Formulation and Evaluation of Bilayer
Floating Tablets of Metformin Hydrochloride and Glibenclamide
Srujana Kumari D.*,
Balasubramaniam V., Velrajan G., Deepthi N., Sushma R.
Smt. Sarojini Ramulamma College
of Pharmacy, Sheshadrinagar, .Mahabubnagar, Andhra Pradesh, India-509001
*Corresponding Author E-mail: devani.srujana@gmail.com
ABSTRACT:
The present research work was an
attempt to design a formulation of Bilayer floating tablets with
Metformin HCl as sustained release layer and Glibenclamide as immediate
release layer for the treatment of type II diabetes mellitus. The
extended release was prepared by wet granulation method using HPMC K 100M
as sustained release polymer and sodium bicarbonate as gas generating
agent to reduce floating lag time. Immediate release layer were prepared by
direct compression using sodium starch glycolate as super disintegrant.
Gastro retentive floating drug delivery systems have been designed to increase
its residence time in the stomach. The granules were evaluated for
bulk density, tapped density, Compressibility index, and Hausner’s
ratio. The granules showed satisfactory flow properties. The tablets were
subjected to weight variation test, hardness test, friability test, drug
content test and swelling index. All the tablets were passed the tests. With
the incorporation of a gas generating agent the floating lag time was 27 sec,
and the duration of floating was >8hrs. The drug release from the prepared
tablets was sufficiently sustained (more than 8hrs). The release kinetics of
the Bilayer floating tablet was evaluated using regression coefficient
analysis. The formulated tablets shows a Zero order drug release and the
mechanism is correlated well with Korsmeyer peppas mode with super case II
transport mechanism. Stability studies did not show any changes in physical
appearance, physicochemical properties, and drug release.
KEYWORDS: Bilayer tablets, floating drug delivery
system, Metformin Hydrochloride, Glibenclamide
INTRODUCTION:
The oral route is considered as
the most convenient and preferred means of any drug delivery to the systemic
circulation. Over the years oral drug delivery has been used as the most widely
utilized route of administration among all the routes that have been explored
for the systemic delivery of drugs via various pharmaceutical products of
different dosage forms. This oral routes of drug delivery has high patient
acceptability due to its ease of administration , and has flexible design
of dosage form1.
Among the various gastro
retentive systems, gastric floating drug delivery systems (GFDDS) offer
numerous advantages. GFDDS has less density than the gastric fluids and thus
remain buoyant in the stomach without affecting the gastric emptying rate for a
prolonged period of time and the drug is released slowly at a desired rate from
the stomach2.
A significant obstacle may arise
if there is a narrow window for drug absorption in the gastrointestinal tract,
if a stability problem exists in gastrointestinal fluids, or the drug is poorly
soluble in the intestine or acts locally in the stomach. Gastro-retentive
floating drug delivery systems have emerged as an efficient means of enhancing
the bioavailability3. Thus, the real issue in the development of
oral controlled release dosage forms is not just to prolong the delivery of the
drugs for more than 12 h, but to prolong the residence time until all the drug
is released for the desired period of time4.
Metformin HCl (MET) has poor
colonic absorption in healthy human subjects. Release of metformin after the
small intestine is thus, of no therapeutic value. Marathe et al. have also
strongly mentioned that the conventional strategies of prolonging the release
of metformin from the dosage forms throughout the GIT would not be effective
for metformin formulation as it is primarily absorbed from the small intestine.
They have also indicated that the extent of metformin absorption is improved
when the gastro intestinal motility is slow5. Thus, development of
gastro retentive sustained release formulation for metformin hydrochloride
would be a better alternative to the conventional sustained release
formulations.
MET suffers from certain
drawbacks of which, the most prominent being the high dose2 (1.5-2.0g/day), low
bioavailability (40-60%), short biological half-life (0.9-2.6 h) which requires
repeated administrations of high doses to maintain effective plasma
concentrations6. Glibenclamide (GLB) is a second generation
sulphonyl urea capable of stimulating insulin release, but is not capable of
acting on insulin resistance, and metformin hydrochloride able to act on
insulin resistance, whereas they are not able to stimulate insulin secretion.
In the present study we aimed to
fabricate Bilayer floating tablets of metformin HCl and Glibenclamide by
effervescent approach using different grades of polymers and so to deliver
metformin into the upper part of intestine which is its best absorption site,
thus the oral bioavailability and patient compliance of metformin could be
improved.
MATERIALS AND METHODS:
Materials:
Metformin hydrochloride and
Glibenclamide obtained from Baris Pharmaceuticals Pvt. Ltd,. Hyderabad, Sodium
bi carbonate from S.D Fine Chem.Ltd,. Mumbai. Hydroxy propyl methyl cellulose
and Red iron oxide from Colorcon Asia Pvt. Ltd, Goa. Sodium starch Glycolate
and other Excepients from Bright Scientifics, Hyderabad.
