Chapter on Search Results Web results Gastro retentive drug delivery system (GRDDS)

1. SEMINAR ON
GASTRO RETENTIVE DRUG DELIVERY SYSTEM
GRDDS
By:Rajesh L. Dumpala
(B.Pharm, M. Pharm.) PhD. ( Pursuing)
Research Scientist,
Alembic Research Centre. Vadodara
E.Mail:-rdumpala64@gmail.com

2. Presentation Outline
• Introduction
• Merits
• Physiology of stomach
• Gastro-retentive technologies
• Factors affecting GRDDS
• Evaluation of GRDDS
• Demerits
• Market Products
• References

3. Introduction
• Conventional oral delivery is widely used in
pharmaceutical field to treat diseases. However,
conventional delivery had many drawbacks and major
draw-back is non-site specificity.
• Some drugs are absorbed at specific site only. They require
release at specific site or a release such that maximum
amount of drug reaches to the specific site.
• Pharmaceutical field is now focusing towards such drugs
which require site specificity

4. Cont..
• Gastro-retentive delivery is one of the site
specific delivery for the delivery of drugs
either at stomach or at intestine. It is
obtained by retaining dosage form into
stomach and drug is being released at
controlled manner to specific site either in
stomach, duodenum and intestine.

5. Different from SR…
Sustained Release GRDDSAbsorption
window

6. Merits…
• Delivery of drugs with narrow absorption window in the small intestine
region.
• Longer residence time in the stomach could be advantageous for local action
in the upper part of the small intestine, for example treatment of peptic ulcer
disease.
• Improved bio-availability is expected for drugs that are absorbed readily
upon release in the GI tract

7. Effects of the mode of administration of 100 mg riboflavin-5-
phosphate on the resulting (a) mean riboflavin plasma
concentration and (b) cumulative
amount of riboflavin absorbed in dogs (n=6). DF, dosage form;
GRDF, gastro retentive dosage form.

8. Drugs benefited by GRDDS
• Drugs acting locally in the stomach E.g. Antacids
and drugs for H. Pylori
• Drugs that are principally absorbed in the stomach
• Drugs that are poorly soluble at the alkaline pH
• Drugs with a narrow window of absorption E.g.
Furosemide
• Drugs absorbed readily from the GI tract
• Drugs that degrade in the colon

9. Pharmacodynamic consideration:
• Reduce fluctuation in drug effect
• Improve selectivity in receptor activation
• Reduce counter activity of the body
• Extended time over effective concentration
• Minimized adverse effect at colon

10. Physiology of stomach:
• 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.

11. Cont…
The GI tract is in a state of continuous motility
consisting of two modes:
– Interdigestive motility pattern
– Digestive motility pattern
The Interdigestive motility pattern is commonly
Called as “Migrating Motor Complex” (MMC) And
is organized in cycles of activity.

12. No contraction
Intermittent
contraction
Intense distal and proximal
gastric contraction
House keeper wave
4-5 contraction / min
Intermediate
between III-I
Migrating myoelectric complex:

13. Gastro-retentive technologies
A) Low-density systems (Floating drug
delivery)
B) Expandable/Swellable systems
C) Bio/Muco-adhesive systems
D) High density systems
E) Raft forming systems

14. GRDDS

15. A) Low Density Approach
(Floating Drug Delivery)
Widely used approach, where,
To inherent low density of dosage
Form, it floats on gastric fluids.
It is also known as “Hydro-
Dynamically balanced System”

16. Classification of Floating systems
a) Non-effervescent systems b) Effervescent systems
Multiple
units
Single unit
(Monolithic
System)
Multiple unitsSingle unit
(Monolithic System)

17. a) Floating Non-effervescent Systems:
-Monolithic system
i) HBSTM Capsule:
It consists of…
Drug
+
Highly swellable gel forming Hydrocolloids (20-75%)
like HPMC, HEC, Na-CMC, etc.

19. ii) Matrix Tablet
Single layer Tablet Bi-layer Tablet

20. ii) Non-Matrix Bi-layer system
Bi-Layer Capsule Bi-Layer Tablet

21. iii) Tablet with agar and mineral oil
Drug + Mineral Oil
Warm Agar gel solution
Mix Pour in a
tablet mould
Cool
Here, air is entrapped in Agar gel.
Escape of air is prevented by oil
The tablet contains 2% agar.

