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The article describes a series of in vitro test methods that can be used to estimate the total and regional lung doses. The focus of the discussion is on research and development, with the view that the ability to estimate total and regional lung deposition is essential in the design of efficient orally inhaled products. In this context, a new filter-based apparatus that mimics both the aerodynamic particle size and flow rate dependencies of regional lung deposition will be described. 10 August 2023 Inhalation In vitro methods for estimation of total and regional lung deposition of orally inhaled products Introducing a new instrument for estimation of regional lung doses Andrew R. Martin, PhD, PEng, a Conor A. Ruzycki, PhD, b Scott Tavernini, MSc, PEng a and Warren H. Finlay, PhD, PEng a a Aerosol Research Laboratory of Alberta, University of Alberta b Lovelace Biomedical Research Institute Introduction e performance of orally inhaled products is evalu- ated in the laboratory for a variety of purposes, ranging from early-stage research and development to release testing of finished products [1-3]. Standard methods for routine in vitro characterization of emitted doses and aerodynamic particle size distributions are estab- lished in United States and European Pharmacope- ias [4, 5] and referenced in regulatory guidance [6]. ese compendial methods aim to ensure that man- ufactured products placed on the market adhere to quality control metrics describing, for example, the accuracy and repeatability of the delivered dose. Use of the same methods in product development fol- lows naturally, in that it is logical to test prototypes against the identical specifications that marketed products must ultimately meet. Unfortunately, for orally inhaled products, existing compendial methods are known to correlate only weakly with in vivo per- formance [7, 8]. As a result, a reliance on compen- dial methods in research and development may steer inhaler and formulation design adrift, and risks set- ting design targets for in vitro performance that are only tangentially related to in vivo drug delivery. Given the limitations of compendial methods, con- siderable effort has been made to establish alterna- tive, clinically relevant in vitro methods, which have been shown to improve in vitro/in vivo correlations (IVIVCs) [2, 9]. ese alternative methods are fre- quently used in place of, or in addition to, compen- dial methods in the development of orally inhaled products. Presumptive to such use is the assertion that the dose of drug delivered to the lungs, or to specific regions of the lungs, is essential in determin- ing treatment efficacy [10, 11]. With this mindset, understanding and controlling the combination of drug, device and formulation-related parameters that influence total and regional lung doses is a critical step towards achieving desired clinical outcomes. Figure 1 provides a conceptual map between the nominal dose metered by, or loaded into, an inhaler and the total and regional lung doses. It is assumed that a negligible fraction of the dose is ultimately exhaled from the lungs, given that the exhaled frac- tion is small for most single-breath inhalers, including pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Accordingly, the arguments Metered Dose Emitted Dose Lung Dose Alveolar Dose Tracheobronchial Dose Extrathoracic Deposition Retained in Device Figure 1 A cascade of clinically relevant doses delivered from orally inhaled products.

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