Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, University of Greifswald, 17487 Greifswald, Germany.
Bayer AG, 51368 Leverkusen, Germany.
Eur J Pharm Biopharm. 2020 Jun;151:9-17. doi: 10.1016/j.ejpb.2020.03.013. Epub 2020 Apr 5.
The process of gastric emptying is of major importance for the in vivo performance of immediate release dosage forms. In the fed state, this process consists of two phases: the rapid emptying of water along the "Magenstrasse" and the continuous emptying of the chyme. The relevance of these phases for the pharmacokinetic (PK) profile of a drug depends on the release behavior from its dosage form. It was the aim of this study to investigate the role of gastric emptying for the pharmacokinetics of a fast disintegrating and dissolving Aspirin® tablet (FDDT). For this purpose, a three way pharmacokinetic study with 30 healthy volunteers was performed to investigate the performance of the FDDT under fasted and fed conditions and compare it to a regular Aspirin® tablet (RT) administered in the fed state. Plasma samples were taken at predetermined time points and analyzed by LC MS/MS. In the second part of this work, both products were tested in a biorelevant dissolution test device - the GastroDuo. To simulate the occurrence of the Magenstrasse at different time points, two test programs have been applied. The results of the PK study clearly demonstrated the superiority of the FDDT over the RT. We observed an earlier tmax (0.39 h vs. 2.00 h) and a higher Cmax (6.33 ± 2.37 μg/mL vs. 3.23 ± 1.28 μg/mL), whereas the AUC was only slightly different between both formulations. The administration of the FDDT together with food had no marked effect on tmax (0.34 h vs. 0.39 h), but caused a decrease in Cmax compared to fasted intake (14.76 ± 4.81 μg/mL vs. 6.33 ± 2.37 μg/mL). This effect could be explained by the in vitro data collected with the GastroDuo. The FDDT showed a faster drug release and improved emptying kinetics in the GastroDuo. In contrast, the RT showed incomplete emptying in both test programs. Thus, the early tmax observed for the FDDT under fed conditions could be related to the presence of the Magenstrasse. In contrast, drug release from the RT was insufficient to allow gastric emptying via the Magenstrasse, which resulted in later tmax. This study highlighted the importance of gastric emptying for immediate release dosage forms and illustrated that the application of suitable formulation techniques provides a strategy to generate a fast and reliable onset of drug plasma concentrations even in the fed state.
胃排空过程对口服固体制剂的体内性能至关重要。在进食状态下，该过程包括两个阶段：水沿着“Magenstrasse”的快速排空和食糜的连续排空。这些阶段对药物药代动力学（PK）特征的相关性取决于其剂型的释放行为。本研究旨在研究胃排空对快速崩解溶解阿司匹林®片（FDDT）药代动力学的作用。为此，进行了一项有 30 名健康志愿者参与的三向药代动力学研究，以研究空腹和进食条件下 FDDT 的性能，并将其与在进食状态下给予的常规阿司匹林®片（RT）进行比较。在预定时间点采集血浆样本，并通过 LC-MS/MS 进行分析。在这项工作的第二部分，将两种产品在生物相关溶解测试设备 - GastroDuo 中进行了测试。为了模拟不同时间点的 Magenstrasse 的发生，应用了两种测试方案。PK 研究的结果清楚地表明了 FDDT 优于 RT。我们观察到更早的 tmax（0.39 h 比 2.00 h）和更高的 Cmax（6.33±2.37 μg/mL 比 3.23±1.28 μg/mL），而两种制剂的 AUC 仅略有差异。与空腹摄入相比，FDDT 与食物一起给药对 tmax 没有明显影响（0.34 h 比 0.39 h），但 Cmax 降低（14.76±4.81 μg/mL 比 6.33±2.37 μg/mL）。这一作用可以用 GastroDuo 中收集的体外数据来解释。FDDT 在 GastroDuo 中显示出更快的药物释放和改善的排空动力学。相比之下，RT 在两种测试方案中均显示不完全排空。因此，在进食条件下观察到的 FDDT 早期 tmax 可能与 Magenstrasse 的存在有关。相比之下，RT 的药物释放不足以通过 Magenstrasse 进行胃排空，导致 tmax 较晚。这项研究强调了胃排空对口服固体制剂的重要性，并说明了应用合适的制剂技术可以提供一种策略，即使在进食状态下也能快速可靠地产生药物血浆浓度的起始。
