laboratory and animal investigations
`
`Comparison of Breath-Enhanced to
`Breath-Actuated Nebulizers for Rate,
`Consistency, and Efficiency*
`
`Kitty Lcung, BSc; Emily Loner: 830 RBI; and
`Alton L. Carries, B Eng(Etcd), MDCM
`
`
`
`Objectives: To evaluate differences between three new-generation nebulizers—«Pari LC Star
`(Pari Respiratory Equipment; Mississauga, ON, Canada), AeroEclipse (Trudcll Medical Interna-
`tional, London, ON, Canada), and Halolite (Medic-Aid Limited, West Sussex, UK)—irl terms of
`rate and amount of expected deposition as well as the consistency of the doses delivered.
`Methods: The in vitro performance characteristics were determined and then coupled to the
`respiratory pattern of seven patients with cystic fibrosis (age range, 4 to 18 years) in order to
`calculate expected deposition. The Pari LC Star and AeroEclipse were characterized while being
`driven by the Pari ProNcb Ultra compressor (Pari Respiratory Equipment) for home use, and by
`a 50-psi medical air hospital source. The Halolite has its own self-contained compressor.
`Algorithms for the rate of output for the inspiratory flow were developed for each device. Patient
`flow patterns were divided into 5-ms epochs, and the expected deposition for each epoch was
`calculated from the algorithms. Summed over a breath, this allowed the calculation of the
`estimated deposition for each patient’s particular pattern of breathing.
`Results.- The rate of deposition was highest for the Par'i LC Star and lowest for the Halolite. Rate
`of deposition was independent of respiratory pattern for the Pari LC Star and AeroEclipse, hut
`proportional to respiratory rate for the Halolite. The differences between the Pari LC Star and
`AeroEclipse were less when driven by the 50-psi source. The AeroEclipse had the least amount
`of drug wastage. As designed, the Ilalolite delivered a predetermined amount of drug very
`accurately, whereas expected deposition when run to dryness of the other two devices had
`significant variations.
`Conclusions: To minimize treatment time, the Pari LC Star would be best. To minimize drug
`wastage, the AeroEclipse would be best. To accurately deliver a specific drug dose, the Halolite
`would be best.
`(CHEST 2004,- 126:1619—1627)
`
`Key words: aerosols; asthma: hreath—aetuated IIehuliyi-I's: l1I"nth—enhaneml nehulimrs; e}stie lihrosis: pediatrics
`
`liF—— respirahle IraL-tion;
`()”—l— total drug output;
`(I F—— exstic |il11r1sis;(II= confidence i11de\:
`Abbreviations:
`U\—— ultraaiolet \H—— residual \olIIIm
`
`
`
`
`
`
`colytics}3 and is also con‘nnonly used to deliver
`et nehulization is one of the mainstays of treat—
`hronclIodilators
`for
`the emergency department
`ment for cystic fibrosis (CF), where it is used to
`deliver medications ranging from antihiotics' to mu—
`treatment of asthma.4 From previous studies,‘"—T
`
`
`From the l)“hull] of lie511inltor1 Vie'ditim and I ung Biolom
`liesezlreh Hospital
`for Sie Children Research Institute 1o—
`ronto ON ( Iauada
`[‘ht nehulizers studied we re punide‘d tlII'oIItrh the age ne rosit\ or
`PAlil liespimton l‘tlilll‘illlt‘nt lne, "lIudell \le'dital lnternational
`II1(.-.aI1dMe(lit-— Aid Limited.
`Supported from a grant from the Hospital for Sitk (Ihildrtns
`Foundation, made possihle l1\ :1 geneirins donation lroIn Arnold
`and [um [min For cutie hhmsis research.
`
`N'Ianuseript received Septeiuher 5, 9.003: revision accepted May
`:28, 2004.
`Iteprmluetion of this article is 1n1l1il1ited without written permis-
`sion from the Amerieau Col ege of Chest Plusieians (e—IIIail:
`lien1Iissions@ehestuet.:fig).
`(orrm-poademe to. Alien 1’. Comes B I'IIU(I*I'u.').I1HJ( 1!
`Dicisiouoffltspiroforl; Mllttltttnt T'ht Hospiioifin‘ Sick Childru:
`”-555 hitters-in; Ace Tomato ON, (anode ‘1!)0 1X5; alien.
