【作者】 王慧萍；

【导师】 张超灿；

【作者基本信息】 武汉理工大学 ， 材料物理与化学， 2014， 博士

【摘要】 以天然高分子为壁材的微胶囊具有无毒、生物相容性好等优点，在生物医药、控制释放、纳米粒子稳定等领域具有十分重要的应用价值。微胶囊的传统制备方法主要有乳化-交联法、乳化-溶剂蒸发法、喷雾干燥法等,但存在尺寸控制难、制备效率低、重现性差等问题。基于液-液剪切作用的微流控技术已经成功应用于壳聚糖微胶囊的制备上,得到粒径呈单分散的壳聚糖微胶囊,但也存在后期脱除溶剂困难的问题。另一方面,单纯由天然高分子作为壁材的微胶囊存在膜壁软、力学性能差的缺点,作为药物载体时,微胶囊膜的破裂会导致被包埋药物迅速释放,从而对人体造成危害,给临床应用带来风险。针对这些问题,本工作希望能找到一种制备单分散微胶囊的新方法来制备单分散壳聚糖及其衍生物微胶囊,再通过原位复合技术,将无机微粒、纳米粒子引入到微胶囊囊壁中,希望进一步提高微胶囊的综合性能。首先,基于气-液剪切原理设计合适的微流控装置,通过圆形毛细管、方形毛细管同轴组装,再与连接管连接并固定密封得到气-液微流控装置。以壳聚糖溶液为内相液体,氮气为外相剪切气体,十二烷基硫酸钠为接收溶液,通过气-液微流控装置制备壳聚糖微胶囊。通过三维视频显微镜研究气体流速,液体流速对微胶囊尺寸和形态的影响。采用扫描电子显微镜测试观察微胶囊形态和囊壁表面结构。结果表明,制备的壳聚糖微胶囊呈球形,粒径分布均一。增大气体流速,微胶囊粒径明显减小,而液相流速对粒径影响较小。进一步通过将荧光物质和磁性纳米粒子分散在壳聚糖溶液中作为内相溶液,可以得到荧光微胶囊、磁性微胶囊。从而,证实气-微流控方法能够制备单分散微胶囊。采用气-液微流控方法,制备大小可控、粒径分布窄的壳聚糖季铵盐/壳聚糖微胶囊。通过探讨微流控流体参数、内相溶液浓度对微胶囊尺寸的影响,发现最佳的制备条件为:气体流速为0.5~0.8L/min、SDS浓度为2%、壳聚糖/壳聚糖季铵盐的乙酸溶液流速为3m L/h。三维视频显微镜测试表明,壳聚糖/壳聚糖季铵盐微胶囊在不同p H值水溶液中、以及不同电解质溶液中都具有良好的稳定性。紫外可见分光光度测试并证明微胶囊对水杨酸、水杨酸钠、5-氟尿嘧啶具有负载和释放作用,对药物的释放性能受壳聚糖和壳聚糖季铵盐的配比、释放控制条件的影响。采用气-液微流控方法,结合原位沉淀法,以壳聚糖和Ca Cl2混合溶液为内相溶液,海藻酸钠和Na2CO3为接收液,制备尺寸均一的球形壳聚糖季铵盐/海藻酸钠/Ca CO3微胶囊。通过三维视频显微镜研究气体流速、内相溶液浓度、壳聚糖季铵盐、海藻酸钠和碳酸钠的浓度对微胶囊形态和尺寸的影响。扫描电子显微镜观察发现Ca CO3微粒存在于微胶囊的膜壁中。研究了复合微胶囊在不同溶液环境中的溶胀行为,发现复合微胶囊在中性和酸性水溶液中基本不溶胀;碱性溶液中明显溶胀。探讨了复合微胶囊在不同环境中对模型药物水杨酸钠的以天然高分子为壁材的微胶囊具有无毒、生物相容性好等优点,在生物医药、释放行为。随着海藻酸钠用量的增加,微胶囊对模型药物水杨酸钠的释放速度变慢。在碱性环境中水杨酸钠的释放速度明显大于酸性和中性环境,并且在接近人体温度的条件下水杨酸钠释放更加高效。将壳聚糖季铵盐修饰的石墨烯稳定分散到壳聚糖溶液中作为内相溶液,采用气-液微流控方法,制备壳聚糖/石墨烯微胶囊。扫描电子显微镜观察发现微胶囊的囊壁中存在石墨烯。通过三维视频显微镜研究微胶囊的粒径与气体流速、壳聚糖和石墨烯混合溶液浓度的关系。发现,随混合溶液浓度增加,内相溶液粘度增大,微胶囊的粒径增大。在气体流速低于0.7 L/min时,得到的微胶囊粒径分布均一。石墨烯的引入使微胶囊膜力学强度明显增加。通过紫外可见分光光度研究壳聚糖/石墨烯微胶囊对模型药物水杨酸钠的释放行为,发现石墨烯的引入,使微胶囊对药物的释放速度更慢,具有缓释效果。通过可逆加成-断裂链转移(RAFT)聚合技术合成苯乙烯-丙烯酸六氟丁酯梯度共聚物乳液。探讨了两亲性RAFT试剂对于聚合反应和聚合物分子量的控制作用。当RAFT试剂对引发剂的摩尔比大于1时,共聚合反应表现出明显的可控聚合的特点。通过GPC、1H-NMR和DSC测试表征了共聚物分子量和化学结构,并证明苯乙烯-丙烯酸六氟丁酯共聚物具有梯度链结构。以含氟梯度共聚物乳液作为内相溶液,壳聚糖和Ca Cl2的混合溶液为接收液,采用气-液微流控方法,制备梯度共聚物/壳聚糖微球。通过三维视频显微镜研究乳液粘度、壳聚糖和Ca Cl2浓度对微球形成、微球形态的影响。研究发现,乳液粘度对对微球形态影响明显,随气体流速增加对微球粒径明显减小。梯度共聚物/壳聚糖微球具有良好的稳定性,并能负载荧光染料。更多还原

