Drug eluting stent and manufacturing method thereof

Abstract

The invention relates to a drug eluting stent and a manufacturing method thereof.The manufacturing method comprises the following steps that a stent base material is provided, and the material of the stent base material comprises cobalt-chromium alloy and / or magnesium alloy; preparing a medicine solution, taking everolimus medicine, tacrolimus medicine and a biodegradable high-molecular polymer, and dissolving in an organic solvent to obtain the medicine solution; in the organic solvent, the weight content of the biodegradable high-molecular polymer is 1-30%; spraying: spraying the medicine solution to the surface of the stent base material, and enabling the content of everolimus on the surface of the stent base material to be 6-16 mu g / mm < 2 > and the content of tacrolimus to be 2-7 mu g / mm < 2 >; and drying to volatilize the organic solvent to prepare the drug eluting stent. The drug eluting stent disclosed by the invention can mutually control the drug release rate, is excellent in performance in an implanted animal model, has a curative effect of preventing and treating stent postoperative restenosis, and is higher in safety.

Description

Technical Field

[0001] The present disclosure relates to the field of medicine, and in particular to a drug eluting stent and a method for manufacturing the same. Background Art

[0002] Drug Eluting Stent (DES) is a medical device that uses a bare metal stent platform to carry anti-intimal hyperplasia drugs, which are eluted and released locally in the blood vessels to effectively inhibit intimal hyperplasia and prevent restenosis in the stent. The first generation of DES stents can effectively inhibit the restenosis rate in the blood vessels and effectively inhibit the proliferation of vascular smooth muscle cells. Therefore, drug eluting stents are increasingly used in clinical practice, and their excellent clinical efficacy has brought great encouragement to clinicians and good news to patients.

[0003] Although drug-eluting stents have achieved remarkable results in preventing in-stent restenosis, they still face some challenges, such as delayed endothelial repair after stent implantation, which in turn increases the chance of in-stent thrombosis. For this reason, drug-eluting stents are continuously optimized and innovated. At present, the new research and development directions of DES in the domestic and foreign markets mainly focus on improving the three parts of its composition: ① Improvement of drug carriers: After the drug stent is placed in the diseased blood vessel, the carrier effectively controls the release rate of the drug.

[0004] ② Improvement of the stent delivery system: affecting the delivery and support capabilities of the stent, helping the stent to reach the lesion smoothly and achieve accurate and effective expansion.

[0005] ③ Improvement of drug preparations: Innovative drug preparations can inhibit the intimal hyperplasia of the lesion site and effectively reduce the restenosis rate.

[0006] Currently, researchers are constantly trying to improve drug preparations in order to find a safer and more effective drug to meet clinical needs. Drug innovation has gone from the first generation of DES - Cypher's sirolimus and Taxus's paclitaxel, to the later limus drug derivatives, as well as the attempt to combine the two drugs and the development of the latest antibody stents, but existing drug preparations still face some problems, such as the sensitization and inflammatory effects of polymer coatings, the effective release of drugs, and the precise control of drug release. Summary of the invention

[0007] In view of this, the purpose of the present disclosure is to solve at least one of the problems existing in the prior art. More specifically, the present disclosure aims to provide a method for manufacturing a drug eluting stent, comprising the following steps: S1, providing a stent substrate, wherein the material of the stent substrate includes cobalt-chromium alloy and / or magnesium alloy; S2, preparing a drug solution, taking everolimus drug, tacrolimus drug, and biodegradable polymer, dissolving them in an organic solvent to obtain a drug solution; the weight content of the biodegradable polymer in the organic solvent is 1-30%; S3, spraying, spraying the drug solution onto the surface of the stent substrate, and making the content of everolimus on the surface of the stent substrate be 6-16 μg / mm 2 , the content of tacrolimus is 2~7μg / mm 2 ; S4, drying to volatilize the organic solvent to obtain a drug eluting stent.

[0008] In the aforementioned technical scheme, a drug-eluting stent loaded with everolimus and tacrolimus drugs can be prepared, which can effectively inhibit the proliferation of vascular smooth muscle cells while effectively inhibiting the inflammatory response of vascular endothelial cells, thereby reducing the restenosis rate of blood vessels.

[0009] Optionally, in step S2, in preparing the drug solution, 0.12 g of everolimus drug, 0.05 g of tacrolimus drug, and 0.10 g of biodegradable high molecular polymer are dissolved in 10 ml of organic solvent to obtain a drug solution.

