Advances in Controlled Release Gastroretentive Systems

Advances in Controlled Release Gastroretentive Systems: Strategies,

Challenges

Physiological Challenges and Impact on Drug Delivery

Gastric emptying time (GET) varies significantly among individuals due to factors like age,
dietary habits (e.g., high-fat meals delay emptying), posture, and pathological conditions
(e.g., diabetes gastroparesis). This variability complicates the design of oral dosage forms, as
unpredictable GET can lead to erratic drug absorption. For instance, drugs with a short
absorption window, such as levodopa for Parkinson’s disease, may underperform if emptied
too quickly. GRDDS addresses this by prolonging gastric residence time (GRT) from the
typical 1–2 hours to up to 24 hours, ensuring consistent drug release. Recent studies highlight
the role of circadian rhythms in gastric motility, suggesting tailored GRDDS designs for
chronotherapeutic delivery.
Approaches to GRDDS: Mechanisms and Innovations
 Floating Systems: Utilize low-density materials (e.g., polypropylene foam) or gas-
generating agents (e.g., sodium bicarbonate) to achieve buoyancy. Recent innovations
include non-effervescent systems using gel-forming polymers (e.g., hydroxypropyl
methylcellulose) that swell upon contact with gastric fluid, creating a buoyant gel
layer.
 Bioadhesive Systems: Employ mucoadhesive polymers (e.g., chitosan, Carbopol)
that bind to the gastric mucosa. Advances include thiolated polymers with enhanced
adhesion through covalent bonds.
 Swellable Systems: Expand to sizes exceeding the pyloric sphincter diameter (~12
mm). Novel superporous hydrogels (SPHs) exhibit rapid swelling, achieving
retention within Minutes.
 High-Density Systems: Use dense materials (e.g., barium sulfate) to settle in the
stomach, though this approach is less common due to discomfort risks.
 Magnetic Systems: Incorporate magnets guided by external magnetic fields, a
cutting-edge method under preclinical exploration.
Advantages and Disadvantages Revisited
Advantages: Beyond extended dosing intervals, GRDDS reduces systemic toxicity by
localizing drugs (e.g., misoprostol for gastric ulcers) and enhances bioavailability for drugs
like riboflavin, which absorb primarily in the proximal GIT. Patient compliance improves
with once-daily formulations, such as floating ciprofloxacin tablets for H. pylori infections.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 1

Indore
 Advances in Controlled Release Gastroretentive Systems

Disadvantages: Retention reliability remains a challenge; for example, floating systems may
fail in the fed state due to peristaltic waves. Manufacturing complexities, like maintaining
polymer integrity during compression, also hinder scalability.
Characterization Techniques
In vitro tests include buoyancy duration (USP dissolution apparatus with simulated gastric
fluid), swelling ratio calculations, and mucoadhesion strength measured via texture
analyzers. In vivo, gamma scintigraphy and MR
I track real-time retention, while novel biomarkers like CO₂ micro sensors assess intragastric
performance.
Commercial and Patent Landscape
Approved GRDDS products include Madopar® HBS (levodopa/carbidopa floating capsules,
Roche) and Cifran OD® (ciprofloxacin GRT tablets, Ranbaxy). Recent patents (e.g.,
US20220168221A1) describe multi-layer floating systems with pH-triggered release, and
WO2023048756A1 details 3D-printed gastric retentive devices with personalized
geometries.
Future Perspectives and Challenges
Emerging trends include 4D-printed systems adapting to gastric pH changes and hybrid
approaches combining floating and mucoadhesive mechanisms. Nanotechnology integration,
such as drug-loaded nanoparticles within GRDDS, promises enhanced solubility. However,
regulatory hurdles persist, particularly in demonstrating consistent in vivo performance.
Collaborations between pharmacologists and material scientists are critical to overcoming
scalability issues and ensuring clinical translation.

1. INTRODUCTION

NMT GUJARATI COLLEGE OF PHARMACY, Page | 2

Indore
 Advances in Controlled Release Gastroretentive Systems

The oral delivery of drugs is the most favoured route of administration because of ease
of administration. Drug bioavailability of oral dosage forms is subjective by various
factors. One of the significant factor is a gastric residence time (GRT) of these dosage forms.
Truly, gastric retention has received important interest in the past few years as many of
the conventional oral delivery systems have some limits related to fast gastric emptying time.
Gastroretentive dosage form is a type of novel drug delivery system which can persist in
the stomach for prolonged period of time and thus increases the GRT of drugs. Gastro-
retention helps to improve bioavailability of drugs.
The classification of different modes of gastric retention:
 High-density (Sinking) systems
 Low-density (Floating) systems
 Expandable systems
 Superporous hydrogel systems
 Mucoadhesive systems
 Magnetic systems
The conventional drug delivery system achieves and also maintained the drug
concentration in the therapeutically effective range desired for treatment, only when
taken numerous times a day. A drug that has a narrow absorption window in the GIT
may have poor absorption. For these drugs, GRDDS offer the advantages in extending
the gastric emptying time.
Many problems are faced in preparing controlled release systems for better absorption
and improved bioavailability. Drug absorption from the GIT is a complex process and is
subject to several variables. It is broadly recognized that the extent of GIT drug
absorption is correlated to contact time with small intestinal mucosa. GRDDS can persist
in the GI region for many hours and therefore significantly extend the GRT of drugs.
Extended gastric retention increases bioavailability, decreases drug waste and increases
solubility of drugs which are less soluble in high pH environment. To prepare a successful
stomach specific or a gastro retentive DDS, numerous techniques are presently used like
hydrodynamically balanced systems (HBS) floating drug delivery system, low density
system, raft systems incorporating alginate gels, mucoadhesive or bioadhesive systems,
high density systems, super porous hydrogels and magnetic systems.
Current progress in technology has provided feasible dosage alternatives which can
administered by different routes of administration like oral, topical, parenteral, rectal, nasal,
ocular, vaginal, etc. But out of all these routes, oral route is considered as the best

