Expert Opinion on Drug Delivery
`
`ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: https://www.tandfonline.com/loi/iedd20
`
`Adaptive Aerosol Delivery (AAD®) technology
`
`J Denyer, K Nikander & N J Smith
`
`To cite this article: J Denyer, K Nikander & N J Smith (2004) Adaptive Aerosol Delivery (AAD®)
`technology, Expert Opinion on Drug Delivery, 1:1, 165-176, DOI: 10.1517/17425247.1.1.165
`To link to this article: https://doi.org/10.1517/17425247.1.1.165
`
`Published online: 23 Feb 2005.
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`LIQ02814550
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`Technology Evaluation
`
`Adaptive Aerosol Delivery (AAD®)
`technology
`
`J Denyer, K Nikander† & NJ Smith
`†Respironics, Respiratory Drug Delivery Division, 41 Canfield Road, Cedar Grove,
`NJ 07009-1201, USA
`
`Jet nebulisers have, since the 1920s, been used for delivery of inhaled drugs
`for the treatment of asthma, chronic-obstructive pulmonary disease and pul-
`monary infections. During the last two decades, recognition of the shortcom-
`ings of conventional nebulisers has led to the development of new
`‘intelligent’ nebulisers such as the Adaptive Aerosol Delivery (AAD®, Profile
`Therapeutics, a Respironics company) systems. Diseases of the airways have
`traditionally been logical candidates for treatment with inhaled drugs. The
`introduction of the ‘intelligent’ nebulisers has, however, broadened the pos-
`sibilities for inhaled treatment to include drugs targeted for systemic dis-
`eases. These nebulisers offer the possibility to deliver more precise doses of
`drug, maximise lung deposition, enhance adherence to treatment and com-
`pliance with the device through feedback to the patient, and last but not
`least, offer the possibility to reduce nebulisation times.
`
`Keywords: AAD® system, Adaptive Aerosol Delivery, HaloLite®, I-neb, nebuliser, Prodose™
`
`Expert Opin. Drug Deliv. (2004) 1(1):165-176
`
`1. Introduction
`
`The inhaled route for therapeutic aerosols is a common practice in the treatment of
`diseases such as asthma or chronic-obstructive pulmonary disease (COPD). Pulmo-
`nary drug delivery for these diseases limits exposure to systemic drug effects. The
`inhalers used are relatively inefficient conventional pressurised metered-dose inhal-
`ers, dry powder inhalers or jet nebulisers, which deliver drugs with a broad therapeu-
`tic window. The development of new pulmonary drug delivery systems that deliver
`more precise and reproducible doses of drug has, however, broadened the range of
`drugs that could be delivered to, or through, the lungs.
`The forces driving the pharmaceutical industry to consider pulmonary drug delivery
`of new molecules include ever increasing competition, pricing pressures, drug patent
`life, life cycle management, and patient demands. The main customers for pulmonary
`drug delivery are the patients, healthcare payers and investors. This means that new pul-
`monary drug delivery systems, such as the Adaptive Aerosol Delivery (AAD®, Profile
`Therapeutics, a Respironics company) systems, need to provide a sustainable competi-
`tive advantage by creating a technical solution that meets the patient’s demands, is cost
`effective, in order to meet the payer’s demands, and generates a new market or extends
`the commercial life of the drug, in order to meet the demands of the investor.
