GASTRO-RETENTIVE

DRUG
DELIVERY SYSTEM
Section Length Transit pH Microbia Absorbin Absorpti
(m) time (h) l count g surface on
area (m2) pathway
Stomac 0.2 Variabl 1-4 <103 0.1 P, C, A
h e
Small 6-10 3±1 5-7.5 103 – 1010 120-200 P, C, A,
intestine F, I, E,

P – Passive diffusion C – Aqueous channel transport

A – Active transport F – Facilitated transport
I – Ion-pair transport E – Entero-or pinocytosis
Gastric pH:Fasted healthy subject 1.1 ± 0.15
Fed healthy subject 3.6 ± 0.4
Volume: Resting volume is about 25-50 ml
Gastric secretion: Acid, pepsin, gastrin, mucus and some
enzymes about 60 ml with approximately 4 mmol of
hydrogen ions per hour
Effect of food on Gastric secretion:
About 3 liters of secretions are added to the food
Migrating myoelectric complex:

Intermittent
No contraction
contraction

Intense distal and proximal

gastric contraction

Intermediate 4-5 contraction / min

between III-I

House keeper wave

 Each cycle lasts 90-120 mins & consist of four phases.
 The concentration of the hormone motilin controls duration of phases.
 In the fasted state MMC wave migrates from stomach down the GI tract
every 90-120 mins.
 A full cycle consistes of four phases, beginning in the lower oesophageal
sphinter propagating over the whole stomach, the duodenum& jejunum, &
finishing at the ileum.
 Phase III is termed the ‘housekeeper wave’ as powerful contraction in the
phase tend to empty the stomach of its fasting contents & indigestible
debris.
 The administration & subsequent ingestion of food rapidly interrupts the
MMC cycle& digestive phase is allowed to take place.
 The upper part of the stomach stores the ingested food initially, where it is
compressed gradually by the phasic contractions.
 The duration of contraction is depemdent on the physicochemical
characteristics of the ingested meal.
 Generally, a meal of ~450 kcal will interrupt the fasted state motility for
about 3-4 hrs .
 It is reported that antral contractions reduce the size of food particles to <
1mm & propel the food through pylorus.
 Under fasting conditions, the stomach is a collapsed bag with a residual
volume of approximately 50 ml.
 The pH is 1-3 in the fasted state.
 Normal gastric retention time is 1.5-3 hrs.
 Diameter of the pyloric sphincter is 12.8 ± 7 mm.
 The GI tract is in a state of continuous motility consisting of two modes:
 Interdigestive motility pattern
 Digestive motility pattern

 The former is dominant in fasted state with a primary function of

cleaning up the residual content of upper GI tract.

 The Interdigestive motility pattern is commonly Called as

“Migrating Motor Complex” (MMC) And is organized in cycles of
activity.
INTRODUCTION
 Oral route is most acceptable route for drug
administration. Apart from conventional dosage
forms several other forms were developed in
order to enhance the drug delivery for prolonged
time period and for delivering drug to a
particular target site.
 Some drugs with narrow absorption index
and drugs which undergo carrier mediated
transport in the region of stomach and upper
part of small intestine have poor bioavailability
when administered as conventional dosage forms.
 In order to overcome such issues, gastro retentive
drug delivery systems were developed.
 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
 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.

 After the drug release for required

time period the dosage form
should get degraded without
causing any gastric disturbances.
PHYSIOLOGY OF GASTROINTESTINAL
TRACT

1- Floating System
Fundus
Esophagus 2- Bioadhesive System
Cardia 1 3- Swellable System
Body 2 4- High Density System
Pyloric
Sphinctor Pylorus

Duodenum Pyloric Antrum

3 4

STOMACH
 NEED FOR GASTRO RETENTION

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).
 Absorbed by transporter mechanism (paclitaxel).
 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.

o Enhanced bioavailability

o Reduced frequency of dosing

o Targeted therapy for local ailments in the upper GIT

o Reduced fluctuations of drug concentration

o Improved selectivity in receptor activation

o Reduced counter-activity of the body

o Extended effective concentration.

o Minimized adverse activity at the colon.

