Qureshi S A, McGilveray I J
Therapeutic Products Directorate, Health Protection Branch, Ottawa, Canada.
Drug Dev Ind Pharm. 1998 Nov;24(11):995-1005. doi: 10.3109/03639049809089943.
This report describes results of a collaborative study in which samples of the 40-mg strength of furosemide tablets were evaluated following a common protocol based on British (BP), European (Ph. Eur.), and US Pharmacopoeial (USP) specifications. Several tests, including identification, uniformity of mass, and dissolution, were performed. In total, excluding Lasix lots, results for 162 lots obtained from 115 manufacturers or suppliers were submitted. Also, 23 laboratories identified and submitted data for 34 lots of Lasix products available in their countries. There were no reported abnormalities in the physical test requirements of the products analyzed. The summaries (n, mean, and 95% CI) of the assay results for the "standard sample" (a common sample), Lasix lots from participating countries, and for all other furosemide products, respectively, are as follows: 30, 99.8%, 96-104; 33, 100.0%, 94-106; and 162, 99.6, 94-105. About half (approximately 62%) of the reported uniformity of mass results based on tablet weights were in the range 150-175 mg/tablet. However, there appears to be notable variability in tablet weights that would result in significant differences in the ratios (0.14 to 0.40) of active ingredient to excipient. The reported disintegration times ranged from 0 (instantaneous) to 18 min, with most less than 1 min. The drug dissolution testing was conducted with phosphate buffer at pH 5.8 (USP recommended). Another test was conducted with acetate buffer at pH 4.6 (noncompendial). There appears to be remarkable similarity in overall percentage of drug release from the three types of products (standard sample, Lasix lots, and other products). Although apparently there is a very wide spread in dissolution characteristics of the products tested, the analyses of variance did not detect differences among the products tested and, to this extent, would not indicate differences in bioavailability characteristics for most of these products. It is observed that about 20-38% of the variability in dissolution testing is not product related (i.e., it is from the dissolution testing itself), while the remaining 62-80% variability is product related (manufacturing, formulation, etc). The results of this multinational collaborative study showed that most of the furosemide products available in different countries met the required pharmaceutical quality standards, including drug-release characteristics. Based on an extensive statistical analysis, the main concern from the study was that the high variability in drug dissolution testing would require wide tolerance standards (e.g., pharmacopoeial standards). This may result in lack of needed discriminating ability of the test in revealing the impacts of formulation and manufacturing changes on in vitro, and perhaps in vivo, drug-release characteristics.
本报告描述了一项合作研究的结果，该研究按照基于英国药典（BP）、欧洲药典（Ph. Eur.）和美国药典（USP）规范的通用方案，对40毫克规格的速尿片样本进行了评估。进行了多项测试，包括鉴别、重量均匀度和溶出度测试。总共提交了来自115家制造商或供应商的162批产品的结果，不包括速尿批次。此外，23个实验室识别并提交了其所在国家/地区可获得的34批速尿产品的数据。所分析产品的物理测试要求未报告异常情况。“标准样品”（一个通用样品）、参与国的速尿批次以及所有其他速尿产品的含量测定结果总结（n、平均值和95%置信区间）如下：30批，99.8%，96 - 104；33批，100.0%，94 - 106；162批，99.6%，94 - 105。基于片剂重量报告的重量均匀度结果中，约一半（约62%）在每片150 - 175毫克范围内。然而，片剂重量似乎存在显著差异，这将导致活性成分与辅料比例（0.14至0.40）出现显著差异。报告的崩解时间范围为0（瞬间）至18分钟，大多数少于1分钟。药物溶出度测试使用pH 5.8的磷酸盐缓冲液（USP推荐）进行。另一项测试使用pH 4.6的醋酸盐缓冲液（非药典规定）进行。三种类型的产品（标准样品、速尿批次和其他产品）的药物释放总体百分比似乎有显著相似性。尽管所测试产品的溶出特性显然差异很大，但方差分析未检测到所测试产品之间的差异，在这个程度上，也不会表明这些产品中大多数在生物利用度特性方面存在差异。据观察，溶出度测试中约20 - 38%的变异性与产品无关（即来自溶出度测试本身），而其余62 - 80%的变异性与产品有关（制造、配方等）。这项跨国合作研究的结果表明，不同国家可获得的大多数速尿产品符合所需的药品质量标准，包括药物释放特性。基于广泛的统计分析，该研究主要关注的是药物溶出度测试中的高变异性将需要宽泛的公差标准（例如药典标准）。这可能导致该测试在揭示配方和制造变化对体外以及可能对体内药物释放特性的影响方面缺乏所需的确证能力。
