Liquidia's Exhibit 1099
`
`Page 1
`
`Summary
`
`Key words: Ultrasonic nebuliser, Sputum induction; Acquired immunodeficiency syndrome;
`Pneumocystis carinii pneumonia
`Ee
`The DeVilbiss Ultraneb 99 ultrasonic nebuliser is frequently used for sputum induction in AIDS patients undergoing investiga-
`tion of suspected Pneumocystis carinii pneumonia. We set out to characterise this machine under a wide range of operating
`conditions so that theefficiency of the technique might be optimised. The range and frequency of particle sizes remained reasonably
`constant and gave a Gaussian distribution pattem (mean MMD = 5.05 pm, SD=0.34 zm) below a critical volume of nebulised
`solution, this volumebeing related to the intensity setung of the nebuliser. Beyond this volume, the particle size distribution adopted
`abimodal pattern, and nebuliser output subsequently tailed off altogether. The volume ofcouplantwithin the nebuliser chamber was
`critical for efficient nebuliser output. Changes in surface tension and tonicity of solution to be nebulised did not affect
`the
`performance of the nebuliser substantially. Successful sputum induction may rely on both proximal and distal airway deposition,
`hich may be enhanced by changes in both the nebuliser and nebulised solution.
`EAeeeen
`Introduction
`,
`human immunodeficiency virus (HIV) related op-
`portunistic pulmonary infections.
`In this tech-
`The commonest opportunistic lung infection in
`nique, which takes between 20 and 30 min to
`the acquired immunodeficiency syndrome (AIDS)
`perform, the subject, who cannot produce sputum
`is Pneumocystis carinii pneumonia (PCP). This
`spontaneously, inhales a mist of nebulised hyper-
`occurs in up to 85% of all patients with AIDSat
`tonic saline. The resulting sputum specimen allows
`some time during the course of the disease and
`identification of P. carinii cysts and other patho-
`carries a mortality of up to 43% (Murray et al.,
`gens. The mechanisms by which a sputum sample
`1984, 1987; Friedman et al., 1989).
`is generated in this technique are not fully under-
`Ultrasonic nebulisers are increasingly used in
`stood, but may involve several factors including
`the sputum induction technique (Leigh et al.,
`the induction of local
`inflammatory and cough
`1989), which is performed to aid the diagnosis of
`responses, a direct osmotic effect on the bronchial
`mucosa, and variations in the sites of deposition
`of the nebulised particles (related to particle size).
`Correspondence: T.R. Leigh, Dept of Respiratory Medicine,
`In the lung P. car.inii are found predominantly in
`Westminster Hospital, London SW1P 2AP, U.K.
`the alveoli (Rankin et al., 1988), and a nebulised
`
`ernationalJournal ofPharmaceutics, 67 (1991) 275-282
`1991 Elsevier Science Publishers B.V. (Biomedical Division) 0378-5173/91/$03.50
`IONIS 037851739100105F
`
`2 02298
`
`[2 34
`
`275
`
`Performance characteristics of the DeVilbiss Ultraneb 99
`ultrasonic nebuliser with reference to use in sputum induction
`TR. Leigh’, T. Nazir 2 J. Wiggins ’, D. Ganderton 2 and J.V. Collins '
`! DeptofRespiratory Medicine, WestminsterHospital, London SWIP 2AP (U.K.) and? Chelsea Dept ofPharmacy, King’s College,
`
`Manresa Rd, London SW3 6LX (U.K.)
`(Received 16 July 1990)
`(Accepted 8 September 1990)
`
`~,
`
`ail
`
`Liquidia's Exhibit 1099
`Page 1
`
`

`

`274
`
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`
`Page 2
`
`Liquidia's Exhibit 1099
`
`Liquidia's Exhibit 1099
`Page 2
`
`