 LIMITATIONS

 They require a sufficiently high level of fluids in the

stomach for the drug delivery to float and work efficiently.

 Floating systems are not feasible for those drugs that have
solubility or stability problems in gastric fluid.

 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.

 Drugs that are irritant to gastric mucosa are not suitable for
GRDDS.
These systems do not offer significant advantages over the
conventional dosage forms for drugs, which are absorbed
throughout GIT.

The drug substances that are unstable in the acidic

environment of the stomach are not suitable candidates to be
incorporated in the systems.
FACTORS AFFECTING GASTRO RETENTION

1) Size : dosage form units with a diameter of more than 7.5mm are
reported to have an increased GRT compared with those with a
diameter of 9.9mm
2) Shape: Better GRT is possessed by tetrahedron and ring shaped
devices.
3) Caloric content: High meal is responsible for the increased GRT.
4) Age: Elder people have significant longer GIT
5) Posture: GRT can be varied between upright and supine positions
of the patients.
6) Single or multi-unit dosage forms: Multi dosage forms show
more effect comparing to the single unit dosage forms.
7) Density: GRT is a function of dosage form buoyancy that is
dependent on the density.
8) 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.
9) Nature of meal :feeding of indigestible polymers or fatty acid
salts can change the motility pattern of the stomach to a fed state, thus
decreasing the gastric emptying rate and prolonging drug release.
10) Biological factors : diabetes and Crohn’s disease, etc.
11) Frequency of feed: The GRT can be increased by over 400
mins, when succesive meals are given compared with a single meal due
o the low frequency of MMC.
12) Fed or unfed state: Under fasting conditions –GI motility is
characterised by MMC that occurs every 1.5 to 2 hours.However in the
fed state,MMC is delayed and GRT is considerably longer.
CLASSIFICATION
1. HIGH DENSITY
SYSTEM
 Sedimentation has been employed as a retention
mechanism for pellets that are small enough to
be retained in the folds of the stomach body near
the pyloric region, which is the part of the organ
with the lowest position in the upright posture.
 Dense pellets (approx. 3g/cm3) trapped in fold
also tend to withstand the peristaltic movements
of the stomach wall.
 Prepared by coating or mixing drug with heavy
inert material
 With pellets the GI transit time can be extended
from an average of 5.8-25 hrs, depending more
on density than on diameter of the pellets.
 Barium sulphate , zinc oxide, iron powder, and
titanium dioxide are examples for excipients
used.
 Drug release follows simple diffusion through
Polymer membrane.
 Problem with High Density system

 Higher amount of drug require

 The dosage form must stand with peristaltic movement

of stomach
2). FLOATING SYTEMS
The systems which are having a
bulk density lower than the
gastric content is known as
Floating drug delivery systems
The floating sustain release
dosage form present most of the
characteristics of hydrophilic
matrices & are known as
‘Hydrodynamically Balanced
Systems’ (HBS).
Since they are able to maintain
their low apparent density, while
the polymer hydrates & builds a
gelled barrier at the outer surface.
The drug is released progressively
from the swollen matrix, as in the
case of conventional hydrophilic
matrices.
These forms are expected to remain buoyant on the
gastric contents without affecting the intrinsic rate of
emptying b’coz their bulk density is lower than that of
the gastric contents.
Hydrocolloids like cellulose ether polymer is most
popular, especially hydroxy propyl methyl cellulose.
Fatty material with a bulk density lower than 1 may be
added to the formulation to decrease the water intake
rate & increase buoyancy.

