Respiratory Care

Over the past few decades, aerosol delivery devices have been relatively inefficient, wasteful, and difficult for patients to use. These drawbacks have been tolerated because the drugs available for inhalation have wide therapeutic margins and steep dose-response curves at low doses. Recently several forces have converged to drive innovation in the aerosol device industry: the ban on chlorofluorocarbon propellants in metered-dose inhalers, the need for more user-friendly devices, and the invention of expensive inhalable therapies for topical and systemic lung delivery. Numerous devices are in development to improve the efficiency, ease of use, and reproducibility of aerosol delivery to the lung, including systems that force liquid through a nozzle to form the aerosol cloud. The Respimat is a novel, compact, propellant-free, multi-dose inhaler that employs a spring to push drug solution through a nozzle, which generates a slow-moving aerosol. Deposition studies show that the Respimat can deliver 39-44% of a dose to the lungs. Clinical asthma and chronic obstruc- tive pulmonary disease trials with bronchodilators show that the Respimat is 2-8 times as effective as a metered-dose inhaler. Respimat has been tested with bronchodilators and inhaled corticoste- roids. The AERx device uses sophisticated electronics to deliver aerosol from a single-dose blister, using an integral, disposable nozzle array. The electronics control dose expression and titration, timing of aerosol generation with the breath, and provide feedback for proper inhalation technique. Lung deposition ranges from 50 to 80% of the loaded dose, with remarkable reproducibility. AERx has been tested with a variety of drugs, for both topical and systemic delivery, including rhDNase (dornase alfa), insulin, and opioids. These novel devices face competition from other technologies as well as financial and regulatory hurdles, but they both offer a marked improvement in the efficiency of pulmonary drug delivery.

Several electronic nebulizer devices that use a vibrating mesh or plate with multiple apertures to generate a fine-particle, low-velocity aerosol have been marketed or will shortly become available for clinical use. These devices have a high efficiency of delivering aerosol to the lung, such that the nominal dose of drugs to be administered could be substantially reduced. Moreover, the volume of drug solution left in these new devices when the nebulization has ceased is negligible, so there is potential to improve the cost-effectiveness of administering expensive medications. Because these devices nebulize at a faster rate than conventional jet or ultrasonic nebulizers, the duration of each treatment could be shortened. These devices efficiently nebulize solutions and suspensions; they have been successfully used for aerosolizing insulin, other proteins and peptides, and fragments of DNA. They could be employed for a wide variety of clinical applications, including the delivery of aerosols for systemic therapy and gene transfer. These devices have overcome many of the limitations associated with conventional jet and ultrasonic nebulizers, and they offer the versatility to modify the aerosol characteristics according to the clinical application for which they are employed. With these devices clinicians will be able to precisely control drug delivery to the respiratory tract.

This review explains the fundamentals of electrostatic spray (electrospray) atomization, with emphasis on operation in the so called cone-jet mode, which produces droplets with a very narrow size distribution. Since the control of droplet size is key to maximizing distal lung deposition, the electrospray should be well-suited to targeted drug inhalation. Electrospray droplets are a few micrometers in diameter, but they originate from a much larger nozzle, which allows nebulization of suspensions without clogging. Also discussed are: the physical principles of the break-up of the liquid ligament; droplet dispersion by Coulombic forces; and the most important scaling law linking the droplet size to liquid flow rate and liquid physical properties. The effects of the most critical of those properties may result in some restrictions on drug formulation. Droplets produced by electrospray are electrically charged, so to prevent electrostatic image forces from causing upper respiratory tract deposition. The charge is neutralized by generating a corona discharge of opposite polarity. Briefly discussed are the main differences between the laboratory systems (with which the electrospray has been quantitatively characterized during research in the past 10 years) and commercial electrospray inhalers under development at BattellePharma. Some remarkable miniaturization has incorporated liquid pump, power supply, breath activation, and dose counter into a palm-size portable device. The maximum flow rates dispersed from these devices are in the range of 8-16 µL/s, which makes them suitable for practical drug inhalation therapy. Fabrication is economically competitive with inexpensive nebulizers. Dramatic improvements in respirable dose efficiency (up to 78% by comparison with commercial metered-dose inhalers and dry powder inhalers) should ensure the commercialization of this promising technology for targeted drug inhalation.

Physicians are familiar with conventional nebulizers, which deliver aerosols in a relatively uncontrolled manner. As aerosol medications evolve beyond bronchodilators, the need for control of dose variability, the possibility of overdose, and the need for efficient delivery have provoked the industry to redesign aerosol delivery systems. The need to target aerosol delivery to specific lung regions has focused efforts to coordinate aerosol delivery with defined breathing maneuvers. This review summarizes the major factors affecting aerosol deposition, discusses how those factors are guiding new designs for aerosol delivery systems, and describes some examples of the improved precision and efficiency of those systems.

The delivery of nebulized drugs is poorly controlled and the choice of the most appropriate delivery device is poorly understood, particularly because of off-license prescriptions and a lack of evidence-based medicine. Standardized in vitro methods for measuring nebulizer performance have been adopted in Europe, by the 2001 publication of a European Standard, prEN13544-1. These standardized methods were subsequently incorporated within the European Respiratory Society nebulizer guidelines, which will provide clinicians with useful information to improve nebulizer therapies. Standards for measuring nebulizer performance should be considered in North America and elsewhere. Careful consideration should be given to either adopting the methods embodied in the European Standard or developing the basis for developing that standard further through the International Standards Organization. Either way, confusion among clinicians would be reduced and nebulizer safety and aerosol delivery efficiency increased by standardizing in vitro methods of nebulizer performance assessment.

Currently available nebulizers are inefficient, bulky, noisy, and take longer to use than other inhalation devices. Use of nebulizers is increasingly confined to patients who cannot use other devices or who require therapies not available in another form. In the future, nebulizers will be smaller and more efficient. "Smart" nebulizers that can monitor patient use and provide feedback to the patient and the caregiver will be developed. Critical study will be needed to determine whether these innovations improve patient compliance with therapy. Nebulizers will also be refined for delivering complex molecules for both pulmonary and systemic disease. One example is in the use of gene therapy, in which issues such as the best gene vector are unresolved. Nebulizing these complex molecules without damaging them may be difficult, and nebulizers of the future will have to be more efficient to avoid wasting expensive drugs. For the delivery of widely used, less expensive medications, such as some bronchodilators, these innovations will not be cost-effective, so cheaper, less efficient nebulizers will continue to be used.

Most physicians and respiratory therapists are knowledgeable of the use of aerosolized drugs, but many are less familiar with the performance characteristics of the nebulizer. In fact, the general opinion is that the performance of the nebulizer is relatively unimportant. However, there is accumulating evidence that the nebulizer itself does make a difference. The decision to replace a good performing nebulizer with a poor performing nebulizer may decrease the delivered dose in half or more. Although this is less important for routine bronchodilator therapy, it may make a big difference with newer aerosolized drugs. Increasingly, the Food and Drug Administration is approving drugs to be used with a specific nebulizer brand and new nebulizer designs are becoming available for use with these drugs. There are several reasons why I think this conference was important. First, new aerosol drug formulations are becoming available and these will require better performing nebulizers. Second, we as clinicians need to be knowledgeable of the newer generations of nebulizers so that we can make informed purchase decisions. Third, and perhaps most important, we must gain an increased appreciation for aerosol therapy as a science. The proceedings of this conference do much to synthesize the current state-of-the art related to new nebulizer systems. This provides, in a complete and cogent manner, the scientific basis for which clinicians can improve their knowledge of the new generation of nebulizers.