[0010] Optionally, in step S3, during spraying, the drug solution is evenly sprayed onto the surface of the stent substrate by ultrasonic spraying equipment, and the amount of drug applied on the surface of the stent substrate is 460~550ug, wherein the amount of drug applied is the sum of the masses of everolimus drug, tacrolimus drug and biodegradable polymer sprayed onto the surface of the stent substrate.

[0011] In the aforementioned optional scheme, the two drugs after mixing promote each other's release, and an ideal drug release curve can be obtained.

[0012] Optionally, in step S2, preparing the drug solution specifically includes: S21, dissolving a biodegradable polymer and a drug including everolimus in an organic solvent to prepare a first drug solution; S22, dissolving the biodegradable high molecular polymer and drugs including tacrolimus in an organic solvent to prepare a second drug solution.

[0013] Optionally, in step S3, during spraying, the first drug solution and the second drug solution are sprayed layer by layer on the surface of the stent substrate, respectively, and dried layer by layer.

[0014] Optionally, in step S2, in preparing the drug solution, 0.12 g of everolimus, 0.02 g of tacrolimus, and 0.08 g of biodegradable polymer are dissolved in 10 ml of an organic solvent to obtain a first drug solution; 0.06 g of tacrolimus and 0.04 g of biodegradable high molecular polymer were dissolved in 10 ml of organic solvent to obtain a second drug solution.

[0015] Optionally, in step S3, during spraying, the first drug solution is used as the first layer, and the second drug solution is used as the second layer, and they are sprayed layer by layer onto the surface of the stent substrate by an ultrasonic spraying device; Among them, the amount of medicine on the first layer is 280~720ug, and the amount of medicine on the second layer is 280~720ug; The drug application amount is the sum of the masses of everolimus or tacrolimus and biodegradable high molecular polymer sprayed onto the surface of the stent substrate.

[0016] In the above scheme, by spraying everolimus and tacrolimus in layers, the two drugs promote each other's release, and tacrolimus can be quickly released after stent implantation to inhibit the rapid growth of early inflammatory cells; while the everolimus drug on the stent is released for a long time to inhibit the proliferation of endothelial cells for a long time.

[0017] Optionally, the organic solvent is selected from: Tetrahydrofuran, dichloromethane, anhydrous ethanol, chloroform, dimethylformamide or dimethyl sulfoxide.

[0018] Optionally, the biodegradable polymers include: One or more of polylactic acid, polylactic acid-glycolic acid copolymer, difatty acid-sebacate acid copolymer, polylactic acid-sebacate acid copolymer.

[0019] Optionally, in step S3, during spraying, the content of everolimus on the surface of the stent substrate is 8-12 μg / mm 2 , the content of tacrolimus is 3~5μg / mm 2 .

[0020] The present disclosure also provides a drug eluting stent, which is manufactured by the manufacturing method described in the aforementioned technical solution and any optional solution thereof.

[0021] The technical solution disclosed in this disclosure can produce the following beneficial effects: The drug-eluting stent in the technical solution disclosed in the present invention is loaded with everolimus and tacrolimus drugs at the same time, and has the effects of inhibiting smooth muscle and intimal hyperplasia (stronger than a single drug), as well as strong anti-inflammatory effects (especially for the rapid growth of inflammatory cells during stent implantation).

[0022] The disclosed technical solution can obtain a more ideal drug release curve by promoting the release of two drugs loaded on the stent surface. Furthermore, by adjusting the multi-layer spraying of the drug, the release of the drug can be more accurately controlled.

[0023] In summary, the disclosed technical solution aims to make full use of the advantages of high strength of cobalt-chromium alloy, combined with anti-proliferative and anti-inflammatory functional composite drugs, and the carrier advantages of high molecular biodegradable polymer materials. The stent performs well in animal models after implantation. In addition, the disclosed technical solution can still control the release requirements of different drugs according to the different effects of the drugs, and control the drug release within the required range, so as to meet the needs of different clinical applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The above and other features, advantages and aspects of the embodiments of the present disclosure will become more apparent with reference to the following detailed description in conjunction with the accompanying drawings. In the accompanying drawings, the same or similar reference numerals represent the same or similar elements, wherein: Figure 1 This is a release rate curve of the everolimus drug in Comparative Example 1 of the present disclosure; Figure 2 This is a release rate curve of the everolimus drug in Comparative Example 2 of the present disclosure; Figure 3 This is a release rate curve of the everolimus drug in Comparative Example 3 of the present disclosure; Figure 4 is a release rate curve of tacrolimus drug in Comparative Example 4 of the present disclosure; Figure 5 is a release rate curve of tacrolimus drug in Comparative Example 5 of the present disclosure; Figure 6 is a release rate curve of tacrolimus drug in Comparative Example 6 of the present disclosure; Figure 7 is a release rate curve of the mixed drug of everolimus and tacrolimus in Example 1 of the present disclosure; Figure 8 is a release rate curve of the mixed drug of everolimus and tacrolimus in Example 2 of the present disclosure; Fig. 9 This is a vascular imaging diagram of the mixed drug of everolimus and tacrolimus used in animal experiments in Example 1 of the present disclosure. DETAILED DESCRIPTION

