CN101264351B - Composite coating cardiovascular medicaments elution stent and preparation thereof - Google Patents
Composite coating cardiovascular medicaments elution stent and preparation thereof Download PDFInfo
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- CN101264351B CN101264351B CN2008101034758A CN200810103475A CN101264351B CN 101264351 B CN101264351 B CN 101264351B CN 2008101034758 A CN2008101034758 A CN 2008101034758A CN 200810103475 A CN200810103475 A CN 200810103475A CN 101264351 B CN101264351 B CN 101264351B
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Abstract
The invention provides a blood vessel drug elution bracket with coating layers and the preparation method. The blood vessel drug elution bracket with coating layers comprises: a: a bare stents with supporting role; b: a non-degradation bioactive coating coated on the surface of the bare stents; and c: a degradation bioactive drug coating coated on the surface of the bioactive coating. The blood vessel drug elution bracket with coating layers has the advantages of not only obvious anti-restenosis properties, but also ability to decrease the occurrence of thrombus for the stable bioactive coating; simultaneously, the bioactive coating can intensify the adsorption force of the drug coating on the bracket surface, reduce the crack, upwrap and shedding during the using process of the drug coating, thus improving the effectiveness and safety of the drug bracket.
Description
Technical field
The present invention relates to a kind of composite coating cardiovascular medicaments elution stent and preparation method thereof, be specifically related to a kind of restenosis that can suppress simultaneously and take place and promote the injured blood vessel wall to heal to prevent thrombotic NEW TYPE OF COMPOSITE coating stent of medicine and preparation method thereof.
Background technology
The tubulose atherosclerotic heart disease is one of major reason of cardiovascular disease death, serious threat human life and healthy commonly encountered diseases.At present (Percutaneoustransluminal coronary angioplasty PTCA) has become one of the common method for the treatment of coronary heart disease clinically to the percutaneous coronary angioplasty.Compare with traditional surgical technic, interventional therapeutic technique has that wound is little, safety, success rate height, recover advantage such as fast.But the greatest drawback of this technology is a metal rack implants vascular restenosis and thrombosis problem in the after-poppet.Implant in the after-poppet vascular restenosis and thrombosis problem people and adopted physics in order to solve metal rack, methods such as chemistry are carried out modification to metal support surface and are handled and improve its biocompatibility.Wherein, coating stent of medicine has become internationally recognized clinical prefered method at present.
Coating stent of medicine at present commonly used comprises two kinds of non-degraded and degradable carrier medicament coating brackets.Usually select suitable solvent, non-degraded macromolecular polymer or degradable high polymer and antiproliferative or antithrombotic reagent are mixed with mixed solution (also can add suitable crosslinking agent), again mixed solution is coated to metal support surface.Though the coating stent of medicine that adopts is preventing to have obtained excellent results aspect the hypertrophy at present, this class coating stent of medicine is still failing to obtain bigger progress aspect the prevention thrombosis.In order to prevent thrombosis, U.S. Pat 4,613,665 earlier at metal support surface load coupling agent, then by ionic bond with heparin load and rack surface, heparin slowly discharges with certain speed, though improved the antithrombotic property of support to a certain extent, but heparin is stable unsatisfactory rack surface, and incidence of thrombus is still higher, and the anti-hamartoplasia performance of support has much room for improvement simultaneously; U.S. Pat 5,112,457 using plasma technology are at the basic pyrrolidone film of rack surface deposition one deck N-, then by surperficial carbonyl grafting heparin, the antithrombotic property of support is significantly improved, but this patent provides the manufacture method complexity, and the anti-hamartoplasia performance of support remains further to be improved.
Patent documentation 1:US 4,613,665
Patent documentation 2:US 5,112,457
Summary of the invention
The problem that invention will solve
The purpose of this invention is to provide a kind of restenosis that can effectively suppress and take place, can effectively prevent thrombotic cardiovascular arteria coronaria combination drug coating bracket and preparation method thereof again.
Further purpose of the present invention is to prevent that effectively implanting back body fluid with support in the support course of conveying washes away the medication coat obscission of bringing
The means of dealing with problems
In order to address the above problem, the invention provides a kind of composite coating cardiovascular medicaments elution stent, it has following construction unit:
A: the bare bracket of playing a supporting role;
B: the Nondegradable bioactivity coatings that is applied to the bare bracket surface;
C: the biodegradable medication coat that is applied to the biological active coating laminar surface;
Behind composite coating support implant into body, medication coat is through biodegradation and after disappearing, bioactivity coatings is exposed to tissue and blood.
