GASTRORETENTIV

E DRUGDELIVER
Y SYSTEM
➢ WHAT IS
 GRDDS???
Gastroretentive drug delivery is an
approach to prolong gastric residence
time, thereby targeting site-specific drug
release in the upper gastrointestinal tract
(GIT) for local or systemic effects.
➢ NEED FOR GRDDS…???
Oral drug delivery Sustained drug delivery
system systems

These drug delivery systems suffer from mainly two adversities:

short gastric retention time(GRT) and
unpredictable short gastric emptying time (GET)

which can result in incomplete drug release from the dosage form
in the absorption zone (stomach or upper part of small intestine)
leading to diminished efficacy of administered dose.

To formulate a site-specific orally administered controlled release

dosage form, it is desirable to achieve a prolong gastric residence
time by the drug delivery. Prolonged gastric retention time (GRT)
in the stomach could be advantageous for local action e.g.
treatment of peptic ulcer, etc.
Gastro retentive drug delivery is an approach to prolong gastric residence time,
thereby targeting site-specific drug release in the upper gastrointestinal tract
(GIT) for local or systemic effects. Gastro retentive dosage forms can remain in
the gastric region for long periods and hence significantly prolong the gastric
retention time (GRT) of drugs. Over the last few decades, several gastro
retentive drug delivery approaches being designed and developed, including:
high density (sinking) systems that is retained in the bottom of the stomach ,
low density (floating) systems that causes buoyancy in gastric fluid
mucoadhesive systems that causes bioadhesion to stomach mucosa,
unfoldable, extendible or swellable systems which limits emptying of the
dosage forms through the pyloric sphincter of stomach , super porous hydrogel
systems magnetic systems etc.
 FACTORS CONTROLLING GASTRIC RETENTION OF DOSAGE FORMS

The stomach anatomy and physiology contain parameters to be

considered in the development of gastroretentive dosage forms.
To pass through the pyloric valve in to the small intestine the
particle size should be in the range of 1 to 2 mm. The most
important parameters controlling the gastric retention time
(GRT) of oral dosage forms include : density, size and shape of
the dosage form, food intake and its nature, caloric content and
frequency of intake, posture, gender, age, sex, sleep, body mass
index, physical activity and diseased states of the individual ( e.g.
chronic disease, diabetes etc.)
and administration of drugs with impact on gastrointestinal
transit time for example drugs acting as anticholinergic agents
( e.g. atropine, propantheline), Opiates (e.g. codeine) and
prokinetic agents ( e.g. metclopramide, cisapride.)
The molecular weight and lipophilicity of the drug depending on
its ionization state are also important parameters .
 DENSITY OF DOSAGE FORMS

The density of a dosage form also affects the gastric emptying

rate and determines the location of the system in the
stomach. Dosage forms having a density lower than the
gastric contents can float to the surface, while high density
systems sink to bottom of the stomach. Both positions may
isolate the dosage system from the pylorus. A density of < 1.0
gm/ cm3 is required to exhibit floating property.
 SHAPE AND SIZE OF THE DOSAGE FORM

The mean gastric residence times of non- floating dosage

forms are highly variable and greatly dependent on their size,
which may be large, medium and small units. In most cases,
the larger the dosage form the greater will be the gastric
retention time (GRT) due to the larger size of the dosage form
would not allow this to quickly pass through the pyloric
antrum into the intestine. Dosage forms having a diameter of
more than 7.5 mm show a better gastric residence time
compared with one having 9.9 mm Ring-shaped and
tetrahedron-shaped devices have a better gastric residence
time as compared with other shapes .
 FOOD INTAKE AND ITS NATURE

Food intake, viscosity and volume of food, caloric value and

frequency of feeding have a profound effect on the gastric
retention of dosage forms. The presence or absence of food in
the gastrointestinal tract (GIT) influences the gastric retention
time (GRT) of the dosage form. Usually the presence of food in
the gastrointestinal tract (GIT) improves the gastric retention
time (GRT) of the dosage form and thus, the drugs absorption
increases by allowing its stay at the absorption site for a longer
period. Again, increase in acidity and caloric value shows down
gastric emptying time (GET), which can improve the gastric
retention of dosage forms .
 EFFECT OF GENDER, POSTURE AND AGE