NMT GUJARATI COLLEGE OF PHARMACY, Page | 3

Indore
 Advances in Controlled Release Gastroretentive Systems

preferred and practiced way of drug delivery, due to the following reasons:
 Ease of administration
 Ease of production
 More flexibility in designing
 Low cost
Many drugs given by oral route are subjected to absorption through the GIT, with major
absorption from the stomach and intestine. Drugs, which is absorbed from the stomach
or show local effect, should spend extreme time in stomach. This is found very hard to
happen, in case of the conventional dosage forms such as capsules and tablets, due to the
gastric emptying. Gastric emptying of dosage form depends on several factors like
temperature and viscosity of the meal, volume and composition of the meal, emotional
state of the individual, the pH of the stomach, body posture, etc. Prolonged gastric
retention of the drug is required in the following conditions:
 The drug is best absorbed from the stomach. E.g., Aspirin, Phenylbutazone, etc.
 Slow dissolving drugs.
 Dissolution and absorption of drug is stimulated by the food. E.g., Griseofulvin.
 Drug show local effects within the stomach.
 Gastric fluids facilitate and increase the disintegration and dissolution of the drug.
In order to achieve all these situations, various methods of the controlled drug delivery
have been established. One of these types of the methods, which ensure that a particular
drug/dosage form remains in the stomach for longer duration of time, is GRDDS.
However, in following condition gastroretention is considered undesirable:
 For gastro irritant drugs. E.g., Diclofenac sodium, Ibuprofen, Acetylsalicylic acid, etc.
 For acid labile drugs that are stable at gastric pH. E.g., Macrolide antibiotics
 Drugs which get absorbed throughout the GIT equally.

2.Future Perspectives and Challenges

 Emerging trends include 4D-printed systems adapting to gastric pH changes and hybrid
approaches combining floating and mucoadhesive mechanisms. Nanotechnology
integration, such as drug-loaded nanoparticles within GRDDS, promises enhanced
solubility. However, regulatory hurdles persist, particularly in demonstrating consistent in
vivo performance. Collaborations between pharmacologists and material scientists are
critical to overcoming scalability issues and ensuring clinical translation.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 4

Indore
 Advances in Controlled Release Gastroretentive Systems

3.STOMACH- AN OVERVIEW
The stomach is J shaped enlargement of GIT directly inferior to the diaphragm in
epigastric, umbilical and left hypochondriac regions of the abdomen. It connects
esophagus to the duodenum, the first part of the small intestine and provides a barrier to
the delivery of drugs to the small intestine.

Anatomy of stomach:
The stomach has four regions:

Figure 1. Anterior view of regions of stomach Gastric emptying:

The process of gastric emptying happens both during fasting and fed state. In the fasted
state, it is categorized by an interdigestive cycle both through the stomach and small
intestine, every 2-3 hours. This activity is called the interdigestive myoelectric cycle or
migrating myoelectric complex (MMC). It is composed of four phases (Figure 2).
Phase Duration
Phase-I (Basal phase) 30-60 min with infrequent contractions
Phase-II (Preburst phase) 20-40 min with the irregular action potential and
contractions as the phase developments, the intensity
and the frequency also rises gradually
Phase-III (Burst phase) 10-20 min, it contains intense and regular
contractions for short periods. It’s due to this wave
that all the undigested material is swept from

NMT GUJARATI COLLEGE OF PHARMACY, Page | 5

Indore
 Advances in Controlled Release Gastroretentive Systems

stomach to the small

Intestine
Phase-IV 0-5 min and happens between phase three & one of two
successive cycles

Figure 2. Gastrointestinal motility patterns

After the digestion of mixed meal, the pattern of contractions changes from fasted to
feed state. This is also recognized as digestive motility pattern and contains endless
contractions as in phase II of fasted state. The contractions result in decreasing the size
of food particles discovered that an orally administered controlled release dosage form is
primarily subject to two physiological which are propelled towards the pylorus in the
Suspension form. Throughout the fed state onset of mmc is postponed resulting in a
slowdown of the gastric emptying rate. Scintigraphic studies including the measurements of
the gastric emptying rate in healthy human subjects have difficulties:
1. Short GRT
2. Unpredictable gastric emptying rate yet additional major difficulty encountered
through the oral route is first pass effect that leads to decreased systemic bioavailability
of numerous drugs.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 6

Indore
 Advances in Controlled Release Gastroretentive Systems

GASTRORETENTIVE DRUG DELIVERY SYSTEMS

Drugs which are easily absorbed from the gastrointestinal tract and those with short half-
lives are quickly eliminated from the systemic circulation due to which frequent dosing
is required. To overcome this problem, gastro retentive drug delivery systems which
provide effective plasma drug concentration for longer periods thereby reducing the