After above-mentioned composite coating cardiovascular medicaments elution stent was implanted, anti-restenosis medicaments slowly discharged from the Biodegradable high-molecular polymer of medication coat, thereby effectively suppresses the smooth muscle cell hyper-proliferative, the hypertrophy of migration and inner membrance, middle film.After medication coat disappears from rack surface by biodegradation, the surface of bioactivity coatings directly is exposed to tissue and blood, because the stable existence of bioactivity coatings, can the prophylaxis of acute thrombosis, subacute stent thrombosis and advanced thrombus ground take place, and can promote endotheliocyte to adhere on material surface ground and growth, quicken rack surface and blood vessel wall endothelialization process, quicken the healing of injury blood vessel wall ground.Simultaneously, bioactivity coatings has between excellent mechanical property and itself and alloy substrate and the medication coat good bonding force is arranged, therefore making this combination drug coating bracket overcome common drug support blood behind sterilization, operation course of conveying and implantable intravascular washes away in the process, come off easily, influence the phenomenon of therapeutic effect.
Employed bare bracket comprises metal rack or non-metal frame in the composite coating cardiovascular medicaments elution stent of the present invention.Described metal rack can adopt the metal rack of present routine, for example 316L stainless steel stent, Ti-Ni alloy support, cobalt cadmium alloy support, magnesium alloy bracket, platinum alloy support etc.Non-metal frame can adopt polymeric stent, ceramics bracket, complex support etc.Among the present invention, preferably use the cochrome support.
Among the present invention, from reaching the purpose of good anticoagulant effect, the biological active coating layer thickness is preferably 0.01～40 μ m, and bioactive ingredients content counts 0.01～70% with the high molecular polymer weight of non-degraded, is preferably 0.1～55%; Purpose from the degradation speed good binding of the rate of release that makes anti-restenosis medicaments and degradable macromolecule, degradability medication coat thickness is preferably 0.01～100 μ m, anti-restenosis medicaments content counts 1～60% with biodegradable polymer weight, be preferably 7～40%, more preferably 15～40%.Among the present invention, as the Nondegradable biocompatibility macromolecule polymer in the bioactivity coatings, both needed excellent biological compatibility, form good bonding force with bare bracket and medication coat simultaneously again, and then also to be fixed on the bare bracket surface to the anticoagulant property bioactive ingredients by the method that physics twines absorption or chemical crosslinking as the carrier platform of bioactive ingredients.Consider above-mentioned requirements, among the present invention, can suitably select the high molecular polymer that to realize above-mentioned effect for use.Specifically, as the Nondegradable biocompatibility macromolecule polymer in the bioactivity coatings, can adopt alkene-vinyl acetate co-polymers such as ethylene-vinyl acetate copolymer, propylene-vinyl acetate co-polymer, alkene-(methyl) acrylate copolymers such as ethylene-methyl methacrylate methyl terpolymer, ethylene-methyl methacrylate butyl ester copolymer, poly(ethylene oxide), polysiloxane, polyurethane, poly-(methyl) acrylate, at least a in these copolymer, mixture or the derivant of Polyolefin and.Above-mentioned substance not only has excellent biological compatibility, bigger fracture strength and elongation at break and good biological stability, and can guarantee the stable existence of bioactivity coatings.Among the present invention,, preferably use at least a in polyacrylate, polyurethane, polyurethane-acrylate copolymer, the poly(ethylene oxide) as the Nondegradable biocompatibility macromolecule polymer of bioactivity coatings.
Among the present invention, as the bioactive ingredients in the bioactivity coatings, adopt one or more mixture such as reorganization purification hirudin and derivant thereof, factor Xa inhibitor, factors IX a inhibitor, factor VIIa inhibitors, heparin, Low molecular heparin, heparinoid, low molecular sodium heparin, low molecular heparin calcium, activatory PROTEIN C, Antithrombin III, heparin co factor II, tissue factor pathway inhibitor, thrombin receptor antagonism peptide, Coumarins, defibrase, pyridines.By adopting these bioactive ingredients, can the prophylaxis of acute thrombosis, subacute stent thrombosis and advanced thrombus ground takes place, and can promote endotheliocyte to adhere on material surface ground and growth, quicken rack surface and blood vessel wall endothelialization process, quicken the healing of injury blood vessel wall ground.
