Gastro retentive drug
delivery systems

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Contents

 Introduction

 Need of Gastric retention

 Advantages

 Disadvantages

 Physiology of Stomach

 Approaches of Gastric retention

 Evaluation of GRDDS

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Introduction

 Oral drug administration has been the predominant route for
drug delivery.

 However, this route has several physiological problems
Including an unpredictable gastric emptying rate that varies
from person to person, a brief gastrointestinal transit time
(80-12h), and the existence of an absorption window in the
upper small intestine for several drugs.

 One novel approach in this area is GRDDSs (gastro retentive
drug delivery system). Dosage forms that can be retained in
the stomach are called GRDDs.

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 GRDDS are designed to delay gastric emptying.

 Prolonging the gastric retention of the drugs is sometimes
desirable for achieving therapeutic benefits of drug that are
absorbed from the proximal part of the GIT (gastro
intestinal tract) or those are less soluble in or are degraded
by alkaline pH or they encounter at the lower part of the
GIT.

 Gastric residence time is time which a drug resides in

stomach.

 Depends upon fluid and food intake.

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GRDDS are beneficial for such drugs by improving their

 Bioavailability

 Therapeutics efficiency and

 Possible reduction of the dose.

Apart from these advantages, these systems offer various
pharmacokinetic advantages like,

 maintenance of constant therapeutic levels over a prolonged
period and thus reduction in fluctuation in the therapeutic
levels

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Physiology Of The Stomach

 Located between the esophagus and the small intestine.

 Under fasting conditions, the stomach is a collapsed bag
with a residual volume of approximately 50ml and
contains a small amount of gastric fluid (pH 1–3) and air.

 Movements are in lower part.

 State of continuous motility is there.

 Two modes are there namely Inter digestive motility and
digestive phase.

 The inter digestive motility pattern is commonly called
the ‘migrating motor complex (MMC).

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DIFFERENT FEATURES OF STOMACH

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

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Migrating motor complexes
 Help trigger peristaltic waves which facilitate

transportation of indigestible substances from the
stomach, through the small intestine past the ileocecal
sphincter into the colon.

 The MMC originates in the stomach roughly every 75–90
minutes during the interdigestive phase (between meals)

 The MMC is thought to be partially regulated by motilin
which is initiated in the stomach as a response to vagal
stimulation.

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 Composed of four phases.

 Each cycle last for 90-120 min.

 The concentration of the hormone motilin in the blood
controls the duration of the phases.

 Phase I is resting phase/basal phase, the quiescent period
lasts from 30-60 minutes and is characterised by lack of
any secretory and electrical activity and contractile
motions.

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 Phase II exhibits intermittent action potential for 20-
40 minutes with increasing contractile motions. Bile
enters the duodenum during this phase while the
gastric mucus discharge occurs during the later part of
phase II and through out phase III

 Phase III strong electronic waves are generated,
grinding process is there and it propagate for 10 -20
minutes.

 Phase IV is the transition period of 0-5 minutes
between phase III and Phase I

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 Food is reduced to particles of less than 1mm diameter
that are emptied through the pylorus as a suspension.

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Gastro retention is done for:

 Drugs that absorb from stomach ( Levodopa,
Furosemide).

 Acting locally in stomach (Antacids, Antiulcer and
Enzymes).

 Antibiotic therapy.

 Poorly soluble at alkaline pH.( Diazepam, Salbutamol)

 Degrade in colon. (Captopril, Ranitidine, Metronidazole)

 Narrow window of absorption

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Commonly used drugs in formulation of
gastroretentive dosage forms

Sr. Dosage form Drug
No.
1 Floating Aspirin, griseofulvin, p-nitroaniline,

microspheres ibuprofen,terfinadine and Tranilast
2 Floating Diclofenac sodium, indomethacin and

granules prednisolone
3 Floating Chlordiazepoxide hydrogen chloride,

capsules diazepam,furosemide, misoprostol, L-dopa,
benserazide, ursodeoxycholic acid and
pepstatin

4 Floating tablets Acetaminophen, acetylsalicylic acid,
and pills ampicillin, amoxycillin trihydrate, atenolol,

diltiazem, fluorouracil, isosorbide
mononitrate, paminobenzoic acid,
theophylline and verapamil 15

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Gastric retention is unsuitable for:

 Drugs having limited acid solubility. (Phenytoin)

 Instable in gastric conditions. ( Erythromycin)

 Extensive first pass metabolism.

