A novel drug–phospholipid complex enriched with micelles: preparation and evaluation in vitro and in vivo

Hai-jian Xia,^1,2 Zhen-hai Zhang,¹ Xin Jin,¹ Qin Hu,¹ Xiao-yun Chen,¹ Xiao-bin Jia<sup>1

1</sup>Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Nanjing, China; ²College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China

Abstract: Mixed micelles are widely used to increase solubility and bioavailability of poorly soluble drugs. One promising antitumor drug candidate is 20(S)-protopanaxadiol (PPD), although its clinical application is limited by low water solubility and poor bioavailability after oral administration. In this study, we developed mixed micelles consisting of PPD–phospholipid complexes and Labrasol^® and evaluated their potential for oral PPD absorption. Micelles were prepared using a solvent-evaporation method, and their physicochemical properties, including particle size, zeta potential, morphology, crystal type, drug loading, drug entrapment efficiency, and solubility, were characterized. Furthermore, in vitro release was investigated using the dialysis method, and transport and bioavailability of the mixed micelles were investigated through a Caco-2 cell monolayer and in vivo absorption studies performed in rats. Compared with the solubility of free PPD (3 µg/mL), the solubility of PPD in the prepared mixed micelles was 192.41 ± 1.13 µg/mL in water at room temperature. The in vitro release profiles showed a significant difference between the more rapid release of free PPD and the slower and more sustained release of the mixed micelles. At the end of a 4-hour transport study using Caco-2 cells, the apical-to-basolateral apparent permeability coefficients (P_app) increased from (1.12 ± 0.21) × 10⁶ cm/s to (1.78 ± 0.16) × 10⁶ cm/s, while the basolateral-to-apical P_app decreased from (2.42 ± 0.16) × 10⁶ cm/s to (2.12 ± 0.32) × 10⁶. In this pharmacokinetic study, compared with the bioavailability of free PPD (area under the curve [AUC]_0–8), the bioavailability of PPD from the micelles (AUC_0–8) increased by approximately 216.36%. These results suggest that novel mixed micelles can significantly increase solubility, enhance absorption, and improve bioavailability. Thus, these prepared micelles might be potential carriers for oral PPD delivery in antitumor therapies.

Keywords: 20(S)-protopanaxadiol, phospholipid complex, Labrasol, mixed micelles, Caco-2 cell monolayer, bioavailability