Advanced Drug Delivery Reviews 29 (1998) 157–177
`
`L
`
`Nasal delivery systems and their effect on deposition and absorption
`*
`a ,
`b ,c
`H. Kublik
`, M.T. Vidgren
`aAstra GmbH,D-22876 Wedel,Germany
`bDepartment of Pharmaceutics,University of Kuopio,P.O.Box 1627,FI-70211 Kuopio,Finland
`cAstra Draco AB,P.O.Box 34,S-22100 Lund,Sweden
`Received 24 May 1997; accepted 21 June 1997
`
`Abstract
`
`Due to nasal anatomy and physiology, with a non-ciliated area in the anterior part of the nasal cavity and a ciliated region
`in the more posterior part of the nose, the site of deposition is of importance for the nasal mucociliary clearance and
`retainment of a formulation in the nose. Many drug delivery devices for nasal application of liquid, semisolid and solid
`formulations were investigated in respect to their deposition in the nasal cavity. The site of deposition and the deposition
`area depend on several parameters which are related to the delivery device, such as mode of administration, particle size of
`the formulation and velocity of the delivered particles. Several in vitro and in vivo methods have been used to study
`distribution and clearance of intranasally delivered therapeutics. The relationship between deposition, absorption and related
`bioavailability of the nasally applied formulation has been shown. © 1998 Elsevier Science B.V.
`
`Keywords: Nasal drug delivery; Device; Administration mode; Formulation; Deposition; Distribution; Clearance; Absorption
`
`Contents
`
`1. Introduction ............................................................................................................................................................................
`2. Anatomy and physiology of the nose in relation to deposition and clearance................................................................................
`3. Deposition and absorption of inhaled particles...........................................................................................................................
`4. Description of nasal delivery systems .......................................................................................................................................
`4.1. Liquid nasal formulations .................................................................................................................................................
`4.1.1. Instillation and rhinyle catheter ...............................................................................................................................
`4.1.2. Drops ....................................................................................................................................................................
`4.1.3. Unit-dose containers...............................................................................................................................................
`4.1.4. Squeezed bottle......................................................................................................................................................
`4.1.5. Metered-dose pump sprays......................................................................................................................................
`4.1.6. Airless and preservative-free sprays.........................................................................................................................
`4.1.7. Compressed air nebulizers ......................................................................................................................................
`4.2. Powder dosage forms .......................................................................................................................................................
`4.2.1. Insufflators ............................................................................................................................................................
`4.2.2. Mono-dose powder inhaler......................................................................................................................................
`4.2.3. Multi-dose dry powder systems ...............................................................................................................................
`4.3. Pressurized MDIs.............................................................................................................................................................
`4.4. Nasal gels........................................................................................................................................................................
`5. Characterization of nasal delivery devices .................................................................................................................................
`5.1. Determination of particle size distribution..........................................................................................................................
`
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`*Corresponding author.
`
`0169-409X/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved.
`PII S0169-409X( 97 )00067-7
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`Exhibit 1168
`IPR2017-00807
`ARGENTUM
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`5.2. Methods to study deposition .............................................................................................................................................
`5.2.1. Amount of deposition .............................................................................................................................................
`5.2.2. Location of deposition ............................................................................................................................................
`6. Deposition and clearance .........................................................................................................................................................
`6.1. The relationship between clearance, deposition and delivery device .....................................................................................
`6.2. Influence of nasal air-flow ................................................................................................................................................
`6.3. Influence of administration techniques ...............................................................................................................................
`6.4. Influence of application volume and cone angle..................................................................................................................
`6.5. Influence of nasal abnormalities and diseases on deposition and clearance............................................................................
`7. Absorption and pharmacodynamic effect...................................................................................................................................
`8. Conclusions ............................................................................................................................................................................
`References ..................................................................................................................................................................................
`
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`1. Introduction
`
`For many years drugs have been administered
`nasally for both topical and systemic action. Topical
`administration includes the treatment of congestion,
`rhinitis, sinusitis and related allergic or chronic
`conditions, and has resulted in a variety of different
`medications
`including corticoids,
`antihistamines,
`anticholinergics and vasoconstrictors. In recent years,
`increasing investigations of the nasal route have
`focussed especially on nasal application for systemic
`drug delivery.
`It has been estimated that the total sales for nasal
`products in 1996 was about 5 billion US$. A
`remarkable increase of the market for nasal drug
`therapy is expected if the nasal route is successful in
`superseding parenteral application for peptide deliv-
`ery.
