CN111714260A

Movatterモバイル変換

Info

Publication number: CN111714260A
Application number: CN202010694668.6A
Authority: CN
Inventors: 夏佩佩; 晏伟; 魏征
Original assignee: Shanghai Pu Ruitong Medical Technology Co ltd
Current assignee: Yipurun Shanghai Biotechnology Co ltd
Priority date: 2020-07-17
Filing date: 2020-07-17
Publication date: 2020-09-29
Anticipated expiration: 2040-07-17
Also published as: CN111714260B

Abstract

Translated fromChinese

本发明提供一种支架及其应用，所述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。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 invention provides a stent and an application thereof. The stent is used in a urinary system pipeline, and the stent includes a stent base and a drug arranged on the stent base; when the stent is implanted in the urinary system pipeline, The stent matrix plays the role of supporting and draining the urinary system pipeline, the drug is used to prevent or reduce the occurrence of restenosis of the urinary system pipeline, and the stent has a low-dose, high-efficiency treatment effect and a relatively high-efficiency treatment effect. Long drug release cycle and better sustained release ability. In addition, the stent of the present invention can be targeted, effectively avoiding the situation that the liver first needs to metabolize during oral administration, and the dosage is about 10% of that in oral administration or injection, which greatly reduces the side effects of the drug on the whole body.

Description

Translated fromChinese

一种支架及其应用A bracket and its application

技术领域technical field

本发明属于医疗器械领域，涉及一种支架及其应用。The invention belongs to the field of medical devices, and relates to a stent and its application.

背景技术Background technique

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 system stenosis (such as ureteral stenosis, urethral stenosis) is a common disease of the urinary system. In addition to congenital stenosis, inflammation and injury are the main causes of urinary system stenosis. For example, common causes include ureteroscopy, holmium and thulium lasers. Stone crushing, 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 treatment methods for urinary system stenosis include repeated dilation, incision, anastomosis, drag-in operation, and replacement plasty. After surgery, patients need to be implanted with stents for support and drainage. At present, the stents on the market only provide physical support and drainage, and do not repair or treat the injury. After stent implantation, it may stimulate the body and cause inflammation, causing scar tissue to form at the injury site, resulting in restenosis of the urinary system. . In view of the restenosis of the urinary system, repeated operations may easily lead to other complications, which not only bring great pain to the patient's body and mind, 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 urinary tract restenosis.

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, which can support and drain the urinary system pipeline on the one hand, and prevent or reduce the occurrence of restenosis of the urinary system pipeline on the other hand. It has a low-dose and high-efficiency therapeutic effect, as well as a longer drug release cycle and better sustained-release capacity.

为达此目的，本发明采用以下技术方案：For this purpose, 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 objectives of the present invention is to provide a stent for use in a urinary system conduit, the stent comprising a stent base and a drug disposed on the stent base. When the stent is implanted in the urinary system pipeline, the stent matrix plays the role of supporting and draining the urinary system pipeline, and the drug is used to prevent or reduce the occurrence of restenosis of the urinary system pipeline.

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 a urethra, and accordingly, the stent is a ureteral stent and/or a urethral stent. Specifically, the stent implanted in the urinary system pipeline can be a ureteral stent, a urethral stent, or a combination of a ureteral stent and a urethral stent, which can be adjusted by those skilled in the art 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. It plays the role of support and drainage, 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 of the specific embodiments, one or more of the ureteral stents are implanted in the ureter, and those skilled in the art can adjust the specific implantation quantity according to actual needs; similarly, one or more than one ureteral stent is implanted in the urethra. For the urethral stent, those skilled in the art can adjust the specific implantation quantity 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 may be a single J tube, a double J tube, or a straight tube, which can be selected by those skilled in the art 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 a balloon or a Without balloon; those skilled in the art can select and adjust 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-carrying amount of a single stent is 30 μg-200 mg, such as 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 said stent releases a dose of 5 μg-2 mg per day, eg, 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 cycle of a single said stent is 5-90 days, such as 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 5 μg-2 mg of drug per day, and the total drug loading of a single stent is in the range of 30 μg-200 mg, so that the daily drug release and the total drug amount reach the threshold of action, so that effective treatment can be performed. The treatment, at the same time, also makes the amount of the drug released per day and the total amount of the drug controlled within a safe amount, so that the amount of the drug is small but the treatment efficiency is high. In addition, a single said stent releases a dose of 5 μg-2 mg per day, and continues to release 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 said stent is 1h-7 days after the stent is implanted (eg 1h, 6h, 12h, 18h, 1 day, 2 days, 3 days, 4 days, 45 days, 6 days, 7 days, etc.) no release or less than 1 mg (eg, 5 μg, 10 μg, 50 μg, 100 μg, 300 μg, 500 μg, 800 μg, 1 mg, etc.).

