Is the full potential of the biopharmaceutics classification system reached?
Is the full potential of the biopharmaceutics classification system reached?
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DOI：
10.1016/j.ejps.2013.09.010
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发表时间：
2014-06-16
影响因子：
4.6
通讯作者：
Lindahl, Anders
中科院分区：
文献类型：
--
作者：
Bergstrom, Christel A. S.;Andersson, Sara B. E.;Lindahl, Anders
在本文中，我们分析了如何生物药剂学分类系统（BCS）已被用于日期。一项调查的文献导致了242个BCS类化合物的汇编报告。其中，183种化合物已被报道属于一个特定的BCS类，而59种化合物已被分配到多个BCS类在不同的文件。有趣的是，大多数BCS 2类化合物的吸收分数（FA）值> 85%，表明它们在口服给药后完全吸收。通过计算预测BCS 2类化合物在pH 6.8下的溶解度，以探索小肠pH值对溶解度的影响，小肠是大部分吸收发生的地方。此外，天然存在于肠中的脂质聚集体的增溶能力进行了研究计算和实验的一个子集的12种化合物。发现FA > 85%的所有酸性化合物在小肠的pH中完全溶解。此外，在禁食状态模拟肠液（FaSSIF）中使用的浓度下的脂质溶解了所研究的最亲脂性（logD（6.5）>3）化合物的全部剂量。总体而言，生物相关的溶出介质（肠pH或FaSSIF的纯缓冲液）确定，对于FA > 85%的29种BCS 2类化合物中的20种，口服给予的完整剂量将溶解。这些结果表明，与目前使用的BCS溶解度标准相比，对酸和/或含脂质的溶出介质的更相关的pH限制更好地预测了体内溶解度限制吸收。本文中的分析进一步加强了关于为实现BCS的全部潜力而进行的体外溶解度分类所需的更具生理学相关性的溶出介质的讨论。(C)2013爱思唯尔有限公司版权所有。
In this paper we analyse how the biopharmaceutics classification system (BCS) has been used to date. A survey of the literature resulted in a compilation of 242 compounds for which BCS classes were reported. Of these, 183 compounds had been reported to belong to one specific BCS class whereas 59 compounds had been assigned to multiple BCS classes in different papers. Interestingly, a majority of the BCS class 2 compounds had fraction absorbed (FA) values >85%, indicating that they were completely absorbed after oral administration. Solubility was computationally predicted at pH 6.8 for BCS class 2 compounds to explore the impact of the pH of the small intestine, where most of the absorption occurs, on the solubility. In addition, the solubilization capacity of lipid aggregates naturally present in the intestine was studied computationally and experimentally for a subset of 12 compounds. It was found that all acidic compounds with FA > 85% were completely dissolved in the pH of the small intestine. Further, lipids at the concentration used in fasted state simulated intestinal fluid (FaSSIF) dissolved the complete dose given of the most lipophilic (logD(6.5) >3) compounds studied. Overall, biorelevant dissolution media (pure buffer of intestinal pH or FaSSIF) identified that for 20 of the 29 BCS class 2 compounds with FA > 85% the complete dose given orally would be dissolved. These results indicate that a more relevant pH restriction for acids and/or dissolution medium with lipids present better forecast solubility-limited absorption in vivo than the presently used BCS solubility criterion. The analysis presented herein further strengthens the discussion on the requirement of more physiologically relevant dissolution media for the in vitro solubility classification performed to reach the full potential of the BCS. (C) 2013 Elsevier B.V. All rights reserved.