Implantable Trilayer Microneedle Transdermal Delivery System to Enhance Bioavailability and Brain Delivery of Rivastigmine for Alzheimer Treatment: a Proof-of-concept Study

Abstract

Rivastigmine (RV), an acetylcholinesterase inhibitor, is commonly used to treat Alzheimer's disease (ALZ). Regrettably, RV is available in the capsule form, associated with reduced drug bioavailability, and in patch form, which may cause skin irritation after repeated use. A controlled RV release implantable trilayer dissolving microneedle (TDMN) was developed in this study to address the issue of RV administration. RV encapsulated in slow-biodegrading polycaprolactone (PCL) that is used for needle implantation in the first layer. After selecting the best formulation, it was tested for in vitro release, ex vivo permeation, and in vivo pharmacokinetics to ensure its dependability. The mechanical strength and penetration of TDMN allow for cutaneous administration of RV. TDMN penetrated up to 4 layers of parafilm® and needle reduced < 10%, indicating strong mechanical strength. In in vitro and ex vivo drug release, TDMN distributes RV more continuously than the dissolving microneedle (DMN) as a control. After 168 hours, TDMN released 91.34 ± 11.39% RV, while control was 99.40 ± 0.47%. In ex vivo permeation, TDMN provides 2.606 ± 58.9 µg/cm2 RV, while control provides 32.111 ± 782.54 µg/cm2. TDMN sustained RV values of 0.54 ± 0.09 µg/mL and 1.23 ± 0.26 µg/g in plasma and brain throughout 168 hours of in vivo pharmacokinetic testing. Transdermal delivery using TDMN resulted in a 2-fold increase in brain concentration compared to oral administration in pharmacokinetic study, TDMN treatment showed significantly greater area under curve (AUC) and mean residence time (MRT) values than DMN, patch, and oral administration (p < 0.05).