1.
INTRODUCTION:
The buccal mucosa has been investigated for
local and systemic delivery of therapeutic peptides and other drugs that are
subjected to first-pass metabolism or are unstable within the rest of the
gastrointestinal tract1–3. One method of optimizing drug
delivery is by the use of adhesive dosage forms. A bioadhesive has been defined
as a synthetic or biological material, which is capable of adhering to a
biological substrate or tissue4. When the biological substrate is mucus, the term
“mucoadhesive” has been employed5.
Mucosal-adhesive materials are hydrophilic macromolecules containing numerous
hydrogen bond-forming groups6.
Bioadhesive polymers not only cause the adhesion effects, but also control the
release rate of drug7.
Sustained release systems
include any drug delivery system that "achieves slow release of drug over
an extended period of time". If the system can provide some control,
whether if the system is successful in maintaining constant drug levels in the
target tissue or cells, it is considered a controlled release system.
If it is unsuccessful at
this, nevertheless extends the duration of action over that achieved by
conventional delivery; it is considered a prolonged-released system.8
Oral mucosal drug delivery is an alternative method of systemic drug delivery
that offers several advantages over both injectable and eternal methods.
Because the oral mucosa is highly vascularised, drugs that are absorbed through
the oral mucosa directly enter the systemic circulation, bypassing the
gastrointestinal tract and first-pass metabolism in the liver. For some drugs,
this results in rapid onset of action via a more comfortable and convenient
delivery route than the intravenous route.9.
Metoprolol is a b1-selective (cardio
selective) adrenergic receptor blocking agent preferential at higher plasma
concentrations, Metoprolol also inhibits b2-adrenoreceptors, chiefly located in the bronchial and
vascular musculature. Animal and human experiments indicate that Metoprolol
slows the sinus rate and decreases AV nodal conduction. Although b-adrenergic
receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which
sympathetic stimulation is vital. In patients with severely damaged hearts,
adequate ventricular function may depend on sympathetic drive. Metoprolol
Succinate is completely absorbed after oral administration. Owing to the
extensive first-pass effect, the systemic bioavailability of Metoprolol from
single oral dose is approximately 50%. The bioavailability is reduced by about
20-30% for controlled-release preparation compared with conventional tablet.
2.
MATERIAL AND
METHODS:
Material:
Metoprolol Succinate,
Carbopol 934 P & HPMC K4M was obtained from Alkem labs., Navi Mumbai, Magnesium stearate Starch (Vama pharmaceuticals Pvt.
Ltd, Nagpur). All chemicals used were of analytical grade.
Methods:
2.1 FORMULATION OF BUCCOADHESIVE TABLETS:
The buccoadhesive tablets were prepared with selected
polymers by direct compression on sixteen punches tablet machine (Prism Pvt.
Ltd.).
All the ingredients were passed through sieve no. 200
(75 µm); accurately weighed quantities of drug and ingredients viz. polymers,
starch, and Colloidal silicon dioxide were mixed by triturating in a glass
mortar-pestle. The blend was directly compressed at weight of 124 mg, using
flat-faced 8mm diameter punch. The hardness during compression was kept at 100
N. The composition of the formulation batches containing combination of
different polymer in various ratios are specified in table 1.
2.2 Drug content:
Randomly twenty tablets from
each batch were weighed accurately & powdered; the equivalent weight of
100mg Metoprolol succinate was taken & made the volume up to 100ml with
distilled water in a 100ml volumetric flask. From this 1ml was pipette out and
then dilute up to 100ml in 100ml volumetric flask, resulting solution was
analyzed at 280nm using spectrophotometer & content of Metoprolol succinate
was calculated. Results are shown in Table No. 5.
2.3 Surface pH
determination of mucoadhesive buccal tablets:10
The surface pH of the tablets was determined
in order to investigate the possibility of any side effects, on the oral
cavity. As acidic or alkaline pH is found to cause irritation to the buccal
mucosa, hence attempt was made to keep the surface pH close to neutral pH.
Mucoadhesive buccal tablets were left to swell for 2 hours on the surface of an
agar plate. The surface pH was measured by means of a pH paper placed on the
surface of the swollen tablets. A mean of two readings was recorded. Tablets
from all batches had shown a surface pH in the range of 5 to 7. Surface
pH values are shown in Table no.5.
