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药学学报 Acta Pharmaceutica Sinica 2011, 46 (4): 460−465
Preparation of fluconazole buccal tablet and influence of
formulation expedients on its properties
MOHAMED Saifulla P*, MUZZAMMIL Shariff, PRAMOD Kumar TM
(Department of Pharmaceutics, College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagar,
Mysore-570 015, Karnataka, India)
Abstract: The aim of present study was to prepare buccal tablets of fluconazole for oral candidiasis. The
dosage forms were designed to release the drug above the minimum inhibitory concentration for prolonged
period of time so as to reduce the frequency of administration and to overcome the side effects of systemic
treatment. The buccal tablets were prepared by using Carbopol 71G and Noveon AA-1 by direct compression
method. Microcrystalline cellulose was used as the filler and its effect was also studied. The prepared dosage
forms were evaluated for physicochemical properties, in vitro release studies and mucoadhesive properties using
sheep buccal mucosa as a model tissue. Tablets containing 50% of polymers (Carbopol & Noveon) were found
to be the best with moderate swelling along with favorable bioadhesion force, residence time and in vitro drug
release. The in vitro drug release studies revealed that drug released for 8 h, which in turn may reduce dosing
frequency and improved patient compliance in oral candidiasis patients.
Key words: adhesion; Carbopol 71G; fluconazole; mucoadhesive tablet; Noveon AA-1; oral candidiasis
CLC number: R943
Document code: A
Article ID: 0513-4870 (2011) 04-0460-06
Oral candidiasis is an opportunistic fungal infection
in oral cavity usually caused by Candida albicans[1]. It
can infect when predisposing factors such as antibiotic
therapy, corticosteroid therapy, xerostomia (dry mouth),
diabetes mellitus, chemo/radiation therapy, and immunosuppression are present. Recently the advent of the
human immunodeficiency virus infection has resulted
in a resurgence of oral candida infections. General
debilitation, poor oral or dental hygiene, and ill-fitted
dentures are some of the other predisposing factors
responsible for the cause of oral candidiasis. Fungal
opportunistic infections, including oral candidiasis, are
a major cause of morbidity and mortality in cancer
patients. Chronic antimycotic therapy in high doses
is undesirable for treatment of oral infections due to
potential side effects[2−5]. The oral dose of fluconazole
for treatment of oral candidiasis (100 mg/day for 1 or
2 weeks) results in notable side effects varying from
headache, nausea to liver dysfunction and hepatic
failure. Furthermore, oral fluconazole is reported to
interact with a number of medications, including
Received 2010-10-19.
*Corresponding author Tel: 0821-2548353, Fax: 0821-2548359,
E-mail: [email protected]
oral hypoglycemics, coumarin-type anticoagulants,
cyclosporins, terfenadin, theophylline, phenytoin, rifampin
and astemizole[6]. Therefore, to minimize these adverse
effects and the ominous risk of drug resistance, topical
therapy should be considered as the first-line candidate
for the treatment of oral and pharyngeal candidiasis.
These yeast infections are usually treated locally by
application of gels or suspensions. Release of drugs
from these preparations involves initial burst of
activity, whose level rapidly declines to subtherapeutic
concentrations[7].
Recent years have seen an increasing interest in the
development of novel buccal bioadhesive dosage forms.
These are useful for both systemic delivery of drugs,
as well as for local targeting of drugs to a particular
region in the body[8, 9]. A wide range of polymers of
synthetic, semi synthetic and natural origin like Carbopol,
polycarbophil, sodium carboxymethylcellulose (SCMC),
hydroxypropylmethylcellulose, chitosan and xanthan
gum have been described for the formulation of
bioadhesive systems but none of these polymer possess
all the characteristics of an ideal polymer (nontoxic,
nonirritant, strong non covalent adhesion, sustained
release, stable and cheap) for a bioadhesive drug
MOHAMED Saifulla P, et al: Preparation of fluconazole buccal tablet and influence of formulation expedients on its properties · 461 ·
delivery system. Carbopols are excellent bioadhesives
but with potential mucosal irritating character[10].
Irritant properties of Carbopol 971P (CP 971P) can
be reduced by combining it with other non-irritant
bioadhesive polymers like SCMC.
Yehia et al[11] have studied fluconazole mucoadhesive
buccal films prepared using film forming polymers and
bioadhesive polymers alone or in combination.
Yehia et al[12] have formulated novel mucoadhesive
buccal discs of fluconazole and studied the relationship
between swelling, erosion and drug release. However,
in previous literature, no attempt has been taken to
formulate fluconazole buccal tablets.
