ABSTRACT
Polysorbates (PSs) are common protein stabilizers used in biotherapeutic formulations. However, PSs are heterogeneous and unstable in liquid protein formulations [1,2]. The purpose of this work is to explore possible alternatives for polysorbate replacements that demonstrate superior protein protection, superior self-stability, low toxicity, and wide applicability. For this purpose, 8 non-ionic surfactants that have not yet been used as excipients in marketed biotherapeutic products were investigated with PS20/80 as the benchmark. Compared with PS20/80, Brij-58 showed better protein protection ability in the mAb1 formulation under forced degradation conditions when examined by visual inspection, SEC, and dynamic lighting scanning. Additionally, Brij-58 has a better inherent stability than PS20/80 in the protein formulation when detected by UPLC-CAD. Moreover, Brij-58 is an inert excipient that does not affect protein bioactivity and conformation. In addition, the LD50 and hemolysis concentration of Brij-58 were determined, which is relatively safe when used as a parenteral injection. Furthermore, Brij-58 was also an effective protein stabilizer for the other two antibody products (IgG4 subtype and bispecific antibody) in the shaking study. In summary, Brij-58 stands out as a promising PS replacement in biotherapeutic formulations with a safe, stable and effective protein-protection profile among candidate surfactants.
Subject(s)
Biological Products/chemistry , Cetomacrogol/chemistry , Drug Compounding/methods , Excipients/chemistry , Surface-Active Agents/chemistry , Administration, Intravenous , Animals , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/chemistry , Antibodies, Bispecific/toxicity , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/toxicity , Biological Products/administration & dosage , Biological Products/toxicity , Cetomacrogol/toxicity , Chemistry, Pharmaceutical , Drug Stability , Excipients/toxicity , Female , HEK293 Cells , Hemolysis/drug effects , Humans , Immunoglobulin G/administration & dosage , Immunoglobulin G/chemistry , Immunoglobulin G/toxicity , Lethal Dose 50 , Male , Mice , Polysorbates/chemistry , Polysorbates/toxicity , Protein Stability , Rabbits , Surface-Active Agents/toxicity , Toxicity Tests, AcuteABSTRACT
Nanotechnology offers advantages for new drug delivery design by providing drug targeting while minimizing the side effects. Polyoxyethylene 20 cetyl alcohol (CETETH-20) is a surfactant that may form nanostructured systems, such as liquid crystals, when in contact with water/oil, which are structurally similar to biological membranes and may improve skin interaction. The aim of this study was to develop and characterize CETETH 20-based nanostructured systems by combining CETETH-20 with water and different oily phases, including PEG-12-dimethicone for topical drug administration. The systems were characterized by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), rheology, texture profile analyses (TPA), in vitro cytotoxicity and histopathological analyses of rabbits' skin. Lamellar, hexagonal and cubic phases were identified and their viscoelastic moduli varied according to each phase. The stiffness of the cubic phase was 3-fold higher and twice more adhesive than the hexagonal phase. The formulations did not affect the normal macrophages cells, neither promoted skin irritation. They were spontaneously obtained by simply mixing the components, which corroborates for an ease scaled-up. These results suggest that systems composed of CETETH 20, PEG-12-dimethicone and water are a promising new approach for designing nanostructured topical drug delivery systems.
Subject(s)
Administration, Topical , Drug Carriers , Nanoparticles , Silicones , Surface-Active Agents , Animals , Cell Line , Cell Survival/drug effects , Cetomacrogol/administration & dosage , Cetomacrogol/chemistry , Cetomacrogol/toxicity , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Drug Carriers/toxicity , Emulsions/chemistry , Fatty Alcohols/administration & dosage , Fatty Alcohols/chemistry , Fatty Alcohols/toxicity , Male , Mice , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Nanoparticles/toxicity , Oleic Acid/chemistry , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/chemistry , Polyethylene Glycols/toxicity , Rabbits , Silicones/administration & dosage , Silicones/chemistry , Silicones/toxicity , Skin/drug effects , Skin/pathology , Skin Irritancy Tests , Surface-Active Agents/administration & dosage , Surface-Active Agents/chemistry , Surface-Active Agents/toxicityABSTRACT
The mechanism of cetomacrogol 1000-induced hemolysis was investigated. Previous conclusions that peroxides are involved in the hemolytic process were confirmed. The possibility that hydrogen peroxide, superoxide, hydroxyl radical, or singlet oxygen, which are known to induce hemolysis, are involved in cetomacrogol 1000-induced hemolysis was tested by using specific inhibitors and inactivators. The hydroxyl radical (OH.) was shown to be the only apparent oxygen species involved in cetomacrogol 1000-induced hemolysis. Its contribution to the hemolytic potency of the surfactant is approximately 30%.
