PART 4 THERAPEUTIC PRINCIPLES
Aerosol Therapy and Delivery Systems Sunalene G. Devadason, Mark L. Everard, and Peter N. Le Souëf
TEACHING POINTS ● ●
Advances in delivery systems have rendered traditional nebulizers obsolete for use in asthma. Pressurized metered dose inhalers attached to a spacer (pMDI-spacer) are the delivery method of choice for children with asthma. pMDI-spacers must be rendered static-free to perform adequately. For plastic spacers, coating with detergent is the most efﬁcient and cheapest method of achieving this. To treat a plastic spacer for static, the spacer should be immersed in water containing detergent and left to drip dry without rubbing or rinsing. Rinsing will remove the detergent and render the exercise useless. Dry powder inhalers are not recommended for use in young children and, in all patients, require a mouthwash and gargle when used with inhaled steroids. Current drug delivery systems in children do not require that a lower dose be prescribed for younger children because the dose that children receive from a given device is reasonably proportional to the size of the child. Care must be taken to avoid side effects of inhaled drugs and to use the lowest possible dose. Newer nebulizer systems are likely to become the delivery system of choice in the future.
Inhalational drug therapy is the primary mode of treatment for asthma as well as other respiratory diseases such as cystic ﬁbrosis. The efﬁciency of aerosol therapy, both for adults and children, has improved greatly in recent times. Factors such as the development of pro-drugs with greater topical activity and fewer adverse systemic effects 1 ; new formulations to maximize the delivery of drug particles within inhalable size ranges; improved delivery systems to optimize airway targeting, minimize lung deposition, and decrease drug wastage have resulted in marked increases in clinical efﬁcacy. However, the requirement for affordable and disposable inhalers, particularly for the more widespread treatment of asthma, has limited the advances that could be made in this ﬁeld. Greater advancements have been made in the optimization of aerosol devices and drug formulations for the treatment of cystic ﬁbrosis and for the delivery of aerosolized drugs for systemic therapy. The use of aerosols as a noninvasive vehicle to permit rapid absorption of drug into the systemic circulation for the treatment of nonrespiratory diseases
such as diabetes is becoming increasingly important. 2 Because the drugs used to treat these conditions are more costly and tend to have narrower margins between therapeutic efﬁcacy and deleterious side effects, highly efﬁcient aerosol delivery systems are required to deliver strictly quantiﬁed doses to targeted lung regions.
PRINCIPLES OF AEROSOL DELIVERY An aerosol is a biphasic system containing a gaseous phase and a particulate phase. In other words, it is a gaseous suspension: a gas containing solid and/or liquid particles. 3 The deﬁnition of a particle is a body with a deﬁned solid or liquid boundary bordering its gaseous environment. 3 The advantage of using aerosol therapy for the treatment of respiratory disease is that the drug is delivered directly to the site of action, allowing more rapid therapeutic effects using a lower nominal dose. The most important consideration with aerosolized drugs is to maximize drug deposition in the required areas of the respiratory tract. Deposition of aerosolized particles in the respiratory tract is governed by three main factors: inertial impaction, gravitational sedimentation, and diffusion. In addition, the electrostatic charge on both the aerosol and the respiratory mucosa may also affect drug deposition. 2,4-6 The degree of inﬂuence of each of these factors on aerosol deposition in the lungs is dependent on the particle size of the aerosolized particles (Fig. 17-1). The optimal particle size for deposition in the smaller airways is less than 3 µm, 4,6 although particles larger than 5 µm are still considered “respirable” particles. 4 Particles larger than 5 µm generally deposit in the oropharynx or upper airways. 4 Particle size measurement is complicated by the fact that some of the aerosolized droplets may be irregularly shaped rather than strictly spherical. For convenience, particles of different shapes that behave in a similar aerodynamic manner are grouped together and visualized as spherical droplets with a common diameter. This is termed the aerodynamic diameter, which is deﬁned as the diameter of a sphere of unit density with the same terminal sedimentation velocity in air as the particle or droplet in question 2 and is usually determined by the mass of the droplet. Monodisperse aerosols consist of particles with the same aerodynamic diameter. However, aerosols generated by most forms of aerosol therapy are generally polydisperse in nature in that the aerosol is made up of particles of widely variable aerodynamic diameters. Polydisperse aerosols are usually
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Extra-fine particle fraction Fine particle fraction Cumulative 100 distribution (%) 90 80 70
MMAD = [email protected]
60 50 40 30 20
% [email protected]
10 0 0
Particle size (µm) [diam]
Figure 17-1 diameter.
