Purpose

Gastrointestinal hydrodynamics are poorly replicated in vitro and can significantly alter the release kinetics of drug products due to compressive forces in the stomach and peristaltic movement in the intestines. In this work, we describe the development and application of a predictive in vitro dissolution device that simulates gastrointestinal forces for the testing of oral drug products. The peristaltic dissolution device developed herein is designed as an addition to the common USP Apparatus 2 that applies repetitive compressive forces via a piston during dissolution testing of a product to replicate in vivo conditions.

Methods

A dissolution testing device was designed, fabricated, and evaluated against human in vivo pharmacokinetic data to better mimic the physical forces present in the gastrointestinal tract. An optimized compression protocol to predict in vivo dissolution was developed using clinical data from two modified release carvedilol drug products. The apparatus was further evaluated using data from an additional modified release drug product. Finally, additional dissolution studies were performed to evaluate the utility of the apparatus for in vitro analysis of medicated gums, gastric retentive formulations, and long-acting injectable drug depots.

Results

The device was successfully implemented and the protocol to use the device was optimized using two initial drug products and further evaluated using an additional three drug products. The optimized protocol included a 1-h lag time (applicable in the fed state), followed by a cycle of 3 s of compression with 6 s intervals between compressions. Additional applications of the peristaltic dissolution device were also demonstrated through small exploratory studies, with continued potential for further optimization of the testing protocols following further research.

Conclusion

This simple compressive device referred to as the “peristaltic dissolution device” was successfully proven to better predict in vivo performance of modified release drug products, as gastrointestinal mechanical forces have been observed to significantly impact and occasionally cause complete dose dumping of controlled release formulations. In addition, it has proven to be easily adapted for evaluation of other drug products such as medicated gums, gastric retentive formulations, and ex vivo long-acting injectable drug depots.

中文翻译：

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开发与临床相关的溶出方法，以模拟具有USP 2仪器的生理力：“蠕动溶出”

目的

胃肠道流体动力学在体外难以复制，并且由于胃中的压缩力和肠道中的蠕动，会大大改变药物产品的释放动力学。在这项工作中，我们描述了一种预测性体外溶出度装置的开发和应用，该装置可模拟胃肠道力以测试口服药物产品。本文开发的蠕动溶出装置被设计为对普通USP装置2的补充，该装置在产品的溶出度测试过程中通过活塞施加重复的压缩力以复制体内条件。

方法

设计，制造和测试溶出度测试设备，以针对人体体内的药代动力学数据，以更好地模拟胃肠道中存在的物理力。利用来自两种调释卡维地洛药物产品的临床数据，开发了预测体内溶解的优化压缩方案。使用来自另外的调释药物产品的数据进一步评估该设备。最后，还进行了其他溶出度研究，以评估该仪器在体外分析含药口香糖，胃滞留制剂和长效可注射药物贮存库的实用性。

结果

该设备已成功实施，并且使用两种初始药品优化了使用该设备的协议，并使用了另外三种药品进一步进行了评估。优化的方案包括1小时的滞后时间（适用于进给状态），然后是3 s压缩周期，两次压缩之间间隔6 s。蠕动溶出度仪的其他应用还通过小型探索性研究得到了证明，在进一步研究之后，仍有继续优化测试方案的潜力。

结论

该简单的压缩装置被称为“蠕动溶出装置”，已被成功证明可以更好地预测调释药物产品的体内性能，因为已观察到胃肠道机械力会明显影响控释制剂，并有时导致其完全倾泻。此外，它已被证明很容易用于评估其他药物产品，例如药用牙龈，胃固位制剂和离体长效可注射药物仓库。