 Types:

1. Hydrodynamically Balanced System.(HBS)

2. Gas Generating System.
3.. Raft orming System.
5. Low density system
 HYDRODYNAMICALLY BALANCED
SYSTEMS (HBS)
 These systems are single unit dosage forms containing one or more
gel forming hydrophilic polymers such as HPMC, HEC,HPC,Na CMC
etc.
 Usually drug is mixed with a polymer and usually administered in
gelatin capsules. These capsules readily dissolve in gastric fluid. The
hydration and swelling of surface polymers produces a floating mass
HBS CAPSULES

25
 GAS GENERATING SYSTEMS
 These formulations contain carbonates or bicarbonates which generates CO 2 due to
their reaction with acids either as natural gastric acid or coformulated as citric acid,
tartaric acid
 In case of single unit systems, effervescent substances are introduced in the
hydrophilic polymers and CO2 bubbles are trapped in the swollen matrix.
 These buoyant system utilize matrices prepared with swellable polymers like
methocel, polysaccharides like chitosan, effervescent components like
sod.bicarbonate, citric acid & tartaric acid.
 The optimal stoichiometric ratio of citric acid & sod bicarbonate for gas generation
is reported to be 0.76:1.
 The common approach for preparing these systems involves resin beads loaded
with bicarbonate & coated with ethyl cellulose.
 The coating which is insoluble but permeable, allows permeation of water. Thus
carbon dioxide is released, causing the beads to float in the stomach.
 Excipients used most commonly in these systems include HPMC, polyacrylate
polymers, polyvinyl acetate, carbopol, agar, sod.alginate & polyethylene oxide.
MATRIX TABLETS

Single layer matrix tablet is prepared by

incorporating bicarbonates in matrix forming
hydrocolloid gelling agent like HPMC, chitosin,
alginate or other polymers and drug.
Bilayer tablet can also be prepared by gas
generating matrix in one layer and second layer
with drug for its SR effect.
Triple layer tablet also prepared having first
swellable floating layer with bicarbonates, second
sustained release layer of drug and third rapid
dissolving layer of bismuth salt.
 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
 HOLLOW MICROSPHERES
Microballoons loaded with drug in their other polymeric shelf are
prepared by simple solvent evaporation or solvent diffusion .

Polymers used commonly: Polycarbonates, Cellulose acetate, Calcium

alginate, Eudragit S, agar and low methoxylated pectin etc.

Buoyancy and drug release depends on:

 Quantity of polymer
 Plasticizer polymer ratio
 Solvent used
• Multi unit floating dosage forms-cross linked beads
• Prepared by dropping sodium alginate solution into
aqueous solution of calcium chloride, causing the
precipitation of calcium alginate
• Prepared by using calcium and low methoxylated pectin
and calcium low methoxylated pectin and sodium
alginate.
• Freeze dry in liquid nitrogen at -40oc for 24h.
• Beads-spherical and 2.5 mm in diameter.
 System is incorporated with an inflatable
chamber which contains liquid ether - gasifies at
• body temperature to cause the chamber to
inflate in stomach.
Inflatable chamber is loaded with a drug reservoir
which can be a drug, impregnated polymeric then
encapsulated in a gelatin capsule

33
INTRAGASTRIC OSMOTICALLY
CONTROLLED DDS

 Comprised of both an osmotic pressure controlled drug delivery device and an

inflatable floating support in a biodegradable capsule.

 In stomach, the capsule quickly disintegrates and release the intragastric

osmotically controlled drug delivery device.

 Inflatable support forms a deformable hollow polymeric bag containing liquid

that gasifies at body temperature to inflate the bag.
Consists of 2 compartments:
• Drug reservoir
• Osmotically active compartment.

34
INTRAGASTRIC OSMOTICALLY
CONTROLLED DDS

 Comprised of both an osmotic pressure controlled drug delivery device and an

inflatable floating support in a biodegradable capsule.

 In stomach, the capsule quickly disintegrates and release the intragastric

osmotically controlled drug delivery device.

