Formulation and evaluation of floating matrix tablet
of Losartan for gastro-retentive drug delivery
B. Ranga Nayakulu1*, Nakka Ravi Kumar1,
Ch. Kiran Kumar, P. Raja Abhilash2
1Srinivasa Institute of Pharmaceutical Sciences,
Proddatur, A.P.
2S.V.S. Group of Institutions, School of Pharmacy,
Bhemaram, Hanamkonda,Telangana.
*Corresponding
Author E-mail: abhilashmpharm@gmail.com
Asian J. Pharm. Tech. 2016;
6(2): 85-90.
ABSTRACT:
The prime aim of this research was to develop
gastro-retentive delivery system of Losartan which, after oral administration
should have the ability to prolong gastric residence time with desired in
vitro release profile. Losartan was chosen as a model drug because it is
poorly absorbed from the lower gastrointestinal tract. The tablets were
prepared by direct compression technique, using various polymers, alone or in
combination. The tablets were evaluated for physical characteristics viz.
hardness, friability, weight variation, content uniformity, and floating
capacity. Further, tablets were evaluated for in vitro release
characteristics for 12 hr. Among all the formulations, tablets containing
combination of xanthan gum and guar gum showed better floating capacity as well
as sustained release of atenolol at the end of 8 hr. The optimized formulation
F4 contains the average thickness of 2.12, average hardness of 6.7 and
friability of 0.44.The F4 formulation which releases the Losartan in sustained manner in up to
12 hours. The mechanism of release of Losartan from the floating tablets was
found to be diffusion couple with erosion. It was concluded that the tablets
prepared by polymer HPMC K4M( 15%) had efficient floating and sustained release
capacity as compared to tablets prepared by using other polymers.
KEY WORDS: Gastro-retentive floating tablets, Losartan, HPMC K100 and Sustained Release.
INTRODUCTION:
Oral sustained or controlled drug delivery system is
complicated by restricted gastric residence time. Faster gastrointestinal
transit can prevent complete drug release in the absorption window zone and
reduce the efficacy dose since the majority of drugs are absorbed in stomach or
the upper part of small intestine [1]. There are a several
approaches that can be used currently to prolong gastric retention time, such
as floating drug delivery systems, also known as hydrodynamically balanced
systems, swelling and expanding systems, raft system, polymeric bioadhesive
systems, modified-shape systems, high-density systems, and other delayed
gastric emptying devices [2-4].
Among all other above stated approaches floating drug
delivery systems widely used. Floating drug delivery systems either float due
to their low density than stomach contents or due to the gaseous phase formed
inside the system after they come in contact with the gastric environment.
Based on the mechanism of buoyancy, two distinctly different technologies i.e.
non-effervescent and effervescent systems have been utilized in the development
of Floating drug delivery systems.
Losartan is an
angiotensin-receptor blocker (ARB) that may be used alone or with other agents
to treat hypertension. Losartan and its longer acting metabolite, E-3174, lower
blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS);
they compete with angiotensin II for binding to the type-1 angiotensin II
receptor (AT1) subtype and prevents the blood pressure increasing effects of
angiotensin II. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do
not have the adverse effect of dry cough. Losartan may be used to treat
hypertension, isolated systolic hypertension, left ventricular hypertrophy and
diabetic nephropathy. It may also be used as an alternative agent for the
treatment of systolic dysfunction, myocardial infarction, coronary artery
disease, and heart failure[5,6].
It belongs to
class III is soluble in acidic pH. Losartan having narrow therapeutic index,
poor bioavailability (25 to 35%) and short biological half life (1.5 2hrs) [7,8].
Conventional tablets should be administered 3 to 4 times to maintain plasma
drug concentration. Administration of Losartan potassium in a floating drug
delivery system would be more desirable for antihypertensive effects by
maintaining the Losartan plasma concentration well above the minimum effective
concentration.
Development of a controlled delivery system for
Losartan would bring many advantages for patients. The development of oral
controlled release formulations for Losartan is difficult because of in vivo
and in vitro instability. The drug also undergoes from dose dumping and burst
phenomenon (being freely water soluble) when formulated as controlled or
sustained release formulation.
The aim of the present work is to develop floating
drug delivery system for Losartan potassium, which increases the gastric
residence time. The prepared tablets were evaluated for physical
characteristics such as hardness, weight variation, and drug content
uniformity. All the tablets were evaluated for in vitro release
characteristics.
