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A comprehensive review on Gastroretentive Drug Delivery Systems

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Available online at: http://www.iajps.com Review Article
A COMPREHENSIVE REVIEW ON GASTRORETENTIVE DRUG
DELIVERY SYSTEMS
Rajendra Kumar Jadi1* and Krishna Mohan Chinnala2
1Chaitanya College of Pharmacy Education and Research, Hanamkonda, Warangal,Telangana, India.
2School of Pharmacy, Nalla Narasimha Reddy Education Society’s Group of Institutions,
Hyderabad, Telangana, India.
Abstract:
The purpose of writing this review was to investigate, compile, recent, current and past literatures. In recent years
several advancements has been made in research and development of oral drug delivery system. Various drugs, which
are unstable in alkaline pH, soluble in acidic pH, having narrow absorption window, site specific to stomach can be
developed by using this technique. Gastroretentive drug delivery systems (GRDDS) can improve the controlled delivery
of drugs that have an absorption window by continuously releasing the drug for a prolonged period of time before it
reaches absorption site. These include floating system, swelling system, expanding system, low density systems, high
density system, bioadhesive and mucoadhesive systems etc. In fact the buoyant dosage unit enhances gastric residence
time (GRT) without affecting the intrinsic rate of emptying. GRDDS is an approach to prolong gastric residence time,
thereby targeting site-specific drug release in upper gastro intestinal tract improving the oral sustained delivery of
drug. For minimizing the limitations and achieving better gastric retention various combinational approaches like
floating and swelling, floating and bioadhesion, etc., multi-particulate systems, super porous hydrogel etc., have been
discussed. The present review addresses briefly about suitable drug candidates, formulation considerations,
physiological difficulties and classification, factors effecting gastric retention, merits, demerits and limitations of
gastroretentive drug delivery systems.
Keywords: Gastroretentive drug delivery systems, controlled release systems, gastric residence time, gastric emptying
time and absorption window.
Corresponding author:
Rajendra Kumar Jadi
Department of Pharmaceutics
Chaitanya College of Pharmacy Education and Research,
Hanamkonda, Warangal, Telangana, India.
Email: rajendra.rajaji@gmail.com
Mobile: +919866575814
Please cite this article in press as Rajendra Kumar and Krishna Mohan, A Comprehensive Review on Gastroretentive
Drug Delivery Systems, Indo Am. J. Pharm. Sci, 2016; 3(2).
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INTRODUCTION:
Historically, oral drug administration has been the
predominant route for drug delivery. During the past
two decades, numerous oral delivery systems have
been developed to act as drug reservoirs from which
the active substance can be released over a defined
period of time at a predetermined and controlled rate.
However, this route has several physiological problems
including an unpredictable gastric emptying rate that
varies from person to person, a brief gastrointestinal
transit time (8 to 12h), and the existence of an
absorption window in the upper small intestine for
several drugs [1]. Oral drug delivery system is the most
convenient, widely utilized route of drug
administration among all routes that have been
explored for systemic delivery of drugs via
pharmaceutical products of different dosage forms
because of their compact nature, better patient
compliance, ease of administration, low cost, flexibility
in formulation, and also easy to manufacture, pack and
transport. However, there are some drawbacks
associated with oral drug delivery system like short
residence time; unpredictable gastric emptying and
sometimes drug may degrade due to the high reactive
nature of GI contents. Because of this reason, drugs get
absorbed easily from the GIT and are disintegrated
quickly from the systemic circulation and shows short
half life. So, to achieve the desired therapeutic activity
usually frequent dosing is required. The release rate
will be controlled depending upon the type and
concentration of the polymer that swells, leads to
diffusion and erosion of the drug [2, 3].
The problem frequently encountered with extended
release dosage forms is the failure to increase the
residence time of the dosage form in the stomach and
proximal portion of the small intestine. Therefore it
would be beneficial to develop extended release
formulations which remain at the absorption site for an
extensive period of time. One of the possible
approaches for achieving delayed and expected drug
delivery profile in GIT is to control gastric retention
time (GRT) of the formulation. Dosage form with
prolonged GRT, i.e. gastroretentive dosage forms
(GRDFs) will offer new and important therapeutic
options [4].
The real challenge in the development of a
gastroretentive drug delivery system is not just extend
the drug release but also to prolong the presence of the
dosage form in the stomach and due to their inability to
restrain and localise the system at targeted areas of the
gastrointestinal (GI) tract or the upper part of the GIT
until all the drug is completely released [5].
Gastric retention will provide advantages such as the
delivery of drugs with narrow absorption windows in
the small intestinal region. Also, longer residence time
in the stomach could be advantageous for local action
in the upper part of the small intestine, for example
treatment of peptic ulcer disease. These drugs can be
delivered ideally by slow release from the stomach.
Many drugs categorised as once-a-day delivery have
been demonstrated to have sub-optimal absorption due
to dependence on the transit time of the dosage form,
making traditional extended release development
challenging. Therefore, a system designed for longer
gastric retention will extend the time within which drug
absorption can occur in the small intestine [6].
GRDDS are beneficial for such drugs by improving
their [7]
Bioavailability
Therapeutics efficiency
Possible reduction of the dose.
