JPWO2010029753A1 - Drug sustained release member - Google Patents

Abstract

The drug sustained release member (1) includes a substrate (10) and a multilayer film (11) that covers the surface of the substrate (10) and releases the drug. The multilayer film (11) includes a first DLC film (101), a polymer layer (102), and a second DLC film (103). The first DLC film (101) is formed on the surface of the substrate (10). The polymer layer (102) contains a drug and releases the drug slowly. The second DLC film (103) covers the polymer layer (102) and limits the sustained release of the drug.

Description

  The present invention relates to a drug sustained release member.

  In recent years, in order to impart biocompatibility to a stent, the stent surface is coated with a material having antithrombotic properties. In addition, for the purpose of local delivery of drugs, therapeutic devices for drug elution in which in-dwelling medical devices are coated with a material containing a therapeutic agent have been vigorously developed. As this kind of technology, there are those described in Patent Documents 1 to 4.

  The stent described in Patent Document 1 includes a stent frame structure in which a plurality of reservoirs are formed, a drug polymer housed in the reservoir, and a polymer layer attached to the drug polymer, so that Effectively controls drug release.

  Patent Document 2 describes that a diamond-like carbon (DLC) film is excellent in antithrombogenicity, chemical resistance, wear resistance, and insulation. The stent described in Patent Document 2 forms a DLC film on a carbon ion implanted layer, thereby making it difficult to peel the DLC film from the stent base material and reducing the free carbon content.

  Patent Document 3 discloses a drug release article that controls drug release characteristics by providing a substrate with two polymer coatings containing a pharmacologically active compound.

  Furthermore, Patent Document 4 discloses a stent in which a DLC film is formed on the surface of a stent body, and a polymer layer containing a drug is included in the DLC film. By doing so, it is described that a drug that imparts durability to the stent body and prevents restenosis is released.

JP 2004-305753 A Japanese Patent Laid-Open No. 11-313884 JP 2007-190369 A JP 2007-195883 A

  However, the prior art described in the above literature has room for improvement in the following points.

  First, the biocompatibility and antithrombogenicity of the stent could not be controlled only by covering the stent with a DLC film as in Patent Document 2.

  Secondly, as disclosed in Patent Documents 1, 3, and 4, the drug release rate cannot be sufficiently reduced only by including the drug in the polymer layer. There is a possibility of damaging living cells over a long period of time, and the biocompatibility and antithrombogenicity of the stent could not be ensured for a long time. Therefore, a drug eluting stent that can release the drug more slowly and under control has been desired.

  These problems are not limited to stents, and are common problems in indwelling members such as catheters and guide wires.

According to the present invention, a drug sustained release member for indwelling a living body,
A substrate;
A multilayer film covering the surface of the substrate and releasing a drug;
Have
The multilayer film is
A polymer film that contains the drug and that slowly releases the drug;
A protective film covering the polymer film and restricting the sustained release of the drug;
A drug sustained release member is provided.

  According to this invention, the release of the drug from the polymer layer is limited by providing the base material with a multilayer film that includes the drug and that covers the polymer layer that slowly releases the drug with the protective film. Thereby, the rate of drug release from the polymer layer can be further reduced. Therefore, the pharmacological effect in the living body can be obtained for a long time.

  According to the present invention, a local pharmacological effect in a living body can be obtained for a longer period than before.

  The above-described object and other objects, features, and advantages will become more apparent from the preferred embodiments described below and the accompanying drawings.

It is the figure which showed typically the chemical | medical agent sustained release member which concerns on 1st Embodiment. It is the figure which showed typically the chemical | medical agent sustained release member which concerns on 2nd Embodiment. It is the figure which showed the modification of the chemical | medical agent sustained release member which concerns on embodiment. It is a top view which shows the chemical | medical agent sustained release member of an Example. It is a figure which shows the result of an Example.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. In all the drawings, the same reference numerals are given to the same components, and the description will be omitted as appropriate.

(First embodiment)
The present embodiment is a drug sustained release member for living indwelling. FIG. 1 is a diagram showing a structure of a drug sustained release member 1 of the present embodiment. The drug sustained release member 1 has a substrate 10 (base material) and a multilayer film 11 that covers the surface of the substrate 10 and releases the drug. The multilayer film 11 includes a first DLC film 101, a polymer layer (polymer film) 102, and a second DLC film (protective film) 103. The first DLC film 101 is a DLC film that covers the surface of the substrate 10. The polymer layer 102 contains a drug and releases the drug gradually. The second DLC film covers the polymer layer 102 and limits the sustained release of the drug.

