JOURNAL OF AEROSOL MEDICINEVolume 20, Number 1, 2007© Mary Ann Liebert, Inc.Pp. 59–74DOI: 10.1089/jam.2006.0531

Characterization of Deposition from Nasal Spray DevicesUsing a Computational Fluid Dynamics Model of the

Human Nasal Passages

JULIA S. KIMBELL, Ph.D.,1 REBECCA A. SEGAL, Ph.D.,1 BAHMAN ASGHARIAN, Ph.D.,1BRIAN A. WONG, Ph.D.,1 JEFFRY D. SCHROETER, Ph.D.,1 JEREMY P. SOUTHALL, Ph.D.,2

COLIN J. DICKENS,2 GEOFF BRACE,2 and FREDERICK J. MILLER, Ph.D.1

ABSTRACT

Many studies suggest limited effectiveness of spray devices for nasal drug delivery due pri-marily to high deposition and clearance at the front of the nose. Here, nasal spray behaviorwas studied using experimental measurements and a computational fluid dynamics model ofthe human nasal passages constructed from magnetic resonance imaging scans of a healthyadult male. Eighteen commercially available nasal sprays were analyzed for spray character-istics using laser diffraction, high-speed video, and high-speed spark photography. Steady-state, inspiratory airflow (15 L/min) and particle transport were simulated under measuredspray conditions. Simulated deposition efficiency and spray behavior were consistent withprevious experimental studies, two of which used nasal replica molds based on this nasalgeometry. Deposition fractions (numbers of deposited particles divided by the number re-leased) of 20- and 50-�m particles exceeded 90% in the anterior part of the nose for most sim-ulated conditions. Predicted particle penetration past the nasal valve improved when (1) thesmaller of two particle sizes or the lower of two spray velocities was used, (2) the simulatednozzle was positioned 1.0 rather than 0.5 or 1.5 cm into the nostril, and (3) inspiratory airflowwas present rather than absent. Simulations also predicted that delaying the appearance ofnormal inspiratory airflow more than 1 sec after the release of particles produced results equiv-alent to cases in which no inspiratory airflow was present. These predictions contribute tomore effective design of drug delivery devices through a better understanding of the effectsof nasal airflow and spray characteristics on particle transport in the nose.

Key words: computational fluid dynamics, particle desposition, nasal spray, nasal value, spraycharacteristics

59

INTRODUCTION

THE ADMINISTRATION of inhaled therapeutics viathe nasal mucosa can lead to enhanced drugdelivery both locally and systemically.(1) Advan-

tages of nasal drug delivery include a large sur-face area for absorption,(2) relatively rapid deliv-ery to systemic circulation, and avoidance of thegastrointestinal tract with first-pass metabolismin the liver.(3) Intranasal delivery is noninvasive

1The Hamner Institutes for Health Sciences.2Bespak Europe Ltd., Milton Keynes, United Kingdom.

and is considered a potential replacement deliv-ery method for some medications currently re-quiring injection.(1,4) This substitution should im-prove patient compliance with prescriptioninstructions and is especially attractive for chil-dren. In addition, the spectrum of potential ther-apeutic areas is large, ranging from crisis man-agement and vaccination to treatments for manydisease states involving the respiratory tract andother organ systems.(3)

The delivery of drugs via the nasal passagesalso faces some challenges. Experimental studiesindicate that many nasal spray devices depositmost of their material in the anterior portion ofthe nose,(2,5–10) with little of the spray reachingthe turbinates.(5) To be efficacious, nasally deliv-ered drugs must have a high potency, potentiallyleading to side effects including nasal tissue irri-tation(3) and taste aversion. Optimal intranasaldistribution of nasal sprays usually requires thatthe delivered spray penetrate the nasal valvearea.(11) In addition, the drug must survive mu-cociliary clearance and pass through the enzyme-rich nasal mucosa to reach systemic circulation.(3)

Therefore, nasal drug delivery will be improvedby efforts to understand both delivery and for-mulation issues.

Quantitative data on device performance areavailable that allow some comparisons to bemade among different delivery methods, sprayangles, particle sizes, and patient-related factorssuch as inhaler orientation, head position, and in-spiratory airflow rates (Table 1). These studies

imply that nasal sprays result in fairly targeteddeposition patterns(2,5) that cover more area, areretained longer, and may penetrate the nose bet-ter if spray velocity, spray angle, and particle sizeare decreased.(2,7,12) The studies also imply thatinhaler and patient positioning and the speed ofinspiratory airflow do not have much effect onthe regional deposition of nasal sprays.(6,8,10,13,14)

However, no comprehensive study of the sensi-tivity of nasal deposition patterns to a series ofdifferent spray characteristics, particularly parti-cle size, under normal use conditions is available,in part because such a study is complex and theassociated experiments are expensive. Yet this in-formation could provide a better understandingof the interactions between nasal anatomy,sprays, and spray devices that could be used toimprove nasal drug delivery.

The main obstruction to adequate delivery ofnasal sprays is the nasal valve,(15) the region ofmaximum resistance to airflow located in the an-terior part of the nose.(16) The nasal valve is de-scribed in several different ways in the medicalliterature. It is formed by the cartilaginous tissuesof the external area of the nose, the pyriform aper-ture of the skull, and some medical descriptionsinclude the anterior aspects of the middle and in-ferior turbinates.(17,18) Other sources define thenasal valve in conjunction with acoustic rhinom-etry as the part of the nose in which the cross-sectional area of the nasal airways is mini-mized.(16,19) Nasal sprays intended to reach theciliated mucosa of the nose must penetrate the

KIMBELL ET AL.60

TABLE 1. EXPERIMENTAL STUDIES COMPARING METHODS OF NASAL DRUG DELIVERY

Delivery method Experimental findings

Metered aerosol vs. No differences in regionalmetered spray pump deposition(6)

Drops vs. spray Drops coated more nasal Variable delivery tosurface and cleared faster(5) middle meatus(11)

Nebulizer vs. spray Nasal nebulizer enhancedpump posterior and superior nasal

deposition(2)Effect of spray angle Decreased angle lowered Increased angle

particle retention and increased increased anterior nosedeposition area(7) deposition(12)

Effect of particle size Increased size increasedanterior nose deposition(12)

Inhaler orientation No effects on quantity reachingnose or initial distributionpattern(8)

Head position No effect on spray distribution(10)Effect of inspiratory No effect on regional deposition(6) No effect on distribution No effect on distribution

airflow patterns(13) patterns(14)

nasal valve region. More information on the rolesdifferent spray characteristics play in enhancingthe penetration of the spray past the nasal valveis needed in order to improve nasal drug deliv-ery.

