GASTRO RETENTIVE DRUG DELIVERY SYSTEM FROM DR.L.D.PATEL, DIRECTOR & PROFESSOR, C.U.SHAH COLLEGE OF PHARMACY AND RESEARCH, WADHWAN, GUJARAT

1. ADVANCES IN NOVEL DRUG
DELIVERY SYSTEM
DR. L.D. PATEL
DIRECTOR & PROFESSOR
C.U. SHAH COLLEGE OF PHARMACY & RESEARCH
WADHWAN-363030, DIST: SURENDRANAGAR
Email: lakshamandpatel@gmail.com
March 22, 2013 DrLDP 1

2. Various NDDS….
Bio/Muco Adhesive DDS
Colon Targeted DDS
Intelligent Controlled Release DDS
Nanotechnology & Liposomal DDS
Pulmonary DDS (MD inhalers)
Microspheres & Microcapsules DDS
Transdermal DDS
Ocular DDS
Osmotic DDS
Gastro Retentive DDS
March 22, 2013 DrLDP 2

3. GASTRO RETENTIVE DRUG
DELIVERY SYSTEM (GRDDS)
Presentation
Outline:
Introduction
Merits
Stomach Physiology GRDDS
GR Technologies
Factors affecting
GRDDS
Evaluation of GRDDS
Demerits
March 22, 2013 DrLDP 3

4. . The Introduction
oral route is the
most
promising route of drug delivery.
Effective oral drug delivery may
depend upon
- gastric emptying process,
- GI transit & residence time,
- drug release from DF and
- site of absorption of drug.
. Conventional oral dosage forms
possess several physiological
limitations like
- variable gastric emptying,
- variable GI transit & shorter residence
time,
March 22, 2013 DrLDP 4
- incomplete drug release

5. Introduction….
• It may lead to incomplete & non
uniform absorption of the drugs
having absorption window in upper
part of GIT as once the DF passes
down the absorption site, the
remaining quantity goes
unabsorbed.
• Hence, a beneficial DDS would be
one which exhibits the ability to
control & prolong the gastric
emptying time and can deliver drug
in maximum conc. at the absorption
site (i.e. upper part of the small
intestine).
March 22, 2013 DrLDP 5

6. Introduction...
• Gastro Retentive Drug
Delivery System (GRDDS)
is one of the site specific
delivery for the delivery
of drugs either in
stomach or intestine .
This can be obtained by
retaining dosage form
into stomach and drug is
released in controlled
manner to specific site
either in stomach,
duodenum or/and
intestine. Absorption
March 22, 2013 DrLDP window 6

7. Different from SR…
Sustained Release Absorption GRDDS
March 22, 2013 window
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8. Merits of GRDDS
• Deliver the drugs with narrow
absorption window in small
intestine. e.g Furosemide, L. Dopa.
• Efficient delivery for local action in
upper part of small intestine due to
longer residence time in stomach.
e.g. treatment of peptic ulcer.
• Improved bio-availability for
drugs that are absorbed readily upon
release in GIT.
• Better patient compliance by once
a day therapy.
March 22, 2013 DrLDP 8

9. Beneficiary Drugs by
GRDDS
• Drugs that act locally in stomach. e.g.
Antacids.
• Drugs that disturb colonic microbes . e.g.
against Helicobacter Pylori, Misoprostol.
• Drugs that are principally absorbed in the
stomach. e.g. amoxycillin.
• Drugs that are poorly soluble at alkaline pH.
e.g. diazepam, chlordiazepoxide, verapamil.
• Drugs absorbed readily throughout GIT.
e.g. metronidazole, tetracycline.
• Drugs that are unstable in the colon.
e.g. captopril, ranitidine, metformin.
• Drugs with a narrow absorption window in
GIT. e.g. L-DOPA, para aminobenzoic acid,
furosemide, riboflavin.
March 22, 2013 DrLDP 9

10. Drugs unsuitable for
GRDDS
- Drugs unstable in gastric environment.
e.g. erythromycin.
- Drugs intended for selective release in
colon. e.g. 5-aminosalicylic acid,
corticosteroids.
- Drugs having limited acid solubility.
e.g. phynytoin.
- Drugs in enteric coated systems.
March 22, 2013 DrLDP 10

11. Physiology of stomach
Under fasting conditions, stomach is like
a collapsed bag with a residual volume
of 50 ml.
The pH is 1-3 in fasted
state.
Normal GR time is
1.5-3 hrs.
Diameter of pyloric
sphincter is 12 ± 7
mm.
March 22, 2013 DrLDP 11

12. Cont…
GIT exhibits continuous motility of two
modes: Interdigestive &Digestive motility
pattern.
The interdigestive motility pattern is called as
“Migrating Motor Complex” (MMC) . It is
divided in four phases and repeated at every 2-
Phase I: Basal phase
3 hrs.
- Silent, no contractions
Phase II: Pre-burst phase
- Contraction increases
Phase III: Burst phase
- intense & large regular contractions
- efficient evacuation of contents
Phase IV: Transition phase
- Contraction dissipate betw the last part
of phase III & quiescence of phase I.
March 22, 2013 DrLDP 12

