Development of Vaginal In Situ Gel Containing ISN/HP-β-CD Inclusion Complex for Enhanced Solubility and Antifungal Efficacy

Many antifungal agents, including isoconazole nitrate (ISN), suffer from low aqueous solubility and inconsistent dissolution kinetics, which limit their therapeutic potential. To address these challenges, this study aimed to enhance the solubility and stability of ISN through the development of inclusion complexes with hydroxypropyl-β-cyclodextrin (HP-β-CD). HP-β-CD inclusion complexes were prepared using a spray-drying technique and characterized through phase-solubility studies, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (¹H-NMR), and differential scanning calorimetry (DSC). The inclusion complex significantly improved ISN solubility, increasing from 0.5088 mg/mL to 3.6550 mg/mL. These complexes were incorporated into a thermosensitive, mucoadhesive in situ gel system using Pluronic^® F127 and hydroxypropyl methylcellulose (HPMC) to optimize vaginal drug delivery. The formulations were evaluated for gelation temperature, viscosity, swelling behavior, and pH, confirming their suitability for vaginal application. Antimicrobial studies demonstrated that the ISN/HP-β-CD gels exhibited superior activity against <i>Candida albicans</i>, <i>C. glabrata</i>, and <i>C. krusei</i> compared to ISN alone. In vitro release studies further revealed sustained drug release following Peppas-Sahlin kinetics, supporting enhanced bioavailability and prolonged therapeutic action. This study demonstrates that the ISN/HP-β-CD-loaded in situ gel system offers a promising and effective approach for improving the solubility, stability, and antifungal efficacy of ISN for the treatment of vaginal infections.