Functionalized nanocarrier-based intranasal drug delivery of rivastigmine tartrate for enhanced brain exposure: a pharmacokinetic and biodistribution evaluation.

Abstract

AIMS: To develop and evaluate a polyethylene glycol (PEG)-functionalized multi-walled carbon nanotube (MWCNT)-based intranasal delivery system for rivastigmine tartrate (RT) to improve systemic exposure and brain delivery for Alzheimer's disease (AD). MATERIALS AND METHODS: RT-loaded PEGylated MWCNTs were prepared, optimized using a 32 factorial design, and characterized for particle size, zeta potential, entrapment efficiency, morphology, in vitro release, ex vivo nasal permeation, pharmacokinetics, brain biodistribution, cytocompatibility, and neuroprotective activity. RESULTS: The optimized formulation showed an entrapment efficiency of 90.92%, particle size of 176.7 nm, and zeta potential of -24.1 mV. Sustained drug release and efficient permeation across goat nasal mucosa were observed. Intranasal administration increased plasma exposure, producing approximately 5-fold higher relative bioavailability and a 4.1-fold increase in brain exposure compared with oral administration. In SH-SY5Y cells, the formulation reduced rotenone-induced oxidative stress and improved cell viability, indicating neuroprotective potential. CONCLUSIONS: PEGylated MWCNT-mediated intranasal delivery enhanced rivastigmine bioavailability and brain exposure while demonstrating neuroprotective activity in vitro. These findings support further investigation of this nanocarrier platform as a strategy for brain-targeted delivery of rivastigmine. Alzheimer’s disease is a progressive brain disorder that affects memory, thinking, and daily activities. One of the medicines used to manage its symptoms is rivastigmine. However, delivering sufficient amounts of this drug to the brain is challenging because the brain is protected by a natural barrier that prevents many medicines from entering effectively. In this study, we developed a new delivery system using extremely small tube-shaped materials called polyethylene glycol (PEG)-modified multi-walled carbon nanotubes. These nanosized carriers were designed to transport rivastigmine directly from the nose to the brain. The intranasal route offers a non-invasive alternative to traditional drug administration and may help medicines reach the brain more efficiently. The developed formulation was thoroughly characterized and tested in laboratory studies, cell-based experiments, and animal models. The results showed that the rivastigmine-loaded nanotube formulation improved drug permeation across nasal tissues and increased drug levels in the brain compared with a conventional rivastigmine formulation. The treatment also demonstrated protective effects against oxidative stress in neuronal cells. These findings suggest that intranasal PEGylated carbon nanotubes may provide a promising strategy for enhancing brain delivery of rivastigmine and potentially improving the treatment of Alzheimer’s disease. Further studies are required to fully evaluate long-term safety and to determine whether this approach can be translated into clinical use in humans.

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