Special Report

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Nasal formulations for drug administration

and characterization of nasal preparations in
drug delivery
Regina Scherließ*,1
1
Department of Pharmaceutics & Biopharmaceutics, Kiel University, Grasweg 9a, 24118 Kiel, Germany
*Author for correspondence: Tel.: +49 431 880 1330; Fax: +49 431 880 1352; rscherliess@pharmazie.uni-kiel.de

This special report gives an insight in the rationale of utilizing the nasal cavity for drug administration
and the formulation as well as characterization of nasal preparations. As the nose is an easy-to-access,
noninvasive and versatile location for absorption, this route of delivery will play an increasingly important
role in future drug product development both for new and repurposed drugs. The nose can be utilized
for local and systemic delivery including drug delivery to the central nervous system and the immune
system. Typical formulation strategies and future developments are reviewed, which nowadays mostly
comprise liquid formulations. Although they are straight forward to develop, a number of aspects from
choice of solvent, osmolarity, pH, viscosity and more need to be considered, which determine formulation
characteristics, not at least nasal deposition. Nasal powders offer higher stability and, along with more
sophisticated nasal devices, may play a major role in the future.

First draft submitted: 18 November 2019; Accepted for publication: 20 January 2020; Published online:
12 February 2020

Keywords: device • formulation parameters • nasal deposition • nasal vaccines • nose-to-brain delivery • pharma-
copoeial requirements • Repurposing of drugs

“A good drug can be rendered useless, ineffective or mediocre by the choice of an inappropriate formulation. On the other
hand, by selecting an optimal formulation, a mediocre drug can be converted into a more effective and successful product” [1].
This quotation shows the tremendous impact of formulation on drug effect and product success. However, the
research of nasal formulations rather suffers a niche existence so far. Increasing interest in the development of nasal
products only slowly evolves as it becomes obvious that the nose is not only a target for local action of decongestants
and antiallergics, but also an easy-to-access mucosal absorption area with close vicinity to the CNS being equipped
richly with immune competent cells. In this sense, nasal formulations offer a superb possibility for the repurposing
of drugs [2] that have shown their benefit in other routes of administration, but can be converted to a more effective
product in the right nasal formulation.

The nose as absorption tissue

The human adult nose has an inner surface area of about 160 cm2 , which is divided into two sides being separated
by the nasal septum. Oftentimes, the nasal cavity is sectioned in the following parts (from anterior to posterior):
nostrils, nasal valve or vestibule, followed by the nasal cavity with its different turbinates and the olfactory region
in the top [3] and finally the nasopharynx at the rear end where both sides are reunited. The anterior region of the
nose has squamous epithelium which is similar to normal skin [4]. The narrowest part of the nose, the nasal valve,
separates this part from the nasal cavity. It has a free diameter of as little as 0.25 mm [5]. The mucosal epithelium in
the turbinates mostly consists of respiratory epithelium, which is a ciliated pseudostratified cuboidal or columnar
epithelium being covered with a mucus film [4,6]. Systemic absorption of drugs will predominantly take place in
the turbinates with their enhanced surface [7]. Small holes leaving the turbinates allow entrance to the nasal sinuses.
The olfactory bulb, being located in the upper turbinates, has a direct connection to the CNS; thus, this may be
one route for nose to brain transport [8]. By ciliary beating the mucus lining is moved toward the posterior part
of the nose, from where it is swallowed. Nasal clearance has a half-life of about 15 min in healthy adults [9] (as