[0025] The present disclosure will be described more fully below with reference to the accompanying drawings, in which various embodiments are shown. However, the present disclosure can be implemented in many different ways and should not be construed as being limited to the embodiments set forth herein. Instead, these embodiments are provided so that the present disclosure will be exhaustive and complete, and will fully convey the scope of the present disclosure to those skilled in the art.

[0026] The use of the terms "comprising", "having" or "containing", including their grammatical synonyms, should generally be understood as open and non-restrictive, for example not excluding other unrecited elements or steps, unless otherwise specifically stated or otherwise understood from the context.

[0027] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present disclosure is still operable. In addition, two or more steps or actions can be performed simultaneously.

[0028] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0029] Unless otherwise defined, all terms used herein, including technical and scientific terms, have the same meanings as those generally understood by those skilled in the art. Terms defined in commonly used dictionaries should be interpreted as having the same meanings as in the relevant technical context, and unless explicitly defined in the specification, these terms are not interpreted as having formal meanings in an idealized or overly formal sense.

[0030] In addition, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0031] Various reagents, raw materials, instruments or equipment involved in the embodiments, comparative examples and examples can be purchased and obtained from the market.

[0032] For drugs that can be loaded on the surface of drug-eluting stents (DES) (hereinafter referred to as "drug-eluting stents" or "stents"): Rapamycin derivatives (such as everolimus, zotarolimus or bayerolimus, tacrolimus and pimecrolimus, etc.) are more lipophilic than rapamycin and are conducive to the local effect of the drug. Drug-eluting stents loaded with everolimus or tacrolimus can be used as an important tool in interventional cardiology clinical practice.

[0033] Everolimus inhibits the MTOR signaling pathway through molecular inhibition, inhibiting the activity of the MTOR signaling pathway, thereby inhibiting the proliferation of smooth muscle cells; Tacrolimus can effectively inhibit inflammatory cells. In addition, tacrolimus is safe as a drug coating for stents and can significantly reduce vascular intimal hyperplasia.

[0034] Most of the current drug-eluting stents (DES) are single drug-loaded stents, among which drug-eluting stents loaded with everolimus only have the effect of inhibiting smooth muscle and intimal hyperplasia, and have no or only weak anti-inflammatory effect; drug-eluting stents loaded with tacrolimus mainly play an anti-inflammatory role.

[0035] Without wishing to be bound by any theory, the inventors of the present disclosure recognize that inflammation caused by stent implantation can also promote vascular restenosis, so the anti-inflammatory effect of tacrolimus can also indirectly prevent vascular restenosis, that is, inhibit smooth muscle and intimal hyperplasia.

[0036] In view of the above, the inventors of the present disclosure provide a drug-eluting stent having a combination of everolimus and tacrolimus, which, in addition to the respective anti-inflammatory and smooth muscle and intimal hyperplasia inhibition effects of the two drugs, can also play an enhanced role in inhibiting smooth muscle and intimal hyperplasia.

[0037] In the disclosed embodiment, everolimus, tacrolimus and high molecular biodegradable polymer material are dissolved in an organic solution, stirred evenly and then sprayed, so that the two drugs can be released slowly, continuously and stably through the decomposition of the polymer and exert their effects.

[0038] More importantly, after the two drugs are mixed, they can promote each other's release, and an ideal drug release curve that cannot be obtained with a single drug stent can be obtained. On this basis, the disclosed embodiment further proposes a drug stent manufacturing method that sprays layer by layer and controls parameters such as drug concentration in layers, which can make more precise control of drug release, which is in line with the pathological characteristics of patients who have severe inflammation when the stent is just implanted, and need to continue to inhibit the proliferation of endothelial cells for a long time afterwards, and has achieved unexpected and surprising results.

