JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY
`Volume 23, Supplement 1, 2010
`ª Mary Ann Liebert, Inc.
`Pp. S1–S10
`DOI: 10.1089=jamp.2009.0791
`
`Review Articles
`
`The Adaptive Aerosol Delivery (AAD) Technology:
`Past, Present, and Future
`
`John Denyer, B.Sc. and Tony Dyche, B.Sc.
`
`Abstract
`
`Conventional aerosol delivery systems and the availability of new technologies have led to the development of
`‘‘intelligent’’ nebulizers such as the I-neb Adaptive Aerosol Delivery (AAD) System. Based on the AAD tech-
`nology, the I-neb AAD System has been designed to continuously adapt to changes in the patient’s breathing
`pattern, and to pulse aerosol only during the inspiratory part of the breathing cycle. This eliminates waste of
`aerosol during exhalation, and creates a foundation for precise aerosol (dose) delivery. To facilitate the delivery
`of precise metered doses of aerosol to the patient, a unique metering chamber design has been developed.
`Through the vibrating mesh technology, the metering chamber design, and the AAD Disc function, the aerosol
`output rate and metered (delivered) dose can be tailored to the demands of the specific drug to be delivered. In
`the I-neb AAD System, aerosol delivery is guided through two algorithms, one for the Tidal Breathing Mode
`(TBM), and one for slow and deep inhalations, the Target Inhalation Mode (TIM). The aim of TIM is to reduce
`the treatment time by increasing the total inhalation time per minute, and to increase lung deposition by
`reducing impaction in the upper airways through slow and deep inhalations. A key feature of the AAD tech-
`nology is the patient feedback mechanisms that are provided to guide the patient on delivery performance.
`These feedback signals, which include visual, audible, and tactile forms, are configured in a feedback cascade
`that leads to a high level of compliance with the use of the I-neb AAD System. The I-neb Insight and the Patient
`Logging System facilitate a further degree of sophistication to the feedback mechanisms, by providing infor-
`mation on long term adherence and compliance data. These can be assessed by patients and clinicians via a Web-
`based delivery of information in the form of customized graphical analyses.
`
`Key words: Adaptive Aerosol Delivery technology, Adaptive Aerosol Delivery System, AAD, I-neb AAD System,
`I-neb Insight, patient logging system
`
`Introduction
`
`The conventional jet nebulizer powered by a com-
`
`pressor has been used for almost a century for delivery of
`inhaled drugs for the treatment of various respiratory disor-
`ders.(1) The nebulizer has become a well-established alterna-
`tive to pressurized metered dose inhalers (pMDIs) and dry
`powder inhalers (DPIs), as it is ideal for delivery of high doses
`of drug, of drug mixtures, and of new drugs not formulated
`for pMDIs or DPIs.(2) The drawback with conventional jet
`nebulizers has been the waste of drug mainly during exha-
`lation, the large variability in the delivered dose depending on
`the patient’s breathing patterns, and the large residual with
`only 10 to 20% of the nebulizer fill volume delivered as aerosol
`to the patient. Recognition of the possibilities to improve
`
`nebulized drug delivery by addressing some of these short-
`comings led to the development of ‘‘intelligent’’ jet nebulizers
`based on Adaptive Aerosol Delivery (AAD) technology.(3)
`The introduction of nebulizers based on the Vibrating Mesh
`Technology (VMT) has improved the efficiency of the aerosol
`delivery due to a smaller residual. These nebulizers do,
`however, still waste drug during exhalation due to continu-
`ous drug delivery without any adaptation to the patient’s
`breathing patterns.(4) The latest iteration of the AAD tech-
`nology, the I-neb AAD System, combines the mesh technol-
`ogy with the AAD technology.(5)
`The AAD technology was first embodied in the HaloLite
`AAD System, which was codeveloped with Astra, Lund,
`Sweden, and made commercially available in 1997.(3) The
`basic nebulizer technology in the HaloLite AAD System was
`
`Philips Respironics, Respiratory Drug Delivery (UK) Ltd, Chichester, United Kingdom.
