CN115317675A - Drug eluting stent and preparation method and application thereof - Google Patents
Drug eluting stent and preparation method and application thereof Download PDFInfo
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- CN115317675A CN115317675A CN202211011374.4A CN202211011374A CN115317675A CN 115317675 A CN115317675 A CN 115317675A CN 202211011374 A CN202211011374 A CN 202211011374A CN 115317675 A CN115317675 A CN 115317675A
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- drug
- stent
- eluting stent
- hydrogel
- drug eluting
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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
- 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
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- 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
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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
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- 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
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- 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 and a preparation method and application thereof. The drug eluting stent comprises a stent matrix, a drug and hydrogel; micro-pores exist on the surface of the stent matrix, and the medicine is loaded in the micro-pores and sealed by hydrogel. The drug eluting stent has no risk of coating falling off, reduces the occurrence probability of restenosis, wherein drugs are loaded in micropores on the surface of the stent and are not easy to be washed by blood flow; and hydrogel sealing is adopted to avoid the sudden release caused by the too fast dissolution of the medicine.
Description
Technical Field
The invention belongs to the technical field of implantable medical devices, and particularly relates to a drug eluting stent, and a preparation method and application thereof.
Background
Atherosclerosis is one of the serious diseases threatening human health, and stenting is one of the main means for treating atherosclerosis. The simple early-stage naked saccule expansion and naked stent implantation easily cause high restenosis rate and have poor treatment effect. Currently, drug Eluting Stents (DES) are widely used in clinical applications to reduce restenosis rates to below 10%. Although the drug eluting stent can greatly reduce the restenosis rate, the effect of complete radical treatment cannot be achieved. It is probably caused by the fact that the drug is usually carried on a polymer carrier, which itself has side effects on the human body, inducing stent restenosis. Secondly, the combination of the coating and the stent is not firm, the coating is easy to fall off in the process of pressing and expanding the stent, or the coating is not uniformly degraded and falls off in vivo to cause the reduction of the effective action of the drug, thereby influencing the treatment effect. 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 an interlayer after a below-knee artery balloon dilatation molding. The support includes shorter nickel titanium alloy support base member, and the support base member is from expanding grid project organization, and support base member surface has even medicine carrying micro pit, at even medicine carrying micro pit surface coating medicine coating: the preparation method comprises the following steps of 1) processing nickel-titanium alloy into a stent matrix; 2) Treating the surface of the support matrix; 3) Carrying out corrosion treatment on the bracket matrix; 4) Cleaning the corroded bracket matrix; 5) And coating the surface of the stent matrix with the micro-pits with the medicament. The drug-loaded punctiform stent is combined with the design of open pores by shorter longitudinal length, reduces the metal load on arterial blood vessels to the greatest extent, reduces the surface area contacted with the arterial blood vessels, is not easy to break, is suitable for various blood vessel diameters, can control the release of the coated drugs on the surface, fully exerts the supporting and drug treatment effects on the stent matrix, and is beneficial to reducing the incidence rate of restenosis and target lesion blood transportation reconstruction. However, the electrochemical corrosion adopted by the method needs to connect the anode and the bracket, and the joint of the anode and the bracket can be shielded, so that the bracket is not corroded uniformly.
CN1919353A discloses a method for manufacturing a micro blind hole drug-loaded layer on the surface of a metal stent, which comprises the following steps: a. treating the surface of the metal bracket by using a heated NaOH solution to remove existing impurities and oxide films, then washing by using deionized water, and drying; b. at normal temperature, accurately preparing the corrosive liquid by using analytically pure acid, and calibrating the corrosive liquid; c. immersing the treated metal bracket into a calibrated corrosive liquid at normal temperature, taking out, cleaning with deionized water, and drying; d. preparing an organic solution with a certain concentration by using a volatile organic solvent and the medicine carried by the metal bracket at normal temperature; e. at normal temperature, the metal stent with the micro blind holes formed on the surface is put into organic solution in which the loaded medicine is dissolved, and the metal stent is taken out and dried after microwave oscillation. The nickel titanium and the stainless steel are stable, so the reaction rate is slow at normal temperature. Therefore, the method requires an etching time as long as 16h, and the preparation efficiency is low.
