CN106730050B - 一种用于血管支架的多功能药物洗脱涂层的制备方法 - Google Patents
一种用于血管支架的多功能药物洗脱涂层的制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于血管支架的多功能药物洗脱涂层的制备方法，将以重量百分比计的可降解聚合物载体9.8％～30％、药物A和药物B0.2％～20％、溶剂50％～90％置于容器中，以50～1000rpm转速搅拌分散成溶液，用超声雾化喷涂方法均匀喷涂到支架表面，在室温下干燥12～48小时，然后在真空干燥箱25～85℃真空干燥10～72小时。采用该方法制备的药物涂层实现他汀类药物、多酚类药物两类药物的同时载入，能够通过所载药物的控制释放抑制平滑肌细胞的增殖与迁移，促进内皮细胞增殖，实现快速内皮化并具备抗血栓形成和稳定或逆转动新生动脉粥样硬化的作用，减少支架晚期血栓的发生。
Description
技术领域
本发明属于心血管介入治疗器械领域，更具体说涉及一种用于血管支架的多功能药物洗脱涂层的制备方法。
背景技术
冠心病是人类疾病的一种高发病，治疗冠心病的有效手段是血管支架植入，仅中国每年临床使用的血管支架达70万支以上。药物洗脱支架(DES)的植入使得支架植入后再狭窄率由裸金属支架的30％下降到10％以下，但是临床所用的抗增生药物没有选择性，在抑制平滑肌细胞增殖的同时抑制了内皮细胞的生长，导致内皮愈合延迟；新生动脉粥样硬化，药物洗脱支架植入后也存在急性和慢性炎症反应。内皮延迟、炎症反应、支架内新生动脉粥样硬化是药物洗脱支架置入后支架内再狭窄及晚期支架内血栓形成的重要原因，晚期血栓一旦发生引发的死亡率大于50％，因此，血管支架的抗狭窄、抗血栓、稳定或逆转新生动脉粥样硬化斑块性能对于提高冠心病患者术后临床获益和生存率非常重要。
近几年研究表明他汀类药物除了降脂作用以外，还具有促进内皮祖细胞 (EPCs)分化、增加循环EPCs、修复受损内皮、改善内皮功能、抑制血管平滑肌的增殖和迁移、促进血管平滑肌细胞凋亡、减少血小板聚集、血栓形成、抗炎作用，而且他汀类药物还具有独特的稳定或逆转动新生动脉粥样硬化，可以直接作用于斑块，改变其成分和生物学特征，稳定或逆转斑块。他汀类药物的多效性使其在降低心血管事件的发生率和死亡率具有显著的优势，多酚类药物具有抗氧化、抗炎、强化血管壁并防止动脉硬化、血栓形成的作用。
发明内容
鉴于现有药物洗脱血管支架存在以上不足，本发明的目的是提供一种血管支架的多功能药物洗脱涂层的制备方法，采用该方法制备的以可降解高分子材料为载体的药物涂层可实现抗增生、促内皮、稳定或逆转斑块的他汀类药物、抗凝血、抗炎功能的多酚类药物以及两类药物的同时载入，含多功能药物洗脱涂层的血管支架植入血管腔内，能够通过所载药物的控制释放抑制平滑肌细胞的增殖与迁移，促进内皮细胞增殖，实现快速内皮化并具备抗血栓形成和稳定或逆转动新生动脉粥样硬化的作用，减少支架晚期血栓的发生。
为实现上述目的，本发明的技术方案为：一种用于血管支架的多功能药物洗脱涂层的制备方法，主要包括如下步骤：
a.将以重量百分比计的可降解聚合物载体9.8％～30％、药物A和药物B0.2％～20％、溶剂50％～90％置于容器中，以50～1000rpm转速搅拌分散成溶液，其中，药物A和药物B的质量比1：9～9：1；
b.将上述溶液用超声雾化喷涂方法均匀喷涂到支架表面，药物涂层的载药量可以通过控制药物配比、喷涂次数和喷涂量来调节，药物涂层的厚度为0.1～ 100微米；
c.将已经喷涂药物涂层的支架在室温下干燥12～48小时，然后在真空干燥箱25～85℃真空干燥10～72小时。
本发明的多功能药物洗脱涂层的制备方法，其中，可降解聚合物载体为聚三亚甲基碳酸酯、聚乳酸、聚己内酯、聚乙醇酸、乙交酯-丙交酯共聚物、乙交酯 -己内酯共聚物、丙交酯-己内酯共聚物、聚乳酸-聚乙二醇共聚物、聚羟基丁酸酯、聚羟基戊酸酯、聚氨基酸类、聚酸酐类、聚膦腈或胶原的一种或者两种的混合物，分子量为5万～50万道尔顿。
本发明的多功能药物洗脱涂层的制备方法，其中，所述药物A是具有有抗增生、促内皮、稳定或逆转斑块作用的他汀类药物，包括西立伐他汀、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀、匹伐他汀、氨氯地平阿托伐他汀及其钙盐、钠盐药物的一种。
本发明的多功能药物洗脱涂层的制备方法，其中，所述药物B为抗凝血、抗炎的多酚药物包括表没食子儿茶素没食子酸酯、表儿茶素、表没食子儿茶素、表儿茶素没食子酸酯、没食子酸、单宁酸、邻苯二酚、阿魏酸、咖啡酸、黄酮、异黄酮、黄烷酮、黄酮醇或黄烷醇。
本发明的多功能药物洗脱涂层的制备方法，其中，所述的溶剂为乙酸乙酯、二氯甲烷、氯仿、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃、丙酮、乙醚、乙醇、水的一种或者多种混合溶剂。
本发明的多功能药物洗脱涂层的制备方法，其中，超声雾化喷涂循环次数为1～100次，超声功率为0.5～30W，溶液流速为0.05～50ml/min。
