Recent Advances in Nebulizer Technology

Nebulizers have been used for asthma therapy for many years and are used for the delivery of fine droplets of drugs to the lungs. For this reason they have been optimized for aerosol delivery in the upper range of inhalation

Fluorinated Albuterol

Figure 21 Median adhesion between an albuterol particle and the internal walls of five pMDI canisters in model propellant using colloid probe microscopy. Canister coatings were as follows: Aluminum (ALU), anodized aluminum (AN-ALU), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene-polyether sulphone (FEP-PES) and perfluoroalkoxy (PFA). Source: From Ref. 134.

Figure 21 Median adhesion between an albuterol particle and the internal walls of five pMDI canisters in model propellant using colloid probe microscopy. Canister coatings were as follows: Aluminum (ALU), anodized aluminum (AN-ALU), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene-polyether sulphone (FEP-PES) and perfluoroalkoxy (PFA). Source: From Ref. 134.

delivery, that is, 1-6 ^m. Nebulizers can produce a constant stream of aerosol particles, from both solutions and/or suspensions which can be inhaled via tidal breathing. Furthermore, the aerosol droplets produced may be of a smaller range than pMDIs, making them capable of easily penetrating the small airways (135). Nebulizers enable treatment of patients that require higher doses of drugs (i.e. antibiotics), that can, until now, only be formulated to be delivered via a nebulizer (i.e. DNAse for the treatment of cystic fibrosis), or have difficulties with conventional inhalers, such as the very young or elderly patients. However, Nebulizer systems have many draw backs. For example, historically, nebulizers have been cumbersome, often being used at home or in a clinical setting. Furthermore, they deliver medication over a long timescale and have a complexity of device assembly with low efficiency and high variability in drug delivery (136-138).

The most common type of nebulizer is the air-jet nebulizer (139). Jet nebulizer devices utilize a pressurized gas to create the aerosol particles (140). The gas stream is passed over the solution, creating a liquid film. This film breaks apart due to breakage of surface tension forces, forming aerosol particles, with the aerosol droplet size being dependent on the compressed air pressure applied (7). Subsequently, respiratory sized droplets can easily be produced once the large droplets (>10 um) have been filtered out by impaction on the device surfaces or baffles (141).

The major disadvantage of jet-nebulizers is their constant aerosol output during the inhalation, exhalation, and breath-hold, which is not matched to the patient's respiratory effort (142,143). Other disadvantages include: a residual volume (0.5-1.0 ml), a long therapy time (10-15 min for completion), a variable mass output throughout nebulization and an increase in osmolarity of the aerosol/liquid with nebulization time (139,144). Of all the jet nebulizers on the market, the most popular systems are probably those produced by Pari GmbH, for example, the Pari LC Plus® and the Pari LC Star® products. These systems belong to the so called jet enhanced nebulizers. Conventional jet nebulizers aerosolize continuously, resulting in higher losses of dose and shorter nebulization times. Since the aim is to be able to deliver the drug only during inhalation, novel breath-operated nebulizers have been developed. These novel nebulizers have been shown to increase the in vivo mass of the inhaled drug compared with conventional jet nebulizers (145).

Breath-synchronized nebulizers have been reported to effectively reduce drug wastage during the expiratory phase, both in vivo and in vitro (146,147). Examples of breath operated jet nebulizers include the AeroEclipset (Trudell Medical International, London, Ontario, Canada) and the Smartstream® (Medic-Aid, West Sussex, UK). These devices are designed to deliver drug during the whole inspiration, whereas new adaptive electronic dosimetric jet nebulizers, such as the HaloLite® (Medic-Aid) are operated using a different principle, for example, delivering drug during the first ~50% of each inspiration, or the delivery of aerosol only during inhalation, as in the conventional jet nebulizer, the AKITA® (InAMed, Germany). Furthermore, improvements in constant output nebulizers have also been made with the advent of the breath-enhanced nebulizers, for example, the PARI LC Star (PARI, Germany) and the Ventastream® nebulizer (Medic-Aid, UK). In these new devices the aerosol is produced at a higher rate during inhalation than during exhalation, using valves to control air flow and mixing (144). In general, the level of waste of the nebulized dose, in these systems, is reduced by at least 50% in comparison with the original assisted open vent nebulizers. Since droplet size distribution and output rate are also influenced by the physical properties of the drug solution (suspension) and air flow rate from the compressor, it can, be concluded that there are high variations in the performance of different types of such nebulizers (143,148,149).

Adaptive aerosol delivery technology (150) is an approach developed to address the highly variable drug delivery characteristic of conventional delivery systems. These novel types of nebulizers adapt to the individual breathing pattern of the patient (determining the shapes of the inspiratory and expiratory flow pattern) and deliver the aerosol only during inhalation. Such systems pulses aerosol delivery only during inhalation and each pulse is matched to the previously determined inspiration time. The breathing pattern is continuously monitored and the system adapts to the changes in pattern. Furthermore, such systems are programmed to deliver a preset metered dose. An example of this new technology can be found in the HaloLite AAD system (Profile Therapeutics, UK). In a recent study (151), utilizing a modified venturi Venstream® nebulizer (Profile Respiratory Systems, UK) which incorporated an AAD system, nebulized budesonide was administered to 125 Spanish children with moderate to severe asthma for 24 weeks in a double-blind, randomized, parallel group study. A total of 75% of the children received 100% of the programmed dose. Although there was no statistically significant difference between the treatment regimens, there was a clear improvement in the overall health score. Similarly, in another study involving 47 children aged less than 3 years old, a higher number of patients achieved successful treatment with the HaloLite AAD system (81%) compared with the Ventstream nebulizer (66%) (152). Overall the AAD technology appears to be a promising approach for the challenge of delivering reproducible doses of aerosolized drug to the lungs (Fig. 22).