`Numerous types of inhalation devices are available, but the nebuliser can provide
`a faster and more cost-effective route to the market for many new drug delivery
`applications. Conventional nebulised therapy, however, is a rather inexact method of
`drug administration, and wastes a large amount of aerosol during exhalation to the
`environment [1]. An inhalation device that is efficient, and delivers a precise amount
`of aerosol with minimal environmental or care giver exposure will be required for
`the delivery of expensive drugs with the potential to cause adverse reactions. The
`main reason for the inexact drug delivery is the constant drug output of the conven-
`tional nebuliser, which makes the amount of drug inhaled directly dependent on the
`breathing pattern of the patient. The duty cycle of the patient’s breathing pattern is
`
`1. Introduction
`
`2. The Adaptive Aerosol Delivery
`technology
`
`3. In vitro results
`
`4. Adaptive Aerosol Delivery
`systems in clinical studies
`
`5. Conclusion
`
`6. Expert opinion
`
`Ashley Publications
`www.ashley-pub.com
`
`10.1517/17425247.1.1.165 © 2004 Ashley Publications Ltd ISSN 1742-5247
`
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`Adaptive Aerosol Delivery (AAD®) technology
`
`Inspiration
`600
`
`Conventional
`nebuliser
`
`Active
`venturi
`nebuliser
`
`Breath-
`synchronised
`nebuliser
`
`AAD®
`system
`
`40:60
`
`65:35
`
`100:0
`
`100:0
`
`400
`
`200
`
`0
`
`200
`
`400
`
`Flow (ml/s)
`
`600
`Expiration
`
`Mean inspiration:expiration ratio
`Proportion of nebuliser output inspired/breath
`Total nebuliser output during a single respiratory cycle
`
`+
`
`Figure 1. A schematic representation of the tidal volume and inspiration/expiration ratios of four different types of jet
`nebuliser. The drug available for inhalation is indicated by the dark shaded areas, whereas the lightly shaded areas indicate losses to the
`surrounding air. These two areas are used to calculate the mean inspiration/expiration ratios for the aerosol output of the different types
`of nebuliser. Modified from [29] with permission of AstraZenaca, Lund, Sweden.
`AAD: Adaptive Aerosol Delivery.
`
`typically 40:60 [2], which means that the time of inspiration is
`∼ 40% of the single respiratory cycle and the time of expira-
`tion ∼ 60% (Figure 1). This means that at least 60% of the
`drug delivered from the nebuliser will be wasted to the envi-
`ronment and potentially be inhaled by those caring for the
`patient. Active venturi jet nebulisers were developed to
`increase the amount of drug inhaled and decrease the amount
`wasted
`[3]. Breath-synchronised nebulisers have further
`improved the amount inhaled by delivering aerosol only dur-
`ing inhalation. As the aerosol is delivered during the whole
`inspiration, filling the entire anatomical deadspace, some of it
`will be exhaled. Pulsed aerosol drug delivery during only part
`of the inhalation could minimise the amount lost during
`exhalation, and provide the basis for delivery of precise preset
`doses of drug.
`An important feature required in a new inhalation device
`would be feedback from the device to the patient on how to
`inhale, and information on when the preset dose of drug has
`been delivered. Published data on patient adherence to neb-
`ulised treatment indicates that a large proportion of the pre-
`scribed doses are never used [4]. There is a lack of published
`data on how patients comply with the instructions on neb-
`uliser use, as conventional nebulisers lack any data-recording
`features. As a consequence, there are limited data available on
`the patient’s true adherence, that is, the product of adherence
`to treatment × compliance with the device.
`
`2. The Adaptive Aerosol Delivery technology
`
`The AAD technology was developed by Profile Therapeutics
`to minimise the variability of the delivered dose, to minimise
`
`the waste of aerosol to the environment and to improve the
`patient’s adherence to their treatment and compliance with the
`correct use of the device [5,6]. On 1 July, 2004, Respironics,
`Inc. aquired Profile Therapeutics Plc, the developers of AAD
`technology. The AAD systems have been designed to adapt
`delivery of aerosol to the patient’s breathing patterns, eliminat-
`ing the greatest source of variability in drug delivery associated
`with conventional nebulisers. It also provides the patient with
`feedback on how to effectively use the AAD system during the
`treatment. When the preset dose is delivered, the device
`switches off and a buzzer indicates completion of treatment.
`The AAD systems use electronics and sensors within the
`device to constantly monitor and adapt to individual breathing
`patterns, and pulse aerosol during the first part of the inspira-
`tion. The AAD systems have been designed to analyse the
`breathing pattern of each individual patient. The timing of the
`pulse of aerosol to be delivered is determined by this analysis.