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indicated by the saccharin clearance test), but may be prolonged significantly if ciliary function is impaired [10] or
if the formulation creates a highly viscous environment slowing down mucocilliary clearance. With a pH of about
6.4 [11] and lower enzymatic activity compared with the gastrointestinal tract, the nasal mucosa offers pleasant
conditions also for sensitive drugs. The mucosa of the nose as potential first entry for airborne pathogens is richly
equipped with cells of the immune system. As such, the nose can also be used as a target for mucosal vaccination [12]
or the delivery of other immune active preparations. It should be noted that the nose is a highly patient-individual
organ that may differ in size, air passages and obstruction. Physiologically, the nose filters, heats and humidifies the
inspired air, which is why humans should inspire through the nose, not the mouth [6]. It is believed that about 80%
of particles of a size up to 12.5 μm and 100% of particles being larger than 50 μm are deposited and retained in
the nose in vivo [3], whereas about 50% of small particles of 2–4 μm will pass the nose and may enter the lower
airways. However, the nose does not have clear size cutoffs and deposition appears to be highly affected by the
formulation and administration device (e.g., angle and speed of formulation cloud).
Drugs of interest for nasal delivery (utilizing the nasal route for systemic delivery) derive from a broad range
of therapeutic areas including antimicrobial, cardiovascular, pain, Parkinson, Alzheimer, cancer, osteoporosis,
anticoagulation and many more. An ideal drug for rapid systemic uptake via the nose would be lipophilic and
nonpolar (uncharged), of low molecular weight (below 1 kDa) and show rapid dissolution. However, the nose is
currently discussed for a range of rather large biotechnology-derived molecules which may be well water-soluble,
but hydrophilic and of large size which will impair bioavailability [9]. To get absorbed, a drug molecule must pass the
aqueous mucus barrier, avoiding mucocilliar clearance, to reach the epithelium, where the drug can then be taken
up – typically by transcellular diffusion and best avoiding p-glycoprotein-mediated efflux. Specialized uptake routes
are discussed in the course of nose-to-brain transport utilizing the olfactory nerves in the upper turbinates/olfactory
bulb or also the trigeminal nerve pathway [13,14].

Nasal preparations in the European Pharmacopoeia

The current monograph on nasal preparations [15] lists nasal drops and liquid nasal sprays, nasal powders as well as
semi-solid products for nasal application. Further, nasal washes and nasal sticks are mentioned. Nasal preparations
always need a device to be administered, which may be a mechanical pump sprayer or a pressurized metered
dose device, a nasal dry powder device or a simple pipette. Nasal products may be single/bi-dose preparations,
but oftentimes also contain multiple doses, which then also require preservation. The general requirements for
those formulations intended for local or systemic action include no irritant or toxic effects on mucosa and cilie,
they should normally be isotonic and may contain excipients to adjust pH, viscosity, solubility and stability. The
current monograph does not contain detailed characterization methods of such nasal formulations apart from dose
content uniformity tests for systemic preparations and the rather vague requirement that the particle size should
allow predominant nasal deposition. In that aspect the monograph is under revision to include a test to control
small particles/droplets (less than 10 μm) in nasal preparations, which may also result in a new test method to be
described as ‘2.9.56: Nasal preparations: mass fraction less than 10 micrometres’ [16]. Along with this, the EMA
‘Guideline on the pharmaceutical quality of inhalation and nasal products’ (from 2006) is also under revision
(possibly to be published in revised form in 2020) and a concept paper on the revision had already been published
for consultation in 2017.

Formulation strategy
Formulation strategy should always consider the needs of the drug and derive a reasonable quality target product
profile. This should typically take into account local or systemic delivery, single dose or repetitive/chronic adminis-
tration, individual dose to be administered (drug potency), solubility of the drug, toxicity and stability of the drug
(chemical, physical and in terms of compatibility) and if available permeability of the drug and intended deposition
site within the nose [17]. The requirements of the formulation should then be met by the easiest achievable option.
In the course of that, a liquid solution is the easiest formulation option. All substances are dissolved in the
dispersion media, so no inhomogeneity can occur, and the dissolved drug may easily diffuse and penetrate, hence,
the highest bioavailability can be expected. On the other hand, a solution also bears the highest risk of chemical
instability and degradation. If the drug (or excipients) are of limited solubility and the therapeutic dose may thus
not be dissolved in the volume typically being administered with a liquid nasal spray (25–200 μl), a suspension
would be the alternative option. Still, the formulation could be sprayed utilizing a liquid sprayer, but the drug
load can be much higher. The formulation of such a product will be more challenging and particle size of the

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 Nasal formulations for drug administration & characterization of nasal preparations in drug delivery Special Report

drug particles is crucial for product stability, deposition and therapeutic effect. If the drug cannot be formulated as
suspension due to stability issues, a dry powder formulation would be an alternative. This formulation type as such
will offer higher stability as molecular mobility and chemical reactivity are slowed down in solid formulations [18].
However, particle size and particle–particle interactions will play an important role for device emission (a dose of
50 mg may be considered the maximum dose), deposition and dissolution. Nasal powders, although available on
the international market, for example the Rhinocort R
Puvlizer from Teijin (Beclomethasone) or more recently the
R R
Onzetra Xsail (sumatriptan in the Optinose device) and Baqsimi™ from Eli Lilly, a nasal glucagon powder in
the UDS powder device from Aptar, are the least established strategy and may require the most engineering effort.
Liquid formulations, may they be a solution or a suspension, need to take the following aspects into account:

• Solvent & osmolarity

Nasal formulations comprise mostly aqueous formulations, although some nasal oils are on the market. In
solutions, cosolvents to improve API solubility such as glycols, alcohol, and medium chain glycerides can be
utilized as well as the addition of surfactants as solubilizer. It needs to be kept in mind that the choice of solvent
influences formulation viscosity and hence droplet size and subsequent nasal deposition. Further, all dissolved
molecules add to the osmolarity of the formulation, which in turn affects ciliary beat and epithelial cell volume.
As the monograph states, nasal preparations are normally isotonic (about 290 mOsmol/l), which is also best
tolerated [19], but sometimes a deviation from isotonicity may be an advantage. Hypertonic solutions shrink
epithelial cells and inhibit ciliary activity; thus this type of preparation may be used for nasal decongestion and
increased retention time. On the other side, hypotonic solutions can increase drug absorption [1].
• pH & buffer capacity
The physiological pH in the nose is 6.4 on average [11] and this allows normal ciliary function. In this slightly
acidic environment, lysozyme, the natural antimicrobial agent in the nose, is effective in the prevention of growth
of pathogenic bacteria in the nasal passage. A major deviation from that causes irritation of the nasal mucosa.
To avoid that, formulation pH should be kept between 4.5 and 6.5. However, it needs to be kept in mind that
most drugs will be absorbed in their nonionized form, which is dependent on pH, and also drug stability and
functionality of excipients such as preservatives may be affected by pH. Thus, it may be necessary to deviate from
physiological pH in the formulation. To what degree this will be tolerated is also dependent on the osmolarity
as an isotonic solution may make up for a more extreme pH. It should also be considered to include a buffer
into the preparation to ensure the pH of the formulation is maintained upon nasal delivery and mixing with the
nasal fluid if pH is crucial for drug uptake.
• Viscosity of the preparation
The resulting viscosity of the preparation will directly affect droplet size of the spray [20] depending on rheological
properties (newtonian vs shear-thinning) and spray characteristics of the spray plume as nicely demonstrated
by Trows et al. [21]. Although it is known that in vitro spray plume pattern and plume angle determination do
not have a major in vivo meaning, droplet size will affect nasal deposition [22] and the extent of possibly inhaled
formulation being below 10 μm. Further, higher viscosity facilitates muco-adhesiveness, less dripping and thus
increased residence time in the nasal cavity upon delivery [23]. On the other hand, more viscous formulations
provide less efficient systemic nasal drug delivery due to slower diffusion. In nasal suspensions, thixotropic
systems (e.g., prepared with colloidal microcrystalline cellulose) may be advantageous as thixotropic systems
provide high viscosity and thus high stability for suspensions during storage, while the preparation transforms
to a low viscous formulation upon shear during spraying with results in comparably small droplets.
• Microbial stability
For all nasal multidose preparations, microbial stability needs to be ensured. This can be gained either by the use
of preservatives (benzalkonium chloride, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate and others) or
by the primary packaging [24]. Addition of preservatives and especially the chronic use of preserved formulations
has been discussed controversially as benzalkonium chloride had been associated with impaired ciliary function
in several animal studies [25]. However, more recent human studies showed that it is safe and well tolerated also in
chronic use [26]. Nonetheless, there is a trend toward preservative-free preparations in which the microbiological
integrity is ensured by the primary packaging effectively avoiding any contamination (e.g., the continuous
monodose (COMOD) system with silver spring, valve and collapsible inner bag).
• Bioavailability

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If the preparation is intended to deliver the active to the systemic circulation or to the CNS, nasal bioavailability
is crucial. On the other hand, for local delivery, the drug should best not be absorbed to avoid systemic side
effects. Typically, sufficient bioavailability requires more attention and may be supported by the use of permeation
enhancers [27]. Substances acting as those enhancers may comprise solvents and cosolvents, cyclodextrins, EDTA,
surfactants, lipids, bile salts, fatty acids (especially oleic acid) and mucoadhesive polymers (e.g., chitosan). These
materials may have a direct effect on absorption or interfere with normal nasal function by impairing ciliary
function and membrane integrity [9,28–30]. Due to that, safety of the employed substances is of special interest
and must be evaluated along with the formulation.

