a Department of Anaesthesia and Intensive Care , The Danish Poisons Information Centre, Copenhagen University Hospital Bispebjerg , Copenhagen , Denmark.
b Department of Pharmacy, Faculty of Health and Medical Sciences , University of Copenhagen , Denmark.
Clin Toxicol (Phila). 2019 Apr;57(4):271-281. doi: 10.1080/15563650.2018.1513138. Epub 2018 Oct 11.
Extended release (ER) tablets/capsules in massive ingestion overdoses are prone to form pharmacobezoars potentially increasing the risk of late-appearing toxic effects and prolonged symptoms. Oral activated charcoal is often sufficient to prevent drug absorption, but in a recent massive ingestion of highly toxic substances, prior orogastric lavage might be considered. The disintegration characteristics of ER preparations in overdose situations is valuable to understand if the time line and course of the intoxication might be prolonged, but information on these characteristics are unavailable. Slow disintegration and/or pharmacobezoar formation, and the large size makes ER preparation impossible to evacuate using a 30F orogastric lavage tube. This study evaluates the disintegration and pharmacobezoar formation of a simulated massive ER tablet ingestion in an in vitro model, using a selection of extended release tablets, with different disintegrating characteristics when present in therapeutic numbers. Furthermore, the sizes of the formed pharmacobezoars were compared with the dimensions of a 30F orogastric lavage tube.
A standardized model mimicking the physical effects on pharmaceutical preparations in simulated gastric fluid (SGF) was developed and tested on three mono-depot ER tablets (quetiapine/SeroquelXR 50 mg, paracetamol/PinexRetard 500 mg, verapamil/IsoptinRetard 240 mg), one poly-depot ER tablet (carbamazepine/TegretolRetard 200 mg), and one immediate-release tablet (paracetamol/Panodil 500mg). Thirty tablets were placed in polyamide mesh bags, either together in one bag or in separate bags, immersed in 1 L SGF, and incubated at 37 °C for 48 h. Released drugs were quantified at 0.5-48 h.
Visual inspection showed that SeroquelXR, PinexRetard, and IsoptinRetard tablets formed firm pharmacobezoars stable for more than 4 h and intact fractions remained for up to 24 h. Drug releases were reduced by 53%, 40%, and 31%, respectively, for up to 8 h compared to separated tablets. Light microscopy showed that contact with SGF transformed the coating of SeroquelXR and PinexRetard to a diffusion-controlled swelled gel-layer, and the IsoptinRetard tablets into a rigid and slow-releasing matrix. TegretolRetard disintegrated into microspheres within 30 min, and Panodil disintegrated within minutes.
The developed pharmacobezoars of mono-depot ER tablets demonstrated prolonged drug release. Neither the formed pharmacobezoars, nor the single tablets of the tested mono-depot ER preparations, would pass through the lumen of a standard orogastric lavage tube, rendering this modality ineffective for tablet removal in gastrointestinal decontamination.
在大剂量摄入延长释放（ER）片剂/胶囊的情况下，药物容易形成生物凝聚物，从而增加迟发性毒性作用和延长症状出现的风险。口服活性炭通常足以防止药物吸收，但在最近摄入大量高毒性物质的情况下，可能需要考虑进行洗胃。了解 ER 制剂在过量情况下的崩解特性有助于理解中毒的时间线和过程是否会延长，但目前尚不清楚这些特性的信息。缓慢崩解和/或生物凝聚物形成，以及较大的尺寸使得使用 30F 经口洗胃管无法排出 ER 制剂。本研究使用不同崩解特性的延长释放片剂在体外模型中评估模拟大剂量 ER 片剂摄入的崩解和生物凝聚物形成情况，这些片剂在治疗剂量下存在时。此外，还比较了形成的生物凝聚物的大小与 30F 经口洗胃管的尺寸。
开发了一种标准化模型，模拟模拟胃液（SGF）中药物制剂的物理效应，并对三种单储库 ER 片剂（喹硫平/思瑞康 XR 50mg、对乙酰氨基酚/派乃特 XR 500mg、维拉帕米/异搏定 XR 240mg）、一种多储库 ER 片剂（卡马西平/得理多 XR 200mg）和一种即刻释放片剂（对乙酰氨基酚/扑热息痛 500mg）进行了测试。将 30 片放入聚酰胺网袋中，要么一起放入一个袋中，要么分别放入袋中，浸入 1L SGF 中，在 37°C 下孵育 48 小时。在 0.5-48 小时内定量释放药物。
肉眼观察结果表明，思瑞康 XR、派乃特 XR 和异搏定 XR 片剂形成了稳定的、坚固的生物凝聚物，持续超过 4 小时，完整的片剂在 24 小时内保持完整。与分开的片剂相比，药物释放分别减少了 53%、40%和 31%，持续 8 小时。光镜观察显示，与 SGF 接触使思瑞康 XR 和派乃特 XR 的涂层转变为扩散控制的溶胀凝胶层，而异搏定 XR 片剂转变为刚性和缓释基质。得理多 XR 片剂在 30 分钟内崩解成微球，扑热息痛在数分钟内崩解。
单储库 ER 片剂形成的生物凝聚物表现出延长的药物释放。无论是形成的生物凝聚物，还是测试的单储库 ER 制剂的单个片剂，都不会通过标准经口洗胃管的管腔，这使得该方法在胃肠道去污中去除片剂无效。
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