Pak. J. Pharm. Sci., Vol.22, No.2, April 2009, pp.155-161 155
THEOPHYLLINE LOADED GASTRORETENTIVE FLOATING TABLETS BASED
ON HYDROPHILIC POLYMERS: PREPARATION AND IN VITRO EVALUATION
FERDOUS KHAN, MD. SHAIKHUL MILLAT IBN RAZZAK, MD. ZIAUR RAHMAN KHAN,
MOHAMMAD ABUL KALAM AZAD, JAKIR AHMED CHOWDHURY
AND MD. SELIM REZA*
Department of Pharmaceutical Technology, Faculty of Pharmacy,
University of Dhaka, Dhaka-1000, Bangladesh
ABSTRACT
This investigation describes the preparation and in vitro evaluation of gastroretentive floating tablet of
theophylline. Two hydrophilic cellulose derivatives, Methocel K100M and Methocel K15MCR were evaluated
for their gel forming and release controlling properties. Sodium bicarbonate and citric acid were incorporated as
gas generating agents. The effects of soluble components (sodium bicarbonate and citric acid), gel forming
agents and amount variation of theophylline on drug release profile and floating properties were investigated.
Tablets were prepared by direct compression technique. Formulations were evaluated for in vitro buoyancy and
drug release study was evaluated for eight hours using USP XXII paddle-type dissolution apparatus using 0.1N
HCl as dissolution medium. The release mechanisms were explored and explained with zero order, first order,
Higuchi and Korsmeyer equations. The release rate, extent and mechanisms were found to be governed by
polymer and floating agent content. The content of active ingredient was also a vital factor in controlling drug
release pattern. It was found that polymer content and amount of floating agent significantly affected the mean
dissolution time, percentage drug release after 8 hours, release rate constant and diffusion exponent.
Keywords: Gastroretentive dosage form, floating tablet, theophylline, absorption window, hydrophilic polymer.
INTRODUCTION
Rapid and unpredictable gastrointestinal transit could
result in incomplete drug release from the device above
the absorption zone leading to diminished efficacy of the
administered dose (Iannuccelli et al., 1998).
Gastroretentive systems can remain in the gastric region
for several hours and hence can significantly prolong the
gastric residence time of drugs. Prolonged gastric
retention improves bioavailability, reduces drug waste,
and improves solubility for drugs that are less soluble in a
high pH environment of small intestine (Ponchel
and Irache, 1998). It has applications also for local drug
delivery to the stomach and proximal small intestine
(Deshpande et al., 1997). Therefore different approaches
have been proposed to retain the dosage form in the
stomach. Those approaches include synthesis of high
density dosage form (Singh and Kim, 2000); concomitant
administration of drugs or excipients, which slows the
motility of stomach or small intestine (Moes, 1993);
synthesis of bioadhesive or mucoadhesive dosage form
(Akiyama et al., 1998). But the simplest and possibly the
most elegant way to improve drug absorption is to hold a
drug delivery system above the absorption window.
Because most absorption windows are located in the
proximal small intestine (duodenum), the most effective
strategy will be to hold the formulation in the stomach
(Chen et al., 2000).
When a drug is formulated with gel forming hydrocolloid
such as HPMC, and carbon dioxide generating agents like
citric acid and sodium hydrogen carbonate it swells in the
gastric fluid as it gets contact with the aqueous medium.
Formation of CO2 and entrapment of that gas into the
polymeric gel causes swelling of the dosage form
resulting a bulk density less than 1. It then remains
buoyant and floats in the gastric fluid, resulting a
prolonged gastric residence time. This floating dosage
form is well known as a Hydrodynamically Balanced
System (HBS) (Uzdemir, et al., 2000). It has been
suggested that an active material should be formulated in
the form of an HBS to enhance bioavailability of those
drugs having a dissolution or stability problem in the
small intestinal fluid, drugs which are being locally
effective in the stomach and drugs with a narrow
therapeutic window (Jobin, et al., 1985).
