阅读说明：本技术 一种具有药物缓释及抗凝、抗钙化性能的血管支架涂层材料及其制备方法 (Intravascular stent coating material with drug slow release, anticoagulation and calcification resistance and preparation method thereof ) 是由 王云兵 罗日方 杨立 陈梁 于 2021-09-02 设计创作，主要内容包括：本发明提供了一种具有药物缓释及抗凝、抗钙化性能的血管支架涂层材料及其制备方法,制备方法包括以下步骤：制备可有效组装抗钙化药物的大分子载体；将抗钙化的功能组分与大分子载体复合制备出包裹了抗钙化组分的中间载体；将中间载体作为阳离子载体,与改性壳聚糖及肝素分子分别作为聚电解质成分,通过喷涂、旋涂或浸涂的方式在血管支架表面制备涂层；定义单循环的“改性壳聚糖/中间载体/肝素”复合涂层为1层,通过1-20个该循环的喷涂、旋涂或浸涂操作,得目标涂层。本发明所得涂层可用于血管支架材料的改性,使得血管支架获得具有长效药物缓释及抗凝、抗增生、抗钙化性能,有效抑制植入后支架内再动脉粥样硬化及钙化的演变。(The invention provides a vascular stent coating material with drug slow release, anticoagulation and anti-calcification performances and a preparation method thereof, wherein the preparation method comprises the following steps: preparing a macromolecular carrier capable of effectively assembling the anti-calcification drug; compounding the anti-calcification functional component and the macromolecular carrier to prepare an intermediate carrier coated with the anti-calcification component; preparing a coating on the surface of the intravascular stent by using the intermediate carrier as a cationic carrier and the modified chitosan and heparin molecules as polyelectrolyte components respectively through spraying, spin coating or dip coating; defining the single-cycle 'modified chitosan/intermediate carrier/heparin' composite coating as 1 layer, and obtaining the target coating through 1-20 cycles of spraying, spin coating or dip coating operation. The coating obtained by the invention can be used for modifying the vascular stent material, so that the vascular stent has the long-acting drug slow release and the properties of anticoagulation, anti-hyperplasia and anti-calcification, and can effectively inhibit the evolution of atherosclerosis and calcification in the stent after implantation.)

1. A preparation method of an intravascular stent coating material with drug slow release, anticoagulation and calcification resistance is characterized by comprising the following steps:

(1) preparing a macromolecular carrier capable of effectively assembling the anti-calcification drug;

(2) compounding the anti-calcification functional component with the macromolecular carrier obtained in the step (1) to prepare an intermediate carrier coated with the anti-calcification component;

(3) preparing a coating on the surface of the intravascular stent by taking the intermediate carrier obtained in the step (2) as a cationic carrier and taking the modified chitosan and heparin molecules as polyelectrolyte components respectively through spraying, spin coating or dip coating; defining the single-cycle 'modified chitosan/intermediate carrier/heparin' composite coating as 1 layer, and obtaining the target coating through 1-20 cycles of spraying, spin coating or dip coating operation.

2. The method for preparing the vascular stent coating material with drug sustained release, anticoagulation and anti-calcification performances as claimed in claim 1, wherein the macromolecular carrier capable of effectively assembling the anti-calcification drug is modified chitosan and polyacrylic acid.

3. The preparation method of the intravascular stent coating material with drug sustained release, anticoagulation and anti-calcification performances as claimed in claim 2, wherein the modified chitosan is chitosan with a catechol structure modified on a side chain.

4. The method for preparing a vascular stent coating material with drug sustained release, anticoagulation and anti-calcification properties as claimed in claim 1, wherein the anti-calcification functional component is a statin drug and/or copper ions.

5. The method for preparing the vascular stent coating material with drug sustained release, anticoagulation and anti-calcification performances as claimed in claim 4, wherein the statin is at least one of atorvastatin, rosuvastatin, lovastatin, simvastatin and pravastatin.

6. The method for preparing an intravascular stent coating material with drug sustained release, anticoagulation and anti-calcification properties according to claim 4, wherein the copper ion donor is copper sulfate and/or copper chloride.

