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Sanjay Garg is Associate Professor
in the Department of Pharmaceutics
of the National Institute of
Pharmaceutical Education and
Research (NIPER). His areas of
research interest include novel
drug delivery systems, especially
osmotically controlled oral systems,
bioadhesive formulations and
vaginal drug delivery systems.
Professor Garg is involved with
pharmaceutical project management
and with regulatory affairs.
Shringi Sharma is currently working
as Senior Research Fellow in the
Department of Pharmaceutics of
NIPER. He completed his Masters
in pharmaceutics.
160
Drug Delivery ORAL
Gastroretentive Drug Deliver y Systems
Associate Professor and Senior Research Fellow, Department of Pharmaceutics,
National Institute of Pharmaceutical Education and Research (NIPER)
Introduction
Oral delivery of drugs is by far the most preferable
route of drug delivery due to the ease of
administration, patient compliance and flexibility in
formulation, etc. From immediate release to site-
specific delivery, oral dosage forms have really
progressed. However, it is a well-accepted fact that it is
difficult to predict the real in vivo time of release with
solid, oral controlled release dosage forms. Thus, drug
absorption in the gastrointestinal (GI) tract may be very
short and highly variable in certain circumstances.
It is evident from the recent scientific and patent
literature that an increased interest in novel dosage
forms that are retained in the 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 profile in
the GI tract is to control the gastric residence time
(GRT). Dosage forms with a prolonged GRT, i.e.
gastroretentive dosage forms (GRDFs), will provide
us with new and important therapeutic options.
The Multifarious Uses of GRDFs
GRDFs extend significantly the period of time over
which the drugs may be released. Thus, they not
only prolong dosing intervals, but also increase
patient compliance beyond the level of existing
controlled release dosage forms. This application is
especially effective in delivery of 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 address this, oral administration of
sparingly soluble drugs is carried out frequently,
often several times per day.
As a mechanism to override this problem, erodible,
gastroretentive dosage forms have been developed
that provide continuous, controlled administration
of these drugs at the absorption site. In addition,
these dosage forms are useful for delivering drugs
incorporated into vesicles such as liposomes,
a report by
S a n j a y G a r g and S h r i n g i S h a r m a
nanoparticles, proteinoid microspheres and
pharmacosomes, etc. Compared with other
applications, the frequency of dosing may be the
same, but the gastroretentive dosage forms will
alter beneficially the absorption profile of the active
agent, thus enhancing its bioavailability. For
example, a significant increase in the bioavailability
of furosemide from a floating dosage form (42.9%)
has been reported, compared with commercially
available tablets (Lasix ® (33.4%)) and enteric
products (29.5%).
GRDFs greatly improve the pharmacotherapy of the
stomach through local drug release, leading to high
drug concentrations at the gastric mucosa
(eradicating Helicobacter pylori from the submucosal
tissue of the 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. These substances,
for example antiviral, antifungal and antibiotic
agents (sulphonamides, quinolones, penicillins,
cephalosporins, aminoglycosides and tetracyclines,
etc.), are taken up only from very specific sites of the
GI mucosa. In addition, by continually supplying the
drug to its most efficient site of absorption, the dosage
forms allow for more effective oral use of peptide and
protein drugs such as calcitonin, erythropoietin,
vasopressin, insulin, low-molecular-weight heparin,
protease inhibitors and luteinising hormone-releasing
hormone analogues.
Mechanistic Aspects of GRDFS
Various attempts have been made to retain the
dosage form in the stomach as a way of increasing
the retention time. These attempts include
introducing floating dosage forms (gas-generating
systems and swelling or expanding systems),
mucoadhesive systems, high-density systems,
modified shape systems, gastric-emptying delaying
devices and co-administration of gastric-emptying
delaying drugs. Among these, the floating dosage
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Drug Delivery ORAL