Factors affecting gastric retention of dosage forms

 Density,

 Size

 Shape

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Other Drugs affecting transit time

 Increase transit time.

( Opiates, Anti cholinergic agents)

 Decrease in transit time.

( Prokinetic agents e.g. cisapride)

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Gastric emptying time

Factors affecting gastric emptying-

 Particle size

 Feeding state

 Type of meal and its caloric content

 Volume and viscosity

 Increase in acidity, osmolarity and calorific value and a state of depression

slow down gastric emptying

 Stress increases gastric emptying

 Females have slower emptying rate than males

 Obesity and age

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Gastric emptying time Contd.

Liquids
 Fasted condition- The larger the volume, the faster the emptying,
about 8-12 min

 Fed Condition- Emptying time can be increased

Solids
 Fasted condition- All solid dosage forms are emptied quickly
(approx. in 1 hour)
 Fed Condition- Emptying time can be significantly increased
(as long as 10 hours)

 Size of the dosage form

 Mean diameter of the pylorus is 12.8 ± 7 mm

Non-disintegrating formulations with size excess than that of the mean
pyloric diameter can be retained

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Advantages of GRDDS

 Improvement of bioavailability and therapeutic efficacy of the
drugs and possible reduction of dose e.g. Furosemide

 Maintenance of constant therapeutic levels over a prolonged
period and thus reduction in fluctuation in therapeutic levels
minimizing the risk of resistance especially in case of
antibiotics. e.g. b-lactam antibiotics (penicillins and
cephalosporins)

 Retention of drug delivery systems in the stomach prolongs
overall.

 Gastrointestinal transit time thereby increasing bioavailability
of sustained release delivery systems intended for once-a-day
administration. e.g. Ofloxacin

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Disadvantages of GRDDS

 The floating systems in patients with achlorhydria can be
questionable in case of swellable systems, faster swelling
properties are required and complete swelling of the
system should be achieved well before the gastric
emptying time.

 Bioadhesion in the acidic environment and high turnover
of mucus may raise questions about the effectiveness of
this technique. Similarly retention of high density systems
in the antrum part under the migrating waves of the
stomach is questionable.

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 Not suitable for drugs that may cause gastric lesions e.g.

Non- steroidal anti inflammatory drugs. Drugs that are

unstable in the strong acidic environment, these systems

do not offer significant advantages over the

conventional dosage forms for drugs, that are absorbed

throughout the gastrointestinal tract.

 The mucus on the walls of the stomach is in a state of

constant renewal, resulting in unpredictable adherence.

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Approaches for gastric retention

 Floating drug delivery systems

 Mucoadhesive systems

 Swellable System

 High density systems.

 Magnetic systems.

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Floating drug delivery systems

 These are low density systems.

 Have ability to float over gastric contents.

 The drug is released from the system at desired rate.

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Floating Drug Delivery System

 Formulation and technological point of view,

the floating drug delivery system (FDDS) is considerably
easy and logical approaches in development of
Gastroretentive dosage forms.

 Factors controlling gastric retention time of
dosage
 Density of dosage form

 Size of the dosage form,

 Food intake, nature of the food,

 Effect of gender, posture, age

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Floating Drug Delivery System

 DENSITY OF THE DOSAGE FORM

 Dosage forms having density lower than that of the
gastric fluids

 A density of <1.0 gm/cm3 is required to
exhibit the floating property

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Floating Drug Delivery System

 SIZE OF THE DOSAGE FORM

 In fed conditions, the smaller units get emptied from
the stomach during the digestive phase

 In most cases,

the larger the size of the dosage form, the greater
will be the gastric retention time,

because the larger size would not allow the dosage
form to quickly pass through the pyloric antrum into
the intestine.