`The AAD systems analyse the pressure changes of the airflow
`of the first three breaths, to ascertain the correct starting point
`for aerosol delivery. The monitoring of the preceding three
`breaths continues throughout the treatment, and the AAD sys-
`tems continually adapt to the breathing patterns of the patient.
`
`2.1 The HaloLite® AAD system
`In 1997, HaloLite® (Figure 2) became the first AAD system to
`be made commercially available [6]. It was designed on active
`venturi jet nebuliser technology to aerosolise formulations typi-
`cally used for the treatment of asthma patients. The HaloLite
`AAD system consists of a handpiece, including a mouthpiece, a
`medication chamber and an electronic control unit. The com-
`pressor is operated from mains electricity. The HaloLite AAD
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`Denyer, Nikander & Smith
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`Figure 2. The HaloLite® AAD® system. Copyright of Profile
`Therapeutics, a Respironics company.
`AAD: Adaptive Aerosol Delivery.
`
`algorithm enables precise pulses of aerosol to be delivered into
`each inspiration by monitoring the flow characteristics of each
`breath in a breathing pattern. A flow sensor monitors the flow
`of the inhalation and exhalation through the mouthpiece. The
`signal is then transferred to the processor running the AAD
`software, via an analogue-to-digital converter, to enable analysis
`of the breathing pattern. Once the trend of the breathing pat-
`tern has been established in the first three breaths, the start of
`each subsequent breath can be identified rapidly and accurately.
`This allows aerosol to be pulsed into the very beginning of each
`inspiration, ensuring maximum opportunity for the aerosol
`bolus to penetrate deep into the lung. Aerosol pulse times have
`been set to 50% of inspiration time, based on the rolling aver-
`age of the last three inspirations. The amount of medication
`delivered during each pulse is calculated by the AAD software,
`and the total sum over the course of the treatment is deter-
`mined. The patients are given both audible and visual feedback
`to inform them of a successful treatment. Depending on the
`volume of drug in the vial used, a significant amount of drug
`will remain as residual, as HaloLite is preset to deliver only
`0.25 ml/preset dose.
`
`2.2 The HaloLite® Paediatric AAD system
`The HaloLite Paediatric AAD system is a version of HaloLite
`designed expressly for use by children aged 6 months to 5 years.
`This age group breathe with much lower tidal volumes than
`adolescents and adults, and therefore, the minimisation of the
`
`Figure 3. The Prodose™ AAD® system. Copyright of Profile
`Therapeutics, a Respironics company.
`AAD: Adaptive Aerosol Delivery.
`
`equipment deadspace is important. Deadspace becomes an issue
`when the tidal volume approaches the combined anatomical
`and equipment deadspace. With a low deadspace:breath ratio,
`aerosol will be inhaled into the deadspace, and then exhaled
`before it reaches the target deposition site. HaloLite Paediatric
`incorporates a number of features to address the deadspace
`issue, as well as utilising an inflatable cuff facemask to ensure
`adequate sealing of the nebuliser–patient interface. These fea-
`tures called for the introduction of inhalation and exhalation
`valves to the facemask connection to minimise equipment dead-
`space, and the incorporation of a deadspace correction within
`the AAD algorithm, to ensure an accurate calculation of the
`delivered dose. The device is not available at present.
`
`2.3 The Prodose™ AAD system
`The Prodose™ AAD System (Figure 3) is a second-generation
`AAD system, based on the HaloLite design. However, it offers
`significant improvements in convenience and flexibility over
`HaloLite. The Prodose AAD system consists of a compressor
`connected to a self-powered handpiece fitted with a liquid crys-
`tal display. Prodose uses improved versions of the AAD algo-
`rithms designed for HaloLite. The length of the aerosol pulse
`into the inspiration is entirely dependent on the breathing pat-
`tern of the patient, up to a limit of 8 s pulse time. Patients with
`tidal volumes < 1 l will continue to have aerosol pulsed into
`50% of their inspiration. A minority of patients with tidal vol-
`umes > 1 l [2] will reduce the treatment times as the aerosol is
`pulsed into a greater percentage of the inspiration. These
`improvements have been shown to lead to faster and more
`accurate dose delivery for Prodose compared with HaloLite [7].
