GRDDS By Mali Vidhya Vijaykumar.

1. Gastro-retentive Drug Delivery System
By,
Mrs. Mali Vidhya Vijaykumar
Assistant Professor,
R. P. College of Pharmacy
Osmanabad.

2. Contents
 Introduction.
 Anatomy of stomach
 Advantages of GRDDS.
 Disadvantages of GRDDS.
 Factors controlling gastro-retentive dosage forms.
 Approaches for GRDDS
 Floating drug delivery system.
 Bioadhesive or mucoadhesive drug delivery system.
 Expandable, unfoldable and swellable system.
 High density system
 Applications of gastroadhesive system.

3. Introduction
 Gastro-retentive drug delivery system (GRDDS) has gained immense
popularity in the field of oral drug delivery recently.
 It is a widely employed approach to retain the dosage form in the stomach
for an extended period of time and release the drug slowly that can address
many challenges associated with conventional oral delivery, including poor
bioavailability.
 Different innovative approaches like magnetic field assisted gastro-
retention, plug type swelling system, muco-adhesion technique, floating
system with or without effervescence are being applied to fabricate
GRDDS.
Definition:
“Gastroretentive drug delivery system is defined as, one of the site
specific drug delivery system at the stomach it is obtained by
retaining dosage form into stomach and drug is being released at
sustained manner to a specific site either in stomach or intestine.”

4. GRDDS
Dosage form that can be retained in stomach for longer duration that
can be called as Gastroretentive drug delivery system.
a. Conventional systems v/s b. Gastro-retentive drug
delivery systems

5. Anatomy of stomach
 Stomach is a muscular organ located on
the left side of the upper abdomen.
 Stomach is a J shaped enlargement of the
GI tract, connects the oesophagus to the
duodenum.
 Stomach receives food from oesophagus .
 Stomach is the first part of small intestine.
 Stomach secrets acid and enzymes that
digest food.

6. Anatomy of stomach
Stomach is devided into four sections.
 Cardia: where the contents of the oesophagus empty into the stomach.
 Fundus: is formed in the upper curved part of stomach.
 Body: is the main and central region of the stomach.
 Pylorus: is the lower section of the stomach that empties content to the
duodenum.

7. Advantages of GRDDS
 Enhances bioavailability.
 Sustained release of drug by prolonged gastric retention time.
 Site specific or targeted delivery of drug.
 Reduction in dosing frequency.
 Improves patient compliance & Suitable for self administration.
 Minimization of side effects.
 Enhances therapeutic effectiveness.
 Local release of drugs to treat stomach and duodenal ulcers, gastritis and
esophagitis.
 Reduced the risk of stomach carcinoma.
 Various antibiotics, antiviral and antifungal agents can be successfully
administered: e.g., sulphonamides, quinolones, penicillins,
cephallosporines, aminoglycosides and tetracyclines etc.

8. Disadvantages of GRDDS
 Retention in stomach is not desirable for the drugs which cause gastric
lesions/irritations e.g., NSAIDs
 Drugs that may irritates the gastric lining or are unstable in gastric
environment should not be formulated in GRDDS.
 Drugs absorbed by GIT will not be suitable for gastric retention system.
 These systems require a high level of fluid in the stomach for drug delivery
to float and work efficiently.
 Requires the presence of food to delay gastric emptying.
 Drugs which undergo significant first-pass metabolism, may not be
desirable for GRDDS.
 Slow gastric emptying may lead to alter systemic bioavailability.
 Drugs having solubility or stability problems in highly acidic gastric
environment can not be formulated as GRDDS.

9. Factors controlling gastro-retentive dosage forms
Factors
controlling
gastro-retentive
dosage forms
Shape and size
of the
dosage
form
Density of dosage
Effect of gender,
posture and
age
Food intake
and its
nature

10. Factors controlling gastro-retentive dosage forms
Density of dosage:
¤ Dosage form having density lower than gastric fluid shows floating
behaviour and hence gastric retention.
¤ Density ˂1 gm/ml is required for floating.
¤ Floating tendency of dosage form usually decrease with time as dosage
form gel immersed in the gastric fluid, as a result of the development of
hydrodynamic equillibrium.
Shape and size of the dosage form:
¤ The mean gastric residence time of non-floating dosage forms are
highly variable and dependent on their size which may be large,
medium and small units.
¤ In some dosage form, the larger the dosage form the greater will be the
gastric retention time (GRT) due to larger size dosage form cannot
quickly pass through pyloric antrum into the intestine.
¤ Ring shaped and tetrahedron shaped devises has better GRT as
compared to other shapes.

