Soft multiple emulsions demonstrating reversible freeze-thawing capacity and enhanced skin permeability of diclofenac sodium

Multiple emulsions are potential transdermal drug carriers for their remarkable ability to enhance skin permeability, but their intrinsic thermodynamically instability always limits further application. Here, we developed freeze-thawing water-in-oil-in-water multiple emulsion transdermal drug delivery system, which could accomplish solid-liquid transition in freeze-thawing cycles and keep stable under hypothermic storage (4 °C). In this study, freeze-thawing multiple emulsions were prepared by a two-step emulsification method with isopropyl palmitate as the oil phase, which could freeze at 4 °C to gain solid multiple emulsions and regain intact liquid emulsions at a shell temperature (32 °C) upon application on the skin. In vitro skin permeation studies on excised mice skin showed that the cumulative permeation percentages of diclofenac sodium from freeze-thawing multiple emulsions, multiple emulsions, and cream (Dakangfen®) were 41.22 ± 4.27, 36.63 ± 4.71, and 23.96 ± 3.49% separately. Moreover, pharmacokinetic experiments in rabbits indicated that the AUC 0 −  t (area under the curve) of freeze-thawing multiple emulsions (30.872 ± 3.989 μg/mL h) and multiple emulsions (27.337 ± 2.804 μg/mL h) were significantly higher than those of the controlled cream (14.981 ± 1.331 μg/mL h) ( p  < 0.05). These results suggested that freeze-thawing multiple emulsions could be a promising substitute of traditional multiple emulsions for transdermal drug delivery.