GASTRORETENTIVE

DRUG DELIVERY
SYSTEMS

Ch. Sherjeel Adnan

The University of Lahore.

1
 Oral route is the most convenient
and extensively used route in drug
administration , due to ;
high patient acceptability.

2
CONTROLLED RELEASE
 CRDDS release drug at a predetermined rate, as
determined by drug’s pharmacokinetics and desired
therapeutic concentration. This help in achieving
predictable drug plasma concentration required for
therapeutic effect.
CRDDS is determined by-
1. Physicochemical properties of the drug molecule
like, the aqueous solubility, intestinal permeability, pH-
solubility profile, etc.
2. Pharmacokinetic profile of the drug
3. The interaction of these properties with the anatomy and
physiology of the GI tract 3
Dosage form Transit time(hr)

Gastric Small intestine Total

Tablets 2.7±1.5 3.1±0.4 5.8

Pellets 1.2±1.3 3.4±1.0 4.6

Capsules 0.8±1.2 3.2±0.8 4.0

Oral solutions 0.3±0.07 4.1±0.5 4.4

4
REGIONAL VARIABILITY IN INTESTINAL
ABSORPTION__CONCEPT OF ABSORPTION WINDOW

A. Physiochemical factors
1. pH dependent solubility(1-8)
2. pH dependent stability(degradation)
3. Enzymatic degradation
B. Physiological factors
1. Mechanism of absorption(active/facilitated)
2. Microbial degradation(400 species)
C. Biochemical factors
1. Intestinal metabolic enzymes(cytochrome p450)
2. Multidrug efflux pump(p-gp in villus tip)

5
6
Absorption
window
No absorption of drug
Released in region
Preceding the window
7
DEFINITION
 These are the drug delivery
systems which possess the
ability of retaining the drug
in the GIT particularly in the
stomach for prolonged
period of time, and release
the drug in controlled
amount.
 After the drug release for
required time period the
dosage form should get
degraded without causing 8
any gastric disturbances.
INTRODUCTION
 The control of gastrointestinal transit of orally administered
dosage forms using gastro retentive 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.

9
REVIEW OF STOMACH AND GIT
A tube about nine meters long that runs through the middle
of the body from the mouth to the anus and includes ;
 throat (pharynx),
 esophagus,
 stomach,
 small intestine (consisting of the duodenum, jejunum and
ileum) and
 large intestine (consisting of the cecum, appendix, colon and
rectum).
The wall of the gastrointestinal tract has the same general
structure throughout most of its length from the esophagus
to the anus, with some local variations for each region.
10
IMPORTANT IN GIT FOR GRDDS:
 Throat(to determine size of dosage unit)
 Stomach & upper small intestine(chemical environment
to determine drug absorption)

11
SALIENT FEATURES OF UPPER
GASTROINTESTINAL TRACT
Length Transit pH Absorbing Absorption
(m) time surface pathway
(hr) area (m2)

Stomach 0.2 Variable 1-4 0.1 P,C,A

Small P,C,A
Intestine 6-10 3±1 5-7.5 120-200 F,I,E,CM

P –  Passive diffusion                            C – Aqueous channel transport

A –  Active transport                             F – Facilitated transport
I –   Ion-pair transport                          E –  Entero-or pinocytosis
12
CM – Carrier mediated transport
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 inter

digestive motility pattern that is commonly called migrating motor
complex (MMC)(migrating myloelectric cycle)
• This is a series of events
that cycle through the
stomach and small
intestine every
1.2 to 2hrs.
13
 In fed state,
• the gastric emptying rate slowed down because the
onset of Migration Motor Complex (MMC) is delayed
• the feeding state results in a lag time prior to the onset
of gastric emptying
• It is thought that the sieving efficiency of the stomach is
enhanced by the fed pattern or by the presence of food.

14
REQUIREMENTS FOR GASTRIC
RETENTION

 Dosage form must be able to withstand the forces caused

by peristaltic waves in the stomach.

 It must resist premature gastric emptying.

 Once its purpose has been served, the device should be

removed from the stomach with ease.

15
NEED OF GASTRO RETENTIVE
DRUG DELIVERY SYSTEM
A controlled drug delivery system with prolonged
residence time in the stomach is of particular interest for
drugs that;
 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).
16
 Absorbed by transporter mechanism (paclitaxel).
FACTORS CONTROLLING THE
GASTRIC RETENTION TIME OF
DOSAGE FORM

1.Density: GRT is a function of dosage form buoyancy.

