Pharmacology & Pharmacy, 2012, 3, 417-426
http://dx.doi.org/10.4236/pp.2012.34056 Published Online October 2012 (http://www.SciRP.org/journal/pp)
1
A New In-Situ Gel Formulation of Itraconazole for Vaginal
Administration
Sinem Yaprak Karavana*, Seda Rençber, Zeynep Ay Şenyiğit, Esra Baloğlu
Department of Pharmaceutical Technology, Faculty of Pharmacy, Ege University, Bornova, Turkey.
Received August 27th, 2012; revised September 30th, 2012; accepted October 12th, 2012
ABSTRACT
In this paper, mucoadhesive in-situ gel with poloxamer and hydroxypropylmethylcellulose formulations of itraconazole
were prepared for vaginal application. In addition, rheological, mechanical and mucoadhesive properties and sy-
ringeability of the formulations were characterized. The mixtures of Poloxamer 407 and 188 with two different types of
hydroxypropylmethylcellulose were used as polymers for gel formulations. Flow rheometry studies and oscillatory
analysis of each formulation were performed at 20˚C ± 0.1˚C and 37˚C ± 0.1˚C. All formulations exhibited pseudo-
plastic flow and typical gel-type mechanical spectra (G′ > G″) after the determined frequency value at 37˚C. Texture
profile analysis presented that F3 formulation containing 20% poloxamer 407, 10% poloxamer 188 and 0.5% hy-
droxypropylmethylcellulose appeared to offer more suitable mechanical and mucoadhesive performance. Using dif-
ferent hydroxypropylmethylcellulose type in formulations didn’t significantly change syringeability values. The evalua-
tion of the entire candidate formulations indicated that vaginal formulation of itraconazole will be an alternative for the
treatment of vaginal candidiasis with suitable textural and rheological properties. Our results showed that the developed
formulations were found worthy of further studies.
Keywords: Itraconazole; Poloxamer; Hydroxypropylmethylcellulose; Gel; Vaginal Candidiasis
1. Introduction
The azole antifungal agents represent a major advance in
the treatment of both superficial and systemic fungal in-
fections. These drugs can be divided in two main groups:
the imidazoles and the triazoles [1]. Itraconazole is a
broad-spectrum antifungal agent, which can be used
either orally or intravenously. However, a vaginal for-
mulation of itraconazole has not been developed yet [2-
4]. It is a safe and effective active substance in the treat-
ment of vulvovaginal candidiasis. It was shown that, active
amount of the itraconazole may persist in vaginal epithe-
lium for four days after a one-day treatment. It has been
suggested that a cause of relapse in women with vaginal
candidiasis is the re-emergence of Candida organisms
from deeper layers of vaginal tissue [5,6].
Local drug delivery is frequently utilized for the treat-
ment of localized disorders. The main advantages of this
of administration are the ability to deliver the active
agent directly to the site and the maintenance of the re-
quired concentration of active substance at the site for a
prolonged period [7]. For the treatment of vaginitis, local
antimicrobial administration of imidazole derivatives has
been favored due to the numerous side effects of sys-
temically applied drugs. To achieve desirable therapeutic
effect, vaginal delivery systems need to reside at the sites
of infection for a prolonged period [1]. For a long time, a
great deal of attention has been devoted to the develop-
ment of mucoadhesive drug delivery systems. Muco-
adhesives may localize in a particular region and prolong
the residence time, thereby improve the bioavailability of
drugs [8]. Nowadays, in situ-gelling liquids have also
proved as more convenient dosage forms for local appli-
cations because they are easy to administer into desired
body cavities [9]. Poloxamers (Plx) which is chosen to
prepare in-situ gel formulation, are synthetic triblock co-
polymers of poly(ethyleneoxide)-b-poly(propylene oxide)-
b-poly(ethylene oxide) (PEO-PPO-PEO) that exhibit ther-
moreversible behaviour in aqueous solutions [10-12]. A
change in micellar properties occurs as a function of both
environmental temperature and the concentration of Plx
and a reversible gelation can occur at physiological tem-
perature [12,13]. The use of such systems for local
administration of therapeutic agents to the vagina offers
several advantages, including ease of application and
high spreadability at temperatures below the sol-gel
temperature, rheological structuring and hence enhanced
retention at body temperature. They have excellent com-
patibility and good characteristics of prolonged release of
*Corresponding author.