An alternative approach to studying the roleof spray devices and characteristics in nasal valvepenetration is to use three-dimensional com-puter modeling. Anatomically accurate, three-dimensional computer models of the humannasal passages have been constructed from sec-tioned casts,(20,21) computed tomography (CT)scans,(22–25) and magnetic resonance imaging(MRI) scans.(26) Computational fluid dynamics(CFD) methods have been used to simulate air-flow(20–23,26) as well as particle transport(20,23) inthe lumen of the human nose.

In the present study, nasal spray behavior wasstudied using the CFD model of Subramaniamand colleagues,(26) in-house particle transportsoftware,(27) and experimental studies character-izing the sprays from 18 different commerciallyavailable nasal spray devices.(28) The nasal valveregion of the CFD model was identified to allowcalculation of the fraction of sprayed material thatwas predicted to penetrate past this area. Exper-imentally, spray angles ranged in size from 32°to 79°, average spray velocities ranged from 1.5to 14.7 m/sec, and droplet sizes averaged about50 �m.(28) This information was used as the basisfor estimating the effects of three nozzle posi-tions, two spray angles, two spray velocities, twoparticle sizes, and the presence, delayed presence,or absence of inspiratory airflow on the fractionof sprayed material that penetrated the nasalvalve. The main purposes of this study were to(1) confirm that the CFD model could captureparticle and spray behavior as described in pre-vious experimental studies, (2) suggest reasonsfor limitations evident in current drug deliveryvia nasal sprays, and (3) suggest potential waysin which spray penetration could be improved.

MATERIALS AND METHODS

In this section, overviews of the CFD and par-ticle transport models are given with descriptionsof the major assumptions upon which the mod-els and simulations are based. The simulation ofspray releases and estimated nozzle positions inthe nasal vestibule are described. The nasal valvearea of the model is defined and used to estimate

the fraction of particles that were predicted to de-posit in the nose posterior to this location. Thepredicted effects of multiple combinations ofspray characteristics on nasal valve penetrationare described by conducting a series of spray sim-ulations under conditions described below. Com-parisons of total nasal deposition efficiency andspray behavior predicted using the CFD modelwith experimental measurements are made.

Simulation of nasal airflow and particle transport

A three-dimensional, human nasal CFD modelprovided the anatomical shape, computationalmesh, and inspiratory airflow patterns used inthe simulations conducted here. This CFD modeland a comparison of simulated airflow with ex-perimental measurements were described in de-tail by Subramaniam and colleagues.(26) Briefly, afinite-element mesh (Fig. 1A)(29) was constructedfrom 72 cross sections, spaced 1.5 mm apart,based on MRI scans of a healthy, adult, non-smoking male using in-house software(30) and thecommercial CFD package FIDAP (Fluent, Inc.,Lebanon, NH). The mesh was constructed of six-sided, brick-shaped elements and contained ap-proximately 156,000 nodes. FIDAP was also usedto simulate steady-state airflow in the inspiratorydirection at 15 L/min with a uniform velocityprofile (plug flow) imposed at the nostrils, ve-locity set to zero at airway walls (no-slip condi-tion), and the normal velocity gradients set tozero at the outlet. Simulated airflow velocitieswithin the nose were confirmed using publishedmeasurements.(26)

The major patterns of inhaled airflow simu-lated at steady-state were assumed to be similarto those occurring during resting breathing basedon calculation of the Strouhal number, or fre-quency parameter.(26) Unsteady effects may beconsidered insignificant when the frequency pa-rameter is less than 1.(31) The Strouhal number,S � �L/u, where �, L, and u are the breathingfrequency, axial length of the nasal airway, andthe average velocity, respectively, is 0.02 in thehuman, using � � 0.25 Hz, L � 11 cm, and u �144 cm/sec, corresponding to a flow rate of 26L/min and a cross-sectional area of 3 cm2.(26) TheCFD model had rigid nasal walls, lacked mucusmovement and nasal hairs, and did not accountfor gain or loss of heat or humidity. These mod-eling constraints were assumed to contribute in-significantly to error in airflow simulations.

NASAL SPRAY DEPOSITION USING A 3D CFD MODEL 61

Because particles measured in many nasalspray products largely exceeded 5 �m in diame-ter, sedimentation, and inertial impaction arelikely to be the prevailing particle depositionmechanisms. Thus, the equations of motion forparticle transport were solved numerically for thecase when inertial forces are dominant. Particle-to-particle and particle-to-flow interactions wereassumed to be negligible, allowing airflow andparticle transport equations to decouple. Theseinteractions would become increasingly signifi-cant if particle volume density in the breathingair approached unity or if particle inertia becamelarge enough to affect surrounding airflow pat-terns, conditions that did not apply to the simu-lations presented here.