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 described stent does not release or releases less than 1 mg within 1h-7 days after the stent is implanted, in order to avoid the effect of a large amount of drugs in the early stage, reduce 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 medicament includes a glucocorticoid-containing medicament. In the early stage of inflammation, glucocorticoids can stabilize intracellular lysosomal membranes, protect mitochondria, reduce exudation, edema, telangiectasia, leukocyte infiltration and phagocytosis, thereby improving symptoms such as redness, swelling, heat, and pain. Glucocorticoids can inhibit the proliferation of capillaries and fibroblasts, inhibit the synthesis of collagen and mucopolysaccharides and the proliferation of granulation tissue, thereby preventing adhesions and scarring, thereby preventing or reducing the occurrence of urinary system duct restenosis.

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 drugs of a single stent do not release or release less than 1 mg within 1h-7 days after stent implantation. In this way, it is sufficient. Time for the wound to heal before releasing the glucocorticoid-containing drug.

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 clobetasol, amcinonide, triamcinolone acetonide, tranister, budesonide, mometasone furoate, dexamethasone, betamethasone , Flumethasone, Flumetholone, Hydrocortisone Base, Rimexolone, Deoxymetasone, Cortorone, Prednisolone, Triamcinolone, Rofluronide, Ciclesonide, Prednisone, Any one or a combination of at least two of cortisone or cortisone.

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 system infection is a common complication after stent implantation, the drug further includes anti-infective drugs, and the anti-infective drugs include beta-lactams, macrolides Any one of, or a combination of at least two of, quinolones, aminoglycosides, antivirals, or antifungals.

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 polylactide, polylactide-glycolide, polyglycolide, polyglycolic acid/polylactic acid copolymer, polyethylene glycol, polycaprolactone, Any one or a combination of at least two of 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 stent 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 or a combination of at least two of rubber, silicone rubber, polyester, polyvinyl chloride, polyurethane, or metal (eg, Nitinol).

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 base is 60-99A, such as 60A, 65A, 70A, 75A, 80A, 85A, 90A, 95A, 99A, etc.; the stent base with this hardness can ensure the stability of the urinary system. It has a good supporting effect. 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 pipeline, thus affecting the treatment effect. If the hardness of the stent matrix is too high, it is difficult to transport, and May damage the urinary tract.

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 in the entire interior of the stent matrix, so as to achieve an overall therapeutic effect; the drug can also be dispersed in a specific position of the stent matrix, Targeted local treatment according to the injury situation.

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 uniformly dispersed in the entire interior of the stent matrix, so as to achieve an overall therapeutic effect; the drug can also be dispersed non-uniformly throughout the interior of the stent matrix, The severely damaged parts can be scattered more, and the less damaged parts can be scattered less.

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, such as 800 mesh, 1000 mesh, 2000 mesh, 3000 mesh, 4000 mesh, 5000 mesh, 6000 mesh, 7000 mesh, 8000 mesh, 9000 mesh , 10000 mesh, 12500 mesh; control the release rate of the drug by controlling the mesh number of the drug, thereby controlling the drug effect and release cycle; when the mesh number of the drug is too low, the particle size of the drug is larger , it is difficult to dissolve out 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 from the inside of the stent. It will lead to 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 support base is silicone rubber, the support includes a mass percentage of 45-90% (for example, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc.) silicone rubber, 5-50% (eg 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.) crosslinker 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 in the stent, the substances cooperate with each other to control the release rate of the drug, thereby controlling the drug effect and release cycle.

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 of the specific embodiments, the crosslinking 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 comprises any one or a combination of at least two of platinum, platinum complexes, ruthenium complexes or rhodium complexes.

