Itraconazole Loaded Nanoemulsions: Hansen Solubility & Charge-Driven Permeation and GastroPlus based Predicted In vivo Performance.

Abstract

There is limited in vivo investigation for the permeation profiles of itraconazole (ITZ) loaded cationic nanoemulsion after oral delivery. We reported HSPiP and GastroPlus oriented major formulations (MCNE11 and MNE11) as a state-of-the-art study. HSPiP diffusion module predicted the impact of diffusion coefficients on the % drug absorption and absorption-time across intestinal membrane. In vitro dissolution data were used to predict and simulate in vivo performance (GastroPlus) in humans. Finally, confocal laser scanning microscopy (CLSM) study confirmed the extent of penetration across mucosal layer. GastroPlus simulated in vitro dissolution data (only 32% drug release from suspension than 100% released from MCNE11 at 12 h) at pH 6.8 for in vivo performance in humans, wherein it showed the best fit of Weibull model (β ˂ 0.75), suggesting Fickian diffusion of ITZ from MCNE11. The actual plasma concentration (1.9 × 10² µg/mL) was relatively higher than the suspension (1.5 × 10^-2 µg/mL). Parameter sensitivity analysis (PSA) predicted that the AUC (area under the curve), T_max (the time required to reach C_max), and C_max (maximum plasma drug concentration reached) over the size range of 2.5 - 6.96 µm for oral suspension. The dose greatly affected AUC and C_max as predicted in GastroPlus for MCNE11 due to rapid absorption. The reginal absorption compartment model predicted 33.6 % and 100% as overall absorption from the suspension and MCNE11, respectively (upper intestine). The finding was further supported with the CLSM result as nanocarreir based maximized ITZ absorption to treat systemic fungal infection.