Described Nondegradable biocompatibility macromolecule polymer can be dissolved in organic solvent or purified water earlier, mixes with bioactive ingredients and uses.At this moment used solvent is so long as can guarantee bioactive ingredients homodisperse solution in macromolecular solution and get final product, for example can be acetone, oxolane, chloroform, isopropyl alcohol, N-Methyl pyrrolidone, a kind of and composition thereof in methanol, ethanol, purified water, ethyl acetate, the N,N-dimethylacetamide.Wherein, can become macromolecule purified water emulsion to use described Nondegradable biocompatibility macromolecule polymer manufacture, especially suitable the mixing with the purifying water soluble bioactive ingredients of macromolecule purified water emulsion forms equally distributed coating solution.In the preparation process of bioactivity coatings of the present invention, preferably use the purified water emulsion of polyurethane purified water emulsion, polyacrylate purified water emulsion, poly(ethylene oxide) purified water emulsion and copolymer thereof.
Described bioactivity coatings can be made by non-degraded macromolecular polymer purification aqueous emulsion and anticoagulation bioactive ingredients mixed solution; Also can add proper assistant in this mixed solution.Described auxiliary agent for example can be cross-linking agent such as isocyanates etc.
As degradability biocompatibility macromolecule polymer, should have histocompatibility well, again as the carrier of anti-restenosis medicaments and control release rate of drugs, also must combine with the biological activity basal layer simultaneously firmly and have enough intensity and elasticity to bear the support transportation, support expansion and body fluid wash away the various stress in the process.Consider above-mentioned requirements, among the present invention, can suitably select the high molecular polymer that to realize above-mentioned purpose for use.Specifically, can adopt at least a in polylactic acid, poly phosphate, polyglycolic acid, polyesteramide, polyanhydride and copolymer thereof, mixture or the derivant.Preferred polylactic acid, poly phosphate, polyesteramide or the polylactic-co-glycolic acid of using.Wherein, polylactic acid (PLA) is preferably number-average molecular weight (Mn) 70000～150000; Poly phosphate is preferably number-average molecular weight 130000～170000, and more preferably number-average molecular weight 150000; Polyesteramide is preferably number-average molecular weight 70000～120000, and more preferably number-average molecular weight 90000; Polylactic-co-glycolic acid is preferably number-average molecular weight 80000～150000.As degradability biocompatibility macromolecule polymer.These materials have bigger fracture strength and the profound rate of fracture, excellent drug permeability and biocompatibility.As the anti-restenosis medicaments that uses in the medication coat, consider that from having anti-preferably hamartoplasia effect the present invention adopts one or more medicines or its mixture such as paclitaxel, dactinomycin, ciclosporin, rapamycin, vincaleucoblastine, emodin, dexamethasone, mitomycin, D actinomycin D.By using these medicines, can suppress the hyper-proliferative and the migration of smooth muscle cell, solve inner membrance and middle film hypertrophy problem after support is implanted.
Described medication coat can be made by degradability biocompatibility macromolecule polymer and anti-restenosis medicaments mixed solution.
Below, preparation method of the present invention is described.
Preparation method of the present invention comprises the steps:
At first, select suitable solvent, for example: a kind of in acetone, oxolane, the chloroform, to resist restenosis medicaments and degradability biocompatibility macromolecule polymer to be mixed with mixed solution in certain proportion, the total concentration of medicine+high molecular polymer in solution is controlled between the 0.5%-45% (weight %), and this solution is as medication coat solution.
Select suitable solvent, for example: acetone, oxolane, chloroform, isopropyl alcohol, N-Methyl pyrrolidone, methanol, ethanol, purified water, ethyl acetate, N, a kind of and composition thereof in the N-dimethyl acetylamide, Nondegradable biocompatibility macromolecule polymer or its purified water emulsion and bioactive ingredients are mixed with mixed solution in certain proportion, the total concentration of Nondegradable biocompatibility macromolecule polymer or its purified water emulsion+bioactive ingredients is controlled between 0.5%～45% (the weight %), and this solution is as bioactivity coatings solution; Also can add auxiliary agents such as cross-linking agent when preparing this solution,, for example can use isocyanates as cross-linking agent.