Dosing frequency are being formulated. It also has an advantage of minimizing the
fluctuations in plasma drug concentration by delivering the drug in a controlled and
reproducible manner. If the drugs are poorly soluble in intestine because of alkaline pH,
gastric retention may improve the solubility before they emptied resulting in GI
absorption of drugs with narrow therapeutic absorption window and also monitoring the
release of drugs that have site specific-absorption limitation. Drugs that might take
benefit of gastric retention contain the drugs whose solubility is fewer in the higher pH
of the small intestine than stomach (E.g., Cinnarizine, Chlordiazepoxide, etc.), the drugs
prone to degradation in intestinal pH (E.g., Captopril), and drugs for local action in
stomach (E.g., Misoprostol). Sedatives, antibiotics, catecholamines, anticonvulsants,
analgesics, anti-hypertensives, vitamins and muscle relaxants can also be administered
in hydrodynamically balanced systems (HBS) dosage form
Gastroretentive drug delivery systems extend the dosing intervals and therefore improve
patient compliance. The presence of drug in solution form is an important requisite for
the drug to get absorbed. But, if the drug solubility is poor, the time required for drug to
dissolve within stomach will be high and transit time becomes most severe factor, which
might consequently affect the absorption of the drug. So, dose of administration of such
drugs should be kept at repeated intervals in a single day. However, other
formulations/novel dosage forms like liposome, nanoparticle, microspheres, etc. can also
Use for controlled release effect, but GRDDS is considered more desirable alternative
for improved absorption through the stomach.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 7

Indore
 Advances in Controlled Release Gastroretentive Systems

Figure 3. Techniques of GRDDS

FACTORS AFFECTING GASTRIC RETENTION

1. Density: Gastric retention time (GRT) is a function of dosage form buoyancy which is
dependent on the density. The density of the dosage form must be lower than the gastric
contents (1.004 mg/ml).
2. Size: Dosage form units having a diameter of greater than 7.50 mm are stated to have
an improved GRT related with those having a diameter of 9.90 mm.
3. Shape of the dosage form: Tetrahedron and ring shaped devices having a flexural
modulus of 48 and 22.50 kilo pounds per square inch are reported to have a better GRT
at 24 hours compared with other shapes.
4. Single or Multiple unit formulation: Multiple unit formulations show a more
expectable release profile and insignificant damaging of performance because of failure
of units, allow coadministration of units that have dissimilar release profiles related with
single unit dosage forms.
5. Fed/Unfed state: In fasting conditions, gastrointestinal motility is categorized by
periods of strong motor activity that occurs every 1.5 to 2h and if timing of administration of
the formulation overlaps with that of the MMC, the gastric retention time of unit can be
anticipated to be very short. However, in fed state, MMC is postponed and gastric
retention time is significantly longer.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 8

Indore
 Advances in Controlled Release Gastroretentive Systems

6. Nature of meal: Feeding of fatty acid salts or indigestible polymers can modify the
motility pattern of stomach to a fed state, hence reducing the gastric emptying rate.
7. Caloric content: GRT can be improved by 4 to 10 h with a meal which is high in
proteins and fats.
8. Age: Elderly people, mostly those over 70 years, have a significantly longer gastric
retention time.
9. Frequency of feed: Gastric retention time can rise by over 400 minutes, when
consecutive meals are given related with a single meal because of the low frequency of
MMC.
10. Gender: Mean ambulatory gastric retention time in males (3.4 ± 0.6 hours) is less
correlated with their age and race matched female counterparts (4.6 ± 1.2 hours),
regardless of the weight, body surface and height.
11. Posture: Gastric retention time can be differing between supine and upright
ambulatory states of patients.
12. Concomitant drug administration: Anticholinergics like atropine and
propentheline increase the GRT. Metoclopramide and Cisapride decrease GRT.
13. Disease state: Gastric ulcer, diabetes and hypothyroidism increase the GRT.
Hyperthyroidism and duodenal ulcers decrease the GRT.

ADVANTAGES OF GASTRORETENTIVE DRUG DELIVERY

SYSTEMS
 Maintenance of constant therapeutic level over longer period of time.
e.g. Beta lactams antibiotics.
 Enhanced bioavailability of drugs.
e.g. Enhancement of bioavailability of controlled release gastro retentive dosage forms
(CR-GRDF) of riboflavin in comparison of non CR-GRDF polymeric formulation.
 Gastroretentive dosage form improves patient compliance by decreasing dosing
frequency.
 Minimizing mucosal irritation of drugs, by releasing drug slowly at a controlled rate.
e.g. NSAIDs.
 Treatment of GI disorders like GERD, Helicobacter pylori infection, etc.
 Floating drug delivery system is a feasible approach for the drugs that have limited
absorption in the intestine.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 9

Indore
 Advances in Controlled Release Gastroretentive Systems

 The floating drug delivery system can reduce the counter activity of body, leading
to higher drug efficiency.
 For drugs that have comparatively short half-life, sustained release may result in a
flip-flop pharmacokinetics.
 The floating drug delivery systems are beneficial for drugs that are absorbed through
stomach.
e.g. Antacids, Ferrous salts, etc.
 Sustained release drug delivery system reduces dosing frequency of drugs with short
half-life.
 Bioavailability enhances despite the first pass effect as a result of variations in plasma
drug concentration are escaped; a required plasma drug concentration is retained by the
continuous drug release.
 Controlled drug delivery of drugs.