7. The method for preparing the intravascular stent coating material with the drug slow release, anticoagulation and anti-calcification performances as claimed in claim 1, wherein in the step of preparing the modified chitosan/intermediate carrier/heparin composite coating, the spraying mode is ultrasonic atomization spraying, spin coating or dip coating.

8. The preparation method of the intravascular stent coating material with drug sustained release, anticoagulation and anti-calcification performances as claimed in claim 1 or 2, wherein the concentration of the modified chitosan is 1-10mg/mL, the concentration of the polyacrylic acid is 0.5-5mg/mL, and the mass concentration ratio of the modified chitosan to the polyacrylic acid is from 3-10: 1.

9. The method for preparing the vascular stent coating material with drug sustained release, anticoagulation and anti-calcification performances as claimed in claim 1, wherein the material of the vascular stent body comprises a polymer material and a metal/alloy material.

10. The vascular stent coating material with drug sustained release, anticoagulation and anti-calcification performances prepared by the preparation method of the vascular stent coating material with drug sustained release, anticoagulation and anti-calcification performances of any one of claims 1-9.

Technical Field

The invention relates to the technical field of medical materials and medical instruments, in particular to an intravascular stent coating material with drug slow release, anticoagulation and calcification resistance and a preparation method thereof.

Background

At present, the risk of restenosis in a stent is greatly reduced by using a drug eluting stent as a main means for treating atherosclerosis, but the occurrence rate of late thrombus is still high, the main reasons are incomplete repair of neointima of the stent, incomplete endothelialization and neoatherosclerosis in the stent, meanwhile, the development and calcification of the original atherosclerosis are also risk factors, and particularly, the occurrence of calcification can cause the increase of plaque damage risk.

Coronary calcification is accompanied by the progression of atherosclerosis. Coronary artery calcification pathologically begins with microcalcifications (0.5-15.0 mm) and gradually progresses to larger calcium fragments, eventually forming lamellar deposits (> -3 mm). This evolution occurs simultaneously with the progression of plaque. These fragments and calcified sheets can be readily identified by radiology, computed tomography and intravascular imaging. Many imaging methods have proposed that plaque calcification is a predictor of unstable plaque. In elderly patients, the proportion of fibrocalcified plaques and healed plaques that rupture is higher, resulting in higher calcium scores for such plaques. Some of these plaques may remain stable and may develop into severe stenosis or continue to form calcified nodules leading to thrombosis. From a pathological point of view, although CAC scores are clinically practical, the complexity of coronary artery disease is not sufficiently understood by CAC scores alone. Relevant theoretical research tasks the presence of calcium (small, fragmented, speckles) is a marker of unstable plaques. The primary calcification can cause instability of plaque, and the primary microcalcification can affect local tissue stress and increase the risk of rupture of plaque fibrous cap, which is a main cause of ischemic stroke. Intervention in the process of forming calcifications in atherosclerosis is an effective way to reduce the progression of vulnerable plaque.

The latest theoretical view in the field holds that the ideal stent interventional therapy mode is the same, a healthy and complete neointima is formed in the stent after the stent is implanted, the original atherosclerotic plaque is treated, and finally the stent is completely degraded and absorbed by a human body after the neointima is reconstructed.

Researches find that the statins have better functions of removing lipid and inhibiting further deposition of calcified substances; the functional NO gas molecules can effectively inhibit further osteogenic evolution of smooth muscle cells, and can effectively reduce the risk of the neogenetic smooth muscle cell inner membrane tissue transforming to the calcification direction.

Based on the above, the invention adopts the experimental means of spray coating, spin coating or dip coating, and can obtain a novel vascular stent coating material for resisting atherosclerosis after stent implantation through the effective assembly of the anti-calcification functional component and the anti-coagulation and anti-proliferation components, and the coating not only can resist the further evolution of calcification, but also has the functions of anticoagulation, anti-proliferation and drug slow release.

Disclosure of Invention

Aiming at the defect that the intervention and treatment are not carried out on the atherosclerosis process after the stent is implanted in the prior art, the invention provides the vascular stent coating material with drug slow release, anticoagulation and calcification resistance and the preparation method thereof, and effectively solves the problems of low loading capacity of anti-hyperplasia and calcification-resistant drugs of the coating, easy burst release of the drugs and the like.

