Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
J Pharm Sci. 2013 Oct;102(10):3792-9. doi: 10.1002/jps.23696. Epub 2013 Aug 11.
Indirubin and its derivatives have been shown to interrupt the cell cycle by inhibiting cyclin-dependent kinases, explaining their long-time use in traditional Chinese medicine for the treatment of chronic myelocytic leukemia. A potent derivative of indirubin, indirubin-3'-oxime 2,3-dihydroxypropyl ether (E804), has been shown to block the Src-Stat3 and Src-Stat5 signaling pathway in human cancer cells, inducing apoptosis. The anticancer effects of E804, however, cannot be easily examined in vivo because of its poor water solubility and low absorption. The aim of this study was to develop and evaluate a self-nanoemulsifying drug delivery system (SNEDDS) containing E804 for enhancing its solubility and bioavailability. Solubility of E804 was determined in various vehicles, and pseudoternary phase diagram was used to evaluate the self-emulsifying existence area. The SNEDDS composed of Capmul MCM (oil), Solutol HS 15 (surfactant), and polyethylene glycol 400 (cosurfactant) on the ratio of 20.5:62.5:16 loaded 1.5% of E804. The particle size of droplets was found to be 16.8 and 140 nm, and SNEDDS was stable after freeze-thaw cycles and upon dilution in HCl 0.1 N and pH 7.4 HBSS++. The ability of formulation for absorption enhancement was studied in rats in vivo after oral administration. The results showed that the developed SNEDDS increased the E804 bioavailability 984.23% compared with the aqueous suspension. Our studies for the first time show that the developed SNEDDS can be used as a possible formulation for E804 to improve its solubility and oral bioavailability.
靛玉红及其衍生物已被证明通过抑制细胞周期蛋白依赖性激酶来阻断细胞周期，这解释了它们在传统中药中用于治疗慢性髓性白血病的长期应用。靛玉红的一种有效衍生物，靛玉红-3'-肟 2,3-二羟丙基醚（E804），已被证明可阻断人癌细胞中的Src-Stat3 和 Src-Stat5 信号通路，诱导细胞凋亡。然而，由于其较差的水溶性和低吸收率，E804 的抗癌作用在体内不易检测。本研究旨在开发和评价一种含有 E804 的自微乳给药系统（SNEDDS），以提高其溶解度和生物利用度。E804 在各种载体中的溶解度进行了测定，并使用伪三元相图评估了自乳化存在区域。由 Capmul MCM（油）、Solutol HS 15（表面活性剂）和聚乙二醇 400（助表面活性剂）组成的 SNEDDS，其比例为 20.5:62.5:16，负载 1.5%的 E804。发现液滴的粒径为 16.8 和 140nm，并且 SNEDDS 在冻融循环和在 0.1N HCl 和 pH7.4 HBSS++中稀释后均稳定。体内研究了口服给药后制剂吸收增强的能力。结果表明，与水混悬剂相比，所开发的 SNEDDS 使 E804 的生物利用度提高了 984.23%。我们的研究首次表明，所开发的 SNEDDS 可作为提高 E804 溶解度和口服生物利用度的一种可能制剂。