`root:s@sit.kltids. er!
`
`www.chestjournal.org
`
`CHEST! 126 I“ 51' NOVEMBER, 2004
`
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`
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`
`

`

`lireath—t-‘nhanccd nebulizers are more efficient than
`
`unvented nebulizers, but not all breath-enhanced
`nebulizers have the same efficiency," with differ-
`ences in residual volume (VB) and particle size
`resulting in significant differences in expected pul-
`monary deposition. There is a new generation of jet
`nebulizers that are breath actuated, producing med—
`ication only during inspiration, which makes them
`potentially even more efficient
`than the breath-
`enhanced devices. At present, there are little com—
`parative data available to help the clinician choose
`between devices for specific applications.
`All jet nebulizers have a nebulizing chamber con—
`taining liquid medication and a high-pressure, high-
`velocity jet of gas that creates a partial vacuum at the
`exit orifice of the jet, resulting in the medication
`being drawn up toward the high-velocity orifice,
`where shear forces fragment the liquid into a poly—
`disperse aerosol. The aerosol passes around a series
`of baffles, where larger particles are removed by
`inertial impaction and fall back into the reservoir for
`renebulization. Particles that escape the baffles ei-
`ther leave the nebulizer, or “rain out” and fall back
`into the medication chamber under the influence of
`
`gravity. Simplistically, the major difference between
`unvented and breath—enhanced nebulizers is that the
`
`patient’s inspimtory flow is entrained into the device,
`and particles that would otherwise rain out are swept
`along into the patient during inspiration?” Hence,
`the rate of output of breath-enhanced nebulizers
`increases with increasing inspiratory flow and falls
`back to baseline during expiration when no flow is
`entrained. Furthermore, since inertial impaction of
`droplets on the baffles is in part dependent on
`velocity of the particle, increases in entrained flow
`increases the likelihood that
`larger particles will
`impact on the baffles. This may give rise to a smaller
`particle size distribution during inspiration as the
`inspiratory flow increases.“i Particles between i p.111
`and 5 pan in diameter are ideal for pulmonary drug
`delivery, in that they are small enough so as not to be
`removed by inertial impaction at the posterior phar—
`ynx, but large enough to carry a significant amount of
`drug. Given that particle volume is proportional to
`the third power of the radius, particles < 1 pm carry
`little drug. The fraction of the volume of the nebu-
`lizer output carried in particles with a diameter E 5
`pm is defined as the respirable fraction (RF‘)."‘—'3
`In terms of the appropriate choice of device, a
`number of factors come into play. Clearly, the ability
`to produce a high—density aerosol with a large RF
`during the inspiratory phase is the basic principle,
`but other factors such as VB at end nebulization are
`
`an issue, especially if the medication is very expen—
`sive.” Since one of the challenges in the treatment
`of CF is patient adherence to recommended treat-
`
`1620
`
`Air sucked through
`vent on Inspiration
`
`Vent closed
`on expiration
`
`
`
`compressor
`
`Airfrorn
`compressor
`
`Fulliltt‘.
`LC Sttll'.
`
`l. A schematic of the breath—clIliallccd lit-rlrlllizrz-r Pari
`
`ment regimens, devices that reduce treatment time
`would be expected to offer advantages to the already
`very time—consuming daily multifaceted treatment
`activities of these patients.":"'7 The devices should
`therefore be evaluated on the expected pulmonary
`deposition of a specific dose, and the delivery time
`required. The breath—enhanced nebulizer, the Pari
`LC Star (Pari Respiratory Equipment; Mississauga,
`ON, Canada) [Fig i], has been shown to be one of
`the more efficient breath—enhanced nebulizers.“i
`
`Breath—actuated nebulizers, such as the AeroEclipse
`(Trudell Medical International, London, ON, Can—
`ada) [Fig 2] and Halolite (Medic—Aid Limited, West
`Sussex, UK) [Fig 3] have recently been developed.
`The Halolite uses an adaptive aerosol delivery system
`that can adapt the drug delivery to each patient’s
`breathing pattern. Table 1 provides a functional
`comparison of all three devices.
