CN115317675B - Drug eluting stent and preparation method and application thereof - Google Patents

Drug eluting stent and preparation method and application thereof Download PDF

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CN115317675B
CN115317675B CN202211011374.4A CN202211011374A CN115317675B CN 115317675 B CN115317675 B CN 115317675B CN 202211011374 A CN202211011374 A CN 202211011374A CN 115317675 B CN115317675 B CN 115317675B
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drug eluting
stent
eluting stent
drug
preparing
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CN115317675A (en
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赵晟
郭力友
夏洁
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Suzhou Zhongtian Medical Device Technology Co ltd
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Suzhou Zhongtian Medical Device Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

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Abstract

The invention provides a drug eluting stent, a preparation method and application thereof. The drug eluting stent comprises a stent matrix, a drug and hydrogel; the surface of the bracket matrix is provided with micro holes, and the medicine is loaded in the micro holes and sealed by hydrogel. The drug eluting stent has no risk of coating falling off, and reduces the occurrence probability of restenosis, wherein the drug is loaded in micropores on the surface of the stent and is not easy to be scoured by blood flow; and hydrogel hole sealing is adopted to avoid sudden release caused by too fast dissolution of the medicine.

Description

Drug eluting stent and preparation method and application thereof
Technical Field
The invention belongs to the technical field of implantable medical devices, and particularly relates to a drug eluting stent, a preparation method and application thereof.
Background
Atherosclerosis is one of the serious diseases threatening human health, and stent placement is one of the main means for treating atherosclerosis. Early simple bare saccule expansion and bare stent implantation easily lead to high restenosis rate and poor treatment effect. At present, the Drug Eluting Stent (DES) is widely applied to clinic, and can reduce the restenosis rate to below 10 percent. Although the drug eluting stent can greatly reduce restenosis rate, the effect of complete radical cure is not achieved. It is probably due to the fact that, as soon as the drug is usually supported on a polymer carrier, the polymer carrier itself may have side effects on the human body, inducing restenosis of the stent. Secondly, the combination of the coating and the stent is not firm, the stent is easy to fall off in the process of pressing and holding and expanding the stent, or the effective action of the drug is reduced due to uneven degradation and falling in the body, and the treatment effect is affected. Thus, the design concept of the new drug eluting stent is to eliminate the polymer coating.
CN112386377a discloses a drug-loaded punctiform stent and a preparation method thereof, which are mainly used for the interlayer after the below-knee artery saccule dilatation molding operation. The stent comprises a shorter nickel-titanium alloy stent matrix, the stent matrix is of a self-expanding grid design structure, the surface of the stent matrix is provided with uniform drug-carrying micro-pits, and a drug coating is coated on the surface of the uniform drug-carrying micro-pits: the preparation method comprises 1) processing nickel-titanium alloy into bracket matrix; 2) Treating the surface of a bracket matrix; 3) Carrying out corrosion treatment on the bracket matrix; 4) Cleaning the corroded bracket matrix; 5) And (3) coating the surface of the stent matrix with the micro pits with the medicine. The drug-loaded punctiform stent is formed by combining a shorter longitudinal length with an open pore design, so that the metal load on arterial blood vessels is reduced to the greatest extent, the surface area contacted with the arterial blood vessels is reduced, the stent is not easy to break and is suitable for various blood vessel diameters, the coated drugs on the surface of the stent can be released controllably, the stent matrix fully plays the supporting and drug treatment effects, and the occurrence rate of restenosis and target lesion blood transport reconstruction is reduced. However, the electrochemical corrosion adopted by the method needs to connect the anode and the bracket, and the connection part of the anode and the bracket can be shielded, so that the bracket is corroded unevenly.
