Abstract
The purpose of this study was to develop a resveratrol nanosuspension with enhanced oral bioavailability, based on an understanding of the formulation and process parameters of nanosuspensions and using a quality by design (QbD) approach. Particularly, the antisolvent method, which requires no solvent removal and no heating, is newly applied to prepare resveratrol nanosuspension. To ensure the quality of the resveratrol nanosuspensions, a quality target product profile (QTPP) was defined. The particle size (z-average, d90), zeta potential, and drug content parameters affecting the QTPP were selected as critical quality attributes (CQAs). The optimum composition obtained using a 3-factor, 3-level Box–Behnken design was as follows: polyvinylpyrrolidone vinyl acetate (10 mg/mL), polyvinylpyrrolidone K12 (5 mg/mL), sodium lauryl sulfate (1 mg/mL), and diethylene glycol monoethyl ether (DEGEE, 5% v/v) at a resveratrol concentration of 5 mg/mL. The initial particle size (z-average) was 46.3 nm and the zeta potential was −38.02 mV. The robustness of the antisolvent process using the optimized composition conditions was ensured by a full factorial design. The dissolution rate of the optimized resveratrol nanosuspension was significantly greater than that of the resveratrol raw material. An in vivo pharmacokinetic study in rats showed that the area under the plasma concentration versus time curve (AUC0–12h) and the maximum plasma concentration (Cmax) respectively, than those of the resveratrol raw material. Therefore, the prepara values of the resveratrol nanosuspension were approximately 1.6- and 5.7-fold higher,tion of a resveratrol nanosuspension using the QbD approach may be an effective strategy for the development of a new dosage form of resveratrol, with enhanced oral bioavailability.
Highlights
Resveratrol, 3,5,4 -trihydroxystilbene, is a non-flavonoid polyphenolic antioxidant and it is produced by plants in response to injury or attack by bacteria and fungi
When nanosuspensions enter the gastrointestinal tract, nanoparticles provide a larger surface area for the dissolution and molecular dispersion of resveratrol, leading to an increased solubility and concentration gradient on the surface of the nanoparticles, according to the classical passive diffusion theory [15,44]. These results suggested that the oral absorption of resveratrol was significantly increased by its incorporation in a nanosuspension form
This study confirmed that the selection of QTTP and critical quality attributes (CQAs), and preliminary studies followed by stepwise risk assessments (RAs) helped to efficiently achieve optimization of formulation and process parameter by minimizing trial and error without much useless experiments
Summary
Resveratrol, 3,5,4 -trihydroxystilbene, is a non-flavonoid polyphenolic antioxidant and it is produced by plants in response to injury or attack by bacteria and fungi. Resveratrol is a class II compound in the Biopharmaceutical Classification System (BCS) with high permeability (Log P = 3.1) and low aqueous solubility [2]. This property cause of its instability, poor water solubility, short biological half-life, and rapid metabolism and elimination, the therapeutic applications of resveratrol are very limited [1]. Resveratrol can act as a reductant that is oxidized more readily than other components, its oxidative degradation can be accelerated by heating during the manufacturing process of final product. The selection of a suitable process to avoid these negative factors is very important for the manufacturing of the quality ensured final product containing resveratrol
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