`The purpose of this study was to compare the
`three devices in terms of in vitro performance,
`expected in vino rate of deposition, and in tier)
`efficiency using the respiratory pattern of patients
`with CF breathing through a nebnlizer. Significant
`end points are considered to be the percentage of
`the initial dose that would be delivered to the lungs,
`the time required to deliver a “target” dose, and the
`ability to deliver a precise pulmonary dose. It is
`recognized that the importance of these variables
`depends on the expense of the drug being delivered,
`the value in terms of possible greater adherence to
`recommended therapy from rapid delivery, and the
`therapeutic safety profile of the drug in terms of
`accurately delivering a specific amount.
`
`METHODS ANI) MATERIALS
`
`Denice Operation
`
`The nebulizers and compressors used in this study were the
`Part I.(J Star nchulimr driven by the Part Pmnch Ultm compres—
`
`Laboratoryr and Animal Investigations
`
`UNITED THERAPEUTICS, EX. 2043
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`

`

`WWW
`onlopotme
`WWW
`mamanddown
`Wittepaflont
`mmdavtce
`
`tsaduated.
`
`FIGURE 2. A schematic oll the brcatII—enllailet-d. breatlI—aetuated nebulizcr {BAN} AeroEt-Iipse.
`
`sor (Pari Respiratorv Equipment); the AeroEcIipse nebulizer.
`which was also driven by the Pill'i compressor. as no specific
`compressor was i‘t‘couuncndml: and the Ilanlite nebulizer with a
`built-in compressor. The IIanIite is a niicrtJpnJcessor-coutiolled
`
`
`
`1‘
`light
`Ont-u". ‘
`humor“ /
`
`'1' Minor
`.- I'M
`. “I“
`MM"
`
`Hlndpkco
`
`
`
`FIGURE 3. A schematic ol' the In‘eath-actlrated nebulizer I-IanIite.
`which uses adaptive aeiosol delivery teelmology. Insert shows
`h
`breath hut-ind; ( ark areas re resent device adivation,
`
`device that activates the compressor on each inspiration. Three
`exauuples of both the Purl LC Star and the Aerolielipse were
`studied. but only-'11 single llalolite dexice was available, The test
`drug was 2.5 mg (0.5 mL) of albuterol (Ventoliu Respirator
`Solution; (IlasoSulithKline; Mississauga. ON. Canada) diluted
`with 3.5 ml. of saline solution. This was chosen because it lends
`
`itsell' to ultraviolet (UV) spectrophotoinetry for quantification of
`output." The l’ari LC Star and the AemEcIipse were also
`evaluated using (mmpressed dry air (hospital air. 5(l—psi source) at
`8 IJmin, which is the same [low reconnuemlcd by the oniuuflur—
`tul'el'
`for
`the AeroEcIipse. Flow from the compressor was
`measured by a flow calibration instrument (Timeter RTEUU;
`Allied Health Care Products, St. Louis, MO}, and the Ilmvmeters
`on the hospital air line were calibrated to adjust for “back
`pressure."2 so as to deliver the expected driving nebuliziug flow.
`When driving either the AemEelipse or the Pari LC Star, the
`output of the l’roNel) Ultra compressor was 4.9 Umin.
`
`Particle Sty: Distribution and Hetm‘tniutng N abnlimr Output
`
`Both the l’ari LC Star and the AeroEcIipse were characterized
`in terlus of particle size distribution and rate of output during
`steady—state conditions. Briefly. the device was mounted to allow
`aerosol to pass through the laser beam ol'a Malveru Mastersizer
`X (Malvern Instruments; “-"orcestersliire, UK), and particle size
`was measunrd using the Mie theory for transparent dmplets.