CN101869723A discloses a composite drug stent for inhibiting cardiovascular restenosis and a preparation method thereof, wherein the stent is prepared by laser cutting of a metal pipe, nanopores are formed on the surface of the stent through corrosion of electrochemical acid solution, a non-degradable bioactive coating is sprayed on the surface of a main body, the thickness of the coating is 10-50 microns, and a degradable biocompatible polymer drug coating is sprayed on the outer surface of the non-degradable bioactive coating, and the thickness of the coating is 10-100 microns. The non-degradable bioactive coating is prepared by mixing a non-degradable biocompatible high molecular polymer, an active biological component, an organic solvent and the like to form a solution, and performing spraying, drying and other processes. The method also adopts an electrochemical method, and the phenomenon of uneven corrosion caused by the shielding of the clamp and the bracket also exists.
The above patents suffer from more or less such drawbacks. In fact, the ideal drug coating should achieve the effect of uniformly distributing the drug on the surface of the stent, not fall off after being attached to the matrix after implantation, and slowly release the drug in the long-term (> 1 year) service process to achieve the continuous 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 nanometer and submicron-grade corrosion holes on the surface of the stent matrix by a chemical corrosion method, fully dips and loads the medicament in the holes, and then seals the holes by hydrogel.
In order to achieve the purpose, 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 stent matrix has micro-pores, and the drug is loaded in the micro-pores and sealed by hydrogel.
In the invention, the medicine is loaded in the micropore holes on the surface of the stent matrix, the micropores are sealed by the hydrogel, the medicine eluting stent has no risk of coating falling off, and the occurrence probability of restenosis is reduced, wherein the medicine is loaded in the micropores on the surface of the stent and is not easy to be washed by blood flow; and the hydrogel is adopted for sealing the hole, so that the sudden release caused by the too fast dissolution of the medicine is avoided.
Preferably, the microholes are spherical and have a diameter of 0.2 to 0.9. Mu.m, and may be, for example, 0.2. Mu.m, 0.3. Mu.m, 0.4. Mu.m, 0.5. Mu.m, 0.6. Mu.m, 0.7. Mu.m, 0.8. Mu.m, 0.9. Mu.m, etc.
Preferably, the distribution density of the surface micro-pores of the bracket substrate is 4-8 ten thousand/mm 2 For example, it may be 4 ten thousand/mm 2 4.5 ten thousand/mm 2 5 ten thousand pieces/mm 2 5.5 ten thousand/mm 2 6 ten thousand pieces/mm 2 6.5 ten thousand/mm 2 7 ten thousand pieces/mm 2 7.5 ten thousand/mm 2 8 ten thousand/mm 2 And the like.
Preferably, the drug is selected from any one of rapamycin, everolimus, zotarolimus, paclitaxel, gingerol, losartan, daidzein, docetaxel, dexamethasone, methotrexate, dextran, mitomycin, heparin sodium, doxorubicin hydrochloride, hirudin, argatroban, dipyridamole, prostacyclin analogue, nitroglycerin, nitroprusside, suramin, endostatin, serotonin blockers, steroids or oligopeptides or a combination of at least two thereof.
Preferably, the hydrogel is selected from any one of agar, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, hyaluronic acid, gelatin, chitosan, cellulose, fibrin or carbomer or a combination of at least two of the same.
Preferably, the polyvinyl alcohol has a number average molecular weight of 47000 to 98000, and may be, for example, 47000, 50000, 55000, 60000, 65000, 70000, 75000, 80000, 85000, 90000, 95000, 98000, and the like.
Preferably, the polyvinylpyrrolidone has a number average molecular weight of 8000-1300000, which may be, for example, 8000, 10000, 50000, 100000, 200000, 400000, 600000, 800000, 1000000, 1200000, 1300000, etc.
Preferably, the molecular weight of the hyaluronic acid is 400000-2500000, and may be 400000, 600000, 800000, 1000000, 1200000, 1400000, 1600000, 1800000, 2000000, 2200000, 2500000, or the like, for example.
