Efficient Delivery to the Lungs of Flunisolide Aerosol from a New Portable
`Hand-Held Multidose Nebulizer
`
`Received December 22, 1995, from the “Pharmaceutical Profiles Lid., 2 Faraday Building, Highfields Science Park, University Boulevard,
`Nottingham NG7 2QP, U.K., *Boehringer Ingelheim Ltd., Ellesfield Avenue, Bracknell, Berkshire, RG12 8YS, U.K., and *Boehringer
`Accepted for publication June 18, 1996®.
`Ingelheim KG, D-55216, Ingelheim, Germany.
`
`
`S. P. Newman**, K. P. Steep*, S. J. REApert, G. Hooper’, anp B. ZIERENBERG?
`
`PUMP
`
`Abstract 0 In order to provide asthmatic patients with an inhaler that
`does not use chlorofluorocarbon propellants, a novel multidose hand-
`held nebulizer
`(RESPIMAT, Boehringer
`Ingelheim Ltd.) has been
`developed. This device delivers 200 x 15 wL metered doses of drug
`solution, but does not use propellants of any kind.
`In this study of 10
`healthy volunteers, the deposition pattern in the lungs and oropharynx of
`an ethanolic solution of flunisolide delivered via a prototypeIII multidose
`nebulizer has been determined by y scintigraphy. A comparison was
`made with the same dose (250 wg) of
`flunisolide delivered by a
`pressurized metered dose inhaler (MDI) and MDI plus Inhacort spacer.
`Mean (SD) whole lung deposition from the multidose nebulizer (39.7 (9.9)
`% of the metered dose) wassignificantly higher than that from either
`MDI (15.3 (5.1) %, P < 0.01) or MDI plus spacer (28.0 (7.0) %, P =
`0.01). A mean 10.4% of the dose was recovered from an exhaledair
`filter for the multidose nebulizer, but less than 2% of the dose for MDI or
`MDI plus spacer. Oropharyngeal deposition was significantly reduced
`for the multidose nebulizer (39.9 (9.4) %) compared to MDI (66.9 (7.1)
`%), but was reduced further for the MDI plus spacer (27.3 (11.3) %).
`The multidose nebulizer delivers an unusually high percentage of an
`aerosol dose to the lungs, andit “targets” flunisolide to the lungs more
`effectively than the MDI. The multidose nebulizer could constitute a viable
`alternative to MDls in asthma maintenance therapy.
`
`
`
`
`
`
`
`
`
`NOZZLE
`
`
`rc
`|
`SOLUTION
`RESERVOIR | JL
`
`
`
`MOUTHPIECE
`
`DOSE RELEASE ———~
`HANDLE
`
`Figure 1—Prototype III multidose hand-held nebulizer.
`
`Multidose Nebulizer
`
`dose nebulizer against an MDI containing a suspension
`micronized drug since the latter is the formulation current
`marketed.
`
`
`
`
`
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`
`Introduction
`
`Efficient aerosol inhalers are required for delivering asthma
`medications to the lungs. The pressurized metered dose
`inhaler (MDI) has been the cornerstone of asthma mainte-
`nance therapy for several decades, but delivers only a small
`percentage of the drug dose directly into the lungs, with the
`majority of the dose being deposited in the oropharynx.!~3 The
`MDI thus confers poor selectivity of drug deposition, which
`may increase the incidence of both local and systemic side
`effects for high dose inhaled corticosteroids.* The use of a
`spacer attachment to the MDI may reducethe incidence of
`these side effects.>® The MDI uses chlorofluorocarbon (CFC)
`propellants, the production and import of which have been
`banned in many countries because of their contribution to
`ozone depletion.’
`In order to overcome these limitations of
`the pressurized MDI, a novel concept in inhalation therapy
`that operates without the need for propellants, a hand-held
`multidose nebulizer (RESPIMAT, Boehringer Ingelheim Ltd.),
`has been developed.
