Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
Late Stage Pharmaceutical Development, Genentech, Inc. South San Francisco, CA 94080, USA.
J Control Release. 2015 Sep 28;214:94-102. doi: 10.1016/j.jconrel.2015.07.016. Epub 2015 Jul 22.
Subcutaneous (SC) injection is becoming a more common route for the administration of biopharmaceuticals. Currently, there is no reliable in vitro method that can be used to anticipate the in vivo performance of a biopharmaceutical formulation intended for SC injection. Nor is there an animal model that can predict in vivo outcomes such as bioavailability in humans. We address this unmet need by the development of a novel in vitro system, termed Scissor (Subcutaneous Injection Site Simulator). The system models environmental changes that a biopharmaceutical could experience as it transitions from conditions of a drug product formulation to the homeostatic state of the hypodermis following SC injection. Scissor uses a dialysis-based injection chamber, which can incorporate various concentrations and combinations of acellular extracellular matrix (ECM) components that may affect the release of a biopharmaceutical from the SC injection site. This chamber is immersed in a container of a bicarbonate-based physiological buffer that mimics the SC injection site and the infinite sink of the body. Such an arrangement allows for real-time monitoring of the biopharmaceutical within the injection chamber, and can be used to characterize physicochemical changes of the drug and its interactions with ECM components. Movement of a biopharmaceutical from the injection chamber to the infinite sink compartment simulates the drug migration from the injection site and uptake by the blood and/or lymph capillaries. Here, we present an initial evaluation of the Scissor system using the ECM element hyaluronic acid and test formulations of insulin and four different monoclonal antibodies. Our findings suggest that Scissor can provide a tractable method to examine the potential fate of a biopharmaceutical formulation after its SC injection in humans and that this approach may provide a reliable and representative alternative to animal testing for the initial screening of SC formulations.
皮下（SC）注射正成为生物制药给药的一种更为常见的途径。目前，还没有可靠的体外方法可以用于预测用于 SC 注射的生物制药制剂的体内性能。也没有一种动物模型可以预测生物制药在人体内的结果，如生物利用度。我们通过开发一种新的体外系统来解决这一未满足的需求，该系统称为 Scissor（皮下注射部位模拟器）。该系统模拟了生物制药从药物产品制剂条件向 SC 注射后真皮稳态转变过程中可能经历的环境变化。Scissor 使用基于透析的注射室，该注射室可以包含各种浓度和组合的无细胞细胞外基质（ECM）成分，这些成分可能会影响生物制药从 SC 注射部位的释放。该室浸入碳酸氢盐生理缓冲液的容器中，该缓冲液模拟 SC 注射部位和身体的无限吸收池。这种布置允许实时监测注射室内的生物制药，并可用于表征药物的理化变化及其与 ECM 成分的相互作用。生物制药从注射室向无限吸收池室的迁移模拟了药物从注射部位的迁移以及被血液和/或淋巴毛细血管吸收的过程。在这里，我们使用 ECM 元素透明质酸和胰岛素以及四种不同的单克隆抗体的测试制剂对 Scissor 系统进行了初步评估。我们的研究结果表明，Scissor 可以提供一种可行的方法来研究生物制药制剂在人体 SC 注射后的潜在命运，并且这种方法可能为 SC 制剂的初步筛选提供一种可靠且有代表性的替代动物测试的方法。
