JP2009201639A - Implant - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an implant using a safe material, controlling a medical agent sustained-release time and period and having superior biocompatibility. <P>SOLUTION: This implant has a substrate, a plurality of hydroxyapatite layers provided on a substrate surface, a medical agent-supported layer formed between the hydroxyapatite layers. The substrate is coated with hydroxyapatite having biocompatibility, so that this implant has superior biocompatibility. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an implant carrying a drug, and more particularly to an implant having excellent biocompatibility and excellent drug sustained release.

  Titanium (Ti), titanium alloy, stainless steel, cobalt-chromium (Co-Cr) alloy, etc. are used as a base material for in-vivo insertion implants such as stents for expanding stenosis, artificial bones, and artificial roots. . When an implant formed of these metals is inserted and placed in a living body, the implant is adapted to the living body after a long time.

  However, immediately after the implant is inserted, a biological reaction occurs around the metal. This biological reaction changes with the passage of time. The course of the biological reaction is several hours, several days, one month, one year or more immediately after implantation, and the resulting biological reaction is different. It is desired that the implant settles in the living body stably and early without any accident during this period. For this reason, attempts have been made to surface implants.

  For example, using a chemical vapor deposition method such as plasma CVD or a physical vapor deposition method such as an ion beam, diamond-like carbon (hereinafter referred to as “DLC”) is applied to the surface of the implant. Coating is performed (for example, refer nonpatent literature 1). This DLC is excellent in biocompatibility.

Alternatively, the surface of the implant is coated with hydroxyapatite having excellent biocompatibility (see, for example, Non-Patent Document 2).
Eye. Di. Scherder, “The Journal of Invasive Cardiology”, August 2000, Vol. 12, No. 8, pp. 389- Hideki Aoki, "Absurd biological material apatite", published in Bio-Dentals, 1999 Dean-Mo Liu, “Biomaterials”, 2002, Vol. 23, pp 691-698. D M Whelan, “Heart”, 2000, 83, pp 338-345

  Furthermore, in order to alleviate and heal the biological reaction after the implant is implanted in the living body, it has been attempted to carry the drug on the surface of the implant and gradually release it into the living body. The stent for vasodilation is commercialized as a drug-eluting stent (DES).

  However, in the implant described in Non-Patent Document 1, the surface of the coated DLC is lubricious and smooth. Moreover, DLC itself has no adsorptivity. For this reason, a chemical | medical agent cannot be carried closely on the surface of DLC.

  On the other hand, the hydroxyapatite used in Non-Patent Document 2 is also porous. By utilizing this, porous hydroxyapatite is coated on the implant surface, baked, and the pores of the coating film are impregnated and retained (for example, see Non-Patent Document 3). When this implant is embedded in a living body, the drug is released from the pores. Thereby, adaptation to the living body of an implant can be performed smoothly.

  However, the hydroxyapatite coating film is open to the surface. For this reason, when an implant impregnated with a drug is embedded in the living body, elution of the drug into the living body is started immediately after implantation, and the controlled drug release timing cannot be controlled. In addition, porous hydroxyapatite is degraded over time in vivo. For this reason, there also exists a problem that a base material is directly exposed in the living body.

  Moreover, what mixed the chemical | medical agent in the organic polymer and apply | coated to the surface of the implant is disclosed (for example, refer nonpatent literature 4). In this implant, after the implant is inserted, the drug is eluted into the living body together with the organic polymer as a support material and is released slowly.

  However, it has not been confirmed whether the organic polymer as a support material is inflamed or safe even after long-term use.

  That is, the present invention has been made in view of the above problems, and the purpose thereof is an implant that uses a safe material and can control the time and duration of drug sustained release and has excellent biocompatibility. The purpose is to provide.

  As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention are implants using hydroxyapatite and having a plurality of hydroxyapatite layers formed on a base material, the drug being carried between the hydroxyapatite layers. The present invention was completed by finding an implant provided with a layer. The implant of the present invention is as follows.

  The implant of the present invention has a base material, a plurality of hydroxyapatite layers provided on the surface of the base material, and a carrier drug layer formed between the hydroxyapatite layers. Moreover, the carrying | support chemical | medical agent layer may be further formed in the uppermost layer surface of a hydroxyapatite layer.

  In the implant of the present invention, a plurality of hydroxyapatite layers having a laminated structure are formed using hydroxyapatite which is a highly safe inorganic material. Hydroxyapatite is recognized as having excellent biocompatibility and safety even when used for a long time. In addition, the drug can be carried between the hydroxyapatite layers or the layer surface of the laminated structure. Thereby, a required chemical | medical agent can be released gradually according to progress of biological reaction.

  Of the plurality of hydroxyapatite layers, the hydroxyapatite layer in direct contact with the substrate is preferably hydroxyapatite with high crystallinity. Hydroxyapatite with high crystallinity does not elute in vivo. That is, hydroxyapatite excellent in biocompatibility continues to exist on the surface of the implant. As a result, the biocompatibility of the implant is maintained.

  Of the plurality of hydroxyapatite layers, at least one hydroxyapatite layer may have a crystal structure, composition, and layer thickness different from those of other hydroxyapatite layers. Thereby, the chemical | medical agent sustained release time of the carrying | support chemical | medical agent layer formed in the lower side (base material side) of the some hydroxyapatite layer is controllable.