`inhalation medication requires
`Optimization of
`consideration of
`the strong interactions between
`formulation, device, mode of administration and
`patient. The evaluation of each part has to be seen in
`connection with the other influencing factors.
`Regardless of the required means of action—local
`or systemic—there are several factors that should be
`taken into account to optimize nasal administration.
`Having an adequately designed and developed drug
`delivery system and formulation in respect to deposi-
`tion, clearance and absorption the therapeutic effec-
`tiveness can be improved and adverse events mini-
`mized.
`The deposition site for nasally applied drugs
`within the nasal cavity depends upon the type of
`delivery system and the technique of administration
`used. It determines the subsequent translocation of
`the deposited preparation by mucociliary clearance
`and has an influence on absorption and hence
`
`effectiveness of the medication. In several studies the
`relationship between initial deposition pattern and
`mucociliary clearance, which results in a secondary
`deposition of the administered drug, has been in-
`vestigated. Only a few investigations relate these
`results to pharmacokinetic and pharmacodynamic
`data to highlight the relationship between deposition,
`clearance, absorption and effect of the medication.
`Only a few nasal delivery systems used in ex-
`perimental studies are currently on the market
`to
`deliver therapeutics into the nasal cavities, i.e. nasal
`drops as multiple or single-dose formulation, aque-
`ous nasal sprays, a nasal gel pump, pressurized MDIs
`and dry powder inhalers.
`
`2. Anatomy and physiology of the nose in
`relation to deposition and clearance
`
`Nasal anatomy and physiology greatly influence
`primary deposition and mucociliary clearance of
`administered drug substances and are,
`therefore,
`important for nasal absorption. Gizurarson and Bech-
`gaard [1] listed several factors which have an effect
`on nasal absorption. Some of the anatomical factors,
`such as nasal length, the bend from the nostrils into
`the cavity and structure of the turbinates, can directly
`be related to deposition in the nasal cavity. Passing
`the nostrils the nasal passage extends from the nasal
`vestibule to the nasopharynx at a length of about 12
`cm. It is separated by the nasal septum into two
`cavities and further divided by the folds of the
`superior, middle and inferior turbinate, considered to
`be the main nasal passages. The main nasal passages
`with a length of approximately 6 cm end behind the
`turbinates at the arch of the nasal septum.
`At the end of the nostrils the airways are con-
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`stricted in the region of the nasal ostium, which
`results in an acceleration of the inhaled air. In the
`preturbinate region (atrium) because of the construc-
`tion, with a wider cross-sectional area, the air flow is
`decreased and has to change direction to enter the
`main nasal passages of the turbinates. This results in
`higher air flow resistance and increased turbulence.
`Due to nasal anatomy there are two major deposition
`areas. One near the ostium internum where a high
`degree of turbulence occurs because of the constric-
`tion, and another one in the anterior region of the
`middle turbinate due to the change of the airflow
`direction from vertical to horizontal flow. The ves-
`tibule, atrium and the beginning of the turbinates are
`covered by non-ciliated surfaces. Mucus flow in this
`anterior third of the nasal cavity is only 1–2 mm/h
`and occurs mainly by traction of the mucous layer
`due to ciliary movement of posteriorly located cilia
`[2]. The main nasal passages are highly vascularized
`and ciliated. Here the rate of mucus flow is 8–100
`mm/min. It
`is assumed that
`in this region, with
`increased surface area, highest air flow resistance
`and ciliated cells, the main drug absorption takes
`place [3]. If particles are deposited just posterior to
`the ostium internum, they are moving in an anterior
`direction until the nasal area ends and then are blown
`out [2,4].
`Nasal deposition depends on the size and shape of
`the nose [5,6]. It can also be correlated to body
`length and weight and increases with decreasing age
`for a given particle size and flow rate [7]. Zhang and
`Yu [8] could reduce interspecies differences by
`including the total bend angle in the nasopharynx as
`an additional variable in the calculations for the
`prediction of nasal deposition. Cheng et al.