`
`S-1
`
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`Page 1
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`

`

`S-2
`
`DENYER AND DYCHE
`
`based on the Ventstream active venturi jet nebulizer technol-
`ogy. The AAD algorithm predicted the length of the patient’s
`next inhalation based on the duration of the three previous
`inhalations, and delivered a pulse of aerosol into the first
`50% of that inhalation. The HaloLite AAD System consisted
`of a battery-powered handpiece, including a mouthpiece, a
`medication chamber, an electronic control unit, and a com-
`pressor operated from mains electricity. The HaloLite AAD
`System was preset to deliver only 0.25 mL per preset dosage,
`and therefore, depending on the volume of drug in the vial
`used, a significant amount of drug remained as residual.
`The Prodose AAD System was the second-generation
`AAD System, and was developed in conjunction with
`Schering AG (Bayer Schering Pharma AG, Berlin, Germany)
`for delivery of iloprost for treatment of pulmonary arterial
`hypertension, and launched in 2002.(3) Although based on the
`same aerosol generation technology, it offered significant im-
`provements in convenience and flexibility over the HaloLite
`AAD System. The Prodose AAD System consisted of a
`compressor connected to a self-powered handpiece fitted
`with a liquid crystal display. Improved versions of the AAD
`algorithms designed for the HaloLite AAD System were
`used, which allowed the pulse of aerosol to be extended
`beyond 50% in cases when the patient’s inhalation exceeded
`2 sec. The main difference between the HaloLite and the
`Prodose AAD Systems was that instead of using a factory-
`programmed preset dose handset, the Prodose AAD System
`was designed with the AAD Disc to control drug delivery
`and the AAD Disc could be supplied with the drug.
`The I-neb AAD System is the third-generation AAD Sys-
`tem, and is substantially smaller and lighter than the previous
`AAD System nebulizers (Table 1).(5) The main parts of the
`I-neb AAD System (Fig. 1) are the body, the medication
`chamber assembly including the metering chamber, the mesh,
`and the mouthpiece. Due to the mesh design the I-neb AAD
`System is virtually silent.(5) Built into the body are the mi-
`croprocessor that runs the AAD algorithm, the electronic
`aerosol generation circuit, the piezo element connected to the
`horn, the pressure sensor, the LCD screen, the radio frequency
`antenna for the AAD Disc, the patient logging system (PLS),
`the infrared transmitter=receiver for I-neb Insight, the battery,
`buzzer, and the vibration device for the tactile feedback. The
`I-neb AAD System is approved as a general purpose nebu-
`lizer in the European Union, and for the delivery of drugs
`that are approved for use with the I-neb AAD System in the
`United States.(5) For the purpose of this review of the AAD
`technology, the focus will be on the I-neb AAD System.
`
`The AAD Algorithms
`
`The I-neb AAD System can be operated in two breathing
`modes, the Tidal Breathing Mode (TBM; Fig. 2) and the
`
`Target Inhalation Mode (TIM; Fig. 2).(5) The breathing mode
`is selected by using a specific mouthpiece, which can be
`detected by the electronics in the I-neb AAD System (Fig. 1).
`In TBM, the patient breathes tidally though the mouthpiece,
`and this mode of inhalation is suitable for all patients who
`can use a mouthpiece. The results of a clinical study in which
`52 patients with CF (age range 2–17 years) were transferred
`from jet nebulizers to the I-neb AAD System, indicate that
`patients as young as 2 years of age can use the mouthpiece.(6)
`In TIM, the patient is guided through feedback to make a
`slow and deep inhalation, which is suitable for patients who
`can use a mouthpiece and comply with the demands of that
`breathing maneuver.
`
`TBM
`
`The aim of the AAD algorithm in TBM is to continuously
`predict the length of the patient’s next inhalation. Based on
`this information a pulse of aerosol can be delivered at the
`beginning of the next inhalation and end after 50% of the
`predicted inhalation time has expired. The average length of
`the past three inhalations is used by the AAD algorithm for
`the prediction of the length of the next inhalation. This
`means that the I-neb AAD System will only deliver aerosol
`starting on the fourth breath of each new treatment. There-
`after, the average inhalation time is updated after each
`subsequent inhalation. The pulse time is continuously mon-
`itored and adjusted by the algorithm depending on varia-
`tions in the patient’s breathing pattern. In cases when the
`patient’s inhalation exceeds 2 sec, the pulse time is extended
`beyond 50% of the predicted inhalation time and up to
`*1 sec before the start of the predicted exhalation.
