Pure Trans-Resveratrol Nanoparticles Prepared by a Supercritical Antisolvent Process Using Alcohol and Dichloromethane Mixtures: Effect of Particle Size on Dissolution and Bioavailability in Rats

Abstract

The aim of this study was to prepare pure trans-resveratrol nanoparticles without additives (surfactants, polymers, and sugars) using a supercritical antisolvent (SAS) process with alcohol (methanol or ethanol) and dichloromethane mixtures. In addition, in order to investigate the effect of particle size on the dissolution and oral bioavailability of the trans-resveratrol, two microparticles with different sizes (1.94 µm and 18.75 µm) were prepared using two different milling processes, and compared to trans-resveratrol nanoparticles prepared by the SAS process. The solid-state properties of pure trans-resveratrol particles were characterized. By increasing the percentage of dichloromethane in the solvent mixtures, the mean particle size of trans-resveratrol was decreased, whereas its specific surface area was increased. The particle size could thus be controlled by solvent composition. Trans-resveratrol nanoparticle with a mean particle size of 0.17 µm was prepared by the SAS process using the ethanol/dichloromethane mixture at a ratio of 25/75 (w/w). The in vitro dissolution rate of trans-resveratrol in fasted state-simulated gastric fluid was significantly improved by the reduction of particle size, resulting in enhanced oral bioavailability in rats. The absolute bioavailability of trans-resveratrol nanoparticles was 25.2%. The maximum plasma concentration values were well correlated with the in vitro dissolution rate. These findings clearly indicate that the oral bioavailability of trans-resveratrol can be enhanced by preparing pure trans-resveratrol nanoparticles without additives (surfactants, polymers, and sugars) by the SAS process. These pure trans-resveratrol nanoparticles can be applied as an active ingredient for the development of health supplements, pharmaceutical products, and cosmetic products.

Enhanced Oral Bioavailability of Resveratrol by Using Neutralized Eudragit E Solid Dispersion Prepared via Spray Drying

“…In fact, the AUC 0→8 h and C max values of trans -resveratrol increased with the increasing degree and duration of in vitro supersaturation. This tendency is similar to that of trans -resveratrol-loaded composite nanoparticles previously reported [ 20 , 21 ]. Furthermore, the absolute oral bioavailability (F%) of trans -resveratrol was estimated to be 40% for the Eudragit E/HCl solid dispersion (10/90).…”

“…Furthermore, the absolute oral bioavailability (F%) of trans -resveratrol was estimated by dividing the AUC 0→8 h value obtained from oral administration by the AUC 0→8 h value obtained from intravenous administration with dose normalization. The AUC 0→8 h value of trans -resveratrol after intravenous administration used was from our previous study [ 20 ]. As shown in Figure 5 , the oral absorption of trans -resveratrol was significantly enhanced by the Eudragit E/HCl solid dispersion.…”

“…Thus, it is necessary to develop a formulation that uses less surfactant. We recently developed composite nanoparticles and pure trans -resveratrol nanoparticles with high bioavailability using a supercritical antisolvent (SAS) process [ 19 , 20 ]. Furthermore, we demonstrated that the oral bioavailability of trans -resveratrol can be increased by improving the dissolution rate and supersaturation of trans -resveratrol in an in vitro dissolution test.…”

Nanoparticles and Nanocrystals by Supercritical CO2-Assisted Techniques for Pharmaceutical Applications: A Review

“…Nanoparticles and nanocrystals containing APIs can be obtained with different techniques, such as spray-drying, freeze-drying, coacervation, jet-milling, and solvent evaporation [21][22][23][24][25][26][27]. However, toxic organic solvents are widely used in these traditional processes; high temperatures and long postprocess treatments are also employed to remove liquid solvents from the particles/crystals produced.…”

“…High process temperatures can cause possible degradation of the active compound, in addition to the fact that the removal of the solvent from the final product is often not complete. Moreover, traditional micronization/nanonization techniques usually lead to the achievement of products characterized by irregular morphology and broad PSDs [21][22][23][24]. Many literature studies have demonstrated the possibility of overcoming all these drawbacks by using supercritical carbon dioxide (scCO 2 ) for the drug micronization/nanonization [21][22][23][24][28][29][30].…”