  In the present specification, “lower side” means the base material side, and “upper side” means the outermost surface side of the implant.

  The hydroxyapatite layer may have a different layer thickness within the layer. Each hydroxyapatite layer elutes with time from the surface exposed to the living body. The elution time of the same layer can be changed by making the thicknesses different within the same hydroxyapatite layer. As a result, the drug elution period of the supported drug layer formed on the lower side (base material side) of the hydroxyapatite layer can be controlled.

  The implant of the present invention has a base material, a plurality of hydroxyapatite layers provided on the surface of the base material, and a carrier drug layer formed between the hydroxyapatite layers. Since the substrate is coated with hydroxyapatite having biocompatibility, an implant excellent in biocompatibility can be obtained.

  In addition, a carrier drug layer is formed between the hydroxyapatite layers having a laminated structure. The controlled drug release timing can be controlled by controlling the crystal structure, composition, and layer thickness of the hydroxyapatite layer formed on the upper side of the supported drug layer.

The present invention is described in detail below.
[Implant]
FIG. 1 is a conceptual diagram illustrating the structure of the implant of the present invention. As shown in FIG. 1, the implant of the present invention includes a base material 1, a plurality of hydroxyapatite layers 3, 5, 7, 9 provided on the surface of the base material, and the hydroxyapatite layers 3, 5, 7, It has carrier drug layers 4, 6, 8 formed between nine layers. In the example of this figure, no carrier drug layer is formed on the surface of the hydroxyapatite layer 9. In this figure, an antioxidant film 2 is provided between the base material 1 and the hydroxyapatite layer 3.

  The type of the implant of the present invention is not particularly limited as long as it is inserted or embedded in a living body and placed in the living body. For example, a vascular expansion stent, an artificial bone, an artificial tooth root, and the like. In the case where a part thereof is placed in the living body such as an artificial tooth root, the part to be placed in the living body may be the structure of the implant of the present invention. Alternatively, a part of the implant placed in the living body may be the structure of the implant of the present invention.

  As the substrate 1 constituting the implant of the present invention, a known material is used. Known materials include metal materials such as titanium (Ti), titanium (Ti) alloy, stainless steel, cobalt (Co) -chromium (Cr) alloy, and polymer materials such as polyolefin such as polyethylene and polypropylene, and polyester. May be used. A metal material having heat stability is preferable.

The hydroxyapatite layer constituting the implant of the present invention is composed of hydroxyapatite. The hydroxyapatite used in the present invention has Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ as a basic composition. What further doped sodium (Na), magnesium (Mg), etc. to this hydroxyapatite may be used.

  Hydroxyapatite has the above composition. When a drug is coated on the surface of the hydroxyapatite layer, the drug is adsorbed on calcium ions (+) and phosphate groups (−) on the hydroxyapatite surface. Thereby, a carrying | support chemical | medical agent layer can be formed.

  In the present specification, “crystallinity” is a collection of regularly arranged apatite crystal unit cells constituting an apatite layer. High crystallinity means that the ratio of crystallized grains and non-crystallized parts or defective parts is high, and that the ratio of crystallized parts in the whole layer is high, and low crystallinity means that the whole layer This means that the ratio of the ratio of non-crystallized parts and defective parts is high.

  As will be described below, at least one of the hydroxyapatite layers 3, 5, 7, and 9 has a crystal structure, composition, and layer thickness different from those of the other hydroxyapatite layers. Note that the crystal structure includes crystallinity.

  The hydroxyapatite layer 3 provided in direct contact with the base material needs to remain on the surface of the base material 1 even if the hydroxyapatite layers 5, 7, 9 provided on the upper side of the hydroxyapatite layer 3 are eluted. . Thereby, the biocompatibility of the implant can be maintained. For this reason, it is preferable that the hydroxyapatite layer 3 provided in direct contact with the surface of the substrate 1 is composed of hydroxyapatite having high crystallinity.

  In addition, in order to improve the adhesiveness between the base material 1 and the hydroxyapatite layer 3, a hydroxyapatite thin film functioning as the antioxidant film 2 may be provided between the base material 1 and the hydroxyapatite layer 3. Also in this case, the highly crystalline hydroxyapatite layer 3 remaining on the surface of the substrate 1 is defined as the hydroxyapatite layer 3 provided in direct contact with the substrate 1.

  The thickness of the hydroxyapatite layer 3 provided in direct contact with the substrate 1 may be in the range of 50 nm to 800 nm. If the thickness of the hydroxyapatite layer 3 is within this range, the adhesion strength with the substrate 1 can be sufficiently increased.

  The surface of the hydroxyapatite layer 3 provided in direct contact with the substrate 1 is active. For this reason, a drug can be carried on the surface of the hydroxyapatite layer 3. That is, the carrier drug layer 4 can also be provided on the hydroxyapatite layer 3 provided in direct contact with the substrate 1.

