泌尿系统管道狭窄(例如输尿管狭窄、尿道狭窄)是泌尿系统常见疾病，除先天性狭窄外，炎症、损伤是导致泌尿系统管道狭窄的主要原因，比如常见的原因有输尿管镜检查，钬、铥激光碎石，各种盆腔手术，输尿管感染，尿道管腔感染等。Urinary tract stenosis (such as ureteral stenosis and urethral stenosis) is a common urinary system disease. In addition to congenital stenosis, inflammation and injury are the main causes of urinary tract stenosis. Common causes include ureteroscopy, holmium and thulium laser lithotripsy, various pelvic surgeries, ureteral infection, urethral lumen infection, etc.

目前临床上对于泌尿系统管道狭窄的治疗方式有反复扩张术、切开术、吻合术、拖入术、替代成形术等手术方式，术后，患者需要植入支架做支撑、引流。目前市面上的支架只做物理支撑、引流作用，并未对损伤起到修复或治疗作用，支架植入后反而可能会刺激机体引发炎症，使得损伤部位形成瘢痕组织，从而导致泌尿系统管道再狭窄。针对泌尿系统管道再狭窄，若反复进行手术则容易引起其它并发症，不仅给患者身体和精神上带来巨大的痛苦，也会增加经济负担。At present, the clinical treatments for urinary tract stenosis include repeated dilatation, incision, anastomosis, traction, replacement plasty and other surgical methods. After surgery, patients need to implant stents for support and drainage. The stents currently on the market only provide physical support and drainage, and do not repair or treat injuries. After stent implantation, it may stimulate the body to cause inflammation, causing scar tissue to form at the site of injury, thereby leading to restenosis of the urinary tract. In case of restenosis of the urinary tract, repeated surgery is likely to cause other complications, which will not only cause great physical and mental pain to patients, but also increase the economic burden.

因此，提供一种可以预防或降低泌尿系管道再狭窄的支架非常有必要。Therefore, it is very necessary to provide a stent that can prevent or reduce restenosis of the urinary tract.

发明内容Summary of the invention

本发明的目的在于提供一种支架及其应用，所述支架一方面可以对泌尿系统管道起到支撑、引流的作用，另一方面能够预防或降低泌尿系统管道再狭窄的发生，且所述支架具有低药量高效率的治疗效果，以及具有较久的释药周期和较好的缓释能力。The purpose of the present invention is to provide a stent and its application. The stent can support and drain the urinary system duct on the one hand, and can prevent or reduce the occurrence of restenosis of the urinary system duct on the other hand. The stent has a low-dose and high-efficiency therapeutic effect, as well as a longer drug release cycle and better sustained-release ability.

为达此目的，本发明采用以下技术方案：To achieve this object, the present invention adopts the following technical solutions:

本发明的目的之一在于提供一种支架，用于泌尿系统管道，所述支架包括支架基体以及设置在所述支架基体上的药物。当所述支架植入泌尿系统管道中时，所述支架基体对泌尿系统管道起到支撑、引流的作用，所述药物用于预防或降低所述泌尿系统管道再狭窄的发生。One of the purposes of the present invention is to provide a stent for use in a urinary system conduit, the stent comprising a stent matrix and a drug disposed on the stent matrix. When the stent is implanted in a urinary system conduit, the stent matrix supports and drains the urinary system conduit, and the drug is used to prevent or reduce the occurrence of restenosis of the urinary system conduit.

在其中一个具体实施方式中，所述泌尿系统管道为输尿管和/或尿道，相应地，所述支架为输尿管支架和/或尿道支架。具体地，植入泌尿系统管道的支架可以为输尿管支架，可以为尿道支架，也可以为输尿管支架和尿道支架的组合，本领域技术人员可根据实际需要进行调整。其中输尿管支架是置于输尿管中的，一方面可以对输尿管起到支撑、引流的作用，另一方面可以预防或降低输尿管再狭窄的发生；尿道支架是置于尿道中的，一方面可以对尿道起到支撑、引流的作用，另一方面可以预防或降低尿道再狭窄的发生。In one specific embodiment, the urinary system conduit is a ureter and/or urethra, and correspondingly, the stent is a ureteral stent and/or a urethral stent. Specifically, the stent implanted in the urinary system conduit can be a ureteral stent, a urethral stent, or a combination of a ureteral stent and a urethral stent, and those skilled in the art can adjust it according to actual needs. Among them, the ureteral stent is placed in the ureter, on the one hand, it can support and drain the ureter, and on the other hand, it can prevent or reduce the occurrence of ureteral restenosis; the urethral stent is placed in the urethra, on the one hand, it can support and drain the urethra, and on the other hand, it can prevent or reduce the occurrence of urethral restenosis.

在其中一个具体实施方式中，在输尿管中植入一个或一个以上的所述输尿管支架，本领域技术人员可根据实际需要调整具体的植入数量；同理，在尿道中植入一个或一个以上的所述尿道支架，本领域技术人员可根据实际需要调整具体的植入数量。In one specific embodiment, one or more ureteral stents are implanted in the ureter, and those skilled in the art can adjust the specific number of implantations according to actual needs; similarly, one or more urethral stents are implanted in the urethra, and those skilled in the art can adjust the specific number of implantations according to actual needs.

在其中一个具体实施方式中，所述输尿管支架可以是单J管，可以是双J管，也可以是直管，本领域技术人员根据实际需要进行选择即可。In one specific embodiment, the ureteral stent can be a single J tube, a double J tube, or a straight tube, and those skilled in the art can select one according to actual needs.

在其中一个具体实施方式中，所述尿道支架可以是单腔导尿管，可以是双腔导尿管，也可以是三腔导尿管；且尿道支架可以是带球囊的，也可以是不带球囊的；本领域技术人员根据实际需要进行选择及调整即可。In one specific embodiment, the urethral stent can be a single-lumen catheter, a double-lumen catheter, or a triple-lumen catheter; and the urethral stent can be with a balloon or without a balloon; technical personnel in this field can select and adjust it according to actual needs.

在其中一个具体实施方式中，单个所述支架的带药量为30μg-200mg，例如30μg、50μg、100μg、500μg、800μg、1mg、10mg、50mg、100mg、150mg、200mg等。In one specific embodiment, the drug dosage of a single stent is 30 μg-200 mg, for example, 30 μg, 50 μg, 100 μg, 500 μg, 800 μg, 1 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, etc.

在其中一个具体实施方式中，单个所述支架每天释放5μg-2mg的药量，例如5μg、10μg、50μg、100μg、300μg、500μg、800μg、1mg、1.2mg、1.5mg、1.8mg、2mg等。In one specific embodiment, a single stent releases 5 μg-2 mg of drug per day, for example, 5 μg, 10 μg, 50 μg, 100 μg, 300 μg, 500 μg, 800 μg, 1 mg, 1.2 mg, 1.5 mg, 1.8 mg, 2 mg, etc.

在其中一个具体实施方式中，单个所述支架的药物的释放周期为5-90天，例如5天、10天、20天、30天、40天、50天、60天、70天、80天、90天等。In one specific embodiment, the drug release period of a single stent is 5-90 days, for example, 5 days, 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, etc.

单个所述支架可以为单个输尿管支架，也可以为单个尿道支架。The single stent may be a single ureteral stent or a single urethral stent.

单个所述支架每天释放5μg-2mg的药量，且单个所述支架的总带药量在30μg-200mg范围内是为了使得每天释放的药量以及总药量达到作用的阈值，从而可以进行有效治疗，与此同时，还使得每天释放的药量以及总药量控制在安全量内，如此，药物用量少但治疗效率高。另外，单个所述支架每天释放5μg-2mg的药量，并持续释放5-90天，释放速度稳定且释放均匀。A single stent releases 5μg-2mg of drug per day, and the total drug amount of a single stent is within the range of 30μg-200mg in order to make the daily released drug amount and the total drug amount reach the threshold of action, so that effective treatment can be carried out. At the same time, the daily released drug amount and the total drug amount are controlled within the safe amount, so that the drug dosage is small but the treatment efficiency is high. In addition, a single stent releases 5μg-2mg of drug per day, and the release continues for 5-90 days, with a stable release rate and uniform release.

在其中一个具体实施方式中，单个所述支架的药物在支架完成植入后的1h-7天(例如1h、6h、12h、18h、1天、2天、3天、4天、45天、6天、7天等)不释放或释放量低于1mg(例如5μg、10μg、50μg、100μg、300μg、500μg、800μg、1mg等)。In one specific embodiment, the drug of a single stent is not released or the released amount is less than 1 mg (e.g., 5μg, 10μg, 50μg, 100μg, 300μg, 500μg, 800μg, 1mg, etc.) within 1h-7 days (e.g., 1h, 6h, 12h, 18h, 1 day, 2 days, 3 days, 4 days, 45 days, 6 days, 7 days, etc.) after the stent is implanted.

单个所述支架的药物在支架完成植入后的1h-7天不释放或释放量低于1mg，是为了避免前期大量药物作用，降低机体的防御和修复功能，从而导致感染扩散和延缓创口愈合。The drug of a single stent is not released or the release amount is less than 1 mg within 1 hour to 7 days after the stent is implanted, in order to avoid the effect of a large amount of drugs in the early stage, which reduces the body's defense and repair functions, thereby causing the spread of infection and delaying wound healing.

在其中一个具体实施方式中，所述药物包括含有糖皮质激素的药物。在炎症早期，糖皮质激素可稳定细胞内溶酶体膜，保护线粒体，减轻渗出、水肿、毛细血管扩张、白细胞浸润及吞噬反应，从而改善红、肿、热、痛等症状；在炎症后期，糖皮质激素可抑制毛细血管和纤维母细胞的增生，抑制胶原蛋白、粘多糖的合成及肉芽组织增生，从而防止粘连及瘢痕形成，进而可以预防或降低泌尿系统管道再狭窄的发生。In one specific embodiment, the drug includes a drug containing glucocorticoids. In the early stage of inflammation, glucocorticoids can stabilize intracellular lysosomal membranes, protect mitochondria, reduce exudation, edema, capillary dilation, leukocyte infiltration and phagocytic reactions, thereby improving symptoms such as redness, swelling, heat, and pain; in the late stage of inflammation, glucocorticoids can inhibit the proliferation of capillaries and fibroblasts, inhibit the synthesis of collagen and mucopolysaccharides and the proliferation of granulation tissue, thereby preventing adhesion and scar formation, and further preventing or reducing the occurrence of restenosis of the urinary system duct.

需要注意的是，糖皮质激素不利于伤口的愈合，如上述所述，单个所述支架的药物在支架完成植入后的1h-7天不释放或释放量低于1mg，这样，就有足够的时间供伤口愈合后再释放含有糖皮质激素的药物。It should be noted that glucocorticoids are not conducive to wound healing. As mentioned above, the drug in a single stent is not released or the release amount is less than 1 mg within 1 hour to 7 days after the stent is implanted. In this way, there is enough time for the drug containing glucocorticoids to be released after the wound heals.