CN1919353a discloses a method for manufacturing a micro blind hole medicine carrying layer on the surface of a metal bracket, which comprises the following steps: a. treating the surface of the metal bracket by using a heated NaOH solution, removing the existing impurities and oxide films, then washing by using deionized water, and drying; b. accurately preparing corrosive liquid by using analytically pure acid at normal temperature, and calibrating the corrosive liquid; c. immersing the treated metal bracket into the calibrated corrosive liquid at normal temperature, taking out, washing with deionized water, and drying; d. preparing an organic solution with a certain concentration by using a volatile organic solvent and a medicament carried by a metal bracket at normal temperature; e. at normal temperature, the metal bracket with micro blind holes formed on the surface is put into an organic solution containing the carried medicine, and is taken out and dried after microwave oscillation. The nickel titanium and stainless steel are stable, so that the reaction rate is slow at normal temperature. Therefore, the method requires a corrosion time of up to 16 hours, and the preparation efficiency is low.
CN101869723a discloses a composite drug stent for inhibiting cardiovascular restenosis and a preparation method thereof, the stent is made of metal pipe by laser cutting, the surface of the stent is corroded by electrochemical acid solution to form nano holes, a layer of non-degradable bioactive coating is sprayed on the surface of the main body, the thickness is 10-50 microns, and a layer of degradable biocompatible polymer drug coating is sprayed outside the non-degradable bioactive coating, and the thickness is 10-100 microns. Wherein the non-degradable bioactive coating is prepared by mixing a non-degradable biocompatible high polymer, an active biological component, an organic solvent and the like to form a solution, and spraying, drying and other procedures. The method also adopts an electrochemical method, and the phenomenon of uneven corrosion caused by shielding the clamp and the bracket is also existed.
The above patents have more or less such drawbacks. In fact, the ideal effect achieved by the drug coating should be that the drug is uniformly distributed on the stent surface, attached to the matrix after implantation, and released slowly during long-term (> 1 year) service to achieve sustained therapeutic effect.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a drug eluting stent, and a preparation method and application thereof. The invention prepares nano-scale and submicron-scale corrosion holes on the surface of a bracket matrix by a chemical corrosion method, fully impregnates and loads the drugs in the holes, and then seals the holes through hydrogel.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a drug eluting stent comprising a stent matrix, a drug and a hydrogel; wherein, the surface of the bracket matrix is provided with micro holes, and the medicine is loaded in the micro holes and sealed by hydrogel.
In the invention, the drug is loaded in the micropores on the surface of the stent matrix, the micropores are sealed by the hydrogel, the drug eluting stent has no risk of coating falling off, and the occurrence probability of restenosis is reduced, wherein the drug is loaded in the micropores on the surface of the stent, and is not easy to be flushed by blood flow; and hydrogel hole sealing is adopted to avoid sudden release caused by too fast dissolution of the medicine.
Preferably, the micropores are spherical, and the diameter of the micropores is 0.2-0.9 μm, for example, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, etc.
Preferably, the distribution density of the micro holes on the surface of the bracket matrix is 4-8 ten thousand/mm 2 For example, 4 ten thousand pieces/mm 2 4.5 ten thousand/mm 2 5 ten thousand pieces/mm 2 5.5 ten thousand/mm 2 6 ten thousand/mm 2 6.5 ten thousand/mm 2 7 ten thousand/mm 2 7.5 ten thousand/mm 2 8 ten thousand pieces/mm 2 Etc.
Preferably, the drug is selected from any one or a combination of at least two of rapamycin, everolimus, zotarolimus, paclitaxel, gingerol, losartan, daidzein, docetaxel, dexamethasone, methotrexate, dextran, mitomycin, heparin sodium, doxorubicin hydrochloride, hirudin, argatroban, dipyridamole, prostacyclin analogues, nitroglycerin, nitroprusside, suramin, endostatin, serotonin blockers, steroids or oligopeptides.
Preferably, the hydrogel is selected from any one or a combination of at least two of agar, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, hyaluronic acid, gelatin, chitosan, cellulose, fibrin or carbomer.
Preferably, the polyvinyl alcohol has a number average molecular weight of 47000 to 98000, and may be 47000, 50000, 55000, 60000, 65000, 70000, 75000, 80000, 85000, 90000, 95000, 98000, or the like, for example.
Preferably, the number average molecular weight of the polyvinylpyrrolidone is 8000-1300000, and may be 8000, 10000, 50000, 100000, 200000, 400000, 600000, 800000, 1000000, 1200000, 1300000, or the like, for example.