11. Factors controlling gastro-retentive dosage forms
Food intake and its nature:
¤ Nature of food, caloric content, and frequency of feeding may affect
GRT of dosage form.
¤ Presence and absence of food in the stomach may influence GRT of
dosage form.
¤ Presence of food increases the GRT of dosage form.
Effect of gender, posture and age:
¤ Generally females have lower gastric emptying rate than male.
¤ The effect of posture does not have any significant difference in the
mean GRT for individual in upright, ambulatory and supine state.
¤ In case of elderly persons, gastric emptying is slowed down.

12. Gastrointestinal dynamics
 The GIT is always in a state of continuous motility.
 There are two modes of motility pattern:
 the digestive mode and interdigestive (fasting) mode involved in
digestion of food.
 Migrating Myoelectric Complex: In fasting state, it is characterized by
an interdigestive series of electrical events which cycles both through
stomach and small intestine every 2-3 hrs.
MMC is divided into 4 phases;
1. Phase I: No contraction and secretion.
2. Phase II: Intermitent contraction and
bile secretion.
3. Phase III: “Housekeeper waves”
serves to sweep undigested food
materials out of the stomach.
4. Phase IV: Transition period between
Phase III & Phase I.

13. Potential drug candidates for gastroretentive drug
delivery systems
1) Drugs those are locally active in the stomach:
e.g., misroprostol, antacids etc.
2) Drugs that have narrow absorption window in gastrointestinal tract
(GIT):
e.g., L-DOPA, para-aminobenzoic acid, furosemide, riboflavin etc.
3) Drugs those are unstable in the intestinal or colonic environment:
e.g., captopril, ranitidine HCl, metronidazole etc.
4) Drugs that disturb normal colonic microbes:
e.g., antibiotics against Helicobacter pylori etc.
5) Drugs that exhibit low solubility at high pH value:
e.g., diazepam, chlordiazepoxide, verapamil HCl etc.

14. Drugs those are unsuitable for gastroretentive drug
delivery systems
1) Drugs that have very limited acid solubility:
e.g., phenytoin etc.
2) Drugs that suffer instability in the gastric environment:
e.g., erythromycin etc.
3) Drugs intended for selective release in the colon:
e.g., 5- amino salicylic acid and corticosteroids etc.

15. Approaches for GRDDS
1. Floating drug delivery system
2. Mucoadhesive system
3. Swellable drug delivery systems
4. High density drug delivery system
A. Effervescent B. Non-effervescent
a) Gas generating system
b) Volatile liquid containing system
c) Inflatable GI delivery System
d) Intragastric osmotically controlled DDS
a) Colloidal gel barrier system
b) Alginate beads
c) Hollow microspheres
d) Microporous compartment system.

16. Approaches for GRDDS

17. Floating drug delivery system.
 Floating drug delivery system (FDDS) have a bulk density lower than
gastric fluid & thus remains buoyant in stomach for prolonged period of
time, without affecting the gastric emptying rate.
 While the system floats on gastric contents, the drug is released slowly at a
desired rate from the system.
 After release of drug the residual system is emptied from the stomach.
 This results in an increase in gastric retention time and a better control of
fluctuation in plasma drug concentrations.
Floating drug delivery system (FDDS) can be
classified into distinct categories:
1. Effervescent system
2. Non-Effervescent system

18. Floating drug delivery system.
1. Effervescent system
a) Gas generating system
b) Volatile liquid containing system
c) Inflatable GI delivery System
d) Intragastric osmotically controlled
DDS
2. Non-Effervescent system
a) Colloidal gel barrier system
b) Alginate beads
c) Hollow microspheres
d) Microporous compartment
system.

19. a. Gas generating system
Intra-gastric single layer floating tablets or hydrodynamically balanced system
(HBS).
• These type of system can be formed by mixing drug and CO2 generating
agent within the matrix.
• These having bulk density lower than gastric fluids and therefore remain
floating in the stomach unflattering the gastric emptying rate for prolonged
period of time.
• The drug is slowly released at a constant and desired rate from the floating
system and after the complete release the residual system is expelled from
the stomach.
• This leads to an increase in gastric retention time and a better control on
fluctuation in plasma drug concentration.
1. Effervescent system

20. a. Gas generating system
 Floating to a system can also be produced by the gas bubble generation.
 For this, carbon dioxide is generated within the system by incorporating
carbonates and bicarbonate,
 Carbonates or bicarbonates, which will reacts with gastric acid or any
other acid (like citric or tartaric acid) present in the formulation to produce
CO2,
 thus reducing the density of the formulation and making it float on the
media.
1. Effervescent system

21. Intra-gastric single layer floating tablets
 These are also compressed tablets
which containing two layers i.e.,
1. Immediate release layer.
2. Sustained release layer.
Intra-gastric bilayer floating tablets
 These are also compressed tablets
which containing only one layers i.e.,
1. Sustained release layer.

