WO2018032664A1 - 一种可载药钛钉和载药钛钉及其制备方法 - Google Patents

一种可载药钛钉和载药钛钉及其制备方法 Download PDF

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WO2018032664A1
WO2018032664A1 PCT/CN2016/109120 CN2016109120W WO2018032664A1 WO 2018032664 A1 WO2018032664 A1 WO 2018032664A1 CN 2016109120 W CN2016109120 W CN 2016109120W WO 2018032664 A1 WO2018032664 A1 WO 2018032664A1
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titanium
drug
titanium nail
loaded
solution
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PCT/CN2016/109120
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English (en)
French (fr)
Inventor
刘青
蒲丛
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北京派尔特医疗科技股份有限公司
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Priority to US15/504,318 priority Critical patent/US10286117B2/en
Priority to JP2017544353A priority patent/JP6710859B2/ja
Priority to EP16861081.4A priority patent/EP3300671B1/en
Priority to ES16861081T priority patent/ES2746881T3/es
Publication of WO2018032664A1 publication Critical patent/WO2018032664A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/064—Surgical staples, i.e. penetrating the tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00526—Methods of manufacturing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00836—Material properties corrosion-resistant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00889—Material properties antimicrobial, disinfectant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00893—Material properties pharmaceutically effective
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/08—Methods for forming porous structures using a negative form which is filled and then removed by pyrolysis or dissolution

Definitions

  • the invention relates to the technical field of microporous drug loading, in particular to a drug-loadable titanium nail and a drug-loaded titanium nail and a preparation method thereof.
  • the pure titanium kiss is a common surgical instrument for suturing the digestive tract, respiratory tract and skin mucosa, and belongs to the category of surgical implants.
  • Ideal biological materials, such as surgical implants should have no toxic or side effects on the human body when they are in direct contact with human tissues, body fluids or blood. They should not cause hemolysis, cause or cause infection, cause mutations or distortions of human cells. And cancerous, special functional materials that do not cause immune rejection and allergic reactions.
  • a new substance that needs to be metabolized, and the surface of the drug-loaded polymer layer and the metal implant will be peeled off and detached to different extents, and the fragments will enter the blood vessel, causing acute, subacute thrombosis, infection and rejection of the patient. Adverse reactions.
  • the object of the present invention is to create a new type of drug-loadable titanium nail and the defect of the prior art.
  • the preparation method is used as a drug-loading carrier to overcome the above-mentioned deficiencies and defects.
  • the technical problem to be solved by the present invention is to provide a method for preparing a drug-loadable titanium nail, which can prepare a drug-loadable layer which is not easy to produce shedding and has a sustained release function, thereby overcoming the existing kiss (seam). Insufficient fitting titanium nails.
  • the present invention provides a method for preparing a drug-loadable titanium nail, which comprises a titanium nail body and a microporous drug-loadable ceramic layer disposed on a surface of the titanium nail body.
  • the preparation method of the drug-loaded titanium nail includes:
  • pretreatment treating the surface of the titanium nail body with a heated alkaline solution, repeatedly washing and drying;
  • titanium sol solution tetrabutyl titanate is dissolved in ethanol, and sodium alginate solution and acetylacetone are sequentially added under continuous stirring, and stirring is continued to form a stable and uniform titanium sol solution, and is aged at room temperature.
  • the ethanol suspension of the hyaluronic acid-alginic acid microsphere obtained in the step (2) is stirred and mixed with the titanium sol solution obtained in the step (3), and is on the surface of the titanium nail body. Coating, drying, that is, coating a titanium nail; then, the coated titanium nail is heat-treated in hot water, and the surface of the coated titanium nail is formed with the dissolution and dissolution of hyaluronic acid and alginic acid in hot water.
  • Microporous titanium dioxide film
  • the titanium plate coated with the titanium dioxide film obtained in the step (4) is baked in a baking furnace to form a titanium nail with a microporous titanium dioxide ceramic layer, which is washed and dried to obtain a titanium-loadable drug. nail.
  • the step (2) is specifically: weighing equal amounts of sodium hyaluronate and sodium alginate 10 to 30 g, respectively, placed in a high-speed vacuum homogenizer, adding deionized water to dissolve it, and then adding 1% to 3% calcium chloride solution 100 ⁇ 300ml, vacuum homogenization under strong stirring, then add three volumes of ethanol, continue to stir, to form hyaluronic acid-alginic acid microsphere precipitation, and wash with anhydrous ethanol 3 times, freeze-vacuum drying, and then suspended in an anhydrous ethanol solution; wherein the sodium hyaluronate has a viscosity average molecular weight of 80 to 1.5 million Daltons, and the diameter of the formed hyaluronic acid-alginic acid microspheres It is 5 to 10 ⁇ m.
  • step (3) is specifically: measuring 50 to 100 ml of tetrabutyl titanate dissolved in 1000 ml of absolute ethanol, slowly adding 100 to 200 ml of a 1% aqueous solution of sodium alginate, and then adding 3 to 6 ml. Acetylacetone was continuously stirred at room temperature to form a titanium sol solution, which was aged at room temperature for 24 hours.
  • the step (4) is specifically: the ethanol suspension of the hyaluronic acid-alginic acid microsphere obtained in the step (2) and the titanium sol solution obtained in the step (3) are 2 to 4.5: The ratio of 3 is mixed, stirred, and the mixed solution is sprayed on the surface of the titanium nail body by a flow coating method, wherein the thickness of the coating is 10-15 ⁇ m, and dried at 90 ° C to obtain a coated titanium nail; The coated titanium nail is heat-treated in hot water of 95 to 98 ° C. With the dissolution and dissolution of hyaluronic acid and alginic acid in hot water, the surface of the coated titanium nail forms a thin film of titanium dioxide with micropores.
  • the alkaline solution heated in the step (1) is a NaOH solution having a temperature of 70-90 ° C and a concentration of 2-5 mol/L, and the titanium nail body is kept in the NaOH solution for 24 to 48.
  • the baking condition of the baking furnace is to increase the temperature at a constant rate of 2 ° C / min, and the temperature is raised to 300 to 500 ° C and then kept for 3 to 5 hours.
  • the invention also provides a drug-loadable titanium nail prepared by the method for preparing the above-mentioned drug-loadable titanium nail, wherein the titanium dioxide ceramic layer has uniform pore distribution, an average pore diameter of 0.5-6.5 ⁇ m, and the microporous There is continuity.
  • the invention also provides a method for preparing a drug-loaded titanium nail by using the above-mentioned drug-loadable titanium nail, the method step comprising: placing the drug-loadable titanium nail in a vacuum device, and introducing the volatile material under vacuum condition The organic solvent is dissolved in the desired drug, taken out, placed in another vacuum and dried under vacuum.
  • the method is a method for preparing a drug-loaded titanium nail for a drug which is easily soluble in an organic solvent, and the prepared drug-loaded titanium nail is a drug-loaded titanium nail loaded with sulfadiazine or silver sulfadiazine or a drug-loaded titanium loaded with growth factor. nail.
  • the present invention also provides a method for preparing a drug-loaded titanium nail by using the above-mentioned drug-loadable titanium nail, the method comprising: placing the drug-loadable titanium nail in a vacuum device and introducing the vacuum under vacuum The drug solution needs to be loaded, taken out, and dried in a vacuum freeze dryer.
  • the method is a method for preparing a drug-loaded titanium nail for a drug insoluble in an organic solvent, and the prepared drug-loaded titanium nail is a titanium nail loaded with various human tissue cell growth promoting factors.
  • the present invention has at least the following advantages:
  • the invention makes a microporous ceramic layer on the surface of the titanium nail body of the kiss (sew). Since the ceramic has corrosion resistance and wear resistance, the metal ions on the surface of the titanium nail are not easy to penetrate into the human body, and no falling off is generated. And wear debris, and avoid the body to produce "wear disease” and foreign body reaction, on the other hand can be loaded with various drugs such as bacteriostatic drugs and drugs to promote healing, but also targeted positioning and sustained release drugs, with good medical use.
  • the present invention is directed to the deficiencies of the prior art, and provides a chargeable titanium nail having a microporous drug-loaded ceramic layer formed on the surface of a kiss (stitch) titanium nail.
  • the microporous ceramic layer is prepared on the surface of the pure titanium kiss (seam) nail to make it a carrier for the drug, which can not only release the drug but also prevent the metal ions from oozing out, thereby overcoming the shortcomings and disadvantages of the existing titanium nail.
