Development Of Protease-Encapsulated Microcapsules For Improved Digestion In Pancreatic Insufficiency

Abstract

Exocrine pancreatic insufficiency remains a major therapeutic challenge because orally administered enzymes undergo rapid degradation in the acidic gastric environment before reaching the intestine. The present study developed a scalable solid-in-oil (s/o) spray-drying technique for encapsulating protease within semi-permeable ethylcellulose (EC) microcapsules intended for targeted intestinal enzyme delivery. Pre-formulation studies identified a critical thermal deactivation threshold above 55°C, emphasizing the need for effective thermal stabilization during spray drying. Trehalose and sucrose were investigated as thermoprotective excipients, with 1.5 M trehalose demonstrating the highest protective effect by preserving 95.7% of the native enzyme activity following thermal exposure at 75°C. Circular dichroism spectroscopy confirmed the preservation of the native secondary structure in the stabilized formulations. The optimized microcapsules exhibited a production yield of 71.8%, an encapsulation efficiency of 85.3%, a median particle size (dv50) of 5.19 μm, and a narrow particle size distribution (span = 1.80), indicating excellent manufacturing reproducibility and particle uniformity. In vitro release studies demonstrated a biphasic release profile characterized by an initial burst release followed by sustained diffusion through the ethylcellulose membrane. Mathematical modeling revealed excellent agreement with the Higuchi model (R² = 0.9974), confirming that solute transport occurred predominantly through Fickian diffusion across the hydrated polymer matrix. The semi-permeable membrane effectively retained the encapsulated enzyme while allowing diffusion of low-molecular-weight substrates and reaction products. Overall, the developed solid-in-oil spray-dried ethylcellulose microcapsules represent a promising oral enzyme delivery platform with potential applications in enzyme replacement therapy for exocrine pancreatic insufficiency, phenylketonuria, and related metabolic disorders.