Quality by Design (QbD)-Guided Formulation and OptimizationofRutin-Loaded Mucoadhesive in Situ Hydrogel for TargetedManagement of Radiation-Induced Oral Mucositis

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Radiation-Induced Oral Mucositis (RIOM) is a debilitating and nearly universal complication in head-and-neckcancer patients undergoing radiotherapy, severely compromising quality of life and frequently causing treatment interruptions. Conventional therapeutic modalities remain largely palliative, underscoring the urgent need for targetedmucosal drug delivery systems. This study describes the systematic design, optimization, and characterizationof arutin-loaded mucoadhesive in situ hydrogel employing a Quality by Design (QbD) framework. Rutin (quercetin-3-Orutinoside), a naturally occurring flavonoid glycoside, was selected as the bioactive agent owing to its potent antioxidant, anti-inflammatory, and mucoprotective pharmacological profile. A Box-Behnken response surface design(BBD) incorporating three independent variables—poloxamer 407 concentration (X1), carbopol 934P concentration(X2), and HPMC K4M concentration (X3)—was employed to optimize critical quality attributes (CQAs) includinggelation temperature, viscosity, mucoadhesive strength, and cumulative drug release (Q24h). Risk assessment usingIshikawa diagrams and FMEA identified the most influential formulation variables. The optimized formulation(F- Opt) exhibited a gelation temperature of 34.6 ± 0.4°C, viscosity of 1842 ± 38 mPa·s, mucoadhesive strength of 18.7± 0.9 g/cm², and Q24h of 87.3 ± 1.6%, closely aligned with predicted values (prediction error <3%). Scanning electronmicroscopy (SEM), differential scanning calorimetry (DSC), and Fourier-transform infrared (FTIR) spectroscopyconfirmed successful rutin encapsulation and polymer compatibility. Ex vivo mucoadhesion studies on porcine buccal mucosa validated extended residence time (>5 h). In vitro cytotoxicity assays on oral keratinocyte cell linesdemonstrated excellent biocompatibility. Stability studies (40°C/75% RH, 6 months, ICH Q1A) confirmed physico- chemical integrity of the optimized system. These collective findings establish the QbD-optimized rutin insituhydrogel as a scientifically rigorous, mechanistically targeted platform for RIOM management.