1
`
`3M COMPANY 2024
`Mylan Pharmaceuticals Inc. v. 3M Company
`IPR2015-02002
`
`

`
`particularly when attempts have been made to match the per-
`formance of these two systems (aerosol output equivalence).
`This approach of reformulating pMDIs based on bioequiva—
`lency to the CFC pMDIs they have replaced was adopted by
`most companies involved in the transition from CFC to HFAs
`[8]. To achieve equivalence, there are two general strategies
`which can be used to modulate aerosol output and lung depo-
`sition of pMDIs; the first is altering the formulation param-
`eters such as propellant and excipients which we have previ-
`ously reviewed [8, 11]. Secondly, device design can be changed
`rationally to induce changes in aerosol output as we have
`previously shown for actuator nozzle dimensions [12, 13].
`Part of the issue for matching deposition profiles of
`different products has been the difliculty in matching aerosol
`output beyond the mass median aerodynamic diameters and
`other composite measures such as fine particle fraction or
`respirable fractions. Indeed, it has been reported that HFA-
`134 solution formulations displayed multimodal particle size
`distributions. In these studies, varying cosolvent concen-
`trations in HFA—134/ethanol pMDIs influenced particle size
`distribution but did not cause particle size modes to shift
`[5, 11]. This is problematic for formulators wishing to show
`equivalence with monomodal aerosols since changes in par-
`ticle size output modulated by use of cosolvents alone will be
`insuflicient to obtain a match of aerosol deposition profiles.
`In the current studies, we show that by controlling both
`cosolvent and surfactant concentrations, the aerosol particle
`size distributions can be modulated both along the x and y
`axes; that is, HFA 227 solution formulations can be tuned
`within a performance space. Specifically, the aim of these
`studies was to investigate the influence of changing the con-
`centrations of a model surfactant (Pluronic L81) and ethanol
`on the emitted particle size distribution and in vitro aerosol
`deposition studies.
`
`2. Materials and Methods
`
`2.1. Materials. The propellant 1,1,1,2,3,3,3—heptafluoropro—
`pane (HFA 227) was provided as a gift from Solvay Fluorides
`Inc. (Houston, TX, USA). Fluorescein sodium (fluorescein
`Na) was purchased from Sigma—Aldrich (St. Louis, MO,
`USA). Ethanol (EtOH) (HPLC grade) and methanol (HPLC
`grade) were purchased from VWR (West Chester, PA, USA).
`Aluminium aerosol canisters and metered dose valves (25 (AL)
`were provided as a gift from Valois Pharmaceuticals (Marly-
`le—Roi, France). Pluronic L81 was a gift from BASF Corp
`(Parsippany, NI, USA).
`
`2.2. Preparation ofPressurised Metered Dose Inhalers (pMDIs).
`A series of formulations were prepared (Table 1) containing
`various amounts by weight of Pluronic L81 and HFA 227
`propellant with constant ethanol concentration (% w/w) and
`fluorescein Na drug mass (% w/w), as a model drug. Table 2
`represents formulations consisting of different ethanol con-
`centrations (% w/w) but maintaining constant Pluronic
`L81 (% w/w) and fluorescein Na (% w/w) concentrations.
`Significant preformulation, solubility, and stability studies
`
`BioMed Research International
`
`TABLE 1: Composition of HFA 227 formulations maintaining con-
`stant fluorescein Na and ethanol concentration (n = 3).
`
`Formulation
`
`1.22% w/w Pluronic L81
`
`Pluronic L81 Ethanol
`(% w/w)
`(% w/w)
`1.22
`13.3
`
`Fluorescein Na
`(% w/w)
`0-04
`
`5.45% w/w Pluronic L81
`
`5.45
`
`13.4
`
`0-04
`
`0.04
`13.3
`0*
`0% w/w Pluronic L81
`* Formulation 0% w/w Pluronic L81 contained 1.22% w/w of deionized water
`as a replacement for Pluronic L81 to maintain mass balance.
`
`TABLE 2: Composition of HFA 227 formulations maintaining con-
`stant Pluronic L81 and fluorescein Na concentrations (n = 3).
`
`Formulation
`
`5% w/w EtOH
`
`10% w/w EtOH
`
`13% w/w EtOH
`
`15% W/W EtOH
`
`Pluronic L81
`(% w/w)
`5
`
`Ethanol
`(% w/w)
`5
`
`Fluorescein Na
`(% w/w)
`0-04
`
`5
`
`5
`
`5
`
`10
`
`13
`
`15
`
`0-04
`
`0-04
`
`0.04
`
`were performed to ensure compatibility of the model drug,
`excipients, and propellants (data not shown).