13. A) LOW
DENSITY
SYSTEMS
E) RAFT (FLOATING)
FORMING
SYSTEM B)
S EXPANDABLE/
SWELLABLE
GRDDS SYSTEMS
TECHNO
LOGIES
D) HIGH C)
DENSITY BIO/MUCO-
SYSTEM ADHESIVE
S SYSTEMS
March 22, 2013 DrLDP 13

14. E) RAFT A)LOW
FORMING DENSITY
SYSTEM SYSTEMS
S (FLOATING)
GRDDS
TECHNO B)
D) HIGH LOGIES EXPANDABL
DENSITY E/
SYSTEM SWELLABLE
S SYSTEMS
C)
BIO/MUCO
-
ADHESIVE
March 22, 2013 DrLDP 14
SYSTEMS

15. A)LOW DENSITY SYSTEMS
(FLOATING DRUG
DELIVERY)
Widely used approach.
Due to inherent low
density of dosage form,
it floats onto gastric
fluids.
It is known as “Hydro -
Dynamically Balanced
System (HBS)”
March 22, 2013 DrLDP 15

16. Floating systems
a) Non-effervescent b) Effervescent
Single Multiple units Single Multiple units
unit (i-ix) unit (i-ii)
(Monolithi (Monolithi
c c System)
system) (i-vii)
(i-x)
March 22, 2013 DrLDP 16

17. a) Floating Non-
effervescent Systems –
Monolithic (i-x)
HBSTM Capsule
It consists of Drug
+
Highly swellable gel
forming
Hydrocolloids (20-
75%) like HPMC,
HEC, Na-CMC, etc. DrLDP
March 22, 2013 17

18. Cont…
i) Matrix
Tablet
Single layer Tablet Bi-layer Tablet
Bilayer matrix tablet prepared using
polymers responsible for floating in
one layer + drug loaded in other layer.
Other type of bilayer tablet: prepared
by incorporating a loading dose of
drug in one layer + remaining drug in
other layer with hydrocolloid for its
sustained release effect.
Such tablets will float & remain in
March 22, 2013 stomach.
DrLDP 18

19. ii) Non-Matrix Bi-layer
system
Bi-Layer Capsule Bi-Layer Tablet
March 22, 2013 DrLDP 19

20. iii) Tablet with agar &
mineral oil
Drug + Mineral Oil
Mix Pour into Cool
tablet mould
Warm Agar gel solution
Air is entrapped in Agar gel.
Escape of air is prevented by oil.
The tablet contains approx 2% agar.
March 22, 2013 DrLDP 20

21. v) Tablet with
foam
• Polypropylene Foam
• Hydrophobic Powder
• Open-cell Structure
• Highly Porous
• Low Inherent Density
March 22, 2013 DrLDP 21

22. vi) Tablet with
lipid
Glyceryl Mono-oleate
• Swells in water
• Amphiphilic water insoluble lipid
• Converted to liquid crystals
(cubic shape)
It is usually melted & moulded
March 22, 2013 DrLDP 22

23. vii) Tablets in cylinder
viii) Coated
Hollow
globular shell
AIR AIR
March 22, 2013 DrLDP 23

24. ix) Multi-Layer Film
It Sealing at periphery films which are sealed
consists of two
together along their periphery in such a way as
to entrap some air between them & make air
pocket to impart floating.
One film is carrier film made up of water
insoluble polymer matrix having drug
dispersed/dissolved therein.
Other film is barrier film overlaying the carrier
film. Barrier film consists of copolymer of water
insoluble & water and drug permeable polymer.
Floating time & drug release rate can be
modulated by appropriate selection of polymer
March 22, 2013 DrLDP 24

25. x) Micro-porous
reservoir
Floating chamber
Drug reservoir
Microporous wall
It comprised of a drug reservoir encapsulated
in microporous compartment having pores on
its surface.
A floating chamber was attached at one
surface which gives buoyancy to entire device.
Drug slowly dissolves out via micro pores.
March 22, 2013 DrLDP 25

26. a) Floating Non-
effervescent system -
Multiple units (i-ix)
i) Calcium alginate / Pectinate /
chotosan beads
IONOTROPIC GELATION METHOD
Drug + CaCl2 solution
Na alginate solution
Separated & freeze dried Spherical gel beads
Freeze dried calcium alginate beads produced by
dropping Na alginate solution into CaCl 2 solution.
Due to chemical reaction named as Ionotropic
gelation, gelation take place and forms solid
spherical gel beads , which are separated from
solution and they are freeze dried at - 40oC for 24
hours. 2013
March 22, The resultant weight of beads is less
DrLDP 26
giving buoyancy up to 12 hours.