  In the present embodiment, “sustained release” does not include releasing the entire amount of the pre-prepared drug at once, but releasing a part of the drug little by little, and releasing the entire amount of drug over a certain period of time. That means.

The DLC films 101 and 103 are made of a material containing DLC. The DLC film is an amorphous carbon film in which both the sp ³ bond of diamond and the sp ² bond of graphite have a carbon atom skeleton. In general, DLC film has high hardness, high wear resistance, low wear coefficient, high insulation, high chemical stability, high gas barrier property, high seizure resistance, high biocompatibility, high infrared transmittance, etc. Has characteristics. The DLC film has a flat surface and can be synthesized at a low temperature of about 200 ° C.

By controlling sp ³ bonds and sp ² bonds in the DLC films 101 and 103, adhesion and wear resistance can be controlled. Further, the hardness can be controlled by controlling the hydrogen concentration in the DLC films 101 and 103.

  DLC is made by adding charcoal, diamond and hydrogen, but other elements and compounds may be included in the DLC films 101 and 103. For example, antithrombogenicity can be enhanced by containing fluorine in the DLC films 101 and 103. However, the DLC films 101 and 103 are preferably films mainly composed of DLC.

  In the present embodiment, the DLC films 101 and 103 are DLC films, and the drug sustained release member 1 will be described in detail below.

  The substrate 10 is made of at least one of a metal material, a ceramic material, and a polymer material.

  For example, metal materials include silicon, germanium, tungsten, stainless steel, nickel titanium alloy, copper aluminum manganese alloy, tantalum, cobalt chromium alloy, iridium, iridium oxide, niobium, platinum, titanium, chromium, titanium carbide, carbonized. It can be selected from the group consisting of silicon and chromium carbide.

  The polymer material can be selected from the group consisting of polyolefin, polyolefin elastomer, polyamide, polyamide elastomer, polyurethane, polyurethane elastomer, polyester, polyester elastomer, polyimide, polyamideimide, and polyether ketone.

  The substrate 10 may be made of an inorganic material such as hydroxyapatite.

  The first DLC film 101 covers the surface of the substrate 10. Thereby, deterioration of the substrate 10 can be prevented. The first DLC film 101 is a dense and strong film. Therefore, it is considered that the first DLC film 101 does not permeate biological components or is difficult to permeate.

  By covering the surface of the substrate 10 with the first DLC film 101, the surface of the substrate 10 can be smoothed. Thereby, the board | substrate 10 becomes small interaction with a biological component, and can reduce that a biological component adheres to the board | substrate 10. FIG.

  The first DLC film 101 can be formed by either a physical vapor synthesis method (PVD method) or a chemical vapor synthesis method (CVD method). In the PVD method, a film is formed from a solid carbon source in a high vacuum using sputtering, electron beam evaporation, cathodic arc discharge, or laser ablation. On the other hand, in the CVD method, a hydrocarbon gas (ethylene, methane, benzene, etc.) is ionized by plasma discharge in a low vacuum, and the film is formed by accelerated collision with a negative bypass voltage applied to the substrate 10.

  In the PVD method, a film made of only carbon can be synthesized, but in the CVD method, hydrogen is always contained in the film. According to the CVD method, since the amount of hydrogen contained in the DLC film can be easily controlled, a DLC film having desired characteristics can be formed.

  If the film thickness of the first DLC film 101 is too thin, deterioration of the substrate 10 cannot be sufficiently prevented. However, if the film thickness is too large, cracks are a problem when large deformation is applied to the drug sustained release member. Therefore, the thickness of the first DLC film 101 may be 10 nm to 300 nm, preferably 20 nm to 120 nm. By doing so, it is possible to prevent the substrate 10 from being deteriorated and to prevent the occurrence of cracks.

  The polymer layer 102 is formed by fixing a polymer on the surface of the first DLC film 101. The polymer layer 102 fixed to the surface of the first DLC film 101 has the ability to release the drug at a constant rate. In addition, the polymer is desirably biocompatible.

  The polymer means a polymer composed of at least one of a homopolymer, a copolymer, and a mixture of these polymers. Biocompatibility means that a biomolecule is not absorbed or activated.

