ISSN 0974-3618
(Print) www.rjptonline.org
0974-360X (Online)
RESEARCH ARTICLE
Formulation and in vitro
evaluation of once-daily methyldopa sustained release matrix tablets
Ruba Ismail*,
Tamim Hammad and Faten Madani
Pharmaceutics and
Pharmaceutical Technology Department, Faculty of Pharmacy, Tishreen University,
Lattakia, Syrian Arabic Republic.
*Corresponding Author E-mail: losklarita2@hotmail.com
Methyldopa, an anti-hypertensive drug
having a half life of less than 2 hours, and given with a dose of 250 mg 3-4
times daily.
Objective: The present study was for
objective of developing a sustained release (SR) matrix tablets of methyldopa
using hydroxypropyl methylcellulose(HPMC) as release controlling factor, and to
study the effect of some formulation factors on drug release from tablets.
Methods:
Hydrophilic SR matrix tablets containing 250 mg of methyldopa were
prepared using wet granulation method. Granules were evaluated for moisture
content, loose bulk density, tapped bulk density, compressibility index and
hausner’s ratio. Tablets were subjected to physiochemical studies and in vitro dissolution study. Effect of
concentration and viscosity grade of HPMC, both
binder and lubricant concentration on drug release from matrix tablets was evaluated .
Results: All formulations showed
physiochemical properties which appear to be in compliance with pharmacopeial
standards. From the in vitro dissolution
studies, it was clear that as the concentration or viscosity of polymer
increased, the rate of drug release was found to be decreased. Higher concentration of binder (PVP K30)
showed slower release of drug, while the level of lubricant(magnesium stearate
and talc) appeared to insignificantly affect release rates. Drug release
kinetics of about all formulations correspond best to Korsemeyer-Peppas model
and drug release mechanism was found to be anomalous (non-Fickian) diffusion
based on release exponent value. The formulation F6 (containing 15% HPMC K100M
) was selected as the optimized formulation as it sustained the release over 24
hrs.
Conclusion: The results of this study
showed that the drug release from HPMC based matrix tablets using methyldopa as
a drug model could be modulated by varying the polymer concentration, the
polymer viscosity and the binder concentration with no significant effect of
varying the lubricant concentration.
KEYWORDS: Methyldopa; Sustained release; Hydrophilic
matrix; HPMC; Wet granulation.
1. INTRODUCTION:
As the expense and
complications involved in marketing of new drug entities have increased, all
with concomitant recognition of therapeutic advantages of controlled drug
delivery regimes, a greater attention has been focused on the development of
sustained or controlled release drug delivery systems[1]. Sustained release
(SR) drug delivery systems are designed to achieve a prolonged therapeutic
effect by continuously releasing medication over an extended period of time[2].
These dosage forms are recognized to provide a better control of plasma drug
levels, reduce side effects and increase effectiveness of the drug by reducing
the dose required and hence improving
patient compliance[3-5].
Introduction of
matrix tablet as (SR) has given a new breakthrough for novel drug delivery
system (NDDS) in the field of pharmaceutical technology[5,6]. In fact, matrix
tablets may be defined as the “oral solid dosage forms in which the drug or
active ingredient is homogeneously dispersed throughout the hydrophilic or
hydrophobic matrices which serves as release rate retardants”[7]. Because of
their flexibility, hydrophilic polymer matrix systems are widely used in oral
controlled drug delivery to obtain a desirable drug release profile, cost
effectiveness, and broad regulatory acceptance[8,9].
Nonionic cellulose
ethers, and most frequently hydroxypropyl methylcellulose (HPMC, hypromellose)
have been widely studied for their applications in hydrophilic matrix systems
[10]. When in contact with water, HPMC hydrates rapidly and forms a gelatinous
barrier layer around the tablet. The rate of drug release from HPMC matrix is
dependent on various factors such as type and concentration of polymer, drug,
particle size of drug and polymer, and the type and amount of excipients used
in the formulation [10,11].
Methyldopa
(3-hydroxy-α-methyl-L-tyrosine) is an antihypertensive agent which is regarded as first line, first choice
of drug to treat hypertension during pregnancy. It is the only drug which has
been fully assessed and shown to be safe for mother, neonate, and infant
[12,13]. Methyldopa
is slightly soluble in water, freely soluble in dilute mineral acids[12,14].
