Coronary vascular stent as well as preparation method and application thereof

Abstract

The invention discloses a coronary vascular stent, a preparation method thereof and application of the coronary vascular stent to improvement of coronary artery microcirculation disturbance after emergency stent implantation of acute myocardial infarction patients. The coronary artery vascular stent comprises a coronary artery vascular stent body; the first drug-loaded coating is coated on the outer wall of the coronary vascular stent body, and the first drug-loaded coating comprises a biodegradable polymer and a first active drug for resisting intimal hyperplasia; the inner wall of the coronary vascular stent body is coated with the second drug-loaded coating, and the second drug-loaded coating comprises a biodegradable polymer and a second active drug used for improving coronary microcirculation disturbance. The first drug-loading coating plays a targeted anti-intimal hyperplasia role by directly contacting the coronary intima; meanwhile, by controlling the degradation rate of the biodegradable polymer in the second drug-loading coating and the release rate of the second active drug, the released second active drug reaches coronary microcirculation along with blood flow, and the effect of improving CMD after AMI in a targeted mode is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and in particular to a dual-drug coated coronary vascular stent and a preparation method thereof, and an application thereof in improving coronary microcirculation disorders after emergency stent implantation in patients with acute myocardial infarction. Background Art

[0002] Acute myocardial infarction (AMI) is one of the major diseases threatening human health. It is a common heart disease and a clinical symptom of myocardial cell ischemia, hypoxia and even death caused by acute blood flow blockage in the coronary arteries.

[0003] Among the methods for treating AMI, emergency percutaneous coronary intervention (PCI) is an effective treatment method. It is performed by percutaneous puncture into the coronary artery, using a coronary drug-eluting stent to open the occluded blood vessel and restore blood flow in the coronary artery. Currently, the coronary drug-eluting stent products used in clinical practice are all single drug-eluting stents, which are generally sprayed with rapamycin or its derivative coating on the basis of a cobalt-chromium alloy stent. Most of the coatings are biodegradable biocompatible macromolecular materials. By controlling the degradation rate of the stent coating, the drug in the coating is slowly released, directly acting on the coronary endothelium, achieving the effect of anti-intimal hyperplasia and preventing in-stent restenosis.

[0004] However, clinical studies have shown that after emergency PCI, 50%-60% of patients may experience coronary microvascular dysfunction (CMD), which can lead to poor reperfusion at the myocardial tissue level and thus affect the patient's prognosis.

[0005] The possible mechanisms of CMD after AMI include: CM coronary microcirculatory dysfunction, ischemic injury, reperfusion injury, and distal microvascular thromboembolism. Based on the mechanism of CMD, in recent years, clinical attempts have been made to use relevant drug treatments to prevent or reduce the occurrence of CMD and improve patient prognosis. For example, ACEI / ARB (angiotensin converting enzyme inhibitor / angiotensin II receptor antagonist), metoprolol, adenosine, sodium nitroprusside, verapamil, nicorandil, alprostadil, and even Chinese patent medicines.

[0006] At present, studies have confirmed that the representative drugs that are effective in preventing and treating CMD after AMI include nicorandil and alprostadil. Nicorandil has been recommended for improving CMD by the "Chinese Expert Consensus on Microcirculatory Protection Strategies for Emergency PCI in Patients with ST-segment Elevation Myocardial Infarction". At the same time, studies have confirmed that the peripheral intravenous use of nicorandil and alprostadil can improve CMD after AMI, and the efficacy is similar; however, since the study used peripheral intravenous administration, the blood concentration of the drug in CM was relatively low, which restricted its efficacy in improving CMD.

[0007] On this basis, some studies have attempted to use intracoronary intravenous injection of nicorandil or alprostadil to increase the blood concentration of drugs in CM during emergency PCI, which has played a positive role in improving CMD after AMI. However, although intracoronary administration can solve the problem of low blood concentration of CM, it is difficult to continue intracoronary administration, which greatly limits its clinical effect.

[0008] Therefore, it is clinically necessary to develop an effective drug delivery system that can target and efficiently act on the coronary microcirculation to improve CMD after AMI. Summary of the invention

[0009] The technical problem to be solved by the embodiments of the present application is to provide an effective drug delivery system that targets and efficiently acts on the coronary microcirculation to improve coronary microcirculation disorders after emergency stent implantation in patients with acute myocardial infarction.

