eISSN: 2231-0541
PHARMANEST
Revised: 20-09-2014
Available online: 10-11-2014
ABSTRACT
Buccal drug delivery has been considered as an alternative to oral dosing for compounds subjected to degradation in the gastrointestinal tract or to
hepatic first pass metabolism. An attempt has been made to develop buccoadhesive tablets comprising of drug containing bioadhesive layer and
drug free backing layer to release the drug for extended period of time with reduction in dosing frequency. Various formulations of
Fluvastatin buccal tablets were prepared by direct compression method using bioadhesive polymers like Carbopol 940, (HPMC)Methocel K15 and
Karaya gum, The physical characteristics, swelling index, surface pH, in-vitro bioadhesion strength and in-vitro release of formulated tablets were
shown to be dependent on characteristics and composition of bioadhesive materials used. The maximum bioadhesive strength was observed in
tablets formulated with karaya gum alone and strength decreases with its content. The tablets were evaluated for in vitro release in pH 6.8
phosphate buffer upto 12 hours using standardized apparatus. In order to determine the model of release, the data was subjected to Krosmeyer
and Peppas diffusion model. All the formulations followed non- Fickian release mechanism. Carbopol 940P and Methocel K4m can be used to design
effective and stable buccoadhesive tablets of Fluvastatin.
Key Words:
Buccal, Fluvastatin, HPMC K15, Carbopol, Karaya gum, HMG CoA Reductase Inhibitor.
INTRODUCTION
Among the various routes of drug delivery,
oral route is the most suitable and most
widely accepted one by the patients for the
delivery of the therapeutically active drugs.
But, after oral drug administration many drugs
are subjected to presystemic clearance in
liver, which often leads to a lack of correlation
between membrane permeability, absorption
and bioavailability. Within the oral route, the oral
cavity is an attractive site for drug delivery due to
ease of administration and avoids possible drug
degradation in the gastroretentive tract as well as
first pass hepatic metabolism.
Hyperlipidemia is a major cause of atherosclerosis
and its associated disorders like coronary heart
diseases, ischemic cerebrovascular diseases etc.
Recognition of hypercholestermia as a risk factor
has led to the development of drugs that reduces
cholesterol levels. Statins are the most effective
antihyperlipidemic
agents.
Statins
act
as
competitive inhibitors of HMG-CoA reductase which
catalyzes the step of cholesterol synthesis. Statins
also reduces the triglycerides levels caused by
elevated VLDL levels. All the statins are subjected
to extensive first past metabolism by liver and gut
wall enzymes, resulting in low systemic availability
of the parent compound. Fluvastatin is also
administered in its active form as a sodium salt and
is almost completely absorbed, but 50-80% of the
absorbed drug undergoes first pass metabolism
whereby it is converted to its inactive metabolites
which have a very short elimination half life.
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= Angle of repose
h = Height of the heap
r = Radius of the heap
Post-compression parameters:
Tablet Thickness: In this three tablets are
randomly taken and then their thickness and
diameter are measured by using vernier calipers or
by calibrated screw gauze.
Weight Variation Test: Twenty tablets are
selected and weighed individually. Then the
average weight and standard deviation is
calculated. Test passes when not more than two
tablets deviate from the average weight.
Hardness: It is expressed in kg/cm2 and is
measured using Monsanto hardness tester by
randomly picking three tablets. Hardness helps in
knowing the ability of tablet to withstand
mechanical shock during handling.
Friability: Ten tablets are selected, weighed and
then placed in friabilator, which is rotated for 4
minutes at 25 rpm. After 4 minutes, the tablets are
weighed again.
%F= [1-(Wt/W)]*100
If % Friability of tablets is less than 1% is
considered acceptable.
In Vitro Dissolution Studies: Dissolution study is
performed using USP paddle apparatus. Study is
carried out at 37oC temperature and 50 rpm. At
various time intervals, 5 ml sample is withdrawn
and is replaced with same amount of buffer
solution.
Drug Content Uniformity: Ten tablets are taken
and powdered, equivalent weight of drug dose is
measured and transferred to volumetric flask and
then buffer is added. Absorbance is determined
using U.V spectrophotometer.
Swelling Study: Initially tablet is weighed (W0)
and placed in a glass beaker, containing 200 mL of
0.1 N HCl. This is placed in a water bath
maintained at 37 0.5oC. At different time
intervals, the tablet is taken out and the excess of
liquid is carefully blotted by using a filter paper.
The swollen tablet is reweighed (Wt). The swelling
index (SI) is calculated using the formula.
