ISSN 0974-3618 (Print) www.rjptonline.org
0974-360X (Online)
RESEARCH ARTICLE
Formulation and Evaluation of Mucoadhesive Buccal
Films of Diclofenac Potassium
Annapurna
Uppala*, Naga Swapna V, Neelima Devi R, Glory Sheren G, Kishore Kumar B
Department of Pharmaceutics, University College of
Pharmaceutical Sciences, Acharya Nagarjuna University, Nagarjuna Nagar, Andhra
Pradesh, India 522510.
*Corresponding Author E-mail: annapurnampharm@rediffmail.com
ABSTRACT:
The development of mucoadhesive buccal films has
increased dramatically over the past decade because it is a promising delivery
alternative to various therapeutic classes of peptides, vaccines and
nanoparticles. The present investigation highlights the formulation and
evaluation of muco adhesive buccal films of Diclofenac Potassium. The
mucoadhesive buccal films were prepared by solvent casting technique using
polymers like Hydroxy Propyl Methyl Cellulose K4M, Ethyl cellulose and Carbopol
934P. The formulated films were evaluated for their physical parameters like
surface area, folding endurance, swelling studies, drug content and In vitro release studies. The films of
different formulations were found to have good physical appearance, surface
area, optimum swelling capacity and drug release. In vitro drug release studies in pH 6.6 phosphate buffer showed a
prolonged release for over five hours for all formulations. Formulation F1
containing HPMC K4M and Carbopol 934P was selected as best formulation.
Therefore it can be concluded that the polymers and their combination
influenced the physical properties of film and their release characteristics.
KEYWORDS: Diclofenac Potassium, buccal films, solvent
casting technique, In vitro release
studies, mucoadhesive polymers, buccal drug delivery.
1.0 INTRODUCTION:
The rich vascularization of the oral mucosa and its permeability to many
drugs makes the buccal route an attractive alternative to the oral and
parenteral routes, for systemic drug delivery. [1] Substantial
efforts have recently been focused on the delivery of drugs to or via mucous
membrane by the use of mucoadhesive materials to overcome the limitations of
conventional drug delivery system. [2] Transmucosal routes of drug
delivery offers distinct advantages over peroral administration for systemic
effect. Among the various transmucosal routes, buccal mucosa has an excellent
accessibility, an expanse of smooth muscle and relatively immobile mucosa,
bypasses hepatic circulation thereby avoiding first pass metabolism [5],
hence suitable for administration of controlled release dosage forms. [3,6]
Buccal film may be preferred over buccal tablet, in terms of flexibility
and comfort. The film can be defined as a dosage form that employs a water
dissolving polymer, which allows the dosage form to quickly hydrate, adhere and
dissolve when placed on the tongue, or in the oral cavity, which results in
systemic drug delivery. [4,7]
Diclofenac Potassium is a non steroidal anti inflammatory drug which
acts specifically on inflammatory sites by inhibition of prostaglandin
synthesis through cyclo oxygenase enzymes [8,10] It is used in the
long term treatment of rheumatoid arthritis, osteo arthritis and ankylosing
spondylitis. Its biological half life has been reported as 1-2 hr. Gastro
intestinal side effects such as bleeding, ulceration or perforation of
intestinal wall are commonly seen. [9] Diclofenac Potassium
undergoes first pass hepatic metabolism by showing lesser bioavailability Due
to the short biological half life and associated adverse effects, it is
considered as an ideal candidate for controlled drug delivery. [9,11]
2.0 MATERIALS AND METHODS:
2.1 Materials used:
Diclofenac Potassium obtained from Ra Chem Pharma ltd, HPMC K4M, Ethyl
Cellulose, Carbopol 934P obtained from Loba Chemie Pvt. Ltd, Mumbai, India were
used. Ethanol (Jiangsu Hauxi International Trade Co Ltd.), Glycerine (Merck
Specialities Pvt. Ltd), Liquid paraffin (Thermo Electron LLS India Pvt. Ltd.),
Potassium Dihydrogen ortho phosphate, Sodium Hydroxide (Thermo Fischer
Scientific Pvt. Ltd.) and other chemicals of analytical grade were used.
2.2 Preformulation study:
2.2.1 Calibration curve of Diclofenac potassium with 6.6 Phosphate
buffer:
In a 100 ml volumetric flask, standard solution was prepared by
dissolving 100 mg of Diclofenac potassium in 6.6 phosphate buffer and made up to
the volume with 6.6 Phosphate buffer. From the standard solution, 1 ml was
taken and the volume was made up to 100 ml with distilled water and it was
labeled as stock. From this stock solution, serial dilutions were made by
withdrawing 2ml, 4ml, 6 ml, 8 ml and 10 ml and transferred individually into 10
ml standard flask and the volume was made up to the mark using 6.6 Phosphate
buffer. The absorbance of the samples was observed using UV spectrophotometer
at a wavelength of 276 nm and a graph is plotted between concentration taken on
x-axis and absorbance taken on y-axis.