A New In-Situ Gel Formulation of Itraconazole for Vaginal Administration
418
the active ingredient. On the other hand, they have low
mucoadhesive properties.
Hydroxypropylmethylcellulose (HPMC), a well-known
cellulose derivative, is generally used to provide sustained
release. HPMC is frequently used for mucoadhesive for-
mulations due to its nontoxic, nonirritant, high mucoadhe-
sive characteristics, easy incorporation with the drugs
and stability at vaginal pH [14,15].
It is available in a wide range of molecular weights
and is classified by the viscosities of their 2% (w/w)
aqueous solution [16]. In this study, two types of HPMC
were added to improve the mucoadhesive and mecha-
nical properties of in-situ gel formulations.
The objective of this study was to prepare a suitable
mucoadhesive in-situ gel formulation of itraconazole
with Plx and HPMC that possess appropriate mechanical
and rheological properties, retain on the vaginal mucosa
for a long period of a time.
2. Experımental
2.1. Materials
Plx 188 and 407 were kindly gifted by BASF Chemical
Company (GERMANY). Itraconazole was selected as a
model drug and was obtained from Nobel Pharma-
ceutical Company (TURKEY). HPMC E50 (40 - 60
cps) and K100M (80 - 120 cps) were donated by Color-
con (ENGLAND). All other materials were of analy-
tical grade.
2.2. Preparation of Formulations
Vaginal mucoadhesive gel formulations of itraconazole
was prepared with 20% Plx 407:10% Plx 188 mixture;
and adding either 0.5% HPMC E50 or 0.5% HPMC
K100M as mucoadhesive agent. Plx mixture ratio was
decided according to our previous study [6]. Gels were
prepared by a modification of the cold method [17].
Distilled water was cooled to 4˚C. Plx 188 and 407 were
then slowly added to the distilled water with continuous
agitation. The gels were left at 4˚C until a clear solution
was obtained. Then, 0.5% HPMC K100M or HPMC E50
were gradually added and these gels were left at room
temperature for 24 hours. Finally, 2% itraconazole was
added with vigorous stirring. The compositions of gels
are given in Table 1.
2.3. Determination of pH
To investigate the compatibility of the gel bases for
vaginal application, their pH values were measured by a
pH meter (NEL Mod.821) at room temperature (n = 5).
2.4. Measurement of Gelation Temperature and
Gelation Time
Determination of gelation temperature and gelation time
were carried out on Haake Mars rheometer and were
determined graphically. The geometry was a stainless
steal plate/plate (diameter 40 mm), which provided a
homogeneous shear of the sample. The sol-gel transition
temperatures and gelation times of the gels were deter-
mined from oscillation measurements with a fixed fre-
quency of 0.01 Hz. The samples were heated at a rate of
2˚C every 60 s, the temperature changed between 7˚C -
70˚C during the procedure (n = 5). The sol-gel transition
temperature graph was determined by plotting tem-
perature as a function of the viscosity (η′) and the tran-
sition point was defined as the point where the viscosity
was halfway between the values for the solution and the
gel [6].
2.5. Mechanical Properties of Polymer Solutions
Textural analysis was performed using Software-con-
trolled penetrometer [TA-TX Plus, Stable Micro System,
UK] equipped with 5 kg load cell in Texture Profile
Analysis (TPA) mode. Formulations were transferred
into jacketed glass vial (20 mL) at 20˚C and 37˚C. In this,
an analytical probe was twice compressed into each
formulation to a defined depth (15 mm) and at a defined
rate (2 mm/s), allowing a delay period (15 s) between the
end of the first and beginning of the second compression.