Generally females have slower gastric emptying rates than

male. The effect of posture does not have any significant
difference in the mean gastric retention time (GRT) for
individuals in upright, ambulatory and supine state. In case of
elderly persons, gastric emptying is slowed down .
 POTENTIAL DRUG CANDIDATES FOR
GASTRORETENTIVE DRUG DELIVERY SYSTEMS

1)Drugs those are locally active in the stomach e.g.

misroprostol, antacids etc.
2)Drugs that have narrow absorption window in
gastrointestinal tract (GIT) e.g. L-DOPA, para aminobenzoic
acid, furosemide, riboflavin etc..
3)Drugs those are unstable in the intestinal or colonic
environment e.g. captopril, ranitidine HCl, metronidazole,
4) Drugs that disturb normal colonic microbes [Link]
against Helicobacter pylori.
5) Drugs that exhibit low solubility at high pH values e.g.
DRUGS THOSE ARE UNSUITABLE FOR GASTRORETENTIVE DRUG
DELIVERY SYSTEMS

1)Drugs that have very limited acid solubility e.g.

phenytoin etc.
2)Drugs that suffer instability in the gastric environment
e.g. erythromycin etc.
3)Drugs intended for selective release in the colon
e.g. 5- amino salicylic acid and corticosteroids etc.
 APPROACHES TO ACHIEVE GASTRIC RETENTION

High density (sinking) system or non- floating

drug delivery system
This approach involves formulation of dosage forms with the
density that must exceed density of normal stomach content
(~ 1.004 gm/cm3).These formulations are prepared by coating
drug on a heavy core or mixed with inert materials such as iron
powder, barium sulphate, zinc oxide and titanium oxide etc
The materials increase density by up to 1.5- 2.4 gm/cm3. A
density close to 2.5 gm/cm3 seems necessary for significant
prolongation of gastric residence time But, effectiveness of
this system in human beings was not observed and no system
has been marketed.
 FLOATING DRUG DELIVERY SYSTEMS

Floating drug delivery systems is one of the important

approaches to achieve gastric retention to obtain sufficient
drug bioavailability This delivery systems is desirable for drugs
with an absorption window in the stomach or in the upper
small intestine . This have a bulk density less then gastric fluids
and so remain buoyant in the stomach without affecting gastric
emptying rate for a prolonged period and the drug is released
slowly as a desired rate from the system. After release of drug,
the residual system is emptied from the stomach. This result in
an increased gastric retention time (GRT) and a better control
of the fluctuation in plasma drug concentration.
The major requirements for floating drug delivery system are :
•It should release contents slowly to serve as a reservoir.
•It must maintain specific gravity lower than gastric contents
(1.004 – 1.01 gm/cm3).
•It must form a cohesive gel barrier.

The inherent low density can be provided by the entrapment

of air (e.g. hollow chambers) or by the incorporation of low
density materials (e.g. fatty materials or oils, or foam
powder) .
These following approaches have been used for the design of
floating dosage forms of single and multiple-unit systems.
Recently a single-unit floating system was proposed consisting
of polypropylene foam powder, matrix forming polymers, drug
and filler. The good floating behavior of these systems could be
successfully combined with accurate control of the resulting
drug release patterns. Single-unit dosage forms are associated
with problems such as sticking together or being obstructed in
the gastrointestinal tract (GIT) which may produce irritation.
On the other hand multiple-unit floating systems may be an attractive
alternative since they have been shown to reduce the inter- and intra- subject
availabilities in drug absorption as well as to lower the possibility of dose
dumping . Various multiple-unit floating system like air compartment
multiple-unit system , hollow microspheres (microballoons) prepared by the
emulsion solvent diffusion method , microparticles based on low density
foam powder , beads prepared by emulsion gelatin method etc. can be
distributed widely throughout the GIT, providing the possibility of achieving a
longer lasting and more reliable release of drugs.
Based on the mechanism of buoyancy two distinctly different technologies,
i.e. non-effervescent and effervescent systems have been utilized in the
development of floating drug delivery system.
 NON-EFFERVESCENT SYSTEMS