Its absorption from the gastrointestinal tract is incomplete and variable, and
bioavailability after oral administration is about 25% (ranging from 8 to 62%).
Methyldopa has a short half life of about 2 hours and it is typically
administered three or four times
daily[12]. In order to overcome adverse side effects and poor patient
compliance related to this short half life, an oral sustained release dosage
form of methyldopa is desirable. Such systems are also expected to increase
bioavailability, reduce dose and maintain uniform drug levels over the period
of treatment.
The objective of the present study was to
develop sustained release matrix tablets of methyldopa and to examine the
effects of various formulation variables like polymer concentration, polymer
viscosity, binder level and lubricant level on in-vitro drug release.
2. MATERIALS
AND METHODS:
2.1.
Materials
Methyldopa was obtained from Yarrow chemicals (Mumbai,
India). Hydroxypropyl methylcellulose
(Methocel K4M, Methocel K100M) was obtained from Sigma-Aldrich (Steinheim, Germany). Polyvinylpirrolidone K30 (PVP) was purchased from Otokemi
(Mumbai, India). Talc, magnesium stearate and lactose were purchased from S.D.
Fine Chem Ltd. ( Mumbai, India). All other chemicals used were of
analytical grade.
2.2.
Methods
2.2.1. Preparation
of Tablets
Methyldopa sustained release matrix tablets
were prepared using wet granulation method. A well precised quantity of
methyldopa was mixed thoroughly with the required quantities of lactose and
HPMC and a sufficient quantity of binding agent (PVP K-30) was added slowly.
Isopropyl alcohol was added drop wise till that a suitable mass for granulation
was obtained. After, the wet mass was
sieved through 16 mesh. The granules were dried at 50±5°C for 3-4 hours in an
oven until the required moisture level was obtained. The dried granules were
homogenized by passing them through 20
mesh and lubricated with magnesium stearate by further blending for 3 mins and
finally talc was added to the blend. The lubricated granules were compressed on
single punch tablet machine into tablet
each containing 250 mg Methyldopa and a total weight of 400±2mg .
Different formulations of methyldopa
sustained release tablets are listed in (Table 1) .
2.2.2.
Evaluation of granules
Granules were
evaluated for moisture content, bulk
density, tapped density, Carr’s index and Hausner ratio.
2.2.2.1. Determination
of Moisture Content
The percentage of
moisture was calculated using IR balance. Three samples from each mixture
(sample weight=100mg) were placed in the moisture analyzer and the balance
captures the initial weight. An infrared energy heater is used to heat the
sample to 1050C. During the test the balance records the weight.
When the sample no longer loses weight the instrument shuts off the heat and
uses the final weight to calculate percentage moisture content precentage in
the sample [15].
2.2.2.2. Loose
Bulk Density (LDB)
A quantity of 2 g
of granules from each formula was poured into a graduated cylinder. After the
initial volume was noted, LBD was calculated using the following
equation[16,17]:
LBD = weight of
the powder/volume of the packing ….(1)
2.2.2.3. Tapped
Bulk Density(TBD)
The volume was
measured by tapping the powder for 100 times. Tapping was continued until the difference between successive
volumes is less than 2%, and TBD was calculated using the following
equation [16,17]:
TBD = weight of
the powder/tapped volume of the packing …….(2)
2.2.2.4. Carr’s
index (% Compressibility index )
The
Compressibility index of the granules was determined by Carr’s Compressibility
[18]. The compressibility index of the granules was determined using following
equation [16]:
Carr’s index (%) =
[(TBD-LBD)/ TBD] x100 …….. (3)
Table
1:Composition of various formulations of methyldopa sustained release matrix tablets (Weight in mg)
|
Ingredient
|
Formula code
|
|
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
F7
|
F8
|
F9
|
|
Methyldopa
|
250
|
250
|
250
|
250
|
250
|
250
|
250
|
250
|
250
|
|
HPMC
K100M
|
10
|
20
|
30
|
40
|
50
|
60
|
-
|
40
|
40
|
|
HPMC
K4M
|
-
|
-
|
-
|
-
|
-
|
-
|
60
|
-
|
-
|
|
Lactose
|
114
|
104
|
94
|
84
|
74
|
64
|
64
|
64
|
78
|
|
PVP-K30
|
20
|
20
|
20
|
20
|
20
|
20
|
20
|
40
|
20
|
|
Isopropyl
alcohol
|
q.s.
|
q.s.
|
q.s.
|
q.s.
|
q.s.
|
q.s.
|
q.s.
|
q.s.
|
q.s.
|
|
Mg
stearate
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
4
|
|
Talc
|
4
|
4
|
4
|
4
|
4
|
4
|
4
|
4
|
8
|
2.2.2.5. Hausner
Ratio
Hausner ratio is an indirect index of ease of
granules flow. It is calculated by the equation[19] :
Hausner ratio=
TBD/LBD ........ (4)
2.2.3.
