To give knowlege about topic

1. GASTRO RETENTIVE
DRUG DELIVERY
SYSTEM
1
Ms. Harshada. R. Bafna

2. CONTENTS
• INTRODUCTION
• IDEAL CANDIDATE DRUGS FOR GRDDS
• ADVANTAGES
• LIMITATIONS
• APPROACHES
• EVALUATION
• REFERENCES
2
2/28/2024 HRB 2

3. INTRODUCTION
3
• Oral drug delivery is widely used in pharmaceutical field to treat the
diseases.
• Some drugs are absorbed at specific site only, these require release
at that specific site.
• Definition: Gastroretentive drug delivery is an approach to
prolong gastric residence time, thereby targeting site-specific drug
release at controlled manner in the upper gastrointestinal tract
(GIT) for local or systemic effects.
2/28/2024 HRB 3

4. Review of Stomach & GIT
• A tube about nine meters long that runs through the middle
of the body from the mouth to the anus and includes ;
▫ throat (pharynx),
▫ esophagus,
▫ stomach,
▫ small intestine
- duodenum
- jejunum
- ileum
▫ large intestine . Fig.no-1
2/28/2024 HRB 4

5. Gastrointestinal dynamics
• These are the four
motility phases within
the stomach during
fasting stage.
• The dosage form should
be capable of withstanding the
housekeeping action of phase III.
• This cyclic events are known as MMC
(Migrating Motor Complex)
Fig.no-2
2/28/2024 HRB 5

6. Factors Controlling The Gastric Retention
Time of Dosage Form
1. Density: GRT is a function of dosage form buoyancy that is dependent
on the density.
2. 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.
3. Shape of dosage form: Tetrahedron and ring shaped devices.
4. Fed or unfed state: If the timing of administration of the formulation
coincides with MMC, the GRT of the unit can be expected to be very short.
However, in the fed state, MMC is delayed and GRT is considerably longer.
5. Caloric content: GRT can be increased by 4 to 10 hours with a meal that is
high in proteins and fats.
2/28/2024 HRB 6

7. 6. Frequency of feed: The GRT can increase by over 400 minutes, when
successive meals are given compared with a single meal due to the low
frequency of MMC.
7. 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.
8. Age: Elderly people, especially those over 70, have a significantly longer
GRT.
9. Posture: GRT can vary between supine and upright ambulatory states
of the patient.
2/28/2024 HRB 7

8. Fig.no-3
2/28/2024 HRB 8

9. IDEAL CANDIDATE DRUGS FOR GRDDS
9
1. Drugs acting locally in the 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 is poorly soluble at alkaline pH.
E.g. Furosamide, Diazepam, Verapamil, etc.
4. Drugs with a narrow absorption window.
E.g. Cyclosporine, , Levodopa, Methotrexate etc.
2/28/2024 HRB 9

10. 10
5. Drugs which are absorbed rapidly from the GI tract.
E.g. Metronidazole, tetracycline.
6. Drugs that degrade in the colon.
E.g. Ranitidine, Metformin.
7. Drugs that disturb normal colonic microbes
E.g. antibiotics against Helicobacter pylori.
2/28/2024 HRB 10

11. ADVANTAGES
11
• Enhanced bioavailability
• Sustained drug delivery/reduced frequency of dosing
• Targeted therapy for local ailments in the upper GIT
• Reduced fluctuations of drug concentration
• Improved selectivity in receptor activation
• Reduced counter-activity of the body
• Extended effective concentration.
• Minimized adverse activity at the colon.
2/28/2024 HRB 11

12. LIMITATIONS
12
• 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.
2/28/2024 HRB 12

13. APPROACHES FOR PROLONGING THE
GASTRIC RESIDENCE TIME
• High-density systems.
(HDS)
F
S
HD
S
S
S
13
• Floating systems. (FS)
• Swelling and expanding
systems. (SS)
• Mucoadhesive &
Bioadhesive systems.
(AS)
2/28/2024 HRB 13

14. HIGH DENSITY
SYSTEMS
FLOATING
SYSTEMS
HYDRODYNAMICA
LLY BALANCED
SYSTEMS HBS
GAS-GENERATING
SYSTEMS
VOLATILE LIQUID /
VACUUM CONTAINING
SYSTEMS
INTRAGATRIC FLOATING GASTROINTESTINAL
DRUG DELIVERY SYSTEM
INFLATABLE GASTROINTESTINAL DELIVERY
SYSTEMS
INTRAGASTRIC OSMOTICALLY CONTROLLED DRUG
DELIVERY SYSTEM
MATRIX TABLETS
RAFT-FORMING
CLASSIFICATION
14
GRDDS
APPROACHE
S
SYSTEMS
HOLLOW
MICROSPHERES
ALGINATE BEADS
SUPER POROUS
HYDROGELS
EXPANDING
SYSTEMS
SWELLING
SYSTEMS
UNFOLDABLE
SYSTEMS
BIO/MUCOADHESI
VE SYSTEM
MAGNETIC
SYSTEMS
2/28/2024 HRB 14

