Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens , Zografou 15784, Greece.
Product Development, GlaxoSmithKline , Ware SG12 0DP, U.K.
Mol Pharm. 2017 Dec 4;14(12):4181-4191. doi: 10.1021/acs.molpharmaceut.6b01129. Epub 2017 Apr 13.
The purpose of this article was two-fold: first, to optimize a recently proposed two-stage single-compartment in vitro test for the evaluation of dissolution in the lower intestine with the mini-paddle apparatus in the fasted and fed state using two model high dose, low solubility drugs [sulfasalazine (Azulfidine) and micronized aprepitant] and one mesalamine colon targeting product (Asacol, 400 mg/tablet); second, to evaluate the impact of passive absorption from the lower intestine on the overall absorption process using three model high dose, low solubility drugs [micronized aprepitant, SB705498, and albendazole (Zentel)]. The intensity of agitation and the physicochemical characteristics of fluids simulating the environment in the distal ileum and the proximal colon were optimized and the importance of solid particles was evaluated. Dissolution data collected under conditions simulating the upper and lower intestine were coupled with physiologically based oral absorption modeling to simulate the average plasma levels or the average absorption process. Reliability of the modeling approach was evaluated based on previously collected data in adults. The impact of solid particles on dissolution in the lower intestine was found to be clinically insignificant for Asacol tablets, as well as for sulfasalazine (Azulfidine) and micronized aprepitant. Average plasma levels (micronized aprepitant and SB705498) and cumulative amount absorbed (albendazole) could be adequately simulated by referring only to events in the upper gastrointestinal lumen, indicating that the impact of absorption from the lower intestine on actual plasma levels was minimal. Dissolution of Asacol tablets and immediate release formulations in the lower intestine can be adequately evaluated by employing Level II biorelevant media. However, simulation of actual drug particle dissolution in the lower intestine is not typically necessary for adequate prediction of oral absorption from immediate release formulations containing discrete, dispersed particles of lipophilic drugs.
首先，使用两种模型高剂量、低溶解度药物[柳氮磺胺吡啶（Azulfidine）和微粒化阿瑞匹坦]和一种美沙拉嗪结肠靶向产品（Asacol，400mg/片），优化最近提出的用于评估空腹和进食状态下在小肠下部溶解的两阶段单室体外测试；其次，使用三种模型高剂量、低溶解度药物[微粒化阿瑞匹坦、SB705498 和阿苯达唑（Zentel）]评估从小肠下部被动吸收对整体吸收过程的影响。优化了搅拌强度和模拟回肠末端和近端结肠环境的流体物理化学特性，并评估了固体颗粒的重要性。模拟上、下肠道条件下收集的溶解数据与基于生理学的口服吸收模型相结合，以模拟平均血浆水平或平均吸收过程。该建模方法的可靠性是基于成人先前收集的数据进行评估的。研究发现，对于 Asacol 片剂以及柳氮磺胺吡啶（Azulfidine）和微粒化阿瑞匹坦，固体颗粒对小肠下部的溶解影响在临床上可以忽略不计。仅参考上胃肠道腔中的事件，即可充分模拟平均血浆水平（微粒化阿瑞匹坦和 SB705498）和累积吸收量（阿苯达唑），这表明小肠吸收对实际血浆水平的影响很小。可以通过使用二级生物相关介质充分评估 Asacol 片剂和即释制剂在小肠下部的溶解情况。然而，对于包含离散、分散的亲脂性药物颗粒的即释制剂，模拟实际药物颗粒在小肠下部的溶解通常不是充分预测口服吸收所必需的。