22. b. Volatile liquid/vacuum containing system
 These systems can be made to float in the stomach because of
floatation chamber which may be volatile liquid (ether), vacuum or
filled with air or a harmless gas,
 while drug reservoir is encapsulated inside a microporous
compartment.

23. c. Inflatable gastrointestinal delivery system
 In these systems, an inflatable chamber is incorporated which contain
liquid ether that evaporates at body temperature to cause the chamber to
inflate in the stomach.
 Systems can be fabricated by loading the inflatable chamber with a drug
reservoir which can be a drug impregnated polymeric matrix, then
encapsulated in a gelatin capsule.
 After the oral administration, the capsule dissolves to release the drug
reservoir together with the inflatable chamber.
 the inflatable chamber automatically inflates and retains the drug reservoir
compartment in the stomach.
 Drug continuously release from the reservoir into the gastric fluid.

24. d. Intra-gastric osmotically controlled drug delivery system
 It comprised of an osmotic pressure controlled drug delivery device and
an inflatable floating support in a biodegradable capsule.
 In the stomach, the capsule quickly disintegrates to release the intragastirc
osmotically controlled drug delivery device.
 The inflatable support located inside forms a deformable hollow
polymeric bag that contains a liquid which gasifies at body temperature to
inflate the bag.
The osmotic pressure controlled drug delivery device consists of
two components;
A. Drug reservoir compartment
B. Osmotically active compartment

25. d. Intra-gastric osmotically controlled drug delivery system
 The drug reservoir compartment is enclosed by a pressure responsive
collapsible bag which is permeable to vapour and liquid and has a drug
delivery orifice.
 The osmotically active compartment contains osmotically active salt and is
enclosed within semi-permeable housing.
 In stomach water is continuously absorbed by the system into osmotically
active compartment to dissolve the osmotically active salt.
 Thus osmotic pressure created which acts on collapsible bag which forces the
drug reservoir compartment to release the drug solution through delivery
orifice.

26. d. Intra-gastric osmotically controlled drug delivery system
 The floating support is also made to contain a bioerodible plug that
erodes after a predetermined time to deflate the support.
 The deflated drug delivery system is then emptied from the stomach.

27. a. Colloidal gel barrier system
 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., HPMC, NaCMC.
 On coming in contact with gastric fluids forms a viscous core.
 Incorporates H2O and entraps air.
 Density of system falls below 1 gm/cm3. Then it starts floating.
1. Non-Effervescent systems

28. b. Microporous membrane system
 Based on encapsulation of drug reservoir inside a microporous
compartment with pores along its top and bottom walls.
 The peripheral walls of the device were completely sealed to present any
direct contact of the gastric surface with the undissolved drug.
 In the stomach the floatation chamber containing entrapped air causes the
delivery system to float in the gastric fluid.
 Gastric fluid enters through the aperture, dissolves the drug and causes
the dissolved drug for continuous transport across the intestine for drug
absorption.
Gastric
fluid
Solid
drug
Stomach
Microporous
compartment
Microporous
compartment
Dissolved drug

29. c. Alginate beads
 Spherical beads of approximately 2.5 mm in diameter can be prepared by
dropping a sodium alginate solution into 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.

30. d. Hollow Microspheres
 Microballoons / hollow microspheres loaded with drugs in their other
polymer shelf were prepared by simple solvent evaporation or solvent
diffusion / evaporation methods to prolong the gastric retention time
(GRT) of the dosage form.
 Commonly used polymers to develop these systems are polycarbonate,
cellulose acetate, calcium alginate, Eudragit S, agar and low methoxylated
pectin etc.
 The microballoons floated continuously over the surface of an acidic
dissolution media containing surfactant for >12 hours in-vitro.

31. Bioadhesive or mucoadhesive drug delivery system
 Bioadhesive or mucoadhesive drug delivery systems are used to enhance
site specific absorption of drug.
 In this approach bioadhesive polymers are used and they can adhere to
the epithelial surface in the stomach.
 Thus they improve the prologation of gastric retention.

