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10 OCTOBER2016 Inhalation tion of a piezoelectric unit in an aqueous media (i.e., for- mulation). Ultrasonic nebulizers first appeared in the United States in 1949. Initially, they were used as humid- ifiers but doctors rapidly recognized their potential and began adding medications to them, thereby producing therapeutic aerosols. Both conventional and miniaturized nebulizers vary in critical characteristics such as airflow rate, fill volumes and droplet size distribution. 12 The variability is a direct conse- quence of differences in physical design and the interac- tion between device and formulation. 13 For instance, in some cases, mesh nebulizers may show clogging over time, which could affect the consistency of their performance and therefore increase variability. 14 In general, conven- tional nebulization technologies are capable of delivering high doses of a drug since they can typically be filled with 2 ml up to more than 5 ml of aqueous formulation. 14 Types of jet nebulizers Conventional jet nebulizers Conventional jet nebulizers, or pneumatic nebulizers, are operated by a supply of pressurized gas that acts as a dri- ving force for the atomization of the liquid in the nebulizer cup (Figure 3). The pressurized gas is fed through a tube to an orifice (nozzle) where the compressed air rapidly expands and increases in velocity, causing a local negative pressure. The negative pressure is used to suck liquid into a tube, to the point of air expansion, where it is sheared into a liquid film. The film stretches and becomes unsta- ble, thereby breaking up and forming droplets due to sur- face tension forces. 15, 16 The droplets are conveyed towards a baffle situated just above the aerosol production area. The baffle "sieves off" the larger droplets by impaction and returns the liquid from the droplets back into the reservoir while the smaller droplets are transported to the nebulizer outlet (and the patient). More than 99% of the aerosol produced is returned to the reservoir; only about 1% reaches the nebulizer outlet. 17, 18 The nebulizer nozzles have two designs; one where the air and liquid are inter- nally mixed then ejected through a secondary orifice and the other that uses an external mixing design where the secondary nozzle is omitted (Figure 4). Both types are fre- quently seen in various nebulizer brands. Breath-enhanced jet nebulizers Although conventional jet nebulizer technologies have reached maturity, they are still being continuously honed. Over the last several years, jet nebulizers have been improved by the introduction of breath-enhanced deliv- ery. In these devices, the nebulizer operates as a conven- tional jet nebulizer during exhalation, but increased out- put is achieved when the nebulizer is used during inhala- tion (Figure 5). Using these nebulizers, both drug delivery per unit time and total drug delivery are increased and treatment time is shortened. 19 Breath-actuated jet nebulizers Further improvements to nebulizers have been made by the introduction of breath-actuated nebulizers. They have the same working principle as breath-enhanced nebulizers yet they deliver aerosol only when a patient inhales but not Pneumostat with electrical compressor (Image from The Inhalatorium) 7 Figure 2 Jet nebulizer operating principle Figure 3 Typical nebulizer designs Figure 4 Gas stream Solution Aerosol Baffle Liquid Liquid Internal mixing External mixing Gas Gas Liquid Liquid Baffle