Preferably, the molecular weight of the hyaluronic acid is 400000-2500000, and for example, 400000, 600000, 800000, 1000000, 1200000, 1400000, 1600000, 1800000, 2000000, 2200000, 2500000 and the like can be used.
Preferably, the carbomer is selected from any one or a combination of at least two of carbomer 934, carbomer 940, carbomer 941 or carbomer 980.
Preferably, the hydrogel is any one or a combination of at least two of chitosan, polyvinyl alcohol and polyvinylpyrrolidone, and the mass ratio of the chitosan to the polyvinyl alcohol to the polyvinylpyrrolidone is 1 (2-4), for example, 1:2:2, 1:2:3, 1:2:4, 1:3:2, 1:3:3, 1:3:4, and the like.
Preferably, the hydrogel is a combination of chitosan, sodium alginate and polyvinylpyrrolidone, and the mass ratio of the chitosan, sodium alginate and polyvinylpyrrolidone is 1 (0.5-2): (4-6), for example, may be 1:0.5:4, 1:0.5:5, 1:0.5:6, 1:1:4, 1:1:5, 1:1:6, 1:2:4, 1:2:5, 1:2:6, etc.
Preferably, the hydrogel is a combination of gelatin and hyaluronic acid, the mass ratio of gelatin to hyaluronic acid being (5-20): 1, for example, 5:1, 6:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 16:1, 18:1, 20:1, etc.
Preferably, the drug-eluting stent has a drug-loading density of 1-5 mug/mm 2 For example, it may be 1. Mu.g/mm 2 、1.5μg/mm 2 、2μg/mm 2 、2.5μg/mm 2 、3μg/mm 2 、3.5μg/mm 2 、4μg/mm 2 、4.5μg/mm 2 、5μg/mm 2 Etc.
In a second aspect, the present invention provides a method for preparing a drug eluting stent as described in the first aspect, the method comprising the steps of:
(1) Carrying out chemical corrosion treatment on the surface of the bracket matrix, and forming micro holes on the surface of the bracket matrix;
(2) Immersing the stent matrix treated in the step (1) in a drug solution to load the drug into the micropores;
(3) And (3) sealing the stent matrix treated in the step (2) by using hydrogel to obtain the drug eluting stent.
The invention provides a medicine elution branch without coating and a preparation method thereof, in particular to a preparation method of medicine loaded on the surface of a bracket. Wherein, the chemical corrosion method is to accelerate the reaction of the bracket in the reaction kettle under the action of high temperature and high pressure.
Preferably, in step (1), the step of the chemical etching treatment is: placing the bracket matrix and the corrosive liquid into a reaction kettle, and reacting under the conditions of high temperature and high pressure.
Preferably, the etching solution includes an etchant, a surfactant, and a solvent.
Preferably, the corrosive liquid consists of the following components in percentage by mass based on 100% of the total mass of the corrosive liquid: 0.5 to 10 percent (for example, 0.5 percent, 1 percent, 2 percent, 3 percent, 4 percent, 5 percent, 6 percent, 7 percent, 8 percent, 9 percent, 10 percent and the like) of corrosive agent, 0.1 to 5 percent (for example, 0.5 percent, 1 percent, 2 percent, 3 percent, 4 percent, 5 percent and the like) of surfactant, and the balance of solvent.
Preferably, the etchant is selected from any one or a combination of at least two of hydrofluoric acid, ammonium fluoride, ammonium bifluoride, nitric acid, sodium nitrate, ammonium nitrate, potassium nitrate or ammonium bifluoride.
Preferably, the surfactant is selected from any one or a combination of at least two of diisooctyl succinate, sodium dodecyl benzene sulfonate, cetyltrimethylammonium bromide or triethanolamine.
Preferably, the solvent is selected from any one or a combination of at least two of PBS solvent, TES buffer, acetone, diethyl ether, isopropanol, n-pentane, cyclopentane, decane, octadecane or polyethylene glycol.
Preferably, the temperature of the reaction is 110-250deg.C, for example 110 deg.C, 120 deg.C, 140 deg.C, 160 deg.C, 180 deg.C, 200 deg.C, 220 deg.C, 250 deg.C, etc., and the reaction time is 60-360min, for example 60min, 80min, 100min, 150min, 200min, 250min, 300min, 360min, etc.