Maintenance of constant therapeutic levels
over a prolonged period and thus reduction in
fluctuation in the therapeutic levels
Reduce drug wastage
Improves solubility of drugs that are less
soluble at high pH environment
Anatomy of stomach
The stomach is an expanded section of the digestive
tube between the oesophagus and small intestine. The
wall of the stomach is structurally similar to the other
parts of the digestive tube; with the exception that
stomach has an extra, oblique layer of smooth muscle
inside the circular layer, which aids in the performance
of complex grinding motions [8]. In the empty state,
the stomach is contracted and its mucosa and sub-
mucosa are thrown up into distinct folds called Rugae;
figure 1 illustrates the structure of stomach and GIT:
There are images to four major types of secretary
epithelial cells that cover the surface of the stomach
and extend down into gastric pits and glands:
1. Mucous cells: Secrete alkaline mucus that
protects the epithelium against shear stress
and acid.
2. Parietal cells: Secrete hydrochloric acid.
3. Chief cells: Secrete pepsin, a proteolytic
enzyme.
4. G cells: Secrete the hormone, gastrin.
Fig 1: (a) Structure of stomach
(b) Structure of gastrointestinal tract
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Gastroretentive dosage form (GRDF)
It is evident from the recent scientific and patient
literature that an increased interest in novel dosage
forms that are retained in stomach for a prolonged and
predictable period of time exists today in academic and
industrial research groups. One of the most feasible
approaches for achieving a prolonged and predictable
drug delivery in the GI tract is to control the gastric
residence time (GRT), i.e. gastroretentive dosage form
(GRDF).
GRDFs extend significantly the period of time over
which the drugs may be released. They not only
prolong dosing intervals, but also increase patient
compliance beyond the level of existing controlled
release dosage form.
Dosage form with prolonged GRT, i.e. gastroretentive
dosage forms (GRDF), will bring about new and
important therapeutic options such as [9, 10]:
This application is especially effective in
sparingly soluble and insoluble drugs. It is known
that, as the solubility of a drug decreases, the time
available for drug dissolution becomes less
adequate and thus the transit time becomes a
significant factor affecting drug absorption. To
override this problem, erodible, gastroretentive
dosage forms have been developed that provide
continuous, controlled administration of sparingly
soluble drugs at the absorption site.
GRDFs greatly improve the pharmacotherapy of
the stomach through local drug release, leading to
high drug concentration at the gastric mucosa.
(For e.g. Eradicating Helicobacter pylori from the
sub-mucosal tissue of stomach) making it possible
to treat stomach and duodenal ulcers, gastritis and
oesophagitis, reduce the risk of gastric carcinoma
and administer non-systemic controlled release
antacid formulations (calcium carbonate).
GRDFs can be used as carriers for drugs with so-
called absorption windows.
E.g. Antiviral, antifungal and antibiotic agents
(sulphonamides, quinolones, penicillin’s,
cephalosporin’s, amino glycosides, tetracycline’s
etc.) are taken up only from very specific sites of
the GI mucosa.
Absorption window
Drug exhibiting absorption from only a particular
portion of GI tract or showing difference in absorption
from various regions of GI tract are said to have
regional variability in intestinal absorption. Such drugs
show absorption window which signifies the regions of
GI tract from where absorption primarily occurs. Drug
released from the CRDDS after the absorption window
has been crossed goes waste with no or negligible
absorption occurring is shown below figure 2.
This phenomenon drastically decreases the available
drug for absorption, after release of drug from CRDDS.
Fig 2: (a) Conventional drug delivery systems
(b) Gastroretentive drug delivery systems
The CRDDS possessing the ability of being retained in
the stomach are called GRDDS and they can help in
optimizing the oral controlled delivery of drugs having
absorption window by continuously releasing drug
prior to absorption window, for prolonged period of
time thus ensuring optimal bioavailability [11].
Drugs that are required to be formulated into
GRDFs include: [12-17]
Drugs acting locally in the stomach.
E.g. Antacids and drugs for H. Pylori viz.,
misoprostol
Drugs that are primarily absorbed in the
stomach.
E.g. Amoxicillin, calcium supplements,
chlordiazepoxide and cinnarazine.
Drugs that is poorly soluble at alkaline pH
E.g. Furosemide, diazepam, verapamil etc
Drugs with a narrow window of absorption.
E.g. Cyclosporine, methotrexate, riboflavin,
levodopa etc
Drugs rapidly absorbed from the GI tract.
E.g. Metronidazole, tetracycline etc
Drugs that degrade in the colon.
E.g. Ranitidine, metronidazole, metformin
HCl etc
Drugs that disturb normal colonic microbes.
E.g. Antibiotics against helicobacter pylori
Gastric motility and transit time
The GI tract is always in a state of continuous motility.
There are two modes of motility patterns the digestive
mode and inter digestive mode. In case of fasted state
inter digestive series of electrical events occurs in
cyclic manner both through stomach and small
intestine every 2-3 hrs. This electrical activity is termed
as inter digestive myoelectric cycle or migrating
myoelectric complex (MMC), which is further divided
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into four phases. Inter digestive motility pattern shown
below in figure 3.
Fig 3: Schematic representation of inter digestive
motility pattern, frequency of contraction forces
during each phase and average time period for each
phase
Phase-I: A quiescent period with no electrical activity
and no contractions lasting between 40-60 minutes.
Phase-II: The period of random spike activity or
intermittent contractions lasting between 20-40
minutes.
Phase-III: The period of regular spike bursts or regular
maximal contraction lasting between 4-6 minutes.
These are also called as ‘housekeeper waves’, since
these sweep-undigested materials out of the stomach
and down to small intestine.
