A coating for a drug-eluting stent and its preparation method

Abstract

The present invention discloses a coating for a drug-eluting stent, which comprises a phase A and a phase B; the raw materials of the phase A include: carboxymethyl chitosan, ginkgo flavonoids, resveratrol, vascular endothelial growth factor, rapamycin, PEG-30 dimeric hydroxystearate, glycerol, silicone oil, and an aqueous acetic acid solution with a mass fraction of 0.1-0.5%; the raw materials of the phase B include: polylactic acid, polyethylene glycol, and dichloromethane. The coating for a drug-eluting stent proposed by the present invention not only has a good coating effect on drugs, but also can realize the continuous and slow release of the coated drugs from the surface of the stent, which not only restricts the proliferation of local vascular intimal cells, but also reduces the proliferation-promoting factors such as inflammatory reactions, thereby further enhancing the restriction effect on restenosis and improving the clinical practicability.

Description

Technical Field

[0001] The present invention relates to the technical field of drug-eluting stents, and particularly to a coating for a drug-eluting stent, a preparation method thereof, a drug-eluting stent, and a preparation method thereof. Background Art

[0002] In recent years, atherosclerosis has become the number one killer of human health. Percutaneous transluminal angioplasty (PTA for short) refers to inserting a balloon catheter with a constricted stent into a human blood vessel under the guidance of a medical imaging device using a puncture needle, a guide wire, and a guiding sheath, and delivering it to the vascular stenosis. As the balloon expands, the stent is also expanded. After the balloon contracts and retracts, the plastically deformed metal stent remains in place and is embedded in the blood vessel, playing a role in dilating the blood vessel. Currently, with the popularization and application of PTA, vascular stents have developed rapidly. According to statistics, currently more than 80% of cardiovascular and peripheral obstructive diseases are treated by this method.

[0003] Vascular restenosis after stent intervention is the main factor restricting the further application of PTA. From the current statistical figures, the incidence of restenosis after stent intervention is about 25%. The main reasons for in-stent restenosis are that after the stent is implanted into the diseased blood vessel, it will cause varying degrees of mechanical damage to the intima. When the body actively repairs the damaged part, a new intimal layer covers the surface of the stent, and it is mostly an over-repair process, that is, excessive hyperplasia, which ultimately leads to excessive hyperplasia of the peripheral vascular intima and then in-stent restenosis. Currently, there are various drugs that can significantly inhibit vascular intima and smooth muscle cells in vitro, but systemic drug administration has poor effects.

[0004] Using drug-eluting stents to prevent the occurrence of restenosis has achieved obvious curative effects. A drug-eluting stent generally consists of a stent and a drug-loaded coating on its surface. By carrying drugs with the stent, local release of the drugs at the lesion site can be obtained, so as to effectively inhibit the occurrence of vascular restenosis under the condition of high local tissue concentration and low systemic concentration.

[0005] With the wide application of the drug sustained-release stent system and the continuous development of new technologies, peripheral drug-eluting stents are now selected instead of bare metal stents in peripheral vascular interventional therapy. The existing preparation methods of drug-eluting vascular stents are all to dissolve polymers, drugs, and solvents together to form a coating solution, and then coat this solution on the surface of the vascular stent. After evaporating the solvent, a polymer layer containing drugs is formed on the surface of the vascular stent. However, the current peripheral drug-eluting stents have poor sustained-release effects. A serious deficiency in drug release is that the drug release amount reaches about 70% within 24 hours after stent implantation, and the effective drug concentration is significantly insufficient during the subsequent release period, seriously affecting the curative effect of peripheral drug-eluting stents. Summary of the Invention

[0006] The object of the present invention is to solve the drawbacks existing in the prior art, and to propose a coating for a drug-eluting stent and its preparation method, and a drug-eluting stent and its preparation method.

[0007] A coating for a drug-eluting stent comprises a phase A and a phase B.

[0008] The raw materials of phase A include: carboxymethyl chitosan, ginkgo flavonoids, resveratrol, vascular endothelial growth factor, rapamycin, PEG-30 dimer hydroxystearate, glycerol, silicone oil, and an aqueous acetic acid solution with a mass fraction of 0.1-0.5%; the mass ratio of carboxymethyl chitosan, ginkgo flavonoids, resveratrol, vascular endothelial growth factor, rapamycin, PEG-30 dimer hydroxystearate, glycerol, silicone oil, and an aqueous acetic acid solution with a mass fraction of 0.1-0.5% is 10-20:1-2:1-2:0.1-1:0.1-1:1-2:6-8:10-20:50-100.

[0009] The raw materials of phase B include: polylactic acid, polyethylene glycol, dichloromethane; the mass ratio of polylactic acid, polyethylene glycol, and dichloromethane is 10-20:1-5:20-40.

[0010] Preferably, the molecular weight of carboxymethyl chitosan is 5000-35000, and the degree of substitution is 1.1-1.5.

[0011] The preparation method of the above coating for a drug-eluting stent comprises the following steps:

[0012] S1. Add ginkgo flavonoids and resveratrol to glycerol and mix evenly to obtain a prefabricated material a;

[0013] S2. Add carboxymethyl chitosan and vascular endothelial growth factor to the aqueous acetic acid solution and mix evenly, and ultrasonically remove bubbles to obtain a prefabricated material b;

[0014] S3. Mix rapamycin, PEG-30 dimer hydroxystearate, and silicone oil evenly to obtain a prefabricated material c;

[0015] S4. Drop the prefabricated material a into the prefabricated material c for primary homogenization treatment, and then drop the product into the prefabricated material b for secondary homogenization treatment to obtain phase A;

[0016] S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain phase B.