Preferably, in step (2), the solvent of the drug solution is selected from any one or a combination of at least two of methanol, ethanol or dichloromethane.
Preferably, in the step (2), the concentration of the drug solution is 10-50mg/mL, for example, 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 35mg/mL, 40mg/mL, 45mg/mL, 50mg/mL, etc.
Preferably, in the step (2), the temperature of the impregnation is 0 to 20 ℃, for example, 0 ℃,2 ℃,5 ℃, 8 ℃, 10 ℃, 12 ℃, 15 ℃, 20 ℃ and the like, and the time of the impregnation is 30 to 120min, for example, 30min, 40min, 50min, 60min, 80min, 100min, 120min and the like.
Preferably, in the step (3), the step of sealing the hole is: and (3) ultrasonically spraying the mixed solution of the hydrogel onto the surface of a stent matrix, and then solidifying and drying to finish hole sealing to obtain the drug eluting stent.
Or, the hole sealing step is as follows: soaking a stent matrix in a mixed solution of hydrogel, lifting, centrifuging, solidifying and drying to finish hole sealing, and obtaining the drug eluting stent.
Preferably, in step (3), the solvent of the mixed solution of hydrogels is water.
Preferably, in the step (3), the solid content of the mixed solution of the hydrogel is 10 to 50wt%, for example, 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, etc.
Preferably, in the step (3), the power of the ultrasonic spraying is 3-15W, for example, 3W, 4W, 5W, 6W, 7W, 8W, 9W, 10W, 11W, 12W, 13W, 14W, 15W, etc., the frequency is 50-150kHz, for example, 50kHz, 60kHz, 80kHz, 100kHz, 120kHz, 150kHz, etc., and the speed is 0.01-2mL/min, for example, 0.01mL/min, 0.05mL/min, 0.1mL/min, 0.2mL/min, 0.4mL/min, 0.5mL/min, 1mL/min, 1.2mL/min, 1.4mL/min, 1.6mL/min, 1.8mL/min, 2mL/min, etc.
Preferably, in the step (3), the temperature of the impregnation is 20-40 ℃, for example, 20 ℃, 25 ℃,30 ℃, 35 ℃, 40 ℃ and the like, and the time of the impregnation is 0.5-10min, for example, 0.5min, 1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min, 10min and the like.
Preferably, in the step (3), the rotation speed of the centrifugal treatment is 100-1000r/min, for example, 100r/min, 200r/min, 300r/min, 400r/min, 500r/min, 600r/min, 800r/min, 1000r/min, etc.
Preferably, in the step (3), the curing is ultraviolet curing, and the wavelength of ultraviolet curing is 300-380nm, for example, 300nm, 310nm, 320nm, 330nm, 340nm, 350nm, 360nm, 370nm, 380nm, etc., and the time of ultraviolet curing is 20-40min, for example, 20min, 25min, 30min, 35min, 40min, etc.
In a third aspect, the present invention provides the use of a drug eluting stent as described in the first aspect for the preparation of a product for the treatment of atherosclerosis.
Compared with the prior art, the invention has the following beneficial effects:
(1) The drug eluting stent disclosed by the invention does not contain a drug carrier coating, does not have the risk of coating falling off, and reduces the occurrence probability of restenosis;
(2) The medicine in the medicine elution bracket is loaded in the micropores on the surface of the bracket, so that the medicine is not easy to be washed by blood flow;
(3) The drug eluting stent adopts hydrogel hole sealing, so that burst release caused by too fast dissolution of the drug can be well avoided;
(4) The preparation process of the drug eluting stent is simple and is suitable for mass production.
Drawings
FIG. 1 is a schematic diagram of a drug eluting stent provided by the present invention;
wherein 1 is hydrogel grid, 2 is drug nano particles, and 3 is stent matrix.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The sources of the components in the following examples are shown below:
degreasing and deoiling the bracket, and then placing the bracket into an ethanol acetone solution for ultrasonic cleaning and drying by cold air for later use.
