GASTRORETENTIVE DRUG DELIVERY SYSTEMS 1/59

GASTRORETENTIVE DRUG
DELIVERY SYSTEMS
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CONTENTS
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•
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INTRODUCTION
APPROACHES
EVALUATION
CONCLUSION
REFERENCES
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INTRODUCTION
•
The control of gastrointestinal transit of orally administered
dosage forms using gastroretentive drug delivery systems
(GRDDS) can improve the bioavailability of drugs that exhibit
site-specific absorption.

To overcome physiological adversities, such as short gastric
residence times (GRT) and unpredictable gastric emptying
times (GET).

This dosage forms will be very much useful to deliver ‘narrow
absorption window’ drugs.
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•
Need for gastroretentive drug delivery system
•
A controlled drug delivery system with prolonged residence
time in the stomach is of particular interest for drugs

Are locally active in the stomach (misoprostol, antacids
antibiotics against H.pylori).
Have an absorption window in stomach or in the upper small
intestine (L-dopa, P-aminobenzoic acid, furosemide).
Are unstable in the intestine or colonic environment
(captopril).
Exhibit low solubility at high pH values (diazepam, verapamil).
Alter normal flora of the colon (antibiotics).
Absorbed by transporter mechanism (paclitaxel).
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Advantages
•
Improved drug absorption, because of increased GRT and more time spent
by the dosage form at its absorption site.
•
Controlled delivery of drugs.
•
Delivery of drugs for local action in the stomach.
•
Minimizing mucosal irritation by drugs, by drug releasing slowly at a
controlled rate.
•
Treatment of gastrointestinal disorders such as gastro-esophageal reflux.
•
Ease of administration and better patient compliance.
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•
Gastric emptying
•
The process of gastric emptying occurs both during fasting and fed state.
In fasted state, the process of gastric emptying is characterized by an
interdigestive motility pattern that is commonly called migrating motor
complex (MMC).
This is a series of events that cycle through the stomach and small
intestine every 1.2 to 2hrs.
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•
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•
In the fed state, the gastric emptying rate is slowed down because the
onset of MMC is delayed, i.e., the feeding state results in a lag time prior to
onset of gastric emptying.
FACTORS CONTROLLING THE GASTRIC RETENTION TIME OF
DOSAGE FORM
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Density of dosage form.
Size of dosage form.
Food intake and nature of food.
Effects of gender, posture, and age.
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APPROACHES
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High density system
Floating systems
Expandable systems
Superporous hydrogels
Mucoadhesive or bioadhesive systems
Magnetic systems
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High density systems
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Gastric contents have a density close to
water (~1.004).
A density close to 2.5g cm-3 is necessary
for significant prolongation of gastric
residence time.
The commonly used excipients in high
density system includes barium sulphate, zinc
oxide, iron powder, and titanium dioxide.
The major drawback with such systems is
that it is technically difficult to manufacture
them with a large amount of drug (>50%) and
to achieve the required density of 2.42.8g/cm3.
Floating Systems
•
Single-unit floating dosage system
1.
Noneffervescent systems
2.
Effervescent (gas-generating) systems
•
Multiple-unit floating dosage system
1.
3.
Noneffervescent systems
Effervescent (gas-generating) systems
Hollow microspheres
•
Raft-forming systems
2.
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•
Single-Unit Floating Dosage System
•
Noneffervescent Systems