15. HIGH DENSITY SYSTEM
15
• 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.
2/28/2024 HRB 15

16. Drawbacks of high density system
• 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.
• It is unpredictable; whether the dosage form will stand
peristaltic movement or not.
2/28/2024 HRB 16

17. FLOATING DRUG DELIVERY
• These have a bulk density lower than the gastric content.
• They remain buoyant in the stomach for a prolonged period of
time, with the potential for continuous release of drug.
• They include:
Hydrodynamically balanced systems (HBS)
Gas-generating systems
Volatile liquid/ vacuum containing systems
Raft-forming systems
Low-density systems
17
2/28/2024 HRB 17

18. 18
EFFERVESCENT SYSTEMS
2/28/2024 HRB 18

19. 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.
19
2/28/2024 HRB 19

20. MATRIX TABLETS
• Single layer matrix tablet is
prepared by incorporating
bicarbonates in matrix forming
hydrocolloid gelling agent like HPMC,
chitosan, 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.
20
2/28/2024 HRB 20

21. INFLATABLE GASTROINTESTINAL DELIVERY
• 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.
21
2/28/2024 HRB 21

22. 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.
22
2/28/2024 HRB 22

23. 23
• Consists of 2 compartments:
 Drug reservoir
 Osmotically active
compartment.
2/28/2024 HRB 23

24. 24
NON-EFFERVESCENT SYSTEMS
2/28/2024 HRB 24

25. INTRA-GASTRIC FLOATING GASTROINTESTINAL
DRUG DELIVERY SYSTEMS
• System can be float by means of flotation chamber, which may
be vacuum or filled with air or a harmless gas
• Drug reservoir is encapsulated inside
a microporous compartment
25
2/28/2024 HRB 25

26. HYDRODYNAMICALLY BALANCED SYSTEMS
• Prepared by incorporating a high level (20-75%w/w) gel-forming
hydrocolloids. E.g.:- HEC, HPC, HPMC & Sod. CMC into the
formulation and then compressing these granules into a tablets or
capsules.
• It maintains the bulk density less than 1.
26
2/28/2024 HRB 26

27. RAFT FORMING
• 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, forming a continuous layer called raft.
27
2/28/2024 HRB 27

28. HOLLOW MICROSPHERES
28
• Polymers used commonly: Polycarbonates, Cellulose acetate, Calcium
alginate, Eudragit S, agar and methoxylated pectin etc.
• Microballoons / Hollow microspheres loaded with drugs prepared by
solvent evaporation or solvent diffusion / evaporation methods.
• Buoyancy and drug release depends on quantity of polymers, plasticizer
and solvents used.
• The microballoons floated continuously over the surface of an acidic
dissolution media containing surfactant for >12 hours.
• Are the best because they combine the advantages of multiple-unit system
and good floating.
• E.g. ethanol-dichloromethane solution of drug poured in aqueous solution
of PVA
2/28/2024 HRB 28

29. 29
2/28/2024 HRB 29

30. SUPERPOROUS HYDROGELS
ALGINATE BEADS
• Prepared by dropping sodium
alginate solution into aqueous
solution of calcium chloride,
causing the precipitation of
calcium alginate
• Freeze dried in liquid nitrogen
at -40oC for 24h.
• Beads-spherical and 2.5 mm in
• Swellable agents have pore size
ranging between 10nm to
10µm.
• Superporous hydrogels will
swell more than the swelling
ratio 100,This is achieved by
co-formulation of a
hydrophilic particulate
30
diameter. material, and Ac-Di-Sol
(crosscarmellose).
2/28/2024 HRB 30

31. EXPANDABLE SYSTEMS
1.UNFOLDED SYSTEMS 2.SWELLABLE SYSTEMS
 The swelling is usually results
from osmotic absorption of
water.
 The device gradually decreases
in volume and rigidity as a
result depletion of drug and
expanding agent and/or
bioerosion of polymer layer,
enabling its elimination.
31
2/28/2024 HRB 31

