Donepezil nanocrystals-incorporated carboxymethyl cellulose nanopaste for high-payload transdermal delivery with improved skin compatibility.

Donepezil (DPZ), an acetylcholinesterase inhibitor for Alzheimer's disease, suffers from skin irritation during transdermal delivery. Herein, a drug high-payload nanopaste (NP) system was designed employing carboxymethyl cellulose (CMC) to enhance transdermal delivery of DPZ while mitigating cutaneous irritation. DPZ NPs (10, 20, and 27.5% w/v) were fabricated via wet bead-milling with low-molecular-weight CMC (90 K) to obtain submicron particles, followed by incorporation into high-molecular-weight CMC (700 K) matrix. The drug nanocrystals were uniformly distributed in the CMC matrix, preserving crystal size (505.6-563.8 nm), zeta potential (-48.93 to -51.95 mV), and crystallinity. Fourier-transform infrared analysis revealed the electrostatic interaction between the anionic polymers and drug nanocrystals. Pharmacokinetic evaluations in rats revealed that while the 10% NP achieved systemic absorption comparable to the commercial patch, the 20% NP provided a 2.1-fold higher transdermal absorption. Level A IVIVC analysis established a robust correlation (R2 > 0.96) between in vitro dissolution profile and in vivo absorption. Crucially, the CMC-based NPs showed markedly improved dermal tolerability, showing minimal hyperplasia and inflammation compared to acrylic-based commercial patches. Additionally, NPs were chemically stable under accelerated conditions without antioxidants. These findings suggest that CMC-based NP system of DPZ represents a biocompatible transdermal platform for long-term Alzheimer's therapy.