`
`2.4 The AAD Disc™ technology
`The main difference between the HaloLite and the Prodose
`AAD systems is that instead of using a factory-programmed
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`Adaptive Aerosol Delivery (AAD®) technology
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`Figure 4. The I-neb AAD® system. Copyright of Profile
`Therapeutics, a Respironics company.
`AAD: Adaptive Aerosol Delivery.
`
`Figure 5. The Spacer AAD® system as a concept. Copyright of
`Profile Therapeutics, a Respironics company.
`AAD: Adaptive Aerosol Delivery.
`
`preset dose, Prodose utilises the AAD Disc™ (Profile Thera-
`peutics) to control drug delivery. The AAD Disc is a plastic
`disc containing a microchip and an antenna, which, when
`inserted into Prodose instructs the device about the dosage, the
`dosing frequency, and the number of doses which may be
`delivered, together with various control data, including drug
`lot number and expiry date. The AAD Disc is programmed to
`a specific drug formulation, and can be packaged with the
`drug as part of the pharmaceutical packaging process.
`The Prodose AAD system with the AAD Disc technology is
`presently approved in Europe for delivery of colistimethate
`sodium and iloprost.
`
`2.5 The I-neb AAD® system
`I-neb AAD system (Figure 4) is the third-generation AAD sys-
`tem, currently under joint development with Omron Health-
`care (Kyoto, Japan). I-neb will be a device combining a new,
`proprietary vibrating mesh technology, and the AAD system
`with the AAD Disc technology. The third-generation ‘intelli-
`gent’ I-neb AAD system will be a small (150 × 65 × 45 mm),
`lightweight (210 g), virtually silent and fast drug delivery
`device that is designed to significantly reduce the inconven-
`ience of conventional nebuliser/compressor therapy, while
`delivering a precise, reproducible dose. I-neb can deliver a pre-
`set volume in the range 0.25 – 1.4 ml depending on the size
`of the I-neb metering chamber, which has a residual volume
`of ∼ 0.1 ml. The vibrating mesh has a variable power range for
`the optimisation of the aerosol output. The previous genera-
`tions of the AAD systems have incorporated audible patient
`feedback at the end of a completed treatment. I-neb will
`include continuous feedback on the device functions through
`the liquid crystal display, along with tactile patient feedback at
`the end of a completed treatment. The I-neb AAD system will
`include the AAD algorithm used in the Prodose AAD system.
`New algorithms that will guide the patient to a slow and deep
`
`inspiration could also be included (target inhalation mode;
`see Section 6). The I-neb AAD system will be available in
`Europe from early 2005.
`
`2.6 The Spacer AAD® system
`The Spacer AAD system (Figure 5) is applicable to, for exam-
`ple, pressurised metered-dose inhalers with valved holding
`chambers (pMDI VHC). The incorrect use of a pMDI VHC
`can lead to a large variability in the delivered dose. Creaming
`and/or sedimentation of the drug within the pMDI, the sedi-
`mentation of drug within the VHC and the efficiency of the
`facemask seal will determine the delivered dose. The Spacer
`AAD system is based on an algorithm which takes into
`account the creaming and/or sedimentation within the pMDI
`and the sedimentation in the VHC. Patient feedback on
`delivered dose will guide the patient or parent in achieving a
`facemask seal against the face and to deliver the correct dose.
`The device is under development.
`
`3. In vitro results
`
`The in vitro performance of the AAD systems has been exten-
`sively investigated. As the AAD systems are breath-actuated, a
`breathing simulator (MiMiC Breathing Emulator, Profile
`Therapeutics) was developed for simulation of different
`human breathing patterns [2,8,9]. In the following section, the
`main results from some of the in vitro studies are reviewed.
`
`3.1 Impact of pulse time
`The early in vitro studies performed with the HaloLite AAD
`system showed a linear relationship between drug delivery and
`pulse times, in the range 0.1 – 1.0 s [6]. The linear relationship
`was important for accurate drug delivery of the preset dose.
