Conference Proceedings
`
`Design Principles of Liquid Nebulization Devices Currently in Use
`
`Joseph L Ran PhD RRT FAARC
`
`Introduction
`.Iet Nebulizers
`
`Principle of Operation
`’ariahles ol’ Nebnlizer Performance
`
`Advantages anti Disadvantages of .let Nebuliaers
`Design Variations in 'l‘raditioaal .lel Nelnilizers
`Ultrasonic Nebuliaers
`
`Description and Basic Function
`Physics of Ultrasonic Nelnllization
`Theory of Aerosol Production
`Comparison of Ultrasonic and Jet Nebulizers
`Advantages and Disadvantages of Ultrasonic Nebulizers
`Snunnary
`
`Liquid nebuliaation is a comtnon method of medical aerosol generation. 1. 'ebulizers are ot’2 types: jet (or
`pneumatic) small-volume nehulizer, aml ultrasonic ncbulizer. .lct nebulizers are based on the venturi
`principle. whereas ultrasonic nebnliaers use the converse piezoelectric eITect to convert alternating
`current to high-frequency acoustic energy. Important variables for both types of nebulizer are treatment
`time required, particle size produced, and aerosol drug output. There are several advantages to jet
`nebulimtion. including that effective use requires only simple, tidal breathin ’, and that dose modifica-
`tion :qu dose compounding are possible. Disadvantages include the length of treatment titne and
`equipment size. Design modifications to the constant-output nebulizer have resulted in breath-enhanced,
`open-vent nehulizers such as the l’ari LC Plus and the dosimetrie AeroEclipse. Ultrasonic nebnlizers
`generally have a higher output rate than jet ucliulizers, but a larger average particle size. Ultrasonic
`nebnlizers can also substantially increase reservoir solution temperature. the opposite of‘jet nebulizer
`cooling. Drug concentration in the reservoir does not increase with ultrasonic uelniliration, as it does
`with jet nehulization. Ultrasonic nebulizers have the same advantages as jet nelnllizers. Ultrasonic
`nebulizers are more expensive and fragile than jet nellolizers, may cause drug degradation, anti do not
`nelnllize suspensions \vell. Neither type of nebulirer meets tlle criteria for an ideal inhaler: efficient and
`quick dose delivery with reproducibility, cost-el'l'cctivmless, and no ambient contamination by lost aero-
`sol. Krjr n'oi‘rls: m'hnli:orinn. jet ricbrilizer. aerosol. ultrasonic.
`IRespir Care 2002:1170 1):]257—l27fi]
`
`Introduction
`
`The term "nebulizer" derives from the Latin “nebula."
`meaning ”mist." and reportedly was first used in lii'l'l
`followed by an 1874 definition as “an instrument for con-
`verting a liquid into a line spray. especially l'or medical
`
`pul'poses."' The appealing logic ol‘ creating :1 vapor or
`aerosol for the inhalation treatment of lung disease is at
`least as old as written records of medicine. The Aynrvedic
`tradition of medicine in lndia. which dates back perhaps
`
`fitlthlit-.srlna‘t(JttYCakiiiuurnalConlercnce.LiquidNehuliz:ttion:F_merg-
`in; 'i'cchaologies. held June 25—30. Elltll. in Montreal. Quéhce. Canada.
`
`Joseph I. Ran i’hD ItR'I‘ FARRC isat'l'ilialcdwilhCardiopulnionary Care
`Sciences. Georgia State University. Atlanta. Georgia.
`Joseph l. Rim l'hl) RR'I‘ FAARE‘. presented :1 terxion ol‘ this report at the
`
`Cni'l'eswlitleltcc: Joseph 1, Run l’iil) RRT FAARC. Cardiopulntonar}
`Care Sciences. MSCSRUJI‘). Georgia Slate University. 33 Gihncr St SE.
`Unit ti. Atlanta GA 30303—3035. E-niaii: jr:m@gsu.cdu.
`
`RESPIRATORY CARE . Novesnnzn 2002 Vol. LitriNtr‘t'tlmmflF'fld
`attha NLM ard maybe
`EL eject US Copyright Laws
`
`[957
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01621
`
`UNITED THERAPEUTICS, EX. 2044
`
`Page 1 of 24
`
`