  A plurality of hydroxyapatite layers 5, 7, 9 are provided on the surface of the hydroxyapatite layer 3 provided in direct contact with the substrate 1. Carrier drug layers 4, 6, 8 can be provided between the hydroxyapatite layers 3, 5, 7, 9. The plurality of hydroxyapatite layers 5, 7, and 9 are preferably made of hydroxyapatite having low porous crystallinity. This is because, when the hydroxyapatite layers 5, 7, 9 are formed, the drug carried on the carried drug layer formed thereunder is not damaged. Further, in the hydroxyapatite layers 5, 7, and 9 having low crystallinity, since the hydroxyapatite is eluted, the drug supported on the supported drug layers 4, 6, and 8 formed thereunder can be gradually released. Because.

  Moreover, the carrying | support chemical | medical agent layer may be provided in the hydroxyapatite layer 9 surface formed in the uppermost (uppermost layer) among the some hydroxyapatite layers 5, 7, and 9.

  Each hydroxyapatite layer 5, 7, 9 has a hydroxyapatite crystal structure, composition, layer depending on the type, properties, elution period, etc. of the drug supported on the supported drug layers 4, 6, 8 formed below the hydroxyapatite layer 5, 7, 9. The thickness of the can be changed. For example, when the hydroxyapatite crystallinity is low, the elution rate is increased, and when the crystallinity is increased, the elution rate can be decreased. Moreover, elution characteristics can be changed by changing the kind and concentration of sodium (Na), magnesium (Mg), etc., which are doped into hydroxyapatite. Specifically, the higher the doping concentration, the faster the elution rate. If the crystallinity is the same, decreasing the thickness of the layer will increase the elution time of the layer, and increasing the thickness will decrease the elution time of the layer.

  Further, in the same hydroxyapatite layer, the layer thickness may be different within the layer. The hydroxyapatite layer elutes with time from the surface exposed to the living body. When the layer thickness is different within the layer, the time for which the carrier drug layer is exposed differs. As a result, the same drug can be released slowly with a time difference.

  The crystal structure, composition, layer thickness, etc. of hydroxyapatite may be used in appropriate combination in consideration of the drug to be carried. For example, the crystallinity of hydroxyapatite improves as the hydroxyapatite is processed at a higher temperature. It is necessary to form this hydroxyapatite layer at a temperature not higher than the heat resistance temperature of the drug carried on the hydroxyapatite layer formed under the hydroxyapatite layer to be provided. Therefore, the hydroxyapatite layer having the thickness and properties necessary for elution of the drug to be carried may be formed by adjusting the composition of hydroxyapatite, the thickness of the layer, and the like.

  As the drug to be carried, a necessary drug may be appropriately selected and used depending on the purpose of use of the implant of the present invention. Specifically, thrombin inhibitors; antithrombotic agents; thrombolytic agents; fibrinolytic agents; vasospasm suppressants; calcium channel blockers; vasodilators; antihypertensive agents; antibacterial agents such as antibiotics (tetracycline, chlortetracycline) , Bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamide, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxoxax Sol, nitrofurazone, sodium propionate, etc.), antifungal drugs (amphotericin B, miconazole, etc.) and antiviral drugs (idoxuridine, trifluorothymidine, acne Lobil, ganciclovir, interferon, etc.); surface glycoprotein receptor inhibitors; antiplatelet drugs; cytostatic drugs; microtubule inhibitors; antisecretory drugs; active inhibitors; remodeling inhibitors; nucleic acid compounds (plasmid DNA) , Genes, siRNA, type nucleic acid pharmaceuticals (decoy), polynucleotides, oligonucleotides, antisense oligonucleotides, ribozymes, apeters, interleukins, intercellular signal transmitters (cytokines), etc.); antimetabolites; antiproliferative drugs ( Including anti-angiogenic agents; anti-cancer chemotherapeutic agents; anti-inflammatory agents (hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medorizone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometallone, Betamethasone Triamcinolone, triamcinolone, acetonide, etc.); Nonsteroidal anti-inflammatory drugs (salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam, etc.); Antiallergic drugs (sodium cromoglycate, antazoline, metapyridine, chlorpheniramine, cetridine) Antiproliferative drugs (such as 13-cis retinoic acid); anti-inflammatory drugs (such as phenylephrine, naphazoline, tetrahydrazoline); miotic drugs and anticholinesterases (pilocarpine, salicylate, carbachol, chloride) Acetylcholine, physostigmine, eserine, diisopropyl fluorophosphate, phospholine / iodine, deme potassium bromide, etc.); atropinsurface Clopentrate, homatropine, scopolamine, tropicamide, eucatropine, hydroxyamphetamine, etc .; sympathomimetic drugs (epinephrine, etc.); anti-neoplastic drugs (carmustine, cisplatin, fluorouracil, etc.); ); Hormone agents (such as estrogen, estradiol, progesterone, progesterone, insulin, calcitonin, parathyroid hormone, peptides and vasopressin hypothalamic release factor); beta blockers (such as timolol maleate, levobanolol hydrochloride, betaxolol hydrochloride); immunosuppression Agents, growth hormone antagonists, growth factors (epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor beta, somatotropin, fibronectin Carbonic anhydrase inhibitors (dichlorophenamide, acetazolamide, metazolamide, etc.); angiogenesis inhibitors (angiostatin, annecortab acetate, thrombospondin, anti-VEGF antibody, etc.); dopamine agonists; radiation therapy drugs; peptides; Proteins; enzymes; extracellular matrix components; ACE inhibitors; free radical scavengers; chelators; antioxidants; polymerase inhibitors; photodynamic therapy drugs; gene therapy drugs; and other therapeutic drugs such as prostaglandins, Anti-prostaglandin drugs, prostaglandin precursors, etc.