Airflow information was obtained from the FI-DAP simulations described above. Single-particletrajectories were calculated using the airflow in-formation as input to software developed in-house that solved the Lagrangian form of theequations of particle transport numerically.(27) A

computer algorithm, developed in C�� and im-plemented in Java, calculated particle trajectoryusing a Runge-Kutta scheme with variable timesteps. The error in numerical simulations was cal-culated at every particle location and checkedagainst a predetermined tolerance. The time stepwas then either reduced to improve the accuracyof the simulations or increased to shorten run-time. Particle trajectories were calculated until theparticle deposited, exited the nasal airway pas-sages, or the travel time exceeded a predeter-mined time scale typically near the breathing timeor a multiple thereof (e.g., 4 sec based on 15breaths per minute). The in-house particle solverused to track particle movement has been vali-dated and used in other studies involving aerosoltransport.(32)

Simulation of nasal sprays

Particle trajectory calculations allowed the ini-tial velocity of particles to be non-zero to simu-

KIMBELL ET AL.62

FIG. 1. (A) Lateral view of the finite-element mesh used in the computational fluid dynamics simulations. Nostrilsare to the left at arrow, nasopharynx is to the right. Reprinted with permission from Ref. (29). (B) Ventral view ofnostrils (black) showing locations of passive particle release points (white dots) for prediction of nasal deposition ef-ficiency.

http://www.liebertonline.com/action/showImage?doi=10.1089/jam.2006.0531&iName=master.img-000.jpg&w=326&h=305

late launching via a spray device. Particle trajec-tories from simulated spray releases were calcu-lated both in the presence, at 15 L/min, and inthe absence of inspiratory nasal airflow. Whenairflow was present, no spray device was de-picted as present in the nasal vestibule and it wasassumed that there was no disruption of normalinspiratory airflow patterns while particles werebeing transported. To account for time betweenspray activation and inspiration, trajectory calcu-lations included the option to begin trajectory cal-culation with no airflow present and introducenormal inspiratory airflow vectors at a later timepoint.

For each point of release, a group of particlesrepresenting a spray cone was instantaneouslydischarged with a specified spray cone angle andspray velocity. The group of spray particles con-sisted of a center particle launched from a releasepoint with up to three concentric rings of eightparticles each (subsprays) launched around thecenter particle from the same release point. Theinitial direction of the center particle’s motionwas determined by the ray from a fixed nostrilreference point to the particle release point (Fig.2). The initial directions of the subspray particles’

motion were determined by evenly spaced raysat angular intervals from 0° to the spray cone an-gle. The spacing of the subsprays was such thatall sphere sectors formed by initial spray vectortips were of equal area. The duration or lifetimeof the spray, potential effects of sprays on normalinspiratory airflow patterns, and interactions ofspray particles with each other were not simu-lated.

Three sets of particle release points, located 0.5,1.0, and 1.5 cm into the left nostril, representedpossible nozzle tip locations. Comfortable uselimited the angle at which the spray nozzle wastilted to between 55° and 75° from the horizontalin the sagittal plane (Fig. 2). Each set of releasepoints consisted of a curved surface of evenlyspaced lattice of points lying between 55° and 75°from the horizontal plane inside the nasalvestibule, equidistant from a single referencepoint located on the nostril surface (Fig. 3).

All release points at a given nozzle penetrationdepth were considered equally representative ofpotential spray release locations because of vari-ability in patient use of spray devices. Resultsfrom spray releases at all lattice points on a givenrelease surface were therefore aggregated to re-

NASAL SPRAY DEPOSITION USING A 3D CFD MODEL 63

1 cm

75 degrees

55 degrees

FIG. 2. Side view of nasal model and inserted nasal spray device showing a simulated spray originating from a re-lease point in relation to the nostril reference point (black dot), and the range of comfortable nozzle positions from55° from the horizontal to 75° when the spray device is inserted 1 cm into nostril. Nostril reference point (black dot)represents the intersection of the axis of the device with the nostril surface.

duce effects of this variability on nasal valve pen-etration.

The nasal valve

A planar section in the anterior portion of theCFD model with minimum coronal cross-sec-tional area was found by first sweeping a planeperpendicular to the axial direction (90° from thehorizontal in the sagittal plane) through themodel and sampling cross-sectional area.(33) Thisplane was then tilted away from the top of thehead at 1° increments from 90° to 6° from the hor-izontal in the sagittal plane and cross-sectionalarea was sampled by sweeping each tilted planethrough the CFD model. Planes tilted from 90° to65° were also tilted by 1° increments from 0° to25° in the axial plane and swept through themodel to obtain cross-sectional area samples.Minimum cross-sectional area was obtained sep-arately for each side of the nose (Fig. 3).

To confirm model predictions of minimumcross-sectional area for identification of the nasalvalve area, comparisons were also needed withlaboratory and clinical measurements. Thesecomparisons can be difficult to interpret becausehuman nasal anatomy differs significantly amongindividuals. Therefore, two copies of hollow,

plastic molds of the nasal passages were createdfrom the same geometry that underlies the CFDmodel using a computer-aided design/com-puter-aided manufacturing (CAD/CAM) tech-nique called stereolithography.(34–36) Acousticrhinometry (Acoustic Rhinometer, Hood Labora-tories, Pembroke, MA) was then used to measurecross-sectional area in both sides of the nasal pas-sage in both plastic molds for comparison withthe minimum cross-sectional area calculated inthe CFD model and with values reported in theliterature.

