CN112691237A - 一种药物涂覆塑料囊及其制备方法 - Google Patents
一种药物涂覆塑料囊及其制备方法 Download PDFInfo
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- CN112691237A CN112691237A CN202110027343.7A CN202110027343A CN112691237A CN 112691237 A CN112691237 A CN 112691237A CN 202110027343 A CN202110027343 A CN 202110027343A CN 112691237 A CN112691237 A CN 112691237A
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Abstract
本发明公开了一种药物涂覆塑料囊及其制备方法，包括塑料囊本体和涂覆在塑料囊本体表面的药物涂层，药物涂层含有至少两种活性药物，至少两种活性药物包含亲脂性药物和两亲性或亲水性药物，不含有不发挥活性作用的载体、基质、助剂或辅料，活性药物为发挥抗炎、抗凝、抗栓、抗增生或免疫调节活性作用的药物；制备方法，步骤如下：1）将活性药物溶于溶剂，得到药液；2）控制环境温湿度，将药液涂覆至塑料囊表面；3）干燥；4）得到一种药物涂覆塑料囊。本发明避免了引入载体、基质、助剂或辅料对人体血管产生炎症、血栓或狭窄的副作用，并且多种活性药物可以对血管发挥抗炎、抗凝、抗栓、抗增生和免疫调节等多重功效。
Description
技术领域
本发明涉及医疗器械技术领域，具体涉及一种药物涂覆塑料囊及其制备方法。
背景技术
药物涂覆塑料囊是在塑料囊扩张术或塑料囊成形术等介入技术基础上发展起来的新型治疗性塑料囊药物释放技术，药物涂覆塑料囊的原理是：在塑料囊导管的可扩张表面施加活性药物，再利用经皮介入技术将载有活性药物的可扩张塑料囊输送至人体内部的病变部位，通过外部设备（如，塑料囊扩张泵）充压使塑料囊扩张，活性药物自可扩张塑料囊表面释放并发挥瞬时药效。一方面，药物涂层塑料囊上的活性药物能有效抑制平滑肌细胞过度增生从而降低血管再狭窄发生率，另一方面，血管无需置入支架，从而减少了内膜的炎症反应、降低了支架内血栓形成的风险、缩短了双联抗血小板的时间、减少了出血风险。
药物涂层的性能对药物涂覆塑料囊发挥功效至关重要。药物涂层牢固度、在血管靶部位的药物释放能力、药物被血管吸收的能力均由药物涂层性能决定。目前的技术获得的药物涂层中，除含有药物外，均含有碘造影剂成分、聚合物、尿素或虫胶等载体、基质、助剂或辅料。这些载体、基质、助剂或辅料的用途是运载药物，改善药物涂层性能，提高药物的体内生物利用度。这些载体、基质、助剂或辅料自身并不发挥活性作用或药效。药物涂层中的这些载体、基质、助剂或辅料会引入杂质，可能影响载药稳定，引入炎症因子或者造成毒副作用。
因此，如果能够实现优良的药物涂层性能，那这些载体、基质、助剂或辅料对于药物涂覆塑料囊发挥功效就是多余的，不必要存在。不含有这些载体、基质、助剂或辅料的药物涂覆塑料囊可以实现更优的生物相容性，获得更好的远期疗效。当前技术条件下，由于药物涂覆塑料囊的药物涂层性能均需通过这些载体、基质、助剂或辅料实现，这些载体、基质、助剂或辅料在血管内引发的毒性、炎症、血栓或狭窄等毒副作用被忽视。
发明内容
为了解决上述技术问题，本发明提供了如下的技术方案：
首先，本发明提供了一种药物涂覆塑料囊，包括塑料囊和涂覆在塑料囊表面的一种药物涂层，所述药物涂层含有至少两种活性药物，所述至少两种活性药物包含亲脂性药物和两亲性或亲水性药物，不含有不发挥活性作用的载体、基质、助剂或辅料，所述活性药物为发挥抗炎、抗凝、抗栓、抗增生或免疫调节活性作用的药物。
发挥抗炎、抗凝、抗栓、抗增生或免疫调节活性作用药物为雷帕霉素、雷帕霉素衍生物、紫杉醇、紫杉醇衍生物、三氧化二砷、他克莫司、依维莫司、放线菌素-D、地塞米松、麦考酚酸、环孢霉素、雌二醇及其衍生物和类似物、氟尿嘧啶、环磷酰胺、阿霉素、长春新碱、肝素、肝素衍生物、肝素钙、肝素钙衍生物、肝素钠、肝素钠衍生物、利伐沙班、华法林、氯吡格雷、替格瑞洛、阿司匹林、盐酸替罗非班、阿加曲班、比伐芦定、双嘧达莫、吡考他胺、噻吩并吡啶、核苷酸/核苷类似物、西洛他唑、三氟柳、沙格雷酯、阿昔单抗、依替巴肽、前列环素、伊洛前列素、曲前列环素、前列环素衍生物、银杏内酯类、氯克罗孟、地他唑、斯奇康、脾氨肽，乌林体斯、泛福舒、尿激酶、链激酶、重组组织型纤溶酶原激活剂、乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布、塞来昔布、环孢素、他克莫司、吗替麦考酚酯、来氟米特、硫唑嘌呤或环磷酰胺。
