Carrageenan-based multi-unit spheroidal tablets for fenofibric acid: A strategy to minimize food effect via mucoadhesive gel interfaces

Abstract

Fenofibric acid (FA), the active metabolite of fenofibrate, is a potent lipid-modifying agent whose clinical effectiveness is often compromised by pronounced food effects, resulting in variable systemic exposure. In this study, we developed a novel carrageenan-based multi-unit spheroidal tablet (MUST) formulation designed to mitigate the impact of prandial state on FA pharmacokinetics. The matrix system utilized an optimized κ-/ι-carrageenan ratio (30:70) to achieve a balance between mucoadhesive strength and gel integrity, further modulated by hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) to refine the release kinetics.

A Design of Experiments (DoE) approach identified the optimal polymer composition—64 % carrageenan, 24 % HPMC, and 10.1 % EC—yielding dissolution profiles that closely matched those of a reference fenofibrate capsule. Biorelevant dissolution testing across simulated fasted and fed gastrointestinal conditions—including enzymatic, viscous, and lipid-rich environments—demonstrated consistent drug release, with similarity factors (f₂) exceeding 67 in all media.

Sequential dissolution testing combined with a Level A in vitro–in vivo correlation (IVIVC) predicted minimal food effects, characterized by a delayed t_max but preserved C_max and AUC. These findings were validated in beagle dogs, where the MUST formulation demonstrated bioequivalence to the reference product under fasted conditions and comparable systemic exposure under fed conditions (p > 0.05 for AUC and C_max), despite a modest prolongation in t_max.

The robust mucoadhesive and mechanical properties of the carrageenan-based matrix under diverse gastrointestinal environments underscore its consistent in vivo performance. Overall, this multiparticulate platform offers a clinically relevant strategy to mitigate food effects in FA delivery, potentially enhancing dosing flexibility, patient adherence, and therapeutic reliability in lipid-lowering therapy.

Materials

Fenofibric acid was kindly supplied by Hanmi Pharmaceutical Co., Ltd. (Hwaseong, South Korea). κ-Carrageenan (Gelcarin® GP-812 NF) and ι-carrageenan (Gelcarin® GP-379 NF) were purchased from FMC Biopolymer (Philadelphia, PA, USA). Hydroxypropyl methylcellulose (HPMC, Methocel® K4M), ethylcellulose (EC, Ethocel® 10P), and microcrystalline cellulose (MCC, Avicel® PH101) were obtained from Dow Chemical Co. (Midland, MI, USA) and FMC Biopolymer (Philadelphia, PA, USA), respectively.,D-mannitol.

Seong Hun Been, Ju Young Lee, Jung Hyun Cho, Carrageenan-based multi-unit spheroidal tablets for fenofibric acid: A strategy to minimize food effect via mucoadhesive gel interfaces, Journal of Drug Delivery Science and Technology, Volume 115, Part 1, 2026, 107689, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.107689.