M.

Pharm I semester

GASTRORETENTIVE DRUG DELIVERY SYSTEMS

Sri Ramachandra Institute
of Higher Education and
Research
(Deemed to be University)
Porur, Chennai-116
Dr.S.Nagalakshmi
Assistant Professor
Department of Pharmaceutics
Sri Ramachandra Faculty of
Pharmacy
SRIHER(DU)Porur, chennai
116
CONTENTS
• Introduction
• Principles of Gastric Retention
• Advantages
• Disadvantages
• Approaches for modulation of GI
• Evaluation for GRDDS
• Applications
• Conclusion

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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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• 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

• 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

• High density system

• Floating systems
• Expandable systems
• Superporous hydrogels
• Mucoadhesive or bioadhesive systems
• Magnetic systems

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High density systems

 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 2.4-
2.8g/cm3.

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Floating Systems

• Single-unit floating dosage system

1. Noneffervescent systems
2. Effervescent (gas-generating) systems

• Multiple-unit floating dosage system

1. Noneffervescent systems
2. Effervescent (gas-generating) systems
3. Hollow microspheres

• Raft-forming systems

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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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Hydrodynamically balanced system

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A.1 – FLOATING – NON EFFERVESCENT
MONOLITHIC SYSTEMS
MATRIX TABLET

Single Layer Tablet Bilayer Tablet

Loading Dose

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A.1 – FLOATING – NON EFFERVESCENT
MONOLITHIC SYSTEMS
TABLET with AGAR & MINERAL OIL
Drug + Warm Agar
Mineral Oil Gel Solution

mix

Air Entrapped in Agar gel

Pour in
Tablet Mold Escape of Air – prevent by OIL

2% Agar per Tablet

Cool
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TABLET with FOAM TABLET with LIPID
Glyceryl Monooleate
Polypropylene Foam

Hydrophobic Powder Swells in Water

Open-cell Structure Converted to Liquid

Crystals - Cubic Shape
Highly Porous
Melted And Molded
Low Inherent Density

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TABLETS IN The device consisting of
two drug-loaded HPMC
CYLINDER 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 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.
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 Add Calcium Spherical Separate,
Alginate Chloride Gel Freeze Dried (-
to
Solution Solution Beads 40oC)

Calcium Pectinate Gel Beads

Calcium-Alginate-Pectinate Gel Beads
Calcium Alginate + Chitosan Gel Beads
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 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
mix Add Calcium
Emulsion to
Chloride
Edible Solution
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 Rapid

Solution (60oC) Cooling
mix Cooled
Separated
Add to
Emulsion Acetone and
Dried
Preheated
Mineral Oil
At Reduced Pressure – NO AIR – Non Floating Beads
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MULTIPLE UNITS
HOLLOW
MICROBALLOON
MICROSPHERE

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Mechanism of formation of microballoon

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A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
FOAM Containing MICROPARTICLES
Drug,
Solvent Evaporation Method
Polymer
Dissolved

Organic Add Aqueous

Solvent PVA
to Solution
Dispersed
Only FOAM
FOAM Microparticle
FOAM 24/59
A.1 – FLOATING – NON EFFERVESCENT
MULTIPLE UNITS
CALCIUM SILICATE GELUCIRE® GRANULES
As FLOATING CARRIER

Highly Porous Hydrophobic Lipid

Large Pore Volume Diff. Grades – 39/01

43/01
Low Inherent Density
Low Inherent Density
Granules Drug
Granulation
HPMC
Ca-Silicate SR of Highly Soluble Drug
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• Gas-Generating Systems

• 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
Bicarbonate + Carbopol
Triple Layer Tablet - GELLING
due to Alkaline
MICROENVIRONMENT
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Triple-layer system

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• Multiple-Unit Floating Systems

• Hollow Microspheres
• 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.

• 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
Na-Alginate CaCl2 Acetic
NaHCO3 Solution Acid
Solution

mix

- Simultaneous Generation of CO2 & Gelling of Beads

- Escape of CO2 creates Pores in Beads

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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 G
U
HCO3
Resin
DR H+ Cl
DR
HCO3 UG

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
• These systems include Unfoldable and Swellable systems.

• 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.

• 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.

• 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.

• 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
• 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

• 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
• 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
• 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
Water Uptake 2 r2
PR =
Per Unit TimeX Water Density

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 For mucoadhesive
Wilhemy’s plate technique
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 43/59
B. For Multiple Unit Dosage Forms (ex:
microspheres)
• 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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• (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

• 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.

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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 July-Sept 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

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• Formulation and Evaluation of Effervescent Floating Tablet of
Famotidine
International Journal of PharmTech Research July-Sept 2009

• Formulation and Evaluation of Glipizide Floating-

Bioadhesive Tablets
Vol.53, n. 5: pp.1073-1085, September-October 2010

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 Brand Name Drug (dose) Company
Levodopa (100 mg),
Madopar® Roche, USA
Benserazide (25 mg)
Hoffman LaRoche,
Valrelease® Diazepam (15 mg)
USA
GlaxoSmithKlein,
Liquid Gaviscon® Al(OH)3 + MgCO3
India
Pierre Fabre Drug,
Topalkan® Liquid Al – Mg antacid
France
Almagate
Al – Mg antacid
Flotcoat®
Conviron® Ferrous sulfate Ranbaxy, India
Cifran OD® Ciprofloxacin (1 g) Ranbaxy, India
Cytotec® Misoprostal (100/200 g) Pharmacia, USA
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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 European patent Vanderbist et al.,

form (EP) 10697 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

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References
Leon lachman – The theory and practic of industrialpharmacy.
Michael E Alton - Pharmaceutics The science of dosage form
design.
N.K. Jain – Controlled & novel drug delivery.
S.P. Vyas & Khar – Controlled Drug delivery,
Brahmankar – TextBook of Biopharmaceutics
Pharmacokinetics.
Yie.W.Chein- Controlled & Novel Drug Delivery,
CBSpublishers.
Painter,P & Coleman ,M – “ Fundamental of Polymer
science”.
 IUPAC. Glossary of Basic terms in polymer science”. Pure
application -1996.
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