SI=(Wt -W0/W0)*100
Wt (Weight of swollen tablet)
W0 (Initial weight of tablet)
F1
40
30
F2
40
40
2
4
124
2
4
114
Total
200
200
F3
40
50
F4
40
F5
40
F6
40
F7
40
F8
40
F9
40
30
40
50
2
4
104
2
4
124
2
4
114
2
4
104
30
2
4
124
40
2
4
114
50
2
4
104
200
200
200
200
200
200
200
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RESULTS
Determination of max
Vol
of
SSII In ml
Vol Made
Upto
Conc In
g/ml
Absorbance
At 240nm
50 ml
0.00
50ml
0.198
50ml
0.407
50ml
0.600
50ml
0.801
50ml
10
0.986
50ml
12
1.156
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Angle of Repose()
( SD)
23.20.11
23.70.08
24.70.16
24.70.12
24.20.09
25.10.11
24.20.12
23.70.09
24.20.13
Comment
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Formulation
Bulk Density
(g/cc) (
SD)
FM1
FM2
FM3
FM4
FM5
FM6
FM7
FM8
FM9
0.3010.07
0.3060.09
0.3040.09
0.3140.12
0.3080.14
0.3040.08
0.3180.09
0.3040.12
0.3120.15
Tapped
Density
(g/cc) (
SD)
0.350.05
0.340.09
0.360.11
0.350.08
0.350.09
0.350.08
0.360.13
0.340.09
0.360.11
Carrs Index
(%)
( SD)
Hausner
ratio
( SD)
14.10.06
11.70.05
15.50.09
10.20.06
12.30.13
13.30.08
11.90.11
11.30.05
13.80.05
1.160.05
1.110.07
1.180.05
1.110.09
1.130.06
1.150.09
1.130.07
1.120.05
1.160.07
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97.120.005
Wt
variation
1991.24
Thickness
(mm)
Hardness
2
(kg/cm )
%
Friability
2.710.017
7.60.34
0.470.002
F2
97.000.05
1981.20
2.720.020
7.260.23
0.510.005
F3
97.600.01
1991.25
2.720.020
6.130.11
0.520.005
F4
97.200.005
1981.123
2.710.017
7.86011
0.520.005
F5
97.400.05
1991.12
2.720.020
7.460.11
0.530.015
F6
97.000.04
1981.23
2.710.017
7.130.11
0.540.016
F7
97.520.15
1991.12
2.720.020
7.660.11
0.510.005
F8
97.560.17
1971.12
2.710.017
5.660.23
0.520.005
F9
97.280.10
1981.23
2.730.005
4.930.11
0.560.018
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0.5 hour
1 hour
2 hour
4 hour
6 hour
Code
F1
50.010.098
90.711.10
90.711.10
2600.78
275.001.89
F2
42.120.084
77.041.51
170.961.99
2002.12
220.052.22
F3
36.981.01
65.141.33
135.961.33
175.591.12
180.071.11
F4
46.140.088
82.960.052
185.581.01
225.541.23
250.201.99
F5
338.360.99
72.161.05
162.041.21
193.661.34
213.162.01
F6
34.310.65
59.530.78
130.421.57
171.330.95
177.000.00
F7
42.610.95
77.961.01
179.00.58
217.181.04
240.011.11
F8
55.661.16
100.561.47
219.841.99
267.532.01
280.001.66
F9
60.120.69
110.030.95
225.170.49
283.191.41
295.001.59
Dissolution studies:
The prepared tablets were subjected to
dissolution studies in order to know
*Standard deviation, n = 3
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Zero
First
Higuchi
Peppas
Regression Values
0.962
0.92
0.953
0.739
Balancing
Trial l
Trial II
Trial
Average Bioadhesive
Code
weight
F1
6.55gm
22.85
22.50
23.00
23.11
16.56gm
F2
6.55gm
29.99
30.50
30.00
30.16
23.61gm
F3
6.55gm
27.95
28.10
28.00
28.01
21.46gm
F4
6.55gm
36.11
36.00
36.25
36.12
29.57gm
F5
6.55gm
28.97
28.50
29.00
28.82
22.27gm
F6
6.55gm
28.97
28.00
28.40
28.46
21.90gm
F7
6.55gm
32.03
32.30
32.00
32.17
25.62gm
F8
6.55gm
21.84
21.50
22.00
21.78
15.23gm
F9
6.55gm
41.21
41.21
41.00
41.14
III
Strength
34.59gm
P a g e | 2507
F1
0.15
F2
0.23
F3
0.21
F4
0.29
F5
0.21
F6
0.21
F7
0.25
F8
0.14
F9
0.33
DISCUSSION
In the present investigation an attempt was made
to design Mucoadhesive buccal tablets containing
Fluvastatin. It has short biological half life of 3
hours, and is used orally in dose of,20,40,80 g
twice or thrice a day.The conventional dosage
forms
available
are
associated
with
low
bioavailability problems due to extensive first pass
metabolism & characterized by short biological half
life, due to which frequency of dosing is increased,
which results in patient incompliance. The present
investigation was aimed at avoidance of first pass
metabolism
of
Fluvastatin
by
preparing
mucoadhesive tablets for delivery of the drug via
buccal route.