[0017] Preferably, in S4, the primary homogenization treatment time is 2-10 min, and the homogenization speed is 10000-12000 r / min; the secondary homogenization treatment time is 1-5 min, and the homogenization speed is 10000-12000 r / min.

[0018] This application uses the compound of ginkgo flavonoids, resveratrol and rapamycin, which can not only effectively limit the proliferation of local vascular intimal cells, reduce the inflammatory reaction, and further enhance the restriction effect on restenosis.

[0019] However, ginkgo flavonoids and resveratrol are poorly soluble in water and oil, while rapamycin is lipophilic. Therefore, in this application, ginkgo flavonoids and resveratrol are dispersed in glycerol to obtain prefabricated material a, and then prefabricated material c is used to coat prefabricated material a, which can effectively protect ginkgo flavonoids and resveratrol, and the stability of ginkgo flavonoids and resveratrol is good. Rapamycin is added to prefabricated material c and coated on the surface of prefabricated material a, which can achieve different release rates of rapamycin, ginkgo flavonoids and resveratrol. Since rapamycin, as an immunosuppressant, can damage cells and affect endothelial healing, in this application, rapamycin is further dispersed in silicone oil and then coated with vascular endothelial growth factor on the outer layer, which can not only achieve the purpose of high efficiency and safety of local use of rapamycin, but also has excellent anti-acute thrombosis and restenosis effects.

[0020] The drug-eluting stent of the present invention achieves multiple sustained-release effects, which not only prolongs the action time and effect of the active ingredient, but also reduces the irritation of the active ingredient to the blood vessel. At the same time, its drug-controlled release law is adapted to the intimal hyperplasia time window, which can excellently inhibit intimal hyperplasia and achieve the purpose of preventing in-stent restenosis.

[0021] A preparation method of a drug-eluting stent comprises the following steps:

[0022] (1) Add microcrystalline cellulose and corn starch into an ethanol aqueous solution, and stir at 50-60 °C to obtain a stent treatment solution;

[0023] (2) Immerse the vascular stent in the stent treatment solution for 10-20 min, dry at room temperature, keep it at 250-300 °C in a nitrogen atmosphere for 10-30 min, and cool to obtain a pretreated stent;

[0024] (3) Spray the A phase of the coating for the above drug-eluting stent on the pretreated stent, vacuum dry for 20-40 min, and then continue to spray the B phase of the coating for the above drug-eluting stent, and vacuum dry for 20-40 min.

[0025] Preferably, in step (1), the particle size of the microcrystalline cellulose is 50-100 μm, and the limiting degree of polymerization is 100-250; the mass ratio of the microcrystalline cellulose, corn starch and ethanol aqueous solution is 2-10:1-5:20-40, and the concentration of the ethanol aqueous solution is 0.5-1.2 mol / L.

[0026] Preferably, in step (1), stir until the viscosity is 800-1000 cP.

[0027] Preferably, in step (3), an ultrasonic atomization device is used for spraying, the ultrasonic power is 4-10 W, and the spraying cycle times are 2-4 times.

[0028] Preferably, in step (3), the vacuum drying temperature is 40-60 °C and the vacuum degree is 50-70 kPa.

[0029] A drug-eluting stent is prepared by using the preparation method of the above drug-eluting stent.

[0030] In this application, microcrystalline cellulose and corn starch are compounded. The microcrystalline cellulose is in the form of short rod-shaped or powdery porous particles. The corn starch swells in an ethanol aqueous solution and coats the surface of the microcrystalline cellulose. After gelatinization treatment, a stent treatment solution is formed. The vascular stent is immersed in the stent treatment solution. The stent treatment solution is not only safe and non-toxic, but also has excellent adhesion and coating properties, with a high adhesion strength on the vascular stent. After calcination, the porous microcrystalline cellulose is interconnected to form a three-dimensional carbon fiber skeleton, and the swollen corn starch forms a thin porous membrane structure after carbonization to bridge the three-dimensional carbon fiber structure. Then, phase A is sprayed thereon, and the accommodation effect on phase A is good. Then, phase B is sprayed. The carboxymethyl chitosan in phase A combines with polyethylene glycol in phase B, and the combination strength of the two is high, which can effectively protect the inner layer of phase A and further prevent phenomena such as the shedding of the structure of phase A, with extremely high stability.

[0031] The present invention not only roughens the surface of the stent, increases the firm combination of the coating and the surface of the vascular stent and is not easy to fall off, but also has a three-dimensional cavity structure after the roughening treatment, has a good coating effect on drugs, can realize the continuous and slow release of the coated drugs from the surface of the stent, not only restricts the proliferation of local vascular intimal cells, but also reduces hyperplasia-promoting factors such as inflammatory reactions, thereby further enhancing the restrictive effect on restenosis and improving clinical practicability. Description of the Drawings

[0032] Figure 1 It is a comparison chart of the cytotoxicity of the drug-eluting stents obtained in Example 5 and Comparative Examples 1-3.