`Care was taken to avoid vignetting.“ This method has been
`described in detail elsewhere.lg Measurements were made after
`2 min ol' nebulizatiou, which allowed the uebulizer to attain a
`steady-state temlmrature,” after which particle size distribution
`and RF were calculated. In order to mimic entrained flow. air at
`
`40% relative humidity was added at the point of the inspiratory
`valve in Iluw increments of 5 llmili up to El maximum or 35
`
`www.chestjoumal.org
`
`CHESTt126 f 5 3' NOVEMBER, 2004
`
`1621
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`

`

`Table 1—11 Functional Comparison of the Part LC Star, AeroEcIipse, and Hatolt'te
`Pari LC Star
`Halolite
`AeroFIclipse
`Breath enlumcexl
`Breath actuated
`
`Breath enhanced
`
`Breath actuated
`
`Uses adaptive aerosol delivery system,
`which adapts drug delivery to each
`individual patients breathing pattern
`Device has two operating buttons; each
`is designed to deliver the
`manuEleuirer‘s preset volume
`Aerosoliaation begins when the patient
`pushes the appropriate button
`(albuteml For this study) and begins
`breathing
`Halolite analyses the first three breaths
`of the patient to determine the
`breathing pattern
`A pulse of drug is delivered every
`subsequent breath only during the
`first 50% of inspiration
`_\lo entrainlnent or flow on inspiration
`Output is constant For each pulse and
`indeptmdent of the inspiratory How
`Valves divert ventilation around
`
`lnspiratory valve allows air to entrain
`into the chamber during inspiration
`when the flow of patient is greater
`than netmli‘zjng flow
`
`\\-"hen entrained flow is > 8 Um. a
`unique spring—hunted mechanism
`allows the actuator piston to be
`pulled down onto the jet and
`nebulimtion commences
`
`Aerosol is only produced during the
`inspiratory phase, making it
`potentially very efficient
`
`Espiratory valve on mouthpiece prevents
`eshaled gases from entering the
`nebuliwer
`
`Expiratory valve on mouthpiece
`prevents exhaled gases from
`entering the nebuliiaer
`Treatment is complete when the preset
`Treatment complete when device
`Treatment complete when device.
`dose has been delivered
`splitters
`splitters
`
`nebnlizing chamber
`
`I/min. and particle size distributions were measured in each
`situation. For the AemEclipse, the first level of entrained flow
`was 8 Umin because the spring-loaded valve only opens when
`entrained flow reaches this level. The micmpmccssor control of
`the IIalolite makes conventional particle sizing difficult since the
`device is not (ittfiiglltttl
`to run continuously. This intermittent
`operation results in dittierences in temperature of the aerosol
`when nebulized continuously vs pulsed. The increased accuracy
`of 2,000 sweeps during data gathering by the Malvern Master-
`sizer X for particle size distribution calculations in “continuous”
`mode oil-sets the limited data achieved from a “pulse," even with
`(litterences in temperature of the aerosol being particle sized. To
`create a continuous mode, the device was dismantled and the
`back pressure created by the compressor when driving the
`IIalolite handset, which contains the nebnlizing device and
`micmpmcessor, was measured as 28 to 30 psi. The compressor
`uses an elastic reservoir that allows pressure to increase during
`expiration. and contributes to the compressor output during the
`pulse of aerosol, This resulted in a driving pressure that
`is
`c-{nlsiderably higher than that which would have occur if the
`Compressor were driving the nebulizer continuously, The micro—
`processor within the Ilalolite handset was dismantled, and the
`nebuliyer was driven by a dry air gas source at a flow matching
`the back pressure previously measured from the llalolite coin—
`pressor. which resulted in an output flow of 5.4 Umin. The
`mouthpieCe of the handset was positioned to send a continuous
`stream of aerosol across the laser beam. Since there is no
`
`entrained flow, only one measurement condition was necessary,
`Prior to the particle size measurements, devices were weighed
`empty (for the tlalolite, this was only the medication chamber),
`filled, and naveighed using an electronic balance (Bl .150; Sarto—
`rius Coq‘mration; Edgcwood‘ NY). After 4 min of steady—state
`output, the devices were rmveighed. Changes in drug concentra—
`tion due to (walmmtive losses were assessed initially by changes in
`UV spectropluitometry and water vapor pressure osmolarity
`
`1622
`
`(Advanced Micro—()smonleter 3300; Advanced Instruments;
`Norwood, MA), Eventually, only osmolarity was used since the
`simpler technique gives identical results to the more complex UV
`spectropht)tonlctry, The drug output over the nebuliyation pe—
`riod was calculatml from the VB and the changes in concentra—
`tion, as seen in Appendix I.
