Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark; Global Research Technologies, Novo Nordisk A/S, Novo Nordisk Park, Måløv DK-2760, Denmark.
Eur J Pharm Sci. 2020 Mar 30;145:105239. doi: 10.1016/j.ejps.2020.105239. Epub 2020 Jan 24.
Therapeutic proteins and peptides are mainly administrated by subcutaneous injection. In vitro release testing of subcutaneous injectables performed using methods that take the structure and environment of the subcutaneous tissue into account may improve predictability of the in vivo behavior and thereby facilitate establishment of in vitro in vivo correlations. The aim of the study was to develop a biopredictive flow-through in vitro release method with a gel-type matrix for subcutaneously administered formulations and to explore the possibility of establishing a level A in vitro in vivo correlation for selected insulin products. A novel gel-based flow-through method with the incorporation of an injection step was used to assess selected commercial insulin formulations with different duration of action (Actrapid®, Mixtard® 30, Insulatard®, Lantus®). The in vitro release method provided the correct rank ordering in relation to the in vivo performance. For the modified release insulins Insulatard® and Lantus®, an in vitro in vivo correlation using non-linear time scaling was established based on the in vitro release data and in vivo subcutaneous absorption data of the I-labeled insulins taken from literature. Predicted absorption profiles were constructed using the in vitro in vivo correlation and subsequently converted into simulated plasma profiles. The approach taken may be of wider utility in characterizing injectables for subcutaneous administration.
治疗性蛋白和肽主要通过皮下注射给药。考虑到皮下组织的结构和环境，对皮下注射制剂进行体外释放测试的方法，可能会提高体内行为的可预测性，从而有助于建立体外-体内相关性。本研究旨在开发一种用于皮下给予制剂的具有凝胶型基质的生物预测性流通式体外释放方法，并探索为选定的胰岛素产品建立 A 级体外-体内相关性的可能性。采用新型基于凝胶的流通式方法，结合注射步骤，评估了具有不同作用持续时间的几种商业胰岛素制剂（Actrapid®、Mixtard® 30、Insulatard®、Lantus®）。该体外释放方法提供了与体内性能相关的正确排序。对于修饰释放胰岛素 Insulatard®和 Lantus®，根据从文献中获取的 I 标记胰岛素的体外释放数据和体内皮下吸收数据，使用非线性时间标度建立了基于体外释放数据和体内皮下吸收数据的体外-体内相关性。使用体外-体内相关性构建预测的吸收曲线，并将其转换为模拟的血浆曲线。这种方法可能在表征用于皮下给予的制剂方面具有更广泛的适用性。