22. A I R A I R
iv) Tablets in cylinder
v) Coated Hollow globular shell

23. a) Floating Non-effervescent system
-Multiple units
I) Calcium alginate/Pectinate beads
IONOTROPIC GELATION METHOD
Sodium alginate
solution
Calcium Chloride solution
Spherical gel beadsSeparate and freeze dry
Calcium Pectinate gel beads
Calcium Alginate Pectinate Gel beads
Calcium Alginate + Chitosan gel beads

24. Alginate bead in
solution before
drying
Coating before
drying
After drying, shrinkage of bead
Drug
+
Sodium/Potassium
Alginate
+
HPMC/HPC
+
Binder
ii) Alginate beads with air
compartment
iii) Floating powder

25. iv) Oil entrapped gel beads

26. v) Hollow Microsphere vi) Microbaloon
Solvent Evaporation
Method
Emulsion solvent
diffusion method

27. Schematic presentation of the preparation of floating micro particles based on low-
density foam powder, using (a) the solvent evaporation method
or (b) the soaking method.

29. Preparation technique (emulsion-solvent diffusion method) and
mechanism of ‘micro balloon’ formation proposed by
Kawashima et al

31. vii) Foam containing Micro-particles
Drug Polymer
Foam
Organic
Solvent
Aqueous PVA solution
Foam Micro-particle
Dissolved
Dispersed
Only foam
Foam Micro-particles

32. viii) Calcium Silicate as
floating carrier
Highly porous
Large pore volume
Low inherent density
Granules containing
Drug, HPMC and Calcium
Silicate.
ix) GELUCIRE® Granules
Hydrophobic Lipid
Diff. Grades – 39/01
43/01
Low Inherent Density
Melt Granulation
SR of Highly Soluble Drug

33. b) Floating effervescent systems
-Monolithic system
i) Matrix Tablet
Bicarbonate + Polymer
Single Layer Tablet
Bilayer Tablet
Triple Layer Tablet
ii) Matrix tablet with Carbopol
pH dependent Gelling
Only Carbopol
- NO GELLING
(at acidic pH)
Bicarbonate + Carbopol
- GELLING
due to Alkaline
MICROENVIRONMENT

34. DRUG
NaHCO3
Tartaric acid
Swellable polymer
iii) Floating pills

35. iv) Coated effervescent core v) Multiple film
Drug
NaHCO3

36. vi) Programmable drug delivery
Drug release
Fluid in
CO2
vii) Osmotically controlled DDS

37. b) Floating effervescent systems
-Multiple units
i) Porous Alginate beads
NaHCO3 Na-Alginate
Solution
CaCl2
Solution
Acetic
Acid
Simultaneous generation of CO2 and gelling of beads.
Escape of CO2 creates pores in beads.

38. ii) Ion exchange resin beads
Resin
HCO3
HCO3
HCO3
H+ Cl
H+ Cl
H+ Cl
H+ Cl
H+ Cl
Uncoated bead results in no floating and CO2 escapes.

39. B) Expandable Approach
Also called ‘ PLUG
SYSTEM’
Size of the formulation more
than Pyloric sphincter
It should expand for gastric
retention
Should be Collapsed after lag
time

40. B) EXPANDABLE APPROACH
a) Swelling systems b) Unfolding systems

41. a) Swelling systems
i) Polymeric envelope
ii) Tiny pills in matrix

45. b) Unfolding systems
i) Obstructing means ii) Multilayer films
Before
After
Drug
Drug Erodible Polymer film
Gelatin band/Strip

46. iv) Geometric configurations
iii) Recaptacle means

47. A: capsule G: release of medication
B: device H: biodegradable plug
C: pressure generated compartment
D: Retention arm
E: pressure responsive bladder
F: drug reservoir

48. Schematic presentation of the gastroretentive drug delivery system
proposed by Klausner et al.
multilayer polymeric films consisting of
(a) shielding (outer) layers; (b) rigid (frame) strips; (c) polymer-drug
matrix; and (d) anti-adhering layers (microcrystalline cellulose).

