| 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. |
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