Formulation consideration of intranasal corticosteroids.pdf

allergic rhinitis

1. Review
Formulation considerations of intranasal
corticosteroids for the treatment of allergic
rhinitis
Eli O. Meltzer, MD
Objective:To examine how various aspects of an intranasal corticosteroid (INS) formulation may influence the efficacy,
tolerability, and patient preference and adherence to INS therapy.
Data Sources:A PubMed search of the literature was conducted for studies on allergic rhinitis published between January
1977 and January 2006 using the keywordsintranasal corticosteroid, preservatives, benzalkonium chloride,andtonicity.
Study Selection:Prospective studies, retrospective studies, and case reports were selected for inclusion in this review.
Results:Currently available INSs are effective first-line treatments for allergic rhinitis. Differences in patient preference for
a particular INS are largely attributable to sensory attributes of the nasal spray, which arise from characteristics of the
formulation. Additives and preservatives can cause tolerability issues by irritating the mucosal membranes and causing nasal
drying, or they can confer an unpleasant odor or taste to an INS formulation. The relative osmotic pressure, or tonicity, of an INS
can modulate nasal absorption and retention, thereby potentially influencing the clinical efficacy. Characteristics such as delivery
device and spray volume can affect a patient’s perception and experience with a particular INS. Newer INSs, such as ciclesonide,
are in development for the treatment of allergic rhinitis, and consideration of the formulation characteristics of these agents is
an important part of the development process.
Conclusions:INSs are an effective treatment option for patients with allergic rhinitis; however, there is room for formulation
improvement. Optimization of formulation may increase the efficacy, tolerability, and patient preference and adherence to INSs.
Ann Allergy Asthma Immunol.2007;98:12–21.
INTRODUCTION
Allergic rhinitis (AR) affects an estimated 20 million to 40
million people in the United States,
1
representing a signif-
icant economic and societal burden. Direct costs are esti-
mated at $7.3 billion per year (2002 cost estimate).
2
Indi-
rect costs (eg, absenteeism and reduced productivity)
represent a significant loss to employers ($290 million).
2
Patients with AR can experience fatigue, sleep distur-
bances, social function impairment, depressed mood, anx-
iety, and learning impairment, which decrease work or
school performance and productivity.
3
Unfortunately,
some treatments for AR may also cause drowsiness and
impair learning and memory.
4
Intranasal corticosteroids (INSs) relieve the symptoms of
AR
5
—nasal congestion, itching, rhinorrhea, and sneezing—
and improve health-related quality of life
3
without causing
sedation. Furthermore, INSs improve nasal congestion more
effectively
6
and are more cost-effective
2
than nonsedating
antihistamines, the most commonly prescribed AR medica-
tions. Currently available INSs have comparable degrees of
efficacy; therefore, other attributes factor into patient prefer-
ence and adherence to treatment.
7
Formulation and delivery
device may affect the efficacy, drug retention and deposition
in nasal tissue, patient preference and adherence to treatment,
and safety of an INS. This review evaluates the influence of
formulation characteristics on the efficacy and tolerability of
INSs for the treatment of seasonal and perennial AR. A
PubMed search of the literature was conducted for studies on
AR published between January 1977 and January 2006 using
the keywordsintranasal corticosteroid, preservatives, benza-
lkonium chloride,andtonicity. Prospective studies, retrospec-
tive studies, and case reports were selected for inclusion in
this review.
PRESERVATIVES
Currently available INSs contain necessary additives and
preservatives that prevent bacterial growth, absorb extra wa-
ter, and maintain appropriate moisture levels. Although many
of these agents are inert, some (such as polysorbates) irritate
or dry nasal tissue and/or lead to hypersensitivity.
8 –12
Formu-
lations of INSs vary in composition, and concentration of
additives and preservatives can have varying degrees of effect
on the nasal mucosa.
Allergy and Asthma Medical Group and Research Center, San Diego, Cal-
ifornia.
Received for publication March 31, 2006.
Accepted for publication in revised form June 27, 2006.
