CN101336116B

CN101336116B - Bioactive material delivery systems comprising sol-gel compositions

Info

Publication number: CN101336116B
Application number: CN200680052265XA
Authority: CN
Inventors: 迪米特里奥斯·潘泰利迪斯; 约翰·C·布拉夫曼; 乔纳森·罗特巴德; 理查德·L·克莱恩
Original assignee: Leland Stanford Junior University; Medlogics Device Corp
Current assignee: Leland Stanford Junior University; Medlogics Device Corp
Priority date: 2006-02-02
Filing date: 2006-08-08
Publication date: 2013-01-02
Anticipated expiration: 2026-08-08
Also published as: JP2009525124A; WO2007092043A2; EP1979019A2; CN101336116A; WO2007092043A3

Abstract

Implantable medical devices employing a sol-gel composition coatings that functions as a bioactive material reservoir, and the use of sol-gel composition coatings for improved adhesion of organic and inorganic substrates are disclosed.

Description

A kind of bioactive material delivery systems that comprises sol-gel composite

The cross reference of related application

According to 35 U.S.C. § 119 (e), the application requires the U.S. Provisional Patent Application 60/764 submitted on February 2nd, 2006,941 priority, and the application is the application that continues of the part of International Patent Application PCT/US2004/040270 of submitting in 1st of December in 2004, this international patent application requires the U.S. Provisional Patent Application 60/546 submitted on February 18th, 2004,091 priority, above-mentioned patent application are inserted this paper by reference in full.

Technical field

The present invention relates to contain the sol-gel composite of the self assembly of bioactive substance.Particularly, the present invention relates to above-mentioned sol-gel composite and in implantable medical device, be used as drug reservoir, also relate to above-mentioned sol-gel composite for the fusible purposes of improving between organic and the inorganic surfaces.

Background technology

" sol-gel " method is generally used for making porous material, comprises self-assembled film.Colloidal sol is a kind of liquid solution, and it comprises the soliquid that is dissolved in the target substance in the appropriate solvent.Condensation reaction between the dissolving precursor molecule causes forming various structures (granule, branched chain, linear chain etc.) in colloidal sol.The size of these structures, growth rate and form depend on the kinetics in the solvent, and above-mentioned kinetics is decided by parameter and other parameter such as the stirring action of the temperature of the water yield of solution concentration, existence, solvent and pH, solvent.Under the time of abundance, granule or chain that condensation reaction will cause growing are reunited, until finally form gel.Described gel can be regarded as being a large amount of crosslinked precursor molecule, and it forms solid phase continuous, macroscopic view, and described gel has encapsulated the Continuous Liquid Phase that is comprised of surplus solution.In the final step of sol-gel technology, remove packed solvent (usually by dry), and make precursor molecule crosslinked (being called as aging technique), thereby obtain required solid.

The sol-gel synthesis method of material has following advantage with respect to other synthetic method.Described advantage comprises: processing conditions gentle (low temperature, low pressure, medium pH), raw material be cheap, need not the device of vacuum treatment installation or other costliness and resulting structures is had higher controllability, is particularly suitable for poromerics.Shape for end product there is no restriction, because can cast in any form lyosol before gel, described form comprises the granule of monolithic, thin film, fiber and micro-meter scale or the granule of nanoscale.

Can multitude of different ways the porosity of prepared material in the control sol-gel technology.In the simplest sol-gel technology, specific pore former is not added in the colloidal sol, decide the porosity of final solid by the amount of presoma branching or reunion before the gel.The size of the average cell size of porous sol-gel composite, volume and the surface area precursor molecule before along with sol-gel processing and increasing.

The additional materials that also can be in the sol-gel technology process exists in by solvent is regulated and control porosity.When using sol-gel technology, will sacrifice pore former (be specially can by those materials that heat or other method is removed easily) and mix and usually be considered to a kind of effective ways that obtain porosu solid in the colloidal sol.In the past, these effort mainly concentrate on the manufacturing of low-k (low k) dielectric film for microelectronic technique.The sacrifice template also is used in utilizes sol-gel technology to form pore-forming in the inorganic material.Sacrifice template be generally in solution can self assembly amphiphile, amphiphilic molecule (namely having hydrophilic and oil loving those molecules).These amphiphile, amphiphilic molecules produce the structure of high-sequential, thereby the guiding precursor molecule is assembled altogether around this structure.In case precursor molecule is assembled altogether around said structure, then described structure can be removed, thereby stay the negative-appearing image hole.

The peculiar property that centers on the sol-gel composite of template assisted self assembling has carried out large quantity research.For example, 1992, the research team of Mobil Oil Corporation finds, surface active molecules (short amphiphile, amphiphilic molecule) self assembly in the aqueous solution of solvable tripoli, after the tripoli base material solidifies, can remove surfactant, thereby obtain having the material (being also referred to as " MCM-41 ") of the homogeneous that the hexagon honeycomb texture arranges mesoporous (mesoporous is hole dimension in about 2nm hole between about 50nm extremely); Referring to US patent 5,057,296 and 5,102,643, above-mentioned patent is inserted this paper by reference in full.Utilize cationic surfactant alkyl trimethyl quaternary ammonium salt and various silica gel source (such as sodium silicate, tetraethyl orthosilicate or silicon gel) synthetic MCM-41 (Beck etc., 1992, J.Am.Chem.Soc.114,10834) under hydrothermal condition.Can the hole dimension of MCM-41 be regulated between about 10nm at about 1.6nm by using different surfactants or changing synthesis condition.At present, the auxiliary mesoporous material of template utilizes following two class self assembly amphiphilic templates to prepare: the short molecule surfactant is (referring to (Advanced Materials 1999 such as Brinker, 11 No.7) and (the Nature Vol.359 such as Kresge, on October 22nd, 1992)) and triblock copolymer (referring to US patent 6,592,764, described patent is inserted this paper by reference in full).

The porous material that utilizes sol-gel technology to make can be used for conveying bioactivator.For example, and Vallet-Regi etc. (Chem.Mater.2001,13,308-311) described ibuprofen has been carried on the MCM-41 of powdered.In this case, by ibuprofen is dissolved in the hexane, and the MCM-41 chemical compound of powder type is added in the above-mentioned hexane, thereby ibuprofen is loaded among the MCM-41.(the Chem.Mater.2003 such as Munoz, 15,500-503) experiment has been described, this experimental demonstration, ibuprofen can be carried from two kinds of different MCM-41 preparations with different speed, a kind of preparation utilizes the preparation of 16 carbon surface active agents, and a kind of preparation is prepared by 12 carbon surface active agents.

Before International Patent Application PCT/US2004/040270 (PCT ' 270) (this paper is inserted in this patent application by reference in full), there is not list of references to be described below implantable medical device or bioactive substance delivery instrument, described apparatus comprises the face coat that is formed by the sol-gel composite take the triblock copolymer template as the basis, described coating has basically continuous interconnecting channel, and it is designed to play the effect in bioactive substance storehouse.And, there is not list of references to describe the face coat that is formed by the sol-gel composite take the triblock copolymer template as the basis, wherein, be applied to before the implantable medical device surface, there is bioactive substance in the described coating itself, and after being applied to the implantable medical device surface, described face coat has basically continuous interconnecting channel, and it can further play the effect in bioactive substance storehouse.Thereby the invention of describing among the PCT ' 270 provides at least two additional mechanism, can be loaded on the implantable medical device surface by these machine-processed bioactive substances.

Although the materials and methods of describing among the PCT ' 270 has a large amount of important benefits (having described in this patent), still there is leeway for the bioactive substance delivery material preparation that improves by the sol-gel technology preparation.For example, controlling better the bioactive substance granule in the sol gel processing process and behind the implantation instrument may be of value to the amount of controlling more accurately the bioactive substance in particular sol-gel combination and be controlled at better implantation instrument artifact active substance and discharge into speed in the physiological environment by implanted medical apparatus and instruments.The present invention has above-mentioned advantage.Yet, describing in more detail before these advantages, the background technology of other side of the present invention is described.

A challenge that runs in the implantable medical device field is bioactive substance and the coating that contains bioactive substance are sticked on the surface of implantable apparatus, thereby in case implant described apparatus, bioactive substance just to discharge in time.The method that bioactive substance is sticked on the base material (such as the surface of implantable medical device) is to comprise bioactive substance in polymer coating.Polymer coating can make bioactive substance remain on the surface of implantable medical device, and by depolymerization or diffuse into liquid or tissue (in this case, polymer non-degradable) in come release of bioactive substances.Although can use polymer coating that bioactive substance is sticked on the implanted medical device, there are some problems in the application of described polymer coating.A problem is to be difficult to make polymer coating to stick on the diverse base material (such as the backbone metal base material), because various material has different characteristic (different such as hot expansion property).And most of inoganic solids are covered by the hydrophilic surface oxide, and described hydrophilic surface oxide is characterised in that and has surface hydroxyl (M-OH, wherein M represents the atom of inorganic material, such as silicon or aluminum).So under environmental condition, the hydrone that at least one monolayer is adsorbed covers the surface of described inoganic solids, thereby form hydrogen bond with above-mentioned hydroxyl.Thereby because above-mentioned water layer, hydrophobic organic polymer can not spontaneously adhere to the surface of implantable medical device.And, even under drying condition, form polymer/surperficial key (comprising covalent bond), when being exposed to water, these keys also are easy to hydrolysis (fracture).In the application that the apparatus that contains the organic/inorganic interface or assembly must operate in aqueous, corrosive atmosphere (such as human body or other animal body), the above-mentioned particular importance that affects.These difficult points relevant with adhering to two kinds of different kind of material cause between implantable medical device and its polymer coating that covers bonding insufficient usually, thereby cause along with each material of time may separate.In implanted medical device, above-mentioned separation is not make us wishing especially.