  Specifically, the polymer is a silicon-urethane copolymer, polyurethane, phenoxy, polycaprolactone, polysulfone, polyacrylamide, poly (alkyl methacrylate), polyphosphoester, polyorthoester, poly (hydroxybutyrate), poly (diaxanone) ), Poly (hydroxyvalerate), poly (hydroxybutyrate-cobalate), poly (glycolide-co-trimethylene carbonate), polyanhydride, poly (ester-amide), polyphosphazene, poly (phosphoester-urethane ), Polycyanoacrylate, polyethylene oxide, polyethylene carbonate, polyethylene, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polypropylene carbonate, polyamide, VA (ethylene vinyl acetate) polymer, styrene-ethylene-butylene-styrene (SEBS), poly (lactide-co-glycolide), polylactide, elastin, fibrin, fibrinogen, cellulose, starch, collagen, hyaluronic acid, chondroitin sulfate, polylactic acid , Polyglycolic acid, poly (amino acid), MPC (2-methacryloyloxyethyl phosphorylcholine) polymer, N-isopropylacrylamide (NIPAM) polymer.

  As the polymer, any of a hydrophilic polymer and a hydrophobic polymer can be used. Hydrophobic polymers tend to have a slower drug release rate in the blood than hydrophilic polymers. Therefore, the drug release rate can be controlled by appropriately selecting the polymer. A copolymer of a hydrophilic polymer and a hydrophobic polymer can also be used.

  For example, the hydrophilic polymer includes MPC polymer, polyacrylamide, PVA, PEG, and NIPAM polymer.

  In addition, examples of the hydrophobic polymer include EVA polymer and SEBS.

  The polymer may be a homopolymer of a resin having biocompatibility, or a copolymer containing a resin having biocompatibility. Examples of the biocompatible resin include the polymers listed above, but it is more preferable to use EVA polymer, MPC polymer, polyurethane, or a copolymer thereof as the polymer.

  Further, the polymer may be a copolymer including a biocompatible site and a polymerizable site. Examples of the site having biocompatibility include a phosphorylcholine group. The MPC polymer is a polymer having a phosphorylcholine group as a biocompatible site and a methacryloyl group as a polymerizable site, and it is more preferable to use an MPC / n-butyl methacrylate copolymer.

  When the polymer is used as a polyurethane copolymer, a polyurethane elastomer is preferable, a polyether-based thermoplastic polyurethane elastomer is more preferable, and a polytetramethylene glycol (PTMG) -based polyurethane elastomer is particularly preferable. Polyurethane copolymers are generally polymers that are more hydrophobic than MPC polymers but less hydrophobic than EVA polymers.

  In addition, the polymer layer 102 can be formed from a non-degradable polymer having biocompatibility or a degradable polymer that is enzymatically or non-enzymatically degraded in vivo.

  As the degradable polymer, a degradation product that does not exhibit toxicity and can release a drug can be used. An ester plasticizer such as tartaric acid, malic acid or citric acid can also be added to the degradable polymer. In this way, degradation by the living body can be promoted and the drug can be released efficiently.

  The polymer can hold the drug by a known method. For example, a gel polymer and a predetermined concentration of drug are mixed. It can also be included in the three-dimensional structure of the polymer.

  As the drug to be contained in the polymer, a drug suitable for preventing or treating a specific disease is selected. In addition, this drug contains an appropriate concentration in the polymer depending on the treatment method. In the case of slow release of a drug in blood, it is preferable to select a hydrophilic drug. In addition, when the drug is to be released slowly from the skin, it is preferable to select a hydrophobic drug. The hydrophilic drug generally has an octanol-water partition coefficient (log P, pH 7, 20 to 25 ° C.) of 0 or less, and the hydrophobic drug generally has octanol- The water partition coefficient (log P, pH 7, 20 to 25 ° C.) is greater than zero.

  Specifically, the drug contained in the polymer is selected from the group consisting of antithrombotic agents, anticancer agents, immunosuppressive agents, antibiotics and anti-inflammatory agents. The drug may be a low molecular weight compound or a high molecular weight compound having biological activity (biologically active high molecular weight body).

  As the antithrombotic agent, a thrombolytic agent, a platelet aggregation inhibitor, a heparin preparation, an antithrombin agent, and a blood coagulation inhibitor can be used.

  Examples of the thrombolytic agent include alteplase, urokinase, tisokinase, patrixobin, bamiteplase, monteplase, nasalplase, and nateplase. Examples of the platelet aggregation inhibitor include aspirin, salvogrelate hydrochloride, ticlopidine hydrochloride, ozagre sodium, cilostazol, and limaprost alpha desk. Examples of the antithrombin agent include argatropane, daltevaline sodium, and valnaparin sodium. Examples of the blood coagulation inhibitor include warfarin potassium, antithrombin III, protein C, danavaloid sodium, sodium citrate, ethyl icosapentate, and salvogrelate. Examples of heparin preparations include heparin calcium, heparin sodium, protamine sulfate, and leviparin sodium.

