CN1628863A - A kind of preparation method of cardiovascular stent polymer drug-loaded coating - Google Patents

Abstract

The invention discloses a method for preparing a drug-loaded coating of a cardiovascular stent polymer, which belongs to the technical field of in vivo drug delivery and medical devices. A self-assembled monomolecular layer method is used to prepare an intermediate layer that forms a chemical bond with the metal and the polymer respectively between the surface of the metal stent and the polymer drug carrier coating, so as to improve the adhesion of the polymer coating. The preparation method of the stent is as follows: the surface of the metal stent is subjected to surface chemical oxidation treatment, and then the surface is coated with a methacrylate crosslinking agent and subjected to photocuring treatment, and then the stent is immersed in a mixed solution of a polymer carrier and a drug, After taking it out, it is vacuum-dried to obtain the drug-loaded coated cardiovascular stent of the present invention. The drug-loaded coating of the cardiovascular stent polymer of the present invention has strong adhesion on the surface of the metal stent, and can prevent the stent coating from falling off during disinfection, surgical delivery and blood flushing after implantation. It is suitable for the treatment process of coronary artery stent expansion for cardiovascular diseases.

Description

A kind of preparation method of cardiovascular stent polymer drug-loaded coating

technical field

The invention belongs to the technical field of in vivo drug delivery method and medical equipment. It relates to a preparation method of a polymer drug-loaded coating for a coronary stent, especially involves preparing an intermediate layer between the metal stent surface and the polylactic acid drug-loaded coating by self-assembled monolayer technology, so as to improve the adhesion between the polylactic acid coating and the metal surface. Adhesion to avoid peeling off of the coating.

Background technique

Coronary heart disease is a common disease that seriously threatens human life and health. At present, coronary artery stent implantation has become a common method widely used in the treatment of coronary heart disease. However, the biggest defect of this technology is the problem of in-stent restenosis, which limits its curative effect, resulting in 20-30% of patients with postoperative in-stent restenosis. Among the many methods for preventing restenosis, drug-coated stents have become the current The internationally recognized method of choice can reduce the rate of restenosis to less than 10%.

The current commonly used drug-coated stent preparation method is to make a mixed solution of polymers, mostly polylactic acid and its copolymers, and drugs that inhibit restenosis, and apply it to the surface of the metal stent. After the solvent dries, it will form on the surface of the stent. A polymer drug coating. However, since the polymer coating cannot form a chemical bond with the metal surface, the coated stent is easy to fall off during disinfection, surgical delivery, and blood washing after implantation, which affects the therapeutic effect.

Contents of the invention

The purpose of the present invention is to provide a method for preparing a cardiovascular stent polymer drug-loaded coating with coating adhesion that can meet the requirements for use of the stent. Prepare between the metal surface and the polymer coating by the self-assembled monolayer technology with an intermediate layer, which can form a chemical bond with the metal surface and the polymer coating. The purpose of the invention is to overcome the relationship between the polymer coating and the polymer coating. Weak point of poor adhesion between metal surfaces.

The technical idea of the present invention is that the intermediate layer proposed by the present invention is formed by cross-linking three components: (methacryloyloxyalkyl) phosphate, glyceryl trimethacrylate and aminoalkylmethacrylamide. Among them, glyceryl trimethacrylate is mixed with a small amount of photoinitiator to form a crosslinking agent, and the crosslinking is carried out by photocuring. Their chemical formulas are as follows:

(methacryloyloxyalkyl) phosphate

n=2-16; R=H or _CH2 =C( _CH3 )COO(CH) _nO-

Aminoalkylmethacrylamide

n=2-16

Glyceryl trimethacrylate

The drug-loaded coated cardiovascular stent of the invention is composed of a metal stent, an intermediate layer and a polymer drug coating. Said metal stent refers to various metal stents currently used in medicine, including stainless steel, nickel-titanium, and cobalt alloy stents. The biodegradable drug coating carrier is homopolymer or copolymer of glycolide, L-lactide, butyrolactone and ε-caprolactone.