Traditionally, adopt two kinds of interfaces between the diverse ways reinforcement organic/inorganic.First method is to introduce controlled roughness or porosity at inorganic surfaces, thereby impel polymer machinery to engage.Second method is by amphipathic silane coupler inorganic surfaces to be carried out chemical modification, thereby improve wettability, associativity and the interface resistance to water of polymer.Although these methods have some benefits, in all various environment, these methods are ineffective.Thereby, there is certain leeway for improving the method relevant with organic surface with adhering to inorganic surfaces.Some sol-gel embodiment according to the present invention provides above-mentioned improvement.

Summary of the invention

The invention provides a kind of method, the method produces and has strengthened the sol-gel composite that bioactive substance mixes, and a kind of method is provided, and described method is used for further being controlled at clinical use procedure bioactive substance and is discharged into speed in the physiological environment from medical apparatus and instruments.Described method also is used for strengthening the cohesive between inorganic substrate and organic substrate and the material.The sol-gel composite that these methods provide can be used as bioactive substance storehouse and/or the bioactive substance coating of conduct on implantable medical device of sustained release.Thereby the present invention strengthens mixing of bioactive substance by revise chemical environment in the sol gel processing process, revise chemical environment and changed the hydrophobicity that forms material or hydrophilic etc., affect the bioactive substance molecule and how to interact with chemical environment in formation material and the sol gel processing process.It is all right in the sol gel processing process chemical environment to be made amendment, in case be discharged into the mode of the speed in the physiological environment to affect patients with implantation artifact active substance, affects the properties of materials of making after taking out from the sol-gel environment.Particularly, according to the characteristic of specific bioactive substances, regulate the chemical environment of sol-gel technology, thus the control bioactive substance how with sol-gel technology in environmental interaction.As limiting examples to, the hydrophobicity that can increase the gel that forming (mean form structure) in the sol-gel mixture in the sol gel processing process will be added through organically-modified silane.Be not entangled in any theory, the hydrophobicity that increases the gel that is forming is considered to hinder bioactive substance movement between the gel that is forming and aqueous environments in the sol gel processing process, bioactive substance is remained on the gel that is forming more firmly, thereby cause bioactive substance to be retained in better in the sol-gel composite of making.And, can control better patients with implantation artifact active substance and be discharged into speed in the biological environment in case strengthen the hydrophobic content of the material finally make.The method according to this invention can be by the following method even is further improved control implantation instrument artifact active substance and be discharged into ability in the physiological environment: the surface of adopting the sol-gel composite of making through organically-modified silane treatment.Help to prevent that through the hydrophobic trimethyl of organically-modified silane liquid in the physiological environment at implanted medical device is diffused in the compositions and dissolves bioactive substance, thereby cause described bioactive substance to discharge too early.

Can also improve by the following method sol-gel composite of the present invention to the cohesive of base material: the hole of continuous interconnecting channel mode is provided, thereby allows between inorganic substrate and the organic coating strongly interspersed.

Particularly, an embodiment of the invention comprise a kind of medical apparatus and instruments, described medical apparatus and instruments comprises structural detail and bioactive substance storehouse, wherein, described bioactive substance storehouse comprises the lip-deep coating that is applied to described structural detail, wherein, described coating comprises one or more layers, wherein comprise one of at least the base composition that utilizes sol-gel technology to form in each layer, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, in case described design impact in case behind the content of the described bioactive substance in the described base composition after making and/or the patients with implantation described bioactive substance be discharged into speed in the physiological environment.Base composition can comprise, but be not limited to, be selected from following material: sol-gel derived inorganic oxide, sol-gel derived organically-modified silane, comprise the hydridization oxide of organic modified silane and have the mesoporous oxide that the template utilized produces.

In some embodiments, base composition according to the present invention comprises the inorganic oxide of making by above-mentioned sol-gel technology.Described inorganic oxide can be selected from oxide and the titanyl compound of silicon.Described base composition also can be the mesoporous inorganic oxide.The mesoporous inorganic oxide can utilize sacrifices pore-forming template component and self assembly or guides assembling preparation technology to obtain.The template component can be selected from amphiphilic block copolymer, ionic surfactant and nonionic surfactant.The template component can also be polyethylene oxide/polypropylene oxide/polyethylene glycol oxide triblock copolymer.

Mesoporous inorganic oxide according to the present invention can comprise basically continuous interconnecting channel.The inner surface of described basically continuous interconnecting channel can adopt organically-modified silane coating, thereby improves the following characteristic of mesopore oxide: hydrophobicity, electric charge, biocompatibility, engineering properties, bioactive substance affinity, storage capacity and combination thereof.And, be applied on the surface of structural detail in coating after, one or more bioactive substances can be loaded in the interconnecting channel.

In some embodiment according to the present invention, oxide in the base composition can be compound with reagent, thus the following characteristic of modified oxide: hydrophobicity, electric charge, biocompatibility, engineering properties, bioactive substance affinity, storage capacity and combination thereof.In one embodiment, modifying agent is through organically-modified silane.Can be selected from alkyl silane through organically-modified silane, MTMS, MTES, dimethyldiethoxysilane, trimethylethoxysilane, vinyltrimethoxy silane, VTES, ethyl triethoxysilane, the isopropyl triethoxysilane, the butyl triethoxysilane, octyltri-ethoxysilane, the dodecyl triethoxysilane, octadecyltriethoxy silane, the aryl functional silane, phenyl triethoxysilane, amino silane, aminopropyl triethoxysilane, the aminophenyl trimethoxy silane, aminopropyl trimethoxysilane, acrylate-functional silane, the methacrylate functional silane, the acryloyl-oxy propyl trimethoxy silicane, the carboxylate functional silane, phosphate functional silane, the ester functional silane, sulfonate functional silane, isocyanate-functional silane, epoxy functional silane, chlorosilane, trim,ethylchlorosilane, chlorotriethyl silane, three hexyl chloride silane, dimethyldichlorosilane, methyl trichlorosilane, N, O-two (trimethyl silyl)-acetamide (BSA), N, O-two (trimethyl silyl)-trifluoroacetamide (BSTFA), hexamethyldisiloxane (HMDS), N-methyl-trimethyl-silyl-trifluoroacetamide (MSTFA), N-hexyl-N-(t-butyldimethylsilyl) trifluoroacetamide (MTBSTFA), trimethyl chlorosilane (TMCS), trimethyl-silyl-imidazole (TMSI) and combination thereof.

Comprise a kind of medical apparatus and instruments according to an embodiment of the invention, described medical apparatus and instruments comprises structural detail and bioactive substance eluting coatings, wherein, described bioactive substance eluting coatings comprises at least one deck that is applied on the described medical apparatus surface, and wherein said at least one deck utilizes sol-gel technology to form and comprises through organically-modified silane.In some embodiments, described at least one deck is the priming coat that is applied on the described medical apparatus surface, and described medical apparatus and instruments also comprises the top coat that is applied on the described priming coat.Can be in being selected from described priming coat, in the described top coat, between described priming coat and the described top coat and have the spheroid of matters of containing biological activities in the place of combination.The spheroid that contains bioactive substance can be made of biodegradable polymers.

In one embodiment, priming coat and/or top coat comprise sol-gel inorganic oxide compositions.In another embodiment, priming coat comprises the mesopore oxide with basically continuous interconnecting channel.

Comprise medical apparatus and instruments according to another embodiment of the present invention, described medical apparatus and instruments comprises structural detail and bioactive substance eluting coatings, wherein the bioactive substance eluting coatings comprises two-layer at least, wherein, describedly comprise one of at least the base composition that utilizes sol-gel technology to form in two-layer at least, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, in case described design impact in case behind the content of the described bioactive substance in the described base composition after making and/or the patients with implantation described bioactive substance be discharged into speed in the physiological environment.Above-mentionedly two-layerly can include, but not limited to priming coat and top coat.In these embodiments according to the present invention, each layer can comprise respectively the following form that is selected from: the sol-gel oxide skin(coating) that does not have bioactive substance; The sol-gel oxide skin(coating), described sol-gel oxide skin(coating) has the bioactive substance that mixes in the described oxide; Do not have bioactive substance with through the compound sol-gel oxide of organically-modified silane; Have bioactive substance with through the compound sol-gel oxide of organically-modified silane; Do not have bioactive substance through organically-modified silylation layer; Have bioactive substance through organically-modified silylation layer; The mesopore oxide that does not have bioactive substance; Mesopore oxide, described mesopore oxide has the bioactive substance that mixes in the described oxide; Mesopore oxide, described mesopore oxide has the bioactive substance that mixes in the described oxide, and has other bioactive substance that is carried in later on the described surface that described mesoporous material is applied to described medical apparatus and instruments in the interconnecting channel of described oxide; Mesopore oxide, described mesopore oxide does not have the bioactive substance that mixes in the described oxide, but has the bioactive substance that is carried in later on the described surface that described oxide is applied to described medical apparatus and instruments in the interconnecting channel of described oxide; Aggregation with the polymer spheres that contains bioactive substance.Body.

Comprise medical apparatus and instruments according to another embodiment of the present invention, described medical apparatus and instruments comprises structural detail and bioactive substance storehouse, wherein, described bioactive substance storehouse comprises the coating that is applied to described structural detail surface, wherein, described coating comprises the base composition that utilizes sol-gel technology to form, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, in case described bioactive substance is discharged into the speed in the physiological environment behind the content of the described bioactive substance in the described base composition in a single day described design impact is made after and/or the patients with implantation, and when described coating is applied to described structural detail surperficial, described coating has strengthened the cohesive between inorganic surfaces and the organic surface, and described organic surface is selected from polymer, tissue, skeleton and combination thereof.