32. Bioadhesive or mucoadhesive drug delivery system
Adhesion of the polymeric system to the mucosal surface can occur by different
mechanisms:
 Different Stages involved in mechanism of Mucoadhesion are;
1. Contact stage
2. Consolidation stage
 Different theories involved in mechanism of mucoadhesion are;
A. Wetting theory
B. Diffusion theory
C. Adsorption theory
D. Electronic theory
E. Mechanical theory
F. Cohesive theory
Material used for bioadhesion: polyacrylic acid, chitosan, cholestyramine,
sodium alginate, HPMC, tragacanth, dextrin, polyethylene glycol (PEG),
sucralfate and polylactic acid etc

33. Expandable, unfoldable and swellable system
 A dosage form in the stomach will withstand gastric transit if it bigger than
pyloric sphincter. However, the dosage form must be small enough to be
swallowed, and must not cause gastric obstruction either singly or by
accumulation.
Thus, their configurations are required to develop an expandable system to
prolong gastric retention time (GRT):
 1) a small configuration for oral intake,
 2) an expanded gastroretentive form, and
 3) a final small form enabling evacuation following drug release from the
device.

34. Expandable, unfoldable and swellable system
 Unfoldable systems are made of biodegradable polymers.
 They are available in different geometric forms like tetrahedron,
ring or planner membrane (4 - label disc or 4 - limbed cross form) of
bioerodible polymer compressed within a capsule which extends in
the stomach.

35. Expandable, unfoldable and swellable system
• Swellable systems are also retained in the gastro intestinal tract
(GIT) due to their mechanical properties.
• The swelling is usually results from osmotic absorption of water and
the dosage form is small enough to be swallowed by the oral route
to gastric fluid.

36. Swellable/Superporous hydrogel system
 These swellable systems differ sufficiently from the conventional types to
warrant separate classification.
 In this approach to improve gastric retention time (GRT) super porous
hydrogels of average pore size >100 micro miter, 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 (swelling ratio: 100 or more) and are intended to
have sufficient mechanical strength to withstand pressure by gastric
contraction.
 This is advised by co-formulation of hydrophilic particulate material

37. Magnetic Systems
• This approach to enhance the gastric retention time (GRT) is based on
the simple principle that the dosage form contains a small internal
magnet, and a magnet placed on the abdomen over the position of the
stomach.
• Although magnetic system seems to work, the external magnet must
be positioned with a degree of precision that might compromise
patient Compliance.

38. High density system
 This approach involves formulation of dosage forms with the density that
must exceed density of normal stomach content (~ 1.004 gm/cm3).
 These formulations are prepared by coating drug on a heavy core or mixed
with inert materials such as iron powder, barium sulphate, zinc oxide and
titanium oxide etc.
 The materials increase density by up to 1.5- 2.4 gm/cm3.
 A density close to 2.5 gm/cm3 seems necessary for significant prolongation
of gastric residence time. But, effectiveness of this system in human beings
was not observed and no system has been marketed.
 Sedimentation of pellets.

39. Gastroretentive products available in
the market
Brand Name
1. Cifran OD ®
2. Madopar ®
3. Valrelease ®
4. Topalkan ®
5. Almagate FlatCoat ®
6. Liquid Gavison ®
7. Conviron
8. Cytotec®
Active Ingredient(s)
Ciprofloxacin
L-DOPA and Benserazide
Diazepam
Aluminum -magnesium antacid
Aluminum -magnesium antacid
Aluminium hydroxide,
Ferrous sulfate
Misoprostal

40. Applications of gastroadhesive system.
1. Enhanced bioavailability:
– Increased bioavailability of riboflavin GRDF as compared to non-GRDF formulations.
– Increases drug absorption by several processes.
2. Sustained drug delivery/Reduced frequency of dosing:
– Drugs with short biological half life can, sustained and slow input from GRDF result in
improved pharmacokinetics and patient compliance.
– Reduced dosing frequency.
3. Targeted therapy for local ailments in the upper GIT:
– Prolonged and sustained release from GRDF may advantageous for local therapy in
stomach and small intestine.
4. Reduced fluctuation of drug concentration:
– Continuous release of the drug from GRDF Produces blood drug concentration in a
narrow range.
– Fluctuation in the drug effect can be minimized and adverse effect due to concentration
can be prevented. Good for drugs with narrow therapeutic index.

41. Questions
1. Define Gastro-retentive drug delivery system (GRDDS), Explain the
purpose and benefits of Gastro-retentive drug delivery system.
2. Give the advantages and disadvantages of GRDDS.
3. Explain the various Factors controlling gastro-retentive dosage forms.
4. Explain the anatomy of stomach and gastrointestinal dynamics.
5. Enlist the different approaches of GRDDS.
6. Enlist the drugs suitable and unsuitable for GRDDS.
7. Explain the principle and design of floating type of gastro-retentive drug
delivery systems.
8. Describe the design of expandable gastro-retentive drug delivery system.
9. Explain the design of mucoadhesive type gastro-retentive drug delivery
system.
10. Explain the swellable type of drug delivery system.
11. Explain the inflatable systems.
12. Write down the applications of GRDDS.