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cta Otorrinolaringol Esp. 2012;63(5):370---375

www.elsevier.es/otorrino

RIGINAL ARTICLE

asal Gel and Olfactory Cleft�

esús Herranz González-Botas,∗ Anselmo Padín Seara

ervicio de Otorrinolaringología, Complejo Hospitalario Universitario A Coruna, A Coruna, Spain

eceived 6 March 2012; accepted 3 May 2012

KEYWORDSIntranasalpreparations;Distribution;Olfactory cleft

AbstractObjective: To evaluate whether a nasal gel, administered using a radial-hole inhaler, reachesthe olfactory cleft, and if a different administration method influences distribution.Material and method: Sixteen healthy volunteers underwent a nasal endoscopy at 1 and 7 minafter the administration of a intranasal gel, with a different method in each fossa.Results: No dye deposition was identified at the olfactory cleft, middle turbinate or middlemeatus. In all cases the gel was identified at the nasal vestibule. On the right side, the secondmost frequent dye identification area was the inferior turbinate, with a rate of 87% at the firstminute and 75% at 7 min. It was followed by the septum (75% and 62%) and the inferior meatus(6.2% and 12.5%). On the left side, the second most frequent stained area was the septum (18.7%and 13.5%), followed by the inferior meatus (6.5% and 65%). No inferior turbinate staining wasfound in the left side. There was a significant difference in the deposition rate at the septum(P<.01) and inferior turbinate (P<.001), when both administration methods were compared.Conclusions: No nasal gel, administered using a radial-hole inhaler, was found at the olfactorycleft, middle turbinate or middle meatus. Gel distribution was located at the anterior and infe-rior portion of the nose, independent of the administration method used. Significantly differentgel distribution rates were found at the septum and inferior turbinate when the 2 administrationmethods were compared.© 2012 Elsevier España, S.L. All rights reserved.

PALABRAS CLAVEPreparacionesintranasales;Distribución;

Gel nasal y hendidura olfatoria

ResumenObjetivo: Identificar si un gel administrado mediante un inhalador de cabeza radial puede

Hendidura olfatoria alcanzar la hendidura olfatoria y si su distribución intranasal se modifica según el método deaplicación.Material y método: Se estudiaron 16 voluntarios a los que se administró un gel tenido de mododiferente en cada fosa, realizándose una endoscopia tras 1 y 7 min.Resultados: No se identificó gel a nivel de la hendidura olfatoria, cornete medio o meatomedio independientemente del método de administración utilizado. En el vestíbulo se identificó

� Please cite this article as Herranz González-Botas J, Padín Seara A. Gel nasal y hendidura olfatoria. Acta Otorrinolaringol Esp.012;63:370---5.∗ Corresponding author.

E-mail address: jesus.herranz.gonzalez.botas@sergas.es (J. Herranz González-Botas).

173-5735/$ – see front matter © 2012 Elsevier España, S.L. All rights reserved.

Nasal Gel and Olfactory Cleft 371

colorante en todos los casos. En el lado derecho la segunda localización más frecuentefue el cornete inferior con una incidencia del 87% al minuto y del 75% a los 7 min. Le sigu-ieron el tabique, 75 y 62%, y el meato inferior, 6,2 y 12,5%. En el lado izquierdo la segundalocalización más frecuente fue el tabique, 18,7 y 13,5%, seguida del meato inferior, 6,5 y 65%.Las diferencias en la presencia de colorante a nivel del septo (p < 0,01) y el cornete inferiorfueron significativas.Conclusiones: No se ha identificado la presencia de gel a nivel de la hendidura olfatoria, cornetemedio o meato medio. La distribución se localiza a nivel de la parte anterior e inferior de lafosa nasal, con diferencias significativas si se emplean métodos de administración diferentes.

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We conducted statistical analysis using Fisher’s test, with aconfidence interval of 95% (˛=0.05).

Table 1 Visual Assessment of the Olfactory Area.

Right Side Left Side

No. % No. %

Grade 0 0 0 0 0Grade 1 0 0 2 12.5Grade 2 1 6 4 25Grade 3 15 94 10 62.5

Table 2 Inclusion Criteria for Volunteers in the Study.

No use of medication by nasal route in the past monthNo use of medication by general route in the past monthAbsence of acute or chronic systemic involvementAbsence of acute or chronic nasal involvementNo history of sinonasal surgery

© 2012 Elsevier España, S.L

Introduction

The functions of the nasal cavity are filtering, warmingand humidifying inspired air in order to protect the air-way. Particles which become trapped in the nasal mucusare transported through the action of the cilia in the nasalepithelium towards the nasopharynx and the digestive sys-tem. The anatomical design of the nasal fossa facilitatesthe contact of air with the nasal mucosa and conditions air-flow through it. The use of specific intranasal medicationfor local processes is useful as long as it reaches key areassuch as the ostiomeatal complex or the Eustachian tube.Therefore, knowledge of its distribution is important, bothto assess its effects and to evaluate possible side effects onsensitive areas, such as the olfactory epithelium.

Intranasal administration of medication is often used insinus conditions, a problem affecting approximately 1 000000 people per year in Spain,1 and nearly 40 000 000 in theU.S.A.2 Its safety has been confirmed in multiple studies1,3

and its advantages over the oral route include rapid bioavail-ability in the bloodstream, preventing degradation in thegastrointestinal tract and prior passage through the liver. Itsdisadvantages include poor contact with the nasal mucosaand difficulty to reach specific areas, critical to its thera-peutic effect.2---7 There are multiple types of administrationsystems6,8 and head positions for better distribution,6,9 sothere have been numerous key recommendations based onliterature reviews.2 However, studies have shown that, usingthe usual methods, the distribution of intranasally appliedmedication is localised mainly in the anterior portion of thenasal cavity.

Anosmia has been reported as a side effect of intranasalmedication, secondary to zinc content. A possible causewould be the contact of medication with the epitheliumof the olfactory region,10 but the possibility of distribut-ing a nasal gel at the level of the olfactory area is highlyimplausible.6

The aim of this study is to assess whether a viscous gel,administered through a nasal inhaler with a radial head, canreach the olfactory cleft, and whether its nasal distributionvaries depending on the delivery system employed.

Material and Method

Study Population

The study was conducted among healthy volunteers who hadbeen previously informed of its conditions and characteris-tics. As a prerequisite, they had to sign a consent form which

os los derechos reservados.

ncluded the study characteristics, the material used and itsossible side effects. We studied a total of 16 volunteershose medical histories were assessed in order to rule outasal condition or use of medication that could affect studyesults. They all underwent nasal endoscopy in order to con-rm the absence of septal or septopyramidal deformity, asell as to assess the visibility of the olfactory area according

o the following grades: 0, not visible; 1, partially visible;, visible after introducing the endoscope 2 cm; and 3, eas-ly visible. The visualisation characteristics of the olfactoryleft are shown in Table 1.

The mean age of patients was 25 ± 3 years (maximum:8; minimum: 22), distributed equally between men andomen. None of them had a previous history of nasal or sys-

emic disease or of use of topical or systemic medication inhe previous month. The inclusion criteria are summarisedn Table 2.

tudy Period

he study was conducted in January 2012.

tatistical Analysis

Visualisation of the nasal area of grade 1 or higherAbsence of septal or pyramidal deformityInformed consent

3 J. Herranz González-Botas, A. Padín Seara

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Table 3 Ingredients and their Percentages in the Gel.

Ingredient Percentage, % Function

Hydroxyethyl cellulose 1.2 ViscosityGlycerine 1.0 StabilitySodium chloride 0.9 Isotonic bufferBenzalkonium chloride 0.02 Preservative

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72

ethod

fter assessing the visibility of their olfactory cleft, patientsere given indications for nasal gel application, followingifferent instructions for each nostril. In the right nostril,hey had to place the applicator vertically, introducing itspper end into the nostril and breathing deeply at the timef gel application. In the left nostril, they had to place thepplicator in a horizontal position, directing the upper endowards the outer edge of the left eye and without breathingeeply at the time of gel application.

Nasal endoscopies were performed 1 min and 7 min afterpplying the gel, in order to detect presence of dye in theollowing anatomical structures:

Nasal vestibule. Septum. Inferior turbinate. Middle turbinate. Inferior meatus. Middle meatus. Olfactory cleft.

aterial

he radial head applicator used in this study was a med-cation spray which administered 140 �l per dose (Fig. 1),

igure 1 (A) Nasal applicator. (B) Radial design of the appli-ator head.

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Methylene blue 0.01 DyePurified water ∼97 Vehicle

anufactured by Aptar Pharma SAP #10277363. The liquidel was produced by Unicep Packaging (Sandpoint, Idaho).t had no active ingredient and instead contained methy-ene blue (used as a dye), benzalkonium chloride, glycerine,ydroxyethyl cellulose, purified water and sodium chloride.he final viscosity of the product was 5500 cps. Gel ingredi-nts and their percentages are shown in Table 3.

esults

e did not find stained gel at the level of the olfactory cleft,iddle meatus or middle turbinate in any of the volunteers

ested, on either side, in the endoscopy conducted at 1 minr at 7 min.

In all cases we found stained gel at the level of the nasalestibule, in both nostrils and during both endoscopies.

On the right side, the inferior turbinate was the secondocation in frequency, with a percentage of dye of 87% at

min and 75% at 7 min. It was followed in frequency by theeptum, with 75% and 62% at 1 min and 7 min, respectively,nd by the inferior meatus, with 6.2% and 12.5% at 1 min and

min, respectively.The distribution of dye on the left side was more dis-

reet. The second area in frequency was the nasal septum,ith 18.7% and 13.5% at 1 min and 7 min, respectively, fol-

owed by the inferior meatus, which presented 6.5% in bothndoscopies. Dye was not located in the inferior turbinaten this side.

The Fisher test showed significant differences in the dis-ribution of gel at the level of the septum (P<.01) andnferior turbinate (P<.001), when comparing both methodsf application (Table 4).

iscussion

he result of our study shows that a viscous gel adminis-ered through a nasal applicator with radial head was notble to reach the upper portion of the nasal fossa, as noye was found in the olfactory cleft, middle turbinate andiddle meatus. The modification of the application methodid not result in better distribution at the top of the nasalossa and only showed differences in distribution at the lev-ls of the septum and inferior turbinate. Previous studiesave shown that the distribution of medication adminis-ered intranasally is mainly located in the anterior nasalossa (septum, vestibule and inferior turbinate) regardless

f the application method employed.2,7,11 The nasal valverea is the narrowest part of the nasal fossa, separat-ng the vestibule from the fossa itself. This structure isocated about 2 cm from the edge of the nostril and has a

Nasal Gel and Olfactory Cleft 373

Table 4 Summary of Endoscopic Findings and Comparison Between Both Nasal Fossae.

Area Right Side Left Side Value of P

No. % No. %

Vestibule 1 min 16 100 16 100 NSVestibule 7 min 16 100 16 100 NSSeptum 1 min 12 75 3 18.7 .01Septum 7 min 10 62.5 2 13.5 .01Inferior turbinate 1 min 14 87.5 0 0 .001Inferior turbinate 7 min 12 75 0 0 .001Inferior meatus 1 min 1 6.2 1 6.5 NSInferior meatus 7 min 2 12.5 1 6.5 NS

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No., number of cases with positive dye identification; NS, not signValues with significant differences are shown in bold (P<.05).

midsection of about 0.7 cm. The greatest resistance to air-flow takes place at the inferior turbinate head level. Allthese anatomical characteristics justify the difficulties forthe passage and distribution of gel to deeper and superiorareas of the nasal fossa.

This study was performed on healthy individuals withoutprevious nasal condition or nasal obstruction and with a vis-ible olfactory area, so additional obstructive factors wereruled out. We did not use topical anaesthesia or pledgetssoaked in vasoconstrictor so as not to alter the charac-teristics of the nasal mucosa, avoiding the appearance ofrhinorrhea and sneezing which would introduce a bias in thedistribution of gel.12

The stained gel was found in all cases in the nasalvestibule, an area lined with multilayered squamousepithelium, unable to transport and mobilise secretions.Therefore, the gel remained at that location until it dis-appeared or was eliminated by the patient.

Ciliated epithelium, located after the nasal valve, iscapable of transporting nasal mucus and any substancestrapped in it to the nasopharynx. The mean nasal mucusclearance time in healthy individuals is 30 min,12 althoughthis period may vary depending on the anatomical character-istics of each individual, local disease, mucus characteristicsand use of medication.13,14 No significant differences werefound in nasal mucus clearance time when comparing asaline nasal spray and a gel spray, both stained withfluorescein.7

Due to its high viscosity, the nasal gel offered a lowertendency to drip, as well as reducing unpleasant taste sen-sations related to swallowing of the product.5 Since thedirection of transport by ciliated epithelium is towards thenasopharynx and due to the effect of gravity, we can assumethat transport of the gel towards the top of the nose after7 min is very unlikely.

The modifications made on applicators and solutionshave shown best results with sprays in which the pres-sure is obtained by manual pumping rather than pressurisedsprays,15 but no improvement in distribution was obtainedwhen comparing nasal sprays and drops.8,16,17 A previous

study, which used a single-orifice applicator, showed simi-lar results, with examinations performed up to 15 min aftergel application,18 with no changes in explorations con-ducted in 45 patients. Therefore, we decided not to perform

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ndoscopies after 7 min, since this procedure causes dis-omfort for patients and increases rhinorrhea, a factor thatould affect the results of the study.

Modifications were designed to enable passage of theasal valve and thus increase distribution in critical areas,ainly at the level of the nasal infundibulum, a key area in

inonasal conditions.8

Scheibe et al. studied different methods to reach thelfactory area. They considered that, since systemic cor-icosteroids were effective in the treatment of suddennosmia, topical corticosteroids could also be useful, andoncluded that the reason was due to their inability toeach the olfactory area.6 They reached the olfactory arean 73% of cases in which dyed saline solution was injectednto the nostril using a syringe with a needle. This per-entage dropped to 6.6% when the serum was applied with

spray and to 0% when it was administered as drops. vasoconstrictor was used in all subjects 15 min beforepplication of the serum and 3 consecutive doses weresed.

The position of the head also affects intranasal dis-ribution because airflow and gravity hinder the arrivalf medication to the top of the nose, a critical area ininonasal condition.2,8,9,19 Cannady et al. found that, inatients who had previously undergone endoscopic sinusurgery, with 3 drops of fluorescein-dyed dexamethasonepplied to a patient in the nasal vestibule with the head ver-ex placed toward the ground (a position known as ‘‘prayingo Mecca’’), the deposit at the olfactory area level wasigher if the position was maintained for 5 min than if itas maintained for only 1 min.9 They found no differencesetween applying the product and maintaining the headertex toward the ground for 1 min, and application of theroduct through a syringe inserted into the nostril between

and 5 mm and directed towards the external edge of thepsilateral eye.9 Merkus et al. found no differences in dis-ribution at the level of the middle meatus when comparing

different head positions (upright, hyperextended, on oneide and with the vertex toward the ground) and 3 differentpplicator models.8 They concluded that the position with

he vertex towards the ground enabled greater product dis-ribution at the top of the nasal fossa, and that this couldmprove the delivery of medication to the olfactory area inatients with nasal polyposis.8

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Taking a deep breath while administering the product wasot associated with better distribution in the nasal fossa.2,19

e found a better distribution in the head of the inferiorurbinate, but did not identify the presence of gel at theevel of the middle turbinate, middle meatus and olfactoryleft.

Guo et al. analysed intranasal distribution in terms ofifferent viscosities with the product applied and found noifferences when combining different methods of applica-ion. They concluded that different methods of applicationo not alter distribution because airflow has little influencen product distribution and deposition.20 Particles leav-ng the applicator head impact on the vestibule and headf the inferior turbinate, without the ability to change direc-ion and adapt to the airflow present in the area of theurbinate.17

Multiple methods have been used for the study ofntranasal distribution of medication (isotopes, dyes,ndoscopy, collection of product on pledgets), each withifferent advantages and disadvantages.4 This variabilityakes comparisons between studies more difficult.Intranasal endoscopic identification of dyes has been

sed in multiple studies.7,19,21 It is assumed that if the dye isdentified at the level of the head of the middle turbinate,hen it is possible to obtain distribution in that area, which isritical in sinonasal involvement.4 The sample size employedn most studies, as well as the methodology, was similar tohat used in our study, with the difference that we specifi-ally aimed to identify the dye at the level of the olfactoryleft, did not employ vasoconstrictor or anaesthesia, andhe olfactory area was visible in all subjects.

Intersubject variability was minimised because evenhough subjects administered the product themselves, theyere controlled directly by an observer, so as to ensure that

hey followed the correct procedure. There are no studieshich analyse inter- and intrasubject variability, and whichan provide information on the effect of incorrect productpplication due to not following instructions.

There have been reports of anosmia secondary tontranasal use of products containing zinc.10 Also, olfactorypithelium necrosis has been found in human nasal tissueultures and in mice exposed to the product.22 Lim et al.entioned the difficulty of depositing nasal gel in the olfac-

ory area of a non-anaesthetised guinea pig as an argumento criticise the methodology of the study by Slotnick et al.22

n their study, Slotnick et al. found no relationship between gel containing zinc and anosmia.23

Regardless of the effect that zinc may cause on thelfactory epithelium, contact of zinc with the olfactoryucosa is necessary to generate damage in the olfactory

pithelium. Therefore, the hypothesis is unlikely, taking intoccount that in our study we found no presence of dye inhe olfactory area or in its vicinity. In clinical cases asso-iated with the description of anosmia syndrome relatedo zinc, patients clearly reported burning sensation andlfactory impairment immediately or hours after adminis-ration of nasal gel while taking a deep breath. In our study,oth with deep inspiration and without it, with the appli-

ator in a vertical or horizontal position, gel distributionas localised in the anterior portion of the nose. This dis-

ribution did not change in the exploration conducted after min.

1

J. Herranz González-Botas, A. Padín Seara

onclusions

ur study supports the concept that a viscous nasal gel isistributed in the anterior and inferior parts of the nasalossa, primarily at the levels of the vestibule, septum andnferior turbinate, and that this distribution is not affectedy the position of the applicator or by taking a deep breatht the time of application. We did not identify the pres-nce of dyed gel in the middle turbinate, middle meatusnd olfactory cleft, neither after 1 min nor after 7 min ofroduct application. Moreover, this finding was not affectedy different methods of product application. Therefore, weonsider that the contact of a nasal gel with the olfactorypithelium of the olfactory cleft is highly unlikely.

inancing

his work was requested and funded by the company Matrixxnitiatives, Inc., 8515 East Anderson Drive Scottsdale, AZ5255, U.S.A.

onflict of interests

he authors have no conflict of interests to declare.

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