New research may lead to more effective treatment of asthmatic attacks

Electrohydrodynamic atomization (EHDA) is a new technique able to produce droplets of a defined size. Based on techniques new to the field of medical atomization, it seems a promising technique for small hand-held devices

Bethesda, MD – Asthma is a serious chronic condition affecting almost l5 million Americans. Between l982 and l994, there was a 6l percent increase in asthma patients. According to the American Lung Association, asthma accounts for an estimated 3 million lost work days for adults and 10.1 million lost school days in children annually.

Background

Inhalation therapy is the most frequently applied method to administer drugs for the treatment of asthma. Direct local administration into the lungs leads to an immediate effect, and when compared with oral administration, smaller doses are needed. However, when conventional inhalation devices are used, only a fraction of the inhaled drug reaches the lower airways, where it has its therapeutic effect. A large part is deposited in the mouth and throat, after which it is swallowed and subsequently may be absorbed in the gastrointestinal tract.

The low efficiency of the inhalation equipment is related to the less optimal size distribution of the particles released, although recently developed inhalers can show improved distributions. Research has shown that, in adults, monodisperse 2.8-µm bronchodilator particles were optimal in terms of efficacy. It was also shown that administration of these monodisperse aerosols could open the way to reduce the dose emitted from metered or dry powder inhalers by 80 percent without losing any clinical effect.

The means to produce monodisperse or narrow size-ranged steroid aerosols are limited. Present systems, like the spinning-top generator, are cumbersome in their use and are, therefore, confined to a laboratory environment Electrohydrodynamic atomization (EHDA) is a new technique able to produce monodisperse droplets of a defined size in the micrometer range. It is based on techniques that are new to the field of medical atomization, and though in its infancy, it seems a promising technique because of its potential to be converted into small hand-held devices.

The aim of this study was to find out whether EHDA could be used to generate corticosteroid aerosols in a size range between one and five micrometers with a low geometric standard deviation (GSD) and in quantities sufficiently high to make administration to patients feasible.

The authors of the study, “Electro-Hydrodynamic Atomization of Drug Solutions for Inhalation Purposes,” are Jeroen C. Ijsebaert, Kees B. Geerse, and Jan C. M. Marijnissen from the Particle Technology Group, DelftChemTech, Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands; and Jan-Willem J. Lammers and Pieter Zanen from the Department of Pulmonary Diseases, University Hospital Utrecht, Utrecht, The Netherlands. Their findings appeared in the December 2001 edition of the Journal of Applied Physiology.

Methodology

The energy source for EHDA is an electric field. A liquid is supplied to a nozzle, and an electric field is generated between the nozzle and a counterelectrode. When the electrical stress overcomes the surface tension of the liquid, a cone is formed, from which a thin jet emerges. The jet breaks up into monodisperse droplets.

The device spray section in the experiment used a nozzle-ring configuration. The nozzle and the ring were connected to two high-voltage power supplies, which yield the necessary electric field. The ring "focuses" the spray to prevent immediate heavy loss of the charged aerosol. The corona discharge is generated from a grounded sharp needle, placed perpendicular below the nozzle. The distance between the needle and the nozzle can be varied. While they are transported to the exit of the system by a filtered airflow (high-efficiency particle arrester filter), the droplets evaporate, after which the formed particles are sampled and/or inhaled (for accurate size measurements, particles need to be solid).

EHDA produces droplets from a solution. Ethanol was chosen as the solvent because it has excellent liquid properties for EHDA, it is already present in inhalation preparations, and, the steroid intended to be used in human experiments, beclomethasone dipropionate (BDP), is soluble in ethanol. Because BDP is expensive, the initial experiments were performed with a solution of methylparahydroxybenzoate (MPHB) in ethanol.

Results

Key findings of the experiment include the following:

• Influence of the liquid flow and drug concentration on particle size. At increasing flow rates, the size of the particles increases; averaged over all concentrations, the mass median aerodynamic diameter increased by factors of 1.39 and 1.61 when liquid flow was doubled or tripled, respectively.

• Neutralization efficiency. When the ring-needle potential difference was 3 kV (kilovolt), no discharge was apparent: no particles passed the precipitator. At higher potential differences, sufficient production of corona ions starts and the droplets are discharged better until a maximum number of particles is counted. For a ring-needle distance of 7 centimeters, this maximum occurs at a potential difference between 7 and 12 kV and for a 9 centimeter distance at 9 kV. Increasing the potential difference beyond these values causes the number of counted particles to decrease.

• Particle size and mass of monodisperse BDP aerosols. Compared with the initial MPHB experiments, the resulting mass median aerodynamic diameter and particle width of distribution are in good agreement: for the 0.5 percent, 1 ml/h setting, exactly the same particle size was obtained; whereas for the 3 percent, 3 ml/h setting, the BDP size was 0.45 micrometers larger.

Conclusions

The research demonstrated that it is possible to generate BDP aerosols of various particle sizes with very narrow size distributions using EHDA. Up until now, generation of monodisperse aerosols was only possible with complicated laboratory equipment, like the spinning top. Such devices all are characterized by moving mechanical parts, high use of compressed air, complicated operating process, and/or high temperatures. EHDA is characterized by nonmoving parts, no use of compressed air, and easier operation.

An aerosol generator that employs electric fields instead of compressed air could lead to a revolution in inhalation therapy. Easy aerosol production and construction and most of all a small width of the particle size distribution ensures greater efficacy for dispersing the inhalant that will ultimately benefit the patient.

Source
December 2001 edition of the Journal of Applied Physiology.

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.