2. Size
3. Shape of dosage form:Tetrahedron and ring shaped devices.
4. Fed or unfed state:If the timing of administration of the
formulation coincides with MMC, the GRT of the unit can be
expected to be very short. However, in the fed state, MMC is
delayed and GRT is considerably longer.
5. Caloric content:GRT can be increased by 4 to 10 hours with a meal
that is high in proteins and fats.
15
6. Frequency of feed: The GRT can increase by over 400
minutes, when successive meals are given compared
with a single meal due to the low frequency of MMC.

7. Gender: Mean ambulatory GRT in males (3.4±0.6

hours) is less compared with their age and race matched
female counterparts (4.6±1.2 hours), regardless of the
weight, height and body surface.

8. Age: Elderly people, especially those over 70, have a

significantly longer GRT.

9. Posture: GRT can vary between supine and upright

ambulatory states of the patient. 18
Advantages
 Improved drug absorption, because of increased GRT and more time spent
by the dosage form at its absorption site.

 Controlled delivery of drugs.

 Minimizing mucosal irritation by releasing drugs slowly at a controlled

rate.

 Treatment of gastrointestinal disorders such as gastro-esophageal reflux,

providing local action.

 Ease of administration and better patient compliance.

19
LIMITATIONS

 Retention in the stomach is not desirable for drugs that

cause gastric lesions (e.g. Non- steroidal anti-
inflammatory drugs NSAIDs).
 Drugs that are degraded in acidic environment of
stomach (e.g. Insulin).
 Drugs that undergo a significant first-pass metabolism
(e.g. Nifedipine).
 Drugs that have very limited acid solubility (e.g.
Phenytoin).
20
 APPROACHES FOR PROLONGING THE
GASTRIC RESIDENCE TIME
HDS
F
1. High-density systems. S

(HDS) S

A
S
S

2. Floating systems. (FS)

3. Swelling and expanding
systems. (SS)
4. Mucoadhesive &
Bioadhesive systems. (AS)
5. Magnetic systems(MS)
21
6. Superporous
hydrogels(SH)
HIGH DENSITY SYSTEMS

 Gastric contents have a density close to

water (~1.004).
 A density 2.6-2.8g cm-3 is necessary for
significant prolongation of gastric residence
time(threshold value).
 When the patient take high-density pellets ,
they sink to the bottom of the stomach where
they become entrapped in the folds of the
antrum and withstand the peristaltic waves of
the stomach wall.

22
HIGH DENSITY MATERIALS:
The commonly used excipients in high density system
includes high density compounds
such as;
 barium sulphate, (4.9g/cm3)

 zinc oxide,

 iron powder,

 titanium dioxide.

Drug release follows

simple diffusion through
Polymer membrane.
23
DRAWBACKS OF HIGH DENSITY
SYSTEM
 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.
 It is unpredictable;whether the dosage form will stand
peristaltic movement or not.

24
EXPANDABLE SYSTEMS
Expandable systems are also called as plug type systems. They
achieve larger size in stomach.
Based on three configurations:
 A small collapsed configuration which enables sufficient oral
intake
 Expanded form that is achieved in the stomach and thus prevents
passage through the pyloric sphincter.
 A smaller form that is achieved in the stomach when the
retention is no longer required i.e. after the system has released
its active ingredient, thereby enabling evacuation.
These systems include;
Unfold able systems
25
Swelling systems
UNFOLDABLE SYSTEM:
Unfolding systems are systems which are actually
of larger size but they are folded to decrease size
and kept in capsules. In stomach these systems
comes out of capsules and unfolds to larger size.
Made of biodegradable polymers (gelatin). The
concept is to make a carrier, such as a capsule,
incorporating a compressed system which extends
in the stomach.
shape memory

26
Different geometric forms of unfoldable systems
27
SWELLABLE SYSTEMS

 Swelling system are generally matrix system containing

hydrocolloids which by action of hydration and osmosis
get swelled.
 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.

28
IMPORTANT FACTORS:

 Swelling index means how much fold it can increase in

volume
 swelling time are the important factor for such systems.

 Optimum amount of cross linking is required to maintain

balance between swelling and dissolution of hydrogel.