Phase-IV: The transition period of 0-5 minutes
between phase III and phase I.
The pattern and force of the motility vary depending on
whether the human is in fed or fasted state. The above-
mentioned time period is for fasted state. Thus most
dosage forms administered in the fasted state empty in
0-90 minutes. In the fed state, non-disintegrating
tablets and capsules stay in the stomach for 2-6 hour
and are discharged only at the onset of fasted activity;
table 1
Table1: Transit time of different dosage forms
across the segments of GIT
APPROACHES TO GASTRIC RETENTION
A number of approaches have been used to increase the
GRT of a dosage form in stomach by employing a
variety of concepts [18]. Schematic representation of
different approaches of GRDDS given below in figure
4;
Fig 4: Approaches of gastroretentive drug delivery
system
a) Floating systems
Floating drug delivery systems (FDDS) have a bulk
density lower than gastric fluids and thus remain
buoyant in the stomach for a prolonged period of time,
without affecting the gastric emptying rate; figure 5.
Fig 5: Graphic of buoyant tablet which is less dense
than the stomach fluid and therefore remains in the
fundus
While the system is floating on the gastric contents, the
drug is released slowly at a desired rate from the
system. After the release of drug, the residual system is
emptied from the stomach. This results in an increase
in the GRT and a better control of fluctuations in the
plasma drug concentrations. Floating systems can be
classified into two distinct categories, non-effervescent
and effervescent systems [19].
Dosage form
Transit time (h)
Gastric
Total
Tablets
2.7±1.5
5.8
Pellets
1.2±1.3
4.6
Capsules
0.8±1.2
4.0
Oral solution
0.3±0.07
4.4
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b) Bio or mucoadhesive systems
Bio or mucoadhesive systems are those which bind to
the gastric epithelial cell surface or mucin and serve as
a potential means of extending the GRT of drug
delivery system (DDS) in the stomach, by increasing
the intimacy and duration of contact of drug with the
biological membrane.
The surface epithelial adhesive properties of mucin
have been well recognized and applied to the
development of GRDDS based on bio or mucoadhesive
polymers. The ability to provide adhesion of a drug (or
a delivery system) to the GI wall provides a longer
residence time in a particular organ site, thereby
producing an improved effect in terms of local action
or systemic effect.
Binding of polymers to the mucin or epithelial surface
can be divided into three broad categories [20].
Hydration mediated adhesion: Certain hydrophilic
polymers tend to imbibe large amount of water and
become sticky, thereby acquiring bioadhesive
properties.
Bonding mediated adhesion: The adhesion of
polymers to a mucus or epithelial cell surface involves
various bonding mechanisms, including physical-
mechanical bonding and chemical bonding. Physical-
mechanical bonds can result from the insertion of the
adhesive material into the folds or crevices of the
mucosa. Chemical bonds may be either covalent
(primary) or ionic (secondary) in nature. Secondary
chemical bonds consist of dispersive interactions
(i.e.,vander waals interactions) and stronger specific
interactions such as hydrogen bonds. The hydrophilic
functional groups responsible for forming hydrogen
bonds are the hydroxyl and carboxylic groups.
Receptor mediated adhesion: Certain polymers bind
to specific receptor sites on the cell surfaces, thereby
enhancing the gastric retention of dosage forms.
Various investigators have proposed different mucin
polymer interactions, such as:
Wetting and swelling of the polymer to permit
intimate contact with the biological tissue.
Interpenetration of bioadhesive polymer chains
and entanglement of polymer and mucin chains.
Formation of weak chemical bonds.
Sufficient polymer mobility to allow spreading.
Water transport followed by mucosal dehydration.
The bioadhesive coated system when comes in contact
with the mucus layer, various non-specific (Vander
Waals, hydrogen bonding and/or hydrophobic
interactions) or specific interactions occurs between the
complimentary structures and these interactions last
only until the turnover process of mucin and the drug
delivery system should release its drug contents during
this limited adhesion time, in order for a bioadhesive
system to be successful.
c) Swelling and expanding systems
These are the dosage forms, which after swallowing;
swell to an extent that prevents their exit from the
pylorus. As a result, the dosage form is retained in the
stomach for a long period of time. These systems may
be named as “plug type system”, since they exhibit the
tendency to remain logged at the pyloric sphincter if
that exceed a diameter of approximately 12-18 mm in
their expanded state; figure 6
Fig 6: Swelling system
The formulation is designed for gastric retention and
controlled delivery of the drug into the gastric cavity.
Such polymeric matrices remain in the gastric cavity
for several hours even in the fed state
A balance between the extent and duration of swelling
is maintained by the degree of cross-linking between
the polymeric chains. A high degree of cross-linking
retards the swelling ability of the system maintaining
its physical integrity for prolonged period [13].
d) High density systems
These systems with a density of about 3 g/cm3 are
retained in the rugae of the stomach and are capable of
withstanding its peristaltic movements; figure 7.
Fig 7: Graphic of heavy tablet which is denser than
the stomach fluid and therefore sinks to the antrum
A density of 2.6-2.8 g/cm3 acts as a threshold value
after which such systems can be retained in the lower
part of the stomach. High density formulations include
coated pellets. Coating is done by heavy inert material
such as barium sulphate, zinc oxide, titanium dioxide,
iron powder etc. They are retained in the antrum of
stomach [21]
e) Incorporation of passage delaying food agents
Food excipients like fatty acids e.g. salts of myristic
acid change and modify the pattern of the stomach to a
fed state, thereby decreasing gastric emptying rate and
permitting considerable prolongation of release. The
delay in the gastric emptying after meals rich in fats is
largely caused by saturated fatty acids with chain
length of C10-C14 [22].
