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1. GASTRORETENTIVE DRUG
DELIVERY SYSTEM
(GRDDS)

2. Contents
• Introduction
• Need of Gastric retention
• Advantages
• Limitation
• Physiology of Stomach
• Approaches of Gastric retention
• Market products

3. Gastroretentive drug delivery
“ Is an approach to prolong gastric residence time, thereby
targeting site-specific drug release in the upper
gastrointestinal tract (GIT) for local or systemic effects.”
• Gastric residence time is time which a drug resides in
stomach.
• Depends upon fluid and food intake.
• GRDDS are designed to delay gastric emptying.

4. NEED FOR GRDDS
• Oral drug delivery system
• Sustained drug delivery systems
These drug delivery systems suffer from mainly two adversities:
 short gastric retention time(GRT) and
 unpredictable short gastric emptying time (GET)
•Which can result in incomplete drug release from the dosage form in the
absorption zone or absorption window (upper part of small intestine) leading
to diminished efficacy of administered dose.
•To formulate a site-specific orally administered controlled release dosage
form, it is desirable to achieve a prolong gastric residence time by the drug
delivery.
•Prolonged gastric retention time (GRT) in the stomach and proximal part of
esophagous could be advantageous for local action e.g. treatment of peptic
ulcer, etc.

5. Absorption window

10. LIMITATIONS
• The drug substances that are unstable in the acidic environment of the
stomach are not suitable candidates to be incorporated in the systems.
• These systems require a high level of fluid in the stomach for drug
delivery to float and work efficiently.
• Not suitable for drugs that have solubility or stability problem in GIT.
• Drugs which are irritant to gastric mucosa are also not suitable.
• These systems do not offer significant advantages over the conventional
dosage forms for drugs, which are absorbed throughout GIT.

11. ADVANTAGES
• Enhanced bioavailability because of increased GRT and more time spent
by the dosage form at its absorption site.
• Sustained drug delivery/reduced frequency of Dosing
• Targeted therapy for local ailments in the upper GIT
• Reduced fluctuations of drug concentration
• Extended effective concentration.
• Minimized adverse activity at the colon.
• 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.

13. Physiology of the Stomach
• The stomach is divided into three anatomical region; Fundus, Body
and antrum.
• The proximal stomach consisted of Fundus and body, which serves as a
reservoir for ingested materials.
• Whereas the distal region (antrum) is the major site of mixing , acting
as a pump to propel gastric content for gastric emptying.
• 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.
• Gastric emptying occurs both in fasting as well as fed states.

17. POTENTIALDRUGCANDIDATESFOR
GASTRORETENTIVEDRUGDELIVERY
SYSTEMS
• 1. Drugs acting locally in the stomach(active in stomach)
e.g.Antacids and drugs for H. Pylori viz., Misoprostol
• 2. Drugs that are primarily absorbed in the stomach
e.g.Amoxicillin
• 3. Drugs that are poorly soluble at alkaline pH
e.g. Furosemide, Diazepam,Verapamil, etc.
• 4. Drugs that degrade in the colon.
e.g. Ranitidine, Metformin HCl.

18. • 5. Drugs with a narrow absorption window.
e.g. Cyclosporine, Methotrexate, Levodopa, etc.
• 6. Drugs which are absorbed rapidly from the GI tract.
e.g. Metronidazole, tetracycline.
• 7. Drugs that disturb normal colonic microbes
e.g. antibiotics against Helicobacter pylori.

19. DRUGS UNSUITABLE FOR GRDDS
1) Drugs that have very limited acid solubility
phenytoin etc.
2) Drugs that suffer instability in the gastric environment e.g.
erythromycin etc.
3) Drugs intended for selective release in the colon
5-amino salicylic acid and corticosteroids etc.
4) Extensive first pass metabolism
e.g. Nifedipine).
5)Drugs that are degraded in acidic environment of stomach (e.g. Insulin).
6) Retention in the stomach is not desirable for drugs that cause gastric
lesions (e.g. Non- steroidal anti-inflammatory drugs NSAIDs).

