MSD K.K., KITANOMARU SQUARE, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo, 102-8667, Japan.
Department of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan.
Ther Innov Regul Sci. 2021 Sep;55(5):1096-1100. doi: 10.1007/s43441-021-00312-w. Epub 2021 Jun 7.
The International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use M9 Guidelines for Biopharmaceutics Classification System Biowaivers reached harmonization in November 2019. However, guidelines for bioequivalence studies are not internationally harmonized, and water as a dissolution medium is only required in Japanese guidelines, regardless of drug solubility. This study investigated the dissolution profiles of generic products in Japan that differ from those of original drugs in dissolution media defined in guidelines. Dissolution profiles disclosed on websites of generic manufacturers were investigated for 262 active ingredients listed in the bluebook (4638 oral solid products listed in the National Health Insurance drug price list) issued by the Ministry of Health, Labour and Welfare. 5% of all generic products were different from the original products in dissolution media, of which 20% was observed in water only. Among the active pharmaceutical ingredients that showed different dissolution profiles only in water, the ratio of original products that showed slower dissolution profiles to the generics was 73%. The ratio of products showing different dissolution in water only was higher than in other media investigated in this study; however, these do not reflect disintegration and dissolution of drug products in the gastrointestinal tract, since bioequivalence has been confirmed in human studies and the generic products were approved by Japanese authorities. Therefore, a discussion about the required use of water as a dissolution medium in the Japanese guidelines is needed among industry, academia, and regulatory authorities.
国际人用药品注册技术协调会（ICH）关于生物药剂学分类系统生物豁免的 M9 指导原则于 2019 年 11 月达成协调。然而，生物等效性研究的指导原则并未实现国际协调，并且水作为溶解介质仅在日本指南中要求，而不考虑药物溶解度。本研究调查了在指南中定义的溶解介质与原药不同的日本仿制药的溶解曲线。调查了厚生劳动省发布的蓝皮书（国家健康保险药品价格清单中列出的 4638 种口服固体制剂）中列出的 262 种活性成分的仿制药制造商网站上披露的溶解曲线。在所有仿制药中，有 5%在溶解介质上与原研药不同，其中 20%仅在水中观察到。在仅在水中显示不同溶解曲线的活性药物成分中，原研药显示较慢溶解曲线的比例为 73%。仅在水中显示不同溶解曲线的产品比例高于本研究中调查的其他介质；然而，这些并不反映药物产品在胃肠道中的崩解和溶解，因为在人体研究中已经证实了生物等效性，并且日本当局已经批准了仿制药。因此，需要在工业界、学术界和监管机构之间讨论日本指南中使用水作为溶解介质的必要性。
