Azithromycin-Loaded Nanoparticles Incorporated in Chitosan-Based Soft Hydrogels: A Novel Approach for Dental Drug Delivery

<b>Background:</b> Azithromycin (AZC), a BCS class II/IV antibiotic with broad-spectrum antimicrobial activity, has poor water solubility, limiting its formulation potential. This study aimed to develop and optimize AZC-based soft hydrogels for the first time for improved solubility, local controlled drug release, and local dental applications. <b>Methods:</b> AZC nanoparticles (based on polyvinylpyrrolidone) were synthesized via electrospinning enhanced solubility 40-fold. These were incorporated into chitosan (CS) hydrogels with varying concentrations and degrees of deacetylation (DDA), optimized using a factorial design. Hydrogels were characterized for drug release, mucoadhesion, antioxidant, anti-inflammatory, and antimicrobial properties, with Principal Component Analysis (PCA) assessing correlations. <b>Results:</b> Soft hydrogels with 3% CS and 80% DDA achieved sustained drug release (62.9-94.7% over 48 h), strong mucoadhesion, and enhanced biological activity. Higher CS and DDA improved antioxidant and anti-inflammatory effects due to increased free amino groups. Antimicrobial tests showed efficacy against <i>Streptococcus mutans</i> and <i>Staphylococcus aureus</i>. PCA revealed an inverse correlation between AZC release and mucoadhesion and positive correlations between release and anti-inflammatory activity. <b>Conclusions:</b> AZC-based soft hydrogels significantly improved solubility, controlled release, and biological activity, showing strong potential for dental drug delivery. Further clinical validation and optimization are recommended.