A Combinatorial Approach\nwith Microneedle Pretreatment\nand Thermosensitive Gel Loaded with Rivastigmine Lipid Nanoparticle\nFormulation Enables Brain Delivery via the Trigeminal Nerve

Alzheimer’s disease (AD) often leads to dementia,\ncausing\ncognitive decline and increased care needs. Rivastigmine (RV) is a\nkey AD treatment, but its brain delivery is limited by the blood–brain\nbarrier (BBB). Aside from oral, olfactory, and intradermal injection\n(i.d.) routes, the application of polymeric microneedles via the trigeminal\nnerve on the facial skin as a pretreatment, followed by a solid lipid\nnanoparticle RV-loaded thermosensitive gel (PMN-SLN-RV-TG), is an\nalternative to deal with the problems. This study aims to determine\nthe optimal formula for PMN-SLN-RV-TG application and assess its brain\ndelivery ability compared to conventional routes. The optimum SLN-RV\nformula had a particle size <200 nm and sustained release for 72\nh, which was selected for the SLN-RV-TG formulation. SLN-RV-TG was\ntransformed into a gel at normal skin temperature (32–37 °C),\nwith good physical properties and nontoxic behavior. The ideal PMN\nformula was able to penetrate the dermal layer as an alternative to\ni.d. administration. <i>Ex vivo</i> dermatokinetics showed\nsignificant improvement of PMN-SLN-RV-TG application (<i>p</i> < 0.05) compared to without PMN application. <i>In vivo</i> pharmacokinetic studies on rats also revealed that the PMN-SLN-RV-TG\nhad superior pharmacokinetic parameters (<i>C</i><sub>max</sub>, AUC, <i>t</i><sub>1/2</sub>, and MRT) compared to other\ngroups (<i>p</i> < 0.05). Radiolabeling SLN-RV with <sup>99m</sup>Tc showed good physical properties, with a radiochemical\nyield of >95%. <i>In vivo</i> distribution studies of\nPMN-SLN-RV-TG\napplication exhibited a higher brain:blood ratio than i.v. administration\nafter 5 h, as well as being safe for the brain due to a good histological\nprofile. These results show that PMN-SLN-RV-TG application via the\ntrigeminal nerve on the facial skin has strong potential delivery\nto the brain for AD treatment.