 Inflatable support forms a deformable hollow polymeric bag containing liquid

that gasifies at body temperature to inflate the bag.
Consists of 2 compartments:
• Drug reservoir
• Osmotically active compartment.

35
INTRA-GASTRIC FLOATING
GASTROINTESTINAL DRUG DELIVERY
SYSTEMS
System can float by a flotation chamber, which may be vacuum or
filled with air or a harmless gas
Drug reservoir is encapsulated inside a microporous compartment

37
ADVANTAGES OF FLOATING DRUG
DELIVERY
Drugs those are...
 Primarily absorbed in the stomach
 Poorly soluble at an alkaline pH
 Narrow window of absorption
 Degrade in colon
 When there is a vigorous intestinal movement and a short transit time
as might occur in certain type of diarrhoea, poor absorption is
expected.
 Under such circumstances it may be advantageous to keep the drug in
floating condition in stomach to get a relatively better response.
DISADVANTAGES OF FLOATING DRUG
DELIVERY

 Not feasible for those drugs that have solubility OR stability

problem in GIT
 Require high level of fluid in stomach
 The drugs that may irritate the stomach lining OR are unstable
in acidic environment
 The dosage form should be administered with a full glass of
water (200-250 ml)
3. MUCOADHESIVE SYSTEMS
MECHANISM OF BIO / MUCO-
ADHESION

 Hydration – mediated adhesion

 Bonding –mediated adhesion

 Receptor – mediated adhesion

41
PROBLEM OF MUCO-ADHESIVE
SYSTEM

 Rapid removal of mucus.

 We are not sure weather the DF will adhere to the mucus

or epithelial cell layer

 DF may adhere to oesophagus resulting in drug induced

injuries

 Continuous production of mucous may limit muco

adhesion.

 Bio adhesion may cause local irritation.

4. EXPANDABLE SYSTEMS

 These dosage forms are usually small enough to be swallowed.

 In the stomach after coming into contact with the gastric fluids, they get expanded to a larger
size so that gastric retention is achieved.
 After the drug release they should retain into a final small form for easy evacuation.
SWELLABLE SYSTEMS
 Also called ‘ PLUG SYSTEM’
 Size of the formulation more than Pyloric sphincter
 It should expand for gastric retention
 Should be Collapsed after lag time
 Swellable systems are retain because of their
mechanical properties.
 These systems absorb water and then swell.
 Initially the dosage form is very small for swallowing,
after reaching the stomach the dosage form will swell
in their size and cause retention.

 Drawbacks:
 The Dosage form must maintain a
size larger than pyloric sphincter
 The Dosage form must resist premature
gastric emptying
 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.
UNFOLDABLE
SYSTEMS

• The concept is to make a carrier, such as a capsule,

incorporating a compressed system which extends in the
stomach.
• On their contact with gastric fluid these systems get unfolded into forms which
can get unfolded into forms which can be retained in the stomach for definite
time period
• 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).
Different geometric forms of unfoldable
systems
 5).SUPERPOROUS HYDROGELS

 These have a pore size

ranging from 10nm to
10 micrometer
 These super porous

hydrogels swells to an
equilibrium size because of
their nature of rapid water intake by capillary wetting through their
pores.
 They swell to larger size and can withstand a pressure with gastric
contraction. And due to this larger size their passage through the
pyloric sphincter is prevented.
 This is achieved by co-formulation of a hydrophilic particulate

material, and Ac-Di-Sol (crosscarmellose)

 6. MAGNETIC SYSTEMS
 Based upon the principle that dosage form contains
a small internal magnet ,and a magnet placed on
the abdomen over the position of stomach can
enhance the GRT.
 Because of this technique the dosage form with an internal
magnet is retained in the stomach region until the external magnet
remains.

