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*Corresponding Author: Ankur Rohilla, Email: ankurrohilla1984@rediffmail.com
ISSN 0976 – 3333
REVIEW ARTICLE
Available Online at
International Journal of Pharmaceutical & Biological Archives 2011; 2(2): 615-620
www.ijpba.info.
Gastroretentive Dosage Forms: An Approach to Oral Controlled Drug Delivery
Systems
Amarjeet Dahiya
1
, Ankur Rohilla*
1
, Seema Rohilla
1
, M.U. Khan
2
1. Department of Pharmaceutical Sciences, Shri Gopi Chand Group of Institutions, Baghpat-250609, UP, India
2. Sri Sai College of Pharmacy, Badhani, Pathankot-145001, Punjab, India
Received 25 Feb 2011; Revised 28 Mar 2011; Accepted 08 Apr 2011
ABSTRACT
Gastric retentive dosage forms have been developed to provide controlled release therapy for drugs with
reduced absorption in the lower gastrointestinal (GI) tract or for local treatment of diseases of the upper
GI tract. Gastric retentive dosage forms depends on natural GI physiology such as floating or large tablets
that depend on delayed emptying from the fed stomach or the dosage forms that are designed to fight the
physiology and avoid emptying in the fasted state through dosage forms of even larger sizes with or
without flotation or bioadhesion. Floating systems have been considered as one of the important
categories of drug delivery systems with gastric retentive behavior. Floating matrix tablets have been
developed to prolong gastric residence time leading to an increase in drug bioavailability. The review
article explains the various floating drug delivery systems that are formulated in order to enhance the
drug bioavailability. Moreover, the identification of key factors influencing the variability of gastric
retention has been discussed.
Key Words: Gastroretentative, Drug delivery system, Floating systems
INTRODUCTION
The oral route is considered as the most promising
route of drug delivery. Effective oral drug
delivery process depends upon the factors such as
gastric emptying process, gastrointestinal transit
time of dosage form, drug release from the dosage
form and site of absorption of drugs
[1-2]
. Most of
the oral dosage forms possess several
physiological limitations such as variable
gastrointestinal transit because of variable gastric
emptying leading to non-uniform absorption
profiles, incomplete drug release and shorter
residence time of the dosage form in the stomach.
This leads to incomplete absorption of drugs
having absorption window especially in the upper
part of the small intestine, as once the drug passes
down the absorption site, the remaining quantity
goes unabsorbed. The gastric emptying of dosage
forms in humans is affected by several factors
because of which wide inter- and intra-subject
variations are observed
[3-4]
. Since many drugs are
well absorbed in the upper part of the
gastrointestinal tract, such high variability may
lead to non-uniform absorption and makes the
bioavailability unpredictable. Hence, a beneficial
delivery system to control and prolong the gastric
emptying time and can deliver drugs in higher
concentrations to the absorption site to show local
action in the stomach requires a specialized
delivery system. A significant approach for
showing local action and for the treatment of
gastric disorders can be achieved by floating drug
delivery systems (FDDS)
[5-6]
. A number of FDDS
involving various technologies have been
developed such as single and multiple unit hydro
dynamically balanced systems (HBS), single and
multiple unit gas generating systems, hollow
microspheres and raft forming systems
[7-8]
. The
present review article summarizes various
approaches towards prolonging the gastric
emptying time and delivering drugs in higher
concentrations to the absorption site in order to
show enhanced duration of action of the dosage
form. Moreover, many FDDS developed that are
found to increase the bioavailability of the dosage
forms have been delineated.
Ankur Rohilla et al. / Gastroretentive Drug Delivery Systems
616
© 2010, IJPBA. All Rights Reserved.
GASTRORETENTIVE FLOATING DRUG
DELIVERY SYSTEM: REVIEW FROM
PREVIOUS STUDIES
Previous studies reported on the FDDS include
tablets (single layer and double layer), floating
capsule, balloon tablets, multiparticulate systems,
hollow microspheres and floating beads
[9-12]
. The
reports that are available are briefly reviewed as
follows.
Kumar et al.
[13]
El-Kamal et al.
demonstrated works on the
gastroretentive dosage forms for prolonging
gastric residence time. In the study, the concepts
of gastric emptying and absorption windows and
current technological developments in
gastroretentive drug delivery systems were
discussed including their advantages and
disadvantages alongwith various evaluation
techniques and marketed products for
gastroretentive drug delivery. According to the
authors, the bioadhesive superporous hydrogel,
floating and expanding systems showed the most
promising potential for achieving the goal of
gastroretention.