`

`DESIGN PRINCIPLES or: LIQUID NRIIULIZA‘HUN DEVICES CURRiiN'I'l.Y 1N Usn
`
`
`
`6 " length tubing
`
`To patient —)
`
`4.000 years or more, used inhaled substances for manag—
`ing asthma.2 Although inhalation devices were described
`in the l91h century, the modern precursors of small-vol—
`ume nebulizer devices appeared with the glass and hand-
`bulb “atomizers” introduced for asthma treatment in the
`
`1930s. such as the DeVilbiss No. 40 glass nebulirer.I The
`Collison nebulizer became available in the late 1940s; it
`used a baffle to filter out large particles, thus distinguish—
`ing a "nebulizer" from an “atomizer."3 The Wright nebu-
`lirer, which appeared in the 19505;. was engineered l'rom
`cbonile and perspex; it was much more compact than the
`Collison and more closely resembled today's pneumati—
`cally powered nebulizers.4 A different method of creating
`liquid aerosols. the ultrasonic nebulizer, was introduced in
`the [9605.
`It relies on high-frequency sound waves to
`aerosolize the solution. Today the term ”nebulizcr." as
`used clinically in respiratory care. encompasses both gas—
`powercd jet nebulizcrs and ultrasonic nebulizers. This re-
`view considers the physical principles. designs, advan-
`tages. disadvantages. and factors affecting performance of
`jet and ultrasonic nebulizers that are in current clinical use.
`
`Jet Nchnlizers
`
`Principle of Operation
`
`Small—volume jet (pneumatic) nebulizcrs arc 2-lluid at-
`oinizers. The basic principle of operation involves com-
`pressed gas directed through a narrow orifice, with em
`trainmcnt of liquid through one or more capillary feeder
`tubes. The narrow—orifice gas nozzle has traditionally been
`termed a “vertiuri.” with liquid entrainment based on the
`Bernoulli principle. In laminar flow. and keeping height
`constant, Bernoulli’s equation‘ for an incompressible l'luid
`states:
`
`'/2 my1 + P = constant
`
`in which to —' mass. v = velocity, P = pressure. and
`1K2 niv2 represents kinetic energy. Fora gas in laminar flow
`through a tubing system, an increase in velocity. such as
`can occur at a restriction in the tithing. leads to a decrease
`in the lateral pressure. If kinetic energy increases. pressure
`energy must decrease, based on conservation of mass and
`energy. A “venturi‘l is based on Bernoulli's equation and
`uses the pressure drop to entrain a second fluid. The lower
`pressure causes drug solution to be drawn up to the gas jet
`through capillary or feeder tubes that
`lead down to the
`liquid reservoir. The entrainment is also attributed to ma-
`mentum transfer between the power-gas molecules and air
`or liquid in the feeder tubes!’ The high-velocity gas meet-
`ing the liquid causes primary generation of large droplets.
`typically 40—60 am. but with a possible range of 15 to >
`
`Secondary dmpleb
`11-10 pm)
`
`F311;?“firOleF
`
`Prll‘Z ow: = K
`
`tube
`rug solution
`
`
`baffle
`
`aplltary feeder
`
`Powor gas
`[flow motor, comprossori
`
`Fig. 1. The major elements of a jet {pneumatically powered) small-
`volume nebulizer. m = mass. v -- velocity. P = pressure. K =
`constant.
`
`500 am.” Droplets produced by primary generation are
`impacted onto bal'lles within the tichuliaer. producing a
`secondary generation of aerosol with particles of 1—H)
`pm, with typical sires of 4.0 and 5.0 uni.7 Du ring that second
`stage of aerosol generation the larger particles are baffled.
`coalesce. and drain back into the reservoir (Figure l).
`Aerosol droplet size depends on the geometry of the
`nozzle and bal‘t‘lcs. nozzle diameter. gas velocity, mass
`flow of gas, and the physical constants of the power-gas
`and drug solution. Jet nebulixcrs produce a range of par-
`ticle sizes. which is a distribution termed "polydisporse" or
`“heterodispersc.” in contrast with “monodispcrsc” acro-
`sols." The mass median aerodynamic diameter (MM/UH
`is the median droplet size of the cloud of aerosol particles.
`Particles of 1—5 pm diameter have a higher probability of
`reaching the lower respiratory tract than do larger parti—
`cles." However. there is a trade-off between particle size
`and drug amount. With spherical particles.
`the mass of
`drug varies directly as the third power of the particle ra—
`dius. An increase in particle sire gives an exponential
`increase in drug mass. but the converse is also trite. With
`aqueous solutions the extremely large surface area created
`by aerosol particles and a dry power—gas cause consider-
`able ovaporation and substantial cooling of the nebuliacr.
`because ol' latent heat of vaporization.
`to approximately
`If)” C below ambient temperature. within minutes. '” Higher
`power-gas llows can increase the amount of temperature
`drop in some nebulizcrs." The amount of temperature
`drop differs among nebulizer brands," and the amount of
`temperature drop is less with a partially liumidilied power-
`
`l253
`
`arthe Mud and .
`filjlinroav CARE 0 NOVEMBER 2002 VOL 47 No l
`mi‘mmria'“
`Subieet US, Copyright Laws
`
`l
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX. 2044
`
`Page 2 of 24
`
`

