Qiao Hongzhi, Chen Lihua, Rui Tianqi, Wang Jingxian, Chen Ting, Fu Tingming, Li Junsong, Di Liuqing
College of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing.
Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.
Int J Nanomedicine. 2017 Feb 7;12:1033-1046. doi: 10.2147/IJN.S120887. eCollection 2017.
Andrographolide (ADG) is a diterpenoid isolated from with a wide spectrum of biological activities, including anti-inflammatory, anticancer and hepatoprotective effects. However, its poor water solubility and efflux by P-glycoprotein have resulted in lower bioavailability. In this study, ADG nanosuspensions (ADG-NS) were prepared using a wet media milling technique followed by freeze drying. d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), a surfactant that inhibits P-glycoprotein function, and sodium lauryl sulfate were used as surface stabilizers. A Box-Behnken design was used to optimize the nanosuspension preparation. The products of these optimal preparation conditions were amorphous and possessed much faster dissolution in vitro than a coarse powder of ADG. The particle size and redispersibility index of the freeze-dried ADG-NS were 244.6±3.0 nm and 113%±1.14% (n=3), respectively. A short-term stability study indicated that the freeze-dried ADG-NS could remain highly stable as nanosuspensions during the testing period. A test of transport across a Caco-2 cell monolayer revealed that the membrane permeability () of ADG-NS was significantly higher than the permeability of the ADG coarse powder or ADG-NS without TPGS (<0.01). Compared to the ADG coarse powder, a physical mixture, commercial dripping pills and ADG-NS without TPGS, ADG-NS exhibited significantly higher plasma exposure with significant enhancements in and area under the curve of plasma concentration versus time from zero to the last sampling time (AUC ) (<0.01). An evaluation of the anti-inflammatory effect on Carr-induced paw edema demonstrated that the ADG-NS were more effective in reducing the rate of paw swelling, producing a greater increase in the serum levels of nitric oxide (NO), Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) (<0.01) and an increase in superoxide dismutase activity (<0.05) compared to the ADG coarse powder. This study indicated that nanosuspensions could act as an effective delivery device for ADG to enhance its oral bioavailability and biological efficacy.
穿心莲内酯（ADG）是一种从[植物名称未给出]中分离出的二萜类化合物，具有广泛的生物活性，包括抗炎、抗癌和保肝作用。然而，其较差的水溶性以及通过P-糖蛋白的外排作用导致其生物利用度较低。在本研究中，采用湿介质研磨技术制备穿心莲内酯纳米混悬液（ADG-NS），随后进行冷冻干燥。抑制P-糖蛋白功能的表面活性剂维生素E聚乙二醇1000琥珀酸酯（TPGS）和十二烷基硫酸钠用作表面稳定剂。采用Box-Behnken设计优化纳米混悬液的制备。这些最佳制备条件下的产物为无定形，在体外的溶解速度比穿心莲内酯粗粉快得多。冷冻干燥的ADG-NS的粒径和再分散指数分别为244.6±3.0 nm和113%±1.14%（n=3）。短期稳定性研究表明，冷冻干燥的ADG-NS在测试期间可作为纳米混悬液保持高度稳定。跨Caco-2细胞单层转运试验表明，ADG-NS的膜通透性（）显著高于穿心莲内酯粗粉或不含TPGS的ADG-NS的通透性（<0.01）。与穿心莲内酯粗粉、物理混合物、市售滴丸和不含TPGS的ADG-NS相比，ADG-NS表现出显著更高的血浆暴露量，在从零到最后采样时间的血浆浓度-时间曲线下面积（AUC）方面有显著提高（<0.01）。对卡拉胶诱导的爪肿胀的抗炎作用评估表明，与穿心莲内酯粗粉相比，ADG-NS在降低爪肿胀率方面更有效，使血清一氧化氮（NO）、白细胞介素-1（IL-1）和肿瘤坏死因子-α（TNF-α）水平有更大升高（<0.01），超氧化物歧化酶活性增加（<0.05）。本研究表明，纳米混悬液可作为穿心莲内酯的有效给药载体，提高其口服生物利用度和生物学疗效。