在其中一个具体实施方式中，所述含有糖皮质激素的药物包括氯倍他索、安西奈德、曲安奈德、曲尼斯特、布地奈德、糠酸莫米松、地塞米松、倍他米松、氟米松、氟米龙、氢化可的松碱、利美索龙、去氧米松、可托龙、泼尼卡酯、曲安西龙、罗氟奈德、环索奈德、泼尼松、可的松或确炎舒松中的任意一种或至少两种的组合。In one specific embodiment, the glucocorticoid-containing drug includes any one of clobetasol, amcinonide, triamcinolone acetonide, quiniste, budesonide, mometasone furoate, dexamethasone, betamethasone, flumethasone, fluorometholone, hydrocortisone base, rimexolone, desoximetasone, cortolone, prednicarbate, triamcinolone, roflenide, ciclesonide, prednisone, cortisone or triamcinolone, or a combination of at least two thereof.

在其中一个具体实施方式中，考虑到支架植入后，泌尿系统感染是常见的并发症，因此，所述药物还包括抗感染药物，所述抗感染药物包括β内酰胺类、大环内酯类、喹诺酮类、氨基糖苷类、抗病毒类或抗真菌类中的任意一种或至少两种的组合。In one specific embodiment, considering that urinary tract infection is a common complication after stent implantation, the drug also includes an anti-infective drug, which includes any one of β-lactams, macrolides, quinolones, aminoglycosides, antivirals or antifungals, or a combination of at least two of them.

在其中一个具体实施方式中，所述支架基体的材质为可降解材料和/或不可降解材料。In one specific embodiment, the material of the stent matrix is a degradable material and/or a non-degradable material.

在其中一个具体实施方式中，所述支架基体的材质是可降解材料。In one specific embodiment, the material of the stent matrix is a degradable material.

在其中一个具体实施方式中，所述可降解材料包括聚丙交酯、聚丙交酯-乙交酯、聚乙交酯、聚羟基乙酸/聚乳酸共聚物、聚乙二醇、聚己内酯、聚正酯、聚乙醇酸、聚丁二酸丁二醇酯、己内酯-丙交酯共聚物或聚羟基脂肪酸酯中的任意一种或至少两种的组合。In one specific embodiment, the degradable material includes any one or a combination of at least two of polylactide, polylactide-glycolide, polyglycolide, polyglycolic acid/polylactic acid copolymer, polyethylene glycol, polycaprolactone, polyorthoester, polyglycolic acid, polybutylene succinate, caprolactone-lactide copolymer or polyhydroxyalkanoate.

在其中一个具体实施方式中，所述支架基体的材质是不可降解材料。In one specific embodiment, the material of the support matrix is a non-degradable material.

在其中一个具体实施方式中，所述不可降解材料包括橡胶、硅橡胶、聚酯、聚氯乙烯、聚氨酯或金属(例如镍钛合金)中的任意一种或至少两种的组合。In one specific embodiment, the non-degradable material includes any one of rubber, silicone rubber, polyester, polyvinyl chloride, polyurethane or metal (such as nickel-titanium alloy) or a combination of at least two thereof.

在其中一个具体实施方式中，所述支架基体的硬度为60-99A，例如60A、65A、70A、75A、80A、85A、90A、95A、99A等；该硬度的支架基体可以保证对泌尿系统管道具有较好的支撑作用，若支架基体的硬度过低，则容易被挤压变形，难以对泌尿系统管道起到支撑作用，从而影响治疗效果，若支架基体的硬度过高，则不易输送，且可能会损伤泌尿系统管道。In one specific embodiment, the hardness of the stent matrix is 60-99A, for example 60A, 65A, 70A, 75A, 80A, 85A, 90A, 95A, 99A, etc.; the stent matrix of this hardness can ensure good support for the urinary system pipes. If the hardness of the stent matrix is too low, it is easy to be squeezed and deformed, and it is difficult to support the urinary system pipes, thereby affecting the treatment effect. If the hardness of the stent matrix is too high, it is difficult to transport and may damage the urinary system pipes.

根据本发明的其中一个方面，所述药物分散在所述支架基体的内部，形成基质型支架。According to one aspect of the present invention, the drug is dispersed inside the stent matrix to form a matrix-type stent.

在其中一个具体实施方式中，所述药物可以分散在整个所述支架基体的内部，以起到整体治疗的效果；所述药物也可以分散在所述支架基体的某个特定的位置的内部，以根据损伤情况进行针对性的局部治疗。In one specific embodiment, the drug can be dispersed throughout the interior of the stent matrix to achieve an overall therapeutic effect; the drug can also be dispersed within a specific location of the stent matrix to perform targeted local treatment according to the injury condition.

在其中一个具体实施方式中，所述药物可以均匀地分散在整个所述支架基体的内部，以起到整体治疗的效果；所述药物也可以非均匀地分散在整个所述支架基体的内部，损伤严重的部位可以分散多一些，损伤较轻的部位可以分散少一些。In one specific embodiment, the drug can be evenly dispersed throughout the interior of the stent matrix to achieve an overall therapeutic effect; the drug can also be non-uniformly dispersed throughout the interior of the stent matrix, with more drug being dispersed in severely damaged areas and less drug being dispersed in less damaged areas.

在其中一个具体实施方式中，所述药物的粒径为800-12500目，例如800目、1000目、2000目、3000目、4000目、5000目、6000目、7000目、8000目、9000目、10000目、12500目；通过控制所述药物的目数来控制药物的释放速率，从而控制药效以及释放周期；当所述药物的目数过低时，则所述药物的粒径较大，难以从所述支架基体的内部向外溶出，从而影响治疗效果；当所述药物的目数过高时，则所述药物的粒径较小，容易从所述支架的内部向外溶出，会导致血药浓度过高，从而可能引发其他的副反应。In one specific embodiment, the particle size of the drug is 800-12500 mesh, for example 800 mesh, 1000 mesh, 2000 mesh, 3000 mesh, 4000 mesh, 5000 mesh, 6000 mesh, 7000 mesh, 8000 mesh, 9000 mesh, 10000 mesh, 12500 mesh; the release rate of the drug is controlled by controlling the mesh number of the drug, thereby controlling the efficacy and release period; when the mesh number of the drug is too low, the particle size of the drug is large and it is difficult to dissolve outward from the inside of the stent matrix, thereby affecting the therapeutic effect; when the mesh number of the drug is too high, the particle size of the drug is small and it is easy to dissolve outward from the inside of the stent, which will lead to excessively high blood drug concentration, which may cause other side effects.

在其中一个具体实施方式中，当所述支架基体的材质为硅橡胶时，所述支架包括质量百分含量为45-90％(例如45％、50％、55％、60％、65％、70％、75％、80％、85％、90％等)的硅橡胶、5-50％(例如5％、10％、15％、20％、25％、30％、35％、40％、45％、50％等)的药物、0.1-3％(例如0.1％、0.5％、1％、1.5％、2％、2.5％、3％等)的交联剂以及0.1-3％(例如0.1％、0.5％、1％、1.5％、2％、2.5％、3％等)的催化剂；通过控制支架中各物质的添加量，使得各物质相互配合作用，控制药物的释放速率，从而控制药效以及释放周期。In one specific embodiment, when the material of the stent matrix is silicone rubber, the stent includes 45-90% (e.g., 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc.) silicone rubber by mass percentage, 5-50% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc.) drug, 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) cross-linking agent and 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) catalyst; by controlling the amount of each substance added to the stent, the substances cooperate with each other to control the release rate of the drug, thereby controlling the efficacy and release period.

在其中一个具体实施方式中，所述交联剂包括含氢硅油和/或含氢硅氧烷。In one specific embodiment, the cross-linking agent includes hydrogen-containing silicone oil and/or hydrogen-containing siloxane.

在其中一个具体实施方式中，所述催化剂包括铂、铂络合物、钌络合物或铑络合物中的任意一种或至少两种的组合。In one specific embodiment, the catalyst includes any one of platinum, platinum complex, ruthenium complex or rhodium complex, or a combination of at least two thereof.

在其中一个具体实施方式中，所述硅橡胶的交联密度为1000-8000g/mol，例如1500g/mol、2000g/mol、2500g/mol、3000g/mol、3500g/mol、4000g/mol、4500g/mol、5000g/mol、5500g/mol、6000g/mol、6500g/mol、7000g/mol、7500g/mol或8000g/mol等。In one specific embodiment, the crosslinking density of the silicone rubber is 1000-8000 g/mol, for example, 1500 g/mol, 2000 g/mol, 2500 g/mol, 3000 g/mol, 3500 g/mol, 4000 g/mol, 4500 g/mol, 5000 g/mol, 5500 g/mol, 6000 g/mol, 6500 g/mol, 7000 g/mol, 7500 g/mol or 8000 g/mol, etc.

所述硅橡胶的交联密度是指单位体积硅橡胶中所含有的有效网链数目，可表征硅橡胶的交联程度。在测试过程中发现，在相同条件下，硅橡胶的交联密度越大，药物释放量越小。当药物分散在硅橡胶中时，通过控制硅橡胶的交联密度，从而控制药物的释放速率，以达到较好的治疗效果。但是，硅橡胶的交联密度会影响硅橡胶的弹性模量、断裂强度、断裂伸长率等性能。根据测试可得，硅橡胶的交联密度在上述范围内具有最佳的弹性及缓释效果。The cross-linking density of the silicone rubber refers to the number of effective network chains contained in a unit volume of silicone rubber, which can characterize the degree of cross-linking of the silicone rubber. During the test, it was found that under the same conditions, the greater the cross-linking density of the silicone rubber, the smaller the drug release amount. When the drug is dispersed in the silicone rubber, the release rate of the drug is controlled by controlling the cross-linking density of the silicone rubber to achieve a better therapeutic effect. However, the cross-linking density of the silicone rubber will affect the elastic modulus, breaking strength, elongation at break and other properties of the silicone rubber. According to the test, the cross-linking density of the silicone rubber has the best elasticity and sustained-release effect within the above range.

在其中一个具体实施方式中，所述支架的制备方法包括：将硅橡胶、药物、交联剂和催化剂混炼，硫化交联，得到所述支架。In one specific embodiment, the preparation method of the stent includes: mixing silicone rubber, drugs, cross-linking agents and catalysts, and vulcanizing and cross-linking to obtain the stent.

在其中一个具体实施方式中，当所述支架基体的材质为可降解材料时，所述支架包括质量百分含量为49-95％(例如49％、52％、55％、60％、65％、70％、75％、80％、85％、90％、95％等)的可降解材料、4-50％(例如4％、10％、15％、20％、25％、30％、35％、40％、45％、50％等)的药物以及任选的1-20％(例如1％、3％、5％、8％、10％、12％、15％、18％、20％等)的水溶性聚合物。In one specific embodiment, when the material of the stent matrix is a degradable material, the stent includes 49-95% (e.g., 49%, 52%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc.) of degradable material, 4-50% (e.g., 4%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc.) of drugs and optionally 1-20% (e.g., 1%, 3%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, etc.) of water-soluble polymers.