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 1000-8000g/mol, such as 1500g/mol, 2000g/mol, 2500g/mol, 3000g/mol, 3500g/mol, 4000g/mol, 4500g/mol mol, 5000g/mol, 5500g/mol, 6000g/mol, 6500g/mol, 7000g/mol, 7500g/mol or 8000g/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 crosslinking density of the silicone rubber refers to the number of effective network chains contained in a unit volume of the silicone rubber, which can characterize the degree of crosslinking 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. When the drug is dispersed in the silicone rubber, the release rate of the drug can be controlled by controlling the cross-linking density of the silicone rubber to achieve a better therapeutic effect. However, the crosslinking density of silicone rubber will affect the elastic modulus, breaking strength, elongation at break and other properties of silicone rubber. According to the test, the crosslinking density of silicone rubber has the best elasticity and slow 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: kneading silicone rubber, a drug, a cross-linking agent and a catalyst, 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 base is a degradable material, the stent comprises a mass percentage of 49-95% (for example, 49%, 52%, 55%, 60%, 65%) , 70%, 75%, 80%, 85%, 90%, 95%, etc.) degradable materials, 4-50% (eg 4%, 10%, 15%, 20%, 25%, 30%, 35%) %, 40%, 45%, 50%, etc.) and optionally 1-20% (eg, 1%, 3%, 5%, 8%, 10%, 12%, 15%, 18%, 20%) etc.) 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。With the flow of urine, the degradable material is degraded under the action of the optional water-soluble polymer, that is, the scaffold matrix is degraded under the action of the optional water-soluble polymer. With the degradation of the stent matrix, the drug dispersed in the stent matrix is released. By controlling the added amount of the optional water-soluble polymer and the outflow of urine, the degradation rate of the stent matrix can be controlled, so that the slow release of the drug can be controlled to achieve better sustained release and therapeutic effect. It can be found by experiments that the drug release rate is better when 1-20% of the water-soluble polymer is added.

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 chitosan, gelatin, gum arabic, hyaluronic acid, cellulose and its derivatives, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyvinyl acid, Any one or a combination of at least two of polymaleic anhydride, polyquaternium 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 specific embodiment, the preparation method of the stent includes: mixing a degradable material, a drug and an optional water-soluble polymer under a molten condition, and extruding to obtain the stent. In this method, the melting point of the degradable material and the drug should be matched to prevent the drug from being deactivated if the temperature is too high.

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 preparation method of the stent includes: mixing a degradable material, a drug and an optional water-soluble polymer in a solvent, removing the solvent, and heating to form the stent 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 stents, since the drug is dispersed in the stent matrix, when selecting the stent matrix, it is necessary to select materials that can release drugs. In addition to the above-mentioned silicone rubber and degradable materials, polyester can also be used. . The drug release cycle of matrix stents is relatively long, which can be suitable for cases requiring 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 base, and a drug coating is formed on the outer surface of the stent base, 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, chemical cross-linking includes polycondensation cross-linking or polyaddition cross-linking, physical cross-linking Crosslinking includes any one of photocrosslinking, thermal crosslinking, radiation crosslinking or natural crosslinking. The present invention does not specifically limit the specific crosslinking 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 of the specific embodiments, the drug coating is disposed on the outer surface of the stent base 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 of the specific embodiments, 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 may be disposed on the outer surface of the entire stent base, or may be partially disposed on the outer surface of the stent base, which can be adjusted by those skilled in the art 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, and the like.

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 specific embodiment, the stent base includes two opposite ends, wherein one end is an introduction end for introducing urine, and the other end is a leading end for drawing out urine. The thickness of the drug coating at the introduction end is greater than the thickness of the drug coating at the leading 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 the proximal end of the kidney, and the leading end of the ureteral stent is the proximal end of the bladder.

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 the proximal end of the bladder, and the leading end of the urethral stent is the proximal urethral orifice 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, under normal circumstances, 1-2L of urine will be produced every day, and the urine will flow out from top to bottom along the ureter and urethra. The thickness of the drug coating at the introduction end is greater than that of the leading end. It can make up for the difference in drug concentration caused by urine flushing. From the lead-in end to the lead-out end, the thickness of the drug coating can change in a straight line, in a curve, or in a gradient. The present invention does not specifically limit the rules for changing the thickness of the drug coating, as long as the introduction It is sufficient that the thickness of the drug coating at the end is greater than the thickness of the drug coating at the leading 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 scaffold comprises: the mass percentage of 40-98% (for example, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%) %, 80%, 85%, 90%, 95%, 98%, etc.) of biodegradable polymer materials and 2-60% (eg 2%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60%, etc.) of the drug is added (dissolved) into the solvent, mixed evenly to obtain a mixed solution, and the mixed solution is coated on the outer surface of the stent matrix, After the solvent is evaporated, a drug coating is formed to obtain the stent. During use, the drug can be released as the biodegradable polymer material degrades. The stent matrix can be prepared in advance by extrusion molding, weaving molding, etc. The material of the stent matrix is not limited, as long as it can be combined with a biodegradable polymer material as a 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 gelatin, starch, hyaluronic acid, cellulose, chitosan, polylactic acid, polyglycolic acid, polycaprolactone, polylactide-caprolactone or Any one or a combination of at least two of polylactic acid-caprolactone.

