Drug Transport and Delivery Research Group, Department of Pharmacy, University of Tromsø The Arctic University of Norway, Universitetsveien 57, 9037 Tromsø, Norway.
Drug Transport and Delivery Research Group, Department of Pharmacy, University of Tromsø The Arctic University of Norway, Universitetsveien 57, 9037 Tromsø, Norway; Physiological Pharmaceutics, Department of Pharmacy, University of Copenhagen, Universitetsparken 2-4, 2100 Copenhagen, Denmark.
Eur J Pharm Sci. 2019 Apr 30;132:44-54. doi: 10.1016/j.ejps.2019.02.035. Epub 2019 Feb 27.
Intestinal drug absorption following oral administration can be influenced by regional conditions (absorbing surface area, bacterial flora, motility, pH, mucus thickness) and food intake, all of which affect drug solubility and permeability. Therefore, it is crucial to assess the impact of these conditions on the drugability of drugs and formulations. In this study, the ability of the liposome-based mucus-PVPA in vitro permeability model to handle relevant intestinal pH conditions was evaluated, together with the investigation on the pH-dependent solubility and permeability profiles of five model drugs. This study additionally evaluated the impact of all commercially available versions of the fasted and fed state simulated intestinal fluids (SIFs) on the integrity of the barriers, and the permeabilities of one hydrophilic and one lipophilic compound were examined under these conditions. The model was found to be well-functioning in all tested pH conditions, and a pH-dependent trend was found for both solubility and permeability profiles for acidic and basic compounds, according to their degree of ionization. Moreover, the mucus layer and its pH-dependent viscosity particularly influenced the permeation of more lipophilic compounds. The PVPA barriers primarily maintained their functionality in the presence of the fed state SIFs, and the permeability of the two tested compounds showed to be influenced by their hydrophilicity/lipophilicity, their degree of interaction with mucus and by the bile salts and phospholipids content in the SIFs. Overall, the obtained results highlight the relevance of studying the effect that pH, mucus and SIFs have on intestinal drug absorption, and suggest the suitability of the mucus-PVPA model for such investigations.
口服给药后肠道的药物吸收会受到局部条件（吸收表面积、细菌菌群、蠕动、pH 值、黏液厚度）和食物摄入的影响，这些因素都会影响药物的溶解度和渗透性。因此，评估这些条件对药物和制剂可吸收性的影响至关重要。在这项研究中，评估了基于脂质体的黏液-PVPA 体外渗透性模型处理相关肠道 pH 条件的能力，同时还研究了五种模型药物的 pH 依赖性溶解度和渗透性特征。本研究还评估了所有市售的空腹和进食状态模拟肠液（SIF）对屏障完整性的影响，并在这些条件下研究了一种亲水性化合物和一种亲脂性化合物的渗透性。结果表明，该模型在所有测试的 pH 条件下均能正常运行，并且根据化合物的电离程度，发现酸性和碱性化合物的溶解度和渗透性特征均呈现 pH 依赖性趋势。此外，黏液层及其 pH 依赖性黏度特别影响了更亲脂性化合物的渗透。在进食状态 SIF 的存在下，PVPA 屏障主要保持其功能，并且两种测试化合物的渗透性受其亲水性/亲脂性、与黏液的相互作用程度以及 SIF 中的胆汁盐和磷脂含量的影响。总体而言，研究结果强调了研究 pH 值、黏液和 SIF 对肠道药物吸收影响的相关性，并表明黏液-PVPA 模型适合此类研究。
