Development and In Vitro Evaluation of Oral
Floating Matrix Tablet Formulation of Ranitidine Hydrochloride
Dinesh l Dhamecha*, Amit A Rathi, Maria Saifee, Swaroop R Lahoti and Mohd. Hassan G Dehghan
Y.B.Chavan College of Pharmacy, Dr. Rafiq
Zakaria campus, Maulana
Azad Education Trust, Rauza Bagh,
Aurangabad-431001, Maharashtra, India
ABSTRACT
Recently
many drugs are formulated as floating drug delivery systems with an objective
to sustain the release of drug in stomach. Ranitidine hydrochloride, which is
better absorbed in stomach and whose site of action is gastric area was
formulated as floating matrix tablet using gas generating agent (sodium
bicarbonate, citric acid) and polymers like HPMC K4M and polaxomer.
Formulation was optimized on the basis of in vitro release. All other
parameters like physical parameters like thickness and hardness were within
range. In vitro buoyancy was found to be in the range of 17 to 89 seconds and
water uptake in the range of 125 to 280 %. Floating time was more than 24 hrs. In vitro
drug release of the optimized batch was found to be 88% at the end of 8th
hr. Hence, it is evident from this investigation that this gas powered floating
matrix tablet could be promising delivery system of Ranitidine hydrochloride
with sustained release action and improved drug availability at target area.
KEYWORDS: Floating
matrix tablet, Ranitidine hydrochloride, In vitro release.
INTRODUCTION
Ranitidine hydrochloride (RHCl) is a histamine H2-receptor antagonist. It is widely
prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison
syndrome, gastroesophageal reflux disease, and
erosive esophagitis. The recommended adult oral
dosage of ranitidine is 150 mg twice daily or 300 mg once daily. The effective
treatment of erosive esophagitis requires
administration of 150 mg of ranitidine 4 times a day. 1 A
conventional dose of 150 mg can inhibit gastric acid secretion up to 5 hours.
An alternative dose of 300 mg leads to plasma fluctuations; thus a sustained
release dosage form of RHCl is desirable.2
The short biological half-life of drug (~2.5-3 hours) also favors development
of a sustained release formulation. A traditional oral sustained release
formulation releases most of the drug at the colon, thus the drug should have
absorption window either in the colon or throughout the gastrointestinal tract.
Ranitidine is absorbed only in the initial part of the small intestine and has
50% absolute bioavailability.3, 4 Moreover; colonic metabolism of
ranitidine is partly responsible for the poor bioavailability of ranitidine
from the colon. 5 These properties of RHCl
do not favor the traditional approach of sustained release delivery. Hence,
clinically acceptable sustained release dosage forms of RHCl
prepared with conventional technology may not be successful. The gastroretentive drug delivery systems can be retained in
the stomach and assist in improving the oral sustained delivery of drugs that
have an absorption window in a particular region of the gastrointestinal tract.
These systems help in continuously releasing the drug before it reaches the
absorption window, thus ensuring optimal bioavailability. It is also reported
that oral treatment of gastric disorders with an H2-receptor antagonist like
ranitidine or famotidine used in combination with
antacids promotes local delivery of these drugs to the receptor of the parietal
cell wall.
Table
no. 1
Formulation Batches.
|
Materials
|
Optimization
of HPMC
|
Optimization
of Polaxomer
|
Optimization
of amount of sodium bicarbonate to citric acid ratio
|
|
A1
|
A2
|
A3
|
A4
|
A5
|
A6
|
A7
|
A8
|
A9
|
A10
|
A11
|
A12
|
A13
|
A14
|
|
Drug
|
50
|
50
|
50
|
50
|
50
|
50
|
50
|
50
|
50
|
50
|
50
|
50
|
50
|
50
|
|
HPMC
|
15
|
20
|
25
|
30
|
25
|
25
|
25
|
25
|
25
|
25
|
25
|
25
|
25
|
25
|
|
Polaxomer
|
5
|
5
|
5
|
5
|
1
|
3
|
7
|
1
|
1
|
3
|
3
|
5
|
5
|
5
|
|
NaHCO3
|
9
|
9
|
9
|
9
|
9
|
9
|
9
|
7
|
11
|
7
|
11
|
5
|
7
|
11
|
|
Citric acid
|
6.5
|
6.5
|
6.5
|
6.5
|
6.5
|
6.5
|
6.5
|
5
|
8
|
5
|
8
|
3.5
|
5
|
8
|
|
Lactose
|
12.5
|
7.5
|
2.5
|
0
|
6.5
|
4.5
|
0.5
|
10
|
3
|
8
|
1
|
9.5
|
6
|
0
|
|
Magnesium stearate
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
All
the compositions given above are in percentage.