In one embodiment, bioactive substance used in this invention can be selected from: anti-restenosis reagent, anti-inflammatory agents, HMG-CoA reductase inhibitor, antibacterial agent, anti-tumor agent comprising salmosin, angiogenic reagent, anti-angiogenic reagent, thrombus reagent, resisting hypertension reagent, arrhythmia reagent, calcium channel blocker, cholesterol reducing reagent, psychotropic drugs, anti-depressed reagent, anti-epilepsy reagent, contraceptive, analgesic, SGF, skeleton are reinvented the factor, neurotransmitters, nucleic acid, opiate antagonist and combination thereof.Bioactive substance can also be selected from paclitaxel, rapamycin (rampamycin), clothing Wei Mosi (everolimus), tacrolimus (tacrolimus), sirolimus (sirolimus), Des aspartic acid angiotensin I, nitric oxide, 4-hydroxy-3-methoxyacetophenone, Gamma-Tocopherol, recombined human POSTN (pleiotrophin), estradiol, aspirin, atorvastatin (atovastatin), west power is cut down his spit of fland (cerivastatin), fluvastatin (fluvastatin), lovastatin (lovastatin), pravastatin (pravastatin), Rosuvastatin (rosuvastatin), simvastatin (simvastatin) and combination thereof.

Medical apparatus and instruments of the present invention can comprise, but be not limited to vascular (vascular conduit), support, plate, screw, the vertebra cage, dental implant, the dentistry implant, dental aligners, artificial joint, embolus device (embolic device), ventricular assist device (ventricular assistdevice), the artificial heart, cardiac valve, vein filter device (venous filter), nail, clip, stitching thread, artificial net (prosthetic mesh), pacemaker, the pacemaker wire, defibrillator, nerve stimulator, the nerve stimulator wire, implantable sensor and external sensor.

Description of drawings

Fig. 1 represents available sketch map with formwork structure of cubic symmetry.

Fig. 2 is illustrated in the mesoporous sol-gel SiO on the substrate surface ₂The sketch map of film, wherein said hole has cubic symmetry.

Fig. 3 A-3D represents the SEM image of four different amplification of implantable medical device, and described implantable medical device adopts sol-gel composite to apply according to instruction of the present invention.

Fig. 4 represents Des aspartic acid angiotensin I (DAA-1) from the speed of the eluting of implantable medical device, and described implantable medical device adopts sol-gel composite to apply according to instruction of the present invention.

Fig. 5 A-5B represents the amount that DAA-I discharges after 72 hours from implantable medical device, described implantable medical device adopts sol-gel composite to apply according to instruction of the present invention.

Fig. 6 represents that western power cuts down his spit of fland from the amount of implantable medical device eluting, and described implantable medical device adopts sol-gel composite to apply according to instruction according to the present invention.

Fig. 7 A-7B represents that other western power cuts down the release profiles in his spit of fland.

Fig. 8 represents that western power cuts down his release profiles of spit of fland from implantable medical device, and described implantable medical device adopts according to instruction according to the present invention and processes through organically-modified silane.

The definition of term

Term " implantable medical device " refers to not to be any entity of making by organism, and this entity is played a role in organism inside or surface.Implantable medical device includes but not limited to: biomaterial, the bioactive substance conveyer device, vascular, support, plate, screw, the vertebra cage, dental implant, the dentistry implant, dental aligners, artificial joint, the embolus device, ventricular assist device, the artificial heart, cardiac valve, the vein filter device, nail, clip, stitching thread, artificial net, pacemaker, the pacemaker wire, defibrillator, nerve stimulator, nerve stimulator wire and implantable sensor or external sensor.Implantable medical device is not subjected to the restriction of size, comprises micron mechanical system and nano-mechanics.Embodiments of the present invention comprise above-mentioned implantable medical device.

The space that term " storehouse " or " bioactive substance storehouse " not only refer to hold bioactive substance, also refer to comprise the coating of sol-gel substrate compositions, wherein, described base composition encapsulates one or more bioactive substances, and described storehouse or bioactive substance storehouse can be applied on the base material surface of (comprising in an example implantable medical device).

Term used herein " bioactive substance " refers to any reagent that has the organic and inorganic of biological activity or biological dependency or live.For example, bioactive substance can be protein, polypeptide, polysaccharide (for example heparin), oligosaccharide, monosaccharide or disaccharide, organic compound, organo-metallic compound or inorganic compound.Described bioactive substance can comprise bioactive molecule, such as the virus of hormone, somatomedin, generation somatomedin, growth factor receptor inhibitors, growth factor receptors, anti-inflammatory agents, antimetabolite, integrin blocker or sense or part official can have Yi Jiyin or antisense gene fully.Described bioactive substance can also comprise artificial granule or material, and described granule or material are with biofacies closing property material or active material.Example is nano-particle, and described nano-particle comprises with the coating on the nuclear of medicine and the nuclear.Above-mentioned nano-particle can by after be loaded in each hole or with metal ion and jointly deposit.

Bioactive substance can also comprise such as playing the chemical compound of therapeutical effect or the medicine of biologic artifact to biologic artifact.Bioactive substance comprises those that especially can be used for long-term treatment (such as hormonal therapy).Example comprises the medicine and the medicine that is used for the treatment of the disease such as osteoporosis, cancer, epilepsy, Parkinson's disease and pain for contraception and hormone replacement therapy.Suitable biomaterial can comprise, but be not limited to, anti-restenosis reagent, anti-inflammatory agents, HMG-CoA reductase inhibitor, antibacterial, anti-tumor agent comprising salmosin, angiogenic reagent, anti-angiogenic reagent, thrombus reagent, resisting hypertension reagent, arrhythmia reagent, calcium channel blocker, cholesterol reducing reagent, psychotropic drugs, anti-depressed reagent, anti-epilepsy reagent, contraceptive, analgesic, SGF, skeleton are reinvented the factor, neurotransmitters, nucleic acid, opiate antagonist and combination thereof.Other bioactive substance includes but not limited to, paclitaxel, rapamycin, clothing Wei Mosi, tacrolimus, sirolimus, Des aspartic acid angiotensin I, nitric oxide, 4-hydroxy-3-methoxyacetophenone, Gamma-Tocopherol, recombined human POSTN, estradiol, aspirin, atorvastatin, western power are cut down his spit of fland, fluvastatin, lovastatin, pravastatin, Rosuvastatin, simvastatin and combination thereof.

Bioactive substance can also comprise precursor, the in vivo metabolism of these materials, fracture (for example molecular components dissociates) or otherwise have corresponding biological activity after the processed and modification.This can comprise the precursor of this class, before above-mentioned modification its can be considered to biologically inert or for not telling in the particular result relevant with medical disease to be treated.

Can make up, mix or other preparation previous embodiment arbitrarily, and still considered to be in this paper and want the bioactive substance that represents.The various aspects that relate to bioactive substance of the present invention can comprise in the previous embodiment any one or all.

Term " sol-gel " processing refers to a kind of technique, and in described technique, the optional the second material (include but not limited to bioactive substance) of the solvable presoma of target substance in appropriate solvent is dissolved in the liquid flux.Condensation reaction between the dissolving precursor molecule causes forming various structures (granule, branched chain, linear chain etc.) (colloidal sol) in described solution.Formed each structural development forms " gel " in the sol-gel technology, can comprise optional the second material in this gel.In case from described gel, removed all or nearly all liquid flux, formed so the base composition in some embodiment of the present invention.

Term " mesoporous inorganic oxide " refers to the sol-gel composite for preparing in the method according to the invention, wherein, the hole dimension of described sol-gel composite at about 2nm to the scope of about 50nm.

Term " through organically-modified " refers to chemical compound (based on the carbon) part (in one embodiment, referring to direct metal-carbon key (or quasiconductor-carbon bond)) that comprises that at least one is organic.

Term " through organically-modified silane " refers to that following chemical compound, this chemical compound comprise at least one and be bonded to non-hydrolysable on the silicon based on the part of carbon.This compounds is also referred to as ORMOSIL, silane coupler, silane coupling agent, silane adhesion promoter or is called simply silane.The a large amount of different chemical compounds of these compounds represented are because the non-hydrolysable part can be any organic group that can imagine synthetic according to vitochemical principle.Limiting examples comprise alkyl silane (such as, but be not limited to MTMS, MTES, dimethyldiethoxysilane, trimethylethoxysilane, vinyltrimethoxy silane, VTES, ethyl triethoxysilane, isopropyl triethoxysilane, butyl triethoxysilane, octyltri-ethoxysilane, dodecyl triethoxysilane, octadecyltriethoxy silane etc.); Aryl functional silane (such as phenyl triethoxysilane etc.); Amino silane (such as aminopropyl triethoxysilane, aminophenyl trimethoxy silane, aminopropyl trimethoxysilane etc.); Acrylate and methacrylate functional silane (such as acryloyl-oxy propyl trimethoxy silicane etc.); The carboxylate functional silane; Phosphate functional silane; The ester functional silane; Sulfonate functional silane; Isocyanate-functional silane and epoxy functional silane.

Recognize these chemical compounds also to comprise can make they in sol-gel technology, be hydrolyzed/the hydrolyzable groups this point of condensation reaction is very important.Thereby, two or more combination in any in each above-claimed cpd or the above-claimed cpd can be used as the sol-gel presoma, but perhaps they can with the sol-gel presoma of complete hydrolysis, be used in combination such as tetraethoxysilane (TEOS) or isopropyl titanium oxide.The sol-gel composite that obtains thus is not the stoichiometry inorganic oxide.On the contrary, it will be hybrid collosol-gel rubber material, and this hybrid collosol-gelatinous mass has the peculiar body chemical property of particular combinations, engineering properties, physical property and other character that consists of component.

The exemplary silane through organically-modified that is specially adapted to this aspect comprises, chlorosilane, trim,ethylchlorosilane, chlorotriethyl silane, three hexyl chloride silane, dimethyldichlorosilane, methyl trichlorosilane, N, O-two (trimethyl silyl)-acetamide (BSA), N, O-two (trimethyl silyl)-trifluoroacetamide (BSTFA), hexamethyldisiloxane (HMDS), N-methyl-trimethyl-silyl-trifluoroacetamide (MSTFA), N-methyl-N-(t-butyldimethylsilyl) trifluoroacetamide (MTBSTFA), trimethyl chlorosilane (TMCS), trimethyl-silyl-imidazole (TMSI) and combination thereof.These listed chemical compounds are particularly useful for surface treatment, in itself and the leading portion included compounds seemingly, difference is that they do not comprise alkoxy ligand.