  As an anticancer agent, a molecular target drug, an alkylating agent, an antimetabolite, a plant alkaloid, an anticancer antibiotic, a platinum preparation, a hormonal agent, or a biological response modifier can be used.

  Examples of the molecular targeting drug include imatinib, erlotinib, gefitinib, gemtuzumab ozogamicin, sunitinib, sorafenib, tamibarotene, trastuzumab, tretinoin, panitumumab, bevacizumab, bortezomib, rituximab. Examples of the alkylating agent include nitrogen mustard, cyclophosphamide, iosfamide, temozolomide, busulfan, melphalan, and nitrourea agents (dacarbazine, nimustine, ranimustine, brocarbazine). Antimetabolites include antifolate drugs (bemetrexed, sulfadiazine, sulfamethoxazole, diphanylsulfone, methotrexate, trimethoprim, pyrimethamine), pyrimidine metabolism inhibitors (fluorouracil, capecitabine, carmofur, tegafur, tegafur, uracil, tegafur・ Gimeracil oteracil potassium, doxyfluridine), purine metabolism inhibitors (mercaptopurine, azathioprine, pentostatin), ribonucleotide reductase inhibitors (hydroxyurea, hydroxycarbamide), nucleotide analogs (thioguanine, fludarabine phosphate, cladribine, cytarabine, Gemcitabine, cytarabine oxford, nelarabine, fludarabine, and enocitabine). Examples of plant alkaloids include irinotecan, etoposide, sobuzoxan, tocetaxel, nogitane, paclitaxel, vinorelbine, vincristine, vinotecin, and vinblastine. Examples of anticancer antibiotics include actinomycin D, aclarubicin, amrubicin, idarubicin, ebubicin, daunorubicin, doxorubicin, biralubicin, bleomycin, hepromycin, mitomycin C, and mitoxantrone C. Examples of platinum preparations include oxaliplatin, carboplatin, cisplatin, and nedaplatin. Hormonal agents include dexamethasone, finasteride, estrogen, anastrozole, exemestane, estramustine, estinylestradiol, chlormadinone, goserelin, tamoxifen, toremifene, bicalutamide, flutamide, prednisozone, phosfestol, mitotane, methyltestosterone, med Examples are roxiprogesterone, mebiostan, leuprorelin, letrozole. Examples of the biological response modifier include interferon, interleukin, ubenimex, BCG, and lentinan.

  Examples of immunosuppressive agents include steroidal agents such as cyclosporine, tacrolimus (FK-506), prednisozone, and methylprednisozone.

  Antibiotics include aminoglycosides, carbecephems, carbapenems, cephalosporins, macrolides, monobactams, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, chloramphenicol, ethambutol , Fosfomycin, isoniazid, vancomycin and the like can be used.

  Anti-inflammatory agents include steroids and non-steroids. Steroidal anti-inflammatory agents include natural corticosteroids (cortisol, cortisone), synthetic corticosteroids (prednisolone, 6α-methylprednisozone, triamnosinolone, betamethasone, and dexamethasone, fluocinolone acetonide, triamcinolone) Can be used. Non-steroidal anti-inflammatory agents include salicylic acids (aspirin), indoleacetic acid derivatives (indomethacin), phenylacetic acid derivatives (diclofenac), phenamacetic acid derivatives (mefenamic acid), selective COX-2 inhibitors (etodolac, meloxicam, selexicob) ) Can be used.

  In addition, the polymer may contain a bioactive high molecular weight substance selected from the group consisting of proteins, oligopeptides, DNA, ribonucleic acids, DNA plasmids, siRNAs, and antisense molecules whose genes are modified by genetic engineering. Good.

  The content of the drug in the polymer film may be within the range in which the polymer can release the drug slowly, but can be, for example, 5% to 30% by weight, preferably 10% to 20% by weight with respect to the polymer weight. %.

  The polymer can be fixed to the surface of the first DLC film 101 by applying a polymer solution and drying it. Alternatively, the substrate 10 provided with the first DLC film 101 may be immersed in a polymer solution. Further, the polymer solution may be sprayed or dropped on the activated first DLC film 101.

  The polymer solution can be obtained by dissolving the polymer in an arbitrary solvent. The concentration of the polymer solution is not particularly limited. Further, instead of the polymer solution, the polymer may be used in the form of a suspension, dispersion or the like. In the case of a liquid polymer, it may be used neat without using a solvent. Further, the polymer may be used in a molten state.