2.2.2 Determination of saturation solubility: [12]
The saturation solubility study was carried out to determine the
solubility of pure Diclofenac Potassium. Excess amount of drug was added to 250
ml conical flasks containing 100 ml of distilled water and the flasks were
subjected to shaking using rotary shaker. Then, the aliquots were withdrawn and
filtered through whatman filter paper. The absorbance of samples was determined
by UV spectrophotometer at 276 nm. Solubility was calculated using the formula
Solubility= (absorbance of sample/absorbance of standard solution) ×
concentration of standard solution × dilution factor
2.2.3 Determination of melting point by capillary method: [13]
A small amount (0.1-0.2g) of pure drug was transferred onto a watch
glass. One end of capillary tube of 5cm long was sealed and the solid was
introduced into a capillary tube and packed to a height of 3 cm. Then the
capillary tube was placed in melting point apparatus and the temperature at
which the melting of drug started was noted by using the thermometer placed in
the apparatus.
2.2.4 Fourier Transform Infrared spectrophotometry: [14]
FT-IR has been employed as a useful tool to identify the drug polymer
interaction. Pure drug 150mg and mixtures of drug 150mg and different polymers-
HPMC K 4M 225mg, Ethyl Cellulose 300mg, Carbopol 934 P 75mg were analyzed by
potassium bromide pellet method in an IR spectrophotometer in the region of
4000 to 400 cm-1. Then the spectra were compared with the reference spectrum
for diclofenac potassium and analyzed for drug-polymer interaction.
2.3 Formulation study:
2.3.1 Preparation of Buccal Films: [15]
Buccal films of Diclofenac Potassium were prepared by Solvent casting
technique using film forming mucoadhesive polymers. The calculated quantities
of polymers Hydroxy Propyl Methyl Cellulose K4M (HPMC), Ethyl cellulose and
Carbopol 934 P were dispersed in ethanol. An accurately weighed 150 mg of
Diclofenac Potassium was incorporated in polymeric solutions after levigation.
The solution was placed on a magnetic stirrer for 10-15 minutes to mix the
contents well. Then the prepared solution was poured into circular film moulds
which were previously wetted with liquid paraffin. The films were allowed to
dry at room temperature. After drying the films were carefully scraped out of
the moulds and stored properly.
Table
1: Composition of different mucoadhesive buccal films of Diclofenac Potassium
|
S.No
|
INGREDIENTS
|
QUANTITY
|
|
F1
|
F2
|
F3
|
|
1.
|
Diclofenac Potassium
|
150mg
|
150mg
|
150mg
|
|
2.
|
HPMC K4M
|
225mg
|
225mg
|
225mg
|
|
3.
|
Ethyl Cellulose
|
300mg
|
-
|
300mg
|
|
4.
|
Carbopol 934 P
|
-
|
75mg
|
75mg
|
|
5.
|
Ethanol
|
7ml
|
7ml
|
7ml
|
|
6.
|
Glycerine
|
0.15ml
|
0.15ml
|
0.15ml
|
2.4 Evaluation of Buccal Films: [15]
Formulated films were subjected to the evaluation tests for
characteristics such as appearance, surface texture, surface area, folding
endurance, swelling index and drug content. The in vitro release studies
were carried out by using Franz diffusion cell.
2.4.1 Appearance and surface texture:
The formulated films were evaluated for their physical appearance and
surface texture through visual inspection and by feel or touch.
2.4.2 Surface area:
The surface area was evaluated by measuring the diameter of the films
using a measuring scale. The test was performed in triplicate and the average
radius was taken. Surface area for circular films was calculated using the
formula, A = πr2 where r
is the radius of the film
2.4.3 Folding endurance:
Folding endurance of the films was determined by repeatedly folding one
film at the same place till it broke, which is considered satisfactory to
reveal good film properties. The number of times for which the films could be
folded at the same place without breaking gave the value of the folding
endurance. The test was conducted on three different films of each formulation
and the average value was calculated.
2.4.4 Swelling Index:
The film swelling studies were conducted in distilled water. The buccal
film of area 1 sq cm of each formulation was accurately weighed (W1 gm)
and placed in a petridish containing 20 ml of water. The weight of each film (W2
gm) was determined at 5th minute and 10th minute after
pressing the film with a tissue paper to remove the excess fluid. The swelling
index was calculated by the formula - Swelling index= (W2-W1)/W1 where W1 is initial weight
of the film and W2 is the weight of the film after swelling at
particular time period.