The specific embodiment

The present invention comprises sol-gel composite and uses thereof.Particularly, the character that sol-gel composite of the present invention has can be used as them: (1) bioactive substance storehouse, and in some embodiments, controllable release bioactive substance storehouse; (2) as the fusible coating that is used for strengthening between organic and the inorganic surfaces.Prepare the used method of sol-gel composite of the present invention and can strengthen in the sol gel processing process bioactive substance to forming mixing in the gel, and the following sol-gel composite of making can be provided, will help to control the characteristic that bioactive substance discharges into the speed in the physiological environment in case described sol-gel composite has its implanted patient.Particularly, characteristic according to specific bioactive substances, regulate the chemical environment of sol-gel technology, thus the control bioactive substance in sol-gel technology how with described environmental interaction, and in case how from the compositions of making, to be discharged in the physiological environment after implanting.Can be by changing the composition of used solution in the sol gel processing process, more subtly control be embedded in the gel that is forming and from case the elution rate of the various bioactive substances of the sol-gel composite after making.And, adopt and the sol-gel composite of making to be processed bioactive substance after helping to suppress to implant through organically-modified silane and be dissolved in the physiological environment and from sol-gel and be released in the physiological environment.

As what set forth, the sol-gel composite that the present invention comprises can be applied to the surface of implantable medical device, thereby plays the effect of bioactive substance storehouse or bioactive substance coating.Sol-gel composite can be the mesoporous inorganic oxide of making as the sol-gel synthesis approach on basis by take template, described mesoporous material has basically continuously interconnecting channel, these passages are suitable for playing the effect in bioactive substance storehouse, can the retains biological activity material and can be within the time period that limits release of bioactive substances.Sol-gel composite of the present invention can play the effect in bioactive substance storehouse in the following way: had bioactive substance in the material of described composition material itself before on being applied to the implantable medical device surface; And/or after on being applied to the implantable medical device surface bioactive substance is loaded in the interconnecting channel of described material.In one embodiment, in sol-gel technology, will add through organically-modified silane and can strengthen in the solvent or more fine control bioactive substance mixing in the sol-gel composite of the present invention.Can change the chemical environment of sol-gel technology through organically-modified silane, comprise the hydrophobicity/hydrophilic that changes described technique and form gel rubber material, thereby bioactive substance can not move freely between the gel that is forming and aqueous environments.In one embodiment, when gel formation, bioactive substance is owing to the effect of electrostatic force and/or chemical bond or hydrogen bond is retained near the gel.

The surface that mesoporous sol-gel composite of the present invention has high-sequential can enter pore network, and described network is included on the whole film three-dimensional basically continuous interconnecting channel.This orderly interconnection structure provides a kind of mechanism, and by this mechanism, sol-gel composite of the present invention can play the effect in bioactive substance storehouse.The bioactive substance that is applied to the film surface will infiltrate perforated membrane, be carried in the interconnecting channel, and described bioactive substance is induced by diffusion, infiltration or electrochemistry or alternate manner release after a while.

Utilize the triblock copolymer template to make mesoporous sol-gel composite of the present invention, when described triblock copolymer template and sol-gel presoma (being not limited to the alkoxide silicon precursor) can be self-assembled into the three dimensional structure (Fig. 1) of high-sequential when mixing.Heat treatment (or being exposed to UV lamp/ozone source under the room temperature) is removed template and is impelled inorganic phase crosslinked (wearing out) on every side to form mechanically firm network.Thereby final sol-gel composite is negative-appearing image shown in Figure 1, and wherein, block copolymer is removed, thereby stays the interconnecting channel network.The passage that forms thus has predictable homogeneity.In described embodiment, hole and passage have the diameter in mesoporous scope, are generally about 2 to 30nm, and more frequent is about 5 to 30nm.Add the accurately diameter of control channel of hydrophobic swelling reagent by hydrothermal treatment consists or in initial soln.Thereby, can make hole of the present invention and passage have any required diameter, described diameter includes, but are not limited to, and about 2 to 100nm, and about 3 to 75nm, and about 5 to 50nm, and about 7 to 30nm or about 10 to 20nm.

As what set forth, utilize sol-gel composite bioactive substance of the present invention to carry storehouse (with corresponding bioactive substance conveyer device) can realize that sustained release, control discharge and the conveying of long-acting release.By changing the character of sol-gel composite, can make various bioactive substances realize different bioactive substance conveying rate of release and release profiles.For example, bioactive substance can adopt the mode of approximate one-level or approximate second-order kinetics to discharge.Can begin the particular moment when implantable bioartificial active species delivery device or after implantation to carry, and described conveying can increase to flank speed by zero at short notice fast, for example in less than about 1 hour, in less than about 30 minutes, in less than about 15 minutes, or in less than about 5 minutes.The highest above-mentioned transfer rate can continue one period scheduled time, until transfer rate descends suddenly.For example, conveying can continue at least about 8 hours under flank speed, continues about 2 days, continues about 4 days, continues about 7 days, continues about 10 days, continues about 15 days, continues about 30 days, continues about 60 days or continues at least about 90 days.On the other hand, the transfer rate of bioactive substance can be followed approximate bell time dependent curve, and is slowly initial, but makes transfer rate rise to flank speed with exponential form, and then this speed descends with exponential form in time, finally is down to zero point.In the field of the bioactive substance of sustained release, it has been generally acknowledged that the bioactive substance that it is desirable to avoid a large amount of carries " burst ", in " burst " situation, most of bioactive substances are transferred at short notice.Method of the present invention can strengthen bioactive substance to the mixing of the sol-gel composite that is forming, thereby helps to alleviate the problems referred to above.Adopt through the surface of organically-modified silane treatment sol-gel composite and/or speed that the embodiment of passage also can be used for slowing down medicament elution.In this method, suppress liquid through the hydrophobic group of organically-modified silane and diffuse into sol-gel composite and dissolve bioactive substance, thereby avoid causing described bioactive substance to discharge too early.So, according to the present invention, can regulate various parameters, thereby make up the various variations of generation in the desirable delivery profile according to specific bioactive substances/disease/patient.

Bioactive substance loading and releasing properties are (for example, the maximum load amount of bioactive substance, the elution rate of bioactive substance and elution curve mode over time) depends on the two character of sol-gel composite bioactive substance storehouse (comprise whether containing bioactive substance (being coated onto in advance the bioactive substance conveyer device) in the material itself, whether contain bioactive substance (loading after being applied to the bioactive substance conveyer device) or the two in the interconnecting channel of material) and bioactive substance preparation.Inside that can be by the prescription that changes bioactive substance, the hole dimension that changes sol-gel material, coating passage, adopt through surface and/or the through hole of organically-modified silane treatment sol-gel composite or adopt the various materials described material that mixes to change release dynamics.

Exist several known methods to be used to design the hole dimension of sol-gel material.Can change hole dimension by type and the consumption of described mould material in colloidal sol that changes template used material, because the size of amphiphile, amphiphilic molecule hydrophobic part affects hole dimension to a great extent.For example, can be with the hole dimension of MCM-41 in about 1.6nm adjusting to the scope of about 10nm (US patent 5,057,296 and 5,102,643 and Beck etc., 1992, J.Am.Chem.Soc.114,10834).The another kind of method that is used for changing hole dimension is, the hydrophobicity organic cosolvent is mixed in the colloidal sol, and described cosolvent makes the hydrophobic region swelling after the template self assembly.The most frequently used swelling reagent is 1,3,5-trimethylbenzene (TMB) (Schmidt-Winkel etc., Chemistry of Materials, 2000,12, the 686-696 page or leaf), but other many organic materials also can play this effect in principle, such as triisopropylbenzene, perfluorodecalin, alkane, alkene and long-chain amine (comprising N, N-dimethyl hexadecylamine, trioctylphosphine amine, tridodecylamine).Other suitable method comprises: the gel to self assembly synthesizes rear hydrothermal treatment consists (Khushalani etc., Advanced Materials, 1995,7,842 pages) or revises temperature.For example, Galarneau etc. illustrated the structure of the mesoporous material that the synthesis temperature impact forms with dualistic manner at 2003 (New J.Chem.27:73-39).When synthesis temperature was lower than 80 ℃, SBA-15 had the mesoporous of about 5nm diameter, had " ultramicropore " of pact＜1nm diameter.When synthesis temperature was higher than 80 ℃, SBA-15 had the mesoporous of pact＞9nm diameter, does not have ultramicropore.

Also can carry out the release dynamics that modification changes bioactive substance to the surface nature of the passage in the sol-gel composite.After finishing sol-gel synthesis and removing structure direction template (structure-directing template), surface, inside that can the modification duct, thus give desirable surface functionality.Can adopt hydrophobic or hydrophilic coating or can adopt each passage of powered surfaces coating, thus with bioactive substance or with passage in other material of delivering better interact.A method that realizes this is to use through organically-modified silane.Can be used as linking agent through organically-modified silane, thereby give the more hydrophobicity in surface or more hydrophilic, this depends on employed terminal fragment.For example, if carboxyl is used as terminal molecule, will give hydrophilic so; If but use long-chain fatty acid or mercaptan, will give more hydrophobic character so.Various hydrophilic segment and hydrophobic fragment are well known in the art.

Perhaps, conduit wall can be exposed to (Cl by the UV photoactivation ₂→ Cl ^*) Cl ₂Process in the gas and carry out modification, channel surface has covered chloro silicyl (Si-Cl) as a result, then can make the chloro silicyl further change into the functional group of any hope by various processing according to vitochemical principle.For example, also can adopt other to process gas and (comprise that phosgene (SOCl), isocyanates (N=C=O), malamide and other) carry out initial treatment to hole wall surface, thereby obtain similar result.Above-mentioned chemicals is easy to react with silanol (Si-OH) group of hole wall surface, thereby silanol is substituted by alternative group (for example being Si-Cl in the situation of phosgene), then alternative group can react in step subsequently, thereby gives the chemical functional group of any hope of hole wall.