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 of chitosan, polyvinyl alcohol and polyvinylpyrrolidone or a combination of at least two of them, and the mass ratio of chitosan, polyvinyl alcohol and polyvinylpyrrolidone is 1 (2-4): 2-4, and can be, for example, 1.
Preferably, the hydrogel is a combination of chitosan, sodium alginate and polyvinylpyrrolidone, and the mass ratio of chitosan, sodium alginate and polyvinylpyrrolidone is 1 (0.5-2): 4-6, and can be 1.
Preferably, the hydrogel is a combination of gelatin and hyaluronic acid, the mass ratio of gelatin and hyaluronic acid is (5-20) and can be, for example, 5.
Preferably, the drug-loaded density of the drug-eluting stent is 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 And the like.
In a second aspect, the present invention provides a method of 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 substrate to form a micropore on the surface of the bracket substrate;
(2) Dipping the stent matrix treated in the step (1) in a drug solution to load drugs in the micro-pores;
(3) And (3) sealing the holes of the stent matrix treated in the step (2) by using hydrogel to obtain the drug eluting stent.
The invention provides a uncoated drug eluting stent and a preparation method thereof, and particularly relates to a preparation method of a stent surface loaded drug. Wherein, the chemical corrosion method is that the bracket accelerates the reaction in a reaction kettle by the action of high temperature and high pressure.
Preferably, in step (1), the chemical etching treatment comprises: and placing the support matrix and the corrosive liquid in a reaction kettle, and reacting under the conditions of high temperature and high pressure.
Preferably, the etching liquid includes an etchant, a surfactant, and a solvent.
Preferably, the corrosion solution consists of the following components in percentage by mass based on 100% of the total mass of the corrosion solution: the etchant is 0.5-10% (e.g., 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc.), the surfactant is 0.1-5% (e.g., 0.5%, 1%, 2%, 3%, 4%, 5%, etc.), and the balance is the solvent.
Preferably, the corrosive agent is selected from any one of hydrofluoric acid, ammonium fluoride, ammonium bifluoride, nitric acid, sodium nitrate, ammonium nitrate, potassium nitrate, or ammonium hydrogen nitrate, or a combination of at least two thereof.
Preferably, the surfactant is selected from any one of or a combination of at least two of diisooctyl succinate sodium sulfonate, sodium dodecylbenzene sulfonate, cetyl trimethyl ammonium bromide or triethanolamine.
Preferably, the solvent is selected from any one of 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 reaction temperature is 110-250 deg.C, such as 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, such as 60min, 80min, 100min, 150min, 200min, 250min, 300min, 360min, etc.
Preferably, in the step (2), the solvent of the drug solution is selected from any one of methanol, ethanol or dichloromethane or a combination of at least two thereof.
Preferably, in step (2), the concentration of the drug solution is 10 to 50mg/mL, and may be, for example, 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 35mg/mL, 40mg/mL, 45mg/mL, 50mg/mL, or the like.
Preferably, in step (2), the temperature of the impregnation is 0-20 ℃, for example, 0 ℃,2 ℃,5 ℃, 8 ℃, 10 ℃, 12 ℃, 15 ℃, 20 ℃ and the like, and the time of the impregnation is 30-120min, for example, 30min, 40min, 50min, 60min, 80min, 100min, 120min and the like.
Preferably, in the step (3), the step of sealing the pores is as follows: and ultrasonically spraying the mixed solution of the hydrogel on the surface of the stent matrix, and then curing and drying to complete hole sealing to obtain the drug eluting stent.
Or, the hole sealing step is as follows: firstly, soaking a stent matrix in a mixed solution of hydrogel, carrying out centrifugal treatment after lifting, and finally carrying out solidification and drying to complete hole sealing to obtain the drug eluting stent.
Preferably, in step (3), the solvent of the mixed solution of hydrogels is water.
Preferably, in step (3), the solid content of the mixture of the hydrogel is 10 to 50wt%, for example, 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, etc.