Evaluation of Tablets
2.2.3.1. Uniformity of Weight
Twenty
tablets of each formulation were weighed
individually and collectively , then the average weight was determined. The
percentage deviation from the average weight was calculated and checked for
weight variation. The percentage difference in the weight variation should be
within the permissible limits (±5%). The tablets meet the European Pharmacopeia (5th
edition) weight uniformity test if not more than two of the individual weights
deviate from the average weight by more than the percentage limit
2.2.3.2. Drug Content Uniformity
Ten tablets of each formulation were selected
randomly and individually assayed for their content. Each tablet of was weighed individually and dissolved in HCl
(0.1N). These solutions were filtered through 0.45μ membrane and
absorbance was observed at 280 nm in UV-Visible spectrometer according to the
European pharmacopeia. The preparation complies with the test if each
individual content is 85 to 115 per cent of the average content. If one
individual content is outside the limits of 85 to 115 % of the average content
but within the limits of 75 to 125 %, the determination is repeated using
another 20 dosage units. The preparation complies with the test if not more
than three of the individual contents of the total sample of 30 dosage units is
outside the range from 85 to115 % of the average content and none is outside
the limits of 75 to 125 % of the average content.
2.2.3.3. Hardness test
Hardness test was conducted for 10 tablets
from each batch using hardness tester and the values were given in Kg/cm2 with
their mean and standard deviation SD. The tablet hardness of 5kg is considered
as suitable for handling the tablet [20].
2.2.3.4. Friability Test
Weighed amount of
10 dedusted tablets were subjected to rotating drum of friability test
apparatus. The drum rotated at a speed of 25 rpm and the apparatus was operated
for 4 minutes. At the end of test, tablets were dedusted and reweighed; the loss
in the weight of tablet is the measure of friability and is expressed in
percentage as:
% Friability =
(loss in weight / initial weight)x100 ……….(5)
A maximum loss of
not more than 1% is generally considered acceptable according to the European
Pharmacopeia (5th ed.) .
2.2.3.5. In Vitro Drug Release Studies
The release of
methyldopa from matrix tablets was carried out using USPXXIV Type II
dissolution apparatus(basket method) at
a rotation speed of 75 rpm, and a temperature of 37±0.5°C. In order
to simulate the gastrointestinal transit conditions ,the tablets were subjected
to different dissolution media. Initially ,the drug release was carried out for
2 hrs in 0.1 N HCl, and then in phosphate buffer pH 6.8 up to 24 hrs (900 ml).
Samples were withdrawn at predetermined time intervals during 24 hours,
filtered by passing through 0.45 μm membrane filters, diluted suitably and
analyzed spectrophotometrically at 280 nm. Each test was conducted in
triplicate (6 tabets in set) for each formulation .
2.2.3.6. Drug release kinetics
The release data
obtained were treated according to zero-order (cumulative amount of drug
release versus time), first order (log cumulative percentage of drug released
versus time), Higuchi (cumulative percentage of drug release versus square root
of time).In order to further determine the mechanism of drug release,
dissolution data were also fitted according to the well-known exponential
equation (Korsmeyer equation); which is often used to describe the drug release
behavior from polymeric systems [21]:
log (Mt/Ma)= n.log
t+ log K …………..(7)
Where, Mt is the
amount of drug release at time t, Ma is the amount of drug released after
infinite time; k is a release rate constant incorporating structural and
geometric characteristics of the tablet and n is the diffusion exponent
indicative of the mechanism of drug release [22].
3. RESULTS
AND DISCUSSION:
3.1.