Methodology:
Characterization of active
pharmaceutical ingredient and polymer using FT-IR7:
MET,GLB and their mixture discs
were prepared by pressing their respective drug, polymer and superdisintegrant
with potassium bromide by using FT – IR Spectrophotometer. Spectrum was
observed between 4000-1cm to 400 -1cm under the
operational conditions.
Preparation of Bilayer tablets
with floating layer:
Bilayer floating tablets
consisting of MET as floating layer and GLB as immediate release layer. The
floating layer was prepared by using wet granulation method8. Weighed
quantities of MET 500mg; was mixed properly in a mortar with weighed amount of
polymer and Excepients as shown in table no 1.The well mixed powder was
compressed by the tablet compression machine and the hardness was adjusted for
the required amount. The immediate release layer containing Glibenclamide 5mg;
sodium starch glycollate 4mg which is considered as optimum percentage(4%)9
, magnesium stearate, talc ,red iron oxide each of 1mg and
microcrystalline cellulose of sufficient quantity required to make the
immediate release layer for 100mg was added and mixed properly. This mixture of
immediate release portion was compressed directly8 on the sustained
release layer with direct compression technique with caplet shaped plain
pinches in an average weight of 1100mg per tablet.
Precompression parameters8:
Evaluation of sustained release
granules: Evaluation
was done for bulk density, tapped density, angle of repose, %compressibility
and hausner ratio. Results are tabulated in table no 2.
Post compression evaluation of
tablets:
Weight variation test:
20 tablets were randomly
selected from each formulation and their average weight was calculated using
digital balance. Individual weight of each tablet was also calculated using the
same and compared with the average weight.
Hardness:
Monsanto hardness tester was
used for the determination of hardness of tablets.
Thickness:
Thickness was determined using a
digital vernier scale and the average thickness was determined in mm.
Percentage Friability:
The friability of tablets was
tested using Roche friabilator. Loss of less than 1% weight is desirable. The
percentage friability is expressed as the loss of weight and is calculated by
the formula:
(Where, A = Initial weight of tablets;
B = Final weight of tablets after 100 revolutions).Results are tabulated in
table no.3
Table .No.1: Formulation of sustained
release layer.
|
Code
|
SF1 (mg)
|
SF2 (mg)
|
SF3 (mg)
|
SF4
(mg)
|
SF5
(mg)
|
SF6 (mg)
|
SF7 (mg)
|
SF8 (mg)
|
SF9 (mg)
|
|
Drug
|
500
|
500
|
500
|
500
|
500
|
500
|
500
|
500
|
500
|
|
HPMCK4M
|
100
|
200
|
300
|
-
|
-
|
-
|
-
|
-
|
-
|
|
HPMCK15M
|
-
|
-
|
-
|
100
|
200
|
300
|
-
|
-
|
-
|
|
HPMCK100M
|
-
|
-
|
-
|
-
|
-
|
-
|
100
|
200
|
300
|
|
NaHCO3
|
120
|
120
|
120
|
120
|
120
|
120
|
120
|
120
|
120
|
|
Povidone K 30
|
q.S
|
q.S
|
q.S
|
q.S
|
q.S
|
q.S
|
q.S
|
q.S
|
q.s
|
|
IPA
|
q.S
|
q.S
|
q.S
|
q.S
|
q.S
|
q.S
|
q.S
|
q.S
|
q.s
|
|
Mg.stearate
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
|
Talc
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
|
MCC
|
260
|
160
|
60
|
260
|
160
|
60
|
260
|
160
|
60
|
Floating Test1,11:
The tablets were placed in a 100
ml beaker containing simulated gastric fluid. The time between introduction of
dosage form and its buoyancy on simulated gastric fluid, and the time during
which the dosage form remains buoyant were measured. The time taken for the
dosage form to emerge on surface of medium is called Floating Lag Time (FLT) or
Buoyancy Lag Time (BLT) and total duration of time during which the dosage form
remains buoyant is called Total Floating Time (TFT). Results of floating
property was shown in table no.4
Swelling Study1:
The study was done by immersing
the dosage form in simulated gastric fluid at 37°C and determining these
factors at regular intervals up to a period of 5 hours. Water uptake was
measured in terms of percent weight gain, as given by the equation.
Wt = Weight of the dosage form
at time ‘t’.