`The particle size was also measured for pulse times in the range
`0.1 – 1.0 s. The results showed that ∼ 80% of the output was
`in particles < 5 µm in diameter, irrespective of pulse time [6].
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`1
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0
`
`Delivered dose (mg)
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Breathing pattern
`
`Figure 6. The mean delivered dose of salbutamol has been plotted against 46 simulated adolescent and adult breathing
`patterns, which were used for the test of the Prodose™ AAD system. The dashed lines represent ± 25% and the solid lines ± 35%
`of the nominal dose.
`AAD: Adaptive Aerosol Delivery.
`
`r2 = 0.9998
`
`100
`
`200
`
`600
`500
`400
`300
`Nominal disc volume (µl)
`
`700
`
`800
`
`800
`700
`600
`500
`400
`300
`200
`100
`0
`
`0
`
`Delivered volume (µl)
`
`Figure 7. The mean delivered volume of salbutamol has
`been plotted against the programmed (AAD Disc™) volume
`of salbutamol. The Prodose™ AAD® system was used in the
`study.
`AAD: Adaptive Aerosol Delivery.
`
`amount of drug was tested using five AAD Discs [11]. The five
`AAD Discs were programmed to deliver 35, 56, 250, 500 and
`625 µl volumes of salbutamol (2 mg/ml). In the test set-up,
`Prodose was connected to a breathing simulator, a AAD Disc
`was fitted to Prodose, and the device was activated. The mean
`delivered volumes of salbutamol were 37, 61, 263, 547 and
`686 µl, respectively. The highly linear results (r2 = 0.9998;
`Figure 7) showed that the AAD Disc can be programmed with
`
`3.2 Drug delivery
`The HaloLite AAD system targets aerosol delivery into the
`first 50% of a patient’s inhalation, and is designed to deliver a
`preset dose of 0.25 ml/actuation. In order to test the accuracy
`of the preset dose, 50 adult/adolescent/paediatric breathing
`patterns (tidal volume [VT] 0.1 – 1.24 l, peak inspiratory
`flow [PIF] 9 – 89 l/min, inspiration:expiration [I:E] ratio
`1:0.6 – 1:1.97) were selected to be used on the MiMiC
`Breathing Emulator [2,10]. The mean delivered dose was 97%
`(0.244 ml) of the preset dose with a coefficient of variation
`(CV) of 17%, and with 92% of doses within ± 25% of the
`nominal dose.
`The Prodose AAD system has been tested in a similar test
`set-up [7]. A total of 46 ‘real life’ adult/adolescent breathing
`patterns (VT 0.24 – 1.24 l, PIF 18 – 89 l/min, I:E ratio
`1:0.6 – 1:1.97) were selected. The mean amount of marker on
`the filters was equal to a liquid volume of 0.243 ml (s.d.
`± 0.026), with 98% of the doses delivered within 0.25 ml ±
`25% (Figure 6). The mean treatment time was 264 s. The
`results for Prodose are similar to those for HaloLite, but the
`mean treatment time was somewhat shorter (i.e., 264 versus
`293 s). Thus, Prodose delivers a preprogrammed dose consist-
`ently across a wide range of human breathing patterns in a
`shorter treatment time than HaloLite.
`
`3.3 Flexible dosing
`The AAD Disc is an important feature of the new Prodose
`AAD system. The accuracy of Prodose to deliver an accurate
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`Adaptive Aerosol Delivery (AAD®) technology
`
`different dosages of drug, which the Prodose AAD system can
`deliver accurately during inhalation.
`In conclusion, these in vitro studies have shown that the
`AAD systems can deliver a range of doses of drug reproducibly
`within different patient breathing patterns.
`
`4. Adaptive Aerosol Delivery systems in
`clinical studies
`
`Some of the AAD systems have been included in clinical stud-
`ies of lung deposition, adherence and compliance, and clinical
`efficacy and safety. In the following section, the main results
`from these studies will be reviewed.