`For each 4—min run under each condition of entrained flow, the
`total rate of output zmd that in the RF was calculated, and the
`mean taken for the three examples oFboth the Pari LC Star and
`the AeroEclipse. Polynomial curve—fitting techniques were used
`to create the algorithm for the rate of output—total and within
`the “Fl—over the range of entrained Flow. Finally, both the Pari
`LC Star and the AemFIclipse were run to dryness, defined as the
`absence of mist for at least 10 sf” to allow the calculation of the
`total output of the device. The details of these techniques have
`been describedfi-m-i” Output data for the IIalolite were collected
`by connecting it
`to a modified Harvard pump (Model 613;
`Harvard Apparatus; llolliston, MA) that delivered two half—sine
`\\"“(I.\"¢;?S
`with an inspiratory time/total time of respiratory cycle
`(TI/T'I‘UT) oI'II,4, a tidal volume (if-500 ml., and a respiratoly rate
`of 20 breaths/min. These settings amprosimate the tidal volumes
`and timing of actual patient tlow traCes (see below). The Harvard
`pump was run until the lialolite sensed that the preset volume
`had been delivered. The output was calculated from the drug
`remaining in the nebuliyer cup via gravinletric techniques and
`changes in osmolarity, which had cmnplcte agreement with UV
`spectrophotometry. When the output multiplied by the RF is
`divided by the number of breiths, the result is the expected
`deposition per breath.
`
`Catcatatioa of Ifsriawfcd Pufuwaary Downturn
`
`From a previous study.fll digitiyed breath tracings of seven
`patients with CF (age riuige. 4 to 18 years) breathing through a
`nebulizel' (Table 2} were used. Patients with I'll-CV. values 3 60%
`
`Laboratory and Animal Investigations
`
`UNITED THERAPEUTICS, EX. 2043
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`

`

`Table 2—Demographic Information on the Seven
`Patients Whose Breathing Patterns Were Used To
`Calculate Estimated Pulmonary Deposition and In
`Vivo Eflicierwyi‘
`
`Respiratory liate,
`FEV], “it;
`“’eight,
`Patient Age, Height.
`
`
`
` _\Io. yr em kg Predicted Breatbshniu
`
`
`l
`I I
`138
`28
`84
`l T. l
`2
`l. l
`141
`I34
`76
`13. T
`3
`T
`122
`22
`58
`31.4
`4
`I8
`174
`55
`l 13
`13. 9
`5
`T
`122
`93
`78
`41.6
`ti
`I 4
`l 42
`3 l
`25
`40.7
`
`4 159 42 55T 24.6
`
`
`
`
`
`*F'uuu {Ionics ('t ill.2|
`
`predicted had essentiaih normal patterns of breathing. although
`the younger ones tended to be a hit taell}-'plleie when breathing
`on the nebulizer. The child with the worse lung function (FEVI
`C 30% predicted) was tacllypneic at rest, The respiratory wave—
`forms were broken into 5-ms epochs and were used to calculate
`the expected deposition. Three breaths were chosen iron] a
`pattern that showed regular respiration, and the same three
`breaths were used to calculate expected deposition for each
`apparatus. Entrained flow was calculated by subtracting the
`nebulizer driving flow from the inspir'ator'y flow.
`\Vlien this
`resulted in a negative number it was defined as zero. since the
`one—way inspiratory valve would be closed. The spring—loaded
`valve on the AeroEelipse does not open until the entrained [low
`reaches 8 Umin; output was considered zero until this occurred.
`From the algorithms of the total rate of output and that in the RF
`for the l’ari LC Star and the AeroEelipse. the output in each 5
`ms-epoeh for the specific entrained {low of the epoch was
`calculated and summed over the entire breath. These calculations
`
`are illustrated in Appendix 2. The results are reported as the
`mean of three breaths for each patient. This allows the in ciao
`elliciency, defined as the output during inspiration in the RF
`divided by total output over the entire respiratory cycle,“ to be
`calculated. For the llalolite. in also efficiency was equal to the
`output in the BF during inspiration since there is no expiratory
`drug loss.
`
`Validation of Assrnnptions
`
`To test the assumption that the output of the l’ari LC Star aml
`the AeroEclipse that was determined under steady-state condi-
`tions were valid under dynamic conditions, they were urnneeted
`to the llarvard pump with the settings described above and run
`for 3 min. Total drug output (Or) was calculated as described
`above. The two half eaves From the Ilarvard pump were Icnown
`Irulthematicall}! and were entered as the “patients" breathing
`pattern, Using the algorithm for rate of drug output, the output
`over 3 min was calculated and compared to the measured output.