Preferably, in step (3), the power of the ultrasonic spraying is 3-15W, such as 3W, 4W, 5W, 6W, 7W, 8W, 9W, 10W, 11W, 12W, 13W, 14W, 15W, etc., the frequency is 50-150kHz, such as 50kHz, 60kHz, 80kHz, 100kHz, 120kHz, 150kHz, etc., and the rate is 0.01-2mL/min, such as 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 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 step (3), the rotation speed of the centrifugal treatment is 100-1000r/min, such as 100r/min, 200r/min, 300r/min, 400r/min, 500r/min, 600r/min, 800r/min, 1000r/min, etc.
Preferably, in step (3), the curing is ultraviolet curing, the wavelength of the ultraviolet curing is 300-380nm, such as 300nm, 310nm, 320nm, 330nm, 340nm, 350nm, 360nm, 370nm, 380nm, etc., and the time of the ultraviolet curing is 20-40min, such as 20min, 25min, 30min, 35min, 40min, etc.
In a third aspect, the present invention provides the use of a drug-eluting stent as defined in the first aspect, in the manufacture 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 does not contain a drug carrier coating, so that the risk of coating falling does not exist, and the occurrence probability of restenosis is reduced;
(2) The medicine in the medicine eluting stent is loaded in micropores on the surface of the stent and is not easily washed by blood flow;
(3) The drug eluting stent adopts hydrogel hole sealing, so that the phenomenon that the drug is dissolved too fast to generate burst release can be well avoided;
(4) The drug eluting stent has simple preparation process and is suitable for mass production.
Drawings
FIG. 1 is a schematic structural view of a drug eluting stent provided in accordance with the present invention;
wherein, 1 is hydrogel grid, 2 is drug nano-particles, and 3 is a bracket matrix.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention.
The sources of the components in the following examples are as follows:
degreasing and deoiling the bracket, putting the bracket into an ethanol acetone solution for ultrasonic cleaning, and drying the bracket by cold air for later use.
Example 1
This example provides a drug eluting stent 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 the mixture is subjected to ultrasonic treatment at 300W for 30min to prepare a corrosive liquid; then immersing the bracket into the corrosive liquid, locking the reaction kettle, placing the bracket in an oven, setting the temperature at 200 ℃, keeping the temperature for 180min, and taking out the bracket; then ultrasonic cleaning is carried out by using deionized water, ethanol and acetone respectively;
(2) Preparing 10mg/mL rapamycin ethanol solution, fully soaking the stent at 20 ℃ for 50min, taking out and drying;
(3) Preparing 200g of a mixed solution containing 5% of chitosan, 15% of polyvinyl alcohol and 15% of PVP, wherein the solvent is water; ultrasonically spraying the mixture (the spraying power is 10W, the frequency is 100kHz, and the speed is 0.05 mL/min) to the surface of the stent, curing for 30min by using 380nm ultraviolet light, and drying in vacuum for 15min to obtain the drug eluting stent.
Example 2
This example provides a drug eluting stent prepared by the following method:
(1) 1mL of hydrogen fluoride (with the concentration of 40 percent), 3mL of nitric acid (with the concentration of 68 percent), 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 of the mixture is subjected to ultrasonic treatment for 30min to prepare a corrosive liquid; then immersing the bracket into the corrosive liquid, locking the reaction kettle, placing the reaction kettle in an oven, setting the temperature to be 180 ℃, keeping the temperature for 60min, and taking out the reaction kettle; then ultrasonic cleaning is carried out by using deionized water, ethanol and acetone respectively;
(2) Preparing 10mg/mL rapamycin ethanol solution, fully soaking the stent at 10 ℃ for 30min, taking out and drying;
(3) Preparing 200g of a mixed solution containing 5% of chitosan, 5% of sodium alginate and 25% of PVP, wherein the solvent is water; fully soaking the stent at 20 ℃ for 1min, lifting, placing in an ultrafiltration centrifugal tube for 550r/min for whirl coating, taking out, curing with 350nm ultraviolet light for 30min, and finally vacuum drying for 15min to obtain the drug eluting stent.