[0039] The method for manufacturing a drug eluting stent provided in the embodiment of the present disclosure specifically comprises the following steps: S1, providing a stent substrate, wherein the material of the stent substrate includes cobalt-chromium alloy and / or magnesium alloy; S2, preparing a drug solution, taking everolimus drug, tacrolimus drug, and biodegradable polymer, dissolving them in an organic solvent to obtain a drug solution; the weight content of the biodegradable polymer in the organic solvent is 1-30%; S3, spraying, spraying the drug solution onto the surface of the stent substrate, and making the content of everolimus on the surface of the stent substrate be 6-16 μg / mm 2 , the content of tacrolimus is 2~7μg / mm 2 ; S4, drying to volatilize the organic solvent to obtain a drug eluting stent.

[0040] The structural features of the stent substrate involved in the embodiments of the present disclosure are the same as those of the prior art and can be selected as appropriate according to specific medical needs. Due to space limitations, the structural features of the stent substrate are not described in detail in this disclosure.

[0041] According to the embodiments of the present disclosure, the support substrate can be made of cobalt-chromium alloy, magnesium alloy, or a combination of cobalt-chromium alloy and magnesium alloy. The components of the cobalt-chromium alloy are, for example, chromium 15-26%, tungsten 10-20%, nickel 9.0-11.0%, iron 3-6%, and the rest is cobalt.

[0042] In the aforementioned steps, the organic solvent may be selected from tetrahydrofuran, dichloromethane, anhydrous ethanol, chloroform, dimethylformamide or dimethyl sulfoxide (DMSO).

[0043] In the aforementioned steps, the biodegradable high molecular polymer can be selected from one or more of the following mixtures: polylactic acid, polylactic acid-glycolic acid copolymer, difatty acid-sebacate copolymer, polylactic acid-sebacate copolymer. The two drugs used in the present disclosure can be released slowly, continuously and stably and exert their effects through the decomposition of the aforementioned polymers.

[0044] In the aforementioned steps, the weight content of the biodegradable high molecular polymer in the organic solvent is preferably 1% to 1.4%, more preferably 1.12% to 1.35%, preferably 1.34% to 1.35%, and preferably 1.12% to 1.13%.

[0045] In a typical embodiment, in step S2, in preparing the drug solution, 0.12 g of everolimus drug, 0.05 g of tacrolimus drug, and 0.10 g of biodegradable high molecular polymer are dissolved in 10 ml of organic solvent to obtain a drug solution.

[0046] In a further preferred embodiment, in step S3, during spraying, the drug solution is evenly sprayed onto the surface of the stent substrate by an ultrasonic spraying device, and the amount of drug applied to the surface of the stent substrate is 460~550ug, wherein the amount of drug applied is the sum of the masses of everolimus drug, tacrolimus drug and biodegradable polymer sprayed onto the surface of the stent substrate.

[0047] Preferably, the above-mentioned drug amount is 460ug~485ug, or 470ug~500ug, or 530ug~550ug, or 490ug~512ug.

[0048] In further experiments, the inventors of the present disclosure found that the above embodiment of mixing two drugs into a solution and spraying them in a single layer is particularly suitable for two drugs with a large difference in molecular weight. For example, an inorganic compound drug and an organic compound drug with a large molecular weight (such as a macrolide structure) are mixed and sprayed in the same layer. The reason may be that in this case, the release of the macromolecular drug can provide a release channel for the small molecule drug, thereby promoting the release of the small molecule drug.

[0049] In the above embodiment, since the molecular weight of everolimus is 958.224 and the molecular weight of tacrolimus is 804.02, everolimus is a larger molecule than tacrolimus, and its release can promote the rapid release of tacrolimus and effectively inhibit the inflammatory response of vascular endothelial cells. Conversely, the release of the smaller molecule of tacrolimus can make the larger molecule of everolimus be released evenly and persistently, which can inhibit the proliferation of endothelial cells for a long time.

[0050] In the aforementioned embodiments, by simultaneously selecting the type and content control of the biodegradable polymer and controlling the content of everolimus and tacrolimus in the coating, both drugs can obtain an ideal release curve that matches the pathological characteristics of the patient.

[0051] The inventors of the present disclosure further considered that although the molecular weights of everolimus and tacrolimus are different, the difference in molecular size between the two is not as obvious as the size difference between inorganic compounds and organic compounds. In order to more accurately regulate the drug release rates of everolimus and tacrolimus, the present disclosure provides the following layered spraying drug embodiments, which are different from the mixed spraying of the aforementioned embodiments: In the aforementioned step S2, preparing the drug solution further comprises: S21, dissolving a biodegradable polymer and a drug including everolimus in an organic solvent to prepare a first drug solution; S22, dissolving the biodegradable high molecular polymer and drugs including tacrolimus in an organic solvent to prepare a second drug solution.