  Note that the surface of the first DLC film 101 may be activated in advance by irradiation with plasma generated by argon or the like. By doing so, the carbon-carbon bond on the surface of the first DLC film is cleaved, and a functional group such as a carboxyl group or a hydroxyl group can be introduced. Therefore, the polymer layer 102 can be firmly fixed to the surface of the first DLC film 101.

  The thickness of the polymer layer 102 is 0.1 μm or more and 200 μm or less, preferably 1 μm or more and 100 μm or less. If it is too thin, the layer thickness of the polymer layer 102 becomes non-uniform and biocompatibility decreases. On the other hand, if it is too thick, cracks will occur.

  The second DLC film 103 covers the surface of the polymer layer 102 and has a continuous layer structure.

  If the film thickness of the second DLC film 103 is too thin, the film thickness of the second DLC film 103 becomes non-uniform and biocompatibility is lowered. On the other hand, if it is too thick, cracks will occur. Therefore, the thickness of the second DLC film 103 may be 10 nm to 300 nm, preferably 20 nm to 120 nm. By doing so, the occurrence of cracks can be prevented even if a large deformation is applied to the drug sustained release member.

  The second DLC film 103 can be formed by the same method as the first DLC film 101.

  The drug sustained release member 1 configured as described above includes a stent, a stent graft, a surgical instrument, an anastomosis device, an artificial blood vessel, a blood vessel graft, a heart prosthetic valve, a blood vessel patch, an atrioventricular shunt, and a catheter. , Guide wire, balloon balloon for expansion, filter, drip tube, medical tube, medical electrode, artificial organ, artificial joint, medical clip, and medical device selected from the group consisting of medical needles. .

  It continues and demonstrates the effect of the chemical | medical agent sustained release member of this Embodiment. According to the drug sustained-release member 1, the release of the drug from the polymer layer is limited by providing the base material with a multilayer film that contains the drug and covers the polymer layer 102 that gradually releases the drug with the second DLC film 103. Thereby, the release rate of the drug from the polymer layer 102 can be further reduced. Therefore, the pharmacological effect in the living body can be obtained for a long time.

  Polymers are inherently poorly biocompatible. Therefore, there is a problem that the polymer layer 102 which has finished releasing the contained drug is attacked by in-vivo substances for biological defense. Therefore, according to the conventional configuration, there is a problem in that after releasing the whole amount of the drug, a thrombus is formed on the surface of the polymer layer or the substrate, and a stenosis occurs in a biological tube such as a blood vessel.

  On the other hand, in the present embodiment, the second DLC film 103 is provided on the surface of the polymer layer 102. Since the DLC film is excellent in biocompatibility, it is difficult to be attacked by in vivo substances even after the drug is released. Therefore, recurrence / deterioration of the treatment site can be prevented.

  The mechanism by which the second DLC film 103 limits the release of the drug from the polymer layer 102 is not clear. However, it is considered that the release of the drug is restricted by the drug gradually permeating through the second DLC film 103 by some mechanism.

(Second Embodiment)
FIG. 2 is a diagram showing the structure of the drug sustained release member 2 of the present embodiment. In the present embodiment, the second DLC film 203 has a segment structure. The drug sustained release member 2 includes a second DLC film 203 instead of the second DLC film 103, and other components are the same as those of the drug sustained release member 1.

  In other words, the drug sustained release member 2 has the second DLC film 203 patterned on the surface of the polymer layer 102. Therefore, the medicine sustained release member 2 has a plurality of openings 204 and the surface of the polymer layer 102 is exposed.

  FIG. 2B is a plan view of the drug sustained release member 2. As shown in the figure, the second DLC film 203 is discretely provided on the surface of the polymer layer 102 like a grid.

  The second DLC film 203 can be formed by covering the surface of the polymer layer 102 with a mesh mask. By doing so, the second DLC film 203 can be patterned on the surface of the polymer layer 102. Further, an additive such as a fluororesin may be added to the opening 204 by spraying or the like.

  The drug sustained release member 2 has the opening 204 to absorb the strain when the substrate 10 is deformed. Therefore, the destruction of the second DLC film 203 can be suppressed. Furthermore, by controlling the pattern / size of the second DLC film, the drug release rate from the polymer layer 102 can be controlled more precisely.

  As mentioned above, although embodiment of this invention was described with reference to drawings, these are the illustrations of this invention, Various structures other than the above are also employable.