Aerosol particle size. GSD, geometric standard deviation; MMAD, mass median aerodynamic
characterized by their mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). 4 That is, one half the mass of the aerosol will have an aerodynamic diameter below the MMAD, and one half of the mass will be in particles with diameters greater than the MMAD. Lung deposition for a highly polydisperse aerosol with an MMAD of 3 µm would be much lower than that for a monodisperse aerosol of the same diameter, and the reverse would occur if the MMAD was >5 µm. 7 Minimizing the particle size of aerosolized drugs is essential because larger particles carry a much greater volume of drug than smaller particles owing to the cubic increase in volume with a unit increase in the diameter of the particles. Hence, aerosols that contain a large proportion of particles >15 µm in diameter will deliver most of the drug available for inhalation to the oropharynx—resulting in little therapeutic effect and increased systemic availability. Physical Mechanisms of Deposition
INERTIAL IMPACTION Inertial impaction has a greater effect on larger particles (>3 µm), 8 and in the oropharynx and upper airways where the velocity of the inhaled particles is highest. This is because particles carried by a gas or propellant possess momentum, which is determined by both the mass and the velocity of the particle. 5,6 When the particles approach a surface such as the back of the throat or a bifurcation of the airways, the direction of air ﬂow will change. Inhaled particles may not follow the direction of air ﬂow, and will instead accumulate on the surface. Particles with a higher momentum (i.e., larger particles or those with higher velocities) are more likely to accumulate in the oropharynx or the larger airways. Particles >15 µm are unlikely to enter the trachea. 7 Even for particles <15 µm, further deposition of the larger particles will occur at airway bifurcations. 6 As the larger particles get ﬁltered out and as the velocity of the particles decreases,
impaction becomes less important as a mechanism of deposition in the smaller airways. 7 SEDIMENTATION Particles <3 µm will probably not deposit owing to inertial impaction. Sedimentation caused by gravity is the most important mechanism for deposition in the smaller airways. The effect of sedimentation is greatest on the larger particles (>0.5 µm) 6 that have escaped deposition owing to inertial impaction. Breath-holding after inhalation of the aerosolized particles helps deposition in the airways owing to sedimentation. 46 DIFFUSION Particles <0.5 µm will move by diffusion (impaction with gas molecules) toward the surface of the respiratory tract. Movement of particles by diffusion decreases with increasing particle diameter, and hence has a greater effect on small particles (<0.1 µm). 6 Deposition in the airways due to diffusion is helped by breath-holding after inhalation. Without breath holding, most small particles <0.1 µm are likely to be exhaled rather than deposited. ELECTROSTATIC ATTRACTION Deposition may occur because of attraction between charged particles in the inhaled aerosol and an induced charge on the mucosa of the respiratory tract. 5 The importance of this factor for aerosol therapy has not been investigated in detail but will presumably vary greatly depending on the drug formulation being administered. In addition to the factors just discussed, irregularities in airway structure and inhalation ﬂow patterns lead to nonuniform deposition of aerosolized drugs. “Hot spots” usually occur at airway bifurcations, 4,5 where large amounts of drug tend to deposit. The greater the degree of airway obstruction due to disease, the more central the deposition in the
C H A P T E R 17 ■ Aerosol Therapy and Delivery Systems
airway—thereby reducing the therapeutic efﬁciency. 9 The depth of penetration of aerosolized particles in the airways also depends on physiologic factors such as tidal volume, respiratory rate, and breath-hold capability. 10 Therapeutic Aerosol Devices The relative merits of the devices used in children are summarized in Table 17-1. The pressurized metered dose inhaler with valved holding chamber or spacer (e.g., Aerochamber [ForestPharmacaticals, St. Louis, Mo], Volumatic [GlaxoSmithKline, London]) continues to be the delivery system of choice for use by children (Figs. 17-2 and 17-3), particularly in the younger age groups (infants and children younger than 6 to 7 years of age). Pressurized metered dose inhalers (pMDIs) are inexpensive, easy to use, and disposable; in particular pMDIs require no inspiratory effort on the patient’s part in order for the metered dose to be dispensed. When used without a spacer, pMDI actuation must be closely coordinated with the start of the patient’s inhalation; a difﬁcult feat for many older children, and impossible for young children to achieve. Valved holding chambers or spacers eliminate the need for coordination, but are less convenient and portable. However, spacers must be used with pMDIs when treating children younger than 6 to 7 years of age, and are highly recommended for all patients when using corticosteroids. Facemasks must be used for infants and toddlers
Spacers for use with pressurized metered dose inhalers.
