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`A review of the technical aspects of
`drug nebulization
`
`P. Le Brun, Harry Heijerman
`
`Pharmacy world & science : PWS
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`Article
`
`A review of the technical aspects of drug nebulization
`
`• P. P. H . L e B r u n , A . H . d e B o e r, H . G . M . H e i j e r m a n a n d H . W. F r i j l i n k
`
`Pharmacy World & Science
`
`Volume 22 Nr. 3 2000
`
`75
`
`Pharm World Sci 2000;22(3): 75-81.
`© 2000 Kluwer Academic Publishers. Printed in the Netherlands.
`
`P.P.H. Le Brun (correspondence): Central Hospital Pharmacy
`The Hague, P.O. Box 43100, 2504 AC Den Haag,
`The Netherlands, e-mail: AHZ@wxs.nl
`A.H. de Boer and H.W. Frijlink: Department of
`Pharmaceutical Technology and Biopharmacy,
`University of Groningen, Groningen, The Netherlands
`H.G.M. Heijerman: Adult Cystic Fibrosis Center, Department of
`Pulmonology, Leyenburg Hospital, Den Haag, The Netherlands
`
`Keywords
`Jet nebulizer
`Patient factors
`Performance
`Pulmonary drug delivery
`Technical considerations
`Ultrasonic nebulizer
`
`Abstract
`Nebulizers are widely used for the inhalation of drug
`solutions in a variety of respiratory diseases. The efficacy of
`nebulizer therapy is influenced by a great number of factors,
`including the design of the device and the characteristics of
`the drug solution. Incorrect cleaning, maintenance and
`disinfection procedures may change the nebulizer
`performance in time, whereas patient factors can influence
`the lung deposition of the generated aerosol. In this review
`the technical aspects of nebulization of drug solutions will be
`discussed. Two main parameters are generally used to
`evaluate the performance of nebulizers: the droplet size
`distribution of the aerosol and the drug output rate. The
`droplet size distribution and the drug output rate are
`basically determined by the design and user conditions of the
`nebulizer. A higher gas flow of the compressor in a jet
`nebulizer or a higher vibration frequency of the piezo electric
`crystal in an ultrasonic nebulizer, decreases the droplet size.
`The choice of the type of nebulizer for nebulization of a
`certain drug solution may initially be based on laboratory
`evaluation. The major part of the mass or volume distribution
`should preferably correspond with aerodynamic particle
`diameters in the range of 1 to 5 micrometer. The intended
`drug output must be realized within a reasonable
`nebulization time (less than 30 min). From the drug output
`only a minor fraction will be deposited in the lung. The
`relation between in vitro and in vivo deposition is only partly
`understood and to date it has not been possible to predict
`drug delivery only from in vitro studies on nebulizers.
`Therefore, studies in patients should be performed before a
`drug solution for nebulization can be recommended for
`clinical practice.
`The mechanical properties of nebulizers are likely to change
`during use. An average utilization time of nebulizers is not
`available. Therefore, the performance of nebulizers should be
`checked periodically.
`Patient compliance in nebulizer therapy is relatively low. This
`is partly due to the fact that, at present, drug solutions for
`nebulizers cannot be administered efficiently within a short
`period of time. More efficient systems should be developed.
`If possible, nebulizers should be substituted to more efficient
`systems, e.g. dry powder inhalers or metered dose inhalers.
`
`Accepted May 2000
`
`Introduction
`Inhalation is a common technique of drug administra-
`tion to patients with a variety of lung diseases [1 2].
`Several classes of drugs are available for inhalation,
`e.g. ß2-agonist drugs, corticosteroids and anticholi-
`nergic drugs. Next to these anti-asthma drugs, inha-
`lation of antibiotics is frequently applied for patients
`with Cystic Fibrosis (CF) [3 4]. Whereas pentamidine
`has been used for the prophylaxis of Pneumocystis
`pneumonia in patients infected with HIV virus [5 6].
`Recently, the pulmonary route is proposed to increas-
`
`ing extent for the administration of drugs with
`systemic action that can either not be absorbed by
`the gastro-intestinal tract or suffer from a first pass
`effect.
`In inhalation therapy the drugs are administered
`directly to the site of action. As a result, the lag time of
`the action onset of the drug is short, less drug sub-
`stance is needed and systemic side effects are reduced.
