CN105903091A - Vascular stent with degradable drug-loaded coating and preparation method thereof - Google Patents
Vascular stent with degradable drug-loaded coating and preparation method thereof Download PDFInfo
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- CN105903091A CN105903091A CN201610231289.7A CN201610231289A CN105903091A CN 105903091 A CN105903091 A CN 105903091A CN 201610231289 A CN201610231289 A CN 201610231289A CN 105903091 A CN105903091 A CN 105903091A
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/606—Coatings
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Abstract
The invention relates to a vascular stent with a degradable drug-loaded coating and a preparation method thereof. The vascular stent includes a stent body, and also includes a calcium-phosphorus transition layer and a regenerated drug-loaded coating. The calcium-phosphorus transition layer is located on the surface of the stent body, the regenerated drug-loaded coating is located on the surface of the calcium-phosphorus transition layer, and the regenerated drug-loaded coating and the calcium-phosphorus transition layer have same ingredients and fix drugs. The contribution of the invention lies in that the vascular stent can fix drugs in a biodegradable coating without using polymer, and can control drug release by adjusting the regenerated drug-loaded coating. The experimental result shows that the polymer-free degradable drug-loaded coating can effectively inhibit vascular intimal hyperplasia and avoids the occurrence of restenosis.
Description
Technical field
The invention belongs to technical field of medical instruments, relate to a kind of intravascular stent with degradable drug-carried coat and preparation method thereof.
Background technology
Along with the seventies percutaneous transluminal angioplasty in late period (PCI) and the appearance of the eighties late vessel support, reangiostenosis is the major defect that PCI exists always.And the appearance of medicine carrying angiocarpy bracket greatly reduces the generation of ISR.The inert coatings before used, the blood vessel deposition of non-degradable polymer carrier and long-term harmful effect also cause many new problems.The preparation method of the most conventional coating stent of medicine is by polymer, mostly is polylactide and its copolymer, makes mixed solution with the medicine of suppression ISR, is coated to intravascular stent surface, i.e. forms one layer of polymeric medication coat at rack surface after solvent seasoning.But, the polymer coating that tradition uses can not keep completely inert, polymer and the allergic reaction that causes frequently are in the news, as increased the inflammation of vascular wall, thrombus reacts, Vascular Smooth Muscle Cell Apoptosis, and polymer is poor with intravascular stent adhesion, after sterilization, operation course of conveying and implantable intravascular in the scour process of blood, easily coming off, this defect greatly limit the development at medicament intravascular stent of the degradable polymer supported medicine coating.As disclosed a kind of intravascular stent with anti-restenosis coating layer and preparation method thereof in patent CN101703428B, wherein intravascular stent surface Ultrasonic spraying has polymer drug-laden coating.This patent employs polymer as drug-carried coat, therefore there is the above-mentioned defect caused by polymer.
Summary of the invention
In order to overcome the deficiencies in the prior art, the present invention provides a kind of intravascular stent with degradable drug-carried coat and preparation method thereof, the present invention had both met non-polymer and had added, can carry out biodegradable in vivo, improve again coating and intravascular stent adhesion, at a temperature of active medicine can be survived, utilize fixed drug during the calcium phosphor coating generation of loose structure, raising drugloading rate can be played, give full play to pharmaceutically active, the purpose of release can be regulated and controled again.
The invention provides following technical scheme:
A kind of intravascular stent with degradable drug-carried coat, including rack body, also include calcium phosphorus transition zone and regeneration drug-carried coat, described calcium phosphorus transition zone is positioned at the surface of described rack body, described regeneration drug-carried coat is positioned at the surface of described calcium phosphorus transition zone, and described regeneration drug-carried coat is identical with the composition of described calcium phosphorus transition zone and fixed drug.
Intravascular stent is firmly combined with transition zone, and drug-carried coat is the calcium phosphor coating of one layer of identical component of regeneration on the basis of transition zone, medicine carrying during coatings growth, had both secured medicine, and had also laid a good groundwork for release.Having higher adhesion between described transition zone and intravascular stent, simultaneously and combine more firmly because being of identical composition between regeneration drug-carried coat, the existence of transition zone strengthens the adhesion between intravascular stent and regeneration drug-carried coat.Drug-carried coat is discharged by two aspects, and one is the coating structure of porous, and one is the gradually degraded of biodegradable coating.
In such scheme preferably, described calcium phosphorus transition zone, at the Surface Creation of described rack body, is fixed together with described rack body.