2.4.5 Drug Content:
A film of area 1cm2 was placed in a volumetric flask
containing 50 ml of phosphate buffer of pH 6.6 and kept aside for some time to
release the total drug present in the film and the volume was made up to 100 ml
with the same buffer. Then the absorbance was measured after suitable dilution
of sample at 276 nm against the blank solution as phosphate buffer of pH 6.6
and the content of Diclofenac potassium was calculated using standard graph.
2.4.6 In vitro drug release:
In vitro release studies were carried out by using Franz diffusion cell of 50 ml
capacity. A film of 1 sq cm area of each formulation was placed in the donor
compartment. The receptor compartment was filled with 50 ml of phosphate buffer
of pH 6.6. A teflon coated magnetic bead was placed in the receptor compartment
and the whole assembly was placed on magnetic stirrer operated at 50 rpm and
the temperature was maintained at 37±0.50C. Samples of 1 ml were withdrawn at regular
intervals, suitably diluted and absorbance was measured at 276 nm. The volume
of the receptor compartment was maintained constant by replacing equal volume of
buffer. A similar film devoid of drug but of same composition was taken and
diffusion study was carried out in a separate cell and the results were
tabulated.
3.0 RESULTS AND DISCUSSION:
The average saturation solubility of pure drug was found to be 7.214
mg/ml. The melting point for pure drug was found to be 2740 C. The
IR studies show no interaction between drug and excipients. However, additional
peaks were observed in physical mixtures which could be due to the presence of
polymers and indicated that there was no chemical interaction between the drug
and other excipients. The spectra of the polymers and the pure drug are given
in the figures 2, 3, 4, 5.
The films were white in colour with a smooth surface texture. The
physical evaluation of buccal films of Diclofenac potassium was given in table
2. The average surface area of all the formulations was found to be 30.17
square cm. The folding endurance was measured manually, by folding the films
repeatedly at a point till they broke. The breaking of the film was considered
as the end point. Flexible films were obtained for the formulations F2 and F3
while the formulation F1 containing HPMC and Ethyl cellulose polymers was
relatively more rigid. The swelling index values were given in table 3 and the
order of swelling index was found to be F2>F3>F1 and within the range of
0.96-3.42. Drug content for the formulations was found to be in the range of
91.58-98.65 % and the values were indicated in table 4. The in vitro
release studies were given in table 5 and the drug release profile implies that
there is a scope to obtain a sustained release for more than eight hours by
increasing the concentration.
Table 2: Development of
Calibration curve
|
S.No.
|
Concentration (µg/ml)
|
Absorbance
|
|
1.
|
2
|
0.061
|
|
2.
|
4
|
0.118
|
|
3.
|
6
|
0.186
|
|
4.
|
8
|
0.233
|
|
5.
|
10
|
0.297
|
Table 3: Solubility studies for
Diclofenac potassium
|
Trial number
|
Absorbance
|
Dilution factor
|
Solubility(mg/ml)
|
|
Trial 1
|
0.229
|
1000
|
7.387
|
|
Trial 2
|
0.233
|
1000
|
7.516
|
|
Trial 3
|
0.208
|
1000
|
6.709
|
Table 4: Melting point determination
by capillary method
|
Trial number
|
Melting point (0C)
|
|
Trial 1
|
274
|
|
Trial 2
|
274
|
|
Trial 3
|
275
|
Table 5: Physical evaluation of
Buccal films of Diclofenac potassium
|
S.No.
|
Formulation code
|
Colour
|
Surface texture
|
|
1.
|
F1
|
White
|
Smooth
|
|
2.
|
F2
|
White
|
Smooth
|
|
3.
|
F3
|
White
|
Smooth
|
Table 6: Swelling
index of buccal films
|
Formulations
|
Initial wt of
Film in mg (W1)
|
Final wt of
the film in mg (W2)
|
Swelling Index
(W2-W1)/W1
|
|
F1
|
66
|
130
|
0.96
|
|
F2
|
190
|
840
|
3.42
|
|
F3
|
105
|
420
|
3
|
4.0
CONCLUSION:
The present study indicates a good potential of
erodible mucoadhesive buccal films containing Diclofenac potassium for systemic
delivery with an added advantage of circumventing the hepatic first pass
metabolism. The results of the study show that therapeutic levels of the drug
can be delivered buccally. It may be concluded that films containing combination
of polymers HPMC K4M and Carbopol 934P showed good physical characteristics,
optimum swelling capacity and promising controlled drug release, thus seems to
be potential candidates for the development of buccal film for effective
therapeutic use.
5
.0 ACKNOWLEDGEMENT:
The authors wishes to acknowledge the authority of the
Acharya Nagarjuna University for providing the necessary chemicals and the
infrastructure required in the laboratory for the research work.
6.0
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