Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
Pfizer Drug Product Design, Sandwich CT13 9NJ, U.K.
Mol Pharm. 2021 Apr 5;18(4):1530-1543. doi: 10.1021/acs.molpharmaceut.0c00807. Epub 2021 Mar 3.
The aim of the study was to investigate the impact of Crohn's disease (CD) on the performance of a lipid-based formulation of ciprofloxacin in a complex gastrointestinal simulator (TIM-1, TNO) and to compare the luminal environment in terms of bile salt and lipid composition in CD and healthy conditions. CD conditions were simulated in the TIM-1 system with a reduced concentration of porcine pancreatin and porcine bile. The bioaccessibility of ciprofloxacin was similar in simulated CD and healthy conditions considering its extent as well as its time course in the jejunum and ileum filtrate. Differences were observed in terms of the luminal concentration of triglycerides, monoglycerides, and fatty acids in the different TIM-1 compartments, indicating a reduction and delay in the lipolysis of formulation excipients in CD. The quantitative analysis of bile salts revealed higher concentrations for healthy conditions (standard TIM-1 fasted-state protocol) in the duodenum and jejunum TIM-1 compartments compared to published data in human intestinal fluids of healthy subjects. The reduced concentrations of bile salts in simulated CD conditions correspond to the levels observed in human intestinal fluids of healthy subjects in the fasted state.A lipidomics approach with ultra performance liquid chromatography (UPLC)/mass spectrometry (MS) has proven to be a time-efficient method to semiquantitatively analyze differences in fatty acid and bile salt levels between healthy and CD conditions. The dynamic luminal environment in CD and healthy conditions after administration of a lipid-based formulation can be simulated using the TIM-1 system. For ciprofloxacin, an altered luminal lipid composition had no impact on its performance indicating a low risk of altered performance in CD patients.
这项研究的目的是调查克罗恩病 (CD) 对环丙沙星脂质体制剂在复杂胃肠模拟器 (TIM-1，TNO) 中性能的影响，并比较 CD 和健康条件下胆汁盐和脂质组成方面的腔内环境。在 TIM-1 系统中，通过降低猪胰酶和猪胆盐的浓度来模拟 CD 条件。考虑到环丙沙星在空肠和回肠滤液中的程度和时间过程，其生物利用度在模拟 CD 和健康条件下相似。在不同 TIM-1 隔室中的甘油三酯、单甘酯和脂肪酸的腔内浓度方面观察到差异，表明制剂赋形剂的脂肪分解在 CD 中减少和延迟。胆汁盐的定量分析显示，与健康受试者的人肠液中的公布数据相比，十二指肠和空肠 TIM-1 隔室中的健康条件（标准 TIM-1 空腹状态方案）的胆汁盐浓度更高。模拟 CD 条件下胆汁盐浓度降低，与健康受试者空腹状态下人肠液中的观察水平相对应。超高效液相色谱 (UPLC)/质谱 (MS) 的脂质组学方法已被证明是一种高效的方法，可对半定量分析健康和 CD 条件下脂肪酸和胆汁盐水平的差异。给药后，CD 和健康条件下的动态腔内环境可以使用 TIM-1 系统进行模拟。对于环丙沙星，腔内脂质组成的改变对其性能没有影响，表明 CD 患者的性能改变风险较低。