[0033] Figure 2 It is a comparison chart of the sustained release performance curves of the drug-eluting stents obtained in Example 5 and Comparative Examples 1-3. Detailed Embodiments

[0034] The present invention will be further explained below with reference to specific embodiments.

[0035] Example 1

[0036] A coating for a drug-eluting stent includes phase A and phase B.

[0037] The raw materials of Phase A include: 10 kg of carboxymethyl chitosan, 1 kg of ginkgo flavone, 1 kg of resveratrol, 0.1 kg of vascular endothelial growth factor, 0.1 kg of rapamycin, 1 kg of PEG-30 dimer hydroxystearate, 6 kg of glycerol, 10 kg of silicone oil, and 50 kg of acetic acid aqueous solution with a mass fraction of 0.1%.

[0038] The raw materials of Phase B include: 10 kg of polylactic acid, 1 kg of polyethylene glycol, and 20 kg of dichloromethane.

[0039] The preparation method of the coating for the drug-eluting stent includes the following steps:

[0040] S1. Add ginkgo flavone and resveratrol to glycerol and mix evenly to obtain prefabricated material a;

[0041] S2. Add carboxymethyl chitosan and vascular endothelial growth factor to the acetic acid aqueous solution, mix evenly, and remove bubbles by ultrasonic treatment to obtain prefabricated material b;

[0042] S3. Mix rapamycin, PEG-30 dimer hydroxystearate, and silicone oil evenly to obtain prefabricated material c;

[0043] S4. Drop prefabricated material a into prefabricated material c and perform primary homogenization treatment for 2 min at a homogenization speed of 10,000 r / min, and then drop the product into prefabricated material b for secondary homogenization treatment for 1 min at a homogenization speed of 10,000 r / min to obtain Phase A;

[0044] S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain Phase B.

[0045] A preparation method of a drug-eluting stent includes the following steps:

[0046] (1) Add 2 kg of microcrystalline cellulose and 1 kg of corn starch to 20 kg of ethanol solution with a concentration of 0.5 mol / L, stir at 50 °C until the viscosity reaches 800 cP, and the stirring speed is 1000 r / min to obtain a stent treatment solution;

[0047] (2) Immerse the vascular stent in the stent treatment solution for 10 min, dry at room temperature, add it to a calcination furnace, keep it at 250 °C for 10 min in a nitrogen atmosphere, and cool to obtain a pretreated stent;

[0048] (3) Spray the A phase of the coating for drug-eluting stent on the pretreated stent using an ultrasonic atomization device with an ultrasonic power of 4 W and a spraying cycle of 2 times; place it in a vacuum drying oven for drying for 20 min at a drying temperature of 40 °C and a vacuum degree of 50 kPa; continue to spray the B phase of the coating for drug-eluting stent with a spraying cycle of 2 times, place it in a vacuum drying oven for drying for 20 min at a drying temperature of 40 °C and a vacuum degree of 50 kPa.

[0049] Example 2

[0050] A coating for drug-eluting stent, comprising a phase A and a phase B.

[0051] The raw materials of phase A include: 20 kg of carboxymethyl chitosan, 2 kg of ginkgo flavone, 2 kg of resveratrol, 1 kg of vascular endothelial growth factor, 1 kg of rapamycin, 2 kg of PEG-30 dimeric hydroxystearate, 8 kg of glycerol, 20 kg of silicone oil, and 100 kg of acetic acid aqueous solution with a mass fraction of 0.5%.

[0052] The raw materials of phase B include: 20 kg of polylactic acid, 5 kg of polyethylene glycol, and 40 kg of dichloromethane.

[0053] The preparation method of the above coating for drug-eluting stent comprises the following steps:

[0054] S1. Add ginkgo flavone and resveratrol to glycerol and mix evenly to obtain a prefabricated material a;

[0055] S2. Add carboxymethyl chitosan and vascular endothelial growth factor to the acetic acid aqueous solution and mix evenly, and remove bubbles by ultrasonic to obtain a prefabricated material b;

[0056] S3. Mix rapamycin, PEG-30 dimeric hydroxystearate and silicone oil evenly to obtain a prefabricated material c;

[0057] S4. Drop the prefabricated material a into the prefabricated material c and perform primary homogenization for 10 min at a homogenization speed of 12,000 r / min, then drop the product into the prefabricated material b for secondary homogenization for 5 min at a homogenization speed of 12,000 r / min to obtain phase A;

[0058] S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain phase B.

[0059] A preparation method of a drug-eluting stent comprises the following steps:

[0060] (1) Add 10 kg of microcrystalline cellulose and 5 kg of corn starch to 40 kg of ethanol solution with a concentration of 1.2 mol / L, stir at 60 °C until the viscosity reaches 1000 cP, and the stirring speed is 1500 r / min to obtain a stent treatment solution;

[0061] (2) Immerse the vascular stent in the stent treatment solution for 20 min, dry it at room temperature, add it to a calcination furnace, keep it at 300 °C for 30 min in a nitrogen atmosphere, and cool to obtain a pretreated stent;

[0062] (3) Use the A phase of the coating for the drug-eluting stent to spray the pretreated stent with an ultrasonic atomization device, with an ultrasonic power of 10 W and a spraying cycle number of 4 times; place it in a vacuum drying oven to dry for 40 min, with a drying temperature of 60 °C and a vacuum degree of 70 kPa; continue to spray the B phase of the coating for the drug-eluting stent, with a spraying cycle number of 4 times, place it in a vacuum drying oven to dry for 40 min, with a drying temperature of 60 °C and a vacuum degree of 70 kPa.