随着尿液的流出，可降解材料在任选的水溶性聚合物的作用下进行降解，即支架基体在任选的水溶性聚合物的作用下进行降解。随着支架基体的降解，分散在支架基体内部的药物随之释放。通过控制任选的水溶性聚合物的添加量以及尿液的流出量可以控制支架基体的降解速率，从而可以控制药物缓慢释放，达到较好的缓释以及治疗效果。通过实验可得，加入1-20％的水溶性聚合物时，药物释放速率较佳。Along with the outflow of urine, the degradable material is degraded under the action of the optional water-soluble polymer, that is, the support matrix is degraded under the action of the optional water-soluble polymer. Along with the degradation of the support matrix, the medicine dispersed in the support matrix is released therewith. The degradation rate of the support matrix can be controlled by controlling the addition amount of the optional water-soluble polymer and the outflow of urine, thereby controlling the slow release of the medicine to achieve a good sustained release and therapeutic effect. It can be obtained through experiments that when 1-20% of the water-soluble polymer is added, the drug release rate is better.

在其中一个具体实施方式中，所述水溶性聚合物包括壳聚糖、明胶、阿拉伯胶、透明质酸、纤维素及其衍生物、聚丙烯酰胺、聚丙烯酸、聚乙烯吡咯烷酮、聚乙烯酸、聚马来酸酐、聚季铵盐或淀粉中的任意一种或至少两种的组合。In one specific embodiment, the water-soluble polymer includes any one or a combination of at least two of chitosan, gelatin, gum arabic, hyaluronic acid, cellulose and its derivatives, polyacrylamide, polyacrylic acid, polyvinyl pyrrolidone, polyvinyl acid, polymaleic anhydride, polyquaternary ammonium salt or starch.

在其中一个具体实施方式中，所述支架的制备方法包括：将可降解材料、药物以及任选的水溶性聚合物在熔融条件下混合，挤出成型，得到所述支架。此种方法要匹配可降解材料与药物的熔点，以防温度太高，药物失活。In one embodiment, the preparation method of the stent includes: mixing a degradable material, a drug, and an optional water-soluble polymer under molten conditions, and extruding to obtain the stent. This method requires matching the melting points of the degradable material and the drug to prevent the drug from being inactivated due to too high a temperature.

在其中一个具体实施方式中，所述支架的制备方法包括：将可降解材料、药物以及任选的水溶性聚合物在溶剂中混合，去除溶剂，加热定型，得到所述支架。In one specific embodiment, the method for preparing the stent comprises: mixing a degradable material, a drug and an optional water-soluble polymer in a solvent, removing the solvent, and heating to shape the mixture to obtain the stent.

对于基质型支架来说，由于药物分散在支架基体的内部，因此，支架基体在选材时，需要选择能够释放药物的材料，除了上述所述的硅橡胶、可降解材料外，还可以是聚酯。基质型支架的药物释放周期相对较长，可以适用于需要长期植入支架的病例。For matrix-type stents, since the drugs are dispersed inside the stent matrix, the stent matrix needs to be selected to release the drug. In addition to the silicone rubber and degradable materials mentioned above, polyester can also be used. The drug release cycle of matrix-type stents is relatively long, which can be applied to cases that require long-term stent implantation.

根据本发明的另一个方面，所述药物分散在所述支架基体的外表面上，在所述支架基体的外表面上形成药物涂层，所述支架为涂层型支架。According to another aspect of the present invention, the drug is dispersed on the outer surface of the stent matrix to form a drug coating on the outer surface of the stent matrix, and the stent is a coated stent.

在其中一个具体实施方式中，药物涂层和支架基体是通过交联作用连接在一起的，其中交联包括化学交联和物理交联，化学交联包括缩聚交联或加聚交联，物理交联包括光交联、热交联、辐射交联或自然交联中的任意一种，本发明对具体的交联方式不做具体限定，本领域技术人员可根据实际需要进行调整。In one specific embodiment, the drug coating and the stent matrix are connected together by cross-linking, wherein the cross-linking includes chemical cross-linking and physical cross-linking, the chemical cross-linking includes condensation cross-linking or addition cross-linking, and the physical cross-linking includes any one of photocross-linking, thermal cross-linking, radiation cross-linking or natural cross-linking. The present invention does not specifically limit the specific cross-linking method, and those skilled in the art can adjust it according to actual needs.

在其中一个具体实施方式中，所述药物涂层以涂覆或包覆的方式设置在支架基体的外表面上。In one specific embodiment, the drug coating is disposed on the outer surface of the stent matrix in a coating or coating manner.

在其中一个具体实施方式中，所述涂覆的方式包括浸渍、纺丝、喷涂或涂刷中的任意一种，优选喷涂。In one specific embodiment, the coating method includes any one of dipping, spinning, spraying or brushing, preferably spraying.

在其中一个具体实施方式中，所述药物涂层可以设置在整个支架基体的外表面上，也可以在支架基体的外表面上局部设置，本领域的技术人员可根据实际需要进行调整。In one specific embodiment, the drug coating can be disposed on the entire outer surface of the stent matrix, or can be disposed partially on the outer surface of the stent matrix, and those skilled in the art can adjust it according to actual needs.

在其中一个具体实施方式中，所述药物涂层的厚度为0.01-1mm，例如0.01mm、0.05mm、0.1mm、0.3mm、0.5mm、0.7mm或1mm等。In one specific embodiment, the thickness of the drug coating is 0.01-1 mm, such as 0.01 mm, 0.05 mm, 0.1 mm, 0.3 mm, 0.5 mm, 0.7 mm or 1 mm.

在其中一个具体实施方式中，所述支架基体包括相对的两端，其中一端为引入端，用于引入尿液，另一端为引出端，用于引出尿液。所述引入端的药物涂层的厚度大于所述引出端的药物涂层的厚度。In one embodiment, the stent matrix includes two opposite ends, one end is an introduction end for introducing urine, and the other end is an extraction end for extracting urine. The thickness of the drug coating at the introduction end is greater than the thickness of the drug coating at the extraction end.

在其中一个具体实施方式中，所述输尿管支架的引入端为近肾脏端，所述输尿管支架的引出端为近膀胱端。In one specific embodiment, the introduction end of the ureteral stent is near the kidney end, and the exit end of the ureteral stent is near the bladder end.

在其中一个具体实施方式中，所述尿道支架的引入端为近膀胱端，所述尿道支架的引出端为近尿道口端。In one specific embodiment, the introduction end of the urethral stent is near the bladder end, and the exit end of the urethral stent is near the urethral opening end.

考虑到在泌尿系统中，正常情况下每天会有1-2L尿液的产生，尿液会沿输尿管、尿道自上而下流出，引入端的药物涂层的厚度大于引出端的药物涂层的厚度，可以弥补因尿液冲刷导致的药物浓度差。从引入端至引出端，药物涂层的厚度可以呈直线型变化，也可以呈曲线型变化，还可以呈梯度型变化，本发明对药物涂层厚度变化的规则不做具体限定，只要满足引入端的药物涂层厚度大于引出端的药物涂层厚度即可。Considering that in the urinary system, 1-2L of urine is normally produced every day, and urine flows from top to bottom along the ureter and urethra, the thickness of the drug coating at the introduction end is greater than the thickness of the drug coating at the lead-out end, which can make up for the drug concentration difference caused by urine flushing. From the introduction end to the lead-out end, the thickness of the drug coating can change in a linear manner, in a curved manner, or in a gradient manner. The present invention does not specifically limit the rule for the change of the drug coating thickness, as long as the thickness of the drug coating at the introduction end is greater than the thickness of the drug coating at the lead-out end.

在其中一个具体实施方式中，所述支架的制备方法包括：将质量百分含量为40-98％(例如40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％、98％等)的生物可降解高分子材料以及2-60％(例如2％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％或60％等)的药物加入(溶解)到溶剂中，混合均匀得到混合液，将所述混合液涂覆在支架基体的外表面上，溶剂挥发后形成药物涂层，得到所述支架。使用时，药物可随着生物可降解高分子材料的降解而释放。其中，支架基体可以预先通过挤出成型、编织成型等方法制备，支架基体的材质不限，只要能够与作为载药基材的生物可降解高分子材料相结合即可。In one specific embodiment, the preparation method of the stent includes: adding (dissolving) a biodegradable polymer material having a mass percentage of 40-98% (e.g., 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, etc.) and a drug having a mass percentage of 2-60% (e.g., 2%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60%, etc.) into a solvent, mixing them evenly to obtain a mixed solution, coating the mixed solution on the outer surface of the stent matrix, and forming a drug coating after the solvent evaporates to obtain the stent. When used, the drug can be released as the biodegradable polymer material degrades. Among them, the stent matrix can be prepared in advance by extrusion molding, weaving molding, etc., and the material of the stent matrix is not limited, as long as it can be combined with the biodegradable polymer material as the drug-carrying substrate.

在其中一个具体实施方式中，生物可降解高分子材料是明胶、淀粉、透明质酸、纤维素、壳聚糖、聚乳酸、聚乙醇酸、聚己内酯、聚丙交酯-己内酯或聚乳酸-己内酯中的任意一种或至少两种的组合。In one specific embodiment, the biodegradable polymer material is any one of gelatin, starch, hyaluronic acid, cellulose, chitosan, polylactic acid, polyglycolic acid, polycaprolactone, polylactide-caprolactone or polylactic acid-caprolactone, or a combination of at least two thereof.

在其中一个具体实施方式中，溶剂可以是水、二氯甲烷、三氯甲烷、丙酮、异丙醇、乙醇、四氢呋喃、六氟异丙醇、六氟丙酮、二甲基亚砜、乙腈、乙醚、醋酸乙酯、正己烷、吡啶、甲苯、苯、二甲基甲酰胺、正庚烷、甲醇、乙胺、乳酸、石油醚、甘油、辛酸、正己醇或环己烷中的任意一种或至少两种的组合。In one specific embodiment, the solvent can be any one of water, dichloromethane, chloroform, acetone, isopropanol, ethanol, tetrahydrofuran, hexafluoroisopropanol, hexafluoroacetone, dimethyl sulfoxide, acetonitrile, ether, ethyl acetate, n-hexane, pyridine, toluene, benzene, dimethylformamide, n-heptane, methanol, ethylamine, lactic acid, petroleum ether, glycerol, caprylic acid, n-hexanol or cyclohexane, or a combination of at least two thereof.

在其中一个具体实施方式中，使用雾化设备将所述混合液雾化成微粒后涂覆在支架基体的外表面上。In one specific embodiment, the mixed solution is atomized into microparticles using an atomization device and then coated on the outer surface of the stent matrix.

在其中一个具体实施方式中，将所述微粒在湿润或半干燥状态下涂覆在支架基体的外表面上。In one embodiment, the microparticles are coated on the outer surface of the stent matrix in a wet or semi-dry state.

在其中一个具体实施方式中，所述微粒的粒径为50nm-500μm(例如50nm、100nm、300nm、500nm、800nm、1μm、5μm、10μm、50μm、100μm、150μm、200μm、250μm、300μm、350μm、400μm、450μm、500μm等)，优选500nm-200μm。In one specific embodiment, the particle size of the microparticles is 50nm-500μm (for example, 50nm, 100nm, 300nm, 500nm, 800nm, 1μm, 5μm, 10μm, 50μm, 100μm, 150μm, 200μm, 250μm, 300μm, 350μm, 400μm, 450μm, 500μm, etc.), preferably 500nm-200μm.