Figure 1: The Mechanism of Floating Systems

Fgravity

Swelling system RW +ve Gas-generating

system

Imbibition of GF GF CO2 released GF

provides F buoyancy
RW -ve
Fbuoyancy

a b c
GF = Gastric fluid

forms have been used most commonly. However,
most of these approaches are influenced by a
number of factors that affect their efficacy as a
gastroretentive system:1–3
• density – GRT is a function of dosage form
buoyancy that is dependent on the density;
• size – dosage form units with a diameter of more
than 7.5mm are reported to have an increased
GRT compared with those with a diameter of
9.9mm;
GRT of the unit can be expected to be very
short. However, in the fed state, MMC is delayed
and GRT is considerably longer;
• nature of meal – feeding of indigestible polymers
or fatty acid salts can change the motility pattern
of the stomach to a fed state, thus decreasing the
gastric emptying rate and prolonging drug release;
• caloric content – GRT can be increased by four
to 10 hours with a meal that is high in proteins
and fats;

• shape of dosage form – tetrahedron and ring-
shaped devices with a flexural modulus of 48
and 22.5 kilopounds per square inch (KSI) are
reported to have better GRT ≈ 90% to 100%
retention at 24 hours compared with other
shapes;
• single or multiple unit formulation – multiple unit
formulations show a more predictable release
profile and insignificant impairing of performance
due to failure of units, allow co-administration of
units with different release profiles or containing
incompatible substances and permit a larger
margin of safety against dosage form failure
compared with single unit dosage forms;
• frequency of feed – the GRT can increase by over
400 minutes when successive meals are given
compared with a single meal due to the low
frequency of MMC;
• gender – mean ambulatory GRT in males (3.4±0.6
hours) is less compared with their age and race-
matched female counterparts (4.6±1.2 hours),
regardless of the weight, height and body surface);
• age – elderly people, especially those over 70,
have a significantly longer GRT;
• posture – GRT can vary between supine and
upright ambulatory states of the patient;

• fed or unfed state – under fasting conditions, the
GI motility is characterised by periods of strong
motor activity or the migrating myoelectric
complex (MMC) that occurs every 1.5 to 2 hours.
The MMC sweeps undigested material from the
stomach and, if the timing of administration of the
formulation coincides with that of the MMC, the
• concomitant drug administration – anticholinergics
like atropine and propantheline, opiates like
codeine and prokinetic agents like metoclopramide
and cisapride; and
• biological factors – diabetes and Crohn’s disease,
etc.

1. B M Singh and K H Kim, “Floating drug delivery systems: an approach to controlled drug delivery via gastric retention”,
J. Control. Rel., 63 (2000), pp. 235–259.
2. J Timmermans and A J Moes, “Factors controlling the buoyancy and gastric retention capabilities of floating matrix capsules:
new data for reconsidering the controversy”, J. Pharm. Sci., 83 (1994), pp. 18–24.
3. P Mojaverian, P H Vlasses, P E Kellner and M L Rocci, Jr., “Effects of gender, posture, and age on gastric residence time
162 of an indigestible solid: pharmaceutical considerations”, Pharm. Res., 10 (1988), pp. 639–644.