`Aliquots of Pluronic L81, ethanol, and fluorescein Na,
`as represented in Tables 1 and 2, were added by weight to
`aluminium aerosol canisters. Metered dose valves were then
`
`crimped onto the canisters using a manual canister crimper
`(Aero—Tech Laboratory Equipment Company, Worcester,
`NY) and filled with the desired weight of HFA 227 propellant
`using a pressure burette (Aero—Tech Laboratory Equipment
`Company, Worcester, NY, USA). All canisters were equipped
`with a 0.33 {JIII actuator (Valois Pharmaceuticals, Marly—le—
`Roi, France) and prepared on the same day as testing.
`
`2.3. Particle Size Analysis ofDrug (Fluorescein Na) Using Laser
`Difiraction. Particle size characteristics of each of the formu-
`lations were determined using a Sympatec Helos laser diffrac-
`tion instrument (Sympatec GmbH, Germany). The pMDI
`was positioned at a set distance from the laser beam and at
`a fixed height ensuring that the aerosol plume was projected
`across the laser. This was achieved by placing the aerosol
`device such that the actuator orifice was within the lens cut-
`
`off distance and was aligned with the height of the laser path.
`Particle size distribution was measured using four actuations
`shaking the canister between actuations five times and
`expressed as the volume median diameter (VMD) (n = 4).
`
`2.4. Aerodynamic Particle Size Distributions of Drug (Flu-
`orescein Na) Using the Next Generation Impactor (NGI).
`Aerodynamic particle size distributions were determined
`from cascade impaction studies using a Next Generation
`Impactor (NGI) (MSP Corp, MN, USA) containing a United
`States Pharmacopeia induction port and operated at a flow
`rate of 30 L/min, precalibrated using a Gilmont Flowmeter
`Base Model F—4001 (Barnant Company, Barrington, IL, USA).
`The metering valves were primed by discharging three shots
`to waste. The pump was switched on 5 seconds prior to
`
`2
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`BioMed Research International
`
`TABLE 3: Comparison of formulations with different concentrations
`of Pluronic L81 (data represent mean i SD, n = 3).
`
`Pluronic L81 Concentration (% w/w)
`0
`1.22
`5.45
`
`ED (pig)
`FPF (%)
`FPD (pig)
`MMAD (am)
`GSD
`
`170.69 J; 21.85**
`49.63 J; 2.00
`84.61 J; 10.19
`1.56 J; 005$
`3.22 J; 0.31
`
`211.14 J; 9.63
`50.72 J; 0.69
`107.05 J; 3.53
`3.70 J; 008*
`2.00 J; 0.05
`
`215.14 J; 11.55
`33.20 J; 337*
`71.17 J; 379*
`5.93 J; 049*
`1.78 J; 0.07
`
`11.04 J; 046*
`8.39 J; 0.11
`7.07 J; 0.14
`VMD (am)
`ED: emitted dose, MMAD: mass median aerodynamic diameter, FPF: fine
`particle fraction, FPD: fine particle dose, and GSD: geometric standard
`deviation. “P < 0.05 (ANOVA/Tukey’s) 0% w/w Pluronic L81 versus
`1.22 and 5.45% w/w Pluronic L81, *P < 0.05 (ANOVA/Tukey’s) 5.45%
`w/w Pluronic L81 versus 0 and 1.22% w/w Pluronic L81, #P <
`0.05
`(ANOVA/Tukey’s) 5.45% w/w Pluronic L81 versus 1.22% w/w Pluronic L81,
`and $P < 0.05 comparing all formulations.
`
`pMDI discharge, and pMDI was actuated ten times (n = 3).
`The emitted dose (ED) was expressed as the total mass of
`drug emitted from the inhaler. The fine particle fraction (%
`FPF) (defined as the mass of drug deposited (dae S 4.6 (1111)
`was expressed as a percentage of the emitted dose and the
`fine particle dose (FPD) was expressed as the mass of drug
`deposited in the NGI (dae S 4.6 (4111). Furthermore, inertial
`impaction data was also subjected to log—probability analysis
`to allow the derivation ofmass median aerodynamic diameter
`(MMAD) and geometric standard deviation (GSD) for each
`formulation [14].
