post-processing process)
If a stent with a nanoparticle layer formed on the surface is used as it is, the nanoparticle layer may be removed from the stent body due to friction between the stent and the inner wall of the blood vessel or deformation when the stent is expanded after reaching the diseased site. May peel off. Therefore, after the nanoparticle layer is formed by the nanoparticle adhesion step, it is exposed to a vapor of a volatile organic solvent capable of dissolving the biodegradable polymer forming the nanoparticles for a certain period of time.

  FIG. 4 is a partial cross-sectional view showing a state after the stent having the nanoparticle layer shown in FIG. 3 is exposed to vapor of an organic solvent. When the nanoparticle layer 11 formed on the surface of the metal fiber 10 is exposed to the vapor of a volatile organic solvent capable of dissolving the biodegradable polymer, the surface of each nanoparticle 1 forming the nanoparticle layer 11 is exposed. It becomes a slightly dissolved state by the vapor of the organic solvent. When the organic solvent remaining in the nanoparticle layer 11 is volatilized after a certain time, the adjacent nanoparticles 1 and the surfaces of the nanoparticles 1 and the metal fibers 10 are melted as shown in FIG. The deposited nanoparticle layer 11 is formed. Thereby, the nanoparticle layer 11 is held extremely firmly on the surface of the metal fiber 10.

  As the organic solvent used in the post-treatment process, a solvent that can dissolve the biocompatible polymer forming the nanoparticles and has high volatility is preferable. Examples of organic solvents that can be used in the post-treatment step include halogenated alkanes, acetone, methanol, ethanol, ethyl acetate, diethyl ether, cyclohexane, benzene, toluene, and the like. Among these, acetone is preferable because it can easily dissolve PLGA, which is particularly suitable as a material for forming nanoparticles, and has little adverse effect on the environment and the human body.

  The exposure time of the organic solvent in the vapor is not particularly limited. However, if the exposure time is too short, fusion between the nanoparticles forming the nanoparticle layer becomes insufficient, and the strength of the nanoparticle layer decreases. Therefore, it is preferable to expose the stent body on which the nanoparticle layer is formed in an organic solvent vapor for 5 minutes or more.

  In the DES obtained as described above, the nanoparticle layer is extremely firmly attached to the stent body by the post-processing step, so that friction with the inner wall surface of the blood vessel when DES is introduced into a diseased site in the blood vessel is reduced. There is no possibility that the nanoparticle layer is peeled off from the stent body due to deformation or the like when the stent is expanded after being introduced into the diseased site, and the DES is excellent in handleability. Furthermore, since the post-treatment is completed by simply exposing the stent body with the nanoparticle layer formed in an organic solvent vapor for a certain period of time, it can also be applied to nanoparticles carrying bioactive substances that are easily deactivated or denatured by heat. Is possible. In addition, special equipment and materials for the post-treatment process and a drying process after the post-treatment are not required, and the manufacturing process can be greatly simplified.

  Moreover, when the surface of the nanoparticle adhering to the stent body is positively charged, the cell adhesiveness of the nanoparticle eluted from the stent surface is increased. Thereby, compared with the conventional DES, the introduction efficiency of the nanoparticles into the stenosis site cell where the stent is placed can be increased.

  Further, a plurality of types of nanoparticles having different types of physiologically active substances to be encapsulated may be prepared, and the nanoparticles may be attached in layers or mosaics. At this time, if the nanoparticles encapsulating the physiologically active substance to be eluted in a short time after DES placement are attached to the outer layer, the nanoparticles encapsulating the physiologically active substance to be eluted after a long time have been adhered to the inner layer, The elution time from DES of two or more kinds of physiologically active substances can be systematically controlled. Further, two or more types of physiologically active substances may be enclosed in nanoparticles having different types and molecular weights of biocompatible polymers to control the elution time.

In addition, the present invention is not limited to the above-described embodiments, and various modifications are possible. Embodiments obtained by appropriately combining technical means disclosed in different embodiments are also included in the present invention. Included in the technical scope. For example, in the above-described embodiment, as an example of the method for producing the drug-eluting device of the present invention, DES has been described as an example. However, the present invention includes an expandable catheter such as a balloon catheter, an artificial bone, a screw, Of course, the present invention can be similarly applied to the manufacture of various medical devices placed in the living body, such as surgical implants such as plates. Hereinafter, preparation of PLGA nanoparticles whose surface is positively charged, preparation of DES of the present invention in which it is electrically attached and then post-treated in acetone vapor, and nanoparticles in the prepared DES The effect of preventing peeling of the layer will be specifically described along with examples.
[Preparation of PLGA nanoparticles]

[Example 1]
A 0.5% by weight aqueous solution of polyvinyl alcohol (PVA403, manufactured by Kuraray Co., Ltd.) and a 0.02% by weight aqueous solution of chitosan (Moiscoat PX, manufactured by Katakura Chikkarin) were mixed to form a poor solvent. 2 g of a lactic acid / glycolic acid copolymer (PLGA7520, manufactured by Wako Pure Chemical Industries), which is a biocompatible polymer, was dissolved in 40 mL of acetone to obtain a good solvent. This good solvent was dropped into the above poor solvent at 40 ° C. and 400 rpm at a constant rate (4 mL / min), and the diffusion of the good solvent into the poor solvent caused the suspension of PLGA nanoparticles not encapsulated with the physiologically active substance. A turbid liquid was obtained.