The aim of the present study was to prepare and
characterize extended-release floating matrix tablets of
theophylline using two hydrophilic cellulose derivatives;
Methocel K100M and Methocel K15MCR. Investigations
were performed whether there was any effect of floating
agent content and theophylline content upon the floating
lag time of the tablets. The impact of formulation
variables upon the release rate, mean dissolution time and
release mechanism were also evaluated with the help of
various mathematical models.
*Corresponding author: Ph: +880-2-8612069; Fax: +880-2-8615583, e-mail: selimreza_04@yahoo.com
Theophylline loaded gastroretentive floating tablets based on hydrophilic polymers
Pak. J. Pharm. Sci., Vol.22, No.2, April 2009, pp.155-161156
MATERIALS AND METHODS
Materials
Theophylline was a kind gift from Square Pharmaceuticals
Limited. The source of Methocel K15MCR,
Methocel K100M and ludipress were Colorcon, USA and
BASF, Germany respectively. Two gas generating agents
citric acid anhydrous and sodium hydrogen carbonate
were obtained from Loba Cheme Pvt. Ltd., India. Aerosil
200 and magnesium stearate were sourced respectively
from Degussa, Germany and Wilfrid Smith Ltd. UK. All
other chemicals and reagents used were of analytical and
pharmaceutical grade.
Preparation of floating tablets of theophylline
The active ingredient and other excipients were accurately
weighted for thirty tablets according to the formulations
(table 1). Particular attention has been given to ensure
thorough mixing and phase homogenization. The
appropriate amounts of the mixture were accurately
weighted in an electronic balance for the preparation of
each tablet and finally compressed using a Perkin-Elmer
laboratory hydraulic press. Before compression, the
surfaces of the die and punch were lubricated with
magnesium stearate. All the preparations were stored in
airtight containers at room temperature for further study.
Determination of in vitro floating lag time
The in vitro buoyancy was determined by floating lag
time, as per the method described by Rosa and his coworkers.
The tablets were placed in a 100 mL beaker
containing 0.1N HCl. The media was kept in stagnant
condition and the temperature was maintained at 37o
C.
The time required for the tablet to rise to the surface and
float was determined as floating lag time (Rosa et al.,
1994).
Dissolution study
The release of theophylline from floating tablets was
determined by using Dissolution Tester USP XXII in
paddle method. The dissolution test was performed using
900ml 0.1N HCl solution at 37°C ± 0.5o
C temperature
and at 50 rpm. At every 1 hour interval samples of 10ml
were withdrawn from the dissolution medium and that
amount was replaced with fresh medium to maintain the
volume constant. The samples were filtered and diluted to
a suitable concentration with 0.1 N HCl solution. The
absorbances of the solutions were measured at 271nm for
theophylline by using a Shimadzu 1201 UV-Visible
double beam spectrophotometer (Shimadzu, Japan).
Cumulative percentage drug release was calculated using
an equation obtained from standard curve.
Kinetic modeling of drug release
The dissolution profiles of all the batches were fitted to
zero order, first order (Wagner, 1969) and Higuchi
equations (Higuchi, 1961) (equation 1-3 respectively).
Mt = M0 + k0t (1)
lnMt = lnM0 + k1t (2)
Mt = M0 – kHt1/2
(3)
In these equations, Mt is the cumulative amount of drug
released at any specified time (t) and M0 is the dose of the
drug incorporated in the delivery system. k0, k1 and kH are
rate constants for zero order, first order and Higuchi
model respectively. These models fail to explain drug
release mechanism due to swelling (upon hydration)
along with gradual erosion of the matrix. Therefore the
dissolution data were also fitted to well-known
Korsmeyer and Peppas semi-empirical model (Peppas,
1985; Korsmeyer et al., 1983) to ascertain the mechanism
of drug release.
