The application of nicotine in the research phase of Alzheimer's disease (AD) treatment has shown promise. The present study was aimed at understanding the incorporation of nicotine into polylactic acid (PLA) and poly(D,L-lactic-co-glycolic) acid (PLGA) microparticles which were then re-incorporated into a cross-linked zinc-alginate-pectinate polyspheric multi-particulate system to be employed as a possible brain implant for the treatment of AD. The Box-Behnken design was employed to prepare 15 PLA-PLGA formulations, which were tested for their drug incorporation efficiency and release potential and subsequently optimized using multiple regression and an artificial neural network generalized feed-forward model. Based on the rapid burst effect from the microparticles, further incorporation was conducted in a zinc-alginate-pectinate system using ionotropic gelation. Although double incorporation continued to provide a burst effect, this was followed by a lag period for 7 days and a second phase of drug release.