These systems contain one or more hydrocolloids and are
made into a single unit along with drug and other additives.
When coming in contact with water, the hydrocolloids at the
surface of the system swell and facilitate floating.
The coating forms a viscous barrier, and the inner polymer
slowly gets hydrated as well, facilitating the controlled drug
release. Such systems are called “hydrodynamically balanced
systems (HBS)”.
The
polymers
used
in
this
system
includes
hydroxypropylmethylcellulose,hydroxyethylcellulose,
hydroxypropylcellulose, sodium carboxymethylcellulose, agar,
carrageenans, and alginic acid.
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
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Hydrodynamically balanced system
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A.1 – FLOATING – NON EFFERVESCENT
MONOLITHIC SYSTEMS
MATRIX TABLET
Single Layer Tablet
Loading Dose
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Bilayer Tablet
A.1 – FLOATING – NON EFFERVESCENT
MONOLITHIC SYSTEMS
TABLET with AGAR & MINERAL OIL
Drug +
Mineral Oil
Warm Agar
Gel Solution
mix
Pour in
Tablet Mold
Air Entrapped in Agar gel
Escape of Air – prevent by OIL
2% Agar per Tablet
Cool
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TABLET with FOAM
Polypropylene Foam
Hydrophobic Powder
Open-cell Structure
TABLET with LIPID
Glyceryl Monooleate
Swells in Water
Converted to Liquid
Crystals - Cubic Shape
Highly Porous
Low Inherent Density
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Melted And Molded
The device consisting of
two
drug-loaded
HPMC
matrix tablets, which are
placed
within
an
HPMC matrix
impermeable,
hollow
tablets
polypropylene cylinder (open
polypropylene
at both ends). Each matrix
tablet closed one of the
cylinder’s ends so that an airfilled space was created in
AIR
between, providing a low
total system density. The
device remained floating
until at least one of the
HPMC matrix tablets is dissolved.
TABLETS IN
CYLINDER
tablets
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MICROPOROUS
RESERVIOR
This device comprised of a
drug reservoir encapsulated
in microporous compartment
having pores on its surface.
A floating chamber was
attached at one surface
which gives buoyancy to
entire device. Drug is slowly
dissolves out via micro pores
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A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
CALCIUM ALGINATE/PECTINATE BEADS
IONOTROPIC GELATION METHOD
Sodium
Alginate
Solution
Add
to
Calcium
Chloride
Solution
Spherical
Gel
Beads
Calcium Pectinate Gel Beads
Calcium-Alginate-Pectinate Gel Beads
Calcium Alginate + Chitosan Gel Beads
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Separate,
Freeze Dried (40oC)
ALGINATE BEADS with
AIR COMPARTMENT
During the preparation of calcium alginate beads
before drying process the beads are coated with the
coating solution which may be calcium alginate or mixture
of calcium alginate and PVA, and then they are dried
Alginate Bead
in Solution,
before Drying
Coating
before Drying
After Drying
Shrinkage of Bead
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A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
OIL ENTRAPPED GEL BEADS
Oil – Light weight and Hydrophobic
Pectin has some Emulsification property
Aqueous
Solution of
Pectin
Calcium
Add
mix
Chloride
Emulsion to
Solution
Edible
Veg. OIL
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A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
CASEIN – GELATIN BEADS
Casein has Emulsification property- Entraps Air Bubbles
Casein Gelatin
Solution (60oC)
Rapid
Cooling
mix
Emulsion
Add to
Cooled
Acetone
Preheated
Mineral Oil
At Reduced Pressure – NO AIR – Non Floating Beads
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Separated
and
Dried
MULTIPLE UNITS
HOLLOW
MICROSPHERE
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MICROBALLOON
Mechanism of formation of microballoon
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A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
FOAM Containing MICROPARTICLES
Drug,
Polymer
Solvent Evaporation Method
Dissolved
Organic
Solvent
Add
to
Dispersed
FOAM
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Aqueous
PVA
Solution
Only
FOAM
FOAM
Microparticle
A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
CALCIUM SILICATE
As FLOATING CARRIER
GELUCIRE® GRANULES
Highly Porous
Hydrophobic Lipid
Large Pore Volume
Diff. Grades – 39/01
43/01
Low Inherent Density
Granules Drug
HPMC
Ca-Silicate
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Low Inherent Density
Granulation
SR of Highly Soluble Drug
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Gas-Generating Systems
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Carbonates or bicarbonates, which react with gastric acid or any
other acid (e.g., citric or tartaric) present in the formulation to
produce CO2, are usually incorporated in the dosage form, thus
reducing the density of the system and making it float on the media.
•
An alternative is incorporation of matrix containing portions of
liquid, which produce gas that evaporates at body temperature.