[14]
prepared and evaluated
ketoprofen floating oral delivery system. They
designed sustained release system for ketoprofen
to increase its residence time in the stomach
without contact with the mucosa which was
achieved through the preparation of floating
microparticles by the emulsion-solvent diffusion
technique. They used four different ratios of
Eudragit S100 with Eudragit RL to form the
floating microparticles. It was found that release
rates were generally low in 0.1 N HCl especially
in presence of high content of Eudragit S100
while in phosphate buffer pH 6.8, high amounts of
Eudragit S100 tended to give a higher release rate.
Ali et al.
[15]
Patel et al.
formulated hydrodynemically-
balanced system for metformin as a single unit-
floating capsule. The formulation was optimized
on the basis of in vitro buoyancy and in vitro
release in simulated fed state gastric fluid. Effect
of various release modifiers was studied to ensure
the delivery of drug from the HBS capsules over a
prolonged period. Capsules prepared with HPMC
K4M and ethyl cellulose gave the best in vitro
percentage release and were taken as the
optimized formulation.
[16]
developed and optimized a
controlled-release multiunit floating system of
ranitidine HCl using compritol, gelucire 50/13 and
geliucire 43/01 as lipid carriers. Ranitidine HCl
lipid granules were prepared by the melt
granulation technique and evaluated for in vitro
floating and drug release. Ethyl cellulose,
methylcellulose and hyroxypropyl methylcellulose
were evaluated as release rate modifiers. They
concluded that the hydrophobic lipid Gelucire
43/01 could be considered an effective carrier for
design of a multiunit floating drug delivery system
for highly water-soluble drugs such as ranitidine
HCl.
Sahoo et al.
[17]
formulated floating microspheres
of Ciprofloxacin HCl by cross-linking technique.
A polymeric mixture of sodium alginate and
hydroxy propyl methyl cellulose (HPMC) was
used. Sodium bicarbonate was used as gas
forming agent. The solution was dropped to 1%
calcium chloride solution containing 10% acetic
acid for carbon dioxide release and gel formation.
The prepared floating microspheres were
evaluated with respect to particle size distribution,
floating behavior, drug content, entrapped
morphology and in vitro release study. Effect of
sodium bicarbonate on the above mentioned
parameters were evaluated and it was found that
sodium bicarbonate had a pronounced effect on
various parameters.
Choia et al.
[18]
reported preparation of alginate
beads for floating drug delivery system and
studied the effects of CO
2
gas forming agents.
Floating beads were prepared from a sodium
alginate solution containing CaCO
3
or NaHCO
3
as gas-forming agents. They studied the release
characteristics of riboflavin as a model drug.
Release rate of riboflavin increased proportionally
with addition of NaHCO
3
. The results of these
studies indicate that CaCO
3
is superior to
NaHCO
3
as gas forming agent in alginate bead
preparations.
Sharma and Pawar
[19]
developed low-density
multi particulate system for pulsatile release of
meloxicam for which they combined the
principles of floating and pulsatile drug delivery
system. They prepared multi particulate floating
pulsatile drug delivery system using porous
calcium silicate and sodium alginate for time and
site-specific drug release of Meloxicam.
Jaimini et al.
[20]
IJPBA, Mar - Apr, 2011, Vol. 2, Issue, 2
formulated and evaluated
Famotidine floating tablets. They used Methocel
K100 and Methocel K 15 M with effervescent
mixture. It was observed that decrease in the citric
acid level increased the floating lag time but
tablets floated for longer duration. A combination
of sodium bicarbonate (130 mg) and citric acid
(10mg) was found to achieve optimum in vitro
buoyancy. They reported that tablets prepared
Ankur Rohilla et al. / Gastroretentive Drug Delivery Systems
617
© 2010, IJPBA. All Rights Reserved.
with k 100 had longer floating time compared
with formulations containing Methocel K15 M.
Dave et al.
[21]
Narendra et al.
reported a gastroretentive drug
delivery system of ranitidine hydrochloride. Guar
gum, xanthan gum, and hydroxy propyl
methylcellulose were evaluated for gel forming
properties. Sodium bicarbonate was incorporated
as a gas-generating agent. They investigated the
effect of citric acid and stearic acid on drug
release profile and floating properties. They
concluded that the proper balance between a
release rate retardant and a release rate enhancer
could produce a drug dissolution profile similar to
a theoretical dissolution profile.
[22]
reported optimization of
bilayer floating tablet containing metoprolol
tartrate as a model drug for gastric retention. They
employed a 2
3
factorial design in formulating the
GFDDS with total polymer content-to-drug ratio
(X
1
), polymer-to-polymer ratio (X
2
), and different
viscosity grades of HPMC (X
3
) as independent
variables. The results indicate that X
1
andX
2 -
significantly affected the floating time and release
properties but the effect of different viscosity
grades of HPMC (K4M and K10M) was non-
significant.