`

`we
`
`276
`
`particle size of between 1.0 and 2.0 ym is neces-
`sary for preferential deposition at this site (Task
`group on lung dynamics, 1966).
`the De-
`Several groups have suggested that
`Vilbiss Ultraneb 99 ultrasonic nebuliser is the
`most suitable device available for use in sputum
`induction (Leigh et al., 1989; Miller et al., 1990).
`However, its performance characteristics have not
`been fully documented. This
`study aimed to
`evaluate the performance of the nebuliser using a
`range of different control settings, a variety of
`nebulised solutions and volumes,
`to define the
`best conditions for use of this nebuliser in the
`sputum induction technique.
`
`Materials and Methods
`
`Nebuliser description
`
`General
`The DeVilbiss Ultraneb 99 ultrasonic nebuliser
`(DeVilbiss, Heston, Middx, U.K.) can operate in
`one of two ways. In the first of these, the solution
`to be nebulised is fed continuously into the nebu-
`liser chamber from a reservoir suspended above
`the apparatus, so that the solution to be nebulised
`is in direct contact with the nebulising ultrasonic
`transducer.
`In the second,
`the solution to be
`nebulised is contained in a plastic cup resting on a
`plastic ring inserted around the top of the nebu-
`liser chamber. The energy from the transducer is
`transferred through water (which acts as an energy
`couplant) to the plastic cup containing the solu-
`tion to be nebulised. The advantage of this second
`method is that sterilisation of the equipment after
`use is easily performed by removing the tubing
`and plastic cup which have been in contact with
`the patient. However, in the former method, the
`whole nebuliser chamber would require sterilisa-
`tion. We thus studied the performance characteris-
`tics of the latter mode of operation, which is more
`suitable for use with potentially infectious pa-
`tients. The presenceof the plastic ring at the top
`of the nebuliser chamberis important, as without
`it
`the plastic cup seats lower in the nebuliser
`chamberaltering the position of the cup relative
`to the couplantfluid level (see later).
`
`Nebuliser control settings
`The nebuliser has two variable controls, a but-
`terfly valve regulating the flow of air over the
`solution to be nebulised, and an intensity control
`which changes the amplitude of ultrasonic im-
`pulses administered to the solution. The butterfly
`valve has four marked settings; setting No.
`1
`reflected 25% valve opening, setting No. 2 was
`50% opening, etc. The intensity control is a con-
`tinuously variable rheostat which has no marked
`gradations;
`to define accurately the position of
`this control for our experiments we placed a scale
`marked from 0 to 100% aroundit, coinciding with
`its maximal anticlockwise and clockwise positions,
`respectively.
`
`Nebuliser chamber level
`In addition to the two manual nebuliser con-
`trols, the other performance variable of the De-
`Vilbiss Ultraneb 99 is the volume of water (acting
`as the energy couplant) placed into the nebuliser
`chamber. Marks to indicate the manufacturer’s
`suggested maximum and minimum levels are dis-
`played on the outside of the nebuliser chamber.
`
`Measurementof particle size and nebulisation rate
`
`Measurements ofparticle sizes produced by the
`nebuliser were made at steady state (after 1 min)
`by a Malvern 2604c particle sizer (Malvern Instru-
`ments, Malvern, U.K.), which uses laser beam
`diffraction to determine the range of particle sizes
`passing through it. Two values are quoted,
`the
`mass median diameter (MMD) and the v.90%
`which represent
`the size of particles contained
`within 50% and 90% by mass of the nebulised
`mist, respectively. This assumes that the particles
`are of a constant density. Calculations of nebulisa-
`tion rate were made by measuring the rate of
`weight loss from the plastic nebulising cup during
`a fixed time period, correcting for dead space
`condensation.
`
`Experiments performed
`
`Effect of varying nebuliser control settings and
`volume of solution to be nebulised on nebulised
`particle size and nebuliser output
`
`
`
`Liquidia's Exhibit 1099
`Page 3
`
`Liquidia's Exhibit 1099
`Page 3
`
`

