Bipartite 5-fluorouracil and lepidine-based nanoemulsion gel: <i>in vitro</i> and dermatokinetic evaluation

Skin cancer is the most prevalent malignancy, with rising incidence and morbidity, particularly among the white population. This study aims to develop a dual drug-loaded nanoemulsion (NE) gel incorporating 5-fluorouracil (5-FU) and lepidine (LPD) to enhance drug deposition in the stratum corneum and dermal layer for improved skin cancer therapy. Oil-in-water (o/w) NEs were prepared using peppermint oil, Tween 80 and PEG-400 via aqueous phase titration method and optimised through pseudo-ternary phase diagrams. The optimised dual drug-loaded NE showed particle size of 131.7 ± 3.21 nm, PDI of 0.21 ± 0.005 and zeta potential of −26.24 ± 1.532 mV. This NE was then dispersed into a 1% carbopol 934 gel for topical application. <i>In vitro</i> and <i>ex vivo</i> studies demonstrated significantly enhanced drug deposition and prolonged release (**<i>p</i> &lt; .001) compared to a conventional gel. Furthermore, dermatokinetic and CLSM studies confirmed enhanced skin permeation and deeper drug distribution. Skin irritation studies indicated that the NE gel was safe and non-irritant. It is concluded that the developed 5-FU and LPD co-loaded NE gel enhances topical drug delivery against skin cancer by improving drug absorption and distribution between the epidermis and dermis in rodent skin model, which could represent promising strategy for the management of skin cancer.