Evaluation of granules
The granules of all the formulations (F-1
to F-9) were evaluated for loose bulk
density(LBD), tapped bulk density(TBD), Carr’s index(CI), Hausner’s ratio (HR)
and moisture content (Table 4). The loose densities and tapped densities for
all the batches were found in the range of 0.561±0.023 to 0.621±0.021 g/cm3 and
0.661±0.015 to 0.741±0.031 g/cm3 respectively. Compressibility index values
were ranging from 11.186% to 16.194% . Generally, compressibility index values
up to 15 % result in good to excellent flow properties . The results of
Hausner’s ratio ranged from 1.134 to 1.193 which indicated good flow properties
of granules . All these results indicate
that the granules possessed satisfactory flow properties and compressibility.
Moisture content of all the formulations was found to be satisfactory as it
ranged from 3.44±0.22% to 5.36±0.18% as shown in (Table 4).
3.2.
Evaluation of tablets
3.2.1.
Physical parameters
The tablets of the
proposed formulations were evaluated for weight variation, drug content,
friability and hardness (Table 5). The average percentage deviation of 20
tablets of each formula was less than 5%. Drug content in different batches of
tablets ranged from 96.17±1.63 % to 102.43±1.41% of the average content. The
hardness of tablets of each batch ranged between 5.71±0.38 and 8.9±0.41 kg/cm2.
This ensures good handling characteristics for all batches. The friability
percentage of all formulations was found to be less than 1% ensuring that the
tablets were mechanically resistant.
3.2.2. In vitro drug release studies
HPMC present on the surface of matrix
tablets initially hydrates during dissolution and forms an outer gel layer on
matrix tablet surface. Progressive contact with the medium leads to subsequent
bulk hydration of the matrix. Eventually, this leads to HPMC chain relaxation,
followed by erosion of the matrix. The drug release rate and mechanism is
controlled by the matrix swelling, diffusion of drug through the gel layer
and/or matrix erosion.
3.2.2.1. Effect
of HPMC K100M concentration
In order to investigate the effect of
polymer concentration on drug release profile, different formulations
containing various percentages of HPMC K100M were used. The release profiles of
different formulations (F-1 to F-6) of methyldopa sustained release matrix
tablets are shown in Fig.1. When HPMC K100M concentration was increased from
2.5% to 15% the drug release rate was found to be decreased. Formulations F1,
F2, F3, F4 and F5 released 73.68%, 54.56%, 42.99% and 39.70% and 36.77% of
methyldopa at the end of 2 hours; and 99.04%, 97.79% , 97.96% 98.24% and 99.46% of drug at the end of 5 hours, 8
hours, 10 hours,16 and 20 hours respectively.
While F6 that contains 15% HPMC K100M
released 26.20% of drug at the end of 2 hours and was able to sustain the
release up to 24 hour (98.51% of drug was released at the end of 24 hours) . By
increasing the polymer level a stronger viscous gel susceptible to resist to
erosion of polymer and diffusion of drug layer may be formed. Furthermore,
several factors associated with hydrophilic swellable systems like differences
in water penetration rate, water absorption capacity and by consequent swelling
and polymer erosion, which result from changes in the polymer content, may
contribute to this behavior [23]. These findings assert the suggestions made by
earlier reports where the polymer concentration is known to be one of the key
factors affecting the rate of release from HPMC matrices [24-26].