`Device ewlluation and comparison included the expected
`pulmonary drug deposition per breath and per minute, in [Jim
`efficiency, overall efficiency in terms of expected deposition in
`relation to the initial charge in the nebnliner, and for the llalolite
`the aflcllnufir‘r {If the dc’v‘lcc t” delivcr El. ljrvst't tulltlllllt (1f (ll'llg, The
`calculated output and expected pulmonary deposition of the Pari
`LC Star and AeroEclipse, as well as the length of' time to run to
`(In-ness were compared to the llanlite. To have compamble data,
`the time to deliver a selected predetermined dose was calculated
`for each device. The predetermined dose was defined as the dose
`delivered by the llalolite alter four button presses, which was
`
`found to be (-'ss(-'Iltiall_\-' (-‘quivaliz‘nt to its point (ii-dryness. The time
`(lillerence between the devices for each of the seven patients was
`calculated. The results are expressed as means i 95% confidence
`limits. Differences in patient size and deviee performance were
`esplorul by regression analisis.
`
`RESULTS
`
`The steady-state in vitro assessment of both the
`total rate of output and that in the BF for the Pari
`LC Star and AeroEclipse is shown in Figure 4. With
`increasing entrained How, the Pari LC Star increases
`both the OT and that in the RF. The AeroEclipse
`begins producing aerosol when the entrained flow
`reaches 8 Uinin (patient inspiratory flow is 13 L/min
`when the compressor driving flow is taken into
`consideration), and there is a slight fall oil'in OT with
`increasing entrained flow, but there is an initial small
`increase in the RF, indicating a smaller particle size
`distribution with increasing flows. Given the design,
`the H anIite provides a constant output of 0.0029 mg
`per breath when it is activated.
`When the mathematically predicted output of the
`l’ari LC Star and the AeroEclipse for the two half
`sinusoidal waveforms for the Harvard ventilator are
`
`compared to the actual output, there is no diilerence
`between the two (0.0089 i 0.000] mg per breath
`vs 0.0090 : 0.0000 mg per breath, and 0.0046 i
`0.0001 mg per breath vs 0.0045 i 0.0002 mg per
`breath for the Pari LC Star and the AeroEclipse,
`respectively [mean i 95% confidence index (61)].
`
`
`
`0
`
`5
`
`.i
`
`F:.32;
`
`I mwwmdmnm
`‘ Mammalian-IV}
`Q Pomona swim
`i wunamm
`
`0.2
`
`0.]
`
`
`
`P w____I___..__I_____l____1___._..
`
`0.0
`
`'
`
`‘
`
`I
`
`'
`
`‘
`
`1
`
`‘
`
`‘
`
`r""
`
`'
`
`1
`
`'
`
`0
`
`10
`
`20
`
`30
`
`40
`
`Entrained flow (limin)
`
`FIGURE. 4. Rate of output (total and in RF} in relation to
`entrained flow For the Pari IIC Star and AeroEelipse. while being
`driven by the compresstu'.
`
`www.chestjournal.org
`
`CHEST! 112I3al'5alI NOVEMBER. 2004
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`

`

`This gives credibility to the use of the mathematical
`model derived from steady-state data for the predic-
`tion of drug deposition during dynamic conditions.
`In other words, the quadratic equations that charac—
`terize the device performance during steady-state
`conditions can be applied during dynamic in vivo
`conditions.
