按照 GMP 标准设计和制造冻干粪便微生物胶囊配方。
Design and manufacture of a lyophilised faecal microbiota capsule formulation to GMP standards.
机构信息
Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
Department of Informatics, Faculty of Natural, Mathematical and Engineering Sciences, King's College London, United Kingdom.
出版信息
J Control Release. 2022 Oct;350:324-331. doi: 10.1016/j.jconrel.2022.08.012. Epub 2022 Aug 26.
Faecal microbiota transplant (FMT) is an established and effective treatment for recurrent Clostridioides difficile infection (CDI) and has many other potential clinical applications. However, preparation and quality of FMT is poorly standardised and clinical studies are hampered by a lack of well-defined FMT formulations that meet regulatory standards for medicines. As an alternative to FMT suspensions for administration by nasojejunal tube or colonoscopy, which is invasive and disliked by many patients, this study aimed to develop a well-controlled, standardised method for manufacture of lyophilised FMT capsules and to provide stability data allowing storage for extended time periods. Faecal donations were collected from healthy, pre-screened individuals, homogenised, filtered and centrifuged to remove dietary matter. The suspension was centrifuged to pellet bacteria, which were resuspended with trehalose and lyophilised to produce a powder which was filled into 5 enteric-coated capsules (size 0). Live-dead bacterial cell quantitative PCR assay showed <10 fold viable bacterial load reduction through the manufacturing process. No significant loss of viable bacterial load was observed after storage at -80 °C for 36 weeks (p = 0.24, n = 5). Initial clinical experience demonstrated that the capsules produced clinical cure in patients with CDI with no adverse events reported (n = 7). We provide the first report of a detailed manufacturing protocol and specification for an encapsulated lyophilised formulation of FMT. As clinical trials into intestinal microbiota interventions proceed, it is important to use a well-controlled investigational medicinal product in the studies so that any beneficial results can be replicated in clinical practice.
粪便微生物群移植(FMT)是一种已确立且有效的复发性艰难梭菌感染(CDI)治疗方法,具有许多其他潜在的临床应用。然而,FMT 的准备和质量尚未得到很好的标准化,并且由于缺乏符合药品监管标准的定义明确的 FMT 配方,临床研究受到阻碍。为了替代通过鼻空肠管或结肠镜进行的 FMT 混悬液,该方法具有侵入性且许多患者不喜欢,本研究旨在开发一种经过良好控制的、标准化的冻干 FMT 胶囊制造方法,并提供稳定性数据,以允许延长储存时间。从健康的、经过预筛选的个体中收集粪便供体,将其均质化、过滤和离心以去除饮食物质。将悬浮液离心以沉淀细菌,然后用海藻糖重新悬浮并冻干以产生粉末,将粉末填充到 5 个肠溶胶囊(0 号)中。实时荧光定量 PCR 检测表明,通过制造过程,活菌负载减少了 <10 倍。在 -80°C 下储存 36 周后,未观察到活菌负载的显著损失(p=0.24,n=5)。初步临床经验表明,该胶囊在 CDI 患者中产生了临床治愈,无不良反应报告(n=7)。我们首次报道了一种详细的制造方案和规格,用于封装的冻干 FMT 配方。随着肠道微生物群干预的临床试验的进行,在研究中使用经过良好控制的研究药物非常重要,以便可以在临床实践中复制任何有益的结果。