`(The RESPIMAT device was formerly
`known as the BINEB.)
`In this scintigraphic study, we have
`compared in a group of healthy volunteers the deposition
`patterns of the corticosteroid flunisolide (Inhacort, Boehringer
`Ingelheim Ltd.) delivered by a prototype III multidose nebu-
`lizer as an ethanol-based solution, by pressurized MDI, and
`by MDI plus spacer device. We chose to compare the multi-
`
`
`® Abstract published in Advance ACS Abstracts, August 1, 1996.
`
`(Figure 1) comprises a fluigé
`The multidose nebulizer
`reservoir of volume 3.5 mL, from which individual metereé:
`doses of 15 wL are delivered. Whenthe base of the device i5
`rotated through 180°, a spring is compressed, and the energy:
`required for the nebulization process is stored. Simulta.
`neously, fluid is pumped into a dosing chamber, and whee
`the dose release handle is operated, decompression of thé
`spring forces the fluid through a fine nozzle in the mouthpiec
`The nozzle contains channels of approximate diameter 8 u
`
`in a silicone wafer, together with a filter system to prevert
`clogging.
`The spray produced has a mass median diameter of <6 uth
`and an initial droplet velocity of approximately 10 m s-§
`which are markedly less than the size and velocity of droplets
`emerging from a pressurized aerosol canister. This systerd
`differs from a conventional unit-dose nebulizer since ig
`contains over 200 metered doses, delivers a dose in about 1.2
`s, and offers levels of compactness, portability, and convert
`ience comparable to those of a pressurized MDI.
`In this studY
`the multidose nebulizer was used to deliver doses of 250 ug
`of flunisolide in a 96% solution of ethanol, without the addition
`of preservatives or any other excipients. The relative standard
`deviation of the delivered dose for a 96% ethanol solution is
`less than 5%.8
`
`Experimental Section
`Subjects—Ten healthy nonsmoking volunteers (6 male, 4 female;
`age range 19—28 years) took part in a randomized three-way crossover
`study to assess the deposition patterns of flunisolide. Their forced
`
`960 / Journal of Pharmaceutical Sciences
`Vol. 85, No. 9, September 1996
`
`$0022-3549(95)00522-3 CCC: $12.00
`
`© 1996, American Chemical Society and
`American Pharmaceutical Association
`
`IPR2021-00406
`United Therapeutics EX2081
`
`IPR2021-00406
`United Therapeutics EX2081
`
`

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`Figure 2—Radiolabeling validation data. Distribution of “unlabeled”drug, “labeleg?
`drug, and radiolabel amongdifferent particle size bandsfor(a) (top) pressurizeg:
`MDI and (b) (bottom) multidose nebulizer. Locations in impinger asfollows: A
`= actuator; MP = nebulizer mouthpiece; T = throat; S14 = stages 1-4; F =
`final filter. All data are expressed as mean (SD)offive replicates from differen
`inhalers.
`:
`
`On onestudy daya posterior lung ventilation scan was performed
`using the radioactive inert gas 8!™Kr. The lung outlines from th
`81mK r ventilation scan were used to define the edgesof the lung fields
`on the aerosol views, and the lungs were subdivided into centraf,
`intermediate, and peripheral zones, representing approximately larg¢,
`medium, and small airways, respectively. The peripheral lung zone}
`central lung zone ratio (penetration index) wascalculated.
`gs
`FEVi, forced vital capacity (FVC), and peak expiratory flow rate
`(PEFR) were recorded on each study daybefore inhalation, and the
`15, 30, and 60 min postdose by Vitalograph Compact Spirometeg
`(Vitalograph, Buckingham, U.K.).
`&
`Statistical Tests—The Wilcoxon matched-pairs signed ranks test
`was used to assess the significance of the differences between th¢
`deposition patterns for the three devices. A P value of <0.05 was
`considered statistically significant.
