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.

Charlotte Peloso,Jacques Descotes,Christophe Roberge,Adolfo Lopez-Noriega,Anne-Pascale Trichet,Joël Richard

doi:10.3390/ijms22179250

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.

Highlights

Over the past few decades, the field of smart and controlled delivery systems has been continuously expanding, investigating approaches from the nano to the macrometric scale [1] and from nondegradable implants to bioresorbable systems [2,3]
Among the available formulation approaches, in situ forming depots (ISFD) are attractive as they are designed to bio-resorb and are often easier to administer compared to preformed delivery systems [5]
The ISFD BEPO® technology is based on the combination of a drug substance with an injectable vehicle solution made of a diblock and a triblock poly(ethylene glycol) (PEG)–PLA copolymer solubilized in an organic solvent

Summary

Introduction

Over the past few decades, the field of smart and controlled delivery systems has been continuously expanding, investigating approaches from the nano to the macrometric scale [1] and from nondegradable implants to bioresorbable systems [2,3]. Most of these drug delivery strategies are designed to improve the bioavailability and pharmacokinetics of target therapeutic molecules, with a view to reducing dosing frequency compared to immediate release dosage forms and, improving treatment compliance [4]. In addition to the biocompatibility of the formulation components, factors linked to the injection procedure are being increasingly evaluated for their influence on loco-regional tolerability, in particular, with classic aqueous-based injectable products, such as insulin or heparin

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