`

`277
`
`The first study was to observe the effect on
`particle size of varying both the nebuliser Intensity
`control setting and volumeofsolution to be nebu-
`lised. Intensity settings ranged from 10 to 100%
`with solution volumes of between 5 and 80 ml. 3%
`saline was used with a butterfly valve setting of 4
`(maximum). Preliminary studies had shown that
`the nebuliser was unable to nebulise a solution
`once a given volume of the solution had been
`exceeded. This ‘critical’ cup volume was measured
`for different intensity settings using 3% saline with
`a maximum butterfly valve setting.
`The effect of changes in the butterfly valve
`setting on particle size at different intensity set-
`tings was measured with 30 ml of 3% saline.
`Reproducibility of results was assessed by tak-
`ing measurements of particle size on five separate
`occasionswith identical nebuliser settings and fluid
`
`volumes. These were analysed to establish the
`coefficient of variation.
`
`Relationship between couplant volume and nebuliser
`performance
`in the
`The effects of varying the fluid level
`nebuliser chamber (couplant volume) were de-
`termined by measuring changes in both the MMD
`and the nebuliser output. 30 ml of 3% saline
`solution were nebulised with a maximum butterfly
`valve setting, intensity settings varying between 60
`and 100% inclusive, and couplant fluid volumes
`ranging between 120 and 220 ml.
`
`Effect of varying tonicity and character of solution to
`be nebulised
`Tonicity. The effect on MMD of changing the
`tonicity of the solution to be nebulised was studied
`
`TABLE1
`MMD+ (v.90%) values at different intensity settings and solution volumes (nebulised solution, 3% saline; butterfly valve, 4; solid line
`separates normal from bimodalparticle size profiles)
`
`Intensity (%)
`Volume
`
`100
`80
`60
`50
`40
`30
`20
`10
`(mi)
`0
`80
`15
`70
`
`19
`(47)
`
`46
`(10.0)
`53
`5.3
`5.3
`(10.8)
`(10.9)
`(10.9)
`6.1
`5.6
`58
`5.3
`;
`
`
`
`
`(10.4) (12.2) (11.0) (12.0) (1a)
`
`2.0
`
`47
`(9.9)
`
`4.7
`(9.9)
`
`.
`(10.7)
`
`Page 4
`
`Liquidia's Exhibit 1099
`
`65
`60
`
`55
`50
`
`45
`
`40
`
`35
`30
`
`25
`
`20
`
`15
`
`10
`
`3.7
`(9.5)
`
`49
`(10.3)
`
`5.0
`(10.9)
`
`0
`
`38
`(9.1)
`
`48
`(10.0)
`
`0
`
`15
`(3.2)
`
`0
`2.5
`(39.1)
`3.2
`(8.4)
`3.5
`(8.8)
`
`5.2
`(11.3)
`
`47
`(9.9)
`
`47
`(9.9)
`
`48
`(9.6)
`
`0
`
`4.0
`(9.1)
`
`0
`
`0
`
`0
`
`(6.4) 5
`
`Liquidia's Exhibit 1099
`Page 4
`
`

`

`278
`
`using 1, 3, 6 and 10% saline, with variable nebu-
`liser intensity settings; 30 ml of solution were used
`with a couplant volume of 160 ml and a butterfly
`valve setting at maximum.
`Pentamidine isethio-
`Nebulised pentamidine.
`nate was also studied at its therapeutic concentra-
`tion of 600 mg in 10 m! water. Both MMD and
`nebuliser output were measured over a range of
`intensity settings
`(40-100%) with a couplant
`volume of 170 ml.
`
`Surface tension is believed to
`Surface tension.
`be an important determinant of nebulised particle
`size. Thus, the effect of a surface tension lowering
`agent (Tween 80) on MMDwasstudied. 30 ml of
`1 and 5% saline, with and without 0.5% Tween 80,
`were studied; surface tension coefficients were
`measured on a torsion balance. MMD was mea-
`sured for all four solutions with an intensity set-
`ting of 100% and a butterfly valve setting at
`maximum.
`
`Below solid line in tabte 1
`
`
`©
`
`0
`
`1.9- 24- 3.0- 3.8- 48- 6.2- 79- 10-
`13.
`24 30 38 48 62 79
`
`13-
`417
`
`17-
`22
`
`22- 28- 38- 54-
`28
`38
`54
`87
`
`Particle size range (microns)
`
`oftotalmass
`
`°lo
`
`oftotalmass
`
`°lo
`
`
`a
`
`oy)
`hilt.
`
`Above solid line in table 1
`
`
`20-—
`
`19- 2.4- 3.0- 38- 48- 6.2- 79- 10- ” 17- 2 28 38- 54-
`
`24 30 38 48 62 79
`
`10
`
`13
`
`22
`
`54
`
`87
`
`Fig. 1. Graphs showing the two forms ofparticle size distribution curves, depending on whether nebuliser settings fall above or below
`the solid line in Table 1.
`
`Particle size range (microns)
`
`Page 5
`
`Liquidia's Exhibit 1099
`
`Liquidia's Exhibit 1099
`Page 5
`
`