Drawbacks:
 Although these systems seem to work, the external
magnet must be positioned with a degree of precision
that might compromise patient compliance.
 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.
b) Floating Time
Test for buoyancy is usually performed in SGF(Simulated Gastric Fluid) maintained at 37 0C.
“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.
2)Swelling system

1)Swelling Index

2)Water Uptake / Weight Gain

WU = (Wt – Wo) * 100 / Wo

3)Penetration Rate

Water Uptake 2 r2

PR = X Water Density
Per Unit Time
 Swelling studies :
 Tablets weighed individually (W1) and placed in Petri dishes containing 15ml of 0.1N HCl.
At regular intervals they are removed from Petri dishes and excess surface water was
removed using filter paper The swollen tablets were reweighed (W2).
 The swollen tablets are dried at 60° C at 24hrs in an oven and kept in desiccators for 24hrs
and reweighed (W3).

Degree of swelling = W2 - W1 W1
%Erosion = W1 - W3 X 100 W1
3)Bio/ Muco adhesive system: Force measuring
Bioadhesion strength device
(modified precision
measurement
balanceOr
Upper automated
texture
jaw analyzer.

Membran Polyme
e r
Lower
jaw
 Methods to measure gastroretentivity
of GRDFs
Magnetic Resonance Imaging
•Itis a non invasive 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 super para magnetic 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.
•This method if the state of art in preclinical evaluation of gastro
retentivity.
•Its major advantages as compared to γ-Scintigraphy are simplicity
and cost.
•However, use of X-ray is declined due to strict limitations, regarding
the
amount of exposure and it’s often requirement in high quantity.
•A commonly used contrast agent is barium sulphate.
 γ- Scintigraphy
 γ-Emitting radioisotopes compounded into CR-DFs has become the state of art for evaluation
of gastro retentive formulation in healthy volunteers.
 The main drawbacks of γ-Scintigraphy are the associated ionizing radiation for the patient, the
limited topographic information, low resolution inherent to the technique then the complicated
and expensive preparation of radiopharmaceuticals.
Gastroscopy
 It comprises of perusal endoscopy, used with a fibreoptic and video systems.
 It is suggested that gastroscopy may be used to inspect visually the effect of prolonged stay in
stomach milieu on the FDDS.
 Alternatively, FDDS may be drawn out of the stomach for more detailed evaluation.
Ultrasonography
 Ultrasonic waves reflected substantially different acoustic impedances across interface enable
the imaging of some abdominal organs.
 Most DFs do not sharp acoustic mismatches across their interface with the physiological
milieu. Therefore, ultra sonography is not routinely used for the evaluation of
FDDS.
 The characterization included assessment of intragastric location of the hydrogels, solvent
penetration into the gel and interactions between gastric wall and FDDS during
peristalsis.
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.
Marketed Products of GRDDS
Brand name Delivery system Drug (dose) Company name

Valrelease® Floating capsule Diazepam (15mg) Hoffmann-LaRoche,

USA

Madopar® HBS Floating, CR capsule Benserazide (25mg) and L- Roche Products, USA
(Prolopa® HBS) dopa (100mg)
Liquid Gaviscon® Effervescent Floating liquid Al hydroxide (95 mg), Mg GlaxoSmithkline,
alginate preparations Carbonate (358 mg) India

Topalkan® Floating liquid alginate Al – Mg antacid Pierre Fabre Drug,

Preparation France
Conviron® Colloidal gel forming Ferrous sulphate Ranbaxy, India
FDDS
Cytotech® Bilayer floating capsule Misoprostol (100μg/200μg) Pharmacia, USA

Cifran OD® Gas-generating floating Ciprofloxacin (1gm) Ranbaxy, India

form
 CONCLUSION
 Gastroretentive drug delivery systems are the most
preferable systems in order to deliver the drugs which
have a narrow absorption window near the gastric
region.
 Now a days a number of drug delivery devices are

being developed which aim at releasing the drug at

gastric region.
 Even though these drug delivery systems have several

advantages they also have disadvantages like their

invitro – invivo correlation is very less.