INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The potential efficacy of inhaled medication in young children and infants is often compromised by the difficulty of delivery of therapy (1). With the aim of overcoming the disadvantages of existing inhaler systems (Table 1), a novel system is suggested in which a spacer constructed from nonelectrostatic material is combined with a dry powder inhaler (DPI; Turbuhaler), and the DPI is activated mechanically into the spacer. Suction is provided by the generation of a partial vacuum in the spacer on release of a spring-driven piston, which can be reloaded manually (Figure 1). The metered drug powder is drawn into the spacer as an aerosol, where it remains stable, ready for inhalation. This concept is likely to improve our ability to treat young children with inhaled drug aerosols, as it provides a stable aerosol with a long half-life and without additives and propellants.

View larger version (23K): [in this window] [in a new window]   View larger version (34K): [in this window] [in a new window]   Figure 1.   A series of scale drawings illustrating the mode of action of the automatic spacer. (A) A section through the device in the resting state. The drug is delivered from a standard dry powder inhaler (Turbuhaler), seen on the left. On the right is the spacer chamber in its closed state, beneath which is a spring under tension. (B) Actuation of the device is accomplished by lifting the spacer chamber on the body of the device, and then twisting it through 90°. This action primes the Turbuhaler, via a gearing system, and also releases the spring. (C ) Release and expansion of the spring lead to rapid expansion in volume of the spacer chamber. The mouthpiece is closed by the one-way valve, so the resulting partial vacuum draws air through the Turbuhaler, into the tower-shaped spacer. The drug aerosol created by this action persists as a stable cloud in the spacer chamber with a long half-life of 82 s for the fine particle fraction. (D) An external view of the device, showing the aerosol path through the mouthpiece. A face mask can be fitted when the device is used by younger children.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Automatic Spacer Prototype

The spacer is constructed from nonelectrostatic material and is 275 ml in volume. The spacer is combined with a DPI (Turbuhaler), and the DPI is activated mechanically into the spacer. Suction is provided by the generation of a partial vacuum in the spacer on release of a spring-driven piston, which can be reloaded manually (Figure 1). The suction time is 250 ms, with a rise time of 160 ms to reach the peak flow of approximately 60 L/min. The metered drug powder is drawn into the spacer as an aerosol, where it remains stable, ready for inhalation. Normal tidal breathing by the patient, through either a mouthpiece or a specially adapted face mask, delivers aerosolized drug to the patient. The mouthpiece is equipped with a one-way valve to prevent rebreathing back into the holding chamber, and the face mask is equipped with an exhalation valve to permit exhalation, so in both systems the inspiratory and expiratory lines are separated without common dead space.

Test Drug

The test drug, budesonide, is administered by Turbuhaler at 400 µg/ dose.

Ventilator

A Pari Sinus breath simulator was used to withdraw drug aerosol from the spacer by simulated tidal breathing. The settings selected to mimic the breathing of a young child were as follows: tidal volumes of 100 and 200 mL; inhalation-to-exhalation ratio, 1:2; frequency, 25 breaths/ min; duration, 30 s (unless otherwise indicated).

Dose Ex-spacer, Constant Flow

The spacer was connected to a filter (Vital Signs, model 5098E) 2 s after actuation, and a constant flow of 30 L/min was drawn through the spacer for the next 5 s. Dose ex-spacer was collected on the filter during this period.

Dose Ex-spacer, Ventilator

A filter (Vital Signs, model 5098E) was placed in the inspiratory line between ventilator and the spacer. Inspiratory and expiratory flow passed through separate lines, ensuring unidirectional inspiratory flow through the filter. The ventilator was started 2 s after actuation of the Turbuhaler. Dose ex-spacer was collected on the filter.

Particle Size Distribution

The budesonide dose ex-spacer was collected in an Andersen sampler with a modified BP twin impinger inlet by applying a constant flow of 28.3 L/min through the impactor for 10 s. The spacer was connected to the impactor 2 s after actuation of Turbuhaler (unless otherwise indicated). The amount of budesonide on each stage of the sampler was determined.

Quantification of Budesonide

The budesonide on the filters and the stages of the sampler was dissolved in ethanol containing internal standard (fluocinolone acetonide). The amount of budesonide was quantified by high-pressure liquid chromatography (relative standard deviation, < 2%). The limit of detection is 0.6 µg of budesonide.

Study Design

Four automatic spacers were used throughout the study, and were combined with different Turbuhaler inhalers in balanced designs. Before and after each experiment the delivered dose from each individual Turbuhaler was determined by five replicate filter tests.

Dose-to-dose repeatability. Dose-to-dose repeatability was determined by measuring dose ex-spacer in the 4 automatic spacers with 4 different Turbuhaler inhalers, giving a total of 16 combinations with 5 replicates of each.

Dose ex-spacer during constant flow and tidal breathing. Doses were withdrawn both with a constant flow of 30 L/min and with a breathing simulator (tidal volume, 200 mL) from four automatic spacers in replicates of five.

Number of breaths to empty spacer. Doses obtained by the breathing simulator were measured after 1, 2, 3, 4, 5, 6, and 10 breaths with tidal volumes of 100 and 200 mL. The study was performed five times for each number of breaths, with one automatic spacer and one Turbuhaler.

Particle size distribution. Particle size distribution was determined 2 s after actuation by applying a constant flow of 28.3 L/min into an Andersen sampler. Particles of < 4.7 µm were termed fine particles, and those with larger diameters were termed coarse particles.