2.4 In-Vitro Mucoadhesive Study:11
Mucoadhesive strength of the tablets was
measured on a modified physical balance. The apparatus consist of a modified
double beam physical balance in which the right pan had been replaced by a
lighter pan and the left pan had been replaced by Teflon cylinder (1.5 cm
diameter and 3 cm height) suspended by Teflon rings and copper wire. Porcine
buccal mucosa was used as the model membrane and phosphate buffer pH 6.8 was
used as the moistening fluid. The goat cheek mucosa obtained from abattoir
house was kept in Krebs buffer at 37 0C for 2 hours. The underlying
mucous membrane was separated and was washed thoroughly with phosphate buffer
pH 6.8. It was then tied over the protrusion in the Teflon block using a
thread. The block was then kept in Petri dish. The glass container filled with
moistening fluid i.e. phosphate buffer pH 6.8 was used to keep the mucosal
membrane moistened. The weights on the right hand side were slowly added in an
increment of 0.5g till the tablet just separated from the membrane surface. The
excess weight on the right pan i.e. total weight minus 5g was taken as a
measure of the mucoadhesive strength. From the mucoadhesive strength following
parameters was calculated
Mucoadhesive
strength
Force of adhesion (N) =
---------------------------- X 9.81
100
The measured values of various mucoadhesion
parameters are summarized in Table No.6 and plot of force of adhesion (N) v/s
batch code is depicted in Figure No 2.
Figure No. 1: Mucoadhesive test assembly
Where,
A – Right pan, B – Left light pan, C –
Teflon Block, D – Goat cheek membrane, E – Teflon coated glass slide, F –
Beaker containing 6.8 pH phosphate buffer, G – Threads, H – Pointer, I – Scale
2.5 In Vitro Release Study:
2.5 A. In vitro release study in phosphate buffer pH
6.8:
Standard USP II six station
dissolution apparatus have been used to study in vitro release profile using
paddle. In vitro release rate study of mucoadhesive tablet of Metoprolol
succinate was carried out using the Apparatus 2 (paddle apparatus) method.
Place the tablet in a dry basket at the beginning of each test. Lower the
basket before rotation operates the apparatus immediately at 50 rpm. Operating
parameters are given in table No 2.The results was shown in Table No. 8 and
Figure No. 4.
Table No. 2: Operating parameters for in vitro
release studies of Metoprolol
succinate tablets in phosphate buffer pH 6.8.
|
Sr. no
|
 Operating parameters
|
Value
|
|
1
|
Method and rotation speed Paddle
|
50 rpm
|
|
2
|
Dissolution medium (pH and volume)
|
pH 6.8 solution; 500 ml
|
|
3
|
Temperature
|
37 ± 0.5 0C Crystals
|
|
4
|
Time interval for sampling
|
60 min.
|
|
5
|
Sample volume
|
10 ml
|
|
6
|
Wavelength
|
280
|
The % cumulative release of Metoprolol
succinate was calculated .The observations for different batches are shown in
succeeding tables. The cumulative percentage release of Metoprolol succinate
with respect to time for each batch, are graphically shown below.
2.5 B. In vitro release study in Simulated
Saliva Fluid pH 6.2
Standard USP II six station dissolution
apparatus have been used to study in vitro release profile using paddle.
In vitro release rate study of mucoadhesive tablet of Metoprolol succinate was
carried out using the Apparatus 2 (paddle apparatus) method. Place
the tablet in a dry basket at the beginning of each test. Lower the basket
before rotation operates the apparatus immediately at 50 rpm. Operating
parameters are given in table No 3. The results are recorded in Table No. 9 and
Figure No. 5.
Table No. 3: Operating parameters for in vitro
release studies of Metoprolol
succinate tablets in saliva fluid.
|
Sr. no
|
Operating parameters
|
Value
|
|
1
|
Method and rotation speed Paddle
|
50 rpm
|
|
2
|
Dissolution medium (pH and volume)
|
pH 6.2 solution; 500 ml
|
|
3
|
Temperature
|
37 ± 0.5 0C
Crystals
|
|
4
|
Time interval for sampling
|
60 min.
|
|
5
|
Sample volume
|
10 ml
|
|
6
|
Wavelength
|
280 nm
|
The % cumulative release of Metoprolol
succinate was calculated .The observations for different batches are shown in
succeeding tables. The cumulative percentage release of Metoprolol succinate
with respect to time for each batch, are graphically shown below.
