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Purpose: This study aims to overcome the challenges of the current oral targeted drug delivery system, such as the complex preparation process, poor biocompatibility, and delayed drug release. Methods: Here, a non-covalent polymer hydrogel was prepared using the mechanochemical method, and the solid phase loading of 5-amino salicylic acid (5-ASA) was realized. Results: The results obtained from the thermodynamics study, particle size analysis, and electron microscopy show that chitosan (CS) and sodium alginate (SA) form a pH-sensitive hydrogel under the mechanochemical force and also maintain good stability in aqueous solution. Fluorescent tracers study showed that the pH-sensitive hydrogel could achieve the targeted drug release in the colon and the retention time was over 12 h. Next, in vivo efficacy studies, change in mice body weight, DAI (disease activity index) score, thymus, and spleen index, and the diseased state of the mice colon revealed that the pH-sensitive hydrogel is an improved drug delivery system over 5-ASA API commercial preparations as observed in the efficacy and toxicological studies. Conclusion: This method uses an innovative preparation technology that without the need of cross-linking agent to produce an efficient colon-targeted drug delivery system for the treatment of ulcerative colitis. [ABSTRACT FROM AUTHOR]