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 water, dichloromethane, trichloromethane, acetone, isopropanol, ethanol, tetrahydrofuran, hexafluoroisopropanol, hexafluoroacetone, dimethyl sulfoxide, acetonitrile, diethyl ether , any one of 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.

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 particles by an atomizing device and then coated on the outer surface of the stent base.

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 specific embodiment, the microparticles are coated on the outer surface of the stent matrix in a wet or semi-dried 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 particles is 50 nm-500 μm (eg 50 nm, 100 nm, 300 nm, 500 nm, 800 nm, 1 μm, 5 μm, 10 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, etc.), preferably 500 nm-200 μm.

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 is performed, the preparation method of the stent further comprises pre-processing 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 or a combination of at least two of plasma treatment, swelling treatment, sandblasting treatment, frosting treatment, dermatoglyphic treatment, electrostatic treatment or wetting treatment.

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 further includes a long-degradable or non-degradable polymer, and the mass percentage of the long-degraded 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%, The mass percentage of the medicine 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 of the specific embodiments, the polymer with a long degradation cycle is any one or at least two of polylactic acid, polyacetic acid alcohol, a blend containing polyglycolic acid, polyglycolic acid copolymer or polyvinyl alcohol combination of species.

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 or a combination of at least two of polyvinylpyrrolidone, parylene, silicone oil, silicone gel, silicone rubber or polyethylene glycol.

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 comprises: the mass percentage is 24-80% (for example, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%) %, 65%, 70%, 75%, etc.) silicone rubber, 18-70% (eg 20%, 30%, 40%, 50%, 60%, 70%, etc.) micronized drug, 0.1-3% (eg 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) of crosslinking agent and 0.1-3% (eg 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.) catalysts are uniformly kneaded to obtain a kneaded product, and then the kneaded product and the stent matrix are combined by curing to obtain a stent. The stent matrix can be prepared in advance by extrusion molding, braiding molding and other methods.

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: 24-80% by mass of silicone rubber, 18-70% of micronized drug, 0.1-3% of cross-linking agent and 0.1-3% of 3% of the catalyst is uniformly mixed to obtain a mixture, and the mixture is cured to obtain a drug film (that is, the drug coating on the outer surface of the stent base after the stent is prepared), and then the drug film and the stent base are passed through. Secondary curing or gluing are combined together to obtain the stent. The material of the base of the stent is not limited, as long as it can be bonded with the silicone rubber coating or combined with secondary curing. The stent matrix can be prepared in advance by extrusion molding, braiding 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。The secondary curing is suitable for the stent matrix made of silicone rubber. The incompletely cured drug film and the stent matrix are subjected to secondary vulcanization under pressure and/or heating, so that the stent matrix and the drug film are completely combined. This method does not need to add new materials, the combination of the two is stronger 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 suitable for all materials of stent bases, and the selected glue can be any one or a combination of at least two of silicone rubber, UV glue, resin glue, hot melt adhesive, pressure-sensitive adhesive, latex, etc., 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 drug film will affect the concentration gradient of the drug, and the drug film of different thickness will cause the drug to form different degrees of exudation during the release process, thereby having different release rates. When the thickness of the drug film is 0.01-1 mm, it has better efficacy and longer release period.

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 crosslinking 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 or a combination of at least two of platinum, platinum complex, ruthenium complex or rhodium complex.