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f) Ion exchange resins
A coated ion exchange resin bead formulation has been
shown to have gastric retentive properties, which was
loaded with bicarbonates. Ion exchange resins are
loaded with bicarbonate and a negatively charged drug
is bound to the resin. The resultant beads were then
encapsulated in a semi-permeable membrane to
overcome the rapid loss of carbon dioxide. Upon
arrival in the acidic environment of the stomach, an
exchange of chloride and bicarbonate ions take place.
As a result of this reaction carbon dioxide was released
and trapped in the membrane thereby carrying beads
towards the top of gastric content and producing a
floating layer of resin beads in contrast to the uncoated
beads, which will sink quickly [23].
g) Osmotic regulated systems
It is comprised of an osmotic pressure controlled drug
delivery device and an inflatable floating support in a
bio-erodible capsule. In the stomach the capsule
quickly disintegrates to release the intra-gastric
osmotically controlled drug delivery device. The
osmotic controlled drug delivery device consists of two
components drug reservoir compartment and
osmotically active compartment [24].
h) Raft forming systems
Raft forming systems have received much attention for
the delivery of antacids and drug delivery for
gastrointestinal infections and disorders. A simple
meaning of Raft is a flat structure, typically made of
planks, logs, or barrels, that floats on water and is used
for transport or as a platform for swimmers. Here also
we are considering something that floats on gastric
content of stomach. The mechanism involved in the
raft formation includes the formation of viscous
cohesive gel in contact with gastric fluids, wherein
each portion of the liquid swells forming a continuous
layer called a raft. This raft floats on gastric fluids
because of low bulk density created by the formation of
CO2. Usually, the system contains a gel forming agent
and alkaline bicarbonates or carbonates responsible for
the formation of CO2 to make the system less dense and
float on the gastric fluids; figure 8.
Fig 8: Schematic representation of raft forming
system
The system contains a gel forming agent (e.g. alginic
acid), sodium bicarbonate and acid neutralizer, which
forms a foaming sodium alginate gel (raft) when in
contact with gastric fluids. The raft thus formed floats
on the gastric fluids and prevents the reflux of the
gastric contents (i.e. gastric acid) into the oesophagus
by acting as a barrier between the stomach and
oesophagus [25].
i) Super porous hydrogels
Conventional hydrogels, with pore size ranging
between 10 nm and 10 µm has very slow process of
water absorption and require several hours to reach an
equilibrium state during which premature evacuation of
the dosage form may occur while the super porous
hydrogel, having average pore size (>100 µm), swell to
equilibrium size within a minute, due to rapid water
uptake by capillary wetting through numerous
interconnected open pores [26]. Moreover they swell to
a large size (swelling ratio 100 or more) and are
intended to have sufficient mechanical strength to
withstand pressure by gastric contractions. This is
achieved by a co-formulation of a hydrophilic
particulate material, Ac-Di-Sol or CCS
(crosscarmellose sodium); figure 9
Fig 9: Schematic illustration of the transit of
superporous hydrogel
Types of floating drug delivery systems (FDDS)
Based on the mechanism of buoyancy, two distinctly
different technologies have been utilized in
development of FDDS which are:
A. Effervescent system
B. Non- effervescent system
A. Effervescent system
Effervescent systems include use of gas generating
agents, carbonates (ex. Sodium bicarbonate) and other
organic acid (e.g. citric acid and tartaric acid) present
in the formulation to produce carbon dioxide (CO2)
gas, thus reducing the density of the system and
making it float on the gastric fluid. An alternative is the
incorporation of matrix containing portion of liquid,
which produce gas that evaporate at body temperature
These effervescent systems further classified into two
types.
I. Gas generating systems
II. Volatile liquid or vacuum containing systems
I. Gas generating Systems
These are formulated by intimately mixing the CO2
generating agents and the drug within the matrix tablet.
These systems are again classified into 3 categories
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a. Intra-gastric single layer floating tablets (or)
hydrodynamically balanced system (HBS)
b. Intra-gastric bi layer floating tablets
c. Multiunit type floating pills
a. Intra-gastric single layer floating tablets: These
have a bulk density lower than gastric fluids and
therefore remain floating in the stomach unflattering
the gastric emptying rate for a prolonged period. The
drug is slowly released at a desired rate from the
floating system and after the complete release the
residual system is expelled from the stomach [27]. This
leads to an increase in the GRT and a better control
over fluctuations in plasma drug concentration; figure
10.a.
b. Intra-gastric bi-layer floating tablets: These are
also compressed tablet and containing two layers
(Mamajek and Moyer, 1980). i.e., immediate release
layer and sustained release layer; figure 10.b.
Fig 10: (a) Intra-gastric single layer floating table
(b) Intra-gastric bi layer floating tablet
c. Multiple unit type floating pills: These systems
consist of consist of sustained release pills as ‘seeds’
surrounded by double layers. The inner layer consists
of effervescent agents while the outer layer is of
swellable membrane layer. When the system is
immersed in dissolution medium at body temp, it sinks
at once and then forms swollen pills like balloons,
which float as they have lower density [28]. This lower
density is due to generation and entrapment of CO2
within the system; figure 11.
