Application of microemulsion for enhancing topical skin absorption of 20(S)-protopanaxadiol and oral absorption of rebamipide

Abstract

20(S)-protopanaxadiol (20S-PPD) is an aglycosylated metabolite of ginsenosides such as compound K and ginsenoside Rb1, and possesses a potent skin anti-aging activity. However, due to its low aqueous solubility and large molecular size, a suitable formulation strategy is required in order to enhance skin deposition of 20S-PPD by improving its solubility and skin permeability. Rebamipide (RBP) is a potent anti-ulcer and anti-oxidative agent, which belongs to biopharmaceutics classification system (BCS) class IV with a poor oral bioavailability of less than 10%. Thus, enhancing the systemic exposure of RBP may increase its pharmacological activities after oral administration. The objective of the study was to develop microemulsion (ME)-based systems for the topical skin delivery of 20S-PPD and for the oral delivery of RBP. 20S-PPD-loaded ME and ME-based hydrogel (MEH) formulations were prepared and evaluated in terms of their particle size distribution, morphology, maximum loading capacity, viscosity, and pH value. Then, the in vitro and in vivo deposition or permeation profiles of 20S-PPD in the selected MEH formulation were studied using hairless mouse skin model and artificial skin model, Strat-M® membrane. A Carbopol-based MEH system of 20S-PPD was successfully prepared with a mean droplet size of 110 nm and polydispersity index of 0.436. The formulation was stable at least for 56 days, and its viscosity was high enough for its topical skin application. It significantly enhanced the in vitro and in vivo skin deposition of 20S-PPD with no influence on its systemic absorption in hairless mice. Notably, it was found that the rank of the tested formulaions in the order of decreasing deposition of 20S-PPD in in vitro Strat-M® membrane and in vitro/in vivo hairless mouse skin was same. For RBP-loaded ME, characterization study (i.e. maximum loading capacity, particle size distribution, and morphology), in vitro drug release study, in vivo pharmacokinetic study, and intestinal toxicity study were performed. Capmul MCM EP and Solutol HS15-based ME system of RBP had spherical nano-sized droplets with polydispersity index of 0.265 and neutral zeta potential. Moreover, the prepared ME significantly enhanced the dissolution and oral bioavailability of RBP with no discernible intestinal toxicity. Taken together, the ME-based systems developed in this study could serve as a potentially effective topical skin and oral delivery system for enhancing the absorption of poorly soluble compounds including 20S-PPD and RBP.