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

Background: 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. Methods: 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. Results: 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 Streptococcus mutans and Staphylococcus aureus. PCA revealed an inverse correlation between AZC release and mucoadhesion and positive correlations between release and anti-inflammatory activity. Conclusions: 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.