Remimazolam Tosylate

In recent years, among the new anesthetic sedation drugs launched on the market, Remazolam has undoubtedly aroused widespread concern in the industry. The drug was designed and synthesized by GlaxoSmithKline (GSK) in 1999, and after several corporate transfers, it was approved for market in China, the United States, Europe and other countries and regions around 2020. However, there are significant differences in the market performance of remazolam across countries. According to 2023 data, the drug's sales in China are about $40 million, while in the United States it is only $800,000, accounting for only 2% of the Chinese market. The reasons for this difference are worth exploring in depth. Remazolam is an ultra-short-acting GABAA receptor agonist whose design is inspired by midazolam and remifentanil, combining the properties of both. It is rapidly metabolized by carboxylesterases in the liver to produce inactive metabolites, resulting in rapid sedation resolution and short sedation recovery time. Remazolam's development history dates back to 1999, when GSK designed and synthesized the drug based on remifentanil's properties and filed a patent application. The patent was then transferred to TheraSci in the United Kingdom. Paion began developing the drug in 2008. Due to the instability of remazolam's free base, Paion developed remazolam benzenesulfonate, while Hengrui Pharmaceuticals adopted remazolam in the form of (toluene sulfonate) salt. At present, these two salt types of remazolam have been listed, of which Remazolam toluene sulfonate is only listed in China, while Remazolam benzenesulfonate is listed in China, Japan, the United States, Europe and other countries, but there are differences in indications. In the Chinese market, RenFCM obtained the Chinese market rights of Remazolam besylate in 2012, and was approved by the State Food and Drug Administration for sedation in colonoscopy in 2020, followed by the induction and maintenance of general anesthesia and the indication of bronchoscopic sedation. In the United States, Remazolam besylate was approved in July 2020 under the trade name Byfavo for a 30-minute sedation procedure marketed by Eagle. Remazolam besylate is approved for induction and maintenance of general anesthesia in Japan and South Korea. It is worth noting that in the first quarter of 2024, Paion was acquired by China's Renfu Pharmaceutical, which means that the global interests of Remazolam besylate have been vested in Renfu Pharmaceutical. Remazolam toluene sulfonate was first approved for sale in China in 2019 for indications including induction and maintenance of general anesthesia and sedation during colonoscopy. The difference in sales in the U.S. and China markets may be related to the different range of indications approved for remazolam in different countries. In the United States, Remazolam is only approved for procedural sedation, while in China, its approved indications include general anesthesia and sedation, and sales are significantly higher than in the United States. In addition, the difference in sales performance between China and the United States may also be related to concerns about remazolam metabolites. Remazolam is metabolized in the body to produce methanol, which may be further