A novel concept of overcoming the skin barrier using augmented liquid nanocrystals: Box-Behnken optimization, ex vivo and in vivo evaluation.

Agomelatine suffers from extensive inactivation through 1st pass effect with a limited oral bioavailability (5%). The aim of this study was to formulate and optimize liquid nanocrystals (LNC) containing agomelatine to enhance the transdermal permeation of the drug. The independent factors of the employed Box-Behnken design were the Pluronic F127, deoxycholic acid sodium salt and propylene glycol percentages. On the other hand, particle size, polydispersity index, zeta potential, entrapment efficiency, cumulative amount permeated at certain time intervals and permeation enhancement ratio were considered as dependent responses. The optimized formulation was composed of 1.5% Pluronic F127 and 1.5% deoxycholic acid sodium salt and it was found to have significantly higher AUC0-24h , AUC0-∞ and elimination t1/2 than that of the employed reference indicating the enhancement of the drug permeation. The obtained findings indicated the ability of the optimized LNC formulation to improve the drug bioavailability after its transdermal application.