Preparation of mixed monoterpenes edge activated PEGylated transfersomes to improve the in vivo transdermal delivery efficiency of sinomenine hydrochloride

Abstract Surfactants generally have been used as edge activators of transfersomes. However, surfactants edge activated transfersomes frequently lead to cutaneous irritation, skin lipid loss and other side effects after dermal administration. In this study, mixed monoterpenes edge activated PEGylated transfersomes (MMPTs) were prepared by ethanol injection process with sinomenine hydrochloride as a model drug. The formulation of MMPTs was optimized by an orthogonal design. We investigated skin permeation/deposition characteristics and pharmacokinetics of sinomenine hydrochloride loaded in MMPTs by comparing with liposomes using in vitro skin tests and in vivo cutaneous microdialysis. In in vitro study, the accumulative skin permeated quantity (ASPQ) and skin permeation rate (SPR) of simonenine (SIN) in the optimized MMPTs were prominently higher than that in the other MMPTs. The optimized MMPTs had a SIN ASPQ of over three times of SIN ASPQ in the liposomes and much larger SPR of SIN compared with the latter. In contrast, the drug deposition of the optimized MMPTs in the stratum corneum was much less than that of the conventional liposomes. It was noteworthy that the drug deposition curve in the whole skin (stratum corneum-stripped skin, either) for the optimized MMPTs increased initially and then decreased with an obvious peak deposition amount at 12 h, while, a relatively steady curve was observed for the liposomes. In in vivo cutaneous pharmacokinetic study, the steady state concentration (C ss ) and the area under the curve (AUC 0 → t ) of SIN from the optimized MMPTs was 8.7 and 8.2 folds higher than those from the liposomes, respectively. Moreover, the MRT 0-inf of SIN from optimal MMPTs got shorter than that from the liposomes. It can be concluded that the optimized MMPTs obviously enhance the percutaneous absorption of sinomenine.