新型有机无机复合载药微囊的制备与性能研究
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摘要
本文采用层层自组装法和原位凝聚法制备功能性载药微囊,并研究其缓释性能。层层自组装法制备的聚电解质中空微胶囊具有结构的易调控性、尺寸与壁厚的均一性等优点,通过引入功能性组份,可获得具有各种功能的微胶囊,因此层层组装聚电解质微胶囊作为药物缓释载体获得广泛的研究和应用开发,本文在组装过程中引入无机层状颗粒和磁性颗粒赋予微囊一定特殊功能。另外为改善层层自组装法繁复的制备过程,本文中又采用原位凝聚法简便快捷地制备聚电解质微胶囊。
为改善微囊的释药性能、实现微囊的多功能化,本文在层层自组装过程中引入无机颗粒,成功合成了有机无机复合微囊。即以磺化处理过的PS微球为模板,通过层层自组装法制备了聚苯乙烯磺酸钠(PSS)和聚二烯二甲基氯化铵(PDDA)聚电解质微囊，并将无机锂藻土颗粒或Fe3O_4颗粒组装到微囊上,获得两种有机无机复合微囊,微囊直径在1-2μm之间,锂藻土和Fe3O_4颗粒在微囊上均匀分布。掺杂锂藻土的载药微囊负载盐酸阿霉素(DOX)的量为195.1μg/(mg微囊),且其释放50%药量时间相比于未组装锂藻土的载药微囊延长,说明层状锂藻土颗粒具有延缓药物释放的功能；而磁性微囊载药量为180.3μg/(mg微囊),在永久磁场中表现出明显的磁导向性,负载DOX的磁性微囊在交变磁场作用下表现出了磁响应性,可能由于磁热效应使得聚电解质膜结构发生变化,导致载药微囊出现了突释现象。
为缓解药物释放前期的突释现象,采用具有粗糙表面和孔洞结构CaCO3微球作为模板,装载药物布洛芬(IBU)后再在载药微球表面组装聚电解质,制备核-壳型载药体系。研究发现,CaCO3微球负载IBU的载药量为28.487mg／g。合成的核-壳型载药体系具有一定的缓释特性,而将聚电解质与无机颗粒锂藻土同时组装到载药CaCO3上,能进一步改善该体系的缓释效果,组装有锂藻土的微球释放50%药量时间相比于未组装锂藻土的载药微球有所延长,证明了片层状的锂藻土具有延缓药物释放的功能。
为改善层层自组装法繁复的制备过程,本文采用原位凝聚法一步合成载药微囊,即先制备掺杂PSS的CaCO3微球,并以此作为模板,组装一层强聚电解质PDDA,然后用EDTA除核,除核过程中PSS和PDDA发生凝聚形成微囊。通过Zeta电位分析发现微囊外层带负电,可以推测溶解的CaCO3中释放出来的PSS重新组装到微囊外围。通过在除核过程中添加PDDA可以实现微囊带电荷性质的反转,同时微囊厚度增加。以DOX为模型药物,考察微囊的载药性能,微囊载药量随着药物初始浓度和培养温度的升高而增加,当培养温度为37℃,药物初始浓度为100gg／ml时,药物负载量约为300μg/(mg微囊)。载药微囊的释药特性显示,CaCO3制备中PSS的用量对载药微囊缓释效果影响显著,PSS用量越大,缓释时间增长,当PSS用量为12g/L时其释放50%药量时间相比于PSS用量为4g／L时延长了4h。
In this paper, functional microcapsules loaded with drug was fabricated by the layer-by-layer self-assembly(LbL) or in-situ coacervation. The advantage of LbL assembly is that the structure, size, thickness and composition of the polyelectrolyte microcapsules are easy to be controlled. In this study, inorganic clay nanoparticles and magnetic particles were used in the LbL assembly to fabricate microcapsules with special functions. In another part of this study, in-situ coacervation was selected to prepare microcapsules in order to simplify the complicated preparation process of LbL assembly,.