`Three types of devices are commonly used for the
`administration of drugs to the respiratory tract: nebu-
`lizers, pressurized metered dose inhalers (pMDI) and
`dry powder inhalers (DPI). An adequate understand-
`ing of the advantages and disadvantages of the differ-
`ent systems is required to make a proper choice
`between the systems [7 8].
`For a long time the MDI has been considered as a
`convenient device most commonly used in inhalation
`therapy [9 10]. MDIs contain the drug in suspension,
`emulsion or solution to which a propellant has been
`added. When the device is activated, a metered dose
`is released at high velocity, which requires a simulta-
`neous inhalation by the patient. Therefore, a precise
`coordination of both actions (activation and inhala-
`tion) by the patient is mandatory. Obviously the
`device as such is unsuitable for young children who
`lack the required coordination [11]. The high velocity
`of the aerosol constitutes an inherent disadvantage of
`the system because it leads to a significant oropharyn-
`geal deposition. To facilitate the coordination, breath
`actuated MDIs have been introduced. In these devic-
`es the inspiratory flow triggers dose release. A disad-
`vantage of MDIs is the so called “cold freon effect”
`caused by rapid evaporation of the propellant. The
`cooled aerosol can cause bronchoconstriction. The
`use of a spacer can partly overcome these disadvan-
`tages. Until recently chlorofluorocarbons (CFC) were
`used as propellant. Because of the environmental bur-
`den caused by the CFC most devices are being refor-
`mulated with HFA227 or 134A or exchanged by alter-
`native devices.
`A dry powder inhalation system consists of a dry
`powder formulation, a dosing principle and an inhaler
`device [7]. In most systems the micronized drug is
`formulated with an inert excipient, like crystalline
`alpha lactose monohydrate, but excipient free DPIs
`have also been developed (e.g. the Pulmicort
`Turbuhaler). Dry powder inhalers use the inspiratory
`flow of the patient for dose entrainment and disinte-
`gration of the powder formulation. The dose is deliv-
`ered from a multiple dose reservoir or from a single
`dose unit (capsule or blister) during inhalation. The
`first inhaler on the market was the Spinhaler, a single
`dose DPI based on encapsulated powder. Some DPIs
`require a relatively high inspiratory flow rate in order
`to deliver an acceptable mass fraction of the dose as
`fine particles. For other types of dry powder inhalers,
`the flow increase rate is rather the relevant flow
`parameter [12]. The required inspiratory flow curve
`can not always be attained, especially not by patients
`with severe bronchoobstruction or young children.
`Nebulizers are used to aerosolize drug solutions
`
`

`

`and sometimes drug suspensions for inhalation. They
`are typically used in situations when severe obstruc-
`tion of the airways or insufficient coordination by the
`patient does not allow the use of other systems. They
`are for example recommended for young patients
`who cannot manage other devices. Furthermore,
`nebulizers are used for drugs that cannot or have not
`yet been formulated as DPI or MDI, such as antibio-
`tics, enzymes or mucolytic drugs. Finally, nebulization
`of ß2-agonists and anticholinergic drugs is common
`practice in acute asthma.
`A drawback of inhalation therapy with nebulizers is
`the low deposition efficiency of the drug in the target
`area. On average, only 10% of the dose released from
`the nebulizer will reach the site of action, which is low
`compared to dry powder inhalers for which lung depo-
`sition between 20 and 30% of the dose have been
`reported [13]. The variability of the inhaler perfor-
`mance is high and the deposition in the lung can range
`from 0 to 30% of the released dose [14]. For potent
`drugs, like ß2-agonists and corticosteroids, which are
`dosed in quantities below 1 milligram, the desired clini-
`cal effect will still be obtained with nebulizers in spite of
`low efficiency of the drug delivery. However, for the
`delivery of antibiotics which are dosed in milligrams,
`efficient systems are paramount in order to reduce the
`time needed for inhalation of the total required dose
`and
`to
`attain
`sufficient
`therapeutic efficacy.
`Furthermore, pulmonary delivery of new drug sub-
`stances like proteins and peptides and complex formu-
`lations of liposomes or genetic material containing viral
`vectors require improved efficiency [15].
`An appropriate device and an appropriate formula-
`tion allows nebulization of many drugs in a wide
`range of doses [16]. However, a proper understand-
`ing of the working principle and the factors influenc-
`ing the performance of nebulizers is essential for an
`effective use [1 17]. Knowledge of the basics of neb-
`ulization is required in order to be able to prescribe
`the proper dose and to understand the difference
`between the prescribed nominal dose and the
`amount thereof delivered to the lung [18]. In this
`paper we will discuss the technical aspects of the neb-
`ulization of drug solutions.