Then, select suitable solvent, for example acetone, oxolane, isopropyl alcohol, ethanol, toluene, deionization purified water or its mixed solution carry out surface cleaning processing to bare bracket.Elder generation's ultrasonic cleaning 2～5 minutes, reuse solvent clean 2～5 minutes is cleaned the back that finishes 50 ℃ of following forced air dryings 2～30 minutes.
Adopt conventional method,, above-mentioned bioactivity coatings solution is coated in the bare bracket surface as the dipping or the spraying coating process of US2001/0014717A1 patent disclosure.Wherein, described impregnation technology is that bare bracket is immersed in the bioactivity coatings solution, and described spraying coating process is to place nebulizer to make its atomizing bioactivity coatings solution, is sprayed at the bare bracket surface then.To flood or be coated with in the support immigration air dry oven of bioactivity coatings solution, forced air drying at a certain temperature 1～72 hour, to guarantee that the organic solvent volatile quantity reaches the tolerant degree of human body, guarantee that simultaneously bioactivity coatings obtains enough intensity, evenly, stably covers rack surface.
Adopt dipping or spraying coating process the said medicine coating solution to be coated in the rack surface that is coated with bioactivity coatings.Described impregnation technology is for to be immersed in bare bracket in the medication coat solution; Described spraying coating process makes its atomizing for medication coat solution being placed nebulizer, is sprayed at the rack surface that is coated with bioactivity coatings then.Support behind dipping or the spraying medication coat solution is moved in the vacuum drying oven, vacuum drying is 1～72 hour at a certain temperature, to guarantee that the organic solvent volatile quantity reaches the tolerant degree of human body, guarantee the activity of medicine, guarantee that simultaneously medication coat obtains enough intensity, covers the base coating surface uniformly and stably.
The composite coating bracket for eluting medicament that obtains by method for preparing, bioactivity coatings and medication coat have enough intensity, can cover uniformly and stably, make medication coat bring into play antiproliferative effect, thereby be prevented the effect that restenosis takes place, after medication coat disappeared owing to biodegradation, bioactivity coatings was exposed to tissue or blood, thereby can prevent the generation of tampon.
The invention effect
Utilize composite coating cardiovascular medicaments elution stent of the present invention, can not only effectively suppress restenosis and take place, and can effectively prevent thrombosis, can prevent that implanting back body fluid with support in the support course of conveying washes away the medication coat obscission of bringing simultaneously.
Description of drawings
Fig. 1 is the drug release curve chart of an embodiment of the invention.
The specific embodiment
Describe the present invention in further detail below by specific embodiment, but the invention is not restricted to following embodiment.
In an embodiment, abbreviate bioactivity coatings as " bottom ", medication coat is abbreviated as " top layer ".
The first step: by following formulated bottom solution
Polyurethane (Biospan, U.S. Polymer Technology Group company) (15% solid content, dimethylacetamide solvent) 10 grams
N,N-dimethylacetamide 90 grams
Heparin 1.0 grams
Polyisocyanate (Desmodur N3400, Bayer AG) 0.8 gram
Second step: by following formulated surface solution
PLA (Mn=120000) 2.2 grams
Oxolane (chromatographic grade) 250 grams
Paclitaxel (purity＞99.5%) 0.4 gram
The 3rd step: make support
Magnesium alloy bracket is used isopropyl alcohol ultrasonic cleaning 5 minutes, 50 ℃ of following forced air dryings 20 minutes, drying finish the back with the spraying or the method for flooding make bottom solution even and complete cover the alloy bracket surface, the back 30 ℃ of dryings that finish 50 minutes, back 60 ℃ of forced air dryings 2 hours finish, drying finish the back with the spraying or the method for flooding make surface solution even and complete cover the alloy bracket surface that covers bottom, back 40 ℃ of vacuum dryings 48 hours finish.