Predictions of nasal spray behavior

Particle transport simulations were based onanalyses of 18 nasal sprays for particle size dis-tribution and spray characteristics.(28) Particletransport in the left-hand side of the nose undermeasured spray conditions was simulated, andeffects of three nozzle positions, two particlesizes, two spray angles, two spray velocities, andthe presence, delayed presence, or absence of in-spiratory airflow on particle penetration past thenasal valve area were calculated. Southall andcolleagues(28) measured particle size distributionsand found that most particles were between 50and 70 �m (mass median aerodynamic diameter),with sizes ranging from 20 to 150 �m. Simula-tions were conducted for 20- and 50-�m particlesreleased from nozzle penetration distances of 0.5,1.0, and 1.5 cm. These particle sizes were chosento better understand published studies (Table 1;50 �m) as well as to extend this understanding inan attempt to improve nasal valve penetration (20�m). Spray cone angles of 32° and 79° were used,representing the extremes of the range of mea-sured angles. Spray velocities were set to 1 and10 m/sec, representative of sprays in the mea-sured range from 1.5 to 14.7 m/sec. Simulationsalso included either the presence or absence ofnasal inspiratory airflow at 15 L/min, resultingin a total of 48 simulation cases. In addition, theeffect of time delays of 0.5 and 1.0 sec betweenthe release of particles and the presence of inspi-ratory airflow was studied for several cases. Sim-ulations were also conducted in which 20- and50-�m particles were passively released from theleft nostril inlet surface (Fig. 1B) with steady-state, inspiratory airflow present at 15 L/min forcomparison with spray simulations. The effect of30 L/min inspiratory airflow on left nasal valvepenetration of 20- and 50-�m particles released

KIMBELL ET AL.64

1.5 cm

1.0 cm

0.5 cmLeft Nasal Valve

FIG. 3. Locations of potential spray release points andleft nasal valve. White spherical pieces indicate all pointsin left side of the nose that are located 0.5, 1.0, and 1.5 cmfrom the nostril reference point (black dot). Areas of po-tential spray release (black patches on white sphericalpieces) appear as subsets of the white spherical pieceswhen the nozzle tip was allowed to vary between 55° and75° from the horizontal. Closeups show the most coarselattice of spray release points (gray dots) used in the sim-ulations.

from 1 cm into the nostril with a 1 m/sec, 79°spray was also studied in an attempt to identifyconditions that improved nasal valve penetra-tion.

The influence of the density of release pointsand the density of particles released in each spraycone on these results were examined for the casewhere nozzle penetration distance was set to 1cm. Three release point densities were used: abase mesh (6 points � 8 points), a refined mesh(9 points � 12 points), and a fine mesh (12points � 16 points). Three spray densities wereused: a coarse spray (center particle and one sub-spray released at the spray angle), a refined spray(center particle and two subsprays), and a finespray (center particle and three subsprays).

The deposition fractions reported here werecalculated as aggregates over all release points ona surface representing most potentially comfort-able nozzle positions. In a study using a physicalmodel based on the same nasal geometry as theCFD model used here, Cheng and colleagues(12)

studied spray deposition patterns that were theresult of sprays released from one (unspecified)nozzle position. In order to compare simulatedresults with the Cheng study,(12) nasal valve pen-etration predicted for the best 20- and 50-�m sim-ulation cases was also examined for each indi-vidual release point.

Confirmation of particle deposition predictions

To confirm CFD model predictions, compar-isons of simulation results with two types of ex-perimental studies were made: measurements ofnasal spray deposition and measurements ofnasal deposition efficiency. Results from the sim-ulation of nasal spray behavior as describedabove for 20- and 50-�m particles were comparedwith the results reported by the studies cited inTable 1. Because nasal deposition efficiency is ap-proximately 100% for particles 20 �m or greaterthat are inhaled at 15 L/min,(37) comparisons ofpredicted deposition efficiency with experimen-tal studies were made for particle sizes less than20 �m.

Most of the experiments that have been con-ducted to measure nasal deposition efficiency invivo have produced estimates from inhalation ofparticle-laden atmospheres.(38–44) In two of thesestudies, air was drawn in through the nose fromthe mouth at several flow rates while the subjectheld their breath.(38,40) Measurements of the de-

position of either 1- to 9-�m methylene blue so-lution aerosols(38) or radioactive polystyrene par-ticles, approximately 2 to 8 �m in aerodynamicdiameter,(40) were made using filters.

Nasal deposition efficiency was also measuredin copies of the hollow plastic replica molds usedfor acoustic rhinometry, as described in the NasalValve section above.(36) In these experiments, liq-uid droplets between 1 and 10 �m in aerody-namic diameter were drawn through the hollowmold at several flow rates. Particle concentrationswere measured at the inlet and outlet of the nasalmold and were used to calculate deposition effi-ciency.

The present study focused on large particletransport in which sedimentation and inertialforces are dominant. Comparisons of model pre-dictions with experimental measurements weretherefore confined to particles �5 �m in diame-ter. To compare model predictions with thesemeasurements, simulations were conducted inwhich particles ranging from 6 to 10 �m in di-ameter were passively released from both nostrilinlet surfaces (Fig. 1B) with steady-state, inspira-tory airflow present at 20 L/min. This flow ratewas selected as one used by all three of the Pat-tle,(38) Hounam,(40) and Kelly(36) studies that wasclose to the flow rate of 15 L/min used in the sim-ulations of nasal sprays. Deposition efficiencywas calculated by weighting each particle that de-posited by the proportion of flow through thenostril element from which the particle originatedand aggregating these results for all depositedparticles.

Data analysis

Predictions of the number of particles that de-posited, deposition locations, and particle trajec-tories were recorded. Deposition fractions, de-fined as the number of deposited particlesdivided by the number of particles released andexpressed as a percentage, were calculated for theentire nasal passages and for the nasal vestibuleanterior to the nasal valve plane. Of the particlespredicted to deposit, those that passed the nasalvalve plane were identified.

An analysis was conducted to determinewhether there were statistically significant dif-ferences among nasal valve penetration fractionswhen individual simulation parameters werechanged. The simulation data represented a com-pletely randomized design with five factors: dis-

NASAL SPRAY DEPOSITION USING A 3D CFD MODEL 65

tance of the spray nozzle from the nostril, airflowpresence or absence, particle size, spray velocity,and spray angle. Distance from the nostril hadthree values whereas the other factors had twoeach, resulting in a total of 48 factor combinations.The outcome variable was the percent of de-posited particles penetrating the nasal valve. Anarcsine transformation,(45) which is commonlyused with percentage data, was applied to theoutcome variable to ensure adherence to the as-sumptions needed for analysis of variance(ANOVA). Given the large number of factor com-binations of interest (48 cases), ANOVA methodswere preferable to less powerful nonparametricmethods. The ANOVA included all five main ef-fects and all 10 first-order interactions.