49. C) Bio-Muco-adhesive Approach
4
Here, the drug is incorporated with bio/
Muco-adhesive agents, enabling the
Device to adhere to the stomach walls,
Thus resisting gastric emptying.
However, the mucus on the walls of the
Stomach is in a state of constant renewal,
Resulting in unpredictable adherence.
Thus, this approach is not widely used.

50. MICROSPHERE WITH FLOATING AND MUCOADHESIVE PROPERTY:

51. Mechanism of bioadhesion:
• Hydration-mediated adhesion
• Bonding-mediated adhesion
• Receptor-mediated adhesion.

52. 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 esophagus resulting in drug induced
injuries

53. D) High density approach
Density should be more then stomach
content i.e. 3 g/cm3
Threshold density: 2.4-2.8 gm/cm3
Capable to withstand with peristaltic
movement of stomach
Prepared by coating or mixing drug
with heavy inert material

54. Diluents such as…
• barium sulphate (density = 4.9),
• zinc oxide,
• titanium dioxide,
• iron powder
must be used to manufacture such high-density
formulations.

55. E) Raft forming systems
RAFT
Raft systems incorporate
alginate Gels which have
carbonate Component.
These upon reaction with the
gastric Acid, causes the
bubbles to form and
This enables floating.
Generally, it is used for
antacids.

56. FACTORS AFFECTING THE
PERFORMANCE OF GRDDS
Formulation factors Idiosyncratic factors
• Type of dosage form
• Density of dosage form
• Size of dosage form
• shape
• Viscosity grade pf polymer
• Food intake and nature of food.
• Effect of gender, posture, age and
Diseases, body mass index

57. Evaluation of GRDDS

58. 1) For floating system
• Buoyancy lag time:
• Floating time:
• Specific
gravity/density:
• Resultant weight:

59. For muco adhesive system:
• The bioadhesive strength of a polymer can be
determined by…
• measuring the force required to separate the
polymer specimen sandwiched between the layers of
either an artificial (e.g., cellophane) or biological
(e.g., rabbit stomach tissue) membrane .
• This force can be measured by using modified
precision balance or an automated texture analyzer.

60. 2) For swelling system
i) Swelling Index
ii) Water uptake/Weight gain
WU = (Wt – Wo) * 100 / Wo
iii) Penetration rate
PR = Water uptake per unit time X 2 r2
Water density

61. EVALUATION OF SWELLING SYSTEM:

62. In-vitro evaluation for swelling system
HEATERBALANCE

63. In-vitro dissolution
Dosage form may float or swell so irreproducible result:

64. In-vitro dissolution
To prevent sticking and to improve movement of dosage form:

65. Attachment with some small, loose, non reactive material:
e.g. few turns of wire helix..
Inhibit swelling.. And drug release..

66. DF submerged under ring or mess:

67. Between two mess or ring:

68. More area is given to swell:

69. HEATER
Modified Rossett-
Rice Test
Modified Rossett-Rice Test

70. In-vivo evaluation
-Scintigraphy:
• A small amount of a stable isotope e.g.
Sm (152) is compounded into the DF
during its preparation. Prior to the study
the DF is irradiated in a neutron source
to convert the isotope into a  -emitting
material e.g. Sm (153)

71. Radiology:
• Its major advantages as compared to
 -Scintigraphy are simplicity and cost. However, use of X-
ray experiment in biopharmaceutical studies involving
healthy volunteers [130]
• Barium sulphate high concentration:
e.g. 40%
• Aluminum thread contrast medium

72. Gastroscopy:
•It is generally used for diagnosis purpose, endoscopy,used with
fiberoptic or video systems.
•No adverse effect.
Magnetic Marker Monitoring:
•Magnetically marked DF by magnetic source.
•Therefore require very sensitive biomagnetic measurement
instrument.
•No radiation
•Completely safe

73. Limitation of GRDDS:
1) It is not recommended for drugs which are unstable at
gastric/acidic pH, insoluble or very low soluble drugs and
drugs which causes gastric irritation.
2) For floating high level of fluid is required in GIT. Also
sleeping condition is favorable for the better results of
GRDDS.
3) Adhesive systems cannot prevail longer due to high turn-over
rate of mucus layer and presence of soluble mucin
4) For swelling systems, it is necessary that the formulation
should not exit before the appropriate swelling

74. Conclusions
• GRDDS, comprised mainly of floating, bioadhesive, and swellable
systems, have emerged as an efficient means of enhancing the BA and
controlled delivery of drugs that exhibit an absorption window.
• By prolonging the gastric emptying time of the dosage form, these
systems not only provide controlled release of the drug for a prolonged
period, but also present the drug in an absorbable form at regions of
optimal absorption.
• These systems achieve this by retaining the dosage form in the gastric
region, from where the drug is presented at the absorption window.
• This ensures maximal absorption of the drug for the desired period.

