Vol-3, Issue-4, Suppl-1, Nov 2012 ISSN: 0976-7908 Bhavsar et al www.pharmasm.com IC Value – 4.01 2559 PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES FORMULATION AND IN-VITRO EVALUATION OF MUCOADHESIVE BUCCAL TABLET OF FAMOTIDINE Jalpeshkumar D. Bhavsar*, Mukesh R. Patel, Kanu R. Patel, N.M.Patel Shri B. M. Shah College of Pharmaceutical Education & Research, College Campus, Dhansura Road, Modasa, Dist. Sabarkantha, 383350, Gujarat, India. ABSTRACT Famotidine is histamine –H 2 receptor antagonist. It has bioavailability of 40 to 45% and it has shorter plasma half-life of 2.5 to 3.5 hrs. The effective treatment of erosive esophagitis and Zolinger-Elisons syndrome requires administration of 20 mg of Famotidine 4 times a day. A conventional dose of 20 mg can inhibit gastric acid secretion up to 5 hours but not up to 10 hours. An alternative dose of 40 mg leads to plasma fluctuations; thus a sustained release dosage form of famotidine is desirable. Direct access to the systemic circulation bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Moreover, the buccal route is easily accessible, has a good patient compliance and can be used in patients who can’t swallow. Bilayer buccal tablet was prepared by using mucoadhesive polymers combination of Sodium CMC and Carbopol934P, by direct compression with backing layer of Ethyl cellulose. The formulation was optimized by 3 2 full factorial statistical design by selecting independable variables Ratio of polymer as factor X 1 and Concentration of polymer as factor X 2. The prepared formulations were evaluated for various evaluation studies. Statistical analysis as well as kinetic studies performed. Statistical study showed that both factors X 1 and X 2 had significant effect on dependable variables Q4 (P=0.005), Q8 (P=0.013), Mucoadhesive strength (P=0.000) and Swelling index (Except factor X 1 for swelling index) (P=0.001). Formulation F1 was selected as an optimum formulation as it shows more similarity in dissolution profile with theoretical profile (f 2 = 65.76 and f 1 = 7.04). The optimized formulation F1 had given release of 102.57% in 8hrs and it had optimum swelling, mucoadhesive property and permeation from buccal mucosa. It also had desired drug release kinetics and found to be stable for the period of 1 month. Keywords: Buccal tablet, Swelling index, Bioadhesive strength, Famotidine. INTRODUCTION After oral administration many drugs are subjected to presystemic clearance extensive in liver, which often leads to a lack of significant correlation between membrane permeability, absorption, and bioavailability. Difficulties associated with parenteral delivery and poor oral availability provided the impetus for exploring alternative routes for the delivery of such drugs. These include routes such as pulmonary, ocular, nasal, rectal, buccal, sublingual, vaginal, and transdermal. Among the various transmucosal
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Vol-3, Issue-4, Suppl-1, Nov 2012 ISSN: 0976-7908 Bhavsar et al
www.pharmasm.com IC Value – 4.01 2559
PHARMA SCIENCE MONITOR
AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES
FORMULATION AND IN-VITRO EVALUATION OF MUCOADHESIVE
BUCCAL TABLET OF FAMOTIDINE
Jalpeshkumar D. Bhavsar*, Mukesh R. Patel, Kanu R. Patel, N.M.Patel
Shri B. M. Shah College of Pharmaceutical Education & Research, College Campus, Dhansura Road, Modasa, Dist. Sabarkantha, 383350, Gujarat, India.