`
`The rate of deposition as a function of respira-
`tory rate (Fig 5) is greatest for the Pari LC Star; it
`is intermediate for the AeroEclipse, and not re—
`lated to respiratory rate. In contrast, the Halolite
`has the lowest rate of deposition with most respi—
`ratory rates, but shows a linear increase with
`increasing rates until > 40 breaths/min, where the
`expected deposition is comparable to the other
`two devices. As expected, the opposite is true with
`tidal volume since those subjects with the greatest
`lung disease had the highest respiratory rates and
`the lowest tidal volumes. The mean rate of depo—
`sition i 95% C1 was highest for the Pari LC Star
`(0.093 t 0.0084 rug/min with
`compressor
`vs
`0.120 i 0.0122 rug/min for dry air),
`lowest for
`the Halolite (0.055 : 0.016 mg/min, compressor
`only), and the AeroEclipse is in between (0.075 i
`0.0064 mg/min with corupressor, and 0.108 i
`0.014 mg/min for dry air). The difference between
`the I’ari LC Star and the AeroEclipse was signif—
`icant, but there was variability among the patients,
`resulting in overlap in the 95% CI between the
`AeroEclipse and the Halolite. The in vino efficien-
`cies of Pari LC Star and AeroEclipse range from
`51 to 55% and 71 to 77%, respectively, for the
`older group of children. For the younger group,
`
`0.12
`
`0.10
`
`0.08
`
`004
`
`0.02
`
`I HalaLite
`
`I Pan Lc Star
`7 AeroFxlipse
`
`I 5
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Respiratory Rate (breath! min)
`
`FIGURE 5, Hate of deposition as a function of rcspimtory mtc for
`the Pari LC Star. AeroEclipse. and Halolite.
`
`1624
`
`the in uivo efficiencies are found to be 52 to 54%
`
`and 68 to 73%. The Halolite has an RF of 80%,
`which is equivalent to the in ciao efficiency. For
`the breath—actuated devices, the in viva efficiency
`was essentiall I the RF since no drug is lost during
`expiration. For the Halolite, this is constant and
`independent of the subject, which is not the case
`for the AeroEclipse since increasing entrained
`{low played a role by increasing the RF (Fig 4). If
`the devices are run to dryness or “four button
`presses” for
`the Halolite,
`total expected drug
`deposition is greatest for the AeroEclipse (1.3032 i
`0.0296 mg, compressor; 1.4719 : 0.0204 mg, dry
`air), least for the Halolite (0.8400 i 0.0000 mg), and
`intermediate for the Pari LC Star (0.9421 : 0.0307
`mg, compressor; 0.9719 : 0.0395 mg, dry air) and all
`independent of size of the subject. There is virtually
`no variation (95% CIs < 0.00005 mg of the initial
`dose of 2.5 mg of albuterol) in the expected dose
`delivered by the Halolite, despite large differences in
`size and breathing patterns. There was no relation—
`ship between the rate of deposition and the si7e of
`the subject, either in height or in weight. The larger
`(taller) subjects wordd have received less drug on a
`milligram per kilogram basis than the smaller sub-
`jects. This was most pronounced for the Aero-
`Eclipse, in which the 115—cm—tall subject would have
`received almost
`three times the amount in milli—
`
`grams per kilogram body weight than the subject 174
`cm in height. Furthermore, dosing differences due
`to device performance are greatest for the smaller
`subjects with much less discrepancy for the larger
`ones. With increasing entrained flow, the output and
`deposition are also increased, but the rate of OT
`starts to level off at approximately 20 Umin for the
`AeroEclipse and approximately 30 L/min for the Pari
`LC Star.
`
`When evaluating the devices in terms of time to
`deliver a dose of medication, the Halolite consis-
`tently results in an expected pulmonary deposition of
`0.8400 mg with four button presses, which is there-
`fore selected as the comparing dose. Using the
`compressor, the Pari LC Star is fastest with expected
`pulmonary delivery in 9.2 t 0.8 min (mean i 95%
`CI) with the AeroEclipse taking 2.2 i 0.4 min
`longer, and the Halolite requiring 8.0 i 4.2 min
`longer. The much larger CIs with the Halolite are
`explained by the relationship of rate of output and
`respiratory rate with this device, whereas the other
`two devices are much less dependent on the respi—
`ratory pattern of the child. When driving the devices
`with hospital dry compressed air, the Pari LC Star
`delivers the dose in 7.1 i 0.7 min, with the Aero-
`Eclipse requiring 0.9 i 0.6 min longer.
`
`Laboratory and Animal Investigations
`
`UNITED THERAPEUTICS, EX. 2043
`
`WATSON LABORATORIES V. UNITED TH ERAPEUTICS, |PR2017—01622
`
`Page 6 of 9
`
`

`

`DISCUSSION
`
`This study demonstrates that three of the new
`generation of nebulizers each has pai'ticulzu‘ strengths
`and weaknesses. In terms of rapid drug delivery, a
`factor that may shorten treatment time and improve
`adherence with recommended therapy in a disease
`like CF,"“7 the Pari LC Star appears to be the
`superior device when using a compressor. If the
`nebulizers are driven at 8 Umin from a compressed
`air source, as would be likely in a hospital setting, the
`rate of output for the Pari LC Star increases 29%.