`
`lépIogjouAjo
`
`Results
`
`In Vitro Radiolabeling Data—The distributions of unla-
`beled drug, labeled drug, and radiolabel from MDIs delivering
`flunisolide are shown in Figure 2a. Mean respirable fractions
`for these three quantities were 25.8%, 27.8%, and 25.8%,
`respectively. Data are also shown in Figure 2b for the
`multidose nebulizer. The agreement between distributions
`
`Journal of Pharmaceutical Sciences / 961
`Vol. 85, No. 9, September 1996
`
`expiratory volumes in 1s (FEV1) ranged from 92 to 114% predicted.°
`Each subject underwent a medical examination before entering the
`study to ensure that they were healthy and gave written informed
`consent to taking part. The Quorn Research Review Committee,
`Leicestershire, U.K., approved the study protocol, and permission to
`administer radioactive aerosols was granted by the Departmentof
`Health, London. The study was performed in accordance with the
`Declaration of Helsinki.
`Radiolabeling—Theaerosol formulations were radiolabeled by the
`addition of the radionuclide 99"Tc, such that each metered dose
`delivered not only 250 xg of flunisolide but also 10 MBq of 9™Tc.,
`Pressurized MDIs were radiolabeled using a previously described
`technique,?%" by which 99"Tc was placed in an empty canister and
`evaporated to dryness, following which the contentsofa filled canister
`were added at below —60 °C and a valve was crimped in place.
`In
`order to radiolabel the contents of the multidose nebulizer, 9°"Tc as
`sodium pertechnetate was extracted into butanone, which was then
`evaporated to dryness before addition of 3.5 mL offlunisolide solution.
`Theflunisolide and radiolabel were mixed for 10 min by an ultrasonic
`shaker before being transferred to the reservoir of a multidose
`nebulizer. Both MDI and multidose nebulizer were primed before
`use until a constant plume of spray was emitted per metered dose,
`and the multidose nebulizer was weighed during the priming proce-
`dure to ensure that a constant dose weight was released.
`The radiolabeling methods were validated by examination of
`particle size distributions in a high-precision multistage liquid
`impinger (HPMLI, Copley Instruments, U.K.) operated at a flow rate
`of 60L/min.12. The size distribution of drug to which no radiolabel
`had been added (“unlabeled” drug) was compared with that of
`“labeled” drug from inhalers containing 99™Tc, and with that of the
`radiolabel itself. The HPMLI consisted of a 90° inlet (throat) and
`four impaction stages. The impinger stages were washed with
`ethanol, and the washings were assayed for drug content(either by
`HPLC at Boehringer Ingelheim, Germany, or by UV spectrophotom-
`etry at Pharmaceutical Profiles Ltd.) and for radioactive content by
`scanning with a y camera (General Electric Maxi camera). The
`“respirable fraction" was determined as the amount of drug or
`radiolabel penetrating to stages 3 and 4 of the HPMLI expressed as
`a percentage of total recovery. Stage 3 collected droplets between
`3.1 and 6.8 um, while stage 4 collected droplets of <3.1 um diameter.
`Clinical Procedures—Each volunteer received a single dose (250
`ug) of flunisolide on each of three randomized study days involving
`(a) a prototype II1 multidose nebulizer equipped with a C16a nozzle,
`(b) a pressurized metered dose inhaler (MDI), and (c) an MDI coupled
`to an Inhacort spacer device (volume 250 mL). The same inhalation
`maneuvre wasusedfor each device, and this maneuvre waspracticed,
`prior to administration of the radiolabeled aerosol, using a placebo
`MDI or a placebo multidose nebulizer until it could be performed
`reproducibly. Subjects were taught to inhale slowly and deeply and,
`after a 10 s breath-holding pause, to exhale through a filter in order
`to trap any aerosol particles in the expired air. The device was fired
`by the investigator approximately 1s after the subject began to inhale.
`Subjects wore a nose clip wheninhaling from the multidose nebulizer,
`to ensure that very small ethanol droplets were notlost via the nose.