Dry powder formulations

In a nasal dry powder preparation, particle size and dispersibility are the main aspects being looked at. As mentioned,
all preparations need to ensure predominant nasal deposition, which typically requires a particle size above 10 μm
and Garmise et al. even recommend particles >50 μm for nasal powder deposition [31]. Formulation options are
basically similar to dry powder inhalation and comprise pure drug in the required particle size, powder blends,
agglomerated powders or engineered particles [32]. Powder blends can be utilized to improve bulk powder properties
or to adjust nasal deposition if the drug material is too small and will be inhaled if not adhered to a larger carrier.
Unlike in oral inhalation, where interactive blends are used to create a high dose of fine particles as the powder will
be dispersed intensively by the inhaler device, nasal devices are typically less effective in powder dispersion and thus,
fine material may stay adhered to a carrier and will then deposit together with the carrier material [33]. By spray
drying, particles can be engineered to match nasal requirements in terms of size and other characteristics [34] and
this also allows to create composite materials, comprising nanoparticles for example [35]. However, all other aspects
mentioned for liquid preparations above also play a role as the powder composition either has a direct impact or
the components will dissolve in the nasal fluid and with this will influence properties such as osmolarity. These
aspects only recently came into research focus [32,36,37] and many further aspects related to sensory effects such as
irritancy, smell and taste of nasal (powder) preparations are poorly understood so far – but may play an important
role in terms of patient acceptance and adherence.

Formulations for nasal vaccines & CNS targeting

These two applications may serve as examples for the use of nanoparticulate formulations in nasal delivery. In
general, nanocarrier systems are only reasonable in drug delivery if they can fulfill special prerequisites of the
intended route of delivery/uptake, which may be load protection, sustained release and targeted uptake [38]. As
such, nanoparticles are not absorbed to a major extent via intact epithelia. Thus, they need to make use of uptake
mechanisms such as phagocytosis into cells of the immune system (macrophages and dendritic cells) or gaps
which nanoparticles can pass due to their miniature size. For nasal vaccination, immunocompetent cells of the
mucosal immune system are targeted to deliver an antigen. They are found throughout the nasal epithelium and are
concentrated in the Waldeyer’s ring in the nasopharynx [39]. To provoke a mucosal immune response consisting of
humoral and cellular response, the antigen needs to be in particulate form [40]. In the course of that, many studies
use polymer nanoparticles of poly-lactic-co-glycolic acid and the biopolymer chitosan [41–43] to effectively deliver
antigens to the nose-associated lymphoid tissue. Nanoparticles have also been shown to foster drug delivery to the
brain [44–47], although the actual mechanism is not fully elucidated yet. In general, drugs may either be absorbed
from the nasal cavity to the blood to then travel to the brain via systemic circulation and passage of the blood–brain
barrier or they may more directly access the brain via the olfactory/trigeminal nerve route. It is hypothesized that
nanoparticles may enhance nose-to-brain delivery by protection of drug against degradation and p-GP efflux and
possibly also direct uptake [46,48–50]. In the course of that it becomes crucial to maximize the amount of drug at the
target for uptake, in other words, the olfactory region with an enabling formulation and delivery [8].

Characterization of regional nasal deposition

Apart from a number of compendial tests and other characterization methods that are nicely reviewed in a recent
paper from Salade et al. [51], the regional deposition of a nasal formulation in the nasal geometry is of special interest
as this may determine its therapeutic effect. Unlike in pulmonary administration, where the use of impactor studies
to determine aerodynamic performance is state of the art and calculation of fine particle fraction as a measure for
lung deposition is widely accepted, there is no such model for nasal deposition yet. Nonetheless, it is important
to determine the fraction of a formulation, which is retained in the nasal cavity upon nasal administration in