`but 44% for the AeroEclipse, making the perfor—
`mance equivalent for the two devices. In terms of
`maximizing drug delivery, an important factor if the
`drug is very expensive, the AeroEclipse is the supe-
`rior device. From the perspective of a drug with a
`narrow therapeutic safety margin,
`the Halolite is
`much more predictable for drug delivery. Regardless
`of device, if a specific dose based on milligrams of
`drug per kilogram of body weight is desired, the
`initial dose put into the nebulizer will have to be
`individualized for the size of the patient. If the drug
`being nebulized is an antibiotic and minimal envi-
`ronmental contamination is desired, neither the
`AeroEclipse nor the Halolite allows significant (or
`any) antibiotic to leave the device except that which
`is exhaled by the patient.
`There are some potential limitations to this study.
`The most obvious is that in oitm data are combined
`
`with in oivo respiratory patterns to estimate, as
`opposed to measure,13 pulmonary deposition. \Vhile
`there is no doubt that nuclear medicine techniques
`would have to be considered the “gold standard,”
`comparison studies would mean multiple exposures
`to radioactive material that would not be allowed
`
`under the current regulations for ethical research in
`children. The comparisons are estimates, and the
`following issues are the potential sources of error in
`the calculations. The first is whether or not output
`data derived under steady—state conditions can be
`applied to the dynamic situation of regular breath—
`ing. In terms of total rate of output, the agreement
`between the data generated by the modified Harvard
`pump, which produces perfect half-sine waves, and
`the mathematical data using the model of the device
`output coupled to the mathematical expression of
`the sine waves suggests that steady—state data could
`be applied with no loss of accuracy. The second issue
`that is not addressed in this study is whether or not
`particle size distribution measured under steady-
`state conditions would apply to the dynamic situa-
`tion. In a previous study“3 using the Pari LC Jet
`nebuIizer in normal adults, very close agreement was
`found between the RF measured by laser diffraction
`and the in viva HF measured by scintigraphy. How-
`
`ever, in children, the definition of an RF as the mass
`of aerosol carried in particles 3 5 |.I.m could be
`questioned. Recalculating the data of W'ildhaber
`et al,22 it would appear that in smaller children a
`definition of E 5 pm for the RF is too large. Support
`for this comes from Geller and colleagues.” who did
`not find evidence that smaller children received
`
`more tobramycin per kilogram of body weight from
`a Pari LC Jet nebulizer. They suggested that the
`lower RF in the small children limited pulmonary
`deposition. Since no specific data exist to give a valid
`estimate of HF based on size,
`this is a potential
`limitation that can be acknowledged but not scien—
`tifically corrected. Finally, the breaths used in the
`mathematical model assume a stable breathing pat-
`tern, by both the choice of where on the ventilatory
`pattern that the representative breaths are chosen,
`and the expression of the results as a mean of the
`three representative breaths. Such a stable pattern is
`frequently not the case in children. The device that
`would be most affected by an irregular pattern would
`be the Halolite because the timing of the output
`pulse is based on the previous three breaths. In a
`situation when breathing is irregular, the intended
`delivery of the pulse during the first half of inspira-
`tion may be rnistimed. However, as a comparative
`study, the performance of each nebulizer is calcu—
`lated on the same three breaths from each patient,
`thereby minimizing physiologic variations in device
`performance. Another theoretical issue is that the
`manufacturer of the Halolite suggests that a better
`distribution of drug will occur if the pulse is deliv—
`ered only during the first part of inspiration, as
`compared to throughout the inspiratory cycle for the
`Pari LC Star and whenever inspiratory flow is > I3
`1/111 in the case of the AeroEclipse. There is no
`specific comparative data to support or refute this
`claim, but a comparison between the Halolite and
`the Par-i LC Jet, a less efficient precursor of the Pari
`LC Star?“ did not support more unifonn distribution
`in patients with CF.
`There are differences in the in vitro performance
`between the I’ari LC Star and the AeroEclipse. As in
`all breath-enhanced nebulizers, the entrained flow
`d