`

`Disstos PRINCIPLES or: LIouto NEBUUZA'I‘IUN Dimer-1: Coronas-rm lN Use
`
`0.5
`
`
`output ralo
`.-—-G—
`tempernlu r:
`cone. nlrallon—CI-
`
`.-.
`e
`_
`9:. 20
`E
`'57 93 «g-
`.-
`:I.
`e
`g
`'5
`-—
`a.
`g
`'5
`0 10
`o
`E
`g
`0:
`
`0.4
`
`0.2
`
`0.1
`
`D
`
`dead volume
`point
`
`
`
`
`
`t]
`
`5
`
`10
`
`.
`15
`
`1.5
`
`3
`E
`r
`g
`1.0 E
`c
`3
`8
`u
`.e
`o
`E
`hI:
`
`0.5
`
`0.0
`
`10
`
`
`
`
`
`NebulizatianTimetrninj
`
`
`
`0 ."amt. 4mL 5mL
`:15 Ll'rnin
`
`
`
`nt. mL 5 mL
`3 mL.
`al‘tfl Umin
`
`amt 4mL. Smt.
`at B Limin
`
`Fig. 3. Nebutization time is a function of both the power-gas flow
`rate and the fill volume. Lower flow rates and higher fill volumes
`increase the nebulization time, 'I he graph shows pooled data tron't
`1? nebulizers. {From Reference 1?. with permission]
`
`’ariahles of Nehulizer Performance
`
`Several variables describe the uebulizer performance.
`including the time required for Itebttlizalion. droplet size
`produced. and drug output.
`
`Nebuliaaliou Time. The time required is directly propor-
`tional to the volume oi solution placed in the reservoir and
`inversely proportional to the power—gas ttow (Fig. 3).”-17
`l)etcrmination ot' nebuliration titne in studies differs
`be ‘ause it
`is dil'l'icttlt to decide when aerosolization has
`ceased. The ucbttlization time depends on how the end
`point ol‘ nehulizalion is defined. Kradjan and Lakshmi—
`uarayan defined 3 possible end points for Itebulizalion:
`sputtering time. total time. and clinical time.” Sputtering
`is the point when aerosolization becomes en'atic. as noted
`by seeing and hearing. Total titne is when production ol‘
`aerosol ceases. Clinical
`time is between sputtering and
`total time. and approximates the point when a patient or
`therapist typically stops a treattnettt. With a 3 mL voltnne.
`averaged over 5 nebuliecr brands. the sputtering. clinical.
`and total times were measured as 13. 9.9. and |2.8 tuitt.
`
`respectively. by Kradjau and Laksluninarayau.‘3 Nebuli—
`zation time may also be defined as the point 30 seconds
`utter sputter. with or without tapping. although this can
`introduce greater subjectivity in the measurement. Regard—
`less ot' the end point chosen.
`it
`is important that studies
`define the end point clearly. in ordcrto allow comparisons.
`There is evidence to suggest that Itcbulizatiott titnc var-
`ies directly with the viscosity of solutions. Antibiotic so—
`lutions cart be more viscous than aqueous bronehodilator
`solutioits and can require more [Kiwcrful compressors tie,
`higher power-gas flows) to keep Itehulization times from
`being prolonged. Hess et al found that the average nebu-
`li‘ealion time pooled tor
`I? Itcbulizcrs, using albttterol,
`
`Nebulization time (mm
`
`Fig. 2. Functioning of a small-volume jot nebulizer with respect to
`output rate, solution temperature. and concentration of solute in
`the solution during nebulization. The data are lwpotheticat and not
`based on actual measurements of a particular brand of nebulizer.
`
`gas. such as l'rom a compressor. tltan with a drier gas. such
`as from a cylinder or wall outlet.l2 ’l‘he evaporation also
`increases llte solution's drug concentration during tlte tittte
`ol‘operation.”W-H lJemtis ct al l‘ottntl an increase from 1%
`to 38'»?- using 5 ml. of a solution at sodittttt fluoride in a
`Wright nehuliacr—a 200% increase in conecntration.'-‘
`Concentration increases ranging from 5% to over 3754-
`have been l‘ound with other jet nebuliaers. using albuterol
`solttlion.“' Figure 2 shovvs a generic illustration of otltptlt
`rate. temperature. and solution concentration for a typi ‘ztl
`small-volume jet nebulixer. In the first minutes the output
`rate falls as the soltttiott temperature drops and viscosity
`and surl'ace tension increase.” A plateau is tltctt reached in
`hotlt output and temperature. until a point at which output
`decreases precipitalcly; this is usually the point at whiclt
`the level ol‘ liquid in tlte reservoir falls below the bottom
`of the capillary t‘eeder tube. At that point. gas is drawn up
`with the liquid. the nehuliitcr begins to sputter. and aerosol
`creation is intermittent.
`'I'appiug the nebulizer can cause
`bal‘l'led tlroplcts to coalesce. run down the walls of the
`reservoir. increase the solution level. and temporarily re—
`store aerosoliaation. Ultimately nebulimtion ceases.
`al—
`though the nehulizer contains some residual solution on
`the apparatus walls. battles. and at the bottom of tire res-
`ervoir chamber. The amount ol‘ that remaining liquid is
`termed the "dead voluttte.“ which in most small—volume
`Itebttliaers is approximately l ml.."' The l‘act
`that most
`nebulirers canttot aerosolize well below 1 mL is the reason
`that a bland diluent ot‘ saline or water is added to a 0.5 ml.
`
`drug dose; for example. albtilerol from a multi-use bottle
`(110.5% solution. Addition of the diluent is not to weaken
`the drug solution. btll is in tact needed it atty aerosol is to
`be produced. and iuet'eases the amount of drug entitled by
`llte nebulizer.”
`
`
`
`
`
`5.__A.___§.._A_...............-.__.-_‘.____4-e_-_.__-p.._4-.......—.....-,--_—._.___._....—..
`
`Resrnm‘rotw Carat - NOVEMBER 2002 Vol. clit‘i’d'etalililmsmiid
`atthENLll-lardrnaybe
`Subject 05 Copyright Laws
`
`I.
`
`1259
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017—01621
`
`UNITED THERAPEUTICS, EX. 2044
`
`Page 3 of 24
`
`