Figure no.1 Water uptake study
Local
delivery also increases the stomach wall receptor site bioavailability and
increases the efficacy of drugs to reduce acid secretion. 6 This
principle may be applied for improving systemic as well as local delivery of RHCl, which would efficiently reduce gastric acid
secretion. Several approaches are currently used to prolong gastric retention
time. These include floating drug delivery systems, also known as hydrodynamically balanced systems, swelling and expanding
systems, polymeric bioadhesive systems,
modified-shape systems, high-density systems, and other delayed gastric
emptying devices. 7,8 The principle of buoyant preparation offers a
simple and practical approach to achieve increased gastric residence time for
the dosage form and sustained drug release. In context of the above principles,
a strong need was recognized for the development of a dosage form to deliver RHCl in the stomach and to increase the efficiency of the
drug, providing sustained action.
MATERIALS AND
METHODS:
MATERIALS:
RHCl, HPMC K4M, Polaxomer WSR 1105
were obtained as a gift sample from Wockhardt Ltd., Aurangabad. All other
chemicals used were of research grade.
METHODS:
Formulation of RHCl floating tablets:
Tablets were prepared
by conventional direct compression method. The various excipients
used are listed in table no 1. RHCl (300mg) was mixed with required quantities of excipients as per table no 1. The
blend was compressed
directly on the Karnawati
multistation automated tablet press. The tablets were
round flat beveled. The formulations of batches (A1-A14) are shown in Table no
1.
Evaluation of floating
tablets:
The
prepared tablets were evaluated for hardness, weight variation, thickness,
floating time, in vitro Buoyancy, in vitro dissolution and water uptake. The
hardness of the tablet was determined using Monsanto hardness
tester. The thickness was measured by Vernier
calipers.
Figure no.2 Optimization of HPMC.
In vitro Buoyancy
studies:
The in vitro buoyancy
was determined by floating lag time, as per the method described by Rosa et al.
9 The tablets were placed in a 100-mL beaker containing 0.1N HCl. The time required for the tablet to rise to the
surface and float was determined as floating lag time.
In vitro dissolution
studies:
The release rate of RHCl from floating tablets (n = 3) was determined using
United States Pharmacopeia (USP) 24. Dissolution Testing Apparatus 2
(paddle method). The dissolution test was performed using 900 mL of 0.1N HCl, at 37 ± 0.5°C and
75 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus
hourly for 8 hours, and the samples were replaced with fresh dissolution
medium. The samples were filtered through a 0.45-µ membrane filter and diluted
to a suitable concentration with 0.1N HCl. Absorbance
of these solutions was measured at 315 nm using a Jasco
V630 UV/Vis double-beam spectrophotometer. Cumulative percentage drug release
was calculated using an equation obtained from a standard curve.
Water uptake study:
The swelling of the polymers can
be measured by their ability to absorb water and swell. The swelling property
of the formulation was determined by various techniques 11, 12.
The water uptake study of the tablet was done using USP dissolution
apparatus II. The medium (0.1 M HCl) 900ml, rotated
at 75 rpm, was maintained at 37±0.5 ◦C throughout the study.
After a selected time intervals, the tablets were withdrawn, blotted to remove
excess water and weighed. Swelling characteristics of the tablets were
expressed in terms of water uptake (WU) 13 as
Kinetic Modeling of
Drug Release:
The dissolution
profile of all the batches was fitted to first-order, 14,15 Higuchi
(Matrix), 16-18 Hixon-Crowell, 19
Korsemeyer and Peppas,
10,20,21 to ascertain the kinetic modeling of drug release. PCP DISSO V 2.08 software was used to
determine the best fit model
RESULTS AND
DISCUSSION:
Table
no. 2 depicts the physical parameters (hardness
and thickess), floating lag time (Buoyancy), best fit
model (A1 toA14). Hardness and thickness were within the range. In-vitro
buoyancy was found to be maximum in case of A1 and minimum in case of A13, it
depends upon the concentration of effervescent system (sodium bicarbonate and
citric acid) and lactose. As the concentration of effervescent system and
lactose increases in-vitro buoyancy decreases. Results of water uptake study
are shown in figure no. 1, in which A4 showed highest while A1 showed lowest
water uptake which depends upon concentration of HPMC. Floating time was found to be more than 24 hrs in
all the formulation batches.
Figure no.3
Optimization of Polaxomer WSR 1105.
RHCl tablets prepared using polymers such as HPMC K4M
and polaxomer did not exhibit sufficient swelling to
provide in vitro buoyancy (results not shown). An effervescent approach was
then adopted. Batches (A1 to A14) were developed with varying concentrations of
polaxomer, HPMC K4M, sodium bicarbonate, citric acid
and lactose. HPMC and polaxomer were used as gelling
agent and sustaining agent, sodium bicarbonate acts as a gas generating agent,
it generates CO2 in the
presence of dissolution medium (0.1N HCl). The gas
generated is trapped and protected within the gel, formed by hydration of
polymer, thus decreasing the density of the tablet. As the density of the
tablet falls below 1, the tablet becomes buoyant. Since the pH of stomach is
elevated under fed condition (~3.5), citric acid was incorporated in the
formulation to provide an acidic medium for sodium bicarbonate. Moreover,
citric acid has a stabilizing effect on RHCl
formulations.