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Types of System
Floating Drug Delivery Systems1
Floating drug delivery systems (FDDS) have a bulk
density less than gastric fluids and so remain buoyant in
the stomach without affecting the gastric emptying rate
for a prolonged period of time. While the system is
floating on the gastric contents (see Figure 1a), the drug
is released slowly at the desired rate from the system.
After release of drug, the residual system is emptied
from the stomach. This results in an increased GRT
and a better control of the fluctuations in plasma drug
concentration. However, besides a minimal gastric
content needed to allow the proper achievement of the
buoyancy retention principle, a minimal level of
floating force (F) is also required to keep the dosage
form reliably buoyant on the surface of the meal. To
measure the floating force kinetics, a novel apparatus
for determination of resultant weight (RW) has been
reported in the literature.4 The RW apparatus operates
by measuring continuously the force equivalent to F (as
a function of time) that is required to maintain the
submerged object. The object floats better if RW is on
the higher positive side (see Figure 1b). This apparatus
helps in optimising FDDS with respect to stability and
durability of floating forces produced in order to
prevent the drawbacks of unforeseeable intragastric
buoyancy capability variations.
RW or F = F buoyancy - F gravity
= (Df - Ds) gV,
where RW = total vertical force, Df = fluid density,
Ds = object density, V = volume and g =
acceleration due to gravity.
The FDDS can be divided into gas-generating and
non-effervescent systems.
Gas-generating Systems
These buoyant systems utilise matrices prepared with
swellable polymers like methocel, polysaccharides like
chitosan, effervescent components like sodium
bicarbonate, citric acid and tartaric acid or chambers
containing a liquid that gasifies at body temperature.
The optimal stoichiometric ratio of citric acid and
sodium bicarbonate for gas generation is reported to be
0.76:1. The common approach for preparing these
systems involves resin beads loaded with bicarbonate
and coated with ethylcellulose. The coating, which is
insoluble but permeable, allows permeation of water.
Thus, carbon dioxide is released, causing the beads to
float in the stomach (see Figure 1c). Other approaches
and materials that have been reported are highly
swellable hydrocolloids and light mineral oils, a
164 4. J Timmermans and A J Moes, “How well do floating dosage forms float?”, Int. J. Pharm., 62 (1990), pp. 207–216.
mixture of sodium alginate and sodium bicarbonate,
multiple unit floating pills that generate carbon dioxide
when ingested, floating minicapsules with a core of
sodium bicarbonate, lactose and polyvinyl pyrrolidone
coated with hydroxypropyl methylcellulose (HPMC),
and floating systems based on ion exchange resin
technology, etc.
Non-effervescent Systems
This type of system, after swallowing, swells
unrestrained via imbibition of gastric fluid to an
extent that it prevents their exit from the stomach.
These systems may be referred to as the ‘plug-type
systems’ since they have a tendency to remain lodged
near the pyloric sphincter. One of the formulation
methods of such dosage forms involves the mixing of
drug with a gel, which swells in contact with gastric
fluid after oral administration and maintains a relative
integrity of shape and a bulk density of less than one
within the outer gelatinous barrier. The air trapped
by the swollen polymer confers buoyancy to these
dosage forms (see Figure 1a).
Other approaches reported in the literature are
hydrodynamically balanced systems developed by
Sheth and Tossounian, which contain a mixture of
drug and hydrocolloids, sustained release capsules
containing cellulose derivatives like starch and a
higher fatty alcohol or fatty acid glyceride, bilayer
compressed capsules, multilayered flexible sheet-like
medicament devices, hollow microspheres of acrylic
resins, polystyrene floatable shells, single and multiple
unit devices with floatation chambers and
microporous compartments and buoyant controlled
release powder formulations, etc.
Recent developments include use of superporous
hydrogels that expand dramatically (hundreds of
times their dehydrated form within a matter of
seconds) when immersed in water. Oral drug
delivery formulations made from the gels would
swell rapidly in the stomach, causing medications to
move more slowly from the stomach to the intestines
and be absorbed more efficiently by the body.
Drugs reported to be used in the formulation of
floating dosage forms are floating microspheres (aspirin,
griseofulvin, p-nitroaniline, ibuprofen, terfinadine and
tranilast), floating granules (diclofenac sodium,
indomethacin and prednisolone), films (cinnarizine),
floating capsules (chlordiazepoxide hydrogen chloride,
diazepam, furosemide, misoprostol, L-Dopa,
benserazide, ursodeoxycholic acid and pepstatin) and