24. FACTORSAFFECTINGTHE GASTRORETENTIVE
SYSTEM.
1. DENSITY(should be less than the gastric contents
1.004gm/ml)) .
2. SIZE.
3. SHAPE OF DOSAGE FORM.
4. FED OR UNFED STATE.
5. NATURE OF MEAL
6. FREQUENCY OF FEED
7. GENDER.
8. AGE.
9. POSTURE.
10. CONCOMITANT DRUG.
11. BIOLOGICAL FACTORS.

25. Approaches for gastric retention
• Floating drug delivery systems (low density)
• Mucoadhesive systems
• Swellable Systems (Plug system) expension
• High density systems (Sinking system) sedimentation
(not use now).
• Magnetic system
• Modified shape ( receptor bind)
• Slow down parastalting movement
By simultaneous administration of pharmacological agents
that delay emptying.

27. Floating drug delivery systems
• These are low density systems.
• They remain floating in the stomach for a prolonged period of time,
with the potential for continuous release of drug
• It must maintain an overall specific gravity lower than that of gastric
contents (1.004 – 1.010 gm/cm3).
• Have ability to float over gastric contents.
• The drug must have sufficient structure to form a cohesive gel barrier.
•The inherent low density can be provided by the
Entrapment of air (e.g. hollow chambers) or
By the incorporation of low density materials (e.g. fatty materials or
oils, or foam powder).
• Multiple unit floating preffered over single unit dosage because of dose
dumping.

28. FloatingTechniques
Effervescent
• Volatile liquid containing systems
• Gas generating systems
Non-Effervescent
• Colloidal gel barrier systems
• Alginate beads
• Hollow Microspheres
• Microporous Compartment System
• Raft forming system/ magnetic system

30. Effervescent systems
produce gases within system density decreased
and float.
1.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.
• CO2 is released in presence of H2O.
• When tablet is put in beaker it will sink
2NaHCO3+C4H6O6 C4H4Na2O6+2CO2+2H2O
• With production of gas it rises up and floats.

31. • 4 layered system

33. 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 polymer 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.
• Polymer degrade after 24hr.
2 chambers:
• 1.Reservoir for drug
• 2.Reservoir for volatile oil
• 3. coating of these chamber with porous membrane polymer
V.O chamber (Inflatable chamber) is loaded with a drug reservoir which can be
a drug, impregnated with polymeric plug then encapsulated in a gelatin capsule.
• These systems are very less used as the gas generating systems are more safe.

35. Non-effervescent systems
• Prepared from gel-forming or highly swellable cellulose type
hydrocolloids, polysaccharides or matrix forming polymers
like polyacrylate, polycarbonate, polystyrene and
polymethacrylate.
•The air trapped by the swollen polymer confers buoyancy to
these dosage forms.
•Excipients used are HPMC, polyacrylates, polyvinyl acetate,
carbopol, agar, sodium alginate, calcium chloride,
polyethylene oxide and polycarbonates.

36. 1.Colloidal gel barrier systems
• Such systems contains drug with gel forming hydrocolloids meant to
remain buoyant on stomach contents.
• Also called Hydrodynamically balanced system.
• 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.
• Incorporates H2O and entraps air.
• Density of system falls below 1gm/cm3.Then it starts floating.
DRUG + GEL- FORMING HYDROCOLLOID= BUOYANT

38. 2.Microporous membrane systems
• Based on the encapsulation of drug reservoir inside a
Microporous compartment with pores along its top and
bottom walls.
• 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.

41. 3.Alginate beads
• Multiple unit floating dosage forms have been developed from freeze-dried
calcium alginate.
• 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 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.
• These beads improve gastric retention time (GRT) more than 5.5 hours.

42. 4.Hollow microspheres
• Microballoons / hollow microspheres loaded with drugs are prepared by
simple solvent evaporation method or diffusion. multiple unit
• Commonly used polymers to develop these systems are polycarbonate,
cellulose acetate, calcium alginate, Eudragit S, agar and pectin etc.have
ability to give hollow nature.
• Buoyancy and drug release depends on quantity of polymers, and
solvents used.
• These systems have capacity to float on acidic dissolution media containing
surfactant for about 12 hours in vitro.
• Are the best because they combine the advantages of multiple-
unit system and good floating.

