Evaluation of Loco-Regional Skin Toxicity Induced by an In Situ Forming Depot after a Single Subcutaneous Injection at Different Volumes and Flow Rates in Göttingen Minipigs.

ABSTRACT

The present study aims to investigate the loco-regional tolerability and injection parameters (i.e., flow rate and administration volume) of an in situ forming depot (ISFD) in Göttingen minipigs, to secure both the therapeutic procedure and compliance in chronic medical prescriptions. The ISFD BEPO® technology (MedinCell S.A.) is investigated over 10 days, after a single subcutaneous injection of test item based on a DMSO solution of diblock and triblock polyethylene glycol-polylactic acid copolymers. Injection sites are systematically observed for macroscopic loco-regional skin reactions as well as ultrasound scanning, enabling longitudinal in vivo imaging of the depot. Observations are complemented by histopathological examinations at 72 h and 240 h post-injection. Overall, no treatment-emergent adverse effects are macroscopically or microscopically observed at the subcutaneous injection sites, for the tested injection flow rates of 1 and 8 mL/min and volumes of 0.2 and 1 mL. The histopathology examination confirms an expected foreign body reaction, with an intensity depending on the injected volume. The depot morphology is similar irrespective of the administration flow rates. These results indicate that the ISFD BEPO® technology can be considered safe when administered subcutaneously in Göttingen minipigs, a human-relevant animal model for subcutaneous administrations, in the tested ranges.