A number of drug inhalers are now candidates for generic substitution due to patent expiration. However, the regulatory route to approval of generics is complex. This is due partly to the fact that most inhaled drugs are designed to act topically, within the airways, but also because their regional deposition in the lung is presently unpredictable given the data from existing laboratory test methods. Thus, for inhalers, proof of bioequivalence is a problem. While data exists in the clinical literature that shows how different inhalers distribute drugs as aerosols within the lungs of patients and volunteers, and methods exist to characterize aerosols leaving inhalers, the present methods fail to provide data that enables effective prediction of drug deposition in the airways. Our recent work to develop biorelevant test methods through geometrically improved mouth-throat (MT) models has shown that it is possible to estimate total lung deposition in vitro, provided the inhalation maneuvers are representative of those used in practice. Furthermore, because most aerosol drug impaction from inhalers occurs in the MT region, the aerodynamic particle size distribution (APSD) of the drug aerosol exiting that region is likely to define its fate (and regional deposition in the lung). Thus, there are compelling reasons to (a) select optimal MT models and (b) refine methods to size the aerosols exiting MT models under realistic, but variable, flow regimes, like those used by humans. This grant proposal is designed to address this topic by creating methods to investigate and compare the total dose and the aerodynamic particle size distribution of different orally inhaled drug products exiting different MT models under realistic inhalation flow conditions. By comparing the results from these methods to the drug deposition reported in the clinical literature, we will evaluate and assess which in vitro method [e.g. which MT model(s) and/or breath profile(s)] offer the best in vivo in vitro correlations. When development is complete, the proposed methods and the data derived from them will improve the characterization of aerosol drugs and help to evaluate the regional drug deposition to be expected in the lungs of patients who use orally inhaled drug products. This will assist in the assessment of bioequivalence and/or bridging between inhaler variants, because the proposed methods better mimic the clinical use of inhalers. The project will enable the new methods to be assessed and, in future, enable improved inhaler designs in advance of clinical testing.

Public Health Relevance

For less expensive generic drug inhalers to be approved by FDA, bioequivalence (BE) must be demonstrated with the innovator products. Proof of BE is complex because the drugs used in these products act topically and existing laboratory test methods fail to predict drug aerosol deposition in different airway regions. This study is designed to overcome this problem by developing and evaluating biorelevant methods capable of comparing both the total dose and the aerodynamic particle size distribution of different orally inhaled drug products exiting geometrically realistic mouth- throat models under realistic inhalation flow conditions.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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Virginia Commonwealth University
United States
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