O'Dwyer Patrick J, Box Karl J, Koehl Niklas J, Bennett-Lenane Harriet, Reppas Christos, Holm Rene, Kuentz Martin, Griffin Brendan T
Pion Inc. (UK) Ltd., Forest Row RH18 5DW, East Sussex, U.K.
Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Zografou 157 72, Greece.
Mol Pharm. 2020 Sep 8;17(9):3342-3352. doi: 10.1021/acs.molpharmaceut.0c00427. Epub 2020 Aug 21.
The absence of an intestinal absorption sink is a significant weakness of standard lipolysis methods, potentially leading to poor prediction of performance and an overestimation of drug precipitation. In addition, the majority of the described lipolysis methods only attempt to simulate intestinal conditions, thus overlooking any supersaturation or precipitation of ionizable drugs as they transition from the acidic gastric environment to the more neutral conditions of the intestine. The aim of this study was to develop a novel lipolysis method incorporating a two-stage gastric-to-intestinal transition and an absorptive compartment to reliably predict performance of lipid-based formulations (LBFs). Drug absorption was mimicked by quantification of drug partitioning into a decanol layer. The method was used to characterize LBFs from four studies described in the literature, involving three model drugs (i.e., nilotinib, fenofibrate, and danazol) where bioavailability data have previously been reported. The results from the novel biphasic lipolysis method were compared to those of the standard pH-stat method in terms of reliability for predicting the performance. For three of the studies, the novel biphasic lipolysis method more reliably predicted the bioavailability compared to the standard pH-stat method. In contrast, the standard pH-stat method was found to produce more predictive results for one study involving a series of LBFs composed of the soybean oil, glyceryl monolinoleate (Maisine CC), Kolliphor EL, and ethanol. This result was surprising and could reflect that increasing concentrations of ethanol (as a cosolvent) in the formulations may have resulted in greater partitioning of the drug into the decanol absorptive compartment. In addition to the improved predictivity for most of the investigated systems, this biphasic lipolysis method also uses analysis and avoids time- and resource-intensive sample analysis steps, thereby facilitating a higher throughput capacity and biorelevant approach for characterization of LBFs.
缺乏肠道吸收池是标准脂解方法的一个显著弱点，这可能导致对制剂性能的预测不佳以及对药物沉淀的高估。此外，大多数已描述的脂解方法仅试图模拟肠道条件，因此忽略了可电离药物从酸性胃环境转变为肠道更中性条件时的任何过饱和或沉淀情况。本研究的目的是开发一种新型脂解方法，该方法结合两阶段胃到肠道的转变以及一个吸收室，以可靠地预测脂质体制剂（LBFs）的性能。通过定量药物分配到癸醇层中来模拟药物吸收。该方法用于表征文献中描述的四项研究中的脂质体制剂，涉及三种模型药物（即尼洛替尼、非诺贝特和达那唑），此前已报道了它们的生物利用度数据。将新型双相脂解方法的结果与标准pH计法在预测制剂性能的可靠性方面进行了比较。对于其中三项研究，与标准pH计法相比，新型双相脂解方法能更可靠地预测生物利用度。相比之下，发现标准pH计法在一项涉及由大豆油、单亚油酸甘油酯（Maisine CC）、聚氧乙烯蓖麻油EL和乙醇组成的一系列脂质体制剂的研究中产生了更具预测性的结果。这一结果令人惊讶，可能反映出制剂中乙醇（作为助溶剂）浓度的增加可能导致药物在癸醇吸收室中的分配增加。除了对大多数研究系统具有更高的预测性外，这种双相脂解方法还采用了 分析，避免了耗时和资源密集的样品分析步骤，从而促进了更高的通量能力以及用于脂质体制剂表征的生物相关性方法。 （原文中“ analysis”部分缺失具体内容，请补充完整后再进行准确翻译）