Example 3
This example provides a drug eluting stent 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 the mixture is subjected to ultrasonic treatment at 300W for 30min to prepare corrosive liquid; then immersing the bracket into the corrosive liquid, locking the reaction kettle, placing the bracket in an oven, setting the temperature at 150 ℃, keeping the temperature for 100min, and taking out; then ultrasonic cleaning is carried out by using deionized water, ethanol and acetone respectively;
(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; fully soaking the stent at 30 ℃ for 1min, lifting, placing in an ultrafiltration centrifugal tube for 300r/min for whirl coating, taking out, curing with 380nm ultraviolet light for 30min, and finally vacuum drying for 15min to obtain the drug eluting stent.
Example 4
This example provides a drug-eluting stent, which differs from example 1 only in that rapamycin was replaced with everolimus of equal mass, and the other steps were exactly the same as example 1.
Example 5
This example provides a drug-eluting stent, which is different from example 1 only in that rapamycin was replaced with daidzein of equal mass, and the other steps were exactly the same as example 1.
Example 6
This example provides a drug eluting stent, which differs from example 1 only in that rapamycin is replaced with paclitaxel of equal mass, and the other steps are exactly the same as example 1.
Example 7
This example provides a drug eluting stent, which is different from example 1 only in that ammonium bifluoride is replaced with sodium fluoride of equal mass, and the other steps are exactly the same as example 1.
Example 8
This example provides a drug eluting stent, differing from example 1 only in that, without the addition of ammonium nitrate, the ammonium bifluoride content was increased to 5.5g, and the other steps were exactly the same as example 1.
Example 9
This example provides a drug eluting stent, differing from example 1 only in that triethanolamine was not added and the other steps were exactly the same as example 1.
Example 10
This example provides a drug eluting stent, which is different from example 1 only in that, in step (1), the temperature is set at 100 ℃, and the stent is taken out after keeping the temperature constant for 400min, and the other steps are completely the same as example 1.
Example 11
This example provides a drug-eluting stent, which is different from example 1 only in that, in step (1), the temperature is set at 300 ℃, and the stent is taken out after being kept at a constant temperature for 50min, and the other steps are completely the same as example 1.
Example 12
This example provides a drug-eluting stent, which is different from example 1 only in that 200g of a mixed solution of 5% chitosan, 15% carbomer and 15% methylcellulose is prepared in step (3), and the other steps are exactly the same as example 1.
Example 13
This example provides a drug-eluting stent, which is different from example 1 only in that 200g of a mixed solution of 5% chitosan, 15% alginic acid and 15% hyaluronic acid is prepared in step (3), and the other steps are exactly the same as example 1.
Comparative example 1
The present comparative example provides a drug eluting stent without holes, prepared by the following method:
(1) Dissolving 1mL of hydrogen fluoride (with the concentration of 40 percent), 3mL of nitric acid (with the concentration of 68 percent), 50mL of polyethylene glycol 400, 5g of AOT, 30mL of decane and 100mL of PBS in a tetrafluoroethylene container in a mixing manner, and carrying out ultrasonic treatment at 300W for 30min to prepare a corrosive solution; then immersing the bracket into the corrosive liquid, locking the reaction kettle, placing the reaction kettle in an oven, setting the temperature to be 180 ℃, keeping the temperature for 60min, and taking out the reaction kettle; then ultrasonic cleaning is carried out by deionized water, ethanol and acetone respectively;
(2) Preparing 10mg/mL rapamycin ethanol solution, fully soaking the stent at 15 ℃ for 35min, taking out and drying to obtain the drug eluting stent without holes.