In any of the above-described scheme preferably, described calcium phosphorus transition zone passes through ion-beam assisted deposition, electrochemical deposition method, ion implantation, plasma spraying method or the laser cladding Surface Creation at described rack body.
In any of the above-described scheme preferably, described regeneration drug-carried coat is the coating of fixed drug simultaneously during the generation of calcium phosphorus transition zone.
Described regeneration drug-carried coat is made up of biodegradable calcium phosphor coating and lift-launch medicine, and fixing the generation with calcium phosphor coating of medicine is carried out simultaneously, and medicine is fixed in the loose structure of calcium phosphor coating.
In any of the above-described scheme preferably, the material of described calcium phosphorus transition zone is the material comprising calcium ion and phosphate anion.
In any of the above-described scheme preferably, the material of described calcium phosphorus transition zone is hydroxyapatite.
In any of the above-described scheme preferably, in described hydroxyapatite, calcium phosphorus ratio is 1.2-3.
In any of the above-described scheme preferably, in described hydroxyapatite, calcium phosphorus ratio is 1.66.
In any of the above-described scheme preferably, the thickness of described calcium phosphorus transition zone is 1-30 μm.Transition zone is 30-100MPa with the bond strength of blood vessel basement.
In any of the above-described scheme preferably, the various intravascular stents medically used before described intravascular stent feeling the pulse with the finger-tip.Described rack body is preferably balloon-expandable support, self-expansion type support, silk material braided blood vessel stent, tubing laser cutting intravascular stent, molding intravascular stent, welding intravascular stent.
In any of the above-described scheme preferably, described rack body is preferably stainless steel intravascular stent, nickel-titanium alloy intravascular scaffold or cochrome intravascular stent.
In any of the above-described scheme preferably, the process that the medicine of described regeneration drug-carried coat is fixed is: described medicine is dissolved in organic solvent, dilute with saturated salt solution, then the described organic solution after the rack body having formed described calcium phosphorus transition zone being immersed dilution seals 6-24h, is statically placed in the drying box of 35-40 DEG C.Along with the calcium phosphor coating of porous increasingly generates, in the middle of the loose structure of the coating that medicine is fixed on generation.
General medicine is difficult to be dissolved in saturated salt solution, is first dissolved in organic solvent so using, and the most again by the method for saturated solution dilution, organic solvent is by described medicine dissolving.
In any of the above-described scheme preferably, described saturated salt solution is the saturated salt solution containing calcium P elements.
In any of the above-described scheme preferably, the process that the medicine of described regeneration drug-carried coat is fixed is: described medicine is dissolved in organic solvent, dilute with saturated salt solution, then the described organic solution after the rack body having formed described calcium phosphorus transition zone being immersed dilution seals 6,12 or 24h, is statically placed in the drying box of 37 DEG C.
In any of the above-described scheme preferably, described medicine includes heparin, aspirin, hirudin, colchicin, antiplatelet acceptor knot anti-agent, white methotrexate (MTX), purines, miazines, plant bases, mycin class is broken on angstrom slope, thunder godvine series compound, antibiotic, hormone, antibody curing cancer drug, cyclosporin, tacrolimus and homologue, 15-is crystalline deoxyspergualin, MMF, rapamycin and derivative thereof, depsidone mycin, Kanglemycin, this Burger Eyring, prodigiosin, immunodepressant, tranilast, myriocin, cyclosporin C, Bredinin, Mycophenolic Acid, mine-laying is luxuriant and rich with fragrance obtains rhzomorph, glucocorticosteroid, tirofiban, Abciximab, Eptifibatide, taxol, one or more in actinomycin D.
In any of the above-described scheme preferably, one or more during described organic solvent includes oxolane, acetone, chloroform, dimethyl sulfoxide (DMSO), dichloromethane.
In any of the above-described scheme preferably, described rack body to pre-process before use, remove impurity and the greasy dirt on surface, it is beneficial to the preparation of transition zone, its process is: by described rack body ultrasonic cleaning 5-15 minute in organic solvent, ultrasonic cleaning 5-15 minute in ethanol solution, the most in deionized water ultrasonic cleaning 5-15 minute again, takes out nature and dries.
In any of the above-described scheme preferably, described rack body to pre-process before use, its process is: by described rack body ultrasonic cleaning 10 minutes in organic solvent, ultrasonic cleaning 10 minutes in ethanol solution again, ultrasonic cleaning 10 minutes the most in deionized water, take out nature and dry.
