Department of Pharmacy, Uppsala Biomedical Centre, P.O. Box 580, Uppsala University, Uppsala SE-751 23, Sweden.
Division of Nanotechnology and Functional Materials, Department of Engineering Sciences, Uppsala University, Uppsala SE-75121, Sweden.
Int J Pharm. 2024 Sep 30;663:124437. doi: 10.1016/j.ijpharm.2024.124437. Epub 2024 Aug 9.
A variety of enabling formulations has been developed to address poor oral drug absorption caused by insufficient dissolution in the gastrointestinal tract. As the in vivo performance of these formulations is a result of a complex interplay between dissolution, digestion and permeation, development of suitable in vitro assays that captures these phenomena are called for. The enabling-absorption (ENA) device, consisting of a donor and receiver chamber separated by a semipermeable membrane, has successfully been used to study the performance of lipid-based formulations. In this work, the ENA device was prepared with two different setups (a Caco-2 cell monolayer and an artificial lipid membrane) to study the performance of a lipid-based formulation (LBF), an amorphous solid dispersion (ASD) and the potential benefit of combining the two formulation strategies. An in vivo pharmacokinetic study in rats was performed to evaluate the in vitro-in vivo correlation. In the ENA, high drug concentrations in the donor chamber did not translate to a high mass transfer, which was particularly evident for the ASD as compared to the LBF. The solubility of the polymer used in the ASD was strongly affected by pH-shifts in vitro, and the ph_dependence resulted in poor in vivo performance of the formulation. The dissolution was however increased in vitro when the ASD was combined with a blank lipid-based formulation. This beneficial effect was also observed in vivo, where the drug exposure of the ASD increased significantly when the ASD was co-administered with the blank LBF. To conclude, the in vitro model managed to capture solubility limitations and strategies to overcome these for one of the formulations studied. The correlation between the in vivo exposure of the drug exposure and AUC in the ENA was good for the non pH-sensitive formulations. The deconvoluted pharmacokinetic data indicated that the receiver chamber was a better predictor for the in vivo performance of the drug, however both chambers provided valuable insights to the observed outcome in vivo. This shows that the advanced in vitro setting used herein successfully could explain absorption differences of highly complex formulations.
已经开发出了各种赋形剂配方，以解决由于在胃肠道中溶解不足而导致的口服药物吸收不良的问题。由于这些制剂的体内性能是溶解、消化和渗透之间复杂相互作用的结果，因此需要开发合适的能够捕捉这些现象的体外检测方法。赋形吸收（ENA）装置由一个供体室和一个受体室组成，两者之间由半透膜隔开，该装置已成功用于研究基于脂质的制剂的性能。在这项工作中，ENA 装置采用两种不同的设置（Caco-2 细胞单层和人工脂质膜）来研究基于脂质的制剂（LBF）、无定形固体分散体（ASD）和结合两种制剂策略的潜在益处。在大鼠体内进行了药代动力学研究，以评估体外-体内相关性。在 ENA 中，供体室内的高药物浓度并没有转化为高质量转移，这对于 ASD 来说尤为明显，与 LBF 相比，这一点更为明显。ASD 中所用聚合物的溶解度在体外受到 pH 变化的强烈影响，制剂的体内性能较差。然而，当 ASD 与空白基于脂质的制剂结合使用时，体外的溶解度增加。这种有益的效果在体内也观察到了，当 ASD 与空白 LBF 共同给药时，ASD 的药物暴露显著增加。总之，该体外模型成功地捕捉到了其中一种制剂的溶解度限制及其克服这些限制的策略。对于非 pH 敏感制剂，药物暴露的体内暴露与 ENA 中的 AUC 之间的相关性良好。去卷积药代动力学数据表明，受体室是预测药物体内性能的更好指标，但两个室都为体内观察到的结果提供了有价值的见解。这表明，本文中使用的先进体外设置能够成功解释高度复杂制剂的吸收差异。
