Topical nanostructured lipid carriers/inorganic sunscreen combination for alleviation of all-trans retinoic acid-induced photosensitivity: Box-Behnken design optimization, in vitro and in vivo evaluation.

All-trans retinoic acid is a natural retinoid and the physiologically active metabolite of vitamin A. The aim of the present study is to develop and optimize a nanostructured lipid carrier formulation to enhance the photostability of all-trans retinoic acid and alleviate its skin photosensitivity. Box-Behnken design was used for optimizing dependent variables such as particle size, zeta potential and viscosity. The total lipid (%), liquid lipid (%) and total surfactant (%) were selected as independent variables. The optimized formulation was characterized by particle size of 151 nm, zeta potential of -31 mV and viscosity of 2064 cps. In vitro photoprotection effect of the optimized formulation containing different types and concentrations of inorganic sunscreens was evaluated employing Transpore® tape assay. Sun protection factor and other spectroscopic indices revealed that 6% titanium dioxide was the best choice to be combined with the optimized formulation. After 6 h of ultraviolet A exposure, the optimized formulation and the optimized formulation combined with 6% titanium dioxide enhanced the photostability of all-trans retinoic acid by about 1.5 and 2 times, respectively, compared to its methanolic solution. In vivo photoprotection effect of the developed formulations was conducted on mice exposed to direct sun light for 4 days. Photographs of the mice's skin, biochemical analysis of the pro-inflammatory cytokines in the skin as well as histopathological examination, depicted that the optimized formulation promoted an obvious alleviation of the all-trans retinoic acid-induced photosensitivity, which was further potentiated by the addition of 6% titanium dioxide, compared to the marketed product.