DISADVANTAGES OR LIMITATION OF GASTRORETENTIVE

DRUG DELIVERY SYSTEMS
 Drugs, that undergo significant first pass metabolism, are not desirable candidate.
 Drugs having solubility or stability problems in the highly acidic gastric environment
cannot be formulated as GRDDS.
 For sellable systems, the dosage forms must maintain size larger than the aperture of the
resting pylorus for the required time period.
 These systems do not offer important advantages over the conventional dosage forms
of drugs, which are absorbed throughout the gastrointestinal tract.
 Some drugs cause irritation to the gastric mucosa.
 The dosage form must be taken with a full glass of water.
 Violent gas generation, disintegration of dosage forms, burst release, dose dumping,
and alkaline microenvironment are the limitation for floating drug delivery.
 Patients cannot be dosed these formulations just before going to bed.
 It is effective only when the fluid level in the stomach is sufficiently high.
 However, as the stomach empties and the dosage form is at the pylorus, the buoyancy
of the dosage form may be impeded.
 The major challenge for a bioadhesive system is the high turnover rate of gastric
mucus. There is also the possibility of esophageal binding with bioadhesive drug
delivery systems. The Hydrogel based swelling system takes longer time to swell.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 10

Indore
 Advances in Controlled Release Gastroretentive Systems

CRITERIA FOR SELECTION OF DRUG CANDIDATE FOR GRDDS

The gastro retentive drug delivery systems are suitable for following types of drug
therapy:
 Absorption from upper GIT: Drugs have a particular site for maximum absorption.
Example: Ciprofloxacin
 Drug having low pKa, which remains unionized in stomach for better absorption.
 Drugs having a reduced solubility at higher pH. Example: Captopril
 Local action as it is seen in the treatment of H. pylori by Amoxicillin trihydrate as in
case of ulcers. The bioavailability of drugs that get degraded in alkaline pH can be
increased by formulating gastro retentive dosage forms. Example: Doxifluridine;
which degrades in the small intestine.
 To minimize gastric irritation this may be caused by the sudden increase of drug
concentration in the stomach. Example: NSAIDs
 Drugs that act locally in the stomach. Example: Antacids, Antibiotics for bacterially
based ulcers
 Drugs that are absorbed primarily in the stomach. Example: Albuterol
 Drugs that are poorly soluble in alkaline pH.
 Drugs that have a narrow window for absorption, i.e., Drugs that are absorbed mainly
from the proximal part of small intestine. Example: Riboflavin, Levodopa.
 Drugs that are absorbed rapidly from the GI tract. Example: Amoxicillin.

NEED OF GASTRORETENTIVE DRUG DELIVERY SYSTEMS

Oral dosage forms pose low bioavailability problems because of their fast gastric
transition from the stomach, particularly in case of drugs that are less soluble at an
alkaline pH of the intestine. Also the drugs that produce their local action in the stomach
get quickly emptied and do not get sufficient residence time in the stomach. Therefore,
frequency of dose administration in such condition is increased. To avoid such problem
floating drug delivery system has been developed.

APPROACHES FOR GRDDS

The different approaches established for formulating dosage form to produce a

NMT GUJARATI COLLEGE OF PHARMACY, Page | 11

Indore
 Advances in Controlled Release Gastroretentive Systems

satisfactory gastric retention and release within gastric region, are as follows:
 High-density system
 Floating system
 Hydrodynamically balanced system
 Gas-generating system
 Raft-forming system
 Low-density system
 Expandable system
 Super porous hydrogels
 Mucoadhesive or bioadhesive system
 Magnetic system
 Self-unfolding systems

STOMACH SPECIFIC FLOATING DRUG DELIVERY SYSTEM

Stomach specific FDDS has a bulk density lesser than gastric fluids and therefore remain
buoyant in the stomach without altering the gastric emptying rate for a longer period of
time. However, the system is float on gastric contents, the drug is released gradually at a
preferred rate from the system. After releasing drug, the residual system is emptied from
stomach. It results in an increased gastric residence time and a better control of variations in
plasma drug concentration. The floating SRDF present most of the characteristics of
hydrophilic matrices and called ‘hydrodynamically balanced systems’ (HBS) as they are
able to preserve their low apparent density, however the polymer hydrates and builds a
gelled barrier on the outer surface. The drug is released gradually from the swollen
matrix, as in case of conventional hydrophilic matrices. These forms are anticipated to
remain buoyant (3-4 hrs) on the gastric contents without altering the intrinsic rate of
emptying because their bulk density is lesser than that of the gastric contents. Amongst
the different hydrocolloids suggested for floating form formulations, cellulose ether
polymers are common, particularly hydroxyl propyl methyl cellulose (HPMC). A fatty
material with bulk density 1 may be added to the formulation to increase the buoyancy
and reduce the water intake rate. Similar to formulation studies, research has been take
on humans and animals to evaluate intragastric retention performances of floating forms.
These calculations were realized either directly by gamma scintigraphic and X-ray
monitoring of the form transit in the GIT or indirectly by pharmacokinetic studies with
drug tracer.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 12

Indore
 Advances in Controlled Release Gastroretentive Systems

MECHANISM OF FLOATING DRUG DELIVERY SYSTEM

While the system is floating on the stomach, the drug is released gradually at the desired
rate from system. After releasing drug, the residual system is flattened from the stomach
besides a minimal gastric content needed to permit suitable attainment of the buoyancy
retention principle, a minimal level of floating force (F) is also essential to retain dosage
form constantly buoyant on surface of the meal. The apparatus used to measure the
floating force kinetics operates by measuring continuously the force equivalent to F (as a
function of time) that is mandatory to main submerged object. If F is on the higher
positive side, object floats better. The apparatus helps in optimizing floating drug delivery
system with respect to stability and durability of floating forces formed in order to stop
the problems of unexpected intragastric buoyancy capability variations (Figure 4).