32. MUCOADHESIVE SYSTEMS
32
• The basis of mucoadhesion is that a dosage form can stick to the
mucosal surface by different mechanisms.
• Examples for Materials commonly used for bioadhesion are
poly(acrylic acid), chitosan, cholestyramine, tragacanth, sodium
alginate.
2/28/2024 HRB 32

33. Drawbacks:
• Continuous production of mucous may limit muco adhesion.
• Bio adhesion may cause local irritation.
2/28/2024 HRB 33

34. 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.
Drawbacks:
• Although these systems seem to work, the external magnet
must be positioned with a degree of precision that might
compromise patient compliance.
34
2/28/2024 HRB 34

35. EVALUATION OF GRDDS :
A.FLOATING SYSTEM
1. FLOATING TIME :
• Test for buoyancy
• It is performed in simulated gastric & intestinal fluid maintain at 370C.
The floating time is determined using USP dissolution apparatus
containing 900 ml of testing medium.
• The time for which the dosage form float is termed as FLOATING or
FLOATING TIME.
2. DISSOLUTION TESTING :
• It is performed same as that conventional dosage form except that only
acidic buffer is used.
2/28/2024 HRB 35

36. B. BIO/MUCOADHESIVE SYSTEM :
1. BIOADHESIVE STRENGTH :
• Bioadhesive strength of a polymer can be determined by the measurement
of force required to separate the polymer specimen sandwiched between
the layers of either an artificial (e.g. cellophane) or biological (rabbit
stomach tissue) membrane.
• This force can be measured by using either a modified precision balance or
an automated texture analyzer.
2/28/2024 HRB 36

37. Bioadhesion strength measurement
Force measuring
device
Upper jaw
Polymer
Lower jaw
Membrane
Fig.no-9
2/28/2024 HRB 37

38. 38
C. SWELLING SYSTEMS :
1. WEIGHT GAIN AND WATER UPTAKE :
• The swelling behavior of dosage unit can be measured either by studying it’s
dimensional changes, weight gain or water uptake.
• The study is done by immersing the dosage form in the simulated gastric
fluid at 370C and determining the factor at regular interval.
• 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 as given below :
WU = ( Wt – Wo ) * 1OO/Wo.
WU= Water uptake.
Wt = Weight of dosage form at time t.
Wo = Weight of dosage form initially.
2/28/2024 HRB 38

39. 39
2. SPECIFIC GRAVITY /DENSITY
• Density can be determined by the displacement method using
Benzene as displacement medium
3. GASTRORETENTION :
• The in-vivo gastro retention of dosage form can be evaluated by inclusion
of a radio-opaque material into a solid dosage form which can be observed
by using X-rays.
• Similarly, the inclusion of a γ-emiting radio nuclide in a formulation
allows external observation using γ-camera or scintiscanner which helps to
monitor the location of the dosage form in the GI tract.
2/28/2024 HRB 39

40. • Methods to measure gastroretentivity of GRDFs
1. Magnetic Resonance Imaging (MRI)
• 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 dosage forms, the incorporation of a super-paramagnetic
compound such as ferrous oxide enables their visualization by MRI.
2. Radiology (X-Ray)
• In this technique a radio-opaque material has to be incorporated in
the dosage forms, and its location is tracked by X-ray picture.
2/28/2024 HRB 40

41. 3. ɣ-Scintigraphy
• Gamma scintigraphy relies on the administration of a dosage forms
containing a small amount of radioisotope, e.g., 152Sm,which is a
gamma ray emitter with a relatively short half life.
4. Gastroscopy
• Gastroscopy is commonly used for the diagnosis and monitoring of
the GI tract.
• This technique utilizes a fiber optic or video system and can be
easily applied for monitoring and locating GRDFs in the stomach.
2/28/2024 HRB 41

42. Ultrasonography
• Used sometimes, not used generally because it is not traceable at
intestine.
13 C octanoic acid breath test
• After ingestion of the dosage form, the time duration after which
13C octanoic acid 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.
2/28/2024 HRB 42

43. 43
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
FDDS
Ferrous sulphate Ranbaxy, India
Cytotech® Bilayer floating capsule Misoprostol (100μg/200μg) Pharmacia, USA
Cifran OD® Gas-generating floating
form
Ciprofloxacin (1gm) Ranbaxy, India
2/28/2024 HRB 43

44. REFERENCE
44
• N K Jain. Gastroretentive drug delivery systems:
Garima Chawla, Piyush Gupta and Aravind K.
Bansal, editors. Progress in controlled and novel drug
delivery systems.New delhi.
• S.P.vyas, roop K.khar controlled drug delivery
concepts and advances page no.196-217.
2/28/2024 HRB 44

45. 45
2/28/2024 HRB 45