【作者】 李璐；

【导师】 杨卓如；

【作者基本信息】 华南理工大学 ， 化学工程， 2006， 博士

【摘要】 多孔聚合物微球作为一种新型的活性物载体系统,在药物或化妆品的控缓释领域得到了广泛的研究和应用。多孔聚合物微球载体系统能够克服现有化妆品体系中的一些弊端,利用自身较大的比表面积和多孔结构,改变活性物的添加和释放方式,从而达到延长有效作用时间、降低毒副作用的缓释目的。聚苯乙烯-二乙烯苯(PSt-DVB)多孔微球因其化学稳定性好,适用的pH范围宽,得到的多孔结构稳定,是近年来备受关注的一种载体材料。本文采用改进的二步种子溶胀法制备了单分散、小粒径的多孔PSt-DVB微球,并将优化合成的多孔微球用于负载化妆品活性组分,考察了其吸附和释放性能,发现制备的多孔聚合物微球具有良好的缓释性能。多孔PSt-DVB交联微球的均匀性是影响其使用性能的主要因素之一,经典的制备方法是悬浮聚合法,由于所得粒子的粒径范围宽,必须进行反复的筛分才能使用。本文采用超声分散的方式对其进行了改进,得到粒径相对较均匀的PSt-DVB微球(粒径在10～50μm),并讨论了致孔剂的种类及组成、交联单体浓度、分散稳定剂用量和抽提溶剂等因素对多孔微球表面形貌和孔结构的影响。研究发现,随着非溶胀剂使用比例的增大,孔径和比表面积增大;高的DVB浓度则导致比表面积上升和孔径下降;分散稳定剂可以增大界面粘度,适量的分散剂有利于得到粒径均匀的多孔聚合物微球;后续处理时用二氯甲烷作为抽提溶剂得到比甲苯更好的成孔效果。对于本实验条件来说,当甲苯与环己醇的体积比为1:2,DVB体积浓度为40～60%,分散剂用量为1.2%时,所得微球的形貌及性能较好。本文利用超声分散改进的二步种子溶胀法成功合成了单分散PSt-DVB多孔微球,并将二步种子溶胀时间由传统的48h缩短至15～20h。首先采用分散聚合法制备单分散的聚苯乙烯种球,系统地研究了单体浓度、引发剂用量、分散剂用量、反应介质组成和反应温度等各种聚合参数对聚合产物粒径及其分散度的影响,得到比较优化的合成条件为:引发剂用量1.0%(wt)、分散剂用量6.0%(wt)、单体体积25ml(总反应体积125ml)、反应温度70℃、反应介质采用无水乙醇或无水乙醇/水(90/10),在此条件下可以聚合得到粒径1.5～4μm的单分散聚苯乙烯种球。再以单分散的聚苯乙烯种球为模板,用溶胀剂和单体依次对种球进行二步活化溶胀,升温引发聚合即可得到单分散的多孔PSt-DVB微球。并对聚苯乙烯种球的活化条件、超声分散时间、种球类型、种球和溶胀剂以及交联单体比率、不同辅助致孔剂等诸多影响因素进行了讨论。研究结果表明,用邻苯二甲酸二丁酯作为溶胀剂,在35℃下溶胀5～10h即能取得较好的种球活化效果;种球的单分散性对最终产物的形貌有决定性影响,它的任何形貌缺陷都将在最终产物中被扩大;随着溶胀剂/种球比率(DBP/Seed)和交联单体/种球比率(DVB/Seed)的增加,交联微球比表面积上升,孔径下降。在本实验条件下,当DBP/Seed=1.0mL/g,DVB/Seed=8～10mL/g时,以甲苯或庚烷为辅助致孔剂,能够得到粒径为2～9μm单分散性良好的多孔PSt-DVB微球。以对苯二酚、熊果苷和防晒剂parsol 1789为模型组分考察了多孔聚合物微球的活性物负载能力以及体外释放性能,结果表明非极性的多孔PSt-DVB微球对非极性的小分子对苯二酚有着良好的负载作用。而多官能团单体甲基丙烯酸甲酯(MMA)的引入,则可使多孔微球成为表面同时具有亲水和疏水基团的中极性载体,从而提高了对极性分子熊果苷和parsol 1789的负载能力。从总体上看,多孔聚合物微球对对苯二酚的负载能力要优于对熊果苷和parsol 1789的负载能力。体外释放研究表明,制备的多孔聚合物微球载药体系具有良好的缓释效应,与水亲和力较高的熊果苷从微球中释放速度较快,而不溶于水的parsol 1789的释放则表现出了更为明显的缓释效果。采用多种常用药学体外释放模型对负载活性物的多孔聚合物微球体外释放进行了拟合,发现一级动力学模型能够较好的拟合多种情况下的释放情况,Higuchi模型的拟合状况稍差,而零级动力学模型只对parsol 1789体外释放情况表现出一定的拟合效果。针对parsol 1789这类难溶性活性物的特点,综合考虑活性物释放中扩散和溶解速率等因素,提出了一种新的溶解扩散模型,并利用数学方法对模型进行了求解。采用提出的模型对三种活性物的体外释放实验数据进行拟合,求得不同活性物的有效扩散系数和溶解速率常数,揭示了微球结构、活性物性质和释放性能关系的一些基本规律,为指导微球合成、改善和控制活性物的释放性能提供了基础。更多还原