在其中一个具体实施方式中，在进行所述涂覆之前，所述支架的制备方法还包括预先对支架基体的外表面进行处理。In one specific embodiment, before the coating, the method for preparing the stent further comprises pre-treating the outer surface of the stent matrix.

在其中一个具体实施方式中，所述处理的方式包括等离子处理、溶胀处理、喷砂处理、磨砂处理、皮纹处理、静电处理或润湿处理中的任意一种或至少两种的组合。In one specific embodiment, the treatment method includes any one of plasma treatment, swelling treatment, sandblasting treatment, frosting treatment, dermatoglyphics treatment, electrostatic treatment or wetting treatment, or a combination of at least two thereof.

在其中一个具体实施方式中，所述混合液中还包括降解周期长或不可降解的聚合物，所述降解周期长或不可降解的聚合物的质量百分含量为0.5％-10％(例如1％、2％、3％、4％、5％、6％、7％、8％、9％等)，此时，所述生物可降解高分子材料的质量百分含量为40-95％，所述药物的质量百分含量为2-50％。如此，可以降低药物的释放速率。In one specific embodiment, the mixed solution also includes a polymer with a long degradation period or non-degradable polymer, and the mass percentage of the polymer with a long degradation period or non-degradable polymer is 0.5%-10% (for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, etc.), at this time, the mass percentage of the biodegradable polymer material is 40-95%, and the mass percentage of the drug is 2-50%. In this way, the release rate of the drug can be reduced.

在其中一个具体实施方式中，所述降解周期长的聚合物是聚乳酸、聚乙酸醇、含有聚乙醇酸的共混物、聚乙醇酸共聚物或聚乙烯醇中的任意一种或至少两种的组合。In one specific embodiment, the polymer with a long degradation period is any one of polylactic acid, polyacetic acid alcohol, a blend containing polyglycolic acid, a polyglycolic acid copolymer or polyvinyl alcohol, or a combination of at least two thereof.

在其中一个具体实施方式中，所述不可降解的聚合物是聚乙烯吡咯烷酮、聚对二甲苯、硅油、硅凝胶、硅橡胶或聚乙二醇中的任意一种或至少两种的组合。In one specific embodiment, the non-degradable polymer is any one of polyvinyl pyrrolidone, polyparaxylene, silicone oil, silicone gel, silicone rubber or polyethylene glycol, or a combination of at least two thereof.

在其中一个具体实施方式中，所述支架的制备方法包括：将质量百分含量为24-80％(例如25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％等)的硅橡胶、18-70％(例如20％、30％、40％、50％、60％、70％等)的微粉化药物、0.1-3％(例如0.1％、0.5％、1％、1.5％、2％、2.5％、3％等)的交联剂以及0.1-3％(例如0.1％、0.5％、1％、1.5％、2％、2.5％、3％等)的催化剂混炼均匀得到混炼物，而后将所述混炼物和支架基体通过固化结合，得到支架。支架基体可以预先通过挤出成型、编织成型等方法制备。In one specific embodiment, the preparation method of the stent includes: mixing 24-80% (e.g., 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, etc.) of silicone rubber by mass percentage, 18-70% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, etc.) of micronized drug, 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of cross-linking agent and 0.1-3% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of catalyst to obtain a mixture, and then combining the mixture with the stent matrix by curing to obtain the stent. The stent matrix can be prepared in advance by extrusion molding, weaving molding, etc.

在其中一个具体实施方式中，所述支架的制备方法包括：将质量百分含量为24-80％的硅橡胶、18-70％的微粉化药物、0.1-3％的交联剂以及0.1-3％的催化剂混炼均匀得到混炼物，所述混炼物固化得到药膜(即支架完成制备后，位于支架基体外表面上的药物涂层)，而后将所述药膜和支架基体通过二次固化或胶粘的方式结合在一起，得到所述支架。支架基体的材质不限，只要能够与硅橡胶药膜胶粘或二次固化结合即可。支架基体可以预先通过挤出成型、编织成型等方法制备。In one specific embodiment, the preparation method of the stent includes: mixing 24-80% silicone rubber, 18-70% micronized drug, 0.1-3% cross-linking agent and 0.1-3% catalyst by weight to obtain a mixture, curing the mixture to obtain a drug film (i.e., a drug coating on the outer surface of the stent matrix after the stent is prepared), and then combining the drug film and the stent matrix by secondary curing or gluing to obtain the stent. The material of the stent matrix is not limited, as long as it can be bonded or secondary cured with the silicone rubber drug film. The stent matrix can be prepared in advance by extrusion molding, weaving molding and other methods.

二次固化适用于硅橡胶材质的支架基体，将未完全固化的药膜和支架基体经过加压和/或加热进行二段硫化，使支架基体与药膜完整结合。此方法不需要添加新材料，两者结合更牢固，性能稳定。Secondary curing is suitable for stent matrix made of silicone rubber. The incompletely cured drug film and stent matrix are subjected to two-stage vulcanization by pressurization and/or heating to completely combine the stent matrix with the drug film. This method does not require the addition of new materials, and the combination of the two is more solid and the performance is stable.

胶粘适用于所有材质的支架基体，所选胶可以为硅橡胶、UV胶、树脂胶、热熔胶、压敏胶、乳胶等中的任意一种或至少两种的组合，优选硅橡胶。Adhesion is applicable to bracket substrates of all materials, and the selected adhesive can be any one of silicone rubber, UV adhesive, resin adhesive, hot melt adhesive, pressure sensitive adhesive, latex, etc., or a combination of at least two, preferably silicone rubber.

药膜厚度会影响药物的浓度梯度，不同厚度的药膜会使得药物在释放过程中形成不同程度的渗出，从而有不同的释放速率。当药膜厚度为0.01-1mm时，有较好的药效以及较长的释放周期。The thickness of the film will affect the concentration gradient of the drug. Films of different thicknesses will cause different degrees of drug exudation during the release process, resulting in different release rates. When the film thickness is 0.01-1mm, it has better efficacy and a longer release cycle.

在上述两个具体实施方式中，所述交联剂包括含氢硅油和/或含氢硅氧烷。In the above two specific embodiments, the cross-linking agent includes hydrogen-containing silicone oil and/or hydrogen-containing siloxane.

在上述两个具体实施方式中，所述催化剂包括铂、铂络合物、钌络合物或铑络合物中的任意一种或至少两种的组合。In the above two specific embodiments, the catalyst includes any one of platinum, platinum complex, ruthenium complex or rhodium complex, or a combination of at least two thereof.

在上述两个具体实施方式中，微粉化药物的粒径为800-12500目，例如800目、1000目、2000目、3000目、4000目、5000目、6000目、7000目、8000目、9000目、12500目等；通过控制药物的目数来控制药物的释放速率，从而控制药效以及释放周期。药物的目数与药物的释放速率的关系如前述所述，此处不再赘述。In the above two specific embodiments, the particle size of the micronized drug is 800-12500 mesh, such as 800 mesh, 1000 mesh, 2000 mesh, 3000 mesh, 4000 mesh, 5000 mesh, 6000 mesh, 7000 mesh, 8000 mesh, 9000 mesh, 12500 mesh, etc. The release rate of the drug is controlled by controlling the mesh size of the drug, thereby controlling the efficacy and release period. The relationship between the mesh size of the drug and the release rate of the drug is as described above, and will not be repeated here.

在上述两个具体实施方式中，所述硅橡胶的交联密度为1000-8000g/mol，例如1500g/mol、2000g/mol、2500g/mol、3000g/mol、3500g/mol、4000g/mol、4500g/mol、5000g/mol、5500g/mol、6000g/mol、6500g/mol、7000g/mol、7500g/mol或8000g/mol等。通过控制药物涂层中硅橡胶的交联密度来控制药物的释放速率，从而控制药效以及释放周期。硅橡胶的交联密度与药物的释放速率的关系如前述所述，此处不再赘述。In the above two specific embodiments, the cross-linking density of the silicone rubber is 1000-8000g/mol, for example 1500g/mol, 2000g/mol, 2500g/mol, 3000g/mol, 3500g/mol, 4000g/mol, 4500g/mol, 5000g/mol, 5500g/mol, 6000g/mol, 6500g/mol, 7000g/mol, 7500g/mol or 8000g/mol etc. The release rate of the drug is controlled by controlling the cross-linking density of the silicone rubber in the drug coating, thereby controlling drug efficacy and release cycle. The relationship between the cross-linking density of the silicone rubber and the release rate of the drug is as described above, and will not be repeated here.

在上述两个方面中的任一方面的基础上，所述支架基体的外表面上或者所述药物涂层的外表面上还设置有控释层和/或亲水涂层。Based on any one of the above two aspects, a controlled release layer and/or a hydrophilic coating is further provided on the outer surface of the stent matrix or the outer surface of the drug coating.

控释层可以控制药物的释放速率，从而控制药效以及释放周期。The controlled-release layer can control the release rate of the drug, thereby controlling the efficacy and release period.

支架在植入泌尿系统管道的过程中，会与泌尿系统管道的管壁产生一定的摩擦，从而会致使患者出现一定程度的疼痛感。为降低植入过程中的摩擦力，可在支架基体外表面上或者药物涂层外表面上设置一层亲水涂层，当亲水涂层与水或者含水的组织接触时，水滴在亲水涂层表面形成较小的接触角，从而可以使水滴拥有较大的铺展面积，形成一层超润滑的表面水膜，从而降低支架植入泌尿系统管道的过程中的摩擦力。During the implantation of the stent into the urinary system, there will be some friction between the stent and the wall of the urinary system, which will cause a certain degree of pain to the patient. In order to reduce the friction during the implantation process, a hydrophilic coating can be provided on the outer surface of the stent matrix or the outer surface of the drug coating. When the hydrophilic coating contacts water or water-containing tissue, the water droplets form a smaller contact angle on the surface of the hydrophilic coating, so that the water droplets have a larger spreading area and form a super-lubricating surface water film, thereby reducing the friction during the implantation of the stent into the urinary system.

在其中一个具体实施方式中，所述控释层的厚度为0.01-1mm，例如0.01mm、0.05mm、0.1mm、0.2mm、0.3mm、0.4mm、0.5mm、0.6mm、0.7mm、0.8mm、0.9mm、1mm等。In one specific embodiment, the thickness of the controlled release layer is 0.01-1 mm, for example, 0.01 mm, 0.05 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, etc.

在其中一个具体实施方式中，所述控释层的材质为硅橡胶。In one specific embodiment, the controlled release layer is made of silicone rubber.

在其中一个具体实施方式中，所述硅橡胶的交联密度为1000-8000g/mol，例如1000g/mol、1500g/mol、2000g/mol、2500g/mol、3000g/mol、3500g/mol、4000g/mol、4500g/mol、5000g/mol、5500g/mol、6000g/mol、8000g/mol等。In one specific embodiment, the crosslinking density of the silicone rubber is 1000-8000 g/mol, for example 1000 g/mol, 1500 g/mol, 2000 g/mol, 2500 g/mol, 3000 g/mol, 3500 g/mol, 4000 g/mol, 4500 g/mol, 5000 g/mol, 5500 g/mol, 6000 g/mol, 8000 g/mol, etc.