12 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

2. Benzalkonium Chloride
Benzalkonium chloride (BKC) is a cationic surfactant used as
a preservative in nasal and ophthalmic solutions and is com-
monly found in INSs, including fluticasone propionate (Flo-
nase, GlaxoSmithKline, Research Triangle Park, NC), triam-
cinolone acetonide (Nasacort AQ, Aventis Pharmaceuticals,
Inc., Bridgewater, NJ), flunisolide (Nasarel, TEVA Pharma-
ceuticals, Petach Tikva, Israel [formerly Ivax Laboratories,
Inc]), and mometasone furoate (Nasonex, Schering Corpora-
tion, Kenilworth, NJ) (Table 1). BKC is a skin irritant,
13
and
a number of studies have reported adverse effects that involve
the nasal mucosa as a result of contact with BKC.
14 –17
How-
ever, reviews of INS and BKC data suggest that the effects on
the nasal mucosa are unclear.
18 –21
A number of studies have reported pathologic changes to
the nasal mucosa because of BKC exposure. Squamous cell
metaplasia of the nasal mucosa was reported in 2 animal
models administered nasal sprays that contained BKC.
14,15
In
the first study, changes to the mucosa were observed only
among animals treated with topical nasal steroids that con-
tained BKC and not in groups treated with BKC-free nasal
steroids or 0.9% sodium chloride.
14
In the second study,
administration of BKC alone induced degenerative changes
in supportive and olfactory cells, deformation of nuclei, an
increase in heterochromatin, and squamous cell metaplasia.
15
Results of in vitro and in vivo studies that assessed the
effect of BKC on ciliary movement are also mixed. An in
vitro study of fluticasone propionate and mometasone furoate
intranasal preparations (both containing BKC) reported a
decrease in ciliary beat frequency when incubated at a 10%
dilution with cultured human nasal mucosal cells devoid of
the mucous blanket; complete irreversible ciliostasis was
observed at a 50% dilution of INS.
22
Riechelmann et al
23
studied the effects of BKC, both in vitro using isolated human
nasal epithelia and in vivo in 16 healthy volunteers. In vitro,
BKC was ciliotoxic. In vivo, however, BKC did not alter
saccharin transport time, indicating that normal ciliary move-
ment was maintained. The authors suggested that nasal tox-
icity of BKC is neutralized by nasal secretions in healthy
individuals. Notably, there was a consistent and significant
increase in nasal irritation (P .001), burning sensation (P
.0003), and nasal hypersecretion (P .006) immediately
after administration of 0.05% BKC.
Similar effects on ciliary movement were reported with
betamethasone and fluticasone propionate (both contain
BKC).
24 –26
In vitro treatment with betamethasone was cilio-
toxic; however, in vivo treatment did not have a measurable
effect on nasal mucociliary clearance or ciliary beat frequen-
cy.
24
Although treatment with 0.02% BKC for 10 minutes
slightly prolonged saccharin clearance time, 2 weeks’ treat-
ment with fluticasone propionate had no effect on saccharin
clearance time or ciliary beat frequency.
25
In a study com-
paring treatment with fluticasone propionate aqueous nasal
spray (containing BKC), BKC plus placebo, and placebo
alone for 6 weeks in patients with perennial AR,
26
fluticasone
propionate or placebo that contained BKC did not alter in-
digocarmine saccharin transport time or the number of cili-
ated cells on nasal epithelium vs placebo alone.
In contrast, 2 weeks’ treatment with an aqueous budes-
onide nasal spray (no BKC) vs a mometasone furoate nasal
spray (containing BKC) demonstrated a significant difference
in nasal clearance, measured using a colloid-tagged radioac-
tive spray, between treatment groups, with reduced nasal
clearance in patients treated with the BKC-containing mo-
metasone furoate.
27
Rhinitis medicamentosa is an inflammation of the nasal
mucosa caused by rebound vasodilation subsequent to long-
term use of intranasal vasoconstricting agents. The presence
of BKC in nasal sprays has been associated with exacerbation
of rhinitis medicamentosa. Short-term use of the BKC-con-
taining nasal decongestant oxymetazoline does not appear to
have a measurable effect on the development of rhinitis
medicamentosa.
