Vol.2, No.2, 79-84 (2010) Natural Science
http://dx.doi.org/10.4236/ns.2010.22012
Hydroxypropylmethylcellulose gel application delays
Der p 1 diffusion in vitro
B. Diethart1, J. C. Emberlin2, R. A. Lewis3
1School of Human and Health Sciences, Swansea University, Swansea, United Kingdom;
2National Pollen and Aerobiology Research Unit, University of Worcester, Worcester, United Kingdom
3Worcestershire Royal Hospital, Worcester, United Kingdom
Received 16 November 2009; revised 10 December 2009; accepted 30 December 2009.
ABSTRACT
Background: A special hydroxypropylmethyl-
cellulose powder (Nasaleze®) has been used for
the alleviation of nasal symptoms of allergic
rhinitis since 1994. The efficacy of the product
has been recently proven but the mechanism of
action was still largely unknown. The aim of the
study was to investigate the hypothesis that the
gel formed after moisture absorption in the nose
might act as mechanical barrier that prevents
allergen diffusion towards the nasal epithelium.
Methods: The diffusion of Der p 1 through
HPMC and agar gels was measured in vitro after
15, 30, 60, 180 and 360 minutes using ELISA.
Agar blocks were used to simulate the nasal
mucosa. Control samples without gel layer were
obtained. Results: The control samples with no
applied gel barrier absorbed 72.2 % of the Der p
1 solution after 15 minutes and 100 % after 60
minutes. In comparison, the HPMC and agar gel
layers both significantly delayed Der p 1 diffu-
sion. After 15 minutes 0.76 % had diffused
through the HPMC gel layer compared to 28.1 %
which diffused through the agar layer. After 360
minutes, 14.1 % of the baseline Der p 1 crossed
the HPMC gel layer while 100 % had diffused
through the agar layer. Conclusions: HPMC gel
significantly reduces Der p 1 diffusion in vitro
compared to no barrier and an agar gel layer.
This is likely to be due to the small mesh size of
the polymer network of HPMC and could have
important implications for a preventative treat-
ment of allergic rhinitis.
Keywords: Allergic Rhinitis; Der p 1;
Diffusion Barrier; Hydroxypropylmethylcellulose
1. INTRODUCTION
Allergic rhinitis (AR) is a global health problem which
affects up to 25 % of the adult population in industrial-
ised countries and more than 40 % of children [1,2]. The
rising prevalence of allergic rhinitis imposes a huge
burden on the economy due to costs of treatment and
loss of work productivity. Recent estimates of annual
costs range from $2 to 5 billion in the U.S. alone [3-5].
The pathology of AR is associated with a severe im-
pairment of the quality of life for those who suffer from
it [6,7]. A reduction of quality-of-life impairment can be
achieved by appropriate treatment of allergic rhinitis
[7,8]. Modern medications such as antihistamines or
corticosteroids can do a lot to help to alleviate symptoms
and restore a normal lifestyle but many of them have
unwanted adverse effects or are limited in their applica-
tion [1,3,4]. Many people distrust these conventional
medicines and therefore prefer to use complementary
and alternative treatments. However, the therapeutic
efficacy of many of these treatments is not supported by
evidence and they might not be devoid of side effects
[3,9].
A recent approach is offered by the use of an inert hy-
droxypropylmethylcellulose (HPMC) powder (Nasaleze
®) for allergy prevention and alleviation in the nose.
Although the product has been registered as a class 1
medical device with the MHRA since 1991 and is sold
over the counter in more than 50 countries worldwide,
little work has been done on the effect of the powder on
nasal symptoms. However, the efficacy of HPMC in
decreasing symptoms of allergic rhinitis caused by grass
pollen and house dust mite allergens was recently proven
[10-12]. The investigators observed an improvement of
symptoms when using HPMC for treatment of SAR and
PAR. Nasal peak inspiratory flow (PIF) and peak expi-
ratory flow (PEF) increased compared to placebo and
some symptoms of allergic rhinitis including sneezing,
itching and runny nose were alleviated significantly.
