title: Effect of formulation on the stability and aerosol performance of a nebulized antibody.
abstract: Most monoclonal antibodies (mAbs) are administered to patients intravenously to ensure high bioavailability as rapidly as possible. The airways, however, are an attractive delivery route for mAbs for the treatment of lung diseases, making it possible to increase their concentration in the target organ while limiting their systemic passage. Several challenges must be overcome for translation into clinical practice. For example, the drug and device must be paired for the efficient and reliable deposition of a pharmacologically active and safe mAb in the lung region of interest. Mesh nebulizers appear to be the most effective aerosol-producing devices for delivering large amounts of biopharmaceutical while limiting protein instability during nebulization. We used metrological and analytic methods to analyze the effect of both antibody concentration and surfactant addition on aerosol performance and antibody integrity. These two factors had a limited effect on aerosol performance, but affected antibody aggregation. The addition of surfactants to antibody formulations at concentrations appropriate for lung administration markedly reduced the formation of medium or large aggregates, as shown by dynamic light scattering and fluorescence microscopy. Aggregation was also dependent on the type of mesh nebulizer, highlighting the need to optimize drug and device together.
authors.affiliation: a Génétique, Immunothérapie, Chimie et Cancer; UMR 7292/EA6306 ; Tours , France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Respaud
authors.forename: Denis
authors.initials: D
authors.lastname: Marchand
authors.forename: Christelle
authors.initials: C
authors.lastname: Parent
authors.forename: Thibaut
authors.initials: T
authors.lastname: Pelat
authors.forename: Philippe
authors.initials: P
authors.lastname: Thullier
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tournamille
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Viaud-Massuard
authors.forename: Patrice
authors.initials: P
authors.lastname: Diot
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.forename: Laurent
authors.initials: L
authors.lastname: Vecellio
authors.forename: Nathalie
authors.initials: N
authors.lastname: Heuzé-Vourc'h
mesh_terms: D000336:Aerosols / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002850:Chromatography, Gel; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000737:chemistry; D008027:Light; D008168:Lung / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D066329:Protein Aggregates; D055503:Protein Multimerization; D012542:Scattering, Radiation; D013501:Surface-Active Agents / Q000737:chemistry; D014783:Viscosity
chemical_list: D000336:Aerosols; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D066329:Protein Aggregates; D013501:Surface-Active Agents
keywords: B-35, Brij-35; CMC, critical micellar concentration; DLS, dynamic light scattering; DPI, dry powder inhaler; IgG, immunoglobulin G; mAbs, monoclonal antibodies; MALLS, multi-angle laser light scattering; NaCl, sodium chloride; PBS, phosphate-buffered sali; aggregation; airways; antibody; formulation; nebulization