28
However, long-term (30 days) use of BKC-
containing oxymetazoline preparations accentuated the sever-
ity of rhinitis medicamentosa induced by oxymetazoline
alone.
29
In another study in healthy volunteers, 28 days’ use
of a nasal spray that contained BKC resulted in increased
nasal mucosal swelling.
30
Long-term use of BKC-containing
oxymetazoline appears to increase susceptibility to rhinitis
medicamentosa during subsequent short-term exposures, in-
dicating that BKC induces enduring change in nasal muco-
sa.
31
Table 1. Formulation Characteristics of Intranasal Corticosteroids
Intranasal corticosteroid Tonicity BKC
Potassium
sorbate
Alcohol Polysorbate
Propylene
glycol
CMC
Ciclesonide Hypotonic
Fluticasone propionate (Flonase) Isotonic *
Triamcinolone acetonide (Nasacort AQ) Isotonic
Flunisolide (Nasarel) Isotonic †
Mometasone furoate (Nasonex) Isotonic
Budesonide (Rhinocort Aqua) Isotonic
Abbreviations: BKC, benzalkonium chloride; CMC, carboxymethylcellulose.
Symbols: –, negative;, positive.
* Phenylethyl alcohol.
† Sorbitol.
VOLUME 98, JANUARY, 2007 13

3. Potassium Sorbate
Potassium sorbate, which inhibits microbial growth, is most
commonly used in food preservatives, because it is physio-
logically inert and has a neutral taste. Potassium sorbate is
used as a preservative in budesonide (AstraZeneca LP, Wil-
mington, Del) and the intranasal formulation of a new INS,
ciclesonide (ALTANA Pharma US, Inc, Florham Park, NJ)
(Table 1).
Potassium sorbate in INSs has not been associated with
adverse effects in humans. In a large study in patients with
asthma or rhinitis (N504) who were orally administered
various analgesics, preservatives, and food colorants, no pa-
tients demonstrated a reaction to potassium sorbate.
32
In
contrast, long-term intranasal administration of potassium
sorbate, BKC, or steroid formulations with either preservative
has been reported to induce nasal lesions in rats.
33,34
Improve-
ment in nasal lesions was observed in rats continuously
treated with formulations that contain a corticosteroid with
potassium sorbate.
33
The effects of potassium sorbate on ciliary beat frequency
were evaluated in vitro using cultured human nasal mucosal
cells.
22
Cells exposed to potassium sorbate showed no change
in ciliary beat frequency. Cells exposed to budesonide, pre-
served with potassium sorbate, did not alter ciliary beat
frequency. In contrast, ciliary beat frequency in cultured nasal
mucosal cells was slowed or halted after exposure to flutica-
sone propionate or mometasone furoate (both contain BKC).
Other Commonly Used Additives
Alcohols are used to enhance the sensory attributes of nasal
sprays. Phenylethyl alcohol, a component of fluticasone pro-
pionate, is an additive that confers both taste and smell to
perfumes and foods. Sorbitol, an additive in flunisolide, is a
sugar alcohol used as an artificial sweetener. Although po-
tentially masking unpleasant sensory attributes of an INS, the
addition of alcohol may irritate and cause drying of the nasal
mucosa, leading to epistaxis.
The polysorbates (or Tweens) are nonionic surfactants and
emulsifying agents used as additives in food, shampoo, and
lotions. Polysorbates are found in all commercially available
INSs (Flonase, Nasacort AQ, Nasarel, Nasonex, and Rhino-
cort Aqua) (Table 1). Case reports have described contact
allergy or sensitivity to polysorbates, most often polysorbate
80.
8 –11
A contact allergy to polysorbate 80 in budesonide
preparations (Pulmicort; AstraZeneca LP, Wilmington, Del)
has been reported in a patient with asthma.