  In particular, when a nucleic acid compound is carried on a stent, the nucleic acid compound can be safely and efficiently introduced into the stenosis using the stent. For this reason, it becomes an effective treatment method with little possibility of recurrence treating the stenosis part at the nucleic acid level. As the nucleic acid compound, plasmid DNA, gene, decoy, siRNA, oligonucleotide, antisense oligonucleotide, ribozyme, and apter are particularly preferable.

The drug may be supported by selecting a hydroxyapatite layer according to the time of sustained release. For example, the biological reaction after the vascular expansion stent is inserted into the blood vessel is generated as follows.
(Phase 1) Thrombin clotting stage of platelets (~ 14 days)
(Phase 2) Acute inflammation stage (~ 3 months)
(Phase 3) Micro-organization stage (~ smooth muscle cell proliferation)
(Phase 4) Tissue cell expansion stage (~ 1 year or more)
(5th) Reorganization stage (~ 18 months or more)

  In the implant of the present invention, for example, on the upper layer of the laminated hydroxyapatite layer (the hydroxyapatite layer 7 provided on the side away from the base material), the initial stage: (first stage), (second stage) On the inner layer of the laminated hydroxyapatite layer (hydroxyapatite layers 3 and 5 provided on the base material side) carrying an antithrombotic agent or an anti-inflammatory agent as a therapeutic agent, (phase 3), ( A drug such as an anticancer agent, an immunosuppressive agent, and other cell growth inhibitor capable of coping with the biological reaction of (4th stage) and (5th stage) is carried. Thereby, the chemical | medical agent according to the change of the biological reaction can be released gradually.

[Method for producing implant]
The implant of the present invention can be produced, for example, as follows.
In the implant of the present invention, the hydroxyapatite layer is formed by excimer laser ablation.

  FIG. 2 is a diagram for explaining an outline of an excimer laser ablation apparatus for forming a hydroxyapatite layer. The excimer laser ablation apparatus of FIG. 2 includes a vacuum film forming chamber 11, an evacuation pump 12, a coating object setting table 13, a coating object heater 14, a coating target table 15, and a gas introduction nozzle 16. , ArF excimer laser source 17, thermometer 23, and film thickness meter 24.

  For example, in the case of forming a hydroxyapatite layer having high crystallinity, a substrate to be coated is placed on the substrate set base 13 in the vacuum film forming chamber 11 of the apparatus, and the hydroxyapatite target is placed on the coating target base 15. (For example, calcium phosphate) is installed. Next, the vacuum film formation chamber 11 is evacuated to a predetermined degree of vacuum using a rotary pump and a turbo molecular pump which are vacuum pumps 12. After evacuation, the inside of the vacuum film forming chamber 11 is heated to a predetermined temperature using the coating object heater 14. The coating object heater 14 is provided with a heater temperature controller 22 so that the inside of the vacuum film forming chamber 11 can be set to a predetermined temperature.

  Next, water vapor or water vapor-containing gas is introduced from the gas introduction nozzle 16 into the vacuum film formation chamber 11. Examples of the water vapor-containing gas include a mixed gas of oxygen and water vapor, a mixed gas of argon and water vapor, a mixed gas of helium and water vapor, a mixed gas of nitrogen and water vapor, and a mixed gas of air and water vapor. It is done. The water vapor-containing gas is produced as follows, for example. A high-purity gas is introduced from the gas supply source 25 such as the cylinder into the pure water in the tank 26 and bubbled. Thereby, water vapor containing gas is obtained.

  Next, the laser is oscillated from the ArF excimer laser source 17, the direction of light is changed by the mirror 18, the light is condensed by the lens 19, and the laser passing through the slit 21 is incident from the window 20 of the vacuum film forming chamber 11, Irradiate an apatite target. Atoms, molecules, ions, and the like generated by this ablation are deposited on the substrate on the coating set base 13 installed at the opposing position. Whether or not the hydroxyapatite layer has reached a predetermined thickness is measured using a film thickness meter 24.

  In order to coat hydroxyapatite with high crystallinity, the coating may be performed at a high coating temperature (300 ° C. or more and 600 ° C. or less) in an atmosphere of water vapor or water vapor-containing gas. If hydroxyapatite is coated under such conditions, the hydroxyapatite grows on the substrate while crystallizing.

  On the other hand, in order to coat hydroxyapatite having low crystallinity, it may be performed at a low coating temperature (room temperature or higher and lower than 300 ° C.) in an atmosphere of water vapor or water vapor-containing gas. If hydroxyapatite is coated under such conditions, amorphous hydroxyapatite grows on the substrate. After such an amorphous hydroxyapatite layer is formed, the amorphous hydroxyapatite can also be crystallized by heat treatment in water vapor (post-annealing method) (300 ° C. or more and 600 ° C. or less).

