Novel Applications of an In Vitro Injection Model System to Study Bioperformance: Case Studies with Different Drug Modalities

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.