Abstract
Hydrophobic drug delivery via oral or pulmonary 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. This composite system was designed to encapsulate and deliver Efavirenz (EFV) under simulated gastrointestinal conditions. 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 various gastrointestinal pH conditions compared to the unformulated drug (p < 0.0001). Cytotoxicity assays confirmed the composite's cytocompatibility, supporting its potential safety for future mucosal administration. 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 and pulmonary delivery of hydrophobic antiviral drugs.