`

`DESIGN PRINCIPLES or: Ltotnn Neeuuzarton DIiVICI-IS CURRIiN'I'l.Y {N U51;
`
`'9
`
`
`
`
`
`DeadVolumetmgalbuterelj
`
`.L.L 3:30|
`
`_|
`
`-|-is:r
`
`LiI
`
`"Th—l
`
`
`
`
`
`0'1sz 4111!. 5mL
`at 6 Umin
`
`:imL amt 5mL
`at I! Urnin
`
`:FnL 4mL Smt.
`at IIIILl‘mIn
`
`Fig. 5. Effect of power‘gas [low rate [6. 8. or it] Umin] and till
`volume [3. 4. or 5 mL} on amount of drug remaining in the dead
`volume. The graph shows pooled data from 17 nebulizers. [From
`Reference 1?. with permissmn.)
`
`ccntage of 1—5 pm particles ranged from slightly over
`30% to 60%. Clay et al
`found an inverse relationship
`between the M MA!) and the geometric standard deviation.
`indicating that the MMAD was stttallerhul the aerosol was
`more hctct‘odispersc at higher llow rates.2|
`
`The primary factors affecting
`Aerosol [)rng Output.
`the amount of aerosolircd drug released front a jet nehu—
`liver are the till volume and. secondarily. the type of nett—
`tlli‘rcr. Increasing the till volume results in lower concen—
`trations of drug remaining in the dead volume of the
`ttchulizcr. when nchttlization ceases. This is hosed on the
`following relationship:
`
`[)eatl volume drug (mg) 2 dead volume toil.)
`
`K concentration {ntglntL}
`
`Willi a theoretical dead volume of Lt) ml. and assuming
`no increase in concentration ofthc residual solution due to
`
`evaponttion. a 2 ml. fill volume would leave at least half
`of the drug in the dead volttnte. A 4 ml. fill volume would
`only leave a quarter of the drttg in the dead volume. In
`reality. evaporation increases the concentration of the so-
`lution remaining in the nchttlizcr.‘5 Increasing the fill vol-
`tIIttc therefore reduces or "dilutes" the concentration of
`
`drug it] the dead volume. httt also increases nehttliaation
`little (Fig 5).” In the case of a 2.5 mg tlose of Itehulized
`albtttet'ol.
`l'ill volumes of 3. 4. and 5 ml. decrease the
`amount of drug left
`it]
`the dead volume from approxi—
`mately [.4 mg to approximately l.lS mg and LI mg.
`respectively.” Determination of aerosol output. dead vol—
`ume. and remaining drug amount depends on the defini—
`tiott of “end of itehulization."
`
`The type of nehuIizcr can also affect tltc amount of drug
`available for inhalation. Devatlasott ct al compared 4 neb-
`
`u
`
`
`
`MMAD[11ml M
`
`A I
`
`:
`
`e
`
`_a
`nebultzer flow
`
`10
`
`J
`
`U3
`
`a3
`
`
`
`(pm!0-‘N(-93|-0|MMAD
`
`ABCDEFGHIJKLMNOPD
`
`nebulizer brand
`
`Fig. 4. A. Effect of power-gas new rate on mass median aerody-
`namic diameter tMMAD), with smaller particle sizes at higher pow-
`er—gas flow rates. The graph shows pooled data from 1? nebuliz-
`ers. B. MMAD for 1'." nebulizer brands. pooled for all power—gas
`flow rate settings. (From Reference 1?, with permission.)
`
`with 4 ml, voltttne and 6 Limit: power—gas flow, was ap—
`proximately 13 min." Newman et al
`investigated neltu-
`Iized gentamicin solution with 4 different nchnliacrs and
`found tltat 4 mL (I60 mg) at 6 Until: power-gas flow
`required between I? and 25 min.” The approximate av-
`erage time pooled for the 4 nebulizcrs was 20 min. That
`study recommended flows of Ill—l2 limit] or a high-flow
`compressor for nebulization of antihiotic solutions.
`
`Particle size is a major factor influencing
`Particle Size.
`the probability ofdrug particles reaching the various levels
`of airway generation?“ Particle size produced by a small-
`volume jet nehuliaer is inversely proportional to power-
`gas flow (or compressor pressure).
`l-Iess et al found that
`the MMAD varied inversely with power—gas flow rates
`between o and Ill IJmin (Fig. 4A).” In that study the
`percentage of l—S pm particles increased with higher pow-
`er-gas flow rates. Similar data were reported from the
`United Kingdom by Clay et al for 4 disposable jet nehn-
`liaers.21 Increasing the power-gas flow rate produced
`smaller particles and reduced nebulization time. Particle
`size is also affected by the physical characteristics of the
`drug solution, such as surface tension and viscosity”:2
`lless et al found that the MMAD produced by I? ttchtt-
`Iizers differed significantly (see Fig. 48).” and the per-
`
`1260
`
`Thismaterialwasfiestttttarottv Cato; 0 NOVEMBER 2002 V01, 47 No I
`atthe NLM 3rd may be
`Subject: US Copyright Laws
`
`l
`
`WATSON LABORATORIES v. UNITED TH ERAPEUTICS, |PR2017—0162‘l
`
`UNITED THERAPEUTICS, EX. 2044
`
`Page 4 of 24
`
`