The main drawback of single unit dosage systems are high variability
of gastrointestinal transit time when orally administered because of
all-or-nothing nature of their gastric emptying.
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A.2 – FLOATING – EFFERVESCENT
MONOLITHIC SYSTEM
MATRIX TABLET
MATRIX TABLET
with CARBOPOL
Bicarbonate + Polymer
pH dependent Gelling
Single Layer Tablet
Only Carbopol
- NO GELLING
Bilayer Tablet
Triple Layer Tablet
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Bicarbonate + Carbopol
- GELLING
due to Alkaline
MICROENVIRONMENT
Triple-layer system
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Multiple-Unit Floating Systems
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Hollow Microspheres
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Hollow microspheres possess the unique advantages of multiple-unit
systems and better floating properties as a result of the central hollow
space inside the microsphere.
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The general techniques involved in their preparation include simple solvent
evaporation and solvent diffusion and evaporation.
•
The drug release and better floating properties mainly depend on the type
of polymer, plasticizer, and solvent employed for the preparation.
•
Polymers such as polycarbonate, Eudragit S, and cellulose acetate were
used in the preparation of hollow microspheres.
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A.2 – FLOATING – EFFERVESCENT
MULTIPLE UNITS
POROUS ALGINATE BEADS
NaHCO3
Na-Alginate
Solution
CaCl2
Solution
mix
- Simultaneous Generation of CO2 & Gelling of Beads
- Escape of CO2 creates Pores in Beads
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Acetic
Acid
A.2 – FLOATING – EFFERVESCENT
MULTIPLE UNITS
FLOATING PILLS
NaHCO3
Tartaric Acid
DRUG
Swellable Polymer
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A.2 – FLOATING – EFFERVESCENT
MULTIPLE UNITS
ION EXCHANGE RESIN BEADS
H+ Cl
H+ Cl
HCO3
HCO3
Resin
H+ Cl
HCO3
H+ Cl
H+ Cl
Uncoated Beads – No Floating – Escape of CO2
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Osmotically controlled DDS
This system consists of mainly
two different part attached with
each other, one is floating part and
other is osmotic controlled part
Floating part made up
of
deformable polymeric bag containing
liquid
that gasify at body
temperature.Osmotic
pressure
controlling part consists
of two
part, drug reservoir & osmotically
active compartment.
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•
Raft-Forming Systems
•
this system is used for delivery of antacids and drug delivery for
treatment of gastrointestinal infections and disorders.
The mechanism involved in this system includes the formation of a
viscous cohesive gel in contact with gastric fluids, wherein each
portion of the liquid swells, forming a continuous layer called raft.
This raft floats in gastric fluids because of the 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 more apt to float on the gastric
fluids.
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Expandable systems
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These systems include Unfoldable and Swellable systems.
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Unfoldable systems are made of biodegradable polymers. The
concept is to make a carrier, such as a capsule, incorporating a
compressed system which extends in the stomach.
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Swellable systems are retained because of their mechanical
properties. The swelling is usually results from osmotic absorption
of water.
•
The dosage form is small enough to be swallowed, and swells in
gastric liquids. The bulk enables gastric retention and maintain the
stomach in fed state, suppressing housekeeper waves.
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The whole system is coated by an elastic outer polymeric
membrane which was permeable to both drug and body fluids and
could control the drug release.
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The device gradually decreases in volume and rigidity as a result
depletion of drug and expanding agent and/or bioreosion of
polymer layer, enabling its elimination.
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Different geometric forms of unfoldable systems
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Prior to administration(A) Drug reservoir (B) Swellable expanding
agent (C) and the whole enclosed by elastic outer polymeric envelope.
Post administration Pressure of the expanding agent (B) swells the
elastic polymer (C). Drug is released from the dosage form through the
elastic polymeric envelope (C) as indicated by the arrow
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Superporous hydrogels
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Swellable agents with pore size ranging between 10nm and 10µm,
absorption of water by conventional hydrogel is very slow process
and several hours may be needed to reach as equilibrium state
during which premature evacuation of the dosage form may occur.
•
Superporous hydrogels swell to equilibrium size with in a minute,
due to rapid water uptake by capillary wetting through numerous
interconnected open pores.
•
They swell to large size and are intended to have sufficient
mechanical strength to withstand pressure by the gastric
contraction.
•
This is achieved by co-formulation of a hydrophilic particulate
material, Ac-Di-Sol.
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Mucoadhesive or bioadhedive system
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The technique involves coating of microcapsules with
bioadhesive polymer, which enables them to adhere to
intestinal mucosa and remain for longer time period in the GI
while the active drug is released from the device matrix.
•
The cationic chitosan polymers are pharmaceutically
acceptable to be used in the preparation of bioadhesive
formulations owing to their known ability to bind well to
gastric mucosa.
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•
Magnetic systems
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This system is based on a simple idea: the dosage form
contains a small internal magnet, and a magnet placed on the
abdomen over the position of the stomach.
•
Although these systems seem to work, the external magnet
must be positioned with a degree of precision that might
compromise patient compliance.
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EVALUATION OF GRDDS
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
For Single Unit Dosage Forms (ex: tablets)
(i)Floating lag time: It is the time taken by the tablet to emerge onto the
surface of dissolution medium and is expressed in seconds or minutes.