本发明以他汀类药物和多酚类药物联用，采用可降解的聚合物作为药物载体，在抑制平滑肌细胞增生的同时促进内皮快速修复、减少炎症反应，稳定或逆转动新生动脉粥样硬化；可降解高分控制药物稳定释放的同时在体内降解产生无毒无害的物质随代谢排出体外，减少了聚合物长期留在血管内造成的炎症反应，对减少临床支架植入后晚期血栓的发生率具有重大意义。
附图说明
图1为实施例3本发明的血管支架药物涂层的光学显微镜观察的表面形貌。
图2为实施例3本发明的血管支架药物涂层的电子显微镜观察的表面形貌。
图3为本发明的实施例2血管支架药物涂层的光学显微镜观察的表面形貌。
图4为本发明实施例6血管支架药物涂层的电子显微镜观察的表面形貌。
具体实施方式
实施例1
配制如下成分的溶液：
将上述混合体系在以50rpm转速搅拌分散成溶液。
将清洗干净的支架置于超声雾化喷涂系统的支架运动轴上，超声功率2W，溶液流速为2.00ml/min，喷涂次数为10次，然后将喷涂好的支架在室温下干燥 18小时，然后在真空干燥箱30℃真空干燥12小时，涂层厚度约5微米。
实施例2
配制如下成分的溶液：
将上述混合体系在以300rpm转速搅拌分散成溶液。
将清洗干净的支架置于超声雾化喷涂系统的支架运动轴上，超声功率10W，溶液流速为0.50ml/min，喷涂次数为20次，然后将喷涂好的支架在室温下干燥 12小时，然后在真空干燥箱20℃真空干燥10小时，涂层厚度约3微米。
实施例3
配制如下成分的溶液(用于药物涂层)：
将上述混合体系在以500rpm转速搅拌分散成溶液。
将清洗干净的支架置于超声雾化喷涂系统的支架运动轴上，超声功率5W，溶液流速为1.00ml/min，喷涂次数为30次，然后将喷涂好的支架在室温下干燥 24小时，然后在真空干燥箱25℃真空干燥24小时，涂层厚度约10微米。该支架涂层在显微镜和电镜下观察，支架撑开前后撑开后的形貌都很好，涂层没有剥落，没有产生交联，涂层均匀，没有局部富集。
实施例4
配制如下成分的溶液：
将上述混合体系在以1000rpm转速搅拌分散成溶液。
将清洗干净的支架置于超声雾化喷涂系统的支架运动轴上，超声功率15W，溶液流速为0.3ml/min，喷涂次数为40次，然后将喷涂好的支架在室温下干燥 36小时，然后在真空干燥箱30℃真空干燥24小时，涂层厚度约4微米。
实施例5
配制如下成分的溶液(用于药物涂层)：
将上述混合体系在以100rpm转速搅拌分散成溶液。
将清洗干净的支架置于超声雾化喷涂系统的支架运动轴上，超声功率0.5W，溶液流速为0.1ml/min，喷涂次数为40次，然后将喷涂好的支架在室温下干燥 24小时，然后在真空干燥箱30℃真空干燥24小时，涂层厚度约8微米。
实施例6
配制如下成分的溶液：
将上述混合体系在以300rpm转速搅拌分散成溶液。
将清洗干净的支架置于超声雾化喷涂系统的支架运动轴上，超声功率10W，溶液流速为0.50ml/min，喷涂次数为20次，然后将喷涂好的支架在室温下干燥 12小时，然后在真空干燥箱20℃真空干燥10小时，涂层厚度约3微米。
Claims (2)
1.一种用于血管支架的多功能药物洗脱涂层的制备方法，主要包括如下步骤：
a.将以重量百分比计的可降解聚合物载体9.8％～30％、药物A和药物B0.2％～20％、溶剂50％～90％置于容器中，以50～1000rpm转速搅拌分散成溶液，其中，药物A和药物B的质量比1：9～9：1；
b.将上述溶液用超声雾化喷涂方法均匀喷涂到支架表面，药物涂层的载药量可以通过控制药物配比、喷涂次数和喷涂量来调节，药物涂层的厚度为0.1～100微米；
c.将已经喷涂药物涂层的支架在室温下干燥12～48小时，然后在真空干燥箱25～85℃真空干燥10～72小时；
其中，可降解聚合物载体为聚三亚甲基碳酸酯，分子量为5万～50万道尔顿；
所述药物A是,阿托伐他汀；
所述药物B为抗凝血、抗炎的多酚药物包括表没食子儿茶素没食子酸酯、表儿茶素、表没食子儿茶素、表儿茶素没食子酸酯、没食子酸；
所述的溶剂为二氯甲烷、四氢呋喃的一种或者多种混合溶剂。
2.按照权利要求1所述的多功能药物洗脱涂层的制备方法,其特征在于,其中，超声雾化喷涂循环次数为1～100次，超声功率为0.5～30W，溶液流速为0.05～50ml/min。
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| CN112516391A (zh) * | 2020-12-21 | 2021-03-19 | 辽宁垠艺生物科技股份有限公司 | 一种带膜支架的载药方法 |
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| CN114796627A (zh) * | 2022-05-19 | 2022-07-29 | 东莞市人民医院 | 一种基于白蛋白的双面血管支架及其制备方法 |
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