The present invention has the preparation method of intravascular stent of degradable drug-carried coat, including with each lower step described in also providing for:
(1) intravascular stent cleans: described rack body needs to pre-process before use, remove impurity and the greasy dirt on surface, it is beneficial to the preparation of transition zone, its process is: ultrasonic cleaning 5-15 minute in organic solvent, ultrasonic cleaning 5-15 minute in ethanol solution again, ultrasonic cleaning 5-15 minute the most in deionized water, takes out nature and dries；
(2) calcium phosphorus transition zone is prepared: formed the calcium phosphorus transition zone of densification by ion-beam assisted deposition, electrochemical deposition method, ion implantation, plasma spraying method or laser cladding described intravascular stent surface after cleaning；
(3) preparation regeneration drug-carried coat: described medicine is dissolved in organic solvent, dilutes with saturated salt solution, the described intravascular stent after step (2) being processed immerses and seals 6-24h in the described organic solution after dilution, is statically placed in the drying box of 35-40 DEG C；
(4) take out rack body, be placed in vacuum drying chamber and be dried 45-50 hour, room temperature, pressure 2-14pa, finally obtain finished product.
, rack body described in step (1) is balloon-expandable support, self-expansion type support, silk material braided blood vessel stent in such scheme preferably, tubing laser cutting intravascular stent, molding intravascular stent, welding intravascular stent.
In any of the above-described scheme preferably, rack body described in step (1) is stainless steel intravascular stent, nickel-titanium alloy intravascular scaffold or cochrome intravascular stent.
In any of the above-described scheme preferably, described in step (1), rack body needs to pre-process before use, its process is: ultrasonic cleaning 10 minutes in organic solvent, ultrasonic cleaning 10 minutes in ethanol solution again, ultrasonic cleaning 10 minutes the most in deionized water, take out nature and dry.
In any of the above-described scheme preferably, organic solvent described in step (1) easily mixes with ethanol.Preferably acetone, toluene etc..
In any of the above-described scheme preferably, described in step (2), the material of calcium phosphorus transition zone is the material comprising calcium ion and phosphate anion.
In any of the above-described scheme preferably, described in step (2), the material of calcium phosphorus transition zone is hydroxyapatite.
In any of the above-described scheme preferably, described in step (2), in hydroxyapatite, calcium phosphorus ratio is 1.2-3.
In any of the above-described scheme preferably, described in step (2), in hydroxyapatite, calcium phosphorus ratio is 1.66.
In any of the above-described scheme preferably, described in step (2), the thickness of calcium phosphorus transition zone is 1-30 μm.
In any of the above-described scheme preferably, described in step (3), medicine includes heparin, aspirin, hirudin, colchicin, antiplatelet acceptor knot anti-agent, white methotrexate (MTX), purines, miazines, plant bases, mycin class is broken on angstrom slope, thunder godvine series compound, antibiotic, hormone, antibody curing cancer drug, cyclosporin, tacrolimus and homologue, 15-is crystalline deoxyspergualin, MMF, rapamycin and derivative thereof, depsidone mycin, Kanglemycin, this Burger Eyring, prodigiosin, immunodepressant, tranilast, myriocin, cyclosporin C, Bredinin, Mycophenolic Acid, mine-laying is luxuriant and rich with fragrance obtains rhzomorph, glucocorticosteroid, tirofiban, Abciximab, Eptifibatide, taxol, one or more in actinomycin D.
In any of the above-described scheme preferably, described in step (3), organic solvent includes one or more in oxolane, acetone, chloroform, dimethyl sulfoxide (DMSO), dichloromethane.
In any of the above-described scheme preferably, described in step (3), saturated salt solution is the saturated salt solution containing calcium P elements.
In any of the above-described scheme preferably, the process regenerating the medicine of drug-carried coat described in step (3) fixing is: described medicine is dissolved in organic solvent, dilute with saturated salt solution, then the described organic solution after the rack body having formed described calcium phosphorus transition zone being immersed dilution seals 6,12 or 24h, is statically placed in the drying box of 37 DEG C.
The present invention solves problem of the prior art, change non-degradable material into Biodegradable material, remove the adverse effect of polymer, use calcium phosphor coating instead.Calcium phosphor coating has the biocompatibility of excellence, biologically active and Bioabsorbable.By ion-beam assisted deposition, electrochemical deposition method, ion implantation, plasma spraying method, the calcium phosphor coating that laser cladding is formed, compact structure, it is firmly combined with intravascular stent.It addition, as the medicine carrying calcium phosphor coating of regeneration, the structure of its porous allows it become a kind of preferable pharmaceutical carrier and the advantage of its degradability will not be made to disappear.