`The inhalation maneuvre was recorded by a respiratory inductance
`plethysmograph(Respitrace, PK Morgan Ltd., U.K.) from which the
`average inhaled flow rate, inhaled volume, duration of inhalation,
`and breath-holding pause could be calculated.
`Immediately following inhalation of the radioaerosol, posterior and
`anterior images of the chest (each 100 s) were taken by General
`Electric Maxi camera coupled to a Bartec Micas V data processing
`system. These images were followed by a lateral
`image of the
`oropharynx (30 s), and by further images of the abdomenif any of
`the radioactivity had spread beyond the field of view in the chest
`images. The MDI actuator, the nebulizer mouthpiece (detached from
`the nebulizer), the spacer device, and the exhaled air filter were
`imaged.
`In order to ensure that all the radioactivity released from
`the nozzle was counted, the nozzle was wiped after use with a swab,
`and the counts of the wipings were added to those of the multidose
`nebulizer mouthpiece. Counts were corrected for background radio-
`activity and, where appropriate, decay and attenuation of y-rays by
`tissue.‘?_ The geometric mean of anterior and posterior lung and
`abdomen counts wascalculated. !4 In this way, the metered dose was
`fractionated between amountsinitially deposited in the lungs,
`deposited in the oropharynx,retained on the actuator/mouthpiece and
`spacer, and recovered from the exhaled air filter.
`
`€
`

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`0907S
`Scintigraphic Data—The fractionation of the dose be
`tween lungs, oropharynx, apparatus, and exhaled air is show&
`in Table 1, and typical scans for each device are shown iff
`Figure 3. Mean (SD) whole lung deposition was 39.7 (9.9) %
`of the metered dose for the multidose nebulizer, compared t
`15.3 (5.1) % for the MDI (P < 0.01) and 28.0 (7.0) % for thé
`28.0 (7.0)
`Lungs (%)
`27.3 (11.3)
`Oropharynx (%)
`MDI plus spacer (P = 0.01). Lung deposition for the MDI plug
`16.0 (2.2)
`Mouthpiece/actuator(%)#
`spacer was also significantly (P < 0.01) higher than that for
`27.9 (9.3)
`Spacer(%)
`the MDI alone. Depositions in eachof the central, intermedé
`
`
`Exhaledair (%) 10.4(4.9)—1.4(1.3) 0.8 (0.4)
`ate, and peripheral lung zones followed the same rank ordeg
`Central lung zone (%)
`10.7(2.5)
`4.5 (1.8)
`8.6 (2.1)
`as that for whole lung deposition (Table 1), although the
`Intermediate lung zone (%)
`14.9(3.6)
` 5.4(1.9)
`10.3 (2.5)
`peripheral lung zone/central lung zone deposition ratio aver=
`Peripheral lung zone (%)
`14.1 (4.3)
` 5.4(1.4)
`9.1 (3.0)
`aged less for the MDI plus spacer than for either MDI
`o£
`Of:
`
`Peripheral zone/central zone ratio 1.08 (0.27) 1.31 (0.22) 1.28 (0.23)
`multidose nebulizer, and this difference was significant (P
`
`
`32
`0.02) in comparison with the multidose nebulizer.
`é
`Oropharyngeal deposition (Table 1) was highest for the MDi
`(mean 66.9%) and was lowest for the MDI plus spacer (meag
`27.3%, P <0.01). The multidose nebulizer gave an orophay
`ryngeal deposition (mean 39.9%) significantly higher thag
`MDI plus spacer (P = 0.02), but significantly (P < 0.01) lowég
`than the MDI.
`z
`A mean 10.4% of the dose was recovered from the exhaled
`air filter for the multidose nebulizer, compared with means,
`of only 1.4% and 0.8% of the dose for MDI and for MDI plus
`spacer,
`respectively. A mean of 27.9% of the dose wa§
`deposited on the walls of the spacer. The remainder of thg
`dose not accounted for elsewhere was retained on the mouth
`piece or actuator.