Table 4: Granules
properties of different formulations of methyldopa sustained release matrix
tablets
|
Batch Code
|
LBD* (g/cm3)
|
TBD* (g/cm3)
|
Hausner’s ratio
|
Carr’s index(%)
|
Moisture Content*(%)
|
|
F1
|
0.561±0.023
|
0.665±0.016
|
1.163
|
13.985
|
3.44±0.22
|
|
F2
|
0.581±0.017
|
0.676±0.019
|
1.164
|
14.053
|
4.25±0.12
|
|
F3
|
0.583±0.014
|
0.661±0.011
|
1.134
|
11.800
|
3.71±0.38
|
|
F4
|
0.612±0.026
|
0.694±0.022
|
1.134
|
11.816
|
3.92±0.33
|
|
F5
|
0.621±0.021
|
0.741±0.031
|
1.193
|
16.194
|
4.8±0.11
|
|
F6
|
0.618±0.17
|
0.725±0.012
|
1.173
|
14.759
|
5.63±0.18
|
|
F7
|
0.599±0.032
|
0.683±0.028
|
1.140
|
12.299
|
5.12±0.32
|
|
F8
|
0.571±0.012
|
0.661±0.015
|
1.158
|
13.616
|
4.52±0.24
|
|
F9
|
0.613±0.054
|
0.701±0.034
|
1.144
|
12.566
|
3.78±0.21
|
*All
the values are expressed as mean ± Standard deviation ,n=3
Table 5: Tablets properties of different formulations of methyldopa
sustained release matrix tablets
|
Batch Code
|
Weight**
(mg) (n=20)
|
Hardness**
(Kg/cm2) (n=10)
|
Friability**
(%) (n=10)
|
Uniformity content**
(%) (n=10)
|
|
F1
|
0.3989±1.55
|
5.71±0.38
|
0.57±0.015
|
102.43±1.41
|
|
F2
|
0.3991±1.52
|
5.99±0.61
|
0.41±0.011
|
98.82±0.96
|
|
F3
|
0.3990±1.9
|
7.12±0.42
|
0.48±0.09
|
96.54±1.57
|
|
F4
|
0.3988±1.6
|
7.19±0.33
|
0.36±0.022
|
99.74±1.32
|
|
F5
|
0.3981±1.2
|
7.52±0.54
|
0.68±0.017
|
99.64±1.05
|
|
F6
|
0.3992±1.75
|
8.25±0.42
|
0.27±0.019
|
101.53±0.87
|
|
F7
|
0.3987±1.55
|
8.12±0.36
|
0.35±0.08
|
96.17±1.63
|
|
F8
|
0.3985±1.83
|
8.99±0.41
|
0.51±0.016
|
98.14±1.18
|
|
F9
|
0.3994±2.1
|
7.95±0.26
|
0.73±0.015
|
101.28±0.78
|
**All the values are expressed as mean ±
Standard deviation
Figure 1:In
vitro drug release plots of methyldopa sustained release matrix tablets
formulations F1-F6
3.2.2.2. Effect of HPMC viscosity grade
To study the effect of different viscosity
grades on drug release, formulation F7 was prepared by using 15% HPMC K4M
instead of HPMC K100M. In comparision to F6 which contains 15% HPMC K100M. The
drug release was remarkably faster from formulation F7 as it released 52.28%
and 97.21% of drug at the end of 2 and 10 hours, respectively versus F6 that
released 26.20% and 98.51% of drug at the end of 2 and 24 hours, respectively
(Figure 2). As a result, the rate of drug release was found to be inversely
related to the viscosity grade of HPMC (K4M, K100M) present in the matrix
structure. At the same amount of polymer, HPMC of higher viscosity induces
greater chain entanglement than a HPMC of low viscosity. With the increase of
the viscosity degree of HPMC, the swelling of its side chains undergoes faster
to form a very strong gel, which had more ability to resist the drug diffusion
and gel erosion, thus decreasing the drug release rate [27].
3.2.2.3. Effect of binder concentration
The effect of concentration of PVP-K30 on
drug release was studied by preparing a formula containing 10% of
PVP K-30 and comparing it to the
formulation which contains 5% of PVP-K30
as shown in Table 3. When concentration of PVP-K30 was increased to 10 %
as in F8, the release rate was slower and drug release was 29.33% and 98.81%
within 2 and 20 hours, respectively (Figure 3). It was indicated that increase
in concentration of PVP-K30 will
better retard the release of methyldopa
from HPMC matrix tablets [28] .
3.2.2.4. Effect of lubricant concentration :
The effect of lubricant on release profile of HPMC K100M matrix
tablets was studied by preparing a formula (F9) containing 3% of lubricants and comparing it to F4 that
contains 1.5% of lubricants. As shown in Fig.2, F9 released 39.49 % of
methyldopa at the end of 2 hours, and 96.83% of the drug at the end of 16
hours. There was no significant difference in the release profile when mixture
of lubricants was incorporated at concentration of 1.5 % (F4) or 3% (F9) (Figure 4). This may be
due to the high strength of HPMC gel
that results in neutralization of the
hydrophobic effect of lubricants
especially at short periods of release where the gel formed had not yet
hydrated enough and the matrix erosion is at its minimum.