`

`Drasrotsl PRINCIPLES or LIQUID Nerturam'rron Dravrcr-s CURREN'I'LY IN USE
`
`trliver systems (Acorn. Acorn plus Mizer. Ventstrcam. and
`am LC) and fotrnd significant differences in the delivery
`of albtttet'ol to inspirator‘y tillers. ranging from 9.35% to
`l‘)% of tltc nominal dose?“ Barry et al compared outputs
`of a oehulired corticosteroid thudesonidc) from the Vent-
`stream. the lari LC Plus. and tlte l’ari LC Star. rising tlte
`compressors specified for each. The nebuliacrs differed in
`hell] the rate of otttpul (13—145 ugt'min] and the total
`output of drug collected on irtspiralory litters {32.3—‘)l.‘)
`lug). using simulated conditions of breathing?"
`The physical properties of the power-gas and the solit-
`tion to he nebulixed also affect uebulirer output. Substi-
`tuting helios for air decreased particle size and inhaled
`drug mass significantly. using albuterol.” Nebulired al-
`buterol a 'ailability was greater from a solution containing,
`the preservative benmlkoniunt chloride. becatrse of the
`lower surface tension produced by the preservative (35.0 i
`[1.5 millinewtons per meter with preservative vs 'lt).5 : 0.5
`nrillinewtotts per rrteter without)? The foaming seen with
`the lower surface tension from the preservative resulted in
`tnore return of liquid to the reservoir and a snraller dead
`volume than with the preservative-free solution. with which
`large droplets adhered to the nebulizer walls and increasctl
`the dead volume. Coates et al also found that nebuliver
`
`output of aerosolived tohrarnyciu was greater with the ad—
`ditiouot'albutero] containinghenzalltouiurnchloride. which
`lowered the sttrface tension?"
`
`Advantages and Disadvantages ol'.let Nehulizers
`
`lists the advantages and disadvantages ofsmall-
`Table 1
`voltrrne jet nehtrlizers. Chief among the advantages is tlte
`
`Advantages and Disadvantages of Small—Volume Jet
`Table l.
`tl’nerrrnalie: Nebulixers
`
`Atlmtrtrrgca'
`'
`l‘atient lizard-breathing emirdination not required
`IEI'I'ective when used with normal tidal breathing patterns. with no
`hrealh-Itold
`Effective with low inspiralory flows or volumes
`Ability to acrosolire many drugI solutions
`Ability to acrosolize drug mixtures (3’
`| drug}. assuming suitable
`testing of drug activity
`' Drug crutccntrations cart he modified and high doses are port-tilde
`“twirlt'rrtttrtgr'x
`- Expense of equipment
`liqoipment is cumbersome attd lacks portabiiity
`Treatment tunes are lengthy and include set-up and cleaning time
`Variability in performance characteristics
`Possible patient auto-contaminalion with inadequate cleaning
`Wet. cold spray is produced. which is unpleasant with face-mask
`delivery
`Need for an external power source teleelricity Illlllllflr compressed
`gas}
`
`tidal breathing pattern used. Complex breathing
`simple.
`maneuvers or coordination of breathing with device func-
`tion is not needed. Drug delivery to the airt 'ay is over a
`period of rnirttttes. with [10—90 breaths, rather than depen-
`dent on | or 2 carefully tinted inspirations with particular
`flow rates, as with a tneteretl‘tlose inhaler (MDI) or dry
`powder inhaler tDPI). A second major advantage is the
`ability to nebulize various solutions arid to modify solution
`concentration artd thereby the amottnt of drug delivered.
`Many of the drugs currently used in the United States for
`inhalation treatment ofpulmonary disease are available as
`ttchtllizel‘ solutions. and some of these drugs, strclt as dor—
`nase alfa (Puln‘rozyme) and inhaled tobr‘atnycin (TOBI)
`are only available In solution form for nebulixation. In the
`United States the use of ncbulirers in home therapy is paid
`for by Medicare. whereas other inhaled drug formulations
`such as MDI and DP] are not. since drug therapy for
`nonhospitalized patients is not generally covered by Medi—
`care at
`this time. This provides an additional economic
`advantage to nebulizcd drug therapy for a certain sector of
`patients.
`The chiefdisadvantages of small-volume jet nebulizers
`are the size of the equipment (which requires a power
`source]. the inconvenicntly long treatment time. and the
`equipment set-up antl cleaning. In addition to the lack of
`portability and slow dosing. disposable jet nebulizers vary
`in performance among samples of the satire brand and
`among different brands. Ilollie et al showed both intmncbu—
`litter arid intcrnebulizer variability in output and respira-
`bte-range output
`(the “fine particle fraction") for the
`IJcVilbiss 6-16 jet nebtrliaer.27 Alvine et at examined 8
`disposable jet nebttlixer models. from o manufacturers,
`and fottnd that 4 of the 8 models showed visual signs of
`malfunction. which included spraying of large. visible drop-
`lets. leakirtg of solution. and air leaks that prevented ttebuli-
`ration completely. Variability of the nebtrlimtiou rate within
`a specific model ranged from 57% to |39%.3’* The studies by
`llollie el al and Alvinc et al attribttted the lack of reliability
`in performance to poor quality control by manufacturers.
`
`Design Variations in Traditional .let Nebuliaers
`
`Although the basic design ofjct nebulizcrs has remained
`the satire over the last 40—50 years. within the last It) years
`there have been modifications aimed at reducing device
`loss and exhaled toss and improving drug availability to
`the patient. These modifications are in current clinical use.
`although newer developments in nebttlization of liquids
`are also occurring. Investigational developments are not
`reviewed herein.
`
`Dennis conceptualized 3 categories ofjet nebulizer: con-
`stant-output. breatlr-enhanecd. anti dosimetrie.” Figure (1
`
`Rnsr‘rrtarortv Cara; - Novrsrsuuart 2002 Vor. 47rbtarsttriamascapied
`at: the NLM are! may be
`Subject US Copwight Laws
`
`126]
`
`WATSON LABORATORIES V- UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX. 2044
`
`Page 5 of 24
`
`

