20.500.12556/RUL-155599 The search for novel proline analogs for viscosity reduction and stabilization of highly concentrated monoclonal antibody solutions Administration of monoclonal antibodies (mAbs) is currently focused on subcutaneous injection associated with increased patient adherence and reduced treatment cost, leading to sustainable healthcare. The main bottleneck is low volume that can be injected, requiring highly concentrated mAb solutions. The latter results in increased solution viscosity with pronounced mAb aggregation propensity because of intensive protein-protein interactions. Small molecule excipients have been proposed to restrict the protein-protein interactions, contributing to reduced viscosity. The aim of the study was to discover novel compounds that reduce the viscosity of highly concentrated mAb solution. First, the chemical space of proline analogs was explored and 35 compounds were determined. Viscosity measurements revealed that 18 proline analogs reduced the mAb solution viscosity similar to or more than proline. The compounds forming both electrostatic and hydrophobic interactions with mAb reduced the viscosity of the formulation more efficiently without detrimentally effecting mAb physical stability. A correlation between the level of interaction and viscosity-reducing effect was confirmed with molecular dynamic simulations. Structure rigidity of the compounds and aromaticity contributed to their viscosity-reducing effect, dependent on molecule size. The study results highlight the novel proline analogs as an effective approach in viscosity reduction in development of biopharmaceuticals for subcutaneous administration. proline analogs monoclonal antibodies subcutaneous administration viscosity reducers high concentration farmacevtska kemija prolinovi analogi monoklonska protitelesa subkutana aplikacija sredstva za zmanjševanje viskoznosti visoka koncentracija true false true Angleški jezik Slovenski jezik Članek v reviji 2024-04-08 10:42:24 2024-04-08 10:42:28 2024-05-21 14:11:18 0000-00-00 00:00:00 2024 0 0 13 str. art. 124055 Vol. 655 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 0378-5173 10.1016/j.ijpharm.2024.124055 191471875 1-s2.0-S0378517324002898-main.pdf 1-s2.0-S0378517324002898-main.pdf 1 8F36BC87E9F56EBECB0C3E3F62BFD783 c3edd19c32e821d7d27ad149153d3ebb641a3fd21cb9cd932e877f63f5054493 76b1957c-f584-11ee-937a-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=182568 https://www.sciencedirect.com/science/article/pii/S0378517324002898 1 ef3b315e-f583-11ee-937a-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=182567 Fakulteta za farmacijo 0 0 0