`
`4.1 Lung deposition
`The HaloLite AAD system was used in a study designed to
`determine the delivered dose, lung deposition and exhaled dose
`of 99mTc–DTPA in 10 adult asthmatic patients and 9 adult
`healthy subjects [12]. HaloLite was filled with 2.5 ml of radiola-
`belled saline, and was preset to deliver 315 mg of aerosol. Lung
`deposition was measured using a gamma camera. The results
`showed a mean delivered dose of 315 mg (s.d. ± 50 mg, CV
`17%), a mean whole lung deposition of 60% of the preset
`dose, and a mean exhaled fraction of ∼ 3%. There was no sig-
`nificant difference in the drug distribution profile between the
`asthmatic patients and the healthy subjects.
`One Australian and three British research groups have com-
`pared the HaloLite AAD system with active venturi jet neb-
`ulisers in terms of lung deposition. Devadason et al. [13]
`determined the lung deposition of radiolabelled recombinant
`human DNase in 15 children with cystic fibrosis (CF) aged
`3 – 16 years, using, HaloLite and a conventional active ven-
`turi jet nebuliser (Pari LC Plus®, Pari Medical Ltd, UK). The
`fill volumes were 1.25 mg/1.25 ml with HaloLite, and
`2.5 mg/2.5 ml with Pari LC Plus. The results showed a signif-
`icantly higher peripheral lung deposition with HaloLite com-
`pared with the Pari LC Plus nebuliser (right lung p = 0.015,
`left lung p = 0.040). The mean lung deposition was 115.3 µg
`(s.d. ± 47.2) for each actuation with HaloLite and 230.2 µg
`(s.d. ± 103) with Pari LC Plus. The lung dose in 7 children
`after two actuations of HaloLite was 246.5 µg (s.d. ± 72.4).
`There was no drug lost to environment with HaloLite,
`whereas a mean of 600 µg was lost with Pari LC Plus.
`Byrne et al. [14] compared the HaloLite AAD system with
`the Pari LC Plus nebuliser in terms of lung deposition of col-
`istin in 15 CF patients > 6 years of age. A standard 1 mega
`unit of colistin in a 3 ml diluent – labelled with 99mTc-DTPA
`– was used to measure the lung deposition. The Pari LC Plus
`nebuliser was run to dryness and HaloLite was used with a
`single dose. The patients inhaled colistin twice-daily for
`7 days with both devices. As a smaller amount of colistin was
`delivered with HaloLite due to the single dose strategy, the
`total lung dose of radiolabelled colistin was significantly
`higher with Pari LC Plus (2.96 MBq versus 9.0 MBq;
`p < 0.0001). The lung dose was, however, significantly
`
`higher for HaloLite when calculated as a percentage of the
`amount of drug used (30.79 versus 19.75%; p < 0.04).
`Kastelik et al. [15] compared the HaloLite AAD system with
`the Pari LC Plus nebuliser in terms of lung deposition in a
`scintigraphy study in 10 healthy adult subjects and 6 adult CF
`patients. Lung deposition of the 99mTc–DTPA radiolabelled
`aerosol was measured using planar scintigraphy. HaloLite
`delivered, on average, 2.1 times (p = 0.003) as much aerosol to
`the lungs as Pari LC Plus. Aerosol deposition with HaloLite
`had higher central distribution than that obtained with Pari
`LC Plus. Two subjects had higher lung deposition from Pari
`LC Plus than from HaloLite. There was marked inter-individ-
`ual variation in the lung deposition pattern in the CF patients.
`The overall inter-subject variability of the delivered dose was
`56% with Pari LC Plus and 24% with HaloLite (p < 0.05).
`Coldham et al. [16] recently presented a lung deposition
`study comparing the Prodose AAD system with the Pari LC
`Plus nebuliser in 8 adult patients diagnosed with CF. The
`nebulisers were charged with 150 MBq of 99mTc–DTPA in
`3 ml of saline and the nebulisation time was 6 min. γ-Scintig-
`raphy was performed immediately after nebulisation. Anterior
`and posterior images of the lungs were taken simultaneously,
`after which images of the nebuliser chambers, mouthpieces
`and exhalation filters were taken. The mean total dose deliv-
`ered to the lungs was 3.31% with Pari LC Plus and 5.12%
`with Prodose. The mean amounts deposited in the mouth-
`pieces and exhalation filters were ∼ 38 and 4%, respectively.