`
`2.5. Chemical Analysis. Fluorescein Na captured on the actu-
`ator, induction port, and stages was extracted with methanol
`(HPLC grade). The aerodynamic particle size distribution
`was determined by analyzing each of the collected samples
`for fluorescein Na content by HPLC using a Hitachi Elite
`LaChrom (Hitachi, CA, USA) with UV detection at 490 nm
`using a Kromasil C8 column (150 mm X 4.6mm i.d., Col-
`umn Engineering, CA, USA). The mobile phase consisted
`of methanol:water (60:40) at a flow rate of 1.0 mL/min,
`injection volume 10 (JL, and quantification was by peak area
`using a standard curve in the range 0-25 (Ag/mL.
`
`2.6. Statistical Analysis. The formulations were compared
`with each other by means of a one—way ANOVA with Tukey’s
`comparison test. The statistical significance level was set at
`P S 0.05.
`
`3. Results
`
`3.1. Efizct of Surfactant Concentration on Particle Size Distri-
`butions Emittedfrom HFA 227pMDIs. Investigations looked
`at the influence of altering surfactant levels in the HFA 227
`pMDIs on aerosolization and particle size. Laser diffraction
`data (Table 3) illustrated a direct correlation between increas-
`ing surfactant concentration resulting in larger particle size
`(VMD).
`This was further reflected in the MMAD and emitted dose
`
`data from cascade impaction studies. However, a significant
`
`r—->J>5
`
`r—-NO
`
`r—- OO
`
`v
`
`(yg) N.:>GG Q
`Massofdrugdeposited
`
`
`00O
`
`O\0
`
`0%w/wPluronicL81
`
`1.22%w/wPluronicL81
`
`5.45%w/wPluronicL81
`
`FIGURE 1: Comparison of HFA 227 formulations with varying
`concentrations of Pluronic L81 in terms of drug deposited in USP
`throat of NGI maintaining constant concentration of fluorescein
`Na and ethanol (data represent mean i SD, n = 3). ‘P < 0.05
`(ANOVA/Tukey’s) 5.45% w/w Pluronic L81 versus 1.22 8: 0% w/w
`Pluronic L81.
`
`decrease in FPD and FPF was observed as the surfactant
`concentration was increased from 1.22% w/w to 5.45% w/w
`
`(P < 0.05, ANOVA/Tukey’s). Similarly, USP induction port
`deposition was positively correlated with surfactant concen-
`trations, with 5.45% w/w Pluronic L81 formulations resulting
`in significantly greater throat deposition compared to the
`other formulations (P < 0.05, ANOVA/Tukey’s) (see Fig-
`ure 1). In addition, increasing the concentration of surfactants
`caused the fine particle mode (population of particles less
`than ~10 microns) to shift along the abscissa. High surfactant
`concentrations (5.45% w/w) significantly dominated at cut-
`off diameters 26.4 yin (P < 0.05, ANOVA/Tukey’s), with 1%
`w/w Pluronic L81 dominating between 3.99-1.36 yin (P <
`0.05, ANOVA/Tukey’s) (see Figure 2).
`
`3.2. Efiect of Ethanol Concentration on Particle Size Distri-
`butions Emitted from HFA 227 pMDIs. A summary of the
`studies for fluorescein Na labelled pMDI formulations with
`varying levels of cosolvent is presented in Table 4. There was
`a direct correlation between increasing ethanol concentration
`resulting in enhanced particle size (VMD) and MMAD, with
`significant differences noted between formulations contain-
`ing 15% w/w versus 10 or 5% w/w ethanol (P < 0.05, ANOVAI
`Tukey’s).
`Although a decrease was noted in MMAD between
`formulations containing 5 and 10% w/w EtOH, this was
`not significant (P
`>
`0.05, ANOVA/Tukey’s). Further-
`more, as MMAD values increased, this corresponds to a
`significantly decreased FPD between all formulations from
`105.07 J; 2.31 (Ag to 61.28 J; 1.79 yg (Table 4) (P < 0.05,
`ANOVA/Tukey’s). In addition, a decrease in FPF was also
`noted with significant difference comparing formulations
`with 15 and 13% w/w versus 10 and 5% w/w EtOH (P <
`0.05, ANOVA/Tukey’s). However, there was no significant
`difference in emitted doses between the formulations (P >
`0.05, ANOVA/Tukey’s). These observations are not surprising
`
`3
`
`

`
`4
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`BioMed Research International
`
`TABLE 4: Comparison of HFA 227 formulations with different concentrations of ethanol (data represent mean i SD, n = 3).
