In Vivo Fate of Biomimetic Mixed Micelles as Nanocarriers for Bioavailability Enhancement of Lipid–Drug Conjugates

The transformation of lipid-based nanovehicles into mixed micelles (MMs) upon lipolysis plays an indispensable role in enhancement of the oral bioavailability of poorly water-soluble drugs. Therefore, this study employs biomimetic MMs as functional vehicles to enhance the oral bioavailability of the lipid conjugates of a model drug silybin. The main objective is to explore the in vivo fate and underlying mechanisms of facilitated absorption by MMs. Pharmacokinetics in rats indicate bioavailability enhancement by 7-9 folds as compared to a fast-release silybin solid dispersion formulation. Confocal laser scanning microscopy reveals evidence of cellular uptake of integral MMs into the cytoplasm of both Caco-2 and Caco-2/HT29-MTX coculture cells lines. The recovery of a definite amount of prototype silybin but negligible or traces of lipid-silybin conjugates from the cells, as well as the limited trans-monolayer transport, confirms fast disruption of MMs and fast degradation of the conjugates as well. The MMs survive the gastrointestinal environment with relatively high integrity for about 4 h, and are found accumulating in intestinal villi surface layers in higher density but in lower density to the basolateral tissues. By scanning the organs, a small amount of integral MMs are observed to distribute mainly to the livers with peak time around 4-8 h. The total amount of lymphatic absorption monitored by cannulation is negligible. It is concluded that biomimetic MMs might be taken up by enterocytes and be digested there to release the prototype drug, which is further transported to the circulation, and only a limited amount of integral MMs could be absorbed into the circulation.