(W1030-07-41) Enhanced Oral Bioavailability of Resveratrol Using Various Formulation Strategies

Purpose: The aim of this study was to develop several different strategies such as solid dispersions, nanoparticles, and nanosuspensions to enhance the dissolution and oral bioavailability of trans-resveratrol.

Methods: In this study, we designed amorphous solid dispersions, nanoparticles, and nanosuspensions using various methods such as Spray Drying, Supercritical Antisolvent (SAS) Process, and the Antisolvent Precipitation Method to improve the oral bioavailability. The amorphous Eudragit E/HCl solid dispersion at a trans-resveratrol/polymer ratio of 10/90 was prepared using the Spray Drying Process. The pure trans-resveratrol nanoparticles without additives were created by the SAS process using the ethanol/dichloromethane mixture at a ratio of 25/75 (w/w). The trans-resveratrol/hydroxylpropylmethyl cellulose (HPMC)/poloxamer 407 (1/4/1) nanoparticles were produced using a supercritical antisolvent (SAS) process. The antisolvent process was used to develop a resveratrol nanosuspension of the optimized composition conditions, based on a quality by design (QbD) approach. The physicochemical properties of nanoparticles, solid dispersion and nanosuspension were characterized using scanning/transmission electron microscopy, powder X-ray diffraction, and a particle size analyzer. In addition, an in vitro dissolution study, and an in vivo pharmacokinetic study in rats were performed.

Results: The morphology characterization of different formulations of trans-resveratrol was evaluated using a scanning/transmission electron microscope. The particle size of nanosuspension was 46.3 nm at the initial stage and was increased to about 200 nm after 6 months. The amorphous solid dispersion powders, pure nanoparticles, and composite nanoparticles had a mean particle size of 3.92 µm, 151.2 nm, and 258.5 nm, respectively. As a result, the particle size of raw trans-resveratrol with a mean particle size of 108.94 µm was significantly decreased by the SAS process using EtOH/DCM (25:75) mixture, and pure nanoparticles had the smallest particle size among the prepared samples. The in vitro dissolution data and the in vivo pharmacokinetic data for various formulations of trans-resveratrol were compared with those of the raw material. Amorphous solid dispersion was completely dissolved within 30 min. Both pure and composite nanoparticles created by SAS Process dissolved approximately 90% within 3 minutes and the dissolution rate of nanosuspension also reached 99.4% after 2 min. The oral absorption of trans-resveratrol was significantly enhanced by solid dispersion, nanoparticles, and nanosuspension. The Eudragit E/HCl (10/90) solid dispersion was 4.2 fold higher in AUC_{0→8 h} value than raw material. AUC_{0→12 h} values of composite nanoparticles and nanosuspension were 9.7 fold and 1.6 fold higher, respectively than those of raw trans-resveratrol. In addition, the absolute bioavailability of pure trans-resveratrol nanoparticles was estimated using the mean value of the intravenously administered AUC_{0→8 h} and was derived as 25.2%. The pure nanoparticles created by the SAS process achieved C_max within 0.5 h and had the highest concentration (734.0 ng/mL) among other formulations prepared in this study.

Conclusion: The in vitro dissolution rate for various formulations of trans-resveratrol prepared in this study was higher than that of raw materials by effectively reducing particle size using Spray Drying, SAS process, and the Antisolvent Precipitation. In particular, pure trans-resveratrol nanoparticles without additives showed a maximized dissolution and pharmacokinetic profiles than other formulation strategies. These findings indicate that solid dispersions, nanoparticles, and nanosuspensions prepared by different methods including Spray Drying, SAS Process, and the Antisolvent Precipitation Method can be enhanced the oral bioavailability of trans-resveratrol. Therefore, various formulation technologies used in this study offer a promising strategy with high oral bioavailability for developing high-quality health supplements, nutraceutical, and pharmaceutical products.

Acknowledgments: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C4002166).