75. Continue…
• Designing GRDDS requires a thorough understanding
of the physicochemical properties of the drug, the
physiological events of the GIT, and formulation
strategies.
• A careful consideration of the interplay of these
parameters can help in designing a successful
GRDDS.
• Growth in the understanding of the effect of GI
physiology on drug delivery and the increasing
sophistication of delivery technology will ensure the
development of an increasing number of GRDDS to
optimize delivery of drug molecules that exhibit
regional variability in intestinal absorption.

76. Marketed products
Brand Name Drug (dose) Company
Madopar® Levodopa (100 mg),
Benserazide (25 mg)
Roche, USA
Valrelease® Diazepam (15 mg)
Hoffman LaRoche,
USA
Liquid Gaviscon® Al(OH)3 + MgCO3
GlaxoSmithKlein,
India
Topalkan® Liquid Al – Mg antacid
Pierre Fabre Drug,
France
Almagate
Flotcoat® Al – Mg antacid
Conviron® Ferrous sulfate Ranbaxy, India
Cifran OD® Ciprofloxacin (1 g) Ranbaxy, India
Cytotec® Misoprostal (100/200
g)
Pharmacia, USA

77. Tablets:
Chlorpheniramine maleate, Theophylline, Furosemide, Ciprofolxacin,
Pentoxyfillin, Captopril, Acetylsalicylic acid, Nimodipine, Amoxycillin trihydrate, Verapamil ,
Isosorbide di nitrate, Sotalol, Atenolol.Isosorbide mono nitrate, Acetaminophen,Ampicillin,
Cinnarazine,Diltiazem, Florouracil, Piretanide, Prednisolone,Riboflavin- 5′Phosphate.
Capsules:
Nicardipine, L- Dopa and benserazide, hlordiazepoxide HCl, Furosemide, Misoprosta ,Diazepam
Propranlo, Urodeoxycholic acid
Microspheres :
Verapamil, Aspirin, griseofulvin, p-nitroaniline, Ketoprofen, Tranilast,
Iboprufen, Terfenadine.
Granules:
Indomathacin, Diclofenac sodium, Prednisolone.
Films:
Drug delivery device. Cinnarizine. Powders:
Several basic drugs.

78. FURTHER READING….
• S. P. Vyas, Roop K. Khar, CONTROLLED DRUG DELIVERY – Concepts & Advances, Vallabh Prakashan, page no.
196-217
• N. K. Jain, Progress in Controlled & Novel Drug Delivery Systems, 1st edition 2004, CBS Publishers, page no.76-97
• G. Chawla, P. Gupta, V. Koradia, A. K. Bansal, Pharmaceutical Technology July 2003, 50-68
• Drs Jose Gutieerez-Rocca, Hossein Omedian and Khalid Shah. Progresses in Gastro-retentive drug delivery system-A
report. Buisness briefing, Pharmtech 2003. Pg No: 152-156.
• S.R.Parakh, A.V.Gothoskar, M.T.Karad, Pharmaceutical Technology MAY 2003,,40-48
• M. C. Gohel, P. R. Mehta, R. K. Dave, N. H. Bariya, Dissolution Technologies, NOVEMBER 2004,
• Stanley s. davis, formulation strategies to absorption window,DDT,volume-10,number-4, February 2005
• Eytan A. Klausnera, Eran Lavyb, Michael Friedmana, Amnon Hoffmana, expandable gastro retentive dosage forms,
Journal of Controlled Release 90 (2003) 143–162
• Alexander Streubel1, Juergen Siepmann1,2 and Roland Bodmeier, Drug delivery to the upper small intestine window
using gastroretentive technologies, Current Opinion in Pharmacology 2006, 6:501–508