The Therapeutic Index of Locally Acting Inhaled Drugs as a Function of their Fine Particle Mass and Particle Size Distribution – A Literature Review

Marjolein      Weda; Pieter      Zanen; Anne   H.   de Boer; Dirk   M.   Barends; Henderik   W.   Frijlink

Abstract

The therapeutic index (TI) of locally acting inhaled drug products depends on a number of parameters and processes: the particle size distribution of the inhaled aerosol, the dose-efficacy response curves at the deposition sites, the amount of drug absorbed into the systemic circulation from the lung as well as the gastrointestinal (GI) tract, and the dose-effect curves for the different adverse drug reactions. In this review, we present qualitative scenarios, combining these effects and showing the possible influence of an envisaged change in the particle size distribution in the inhaled dose of a locally acting drug product on the TI. These scenarios are a valuable tool in the development of inhalation drug products. As a surrogate for the inhaled dose in vivo, we use the fine particle mass (FPM), measured by in vitro measurements. Using these scenarios, we reviewed the literature on bronchodilators and corticosteroids for reported associations between a change in the FPM and/or particle size distribution within the FPM, and the TI. We conclude that decreasing the particle size of an inhalation product may alter the TI both in a positive as well as a negative sense. So, smaller particle are not always better.

Keywords: Fine particle mass, particle size distribution, inhaled drugs, adverse drug reactions, efficacy, therapeutic index

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