Study on Central Composite Design Method to Optimize the Preparation Process of Chrysophanol‐Pluronic F127 Nanomicelles and Pharmacokinetics

Abstract

Objective. In order to find the best process for the preparation of Chrysophanol‐Pluronic F127 nanomicelles in the laboratory, the preparation of Chrysophanol‐Pluronic F127 nanomicelles was optimized using the central composite design method. In order to investigate the properties of the prepared Chrysophanol‐Pluronic F127 nanomicelles, physicochemical properties were examined and in vitro dissolution experiments were performed, and the pharmacokinetics of Chrysophanol and Chrysophanol‐Pluronic F127 nanomicelles were investigated in rabbits. Methods. In the preexperimental study, the best physical solubilization method and organic solvent for Chrysophanol were selected. The ratio of drug dosage to excipient dosage and the amount of organic solvents were evaluated by single‐factor test. Based on the single‐factor test, the optimal prescription was obtained by screening the formulation and optimizing the preparation process using the central composite design method with the encapsulation efficiency as the index. Chrysophanol‐Pluronic F127 nanomicelles were prepared according to the optimal prescription, and their particle size, potential, appearance, and in vitro release experiments were carried out. Chrysophanol and Chrysophanol‐Pluronic F127 nanomicelles were injected intravenously through the ear margins to rabbits, and the drug concentrations in the blood were measured at different time points by HPLC. The obtained blood concentration data were fitted with PK Solver 2.0 program to obtain pharmacokinetic parameters. Results. In the preexperimental study, ultrasonic method was selected as the physical solubilization method, and acetone was selected as the organic solvent. In single‐factor test, the highest encapsulation efficiency was achieved when the ratio of drug dosage to excipient dosage was 1 : 15; the highest encapsulation efficiency was achieved when the amount of organic solvent (acetone) was 8 mL. The equation fitted to the model for the optimized prescription by the central composite design method is as follows: R1 = −166.93629 + 16.86478A + 32.55582B − 0.169750AB − 0.4826752 − 2.25797B2(R2 = 0.9457). The best prescription for the preparation of Chrysophanol‐Pluronic F127 nanomicelles was obtained in the ratio of drug dosage to excipient dosage of 1 : 16.309 and the dosage of organic solvent was 6.595 mL. The prepared nanomicelles have a particle size of 152.8 nm and a potential of ‐23.9 mV. It was observed by transmission electron microscope that the prepared nanomicelles are uniform and spherical in appearance. The drug metabolism of Chrysophanol and nanomicelles in rabbits conforms to the two‐compartment open model, and both of them show linear kinetics in the drug dose range. T(1/2α) was 0.31 ± 0.21 h and 0.47 ± 0.35 h, and T(1/2β) was 2.06 ± 1.14 h and 7.72 ± 2.04 h for Chrysophanol and Chrysophanol‐Pluronic F127 nanomicelles, respectively. Conclusions. The adopted central composite design method can well optimize the prescription process of Chrysophanol‐Pluronic F127 nanomicelles prepared by dialysis, and the method is simple and easy to be prepared in the laboratory. The prepared nanomicelles have uniform particle size and good zeta potential and appear as uniform black spherical shape under transmission electron microscopy. In vitro release studies showed that the Chrysophanol‐Pluronic F127 nanomicelles released significantly better than Chrysophanol. The results of pharmacokinetics of Chrysophanol and Chrysophanol‐Pluronic F127 nanomicelles in rabbits showed that the Chrysophanol‐Pluronic F127 nanomicelles did not change the metabolic process of the drug in vivo but could stay in vivo for a longer period of time and exert longer effects. It is hoped that this study can provide a laboratory basis for the preparation of Chrysophanol‐Pluronic F127 nanomicelles and a reference for further in vivo studies of Chrysophanol.