`[6]
`considered that nasal geometry is a main factor
`affecting aerosol deposition. They measured the
`nasal morphometry of four male adults by a mag-
`netic resonance imaging technique. The coronal
`sections of the nasal airways at different distances
`from the nostrils were illustrated. In the main nasal
`passage, which is located 3–8 cm behind the begin-
`ning of
`the nostrils,
`the most complicated and
`asymmetrical profile, due to the folds of the turbi-
`nates, is seen at a distance of approximately 5–7 cm
`from the nostrils. Hence the surface area of the nasal
`passages from the nostril to the nasopharynx shows
`2
`its maximum at this distance: 11–14 cm depending
`on the individual morphology. The cross-sectional
`
`area had local maxima and minima and increased
`from the anterior vestibule to the turbinate region
`with its maximum in the nasopharynx. The geomet-
`ric parameter was calculated for each individual area,
`2
`dividing the total surface area (180–240 cm ) by the
`2
`mean cross-sectional area (2.0–3.8 cm ). The nasal
`deposition efficiency increased with increasing
`geometric factor, i.e. with increasing surface area or
`decreasing cross-sectional area.
`
`3. Deposition and absorption of inhaled
`particles
`
`Inhaled particles are deposited by five mechanisms
`[9]: interception, impaction, sedimentation, diffusion
`and electrostatic precipitation. Only three of these
`mechanisms have importance for nasal deposition:
`inertial
`impaction, gravitational sedimentation and
`Brownian diffusion [10–12].
`Deposition by interception only occurs to fibrous
`particles, when the trajectory of the particle brings it
`close to the surface and the edge contacts the
`surface. Usually fibrous particles are orientated par-
`allel to the air flow streamlines [13]. Small particles
`which are highly charged and have a high electric
`mobility are deposited by inducing image charges on
`the surface of the airways. However, deposition due
`to these mechanisms is usually of minor importance.
`Inertial impaction may occur whenever the air-
`stream carrying the particles changes its direction. If
`the particles are heavy, large or moving fast, they
`may be unable to follow the airstream as it changes
`direction. Instead, they fly off tangentially and strike
`the airway wall [11]. The probability of impaction in
`a bent airway is:
`
`2
`Ud sin u/R
`
`(1)
`
`where: u, angle of the bend; U, airstream velocity; d,
`particle aerodynamic diameter; R, airway radius.
`It can be derived from Eq. (1), that the airway
`geometry, the size of the inhaled particle and the
`inhalation flow have a major influence on deposition
`due to inertial
`impaction. Considering the nasal
`delivery device,
`the aerodynamic diameter of the
`delivered particles can be varied. In addition, the
`technical construction of the device has an influence
`on airstream velocity, and thus it
`is possible to
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`influence deposition. Impaction is the major deposi-
`tion mechanism for particles larger than 0.5–1 mm in
`the nose and the oropharynx. Deposition in these
`regions is further increased with obstruction and high
`inspiratory flow rates, when turbulent air flows are
`created [14].
`In the small conducting airways, deposition occurs
`mainly by gravitational sedimentation [15]. A par-
`ticle settling under gravity accelerates to a steady
`terminal settling velocity, at which gravitational
`force is balanced by the resistance of the air through
`which the particle falls [16]. The rate of settling is
`proportional to the square of the particle diameter
`according to the Stokes equation [17]. The smaller
`the particle the more slowly it sediments. The
`terminal settling velocity is described by:
`
`2
`(r2 s)gd /g
`
`(2)
`
`where: r, density of the particle; d, diameter of the
`particle; s, density of the air; g, viscosity of the air;
`g, gravitational acceleration.
`Deposition by gravitational sedimentation can only
`be influenced by the variation of the particle size.
`The density is already fixed by the character of the
`drug substance.
`The third deposition mechanism, Brownian diffu-
`sion, is restricted to particles whose diameter is less
`than 0.5 mm. Particles of this size can be pushed
`towards a surface by the random collision of gas
`molecules. Higher deposition is predicted with an
`increasing diffusion coefficient and decreasing flow
`rate [6].
`Usually this mechanism can be ignored for the
`administration of nasal delivery systems, since the
`diameter of drug particles in nasal dosage forms are
`seldom 0.5 mm or less.
`Aerodynamic particle size is the key factor of
`nasal deposition. Correlation of aerodynamic particle
`diameter and nasal deposition efficiency at a given
`flow rate shows a minimum deposition of particles of
`approximately 0.5–1 mm [18]. Above this particle
`size deposition increases due to inertial forces, below
`it increases due to turbulent diffusion. Inertial impac-
`tion, dominant for particles above 0.5 mm, is the
`main deposition mechanism in the nose. For particles
`larger
`than 0.5 mm inspiratory nasal deposition
`increases with increasing particle diameter and with
`increasing inhalation flow rate. Although the nose
`
`filters particles more efficiently during expiration
`than during inspiration,
`in the investigations of
`Heyder and Rudolf [19] expiratory deposition was
`lower than inspiratory nasal deposition due to par-
`ticle deposition in the lungs. At
`low flow rates
`particle deposition in the lungs is higher, with
`increasing flow rates the deposition in the nose
`increases. The main deposition mechanism for par-
`ticles smaller than 0.2 mm is diffusion. With this
`mechanism nasal deposition increased with decreas-
`ing particle size and with decreasing flow rate.