`The mean residual volumes were 59.6 and 84.5% with Pari
`LC Plus and Prodose, respectively. The images showed a
`greater lung deposition for Prodose, but with a higher level of
`radiation in the stomach and central airways than with the
`Pari LC Plus (data on file).
`The results of these studies show consistently that the lung
`deposition achieved with the AAD systems tested was superior
`to that of conventional active venturi jet nebulisers. This
`means that when switching a patient from a conventional neb-
`uliser to an AAD system, the clinician should consider the
`dosage of the drug used. The results also highlighted how effi-
`ciently the pulsed aerosol delivery minimised the amount of
`drug released to the environment during nebulisation. This is,
`however, not the case with conventional nebulisers, which may
`expose those caring for the patient to the risk of inadvertent
`topical or inhaled drug exposure.
`
`4.2 Adherence and compliance
`Adherence to treatment and compliance with the nebuliser
`used are some of the keystones in successful domiciliary neb-
`uliser therapy. The HaloLite AAD system supplied with a
`patient logging system (see Section 6) was used in a 4-week,
`open-label, multi-centre study assessing adherence to treat-
`ment and compliance with HaloLite [17]. A total of
`121 patients with asthma, COPD and emphysema, who
`used HaloLite for the administration of salbutamol or terbu-
`taline and/or budesonide, completed the study. Of the
`patients, 38% also continued to take another nebulised
`
`170
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`medication using their standard conventional nebuliser. The
`adherence was 51% for patients using only HaloLite, and
`30% for patients using HaloLite and another nebuliser. A
`total of 4801 treatments were recorded with HaloLite, and
`in 96% of these the patients took their preset doses of drug.
`The co-efficient of correlation between the total number of
`treatments and the dose received over the study period was
`1.00 (p < 0.001) for HaloLite and 0.67 (p < 0.001) for the
`patients’ standard nebuliser.
`The HaloLite Paediatric AAD system has been compared
`with a pMDI and a valved holding chamber (pMDI VHC,
`Aerochamber, Trudell Medical, London, ON Canada) in
`terms of drug delivery, adherence to treatment, compliance
`with device, true adherence, and acceptability [18]. A total of
`14 children aged 11 – 36 months, diagnosed with asthma and
`on regular treatment with inhaled corticosteroids, were
`enrolled into an open-label, randomised, crossover study. They
`received budesonide for 2 weeks with each delivery system.
`The HaloLite Paediatric device was supplied with a patient
`logging system (see Section 5), whereas the pMDI VHC incor-
`porated a data-logger, which recorded information on how the
`device was used. HaloLite Paediatric was preset to deliver
`budesonide 25 µg to the patient. A single actuation of budeso-
`nide 200 µg was used with the pMDI VHC. The median
`delivered dose of budesonide was 36 µg (range: 31 – 45 µg;
`CV 15%) with HaloLite Paediatric and 53 µg (range: 17 – 85
`µg; CV 47%) with the pMDI VHC. The median adherence
`was 68% (range: 11 – 96%) with HaloLite Paediatric and 71%
`(range: 11 – 100%) with the pMDI VHC. The median device
`compliance was 30 and 51%, and the median true adherence
`was 23 and 36%, respectively. The size of the HaloLite Paedi-
`atric was generally less acceptable than the size of the pMDI
`VHC with a data-logger.
