Particle Engineering to Optimise the Performance of Inhaled Therapeutics

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INTRODUCTION
Aerosol dispersion and deposition performance of Dry Powder Inhalers (DPIs) are dependent on the Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) of drug particles, formulation composition and associated excipient particle characteristics, as well as the inhaler device and its operation by the patient. This article will focus on ‘bottom-up’ technologies where the drug is dissolved in a suitable solute and particles are formed by drying the drug solution using a single-step process. Drug particles between 5 and 10 µm will generally be deposited in the upper airways, 0.5-5 µm will sediment in the deep lung, whilst those of <0.5 µm will undergo Brownian motion and are likely to be exhaled by patients. The larger the GSD, the more sites that the aerosol will deposit in the respiratory tract. Ideally aerosols should have a GSD of <2 and be as close to monodispersity as possible to increase deposition at the desired site of action, in turn increasing efficacy of the treatment (1). Often the drug is highly potent and with the limitation of powder filling equipment and the propensity of particles with a geometric diameter of <5 µm to exhibit cohesion and agglomeration, blending to adsorb drug particles onto surfaces of coarse carrier particles (50-100 µm) through Van der Waals interaction, electrostatics, capillary or mechanical interaction is used. The mixing of drug powders size reduced by micronisation, a ‘top down’ size reduction operation, to form homogenous systems that exhibit good aerosol performance and low batch to batch variability is challenging. This is due to a number of factors including the elevated surface energy and cohesivity of the high surface area powders. The blending step for micronised inhalation powders is a critical attribute to produce uniform blends and for achieving good aerosol performance (2).