Non-effervescent floating drug delivery systems are normally prepared

from gel-forming or highly swellable cellulose type hydrocolloids,
polysaccharides or matrix forming polymers like
polyacrylate,polycarbonate, polystyrene and polymethacrylate. In one
approach, intimate mixing of drug with a gel forming hydrocolloid which
results in contact with gastric fluid after oral administration and maintain a
relative integrity of shape and a bulk density less than unity within the
gastric environment . The air trapped by the swollen polymer confers
buoyancy to these dosage forms. Excipients used most commonly in these
systems include hydroxypropyl methylcellulose (HPMC) polyacrylates,
polyvinyl acetate, carbopol agar, sodium alginate, calcium chloride,
polyethylene oxide and polycarbonates.
This system can be further divided into the sub-types:
HYDRODYNAMICALLY BALANCED SYSTEMS:
These systems contains drug with gel-forming hydrocolloids meant to
remain buoyant on the stomach content. These are single-unit dosage form,
containing one or more gel-forming hydrophilic polymers. Hydroxypropyl
methylcellulose (HPMC), hydroxethyl cellulose HEC), hydroxypropyl
cellulose (HPC), sodium carboxymethyl cellulose (NaCMC), polycarbophil,
polyacrylate, polystyrene, agar, carrageenans or alginic acid are commonly
used excipients to develop these systems . The polymer is mixed with drugs
and usually administered in hydrodynamically balanced system capsule. The
capsule shell dissolves in contact with water and mixture swells to form a
gelatinous barrier, which imparts buoyancy to dosage form in gastric juice
for a long period. Because, continuous erosion of the surface allows water
penetration to the inner layers maintaining surface hydration and buoyancy
Effective drug deliveries depend on the balance of drug loading and the effect
of polymer on its release profile.
Several strategies have been tried and investigated to improve efficiencies of
the floating hydrodynamically balanced systems .
MICROBALLOONS/HOLLOW MICROSPHERES:
Microballoons / hollow microspheres loaded with
drugs in their other polymer shelf were prepared by simple solvent
evaporation or solvent diffusion / evaporation methods (Figure 1) to prolong
the gastric retention time (GRT) of the dosage form. Commonly used
polymers to develop these systems are polycarbonate, cellulose acetate,
calcium alginate, Eudragit S, agar and low methoxylated
pectin etc. Buoyancy and drug release from dosage form are dependent on
quantity of polymers, the plasticizer polymer ratio and the solvent used for
formulation.
Figure 1. Formulation of floating hollow microsphere or microballoon
ALGINATE BEADS: Talukdar and Fassihi recently developed a
multiple-unit floating system based on cross-linked beads. They
were made by using Ca2+ and low methoxylated pectin (anionic
polysaccharide) or Ca2+ low methoxylated pectin and sodium
alginate. In this approach, generally sodium alginate solution is
dropped into aqueous solution of calcium chloride and causes
the precipitation of calcium alginate. These beads are then
separated and dried by air convection and freeze drying,
leading to the formulation of a porous system, which can
maintain a floating force for over 12 hrs. These beads improve
gastric retention time (GRT) more than 5.5 hrs.
MICROPOROUS COMPARTMENT SYSTEM: This approach is
based on the principle of the encapsulation of a drug reservoir
inside a microporous compartment with pores along its top and
bottom walls . The peripheral walls of the device were
completely sealed to present any direct contact of the gastric
surface with the undissolved drug. In the stomach the floatation
chamber containing entrapped air causes the delivery system to
float in the gastric fluid . Gastric fluid enters through the
aperture, dissolves the drug and causes the dissolved drug for
continuous transport across the intestine for drug absorption.
 EFFERVESCENT (GAS GENERATING) SYSTEMS