In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows: provides a preparation method of a vascular stent coating material with drug slow release, anticoagulation and calcification resistance, which comprises the following steps:

(1) preparing a macromolecular carrier capable of effectively assembling the anti-calcification drug;

(2) compounding the anti-calcification functional component with the macromolecular carrier obtained in the step (1) to prepare an intermediate carrier coated with the anti-calcification component;

(3) preparing a coating on the surface of the intravascular stent by taking the intermediate carrier obtained in the step (2) as a cationic carrier and taking the modified chitosan and heparin molecules as polyelectrolyte components respectively through spraying, spin coating or dip coating; defining the single-cycle 'modified chitosan/intermediate carrier/heparin' composite coating as 1 layer, and obtaining the target coating through 1-20 cycles of spraying, spin coating or dip coating operation.

Furthermore, the macromolecular carrier capable of effectively assembling the anti-calcification drug is modified chitosan and polyacrylic acid.

Further, the modified chitosan is chitosan with a side chain modified with a catechol structure.

Further, the modified chitosan is catechol modified chitosan.

Further, the anti-calcification functional component is statins and/or copper ions.

Further, the statin is at least one of atorvastatin, rosuvastatin, lovastatin, simvastatin, and pravastatin.

Further, the copper ion donor is copper sulfate and/or copper chloride.

Furthermore, the concentration of the statins is 0.01mg/mL-2mg/mL, the molar concentration of the used copper ions is 50uM-10mM, and the functional components are independent from macromolecules.

Further, the intermediate carrier is a nanoparticle carrier.

Further, in the step of preparing the modified chitosan/intermediate carrier/heparin composite coating, the spraying mode is ultrasonic atomization spraying, spin coating or dip coating.

Further, the concentration of the modified chitosan is 1-10mg/mL, the concentration of the polyacrylic acid is 0.5-5mg/mL, and the mass concentration ratio of the modified chitosan to the polyacrylic acid is from 3-10: 1. .

Further, the body material of the blood vessel stent comprises a polymer material and a metal/alloy material.

Further, in the process of preparing the coating, the concentration of the modified chitosan is 0.5-5mg/mL (the molecular weight range is from 5000-.

The vascular stent coating material with the drug slow release, anticoagulation and calcification resistance performance is prepared by the preparation method of the vascular stent coating material with the drug slow release, anticoagulation and calcification resistance performance.

In summary, the invention has the following advantages:

1. by the coating preparation method, the following functions can be endowed to the vascular stent: 1) the statins can effectively remove fat and reduce calcium salt deposition, and can reduce the proliferation rate of smooth muscle cells to a certain extent; 2) the release of copper ions can effectively catalyze and generate NO in blood, promote the growth of endothelial cells in the neointima and inhibit the proliferation of smooth muscle cells; 3) NO gas can inhibit osteogenic differentiation of smooth muscle cells in the plaque to inhibit the occurrence of late calcification of the original plaque; 4) due to the presence of the catechol group in the coating, the release rate of the statins in the coating can be effectively reduced, and the plaque can be treated by reducing the blood lipid level and the inflammatory reaction of the plaque through long-acting slow release.

2. NO and statins can synergistically inhibit calcification; the drug combination mode of the invention can not only resist calcification and hyperplasia, but also reduce the blood lipid level of the plaque; both NO and statin drugs act by being released to the blood/tissue interface, and anti-calcification is a relatively long-lasting process, so the presence of long-acting sustained release can make long-acting anti-calcification possible.

Drawings

FIG. 1 is a reaction scheme of modified chitosan;

FIG. 2 is a nuclear magnetic spectrum of modified chitosan;

FIG. 3 is a TEM image of an intermediate nanocarrier formed by the complex of the macromolecular carrier and the anticalcification component obtained in example 1;

fig. 4 is a comparison of the therapeutic effect of the stent of different coatings prepared in example 1 after implantation in calcification model vessels.