Embodiment 2
The first step: by following formulated bottom solution
Aqueous emulsion of polyurethane (NeoRez-972, Zeneca Resins company) 10 grams
Water 90 grams
Heparin 3 grams
Second step: by following formulated surface solution
PLA (Mn=130000) 5.5 grams
Oxolane (chromatographic grade) 270 grams
Rapamycin (purity＞95%) 1.65 grams
The 3rd step: make support
The cochrome support is used isopropyl alcohol ultrasonic cleaning 5 minutes, reuse deionization purified water was cleaned 5 minutes, 50 ℃ of following forced air dryings 20 minutes, drying finish the back with the spraying or the method for flooding make bottom solution even and complete cover the alloy bracket surface, the back 30 ℃ of dryings that finish 50 minutes, back 60 ℃ of forced air dryings 2 hours finish, drying finish the back with the spraying or the method for flooding make surface solution even and complete cover the alloy bracket surface that covers bottom, back 40 ℃ of vacuum dryings 48 hours finish.
Embodiment 3
The first step: by following formulated bottom solution
Aqueous emulsion of polyurethane (Sancure 1601, Lubrizol company) 10 grams
Water 90 grams
Heparin 3 grams
Second step: by following formulated surface solution
Polylactic-co-glycolic acid (PLGA, Mn=130000, LA/GA=80/20) 3.5 grams
Oxolane (chromatographic grade) 250 grams
Rapamycin (purity＞99.5%) 1.1 grams
The 3rd step: make support
The cochrome support is used isopropyl alcohol ultrasonic cleaning 5 minutes, reuse deionization purified water was cleaned 5 minutes, 50 ℃ of following forced air dryings 20 minutes, drying finish the back with the spraying or the method for flooding make bottom solution even and complete cover the alloy bracket surface, the back 30 ℃ of dryings that finish 50 minutes, back 60 ℃ of forced air dryings 2 hours finish, drying finish the back with the spraying or the method for flooding make surface solution even and complete cover the alloy bracket surface that covers bottom, back 40 ℃ of vacuum dryings 48 hours finish.
Embodiment 4
The first step: by following formulated bottom solution
Acrysol (Acronal DS 6250, BASF AG) 10 grams
N-Methyl pyrrolidone 50 grams
Low molecular heparin calcium 3 grams
Polyisocyanate (Desmodur DA-L, Bayer AG) 1.2 grams
Second step: by following formulated surface solution
PLA (Mn=70000) 2.2 grams
Oxolane (chromatographic grade) 250 grams
Ciclosporin (purity＞95%) 0.8 gram
The 3rd step: make support
Magnesium alloy bracket is used AG isopropyl alcohol ultrasonic cleaning 5 minutes, reuse deionization purified water was cleaned 5 minutes, 50 ℃ of following forced air dryings 20 minutes, drying finish the back with the spraying or the method for flooding make bottom solution even and complete cover the alloy bracket surface, back 80 ℃ of forced air dryings 3 hours finish, drying finish the back with the spraying or the method for flooding make surface solution even and complete cover the alloy bracket surface that covers bottom, back 40 ℃ of vacuum dryings 48 hours finish.
The first step: by following formulated bottom solution
Acrysol (Acronal DS 6250, BASF AG) 10 grams
Water 50 grams
Activatory PROTEIN C 1.5 grams
Second step: by following formulated surface solution
Polylactic-co-glycolic acid (PLGA, Mn=80000, LA/GA=90/10) 3.5 grams
Oxolane (chromatographic grade) 250 grams
Mitomycin (purity＞95%) 1.0 grams
The 3rd step: make support
Magnesium alloy bracket is used AG isopropyl alcohol ultrasonic cleaning 5 minutes, reuse deionization purified water was cleaned 5 minutes, 50 ℃ of following forced air dryings 20 minutes, drying finish the back with the spraying or the method for flooding make bottom solution even and complete cover the alloy bracket surface, back 80 ℃ of forced air dryings 3 hours finish, drying finish the back with the spraying or the method for flooding make surface solution even and complete cover the alloy bracket surface that covers bottom, back 40 ℃ of vacuum dryings 48 hours finish.
