Nebulizer Performance

When a therapeutic agent is formulated into a nebulizer solution or suspension, the quality of the aerosol generated, in terms of aerodynamic particle size, can be markedly dependent on the type of nebulizer used and its operation. This issue has been studied for over 30 years but is still a major challenge for the pharmaceutical industry today. Although having absolute control of the nebulizer formulation per se, the formulator (or the pharmaceutical company supplying the solution for nebulization) has very little control over the nebulizer system prescribed to the patient and of the operational parameters used by the health care professional during dosing. However, there is a strong desire on the part of drug regulators to control the patient's exposure by having drug products (nebulizer formulations) that have operational data collected during the development phase with one or more suitable nebulizers (e.g., DNAase™ [23]).

The literature abounds with examples of nebulizer performance variability, in terms of both output and aerodynamic particle size generated. Furthermore, frequently the manufacturer's information provides inadequate detail. Newman and colleagues [24,25] investigated 11 air-jet nebulizers in terms of mass median aerodynamic diameter (determined by Malvern laser light scattering), geometric standard deviation, and the respirable aerosol mass (i.e., particles < 5 mm). Considerable performance variation was noted between the nebulizer brands and, indeed, within different units of the same brand. Aerodynamic particle size also decreased with increasing compressed gas flowrate. As a consequence, they concluded that the quantity of drug available to the subject was dependent on the choice of air-jet nebulizer and its operation in terms of compressed gas flow. Other investigators have evaluated different drug/nebulizer combinations and reached similar conclusions [26].

Drug delivery from an air-jet nebulizer is a complex process. Here are some of the various issues that merit careful consideration when evaluating nebulizer delivery.

The variability between different nebulizer brands and of individual units within a given brand

The calculation of a true dose delivered (in relation to evaporative losses, residual volume, etc.)

The aerodynamic particle size of the nebulized dose (i.e., respirable dose delivered)

The airflow (and the variability thereof) and its effect on nebulizer output (mass) and the respirable dose

Changes in ambient and nebulizer solution temperatures during the time course of nebulization and their effect on evaporative losses

Changes in drug concentration during nebulization (i.e., potential changes in drug delivered versus time)

These parameters may compound those inherent intersubject and intrasubject variables, such as breathing pattern, respiratory performance (e.g., tidal volume), and airway function, and thus further complicate pulmonary drug delivery. As a consequence, given such variables (to provide standardization), various studies have concluded that a designated nebulizer should be calibrated before use. Guidelines are now available for the effective and consistent clinical use of these devices [27].

The performance of ultrasonic nebulizers has received less attention than that of air-jet nebulizers, perhaps because they are perceived as being intrinsically less variable [28]. However, it is important to note that brands of the ultrasonic nebulizer have significantly different features. Transducer frequency (based on manufacturer's information) varies over a range of several megahertz. This operating frequency may also shift slightly in aged units. Many ultrasonic nebulizers have electrical "power" settings and variable-airflow features. As a consequence, the nebulizer solution output per liter of air under extreme operating conditions can vary considerably between different device brands [29].

In general, ultrasonic nebulizers are capable of greater output (when parameters are optimized) than air-jet units, although they often retain a higher dead volume. Intrinsically, the aerodynamic particle size generated by ultrasonic nebulizers is dependent on the brand used and its operational parameters. Similarly, ultrasonic nebulizers produce a coarser aerosol (higher median aerodynamic diameter) than air-jet nebulizers. It is critical that careful evaluation of the performance of the pharmaceutical product with the nebulizer that is ultimately designed for use with be conducted prior to clinical use. Differences in dosing of potent drugs may result if the inappropriate operating conditions are used [30].

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