The method of another kind of designed channel character is to adopt highly acid or akaline liquid solution to process, thereby gives surface charge.Particularly, be exposed in the solution that pH is lower than surperficial isoelectric point, IP (tripoli is PI=2), so that the protonated (Si-OH → Si-OH of surface silanol groups ²⁺), therefore the surface is with positive charge.Similarly, the solution that adopts pH to be higher than surperficial PI is processed, thereby causes surface silicon alkanol deprotonation, and the surface is with net negative charge (Si-OH → Si-O ^-).Importantly, can be attached to the solute with opposite charges on the powered surfaces by electrostatic attraction unless notice that solution also comprises, otherwise above-mentioned electric charge can not be kept when taking out from acidity or alkaline solution.Also comprise at solution in the situation of the solute with opposite charges, even after taking out from acidity or alkaline solution, surface still charged and solute still is attached on this surface.These character can be used for stimulating polarity or charged bioactive molecule eluting (following further discussion) on the mesoporous substrate.

Can select in the said method one or more according to being loaded into specific bioactive substance in the passage or various bioactive substance because different bioactive substances size, hydrophobicity with charged aspect have different character.Above-mentioned character will affect the loading of bioactive substance and the release from sol-gel composite.For example, paclitaxel is that size is about 1 to 2nm hydrophobicity (lipotropy) molecule.Other hydrophobicity bioactive substance comprises, such as but not limited to, most of psychosis, antibiotic is such as amphotericin, dexamethasone and flutamide.Paclitaxel is slightly stronger than the hydrophobicity of rapamycin, and corticosteroid is usually a little less than the hydrophobicity than rapamycin or paclitaxel.If use the hydrophobicity bioactive substance, wish so to adopt hydrophobic coating coating passage, thereby make the loading maximization of bioactive substance.Highly-hydrophilic and water-soluble bioactive substance can be benefited from hydrophilic coating, thereby make the loading maximization of bioactive substance.The hydrophilic bioactive substance comprises, but be not limited to, most of hormone polypeptide, antibiotic (such as vancomycin and phenobarbital), cimetidine, atenolol, aminoglycoside, hormone (for example thyroliberin hormone), p-nitrophenyl beta fibers five glycosides (p-nitrophenyl beta-cellopentaoside), short corpus luteum generate hormone and discharge hormone and other.Known cation bioactive substance comprises, but be not limited to vincristine (vincristine), amiloride (amiloride), digoxin (digoxin), morphine, Shandong Procaine amide (procainamide), quinidine (quinidine), quinine (quinine), ranitidine (ranitidine), triamterene (triamterene), trimethoprim (trimethoprim), vancomycin (vancomycin) and aminoglycoside.The anionic bioactive material includes, but not limited to penicillin and many diuretic.Therefore, determining that whether useful passage process when, should consider characteristic and the required release profiles of bioactive substance to be loaded.

In case be in according in substrate of the present invention or the passage, bioactive substance can be with the several means eluting.Can come release of bioactive substances with simple diffusion, in this case, bioactive substance moves in the environment solution (body fluid) along Concentraton gradient.Can also use osmosis, thereby can deliver to lower osmotic potential zone from higher osmotic potential (osmoticpotential) zone by the bioactive substance of large volume flow with dissolving.Can also use osmosis to drive bioactive substance from substrate.For example, the aqueous solution filling substrate that can increase gradually with volume, thus drive the hydrophobicity bioactive substance from substrate.For example, this can carry out in the following way: the hydrophobicity bioactive substance is filled in half of sol-gel substrate compositions, and adopts soluble salt to fill second half.When in the patients with implantation, the water in the body fluid sucks dissolving salt in the substrate with water thereby produce strong osmotic potential.The water displacement hydrophobicity bioactive substance of introducing enters in the physiological environment on every side thereby force the hydrophobicity bioactive substance to leave substrate.Said system can design in many ways, and osmotic pumps can be separated from sol-gel substrate compositions.

Can also by changing the physical characteristic of bioactive substance preparation itself, such as net charge, hydrophobicity and the rheological equationm of state of bioactive substance preparation, regulate the release dynamics of bioactive substance.

Be used for bioactive substance is comprised from sol-gel composite eluting other method out: use electrophoresis mechanism for charged bioactive substance granule; Use the physics gate, be exposed to the surface area of environment such as control bioactive substance storehouse; And use various biodegradable barrier film and the semi-transparent barrier films that can be used for controlling the rate of release of bioactive substance from the storehouse.

An importance of the present invention is to carry anti-restenosis bioactive substance.Especially effectively a kind of anti-restenosis bioactive substance be lipophilic bioactive material paclitaxel (N-benzyl-beta-phenyl isoerine ester, M.W.853.9) and the anti-tumor agent comprising salmosin of from the bark of yew tree, separating.

As what set forth, sol-gel composite of the present invention is very suitable for strengthening the cohesive between organic surface and the inorganic surfaces, because high-sequential, opening, surperficial enterable channel network are continuously interconnection at whole volume.For example, be deposited on the polymer that contains the organic biological active material on the top surface of inorganic sol-gel combination of the present invention and can enter and in the thickness range of perforated membrane, infiltrate described film, thereby form the lip-deep hard nano composite phase of inorganic substrate that always extends to the below.This molecule between polymer and the sol-gel composite intert produced very strong bonding, corrosion-resistant and anti-machinery is removed.

Fig. 2 shows three-decker 10 of the present invention, and this structure is used for strengthening the cohesive between organic surface and the inorganic surfaces.In this embodiment, sol-gel composite 110 is deposited on the inorganic substrate 100.Organic polymer 120 interts by sol-gel composite 110.In typical sols-gel combination of the present invention, the average diameter in hole 130 can be about 5-30nm, and the surface density of film top-portion apertures (to the inlet point of channel network) can be about 10 ¹²/ cm ²

Using sol-gel composite of the present invention to strengthen in the fusible process, by spin coated forerunner preparation or any other suitable method, with polymer deposition to be bonded top at sol-gel composite.Then, polymeric material enters in each hole of sol-gel composite by capillarity or pressure treatment or thermal processes act (but being not limited to this), thereby the infiltration sol-gel composite is in one embodiment in the substantially whole thickness range of described sol-gel composite.After the above-mentioned infiltration, make crosslinked polymer by heat cure, light-operated reaction or other suitable method.Alternatively, in above-mentioned steps or afterwards, organic polymer 120, hole 130 between the surface of modification wall and inorganic substrate 100, form covalent bond or other chemical bond, thereby further improved cohesive.

No matter be in order to provide the bioactive substance storehouse or in order to strengthen cohesive, sol-gel composite of the present invention can and be deposited on the base material by following non-limiting method preparation: (1) at first, base material is provided, such as but not limited to, surgery steel, Ni-Ti alloy (NiTi), cochrome (Co-Cr), carbon fibre material, plastics or other suitable biocompatible materials; (2) then, dispose the pollutant that substrate surface is taken up an official post and why not expected; (3) base material is carried out little blasting treatment; (4) by preparing sol-gel composite with inorganic precursor and amphiphilic triblock copolymer template reagent, one or more bioactive substances with through organically-modified silane mixture.The limiting examples of typical inorganic precursor comprises SiO ₂And TiO ₂, such as tetraethoxysilane and positive the third titanium oxide.In this stage, if necessary, can also add other solvent, rheology modifier for example, such as ethanol, and sweller, such as 1，3，5-trimethyl-benzene; (5) then, the compositions that template is auxiliary usually but be not limited to by spin coated, dip-coating or spraying or by application article to be coated with on the surface that is deposited on base material.And, in some embodiments, can adopt through on the surface of organically-modified silane at sol-gel composite or in its passage it being processed.

The suitable silane through organically-modified that can be used among the present invention comprises, but be not limited to, alkyl silane (such as, but be not limited to MTMS, MTES, dimethyldiethoxysilane, trimethylethoxysilane, vinyltrimethoxy silane, VTES, ethyl triethoxysilane, isopropyl triethoxysilane, butyl triethoxysilane, octyltri-ethoxysilane, dodecyl triethoxysilane, octadecyltriethoxy silane etc.); Aryl functional silane (such as phenyl triethoxysilane etc.); Amino silane (such as aminopropyl triethoxysilane, aminophenyl trimethoxy silane, aminopropyl trimethoxysilane etc.); Acrylate and methacrylate functional silane (such as acryloyl-oxy propyl trimethoxy silicane etc.); The carboxylate functional silane; Phosphate functional silane; The ester functional silane; Sulfonate functional silane; Isocyanate-functional silane; Epoxy functional silane; Chlorosilane (such as trim,ethylchlorosilane, chlorotriethyl silane, three hexyl chloride silane, dimethyldichlorosilane, methyl trichlorosilane etc.); N, O-two (trimethyl silyl)-acetamide (BSA); N, O-two (trimethyl silyl)-trifluoroacetamide (BSTFA); Hexamethyldisiloxane (HMDS); N-methyl-trimethyl-silyl-trifluoroacetamide (MSTFA); N-methyl-N-(t-butyldimethylsilyl) trifluoroacetamide (MTBSTFA); Trimethyl chlorosilane (TMCS); Trimethyl-silyl-imidazole (TMSI) and combination thereof.

Dip-coating or spraying can easily be used for the article that coating has complicated shape and any curvature, such as support.The final thickness of sol-gel composite can be controlled and optimization in the following way: dilute solution, it is concrete by more solvent (being generally ethanol) is added in the solution, thereby in final working solution, the concentration of all the components is lowered identical multiple, and their relative concentration and mol ratio keep constant.As described in the embodiment, can also be by changing speed or the speed of dip-coating or the thickness that the two regulates sol-gel composite of spin coated.Then remove the mould material that limits passage under UV lamp/ozone source by heat treatment or by at room temperature being exposed to.This step is removed template and is impelled inorganic phase on every side to be cross-linked to form mechanically firm network.If inorganic precursor is temperature-sensitive, the UV/ ozonization is useful especially so.