The objective of the present study is ① to prepare
mucoadhesive fluconazole tablets using Carbopol 71G
and Noveon AA-1, ② to examine the in vitro release of
fluconazole from formulated tablets by varying type
and composition of matrix blend, ③ to study the effect
of microcrystalline cellulose on in vitro drug release.
The 8 h drug release is desired in accordance to
patient compliance and to reduce the frequency of
administration. The prepared formulation containing
fluconazole for oral candidiasis should ensure satisfactory
drug level in the mouth for prolonged duration of time
and reduce side effects and drug interaction during
systemic therapy.
Materials and methods
Materials Fluconazole obtained from Mayer’s
Health Care PVT Ltd., Bangalore, India. Carbopol 71G
(Arihantt Trading Co., Mumbai, India, acrylic acid
polymer, carboxylic acid content, assay %: 56.0 − 68.0,
viscosity: 4 000 − 11 000, loss on drying: 2% max, heavy
metals: 20 parts per million max). Noveon AA-1
(Arihantt Trading Co., Mumbai, India, polycarbophil,
MW ranges from 700 000 to 3 − 4 billion, viscosity:
2 000 − 12 000 cPs at 25 ℃, loss on drying: 1.5% max,
pH 1% dispersion: 4 max). Microcrystalline cellulose
and Talc were from Zydus Cadila, India. All other
chemicals and reagents used were of analytical grade.
Preparation of fluconazole buccal tablets
Bioadhesive tablets were fabricated by direct compression
method as shown Table 1. The accurate quantity of
drug and excipients were weighed. They were passed
through sieve and thoroughly mixed using mortar and
pestle. The blend was lubricated and then compressed
into tablets by the direct compression method using
8-mm flat-faced punches in KBr press (Technosearch,
Mumbai, India) at 1 ton pressure.
Table 1
Formulation chart of the prepared buccal tablets
Formulation code (wt in mg)
Ingredient
F1
F2
F3
F4
F5
Fluconazole
20
20
20
20
20
20
Carbopol 71 G
30
50
−
−
15
25
Noveon AA-1
−
−
30
50
15
25
Microcrystalline cellulose
45
25
45
25
45
25
5
5
5
5
5
5
Talc
F6
Evaluation of buccal tablets All the formulations
were evaluated for uniformity of weight, and drug
content as per pharmacopoeial method. The average
weight was obtained for at least 20 units. The
fluconazole quantification was analyzed at 261 nm by
UV spectrophotometer (UV-1700 Shimadzu, Japan).
The thickness was measured using Mitotoyo screw
gauge (Mitotoyo, Japan). Hardness was determined
for at least 10 tablets using Erweka hardness tester
(Erweka, India) and friability was evaluated for a
sample of 20 tablets using Electrolab EF-2 friabilator
(Electrolab, India). Technological parameters of the
formulations are shown in Table 2.
Table 2 Physicochemical properties of fluconazole buccal
tablets (Mean ± SD)
Formulation Thickness
code
/mm
% Friability/
Microenvironment
Hardness
kg·cm−2
pH
F1
1.2 ± 0.01
0.31 ± 0.005 4.2 ± 0.2
6.54 ± 0.11
F2
1.3 ± 0.02
0.27 ± 0.01
4.8 ± 0.4
6.62 ± 0.10
F3
1.3 ± 0.01
0.24 ± 0.005 5.1 ± 0.1
6.61 ± 0.15
F4
1.2 ± 0.03
0.41 ± 0.005 4.0 ± 0.1
6.73 ± 0.13
F5
1.3 ± 0.01
0.36 ± 0.005 4.3 ± 0.3
6.66 ± 0.15
F6
1.2 ± 0.02
0.28 ± 0.01
6.72 ± 0.16
4.8 ± 0.2
Microenvironment pH The microenvironment
pH of the prepared buccal bioadhesive fluconazole
tablets were determined to evaluate the possible irritation
effects on the mucosa. The microenvironment pH was
determined by using Elico, LI-120 (Ahmadabad, India).
The tablets were left to swell in 5 mL of distilled water
(pH 6.8) in small beakers, and the pH was measured at
time intervals of 2, 4, 6 and 8 h by placing the electrode
in contact with the microenvironment of the swollen
tablets. The average pH of five determinations was
reported[13, 14].
Swelling studies The swelling index of the
prepared buccal bioadhesive fluconazole tablets was
determined by weighing five tablets and recording their
weights before placing them separately in weighed
beakers. The total weight was recorded (W1 ). Four
milliliters of phosphate buffer (pH 6.8) was added
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药学学报 Acta Pharmaceutica Sinica 2011, 46 (4): 460−465
to each beaker and then placed in an incubator at 37 ±
0.5 ℃. At time intervals of 2, 4, 6 and 8 h excess
water was carefully removed, and the swollen tablets
were weighed (W2)[15−17]. The experiment was repeated
three times, and the average W1 and W2 were reported.