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 Nasal formulations for drug administration & characterization of nasal preparations in drug delivery Special Report

comparison with the postnasal fraction which possibly gets inhaled to the lung. Further, more detailed knowledge
about the site of deposition and distribution of a formulation within the nasal cavity is favorable in case the
formulation should be targeted to a certain region (e.g., the olfactory bulb for nose-to-brain transport or the
nasopharynx for targeting of the nasal associated lymphoid tissue) or shall be spread uniformly over the inner
surface as for systemic uptake. Within the last decades, nasal cast models gained increasing interest to simulate
deposition within the nasal cavity. These are generally replicas of individual noses. The first nasal casts were made
from cadavers, where the nasal cavity was filled with modeling material or wax to obtain a negative which could
then be transformed to a nasal cast model [52]. The dimensions of cadaver casts are often too large with respect to
the cavity as the mucosa shrinks rapidly after death due to desiccation leaving an open space which is normally filled
with mucosal excrescences. For this reason, it is more appropriate to use a vital nose as model for the respective
nasal cast. The dimensions can be obtained by means of computer tomography (CT) or similar techniques and
casts can be built that exactly mimic the inner dimensions of a nose [53]. After having obtained CT data, these are
modified to obtain computer-aided design data ready for the use for stereolithography or rapid prototyping. The
models may differ in precision depending on the rate/thickness of scans used to calculate computer-aided design
data, the material they are made of, the sectioning and anatomical differences such as presence of sinoids, open
or closed nasopharynx and age of the patient data were obtained from. It is shown in literature that differences
in the manufacturing precision resulting in differences in surface roughness, for example, can lead to differences
in the deposition profile [53] with the effect of a larger nasal fraction being collected in a coarser model. One of
the first nasal cast models were the so-called ANOT1 and ANOT2 models, the first being a cadaver cast of a
human adult’s upper airways and the second a hybrid of a cadaver cast improved by MRI data [52]. Dalby et al. uses
the transparent Koken cast model originally made for medical education to look at regional deposition of liquid
nasal formulations [20,54]. This model cannot be sectioned; hence a color-based method is used for visualization
of formulation distribution. A model from CT data is the bespeak nasal cast [55], which is made from nylon and
is cut to sections representing the nasal valve, front and rear turbinates, olfactory region and nasopharynx after
manufacturing the complete cast. The model can be set up in different angles and simulated inspiration airflow
can be applied. More sophisticated cast models are the step joint-free CT cast model from Boehringer [56] and the
cast model from the University of Tours [57]. Further, an idealized nasal cast is in development [58]. For most nasal
cast studies, an inspiration airflow of about 15 l/min is used, representing the mean airflow through an adult’s nose
at 40% maximum physical work capacity [59]. Consequently, for a child’s cast, 10 l/min can be used for deposition
studies with inspiration airflow. More realistically, an inspiration airflow profile should be used for deposition
testing similar to lung deposition simulation. It has been shown that deposition is lower upon application of a
normal breathing pattern compared with constant airflow [60] and that this effect is more pronounced for small
particles. This would lead to overestimation of nasal deposition of small particles when using constant inhalation
airflow. The effect becomes less prominent with increasing particle size and can be neglected for particles larger
than 6 μm. With regard to the application of a nasal spray by the patient, it might be favorable not to advise for
concomitant nasal inspiration at all, as patient variability in flow rate and flow profile will be unpredictable and
may further influence regional nasal deposition. Interestingly, for the estimation of nasal versus postnasal fraction, a
simple glass bulb (nasal adapter) being attached on top of an impactor instead of the USP throat may be sufficient
as it quite efficiently collects the nasal fraction allowing further assessment of the postnasal fraction in terms of
inhalable particles at the same time [61,62]. In a similar manner, a nasal adapter (nasal inlet port) has been proposed
to assess the fraction of inhalable particles [63]. In general, an in vitro–in vivo correlation is probably difficult due
to patient-to-patient variability and several physiological conditions unaccounted for in a nasal cast model such as
nasal tissue flexibility and mucocilliary clearance which will change nasal deposition with time. Thus, a much more
realistic image of regional nasal deposition of nasal preparations is achieved by in vivo imaging studies [22,64].