(ii) Invitro drug release and duration of floating: This is determined
by using USP II apparatus (paddle) stirring at a speed of 50 or 100 rpm at
37 ± 0.2 °c in simulated gastric fluid (pH 1.2 without pepsin). Aliquots of
the samples are collected and analysed for the drug content. The time (hrs)
for which the tablets remain buoyant on the surface of the dissolution
medium is the duration of floating and is visually observed.

(iii) In vivo evaluation for gastro-retention: This is carried out by
means of X-ray or Gamma scintigraphic monitoring of the dosage form
transition in the GIT. The tablets are also evaluated for hardness, weight
variation, etc.
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For swelling system
1)Swelling Index
2)Water Uptake / Weight Gain
WU = (Wt – Wo) * 100 / Wo
3)Penetration Rate
2
2
r
Water Uptake
PR =
Per Unit TimeX Water Density
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For mucoadhesive
Wilhemy’s plate technique
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This
involves
the
use
of
a
microtensiometer and a microforce
balance and is specific, yielding both
contact sngle and surface tension. The
mucous membrane is placed in a small
mobile chamber with both pH and
physiological temperature controlled. A
unique microsphere is attached by a
thread to the stationary microbalance.
The
chamber
with
the
mucous
membrane is raised until it comes into
contact with the microsphere and, after
contact time, is lowered back to the initial
position
B. For Multiple Unit Dosage Forms (ex:
microspheres)
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Apart from the In vitro release, duration of floating and in
vivo gastro-retention tests, the multiple unit dosage forms
are also evaluated for –
(i) Morphological and dimensional analysis with the
aid of scanning electron microscopy (SEM). The
size can also be measured using an optical
microscope.
(ii) % yield of microspheres: This is calculated from
weight of microspheres obtained ×100
total weight of drug and polymer
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(iii)Entrapment efficiency: The drug is extracted by a suitable
method, analysed and is calculated from
Practical amount of drug present ×100
Theoretical drug content
(iv) In vitro floating ability (Buoyancy %):
A known quantity of microspheres are spread over the surface of
a USP (Type II) dissolution apparatus filled with 900 ml of 0.1 N
HCl containing 0.002% v/v Tween 80 and agitated at 100 rpm for
12 hours. After 12 hours, the loating and settled layers are
seperated, dried in a dessicator and weighed. The buoyancy is
calculated from the following formula.
Buoyancy (%) = Wf / ( Wf + Ws) * 100
where Wf and Ws are the weights of floating and settled
microspheres respectively.
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
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(v) Drug-excipient (DE) interactions: This is done
using FTIR. Appearance of a new peak, and/or
disappearance of original drug or excipient peak
indicates the DE interaction.
Apart from the above mentioned evaluation parameters,
granules (ex:Gelucire 43/01) are also evaluated for the
effect of ageing with the help of Differential Scanning
Calorimeter or Hot stage polarizing microscopy.
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•
Methods to measure gastroretentivity of GRDFs
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Magnetic Resonance Imaging
•
It is a noninvasive technique and allow observation of total anatomical
structure in relatively high resolution.
The visualization of GI tract by MRI has to be further improved by the
administration of contrast media.
For solid DFs, the incorporation of a superparamagnetic compound such
as ferrous oxide enables their visualization by MRI.
•
•
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Radiology (X-Ray)
•
In this technique a radio-opaque material has to be incorporated in the DF,
and its location is tracked by X-ray picture.
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•
ɣ-Scintigraphy
•
Gamma scintigraphy relies on the administration of a DF
containing a small amount of radioisotope, e.g.,152Sm,which is
a gamma ray emitter with a relatively short half life.
•
Gastroscopy
•
Gastroscopy is commonly used for the diagnosis and
monitoring of the GI tract.
This technique utilizes a fiberoptic or video system and can be
easily applied for monitoring and locating GRDFs in the
stomach.
•
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Ultrasonography
In this technique, ultrasonic waves are reflected at
substantially different acoustic impedances across an
interface, enabling the imaging . By transmission of
ultrasonic waves, the acoustic mismatch is traced out
across the interface between dosage form and
physiological surface. However, this method is not
popular due to lack of ultrasound traceability at the
intestine. Another drawback of this method is some of
the dosage forms may not exhibit a sharp acoustic
mismatch.
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13 C octanoic acid breath test
Octanoic acid is a medium chain fatty acid absorbed by the upper
part of the small intestine, rapidly transported to the liver and
immediately oxidised by mitochondria to form CO 2, which is
exhaled out in the breath. In this method, 13 C octanoic acid is
incorporated into the GRDDS.The carbon atom of octanoic acid
which essentially forms CO 2 is replaced with the 13 C isotope.
After ingestion of the dosage form, the time duration after which
13 CO 2 gas is observed in the breath indicates the transfer of
the dosage form from the stomach to the upper part of the small
intestine, which may be considered as the gastric retention time
of the dosage form
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Limitations
Floating system
•

They require a sufficiently high level of fluids in the stomach
for the drug delivery buoyancy, to float therein and to work
efficiently.