Wo = Initial weight of the
dosage form. Results of swelling study are shown in table no.5
Determination of Drug Content12:
Tablet powder containing 0.1g of
Metformin HCl was shaken with 70 ml of water for 15 minutes, diluted to 100 ml
with water and filtered, discarding the first 20 ml. 10 ml of the filtrate was
diluted to 100 ml with water, and from the resulting solution 10ml was further
diluted to 100 ml with water. The absorbance of the resulting solution was
measured at the maximum at 218 nm and the content of Metformin HCl was
calculated. And for the Bilayer tablet a known number of tablets were weighed
and individual weights was noted and these tablets were crushed in a mortar and
the powder was weighed. Average weight of the powder was taken and placed in
100ml vol flask, diluted with 30 ml of 0.1N HCl and sonicated for 20 min, and
then it was made up to the mark with 0.N HCl and sonicated for few minutes.
From this 1ml in 10ml was taken in VF. A dilution was made till the required
absorbance of <1 was obtained. The amount of GLB in the tablet was
determined using simultaneous equation method. All the formulations passes the
test as per the specifications.
In vitro dissolution test:
In vitro dissolution studies were carried out using
USP type II apparatus at 50 rpm. The dissolution medium consisted of 900ml pH
1.2 0.1N HCl. maintained at 37 ± 0.5°C. the rest sample 5ml was withdrawn at
specific intervals of time and it was replaced with fresh buffer at specific
intervals and the absorbance was measured at 228nm for Glibenclamide and 218nm
for metformin hydrochloride. Cumulative drug release was calculated using
simultaneous equation method. Drug release profile was shown in figures 7-10.
Simultaneous equation method7,10:
If a sample contains two
absorbing drugs (X and Y) each of which absorbs at the λmax of the other,
it may be possible to determine both drugs by the technique of simultaneous
equations provided that certain criteria apply.
The concentration of substances in
diluted solutions Cx and Cy are given by the equation.
Drug release kinetics:13
The rate and mechanism of
release of drug were analyzed by fitting the Dissolution data in Zero order,
First order, Higuchi equations and korsemeyer pappas equation .Results are
summarized in table no.6.and the release pattern of optimized formula was shown
in figure 11.
RESULTS:
The results obtained in
precompression and post compression evaluation studies are summarized in the following
tables from table no 2-6 and figure numbers 1-7.
Table 2: Evaluation of micrometric
properties of the granules
|
Formulation
|
Bulk density (gm/ml)
|
Tapped density (gm/ml)
|
Carr’s index (%)
|
Hausner's ratio
|
Angle of repose(o)
|
|
SF1
|
0.300313
|
0.320333
|
6.25
|
1.066667
|
30.54
|
|
SF2
|
0.312903
|
0.334483
|
6.451613
|
1.068966
|
29.24
|
|
SF3
|
0.318
|
0.328966
|
3.333333
|
1.034483
|
28.81
|
|
SF4
|
0.311935
|
0.322333
|
3.225806
|
1.033333
|
30.54
|
|
SF5
|
0.309355
|
0.319667
|
3.225806
|
1.033333
|
29.24
|
|
SF6
|
0.309677
|
0.342857
|
9.677419
|
1.107143
|
30.54
|
|
SF7
|
0.307188
|
0.338966
|
9.375
|
1.103448
|
29.63
|
|
SF8
|
0.315161
|
0.348929
|
9.677419
|
1.107143
|
30.11
|
|
SF9
|
0.306563
|
0.350357
|
12.5
|
1.142857
|
29.63
|
Table 3:Post compression evaluation
parameters of Bilayer floating tablet
|
Formulation
|
Weight variation(mg)
|
Hardness (kg/cm2)
|
Thickness(mm)
|
Friability (%)
|
|
SIF1
|
1102±1
|
3.32±0.04
|
5.32±0.03
|
0.96
|
|
SIF2
|
1105±2
|
4.01±0.07
|
6.01±0.02
|
0.89
|
|
SIF3
|
1098±2
|
4.3±0.06
|
5.3±0.05
|
0.98
|
|
SIF4
|
1097±1
|
4.73±0.04
|
5.73±0.04
|
1.01
|
|
SIF5
|
1103±5
|
3.69±0.03
|
5.69±0.05
|
0.94
|
|
SIF6
|
1102±4
|
4.48±0.09
|
5.48±0.06
|
1.03
|
|
SIF7
|
1102±2
|
4.52±0.08
|
5.52±0.06
|
0.89
|
|
SIF8
|
1098±2
|
3.82±0.05
|
5.62±0.03
|
0.95
|
|
SIF9
|
1101±3
|
3.86±0.02
|
5.86±0.01
|
1.01
|
Table4: Results of floating property of the
tablets
|
Formulation
|
Floating lag time
|
Total floating time
|
|
SF1
|
4min
|
>12
|
|
SF2
|
6min
|
>12
|
|
SF3
|
6min 20 sec
|
>12
|
|
SF4
|
4min 28sec
|
>12
|
|
SF5
|
6 min 30 sec
|
>12
|
|
SF6
|
7 min 5 sec
|
>12
|
|
SF7
|
23sec
|
>12
|
|
SF8
|
4min 16 sec
|
>12
|
|
SF9
|
6min 50sec
|
>12
|
Floating lag time:
At 0 seconds
At 19 seconds
At 27 seconds
Fig 1:Floating tablet buoyancy
time study of the optimized formulation
Swelling study:
Table 5:Swelling index of tablets using
different polymers.
