Formulation and Evaluation of pH and Enzyme-Responsive In-situ Gel Drug Delivery System using Bio-responsive Polymers for Sulfasalazine in the Treatment of Inflammatory Bowel Disease: A Molecular Docking-Based Lead Optimization Approach

Background: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic inflammatory disorder of the gastrointestinal tract characterized by damage to the mucosa and dysfunction in colonic homeostasis. Because conventional oral therapies do not meet the needs of colon-targeted drug delivery, it leads to insufficient therapeutic results. Problem: Sulfasalazine (SSZ) is an IBD-prodrug and BCS Class IV drug with low solubility, low permeability, premature GI release and systemic side-effects leading to variable colonic bioavailability. Objective: This investigation was to design and evaluate a pH-and-enzyme responsive in situ gel system of the systemic antiinflammatory drug sulfasalazine (SSZ) by utilizing bio-responsive polymers, prepared through formulation strategy rationally defined with molecular docking-based lead optimization approaches for improved colonic targeting-featured drug–polymer interaction capacity. Methods: A pH and enzyme-sensitive colonic drug delivery was achieved using a designed polymer blend of Poloxamer 407, Eudragit® S100, Pectin, HPMC K15M, Sodium Alginate and Carbopol 934P. Utilizing Box–Behnken Design, cold method to prepare, nine different formulations were optimized (F1–F9). AutoDock Vina molecular docking of COX2 (PDB: 5F19) and TNF-α confirmed SSZ as the best lead candidate. Investigation of different pre-formulation studies such as DSC, FTIR, solubility and compatibility. The characteristics of formulations were assessed pre-gel and postgel, and also the in vitro drug release was first determined under sequential pH conditions with and without pectinase enzyme. Results: Molecular docking revealed SSZ with the highest intrinsic binding affinity on COX-2 as ΔG = −9.850 kcal/mol among other derivatives, being chosen as a lead compound. FTIR proved the full compatibility between SSZ and selected polymers. The optimized in situ gel had a sol-to-gel transition temperature of 35–37°C, drug content of 98-102%, good strength and excellent mucoadhesion properties. Less than 20% release in SGF, less than 30% in SIF and ≥80% at colonic pH over 8 h were obtained indicating controlled release. Release due to application of pectinase confirms responsiveness to the enzyme. In vivo, the kinetics of drug release conformed to Korsmeyer–Peppas model (r² = 0.9921; n = 0.78) confirming non-Fickian transport.Conclusion: The study indicates the establishment of pH- and enzyme-responsive SSZ in situ gel represents a viable colon-targeted system for IBD, with site-specific delivery demands, sustained release patterns, reduced systemic adverse effects and increased therapeutic efficacy over that offered by oral sulfasalazine therapy.