Detailed Description

The synthesis steps of the modified chitosan are as follows:

500mg of chitosan (molecular weight 100000) was dissolved in 10mL of hydrochloric acid solution (1mol/L), diluted by adding 30mL of deionized water, and the pH of the solution was adjusted to 5.0 with HCl solution (1 mol/L). Thereafter, 1g of 3, 4-dihydroxybenzaldehyde was dissolved in 30mL of a mixed solvent of water and methanol (water/methanol volume ratio: 2:1), and the mixed solvent was slowly added to the chitosan solution previously having pH 5.0 while stirring at 25 ℃ and the temperature and pH were maintained for reaction for 3.5 hours. Slowly adding 250mg of NaBH4 into the reaction solution until no bubbles are generated, adjusting the pH of the solution to 5.0 by using hydrochloric acid (1mol/L) to fully dissolve the NaBH4, finally adding the reaction solution into a 3500Da dialysis bag, dialyzing the solution in deionized water with the pH of 5.0 for 2 days, replacing the deionized water in the process to ensure the smooth operation of the dialysis process, removing unreacted substances, and freeze-drying to obtain the catechol-modified chitosan product.

The reaction scheme of the modified chitosan is shown in fig. 1, and then the nuclear magnetic spectrum of the obtained modified chitosan is obtained, which is shown in fig. 2.

As can be seen from FIG. 2, the peak at position a demonstrates that catechol is successfully modified on chitosan molecules, and chitosan is successfully modified.

Example 1

A vascular stent coating material with drug slow release, anticoagulation and anti-calcification performances, and a preparation method thereof, comprises the following steps:

(1) preparing catechol-modified chitosan;

(2) compounding rosuvastatin (0.5 mg/mL)/copper ions (100uM), catechol-modified chitosan (5mg/mL) and polyacrylic acid (2mg/mL) to respectively prepare intermediate carriers wrapping rosuvastatin and copper ions;

(3) preparing a coating on the surface of the polylactic acid intravascular stent in a spraying manner by taking the intermediate carrier prepared in the step (2) as a cationic carrier (1mg/mL) and modified chitosan (5mg/mL) and heparin molecules (2mg/mL) as polyelectrolyte components respectively;

(4) and (4) repeating the step (3) for 10 times to obtain the target coating.

Example 2

A vascular stent coating material with drug slow release, anticoagulation and anti-calcification performances, and a preparation method thereof, comprises the following steps:

(1) preparing catechol-modified chitosan;

(2) compounding atorvastatin (1 mg/mL)/copper ions (300uM), catechol-modified chitosan (3mg/mL) and polyacrylic acid (1mg/mL) to respectively prepare intermediate carriers wrapping the atorvastatin and the copper ions;

(3) preparing a coating on the surface of the cobalt-chromium alloy intravascular stent in a spraying manner by taking the intermediate carrier prepared in the step (2) as a cationic carrier (0.5mg/mL) and modified chitosan (3mg/mL) and heparin molecules (3mg/mL) as polyelectrolyte components respectively;

(4) and (5) repeating the step (3) to obtain the target coating.

Example 3

A vascular stent coating material with drug slow release, anticoagulation and anti-calcification performances, and a preparation method thereof, comprises the following steps:

(1) preparing catechol-modified chitosan;

(2) lovastatin (1 mg/mL)/copper ions (500uM) are compounded with catechol-modified chitosan (8mg/mL) and polyacrylic acid (1mg/mL) to respectively prepare intermediate carriers wrapping rosuvastatin and copper ions;

(3) taking the intermediate carrier prepared in the step (2) as a cationic carrier (2mg/mL), and taking the modified chitosan (2mg/mL) and heparin molecules (5mg/mL) as polyelectrolyte components respectively, and preparing a coating on the surface of the polylactic acid vascular stent in a dip-coating manner;

(4) and (4) repeating the step (3) for 20 times to obtain the target coating.

A TEM image of the intermediate nanocarrier formed by the combination of the macromolecular carrier and the anti-calcification component obtained in example 1 is obtained, as shown in FIG. 3; comparison of the therapeutic effects after implantation of the stents of different coatings prepared in example 1 in calcification model vessels.

As can be seen from fig. 3, the intermediate carrier formed was confirmed to be a nanocarrier. As can be seen in fig. 4, NO, statin or a combination of both may be effective in reducing further progression of calcification or atherosclerosis.

While the present invention has been described in detail with reference to the illustrated embodiments, it should not be construed as limited to the scope of the present patent. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.