11
The adverse
effects resolved and lung function improved when the patient
switched to a fluticasone propionate pressurized metered-
dose inhaler. Polysorbate 80 reversibly inhibited ciliary beat
frequency in cultured human nasal epithelial cells.
35
Polysor-
bate has also been associated with hypersensitivity (pruritus,
erythema, and orofacial angioedema) and alteration of drug
disposition when administered via a subcutaneous or intrave-
nous route.
12,36
Propylene glycol, an additive in flunisolide, is used in
cosmetics and antifreeze and deicing solutions. Although a
combination of propylene glycol and polyethylene glycol has
been used as a wetting agent for nasal tissue to treat perennial
rhinitis
37
and is available over the counter (Rhinaris, Pharma-
science, Inc, Montreal, Quebec), propylene glycol has been
associated with adverse effects when administered intrana-
sally. In a toxicology study, nose-only inhalation of high
doses of propylene glycol in rats caused changes to the nasal
mucosa, including an increase in the number and mucin
content of goblet cells and nasal hemorrhage.
38
Contact der-
matitis has been reported with propylene glycol applied to the
skin or mucous membranes.
39
In a comparison of 2 formula-
tions of flunisolide (original formulation vs a new formula-
tion that contained less propylene glycol), the new formula-
tion reduced nasal burning, nasal stinging, and throat
irritation compared with the original formulation.
40
However,
the frequency of stinging with the newer formulation is still
higher compared with other INSs. Reports of reactions to
propylene glycol are less common than reports of reactions to
BKC. In a study by Bennett et al,
41
none of the 30 patients
treated with inhaled corticosteroids or INSs demonstrated
cutaneous allergy or sensitivity to propylene glycol vs 2
patients (7%) with positive patch test results to BKC. Similar
to BKC and polysorbate, propylene glycol reduced ciliary
beat frequency in human nasal cilia.
42
Many commercially available INSs contain thixotropic
agents, such as carboxymethylcellulose.
43
Because thixo-
tropic agents confer high viscosity, INS suspensions must be
shaken before use. As the suspension is shaken and subjected
to shear, the viscosity of the suspension declines, allowing the
INS to be administered as a mist to the nasal mucosa. After
the suspension dries, the INS and the thixotropic agent re-
main as a residue on the nasal mucosa. Thixotropic agents
exert a drying effect on the nasal mucosa that may contribute
to the increased rates of epistaxis in patients receiving INSs.
44
Rare cases of allergic anaphylactic reactions to carboxymeth-
ylcellulose have been reported with corticosteroids.
45,46
FORMULATION CONSIDERATIONS
Sensory Attributes
Because the efficacies of INSs are largely comparable, sen-
sory attributes are an important factor in patient preference
and adherence to INS treatment. According to a recent sur-
vey,
47
the most important sensory attribute to patients treated
with INSs is aftertaste. Patients also ranked taste, nose
runout, throat rundown, smell, and feel of the spray as im-
portant in deciding on INS treatment. The higher the intensity
of an unfavorable sensory attribute, the less preference a
patient will have for that INS. Different aspects of the for-
mulation confer potentially unpalatable attributes to an INS.
For example, an INS that contains BKC would be less favor-
able than an INS without BKC, because BKC has an unpleas-
ant, bitter taste that may negatively affect patient preference
and adherence to INS therapy.
47
In 2 independent studies,
significantly fewer patients who received budesonide (does
not contain BKC) perceived taste compared with patients
14 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

4. who received fluticasone propionate (0.02% BKC [wt/wt];
P.001).
48
Most patients in both studies preferred budes-
onide over fluticasone propionate for the treatment of AR.
Several studies have compared patient preference for INS
based on efficacy and sensory attributes. In a study that
compared efficacy and patient preference for budesonide vs
beclomethasone dipropionate in 40 patients with perennial
AR, more patients preferred budesonide based on efficacy,
adverse effects, and overall treatment experience.
49
Budes-
onide was also preferred when compared with fluticasone
propionate in 2 randomized, single-blind, single-dose, cross-
over studies in 371 adults with mild to moderate AR.
