A novel peptide excipient stabilizes DaxibotulinumtoxinA.

Abstract

Surface adsorption of proteins in bulk drug product formulations and loss of protein structural integrity during manufacturing processes can diminish drug potency. In formulations containing low biologic drug substance, such as botulinum toxin type A (BoNTA) products, loss of active protein is a major concern. To mitigate the risk of activity loss, most commercial BoNTA products contain an abundance of human serum albumin (HSA, 125-1000 µg/vial) to prevent adsorption of BoNTA to container surfaces by competing for nonspecific binding sites. The stabilizing ability of HSA is well established; however, there are notable potential safety concerns surrounding its use as an excipient. Our data suggests that at pH 5.5, in the presence of increasing concentrations of HSA the 150 kDa BoNTA core neurotoxin (RTT150) may form aggregate complexes with HSA when heated to 45-50 °C, in a dose-dependent manner. A new BoNTA product has recently been approved with a unique formulation which uses a proprietary synthetic cationic peptide (RTP004) to replace HSA as a stabilizer. Here, we show that RTP004 binds to the core neurotoxin and enhances its thermostability. In combination with polysorbate 20 (PS20), RTP004 efficiently and completely prevents surface adsorption of the 150 kDa core neurotoxin and stabilizes the biologic drug substance during manufacturing processes, even at concentrations 10- to 100-fold less than those used for HSA in commercial BoNTA products. Thus, the combination of RTP004 and PS20 forms the basis for a novel and effective BoNTA formulation, removing the need for HSA and thereby avoiding its theoretical safety risks and documented limitations.