Example 1
The embodiment provides a drug eluting stent, which is prepared by the following method:
(1) 2g of ammonium bifluoride, 3.5g of ammonium nitrate, 3g of triethanolamine, 50mL of n-pentane and 30mL of PBS are mixed and dissolved in a tetrafluoroethylene container, and 300W of ultrasonic waves are carried out for 30min to prepare corrosive liquid; immersing the bracket into corrosive liquid, locking the reaction kettle, placing the reaction kettle in an oven, keeping the temperature at 200 ℃ for 180 minutes, and taking out the reaction kettle; respectively carrying out ultrasonic cleaning by deionized water, ethanol and acetone;
(2) Preparing 10mg/mL rapamycin ethanol solution, fully soaking the stent at 20 ℃ for 50min, taking out and drying;
(3) 200g of mixed solution of 5% chitosan, 15% polyvinyl alcohol and 15% PVP is prepared, and the solvent is water; and (3) carrying out ultrasonic spraying (the spraying power is 10W, the frequency is 100kHz, the speed is 0.05 mL/min) on the surface of the stent, then carrying out ultraviolet curing for 30min at 380nm, and carrying out vacuum drying for 15min to obtain the drug eluting stent.
Example 2
The embodiment provides a drug eluting stent, which is prepared by the following method:
(1) 1mL of hydrogen fluoride (concentration is 40%), 3mL of nitric acid (concentration is 68%), 50mL of polyethylene glycol 400, 5g of AOT, 30mL of decane and 100mL of PBS are mixed and dissolved in a tetrafluoroethylene container, and 300W ultrasonic treatment is carried out for 30min to prepare corrosive liquid; immersing the bracket into corrosive liquid, locking the reaction kettle, placing the bracket in an oven, setting the temperature to 180 ℃, keeping the temperature for 60 minutes, and taking out the bracket; respectively carrying out ultrasonic cleaning by deionized water, ethanol and acetone;
(2) Preparing 10mg/mL rapamycin ethanol solution, fully soaking the stent at 10 ℃ for 30min, taking out and drying;
(3) Preparing 200g of mixed solution of 5% chitosan, 5% sodium alginate and 25% PVP, wherein the solvent is water; soaking the stent at 20 ℃ for 1min, lifting, placing the stent in an ultrafiltration centrifuge tube for spin coating at 550r/min, taking out, solidifying for 30min by using 350nm ultraviolet light, and finally drying in vacuum for 15min to obtain the drug eluting stent.
Example 3
The embodiment provides a drug eluting stent, which is prepared by the following method:
(1) 5g of ammonium bifluoride, 5.5g of potassium nitrate, 3.3g of polyethylene glycol 400, 20mL of diethyl ether, 10g of octadecane and 66mL of PBS are mixed and dissolved in a tetrafluoroethylene container, and 300W ultrasonic treatment is carried out for 30min to prepare corrosive liquid; immersing the bracket into corrosive liquid, locking the reaction kettle, placing the reaction kettle in an oven, setting the temperature to 150 ℃, keeping the temperature for 100min, and taking out; respectively carrying out ultrasonic cleaning by deionized water, ethanol and acetone;
(2) Preparing 15mg/mL rapamycin ethanol solution, fully soaking the stent at 10 ℃ for 60min, taking out and drying;
(3) 200g of mixed solution of 10% carbomer, 5% gelatin and 2% hyaluronic acid is prepared, and the solvent is water; soaking the bracket at 30 ℃ for 1min, lifting, placing the bracket in an ultrafiltration centrifuge tube for 300r/min for spin coating, taking out, solidifying for 30min by using 380nm ultraviolet light, and finally drying for 15min in vacuum to obtain the drug eluting bracket.
Example 4
This example provides a drug eluting stent that differs from example 1 only in that rapamycin is replaced with equal mass of everolimus, and the other steps are exactly the same as in example 1.
Example 5
This example provides a drug eluting stent differing from example 1 only in the substitution of rapamycin for equal mass daidzein, and the other steps are exactly the same as in example 1.
Example 6
This example provides a drug eluting stent that differs from example 1 only in that rapamycin is replaced with equal mass paclitaxel, and the other steps are identical to example 1.
Example 7
This example provides a drug eluting stent that differs from example 1 only in that ammonium bifluoride is replaced with equal mass of sodium fluoride, the other steps being exactly the same as example 1.