`
`Types of nebulizers
`There are two basic types of nebulizers, the jet and
`the ultrasonic nebulizer. The jet nebulizer uses com-
`pressed air to aerosolize the drug solutions, whereas
`the ultrasonic nebulizer uses energy from high fre-
`quency sound waves.
`Jet nebulizers have evolved from the conventional
`type to the open vent and finally to the breath assist-
`ed type. In jet nebulizers, the droplet generator is a
`two-fluid atomizer. Different designs of the same
`basic principle are used. For a typical jet nebulizer,
`compressed air passes through a narrow hole and
`entrains the drug solution from one or more capillar-
`ies mainly by momentum transfer. The complex liquid
`break-up process is largely depending on the nozzle
`design and usually a combination of turbulent rup-
`ture of the instable liquid column and secondary
`droplet break-up. In its simplest form, the air imping-
`es directly on a solid jet of liquid (e.g figure 1, show-
`ing the Hudson T Updraft®, Tefa, Nieuwegein, The
`Netherlands). Large droplets impact on one or more
`
`baffles, in order to refine the droplet size distribution
`to the required range for inhalation. Only smaller
`droplets with less inertia can follow the streamlines of
`the air and pass the baffle.
`A different nebulizer design with an open vent is
`shown in figure 2 (Sidestream® Medic-Aid, Romedic,
`
`Figure 1
`In this figure the working principle of the jet nebulizer is
`explained using a schematic presentation of the Hudson
`T Updraft nebulizer. The gas flow from the compressor
`(DeVilbiss Pulmo-Aide) passes through a narrow hole,
`impinges on the entrained drug solution and droplets
`are formed. Larger droplets are trapped by the baffle.
`Small particles pass the baffle and are available for inha-
`lation by the inspiratory flow.
`
`Figure 2
`A schematic presentation of the Sidestream open vent
`nebulizer. Part of the inspiratory air (auxiliary flow) is
`leaded through the nebulization chamber. This improves
`droplet entrainment from the nozzle area. The nebulizer
`is combined to a PortaNeb compressor.
`
`Pharmacy World & Science
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`Volume 22 Nr. 3 2000
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`76
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`

`

`Meersen, The Netherlands). The vent allows part of
`the inspiratory air flow to pass through the nebuliza-
`tion chamber. The auxiliary air flow improves droplet
`entrainment from the nozzle area, thereby reducing
`the droplet concentration inside this chamber. This
`results in less coalescence of droplets and less collision
`between droplets and the inner wall of the nebuliza-
`tion chamber. Consequences are a reduced droplet
`size and an increased drug output rate. The latter may
`lead to shorter nebulization times. A further reduction
`of the droplet size is possible (although not proven
`yet) from faster solvent evaporation. It is sometimes
`claimed that the auxiliary air flow can reduce the jet
`flow for the same respirable output. This is a miscon-
`ception which may let to reduced lung deposition.
`The higher drug output rate to the patient with auxil-
`iary flow through the open vent is solely a conse-
`quence of the better entrainment. The rate of droplet
`generation is entirely determined by the jet flow rate
`(for a given nozzle design in combination with a
`given drug solution). The jet flow rate also influences
`the droplet size distribution. Reducing the jet flow
`results in increasing median droplet size. Therefore,
`only the recommended jet flow rate should be used,
`unless the droplet size distribution at deviating flow
`rates has been checked previously.
`The nozzle design of the Sidestream® is depicted
`more in detail in figure 3. The two-fluid nozzle con-
`sists of a central air jet, surrounded by four liquid cap-
`illaries. The air flow impacts on a beam and is forced
`to skim the capillary tube orifices, thereby entraining
`the drug solution. Disintegration of the liquid column
`results in droplets with various sizes. As for the
`Hudson T Updraft® (figure 1), only smaller droplets
`are entrained past the baffle. Larger droplets are col-
`lected and returned to the reservoir. The vent of this
`type of nebulizer has no valve. With a continuously
`working compressor (continuous droplet generation),
`
`part of the aerosol cloud may be wasted to the envi-
`ronment through this vent when the patient stops or
`interrupts inhalation or does not inhale fast enough.