Figure 4. Mechanism of floating system, GF = Gastric Fluid

F = F Buoyancy - F Gravity = (DF-Ds) × gv --- (1)

Where; F = Total vertical force,
DF = Fluid density,
Ds = Object density,
g = Acceleration due to gravity,
v = Volume
CLASSIFICATION OF FDDS BASED ON THE MECHANISM OF BUOYANCY
A. Single Unit Floating Dosage Systems

NMT GUJARATI COLLEGE OF PHARMACY, Page | 13

Indore
 Advances in Controlled Release Gastroretentive Systems

a) Effervescent Systems b) No effervescent Systems

B. Multiple Unit Floating Dosage Systems
a) No effervescent Systems b) Effervescent Systems c) Hollow Microspheres
C. Raft-Forming Systems

[A] SINGLE UNIT FLOATING DOSAGE SYSTEMS:

a) Effervescent Systems (Gas-generating Systems): These systems used matrices
prepared with sellable polymers such as polysaccharides like chitosan, HPMC, citric
acid and tartaric acid, effervescent components like sodium bicarbonate or chambers
containing liquid that gasifies at body temperature. The optimum stoichiometric ratio of
sodium bicarbonate and citric acid for gas generation is described to be 1:0.76. The
commonest approach for preparing these systems contains resin beads loaded with
bicarbonate and coated with ethyl cellulose. The coating, that is insoluble but permeable,
allows permeation of water. So, Co2 is released, causing the beads to float in stomach.
Excipients used in these systems include Carbopol®, polyacrylate polymers, HPMC,
polyvinyl acetate, sodium alginate, polyethylene oxide, agar, polycarbonates and
calcium chloride.
b) Non-effervescent Systems: These types of systems, after swallowing, swell
unrestrained via imbibition of gastric fluid to a level that it stops their exit from stomach.
The systems can be discussed as ‘plug-type systems’ as they have a tendency to persist
lodged near pyloric sphincter. One of the formulation approaches of such dosage forms
contains the mixing of drug and gel that swells in contact with GI fluid after oral
administration and keeps a relative integrity of shape and a bulk density within outer
gelatinous barrier. The air surrounded by swollen polymer discusses buoyancy to these
dosage forms. E.g., Colloidal gel barrier, micro porous compartment system, alginate
beads and hollow microspheres. Additional type is fluid-filled floating chamber that
comprises addition of a gas-filled floatation chamber into micro porous component that
houses a drug reservoir. Apertures are present along the top and bottom walls through
which the GI fluid enters to dissolve drug. Other two walls in contact with fluid are
sealed.
Therefore the undissolved drug stay therein. The fluid present could be air, under partial
vacuum or any other appropriate solid, liquid or gas having an appropriate specific
gravity and an inert behaviour. The device is of swallow able size, remains afloat in
stomach for longer period of time, and after the complete release shell disintegrates,

NMT GUJARATI COLLEGE OF PHARMACY, Page | 14

Indore
 Advances in Controlled Release Gastroretentive Systems

passes off to intestine and eliminated (Figure 5).

Figure 5. Gas filled floatation chamber

[B] MULTIPLE UNIT FLOATING DOSAGE SYSTEMS: In spite of intensive

research and development in the area of hydrodynamically balanced system and other
floating tablets, these systems undergo a significant drawback of the high variability of
GI transit time, when orally administered, due to their all or nothing gastric emptying
nature. With the intension to solve the above difficulty, multiple unit floating systems
were established, that decrease the inter-subject variability in absorption and reduce the
chance of dose dumping. Reports are obtained in the development of both effervescent
and no effervescent multiple unit systems. Much research has been intensive and the
scientists are still discovering the field of hollow microspheres, able to float on gastric
fluid and having better GI retention properties.
a) Non-effervescent Systems: No far report was found in literature on noneffervescent
multiple unit systems, when compared with effervescent systems. Though, few workers
have described the probability of developing such system comprising Indomethacin, by
Using chitosan as polymeric excipient. A multiple unit hydrodynamically balanced system
comprising Indomethacin as a model drug produced by extrusion method is described. A
mixture of drug, acetic acid and chitosan is extruded through a needle, and extradite is

NMT GUJARATI COLLEGE OF PHARMACY, Page | 15

Indore
 Advances in Controlled Release Gastroretentive Systems

cut and dried. Chitosan hydrates floats in acidic media, and required drug release could
be achieved by altering drug-polymer ratio.

b) Effervescent Systems (Gas-generating Systems): Ikura et al. described sustained

release floating granules comprising tetracycline hydrochloride. The granules are the
mixture of drug granulates of two stages A and B (A contains 60% of HPMC, 40% of
polyacrylic acid and 20% of the drug and B contains 70% of sodium bicarbonate and 30%
of tartaric acid). 60% by weight of granules of stage A and 30% by weight of granules of
stage B are mixed with a lubricant and packed into capsules. In dissolution media, the
capsule shell dissolve and liberate the granules, that showed a floating time of more than
8 hrs and sustained drug release of 80% in about 6.5 hrs. Floating minicapsules of pep
statin that have a diameter of 0.1-0.2 mm has been described by Umezawa.

Figure 6. (A) Multiple-unit oral floating drug delivery system

(B) Mechanism of floatation via Co2 generation
These mini capsules comprise a central core and a coating. The central core comprises of
a granule composed of lactose, sodium bicarbonate and a binder that is coated with
HPMC. Pep statin is coated on top of HPMC layer. The system floats due to the release
of carbon dioxide in gastric fluid and pep statin exist in the stomach for longer periods
(Figure 6).

