In vitro and in vivo comparative study of itraconazole bioavailability when formulated in highly soluble...

A semisolid self-emulsifying system (SES) of itraconazole consisting of oleic acid, polysorbate 80 and coajuvant (citric acid) was prepared by a hot-melt technique and then compared with hydroxypropylmethylcellulose (HPMC) solid dispersion (SD) coated onto inert sugar spheres as a reference formulation for in vitro and in vivo disposition in rats. The optimal SES greatly increased dissolution rates in gastric (pH 1.2) and intestinal fluid (pH 6.8) by forming a microemulsion (150-250 nm), whereas that of SD was minimal. The tissue uptake of itraconazole from SES in whole intestine, liver and Peyer's patches of the rats was more favorable than that from SD and linearly increased as a function of administering dose. Interestingly, the uptake ratio of Peyer's patches relative to liver also increased linearly in the case of SES while that of SD was almost unchanged. After repeated dosing for 1 week, both SES and SD increased the areas of Peyer's patch region in intestinal tissues but no distinct histopathological damage of the intestine was observed except the hepatocytes. Due to the biopharmaceutical differences of SES in terms of efficient solubilization, easy dispersibility and higher lymphatic transport, the in vivo bioavailability of SES was about twice greater than that of SD in rats.