摘要
微乳因其具有稳定好、溶解能力强、透皮能力强等特点,作为经皮给药制剂的载体,受到了广泛的关注。在湖北省科技攻关项目“鬼臼毒素微乳凝胶剂的研制”(2005AA301B10)的支持下,本课题选取了酯类药物鬼臼毒素作为药物模型,对它的微乳及微乳凝胶经皮给药系统进行了研究,主要研究结果如下:
1.研究了鬼臼毒素原料药的稳定性。结果显示,鬼臼毒素原料药本身具有较强的稳定性,但溶液稳定性差,酯基团易发生亲核取代反应。加速实验显示,10天内鬼臼毒素在甲醇溶液中杂质增长高达18%,乙醇中达4%。控制溶液pH值在3.5~3.9,可有效的抑制杂质的增长。
2.依据微乳伪三元相图设计微乳处方,研究了微乳对鬼臼毒素的增溶作用,考察了0.5%鬼臼毒素在微乳中稳定性的改善情况。结果显示,微乳对鬼臼毒素的增溶作用不仅与药物在微乳各组分中的溶解度有关,与微乳的结构同样有联系;同时稳定性考察结果显示,由Tween 80和PG组成的界面膜将鬼臼毒素包裹于内相,起到了良好的保护作用。
3.制备了用于透皮给药的0.5%鬼臼毒素微乳凝胶,分别考察了凝胶化对微乳结构、药物经皮渗透行为及药物稳定性的影响。PCS和TEM结果显示,经卡波姆940凝胶化后的微乳结构未发生显著变化;与鬼臼毒素微乳比较,凝胶化对鬼臼毒素的透皮速率无影响,符合Fick’s第一扩散定律;激光共聚焦图片显示微乳凝胶促进鬼臼毒素透过角质层到达皮肤靶部位的能力强于酊剂;影响因素试验结果显示,凝胶化导致载体pH升高,对鬼臼毒素的稳定性产生了负面影响。
4.在80℃的条件下,设计制备了由Cremphor RH40、Comprotol 888、PG、水和卡波姆940组成的鬼臼毒素新型微乳凝胶,初步考察了其制备工艺影响微乳凝胶内相液滴的形成情况及该新型微乳凝胶的经皮渗透行为。结果表明该凝胶制备过程中冷却温度的变化可改变其内相液滴的粒度,并进一步影响其经皮渗透行为;初步实验显示,-76℃和-15℃冷冻制得的样品的靶向效率te分别为1.32和1.03,该新型微乳凝胶显现出了一定的皮肤靶向性的特征。
In the past 2 decades, microemulsion has been extensively used in transdermal drug delivery system due to many advantages including the thermodynamic stability, high solubility, rapid absorption and so on. It is very interesting to study drug-loaded microemulsion with special release properties of drug. In this study, podophyllotoxin microemulsion and microemulsion-based hydrogel were investigated with the support of Hubei Province Key Technology R&D Program“Research of Podophyllotoxin-loaded Microemulsion-based hydrogel”(2005AA301B10). The main findings are as follows:
1. The stability of podophyllotoxin was studied by the RP-HPLC analysis method. The results showed that podophyllotoxin had a strong stability but it had a poor stability in solution, in which the ester group of podophyllotoxin would be controlled nucleophilic substitution reactions. The accelerated test showed that the contents of impurity were 18% in methanol and 4% in ethanol in 10 days. The pH values ranging from 3.5 to 3.9 would be advantageous to the stability of podophyllotoxin.
2. According to the pseudo-ternary phase diagrams, microemulsion formulations were designed, and the capability of these microemulsions to improve the podophyllotoxin solubility and the stability of podophyllotoxin were studied. The results showed that microemulsion could effectively improve the solubility. The solubilization of podophyllotoxin in microemulsions was relative with the composition and structure of the microemulsions. Additionally, the stability study showed that the interfacial film comprised of Tween 80 and PG would parcel podophyllotoxin inside oily phase, which provide a good protection effect.
3. The microemulsion-based hydrogels containing 0.5% podophyllotoxin for transdermal drug delivery were prepared using carbomer 940 as thickening agent of microemulsions. The influence of carbomer 940 on the structure of microemulsion, permeation rate and stability of podophyllotoxin was investigated. The results showed that the gelation didn’t affect the structure of microemulsion and the microemulsion-based hydrogels still had good permeation ability, which followed the Fick’s first diffusion law. The confocal laser scanning microscopy (CLSM) showed that podophyllotoxin from the microemulsion-based hydrogel could target skin when compared with tincture. The impact factors experiment showed that the increasing pH value of the system after gelation had adverse effect on the stability of podophyllotoxin.
4. The novel microemulsion-based hydrogel (NMBH) consisting of Cremphor RH40, Comprotol 888, PG, water and cabmer 940 were prepared, and the properties of this NMBH including the formation of droplets in inner phase and permeation ability were studied. The results showed that the cooling temperature of this system could lead to various diameters of these microemulsions, and permeation rate could be further influenced. The targeting efficiencies (te) of the NMBH obtained at -76℃and -15℃were 1.32 and 1.03, respectively. It would seem that the NMBH had a certain feature of skin targeting effect of drug.
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