NMT GUJARATI COLLEGE OF PHARMACY, Page | 16

Indore
 Advances in Controlled Release Gastroretentive Systems

c) Hollow Microspheres: Hollow microspheres are regarded as the most promising

buoyant systems, as they’ve exclusive advantages of multiple unit systems and also better
floating properties, due to central hollow space inside microsphere. The general methods
involved in their preparation contain simple solvent evaporation, solvent diffusion &
evaporation. The drug release and better floating properties generally depend on
plasticizer, type of polymer and solvents employed for preparation. Polymers like
cellulose acetate and Eudragit were used in preparation of hollow microspheres, and
drug release can be moderated by enhancing polymer quantity and polymer plasticizer
ratio.
[C] RAFT FORMING SYSTEMS: These systems have established much attention for
delivery of antacids and drug delivery for GI disorders and infections. The mechanism
complied in the raft formation contains the development of viscous cohesive gel in
contact with GI fluids, in which each portion of liquid swells forming a continuous layer
known as raft. The raft floats on gastric fluids due to low bulk density produced by the
development of Co2. Generally, the system comprises a gel forming agent and alkaline
carbonates or bicarbonates liable for the development of Co2 to make the system fewer
dense and float on the GI fluids. Jorgen et al. defined an antacid raft forming floating
system. The system comprises gel forming agent, acid neutralizer and sodium
bicarbonate that forms a foaming sodium alginate gel when in contact with GI fluids.
The raft thus formed, floats on GI fluids and stops the reflux of the GI contents into the
esophagus by acting as a barrier amongst the esophagus and stomach.

Table 1 COMPARISONS BETWEEN CONVENTIONAL AND GASTRORETENTIVE

DRUG DELIVERY SYSTEM

NMT GUJARATI COLLEGE OF PHARMACY, Page | 17

Indore
 Advances in Controlled Release Gastroretentive Systems

Parameters Gastro retentive Drug Conventional Drug Delivery

Delivery System System
Risk of toxicity Lower Higher
Patient High compliance level Less compliance level
compliance
Dose dumping High risk No risk
Drugs Beneficial for drugs: Not beneficial for drugs:
That have rapid GI That have low GI absorption Degrade
absorption in colon
Degrade in colon That show local action in the stomach
That show local action
in the stomach

Table 2 LIST OF DRUGS FORMULATED AS SINGLE AND MULTIPLE UNIT

FORMS OF FLOATING DRUG DELIVERY SYSTEMS

DOSAGE FORMS DRUGS

Floating Aspirin, p-nitro aniline, Griseofulvin, Ketoprofen, Ibuprofen,
microspheres Verapamil and Terfinadine
Floating Films Cinnarizine, p-Aminobenzoic acid, Prednisolone and Piretanide
Floating tablets and Acetaminophen, Isosorbide mononitrate, Ampicillin, Atenolol,
Pills Theophylline, p-aminobenzoic acid, Aspirin, Verapamil
hydrochloride, Sotelo
Floating Capsules Diazepam, Furosemide, Misoprostol, L-Dopa and Benserazide,
Pep statin, Verapamil HCL and Nicardipine
Floating powders Riboflavin, Phosphate, Sotalol and Theophylline
Floating granules Diclofenac sodium, Indomethacin, Prednisolone, Cinnarizine,
Diltiazem, Fluorouracil and Isosorbide mononitrate

POLYMERS AND OTHER INGREDIENTS USED IN THE FORMULATIONS OF

GASTRORETENTIVE DOSAGE FORMS

NMT GUJARATI COLLEGE OF PHARMACY, Page | 18

Indore
 Advances in Controlled Release Gastroretentive Systems

 Hydrocolloids (20%-75%): They may be anionic, synthetics or non-ionic like

modified cellulose derivatives, hydrophilic gums. E.g., Acacia, Agar, Chitosan,
Casein, Bentonite, Veegum, Gellan gum, Sodium CMC, Pectin, MC, HPC, HPMC
K4 M, HPMC K15 M, Eudragit S100, Calcium alginate, HPMC K100 M, Eudragit,
Propylene foam, Ethyl cellulose, Polyethylene oxide, β Cyclodextrin, Polyethylene
glycol, Sodium alginate, PVA, Polycarbonate, Carbopol, PVP, E4 M, Acrylic polymer
and CP 934P.
 Inert fatty materials (5%-75%): Edible, inert fatty materials that have specific
gravity 1 can be used to reduce the hydrophilic property of the formulation and
therefore increase buoyancy. E.g., Fatty acids, Beeswax, Gelucires® 39/01 &
43/01, long chain fatty alcohols, etc.
 Effervescent agents: Citric acid, Sodium bicarbonate, Tartaric acid, Citroglycine,
DiSodium Glycine Carbonate, etc.
 Release rate accelerants (5%-60%): Lactose, Mannitol, etc.
 Release rate retardants (5%-60%): Dicalcium phosphate, Talc, Magnesium
stearate, etc.
 Low density material: Polypropylene foam powder.
 Buoyancy increasing agents (up to 80%): Ethyl cellulose.
Characterization OF GASTRORETENTIVE DOSAGE FORMS
1) Measurement of buoyancy capabilities of the GRDF: The floating behaviour is
estimated with resultant weight measurements. The high molecular weight polymers
with slow rate of hydration has greater floating behavior and it is observing more in the
simulated meal medium compared to deionized water.
2) Floating time and dissolution: Floating time measurement test is generally carried
out in stimulated gastric fluid or in 0.1 N Hall kept at 37 ºC. It is carried out by using
USP dissolution apparatus comprising 900 ml of 0.1 N Hall as dissolution medium. The
time
Occupied by the dosage form to float is called floating lag time. The time for which
dosage form float is called as the floating time.
3) Drug loading, particle size analysis and surface characterization: In case of
floating beads and microspheres; drug loading is evaluated by crushing precisely weighed
sample of microspheres/beads in a mortar and added to the suitable dissolution medium
that is then centrifuged, filtered and analyzed by several analytical techniques such as
spectrophotometry. The particle size and size distribution of microspheres or beads are