`A combination of a pressure sensor and a flexible valve in
`the I-neb AAD System is used to monitor the patient’s in-
`spiratory flow pattern (Fig. 1). The valve has a known
`pressure to flow characteristic, which allows the pressure
`measurement to be transferred, via an analogue-to-digital
`converter, to the processor running the AAD software and
`interpreted as a flow measurement. A waveform analysis
`program is used to ensure that the I-neb AAD System can
`operate effectively with breathing patterns typical for chil-
`dren from *2 years of age to adults.(7) This ensures that the
`AAD algorithm remains sensitive for children without gen-
`erating false triggers in adults. The waveform is monitored
`every 30 msec through the AAD software, which determines
`the slope of the curve over three consecutive 30 msec mea-
`surements (Fig. 2). A ‘‘positive’’ flow curve—two consecutive
`increases of at least 0.65 L=min—indicates that an inhalation
`is about to start. When the inspiratory flow rate is greater
`than 1.5 L=min the pulse of aerosol is triggered. Once an
`inhalation has started, the waveform is continuously moni-
`tored by the AAD software, to detect a ‘‘negative’’ slope—
`
`Table 1. A Table Comparing the Different Features of the HaloLite, Prodose, and I-neb AAD Systems
`
`Year of
`launch
`
`1997
`2002
`2004
`
`Size (cm;
`hwd)
`142918
`181429
`156.54.5
`
`Weight
`(g)
`
`Power
`(W)
`
`2700
`3190
`210
`
`200
`200
`6
`
`Voltage
`(V)
`
`240 AC
`240 AC
`3.8 DC
`
`AAD
`TBM
`
`ü
`ü
`ü
`
`PLS
`
`ü
`ü
`ü
`
`AAD
`Disc
`
`AAD
`TIM
`
`ü
`ü
`
`ü
`
`HaloLite
`Prodose
`I-neb
`
`AAD, Adaptive Aerosol Delivery; PLS, patient logging system; TBM, Tidal Breathing Mode; TIM, Target Inhalation Mode.
`
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`Page 2
`
`

`

`AAD TECHNOLOGY
`
`S-3
`
`FIG. 1. The I-neb Adaptive Aerosol Delivery (AAD) System. The main components of the device are the mouthpiece, the
`medication chamber assembly, and the body. The I-neb AAD System has been designed to deliver aerosol with two different
`breathing pattern algorithms, the Tidal Breathing Mode (TBM) and the Target Inhalation Mode (TIM). In TIM the inspiratory
`flow through the valve in the mouthpiece is limited to *20 L=min.
`
`two consecutive decreases of at least 0.65 L=min—which
`would indicate the start of an exhalation. Once the flow
`reaches zero, the AAD software identifies this point as the
`end of inhalation. The analysis performed by the AAD
`software facilitates both an accurate triggering of the aerosol
`pulse, and the measurement of the inhalation time, which is
`
`Table 2. A Summary Table of the Level of Compliance
`with the Correct Use of AAD System Nebulizers
`Documented in Clinical Studies
`
`AAD System
`
`AAD System
`prototype
`HaloLite
`AAD System
`HaloLite ped
`AAD System
`HaloLite
`AAD System
`Prodose
`AAD System
`I-neb AAD System
`I-neb AAD System
`I-neb AAD System
`
`Number
`of patients
`
`Age range
`(years)
`
`Compliance
`level (%) Reference
`
`125
`
`121
`
`47
`
`50
`
`19
`
`96
`70
`42
`
`<1–6
`
`<1–65
`
`<1–3
`
`7–53
`
`11–45
`
`a
`
`53–80
`12–57
`
`90%
`
`98%
`
`81%
`
`84%
`
`90%
`
`96%
`95%
`97%
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`12
`11
`
`aInformation not available.
`
`used in a calculation of the moving average over three
`breaths to predict the next aerosol pulse time.
