JOURNAL OF AEROSOL MEDICINEVolume 12, Number 2, 1999Mary Ann Liebert, Inc.Pp. 47-53

The Conventional Ultrasonic Nebulizer ProvedInefficient in Nebulizing a Suspension

K. NIKANDER, B.A.,1-3 M. TURPEINEN, M.D., Ph.D.,2 and P. WOLLMER, M.D., Ph.D.3

ABSTRACT

A study was undertaken to compare the amount of nebulized budesonide suspension andnebulized terbutaline sulphate solution inhaled by healthy adult subjects when conventionaljet and ultrasonic nebulizers were used. Ten healthy subjects (5 male; age range, 16-52 years)used two conventional nebulizers: the Spira Elektro 4 jet nebulizer (Respiratory Care Center,Hämeenlinna, Finland) and the Spira Ultra ultrasonic nebulizer (Respiratory Care Center) ina breath-synchronized mode with each drug. The amount of drug inhaled, the inhaled mass,was defined as the amount of drug deposited on a filter between the inspiratory port of thenebulizer and the mouthpiece. The amount of budesonide and terbutaline sulphate was de-termined by reversed-phase high-performance liquid chromatography. Single-dose respuleswere used (0.5 mg of budesonide and 5.0 mg of terbutaline sulphate), and nebulization timeup to the defined gravimetric output was recorded. The inhaled mass of budesonide varieddepending on the nebulizer used, whereas the inhaled mass of terbutaline was unaffected bythe choice of nebulizer. The median inhaled mass of budesonide was 31.4% of the nominaldose (i.e., dose of drug in the respule per label claim) with the Spira Elektro 4 and 9.9% withthe Spira Ultra, whereas the median inhaled mass of terbutaline was 50% with the Spira Elek-tro 4 and 52% with the Spira Ultra. It appears that a suspension is generally more difficult tonebulize than a solution and that the budesonide suspension should not be used in conven-

tional ultrasonic nebulizers.

Key words: jet nebulizer, ultrasonic nebulizer, budesonide

INTRODUCTION later became widely used for the treatment ofasthma and chronic bronchitis due to the intro-

Conventional jet nebulizers driven by com- duction of new drugs, specifically, /32-agonistspressed air from electrical compressors have and anticholinergics in aqueous solutions,

been used for the aerosolization of aqueous drug In 1987, Godfrey et aH3) reported on the effec-solutions since the beginning of the century.W In tiveness of an aqueous budesonide suspensionthe 1960s, ultrasonic nebulizers were introduced for nebulization in an infant with severe oralfor the same purpose/2) These inhalation devices steroid-dependent asthma. This first report was

1Astra Draco AB, Lund, Sweden.2Department of Allergic Diseases, Helsinki University Central Hospital, Helsinki, Finland.3Department of Clinical Physiology, Malmö General Hospital, Malmö, Sweden.

47

48

followed by a number of studies showing nebu-lized budesonide to be clinically effective in asth-matic infants, children, and adults at a nominaldose ranging from 250 /¿.g administered once

daily to 1000 u.g administered two timesdaily.(4_7) In 1990, the budesonide suspensionwas

approved for the treatment of asthma by jet neb-ulization.A drug suspension consists of insoluble mi-

cronized particles dispersed in a liquid medium,often water. During nebulization of a drug sus-

pension, the aerosol droplets are potential carri-ers of the solid drug particles provided that thewater droplets are larger than the particles. Whennebulizing a suspension, both the nebulizer'sdroplet size and the drug particle size distribu-tions affect the output of drug. Jet nebulizers pro-ducing aerosols with large droplets therefore de-liver more budesonide than do jet nebulizers withsmall droplets as shown in a comparison betweenthe Pari LC Jet nebulizer (Pari-Werk GmbH,Starnberg, Germany) and Ventstream jet nebu-lizer (Medic-Aid Ltd, Bognor Regis, UK)/8) Theprimary particle size of micronized budesonidehas been reported to be approximately 2.4 u.m.(9>

There are limited data on the behaviour of sus-pensions in conventional ultrasonic nebulizers.Dahlbäck(10) presented preliminary in vitro resultsindicating that a solution of sodium chloride was

more readily nebulized with a Pulmosonic ultra-sonic nebulizer (DeVilbiss Health Care, Inc., Som-erset, PA) than was a suspension of budesonide.Berlinski and Waldrep*11' showed that budesonideoutput was lower using ultrasonic nebulizationcompared with jet nebulization. There is, however,a lack of data on the amount of budesonide deliv-ered to the patient in an ordinary clinical treatmentsituation, that is, the inhaled mass of budesonide.*12'During nebulization, the inhaled mass of drug (theamount of drug inhaled by the patient) is mainly a

product of the nebulizer's drug output rate and thepatient's duty cycle.*13' In vivo comparisons of theinhaled mass of the budesonide suspension and a

solution of a ft-agonist using conventional jet andultrasonic nebulization are not currently available.