An alternative popular type of nebulizer is the ultrasonic nebulizer. Ultrasonic nebulizers generate high frequency ultrasonic waves, produced by a rapidly vibrating piezoelectric crystal. A given solution presented to the piezoelectric crystal surface is broken into fine droplets where the aerosol droplet size is inversely proportional to the power of the acoustic frequency. In a similar way to jet nebulizers, baffles within the nebulizer remove large droplets. Ultrasonic nebulizers have many advantageous over compressed

Conventional Jet Nebulizer
Figure 22 Comparison of drug output during inspiration and expiration for a conventional jet nebulizer, active venture nebulizer, and an ADD system. The shaded areas represent drug output. Source: From Ref. 153.

air systems, including the small size of device, the minimal patient coordination required, and rapid drug delivery (138). However, it is important to note, that these systems also have disadvantages, including the high device costs, susceptibility to mechanical breakdowns and potential for contamination. Depending on the method (direct or indirect) used to produce the aerosol droplets the ultrasonic class of nebulizers can be sub-classified into passive and active vibrating devices. Passive vibrating mesh ultrasonic devices [e.g. the Omron MicroAir NE-U22 (Omron Healthcare, Ltd., Milton Keynes, UK)] are small battery-operated nebulizers which utilize a piezoelectric crystal in an ultrasonic horn to force drug solutions through a mesh of hundreds (or thousands) of micron-sized holes to creating an aerosol (154). The example given here (the MicroAir), in comparison to many conventional devices, results in primary droplets that are sufficiently small so that no baffles are required to filter the spray, thus allowing the use of a smaller volume fill.

Active vibrating mesh ultrasonic nebulizers (155) ensure the mesh in contact with the reservoir fluid is vibrated directly by a piezoelectric crystal to generate the aerosol cloud. These devices use a perforate membrane and a micro-pumping action to draw jets of fluid though the holes in the membrane, dispersing the jets into a drug cloud. The size of the aerosol droplets is controlled by the shape/size of the holes and the surface chemistry and composition of the drug solution. Examples of such types of nebulizers are: the AeroNeb®Pro and AeroNebGo (Nektar Therapeutics) (156), the e-FlowTM (Pari GmbH) (157,158) and the TouchSpray™ (ODEM Ltd.) (159).

In comparison, a novel class of nebulizer device which has been investigated by Battelle Pharma, Ohio, is the Electrodynamic Aerosol Devices (EAD) (160). This novel device uses a powerful electric field to create near monodisperse, low velocity charged aerosols from a liquid formulation. As the solvent in the droplets evaporate in entrained air, the surface charges on each droplet repel each other and cause the droplets to separate, producing an aerosol cloud with a small particle size. The limitation of this technique is that electric charge is known to affect aerosol deposition, both in vitro and in vivo (161,162). To the authors' knowledge no devices with the EHD technology are on the market as yet, however, early performance results have shown promise (156).

In general, there have been few recent advances in nebulizer technology. In 2003 Boehringer Ingelheim introduced a new nebulizer, the Respimat® Soft MistTM Inhaler which is a propellant-free, multidose system (163). This nebulizer system uses an innovative approach for inhalation therapy combining a mixed form of nebulizer and pMDI. The medication is stored in a sealed plastic container inside of the cartridge. When the dose-release button is pressed, the energy released from the spring forces the solution through a "uniblock", releasing a slow-moving aerosol mist. Observations concerning the use of this kind of system with suspensions has not been reported. Furthermore, recently, Aradigm launched AERx® (164) Pulmonary Delivery System in 2000. This nebulizer generates an aerosol by mechanically pressurizing a disposable blister pack, forcing the liquid through an array of micromachined holes (165). This device has been used with a vast array of drug molecules with various successes including: morphine, rhDNase, insulin, and fentanyl. Finally, Chrysalis Technologies (a division of Philip Morris, USA) has developed a novel proprietary capillary aerosol generation system in which the aerosol is formed by pumping the drug formulation through a small, electrically heated capillary (166,167). This device enables thermally stable drugs and vehicles to be evaporated and subsequently condensed in entrained air in a controlled fashion, producing a soft aerosol. Although this device has the advantage of being able to exhibit very high delivery efficiencies (fraction of milliliter), one envisaged disadvantage is that it is unlikely that all drugs can be aerosolized in this way without some degree of drug degradation occurring.

At the present, there is a great deal of debate between health professionals in how to decide which nebulizer to use for a particular application or situation. Pharmaceutical companies still supply drugs to be used for nebulization independently of which device is going to be used for its aerosol delivery. This approach may seriously affect the intended therapeutic benefit. At the moment it is considered to be sufficient to merely characterize nebulizer performance using a simple saline solution at or near physiological concentration (168,169). It seems reasonable that in view of this testing methodology and the examples given here, that there is a need for a more stringent evaluation standardization test that will improve the future health care of patients.

Continue reading here: Conclusions

Was this article helpful?

+1 0


  • uta
    Is HaloLite AAD nebulizer still on market?
    1 year ago
  • janina barth
    How are drugs formulated for nebulizers?
    2 years ago