Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology , University of Greifswald , Felix-Hausdorff-Straße 3 , 17489 Greifswald , Germany.
Mol Pharm. 2019 Sep 3;16(9):3938-3947. doi: 10.1021/acs.molpharmaceut.9b00534. Epub 2019 Aug 7.
The characterization of intestinal dissolution of poorly soluble drugs represents a key task during the development of both new drug candidates and drug products. The bicarbonate buffer is considered as the most biorelevant buffer for simulating intestinal conditions. However, because of its complex nature, being the volatility of CO, it has only been rarely used in the past. The aim of this study was to investigate the effect of a biorelevant bicarbonate buffer on intestinal supersaturation and precipitation of poorly soluble drugs using a gastrointestinal (GI) transfer model. Therefore, the results of ketoconazole, pazopanib, and lapatinib transfer model experiments using FaSSIF were compared with the results obtained using standard FaSSIF. Additionally, the effect of hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor was investigated in both buffer systems and compared to rat pharmacokinetic (PK) studies with and without coadministration of HPMCAS as a precipitation inhibitor. While HPMCAS was found to be an effective precipitation inhibitor for all drugs in FaSSIF, the effect in FaSSIF was much less pronounced. The PK studies revealed that HPMCAS did not increase the exposure of any of the model compounds significantly, indicating that the transfer model employing bicarbonate-buffered FaSSIF has a better predictive power compared to the model using phosphate-buffered FaSSIF. Hence, the application of a bicarbonate buffer in a transfer model set-up represents a promising approach to increase the predictive power of this in vitrotool and to contribute to the development of drug substances and drug products in a more biorelevant way.
对难溶性药物在肠道中的溶解特性进行描述是候选新药和药物制剂研发过程中的一项关键任务。碳酸氢盐缓冲液被认为是模拟肠道条件最相关的缓冲液。然而，由于其复杂的性质，包括 CO 的挥发性，过去很少使用。本研究旨在使用胃肠道（GI）传递模型，研究生物相关碳酸氢盐缓冲液对难溶性药物肠道超饱和和沉淀的影响。因此，使用 FaSSIF 的酮康唑、帕唑帕尼和拉帕替尼传递模型实验的结果与使用标准 FaSSIF 获得的结果进行了比较。此外，还研究了羟丙甲纤维素醋酸琥珀酸酯（HPMCAS）作为沉淀抑制剂在两种缓冲液系统中的作用，并与作为沉淀抑制剂的 HPMCAS 联合给药的大鼠药代动力学（PK）研究进行了比较。虽然 HPMCAS 被发现是 FaSSIF 中所有药物的有效沉淀抑制剂，但在 FaSSIF 中的效果要小得多。PK 研究表明，HPMCAS 并没有显著增加任何模型化合物的暴露量，这表明使用碳酸氢盐缓冲的 FaSSIF 的传递模型与使用磷酸盐缓冲的 FaSSIF 的模型相比，具有更好的预测能力。因此，在传递模型设置中应用碳酸氢盐缓冲液是一种很有前途的方法，可以提高该体外工具的预测能力，并以更相关的方式促进药物物质和药物制剂的开发。
