Schlesinger Erica B, Bernards Daniel A, Chen Hunter H, Feindt James, Cao Jingtai, Dix Daniel, Romano Carmelo, Bhisitkul Robert B, Desai Tejal A
Graduate Program in Bioengineering University of California San Francisco CA 94158.
Formulation Development Group Regeneron Pharmaceuticals Tarrytown NY 10591.
Bioeng Transl Med. 2018 Dec 3;4(1):152-163. doi: 10.1002/btm2.10121. eCollection 2019 Jan.
Despite years of effort, sustained delivery of protein therapeutics remains an unmet need due to three primary challenges - dose, duration, and stability. The work presented here provides a design methodology for polycaprolactone reservoir-based thin film devices suitable for long-acting protein delivery to the back of the eye. First, the challenge of formulating highly concentrated protein in a device reservoir was addressed by improving stability with solubility-reducing excipients. Next, predictive correlations between design parameters and device performance were developed to provide a methodology to achieve a target product profile. Prototype devices were designed using this methodology to achieve desired device size, release rate, therapeutic payload, and protein stability, assessed by studies. Finally, prototype tolerability was established in a non-human primate model. The design methodology presented here is widely applicable to reservoir-based sustained delivery devices for proteins and provides a general device design framework.
尽管经过多年努力，但由于三个主要挑战——剂量、持续时间和稳定性，蛋白质疗法的持续递送仍是一项未得到满足的需求。本文介绍的工作提供了一种基于聚己内酯储库的薄膜装置的设计方法，该装置适用于向眼后段进行长效蛋白质递送。首先，通过使用降低溶解度的辅料提高稳定性，解决了在装置储库中配制高浓度蛋白质的挑战。其次，建立了设计参数与装置性能之间的预测相关性，以提供实现目标产品特性的方法。利用该方法设计了原型装置，以实现所需的装置尺寸、释放速率、治疗载荷和蛋白质稳定性，并通过研究进行评估。最后，在非人类灵长类动物模型中确定了原型的耐受性。本文介绍的设计方法广泛适用于基于储库的蛋白质持续递送装置，并提供了一个通用的装置设计框架。