`The dimensions of the nozzle and the baffle exhibit
`the inevitable spread of molded products. Because
`the droplet size distribution is directly related to these
`dimensions, a certain inter-device variation may be
`expected.
`Reduction of the waste by at least 50% of the neb-
`ulized dose may be achieved by so-called breath
`assisted open vent nebulizers. Figure 4 shows the
`Ventstream®, which has exactly the same nebuliza-
`tion chamber as the Sidestream® but a different vent
`for the inspiratory air. This vent has a flexible mem-
`brane (valve) which opens only during inhalation.
`Meanwhile, a similar membrane in the outlet tube
`closes the route for exhalation. Also in contrast with
`the Sidestream®, nearly the complete inspiratory flow
`is directed through the nebulization chamber. During
`exhalation, the inlet vent closes and the valve in the
`exhaust tube opens in order to discharge the used air.
`When the patient does not inhale, both valves are
`closed in order to prevent waste of the produced
`drug aerosol to the environment.
`In practice, there exists a wide variation in the per-
`formance of different types of nebulizers [9 19 20].
`Droplet size distribution and output rate are also influ-
`enced by the physical properties of the drug solution
`(suspension) and air flow rate from the compressor.
`These variables make a careful selection critical for an
`optimal therapy with this type of inhalation system.
`In an ultrasonic nebulizer, droplets are produced by
`a rapidly vibrating piezoelectric crystal. The frequency
`of the vibrating crystal determines the droplet size for
`a given solution. In most ultrasonic nebulizers the
`
`Pharmacy World & Science
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`Volume 22 Nr. 3 2000
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`77
`
`Figure 3
`A detailed presentation of the nozzle design of the
`Sidestream and the Ventstream nebulizer
`
`Figure 4
`A schematic presentation of the Ventstream nebulizer. In
`this breath assisted nebulizer an extra vent opens during
`inhalation only. The extra vent is closed during exhala-
`tion resulting in a reduction of aerosol wasted to the
`surrounding.
`
`

`

`vibrations are transferred directly to the surface of the
`drug solution in a drug reservoir. Ultrasonic nebulizers
`are more quiet and generally smaller than jet nebuliz-
`ers. Therefore, they are easier to handle and preferred
`by many patients [16]. The performance in the clini-
`cal practice of both types of nebulizers is influenced
`by several factors which will be discussed in more
`detail in the next paragraphs.
`
`Performance of nebulizers
`There are two main parameters which determine the
`performance of nebulizers: the droplet size distribu-
`tion of the aerosol and the drug output rate.
`However, it should be taken into account that the
`performance of the nebulizer is also influenced by
`patient related factors [21].
`
`Droplet size distribution
`The droplet size distribution is important for the actu-
`al deposition in the lung. The fraction of droplets with
`an aerodynamic diameter between 1 and 5 microme-
`ter is preferable for central and deep lung penetration
`at moderate flow rates of 60 l/min [14 22]. Smaller
`droplets will be exhaled to great extent while the
`larger ones will impact in the oropharynx and the
`upper airways. It is difficult to compare particle sizing
`results from different studies. The set up of the equip-
`ment, the measuring equipment and its software, the
`characteristics of the drug solution and, in case of jet
`nebulizers, the compressor used, are all factors that
`affect the final result. Therefore, only the basic aspects
`will be discussed in this paper.
`The droplet size distribution of an aerosol can be
`described statistically. Aerosols from a nebulizer are
`heterodisperse and, in most cases, conform to a log
`normal distribution [16]. The particle size distribution
`of an aerosol can be determined by laser diffraction
`analysis [20 23]. Other suitable techniques are cas-
`cade impactor analysis and aerosol electrical mobility
`[20 24 25]. Laser diffraction analysis is based on the
`principle of light scattering by particles. The diffrac-
`tion pattern of a particle is related to the particle
`diameter and particle shape. Different light scattering
`theories may be used to transform the complex dif-
`fraction pattern into a size distribution. Diffraction
`patterns of irregular particles are too complex, and
`therefore the calculations are based on the assump-
`tion that the particles are spherical.