Also the need to use rescue medication was found to be
reduced. Considerable variance was observed in the re-
sults and some participants did not show any improve-
ment. This was partly attributed to the application device
which is suspected not to deliver constant doses [12,13].

B. Diethart et al. / Natural Science 2 (2010) 79-84
80
The HPMC powder is applied to the nose using a spe-
cially designed dry powder dispenser bottle and forms a
gel on the nasal lining by absorbing moisture from the
nasal mucosa. It was hypothesised that this gel might act
as a mechanical barrier preventing allergens from enter-
ing the mucosa [11,12]. However, no investigations on
the mechanism of action of HPMC as an allergy treat-
ment have been published as yet leaving the question
how an inert cellulose derivative can offer relief to indi-
viduals affected by allergic rhinitis unanswered. Similar
HPMC powders which also form hydrogels upon contact
with liquids are widely used in controlled drug release
formulations where they restrict the release of drug
molecules through the tablet by serving as a barrier to
drug diffusion [14]. Also, high-viscosity HPMC gels
have been shown to limit glucose and cholesterol ab-
sorption in the gastrointestinal tract by creating a me-
chanical barrier [15,16]. Thus, it is assumed that HPMC
gel might impede the passage of allergens in a similar
manner.
The aim of this study was to investigate the possibility
that HPMC gel might constitute a mechanical barrier to
house dust mite allergen in vitro in order to gain infor-
mation about the mechanism of action of HPMC in the
alleviation of symptoms of allergic rhinitis.
2. METHODS
2.1. Materials
Hydroxypropylmethylcellulose powder was supplied by
Colorcon Limited, Kent. Der p 1 solution (in house ref-
erence, 7.5 μg Der p 1 per millilitre) was provided by
Alk-Abello, Madrid.
2.2. Sample Preparation
Preparation of the samples took place in a cleanroom to
minimise contamination by dust or allergens. All equip-
ment needed for preparation was washed in isopropyl
alcohol (70 %) for sterilisation and dried before each use.
Ten ml of agar (1.5 %, prepared with 0.9 % saline solu-
tion) were cast into a petri dish. After cooling, small
rectangles of equal dimensions (1 x 1 cm) were cut from
the agar and then transferred to cleaned slides. Two lines
of warm and therefore liquid Vaseline were drawn with a
brush from the two edges of one side of the agar block to
the edges of the slides to avoid diffusion of allergens
through the side of the block (Figure 1). The position of
the agar was marked on the bottom of the slide and the
agar block was covered by a cover slip that sealed the
upper surface of the agar. Allergen solution could there-
fore diffuse into the agar through only one free edge
(Figure 1).
To test the barrier function of HPMC, a thin layer of
HPMC gel was applied covering the edge of the agar
which was used for allergen application. For this, 50 mg
of HPMC powder were mixed with 1 ml physiological
saline solution (0.9 %) to form a 5 % gel. Immediately
after the mixing of the gel, 0.2 ml was applied to the
open edge of the agar block using a 1 ml sterile syringe.
The initial thickness of the gel layer was measured at 3
standard points. After covering with a cover slip, 20 µl
of the allergen solution were applied to the HPMC gel
covering the one side of the agar blocks limited by the
Vaseline lines.
The slides were incubated at 35°C and 90 % relative
humidity to simulate nasal conditions for 15, 30, 60, 180
and 360 minutes. After incubation the thickness of the
HPMC layer was again measured. The agar blocks were
then carefully removed from the slides and transferred to
labelled microtubes containing 0.5 ml PBS-T as elution
medium. Samples were shaken on an Autovortex for 20
seconds followed by shaking overnight on a lab shaker.
Samples were stored frozen at -20°C.
2.3. Reference and Control Samples
To investigate the difference of diffusion through HPMC
and agar, control samples were produced with an addi-
tional agar layer of 1.5 mm (average thickness of the
HPMC gel layer calculated from measurements of
HPMC samples using a digital caliper) to replace the
HPMC gel and treated in exactly the same way as the
HPMC samples.