在其中一个具体实施方式中，所述硅橡胶和支架基体或药物涂层是通过胶粘结在一起的。In one specific embodiment, the silicone rubber and the stent matrix or the drug coating are bonded together by glue.

在其中一个具体实施方式中，所述硅橡胶和支架基体或药物涂层是在半固态的状态下固化在一起的。In one specific embodiment, the silicone rubber and the stent matrix or the drug coating are cured together in a semi-solid state.

当控释层的材质为硅橡胶时，通过控制控释层的交联密度来控制药物的释放速率，从而控制药效以及释放周期。硅橡胶的交联密度与药物的释放速率的关系如前述所述，此处不再赘述。When the material of the controlled release layer is silicone rubber, the release rate of the drug is controlled by controlling the crosslinking density of the controlled release layer, thereby controlling the drug efficacy and release cycle. The relationship between the crosslinking density of silicone rubber and the release rate of the drug is as described above and will not be repeated here.

在其中一个具体实施方式中，所述亲水涂层的厚度为0.01-0.5mm，例如0.01mm、0.12mm、0.15mm、0.17mm、0.2mm、0.22mm、0.25mm、0.27mm、0.3mm、0.5mm等。In one specific embodiment, the thickness of the hydrophilic coating is 0.01-0.5 mm, for example, 0.01 mm, 0.12 mm, 0.15 mm, 0.17 mm, 0.2 mm, 0.22 mm, 0.25 mm, 0.27 mm, 0.3 mm, 0.5 mm, etc.

在其中一个具体实施方式中，所述亲水涂层的材质为聚氧化乙烯、聚丙烯酸、聚丙烯酸酰胺、聚乙烯醇、聚乙烯吡咯烷酮、聚异氰酸酯、透明质酸钠或马来酸中的任意一种或至少两种的组合。如此，亲水涂层不会与药物发生化学反应致使药物改性或失活。In one embodiment, the material of the hydrophilic coating is any one of polyethylene oxide, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinyl pyrrolidone, polyisocyanate, sodium hyaluronate or maleic acid, or a combination of at least two of them. In this way, the hydrophilic coating will not chemically react with the drug to modify or inactivate the drug.

在其中一个具体实施方式中，亲水涂层的厚度为0.01-0.5mm，一方面能够均匀充分的与水接触，迅速铺展，形成超光滑的表面水膜，另一方面通过亲水涂层的设置，可以进一步控制药物的释放速率，从而控制药效和释放周期。In one specific embodiment, the thickness of the hydrophilic coating is 0.01-0.5 mm. On the one hand, it can be evenly and fully in contact with water, spread rapidly, and form an ultra-smooth surface water film. On the other hand, the setting of the hydrophilic coating can further control the release rate of the drug, thereby controlling the efficacy and release period.

在其中一个具体实施方式中，所述支架同时包括控释层和亲水涂层，所述控释层设置在支架基体的外表面上或药物涂层的外表面上，亲水涂层设置在控释层的外表面上。In one specific embodiment, the stent includes both a controlled release layer and a hydrophilic coating, wherein the controlled release layer is disposed on the outer surface of the stent matrix or the outer surface of the drug coating, and the hydrophilic coating is disposed on the outer surface of the controlled release layer.

设置药物涂层和/或控释层和/或亲水涂层，使最终得到的支架的直径比市面常规的支架的直径大0.1-1mm，这样可以增加支架的贴壁性，即，可以使得支架与泌尿系统管道的管壁紧密结合，而管壁具有一定的弹性，经反复实验可知，1mm以内的扩张不会影响尿道支架的植入，也不会导致因管壁扩张而额外增加不适感。支架与泌尿系统管道的管壁紧密结合，有利于药物被管壁的粘膜层吸收。The drug coating and/or controlled release layer and/or hydrophilic coating are provided so that the diameter of the final stent is 0.1-1 mm larger than the diameter of conventional stents on the market, which can increase the wall adhesion of the stent, that is, the stent can be tightly combined with the wall of the urinary system pipe, and the wall has a certain elasticity. After repeated experiments, it is known that expansion within 1 mm will not affect the implantation of the urethral stent, nor will it cause additional discomfort due to the expansion of the wall. The stent is tightly combined with the wall of the urinary system pipe, which is conducive to the absorption of the drug by the mucosal layer of the wall.

另外，对于涂层型支架来说，通过设置控释层和/或亲水涂层，可以避免在植入的过程中，药物涂层因摩擦而脱落。In addition, for coated stents, by providing a controlled release layer and/or a hydrophilic coating, it is possible to prevent the drug coating from falling off due to friction during the implantation process.

本发明的目的之二在于提供一种如目的之一所述的支架在制备药物缓释系统中的应用。A second object of the present invention is to provide a use of the stent as described in the first object in the preparation of a drug sustained-release system.

在其中一个具体实施方式中，支架用于泌尿系统管道的支撑、引流以及预防或减少泌尿系统管道再狭窄的发生；进一步地，用于输尿管和/或尿道。In one specific embodiment, the stent is used for supporting and draining the urinary system conduits and preventing or reducing the occurrence of restenosis of the urinary system conduits; further, it is used for the ureter and/or urethra.

相对于现有技术，本发明具有以下有益效果：Compared with the prior art, the present invention has the following beneficial effects:

本发明的支架用于泌尿系统管道，包括支架基体以及设置在所述支架基体上的药物，当所述支架植入所述泌尿系统管道中时，所述支架基体对所述泌尿系统管道起到支撑、引流的作用，所述药物用于预防或降低泌尿系统管道再狭窄的发生，且支架具有低药量高效率的治疗效果以及具有较久的释药周期和较好的缓释能力。另外，本发明的支架可以靶向作用，有效避免了口服用药时肝脏首先要进行代谢的情况，使用剂量是口服或者注射方式的10％左右，大大降低了药物对全身的副作用。The stent of the present invention is used for a urinary system conduit, and includes a stent matrix and a drug arranged on the stent matrix. When the stent is implanted in the urinary system conduit, the stent matrix supports and drains the urinary system conduit, and the drug is used to prevent or reduce the occurrence of restenosis of the urinary system conduit, and the stent has a low-dose, high-efficiency therapeutic effect, a longer drug release cycle, and better sustained-release ability. In addition, the stent of the present invention can act in a targeted manner, effectively avoiding the situation where the liver must first metabolize when taking the drug orally, and the dosage used is about 10% of that of oral or injection methods, which greatly reduces the side effects of the drug on the whole body.

具体实施方式Detailed ways

下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only used to help understand the present invention and should not be regarded as specific limitations of the present invention.

实施例1Example 1

本实施例提供一种支架，包括支架基体以及分散在支架基体中的含有糖皮质激素的药物，其中含有糖皮质激素的药物为糠酸莫米松，平均粒径为5000目，支架基体的材质为硅橡胶，硅橡胶的交联密度为5000g/mol。The present embodiment provides a stent, comprising a stent matrix and a glucocorticoid-containing drug dispersed in the stent matrix, wherein the glucocorticoid-containing drug is mometasone furoate, with an average particle size of 5000 mesh, and the material of the stent matrix is silicone rubber, and the cross-linking density of the silicone rubber is 5000 g/mol.

本实施例提供一种支架的制备方法，包括：将10重量份药物(糠酸莫米松)与30重量份硅橡胶(HTV医用硅橡胶，分子量20-100万)，1.2重量份交联剂(羟基硅油)，1.2重量份催化剂(铂)，在炼胶机上混炼至均匀，硫化交联，在挤出机上挤出成支架。The present embodiment provides a method for preparing a stent, comprising: mixing 10 parts by weight of a drug (mometasone furoate) with 30 parts by weight of silicone rubber (HTV medical silicone rubber, molecular weight 200,000-1,000,000), 1.2 parts by weight of a cross-linking agent (hydroxy silicone oil), and 1.2 parts by weight of a catalyst (platinum) on a rubber mixer until uniform, vulcanizing and cross-linking, and extruding the mixture into a stent on an extruder.

按照标准GB/T531的测试方法对本实施例的支架测试其物理性能，可知：支架基体的硬度为80A。The physical properties of the bracket of this embodiment were tested according to the test method of standard GB/T531, and it was found that the hardness of the bracket matrix was 80A.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为106N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 106N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用高效液相色谱(HPLC)测试溶出药物量，可见在30天内，前7天药物溶出最大量为200μg/d，前7天的药物释放总量为1055μg，30天内平均释放度为80μg/d。The drug content in the sample was calculated by weight, and the sample was subjected to drug dissolution testing in a simulated urine solution at 37°C. The amount of dissolved drug was tested by high performance liquid chromatography (HPLC). It was found that within 30 days, the maximum amount of drug dissolution in the first 7 days was 200 μg/d, the total amount of drug released in the first 7 days was 1055 μg, and the average release within 30 days was 80 μg/d.

采用上述方法制备8F规格的输尿管支架，对其进行动物实验：The above method was used to prepare 8F ureteral stents, and animal experiments were performed on them:

建立输尿管瘢痕机制动物模型，取10只雌性新西兰兔(每只兔子具有2个输尿管)，在输尿管中使用钬激光建立损伤模型，清创后，造影测量狭窄段直径D1和狭窄段远端正常输尿管直径D2，利用计算输尿管狭窄程度。To establish an animal model of ureteral scar mechanism, 10 female New Zealand rabbits (each rabbit had two ureters) were selected and the injury model was established in the ureter using holmium laser. After debridement, the diameter of the stricture segment D1 and the diameter of the normal ureter distal to the stricture segment D2 were measured by angiography. Calculate the degree of ureteral stenosis.

将动物分为实验组和对照组，将实验组5只植入自制的输尿管支架(8F规格，带糠酸莫米松，30天内每天平均释放药量为80μg)，对照组植入市面常规不带药8F规格输尿管支架。分别于1个月后拔管，测量观察瘢痕情况以及狭窄程度，并随访1个月，观察结果见表1。The animals were divided into an experimental group and a control group. Five animals in the experimental group were implanted with a homemade ureteral stent (8F specification, with mometasone furoate, with an average daily release of 80 μg within 30 days), and the control group was implanted with a conventional 8F ureteral stent without drug on the market. The catheters were removed after 1 month, and the scar condition and stenosis degree were measured and observed. The animals were followed up for 1 month. The observation results are shown in Table 1.

表1Table 1

从表1可知，随机植入实验支架和对照支架，采用造影测量尿道狭窄程度，植入一个月后拔管时，实验组狭窄程度为12.94±2.02％，对照组狭窄程度为21.8±11.8％，P为0.043＜0.05，具有显著性差异；拔管1个月后，实验组狭窄程度为7.00±4.57％，对照组狭窄程度为22.1±19.1％，P为0.035＜0.05，具有显著性差异。As can be seen from Table 1, the experimental stent and the control stent were randomly implanted, and the degree of urethral stenosis was measured by angiography. When the catheter was removed one month after implantation, the degree of stenosis in the experimental group was 12.94±2.02%, and the degree of stenosis in the control group was 21.8±11.8%, P was 0.043＜0.05, which was a significant difference; one month after the catheter was removed, the degree of stenosis in the experimental group was 7.00±4.57%, and the degree of stenosis in the control group was 22.1±19.1%, P was 0.035＜0.05, which was a significant difference.

