CN103341169B - 一种针对小分子亲水药物控释的包裹方法 - Google Patents
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Abstract
药物表面实行聚电解质逐层包裹是基于带相反电荷的聚电解质大分子通过静电作用,在无定型碳酸钙基质上交替沉积、吸附而成的多层超薄膜结构；其表面进一步实行硅烷化是基于戊二醛的连接和硅烷自身的交联作用；通过控制硅烷分子之间交联形成的孔径尺寸，可以有效控制了内部药物的释放速度。
Description
技术领域：
对小分子的亲水性药物表面实行逐层聚赖氨酸、核酸和硅烷化修饰，在药物缓释制剂中的应用属于新剂型、制剂技术领域。
背景技术：
当今，药物包裹停留在非纳米级水平，对药物包裹控制在对大型药物表面的糖衣化等修饰水平，这些修饰方法会致使药物胶囊物直径极大，直径过大会在血管内部形成血栓，被巨噬细胞吞噬，同时大的修饰药物在降解过程中肝脏首过效应高，造成肝的极大负担，副作用极大，并且在降解过程中，药物释放速度快，药物药效作用时间维持较短，不能发挥持久的疗效。
发明内容：
发明目的：纳米水平对小分子亲水药物包裹可以把药物胶囊物的粒径控制在纳米级，避免了肝脏首过效应，使药物分散度提高，药物的释放速度下降，达到缓释效果，延长药物作用时间。
发明技术方案：首先采用共沉淀的方法使小分子的亲水性药物与CaCO3纳米颗粒共沉淀得到纳米颗粒药物，实验中采用加入表面活性剂的方法控制CaCO3的尺度在50-100nm，然后在纳米颗粒药物表面逐层包裹赖氨酸、核酸，再用硅烷修饰，最后溶掉内部的纳米颗粒得到被包被的药物。
本发明采用药物与纳米颗粒共沉淀的目的是借助合成纳米颗粒的技术来控制药物颗粒的粒径，粒径控制在纳米级避免药物在血管内部形成血栓而且能免除巨噬细胞的吞噬。包裹赖氨酸和核酸主要借助了电荷的经典吸引，通过正负电荷相互吸引逐层包裹，工艺简单易于操作，而且两种聚电解质都是生物可降解的，不会对生物体造成危害。包裹硅烷，主要借助了戊二醛两端的两个醛基分别与赖氨酸的氨基和（3-氨丙基）三乙氧基硅烷的氨基结合，生成碳氮双键完成连接。具体过程见图1。
一种针对小分子亲水药物控释的包裹方法，运用共沉淀的方法使小分子亲水性药物与CaCO3纳米颗粒共沉淀得到纳米颗粒药物，在纳米颗粒药物表面逐层包裹可生物降解的两种聚电解质，再用硅烷修饰。
CaCO3纳米颗粒直径范围为50-100nm。
CaCO3纳米颗粒用加入可食性表面活性剂的方法控制其直径。
两种聚电解质为聚赖氨酸和核酸。
硅烷为（3-氨丙基）三乙氧基硅烷。
戊二醛起连接作用。
有益效果：
1、许多治疗关节疼痛的药物，采用表面修饰包裹，用药之后可以使药物在疼痛部位持续释放达到缓释的作用，减少不必要平凡用药的麻烦。
2、粒径控制在纳米水平，能够避免药物在血管内部形成血栓而且能免除巨噬细胞的吞噬。
3、聚电解质都是生物可降解的，不会对生物体造成危害。
4、一方面硅烷分子比较小，另一方面硅烷分子之间交联形成了致密的网状结构，这样就在纳米颗粒药物表面形成了包被结构，控制了内部药物的释放，延长了药物的释放时间，意味着延长了药物的作用时间。
5、通过硅烷化修饰的胶囊壁可以将孔径大大减小，从而可以实现小分子亲水药物的缓释。
附图说明：
图1、纳米药物颗粒表面核酸、聚赖氨酸、硅烷化修饰流程图
图2、纳米药物颗粒的显微镜拍摄图片
图3、纳米药物颗粒的表征
图4、纳米药物颗粒包裹后的激光共聚焦显微镜拍摄图片
图5、大肠杆菌抑菌圈实验[（a、b青霉素钠纳米药物微胶囊）/（c、d青霉素钠）]
具体实施方式：
1、实验方法：
（1）采用共沉淀法合成纳米药物颗粒
（2）采用层层自组装包裹技术逐层包裹核酸、聚赖氨酸
（3）采用戊二醛法进行硅烷化修饰
（4）采用抑菌圈对比实验验证青霉素钠的释放
2、实验过程：
（1）共沉淀法合成纳米药物颗粒
①取5mL0.33mol/LCaCl2溶液（含tween80）于一洁净烧杯中，加5000单位的青霉素钠粉末，1040r/min充分搅拌；
②采用10uL的枪间隔3s滴一滴，1040r/min持续搅拌，直到5mL0.33mol/LNaCO3全部加入为止；
③显微镜镜检及粒度仪表征。纳米药物颗粒的粒径为10nm（见图2、3）。
（2）纳米药物颗粒的核酸、聚赖氨酸包裹
①取实验过程（1）所得溶液1mL于一洁净的EP管中，加0.0005gDNA，轻摇1min，静置10min，3000r/min离心5min，由于CaCO3纳米药物颗粒表面呈无定形态而吸附DNA，得到表面包被有DNA的CaCO3纳米药物颗粒；
②弃上清液，Milli-Q水洗涤三次，充分除去未吸附的DNA；
③再加0.0005g聚赖氨酸，轻摇1min，静置10min，3000r/min离心5min，由于DNA带负电会吸附带正电的聚赖氨酸，得到包被有DNA和聚赖氨酸的CaCO3纳米药物颗粒；