48
Fewer
patients reported unpleasant scent, taste, forceful spray, or a
wet feeling in the nose or throat when treated with budes-
onide vs fluticasone propionate. Patients expressed greater
satisfaction with the sensory attributes of budesonide vs flu-
ticasone propionate.
Bachert and El-Akkad
50
compared the sensory attributes of
fluticasone propionate, mometasone furoate, and triamcino-
lone acetonide in a randomized, double-blind, crossover
study in 95 patients with AR. In terms of taste and odor
immediately after administration, patients preferred triamcin-
olone acetonide vs fluticasone propionate or mometasone
furoate (P .05). Patients reported a greater sensation of
moisture with triamcinolone acetonide vs fluticasone propi-
onate or mometasone furoate (P.01). However, triamcin-
olone acetonide was associated with more nose and throat
rundown than the comparators (P.05). Overall, patients
preferred triamcinolone acetonide to fluticasone propionate
or mometasone furoate and stated that they would be more
compliant with treatment if given triamcinolone acetonide vs
fluticasone propionate or mometasone furoate. A study that
compared mometasone furoate with phenylethyl alcohol and
triamcinolone acetonide without phenylethyl alcohol used a
questionnaire to measure preference for INSs among patients
with AR (N48).
51
Patients preferred triamcinolone ace-
tonide over the scented mometasone furoate in terms of
immediate taste and smell and overall satisfaction, prefer-
ence, and compliance (P .05).
51
In a single-blind, crossover
study that compared beclomethasone dipropionate, budes-
onide, fluticasone propionate, and mometasone furoate in
patients with AR (N114), mometasone furoate was pre-
ferred based on lower levels of irritation, pleasant odor,
increased sensation of moisture, and less aftertaste vs the
other INSs.
52
Most patients (80%) reported an increased like-
lihood of compliance if treated with their preferred INS.
Increased preference and likelihood of compliance with un-
scented mometasone furoate were also reported vs fluticasone
propionate in patients with symptomatic AR (N100; Fig
1).
53
These data support the development of tasteless and
odorless INSs.
Tonicity
Tonicity refers to the effective osmolarity of a solution and,
therefore, reflects the difference between the osmolarity of a
cell or tissue and the solution. An isotonic (or physiologic)
solution has an equivalent osmolarity to the cell or tissue to
which it is exposed. Solutions that are more dilute than the
Figure 1. Patient preference ratings after crossover administration of mometasone furoate nasal spray (MFNS) or fluticasone propionate nasal spray (FPNS).
NS indicates not significant. *Based on patient preference determined using the Mainland-Gart test. Reproduced with permission from Meltzer et al.
53
VOLUME 98, JANUARY, 2007 15

5. physiologic cell or tissue are hypotonic; solutions that are
more concentrated are hypertonic. Tonicity is an important
consideration for drug formulation and can affect its uptake,
retention, and consequent efficacy and safety. Tonicity can
even affect the disposition of inhaled medication.
The influence of tonicity on drug delivery has been eval-
uated for several modes of drug administration. Studies of
lung distribution of saline solutions for inhalation have dem-
onstrated that the penetration index (ie, extent of deposition
in peripheral airways) of a hypotonic solution is greater than
that of a hypertonic solution.
54
The effects of tonicity have
also been examined for intrapleural
55
or intraperitoneal
56
ad-
ministration of chemotherapy. These studies indicate that
drug uptake is enhanced when chemotherapy is administered
as a hypotonic solution vs an isotonic or hypertonic solution.
Survival of mice with intrapleural tumors was significantly
increased by the administration of cisplatin as a hypotonic
(154 mOsm/L) rather than an isotonic (308 mOsm/L) solu-
tion.
55
Tonicity is also important in the formulation of drugs
for ocular administration.
57,58
In a comparison of different
atenolol formulations in rabbits, lowering the tonicity of the
solution to 80 mOsm/kg increased the ratio of ocular to
systemic drug uptake by 2- to 3-fold.