NMT GUJARATI COLLEGE OF PHARMACY, Page | 19

Indore
 Advances in Controlled Release Gastroretentive Systems

determined in dry state by using optical microscopy technique. The cross-sectional and
external morphology is done by SEM.
4) In-vitro release study: It is performed to provide the amount of drug that is released
at a definite time period. It is carried out by synthetic membrane, Franz diffusion cell
system and also by different types of dissolution apparatus.
5) X-Ray/Gamma Scintigraphy: It locates dosage form in GIT and by that one can
predict and correlate the GET and the passage of dosage form in gastrointestinal tract.
The inclusion of radio opaque material in a solid dosage form allows it to be envisioned
by X- rays. Also, the inclusion of a γ-emitting radionuclide in formulation permits indirect
external observation using γcamera/scintiscanner. In case of γ-scintigraphy, the γ-rays
emitted by radionuclide are focused on camera that helps to monitor the position of
dosage form in the gastrointestinal tract.
6) Swelling study: It is performed to calculate molecular parameters of swollen
polymers. It is determined by using optical microscopy, dissolution apparatus and other
sophisticated techniques that include Confocal laser scanning microscopy, 1H NMR
imaging, Light scattering imaging, Cryogenic SEM, etc. The swelling study by using
dissolution apparatus is calculated by following formula:
7) Determination of the drug content: % Drug content provides how much amount of
drug which is present in formulation. It must not exceed the limits acquired by standard
monographs. It is determined by using HPTLC, HPLC, Inductively Coupled Plasma
Atomic Emission Spectrometer, Micro titrimetric methods, near infrared spectroscopy,
etc.
8) Percentage entrapment efficiency: % Entrapment efficiency is dependable
for Quantifying phase distribution of drug in prepared formulation. It is calculated by
using pressure ultra-filtration, ultra-centrifugation or micro dialysis method.
9) Mucoadhesive Strength Measurement: This evaluates the adhesive interaction between
the formulation and the gastrointestinal mucosa, critical for formulations designed to adhere
to the mucosal lining for prolonged retention. Methods include in vitro tensile testing using
texture analyzers, where the force required to detach the dosage form from excised mucosal
tissue is measured. Alternatively, modified balances or flow-through systems simulate
physiological conditions to assess mucoadhesion. Parameters such as detachment force, work
of adhesion, and residence time on mucosal surfaces are quantified to optimize bioadhesive
polymers.
10) Stability Testing and Shelf-Life Assessment: Stability studies ensure the formulation

NMT GUJARATI COLLEGE OF PHARMACY, Page | 20

Indore
 Advances in Controlled Release Gastroretentive Systems

retains its physicochemical integrity, buoyancy, and drug release profile under specified
storage conditions (e.g., temperature, humidity). Accelerated stability testing (e.g., 40°C/75%
RH) and long-term studies (25°C/60% RH) are conducted over months. Parameters
monitored include drug degradation (via HPLC), polymer hydration kinetics, floating lag
time, and physical changes (cracking, discoloration). Shelf-life is extrapolated using
Arrhenius models or real-time data to guarantee performance throughout the product’s
lifecycle.
APPLICATION OF GASTRORETENTIVE DRUG DELIVERY SYSTEMS
1) Enhanced Bioavailability: Bioavailability of riboflavin controlled release gastro
retentive dosage forms is significantly improved compared to administration of no
controlled release gastro retentive dosage forms polymeric formulations. There are
numerous different procedures, related to absorption and transit of drug in the GIT,
which act concomitantly to impact the magnitude of drug absorption. (Cook JD et al.,
1990)
2) Sustained Drug Delivery: Oral controlled release formulations are faced with
problems like GRT in the gastrointestinal tract. HBS systems can be used to overcome
the problems that can remain in stomach for prolonged period of time and have bulk
density1 as a result of which they can float on the GI contents. The systems are
comparatively large in size & passing from pyloric opening is prohibited.
3) Site Specific Drug Delivery Systems: These systems are frequently beneficial for
drugs which are especially absorbed from stomach or the proximal part of small intestine.
The controlled/slow delivery of drug to the stomach offers adequate local therapeutic
levels and limits the systemic exposure to drug. This decreases side effects that are
produced by drug in blood circulation. Also, the extended gastric availability of a site
directed delivery system may reduce the frequency of dosing. E.g., Furosemide and
Riboflavin. (Menno A et al., 1994)
4) Absorption Enhancement: Drugs that are having poor bioavailability due to site
specific absorption from upper part of the gastrointestinal tract are potential candidates
to be formulated as FDDS, thus maximizing their absorption. (Rouge N et al., 1998)

CONCLUSION
The development of efficient gastro retentive drug delivery systems (GRDDS) remains a
critical yet challenging frontier in pharmaceutical sciences, driven by the need to overcome

NMT GUJARATI COLLEGE OF PHARMACY, Page | 21

Indore
 Advances in Controlled Release Gastroretentive Systems

physiological barriers such as short gastric residence time (GRT) and variable gastric
emptying. Among the array of strategies explored—including bioadhesive, Swellable, high-
density, and magnetic systems—floating drug delivery systems (FDDS) have emerged as the
most clinically viable and widely researched approach. By leveraging buoyancy mechanisms,
such as gas-generating agents (e.g., sodium bicarbonate) or low-density polymers, FDDS
prolong retention in the stomach, enabling sustained drug release and improved
bioavailability for drugs with narrow absorption windows (e.g., riboflavin, levodopa) or those
requiring local action (e.g., misoprostol for ulcers). This extended retention enhances
therapeutic efficacy by ensuring optimal drug absorption in the upper gastrointestinal tract
(GIT) while reducing dosing frequency, thereby improving patient compliance.

