Formulation and Evaluation of Gastro-Retentive Drug
Delivery System of Some Selected Drugs
Patil NarayanVenkatrao*, S. Appala Raju.
Department of Pharmaceutical Analysis,
HKES’s College of Pharmacy, Sedam Road, Gulbarga, Karnataka-585105, India.
*Corresponding Author E-mail: patilnarayanv@gmail.com
ABSTRACT:
Itopride hydrochloride is a novel gastroprokinetic, widely
absorbed from the stomach and upper part of the small intestine and absorption
becomes less as the drug passes beyond this. The bioavailability can be
improved by making the drug completely absorbed in the stomach and upper part
of the small intestine. It has a half life of 5h2. The short half life of
Itopride hydrochloride necessitates frequent administration. Therefore it is
highly desirable to have a controlled release dosage form for Itopride
hydrochloride. The objective of this present investigation was to formulate
gastro-retentive tablets of itopride hydrochloride using a gas generating
agent. We attempted to formulate to retain the matrix tablet in the stomach and
subsequently to provide delivery of the drug over the period of time of GRT.
KEYWORDS: Itopride hydrochloride , Invitro drug release.
INTRODUCTION:
The gastric emptying time has been reported
to be from 2-6 h in humans in the fed state. So when a sustained release dosage
form is administered orally, sufficient bioavailability could not be obtained,
especially for drugs having a limited absorption site in the intestinal tract.
Therefore modern oral controlled release dosage forms must be based on
gastrointestinal physiology, so that the drug is fully available for absorption1.
EXPERIMENTAL:
Chemical and Reagents:
Itopride hydrochloride, Eudragit RSPO, HPMC E15 and
Aerosil were obtained as a gift sample from Hetero Drugs Ltd., Hyderabad. HPMC
K4M, HPMC K15M were obtained as a gift sample from Micro Labs., Bangalore.
Sodium bicarbonate and dicalcium phosphate were obtained from S.D. Fine Chem.
Ltd. Mumbai. All other chemicals and solvents used were of analytical reagent
grade.
Formulation of Itopride hydrochloride gastro-retentive
drug delivery system:
Gastro-retentive tablets of
itopride hydrochloride were prepared by direct compression method using sodium
bicarbonate as gas generating agent and water soluble polymer (different grades
of HPMC) as hydrophilic matrix in each formulation. The composition of
formulation is given in the Table 1. Based on the trial bases the compositions
of the formulation were made by using different swellable polymers to float
more than 5 h. HPMC used as swellable polymer i.e. to float but not to retard
the release. All the ingredients except aerosil were blended in glass mortar
uniformly. After sufficient mixing of drug as well as other excepients, aerosil
was added and further mixed for additional 2-3 min. Powder thus obtained was
compressed into tablets on a 10 station single punch rotary tablet compression
machine (Rimek). A flat-faced punch 12mm in diameter was used for tableting.
Compression force of the machine was adjusted to obtain the hardness of 4 kg/cm2
and6 kg/cm2 for different batches.
Evaluation of gastro-retentive drug delivery system:
The prepared gastro-retentive tablets were evaluated
for weight variation, thickness, buoyancy, and in vitro release
characteristics. All the formulations were subjected to detailed dissolution
study. The hardness of the tablets was measured by Monsanto hardness tester and
thickness of the tablets was measured by using Vernier calipers.
Table 1: Formulation of Itopride Hydrochloride
Gastro-Retentive Tablet
|
Ingredients
|
Quantity Per
Tablet (mg)
|
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
F7
|
F8
|
F9
|
F10
|
F11
|
F12
|
ItoprideHCl
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
100
|
|
HPMC K4M
|
150
|
150
|
200
|
200
|
---
|
---
|
---
|
---
|
---
|
---
|
---
|
---
|
HPMC K15M
|
---
|
---
|
---
|
---
|
150
|
150
|
200
|
200
|
---
|
---
|
---
|
---
|
HPMC E15
|
---
|
---
|
---
|
---
|
---
|
---
|
---
|
---
|
150
|
150
|
200
|
200
|
Eudragit RSPO
|
30
|
30
|
40
|
40
|
30
|
30
|
40
|
40
|
30
|
30
|
40
|
40
|
|
Sodium
bicarbonate
|
40
|
40
|
40
|
40
|
40
|
40
|
40
|
40
|
40
|
40
|
40
|
40
|
|
Di-calcium
phosphate
|
64
|
64
|
4
|
4
|
64
|
64
|
4
|
4
|
64
|
64
|
4
|
4
|
|
Aerosil
|
16
|
16
|
16
|
16
|
16
|
16
|
16
|
16
|
16
|
16
|
16
|
16
|
Each tablet
weight
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
400
|
Compression force used to get hardness (kg/cm2)
|
4
|
6
|
4
|
6
|
4
|
6
|
4
|
6
|
4
|
6
|
4
|
6
|
Table 2: Evaluation Data of Gastro-retentive
Tablet of Itopride Hydrochloride.