EXPERIMENTAL WORK:
Materials and Method
Losartan potassium was obtained as a gift sample from
Torrent Pharmaceuticals Ltd, Ahmadabad. Hydroxy Propryl Methyl Cellulose
(HPMC), K4M, K100M, Ethyl cellulose, Talc, sodium bicarbonate, magnesium
sterate, Microcrystalline and talc were obtained from CDH (P) Ltd, New Delhi.
Floating matrix tablet of Losartan potassium were
prepared by direct compression method according to the formula given in Table
1. Losartan potassium (100 mg) was mixed with the required quantity of polymers
HPMC K4M or K100M or Ethylcellulose or in combination, PVP K30 (5%), sodium
bicarbonate (10%), and Microcrystalline (Q.S) in mortar and pastel for 15 min.
The powder blend was then lubricated with talc (2.5 mg) and magnesium stearate
(2.5 mg) for additional 3 min and prior to the compression; the prepared powder
blend was evaluated for several tests as mentioned below. The powder blend was
then compressed into tablets manually on single punch tablet punching machine
using 6 mm standard flat punch.
Evaluation of powder blend
Bulk density and tapped density
Both poured bulk and tapped bulk densities were
determined, by a quantity (3 g) of granules from each formula, previously
lightly shaken to break any agglomerates formed, was introduced into a 10 mL
measuring cylinder. After the initial volume was observed, the cylinder allowed
tofall under its own weight onto a hard surface from the height of 2.5 cm at 2
sec intervals. The tapping was continued until no further change in the volume
was noted. The value of bulk density and tapped density were calculated by
using equation:
Bulk density = M / V0
Where M= mass of the powder; V0=bulk volume
of the powder.
Tapped density = M / Vr
Where M = mass of the powder, Vr = final tapping
volume of the powder.
Compressibility index
The Carr’s compressibility index and Hausner’s ratio were
calculated from the values of bulk density and tapped density.
Table 1: Composition of
Floating Tablets of Losartan
|
Ingredients
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
F7
|
F8
|
F9
|
|
Losartan(mg)
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
|
HPMC K4M(%)
|
10
|
--
|
--
|
15
|
--
|
--
|
10
|
15
|
15
|
|
HPMC K100M(%)
|
--
|
10
|
--
|
--
|
15
|
--
|
10
|
10
|
15
|
|
EC (%)
|
--
|
--
|
10
|
--
|
--
|
15
|
--
|
--
|
--
|
|
PVP K30 (%)
|
5
|
5
|
5
|
5
|
5
|
5
|
5
|
5
|
5
|
|
Sodium
bicarbonate(%)
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
|
Talc (%)
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
|
Magnesium
stearate(%)
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
2.5
|
|
MCC(mg)
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
|
Total weight (mg)
|
200
|
200
|
200
|
200
|
200
|
200
|
200
|
200
|
200
|
Evaluation of tablet
Prepared tablet were evaluated for quality control
tests like weight variation test, hardness test, friability test, content
uniformity study, and in vitro release study.
Weight variation test
To study weight variation, tablets from each
formulation were selected at random and average weight was determined using an
electronic balance. Then individual tablets were weighed and the individual
weight was compared with an average weight. Weight values were reported in mg.
Mean and SD were calculated.
Hardness test
For each formulation, the hardness of six tablets was
determined using a hardness tester (Monsento, Mumbai, India). Hardness values
were reported in kg/cm2. Mean and SD were calculated.
Friability test
For each formulation, six tablets were weighed. The
tablets were placed in a Roche friabilator (Labotech, Mumbai, India) and
subjected to 100 rotations in 4 min. The tablets were then dedusted and
reweighed. The friability was calculated as the percent weight loss.
Drug content uniformity study
Five tablets were weighed individually, then placed in
a mortar and powdered with a pestle. An amount equivalent to 25 mg drug (100
mg) was extracted with 100 mL of 0.1M HCl (pH 1.2), stirred for 15min using
magnetic stirrer (Labotech, Mumbai, India). The solution was filtered through a
filter (0.22 μm pore size), properly diluted with 0.1 M hydrochloric acid
and the drug content was measured using UV-VIS spectrophotometer at 234 nm.
Buoyancy study
The in vitro buoyancy was characterized by floating
lag time and total floating time. The test was performed using USP 24 type II
apparatus (Timestan, Kolkata, India) at 100 rpm in 900 mL of 0.1M HCl (pH 1.2)
maintained at 37±0.5°C. The time required for tablet to rise to the surface of
dissolution medium and duration of time the tablet constantly float on
dissolution medium were noted as floating lag time and total floating time,
respectively (n = 3)21
In vitro drug release study.
