Development of a Resveratrol Nanosuspension Using the Antisolvent Precipitation Method without Solvent Removal, Based on a Quality by Design (QbD) Approach

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 (AUC_0-12h) and the maximum plasma concentration (C_max) 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.

Keywords: bioavailability; dissolution; nanosuspension; optimization; quality by design; resveratrol.

Figure 1

Development flow (a) and manufacturing process (b) of resveratrol nanosuspension based on the quality by design approach.

Figure 1

Development flow (a) and manufacturing process (b) of resveratrol nanosuspension based on the quality by design approach.

Figure 2

Solubility of resveratrol in various solvents at 25 °C.

Figure 3

Inhibitory effects of PVP, HPC, and HPMC on resveratrol precipitation.

Figure 4

Perturbation plots (a) and response surface plots (b) showing the effects of various formulation parameters on the responses Y₁, Y₄, and Y₉.

Figure 5

Overlay plots (a) and probability maps (b) that satisfy the target value for the responses Y₁–Y_9.

Figure 6

Probability maps that satisfy the target value for the responses when the mixing speed is 500 rpm, 750 rpm, and 1000 rpm in Monte Carlo simulations.

Figure 7

Dissolution profiles of resveratrol in the optimal nanosuspension formulation and the resveratrol raw material.

Figure 8

Plasma concentration-time profile of resveratrol in rats after oral administration of the resveratrol nanosuspension and the resveratrol raw material. Data are expressed as the mean ± standard deviation (n = 4).

Figure 9

TEM images and particle size distributions of resveratrol nanosuspension. (a) Initial (1 day) TEM image, (b) 6-month TEM image, (c) initial (1 day) particle size distribution, and (d) 6-month particle size distribution.

Figure 9

TEM images and particle size distributions of resveratrol nanosuspension. (a) Initial (1 day) TEM image, (b) 6-month TEM image, (c) initial (1 day) particle size distribution, and (d) 6-month particle size distribution.

Figure 10

Long-term stability of the optimized resveratrol nanosuspension. (a) Particle size (z-average and d90) and (b) drug content.