  There is no particular limitation on how the hydroxyapatite is coated on the implant, and an appropriate method may be selected depending on the implant to be used. For example, in order to coat hydroxyapatite on the entire surface of the implant, a rotary set base 13 is used. Coating may be performed while rotating so that the entire implant surface is coated. Moreover, what is necessary is just to coat the part which does not need coating by shielding using a shielding slit, and a part other than that.

  In addition, in order to form hydroxyapatite layers having different layer thicknesses within the layer, the hydroxyapatite may be deposited by inclining the coating set base 13 installed at the facing position.

  The carrier drug layer is formed as follows. For example, an implant with a hydroxyapatite layer formed is immersed in a solution in which the drug is dissolved and dried, or the surface of the hydroxyapatite layer adsorbed and applied by spraying is dried. To do. When it is desired to release the same component drug over a long period of time, the above operation is repeated to form a thick supported drug layer or, as will be described later, the same supported drug layer and the hydroxy layer formed thereon. This can be done by laminating the apatite layer a desired number of times.

  A hydroxyapatite layer is formed on the formed supporting drug layer. The hydroxyapatite layer may be formed by the excimer laser ablation. In this case, it is necessary to perform coating at a temperature lower than the heat resistance temperature of the supported drug. Therefore, in order to delay the dissolution of the supported drug, the thickness of the hydroxyapatite layer may be increased.

  The hydroxyapatite layer to be coated need not be formed directly on the supported drug layer. For example, a separately formed hydroxyapatite layer may be placed on the carrier drug layer. Specifically, the following may be performed. Hydroxyapatite is coated on the surface of a smooth plate or single crystal flat plate soluble in a solvent by the excimer laser ablation. Thereafter, a smooth plate or a single crystal plate is dissolved with a solvent to produce a hydroxyapatite thin film (film thickness of about 1 μm). A hydroxyapatite layer can be formed by adsorbing and adhering this hydroxyapatite thin film to the upper surface of the carrier drug layer. According to this method, it is possible to form a hydroxyapatite layer to be coated without considering the heat resistant temperature of the supported drug. As a result, a hydroxyapatite thin film with controlled crystallinity is obtained. Thereby, even if the film thickness of the hydroxyapatite layer to be formed is thin, the elution of the drug from the supported drug layer can be delayed. Alternatively, a hydroxyapatite thin film in which a drug for forming the next supported drug layer is previously supported on the surface opposite to the surface to be applied to the supported drug layer may be adsorbed and attached to the upper surface of the supported drug layer.

  The formation of the carrier drug layer and the hydroxyapatite layer coated thereon can be repeated a plurality of times to obtain an implant carrying a desired drug.

  The carrier drug layer may be formed using a single drug, or may be formed by mixing a plurality of drugs. If necessary, a plurality of supported drug layers made of the same type of drug may be formed.

When the above method is used, an implant having the structure exemplified below can be obtained.
(Stent)
FIG. 3 is a conceptual diagram showing an outline of an example of a stent for expanding a blood vessel stenosis. The stent for expanding a blood vessel stenosis part shown in the example of this figure has a shape of a substantially tubular body 31 having both ends opened and having an outer diameter suitable for a blood vessel to be treated. This stent has a fine wire mesh shape having pores 30 on the surface of the tubular body 31 so that the stent can be expanded after being inserted and installed in the affected area.

  The stent for expanding a blood vessel stenosis is used as follows. Such a stent is extrapolated and supported on the balloon portion of the balloon catheter, and is inserted into the affected portion of the vascular stenosis. After installation on the affected blood vessel, internal pressure is applied to the balloon catheter to expand the balloon. At the same time, the extrapolated stent is expanded, and the stent is placed in the affected area in the blood vessel. After the stent is installed, the internal pressure of the balloon catheter is reduced, and the balloon portion is contracted and folded. Thereafter, the balloon catheter is pulled out of the body, and the stent placement operation is completed.

  FIG. 4 is a diagram for explaining an example of a case where the stent for expanding a blood vessel stenosis portion has a laminated structure of the implant of the present invention. In FIG. 4, a base material 32, an antioxidant film 33, a first hydroxyapatite layer 34, a supported drug first layer 35, a second hydroxyapatite layer 36, a supported drug second layer 37, 3, a hydroxyapatite layer 38, a third carrier drug layer 39, and a fourth hydroxyapatite layer 40. Such an implant is produced, for example, as follows.

  First, the surface of a stent made of a metal material having a good biocompatibility such as a SUS material or a Co—Cr alloy is cleaned. Next, pickling or electropolishing is performed to remove the oxide film. Next, a temperature rise process is performed in vacuum to remove the occluded gas in the stent.

The stent is placed on the rotary set base 13 in the vacuum film forming chamber 11 provided in the excimer laser ablation apparatus shown in FIG. Next, the vacuum exhaust system pump 12 is used to exhaust to a vacuum degree of about 1.33 × 10 ⁻⁵ Pa (1 × 10 ⁻⁷ Torr). The temperature is raised to a predetermined temperature of about 300 ° C. by the heater of the rotary set table 13. After the temperature rise, a laser is oscillated from the ArF excimer laser source 17 to pre-coat the target hydroxyapatite on the surface of the stent (base material 32). This hydroxyapatite layer functions as the antioxidant film 33 and is not an essential layer for the hydroxyapatite layer of the implant of the present invention. The hydroxyapatite layer provided as the antioxidant film 33 may be an extremely thin film of about 30 nm, for example.

