Natural polysaccharide-based multiparticulate systems are promising alternatives to synthetic polymers for oral modified-release applications due to their biocompatibility, low toxicity, and tunable network properties, particularly for drugs associated with gastrointestinal irritation, such as aceclofenac. Here, κ-carrageenan/agar beads were prepared by ionotropic gelation and modified with proanthocyanidin (PA) and tannic acid (TA) as physical crosslinking agents, or carboxymethylcellulose (CMC) as a release-modifying agent. Their effects on drug entrapment efficiency, gastro-resistance, and in vitro aceclofenac release were evaluated. All formulations showed entrapment efficiencies ranging from 78.8 to 92.9%, although lower values were observed for TA-containing beads, likely due to pH-dependent effects. In simulated gastric fluid, PA-modified beads exceeded the predefined 10% release threshold adopted from the USP criterion for delayed-release dosage forms, whereas CMC improved gastric-phase drug retention, with CMC2 limiting aceclofenac release to 8.4%. Selected CMC-modified beads exhibited concentration-dependent swelling and sustained release in simulated intestinal fluid, with a significantly slower release profile than the commercial reference formulation. Kinetic modeling suggested release governed by diffusion coupled with polymer relaxation and/or surface erosion. Physicochemical characterization indicated that CMC promoted structural changes consistent with a more restrictive polymer network, resulting in reduced aceclofenac release under simulated gastric conditions and prolonged release at intestinal pH. Overall, CMC effectively modulated the structural and release properties of κ-carrageenan/agar beads, supporting their potential as a natural polymer-based platform for gastric-phase drug retention and controlled oral delivery of aceclofenac.