Fig 11: (i) Multi-unit oral floating dosage system
(ii) Stages of floating mechanism:
(A) Penetration of water (B) Generation of CO2 and
floating (C) Dissolution of drug key.
(a) Conventional SR pills; (b) Effervescent layer;
(c) Swellable layer; (d) Expanded swellable
membrane layer; (e) Surface of water in the beaker
II. Volatile liquid or vacuum Containing Systems
These systems are classified into 3 categories
a. Intra gastric floating drug delivery system
b. Inflatable gastrointestinal delivery systems
c. Intra-gastric osmotically controlled drug delivery
system
a. Intra-gastric floating gastrointestinal drug
delivery system: These systems can be made to float
in the stomach because of floatation chamber, which
may be a vacuum or filled with air or a harmless gas,
while drug reservoir is encapsulated inside a
microprous compartment [29]; figure12.
Fig 12: Intra-gastric floating gastrointestinal drug
delivery device
b. Inflatable gastrointestinal delivery systems: In
these systems an inflatable chamber is incorporated,
which contains liquid ether that gasifies at body
temperature to cause the chamber to inflate in the
stomach; figure 13.
These systems are fabricated by loading the inflatable
chamber with a drug reservoir, which can be a drug,
impregnated polymeric matrix, then encapsulated in a
gelatin capsule. After oral administration, the capsule
dissolves to release the drug reservoir together with the
inflatable chamber. The inflatable chamber
automatically inflates and retains the drug reservoir
compartment in the stomach.
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Fig 13: Inflatable gastrointestinal delivery system
The drug continuously released from the reservoir into
the gastric fluid [30].
c. Intra-gastric osmotically controlled drug delivery
system: It is comprised of an osmotic pressure
controlled drug delivery device and an inflatable
floating support in a biodegradable capsule. In the
stomach, the capsule quickly disintegrates to release
the intra-gastric osmotically controlled drug delivery
device. The inflatable support inside forms a
deformable hollow polymeric bag that contains a liquid
that gasifies at body temperature to inflate the bag. The
osmotic pressure controlled drug delivery device
consists of two components; drug reservoir
compartment and an osmotically active compartment
[31]. The drug reservoir compartment is enclosed by a
pressure responsive collapsible bag, which is
impermeable to vapour and liquid and has a drug
delivery orifice. The osmotically active compartment
contains an osmotically active salt and is enclosed
within a semi-permeable housing. In the stomach, the
water in the GI fluid is continuously absorbed through
the semi-permeable membrane into osmotically active
compartment to dissolve the osmotically active salt. An
osmotic pressure is thus created which acts on the
collapsible bag and in turn forces the drug reservoir
compartment to reduce its volume, activate the drug
reservoir compartment to reduce its volume and
activate the drug release of a drug solution formulation
through the delivery orifice; figure 14.
The floating support is also made to contain a bio-
erodible plug that erodes after a predetermined time to
deflate the support. The deflated drug delivery system
is then emptied from the stomach.
Fig 14: Intra-gastric osmotically controlled drug
delivery system
B. Non-effervescent systems
The Non-effervescent FDDS based on mechanism of
swelling of polymer or bioadhesion to mucosal layer in
GI tract. The most commonly used excipients in non-
effervescent FDDS are gel forming or highly swellable
cellulose type hydrocolloids, polysaccharides and
matrix forming material such as polycarbonate,
polyacrylate, polymethacrylate, polystyrene as well as
bioadhesive polymer such as chitosan and carbopol.
The various types of this system are as [32, 33]
i. Single layer floating tablets
They are formulated by intimate mixing of drug with a
gel-forming hydrocolloid, which swells in contact with
gastric fluid and maintain bulk density of less than
unity. The air trapped by the swollen polymer confers
buoyancy to these dosage forms.
ii. Bi-layer floating tablets
A bi-layer tablet contain two layer one immediate
release layer which release initial dose from system
while the another sustained release layer absorbs
gastric fluid, forming an impermeable colloidal gel
barrier on its surface, and maintain a bulk density of
less than unity and thereby it remains buoyant in the
stomach.
iii. Alginate beads
Multi unit floating dosage forms were developed from
freeze-dried calcium alginate. Spherical beads of
approximately 2.5 mm diameter can be prepared by
dropping a sodium alginate solution into aqueous
solution of calcium chloride, causing precipitation of
calcium alginate leading to formation of porous
system, which can maintain a floating force for over 12
hours. When compared with solid beads, which gave a
short residence, time of 1 hour, and these floating
beads gave a prolonged residence time of more than
5.5 hours [34].
iv. Hollow microspheres
Hollow microspheres (microballoons), loaded with
drug in their outer polymer shells were prepared by a
novel emulsion-solvent diffusion method. The ethanol:
dichloromethane solution of the drug and an enteric
acrylic polymer was poured into an agitated aqueous
solution of PVA that was thermally controlled at 400C.
The gas phase generated in dispersed polymer droplet
by evaporation of dichloromethane formed an internal
cavity in microsphere of polymer with drug [35]. The
micro-balloons floated continuously over the surface of
acidic dissolution media containing surfactant for more
than 12 hours; figure 15.
Fig 15: Hallow microspheres
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EVALUATION OF GASTRORETENTIVE
DOSAGE FORM
Evaluation of a drug product is a tool to ensure:
1. Performance characteristics
2. Control batch to batch quality
Apart from routine tests like general appearance,
hardness and friability, drug content, weight variation,
uniformity of content, disintegration time, drug release,
etc., GRDDS need to be evaluated for gastroretentive
performance by carrying out specific tests [36, 37].