[0052] The first drug solution and the second drug solution are sprayed layer by layer on the surface of the stent substrate.

[0053] Specifically, in step S3, during spraying, the first drug solution and the second drug solution are sprayed layer by layer on the surface of the stent substrate, and dried layer by layer.

[0054] In the aforementioned embodiment, based on the mutual regulation of release rates among everolimus, tacrolimus, and the polymer, the drugs are further sprayed in layers, and in subsequent implementations, the content of everolimus and tacrolimus, the content of polymer, and the amount of drug applied are precisely adjusted layer by layer, thereby achieving more accurate control of the release curves of the two drugs and overcoming the problem that the molecular sizes of everolimus and tacrolimus are not very different, and the release rate control effect is limited in mixed spraying.

[0055] In a typical embodiment, the first drug solution includes not only everolimus and a biodegradable polymer but also a portion of tacrolimus, while the second drug solution includes only a biodegradable polymer and tacrolimus.

[0056] For example, in step S2, 0.12 g of everolimus drug, 0.02 g of tacrolimus drug, and 0.08 g of biodegradable polymer are dissolved in 10 ml of organic solvent to obtain a first drug solution; 0.06 g of tacrolimus drug and 0.04 g of biodegradable polymer are dissolved in 10 ml of organic solvent to obtain a second drug solution.

[0057] Further, in step S3, during spraying, the first drug solution is used as the first layer, and the second drug solution is used as the second layer, and they are sprayed layer by layer onto the surface of the stent substrate through an ultrasonic spraying device; the amount of drug applied on the first layer is 280~720ug, and the amount of drug applied on the second layer is 280~720ug; it should be understood that the amount of drug applied is the sum of the masses of everolimus drug or tacrolimus drug and biodegradable polymer sprayed onto the surface of the stent substrate.

[0058] In the aforementioned steps, the weight content of the biodegradable high molecular polymer in the organic solvent may be 0.8% to 0.9%, or 0.4% to 0.5%.

[0059] In the above embodiments or their preferred and optional embodiments, more preferably, in step S3, during spraying, the content of everolimus on the surface of the stent substrate is 8-12 μg / mm 2 , the content of tacrolimus is 3~5μg / mm 2 .

[0060] Preferably, in step S3, during spraying, the content of everolimus on the surface of the stent substrate is 10 μg / mm 2 , the content of tacrolimus is 4μg / mm 2 .

[0061] In an optional embodiment, the weight ratio of everolimus, tacrolimus and biodegradable high molecular polymer is controlled in the range of 2~35: 1~10:1~100, preferably 2.3~3.2:0.9~2.1:1.8~3.2, preferably 3:2:3, preferably 2.4:1:2.

[0062] In alternative embodiments, the biodegradable polymers in different layers may be the same or different.

[0063] In an optional embodiment, the organic solvents in the first drug solution and the second drug solution may be the same or different.

[0064] In an optional embodiment, the drying time after spraying is about 36 hours, and the drying method is vacuum drying.

[0065] The present disclosure further provides an embodiment of a drug eluting stent product, which is manufactured by the method described in the aforementioned manufacturing method embodiment or any one of its preferred and optional embodiments.

[0066] The embodiment of the drug eluting stent product provided by the present disclosure typically includes a stent substrate made of cobalt-chromium alloy and / or magnesium alloy, on which there is a coating comprising everolimus drug, tacrolimus drug, and biodegradable polymer. The content of everolimus in the coating is 6-16 μg / mm 2 , the content of tacrolimus is 2~7μg / mm 2 More preferably, the content of everolimus is 8-12 μg / mm 2 , the content of tacrolimus is 3~5μg / mm 2 .

[0067] In an embodiment of a typical drug eluting stent product, the total drug loading of the stent is 460-550 ug, which is the sum of the masses of the everolimus drug, tacrolimus drug and biodegradable high molecular polymer sprayed onto the surface of the stent substrate.

[0068] In a typical embodiment of a drug eluting stent product, the stent has two coatings, including an inner first coating and an outer second coating, the first coating including everolimus and a biodegradable polymer, and may also include tacrolimus. The second coating includes tacrolimus and a biodegradable polymer. Preferably, the drug amount on the first coating is 280-720 ug, and the drug amount on the second coating is 280-720 ug.

[0069] In order to demonstrate the control effect of the everolimus-tacrolimus composite drug eluting stent on the drug release rate in the embodiments of the present disclosure, 6 groups of release rate experiments of single drug eluting stents are provided as comparative examples of the present disclosure as follows; and 2 groups of examples are provided, which are release rate experiments of single-layer double drug coating and multi-layer double drug coating products made according to the embodiments of the present disclosure, for comparison with the comparative examples.

