Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
Mol Pharm. 2010 Oct 4;7(5):1498-507. doi: 10.1021/mp100144v. Epub 2010 Sep 1.
The purpose of this work is to evaluate the roles of lecithin and bile salts in a new generation of fasted simulated small intestinal fluid (FaSSIF-II), thus enhancing the closer mimic of simulated fluids to the real human intestinal fluids (HIF) in drug discovery and drug product development. To assess the effects of lecithin in FaSSIF-II, solubility studies were conducted at 37 °C using four media including first generation simulated intestinal fluid (FaSSIF-I), FaSSIF-II, phosphate pH 6.5 buffer, and HIF. A total of 24 model compounds representing a wide range of biopharmaceutic properties were included. The drug solubility values measured in the FaSSIF-II were compared with those in FaSSIF-I, pH 6.5 buffer and HIF. To assess the effects of bile acids, solubility was measured for 4 compounds in the FaSSIF-I containing five different bile acids of various concentrations. The lecithin concentration in the FaSSIF-II is lowered from 0.75 mM to 0.2 mM. The results suggested that the FaSSIF-II is a better medium to reflect HIF, compared with pH 6.5 phosphate buffer and FaSSIF-I. Solubility of neutral compounds including atovaquone, carbamazepine, cyclosporine, danazol, diethylstilbestrol, felodipine, griseofulvin and probucol in FaSSIF-II showed improvement in predicting the in vivo solubility. The relative standard deviation (SD) of solubility measurement in FaSSIF-II is comparable with FaSSIF-I. For the acidic and basic tested compounds, the FaSSIF-II performs similarly to the FaSSIF-I. Experimental results showed that the level of bile salts typically is less than 5 mM under fasted state. Among the five studied bile acids, the conjugation (glycine or taurine) has no impact on the drug solubilization, while there may be a minimal effect of the degree of hydroxylation of the steroid ring system on solubilization. The lecithin concentration of 0.2 mM in FaSSIF-II has been demonstrated to closely represent HIF, for both neutral and ionizable compounds. In the composition of simulated intestinal fluids, the structure of bile acids has minimal effect, providing the flexibility of choosing one bile salt to represent complex in vivo bile acids.
本工作旨在评估磷脂和胆汁盐在新一代空腹模拟肠液（FaSSIF-II）中的作用，从而更接近地模拟药物发现和药物产品开发过程中的真实人体肠液（HIF）。为了评估磷脂在 FaSSIF-II 中的作用，在 37°C 下进行了溶解度研究，使用了包括第一代模拟肠液（FaSSIF-I）、FaSSIF-II、磷酸盐 pH6.5 缓冲液和 HIF 在内的四种介质。共包括 24 种代表广泛生物制药特性的模型化合物。在 FaSSIF-II 中测量的药物溶解度值与 FaSSIF-I、pH6.5 缓冲液和 HIF 中的值进行了比较。为了评估胆汁酸的作用，在含有五种不同浓度的各种胆汁酸的 FaSSIF-I 中测量了 4 种化合物的溶解度。将 FaSSIF-II 中的磷脂浓度从 0.75mM 降低至 0.2mM。结果表明，与 pH6.5 磷酸盐缓冲液和 FaSSIF-I 相比，FaSSIF-II 是一种更好的反映 HIF 的介质。包括阿托伐醌、卡马西平、环孢素、炔雌醇、己烯雌酚、非洛地平、灰黄霉素和普罗布考在内的中性化合物在 FaSSIF-II 中的溶解度提高，这有助于预测体内溶解度。FaSSIF-II 中溶解度测量的相对标准偏差（SD）与 FaSSIF-I 相当。对于酸性和碱性测试化合物，FaSSIF-II 的性能与 FaSSIF-I 相似。实验结果表明，空腹状态下胆汁盐的水平通常低于 5mM。在研究的五种胆汁酸中，结合（甘氨酸或牛磺酸）对药物增溶没有影响，而甾体环系统的羟化程度对增溶可能有最小的影响。已证明 FaSSIF-II 中的 0.2mM 磷脂浓度可紧密代表中性和可离子化化合物的 HIF。在模拟肠液的组成中，胆汁酸的结构几乎没有影响，这为选择一种胆汁盐来代表复杂的体内胆汁酸提供了灵活性。
