以聚酯类材料为载体的阿司匹林/环糊精药物控制释放体系的研究

【作者】 王琛；

【导师】 朱康杰；

【作者基本信息】 浙江大学 ， 高分子化学与物理， 2004， 硕士

【摘要】 药物的控制释放和在人体内的靶向性给药研究是当今化学、医学和药学领域中的一项热点研究课题。无论是传统的药物还是现代基因工程药物对人体都有一定的毒副作用。如何使药物快速准确的到达病灶部位和使药物在安全疗效范围内长效释放是当今给药技术的一个重要课题。 本论文的主要工作是用聚乳酸及其共聚物作为阿司匹林药物的载体材料，考察了将阿司匹林用环糊精包合前后制备微球的方法，并进行了一系列的表征及体外药物释放行为的研究。 本论文的主要工作和结果为： 1．采用O／W、O／O乳液—溶剂挥发法及O／W乳液—相分离法制备了载有阿司匹林的PLGA微球。因阿司匹林具有一定的水溶性(0.33g／100ml)，采用O／W所得微球的包埋率很低，改变制备工艺，比如改变投料比、增加聚合物浓度及在内油相中加丙酮时，包埋率提高均不明显，最大包埋率不超过15％。减少外水相体积时，发现大量的阿司匹林还是通过扩散到了外水相，包埋率也相当低，为9.2-21％。而进一步减少外水相体积又会影响微球的形态，使微球聚集，因此采用O／W法很难得到高包埋率的阿司匹林微球。为了减少阿司匹林在微球制备过程中的损失，我们又考察了O／O乳液—溶剂挥发法制备微球，结果发现所得微球的包埋率仍然较低。通过实验发现，在外油相中加入乳化剂司班后，大豆油对阿司匹林的溶解度增大，而当使用较少量的司班，并将外油相用阿司匹林饱和后，发现微球的实际包埋率还是偏低，最大包埋率只能达到24.8％。O／W乳液—相分离法得到了几乎同样的结果。分析其原因是因为阿司匹林是一种既溶于水相，又溶于油相的药物，在微球制备过程中，很容易损失掉。而将外水相或外油相用阿司匹林饱和后，微球中药物包埋率不高的原因在于在内油相溶剂挥发或提取的过程中，阿司匹林以针状结晶的方式从内油相中析出而脱离了乳液滴，偏光显微镜观察明确证实了这一点。因此，要得到高阿司匹林包埋率的载药微球，就必须解决阿司匹林随着溶剂挥发而结晶析出的问题。 2．分别采用饱和水溶液法和冷冻干燥法制备了阿司匹林和β-环糊精及HP-β-环糊精的包合物。阿司匹林和β-环糊精及HP-β-环糊精是以1：1摩尔比包合的。通过紫外光谱，红外光谱及差示扫描量热法对所得包合物的结构进行了表征，证实了阿司匹林与环糊精包合物的形成。当形成包合物后，阿司匹林的水溶性增大，稳定性增加。 分别采用油包油包粉末(5/0/0)乳液一溶剂挥发法及油包油包水 (W/0/0)溶剂挥发法制备了阿司匹林/p一环糊精包合物的PLA、PLGA、P(LA一co一CL)及P(LA一co一TMC)的微球和阿司匹林舰P一p一环糊精包合物的PLGA、PLEG的微球。将阿司匹林用p一环糊精包合，并以粉末的状态用超声波分散在聚合物溶液中后，阿司匹林不会再溶解在内油相溶剂中，而是以包合物的形式稳定存在，因此就不会在溶剂挥发的过程中以针状结晶形式析出，此时微球中药物包埋率可达100%。但由于受固体粉末颗粒大小的影响，当微球的粒径<100 pm时，包埋率下降，可能是由于在微球形成过程中包合物粉末部分脱离乳液滴。将阿司匹林用HP一p一环糊精包合后，阿司匹林在水中的溶解度大大提高，因此可以用W/0/O乳液一溶剂挥发法以制备粒径较小的微球(<20 pm)。但由于在水溶液中，阿司匹林与包合物之间存在动态平衡，阿司匹林可通过内水相溶扩散到内油相中，而进一步扩散到外油相中，导致微球的包埋率降低。由于这一过程受扩散时间的限制，故包埋率基本上稳定在60%左右。 对采用不同方法和不同聚合物制备的阿司匹林载药微球，进行了体外释药行为的研究。选用的聚合物及聚合物与药物的比例的不同对微球的释药行为的影响较大。此外，在制备微球的过程中内油相加入丙酮(0/W溶剂挥发法)和二氯甲烷(W/O/0溶剂挥发法)对微球结构的致密程度有影响，因而释药行为亦有一定的差别。阿司匹林/环糊精包合物微球在释药过程中阿司匹林的稳定性比单独的阿司匹林微球要好。更多还原

