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There has been significant progress and research activity within the field of inhalation therapy over the past decade but only a handful of new inhaled products have successfully progressed to market over the past five years [1, 2]. 10 February 2023 Inhalation Application of biological models to inform research and development of inhalation products Advancements in in vitro methodologies provide more options in drug development and could reduce the need for animal testing. Juhura Gania Almazi, BSc (Hons), PhD and Hui Xin Ong, B Pharm (Hons), PhD Ab Initio Pharma Introduction ere has been significant progress and research activity within the field of inhalation therapy over the past decade but only a handful of new inhaled products have successfully progressed to market over the past five years [1, 2]. is is due to the complex- ity that is inherent in the development of inhaled formulations, where the respiratory system presents a unique challenge in terms of its complex anatomi- cal structure, physiological and biological properties compared to other organs. To establish relevant biological models for the devel- opment of inhalation products, it is essential to understand the unique and complex network of cells, structures and mechanisms that make up the respi- ratory system. e human respiratory system begins at the nasal cavity and follows through the pharynx and larynx to the series of sub-dividing airways with diminishing diameter from the trachea, through the bronchi and bronchioles and finally to the alveolar ducts and sacs, the sites of gas exchange with a rich bed of systemic vasculatures [3]. ere are significant differences between the cells located at the different regions of the airways (trachea to the bronchioles), and the nasal cavity compared to the alveolar epithe- lium. e airways are composed of pseudostratified columnar epithelium containing goblet-secreting mucus cells and ciliated cells that constitute the mucociliary clearance mechanism of the lungs. In the alveoli, the columnar epithelial cells are replaced by pneumonocytes, the broad and thin type 1 and type 2 cells and alveolar macrophages. erefore, when selecting biological models for testing inhala- tion products, careful consideration must be made regarding the area of the respiratory tract that is the target site for a product. As an example, nasal cells and cell lines can be selected for products that aim to deliver locally to the nose and brain, whereas bron- chial cells can be selected for testing products that aim for localized delivery to the airways, and for products to be delivered systemically, alveolar cell lines can be selected. Secondly, the respiratory tract has several biolog- ical and physical barriers that can limit product uptake (transport, absorption) and subsequent effi- cacy (Figure 1) [4]. Following inhalation of an aero- sol drug, the particles will first encounter a mucus barrier of varying thickness lining the conducting airways down to the alveolar regions [5]. is impac- tion and deposition process will subsequently create a concentration gradient across the mucus barrier that will help drive the drug across the epithelium. e epithelial cells that line the airways from the nasal region down to the alveolar region form tight junctions, which affect drug uptake and therefore therapeutic efficacy. ese pulmonary processes are determined, or at least influenced, by one or more aspects of the inhaled drug, including physicochem- ical characteristics of the drug, the drug formulation and the inhalation device.