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Floating Drug Delivery System

 FOOD INTAKE AND NATURE OF THE FOOD
 Usually the presence of food increases the GRT (Gastric

retention time) of the dosage form and increases drug
absorption by allowing it to stay at the absorption site
for a longer time.

 In a gamma scintigraphic study of a bilayer floating
capsule of misoprostol,

Mean Gastric Residence Time

after a light breakfast after the meal

199 ± 69 minutes 618 ± 208 minutes

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Floating Drug Delivery System

 EFFECT OF GENDER, POSTURE AND AGE
 Females showed comparatively shorter mean ambulatory GRT

than that of the males

 In the upright position, the floating systems floated to the top of
the gastric contents and remained for longer time, showing
prolonged GRT.

 Because of the changes in physiology with increasing age and the
hormonal responses responsible for gastric emptying, the GRT of
the dosage forms may vary with the age of the individual.

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Floating Drug Delivery System
Approaches

 Non Effervescent System
 Hydro dynamically Balanced System (HBS)

 Micro particulate system

 Micro porous Compartment system

 Intragastric osmotic controlled drug delivery system

 Raft Forming system

 Effervescent System
 Gas-generating system

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Formulation of this device must comply
with the following criteria

 It must have sufficient structure to form a cohesive gel
barrier.

 It must maintain an overall specific gravity lower than
that of gastric contents (1.004 – 1.010).

 It should dissolve slowly enough to serve as a drug
reservoir.

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Floating Techniques

 Effervescent
 Volatile liquid containing systems

 Gas generating systems

 Non-Effervescent
 Colloidal gel barrier systems

 Alginate beads
 Hollow Microspheres

 Microporous Compartment System

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Effervescent systems

1. Gas generating systems

 Effervescence is there.

 Utilizes effervescent reactions between
carbonate/bicarbonate salts and citric/tartaric acid.

 CO2 is released in presence of H2O.

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 When tablet is put in beaker it will sink

 2NaHCO3+C4H6O6 C4H4Na2O6+2CO2+2H2O

 With production of gas it rises up and floats.

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2. Volatile liquid containing systems

 Incorporates an inflatable chamber, which contains a liquid
e.g. ether, cyclopentane, that gasifies at body temperature
to cause the inflatation of the chamber in the stomach.

 The device may also consist of a bioerodible plug made up
of PVA, Polyethylene, etc. that gradually dissolves causing
the inflatable chamber to release gas and collapse after a
predetermined time to permit the spontaneous ejection of
the inflatable systems from the stomach.

 There systems are very less used as the gas generating
systems are more safe.

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Non-effervescent systems
1. Colloidal gel barrier systems

 Such systems contains drug with gel forming
hydrocolloids meant to remain buoyant on stomach
contents.

 These systems incorporate a high level of one or more
gel forming highly Swellable cellulose type hydrocolloids.
e.g.HEC, HPMC, NaCMC.

 On coming in contact with gastric fluids forms a viscous
core.

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 Incorporates H2O and entraps air.

 Density of system falls below 1gm/cm3. Then it starts
floating

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2. Microporous membrane systems

 Based on the encapsulation of drug reservoir inside a
Microporous compartment.

 The peripheral walls of the drug reservoir compartment
are completely sealed to prevent any direct contact of the
gastric mucosal surface with the undissolved drug.

 In stomach the floatation chamber containing entrapped
air causes the delivery system to float over the gastric
contents.

 Gastric fluid enters through the apertures, dissolves the
drug, and carries the dissolve drug for absorption.

 Fabrication of pocket is difficult process.

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3. Alginate beads

 Spherical beads of approximately 2.5 mm in diameter can
be prepared by dropping a sodium alginate solution in to
aqueous solutions of calcium chloride, causing
precipitation of calcium alginate.

 Sodium alginate+ Calcium chloride Calcium
alginate+ NaCl

 The beads are then separated snap and frozen in liquid
nitrogen, and freeze dried at -40°C for 24 hours, leading
to the formation of porous system.

 Maintain a floating force of over 12 hours.

