Engineering Cubosomes-Based Nanocarriers for Burn Wound Healing: Formulation and Optimization of aTriple-Drug Delivery System

Abstract

Objectives: The present study was designed to prepare and optimize a cubosomal gel co-loaded with silver sulfadiazine (SSD), Vitamin D, and tretinoin for enhanced burn wound healing. Materials and Methods: The
drugs’ active pharmaceutical ingredients (APIs) were characterized for the preformulation study (organoleptic properties, melting point, ultraviolet [UV] spectroscopy, Fourier-transform infrared [FTIR] spectroscopy, and
solubility). Cubosomes of SSD were prepared and optimized using a factorial design and response surface methodology (RSM) with particle size (PS), entrapment efficiency (EE), and polydispersity index (PDI) as dependent variables. The optimized cubosomal dispersion was combined into a topical cubosomal gel and characterized for physicochemical characteristics, in vitro drug release, rheological behavior, release kinetics, and in vivo wound healing activity using an excision burn wound model in rats and stability over 90 days. Results: Preformulation studies of API confirmed the purity of SSD and tretinoin, with melting points of 281–285°C and 178–182°C, respectively. UV and FTIR analyses of the drug confirmed characteristic absorption peaks without evidence of drug–excipient incompatibility. Optimize cubosomal (CF11, 2%) formulation showing a PS of 186.7 nm, PDI of 0.286, and EE of 85.33%. The formulation showed a negative zeta potential and definite cubic structure as observed by Field Emission Scanning Electron Microscopy. The cubosomal gel was stable, homogeneous, and skin compatible, with a pH range of 6.22–6.78 and pseudoplastic shear-thinning behavior. In vitro release studies of cubosomal gel formulation showed sustained drug release over 8 h, with cumulative releases of 93.7%, 87.3%, and 86.3% for SSD, Vitamin D and tretinoin, respectively. SSD release showed the Higuchi model (R2
 = 0.9966), whereas tretinoin and Vitamin D release were best fitted by the Korsmeyer–Peppas model (R2 = 0.9992). Stability studies confirmed negligible changes in physicochemical parameters during 90 days of storage. In vivo burn wound studies exposed significantly greater wound contraction and faster healing in animals treated with the optimized cubosomal gel formulation compared with control and standard treatment groups. Conclusion: The optimized cubosomal gel of SSD, tretinoin, and Vitamin D confirmed favorable physicochemical properties, high drug EE, sustained release, suitable stability, and enhanced burn wound healing activity. This optimize formulation represents a capable multi-drug topical nanocarrier system for the effective management of thermal burn injuries.