(less than 3 years of age); however these encourage nasal inhalation which will ﬁlter out much of the aerosolized drug. Children more than 3 years of age can be taught to use a mouthpiece; this greatly increases the amount of drug delivered to the lungs. Comparison of bronchodilator delivery with pMDI-spacer and nebulizer has shown increased efﬁciency of drug delivery via pMDI-spacer 11 and equivalent clinical outcomes in both adults and children, 12-14 even during severe exacerbations. The use of pMDI-spacers for delivery of bronchodilators in hospital emergency departments is becoming much more widespread. Electrostatic charge greatly reduces drug delivery from plastic spacers, 15 but this problem can be reduced or eliminated by coating the inner surface of the spacer with detergent, 16 use of a metal spacer, 17 or by constructing spacers from patented plastic materials, which are more resistant to the build-up of electrostatic charge (Aerochamber Max, Trudell Medical, London, Ontario, Canada). Proper care must be exercised in using a detergent-coated plastic spacer. The spacer should be washed in water containing a diluted ionic detergent and then left to drip dry. The surfaces of the spacer should not be rubbed or touched and, most importantly, the spacer should NOT be rinsed because this will remove the detergent. A detergent-coated plastic spacer will have minimal static and detergent coating has been shown to
Figure 17-3 spacer.
Child inhaling from a pressurized metered dose inhaler and
Table 17-1 Relative Merits of Devices for Aerosol Delivery in Children
Age Range Expense Efﬁciency Dependency on Technique Major Disadvantage Major Advantage Recommended for Use in Children with Asthma
All High Low Low Inefﬁcient, expensive, slow Delivery of drugs in cystic ﬁbrosis No
Pressurized Metered Dose Inhaler
Pressurized Metered Dose Inhaler-Spacer
6 Years and over Low Moderate to good High Reliance on technique
All Low Good to excellent Low Bulky, must be designed or treated to reduce static Easy and efﬁcient to use in children with asthma Yes, device of choice
Portability, use for bronchodilators Yes, but only for bronchodilators
Dry Powder Inhaler 6 Years and over Low Good to excellent Low to moderate High oropharyngeal deposition, gargle with steroids Portability Yes, but limited age range
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last for a month without static returning. Plastic spacers should not be stored in plastic bags or wrappings. Breath-actuated pressurized inhalers, such as the Autohaler (3M, St. Paul, Minn), eliminate the need for patient coordination of actuation with inhalation, without the use of a holding chamber. Once the device has been primed, the patient’s inhalation ﬂow triggers actuation and release of the drug, which has been shown to improve drug delivery in adults with poor coordination. 18 Breath-actuated devices still require a 2 to 4 second inspiratory time, which may be difﬁcult for some children (particularly those younger than 6 years of age) to achieve. 19 Most older children and adolescents prefer dry powder inhalers (DPIs) because of their convenience and portability, and giving them a choice of inhalation device may be an important factor in improving adherence in this age group. However, the more common DPIs available for asthma therapy (e.g., Turbuhaler [AstraZeneca, London], Accuhaler/ Diskus [GlaxoSmithKline]) require a forced inspiratory maneuver for the drug dose to be dispensed. Hence, the patient must be able to remember and consistently reproduce the optimal inhalation technique when using these devices. The higher the inspiratory ﬂow, the greater the amount of respirable drug delivered, particularly when using the Turbuhaler. Because of the high resistance when inhaling through the Turbuhaler, greater inspiratory effort may be required from the patient to achieve an equivalent dose compared to the Accuhaler. 