[0063] Example 3

[0064] A coating for a drug-eluting stent, comprising a phase A and a phase B.

[0065] The raw materials of phase A include: 12 kg of carboxymethyl chitosan, 1.8 kg of ginkgo flavone, 1.3 kg of resveratrol, 0.8 kg of vascular endothelial growth factor, 0.3 kg of rapamycin, 1.7 kg of PEG-30 dimeric hydroxystearate, 6.5 kg of glycerol, 17 kg of silicone oil, and 90 kg of acetic acid aqueous solution with a mass fraction of 0.2%.

[0066] The raw materials of phase B include: 12 kg of polylactic acid, 4 kg of polyethylene glycol, and 25 kg of dichloromethane.

[0067] The preparation method of the above coating for a drug-eluting stent includes the following steps:

[0068] S1. Add ginkgo flavone and resveratrol to glycerol and mix evenly to obtain a prefabricated material a;

[0069] S2. Add carboxymethyl chitosan and vascular endothelial growth factor to the acetic acid aqueous solution, mix evenly, and ultrasonically remove bubbles to obtain a prefabricated material b;

[0070] S3. Mix rapamycin, PEG-30 dimeric hydroxystearate and silicone oil evenly to obtain a prefabricated material c;

[0071] S4. Drop the prefabricated material a into the prefabricated material c and perform primary homogenization treatment for 8 min at a homogenization speed of 10500 r / min, then drop the product into the prefabricated material b for secondary homogenization treatment for 4 min at a homogenization speed of 10500 r / min to obtain phase A;

[0072] S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain phase B.

[0073] A preparation method of a drug-eluting stent includes the following steps:

[0074] (1) Add 8 kg of microcrystalline cellulose and 2 kg of corn starch to 35 kg of an ethanol solution with a concentration of 0.6 mol / L, stir at 57 °C until the viscosity reaches 850 cP, and the stirring speed is 1400 r / min to obtain a scaffold treatment solution;

[0075] (2) Immerse the vascular stent in the scaffold treatment solution for 13 min, dry at room temperature, add it to a calcination furnace, keep it at 280 °C for 15 min in a nitrogen atmosphere, and cool to obtain a pretreated stent;

[0076] (3) Spray the pretreated stent with the A phase of the coating for the drug-eluting stent using an ultrasonic atomization device, with an ultrasonic power of 8 W and the spraying cycle number of 3 times; place it in a vacuum drying oven and dry for 25 min, with a drying temperature of 55 °C and a vacuum degree of 55 kPa; continue to spray the B phase of the coating for the drug-eluting stent, with the spraying cycle number of 3 times, place it in a vacuum drying oven and dry for 35 min, with a drying temperature of 45 °C and a vacuum degree of 65 kPa.

[0077] Example 4

[0078] A coating for a drug-eluting stent, comprising a phase A and a phase B.

[0079] The raw materials of phase A include: 18 kg of carboxymethyl chitosan, 1.2 kg of ginkgo flavone, 1.7 kg of resveratrol, 0.2 kg of vascular endothelial growth factor, 0.7 kg of rapamycin, 1.3 kg of PEG-30 dimeric hydroxystearate, 7.5 kg of glycerol, 13 kg of silicone oil, and 70 kg of an aqueous acetic acid solution with a mass fraction of 0.4%.

[0080] The raw materials of phase B include: 18 kg of polylactic acid, 2 kg of polyethylene glycol, and 35 kg of dichloromethane.

[0081] The preparation method of the above coating for a drug-eluting stent comprises the following steps:

[0082] S1. Add ginkgo flavone and resveratrol to glycerol and mix evenly to obtain a prefabricated material a;

[0083] S2. Add carboxymethyl chitosan and vascular endothelial growth factor to the aqueous acetic acid solution and mix evenly, and ultrasonically remove bubbles to obtain a prefabricated material b;

[0084] S3. Mix rapamycin, PEG-30 dimeric hydroxystearate and silicone oil evenly to obtain a prefabricated material c;

[0085] S4. Add the prefabricated material a dropwise to the prefabricated material c for a single homogenization treatment for 4 min at a homogenization speed of 11,500 r / min, and then add the product dropwise to the prefabricated material b for a secondary homogenization treatment for 2 min at a homogenization speed of 11,500 r / min to obtain Phase A;

[0086] S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain Phase B.

[0087] A preparation method of a drug-eluting stent comprises the following steps:

[0088] (1) Add 4 kg of microcrystalline cellulose and 4 kg of corn starch to 25 kg of an ethanol solution with a concentration of 1 mol / L, stir at 53 °C until the viscosity reaches 950 cP at a stirring speed of 1,200 r / min to obtain a stent treatment solution;

[0089] (2) Immerse the vascular stent in the stent treatment solution for 17 min, dry at room temperature, add it to a calcination furnace, keep it at 260 °C for 25 min in a nitrogen atmosphere, and cool to obtain a pretreated stent;

[0090] (3) Spray the pretreated stent with Phase A of the coating for the drug-eluting stent using an ultrasonic atomization device with an ultrasonic power of 6 W and a spraying cycle number of 3 times; place it in a vacuum drying oven to dry for 35 min at a drying temperature of 45 °C and a vacuum degree of 65 kPa; continue to spray Phase B of the coating for the drug-eluting stent, with a spraying cycle number of 3 times, and place it in a vacuum drying oven to dry for 25 min at a drying temperature of 55 °C and a vacuum degree of 55 kPa.