`

`Dt-LsniN PRINCIPLE-IS or LIQUID Ntzntrtizn'rtoa Dcvtcns Ctrtzsr;.v‘t't.‘r IN Usr:
`
`
`Inspiration
`Expiration
`
`
`6 “ length tubing
`To patient
`
`Output
`
`4. Power gas
`CONSTANT OUTPUT
`
`Mouth Piece
`
`Output
`
`Off
`
`On
`
`Exhale
`
`\_
`—> Patient
`
`
`
`
`4-Power Gas
`
`Output
`
`
`
`
`
`
`
`BREATH ENHANCED (OPEN VFNT}
`
`
`Inspiration
`
`
`[Expiration
`
`Inspiration
`
`[Expiration
`
`DOSIMETRIC (BREATH ACTUATED)
`
`Fig. 6. Jet nebulizer designs. Aerosol generation and delivery are shown for inspiration and expiration. for each type of jet nebulizer:
`constant—output, breath—enhanced (operhvent). and dosimetric. [Partially based on an illustration lrom Reference 13.}
`
`types of nebulircr and
`shows the basic designs of the Cl
`theiraerosol production in relation to the respiratory cycle.
`In a constant-output device. aerosol
`is produced and
`released constantly. during inspiration and expiration. so
`aerosol can he lost to the environment whenever inhalation
`is not occurring, An example is the traditional JIL'I‘Illli'fCl'
`with a mouthpiece connected to a 'I‘—piece on the ncliulirer
`cttp. such as the Allegiance Air-lite Misty-Net).
`A breath-enhanced Iiebulizcr routes inhaled flow through
`the nehnlizer. using a one—way inspiratory valve. thereby
`increasing the number of aerosol particles in the inspired
`volume. Daring exhalation the inspiratory valve closes and
`aerosol is somewhat contained in the nehuliaer. although
`
`aerosol generation continues and there is exhaled loss.
`This design has been referred to as "open vent. hreatli
`assistcti."-‘ [Example IIICIlltIt: the Ventstrcam and the l’ari
`LC I’Ius.
`
`A dosimclric nehulixcr releases aerosol only during the
`inhalation cycle.” This can he achieved lay generating
`aerosol only during inspiration, using a manual interrupter
`for the power-gas [as in the l’ari LI.) or a spring-loaded
`valve (as in the Acroliclipse) or by containing all aerosol
`in the device. with no release during expiration (as with
`the Circtilaire). Classifying the Circulaire as a dosimetric
`device could he questioned because the device nebulires
`continuously, but by providing a system ol‘ aerosol storage
`
`1262
`
`rm:mntmalwssflmnitm'roav CARE 0 Novrisaasa 2002 Vol. 47 No 1]
`attire NLM and may he
`Subject USCopyi-igh'. Laws
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-O1621
`
`UNITED THERAPEUTICS, EX. 2044
`
`Page 6 of 24
`
`