④弃上清液，Milli-Q水洗涤三次，充分除去未吸附的聚赖氨酸；
⑤重复交替包裹DNA和聚赖氨酸3次。
（3）硅烷的修饰
①取40uL(3-氨丙基)三乙氧基硅烷；
②与实验过程（2）所得的溶液混合，加40uL戊二醛，轻摇1min，静置10min，3000r/min离心5min，戊二醛两端的两个醛基分别与赖氨酸的氨基和（3-氨丙基）三乙氧基硅烷的氨基结合完成硅烷的修饰连接；
③弃上清液，Milli-Q水洗涤三次，充分除去未连接的硅烷分子以及两个硅烷的自行连接体。
（4）染料荧光素钠的修饰
取一定量实验过程（3）制备的青霉素钠胶囊物于载玻片中心，滴加10μL荧光素钠溶液，静置5min，然后滴加10μL Milli-Q水，重复多次，洗去未被吸附的荧光素钠，用激光共聚焦显微镜观察（见图4）。
（5）内部CaCO3的去除
取实验过程（3）制备的青霉素钠胶囊物，加适量的EDTA（乙二胺四乙酸二钠）溶液，充分搅拌、离心，去除上清液，得到青霉素钠纳米药物微胶囊。
（6）青霉素钠的释放
取等量的青霉素钠纳米药物微胶囊和等效量的青霉素钠，分别设置抑菌（大肠杆菌、金黄色葡萄球菌）圈实验，观察、统计、比较出现抑菌圈的时间以及抑菌圈的大小（见图5）。
3、实验数据记录：见图2、图3、图4、图5。
4、实验结果：
纳米药物颗粒的平均粒径为10nm，与青霉素直接作用大肠杆菌、金黄色葡萄球菌实验相比，青霉素钠纳米药物微胶囊实验出现的抑菌圈较缓慢，且在相同的时间范围内抑菌圈的直径较小。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内，本发明要求保护范围由所附的权利要求书其等效物界定。
Claims (3)
1.一种针对小分子亲水药物控释的包裹方法，其特征在于，运用共沉淀的方法使小分子亲水性药物与CaCO3纳米颗粒共沉淀得到纳米颗粒药物，在纳米颗粒药物表面逐层包裹可生物降解的两种聚电解质，再用硅烷修饰，CaCO3纳米颗粒直径范围为50-100nm。
2.根据权利要求1所述的针对小分子亲水药物控释的包裹方法，其特征在于，CaCO3纳米颗粒用加入可食性表面活性剂的方法控制其直径。
3.根据权利要求1所述的针对小分子亲水药物控释的包裹方法，其特征在于，两种聚电解质为赖氨酸和核酸。
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| CN1771917A (zh) * | 2005-11-01 | 2006-05-17 | 浙江大学 | 一种包埋抗癌药物的微胶囊的制备方法 |
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| US20120156256A1 (en) * | 2010-12-17 | 2012-06-21 | Flamel Technologies | Nanoparticles having at least one active ingredient and at least two polyelectrolytes |
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| CN1771917A (zh) * | 2005-11-01 | 2006-05-17 | 浙江大学 | 一种包埋抗癌药物的微胶囊的制备方法 |
| CN101099727A (zh) * | 2007-07-20 | 2008-01-09 | 浙江大学 | 一种具有与肿瘤细胞特异性结合功能的微胶囊的制备方法 |
| CN101129342A (zh) * | 2007-07-31 | 2008-02-27 | 浙江大学 | 一种肝靶向性药物微胶囊的制备方法 |
| US20120156256A1 (en) * | 2010-12-17 | 2012-06-21 | Flamel Technologies | Nanoparticles having at least one active ingredient and at least two polyelectrolytes |
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| Polymer-Coated Nanoparticles: A Universal Tool for Biolabelling Experiments;Feng Zhang et al.;《small》;20110731(第22期);3113-3127 * |
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