[0091] Example 5

[0092] A coating for a drug-eluting stent comprises Phase A and Phase B.

[0093] The raw materials of Phase A include: 15 kg of carboxymethyl chitosan, 1.5 kg of ginkgo flavone, 1.5 kg of resveratrol, 0.5 kg of vascular endothelial growth factor, 0.5 kg of rapamycin, 1.5 kg of PEG-30 dimeric hydroxystearate, 7 kg of glycerol, 15 kg of silicone oil, and 80 kg of an aqueous acetic acid solution with a mass fraction of 0.3%.

[0094] The raw materials of Phase B include: 15 kg of polylactic acid, 3 kg of polyethylene glycol, and 30 kg of dichloromethane.

[0095] The preparation method of the above coating for a drug-eluting stent comprises the following steps:

[0096] S1. Add ginkgo flavone and resveratrol to glycerol and mix evenly to obtain prefabricated material a;

[0097] S2. Add carboxymethyl chitosan and vascular endothelial growth factor into an acetic acid aqueous solution, mix evenly, and remove air bubbles by ultrasonic treatment to obtain preform b;

[0098] S3. Mix rapamycin, PEG-30 dimer hydroxystearate and silicone oil evenly to obtain preform c;

[0099] S4. Drop preform a into preform c and perform primary homogenization treatment for 6 min at a homogenization speed of 11000 r / min, then drop the product into preform b and perform secondary homogenization treatment for 3 min at a homogenization speed of 11000 r / min to obtain phase A;

[0100] S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain phase B.

[0101] A preparation method of a drug-eluting stent, comprising the following steps:

[0102] (1) Add 6 kg of microcrystalline cellulose and 3 kg of corn starch into 30 kg of an ethanol solution with a concentration of 0.8 mol / L, stir at 55 °C until the viscosity reaches 900 cP, and the stirring speed is 1300 r / min to obtain a stent treatment solution;

[0103] (2) Immerse the vascular stent in the stent treatment solution for 15 min, dry at room temperature, add it into a calcination furnace, keep it at 270 °C for 20 min in a nitrogen atmosphere, and cool to obtain a pretreated stent;

[0104] (3) Spray the pretreated stent with phase A of the coating for the above drug-eluting stent using an ultrasonic atomization device, with an ultrasonic power of 7 W and a spraying cycle number of 3 times; place it in a vacuum drying oven and dry for 30 min, with a drying temperature of 50 °C and a vacuum degree of 60 kPa; continue to spray phase B of the coating for the above drug-eluting stent, with a spraying cycle number of 3 times, place it in a vacuum drying oven and dry for 30 min, with a drying temperature of 50 °C and a vacuum degree of 60 kPa.

[0105] Place the drug-eluting stent obtained in this example in a phosphate buffer solution at a temperature of 37 °C and pH = 7.4 for an in vitro degradation experiment. After 5 d, observe under a scanning electron microscope and find that the surface of the drug-eluting stent obtained in this example is rough, undergoes erosion degradation, the drug is released, but no shedding occurs.

[0106] Mouse endothelial cells were cultured in DMEM low-glucose medium (5.6 mmol / L), placed in an incubator at 37°C with 5% CO2, and cultured until most of the cells adhered and grew into a network. Then, they were digested with 0.25% trypsin and reserved. The above-mentioned mouse endothelial cells were continuously cultured in DMEM low-glucose medium until they adhered and grew to 60%. Then, the drug-eluting stent obtained in this example was added and cultured for another 7 days. Observation with an inverted microscope found that the endothelial cells adhered well and grew densely.

[0107] The above situation shows that the coating drug of the drug-eluting stent obtained in this example is slowly released, which can play a role in inhibiting the proliferation of endothelial cells, thereby reducing the occurrence of restenosis.

[0108] Comparative Example 1

[0109] A coating for a drug-eluting stent, comprising Phase A and Phase B.

[0110] The raw materials of Phase A include: 15 kg of carboxymethyl chitosan, 1.5 kg of ginkgo flavonoids, 1.5 kg of resveratrol, 0.5 kg of vascular endothelial growth factor, 7 kg of glycerol, and 80 kg of acetic acid aqueous solution with a mass fraction of 0.3%.

[0111] The raw materials of Phase B include: 15 kg of polylactic acid, 3 kg of polyethylene glycol, and 30 kg of dichloromethane.

[0112] The preparation method of the above coating for a drug-eluting stent includes the following steps:

[0113] S1. Add ginkgo flavonoids and resveratrol to glycerol and mix evenly to obtain prefabricated material a;

[0114] S2. Add carboxymethyl chitosan and vascular endothelial growth factor to the acetic acid aqueous solution, mix evenly, and remove air bubbles by ultrasonic treatment to obtain prefabricated material b;

[0115] S3. Drop prefabricated material a into prefabricated material b and perform homogenization treatment for 3 minutes at a homogenization speed of 11000 r / min to obtain Phase A;

[0116] S4. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain Phase B.