The in vitro drug release study was performed using
USP 24 type II apparatus at 50 rpm in 900 mL of 0.1M HCl (pH 1.2) maintained at
37±0.5°C. The samples were withdrawn at predetermined time intervals for period
of 8 hr and replaced with the fresh medium. The samples were filtered through
0.45 μm membrane filter, suitably diluted and analyzed at 234 nm using
double beam UV-VIS spectrophotometer. The content of drug was calculated using
equation generated from calibration curve. The test was performed in triplicate
and the mean value was used to construct the release profile.
Determination of release
kinetics and release mechanism
The rate and mechanism of release of atenolol from the
prepared floating tablets were analyzed by fitting the dissolution data into
following equations:
Zero order: C = K0 t
where, K0 is zero-order rate constant expressed in
units of concentration/time and t is the time.
First Order: LogC = LogC0 - K1 t / 2.303
where, C0 is the initial concentration of drug and K1
is first order constant.
To describe the drug release behavior from polymeric
systems, the dissolution data were also fitted according to the well-known
exponential Korsmeyer-Peppas equation.
Mt / M∞ = Ktn
where Mt / M∞ is fraction of drug released at
time t, K is the release rate constant
incorporating structural and geometric characteristics of the tablet, and n is
the release exponent.
RESULTS
AND DISCUSSION:
Losartan floating tablets were prepared by using HPMC
K4M orK100M or Ethylcellulose or in combination as a polymeric retardant
materials and sodium bicarbonate as gas forming agent to float the tablets in
stomach. Carbon dioxide which is formed by combination of citric acid with
sodium bicarbonate is just entrapped by the polymer and decreases the density
of tablet below the density of gastric fluid which results in floating of the
tablet.
The micromeritics parameters of the powder blend of
different formulation batches are shown in Table 2. Angle of repose and
compressibility index was found to be in the range of 26.1 to 29.6 and 13.16 to
17.78, respectively. The bulk density and tapped density of the prepared powder
blend was found to be in the range of 0.31 to 0.37gm/cm3 and 0.37to
10.45gm/cm3, respectively. The result of angle of repose indicates
good flow property of the granules and the value of compressibility index
further support for the good flow property.
Table 2: Micromeritics
properties of powder blend of different formulations
|
Formulations
|
Angle of Repose (θ)
|
Loose Bulk
|
Tapped Bulk
|
%Compressibility
|
Hausner’s ratio
|
|
Density (g/ml)
|
Density (g/ml)
|
|
F1
|
26.1
|
0.37
|
0.45
|
17.78
|
1.22
|
|
F2
|
25.7
|
0.33
|
0.38
|
13.16
|
1.15
|
|
F3
|
27.4
|
0.32
|
0.37
|
13.51
|
1.16
|
|
F4
|
27.3
|
0.38
|
0.44
|
13.64
|
1.16
|
|
F5
|
29.6
|
0.31
|
0.37
|
16.22
|
1.19
|
|
F6
|
28.4
|
0.37
|
0.45
|
17.78
|
1.22
|
|
F7
|
27.1
|
0.32
|
0.37
|
13.51
|
1.16
|
|
F8
|
26.7
|
0.33
|
0.38
|
13.16
|
1.15
|
|
F9
|
26.3
|
0.38
|
0.44
|
13.64
|
1.16
|
The tablets of all formulations was found to be off
white, smooth, flat faced circular with no visible cracks. The physicochemical
properties of all the formulations are shown in Table 3. The hardness of the
tablets was measured by Monsento hardness tester and was found in between 6.2
to 6.6 kg/cm2. The friability was measured by Roche friabilator and
was found to be within acceptable range i.e. 0.39 to 0.48. The weight variation
of the tablet formulations was found to be in the range of 199 to 204 mg, which
reflects good uniformity in drug content among different formulations. All the
formulations showed values within the prescribed limits for tests like
hardness, friability and weight variation which indicate that the prepared
tablets are of standard quality.
