A system for the production and delivery of monodisperse salbutamol aerosols to the lungs

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Abstract

An aerosol system is described for the generation and delivery of measured doses of monodisperse therapeutic drug particles to the human lungs. The system comprises a spinning top aerosol generator (STAG), aerosol chamber and inhalation control unit. Monodisperse aerosols allow drug particle size effects to be studied as the dose is within a narrow size distribution and when combined with controlled inhalation may lead to more precise targeting of therapeutic drug to the airways. Using the STAG, particles in the size range 1.5–12 μm were generated and their mass median aerodynamic diameter (MMAD) and concentration measured using an aerodynamic particle sizer (APS). The application and validation of the system with the bronchodilator drug salbutamol sulphate is described, and its potential use in the study of aerosol particle size effects is discussed.

Introduction

Aerosol particle size and mode of inhalation are the two most important factors to consider for achieving optimal drug delivery to the lungs. The main physical processes governing the deposition of inhaled drug particles and droplets in the airways are inertial impaction, gravitational sedimentation and diffusion. The relative contribution of each of these to the total amount of drug deposited is primarily determined by the particle aerodynamic diameter. Most commercial inhalers produce polydisperse particles with a wide range of sizes, and it has been shown that approximately 20% of the dose from a correctly used metered dose inhaler (MDI) is delivered to the lungs (Melchor et al., 1993). The ‘respirable fraction’ is the aerosol dose contained within particles between 2 and 6 μm aerodynamic diameter, which is thought to be the ideal size range for inhalation throughout the airways. This has been predicted by mathematical and experimental modelling of deposition efficiency as a function of particle aerodynamic diameter (Kobrich et al., 1994, Heyder et al., 1986). These models also indicate that particles with aerodynamic diameters less than 2 μm will mainly deposit in the alveolar region or may be exhaled, whilst particles greater than 6 μm are likely to impact in the oropharynx. In order to study the particle size effects of drugs within the airways it is important to use aerosols of narrow size dispersity. Monodisperse aerosols are ideal for these studies as they have a geometric size distribution (GSD) of <1.22 (Morrow, 1981).

The STAG is one of the best-known instruments for generating particle aerosols of narrow size dispersity. It is capable of producing aerosol particles over a wide range of sizes. The principle of using a spinning disc to produce a spray of droplets of almost uniform size was first demonstrated in 1947 (Johnson and Walton, 1947). It was noted that the aerosol droplet size could be varied by changing the speed of the disc. A later design used compressed air to drive the disc (Walton and Prewett, 1949). May (1949) made further significant changes to the design to produce the forerunner of the present day device and later designed the first commercial version of the apparatus known as the STAG Mark I (May, 1966). The Mark II version, reviewed in 1991 (Melton et al., 1991), added further important improvements to the design enabling it to be used more easily and efficiently.

The STAG is considered an important research instrument for delivering inert monodisperse particles to the lung for the measurement of aerosol penetration and mucociliary clearance (Thomson and Short, 1969, Pavia et al., 1977, Pavia et al., 1980, Hasani et al., 1992). It has also been used to produce radiolabelled Teflon particles, which have been used as indirect markers of drug incorporated into an MDI in place of the drug (Newman et al., 1981) or in an MDI and a dry powder inhaler (DPI) in addition to the drug (Zainudin et al., 1990). More recently, the STAG has been used to generate unlabelled monodisperse drug particles (Zanen et al., 1996) in order to investigate the optimal particle size of β2-agonist for delivery to the lungs of asthmatics.

The aim of this research was to develop a versatile system able to produce and deliver stable pharmacologically active monodisperse drug particles of various sizes. We describe the methods and validation of the production of monodisperse salbutamol sulphate aerosols using the STAG Mark II (Research Engineers Ltd., London, UK), and its use as a potentially valuable tool capable of delivering aerosols for inhalation and for the investigation of bronchodilator particle size effects within the human airways in vivo.

Section snippets

Apparatus

A diagram of the aerosol generation and delivery apparatus is shown in Fig. 1. The STAG comprises an air driven steel disc (also known as a top), a stator and support assembly, a liquid feed needle assembly with remote height adjustment, a control unit housing the disc and exhauster air pressure regulators, and a digital disc speed indicator. It is housed in a purpose-built Perspex tank (aerosol chamber) with a volume of 150 litres in which the aerosol particles accumulate. It is supported on a

Results

We have shown that it is possible to generate a range of salbutamol particle sizes using the STAG, by varying the disc speed and solution concentration. Fig. 3 shows the relationship between particle size and disc speed for the three different concentrations of salbutamol, water and ethanol. Mean values of four repeat measurements are shown with error bars indicating the S.D. of each value. As the particle diameter d is inversely proportional to the angular velocity ω Eq. (1), increasing the

Discussion

The aerosol generation and delivery system described is a versatile investigative tool for generating monodisperse aerosol distributions of therapeutic drug particles and allows them to be delivered to the airways in a controlled manner. The spinning top aerosol generator is capable of producing well-defined salbutamol sulphate particles of a wide range of sizes. We have validated the aerosol output characteristics for three particle sizes of monodisperse salbutamol (1.5, 3 and 6 μm) and showed

Conclusions

We have established an aerosol system capable of providing better understanding of important drug delivery concepts. It has the potential to deliver aerosols to patients in a controlled manner for investigating bronchodilator particle size effects in vivo.

Future clinical studies may yield information that can help in the development of more efficient and user-friendly inhaler systems. If indeed there is an optimum particle size or range of sizes that aerosols should be delivered at, then in

Acknowledgements

This research is supported by an academic grant from GlaxoSmithKline, Research and Development, UK.

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