  • the material of the kiss (sew) titanium nail of the invention is pure titanium, which is a medical material which meets the requirements of national standards and can be used for making various types of kisses (slit) of digestive tract, respiratory tract and skin mucosa surgery. Device. The specific structure and preparation method of the drug-loadable titanium nail of the present invention are described below.
  • the chargeable titanium nail of the present invention comprises a titanium nail body and a microporous drug-loadable ceramic layer disposed on the surface of the titanium nail body.
  • the microporous drug-loadable ceramic layer is a microporous titanium dioxide ceramic layer calcined by a calciner.
  • the titanium dioxide ceramic layer has a uniform pore distribution and an average pore diameter of 0.5 to 6.5 ⁇ m.
  • Such a multi-aperture titanium dioxide ceramic layer can increase the surface area of the kiss (slot) titanium nail, can be used as a drug storage place when the drug is loaded, and can also be relatively stable and evenly distributed in the kiss (sew) titanium The nail surface is in the micropore.
  • the drug-loadable titanium nail is introduced into the desired drug under vacuum conditions, that is, the drug-loaded titanium nail is obtained.
  • the drug introduced into the drug-loading titanium nail may be sulfadiazine or silver sulfadiazine dissolved in concentrated ammonia solution, or a growth factor dissolved in ether, or various human tissue cell growth promoting factors, etc. Under the action of the kiss (seam), it can be targeted to the tissue, and slowly and directionally release the drug in the tissue, which plays a role in inhibiting bacteria and promoting healing.
  • the preparation method of the drug-loadable titanium nail of the invention comprises the following steps:
  • Pretreatment the surface of the titanium nail body is treated with a heated NaOH solution to remove impurities such as oil stains and oxide film on the surface of the titanium nail body, and then repeatedly washed and dried with deionized water in ultrasonic waves; of course, other alkalis may also be used.
  • the surface of the titanium nail body is treated with a solution such as a KOH solution or the like.
  • titanium sol solution At room temperature, tetrabutyl titanate is dissolved in ethanol, and sodium alginate solution and acetylacetone are sequentially added under stirring, and stirring is continued to form a stable and uniform titanium sol solution, and at room temperature. Under the age of 24 hours;
  • the titanium plate coated with the titanium dioxide film obtained in the step 4 is baked in a baking furnace to form a titanium nail with a microporous titanium dioxide ceramic layer, and then washed and dried to obtain a drug-loadable titanium nail.
  • the method for preparing the drug-loaded titanium nail is as follows:
  • a titanium nail having a microporous ceramic layer formed on the surface is placed in a vacuum apparatus, and an organic solution prepared by using a volatile organic solvent and a drug to be loaded is introduced under vacuum, and another vacuum is replaced. Vacuum drying is available.
  • the titanium nail which forms the microporous ceramic layer on the surface can be placed in a vacuum device, directly introduced into the drug solution under vacuum conditions, and dried in a vacuum freeze dryer. Got it.
  • the gel formed by adding the calcium chloride to the hyaluronic acid-alginic acid solution can generate microspheres having a diameter of 5 to 10 ⁇ m in a three-volume ethanol under strong stirring, and can be incorporated into the titanium sol solution.
  • the coated titanium nail is placed in hot water above 95 ° C.
  • the calcium chloride in the coated microspheres is first precipitated, then the hyaluronic acid-alginic acid gel is depolymerized, and hyaluronic acid and alginic acid are dissolved and dissolved.
  • Micropores having a uniform distribution and a pore diameter of 5 to 10 ⁇ m are formed on the plating film.
  • alginic acid not only participates in the formation of pores, but also increases the adhesion of titanium sol solution, and together with acetylacetone slows the violent hydrolysis of titanate.
  • the titanium sol film on the surface of the titanium nail is under the action of hot water of 95-98 ° C.
  • the dissolution and dissolution of the hyaluronic acid-alginate microspheres form a porous structure, causing the anatase type titanium dioxide to uniformly nucleate and grow in the film to form an anatase-type titanium dioxide film.
  • anatase type titanium dioxide has a degrading effect on organic substances such as drugs under the action of light
  • the titanium alloy surface anatase type titanium dioxide film is converted into a strong super-adhesive tape by a high-temperature baking method.
  • a microporous rutile titanium dioxide ceramic layer is formed.
  • the rutile-type titanium dioxide ceramic layer has a lower photocatalytic activity than the anatase-type titanium dioxide film, and to a certain extent, can avoid degradation of the drug loaded in the micropores of the ceramic layer.
  • the related research of the present invention also confirmed that the porous structure formed by the dissolution and dissolution of hyaluronic acid-alginic acid microspheres has a certain degree of shrinkage during hot water and roasting, so the titanium dioxide ceramic on the surface of the titanium nail body is finally obtained.
  • the microporous pore size generated by the layer is between about 0.5 and 6.5 ⁇ m.
  • the invention is characterized in that the basic properties and properties of the titanium nail body are not changed, and the reagents used have no toxic and side effects on the human body.
  • the molecular weight of hyaluronic acid, the concentration of hyaluronic acid, alginic acid and calcium chloride, the amount of anhydrous ethanol, the stirring speed, the reaction time, etc. By strictly controlling the molecular weight of hyaluronic acid, the concentration of hyaluronic acid, alginic acid and calcium chloride, the amount of anhydrous ethanol, the stirring speed, the reaction time, etc., the size and number of micropores in the titanium dioxide ceramic layer on the surface of the titanium nail body can be obtained. Indirect control. Antibiotics, growth promoting factors, etc. used in clinical practice, the molecular weight of which is mostly between several hundred nanometers. With a micropore diameter in the titanium dioxide ceramic layer on the surface of the titanium nail body, a certain dose of the drug can be completely loaded.
  • the presence of the micropores of the titanium dioxide ceramic layer on the surface of the titanium nail body correspondingly increases the surface area of the titanium nail body and the drug loading space, on the one hand, the drug is relatively firmly attached to the ceramic layer, and on the other hand, the distribution of the micropores is relatively uniform.
  • the drug can also be uniformly and targetedly released in the tissue around the titanium nail; since there is communication between many micropores, it can also play a role of sustained release.
  • the invention prepares a drug-loadable titanium nail to prepare a kiss (slot) titanium nail as an example, and describes a specific embodiment of the present invention as follows:
  • the kiss (seam) titanium nails are ultrasonically cleaned in deionized water to wash off the surface deposits.
  • the kiss (seam) titanium nails are ultrasonically cleaned in deionized water to wash off the surface deposits.
  • 1000ml of 2mol / L NaOH solution heat at 80 ° C for 24hr, remove surface impurities and natural oxide layer, and then repeatedly ultrasonic cleaning with deionized water, drying;
  • the aged titanium sol solution is stirred and mixed with 2/3 times of the hyaluronic acid-alginic acid microsphere ethanol suspension at room temperature, and the surface of the titanium body of the kiss (sew) is sprayed by a flow coating method to control the film.
  • the thickness is between about 10 and 15 ⁇ m;
  • the film-coated kiss (stitch) titanium nail is dried at 90 ° C, and then heat treated in 98 ° C hot water for 5 hr, with the complete dissolution and complete dissolution of hyaluronic acid and alginic acid in hot water, a titanium dioxide film with micropores is formed on the surface of the titanium body of the kiss (sew), and the pore diameter is about 5-10 ⁇ m;
  • the coated kiss (stitch) titanium nail is placed in a roasting furnace for firing, and the temperature is raised at a constant rate of 2 ° C / min. After heating to 500 ° C, the temperature is kept for 3 hr, and after natural cooling, it is taken out, and the surface of the titanium nail is kissed.
  • the kiss (seam) titanium nails were ultrasonically cleaned in deionized water, the surface deposits were washed away, placed in 1000 ml of 5 mol/L NaOH solution, and kept at 70 ° C for 48 hr to remove surface impurities and natural oxide layers. And then repeatedly ultrasonically washed with deionized water and dried;
  • the aged titanium sol solution is stirred and mixed with an equal volume of hyaluronic acid-alginic acid microspheres ethanol suspension, and the surface of the titanium body of the kiss (sewer) is sprayed to control the thickness of the film. Between approximately 10 and 15 ⁇ m;
  • the film-coated kiss (stitch) titanium nail is dried at 90 ° C, and then heat treated in 98 ° C hot water for 5 hr, with the complete dissolution and complete dissolution of hyaluronic acid and alginic acid in hot water, kiss (Sew) the surface of the titanium nail body of the combiner forms a titanium dioxide film with micropores, and the pore diameter is about 5-10 ⁇ m;
  • the coated kiss (stitch) titanium nail is placed in a roasting furnace for firing, and the temperature is raised at a constant rate of 2 ° C / min. After heating to 500 ° C, the temperature is kept for 3 hr, and after natural cooling, the titanium nail body is removed in the kiss (seam).