拔管1个月后解剖，取组织切片，使用Image-Pro Plus 6.0软件分析，每张切片选取8处，测量组织的损伤深度。实验组损伤深度为1554±115μm，对照组损伤深度为1777±139μm，P为0.001＜0.05，具有显著性差异。One month after extubation, the tissue sections were dissected and analyzed using Image-Pro Plus 6.0 software. Eight locations were selected from each section to measure the depth of tissue injury. The depth of injury in the experimental group was 1554±115μm, and that in the control group was 1777±139μm, with a P value of 0.001＜0.05, indicating a significant difference.

取组织切片，对组织切片染色，使用Image-pro plus 6.0分析软件测量胶原纤维面积百分比，实验组胶原纤维面积百分比为51.78±5.96％，对照组胶原纤维面积百分比为69.96±3.88％。P为0.000＜0.05，具有显著性差异。Tissue sections were taken and stained, and the percentage of collagen fiber area was measured using Image-pro plus 6.0 analysis software. The percentage of collagen fiber area in the experimental group was 51.78±5.96%, and the percentage of collagen fiber area in the control group was 69.96±3.88%. P was 0.000＜0.05, which was significantly different.

动物实验证明，实验组治疗效果比对照组好。Animal experiments have shown that the treatment effect of the experimental group is better than that of the control group.

采用上述方法制备尿道支架，对其进行动物实验：The urethral stent was prepared by the above method and subjected to animal experiments:

用免疫组织化学SP法检测切片组织中PCNA、bcl-2的表达水平变化。Immunohistochemical SP method was used to detect the changes in the expression levels of PCNA and bcl-2 in the slice tissues.

标本选择正常尿道段及尿道瘢痕段，实验组、对照组拔管1个月后，瘢痕段选取1cm长度。The specimens included normal urethra segments and urethra scar segments. One month after the catheter was removed in the experimental group and the control group, the scar segment was selected with a length of 1 cm.

切片切取后以体积分数10％的甲醛溶液固定，石蜡包埋，1mm厚连续切片。After the slices were cut, they were fixed with 10% formaldehyde solution, embedded in paraffin, and cut into 1 mm thick serial sections.

将切片常规脱蜡，用体积分数为3％的过氧化氢消除内源性过氧化物酶，抗原修复后，正常羊血清封闭，依次加入一抗、二抗，DAB显色，苏木精复染，封片观察。The sections were routinely dewaxed, and endogenous peroxidase was eliminated with 3% hydrogen peroxide. After antigen repair, the sections were blocked with normal goat serum, and primary and secondary antibodies were added in sequence. DAB was used for color development, and hematoxylin was used for counterstaining, and the sections were sealed for observation.

细胞核内含有棕黄色颗粒者为PCNA阳性表达细胞，细胞浆中含有黄色或棕黄色颗粒者为bcl-2阳性表达细胞，见表2。Cells with brown-yellow granules in the nucleus are PCNA-positive cells, and cells with yellow or brown-yellow granules in the cytoplasm are bcl-2-positive cells (see Table 2).

表2Table 2

由表2可知，瘢痕组织中可见大量PCNA和bcl-2阳性表达细胞，与正常尿道相比有显著性差异(P＜0.05)。实验组和对照组拔管1个月后，实验组尿道狭窄率与对照组有显著性差异，实验组狭窄率明显小于对照组；并且对照组可见大量PCNA和bcl-2阳性表达细胞，与实验组相比有显著性差异。As shown in Table 2, a large number of PCNA and bcl-2 positive cells were observed in scar tissue, which was significantly different from that in normal urethra (P < 0.05). One month after the catheter was removed from the experimental group and the control group, the urethral stricture rate in the experimental group was significantly different from that in the control group, and the stricture rate in the experimental group was significantly lower than that in the control group; and a large number of PCNA and bcl-2 positive cells were observed in the control group, which was significantly different from that in the experimental group.

对比例1Comparative Example 1

与实施例1的区别仅在于药物的粒径为500目，其余组成以及制备方法均与实施例1相同。The only difference from Example 1 is that the particle size of the drug is 500 mesh, and the rest of the composition and preparation method are the same as those of Example 1.

按照实施例1的测试方法对本对比例的支架测试其物理性能，可知：支架基体的硬度为78A。The physical properties of the bracket of this comparative example were tested according to the testing method of Example 1, and it was found that the hardness of the bracket matrix was 78A.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为108N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 108N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为60μg/d，后面逐渐平稳趋缓，30天内平均释放度为12μg/d。The drug content in the sample was calculated by weight, and the sample was dissolved in a simulated urine solution at 37°C using a drug dissolution tester. The dissolved drug amount was tested using HPLC, and it was found that within 30 days, the maximum amount of drug dissolution was 60 μg/d in the first 7 days, and then gradually stabilized and slowed down. The average release within 30 days was 12 μg/d.

通过实施例1和对比例1的对比可知，药物目数越低，则药物粒径越大，药物释放量越低。By comparing Example 1 with Comparative Example 1, it can be seen that the lower the drug mesh number, the larger the drug particle size and the lower the drug release amount.

对比例2Comparative Example 2

与实施例1的区别仅在于药物的粒径为15000目，其余组成以及制备方法均与实施例1相同。The only difference from Example 1 is that the particle size of the drug is 15000 mesh, and the rest of the composition and preparation method are the same as those of Example 1.

按照实施例1的测试方法对本对比例的支架测试其物理性能，可知：支架基体的硬度为82A。The physical properties of the bracket of this comparative example were tested according to the testing method of Example 1, and it was found that the hardness of the bracket matrix was 82A.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为105N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 105N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为479μg/d，后面逐渐平稳趋缓，30天内平均释放度为213μg/d。The drug content in the sample was calculated by weight, and the sample was dissolved in a simulated urine solution at 37°C using a drug dissolution tester. The dissolved drug amount was tested using HPLC, and it was found that within 30 days, the maximum amount of drug dissolution was 479 μg/d in the first 7 days, and then gradually stabilized and slowed down. The average release within 30 days was 213 μg/d.

通过实施例1和对比例2的对比可知，药物目数越高，则药物粒径越小，药物释放量越高。By comparing Example 1 and Comparative Example 2, it can be seen that the higher the drug mesh number, the smaller the drug particle size and the higher the drug release amount.

对比例3Comparative Example 3

与实施例1的区别仅在于硅橡胶的交联密度为2000g/mol，其余组成以及制备方法均与实施例1相同。The only difference from Example 1 is that the crosslinking density of the silicone rubber is 2000 g/mol, and the rest of the composition and preparation method are the same as those of Example 1.

按照实施例1的测试方法对本对比例的支架测试其物理性能，可知：支架基体的硬度为60A。The physical properties of the bracket of this comparative example were tested according to the testing method of Example 1, and it was found that the hardness of the bracket matrix was 60A.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为83N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 83N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为305μg/d，后面逐渐平稳趋缓，30天内平均释放度为118μg/d。The drug content in the sample was calculated by weight, and the sample was dissolved in a simulated urine solution at 37°C using a drug dissolution tester. The dissolved drug amount was tested using HPLC, and it was found that within 30 days, the maximum amount of drug dissolution was 305 μg/d in the first 7 days, and then gradually stabilized and slowed down. The average release within 30 days was 118 μg/d.

通过实施例1和对比例3的对比可知，交联密度低会增加药物释放量，降低支架基体的硬度。By comparing Example 1 and Comparative Example 3, it can be seen that low cross-linking density will increase the drug release amount and reduce the hardness of the stent matrix.

对比例4Comparative Example 4

与实施例1的区别仅在于硅橡胶的交联密度为10000g/mol，其余组成以及制备方法均与实施例1相同。The only difference from Example 1 is that the crosslinking density of the silicone rubber is 10000 g/mol, and the rest of the composition and preparation method are the same as those of Example 1.

按照实施例1的测试方法对本对比例的支架测试其物理性能，可知：支架基体的硬度为92A。The physical properties of the bracket of this comparative example were tested according to the testing method of Example 1, and it was found that the hardness of the bracket matrix was 92A.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为136N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 136N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为72μg/d，后面逐渐平稳趋缓，30天内平均释放度为11μg/d。The drug content in the sample was calculated by weight, and the sample was dissolved in a simulated urine solution at 37°C using a drug dissolution tester. The dissolved drug amount was tested using HPLC, and it was found that within 30 days, the maximum amount of drug dissolution was 72 μg/d in the first 7 days, and then gradually stabilized and slowed down. The average release within 30 days was 11 μg/d.

通过实施例1和对比例4的对比可知，交联密度高会降低药物释放量，增加支架基体的硬度。By comparing Example 1 with Comparative Example 4, it can be seen that a high cross-linking density will reduce the drug release amount and increase the hardness of the stent matrix.

实施例2Example 2

本实施例提供一种支架，包括支架基体和分散在支架基体中的含有糖皮质激素的药物，其中支架基体的材质为己内酯-丙交酯共聚物，含有糖皮质激素的药物为布地奈德。This embodiment provides a stent, comprising a stent matrix and a drug containing glucocorticoid dispersed in the stent matrix, wherein the material of the stent matrix is caprolactone-lactide copolymer, and the drug containing glucocorticoid is budesonide.

本实施例提供一种支架的制备方法，包括：将20重量份可降解材料(己内酯-丙交酯共聚物)、1.5重量份含有糖皮质激素的药物(布地奈德)溶解在50ml丙酮中，再加入2重量份水溶性聚合物(纤维素，纤维素先溶解在5ml水中，再加入到丙酮溶液中)混合，去除溶剂，加热定型，得到支架。The present embodiment provides a method for preparing a stent, comprising: dissolving 20 parts by weight of a degradable material (caprolactone-lactide copolymer) and 1.5 parts by weight of a drug containing glucocorticoid (budesonide) in 50 ml of acetone, adding 2 parts by weight of a water-soluble polymer (cellulose, cellulose is first dissolved in 5 ml of water and then added to the acetone solution), mixing, removing the solvent, heating and shaping, and obtaining a stent.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为92N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 92N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出和降解实验，用HPLC测试溶出药物量，30天内平均释放度为73μg/d；7天时取出支架测试径向支撑力，压缩10％的力值为51N，质量损失为12％；30天取出支架测试径向支撑力，压缩10％的力值为13N，质量损失为82％。The drug component content in the sample was calculated according to the weight, and the drug dissolution and degradation experiments were carried out on the samples in a simulated urine solution at 37°C using a drug dissolution tester. The dissolved drug amount was tested using HPLC, and the average release rate within 30 days was 73μg/d. The stent was taken out after 7 days to test the radial support force, and the force value of 10% compression was 51N, and the mass loss was 12%. The stent was taken out after 30 days to test the radial support force, and the force value of 10% compression was 13N, and the mass loss was 82%.