Mechanical parameters (hardness, compressibility, adhe-
siveness, cohesiveness and elasticity) were derived and
calculated from the resultant force-time curve [18]. Ex-
periments were carried out at least three times. From the
resultant force-time plots, several mechanical parameters
may be derived [19]. These include:
 hardness (the force required to attain a given defor-
mation)
Table 1. The composition of formulations.
Codes of formulation Plx 407 (%)Plx 188 (%) HPMC K100M (%)HPMC E50 (%) Itraconazole (%) Distilled water (%)
F1 20 10 0.5 - - 69.5
F2 20 10 - 0.5 - 69.5
F3 20 10 0.5 - 2 67.5
F4 20 10 - 0.5 2 67.5

A New In-Situ Gel Formulation of Itraconazole for Vaginal Administration 419
 compressibility (the work required to deform the sample
during the first compression of the probe)
 adhesiveness (the work required to overcome the at-
tractive forces between the surface of the sample and
the surface of the probe)
 cohesiveness (the ratio of the area under the force-
time curve produced on the second compression cycle
to that on the first compression cycle, where succes-
sive compressions are separated by a defined recovery
period)
 elasticity (the rate at which the deformed sample re-
turns to its undeformed condition after the removal of
the deforming force)
2.6. Evaluation of the Mucoadhesive Properties
The mucoadhesive strength of the formulations was
evaluated by measuring the force required to detach the
formulation from a mucin disc using a 5 kg load cell
TPA in tension mode [18,20]. Mucin discs (250 mg)
were hydrated with 50 µL mucin solution before the ex-
periment and they were attached to the lower end of the
probe (P 10 Perspex, θ: 10 mm). The gels were packed
into the beaker. The probe holding the mucin disc was
lowered on to the surface of the gel with a constant speed
of 0.1 mm·s−1 and a contact force of 0.05 N were applied.
After keeping in contact surfaces for 120 s, the probe was
then moved vertically upward at a constant speed of 0.1
mm·s−1. Maximum detachment force (F) was obtained
from the force-distance graph. The area under the curve
(AUC) was calculated from force-distance plot as the
mucoadhesion (M). The tests were conducted at 37˚C
and each experiment was carried out five times.
2.7. Syringeability of the Formulations
The syringeability of the formulations was examined
using a software controlled penetrometer in compression
mode. A filled 2 mL syringe was held in place with a
clamp and the upper probe of the texture analyzer moved
downwards until it came in contact with the syringe bar-
rel base. A constant force of 0.5 N was applied to the
base and the work required to expel the contents for a
barrel length of 30 mm was measured. The area under the
resulting curve was used to determine the work of expul-
sion ([22]). The tests were conducted at room tempera-
ture and each experiment was carried out five times. The
syringeability device is described in Figure 1.
2.8. Rhelogical Studies
All the formulations were characterized rheologically
using Haake Mars rheometer. Continuous shear analysis
of each formulation was performed at 20˚C ± 0.1˚C and
37˚C ± 0.1˚C, in flow mode, and in conjunction with
parallel steel plate geometry (diameter 40 mm) and gap
Figure 1. Experimental set-up for the measurement of the
syringeability force developed during injection: 1) metallic
support; 2) plastic clamping ring; 3) force transducer and 4)
syringe (adapted from reference [22]).
of 0.3 mm. Samples were carefully applied to the lower
plate of enstrument, ensuring that formulation shearing
was minimized and allowed to equilibrate for at least 1
min prior to analysis. Upward and downward flow curves
were measured over a range of shear rates (10 - 1000 s−1).
The flow properties of at least five replicate samples
were determined [23,24].
Oscillatory analysis of each formulation under exami-
nation was performed after determination of its linear
viscoelastic region at 20˚C ± 0.1˚C and 37˚C ± 0.1˚C,
where stress was directly proportional to strain and the
storage modulus remained constant. Frequency sweep
analysis was performed over the frequency range of 0.1 -
10 Hz following application of a constant stress and
standard gap size was 0.3 mm for each sample. Storage
modulus (G′) and loss modulus (G″), the dynamic vis-
cosity (η'), and the loss tangent (tanδ) were determined.
In each case, the dynamic rheological properties of at
least five replicates were examined [25,26].
