Fatouros Dimitrios G, Deen G Roshan, Arleth Lise, Bergenstahl Bjorn, Nielsen Flemming Seier, Pedersen Jan Skov, Mullertz Anette
Department of Pharmaceutics and Analytical Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100, Copenhagen, Denmark,
Pharm Res. 2007 Oct;24(10):1844-53. doi: 10.1007/s11095-007-9304-6. Epub 2007 Apr 26.
To investigate the structural development of the colloid phases generated during lipolysis of a lipid-based formulation in an in vitro lipolysis model, which simulates digestion in the small intestine.
Small-Angle X-Ray scattering (SAXS) coupled with the in vitro lipolysis model which accurately reproduces the solubilizing environment in the gastrointestinal tract and simulates gastrointestinal lipid digestion through the use of bile and pancreatic extracts. The combined method was used to follow the intermediate digestion products of a self nano emulsified drug delivery system (SNEDDS) under fasted conditions. SNEDDS is developed to facilitate the uptake of poorly soluble drugs.
The data revealed that a lamellar phase forms immediately after initiation of lipolysis, whereas a hexagonal phase is formed after 60 min. The change of the relative amounts of these phases clearly demonstrates that lipolysis is a dynamic process. The formation of these phases is driven by the lipase which continuously hydrolyzes triglycerides from the oil-cores of the nanoemulsion droplets into mono- and diglycerides and fatty acids. We propose that this change of the over-all composition of the intestinal fluid with increased fraction of hydrolyzed nanoemulsion induces a change in the composition and effective critical packing parameter of the amphiphilic molecules, which determines the phase behavior of the system. Control experiments (only the digestion medium) or the surfactant (Cremophor RH 40) revealed the formation of a lamellar phase demonstrating that the hexagonal phase is due to the hydrolysis of the SNEDDS formulation.
The current results demonstrate that SAXS measurements combined with the in vitro dynamic lipolysis model may be used to elucidate the processes encountered during the digestion of lipid-based formulations of poorly soluble drugs for oral drug delivery. Thus the combined methods may act as an efficient screening tool.
在体外脂解模型中研究基于脂质的制剂在脂解过程中产生的胶体相的结构发展，该模型模拟小肠中的消化过程。
小角X射线散射（SAXS）与体外脂解模型相结合，该模型能准确再现胃肠道中的增溶环境，并通过使用胆汁和胰腺提取物模拟胃肠道脂质消化。采用该联合方法追踪禁食条件下自纳米乳化药物递送系统（SNEDDS）的中间消化产物。SNEDDS的开发是为了促进难溶性药物的吸收。
数据显示，脂解开始后立即形成层状相，而60分钟后形成六方相。这些相相对含量的变化清楚地表明脂解是一个动态过程。这些相的形成是由脂肪酶驱动的，脂肪酶将纳米乳液滴油核中的甘油三酯持续水解为单甘油酯、二甘油酯和脂肪酸。我们认为，随着水解纳米乳液比例的增加，肠液总体组成的这种变化会导致两亲分子的组成和有效临界堆积参数发生变化，这决定了系统的相行为。对照实验（仅消化介质）或表面活性剂（聚氧乙烯蓖麻油RH 40）显示形成了层状相，表明六方相是由于SNEDDS制剂的水解所致。
目前的结果表明，SAXS测量与体外动态脂解模型相结合可用于阐明口服给药的难溶性药物脂质制剂消化过程中所遇到的过程。因此，联合方法可作为一种有效的筛选工具。
