幽灵丸破解者：溶出度试验后完整的左乙拉西坦控释片案例研究。
Ghost-Pill-Buster: A Case Study of Intact Levetiracetam Extended-Release Tablets after Dissolution Testing.
机构信息
US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA.
出版信息
CNS Drugs. 2016 May;30(5):455-60. doi: 10.1007/s40263-016-0332-9.
BACKGROUND
Orally administered medications in extended-release (ER) dosage forms continue to play a pivotal role in the treatment of various central nervous system disorders. For certain ER dosage forms, pharmaceutical scientists have been familiar with the passage of intact tablet-like objects in patients' feces after administration of ER tablets or capsules based on water-insoluble or slowly dissolving excipients. Nevertheless, because of lack of awareness of the "ghost pill" phenomenon, anxiety has ensued among some patients and clinicians, who have less understanding of how drugs are released from these tablets once ingested. It has been brought to the attention of the US Food and Drug Administration (FDA) that epilepsy patients administered with Teva's levetiracetam ER tablets have noticed intact tablets in their stools and been concerned that they were not getting the needed dose of the drug. In response to neurologists' clinical reporting, the FDA has conducted investigations to confirm a minimal risk of incomplete drug release of Teva's drug product.
OBJECTIVE
The objective of this study was to evaluate the risks of incomplete drug release associated with the passing of intact levetiracetam ER tablets, by conducting in vitro dissolution testing.
METHODS
Dissolution testing of Teva's drug product was performed in accordance with the US Pharmacopeia monograph for levetiracetam ER tablets in phosphate buffer and bio-relevant buffers at different pH values. In addition, dissolution testing was conducted with split and crushed tablets. At the end of the dissolution testing, all samples were visually inspected for any undissolved pieces.
RESULTS
Approximately 90 % of levetiracetam had been released in all dissolution media after 8 h of dissolution. The levetiracetam ER tablets after dissolution testing remained fully intact in all dissolution media. The rates of drug release were significantly faster from split and crushed tablets than that from whole tablets.
CONCLUSION
On the basis of these findings, Teva's levetiracetam ER tablets may appear intact in the stools but have released the drug successfully. The FDA has requested Teva to revise its product labeling to include remarks regarding the potential passing of intact tablets. Since patients who notice ghost pills in their stools may impetuously crush or split the tablets of subsequent doses on their own, healthcare providers should instruct patients to swallow whole tablets throughout the treatment, in accordance with the drug label.
背景
口服缓控释制剂在治疗各种中枢神经系统疾病方面仍发挥着关键作用。对于某些缓控释制剂，基于不溶或缓慢溶解的赋形剂，制药科学家们已经熟悉了患者粪便中完整的片剂状物体的出现，这是在给予缓控释片剂或胶囊后发生的。然而，由于缺乏对“幽灵丸”现象的认识，一些患者和临床医生感到焦虑，他们对这些片剂一旦被摄入后药物是如何释放的了解较少。美国食品和药物管理局（FDA）已经注意到，服用梯瓦公司左乙拉西坦控释片的癫痫患者注意到粪便中有完整的片剂，并担心他们没有得到所需剂量的药物。针对神经科医生的临床报告，FDA 进行了调查，以确认梯瓦药品产品不完全释放药物的风险极小。
目的
本研究旨在通过进行体外溶出度试验，评估完整左乙拉西坦控释片通过时与不完全药物释放相关的风险。
方法
按照美国药典左乙拉西坦控释片磷酸盐缓冲液和不同 pH 值的生物相关缓冲液的专论，对梯瓦药品进行溶出度试验。此外，还对分割和粉碎的片剂进行了溶出度试验。在溶出度试验结束时，对所有样品进行了目视检查，以确定是否有未溶解的部分。
结果
在 8 小时的溶出后，所有溶出介质中约有 90%的左乙拉西坦已经释放。在所有溶出介质中，经过溶出度试验的左乙拉西坦控释片仍保持完整。分割和粉碎的片剂的药物释放速度明显快于完整片剂。
结论
基于这些发现，梯瓦的左乙拉西坦控释片可能在粪便中看起来完整，但已成功释放药物。FDA 已要求梯瓦修改其产品标签，以包含关于潜在完整片剂通过的说明。由于注意到粪便中有幽灵丸的患者可能会冲动地自行压碎或分割后续剂量的片剂，医疗保健提供者应根据药物标签指示患者在整个治疗过程中吞下完整的片剂。
Zotero 插件