2.9. Statistical Data Analysis
Statistical data analysis was performed using the Student
t-test with P < 0.05 as the minimal level of significance.
3. Results
The gelation temperatures of the F1, F2, F3 and F4 for-
mulations were found to be 34.47˚C ± 0.03˚C, 34.47˚C ±
0.02˚C, 34.47˚C ± 0.02˚C and 34.46˚C ± 0.03˚C, respec-
tively. Gelation time is also an important parameter for
determining vaginal retention of formulation [21]. For
our formulations these value were between 326.63 ± 0.35
sec and 326.98 ± 0.17 sec. The pH values of the F1, F2,

A New In-Situ Gel Formulation of Itraconazole for Vaginal Administration
420
F3 and F4 formulations were found to be 6.52 ± 0.06,
7.25 ± 0.07, 6.95 ± 0.04 and 7.01 ± 0.04, respectively.
The TPA graphs of formulations at 37˚C are presented in
Figure 2 and the mechanical properties of formulations
are presented in Table 2.
Mucoadhesive formulations have been reported to
prolong the residence time of the formulation at the site
of application [6]. Mucoadhesive studies were carried out
only at body temperature because the formulations were
in liquid form at room temperature. In this study the
work of adhesion was used to quantify adhesion. This
measure provides a more comprehensive evaluation of
the detachment phenomenon [27]. The related data of the
detachment force, mucoadhesion and work of adhesion
of the formulations are listed in Table 3. The syringe-
ability of each formulation is also presented in Table 3.
Representative flow curves of in-situ gel formulations
were graphically presented in Figure 3.
Oscillatory analysis was also carried out at both room
and body temperature. Thereby, the changes of the struc-
Figure 2. TPA analysis graphs of F1, F2, F3 and F4 at 37˚C.
Table 2. Mechanical properties of formulations.
Codes H (N) ± SD C (N.mm) ± SD A (N.mm) ± SD E ± SD Ch ± SD
F1-20˚C 0.016 ± 0.003 0.103 ± 0.037 0.036 ± 0.006 0.931 ± 0.047 0.915 ± 0.009
F1-37˚C 0.196 ± 0.011 0.779 ± 0.030 0.662 ± 0.026 1.102 ± 0.137 0.725 ± 0.041
F2-20˚C 0.017 ± 0.003 0.125 ± 0.058 0.039 ± 0.006 0.954 ± 0.066 0.889 ± 0.012
F2-37˚C 0.156 ± 0.009 0.426 ± 0.048 0.38 ± 0.029 1.097 ± 0.025 0.572 ± 0.007
F3-20˚C 0.009 ± 0.002 0.021 ± 0.001 0.035 ± 0.000 0.944 ± 0.036 0.864 ± 0.069
F3-37˚C 0.394 ± 0.053 0.900 ± 0.026 0.961 ± 0.018 1.713 ± 0.447 1.050 ± 0.095
F4-20˚C 0.007 ± 0.000 0.011 ± 0.0001 0.028 ± 0.004 0.823 ± 0.050 0.751 ± 0.057
F4-37˚C 0.131 ± 0.003 0.762 ± 0.013 0.579 ± 0.021 0.993 ± 0.107 0.714 ± 0.152
*H: Hardness, C: Compressibility, A: Adhesiveness, E: Elasticity, Ch: Cohesiveness.
Table 3. Results of mucoadhesion studies of the formulations with mucin disc and syringeability studies.
Codes F (N) ± SD M (mJ) ± SD W (mJ/cm2) ± SD Syringeability (N.sn) ± SD
F1 0.151 ± 0.035 0.077 ± 0.056 0.094 ± 0.068 11.130 ± 1.986
F2 0.215 ± 0.052 0.082 ± 0.040 0.100 ± 0.048 13.663 ± 2.893
F3 0.230 ± 0.067 0.064 ± 0.037 0.078 ± 0.045 16.425 ± 2.065
F4 0.163 ± 0.046 0.042 ± 0.011 0.051 ± 0.013 16.900 ± 2.788
*F: Detachment force, M: Mucoadhesion, W: Work of adhesion.