20 DPIs generally result in a higher oropharyngeal drug dose and patients should wash their mouths and gargle after inhaling corticosteroids. In addition, younger patients may not be able to consistently generate a sufﬁciently high inspiratory ﬂow through DPIs—hence these devices are not recommended for children younger than the age of 6 to 7 years. Much more efﬁcient dry powder delivery systems have been developed (e.g., Pulmonary Inhaler, Nektar, San Carlos, Calif)—the patient’s inspiratory effort is not required to dispense the metered dose because the drug is automatically dispensed into a holding chamber. These devices would not be cost effective when compared to current inhalers used for asthma therapy. A similar concept (namely, the use of a holding chamber) was tested for use with the Turbuhaler, 21 but did not achieve widespread use. The use of jet nebulizers for asthma treatment has now ceased in many places in the world and is decreasing in most other places. Nebulizers still have a role in the treatment of cystic ﬁbrosis. This has occurred as traditional nebulizers are less efﬁcient in delivering drug to the lower airways, and are expensive, inconvenient and cumbersome as they generally require an external compressor and power supply. Ultrasonic nebulizers are not widely used, as they are not suitable for delivery of some drugs, particularly those in suspension formulations. Several new generation nebulizers or liquid aerosol delivery systems (e.g., Aeroneb [Nektar], eFlow [PARI Pharma, Munich], AERx [NovoNordisk, Hayward, Calif], I-neb [Respironics, Murrysville, Pa) have been developed that address most of these problems. These vibrating menbrane devices are battery powered and compact, and may even be breath actuated (i.e., releasing drug only during the optimal portion of the patient’s inhalation). These devices are too costly to compete with pMDIs for the treatment of asthma,
but may have a role in the treatment of cystic ﬁbrosis for the delivery of DNase and antibiotics because the increased delivery efﬁciency of these expensive medications easily justiﬁes the use of a more costly delivery system. Drugs for Pediatric Use ASTHMA THERAPY When prescribed and administered correctly, inhaler therapy is able to control asthma symptoms in most patients by reversing airway obstruction and reducing airway inﬂammation. 22 The primary aerosolized medications currently used to treat asthma include short-acting beta2 agonists, longacting beta2 agonists, and corticosteroids. These medications are generally delivered using either pressurized metered dose inhalers, or dry powder inhalers. Nebulizer use for asthma therapy has decreased signiﬁcantly over the last decade and traditional nebulizers may now be obsolete for use in asthma. Beta2 Agonists
Short-acting beta2 agonists such as salbutamol (albuterol) provide immediate relief of acute asthma symptoms by binding to the beta2 receptors on the smooth muscles of the bronchioles, causing them to bronchodilate. Symptom relief lasts up to 3 to 4 hours. 23,24 Short-acting beta2 agonists should be used only to relieve acute symptoms, and if required more than three times a week, anti-inﬂammatory therapy should be commenced. Long-acting beta2 agonists such as salmeterol or eformoterol enhance bronchodilation for up to 12 hours after administration. 23 Eformoterol also has an immediate bronchodilatory effect, similar to salbutamol, whereas salmeterol has a more delayed onset of action and must be used with short-acting bronchodilators for acute relief of symptoms. Long-acting beta2-agonists are often prescribed with corticosteroids in combination inhalers for treatment of severe, chronic, or refractory asthma. Corticosteroids
Long-term therapy for chronic or severe asthma in children requires the use of prophylactic inhaled corticosteroids for suppression of airway inﬂammation. Corticosteroids are the most potent and effective form of anti-inﬂammatory treatment for severe asthma. 25 Long-term use of inhaled corticosteroids reduces airway inﬂammation and bronchial hyper-responsiveness, thereby decreasing asthma exacerbations and symptom severity. 26,28 Fluticasone propionate (FP), currently one of the most widely used corticosteroids available, combines the advantage of high topical activity with low gastrointestinal bioavailability. 29 Adverse local effects 30 and systemic effects due to the systemic absorption of ﬂuticasone via the airway mucosa have been reported 31-33 even within therapeutic dose ranges, particularly in children. Budesonide is still widely used, particularly via Turbuhaler, but it has lower gastrointestinal bioavailability than beclomethasone dipropionate (BDP) and is less topically active than FP. 29,34 However, budesonide is highly protein bound in plasma, reducing the effect of absorption through the airway mucosa into the systemic circulation. 34 The development of newer synthetic steroids for inhalation may alleviate some of these concerns. 1 Ciclesonide is
