Mechanistic and Biorelevant Validation of a pH–Microbiota–Time Responsive Budesonide Tablet for Regioselective Colonic Delivery: Sequential Dissolution, Tissue Retention, Gastrointestinal Localization and Functional Stability

Abstract

Background: Colon-targeted dosage forms are commonly evaluated using pH-shift dissolution; however, gastrointestinal pH alone cannot establish anatomical specificity because pH, transit and microbiota vary substantially among subjects and disease states. A more rigorous demonstration of regioselectivity requires sequential evidence linking upper-gastrointestinal protection, target-stage activation, microbiota responsiveness, tissue retention and anatomical localization.

Objective: To investigate the mechanistic and biorelevant performance of a multi-trigger budesonide tablet designed for preferential colonic delivery using pH-, microbiota- and time-dependent release mechanisms.

Methods: A 9-mg budesonide core was surrounded by a 250-mg compression coat containing pectin, guar gum and hydroxypropyl methylcellulose and subsequently coated with a methacrylate enteric film. The optimized formulation was evaluated for physical quality, swelling, erosion, sequential gastrointestinal dissolution, microbial/enzyme-responsive release and release kinetics. Ex vivo colonic tissue retention was compared with plain budesonide and a pH-responsive control. Gastrointestinal localization was assessed using an imaging analogue. Functional stability was evaluated after storage at 40 ± 2°C/75 ± 5% RH. Dissolution profiles were compared using f1 and f2.

Results: Illustrative cumulative release from the optimized formulation was 1.67 ± 0.16% at 2 h, 7.12 ± 0.22% at 5 h and 84.42 ± 0.41% at 8 h†. Target-stage release increased markedly in enzyme/microbial medium compared with corresponding sterile buffer†. Ex vivo colonic budesonide retention increased from 4.15 ± 0.33 µg/g with plain drug to 14.84 ± 1.09 µg/g with the optimized system†. Mean simulated colonic arrival and major dosage-form activation occurred at 5.68 ± 0.35 and 7.08 ± 0.23 h, respectively†. After 6 months of accelerated storage, release remained 2.31% at 2 h, 8.65% at 5 h and 81.84% at 8 h, with f2 ≈ 86.1 relative to the initial profile†.

Conclusion: Integration of sequential dissolution, microbiota responsiveness, matrix-transformation studies, tissue retention, localization and functional stability provides a substantially stronger demonstration of regioselective delivery than pH-shift dissolution alone. The proposed platform represents a mechanistically rational approach for regional budesonide delivery to the colon.