Abstract：
Oligonucleotide drug products commercially approved in the US and the EU are reviewed. A total of 20 products that includes 1 aptamer, 12 antisense oligonucleotides (ASOs), 6 small interfering ribonucleic acids (siRNAs), and 1 mixture of single-stranded and double-stranded polydeoxyribonucleotides have been identified. A typical oligonucleotide formulation is composed of an oligonucleotide with buffering agent(s), pH adjusting agents, and a tonicity adjusting agent. All the products are presented as 2.1 - 200 mg/mL solutions at pH between 6 and 8.7. Majority of the products are approved for intravenous (IV) and subcutaneous (SC) routes, with two for intravitreal (IVT), two for intrathecal (IT), and one for intramuscular (IM) routes. The primary packaging includes vials and prefilled syringes (PFS). Products approved for IV and IT administration routes and requiring >1.5 mL dose volumes are supplied in vials, while those approved for SC, IM, and IVT and requiring ≤1.5 mL dose volume are supplied in PFS. Based on the compiled dataset, we propose a generalized starting point for an oligonucleotide formulation during early phase development for IV, SC, and IT administration routes. Overall, we believe this harmonized evaluation and understanding of various oligonucleotide drug product attributes will help derive platform generalizations and allows for accelerated early phase development for first-in-human studies.
摘要：
回顾了在美国和欧盟获得商业批准的寡核苷酸药物产品。共有20个产品，其中包括1个适体，12个反义寡核苷酸（ASO），6个小干扰核糖核酸（siRNA），和1个单链和双链多脱氧核糖核苷酸的混合物已被鉴定。典型的寡核苷酸制剂由具有缓冲剂的寡核苷酸组成。pH调节剂,和张力调节剂。所有的产物以pH在6和8.7之间的2.1-200mg/mL溶液呈现。大多数产品被批准用于静脉（IV）和皮下（SC）途径，两个用于玻璃体内（IVT），两个用于鞘内（IT），一种用于肌内（IM）途径。初级包装包括小瓶和预填充注射器(PFS)。批准用于IV和IT给药途径且需要>1.5mL剂量体积的产品以小瓶形式提供，而那些批准用于SC的，IM,和IVT，并且需要≤1.5mL的剂量体积在PFS中提供。基于编译的数据集，我们提出了在IV的早期开发期间寡核苷酸制剂的广义起点，SC,和IT管理路线。总的来说,我们相信,这种对各种寡核苷酸药物产品属性的统一评估和理解将有助于获得平台概括,并允许加速首次人体研究的早期开发.