The aim of this study was therefore to com-

pare conventional jet and ultrasonic nebuliza-tion of budesonide suspension and terbutalinesulphate solution using a filter technique formeasurement of the inhaled mass(12) in healthyadult subjects.

NIKANDER ET AL.

MATERIAL AND METHODS

Study designThe study was designed as a randomized,

crossover, single-center trial and was performedover 2 days in a clinical setting. The two nebu-lizers selected for the study were of a conven-

tional design: a conventional jet nebulizer (SpiraElektro 4, Respiratory Care Center, Hämeenlinna,Finland) (Fig. 1A) and a conventional piezoelec-trical ultrasonic nebulizer (Spira Ultra, Respira-tory Care Center) (Fig. IB). The nebulizers were

charged with budesonide suspension (0.25mg/mL-1, 2 mL suspension; Astra Draco AB,Lund, Sweden) or terbutaline sulphate solution(2.5 mg/mL-1, 2 mL solution; Astra Draco AB).Ten healthy subjects used a Spira Elektro 4 jetnebulizer and a Spira Ultra ultrasonic nebulizer

FIG. 1. Nebulizer setups. The inhalation port of theSpira jet nebulizer (S) was connected in series with an in-spiratory filter (I), a Magtrac (R) respiratory flow sensorwith rotameter, and a mouthpiece. An expiratory filter (E)was connected to the exhalation port of the nebulizer. Thesynchronizer (D) with flow sensor was (A) connected be-tween the compressor and the nebulizer (Spira Elektro 4)or (B) added to the nebulizer setup (Spira Ultra).

NEBULIZATION OF A SOLUTION AND A SUSPENSION 49

in a breath-synchronized mode with each drug.The jet nebulizers were connected to a Spira com-

pressor (Respiratory Care Center) and run at a

flow of 7.5 L/min-1 through the nebulizers at a

room temperature of ~20°C. The ultrasonic neb-ulizers were operated at a preset frequency of 2MHz.

The nebulizers were used in a breath-synchro-nized mode in order to minimize the impact ofbreathing pattern variability on the inhaled mass

of drug.(13) Breath synchronization was achievedthrough the use of inspiratory flow-activatedelectronic synchronizers (D, see Fig. 1A and B).The synchronizer was set to pulse compressed airthrough the jet nebulizer during the whole in-spiration or to the synchronizer'smaximum pulsetime of 3 seconds. When the ultrasonic nebulizerwas used, the synchronizer was set to activate thenebulizer during the whole inspiration or to thesynchronizer's maximum pulse time of 2.5 sec-

onds.

Drug outputThe total output of solution and suspension

from the nebulizer was determined gravimetri-cally. The weight of the nebulizer cup, includingthe nebulizer charge of drug, was measured be-fore and during nebulization. During constantnebulization of budesonide suspension on thebench, the Spira jet nebulizer reached the sput-tering phase when approximately 0.6 mL of sus-pension (0.6 g) remained in the nebulizer cup. Theoutput of both the suspension and the budes-onide was linear up to the sputtering phase. Asimilar in vitro test could not be performed on thebench with the ultrasonic nebulizer, as it couldnot be disconnected from the synchronizer andrun in a constant output mode. Nebulization was

therefore stopped for both the jet nebulizer andthe ultrasonic nebulizer when 75% of the nebu-lizer charge had been nebulized. This meant thatof a 2 mL budesonide suspension or terbutalinesulphate solution volume, 1.5 mL (1.5 g) left thenebulizer. The change in the weight of the nebu-lizer was tested at regular intervals throughoutthe nebulization process. When 1 mL of the neb-ulizer charge had been nebulized, the weightchange was checked at shorter intervals to ensure

a total output of 1.5 mL. The maximum nebulizercharge volumes are 20 mL for the Spira Elektro 4

and 18 mL for the Spira Ultra. Single-dose res-

pules were used, and nebulization time up to thedefined gravimetric output was recorded.

