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.

译文

:皮下(SC)注射正在成为生物药物给药的一种更为普遍的途径。当前,没有可靠的体外方法可用于预期用于SC注射的生物药物制剂的体内性能。也没有一种动物模型可以预测体内的结果,例如人类的生物利用度。我们通过开发称为Scissor(皮下注射部位模拟器)的新型体外系统来满足这一未满足的需求。该系统对生物药物在从SC注射后从药物制剂的状态转变为皮下组织的稳态状态时可能经历的环境变化进行建模。 Scissor使用基于透析的注射腔室,该腔室可以合并各种浓度和脱细胞细胞外基质(ECM)成分的组合,这些成分可能会影响生物药物从SC注射部位的释放。该腔室浸入一个基于碳酸氢盐的生理缓冲液的容器中,该缓冲液模仿了SC注射部位和身体的无限深处。这样的布置允许对注射室内的生物药物进行实时监控,并且可以用于表征药物的物理化学变化及其与ECM成分的相互作用。生物药物从注射室向无限的水槽隔室的运动模拟了药物从注射部位的迁移以及血液和/或淋巴毛细血管的吸收。在这里,我们介绍了使用ECM元素透明质酸和胰岛素以及四种不同单克隆抗体的测试制剂对Scissor系统的初步评估。我们的发现表明,剪刀式剪可提供一种易于处理的方法来检查生物药物制剂在人体中的SC注射后的命运,并且这种方法可为动物试验中SC制剂的初步筛选提供可靠且有代表性的替代方法。

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