In some embodiment according to the present invention, can use patterning techniques, thereby make the sol-gel composite templating with the different lengths yardstick.For example, the coating of sol-gel mesopore oxide (such as tripoli) need to have the water-wetted surface of available-OH group, should-the OH group can participate in and the sol-gel precursor molecule between condensation reaction.If before deposition, use traditional imprint lithography or soft lithography (Whitesides etc., Angew.Chem.Intl.Ed, 1998,37,550 pages) or any other patterned surface method peel off surf zone through selecting-OH functional group, so correspondingly mesoporous coating is patterned.Perhaps, can be by such as in capillary tube, carrying out micro shaping (Trau etc., Nature.1997,390,674 pages), thus make the sol-gel composite patterning, wherein can between flexible silicon sealing rubber die and substrate surface, compress limited amount lyosol.

Perhaps, can adopt second to sacrifice pore former, thereby make the deposit patterned of sol-gel composite coating.For example, known definite method produces macropore inorganic material (100nm＜d＜10 μ m) by the following method: with commercially available or latex particle that customization is synthetic (such as the monodisperse polystyrene ball (Stein etc. of radius in 100 to 500nm scopes, Science, 998,281, the 538-540 page or leaf)), or the emulsion that is separated is (such as Methanamide bag oil systems (Pine etc., Nature, 1997,389,948-951 page or leaf)) templating.These and other relevant method can make up with the self assembly template method, thereby generates sol-gel composite described herein.Final result is to obtain having the orderly inoganic solids (Whitesides etc., Science, 1998,282,2244 pages) of graduation of multiple yardstick porosity.This method is particularly useful in plastic surgery is used, and in plastic surgery is used, need macropore yardstick porous implant surface, thereby make cell migration and make skeleton/implant integrated, and the porosity of mesoporous yardstick can be used for the conveying of local bioactive substance.

That the mesoporous material (such as tripoli) that relatively easily obtains is as the purposes of intermediate mold according to another embodiment of the present invention, described intermediate mold is used for other inoganic solids that does not have suitable sol-gel presoma to exist of patterning, comprise that noble metal (for example, but be not limited to gold and platinum) and expand to even based on the polymer of carbon always.For example, mesoporous tripoli coating can at first be deposited on the implantable apparatus, follow volatility presoma or the liquid-based suspension of " casting " Pd or Au nanoparticle (but being not limited to this), then make mesoporous tripoli dissolving by for example hydrofluoric acid treatment, thereby obtain the mesoporous noble metal copy (Schuth with the tripoli framework, Surface Science and catalyticing research (studies inSurface Science and Catalysis), v.135, the 1-12 page or leaf).

Embodiment

Example I

0.1M tetraethoxysilane (TEOS) sol-gel solution prepare by the following method: at first in 200mL glass scintillation pipe with the dense HCl (12M) of 25 μ L thus mix the dealing with alcohol hydrochloric acid for preparing 0.3M with 860 μ L deionized waters and 3mL straight alcohol.In the micro-centrifuge tube of 1.5mL, 1mL ethanol and 112 μ LTEOS are merged.TEOS solution was added drop-wise in the ethanol of acidify in 30 seconds, and with gained TEOS solution hydrolysis 45 minutes.When hydrolysis finishes, with 2mL through the TEOS solution of hydrolysis be added in the glass tubing (1 dram (dram)) go aspartic acid angiotensin I (DAA-I) (2.5mg) in.Carry out of short duration ultrasonic, to guarantee the polypeptide dissolving and to mix.Gained solution is transferred to after by 5 micron filters in the 5mL air-tightness Hamilton syringe.Be placed on syringe in the Harvard Scientific syringe pump and be connected on the ultrasonic nebulizer.

Utilize to suspend with the groove cone is arranged, two clean 12mm supports or four clean 6mm supports are installed on the coating axle.Axle is connected on the sprayer unit, by making axle repeatedly by shower nozzle, adopts the sol-gel solution spraying support that contains DAA-I of q.s, thereby has deposited about 20 μ g gels 40 ℃ of lower dry 30 minutes rear surfaces.0.1M the top coat of TEOS is used as extra barrier layer, so that DAA-I tool rate of release likely.Such as the TEOS solution of aforementioned preparation 0.1M, but do not add DAA-I.Adopt the TEOS spraying support of capacity, thereby obtain the top coat of 50 μ g 40 ℃ of lower dryings after 30 minutes.

With reference to Fig. 3 A-3D, utilize the Hitachi S-3000N scanning electron microscope with Oxford Instruments INCA X-Sight Model 7021 to gather the scanning electron microscopy (SEM) that applies support through DAA-I.Before finding time in the chamber, utilize two-sided conducting resinl disk to place on the turntable of scanning electron microscope through the support of DAA-I/TEOS coating in advance several.Draw the marked graph of each support, thereby show the position and identify according to the orientation between each support subsequently.Imaging was not carried out surface treatment to support in the past.Utilize interior visible photographing unit and external control that each support is directed in the SEM field.When orientation can be accepted, energize for the Electronic Speculum system, and at different amplification 60X (Fig. 3 A); 500X (Fig. 3 B); Under 1000X (Fig. 3 C) and the 2000X (Fig. 3 D) to interested regional imaging.After automatic regulating lightness and contrast, gather the sem image of interested specific region.

With reference to Fig. 4, when support when in following medium, cultivating under 37 ℃, measure the eluting of DAA-I from the support that applies through TEOS by analyzing the amount of DAA-I in the ammonium acetate buffer (pH 5.0) of 0.1% Solutol and the functional relationship of time.To utilizing the DAA-I peak among high performance liquid chromatography (HPLC) figure that Altima C-8 post (Altech, Chicago IL.) obtains to carry out integration, and compare the content of determining DAA-I with standard curve.As seen from Figure 4, the increase of the mol ratio between TEOS and the DAA-I can delay the speed of DAA-I eluting.

Example II

For the increase of probing into the TEOS consumption impact on the DAA-I elution rate, according to said method and scheme, the TEOS of increment (0.1 to 0.5M) is added among the DAA-I (1.25mg/mL) of constant basis.As mentioned above, adopt each support (9mm, n=4) of each solution spraying, weigh, and compare the elution amount of 24 hours DAA-I.Fig. 5 A represents the total volume of 72 hours bioactive substances, and Fig. 5 B represents the functional relationship of elution curve and time.By Fig. 5 A-5B as seen, the mol ratio that increases TEOS and medicine has significantly postponed the speed of drug release in the aqueous environments.

EXAMPLE III

Only relatively hydrophilic by TEOS or the sol-gel that forms of tetramethoxy-silicane (MEOS) of hydrolysis, even they can more effectively capture bioactive substance, but they can not provide the chemical compatibility environment for most hydrophobic medicine (having the chemical compound of limited water-soluble such as paclitaxel, rapamycin, cyclosporin and other).In order to increase the hydrophobic property of gained sol-gel, various alkylating Ethoxysilanes can be added sol-gel and form in the solution.Chemical compound such as MTES, tert-butyl group triethoxysilane, isobutyl triethoxy silane, hexyl triethoxysilane, phenyl triethoxysilane, octyltri-ethoxysilane, dodecyl triethoxysilane and octadecyltriethoxy silane can add in the mixture with different mol ratios, thereby obtains visibly different sol-gel coating.It is significantly different to comprise the ability that above-claimed cpd causes a series of chemical compound to mix gel, and affects these chemical compounds be discharged into speed in the aqueous solution from gel.Fig. 6 shows the example of above-mentioned impact.Sol-gel solution prepares by the following method: phenyl triethoxysilane, octyltri-ethoxysilane and the dodecyl triethoxysilane of variable concentrations (10 to 90%) are mixed with TEOS, and wherein the total concentration of (TEOS+ silane) is 0.1M.

Thereby each solution comprises the western power of q.s and cuts down Ta Ting and make each support be coated with the medicine of 10 μ g.After with support spraying and drying, they are immersed in respectively in the 1mL water in the polypropylene microcentrifugal tube.After 5 minutes, the western power in the analysis equal portions solution is cut down the content in his spit of fland.As shown in Figure 6, when the stronger silane of hydrophobicity mixed in the gel, the bioactive substance that elutes was less.Dodecyl triethoxysilane the most effectively, wherein optimum content is greater than about 30%, less than about 90%.

According to above knowledge, when prepare support in the TEOS of 0.5M 100% or in the situation about being coated with in the TEOS of the dodecyl triethoxysilane of 0.2M 40%/60%, directly more western power is cut down the elution curve in his spit of fland.What is interesting is that rear kind of compositions of higher concentration structurally is unsettled.Observing at the support of the TEOS coating of adopting 40% dodecyl triethoxysilane of 0.3M and higher concentration/60% obviously has tablet and granule to form.Important being characterised in that, for two kinds of sol-gels, the elution curve that 4 μ g and 8 μ g west power are cut down under his spit of fland is equal to, and the result shows, in order to obtain a certain elution rate, comprise the total amount (referring to Fig. 7 A-7B) that hydrophobic silane can reduce required sol-gel presoma in the gel.

EXAMPLE IV

Another non-limiting method that the regulation and control bioactive substance discharges from sol-gel substrate compositions is to adopt reactive chlorosilane that collosol and gel is carried out chemical treatment.In this embodiment, the 10 μ gs west power of employing in 0.5M TEOS is cut down his spit of fland and sprayed each support, and is then dry.Then, coating does not contain the 0.5M TEOS of any bioactive substance as the second layer.Then, each support is processed as follows: immersed in the 1M trim,ethylchlorosilane solution about 10 minutes or about 30 minutes, then drying is whole night in 40 ℃ baking oven.In order to determine above-mentioned " silanization " to the impact on sol-gel surface, western power is cut down his spit of fland and is compared from elution rate and the elution rate from undressed coating support on the above-mentioned support.As seen from Figure 8, by trim,ethylchlorosilane sol-gel is carried out modification and reduced elution rate, wherein longer impact on elution curve of open-assembly time is larger.

There is multiple application of the present invention.A limiting examples is replacement of total hip.The inefficacy that has realized that polymethacrylates (PMMA) the adhesive/metal interface in the femoral component is that aseptic loosening main cause occurs the hip joint implant of fixing.Experiment and data research show that the combination at interface is loosening can significantly to increase the stress of binding agent ring on every side, thereby cause PMMA to break and all implant losing efficacy.