The swelling index was determined from the formula.
Swelling index = W2 −W1
(1)
W1
In vitro release of fluconazole tablets The drug
release rate from buccal compacts was studied using the
orbital shaking incubator using (Remi CIS 24, India)
30 mL of phosphate buffer pH 6.8. The temperature
was maintained at 37 ± 0.5 ℃ and 50 RPM (rotation per
min). For every one hour of time interval 3 mL sample
was withdrawn, filtered through a millipore filter of
0.45 µm pore size and assayed spectrophotometrically
at 261 nm. Immediately after each sample withdrawal,
a similar volume of phosphate buffer pH 6.8 was added
to the release medium to maintain the volume in the
vessel constant. The absorbance of the polymeric
additives was negligible and did not interfere with
λmax of the drug. The release data were kinetically
analyzed using different kinetic models to determine
the mechanism of drug release[18, 19].
Residence time for tablets The in vitro residence
time was determined using a locally modified USP
disintegration apparatus (Disintegration tester, Veego
Instruments Corporation, Mumbai, India). The medium
was composed of 500 mL phosphate buffer (pH 6.8) in
1 L beaker and maintained at 37 ± 0.5 ℃. A segment
of sheep buccal mucosa, was glued on the inside curved
surface of 1 L beaker above the level of 500 mL
phosphate buffer (pH 6.8). A glass cylinder (100 mL)
was vertically fixed to the apparatus. The bioadhesive
tablet was hydrated from one surface using phosphate
buffer (pH 6.8) and then the hydrated surface was
brought into contact with the mucosal membrane. The
glass cylinder was vertically fixed to the apparatus and
allowed to move up and down so that the tablets was
completely immersed in the buffer solution at the
lowest point and was out at the highest point. The
time necessary for complete erosion or detachment of
the tablet from the mucosal surface was recorded[20, 21].
The experiment was performed in triplicate.
Bioadhesive strength The force required to detach
the bioadhesive tablets from the mucosal surface was
applied as a measure of the bioadhesive performance.
The method of Parodi et al[22] was slightly modified for
measuring the bioadhesion strength of the tablets. The
instrument is broadly composed of a modified two
arm physical balance in which the right pan had been
replaced by a formulation holding glass plate (10 cm ×
5 cm) and counter balanced by a water collecting pan
suspended to the left arm. The pan received a siphon
tube from a 10 L bottle, which was kept at a high place
in such a way that water head in the bottle, always
remaining above the water collecting pan. The siphon
tube bears a flow regulating device. Nylon thread was
used to suspend both the glass plate and the pan. An
acrylate tissue mounting stage (1.8 cm × 1.8 cm × 8 cm)
was attached to the center of a glass beaker (16 cm
diameter and 18 cm height). Glass beaker was filled
with phosphate buffer (pH 6.8) to simulate in vivo
saliva conditions. A magnetic stirrer provided with
temperature control was used to maintain the temperature
of phosphate buffer (pH 6.8) in glass dish at 37 ± 0.5 ℃.
A piece of sheep buccal mucosa was tightly secured on
the upper surface of the acrylate tissue mounting stage
with thread. Tablets were fixed on the centre of the
formulation holding glass plate with an adhesive (Fevi
Quick®). The exposed tablet surface was moistened
with phosphate buffer (pH 6.8) and left for 30 s for
initial hydration and swelling. Then glass plate (with
the film) was kept on the mucosal tissue secured on
the tissue mounting stage in such a way that films
completely remained in contact with mucosa. The
whole assembly was kept undisturbed for 3 min
(preload time) to establish the adhesion between the
tablets and mucosal tissue. The glass plate (weight
50 g) itself acted as a preload. After the preload time,
water collecting pan was suspended to the left arm and
water was added in it, by the siphon tube, at a constant
rate of 200 drops per minute until detachment of the
film from mucosal surface took place. A support
was kept under the water collecting pan to hold it at
the time of detachment. Weight of water collected in
the pan at the time of detachment was measured[22].
The experiment was performed in triplicate.
Stability studies The optimized formulation was
subjected to stability testing as per ICH guidelines at
30 ± 2 ℃, 65% ± 5% RH & 40 ± 2 ℃, 75% ± 5% RH for
three months. Compacts were evaluated periodically
for drug content and in vitro drug release studies.