3. STATISTICAL DATA ANALYSIS:12-15
To characterize the release mechanism of Metoprolol succinate from sustained release
mucoadhesive tablets, the results of the in vitro dissolution study of the
optimized batch of mucoadhesive tablet was fitted with various kinetic
equations like
I Zero order (% release =K t),
II First order (log %Unreleased
=Kt/2.303),
III Higuchi’s model (%Release =Kt0.5)
and
IV Peppas- Korsmeyer
Equation (% Release=Ktn)
(Or) empirical equation of Mt / M∞
= K tn
Where,
Mt/ M∞ = fractional drug release,
K = constant characteristics, and
n = Diffusional exponent
If n = 0.5 indicates Fickian diffusion mechanism (Higuchi
matrix)
n = 0.5 to 1 indicates Anomalous Transport or Non Fickian
transport.
n = 1 indicates Case II Transport (Zero
order release)
n > 1 indicates Super case –II
transport
Coefficient of correlation (r2)
values were calculated for the
linear curves obtained by regression analysis. The values of n as estimated by
linear regression of log (Mt / M∞) versus log (t)
of different formulations are shown in Table No.4.
Table No. 4: Estimated values of n and k by regression
of log (Mt / M∞) on log (t).
|
Batch
|
N
|
K
|
r2
|
|
F1
|
0.7494
|
0.1307
|
0.9595
|
|
F2
|
0.7044
|
0.1179
|
0.9804
|
|
F3
|
0.7082
|
0.1057
|
0.9972
|
|
F4
|
0.7416
|
0.1076
|
0.9925
|
|
F5
|
0.6841
|
0.1024
|
0.9985
|
|
F6
|
0.7082
|
0.1057
|
0.9972
|
4. RESULTS AND DISCUSSION:
4.1 EVALUATION OF MUCOADHESIVE BUCCAL TABLETS
All tablets were found to
comply as per IP standard.
The average weight of the tablet was found
to be between 132.04 mg to 119.70 mg. Maximum % deviation was found to be ±
0.75 from all formulation.
Thickness of tablets for all formulation was
found to be between 2.05 mm and 2.01 mm, with average of 2.03 mm. The %
deviation in thickness was 0.046 to 0.013.
% Drug content for all the formulation was
found to be 96 % to 73.83 %.
Surface pH of all the formulation was found
to be 6.9 to 6.3. These results reveals that’s all formulations provide an
acceptable ph in the range of salivary pH (6.2 to 7.4). They did not produce
any local irritation to the mucosal surface.
4.2 IN VITRO MUCOADHESIVE STUDY 11
Effect of hydrophilic polymer on mucoadhesion
force and bioadhesion force are shown in table no.6.
Table
No. 6: In-vitro mucoadhesive strength study of prepared mucoadhesive tablet of
Metoprolol succinate.
|
Bath code
|
Mucoadhesive
strength (g)
|
Mucoadhesion
force (N)
|
|
F1
|
24.36
|
2.39± 0.02
|
|
F2
|
20.89
|
2.05± 0.05
|
|
F3
|
17.34
|
1.70 ±0.075
|
|
F4
|
22.42
|
2.20±0.02
|
|
F5
|
19.65
|
1.93±0.0153
|
|
F6
|
19.87
|
1.95±0.0153
|
Figure No. 2: In vitro mucoadhesion
profile of prepared mucoadhesive tablet of Metoprolol succinate.
In the formulation batches, F1 to F6, which contain
Carbopol 934 P, with HPMC K4M in different ratio, bioadhesive force was found
to decrease with decrease in proportion of HPMC K4M.The maximum adhesion force
i.e. bioadhesive force was observed in formulation F1 (2.39 N).