Subsequently, the organic solvent was distilled off while continuing stirring at 40 ° C. under reduced pressure at 400 rpm. After the solvent was distilled off for about 2 hours, the suspension was filtered and the filtrate was lyophilized overnight. Thus, a dry powder of PLGA composite nanoparticles having an average particle size of 260 nm and good redispersibility in water and a positive charge of zeta potential of +17.3 mV was obtained.
[Coating of stent body with PLGA nanoparticles]

[Example 2]
The PLGA composite nanoparticles prepared in Example 1 were diluted with purified water to obtain a 0.75% suspension. On the other hand, a cobalt-chromium alloy pipe having an inner diameter of 2.5 mm and a length of 17 mm was cut into a mesh shape with a laser cutter to produce a stent body. The inner diameter of the stent body was slightly expanded and extrapolated into a stainless steel (SUS316L) pipe.

  FIG. 5 is a schematic configuration diagram of a nanoparticle coating apparatus by electrophoresis used in this example. The nanoparticle suspension 13 is filled in a cylindrical container 14 (electrolytic bath) made of stainless steel (SUS304) having an inner diameter of 8.5 mm, an outer diameter of 9.5 mm, a wall thickness of 0.5 mm, and a height of 23 mm, the upper surface of which is open, The stainless steel pipe 15 to which the stent body 8 is mounted is placed in the cylindrical container 14 so that the stent body 8 is completely immersed in the nanoparticle suspension 13 and a part of the stainless steel pipe 15 protrudes from the liquid surface. I stood up. A silicon tube 16 was attached to the tip of the stainless steel pipe 15 to ensure insulation from the cylindrical container 14.

Then, an external power source 17 and an ammeter 18 were connected so that the cylindrical container 14 was a positive electrode and the stainless steel pipe 15 was a negative electrode, and energized for 60 minutes at a voltage of 2 V and a current of 5 mA. Since the stent body 8 and the stainless steel pipe 15 (negative electrode) are made of the same material and have the same conductivity, the stent body 8 can be energized uniformly. After energization, the stent body 8 was removed from the stainless steel pipe 15 and dried.
[Post-treatment of the PLGA nanoparticle layer coated on the stent body]
[Example 3]

After passing the wire through the lumen of the stent body 8 coated with PLGA nanoparticles in Example 2, it was stood in a 50 mL glass bottle. Thereafter, a 5 mL glass bottle containing 4 mL of acetone was placed in a 50 mL glass bottle without a lid, and the 50 mL glass bottle was sealed. Ten minutes later, the stent body 8 was taken out and allowed to stand at room temperature for a while, or acetone was volatilized by vacuum drying to prepare the DES of the present invention. When the surface of the obtained DES was observed with an optical microscope, it was confirmed that the PLGA nanoparticles were uniformly attached to the surface of the stent body.
[Comparative example]

The stent body 8 coated with PLGA nanoparticles in Example 2 was dried as it was without being exposed to acetone vapor, to produce a comparative DES.
[Evaluation of peelability of nanoparticle layer from DES surface]
[Example 4]

(Simple peeling test)
The DES of the present invention produced in Example 3 and the DES produced in the comparative example were wetted with purified water, and then a soft silicon tube was lightly pressed against the nanoparticle layer of DES. In this state, the soft silicon tube was reciprocated 50 times, and the peeling state of the nanoparticle layer due to friction was observed with an optical microscope. As a result, separation of the nanoparticle layer was not observed in the DES of the present invention prepared in Example 3, whereas in the case of DES prepared in the comparative example, the nanoparticle layer was separated and the metal surface of the stent body was exposed. It was confirmed that
[Example 5]

(Peeling test using a blood vessel model)
As shown in FIG. 6, the balloon 21a of the balloon catheter 21 was inserted into the lumens of the DES 20 of the present invention produced in Example 3 and the DES 20 produced in the comparative example, and contracted and fixed. The peeling state of the nanoparticle layer at this time was observed with an optical microscope. On the other hand, a soft tube 23 made of polyester having a length of 1 m and an inner diameter of 2 mm was prepared as a pseudo blood vessel model. As shown in FIG. 7, it was curved and fixed to a wave shape (wavelength 6 cm, amplitude 5 cm, wave number 3). The operation of inserting and pulling out the balloon catheter 21 equipped with the DES 20 into the soft tube 23 filled with physiological saline was repeated three times, and the peeling state of the nanoparticle layer due to friction was observed with an optical microscope.