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one of the more promising candidates, having already been granted regulatory approval in many countries for use in adults and children older than 4 years of age for the treatment of asthma. Ciclesonide is inhaled as an inactive pro-drug and is activated intracellularly within the airways to a highly topically active form. 35 Because of a number of factors (low oral and gastrointestinal bioavailability of the inactive prodrug and high protein binding of the active drug in plasma prior to hepatic inactivation), ciclesonide appears to have markedly reduced local and systemic effects, 36,37 even in children. 38 Currently, inhaled corticosteroids are the most widely used drugs of concern in the pediatric age group. BDP has been reformulated as an extra-ﬁne propellant-based aerosol (QVAR) that maximizes lung deposition in both adults 39 and children. 19 However, there is the potential for increased adverse side effects using this formulation because of high gastrointestinal bioavailability and increased absorption through the airway mucosa. The recommended prescribed dose of BDP is halved when switching to QVAR. 40 Although administering corticosteroids via inhalation is associated with fewer adverse effects when compared to oral administration, local and systemic effects can still occur particularly when children are prescribed high daily doses over a prolonged period. Thus, to reduce unwanted side effects, the lowest effective dose required for effective symptom control should be used, and the delivery of drug to the lungs should be optimized. Local adverse effects in both adults and children can include dysphonia and oropharyngeal candidiasis due to deposition of drug particles in the mouth and throat. These effects can be minimized by rinsing the mouth and gargling after inhaler use. Other adverse side-effects include adrenal suppression and decreased bone density. 27,28,37 Long-term use of inhaled corticosteroids in young children is of concern because of the potential impact on bone turnover and growth. These effects may include inhibition of new bone formation and bone reabsorption. 27 However, studies examining the effects of moderate corticosteroid use (<400 µg/day of FP) have found little effect on bone turnover 41 and ﬁnal height. CYSTIC FIBROSIS THERAPY A number of different drugs for cystic ﬁbrosis (CF) therapy (antibiotics, recombinant human DNase, mucolytics, hypertonic saline) are delivered via aerosol—generally using jet nebulization. Bronchodilators and corticosteroids are also sometimes prescribed for CF patients (via pressurized or dry powder inhaler). This section will focus primarily on inhaled antibiotics and DNase delivery. Recombinant Human Deoxyribonuclease (rhDNase)
The presence of excessive levels of DNA has been found to contribute to the increased viscosity of the sputum of CF patients. 42 In addition, by binding to aminoglycoside antibiotics in sputum, DNA could reduce their efﬁcacy. 43 The use of recombinant human deoxyribonuclease 1 (dornase alpha, rhDNase, Pulmozyme), delivered via jet nebulizer, has been shown to reduce the viscosity of CF sputum, 42 improve lung function, and reduce exacerbations in CF patients. 44 rhDNase can be aerosolized using a number of different jet
nebulizer-compressor combinations; however, a small particle size, high-output system is recommended. 45 Inhaled Antibiotics