29
 Gastric
Fluid

High degree of
Cross-linking

Time
Low degree of
Cross-linking
Gastric
Fluid
POLYMERIC ENVELOP AND TINY PILLS
IN THE MATRIX:

31
Picture of tablet in Dry and Wetted state
32
DRAWBACKS:

 The Dosage form must maintain a size larger than

pyloric sphincter

 The Dosage form must resist premature gastric

emptying

33
SUPER POROUS HYDRO GELS

• Swellable agents with pore size ranging between 10nm and 10µm
are used.
• 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. 34
POLYMERS:
 This is achieved by co-formulation of a hydrophilic
particulate material , and Ac-Di-Sol. (crosscarmellose)

35
MUCOADHESIVE OR BIOADHEDIVE
SYSTEM
 The technique involves coating of microcapsules with
bioadhesive or mucoadhessive polymer, which enables them
to adhere to the gastric epithelial cells or mucin and remain
for longer time period in the GI while the active drug is
released from the device matrix.
Bioadhesion(Ab) is dependent on polymer concentration
(c),represented by quadratic equation as;
c + a2c²
Where a2 are constants.

36
MECHANISM OF BIO/MUCO-
ADHESION
 Hydration – mediated adhesion
 Bonding –mediated adhesion

 Receptor – mediated adhesion

37
MUCOADHESIVE ORAL DRUG DELIVERY
SYSTEMS
Drug Dosage form Mucoadhesive
polymer

Glipizide Microcapsules HPMC, Sodium

CMC,MC,Carbopol

Metoclopramide Microcapsules Chitosan

Diltiazem Hcl Tablet HPMC, Sodium CMC

Sucralfate Tablet Methocel E4M

DRAWBACKS:

 Continuous production of mucous may limit muco

adhesion.
 Bio adhesion may cause local irritation.

39
MAGNETIC SYSTEMS

• 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.
Drawbacks:
• Although these systems seem to work, the external
magnet must be positioned with a degree of precision
that might compromise patient compliance.

40
FLOATING SYSTEMS:
 Floating drug delivery systems (FDDS) have a bulk
density less than gastric fluids and so remain buoyant
in the stomach without affecting gastric emptying rate
for a prolonged period of time.
 While the system is floating the drug is released slowly
at the desired rate from the system.
 After release of drug, the residual system is emptied
from the stomach. This results in an increased GRT and a
better control of the fluctuations in plasma drug
concentration.

41
CLASSIFICATION:
• Noneffervescent systems
1. Single-unit floating dosage system
2. Multiple unit floating dosage system

• Effervescent (gas-generating) systems

1. Single-unit floating dosage system
2. Multiple unit floating dosage system

• Raft-forming systems

42
NON EFFERVESCENT SYSTEMS
Single unit
1. Floating tablets(MATRIX TABLET)
2. Floating capsules(HBS capsules)
3. Tablets with hollow cylinder
4. Microporous reservior
5. Multilayer flexible film

43
1.MATRIX TABLET
 Incorporating gel forming hydrocolloids HPMC, which
is the most commonly used polymer for floating.
 Out of various grades of HPMC, low viscosity grade are
used for floating purpose.
 Mixture of alginate and HPMC also prepared for
floating tablet.

44
Single Layer Tablet Bilayer Tablet

Loading Dose

45
2.FLOATING CAPSULES:

HBS Capsules:
 It is Hydrodynamically Balanced System. It is a hard gelatin
capsule containing drug with high level of one or more highly
swellable gel forming hydrocolloids (20-75%) like HPMC,
HPC, HEC, Na-CMC etc.
 When coming in contact with water, the hydrocolloids at the

surface of the system swell and facilitate floating.

 Gel structure controls rate of diffusion of fluid-in and drug- out
making “Receding Boundary”.
 After exterior surface dissolves/erodes, the immediate adjacent
hydrocolloid layer is hydrated and process continues to give 46
floating for extended period of time.
1. HBS CAPSULES

47
3.TABLETS IN The device consisting of
two drug-loaded HPMC
CYLINDER matrix tablets, which are
placed within an
HPMC matrix impermeable, hollow
tablet polypropylene cylinder (open
polypropylene
at both ends). Each matrix
tablet closed one of the
cylinder’s ends so that an air-
filled 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.
48
tablet
4.MICROPOROUS
• Drug reservoir encapsulated
RESERVIOR
in microporous compartment
having pores on its top and
bottom walls
• Peripheral walls are sealed,to
prevent direct contact with
gastric fluid
• A floating chamber was
attached at one surface
which gives buoyancy to
entire device. Drug slowly
dissolves out via micro pores
49
5.MULTI-LAYER FLEXIBLE FILM:
The device consist of two films which are sealed together
along their periphery and in such a way as to entrap some air
between two films and so make air pocket which imparts
buoyancy.