Floatability can be achieved by generation of gas bubbles. These

buoyant systems utilize matrices prepared with swellable
polymers such as polysaccharides (e.g. chitosan), effervescent
components (e.g. sodium bicarbonate, citric acid or tartaric acid)
. The optimal stoicheometric ratio of citric acid and sodium
bicarbonate for gas generation is reported to be 0.76: 1. In this
system carbon dioxide is released and causes the formulation to
float in the stomach (Figure 2 and Figure 3).
Other approaches and materials that have been reported are a
mixture of sodium alginate and sodium bicarbonate, multiple
unit floating dosage forms that generate gas (carbon dioxide)
when ingested, floating mini capsules with a core of sodium
bicarbonate, lactoseand polyvinyl pyrrolidone (PVP) coated
with hydroxypropyl methylcellulose (HPMC), and floating system
based on ion exchange resin technology etc . Bilayer or
multilayer system has also been designed .
Drugs and excipients can be formulated independently and
the gas generating material can be incorporated in to any of the
layers. Further modifications involve coating of the matrix with
a polymer which is permeable to water, but not to carbon
dioxide. The main difficulty of these formulations is finding a
good compromise between elasticity, plasticity and
permeability of the polymers.
BIOADHESIVE OR MUCOADHESIVE DRUG DELIVERY SYSTEMS

Bioadhesive drug delivery systems are used as a delivery

device within the human to enhance drug absorption in a site-
specific manner. In this approach, bio adhesive polymers are
used and they can adhere to the epithelial surface in the
stomach . Thus, they improve the prolongation of gastric
retention. The basis of adhesion in that a dosage form can
stick to the mucosal surface by different mechanism. These
mechanisms are:
1)The wetting theory, which is based on the ability of bioadhesive
polymers to spread and develop intimate contact with the
mucous layers.
2)The diffusion theory, which proposes physical entanglement of
mucin strands the flexible polymer chains, or an
interpenetration of mucin strands into the porous structure of
the polymer substrate.
3)The absorption theory, suggests that bioadhesion is due to
secondary forces such as Vander Waal forces and hydrogen
bonding.
4)The electron theory, which proposes attractive electrostatic
forces between the glycoprotein mucin net work and the bio
Materials commonly used for bioadhesion are poly acrylic acid,
chitosan, cholestyramine, sodium alginate, hydroxypropyl
methylcellulose (HPMC), sucralfate, tragacanth, dextrin,
polyethylene glycol PEG) and polylactic acids etc. Even though
some of these polymers are effective at producing bioadhesive,
it is very difficult to maintain it effectively because of the rapid
turnover of mucus in the gastrointestinal tract (GIT).
 EXPANDABLE, UNFOLDABLE AND SWELLABLE SYSTEMS

A dosage form in the stomach will withstand gastric transit if it

bigger than pyloric sphincter. However, the dosage form must
be small enough to be swallowed either singly or by
accumulation. Thus, their configurations [46, 47] are required to
develop an
expandable system to prolong gastric retention time (GRT):
1)a small configuration for oral intake,
2)an expanded gastroretentive form, and
3)a final small form enabling evacuation following drug
release from the device.
Thus, gastroretentivity is improved by the combination of
substantial dimension with high rigidity of dosage form to
withstand peristalsis and mechanical contractility of the
stomach. Unfoldable and swellable systems have been
investigated and recently tried to develop an effective
gastroretentive drug delivery.
Unfoldable systems are made of biodegradable polymers. They
are available in different geometric forms like tetrahedron, ring
or planner membrane (4 - label disc or 4 - limbed cross form)
of bioerodible polymer compressed within a capsule which
extends in the stomach
Swellable systems are also retained in the gastro intestinal tract
(GIT) due to their mechanical properties. The swelling is usually
results from osmotic absorption of water and the dosage form
is small enough to be swallowed by the gastric fluid (Figure 4).
Expandable systems have some drawbacks like problematical
storage of much easily hydrolysable, biodegradable polymers
relatively short-lived mechanical shape memory for the
unfolding system most difficult to industrialize and not cost
effective. Again, permanent retention of rigid, large single-
unit expandable drug delivery dosage forms may cause brief
obstruction, intestinal adhesion and gastropathy .
 Super porous hydrogel systems

