Lipid nanocapsule-chitosan and iota-carrageenan hydrogel composite for sustained hydrophobic drug delivery

Hydrophobic drug delivery via oral routes presents significant challenges for clinical translation, particularly for poorly soluble antiviral drugs. Physiological barriers, such as enzymatic degradation, harsh pH, and rapid transit in the gastrointestinal tract, or mucociliary clearance and alveolar macrophage uptake in the lungs, can severely limit therapeutic efficacy. To address these challenges, we developed a novel lipid nanocapsule (LNC) and chitosan/iota-carrageenan hydrogel composite tailored for sustained delivery of hydrophobic antiviral agents. A rational, data-driven approach was employed, using Design-Expert software to construct an I-optimal mixture design for hydrogel composition optimization and a customized D-optimal design for EFV encapsulation modeling. These predictive models enabled selection of an optimized hydrogel formulation with high swelling capacity and an EFV loading strategy with maximized encapsulation efficiency, which were confirmed experimentally. EFV was first encapsulated in LNCs, which were subsequently embedded within a mucoadhesive hydrogel matrix to form the EFV-LNC hydrogel composite. The LNCs significantly enhanced EFV solubility compared to water alone (p < 0.0001), and droplet size was controlled (57.4 ± 0.5 nm). The hydrogel composite exhibited an optimized swelling ratio (~ 300 g water per 1 g hydrogel) and achieved an encapsulation efficiency of approximately 53%. Importantly, EFV release from the composite was significantly prolonged under two physiologically relevant pH conditions compared to the unformulated drug (p < 0.0001). Preliminary cytotoxicity assays using HeLa cells suggest that the composite is not acutely cytotoxic under the tested conditions, supporting its potential for further safety evaluation in gastrointestinal-relevant models. Together, these results illustrate how statistical design of experiments can be effectively combined with nanocarrier-hydrogel engineering to rationally optimize formulation performance. These findings suggest that the LNC-hydrogel composite enhances solubility, enables controlled release, and may improve mucosal retention, supporting its utility as a versatile platform for oral delivery of hydrophobic antiviral drugs.