CN107715169B - 含plga纳米微粒的海藻酸钠载药复合栓塞微球的制备方法及产品 - Google Patents
含plga纳米微粒的海藻酸钠载药复合栓塞微球的制备方法及产品 Download PDFInfo
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Abstract
本发明公开了一种载含紫杉醇的PLGA纳米微球的海藻酸钠复合栓塞微球及其制备方法，其步骤包括先制备紫杉醇‑PLGA纳米微球，再溶解海藻酸钠，将所得悬浮液用气相微流体技术喷至氯化钙溶液中固化，制备成栓塞微球。本发明复合栓塞微球中的海藻酸钠和PLGA均有很好的生物相容性，可被生物降解，使微球起到栓塞效果的同时延长药物的作用时间。
Description
技术领域
本发明涉及一种载药复合栓塞微球的制备，具体是使用气相微流体技术制备载含紫杉醇的PLGA纳米微球的海藻酸钠复合栓塞微球。
背景技术
肝癌是危害人类健康的严重疾病之一，在全球范围内，肝癌占恶性肿瘤发病率的第6位、病死率的第3位，且每年约有50万的新增病例。在我国，每年约有38.3万人死于肝癌，占全球肝癌死亡病例数的51％。由于肝癌早期常症状无特异性，所以患者诊断时多是肝癌晚期，其5年生存率仅为5％。针对肝癌的主流治疗方法现在大致为三种：手术治疗(包括切除和肝移植)，化学疗法及放射疗法，以经导管动脉栓塞疗法(transcatheter arterialembolization，TAE)为代表的介入疗法。其中TAE技术是一种在不开刀暴露病灶的前提下，通过在皮肤上开出微小孔道或者利用人体中原有的管道，在影像设备的帮助下注入栓塞微球等栓塞物质，使血管闭塞从而达到预期疗效的手段，它有着手术精度高，创口小，恢复快等优点。
化疗栓塞术则是将化疗与TAE技术相结合，利用栓塞微球包载抗癌药物并注入肿瘤供血靶血管中，一方面利用栓塞微球阻隔癌组织供血，起到栓塞效果，另一方面又可以释放抗癌药物灭杀癌细胞，起到化疗作用。
合适的抗癌药物和栓塞微球材料对化疗栓塞术的疗效有着决定作用，而紫杉醇和海藻酸钠正是适用于化疗栓塞术的优良药物和栓塞材料。紫杉醇(paclitaxel，PTX)是一种从太平洋红豆杉树皮中提取的有效抗肿瘤药物，能够对抗肝癌、肺癌和乳腺癌等多种实体癌症。海藻酸钠(Sodium alginate，SA)是一种从海藻或海带中提取的天然多糖类化合物，具有良好的生物相容性和生物可降解性。海藻酸钠其中的钠离子极易被Ca2+等二价阳离子所取代，能够形成具有交联网状结构的凝胶，而且反应速度极快，这为以海藻酸钠为原料，用气相微流体技术制备栓塞微球提供了基础。
但由于紫杉醇是油溶性药物，在海藻酸钠溶液中的分散性并不好，而且紫杉醇直接分散在海藻酸钠栓塞微球中后，在体内的释放过快。因此我们首先采用聚乳酸-羟基乙酸共聚物(PLGA)这一生物可相容高分子材料包裹紫杉醇以制备纳米微球，然后再包载到海藻酸钠栓塞微球中，以达到缓慢释放药物的目的。
发明内容
本发明的目的之一在于提供一种新型的载药复合栓塞微球，该微球使用的都是具有良好生物可相容性的降解材料，对人体没有毒害副作用，具有较好的阻碍癌组织血液供养的作用，同时可以缓慢释放紫杉醇，达到长期释药灭杀肝癌细胞的作用。
本发明的另一目的是提供一种新的载紫杉醇复合海藻酸钠栓塞微球的制备方法。
本发明所提供的制备载紫杉醇复合海藻酸钠栓塞微球的示意图如附图1所示，其技术方案如下：
(1)制备载紫杉醇的PLGA纳米微球
20-200mg的紫杉醇和100mg PLGA溶于二氯甲烷中制成油相溶液，300-1500mg聚乙烯醇溶于60mL水中制成浓度为0.5-2.5％的水相溶液，将油相溶液和吐温-80加入水相溶液中，搅拌并超声分散均匀后，于30℃下搅拌2小时。
(2)制备海藻酸钠载药复合微球
