Thin film hydration versus modified spraying technique to fabricate intranasal spanlastic nanovesicles for rasagiline mesylate brain delivery: Characterization, statistical optimization, and in vivo pharmacokinetic evaluation

Abstract

Rasagiline mesylate (RM) is a monoamine oxidase inhibitor that is commonly used to alleviate the symptoms of Parkinson's disease. However, it suffers from low oral bioavailability due to its extensive hepatic metabolism in addition to its hydrophilic nature which limits its ability to pass through the blood-brain barrier (BBB) and reach the central nervous system where it exerts its pharmacological effect. Thus, this study aims to form RM-loaded spanlastic vesicles for intranasal (IN) administration to overcome its hepatic metabolism and permit its direct delivery to the brain. RM-loaded spanlastics were prepared using thin film hydration (TFH) and modified spraying technique (MST). A 2³ factorial design was constructed to study and optimize the effects of the independent formulation variables, namely, Span type, Span: Brij 35 ratio, and sonication time on the vesicles᾽ characteristics in each preparation technique. The optimized system prepared using MST (MST 2) has shown higher desirability factor with smaller PS and higher EE%; thus, it was selected for further in vivo evaluation where it revealed that the extent of RM distribution from the intranasally administered spanlastics to the brain was comparable to that of the IV drug solution with significantly high brain-targeting efficiency (458.47%). These results suggest that the IN administration of the optimized RM-loaded spanlastics could be a promising, non-invasive alternative for the efficient delivery of RM to brain tissues to exert its pharmacological activities without being dissipated to other body organs which subsequently may result in higher pharmacological efficiency and better safety profile.

Keywords: Brain targeting; Intranasal; Modified spraying technique; Rasagiline mesylate; Spanlastics; Thin film hydration.

Fig. 1

3D surface plot for the effect of Span type and Span: Brij 35 ratio on the PS (a), line plot for the main effect of sonication time on the PS (b), the main effect of Span: Brij 35 ratio on the ZP (c), and the main effect of Span type on the EE% (d) of RM-loaded spanlastics prepared by TFH

Fig. 2

3D surface plot for the effect of Span type and Span: Brij 35 ratio on the PS (a), line plot for the main effect of sonication time on the PS (b), the main effect of Span type on the ZP (c), and EE% (d) of RM-loaded spanlastics prepared by MST

Fig. 3

In vitro release profile of RM from TFH-optimized system (TFH 8), MST-optimized system (MST 2), and RM solution (RM concentrations are represented as mean ± SD)

Fig. 4

Transmission electron micrographs of TFH-optimized system (TFH 8) (a: magnification power = 40,000 ×) and MST-optimized system (MST 2) (b: magnification power = 25,000 ×)

Fig. 5

Mean RM concentration (mean ± SD) in brain upon IN administration of MST 2 and IV RM solution to healthy rats (n = 3). *significant difference and n.s, non-significant difference