García Mauricio A, Aceituno Alexis, Díaz Nicole B, Tapia Eduardo M, Contreras Danae, López-Lagos Constanza, Sánchez Virginia, González Pablo M
Departamento de Farmacia, Escuela de Química y Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile.
National Drug Agency Department, Instituto de Salud Pública de Chile (ISP), Santiago 7780050, Chile.
Pharmaceutics. 2025 Aug 26;17(9):1110. doi: 10.3390/pharmaceutics17091110.
The static in vitro permeability assay based on cell monolayers has been widely used in the pharmaceutical industry and recognized by regulatory agencies as a surrogate method for BCS classification. However, the application of such an experiment to study the effects of formulations is limited by the oversensitivity to the excipient effect on drug permeability. In this article, we studied the effects of common excipients on the permeability of moderately and poorly absorbed model compounds across cell monolayers, using two approaches to control said oversensitivity. Drug permeability across MDCK-wt was assessed in the absence (control) or presence (treatment) of excipients, using minoxidil as a high-permeability marker. The effects of excipients were parameterized as a permeability ratio (PR = treatment/control) without or with normalization (nPR) by minoxidil permeability. Metrics were compared by either ANOVA ( < 0.01) or confidence intervals (CI90, as per bioequivalence metrics) to identify excipient effects. Acyclovir and hydrochlorothiazide showed the highest and lowest number of interactions, respectively. The most impactful excipients were sodium lauryl sulfate, microcrystalline cellulose, and sodium starch glycolate. Unexpectedly, nPR increased the number of excipient effects across model drugs (19 vs. 21). Alternatively, the CI90 approach was more sensitive than ANOVA in identifying excipient effects (41 vs. 32). Minoxidil was not able to control the anticipated oversensitivity of cell-based permeability experiments. Meanwhile, ANOVA was overall able to reduce oversensitivity to excipient effects on drug permeability compared to CI90. Nonetheless, there might be a niche for CI90 analysis when comparing the performance of two formulations on the permeability of moderately and poorly absorbed drugs.
基于细胞单层的静态体外通透性测定法已在制药行业中广泛应用，并被监管机构认可为生物药剂学分类系统（BCS）分类的替代方法。然而，将此类实验用于研究制剂的效果时，会受到对辅料对药物通透性影响过度敏感的限制。在本文中，我们研究了常见辅料对中度和低吸收模型化合物跨细胞单层通透性的影响，采用了两种方法来控制上述过度敏感性。在不存在（对照）或存在（处理）辅料的情况下，使用米诺地尔作为高通透性标志物，评估药物跨MDCK-wt细胞的通透性。将辅料的影响参数化为通透性比（PR = 处理/对照），不进行或通过米诺地尔通透性进行归一化（nPR）。通过方差分析（<0.01）或置信区间（CI90，按照生物等效性指标）比较各项指标，以确定辅料的影响。阿昔洛韦和氢氯噻嗪分别显示出最多和最少的相互作用数量。最具影响力的辅料是十二烷基硫酸钠、微晶纤维素和淀粉乙醇酸钠。出乎意料的是，nPR增加了模型药物中辅料影响的数量（19对21）。另外，CI90方法在识别辅料影响方面比方差分析更敏感（41对32）。米诺地尔无法控制基于细胞的通透性实验中预期的过度敏感性。同时，与CI90相比，方差分析总体上能够降低对辅料对药物通透性影响的过度敏感性。尽管如此，在比较两种制剂对中度和低吸收药物通透性的性能时，CI90分析可能有其用武之地。