Fluvastatin
is
an
antilipemic
agent
that
competitively inhibits hydroxyl methyl glutarylcoenzyme A (HMG-CoA) reductase. HMG-CoA
reductase catalyzes the conversion of HMG-CoA to
mevalonic acid, the rate-limiting step in cholesterol
biosynthesis. Fluvastatin belongs to a class of
medications called statins and is used to reduce
plasma
cholesterol
levels
and
prevent
cardiovascular disease. It is also the first entirely
synthetic HMG-CoA reductase inhibitor and is
structurally distinct.
PREFORMULATION STUDIES:
SPECTROSCOPIC STUDIES: Determination of
max
A solution of 10g/ml of Fluvastatin was
scanned in the range of 200 to 400nm. The
drug exhibited max at 240nm in Phosphate
buffer pH 6.8 and had good reproducibility.
Correlation between the concentration and
absorbance was found to be nearer to 1, with a
slope of 0.999.
COMPATIBILITY STUDIES:
Drug polymer compatibility studies were carried
out
using
Fourier
Transform
Infra
Red
spectroscopy to establish any possible interaction
of Fluvastatin with the polymers used in the
formulation. The FT-IR spectra of the formulations
were compared with the FT-IR spectra of the pure
drug.The results indicated that the characteristic
absorption peaks due to pure Fluvastatin have
appeared in the formulations, without any
Among
the
non-invasive
routes
buccal
administration has a promising potential and is a
viable alternative for systemic medication of drugs.
The buccal cavity offers a large surface area,
highly vascularised mucosal layer for efficient
absorption; also blood is drained directly from
buccal cavity into the systemic circulation, thereby
avoiding the first pass effect, combined with other
features
like
ease
and
convenience
of
administration.
Mucoadhesive tablets have the ability to increase
the drug residence in the buccal cavity, control the
rate of drug clearance as well as protect the drug
form enzymatic degradation (in stomach). The
mucoadhesive buccal tablets release the drug in a
sustained manner, leading to reduced fluctuations
in the plasma level which results in reduced
toxicity and adverse reactions.
In the present study, mucoadhesive tablets were
prepared by direct compression method, using
different polymers like Carbopol, HPMC K15M &
Karaya gum, in different ratios in O r d e r t o
release the drug in unidirectionally.
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P a g e | 2509
variation
content
uniformity and showed
acceptable results with respect to drug
content and percentage friability (0.47-0.56%).
S w e l l i n g index was calculated with respect
to time. Swelling index increased as
the
weight
gain
by
the
tablets
increased
proportionally with rate of hydration. The
swelling indices of tablets with Carbopol and
HPMC increased with increasing amounts of
Carbopol. Maximum swelling was seen with
formulations (F9, F10, F8 and F1) containing
NaCMC and or Carbopol, the values increased
with increasing amounts of NaCMC and or
Carbopol.
Analysis of drug release mechanism showed
that the drug release followed non-Fickian
diffusion and the best fit model was found to be
st
1 order.
The bioadhesion characteristics were found to
be affected by the nature and proportions of
bioadhesive
polymers
used.
The
highest
adhesion
force
i.e. highest
strength of
muccoadhesive
bond
was
observed
with
formulation F1 containing only Carbopol this
followed by F4 and F7 formulations containing
Carbopol: HPMC K4M and Carbopol:
HPMC
K15M, respectively. Adhesion force decreased
as another polymer is mixed with Carbopol.
Tablets containing NaCMC showed least adhesion
force than tablet of all other formulations, which
is due to low viscosity of NaCMC. These
observations indicate that the bioadhesive
strength of Carbopol is much more than NaCMC.
After all the evaluation tests formulation
coded F9 was selected for stability studies and
the results revealed no significant change in %
drug content and physical characters. Stability
studies indicated that the selected formulation
was stable.
Based on the results of evaluation tests and
stability tests formulation F9 was concluded as
best formulation for buccal drug delivery system.
CONFLICT OF INTEREST
Authors declare no Conflict of Interest.
REFERENCES
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