Comparative example 2
This comparative example provides a drug eluting stent prepared by the method of:
(1) 1mL of hydrogen fluoride (with the concentration of 40 percent), 3mL of nitric acid (with the concentration of 68 percent), 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 of the mixture is subjected to ultrasonic treatment for 30min to prepare a corrosive liquid; then immersing the bracket into the corrosive liquid, locking the reaction kettle, placing the reaction kettle in an oven, setting the temperature to be 180 ℃, keeping the temperature for 60min, and taking out the reaction kettle; then ultrasonic cleaning is carried out by using deionized water, ethanol and acetone respectively;
(2) Preparing 10mg/mL rapamycin ethanol solution, fully soaking the stent at 5 ℃ for 20min, taking out and drying;
(3) Preparing 200g of a mixed solution of 5% of phosphatidylglycerol, 5% of DSPE-PEG and 25% of soybean lecithin, wherein the solvent is ethyl acetate; and carrying out ultrasonic spraying (the spraying power is 15W, the frequency is 130kHz, and 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 occurrence test of restenosis
Test samples: the drug eluting stents provided in examples 1-13, the drug eluting stents provided in comparative examples 1-2;
the test method comprises the following steps: the experiment selects 35kg of healthy common white pigs and male pigs as test pigs, intramuscular injection induction anesthesia is performed before operation, inhalation anesthesia is performed after anesthesia induction is successful, and then tracheal intubation and ear edge venipuncture are performed to establish a respiratory pathway and a vein pathway. After the animal is moved into an operating table, the area near femoral artery puncture positions on two sides is disinfected, the femoral artery puncture is carried out, a vascular sheath is inserted, and an artery passage is established. Injecting low molecular heparin intravenously to heparinize the experimental animal, inserting a contrast catheter for radiography, and implanting different stents. After the animal is normally fed for 2 weeks after operation, taking a blood vessel of a transplant section, respectively extracting RNA, carrying out dot hybridization detection on transfection expression conditions and carrying out pathological morphology analysis, and determining the degree of intimal hyperplasia;
the specific test results are shown in table 1 below:
TABLE 1
As shown in Table 2, the loss rate of the matrix lumen of the stent prepared by the invention is below 4%; the medicine is loaded in the micropore holes on the surface of the stent matrix, the micropores are sealed by the hydrogel, the medicine eluting stent has no risk of coating falling off, and the occurrence probability of restenosis is reduced.
Test example 2
Burst release test
Test samples: 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 test 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 disodium hydrogen orthophosphate, 1.36g potassium hydrogen orthophosphate, and 7.02g sodium chloride in 1000mL HPLC grade water. The solution is kept for 10min in an ultrasonic cleaning machine for dissolution;
(2) The peristaltic pump and the silicone tube are used for simulating arterial blood flow, the diameter of a target blood vessel is 3mm, the constant temperature is set at 37 ℃, and the rotating speed of the peristaltic pump is corrected at the flow rate of 200 mL/min. And expanding the stent to the inner wall of the silicone tube, starting a peristaltic pump, and extracting 10mL of eluent at 1d, 15d and 30d respectively.
(3) And adding methanol into the extracted eluent to a constant volume of 50mL, and quantitatively detecting the content by liquid chromatography. Measuring the content of the medicine by liquid chromatography: selecting an instrument: liquid chromatograph agilent 1260 definition; a chromatographic column: c18, 4.6X 500,5 μm; the working parameters of the instrument are as follows: detection wavelength: rapamycin drug 278nm, column temperature: 50 ℃, sample introduction: 10 μ L, 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 micropores on the surface of the stent matrix, the micropores are sealed by hydrogel, the drug eluting stent has no risk of coating falling off, the hydrogel is used for sealing, 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 present invention is illustrated by the above examples to the drug eluting stent and its preparation method and application, but the present invention is not limited to the above process steps, i.e. it is not meant to imply that the present invention must rely on the above process steps to be carried out. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.
Claims (10)
1. A drug eluting stent, comprising a stent matrix, a drug, and a hydrogel; wherein, the surface of the stent matrix has micro-pores, and the drug is loaded in the micro-pores and sealed by hydrogel.
2. The drug-eluting stent of claim 1, wherein the micro-cavities are spherical, the diameter of the micro-cavities being 0.2-1 μm;
preferably, the distribution density of the surface micro-pores of the bracket substrate is 4-8 ten thousand/mm 2 。
3. A drug eluting stent according to claim 1 or 2, 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 hcl, hirudin, argatroban, dipyridamole, prostacyclin analogue, nitroglycerin, nitroprusside, suramin, endostatin, serotonin blockers, steroids or oligopeptides.