ABSTRACT Famotidine is histamine –H2 receptor antagonist. It has bioavailability of 40 to 45% and it has shorter plasma half-life of 2.5 to 3.5 hrs. The effective treatment of erosive esophagitis and Zolinger-Elisons syndrome requires administration of 20 mg of Famotidine 4 times a day. A conventional dose of 20 mg can inhibit gastric acid secretion up to 5 hours but not up to 10 hours. An alternative dose of 40 mg leads to plasma fluctuations; thus a sustained release dosage form of famotidine is desirable. Direct access to the systemic circulation bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Moreover, the buccal route is easily accessible, has a good patient compliance and can be used in patients who can’t swallow. Bilayer buccal tablet was prepared by using mucoadhesive polymers combination of Sodium CMC and Carbopol934P, by direct compression with backing layer of Ethyl cellulose. The formulation was optimized by 32 full factorial statistical design by selecting independable variables Ratio of polymer as factor X1 and Concentration of polymer as factor X2. The prepared formulations were evaluated for various evaluation studies. Statistical analysis as well as kinetic studies performed. Statistical study showed that both factors X1 and X2 had significant effect on dependable variables Q4 (P=0.005), Q8 (P=0.013), Mucoadhesive strength (P=0.000) and Swelling index (Except factor X1 for swelling index) (P=0.001). Formulation F1 was selected as an optimum formulation as it shows more similarity in dissolution profile with theoretical profile (f2 = 65.76 and f1 = 7.04). The optimized formulation F1 had given release of 102.57% in 8hrs and it had optimum swelling, mucoadhesive property and permeation from buccal mucosa. It also had desired drug release kinetics and found to be stable for the period of 1 month. Keywords: Buccal tablet, Swelling index, Bioadhesive strength, Famotidine. INTRODUCTION
After oral administration many drugs are subjected to presystemic clearance extensive in
liver, which often leads to a lack of significant correlation between membrane
permeability, absorption, and bioavailability. Difficulties associated with parenteral
delivery and poor oral availability provided the impetus for exploring alternative routes
for the delivery of such drugs. These include routes such as pulmonary, ocular, nasal,
rectal, buccal, sublingual, vaginal, and transdermal. Among the various transmucosal
Vol-3, Issue-4, Suppl-1, Nov 2012 ISSN: 0976-7908 Bhavsar et al
www.pharmasm.com IC Value – 4.01 2560
routes, buccal mucosa has excellent accessibility, an expanse of smooth muscle and
relatively immobile mucosa, hence suitable for administration of retentive dosage forms.
Direct access to the systemic circulation through the internal jugular vein bypasses drugs
from the hepatic first pass metabolism leading to high bioavailability [1].
Buccal route is advantageous due to, No hepatic first-pass effect, No pre-systemic
metabolism in the gastrointestinal tract, Ease of administration, Fast onset of action, No,
or little, irritation expected, Patient compliance, Low enzymatic activity, Painless
administration, Easy drug withdrawal, Facility to include permeation enhancer/enzyme
inhibitor or pH modifier in the formulation, Versatility in designing as multidirectional or
unidirectional release systems for local or systemic actions [2].
Famotidine is a competitive inhibitor of histamine H2-receptors. Primary clinically
important pharmacological activity of famotidine is inhibition of gastric secretion [3].
Both the acid concentration and volume of basal, nocturnal and stimulated gastric
secretion are suppressed by famotidine. It is commonly used in benign gastric ulcer,
duodenal ulcer, Gastro esophageal reflux disease and Zolinger-Elisons syndrome. It has
bioavailability of 40 to 45% due to extensive first pass metabolism and peak plasma
reaches within 1 to 3 hrs. It has a half-life of 2.5 to 3.5 hours [4]. The effective treatment
of erosive esophagitis and Zolinger-Elisons syndrome requires administration of 20 mg
of Famotidine 4 times a day [5]. A conventional dose of 20 mg can inhibit gastric acid
secretion up to 5 hours but not up to 10 hours. An alternative dose of 40 mg leads to
plasma fluctuations; thus a sustained release dosage form of famotidine is desirable.
