Investigation of Tretinoin-Loaded Cubosomal Hydrogel for Actinic Keratosis: Enhanced Skin Permeation, Confocal Microscopy Visualization, and Stability Assessment

Tretinoin is a well-established topical agent for dermatological conditions such as actinic keratosis but faces challenges including poor skin permeation, irritation, and photo-instability. This study aimed to develop a tretinoin-loaded cubosomal hydrogel (cubogel) to enhance skin permeation, prolong drug release, and improve safety. Cubosomes were formulated using glyceryl monooleate and poloxamer 407 and incorporated into hydrogels containing different concentrations of Carbopol 940. The optimized formulation (CG2) was characterized for particle size, entrapment efficiency, pH, viscosity, spreadability, drug release kinetics, and stability under ICH guidelines. Skin permeation was visualized using Confocal Laser Scanning Microscopy (CLSM) with Rhodamine B as a fluorescent marker, while histopathological studies evaluated dermal safety in animal models. CLSM confirmed enhanced skin penetration compared to conventional formulations, while histopathology showed no irritation or structural damage. In vitro drug release kinetics followed Higuchi kinetics (R² = 0.9988), indicating diffusion-controlled drug release. Stability studies demonstrated formulation integrity under refrigeration for 3 months. Tretinoin-loaded cubogels significantly improved skin permeation, sustained drug release, and dermatological safety over conventional creams. This formulation shows strong potential for topical management of actinic keratosis and warrants further clinical investigation.