【Abstract】 Porous polymer microspheres are widely researched and used as new active carrier systems in cosmetics or pharmaceuticals. Because of the large surface area and controllable porous structure, porous polymer microspheres have advantageous of sustained release of actives over prolong time to increase efficiency time, low toxicity to skin and favorable biocompatibility of the cosmetics systems. Poly (styrene-divinylbenzene) (PSt-DVB) microspheres are very efficient carrier materials because of their chemical stability in the entire pH range and stable porous structure. In this article, monodisperse PSt-DVB microspheres in the size range of 2~9μm are prepared by the modified two-step swelling and polymerization method. The produced porous microspheres are applied as a carrier to study the adsorption and release behaviors of cosmetic actives. The produced actives-carrying porous microspheres exhibit an effectively slow release behavior.The uniformity of PSt-DVB microspheres is one of the main factors to affect carrier efficiency. Such polymer microspheres are normally produced by suspension polymerization. However, the suspension process gives relatively large particles with a broad particle size distribution, even if the polymerization conditions are strictly controlled. The relatively uniform porous PSt-DVB microspheres in the size range of 10~50μm were prepared by modified suspension polymerization of styrene (St) with divinylbenzene (DVB) in the presence of toluene, cyclohexanol and heptane as porogenic diluents. In this paper, the use of ultrasonic dispersion decreased the beads’size and improved the uniformity. The effects of the porogen mixture, DVB content, the amount of dispersant and solvent extraction on the surface performance of the synthesized beads were studied. It was found that a great proportion of the non-solvating porogen increases the pore diameter and the specific surface area. High DVB concentration also results in the great specific surface area and porosity. The dispersant has advantageous to obtain uniform microspheres by increase the interface viscosity. In the experiment condition of this article, when the volume ratio of toluene/cyclohexanol is 1:2, DVB content is at the range of 40~60%, the amount of dispersant is 1.2% and methylene chloride was used as extractant, the beads with good spherical shape and pore size were obtained.Monodisperse PSt-DVB porous microspheres in the size range of 2~9μm were prepared by modified two-step swelling and polymerization method, the use of ultrasonic assistant dispersion reduced the swelling time from traditional 48h to 15～20h. The uniform polystyrene (PS) particles are synthesized by dispersion polymerization, the effects of the concentration of monomer, amount of initiator, amount of stabilizer, composition of medium and reaction temperature on particle distribution and diameter were systematically investigated. The optimized reaction conditions were obtained as following: the amount of initiator is 1.0% (wt), the amount of stabilizer is 6.0%(wt), the volume of St is 25ml (total reaction volume 125ml), reaction temperature is 70℃, the reaction medium is ethanol or ethanol/water (90/10). The monodisperse polystyrene particles in the range of 1.5~4μm were prepared under above condition. The obtained PS beads were used as the seed particles and swollen by the activated agent and monomers , then the monodisperse porous PSt-DVB microspheres in the size range of 2~9μm may be synthesized by the polymerization in 75℃for 24h. The effects of activated conditions, ultrasonic dispersion time, seed type, assistant porogen type, and DBP/Seed and DVB/Seed ratios on the performances of the produced porous microspheres were discussed. It was found that the DBP used as activated agent in 35℃swelling for 5~10h may achieve a good activated result. The PSt-DVB porous microspheres diameter and distribution were largely influenced by the PS characteristics. The surface area increased and the pore diameter decreased with the DBP/Seed and DVB/Seed ratios. When the ratios of DBP/Seed and DVB/Seed are 1.0ml/g and 8~10ml/g respectively, toluene or heptane as the assistant porogen, the aimed porous microspheres were obtained satisfactorily.By using hydroquinone, arbutin and avobenzone as model actives, the adsorption and release behaviors were discussed. It was found that the hydrophobic PSt-DVB porous microspheres had excellent adsorption ability to little nonpolar molecular hydroquinone. By introducing the MMA, the porous microspheres would become intermediate polar materials because of the occurrence of hydrophobic group and hydrophilic group, then the adsorption ability to polarity arbutin and avobenzone was increased. The produced actives-carrying microspheres exhibited a slow release behavior, the release of hydrophilic arbutin was much faster than parsol 1789 and hydroquinone with a burst effect.Several mathematical models of drug release were used to fit the release of cosmetic actives from porous microspheres. The first order model could fit all release profiles, and Higuchi model or zero order model may only fit the release profile for one of the mentioned actives. Parsol 1789 was studied as a model hydrophobic ingredient. By taking consideration of diffusion and dissolution effects, a new model was developed for description of the release behaviors. The model was used to fit the release profiles of the above three different actives, and the diffusion coefficient and dissolution rate constant were obtained. Based on the modeling study, the relationship of porous microspheres structure, actives performances and release behavior was found, hence a theoretical basis was provided to optimize the microsphere synthesis and desired actives release profile.更多还原