I) IN VITRO EVALUATION
1) Floating systems
a) Floating lag time: It is determined in order to assess
the time taken by the dosage form to float on the top of
the dissolution medium, after it is placed in the
medium. These parameters can be measured as a part
of the dissolution test.
b) Floating time: Test for buoyancy is usually
performed in SGF Simulated Gastric Fluid maintained
at 370C.The time for which the dosage form
continuously floats on the dissolution media is termed
as floating time [29].
c) Specific gravity or density: Density can be
determined by the displacement method using Benzene
as displacement medium.
d) Resultant weight: Now we know that bulk density
and floating time are the main parameters for
describing buoyancy. But only single determination of
density is not sufficient to describe the buoyancy
because density changes with change in resultant
weight as a function of time. For example a matrix
tablet with bicarbonate and matrixing polymer floats
initially by gas generation and entrapment but after
some time, some drug is released and simultaneously
some outer part of matrixing polymer may erode out
leading to change in resultant weight of dosage form
[38]. The magnitude and direction of force or resultant
weight (up or down) is corresponding to its buoyancy
force (Fbuoy) and gravity force (Fgrav) acting on dosage
form; figure16.
Fig 16: Swelling systems-water uptake
F = Fbuoy Fgrav
F = Df g V Ds g V
F = (Df Ds) g V
F = (Df M/V) g V
Where,
F = resultant weight of object
Df = Density of Fluid
DS = Density of Solid object
g = Gravitational force
M = Mass of dosage form
V = Volume of dosage form
So when Ds, density of dosage form is lower, F force is
positive gives buoyancy and when it is Ds is higher, F
will negative shows sinking.
2) Swelling systems
a) Swelling index: After immersion of swelling dosage
form into SGF at 370C, dosage form is removed out at
regular interval and dimensional changes are measured
in terms of increase in tablet thickness or diameter with
time.
b) Water uptake: It is an indirect measurement of
swelling property of swellable matrix. Here dosage
form is removed out at regular interval and weight
changes are determined with respect to time.
So it is also termed as Weight Gain.
Water uptake = WU = (Wt Wo) * 100 / Wo
Where, Wt = Weight of dosage form at time t; Wo =
Initial weight of dosage form
II) IN VITRO DISSOLUTION TESTS
In vitro dissolution test is generally done by using USP
apparatus with paddle and GRDDS is placed normally
as for other conventional tablets [39, 40].
i. But sometimes as the vessel is large and
paddles are at bottom, there is much lesser paddle
force acts on floating dosage form which
generally floats on surface. As floating dosage
form not rotates may not give proper result and
also not reproducible results. Similar problem
occur with swellable dosage form, as they are
hydrogel may stick to surface of vessel or paddle
and gives irreproducible results. In order to
prevent such problems, various types of
modification in dissolution assembly made are as
follows
ii. To prevent sticking at vessel or paddle and to
improve movement of dosage form, method
suggested is to keep paddle at surface and not too
deep inside dissolution medium.
iii. Floating unit can be made fully submerged, by
attaching some small, loose, non- reacting
material, such as few turns of wire helix, around
dosage form. However this method can inhibit
three dimensional swelling of some dosage form
and also affects drug release. Figure 17 shows in
vitro dissolution test for different GRDDS.
iv. Other modification is to make floating unit
fully submerged under ring or mesh assembly and
paddle is just over ring that gives better force for
movement of unit.
v. Other method suggests placing dosage form
between 2 ring/meshes.
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Fig 17: In vitro Dissolution tests
vi. In previous methods unit have very small area,
which can inhibit 3D swelling of swellable units,
another method suggest the change in dissolution
vessel that is indented at some above place from
bottom and mesh is place on indented
protrusions, this gives more area for dosage form.
In-spite of the various modifications done to get the
reproducible results, none of them showed correlation
with the in vivo conditions. So a novel dissolution test
apparatus with modification of Rossett-Rice test
apparatus was proposed [41].
III) IN VIVO EVALUATION
Different tests were included, such as radiology,
scintigraphy, gastroscopy, magnetic marker monitoring
and ultrasonography etc., [42].
a) Radiology: X-ray is widely used for examination of
internal body systems. Barium Sulphate is widely used
Radio Opaque Marker. So, BaSO4 is incorporated
inside dosage form and X-ray images are taken at
various intervals to view gastric residence (GR).
b) Scintigraphy: Similar to X-ray, emitting materials
are incorporated into dosage form and then images are
taken by scintigraphy. Widely used emitting material is
Tc99.
c) Gastroscopy: It is peroral endoscopy used with
fiber optics or video systems. Gastroscopy is used to
inspect visually the effect of prolongation in stomach.
It can also give the detailed evaluation of GRDDS.
d) Magnetic marker monitoring: In this technique,
dosage form is magnetically marked with incorporating
iron powder inside, and images can be taken by very
sensitive bio-magnetic measurement equipment.
Advantage of this method is radiation less and so, not
hazardous.
e) Ultrasonography: Used sometimes, not used
generally because it is not traceable at intestine.
f) 13C Octanoic acid breath test: In stomach due to
chemical reaction, octanoic acid liberates CO2 gas
which comes out in breath. The important Carbon atom
which will come in CO2 is replaced with 13C isotope.