Table 1: Composition of different formulations of floating tablets
Formula
Theophylline
(mg)
Methocel
K100M (mg)
Methocel
K15MCR (mg)
Citric acid
anhydrous (mg)
Sodium
bicarbonate (mg)
Total
(mg)
F-1 100 100 - 25 50 306
F-2 100 100 - 50 75 356
F-3 200 100 - 25 50 406
F-4 200 100 - 50 75 456
F-5 300 100 - 25 50 506
F-6 300 100 - 50 75 556
F-7 100 - 100 25 50 306
F-8 100 - 100 50 75 356
F-9 200 - 100 25 50 406
F-10 200 - 100 50 75 456
F-11 300 - 100 25 50 506
F-12 300 - 100 50 75 556
Besides these ingredients each tablet contains 25 mg ludipress, 4 mg aerosil and 2 mg magnesium stearate.
Ferdous Khan et al.
Pak. J. Pharm. Sci., Vol.22, No.2, April 2009, pp.155-161 157
log (Mt/M∞) = logk + nlogt (4)
Where, M∞ is the amount of drug release after infinite
time; k is the release rate constant which considers
structural and geometric characteristics of the tablet; and
n is the diffusional exponent; indicative of the mechanism
of drug release. For a tablet having cylindrical shape n
value below 0.45 indicate Fickian diffusion and n value
between 0.45 and 0.89 indicate anomalous transport, often
termed as first-order release. If the n value reaches 0.89 or
above, the release can be characterized by case II and
super case II transport, which means the drug release rate
does not change over time and the drug is released by
zero-order mechanism. In this case, the drug release is
dominated by the erosion and swelling of the polymer
(Ritger and Peppas, 1987). Mean dissolution time (MDT)
was calculated from dissolution data using the following
equation (Mockel and Lippold, 1993):
n
k
n
n
MDT /1
)
1
( −
+
=
Table 2: Floating lag time and release parameters of folating tablets of theophylline
Zero Order Higuchi Korsemeyer
Formula
Floating
Lag Time
(sec)
%
Release
MDT
(Hour)
Ko R2
Kh R2
n R2
F-1 25.3±3.27 60.4±1.41 6.2±0.45 7.73 0.995 22.84 0.935 0.949 0.998
F-2 20.5±3.02 71.8±3.33 4.1±0.74 8.05 0.933 25.39 0.998 0.533 0.998
F-3 38.5±4.46 41.9±2.11 9.8±0.62 5.21 0.995 15.31 0.925 0.909 0.991
F-4 30.2±5.04 58.4±3.82 5.4±0.67 6.28 0.870 20.46 0.994 0.426 0.995
F-5 56.5±6.83 39.7±2.42 9.5±0.77 4.99 0.988 14.91 0.949 0.937 0.991
F-6 45.7±6.19 47.5±5.53 9.1±0.93 5.56 0.980 16.87 0.973 0.668 0.994
F-7 25.0±3.85 61.1±2.76 6.1±0.32 7.68 0.991 22.90 0.949 0.897 0.997
F-8 20.5±3.25 89.1±5.17 1.2±0.36 8.66 0.705 30.24 0.924 0.283 0.970
F-9 38.5±4.46 54.6±3.43 8.9±0.45 5.45 0.983 16.51 0.970 0.774 0.998
F-10 30.2±5.04 69.8±4.52 3.7±0.77 7.54 0.888 24.31 0.994 0.419 0.984
F-11 56.5±6.83 51.4±4.15 8.5±0.88 5.77 0.974 17.55 0.970 0.644 0.992
F-12 45.7±6.19 69.1±3.10 3.6±0.95 7.49 0.864 24.43 0.991 0.428 0.993
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
F-1
F-2
F-3
F-4
F-5
F-6
F-7
F-8
F-9
F-10
F-11
F-12
Formulation
Time(sec)
Fig. 1: In vitro floating lag time of gastroretentive floating tablets of Methocel K100M (F1~F-6) and K15MCR (F-
7~F-12).