`
`Table 1—Mean(SD) Percentages of the Metered Dose Located at Various
`Sites, and Distribution Pattern within the Lungs for Studies with
`Multidose Nebulizer, MDI, and MDI Plus Spacer
`
`
` Deposition Site Nebulizer MDI MDI + Spacer
`
`
`
`
`
`39.7 (9.9)
`39.9 (9.4)
`10.0(7.8)
`
`15.3 (6.1)
`66.9 (7.1)
`16.4 (3.8)
`
`4 Includes wipings of nebulizer nozzle.
`
`for the
`labeled drug, and radiolabel
`of unlabeled drug,
`multidose nebulizer was less precise than for the MDI, and
`the respirable fractions for these three quantities were 54.5%,
`57.8%, and 65.1%, respectively. Since both drug and radio-
`label were in solution,
`it was anticipated that they were
`distributed uniformly through different size bands according
`to droplet volume. However, for logistic reasons it was not
`possible to use the same nozzle throughout these jn vitro
`experiments, and the differences between drug and radiolabel
`size distributions were ascribed mainly to internozzle varia-
`tions. The radiolabeling validation data were considered
`adequate to perform a scintigraphic study.
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`Figure 3—Typical scansin oneindividual from (a) multidose nebulizer, (b) pressurized MDI, and (c) MDI with spacer. The distribution of aerosol on the walls of the
`spacer is shownin scan c.
`
`962 / Journal of Pharmaceutical Sciences
`Vol. 85, No. 9, September 1996
`
`

`

`
`
`
`
` Parameter Nebulizer MDI MDI+ Spacer
`
`Table 2—Mean(SD)Details of Inhalation Maneuvres and Changesin
`FEV, for Studies with Multidose Nebulizer, MDI, and MDI Plus Spacer
`
`Inhaled flow rate (L/min)
`18.8 (12.2)
`26.7 (14.6)
`32.3 (15.0)
`Inhaled volume(L)
`1.24 (0.53)
`1.96 (0.70)
`2.00 (0.71)
`Duration ofinhalation (s)
`5.0 (2.0)
`4.9 (1.5)
`4.1 (1.6)
`Breath-holding pause (s)
`9.2 (0.7)
`9.4 (0.9)
`9.8 (0.9)
`FEV , predosing(L)
`4.60 (0.75)
`4.54 (0.84)
`4.45 (0.81)
`FEV;15 min postdosing (L)
` 4.66(0.83)
`4.81 (1.03)
`4.55 (0.75)
`FEV +30 min postdosing (L)
` 4.67(0.88)
`4.84 (1.03)
`4.54 (0.80)
`
`4.69(0.84) 5.08 (1.20)FEV ;60 min postdosing (L) 4.62 (0.83)
`
`
`
`Inhalation Details and Lung Function Parameters—
`Parameters of inhalation (Table 2) were similar for MDI
`(mean flow rate 26.7 L/min) and for MDI plus spacer (mean
`32.3 L/min), but when using the multidose nebulizer, subjects
`took slower (mean 18.8 L/min) breaths and inhaled a smaller
`volume of air. There was no evidence of bronchoconstriction
`in any subject following inhalation of flunisolide solution.
`Values of FEV1 (Table 2) and of FVC and PEFR before and
`after inhalation were similar.