Sunil et al.
[23]
prepared floating microspheres
consisting of calcium silicate as porous carrier and
Eudragit S as polymer by solvent evaporation
method and evaluated their gastroretentive and
controlled release properties. They studied the
effect of various formulation and process
variables on the particle morphology,
micromeritic properties, in vitro percentage drug
entrapment and in vitro drug release. Prolonged
gastric residence time of over 6 hours was
achieved in rabbits for calcium silicate based
floating microspheres of orlistate. The enhanced
elimination half-life observed after
pharmacokinetic investigation is due to the
floating nature of the designed formulations.
Umamaheswari et al.
[24]
prepared floating-
bioadhesive microspheres containing
acetohydroxamic acid for clearance of
Helicobacter Pylori. They explored a synergism
between a floating and a bioadhesive system.
Floating microspheres containing the antiurease
drug acetohydroxamic acid were prepared by a
novel quasiemulsion solvent diffusion method.
The microballons were coated with 2% w/v
solution of polycarbophil by the air suspension
coating method. The results suggested that AHA-
loaded floating microspheres were superior as
potent urease inhibitor whereas urease plays an
important role in the colonization of H. Pylori.
Patel et al.
[25]
developed ranitidine floating
tablets; in which they optimized types of filler,
different viscosity grades of HPMC and its
concentration. Two fillers namely Avicel pH 102
and Tablettose 80 were used. Study revealed that
type of filler had significant effect on release of
drug from hydrophilic matrix tablets (f2 value
41.30) and floating properties. Three different
viscosity grades of HPMC namely K100 LV,
K4M and K15M were used. Viscosity had a major
influence on drug release from hydrophilic
matrices as well as on floating properties. The
drug release from hydrophilic matrices occurred
via diffusion mechanisms following square root of
time profile. Hardness of tablets had grater
influence on floating lag time which might be due
to decreased porosity whereas the position of
paddle and types of dissolution medium had no
significant effect on drug release.
Srivastava et al.
[26]
prepared floating matrix
tablets of atenolol to prolong gastric residence
time and increase drug bioavailability. The tablets
were prepared by direct compression technique,
using polymers such as HPMC K15M, K4M,
Guargum (GG), and sodium carboxy
methylcellulose (SCMC), alone or in combination
and other standard excipients. Tablets were
evaluated for physical characteristics like
hardness, swelling index, floating capacity,
thickness and weight variation. The effect of
effervescent on buoyancy and drug release pattern
was also studied. In vitro release mechanism was
evaluated by linear regression analysis. GG- and
SCMC-based matrix tablets showed significantly
greater swelling indices compared with other
batches. The tablets exhibited controlled and
prolonged drug release profiles while floating
over the dissolution medium.
Gohel et al.
[27]
IJPBA, Mar - Apr, 2011, Vol. 2, Issue, 2
developed a more relevant in vitro
dissolution method to evaluate a carbamazepine
floating drug delivery systems. The glass beaker
was modified by adding a side arm at the bottom
of the beaker so that the beaker can hold 70 ml of
0.1 N HCl dissolution mediums and allow
collection of samples. The tablet did not stick to
the agitating device in the proposed dissolution
method. The drug release followed zero order
kinetics in the proposed method. The proposed
test may show good in vitro in vivo correlation
(IVIVC) since an attempt is made to mimic the in
vivo conditions.
Ankur Rohilla et al. / Gastroretentive Drug Delivery Systems
618
© 2010, IJPBA. All Rights Reserved.
Amin et al.
[28]
developed a gastroretentive drug
delivery system of ranitidine hydrochloride which
was designed using guar gum, xanthan gum and
HPMC. Sodium bicarbonate was incorporated as a
gas-generating agent. The effect of citric acid and
stearic acid on drug release profile and floating
properties was investigated. The addition of
stearic acid reduces the drug dissolution due to its
hydrophobic nature. A 3
2
Streubel et al.
full factorial design was
applied to systemically optimize the drug release
profile and the results showed that a low amount
of citric acid and a high amount of stearic acid
favor sustained release of ranitidine HCl from a
gastroretentive formulation.
[29]
prepared single-unit floating
tablets based on polypropylene foam powder and
matrix-forming polymer. Incorporation of highly
porous foam powder in matrix tablets provided
density much lower than the density of the release
medium. A 17% w/w foam powder was achieved
in vitro for at least 8 hours. It was concluded that
varying the ratios of matrix-forming polymers and
the foam powder could alter the drug release
patterns effectively.
Li et al.