4. A drug eluting stent according to any of claims 1-3, wherein 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 47000-98000;
preferably, the number average molecular weight of the polyvinylpyrrolidone is 8000-1300000;
preferably, the molecular weight of the hyaluronic acid is 400000-2500000;
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 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) to (2-4);
preferably, the hydrogel is a combination of chitosan, sodium alginate and polyvinylpyrrolidone, and the mass ratio of the chitosan to the sodium alginate to the polyvinylpyrrolidone is 1 (0.5-2) to (4-6);
preferably, the hydrogel is a combination of gelatin and hyaluronic acid, and the mass ratio of the gelatin to the hyaluronic acid is (5-20): 1.
5. A drug eluting stent according to any one of claims 1 to 4, wherein the drug eluting stent has a drug loading density of 1 to 5 μ g/mm 2 。
6. A method of manufacturing a drug eluting stent as defined in any of claims 1-5, comprising the steps of:
(1) Carrying out chemical corrosion treatment on the surface of the bracket substrate to form a micropore on the surface of the bracket substrate;
(2) Dipping the stent matrix treated in the step (1) in a drug solution to load drugs in the micropore;
(3) And (3) sealing the stent matrix treated in the step (2) with hydrogel to obtain the drug eluting stent.
7. The method for preparing a drug eluting stent according to claim 6, wherein in the step (1), the chemical etching treatment comprises the steps of: placing the support matrix and the corrosive liquid in a reaction kettle, and reacting under the conditions of high temperature and high pressure;
preferably, the etching solution comprises an etchant, a surfactant and a solvent;
preferably, the corrosion solution consists of the following components in percentage by weight based on 100% of the total mass of the corrosion solution: 0.5-10% of corrosive agent, 0.1-5% of surfactant and the balance of solvent;
preferably, the corrosive agent 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 hydrogen nitrate;
preferably, the surfactant is selected from any one of or a combination of at least two of diisooctyl sulfosuccinate, sodium dodecyl benzene sulfonate, cetyl trimethyl ammonium bromide or triethanolamine;
preferably, the solvent is selected from any one of or a combination of at least two of a PBS solvent, a TES buffer, acetone, diethyl ether, isopropanol, n-pentane, cyclopentane, decane, octadecane or polyethylene glycol;
preferably, the reaction temperature is 110-250 ℃, and the reaction time is 60-120min.
8. The method for preparing a drug-eluting stent according to claim 6 or 7, wherein in the step (2), the solvent of the drug solution is selected from any one of methanol, ethanol or dichloromethane or a combination of at least two thereof;
preferably, in the step (2), the concentration of the medicine solution is 10-50mg/mL;
preferably, in the step (2), the temperature of the impregnation is 0-20 ℃, and the time of the impregnation is 30-120min.
9. The method for preparing a drug eluting stent according to any one of claims 6 to 8, wherein in the step (3), the step of sealing the pores is: ultrasonically spraying the mixed solution of the hydrogel on the surface of the stent matrix, and then curing and drying to complete hole sealing to obtain the drug eluting stent;
or, the hole sealing step is as follows: firstly, dipping a stent matrix in a mixed solution of hydrogel, carrying out centrifugal treatment after lifting, and finally carrying out solidification and drying to complete hole sealing to obtain the drug eluting stent;
preferably, in the step (3), the solvent of the mixed solution of the hydrogel is water;
preferably, in the step (3), the solid content of the mixed solution of the hydrogel is 10-50wt%;
preferably, in the step (3), the power of the ultrasonic spraying is 3-15W, the frequency is 50-150kHz, and the speed is 0.01-2mL/min;
preferably, in the step (3), the dipping temperature is 20-40 ℃, and the dipping time is 0.5-10min;
preferably, in the step (3), the rotation speed of the centrifugal treatment is 100-1000r/min;
preferably, in the step (3), the curing is ultraviolet curing, the wavelength of the ultraviolet curing is 300-380nm, and the time of the ultraviolet curing is 20-40min.
10. Use of a drug eluting stent according to any of claims 1-5 in the manufacture of a product for the treatment of atherosclerosis.
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