`

`DESIGN PRINCIPLES m: LIQUID NEBULIZATION DEVICES CURRENTLY IN USP.
`
`Table '2. Aernxui Output and Dispnsiiiun I'rnm Icl Nehuiizem’I‘
`
`Rcl'crenec nr
`. nuru.
`”I‘ntul Inhaled
`Lung
`O-I‘I'htunmch
`Device
`Exhaled
`Methods
`q
`..
`
`Cnnstttnt Output
`
`Tnlnl Salute ($12]
`
`14 {5. I)
`-
`0.359.714}
`11855.45]
`
`12.4-01.5)
`3.60.6}
`—
`—
`
`1.5 (0.9]
`51'! [3.3)
`—
`i
`
`65.3 {II-(1)
`3'? [9]
`54.5 “8.21
`55.? [Ill] plus
`'11.? (5.5] in Mixer
`
`19.? [3.9)
`31.56.81
`—-
`——
`
`Ratliuiul‘tcl
`RIItIIuIIIIIc]
`Insp filler
`[nx‘p tiller
`
`2‘}
`3t]
`23
`3]
`
`15.3
`22.2
`”L3
`321! tilti)
`
`31
`CIICIII 1FdCtlr
`35-4
`59-3
`NA
`123T
`3|
`Chem tracer
`2.2.3
`55.5
`NA
`13.41
`[(1.61
`NA
`(12.3
`18.9
`Chem tracer
`3|
`
`l5.2 [mm
`NA
`NA
`—
`Spectmphut
`32
`
`[Iruttlll Enhanced
`
`
`in Vim
`
`Mitti-NL‘I‘I (II Utttill]
`Miny-Nch [7 Umin}
`Atom [(3 IJIniII]
`AcmnIMILer {t1 Uminl
`
`In Vilru
`SIlIL‘bII‘L‘JlIII. I‘urttuleh
`Hutlmn, I’IIIIIInAitle
`Cirrus. I’IIIIIIIIAitle
`Aern’I'ee tt’I IJIIIiIIl
`
`In Vivu
`
`I’ttri LC. I’uriiitly
`I’ttri1.C Slur. I’mnch Turbo
`Puri 1542 tuwu L‘mupressnrl
`It] Vilm
`
`—
`—-
`—
`
`12.1103}
`11.1 (1.?)
`17.1 [8.36)
`
`142 (13)
`13.11111)
`NA
`
`56.3 (13.”
`55.! (3.4}
`NA
`
`16.2 (2.?)
`20.0 {1.21
`NA
`
`Radiolnhc]
`Rudiohtbei
`Rildifiiilhtl
`
`33
`34
`35
`
`I’ari [.C Plus. I’urI'IItIy
`l’uri I52. I’nri Muster
`Venthtreum. CR 50
`I'uri [.L‘. Inhalt‘rlin}.I
`Venlstrettm [It ”mint
`Part LC I‘IIIN. Turhnliny
`Ventslrcnm. l‘nrlanch
`I’uri LC Slur. 'I'urlufliny
`
`31
`Chem {meet
`ItI.'I'
`6-1.]
`—
`Illl‘i
`25.2
`31
`Chem truecr
`15.9
`44.?
`—
`334+
`30.4
`3i
`Chem tracer
`4.3
`70.9
`—
`1101'
`24.3
`23
`Ittsp filter
`—
`519(14]
`—
`NA
`19112633)
`23.
`Inst: IIIIt'r
`—
`563(115)
`—
`NA
`”-2 (6.83]
`’14
`Imp litter
`—-
`——
`—
`15.51:
`22.2 (LII)
`'JII (2.4]
`8.35:
`-—
`—-
`—-
`Imp tilter
`2.1.
`
`EILIII {11.4)
`lifti
`—
`—
`—-
`Insp filler
`2-1
`
`[)usimetric
`
`
`In Vivn
`
`Cireuhtirc [7 [.IIIIIIIII
`I‘ilri I.I.. I’uri
`I‘lny
`III Vitru
`Circuiaire t (1 limit”
`AeInI-chipxe [ti Uminl
`At'rnIEL-Iirnc (II ”mini
`
`—
`—
`
`12.85.11
`II.I I411}
`
`1.1 (0.5}
`I156.”
`
`3301'
`«Imam
`
`13.99.81
`13-20.“)
`
`Rntiiuluhci
`Radiolubct
`
`3t]
`33
`
`12.8 ttl.-l)
`fitlfi
`38.? £1.34}
`
`3.210.411
`41.2
`34.” [L251
`
`—
`9.!1teuicuiuted]
`-—
`
`—
`4M tcnicuialctll
`5|.llt2.|]
`
`—-
`3-1
`(1.68.1)
`
`32
`SpecImphnt
`Filler. “I’LC Manufacturer
`Spurtruphm
`Ari el
`til.
`EIK12§
`
`In mmn' in win. Mimic: II» lung. lllN' n- u tilI 'IIIIIIcII :unuunt hnml nn the particle sin- drumming" Ur th‘ 3mm"
`'Ji't Ik'hulin'n i-. l NIL-gqu [UII‘ILI'I‘ uulpIIl. I‘IIL'ilIII enlmm‘ml .‘uIII IIuhiIIK‘IIiC.
`
`I‘INIHCL‘II a-nl tin:
`llll'|I inlmlul man. 1|..- |Ill‘lIIlilI\ rnlumn IlilIIl'jl‘C'I Ilu- pmmry “than 01' :lIug enllcn-Iinn :Iml Int-autumn
`.
`chemical Irm'cr. Sven-null“ — LpL-u-tnIIIEuunIlerir. ILInliuluhei —‘ rmlinl.tht.'|I.-Il.
`I! I' — IntgllI.IIyIIgI-:Il. Imp liltcr --
`|!1\|'|lFiI|U')t I'llrt'r L'I’II‘1'II!‘I'I.(.III'III"all?! -=
`”lid“ ’ 5 put
`tMms I'. 0.1 “III
`II!‘1.(' : tug-II p\'l[0ITII.IIIL\’ IIquid (Itnltmlllymley
`§UII|||IIII|\11ct'. il:.t;|. Ali l'l .II. Iii-tight .‘ilatt' Illnu'nity. 1m}.
`
`
`
`between breaths. aerosol is released nuly during iIIIIuIII-
`titan, which is the defining feature of :1 [Insimctric device.13
`Table 2 summarizes studies of aerosol output and dispo-
`sititm t‘or constant-output. open-vent breath-enhanced. :uItl
`dusimctric IchtIIimI-s.
`
`Cunstant-Oulput Designs.
`Most dispusuble Ismail-v01-
`umcjcl nebulizcrs typify this functional category. Figure 7
`sltuws data from :1 study by Lewis and Fleming on drug
`disposition with :1 ConsttInt-uutput
`IICbLIIIZCI‘, along with
`cmnpnrisun data from an NIDI.2"'-"‘ That study found that
`
`RESPIRATORY CARI-2 o NOVIEMIlE-ZR 2002 VOL 4Wuafiialmsmiad
`51th: NLM ard may I}!
`Subject US Copyright Laws
`
`1263
`
`WATSON LABORATORIES V- UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX. 2044
`
`Page 7 of 24
`
`
`l"_..,_._.-._._i..__._.___._....
`
`,.._..__
`
`

