**1. Introduction**

*Trans*-resveratrol is abundant in various foods, such as grapes, peanuts, and berries, and is usually taken as a dietary supplement. Chemically, *trans*-resveratrol is known as 3,5,4'-trihydroxystilbene, a non-flavonoid polyphenolic compound produced by plants in response to injury or attack by bacteria and fungi [1]. When exposed to UV light, the typically low transformation of *trans*-resveratrol to *cis*-resveratrol is accelerated [2]. *Trans*-resveratrol has been shown to have several beneficial properties, including anti-aging, anticancer, antidiabetic, anti-inflammatory, antioxidant, cardioprotective, and neuroprotective activities [3–6]. Unfortunately, due to its poor water solubility, instability, short plasma half-life, and extensive metabolism in the intestine and liver, clinical uses of

*trans*-resveratrol are limited to oral administration [1,7–9]. *Trans*-resveratrol is a Biopharmaceutical Classification System (BCS) class II compound with an insolubility in aqueous solutions of pH 1.0 to pH 7.5 and high permeability [1]. Due to these properties, *trans*-resveratrol is quickly metabolized, therefore skin application may be an alternative to oral administration [10–12]. Various formulation strategies, including the use of liposomes, solid dispersions, cyclodextrin complexes, solid lipid nanoparticles, emulsions, polymeric micelles, polymeric nanoparticles, and nanocrystals, have been evaluated to attempt to overcome current limitations of *trans*-resveratrol [13–21]. In particular, a pharmacokinetic study of twelve healthy volunteers given an oral administration of a capsule formulation of resveratrol via solubilization with micelles consisting of polysorbate 80, polysorbate 20, and medium chain triacylglycerol yielded increases in the area under the plasma concentration versus time curve (*AUC*) and maximum plasma concentration ( *C*max) of resveratrol of 5.0-fold and 10.6-fold, respectively, compared to volunteers ingesting a resveratrol powder [19]. In a study with rabbits, a solid dispersion of resveratrol produced an *AUC* value that was 3-fold higher compared to rabbits who ingested a resveratrol/magnesium dihydroxide solid dispersion [20]. However, in a study of resveratrol and piperine cocrystals, concentration of resveratrol in saturated solution at various conditions was decreased compared to pure resveratrol, resulting in decreased oral bioavailability [21]. It is, thus, critical to enhance the in vitro solubility and dissolution properties of resveratrol to improve its absorption by the body, and thus increase its biological performance [22,23].

We hypothesize that the rapid dissolution rate and high degree of supersaturation (solubility) of *trans*-resveratrol formulated with amorphous composite nanoparticles is directly related to increases in *trans*-resveratrol absorption. In this study, composite nanoparticles containing hydrophilic additives were produced using the supercritical antisolvent (SAS) process to increase the solubility and dissolution properties of *trans*-resveratrol for application by oral and skin delivery. Supercritical carbon dioxide (SC-CO2) was used as an antisolvent, and it has significant safety advantages. The airborne concentration at 25 ◦C, considering a high threshold limit value (TLV) of 5000 ppm, is a safe environment that a workforce may be exposed to daily without adverse e ffects. In addition, SC-CO2 is highly dense, permeable, has a high solvent power and di ffusion rate, and is usually miscible with organic solvents [24]. These properties can cause a higher supersaturation during the SAS process, hence reducing the critical energy barrier for nucleation, which leads to faster nucleation, and therefore the precipitation of more and smaller particles [25]. Physicochemical characterization of composite nanoparticles was carried out using particle size and specific surface measurements, scanning electron microscopy, powder X-ray di ffraction, di fferential scanning calorimetry, and kinetic solubility analysis. In addition, an in vitro dissolution–permeation study was performed to compare the *trans*-resveratrol flux of di fferent composite nanoparticles prepared by an SAS process. An in vivo pharmacokinetic study in rats was also performed. We also investigated the correlation between in vitro flux data and in vivo pharmacokinetic data on *trans*-resveratrol. Finally, we performed ex vivo skin permeation studies using rats to investigate the use of *trans*-resveratrol-loaded composite nanoparticles for skin delivery.

#### **2. Materials and Methods**