[0070] In the following comparative examples and graphs, the horizontal axis is time (d / day) and the vertical axis is release rate (%). The specific method for measuring the release rate in the examples is as follows: The prepared drug-eluting stents were immersed in PBS (Phosphate Buffered Saline) solution and placed in a shaker (oscillation speed 80 r / min). After the corresponding time periods (1d, 7d, 14d, 21d, 28d) (at least 3 stents at each time point), the stents were taken out and the concentrations of everolimus and tacrolimus were tested.

[0071] Comparative Example Single everolimus drug-eluting stent: Comparative Example 1 Dissolve 0.12g of everolimus and 0.24g of polymer in 10mL of tetrahydrofuran solution and stir thoroughly. Use ultrasonic spraying equipment to evenly spray the solution onto the surface of the stent, so that the amount of drug on each stent surface is 500-600ug, and vacuum dry for more than 36 hours to obtain everolimus drug eluting stent. The release results of everolimus drug are shown in Figure 2. Figure 1 shown.

[0072] Comparative Example 2 Dissolve 0.12g of everolimus and 0.10g of polymer in 10mL of tetrahydrofuran solution and stir thoroughly. Use ultrasonic spraying equipment to evenly spray the solution onto the stent surface, so that the amount of drug on each stent surface is 370-450ug, and vacuum dry for more than 36 hours to obtain everolimus drug eluting stent. The release results of everolimus drug are shown in Figure 2. Figure 2 shown.

[0073] Comparative Example 3 Dissolve 0.12g of everolimus and 0.06g of polymer in 10mL of tetrahydrofuran solution and stir thoroughly. Use ultrasonic spraying equipment to evenly spray the solution onto the stent surface, so that the amount of drug on each stent surface is 300-360ug. Vacuum dry for more than 36 hours to obtain everolimus drug eluting stent. The release results of everolimus drug are shown in Figure 2. Figure 3 shown.

[0074] It can be seen that in the comparative examples of the above three single everolimus drug-eluting stents, the highest everolimus release rate is only about 50%, and the overall release rate within 28 days is low. More importantly, the release curve is flat and has no gradient (slope), and the sustained release effect is poor. The long-term sustained release of everolimus cannot be achieved, and it is difficult to inhibit the proliferation of endothelial cells for a long time.

[0075] Single tacrolimus drug control method: Comparative Example 4 Dissolve 0.05g tacrolimus and 0.10g polymer in 10mL tetrahydrofuran solution and stir thoroughly. Use ultrasonic spraying equipment to evenly spray the solution onto the stent surface, so that the amount of drug on each stent surface is 425-510ug. Vacuum dry for more than 36 hours to obtain tacrolimus drug eluting stent. The release results of tacrolimus drug are shown in Figure 4 shown.

[0076] Comparative Example 5 Dissolve 0.05g tacrolimus and 0.05g polymer in 10mL tetrahydrofuran solution and stir thoroughly. Use ultrasonic spraying equipment to evenly spray the solution onto the stent surface, so that the amount of drug on each stent surface is 120-150ug. Vacuum dry for more than 36 hours to obtain tacrolimus drug eluting stent. The release results of tacrolimus drug are shown in Figure 5 shown.

[0077] Comparative Example 6 Dissolve 0.05g tacrolimus and 0.02g polymer in 10mL tetrahydrofuran solution and stir thoroughly. Use ultrasonic spraying equipment to evenly spray the solution onto the stent surface, so that the amount of drug on each stent surface is 360-910ug. Vacuum dry for more than 36 hours to obtain tacrolimus drug eluting stent. The release results of tacrolimus drug are shown in Figure 6 shown.

[0078] As mentioned above, when a patient has just had a stent implanted, inflammation is more severe and more tacrolimus needs to be released to combat inflammation. Figures 4 to 6 As shown, the initial release rates of tacrolimus in Comparative Examples 4 to 6 were not high, ranging from less than 20% to less than 50%, respectively.

[0079] In addition, according to the comparison of Comparative Examples 1 to 6, it can be seen that when simply adjusting the ratio of a single drug and a polymer, it is difficult to have a release process with different gradients of drug release from 1 day to 28 days. The drug release process is extremely slow, the release process is not ideal, and does not match the patient's pathological characteristics.