`

`0 Exhaled
`Storage Bag
`
`B
`
`Patient
`i
`
`Arousal
`
`Exhalatlon port
`IL.__
`—I- Patient
`
`T-plece
`——-—%*
`Patient 4—-
`..
`1-wayI I“! I
`[Inspiramryi
`
`A
`
`Mlzer
`
`{expiratory}
`1-way
`
`Hemispherical
`Deflector
`
`
`
`
`Acorn
`"‘ Nebulizer
`
`4- Power Gas
`
`DESIGN PRINCIPLES or LIQUtn Ntsnurtza’rton Dmcas CURRENTLY IN Usts
`
`100
`
`90
`
`__— 80
`5 " length tuhing
`To patient +
`
`T0
`
`80
`
`50
`
`40
`
`30
`
`20'
`
`1 0
`
`Capillary
`louder
`
`tube
`
`Drug
`- solution
`
`Power gas
`[flow meter,
`
`comprnssor]
`
`Fig. T. Disposition of total drug dose with a constant-output jet nebulizer (MiniNeb) versus a metered-dose inhaler {MIDI}. O-P = oropha‘
`ryngeal. SUN = Small-VOIUI’TIB nebutizer. {Modified from Relerence 29.)
`
`SVN
`
`MD]
`
`Negative
`pressure —
`area
`
`
`
`
`... Power Gas
`
`4- Power Gas
`
`Fig. 8‘ Three examples of constant—output nebulizers. A. Acorn with Mizer reservoir chamber attached. B. Slde
`air entrainment by nebulizer venturi effect. C. AeroTee with aerosol storage bag.
`
`stream with open vent for
`
`12% ofthc nominal dost: reached the lungs. with 2% to the
`mouth and stomach. 66% left in the apparatus. and ’lU‘i’r-
`exhaled?" Combining tlte I296 delivered to the lungs with
`the 2% lost to the (‘irUplltIl‘yilx and stomach gives a total
`inhaled amount of 14% of the total dose. The dcad~vo|ttme
`
`loss of 66% agrees well with the data ol‘ Kratljan and
`Lakshtninarayatt. who found that -’l l 416% of the total dose
`stayed in the nebulizcl' untler simulated clinical condi—
`lions}K Constant-output ttcbttlizcrs have been criticized as
`
`more inefficient than other aerosol delivery tncthods such
`as the MDl. because of the amount of drug lull
`in the
`
`apparatus and exhaled. The traditional jcl ttchttlizcr is I10
`more incl‘l‘icicut itt delivery of aerosol drug to the airways
`tltatt other lratlitional aerosol devices. The patlcrn of loss.
`however. tlil'l’ers among jct nchuliaers. MDls. and Dl‘ls.
`The sizable traction lost to the ttcbulirer apparatus is bal-
`anced by the (10—80% ot‘opharyngual and stomach thPU'
`sition with an MDI or the apparatus and oropharyngeal
`deposition with a I)l’l.-“"--” A convincing study by Zainu-
`tlin et al showed that only about
`IU% of aerosolixcd albu-
`tcrol reaches the lung. regardless of whether a nebulizcr.
`MDI. or DH is ttst:tJ.-‘T though that finding might not apply
`
`[264
`
`to;materratwasl-‘ttaaatta'rortv Came c NOVEMBER 2002 V01- 47 No II
`atthe NLM arcl maybe
`Subject L'S Copyright Laws
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR201?—01621
`
`UNITED THERAPEUTICS, EX. 2044
`
`Page 8 of 24
`
`

`

`DizsioN Prostitutes or: LIQUID Niiituumriou Devices CURRENTLY IN USE
`
`Inspiration
`
`Exhale
`Valve
`
`1-way
`valve
`
`Mouth Piece \
`
`
`
`Power Gas -D-
`
`
`
`1-way
`(expiratory)
`
`1-way
`(inhaled)
`
`Patientw- T-pteee
`
`
`
`
`Fig. 9. Two examples of breath-enhanced. open-vent nebulizers. Left: Par] LC Plus. Right: Ventstream.
`
`to newer aerosol devices. some of which are discussed
`elsewhere in the conference proceedings in this and the
`
`following issue of RF—ZSI’iItATORt‘ Cain-z.
`The loss ol‘ aerosol from the 'I‘-piece of a co