The present invention can be ideally be used for guaranteeing adopting the fixing of femoral component that polymer adhesive carries out.Can select sol-gel composite according to the embedded material of selecting.SiO ₂Film can be deposited on the Co-Cr-Mo, and on the Ti6-A14-V parts TiO ₂Film may be desirable.In the situation of combination with suitable silane adhesion promoter, can form excellent combination between implant and the precoating PMMA material.In addition, the surface roughness of sol-gel composite is wanted little several orders of magnitude.This characteristic should be useful in preventing fragment and bone loss (bone loss).

Shown and be deposited on the Ti6-A14-V alloy base material and be exposed to SiO in the simulated body fluid ₂Mesoporous film can impel the hydroxyapatite crystal settling.Yet, because the hole dimension scope, mesoporous film unlikely as in the above-mentioned research hint be used in the application of adhesive-free joint replacement.Reported that the hole of size in 50 to 100 mu m ranges is essential minimum aperture for skeletal tissue is given birth on whole porous coating.In contrast, discuss as the present invention, for holding polymer molecular chain, mesoporous scope is very desirable.

In an embodiment of the invention that comprise the hydrophobic drug paclitaxel, substrate can be comprised of following: inorganic oxide, ion-type or the nonionic surfactant and block copolymer or its combination in any that adopt sol-gel synthesis (as above-mentioned) to obtain, above-mentioned each component has any mol ratio in wide region.By suitably selecting mol ratio and coated technique parameter, can impel this material system self assembly, thereby the substrate encapsulated drug and control described medicine by the diffusion sustained release.Self assembling process can also comprise, being separated of each matrix components, and wherein surfactant and/or block copolymer are as template and can guide sol-gel inorganic material (as above-mentioned) to assemble.Remove subsequently the template component and can be provided for controlling the optional mechanism that medicine discharges by the interconnection pore network in the gained inorganic matrix.

In another embodiment, substrate only is comprised of sol-gel silicon dioxide, the mol ratio of paclitaxel/TEOS at about 10: 1 to about 1: 200 scope.For example, preparing by the following method paclitaxel/TEOS mol ratio is that about 1: 10 and drug level are the solution of about 5 μ g/ μ L: will about 5mg paclitaxel and about 50 μ LTEOS be dissolved in the solvent that is formed by about 0.9mL ethanol and about 50 μ L deionized waters.Can be by the auxiliary coating process of capillary tube with 2 μ L solution coat supports, thus the loading medicine of about 10 μ g altogether.

In another embodiment, can at first paclitaxel (or other bioactive substance) be encapsulated in polylactic acid (PLA) or block (polylactic acid)-block (polyglycolic acid) (PLGA) in the polymer spheres, wherein, the mol ratio of polymer/drug can be at about 200: 1 to about 1: 1 scope, in another embodiment, at about 10: 1 to about 3: 1 scope.Can be with the polymer/drug ball suspending in deionization (DI) water, thus stable suspension formed.Then, can for example by spraying this aqueous solution above-mentioned spheroid be deposited on the support, then the top coating sol-gel composite.The biodegradable polymers spheroid can provide lasting drug release, thereby the sol-gel composite top coat can provide mechanical strength, improve the cohesive on spheroid and apparatus surface and can be used as diffusion impervious layer and further control medicament elution simultaneously.

In specific embodiment, the PLA/ paclitaxel spheroid (drug level is about 18wt%) of about 40mg can be suspended in the DI water of about 2mL.Then, obtain aerosol beam with the rate-allocation mentioned solution of about 40 μ L/min and at about 2.0 watts of lower operation vibration components, support is passed above-mentioned aerosol beam spray for 20 times.This process obtains total drug load of about 20 μ g.And, can utilize the TEOS solution spraying sol-gel silicon dioxide top coat of hydrolysis.Hydrolysis can be carried out in aqueous solution, optional for example by acidity or alkali condition, by stirring or ultrasonic vacuum is stirred, added organic solvent or above-mentioned combination in any is come facilitation of hydrolysis.In specific embodiment, the PH ≈ 3 of top coat solution and can preparing by the following method: the ethanol of the DI water of the TEOS of about 210 μ L, about 9.25mL, about 0.5mL and rare (0.1M) hydrochloric acid (HCl) of about 100 μ L are mixed, and adopted magnetic stirring bar vigorous stirring under about 1500rpm about 1 hour.Top coating comprises: about 20 supports are passed fuel spray, and simultaneously solution is with the rate-allocation of about 40 μ L/min and with the power aerosolization of about 2.0W.

In another embodiment, PLA/ west power is cut down his intermediate layer of spit of fland spheroid and can be clipped between the priming coat and sol-gel composite top coat that contains medicine.This intermediate layer can obtain by the following method: will be for example about 20mg PLA/ west power is cut down his spit of fland spheroid and is dissolved in about 1mL DI water, and sprays about 20 times with the distribution speed of about 40 μ L/min and the aerosolization power of about 1W.The purpose in above-mentioned intermediate layer is, by the release of the further prolong drug of interaction between diffusion molecule and the spheroid.

Priming coat in these embodiments of the present invention is passable, but unessential, comprises other bioactive substance.The bioactive substance that is included in the priming coat can be identical or different with other bioactive substance that maybe can be selected in inorganic sol-gel combination top coat in the spheroid.For example, described in co-pending US patent disclosure No.2006-0051397, priming coat can be the metal level of inanimate object active substance, wherein, is contained in this about the full content without the deposition of medicine metal level with above-mentioned patent is disclosed by reference.Perhaps, described in co-pending US patent disclosure No.2006-0062820,2006-0051397 and 2006-0115512, priming coat can be metal level, wherein bioactive substance directly is deposited on the metal level by electrochemical method or is carried in the hole that produces by electrochemical method, by reference the disclosed full content about these technology of above-mentioned patent is contained in this.Perhaps, priming coat can be inorganic sol-gel combination, and said composition is matters of containing biological activities not, comprises bioactive substance before it is applied to medical apparatus surface in described compositions; Or until be applied to that matters of containing biological activities and bioactive substance are not loaded in the described compositions interconnecting channel yet on the apparatus; Or such sol-gel composite can comprise bioactive substance by above-mentioned two kinds of mechanism.Priming coat of the present invention can also equal according to Ragheb the US patent No.6 of mandate on May 4th, 2004,730, method described in 064 applies, and that by reference above-mentioned patent is instructed is contained in this about the full content with the coating coating that contains bioactive substance the inanimate object active substance.

The scope of foregoing description clearly illustrates that various useful embodiments are contained in the present invention.These embodiments can comprise a plurality of coatings or multilamellar, and the thickness of each layer only is subject to the physical function of apparatus.In some embodiments, above-mentioned thickness is no more than about 5 microns.And different layers can comprise different bioactive substances, the identical or different bioactive substance of variable concentrations and/or at the mixture of specific bioactive substance in one or more layers.As non-limiting example, one deck can comprise two kinds of different bioactive substances, and two different layers can comprise two kinds of different bioactive substances, and perhaps multilamellar can comprise the same bioactive substance of variable concentrations.As specific limiting examples, an apparatus can comprise three layers: bottom can comprise paclitaxel; The intermediate layer is matters of containing biological activities not, and outer top coat can comprise the antiinflammatory bioactive substance, such as inhibin.In this embodiment, inhibin discharges fast behind implantation instrument, and the release of paclitaxel will be delayed.Perhaps, outer top coat can become hydrophobic with dodecyl silane (but being not limited to this), thereby the water barrier layer is provided.As the non-limiting example in the scope of the invention, should be appreciated that the sol-gel composite of random layer can be sol-gel derived inorganic oxide; Sol-gel derived through organically-modified silane; Comprise hydridization oxide and the mesoporous oxide with the template utilized generation through organically-modified silane.

Can carry out various adaptations and modification to above-mentioned embodiment, and not depart from the scope of the present invention and spirit, scope and spirit of the present invention can be implemented to be different from this specifically described mode.Top description is intended to be illustrated, and is not for restriction.Scope of the present invention only limits by claims.

Term used herein and expression are used as descriptive and non-limiting term.In the use of described term and expression, shown in getting rid of and equivalent or its part of the feature of explaining, will be appreciated that, can in the present invention's scope required for protection, carry out various modifications.And, any one in any embodiment of the present invention or a plurality of feature can with other embodiment of the present invention in the combination of any one or a plurality of further feature, do not depart from the scope of the present invention.

Unless otherwise, that uses in the specification and claims is expressed as dosis refracta, and all numerals of character such as molecular weight, reaction condition etc. all are appreciated that: in all cases, modified with term " approximately ".Therefore, unless the explanation of contrary is arranged, the quantity parameter shown in this specification and the appended claims all is approximate number, the character that they can go for according to the present invention and changing.At least, and be not that application to claims scope doctrine of equivalents is limited, each quantity parameter at least should be according to the number of the significant digits of report, and uses the common technology of rounding up and explain.Although it is approximate number that digital scope and the parameter of broad range of the present invention are shown, the numerical value shown in the specific embodiment is but accurately reported as much as possible.But any numerical value must contain certain error, and this is that the standard deviation of finding in their checking measurements methods separately must cause.

Unless this paper indicates in addition, or with the obvious contradiction of context, describe term " ", " a kind of " and " this " and the similar lifting manipulation used in the context of the present invention and be appreciated that and not only comprise odd number but also comprise plural number.The narration of numerical range herein only is used as the stenography method of each independent value in this scope.Unless this paper indicates in addition, each independent value is included into description, this with narrate individually the same at this paper.All methods as herein described can be carried out with any suitable order, unless this paper indicate in addition, or with the obvious contradiction of context.Unless otherwise, any and all examples provided herein, perhaps exemplary language (for example, " such as ") only is used for setting forth better the present invention, but not invention scope is limited.Any statement should not be interpreted as in the description: expression is key element necessary, that do not require protection concerning enforcement of the present invention.