Example 8
This example provides a drug eluting stent differing from example 1 only in that ammonium nitrate is not added and the ammonium bifluoride content is increased to 5.5g, the other steps being exactly the same as in example 1.
Example 9
This example provides a drug eluting stent that differs from example 1 only in that no triethanolamine is added and the other steps are exactly the same as in example 1.
Example 10
The present example provides a drug eluting stent differing from example 1 only in that in step (1), the temperature was set at 100 ℃, and the stent was taken out after keeping the temperature for 400 minutes, and the other steps were exactly the same as in example 1.
Example 11
The present example provides a drug eluting stent differing from example 1 only in that in step (1), the temperature was set at 300 ℃, and after 50min of constant temperature, the stent was taken out, and the other steps were exactly the same as in example 1.
Example 12
This example provides a drug eluting stent differing from example 1 only in that in step (3), 200g of a mixed solution of 5% chitosan, 15% carbomer, and 15% methylcellulose was prepared, and the other steps were exactly the same as in example 1.
Example 13
This example provides a drug eluting stent differing from example 1 only in that in step (3), 200g of a mixed solution of 5% chitosan, 15% alginic acid, and 15% hyaluronic acid was prepared, and the other steps were exactly the same as in example 1.
Comparative example 1
The comparative example provides a non-hole-sealing drug eluting stent, which is prepared by the following method:
(1) 1mL of hydrogen fluoride (concentration is 40%), 3mL of nitric acid (concentration is 68%), 50mL of polyethylene glycol 400, 5g of AOT, 30mL of decane and 100mL of PBS are mixed and dissolved in a tetrafluoroethylene container, and 300W ultrasonic treatment is carried out for 30min to prepare corrosive liquid; immersing the bracket into corrosive liquid, locking the reaction kettle, placing the bracket in an oven, setting the temperature to 180 ℃, keeping the temperature for 60 minutes, and taking out the bracket; respectively carrying out ultrasonic cleaning by deionized water, ethanol and acetone;
(2) Preparing 10mg/mL rapamycin ethanol solution, fully soaking the stent at 15 ℃ for 35min, taking out and drying to obtain the non-hole-sealing drug eluting stent.
Comparative example 2
The comparative example provides a drug eluting stent prepared by the following method:
(1) 1mL of hydrogen fluoride (concentration is 40%), 3mL of nitric acid (concentration is 68%), 50mL of polyethylene glycol 400, 5g of AOT, 30mL of decane and 100mL of PBS are mixed and dissolved in a tetrafluoroethylene container, and 300W ultrasonic treatment is carried out for 30min to prepare corrosive liquid; immersing the bracket into corrosive liquid, locking the reaction kettle, placing the bracket in an oven, setting the temperature to 180 ℃, keeping the temperature for 60 minutes, and taking out the bracket; respectively carrying out ultrasonic cleaning by deionized water, ethanol and acetone;
(2) Preparing 10mg/mL rapamycin ethanol solution, fully soaking the stent at 5 ℃ for 20min, taking out and drying;
(3) 200g of mixed solution of 5% phosphatidylglycerol, 5% DSPE-PEG and 25% soybean lecithin is prepared, and the solvent is ethyl acetate; and (3) carrying out ultrasonic spraying (the spraying power is 15W, the frequency is 130kHz, the speed is 0.5 mL/min) on the surface of the stent, and carrying out vacuum drying for 30min to obtain the drug eluting stent.
Test example 1
Probability of restenosis test
Test sample: the drug eluting stents provided in examples 1-13, the drug eluting stents provided in comparative examples 1-2;
the testing method comprises the following steps: the experiment selects a healthy normal white pig with 35kg of test pig, performs pre-operation myoinfusion to induce anesthesia, performs suction anesthesia after successful anesthesia induction, and then performs tracheal intubation to establish a respiratory pathway and ear margin venipuncture to establish a vein pathway. After the animal is moved into an operating table, the region near femoral artery puncture parts at two sides is disinfected, femoral artery puncture is performed, a vascular sheath is inserted, and arterial access is established. The experimental animals are heparinized by intravenous injection of low molecular heparin and then are inserted into a contrast catheter for contrast, and different stents are implanted. Taking graft segment blood vessels after normal feeding of the animal after operation for 2 weeks, respectively extracting RNA, carrying out spot hybridization detection on transfection expression condition and carrying out pathological morphological analysis, and measuring the intimal hyperplasia degree;
the specific test results are shown in table 1 below:
TABLE 1
As shown in Table 2, the loss rate of the lumen of the stent matrix prepared by the invention is below 4%; the medicine is loaded in the micropores on the surface of the stent matrix, the micropores are sealed by the hydrogel, the medicine elution stent has no risk of coating falling off, and the occurrence probability of restenosis is reduced.