oxidized to formaldehyde and formic acid, and formaldehyde is potentially cytotoxic. As a result, the FDA requires remazolam to be administered only within 0.5 hours to avoid the buildup of methanol and its metabolites to dangerous levels. At present, other anesthetic sedatives commonly used in clinical practice, such as propofol, benzodiazepines (represented by midazolam), and α-receptor agonists (represented by dexmetropil), all have their own shortcomings. Although Remazolam still has room for improvement in some aspects, its unique advantages, such as rapid onset, rapid metabolism, rapid sedation recovery, etc., make it a potential application value in the field of anesthesia sedation. With the advancement of medical technology and the in-depth exploration of clinical applications, there may be an improved version of remazolam in the future, bringing new options to the field of anesthesia sedation.

提及近几年上市的麻醉镇静类创新药，瑞马唑仑无疑是一个值得关注的品种。 瑞马唑仑自1999年由GSK公司设计合成，经历多次转手后，近乎同步于2020年前后在中国、美国、欧洲等多个国家获批上市。 不过，笔者查询发现，该药上市后在不同国家之间的销量却有很大差异。2023年瑞马唑仑中国销售额约4000万美元，而美国仅80万美元，约为中国市场的2%。为何会出现这种差异？ 01 麻醉领域的“新星” 据悉，瑞马唑仑是一种超短效的GABAA受体激动剂，它结合了咪达唑仑和瑞芬太尼这两种麻醉药的特性，同咪达唑仑一样作用于GABA受体，但又像瑞芬太尼一样不依赖器官代谢，在体内能够快速被肝脏中的羧酸酯酶代谢生成无活性代谢产物，从而使其镇静作用快速消退、镇静恢复时间短。 图1 瑞马唑仑结构式 图片来源：药智数据 该药的设计与发现可追溯到1999年，GSK公司受瑞芬太尼的启发，成功设计并合成了瑞马唑仑，并提交了专利申请。然而，不久之后，GSK将这一专利转让给了英国公司TheraSci。历经多次企业兼并重组后，2008年，Paion公司开始开发这款药物。 在早期相关研究中，由于瑞马唑仑游离碱不稳定，瑞马唑仑游离分子只能在低温5℃的条件下保存，需要成盐改善其理化特性。Paion公司开发了苯磺酸瑞马唑仑，恒瑞医药使用了稍有不同的（甲苯磺酸）盐形式的瑞马唑仑。目前这两款盐型的瑞马唑仑均已获批上市，其中甲苯磺酸瑞马唑仑仅在中国获批上市；而苯磺酸瑞马唑仑已在中国、日本、美国、欧洲等多个国家获批上市，但是适应症上差异较大。 在中国市场，2012年，人福医药以首付300万欧元成功获得苯磺酸瑞马唑仑的中国市场权益。2020年7月，国家药监局批准注射用苯磺酸瑞马唑仑用于“结肠镜检查的镇静”，并于2022年3月和7月分别新增“全身麻醉的诱导与维持”和“支气管镜诊疗镇静”两项适应症。 在美国市场，2020年7月，苯磺酸瑞马唑仑以商品名Byfavo获批上市，适应症为30分钟内的程序镇静。目前由Eagle公司销售。 在日本和韩国，苯磺酸瑞马唑仑被批准用作全身麻醉的诱导与维持。 值得一提的是，2024年第一季度，Paion公司被人福医药收购，意味着苯磺酸瑞马唑仑的全球权益都已归属人福医药。 而甲苯磺酸瑞马唑仑最早于2019就已在中国获批上市，适应症包括全身麻醉的诱导和维持、结肠镜检查时的镇静。 02 中美市场销量额差异背后 虽然瑞马唑仑几乎同期在中国和美国获批上市，但是在商业化表现上却出现了较大差异，引起行业人士的关注与讨论。 一方面，有专家认为瑞马唑仑在不同国家获批的适应症范围不同，从而导致其在各国市场上的销售额差异较大。 在美国，瑞马唑仑仅获批了程序镇静，2023年销售额仅约80万美元。而在中国，瑞马唑仑获批了全身麻醉和镇静等多个适应症，2023年销售额约4000万美元，占据全球销售额的大部分份额。同样，在日本和韩国，瑞马唑仑也获批了全身麻醉适应症，两地合计销售额约800万美元，远超美国市场，可见瑞马唑仑在全身麻醉领域比镇静领域拥有更大的销售市场。 另一方面，也有专家认为瑞马唑仑中美两国市场销售表现迥异，这背后或许还有对其代谢产物的担忧。 她指出，“瑞马唑仑输注进入体内后，在肝脏中被酯酶水解为其羧酸代谢物（CNS7054）及甲醇；甲醇在体内可能会被氧化成甲醛和甲酸。甲醛化学性质活泼，易与DNA、蛋白质等分子发生反应，引发DNA变构、细胞损伤和组织毒性，具有安全隐患。有研究表明，当食蟹猴或恒河猴吸收大量甲醇后，体内只能检测到甲醇和少量甲酸，难于检测出甲醛。” 图片来源：上文行业专家提供 “另外，瑞马唑仑代谢物中的甲酸也可能抑制羧酸酯酶活性，进而影响瑞马唑仑在体内的代谢分解。日本Ono公司在II期临床试验中，曾发现部分受试者中瑞马唑仑存在不明原因的血药浓度偏高，从而导致其退出瑞马唑仑的开发，这可能与上述代谢物对羧酸酯酶活性的影响有关。迄今为止，FDA规定瑞马唑仑只能在0.5小时内输注，这可能是基于对药物代谢产物积累的潜在危害的高度警惕,旨在确保其使用不会导致甲醇及其代谢产物（甲醛、甲酸）积累至危险水平，从而避免对患者造成毒性影响。” 她还补充道：“在红酒生产发酵过程中同样可能会生成少量的甲醇。因此，国家对葡萄酒甲醇含量有明确的规定，红葡萄酒中的甲醇含量必须小于或等于400mg/L，白葡萄酒和桃红葡萄酒中的甲醇含量必须小于或等于250mg/L。不过，葡萄酒销售群体为健康人群，人体能够通过一些生理机制来处理和代谢少量的甲醇和甲醛带来的毒性。因此酒类所含的少量甲醇通常不会对健康人造成危害。 但瑞马唑仑针对的是衰弱的病人，其身体的生理机能下降，对甲醇、甲醛危险的反应更为敏感。为避免可能的手术风险，注射剂药品中甲醇的含量控制非常严格。ICH（国际人用药品技术要求协调委员会）的药物中残留溶剂指导原则（ICH-Q3C）规定，甲醇限度应控制在3000PPM以内。” 03 结语 目前临床常用的麻醉镇静药包括丙泊酚、苯二氮䓬类(以咪达唑仑为代表)、α受体激动剂(以右美托嘧啶为代表)等均有各自的缺点：咪达唑仑代谢产物仍具有活性，显著延长患者苏醒时间；丙泊酚对循环系统和呼吸系统影响较大。 尽管瑞马唑仑在某些方面仍存在改进空间，但也不能忽视其独特的优势，例如起效快、代谢快、镇静恢复快等。随着医药技术的进步和临床应用的深入探索，未来或许还有“改良版的瑞马唑仑”上市，给麻醉镇静领域带来新的选择。 声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。 责任编辑 | 小月石 转载开白 | 马老师 18996384680（同微信） 商务合作 | 王存星 19922864877（同微信）  阅读原文，是受欢迎的文章哦