Purpose

In the biopharmaceutical industry, in vitro models are not commonly used to assess formulation risks of injectables. With limited knowledge, their impact on predicting altered pharmacokinetic (PK) or injection site responses is modest. In this paper, we address this gap by testing five injectable therapeutic modalities in the subcutaneous injection site simulator (SCISSOR). The goal was to assess if formulation risks for these modalities can be identified, characterized, and mitigated to support clinical formulation design.

Methods

SCISSOR was used to measure drug release of a small molecule (BMS-A), cyclic peptide (BMS-B), protein (Humulin®), conjugated-protein (BMS-C), and fusion protein (Orencia®). The % drug released from the extracellular matrix (ECM) to the circulating fluid and change in % transmittance were measured over time. Phase changes were analyzed by high-resolution camera, FTIR spectroscopy, or polarized light microscopy (PLM). In vitro observations were confirmed with camera images in the excised rat-skin subcutaneous model.

Results

Orencia® and Humulin® showed rapid release with no detectable phase change in the ECM. BMS-A, BMS-B, and BMS-C showed varying degrees of formulation risk. BMS-A and BMS-B precipitated in the ECM leading to crystalline and amorphous material, respectively, that corroborated reduced systemic PK. BMS-C formulations showed subtle differences in drug release that were detectable by PLM and FTIR spectroscopy.

Conclusion

On injection, drug-ECM interactions trigger phase changes, which can go unnoticed under the skin. In vitro method such as SCISSOR can be an effective tool to identify drug and formulation risks, diagnose the cause, and assess mitigation strategies in formulation design.

中文翻译：

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体外注射模型系统在研究生物性能方面的新应用：具有不同药物模式的案例研究

目的

在生物制药工业中，通常不使用体外模型来评估注射剂的配制风险。以有限的知识，它们对预测改变的药代动力学（PK）或注射部位反应的影响是适度的。在本文中，我们通过在皮下注射部位模拟器（SCISSOR）中测试五种可注射的治疗方式来弥补这一空白。目的是评估是否可以识别，表征和缓解这些模式的制剂风险，以支持临床制剂设计。

方法

SCISSOR用于测量小分子（BMS-A），环肽（BMS-B），蛋白质（Humulin®），结合蛋白（BMS-C）和融合蛋白（Orencia®）的药物释放。随时间测量从细胞外基质（ECM）释放到循环液中的药物百分比以及透射率百分比的变化。通过高分辨率相机，FTIR光谱或偏振光显微镜（PLM）分析相变。在切除的大鼠皮肤皮下模型中，通过相机图像确认了体外观察。

结果

Orencia®和Humulin®显示了快速释放，在ECM中没有可检测到的相变。BMS-A，BMS-B和BMS-C显示不同程度的配方风险。BMS-A和BMS-B在ECM中沉淀，分别导致结晶和无定形物质，证实了系统性PK降低。BMS-C配方在药物释放方面显示出细微的差异，可通过PLM和FTIR光谱检测到。

结论

注射时，药物-ECM相互作用会触发相变，在皮肤下可能不会引起注意。诸如SCISSOR之类的体外方法可以是识别药物和制剂风险，诊断原因并评估制剂设计中的缓解策略的有效工具。