So time up to which 13CO2 gas is observed in breath
can be considered as gastric retention time of dosage
form. As the dosage form moves to intestine, there is
no reaction and no CO2 release. So this method is
cheaper than other.
FACTORS AFFECTING GASTRIC RETENTION
TIME OF THE DOSAGE FORM
Posture: Floating can vary between supine and upright
ambulatory states of the patient
Age: People with age more than 70 have a significant
longer GRT.
Density: The density of the dosage form should be less
than that of the gastric contents (1.004g/ml)
Size: Dosage form having diameter of more than
7.5mm have more gastric residence time than that of
9.9mm diameter dosage form [43].
Shape of the dosage form: The tetrahedron resided in
the stomach for longer period than other devices of
similar size.
Single or multiple unit formulation: Multiple unit
formulation show a more predictable release profile
and insignificant impairing of the performance due to
failure of the units. Allow co-administration of units
with different release profile or containing
incompatible substances and permit larger margin of
safety against dosage form failure compared with
single unit dosage form.
Fed or unfed state: Under fasting conditions, the GI
motility is characterized by periods of strong motar
activity that occur every 1.5 to 2 hrs. The MMC
sweeps undigested material from the stomach and if the
timing of the formulation coincides with that of MMC,
the GRT of the unit can be very short, however in fast
state MMC is delayed and GRT is longer [44].
Nature of meal: Feeding of indigestible polymers or
fatty acids can change the motility pattern of the
stomach to a fed state, thus decreasing gastric emptying
rate and prolonging drug release [45].
Caloric content: GRT can be increased by 4-10 with a
meal that is high in protein and fat.
Frequency of feed: The GRT can be increasing over
400 min. when successive meals given are compared
with the single meal due to low frequency of MMC.
Gender: Mean ambulatory GRT in male (3.4hrs) is
less compared with the age and race matched female
counter parts (4.6hrs) regardless of height, weight and
body surface [46].
Concomitant drug administration: Anti-cholinergic
like atropine and propetheline, opiates like codeine can
prolong GRT.
MERITS
GRDDS have following advantages [47, 48]:
Delivery of drugs with narrow absorption window
in the small intestine region.
Longer residence time in the stomach could be
advantageous for local action in the upper part of
the small intestine, for example treatment of
peptic ulcer disease.
Improved bioavailability is expected for drugs
that are absorbed readily upon release in the GIT
such as cyclosporine, ciprofloxacin, ranitidine,
amoxycillin, captopril, etc.
Patient compliance by making a once a day
therapy.
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Improved therapeutic efficacy.
Improved bioavailability due to reduced P-
glycoprotein activity in the duodenum.
Reduces frequency of dosing.
Targeted therapy for local ailments in the upper
GIT.
DEMERITS
GRDDS have some disadvantages given below [49]
× Unsuitable for drugs with limited acid solubility.
E.g. Phenytoin
× Unsuitable for drugs those are unstable in acidic
environment.
E.g. Erythromycin
× Drugs that irritates or causes gastric lesions on
slow release.
E.g. Aspirin and other NSAID’s
× Drugs that absorb selectively in colon.
E.g. Corticosteroid
× Drugs that absorb equally well through GIT.
E.g. Isosorbide dinitrate, nifidipine
LIMITATIONS
GRDDS have potential in improving bioavailability of
drugs exhibiting ‘absorption window’. However they
have certain limitations
They require high levels of fluids in stomach for
the delivery system to float and work efficiently.
So more water intake is prescribed with such
dosage form.
In supine posture (like sleeping), floating dosage
form may swept away (if not of larger size) by
contractile waves. So patient should not take
floating dosage form just before going to bed.
Drugs having stability problem in high acidic
environment, having very low solubility in acidic
environment and drugs causing irritation to
gastric mucosa cannot be incorporated into
GRDDS.
Bio or mucoadhesives systems have problem of
high turnover rate of mucus layer, thick mucus
layer and soluble mucus related limitations.
Swellable dosage form must be capable to swell
fast before its exit from stomach and achieve size
larger than pylorus aperture. It must be capable to
resist the housekeeper waves of Phase III of
MMC.
Table 2: List of various drugs commonly used in GRDDS
Dosage Forms
Drugs
Floating Tablets
Aceclofenac [50], ambroxol [51], Amoxycillin trihydrate [52], Atenolol [53], Captopril [54],
cephalexin [55], Cinnerazine [56], Bergenin and Cetirizine dihydrochloride [57],
Ciprofloxacin [58], Diclofenac sodium [59], Diltiazem hydrochloride [60], Fluorouracil
[61], Glipizide [62],Ibruprofen [63], Ketoprofen [64], Pioglitazone [65], Nimodipine [66],
Ranitidine hydrochloride [67], Theophylline [68, 69], Tizanidine hydrochloride [70],
Venlafaxine hydrochloride [71], Verapamil hydrochloride [72] etc.
Floating Granules
Diclofenac sodium [73], Indomethacin [74] etc.
Floating Capsules
Furosemide [75], Nicardipine [76], Misoprostol [77], Propranolol hydrochloride [78],
Cephalosporin [79] etc.
Floating Microspheres
Atenolol [80], Griseofulvin [81], Famotidine[82], Ibuprofen [83], Terfenadine [84],
Tranilast Cinnarizine [85] etc.