The present invention is prepared for one layer of biodegradable drug-carried coat of non-polymer at rack surface, by preparing one layer of transition zone between intravascular stent and drug-carried coat, and there is chemical bond between intravascular stent, and it is same sample ingredient between regenerated coated, forming core particle is provided for regenerated coated, it is beneficial to generate calcium phosphor coating, strengthens the adhesion between coating and blood vessel matrix.The present invention obtains non-polymer drug-carried coat on intravascular stent surface, result show that intravascular stent is formed densification is homogeneous and also transition zone that bond strength is high, preferred thickness is between 1-30 μm, improve adhesion, and with the presence of the calcium phosphorus of identical component as forming core particle, it is beneficial to regenerate calcium phosphor coating on transition zone, is favorably improved the load factor of medicine.The contribution of the present invention is fixed drug in the biodegradable coatings not using polymer, and can carry out Drug controlled release by regulation regeneration drug-carried coat.Test result indicate that this non-polymer degradable drug-carried coat effectively suppresses vascellum endometrial hyperplasia, it is to avoid the generation of ISR.
Accompanying drawing explanation
Fig. 1 is the support SEM pattern of the cochrome calcium phosphor coating system formed in a preferred embodiment of a kind of intravascular stent with degradable drug-carried coat of the present invention and preparation method thereof, support before wherein (a) and (b) is expansion, c () and (d) is the support after expansion, (b) and (d) is the magnification at high multiple image of (a) and (c) respectively；
Fig. 2 is the experimental example 1 medium vessels smooth muscle cell of a kind of intravascular stent with degradable drug-carried coat of the present invention and preparation method thereof the growing state comparison diagram on different support surface；
Fig. 3 be a kind of intravascular stent with degradable drug-carried coat of the present invention and preparation method thereof experimental example 1 in degradable drug-carried coat intravascular stent on the release profiles of rapamycin.
Detailed description of the invention
In order to further appreciate that the technical characteristic of the present invention, below in conjunction with specific embodiment, the present invention is set forth in.Embodiment only has exemplary effect to the present invention, and does not have any restrictive effect, and the amendment of any unsubstantiality that those skilled in the art makes on the basis of the present invention all should belong to protection scope of the present invention.
Embodiment
1
: a kind of intravascular stent ion-beam assisted deposition with degradable drug-carried coat
There is the preparation method of the intravascular stent of degradable drug-carried coat, including following steps described in the present embodiment:
(1) intravascular stent cleans: by cochrome support ultrasonic cleaning 10min in acetone, then ultrasonic cleaning 10min in ethanol, ultrasonic cleaning 10min the most in deionized water, is dried.
(2) prepare calcium phosphorus transition zone: the vacuum plant of ion beam assisted depositing put into by the cochrome support after cleaning, by joining preparation in HA powder with 37%CaO powder, there is the calcium phosphor coating of higher Ca/P ratio.Use electron-beam evaporator and the ion gun of bulbous end degree of lip-rounding formula.Before deposition, substrate 120V, 2A ar-ion beam sputter clean 20min, it is thus achieved that suitably vacuum (basic pressure 2 × 10 7Torr).Through the ion beam bombardment of 20min, the water vapor flux of evaporation generates on electron-beam evaporator, and deposits to certain thickness on rotary plate.Base reservoir temperature in deposition keeps below 100 DEG C.Take sample and at 250 DEG C of annealing 2h and immerse 30min in 100 DEG C of deionized waters.
(3) preparation regeneration drug-carried coat: preparation rapamycin/dichloromethane solution SM, concentration is 1mg/ml, takes the SM solution of 0.2ml, dilutes with 20mlDPBS solution, putting in dilute solution by the intravascular stent of ion beam assisted depositing calcium phosphor coating, 37 DEG C stand 12h.
(4) taking out support, 37 DEG C of drying boxes are vacuum dried 48 hours, and product SEM figure is shown in Fig. 1.
According to Fig. 1 it can be seen that before and after Peng Zhanging coating all keep fine and close homogeneous, after expansion, figure layer does not the most come off appearance, is firmly combined with.