Additionally, control samples with no allergen addi-
Figure 1. Photograph (A) and diagram (B) of experimental
setup for sample preparation for ELISA measurements of Der p
1 diffusion through HPMC gel.

B. Diethart et al. / Natural Science 2 (2010) 79-84
81
tion and no barrier addition, respectively were obtained.
Baseline measurements of the allergen amount in 20
µl of allergen solution were conducted by applying 20 μl
of allergen solution directly to a microtube containing
0.5 ml of PBS-T. The microtubes were then treated in
the same way as the microtubes containing the agar
blocks.
2.4. ELISA Measurements
The monoclonal antibodies (mAbs) and Der p 1 allergen
standards used in the assays were purchased from Indoor
Biotechnologies, and the assays were performed accord-
ing to the manufacturer’s instructions.
2.5. Statistical Analysis
One-way ANOVA was applied for statistical analysis of
the differences between Der p 1 diffusion in HPMC gel,
agar gel and control samples, respectively. No serious
violations of assumptions were observed. P values of
0.01 or less were considered to be statistically signifi-
cant.
3. RESULTS
The mean baseline allergen content in 20 µl of the stan-
dard solution used was found to be 151.0 ng/ml (SD =
4.0 ng/ml). This is in good agreement with the calculated
value of 150 ng/ml for the given dilution of a 7.5 µg/ml
stock solution. All control samples with no allergen ap-
plication were negative in the ELISA measurements.
The diffusion of Der p 1 molecules into the 1 x 1 cm
agar blocks eluted for measurements was delayed with
both gel barriers applied (Table 1 and Figure 2). The
amount of allergen diffused through 1.5 mm of 1.5 %
agar gel was significantly different from the baseline
values for the first 180 minutes (p < 0.005) but did not
reach statistical significance after 360 minutes (p =
0.628). After 15 minutes of incubation, 28.1 % of the
baseline allergen amount had diffused through the gel
into the agar block (Table 2, p < 0.0001). The amount of
allergen detected in the elutes of the agar blocks then
steadily increased until it reached baseline level after
360 minutes of incubation (Figure 2 and Table 2). The
thickness of the agar layer applied as a barrier did not
change during the measurement times from 15 to 360
minutes. In contrast, an initially 1.50 mm thick HPMC
gel layer swelled to an average 3.34 mm in 360 minutes
upon allergen solution application. Diffusion of Der p 1
molecules through 5 % HPMC gel showed a significant
reduction of diffused allergen for all test times (p <
0.001). After 15 minutes 0.76 % of the baseline amount
had diffused through the HPMC gel layer into the agar
block compared to 28.1 % which diffused through the
agar layer (Table 2). After 360 minutes, 14.1 % of the
baseline Der p 1 crossed the HPMC gel layer while 100
% had diffused through the agar layer (Table 2). How-
ever, the HPMC data include several outliers and the
standard deviation is high (Table 1). The mean coeffi-
cient of variation for all measurements for the HPMC
gel was found to be 201.9 % which is very high com-
pared to 37.8 % for agar.
Control samples with no barrier had absorbed 72.2 %
of the baseline allergen content after 15 minutes and
differences to baseline did not reach statistical signifi-
cance after 60 minutes using a 99 % confidence interval
(p60min=0.042, p360min=0.990).
4. DISCUSSION
Most of the commonly available treatments of allergic
rhinitis affect the inflammatory processes (e.g. by abat-
ing mediator release or blocking receptors) initiated after
0
20
40
60
80
100
120
140
160
180
050100 150 200 250 300 350 400
Time (in minutes)
Amount of Der p 1 (in ng/ml
)
HPMC
Agar
Base line
No barrier
Figure 2. Amount of Der p 1 diffused through a 1.5 mm thick
HPMC and agar gel layer, respectively compared to control (no
barrier) and baseline allergen amount.
Table 1. Amount of Der p 1 diffused through a 1.5 mm thick HPMC and agar gel layer, respectively, amount of allergen absorbed
without barrier (control) and baseline allergen amount in 20 µl of the applied solution.