Embodiment 6
The first step: by following formulated bottom solution
Polyurethane-acrylate copolymer (NeoPac E-121, Zeneca Resins company) 10 grams
N-Methyl pyrrolidone 30 grams
Hyaluronic acid 4 grams
1-azacyclopropane (XAMA-7, EIT Industries company) 1.2 grams
Second step: by following formulated surface solution
Poly phosphate (Mn=150000) 5.5 grams
Oxolane (chromatographic grade) 270 grams
Rapamycin (purity＞95%) 1.65 grams
The 3rd step: make support
The cochrome support is used AG isopropyl alcohol ultrasonic cleaning 5 minutes, reuse deionization purified water was cleaned 5 minutes, 50 ℃ of following forced air dryings 20 minutes, drying finish the back with the spraying or the method for flooding make bottom solution even and complete cover the alloy bracket surface, back 80 ℃ of vacuum dryings 3 hours finish, drying finish the back with the spraying or the method for flooding make surface solution even and complete cover the alloy bracket surface that covers bottom, back 40 ℃ of vacuum dryings 48 hours finish.
Embodiment 7
The first step: by following formulated bottom solution
Polyurethane-acrylate copolymer (NeoPac E-121, Zeneca Resins company) 10 grams
N-Methyl pyrrolidone 30 grams
Heparin 1.5 grams
Polyfunctional aziridines (CX-100, Zeneca Resins company) 1.2 grams
Second step: by following formulated surface solution
Polyesteramide (Mn=90000) 3.2 grams
Oxolane (chromatographic grade) 250 grams
Dexamethasone (purity＞95%) 0.7 gram
The 3rd step: make support
The cochrome support is used AG isopropyl alcohol ultrasonic cleaning 5 minutes, reuse deionization purified water was cleaned 5 minutes, 50 ℃ of following forced air dryings 20 minutes, drying finish the back with the spraying or the method for flooding make bottom solution even and complete cover the alloy bracket surface, back 80 ℃ of vacuum dryings 3 hours finish, drying finish the back with the spraying or the method for flooding make surface solution even and complete cover the alloy bracket surface that covers bottom, back 45 ℃ of vacuum dryings 48 hours finish.
Embodiment 8
The first step: by following formulated bottom solution
Acrysol (Acronal DS 6250, BASF AG) 10 grams
Water 50 grams
Factor VIIa inhibitors 2.0 grams
Second step: by following formulated surface solution
Polylactic-co-glycolic acid (PLGA, Mn=150000, LA/GA=50/50) 3.5 grams
Oxolane (chromatographic grade) 250 grams
Ciclosporin (purity＞95%) 0.7 gram
The 3rd step: Biodegradable scaffold is made
25mg PLLA (Mw=640,000) is dissolved in the chloroform, is mixed with the solution of M=35wt%; (thickness 0.15mm) is immersed in the PLLA solution with the Nitinol quoit, treat solution evaporation after, make the biodegradable stent original shape; The reuse laser cutting machine cuts into Biodegradable scaffold (stent size 3.0 * 25mm, wall thickness 0.1mm)
With the method for spraying or dipping make bottom solution even and complete cover the Biodegradable scaffold surface, back 80 ℃ of vacuum dryings 3 hours finish, drying finish the back with the spraying or the method for flooding make surface solution even and complete cover the alloy bracket surface that covers bottom, back 45 ℃ of vacuum dryings 48 hours finish.
Embodiment 9
Anchoring strength of coating is estimated:
The coating stent of medicine of the embodiment for preparing is expanded to a certain size,, washed away under the liquid flow rate 50ml/min 24 hours then 37 ℃ of temperature.Take out, vacuum drying is removed the remained on surface purified water.The JSM-6360LV type scanning electron microscope (SEM) of producing in NEC company (JEOL) is observed the micro structure of rack surface coating then, and the drug prepared coating surface is smooth, and is smooth, do not see obscission.Explanation is combined with metal rack firmly by the prepared cardiovascular medicaments elution stent composite coating of embodiment, and coating has the good mechanical performance.
The vitro drug release measurement device is adopted in the release evaluation of anti-restenosis medicaments; With the Ox blood serum is to discharge liquid simulation human body environment, and medication coat Chinese medicine burst size is detected, and detects with chromatograph of liquid.
1. instrument
High performance liquid chromatograph ultrasonic cleaner Vankel drug release instrument
2. reagent
Acetonitrile chromatographically pure nitrine is received analytical pure bovine serum albumin analytical pure
3. the mensuration of rapamycin concentrations standard curve
A mark=aC mark+b
A mark: standard substance peak area
C mark: standard substance concentration (ug/mL)
A: linear equation slope
B: linear equation intercept
4. test procedure
4.1 the preparation of dissolution medium: the buffer solution 1000mL for preparing the pH=7.4 that contains 0.1% Sodium Azide and 4% bovine serum albumin is standby.