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4. Hollow microspheres

 Microballoons / hollow microspheres loaded with
drugs are prepared by simple solvent evaporation
method.

 Commonly used polymers to develop these systems
are polycarbonate, cellulose acetate, calcium alginate,
Eudragit S, agar and pectin etc.

 These systems have capacity to float on acidic
dissolution media containing surfactant for about 12
hours invitro.

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Commercial Gastroretentive Formulation

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Mucoadhesive systems

 Involves the use of bioadhesive polymers, which can
adhere to the epithelial surface in the stomach.

 Dosage form can stick to mucosal surface by following
mechanisms:

1. The wetting theory, which is ability of polymer to
spread and develop intimate contact with the mucous
layers.

2. The diffusion theory, which proposes physical
entanglement of mucin strands into the porous
structure of the polymer substrate.

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3. The absorption theory suggesting that bioadhesion is due
to secondary forces such as Vander walls forces and
hydrogen bonding.

4. The electron theory, which proposes attractive
electrostatic forces between the glycoprotein mucin
network and the bio adhesive material.

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Cationic Anionic Neutral

Polybrene Dextran sodium Dextran

Poly-L-lysine Poly acrylic acid Ficoll

Polylysine Poly L aspartic acid Polyethylene glycol

Polyvinyl methyl Poly glutamic acid Polyvinyl pyrrolidone
imidazole

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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

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Swellable systems

 A dosage form in the stomach will withstand gastric
transit if it bigger than pyloric sphincter, but should be
small enough to be swallowed.

 These systems swells many times its original size.

 Cross linking should be optimum highly cross linked
don’t swell.

 Chitosan, HPMC, sodium starch glycolate, carbopol
are used.

 Diclofenac, Ciprofloxacin, Furosemide are reported
with these systems.

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High density systems

 These have density greater than that of gastric fluids (1.4
g/cc).

 Above 1.6g/cc is preferable, tend to withstand peristaltic
movements of stomach.

 Zinc oxide, Iron oxide, Titanium dioxide, barium sulfate
are used as inert heavy core.

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 These systems contain a small internal magnet.

 A magnet is placed on the abdomen over the position of
stomach.

 The external magnet should be placed with high degree
of precision.

 Patient compliance is a problem in magnetic systems.

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Evaluation

 It is a tool to ensure
1. Performance characteristics
2. Control batch to batch quality
 GRDDS are evaluated for
 Floating lag time(FDDS)
 Swelling Index
 Total Retention time
 Total Adhesion time (Muco-Adhesive DDS)
 In-vitro Dissolution study
 In-vivo study

 Carried out by means of X-ray or gamma scintigraphic
monitoring of the dosage form transit in the GI tract.
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Floating System

Floating time

 Determined by using the USP dissolution apparatus
containing 900 ml of 0.1 N HCL maintained at 37o C

 The time for which the dosage form floats is termed as
the floating time.

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Muco – Adhesion system

 Measurement of either tensile or shear strength is the
most commonly used invitro method to measure
bioadhesion strength

 Measurement of tensile strength involves quantiting the
force required to break the adhesion bond between the
test polymer and model membrane

 The method typically uses modified balance or tensile
tester

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 A section of freshly excised rabbit stomach tissue with
the mucosal side exposed is secured on a weighed glass
vial and placed in a baker containing USP simulated gastric
fluid

 Another section of same tissue is secured of a rubber
stopper with a vial cap with the mucus side exposed

 A small quantity of test polymer is placed between the
two mucosal tissues the force required to detach the
polymer from the tissue is recorded.

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Bioadhesion strength measurement

Force measuring device

Upper jaw

Polymer
Membrane

Lower jaw

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Swelling systems

Weight gain and water uptake

 Done by immersing the dosage in simulated gastric fluid
at 37oC and determining these factors at regular intervals.

 Dimensional changes can be measured in terms of
increase in the tablet diameter or thickness with time

 Water uptake is measured in terms of %weight gain

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WU = (Wt-Wo) X 100

Wo

Where WU – Water uptake

Wt weight of dosage form at time t

Wo weight of dosage form initially

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