44. HIGH DENSITY SYSTEM
• Gastric contents have a density close to water ( 1.004 g cm−3).
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.
• A density close to 2.5 g cm−3 seems necessary for significant
prolongation of gastric residence time.
• Barium sulphate , zinc oxide, iron powder, and titanium
dioxide are examples for excipients used.
• Not use now because they cause defective absorption of
mucous of layer.
• density of system is 3 then cant use.

45. Mucoadhesive systems
 Delivery device within the human to enhance drug absorption in a
site-specific manner.
• Bio adhesive polymers used which adhere to the epithelial surface in
the stomach & improves the prolongation of gastric retention.
• The basis of mucoadhesion is that a dosage form can stick to the
mucosal epithelial surface by different mechanisms.
• Materials commonly used for bioadhesion are polyacrylic acid,
chitosan, cholestyramine, sodium alginate, hydroxypropyl
methylcellulose (HPMC), sucralfate, tragacanth, dextrin, polyethylene
glycol and polylactic acids etc.

52. Swellable systems / Expandable/
suprahydrogells
• 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 when incontact with git fluid.
• Must not cause gastric obstruction.
• The swelling is usually results from osmotic absorption of water.
• The device gradually decreases in volume and rigidity as a result of depletion of
drug and expanding agent and/or bioerosion of polymer layer, enabling its
elimination.
• Polymer Cross linking is hydrophilic should be optimum highly cross linked
swell.
• Chitosan, HPMC, sodium starch glycolate, carbopol are used.
• Ciprofloxacin, Furosemide are reported with these systems.
• Plug like linked with ion exchanged.

54. Super porous hydrogels
• In this approach to improve gastric retention time (GRT) super
porous hydrogels of average pore size >100 micro meter is used.
• Super porous hydrogels will swell to equilibrium size within a
minute due to rapid water uptake by capillary wetting through
numerous interconnected open pores.
• They swell to a large size and are intended to have sufficient
mechanical strength to withstand pressure by gastric contraction.
• This is achieved by co-formulation of a hydrophilic particulate
material, andAc-Di-Sol (cross carmellose).

56. MAGNETIC SYSTEM
• 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.

63. Evaluation of GRDDS
Floating drug delivery systems
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.

64. Muco –Adhesive system
• Measurement of either tensile or shear strength is the most
commonly used in vitro method to measure bioadhesion
strength.
• Measurement of tensile strength involves quantizing the force
required to break the adhesion bond between the test
polymer and model membrane.
• The method typically uses modified balance or tensile tester.

65. 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
weight with time.
• Water uptake is measured in terms of %weight gain
WU = (Wt-Wo) X 100
Wo
WhereWU –Water uptake
Wt weight of dosage form at time t
Wo weight of dosage form initially

66. Commonly used drugs in formulationof
gastroretentive dosages forms
 Floating tablets
 Floating capsules
 Floating microspheres
 Floating granules
 Ampicillin, Amoxicillin trihydrate,
 Atenolol, Captopril.
 Chlorpheniramine maleate, Cipro.
 Diltiazem, Fluorouracil, Isosorbide
dinitrate and mononitrate,
 PABA, Prednisolone,
 Theophylline, Verapamil
 Diazepam,
 Furosemide, L-DOPA
 Nicardipine, Misoprostol, Propranolol,
 Griseofulvin, p-nitro aniline,

67. Marketed Products of GRDDS
Brand name Delivery system Drug (dose) Company
name
Valrelease® Floating capsule Diazepam (15mg) Hoffmann-LaRoche,
USA
Madopar® HBS
(Prolopa® HBS)
Floating, CR capsule Benserazide (25mg) and L-
dopa (100mg)
Roche Products,
USA
Liquid Gaviscon® Effervescent Floating
liquid alginate
preparations
Al hydroxide (95 mg), Mg
Carbonate (358 mg)
GlaxoSmithkline,
India
Topalkan® Floating liquid alginate
Preparation
Al – Mg antacid Pierre Fabre Drug,
France
Conviron® Colloidal gel forming
GRDDS
Ferrous sulphate Ranbaxy, India
Cytotech® Bilayer floating capsule Misoprostol (100μg/200μg) Pharmacia, USA
Cifran OD® Gas-generating floating
form
Ciprofloxacin (1gm) Ranbaxy, India