Roche Pharmaceutical Development & Supplies, PTD Biologics Europe, F. Hoffmann-La Roche Ltd, Basel, Switzerland; Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Eur J Pharm Biopharm. 2018 Aug;129:80-87. doi: 10.1016/j.ejpb.2018.05.029. Epub 2018 May 23.
Oligonucleotide-based therapeutics have been implemented as a new therapeutic modality in biotech industry, which offers the opportunity to develop formulation platforms for robust parenteral formulations. The aim of this study was to gain a better understanding of stabilizing/de-stabilizing effects of different formulation parameters on unconjugated and N-acetylgalactosamine (GalNAc) conjugated single stranded oligonucleotides with locked nucleic acid modifications (LNA SSO), as model oligonucleotides. Various buffer systems, pH levels and different excipients were evaluated to optimize conditions for LNA SSO in liquid formulations. LNA SSO were exposed to different temperature conditions, mechanical stress as well as oxidative conditions, and the maximum feasible LNA SSO concentrations regarding handling and processing were determined. Finally, options for terminal sterilization of LNA SSO were evaluated. Results show that the tested LNA SSO were most stable under slightly alkaline conditions. A decrease in viscosity was best accomplished in the presence of spermine and lysine. Heat treatment and gamma irradiation caused high levels of degradation of the LNA SSO. Crucial formulation parameters, as identified in this study, should contribute to a significant increase in future productivity in drug product development for single-stranded oligonucleotides.
寡核苷酸类药物已被应用于生物技术行业的一种新的治疗模式，为开发稳健的注射制剂配方平台提供了机会。本研究旨在更好地了解不同制剂参数对未修饰和 N-乙酰半乳糖胺（GalNAc）修饰的单链寡核苷酸（LNA SSO）的稳定/不稳定作用，这些寡核苷酸作为模型寡核苷酸。评估了各种缓冲体系、pH 值和不同赋形剂，以优化 LNA SSO 在液体制剂中的条件。将 LNA SSO 暴露于不同的温度条件、机械应力和氧化条件下，并确定了关于处理和加工的最大可行 LNA SSO 浓度。最后，评估了 LNA SSO 的终端灭菌选择。结果表明，所测试的 LNA SSO 在略碱性条件下最稳定。在精胺和赖氨酸存在下，可最好地降低粘度。热处理和γ辐照会导致 LNA SSO 高度降解。本研究中确定的关键制剂参数，应有助于未来单链寡核苷酸药物产品开发中的生产力显著提高。
