【作者】 陆杨燕；

【导师】 顾宁； 夏强；

【作者基本信息】 东南大学 ， 材料物理与化学， 2005， 硕士

【摘要】 本论文研究了一种特殊微乳液体系的相行为，并以此为基础实现了纳米药物载体的可控制备。 从上世纪九十年代初期开始，固体脂质纳米粒(SLN)的研究受到了广泛的重视。在多数情况下，SLN的制备取决于载药微乳液的性质。因此，对载药微乳液的性质如相行为进行深入研究，对于SLN的可控制备和应用具有重要意义。用于SLN制备的微乳液是一种特殊的微乳液，即脂质材料在常温下是固态，熔融的脂质材料作为油相。因此，微乳液的制备温度需介于60～80℃之间，而一般的微乳液在常温下就可以形成。传统的滴定法可用于绘制微乳液相图，但对于本文研究的特殊微乳液存在较大的局限，必须作出改进以适应研究的需要。 本论文的主要工作有：研制了适合特殊微乳体系相图绘制的装置；研究了不同乳化剂体系的相行为；基于相图结果，实现了对SLN的可控制备。具体内容如下： 1．用于绘制纳米乳液控温相图的检测装置的研制 该装置由五部分构成：控温部分、搅拌部分、加液部分、检测部分和开关控制部分。优点有：1)准确、方便地控制温度且能使体系维持恒温；2)利用搅拌器或漩涡混合仪使体系充分混合，更利于相变的判断；3)利用暗箱，操作简单且可以比较准确地判断液晶区。 2．S-40／F-68／GMS／水体系相行为的研究及应用 利用自行研制的装置，绘制了S-40／F-68／水体系的相图，根据相图结果和实验现象，确定了S-40和F-68最优的配比为7∶3。加入油相GMS，绘制了S-40／F-68／GMS／水的拟三元相图。相图结果表明温度和药物对相行为的影响很小，特别是O／W微乳区。基于相图研究结果制备了纳米药物载体，然后以维甲酸为模型药物制备了维甲酸固体脂质纳米粒(RA-SLN)悬浮液，并通过冷冻干燥将其制成了冻干粉。对其进行表征的结果如下：(1)粒子粒径在10～20nm，呈不规则的球形，粒径与温度之间呈现一定的规律；(2)RA-SLN最高载药量达到327μg／mL；(3)物理稳定性好，冷冻离心(4℃，12000r／min)120min或纯载体保存1年后粒径分布仍然基本不变；(4)RA-SLN的体外透皮实验，说明其对皮肤通透性很好。 3．Brij78／脱氧胆酸钠／GMS／水体系的研究及应用 研究了不同的脂质含量对相态的影响。在脂质含量分别为10％、20％、33％、50％时，绘制拟三元相图，结果表明只有在脂质含量比较低的时候，才出现O／W微乳区。经过比较，选取脂质含量为20％，绘制载药相图，发现药物对相行为有一定的影响，特别是O／W微乳区，该区域略有扩大。基于相图结果制备了RA-SLN，对其进行了表征：粒子平均粒径在10～20nm；RA-SLN最高载药量达到1.039mg／mL；物理稳定性较好；RA-SLN滴眼液抑制后发性白内障的实验，说明它能有效抑制晶状体上皮细胞的增殖，预防兔后发性白内障的形成。更多还原

【Abstract】 In this paper, phase behavior of a special microemulsion was studied, based on which the controllable preparation of nano drug carrier was realized.From the beginning of 1990’s, Solid Lipid Nanoparticles (SLN) have been attached great importance. In most cases, the preparation of SLN lies on the property of microemulsion. So the study on the phase behavior of hot drug-loaded microemulsions is significative for the controllable preparation of SLN. In this paper, the microemulsion is quite different from normal microemulsion for the melt lipid as oil phase, so the temperature should remain between 60-80 ℃. Phase diagram of normal microemulsion is drawn through titration method, but it’s not much suitable for the special microemulsion.The major achievements in this paper include: making of a microemulsion phase diagram detection instrument; studying on the phase behavior of different emulsifiers systems; succeeding in preparing SLN based on the phase behaviors results. As follows are the details:1. Making a microemulsion phase diagram detection instrument with high temperature accuracyIt consists of thermostatic unit, stirrer unit, sample cell, detector unit, and switch unit. Advantages are: 1) it can control temperature accurately and easily; 2) the use of stirrer makes it easier to observe phase variety; 3) the dark box is helpful to estimate the liquid crystal region .2. Studying on the phase behaviors of S-40/ F-68/glycerol monostearate (GMS)Water systemThe phase diagrams for the system S-40/F-68/water were obtained at 60°C with self-made device. The optimal mass ratio of S-40 and F-68 was chosen as 7:3 according to the phase behaviors results and experiment phenomena. With GMS added, the pseudoternary phase diagrams for the system S-40/F-68/GMS/water were obtained. It was concluded that the temperature and the introduction of retinoic acid (RA) has little influence on the phase behaviors of hot drug-loaded microemulsions. RA-SLN has been gotten when RA was chosen as model drug. It can also be obtain by freeze-drying. The mean particle size was measured by Photon Correlation Spectroscopy (PCS) method and the morphology of RA-SLN was characterized by Transmission Electron Microscope (TEM). The results show that the mean diameter of RA-SLN is between the 10-20nm. RA-SLN of various drug loading was prepared and the maximum can reach 327μg/mL. As far as stability of RA-SLN is concerned, it remains stable after 120 min centrifugation (4℃,10000 r/min) or 1 year storage for nano drug carrier. The transdermal permeation through rabbit skin in vitro indicated that RA-SLN is of better skin penetrating capacity.3. Studying on the phase behaviors of Brij78/ deoxycholic acid sodium(DAS)/GMS/Water system The pseudoternary phase diagrams of Brij78/DAS/GMS/water systems with different ratio of GMS were obtained at 60 ℃, the ratio separately was 10%, 20%, 33%, 50%. Only when the lipid content was comparatively low, O/W microemulsion region appeared in phase diagram. The ratio of 20% was considered optimal after comparing. It was concluded that the introduction of RA has some influence on the phase behaviors, especially for O/W microemulsion region and its region appeared to expand. Research of RA-SLN showed that: The mean particle size kept between 10-20nm. RA-SLN of various drug loading was prepared and the maximum can reach 327μg/mL. Besides, it has a good stability. Eyedrop loading with RA-SLN can inhibit metaplasia and proliferation of lens epithelial cells in rabbit eyes and prevent the development of posterior capsular opacification.更多还原