进一步地，所述药物涂层中，活性药物含量为0.1μg/mm2-100μg/mm2。
其次，本发明提供了一种药物涂覆塑料囊的制备方法，包括以下步骤：
方法一
（1）将多种活性药物分别溶于溶剂，分别得到药液；
（2）将多种药液混合均匀；
（3）控制环境温湿度，将混合药液涂覆至塑料囊表面；
（4）干燥；
（5）得到所述的一种药物涂覆塑料囊。
方法二
（1）将多种活性药物分别溶于溶剂，分别得到药液；
（2）控制环境温湿度，将一种药液涂覆至塑料囊表面，干燥；
（3）控制环境温湿度，将另一种药液涂覆至塑料囊表面，干燥；
（4）得到所述的一种药物涂覆塑料囊。
方法三
（1）将多种活性药物一同溶于溶剂，得到混合药液；
（2）控制环境温湿度，将混合药液涂覆至塑料囊表面；
（3）干燥；
（4）得到所述的一种药物涂覆塑料囊。
进一步地，上述步骤中所述控制环境温湿度，是指温度控制在18℃-28℃，相对湿度控制在45%-65%。控制环境温湿度有助于得到均匀稳定的药物涂覆塑料囊。
进一步地，所述一种药物涂覆的溶剂选自水、四氢呋喃、丙酮、甲醇、乙醇、异丙醇、甲基乙烯基酮、二甲基亚砜、乙酸乙酯、乙腈、二氯甲烷、三氯甲烷、正庚烷、乙酸甲酯、乙酸丁酯、乙醚、笨、甲苯、二甲苯、己烷、辛烷中的一种或多种的混合。
塑料囊表面搭载抗凝、抗栓、抗炎、免疫调节药物和抗增生药物，利用扩张压力使塑料囊在扩张瞬间碎栓，药物快速渗透到血管壁，抗凝，抑制新生血栓，减少炎症产生，抗血管狭窄处内皮细胞增殖，达到改善血流动力学水平，抑制血栓和炎症产生的目的。
与现有技术相比，本发明的有益效果为：避免了引入载体、基质、助剂或辅料对人体血管产生毒性、炎症、血栓或狭窄的副作用，并且多种活性药物可以对血管同时发挥抗炎、抗凝、抗栓、抗增生和免疫调节等多重功效。
附图说明
图1为示意图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
本发明中，活性药物选自雷帕霉素、雷帕霉素衍生物、紫杉醇、紫杉醇衍生物、三氧化二砷、他克莫司、依维莫司、放线菌素-D、地塞米松、麦考酚酸、环孢霉素、雌二醇及其衍生物和类似物、氟尿嘧啶、环磷酰胺、阿霉素、长春新碱、肝素、肝素衍生物、肝素钙、肝素钙衍生物、肝素钠、肝素钠衍生物、利伐沙班、华法林、氯吡格雷、替格瑞洛、阿司匹林、盐酸替罗非班、阿加曲班、比伐芦定、双嘧达莫、吡考他胺、噻吩并吡啶、核苷酸/核苷类似物、西洛他唑、三氟柳、沙格雷酯、阿昔单抗、依替巴肽、前列环素、伊洛前列素、曲前列环素、前列环素衍生物、银杏内酯类、氯克罗孟、地他唑、斯奇康、脾氨肽，乌林体斯、泛福舒、尿激酶、链激酶、重组组织型纤溶酶原激活剂、乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布、塞来昔布、环孢素、他克莫司、吗替麦考酚酯、来氟米特、硫唑嘌呤或环磷酰胺中的二种或多种。
实施例1
将0.5mg肝素和50mg紫杉醇与10mL丙酮混合配制药物溶液，环境温度18摄氏度，相对湿度45%时，将药物溶液喷涂至塑料囊（直径4mm，长度20mm）表面，干燥后得到本实施例的药物涂覆塑料囊。
实施例2
将100mg肝素钠和50mg紫杉醇与10mL乙醇混合配制药物溶液，环境温度28摄氏度，相对湿度65%时，将药物溶液浸涂至塑料囊（直径4mm，长度20mm）表面，干燥得到本实施例的药物涂覆塑料囊。
实施例3
将50mg肝素钙溶于5mL乙酸乙酯配制肝素钙药液，将50mg雷帕霉素溶于5mL乙酸乙酯配制雷帕霉素药液，环境温度22摄氏度，相对湿度55%时，将肝素钙药液涂抹至塑料囊（直径4mm，长度20mm）表面，干燥，环境温度22摄氏度，相对湿度55%时，将雷帕霉素药液涂抹至塑料囊（直径4mm，长度20mm）表面，干燥得到本实施例的药物涂覆塑料囊。
实施例4