`
`TIM
`
`The main aim of the long and slow inhalation is to reduce
`nebulization time in comparison with the TBM breathing
`pattern as a result of the increase in the total inhalation time
`per minute of treatment.(5) An improvement in lung depo-
`sition by reducing impaction in the upper airways is also
`achieved.(8) The aim of the AAD algorithm in TIM is to
`provide the patient with an optimal target time for each slow
`and deep inhalation. The AAD algorithm is used in con-
`junction with a mouthpiece designed with a special inhala-
`tion valve to restrict the inspiratory flow to *20 L=min (Fig.
`1). The initial target inhalation time for the slow and deep
`inhalation is set at 3 sec, which is equivalent to an inhaled
`volume of *0.75 L. When the target
`inhalation time is
`reached, a vibrator informs the patient to end the inhalation.
`For the duration of the initial 3 sec of inhalation, aerosol is
`delivered during the first 2 sec followed by inhalation of
`room air without aerosol during the remaining 1 sec. This is
`to ensure that the aerosol is inhaled deep into the lung and
`remains there long enough to be deposited and not ex-
`haled.(8) The AAD algorithm monitors the time ‘‘DT’’ be-
`tween the vibrator signal and the moment when the patient
`stops inhaling (Fig. 2). During breathing, the inspiratory and
`
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`DENYER AND DYCHE
`
`∆T (white area)
`
`Inhalation
`target time
`
`Pulse time
`
`Time
`
`S-4
`
`1.5 L/min
`
`30 ms flow
`measurements
`
`1 s
`
`Pulse time
`
`Slope calculated
`
`Not to
`scale
`
`Mode and stage of use
`
`TBM
`
`Early stage of
`TIM use
`
`Ongoing TIM use
`
`TIM duration at patient
`maximum
`
`60
`
`40
`
`20
`
`0
`
`-20
`
`-40
`
`-60
`
`Inhalation
`
`)nim/L( etar-wolF
`
`Exhalation
`
`∆T
`
`Large ∆T
`
`Decreasing ∆T
`
`Small ∆T
`
`FIG. 2. Graphical presentation of the two breathing patterns used with the I-neb Adaptive Aerosol Delivery (AAD) System.
`The first part of the graph shows the patient’s tidal breathing when using the I-neb AAD System in Tidal Breathing Mode
`(TBM). The second, third, and last parts of the graph show the process to extend the patient’s slow and deep inhalations from
`a 3-sec inhalation (1-sec aerosol pulse) to an 8-sec inhalation (7-sec aerosol pulse) when using the I-neb AAD System in Target
`Inhalation Mode (TIM). The magnified area above to the left shows how the waveform is monitored every 30 msec through
`the AAD software, which determines the slope of the curve over three consecutive 30-msec measurements. Two consecutive
`increases of at least 0.65 L=min indicate that an inhalation is about to start, and when the inspiratory flow rate >1.5 L=min the
`pulse of aerosol is triggered. The magnified area above to the right shows the end of the inhalation during TIM. The DT time
`provides a measurement of when the patient has reached his or her instantaneous residual lung capacity, and allows the
`AAD algorithm to increase or decrease the length of the target inhalation time.
`
`expiratory maneuvers are driven by different muscle groups.
`The inspiratory muscles are working against the flow re-
`striction of the mouthpiece and if the lung is only partially
`inflated, it takes longer for the muscles to relax so that ex-
`halation can start than it would if the lung was initially fully
`inflated.(9) Thus, the change from inhalation to exhalation is
`slower for a partially inflated lung than for a fully inflated
`lung. The DT time provides a measurement of when the
`
`patient has reached the instantaneous residual lung capacity,
`and allows the AAD algorithm to increase or decrease the
`length of the target inhalation time. The aim is to optimize
`the length of the target inhalation time to approximately 80%
`of the patient’s forced vital capacity (FVC). Once the optimal
`target inhalation time has been set, the algorithm will adjust
`it to meet the patient’s effort on each inhalation. At the end of
`the treatment, the achieved length of the target inhalation
`
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`AAD TECHNOLOGY
`
`S-5
`
`time is filed in the memory for subsequent treatments.