  • the surface is formed with a firm titanium dioxide ceramic layer with micropores, washed with water, dried, and the ceramic layer is about 5-10 ⁇ m thick, the pores are evenly distributed, and the pore diameter is about 0.5-6.5 ⁇ m.
  • the kiss (seam) titanium nails were ultrasonically cleaned in deionized water, the surface deposits were washed away, placed in 1000 ml of 5 mol/L NaOH solution, and kept at 90 ° C for 24 hr to remove surface impurities and natural oxide layers. And then repeatedly ultrasonically washed with deionized water and dried;
  • the aged titanium sol solution is stirred and mixed with an equal volume of hyaluronic acid-alginic acid microspheres ethanol suspension, and the surface of the titanium body of the kiss (sewer) is sprayed to control the thickness of the film. Between approximately 10 and 15 ⁇ m;
  • the film-coated kiss (stitch) titanium nail is dried at 90 ° C, and then heat treated in 98 ° C hot water for 5 hr, with the complete dissolution and complete dissolution of hyaluronic acid and alginic acid in hot water, a titanium dioxide film with micropores is formed on the surface of the titanium body of the kiss (sew), and the pore diameter is about 5-10 ⁇ m;
  • the coated kiss (stitch) titanium nail is placed in a roasting furnace for firing, and the temperature is raised at a constant rate of 2 ° C / min. After heating to 500 ° C, the temperature is kept for 3 hr, and after natural cooling, the titanium nail body is removed in the kiss (seam).
  • the surface is formed with a firm titanium dioxide ceramic layer with micropores, washed with water, dried, and the ceramic layer is about 5-10 ⁇ m thick, the pores are evenly distributed, and the pore diameter is about 0.5-6.5 ⁇ m.
  • the kiss (seam) titanium nails were ultrasonically cleaned in deionized water, the surface deposits were washed away, placed in 1000 ml of 3.5 mol/L NaOH solution, and incubated at 80 ° C for 24 hr to remove surface impurities and natural oxidation. Layer, then repeated ultrasonic cleaning with deionized water, drying;
  • hyaluronic acid-alginic acid microsphere has a diameter of about 5-10 ⁇ m;
  • the aged titanium sol solution is stirred and mixed with 1.5 times the volume of the hyaluronic acid-alginic acid microspheres ethanol suspension, and the surface of the titanium body of the kiss (sew) is coated by a flow coating method to control the film.
  • the thickness is between about 10 and 15 ⁇ m;
  • the film-coated kiss (stitch) titanium nail is dried at 90 ° C, and then heat treated in 98 ° C hot water for 5 hr, with the complete dissolution and complete dissolution of hyaluronic acid and alginic acid in hot water, a titanium dioxide film with micropores is formed on the surface of the titanium body of the kiss (sew), and the pore diameter is about 5-10 ⁇ m;
  • the coated kiss (stitch) titanium nail is placed in a roasting furnace for firing, and the temperature is raised at a constant rate of 2 ° C / min. After heating to 500 ° C, the temperature is kept for 3 hr, and after natural cooling, the titanium nail body is removed in the kiss (seam).
  • the surface is formed with a firm titanium dioxide ceramic layer with micropores, washed with water, dried, and the ceramic layer is about 5-10 ⁇ m thick, the pores are evenly distributed, and the pore diameter is about 0.5-6.5 ⁇ m.
  • the kiss (stitch) titanium nails were ultrasonically cleaned in deionized water, the surface deposits were washed away, placed in 1000 ml of 5 mol/L NaOH solution, and kept at 80 ° C for 24 hr to remove surface impurities and natural oxide layers. And then repeatedly ultrasonically washed with deionized water and dried;
  • the aged titanium sol solution is stirred and mixed with an equal volume of hyaluronic acid-alginic acid microspheres ethanol suspension, and the surface of the titanium body of the kiss (sewer) is sprayed to control the thickness of the film. Between approximately 10 and 15 ⁇ m;
  • the film-coated kiss (stitch) titanium nail is dried at 90 ° C, and then heat treated in hot water at 95 ° C for 5 hr, with the complete dissolution and complete dissolution of hyaluronic acid and alginic acid in hot water, a titanium dioxide film with micropores is formed on the surface of the titanium body of the kiss (sew), and the pore diameter is about 5-10 ⁇ m;
  • the coated kiss (stitch) titanium nail is placed in a roasting furnace for firing, and the temperature is raised at a constant rate of 2 ° C / min. After heating to 500 ° C, the temperature is kept for 3 hr, and after natural cooling, the titanium nail body is removed in the kiss (seam).
  • the surface is formed with a firm titanium dioxide ceramic layer with micropores, washed with water, dried, and the ceramic layer is about 5-10 ⁇ m thick, the pores are evenly distributed, and the pore diameter is about 0.5-6.5 ⁇ m.
  • the kiss (seam) titanium nails were ultrasonically cleaned in deionized water, the surface deposits were washed away, placed in 1000 ml of 3.5 mol/L NaOH solution, and incubated at 80 ° C for 24 hr to remove surface impurities and natural oxidation. Layer, then repeated ultrasonic cleaning with deionized water, drying;
  • the aged titanium sol solution is stirred and mixed with an equal volume of hyaluronic acid-alginic acid microspheres ethanol suspension, and the surface of the titanium body of the kiss (sewer) is sprayed to control the thickness of the film. Between approximately 10 and 15 ⁇ m;
  • the film-coated kiss (stitch) titanium nail is dried at 90 ° C, and then heat treated in 98 ° C hot water for 5 hr, with the complete dissolution and complete dissolution of hyaluronic acid and alginic acid in hot water, a titanium dioxide film with micropores is formed on the surface of the titanium body of the kiss (sew), and the pore diameter is about 5-10 ⁇ m;
  • the coated kiss (stitch) titanium nail is placed in a roasting furnace for firing, and the temperature is raised at a constant rate of 2 ° C / min. After heating to 500 ° C, the temperature is kept for 3 hr, and after natural cooling, the titanium nail body is removed in the kiss (seam).
  • the surface is formed with a firm titanium dioxide ceramic layer with micropores, washed with water, dried, and the ceramic layer is about 5-10 ⁇ m thick, the pores are evenly distributed, and the pore diameter is about 0.5-6.5 ⁇ m.
  • the kiss (stitch) titanium nails were ultrasonically cleaned in deionized water, the surface deposits were washed away, placed in 1000 ml of 5 mol/L NaOH solution, and kept at 80 ° C for 24 hr to remove surface impurities and natural oxide layers. And then repeatedly ultrasonically washed with deionized water and dried;
  • the aged titanium sol solution and an equal volume of hyaluronic acid-alginic acid microsphere B at room temperature The alcohol suspension is stirred and mixed, and is sprayed on the surface of the titanium body of the kiss (sew), and the thickness of the control film is about 10-15 ⁇ m;
  • the film-coated kiss (stitch) titanium nail is dried at 90 ° C, and then heat treated in hot water at 95 ° C for 5 hr, with the complete dissolution and complete dissolution of hyaluronic acid and alginic acid in hot water, a titanium dioxide film with micropores is formed on the surface of the titanium body of the kiss (sew), and the pore diameter is about 5-10 ⁇ m;
  • the coated kiss (stitch) titanium nail is placed in a roasting furnace for firing, and the temperature is raised at a constant rate of 2 ° C / min. After heating to 500 ° C, the temperature is kept for 3 hr, and after natural cooling, the titanium nail body is removed in the kiss (seam).
  • the surface is formed with a firm titanium dioxide ceramic layer with micropores, washed with water, dried, and the ceramic layer is about 5-10 ⁇ m thick, the pores are evenly distributed, and the pore diameter is about 0.5-6.5 ⁇ m.
