A Combinatorial Approach with Microneedle Pretreatment and Thermosensitive Gel Loaded with Rivastigmine Lipid Nanoparticle Formulation Enables Brain Delivery via the Trigeminal Nerve

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