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 Mesh, 12500 mesh, etc.; the release rate of the drug is controlled by controlling the mesh number of the drug, thereby controlling the efficacy and release period. The relationship between the mesh number 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 crosslinking density of the silicone rubber is 1000-8000g/mol, such as 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 crosslinking density of the silicone rubber in the drug coating, thereby controlling the drug efficacy and release period. The relationship between the crosslinking 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, the outer surface of the stent matrix or the outer surface of the drug coating is further provided with a controlled release layer and/or a hydrophilic 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 drug 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。When the stent is implanted into the urinary system pipeline, a certain degree of friction will be generated with the tube wall of the urinary system pipeline, 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 arranged on the outer surface of the stent base or the outer surface of the drug coating. The surface of the coating forms a smaller contact angle, so that the water droplets have a larger spreading area, forming a super-lubricating surface water film, thereby reducing the friction during the stent implantation in 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, such as 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 , 0.9mm, 1mm, 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 material of the controlled release layer is 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 1000-8000g/mol, such as 1000g/mol, 1500g/mol, 2000g/mol, 2500g/mol, 3000g/mol, 3500g/mol, 4000g/mol mol, 4500g/mol, 5000g/mol, 5500g/mol, 6000g/mol, 8000g/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 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 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 the release period. The relationship between the crosslinking density of the 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 0.01-0.5mm, such as 0.01mm, 0.12mm, 0.15mm, 0.17mm, 0.2mm, 0.22mm, 0.25mm, 0.27mm, 0.3mm, 0.5mm, 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 specific embodiment, the material of the hydrophilic coating is any of polyethylene oxide, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyisocyanate, sodium hyaluronate or maleic acid one or a combination of at least two. In this way, the hydrophilic coating does 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 contact water evenly and sufficiently, spread rapidly, and form an ultra-smooth surface water film. The setting can further control the release rate of the drug, thereby controlling the drug 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, 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 stent matrix or the outer surface of the drug coating. 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 the controlled release layer and/or the hydrophilic coating are arranged, so that the diameter of the final stent is 0.1-1 mm larger than the diameter of the conventional stent in the market, so that the adherence of the stent can be increased, that is, the stent can be made The stent is closely combined with the tube wall of the urinary system, and the tube wall has a certain elasticity. After repeated experiments, it is known that the expansion within 1mm will not affect the implantation of the urethral stent, nor will it cause additional discomfort due to the expansion of the tube wall. . The stent is closely combined with the tube wall of the urinary system, which is conducive to the absorption of the drug by the mucosal layer of the tube 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 a coated stent, by providing a controlled release layer and/or a hydrophilic coating, the drug coating can be prevented from peeling 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。The second purpose of the present invention is to provide an application of the stent according to the first purpose 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 of the specific embodiments, the stent is used for the support and drainage of the urinary system pipeline and the prevention or reduction of the occurrence of restenosis of the urinary system pipeline; further, it is used for the ureter and/or the 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 pipeline, and includes a stent base and a drug arranged on the stent base. When the stent is implanted in the urinary system pipeline, the stent base plays a role in the urinary system pipeline. With the functions of support and drainage, the drug is used to prevent or reduce the occurrence of restenosis in the urinary system, and the stent has a low-dose and high-efficiency treatment effect, as well as a longer drug release cycle and better sustained release capability. In addition, the stent of the present invention can be targeted, effectively avoiding the situation that the liver first needs to metabolize during oral administration, and the dosage is about 10% of that in oral administration or injection, 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 solutions of the present invention are further described below through specific embodiments. It should be understood by those skilled in the art that the embodiments are only for helping the understanding of the present invention, and should not be regarded as a specific limitation 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。This embodiment provides a stent, including a stent matrix and a glucocorticoid-containing drug dispersed in the stent matrix, wherein the glucocorticoid-containing drug is mometasone furoate, the average particle size is 5000 mesh, and the stent matrix is made of Silicone rubber, the crosslinking density of silicone rubber is 5000g/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 million), 1.2 parts by weight of a cross-linking agent ( Hydroxy silicone oil), 1.2 parts by weight of catalyst (platinum), kneaded on a rubber mixing machine until uniform, vulcanized and cross-linked, and extruded 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。According to the test method of standard GB/T531, the physical properties of the stent of this embodiment are tested, and it can be known that the hardness of the stent matrix is 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37°C, and use high performance liquid chromatography (HPLC) to test the amount of the dissolved drug. It can be seen that within 30 days, the first 7 The maximum amount of drug dissolution in one day was 200 μg/d, the total drug release in the first 7 days was 1055 μg, and the average release rate 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：Adopt the above-mentioned method to prepare the ureteral stent of 8F specification, and carry out animal experiment on it:

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 has 2 ureters) were used to establish an injury model in the ureter using a holmium laser. After debridement, angiography was used to measure the diameter of the stenotic segment D1 and the normal ureter at the distal end of the stenotic segment. Diameter D2, using

Calculate the degree of ureteral stricture.