  Next, a mixed gas of oxygen and water vapor is introduced into the vacuum film forming chamber 11. The atmospheric pressure in the vacuum film forming chamber 11 is set to about 1.1 Pa (0.8 mTorr). A hydroxyapatite layer 34 is formed by coating the antioxidant film 33 with hydroxyapatite. This coating is performed at a temperature of 100 to 300 ° C., and heat treatment is performed at 450 ° C. after film formation. As a result, the obtained first hydroxyapatite layer 34 has high crystallinity.

  Next, the stent on which the first hydroxyapatite layer 34 is formed is taken out from the vacuum film formation chamber 11. The stent is immersed in a solution in which the drug is dissolved. After soaking, the carrier drug first layer 35 is formed by lifting and drying. In order to increase the amount of drug carried, dipping and coating may be repeated. This is the lowermost layer of the carrier drug first layer 35. The drug to be carried is a drug to be finally released gradually. For example, a drug such as an anticancer agent, an immunosuppressive agent, or a cell growth inhibitor used in the (5th stage) reorganization stage (up to 18 months or more) may be used.

  Next, the implant provided with the first carrier drug layer 35 is placed on the rotary set base 13 in the vacuum film formation chamber 11 again. The next hydroxyapatite coating is performed at a temperature lower than the heat resistance temperature of the supported drug. The obtained second hydroxyapatite layer 36 has low crystallinity and is in an amorphous state. The thickness of the second hydroxyapatite layer 36 controls the timing of sustained release of the drug carried on the carried drug first layer 35.

  In order to coat amorphous hydroxyapatite with low crystallinity, a gas atmosphere pressure of about 0.1 Pa (0.8 mTorr) may be used using a mixed gas of oxygen and water vapor. At this level of gas atmosphere pressure, the gas pressure is relatively high, the coating wraps around well, and the inside of the fine mesh wire existing on the surface of the stent tubular body can be efficiently coated.

  Similarly to the above, by immersing the stent in a solution in which the drug is dissolved, the carrier drug second layer 37 is formed on the second hydroxyapatite layer 36 coated with hydroxyapatite having low crystallinity and amorphous state. Form. The medicine carried on the carried medicine second layer 37 may be the same as or different from the above. Preferably, it is a drug used in the (stage 4) tissue cell expansion stage (~ 1 year or more).

  In the same manner as described above, an amorphous third hydroxyapatite layer 38, a supported drug third layer 39, and a fourth hydroxyapatite layer 40 are sequentially formed on the supported drug second layer 37, as shown in FIG. A stent having a laminated structure is obtained. Since the drug carried on the carried drug third layer 39 elutes relatively early, the drug used in the (first stage) platelet thrombin clotting stage (~ 14 days), (second stage) acute inflammation stage (~ 3 months) May be carried.

(Artificial bone)
FIG. 5 is a conceptual diagram showing an example of an artificial bone for a hip joint. The artificial hip joint shown in the example of this figure includes a stem 41 on the femoral side made of metal such as cobalt-chromium alloy or titanium alloy, and a head 42 on the pelvis side made of polyethylene in a metal shell. Has been. This stem 41 is inserted into the bone marrow of the femur and is placed. The inserted artificial bone insertion portion needs to be fixed by the surrounding femoral tissue and new bone. For this reason, a laminated structure may be formed on the surface of the stem 41 including a carrier drug layer that carries a drug such as an anti-inflammatory drug in the same manner as in the case of the stent for expanding a vascular stenosis.

(Artificial root implant fixture)
FIG. 6 is a diagram showing a usage mode when an artificial tooth is provided on the artificial tooth root using the implant of the present invention. As shown in FIG. 6, an artificial body (superstructure) 43, which is a part formed from ceramic and the like and protrudes from the gingiva 45 like the natural tooth 44, and an implant body that is an implant corresponding to a root part. (Fixture) 46 and an abutment 47 which is a part for connecting the implant body (fixture) 46 and the artificial tooth of the superstructure.

  FIG. 7 is a conceptual diagram for explaining the structure of the implant body (fixture) 48. This implant body (fixture) 48 is implanted into the rough bone tissue in the gingiva and placed therein. The implant body (fixture) 48 is made of a metal having good biocompatibility such as titanium and titanium alloy, and a laminated structure 49 of a hydroxyapatite layer and a carrier drug layer is formed on the surface thereof. It is composed.

  Said implant body (fixture) can be manufactured as follows, for example. FIG. 8 is a conceptual diagram showing an example of a laminated structure of a hydroxyapatite layer and a carrier drug layer formed on the implant body (fixture) surface. In the example of FIG. 8, the substrate 50, the antioxidant film 51, the first hydroxyapatite layer 52, the carrier drug first layer 53, and the second hydroxyapatite layer 54 are configured.

