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喷雾冷冻干燥微丸制剂概念验证用于黄热病疫苗候选物。

A spray freeze dried micropellet based formulation proof-of-concept for a yellow fever vaccine candidate.

机构信息

Bioprocess R&D Department, Sanofi Pasteur, Marcy l'Etoile, France.

MTech Department, Sanofi Pasteur, Marcy l'Etoile, France.

出版信息

Eur J Pharm Biopharm. 2019 Sep;142:334-343. doi: 10.1016/j.ejpb.2019.07.008. Epub 2019 Jul 12.

Abstract

The stability of live-attenuated viruses is very challenging due to thermal sensitivity; therefore, solid form is usually required (often freeze-dried products). Micropellet technology is a lyophilization technology that has the potential to provide greater flexibility in the presentation of a given vaccine particularly in multi-dose format or in combination of different vaccines. As a novel vaccine alternative process, this spray freeze-dried (SFD) micropellet technology was evaluated using as a model a yellow fever virus produced in Vero cells (vYF). Screening of excipients was performed in order to optimize physico-chemical properties of the micropellets. Sugar/polymer-based formulations induced high glass transition temperature (Tg), adequate breaking force and attrition resistance of the SFD micropellets. These mechanical parameters and their stability are of considerable importance for the storage, the transport but also the filling process of the SFD micropellets. By adding excipients required to best preserve virus infectivity, an optimal sugar/polymer-based formulation was selected to build micropellets containing vYF. Monodisperse and dried micropellets with a diameter of about 530 µm were obtained, exhibiting similar potency to conventional freeze-dried product in terms of vYF infectious titer when both solid forms were kept under refrigerated conditions (2-8 °C). Comparable kinetics of degradation were observed for vYF formulated in micropellets or as conventional freeze-dried product during an accelerated stability study using incubations at 25 °C and 37 °C over several weeks. The results from this investigation demonstrate the ability to formulate live-attenuated viruses in micropellets. Pharmaceutical applications of this novel vaccine solid form are discussed.

摘要

减毒活病毒的稳定性由于对热敏感而极具挑战性;因此,通常需要固态形式(通常为冷冻干燥产品)。微球技术是一种冻干技术,具有在特定疫苗制剂中提供更大灵活性的潜力,特别是在多剂量制剂或不同疫苗联合使用的情况下。作为一种新型疫苗替代工艺,使用在 Vero 细胞中生产的黄热病病毒(vYF)对这种喷雾冷冻干燥(SFD)微球技术进行了评估。为了优化微球的物理化学性质,进行了赋形剂筛选。糖/聚合物基配方可诱导高玻璃化转变温度(Tg),赋予 SFD 微球足够的断裂力和抗磨损性。这些机械参数及其稳定性对于 SFD 微球的储存、运输以及填充过程都非常重要。通过添加有助于最佳保留病毒感染力的赋形剂,选择了最佳的糖/聚合物基配方来构建含有 vYF 的微球。获得了粒径约为 530 µm 的单分散且干燥的微球,当冷藏条件(2-8°C)下保存两种固态形式时,其 vYF 感染滴度与传统冷冻干燥产品相似。在使用 25°C 和 37°C 孵育数周进行加速稳定性研究时,观察到在微球中配制的 vYF 与作为传统冷冻干燥产品的 vYF 具有相似的降解动力学。该研究的结果表明能够将减毒活病毒配制在微球中。讨论了这种新型疫苗固体形式的药物应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b539/6727866/59c10573bfaa/ga1.jpg

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