RESULTS

Anatomical factors affecting spray deposition

Based on the geometric constraints on nozzleposition used in these studies, namely, that thenozzle did not penetrate further than 1.5 cm intothe nose and that nozzle tilts in the sagittal planefrom 55° to 75° represented limits of a comfort-able range of nozzle positions, CFD predictionsindicated that spray devices release particleswithin very small, constricted regions in the nasalvestibule (Fig. 3). The approximate surface areaof each the three release surfaces identified in thisstudy was less than 0.20 cm2.

The minimum cross-sectional area for the leftside of the nose, defined as the position of thenasal valve for this study, was estimated to be0.72 cm2, located on a plane tilted 90° towardthe top of the head in the sagittal plane and 7°toward the left side of the nose in the axialplane, at an average distance of about 3 cm fromthe nostril surface (Table 2). The minimumcross-sectional area for the right side of the nose

was estimated to be 0.64 cm2, located on a planetilted 70° toward the top of the head in thesagittal plane and 15° toward the left side of thenose in the axial plane, at an average distancefrom the nostril on the left side of about 3 cm.Minimum cross-sectional area for the left sideas measured by acoustic rhinometry was 0.65cm2 in one stereolithography mold and 0.68 cm2

in the other, at an approximate distance of 2.3cm from the nostril. Minimum cross-sectionalarea for the right side as measured by acousticrhinometry was 0.64 cm2 in one stereolithogra-phy mold and 0.66 cm2 in the other, at an ap-proximate distance of 2.3 cm from the nostril.The plane where cross-sectional area on the leftside of the nose was minimized was used to de-fine the nasal valve for the purposes of the stud-ies described here.

Predictions of nasal spray behavior

In all simulated cases described in this paper,no particles were predicted to pass entirelythrough the nasal passages, i.e., all spray deposi-tion fractions of 20- and 50-�m particles were100% in the nasal passages, except in three casesin which some of the released particles were pre-dicted to fall out of the nose through the nostrilbecause of sedimentation (Table 3). Out of 48spray simulation cases, 15 resulted in a non-zeropercentage of particles predicted to penetrate theleft nasal valve (Table 3). Deposition fractions inthe nasal vestibule exceeded 90% under mostsimulated conditions. Most particles that pene-trated the nasal valve were predicted to depositon the middle and inferior turbinates and the ad-jacent lateral walls and septum. Simulations pre-dicted that spray deposition patterns were gen-erally dorsal when the spray nozzle was placed1.5 cm into the nostril and showed ventral depo-sition when the nozzle was placed at 0.5 cm intothe nostril (Fig. 4).

KIMBELL ET AL.66

TABLE 2. MINIMUM CROSS-SECTIONAL AREA IN A CFD MODEL AND PLASTIC MOLDS OF THE CFD MODEL

Left side Right sideDistance from Distance from

Model Area (cm2) nostril (cm) Area (cm2) nostril (cm)

Plastic Mold Aa 0.65 2.3 0.64 2.3Plastic Mold Ba 0.68 2.3 0.66 2.3CFD Modelb 0.72 3.0 0.64 3.0

aMeasured using an acoustic rhinometer.bPredicted by planar cross-sectional area.

More particles were predicted to pass the nasalvalve before depositing when the spray nozzlewas placed 1 cm into the nostril, airflow was pre-sent, and 20-�m particles were released with avelocity of 1 m/sec and a cone angle of either 32°or 79° than when sprays were simulated underother combinations of conditions (Fig. 4; Table 3).Simulations predicted that no more than about20% of spray particles passed the nasal valve be-fore depositing under the conditions of this study(Table 3).

Predictions of the fraction of particles thatpassed the nasal valve before depositing showedstatistically significant improvement (Fig. 5)when (1) particle size and spray velocity de-creased (p � 0.001), (2) nozzle penetration dis-tance was equal to 1 cm (p � 0.002), and (3) air-flow was present (p � 0.001). Effects of sprayangle on predicted nasal valve penetration werenot statistically significant, though there was gen-erally a slight increase in the fraction penetratingthe nasal valve when spray angle increased. Ofall the simulation conditions studied, particlepenetration past the nasal valve was most sensi-tive to the presence of inspiratory airflow, sprayvelocity, and particle size.

NASAL SPRAY DEPOSITION USING A 3D CFD MODEL 67

TABLE 3. PREDICTED PENETRATION OF NASAL VALVE BY PARTICLES RELEASEDFROM CURRENTLY MARKETED NASAL SPRAY DEVICES (NONZERO CASES)

Distance from Airflow rate Particle Spray velocity Spray angle % % Falling % Passingnostril (cm) (L/min) size (�m) (m/sec) (degrees) Deposition out nostril left NV

0 15 20 NAa NA 100 0 90 15 20 NAa NA 100 0 20.5 0 50 1 79 98 2 0.b0.5 0 20 1 32 55 45 0.b0.5 0 20 1 79 52 48 0.b0.5 15 50 1 32 100 0 30.5 15 50 1 79 100 0 20.5 15 20 10 32 100 0 10.5 15 20 10 79 100 0 20.5 15 20 1 32 100 0 60.5 15 20 1 79 100 0 61 15 50 10 79 100 0 11 15 50 1 32 100 0 41 15 50 1 79 100 0 41 15 20 10 79 100 0 11 15 20 1 32 100 0 181 15 20 1 79 100 0 191.5 15 50 1 79 100 0 11.5 15 20 1 32 100 0 31.5 15 20 1 79 100 0 4

aNA, not applicable. These studies represent simulations of particles passively released from the left nostril surface.

bThese cases are included to show predicted loss of sprayed particles through nostril by sedimentation.NV, nasal valve.

