通过体外自乳化性能评价和体内药代动力学研究对葛根素自乳化制剂进行处方优化

Formulation optimization of self-emulsifying preparations of puerarin through self-emulsifying performances evaluation in vitro and pharmacokinetic studies in vivo.

作者信息

Quan Dong-Qin, Xu Gui-Xia

机构信息

Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.

出版信息

Yao Xue Xue Bao. 2007 Aug;42(8):886-91.

DOI:
Abstract

The main purpose of this work is to prepare self-emulsifying drug delivery system (SEDDS) of a poorly water soluble drug, puerarin. Solubility of puerarin was determined in various oils and surfactants. Oleic acid and Tween 80 provided higher solubility. Addition of propylene glycol as cosurfactant improved solubility of puerarin and the spontaneity of self-emulsification. A series of mixtures comprising oleic acid, propylene glycol and Tween 80 were prepared and their self-emulsifying properties were studied. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region and particle sizes of the resultant emulsions were determined using a laser diffraction sizer. The pharmacokinetic behaviors of three different SEDDS formulations (F2, F3, F4) were investigated in Beagle dogs. The bioavailability was compared using the pharmacokinetic parameters, peak plasma concentration (C(max)), time to reach peak plasma concentration (T(max)) and total area under the plasma concentration-time curve (AUC(0-t)). AUC(0-t) was significantly higher in formulation F2 group (5.201 +/- 0.511) ng x mL(-1) x h and formulation F3 group (5.174 +/- 0.498) ng x mL (-1) x h than that in formulation F4 group (3.013 +/- 0.623) ng x mL(-1) x h. Also, C(max) was significantly higher in formulation F2 group (1.524 +/- 0.125) ng x mL(-1) and formulation F3 group (1.513 +/- 0.157) ng x mL(-1) than that in formulation F4 group (0.939 +/- 0.089) ng x mL(-1). Further analysis of the data showed a statistically significant difference between F2 and F4 (P < 0.01) as well as F3 and F4 (P < 0.01) with regard to the values of AUC(0-infinity) and C(max) for three SEDDS formulations, but not between those of F2 and F3 (P > 0.05). From these studies, the SEDDS formulation containing oleic acid (17.5%), Tween 80 (34.5%) and propylene glycol (34.5%) (w/w) was selected as an optimized SEDDS formulation of puerarin. The data suggest the potential use of SEDDS to improve oral absorption of puerarin.

摘要

本研究的主要目的是制备难溶性药物葛根素的自乳化给药系统(SEDDS)。测定了葛根素在各种油和表面活性剂中的溶解度。油酸和吐温80能提供更高的溶解度。添加丙二醇作为助表面活性剂可提高葛根素的溶解度和自乳化的自发性。制备了一系列包含油酸、丙二醇和吐温80的混合物,并研究了它们的自乳化性能。构建了伪三元相图以确定有效的自乳化区域,并使用激光衍射粒度仪测定所得乳液的粒径。在比格犬中研究了三种不同SEDDS制剂(F2、F3、F4)的药代动力学行为。使用药代动力学参数,即血浆峰浓度(C(max))、达峰时间(T(max))和血浆浓度-时间曲线下的总面积(AUC(0-t))比较生物利用度。F2组(5.201±0.511)ng·mL(-1)·h和F3组(5.174±0.498)ng·mL (-1)·h的AUC(0-t)显著高于F4组(3.013±0.623)ng·mL(-1)·h。此外,F2组(1.524±0.125)ng·mL(-1)和F3组(1.513±0.157)ng·mL(-1)的C(max)显著高于F4组(0.939±0.089)ng·mL(-1)。对数据的进一步分析表明,三种SEDDS制剂在AUC(0-∞)和C(max)值方面,F2与F4之间(P<0.01)以及F3与F4之间(P<0.01)存在统计学显著差异,但F2与F3之间无差异(P>0.05)。从这些研究中,选择含有油酸(17.5%)、吐温80(34.5%)和丙二醇(34.5%)(w/w)的SEDDS制剂作为葛根素的优化SEDDS制剂。数据表明SEDDS在改善葛根素口服吸收方面具有潜在应用价值。

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