[0117] A preparation method of a drug-eluting stent includes the following steps:

[0118] (1) Add 6 kg of microcrystalline cellulose and 3 kg of corn starch to 30 kg of ethanol solution with a concentration of 0.8 mol / L, stir at 55°C until the viscosity reaches 900 cP, and the stirring speed is 1300 r / min to obtain a stent treatment solution;

[0119] (2) Immerse the vascular stent in the stent treatment solution for 15 min, dry it at room temperature, add it to a calcination furnace, keep it at 270 °C in a nitrogen atmosphere for 20 min of heat preservation calcination, and cool it to obtain a pretreated stent;

[0120] (3) Use the A phase of the coating for the drug-eluting stent to spray the pretreated stent with an ultrasonic atomization device, with an ultrasonic power of 7 W and a spraying cycle number of 3 times; put it into a vacuum drying oven to dry for 30 min, with a drying temperature of 50 °C and a vacuum degree of 60 kPa; continue to spray the B phase of the coating for the drug-eluting stent, with a spraying cycle number of 3 times, put it into a vacuum drying oven to dry for 30 min, with a drying temperature of 50 °C and a vacuum degree of 60 kPa.

[0121] Place the drug-eluting stent obtained in this comparative example in a phosphate buffer solution at a temperature of 37 °C and pH = 7.4 for an in vitro degradation experiment. After 5 days, observe it under a scanning electron microscope and find that the surface of the drug-eluting stent obtained in this comparative example is rough, undergoes erosion degradation, the drug is released, but no shedding occurs.

[0122] Culture mouse endothelial cells with DMEM low-glucose medium (5.6 mmol / L), place them in an incubator at 37 °C with 5% CO2 for culture. When most cells adhere and grow into a network, digest them with 0.25% trypsin and set aside. Take the above mouse endothelial cells and continue to culture them with DMEM low-glucose medium until they adhere and grow to 60%. Then add the drug-eluting stent obtained in this comparative example and continue to culture for 7 d. Observe with an inverted microscope and find that: endothelial cell islands appear, the density increases, and the growth condition is good.

[0123] The above situation shows that the coating drug of the drug-eluting stent obtained in this comparative example can be slowly released, but the effect of inhibiting endothelial cell proliferation is weak, and restenosis may occur during actual application.

[0124] Comparative Example 2

[0125] A coating for a drug-eluting stent, including a phase A and a phase B.

[0126] The raw materials of phase A include: 1.5 kg of ginkgo flavonoids, 1.5 kg of resveratrol, 0.5 kg of rapamycin, 1.5 kg of PEG-30 dimeric hydroxystearate, 7 kg of glycerol, and 15 kg of silicone oil.

[0127] The raw materials of phase B include: 15 kg of polylactic acid, 3 kg of polyethylene glycol, and 30 kg of dichloromethane.

[0128] The preparation method of the above coating for a drug-eluting stent includes the following steps:

[0129] S1. Add ginkgo flavonoids and resveratrol to glycerol and mix evenly to obtain a prefabricated material a;

[0130] S2. Mix rapamycin, PEG - 30 dimer hydroxystearate, and silicone oil evenly to obtain the pre - material c;

[0131] S3. Drop the pre - material a into the pre - material c and perform homogenization treatment for 6 min at a homogenization speed of 11000 r / min to obtain the A phase;

[0132] S4. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain the B phase.

[0133] A preparation method of a drug - eluting stent, comprising the following steps:

[0134] (1) Add 6 kg of microcrystalline cellulose and 3 kg of corn starch to 30 kg of an ethanol solution with a concentration of 0.8 mol / L, stir at 55 °C until the viscosity reaches 900 cP, and the stirring speed is 1300 r / min to obtain the stent treatment solution;

[0135] (2) Immerse the vascular stent in the stent treatment solution for 15 min, dry at room temperature, add it to a calcination furnace, keep it at 270 °C for 20 min in a nitrogen atmosphere, and cool to obtain the pretreated stent;

[0136] (3) Use the A phase of the coating for the above - mentioned drug - eluting stent to spray the pretreated stent with an ultrasonic atomization device, the ultrasonic power is 7 W, and the spraying cycle times are 3 times; place it in a vacuum drying oven to dry for 30 min, the drying temperature is 50 °C, and the vacuum degree is 60 kPa; continue to spray the B phase of the coating for the above - mentioned drug - eluting stent, the spraying cycle times are 3 times, place it in a vacuum drying oven to dry for 30 min, the drying temperature is 50 °C, and the vacuum degree is 60 kPa.

[0137] Place the drug - eluting stent obtained in this comparative example in a phosphate buffer solution at 37 °C and pH = 7.4 for in vitro degradation experiments. After 5 days, observe under a scanning electron microscope and find that the surface of the drug - eluting stent obtained in this comparative example is rough, undergoes erosion degradation, the drug is released, but no shedding occurs.

[0138] Culture mouse endothelial cells with DMEM low - glucose medium (5.6 mmol / L), place them in an incubator at 37 °C with 5% CO2. After most of the cells adhere and grow into a network, digest them with 0.25% trypsin and set aside. Take the above - mentioned mouse endothelial cells and continue to culture them with DMEM low - glucose medium until they adhere and grow to 60%. Then add the drug - eluting stent obtained in this comparative example and continue to culture for 7 d. Observe with an inverted microscope and find that: the cell morphology is irregular and there are many floating cells.

[0139] The above situation shows that the coating drug of the drug - eluting stent obtained in this comparative example can be slowly released, but it will induce endothelial cell apoptosis.