A B

DC

FIG. 4. Examples of deposition patterns in cases forwhich nasal valve penetration was high. The left nasalvalve is indicated as a black cross section in all views.Steady-state, inspiratory airflow at 15 L/min was present,spray velocity was 1 m/sec, and spray angle was 79° inall cases shown here. (A) Nasal valve penetration, 19%(highest case); particle size, 20 �m; nozzle penetration dis-tance, 1.0 cm. (B) Nasal valve penetration, 6%; particlesize, 20 �m; nozzle penetration distance, 0.5 cm. (C) Nasalvalve penetration, 4%; particle size, 20 �m; nozzle pene-tration distance, 1.5 cm. (D) Nasal valve penetration, 4%(highest 50–�m case); particle size, 50 �m; nozzle pene-tration distance, 1.0 cm.

The statistically significant improvements inpredicted nasal valve penetration were repre-sented graphically by grouping all 48 spray sim-ulation cases by each of three variables: particlesize (Fig. 5A), spray velocity (Fig. 5B), and noz-zle position (Fig. 5C). When the 48 cases in eachgraph were further marked by whether inspira-tory airflow was present (Fig 5, open circles) ornot (Fig. 5, closed circles), the advantage of hav-ing airflow present was evident. Otherwise, eachgraph showed the trend for one variable at a time.

The effect of a time delay of 0.5 sec betweenthe release of particles and the appearance of nor-mal inspiratory airflow was studied for the casesin which the number of particles predicted to passthe nasal valve before depositing was highest.The simulated time delay did not change thenumber of particles predicted to pass the nasalvalve, but the predicted deposition sites of theseparticles changed. With no time delay, approxi-

mately 1% of released particles were predicted todeposit on the inferior turbinate and approxi-mately 9% were predicted to deposit on the mid-dle turbinate. With a 0.5-sec delay in the presenceof normal inspiratory airflow, 4% to 5% of re-leased particles were predicted to deposit on theinferior turbinate and no particles were predictedto deposit on the middle turbinate (Fig. 6). A timedelay of 1 sec produced results equivalent to thecases in which no inspiratory airflow was everpresent.

Simulation results for the 1-cm nozzle positionwere unaffected by refinement of the density ofparticle release points and were not sensitive tothe density of particles released in each spraycone. Left nasal valve penetration fractions of 20-and 50-�m particles released from 1 cm into thenostril in a 1-m/sec, 79° spray were predicted tobe 15% and 5% with 30 L/min inspiratory airflowpresent, respectively.

KIMBELL ET AL.68

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ve

20 30

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40 50

15 L/minNo airflow

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12

14

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18

20A

0 2

Per

cent

of D

epos

ited

Par

ticle

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at P

asse

dth

e N

asal

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ve

4 6

Spray Velocity (m/s)

8 101 3 5 7 90

2

4

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8

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20B

0

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asal

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ve

Distance from Nostril (cm)

1.50.5 10

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20C

FIG. 5. Effects of (A) particle size, (B) spray velocity, (C)nozzle penetration distance and nasal airflow (black cir-cles � no nasal airflow present; open circles � 15 L/mininspiratory airflow present) on nasal valve penetration.Each graph shows all 48 spray simulation cases.

Confirmation of particle deposition predictions

Simulations predicted that nasal sprays depositprimarily in the anterior part of the nose and thatincreased particle size decreased nasal valve pen-etration, in agreement with most experimentalstudies. Simulations also predicted that better

penetration of the nasal valve was achieved atlower initial spray velocities, in agreement withthe finding that particles from a nasal nebulizerdeposited more posteriorly in the nose than par-ticles from a spray pump.(2)

Simulations of the passive release of particlesat the nostril surface did not predict an improve-ment in nasal valve penetration over low-veloc-ity sprays for 20- and 50-�m particles (Table 3).However, previous simulations with the CFDmodel used here predicted that the passive re-lease of particles from locations inside the nasalvestibule have greater turbinate deposition thanparticles passively released at the nostril surfaceunder the same flow conditions.(29) In the nebu-lizer vs. spray pump study, Suman and col-leagues(2) used “a nasal adapter specifically de-signed to simultaneously administer aerosol intoboth nostrils without depositing activity on theoutside of the nose.” Particles emitted from thisadapter may have been released inside the nasalvestibule, somewhat distal to the nostril surface.If this were the case, then simulation results werein general agreement with the Suman study find-ings. However, in that study the nasal nebulizeralso produced much smaller particles (approxi-mately 6 �m) than the spray (approximately 79�m), which would contribute to the difference indeposition patterns.

Simulations predicted a statistically significanteffect (p � 0.001) of the presence of inspiratory air-flow at 15 L/min on the number of particles pen-etrating the nasal valve, but this effect was con-siderably smaller at the higher spray velocity of10 m/sec. This result agreed with the observationthat the presence or absence of 10 L/min airflowdid not affect regional particle deposition in an ex-perimental study in which spray velocities werehigher than 3 m/sec.(6) The highest fractions of 20-and 50-�m particles that were predicted to pene-trate the left nasal valve from 1 cm into the nos-tril did not change appreciably when inspiratoryairflow was increased from 15 L/min to 30 L/min.These results are in agreement with the observa-tions that (1) there were no statistically significantdifferences in nasal distribution patterns of budes-onide particles inhaled at 30 or 45 L/min wheremost particles were larger than 10 �m,(13) and (2)spray deposition was unaffected by gentle or vig-orous sniffing in a study where most particleswere likely to be larger than 50 �m.(14)

Estimates of nasal deposition efficiency pre-dicted by the CFD model for 6- to 10-�m parti-

NASAL SPRAY DEPOSITION USING A 3D CFD MODEL 69

No airflow

0 sec airflow delay

0.5 sec airflow delay

FIG. 6. Effect of a 0.5-sec time delay in the appearanceof inspiratory airflow at 15 L/min on the deposition pat-tern of 20-�m particles released from a nozzle placed 1cm into the nostril with a velocity of 1 m/sec and a sprayangle of 32°.

cles inhaled at the nostrils at 20 L/min were alsocompared with experimental measurements ofinhaled particles in the same size range at thisflow rate. CFD model predictions for the 6- to 10-�m size range agreed well with experimentallymeasured values (Fig. 7).