The organic-inorganic hybrid microcapsules were synthesized successfully by introduce inorganic particles during LbL assembly in order to improve the properties of the microcapsules. Two kinds of organic-inorganic hybrid microcapsules were made introducing laponite or Fe3O4 into microcapsules and using polystyrene(PS) microspheres as template. The laponite or Fe3O4 nanoparticles distributed uniformly in the wall of microcapsule. For the microcapsules doped with laponite, the amount of DOX loaded was 195.1μg/(mg microcapsules). The time of releasing 50% loaded DOX from microcapsules was extended compared to pure polyelectrolyte microcapsules, which means layered laponite particles could delay the drug release. For the microcapsules doped with Fe3O4, the amount of DOX loaded was 180.3μg/(mg microcapsules). The microcapsules showed significant magnetic orientation in the permanent magnetic field. The DOX loaded magnetic microcapsules showed magnetic response in the alternating magnetic field, in which the durg burst released probably because of magnetocaloric effect making the structure of polyelectrolyte membrane changed.
For the purpose of improving the drug releasing property, core-shell drug carrier was prepared by using CaCO3 microspheres with rough surface and pore structure as templates. Ibuprofen(IBU) were loaded inside the pores of CaCO3, which were then coated with polyelectrolyte and laponite on the surface. The amount of IBU loaded in the CaCO3 was 28.487mg/g. The core-shell microspheres doped with laponite had better durg release effect compared to normal core-shell microspheres without inorganic particles.
In-situ coacervation was used to simplify the preparation process of microcapsules, in which CaCO3 microspheres doped with PSS were using as templates. PDDA was then adsorbed on the templates, which followed by dissolving CaCO3 in EDTA. The microcapsules was obtained by coacervation of PDDA and PSS during the dissolvation of CaCO3. Zeta potential analysis showed that the outer layer of microcapsules is negatively charged. The more the PSS involved in the CaCO3, the thicker the membrane is. When the PDDA was added in the EDTA solution, the zeta potential of outer layer of microcapsules conversed to positive, which means the PDDA assembled on the outer layer of microcapsules. DOX loading amount of the positive microcapsules could be 300μg/(mg microcapsules) When the incubating temperature is 37℃and the initial concentration of drug is 100μg/ml. The drug release of the thicker microcapsules showed better sustained-release.
为改善微囊的释药性能、实现微囊的多功能化,本文在层层自组装过程中引入无机颗粒,成功合成了有机无机复合微囊。即以磺化处理过的PS微球为模板,通过层层自组装法制备了聚苯乙烯磺酸钠(PSS)和聚二烯二甲基氯化铵(PDDA)聚电解质微囊，并将无机锂藻土颗粒或Fe3O_4颗粒组装到微囊上,获得两种有机无机复合微囊,微囊直径在1-2μm之间,锂藻土和Fe3O_4颗粒在微囊上均匀分布。掺杂锂藻土的载药微囊负载盐酸阿霉素(DOX)的量为195.1μg/(mg微囊),且其释放50%药量时间相比于未组装锂藻土的载药微囊延长,说明层状锂藻土颗粒具有延缓药物释放的功能；而磁性微囊载药量为180.3μg/(mg微囊),在永久磁场中表现出明显的磁导向性,负载DOX的磁性微囊在交变磁场作用下表现出了磁响应性,可能由于磁热效应使得聚电解质膜结构发生变化,导致载药微囊出现了突释现象。
为缓解药物释放前期的突释现象,采用具有粗糙表面和孔洞结构CaCO3微球作为模板,装载药物布洛芬(IBU)后再在载药微球表面组装聚电解质,制备核-壳型载药体系。研究发现,CaCO3微球负载IBU的载药量为28.487mg／g。合成的核-壳型载药体系具有一定的缓释特性,而将聚电解质与无机颗粒锂藻土同时组装到载药CaCO3上,能进一步改善该体系的缓释效果,组装有锂藻土的微球释放50%药量时间相比于未组装锂藻土的载药微球有所延长,证明了片层状的锂藻土具有延缓药物释放的功能。
为改善层层自组装法繁复的制备过程,本文采用原位凝聚法一步合成载药微囊,即先制备掺杂PSS的CaCO3微球,并以此作为模板,组装一层强聚电解质PDDA,然后用EDTA除核,除核过程中PSS和PDDA发生凝聚形成微囊。通过Zeta电位分析发现微囊外层带负电,可以推测溶解的CaCO3中释放出来的PSS重新组装到微囊外围。通过在除核过程中添加PDDA可以实现微囊带电荷性质的反转,同时微囊厚度增加。以DOX为模型药物,考察微囊的载药性能,微囊载药量随着药物初始浓度和培养温度的升高而增加,当培养温度为37℃,药物初始浓度为100gg／ml时,药物负载量约为300μg/(mg微囊)。载药微囊的释药特性显示,CaCO3制备中PSS的用量对载药微囊缓释效果影响显著,PSS用量越大,缓释时间增长,当PSS用量为12g/L时其释放50%药量时间相比于PSS用量为4g／L时延长了4h。