`

`Statistical analysis. Non-parametricstatistical
`analysis was performed using the Mann-Whitney
`U test.
`
`Results
`
`Effect of varying nebuliser control settings and
`volume of solution to be nebulised on nebulised
`particle size and nebuliser output
`The results are shown in Table 1. It was found
`that within a specified range of nebuliser settings
`(the area below the solid line in Table 1),
`the
`nebulised particle sizes gave a Gaussian distribu-
`tion (mean MMD=5.05 pm, SD=0.34 pm).
`However, as these settings were progressively al-
`tered (abovethe solid line), the particle size distri-
`bution curvesinitially became bimodal (with an
`associated fall in MMD, mean MMD = 3.94 pm,
`SD = 1.32 wm, p < 0.05 (see Fig. 1)).
`Volume of solution to be nebulised was found
`to be important for nebuliser output. For a given
`intensity setting a ‘critical’ volume was detected
`above which nebuliser output became negligible
`(as defined by the inability of the particle sizer to
`detect nebulised particles). This critical volume
`was found to increase in proportion to the inten-
`sity setting (Fig. 2).
`Changing the butterfly valve setting caused only
`small changes in particle MMD (Table 2), with a
`maximum variation of 0.5 »m at a given intensity
`setting.
`
`279
`
`TABLE 2
`
`MMD (um) response to changing butterfly settings at different
`intensities (nebulised solution, 3% saline; cup volume, 30 ml)
`
`
`Butterfly
`Intensity (%)
`setting
`100
`80
`60
`
`1
`5.4
`5.2
`$.1
`2
`5.6
`5.7
`5.4
`3
`5.2
`5.2
`5.0
`
`5.2 5.24 5.0
`
`
`
`Measurements of particle size were found to be
`highly reproducible, with coefficients of variation
`between 0.6 and 2.4% over the range of intensity
`settings and solution volumes studied.
`
`Relationship of couplant volume to nebuliser perfor-
`mance
`Nebuliser output was found to besignificantly
`affected by both the nebuliser chamber (couplant)
`fluid volume andthe intensity setting (Table 3). In
`addition,
`the optimum couplant volume varied
`with the selected intensity setting from 160 ml at
`100% intensity to 180 mi at 60% intensity (Fig. 3).
`However,
`the upper and lower
`limits for
`the
`couplantfluid level indicated by the manufacturer
`corresponded to volumes of 212 and 148 ml, re-
`spectively. MMD was minimally affected by
`
`TABLE3
`
`Nebuliser output and MMDresponse to changing couplant fluid
`volume (nebulised solution, 3% saline; butterfly setting, 4)
`
`
`200
`
`180
`
`Couplant
`Intensity (%)
`volume(ml)
`Flow rate (ml/min) +(MMD pm)
`
`100
`80
`60
`
`220
`0.6
`0.5
`0.5
`(4.0)
`(4.5)
`(4.6)
`0.9
`0.6
`0.4
`(4.2)
`(4.3)
`(4.3)
`2.1
`1.8
`11
`(48)
`(5.2)
`(5.2)
`2.5
`1.0
`0.3
`(5.4)
`(5.3)
`(4.9)
`0.8
`0.2
`-
`(4.8)
`(2.2)
`-
`0.1
`-
`(3.6)
`
`160
`
`140
`
`120
`
`
`~
`~
`
`—O- Critical volume
`
`OO
`
`80:
`4
`SO
`
`40
`
`=
`£
`>
`
`E3
`
`>
`
`:v 5
`
`
`
`3
`100
`
`1
`86
`
`\
`80
`
`
`
`aB
`,
`1
`1
`1
`70-——~C*SS~C<C8—CSCD
`Intensity (%o)}
`
`a
`
`Fig. 2. Graph showing the critical volume of solution to be
`nebulised for different intensity settings, beyond which thereis
`no detectable nebuliser output.
`
`
`
`Liquidia's Exhibit 1099
`Page 6
`
`Liquidia's Exhibit 1099
`Page 6
`
`