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, and 5 in the experimental group were implanted with self-made ureteral stents (8F specification, with mometasone furoate, and the average daily drug release within 30 days was 80 μg), and the control group was implanted in the market without conventional stents. Medicine 8F specification ureteral stent. The patients were extubated after 1 month, and the scar and stenosis degree were measured and observed. The patients were followed up for 1 month. The 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。It can be seen from Table 1 that the experimental stent and the control stent were randomly implanted, and the degree of urethral stenosis was measured by angiography. When the catheter was extubated after one month of 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, with a significant difference; 1 month after extubation, 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%, and P was 0.035<0.05, with 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 patients were dissected, and tissue sections were taken and analyzed using Image-Pro Plus 6.0 software. Eight locations were selected for each section to measure the depth of tissue damage. The damage depth of the experimental group was 1554±115 μm, and the damage depth of the control group was 1777±139 μm, P was 0.001<0.05, and there was 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。Take tissue sections, stain the tissue sections, and use Image-pro plus 6.0 analysis software to measure the area percentage of collagen fibers. P is 0.000<0.05, there is a significant difference.

动物实验证明，实验组治疗效果比对照组好。Animal experiments proved that the treatment effect of the experimental group was 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 animal experiments were carried out on it:

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。The expression levels of PCNA and bcl-2 in sliced tissues were detected by immunohistochemical SP method.

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 normal urethral segment and the urethral scar segment were selected as the specimens. The length of the scar segment was 1 cm after extubation for one month in the experimental group and the control group.

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 cutting, the sections were fixed with 10% formaldehyde solution, embedded in paraffin, and serially sectioned with a thickness of 1 mm.

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 retrieval, normal goat serum was used to block the sections. Primary antibody and secondary antibody were added in sequence. stained and mounted 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。The cells containing brown-yellow granules in the nucleus were PCNA-positive cells, and those containing yellow or brown-yellow granules in the cytoplasm were bcl-2-positive cells, as shown in 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。It can be seen from Table 2 that a large number of PCNA and bcl-2 positive cells can be seen in the scar tissue, which is significantly different from that of the normal urethra (P<0.05). One month after extubation between the experimental group and the control group, the urethral stenosis rate in the experimental group was significantly different from that in the control group, and the stenosis 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 found in the control group, which was different from the experimental group. There was a significant difference between the groups.

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 meshes, and other compositions and preparation methods 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 stent of this comparative example were tested according to the test method of Example 1, and it was known that the hardness of the stent 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 60μg/d, and then gradually stabilized and slowed down, and the average release rate within 30 days was 12μg/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。It can be seen from the comparison between Example 1 and Comparative Example 1 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 15,000 meshes, and other compositions and preparation methods 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 stent of this comparative example were tested according to the test method of Example 1, and it was known that the hardness of the stent 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 479μg/d, and then gradually stabilized and slowed down, and the average release rate within 30 days was 213μg/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。From the comparison between Example 1 and Comparative Example 2, it can be known 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 stent of this comparative example were tested according to the test method of Example 1, and it was known that the hardness of the stent 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 305μg/d, and then gradually stabilized and slowed down, and the average release rate within 30 days was 118μg/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。From the comparison between Example 1 and Comparative Example 3, it can be known that the low crosslinking density will increase the amount of drug release 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 10,000 g/mol, and the rest of the composition and preparation method are the same as in 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。According to the test method of Example 1, the physical properties of the stent of this comparative example were tested, and it was known that the hardness of the stent 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 72μg/d, then gradually stabilized and slowed down, and the average release rate within 30 days was 11μg/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。It can be seen from the comparison between Example 1 and Comparative Example 4 that high crosslinking density will reduce the amount of drug release 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, including 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 Germany.

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。This 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 glucocorticoid-containing drug (budesonide) in 50 ml of acetone 2 weight parts of water-soluble polymer (cellulose, cellulose is first dissolved in 5 ml of water, and then added to the acetone solution) is added and mixed, the solvent is removed, and the stent is obtained by heating.