57
Ciliary Beat Frequency and Nasal Physiology
Tonicity of intranasally administered solutions affects ciliary
movement and nasal physiology. In vitro studies have dem-
onstrated that physiologic or hypertonic saline solutions im-
pair movement of nasal mucosa cilia.
59,60
Boek et al
59
studied
cryopreserved mucosal samples from sphenoidal sinus after
incubation with physiologic saline (0.9% sodium chloride),
hypertonic saline (7% and 14.4% sodium chloride), or iso-
tonic Locke-Ringer solution. Physiologic and hypertonic so-
lutions reduced ciliary beat frequency, with greater inhibitory
effect (ciliostasis) resulting from hypertonic solutions. Cil-
iostasis with the 14.4% sodium chloride solution was irre-
versible. The isotonic solution had no effect on ciliary beat
frequency. Min et al
60
examined the effects of saline solutions
of varying tonicity (0.06%, 0.12%, 0.9%, 3%, 7%) on ciliary
beat frequency in human nasal epithelium in vitro. Hypotonic
and isotonic saline solutions did not inhibit ciliary beat fre-
quency; however, 3% and 7% (both hypertonic) saline solu-
tions caused ciliostasis within a few minutes after incubation.
This effect was reversible when the hypertonic saline solution
was replaced by a hypotonic solution, although an isotonic
solution did not reverse ciliostasis. Hypertonic saline dis-
rupted nasal epithelial cells, with changes to intercellular
junctions and nuclei apparent by transmission electron mi-
croscopy.
Contrary to these studies, a report by Pujara et al
61
suggests
that hypotonic solutions are more damaging to the nasal
mucosa vs isotonic or hypertonic solutions. Investigators
evaluated the amount of lactate dehydrogenase release from
the rat nasal cavity after perfusion with sodium chloride
ranging in osmolarity from 0 to 600 mOsm/kg. Release of
lactate dehydrogenase reflects the amount of cell leaching
and/or cell lysis and was used as a surrogate measure of nasal
mucosal irritation. Lactate dehydrogenase release was sub-
stantial after perfusion with pure water and decreased after
perfusion with a 50-mOsm/kg solution (hypotonic), reaching
a minimum at 300-mOsm/kg (isotonic) solution. Little
change in lactate dehydrogenase release was observed when
rat nasal cavities were perfused with 300- or 600-mOsm/kg
H
2O solutions. Notably, no data points were tested in the
range of 50 to 300 mOsm/kg. It is possible that formulations
of tonicity between 50 and 300 mOsm/kg may have effects
similar to those observed with 300- and 600-mOsm/kg solu-
tions. Although the effect of the tonicity of intranasally
administered solutions on ciliary movement and nasal phys-
iology has been examined in in vitro studies, similar studies
have not been conducted in patients with AR.
Absorption in the Nasal Mucosa
Along with pH and drug concentration,
62– 65
tonicity may
affect the intranasal absorption and retention of drugs. When
a hypotonic suspension is administered intranasally, the dif-
ference in osmolarity between the suspension and the nasal
mucosa drives water molecules to rapidly diffuse into the
nasal mucosa (Fig 2). Increased viscosity and adherence of
the suspending agents resulting from dehydration of the so-
lution or suspension delay mucociliary clearance of the cor-
ticosteroid and may increase the local drug concentration in
nasal mucosa. In contrast, water droplets in an isotonic sus-
pension slowly diffuse along with the drug into nasal mucosa.
A secondary consequence of the isotonic mode of action may
be rapid clearance of the suspension into the esophagus,
causing runoff down the back of the throat. Hypotonic sus-
pensions, however, are retained in the mucosa, decreasing the
amount of solution runoff down the back of the throat.
Hypotonic or hypertonic formulations of a variety of drugs
and peptides achieve greater uptake compared with isotonic
formulations in nasal tissue of animals, depending on at-
tributes of the target tissue. Dua et al
66
compared pharmaco-
kinetic parameters of various formulations of a polypeptide
hormone, salmon calcitonin, administered intranasally to rab-
bits. Absorption of salmon calcitonin in a hypertonic or
hypotonic solution was significantly greater than in the iso-
tonic solution, with area under the curve values more than 3
times higher in hypotonic or hypertonic formulations vs the
comparable isotonic formulation (Table 2).