The advantages of FDDS extend beyond pharmacokinetic benefits. These systems

demonstrate superior stability and controlled release profiles compared to conventional
dosage forms, minimizing systemic toxicity and side effects. For instance, floating
formulations of antibiotics like ciprofloxacin (e.g., Cifran OD®) have proven effective in
targeting Helicobacter pylori infections by maintaining localized drug concentrations in the
stomach. Furthermore, advancements in polymer technology, such as the use of pH-
responsive hydrogels and 3D-printed architectures, have refined drug release precision and
retention reliability.

However, challenges persist in translating laboratory success to clinical practice.

Physiological variables—such as fed vs. fasting states, posture, and pathological conditions
(e.g., gastroparesis)—can compromise retention efficacy. Manufacturing complexities,
including maintaining buoyancy during compression and scalability of mucoadhesive
polymers, also hinder commercialization. Despite these hurdles, pharmaceutical companies
are actively investing in GRDDS, as evidenced by recent patents (e.g., multi-layered floating
tablets with pulsatile release) and FDA-approved products like Madopar® HBS for
Parkinson’s disease.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 22

Indore
 Advances in Controlled Release Gastroretentive Systems

REFERENCES
1. Kagan L, Hoffman A; Systems for region selective drug delivery in gastrointestinal tract;
biopharmaceutical considerations; Expert Opinion on Drug Delivery; 2008; 5(6); 681-
692.
2. Bardonnet P, Faivre V, Pugh W, Piffaretti J, Falson F; Gastroretentive dosage forms,
Overview and special case of Helicobacter pylori; Journal of Controlled Release; 2006;
111; 1-18.
3. Deshpande AA, Shah NH, Rhodes CT, Malick W; Development of a novel controlled
release system for gastric retention; Pharmaceutical Research; 1997; 14(6); 815-819.
4. Patil, JM, Hirlekar RS, Gide PS, Kadam VJ; Trends in floating drug delivery system;
Journal of Scientific and Industrial Research; 2006; 65; 11-21.
5. Arunachalam A, Karthikeyan M, Konam K, Prasad HP, Sethuraman S, Ashutoshkumar S,
Manidipa S; Floating drug delivery systems: A Review; International Journal of
Pharmaceutical Science and Research; 2011; 2(1); 76- 83.
6. Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology; New York; John
Wiley and Sons; 2002.
7. Marinaganti RK, Bonthu S, Nagakanyaka DP, Sheik M; A comprehensive review on
gastro retentive drug delivery system; 2013; 3(2); 149-164.
8. Garg S, Sharma S; Gastroretentive Drug Delivery System; Business Briefing:
Pharmatech; 2003; 160-166.
9. Brahmankar DM, Jaiswal SB; Biopharmaceutics and pharmacokinetics a treatise;
New Delhi; Vallabh Prakashan; 2003.
10. Patel GM, Patel HR, Patel M; floating drug delivery system: An innovative approach
to prolong gastric retention; Pharmainfo.net 2007; 5(6).
11. Jain NK; Progress in controlled and novel drug delivery system; Delhi; CBS
Publishers; 2003.
12. Babu VBM, Khar RK; In vitro and In vivo studies of sustained release floating
dosage forms containing salbutamol sulphate; Pharmazie; 1990; 45(4); 268-270.

NMT GUJARATI COLLEGE OF PHARMACY, Page | 23

Indore
 A REVIEW ON GASTRORETENTIVE DRUG DELIVERY SYSTEM

13. Nasa P, Mahant S, Sharma D; Floating systems: a novel approach towards gastro
retentive drug delivery systems; International Journal of Pharmacy and Pharmaceutical
Sciences; 2010; 2(3); 2-7.
14. Reddy LH, Murthy RS; Floating dosage systems in drug delivery; Critical reviews in
therapeutic drug carrier systems; 2002; 19(6); 553-585.
15. Shah SH, Patel JK, Pundarikakshudu K, Patel NV; An overview of a gastro retentive
floating drug delivery system; Asian Journal of Pharmaceutical Sciences; 2009; 4(1); 65-
80.
16. Gupta G, Singh A; A Short Review on Stomach Specific Drug Delivery System;
International Journal of PharmTech Research; 2012; 4(4); 1527-1545.
17. Rubinstein A, Friend DR; Specific delivery to the gastrointestinal tract; In: Domb
AJ, editor; Polymeric SiteSpecific Pharmacotherapy; Wiley & Chichester; 1994; 282-
283.
18. Ikura, H, Suzuki Y, Nagai T, Machida Y, inventors; Teijin Limited, assignee;
Cellulose ether, polyacrylic acid, foaming agent, drug; United States Patent US 4777033 A;
1988 Oct 11.
19. Umezawa H, inventor; Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai, assignee; Pep
statin floating minicapsules; United States Patent US 4101650 A; 1978 Jul 18.
20. Fabrcgas JL, Cucala CG, Pous J; Sites R.A. In vitro testing of an antacid formulation
with prolonged gastric residence time; Drug Development and Industrial Pharmacy; 1994;
20; 1199-1212.
21. Agnihotri SA, Jawalkar SS, Aminabhavi TM; Controlled release of cephalexin
through gellan gum beads: Effect of formulation parameters on entrapment efficiency,
size, and drug release, European Journal of Pharmaceutics and Biopharmaceutics; 2006;
63(3); 249-261.
22. Harries D, Sharma HL; GI transit of potential bioadhesive formulations in man: A
scintigraphic study; Journal of Controlled Release; 1990; 12(1); 45-53.

NMT GUJARATI COLLEGE OF PHARMACY, Indore Page | 24