在(1)溶液中加入0.6-1.8g的海藻酸钠，搅拌溶解后制成原液。将原液吸入注射器中，置于气相微流体设备中，以10-50mL/h的注射速度，1.5-3.0L/min的气流流速，将0.3-2.0g氯化钙溶于100mL蒸馏水中制备而成0.3-2.0％的氯化钙溶液作为接收域，制备复合海藻酸钠微球。用水离心洗涤3遍后水封保存。
与现有技术相比较，本发明具有以下优点：
(1)利用PLGA包裹紫杉醇形成纳米微球，使得紫杉醇在海藻酸钠微球中的分散更加均匀。同时PLGA纳米微球的包裹使得紫杉醇在体内进行缓释，延长了紫杉醇的作用时间。
(2)与同类微流体制备技术相比，因为采用气体而不是有机溶剂作为流动相，减少了有机溶剂残留对人体带来的毒性作用，同时简化了成球后的后处理工艺。
附图说明
图1是本发明制备载紫杉醇复合海藻酸钠栓塞微球的示意图。
图2是本发明载药微球的体外释放曲线。
具体实施方式
下面结合实施例和对比例对本发明进行详细说明，下述实施例仅用来对说明书的详细解释，并不作为对于本发明的限制。
实施例1
将20mg的紫杉醇和100mg PLGA溶于10ml二氯甲烷中制成油相溶液，300mg的聚乙烯醇溶于60mL水中制成0.5％的水相溶液，将油相溶液和3滴吐温-80加入水相溶液中，搅拌10分钟，超声分散2分钟后，于30℃下搅拌2小时得到载药PLGA纳米微球悬浮液。在悬浮液中加入0.6g的海藻酸钠，搅拌溶解后制成原液。将原液吸入注射器中，置于气相微流体设备中，以10mL/h的注射速度，1.5L/min的氮气流速，将0.3g氯化钙溶于100mL蒸馏水中制备而成0.3％的氯化钙溶液作为接收域，制备复合海藻酸钠微球。用水离心洗涤3遍后水封保存。
实施例2
将60mg的紫杉醇和100mg PLGA溶于10ml二氯甲烷中制成油相溶液，600mg的聚乙烯醇溶于60mL水中制成1.0％的水相溶液，将油相溶液和3滴吐温-80加入水相溶液中，搅拌10分钟，超声分散2分钟后，于30℃下搅拌2小时得到载药PLGA纳米微球悬浮液。在悬浮液中加入1.0g的海藻酸钠，搅拌溶解后制成原液。将原液吸入注射器中，置于气相微流体设备中，以20mL/h的注射速度，2.0L/min的氮气流速，将10g氯化钙溶于100mL蒸馏水中制备而成1.0％的氯化钙溶液作为接收域，制备复合海藻酸钠微球。用水离心洗涤3遍后水封保存。
实施例3
将120mg的紫杉醇和100mg PLGA溶于10ml二氯甲烷中制成油相溶液，900mg的聚乙烯醇溶于60mL水中制成1.5％的水相溶液，将油相溶液和3滴吐温-80加入水相溶液中，搅拌10分钟，超声分散2分钟后，于30℃下搅拌2小时得到载药PLGA纳米微球悬浮液。在悬浮液中加入1.2g的海藻酸钠，搅拌溶解后制成原液。将原液吸入注射器中，置于气相微流体设备中，以30mL/h的注射速度，2.5L/min的氮气流速，将1.5g氯化钙溶于100mL蒸馏水中制备而成1.5％的氯化钙溶液作为接收域，制备复合海藻酸钠微球。用水离心洗涤3遍后水封保存。
实施例4
将160mg的紫杉醇和100mg PLGA溶于10ml二氯甲烷中制成油相溶液，1200mg的聚乙烯醇溶于60ml水中制成2.0％的水相溶液，将油相溶液和3滴吐温-80加入水相溶液中，搅拌10分钟，超声分散2分钟后，于30℃下搅拌2小时得到载药PLGA纳米微球悬浮液。在悬浮液中加入1.2g的海藻酸钠，搅拌溶解后制成原液。将原液吸入注射器中，置于气相微流体设备中，以40mL/h的注射速度，3.0L/min的氮气流速，将2.0g氯化钙溶于100mL蒸馏水中制备而成2.0％的氯化钙溶液作为接收域，制备复合海藻酸钠微球。用水离心洗涤3遍后水封保存。
实施例5
将200mg的紫杉醇和100mg PLGA溶于10ml二氯甲烷中制成油相溶液，1500mg的聚乙烯醇溶于60mL水中制成2.5％的水相溶液，将油相溶液和3滴吐温-80加入水相溶液中，搅拌10分钟，超声分散2分钟后，于30℃下搅拌2小时得到载药PLGA纳米微球悬浮液。在悬浮液中加入1.8g的海藻酸钠，搅拌溶解后制成原液。将原液吸入注射器中，置于气相微流体设备中，以50mL/h的注射速度，2.5L/min的氮气流速，将1.0g氯化钙溶于100mL蒸馏水中制备而成1.0％的氯化钙溶液作为接收域，制备复合海藻酸钠微球。用水离心洗涤3遍后水封保存。