66
The bioavail-
ability after intranasal administration of hypotonic and hy-
pertonic formulations was 4- to 5-fold greater vs the isotonic
formulation. In a preclinical study, intranasal hypo-osmotic
or hyperosmotic formulations of insulin lowered blood glu-
cose levels in rats more effectively than an isotonic formu-
lation.
63
Previous experience with oral rehydration solutions
indicated that hypotonic formulations promoted significantly
greater absorption of water and sodium in the small intestine
and colon of perfused rats compared with isotonic oral rehy-
dration solutions (P .05).
67
Wapnir and Lifshitz
68
reported
that mean jejunal water transport rates were approximately 2-
to 3-fold higher in an in vivo rat intestinal system perfused
16 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

6. with hypotonic oral rehydration solutions compared with
standard solutions (P .001).
Hypotonic solutions increase the pharmacologic activity
and absorption of nasally administered drugs vs solutions of
increased osmolarity. In rats, a hypotonic formulation en-
hanced pharmacologic activity of recombinant human eryth-
ropoietin compared with solutions of higher osmolarity ad-
justed with mannitol.
64
In contrast, a similar solution with
osmolarity adjusted by the addition of sodium chloride did
not significantly affect the pharmacologic effects of recom-
binant human erythropoietin. Also, an in situ study of nasal
uptake of midazolam in rats reported significant absorption
only when administered as a hypotonic solution.
65
The same formulation enhancements related to tonicity can
be applied to INSs. Commercially available INSs are formu-
lated in isotonic solutions (Table 1). Differences in absorp-
Figure 2. Schematic of the interaction of a hypotonic or isotonic solution with the nasal mucosa.
Table 2. Effect of Tonicity on Pharmacokinetic Parameters of Salmon Calcitonin*
Parameter T
max, min
C
max,
meanSD, ng/mL
AUC
0–5,
meanSD, ngmin per mL
Bioavailability,
%
IV administration 14 252.9 1,10219.8 100
Intranasal low viscosity
Isotonic (300 mOsm) 40 104.2 714.215.7 0.16
Hypertonic (600 mOsm) 90 4219.6 3,5081,280 0.80
Hypotonic (100 mOsm) 90 267.6 3,171258 0.71
Intranasal high viscosity
Isotonic (300 mOsm) 58 129.7 60497.7 0.14
Hypertonic (600 mOsm) 90 3219.6 2,183258 0.62
Hypotonic (100 mOsm) 120 232.4 3,5791,030 0.81
Abbreviations: AUC
0–5, area under the curve from 0 to 5 hours; C
max, maximum concentration; IV, intravenous; T
max, time to maximum
concentration.
* Adapted with permission from Dua et al.
66
VOLUME 98, JANUARY, 2007 17

7. tion of hypotonic vs isotonic suspensions in the nasal mucosa
of rabbits have been evaluated for ciclesonide, a corticoste-
roid originally developed for asthma with an INS formulation
currently in clinical development for the treatment of AR.
69
In
a single-dose, preclinical study in rabbits, delivery of
ciclesonide via a hypotonic suspension generated higher cel-
lular concentrations of ciclesonide from 0.5 to 4 hours after
administration vs a single dose of the isotonic suspension (16-
to 34-fold; Fig 3). Concentrations of the pharmacologically
active metabolite of ciclesonide, desisobutyryl-ciclesonide,
were higher at all time points for the hypotonic vs isotonic
suspension (6- to 13-fold;P.05). These data indicate that
a hypotonic INS formulation can increase absorption and
retention in the nasal mucosa of rabbits, which may suggest
a similar response in human nasal mucosa. However, the
clinical relevance of this finding has not been demonstrated.
Delivery Device
Intranasal corticosteroids were initially delivered via Freon-
propelled aerosols; however, these devices yielded poor in-
tranasal drug distribution.