  • the kiss (stitch) titanium nails were ultrasonically cleaned in deionized water, the surface deposits were washed away, placed in 1000 ml of 5 mol/L NaOH solution, and kept at 80 ° C for 24 hr to remove surface impurities and natural oxide layers. And then repeatedly ultrasonically washed with deionized water and dried;
  • the aged titanium sol solution is stirred and mixed with an equal volume of hyaluronic acid-alginic acid microspheres ethanol suspension, and the surface of the titanium body of the kiss (sewer) is sprayed to control the thickness of the film. Between approximately 10 and 15 ⁇ m;
  • the film-coated kiss (stitch) titanium nail is dried at 90 ° C, and then heat treated in 98 ° C hot water for 5 hr, with the complete dissolution and complete dissolution of hyaluronic acid and alginic acid in hot water, a titanium dioxide film with micropores is formed on the surface of the titanium body of the kiss (sew), and the pore diameter is about 5-10 ⁇ m;
  • the coated kiss (seam) titanium nail is placed in a roasting furnace for firing, and the temperature is raised at a constant rate of 2 ° C / min. After heating to 300 ° C, the temperature is kept for 5 hr, and after natural cooling, the titanium nail body is removed in the kiss (seam).
  • the surface is formed with a firm titanium dioxide ceramic layer with micropores, washed with water, dried, and the ceramic layer is about 5-10 ⁇ m thick, the pores are evenly distributed, and the pore diameter is about 0.5-6.5 ⁇ m.
  • the drug-loadable titanium nails obtained above can be used for loading a drug to form a drug-loaded titanium nail, and the implementation is as follows:
  • the above-mentioned drug-loadable kiss (stitch) titanium nail is placed in a vacuum apparatus, and a 15% concentration of sulfadiazine or sulfadiazine silver concentrated ammonia solution is introduced under vacuum, and then taken out for another vacuum.
  • the device is vacuum dried, that is, a drug-loaded kiss (stitch) titanium nail loaded with sulfadiazine or silver sulfadiazine.
  • the above-mentioned drug-loadable kiss (stitch) titanium nail is placed in a vacuum apparatus at room temperature, and a concentration of 15% growth factor diethyl ether solution is introduced under vacuum, and then taken out and vacuum-dried by another vacuum, that is, It is loaded with a drug-loaded kiss (sew) titanium screw with growth factor.
  • the above-mentioned drug-loadable kiss (stitch) titanium nail was placed in a vacuum apparatus at room temperature, and an epidermal growth factor solution of one of various human tissue cell growth promoting factors at a concentration of 65% was introduced under vacuum. Then, it is taken out and dried by a vacuum freeze dryer to obtain a kiss (slit) titanium staple of epidermal growth factor loaded with various human tissue cell growth promoting factors.
  • the invention utilizes the characteristics of pure titanium, titanium dioxide, hyaluronic acid and alginic acid to surface-treat the existing kiss (stitch) titanium nail, so that pure titanium, titanium dioxide and hyaluronic acid-alginic acid interact, in the kiss (Slit)
  • the surface of the titanium nail forms a firm titanium dioxide ceramic layer with micropores.
  • the pore distribution is relatively uniform, and the average pore diameter is 0.5-6.5 ⁇ m, which increases the surface area of the titanium staple of the kiss (slit).
  • the drug can be relatively stably and evenly distributed in the micropores of the titanium nail surface of the kiss (sew), and slowly and directionally release the drug in the tissue, thereby inhibiting bacteria and promoting healing. .
  • the invention can be loaded with a titanium nail, which is convenient for loading a bacteriostatic drug and a medicine for promoting healing and has a sustained release function.