`However, as the initial target inhalation time of 3 sec requires
`an inhaled volume of *0.75 L, the patient should have
`an FVC1.75 L to manage the slow and deep inhalation
`maneuver.(10) These requirements might make the use of the
`I-neb AAD System in TIM challenging for children, and for
`patients with poor lung capacity as these will not generate a
`significant DT.
`
`Clinical experience with TBM and TIM
`
`The I-neb AAD System is presently used in the treatment
`of patients with cystic fibrosis (CF), and pulmonary arterial
`hypertension.(5) A number of clinical studies have been
`performed to evaluate the I-neb AAD System in terms of
`patient acceptability and lung deposition.
`The acceptability of the TIM breathing maneuver has been
`evaluated in 20 patients with CF during up to eight simu-
`lated nebulizer treatments with 10 min pauses between the
`treatments.(10) The study design involved lengthening of the
`patient’s inhalation time over successive breaths with guid-
`ance from auditory and tactile (vibratory) feedback from the
`prototype I-neb AAD System. At the end of the first treat-
`ment, most patients felt that the instructions were easy to
`understand (90%) and that
`the vibratory feedback was
`pleasant (65%). Half of the patients found the procedure to
`be comfortable. At the end of the final treatment, most pa-
`tients felt that the breathing maneuver was easy to under-
`stand (90%) and use (80%), but that the duration of the
`breath was too long (100%). Logged data revealed that 90%
`of patients were able to comply with the breathing maneu-
`ver. The two patients unable to comply had a forced vital
`capacity of <1.75 L. The average treatment time decreased
`from 288.4 to 141.6 sec during the first and final treatments,
`respectively. This study provided preliminary evidence of
`the acceptability of the TIM breathing maneuver in patients
`with CF and their ability to perform repeated TIM maneu-
`vers during simulated nebulizer therapy with the I-neb AAD
`System.
`A 3-month patient handling study of the I-neb AAD
`System in 42 patients with CF aged 12–57 years has been
`performed with the aim to evaluate compliance with the
`correct use of the I-neb AAD System, and treatment times.(11)
`The secondary variables included ease of use with the I-neb
`AAD System based on a questionnaire at the end of the
`study. The I-neb AAD System was supplied in both TBM
`and in TIM, and the patients were trained to use the TIM
`maneuver for the delivery of all their inhaled medications. If
`they were not comfortable with the TIM maneuver they
`could change to the TBM maneuver. There were a total of
`10,240 complete treatments and of these 88% were in TIM.
`Compliance with the correct use of the I-neb AAD System
`was 97.6%. The mean treatment time for complete treatments
`in TIM was 4.20 min, compared with 6.83 min when using
`the I-neb AAD System in TBM. The responses to the ques-
`tionnaires indicated that over 77% of the patients found the
`I-neb AAD System in TIM to be either: very easy, easy, or
`acceptable to use.
`The I-neb AAD System in TBM has been compared with
`the patients’ previous nebulizers in a multicenter study with
`98 patients with chronic obstructive pulmonary disease aged
`53 to 80 years.(12) The primary variables were ease of use and
`
`satisfaction assessed after 3 months of use of the I-neb AAD
`System (assessed at visit 2) and after 3 months of use of the
`patient’s previous nebulizer system (assessed at visit 1) using
`matched questions from pre- and poststudy questionnaires.
`Quality of life was also assessed at visits 1 and 2 using a
`validated Chronic Respiratory Questionnaire (CRQ), which
`consists of dyspnea, emotional function, fatigue, and mastery
`domains. Patient responses on the ease of use and satisfac-
`tion questions significantly ( p 0.001) favored the I-neb
`AAD System compared with the patient’s previous nebulizer
`system. In addition, significant ( p 0.015) improvements in
`the CRQ dimensions of dyspnea and fatigue were reported
`with the I-neb AAD System compared with the patients’
`previous nebulizer systems.