Technical solution of the present invention comprises the following steps:

(1) Metal bracket cleaning, the process is ultrasonic oscillation in acetone solution for 2-5 minutes, then ultrasonic oscillation in absolute ethanol solution for 2-5 minutes, then take out and dry naturally;

(2) Carry out chemical oxidation treatment on the surface of the stent, the formula of the oxidation solution is NaOH 600-700g/L, NaNO ₂ 200-250g/L, K ₂ Cr ₂ O ₇ 25-35g/L, the solvent is water, the oxidation temperature 130°C, oxidation time 15 minutes;

(3) cleaning the bracket, the process is ultrasonic oscillation in deionized water for 2-5 minutes, then ultrasonic oscillation in absolute ethanol solution for 2-5 minutes, and then take out and dry naturally;

(4) the chloroform solution of phosphate (methacryloyloxyalkyl) ester is coated on the surface of the support and dried; the crosslinking agent is coated on the surface, and the crosslinking agent composition includes trimethacrylate triglyceride, photoinitiator and chloroform, and then the surface is light-cured;

(5) When the crosslinking agent hardens, the chloroform solution of the crosslinking agent and aminoalkylmethacrylamide is coated sequentially thereon, and photocured again, so far the intermediate layer is prepared;

(6) Immerse the stent in the polymer drug solution for 1-2 minutes, which solution includes polymer carrier, anti-proliferative drug, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and organic solvents. Said polymer carrier comprises homopolymer or copolymer of glycolide, L-lactide, butyrolactone or ε-caprolactone; said organic solvent comprises tetrahydrofuran, acetone, chloroform or dichloromethane, Said anti-proliferation drugs are drugs with the function of inhibiting restenosis.

(7) Take out the support until the surface of the support is dry, then place it in a vacuum drying oven to dry for 48 hours, the temperature is room temperature, and the pressure is 2-14pa, and finally the finished product is obtained.

According to the above-mentioned technical scheme, the present invention coats a layer of polymer drug coating on the surface of the stent, and prepares an intermediate layer between the metal stent and the polymer drug coating to form chemical bonds with the metal and the polymer respectively to enhance Adhesion between polymer coatings and metal substrates. The interlayer reacts chemically with metals and polymers as follows:

When (methacryloyloxyalkyl) phosphates come into contact with the oxide layer on the metal surface, chemisorption occurs, forming a self-assembled monolayer on the metal surface. The products of spontaneous adsorption are as follows:

After the (methacryloyloxyalkyl) phosphate solution is volatilized, the crosslinking agent and the aminoalkylmethacrylamide solution are applied and cured by light, and the following structure will be formed. So far, the intermediate layer is prepared.

When the surface of the stent is hardened, the surface is coated with PLGA solution. Under the catalysis of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, PLGA can react with the middle layer to form chemical bonds. as follows:

The beneficial effect of the invention is that the drug-loaded coating of the cardiovascular stent polymer has strong adhesion on the surface of the metal stent, and can prevent the stent coating from falling off during disinfection, surgical delivery and blood flushing after implantation.

Description of drawings

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

Fig. 1 is the state diagram of the surface coating after the drug stent of the present invention is manufactured.

Fig. 2 is a partially enlarged view of the drug-coated stent of the present invention.

Fig. 3 is a physical photo of the polymer drug-coated stent of the present invention.

In the figure, 1. stent matrix, 2. intermediate layer, 3. polymer drug-loaded coating.

Detailed ways

The coating preparation process is divided into two steps: the first step: the preparation of the intermediate layer; the second step: the preparation of the polymer drug coating. The specific implementation method is as follows.

Embodiment one:

The first step: the preparation of the middle layer

The surface of the 316L stainless steel stent that has undergone chemical oxidation treatment is coated with a chloroform solution of (methacryloyloxyethyl) phosphate, then dried, and then coated with a crosslinking agent, followed by photocuring treatment. Then, a cross-linking agent and a chloroform solution of aminoethylmethacrylamide are sequentially coated on it, and then photocured for use.

