【作者】 曲剑波；

【导师】 褚良银；

【作者基本信息】 四川大学 ， 生物化工， 2005， 硕士

【摘要】 控制释放膜是膜科学技术领域的一个重要分支,在药物控制释放领域受到了广泛关注。人体内不同部位的pH值是不一样的,特定病灶也会引起局部pH变化,因此,pH感应型给药系统的研究引起了国际上广泛的关注和重视。pH感应型控制释放系统由于具有对环境pH信息感知、信息处理以及响应执行一体化的“智能”,被认为可以用来实现体内不同消化部位和肿瘤部位的智能给药,实现药物的定点、定量、定时释放。迄今的研究工作在给药系统的快速应答释放速度方面还不能令人满意,主要是受以浓度差为推动力的溶质扩散速度限制,目前的给药系统从释放原理上讲其应答速度不可能突破此限,需要进一步研究和解决。针对上述问题,本文构造了一种具有“泵送”功能的耦合型pH感应控制释放膜系统,系统研究了pH感应型阴离子水凝胶的接枝率对开关膜水通量、溶质透过膜的扩散系数的pH感应特性的影响,并用Hagen-Poiseuille方程研究了接枝率对开关膜pH感应孔径变化倍数的影响;研究了单体浓度、交联剂浓发对pH感应型阳离子水凝胶的pH感应特性、体积相变速率以及模拟药物释放的影响,为给药系统中“泵”元素的选择提供依据;实验考察了模型药物VB₁₂在该耦合系统中的pH感应释放行为,取得了创新性研究成果。 首先,采用等离子体诱导填孔接枝法在聚偏氟乙烯（PVDF）多孔膜上成功接枝了聚甲基丙烯酸（PMAA）,SEM断面观察、XPS光电子能谱分析和水通量过滤性能实验结果都表明,PMAA均匀地接枝在PVDF膜表面和膜孔内。在低接枝率情况下,接枝物主要集中在膜孔内:随着接枝率的增大,膜表面接枝物厚度增加。系统研究了接枝率对开关膜感应pH水通量的影响,结果表明:接枝率适中的膜（0.38%～13.38%）的水通量在pKa附近（pH3～pH6）发生了较显著的变化。接枝率达到一定程度时开关膜表现出pH值阀效应,Y≤5.98%时,pH感应开关系数（开关膜在pH2.1和pH7时的水通量之比）随接枝率的增加而更多还原

【Abstract】 Controlled-release membrane system is one of the important branches of membrane science and technology, and it has received much attention in the field of drug controlled-release. It is well known that pH values are different in different organs in the human and animal body, and some diseases such as tumour also cause local pH abnormity. Therefore, development of pH-responsive drug delivery system has been a hot topic in the world. Due to their intelligent responsiveness and self-regulated controlled-release behavior to ambient pH change, pH-responsive controlled-release systems are considered to be competent to achieve improved drug treatments through rate- and time-programmed and site-specific drug delivery at targeted gastrointestinal or tumour sites. Up to now, there have been many investigations on the pH-responsive controlled-release systems. However, the pH-responsive release rates of previous systems were not as quick as expected. Because the driving force for the drug release from those systems was the concentration gradient of drug, the release rate was limited by the solute diffusion. In this paper, we developed a pH-responsive coupling controlled-release membrane system with pumping effects, in order to improve the release rate of pH-responsive drug delivery system. The effects of grafting yield on water flux and solute diffusion through pH-responsive gating membranes were investigated systematically. The pH-responsive gating characteristics of membrane pore size were studied by using Hagen-Poiseuille’s equation. pH-responsive cationic hydrogels were chosen as the"pump" elements in the pH-responsive drug delivery system, and the effects of monomer and cross-linker concentrations in the preparation of hydrogels on the pH-responsive volume phase transition and drug release characteristics were investigated. pH-responsive release rate of model drug VB12 in the coupling device with gating membrane and hydrogel "pump" was studied, and very exciting experimental results were obtained.First, a series of pH-responsive gating membranes were successfully prepared by grafting poly(methacrylic acid) (PMAA) onto porous polyvinylidene fluoride (PVDF) membrane substrates with plasma-induced pore-filling polymerization. SEM images, XPS spectra and water flux results all indicated that PMAA were grafted uniformly onto membrane surfaces and inside membrane pores. The grafting yield heavily affected both the water flux responsiveness coefficient and the pH-responsivity of the membrane pore size. When the grafting yield was smaller than 5.98%, both the flux responsiveness coefficient and the pH-responsivity of the membrane pore size increased with an increase in the grafting yield; however, when the grafting yield was higher than 5.98%. both the flux responsiveness coefficient and the pH-responsivity of the membrane pore size decreased with an increase in the grafting yield, till equal to 1.0 (no gating characteristics existed anymore). The diffusion coefficients of VB12 through the PMAA-g-PVDF membranes in solution with pH=2 were always larger than those with pH=7. With increasing the grafting yield of PMAA, the difference between the diffusion coefficients with pH=2 and pH=7 became larger.Then, poly(7V,iV-Dimethylaminoethyl methacrylate) (PDM) hydrogels were prepared by introducing radical polymerization. SEM images of hydrogels showed that the dry hydrogels prepared by freeze-dried method were featured with three-dimensional porous network structure, whereas those prepared by ordinary vacuum-dried method were featured with dense structure. Experimental on the swelling kinetics showed that three-dimensional porous network structure was better than dense structure. With decreasing the monomer and cross-linker concentrations in the preparation of PDM hydrogels, the network density and the elasticity of thehydrogels became weak, as a result the swelling ratio of hydrogels gradually increased. Volume phase transition of PDM hydrogels occurred near the pKa (pH3~~pH6). In order to achieve larger and faster responsiveness of PDM hydrogels, the monomer and cross-linker concentrations should be controlled at lower level.Finally, the PMAA-g-PVDF gating membrane and the PDM hydrogel were coupled with a diffusion device, and pH-responsive release rate of VB12 in the coupling device were studied. The release rate of VB12 in the coupling device with PDM hydrogels and PMAA-g-PVDF gating membrane showed that, the release rate of VB12 was very low in solution with pH=7 because of the swollen PMAA chains in the membrane pores and the collapsed PDM hydrogels inside the diffusion device; whereas when the pH value changed into 2, the release rate of VB12 increased abruptly because of the collapsed PMAA chains in the membrane pores and the swollen PDM hydrogels inside the diffusion device. The grafting yield of PMAA-g-PVDF gating membranes and the monomer and cross-linker concentrations of PDM hydrogels were important factors influencing the release rate of VB12. The pH-responsive controlled-release factor in the optimal coupling system was as large as 6.5. The results showed that the pH-responsive release rate was effectively improved in the coupling membrane system by introducing the pumping effects. The achievements in this study provided valuable theoretical and experimental guidance for further developing pH-responsive drug delivery systems with quick responsivity and fast release rate.更多还原