  First, an antioxidant film 51 made of hydroxyapatite is formed on the surface of a base material 50 that is an implant body (fixture) under the same conditions as in the case of the stent for expanding a vascular stenosis. Next, the first hydroxyapatite layer 52 having a high degree of crystallinity is formed on the surface of the antioxidant film 51 under the same conditions as in the case of the stent for expanding a stenosis. The total thickness of these laminated layers may be about 2 μm.

  The implant body (fixture) on which the first hydroxyapatite layer 52 is formed is immersed in a solution in which the drug is dissolved to adsorb the drug. This is dried to form the carrier drug first layer 53. As the drug to be carried, an anti-inflammatory agent or the like is used in order to alleviate a biological reaction, accelerate treatment and colonization, and improve the reaction.

  The second hydroxyapatite layer 54 provided on the carrier drug first layer 53 is formed as follows. First, a hydroxyapatite thin film is prepared. For example, hydroxyapatite is coated on a water-soluble smooth flat plate such as a salt crystal thin plate by excimer laser ablation. The film thickness of hydroxyapatite should be 1 μm or less. Thereafter, a smooth flat plate coated with hydroxyapatite is put into water. Thereby, a smooth flat plate melt | dissolves in water. The hydroxyapatite thin film floats on the water surface. This hydroxyapatite thin film is adsorbed and coated on the surface of the carrier drug first layer 53. Thereby, a laminated structure including the carried drug first layer 53 carried in the same manner as in the case of the above-described stent for expanding a vascular stenosis part is formed.

  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to the examples.

(Drug dissolution test)
The elution of the drug in the supported drug layer was measured as follows.
The dissolution of the drug in the supported drug layer was measured by a quartz crystal microbalance (hereinafter referred to as “QCM”) method. FIG. 9 is a diagram for explaining the shape of the crystal oscillator used in this measurement. In FIG. 9, a crystal oscillator 59 (AFFINIX-Q, manufactured by Initiam Co., Ltd.) includes a crystal oscillator probe case 55, a crystal oscillator front-side gold electrode 56 of the probe case, and a crystal oscillator back-side gold electrode ( (Not shown), a front-side gold electrode terminal 57, and a back-side gold electrode terminal 58. The front gold electrode 56 is exposed on the surface of the probe case 55.

  A laminated structure used for the drug elution test was formed on the surface of the front side gold electrode 56. FIG. 10 is a diagram showing a laminated structure formed in this example. First, a crystal oscillator was placed on the object set base 13 of the vacuum film forming chamber 11 of the excimer laser ablation apparatus of FIG. The probe case 55 of the crystal oscillator 59 to be coated includes a crystal oscillator back side gold electrode 60, a crystal oscillator 59, and a crystal oscillator front side gold electrode 61.

  Next, a hydroxyapatite layer (not shown) was formed on the surface of the crystal oscillator gold electrode 61 at room temperature without energizing the coating object heater 14.

  Next, the vacuum film formation chamber 11 was evacuated using the vacuum pump 12. Next, the first hydroxyapatite layer having a thickness of 0.25 μm is introduced into the vacuum film forming chamber 11 in a gas atmosphere having a gas pressure of 0.1 Pa (0.8 mTorr). 62 was formed. Since the first hydroxyapatite layer 62 was formed at room temperature, it was amorphous.

  As the drug to be carried, dsDNA (double-stranded deoxyribonucleic acid) was used. A solution obtained by diluting dsDNA at a concentration of 13 mg / mL with 570 μL of pure water (diluted 20 times) was used as a drug solution.

The surface of the quartz oscillator front side gold electrode 61 of the probe case in which the first hydroxyapatite layer 62 was formed was immersed in the solution for 2 hours to adsorb dsDNA. Thereafter, the probe was pulled up and water was removed with a blower to form the first carrier drug layer 63. The amount of dsDNA supported on the supported drug first layer 63 was 17 pmol / mm ² . The area of the crystal oscillator front side gold electrode 61 is 4.95 mm ² . From this, the amount of dsDNA supported on the supported drug first layer 63 was 89 pmol.

  Next, a second hydroxyapatite layer 64 was formed in the same manner as described above. Further, a second carrier drug layer 65 was formed in the same manner as described above. The drug carried on the carried drug second layer 65 is dsDNA as described above. The amount of dsDNA supported was also the same as above.

  The hydroxyapatite layers 62 and 64 and the carrier drug layers 63 and 65 were formed on the surface of the gold electrode 46 on the front side of the crystal oscillator by using a crystal oscillator microbalance (QCM) method (AFFINIX-Q manufactured by Initiam Co., Ltd.). Quartz crystal drug elution was measured. As a drug elution measurement solution, 1 mol tris-hydrochloric acid (2-amino-2-hydroxymethyl-1,3-propanediol-hydrochloric acid) (pH 8.0) was diluted 100 times with distilled water. 8 mL was used.

  The measurement was performed as follows. The immersion part of the probe in FIG. 9 was immersed in the measurement solution, and the crystal resonator was continuously operated to obtain the resonance frequency of the crystal resonator. The results are shown in FIG.