Results and discussions
The bioadhesive buccal tablets containing
fluconazole were successfully prepared by direct
compression method. Different tons of pressures were
MOHAMED Saifulla P, et al: Preparation of fluconazole buccal tablet and influence of formulation expedients on its properties · 463 ·
initially investigated in our laboratory to obtain the
optimum hardness and friability. An optimum of 1 ton
pressure was selected.
1 Drug polymer compatibility studies
The FTIR studies of pure fluconazole and polymer.
The spectrum exhibits no or little variation in the
peak position. The FTIR studies confirmed there is no
interaction and can be used in formulation.
2 Microenvironment pH
Microenvironment pH is the most important
criteria of the formulation for the patient compliance.
Microenvironment pH is determined to evaluate the
possible irritation effects on the mucosa. As acidic or
alkaline pH is found to cause irritation to the buccal
mucosa, leads to patient incompliance.
In buccal tablets formulations containing combination of polymers showed microenvironment pH nearer
to neutral. The Carbopol 71G containing formulations
showed microenvironment pH around 6.6, this may be
due to high concentration of carboxylic acid in the
Carbopol 71 G. Noveon AA-1 containing formulations
showed microenvironment pH of about 6.73, this may
be due to the polyacrylic acid. Polyacrylic acid is less
acidic than the carboxylic acid present in the Carbopol
71G.
3 Swelling index studies
The swelling studies of the formulation were the
critical for its bioadhesion. In beginning adhesion is
minimal because the bond formed between mucosal
layer and polymer is very weak.
The adhesion will increase with the degree of
hydration until a point where over hydration leads to an
abrupt drop in adhesive strength due to disentanglement
at the polymer/tissue interface.
In buccal tablets all formulations shows the swelling
up to 8 h. Swelling index increased with the weight
gain by the compacts, increased proportionally with the
rate of hydration as shown in Figure 1. Swelling index
measurement was carried up to 8 h. Carbopol 71 G
being acidic in nature swells more in the basic pH and
in neutral pH compared to Noveon AA-1 because of its
less acidic in nature. All formulation showed rate of
swelling more than the rate of erosion. The polymer
chain in the tablets remains intact and doesn’t cause
the erosion. Microcrystalline cellulose a hydrophobic
and water insoluble compound, with variation in the
concentration of microcrystalline cellulose did not
influenced greatly the swelling of the mucoadhesive
polymers.
Figure 1
4
Swelling studies of formulations
In vitro drug release studies
The in vitro release profile is showed in Figure 2.
The rate and extent of drug release decreased with
increase in the concentration of polymers for prepared
tablets.
In buccal tablets the drug was slowly released
over a period of 8 h. As the concentration of polymer/
polymers increased the drug release decreased. In the
buccal tablets (dry state), the fluconazole is trapped in
a glassy core. As the external surface of the buccal
tablet is hydrated, it forms a gelatinous layer. The
gelatinous layers are not entangled chains of polymer,
but discrete microgels made up of many polymer
particles, in which the fluconazole is dispersed. The
crosslink network is responsible for the entrapment of
fluconazole in the gelationous layer. The osmotic
pressure from within the gelatinous layer works to
break up the structure, and the drug continued to diffuse
through the gel layer at a uniform rate. Increasing the
amount of Carbopol 71G in the formulations showed
linearity in drug release and resulted in more consistent
performance. As the concentration of Carbopol 71G
further increased, the release rate became slower and
more linear. This may be due to the fact that the gel
layer formed around the tablet becomes stronger, with
fewer interstitial spaces between the microgels. One
of the reasons for slow drug release from the Carbopol
containing formulations may be due to the closing of
the micro pores and a reduction in regions of low micro
viscosity in the swollen compacts. The other reason
may be that at higher concentration of Carbopol polymer
the gel layer is thicker and stronger. The thicker the
gel layer, the more the time for the drug to diffuse to
the surface. The increase in polymer concentration
decreased the drug release in all the formulations as
shown in Figure 2. As both the polymers have the
hydroxyl group, the drug release is almost the same.
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药学学报 Acta Pharmaceutica Sinica 2011, 46 (4): 460−465
The formulations containing both Noveon and Carbopol
showed the drug release in a similar manner as that of
other formulations. F1, F3 formulations showed the
drug release above 90% with polymer concentration 30%.
Whereas F2 and F4 formulations showed decreased
release with increase in the polymer concentration.
About 70% of drug was release with 50% of polymer,
this decrease in the drug release may be due to gel layer
around the tablet or due to closing of micro pores in the
polymer channels.