`

`
`
`280
`
`iw
`
`@——Manufacturer’s limits-——»
`\
`
`hm cou}
`
`Oo
`
` ~x-Intensity = 60 % blowrate(ml/min)
`
`-O-Intensity = 100 %e
`~+-Intensity = 80 %
`
`hoSTet
`
`\\iI/-
`
`oO
`
`iO{3— oO
`
` 1 : \
`
`
`
`oO5
`Ax3
`189
`200
`220
`Couptant volume (ml;
`
`TABLE5
`
`MMDvalues and flow rates of nebulised pentamidine isethionate
`at different intensity settings
`
`
`Intensity (%)
` 100 80 60 40
`
`
`
`
`
`
`MMD (pm)
`
`Mean
`
`Flow rate
`
`5.3
`5.5
`5.4
`
`5.39
`
`5.4
`5.5
`5.5
`
`5.48
`
`5.7
`5.6
`5.6
`
`5.64
`
`6.1
`5.6
`5.8
`
`5.84
`
`0.67
`0.79
`0.94
`1.14
`(ml/min)
`
`
`
`
`68.32 56.44 47.53mg/min 40.1
`
`torsion value falling from 0.047 to 0.040 N/m
`with 1% saline and from 0.057 to 0.039 N/m with
`5% saline. Small but significant increases in MMD
`were observed with both 1% (mean MMD5.1-5.6
`um, p<0.01) and 5% (mean MMD 5.1-5.3 pm,
`Pp < 0.01) saline solutions following the addition of
`Tween 80.
`
`Discussion
`
`The purpose of this study was to define the
`performance characteristics of the DeVilbiss Ul-
`traneb 99 ultrasonic nebuliser under a variety of
`operating conditions andto relate these character-
`istics to its use in sputum induction. It was shown
`that particle MMD of nebulised saline remains
`almost constant (3.8—6.1 2m) over a wide range of
`nebuliser operating conditions, which are indi-
`cated by the area below the solid line in Table 1.
`For example, to achieve a constant MMD with an
`intensity setting of 100% the volumeofsolution to
`be nebulised should not exceed 50 ml. However,at
`an intensity setting of 60% this volume should not
`exceed 30 ml. Beyond this operational
`range,
`MMDvalues were shown to fall and adopt a
`bimodal distribution. The reasons for this change
`in distribution are unclear, but a combination of
`insufficient energy to nebuliselarger particles, and
`the coalescence of smaller particles to produce a
`group of larger ones may be involved.
`
`Fig. 3. Graph showing the effect of couplant volume on
`nebuliser output at different
`intensity settings. The vertical
`dotted lines give the suggested limits for couplant volume as
`recommended by the manufacturer.
`
`changes in couplant volume, mean MMD = 4.5
`pm (range 2.2-5.4 ym).
`
`Effect of varying tonicity and characterof solution to
`be nebulised
`Tonicity of saline. The effect on MMD of
`varying the tonicity of nebulised saline solutions
`was small (Table 4). Over the tested range of
`1-10% saline with intensity settings between 60
`and 100% the measured MMDvaried between 3.7
`and 5.7 pm.
`Nebulised pentamidine. The MMD of nebu-
`lised pentamidineisethionate wasnotsignificantly
`different from that of nebulised saline (Table 5).
`The MMDvaried between 5.3 pm at 100% inten-
`sity and 6.1 pm at 40% intensity. The rate of
`nebulisation rose from 0.7 ml/min (40 mg/min)
`at 40% intensity to 1.1 ml/min (68 mg/min) at
`100% intensity.
`Surface tension of both solu-
`Surface tension.
`tions fell following the addition of Tween 80, the
`
`TABLE4
`
`MMDresponse to different
`varying intensity settings
`
`
`tonicity of nebulised solution at
`
`Nebulised solution concentration
`Intensity
`setting
`1%
`3%
`6%
`10%
`(%)
`
`
`$.1
`5.7
`5.4
`5.6
`100
`4.9
`5.2
`5.2
`5.5
`80
`
`
`
`
`$.2 48 4.660 3.7
`
`aeele( A
`
`Liquidia's Exhibit 1099
`
`Liquidia's Exhibit 1099
`Page 7
`
`