  FIG. 11 is a graph showing a change in the resonance frequency of the quartz crystal resonator as the carrier on the quartz crystal resonator is eluted into the liquid. In this figure, the horizontal axis indicates the time (hr) from the start of measurement, and the vertical axis indicates the resonance frequency (Hz) of the crystal resonator. When the QCM method is used, molecular elution can be detected by a change in the resonance frequency of the crystal oscillator. For example, the resonance frequency changes depending on the load of the carrier drug layer laminated on the gold electrode of the crystal oscillator. The resonance frequency increases as the load decreases due to the dissolution of hydroxyapatite and the supported drug layer into the solution. Thereby, the amount of elution into the solution is known. In addition, the rate of change in the increase of the resonance frequency changes depending on the substance to be eluted, and it can be seen which layer is eluted. In FIG. 11, the carrier drug layer (described as “DNA” in the figure) formed on the outermost surface of the gold electrode of the crystal oscillator is first eluted over 35 hours. Thereafter, the hydroxyapatite layer (described as “HAp” in the figure) is eluted over 205 hours. Next, it can be seen that the drug supported on the supported drug layer is eluted over 36 hours.

  From the above results, it can be seen that when the supported drug layer is provided via the hydroxyapatite layer, the supported drug can be released slowly with a time difference. It can also be seen that by changing the number of layers, the drug can be gradually released step by step at a number corresponding to the number of layers.

FIG. 1 is a conceptual diagram illustrating the structure of the implant of the present invention. FIG. 2 is a diagram for explaining an outline of an excimer laser ablation apparatus for forming a hydroxyapatite layer. FIG. 3 is a conceptual diagram showing an outline of an example of a stent for expanding a blood vessel stenosis. FIG. 4 is a diagram for explaining an example of a case where the stent for expanding a blood vessel stenosis portion has a laminated structure of the implant of the present invention. FIG. 5 is a conceptual diagram showing an example of an artificial bone for a hip joint. FIG. 6 is a diagram showing a usage mode when an artificial tooth is provided on the artificial tooth root using the implant of the present invention. FIG. 7 is a conceptual diagram for explaining the structure of an implant body (fixture). FIG. 8 is a conceptual diagram showing an example of a laminated structure of a hydroxyapatite layer and a carrier drug layer formed on the implant body (fixture) surface. FIG. 9 is a diagram for explaining the shape of the crystal oscillator used in this measurement. FIG. 10 is a diagram showing a laminated structure formed in this example. FIG. 11 is a graph showing a change in the resonance frequency of the quartz crystal resonator as the carrier on the quartz crystal resonator is eluted into the liquid.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Base material 2 Antioxidation film 3 Hydroxyapatite layer 4 Carrying drug layer 5 Hydoxyapatite layer 6 Carrying drug layer 7 Hydroxyapatite layer 8 Carrying drug layer 9 Hydoxyapatite layer 11 Vacuum film formation chamber 12 Vacuum exhaust system pump 13 Coating object setting table 14 Coating object heater 15 Coating target table 16 Gas introduction nozzle 17 ArF excimer laser source 18 Mirror 19 Lens 20 Window 21 Slit 22 Heater temperature controller 23 Thermometer 24 Film thickness meter 25 Gas supply source 26 Tank 30 Pore 31 Tubular body 32 Base material 33 Antioxidant film 34 First hydroxyapatite layer 35 First drug loaded layer 36 Second hydroxyapatite layer 37 Second drug loaded layer 38 Third hydroxyapatite layer 39 Carrier medicine third layer 40 4 Hyde apatite layer 41 stem 42 head 43 artificial teeth 44 natural tooth 45 gingiva 46 implant body (fixture)
47 Abutment 48 Implant (Fixture)
49 Laminated Structure of Hydroxyapatite Layer and Supported Drug Layer 50 Base Material 51 Antioxidant Film 52 First Hydroxyapatite Layer 53 Supported Drug First Layer 54 Second Hydroxyapatite Layer 55 Measuring Element Case 56 Crystal Oscillator Front Side Gold electrode 57 Front side gold electrode terminal 58 Back side gold electrode terminal 59 Crystal oscillator 60 Crystal oscillator back side gold electrode 61 Crystal oscillator front side gold electrode 62 First hydroxyapatite layer 63 Supported drug first layer 64 Second hydroxyapatite layer 65 Carrier drug second layer

Claims (6)

A substrate;
A plurality of hydroxyapatite layers provided on the surface of the substrate;
A carrier drug layer formed between the hydroxyapatite layers;
Having an implant.   The implant according to claim 1, wherein the carrier drug layer is further formed on the uppermost surface of the hydroxyapatite layer.   The implant according to claim 1 or 2, wherein a hydroxyapatite layer in direct contact with a substrate among the plurality of hydroxyapatite layers is composed of hydroxyapatite having high crystallinity.   The implant according to any one of claims 1 to 3, wherein at least one hydroxyapatite layer among the plurality of hydroxyapatite layers has a crystal structure, a composition, and a layer thickness different from those of the other hydroxyapatite layers.   The implant according to any one of claims 1 to 4, wherein the hydroxyapatite layer has a different layer thickness within the layer. The implant according to any one of claims 1 to 5, wherein the supported drug layer is loaded with a different drug from the implant surface toward the base material according to a sustained release order.

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