Step 2: Preparation of polymer drug coating

After dissolving 0.1g of poly(lactide-glycolide), wherein lactide/glycolide=80/20 (mol/mol), in 9.9g of chloroform, add 10mg of rapamycin and 0.1g N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide was fully dissolved, and a 316L stainless steel bracket was immersed in it, and then the bracket was dried at room temperature. This coating process was repeated twice, and then the stent was vacuum desolvated at room temperature for 48 hours to obtain a polymer drug coating with a rapamycin content of 40 μg on the surface of the stent.

Embodiment two

The first step: the preparation of the middle layer

The surface of the 316L stainless steel stent that has undergone chemical oxidation treatment is coated with a chloroform solution of (methacryloxybutyl) phosphate, then dried, and then coated with a cross-linking agent for photocuring treatment. Afterwards, a cross-linking agent and a chloroform solution of aminopropyl methacrylamide are sequentially coated thereon, and then photocured again for use.

Step 2: Preparation of polymer drug coating

After dissolving 0.2g poly(lactide-glycolide), wherein lactide/glycolide=70/30 (mol/mol), in 9.8g chloroform, add 40mg rapamycin and 0.2g N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide was fully dissolved, and a 316L stainless steel bracket was immersed in it, and then the bracket was dried at room temperature. This coating process was repeated twice, and finally the stent was vacuum desolvated at room temperature for 48 hours to obtain a polymer drug coating with a rapamycin content of 100 μg on the surface of the stent.

Embodiment Three

The first step: the preparation of the middle layer

The surface of the 316L stainless steel stent that has undergone chemical oxidation treatment is coated with a chloroform solution of (methacryloyloxydecyl) phosphate, then dried, and then coated with a crosslinking agent for photocuring. Afterwards, a chloroform solution of a cross-linking agent and aminopentylmethacrylamide is coated sequentially thereon, and then photocured again.

Step 2: Preparation of polymer drug coating

With 0.3g poly(lactide-glycolide), wherein lactide/glycolide=50/50 (mol/mol), after it is dissolved in 9.7g chloroform, add 15mg rapamycin and 0.3g N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, after fully dissolving, and immerse the 316L stainless steel stent prepared with an intermediate layer in it, take out the stent and place it at room temperature dry. This coating process was repeated twice, and then the solvent was removed under vacuum at room temperature for 48 hours to obtain a polymer drug coating with a rapamycin content of 65 μg on the surface of the stent.

Embodiment four

The first step: the preparation of the middle layer

The surface of the 316L stainless steel stent that has undergone chemical oxidation treatment is coated with a chloroform solution of (methacryloyloxydodecyl) phosphate, then dried, and then coated with a cross-linking agent, and then subjected to photocuring treatment. Afterwards, a chloroform solution of a cross-linking agent and aminodecylmethacrylamide is sequentially coated on it, and then photocured again.

Step 2: Preparation of polymer drug coating

Dissolve 0.2g of poly(lactide-glycolide-butyrolactone), where lactide/glycolide/butyrolactone=50/40/10 (mol/mol/mol), into 9.8g After tetrahydrofuran, add 20mg of paclitaxel and 0.2g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, after fully dissolving, immerse the 316L stainless steel bracket prepared with the middle layer in it, Take it out and dry it at room temperature. This coating process was repeated twice, and then the scaffold was vacuum desolvated at room temperature for 48 hours, and the content of paclitaxel on the surface of the scaffold was 85 μg.

Embodiment five

The first step: the preparation of the middle layer

The surface of the 316L stainless steel stent that has undergone chemical oxidation treatment is coated with a chloroform solution of (methacryloyloxypentadecyl) phosphate, then dried, and then coated with a crosslinking agent for photocuring. Afterwards, a cross-linking agent and a chloroform solution of aminododecylmethacrylamide are sequentially coated on it, and then photocured again.