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 of 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％。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to conduct drug dissolution and degradation experiments on the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of dissolved drug. The average release rate within 30 days is 73 μg/d; At 7 days, the stent was taken out to test the radial support force, the force of 10% compression was 51N, and the mass loss was 12%; at 30 days, the stent was taken out to test the radial support force, the force 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, including a stent matrix and a drug containing glucocorticoid dispersed in the stent matrix, wherein the material of the stent matrix is polyglycolic acid, and the drug containing glucocorticoid 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。This embodiment provides a method for preparing a stent, including: 80 parts by weight of a degradable material (polyglycolic acid), 5 parts by weight of a glucocorticoid-containing drug (mometasone furoate) and 10 parts by weight of a water-soluble polymer ( Chitosan) was mixed uniformly under melting conditions (140° C.), extruded and shaped 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103N。The support force of the stent was tested using a radial support dynamometer, and the force value of 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％。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to conduct drug dissolution and degradation experiments on the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. The average release rate within 30 days is 61 μg/d; At 7 days, the stent was taken out to test the radial support force, the force of 10% compression was 58N, and the mass loss was 20%; at 30 days, the stent was taken out to test the radial support force, the force 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 base and a drug coating containing a glucocorticoid-containing drug on the outer surface of the stent base, wherein the stent is made of polyurethane, and the drug coating of the glucocorticoid-containing drug is The thickness is 0.2mm.

本实施例提供一种支架的制备方法，包括：The present 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 part by weight of a polymer with a long degradation cycle (polylactic acid), and 0.1 part by weight of a drug containing glucocorticoid (molar furoate) Methasone) was 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) Polyurethane is melt-extruded 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 matrix obtained in step (2) is treated with plasma for 30 s, and the mixed solution obtained in step (1) is atomized into particles with a particle size of 50 nm-500 μm using tooling equipment, and uniformly sprayed on the outside of the treated stent matrix. On the surface, air blowing is used for semi-drying in the spraying process, and after the spraying is completed, it is dried in a drying oven at 40° C. to completely volatilize the solvent 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113N。The support force of the stent was tested using a radial support dynamometer, and the force value of 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。Calculate the content of the drug components in the sample according to the weight, use the drug dissolution tester to carry out the drug dissolution test on the sample in the simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. Within 30 days, the maximum amount of drug dissolution in the first 7 days is 273 μg/d, the total release in the first 7 days was 1396 μg, and the average release rate 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。The ureteral stent of 8F specification was prepared by the above method, and the same animal experiment as in Example 1 was carried out. Two female New Zealand rabbits were taken and extubated one month after implantation. The degree of stenosis in the group was 21.8±11.8%, P was 0.024<0.05, and there was a significant difference; 1 month after extubation, the degree of stenosis in the experimental group was 6.09±3.54%, and the degree of stenosis in the control group was 22.1±19.1%, P=0.029 <0.05, there is 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 patients were dissected, and tissue sections were taken and analyzed using Image-Pro Plus 6.0 software. Eight locations were selected for each section to measure the depth of tissue damage. The damage depth of the experimental group was 1470±173 μm, and the damage depth of the control group was 1777±139 μm, P was 0.034<0.05, and there was 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。Take tissue sections, stain the tissue sections, and use Image-pro plus 6.0 analysis software to measure the area percentage of collagen fibers. P is 0.000<0.05, there is a significant difference.

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 base and a drug coating containing a glucocorticoid drug coated on the outer surface of the stent base, wherein the stent is made of silicone rubber, and the drug coating containing a glucocorticoid drug The thickness is 0.3mm.

(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 glucocorticoid (dexamethasone, particle size of 3000 mesh), 0.6 parts by weight of a cross-linking agent (hydroxysilicone oil) ) and 0.6 parts by weight of catalyst (platinum) are uniformly mixed to obtain a kneaded product;