`A simple characterization of the aerosol cloud from
`a nebulizer is by the median diameter of the droplets
`in the cloud. With laser diffraction analysis, a volume
`median diameter (VMD) is obtained. VMD corre-
`sponds with the particle diameter that divides the vol-
`ume distribution curve in two equal parts. Assuming
`that the particles density is independent of particle
`diameter, the VMD equals the mass median diameter
`(MMD). Diameters measured with laser diffraction
`technique are based upon geometric particle dimen-
`sions. For the spherical droplets in the aerosol cloud
`from nebulizers, the equivalent volume diameter (De)
`equals the measured (mass) median geometric diam-
`eter. This simplifies calculation of the measured
`(mass) median geometric diameter into a (mass)
`median aerodynamic size with the equation [26]:
`
`78
`
`Da = De(rp/i)0.5
`
`where rp is the particle true density, i the dynamic
`shape factor and Da is the aerodynamic particle diam-
`eter, which is the diameter of a unit density sphere
`that has the same terminal settling velocity in still air
`as the considered particle. For spherical droplets from
`aqueous drug solutions (in low concentrations), also
`the dynamic shape factor and droplet density have
`unity and so, the aerodynamic diameter equals the
`measured geometric diameter. No corrections are
`necessary and the volume distribution curve from
`laser diffraction analysis (calculated on the basis of
`spherical particles too) yields a correct mass median
`aerodynamic diameter (MMAD). Only for drug solu-
`tions in high concentrations, a correction for the true
`droplet density may be desirable.
`
`Drug output rate
`The drug output rate is another important factor to
`compare nebulizers. For delivery of a high dose to the
`lungs, nebulizers with a high output rate are preferred
`in order to confine the nebulization time. The output
`of nebulizers can be described by the aerosolized vol-
`ume or the aerosolized mass of drug [8]. The output
`rate is defined as the mass of drug converted to aero-
`sol per unit time. The nebulized volume can be deter-
`mined simply by weighing the nebulizer before and
`after use. Results may be misleading because they do
`not take into account the increase in drug concentra-
`tion within the nebulizer caused by evaporation of
`the solvent. Therefore drug output rate in mg/min is
`a better parameter for the nebulizer output [20 27].
`
`Physical factors of the drug solution
`
`Droplet size distribution
`The droplet size distribution and the drug output rate
`are basically determined by the design and user con-
`ditions of the nebulizer. The physical characteristics of
`the drug solution will also influence the droplet size. A
`higher gas flow of the compressor in a jet or a higher
`vibration frequency of the piezo electric crystal in an
`ultrasonic nebulizer, decrease the droplet size.
`The primary droplet size from specific nozzle designs
`has been expressed in mathematical formulas, con-
`taining the relevant variables, such as the nozzle
`diameter, the mass flow rates of the air and drug solu-
`tion and physical constants of the air and the drug
`solution [e.g. 24 28]
`A higher gas flow and a smaller diameter of the
`nozzle, theoretically decrease the primary droplet
`size. Practically, smaller droplets at a higher gas flow
`from the compressor have indeed been found for sev-
`eral jet nebulizers [23 29]. It is not possible to use
`these formulas to calculate the size of the droplets
`leaving the mouthpiece of the nebulizer. The primary
`droplet size distribution is modified by the classifying
`effect of the baffle(s). Only relatively small droplets
`can pass these baffle(s). Furthermore, droplet size
`changes during its way to the mouthpiece, due to
`evaporation of the liquid, droplet aggregation, con-
`densation and deposition on the inner walls of the
`nebulization chamber and tubing.
`In an ultrasonic nebulizer the vibrations of the pie-
`zoelectric crystal are transmitted to the surface of the
`drug solution in a reservoir. If the transmitted energy
`is sufficient, standing capillary waves are formed on
`
`Pharmacy World & Science
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`Volume 22 Nr. 3 2000
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`Pharmacy World & Science
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`Volume 22 Nr. 3 2000
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`
`the surface of the solution. Droplets are disrupted
`from the crests of the capillary waves [8]. According
`to Mercer [24] the threshold amplitude for the gener-
`ation of capillary waves is given by
`
`A = 4n/fl
`
`where
`A = threshold amplitude
`n = viscosity of liquid
`f = frequency of acoustic signal
`l = capillary wavelength
`
`Droplets are formed from the crests of the waves
`when the amplitude exceeds the threshold amplitude
`by a factor of about four. The mean diameter of drop-
`lets is proportional to the capillary wavelength (l). The
`proportionality constant is independent of the acous-
`tic frequency, the nature of the liquid and the mode
`of atomization [24]. The capillary wavelength is given
`by the formula:
`
`l = (8pg/rf2)1/3
`
`where
`g = surface tension of the solution
`r = density of the solution
`f = frequency of acoustic signal
`
`A common value for the proportionality constant
`when related to the number median droplet diameter
`(Dnm) was found by Lang [30]:
`
`Dnm = 0.34l
`
`It is apparent from these formulas that the droplet
`size is inversely proportional to the 2/3 power of the
`acoustic frequency. The gas flow in a jet nebulizer or
`the frequency of the crystal in an ultrasonic nebulizer
`are elements of their basic designs.