`Absorption by the nasal route is facilitated by a
`highly vascularized epithelial
`layer with a good
`blood flow, the rich lymphatic plexus and a relatively
`thin and porous endothelial membrane. The absorp-
`tion routes via the nose include transcellular and
`paracellular passive
`absorption,
`carrier-mediated
`transport and absorption by transcytosis [20]. The
`main mechanism is transcellular passive diffusion.
`Therefore the solubility, the partition coefficient and
`the molecular weight of
`the drug are of major
`importance [21]. However, the absorption rate with
`regard to the nasal deposition site has not yet been
`elucidated.
`
`4. Description of nasal delivery systems
`
`Depending on the physico-chemical properties of
`the drug, the therapeutic aims, the basic compliance
`of
`the patients and marketing issues,
`the most
`suitable delivery system and formulation strategy
`have to be chosen. A lot of nasal devices, especially
`for systemic medication, have only been used for
`experimental studies [22]. Four basic formulations
`must be considered, i.e. solution, suspension, emul-
`sion and dry powder systems. Liquid preparations
`often contain aqueous formulations, but also alcohol,
`oils or other organic solvents. Compatibility with
`additional excipients and the solvent have to be
`considered in choosing the delivery device.
`If accurate dosing is required the most widely used
`delivery
`devices
`are mechanical
`pumps
`and
`pressured aerosol systems. Su and Campanale [23]
`discussed five different areas regarding the consid-
`eration of the requirements for an aerosol or pump
`system,
`including
`formulation
`aspects,
`valve,
`container and actuator
`requirements and quality
`control issues. With regard to formulation, physico-
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`solubility, chemical, mi-
`chemical compatibility,
`crobiological and physical stability of the active
`ingredient, and necessary additives, determine their
`own specific requirements for a delivery system.
`
`4.1. Liquid nasal formulations
`
`Liquid preparations are the most widely used
`dosage forms for nasal administration. They are
`mainly based on aqueous
`formulations. Their
`humidifying effect is convenient and useful, since
`many allergic and chronic diseases are often con-
`nected with crusts and drying of mucous membranes.
`One major drawback of water-based dosage forms is
`their microbiological stability, because the required
`preservatives impair mucociliary function [24,25].
`Especially in long-term nasal
`treatment, preserva-
`tives can be the major cause of irritation and allergic
`rhinitis [26]. Besides microbiological stability, the
`reduced chemical stability of the dissolved drug
`substance and the short residence time of the formu-
`lation in the nasal cavity are major disadvantages of
`liquid formulations [27,28]. The site of deposition
`and deposition pattern of nasally applied liquid
`formulations is dependent on the delivery device, the
`mode of administration and the physico-chemical
`characteristics of the formulation. Usually a wide
`distribution of the preparation in the nasal cavity is
`desired wether the drug substance is administered for
`local or for systemic application.
`Other requirements such as patient compliance,
`cost effectiveness and risk assessment result
`in a
`variety of different dosage forms for liquid nasal
`formulations.
`
`4.1.1. Instillation and rhinyle catheter
`An easy way to deliver drops to a defined region
`in the nasal cavity is the use of a catheter. The
`combination of an instillation catheter to a Hamilton
`threaded plunger syringe was used by Hughes et al.
`[29] in order to compare the deposition of drops,
`nebulizers and sprays in rhesus monkeys. In a study
`by Harris et al. [30], 0.2 ml of the formulation were
`placed in a tube. One end of the tube was positioned
`in the nose, and the solution was delivered into the
`nasal cavity by blowing through the other end by
`mouth. Dosing of catheters is determined by the
`filling prior to administration and accuracy of the
`system. Nasal deposition and distribution of catheter-
`
`applied solutions depend strongly on the means of
`administration. This system is only used for ex-
`perimental studies.