`

`The mechanism by which inhalation of a mist
`of nebulised saline leads to expectoration of a
`sputum specimen containing P. carinii cysts is
`unknown. Although the success of sputum induc-
`tion may be dependent on several factors includ-
`ing stimulation of cough and alveolar deposition
`of nebulised particles (to ‘wash out? P. carinii
`cysts). The sites of distribution of a nebulised mist
`have been shown to be directly related to its
`particle size (Task group on lung dynamics, 1966).
`Theoretically, the ideal mist for sputum induction
`purposes would contain large particles to induce
`cough by deposition in proximal airways, and
`smaller particles for alveolar deposition. Thus, a
`mist of bimodal particle size distribution with
`particle size peaks at approx. 2 and 7 4m would be
`most suitable. Although this distribution pattern
`was obtained from the DeVilbiss nebuliser under
`certain operating conditions (above the solid line
`in Table 1) it was also found that the nebuliser
`outputfell significantly when these conditions were
`used. This mode of use is impractical for sputum
`induction as nebulisation of the required volume
`of solution would take too long. A compromise
`between obtaining the ideal bimodal size distribu-
`tion and an adequate nebuliser output would be
`achieved by delivering a mist with a normally
`distributed particle size curve at a high flow rate:
`this is indicated by the solution volumes and in-
`tensity settings shown below the solid line in Ta-
`ble 1. The spread of particle sizes is reflected by
`the v.90% figure, which,
`if greater than 7 ym,
`indicates a mist with a significant numberof par-
`ticles in the desired size band. For example, at an
`intensity setting of 80% with a volumeof solution
`to be nebulised of 30 ml the MMDis 4.7 pm and
`the v.90% is 9.9 pm. This implies that 40% of the
`nebulised solution has a particle size between 4.7
`and 9.9 wm.
`Wefound that the MMD and (v.90%) obtained
`from the DeVilbiss Ultraneb 99 ultrasonic nebu-
`liser were significantly greater than those obtained
`from the Acorn System 22 jet nebuliser (Medic-aid,
`Pagham,Sussex, U.K.) (unpublished observations),
`which is used for both sputum induction and the
`treatment and prophylaxis of PCP. The produc-
`tion of the larger particles by the DeVilbiss Ultra-
`neb 99 suggest that
`this system is less suitable
`
`281
`
`than the Acorn for the treatment of PCP. Con-
`versely,
`the latter nebuliser is theoretically less
`suitable for use in sputum induction, and pre-
`liminary observations showing a lower diagnostic
`sensitivity of the technique when the Acorn nebu-
`liser is used, support this contention.
`The effect of correct couplant volume on nebu-
`liser output is clearly shown in Fig. 3. The data
`show that for optimum nebuliser performance(i.e.
`a flow rate>1.5 ml/min) at a given intensity
`setting, couplant volume should be within a de-
`fined range, beyond which the output of
`the
`nebuliser falls sharply. This range is narrower than
`that recommended by the manufacturer. We have
`also demonstrated that
`the optimum couplant
`volume varies with nebuliser intensity setting, and
`this should therefore be taken into account when
`setting up the device.
`The MMDsof the mist produced when saline
`solutions of different tonicities were nebulised by
`the DeVilbiss Ultraneb 99 were similar. Thus,
`possible differences in the efficacy of sputum in-
`duction resulting from the use of saline solutions
`of varying tonicity are probably due to factors
`other than the size of
`the nebulised particles.
`These may include differences in either stimula-
`tion of the cough response, production of a local
`inflammatory reaction, or effects on mucociliary
`clearance.
`Wefound that the addition of a surface tension
`lowering agent (Tween 80) increased the MMDof
`the nebulised particles generated by the DeVilbiss
`Ultraneb 99 nebuliser by about 0.5 wm. This in-
`crease was unexpected, as a fall in surface tension
`would normally result in an increase in interfacial
`surface area with a corresponding reduction in
`particle size. This suggests that other factors apart
`from surface tension are involved in determining
`the nebulised particle size. Although this change
`in MMDis probably too small to be of practical
`benefit, larger changes in particle size might be
`obtainable if greater alterations in surface tension
`could be achieved.
`In conclusion, we have characterised and de-
`fined the operating conditions of the DeVilbiss
`Ultraneb 99 ultrasonic nebuliser. The clinical ef-
`ficacy of different nebulisers in sputum induction
`may be the result of both nebuliser output and a
`
`
`
`Liquidia's Exhibit 1099
`aa\¢(oa
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`Liquidia's Exhibit 1099
`Page 8
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`

