title: Protein stability in pulmonary drug delivery via nebulization.
abstract: Protein inhalation is a delivery route which offers high potential for direct local lung application of proteins. Liquid formulations are usually available in early stages of biopharmaceutical development and nebulizers are the device of choice for atomization avoiding additional process steps like drying and enabling fast progression to clinical trials. While some proteins were proven to remain stable throughout aerosolization e.g. DNase, many biopharmaceuticals are more susceptible towards the stresses encountered during nebulization. The main reason for protein instability is unfolding and aggregation at the air-liquid interface, a problem which is of particular challenge in the case of ultrasound and jet nebulizers due to recirculation of much of the generated droplets. Surfactants are an important formulation component to protect the sensitive biomolecules. A second important challenge is warming of ultrasound and vibrating mesh devices, which can be overcome by overfilling, precooled solutions or cooling of the reservoir. Ultimately, formulation development has to go hand in hand with device evaluation.
authors.affiliation: Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilians-Universitaet Muenchen, Butenandtstr. 5, 81377 Munich, Germany.
authors.forename: Sebastian P
authors.initials: SP
authors.lastname: Hertel
authors.affiliation: Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilians-Universitaet Muenchen, Butenandtstr. 5, 81377 Munich, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Winter
authors.affiliation: Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilians-Universitaet Muenchen, Butenandtstr. 5, 81377 Munich, Germany. Electronic address: wolfgang.friess@cup.uni-muenchen.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Friess
mesh_terms: D000280:Administration, Inhalation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D009330:Nebulizers and Vaporizers; D055550:Protein Stability; D011506:Proteins / Q000008:administration & dosage* / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry*; D014463:Ultrasonography; D014732:Vibration
chemical_list: D011506:Proteins; D013501:Surface-Active Agents
keywords: Aerosol collection; Aerosolization; Air–liquid-interface; Nebulization; Protein aggregation; Protein instability; Protein unfolding; Subvisible particles