Inhaled mass

The inhaled mass of drug was defined as theamount of drug deposited on an inspiratory fil-ter (Marquest MQ-303 viral filters, MarquestMedical Products, Inc., Englewood, CO) locatedbetween the mouthpiece and the nebulizer's in-spiratory port. The amounts of drug aerosolizedduring expiration were deposited on an expira-tory filter (see Fig. 1A and B). In vitro tests haveshown that the Marquest filter can catch approx-imately 99.8% of the budesonide sucked throughthe filter.(14) The addition of the inspiratory filterto the nebulizer introduced an equipment deadspace of approximately 30 mL which was equalto half of the filter housing volume. Budesonidewas eluted from the filters with a water ethanolsolution, whereas terbutaline was eluted with a

sulphuric acid solution. The concentration andmass of budesonide and terbutaline were deter-mined by high-performance liquid chromatogra-phy at the Analytical Chemistry Department ofAstra Draco AB, Lund, Sweden.

Droplet size determinationThe aerosol droplet size was characterized with

a Malvern Mastersizer Model MSI000 (MalvernInstruments Ltd., Malvern, UK). Three conven-

tional constant output Spira jet nebulizers were

run continuously three times each with budes-onide and three times each with isotonic saline.The mass median diameter (MMD) of thedroplets was 3.7 ftm (range 3.5-4.1 /m\; SD = 0.2)with budesonide and 3.6 fim (range 2.7-4.2 yum;SD = 0.6) with isotonic saline. As the jet nebuliz-ers showed no difference between budesonideand saline, two breath-synchronized Spira Ultranebulizers were tested two times each chargedonly with budesonide in 0.7-second pulses dur-ing 6 seconds of measurement. The MMD was 5/¿m (range 4.5-5.6 /un; SD = 0.5).

SubjectsTen healthy adult subjects (5 male) were in-

cluded. Their mean age was 39 years (range16-52 years), their mean height was 169 cm

50 NIKANDER ET AL.

(range 158-178 cm), and their mean weight was64 kg (range 52-75 kg). Their mean forced expi-ratory volume in 1 second and forced vital ca-

pacity were 107.7% (84.3-159.9) and 111.9%(85.1-149.5), respectively, of predicted normalvalues/15' The study was performed in accor-dance with the principles stated in the Declara-tion of Helsinki and was approved by the localEthics Committee of the Department of AllergicDiseases, Helsinki University Central Hospital,Helsinki, Finland.

The subjects were instructed to inhale duringtidal breathing through mouthpieces connectedto the nebulizers and used nose clips duringthe whole maneuver. The subjects' inspirationthrough the nebulizer was recorded throughoutnebulization with a Magtrac II general purposerespiratory flow sensor (Ferraris Medical Ltd.,London, UK) which updated the recorded inspi-ratory minute volume (Vi) every 20 seconds.Lung function measurements (i.e., forced expira-tory volume in 1 second and forced vital capac-ity were performed with a Vitalograph Compactspirometer (Vitalograph Ltd, Buckingham, UK).

StatisticsThe two drugs were compared within each

nebulizer system using a nonparametricWilcoxon rank-sum test. The same test was used

for a comparison between the two nebulizer sys-tems for each drug.

RESULTS

Inhaled mass of drugThe median inhaled mass of budesonide was

31.4% of the nominal dose with the Spira Elektro4 and 9.9% with the Spira Ultra, whereas the me-dian inhaled mass of terbutaline was 50.0% withthe Spira Elektro 4 and 52.0% with the Spira Ul-tra (Table 1). The difference in the median inhaledmass between budesonide and terbutaline was

statistically highly significant within each nebu-lizer system (P < 0.001, Fig. 2). For budesonide,the nebulizer system used had a statistically sig-nificant effect on the inhaled mass (P < 0.001, seeFig. 2), whereas for terbutaline, there was no sta-tistically significant difference.

Inhaled mass as percentage of total drug outputA qualitative analysis of the inhaled mass in

relation to the total drug output (i.e., sum of drugon inspiratory and expiratory filters) gives an es-timate of the function of the breath synchronizer.When using a breath-synchronized nebulizer sys-tem, one would expect the inhaled mass to beclose to 100% of the total drug output. The me-

Table 1. Data on Amount of Drug on Filters, Total Drug Output,Gravimetric Output, Nebulization Time, and Inspiratory Minute Volumes

Variable

Budesonide,Spira

Elektro 4Budesonide,Spira Ultra

Terbutaline,Spira

Elektro 4Terbutaline,Spira Ultra

Inhaled mass 31.4 9.9 50.0 52.0(median and range as (27.0-38.0) (9.4-10.4) (30.0-52.0) (26.0-56.0)percentage of nominal dose)