[0010] In order to solve the above technical problems, in a first aspect, an embodiment of the present application provides a coronary stent, wherein the coronary stent comprises:

[0011] Coronary stent body;

[0012] A first drug-loaded coating is applied to the outer wall of the coronary stent body, wherein the first drug-loaded coating comprises a biodegradable polymer and a first active drug for preventing intimal hyperplasia;

[0013] The second drug-loaded coating is coated on the inner wall of the coronary stent body, and the second drug-loaded coating comprises a biodegradable polymer and a second active drug for improving coronary microcirculation disorders.

[0014] Preferably, the outer wall of the vascular stent body is provided with a groove, and the first drug-loaded coating is coated in the groove.

[0015] Preferably, the biodegradable polymer is any one of polylactic acid, polylactic acid-co-glycolic acid, polycaprolactone, polyglycolic acid, poly(L-glutamic acid), polymethacrylic acid, polymethacrylic acid-N,N-dimethylaminoethyl ester, and poly-4-vinylpyridine.

[0016] Preferably, the first active drug is any one of everolimus, rapamycin, paclitaxel, enoxaparin, bivalirudin, clopidogrel, prasugrel and ticagrelor.

[0017] Preferably, the second active drug is alprostadil or nicorandil.

[0018] In a second aspect, the present application also provides a method for preparing the above-mentioned coronary stent, the preparation method comprising the following steps:

[0019] Preparing the coronary stent body;

[0020] Cleaning the coronary stent body;

[0021] A groove is etched on the outer wall of the coronary stent body, and a first mixed drug solution is dripped into the groove by a fixed-point drip irrigation method, and a first drug-loaded coating is formed after vacuum volatilization; the first mixed drug solution includes a biodegradable polymer and a first active drug for preventing intimal hyperplasia;

[0022] A second mixed drug liquid is sprayed on the outer wall of the coronary stent body, and a second drug-loaded coating is formed after vacuum volatilization; the second mixed drug liquid includes a biodegradable polymer and a second active drug for improving coronary microcirculation disorders.

[0023] Preferably, the coronary stent body is a cobalt-chromium stent;

[0024] Preferably, cleaning the coronary stent body comprises:

[0025] The coronary stent body is ultrasonically cleaned in acetone, alcohol and deionized water respectively, and then the surface of the coronary stent body is deeply cleaned by plasma technology;

[0026] The cleaned coronary stent body is immersed in an acid solution, and is etched in an ultrasonic manner. The etched coronary stent body is taken out and ultrasonically cleaned with deionized water. After cleaning, the body is dried for later use.

[0027] Preferably, the acid solution is a mixed acid solution of HNO3, HF and H2O2; and the mixed acid solution is prepared by first adding HF and H2O2, and then adding HNO3 in that order.

[0028] Preferably, etching the groove on the outer wall of the coronary stent body specifically comprises: etching the groove on the outer wall of the coronary stent body using laser etching technology;

[0029] Preferably, the groove has a depth of 20 to 30 μm.

[0030] On the third aspect, the embodiments of the present application also provide the application of the above-mentioned coronary vascular stent in improving coronary microcirculation disorder CMD after emergency stent implantation AMI in patients with acute myocardial infarction. The first drug-loaded coating on the outer wall of the coronary vascular stent exerts a targeted anti-intimal hyperplasia effect by directly contacting the coronary intima; at the same time, by controlling the degradation rate of the biodegradable polymer in the second drug-loaded coating on the inner wall of the coronary vascular stent, the release rate of the second active drug is controlled, and the released second active drug flows with the blood to the coronary microcirculation, thereby exerting a targeted improvement of CMD after AMI.

[0031] One or more technical solutions provided in the embodiments of the present application have at least the following technical effects or advantages:

[0032] 1. The present application provides a novel dual-drug coated coronary vascular stent, the outer wall of which is loaded with an anti-proliferative drug coating, which exerts a targeted anti-intimal hyperplasia effect by directly contacting the coronary endothelium; at the same time, a drug coating for improving microcirculation is sprayed on the inner wall of the stent, and the drug release rate is controlled by controlling the coating degradation rate. The released drug flows with the blood to the coronary microcirculation, which can play a targeted and efficient role in improving CMD after AMI.

[0033] 2. In the preparation method of the coronary stent of the present application, laser etching technology and digital fixed-point drip irrigation are used. Laser etching technology can achieve micron-level precision, which is crucial for the manufacture of coronary stents. The periodic grooves induced on the surface of the stent by laser technology can accurately set the drug distribution and increase the drug loading. At the same time, the drug is precisely poured onto the stent through digital fixed-point drip irrigation, which can ensure that the drug is evenly distributed and will not fall off during the stent delivery process, thereby improving the release efficiency of the drug and ensuring the therapeutic effect of the stent.

