Programmable delayed-release container system (PDRCS) for chronotherapeutic delivery: application in personalized treatment for Addison’s disease

Abstract

Chronopharmaceutical systems aim to synchronize drug release with the body’s biological rhythms to enhance therapeutic efficacy and minimize side effects. Current oral delivery technologies largely depend on coating technologies and pH-sensitive polymers, which are limited by significant inter- and intra-patient variability, as well as technical constraints in coating reproducibility. To address these challenges, we present a novel 3D-printed Programmable Delayed-Release Container System (PDRCS) for pH-independent, time-specific pulsatile drug delivery. Hydrocortisone was selected as the model drug to demonstrate chronotherapeutic targeting for primary adrenal insufficiency (Addison’s disease). The system consists of an ethyl cellulose shell manufactured via fused deposition modeling (FDM), encapsulating a layered core comprising a swelling hydrogel disc, a separating barrier, and an immediate-release hydrocortisone tablet. Upon immersion in dissolution media, water enters through engineered perforations, triggering the swelling disc to expand and build internal pressure until rupture of the shell occurs, resulting in drug release. By adjusting perforation diameters 1.0, 1.5, and 2.0 mm, lag times of 28, 20, and 12 h, respectively, were achieved. In vitro studies confirmed the system’s pH-independent behavior. Solid-state characterization (PXRD, FTIR, DSC, TGA) validated formulation stability, processing integrity, and revealing an increase in crystallinity after extrusion followed by reduction upon 3D printing. SEM imaging, rupture force analysis, and hydrogel swelling test were conducted to characterize the rupture behavior. This mechanically governed, rupture-based delivery platform enables customizable and reliable time-controlled oral drug administration, supporting personalized chronotherapeutic regimens.