A New In-Situ Gel Formulation of Itraconazole for Vaginal Administration 421
cture of the formulation were investigated in both tem-
peratures. Figure 4 shows the rheological properties of
the formulations.
In Table 4 and Figure 5, effect of temperature on the
loss tangent and dynamic viscosity of formulation at
certain frequencies were presented.
4. Discussion
Poloxamer molecules in solution exhibit a zigzag con-
figuration, initially transforming into a close-packed con-
figuration and then to a viscous gel due to the increasing
temperature [28]. Sol-gel transition temperature is the
temperature at which the liquid phase makes transition
into a gel. The transformation from the solution to the
form after the application is important for efficient therapy
due to the covering mucosal tissue and the decreasing the
vaginal leakage. Ideally the gelation temperature of
mucosal formulations should be 30˚C - 36˚C [11,17,29].
If the gelation temperature is high, the formulation
exhibits liquid properties at physiological temperatures
and leakage results. Conversely, lower gelation tem-
peratures may result in problems concerning application
due to the viscous nature of the formulation. It is known
that the sol-gel transition temperature can be changed by
addition of the active substance or additivies [30]. But
for our formulations, addition of active substance didn’t
affect gelation temperatures. Gelation temperatures of
our formulations were found suitable for the vaginal
F1 F2
F3 F4
Figure 3. Flow curves of itraconazole formulations at 20˚C and 37˚C.
Table 4. Effect of temperature on the dynamic viscosity (η′) of formulations at five representative frequencies.
η* (Pa.s) values at different ossilasion frequency
Codes of Formulations Temperature (˚C)
0.60 Hz 2 Hz 5 Hz 7 Hz 10 Hz
20 14.481 ± 0.880 3.465 ± 0.764 1.482 ± 0.659 1.338 ± 0.538 1.152 ± 0.494
F1
37 679.625 ± 0.500213.800 ± 0.43192.988 ± 0.324 67.330 ± 0.510 50.143 ± 0.402
20 10.433 ± 0.235 2.886 ± 0.12 1.288 ± 0.096 0.925 ± 0.023 0.601 ± 0.052
F2
37 471.300 ± 0.654203.267 ± 0.235101.093 ± 0.36577.237 ± 0.652 58.403 ± 0.265
20 30.347 ± 0.485 5.158 ± 0.251 4.335 ± 0.159 1.674 ± 0.571 2.049 ± 0.485
F3
37 804.850 ± 0.396126.743 ± 0.25444.638 ± 0.158 17.790 ± 0.654 14.264 ± 0.478
20 10.415 ± 0.096 3.907 ± 0.098 2.010 ± 0.065 1.009 ± 0.030 0.917 ± 0.002
F4
37 1005.600 ± 0.216299.300 ± 0.365117.650 ± 0.65279.205 ± 0.521 47.640 ± 0.321

A New In-Situ Gel Formulation of Itraconazole for Vaginal Administration
422
F1
(
20˚C
)
F1
(
37˚C
)
F2
(
20˚C
)
F2
(
37˚C
)
F3 (20˚C)
F3
(
37˚C
)
F4
(
20˚C
)
F4
(
37˚C
)
Figure 4. Frequency-dependent changes of viscoelastic properties of the formulations.
application. Our formulations behaved as viscous liquid
at room temperature and transformed to gel at body tem-
perature. So, their application will be easy with a catheter
and increased viscosity could be a solution of leakage.
