Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom.
Eur J Pharm Biopharm. 2020 May;150:14-23. doi: 10.1016/j.ejpb.2020.01.016. Epub 2020 Feb 7.
It is widely recognised that drug solubility within the gastrointestinal tract (GIT) differs from values determined in a simple aqueous buffer and to circumvent this problem measurement in biorelevant fluids is determined. Biorelevant fluids are complex mixtures of components (sodium taurocholate, lecithin, sodium phosphate, sodium chloride, pancreatin and sodium oleate) at various concentrations and pH levels to provide systems simulating fasted (FaSSIF) or fed (FeSSIF) intestinal media. Design of Experiment (DoE) studies have been applied to investigate FaSSIF and FeSSIF and indicate that a drug's equilibrium solubility varies over orders of magnitude, is influenced by the drug type and individual or combinations of media components, with some of these interactions being drug specific. Although providing great detail on the drug media interactions these studies are resource intensive requiring up to ninety individual experiments for FeSSIF. In this paper a low sample number or reduced DoE system has been investigated by restricting components with minimal solubility impact to a single value and only investigating variations in the concentrations of sodium taurocholate, lecithin, sodium oleate, pH and additionally in the case of fed media, monoglyceride. This reduces the experiments required to ten (FaSSIF) and nine (FeSSIF). Twelve poorly soluble drugs (Ibuprofen, Valsartan, Zafirlukast, Indomethacin, Fenofibrate, Felodipine, Probucol, Tadalafil, Carvedilol, Aprepitant, Bromocriptine and Itraconazole) were investigated and the results compared to published DoE studies and literature solubility values in human intestinal fluid (HIF), FaSSIF or FeSSIF. The solubility range determined by the reduced DoE is statistically equivalent to the larger scale published DoE results in over eighty five percent of the cases. The reduced DoE range also covers HIF, FaSSIF or FeSSIF literature solubility values. In addition the reduced DoE provides lowest measured solubility values that agree with the published DoE values in ninety percent of the cases. However, the reduced DoE only identified single and in some cases none of the major components influencing solubility in contrast to the larger published DoE studies which identified multiple individual components and component interactions. The identification of significant components within the reduced DoE was also dependent upon the drug and system under investigation. The study demonstrates that the lower experimental number reduces statistical power of the DoE to resolve the impact of media components on solubility. However, in a situation where only the solubility range is required the reduced DoE can provide the desired information, which will be of benefit during in vitro development studies. Further refinements are possible to extend the reduced DoE protocol to improve biorelevance and application into areas such as PBPK modelling.
人们普遍认识到，药物在胃肠道（GIT）中的溶解度与在简单的水性缓冲液中测定的值不同，为了解决这个问题，人们测定了生物相关流体中的溶解度。生物相关流体是各种成分（牛磺胆酸钠、卵磷脂、磷酸钠、氯化钠、胰酶和油酸钠）的复杂混合物，其浓度和 pH 值各不相同，可提供模拟空腹（FaSSIF）或进食（FeSSIF）肠道介质的系统。已应用实验设计（DoE）研究来研究 FaSSIF 和 FeSSIF，并表明药物的平衡溶解度在数量级上变化很大，受药物类型和单个或组合介质成分的影响，其中一些相互作用是药物特异性的。尽管这些研究详细说明了药物与介质的相互作用，但它们需要大量资源，FeSSIF 最多需要进行九十项单独的实验。在本文中，通过将对溶解度影响最小的成分限制为单个值，并仅研究牛磺胆酸钠、卵磷脂、油酸钠、pH 值的浓度变化，以及在进食介质的情况下，单甘油酯的浓度变化，研究了减少样本数量或减少 DoE 系统的方法。这将实验减少到十个（FaSSIF）和九个（FeSSIF）。研究了十二种难溶性药物（布洛芬、缬沙坦、扎鲁司特、吲哚美辛、非诺贝特、硝苯地平、普罗布考、他达拉非、卡维地洛、阿瑞匹坦、溴隐亭和伊曲康唑），并将结果与发表的 DoE 研究和人类肠液（HIF）、FaSSIF 或 FeSSIF 中的文献溶解度值进行了比较。减少的 DoE 确定的溶解度范围在超过 85%的情况下在统计学上等同于更大规模的已发表的 DoE 结果。减少的 DoE 范围还涵盖了 HIF、FaSSIF 或 FeSSIF 文献溶解度值。此外，减少的 DoE 提供了最低测量的溶解度值，这些值在 90%的情况下与发表的 DoE 值一致。然而，减少的 DoE 仅在一些情况下确定了单个或没有一个主要成分会影响溶解度，而较大的已发表的 DoE 研究则确定了多个单独的成分和成分相互作用。在减少的 DoE 中，重要成分的识别也取决于正在研究的药物和系统。该研究表明，实验数量的减少降低了 DoE 确定介质成分对溶解度影响的统计能力。然而，在仅需要溶解度范围的情况下，减少的 DoE 可以提供所需的信息，这将有助于体外开发研究。可以进一步改进减少的 DoE 方案，以提高生物相关性，并将其应用于 PBPK 建模等领域。