Step 2: Preparation of polymer drug coating

Dissolve 0.3g of poly(lactide-glycolide-caprolactone), where lactide/glycolide/caprolactone=50/40/10 (mol/mol/mol), into 9.7g After tetrahydrofuran, add 60mg rapamycin and 0.3g N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, after fully dissolving, immerse the 316L stainless steel bracket with the intermediate layer In it, it was taken out and dried at room temperature. This coating process was repeated twice, and then the solvent was desolvated in vacuum at room temperature for 48 hours, and the content of rapamycin on the surface of the stent was 120 μg.

Embodiment six

The first step: the preparation of the middle layer

The surface of the 316L stainless steel stent that has undergone chemical oxidation treatment is coated with a chloroform solution of (methacryloyloxyhexadecyl) phosphate, then dried, and then coated with a crosslinking agent for photocuring. Thereafter, a cross-linking agent and a chloroform solution of hexadecylmethacrylamide were coated sequentially thereon, and then photocured again.

Step 2: Preparation of polymer drug coating

After dissolving 0.3g of poly(lactide-glycolide-caprolactone), where lactide/glycolide/caprolactone=60/30/10mol/mol/mol) in 9.7g of tetrahydrofuran , add 10mg rapamycin and 0.3g N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, after fully dissolved, immerse the 316L stainless steel bracket prepared with the middle layer in it , taken out and dried at room temperature, repeated three times, and then vacuum desolventized at room temperature for 48 hours, the content of rapamycin on the surface of the scaffold was 50 μg.

Claims (5)

1. preparation of polymer drug-laden coating on cardiovascular stent, the drug-carried coat angiocarpy bracket is made up of metal rack, intermediate layer and the biodegradable polymers coating that coats anti-restenosis medicaments, it is characterized in that, preparation one deck intermediate layer between metal support surface and polymer drug carrier coating, the intermediate layer adopts the method for photocuring to be prepared, and preparation process is as follows:

(1) metal rack is carried out the surface chemistry oxidation processes;

(2) above-mentioned support is cleaned up, carry out the preparation in intermediate layer then, promptly on its surface-coated surface

The chloroformic solution of activating agent methacryloxypropyl alkyl phosphate also dries; Coat cross-linking agent on the surface then, the cross-linking agent main component comprises methacrylic acid glyceryl ester and light trigger, and surface light is solidified then;

(3) after the cross-linking agent sclerosis, apply the chloroformic solution of cross-linking agent and aminoalkyl methacrylic acid amide thereon successively, once more photocuring;

(4) mixed solution of prepared polymer and medicine, the concentration of polymer are 1-3wt%;

(5) support be impregnated in the polymer and medicament mixed solution in the requirement (4);

(6) support is lifted out and promptly obtains after at room temperature vacuum drying 24-48 hour drug-carried coat angiocarpy bracket of the present invention from solution.

2. a kind of preparation of polymer drug-laden coating on cardiovascular stent according to claim 1, it is characterized in that, the intermediate layer can be divided into three-decker, ground floor, methacryloxypropyl alkyl phosphate, contact with metallic matrix, can form chemical bond with the metal surface, the second layer is by the methacrylic acid glyceryl ester and light trigger constitutes and carry out the photocuring processing, and the 3rd layer is the aminoalkyl Methacrylamide, it and polymer support form chemical bond, strengthen adhesion.

3. a kind of preparation of polymer drug-laden coating on cardiovascular stent according to claim 1 is characterized in that, metal rack comprises rustless steel, NiTi or the cobalt alloy support that medically uses at present.

4. a kind of preparation of polymer drug-laden coating on cardiovascular stent according to claim 1 is characterized in that, the main component in intermediate layer is methacryloxypropyl alkyl phosphate, methacrylic acid glyceryl ester and aminoalkyl Methacrylamide and light trigger.

5. a kind of preparation of polymer drug-laden coating on cardiovascular stent according to claim 1 is characterized in that, biodegradable coating comprises the homopolymer or the copolymer of Acetic acid, hydroxy-, bimol. cyclic ester, L-lactide, butyrolactone or 6-caprolactone.

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