Rationale for development of this formulation is improvement of bioavailability by
avoiding first pass metabolism through buccal delivery of drug; More absorption of drug
due to pka value of 7.1 which gives more unionized species for absorption at pH between
6.8 to 7.4 in buccal region; Low molecular weight (<500 D) of drug also contributes to
permeability of it through buccal mucosa; Half life of drug between 2.5 to 3.4 hr
promotes for sustained delivery of drug through buccal mucosa; Develop formulation
with unidirectional drug release.
MATERIALS AND METHODS
Materials
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Famotidine was received as a gift sample from Panchsheel organics ltd. (Ahmedabad,
India). Sodium Carboxy methyl cellulose and Carbopol 934P were purchased from Loba
chemie ltd. (Mumbai, India). Lactose were purchased from Finar Chemicals Ltd.
(Ahmedabad, India). Aspartame were provided from college. All ingredients used in
study are of analytical grade.
Formulation of mucoadhesive buccal tablet:
Direct double compression technique was employed for the formulation. In this
technique, first intermediate layer was formed and blend of second layer was placed on
first intermediate layer and compressed to get bilayer tablet (Figure 1). Compositions of
the core layer contain drug, mucoadhesive polymers (carbopol-934P, Sodium carboxy
methyl cellulose), lactose, Aspartame and lubricant, for backing layer ethyl cellulose
was used. The physical blend of drug, polymers and excipients was properly mixed and
passed through 60 mesh screen, and then it was slightly compressed by using 8 mm flat
faced punch in Rimek 10 station rotary press to obtain intermediate tablet or loose
compact. Similarly, blend of backing layer containing ethyl cellulose was mixed, sieved
and compressed on the previously compressed intermediate tablet or loose compact to
get bilayer tablet. The hardness of the obtained tablets was found 6-7 kg/cm2.
.
Bilayer buccal tablet. EXPERIMENTAL DESIGN:
A 32 randomized full factorial design was employed in the present study. In this design 2
factors were evaluated, each at 3 levels, and experimental trials were performed for all 9
possible combinations. The ratio of polymer (Sodium CMC: Carbopol 934P) (X1) and
concentration of polymer (X2) were chosen as independent variables in 32 full factorial
design, while Q4, Q8 (% drug release after 4, 8 hours respectively), % swelling index,
Bioadhesive strength, diffusion coefficient (n), release rate constant (K) were taken as
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dependent variables. The composition of factorial design batches (F1-F9) is shown in
Table 1 and Table 2. The prepared formulations were evaluated for in vitro release study,
Swelling index, Bioadhesive strength, in vitro residence time, Surface pH, hardness,
friability, drug content, weight variation test. Statistical treatment was carried out to the
factorial design batches using statistica software.
TABLE 1: CODING OF VARIABLE
32 Full factorial design
X1 Polymer ratio (Sodium CMC: Carbopol 934P)
X2 Polymer concentration
Levels
-1 1:2
Levels
-1 15%
0 1:1 0 20%
1 2:1 1 25%
TABLE 2: FORMULATION OF FACTORIAL BATCHES
Formulation Code F1 F2 F3 F4 F5 F6 F7 F8 F9
Ingr
edie
nts
(m
g)
Famotidine 20 20 20 20 20 20 20 20 20
Sodium CMC 5 8 10 7 10 13 8 13 17
Carbopol 934P 10 8 5 13 10 7 17 13 8
Lactose 60 60 60 55 55 55 50 50 50
Magnesium Stearate
1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1
Aspartame 2 2 2 2 2 2 2 2 2
Ethyl Cellulose 50 50 50 50 50 50 50 50 50
Total weight in mg 150 150 150 150 150 150 150 150 150
CHARACTERIZATION OF BUCCAL TABLET:
Drug Excipient Compatibility Study:
Ø FTIR Spectral studies:
Drug- excipients interactions play a vital role in the release of drug from formulation.
