Reversible protein complexes: Advancing subcutaneous delivery with controlled and sustained release of high concentration biologics

Abstract

High concentration formulations are crucial in developing biological drugs, especially for subcutaneous (SC) administration where the administered dose is adversely impacted by the limited injection volume. In this study, we evaluated the fate and behavior of high concentration formulations of biologics, using the previously described reversible protein complex (RPC) approach and a novel in vitro tool called Subcutaneous Injection Site Simulator (Scissor). The Scissor simulates the changes that a biological drug could encounter as it transitions from a drug product formulation to the homeostatic state of the hypodermis following SC injection. The RPC formulation was injected in a cartridge filled with synthetic extracellular matrix, which was immersed in a release chamber filled with a bicarbonate-based physiological buffer that mimicked the SC injection site and the infinite sink conditions of the body. The system enabled continuous monitoring of the RPC formulation within the cartridge and could be used to characterize physicochemical changes of the drug. The dissociation of RPC and the release of the therapeutic protein from the cartridge to the infinite sink compartment simulated the drug migration from the injection site and uptake to the systemic circulation. Here, we present the evaluation of high concentration RPC formulations using five therapeutic proteins of different formats. Our findings suggest that the Scissor can provide a suitable tool to predict the stability of biological drugs in the subcutaneous environment. Also, the in vitro drug release data obtained from the Scissor highlighted a sustained and controlled release of RPC formulations and a surface erosion-based release mechanism was elucidated thanks to in vitro release models.