银杏叶提取物类脂质体成型工艺及体外细胞摄取、转运机制的研究
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摘要
银杏叶提取物（Ginkgo biloba Extract，EGB）是目前治疗心脑血管疾病的有效药物之一，具有确切的心脑血管药理活性，且毒副作用低。但目前EGB口服制剂存在生物利用度低、半衰期短，每天需服药多次，有效成分不能跨过血脑屏障发挥疗效的不足。因此，本文制备EGB类脂质体制剂（EGBN），用来控制药物的释放速度，使血药浓度稳定，且使EGB的有效成分向大脑的转运，增强EGB对脑部疾病的治疗作用。并建立Caco-2细胞模型和体外血脑屏障（BBB）模型，对EGBN在细胞模型的摄取和转运特征进行考察，探讨其跨血脑屏障的机制。
本文采用反相高效液相色谱法，建立体外分析EGBN中黄酮醇苷的方法，结果表明本法操作简便、灵敏度高，重现性好。对黄酮醇苷的强降解实验和pH稳定性实验进行考察，并计算其在不同条件下的降解速率常数，结果表明黄酮醇苷在酸性条件下稳定，在pH4.5和pH5.5的磷酸盐缓冲液中稳定。
为了提高EGBN的稳定性，便于服用、贮存及运输，本文采用喷雾干燥法将EGBN混悬液制备成类脂质体粉末，以粒径分布、包封率为检测指标，通过单因素和正交设计试验法优化喷雾干燥法制备EGBN粉末的工艺，确定最佳工艺条件为：进口温度130°C、混悬液与载体材料的比例为10︰0.8（ml/g）、空气流量357L/h、蠕动泵速度1.5ml/min。
本文对EGBN粉末进行质量评价研究，用激光粒度分析仪测定粒径大小为680.2±90.0nm；用扫描电镜观察其形态，大多呈球形；zeta电位仪测定zeta电位为-33.6±1.6mV；测定黄酮醇苷包封率为77.5±1.0%；比较EGB原药、辅料、EGBN的DSC曲线，结果证明EGB被高度包封在类脂质体内；初步稳定性试验结果表明EGBN粉末在不同温度（4～8°C、25±2°C）下放置3个月后，包封率稳定（p>0.05），稳定性良好。采用透析法考察黄酮醇苷的体外释放度，结果表明黄酮醇苷的累积释放率在不同的介质中有显著差异（p<0.05）,累积释放率的排序为：磷酸缓冲液（pH6.8）>醋酸缓冲液（pH4.0）>盐酸溶液(pH1.0),在磷酸缓冲液（pH6.8）中的释放情况最好，在12h内其累积释放率达到80%以上，且可持续释放至48h。
为了提高EGBN粉末患者使用的顺应性，本文考察了EGBN胶囊的成型工艺研究。测定粉末的休止角，结果表明加入0.2%的微粉硅胶作为助流剂，可以改善EGBN粉末的流动性；并对EGBN胶囊吸湿性、装量差异、崩解时限等进行考察，均符合2010版《中国药典》（一部）附录胶囊项下规定。
本文成功地建立了Caco-2体外模型，并考察EGBN在Caco-2单层细胞的摄取和转运特征，用于评价EGBN在肠道的吸收机理。结果表明EGBN在Caco-2单层细胞的转运是通过细胞内吞的主动转运和被动扩散相结合的方式进行的。EGBN能增加药物被Caco-2细胞的摄取，并且能阻止P-gp的外排作用，从而增加药物被小肠吸收的能力，提高药物的口服生物利用度。
本文建立了RBE4细胞模型，并进行EGBN的细胞摄取研究，结果表明类脂质体能增加药物被微血管内皮细胞的摄取。本文采用RBMVEC和星形胶质细胞共培养成功地建立了体外BBB模型，并考察EGBN在体外BBB模型的转运行为。结果表明，EGBN能阻止P-gp的外排作用，转运可能是通过细胞内吞的主动转运和被动扩散相结合的方式进行。
综上所述，类脂质体可以包封银杏叶提取物，具有缓释作用，能提高药物在肠道的吸收，增加药物向BBB的转运。类脂质体可以代替传统普通剂型作为EGB的新型口服给药系统。
Ginkgo biloba Extract (EGB) was reported as one of the most effictive drugs forthe treatment of cerebrovascular disease. However, the oral administration of thecurrent EGB products faces several challenging issues such as low bioavailability,short half time of flavonoid glycosides in vivo and the difficulties in drug transportingacross BBB. Based on the above reasons, the aim of the current study was to developa niosomal formulation (EGBN) as a new oral carrier for EGB. Caco-2cell modeland in vitro BBB cell model were established successfully in order to investigate themechanism of cellular uptake and transport for EGBN.