Fourier transform infrared spectroscopy has been used to study the physical and chemical
interactions between drug and the excipients used. Fourier transform infrared (FTIR)
spectra of Famotidine and mixture of Famotidine: Sodium carboxy methyl cellulose:
Vol-3, Issue-4, Suppl-1, Nov 2012 ISSN: 0976-7908 Bhavsar et al
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Carbopol 934P were recorded using KBr mixing method on FTIR instrument of the
institute.
Ø Differential Scanning Calorimeter (DSC):
Thermograms were obtained by using differential scanning calorimeter at a heating rate
20°C/min. over a temperature range of 50-300°C by using instrument DSC instrument.
The sample was hermetically sealed in an aluminum crucible. Thermograms of drug and
formulation were compared for any disappearance or shifting in characteristic peak of
drug melting point.
Weight Variation Test [6]:
Twenty tablets were selected at random, weighed and the average weight was calculated.
Not more than two of the individual weights should deviate from the average weight by
more than 7.5 % as per IP.
Friability [6]:
For each formulation, pre weighed tablet sample (20 tablets) were placed in the Roche
friabilator which is then operated for 100 revolutions. The tablets were deducted and
reweighed. Conventional compressed tablets that loose <1% of their weight are
considered acceptable.
Hardness [6]:
Hardness of tablet was determined using Monsanto hardness tester.
Content Uniformity [6]:
Twenty tablets were weighed and powdered in a glass mortar. Quantity of powder
equivalent to 20 mg of Famotidine was accurately weighed and transferred to 100 ml pH
6.8 phosphate buffer in volumetric flask. From the resulting solution 10 ml of the sample
was withdrawn and adjusted final volume in volumetric flask up to 100 ml using pH 6.8
phosphate buffer. The solution was analyzed at λmax value of 272 nm by using UV-
Visible spectrophotometer. The content of drug was calculated from calibration curve.
In Vitro Swelling or Swelling Index [7]:
This test was carried out by using Petri dishes having 10 ml of phosphate buffer of pH 6.8
and tablet was placed in Petri dish. The initial weights of the drug loaded tablets in each
batch were determined (W0) using an electronic balance. Tablets from each batch were
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removed at different time intervals (1, 2, 3, 4, 6 and 8 hrs), wiped with filter paper to
remove excess water from the tablet surface, and then reweighed (W1). The swelling
index (% w/w) was determined from the following relationship and plotted against time.
The experiment was performed in triplicate. (Eq.1)
Swelling index (1)
In Vitro Mucoadhesive strength test [8]:
Mucoadhesive strength of the buccal tablets was measured by using the modified
physical balance. The test assembly was fabricated as shown in schematic presentation
(Figure 1). This method involves the use of goat buccal mucosa as the model mucosal
membrane. The fresh goat buccal mucosa was purchased from slaughter house and it was
then washed in isotonic phosphate buffer pH 6.8. The two sides of the balance were
balanced with a 5 gm weight on the right hand side. A piece of fresh membrane was
glued to a support (glass block) with cyanoacrylate adhesive. The block was then lowered
into the glass container, which was then filled with isotonic phosphate buffer pH 6.8 kept
at 37± 1 °C, such that the buffer just reaches the surface of mucosal membrane, and keeps
it moist. This was then kept below the left hand setup of the balance. The test
mucoadhesive tablet was glued with the same adhesive to a rubber block hanging on the
left hand side and the balance beam raised with the 5 gm weight on the right pan was
removed off the weight. This lowered the rubber block along with the tablet over the
mucosa with a weight of 5 gm. The balance was kept in this position for 3 minutes and
then slowly water was added to the plastic container in the right pan by pipette. The
detachment of two surfaces was obtained. Weight of water was measured. Then the
Mucoadhesive strength of tablet was calculated. Three tablets were tested on each goat
buccal mucosal membrane. After each measurement, the tissues were gently and
thoroughly washed with phosphate buffer pH 6.8 and left for 5 minutes before the next
experiment. Fresh membrane was used for each batch of tablets. The experiment was
performed in triplicate.