`The first long-term proof of concept study of the use of the
`AAD system in children was performed in 10 centres
`throughout Spain with a modified active venturi Ventstream
`jet nebuliser (Profile Therapeutics), which incorporated an
`AAD system [19]. The study was of a 24-week, double-blind,
`randomised, parallel-group design, with budesonide inhala-
`tion suspension delivered twice-daily by parents to 125 young
`children with mild-to-moderate asthma. Data on the parents’
`adherence to their child’s prescribed nebuliser treatment regi-
`men and compliance with the demands of the nebuliser, the
`face mask and the AAD system, was recorded through a pro-
`totype patient logging system [20]. A total of 35,481 treat-
`ments were recorded and analysed together with a study
`questionnaire regarding the parents’ and childrens’ acceptance
`of the AAD system. The adherence to the treatment regimen
`was 91.3% and the compliance with the AAD system was
`90.4%. True adherence, the product of adherence and com-
`pliance, was 82.5%. Approximately 90% of the parents found
`the face mask easy to seal and the equipment easy to use, and
`> 90% of the children accepted it within 1 week. These results
`show that the AAD system could be of real clinical advantage
`for delivery of reproducible doses of drug to young children.
`
`Denyer, Nikander & Smith
`
`The results of the studies indicate that the level of adherence
`to treatment and compliance with the AAD system was rela-
`tively high. The high level of true adherence indicates that when
`a patient had started the treatment, the procedure was followed
`until the feedback system indicated completed drug delivery.
`This positive effect of the AAD system on adherence/compli-
`ance over the conventional nebuliser is supported by the results
`of a study conducted in CF (see Section 4.4). It is, however, dif-
`ficult to put these results fully into context as there is little com-
`parable information published on conventional nebulisers as
`these lack the features required to collect the necessary data.
`
`4.3 Asthma
`In the above described paediatric 24-week double-blind, ran-
`domised, parallel-group
`study, budesonide
`inhalation
`suspension was delivered with the AAD system to 125 young
`children with mild-to-moderate asthma [19]. The initial deliv-
`ered dose was 100 µg b.i.d. and the maintenance delivered
`dose was 25 µg b.i.d. These doses were delivered in an ini-
`tial:maintenance ratio of 2:22, 6:18 or 12:12 weeks. There was
`a clear improvement in the overall health score as assessed by a
`visual analogue scale with all three treatment regimens and a
`marked reduction in daytime and night time asthma symptom
`scores (range: 0 – 3), but no statistically-significant differences
`between the treatment regimens (Figure 8). The incidence of
`oral candida was low throughout the study, indicating low
`drug deposition into the upper airways. Improvements in the
`mean daytime asthma score for the different treatment regi-
`mens averaged ∼ 1.0 (2:22), 0.8 (6:18) and 0.9 (12:12). It is
`difficult to evaluate the clinical impact of the changes in symp-
`tom scores as the ethics committees did not approve of the
`inclusion of a placebo group in the study. One can, however,
`compare the magnitude of change with those of a paediatric,
`12-week, double-blind, randomised, parallel-group study with
`budesonide inhalation suspension delivered with the Pari LC
`Plus nebuliser to 480 young children with moderate persistent
`asthma, performed in 38 centres throughout the US [21].
`Patients in this study were started on one of five treatment reg-
`imens receiving either placebo, or budesonide in nominal
`doses of 0.25 mg/q.d., 0.25 mg b.i.d., 0.5 mg b.i.d. or 1.0 mg
`q.d. Both day and night-time asthma symptom scores were
`recorded on a diary card (range: 0 – 3). The improvements in
`the mean daytime asthma symptom score for the different
`treatment regimens averaged 0.19 (placebo), 0.28 (0.25 mg
`q.d.), 0.4 (0.25 mg b.i.d.), 0.46 (0.5 mg b.i.d.) and 0.37
`(1.0 mg q.d.). The difference in improvement of the symp-
`toms scores in the two studies is remarkable. Assuming a lung
`deposition of 5 – 10% of the nominal doses in the study by
`Baker et al. [21], the relevant lung doses of budesonide should
`have been 12 – 25 µg (0.25 mg q.d.) to 50 - 100 µg (1.0 mg
`q.d.). Thus, the lung doses of budesonide should have been
`comparable to those of the Spanish study. The differences in
`improvement could only be related to the type of patients
`included, to the parents’ appreciation of the child’s asthma sta-
`tus, and to the drug delivery systems used. As the delivery sys-
`
`Expert Opin. Drug Deliv. (2004) 1(1)
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`Adaptive Aerosol Delivery (AAD®) technology