实施例6
将200mg的紫杉醇和100mg PLGA溶于10ml二氯甲烷中制成油相溶液，600mg的聚乙烯醇溶于60mL水中制成1.0％的水相溶液，将油相溶液和3滴吐温-80加入水相溶液中，搅拌10分钟，超声分散2分钟后，于30℃下搅拌2小时得到载药PLGA纳米微球悬浮液。在悬浮液中加入1.2g的海藻酸钠，搅拌溶解后制成原液。将原液吸入注射器中，置于气相微流体设备中，以50mL/h的注射速度，2.5L/min的氮气流速，将1.0g氯化钙溶于100mL蒸馏水中制备而成1.0％的氯化钙溶液作为接收域，制备复合海藻酸钠微球。用水离心洗涤3遍后水封保存。
分别测定实例1-6制备而得的载药复合海藻酸钠栓塞微球的粒径和药物包封率，其结果见表1。
对比实施例1
将200mg的紫杉醇分散于60mL水中，超声分散2分钟后，在悬浮液中加入1.2g的海藻酸钠，搅拌溶解后制成原液。将原液吸入注射器中，置于气相微流体设备中，以50mL/h的注射速度，2.5L/min的氮气流速，将1.0g氯化钙溶于100mL蒸馏水中制备而成1.0％的氯化钙溶液作为接收域，制备复合海藻酸钠微球。用水离心洗涤3遍后水封保存。
对比实施例1的结果，以此对比药物加入方式对载药微球粒径和包封率性能的影响，其结果见表1。
称取相同质量的实施例6和对比实施例1中的产品进行体外释放测试，具体步骤如下：精确称取20mg载药微球置于离心管中，加入50mL pH6.5的PBS缓冲溶液，置于37℃水浴中恒温振荡，定时取样5mL于230nm处测定吸光度，同时补加等量同质的缓冲溶液。根据紫杉醇的标准曲线计算药物含量，绘制释放曲线，所有样品平行测定3次，取其平均值。
结果如图2所示。对比可以看出，本发明的产品药物释放过程的突释现象明显减小，可以达到更好的缓释效果。
表1 不同条件下制备得海藻酸钠复合载药栓塞微球的粒径和药物包封率
有益效果
从图2可以看出，对比实施例1中海藻酸钠栓塞微球在第1h内药物释放率25.50％，而实施例6中含纳米PLGA微粒的复合海藻酸钠栓塞微球在第1h的药物释放率降低到14.03％，药物突释现象明显降低，并且可以达到更长的释放时间。
上述仅对本发明中的几种具体实施例加以说明，但并不能作为本发明的保护范围，凡是依据本发明中的设计精神所作出的等效变化或修饰或等比例放大或缩小等，均应认为落入本发明的保护范围。
Claims (1)
1.一种载含紫杉醇的PLGA纳米微球的海藻酸钠复合栓塞微球的制备方法，其特征在于，包括以下步骤：
(1)制备载紫杉醇的PLGA纳米微球：20-200mg的紫杉醇和100mgPLGA溶于二氯甲烷中制成油相溶液，300-1500mg聚乙烯醇溶于60mL水中制成浓度为0.5-2.5%的水相溶液，将油相溶液和吐温-80加入水相溶液中，搅拌并超声分散均匀后，于30°C下搅拌2小时；
(2)制备海藻酸钠载药复合微球：在(1)溶液中加入0.6-1.8g的海藻酸钠，搅拌溶解后制成原液，将原液吸入注射器中，置于气相微流体设备中，以10-50mL/h的注射速度，1.5-3.0 L/min的气流流速，将0.3-2.0g氯化钙溶于l00mL蒸馏水中制备而成0.3-2.0%的氯化钙溶液作为接收域，制备载PLGA纳米粒子的海藻酸钠复合微球，用水离心洗涤3遍后水封保存；所述的紫杉醇是一种从红豆杉中提取出的天然抗癌药物；所述的PLGA是一种具有良好的生物相容性和降解性的功能性高分子材料；所述的海藻酸钠是从褐藻类的海带或马尾藻中提取碘和甘露醇之后的副产物，是一种可降解的天然高分子材料；所述的气相微流体设备是一种以氮气为外流动相的微流体装置。
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