Intestinal Permeation Characteristics via Non-Everted Gut Sac of Diterpene Lactones from Pure Andrographolide and...

Objectives: This study aimed to assess the intestinal permeation behaviors of andrographolide (AG) and 14-deoxy-11,12-didehydroandrographolide (DDAG), diterpene lactones from Andrographis paniculata extract (APE), pure AG, and three distinct source APEs. The effects of different solvents were also investigated. Methods: Solubility investigation was performed using APE. APEs and pure AG were prepared as liqui-masses, cohesive mixtures of APE, solvents, and solid carriers. PXRD, in vitro release, and ex vivo intestinal permeation using the non-everted gut sac method were investigated. Results: Solubility of AG and DDAG in N-methyl-2-pyrrolidone (NMP) > NMP/diethylene glycol monoethyl ether (DG) mixtures > DG. PXRD indicated that crystallinity loss of liqui-mass was affected by solvent's solvency capacity. The release behaviors of AG and DDAG in phosphate buffer from pure AG and APEs varied depending on their solid state. The release efficiencies of AG and DDAG from liqui-mass systems increased significantly. The apparent permeability (P_app) of AG from pure AG was 0.11 ± 0.05 ×10^-5 cm·s^-1, which was 11-25 times less than that of APEs. The P_app of DDAG from various APEs was comparable, ranging between 5.95 and 7.37 × 10^-5 cm·s^-1. The presence of a solvent, specifically NMP, in liqui-mass significantly enhanced the release rate and permeation flux. The P_app of AG and DDAG from liqui-mass increased by factors of 1.0-2.3 and 1.1-2.7, respectively. Conclusions: This study is the first to emphasize the differences in the release and intestinal permeation characteristics of AG and DDAG from APEs. These findings offer essential insights into the intestinal permeation behavior of diterpene lactones, along with a straightforward mechanistic strategy for enhancement.