`

`282
`
`compromise between proximal and distal deposi-
`tion of nebulised particles, producing cough and
`alveolar washout, respectively.
`
`References
`
`Friedman, Y., Franklin, C., Rackow, E.C. and Weil, M.H.,
`Improved survival
`in patients with AIDS, Pneumocystis
`carinii pneumonia, and severe respiratory failure. Chest, 96
`(1989) 862-866.
`Leigh, T.R., Parsons, P., Hume, C., Husain, O.A.N., Gazzard,
`B.G. and Collins, J.V., Sputum induction for diagnosis of
`Pneumocystis carinii pneumonia. Lancet, ii (1989) 205-206.
`Miller, R.F., Semple, S.J.G. and Kocjan, G. Difficulties with
`
`sputum induction for diagnosis of Pneumocystis carinii
`pneumonia. Letter to Lancet, i (1990) 112.
`Murray,
`J.F., Felton, C.P., Garay, §$.M., Gottlieb, M.S.,
`Hopewell, P.C., Stover, D.E. and Teirstein, A.S., Pulmonary
`complications of the acquired immunodeficiency syndrome.
`Report of a National Heart, Lung, and Blood Institute
`Workshop. N. Engl. J. Med., 310 (1984) 1682-1688.
`Murray, J.F., Garay, S.M., Hopewell, P.C., Mills, J., Snider,
`G.L. and Stover, D.E., Pulmonary complications of the
`acquired immunodeficiency syndrome: An update. Am Rev
`Resp Dis., 135 (1987) 504-509.
`Rankin, J.A., Coliman, R. and Daniele, R.P. Acquired immune
`deficiency and the lung. Chest, 94 (1988) 155-164.
`Task group on lung dynamics, Deposition and retention mod-
`els for internal dosimetry of the human respiratory tract.
`Health Phys., 12 (1966) 173-207.
`
`
`
`Liquidia's Exhibit 1099
`Page 9
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`Liquidia's Exhibit 1099
`Page 9
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`