Embodiment
2
: a kind of intravascular stent electrochemical deposition method with degradable drug-carried coat
There is the preparation method of the intravascular stent of degradable drug-carried coat, including following steps described in the present embodiment:
(1) intravascular stent cleans: by nick-eltitanium alloy stent ultrasonic cleaning 10min in acetone, then ultrasonic cleaning 10min in ethanol, ultrasonic cleaning 10min the most in deionized water, is dried.
(2) preparing calcium phosphorus transition zone: use galvanostatic deposition pattern, current density controls as about 1.0mA/cm2；Using the nick-eltitanium alloy stent that etches through peracidity as the negative electrode of electrochemical reaction, electrode is selected platinized platinum；Electrolyte is the mixed solution of CaCl2 and Na2HPO4 of 10-4mol/l, and PH regulates between 5.5-7.0, deposits under the conditions of boiling, and sedimentation time is 10-60 minute.
(3) preparation regeneration drug-carried coat: preparation rapamycin/dichloromethane solution SM, concentration is 1mg/ml, takes the SM solution of 0.2ml, dilutes with 20mlDPBS solution, putting in dilute solution by the intravascular stent of ion beam assisted depositing calcium phosphor coating, 37 DEG C stand 12h.
(4) taking out support, 37 DEG C of drying boxes are vacuum dried 48 hours.
Embodiment
3
: a kind of intravascular stent plasma spraying method with degradable drug-carried coat
There is the preparation method of the intravascular stent of degradable drug-carried coat, including following steps described in the present embodiment:
(1) intravascular stent cleans: by cochrome support ultrasonic cleaning 10min in acetone, then ultrasonic cleaning 10min in ethanol, ultrasonic cleaning 10min the most in deionized water, is dried.
(2) calcium phosphorus transition zone is prepared: the preparation of transition zone: wait and stainless steel stent is put into plasma spray apparatus, coating composition is highly purified hydroxyapatite.Main technologic parameters is as follows: main gas: argon gas 80scfh, secondary gas: hydrogen 8scfh, spraying current: 500A, spray voltage: 50V, spray distance: 150mm.The thickness obtaining transition zone is 80 μm, is 75Mpa with the bond strength of matrix.
(3) preparation regeneration drug-carried coat: preparation rapamycin/dimethyl sulphoxide solution SD, concentration is 1mg/ml, takes the SD solution of 0.2ml, dilutes with 20mlDPBS solution, the cochrome support that plasma spraying method deposits calcium phosphor coating is put in dilute solution, and 37 DEG C stand 12h.
(4) taking out support, 37 DEG C of drying boxes are vacuum dried 48 hours.
Embodiment
4
: a kind of intravascular stent laser cladding with degradable drug-carried coat
There is the preparation method of the intravascular stent of degradable drug-carried coat, including following steps described in the present embodiment:
(1) intravascular stent cleans: by stainless steel stent ultrasonic cleaning 10min in acetone, then ultrasonic cleaning 10min in ethanol, ultrasonic cleaning 10min the most in deionized water, is dried.
(2) calcium phosphorus transition zone is prepared: adjusting laser cladding apparatus parameter, laser power is 8W, laser spot diameter is set to 0.6mm, laser pulse frequency is set to 2.0Hz.The intravascular stent scribbling hydroxyapatite is placed on experimental bench and carries out Laser Cladding Treatment by setup parameter.
(3) preparation regeneration drug-carried coat: the preparation of regeneration drug-carried coat: preparation taxol/chloroformic solution, concentration is 1mg/ml, takes the drug solution of 0.1ml, dilutes with 20mlDPBS solution, the stainless steel stent that laser cladding deposits calcium phosphor coating is put in dilute solution, and 37 DEG C stand 12h.
(4) taking out support, 37 DEG C of drying boxes are vacuum dried 48 hours.
Embodiment
5
: a kind of intravascular stent ion implantation with degradable drug-carried coat
There is the preparation method of the intravascular stent of degradable drug-carried coat, including following steps described in the present embodiment:
(1) intravascular stent cleans: by nick-eltitanium alloy stent ultrasonic cleaning 10min in acetone, then ultrasonic cleaning 10min in ethanol, ultrasonic cleaning 10min the most in deionized water, is dried.
(2) calcium phosphorus transition zone is prepared: calcium, phosphonium ion are injected nick-eltitanium alloy stent with the energy of 110eV, 80keV and the dosage of 2x1017ion/cm2,1x1017ion/cm2 respectively.Mean current density 8.0 μ A/cm-2, injection period vacuum is maintained at below 1x10-3Pa.