Three automatic spacers were used, each with three inhalers (i.e., nine measurements in total). In each measurement, 10 doses were collected. These measurements were repeated after the spacer had been used to withdraw 1,500 doses.

Dose half-life (total dose). Dose ex-spacer was measured with delays of 2, 10, 20, 40, and 60 s after actuation five times from each of three unused automatic spacers. These measurements were repeated after the automatic spacer had been used to withdraw 1,500 doses.

Dose half-life (fine and coarse particle dose). The half-life of the coarse and fine particles was determined by measuring the amounts collected on the various stages of the Andersen sampler with delays after actuation of 2, 10, 20, 40, and 60 s and using three different Turbuhaler inhalers and a single automatic spacer.

Statistical Evaluation

The recovered doses were converted to percentages of the mean delivered dose for each Turbuhaler, as measured in replicates of five, before and after each test. All experiments were complete and balanced. The means given are therefore the observed arithmetic means. Repeatability is expressed as the relative standard deviation (RSD) calculated as the SD per mean. The half-life of the aerosol was estimated by fitting a linear line to the logged mean recovered doses versus time. The dose half-life could then be estimated as ln(2)/slope.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Dose-to-dose repeatability. The RSD of dose delivery from the four Turbuhaler was 10%. Using the same inhalers the RSD of the Turbuhaler-spacer combination was 12%.

Dose ex-spacer during constant flow and tidal breathing. The dose obtained ex-spacer by constant flow was 40% of the delivered dose from Turbuhaler as compared with 38% when obtained by tidal breathing, which was not statistically different (difference, 1.4%; 95% CI, 1.1-4.0).

Number of breaths to empty spacer. After three breaths of 200 mL or four breaths of 100 mL no increase in dose ex-spacer was obtainable with further breathing.

Particle size distribution. Particle size distribution is shown in Table 2.

Dose half-life. The half-life of the dose ex-spacer was estimated to be 68 s (95% CI, 62-76 s) with no significant difference between a new and a used automatic spacer. The estimated half-life of the fine particle dose was 82 s (95% CI, 66- 109 s), whereas the estimated half-life of the coarse particle dose was 36 s (95% CI, 29-47 s) (Figure 2).

View larger version (17K): [in this window] [in a new window]   Figure 2.   Passive fallout of aerosol in spacer. The spacer was emptied after increasing delay periods after actuation. The estimated half-life of the total dose of aerosol was 67 s (95% CI, 56-82 s). The estimated half-life of the fine particle dose was 82 s (95% CI, 66-109 s), whereas the half-life of the coarse particle dose was 36 s (95% CI, 29-47 s).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Spacer devices are convenient for the treatment of young children as they allow aerosol to be inhaled during tidal breathing, without the need for coordination or forced inhalation. They generally improve the safety of inhaled medication, as they lead to a reduced pharyngeal dose and an increased lung dose and clinical effect.

The mechanical actuation of a DPI (Turbuhaler) into a spacer, the "automatic spacer," provides a new form of spacer device for aerosol treatment. The new system can be expected to retain the advantages of existing spacers. In addition, the automatic spacer provides the advantage of a drug aerosol delivered without use of any harmful additives. The DPI within the device (Turbuhaler) delivers respiratory medication with no propellants, lubricants, or surfactants, avoiding unwanted irritant effects in the airways of the patients as seen from use of propellant-metered dose inhalers (pMDIs) (2), and environmental damage including the ozone-depleting effect and the greenhouse gas effect as caused by available pMDI propellants (1).

There is no requirement for forced inspiration or good coordination, as opposed to the use of a DPI or pMDI alone. As a consequence of the standardized nature of the mechanical actuation repeatability of dosing was high in this study (RSD, 12%). This is likely to improve on repeatability of drug delivery to the lungs, as the variation ascribed to changes in inspiratory flow is avoided.

The use of nonelectrostatic materials together with elimination of dead space in the inspiratory line ensure a high yield of drug from the spacer. The dose ex-spacer was 40% of the dose delivered to the spacer from the Turbuhaler. This efficiency is comparable to the efficiency of a nonelectrostatic spacer for use with pMDIs (5, 6).

The residence time of the aerosol is prolonged compared with traditional spacers. The half-life of 82 s for the fallout of the aerosol cloud of fine particles (diameter, < 4.7 µm) compares favorably with a half-life of about 10 s for the fallout of fine particles in most standard plastic spacers (7). The slow, passive fallout is assured by the nonelectrostatic material of the spacer avoiding attraction of the aerosol particles to the wall of the traditional plastic spacers (1), and by the tower shape of the spacer, which maximizes the settling distance for the particles. The long residence time of the aerosol provides an extended period for the young child or infant to inhale the required dose. During normal breathing, a 1-yr-old child inhales the available dose in three or four breaths, but even in the case of a noncompliant toddler, who may breath-hold or perform periods of shallow breathing, passive fallout of aerosol will have little effect on the dose obtained. The requirements for even passive acceptance are therefore minimal, and the prolonged residence time of aerosol ensures both a high and repeatable drug delivery, and should permit effective inhalation, even by children who have previously been unable to use spacer devices effectively for lack of compliance.

In conclusion, the novel automatic spacer device combines the advantages of a spacer and DPI without the disadvantages of either, which should improve our ability to treat young children with inhaled drug aerosols.