|
Formulation
|
Buoyancy Lag. Time
(min)
|
Total Buoyancy
Time (h)
|
Diameter
mm ± SD
|
Thickness mm ±
SD
|
Drug content uniformity
(%)
|
Per cent Drug
Released
|
|
3 h
|
6 h
|
9 h
|
12 hrs
|
|
F1
|
7.43
|
8
|
11.12 ± 0.1
|
4.36 ± 0.1
|
99.78
|
44.06
|
63.25
|
78.71
|
99.190
|
|
F2
|
8.20
|
9.5
|
11.21 ± 0.1
|
4.14 ± 0.1
|
97.56
|
30.29
|
48.59
|
68.13
|
88.032
|
|
F3
|
8.48
|
9
|
11.97 ± 0.1
|
4.28 ± 0.1
|
99.50
|
35.89
|
53.03
|
70.27
|
91.184
|
|
F4
|
9.45
|
10
|
11.02 ± 0.1
|
4.15 ± 0.1
|
96.85
|
26.92
|
46.19
|
65.03
|
85.723
|
|
F5
|
5.33
|
9.5
|
11.07 ± 0.1
|
4.61 ± 0.1
|
97.23
|
38.02
|
52.14
|
70.03
|
88.210
|
|
F6
|
6.22
|
10.5
|
11.18 ± 0.1
|
4.55 ± 0.1
|
98.91
|
27.27
|
42.73
|
59.61
|
84.657
|
|
F7
|
5.50
|
10
|
10.95 ± 0.1
|
4.35 ± 0.1
|
96.98
|
30.11
|
46.99
|
63.60
|
86.078
|
|
F8
|
6.29
|
11
|
11.08 ± 0.1
|
4.18 ± 0.1
|
97.12
|
25.05
|
40.60
|
56.59
|
81.015
|
|
F9
|
7.56
|
10
|
11.15 ± 0.1
|
4.55 ± 0.1
|
98.36
|
36.95
|
56.14
|
73.38
|
87.233
|
|
F10
|
9.38
|
11.5
|
11.22 ± 0.1
|
4.26 ± 0.1
|
98.56
|
27.98
|
50.19
|
69.11
|
78.883
|
|
F11
|
6.51
|
11
|
11.12 ± 0.1
|
4.34 ± 0.1
|
99.01
|
30.74
|
54.99
|
71.24
|
82.969
|
|
F12
|
9.16
|
12
|
11.23 ± 0.1
|
4.22 ± 0.1
|
98.39
|
25.49
|
47.17
|
65.03
|
74.263
|
Stability studies:
The stability of the drug in the formulation was
confirmed by FTIR spectral analysis. FTIR spectra of the pure and all the
formulations were determined using Shimadzu FTIR spectrophotometer by KBr disc
method.
Buoyancy determination:
Buoyancy time was determined by using USP XXIV paddle
dissolution apparatus,3 at 100rpm using 900ml of 0.1N HCl and
temperature was maintained at 37±0.5°C throughout the study. The duration of
buoyancy (buoyancy time) is the time the tablet floats in the dissolution
medium (including buoyancy lag time).
Swelling Study4: The swelling behavior of a dosage form was
measured by studying its weight gain or water uptake. The dimensional changes
could be measured in terms of the increase in tablet diameter and/or thickness
over time. Water uptake was measured in terms of per cent weight gain, as given
by the equation.
WU = (W1 – W0) X 100
W0
W1 = Weight of dosage form at time t.