50
MULTIPLE UNIT:
 Reduce the inter subject variability in absorption
 Lower the probability of dose dumping.

 Available as
 Beads,
 Micro-spheres,
 Micro-balloons,
 Carrier system.

51
A. Beads

1.CALCIUM ALGINATE/PECTINATE BEADS

2.ALGINATE BEADS with AIR COMPARTMENT
3.OIL ENTRAPPED GEL BEADS
4.CASEIN – GELATIN BEADS

52
 1.CALCIUM ALGINATE/PECTINATE BEADS
IONOTROPIC GELATION METHOD
porous beads with about 12 hrs buoyancy period &
residence time of 5.5 hrs

Sodium Calcium Spherical Separate,

Alginate Dropped to Freeze Dried
Chloride Gel
Solution Solution Beads(2.5 (-40oC)
mm) 24hrs

Calcium Pectinate Gel Beads

Calcium-Alginate-Pectinate Gel beads(fasten drug release)
Calcium Alginate + Chitosan Gel Beads(air entrapement53
gives Better buoyancy)
2.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(water soluble additive in coating composition which
increase membrane permeability), and then they are dried
Alginate Bead
in Solution,
before Drying

Coating
before Drying
After Drying
Shrinkage of Bead 54
 3.OIL ENTRAPPED GEL BEADS
Oil – Light weight and Hydrophobic

Pectin has some Emulsification property

Aqueous
Solution of
Pectin
homogenization extruded to Calcium
Emulsion Chloride
Edible Solution
Veg. OIL

55
56
 4.CASEIN – GELATIN BEADS

• Casein has Emulsification property- Entraps Air Bubbles

• Biodegradable beads

Casein Gelatin
Solution (60oC) Rapid
Cooling
Rapidly stirred (5co ) Cooled Separated
Emulsion Acetone and
Add to
Preheated
Dried
Mineral Oil
57
At Reduced Pressure – NO AIR – Non Floating Beads
B.HOLLOW MICROSPHERE
Or MICROBALLOON
Emulsion-solvent diffusion method

• Agitate solution of PVA and thermally control at 40 degree Celsius.

• Ethanol-dichloromethane solution of drug and polymer was poured
into it.

Polymers such as polycarbonate and cellulose acetate were used in the 58

preparation of hollow microspheres.
 Mechanism of drug release:

When microspheres come in contact with gastric fluid

the polymer forms a colloidal gel barrier that controls
the rate of fluid penetration into the device and
consequent drug release.

59
d) Carrier systems

CALCIUM SILICATE AS FLOATING CARRIER

• Granules of calcium silicate as a floating
carrier, which has a characteristically porous
structure .
• Air trapped in the pores of calcium silicate when
they were coated with polymer(HPC).

Highly Porous

Large Pore Volume

Low Inherent Density 60

EFFERVESCENT SYSTEMS:
 Gas generating system
 Matrix tablets
 Single layer tablets
 Bilayer tablets

 Multi unit floating pills

 Floating based on ion exchange resin
 Volatile liquid containing system
 Deformable unit with inflatable chamber
 Osmotically controlled DDS

61
1.GAS GENERATING SYSTEM
Effervescent reaction between carbonate/ bicarbonate salts
and citric/tartaric acid to liberate CO2,which get enrtapped
in the gellified hydrocolloid layer of the system,decreasing
its bulk density and making it float over chyme.
Matrix tablets:
 Single layer:
CO2 generating components intimately mixed within tablet
matrix.(HPMC,Chitosan,alginate)
 Bilayer tablets:
Gas generating components comprssed in one hydrocolloid
containing layer and drug in other formulated for SR. 62
FLOATING PILLS

NaHCO3

Tartaric Acid
DRUG

Swellable Polymer
(PVA and shellac)
63
ION EXCHANGE RESIN BEADS

H+ Cl
H+ Cl

HCO3 G
U
HCO3
Resin
DR H+ Cl
DR
HCO3 UG

H+ Cl H+ Cl 64
Uncoated Beads – No Floating – Escape of CO2
Volatile liquid containing system:
1.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.