实施例3Example 3

本实施例提供一种支架，包括支架基体和分散在支架基体中的含有糖皮质激素的药物，其中支架基体的材质为聚乙醇酸，含有糖皮质激素的药物为糠酸莫米松。This embodiment provides a stent, comprising a stent matrix and a glucocorticoid-containing drug dispersed in the stent matrix, wherein the stent matrix is made of polyglycolic acid, and the glucocorticoid-containing drug is mometasone furoate.

本实施例提供一种支架的制备方法，包括：将80重量份可降解材料(聚乙醇酸)、5重量份含有糖皮质激素的药物(糠酸莫米松)以及10重量份水溶性聚合物(壳聚糖)在熔融条件(140℃)下混合均匀，挤出定型，得到支架。The present embodiment provides a method for preparing a stent, comprising: uniformly mixing 80 parts by weight of a degradable material (polyglycolic acid), 5 parts by weight of a drug containing glucocorticoid (mometasone furoate), and 10 parts by weight of a water-soluble polymer (chitosan) under a melting condition (140° C.), extruding and shaping, and obtaining a stent.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为103N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 103N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出和降解实验，用HPLC测试溶出药物量，30天内平均释放度为61μg/d；7天时取出支架测试径向支撑力，压缩10％的力值为58N，质量损失为20％；30天取出支架测试径向支撑力，压缩10％的力值为9N，质量损失为88％。The drug component content in the sample was calculated according to the weight, and the drug dissolution and degradation experiments were carried out on the samples in a simulated urine solution at 37°C using a drug dissolution tester. The dissolved drug amount was tested using HPLC, and the average release rate within 30 days was 61μg/d. The stent was taken out after 7 days to test the radial support force, and the force value of 10% compression was 58N, and the mass loss was 20%. The stent was taken out after 30 days to test the radial support force, and the force value of 10% compression was 9N, and the mass loss was 88%.

实施例4Example 4

本实施例提供一种支架，包括支架基体以及涂覆在支架基体外表面上的含有糖皮质激素的药物的药物涂层，其中支架的材质为聚氨酯，含有糖皮质激素的药物的药物涂层的厚度为0.2mm。This embodiment provides a stent, including a stent matrix and a drug coating containing glucocorticoid drugs coated on the outer surface of the stent matrix, wherein the material of the stent is polyurethane, and the thickness of the drug coating containing glucocorticoid drugs is 0.2 mm.

本实施例提供一种支架的制备方法，包括：This embodiment provides a method for preparing a stent, comprising:

(1)将2重量份的生物可降解高分子材料(聚己内酯)、0.2重量份的降解周期长的聚合物(聚乳酸)、0.1重量份的含有糖皮质激素的药物(糠酸莫米松)在50mL丙酮中混合，得到混合液；(1) 2 parts by weight of a biodegradable polymer material (polycaprolactone), 0.2 parts by weight of a polymer with a long degradation period (polylactic acid), and 0.1 parts by weight of a drug containing a glucocorticoid (mometasone furoate) are mixed in 50 mL of acetone to obtain a mixed solution;

(2)将聚氨酯熔融挤出成型得到支架基体；(2) melt-extruding the polyurethane to obtain a stent matrix;

(3)将步骤(2)得到的支架基体用等离子处理30s，使用工装设备将步骤(1)得到的混合液雾化成粒径为50nm-500μm的微粒，均匀喷涂在处理后的支架基体的外表面上，在喷涂过程中采用吹气半干燥，喷涂结束后在40℃干燥箱中干燥使溶剂完全挥发，得到支架。(3) The stent substrate obtained in step (2) is treated with plasma for 30 seconds, and the mixed solution obtained in step (1) is atomized into particles with a particle size of 50nm-500μm using tooling equipment, and the particles are evenly sprayed on the outer surface of the treated stent substrate. During the spraying process, air blowing is used for semi-drying. After spraying, the stent is dried in a drying oven at 40°C to completely evaporate the solvent, thereby obtaining a stent.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为113N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 113N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出实验，用HPLC测试溶出药物量，在30天内，前7天药物溶出最大量为273μg/d，前7天的释放总量为1396μg，30天内平均释放度为92μg/d。The drug content in the sample was calculated by weight, and the sample was subjected to a drug dissolution test in a simulated urine solution at 37°C using a drug dissolution tester. The amount of dissolved drug was tested using HPLC. Within 30 days, the maximum amount of drug dissolved in the first 7 days was 273 μg/d, the total amount released in the first 7 days was 1396 μg, and the average release within 30 days was 92 μg/d.

通过上述方法制备8F规格的输尿管支架，对其进行和实施例1相同的动物实验，取2只雌性新西兰兔，植入一个月后拔管时，实验组平均狭窄率为11.54±1.58％，对照组狭窄程度为21.8±11.8％，P为0.024＜0.05，具有显著性差异；拔管1个月后，实验组狭窄程度为6.09±3.54％，对照组狭窄程度为22.1±19.1％，P为0.029＜0.05，具有显著性差异。An 8F ureteral stent was prepared by the above method, and the same animal experiment as in Example 1 was performed on it. Two female New Zealand rabbits were taken, and when the tube was removed one month after implantation, the average stenosis rate of the experimental group was 11.54±1.58%, and the stenosis degree of the control group was 21.8±11.8%, P was 0.024＜0.05, which was significantly different; one month after the tube was removed, the stenosis degree of the experimental group was 6.09±3.54%, and the stenosis degree of the control group was 22.1±19.1%, P was 0.029＜0.05, which was significantly different.

拔管1个月后解剖，取组织切片，使用Image-Pro Plus 6.0软件分析，每张切片选取8处，测量组织的损伤深度。实验组损伤深度为1470±173μm，对照组损伤深度为1777±139μm，P为0.034＜0.05，具有显著性差异。One month after extubation, the tissue sections were analyzed by Image-Pro Plus 6.0 software, and 8 sites were selected from each section to measure the depth of tissue injury. The depth of injury in the experimental group was 1470±173μm, and the depth of injury in the control group was 1777±139μm, with a P value of 0.034＜0.05, which was significantly different.

取组织切片，对组织切片染色，使用Image-pro plus 6.0分析软件测量胶原纤维面积百分比，实验组胶原纤维面积百分比为46.75±2.59％，对照组胶原纤维面积百分比为69.96±3.88％。P为0.000＜0.05，具有显著性差异。Tissue sections were taken and stained, and the percentage of collagen fiber area was measured using Image-pro plus 6.0 analysis software. The percentage of collagen fiber area in the experimental group was 46.75±2.59%, and the percentage of collagen fiber area in the control group was 69.96±3.88%. P was 0.000＜0.05, which was significantly different.

实施例5Example 5

本实施例提供一种支架，包括支架基体以及包覆在支架基体外表面上的含有糖皮质激素的药物的药物涂层，其中支架的材质为硅橡胶，含有糖皮质激素的药物的药物涂层的厚度为0.3mm。This embodiment provides a stent, including a stent matrix and a drug coating containing glucocorticoid drugs coated on the outer surface of the stent matrix, wherein the material of the stent is silicone rubber, and the thickness of the drug coating containing glucocorticoid drugs is 0.3 mm.

(1)将30重量份的硅橡胶(RTV-2)、10重量份的含有糖皮质激素的微粉化药物(地塞米松，粒径为3000目)、0.6重量份的交联剂(羟基硅油)和0.6重量份的催化剂(铂)混炼均匀，得到混炼物；(1) 30 parts by weight of silicone rubber (RTV-2), 10 parts by weight of a micronized drug containing a glucocorticoid (dexamethasone, with a particle size of 3000 mesh), 0.6 parts by weight of a cross-linking agent (hydroxy silicone oil) and 0.6 parts by weight of a catalyst (platinum) are uniformly mixed to obtain a mixture;

(2)将60重量份的硅橡胶(RTV-2)通过挤出加工定型，得到支架基体；(2) Extruding 60 parts by weight of silicone rubber (RTV-2) to obtain a stent matrix;

(3)将步骤(1)得到的混炼物和步骤(2)得到的支架基体置于模具中，固化(固化的温度为100℃，固化的压力为13MPa，固化的时间为10min)，得到支架。(3) The mixed product obtained in step (1) and the bracket matrix obtained in step (2) are placed in a mold and cured (the curing temperature is 100° C., the curing pressure is 13 MPa, and the curing time is 10 min) to obtain a bracket.

按照实施例1的测试方法对本实施例的支架测试其物理性能，可知：支架基体的硬度为86A。The physical properties of the stent of this embodiment were tested according to the testing method of embodiment 1, and it was found that the hardness of the stent matrix was 86A.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为118μg/d，30天内平均释放度为76μg/d。The drug content in the sample was calculated by weight, and the sample was subjected to drug dissolution testing in a simulated urine solution at 37°C. The amount of dissolved drug was tested by HPLC, and it was found that within 30 days, the maximum amount of drug dissolution in the first 7 days was 118 μg/d, and the average release within 30 days was 76 μg/d.

实施例6Example 6

本实施例提供一种支架，包括支架基体以及包覆在支架基体外表面上的含有糖皮质激素的药物的药物涂层，其中支架的材质为镍钛合金丝，含有糖皮质激素的药物的药物涂层的厚度为0.1mm。This embodiment provides a stent, including a stent matrix and a drug coating containing glucocorticoid drugs coated on the outer surface of the stent matrix, wherein the stent is made of nickel-titanium alloy wire, and the drug coating containing glucocorticoid drugs has a thickness of 0.1 mm.

(1)将25重量份的热硫化型双组份硅橡胶A(道康宁)、6重量份的含有糖皮质激素的微粉化药物(地塞米松，粒径为6000目)、和1.5重量份的催化剂(型号5000PPM，来源天桉)混炼均匀；将25重量份的热硫化型双组份硅橡胶B(道康宁)、6重量份的含有糖皮质激素的微粉化药物(地塞米松，粒径为6000目)、和1.5重量份的交联剂(型号PMX-0930，来源道康宁)混炼均匀；取混炼好的含药A/B取等量混炼均匀，并置于模具中固化(固化的温度为106℃，固化的压力为13MPa，固化的时间为20min)，得到药膜；(1) 25 parts by weight of heat-curable two-component silicone rubber A (Dow Corning), 6 parts by weight of micronized drug containing glucocorticoid (dexamethasone, particle size 6000 mesh), and 1.5 parts by weight of catalyst (model 5000PPM, source Tian Eucalyptus) are mixed evenly; 25 parts by weight of heat-curable two-component silicone rubber B (Dow Corning), 6 parts by weight of micronized drug containing glucocorticoid (dexamethasone, particle size 6000 mesh), and 1.5 parts by weight of cross-linking agent (model PMX-0930, source Dow Corning) are mixed evenly; take equal amounts of the mixed drug-containing A/B, mix evenly, and place in a mold for curing (curing temperature is 106° C., curing pressure is 13 MPa, and curing time is 20 min) to obtain a drug film;

(2)将镍钛合金丝编织定型得到支架基体；(2) braiding and shaping the nickel-titanium alloy wire to obtain a stent matrix;

(3)将步骤(1)得到的药膜和步骤(2)得到的支架基体采用硅橡胶胶(瓦克E41)粘在一起，得到支架。(3) The drug film obtained in step (1) and the stent matrix obtained in step (2) are bonded together using silicone rubber glue (Wacker E41) to obtain a stent.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为73N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 73N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见30天内，前7天药物溶出最大量为296μg/d，平均释放度为97μg/d。The drug content in the sample was calculated by weight, and the sample was subjected to drug dissolution in a simulated urine solution at 37°C using a drug dissolution tester. The amount of dissolved drug was tested using HPLC, and it was found that within 30 days, the maximum amount of drug dissolution in the first 7 days was 296 μg/d, and the average release rate was 97 μg/d.

