Department of Pharmacy, Uppsala University, P.O. Box 580, SE-751 23, Uppsala, Sweden; Laboratory of Pharmaceutical Technology, Department of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124, Thessaloniki, Greece.
Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Universitätsstraße 1, DE-40225, Düsseldorf, Germany.
Eur J Pharm Sci. 2023 Oct 1;189:106524. doi: 10.1016/j.ejps.2023.106524. Epub 2023 Jul 9.
Solid lipid-based formulations (sLBFs) have the potential to increase the oral bioavailability of drugs with poor solubility in water, while counteracting some of the disadvantages of liquid LBFs. The most common experimental set-up to study the performance of LBFs in vitro is the lipolysis assay, during which the LBFs are digested by lipases in an environment mimicking the human small intestine. However, this assay has failed in many cases to correctly predict the performance of LBFs in vivo, highlighting the need for new and improved in vitro assays to evaluate LBFs at the preclinical stage. In this study, the suitability of three different in vitro digestion assays for the evaluation of sLBFs was assessed; the classic one-step intestinal digestion assay, a two-step gastrointestinal digestion assay and a bicompartmental assay permitting the simultaneous monitoring of digestion and permeation of the active pharmaceutical ingredient (API) across an artificial membrane (Lecithin in Dodecane - LiDo). Three sLBFs (M1-M3) with varied composition and ritonavir as model drug were prepared and examined. When comparing the ability of these formulations to keep the drug solubilized in the aqueous phase, all three assays show that M1 performs better, while M3 presents poor performance. However, the classic in vitro intestinal digestion assay fails to provide a clear ranking of the three formulations, something that is more evident when using the two modified and more physiologically relevant assays. Also, the two modified assays provide additional information about the performance of the formulations including the performance in the gastric environment and intestinal flux of the drug. These modified in vitro digestion assays are valuable tools for the development and evaluation of sLBFs to make better informed decisions of which formulations to pursue for in vivo studies.
固体脂质基制剂（sLBFs）有可能提高水中溶解度差的药物的口服生物利用度，同时克服液体 LBFs 的一些缺点。研究 LBFs 体外性能最常用的实验设置是脂肪酶水解测定，在此过程中，LBFs 在模拟人体小肠的环境中被脂肪酶消化。然而，这种测定方法在许多情况下未能正确预测 LBFs 在体内的性能，这突出表明需要新的和改进的体外测定方法来在临床前阶段评估 LBFs。在这项研究中，评估了三种不同的体外消化测定法用于评估 sLBFs 的适用性；经典的一步肠内消化测定法、两步胃肠消化测定法和允许同时监测活性药物成分（API）在人工膜（大豆卵磷脂在十二烷 - LiDo）上的消化和渗透的双室测定法。制备并检查了三种组成和利托那韦变化的 sLBF（M1-M3）作为模型药物。当比较这些制剂保持药物在水相中的溶解度的能力时，所有三种测定法都表明 M1 表现更好，而 M3 表现不佳。然而，经典的体外肠内消化测定法未能对三种制剂的能力进行明确排序，当使用两种更具修饰性和更具生理相关性的测定法时，这种情况更为明显。此外，这两种改良的测定法提供了有关制剂性能的其他信息，包括在胃环境中的性能和药物的肠通量。这些改良的体外消化测定法是开发和评估 sLBFs 的有价值的工具，可更明智地决定进行体内研究的制剂。