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Figure 1 Modified balance assembly for in vitro mucoadhesive strength test
1. Rubber block
2. Mucoadhesive tablet
3. Glass block
4. pH 6.8 phosphate buffer
5. Buccal mucosa
In Vitro Residence time test [9]:
The in vitro residence time is one of the most important physical parameters of buccal
tablet. A buccal tablet was pressed over the excised goat buccal mucosa for 30 sec after
previously being secured on a glass slide and was immersed in a beaker containing 500
ml of pH 6.8 isotonic phosphate buffer, at 37±0.2°C. One stirrer was fitted at a distance
of 5 cm from the tablet and rotated at 25 rpm. The time for complete erosion or
detachment of the tablet from the mucosa was recorded.
Surface pH measurement [7]:
The buccal tablets were first allowed to swell by keeping them in contact with 5 ml of pH
6.8 phosphate buffer for 2 hrs. The surface pH was then found by bringing a combined
glass electrode near the surface of the tablets and allowing the reading to stabilize for at
least 1 min. The measurements were taken in triplicate for each batch of the buccal
tablets.
In Vitro Dissolution study [7]:
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The USP type II rotating paddle method was used to study the drug release from the
bilayer tablet. The dissolution medium consisted of 500 ml of pH 6.8 phosphate buffer.
The release study was performed at 37 ± 0.5°C, with a rotation speed of 50 rpm. The
backing layer of the buccal tablet was attached to the glass slide with cyanoacrylate
adhesive. The disk was placed at the bottom of the dissolution vessel. Aliquots were
withdrawn at regular time intervals and replaced with fresh medium to maintain sink
conditions. The samples were filtered, made appropriate dilutions with phosphate buffer
and were thereafter analyzed spectrophotometrically at λmax value of 272 nm using a
Shimadzu UV-Visible1800 double-beam spectrophotometer. Cumulative percentage drug
release was calculated using an equation obtained from a calibration curve which was
developed in the range of 5-35µg/ml for pH-6.8 phosphate buffer. The experiment was
performed in triplicate.
Ex vivo permeation study [10]:
Figure 2 Ex vivo permeation study by Franz-diffusion apparatus
The fresh goat buccal mucosal membrane was obtained from slaughter house. It was than
excised by removing the underlying connective and adipose tissue and was equilibrated at
37 ± 1.0 C for 30 min in pH 6.8 isotonic phosphate buffer. The buccal epithelium was
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carefully mounted in between the two compartments of Franz Diffusion Cell. Tablets
were stuck to the mucosa in the donor side containing pH 6.8 phosphate buffer. Receiver
medium was 20 ml of pH 6.8 phosphate buffer maintained at 37 ± 0.5 C under gentle
stirring. From the receiver compartment, 5 ml aliquots were collected at predetermined
time intervals and replaced by an amount of fresh buffer. The samples removed were
filtered, diluted and analyzed at λmax value of 272 nm using a Shimadzu UV-Visible 1800
double-beam spectrophotometer. The schematic representation of franz diffusion
apparatus was displayed in Figure 2.
Kinetic Modeling of Dissolution Data:
The dissolution profile of all batches were fitted to various models such as zero order[11],
first order[11], Higuchi [12], Korsmeyer and Peppas [13] to ascertain the kinetic of drug
release.
Comparison of Dissolution Profiles for Selection Optimum Batch [14]:
Ø Similarity factor (f2):
The similarity factor (f2) given by SUPAC guidelines for a modified release dosage
form was used as a basis to compare dissolution profiles. The dissolution profiles are
considered to be similar when f2 is between 50 and 100. The dissolution profile of
products were compared using a f2 which is calculated from following formula:
(Eq.2)
( )
−
+=
−
=∑ 10011logX50 X
5.02
12
n
tttt TRw
nf (2)
Where, n is the dissolution time and Rt and Tt are the reference (here is the theoretical
dissolution profile of Famotidine) and test dissolution value at time t respectively.