【Abstract】 Owing to its excellent biological features such as non-toxicity, biocompatibility, and biodegradation, chitosan is always considered for various biomedical and pharmaceutical applications. Microcapsules have been generated by different techniques, such as coacervation, emulsification solvent-evaporation and layer-by-layer assembly. The main disadvantage of the above methods is that the size and size distribution of the microcapsules are uncontrollable and non-uniform. Uniform-sized microcapsules can increase their bioavailability, reproducibility and repeatable release behavior. In order to obtain microcapsules with a controlled shape and uniform size, liquid-liquid microfluidic technique is employed to prepare chitosan microcapsules and nanoparticles. One of problem of this method is solvent-evaporation in the post-processing. Moreover, the wall of microcapsules prepared only by natural polymers always have low mechanical strength, which is a risk for drug delivery system since the pre-released chemicals possibly have bad effects for human body. In this work, we hope to develop a new method to prepare monodisperse microcapsules of chitosan and their derivatives. Moreover, it is possible to improve integrated properties through introducing inorganic microparticles or nano particles into the wall of microcapsules.Monodisperse chitosan microcapsules were prepared by using gas-liquid microfluidic technique. The effects of gas flow rate and liquid flow rate on the size and size distribution of the microcapsules were studied in detail. The optical microscope and SEM were used to characterize the size and morphology of microcapsules. The results showed that the prepared microcapsules were spherical and monodisperse. With the increase of gas flow rate, the size of microcapsules decreased. The liquid flow rate had a little influence on the size of the microcapsules. Gas-liquid microfluidic technique was also applied to embed the fluorescent substances or magnetic nanoparticles into the core of microcapsules, obtaining monodisperse microcapsules with characteristic fluorescence or magnetism.Chitosan/quaternized chitosan microcapsules with controlled dimension and narrow dimension distribution were obtained by gas-liquid microfluidic technique. The optimal condition was the gas rate at 0.5~0.8L/min, the concentration of SDS of 2wt% and a liquid phase(chitosan/quaternized chitosan acetic acid solution) rate at 3m L/hrs. The results of 3D video microscope test showed that the microcapsules had good p H stability and ionic stability. UV-VIS spectrum test proved that salicylic acid, sodium salicylate and 5-Fluorouracil could be loaded by the microcapsules. The drug release ratio was affected by the weight ratio of chitosan/quaternized chitosan and the release conditions.A quaternized chitosan/alginate/Ca CO3 composite microcapsule was prepared by the coacervation effect of quaternized chitosan and alginate, and in-situ precipitation of Ca CO3 particle. The composite microcapsules were formed in a microfluidic device based on gas-liquid shearing interaction. The effects of gas flow rate, liquid flow rate, the composition of liquid phase on the size and size distribution of the microcapsules were studied in detail. The morphology and average particle size were characterizated and analyzed by 3D video microscope and SEM. Swelling behavior of the composite microcapsules was studied in aqueous solutions with different p H values and ionic strength. The encapsulation and release of the microcapsules for model drug were evaluated by ultraviolet spectrophotometry. The microcapsules presented a more efficient drug release rate in alkaline solution and at 37 oC.Based on the electrostatic interaction between SDS and graphene modified by quaternized chitosan, a kind of chitosan/graphene microcapsule was fabricated by the gas-liquid microfluidic technique. Particle sizes and distribution of the microcapsules were related to gas rate, the concentration of chitosan and graphene dispersion. Uniform microcapsules were obtained when the gas rate was below 0.7 L/min. The introduction of graphene improved the mechanical strength of microcapsules. The release testing of model drug sodium salicylate revealed that the chitosan/graphene microcapsules had sustained release effects, compared with chitosan microcapsules.The gradient copolymers of styrene and fluorinated acrylate were synthesized by a emulsifier-free RAFT polymerization. Molecular weights and chemical structures were measured by GPC, 1H-NMR, FTIR and DSC. The gradient copolymer latex was used as an inner phase solution to build micro-particles, with the mixed soluiton of chitosan and Ca Cl2 as receiver. 3D microscopy is applied to study the effect of The latex viscosity, chitosan concentration and Ca Cl2 concentration on the formation of micro-particles. The results proved that the viscosity of the latex had an important effect on the morphology and size of micro-particles. The obtained micro-particles had good stability and could load fluorescent dyes.更多还原