`The lung deposition of a radiolabeled aerosol from the
`I-neb AAD System with TBM and TIM breathing patterns
`was evaluated in a randomized, open-label, crossover study
`of 12 healthy subjects.(8) The results showed that the mean
`lung deposition was significantly higher when using the
`I-neb AAD System in TIM (73.3%) than in TBM (62.8%). The
`mean exhaled fractions were low (<1%) for both breathing
`patterns. The nebulization time was significantly shorter in
`TIM (3.0 min) than in TBM (4.7 min). With the combination
`of a high lung deposition, almost no loss of aerosol during
`exhalation, and a short nebulization time the I-neb AAD
`System with the TIM breathing pattern should be of special
`value to patients who require multiple daily dosing of aero-
`solized medication, are using drugs that should not be
`wasted into the room air, or would benefit from a more
`efficient delivery system.
`
`Aerosol Generation and the VMT
`
`The I-neb AAD System has been designed with a specific
`VMT to generate an aerosol. The VMT consists of an ultra-
`sonic horn driven by a piezo element and a platinum mesh
`with *7000 holes with an average diameter of 2 mm (Fig. 3).
`The liquid (solution or suspension) fills the gap between the
`horn and the mesh by gravity, and is pumped through the
`mesh by the vibrations of the horn (178 kHz; Fig. 1). When
`the liquid in the medication chamber has been delivered, an
`electronic control circuit detects the change in power re-
`quired by the horn, signaling the end of nebulization. The
`piezo element connected to the horn has a variable power
`range for the optimization of the aerosol output rate, which
`allows the performance of the aerosol generator to be tai-
`lored to the specific drug formulation.
`The mass median aerodynamic diameter (MMAD) of the
`aerosol pumped through the mesh has been determined
`using an albuterol solution and the Next Generation Im-
`pactor (NGI; MSP Corporation, St. Paul, MN, USA). The
`I-neb AAD System was configured with a 0.25 mL metering
`chamber and programmed to operate in a continuous mode
`to facilitate continuous aerosol production at power level 10.
`The MMAD of the albuterol solution was 3.9 mm, the geo-
`metric standard deviation 1.7, and the fine particle fraction
`67%.(13)
`The piezo element used in conventional ultrasonic nebu-
`lizers has made these nebulizers less suitable for use with
`drug suspensions and drugs that are heat sensitive. The
`piezo element driving the ultrasonic horn in the I-neb AAD
`System operates at *10% of the power of the piezo element
`
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`S-6
`
`DENYER AND DYCHE
`
`FIG. 3. The vibrating mesh of the I-neb Adaptive Aerosol Delivery (AAD) System in two different magnifications.
`
`in the conventional ultrasonic nebulizers. Despite the lower
`power consumption, drug suspensions can be delivered with
`the I-neb AAD System.(13)
`
`Medication Chambers
`
`In the I-neb AAD System the aerosol is only generated in
`pulses during inhalation minimizing any losses. As a result
`of these design features a much smaller volume of drug is
`required to deliver the same volume to the lung compared
`with a pneumatic nebulizer.(13)
`
`Metering and nonmetering chambers
`
`To deliver precise, metered doses of aerosol to the patient
`with the I-neb AAD System, a metering chamber design has
`been developed (Fig. 4). As drug vials with volumes ranging
`from 2 to 5 mL designed for pneumatic nebulizers may be
`used with the I-neb AAD System, a range of metering
`chambers are available for metering of the correct volume.
`The metering chamber has a central section around the horn,
`
`and it is the volume of this section which determines the
`dose (Fig. 4). The patient pours the medication into the
`central section and when full, any additional solution over-
`flows into an outer chamber. When the lid is closed, the
`solution in the central section is sealed from the overflow and
`only that volume of drug in the central section is delivered as
`aerosol to the patient.
`The I-neb AAD System can also be supplied with a non-
`metering chamber that has been designed for use with vol-
`umes from 0.25 to 1.7 mL. These are filled by using a pipette
`for the correct dosage.