  For example, in the embodiment, the DLC film has been described as an example of the protective film. However, not only the DLC film but any material having biocompatibility can be used. For example, a metal material such as cobalt titanium or a nanocarbon material (filament, fullerene, carbine, nanotube, graphite, glassy carbon) may be used. Further, as shown in the embodiment mode, a protective film may be formed by patterning, or the protective film may be formed by performing surface treatment such as electron beam irradiation or electrosping coating.

  Further, a multilayer film (second multilayer film) may be further provided on the surface of the multilayer film 11 (multilayer film 21).

  FIG. 3 shows a modified example of the drug sustained release member of the present embodiment. 3 (a) and 3 (b) show modified examples of the drug sustained release member 1, and FIGS. 3 (c) and 3 (d) show modified examples of the drug sustained release member 2. FIG.

  FIG. 3A shows a drug sustained-release member having a multilayer film (first multilayer film) 11 and a multilayer film 31 (second multilayer film) that covers the surface of the multilayer film 11. FIG. 3B shows a drug sustained-release member having a multilayer film (first multilayer film) 11 and a multilayer film 41 (second multilayer film) that covers the surface of the multilayer film 11. FIG. 3C shows a drug sustained-release member having a multilayer film (first multilayer film) 21 and a multilayer film 31 (second multilayer film) covering the surface of the multilayer film 21. FIG. 3D shows a drug sustained release member having a multilayer film (first multilayer film) 21 and a multilayer film 41 (second multilayer film) covering the surface of the multilayer film 21. The multilayer film 31 includes a polymer layer 302 (second polymer layer) and a third DLC film 303 having a continuous structure covering the polymer layer 302. On the other hand, the multilayer film 41 includes a polymer layer 402 (second polymer layer) and a third DLC film 403 having a segment structure. The polymer layers 302 and 402 each contain a drug and release it gradually. The drug contained in the polymer layer 102 (first polymer layer) and the drug contained in the polymer layers 302 and 402 may be the same or different.

  In the example of FIG. 3A, the third DLC film 303 covers the entire surface of the polymer layer 302. Therefore, the drug contained in the polymer layer 102 passes through the second DLC film 103, the polymer layer 302, and the third DLC film 303 in order and is released.

  In the example of FIG. 3B, the third DLC film 403 partially covers the polymer layer 402. Accordingly, the drug contained in the polymer layer 102 may be released through the second DLC film 103 and the polymer layer 402, or may be released through the third DLC film 403.

  In the example of FIG. 3C, the second DLC film 203 partially covers the polymer layer 102, but the third DLC film 303 covers the entire surface of the polymer layer 302. Accordingly, the drug contained in the polymer layer 102 may be sequentially released through the second DLC film 203, the polymer layer 302, and the third DLC film 303, or may not be transmitted through the second DLC film 203, and the polymer layer 302, The light may be emitted through the third DLC film 303.

  In the example of FIG. 3D, the second DLC film 203 partially covers the polymer layer 102, and the third DLC film 403 partially covers the polymer layer 402. Therefore, the drug contained in the polymer layer 102 may be directly released from the polymer, or may be released through the second DLC film 203, the polymer layer 402, and the third DLC film 403 at random.

  Therefore, the drug release rate of the polymer layer 102 can be designed to a desired rate by appropriately selecting the configurations shown in FIGS.

  The polymer layers 302 and 402 can be formed by fixing a polymer to the surface of the second DLC film 103, respectively. The immobilization of the polymer can be performed using a method similar to the method of immobilizing the polymer on the surface of the first DLC film 101.

  As described above, by adopting the modification shown in FIG. 3, the drug release rate can be further reduced. In addition, by appropriately designing the type and size of the DLC film pattern, the drug release rate can be controlled more precisely. Furthermore, the release rate of each medicine can be controlled by combining a plurality of kinds of medicines. For example, a fast release agent may be included in the polymer layers 302 and 402, respectively, and a slow release agent may be included in the polymer layer 102.

  Needless to say, the above-described embodiment and a plurality of modifications can be combined within a range in which the contents do not conflict with each other. Further, in the above-described embodiments and modifications, the structure of each part has been specifically described, but the structure and the like can be changed in various ways within the scope of the present invention.