Expiratory filter 10.9 1.4 9.6 4.1(median and range as (8.0-14.0) (0.6-2.0) (7.6-16.4) (1.6-5.8)percentage of nominal dose)

Total drug output 42.8 11.0 61.2 56.8(median and range as (37.8-47.6) (10.6-12.0) (39.0-64.4) (30.4-61.8)percentage of nominal dose)

Gravimetric output 1.55 1.50 1.50 1.50(median and range in milliliters) (1.54-1.58) (1.49-1.53) (1.49-1.52) (1.49-1.51)

Nebulization time 7.9 11.0 8.6 6.6(mean and range in minutes) (6.0-9.5) (9.0-12.6) (6.8-10.7) (5.4-8.4)

Vi in first minute 10.5 11.5 12.7 12.0(mean and range in liters) (6.5-15.5) (8.6-15.2) (8.7-21.1) (8.2-16.8)

Vi in last minute 13.2 12.2 13.9 13.0(mean and range in liters) (8.9-17.7) (7.2-17.0) (8.9-22.0) (10.3-16.5)

NEBULIZATION OF A SOLUTION AND A SUSPENSION 51

Spira U Spira U Spira E4Budesonide Terbutaline Budesonide

Spira E4Terbutaline

FIG. 2. The inhaled mass of drug (solid black) and theamount of drug wasted (gray grid) during expirationwere expressed as percentages of the nominal dose ofdrug plotted for each nebulizer setup and drug. The re-sults are given as median values. The difference in themedian inhaled mass between budesonide and terbu-taline was statistically significant within each nebulizersystem (P < 0.001). For budesonide, the nebulizer systemused had a statistically highly significant effect on the in-haled mass (P < 0.001), whereas for terbutaline, there wasno statistically significant difference.

dian inhaled mass using the ultrasonic nebulizerwas 87.5% of the total drug output for budes-onide and 91.7% of the total drug output forterbutaline. When using the jet nebulizers, how-ever, the median inhaled mass decreased as a per-centage of the total drug output and was 75.8%for budesonide and 84.2% for terbutaline.

Inhalation technique and other variablesThe Vi values for the first and last minutes of

nebulization are displayed in Table 1. The resultsindicate that the subjects inhaled within approx-imately the same range ofVi through all four neb-ulizers. The amount of drug deposited on the ex-halation filters, total drug ouput, gravimetricsolution and suspension output, and nebulizationtimes are also displayed in Table 1.

DISCUSSION

The study was designed to determine the in-haled mass of drug nebulized by conventional jetand ultrasonic nebulizers. The inhaled mass ofnebulized drug was defined as the amount ofdrug deposited on filters located between thenebulizers and the subjects. Breath synchroniza-tion was mainly used to minimize the impact ofthe subjects' breathing pattern variability on the

inhaled mass of drug/13) Inspiratory time andnebulization time should have been approxi-mately equal when using a breath-synchronizedsystem. A change in the duty cycle would mainlyhave affected the nebulization time, as the timeto reach an output of 1.5 mL would have requiredapproximately the same total inspiratory time.The two brands of Spira nebulizers selected forthe comparison were both designed as conven-tional T-piece nebulizers. As the T-piece designof the nebulizers was similar, the impact of a sub-ject's breathing pattern (i.e., tidal volume, inspi-ratory flow, and duty cycle) should not have dif-fered between the nebulizers. The inhaled mass

of nebulized budesonide has previously been in-vestigated in children^4) but not in adults; the in-haled mass of nebulized terbutaline sulphate hasnot been previously investigated using the filtertechnique/12^

When using the ultrasonic nebulizer, the differ-ence in inhaled mass between the budesonide sus-

pension and terbutaline solution was approximatelyfivefold. This result is in agreementwith preliminaryin vitro results which indicated that a solution ofsodium chloride was more readily nebulized than a

suspension of budesonide with a Pulmosonic ultra-sonic nebulizer/10) The Pulmosonic ultrasonic nebu-lizer's dropletMMD was, however, reported to be 1/xm, whereas the diameter of the budesonide parti-cles has been reported to be 2.4 ¿im/9) The questionremains as to whether the budesonide suspensioncould have been successfully nebulized if the ultra-sonic nebulizer's droplet size had beenmore in agree-mentwith the budesonide particle size, that is, closerto 3 /um. In the in vitro study by Berlinski and Wal-drep/11) the Aerosonic nebulizer's (DeVilbiss HealthCare, Inc., Somerset, PA) droplet mass median aero-

dynamic diameter was reported to be 2.9 /urn/11)There was a four- to fivefold difference between theoutput of budesonide between the Aerosonic nebu-lizer and the Sidestream jet nebulizer (MarquestMedical Products, Inc., Englewood, CO) (mass me-

dian aerodynamic diameter = 3.6 /um) in that study.This is close to the threefold difference between thebudesonide output from the Spira ultrasonic(MMD = 5.0 /jxrv) and jet nebulizers (MMD = 3.7/urn) in the present study. The results from the pre-sent study and the in vitro results by Berlinski andWaldrep*11) indicate that the poor budesonide out-

put is due to factors other than the conventional ul-trasonic nebulizer's droplet size distribution.