Chronic bacterial infection of the lower airways is present in most CF patients from early life. Early prophylactic antibiotic treatment can reduce lung damage caused by these infections, and improve quality of life. The use of inhaled antibiotics such as tobramycin has been shown to improve clinical outcomes in patients chronically infected with Pseudomonas aeruginosa. 46,47 Other antibiotics, such as colomycin, are also widely used, although controlled trial evidence supporting the use of colomycin is not as convincing as for tobramycin. 48 A number of jet nebulizer-compressor systems may be used for aerosolization of antibiotics. Ventilator Circuits Traditionally, jet nebulizers were used to deliver medication to patients through ventilator circuits, but there are many problems with this form of therapy, since only a small proportion of the nebulized drug is actually delivered to the patient. The use of pMDIs with suitable adaptors allows more efﬁcient delivery, particularly when used with small-volume chambers, which appear to be suitable for all patients from preterm baby to adult. 49-51 Medication delivery via endotracheal tubes is also possible using ultrasonic nebulizers. 51,52 Doses approaching 100% of the nominal dose can be delivered into the lower respiratory tract by actuating the medication through a catheter passed through the endotracheal tube. 53 However, not all drugs required for delivery to ventilator patients are available in pMDI formulations, requiring the continued use of nebulizers for this purpose. 54 More recently, vibrating membrane nebulizers have been investigated for use in ventilator circuits, and have been shown to markedly improve drug delivery. 55
DOSE CONSIDERATIONS Given that lung deposition studies for most inhalation devices in children from infancy up to about 10 years of age show that the amount reaching the lung is generally proportional to the size of the child, the same prescribed dose can be used in all children. Most drug dosage schedules recommend progressively lower doses with reducing age of the child, but these schedules appear to have been designed without reference to the available scientiﬁc data and with no proper evidence basis to this practice. Extreme care should be taken with prescribing high doses of inhaled drugs to all children, regardless of age, and every attempt should be made to ensure that side effects are avoided and that the lowest possible therapeutic dose is used.
CONCLUSIONS In recent times, pMDI-spacers have become the most commonly used approach to aerosol therapy in children. They can be used for all ages and for both long-term, preventive therapy, and for short-term treatment of acute exacerbations. One of the main advantages of pMDI-spacer use is that normal tidal breathing can be used during aerosol administration, which makes them ideal for infants and younger children. However,
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newer and more innovative devices are gradually becoming available and these may offer therapeutic advantages in terms of increased efﬁcacy, convenience, and compliance—particularly for older children and adolescents. The ability of a child
to utilize an inhaler device and to perform the required inhalation technique consistently must be evaluated when making the choice of an appropriate delivery system for children of different ages.
SUGGESTED READINGS Barry PW, O’Callaghan C: The inﬂuence of inhaler selection on efﬁcacy of asthma therapies. Adv Drug Delivery Rev 55(7):879923, 2003. Devadason SG: Recent advances in aerosol therapy for children with asthma. J Aerosol Med 19(1):61-66, 2006. Devadason SG, Le Souëf PN: The use of current commercial inhalers in the paediatric population. J Aerosol Med 15:343-345, 2002. Dolovich M: Physical principles underlying aerosol therapy. J Aerosol Med 2:171-186, 1989. Dolovich MB, Ahrens RC, Hess DR, et al: Device selection and outcomes of aerosol therapy: Evidence-based guidelines: Am Coll
Chest Phys/Am Coll Asthma Allergy Immunol Chest 127(1):335371, 2005. Everard ML: Aerosol delivery to children. Pediatr Ann 35(9):630636, 2006. Le Souëf PN, Devadason SG: Lung dose of inhaled drugs in children with acute asthma. J Aerosol Med 15(3):347-349, 2002. Wildhaber JH, Devadason SG, Eber E, et al: Effect of electrostatic charge, ﬂow, delay and multiple actuations on the in vitro delivery of salbutamol from different small volume spacers for infants. Thorax 51:985-988, 1996.
REFERENCES The references for this chapter can be found at www.pedrespmedtext.com.