Drugs which are well absorbed along the entire GI tract and
which undergoes significant first- pass metabolism, may not be
desirable candidates for GRDDS since the slow gastric
emptying may lead to reduced systemic bioavailability.

.
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Drugs
Unstable in Stomach / Acidic pH
Very Low Soluble / insoluble
Causes irritation
Adhesive
High Turn Over Rate of MUCUS LAYER
Thick Mucus Layer
Presence of Soluble Mucin
Swelling
Exit before Swells – Slow Swelling Rate
Capable to Resist House Keeper Waves
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Recent work



Formulation and Evaluation of an Oral Floating
Tablet of Cephalexin
Indian J.Pharm. Educ. Res. 44(3), Jul-Sep, 2010
Development and Evaluation of Rosiglitazone
Maleate Floating Tablets using Natural Gums
International Journal of PharmTech Research JulySept 2010
Development of Floating Drug Delivery System with
Biphasic Release for Verapamil Hydrochloride: In vitro
and In Vivo EvaluationJournal of Pharmaceutical Science and
Technology Vol. 2 (11), 2010,361-367
53/59

Formulation and Evaluation of Effervescent
Floating Tablet of Famotidine
International Journal of PharmTech Research
July-Sept 2009

Formulation and Evaluation of Glipizide FloatingBioadhesive Tablets
Vol.53, n. 5: pp.1073-1085, September-October 2010
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Brand Name
Drug (dose)
Company
Madopar®
Levodopa (100 mg),
Benserazide (25 mg)
Roche, USA
Valrelease®
Diazepam (15 mg)
Hoffman LaRoche,
USA
Liquid Gaviscon®
Al(OH)3 + MgCO3
GlaxoSmithKlein,
India
Topalkan® Liquid
Al – Mg antacid
Pierre Fabre Drug,
France
Almagate
Flotcoat®
Al – Mg antacid
Conviron®
Ferrous sulfate
Ranbaxy, India
Cifran OD®
Ciprofloxacin (1 g)
Ranbaxy, India
Cytotec®
Misoprostal (100/200 g)
Pharmacia, USA
55/59
S.No
Type of formulation
Patent no
. Ref
1
Gastro retentive dosage form
U.S-7,413,752
Devane et al.,
2008.
2
Multiple unit floating dosage
form
European patent
(EP) 10697
Vanderbist et al.,
2007
3
Bilayer tablet
EP-002445
Lohray et al.,
2004
4
Floating Tablet
U.S-66,352279
Kolter et al.,
2003.
5
3-layer tablet
U.S-5780057
Conte et al.,
1998
6
Floating capsules
U.S-4126672
Sheth et al., 1978
7
Foams (or) hollow bodies
U.S-5626876
Muller et al.,
1997
56/59
REFERENCES
•
•
•
•
•
Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F.
Gatroretentive dosage forms: Overview and special case of
Helicobacter pylori. J Control Release. 2006;111:1-18.
Ecyclopedia of Pharmaceutical Technology.
Hari Vardhan Reddy L and Murthy RSR. Floating Dosage
Systems in Drug Delivery. Critical Revises in Therapeutic Drug
Carrier Systems. 2002;19(6):553-585.
Julan UD. Floating Drug Delivery Dystem: An Approach to
Gastroretension. Latest Reviews. 2007;5(1).
Shweta A, Javed A, Alka A, Roop K, and Sanjula B. Floating drug
delivery systems: a review. AAPS PharmSciTech. 2005;6 (3)
Article 47.
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•
•
•
•
Rouge N, Buri P, Doelker E. Drug absorption sites in the
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Wilson C.G, Washington N., Physiological Pharmaceutics:
Biological Barriers to Drug Absorption, Horwood Ellis,
Chichester, 1989; 47-70.
Groning R, Heun G. Oral dosage forms with controlled
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Deshpande A.A., Shah N.H., Rhodes C.T., Malick W.,
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