W0 = Initial weight of dosage form
In vitro drug release studies:
The in vitro release studies were carried by
using fabricated equipment called Modified Rossett-Rice test5 Tablet
was placed in the modified beaker containing 100ml of 0.1NHCl at 37±0.5°C and
at 75rpm. 5ml of the sample was collected at regular intervals for 12h and the
same volume of fresh medium was added. The samples withdrawn were filtered and
drug content in each sample was analysed after suitable dilution by Elico
UV/Visible spectrophotometer at 249nm.
RESULTS AND DISCUSSION:
The physical parameters (thickness and diameter),
buoyancy time, drug content and in vitro drug release of all the
formulation are shown in Table 2. The thickness of the tablets prepared was in
the range of 4.14 to 4.61mm and the diameter was in the range of 12.00 to 12.25mm.
FTIR spectra analytical reports confirmed that there was no interaction between
drug and excipients used.
Carbon dioxide is formed within the tablet
containing effervescent agent when the tablet is brought in contact with the
acidic dissolution medium. The low density of hydroxypropyl methylcellulose
assists in floating the tablet. Moreover, the gelling capacity of HPMC also
helps to float the tablet by entrapping carbon dioxide gas in the gel network of
HPMC. The gelling capacity of HPMC prevents disintegration of the tablet during
the dissolution study.
Fig 1: Swelling index of tablets of all
formulations
From the results it can be concluded that the tablets
compressed at low compression force showed good buoyancy lag time; this may be
due to increase in bulk volume and porosity but total buoyancy time is less.
The tablets compressed at high compression force showed increased buoyancy lag
time; this may be due to reduction in bulk volume and porosity but total
buoyancy time is more.
Different grades of HPMC were chosen as swellable
polymer because it is widely used as low-density hydrocolloid system, upon
contact with water a hydrogel layer would be formed to act as a gel boundary
for the delivery system, but it would fail to retard the release of drug
through the matrix because of its solubility in stomach pH6.
Eudragit RSPO is used in combination with HPMC to slow the drug release;
Eudragit ability to do this may be caused by the low solubility in gastric pH.
Sodium bicarbonate is used as gas generating agent which induces floatability
of the tablet and it makes tablet remain to float in stomach. Aerosil is used
as lubricant and glidant to improve flow property of powder blend. Aerosil also
imparts hydrophilic environment and increases wettability of polymers which
leads to uniform swelling and uniform drug release.
Swelling ratio describes the amount of water that is
contained within the hydrogel at equilibrium and is a function of the network
structure, hydrophilicity and ionization of the functional groups.
Bar graph of % swelling index against time is shown in
fig 1. From the results it was concluded that swelling increases with respect
to time, because the polymer gradually absorb water due to hydrophilicity of
polymer. The outermost hydrophilic polymer hydrates and swells and a gel
barrier is formed at the outer surface. As the gelatinous layer progressively
dissolves and/or is dispersed, the hydration swelling release process is
repeated towards new exposed surfaces, thus maintaining the integrity of the
dosage form.
In the present study, the higher swelling index was
found for tablets containing HPMC K15M having nominal viscosity of
15,000 cps. Thus, the viscosity of the polymer had major influence on swelling
process, matrix integrity, as well as floating capability, hence from the above
results it can be concluded that linear relationship exists between swelling
process and viscosity of polymer.
The drug release profile of the tablets having total
buoyancy time of 11h or more are shown in fig 2.
Among all the formulations, formulation F12
contains polymer HPMC E15 (Drug: Polymer is 1:2) compressed to get 6
kg/cm2 hardness showed maximum release retardation with total
buoyancy time of 12h.
Fig 2: Release Profile of Itopride hydrochloride in
0.1N HCl
In conclusion, controlled release gastro-retentive
tablets can be prepared by incorporating sodium bicarbonate as gas generating
agent in HPMC E15 and Eudragit RSPO.
ACKNOWLEDGMENT:
The author are grateful to the principal, H.K.E.S s’ college
of pharmacy, Gulbarga for his support & encouragement and for providing
research facilities.
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Shyamala, B., and
Harsha., The Eastern Pharmacist., 2001, 44, 105.
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Itopride Drug Profile (Online).,
2007.
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The United States
Pharmacopoeia 24., The United states Pharmacopoeial Convention., Rockville, MD.,
2000, 1942.
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Gao, P., and Meury, H.R.,
J. Pharm. Sci ., 2000, 85(7), 725.
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Gohel,C.M., Mehta,R.P.,
Dave,K.R., and Bariya,H.N., Dissolution Technologies., 2004, 1, 22.
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article 34