Comment on: Devices and formulations for pulmonary vaccination

In the review by Tonnis et al., ‘Devices and formulations for pulmonary vaccination' [1], a major class of nebulizers was overlooked—namely, mesh nebulizers. As illustrated below, mesh nebulizers overcome many of the problems that were highlighted for jet and ultrasonic variants and would, in our opinion, be the nebulizer type of choice when considering the delivery of vaccines and other macromolecules to the respiratory tract.

Mesh nebulizers generate aerosol by passing the formulation through an ultrasonically vibrating mesh, containing holes approximately 2.5 µm in diameter, which results in aerosol with a median droplet size of approximately 4 µm. Mesh nebulizers fall into two categories. The first are those that have a piezoceramic element directly bonded to the mesh, causing it to vibrate (e.g., the PARI eFlow, PARI GmbH, Starnberg, Germany, and the Aeroneb Go, Aerogen, Galway, Ireland). The second are those that have a piezoceramic element bonded to a horn, which then vibrates and pulses fluid through a static mesh (e.g., the I-neb AAD System, Respironics Respiratory Drug Delivery (UK) Ltd, Chichester, UK, and the MicroAir U22, OMRON Healthcare, Kyoto, Japan). These mesh nebulizers are small, light (<200 g), portable, and do not require an AC power source; they also offer fast nebulization times, have low residual volumes, and do not require a pressurized external air source. Thus, they overcome many of the factors that were identified in the paper as making nebulization unsuitable for vaccine delivery. Mesh nebulizers are described and discussed more fully in papers by Kisser et al. and Hardaker et al. [2,3].

The review also highlighted that degradation of a vaccine can occur, either due to shear forces in the jet nebulizers, or due to ultrasonic pulsing (plus heating) in the ultrasonic nebulizers. Due to the recirculation of droplets in the jet and ultrasonic nebulizers, a labile molecule can be subjected to these shear forces a number of times before it leaves the nebulizer. Mesh nebulizers, by contrast, have no recirculation, and pass the labile molecule only once through the aerosol generation mesh; the passage through the mesh itself is subject to low shear. This makes mesh nebulizers ideally suited to delivery of labile molecules, and successful delivery, without loss of activity, has been demonstrated with a range of macromolecules and biological materials [2,4-10].

Another feature of nebulizers raised in the Tonnis et al. review, which limited their use for vaccine delivery, was inaccuracy of dose. This can be overcome by breath activation, implementation of volumetric metering, and use of controlled breathing patterns; these features are found in the I-neb nebulizer and can result in lung deliveries of over 70% of the total inhaled drug [11]. Although cost could be an issue with single-patient use devices, the relatively simple design of the mesh nebulizer, and advances in materials, provide for the possibility of multi-patient mesh nebulizers, enabling multiple doses to be delivered at minimum cost per dose.

In summary, mesh nebulizers overcome many of the issues identified by Tonnis et al. for jet and ultrasonic nebulizers, and, contrary to their conclusion that ‘nebulization cannot be the standard for routine vaccination' [1], nebulization should not be discounted as a potential means of effective and efficient delivery of vaccines.

Declaration of interest

The authors state no conflict of interest and have received no payment in the preparation of this manuscript.

Rebuttal from the authors

Affiliation

Wouter F Tonnis^†, Anne J Lexmond, Henderik W Frijlink, Anne H de Boer & Wouter LJ Hinrichs

^†Author for correspondence

University of Groningen, Department of Pharmaceutical Technology and Biopharmacy, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands E-mail: [email protected]

We appreciate Ross Hatley's & John Pritchard's interest in and comments on our review.

They point out that we overlooked a class of nebulizers, namely the mesh nebulizers. They argue that mesh nebulizers overcome many of the problems that we described for jet and ultrasonic nebulizers, and thus, that these devices should be recognized as potential means of vaccine delivery. We agree with Hatley and Pritchard that it may be possible to administer specific vaccine formulations with a mesh nebulizer, but this does not necessarily make them devices of choice. Still, we acknowledge that our rationale for not addressing these nebulizers separately is missing in the article. Therefore, we would like to take this opportunity to elaborate on the reasons why we believe mesh nebulizers are not well suited for pulmonary vaccine delivery.

First of all, the stability of the vaccine formulation determines whether administration with a mesh nebulizer is feasible at all. As explained by [the authors], a mesh nebulizer uses high frequency oscillation for the formation of the aerosol. Conventional ultrasonic nebulizers produce droplets by applying high frequency pulses from an oscillating piezo element to the solution (or suspension) either directly through the wall of the drug reservoir or indirectly through a water bath. The high frequency waves create standing waves on the liquid surface from which droplets are released. There is a prolonged energy transfer to the solution, which has been shown to be an important cause of degradation of the active compound [1,2]. In vibrating mesh nebulizers, the piezo technology is combined with a perforated membrane (mesh) that is in contact with the solution. These mesh nebulizers generally deliver highly concentrated aerosols in a reduced nebulization time, although the time reduction is limited. Both of these features result in a reduced energy transfer to the solution, and therefore, degradation may be reduced. However, what worries us is the effect of forcing large, complex molecules or delivery systems (whole inactivated virus vaccines, virosomes, liposomes, nano/microparticles) through small holes, which may induce substantial shear stress due to various wall effects. For the labile molecules referred to by [the authors], the energy transfer and shear stress may be low enough to prevent activity loss, but this must be investigated for every individual vaccine formulation, before one can say that a mesh nebulizer is suitable for the delivery of that specific vaccine.

The next point, which Hatley and Pritchard address as a benefit of mesh nebulizers, is that many of the currently available mesh nebulizers are equipped with features for improved lung delivery, as for instance obtained with inhalation profile adapted aerosol generation. However, such features make these devices expensive. Therefore, their use is mainly confined to therapies against diseases like cystic fibrosis in rich industrialized countries, which is in stark contrast to use in vaccination programs in developing countries. Only when new mesh nebulizers are developed that do not have such features, lower costs, and thus wider applicability, can be realized.

This leads us to our main concern about (mesh) nebulizers. Vaccination programs often take place in poor countries with a warm climate, where neither clean (tap) water, nor a cold chain may be available. Clean water for reconstitution is therefore not available, or it should be supplied in ampoules, which would require the use of needles, thereby reintroducing some of the problems identified in the first place. Further, mesh nebulizers are battery powered, thus reusable devices, regardless of whether the production costs can be low. Therefore, our objections concerning multipatient use also apply to these devices. Other issues that we consider relevant are the following:

• Even though administration time is reduced compared to conventional nebulizers, it still takes several minutes, which is a long period of time compared to a single inhalation that takes only seconds.

• Residues, albeit low, require that the nebulizer cup should be emptied and cleaned (with clean water) before it can be used again.

• The membrane should be carefully flushed with clean water after each use to prevent clogging of the holes.

These issues add up to a significant time burden compared to vaccination by injection, or alternatively, dry powder inhalation. For small-scale studies, this may not be a problem, but it is far from ideal for mass vaccination programs.

In summary, we agree with Hatley and Pritchard that we should have mentioned the vibrating mesh nebulizers in our review, because in some cases, these devices can be used for administration of vaccines. However, many of the concerns that apply to nebulization in general also apply to mesh nebulizers. Because of these concerns, and because of the extra benefits of dry powder inhalation described in our review, we believe that cheap and disposable dry powder inhalers are the devices of first choice.

Acknowledgments

S Keen (PS5 Consultants Ltd) provided editorial assistance to the authors.

Declaration of interest

This article was sponsored by Respironics Respiratory Drug Delivery (UK) Ltd. R Hatley and J Pritchard are both employees of this company.