`

`+
`
`International Journal of Pharmaceutics, 67 (1991) 283-285
`© 1991 Elsevier Science Publishers B.V. (Biomedical Division) 0378-5173/91/$03.50
`
`283
`
`Author Index
`
`Al-Gohary, O.M.N.
`An in vitro study of the interaction between mebeverine
`hydrochloride and magnesium trisilicate powder (67) 89
`Alonso, M.J., see Egea, M.A. (67) 103
`Alsina, M.A., see Egea, M.A. (67) 103
`Arafat, T., see Sallam, E. (67) 247
`Aramaki, Y., see Hara, T. (67) 123
`Asano, M., Fukuzaki, H., Yoshida, M., Kumakura, M.,
`Mashimo, T., Yuasa, H., Imai, K., Yamanaka, H., Kawa-
`harada, U. and Suzuki, K.
`In vivo controlled release of a luteinizing hormone-releas-
`ing hormone agonist from poly(DL-lactic acid) formula-
`tions of varying degradation pattern (67) 67
`Awad, R., see Sallam, E. (67) 247
`
`Baghal, T., see Sallam, E. (67) 247
`Beckett, A.H., see Hadzija, B.W. (67) 185
`Beijnen, J.H., see Van der Houwen, 0.A.G.J. (67) 155
`Bekers, O., see Van der Houwen, O.A.G.J. (67) 155
`Bos, C.E., Vromans, H. and Lerk, C.F.
`Lubricantsensitivity in relation to bulk density for granula-
`tions based on starch or cellulose (67) 39
`Bouzon,J., see Laghoueg-Derriche, N. (67) 163
`Bult, A., see Van der Houwen, O.A.G.J. (67) 155
`
`Calvo, M.B., Pedraz, J.L., Vicente, M.T. and Dominguez-Gil,
`A.
`Pharmacokinetics of cefazoline and dibenzylamine adminis-
`tered in a sustained drug delivery system to healthy volun-
`teers (67) 259
`Carstensen, H., Miiller, B.W. and Miller, R.H.
`Adsorption of ethoxylated surfactants on nanoparticles. I.
`Characterization by hydrophobic interaction chromatogra-
`phy (67) 29
`Chafi, N., Monthéard, J.P. and Vergnaud, J.M.
`Release of 2-aminothiazole from polymer carriers (67) 265
`Chang, H.W., see Yoon, E.J. (67) 177
`Collins, J.V., see Leigh, T.R. (67) 275
`Concheiro, A., see Pérez-Marcos, B. (67) 113
`
`De Muynck, C., see Vandenbossche, G.M.R. (67) 195
`De Pablos Pons, F., see Gonzalez, A.G. (67) R1
`Dominguez-Gil, A., see Calvo, M.B. (67) 259
`
`.
`Eerikainen, S., see Laakso, R. (67) 79
`Egea, M.A., Valls, O., Alsina, M.A., Garcia, M.L., Losa, C.,
`Vila-Jato, J.L. and Alonso, M.J.
`Interaction of amikacin loaded nanoparticles with phos-
`phatidylcholine monolayers as membrane models (67) 103
`
`Fernandez-Arévalo, M., see Rabasco, A.M. (67) 201
`Fukuzaki, H., see Asano, M. (67) 67
`
`Ganderton, D., see Leigh, T.R. (67) 275
`Garcia, M.L., see Egea. M.A. (67) 103
`Ginés, J.M., see Rabasco, A.M. (67) 201
`Gémez-Amoza, J.L., see Pérez-Marcos, B. (67) 113
`Gonzalez, A.G. and De Pablos Pons, F.
`Evaluation of acidity constants for sparingly soluble com-
`pounds from fluorescence measurements (67) R1
`Gutiérrez, C., see Pérez-Marcos, B. (67) 113
`
`Hadzija, B.W., Obeng, E.K., Ruddy, S.B., Noormohammadi,
`A. and Beckett, A.H.
`Bioavailability of a controlled release indomethacin formu-
`lation in healthy subjects (67) 185
`Hara, T., Ishihara, H., Aramaki, Y. and Tsuchiya, S.
`Characteristics of the binding of asialofetuin-labeled lipo-
`somes to isolated rat hepatocytes (67) 123
`Hassan, M.A., Najib, N.M. and Suleiman, M.S.
`Characterization of glibenclamide glassy state (67) 131
`Hiestand, E.N. and Smith, D.P.
`Tablet bond. IH. Experimental check of model (67) 231
`Hiestand, E.N.
`Tablet bond. I. A theoretical model (67) 217
`Hjartstam, J., see Lindstedt, B. (67) 21
`Holgado, M.A., see Rabasco, A.M.(67) 201
`
`Ibrahim, H., see Sallam, E. (67) 247
`Imai, K., see Asano, M. (67) 67
`Imai, T., Shiraishi, S., Saité, H. and Otagiri, M.
`Interaction of indomethacin with low molecular weight
`chitosan, and improvements of some pharmaceutical prop-
`erties of indomethacin by low molecular weight chitosans
`(67) 11
`:
`Ishihara, H., see Hara, T. (67) 123
`
`Kawaharada, U., see Asano, M. (67) 67
`Kim, C.K., see Yoon, E.J. (67) 177
`Kimura, T., see Kurosaki, Y. (67) 1
`Klimek, R., see Thoma, K. (67) 169
`Kohli, D.V., see Tripathi, M. (67) 207
`Kumakura, M., see Asano, M. (67) 67
`Kurosaki, Y., Nagahara, N., Tanizawa, T., Nishimura, H.,
`Nakayama, T. and Kimura, T.
`Useoflipid disperse systems in transdermal drug delivery:
`Comparative study of flufenamic acid permeation among
`rat abdominal skin, silicon rubber membrane and stratum
`corneum sheet isolated from hamster cheek pouch (67) 1
`
`
`
`Liquidia's Exhibit 1099
`Page 10
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`Liquidia's Exhibit 1099
`Page 10
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`