(Production of drug-containing polymer)
MPC polymer (manufactured by NOF Corporation, bio-inspired YA01, 2-methacryloyloxyethyl phosphorylcholine / n-butyl methacrylate copolymer, copolymer composition 25 to 35 mol%) as hydrophilic polymer, EVA polymer (Sigma-) as hydrophobic polymer Aldrich, product number: 340502, vinyl acetate 40% by weight) was prepared. First, the MPC polymer was dissolved in ethanol and prepared to be a 1.8 wt% solution to obtain an MPC polymer solution. Moreover, the EVA polymer was dissolved in chloroform and prepared to be a 3 wt% solution to obtain an EVA polymer solution. Curcumin was dissolved in the above polymer solution as a placebo and stirred uniformly. The amount of curcumin was 20% by weight with respect to the polymer weight.

Example 1
A drug sustained-release member having the configuration shown in FIG. 1 was produced as follows. First, a 10 mm × 10 mm Si substrate 10 was placed on the electrode, and the inside of the chamber was decompressed to about 0.45 Pa using a rotary pump and a mechanical booster pump. Subsequently, ethylene gas was flowed into the chamber, and the pressure was adjusted to about 13.3 Pa. Next, plasma was generated by applying a high-frequency output of 200 W to produce a first DLC film 101 having a thickness of 0.1 μm. Next, 50 μL of the MPC polymer solution was applied and then left in a vacuum oven at 40 ° C. for about 1 day to prepare a curcumin-containing polymer layer 102. Thereafter, the substrate 10 was taken out from the vacuum oven, and a second DLC film 103 having a thickness of 0.1 μm was formed in the same manner as the first DLC film 101.

(Example 2)
Except that 50 μL of the EVA polymer solution was applied, the same operation as in Example 1 was performed to produce a drug sustained-release member having the configuration shown in FIG.

(Example 3)
A drug sustained-release member having the configuration shown in FIG. 2 was produced as follows. The same operation as in Example 1 was performed to prepare a curcumin-containing polymer layer 102. Next, after placing a cloth (trade name: SEFAR PETEX PET15hc) having fine holes on the surface of the polymer layer 102, the substrate 10 is placed on the electrode again, and a rotary pump and a mechanical booster pump are installed in the chamber. The pressure was reduced to about 0.45 Pa. Subsequently, ethylene gas was flowed into the chamber, and the pressure was adjusted to about 13.3 Pa. Thereafter, plasma was generated by applying a high-frequency output of 200 W to produce a second DLC film 203 having a thickness of 0.1 μm. Fig.4 (a) is a top view of the obtained chemical | medical agent sustained release member. As shown in the figure, a DLC pattern of 30 μm × 30 μm was observed.

Example 4
Except that the polymer layer 102 was made of an EVA polymer solution, the same operation as in Example 3 was performed to produce a drug sustained-release member having the configuration shown in FIG. FIG.4 (b) is a top view of the obtained chemical | medical agent sustained release member. As shown in the figure, a DLC pattern of 30 μm × 30 μm was observed.

(Comparative Example 1)
The second DLC film 103 was not formed on the drug sustained release member of Example 1.

(Comparative Example 2)
For the drug sustained release member of Example 2, the second DLC film 203 was not formed.

(Drug release)
In order to simulate biological conditions, 2 mL of a phosphate buffer solution (PBS, pH 7.4): ethanol = 9: 1 (hereinafter referred to as “dispersion medium”) at 37 ° C. was placed in a screw tube. Next, the drug sustained-release members obtained in Examples 1 to 4 and Comparative Examples 1 and 2 were each wetted with a dispersion medium. Thereafter, the dispersion medium was collected every other day and stored in another screw tube, and 2 mL of a new dispersion medium was put into the screw tube containing the drug sustained-release member. Then, the collected dispersion medium was measured with a spectrophotometer (U-2810 HITACHI), and the amount of drug released was measured by comparing the absorbance of the 350 nm peak.

(result)
The results are shown in FIG. FIG. 5A shows the results of Examples 1 and 3 and Comparative Example 1. FIG. 5 (b) shows the results of Examples 2 and 4 and Comparative Example 2. The horizontal axis represents time, and the vertical axis represents the cumulative value of the relative amount of absorbance. The relative amount of absorbance was determined by the following formula.
・ Relative amount of absorbance = absorbance of dispersion medium on day x / absorbance of dispersion medium on day 1

  As shown in FIG. 5, the curcumin release rate was slower when the EVA polymer was used compared to the MPC polymer. Moreover, the curcumin release rate could be further suppressed by using the patterned DLC film. In the MPC polymer, patterning of the DLC film suppressed curcumin release rate by about 0.7 times. On the other hand, in the EVA polymer, the curcumin release rate was suppressed to about 0.5 times by patterning the DLC film.