`As can be derived from the above mentioned for-
`mulas, the physical properties of the drug solution,
`such as viscosity, surface tension, and related factors
`like temperature and concentration, affect the droplet
`size. However, it is difficult to find confirmation of
`these effects in practice. Furthermore, the prediction
`of the effect of the solution characteristics is difficult.
`The formulas are developed in order to estimate the
`primary droplet size, whereas the emitted aerosol is
`affected by the baffle design and the geometry of the
`nebulizer too. Consequently, over 99% of the drop-
`lets are recycled back into the drug reservoir.
`Theoretically, the viscosity of the drug solution must
`influence the mass flow rate of the liquid through the
`nozzles of jet nebulizers. According to derived empiri-
`cal formulas for the droplet size [e.g. 24], this must
`affect the average primary droplet size too. Practically
`however, conflicting experimental results have been
`found.
`Newman et al. reported that several jet nebulizers
`tend to produce smaller droplets as the viscosity of
`the solution increases [31]. These results are in agree-
`ment with those of McCallion et al. [32] for glycerol-
`water and propylene glycol-water mixtures, whereas
`for silicon fluids an increase in droplet size was found
`for higher viscosities. Le Brun et al. investigated the
`droplet size distribution of tobramycin solutions (0-
`
`30% w/v) [27]. Initially a decrease was found in the
`range from 0 to 10%; from 10 to 30% no further
`decrease in droplet size distribution was found where-
`as the viscosity increased from 2.6 to 6.7 mPa/s.
`Hinds et al. also found small changes in droplet size
`for several solutions with different viscosities [33].
`For ultrasonic nebulizers the relation between vis-
`cosity and droplet size distributions seems more obvi-
`ous. In the above mentioned study by McCallion et al.
`[32] two ultrasonic nebulizers were compared too.
`The droplet size was proportional to the viscosity. This
`can be explained from the formula for the threshold
`amplitude. Since the threshold is higher for increased
`viscosities many viscous solutions can not be nebu-
`lized at all by this type of nebulizers. Boucher et al.,
`reported that solutions with a viscosity above 10 cp
`are difficult to aerosolize with ultrasonic nebulizers
`[34]. Temperature and concentration of the drug
`solution influence the viscosity of the solution and
`thereby the performance of the ultrasonic nebulizers.
`According to proposed formulas for droplet size
`from jet nebulizers [24] the surface tension of the
`solution is expected to be directly related to the diam-
`eter of the primary droplets. McCallion et al. [32]
`summarized several studies and concluded that the
`expected relation is not clearly reflected in experi-
`mental results.
`The equations given for droplet formation by ultra-
`sonic nebulizers suggest that the median droplet
`diameter increases with increasing surface tension of
`the drug solution. McCallion et al. indeed found a
`trend suggesting this proportionality [35], however
`no clear relationship was established. An increased
`surface tension can cause the formation of a foam,
`which might limit the formation of an aerosol.
`The different results in above mentioned studies
`might be explained from the use of different solu-
`tions. Viscosity and surface tension both influence the
`primary droplet size. In combination with other fac-
`tors, these parameters, with different effects upon
`droplet formation, complicate interpretation of pos-
`sible correlations. Furthermore, as mentioned above,
`only the primary droplet size can be estimated from
`the physical properties of the solution. The final drop-
`let size distribution leaving the mouthpiece will
`always be limited by the mechanical construction of
`the nebulizer. Therefore, the size distribution of the
`aerosol cloud leaving the nebulizer should be estab-
`lished experimentally for each solution to nebulized.
`
`Drug output and drug output rate
`As explained above for the several types of jet nebuliz-
`ers, the output rate of the breath assisted, open vent
`type is larger than the output rate of the open vent
`nebulizer, which consequently has a higher output
`rate when compared to the conventional nebulizer
`[20 36 37 38]. Above mentioned factors for the
`droplet size distribution are also applicable to the
`drug output rate. Gas flow in jet nebulizers and vibra-
`tion frequency in ultrasonic are proportionally related
`to drug output rate [25 39].
