**Preparation and Evaluation of Resveratrol-Loaded Composite Nanoparticles Using a Supercritical Fluid Technology for Enhanced Oral and Skin Delivery**

#### **Eun-Sol Ha 1, Woo-Yong Sim 1, Seon-Kwang Lee 1, Ji-Su Jeong 1, Jeong-Soo Kim 2, In-hwan Baek 3, Du Hyung Choi 4, Heejun Park 5, Sung-Joo Hwang 6 and Min-Soo Kim 1,\***


Received: 2 November 2019; Accepted: 13 November 2019; Published: 14 November 2019

**Abstract:** We created composite nanoparticles containing hydrophilic additives using a supercritical antisolvent (SAS) process to increase the solubility and dissolution properties of *trans*-resveratrol for application in oral and skin delivery. Physicochemical properties of *trans*-resveratrol-loaded composite nanoparticles were characterized. In addition, an in vitro dissolution–permeation study, an in vivo pharmacokinetic study in rats, and an ex vivo skin permeation study in rats were performed. The mean particle size of all the composite nanoparticles produced was less than 300 nm. Compared to micronized *trans*-resveratrol, the *trans*-resveratrol/hydroxylpropylmethyl cellulose (HPMC)/poloxamer 407 (1:4:1) nanoparticles with the highest flux (0.792 μg/min/cm2) exhibited rapid absorption and showed significantly higher exposure 4 h after oral administration. Good correlations were observed between in vitro flux and in vivo pharmacokinetic data. The increased solubility and flux of *trans*-resveratrol generated by the HPMC/surfactant nanoparticles increased the driving force on the gastrointestinal epithelial membrane and rat skin, resulting in enhanced oral and skin delivery of *trans*-resveratrol. HPMC/surfactant nanoparticles produced by an SAS process are, thus, a promising formulation method for*trans*-resveratrol for healthcare products (owing to their enhanced absorption via oral administration) and for skin application with cosmetic products.

**Keywords:** resveratrol; solubility; nanoparticle; correlation; supercritical fluid; bioavailability
