SP loaded NLC was prepared using the probe-ultrasonication method as described elsewhere [17]. Briefly, solid lipid (stearic acid 2.8 g) in combination with liquid lipid (oleic acid 1.2 g), lipophilic surfactant (Span 80 2.5 g) and SP (1 g), were melted at 85 ◦ C using a hot plate. The hot lipid phase produced was dispersed in a 1/3 (28.77 g) of the aqueous solution of hydrophilic surfactant (Tween 80) prepared by weighing out 1.67 g Tween 80 heated at the same temperature and sonicated by using a probe sonicator (Bandelin sonopuls, Berlin, Germany) for 5 min (Model HD 3200, Prob TT25, 50% power and 19.82 KJ) to form a coarse pre-emulsion. At the end of the sonication, the mixture was dispersed into the remaining 2/3 of the hydrophilic surfactant solution (containing 3.33 g Tween 80) maintained in an ice bath. The final mixture was sonicated again for 10 min (50% power and 51.77 KJ) whilst still immersed in the ice-bath. This cooling step promoted the formation of the lipid nanoparticles. SP-NLC dispersion was incorporated into 1% w/v Carbopol gel containing 0.2 g methyl paraben as preservative. The obtained gel was allowed to hydrate for 24 h. The resulting mixture was then stirred followed by neutralization with tri-ethanolamine (approximately 10 drops) to obtain an adequate semisolid carbopol gel matrix (for a full composition of each formulation refer to Table 1S in the Supplementary material).