[0034] 3. The coronary stent provided in this application is powerful and low-cost. It has broad application prospects in the fields of biomedical engineering, materials science and cardiovascular disease treatment, has huge market demand, and is expected to play an important role in the future medical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and, together with the description, serve to explain the principles of the present application.

[0036] Figure 1 A schematic diagram of the inner wall structure of a coronary stent provided in an embodiment of the present application;

[0037] Figure 2 This is a schematic diagram of the outer wall structure of the coronary stent provided in the embodiment of the present application;

[0038] The above drawings have shown clear embodiments of the present application, which will be described in more detail later. These drawings and text descriptions are not intended to limit the scope of the present application in any way, but to illustrate the concept of the present application to those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION

[0039] In order to better understand the above technical solution, exemplary embodiments will be described in detail here, and examples thereof are shown in the accompanying drawings. When the following description refers to the drawings, unless otherwise indicated, the same numbers in different drawings represent the same or similar elements. The implementations described in the following exemplary embodiments do not represent all implementations consistent with the present application. Instead, they are only examples of devices consistent with some aspects of the present application as detailed in the attached claims.

[0040] Figure 1 and Figure 2 This is a schematic diagram of the structure of the coronary stent provided in the embodiment of the present application, wherein the coronary stent comprises:

[0041] Coronary artery stent body 1;

[0042] A first drug-loaded coating layer is coated on the outer wall of the coronary stent body 1, wherein the first drug-loaded coating layer comprises a biodegradable polymer and a first active drug for preventing intimal hyperplasia;

[0043] The second drug-loaded coating is coated on the inner wall of the coronary stent body 1, and the second drug-loaded coating comprises a biodegradable polymer and a second active drug for improving coronary microcirculation disorders.

[0044] In a preferred embodiment, a groove 2 is provided on the outer surface of the vascular stent body 1 , and the first drug-loaded coating is coated in the groove 2 .

[0045] Furthermore, the biodegradable polymer is any one of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), polyglycolic acid (PGA), poly(L-glutamic acid) (PGA), polymethacrylic acid (PMAA), polymethacrylate-N,N-dimethylaminoethyl ester (PDMAEMA), and poly 4-vinylpyridine (P4-VP).

[0046] Furthermore, the molecular weight of the PLGA is 2000Da to 5000Da, and the ratio of lactic acid monomer to glycolic acid monomer in the PLGA is 50:50.

[0047] Furthermore, the first active drug is any one of everolimus, rapamycin, paclitaxel, enoxaparin, bivalirudin, clopidogrel, prasugrel, and ticagrelor.

[0048] Furthermore, the second active drug is alprostadil or nicorandil.

[0049] The preparation method of the above coronary stent is as follows:

[0050] Step 1: Prepare the coronary stent body;

[0051] In this embodiment, the coronary artery stent body adopts a cobalt-chromium stent.

[0052] For example, a cobalt-chromium stent with a diameter of 3.0 mm and a length of 15 mm is selected, and the material of the stent is a cobalt-chromium alloy containing 60% cobalt, 30% chromium, and 10% nickel.

[0053] Step 2: Clean the coronary stent body;

[0054] First, the cobalt-chromium stent was ultrasonically cleaned in acetone, alcohol, and deionized water for 10 minutes, and then the surface of the cobalt-chromium stent was deeply cleaned using plasma technology.

[0055] The cleaned cobalt-chromium stent is immersed in the prepared acid solution, and etched in ultrasound for a certain period of time. The cobalt-chromium stent after acid etching is taken out and ultrasonically cleaned three times with deionized water. After cleaning, it is dried for use.

[0056] The acid solution is a mixed acid solution prepared in a centrifuge tube according to a volume ratio of HNO3:HF:H2O2=1:1:1, and the mixed acid solution is prepared by first adding HF and H2O2 and then adding HNO3 in this order.

[0057] Step 3: etching a groove on the outer wall of the coronary stent body, and dripping a first mixed drug solution into the groove by fixed-point drip irrigation, and forming a first drug-loaded coating after vacuum volatilization; the first mixed drug solution includes a biodegradable polymer and a first active drug for anti-intimal hyperplasia;

[0058] Specifically, a laser etching technique is used to etch a groove with a depth of 20 to 30 μm on the outer wall of the cobalt-chromium stent;

[0059] Subsequently, a PLA / everolimus solution of a certain concentration is prepared. PLA (polylactic acid) is a biodegradable polymer, and everolimus is an mTOR inhibitor used to inhibit intimal hyperplasia. Everolimus is dissolved in a solution containing PLA (polylactic acid) to obtain a PLA / everolimus solution.