|
Time (hrs)
|
% Cumulative Drug Release
|
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
|
1
|
12.8
|
8.6
|
20
|
10.7
|
18.6
|
19.5
|
|
2
|
23.4
|
26.9
|
35.3
|
24.9
|
31
|
33.4
|
|
3
|
30.1
|
41.5
|
47.9
|
37.3
|
43.2
|
45.6
|
|
4
|
35.9
|
59.1
|
60.7
|
50.5
|
52.2
|
53.8
|
|
5
|
41.2
|
73.1
|
70.5
|
63.1
|
66.8
|
67.4
|
|
6
|
49.4
|
79.1
|
79.6
|
77.8
|
72.3
|
73.6
|
|
7
|
60.1
|
80
|
85.2
|
90.7
|
79.7
|
81
|
|
8
|
73.8
|
83.9
|
89.5
|
96
|
87.8
|
88.5
|
4.3 IN-VITRO SWELLING STUDY:
|
Batch
|
Time (h)
|
|
1
|
2
|
4
|
6
|
8
|
|
F1
|
1.234
|
1.879
|
2.688
|
3.463
|
3.986
|
|
F2
|
0.757
|
1.263
|
1.765
|
1.849
|
2.374
|
|
F3
|
1.161
|
1.643
|
1.974
|
2.495
|
2.895
|
|
F4
|
0.657
|
1.035
|
1.537
|
1.979
|
2.368
|
|
F5
|
0.469
|
0.962
|
1.126
|
1.253
|
2.026
|
|
F6
|
0.435
|
0.975
|
1.096
|
1.198
|
2.011
|
Table No. 7: Swelling index of prepared mucoadhesive
tablet of Metoprolol
succinate
Figure No. 3: Swelling index of batches (F1 to F6)
The swelling properties of formulations
batches F1 to F6 were determined. Result of swelling study indicates that all
the batches were shown good swelling index, appropriate swelling is an
essential property for uniform and prolonged release of drug release. The
formulation F1 containing Carbopol 934P and HPMC K4M in 1:2 ratios shows
maximum swelling index. In vitro swelling index of formulations are
shown in Table No.7 and the plot of swelling index versus time (hrs) was shown
in Figure No. 3.
4.4
IN VITRO RELEASE
STUDY:
4.4 A. In vitro release study in phosphate buffer pH
6.8
Drug release tests were carried out for all
formulations i.e. F1 to F6 according to official pharmacopoeia. It was observed
that all the formulation except F1, F2 how satisfactory drug release after
8hrs.
Maximum % cumulative drug release was found to
be in F4 formulation batch as 96 %. The results of all formulation i.e. F1 TO
F6 was shown comparatively in table No. 8 and Fig. No.4
Table No. 8: Dissolution profile of batch F1 TO F6 in
phosphate buffer pH 6.8
Figure No. 4: Dissolution profile of batches
F1 TO F6
4.4
B. In vitro
release study in Simulated Saliva Fluid pH 6.2:
Drug release tests were carried out for all
formulations i.e. F1 to F6 according to official pharmacopoeia. It was observed
that all the formulation except F1, F2 show satisfactory drug release after
8hrs.
Maximum % cumulative drug release was found
to be in F4 formulation batch as 94.9 % saliva fluid pH 6.2. The results of all
formulation i.e. F1 TO F6 was shown comparatively in table No. 9 and Fig. No. 5
Table No. 9: Dissolution profile of batch F1 TO F6 in
saliva fluid pH 6.2
|
Time (hrs)
|
% Cumulative Drug Release
|
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
|
1
|
10.4
|
8.7
|
20.5
|
11.9
|
20.5
|
20.1
|
|
2
|
20.9
|
22.1
|
35.1
|
24.0
|
33.2
|
32.6
|
|
3
|
26.5
|
39.8
|
46.2
|
36.5
|
46.4
|
45.0
|
|
4
|
34.3
|
53.2
|
60.5
|
48.4
|
57.7
|
57.4
|
|
5
|
39.8
|
63.9
|
73.1
|
62.1
|
63.1
|
69.4
|
|
6
|
49.0
|
76.6
|
79.6
|
75.7
|
73.4
|
75.2
|
|
7
|
59.4
|
80.2
|
85.9
|
87.5
|
79.3
|
82.2
|
|
8
|
71.3
|
83.8
|
90.3
|
94.9
|
85.6
|
87.3
|
Figure No. 5: Dissolution profile of batches F1 TO F6 in Simulated Saliva Fluid
5. CONCLUSION:
The main objective of the study was to develop the
mucoadhesive buccal tablets of Metoprolol succinate that is used in the
treatment of cardiovascular disorders such as hypertension, angina pectoris,
cardiac arrhythmias and myocardial infarction. In present investigation an attempt
was made to increase the bioavailability of Metoprolol succinate that maintains constant, effective drug level in the body
with concomitant minimization of undesired side effects.
The following conclusion can be made
according to the results of study.
·
The preliminary study
showed the satisfactory results for drug and polymers. The entire test was
complies the specification according to I.P.
·
Hardness and friability
are the important parameters that reflect the ability to withstand shocks,
which may be encountered during transportation and packing. All the
formulations showed % friability less than 1% and hardness was found in the
range of 90 -118 N.
·
Swelling behavior should
be optimum for the tablet in order to achieve a uniform drug release pattern.
All the formulation showed the maximum swelling index in 8 hrs. From the study
it was also concluded that swelling rate of the tablets increases with
increasing in the concentration of Carbopol 934 P.
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