High-concentration protein formulations: How high is high?
High-concentration protein formulations: How high is high?
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DOI：
10.1016/j.ejpb.2017.06.029
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发表时间：
2017-10-01
影响因子：
4.9
通讯作者：
Blech, Michaela
中科院分区：
文献类型：
--
作者：
Garidel, Patrick;Kuhn, Alexander B.;Blech, Michaela
高浓度蛋白制剂（HCPF）是一个术语，用于描述高蛋白浓度的蛋白制剂，主要是单克隆抗体（mAb）药物。浓度很少定义，mAb的典型范围在50和150 mg/ml之间变化。术语HCPF意在包括和表达制剂的特定溶液性质，其倾向于在高蛋白质浓度下出现，例如高粘度、高乳光、相分离、凝胶形成或蛋白质颗粒形成的增加的倾向。因此，术语HCPF可以理解为蛋白质制剂的描述符，通常在高蛋白质（单克隆抗体）浓度下，其具有不同于低蛋白质浓度（例如10 mg/ml）制剂的特定溶液、稳定性和胶体性质。特别是，氟氯烃浓缩厂可实现的最高浓度制度仍不清楚。基于几何的考虑，涉及包装单克隆抗体在一个格子中，我们绘制出一个最大的浓度范围，理论上可能是可以实现的。不同的几何假设和包装模型进行了比较，并严格讨论了它们的相关性，特别是关于单克隆抗体的物理化学性质对它们的溶解度的影响，这是忽略了在简单的几何模型。根据我们的估计，达到500 mg/ml以上的单克隆抗体浓度将非常具有挑战性。我们的研究结果具有现实的药品开发策略，并为制定令人信服的药物目标产品的发展概况的影响。(C)2017爱思唯尔B. V.保留所有权利。
High-concentration protein formulation (HCPF) is a term that is used to describe protein formulations, mostly monoclonal antibody (mAb) drugs, at high protein concentration. The concentration is rarely defined, with typical ranges varying between 50 and 150 mg/ml for mAbs. The term HCPF is meant to include and express specific solution properties of formulations that are prone to appear at high protein concentrations such as high viscosity, high opalescence, phase separation, gel formation or the increased propensity for protein particle formation. Thus the term HCPF can be understood as a descriptor of protein formulations, usually at high protein (monoclonal antibody) concentrations, which have specific solution, stability and colloidal properties that differ from formulations at low protein concentration (e.g. at 10 mg/ml).The current paper highlights in brief the development challenges that might occur for high concentration protein/monoclonal antibody formulations. In particular, the maximum concentration regimes achievable in HCPF remained unclear. Based on geometrical considerations involving packing of monoclonal antibodies in a lattice we map out a maximum concentration range that might be theoretically achievable. Different geometrical assumptions and packing models are compared and their relevance is critically discussed, in particular concerning the influence of the physicochemical properties of the monoclonal antibodies on their solubility, which is neglected in the simple geometrical model. According to our estimates, monoclonal antibody concentration above 500 mg/ml will be very challenging to achieve. Our results have implications for setting up realistic drug product development strategies and for preparing convincing drug target product profiles for development. (C) 2017 Elsevier B.V. All rights reserved.