Sato Vilasinee Hirunpanich, Sato Hitoshi, Sangfuang Manaw, Nontakham Jannarin, Junyaprasert Varaporn Buraphacheep, Teeranachaideekul Veerawat, Morakul Boontida
Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand.
Division of Pharmacokinetics and Pharmacodynamics, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, Tokyo, 142-855, Japan.
Sci Rep. 2024 Dec 30;14(1):32148. doi: 10.1038/s41598-024-84063-2.
This study aims to develop a self-nanoemulsifying drug delivery system (SNEDDS) to solve the limited oral bioavailability problem of apigenin, a bioactive flavonoid. Apigenin-loaded SNEDDS consisting of Gelucire 44/14, Tween 80, and PEG 400 in the mass ratios of 25:37.5:37.5 and 30:35:35 were prepared, and designated as GTP2575 and GTP3070, respectively. The physicochemical stability at 30 and 40 ºC for 6 months was evaluated and a good stability was found. The in vitro transport of apigenin across Caco-2 monolayers from the SNEDDS and the in vivo pharmacokinetics in rats were investigated and compared with apigenin intact form. The in vitro permeation results demonstrated an increased transcellular permeability compared to the apigenin coarse powder (p < 0.05), while there was comparable permeation of apigenin in GTP2575 and GTP3070 formulations, with the permeability constants (P) being 2.97 × 10 and 3.13 × 10, respectively (p > 0.05). The pharmacokinetic analysis in rats revealed that the pharmacokinetic parameters, such as C, AUC, and AUC, were significantly higher with apigenin-loaded SNEDDS than with apigenin coarse powder (p < 0.05). Apigenin's oral relative bioavailability increased by 3.8 and 3.3 times for GTP2575 and GTP3070, respectively, due to SNEDDS's effect on solubilization and transcellular permeability. The in vivo acute oral toxicity according to OECD 425 was evaluated and revealed low toxicity with an LD exceeding 2,000 mg/kg in all apigenin's formulations. These findings suggest that apigenin-loaded SNEDDS may represent a promising strategy for improving the oral delivery of apigenin.
本研究旨在开发一种自纳米乳化药物递送系统（SNEDDS），以解决生物活性黄酮芹菜素口服生物利用度有限的问题。制备了质量比为25:37.5:37.5和30:35:35的由Gelucire 44/14、吐温80和聚乙二醇400组成的载芹菜素SNEDDS，分别命名为GTP2575和GTP3070。评估了其在30℃和40℃下6个月的物理化学稳定性，发现稳定性良好。研究了芹菜素从SNEDDS跨Caco-2单层的体外转运以及大鼠体内的药代动力学，并与芹菜素完整形式进行了比较。体外渗透结果表明，与芹菜素粗粉相比，跨细胞通透性增加（p < 0.05），而在GTP2575和GTP3070制剂中芹菜素的渗透相当，渗透常数（P）分别为2.97×10和3.13×10（p > 0.05）。大鼠药代动力学分析表明，载芹菜素SNEDDS的药代动力学参数，如Cmax、AUC0-t和AUC0-∞，显著高于芹菜素粗粉（p < 0.05）。由于SNEDDS对溶解和跨细胞通透性的作用，芹菜素的口服相对生物利用度在GTP2575和GTP3070中分别提高了3.8倍和3.3倍。根据经合组织425号准则评估了体内急性口服毒性，结果显示所有芹菜素制剂的毒性较低，LD50超过2000 mg/kg。这些发现表明，载芹菜素SNEDDS可能是改善芹菜素口服给药的一种有前景的策略。