[0060] Finally, the prepared PLA / Evermox solution was dripped into the groove using a digital fixed-point drip irrigation method, and the solvent was evaporated in a vacuum to obtain a cobalt-chromium stent with an outer wall coated with a PLA / Evermox coating.

[0061] Here, laser etching technology can achieve micron-level precision, which is crucial for the manufacture of coronary stents. The periodic grooves induced by laser technology on the surface of the stent can accurately set the drug distribution and increase the drug loading. At the same time, the drug is precisely injected into the stent through digital fixed-point drip irrigation, which can ensure that the drug is evenly distributed and will not fall off during the stent delivery process, improve the release efficiency of the drug, and ensure the therapeutic effect of the coronary vascular stent.

[0062] Here, Everolimus can also be replaced by other drugs with anti-intimal hyperplasia function, such as rapamycin, paclitaxel, enoxaparin, bivalirudin, clopidogrel, prasugrel, ticagrelor, etc.; PLA can also be replaced by other polymers with biodegradable function, such as polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), polyglycolic acid (PGA), poly (L-glutamic acid) (PGA), polymethacrylic acid (PMAA), polymethacrylate-N,N-dimethylaminoethyl ester (PDMAEMA), poly 4-vinylpyridine (P4-VP), etc.

[0063] Step 4: spray a second mixed drug solution on the outer wall of the coronary stent body, and form a second drug-loaded coating after vacuum evaporation; the second mixed drug solution includes a biodegradable polymer and a second active drug for improving coronary microcirculation disorders.

[0064] Specifically, a PLGA / alprostadil solution of a certain concentration is prepared. PLGA is a biodegradable polymer, and alprostadil is an effective drug for preventing and treating CMD after AMI. PLGA is dissolved in an acetone / dimethylformamide mixed solution, and alprostadil is added to obtain a PLGA / alprostadil solution.

[0065] By changing factors such as the molecular weight of PLGA, the copolymer ratio and the preparation process, the degradation rate of PLGA can be adjusted, thereby adjusting the release rate of the alprostadil drug. For example, the solvent is a mixture of acetone / dimethylformamide with a volume ratio of 2:1, the PLGA molecular weight can be selected from 2000Da, 3000Da, 5000Da, the PLGA concentration can be selected from 10%, 15%, 20%, 25%, and the alprostadil drug concentration can be selected from 1%, 5%, 10%, 15%.

[0066] Finally, the prepared PLGA / alprostadil solution was sprayed on the cobalt-chromium stent, and the solvent was evaporated by vacuum drying to obtain a dual-drug coated cobalt-chromium stent with the inner wall surface coated with a PLGA / alprostadil coating and the outer wall surface coated with a PLA / everolimus coating.

[0067] Here, alprostadil can also be replaced by other drugs that are effective in preventing and treating CMD after AMI, such as nicorandil; PLGA can also be replaced by other biodegradable polymers, such as polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly(L-glutamic acid) (PGA), polymethacrylic acid (PMAA), polymethacrylate-N,N-dimethylaminoethyl ester (PDMAEMA), poly-4-vinylpyridine (P4-VP), etc.

[0068] Through the above steps, a new type of dual-drug coated coronary vascular stent can be obtained, whose outer wall is loaded with anti-proliferative drug coating, which exerts targeted anti-intimal hyperplasia effect by directly contacting the coronary endothelium. At the same time, its inner wall is sprayed with a drug coating that improves microcirculation. The drug release rate is controlled by controlling the coating degradation rate. The released drug flows with the blood to the coronary microcirculation, which can play a targeted and efficient role in improving CMD after AMI.

[0069] The dual-drug coated coronary vascular stent prepared in this embodiment improves the drug loading and drug types of the drug-coated stent, and has the dual functions of resisting intimal hyperplasia and improving coronary microcirculation disorders. It is particularly effective in improving coronary microcirculation disorders after emergency stent implantation in patients with acute myocardial infarction.

[0070] The coronary stent provided in this application is powerful and low-cost, has broad application prospects in the fields of biomedical engineering, materials science, and cardiovascular disease treatment, has huge market demand, and is expected to play an important role in the future medical field.

