Effect of particle size versus surface charge on the brain targeting behavior of elastic nanovesicles: In-vitro characterization, comparison between I-optimal and D-optimal statistical optimization and in-vivo pharmacokinetic evaluation

Abstract

Rasagiline mesylate (RM) is a potent monoamine oxidase-B inhibitor that suffers from extensive hepatic metabolism, low bioavailability, and low brain distribution. Thus, this study aimed to formulate an intranasal nanovesicular system with high RM encapsulation (EE%) and enhanced delivery to the brain tissues. In this perspective, negatively and positively charged RM-transfersomal vesicles were prepared, characterized and the formulation parameters were statistically optimized as per two different response surface methodologies namely, I-optimal and D-optimal design. Although both statistical designs acted almost similarly in terms of experimental response analysis; the I-optimal design might be functioning better in terms of formulations’ optimization and response prediction with higher desirability factors. Consequently, the optimized negative transfersomes (particle size: 213 nm, EE%:62.55 %) and positive transfersomes (particle size: 515 nm, EE%:70.9 %) suggested by the I-optimal design were furtherly formulated, characterized for their in-vitro release, elasticity, transmission electron microscope and pH. Finally, both systems were administered intranasally and compared to an intravenous RM solution where the optimized positive transfersomes has shown significantly higher brain targeting efficiency, positive direct transfer percentage values and longer brain mean residence time. These results suggested that the surface charge of the formulated vesicles could be more effective factor -than the particle size-in enhancing the brain bioavailability of the administered drugs.