Department of Pharmacy, Uppsala Biomedical Center, P.O. Box 580, Uppsala University, Uppsala SE-751 23, Sweden.
Division of Nanotechnology and Functional Materials, Department of Materials Science and Engineering, Uppsala University, Uppsala SE-75121, Sweden.
Eur J Pharm Biopharm. 2020 Apr;149:21-29. doi: 10.1016/j.ejpb.2020.01.010. Epub 2020 Jan 23.
Advanced drug delivery systems (ADDS) are widely explored to overcome poor aqueous solubility of orally administered drugs. However, the prediction of their in vivo performance is challenging, as in vitro models typically do not capture the interplay between processes occurring in the gut. In additions, different models are used to evaluate the different systems. We therefore present a method that allows monitoring of luminal processing (dissolution, digestion) and its interplay with permeation to better inform on the absorption of felodipine formulated as ADDS. Experiments were performed in a µFLUX-apparatus, consisting of two chambers, representing the intestinal and serosal compartment, separated by Caco-2 monolayers. During dissolution-digestion-permeation experiments, ADDS were added to the donor compartment containing simulated intestinal fluid and immobilized lipase. Dissolution and permeation in both compartments were monitored using in situ UV-probes or, when turbidity interfered the measurements, with HPLC analysis. The method showed that all ADDS increased donor and receiver concentrations compared to the condition using crystalline felodipine. A poor correlation between the compartments indicated the need for an serosal compartment to evaluate drug absorption from ADDS. The method enables medium-throughput assessment of: (i) dynamic processes occurring in the small intestine, and (ii) drug concentrations in real-time.
高级药物传递系统（ADDS）被广泛探索用于克服口服药物的低水溶性。然而，预测其体内性能具有挑战性，因为体外模型通常无法捕捉肠道中发生的各种过程之间的相互作用。此外，不同的模型用于评估不同的系统。因此，我们提出了一种方法，可以监测腔室处理（溶解、消化）及其与渗透的相互作用，以更好地了解作为 ADDS 配制的非洛地平的吸收情况。实验在 µFLUX 仪器中进行，该仪器由两个腔室组成，代表肠和浆膜腔室，由 Caco-2 单层隔开。在溶解-消化-渗透实验中，将 ADDS 添加到含有模拟肠液和固定化脂肪酶的供体腔室中。使用原位 UV 探针监测两个腔室中的溶解和渗透，或者当浊度干扰测量时，使用 HPLC 分析。该方法表明，与使用结晶非洛地平的条件相比，所有 ADDS 都增加了供体和受体浓度。腔室之间的相关性较差表明需要浆膜腔室来评估 ADDS 中药物的吸收情况。该方法能够进行高通量评估：（i）小肠中发生的动态过程，以及（ii）实时药物浓度。