将10 mg双嘧达莫溶于5mL甲醇配制双嘧达莫药液，将50mg雷帕霉素溶于5mL甲醇配制雷帕霉素药液，将两个药液混合均匀，环境温度25摄氏度，相对湿度60%时，将混合药液微量移液至塑料囊（直径4mm，长度20mm）表面，干燥得到本实施例的物涂覆塑料囊。
实施例5
将5mg碘普罗胺和50mg紫杉醇与10mL丙酮混合配制药物溶液，环境温度20摄氏度，相对湿度50%时，将药物溶液喷涂至塑料囊（直径4mm，长度20mm）表面，干燥后得到本实施例的药物涂覆塑料囊，碘普罗胺为药物涂覆塑料囊常用载体基质之一。
将实施例1-5制备的药物涂覆塑料囊样品以新鲜抗凝兔血检测溶血率，溶血率越高表明样品对血液的毒性越大，测试结果见下表：
| 溶血率% | |
| 实施例1 | 0.2 |
| 实施例2 | 0.1 |
| 实施例3 | 0.2 |
| 实施例4 | 0.1 |
| 实施例5 | 3.6 |
实施例6
复合功效的药物涂层优选地采用超声喷涂工艺制备得到，图1示出了塑料囊本体及涂覆于所述塑料囊本体表面的药物涂层示意图。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，但是本发明并不局限于上述的具体实施方式，上述的具体实施方式仅仅是示意性的，而不是限制性的，本领域的普通技术人员在本发明的启示下，在不脱离本发明宗旨和权利要求所保护的范围情况下，还可做出很多形式，这些均属于本发明的保护之内。
Claims (10)
1.一种药物涂覆塑料囊，包括塑料囊本体及涂覆于所述塑料囊本体表面的药物涂层，其特征在于所述药物涂层含有至少两种活性药物，所述至少两种活性药物包含亲脂性药物和两亲性或亲水性药物，不含有载体、基质、助剂或辅料，所述活性药物为发挥抗炎、抗凝、抗栓、抗增生或免疫调节活性作用的药物。
2.根据权利要求1所述的一种药物涂覆塑料囊，其特征在于所述发挥抗炎、抗凝、抗栓、抗增生或免疫调节活性作用的药物为雷帕霉素、雷帕霉素衍生物、紫杉醇、紫杉醇衍生物、三氧化二砷、他克莫司、依维莫司、放线菌素-D、地塞米松、麦考酚酸、环孢霉素、雌二醇及其衍生物和类似物、氟尿嘧啶、环磷酰胺、阿霉素、长春新碱、肝素、肝素衍生物、肝素钙、肝素钙衍生物、肝素钠、肝素钠衍生物、利伐沙班、华法林、氯吡格雷、替格瑞洛、阿司匹林、盐酸替罗非班、阿加曲班、比伐芦定、双嘧达莫、吡考他胺、噻吩并吡啶、核苷酸/核苷类似物、西洛他唑、三氟柳、沙格雷酯、阿昔单抗、依替巴肽、前列环素、伊洛前列素、曲前列环素、前列环素衍生物、银杏内酯类、氯克罗孟、地他唑、斯奇康、脾氨肽，乌林体斯、泛福舒、尿激酶、链激酶、重组组织型纤溶酶原激活剂、乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布、塞来昔布、环孢素、他克莫司、吗替麦考酚酯、来氟米特、硫唑嘌呤或环磷酰胺。
3.根据权利要求1所述的一种药物涂覆塑料囊，其特征在于，所述药物涂层中，活性药物含量为0.1μg/mm2-100μg/mm2。
4.一种药物涂覆塑料囊制备方法，其特征在于，所述制备方法包括以下步骤：
1）将活性药物溶于溶剂，得到药液；
2）控制环境温湿度，将药液涂覆至塑料囊表面；
3）干燥；
4）得到所述的一种药物涂覆塑料囊。
5.根据权利要求4所述的一种药物涂覆塑料囊制备方法，其特征在于，所述步骤1）将活性药物溶于溶剂，得到药液，是指将多种活性药物分别溶于溶剂，分别得到多种药液。
6.根据权利要求4所述的一种药物涂覆塑料囊制备方法，其特征在于，所述步骤1）将活性药物溶于溶剂，得到药液，是指将多种活性药物溶于溶剂，得到一种药液。
7.根据权利要求4所述的一种药物涂覆塑料囊制备方法，其特征在于，所述步骤2）中药液是指将多种药液混合均匀后得到的药液。
8.根据权利要求4所述的一种药物涂覆塑料囊制备方法，其特征在于，所述步骤2）中控制环境温湿度，是指温度控制在18℃-28℃，相对湿度控制在45%-65%。
9.根据权利要求4所述的一种药物涂覆塑料囊制备方法，其特征在于，所述溶剂为水、四氢呋喃、丙酮、甲醇、乙醇、异丙醇、甲基乙烯基酮、二甲基亚砜、乙酸乙酯、乙腈、二氯甲烷、三氯甲烷、正庚烷、乙酸甲酯、乙酸丁酯、乙醚、笨、甲苯、二甲苯、己烷、辛烷。
10.根据权利要求4所述的一种药物涂覆塑料囊制备方法，其特征在于，所述的涂覆为浸涂、涂抹、喷涂、微量移液、打印、印刷的一种或多种。
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