  • a titanium nail which is convenient for loading a bacteriostatic drug and a medicine for promoting healing and has a sustained release function.
  • the corrosion-resistant ceramic property due to the corrosion-resistant ceramic property, the surface thereof is less likely to cause shedding, thereby overcoming the existing The side effects of titanium ions implanted in the body by a kiss (sew).
  • titanium-loaded titanium nail of the present invention and the preparation method thereof can also be used in other medical instruments requiring titanium nails, and the drug-loaded titanium nails loaded with other drugs can be prepared according to clinical needs.

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Abstract

一种可载药钛钉及其制备方法，以及应用该可载药钛钉制备的载药钛钉及其制备方法。可载药钛钉包括钛钉本体和设置在钛钉本体表面的微孔可载药陶瓷层，其制备方法包括以下步骤：钛钉本体表面预处理、微孔模具透明质酸-海藻酸微型球体制备、钛溶胶液制备、镀膜、造孔和焙烧。通过在钛钉本体表面制作具有耐腐蚀、耐磨损性质的微孔陶瓷层，使钛钉表面金属离子不易渗入人体，同时不会产生脱落物和磨屑，并且可以装填各种药物。

Description

一种可载药钛钉和载药钛钉及其制备方法 技术领域
本发明涉及微孔载药技术领域，特别是涉及一种可载药钛钉和载药钛钉及其制备方法。
背景技术
纯钛吻(缝)合器是目前消化道、呼吸道和皮肤黏膜术后缝合的常用手术器具，属于外科植入物范畴。理想的生物材料如外科植入物，是在与人体组织、体液或血液直接接触或作用时，应该对人体无毒副作用，不溶血，不引起或不间接引起感染、不引起人体细胞突变、畸变和癌变，不引起免疫排异和过敏反应的特殊功能材料。目前最常用的为医用金属材料、医用天然高分子材料、医用合成高分子材料和医用陶瓷等，特别是医用金属材料，由于其与人体具有较大的相容性、适应范围广的优点，是应用最早，在目前临床界应用也最为广泛。但这类医用植入材料存在一个普遍的不足，即由于磨损而产生的磨屑，在体内引发毒性和免疫反应、变态反应、甚至在局部形成肿瘤等。另一方面，如消化道、呼吸道和皮肤黏膜吻(缝)合器钉合创伤组织时，很有可能穿透组织表面下丰富的血管，而该部位的组织表面常常寄生着各种致病菌和非致病菌，容易引起继发性感染等。为改正上述不足，科研工作者尝试采用高分子化合物作为粘着剂和载药层，但这又引发新的问题出现，即由高分子化合物组成的黏着层、载药层，一方面又使人体增加了新的需要代谢的物质，同时载药高分子层与金属植入物表面会发生不同程度的剥离和脱落，其碎片进入血管内，导致患者出现急性、亚急性血栓、感染和排异反应等不良反应。
本发明目的是针对现有技术的缺陷，创设一种新型的可载药钛钉及其 制备方法，使其作为装填药物的载体，克服上面述及的不足和缺陷。
发明内容
本发明要解决的技术问题是提供一种可载药钛钉的制备方法，使其制备得到的可载药层既不易产生脱落物，又具有缓释功能，从而克服现有的吻(缝)合器钛钉的不足。
为解决上述技术问题，本发明提供一种可载药钛钉的制备方法，所述可载药钛钉包括钛钉本体和设置在钛钉本体表面的微孔可载药陶瓷层，所述可载药钛钉的制备方法包括：
(1)预处理：采用加热的碱性溶液处理所述钛钉本体的表面，反复清洗后干燥；
(2)透明质酸-海藻酸微型球体的制备：称取等质量的透明质酸钠和海藻酸钠，放置于高速真空均质机中，依次加入去离子水和氯化钙溶液，在强力搅拌下真空均质化，再加入乙醇，持续搅拌，生成透明质酸-海藻酸微型球体沉淀，并用无水乙醇洗涤，冷冻真空干燥，然后悬浮于无水乙醇溶液中；
(3)钛溶胶液的制备：取钛酸四丁酯溶于乙醇中，在不断搅拌下依次加入海藻酸钠溶液和乙酰丙酮，继续搅拌，生成稳定均匀的钛溶胶液，并于室温下陈化；
(4)镀膜和造孔：将所述步骤(2)得到的透明质酸-海藻酸微型球体的乙醇悬浮液与步骤(3)得到的钛溶胶液搅拌混合，并在所述钛钉本体表面镀膜，干燥，即得镀膜钛钉；然后将所述镀膜钛钉置于热水中热处理，随着透明质酸和海藻酸在热水中的溶解和溶出，所述镀膜钛钉表面形成带有微孔的二氧化钛薄膜；
(5)焙烧：将所述步骤(4)得到的镀有二氧化钛薄膜的钛钉在焙烧炉中焙烧，形成带有微孔二氧化钛陶瓷层的钛钉，水洗、干燥即得可载药钛 钉。
进一步改进，所述步骤(2)具体为：分别称取等质量的透明质酸钠和海藻酸钠10～30g，均放置于高速真空均质机中，加入去离子水将其溶解，再加入1％～3％的氯化钙溶液100～300ml，在强力搅拌下真空均质化，再加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体沉淀，并用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于无水乙醇溶液中；其中，所述透明质酸钠的粘均分子量为80～150万道尔顿，所形成的透明质酸-海藻酸微型球体的直径为5～10μm。
进一步改进，所述步骤(3)具体为：量取50～100ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100～200ml的1％海藻酸钠水溶液，再加入3～6ml乙酰丙酮，在室温下不断搅拌，生成钛溶胶液，并于室温下陈化24小时。
进一步改进，所述步骤(4)具体为：将所述步骤(2)得到的透明质酸-海藻酸微型球体的乙醇悬浮液与所述步骤(3)得到的钛溶胶液以2～4.5：3的比例混合，搅拌，并将混合后的溶液在所述钛钉本体表面采用流涎法镀膜，其中镀膜的厚度为10～15μm，并于90℃干燥，即得镀膜钛钉；然后将所述镀膜钛钉置于95～98℃的热水中热处理，随着透明质酸和海藻酸在热水中的溶解和溶出，所述镀膜钛钉表面形成带有微孔的二氧化钛薄膜。
进一步改进，所述步骤(1)中加热的碱性溶液为温度在70～90℃、浓度在2～5mol/L的NaOH溶液，且所述钛钉本体在所述NaOH溶液中保温24～48小时；所述步骤(5)中焙烧炉的焙烧条件为以2℃/min的匀速升温，升温至300～500℃后保温3～5小时。
本发明还提供了一种应用上述可载药钛钉制备方法制得的可载药钛钉，所述二氧化钛陶瓷层中微孔分布均匀，平均孔径为0.5～6.5μm，且所述微孔之间有贯通。
本发明还提供了一种应用上述可载药钛钉制备载药钛钉的方法，所述方法步骤包括：将所述可载药钛钉置于真空器中，在真空条件下导入用易挥发有机溶剂溶解的所需载入药物，取出，置于另一真空器中真空干燥。该方法是针对易溶于有机溶剂的药物的载药钛钉制备方法，其制得的载药钛钉为装载磺胺嘧啶或磺胺嘧啶银的载药钛钉；或者装载有生长因子的载药钛钉。
另外，本发明还提供了一种应用上述可载药钛钉制备载药钛钉的方法，所述方法步骤包括：将所述可载药钛钉置于真空器中，在真空条件下导入所需载入药物溶液，取出，置于真空冷冻干燥机中干燥。该方法是针对不溶于有机溶剂的药物的载药钛钉制备方法，其制得的载药钛钉为装载有各种人用组织细胞生长促进因子的钛钉。
采用上述的技术方案，本发明至少具有以下优点：
本发明通过在吻(缝)合器钛钉本体表面制作微孔陶瓷层，由于陶瓷具有耐腐蚀、耐磨损的性质，使其钛钉表面的金属离子不易渗入人体，同时不会产生脱落物和磨屑，并避免人体产生“磨屑病”和异物反应，另一方面可以装填各种药物如抑菌药物和促进愈合的药物等，又能靶向定位且缓释药物，具有良好的医用用途。
具体实施方式
本发明是针对现有技术的不足，提供的一种在吻(缝)合器钛钉表面形成具有微孔载药陶瓷层的可载药钛钉。在纯钛吻(缝)合钉表面制备微孔陶瓷层，使其作为药物的载体，既能缓释药物，又防止金属离子的渗出，从而克服现有钛钉的缺点和不足。本发明吻(缝)合器钛钉的材料为纯钛，是医用的并符合国家标准要求的医用材料，可用于制造消化道、呼吸道和皮肤黏膜外科手术的各种型号的吻(缝)合器。本发明可载药钛钉的具体结构和制备方法叙述如下。
本发明可载药钛钉包括钛钉本体和设置在钛钉本体表面的微孔可载药陶瓷层。该微孔可载药陶瓷层为由焙烧炉焙烧而成的带有微孔的二氧化钛陶瓷层。该二氧化钛陶瓷层中微孔分布均匀，平均孔径为0.5～6.5μm。这样多孔径的二氧化钛陶瓷层，可增加吻(缝)合器钛钉的表面积，载入药物时可作为药物的储存处，也可使药物相对稳定、均匀地分布在吻(缝)合器钛钉表面微孔中。