52 NIKANDER ET AL.

Drug solutions and suspensions in the jet neb-ulizer cup have been shown to concentrate dur-ing use. Evaporation of solvent in the jet nebu-lizer has been claimed to be the major reason forthe increase in concentration/16'17' The evapora-tion of solvent has been shown to be related toboth saturation of compressed air within the jetnebulizer and jet nebulizer design/18' Dennis etal(18' did not find any evaporation of solventwhen using a Microinhaler ultrasonic nebulizer(Vestric, Runcorn, UK), however, and reported a

close correlation between aerosol output as de-termined by the fluoride tracer method and neb-ulizer weight loss. The results of the presentstudy did, however, show that evaporation oc-

curred during ultrasonic nebulization of terbu-taline solution. Approximately 50% of the nebu-lizer charge of terbutaline was aerosolizedcompared with 75% of the solvent.With the use of breath-synchronized nebuliz-

ers, the aerosolized drug should mainly be de-posited on the inspiratory filter, and the amount

deposited on the expiratory filter should be neg-ligible. The amount of drug "wasted" to the ex-

piratory filters was therefore surprisingly high,especially following jet nebulization. The wasteof drug to the expiratory filters could mainly beattributed to two factors. The first factor is relatedto the ventilated dead space in the nebulizer andthe filter housing. At the end of inspiration, partof the nebulizer and half of the filter housing are

filled with aerosol which is deposited on the ex-

piratory filter during expiration. The second fac-tor is related to how fast the nebulizer stops theproduction of aerosol after cessation of the inspi-ratory flow over the flow sensor. The comparisonof the two nebulizer systems showed that theSpira Ultra wasted less drug at the expiratory fil-ter than did the Spira Elektro 4. The ventilateddead space was approximately the same in bothnebulizer systems, indicating that the jet nebu-lizer produced slightly more aerosol after inspi-ration, which was deposited on the expiratory fil-ter during expiration.

Nebulizers have been shown to vary in termsof inhaled mass of drug, total drug output,droplet size, and nebulization time/19' There is a

growing demand for well-defined nebulizer drugouput characteristics for different drugs/20' Thecharacterization of nebulizers is usually per-formed in vitro, and current best practice requires

that these in vitro tests mimic patients' breathingpatterns/20' This can be achieved with a numberof pumps/12'21'22' There is, however, no compar-ative study proving that any of the availablepumps can accuratelymimic the patient's breath-ing pattern and produce the same inhaled mass

of drug as the patient. The in vitro results are

therefore difficult to put into a clinical perspec-tive. The filter technique used to measure inhaledmass in vivo may therefore be used to bridge invitro and clinical results.

The results of the present study indicate thata solution of terbutaline and a suspension ofbudesonide behave rather differently in con-

ventional jet and ultrasonic nebulizers. The in-haled mass of budesonide varied depending on

the nebulizer used, whereas the inhaled mass ofterbutaline sulphate was unaffected by thechoice of nebulizer. In conclusion, it appears thata suspension is generally more difficult to neb-ulize than a solution and that the budesonidesuspension should not be used in conventionalultrasonic nebulizers.

ACKNOWLEDGMENT

This study was funded by Astra Draco AB,Lund, Sweden, and there is no conflict of inter-est.

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NEBULIZATION OF A SOLUTION AND A SUSPENSION 53

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15. Quanjer, P.H., G.J. Tammeling, J.E. Cotes, R. Peder-sen, R. Peslin, and J.C. Yernault. 1993. Lung volumesand forced ventilatory flows: Report of WorkingParty, Standardization of lung function tests, Euro-pean Community for Steel and Coal-official state-ment of the European Respiratory Society. Fur. Respir.J. 6(Suppl 16):5^40.

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Article received on July 1, 1998in final form, January 22, 1999

Reviewed by: M.J. O'Doherty, M.D.

Address reprint requests to:Kurt Nikander

Astra Draco ABP.O. Box 34

S-221 00 LundSweden

E-mail: kurt.nikander@draco.se.astra.com

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