【作者】 曹丽萍；

【导师】 李卫民；

【作者基本信息】 广州中医药大学 ， 中药学， 2011， 硕士

【摘要】 多西他赛是一种新型抗肿瘤药物,对卵巢癌、乳腺癌、非小细胞肺癌、食管癌、头颈部癌等肿瘤疾病均有良好疗效。目前,多西他赛上市的注射剂用Tween80增溶、乙醇助溶,将其制成一个注射剂浓缩液和一个溶剂的两瓶装。虽然处方中使用了毒性相对较小的Tween80和乙醇作为溶剂体系,但临床使用时仍存在着操作繁琐,Tween80易引起过敏和溶血作用。为了消除现有多西他赛制剂所产生的一系列问题并解决多西他赛溶解度低的缺点,本课题研制注射用的多西他赛自乳化制剂,以期为多西他赛的新剂型开发提供研究基础。本课题研究的主要内容包括：一、处方前研究：处方前研究中建立了多西他赛自乳化系统的HPLC含量测定方法,该方法灵敏、精密、便捷、专属性强,适用于自乳化系统中药物含量的测定。测定了多西他赛在不同油相中的溶解度。本文以高效液相色谱法测定DOC含量。药物在水及各辅料中溶解度的测定表明药物在水中不溶,在各种油相,乳化剂及助乳化剂中溶解较多。药物的油水分配系数的测定说明药物的亲脂性较强。二、多西他赛自乳化系统的制备：在处方前研究的基础上,通过对各种油相和不同乳化剂的配伍变化的观察,选出具有较强乳化能力的乳化剂和对药物有较大溶解度的油相和助乳化剂。根据药物在各注射级辅料中的溶解性、通过绘制空白伪三元相图、进行了自乳化给药系统基本处方的初步筛选。最后通过考察载药量对粒径、制剂稳定性的影响,对注射用DOC自乳化微乳制剂进行了处方优化,确定处方组成为：m(MCT):m(Soultol HS15):m(PEG 400)=3:8:4,其中药物含量的质量分数为2%。三、多西他赛自乳化系统的理化性质研究及其稳定性：对DOC-SEDDS和其自乳化后乳剂的外观性状进行观察,同时对自乳化时间,自乳化后的粒径进行了测定。考察了不同温度,分散介质,分散方法对系统自乳化效率的影响以及不同的分散介质,稀释倍数对自乳化后乳剂粒径的影响。稳定性试验结果表明DOC-SEDDS初步稳定性良好。四、注射用的多西他赛自乳化制剂在大鼠体内药物动力学研究：建立了大鼠血浆中多西他赛的高效液相色谱法,考察了尾静脉注射多西他赛普通注射剂和多西他赛自乳化后大鼠体内的药物动力学过程。建立了多西他赛体内药物测定的HPLC法,以甲醇处理血浆样品后进行测定。该法简单、快捷、灵敏度高,适合多西他赛的体内分析研究。结果表明多西他赛自乳化药液和参照制剂大鼠尾静脉注射给药后药动学过程均符合双室模型。更多还原

【Abstract】 Docetaxel is a novel anticancer drugs. It is effective for ovarian cancer,breast cancer、non-small cell lung cancer、esophageal cancer、head and neck cancer and other tumor diseases.At present, the commercial product of docetaxel still adopted Tween 80 and ethanol as injection solvents, Tween 80 was used as solubilizer and ethanol as auxiliary solvent, which was packed separated as condensed injection solution and solvent in two packages. Although the prescription use a relatively less toxic solubilizer Tween 80 and ethanol as solvents, but still exsit complicated operation in clinical use and Tween 80 is easy cause allergies and hemolytic effects.In order to eliminate the existed a series of problems which docetaxel produced in clinical use and solve the lower solubility of docetaxel, a docetaxel self-microemulsion for intravenous injection was developed in this study, so as to provide fundmental work for new dosage form research of docetaxel. The main contents of the research are follows.1. Preformulation research of docetaxel self-microemulsion.An HPLC method was developed for the assay determination of docetaxel self-emulsifying system on the preformulation study, this method is sensitive、precise、convenient specific to self-emulsifying system for the determination of the drug.The solubility of docetaxel in various oils phase and surfactant and cosurfactant was measured, also observed the effect through a variety of oil phase and surfactant of the compatibility, choose with strong emulsifier and higher solubility for drug an, as the self-emulsifying drug delivery system of basic prescription screening. Determinnation of drug solubility in water and adjuvants showed DOC was insoluble in water and relatively more soluble in various oil、emulsifier and co-emulsifier.The oil-water participate coefficient showed relatively strong lipophlic property of drug.2. The preparation of docetaxe self-emulsifying system.Based on the results of the study before formulation, we search for the optimum formulation for the self-microemulsifying drug delivery system of DOC, the drawing of pseudo-ternary phase diagram of blank self-microemulsifying drug delivery system and analysis partical size. The constitution of optimum formulation is as follows:m(MCT): m(Soultol HS15):m(PEG 400)= 3:8:4, with content 2% of drug.3. Docetaxel self-emulsifying system and the stability of the physical and chemical properties.According to the appearance of SEDDS, before and after emulsiyfing, the emulsified time, the droplet size after self-emulsification, content and stability test of DOC, the quality of SEDDS of DOC was evaluated.Meanwhile, we also studied the shifts of the self-emulsifying efficiency by changing temperature, dispersed media and dispersed methods and the effect of the different dispersed mdedium, dilution on the droplet size.4. The pharmacodynamic study of docetaxel self-microemulsion in rats.An HPLC method was developed for the determination of docetaxel in mouse plasma. Pharmacokinetics of docetaxel injection and docetaxel self-microemulsion in mouse after iv administration were investigated.The plasma samples were dealt with methanol before determination.The method was simple、quick、sensive and very suitable for the drug determination in vivo. The pharmmacokinetics results of docetaxel self-microemulsions showed that docetaxel injection and docetaxel self-microemulsion was accored with double-room double.更多还原