`Also the drug concentration is directly related to
`the output rate, although the improvement that can
`be obtained by increasing the concentration is limit-
`ed. Higher concentrations may also result in higher
`viscosities which, as reported, can cause an opposite
`effect. In a range of tobramycin concentrations Le
`
`

`

`Brun et al. found an optimum at a concentration of
`20% w/v tobramycin (as sulfate) in water for both
`ultrasonic and jet nebulizers [27]
`The volume of the drug solution is a factor that
`affects the total drug output. There is a residual vol-
`ume for every nebulizer that can not be aerosolized.
`For reasons of efficiency it is preferred that the residu-
`al volume is only a small fraction of the total volume
`fill [29]. A nebulizer with a residual volume of 1 ml
`filled with a drug solution of 2 ml will release only
`50% of the drug solution. This percentage will be
`75% if the nebulizer can and will be filled with 4 ml.
`However, a disadvantage of a larger volume can be a
`longer nebulization time required to aerosolize the
`solution. In clinical practice a nebulization time of 15
`to 30 minutes is acceptable. Longer periods will jeop-
`ardize the patient compliance. Consequently it can be
`concluded that there is an optimum with respect to
`fill volume and concentration.
`
`Patient factors
`Laboratory evaluation of nebulizers with a specific
`drug solution provide information on the droplet size
`distribution, drug output rate and thus the expected
`performance of the tested combination of nebulizer
`and drug solution. Laboratory evaluation is mandato-
`ry before the combination can be used by the patient.
`However, patient factors complicate the prediction of
`the final in vivo performance and are a further factor
`to be considered in the evaluation of the therapy. In
`an in vitro study Le Brun et al. found differences in the
`performance with regard to droplet size distribution
`for jet and ultrasonic nebulizers both loaded with
`solutions of tobramycin [20 27]. The
`in vitro
`observed differences were not reflected in two separ-
`ate patient studies with these nebulizers. The pharma-
`cokinetics after inhalation, used as an indirect meas-
`ure for evaluation of drug deposition, were compar-
`able in both studies with six patients [40 41].
`It is a known fact that patient compliance is poor in
`inhalation therapy. A few evaluating studies are
`known referring to compliance. In a study on children
`with respiratory diseases a compliance of 47.6% with
`the prescribed inhalation therapy was found [42].
`Whereas Cochrane found a mean compliance of only
`56.8% in a study with 93 patients on inhalation thera-
`py [43]. The low compliance is understandable
`because it usually takes a lot of time and energy to
`inhale the prescribed medication on a daily basis.
`Another aspect of the daily routine is the mainte-
`nance of the nebulizer. Cleaning and disinfection is
`necessary in order to prevent contamination of the
`nebulizer and subsequently possible infections [44].
`Cleaning and disinfection procedures might influence
`the performance of nebulizers. Therefore, the perfor-
`mance of nebulizers should be checked periodically.
`Furthermore, the breathing pattern through the
`nebulizer influences the actual inhaled dose. It influ-
`ences the sites of deposition. However, the deposition
`in the lung is complicated by the physiology of the
`lung and its clinical situation which determines the
`geometry of the inspiratory system. Gamma scintigra-
`phy studies with CF patients by Laube in 1998 indicat-
`ed that a high inspiratory flow rate resulted in a more
`central airway deposition, whereas lower inspiratory
`flow rates resulted in a more peripheral deposition
`
`[45]. Studies with radio isotopes are useful to deter-
`mine the deposition patterns in patients. As expected,
`it could be shown that lung deposition varies with age
`and particle size distribution of the inhaled aerosol
`[46 47]. Eventually, only clinical efficacy studies can
`proof the relevance of nebulizer therapy.
`
`Developments
`A new type of nebulizer with the so called adaptive
`aerosol delivery (AAD) technology seems promising.
`A nebulizer with AAD adapts to the individual breath-
`ing pattern of the patient and delivers the aerosol
`only during inhalation. In an AAD nebulizer the
`breathing pattern of the patient is analyzed to deter-
`mine the shape of the inspiratory and expiratory flow
`pattern. The system then pulses aerosol during inha-
`latio