Most of the studies which used Plx as a polymer have
focused only on rheological properties, and sustained
release action of thermosensitive hydrogels. There is a
lack of knowledge on practical administration of formu-
lation to the body such as syringeability and gelation
time. But, these two factors are crucial in the develop-

A New In-Situ Gel Formulation of Itraconazole for Vaginal Administration 423
0 5 10
Frequency (Hz)
20˚C
F1
F2
F3
F4
40.000
35.000
30.000
25.000
20.000
15.000
10.000
5.000
0.000
tanδ
0 5 10
Frequency (Hz)
37˚C
F1
F2
F3
F4
1.600
1.400
1.200
1.000
0.800
0.600
0.400
0.200
0.000
tanδ
Figure 5. Frequency-dependent changes of loss tangent
(tanδ) of the formulations.
ment of a desirable thermosensitive hydrogel that is easy
to administer to the body and gels rapidly, enabling prac-
tical use in pharmaceutical preparations [31]. Because of
this reason, we examined these two parameters of formu-
lation with other properties. The determination of the
gelation time of a gel formulation requires a knowledge
of the viscosity of the solution as a function of time. The
short gelation time was advantageous to prevent the drai-
nage from the site of application leading to a prolonged
retention of the active substance on the mucosal tissue
[32]. In our previous studies, we know that the formu-
lations include Plx alone has short gelation times [7]. Ad-
ding HPMC to the formulations caused increased gela-
tion time of the formulations. However, gelation time
values were still suitable for vaginal applications.
The pH values of the prepared formulations were
found in physiological limitations and they were deemed
to be suitable for vaginal administration.
TPA is a mechanical test that describes the resistance
of pharmaceutical formulations to compressive stresses
and subsequent relaxation. The parameters derived from
this technique (hardness, compressibility, adhesiveness,
elasticty and cohesiveness) have been proven to be relevant
to the performance of local formulations, e.g. ease of re-
moval from the container, ease of application to the sur-
face and retention of the product at the site of application.
For this reason, TPA is frequently used to identify for-
mulations that may be suitable for clinical application
[22]. Hardness and compressibility describe the stress/
work required to remove the sample from the container
and to subsequently apply this to the site of application.
These characteristics quantify sample deformation under
compression and should be low to allow the gel to be
easily removed from the container and spread onto the
mucosal epithelia. The hardness and compressibility
values of the gels increased significantly due to the in-
creases in polymer concentration. Adhesiveness, a pro-
perty related to mucoadhesion, is defined as the work
required to detach probe from the sample in which its
cohesive bonds were broken and describes the relative
properties of each candidate formulation. Product elasti-
city represents the rate at which the deformed sample
returns to its undeformed condition. Lower numerical
values as determined by TPA in the elasticity mode in-
dicate greater product elasticity [33]. TPA also provides
information on the effects of repeated shearing stresses
on the structural properties of formulations, a property
termed its “cohesiveness” [34-36]. As it can be seen from
the Table 2, compressibility, adhesiveness and cohesive-
ness values of the gels not significantly increased with
addition of active substance. The gel structure of F3,
containing 0.5% HPMC K100M and itraconazole 2%,
exhibited the greatest compressibility, adhesiveness and
cohesiveness. Based on these properties, F3 appeared to
offer more suitable performance than other formulations.
The contact time of a formulation on the mucosa is of
high importance for vaginal drug delivery. Mucoadhesive
formulations have been reported to prolong the residence
time of the formulation at the site of application. Quanti-
fication of mucoadhesion is important to ensure that the
adhesion offered by formulations is sufficient to ensure
prolonged retention at the site of application [37]. Im-
portantly, the formulations under examination displayed
significant mucoadhesion, similar to other systems that
have been used for implantation into body cavities. It is
known that HPMC exhibits a mucoadhesive property.
Although Plx is not as mucoadhesive as HPMC, its sol-
gel transition ability increases the viscosity of the solu-
tion at physiological temperature. Hence, combinations of
HPMC and Plx showed higher mucoadhesiveness at
37˚C. Using two different viscosity type of HPMC did
not significantly effect the mucoadhesive properties of
the formulations. Also, our experimental datas indicated
that F3 formulation has higher mucoadhesive properties
than other formulations. Result of mucoadhesive studies
showed similarity with TPA analysis.
Syringeability of the in-situ gel formulations presented
the effect that content of the formulation have on the
force required to expel the product. Although, our for-
mulations viscous liquid at 20˚C, syringeability is still

A New In-Situ Gel Formulation of Itraconazole for Vaginal Administration
424
important parameter to show easy application of our for-
mulations. According to the result our study, addition of
active substance did not significantly affect syringeability
of formulations. On the other hand, using different HPMC
polymer types in formulation did not significantly change
syringeability values of formulations.