`
`Discussion
`
`This study has shown that the multidose nebulizer device
`is able to deliver an unusually high percentage of the metered
`aerosol dose to the lungs of healthy volunteers. This results
`in part from the formulation of drug in an ethanolic solution,
`which evaporates rapidly, leaving many fine droplets in the
`spray, such that over 10% of the metered dose was contained
`in droplets small enough to enter the lungs but to be exhaled
`subsequently. Whole lung deposition values as high as the
`mean value of 39.7% in this study have also been reported
`previously for MDI
`formulations containing a propellant
`soluble radiolabel,>?6 which would also comprise rapidly
`evaporating droplets. When an aqueous solution of fenoterol
`was delivered by the multidose nebulizer, lung deposition of
`>30% of the dose was recorded.!’ However, aqueous and
`ethanolic solutions have different spray characteristics, and
`it
`is necessary to assess the lung deposition of the two
`formulations separately. A mean whole lung deposition value
`exceeding 30% of the dose has also been reported recently for
`terbutaline sulfate pressurized aerosol delivered via a large-
`volume spacer device, 18 although lung deposition measured
`in other studies with pressurized MDIs has generally aver-
`aged <20% of the dose, as described in a recent review. !9
`The data in the present study were obtained in healthy
`volunteers, and lung deposition from the multidose nebulizer
`has not yet been determined in patients. The results of
`previous studies suggest that whole lung deposition values
`from the multidose nebulizer would be similar in asthmatic
`patients, while a reduction in the penetration of aerosol to
`the peripheral lung zone would be expected. 2° The airways
`of patients with obstructive airways disease are narrowed by
`a combination of bronchospasm, edema, and mucus hyperse-
`cretion, making impaction of particles in large central airways
`more likely. An alternative possibility is that whole lung
`deposition from the multidose nebulizer would be higher in
`patients than in healthy volunteers. We recorded 10% of the
`dose in the exhaled air, a figure which is unusually high for
`portable asthma inhalers, and it is possible that the exhaled
`fraction would be reduced in patients with asthma, leading
`to even higher lung deposition.
`Drug delivery from MDIs varies according to the nature of
`the drug formulation,2! but the value obtained in this study
`(mean 15.3%) was comparable with that observed in other
`studies for MDIs delivering similar amounts of drug per
`
`z‘Novozs1
`
`reduced oropharyngeal deposition compared to the MDI,
`
`metered dose, and contained in similar propellant mixtures.
`The increased whole lung deposition from the multidosg
`nebulizer compared with the MDI was also reflected in au,
`increased respirable fraction in the in vitro radiolabeling,
`validation experiments.
`If the multidose nebulizer were te
`double the amountof drug deposited in the lungs of asthmatig
`patients compared to an MDI, then it might prove possible tg
`control asthma with the multidose nebulizer using a smalle¥
`daily dose of flunisolide. This would in turn reduce thé
`amount of drug delivered to the oropharynx, which might
`lower the incidence of local oropharyngeal side effects associg
`ated with topical corticosteroid treatment.> In addition, the
`multidose nebulizer reduced the percentage of
`the dose
`deposited in the oropharynx, which would further decrease
`the potential for oropharyngeal side effects.
`£
`Since the multidose nebulizer enhanced lung deposition ang
`improved the “targeting” of drug to the site of action and would
`be likely to result in an improved therapeutic ratio,i.e., ratig
`of desired effects to side effects for a given administered dos&
`Spacer devices always decrease oropharyngeal depositiog
`compared to an MDI,23 and they may increase drug delivery
`to the lungs, dependent upon the design of the spacer, thé.
`characteristics of the formulation, the inhalation techniqué:
`adopted by the subject, and the extent to which theeffects df
`electrostatic charge on the spacer walls are controlled.24-a
`In this study,
`lung deposition from the spacer was almosk
`double the value obtained from the MDI.
`If the lung deposi
`tion is expressed as a fraction of the total amount of dru
`deposited in the body, then this parameter averaged 0.19 fof
`the MDI, 0.51 for the spacer, and 0.50 for the multidose
`nebulizer. Thus both the multidose nebulizer and space¢
`produce comparable selectivity of lung deposition, althoug&
`the multidose nebulizer is significantly more compact ang
`convenient to use in routine clinical practice.
`It is possibte
`that the absolute amountof oropharyngeal deposition coul
`be reduced by adding a spacer or other attachment to thé
`UeOS
`multidose nebulizer, but this remains to be investigated.
