Spray-dried L-Cysteine Chitosan microparticles enable prolonged intranasal delivery of Donepezil

Alzheimer’s disease (AD) remains difficult to treat due to frequent side effects associated with oral therapies such as donepezil (DP) and the need to achieve sufficient and sustained drug exposure at the olfactory region as target site in the brain. Intranasal delivery offers a non-invasive alternative that bypasses first-pass metabolism of drugs and provides direct access to the central nervous system, but the long-term safety of nasal carriers is still insufficiently characterised. In this study, we developed spray-dried L-cysteine-modified chitosan (Cys-Chitosan) microparticles as a delivery system upon intranasal administration of DP to the brain. Process optimisation identified inlet temperature and pump rate as the main parameters governing spray-drying performance regarding yield, and thiolation improved the encapsulation efficiency of DP by approximately 4 % compared to unmodified chitosan. In vitro release experiments demonstrated a clear shift from fast release to sustained release with Cys-Chitosan microparticles, reaching ∼95 % cumulative release of DP over 24 h. Ex vivo permeation studies using porcine olfactory epithelium revealed moderate and controlled DP transport, contrasting with the higher permeation observed for chitosan microparticles. To evaluate tissue compatibility, attenuated total reflection Fourier transform infrared spectroscopy was applied to tissues exposed to formulations. Cys-Chitosan microparticles induced only minimal biochemical alterations, whereas chitosan microparticles produced more pronounced spectral changes, consistent with stronger polymer–tissue interactions. Finally, these findings demonstrate that Cys-Chitosan microparticles provide an effective balance between sustained delivery, controlled permeation, and mucosal safety, supporting their potential as a Safe-by-Design intranasal prolonged formulation for more efficiency in the treatment of AD.