【作者】 陈闯；

【导师】 王思玲；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2006， 硕士

【摘要】 β-榄香烯(β-elemene)是莪术抗癌的主要成分，具有很强杀灭肿瘤细胞及抑制肿瘤生长的作用。其抗癌谱广、高效、安全、无毒。β-elemene在水中几乎不溶，口服吸收差，生物利用度低。本文以自乳化药物传递系统(self-emulsifying drug deliverysystem，SEDDS)为载体，将β-elemene制成自乳化软胶囊，可改善其在胃肠道中的吸收，提高其口服生物利用度。β-elemene自乳化制剂的处方前研究表明β-elemene的表观油／水分配系数为logP=2.69，亲脂性较强，在光照和高温条件下不稳定；在各种乳化剂、助乳化剂和不同pH值的水溶液中稳定性良好。建立了HPLC法测定β-elemene的含量和体内的血药浓度，此方法灵敏度高，专属性强，结果准确，能满足本研究中的各项分析要求。本研究分别选用大豆油、中链三甘酯、油酸乙酯为油相，聚氧乙烯蓖麻油、吐温85和聚氧乙烯甘油酸酯为乳化剂，1，2-丙二醇、甘油和乙二醇单乙基醚为助乳化剂，加入占辅料总重约30～40％的β-elemene绘制伪三角相图。结果表明影响SEDDS形成的主要因素是油相、乳化剂和助乳化剂。温度和分散介质对SEDDS形成无影响，分散方法可以加速SEDDS的乳化。采用正交试验，以是否成乳和未乳化的油量(水层上漂浮油的量)为指标，筛选基础处方为油酸乙酯、吐温85和乙二醇单乙基醚。绘制反映粒径和乳化效果的伪三角相图，选出最优处方为β-elemene／油酸乙酯／吐温85／乙二醇单乙基醚(55／45／60／40质量比)。在此基础上考察了影响制备β-elemene SEDDS软胶囊的因素，其中温度对软胶囊囊皮的制备影响最大，在囊皮处方中加入了遮光剂，防止β-elemene见光分解。最终确定了β-elemene SEDDS软胶囊的生产工艺。对β-elemene SEDDS软胶囊进行了质量评价。测得β-elemene SEDDS乳化后的粒径大约在320nm左右，粒径分布较窄，乳滴的动电电位为-3 mV，显微镜下观察乳滴为近似球形。在β-elemene SEDDS软胶囊的稳定性考察试验中，制剂的性状、崩解时限和药物含量以及乳化速度、乳化后平均粒径等各项指标基本无变化，自乳化后所得乳剂的稳定性良好。结果表明β-elemene SEDDS软胶囊放置12个月稳定。β-elemene SEDDS软胶囊用0.1mol／L HCl溶液自乳化的乳剂，稀释后仍为分散均匀的乳剂，未见油滴析出，保证了药物在体内以乳剂的形式存在。以市售elemene口服乳为参比制剂，对研制的β-elemene SEDDS软胶囊在家犬体内进行了药物动力学研究。β-elemeneSEDDS软胶囊和市售elemene口服乳的药时过程均符合双室一级吸收模型。β-elemene SEDDS软胶囊相对于市售elemene口服乳的相对生物利用度120.68％。采用方差分析、双单侧t检验和(1-2α)置信区间法进行生物等效性评价，分析结果表明，β-elemene自乳化软胶囊与市售elemene口服乳生物等效。更多还原

【Abstract】 β-elemene, one of main components of zedoary, had considerable effectiveness for killing tumor cell and inhibiting the growth of tumor cell.β-elemene as anti-tumor drug, has wide antitumor spectrum, high efficiency, high safty and innocuity. Because of the poor solubility in water,β-elemene had low absorption in vivo by oral administration. Self-emulsifying drug delivery system （SEDDS） was selected as the carrier to prepare soft capsules to enhance absorption ofβ-elemene in this work.The basic physic-chemical properties, including stability, solubility and apparent partition coefficients (P_apP) ofβ-elemene, were investigated before establishing prescription. The results show that P_app ofβ-elemene was 2.69, which showed theβ-elemene was lipophilic.β-Elemene is unstable subjecting to lights and heat, whileβ-elemene is well stable in various excipients and aqueous solution at various pH values. In order to assay in vitro release and concentration in plasma ofβ-elemene, a high-performance liquid chromatography method was developed. A good specificity, sensitivity and reproducibility of this method made it particularly suitable for analysingβ-elemene.Soybean oil, ethyl oleate and Labrafac were used as candidates for oils phase. Labrasol, Tween85 and EL-20 were selected as candidates for surfactants. 1,2-propanol, transcutol and labrafil were used as candidates for cosurfactants. The experiments based on orthogonal design were carried out. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region. The basic formulation which had the biggest efficient self-emulsification region was ethyl oleate / tween 85/ transcutol. The effects of oils, surfactants, drug and cosurfactants on formulation of SEDDS were investigated. The preparation process of SEDDS ofβ-elemene was optimized. Taking dissolution and emulsion particle size as indexes, the best formula was screened. The optimum formula of self-emulsification ofβ-elemene isβ-elemene/ethyl oleate/Tween85/transcutol = 55 / 45 / 60 / 40 （mass value） on the pseudo-ternary phase diagrams. After investigating the effect of temperature, disintegration time and dispersed methods on formulation of soft capsule, the optimum technologic process was established.The quality ofβ-elemene SEDDS were evaluated. The particles size was about 320nm and the size distribution was narrow. Zeta potential was about -3mV. emulsion droplet was near spherical shape under electron microscope. Appearance, disintegration time, dug content, emulsifying time and emulsion droplet size after self-emulsification has no change in cold-hot cycling test, accelerated test and long-term test showed the stability of β-elemene SEDDS was good. Meanwhile, the effect of different dispersed media, dispersed methods and the dilution times on the SEDDS were studied, and the the change of drug content and drug precipitation was not observed, which ensured theβ-elemene was in emulsion form in vivo.The pharmacokinetics of SEDDS soft capsules ofβ-clemene and conventional emulsion on dogs were investigated. SEDDS soft capsules ofβ-elemene and conventional emulsion were all followed the tow-compartment one-order dynamic model. Compared withβ-elemene conventional emulsion, the bioavailability of SEDDS soft capsules was 120.68%. The results of variance analysis and two one side t-test showed that the absorption degree of SEDDS soft capsules ofβ-elemcne and conventional emulsion were equal.更多还原