[0080] Examples Control method for dual drug release of single-layer dual drug coating structure Example 1 Dissolve 0.12g of everolimus, 0.05g of tacrolimus and 0.10g of polymer in 10mL of tetrahydrofuran solution and stir evenly. Use ultrasonic spraying equipment to evenly spray the solution onto the surface of the stent, so that the amount of drug on each stent surface is 460-550ug, and vacuum dry for 36 hours to obtain everolimus and tacrolimus mixed drug eluting stent. Release results are shown in Figure 7 shown.

[0081] It can be seen that in the early stage when a large dose of tacrolimus is urgently needed (severe inflammation), the tacrolimus release rate in Example 1 can exceed 50%, and the release curve of everolimus has a significant slope (gradient), which means that everolimus can be continuously and stably released within a 28-day period, from about 30% to about 85%, and can inhibit the proliferation of endothelial cells for a long time.

[0082] Control method for dual drug release of multi-layer dual drug coating structure Example 2 Dissolve 0.12g everolimus, 0.02g tacrolimus and 0.08g polymer in 10mL tetrahydrofuran solution and stir evenly to form a first layer of drug solution. Dissolve 0.06g tacrolimus and 0.04g polymer in 10mL tetrahydrofuran solution and stir evenly to form a second layer of drug solution. Use ultrasonic spraying equipment to evenly spray the solution onto the surface of the stent so that the amount of drug on the first layer of each stent surface is 280-720ug and the amount of drug on the second layer is 280-720ug. Finally, vacuum dry for 36 hours to obtain everolimus and tacrolimus mixed drug eluting stent. The release results are as follows: Figure 8 shown.

[0083] It can be seen that in the early stage when a large dose of tacrolimus is urgently needed, the tacrolimus release rate in Example 2 can exceed 65%, significantly exceeding any of the above-mentioned single tacrolimus comparative examples, and is also better than Example 1. The release curve of everolimus has a significant slope (release gradient), which means that everolimus can be continuously and stably released within a 28-day scale, from about 35% to about 80%, which is significantly better than any of the above-mentioned single everolimus comparative examples, and can inhibit the proliferation of endothelial cells for a long time.

[0084] Obviously, no matter whether the stent has a single-layer or multi-layer dual-drug coating structure, the two drugs therein can promote each other's release, resulting in a release rate that is completely different from that of a single-drug stent, with unexpected effects.

[0085] According to the comparison between comparative examples 1, 2, 3, 4, 5, 6 and examples 1 and 2, it can be seen that when a single drug is mixed with a polymer, the release curve is relatively flat, and an ideal drug release curve cannot be designed. However, after the two drugs are mixed, the two drugs promote each other's release, and an ideal drug release curve is obtained. And the release of the drug can be precisely controlled by adjusting the multi-layer spraying of the drug.

[0086] Compared with the original drugs such as everolimus and tacrolimus, the mixed drug of everolimus and tacrolimus (a combination of two drugs) has better efficacy in preventing and treating restenosis after stent surgery and is safer.

[0087] Animal experiments The stent coated with the mixed drug of everolimus and tacrolimus prepared in Example 1 was subjected to animal testing. One month later, Fig. 9 As shown in the figure, the intravascular optical coherence tomography (OCT) results showed that the thickness of the vascular endothelium after animal testing was 182±146um. The endothelial coverage on the stent surface was complete, and the vascular intima, middle membrane, and outer membrane were clear, with no obvious inflammatory reaction.

[0088] In summary, the method for manufacturing the mixed drug eluting stent of everolimus and tacrolimus provided in the present disclosure, and the drug eluting stent product formed by the manufacturing, can achieve the effect of accurately controlling the appropriate drug release rate. By adjusting the drug release curves of the two drugs, the inflammatory response of vascular endothelial cells can be effectively inhibited while the proliferation behavior of vascular smooth muscle cells can be effectively inhibited, thereby reducing the restenosis rate of blood vessels. In the early stages of stent implantation surgery, there is often a significant inflammatory response, which also promotes restenosis of blood vessels. The drug eluting stent disclosed in the present disclosure can make tacrolimus in the release of the two drugs be released quickly. Therefore, in the early stages of stent implantation surgery, tacrolimus drugs can significantly inhibit the growth of inflammatory cells, achieve a strong anti-inflammatory effect, and can also inhibit smooth muscle and intimal hyperplasia; and everolimus drugs can be controlled to be released for a long time, achieving the effect of long-term inhibition of endothelial cell hyperplasia. Therefore, the drug release system designed in the present disclosure can ensure that both drugs can be continuously released at an appropriate rate from a few hours after stent implantation to a long period of time, which not only achieves long-term inhibition of the MTOR signaling pathway, but also ensures effective control of inflammatory cells, and this process does not interfere with the normal repair process of the vascular endothelium. This feature has significant clinical value in preventing postoperative restenosis.