`
`4.1.2. Drops
`Nasal application devices are often associated with
`drops, one of the oldest delivery systems for nasal
`administration of liquids. They are low-cost devices
`and easy to manufacture. Their disadvantages are
`related to the use of liquid formulations, such as
`microbiological and chemical stability. In addition,
`the mode of administration is of great importance for
`the efficacy of the medication. Correct administration
`of drops requires complex manouvers [31]. The
`delivered volume cannot be clearly controlled and
`the formulation can be easily contaminated by the
`pipette. Depending on the position of the head, the
`delivery of a relatively large volume often results in
`fast clearance down the laryngopharynx.
`
`4.1.3. Unit-dose containers
`The major advantage of disposable unit-dose
`containers compared to other water-based formula-
`tions is the avoidance of preservatives. Due to their
`portability and small size they improve the patients
`comfort. In contrast to multi-dose nasal drops the
`volume is determined by the filling volume of the
`unit-dose. The dose accuracy results from filling
`accuracy and use of the device. There are two
`different devices currently available. The best known
`form is the bottlepack package, which delivers the
`formulation in the form of a drop pressed out of the
`unit-dose pipette. The deposition of the preparation
`is the result of the administration technique.
`The dose accuracy determined by the filling
`volume is higher compared to multiple-dose drops,
`but still lower than the accuracy of metered-dose
`nasal sprays. This fact is due to the lack of a pressure
`point or any other guiding mechanism during action.
`A further increase in dose accuracy can be achieved
`by a second form of unit-dose containers, which
`operates with an actuator with a nasal adaptor and
`has a small chamber with a piston. The liquid
`formulation is kept in a plastic container (Fig. 1a). A
`similar device (Fig. 1b) divides the dose, so that half
`of the total dose is administered in each nostril.
`Depending on the mode of administration a residual
`volume of 10–30% of the formulation can remain in
`these devices after actuation.
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`The reduction or withdrawal of preservatives
`achieved with these devices requires an aseptic
`filling of the device, which is only suitable for cost
`extensive and sensitive drug substances. The con-
`tainers of other unit-dose or bi-dose-systems are
`comprised of a small glass ampoule (Fig. 2), which
`has the advantage of a better compatibility to the
`drug formulation, and that autoclaving of the prepa-
`ration is possible. Compared to the bottlepack
`container, a better distribution of the dose, a more
`controlled and user-friendly application mode and a
`higher dose accuracy can be achieved due to the
`pressure point. Usually, the particle size distribution
`and the spray angle are dependent on the mode of
`actuation. A system based on a pressure point uses
`the inertia of the actuation finger and is therefore
`more independent of an individual manual actuation.
`The increasing use of water-based metered sprays
`can be explained by their simplicity and hygiene.
`The disadvantages of nasal sprays are similar to
`nasal drops mainly due to the requirement of pre-
`servatives. Nasal spray devices include the squeezed
`bottle, the metered-dose pump spray, and new de-
`vices known as airless or preservative-free spray
`pumps.
`
`4.1.4. Squeezed bottle
`Squeezed nasal bottles are mainly used as delivery
`device for decongestants. They include a smooth
`plastic bottle with a simple jet outlet. While pressing
`the plastic bottle the air inside the container is
`pressed out of the small nozzle, thereby atomizing a
`certain volume. By releasing the pressure again air is
`drawn inside the bottle. This procedure often results
`in contamination of the liquid by microorganisms
`and nasal secretion sucked inside. Dose accuracy and
`deposition of liquids delivered via squeezed nasal
`bottles are strongly dependent on the mode of
`administration. Differences between vigorously and
`smoothly pressed application influence the dose as
`well as the droplet size [32]. Thus the dose is hard to
`control. Therefore squeezed bottles with vasocon-
`strictors are not recommended to be used by chil-
`dren.
`
`4.1.5. Metered-dose pump sprays
`Most of the pharmaceutical nasal preparations on
`the market containing solutions, emulsions or sus-
`pensions are delivered by metered-dose pump sprays.
`
`Fig. 1. (a) Nasal unit dose system (Monospray®, Valois S.A., Le
`Neubourg, France). (b) Nasal two-dose system (Bidose®, Valois
`S.A., Le Neubourg, France).
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`Fig. 2. Nasal unit-dose system with glass container (Pfeiffer, Radolfzell, Germany).