|
Time(Hrs)
|
HPMC K4M
|
HPMCK15M
|
HPMCK100M
|
|
0.5
|
22
|
29
|
31
|
|
1
|
31
|
36
|
39
|
|
2
|
37
|
40
|
46
|
|
3
|
45
|
51
|
60
|
|
4
|
50
|
59
|
68
|
|
5
|
58
|
65
|
72
|
|
6
|
63
|
69
|
79
|
|
7
|
68
|
72
|
83
|
Graph showing the swelling index
of three different polymers:
Fig2: Swelling index of the
tablets using the polymers a) HPMC K4M b)HPMC K15M c) HPMC K100M
Cumulative % drug release of
Metformin HCl from formulations SF1-SF9
Fig 3:Comparison of cumulative
percent release of metformin HCL
In vitro drug release profile of
optimized formulations of metformin HCl and Glibenclamide:
Fig 4: %CDR of MET
Fig 5:% CDR of GLB
Drug release profile of the two
drugs in the optimized formula of the Bilayer floating tablet of MET &GLB:
Fig6 : drug release profile of
Bilayer tablet
Drug release kinetics
Table 6:Drug release kinetics of zero
order, First order, Higuchi & Korsemeyer peppas equation.
|
Formulations
|
Zero Order (r2)
|
First order (r2)
|
Higuchi (r2)
|
Korsemeyer-Peppas (n)
|
|
(r2)
|
n
|
|
F1
|
0.9813
|
0.905
|
0.9375
|
0.971
|
0.8
|
|
F2
|
0.9743
|
0.8294
|
0.9363
|
0.8981
|
0.6
|
|
F3
|
0.9814
|
0.9039
|
0.9324
|
0.954
|
1.16
|
|
F4
|
0.9943
|
0.8873
|
0.9691
|
0.98
|
1.11
|
|
F5
|
0.9907
|
0.8825
|
0.9301
|
0.989
|
1.17
|
|
F6
|
0.9949
|
0.9249
|
0.9396
|
0.995
|
1.13
|
|
F7
|
0.9969
|
0.6963
|
0.9539
|
0.996
|
1.20
|
|
F8
|
0.9928
|
0.8263
|
0.9468
|
0.987
|
1.34
|
|
F9
|
0.9847
|
0.847
|
0.9688
|
0.986
|
1.38
|
Release kinetics for the Bilayer
floating tablet:
Zero order release kinetics of
the Bilayer floating tablet containing MET and GLB
Fig 7: Drug release kinetics of
the Bilayer floating tablet containing MET and GLB
DISCUSSION:
The prepared Bilayer floating
tablets were subjected to various evaluation tests.The λmax of Metformin HCl and
Glibenclamide was found to be 218 nm and 228 respectively. Metformin obeyed
Beer’s law in the concentration range of 5-35 μg/ml with regression
coefficient of 0.999 where as Glibenclamide obeyed Beer’s law in the concentration range of 2-10 μg/ml with
regression coefficient of 0.999. The micrometric properties of the granules
were found to be within the acceptable limits and are summarized in table no 2.
Post compression evaluation parameters such as weight variation,thickness,
hardness, friability, was evaluated and found that the average percentage
deviation of all formulations were found to be within the limit and showed
uniform thickness. The percentage of friability for all formulations was below
1% indicating that the friability was within the prescribed limits and the
results were tabulated in table no.3. drug content for all formulations are
also within limits and found satisfactory.
The floating lag time of
optimized formula was 27secs compared to the other formulations where the time
was extended to a maximum of about 7min5secs.and the total floating time was
more than 12 hrs for all formulations. The results of swelling index is given
in Table 5, while the plot of swelling index against time (hr) is depicted in
Figure 6. From the results it can be concluded that swelling increases with
time because polymer gradually absorbs water due to its hydrophilicity.
The in vitro drug release
of MET from different formulations are shown in fig no 7. Maximum drug release
was observed in F7 with 99.7% for 12 hrs. and for Glibenclamide the drug
release was 99.2% at 50min. Drug release kinetics of tablets was evaluated
using regression coefficient analysis. The formulated tablets shows a zero
order drug release and the mechanism of drug release was non Fickian diffusion
by fitting the data to higuchi and korsmeyer peppas equation.
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