Be placed on respectively in the test tube 4.2 get 15 of the coating stent of medicine of embodiment 5, be placed on the drug release instrument.Be added with the 15mL dissolution medium in the test tube.The temperature of drug release instrument is 37 ℃, is provided with according to USP7, and frequency of oscillation is 30 times/minute up and down, and amplitude is 2cm.
4.3 when 2 hours and 1,7,14,28 day, respectively get 3 respectively.Changed once fresh dissolution medium every 7 days.
4.4 support takes out the dissolution medium of back with purified water flushing surface, blots surperficial purification moisture.Put into brown vial, accurately add the 4mL acetonitrile, in Ultrasound Instrument, dissolve 30min, obtain solution (2).Accurately pipette 20ul solution (2) and carry out the HPLC analysis.
4.5 the calculating of rapamycin content in the support (M) (unit: μ g): the concentration (C mark) that obtains extract (1) according to the peak area-concentration standard curve in 3.
The M=4XC mark
The drug release curve chart as shown in Figure 1.
By the method for the foregoing description 10, can record the releasing effect that bracket for eluting medicament of the present invention all can obtain the anti-restenosis medicaments similar to the drug release effect of embodiment 10.
Embodiment 11
The anticoagulation test
According to the support of embodiment 1 method coating bioactivity coatings of the present invention, the anticoagulation function of test anticoagulant coatings of the present invention.Measure with whole blood clotting time method (Lee one ite) and to solidify required time fully after blood exsomatizes, experimental result shows, the support that has applied bioactivity coatings of the present invention according to embodiment 1 method does not occur full blood coagulation phenomenon in test in 15 hours, illustrates that anticoagulant coatings support of the present invention has good anticoagulation function.
Claims (20)
1. composite coating cardiovascular medicaments elution stent, it has following structure:
A: the bare bracket of playing a supporting role;
B: the Nondegradable bioactivity coatings that is applied to the bare bracket surface, described bioactivity coatings comprises antithrombotic bioactive ingredients and Nondegradable biocompatibility macromolecule polymer, antithrombotic bioactive ingredients is fixed in the bare bracket surface by non-degradation biological compatible polymer with the method that physics twines absorption or chemical crosslinking, described Nondegradable biocompatibility macromolecule polymer comprises polyacrylate, polyurethane, at least a in polyurethane-acrylate copolymer or the poly(ethylene oxide), described bioactive ingredients content counts 0.01～70% with Nondegradable biocompatibility macromolecule polymer weight;
C: the biodegradable medication coat that is applied to the biological active coating laminar surface, described medication coat comprises anti-restenosis medicaments and degradability biocompatibility macromolecule polymer, described degradability biocompatibility macromolecule polymer is polylactic acid, poly phosphate, polyesteramide or polylactic-co-glycolic acid, and described anti-restenosis medicaments content counts 1～60% with degradability biocompatibility macromolecule polymer weight.
2. composite coating cardiovascular medicaments elution stent according to claim 1 is characterized in that, described Nondegradable biocompatibility macromolecule polymer is the Nondegradable biocompatibility macromolecule polymer that can guarantee the stable existence of bioactivity coatings.
3. composite coating cardiovascular medicaments elution stent according to claim 1 is characterized in that, the described bioactive ingredients content in the described bioactivity coatings counts 0.1～55% with Nondegradable biocompatibility macromolecule polymer weight.
4. composite coating cardiovascular medicaments elution stent according to claim 1, it is characterized in that described bioactive ingredients comprises and is selected from least a in reorganization purification hirudin and derivant thereof, factor Xa inhibitor, factors IX a inhibitor, factor VIIa inhibitors, heparin, heparinoid, low molecular sodium heparin, low molecular heparin calcium, activatory PROTEIN C, Antithrombin III, heparin co factor II, tissue factor pathway inhibitor, thrombin receptor antagonism peptide, Coumarins, defibrase, the pyridines.