该可载药钛钉在真空条件下导入所需载入药物，即得载药钛钉。该载药钛钉中导入的药物可以为溶于浓氨溶液的磺胺嘧啶或磺胺嘧啶银，或溶于乙醚的生长因子，或者是各种人用组织细胞生长促进因子等，这样载药的钛钉在吻(缝)合器的作用下，可以靶向作用于组织中，并在组织中缓慢、定向释放出药物，起到抑菌和促进愈合等作用。
本发明可载药钛钉的制备方法包括如下步骤：
(1)预处理：用加热的NaOH溶液处理钛钉本体的表面，去除钛钉本体表面油污等杂质和氧化膜，然后在超声波中用去离子水反复清洗，干燥；当然，也可采用其它碱性溶液，如KOH溶液等，对所述钛钉本体的表面进行处理。
(2)透明质酸-海藻酸微型球体的制备：在室温条件下，称取等质量的透明质酸钠和海藻酸钠放置于高速真空均质机中，依次加入去离子水和氯化钙溶液，在强力搅拌下真空均质化，然后再加入乙醇，持续搅拌，生成直径约为5～10μm的透明质酸-海藻酸微型球体沉淀，并用无水乙醇洗涤，冷冻真空干燥，然后悬浮于无水乙醇溶液中；
(3)钛溶胶液制备：在室温条件下，取钛酸四丁酯溶于乙醇中，搅拌下依次加入海藻酸钠溶液和乙酰丙酮，继续搅拌，生成稳定均匀的钛溶胶液，并于室温下陈化24小时；
(4)镀膜和造孔：在室温条件下，将上述步骤2和3得到的透明质酸 -海藻酸微型球体的乙醇悬浮液与钛溶胶液搅拌混合，在钛钉本体表面镀膜，干燥，然后将镀膜钛钉置于热水中热处理，随着透明质酸和海藻酸在热水中的溶解和溶出，该钛钉本体表面形成带有微孔的二氧化钛薄膜；
(5)焙烧：将步骤4得到的镀有二氧化钛薄膜的钛钉在焙烧炉中焙烧，形成带有微孔二氧化钛陶瓷层的钛钉，之后水洗、干燥即得可载药钛钉。
在该可载药钛钉的制备方法基础上，制备载药钛钉的方法步骤如下：
在室温条件下，将表面生成微孔陶瓷层的钛钉置于真空器中，在真空条件下导入用易挥发有机溶剂与所需载入的药物配制成的有机溶液，并换另一真空器真空干燥即得。
当所需载入的药物不溶于易挥发有机溶剂时，可将表面生成微孔陶瓷层的钛钉置于真空器中，在真空条件下直接导入该药物溶液，并换真空冷冻干燥机干燥即得。
本发明可载药钛钉制备原理如下：首先了解钛溶胶液的生成原理，钛酸丁脂在介质乙醇溶液中与水水解，生成钛溶胶液Ti(OH)4，其总反应式为：Ti(OC4H9)+4H2O＝＝＝Ti(OH)4+C4H9OH，该钛溶胶液Ti(OH)4镀在钛钉本体表面后，在超过96℃的水溶液中生成完整的带有微细孔隙的二氧化钛薄膜，但这些微小孔洞的孔径不超过几十纳米，不足以装载药物。而透明质酸-海藻酸溶液在添加氯化钙后所生成的凝胶，于三倍体积乙醇中，在强力搅拌下能生成直径5～10μm的微球，掺入上述钛溶胶溶液中，可作为镀膜造孔的模具。再将镀膜后的钛钉置于95℃以上热水中，镀膜微球中的氯化钙首先析出，然后透明质酸-海藻酸凝胶解聚，透明质酸和海藻酸溶解、溶出，在镀膜上形成分布均匀、孔径5～10μm的微孔。其中，海藻酸不但参与造球造孔，还增加钛溶胶液的附着性，并与乙酰丙酮一起减缓钛酸丁脂的剧烈水解。
并且还研究证实，该钛钉表面钛溶胶薄膜在95～98℃热水作用下，由 于透明质酸-海藻酸微球的溶解和溶出形成了多孔结构，致使锐钛矿型二氧化钛在薄膜中均匀的成核并生长，生成带有锐钛矿型二氧化钛薄膜。由于锐钛矿型二氧化钛在光的作用下，对药物等有机物具有降解作用，因此，采用高温焙烧方法，将该钛钉表面锐钛矿型二氧化钛薄膜，转化为牢固的具有超强附着力的带有微孔的金红石型二氧化钛陶瓷层。该金红石型二氧化钛陶瓷层，光催化作用要低于锐钛矿型二氧化钛薄膜，在相当程度上，可以避免陶瓷层微孔中所装载药物的降解。
本发明的相关研究还证实，透明质酸-海藻酸微球的溶解和溶出所形成的多孔结构，在热水和焙烧过程中，会有一定程度的收缩，所以最终在钛钉本体表面二氧化钛陶瓷层生成的微孔孔径大约在0.5～6.5μm之间。
本发明的特征在于不改变钛钉本体的基本性质和性能，所用试剂对人体均无毒副作用。通过严格控制透明质酸分子量、透明质酸、海藻酸和氯化钙的浓度、无水乙醇加量、搅拌速度、反应时间等，使钛钉本体表面二氧化钛陶瓷层中微孔的大小、数量得以间接控制。临床使用的抗菌素、生长促进因子等，其分子量大多在几百纳米之间。以钛钉本体表面二氧化钛陶瓷层中微孔孔径，完全可以装载一定剂量的药物。该钛钉本体表面二氧化钛陶瓷层微孔的存在，相应地增加了钛钉本体的表面积和载药空间，一方面使药物相对牢固地附着在陶瓷层中，另一方面由于微孔的分布比较均匀，可使药物也能在钛钉周围的组织中比较均匀地靶向释放；由于不少微孔之间有连通，还能起到缓释的作用。
本发明制备可载药钛钉以制备吻(缝)合器钛钉为例，对本发明的具体实施例叙述如下：
实施例1
(1)预处理
先将吻(缝)合器钛钉n个在去离子水中超声清洗，洗掉表面附着物， 放入1000ml的2mol/L的NaOH溶液中，于80℃保温24hr，去除表面杂质和自然氧化层，然后用去离子水反复超声清洗，干燥；
(2)透明质酸-海藻酸微型球体的制备
在室温下，分别称取粘均分子量150万道尔顿的透明质酸钠10g和海藻酸钠10g，于高速真空均质机中，加1000ml去离子水使溶解，再加入1％氯化钙水溶液300ml，在强力搅拌下真空均质化，然后加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体(即为制造微孔的模具)沉淀，用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于1000ml无水乙醇溶液中，该透明质酸-海藻酸微型球体的直径大约在5～10μm之间；
(3)钛溶胶液制备
在室温下，量取50ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100ml的1％海藻酸钠水溶液，之后加入3ml乙酰丙酮，在室温下不断搅拌，30min后生成稳定的均匀的钛溶胶液，于室温陈化24hr；
(4)镀膜和造孔
在室温下，将陈化的钛溶胶液与2/3倍的透明质酸-海藻酸微型球体乙醇悬浮液搅拌混合，并在吻(缝)合器钛钉本体表面采用流涎法镀膜，控制膜的厚度大约在10～15μm之间；
将镀有薄膜的吻(缝)合器钛钉于90℃下干燥，然后置于98℃热水中热处理5hr，随着透明质酸和海藻酸在热水中的完全溶解和完全溶出，在吻(缝)合器钛钉本体表面形成带有微孔的二氧化钛薄膜，孔径大约在5～10μm之间；
(5)焙烧
将镀膜的吻(缝)合器钛钉置于焙烧炉中焙烧，以2℃/min匀速升温，升温至500℃后，保温3hr，自然降温后取出，在吻(缝)合器钛钉表面生成带有微孔的牢固的二氧化钛陶瓷层，用水清洗，干燥，陶瓷层大约厚度 在5～10μm之间，微孔分布均匀，孔径大约在0.5～6.5μm之间，有些微孔之间有贯通。
实施例2
(1)预处理
先将吻(缝)合器钛钉n个在去离子水中超声清洗，洗掉表面附着物，放入1000ml的5mol/L的NaOH溶液中，于70℃保温48hr，去除表面杂质和自然氧化层，然后用去离子水反复超声清洗，干燥；
(2)透明质酸-海藻酸微型球体的制备
在室温下，分别称取粘均分子量150万道尔顿的透明质酸钠20g和海藻酸钠20g，于高速真空均质机中，加1000ml去离子水使溶解，再加入2％氯化钙水溶液200ml，在强力搅拌下真空均质化，然后加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体(即为制造微孔的模具)沉淀，用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于1000ml无水乙醇溶液中，该透明质酸-海藻酸微型球体的直径大约在5～10μm之间；
(3)钛溶胶液制备
在室温下，量取50ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100ml的1％海藻酸钠水溶液，之后加入3ml乙酰丙酮，在室温下不断搅拌，30min后生成稳定的均匀的钛溶胶液，于室温陈化24hr；
(4)镀膜和造孔
在室温下，将陈化的钛溶胶液与等体积的透明质酸-海藻酸微型球体乙醇悬浮液搅拌混合，并在吻(缝)合器钛钉本体表面采用流涎法镀膜，控制膜的厚度大约在10～15μm之间；
将镀有薄膜的吻(缝)合器钛钉于90℃下干燥，然后置于98℃热水中热处理5hr，随着透明质酸和海藻酸在热水中的完全溶解和完全溶出，在吻 (缝)合器钛钉本体表面形成带有微孔的二氧化钛薄膜，孔径大约在5～10μm之间；
(5)焙烧
将镀膜的吻(缝)合器钛钉置于焙烧炉中焙烧，以2℃/min匀速升温，升温至500℃后，保温3hr，自然降温后取出，在吻(缝)合器钛钉本体表面生成带有微孔的牢固的二氧化钛陶瓷层，用水清洗，干燥，陶瓷层大约厚度在5～10μm之间，微孔分布均匀，孔径大约在0.5～6.5μm之间，有些微孔之间有贯通。
实施例3
(1)预处理
先将吻(缝)合器钛钉n个在去离子水中超声清洗，洗掉表面附着物，放入1000ml的5mol/L的NaOH溶液中，于90℃保温24hr，去除表面杂质和自然氧化层，然后用去离子水反复超声清洗，干燥；
(2)透明质酸-海藻酸微型球体的制备