Theophylline loaded gastroretentive floating tablets based on hydrophilic polymers
Pak. J. Pharm. Sci., Vol.22, No.2, April 2009, pp.155-161158
RESULTS AND DISCUSSION
In vitro buoyancy study
Formulations were evaluated for in vitro buoyancy and all
formulations had floating lag times below 1 minute and
constantly floated on dissolution medium for more than 8
hours. Floating lag times were found to be significantly
controlled by citric acid and sodium hydrogen carbonate
content. Floating lag time was reduced due to increase of
amount of floating agent (fig. 1). Increased amount of
floating agent caused rapid formation as well as
entrapment of CO2 gas into the hydrophilic polymeric gel
which eventually resulted in reduction of floating lag
time.
Effect of floating agent content on release of
theophylline
First of all the formulations of Methocel K100M were
compared to explore the effect of changing amount of
floating agent and changing amount of theophylline. To
evaluate the effect of amount variation of floating agent
F-1 which contained 100 mg theophylline and 75 mg
floating agent was compared with F-2 which contained
100 mg theophylline and 125 mg floating agent (table 1).
Similarly F-3 was compared with F-4 and F-5 with F-6.
Percent release of drug at the end of eight hour for F-1
was 60.4% and for F-2 was 71.8%. These values clearly
indicated the increase of drug release as a consequence of
increase of floating agent content. Comparisons of F-3
with F-4 and F-5 with F-6 showed similar pattern of
change. R2
values obtained from zero order equation for
F-1 and F-2 are 0.995 and 0.933 respectively (table 2).
These values indicated that due to the increase of amount
of floating agent the drug release mechanism had been
deviated from zero order release profile. From the table 2
it is also clear that zero order release rates were increased
due to the increase of floating agent content of the
formulation. So it can be claimed that due to increase of
amount of floating agent in a formulation, zero order
release rate was increased but the fitting of formulation
with zero order release pattern was lost significantly (in
single factor ANOVA, p = 0.00000065). Similar results
were found in case comparisons of F-3 with F-4 and F-5
with F-6 (in these cases p values were also less than 0.05).
On the other hand R2
values obtained from Korsmeyer
and Peppas model for F-1, F-2, F-3, F-4, F-5 and F-6
were 0.998, 0.998, 0.991, 0.995, 0.991 and 0.994
respectively (table 2). The values of release exponent (n)
for F-1 and F-2 were 0.949 and 0.533 which indicated that
release of theophylline from these two formulations were
controlled by case II transport mechanism and anomalous
type of diffusion respectively. The n values obtained from
Korsmeyer kinetic model were 0.909 for F-3, 0.426 for F-
4 which also indicated that drug release mechanisms were
shifted from non-Fickian to Fickian direction due to the
increase of amount of floating agent. Similarly n values of
F-5 and F-6 indicated that the drug release mechanism
was shifted towards diffusion dominated mechanism from
case II transport mechanism due to the increase of amount
of floating agent. Being soluble excipients citric acid and
sodium bicarbonate increased the tablet porosity and
stimulated water penetration into the inner parts of the
matrix, which resulted in a faster diffusion of drug and
erosion of polymer, causing rapid release of drug from the
tablets (Sako, et al., 2002). Thus the rapid release of
theophylline from F-2, F-4 and F-6 due to the increase of
soluble component of the formulation could be explained
by the increase of floating agent content in those
formulations. These data are in accordance with some
other studies (Huang and Tsai, 2004)
Similar pattern of changes were also observed among the
formulations of Methocel K15MCR. In all cases the
increases of floating agent content caused increase of zero
order release (fig. 4) and also decrease of fitting with zero
order release mechanisms. All three formulations of
Methocel K15MCR containing 75 mg of floating agent
were found to follow anomalous type of transport
mechanism whereas three other formulations containing
125 mg floating agent were found to follow Fickian
diffusion mechanism (table 2).
At initial time. After 24 seconds After 25 seconds
Fig. 2: Pictorial presentation of in vitro floating behavior of a representative tablet of Methocel K100M.
Ferdous Khan et al.