实施例7Example 7

与实施例1的区别仅在于，支架外表面还包括有控释层，控释层的材质为硅橡胶，硅橡胶的交联密度为1000g/mol，控释层的厚度为0.02mm。The only difference from Example 1 is that the outer surface of the stent further includes a controlled release layer, the material of the controlled release layer is silicone rubber, the cross-linking density of the silicone rubber is 1000 g/mol, and the thickness of the controlled release layer is 0.02 mm.

本实施例还提供一种支架的制备方法包括：This embodiment also provides a method for preparing a stent, comprising:

(1)将硅橡胶混炼均匀后，通过挤出成管状，得到厚度为0.02mm的套管控释层；(1) After the silicone rubber is uniformly kneaded, it is extruded into a tube to obtain a sleeve control release layer with a thickness of 0.02 mm;

(2)将步骤(1)得到的硅橡胶套管控释层沿轴线对剖开，涂胶后套在实施例1制备的支架上，加热固定5min，得到本实施例中的支架。(2) The controlled release layer of the silicone rubber sleeve obtained in step (1) was cut in half along the axis, coated with glue, and sleeved on the stent prepared in Example 1, and heated and fixed for 5 minutes to obtain the stent in this example.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为112N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 112N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为89μg/d，前7天的药物释放总量为796μg，30天内平均释放度为71μg/d。The drug content in the sample was calculated by weight, and the sample was dissolved in a simulated urine solution at 37°C using a drug dissolution tester. The dissolved drug amount was tested using HPLC, and it was found that within 30 days, the maximum amount of drug dissolution in the first 7 days was 89 μg/d, the total amount of drug released in the first 7 days was 796 μg, and the average release within 30 days was 71 μg/d.

实施例8Example 8

与实施例1的区别仅在于，支架外表面还包括有控释层，控释层的材质为硅橡胶，硅橡胶的交联密度为6000g/mol，控释层的厚度为0.2mm。The only difference from Example 1 is that the outer surface of the stent further includes a controlled release layer, the material of the controlled release layer is silicone rubber, the cross-linking density of the silicone rubber is 6000 g/mol, and the thickness of the controlled release layer is 0.2 mm.

(1)将硅橡胶混炼均匀后，通过挤出成管状，得到厚度为0.2mm的套管控释层；(1) After the silicone rubber is uniformly kneaded, it is extruded into a tube to obtain a sleeve control release layer with a thickness of 0.2 mm;

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为128N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 128N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为16μg/d，前7天的药物释放总量为166μg，30天内平均释放度为65μg/d。The drug content in the sample was calculated by weight, and the sample was subjected to drug dissolution in a simulated urine solution at 37°C using a drug dissolution tester. The amount of dissolved drug was tested using HPLC, and it was found that within 30 days, the maximum amount of drug dissolution in the first 7 days was 16 μg/d, the total amount of drug released in the first 7 days was 166 μg, and the average release within 30 days was 65 μg/d.

实施例9Example 9

与实施例1的区别仅在于，支架外表面还设置有亲水涂层，亲水涂层的材质为聚乙烯吡咯烷酮，厚度为0.03mm。The only difference from Example 1 is that a hydrophilic coating is further provided on the outer surface of the stent. The material of the hydrophilic coating is polyvinyl pyrrolidone and the thickness is 0.03 mm.

(1)将聚乙烯吡咯烷酮混合液喷涂在实施例1得到的支架的外表面上，通过紫外光交联固化，得到本实施例中的支架。(1) Spray the polyvinyl pyrrolidone mixed solution onto the outer surface of the stent obtained in Example 1, and crosslink and cure it through ultraviolet light to obtain the stent in this example.

按照实施例1的测试方法对本实施例的支架测试其物理性能，可知：支架的硬度为80A。The physical properties of the bracket of this embodiment are tested according to the testing method of embodiment 1, and it can be found that the hardness of the bracket is 80A.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为5μg/d，前7天的药物释放总量为37μg，30天内平均释放度为53μg/d。The drug content in the sample was calculated by weight, and the sample was subjected to drug dissolution testing in a simulated urine solution at 37°C using a drug dissolution tester. The amount of dissolved drug was tested using HPLC, and it was found that within 30 days, the maximum amount of drug dissolution in the first 7 days was 5 μg/d, the total amount of drug released in the first 7 days was 37 μg, and the average release within 30 days was 53 μg/d.

按照实施例1方法进行输尿管支架的动物实验，随机植入实施例1支架和本实施例支架，1个月拔管后，采用造影测量尿道狭窄程度，实施例1组狭窄程度为12.94±2.02％，本实施例组狭窄程度为9.84±2.70％，P为0.01＜0.05，具有显著性差异；拔管1个月后，实施例1组狭窄程度为7.00±4.57％，本实施例组狭窄程度为2.64±2.54％，P为0.019＜0.05，具有显著性差异。According to the method of Example 1, an animal experiment of ureteral stent was carried out, and the stent of Example 1 and the stent of this example were randomly implanted. After one month of catheter removal, the degree of urethral stenosis was measured by angiography. The degree of stenosis in the Example 1 group was 12.94±2.02%, and the degree of stenosis in the present example group was 9.84±2.70%, P was 0.01＜0.05, which was significantly different. One month after catheter removal, the degree of stenosis in the Example 1 group was 7.00±4.57%, and the degree of stenosis in the present example group was 2.64±2.54%, P was 0.019＜0.05, which was significantly different.

拔管1个月后解剖，取组织切片，使用Image-Pro Plus 6.0软件分析，每张切片选取8处，测量组织的损伤深度。实施例1组损伤深度为1554±115μm，本实施例组损伤深度为1316±134μm，P为0.001＜0.05，具有显著性差异。One month after extubation, the animals were dissected and sliced for analysis using Image-Pro Plus 6.0 software. Eight locations were selected from each slice to measure the depth of tissue injury. The depth of injury in the Example 1 group was 1554±115 μm, and the depth of injury in the present Example group was 1316±134 μm, with a P value of 0.001<0.05, indicating a significant difference.

取组织切片，对组织切片染色，使用Image-pro plus 6.0分析软件测量胶原纤维面积百分比，实施例1组胶原纤维面积百分比为51.78±5.96％，本实施例组胶原纤维面积百分比为40.69±5.43％。P为0.000＜0.05，具有显著性差异。Tissue sections were taken and stained, and the percentage of collagen fiber area was measured using Image-pro plus 6.0 analysis software. The percentage of collagen fiber area in Example 1 group was 51.78±5.96%, and the percentage of collagen fiber area in this example group was 40.69±5.43%. P was 0.000＜0.05, which was significantly different.

动物实验证明，本实施例组比实施例1组治疗效果好。Animal experiments have shown that the treatment effect of this embodiment group is better than that of embodiment 1 group.

实施例10Example 10

与实施例4的区别仅在于，药物涂层外表面还设置有亲水涂层，亲水涂层的材质为马来酸，厚度为0.02mm。The only difference from Example 4 is that a hydrophilic coating is also provided on the outer surface of the drug coating. The material of the hydrophilic coating is maleic acid and the thickness is 0.02 mm.

(1)将马来酸混合液喷涂在实施例4得到的支架的药物涂层外表面上，通过紫外光交联固化，得到本实施例中的支架。(1) The maleic acid mixture was sprayed on the outer surface of the drug coating of the stent obtained in Example 4, and cross-linked and cured by ultraviolet light to obtain the stent in this example.

使用径向支撑测力仪对支架的支撑力进行测试，压缩10％的力值为119N。The support force of the stent was tested using a radial support dynamometer, and the force value for 10% compression was 119N.

根据重量计算样品中的药物成分含量，使用药物溶出试验仪对样品在37℃的模拟尿液溶液中进行药物溶出，用HPLC测试溶出药物量，可见在30天内，前7天药物溶出最大量为3μg/d，前7天的药物释放总量为41μg，30天内平均释放度为62μg/d。The drug content in the sample was calculated by weight, and the sample was subjected to drug dissolution testing in a simulated urine solution at 37°C. The amount of dissolved drug was tested by HPLC, and it was found that within 30 days, the maximum amount of drug dissolution in the first 7 days was 3 μg/d, the total amount of drug released in the first 7 days was 41 μg, and the average release within 30 days was 62 μg/d.

通过上述方法制备8F规格的输尿管支架，对其进行和实施例1相同的动物实验，取2只雌性新西兰兔，植入一个月后拔管时，实验组平均狭窄率为11.06±1.06％，对照组狭窄程度为21.8±11.8％，P为0.019＜0.05，具有显著性差异；拔管1个月后，实验组狭窄程度为5.79±3.09％，对照组狭窄程度为22.1±19.1％，P为0.026＜0.05，具有显著性差异。An 8F ureteral stent was prepared by the above method, and the same animal experiment as in Example 1 was performed on it. Two female New Zealand rabbits were taken, and when the tube was removed one month after implantation, the average stenosis rate of the experimental group was 11.06±1.06%, and the stenosis degree of the control group was 21.8±11.8%, P was 0.019＜0.05, which was significantly different; one month after the tube was removed, the stenosis degree of the experimental group was 5.79±3.09%, and the stenosis degree of the control group was 22.1±19.1%, P was 0.026＜0.05, which was significantly different.

拔管1个月后解剖，取组织切片，使用Image-Pro Plus 6.0软件分析，每张切片选取8处，测量组织的损伤深度。实验组损伤深度为1291±122μm，对照组损伤深度为1777±139μm，P为0.002＜0.05，具有显著性差异。One month after extubation, the tissue sections were analyzed by Image-Pro Plus 6.0 software, and 8 sites were selected from each section to measure the depth of tissue injury. The depth of injury in the experimental group was 1291±122μm, and the depth of injury in the control group was 1777±139μm, with a P value of 0.002＜0.05, which was significantly different.

取组织切片，对组织切片染色，使用Image-pro plus 6.0分析软件测量胶原纤维面积百分比，实验组胶原纤维面积百分比为47.99±5.73％，对照组胶原纤维面积百分比为69.96±3.88％。P为0.002＜0.05，具有显著性差异。Tissue sections were taken and stained, and the percentage of collagen fiber area was measured using Image-pro plus 6.0 analysis software. The percentage of collagen fiber area in the experimental group was 47.99±5.73%, and the percentage of collagen fiber area in the control group was 69.96±3.88%. P was 0.002＜0.05, which was significantly different.

申请人声明，以上所述仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，所属技术领域的技术人员应该明了，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，均落在本发明的保护范围和公开范围之内。The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention are within the protection scope and disclosure scope of the present invention.