The RP-HPLC method was developed in order to quantify the major componentsof EGB, namely Ginkgo flavonoid glycosides. The method was shown to be linear,precise, sensitive, selective and accurate. Then this method was applied in the forceddegradation studies of these three components to give a better understanding of theforced stability for them. The degradation rate constants and half-life were calculated.The results showed that Ginkgo flavonoid glycosides were stable in acid conditionand the phosphate buffer of pH4.5and5.5.
In this study, spray drying method was used to prepare EGBN powder in order toimprove the stability, transport and administration of EGBN. The single factor andorthogonal factorial design were used to optimize the EGBN powder in terms ofparticle size and drug entrapment efficiency (EE). The best condition of preparationfor EGBN was: the aspirator setting, airflow meter, inlet temperature and the speed ofpump were kept at the scale of100%,357L/h,130°C and1.5ml/min, respectively.
EGBN powders were formulated and characterized in terms of morphology,particle size, zeta potential, entrapment efficiency, angle of repose, differentialscanning calorimetry (DSC) analysis and in vitro release study. EGBN had a particlesize of680.2±90.0nm and zeta potential of-33.6±1.6mV. SEM was used to investigate the morphology of prepared niosomes and the result showed that theniosomes were nearly spherical in shape. The entrapment efficiency of Ginkgoflavonoid glycosides from EGBN was77.5±1.0%. The interactions between EGBand niosomes were also studied by DSC analysis and the result suggested that EGBwas entrapped in the lipid bilayer of niosome and formed a new phase instead of asimple physical mix between EGB and excipients. Stability studies showed that theentrapment efficiency of EGBN hardly changed by storing at4-8°C and25±2°C fora period of3months (p>0.05). The in vitro release study suggested that EGBNcould prolong the release of flavonoid glycosides from niosome in phosphate buffersolution (pH6.8) up to48hrs.
The angle of repose, hygroscopicity, content uniformity and disintegration timeof EGBN powder were detected in accordance with Chinese Pharmacopeia.
The monolayer of Caco-2model was established successfully and used toinvestigate the mechanism of cellular uptake and transport for EGBN into epithelialcells. The results showed that EGBN has the ability to enhance the cellular uptake byCaco-2cells and to block the efflux function of P-gp, which could lead to increasingabsorption for drug by intestine tract.
RBE4cell was selected as cellular uptake model for BBB. The results showedthat niosome could enhance the cellular uptake by microvascular endothelial cell. Theco-culture in vitro BBB model was developed and eventually used to elucidate themechanism of brain delivery of EGBN. The results suggested that EGBN has theability to block the efflux function of P-gp thus increase the drug across to brain. Themechanism of transport was a combination process of endocytosis and passivediffusion.
In summary, niosome offers an effective practical means of delivering drugcandidate (EGB) to the brain via oral administration and thus to replace theconventional formulations.
本文采用反相高效液相色谱法，建立体外分析EGBN中黄酮醇苷的方法，结果表明本法操作简便、灵敏度高，重现性好。对黄酮醇苷的强降解实验和pH稳定性实验进行考察，并计算其在不同条件下的降解速率常数，结果表明黄酮醇苷在酸性条件下稳定，在pH4.5和pH5.5的磷酸盐缓冲液中稳定。
为了提高EGBN的稳定性，便于服用、贮存及运输，本文采用喷雾干燥法将EGBN混悬液制备成类脂质体粉末，以粒径分布、包封率为检测指标，通过单因素和正交设计试验法优化喷雾干燥法制备EGBN粉末的工艺，确定最佳工艺条件为：进口温度130°C、混悬液与载体材料的比例为10︰0.8（ml/g）、空气流量357L/h、蠕动泵速度1.5ml/min。
本文对EGBN粉末进行质量评价研究，用激光粒度分析仪测定粒径大小为680.2±90.0nm；用扫描电镜观察其形态，大多呈球形；zeta电位仪测定zeta电位为-33.6±1.6mV；测定黄酮醇苷包封率为77.5±1.0%；比较EGB原药、辅料、EGBN的DSC曲线，结果证明EGB被高度包封在类脂质体内；初步稳定性试验结果表明EGBN粉末在不同温度（4～8°C、25±2°C）下放置3个月后，包封率稳定（p>0.05），稳定性良好。采用透析法考察黄酮醇苷的体外释放度，结果表明黄酮醇苷的累积释放率在不同的介质中有显著差异（p<0.05）,累积释放率的排序为：磷酸缓冲液（pH6.8）>醋酸缓冲液（pH4.0）>盐酸溶液(pH1.0),在磷酸缓冲液（pH6.8）中的释放情况最好，在12h内其累积释放率达到80%以上，且可持续释放至48h。
为了提高EGBN粉末患者使用的顺应性，本文考察了EGBN胶囊的成型工艺研究。测定粉末的休止角，结果表明加入0.2%的微粉硅胶作为助流剂，可以改善EGBN粉末的流动性；并对EGBN胶囊吸湿性、装量差异、崩解时限等进行考察，均符合2010版《中国药典》（一部）附录胶囊项下规定。
本文成功地建立了Caco-2体外模型，并考察EGBN在Caco-2单层细胞的摄取和转运特征，用于评价EGBN在肠道的吸收机理。结果表明EGBN在Caco-2单层细胞的转运是通过细胞内吞的主动转运和被动扩散相结合的方式进行的。EGBN能增加药物被Caco-2细胞的摄取，并且能阻止P-gp的外排作用，从而增加药物被小肠吸收的能力，提高药物的口服生物利用度。