(3) preparation regeneration drug-carried coat: preparation taxol/chloroformic solution, concentration is 1mg/ml, takes the drug solution of 0.1ml, dilutes with 20mlDPBS solution, and the stainless steel stent that laser cladding deposits calcium phosphor coating is put in dilute solution, and 37 DEG C stand 12h.
(4) taking out support, 37 DEG C of drying boxes are vacuum dried 48 hours.
Embodiment
6
:
A kind of intravascular stent with degradable drug-carried coat, including rack body, also include calcium phosphorus transition zone and regeneration drug-carried coat, described calcium phosphorus transition zone is positioned at the surface of described rack body, described regeneration drug-carried coat is positioned at the surface of described calcium phosphorus transition zone, and described regeneration drug-carried coat is identical with the composition of described calcium phosphorus transition zone and fixed drug.
Further, described calcium phosphorus transition zone, at the Surface Creation of described rack body, is fixed together with described rack body.
Further, described calcium phosphorus transition zone passes through ion-beam assisted deposition, electrochemical deposition method, ion implantation, plasma spraying method or the laser cladding Surface Creation at described rack body.
Further, described regeneration drug-carried coat is the coating of fixed drug simultaneously during the generation of calcium phosphorus transition zone.
Further, the material of described calcium phosphorus transition zone is the material comprising calcium ion and phosphate anion.
Further, the material of described calcium phosphorus transition zone is hydroxyapatite.
Further, in described hydroxyapatite, calcium phosphorus ratio is 1.2-3.
Further, in described hydroxyapatite, calcium phosphorus ratio is 1.66.
Further, the thickness of described calcium phosphorus transition zone is 1-30 μm.
Further, described rack body is balloon-expandable support, self-expansion type support, silk material braided blood vessel stent, tubing laser cutting intravascular stent, molding intravascular stent, welding intravascular stent.
Further, described rack body is stainless steel intravascular stent, nickel-titanium alloy intravascular scaffold or cochrome intravascular stent.
Further, the process that described regeneration drug-carried coat is fixed with described medicine is: described medicine is dissolved in organic solvent, dilute with saturated salt solution, then the described organic solution after the intravascular stent having formed described calcium phosphorus transition zone being immersed dilution seals 6-24h, is statically placed in the drying box of 35-40 DEG C.
Further, described saturated salt solution is the saturated salt solution containing calcium P elements.
Further, described medicine is dissolved in organic solvent, dilute with saturated salt solution, the described organic solution after then the intravascular stent having formed described calcium phosphorus transition zone being immersed dilution seals 6,12 or 24h, is statically placed in the drying box of 37 DEG C.
Further, described medicine includes heparin, aspirin, hirudin, colchicin, antiplatelet acceptor knot anti-agent, white methotrexate (MTX), purines, miazines, plant bases, mycin class is broken on angstrom slope, thunder godvine series compound, antibiotic, hormone, antibody curing cancer drug, cyclosporin, tacrolimus and homologue, 15-is crystalline deoxyspergualin, MMF, rapamycin and derivative thereof, depsidone mycin, Kanglemycin, this Burger Eyring, prodigiosin, tranilast, myriocin, immunodepressant, cyclosporin C, Bredinin, Mycophenolic Acid, mine-laying is luxuriant and rich with fragrance obtains rhzomorph, glucocorticosteroid, tirofiban, Abciximab, Eptifibatide, taxol, one or more in actinomycin D.
Further, one or more during described organic solvent includes oxolane, acetone, chloroform, dimethyl sulfoxide (DMSO), dichloromethane.
Further, described intravascular stent to pre-process before use, and its process is: by described intravascular stent ultrasonic cleaning 5-15 minute in acetone soln, then ultrasonic cleaning 5-15 minute in ethanol solution, ultrasonic cleaning 5-15 minute the most in deionized water, takes out nature and dries.
Further, described intravascular stent to pre-process before use, and its process is: by described intravascular stent ultrasonic cleaning 10 minutes in acetone soln, then ultrasonic cleaning 10 minutes in ethanol solution, ultrasonic cleaning 10 minutes the most in deionized water, take out nature and dry.
Further, the described organic solvent pre-processing described rack body easily mixes with ethanol.
Embodiment
7
:
A kind of intravascular stent with degradable drug-carried coat, including rack body, also include calcium phosphorus transition zone and regeneration drug-carried coat, described calcium phosphorus transition zone is positioned at the surface of described rack body, described regeneration drug-carried coat is positioned at the surface of described calcium phosphorus transition zone, and described regeneration drug-carried coat is identical with the composition of described calcium phosphorus transition zone and fixed drug.
