Effinger Angela, O'Driscoll Caitriona M, McAllister Mark, Fotaki Nikoletta
Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
School of Pharmacy, University College Cork, Cork, Ireland.
Eur J Pharm Sci. 2020 Sep 1;152:105459. doi: 10.1016/j.ejps.2020.105459. Epub 2020 Jul 7.
In order to investigate differences in drug solubilisation and dissolution in luminal fluids of Crohn's disease (CD) patients and healthy subjects, biorelevant media representative of CD patients were developed using information from literature and a Design of Experiment (DoE) approach. The CD media were characterised in terms of surface tension, osmolality, dynamic viscosity and buffer capacity and compared to healthy biorelevant media. To identify which drug characteristics are likely to present a high risk of altered drug solubility in CD, the solubility of six drugs was assessed in CD media and solubility differences were related to drug properties. Identified differences in CD patients compared to healthy subjects were a reduced concentration of bile salts, a higher gastric pH and a higher colonic osmolality. Differences in the properties of CD compared to healthy biorelevant media were mainly observed for surface tension and osmolality. Drug solubility of ionisable compounds was altered in gastric CD media compared to healthy biorelevant media. For drugs with moderate to high lipophilicity, a high risk of altered drug solubilisation in CD is expected, since a significant negative effect of log P and a positive effect of bile salts on drug solubility in colonic and fasted state intestinal CD media was observed. Simulating the conditions in CD patients in vitro offers the possibility to identify relevant differences in drug solubilisation without conducting expensive clinical trials.
为了研究克罗恩病（CD）患者与健康受试者管腔液中药物溶解和溶出的差异，利用文献信息和实验设计（DoE）方法开发了代表CD患者的生物相关介质。对CD介质的表面张力、渗透压、动态粘度和缓冲容量进行了表征，并与健康生物相关介质进行了比较。为了确定哪些药物特性可能在CD中呈现药物溶解度改变的高风险，评估了六种药物在CD介质中的溶解度，并将溶解度差异与药物性质相关联。与健康受试者相比，CD患者中确定的差异是胆汁盐浓度降低、胃pH值升高和结肠渗透压升高。与健康生物相关介质相比，CD介质性质的差异主要体现在表面张力和渗透压方面。与健康生物相关介质相比，可电离化合物在胃CD介质中的药物溶解度发生了改变。对于中度至高亲脂性的药物，预计在CD中药物溶解改变的风险较高，因为观察到log P对结肠和禁食状态肠道CD介质中药物溶解度有显著负面影响，而胆汁盐有正面影响。在体外模拟CD患者的情况，为在不进行昂贵临床试验的情况下识别药物溶解的相关差异提供了可能性。
