University of Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074 Würzburg, Germany.
IBMP - Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Straße 19, 90562 Nürnberg-Heroldsberg, Germany; Institute of Pharmacology, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
J Pharm Biomed Anal. 2018 Feb 20;150:318-326. doi: 10.1016/j.jpba.2017.12.019. Epub 2017 Dec 13.
Pharmaceutical manufacturers have to study the stability of drug products before marketing according to ICH guideline Q1A(R2); data of those investigations aim to set expiry dates. The expiry date on the container of a remedy assures the physician and the patient a stability of the drug in its formulation i.e. within a specification of 95-105%. Only few studies show that shelf-lives of pharmaceutical products are often longer than expiration dates. The objective of the study presented here was determining the content of nine expired ampoules manufactured in the last century and identifying the impurity profile by means of HPLC-UV and HPLC-MS, respectively. The ampoules are part of the "PEAK-collection" of long expired finished pharmaceutical products at IBMP, Nürnberg-Heroldsberg, and consists among others of epinephrine (Suprarenin and Adrenalin in Oil), etilefrine (Effortil), synephrine (Sympatol), caffeine and procaine (Impletol), caffeine and sodium salicylate (Caffeinum Salicylicum), dipyridamole (Persantin), furosemide (Lasix), and metamizole (Novalgin). For chromatographic investigations methods of the European Pharmacopoeia for related substances were used; for determining the content, they were validated for linearity, precision, and accuracy. The results were compared to current reference ampoules. Five out of nine ampoules were still within the specified content limits. In Suprarenin and Adrenalin in Oil, both containing epinephrine, Impletol (procaine), and Persantin (dipyridamole) contents were decreased to 70%, 74%, 79%, and 86%, respectively, and therefore out of specification.
制药企业必须按照 ICH 指南 Q1A(R2)在上市前研究药品的稳定性；这些研究的数据旨在设定有效期。容器上的有效期保证了医生和患者药物在其制剂中的稳定性，即在 95-105%的范围内。只有少数研究表明，药品的保质期往往比有效期长。本研究的目的是确定上个世纪生产的 9 支过期安瓿的含量，并通过 HPLC-UV 和 HPLC-MS 分别确定其杂质谱。这些安瓿是 IBMP 长期过期成品药物“PEAK 收藏”的一部分，位于纽伦堡-赫尔多夫，其中包括肾上腺素（油中的肾上腺素和肾上腺素）、依替福林（Effortil）、辛弗林（Sympatol）、咖啡因和普鲁卡因（Impletol）、咖啡因和水杨酸钠（Caffeinum Salicylicum）、双嘧达莫（Persantin）、呋塞米（Lasix）和甲灭酸（Novalgin）。对于色谱研究，使用了欧洲药典中有关物质的方法；为了确定含量，对其进行了线性、精密度和准确性验证。结果与当前的参考安瓿进行了比较。9 支安瓿中有 5 支仍在规定的含量范围内。在含有肾上腺素的肾上腺素和肾上腺素油中，Impletol（普鲁卡因）和 Persantin（双嘧达莫）的含量分别下降到 70%、74%、79%和 86%，因此不符合规定。
