Dai Wei-Guo, Dong Liang C, Li Shu, Deng Zhengyu
ALZA Corporation, 1900 Charleston Road, Mountain View, CA 94039, USA.
Int J Pharm. 2008 May 1;355(1-2):31-7. doi: 10.1016/j.ijpharm.2007.12.015. Epub 2007 Dec 23.
In this study, we screened surfactants and their combinations at low concentrations as potentially potent inhibitors of drug precipitation in an aqueous medium. Nine surfactants (including Pluronic F127, Pluronic F108, and Pluronic F68) were evaluated at concentrations below their critical micelle concentrations (CMCs) using an in vitro precipitation assay. A model compound used in this study showed a sharp pH-dependent solubility profile and was much more soluble in simulated gastric fluid (SGF) (pH 1.2) than in simulated intestinal fluid (SIF) (pH 7.4). The compound was first dissolved in SGF with each surfactant, and the solutions were dispensed into the wells of a 96-well microtiter plate by a TECAN robot and diluted 10-fold with SIF. After a preset incubation time at room temperature, the solutions were filtrated through a 96-well filter plate, and the compound concentration in the filtrate was measured using an HPLC method. At concentrations below their CMCs, Pluronic F127 and Pluronic F108, but not Pluronic F68, inhibited the compound precipitation in SIF. Combinations of Pluronic F127 or Pluronic F108 with Vitamin E TPGS showed significantly stronger inhibition than the individual surfactants, indicating synergistic effects on inhibition of drug precipitation.
在本研究中，我们筛选了低浓度的表面活性剂及其组合，作为水介质中药物沉淀的潜在有效抑制剂。使用体外沉淀试验，在低于其临界胶束浓度（CMC）的浓度下评估了九种表面活性剂（包括泊洛沙姆F127、泊洛沙姆F108和泊洛沙姆F68）。本研究中使用的模型化合物显示出明显的pH依赖性溶解度曲线，并且在模拟胃液（SGF）（pH 1.2）中的溶解度比在模拟肠液（SIF）（pH 7.4）中高得多。首先将该化合物与每种表面活性剂一起溶解在SGF中，然后通过TECAN机器人将溶液分配到96孔微量滴定板的孔中，并用SIF稀释10倍。在室温下经过预设的孵育时间后，将溶液通过96孔滤板过滤，并使用HPLC方法测量滤液中的化合物浓度。在低于其CMC的浓度下，泊洛沙姆F127和泊洛沙姆F108可抑制SIF中的化合物沉淀，但泊洛沙姆F68则不能。泊洛沙姆F127或泊洛沙姆F108与维生素E TPGS的组合显示出比单独的表面活性剂更强的抑制作用，表明对药物沉淀的抑制具有协同作用。