[0140] Comparative Example 3

[0141] A coating for a drug-eluting stent, comprising a Phase A and a Phase B.

[0142] The raw materials of Phase A include: 15 kg of carboxymethyl chitosan, 1.5 kg of ginkgo flavone, 1.5 kg of resveratrol, 0.5 kg of vascular endothelial growth factor, 0.5 kg of rapamycin, 1.5 kg of PEG-30 dimeric hydroxystearate, 7 kg of glycerol, 15 kg of silicone oil, and 80 kg of an aqueous acetic acid solution with a mass fraction of 0.3%.

[0143] The raw materials of Phase B include: 15 kg of polylactic acid, 3 kg of polyethylene glycol, and 30 kg of dichloromethane.

[0144] The preparation method of the above coating for a drug-eluting stent comprises the following steps:

[0145] S1. Add ginkgo flavone and resveratrol to glycerol and mix evenly to obtain prefabricated material a;

[0146] S2. Add carboxymethyl chitosan and vascular endothelial growth factor to the aqueous acetic acid solution, mix evenly, and remove bubbles by ultrasonic treatment to obtain prefabricated material b;

[0147] S3. Mix rapamycin, PEG-30 dimeric hydroxystearate and silicone oil evenly to obtain prefabricated material c;

[0148] S4. Drop prefabricated material a into prefabricated material c and perform primary homogenization treatment for 6 min at a homogenization speed of 11000 r / min, then drop the product into prefabricated material b for secondary homogenization treatment for 3 min at a homogenization speed of 11000 r / min to obtain Phase A;

[0149] S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain Phase B.

[0150] A preparation method of a drug-eluting stent comprises the following steps: Spray the Phase A of the above coating for a drug-eluting stent on a vascular stent by using an ultrasonic atomization device with an ultrasonic power of 7 W and a spraying cycle number of 3 times; Place it in a vacuum drying oven and dry for 30 min at a drying temperature of 50°C and a vacuum degree of 60 kPa; Continue to spray the Phase B of the above coating for a drug-eluting stent with a spraying cycle number of 3 times, place it in a vacuum drying oven and dry for 30 min at a drying temperature of 50°C and a vacuum degree of 60 kPa.

[0151] The drug-eluting stent obtained in this comparative example was placed in a phosphate buffer solution at a temperature of 37°C and pH = 7.4 for an in vitro degradation experiment. After 5 days, observation under a scanning electron microscope revealed that the surface of the drug-eluting stent obtained in this comparative example was rough, undergoing erosion degradation, with local detachment occurring. In the actual application process, a phenomenon similar to thrombus detachment was extremely likely to occur, thus endangering the health and even life of the user.

[0152] Using human umbilical vein endothelial cells (HUVEC cells) as the experimental object, the in vitro cytotoxicity evaluation of the drug-eluting stents obtained in Example 5 and Comparative Examples 1-3 was carried out by the MTT method. The specific operation is as follows:

[0153] M199 medium (containing 20% fetal bovine serum, 100 μg / mL penicillin, 100 μg / mL streptomycin, 0.135% NaHCO3, 15 mmol / L HEPES (N-(2-Hydroxyethyl)piperazine-N'-ethanesulfonic acid), and 2 mmol / L glutamine) was selected for cell culture. The culture flask was placed in an incubator at a temperature of 37°C, a relative humidity of 90%, and containing 5% CO2 for culture. To ensure the health and normal growth of the cells, subculture was carried out every appropriate number of days.

[0154] As Figure 1 shown, the cytotoxicity of the drug-eluting stents obtained in Example 5 and Comparative Example 1 was relatively low, and the cell survival rates of both were greater than 90%. Moreover, Comparative Example 1 was slightly better than Example 5 because there was no rapamycin in Comparative Example 1, so that the drug-eluting stent would not cause harm to endothelial cells.

[0155] In Comparative Example 2, prefabricated material b was not used for coating, so that the rapamycin in prefabricated material c was directly exposed to endothelial cells, resulting in high cytotoxicity of the drug-eluting stent obtained in Comparative Example 2, and the cell survival rate was only about 50%. The drug-eluting stent obtained in Comparative Example 3 did not perform roughening pretreatment on the vascular stent, making its coating effect on the drug inferior to that of Example 5 and Comparative Example 1, resulting in a faster release rate of the coated drug from the stent surface than that of Example 5 and Comparative Example 1, thus reducing its cell survival rate.

[0156] Taking resveratrol as the detection object, the sustained-release performance of the drug-eluting stents obtained in Example 5 and Comparative Examples 1-3 was detected as follows: Weigh 18.171 g of Tris reagent and dissolve it in 3 L of deionized water, and adjust its pH to 7.4 to obtain a Tris-HCl buffer solution; weigh 2.01 g of bovine serum albumin and add it to 3 L of the above Tris-HCl buffer solution to prepare a molar concentration of 10 -5mol / L simulated blood. Vertically fix the stent in a brown graduated stoppered test tube, add 20 mL of simulated blood to each stent as the release medium, seal it, and keep it oscillating at a constant temperature of 37 °C and 100 rpm. Take out the stent on the 1st, 7th, 14th, 28th, and 90th days respectively, put it into a brown dissolution cup containing 20 mL of fresh simulated blood, and continue sustained release. Take 1 mL of the sustained release solution to be measured to detect the concentration of resveratrol, and calculate the cumulative release rate.