In this paper, functional microcapsules loaded with drug was fabricated by the layer-by-layer self-assembly(LbL) or in-situ coacervation. The advantage of LbL assembly is that the structure, size, thickness and composition of the polyelectrolyte microcapsules are easy to be controlled. In this study, inorganic clay nanoparticles and magnetic particles were used in the LbL assembly to fabricate microcapsules with special functions. In another part of this study, in-situ coacervation was selected to prepare microcapsules in order to simplify the complicated preparation process of LbL assembly,.
The organic-inorganic hybrid microcapsules were synthesized successfully by introduce inorganic particles during LbL assembly in order to improve the properties of the microcapsules. Two kinds of organic-inorganic hybrid microcapsules were made introducing laponite or Fe3O4 into microcapsules and using polystyrene(PS) microspheres as template. The laponite or Fe3O4 nanoparticles distributed uniformly in the wall of microcapsule. For the microcapsules doped with laponite, the amount of DOX loaded was 195.1μg/(mg microcapsules). The time of releasing 50% loaded DOX from microcapsules was extended compared to pure polyelectrolyte microcapsules, which means layered laponite particles could delay the drug release. For the microcapsules doped with Fe3O4, the amount of DOX loaded was 180.3μg/(mg microcapsules). The microcapsules showed significant magnetic orientation in the permanent magnetic field. The DOX loaded magnetic microcapsules showed magnetic response in the alternating magnetic field, in which the durg burst released probably because of magnetocaloric effect making the structure of polyelectrolyte membrane changed.
For the purpose of improving the drug releasing property, core-shell drug carrier was prepared by using CaCO3 microspheres with rough surface and pore structure as templates. Ibuprofen(IBU) were loaded inside the pores of CaCO3, which were then coated with polyelectrolyte and laponite on the surface. The amount of IBU loaded in the CaCO3 was 28.487mg/g. The core-shell microspheres doped with laponite had better durg release effect compared to normal core-shell microspheres without inorganic particles.
In-situ coacervation was used to simplify the preparation process of microcapsules, in which CaCO3 microspheres doped with PSS were using as templates. PDDA was then adsorbed on the templates, which followed by dissolving CaCO3 in EDTA. The microcapsules was obtained by coacervation of PDDA and PSS during the dissolvation of CaCO3. Zeta potential analysis showed that the outer layer of microcapsules is negatively charged. The more the PSS involved in the CaCO3, the thicker the membrane is. When the PDDA was added in the EDTA solution, the zeta potential of outer layer of microcapsules conversed to positive, which means the PDDA assembled on the outer layer of microcapsules. DOX loading amount of the positive microcapsules could be 300μg/(mg microcapsules) When the incubating temperature is 37℃and the initial concentration of drug is 100μg/ml. The drug release of the thicker microcapsules showed better sustained-release.
引文
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