Optimization
of HPMC:
From figure no.2, it
is clear that the release is maximum in case of A1 than A2, A3 and A4, but as
the concentration of HPMC was less in case of A1 and A2, The tablet showed
burst release rather than controlled release as that of A3. The release was
very poor in batch A4 and hence HPMC concentration was taken as optimized in
case of A3.
Optimization
of Polaxomer:
From figure no.2, it
is clear that the release is maximum in case of A5 than A3, A6 and A7 due to
presence of less polaxomer in A5.
Figure no.4
Optimization of gas generating system.
Optimization
of amount sodium bicarbonate and citric acid ratio:
All the remaining
batches from A8 to A14 were developed to optimize the amount of effervescent
system (sodium bicarbonate to citric acid ratio). As polaxomer
and this effervescent system has major effect on the release of drug, these
batches A8 to A14 were developed by varying the concentration of polaxomer as well as amount of sodium bicarbonate to citric acid ratio
keeping HPMC constant as found in case of optimized A3. The batch which showed
maximum release in 8th hrs was selected as optimized batch (figure
no. 4).
A8 batch consisting of
polaxomer 1% w/w showed maximum drug release (88%) in
8th hrs. It was observed that increase in the concentration of polaxomer decreases the release. Decrease in the release
may be attributed to the chemical structure of polaxomer
which comprises of central block of relatively hydrophobic polypropylene oxide
(PPO) surrounded on both sides by the blocks
Table
no. 2
Evaluation parameters of batches.
|
Batch
|
Hardness Kg/cm2± SD(n=6)
|
Thickness (mm)(n=6)
|
In-vitro Buoyancy (seconds) ±SD(n=5)
|
Best fit model
|
|
A1
|
3.68±0.2082
|
3.58±0.376
|
17.6±1.1402
|
Peppas
|
|
A2
|
4.22±0.1000
|
3.42±0.492
|
23.8±2.5884
|
Matrix
|
|
A3
|
4.18±0.1169
|
3.50±0.447
|
33.6±2.7019
|
Peppas
|
|
A4
|
3.48±0.1528
|
3.50±0.447
|
38.8±3.3466
|
No
|
|
A5
|
5.18±0.1528
|
3.08±0.492
|
37.803±4.07
|
Hixon-crowel
|
|
A6
|
4.37±0.1000
|
3.00±0.000
|
39.508±10.89
|
First
order
|
|
A7
|
4.17±0.1528
|
3.50±0.548
|
71.6±2.6077
|
Hixon-crowel
|
|
A8
|
4.00±0.2000
|
3.50±0.447
|
65.887±3.92
|
Peppas
|
|
A9
|
4.12±0.3512
|
3.42±0.492
|
43.390±1.18
|
Peppas
|
|
A10
|
4.30±0.2517
|
3.50±0.548
|
87.8±5.6745
|
First
order
|
|
A11
|
3.78±0.1000
|
3.67±0.816
|
31.4±1.5166
|
First
order
|
|
A12
|
4.38±0.2646
|
3.58±0.376
|
75.8±11.4978
|
Hixon-crowel
|
|
A13
|
4.02±0.1528
|
3.75±0.418
|
89.4±6.8044
|
First
order
|
|
A14
|
4.13±0.2517
|
3.17±0.408
|
81.752±4.05
|
Peppas
|
of relatively
hydrophilic polyethylene oxide (PEO). Due to the PEO, PPO, when these molecules
are immersed into the aqueous solvents, they form micellar
structures above critical micellar concentration. The
drug may get entrapped in the micelles formed at critical micellar
concentration, which prevents the release of drug from that network.22
Variation in the amount of citric acid did not affect drug release from the
matrix as observed in figure no 4. But lactose a hydrophilic agent may have
facilitated higher drug release which may be due to its capillary action
without affecting the matrix (thereby floating ability). 23
CONCLUSION:
The batch which
consists of polaxomer 1% w/w, HPMC 25% w/w,sodium bicarbonate 7% w/w, citric acid 5% w/w, lactose
10% w/w showed maximum release (88%) at the end of 8 hrs. Thus, it is evident
from this investigation that this gas powered floating matrix tablet could be
promising delivery system of Ranitidine hydrochloride with sustained release
action and improved drug availability at target area.
ACKNOLEDGEMENT:
We would like to thank
Mrs Fatma Rafiq Zakaria, Hon’ble Chairman of Maulana Azad
Educational Trust, Dr Rafiq Zakaria
Campus for providing all the facilities. We are also thankful to Wockhardt Ltd., Aurangabad,
for providing gift samples.
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