(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) 60 parts by weight of silicone rubber (RTV-2) is shaped by extrusion 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) placing the kneaded product obtained in step (1) and the support matrix obtained in step (2) in a mold, and curing (the curing temperature is 100° C., the curing pressure is 13 MPa, and the curing time is 10 min) to obtain 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。According to the test method of Example 1, the physical properties of the stent of this embodiment are tested, and it is known that the hardness of the stent matrix is 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 118 μg/d, and the average release rate 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 base and a drug coating containing a glucocorticoid drug on the outer surface of the stent base, wherein the stent is made of nickel-titanium alloy wire, and the drug containing a glucocorticoid drug The thickness of the coating is 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 thermally vulcanized two-component silicone rubber A (Dow Corning), 6 parts by weight of a micronized drug containing glucocorticoid (dexamethasone, particle size of 6000 mesh), and 1.5 parts by weight of The catalyst (type 5000PPM, sourced from Eucalyptus) was mixed uniformly; 25 parts by weight of thermally vulcanized two-component silicone rubber B (Dow Corning), 6 parts by weight of a micronized drug containing glucocorticoid (dexamethasone, particle size 6000 mesh) and 1.5 parts by weight of a cross-linking agent (model PMX-0930, sourced from Dow Corning) to mix evenly; take the mixed drug-containing A/B to take an equal amount and mix evenly, and place it in a mold to solidify ( The curing temperature is 106°C, the curing pressure is 13MPa, and the curing time is 20min) 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 glued together by 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37°C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 296μg /d, 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 also includes a controlled release layer, the material of the controlled release layer is silicone rubber, the crosslinking 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：The present 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 tubular shape to obtain a casing controlled 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, and after gluing, it was placed on the bracket prepared in Example 1, and heated and fixed for 5 minutes to obtain the bracket 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 89 μg/d, the total drug release in the first 7 days was 796 μg, and the average release rate 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 also includes a controlled release layer, the material of the controlled release layer is silicone rubber, the crosslinking 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 tubular shape to obtain a casing controlled 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 16 μg/d, the total drug release in the first 7 days was 166 μg, and the average release rate 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 the outer surface of the stent is also provided with a hydrophilic coating, and the material of the hydrophilic coating is polyvinylpyrrolidone, 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) The polyvinylpyrrolidone mixture was sprayed on the outer surface of the stent obtained in Example 1, and the stent in this example was obtained by cross-linking and curing with ultraviolet light.

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。According to the test method of Example 1, the physical properties of the stent of this embodiment are tested, and it can be known that the hardness of the stent 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 5 μg/d, the total drug release in the first 7 days was 37 μg, and the average release rate 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。The animal experiment of the ureteral stent was carried out according to the method of Example 1, and the stent of Example 1 and the stent of this example were randomly implanted. After 1 month of extubation, the degree of urethral stenosis was measured by angiography. The degree of stenosis in Example 1 group was 12.94±2.02%. , the degree of stenosis in this example group was 9.84±2.70%, P was 0.01<0.05, and there was a significant difference; 1 month after extubation, the degree of stenosis in group 1 was 7.00±4.57%, and the degree of stenosis in this example group was 2.64±2.54%, P is 0.019<0.05, there is 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 patients were dissected, and tissue sections were taken and analyzed using Image-Pro Plus 6.0 software. Eight locations were selected for each section to measure the depth of tissue damage. The damage depth of Example 1 group was 1554±115 μm, and the damage depth of this Example group was 1316±134 μm, P was 0.001<0.05, and there was 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。Take tissue sections, stain the tissue sections, and use Image-pro plus 6.0 analysis software to measure the area percentage of collagen fibers. The area percentage of collagen fibers in Example 1 group is 51.78±5.96%, and the area percentage of collagen fibers in this example group is 40.69±5.43%. . P is 0.000<0.05, there is a significant difference.

动物实验证明，本实施例组比实施例1组治疗效果好。Animal experiments proved that the treatment effect of this example group was better than that of Example 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 the outer surface of the drug coating is also provided with a hydrophilic coating, and 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 then cured by ultraviolet light cross-linking 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 of 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。Calculate the content of drug components in the sample according to the weight, use a drug dissolution tester to dissolve the sample in a simulated urine solution at 37 °C, and use HPLC to test the amount of the dissolved drug. It can be seen that within 30 days, the maximum amount of drug dissolution in the first 7 days is 3 μg/d, the total drug release in the first 7 days was 41 μg, and the average release rate 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。The ureteral stent of 8F specification was prepared by the above method, and the same animal experiment as in Example 1 was carried out. Two female New Zealand rabbits were taken and extubated one month after implantation. The degree of stenosis in the group was 21.8±11.8%, P was 0.019<0.05, and there was a significant difference; 1 month after extubation, the degree of stenosis in the experimental group was 5.79±3.09%, and the degree of stenosis in the control group was 22.1±19.1%, P=0.026 <0.05, there is 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 patients were dissected, and tissue sections were taken and analyzed using Image-Pro Plus 6.0 software. Eight locations were selected for each section to measure the depth of tissue damage. The damage depth of the experimental group was 1291±122 μm, and the damage depth of the control group was 1777±139 μm, P was 0.002<0.05, with 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。The tissue sections were taken, stained, and the area percentage of collagen fibers was measured using Image-pro plus 6.0 analysis software. P is 0.002<0.05, there is a significant difference.

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 are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should Changes or substitutions that can be easily conceived within the technical scope all fall within the protection scope and disclosure scope of the present invention.