Amount of Der p 1 measured in samples (in ng/ml)
Time (in min) 15 30 60 180 360
HPMC 1.15 1.57 8.98 13.17 21.34
Agar 42.46 78.98 93.92 116.46 163.59
No barrier 109.26 no value 126.62 no value 154.92
Baseline 151.04 151.04 151.04 151.04 151.04

B. Diethart et al. / Natural Science 2 (2010) 79-84
82
Table 2. Fractions of allergen amount diffused through a 1.5 mm thick HPMC and agar gel layer, respectively and with no barrier
compared to the baseline value of 151.04 ng/ml.
Diffused fraction of Der p 1 (in % of baseline)
Time (in min) 15 30 60 180 360
HPMC 0.76 1.04 5.94 8.72 14.13
Agar 28.11 52.29 62.18 77.11 108.31
No barrier 72.34 no value 83.83 no value 102.57
Baseline 100.00 100.00 100.00 100.00 100.00
allergen penetration into the mucosa and binding to IgE
[1,17,18] and therefore represent symptomatic treatment.
This means that inflammation and the associated damage
of the mucosa are already established and the medication
decreases signs of this inflammation while it is still on
going. An ideal allergy treatment would inhibit the es-
tablishment of an allergic reaction altogether. Anti-IgE
prevents binding of allergen to IgE antibodies and so
inhibits a reaction while the allergens are already inside
the epithelium [19]. HPMC might work at an earlier
stage by preventing allergens from entering the mucosa
in the first place by the generation of a mechanical gel
barrier.
The present study aimed to investigate this possible
barrier function of HPMC to allergens. The results ob-
tained by ELISA-measurements show that HPMC sig-
nificantly delays Der p 1 diffusion and that the amount
of allergen diffused through the gel is even lower than
indicated by preliminary tests [20]. This retardation
might allow the mucosa to recover its physical integrity
and the allergic reaction to decline. However, a complete
barrier to Der p 1 diffusion could not be confirmed.
The retarded diffusion of solutes in hydrogels like
HPMC gel or agar gel is well known and widely used for
biotechnological separation methods such as electro-
phoresis or gel chromatography and in controlled release
formulations [21,22]. The most comprehensible model
developed to explain the diffusion delay of solutes in
gels is the obstruction theory which assumes that the
impenetrable polymer chains are obstacles that cause an
increase in diffusional path length and additionally act as
a sieve [21,24]. Therefore the mesh or pore size of the
polymer network is a crucial parameter in the reduction
of diffusion in hydrogels [25]. Hydrogels consist of high
molecular weight molecules forming a threedimensional
network which is dispersed in a continuous liquid me-
dium [22,25]. Due to cross-links and entanglements of
these molecules hydrogels can be described as a mesh
with solvent filled spaces between the individual poly-
mer chains which act as a filter for molecules larger than
the spaces available [26,27]. Controlled release studies
with FITC-dextran molecules of different molecular
weights revealed that the critical molecular weight for
diffusion in HPMC gels, which are characterised by a
mesh size of 12 nm, lies between 65 and 66.5 kDa de-
pending on the molecular weight of the polymer and the
concentration of the gel [28]. Allergenic proteins usually
have a molecular weight between 5 and 80 kDa [29,30].
This means that a great proportion of allergens theoreti-
cally are small enough to diffuse through the HPMC
mesh spaces. Although Der p 1 (24 kDa) lies well below
the mesh size of HPMC gels, a substantial delay in dif-
fusion has been observed. Even though molecules larger
than 65 kDa are stopped from diffusing through HPMC
almost completely, all other smaller molecules will still
be delayed by the longer diffusional path due to obstruc-
tions by the macromolecular chains and the slower water
movement due to binding of water to the polymer. Fur-
thermore, the mesh size and therefore the size of the
spaces available for diffusion in weakly cross-linked
homogenous gels is not stable but time-dependent and
the size and location of the spaces change due to
Brownian motion of the molecule chains [22,31].