Test example 2
Burst test
Test sample: the drug eluting stent provided in example 13, the drug eluting stents provided in examples 7-13, the drug eluting stents provided in comparative examples 1-2;
the testing method comprises the following steps:
(1) Drug release from the drug eluting stent was studied in vitro with Phosphate Buffered Saline (PBS) at pH 6.4. The PBS solution was prepared by dissolving 1.79g of disodium hydrogen orthophosphate, 1.36g of potassium hydrogen orthophosphate, and 7.02g of sodium chloride in 1000mL of HPLC grade water. The solution is kept in an ultrasonic cleaner for 10min to dissolve;
(2) Arterial blood flow was simulated with peristaltic pump and silicone tubing, target vessel diameter 3mm, constant temperature 37 ℃ was set, and peristaltic pump speed was calibrated at 200mL/min flow. The stent is expanded to the inner wall of the silica gel tube, a peristaltic pump is started, and 10mL of eluent is respectively extracted at 1d, 15d and 30 d.
(3) Adding the extracted eluent into methanol to fix the volume to 50mL, and quantitatively detecting the content by liquid chromatography. Liquid chromatography measures drug content: the instrument is selected as follows: liquid chromatograph agilent 1260 index; chromatographic column: c18, 4.6x 500,5 μm; instrument operating parameters: detection wavelength: 278nm of rapamycin drug, column temperature: sample injection amount at 50 ℃): 10 μl, flow rate: 0.6mL/min.
The specific test results are shown in table 2 below:
TABLE 2
As shown in table 2, in the present invention, the drug is loaded in the micro-holes on the surface of the stent matrix, the micro-holes are sealed by hydrogel, the drug eluting stent has no risk of coating falling, the hydrogel is used for sealing the holes, the drug is prevented from being dissolved too fast to generate burst release, and 3-6% of the drug is released from the assembly of the coated stent at the end of day 1.
The applicant states that the invention is illustrated by the above examples as a drug eluting stent and a method of making and using it, but the invention is not limited to, i.e. it does not mean that the invention has to be carried out in dependence of, the above process steps. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of selected raw materials, addition of auxiliary components, selection of specific modes, etc. fall within the scope of the present invention and the scope of disclosure.

Claims (23)

1. A drug eluting stent, characterized in that the drug eluting stent comprises a stent matrix, a drug and a hydrogel; wherein, micro holes are arranged on the surface of the bracket matrix, and the medicine is loaded in the micro holes and sealed by hydrogel;
the micro holes are spherical, and the diameter of the micro holes is 0.2-1 mu m;
the hydrogel is a combination of chitosan, polyvinyl alcohol and polyvinylpyrrolidone with the mass ratio of (2-4) being 1 (2-4); or the mass ratio is 1 (0.5-2), namely (4-6) the combination of chitosan, sodium alginate and polyvinylpyrrolidone;
the number average molecular weight of the polyvinyl alcohol is 47000-98000;
the number average molecular weight of the polyvinylpyrrolidone is 8000-1300000.
2. The drug eluting stent of claim 1, wherein the surface micro-holes of the stent matrix have a distribution density of 4-8 ten thousand/mm 2 。
3. The drug eluting stent of claim 1, wherein the drug is selected from any one or a combination of at least two of rapamycin, everolimus, zotarolimus, paclitaxel, gingerol, losartan, daidzein, docetaxel, dexamethasone, methotrexate, dextran, mitomycin, heparin sodium, doxorubicin hydrochloride, hirudin, argatroban, dipyridamole, prostacyclin, nitroglycerin, nitroprusside, suramin, endostatin, serotonin blockers, steroids, or oligopeptides.