`The I-neb AAD System can be supplied with a range of
`different metering chambers, from 0.25 to 0.75 mL for dif-
`ferent drug applications, which are color coded for ease of
`identification by the patient. Due to the flexibility of the
`metering chamber design, different doses can be delivered
`while using a single vial of drug. An example is inhaled
`iloprost (Ventavis; Actelion Pharmaceuticals US, Inc., South
`San Francisco, CA, USA) for treatment of pulmonary arterial
`hypertension. Iloprost is available in a 1 mL vial, whereas
`
`Additional liquid
`overflows from
`metering to outer
`chamber
`
`Dosing segment
`
`Nonmetering chamber
`central section
`
`Horn
`
`Part of I-neb
`AAD System
`body
`
`Metering chamber
`central section
`
`Outer chamber
`
`Metering chamber
`
`Nonmetering chamber
`
`FIG. 4. The medication chambers designed for the I-neb Adaptive Aerosol Delivery (AAD) System are shown, including the
`metering chamber (left) and the nonmetering chamber (right).
`
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`

`AAD TECHNOLOGY
`
`S-7
`
`the I-neb AAD System for delivery of iloprost is supplied
`with two metering chambers, one for delivery of a 2.5 mg
`dose (0.25 mL metering chamber), and the other for delivery
`of a 5 mg dose (0.5 mL metering chamber).(12) This gives the
`clinician the flexibility to titrate the dose of iloprost to the
`patient, while the drug supplier manufactures and distrib-
`utes one vial size.
`
`Residual and reproducibility
`
`The gravimetric residual mass of liquid drug formulation
`remaining in the I-neb AAD System postnebulization has
`been evaluated during a standard (breathing simulation)
`output to filter analysis. Twenty-five nonmetering chambers
`were tested in triplicate using a single I-neb AAD System
`body. The I-neb AAD System including the mouthpiece was
`weighed,
`then filled with 0.4 mL of albuterol solution,
`weighed again, and weighed again postnebulization. The
`gravimetric residual mass remaining in the I-neb AAD Sys-
`tem was determined as the weight postnebulization minus
`the filled nebulizer weight. The mean residual amount of
`albuterol was 84 mg (range 57–142 mg) corresponding to a
`mean volume of 84 mL.(13)
`The reproducibility of the delivered dose of albuterol so-
`lution has been assessed in vitro through a breathing simu-
`lation test using fifty 0.3 mL metering chambers with a single
`I-neb AAD System in TBM, a power level 10 AAD Disc, and
`filters. The 0.3 mL metering chamber was designed to deliver
`300 mL of albuterol (600 mg albuterol) ex-mouthpiece, that is,
`the fill volume has been designed to compensate for any
`residual in the metering chamber and mouthpiece to deliver
`the required metered dose. The mean metered dose of
`albuterol was 575.4 mg [95% confidence interval (CI) 563.3–
`587.5 mL], which equated to 288 mL albuterol solution (95% CI
`282–294 mL) in metered volume.(13)
`
`The Design of the Mouthpiece
`
`In the I-neb AAD System, the aerosol is released through
`the VMT at a low velocity, and the patient’s inspiratory flow
`is required to carry the aerosol through the mouthpiece. This
`ensures that there is minimal loss of aerosol in the patient’s
`
`upper airways due to impaction. It is important, however, to
`rapidly mix the dense aerosol plume generated at the surface
`of the mesh with the patient’s airflow to prevent the aerosol
`droplets from coalescing. The mixing must be effective, but
`simultaneously avoid excessive turbulence, which would
`increase deposition on the internal surfaces of the mouth-
`piece and reduce the efficiency of the system. The design of
`the mouthpiece was optimized with the aid of computational
`fluid dynamics. The original design had the base of the
`mouthpiece parallel to the mesh, this caused uneven airflow
`from the single inhalation valve and this resulted in addi-
`tional aerosol disposition on the mouthpiece wall. The re-
`sulting design used an 8 degrees slant to the base of the
`mouthpiece to ensure that the air flow from the inhalation
`valve is fed in evenly around the edge of the mesh, and
`mixes rapidly with the aerosol plume, which is retained in
`the center of the air flow to minimize losses on the internal
`surfaces of the mouthpiece (Fig. 5). In the study of lung de-
`position in healthy subjects following use of the I-neb AAD
`System in TBM versus TIM, the mean deposition of 99mTc-
`DTPA in the mouthpieces in percentage of the loaded doses
`was 5.1% for the TBM breathing pattern, and 5.0% for the
`TIM breathing pattern.(8)
`Generation of excessive saliva during nebulization can
`be a problem for some patients. The mouthpiece has there-
`fore been designed to ensure that saliva cannot run through
`the mouthpiece onto the mesh by channeling saliva into the
`outer mouthpiece chamber.