[0157] As Figure 2 shown, the sustained release curve of Example 5 finally approaches 100%, indicating that the drug-eluting stent obtained in Example 5 can continuously release the drug, making the drug release cycle adapt to the intimal hyperplasia time, effectively restricting local vascular intimal hyperplasia, reducing the inflammatory reaction, and further enhancing the restriction effect on restenosis.

[0158] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution of the present invention and its inventive concept, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

Claims

1. A coating for a drug-eluting stent, characterized in that, including A phase B phase A The phase raw materials include: carboxymethyl chitosan, ginkgo flavonoids, resveratrol, vascular endothelial growth factor, rapamycin, PEG-30 dimer hydroxystearate, glycerol, silicone oil, and an aqueous acetic acid solution with a mass fraction of 0.1-0.5%; The mass ratio of carboxymethyl chitosan, ginkgo flavonoids, resveratrol, vascular endothelial growth factor, rapamycin, PEG-30 dimyristate, glycerol, silicone oil, and an aqueous acetic acid solution with a mass fraction of 0.1 - 0.5% is 10 - 20:1 - 2:1 - 2:0.1 - 1:0.1 - 1:1 - 2:6 - 8:10 - 20:50 - 100; B The raw materials include: polylactic acid, polyethylene glycol, and dichloromethane; the mass ratio of polylactic acid, polyethylene glycol, and dichloromethane is 10-20:1-5:20-40; It is prepared by the following steps: S1. Add ginkgo flavonoids and resveratrol to glycerol and mix evenly to obtain a prefabricated material a ; S2. Add carboxymethyl chitosan and vascular endothelial growth factor into an acetic acid aqueous solution, mix evenly, and remove bubbles by ultrasonic treatment to obtain a preformulation b ; S3. Mix rapamycin, PEG-30 dimer hydroxystearate and silicone oil evenly to obtain a prefabricated material c ; S4. Add the preform a dropwise to the preform c for primary homogenization treatment, and then add the product dropwise to the preform b for secondary homogenization treatment to obtain A phase; S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain B phase.

2. The coating for a drug-eluting stent according to claim 1, wherein The molecular weight of carboxymethyl chitosan is 5000 - 35000, and the degree of substitution is 1.1 - 1.

5.

3. A preparation method of the coating for the drug-eluting stent as described in claim 1 or 2, characterized in that, It includes the following steps: S1. Add ginkgo flavonoids and resveratrol to glycerol and mix evenly to obtain a prefabricated material a ; S2. Add carboxymethyl chitosan and vascular endothelial growth factor into an acetic acid aqueous solution, mix evenly, and remove bubbles by ultrasonic treatment to obtain a preformulation b ; S3. Mix rapamycin, PEG-30 dimer hydroxystearate, and silicone oil evenly to obtain a prefabricated material c ; S4. Add the prefabricated material a dropwise to the prefabricated material c for primary homogenization treatment, and then add the product dropwise to the prefabricated material b for secondary homogenization treatment to obtain A phase; S5. Dissolve polylactic acid and polyethylene glycol in dichloromethane to obtain B phase.

4. The preparation method of the coating for the drug-eluting stent according to claim 3, wherein, In S4, the primary homogenization treatment time is 2 - 10 min, and the homogenization speed is 10000 - 12000 r / min; the secondary homogenization treatment time is 1 - 5 min, and the homogenization speed is 10000 - 12000 r / min.

5. A method for preparing a drug-eluting stent, characterized in that, It includes the following steps: (1) Add microcrystalline cellulose and corn starch into an aqueous ethanol solution, and stir at 50 - 60 °C to obtain a scaffold treatment solution; (2) Immerse the vascular stent in the scaffold treatment solution for 10 - 20 min, dry at room temperature, keep it at 250 - 300 °C for 10 - 30 min in a nitrogen atmosphere, and cool to obtain a pretreated stent; (3) Spray the coating for the drug-eluting stent as described in claim 1 or 2 A onto the pretreated stent, vacuum dry for 20 - 40 min, and then continue to spray the B phase of the coating for the drug-eluting stent as described in claim 1 or 2, and vacuum dry for 20 - 40 min.

6. The preparation method of the drug-eluting stent according to claim 5, wherein, In step (1), the particle size of microcrystalline cellulose is 50 - 100 μm, and the limiting degree of polymerization is 100 - 250; the mass ratio of microcrystalline cellulose, corn starch, and aqueous ethanol solution is 2 - 10:1 - 5:20 - 40, and the concentration of the aqueous ethanol solution is 0.5 - 1.2 mol / L.

7. The preparation method of the drug-eluting stent according to claim 5, wherein In step (1), stir until the viscosity reaches 800 - 1000 cP.

8. The preparation method of the drug-eluting stent according to claim 5, characterized in that, In step (3), use an ultrasonic atomization device for spraying, the ultrasonic power is 4 - 10 W, and the number of spraying cycles is 2 - 4 times.

9. The preparation method of the drug-eluting stent according to claim 5, wherein, In step (3), the vacuum drying temperature is 40 - 60 °C, and the vacuum degree is 50 - 70 kPa.

10. A drug-eluting stent, characterized in that, It is prepared by the preparation method of the drug-eluting stent according to any one of claims 5 - 9.

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