【Abstract】 Controlled drug release is one of the most important tasks in pharmaceutics. Great progress has been made in this field, and many materials and systems have been developed to satisfy the requirements for controlled delivery of a variety of drugs and vaccines. In these systems, the biodegradable polymeric microparticle formulation is one of the most important drug delivery systems.The aim of this paper is preparing aspirin-loaded microspheres, using polylactide (PLA) and its copolymer as the matrices. Different preparation methods were evaluated to prepare aspirin containing microspheres with high drug entrapment efficiency and desirable drug release behaviors. The microspheres obtained were characterized by FT-IR, DSC and SEM, and in vitro drug release was studied as well. Major work and the results of this paper are :1. Preparation of aspirin-loaded PLGA microspheres using O/W, O/O solvent evaporation techniques and O/W emulsion-phase separation technique. Becasue aspirin can be dissolved in water (0.33 g/100 ml), the loading efficiency of microspheres prepared by O/W solvent evaporation technique was very low. Changing polymer/aspirin ratio, increasing the polymer concentration and introducing acetone into the inner oil phase resulted in no increase in the loading efficiency. Most of aspirin was diffused into outer water phase during the course microsphere preparation, and the maximal loading efficiency is about 15%. Decreasing the volume of outer water phase or using O/W emulsion-phase separation technique almost has no effect on the aspirin entrapment efficiency. Consequently, O/O solvent evaporation technique was utilized and similar results were observed, increased aspirin solubility as span 80 was added into outer oil phase might be responsible for these results, and maximal entrapment efficiency was 24.8% in this case. Aspirin crystal, which was separated form the micro-droplet of inner oil phase, was observed during the process of solvent evaporation and this might contribute to the poor entrapment efficiency.2. Aspirin/β - CD and aspirin/HP- β - CD inclusion complexs were prepared using saturated aqueous solution method and freeze-dry technique. The complexs with 1/1 molar ratio were characterized by ultraviolet spectroscopy (UV), FT-infraredspectroscopy (FT-IR) and differential scanning calorimetry(DSC). The solubility and stability of aspirin increased when the inclusion complexs were formed.3. Preparation of aspirin/p - CD or aspirin/HP-β - CD inclusion complex containing microsphere based on PLA and its copolymers using S/O/O or W/O/O solvent evaporation technique respectively. By inclusion aspirin into P - CD, microspheres with high entrapment efficiency (almost 100%) was obtained and no aspirin crystal was observed during the process of solvent evaporation. However, for the limitation of the size of inclusion complex, the loading efficiency decreased when particle size was less than l00μm. The solubility increased dramatically when aspirin was included in HP-β - CD, and microspheres were prepared utilizing W/O/O emulsion solvent evaporation technique accordingly. The particle size of microspheres obtained was less than 20μm and a more sustained in vitro release behavior was observed. For the existence of a dynamical equilibrium between aspirin and its inclusion, aspirin could diffuse across inner oil phase into outer oil phase and the loading efficiency was about 60%.4. Comparison of the in vitro release behaviors of aspirin loaded microspheres prepared with different methods or polymers. The polymer and the ratio of polymer with aspirin or inclusion complexes had a significant effect on the drug release behavior. Adding acetone (O/W solvent evaporation technique) and DMC (W/O/O solvent evaporation technique) into inner oil phase could affect the density of the microspheres. Aspirin released from the inclusion complexs loaded microspheres was more stable than individual aspirin loaded microspheres.更多还原