`
`Compared to squeezed bottles and continuous valve
`sprays, they allow the application of a defined dose
`with a high dosing accuracy and a typical spray
`pattern. Dose volumes between 25 and 200 ml are
`available as standard. Spray characteristics vary
`according to the precompression mechanism,
`the
`type of the selected pump and valve and the physical
`properties of the product. Viscosity, thixotropic be-
`havior, elasticity and surface tension of the liquid
`determine the spray pattern, the particle size of the
`
`drops, the dose and the dosing accuracy. Metered-
`dose pump sprays include the container, the pump
`with the valve and the actuator. The form of the
`actuator has to be adapted to the required use. For
`correct dosing the tip should avoid the collection of
`residual drops. The length of the actuator has an
`influence on deposition of the application into the
`nose. Special adaptors for children are available on
`the market. For safety reasons a captive insert is
`fitted into the actuator in order to avoid risks of
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`
`to decrease the
`liquid ejection without actuation,
`dead volume in the actuator and to reduce contami-
`nation.
`Dependent on the product delivered, especially
`with respect
`to its rheological behavior, surface
`tension and required spray characteristics, the geom-
`etry and dimensions of the pump mechanism can be
`adapted to fulfil these demands.
`Special geometries of the orifice determine the
`spray pattern and distribution. The cone angle varies
`between 35 and 908. A small cone angle results in a
`more posterior deposition, while the wider angle
`shows a broad distribution in the anterior part of the
`nasal cavity [33]. A multiple-channel system in the
`orifice of the nasal adapter, by which the solution is
`sprayed in several different directions, additionally
`ensures a good distribution. The dose accuracy of
`metered-dose pump sprays is dependent on the
`surface tension and viscosity of the formulation. For
`solutions with higher viscosity, special pump and
`valve combinations are on the market.
`
`4.1.6. Airless and preservative-free sprays
`In order to minimize the use of preservatives and
`to increase the stability of products which are very
`sensitive to oxidation, several suppliers have de-
`veloped pumps which prevent the entry of air back
`into the device during dispensing. So far three main
`principles for airless pumps have been realized: the
`collapsible bag,
`the sliding piston system and a
`system which works against a vacuum.
`The pump prevents air entering the package. The
`vacuum created after dispensing is compensated by
`reduction of the container volume, which can be
`done by deformation of
`a
`collapsible plastic
`container (Fig. 3a) or dragging of a sliding piston
`within a glass or plastic bottle (Fig. 3b).
`Some devices function under the low pressure of a
`compressed gas, such as nitrogen or carbon dioxide,
`in order to offset the volumes of product expelled
`outside the bottle.
`Working against a vacuum requires a larger
`container, which is only partly filled because the
`drop of the pressure in the container under about 500
`mbar reduces the performance, especially the dose
`volume.
`Besides the reduction of preservatives and anti-
`oxidants a major advantage of airless pumps is their
`use in any position with unchanged dose accuracy,
`
`which is useful especially for children or bedridden
`patients. However, both systems require an absolute-
`ly tight packaging, as leakage of air into the device is
`a major problem leading to increased control pro-
`cedures.
`A different preservative-free system compensates
`the volume of the dispensed dose by an air flow
`through an aseptic filter into the container (Fig. 4).
`The nasal adapter is protected from contamination by
`a pure mechanical sealing system. An advantage is
`that the microbiological sealing system mechanism is
`directly integrated in the very end of the tip, so that
`not only the content of the bottle, but also the
`content of the pump and the nasal adapter up to the
`orifice is protected.
`
`4.1.7. Compressed air nebulizers
`An often used compressed air nebulizer in nasal
`deposition studies is the Devilbiss Sprayer. Hughes
`et al. [29] carried out deposition studies in rhesus
`monkeys delivering a dose of 70 ml with a com-
`pressed air pressure of 30 p.s.i. for 0.5 s with an
`automatically timed pump. The resulting mass
`medium aerodynamic diameter (MMAD) was 1.5
`mm (geometric standard deviation (GSD)51.5)
`measured with an aerodynamic particle sizer (APS
`3310, TSI, Inc., St. Paul, MN). This delivery device
`offers a variety of parameters such as different
`volumes, different particle sizes by pressure variation
`or different duration of
`the administration. This
`allows the adaptation of the compressed air nebuliz-
`ers especially for study purposes. At the same time
`this device is not suitable for systemic drug delivery
`by the patient himself due to the variety of parame-
`ters and the complicated design with compressed air
`supply.
`
`4.2. Powder dosage forms
`
`Dry powders are less frequently used in nasal drug
`delivery. Major advantages of this dosage form are
`the lack of preservatives and the improved stability
`of
`the formulation. Compared to solutions,
`the
`administration of powders could result
`in a pro-
`longed contact with the nasal mucosa. It has been
`shown by Illum et al. [34] that small volumes of
`liquid and powder particles have almost the same
`clea