Figure 2: In vitro
release of methyldopa from SR matrix
tablets showing the effect of HPMC viscosity on release profile (Formula F6
versus F7)
Figure 3 : : In
vitro release of methyldopa from SR
matrix tablets showing the effect
of PVP concentration on release profile (Formula F8 versus F4)
Figure 4 : In
vitro release profiles of methyldopa from SR
matrix tablets showing the effect
of lubricant concentration on release profile(Formula F9 versus F4)
3.2.3. Drug
release kinetics
The drug release data obtained were
extrapolate d by Zero order, First order, Higuchi and Korsmeyer-Peppas
equations in order to define the pattern of drug release from the matrix
tablets . Correlation coefficients according to each equation for all of the
the formulations are presented in Table 3.
In our study , the in vitro release profiles
of drug from all the formulations could be best expressed by higuchi’s
equation, as the plots showed high
linearity (R2:
0.965 to 0.997). Higuchi equation is followed usually when the release follows
diffusion mechanism. To confirm the mechanism of diffusion, the data were fit
into Korsmeyer-Peppas model (24). All the formulations showed
highest linearity (0.960 to 0.996) with slope (n) values ranging from 0.522 to
0.878 which indicates that the release mechanism was non-Fickian or
anomalous release (0.45 < n <0.89). It can be inferred that the release
was dependent on both drug diffusion and polymer relaxation, which appears to
indicate a coupling of two occurring simultaneous mechanisms: diffusion and
erosion or the so
called anomalous diffusion.
Table 3: Kinetics
of drug release from methyldopa matrix tablets
|
Formulation
|
Correlation Coefficient (R2)
|
Release exponent (n)
|
Mechanism
|
|
Zero order
|
First order
|
Higuchi
|
Korsemeyer and Peppas
|
|
F1
|
0.911
|
0.913
|
0.965
|
0.960
|
0.522
|
anomalous diffusion.
|
|
F2
|
0.940
|
0.941
|
0.993
|
0.995
|
0.525
|
anomalous diffusion.
|
|
F3
|
0.955
|
0.920
|
0.997
|
0.994
|
0.625
|
anomalous diffusion.
|
|
F4
|
0.910
|
0.955
|
0.985
|
0.988
|
0.577
|
anomalous diffusion.
|
|
F5
|
0.904
|
0.918
|
0.989
|
0.992
|
0.600
|
anomalous diffusion.
|
|
F6
|
0.972
|
0.928
|
0.989
|
0.990
|
0.878
|
anomalous diffusion.
|
|
F7
|
0.904
|
0.968
|
0.981
|
0.981
|
0.595
|
anomalous diffusion.
|
|
F8
|
0.916
|
0.982
|
0.985
|
0.989
|
0.615
|
anomalous diffusion.
|
|
F9
|
0.906
|
0.976
|
0.983
|
0.985
|
0.600
|
anomalous diffusion.
|
4. CONCLUSION:
The present study
was carried out to develop once-daily SR matrix tablets of methyldopa based on the matrix tablet technology using
HPMC as release rate retardant . Drug release was found to be affected by the
polymer level, polymer viscosity grade and binder level.
From the Korsmeyer
Peppas study, the n value of about all the formulations show that the release
profile obeys non-Fickian diffusion which suggests that drug is released via,
swelling of matrix and followed by diffusion and erosion mechanism .
Based on in vitro release studies,
formulation F6 containing 15% of K100M showed satisfactory results because the
release of drug could be sustained over 24 hours to give once daily dose .That
is such a formulation appears suitable for further pharmacodynamic and
pharmacokinetic investigation in a convenient animal model.
5.
ACKNOWLEDGEMENTS:
The authors are thankful to faculty of
Pharmacy, Tishreen university, Lattakia, Syria for providing necessary
facilities to carry out this work.
6.
REFERENCES:
1. Rajesh
M et al. Formulation and evaluation of extended release tablets of metformin hydrochloride. Int J Pharm,
Chemical and Biological Sciences. 2 (3); 2012: 318-324.
2. Kumar
KPS et al. Sustained release drug delivery system potential. Pharm Inno.
1 (1); 2012: 46-56.
3. Mote PB
, Rawat PK, Singh KS, et al. Formulation and evaluation of sustained
release matrix tablets of anti-asthmatic agent using various polymers. J Drug
Delivery Therapeutics. 2 (3); 2013: 88-92.
4. Ige P et
al. Design and development of sustained release swelling matrix tablets of
glipizide for type II diabetes mellitus. Farmacia. 61 (5); 2013: 883-901.
5. Rao NGR
et al. Review on matrix tablet as sustained release. Int J Pharm Res Allied
Sci. 2 (3); 2013: 1-17.