Regional particle deposition using nasal spraypumps was previously studied experimentally ina hollow nasal mold constructed from a series ofcomputer-milled plates.(12) Deposition of 50- to 60-�m particles was higher in the turbinate regionthan in the nasal vestibule for three out of four dif-ferent spray pumps, and penetration into the nosewas generally observed to decrease with increas-ing spray angle.(12) A fixed nozzle position wasused, but no other position information was avail-able. Simulations reported here predicted that theaggregated deposition of 50-�m particles washighest in the nasal vestibule and that there wasno statistically significant effect of spray angle onthe number of particles penetrating the nasal valve.However, when each release point was examinedindividually, penetration fractions of 50-�m parti-cles were as high as 21% in the highest aggregatepenetration case where particles were released at1 m/sec with inspiratory airflow present using aspray cone angle of 79°. The highest individualpenetration value increased to 33% when the spraycone angle was decreased to 32° (Fig. 8A).

Cheng and colleagues(12) used a polydisperseaerosol, so we examined individual release pointpenetration for the best 20-�m cases as well. In-

dividual penetration fractions of 20-�m particleswere as high as 91% in the highest aggregate pen-etration case, where particles were released at 1m/sec with inspiratory airflow present using aspray cone angle of 79°. The highest 20-�m pen-etration value increased to 100% when the spraycone angle was decreased to 32° (Fig. 8B). If oneassumes that a combination of these monodis-perse predictions may be used as a crude estimateof actual polydisperse penetration, these resultsare in agreement with the findings from theCheng study.(12)

DISCUSSION

The CFD model study presented here providedquantitative estimates of the effects that nasalanatomy and different combinations of spray andairflow characteristics may have on nasal valvepenetration. This study was undertaken to (1)confirm that the CFD model could capture parti-cle and spray behavior as described in previousexperimental studies, (2) suggest reasons for lim-itations evident in current drug delivery via nasalsprays, and (3) suggest potential ways in whichspray penetration could be improved. A CFD ap-proach was used as a comprehensive way to ex-amine nasal drug delivery in an anatomically cor-rect environment.

The estimates obtained here were consistentwith measurements obtained experimentally. Theability to compare calculations for multiple com-binations of nozzle position and spray character-istics allowed model results to augment existingexperimental measurements and provide addi-tional context. Thus, additional interpretations ofexperimental results were possible, as describedabove, in the context of particle sizes, spray ve-locities, inspiratory airflow rates, and spray noz-zle positions other than those that had been phys-ically examined.

Major factors limiting the effectiveness of nasalspray devices were identified as (1) physical con-straints on the release of particles, such as thesmall size of areas where particles can be releasedcomfortably and the close proximity of the nasalvalve to the tip of the spray device; (2) spray char-acteristics such as large particle size and highspray velocity; and (3) delayed appearance of in-spiratory airflow. Because the physical distanceto the nasal valve was only 1 or 2 cm from thepoint of spray emission (Fig. 3), spray character-

KIMBELL ET AL.70

FIG. 7. Comparison of experimentally measured nasalparticle deposition efficiency (open symbols)(36,38,40) andsimulation results (black circles) for passive release of par-ticles at the nostrils (see Fig. 1B) with 20 L/min steady-state inspiratory airflow present.

izations measured in open air more than 2 cmfrom the nozzle tip may be largely irrelevant inthe nasal passages. In addition, this study sug-gested the existence of “sweet spots” for particlerelease (Fig. 8), which may differ substantiallyamong individual patients.

Among the 48 spray cases simulated, the bestnasal valve penetration was predicted when theparticle size was 20 �m, spray velocity was 1m/sec, spray angle was 79°, the spray nozzle wasinserted 1 cm into the nose, and gentle inspira-tory airflow was present. These results suggested

NASAL SPRAY DEPOSITION USING A 3D CFD MODEL 71

B.

Medial wall

Nasal tipLateral wall

Nasal passages

88 8894

100 85

76

73

67

64

A.

Medial wall

Nasal tip

Nasal passages

Lateral wall

33

24 27

FIG. 8. Nasal valve penetration fractions predicted for each individual release point located 1 cm into the left nasalpassage for two sets of parameter values. Steady-state, inspiratory airflow at 15 L/min was present, spray velocitywas 1 m/sec, and spray angle was 32° in both cases shown here. (A) Plot for the simulated release of 50-�m parti-cles. (B) Plot for the simulated release of 20-�m particles. Note that tall bars predict the presence of a “sweet spot”from which a large fraction of released particles penetrate past the nasal valve.

that nasal valve penetration by nasal sprays couldbe improved if smaller particles were generated,lower spray velocities were used, particles werereleased inside the nasal vestibule, and delays be-tween the release of particles and the presence ofgentle inspiratory airflow were minimized. Theseconclusions were based on aggregated results ofsprays released at multiple possible points foreach nozzle position in order to reduce patientvariation in the use of the spray device.

The CFD model also provided new insightsinto the extent to which the presence and timingof inspiratory airflow could affect nasal spray de-position. For example, the CFD model predictedthat with no inspiratory airflow present, almost50% of 20-�m particles released from 0.5 cm intothe nostril at 1 m/sec fell out of the nose throughthe nostril, with none of the remaining particlespenetrating the nasal valve. Under the samespray conditions but with inspiratory airflow pre-sent, the CFD model predicted that none of theparticles would fall out of the nostril and that 6%of them would able to penetrate past the nasalvalve. In another example, a half-second delay inthe onset of simulated inspiratory airflow relativeto the spray release resulted in a predicted shiftof deposition sites from dorsal to ventral loca-tions. Delays longer than 1 sec were predicted toresult in the same effects as the case when no air-flow had ever been present.