在室温下，分别称取粘均分子量80万道尔顿的透明质酸钠10g和海藻酸钠10g，于高速真空均质机中，加1000ml去离子水使溶解，再加入1％氯化钙水溶液300ml，在强力搅拌下真空均质化，然后加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体(即为制造微孔的模具)沉淀，用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于1000ml无水乙醇溶液中，该透明质酸-海藻酸微型球体的直径大约在5～10μm之间；
(3)钛溶胶液制备
在室温下，量取50ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100ml的1％海藻酸钠水溶液，之后加入3ml乙酰丙酮，在室温下不断搅拌，30min后生成稳定的均匀的钛溶胶液，于室温陈化24hr；
(4)镀膜和造孔
在室温下，将陈化的钛溶胶液与等体积的透明质酸-海藻酸微型球体乙醇悬浮液搅拌混合，并在吻(缝)合器钛钉本体表面采用流涎法镀膜，控制膜的厚度大约在10～15μm之间；
将镀有薄膜的吻(缝)合器钛钉于90℃下干燥，然后置于98℃热水中热处理5hr，随着透明质酸和海藻酸在热水中的完全溶解和完全溶出，在吻(缝)合器钛钉本体表面形成带有微孔的二氧化钛薄膜，孔径大约在5～10μm之间；
(5)焙烧
将镀膜的吻(缝)合器钛钉置于焙烧炉中焙烧，以2℃/min匀速升温，升温至500℃后，保温3hr，自然降温后取出，在吻(缝)合器钛钉本体表面生成带有微孔的牢固的二氧化钛陶瓷层，用水清洗，干燥，陶瓷层大约厚度在5～10μm之间，微孔分布均匀，孔径大约在0.5～6.5μm之间，有些微孔之间有贯通。
实施例4
(1)预处理
先将吻(缝)合器钛钉n个在去离子水中超声清洗，洗掉表面附着物，放入1000ml的3.5mol/L的NaOH溶液中，于80℃保温24hr，去除表面杂质和自然氧化层，然后用去离子水反复超声清洗，干燥；
(2)透明质酸-海藻酸微型球体的制备
在室温下，分别称取粘均分子量80万道尔顿的透明质酸钠20g和海藻酸钠20g，于高速真空均质机中，加1000ml去离子水使溶解，再加入2％氯化钙水溶液200ml，在强力搅拌下真空均质化，然后加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体(即为制造微孔的模具)沉淀，用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于1000ml无水乙醇溶液中， 该透明质酸-海藻酸微型球体的直径大约在5～10μm之间；
(3)钛溶胶液制备
在室温下，量取50ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100ml的1％海藻酸钠水溶液，之后加入3ml乙酰丙酮，在室温下不断搅拌，30min后生成稳定的均匀的钛溶胶液，于室温陈化24hr；
(4)镀膜和造孔
在室温下，将陈化的钛溶胶液与1.5倍体积的透明质酸-海藻酸微型球体乙醇悬浮液搅拌混合，并在吻(缝)合器钛钉本体表面采用流涎法镀膜，控制膜的厚度大约在10～15μm之间；
将镀有薄膜的吻(缝)合器钛钉于90℃下干燥，然后置于98℃热水中热处理5hr，随着透明质酸和海藻酸在热水中的完全溶解和完全溶出，在吻(缝)合器钛钉本体表面形成带有微孔的二氧化钛薄膜，孔径大约在5～10μm之间；
(5)焙烧
将镀膜的吻(缝)合器钛钉置于焙烧炉中焙烧，以2℃/min匀速升温，升温至500℃后，保温3hr，自然降温后取出，在吻(缝)合器钛钉本体表面生成带有微孔的牢固的二氧化钛陶瓷层，用水清洗，干燥，陶瓷层大约厚度在5～10μm之间，微孔分布均匀，孔径大约在0.5～6.5μm之间，有些微孔之间有贯通。
实施例5
(1)预处理
先将吻(缝)合器钛钉n个在去离子水中超声清洗，洗掉表面附着物，放入1000ml的5mol/L的NaOH溶液中，于80℃保温24hr，去除表面杂质和自然氧化层，然后用去离子水反复超声清洗，干燥；
(2)透明质酸-海藻酸微型球体的制备
在室温下，分别称取粘均分子量80万道尔顿的透明质酸钠30g和海藻酸钠30g，于高速真空均质机中，加1000ml去离子水使溶解，再加入3％氯化钙水溶液100ml，在强力搅拌下真空均质化，然后加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体(即为制造微孔的模具)沉淀，用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于1000ml无水乙醇溶液中，该透明质酸-海藻酸微型球体的直径大约在5～10μm之间；
(3)钛溶胶液制备
在室温下，量取50ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100ml的1％海藻酸钠水溶液，之后加入3ml乙酰丙酮，在室温下不断搅拌，30min后生成稳定的均匀的钛溶胶液，于室温陈化24hr；
(4)镀膜和造孔
在室温下，将陈化的钛溶胶液与等体积的透明质酸-海藻酸微型球体乙醇悬浮液搅拌混合，并在吻(缝)合器钛钉本体表面采用流涎法镀膜，控制膜的厚度大约在10～15μm之间；
将镀有薄膜的吻(缝)合器钛钉于90℃下干燥，然后置于95℃热水中热处理5hr，随着透明质酸和海藻酸在热水中的完全溶解和完全溶出，在吻(缝)合器钛钉本体表面形成带有微孔的二氧化钛薄膜，孔径大约在5～10μm之间；
(5)焙烧
将镀膜的吻(缝)合器钛钉置于焙烧炉中焙烧，以2℃/min匀速升温，升温至500℃后，保温3hr，自然降温后取出，在吻(缝)合器钛钉本体表面生成带有微孔的牢固的二氧化钛陶瓷层，用水清洗，干燥，陶瓷层大约厚度在5～10μm之间，微孔分布均匀，孔径大约在0.5～6.5μm之间，有些微孔之间有贯通。
实施例6
(1)预处理
先将吻(缝)合器钛钉n个在去离子水中超声清洗，洗掉表面附着物，放入1000ml的3.5mol/L的NaOH溶液中，于80℃保温24hr，去除表面杂质和自然氧化层，然后用去离子水反复超声清洗，干燥；
(2)透明质酸-海藻酸微型球体的制备
在室温下，分别称取粘均分子量150万道尔顿的透明质酸钠10g和海藻酸钠10g，于高速真空均质机中，加1000ml去离子水使溶解，再加入1％氯化钙水溶液200ml，在强力搅拌下真空均质化，然后加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体(即为制造微孔的模具)沉淀，用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于1000ml无水乙醇溶液中，该透明质酸-海藻酸微型球体的直径大约在5～10μm之间；
(3)钛溶胶液制备
在室温下，量取100ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入200ml的1％海藻酸钠水溶液，之后加入6ml乙酰丙酮，在室温下不断搅拌，30min后生成稳定的均匀的钛溶胶液，于室温陈化24hr；
(4)镀膜和造孔
在室温下，将陈化的钛溶胶液与等体积的透明质酸-海藻酸微型球体乙醇悬浮液搅拌混合，并在吻(缝)合器钛钉本体表面采用流涎法镀膜，控制膜的厚度大约在10～15μm之间；
将镀有薄膜的吻(缝)合器钛钉于90℃下干燥，然后置于98℃热水中热处理5hr，随着透明质酸和海藻酸在热水中的完全溶解和完全溶出，在吻(缝)合器钛钉本体表面形成带有微孔的二氧化钛薄膜，孔径大约在5～10μm之间；
(5)焙烧
将镀膜的吻(缝)合器钛钉置于焙烧炉中焙烧，以2℃/min匀速升温，升温至500℃后，保温3hr，自然降温后取出，在吻(缝)合器钛钉本体表面生成带有微孔的牢固的二氧化钛陶瓷层，用水清洗，干燥，陶瓷层大约厚度在5～10μm之间，微孔分布均匀，孔径大约在0.5～6.5μm之间，有些微孔之间有贯通。
实施例7
(1)预处理
先将吻(缝)合器钛钉n个在去离子水中超声清洗，洗掉表面附着物，放入1000ml的5mol/L的NaOH溶液中，于80℃保温24hr，去除表面杂质和自然氧化层，然后用去离子水反复超声清洗，干燥；
(2)透明质酸-海藻酸微型球体的制备
在室温下，分别称取粘均分子量150万道尔顿的透明质酸钠10g和海藻酸钠10g，于高速真空均质机中，加1000ml去离子水使溶解，再加入1％氯化钙水溶液200ml，在强力搅拌下真空均质化，然后加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体(即为制造微孔的模具)沉淀，用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于1000ml无水乙醇溶液中，该透明质酸-海藻酸微型球体的直径大约在5～10μm之间；
(3)钛溶胶液制备
在室温下，量取50ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100ml的1％海藻酸钠水溶液，之后加入3ml乙酰丙酮，在室温下不断搅拌，30min后生成稳定的均匀的钛溶胶液，于室温陈化24hr；
(4)镀膜和造孔
在室温下，将陈化的钛溶胶液与等体积的透明质酸-海藻酸微型球体乙 醇悬浮液搅拌混合，并在吻(缝)合器钛钉本体表面采用流涎法镀膜，控制膜的厚度大约在10～15μm之间；