  A polyurethane elastomer (Pellethane (registered trademark) 2363-55DE, manufactured by The Dow Chemical Company, Inc.) was used instead of the MPC polymer, and was prepared in the same manner as the above MPC polymer solution. A sustained release member was prepared and drug release was examined. As a result, it was confirmed that curcumin was released.

  In addition, each polymer solution was prepared in the same manner with the amount of curcumin being 10% by weight based on the polymer weight, and then a drug sustained-release member was prepared according to the procedure of Example 1 to examine drug release. As a result, it was confirmed that curcumin was released.

  As mentioned above, although embodiment of this invention was described, these are illustrations of this invention and various structures other than the above are also employable.

Claims (13)

A drug sustained release member for indwelling,
A substrate;
A multilayer film covering the surface of the substrate and releasing a drug;
Have
The multilayer film is
A polymer film that contains the drug and that slowly releases the drug;
A protective film covering the polymer film and restricting the sustained release of the drug;
A drug sustained release member.   The said protective film consists of material containing a diamond-like carbon, The chemical | medical agent sustained release member of Claim 1 characterized by the above-mentioned.   The drug sustained-release member according to claim 1 or 2, wherein the multilayer film includes a diamond-like carbon film that covers a surface of the base material.   The drug sustained-release member according to any one of claims 1 to 3, wherein the protective film is a film patterned on the surface of the polymer film.   The drug sustained-release member according to any one of claims 1 to 4, further comprising at least one or more openings from which the surface of the polymer film is exposed.   The polymer film is made of silicon-urethane copolymer, polyurethane, phenoxy, polycaprolactone, polysulfone, polyacrylamide, poly (alkyl methacrylate), polyphosphoester, polyorthoester, poly (hydroxybutyrate), poly (diaxanone), poly (Hydroxyvalerate), poly (hydroxybutyrate-covalate), poly (glycolide-co-trimethylene carbonate), polyanhydride, poly (ester-amide), polyphosphazene, poly (phosphoester-urethane), poly Cyanoacrylate, polyethylene oxide, polyethylene carbonate, polyethylene, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polypropylene carbonate, polyamide, EVA Ethylene vinyl acetate) polymer, styrene-ethylene-butylene-styrene (SEBS), poly (lactide-co-glycolide), polylactide, elastin, fibrin, fibrinogen, cellulose, starch, collagen, hyaluronic acid, chondroitin sulfate, polylactic acid, poly 2. A polymer selected from the group consisting of glycolic acid, poly (amino acid), MPC (2-methacryloyloxyethylphosphorischoline) polymer, and N-isopropylacrylamide (NIPAM) polymer. 5. The drug sustained-release member according to any one of 5 above. The multilayer film is
A first multilayer film that releases a first drug as the drug;
A second multilayer film that releases the same or different second drug as the first drug and covers the surface of the first multilayer film;
The drug sustained-release member according to claim 1, comprising:   The drug sustained-release member according to any one of claims 1 to 7, wherein the base material is composed of at least one of a metal material, a ceramic material, and a polymer material.   The metal material is silicon, germanium, tungsten, stainless steel, nickel titanium alloy, copper aluminum manganese alloy, tantalum, cobalt chromium alloy, iridium, iridium oxide, niobium, platinum, titanium, chromium, titanium carbide, silicon carbide, The drug sustained-release member according to claim 8, wherein the drug sustained-release member is selected from the group consisting of chromium carbide.   The polymer material is selected from the group consisting of polyolefin, polyolefin elastomer, polyamide, polyamide elastomer, polyurethane, polyurethane elastomer, polyester, polyester elastomer, polyimide, polyamideimide, and polyetherketone. The drug sustained-release member according to 8.   The drug sustained-release member according to any one of claims 1 to 10, wherein the drug is selected from the group consisting of an antithrombotic agent, an anticancer agent, an immunosuppressive agent, an antibiotic and an anti-inflammatory agent.   12. The bioactive high molecular weight substance selected from the group consisting of protein, oligopeptide, DNA, ribonucleic acid, DNA plasmid, siRNA, and antisense molecule, according to any one of claims 1 to 11, The drug sustained-release member as described.   Stents, stent grafts, surgical instruments, anastomosis devices, artificial blood vessels, vascular grafts, cardiac prostheses, vascular patches, atrioventricular shunts, catheters, guidewires, dilatation balloon catheters, filters, infusion tubes The drug sustained-release member according to any one of claims 1 to 12, which is used for a medical device selected from the group consisting of: