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Deposition of Sprayed Particles in the Nasal Cavity
Allris'NaslIs'LarYl1x (Tokyo) 10,109-116 (1983)
DEPOSITION OF SPRAYED PARTICLES IN THE NASAL CAVITY Tokuji
UN NO,
M. D., Kazuhiko HOKUNAN, M. D., Osamu and Satoru ONODERA, M. D.
YANAJ,
M. D.,
Departll/ent 0/ Otolaryngology, Asahikall'a Medical School, Asahikall'a, Japan
Therapeutic effects of topically applied steroids is closely related to the deposition of sprayed particles. To clarify deposition in the nasal cavity, model experiments were undertaken using the gas and powder sprays. Deposits on the moistened filter paper which covered the surface of a nose model were assessed by absorbance of the extracts. The influence of the shape and the effect of continuous suction from the posterior outlet were also studied. When the nasal cavity was kept straight without any abnormal protrusions, the gas spray deposited more than 90 % of particles. The amount was significantly lowered in the model of a concave septum with hypertrophic turbinates. The powder spray deposited approximately 75 % of the original dose. This amount was more than 90 % of actually sprayed particles because some loss was inevitable in spraying the powder. In general, the shape of the cavity more affected the deposition of the gas spray than the powder spray. This difference was probably due to the spray angle and to the size and speed of the aerosol particles. It was concluded that the powder spray was preferable to the gas spray with regard to the deposition in the nasal cavity. Intranasal administration of steroids is now widely accepted for the treatment of nasal allergy and vasomotor rhinitis. Clinical evaluation of the drugs is in general statisfactory (MALM and WlHL, 1976; OKUDA et al. 1979; SAHAY, CHATTERJEE, and ENGLER, 1980; BALLE, PEDERSEN, and ENG BY, 1982). MYGIND (1977) pointed out that the following problems stood to be solved in the future. These are problems of drug distribution, selection of patients for the therapy, the mode of action of a potent corticosteroid on the airway mucosa and the potential risk of local side effects. Some investigators and we reported that sprayed particles in the nose were not so widely distributed as expected (MYGIND and Received for publication April 13, 1983 109
110
T. UNNO, K. HOKUNAN, O. Y ANAl, and S. ONODERA
VESTER HAUGE, 1978; SATOH, Hyo, TAKANO, and OKUDA, 1982; UNNO, OKUDE, YANAI and ONODERA, 1982). No severe side effects were reported in a long term application of the drug (MYGIND, SORENSEN and PEDERSEN, 1978). Other problems have not yet been completely solved. The object of this paper is to clarify how much amount of topically applied particles is distributed in the nasal cavity, since it is closely related to the therapeutic effects as well as systemic side effects. METHODS
A nose model molded from a cadaver with modification for postmortem shrinkage was used for this experiment. Three types of nasal cavity, that is, a straight septum with normal turbinates, a concave septum with hypertrophic turbinates and a convex septum with atrophic turbinates were revised from the
d[
straight septum with normal turbinates
G
concave septum with hypertrophic turbinates
~(
convex septum with atrophic turbinates
Fig. 1. Three types of artificial nose revised from the original model using dental compound and celluloid plate.
Fig. 2. Lateral wall of the nasal cavity completely covered with moistened filter paper except the vestibulum.
DEPOSITION OF SPRAYED PARTICLES
111
original model using dental compound and celluloid plate as shown in Fig. 1. The inner surface of the cavity was covered with moistened filter paper (Toyo Roshi Co., Ltd., No. 526) except the anterior portion corresponding to the vestibulum (Fig. 2). Beclomethasone dipropionate (BD) particles 50 flg at each puff were emitted by fluorinated hydrocarbon (Freon) propellant. This is abbreviated as a gas spray. One thousand ftg BD crystalline was also mixed with 30 mg hydroxy propyl cellulose (HPC) powder in a capsule and the mixture was dispersed completely by more than eight puffs with the insufflator. This is abbreviated as a powder spray. One thousand flg BD crystalline was sprayed in each experiment by 20 puffs at interval of 30 sec for the gas spray and ten puffs for the powder spray. The moistened filter paper was carefully detached from the model, dried in a vacuum dryer and BD was extracted in 50 ml methanol. Absorbance of the solution (x) was then measured by an automatic spectrophotometer at the peak wave length of 239.0 nm. The amount of BD in 1 ml (y) was calculated from the experimental equation y=36.2x- 0.9. The total amount of BD which had been deposited on the filter paper was calculated by multiplying y by 50. Continuous suction at 0.5, 1.0, 1.5 and 2.0 liters/sec from the posterior outlet of the model was also applied to evaluate the effects of inspirations. The mean values with one standard deviation were calculated and statistical analysis was made by t-test. RESULTS
The results were shown in Figs. 3, 4 and 5. In a straight septum where normal turbinates formed an open airway from the nostril to the end of the nasal cavity, the gas spray deposited more than 90 % of BD on the inner surface. The mean value without suction was significantly higher than those with suction (p
112
T. UNNO, K. HOKUNAN, O. Y ANAl, and S. ONODERA 1'9 1000
900
j
800
z i= iii oa.
o
700
w
a
600
500
. : POWDER
T Fig. 3.
o
0.5
1.0
1.5
2.0 lPS
SUCTION SPEED
Deposilion of BD in the model of a straight septum with normal turbinates. 1'9 10
900
800
II
1
I
j
o :GAS .: POWDER
T
0
0.5
1.0
1.5
I
2.0 lPS
SUCTION SPEED
Fig. 4.
Deposition of BD in the model of a concave septum with hypertrophic turbinates.
DEPOSITION OF SPRAYED PARTICLES jl9
I
1000
900
1
800
!
Z 0
i=
(ij 700 0 Q.
w
0
600
I 1
o :GAS 500
T Fig. 5.
113
.: POWDER
o
0.5
1.0
1.5
SUCTION SPEED
2.0
lP~
Deposition of BD in the model of a convex septum with atrophic turbinates.
gas spray. The powder spray with suction speed of more than 1.0 liter/sec showed mean values to be significantly decreased (p < O.OI). DISCUSSION
Deposition of sprayed particles in the nasal cavity has never quantitatively been measured before in spite of numerous reports on the clinical evaluation. It has been vaguely dealt with by the concept that aerosol particles are distributed in the airways during inhalation (STUART, 1973). Although aerosol originally refers to any system of solid particles or liquid droplets that are of sufficient small diameter to maintain some stability as a suspension in air, in practical uses various preparations that can disperse active ingredients as spray, foam and paste are also called aerosol. Liquidified gas is mainly used to propell particles because of such advantages that a compact container is easy to carry with and able to deliver ingredients quantitatively, that application does not require any skill on the part of the patients, and that the content is protected from contamination or chemical changes during periods of disuse. Atomizer and insufflator which can produce relatively fine particles are also utilized for the purpose. Accordingly, we should first understand the characteristics of each type of drugs. Solution, suspension and emulsion aerosols are distinguished according to the
114
T. UNNO, K. HOKUNAN, O. YANAI, and S. ONODERA
condition of active ingredients in liquidified gas (SCIARRA and STOLLER, 1974). Solution aerosols are classified into a surface spray and a space spray. The former is intended to coat a surface of an object by producing larger particles under lower vapor pressure while the latter to remain suspended in air for longer periods of time by producing smaller particles under higher vapor pressure. If active ingredients are insoluble in the propellant, a suspension aerosol is applied. The particles after rapid vaporization of propellant are in general small in size and behave themselves rather like the space spray. The gas spray of BD belongs to this category. Ingredients in an emulsion aerosol are emulsified in the container. The particles emitted from an insufflator and the droplets from an atomizer are larger in size under lower driving pressure, so that deposition ea-ily occurs on the surface of an object. MYGIND et al. (1978) reported the distribution of the sprayed particles in the nasal cavity using suspension aerosols, nebulizers and an atomized pump. They described that dye particles from a pressurized aerosol container hitted the mucosa like a bullet from a gun. This is not surprising if the above mentioned characteristics of the spray forms are understood. The anterior part of the middle turbinates is most densely deposited according to some other studies (SATOH et al., 1981; UNNO et al., 1982). MYGIND et al. (1978) also demonstrated that the best distribution was attained by using an atomized pump and a deVilbiss nebulizer. In practical uses of a suspension aerosol they recommended that the patient should hold the canister strictly in the sagittal plane and take one puff in the upper and one in the lower part of the nose. Our method to assess the amount of BD from the absorbance is reliable since in a certain range the absorbance is directly proportional to the concentration of a solution according to Lambert-Beer's law. The absorbance we measured ranged from 0.318 to 0.628 and these values were completely within the measurable range. The amount deposited on the surface of the nasal cavity was counted from 52 to 91 % of the original dose. The remainder is considered to be deposited at the vestibulum not covered with filter paper and to eliminate from the posterior outlet. Besides, in the powder spray imigration occurs when a capsule is perforated by a needle, and a small amount of the contents is always left in the applicator and the capsule even after repeated puffs. Approximately 20 % of the ingredient in the capsule is not insufflated into the nose in our experiment. Assuming that actually sprayed particles are 80 % of the original dose, more than 90 % of the sprayed ingredients are deposited in three types of the nasal cavity. Continuous suction from the posterior outlet of the model little affected the amount of deposits delivered by the gas spray except the straight septum with normal turbinates. Deposition of ingredient delivered by the powder spray into this model decreased as the speed of suction increased. In the convex and concave septums the effect of posterior suction was shown only in the powder spray at the speed of more than I liter/sec. This is explained from the fact that the
DEPOSITION OF SPRAYED PARTICLES
115
straight septum with normal turbinates brings a good nasal airway and thus smoother air current than narrow airways. The difference between the two spray forms is explained by the fact that the size of the particles delivered by the gas spray is much smaller than that by the powder spray. It was also suggested by MYGIND et al. (1978) that once deposited particles on the surface were again conveyed posteriorly by inspiratory air and that this effect was more clearly observed on larger particles. Deposition of the ingredient delivered by the powder spray was of similar quantity throughout three types of nasal cavity while those delivered by the gas spray were differently deposited. The spread area of the powder spray with wider spray angle is not so restricted as the gas spray with narrower angle. When any obstacles such as protrusion of the septum or turbinates are present in the spray axis, they hinder further spread of the ingredient. While the concave septum with hypertrophic turbinates increased the deposition on the vestibulum from the gas spray, ingredients from the powder spray were able to advance through spaces around the protrusion. Although the results of this experiment are not directly applied to living humans because of rigidity of the cavity and inlet and of different superficial characteristics between filter paper and mucosa, a mode of deposition in the model nose can be applied for the topical treatment. CONCLUSION
Our experiment showed that deposition of the particles in the model nose was approximately 90 %of actually sprayed ingredients. This value is surprisingly high if the deposition of aerosol particles which suspend stably in the inspiratory air is compared. The particles from the spray container hit the localized area in the spray axis and thus deposit there most densely. Wider spray angle is therefore more adequate for further advance of the sprayed particles beyond any obstacles such as a deviated septum or hypertrophic turbinates. It can be said that the powder spray is preferable with regard to deposition and distribution in the nose and that improvement of the applicator and drug forms is still necessary to achieve better clinical effects and easier manipulation by the patients. REFERENCES BALLE, V. H., PEDERSEN, U., and ENGBY. B.: The treatment of perennial rhinitis with a new, nonhalogenated, topical aerosol packed, steroid, Budesonide. Acta Otolaryngol., 94: 169-173,1982. MALM, L., and WIHL, J.: Intranasal bec1omethasone dipropionate in vasomotor rhinitis. Acta Allergol. 31: 245-253, 1976. MYGlND, N.: Effects of bec1omethasone dipropionate aerosol on nasal mucosa. Br. J. Clin. Pharmacol. 4: 287S-291S, 1977. MYGlND, N., and VESTERHAUGE, S.: Aerosol distribution in the nose. Rhinology 16: 79-88, 1978.
116
T. UNNO, K. HOKUNAN, O. Y ANAl, and S. ONODERA
MYGIND, N., S0RENSEN, H., and PEDERSEN, C. B.: The nasal mucosa during long-term treatment with beclomethasone dipropionate aerosol. A light- and scanning electron microscopic study of nasal polyp. Acta Otolaryngol. 85: 437-443, 1978. OKUDA, M. et al.: Effects of intranasal atmization of beclomethasone dipropionate in perennial nasal allergy. Its optimum dose, clinical effects and safety. Otologia (Fllkuoka) 25: 1283-1309, 1979. SAHAY, J. N., CHATTERJEE, S. S., and ENGLER, c.: A comparative trial of fiunisolide and beclomethasone dipropionate in the treatment of perennial allergic rhinitis. Clill. Allergy 10: 65-70, 1980. SATOH, Y., Hyo, N., TAKANO, S., and OKUDA, S.: Particle size, deposition and distribution of sprayed steroids in the nasal cavity. Oto-Rhino-Laryngol. Tokyo 25:137-146, 1982. SCIARRA, J. J., and STOLLER, L. (ed.): The science and technology of aerosol packaging. John Wiley & Sons, New York, 1974. STUART, B. 0.: Deposition of inhaled aerosols. Arch. lilt. Med. 131: 60-72, 1973. UNNO, T., OKUDE, Y., Y ANAl, 0., and ONODERA, S.: Distribution of beclomethasone dipropionate aerosol particles in the nasal cavity. Jpn. J. Otol. (Tokyo) 85: 277-282, 1982.
Request reprints from:
Dr. T. Unno, Department of Otolaryngology, Asahikawa Medical School, 4-5 Nishikagura, Asahikawa 078-11, Japan
DEPOSITION OF SPRAYED PARTICLES IN THE NASAL CAVITY Tokuji
UN NO,
M. D., Kazuhiko HOKUNAN, M. D., Osamu and Satoru ONODERA, M. D.
YANAJ,
M. D.,
Departll/ent 0/ Otolaryngology, Asahikall'a Medical School, Asahikall'a, Japan
Therapeutic effects of topically applied steroids is closely related to the deposition of sprayed particles. To clarify deposition in the nasal cavity, model experiments were undertaken using the gas and powder sprays. Deposits on the moistened filter paper which covered the surface of a nose model were assessed by absorbance of the extracts. The influence of the shape and the effect of continuous suction from the posterior outlet were also studied. When the nasal cavity was kept straight without any abnormal protrusions, the gas spray deposited more than 90 % of particles. The amount was significantly lowered in the model of a concave septum with hypertrophic turbinates. The powder spray deposited approximately 75 % of the original dose. This amount was more than 90 % of actually sprayed particles because some loss was inevitable in spraying the powder. In general, the shape of the cavity more affected the deposition of the gas spray than the powder spray. This difference was probably due to the spray angle and to the size and speed of the aerosol particles. It was concluded that the powder spray was preferable to the gas spray with regard to the deposition in the nasal cavity. Intranasal administration of steroids is now widely accepted for the treatment of nasal allergy and vasomotor rhinitis. Clinical evaluation of the drugs is in general statisfactory (MALM and WlHL, 1976; OKUDA et al. 1979; SAHAY, CHATTERJEE, and ENGLER, 1980; BALLE, PEDERSEN, and ENG BY, 1982). MYGIND (1977) pointed out that the following problems stood to be solved in the future. These are problems of drug distribution, selection of patients for the therapy, the mode of action of a potent corticosteroid on the airway mucosa and the potential risk of local side effects. Some investigators and we reported that sprayed particles in the nose were not so widely distributed as expected (MYGIND and Received for publication April 13, 1983 109
110
T. UNNO, K. HOKUNAN, O. Y ANAl, and S. ONODERA
VESTER HAUGE, 1978; SATOH, Hyo, TAKANO, and OKUDA, 1982; UNNO, OKUDE, YANAI and ONODERA, 1982). No severe side effects were reported in a long term application of the drug (MYGIND, SORENSEN and PEDERSEN, 1978). Other problems have not yet been completely solved. The object of this paper is to clarify how much amount of topically applied particles is distributed in the nasal cavity, since it is closely related to the therapeutic effects as well as systemic side effects. METHODS
A nose model molded from a cadaver with modification for postmortem shrinkage was used for this experiment. Three types of nasal cavity, that is, a straight septum with normal turbinates, a concave septum with hypertrophic turbinates and a convex septum with atrophic turbinates were revised from the
d[
straight septum with normal turbinates
G
concave septum with hypertrophic turbinates
~(
convex septum with atrophic turbinates
Fig. 1. Three types of artificial nose revised from the original model using dental compound and celluloid plate.
Fig. 2. Lateral wall of the nasal cavity completely covered with moistened filter paper except the vestibulum.
DEPOSITION OF SPRAYED PARTICLES
111
original model using dental compound and celluloid plate as shown in Fig. 1. The inner surface of the cavity was covered with moistened filter paper (Toyo Roshi Co., Ltd., No. 526) except the anterior portion corresponding to the vestibulum (Fig. 2). Beclomethasone dipropionate (BD) particles 50 flg at each puff were emitted by fluorinated hydrocarbon (Freon) propellant. This is abbreviated as a gas spray. One thousand ftg BD crystalline was also mixed with 30 mg hydroxy propyl cellulose (HPC) powder in a capsule and the mixture was dispersed completely by more than eight puffs with the insufflator. This is abbreviated as a powder spray. One thousand flg BD crystalline was sprayed in each experiment by 20 puffs at interval of 30 sec for the gas spray and ten puffs for the powder spray. The moistened filter paper was carefully detached from the model, dried in a vacuum dryer and BD was extracted in 50 ml methanol. Absorbance of the solution (x) was then measured by an automatic spectrophotometer at the peak wave length of 239.0 nm. The amount of BD in 1 ml (y) was calculated from the experimental equation y=36.2x- 0.9. The total amount of BD which had been deposited on the filter paper was calculated by multiplying y by 50. Continuous suction at 0.5, 1.0, 1.5 and 2.0 liters/sec from the posterior outlet of the model was also applied to evaluate the effects of inspirations. The mean values with one standard deviation were calculated and statistical analysis was made by t-test. RESULTS
The results were shown in Figs. 3, 4 and 5. In a straight septum where normal turbinates formed an open airway from the nostril to the end of the nasal cavity, the gas spray deposited more than 90 % of BD on the inner surface. The mean value without suction was significantly higher than those with suction (p
112
T. UNNO, K. HOKUNAN, O. Y ANAl, and S. ONODERA 1'9 1000
900
j
800
z i= iii oa.
o
700
w
a
600
500
. : POWDER
T Fig. 3.
o
0.5
1.0
1.5
2.0 lPS
SUCTION SPEED
Deposilion of BD in the model of a straight septum with normal turbinates. 1'9 10
900
800
II
1
I
j
o :GAS .: POWDER
T
0
0.5
1.0
1.5
I
2.0 lPS
SUCTION SPEED
Fig. 4.
Deposition of BD in the model of a concave septum with hypertrophic turbinates.
DEPOSITION OF SPRAYED PARTICLES jl9
I
1000
900
1
800
!
Z 0
i=
(ij 700 0 Q.
w
0
600
I 1
o :GAS 500
T Fig. 5.
113
.: POWDER
o
0.5
1.0
1.5
SUCTION SPEED
2.0
lP~
Deposition of BD in the model of a convex septum with atrophic turbinates.
gas spray. The powder spray with suction speed of more than 1.0 liter/sec showed mean values to be significantly decreased (p < O.OI). DISCUSSION
Deposition of sprayed particles in the nasal cavity has never quantitatively been measured before in spite of numerous reports on the clinical evaluation. It has been vaguely dealt with by the concept that aerosol particles are distributed in the airways during inhalation (STUART, 1973). Although aerosol originally refers to any system of solid particles or liquid droplets that are of sufficient small diameter to maintain some stability as a suspension in air, in practical uses various preparations that can disperse active ingredients as spray, foam and paste are also called aerosol. Liquidified gas is mainly used to propell particles because of such advantages that a compact container is easy to carry with and able to deliver ingredients quantitatively, that application does not require any skill on the part of the patients, and that the content is protected from contamination or chemical changes during periods of disuse. Atomizer and insufflator which can produce relatively fine particles are also utilized for the purpose. Accordingly, we should first understand the characteristics of each type of drugs. Solution, suspension and emulsion aerosols are distinguished according to the
114
T. UNNO, K. HOKUNAN, O. YANAI, and S. ONODERA
condition of active ingredients in liquidified gas (SCIARRA and STOLLER, 1974). Solution aerosols are classified into a surface spray and a space spray. The former is intended to coat a surface of an object by producing larger particles under lower vapor pressure while the latter to remain suspended in air for longer periods of time by producing smaller particles under higher vapor pressure. If active ingredients are insoluble in the propellant, a suspension aerosol is applied. The particles after rapid vaporization of propellant are in general small in size and behave themselves rather like the space spray. The gas spray of BD belongs to this category. Ingredients in an emulsion aerosol are emulsified in the container. The particles emitted from an insufflator and the droplets from an atomizer are larger in size under lower driving pressure, so that deposition ea-ily occurs on the surface of an object. MYGIND et al. (1978) reported the distribution of the sprayed particles in the nasal cavity using suspension aerosols, nebulizers and an atomized pump. They described that dye particles from a pressurized aerosol container hitted the mucosa like a bullet from a gun. This is not surprising if the above mentioned characteristics of the spray forms are understood. The anterior part of the middle turbinates is most densely deposited according to some other studies (SATOH et al., 1981; UNNO et al., 1982). MYGIND et al. (1978) also demonstrated that the best distribution was attained by using an atomized pump and a deVilbiss nebulizer. In practical uses of a suspension aerosol they recommended that the patient should hold the canister strictly in the sagittal plane and take one puff in the upper and one in the lower part of the nose. Our method to assess the amount of BD from the absorbance is reliable since in a certain range the absorbance is directly proportional to the concentration of a solution according to Lambert-Beer's law. The absorbance we measured ranged from 0.318 to 0.628 and these values were completely within the measurable range. The amount deposited on the surface of the nasal cavity was counted from 52 to 91 % of the original dose. The remainder is considered to be deposited at the vestibulum not covered with filter paper and to eliminate from the posterior outlet. Besides, in the powder spray imigration occurs when a capsule is perforated by a needle, and a small amount of the contents is always left in the applicator and the capsule even after repeated puffs. Approximately 20 % of the ingredient in the capsule is not insufflated into the nose in our experiment. Assuming that actually sprayed particles are 80 % of the original dose, more than 90 % of the sprayed ingredients are deposited in three types of the nasal cavity. Continuous suction from the posterior outlet of the model little affected the amount of deposits delivered by the gas spray except the straight septum with normal turbinates. Deposition of ingredient delivered by the powder spray into this model decreased as the speed of suction increased. In the convex and concave septums the effect of posterior suction was shown only in the powder spray at the speed of more than I liter/sec. This is explained from the fact that the
DEPOSITION OF SPRAYED PARTICLES
115
straight septum with normal turbinates brings a good nasal airway and thus smoother air current than narrow airways. The difference between the two spray forms is explained by the fact that the size of the particles delivered by the gas spray is much smaller than that by the powder spray. It was also suggested by MYGIND et al. (1978) that once deposited particles on the surface were again conveyed posteriorly by inspiratory air and that this effect was more clearly observed on larger particles. Deposition of the ingredient delivered by the powder spray was of similar quantity throughout three types of nasal cavity while those delivered by the gas spray were differently deposited. The spread area of the powder spray with wider spray angle is not so restricted as the gas spray with narrower angle. When any obstacles such as protrusion of the septum or turbinates are present in the spray axis, they hinder further spread of the ingredient. While the concave septum with hypertrophic turbinates increased the deposition on the vestibulum from the gas spray, ingredients from the powder spray were able to advance through spaces around the protrusion. Although the results of this experiment are not directly applied to living humans because of rigidity of the cavity and inlet and of different superficial characteristics between filter paper and mucosa, a mode of deposition in the model nose can be applied for the topical treatment. CONCLUSION
Our experiment showed that deposition of the particles in the model nose was approximately 90 %of actually sprayed ingredients. This value is surprisingly high if the deposition of aerosol particles which suspend stably in the inspiratory air is compared. The particles from the spray container hit the localized area in the spray axis and thus deposit there most densely. Wider spray angle is therefore more adequate for further advance of the sprayed particles beyond any obstacles such as a deviated septum or hypertrophic turbinates. It can be said that the powder spray is preferable with regard to deposition and distribution in the nose and that improvement of the applicator and drug forms is still necessary to achieve better clinical effects and easier manipulation by the patients. REFERENCES BALLE, V. H., PEDERSEN, U., and ENGBY. B.: The treatment of perennial rhinitis with a new, nonhalogenated, topical aerosol packed, steroid, Budesonide. Acta Otolaryngol., 94: 169-173,1982. MALM, L., and WIHL, J.: Intranasal bec1omethasone dipropionate in vasomotor rhinitis. Acta Allergol. 31: 245-253, 1976. MYGlND, N.: Effects of bec1omethasone dipropionate aerosol on nasal mucosa. Br. J. Clin. Pharmacol. 4: 287S-291S, 1977. MYGlND, N., and VESTERHAUGE, S.: Aerosol distribution in the nose. Rhinology 16: 79-88, 1978.
116
T. UNNO, K. HOKUNAN, O. Y ANAl, and S. ONODERA
MYGIND, N., S0RENSEN, H., and PEDERSEN, C. B.: The nasal mucosa during long-term treatment with beclomethasone dipropionate aerosol. A light- and scanning electron microscopic study of nasal polyp. Acta Otolaryngol. 85: 437-443, 1978. OKUDA, M. et al.: Effects of intranasal atmization of beclomethasone dipropionate in perennial nasal allergy. Its optimum dose, clinical effects and safety. Otologia (Fllkuoka) 25: 1283-1309, 1979. SAHAY, J. N., CHATTERJEE, S. S., and ENGLER, c.: A comparative trial of fiunisolide and beclomethasone dipropionate in the treatment of perennial allergic rhinitis. Clill. Allergy 10: 65-70, 1980. SATOH, Y., Hyo, N., TAKANO, S., and OKUDA, S.: Particle size, deposition and distribution of sprayed steroids in the nasal cavity. Oto-Rhino-Laryngol. Tokyo 25:137-146, 1982. SCIARRA, J. J., and STOLLER, L. (ed.): The science and technology of aerosol packaging. John Wiley & Sons, New York, 1974. STUART, B. 0.: Deposition of inhaled aerosols. Arch. lilt. Med. 131: 60-72, 1973. UNNO, T., OKUDE, Y., Y ANAl, 0., and ONODERA, S.: Distribution of beclomethasone dipropionate aerosol particles in the nasal cavity. Jpn. J. Otol. (Tokyo) 85: 277-282, 1982.
Request reprints from:
Dr. T. Unno, Department of Otolaryngology, Asahikawa Medical School, 4-5 Nishikagura, Asahikawa 078-11, Japan