将镀有薄膜的吻(缝)合器钛钉于90℃下干燥，然后置于95℃热水中热处理5hr，随着透明质酸和海藻酸在热水中的完全溶解和完全溶出，在吻(缝)合器钛钉本体表面形成带有微孔的二氧化钛薄膜，孔径大约在5～10μm之间；
(5)焙烧
将镀膜的吻(缝)合器钛钉置于焙烧炉中焙烧，以2℃/min匀速升温，升温至500℃后，保温3hr，自然降温后取出，在吻(缝)合器钛钉本体表面生成带有微孔的牢固的二氧化钛陶瓷层，用水清洗，干燥，陶瓷层大约厚度在5～10μm之间，微孔分布均匀，孔径大约在0.5～6.5μm之间，有些微孔之间有贯通。
实施例8
(1)预处理
先将吻(缝)合器钛钉n个在去离子水中超声清洗，洗掉表面附着物，放入1000ml的5mol/L的NaOH溶液中，于80℃保温24hr，去除表面杂质和自然氧化层，然后用去离子水反复超声清洗，干燥；
(2)透明质酸-海藻酸微型球体的制备
在室温下，分别称取粘均分子量150万道尔顿的透明质酸钠10g和海藻酸钠10g，于高速真空均质机中，加1000ml去离子水使溶解，再加入1％氯化钙水溶液200ml，在强力搅拌下真空均质化，然后加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体(即为制造微孔的模具)沉淀，用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于1000ml无水乙醇溶液中，该透明质酸-海藻酸微型球体的直径大约在5～10μm之间；
(3)钛溶胶液制备
在室温下，量取50ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100ml的1％海藻酸钠水溶液，之后加入3ml乙酰丙酮，在室温下不断搅拌，30min后生成稳定的均匀的钛溶胶液，于室温陈化24hr；
(4)镀膜和造孔
在室温下，将陈化的钛溶胶液与等体积的透明质酸-海藻酸微型球体乙醇悬浮液搅拌混合，并在吻(缝)合器钛钉本体表面采用流涎法镀膜，控制膜的厚度大约在10～15μm之间；
将镀有薄膜的吻(缝)合器钛钉于90℃下干燥，然后置于98℃热水中热处理5hr，随着透明质酸和海藻酸在热水中的完全溶解和完全溶出，在吻(缝)合器钛钉本体表面形成带有微孔的二氧化钛薄膜，孔径大约在5～10μm之间；
(5)焙烧
将镀膜的吻(缝)合器钛钉置于焙烧炉中焙烧，以2℃/min匀速升温，升温至300℃后，保温5hr，自然降温后取出，在吻(缝)合器钛钉本体表面生成带有微孔的牢固的二氧化钛陶瓷层，用水清洗，干燥，陶瓷层大约厚度在5～10μm之间，微孔分布均匀，孔径大约在0.5～6.5μm之间，有些微孔之间有贯通。
上述得到的可载药钛钉均可以用于载入药物形成载药钛钉，实施例如下：
载药实施例1
在室温条件下，将上述可载药吻(缝)合器钛钉置于真空器中，在真空条件下导入浓度为15％的磺胺嘧啶或磺胺嘧啶银浓氨溶液，然后取出换另一真空器真空干燥，即得装载磺胺嘧啶或磺胺嘧啶银的载药吻(缝)合器钛钉。
载药实施例2
在室温条件下，将上述可载药吻(缝)合器钛钉置于真空器中，在真空条件下导入浓度为15％的生长因子乙醚溶液，然后取出换另一真空器真空干燥，即得装载有生长因子的载药吻(缝)合器钛钉。
载药实施例3
在室温条件下，将上述可载药吻(缝)合器钛钉置于真空器中，在真空条件下导入浓度为65％的各种人用组织细胞生长促进因子之一的表皮生长因子溶液，然后取出换真空冷冻干燥机干燥，即得装载有各种人用组织细胞生长促进因子的表皮生长因子的吻(缝)合器钛钉。
本发明利用纯钛、二氧化钛、透明质酸和海藻酸的特性，对已有的吻(缝)合器钛钉进行表面处理，使纯钛、二氧化钛和透明质酸-海藻酸相互作用，在吻(缝)合器钛钉表面形成牢固的带有微孔的二氧化钛陶瓷层，微孔分布相对均匀、平均孔径0.5～6.5μm，增加了吻(缝)合器钛钉表面积，载入药物时可作为药物的储存处，也可使药物相对稳定、均匀地分布在吻(缝)合器钛钉表面微孔中，并在组织中缓慢、定向释放出药物，起到抑菌和促进愈合等作用。
本发明可载药钛钉，一方面便于载入抑菌药物和促进愈合的药物并具有缓释功能，另一方面由于具有耐腐蚀的陶瓷性质，使其表面不易产生脱落物，从而克服现有吻(缝)合器钛钉植入人体后钛离子所产生的副作用。
当然，本发明可载药钛钉及其制备方法也可用于其它需用钛钉的医疗器械中，并且可根据临床需要制备装载有其它药物的载药钛钉。
以上所述，仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，本领域技术人员利用上述揭示的技术内容做出些许简单修改、等同变化或修饰，均落在本发明的保护范围内。

Claims (10)

  1. 一种可载药钛钉的制备方法，其特征在于，所述可载药钛钉包括钛钉本体和设置在钛钉本体表面的微孔可载药陶瓷层，所述可载药钛钉的制备方法包括：
    (1)预处理：采用加热的碱性溶液处理所述钛钉本体的表面，反复清洗后干燥；
    (2)透明质酸-海藻酸微型球体的制备：称取等质量的透明质酸钠和海藻酸钠，放置于高速真空均质机中，依次加入去离子水和氯化钙溶液，在强力搅拌下真空均质化，再加入乙醇，持续搅拌，生成透明质酸-海藻酸微型球体沉淀，并用无水乙醇洗涤，冷冻真空干燥，然后悬浮于无水乙醇溶液中；
    (3)钛溶胶液的制备：取钛酸四丁酯溶于乙醇中，在不断搅拌下依次加入海藻酸钠溶液和乙酰丙酮，继续搅拌，生成稳定均匀的钛溶胶液，并于室温下陈化；
    (4)镀膜和造孔：将所述步骤(2)得到的透明质酸-海藻酸微型球体的乙醇悬浮液与步骤(3)得到的钛溶胶液搅拌混合，并在所述钛钉本体表面镀膜，干燥，即得镀膜钛钉，然后将所述镀膜钛钉置于热水中热处理，随着透明质酸和海藻酸在热水中的溶解和溶出，所述镀膜钛钉表面形成带有微孔的二氧化钛薄膜；
    (5)焙烧：将所述步骤(4)得到的镀有二氧化钛薄膜的钛钉在焙烧炉中焙烧，形成带有微孔二氧化钛陶瓷层的钛钉，水洗、干燥即得可载药钛钉。
  2. 根据权利要求1所述的可载药钛钉制备方法，其特征在于，所述步骤(2)具体为：分别称取等质量的透明质酸钠和海藻酸钠10～30g，均放置于高速真空均质机中，加入去离子水将其溶解，再加入1％～3％的氯化钙 溶液100～300ml，在强力搅拌下真空均质化，再加入三倍体积的乙醇，持续搅拌，生成透明质酸-海藻酸微型球体沉淀，并用无水乙醇洗涤3次，冷冻真空干燥，然后悬浮于无水乙醇溶液中；其中，所述透明质酸钠的粘均分子量为80～150万道尔顿，所形成的透明质酸-海藻酸微型球体的直径为5～10μm。
  3. 根据权利要求1所述的可载药钛钉制备方法，其特征在于，所述步骤(3)具体为：量取50～100ml钛酸四丁酯溶于1000ml无水乙醇中，搅拌下缓慢加入100～200ml的1％海藻酸钠水溶液，再加入3～6ml乙酰丙酮，在室温下不断搅拌，生成钛溶胶液，并于室温下陈化24小时。
  4. 根据权利要求1所述的可载药钛钉制备方法，其特征在于，所述步骤(4)具体为：将所述步骤(2)得到的透明质酸-海藻酸微型球体的乙醇悬浮液与所述步骤(3)得到的钛溶胶液以2～4.5：3的比例混合，搅拌，并将混合后的溶液在所述钛钉本体表面采用流涎法镀膜，其中镀膜的厚度为10～15μm，并于90℃干燥，即得镀膜钛钉；然后将所述镀膜钛钉置于95～98℃的热水中热处理，随着透明质酸和海藻酸在热水中的溶解和溶出，所述镀膜钛钉表面形成带有微孔的二氧化钛薄膜。
  5. 根据权利要求1所述的可载药钛钉制备方法，其特征在于，所述步骤(1)中加热的碱性溶液为温度在70～90℃、浓度在2～5mol/L的NaOH溶液，且所述钛钉本体在所述NaOH溶液中保温24～48小时；
    所述步骤(5)中焙烧炉的焙烧条件为以2℃/min的匀速升温，升温至300～500℃后保温3～5小时。
  6. 一种应用如权利要求1至5任一项所述的可载药钛钉制备方法制得的可载药钛钉，其特征在于，所述二氧化钛陶瓷层中微孔分布均匀，平均孔径为0.5～6.5μm，且所述微孔之间有贯通。
  7. 一种应用如权利要求6所述的可载药钛钉制备载药钛钉的方法，其 特征在于，所述方法包括：将所述可载药钛钉置于真空器中，在真空条件下导入用易挥发有机溶剂溶解的所需载入药物，取出，置于另一真空器中真空干燥。
  8. 一种应用如权利要求7所述的制备载药钛钉方法制得的载药钛钉，其特征在于，所述载药钛钉为装载磺胺嘧啶或磺胺嘧啶银的载药钛钉；或者装载有生长因子的载药钛钉。
  9. 一种应用如权利要求6所述的可载药钛钉制备载药钛钉的方法，其特征在于，所述方法包括：将所述可载药钛钉置于真空器中，在真空条件下导入所需载入药物溶液，取出，置于真空冷冻干燥机中干燥。
  10. 一种应用如权利要求9所述的制备载药钛钉方法制得的载药钛钉，其特征在于，所述载药钛钉为装载有各种人用组织细胞生长促进因子的钛钉。
PCT/CN2016/109120 2016-08-19 2016-12-09 一种可载药钛钉和载药钛钉及其制备方法 WO2018032664A1 (zh)

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