`
`ED (fig)
`FPF (%)
`
`FPD (pg)
`
`MMAD (ym)
`GSD
`
`5 (59.8 psi)
`195.08 i 23.25
`54.31 i 5.65
`
`105.07 J; 231*
`
`5.13 i 0.23
`1.74 i 0.12
`
`Ethanol concentration (% w/w)/(vapor pressure, psi)
`10 (54.6 psi)
`13 (52.8 psi)
`194.26 i 14.19
`193.31 i 12.44
`45.39 i 2.90
`35.02 i 2.26”
`
`87.91 J; 173*
`
`5.05 i 0.15
`2.07 i 0.01
`
`67.52 J; 038*
`
`5.55 i 0.18
`1.73 i 0.03
`
`15 (50.2 psi)
`209.52 i 11.02
`29.27 i 0.77*
`
`61.28 J; 179*
`
`5.79 i 0.05*
`1.78 i 0.01
`
`12.0 i 044*
`9.72 i 0.56
`8.03 i 0.36
`5.32 i 0.54
`VMD (ym)
`ED: emitted dose, MMAD: mass median aerodynamic diameter, FPF: fine particle fraction, FPD: fine particle dose, and GSD: geometric standard deviation.
`*P < 0.05 (ANOVA/Tukey’s) 15% w/w EtOH versus 10 and 5% w/w EtOH, “P < 0.05 (ANOVA/Tukey's) 13% w/w EtOH versus 10 and 5% w/w EtOH, and
`iP < 0.05 comparing all formulations (ANOVA/Tukey's).
`
`>J>U1
`
`11.7
`
`6.4
`
`3.99
`
`2.3
`
`0 U
`
`1
`
`U10
`
`
`
`I\lI\lUJ9J>J>OUIO
`Massofdrugdeposited(pg) 5 r—-
`
`r—I O\O
`r—->J>5
`r—-NO
`r—- OO
`
`O\0
`
`(yg) Nasoo3GG O
`Massofdrugdeposited
`
`
`V
`
`1.36
`
`0.83
`
`0.54 MOC
`
`
`
`Aerodynamic cut—off diameters (gun)
`—o— 0% w/w Pluronic L81
`— u — 1.22% w/w Pluronic L81
`---s- -- 5.45% w/w Pluronic L81
`
`5%w/wEtOH
`
`10%w/wEtOH
`
`13%w/wEtOH
`
`15%w/wEtOH
`
`FIGURE 2: Comparison of HFA227 formulations in terms of drug
`deposited on each stage of Next Generation Impactor, maintaining
`constant concentration of ethanol (data represent mean i SD, n =
`3). MOC: microorifice collector. *P <
`0.05 (ANOVA/Tukey’s)
`5.45% w/w Pluronic L81 versus 0 and 1.22% w/w Pluronic L81,
`“P < 0.05 (ANOVA/Tukey’s) comparing all formulations, $P <
`0.05 (ANOVA/Tukey’s) 1% w/w Pluronic L81versus 0 and 5% w/w
`Pluronic L81, and”P < 0.05 (ANOVA/Tukey’s) 0% w/w Pluronic L81
`versus 1.22 and 5% w/w Pluronic L81.
`
`and are consistent with our previous studies conducted using
`HFA 134a propellants [11]. Thus, as expected with increased
`particle size, the USP induction port (throat) deposition
`also increased with increasing ethanol concentrations (see
`Figure 3). Furthermore, increasing ethanol concentrations
`in the HFA 227 formulations caused similar changes to the
`particle size distributions (see Figure 4). Generally, the lower
`ethanol concentrations (5 and 10% w/w), the greater the
`mass of drug deposited at cut—off—diameters 6.4 to 0.83 yin
`(P <
`0.05, ANOVA/Tukey’s). Importantly, the positions
`of the particle size modes were not changed as ethanol
`concentrations are changed, rather their magnitudes were
`altered. These observations are in contrast to those discussed
`
`previously when we varied the surfactant concentration while
`keeping ethanol concentrations constant.
`
`FIGURE 3: Comparison of HFA 227 formulations in terms of drug
`deposited in USP throat of NGI maintaining constant concentration
`of fluorescein Na and Pluronic L81 (data represent mean i SD, n =
`3). ‘P < 0.05 (ANOVA/Tukey’s) 15% w/w EtOH versus 10 8: 5% w/w
`EtOH, * *P < 0.05 (ANOVA/Tukey’s) 13% w/w EtOH versus 5% w/w
`EtOH.
