Intranasal mucoadhesive chitosan microspheres of ranolazine: Formulation, design, and pharmacokinetic evaluation

Ranolazine is an established antianginal agent; however, its oral administration is associated with delayed onset of action and variable systemic exposure due to extensive hepatic first-pass metabolism. Intranasal drug delivery is a non-invasive alternative that enables rapid systemic absorption while bypassing hepatic metabolism, although rapid mucociliary clearance can limit drug residence and absorption. Chitosan, a natural mucoadhesive polymer, has been extensively investigated for intranasal delivery owing to its ability to prolong mucosal residence time and enhance epithelial permeability. The present study aimed to develop and evaluate mucoadhesive chitosan microspheres of ranolazine for intranasal administration to enhance systemic bioavailability and pharmacokinetic performance. Microspheres were prepared using an emulsification cross-linking technique and optimized using Design-Expert® software by systematically varying polymer concentration and stirring speed as independent variables, with particle size and mucoadhesive strength as dependent responses. The optimised formulation (FCH4) was comprehensively characterised for physicochemical properties, particle-size distribution, surface morphology, mucoadhesive strength, in vitro drug release, ex vivo nasal permeation, stability, histopathology, and in vivo pharmacokinetics. The formulations exhibited yields of 80-95% and encapsulation efficiencies of 45-70%. The optimized formulation (FCH4; drug-to-polymer ratio 1:4) demonstrated spherical morphology with a smooth surface, a mean particle size of 37.8 ± 0.3µm, high encapsulation efficiency, and strong mucoadhesive properties. The optimized chitosan microspheres provided sustained drug release over 24 h through diffusion- and polymer relaxation-mediated mechanisms. Ex vivo studies using goat nasal mucosa revealed significantly greater drug permeation (31.5± 2.1% at 240 min), corresponding to a 1.41-fold enhancement over the pure drug suspension, while preserving mucosal integrity. Pharmacokinetic evaluation in New Zealand White rabbits demonstrated significantly increased systemic exposure and prolonged plasma residence of ranolazine compared with the pure drug, confirming effective avoidance of hepatic first-pass metabolism. Collectively, these findings support mucoadhesive chitosan microspheres as a promising intranasal delivery platform for ranolazine and highlight the potential of formulation-driven intranasal strategies for drugs limited by unfavourable oral pharmacokinetics.