`
`Patient Feedback and Compliance
`
`The role of feedback signals to the patient during nebuli-
`zation with the I-neb AAD System is fundamental to a suc-
`cessful drug delivery. Feedback mechanisms—both negative
`and positive—regulate a large number of human physio-
`logical processes. The human body is therefore naturally
`programmed to look for and understand feedback. This
`makes feedback signals a very powerful tool when designing
`the interfaces between the device and the patient. As the
`feedback function is important, the selection of the feedback
`signals must be made carefully and inadvertent feedback
`signals must be avoided for the desired result to be achieved.
`
`Mesh
`
`Horn
`
`Medication chamber
`central section
`
`Mouthpiece base
`angle 8°
`
`Inhalation / exhalation valve
`
`Aerosol to the patient
`
`FIG. 5. The mouthpiece of the I-neb Adaptive Aerosol Delivery (AAD) System. The design with an 8 degrees slant to the
`base of the mouthpiece has been made to ensure that the air flow from the inhalation valve is fed in evenly around the edge of
`the mesh, and mixes rapidly with the aerosol plume, which is retained in the center of the air flow to minimize losses on the
`internal surfaces of the mouthpiece.
`
`Liquidia's Exhibit 1026
`Page 7
`
`

`

`S-8
`
`DENYER AND DYCHE
`
`For example, when using a pMDI, there is no feedback
`mechanism to inform the patient that they have inhaled the
`aerosol. The package insert will inform the patients that
`provided the pMDI was used correctly, they will receive the
`drug. The patient will most probably be looking for feedback
`signals indicating drug release such as the sound of the firing
`of the dose, or the taste of the drug on their tongue. Neither
`of these will indicate that they have inhaled the drug, only
`that they have fired the dose, which, for example, may not
`have been synchronized with inspiration, or which may have
`deposited on the tongue.
`In the I-neb AAD System the aim has been to give the
`patient very clear positive feedback signals at the completion
`of the aerosol delivery. The primary feedback signal is given
`at the end of nebulization, when no liquid remains in the
`metering chamber. The patient is then provided with a
`feedback cascade consisting of a signal with a smiling face on
`the LCD screen, an audio signal (buzzer), and a tactile vi-
`brator signal. Feedback on the compliance with the correct
`use of the AAD System nebulizers have been recorded in
`several clinical studies (Table 2).(11,12,14–19) In these studies,
`over 80% of the patients have completed each nebulization
`started, or in other words used the AAD System until the
`feedback cascade informed them that they had reached the
`end of nebulization.
`In the I-neb AAD System a secondary positive feedback
`signal is provided on each inhalation. In TBM, the vibrator
`operates at the start of each breath to confirm that aerosol
`delivery has started as the VMT aerosol generation process is
`silent. In TIM, the vibrator operates at the end of each inha-
`lation when the patient has reached the inhalation target time.
`
`Customized Drug Delivery through the AAD Disc
`
`Following activation, data programmed onto the AAD
`Disc is accessed by the I-neb AAD System. The AAD Disc,
`which is inserted into a slot on the front panel (Fig. 1), con-
`tains a microchip and an antenna, which communicates
`with the I-neb AAD System using a radio frequency protocol.
`The microchip in the AAD Disc is programmed with oper-
`ational parameters such as power level, drug lot number,
`drug code, number of doses to be delivered, and expiration
`date. One of the key parameters that can be set is the power
`level of the drive circuit for the ultrasonic horn, and changes
`in the power level will adjust the rate of drug delivery.
`Changes in power level may be required for optimization of
`the duration of nebulization required for a specific drug, or
`for adjustment to the physicochemical characteristics of a
`drug such as viscosity and surface tension. The AAD Disc is
`programmed for each drug formulation, and can be pack-
`aged with the drug as part of the pharmaceutical packaging
`process. For example, if t