`
`4. Discussion
`
`This study investigated the effects of ethanol and surfactant
`(Pluronic L81) concentrations on drug particle size distri-
`bution and in vitro drug aerosol deposition using pMDIs
`containing propellant HFA 227. For solution—based pMDIs,
`these two excipient classes are common and often necessary
`for ensuring solubility and performance. Some previous
`studies have developed predictive models for solution—based
`formulations [15], but in general, these approaches have been
`to predict MMAD or fine particle fractions. Due to the
`dependency of pharmacokinetics and pharmacodynamics of
`inhaled products on deposition patterns, particularly in the
`challenging cases of matching performance, it may be more
`useful to match whole distributions rather than measures of
`
`central tendency or respirability.
`Although pluronics are not currently used in marketed
`pMDI products, several recent patents and publications have
`detailed the use of these surfactants in this manner [16—19].
`
`4
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`

`
`BioMed Research International
`
`>J>0
`U1
`
`NNUJUJOU1O
`
`r—- U1
`r—- 0
`
`
`
`
`
`Massofdrugdeposited(yg)
`
`U1 O
`
`11.7
`
`6.4
`
`3.99
`
`2.3
`
`1.36
`
`0.83
`
`0.54 MOC
`
`Aerodynamic cut—off diameters (pan)
`-9- 5% w/w EtOH
`--i-- 13% w/w EtOH
`— o — 10% w/w EtOH
`— I — 15% w/w EtOH
`
`FIGURE 4: The influence of ethanol cosolvent concentrations on the
`
`aerodynamic particle size characteristics of HFA 227 formulations
`as quantified using a Next Generation Impactor. Surfactant concen-
`trations were kept constant (data represent mean i SD, n = 3).
`MOC: microorifice collector. ‘P < 0.05 (ANOVA/Tukey’s) 15% w/w
`EtOH versus 10 and 5% w/w EtOH and “P < 0.05 comparing all
`formulations.
`
`The main motivation for this work was to determine if the in
`
`vitro aerosol performance of these model systems could be
`adequately modulated using the two components mentioned
`previously. Several literature reports confirm that increasing
`either cosolvent or surfactant concentrations resulted in
`
`increased emitted particle sizes. We observed that ethanol
`and the Pluronic L81 surfactant caused very different effects
`on the emitted particle size distributions when their concen-
`trations were altered. This was significant for several reasons.
`Firstly, it appears that the mechanisms by which droplet sizes
`were influenced by cosolvent versus surfactants were very
`different. Differing mechanisms would indicate that particle
`size could be manipulated independently using these two
`approaches. Furthermore, modulating drug particle size is
`important for either optimizing the performance of these
`products or matching the performance of products to those
`already approved by regulatory agencies across the world.
`Secondly, the pathway to regulatory approval of products
`(generic or otherwise) appears to focus on stage—by—stage
`deposition rather than mean or median values that are less
`sensitive markers of deposition. Therefore, the focus of many
`studies and literature reports has been MMAD and FPD
`and the ability to manipulate particle size distribution for
`lung targeting. This is considered an important aspect of
`formulation as the Food and Drug Administration (FDA) and
`other regulatory agencies are interested in cascade impactor
`stage—by—stage in vitro correlation. In this study, consistent
`with several previous investigations, we showed that vary-
`ing concentrations of cosolvent (ethanol) and surfactant
`(Pluronic L81) caused differences in aerosol particle sizes.
`Perhaps the most challenging aspect in reformulating
`pMDIs, with surfactants traditionally employed in CFC-
`based pMDIs and found in FDA—approved products, is the
`limited solubility in the more polar HFAs [7, 20]. Sur-
`factants are generally required in solution and dispersion
`
`formulations as solubilising/dispersing agents and as valve
`lubricants [5]. Cosolvents are generally required in HFA-
`based formulations to aid in the solubilisation of surfactants
`
`[5] which could affect the vapor pressure of pMDI mixtures
`and thus the aerosol respirable fraction. The development
`of novel surfactants for HFA—based pMDIs has been limited
`but several groups focusing on this task using suspension
`based pMDIs [21], and recently pluronic copolymers have
`been investigated as potential surfactants in solution based
`pMDI formulations by Ridder et al. [22] who used Pluronic
`L81 surfactant and found good solubility in HFA 227.
