Design and process parameter evaluation of bilayer capsule systems for targeted ileal drug delivery.

The dynamic and transitory nature of the distal small intestine makes targeted drug delivery to this region particularly challenging. This study aimed to develop a bilayer capsule system for site-specific drug release in the terminal ileum. The capsules consisted of an inner water-soluble layer based on hydroxypropyl methylcellulose (HPMC) and pullulan, combined with an outer ethylcellulose layer incorporating sodium alginate as a pore-forming agent. The influence of alginate concentration and curing conditions (temperature and relative humidity) on capsule structure and performance was systematically investigated. Thermal analysis by differential scanning calorimetry guided plasticizer selection and curing parameters. Capsule morphology and surface properties were characterized by scanning electron microscopy and roughness analysis, while functional performance was evaluated through disintegration, water ingress, and dissolution studies under sequential pH conditions simulating the gastrointestinal tract. Alginate concentration significantly influenced surface morphology and permeability of the outer layer, whereas curing conditions modulated film cohesion and porosity. Lead formulations (4-6% alginate, cured at 70 °C and 40% RH) exhibited low water ingress under acidic conditions, maintained capsule integrity, and enabled delayed release at pH 7.4. Compared with reference enteric capsules (Capsugel® Enprotect® capsules), these systems showed a delayed release profile, with potential for targeting of the distal ileum. Overall, this study highlights the critical role of formulation and process parameters in controlling capsule microstructure and provides a robust platform for site-specific oral drug delivery to the distal small intestine.