floating tablets and pills (acetaminophen, acetylsalicylic
acid, ampicillin, amoxycillin trihydrate, atenolol,
diltiazem, fluorouracil, isosorbide mononitrate, para-
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aminobenzoic acid, piretamide, theophylline and
verapimil hydrochloride, etc.). Excipients used most
commonly in these systems include HPMC,
polyacrylate polymers, polyvinyl acetate, Carbopol®,
agar, sodium alginate, calcium chloride, polyethylene
oxide and polycarbonates. Some of the marketed
formulations are listed as follows:
• Valrelease® – floating capsule of diazepam;
• Madopar® – benserazide and L-Dopa
combination formulation;
• Liquid Gaviscon® – floating liquid alginate
preparations;
• Topalkan® – aluminium – magnesium antacid
preparation; and
• Almagate Flot-Coat® – antacid preparation.
Bioadhesive Systems
Bioadhesive drug delivery systems (BDDS) are used to
localise a delivery device within the lumen to enhance
the drug absorption in a site-specific manner. This
approach involves the use of bioadhesive polymers,
which can adhere to the epithelial surface in the
stomach. A microbalance-based system is reported for
measuring the forces of interaction between the GI
mucosa and the individual polymers, and the Cahn
Dynamic Contact Angle Analyzer has been used to
study the adherence.5
Gastric mucoadhesion does not tend to be strong
enough to impart to dosage forms the ability to resist
the strong propulsion forces of the stomach wall. The
continuous production of mucous by the gastric
mucosa to replace the mucous that is lost through
peristaltic contractions and the dilution of the
stomach content also seems to limit the potential of
mucoadhesion as a gastroretentive force.
Some of the most promising excipients that have
been used commonly in these systems include
polycarbophil, carbopol, lectins, chitosan, CMC and
gliadin, etc. Some investigators have tried out a
synergistic approach between floating and bioadhesion
systems. Other approaches reported include use of a
novel adhesive material derived from the fimbriae
(especially Type 1) of bacteria or synthetic analogues
combined with a drug to provide for attachment to the
gut, thereby prolonging the transit time, a composition
comprising an active ingredient and a material that acts
as a viscogenic agent (for example curdlan and/or a
low-substituted hydroxypropylcellulose), etc.
High-density Systems
Sedimentation has been employed as a retention
5. D E Chickering, J S Jacob and E Mathowitz, “Bioadhesive microspheres II: Characterisation and evaluation of bioadhesion
166 involving hard, bioerodible polymers and soft tissue”, Reactive Polymers, 25 (1995), pp. 189–206.
mechanism for pellets that are small enough to be
retained in the rugae or folds of the stomach body near
the pyloric region, which is the part of the organ with
the lowest position in an upright posture. Dense
pellets (approximately 3g/cm3) trapped in rugae also
tend to withstand the peristaltic movements of the
stomach wall. With pellets, the GI transit time can be
extended from an average of 5.8–25 hours, depending
more on density than on diameter of the pellets,
although many conflicting reports stating otherwise
also abound in literature. Commonly used excipients
are barium sulphate, zinc oxide, titanium dioxide and
iron powder, etc. These materials increase density by
up to 1.5–2.4g/cm-3. However, no successful high-
density system has made it to the market.
Large Single-unit Dosage Forms
These dosage forms are larger than the pyloric
opening and so are retained in the stomach. There
are some drawbacks associated with this approach.
Permanent retention of rigid large-sized single-unit
forms can cause bowel obstruction, intestinal
adhesion and gastroplasty.
Co-administration of Gastric-emptying
Delaying Drugs
This concept of simultaneous administration of a drug
to delay gastric emptying together with a therapeutic
drug has not received the favour of clinicians and
regulatory agencies because of the questionable
benefit-to-risk ratio associated with these devices.
Evaluation of Gastroretentive Dosage
Forms
Evaluation for gastroretention is carried out by means
of X-ray and/or gamma scintigraphic monitoring of
the dosage form transit in the GI tract. The modern
technique of gamma scintigraphy now makes it
possible to follow the transit behaviour of dosage
forms in human volunteers in a non-invasive manner.
Conclusion
Finally, while the control of drug release profiles has
been a major aim of pharmaceutical research and
development in the past two decades, the control of
GI transit profiles could be the focus of the next two
decades and might result in the availability of new
products with new therapeutic possibilities and
substantial benefits for patients. Soon, the so-called
‘once-a-day’ formulations may be replaced by novel
gastroretentive products with release and absorption
phases of approximately 24 hours. ■
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