Abstract
Duloxetine HCl (DXH) is a reuptake inhibitor of serotonin and norepinephrine used to treat the major depressive disorder. Following its extensive hepatic metabolism, acid-labile nature, and limited aqueous solubility, DXH has poor oral bioavailability (40%). The rectal route has been suggested as another route of administration to surmount such challenges. The present study aimed to prepare DXH-loaded glycerosomal (DXH-GLYS) in situ gel for rectal administration to increase DXH permeability and improve its bioavailability. Box-Behnken design (BBD) was adopted to prepare and optimize nanoglycerosomes. The impact of Phospholipon 90G (PL90G), Tween 80 concentrations, and glycerol percentage on encapsulation efficiency, nanoglycerosomal size, % cumulative DXH released, and the cumulative DXH permeated per unit area after 24 h were studied by the design. The pharmacokinetic and pharmacodynamic behavior of optimized formulation was investigated in rats. The formulated DXH-GLYS had a vesicle size ranging between 135.9 and 430.6 nm and an entrapment efficiency between 69.11 and 98.12%. The permeation experiment revealed that the optimized DXH-GLYS in situ gel increased DXH permeation by 2.62-fold compared to DXH solution. Pharmacokinetics studies disclosed that the DXH-GLYS in situ rectal gel exhibited 2.24-times increment in DXH bioavailability relative to oral DXH solution. The pharmacodynamic study revealed that the DXH-GLYS rectal treatment significantly improved the behavioral analysis parameters and was more efficacious as an antidepressant than the oral DXH solution. Collectively, these findings demonstrate that GLYS can be considered a potentially valuable rectal nanocarrier that could boost the DXH efficacy.