Table 3: List of various polymers and other ingredients used in GRDDS
Category
Materials
Polymers
Cellulose polymers: HPMC K4 M, HPMC K15, HPMC K100 and HPMC 4000
etc.
Eudragits: Eudragit S100, eudragit RL, eudragit RS, eudragit S etc.
Alginates: Calcium alginate, sodium alginate etc.
Others: PEO, PVA, PVP, PEG, carbopol, polycarbonate, acrylic polymer etc.
Effervescent agents
Citric acid, citroglycine, di-sodium glycine carbonate, sodium bicarbonate,
tartaric acid etc.
Low density material
Glyceryl palmitostearate, glyceryl behenate, polypropylene foam powder etc.
Buoyancy increasing agents (up to 80%)
Ethyl cellulose
Inert fatty materials (5%-75%)
Beeswax, fatty acids, long chain fatty alcohols, gelucires® 39/01 and 43/01 etc.
Release rate retardants (5% - 60%)
Di-calcium phosphate, talc, magnesium stearate etc.
Release rate accelerants (5% - 60%)
Lactose, mannitol etc.
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Table 4: List of various gastroretentive marketed formulations
Sl. No.
Brand name
Drug
Manufacturer
Country
1
Liquid Gaviscon
Al. Hydroxide and Mg. Carbonate
Glaxosmithkline
India
2
Conviron
Ferrous sulphate
Ranbaxy
India
3
Cifran OD
Ciprofloxacin
Ranbaxy
India
4
Oflin OD
Ofloxacin
Ranbaxy
India
5
Madopar
Levodopa and Benserazide
Roche
USA
6
Cytotec
Misoprostol
Pharmacia
USA
7
Valrelease
Diazepam
Roche
USA
8
Topalkan
Al-Mg antacid
Pierre fabre
France
CONCLUSION:
To derive maximum therapeutic benefits from certain
drug substances, it is desirable to prolong their gastric
residence time. It provides several advantages
including greater flexibility and adaptability gives
clinicians and those engaged in product development
powerful new tools to optimize therapy. The increasing
sophistication of delivery technology will ensure the
development of increasing number of gastroretentive
drug delivery systems to optimize the delivery of
molecules that exhibit narrow absorption window, low
bioavailability and extensive first pass metabolism. The
control of gastro intestinal transit could be the focus of
the next decade and may result in new therapeutic
possibilities with substantial benefits for patient.
FUTURE PROSPECTS:
In the future, it can be easily assumed that GRDDS will
become more popular in delivering drugs to the
systemic circulation with improving efficiency of
various types of pharmacotherapies.
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... However, intrinsic factors related to the nature of the pharmaceutical compound such as solubility, molecular weight, pKa, and affinity for the receptor, as well as extrinsic factors such as the physiological stage of the organism or enzymatic interaction with the surrounding environment, are being considered the major disadvantages of these DDS (Vega-Vásquez et al., 2020).These limitations make the bioactive compound susceptible to degradation or inactivation, decreasing its bioavailability (Chen F. et al., 2018). As a result, a higher frequency of drug administration must be needed, having a direct impact on the cost in addition to increasing the risk of side effects, which can be avoided by applying these processes in the pharmaceutical field (Kumar, 2013). ...
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... Solid dosage forms are more popular because of ease of administration, accurate dosage, selfmedication, pain avoidance and most importantly the patient compliance [3][4][5]. The majority accepted solid dosage forms are tablets and capsules; one of the important drawbacks of solid dosage forms; especially solids are not recommended to pediatrics, geriatrics and unconscious patients [6][7][8]. Gastrointestinal physiology offers additional flexibility in dosage form design than the popularity of other routes [9,10]. ...
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Oral route is considered as the most convenient, accepted and safest way for drug delivery, achieving better therapeutic effectiveness by delivery of drug at specific site in controlled manner is getting more attention now a days and GRDDS is one of the novel approaches which prolongs gastric residence time and releases a drug at specific targeted site of stomach for local or systemic effects. This approach is useful for drugs having narrow absorption window in upper part of GI tract. In this review we have discussed various aspects of GRDDS like merits, demerits, physiology of stomach, and potential drug candidate for GRDDS, factors affecting gastric retention, polymers and other materials used in GRDDS, Various approaches for gastric retention and evaluation of GRDDS concisely.
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In the research and development of ratecontrolled oral drug delivery systems, scientific and technological advances have been made in recent years by overcoming physiological adversities, such as short gastric residence times (GRT) and erratic gastric emptying times (GET). Several methods, including floating drug delivery systems (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and expanding systems, polymeric bioadhesive systems, modifiedshape systems, highdensity systems, and other delayed gastric emptying devices, are currently being used in GRT prolongation. The various strategies used in the development of FDDS by constructing the buoyancy mechanism based on the effervescent and noneffervescent form of floating tablets.FDDS is a method of delivering locally active drugs with a small absorption window in the upper gastrointestinal tract, unstable in the lower intestinal environment, and with higher pH values that have low solubility. Recent advances in floating drug delivery systems include physiological and formulation variables influencing gastric retention time, approaches to the formulation of floating systems for single units and multiple units, and thorough discussion of their classification and formulation aspects. Evaluation criteria and implementation of floating drug delivery systems are also summarized in this study.
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“Completely revised and expanded throughout. Presents a comprehensive integrated, sequenced approach to drug dosage formulation, design, and evaluation. Indentifies the pharmacodynamic and physicochemical factors influencing drug action through various routes of administration.
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