Pak. J. Pharm. Sci., Vol.22, No.2, April 2009, pp.155-161 159
(a)
0
20
40
60
80
100
0 2 4 6 8
Time (hour)
%Release
F-1 F-2
(b)
0
20
40
60
80
100
0 2 4 6 8
Time (Hour)
%Release
F-3 F-4
(c)
0
20
40
60
80
100
0 2 4 6 8
Time (Hour)
%Release
F-5 F-6
Fig. 3: Zero order plot of release kinetics of Theophylline
showing the variation of drug release due to change of
amount of floating agent from various formulations of
Methocel K100M.
(a) Theophylline 100mg, (b) Theophylline 200mg
(c) Theophylline 300mg
0.0
20.0
40.0
60.0
80.0
100.0
0 2 4 6 8
Time (Hour)
%Release
F-7 F-8 F-9
F-10 F-11 F-12
Fig. 4: Zero order release profile of Theophylline from six
different formulations of floating tablet of Methocel
K15MCR.
Increase of floating agent content always displayed a
common phenomenon that the drug release rate and extent
were increased in all cases which were also supported by
MDT (mean dissolution time) values (table 2 and fig. 5).
From the dissolution data, it is clear that as the amount of
floating agents were increased; the percent release of
theophylline was increased abruptly at the initial level.
Increase of soluble component (citric acid and sodium
hydrogen carbonate) of the formulations resulted in the
increase of drug release rate and extent possibly due to the
formation of channels which stimulated water penetration
into the inner part of the matrix and thus exposure of new
surfaces of tablet matrix to the dissolution medium.
Similar observations were found by Sung and coworkers
while they were evaluating the effect of formulation
variables on drug and polymer release from HPMC-based
matrix tablets (Sung et al., 1996). When the amount of
floating agent was increased the control of the polymer
upon the drug release was to some extent lost which is
demonstrated by the standard error bars parallel to Y-axis.
From figs. 3 and 4 it is clearly observed that increasing
amount of floating agent caused the increase of release
rate and extent which was particularly significant at the
initial stages of the dissolution study.
Impact of Theophylline content on release profile
From the zero order release profile it was observed that
the total percent release of theophylline from those three
formulations which contained 75 mg of floating agent
were decreased gradually due to the increase of amount of
theophylline. The results resemble with the previous
finding; the increase of amount of insoluble component
(increase of theophylline which in an insoluble drug)
caused the reduction in the percent release and reduction
of zero order release rate (table 2). Similar pattern of
changes were also observed in case of F-2, F-4 and F-6.
Theophylline loaded gastroretentive floating tablets based on hydrophilic polymers
Pak. J. Pharm. Sci., Vol.22, No.2, April 2009, pp.155-161160
Due to the increase of amount of theophylline, the extent
of drug release had been reduced relatively. Higher values
of n for higher amounts of theophylline indicated that, due
to the increase of the amount of theophylline the release
mechanism shifts from diffusion dominated to erosion
dominated direction. The possible reason may be the
increase of the amount of theophylline resembles with the
relative decrease in the amount of soluble component.
Similar results were also observed by Vueba and coworkers
while they were evaluating the influence of
cellulose ether polymers on ketoprofen release from
hydrophilic matrix tablets (Vueba et al., 2004).
CONCLUSION
It was observed that in all cases the increase of amount of
floating agent caused the decrease of floating lag time. At
relatively higher polymer contents all formulations
displayed better fitting with zero order release kinetics. In
all cases the increase of the floating agent content caused
a lowering of the magnitude of release exponent (n)
indicating the shifting of release mechanism from nonFickian
to Fickian direction. All these results indicated
that a low amount of foloating agent and high amount of
hydrophilic polymer favoured the sustained release of
theophylline from gastroretentive tablet formulations. It
can be concluded that, drug load, amount of soluble
component, polymer type and the polymer content of the
matrix affected the release profile of theophylline from
hydrated HPMC matrices significantly. These studies
indicated that the proper balance between a hydrophilic
matrix former and a soluble component can produce a
drug dissolution profile similar to a theoretical dissolution
profile.
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