These swellable systems differ sufficiently from the conventional

types to warrant separate classification. In this approach to
improve gastric retention time (GRT) super porous hydrogels of
average pore size >100 micro miter, swell to equilibrium size
within a minute due to rapid water uptake by capillary wetting
through numerous interconnected open pores . They swell to a
large size (swelling ratio: 100 or more) and are intended to have
sufficient mechanical strength to withstand pressure by gastric
contraction. This is advised by co-formulation of hydrophilic
particulate material.
 MAGNETIC SYSTEMS

This approach to enhance the gastric retention time (GRT) is

based on the simple principle that the dosage form contains a
small internal magnet, and a magnet placed on the abdomen
over the position of the stomach. Although magnetic system
seems to wok, the external magnet must be positioned with a
degree of precision that might compromise patient compliance.

Commonly used drugs in formulation of gastroretentive dosage

forms and some gastro retentive products available in the
market are listed in Table 1 and Table 2 respectively.
Table 1. Commonly used drug in formulation of gastro retentive dosages forms

Dosage forms Drugs

Floating Tablets Acetaminophen, Acetylsalicylic acid, Ampicillin,

Amoxicillin trihydrate, Atenolol, Captopril,
Chlorpheniramine maleate, Ciprofloxacin, Nimodipine,
Sotalol, Theophylline, Verapamil

Floating Capsules Furosemide, L-DOPA and Benserazide, Nicardipine,

Misoprostol, Propranolol, Pepstatin

Floating Microspheres Aspirin, Griseofulvin, p-nitro aniline, Ibuprofen,

Terfenadine, Tranilast

Floating Granules Diclofenac sodium, Indomethacin, Prednisolone,

Powders Several basic drugs

Films Cinnerzine
 Table 2. Gastroretentive products available in the market

Brand Name Active Ingredient(s

Cifran OD ® Ciprofloxacin

Madopar ® L-DOPA and Benserazide

Valrelease ® Diazepam

Topalkan ® Aluminum -magnesium antacid

Almagate FlatCoat Aluminum -magnesium antacid

Liquid Gavison ® Aluminium hydroxide,

Conviron Ferrous sulfate

Cytotec® Misoprostal
APPROACHES TO GASTRIC RETENTION
 PHYSIOLOGY OF THE STOMACH
 The stomach is an organ with a capacity for storage
and mixing. The antrum region is responsible for the
mixing and grinding of gastric contents.
 Under fasting conditions, the stomach is a collapsed
bag with a residual volume of approximately 50ml and
contains a small amount of gastric fluid (pH 1–3) and
air.
ADVANTAGES OF GASTRORETENTIVE DRUG DELIVERY SYSTEM.

 Improves patient compliance e.g.

Furosemide
 Enhanced
bioavailability.
 Increased Gastric retention
time.
 Enhanced absorption of drugs which solubilise only in
stomach.
 Drug releases in controlled manner for prolonged period e.g. b-
lactams.
 Site-specific drug delivery to stomach can be
achieved.
 Superior to single unit floating dosage -- no risk of dose
dumping.
 Avoids gastric
irritation.
 Better therapeutic effect of short half-life drugs can be
achieved.
 IN-VIVO
a) Radiology EVALUATION
b) Scintigraphy

c) Gastroscopy

d) Magnetic Marker
Monitoring

e) Ultrasonography

f) 13C Octanoic Acid Breath

Test
 REFERENCES:
[Link]
drug-
delivery-system-overview

[Link]
drug-
delivery-system-overview

[Link]
pdf

[Link]
2/4.-
[Link]
THANK
YOU