This has the preparation method of intravascular stent of degradable drug-carried coat, including with each step:
(1) intravascular stent cleans: described rack body needs to pre-process before use, its process is: ultrasonic cleaning 5-15 minute in acetone soln, ultrasonic cleaning 5-15 minute in ethanol solution, the most in deionized water ultrasonic cleaning 5-15 minute again, takes out nature and dries；
(2) calcium phosphorus transition zone is prepared: form calcium phosphorus transition zone by ion-beam assisted deposition, electrochemical deposition method, ion implantation, plasma spraying method or laser cladding described rack body surface after cleaning；
(3) preparation regeneration drug-carried coat: described medicine is dissolved in organic solvent, dilutes with saturated salt solution, the described rack body after step (2) being processed immerses and seals 6-24h in the described organic solution after dilution, is statically placed in the drying box of 35-40 DEG C；
(4) take out rack body, be placed in vacuum drying chamber and be dried 45-50 hour, room temperature, pressure 2-14pa, finally obtain finished product.
Further, rack body described in step (1) is balloon-expandable support, self-expansion type support, silk material braided blood vessel stent, tubing laser cutting intravascular stent, molding intravascular stent, welding intravascular stent.
Further, rack body described in step (1) is stainless steel intravascular stent, nickel-titanium alloy intravascular scaffold or cochrome intravascular stent.
Further, described in step (1), rack body needs to pre-process before use, and its process is: ultrasonic cleaning 10 minutes in organic solvent, then ultrasonic cleaning 10 minutes in ethanol solution, ultrasonic cleaning 10 minutes the most in deionized water, take out nature and dry.
Further, organic solvent described in step (1) easily mixes with ethanol.
Further, described in step (2), the material of calcium phosphorus transition zone is the material comprising calcium ion and phosphate anion.
Further, described in step (2), the material of calcium phosphorus transition zone is hydroxyapatite.
Further, described in step (2), in hydroxyapatite, calcium phosphorus ratio is 1.2-3.
Further, described in step (2), in hydroxyapatite, calcium phosphorus ratio is 1.66.
Further, described in step (2), the thickness of calcium phosphorus transition zone is 1-30 μm.
Further, described in step (3), medicine includes heparin, aspirin, hirudin, colchicin, antiplatelet acceptor knot anti-agent, white methotrexate (MTX), purines, miazines, plant bases, mycin class is broken on angstrom slope, thunder godvine series compound, antibiotic, hormone, antibody curing cancer drug, cyclosporin, tacrolimus and homologue, 15-is crystalline deoxyspergualin, MMF, rapamycin and derivative thereof, depsidone mycin, Kanglemycin, this Burger Eyring, prodigiosin, tranilast, myriocin, immunodepressant, cyclosporin C, Bredinin, Mycophenolic Acid, mine-laying is luxuriant and rich with fragrance obtains rhzomorph, glucocorticosteroid, tirofiban, Abciximab, Eptifibatide, taxol, one or more in actinomycin D.
Further, described in step (3), organic solvent includes one or more in oxolane, acetone, chloroform, dimethyl sulfoxide (DMSO), dichloromethane.
Further, described in step (3), saturated salt solution is the saturated salt solution containing calcium P elements.
Further, the process regenerating the medicine of drug-carried coat described in step (3) fixing is: described medicine is dissolved in organic solvent, dilute with saturated salt solution, then the described organic solution after the rack body having formed described calcium phosphorus transition zone being immersed dilution seals 6,12 or 24h, is statically placed in the drying box of 37 DEG C.
Experimental example
1
1
, cell experiment result
VSMC is at blank metal rack surface, polymer support surface, there is the metal support surface of transition zone, the polymer support surface of medicine carrying, the growing state contrast on the intravascular stent surface with degradable drug-carried coat of embodiment 1 preparation, see Fig. 2, wherein control represents blank metal rack surface, polymer representation polymer support (PLA (PLA)) surface, apatite represents the metal support surface only having transition zone same as in Example 1, polymer+drug represents the polymer support surface of medicine carrying, apatite+drug represents the intravascular stent surface with degradable drug-carried coat of embodiment 1 preparation.Fig. 2 shows that VSMC is being cultivated 1 day, the cell attachment after 3 days and 7 days.For degradable polymer support, in the case of medicine, smooth muscle cell can constantly rise in value；Apatite with apatite+drug, compared with polymer support, all restrained effectively cell proliferation；The apatite coating metallic support of the load rapamycin of embodiment 1 preparation, after display fixed drug, the 3rd day, significantly inhibits SMC propagation, and this suppression in the 7th day becomes apparent from, and slow down cell proliferation rate.Result is it can be seen that there is more SMC cell to be attached on polymer support.Result shows, the non-polymer degradable drug-carried coat of embodiment 1 preparation effectively suppresses vascellum endometrial hyperplasia, it is to avoid the generation of ISR.