Figure 2
In vitro drug release studies for formulations
Influence of MCC on drug release studies
Usually, the addition of fillers is necessary to
obtain solid dosage forms with desirable technological
properties. However, these additives can have significant
effect on the water uptake of the formulations and
dissolution properties of drugs. In this context, it was
reported that water absorption behaviour of polymers
might be influenced by the presence of different
co-excipients[23]. It is well known that MCC is one of
the most commonly used direct compression excipient
as a binder/filler. It is capable of swell and therefore,
different concentrations can modify the drug release
rate by forming a gelatinous layer on the surface of the
compacts. MCC absorbs water at a faster rate, which
causes the polymer to change from a glassy to a
rubbery state, thereby facilitating chain movements.
Unexpectedly, the swelling capacity and the further
drug release rate of the tablets were slightly modified
by replacing swellable MCC. Moreover, release rate
of fluconazole increased with increasing concentration
of MCC. In addition, no initial burst effect was
observed by using MCC up to 50%. Thus, the
dissolution process would be mainly affected by the
water absorption, positively correlated with the gel
forming of the mucoadhesive polymers, working as a
diffusion barrier. Moreover, it should be mentioned
that the incorporation of the highly water-soluble
lactose is not always an effective tool to increase drug
dissolution rates.
6 Bioadhesion studies
Bioadhesion force and ex-vivo residence time of
the prepared tablets on sheep buccal mucosa have been
shown in Table 3.
As expected, bioadhesion characteristics were
found to be affected by the nature and proportions of
the polymers used. The highest mucoadhesion was
observed in the formulations containing combination
of polymers. Due to their chemical nature, these highmolecular-weight polymers readily swell in water,
providing a large adhesive surface for maximum contact
with the mucin (the glycoprotein predominant in
the mucous layer). The Noveon AA-1 containing
formulation showed more mucoadhesive strength than
the Carbopol 71 G containing formulation, this may
be due to the greater hydrophilicity which results in
low contact angle. Thus it interacts with the mucin,
resulting in adhesion of the polymer to the mucin.
The combination of polymers showed the synergistic
action hence greater mucoadhesive strength was observed
in F6 (containing 50% of polymer) formulation.
5
Results of mucoadhesion studies (Mean ± SD)
Table 3
Formulation
code
F1
7
36.5 ± 0.002
Ex-vivo residence
time/h
4.36 ± 0.35
F2
40.3 ± 0.001
4.53 ± 0.15
F3
51.2 ± 0.001
5.24 ± 0.22
F4
57.8 ± 0.001
5.55 ± 0.10
F5
62.3 ± 0.002
6.55 ± 0.24
F6
66.5 ± 0.001
7.21 ± 0.50
Bioadhesion strength/g
Kinetic analysis
To examine further the release mechanism of
fluconazole from buccal compacts, the results were
analyzed according to the Peppas model fitting. The
values of n were greater than 0.5 indicating non-Fickian
transports. Most of the prepared compacts exhibited
n values greater than 0.9. Therefore, the values of
diffusion release exponent n (slope) and coefficients of
correlation r following linear regression of dissolution
data indicated near zero order release. It may be
indicative of drug release by both diffusion and chain
relaxation mechanism. Therefore the drug release
from the prepared compacts is controlled by swelling of
the polymer followed by drug diffusion through the
swollen polymer.
MOHAMED Saifulla P, et al: Preparation of fluconazole buccal tablet and influence of formulation expedients on its properties · 465 ·
8
Stability study
Based on the drug release, microenvironment
pH and swelling studies F5 formulation was selected as
optimized formulation. The optimized formulation F5
was subjected to stability study maintained at 30 ± 2 ℃,
65% ± 5% RH & 40 ± 2 ℃, 75% ± 5% RH for 90 days
(Table 4). The resulting drug content assay and drug
release profiles from these formulations showed no
significant difference over the period of the study.
[8]
Bouckaert S, Remon JP.
In-vitro bioadhesion of a buccal,
miconazole slow release tablet [J].
J Pharm Pharmacol, 1993,
45: 504−507.
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Sampling interval
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Curr Drug Deliv, 2009, 6: 17−27.
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Design and in
25 ℃/60% RH
30 ℃/65% RH
40 ℃/75% RH
vitro/in vivo evaluation of novel mucoadhesive buccal discs of
0th Day
99.723 ± 0.54
99.796 ± 0.89
99.794 ± 0.56
an antifungal drug: relationship between swelling, erosion, and
15thDays
98.365 ± 0.36
98.343 ± 0.56
98.141 ± 0.88
45thDays
97.752 ± 0.27
97.709 ± 0.25
97.690 ± 0.92
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97.695 ± 0.42
97.668 ± 0.98
97.663 ± 0.37
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