(M1230-07-47) Programmable Delayed-Release Container System (PDRCS) for Chronopharmaceutical Drug Delivery: Application to Addison’s Disease

Purpose: The objective of this study was to develop a programmable delayed-release container system (PDRCS) using three-dimensional (3D) printing for chronopharmaceutical delivery of hydrocortisone in Addison’s disease. The system is designed to achieve customizable, time-specific drug release through a rupture mechanism triggered by internal swelling of a pH-independent hydrogel core enclosed within a pH-insensitive ethyl cellulose shell. The release timing can be personalized by modulating perforation sizes in the outer shell, offering a patient-specific oral delivery platform independent of gastrointestinal pH or transit variations.

Methods: Filaments were prepared by hot-melt extrusion of ethyl cellulose (EC) with 10% triethyl citrate (TEC) and 10% hydroxypropyl cellulose (HPC). The outer shell of the PDRCS was fabricated using fused deposition modeling (FDM) 3D printing, incorporating four customizable perforations to control fluid ingress. The internal structure consisted of three compressed discs: a swelling bottom disc composed of HPMC K200M, a separating disc made of EC, and a drug-loaded disc containing hydrocortisone, mannitol, microcrystalline cellulose (MCC), and sodium starch glycolate (SSG). After partial printing of the shell, the compressed core was manually inserted, and the system was sealed via printing of a thin cap. Physicochemical characterization was performed using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FTIR). In vitro swelling studies were conducted under simulated gastrointestinal pH conditions to evaluate pH-independence, along with cap rupture force testing and visual psot-rupture imaging. A mechanistic mathematical model (t = a/d + b) was developed to predict rupture times based on perforation diameter.

Results: The PDRCS demonstrated reliable, programmable rupture behavior correlated with perforation size. Increasing perforation diameter led to faster rupture times, following an inverse relationship accurately described by the fitted model (t = a/d + b), where t represents rupture time (hours) and d represents perforation diameter (mm). Specifically, rupture onset occurred at approximately 28 hours for 1.0 mm perforations, 20 hours for 1.5 mm perforations, and 12 hours for 2.0 mm perforations. Water uptake studies showed robust, pH-independent swelling of the HPMC-based layer, ensuring consistent performance across physiological environments. Cap break force testing revealed an average rupture threshold of approximately 2.7 N. DSC and PXRD data indicated that hot-melt extrusion increased EC crystallinity and TEC miscibility, while FDM printing slightly reduced crystallinity but maintained material stability. FTIR analysis confirmed hydrogen bonding and ester interactions between EC and TEC, supporting a stable, molecularly dispersed polymer matrix. Visual imaging further confirmed the swelling and rupture mechanism of the shell.

Conclusion: The programmable delayed-release container system (PDRCS) offers a customizable platform for time-specific drug delivery, independent of gastrointestinal pH or transit. By tuning perforation size, lag time to release can be precisely controlled, making the system particularly suited for chronopharmaceutical applications such as hydrocortisone replacement in Addison’s disease. The integration of 3D printing, polymer science, and mechanistic modeling enables a robust, patient-specific approach to oral drug delivery with potential adaptability to other circadian-regulated therapies.


Figure 1: (a) Preparation steps including hot-melt extrusion (HME), direct powder compression, and fused deposition modeling (FDM) 3D printing. (b) Diagram of the PDRCS structure showing the shell, cap, and inner disc components.



Figure 2: (a–b) Composition and structural dimensions of the PDRCS. (c) Swelling behavior of the bottom disc at different pH values. (d) Cap rupture force analysis. (e,f) PXRD patterns and crystallinity profiles. (g) FTIR spectra. (h) DSC thermograms.



Figure 3: (a) In vitro rupture profiles of the PDRCS with different perforation sizes (1.0, 1.5, and 2.0 mm). (b) Images of the system before swelling, during swelling, and after rupture. (c) Polynomial and exponential model fitting of swelling behavior for the inner swelling layer and compressed disc. (d) Model fitting of predicted and simulated rupture times compared to experimental results.