2
, insoluble drug release
The drug release patterns of 90 days of the intravascular stent with degradable drug-carried coat of embodiment 1 preparation is shown in Fig. 3.
According to Fig. 3 release profiles it can be seen that the release of rapamycin continue for more than 90 days, had at first day 46% prominent release generation, release afterwards continues and stable, reaches 88% to the 90th day burst size.And existing boundary skill non-polymer micro blind hole drug-loaded (taxol) coronary artery bracket, the release result of medicine shows, release 72% in 10 days.Release 95% in 30 days, release 100% in 60 days.Therefore, the slow release effect of the present invention is notable.
Claims (10)
1. an intravascular stent with degradable drug-carried coat, including rack body, it is characterized in that: also include calcium phosphorus transition zone and regeneration drug-carried coat, described calcium phosphorus transition zone is positioned at the surface of described rack body, described regeneration drug-carried coat is positioned at the surface of described calcium phosphorus transition zone, and described regeneration drug-carried coat is identical with the composition of described calcium phosphorus transition zone and fixed drug.
The intravascular stent with degradable drug-carried coat the most according to claim 1, it is characterised in that: described calcium phosphorus transition zone, at the Surface Creation of described rack body, is fixed together with described rack body.
The intravascular stent with degradable drug-carried coat the most according to claim 2, it is characterised in that: described calcium phosphorus transition zone passes through ion-beam assisted deposition, electrochemical deposition method, ion implantation, plasma spraying method or the laser cladding Surface Creation at described rack body.
The intravascular stent with degradable drug-carried coat the most according to claim 3, it is characterised in that: described regeneration drug-carried coat is the coating of fixed drug simultaneously during the generation of calcium phosphorus transition zone.
The intravascular stent with degradable drug-carried coat the most according to any one of claim 1 to 4, it is characterised in that: the material of described calcium phosphorus transition zone is the material comprising calcium ion and phosphate anion.
The intravascular stent with degradable drug-carried coat the most according to any one of claim 1 to 4, it is characterised in that: the material of described calcium phosphorus transition zone is hydroxyapatite.
The intravascular stent with degradable drug-carried coat the most according to claim 6, it is characterised in that: in described hydroxyapatite, calcium phosphorus ratio is 1.2-3.
The intravascular stent with degradable drug-carried coat the most according to claim 7, it is characterised in that: in described hydroxyapatite, calcium phosphorus ratio is 1.66.
The intravascular stent with degradable drug-carried coat the most according to any one of claim 1 to 4, it is characterised in that: the thickness of described calcium phosphorus transition zone is 1-30 μm.
The most according to claim 1, there is the preparation method of the intravascular stent of degradable drug-carried coat, including following steps:
(1) intravascular stent cleans: described rack body needs to pre-process before use, its process is: ultrasonic cleaning 5-15 minute in organic solvent, ultrasonic cleaning 5-15 minute in ethanol solution, the most in deionized water ultrasonic cleaning 5-15 minute again, takes out nature and dries；
(2) calcium phosphorus transition zone is prepared: form calcium phosphorus transition zone by the surface of ion-beam assisted deposition, electrochemical deposition method, ion implantation, plasma spraying method or laser cladding described rack body after cleaning；
(3) preparation regeneration drug-carried coat: described medicine is dissolved in organic solvent, dilutes with saturated salt solution, the described rack body after step (2) being processed immerses and seals 6-24h in the described organic solution after dilution, is statically placed in the drying box of 35-40 DEG C；
(4) take out rack body, be placed in vacuum drying chamber and be dried 45-50 hour, room temperature, pressure 2-14pa, finally obtain finished product.
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| WO2022021363A1 (en) * | 2020-07-31 | 2022-02-03 | 苏州大学 | Coating composition, hydrogel coating and preparation method therefor, and coated product |
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