`&
`Volunteers took slower, shallower, inhalations from the
`multidose nebulizer in the present study than from the MDE
`or from the MDI plus spacer; this may have been a result é
`wearing a noseclip for the multidose nebulizer leg of the stud
`or
`it may have been coincidence. We believe that an
`difference in lung deposition resulting from inhaling from the
`multidose nebulizer at ca. 20 L/min and from the other tw
`devices at a ca. 30 L/min would be small, since much large¥
`differences in flow rate (say 30 vs 100 L/min) are normall¥
`required before differences in deposition can be shown.
`There was no evidenceof bronchoconstriction in any voluntedg
`taking part in this study. This effect has been observed ie
`some asthmatic patients inhaling ethanol solutions2® althougb
`for larger volumes of inhaled ethanol compared with thosé
`used in the present study. Pressurized MDIs containin
`ethanol have been in widespread use for manyyears in Norte
`America.
`The multidose nebulizer device tested in this study is nde
`
`the only compact multidose nebulizer system to be described
`recently. Other nebulizers in which the aerosol is generated
`by compressed air??3° or by ultrasonic principles*!~33 have
`been developed, and one of these has been assessed by y
`scintigraphy. A mean 8% of the dose was deposited in the
`lungs from one of these devices when used alone, increasing
`to 13% of the dose when the spray was inhaled via a spacer
`device.?939 Portable multidose nebulizers may thus play an
`important futurerole in inhalation therapy and could consti-
`tute a viable alternative to pressurized metered dose inhalers
`and powder inhalers.
`
`Journal of Pharmaceutical Sciences / 963
`Vol. 85, No. 9, September 1996
`
`

`

`1090751
`. Steed, K. P.; Towse, L.J .; Freund, B.; Newman,S. P. Eur. Respifi
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`. Byron, P.R.J . Biopharm. Sci. 1992, 3, 1-9.
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`OnDuFWNY
`
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`. Newman, S. P.; Clark, AA. R.; Talaee, N.; Clarke, S. W. Thorax
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`. Barnes, P.J .; Pedersen, S.Am. Rev. Respir. Dis. 1993, 148, S1—
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`«| Jennings, B.; Lefcoe, N. M.;
`. Toogood, J. H.; Baskerville, J
`J ohansson, S.-A. Am. Rev. Respir. Dis. 1984, 129, 723-729.
`. Brown, P. H.; Blundell, G.; Greening, A. P.; Crompton, G. K.
`Thorax 1990, 45, 736-739.
`. Newman,S.P. Eur. Respir. J . 1990, 3, 495—497.
`. Zierenberg, B.; Eicher, J .; Dunne, S.; Freund, B. In Proceedings
`of Fifth Respiratory Drug Delivery Conference; Dalby, R. N.,
`Byron, P.R., Farr, S.J., Eds.; Interpharm Press: Buffalo, 1996;
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`. Quanjer, P. H.:; Tammeling, G. J .; Cotes, J. E.; Pedersen, O.F.;
`peel,i Yernault, J.-C. Eur. Respir.. 1993, 6, Supplement
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`. Newman, S. P.; Clark, A. R.; Talaee, N.; Clarke, S. W. /nt. J.
`Pharm. 1991, 74, 203-208
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`. United States Pharmacopeia. Pharm. Forum. 1993, 19, 5463.
`. Fleming, . S. Phys. Med. Biol. 1979, 24, 176—180.
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`Tothill,
`P.; Galt, J. M. Phys. Med. Biol. 1971, 16, 625-634.
`. Ashworth, H. L.; Wilson, C. G.; Sims, E, E.; Wotton, P. K.; Hardy,
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`. Harnor, K.J.; Perkins, A. C.; Wastie, M.; Wilson, C. G.; Sims,
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`964 / Journal of Pharmaceutical Sciences
`Vol. 85, No. 9, September 1996
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