In comparison to HPMC, the mesh size of a 1.5 %
agar gel as used in this study has been observed to be
between 70 and 800 nm [21,26]. Even the lowest of
these values is almost six times larger than the mesh size
of HPMC which explains the higher allergen diffusivity
within agar gel.
The values obtained in the present study are valid for
Der p 1 and allergens of the same or very similar mo-
lecular weight. It has been shown that the diffusion coef-
ficient for globular proteins in agar decreases with in-
creasing molecular weight and therefore radius of the
proteins [21]. This leads to the assumption that allergens
smaller than Der p 1 like Bet v 1 (17 kDa) or grass group
2/3 allergens (10-12 kDa) might be expected to diffuse
faster whereas larger allergens like Amb a 1 (38-50 kDa)
or Art v 1 (28-60 kDa) might exhibit slower diffusion
velocities through the HPMC gel network.
The variability of the results of the measurements of
Der p 1 diffusion through HPMC gel was high with a
coefficient of variation (CV) of just over 200 %. In
comparison, the CV of Der p 1 diffusion in agar gel was
only about 37 %. For this reason the variation in the
amount of allergen diffusing through the HPMC gel
layer cannot solely be attributed to limitations in the
methods that were applied. Similarly high variability of
diffusion coefficients was obtained for mucus gels [32].
This was attributed to the heterogeneous nature of the

B. Diethart et al. / Natural Science 2 (2010) 79-84
83
mucous gel producing uneven penetration profiles. Re-
lease from HPMC matrices for controlled drug release
was found to be sensitive to alterations in the chemical
composition and the polymer gel conformation and sub-
stantial batch-to-batch variations in release and swelling
could be observed for a single type of HPMC [33,34].
The authors suspect that this might be due to aggregate
formation in the gel causing transient cross-linking that
could perturb diffusion in some places throughout the
gel which cannot be predicted.
Due to its importance in controlled drug release, the
effect of HPMC as a diffusion barrier for drugs has been
studied extensively. However, no investigations of aller-
gen diffusion in HPMC have been found in the accessi-
ble literature. It was confirmed in this study that HPMC
gel delays Der p 1 diffusion in vitro. Other allergens
need to be tested to extend the evidence for the efficacy
of the product. Also many other factors will influence
the efficiency of the product in vivo. For practicality
reasons, the gel layer used in the experiments is thicker
than the gel layer that can be expected to be established
within the nasal cavity. Diffusion velocity is a crucial
parameter needed to make assumption for in vivo condi-
tions and should therefore be addressed in future re-
search. A complete diffusion barrier is essential for the
retardation of drug release [14] and similarly optimal
coverage of the nasal mucosa is important since uncov-
ered areas may allow free allergen entry and the provo-
cation of an allergic response. Sub-optimum coverage is
likely to reduce the efficiency of the product. The provi-
sion of a suitable powder delivery device therefore poses
an important challenge for the maximisation of the effi-
cacy of HPMC in the alleviation of allergic rhinitis.
In conclusion, a diffusion delay of Der p 1 in HPMC
gel has been confirmed in vitro. This means that even
though HPMC gel does not constitute an impermeable
barrier to allergens, the significant delay of allergen en-
try into the mucosa could be beneficial to hay fever suf-
ferers through the reduction of allergen exposure. This
fairly novel way of treatment reduces the allergen load
itself and not the symptoms caused after allergen entry
into the mucosa. Thus, with the appropriate delivery
device, HPMC could be a valuable, drug-free alternative
for the treatment of allergic rhinitis. The efficacy of
HPMC in hay fever treatment has been recently proven
[10-12]. However, the research presented in this paper is
the first to address the mechanism of action of HPMC in
the alleviation of allergic rhinitis. This knowledge will
allow improvements on the product to be made in order
to increase its benefit to hay fever sufferers.
5. ACKNOWLEDGEMENTS
This study was sponsored by the University of Worcester, UK and
Kisska International Ltd.
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