Table 3: Post compression
parameters of different formulations
|
Formulations
|
Weight variation
|
Hardness
|
Thickness (mm)
|
Friability (%)
|
|
F1
|
200
|
6.6
|
2.17
|
0.39
|
|
F2
|
199
|
6.4
|
2.37
|
0.42
|
|
F3
|
201
|
6.2
|
2.55
|
0.40
|
|
F4
|
202
|
6.7
|
2.12
|
0.44
|
|
F5
|
202
|
6.4
|
2.38
|
0.48
|
|
F6
|
200
|
6.6
|
2.19
|
0.43
|
|
F7
|
201
|
6.5
|
2.54
|
0.42
|
|
F8
|
204
|
6.4
|
2.51
|
0.41
|
|
F9
|
203
|
6.3
|
2.48
|
0.44
|
It was observed that formulation F3 and F4 unable to
hold the carbon dioxide within the tablet matrix as a result they are not
floated. Whereas, all the other formulations shows appreciable floating lag
time less than 6 min. Table 4 shows formulations F4, F7, and F8 are able to float above the
dissolution medium for more than 12hr, which is our desired goal.
Table
4:Buoyancy properties of the tablets of different formulations
|
Formulations
|
Lag Time
|
Floating time
|
|
6 min
|
5hrs
|
|
F2
|
3min
|
3hrs
|
|
F3
|
20 min
|
6hrs
|
|
F4
|
7 min
|
>12hrs
|
|
F5
|
5 min
|
6hrs
|
|
F6
|
6 min
|
8hrs
|
|
F7
|
3 min
|
>12hrs
|
|
F8
|
4 min
|
>12hrs
|
|
F9
|
6 min
|
5hrs
|
The in vitro
release profile of the different formulations is shown in Figure 1. The release
profile of different formulations shows that S1 and S4 released the whole drug
within 6 h. Formulation S2, S3, S5, S6 and S7 released the drug within the
range of 70-80 % within the time of 8 h. Whereas, formulation S2, S3, S5 and S6
shows burst release of drug. The formulation S7 released the drug in the same
manner of theoretical release profile as calculated using Robinson Erickson
equation.
In-Vitro
Drug Release Studies for Floating tablets:
Table 5: Dissolution studies
of different formulations
|
Time(hrs)
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
F7
|
F8
|
F9
|
|
Dissolution
medium 0.1N HCL
|
|
1
|
34.5
|
43.7
|
30.3
|
34.2
|
24.5
|
18.2
|
24.5
|
18.2
|
16.2
|
|
2
|
42.7
|
71.5
|
44.5
|
39.4
|
47.8
|
23.5
|
32.4
|
23.5
|
22.8
|
|
6.8pH phosphate
buffer
|
|
3
|
52.9
|
80.3
|
66.8
|
48.1
|
60.2
|
30.6
|
44.2
|
28.8
|
38.4
|
|
4
|
69.4
|
98.4
|
71.4
|
54.7
|
77.3
|
44.2
|
54.7
|
32.6
|
46.2
|
|
5
|
87.2
|
-
|
84.1
|
64.9
|
84.5
|
68.1
|
64.9
|
39.2
|
49.2
|
|
6
|
95.8
|
-
|
96.8
|
82.4
|
97.6
|
89.3
|
75.4
|
65.5
|
52.8
|
|
8
|
-
|
-
|
-
|
92.1
|
-
|
97.7
|
82.1
|
71.3
|
68
|
Fig No 1- Dissolution graph
for Floating layer formulations
KINETIC RELEASE MODELS:
Table 6: Release kinetics for F4 formulation for
Floating layer
|
|
ZERO
|
FIRST
|
HIGUCHI
|
PEPPAS
|
|
|
% CDR Vs T
|
Log % Remain
Vs T
|
%CDR Vs
√T
|
Log C Vs Log T
|
|
Slope
|
7.786831683
|
-0.15891117
|
30.10021941
|
2.310046705
|
|
Intercept
|
21.71554455
|
2.135240217
|
-0.08296857
|
-0.19489949
|
|
Correlation
|
0.930561471
|
-0.97385361
|
0.985152619
|
0.879950588
|
|
R 2
|
0.865944651
|
0.948390861
|
0.970525683
|
0.774313037
|
SUMMARY
AND CONCLUSION:
The Floating tablets containing Losartan were successfully prepared by
direct compression method.
The physiochemical evaluation results for the powdered
blend of all trials pass the official limits in angle of repose,
compressibility index.
The prepared dry mixer for floating tablets were also
maintained the physiochemical properties of tablets such as thickness,
hardness, weight variation, friability. The optimized formulation F4 contains
the average thickness of 2.12average hardness of 6.7, friability of 0.44.
The F4 formulation which releases the Losartan in sustained manner in up to
12 hours.
Hence it may be summarized that the tablets prepared
by direct compression method for floating tablets might be a perfect and
effective formulation to treat the Hypertension.
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