70
Metered-dose pump sprays deliv-
ered a greater percentage of INS dose to the patient rather
than remaining in the device vs pressurized metered-dose
inhalers. Aqueous pump sprays are the most commonly used
delivery device for INSs. Unlike metered-dose aerosols and
pump sprays, with which the drug is deposited primarily in
the anterior, nonciliated region of the nose,
71,72
aqueous pump
sprays localize drug to the ciliated mucous membrane and
nonciliated regions of the nasal mucosa.
73
Notably, intranasal
distribution from an aqueous pump spray can be affected by
the volume of nasal spray and the spray cone angle.
Symptom relief from INSs appears to be comparable
among delivery devices. Budesonide administered via an
aqueous pump spray or pressurized metered-dose inhaler was
equally effective, with a similar safety profile in 3 weeks’
treatment of ragweed-induced seasonal AR.
74
Comparable
safety and efficacy were reported in a 1-month study of
budesonide administered as a Freon-propelled aerosol or as
an aqueous pump spray.
75
One important consideration for all INS delivery devices is
safety. Improper use of an INS nasal spray (ie, improper
spray direction) can damage nasal tissue and cause further
nasal irritation or epistaxis. Preferably, the spray should be
directed away from the septum. An optimal delivery device
for an INS would be an easy-to-use aqueous pump spray that
presents low risk for nasal tissue damage.
Formulation as nasal drops may enhance delivery of INSs
to the middle meatus in the nasal cavity. Treatment of pa-
tients with severe nasal polyposis, chronic rhinosinusitis, or
both with fluticasone propionate nasal drops reduced nasal
obstruction, rhinorrhea, postnasal drip, and loss of smell
compared with placebo (P .05).
76
Peak inspiratory nasal
scores also increased significantly in patients treated with
fluticasone propionate nasal drops (P.01). Furthermore,
nasal polyp size and the need for nasal surgery were reduced
in patients treated with fluticasone propionate nasal drops.
Spray Volume
A smaller spray volume decreases the amount of drug avail-
able to run down the back of the throat or leak out the nose.
Throat rundown and nose runout are 2 sensory attributes that
patients consider to be important for INS preference.
47
Most
commercially available INSs have spray volumes of 100
L
per actuation (Flonase, Nasacort AQ, Nasarel, Nasonex);
however, the spray volumes of Rhinocort Aqua and
ciclesonide are 50 and 70
L per actuation, respectively. The
ideal INS would have a balance between an adequate spray
Figure 3. Concentrations of ciclesonide and its pharmacologically active metabolite, desisobutyryl-ciclesonide, in rabbit nasal mucosa after administration of
ciclesonide as a hypotonic or isotonic suspension. NS indicates not significant. Data from Wingertzahn et al.
69
18 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

8. volume to achieve optimum nasal distribution and minimal
throat rundown and nose runout.
CONCLUSION
Intranasal corticosteroids are an effective treatment option for
patients with AR; however, there is room for formulation
improvement. Optimization of formulation may increase the
efficacy, tolerability, and patient preference and adherence to
INSs. Currently available INSs are isotonic formulations that
contain a variety of preservatives and additives. The devel-
opment of hypotonic solutions may have the potential to
enhance drug delivery and nasal retention. Additionally, re-
ducing spray volume and minimizing preservatives and ad-
ditives often used in currently available INS formulations
may increase tolerability and reduce unpleasant sensory at-
tributes—key factors in patient preference and adherence to
INS therapy. New-generation INSs in development have the
potential to use these formulation characteristics to improve
patient benefit from INS therapy for AR.
ACKNOWLEDGMENTS
The study was sponsored by ALTANA Pharma AG, Kon-
stanz, Germany. Editorial assistance was provided by Crystal
Murcia, PhD (ProEd Communications, Beachwood, OH).
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Requests for reprints should be addressed to:
Eli O. Meltzer, MD
Allergy and Asthma Medical Group and Research Center
9610 Granite Ridge Drive
Suite B
San Diego, CA 92123-2661
E-mail: eomeltzer@aol. com
VOLUME 98, JANUARY, 2007 21