Development of hyaluronic acid-based microneedles for improved brain delivery of rivastigmine nanoparticles via mystacial pad region

In this study, for the first time, we developed the novel combinatorial approach of poly-lactid-co-glycolid acid (PLGA)-based nanoparticles (PLGA-NPs) containing rivastigmine (RV) and hyaluronic acid-based two-layered dissolving microneedles (DMNs) for the effective delivery of RV through the trigeminal pathway of nasal cavity to the brain via mystacial pad region. In order to optimize the formulations, several evaluations were conducted, producing nanoparticles with particle size of <200 nm with the release percentage of RV from the PLGA-NPs up to 95.42 +/- 8.76 % in sustained-manner after 48 h of investigation. Following the incorporation of PLGA-NPs into hyaluronic acid-based DMNs, the formulations showed the adequate mechanical and insertion properties, exhibiting the suitability of the system. In the ex vivo studies, DMNs exhibited higher dermatokinetic profiles compared to needle-free patch formulation. The formulations were found to cytocompatible to neuro-2a and hCMEC/D3 cell lines. Importantly, in the in vivo studies, with respect to the effectiveness of the brain targeting, the drug targeting effeciency (DTE) value up to > 60-fold and the direct transport percentage (DTP) to > 90 % compared to the oral conventional administration, injection and polyvynyl pyrrolidone-based DMNs without affecting the brain examined through histopathology evaluations. All the results showed the advantageous of delivering RV through the trigeminal pathway to the brain, using the combination of PLGA-NPs and two-layered DMNs. This approach was considered to be a future-novel treatment of Alzheimer's disease that can promote numerous advantages compared to the conventional oral preparation of RV.