The evaluation of the rheological properties for the gel
type dosage forms would be important for predicting
their behavior in vivo. The shear stress changes upon
shear rates have been used to determine whether the
rheological behavior of the formulation is Newtonian or
non-Newtonian. Non-newtonian flow is typical for po-
loxamer formulations at higher temperatures than sol-gel
transition temperature [18]. In continuous shear rheometry,
all formulations exhibited pseudo-plastic flow at 37˚C as
it was expected due to its thermoresponsive property.
Our results showed similarity with the literature [6,21].
Among the all formulations, high shear stress values
were obtained with F3 formulation.
The rheological properties of in-situ gel formulations
affect both the ease of application and retention within
the vagina. Following local application to the vagina, it is
accepted that the equilibrium rheological properties of
the formulations will dominate the subsequent physico-
chemical properties. In polymer solutions, at a sufficiently
high concentration, there are entanglements among the
polymer chains but there is sufficient time for polymer
chains to distangle and flow during a single oscillation at
low frequencies (G″ > G′). Conversely, as the elastic pro-
perties of the sample increase, interchain entanglements
do not have sufficient time to come apart within the period
of single oscillation and G′ becomes higher than G″ [34,
38]. A gel should exhibit a solid-like mechanical spec-
trum, that is, G′ > G″ throughout the experimentally ac-
cessible frequency range, and there should be little fre-
quency dependence of the moduli [39].
In oscillatory rheometry the effects of oscillatory
stresses on the viscoelastic properties are measured, from
which two dynamic moduli, namely, the storage modulus,
G′, a measure of the elasticity, and the loss modulus, G″,
representing viscous components at a given frequency of
oscillation, are obtained [20,21]. Frequency-independent
behaviour presents a gel like material whereas the fre-
quency dependence shows the viscous fluid. According
to the results, F3 formulations were found nearly fre-
quency independent after certain frequency values and
this formulation exhibited typical gel-type mechanical
spectra (G′ > G″) at 37˚C. It was also investigated that
presence of itraconazole and HPMC K100M provided
higher elasticity value for F3 formulation comparing to
other formulations. Greater elasticity of this formulation
would be expected to enhance retention at the site of
application.
The value of phase angle (tanδ = G″/G′), which is a
measure of the relative contribution of viscous compo-
nents to the mechanical properties of the materials, was
<1 for all of the formulations at 37˚C (solid gel response)
but was >1 for all of the formulations at 20˚C (liquid-like
response). Thus, as tanδ becomes smaller, the elasticity
of the formulation increases, while the viscous behavior
is reduced. As it was expected, tanδ values were found
higher for all the formulations at 20˚C than 37˚C [20]. F4
formulation showed more elastic property than other
formulations and this result is accordance with TPA analy-
sis.
Dynamic viscosity (η′) is described as the flow resis-
tance of the sample in the structure state, originating as
viscous or elastic flow resistance to oscillating movement.
The higher value of dynamic viscosity means the greater
the resistance to flow in the structured state [20]. In our
study, the highest η′ was obtained with F4 formulation
due to its more consistent gel structure. The observed
large dynamic viscosities of gels at low oscillatory fre-
quencies are characteristic of viscoelastic systems.
5. Conclusion
This study has described the in-situ gel formulations of
itraconazole and evaluated their textural and rheological
properties. Plx has low mucoadhesive properties but its
termal sensitivity lead to easy application and covering
over the mucosa. Adding HPMC to the formulation de-
creased the sol-gel transition temperature, and affected
the mucoadhesive, mechanical and rheological properties
of the formulation. The results showed that the texture
characterization was in agreement with rheological results
confirming the improved mechanical properties of Plx-
HPMC formulations. As a result, the evaluation of the
entire candidate formulations indicated that vaginal for-
mulation of itraconazole will be a new alternative for the
treatment of vaginal candidiasis with suitable textural
and rheological properties. Our results showed that the
developed formulations were found worthy of further
studies.
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