4. The drug eluting stent of claim 1, wherein the drug loading density of the drug eluting stent is 1-5 μg/mm 2 。
5. A method of preparing a drug eluting stent as defined in any of claims 1 to 4, comprising the steps of:
(1) Carrying out chemical corrosion treatment on the surface of the bracket matrix, and forming micro holes on the surface of the bracket matrix;
(2) Immersing the stent matrix treated in the step (1) in a drug solution to load the drug into the micropores;
(3) And (3) sealing the stent matrix treated in the step (2) by using hydrogel to obtain the drug eluting stent.
6. The method of preparing a drug eluting stent of claim 5, wherein in step (1), the step of chemically etching is: placing the bracket matrix and the corrosive liquid into a reaction kettle, and reacting under the conditions of high temperature and high pressure.
7. The method of preparing a drug eluting stent of claim 6, wherein the etching solution includes an etchant, a surfactant, and a solvent.
8. The method for preparing a drug eluting stent of claim 7, wherein the corrosive liquid is composed of the following components, based on 100% of the total mass of the corrosive liquid: 0.5-10% of corrosive agent, 0.1-5% of surfactant and the balance of solvent.
9. The method of preparing a drug eluting stent of claim 7, wherein the etchant is selected from any one or a combination of at least two of hydrofluoric acid, ammonium fluoride, ammonium bifluoride, nitric acid, sodium nitrate, ammonium nitrate, potassium nitrate, or ammonium bifluoride.
10. The method for preparing a drug eluting stent of claim 7, wherein the surfactant is selected from any one or a combination of at least two of diisooctyl succinate, sodium dodecyl benzene sulfonate, cetyltrimethylammonium bromide, or triethanolamine.
11. The method of preparing a drug eluting stent of claim 7, wherein the solvent is selected from any one or a combination of at least two of PBS solvent, TES buffer, acetone, diethyl ether, isopropanol, n-pentane, cyclopentane, decane, octadecane, or polyethylene glycol.
12. The method for preparing a drug eluting stent of claim 6, wherein the reaction temperature is 110-250 ℃ and the reaction time is 60-120 min.
13. The method of preparing a drug eluting stent of claim 5, wherein in step (2), the solvent of the drug solution is selected from any one or a combination of at least two of methanol, ethanol, or methylene chloride.
14. The method of claim 5, wherein in step (2), the concentration of the drug solution is 10-50 mg/mL.
15. The method of preparing a drug eluting stent of claim 5, wherein in step (2), the temperature of the impregnation is 0-20 ℃ and the time of the impregnation is 30-120 min.
16. The method for preparing a drug eluting stent of claim 5, wherein in step (3), the step of sealing the hole is: ultrasonically spraying the mixed solution of the hydrogel to the surface of a stent matrix, and then solidifying and drying to finish hole sealing to obtain the drug eluting stent;
or, the hole sealing step is as follows: soaking a stent matrix in a mixed solution of hydrogel, lifting, centrifuging, solidifying and drying to finish hole sealing, and obtaining the drug eluting stent.
17. The method of claim 16, wherein in step (3), the solvent of the mixed solution of hydrogels is water.
18. The method of claim 16, wherein in step (3), the solid content of the mixed solution of hydrogels is 10-50-wt%.
19. The method of claim 16, wherein in step (3), the ultrasonic spraying is performed at a power of 3-15W, a frequency of 50-150kHz, and a rate of 0.01-2 mL/min.
20. The method of preparing a drug eluting stent of claim 16, wherein in step (3), the temperature of the impregnation is 20-40 ℃ and the time of the impregnation is 0.5-10 min.
21. The method of claim 16, wherein in step (3), the rotational speed of the centrifugation is 100-1000 r/min.
22. The method of claim 16, wherein in step (3), the curing is ultraviolet curing, the wavelength of ultraviolet curing is 300-380nm, and the time of ultraviolet curing is 20-40 min.
23. Use of a drug eluting stent as defined in any of the claims 1 to 4 for the preparation of a product for the treatment of atherosclerosis.
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