5. composite coating cardiovascular medicaments elution stent according to claim 1 is characterized in that, described degradability biocompatibility macromolecule polymer is the good degradability biocompatibility macromolecule polymer of control drug release speed.
6. composite coating cardiovascular medicaments elution stent according to claim 1, it is characterized in that described degradability biocompatibility macromolecule polymer is that number-average molecular weight is that 70000～150000 polylactic acid, number-average molecular weight are that 100000～170000 poly phosphate, number-average molecular weight are that 70000～120000 polyesteramide or number-average molecular weight are 80000～150000 polylactic-co-glycolic acid.
7. composite coating cardiovascular medicaments elution stent according to claim 1 is characterized in that, the described anti-restenosis medicaments content in the described medication coat counts 7～40% with degradability biocompatibility macromolecule polymer weight.
8. composite coating cardiovascular medicaments elution stent according to claim 7 is characterized in that, the described anti-restenosis medicaments content in the described medication coat counts 15～40% with degradability biocompatibility macromolecule polymer weight.
9. composite coating cardiovascular medicaments elution stent according to claim 1, it is characterized in that described anti-restenosis medicaments comprises at least a in paclitaxel, methyl meticortelone, Ba Dimasitaite, Solenognathus Fu Jinuo, c-protease inhibitor, 3-hydroxylase inhibitors, actinomycin methotrexate, dactinomycin, ciclosporin, rapamycin, vincaleucoblastine, emodin, dexamethasone, mitomycin, the D actinomycin D.
10. according to each described composite coating cardiovascular medicaments elution stent of claim 1～9, it is characterized in that described bare bracket is a balloon expandable stent.
11. composite coating cardiovascular medicaments elution stent according to claim 10 is characterized in that, described bare bracket is macromolecular material support or metal rack.
12. composite coating cardiovascular medicaments elution stent according to claim 11 is characterized in that, described metal rack is 316L stainless steel stent, Ti-Ni alloy support, cochrome support, magnesium alloy bracket or platinum alloy support.
13. composite coating cardiovascular medicaments elution stent according to claim 1 is characterized in that, described biological active coating layer thickness is 0.01～40 μ m.
14. composite coating cardiovascular medicaments elution stent according to claim 1 is characterized in that, described medication coat thickness is 0.01～100 μ m.
15. the preparation method of each described composite coating cardiovascular medicaments elution stent of claim 1～14, it may further comprise the steps:
C: at bare bracket surface-coated bioactivity coatings;
F: at bioactivity coatings surface-coated medication coat.
16. the preparation method of the described composite coating cardiovascular medicaments elution stent of claim 15 wherein, further comprises:
Before the c step, carry out following steps:
A: cleaning treatment is carried out on the bare bracket surface;
B: preparation comprises the bioactivity coatings solution of Nondegradable biocompatibility macromolecule polymer and antithrombotic bioactive ingredients;
After the c step, carry out following steps:
D: the support that obtains among the step c is carried out dried;
Before the f step, carry out following steps:
E: preparation comprises the medication coat solution of degradability biocompatibility macromolecule polymer and anti-restenosis medicaments;
After the f step, carry out following steps:
G: the support that obtains among the step f is carried out dried.
17. preparation method according to claim 16, it is characterized in that, the solvent that uses among step b and the step e is for being selected from acetone, oxolane, chloroform, isopropyl alcohol, N-Methyl pyrrolidone, at least a in methanol, ethanol, purified water, ethyl acetate, the N,N-dimethylacetamide.
18. preparation method according to claim 16 is characterized in that, among the step b, described Nondegradable biocompatibility macromolecule polymer is dissolved in organic solvent, mixes with bioactive ingredients then; Perhaps described Nondegradable biocompatibility macromolecule polymer manufacture is become macromolecule purified water emulsion, this macromolecule purified water emulsion is mixed with the purifying water soluble bioactive ingredients, form equally distributed coating solution.
19. preparation method according to claim 18, it is characterized in that described macromolecule purified water emulsion comprises polyurethane purified water emulsion, polyacrylate purified water emulsion, polyurethane-acrylate copolymer purified water emulsion or poly(ethylene oxide) purified water emulsion.
20. preparation method according to claim 16 is characterized in that, uses isocyanates, 1-azacyclopropane or polyfunctional aziridines as cross-linking agent among the step b.
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