Phospholipid-Based Ultraflexible Nanovesicular Gel of Sertaconazole Nitrate for the Treatment of Skin Fungal Infections: Statistical Optimization, In Vitro and Preclinical Assessment

Sertaconazole nitrate (SN), a broad-spectrum antifungal agent, is clinically employed against diverse dermatophyte infections. Its therapeutic efficacy, however, is constrained by poor aqueous solubility (0.006 mg/mL) and insufficient skin penetration from current commercial formulations. To address these limitations, this research focused on developing, optimizing (using a 3² factorial design), and assessing a topical nanovesicular gel incorporating sertaconazole nitrate-loaded ultraflexible liposomes (SN-UFLs) to enhance antifungal performance. The vesicles exhibited near-spherical morphology, with sizes ranging from 104.40 ± 1.20 to 151.90 ± 2.14 nm, zeta potential (ZP) values between -21.50 ± 1.25 and -51.20 ± 2.25 mV, and entrapment efficiency (EE) values from 77.60 ± 2.50% to 86.04 ± 3.20%. The optimized SN-UFL formulation (OPT-SN-UFL) was then integrated into a carbopol gel base. This SN-UFL-Gel was characterized for pH (6.5 ± 0.20), viscosity (499.66 ± 15 cP), spreadability (205 ± 1.50%), extrudability (154.18 ± 2.48 g/cm²), and drug content (96.7 ± 2.50%), as well as ex vivo skin permeation, skin irritation potential, and in vitro and in vivo antifungal efficacy. Compared with the marketed formulation, higher drug permeation and skin deposition were observed for SN-UFL-Gel. The SN-UFL-Gel exhibited a larger zone of inhibition (25 ± 1.50 mm) against <i>Candida albicans</i> compared to the commercially available formulation (20 ± 1.72 mm). The in vivo animal studies showed that SN-UFL-Gel showed better antifungal activity by efficient inhibition of infection induced in rats with <i>Trichophyton mentagrophytes</i>. The SN-UFL-Gel showed no signs of skin irritation and was stable at 4 ± 1, 25 ± 2, and 40 ± 2 °C for 3 months. Conclusively, the current work divulged successful augmentation of the overall effectiveness of sertaconazole nitrate by using deformable liposomes as a promising nanocarrier.