Huperzine A loaded multiparticulate tablet with sustained release was developed to reduce dosing frequency and increase swallowing. The sustained release was provided by the ethyl cellulose/Poloxamer 127 (EC/F127) microparticles (MPs). F127 was added to facilitate drug release of EC MPs, and the enhanced dissolution mechanism was investigated regarding to the particle size, water uptake, and wettability of MPs. The greater wettability, which highly relied on the medium and formulation components, generated larger water uptake and faster drug release through improving the penetration of the medium into the internal space of MPs. The EC/F127 MPs were further compressed into tablets for dissolution and pharmacokinetic studies. The results demonstrated that the tablet remained unchanged release profile to the MPs, and exhibited profoundly sustained release with a relatively bioavailability of 125.18% to the commercial tablet. Therefore, the multiparticulate tablet was successfully designed based on the drug release mechanism and high compressibility of MPs. (C) 2019 Elsevier B.V. All rights reserved.