Other information obtained from CFD model-ing was the approximate size, shape, and posi-tion of the nasal valve as a potential barrier toparticle transport. The nasal valve is best de-scribed as an area or region in the anterior partof the nose because its size and position can shiftwith congestion and decongestion (personal communication, Dr. David Wexler, M.D., FallonClinic at Worcester Medical Center, Worcester,MA). For the purposes of this study, a singlecross-sectional location was identified so thatnasal valve penetration could be defined quanti-tatively, representing a snapshot in time of an in-dividual’s nasal passages. The nasal valve crosssection used in this study was distal to the ante-rior margin of the inferior turbinate. Particles pre-dicted to deposit on approximately 0.75 cm of theanterior portion of this turbinate were thereforenot included in estimates of the number of parti-cles penetrating the nasal valve. Further study isneeded to determine the effects of normal nasalcycling and other congestion on the size, shape,and position of the nasal valve region.

The minimum cross-sectional area (MCA) inthe left side of the CFD model was located ap-proximately 3 cm from the left nostril, probablyin the vicinity of the pyriform aperture, in agree-ment with a physiological study that placed thelocus of maximal nasal airflow resistance at thisregion.(17) This location does not compare as wellwith the distance of 2.3 cm estimated by acousticrhinometry (AR) in hollow replicas of the CFDmodel. However, comparisons of distances esti-mated using AR and MRI or CT scans can be dif-ficult because the axes of sound waves and scansdo not generally coincide.(46) MCA predicted byplanar cross sections in each side of the CFDmodel showed reasonable agreement with ARmeasurements in plastic replicas of the samegeometry (Table 2). Total MCA (both sides of thenose added together) was predicted by the CFDmodel to be 1.36 cm2 and was in agreement with measurements reported by Millqvist andBende(47) who used AR to show that MCA inmales ranged from 0.40 to 1.00 cm2 per side, witha mean value of 1.56 cm2 for total MCA.

The computational mesh underlying the CFDmodel used here was able to predict total nasaldeposition for 20- and 50-�m particles relativelyaccurately. However, it is possible to skew orgrade the distribution of nodes in a CFD mesh to-ward the walls to improve the accuracy of esti-mates made at the walls such as regional pre-dicted particle deposition sites. To test the effectsof mesh grading on spray simulations, the nasalCFD mesh was truncated just posterior to thenasal valve. More nodes were added to this meshof the nasal vestibule alone, and the mesh wasgraded toward the lateral and septal walls. Pre-dicted penetration of the nasal vestibule was un-changed for 50-�m particles and decreased byabout 14% for 20-�m particles, suggesting that ef-fects of mesh grading may become more signifi-cant as particle size decreases.

With regard to the assumptions underlying theCFD and particle transport models presentedhere, further study is needed to understand thepotential effects of mesh refinements, time-de-pendent airflow, nonuniform airflow velocityconditions at the nostril, regional heat and hu-midity conditions, and interindividual differ-ences in nasal anatomy on the nasal spray sensi-tivity analyses. In the methods used to simulatenasal sprays, the effects of the time dependenceof particle size, spray density (temporal evolutionof concentration), cone angle, and spray velocity

KIMBELL ET AL.72

during spray duration on the sensitivity analysesrequire more study, as do the potential effects ofsprays on inspiratory airflow patterns and inter-actions of spray particles with each other.

In this study, CFD modeling was used to vi-sualize, quantify, and analyze (1) the role of thenasal valve as a barrier to nasal spray deposition,(2) the very small physical size of likely comfort-able particle release areas and their close prox-imity to the nasal valve, (3) the effects of delay-ing the presence of inspiratory airflow afterparticles are released, and (4) the large effects thatthe presence of inspired airflow as well as smallerparticle size and slower spray velocity have onnasal valve penetration. The study suggests thatdevices that produce large particles at high ve-locity with no inspiratory airflow present duringactuation will have very limited if any nasal valvepenetration. Further studies are needed to deter-mine the effects of particle sizes less than 20 �mand of abnormal airway geometry. Along withexperimental measurements in hollow molds andhuman subjects, these predictions contribute tomore effective design of drug delivery devicesthrough a better understanding of the interac-tions between nasal anatomy, sprays, and spraydevices and the effects of these interactions onparticle transport in the nose.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the con-tributions and support of R. Conolly, J. Rubis, J.T. Kelly, D. Kalisak, O. Price, J. M. Sheppard, K.Musgrove, B. Bennett, Y. S. Cheng, O. Moss, F.Miller, M. Andersen, A. Georgieva, R. Subrama-niam, D. Greenwood, D. Joyner, D. House, andD. Wexler. This work was funded by Bespak Eu-rope Ltd. and the American Chemistry Council.

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Received on November 4, 2005 in final form, September 16, 2006

Reviewed by: Beth L. Laube, Ph.D.Chong S. Kim, Ph.D.

Address reprint requests to:Julia S. Kimbell, Ph.D.

CIIT Centers for Health ResearchP.O. Box 12137

Research Triangle Park, NC 27709

E-mail: kimbell@ciit.org

KIMBELL ET AL.74

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16. Mow Yee Foo , Yung-Sung Cheng , Wei-Chung Su , Maureen D. Donovan . 2007. The Influence of Spray Properties onIntranasal Deposition. Journal of Aerosol Medicine 20:4, 495-508. [Abstract] [Full Text PDF] [Full Text PDF with Links]

17. A FARKAS, I BALASHAZY. 2007. Simulation of the effect of local obstructions and blockage on airflow and aerosoldeposition in central human airways. Journal of Aerosol Science 38:8, 865-884. [CrossRef]

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