6. Parshar
T et al. Novel oral sustained release technology: a concise review. Int
J Res Dev Pharm Life Sci. 2 (2); 2013: 262-269 .
7. Dash T and
Verma P. Matrix tablets :an approach towards oral extended release drug
delivery. Int J Pharm Res Rev. 2 (2); 2013: 12-24.
8. Patel H
et al. Matrix type drug delivery system: a review. J Pharm Sci Biosci
Res. 1 (3); 2011: 143-151.
9. Venkatesh
DN et al. Design and development of prochlorperazine maleate sustained
release tablets: the influence of hydrophilic polymers on the release rate and
in-vitro evaluation. Int J Pharm Sci Nanotechnol. 3 (2); 2010: 965-977.
10. Levina
M.and Siahboomi ARR. The influence of excipients on drug release from
hydroxypropyl methylcellulose matrices. J Pharm Sci. 93 (11); 2004: 2746-2754.
11. Rahman
M et al. Formulation and evaluation of hydroxypropyl methylcellulose
based matrix systems as oral sustained
release drug delivery systems for
ciprofloxacine hydrochloride . Int J Pharm Sci Rev Res. 6 (2); 2011: 34-41.
12. Ibrahim
IAA et al. In vitro and in vivo study of effect of α-adrenergic
agonist-methyldopa on the serum biochemical laboratory findings. Clin Exp
Pharmacol. 3 (4); 2013: E1-E4.
13. Jayasutha
J et al. Evaluation on efficacy of methyldopa monotherapy and combination
therapy with Nifedipine in pregnancy-induced hypertension. Der Pharmacia
Lettre. 3 (3); 2011: 383-387.
14. British
Pharmacopoeia Volume I and II
Monographs: Medicinal and Pharmaceutical Substances.
15. Patra
CN et al. Design and evaluation of sustained release bilayer tablets of
propranolol hydrochloride. Acta Pharm. 2007, 57:479-489.
16. Kumar V
et al. Sustained release hydrophilic matrix tablet of ibuprofen: influence of
polymers on in-vitro release and bioavailability. Int J Pharm Res Schlr.
2012,1:69-83.
17. European
pharmacopeia, 5th edition.
18. Aulton
M.E. pharmaceutics: The design and manufacture of medicine. 3rd ed., Churchill
Livingstone, New York, 2007.
19. Baboo S
et al. Formulation and evaluation of fast dissolving tablets salmeterol. Int J
C hem Pharm Sci. 1 (8); 2013: 497-501.
20. Anusha
I et al. Design and evaluation of rapidly disintegrating tablets of
rasagiline mesylate. Int J Pharm Pharm Sci. 4 (4); 2012: 76-77.
21. Doddayya H et al. Effect of gum rosin and ethyl cellulose on in
vitro release of venlafaxine
hydrochloride from hydrophilic matrix tablets. Int J Pharm Biol Archives. 2
(3); 2011: 980-988.
22. Ahsan Q
et al. Development and in-vitro
evaluation of sustained release matrix tablets of salbutamol sulphate using
methocel K100M CR polymer. Int J Pharm Sci Res. 2 (3); 2011: 567-576.
23. Sharma
VJ and Amin PD. Design and optimization of metoprolol succinate formulation using melt granulation
technique. Int J Pharm Pharm Sci. 5 (3);
2013: 230-238.
24.
Hingmire LP and Sarkar DM. Formulation
and development of sustained release matrix tablet using natural polymers. Int
J Pharm Sci Lett. 3 (4); 2013: 238-241.
25.
Jalalia MB et al. Formulation and
evaluation of sustained release dosage form of nifedipine hydrochloride using
hydrophilic polymers. J Rpt Pharm Sci. 2
(1); 2013: 32-37.
26.
Pawan P and Nitin N. Formulation,
evaluation and comparison of sustained release matrix tablet of diclofenac
sodium using natural polymer. Int J Res Pharm Biomed Sci. 4 (1); 2013:
367-379.7
27.
Li Li et al. Optimization of
sustained release matrix tablet of metoprolol succinate using central composite
design. Pak. J. Pharm. Sci. 26 (5);
2013: 929-937.
28.
Dandagi P et al. Formulation of trimetazidine matrix tablet using
methocel and effect of different
parameters on drug release from matrix tablet. Turk J Pharm Sci. 10 (2); 2013:
287-302.