Study On The Enhancement Of Oral Bioavailability Of Paclitaxe Using Solid Dispersion Drug Dilivery System

Oral dosage forms are always on the focus of the development of drug delivery system for paclitaxel.In recent years,the treatment strategy of cancer has gradually moven from completely kill tumor cells to improving life quality with coexisting with tumor tissues in controlled degree.With paclitaxel unique anti-cancer machanism,polymerization and stabilization fo tubulin resulting in tumor cells death,an alternative treatment of low-dose metronoic chemotherapy of paclitaxel is a promising method to implement abover mentioned strategy.However,more than 40 years after discovery,there are no commercially available oral preparation of paclitaxel for its poor solubility and suffering from the eflux of P-glycoprotein.A novel paclitaxel preparation with signifcantly improved oral bioavailability was successfully developed using polymer and porous inorganic salt as carrier,prepared using quasi-emulsion solvent diffusion method,with the purpose of fully applying the difference of solubility between the amorphous form and crystal form of paclitaxel.It was safe and presented significant effect of inhibting tumor growth in the pharmacodynamic experiments.Theoretically,the amorphous form of paclitaxel could be as nearly 47.73 times as its crystal form using the Hoffman equation with the data of enthalpy of the crystal form.The polyer,Hydroxypropyl methylcellulose acetate succinate(HAS),is the best polymer carrier for paclitaxel to prepare the solid dispersion throgh several screenning experiments including the comparation of inhibitting ability of polymer on the prcipitaion from supersaturated state,dissolution tests and oral administration of solid dispersions using different polyer as carrier.Quasi-emulsion solvent diffusion method was introduced to prepare a solid dispersion to bypass the issue associated with the simple solvent method.A novel general regression neuroal network combined with traditional multivariable regression were used to investigate factors affecting the recovery ratio of the preparations.Solid self-emulsifying formualtion was also investigated prepared using the quasi-emulsion solvent method to screen the best strategy to improve oarl bioavailability of paclitaxel.The in vivo results showed that VitE is a good oil phase to improve oral bioavailability.However,the simple solid dispersion without oil phase is also good.So the strategy of using oil phase was discarded for the relatively poor recovery ratio of the preparation.A twelve formulations were used to screen the best formulation for oral administration.The results was analysed using support vector machine,Kriging interpolation with cross validation,and the general regression neuroal network to obtain valubale information which would be failed using the traditional multivarible regression method.Using the best formulation as control,we investigated the effect of Cremophor EL,sodium cholate,Cyclosporin A,Verapamil,and HPMC on the oral absorption of the paclitaxel.The results of tissue distribution showed that the oral absorption of the solid dispersion of paclitaxel was in line with traditional oral absorption process of drug with no spcific tissue distribution.Using QUNMING mice as model animal,self-prepared TAXOL as the control,the inhibiting ratio of tumor strain(H22 and U14)when oral adminstered the solid dispersion were significantly as good as the control group.In summary,it is a promising strategy to develop oral solid dosageform using the solid dispersion with polymer carrier prepared using the quasi-emulsion solvent diffusion method.