The grouping of replaceability key element of the present invention disclosed herein or embodiment should not be understood to restriction.Each group membership can be individually used and be claimed individually, or is used with claimed with any combination of other key element of organizing other member with this or finding herein.Can predict, for the reason of convenient and/or patentability, the one or more members in the group can be included into one group or therefrom deletion.When any this type of comprised or delete generation, description was looked at as the group that contains through changing at this, therefore satisfied the support to whole Ma Kushi groups used in the appended claims.

Described preferred implementation of the present invention herein, it comprises that the inventor is known and is used for implementing best mode of the present invention.Certainly, on the basis of reading aforementioned specification, will be obvious to those skilled in the art to the change in these preferred implementations.The present inventor has predicted those skilled in the art and has adopted suitably this type of to change, and the inventor expects that the present invention can be implemented in the mode except the specifically described mode of this paper.Therefore, as long as applicable law allows, the present invention includes all changes and equivalent that the theme of mentioning in the claims is carried out.In addition, in all possible variation, any combination of key element above-mentioned all is included into the present invention, unless this paper indicate in addition, or with the obvious contradiction of context.

In addition, mention a large amount of lists of references in this description, comprised patent and printing publication.Above-mentioned list of references and printing in the publication every kind are all comprised into this paper by integral body respectively by reference at this.

At last, should be appreciated that embodiment of the present invention disclosed herein is in order to set forth principle of the present invention.Other change that can carry out also falls within the scope of the invention.Therefore, for example, and unrestricted, can use alternative constructions of the present invention according to the instruction of this paper.Therefore, not to be restricted to only be described herein and shown in the present invention.

Claims

1. medical apparatus and instruments, described medical apparatus and instruments comprises structural detail and bioactive substance storehouse, wherein, described bioactive substance storehouse comprises the lip-deep coating that is applied to described structural detail, wherein, described coating comprises one or more layers, and contain the base composition that utilizes the inorganic oxide that sol-gel technology forms comprising one of at least in described each layer, wherein, described inorganic oxide is compound with the reagent that the following characteristic of described inorganic oxide is carried out modification: hydrophobicity, electric charge, biocompatibility, engineering properties, the bioactive substance affinity, storage capacity and combination thereof, described modifying agent is through organically-modified silane, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, in case described design impact in case behind the content of the described bioactive substance in the described base composition after making and/or the patients with implantation described bioactive substance be discharged into speed in the physiological environment.

2. medical apparatus and instruments as claimed in claim 1, wherein, described inorganic oxide is selected from oxide and the titanyl compound of silicon.

3. medical apparatus and instruments as claimed in claim 1, wherein, described base composition is the mesoporous inorganic oxide.

4. medical apparatus and instruments as claimed in claim 3 wherein, utilizes and sacrifices pore-forming template component and self assembly or guide assembling preparation technology to obtain described mesoporous inorganic oxide.

5. medical apparatus and instruments as claimed in claim 4, wherein, described template group is divided and is selected from amphiphilic block copolymer, ionic surfactant and nonionic surfactant.

6. medical apparatus and instruments as claimed in claim 5, wherein, described template group is divided into polyethylene oxide/polypropylene oxide/polyethylene oxide block copolymer.

7. medical apparatus and instruments as claimed in claim 3, wherein, described mesoporous inorganic oxide comprises continuous interconnecting channel.

8. medical apparatus and instruments as claimed in claim 7, wherein, the inner surface of described continuous interconnecting channel is by through organically-modified silane coating, describedly through organically-modified silane the following characteristic of described mesopore oxide carried out modification: hydrophobicity, electric charge, biocompatibility, engineering properties, bioactive substance affinity, storage capacity and combination thereof.

9. medical apparatus and instruments as claimed in claim 8, wherein, be applied on the described surface of described structural detail in described coating after, one or more bioactive substances are loaded in the described interconnecting channel.

10. medical apparatus and instruments as claimed in claim 1 wherein, describedly is selected from through organically-modified silane: alkyl silane; MTMS; MTES; Dimethyldiethoxysilane; Trimethylethoxysilane; Vinyltrimethoxy silane; VTES; Ethyl triethoxysilane; The isopropyl triethoxysilane; The butyl triethoxysilane; Octyltri-ethoxysilane; The dodecyl triethoxysilane; Octadecyltriethoxy silane; The aryl functional silane; Phenyl triethoxysilane; Amino silane; Aminopropyl triethoxysilane; The aminophenyl trimethoxy silane; Aminopropyl trimethoxysilane; Acrylate-functional silane; The methacrylate functional silane; The acryloyl-oxy propyl trimethoxy silicane; The carboxylate functional silane; Phosphate functional silane; The ester functional silane; Sulfonate functional silane; Isocyanate-functional silane; Epoxy functional silane; Chlorosilane; Trim,ethylchlorosilane; Chlorotriethyl silane; Three hexyl chloride silane; Dimethyldichlorosilane; Methyl trichlorosilane; N, O-two (trimethyl silyl)-acetamide (BSA); N, O-two (trimethyl silyl)-trifluoroacetamide (BSTFA); Hexamethyldisiloxane (HMDS); N-methyl-trimethyl-silyl-trifluoroacetamide (MSTFA); N-methyl-N-(t-butyldimethylsilyl) trifluoroacetamide (MTBSTFA); Trimethyl chlorosilane (TMCS); Trimethyl-silyl-imidazole (TMSI) and combination thereof.

11. medical apparatus and instruments as claimed in claim 1, wherein, described bioactive substance is selected from anti-restenosis reagent, anti-inflammatory agents, HMG-CoA reductase inhibitor, antibacterial agent, anti-tumor agent comprising salmosin, angiogenic reagent, anti-angiogenic reagent, thrombus reagent, resisting hypertension reagent, arrhythmia reagent, calcium channel blocker, cholesterol reducing reagent, psychotropic drugs, anti-depressed reagent, anti-epilepsy reagent, contraceptive, analgesic, SGF, skeleton is reinvented the factor, neurotransmitters, nucleic acid, opiate antagonist and combination thereof.

12. medical apparatus and instruments as claimed in claim 1, wherein, described bioactive substance is selected from paclitaxel, rapamycin, clothing Wei Mosi, tacrolimus, sirolimus, Des aspartic acid angiotensin I, nitric oxide, 4-hydroxy-3-methoxyacetophenone, Gamma-Tocopherol, recombined human POSTN, estradiol, aspirin, atorvastatin, western power and cuts down his spit of fland, fluvastatin, lovastatin, pravastatin, Rosuvastatin, simvastatin and combination thereof.

13. medical apparatus and instruments as claimed in claim 1, wherein, described medical apparatus and instruments is to be selected from following apparatus: vascular, support, plate, screw, vertebra cage, dental implant, dentistry implant, dental aligners, artificial joint, embolus device, ventricular assist device, artificial heart, cardiac valve, vein filter device, nail, clip, stitching thread, artificial net, pacemaker, pacemaker wire, defibrillator, nerve stimulator, nerve stimulator wire, implantable sensor and external sensor.

14. medical apparatus and instruments, described medical apparatus and instruments comprises structural detail and bioactive substance eluting coatings, wherein, described bioactive substance eluting coatings comprises two-layer at least, contain the base composition that utilizes the inorganic oxide that sol-gel technology forms comprising one of at least in described each layer, wherein, described inorganic oxide is compound with the reagent that the following characteristic of described inorganic oxide is carried out modification: hydrophobicity, electric charge, biocompatibility, engineering properties, the bioactive substance affinity, storage capacity and combination thereof, described modifying agent is through organically-modified silane, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, in case described design impact in case behind the content of the described bioactive substance in the described base composition after making and/or the patients with implantation described bioactive substance be discharged into speed in the physiological environment.

15. medical apparatus and instruments as claimed in claim 14, wherein, described two-layer at least priming coat and the top coat of comprising, described priming coat is applied to the described surface of described medical apparatus and instruments, and described top coat is applied on the described priming coat.

16. medical apparatus and instruments as claimed in claim 14 wherein, describedly one of at least comprises the following form that is selected from two-layer at least: the sol-gel oxide skin(coating) that does not have bioactive substance; The sol-gel oxide skin(coating), described sol-gel oxide skin(coating) has the bioactive substance that mixes in the described oxide; Do not have bioactive substance with through the compound sol-gel oxide of organically-modified silane; Have bioactive substance with through the compound sol-gel oxide of organically-modified silane; Do not have bioactive substance through organically-modified silylation layer; Have bioactive substance through organically-modified silylation layer; The mesopore oxide that does not have bioactive substance; Mesopore oxide, described mesopore oxide has the bioactive substance that mixes in the described oxide; Mesopore oxide, described mesopore oxide has the bioactive substance that mixes in the described oxide, and has other bioactive substance that is carried in later on the described surface that described mesoporous material is applied to described medical apparatus and instruments in the interconnecting channel of described oxide; Mesopore oxide, described mesopore oxide does not have the bioactive substance that mixes in the described oxide, but has the bioactive substance that is carried in later on the described surface that described oxide is applied to described medical apparatus and instruments in the interconnecting channel of described oxide; Aggregation with the polymer spheres that contains bioactive substance.

17. medical apparatus and instruments, described medical apparatus and instruments comprises structural detail and bioactive substance storehouse, wherein, described bioactive substance storehouse comprise be applied to described structural detail lip-deep one or more layers, wherein, described each layer in one or more layers comprises respectively and contains the base composition that utilizes the inorganic oxide that sol-gel technology forms, wherein, described inorganic oxide is compound with the reagent that the following characteristic of described inorganic oxide is carried out modification: hydrophobicity, electric charge, biocompatibility, engineering properties, the bioactive substance affinity, storage capacity and combination thereof, described modifying agent is through organically-modified silane, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, in case described bioactive substance is discharged into the speed in the physiological environment behind the content of the described bioactive substance in the described base composition in a single day described design impact is made after and/or the patients with implantation, and when described layer is applied on the described surface of described structural detail, described layer has strengthened the cohesive between inorganic surfaces and the organic surface, and described organic surface is selected from polymer, tissue, skeleton and combination thereof.