[0071] It should be understood that although the terms "first", "second", etc. may be used herein to describe various units, these units should not be limited by these terms. These terms are used only to distinguish one unit from another. For example, a first unit may be referred to as a second unit, and similarly, a second unit may be referred to as a first unit without departing from the scope of the exemplary embodiments.

[0072] In addition, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, system, product, or apparatus that includes a series of steps or elements is not necessarily limited to those steps or elements explicitly listed, but may include other steps or elements not explicitly listed or inherent to such process, method, product, or apparatus.

[0073] The above is only a preferred embodiment of the present application, and is not any formal or substantial limitation to the present application. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present application, and these improvements and supplements should also be regarded as the protection scope of the present application. Any technician familiar with this profession can make some changes, modifications and evolutions of the technical content disclosed above without departing from the spirit and scope of the present application, which are equivalent embodiments of the present application; at the same time, any changes, modifications and evolutions of any equivalent changes made to the above embodiments based on the substantial technology of the present application are still within the scope of the technical solution of the present application.

Claims

1. A coronary stent, characterized in that: The coronary artery stent comprises: Coronary stent body; A first drug-loaded coating is applied to the outer wall of the coronary stent body, wherein the first drug-loaded coating comprises a biodegradable polymer and a first active drug for preventing intimal hyperplasia; The second drug-loaded coating is coated on the inner wall of the coronary stent body, and the second drug-loaded coating comprises a biodegradable polymer and a second active drug for improving coronary microcirculation disorders.

2. The coronary stent according to claim 1, characterized in that: The outer wall of the vascular stent body is provided with a groove, and the first drug-loaded coating is coated in the groove.

3. The coronary stent according to claim 1, characterized in that: The biodegradable polymer is any one of polylactic acid, polylactic acid-co-glycolic acid, polycaprolactone, polyglycolic acid, poly(L-glutamic acid), polymethacrylic acid, polymethacrylic acid-N,N-dimethylaminoethyl ester, and poly-4-vinylpyridine.

4. The coronary stent according to claim 1, characterized in that: The first active drug is any one of everolimus, rapamycin, paclitaxel, enoxaparin, bivalirudin, clopidogrel, prasugrel, and ticagrelor.

5. The coronary stent according to claim 1, characterized in that: The second active drug is alprostadil or nicorandil.

6. A method for preparing a coronary stent according to any one of claims 2 to 5, characterized in that: The preparation method comprises the following steps: Preparing the coronary stent body; Cleaning the coronary stent body; A groove is etched on the outer wall of the coronary stent body, and a first mixed drug solution is dripped into the groove by a fixed-point drip irrigation method, and a first drug-loaded coating is formed after vacuum volatilization; the first mixed drug solution includes a biodegradable polymer and a first active drug for preventing intimal hyperplasia; A second mixed drug liquid is sprayed on the outer wall of the coronary stent body, and a second drug-loaded coating is formed after vacuum volatilization; the second mixed drug liquid includes a biodegradable polymer and a second active drug for improving coronary microcirculation disorders.

7. The method for preparing a coronary stent according to claim 6, characterized in that: The coronary stent body is a cobalt-chromium stent; and / or Cleaning the coronary stent body includes: The coronary stent body is ultrasonically cleaned in acetone, alcohol and deionized water respectively, and then the surface of the coronary stent body is deeply cleaned by plasma technology; The cleaned coronary stent body is immersed in an acid solution and etched in ultrasound. The etched coronary stent body is taken out and ultrasonically cleaned with deionized water. After cleaning, it is dried for later use.

8. The method for preparing a coronary stent according to claim 7, characterized in that: The acid solution is a mixed acid solution of HNO3, HF and H2O2; and the mixed acid solution is prepared by first adding HF and H2O2, and then adding HNO3 in that order.

9. The method for preparing a coronary stent according to claim 6, characterized in that: Etching the groove on the outer wall of the coronary stent body specifically comprises: etching the groove on the outer wall of the coronary stent body using laser etching technology; and / or The groove depth is 20-30 μm.

10. Use of the coronary stent as described in any one of claims 2 to 5 in improving coronary microcirculatory disorders (CMD) in patients with acute myocardial infarction who undergo emergency stent implantation (AMI), wherein the first drug-loaded coating on the outer wall of the coronary stent directly contacts the coronary intima to exert a targeted anti-intimal hyperplasia effect; at the same time, by controlling the degradation rate of the biodegradable polymer in the second drug-loaded coating on the inner wall of the coronary stent, the release rate of the second active drug is controlled, and the released second active drug flows with the blood to the coronary microcirculation, thereby exerting a targeted improvement of CMD after AMI.

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