[0089] In summary, the mixed drug of everolimus and tacrolimus in the embodiment of the present disclosure can adjust the drug release curves of the two drugs, effectively inhibit the inflammatory response of vascular endothelial cells, and effectively inhibit the proliferation behavior of vascular smooth muscle cells, thereby reducing the vascular restenosis rate.

[0090] Based on the above, those skilled in the art will understand that the technical solutions claimed in the present disclosure and their equivalent technical solutions will be obvious. In addition, those skilled in the art can also make appropriate modifications and changes to the disclosed technical solutions as needed, and these modified and improved technical solutions are also within the scope of protection of the claims of the present disclosure.

Claims

1. A method for manufacturing a drug eluting stent, characterized in that: The steps include: S1, providing a scaffold substrate; S2, preparing a drug solution, taking everolimus drug, tacrolimus drug, and biodegradable polymer, dissolving them in an organic solvent to obtain a drug solution; the weight content of the biodegradable polymer in the organic solvent is 1-30%; S3, spraying, spraying the drug solution onto the surface of the stent substrate, and making the content of everolimus on the surface of the stent substrate be 6-16 μg / mm 2 , the content of tacrolimus is 2~7μg / mm 2 ; S4, drying to volatilize the organic solvent to obtain the drug eluting stent.

2. The method according to claim 1, characterized in that: In step S2, in preparing the drug solution, 0.12 g of everolimus drug, 0.05 g of tacrolimus drug, and 0.10 g of biodegradable high molecular polymer are dissolved in 10 ml of the organic solvent to obtain the drug solution.

3. The method according to claim 1, characterized in that: In step S3, during spraying, the drug solution is evenly sprayed onto the surface of the stent substrate by ultrasonic spraying equipment, and the amount of drug applied on the surface of the stent substrate is 460-550 ug, wherein the amount of drug applied is the sum of the masses of the everolimus drug, the tacrolimus drug and the biodegradable high molecular polymer sprayed onto the surface of the stent substrate.

4. The method according to claim 1, characterized in that: In step S2, preparing the drug solution specifically includes: S21, dissolving a biodegradable polymer and a drug including everolimus in the organic solvent to prepare a first drug solution; S22, dissolving the biodegradable high molecular polymer and the drug including tacrolimus in the organic solvent to prepare a second drug solution.

5. The manufacturing method according to claim 4, characterized in that: In step S3, during spraying, the first drug solution and the second drug solution are sprayed layer by layer on the surface of the stent substrate respectively, and dried layer by layer.

6. The method according to claim 5, characterized in that: In step S2, in preparing a drug solution, 0.12 g of everolimus, 0.02 g of tacrolimus, and 0.08 g of biodegradable high molecular polymer are dissolved in 10 ml of the organic solvent to obtain the first drug solution; 0.06 g of tacrolimus and 0.04 g of biodegradable high molecular polymer were dissolved in 10 ml of the organic solvent to obtain the second drug solution.

7. The manufacturing method according to claim 5, characterized in that: In step S3, during spraying, the first drug solution is used as a first layer, and the second drug solution is used as a second layer, and they are sprayed layer by layer onto the surface of the stent substrate by an ultrasonic spraying device; The amount of the drug on the first layer is 280~720ug, and the amount of the drug on the second layer is 280~720ug; Wherein, the drug application amount is the sum of the masses of the everolimus drug or the tacrolimus drug and the biodegradable high molecular polymer sprayed onto the surface of the stent substrate.

8. The production method according to any one of claims 1 to 7, characterized in that: The material of the support substrate includes cobalt-chromium alloy and / or magnesium alloy.

9. The production method according to any one of claims 1 to 7, characterized in that: The organic solvent is selected from: Tetrahydrofuran, dichloromethane, anhydrous ethanol, chloroform, dimethylformamide or dimethyl sulfoxide.

10. The production method according to any one of claims 1 to 7, characterized in that: The biodegradable high molecular polymer comprises: One or more of polylactic acid, polylactic acid-glycolic acid copolymer, difatty acid-sebacate acid copolymer, polylactic acid-sebacate acid copolymer.

11. The production method according to any one of claims 1 to 7, characterized in that: In step S3, during spraying, the content of everolimus on the surface of the stent substrate is 8-12 μg / mm 2 , the content of tacrolimus is 3~5μg / mm 2 .

12. A drug eluting stent, characterized in that: The drug eluting stent is manufactured by the manufacturing method according to any one of claims 1 to 11.

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