Emulsification Of Poorly Water-soluble Drugs For Improved Oral Bioavailability

Microemulsion and dry emulsion exhibit high dispersibility and benefical improvement of oral bioavailability of poorly water-soluble drugs.Docetaxel and atorvastatin calcium are both poorly water-soluble drugs with low bioavailability.Therefore,they were selected as the model drugs which were formulated into microemulsion and dry emulsion respectively to improve their solubility,gastrointestinal permeability and even oral bioavailability.Firstly,based on the HPLC analysis method,the solubility determination of docetaxel in various vehicles showed that its solubility in Capryol 90 and Transcutol was both over 100 mg/mL which contributed to the oil selection.Capryol 90 was fixed as the oil phase of the microemulsions and other components were selected by pseudo ternary phase diagrams.Three microemulsions with wide microemulsion area in phase diagrams,low droplet size,viscosity as well as high drug content were optimized which were:Capryol 90:Cremophor EL/PG:water=30:39:31（M-1）;Capryol 90:Cremophor RH40/Transcutol:water=28:36:36（M-2）;Capryol 90:Cremophor EL/Transcutol:water=29: 37:34（M-3）,respectively.The microemulsions were clear and semi-transparent liquid visually observed and well spherical particles could be observed by TEM.The average droplet size was around 30 nm with narrow distribution and low polydispersity index（p.d.＜0.12）.While the absolute zeta potential values of microemulsions were lower than 10.At room temperature,the viscosity of each microemulsion formulation was 98,76 and 79 cP respectively with well fluidity.Microemulsions studied in this research exhibited potential solubilization capacity towards docetaxel and its content was improved to 22.76,32.24 and 29.25 mg/mL by M-1,M-2 and M-3 respectively.Additionally,no precipitation determined as long as 24 h in diluted condition. Docetaxel could release well from microemulsions（more than 80%at 12 h） by dialysis membrane method.Docetaxel microemulsions presented well stability at room temperature at least for 6 months with stable droplet size,viscosity and drug content.However,docetaxel content decreased in highlight or high temperature and it was suggested that microemulsions should be stored at room temperature protecting from highlight.Caco-2 cell monolayer was utilized to perform the transport study to reveal the inhibition effect of microemulsions against P-gp.It was shown that the A-B transport of docetaxel was much improved by microemulsions compared to that of the control group and the A-B transported amount from M-3 was as much as 40 times higher than that of control group （0.62μg/cm² vs 0.016μg/cm²）.On the other hand,the P-gp effiux of docetaxel was inhibited by microemulsions and the efflux amount from M-3（0.61μg/cm²） was significantly lower than that of the control group（0.87μg/cm²）.The A-B and B-A P_app values also exhibited significant deviation compared to that of the control group or TE.An effective HPLC method was developed for the determination of docetaxel in plasma samples.For oral administration,The C_max was enhanced 5.8-fold in M-3 as compared with that of the orally administrated TE（46.39 ng/mL vs.270.48 ng/mL,p＜0.01）.The AUC of docetaxel in M-3 increased 5.2-fold compared with that of orally administrated TE（389.43 ng·h/mL vs. 74.98 ng·h/mL,p＜0.01）.Additionally,M-2 and M-3 significantly improved the absolute oral bioavailability of docetaxel（17.09%and 34.42%）,compared to that of orally administered TE （6.63%）.Atorvastatin calcium was analyzed by HPLC method and its solubility in Plurol Oleique CC 497 was the highest among the oils detected which was higher than 16 mg/mL.To optimize the atorvastatin calcium dry emulsion formulations,orthogonal design was used with the determination of dry emulsion recovery,droplet size,drug content,appearance.The optimized formulation was composed of Plurol Oleique CC 497,Poloxamer 188 and dextrin. Additionally,the selected spry drying condition was:inlet temperature 120℃,aspiration of 100%,drying air flow at 800 N1/h,and feeding rate of the emulsion at 5 ml/min.The optimized formulation was well separated spherical particles with low reconstituted droplet size,improved atorvastatin calcium content,well dispersity,good stability and release.Ussing Chamber was used to study the in vitro permeability of atorvastatin calcium across rat intestine and the cumulative permeated amount was significantly improved by its dry emulsion formulations compared with that of its suspension.