[30]
Sangekar et al.
evaluated the contribution of
formulation variables on the floating properties of
a gastro floating drug delivery system using a
continuous floating monitoring device and
statistical experimental design. The formulation
was conceived using 2x3 full factorial designs for
calcium delivery. HPMC was used as a low-
density polymer and citric acid was incorporated
for gas generation. Analysis of variance
(ANOVA) test on the results from these
experimental designs demonstrated that the
hydrophobic agent magnesium stearate could
significantly improve the floating capacity of the
delivery system. High-viscosity polymers had
good effect on floating properties. The residual
floating force values of the different grades of
HPMC were in the order K4 M~ E4 M~K100
LV> E5 LV but different polymers with same
viscosity, i.e., HPMC K4M, HPMC E4M did not
show any significant effect on floating property.
Better floating was achieved at a higher
HPMC/carbopol ratio and this result demonstrated
that carbopol has a negative effect on the floating
behavior.
[31]
studied the effect of food and
specific gravity on the gastric retention time of
floating (spec. grav. 0.96) and non-floating (spec.
grav. 1.59) tablet formulations was investigated
using gamma scintigraphy in humans. The results
obtained indicate that the presence of food in the
stomach appears to significantly prolong gastric
retention of both the floating and non-floating
tablets while specific gravity does not seem to
play an important role in the residency time of the
tablets in the stomach.
Xiaoqiang et al.
[32]
developed hydrodynamically
balanced sustained release tablets containing drug
and hydrophilic hydrocolloids which on contact
with gastric fluids at body temperature formed a
soft gelatinous mass on the surface of the tablet
and provided a water-impermeable colloid gel
barrier on the surface of the tablets. The drug
slowly released from the surface of the gelatinous
mass that remained buoyant on gastric fluids.
Rahman et al.
[33]
developed a bilayer-floating
tablet (BFT) for captopril using direct
compression technology. HPMC, K-grade and
effervescent mixture of citric acid and sodium
bicarbonate formed the floating layer. The release
layer contained captopril and various polymers
such as HPMC-K15M, PVP-K30 and Carbopol
934p, alone or in combination with the drug. The
floating behavior and in vitro dissolution studies
were carried out in a USP 23 apparatus 2 in
simulated gastric fluid (without enzyme, pH 1.2).
Final formulation released approximately 95%
drug in 24 h in vitro, while the floating lag time
was 10 min and the tablet remained floatable
throughout all studies. Final formulation followed
the higuchi release model and showed no
significant change in physical appearance, drug
content, floatability or in vitro dissolution pattern
after storage at 45 °C/75% RH for three months.
Bomma et al.
[34]
prepared floating matrix tablets
of norfloxcin which were developed to prolong
gastric residence time leading to an increase in
drug bioavialiability by using wet granulation
technique using polymers such as HPMCK4M,
HPMCK100M and Xanthan gum. The tablets
exhibited controlled and prolonged drug release
profile while floating over dissolution medium
was confirmed as drug release mechanism from
these tablets.
Thakkar et al.
[35]
Rao et al.
formulated and evaluated the
levofloxacin hemihydrate floating tablets that
were prepared by direct compression method
using gelucire 43/01 and HPMC polymers in
different ratio. The in vitro release study revealed
the fact that the release rate of drug was decreased
by increasing the proportions of gelucire 43/01 by
5 to 40% matrix tablets containing 25%
HPMCK4M and 15% gelucire 43/01.
[36]
IJPBA, Mar - Apr, 2011, Vol. 2, Issue, 2
formulated and optimized the
floating drug delivery system of cephalexin.
Ankur Rohilla et al. / Gastroretentive Drug Delivery Systems
619
© 2010, IJPBA. All Rights Reserved.
Tablets were prepared by direct compression
method incorporating HPMCK4M, xanthan gum,
guar gum, sodium bicarbonate and tartaric acid as
gas generating agent. The diffusion exponent of
krosmeyer peppas for optimized formulation was
found to be 0.635 which significantly indicated
the mechanism of drug release.
CONCLUSION
The identification of new diseases and the
resistance shown towards the existing drugs felt
the need for the introduction of new therapeutic
molecules. In response, a large number of
chemical entities have been introduced, of which
some have absorption all over the GIT and others
have absorption windows in the upper part of the
small intestine. The drugs that are required for
local action in the GIT require a specialized
delivery system which has been achieved by
FDDS. A number of FDDS have been developed
such as single and multiple unit HBS, single and
multiple unit gas generating systems, hollow
microspheres and raft forming systems.
Development of sustained release formulations is
advantageous in providing prolonged gastric
retention and increased efficacy of the dosage
forms. The floating behavior of the low density
drug delivery systems could successfully be
combined with accurate control of the drug release
patterns in order to boast accurate bioavailability.
Hence further studies are needed in this regard in
order to encompass effective drug delivery
systems.
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IJPBA, Mar - Apr, 2011, Vol. 2, Issue, 2