Optimized batch was compared with theoretical profile for calculation of similarity
factor.
Ø Dissimilarity factor (f1):
The dissimilarity factor (f1) calculates the percent difference between the two curves
at each time point and is a measurement of the relative error between the two curves:
(Eq.3)
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100×Rt /|Tt-Rt|11
1
= ∑∑
==
n
t
n
t
nnf
(3)
Where: n is the number of time points, Rt is the dissolution value of the theoretical
dissolution profile at time t and Tt is the dissolution value of the formulation at time t.
The values should lie between 0-15. For curves to be considered similar f1 values
should be close to 0.
Stability Study of Optimized Batch:
To determine the change in physical properties and in vitro release profile on storage
optimized batch tablets were stored at 40ºC ± 5ºC and 75% ± 5% relative humidity in
stability chamber. Samples were evaluated at 1 month time for in vitro dissolution study.
RESULT AND DISCUSSION
Drug Excipient Compatibility Study
FTIR Spectral studies:
The Famotidine exhibits peaks due to sulphonamide (1331.89 cm-1), amine (3104.53 cm-
1) and alkene (719.47 cm-1, 1161.19 cm-1) groups. It was observed that there were no
changes in these main peaks in the FTIR spectra of a mixture of drug and polymers
(Figure 3). Hence, it was concluded that no physical or chemical interactions of
Famotidine with Sodium CMC, Carbopol 934P and other excipients.
400600800120016002000280036001/cm
15
30
45
60
75
90
105
120
%T
3506
.7034
00.62
3237
.63
3103
.57
1638
.58 1331
.89
1171
.7911
61.19 71
9.47
3505
.7434
00.62
3235
.70
3104
.53
1638
.58 1331
.89
1171
.7911
47.68
720.4
4Famotidine + Formulation
Smooth
Famotidine + Formulation
Figure 3 FTIR spectra of Famotidine + Formulation
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Differential Scanning Calorimeter (DSC):
On comparison with thermogram of pure drug and formulation showed no shift or
disappearance of characteristic peak of drug melting point suggesting that there was no
interaction of Famotidine with Sodium CMC, Carbopol 934P and other excipients.
(Figure 4 and 5)
50.00 100.00 150.00 200.00 250.00 300.00Temp [C]
-30.00
-20.00
-10.00
0.00
mWDSC
167.47 C
Thermal Analysis Result
Figure 4 DSC of Famotidine
50.00 100.00 150.00 200.00 250.00 300.00Temp [C]
-10.00
-5.00
0.00
5.00
mWDSC
164.71 C
249.72 C78.22 C
Thermal Analysis Result
Figure 5 DSC of Formulation
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Physicochemical Evaluation of Factorial Batches:
In weight variation test, the Pharmacopoeia limit (IP) for percent of deviation for tablet is
± 7.5%. The average percent deviation of all tablets was found to be within the limit.
Hence, all formulations complies the weight variation test as per IP. All formulations also
comply friability (<1%) and drug content as per IP. All formulations showed tablet
thickness in range of 2.02 to 2.16 mm and surface pH between 6.24 to 6.75 (Table 3).
TABLE 3: PHYSICOCHEMICAL EVALUATION OF FACTORIAL BATCHES
In vitro Dissolution Study:
For investigation purpose 32 full factorial design was chosen to check the effect of
polymer in matrix tablet, in which Ratio of polymer sodium CMC: carbopol 934P as
factor X1 and Concentration of polymer as factor X2 was selected (Table 1). From result
of in vitro release study of 8 hrs of all 9 (F1 to F9) batches it was observed that as there
was increase in concentration of polymer (X2) there was release retarding effect of
concentration of polymer factor (X2). Factor (X1) ratio of polymer had relative effect on
release profile based on fraction of individual polymer. As the fraction of sodium CMC
increases there was more release retardation due to its viscosity building property, it