本文建立了RBE4细胞模型，并进行EGBN的细胞摄取研究，结果表明类脂质体能增加药物被微血管内皮细胞的摄取。本文采用RBMVEC和星形胶质细胞共培养成功地建立了体外BBB模型，并考察EGBN在体外BBB模型的转运行为。结果表明，EGBN能阻止P-gp的外排作用，转运可能是通过细胞内吞的主动转运和被动扩散相结合的方式进行。
综上所述，类脂质体可以包封银杏叶提取物，具有缓释作用，能提高药物在肠道的吸收，增加药物向BBB的转运。类脂质体可以代替传统普通剂型作为EGB的新型口服给药系统。
Ginkgo biloba Extract (EGB) was reported as one of the most effictive drugs forthe treatment of cerebrovascular disease. However, the oral administration of thecurrent EGB products faces several challenging issues such as low bioavailability,short half time of flavonoid glycosides in vivo and the difficulties in drug transportingacross BBB. Based on the above reasons, the aim of the current study was to developa niosomal formulation (EGBN) as a new oral carrier for EGB. Caco-2cell modeland in vitro BBB cell model were established successfully in order to investigate themechanism of cellular uptake and transport for EGBN.
The RP-HPLC method was developed in order to quantify the major componentsof EGB, namely Ginkgo flavonoid glycosides. The method was shown to be linear,precise, sensitive, selective and accurate. Then this method was applied in the forceddegradation studies of these three components to give a better understanding of theforced stability for them. The degradation rate constants and half-life were calculated.The results showed that Ginkgo flavonoid glycosides were stable in acid conditionand the phosphate buffer of pH4.5and5.5.
In this study, spray drying method was used to prepare EGBN powder in order toimprove the stability, transport and administration of EGBN. The single factor andorthogonal factorial design were used to optimize the EGBN powder in terms ofparticle size and drug entrapment efficiency (EE). The best condition of preparationfor EGBN was: the aspirator setting, airflow meter, inlet temperature and the speed ofpump were kept at the scale of100%,357L/h,130°C and1.5ml/min, respectively.
EGBN powders were formulated and characterized in terms of morphology,particle size, zeta potential, entrapment efficiency, angle of repose, differentialscanning calorimetry (DSC) analysis and in vitro release study. EGBN had a particlesize of680.2±90.0nm and zeta potential of-33.6±1.6mV. SEM was used to investigate the morphology of prepared niosomes and the result showed that theniosomes were nearly spherical in shape. The entrapment efficiency of Ginkgoflavonoid glycosides from EGBN was77.5±1.0%. The interactions between EGBand niosomes were also studied by DSC analysis and the result suggested that EGBwas entrapped in the lipid bilayer of niosome and formed a new phase instead of asimple physical mix between EGB and excipients. Stability studies showed that theentrapment efficiency of EGBN hardly changed by storing at4-8°C and25±2°C fora period of3months (p>0.05). The in vitro release study suggested that EGBNcould prolong the release of flavonoid glycosides from niosome in phosphate buffersolution (pH6.8) up to48hrs.
The angle of repose, hygroscopicity, content uniformity and disintegration timeof EGBN powder were detected in accordance with Chinese Pharmacopeia.
The monolayer of Caco-2model was established successfully and used toinvestigate the mechanism of cellular uptake and transport for EGBN into epithelialcells. The results showed that EGBN has the ability to enhance the cellular uptake byCaco-2cells and to block the efflux function of P-gp, which could lead to increasingabsorption for drug by intestine tract.
RBE4cell was selected as cellular uptake model for BBB. The results showedthat niosome could enhance the cellular uptake by microvascular endothelial cell. Theco-culture in vitro BBB model was developed and eventually used to elucidate themechanism of brain delivery of EGBN. The results suggested that EGBN has theability to block the efflux function of P-gp thus increase the drug across to brain. Themechanism of transport was a combination process of endocytosis and passivediffusion.
In summary, niosome offers an effective practical means of delivering drugcandidate (EGB) to the brain via oral administration and thus to replace theconventional formulations.
引文
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