`As Pluronic L81 concentrations were increased, a pop-
`ulation modal shift to higher particle sizes was observed.
`The elevated MMAD and VMD values associated with
`
`higher concentrations of Pluronic L81 may be attributed to
`strong hydrogen bonding between Pluronic L81 and HFA
`227 and the surface active nature of Pluronic L81 resulting
`in decreased evaporation rates from droplet surfaces [8,
`23]. Similar to cosolvent effects, another explanation is
`the decreased propellant fraction leading to reduced vapor
`pressures and reduction of atomization energy at the nozzle
`[8]. Consequently, the increase in MMAD and VMD with
`increasing Pluronic L81 concentration from 1.22 to 5.45% w/w
`resulted in a greater deposition of drug in the throat, reduced
`the fraction of emitted dose with dae S 4.6 yin, and hence
`reduced FPF and FPD. However, there appear to be important
`differences in the mechanism of particle size modulation
`between ethanol and Pluronic L81 (see Figures 2 and 4). It can
`be seen that the effects of increasing surfactant concentration
`are somewhat different from those patterns observed with
`cosolvents which had the effect of moving the particle size
`distributions along the ordinate axis and not the abscissa.
`Considerable work on solution formulations has been
`
`reported by several groups including Stein et al. from 3M
`[24—28]. The correlation of increasing cosolvent concentra-
`tions resulting in enhanced particle sizes has been attributed
`to the reduced energy available for atomization due to the
`decreased vapor pressures [11] and increased droplet sizes
`owing to either slow or incomplete evaporation [29] at
`these time scales. These studies show that ethanol caused a
`
`decrease in the relative proportion of fine particles due to
`the decrease in vapor pressure of the solution as we add
`ethanol. The amount of fine particles in the aerosol cloud
`is directly proportional to the square root of the pressure-
`as ethanol concentration increases, the vapor pressure of the
`solution decreases; hence, the number of fine particles also
`decreases. This was supported by the observation of greater
`drug deposition in the USP induction port for formulations
`of higher ethanol content in our investigations. Moreover,
`the laser diffraction data (obtained before significant evap-
`oration could occur) appears to support this theory, showing
`much higher particle sizes than those obtained from cascade
`impaction studies [26, 30, 31].
`With these differences in mind, we hypothesize that the
`particle size “fingerprint” for HFA solution formulations may
`be unique to the excipient selection and relative concentra-
`tions. If the mechanisms by which particle size distributions
`are modulated by cosolvents and surfactants are independent
`of each other, a design space may be generated for each
`
`5
`
`

`
`r—- O\O
`_.
`
`D—‘D—‘8388883 Massofdrug
`
`deposited(ug)
`
`9
`
`6.4
`3.99
`2.3
`1.36
`MOCI 0.54 I 0.83
`Aerodynamic cut—off diameters (um)
`
`11.7
`
`FIGURE 5: Concept of the design window illustrated for solution-
`based HFAs containing cosolvent (changing amplitude of the par-
`ticle size mode, vertical tuning) and surfactants (changing location
`of the mode, horizontal tuning) in which particle size modulation
`may be achieved by manipulation of these two components that act
`through independent mechanisms to effect particle size change.
`
`system (see Figure 5). In terms of reformulation efforts
`and development of equivalent generic pMDIs, this type of
`approach could be used to match the stage—by—stage analysis
`or particle size fingerprint more rapidly. Studies in our labs
`are currently underway to thoroughly test these hypotheses
`using surface response analysis.
`
`5. Conclusion
`
`The purpose of these studies was to understand cosolvent
`and surfactant contributions to particle size distributions
`emitted from solution metered dose inhalers based on the
`
`propellant HFA 227. These studies build on several pre-
`vious published investigations using the propellant HFA
`134a. Here, for the first time, we describe how particle size
`distributions can be modulated differently using two different
`formulation excipients by shifting size distribution modes to
`different locations and by modifying the amplitude of the
`modes. The practical implications of using these excipients
`to independently modulate particle size distributions are
`that a formulation window can be generated from which
`reformulation or bioequivalence research and development
`can be facilitated.
`
`Acknowledgments
`
`The authors would like to acknowledge that a portion of this
`work was performed by them when working at the College
`of Pharmacy, University of New Mexico, USA. This research
`received no specific grant from any funding agency in the
`public, commercial, or not—for—profit sectors.
`
`References
`
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`7
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