【作者】 高晓非；

【导师】 邓英杰；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2008， 硕士

【摘要】 本文建立了六甲蜜胺原料药的体外HPLC分析方法,并确立了六甲蜜胺脂质体主药的测定方法,以及确立微柱离心-HPLC法测定六甲蜜胺脂质体包封率,同时也为其制剂的含量测定、理化性质及稳定性等性质的研究提供了可靠的分析方法。采用乙醇注入法制备了六甲蜜胺普通脂质体,并以包封率为指标,对磷脂种类、磷脂用量、水相介质pH、胆脂比、乙醇的用量、制备温度、搅拌速度、投药量、缓冲液浓度等处方工艺进行了单因素考察,又通过正交设计优化处方,制备了包封率大于85%的六甲蜜胺普通脂质体。在此基础上,考察了壳聚糖包衣脂质体的制备工艺,制备成六甲蜜胺壳聚糖包衣脂质体。采用逆向蒸发法制备了六甲蜜胺胆盐脂质体,以脱氧胆酸钠为模型胆盐,以包封率为指标,对总脂量、胆脂比、脱氧胆酸钠与总脂量的摩尔比等进行单因素考察,又通过制备钙黄绿素胆盐脂质体考察以上因素对胆盐脂质体在20 mmol·L^-1胆盐中稳定性的影响,处方优化后得到的六甲蜜胺胆盐脂质体抵抗胆盐破坏的能力较强。考察了六甲蜜胺三种脂质体的体外性质,三种脂质体形状圆整,大小均一;在盐酸溶液中,壳聚糖脂质体的释放速率慢于普通脂质体;在胆盐溶液中,胆盐脂质体的释放速率慢于普通脂质体;在pH7.4的磷酸盐缓冲液中,三种脂质体的释放性质没有显著差异。根据外观、粒径、包封率、pH值、药物含量以及过氧化值对三种脂质体的体外稳定性进行了初步考察,这三种脂质体在低温避光下保存稳定性较好。建立了HPLC法测定大鼠血浆中六甲蜜胺的含量,考察了六甲蜜胺溶液、六甲蜜胺普通脂质体、六甲蜜胺壳聚糖包衣脂质体以及六甲蜜胺胆盐脂质体在大鼠口服给药的体内药动学过程。四者的药动学过程均符合双隔室模型,六甲蜜胺壳聚糖包衣脂质体和胆盐脂质体的半衰期和相对生物利用度均较普通脂质体有所提高。更多还原

【Abstract】 The HPLC analytical method for Hexamethylmelamine(HMM)in vitro was developed.The method of detecting the content of HMM and the encapsulation efficiency of HMM liposome was established,which also used in study of HMM physicochemical property and stability.The entrapment efficiency of HM liposome was determined by minicolum_n centrifuge-HPLC method.The HMM liposome was prepared by ethanol injection method.The single factor investigation and the orthogonal design were adopted to obtain the optimized prescription,the entrapment efficiency of HMM liposome was above 85%.On the base of above,the prepared technology of liposome coated chitosan was investigated and HMM liposome coated by chitosan was prepared.The HMM/DOC liposome was prepared by reverse-phase evaporation method.The single factor was investigated by taking sodium deoxycholate(DOC)as the model of bile salts and entrapment efficiency as the evaluation index.Liposomal membrane integrity was judged by bite salt-induced release of DOC-liposomes encapsulated calcein(Cal/DOC-liposomes).The optimized prescription of HMM/DOC liposome was stable in bile salts solution.The physicochemical properties of HMM liposome,HMM liposome coated by chitosan and HMM/DOC liposome were studied.The there liposomes were all spheroidal and uniform.The releasing rate of HMM/DOC liposome was slower than HMM liposome in bile salts solution;the releasing rate of HMM liposome coated by chitosan was slower than HMM liposome in chlorhydric acid;there’s no difference in releasing rate of three liposomes in phosphate solution of pH 7.4.The results of stability tests indicated that three liposomes should be stored in low temperature.The detection method of HMM in plasma of rats was established.The pharmacokinetic processes in rats for the three liposomes and HMM solution,which were administrated orally, were accorded with two compartmental models.Compared with HMM liposome,the HMM liposome coated by chitosan and HMM/DOC liposome both had longer half-life and higher relative bioavailability.更多还原