(Peel test by expansion in physiological saline)
After the above operation, as shown in FIG. 8, the balloon 21a inserted into the lumen of the DES 20 in physiological saline was expanded at 9 atm and held for 1 minute. Then, DES20 was pulled up from the physiological saline, and the peeling state of the nanoparticle layer was observed with an optical microscope. The results are shown in Table 1. In Table 1, the case where peeling of the nanoparticle layer was not observed was indicated as ◯, the case where slight peeling was observed as Δ, and the case where remarkable peeling was observed as X.

  As shown in Table 1, the DES of the present invention produced in Example 3 is assumed to be expanded after being attached to a balloon catheter, after movement in a soft tube assuming friction when passing through a blood vessel, and at a stenosis. No separation of the nanoparticle layer from the stent body surface was observed after any expansion in the physiological saline.

On the other hand, in the DES of the comparative example in which the exposure in acetone vapor was not performed, the nanoparticle layer was already detached from the surface of the stent body after being attached to the balloon catheter. And further exfoliation of the nanoparticle layer was recognized by subsequent passage through a soft tube and balloon expansion.
[Example 6]

(Examination of treatment time in acetone vapor)
A nanoparticle layer was coated on the surface of a metal plate (cobalt-chromium alloy, width 1 mm, thickness 0.1 mm) using the nanoparticle coating apparatus shown in FIG. And the processing time (exposure time) in acetone vapor | steam in Example 3 was changed into four steps of 1 minute, 5 minutes, 10 minutes, and 30 minutes, and the nanoparticle layer was post-processed.

  Thereafter, a simple peeling test was performed on each metal plate coated with the nanoparticle layer by the same method as in Example 4, and the peeling state of the nanoparticle layer due to friction was observed with an optical microscope. The results are shown in FIG. In FIG. 9, A shows the metal plate before a peeling test, and BE shows the state after the peeling test of the metal plate for 1 minute, 5 minutes, 10 minutes, and 30 minutes, respectively.

  As is clear from FIG. 9, the separation of the nanoparticle layer was observed in the metal plate B with a treatment time of 1 minute, but the separation of the nanoparticle layer was completely observed in the metal plates C to E with a treatment time of 5 minutes or more. There wasn't.

  From the above, after coating the stent body with PLGA nanoparticles, post-treatment in acetone vapor suppresses separation of the nanoparticle layer during stent attachment to the balloon catheter, passage through the blood vessel, and expansion It was confirmed that In addition, it was confirmed that the strength of the nanoparticle layer having no practical problem can be obtained by setting the exposure time in acetone vapor to 5 minutes or longer.

  INDUSTRIAL APPLICABILITY The present invention can be used for manufacturing medical devices such as stents and expandable catheters that are used by being placed in a living body. By utilizing the present invention, there is no possibility that the nanoparticle layer is peeled off from the device body due to external force when introduced into a diseased site, and a drug-eluting device excellent in handleability can be manufactured easily and at low cost. .

DESCRIPTION OF SYMBOLS 1 Biocompatible nanoparticle 2 Polyvinyl alcohol 3 Physiologically active substance 4 Cationic polymer 5 Electrophoresis apparatus 6 Bathtub 7 Suspension 8 Stent body 9 Positive electrode 10 Metal fiber 11 Nanoparticle layer 13 Nanoparticle suspension 14 Cylindrical container 15 Stainless steel pipe 16 Silicon tube 17 External power supply 18 Ammeter 20 DES
21 balloon catheter 21a balloon part 23 soft tube

Claims (6)

A mixed solution of at least a solution of a physiologically active substance and a solution of a lactic acid / glycolic acid copolymer dissolved in an organic solvent is added to the aqueous solution, and the physiologically active substance is encapsulated in the lactic acid / glycolic acid copolymer. A nanoparticle formation process for producing a suspension of biocompatible nanoparticles,
A nanoparticle attachment step of electrically attaching the biocompatible nanoparticles to a cobalt-chromium alloy device body to form a nanoparticle layer;
A post-treatment step of exposing the device body formed with the nanoparticle layer to acetone vapor capable of dissolving the lactic acid / glycolic acid copolymer for 5 minutes or more ;
A method for producing a drug-eluting device, comprising:   2. The nanoparticle forming step generates a suspension of biocompatible nanoparticles whose particle surface is positively charged by dissolving a cationic polymer in an aqueous solution. The manufacturing method of the chemical | medical agent eluting device of description.   The method for producing a drug-eluting device according to claim 2, wherein an anionic drug is further added to the biocompatible nanoparticle suspension. The drug elution according to any one of claims 1 to 3, wherein the nanoparticle adhesion step is performed by any one of an electrophoresis method, an ultrasonic mist method, a spray method, and an air brush method. Type device manufacturing method. The said nanoparticle adhesion process has a 2nd adhesion process of laminating | stacking a nanoparticle layer further on the said nanoparticle layer formed in the said device main body, The any one of Claim 1 thru | or 4 characterized by the above-mentioned. The manufacturing method of the chemical | medical agent elution type device as described in an item. The nanoparticle layer composed of biocompatible nanoparticles in which different physiologically active substances are encapsulated is formed in a laminated shape or a mosaic shape by repeating the nanoparticle adhesion step a plurality of times. The method for producing a drug eluting device according to claim 5.

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