NOVEL NANOEMULSION AS VEHICLES FOR TRANSDERMAL DELIVERY OF CLOZAPINE: IN VITRO AND IN VIVO STUDIES

Objective: The purpose of the present study is to develop and evaluate the potential of nanoemulsions for increasing the solubility and the in vitro transdermal delivery of clozapine. Methods: Clozapine is practically insoluble in water and low (27%) bioavailability mainly due to first pass metabolism. An optimized oil-in-water nanoemulsion of Clozapine was prepared by the spontaneous emulsification method. Pseudoternary phase diagrams were constructed to obtain the nanoemulsion region. Oleic acid was chosen as the oil phase, Tween 20 and Transcutol-P were used as surfactant and cosurfactant respectively, on the basis of solubility studies, in formulation of nanoemulsion. The optimized nanoemulsion was characterized for pH, viscosity, droplet size, droplet shape, and refractive index. The formulations were evaluated for thermodynamic stability testing, in vitro rat skin permeation, skin irritation test and in vivo study. Results: Significant difference in the steady state flux (Jss), permeability coefficient (Kp) and enhancement ratio (Er) was observed in nanoemulsion formulations and control (P* < 0.05). The composition of optimized formulation F1 (Oleic acid 4.54% w/w) showed highest value of flux 391.3357 µg cm-2h-1. At the 24 h post application plasma clozapine was increased 4.4 fold to marketed dosage form. Conclusion: The study suggested that nanoemulsion significantly enhanced bioavailability of transdermally applied clozapine and eliminated the first pass metabolism.