Nebulizers and Soft Mist Inhalers

At the start of the 1990s the only available aqueous solution-based pulmonary delivery systems were the nebulizers that had their routes in technology developed at the turn of the nineteenth century. From a patient perspective, nebulizer therapy is time consuming, equipment costs are high, and cleaning and maintenance can be problematic; from a pharmaceutical perspective, nebulizers exhibit poor delivery efficiency and high variability [22]. However, nebulizers are capable of delivering high doses of medication to the airways, and patients do not seem to need intensive training to be able to use them effectively. Thus efforts have been made to improve nebulizer design. The first and simplest improvements are entrainment designs, where aerosol generation decreases during expiration, and these designs appear to reduce wasted medication and improve delivery efficiency [23]. More recent designs use valves that respond to the inspiratory cycle and completely stop aerosol generation during the expiration phase [24]. Electronic devices, which synchronize delivery with inspiration, have also been developed. The most advanced of these, Adaptive Aerosol Delivery [25], also counts the number of "actuations" and automatically adjusts the number of delivery cycles so as to deliver a constant dose, regardless of the patients' breathing pattern.

Advances have also been made in atomization technology, with ultrasonic mesh atomizers now being used in some commercial nebulizer devices [26]. The promise for the future is that flow monitoring will be more effectively liked to atomization to control delivery and enhance the efficiency, reproducibility, and ease of use of the next generation of nebulizers. This will enable drug-specific dosing regimes to be developed. However, as nebulizer designs become ever more drug specific they run the risk of being regulated as an intergral part of a drug product and losing their "generic" device status. This would mean much heavier regulation and a loss of the design freedoms they currently enjoy.

In the early part of the 1990s a natural extension to nebulizer technology was conceived. The idea was to deliver an effective dose of medication from an aqueous solution in a small number of breaths and to embody this in a device as small and simple as a pMDI. These soft mist inhaler (SMI) concepts, which began development in the early 1990s, were based on three basic atomizer concepts. The first uses small nozzles and high pressures to dispense and atomize metered volumes of solution; trade-offs can be made between the number of nozzles and the pressure used to extrude the solution through the nozzles, and two technologies at opposite ends of the trade-off spectrum have now emerged [27,28]. The second technology uses multiplexed, ultrasonic-driven nozzles (mesh arrays) to atomize droplets, and specific variants of this technique are currently at different stages of development [29,30]. The third, slightly later, entrant uses electrohydrodynamic atomization [31], and this technology has been used in early studies with cancer therapeutics. Some of these technologies have already demonstrated high delivery efficiencies. For example, the Respimat (formerly BINeb) has shown 50% delivery to the lungs [27], and the Aradigm AERx has reported close to 80% [28]. However, in addition to the deviceengineering issues, one of the major challenges has been dealing with the possibility of microbial contamination of the aqueous solution reservoirs and/or mastering aseptic manufacturing techniques for unit-dose devices. Again, as with some dry powder device technologies and the second-generation powder formulations, none of these SMIs have yet made it to market. Although as of summer 2002, Phase III clinical studies with the Respimat had been completed and the AERx was poised to begin Phase III studies with insulin.

Figure 6 summarizes developments in the solution area and illustrates the migration of aqueous solution technology from nebulizer, through "controlled" nebulizer, to SMI technologies. However, it should be remembered that nebulizers still exhibit some unique qualities that will probably ensure their continued use over the coming years.

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