65
2.Deformable unit with inflatable chamber

These type of systems consist of two chambers separated by

an impermeable, pressure-responsive,movable bladder.
• The first chamber contains the drug impregnated polymeric matrix
• and the second chamber contains the volatile liquid(ether).
• Both enclosed in gelatin shell.
The device inflates, and the drug is continuously released from
the reservoir into the gastric fluid.

66
• Raft-Forming Systems

• This system is used for delivery of antacids and drug delivery

for treatment of gastrointestinal infections and disorders.
• These are liquid preparations having gel forming agent(alginic
acid),Na-bicarbonates and drug, which forms foaming Na-
alginate gel, while reacting with gastric acids.
• This raft floats in gastric fluids because of the low bulk density
created by the formation of CO2
• The raft has pH value higher than that of stomach contents so
that in gastric reflux the wall of oesophagus is not subjected to67
irritation by HCl.
 Brand Name Drug (dose) Company
Levodopa (100 mg),
Madopar® (HBS) Roche, USA
Benserazide (25 mg)
Hoffman LaRoche,
Valrelease® (HBS) Diazepam (15 mg)
USA
Liquid Gaviscon® Al(OH)3 + MgCO3 GlaxoSmithKlein, India
(RAFT SYSTEM)
Topalkan® Liquid Pierre Fabre Drug,
Al – Mg antacid
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 68
 EVALUATION OF GRDDS
Evaluation of a drug product is a tool to ensure-
1. Performance characteristics, and
2. Control batch to batch quality
A) IN-VITRO EVALUATION
1) Floating systems
a) Buoyancy Lag Time
It is determined in order to assess the time taken by the dosage
form to float on the top of the dissolution medium, after it is
placed in the medium.

69
b) Floating Time
Test for buoyancy is usually performed in SGF(Simulated
Gastric Fluid) maintained at 370C.
“The time for which the dosage form continuously floats
on the dissolution media is termed as floating time”
c) Specific Gravity / Density
Density can be determined by the displacement
method using Benzene as displacement
medium

70
d)Resultant Weight
The magnitude and direction of force/resultant weight (up or down) is corresponding
to its buoyancy force (Fbuoy) and gravity force (Fgrav) acting on dosage form.
F = Fbuoy – Fgrav
F = Df g V – Ds g V
F = (Df – Ds) g V
F = (Df – M/V) g V
Where,
F = resultant weight of object
Df = Density of Fluid
DS = Density of Solid object
g = Gravitational force
M = Mass of dosage form
V = Volume of dosage form
So when Ds is lower, F force is positive gives buoyancy and when it is Ds is higher, F 71
will negative shows sinking.
72
2)Swelling system

1)Swelling Index

2)Water Uptake / Weight Gain

WU = (Wt – Wo) * 100 / Wo

3)Penetration Rate
Water Uptake 2 r2
PR =
Per Unit TimeX Water Density

73
 3)Bio/Mucoadhesive system:
Bioadhesion strength measurement
Force measuring device
(modified precision
balance
Or automated texture
Upper jaw
analyzer.

Polymer
Membrane

Lower jaw
• Methods to measure gastroretentivity of
GRDFs

• 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.

• 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. 75
• 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 fiber optic or video system and can be
easily applied for monitoring and locating GRDFs in the
stomach. 76
ULTRASONOGRAPHY
Used sometimes, not used generally because it is not
traceable at intestine.

13 C octanoic acid breath test

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.
77
• 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.

78/
59
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
79
Capable to Resist House Keeper Waves
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2006;111:1-18.
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Dosage Systems in Drug Delivery. Critical Revises in
Therapeutic Drug Carrier Systems. 2002;19(6):553-585.
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• Rouge N, Buri P, Doelker E. Drug absorption sites in the
gastrointestinal tract and dosage forms for site specific
delivery. Int J Pharm. 1996; 136:117-139.
• Julan UD. Floating Drug Delivery Dystem: An
Approach to Gastroretension. Latest Reviews. 2007;5(1).
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PharmSciTech. 2005;6 (3) Article 47.

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