Devices for nasal delivery

As in oral inhalation, the device is key to the delivery of the formulation and may substantially determine the
location of deposition. A number of liquid dispersers [24], nasal nebulizers [65] and powder dispersers is available
on the market which all have different performance characteristics. They may use an active or passive dispersion
mechanism or propellant-aided dispersion [66], they can be unit/bi-dose or multidose devices, they have different
metered doses and possibly also utilise targeted delivery strategies (e.g., the Precision Olfactory Delivery [POD]
technology from Impel [67]). Special developments are available to eliminate nasal inhalation to the lung such as
bi-directional delivery (OptinoseR
[68]) or retro-nasal administration via the oral cavity (RetroNose [69]). As in

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Liquid formulations
European Pharmacopoeia - Solution
- Nasal drugs - Suspension
- Liquid nasal sprays
- Nasal powders - Solvent
- Semi-solid products - Osmolarity
- pH
- Nasal washes - Viscosity
- Nasal sticks - Microbial stability
- Bioavailability
Solid formulations
- Pure drug Characterization options
- Powder blends - Particle deposition - Manufacture
- Agglomerated powder - Dissolution rate - Blending
- Engineered particles - Permeability - Particle size
- Particle size - Residency time - Flow properties
- Dispersibility - Immune response - Surface area
- Thermal analysis
- Emitted dose - Stability
- Plume geometry - Toxicity
- Particle size

Deposition
- Nasal adapter
→ nasal vs post-nasal fraction
- Nasal cast model
Devices → deposition within nasal cavity
- In vivo imaging studies
→ realistic image of regional
nasal deposition

Effect of medication
- Local
- Systemic, incl.
→ central nervous system
→ immune system

Figure 1. Considerations, options and methods in designing a nasal product.

inhalation, the nasal device and its formulation need to be fitted to each other and patient-specific needs and
constraints have to be considered. In that sense, more patient-oriented devices accounting for different application
angles, patient-individual anatomy and special patient populations, especially children, are needed in the future.
Overall, the interplay of formulation, deposition and effect of nasal medications needs to be taken into account
when designing a nasal product (Figure 1).

Future perspective
Nasal formulation of drugs will evolve in the next decade not only by repurposing of drugs, but also by the
development of new entities for nasal delivery resulting in more products for systemic delivery and CNS nose-
to-brain delivery utilizing the nasal route. This will go along with an increase in nasal powder preparations
and more sophisticated nasal devices with less user dependent performance being more adapted to the needs of
specific populations. For these developments, more detailed knowledge of the interplay between preparation, nasal
deposition, dissolution and bioavailability will be needed, which will also allow better prediction of in vivo effect
from in vitro characterization. Nasal administration will become the standard route for vaccinations or at least
booster vaccinations as this route allows easy application independent of medical settings and induces a favorable
mucosal immune response.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan-
cial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria,
stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

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 Nasal formulations for drug administration & characterization of nasal preparations in drug delivery Special Report

Executive summary
• The nose is a versatile absorption tissue for systemic delivery that is easy to access, offers mild conditions
compared with the gastrointestinal tract and is rapid in onset of action. Via neural pathways the nasal cavity also
allows direct nose-to-brain absorption and due to the rich equipment with immune competent cells the nose is
also a good target for vaccination.
• Nasal preparations in the European Pharmacopoeia currently focus on liquid preparations, whereas nasal
powders play a minor role. The compendial requirements for characterization of the preparations currently are
rather rudimentary and focus on uniformity of delivered dose.
• The formulation strategy for nasal preparations needs to compile all requirements for the desired quality target
product profile. If possible, a liquid preparation is preferred as this is easier to formulate. However, a number of
aspects need to be considered. Dry powder preparations offer the highest drug stability and will play a major role
in the future.
• Nanocarriers may play an important role in targeted delivery of antigens in terms of nasal vaccination or
nose-to-brain delivery of CNS-active drugs.
• Apart from a number of compendial and noncompendial characterization methods the characterization of
regional deposition is of special interest for nasal preparations. However, the current way of assessing regional
deposition by the use of individual nasal casts is debatable.
• Devices for nasal delivery nowadays are mostly adapted to the needs of liquid preparations and comprise a
number of spray pumps or liquid dispersers with various dosing and spray characteristics. However, more special
delivery devices targeting special regions in the nose or avoiding inhalation to the lung are in development.

References
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•• Very good compilation of various aspects influencing nasal drug absorption.
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