Preparation and in vitro evaluation of pH/enzyme dual-responsive pectin-based hard capsules for colon targeting

Colon-targeted delivery systems are critically needed for treating colonic diseases, yet developing oral hard capsules with dual-responsive release and industrial feasibility remains challenging. This study aimed to develop a coating-free, pH/enzyme-responsive colon-targeted hard capsule based on pectin, and to investigate the effects of incorporating carboxylated cellulose nanofibers (CCNF) and gellan gum (GG) on its properties. Capsules were prepared via dipping method and characterized for physical properties and in vitro release. The optimized formulation containing 3.0 wt% CCNF and 5.0 wt% GG exhibited a tensile strength of 53.5 MPa, an elongation at break of 5.789%, and a moisture content below 12.0%. The capsules remained intact in simulated gastric fluid (pH 1.5) and intestinal fluid (pH 6.8) for 120 min each, and completely disintegrated within 11 min in simulated colonic fluid (pH 7.5 with pectinase), demonstrating precise colon-specific release. Rheological analysis confirmed a gelation temperature of 33 °C, suitable for industrial production. These findings demonstrate that the optimized formulation achieves both pH stability and enzyme-triggered disintegration, enabling colon-specific release without enteric coating. The incorporation of CCNF significantly enhanced capsule physical properties, while the pectin/GG matrix provided dual-responsive release. This study provides a quantitatively validated, industrially feasible formulation strategy for colon-targeted delivery systems.