27. ii) Coated Alginate beads
with air compartment
Coating before drying
Alginate bead in
solution before
drying
Due to shrinkage of internal core bead during
drying, it produces the air compartment which
imparts buoyancy.
March 22, 2013 DrLDP 27

28. iii) Floating powder
Drug
+
Sodium/Potassium
Alginate
+
HPMC/HPC
+
Binder
Floating powder can be filled in capsule or
compressed to tablet
March 22, 2013 DrLDP 28

29. iv) Oil entrapped gel
beads
Vegetable oil is used as floating carrier as it is light weight &
hydrophobic. It is incorporated into gel matrix of beads. Oil
entrapped beads are prepared by both calcium alginate bead
and calcium pectinate bead.
March 22, 2013 DrLDP 29

30. v) Hollow Microspherevi) Microbaloon
Emulsion solvent
Solvent Evaporation diffusion method
Method
March 22, 2013 DrLDP 30

31. vii) Foam containing Micro-
particles
Drug Polymer
Dissolved
Only foam
Organic
Aqueous PVA
Solvent
solution
Dispersed
Foam Micro-particle
Foam
Foam Micro-particles
March 22, 2013 DrLDP 31

32. viii) Calcium
Silicate as
floating
carrier
Highly porous ix) GELUCIRE ®
Large pore volume Granules
Low inherent
density
Granules Hydrophobic Lipid
containing Diff. Grades –39/01,
Drug, HPMC & Ca 43/01
Silicate. Low Inherent Density
March 22, 2013
Melt Granulation
DrLDP 32
SR of Highly Soluble

33. b) Floating effervescent
systems - Monolithic (i-vii)
i) Matrix Tablet ii) Matrix tablet
Bicarbonate + Polymer
with Carbopol
pH dependent Gelling
Single Layer Tablet
Bilayer Tablet Only Carbopol
Triple Layer Tablet - No gelling (at acidic
pH)
Triple layer tablet prepared having Bicarbonate + Carbopol
first swellable floating layer, second - Gelling due to Alkaline
sustained release layer of 2 drugs pH Carbopol gives swelling & gelling.
(Metronidazole & Tetracycline) and But this system do not remain intact
third rapid dissolving layer of for long time. Hence, it can be
bismuth salt. This tablet is used as coated with permeable elastic
single dosage form for Triple polymer like Eudragit to support
Therapy of H. Pylori.
March 22, 2013 integrity of core.
DrLDP 33

34. iii) Floating pills It consists drug pill
surrounded by double layers
Swellable polymer coat.
Inner layer, effervescent
Tartaric acid NaHCO 3
layer, contains two sub-
layers to avoid direct
contact of NaHCO3 &
tartaric acid.
Outer layer, swellable
permeable layer, is made up
DRUG
of PVA and shellac.
As CO2 gas can not go out from outer
membrane makes a balloon like system which
can float upto 5 hrs irrespective of pH &
viscosity22, 2013
March of medium. DrLDP 34

35. iv) Coated effervescent core
v) Multiple film
NaHCO3
Drug
March 22, 2013 DrLDP 35

36. vi) Programmable drug delivery
CO2
Fluid in
Drug release
vii) Osmotically controlled DDS
March 22, 2013 DrLDP 36

37. b) Floating effervescent
systems - Multiple units
(i-ii)
i) Porous Alginate beads
CaCl 2
NaHCO 3 Na-Alginate Acetic
Solution
Solution Acid
Simultaneous generation of CO 2 and gelling of
beads.
Escape of CO 2 creates pores in beads.
March 22, 2013 DrLDP 37

38. ii) Ion exchange resin
beads
H+ Cl H+ Cl
HCO3
HCO3
Resin UG H+ Cl
DR
DR
HCO3 UG
H+ Cl H+ Cl
This system comprised of ion exchange resin beads loaded
with bicarbonate and a negatively charged drug tagged to
resin. The beads were encapsulated in a semi permeable
membrane. Upon contact with gastric fluid, Cl - ion of HCl is
exchanged with bicarbonate and produce CO 2 gas, which
can not escape due to semi permeable membrane. Hence,
March 22, 2013 DrLDP 38
it floats. Uncoated beads don’t show floating due to

39. B) EXPANDABLE
SYSTEMS
Also called ‘ PLUG
SYSTEM’
Size of the formulation
greater than Pyloric
sphincter
Smaller in size for oral
intake
Should expand/swell for
gastric retention
Should be collapsed after
March 22, 2013 DrLDP 39

40. EXPANDABLE
APPROACH
a)Swelling systems b) Unfolding systems
(i-ii) (i-iv)
Superporous hydrogel in its dry (a) & water-
swollen (b) state. On the right, schematic
illustration of the transit of superporous hydrogel.
March 22, 2013 DrLDP 40

41. a) Swelling
i) systems
Polymeric envelope reservoir (A)
It consist of drug in center
surrounded by swellable material (B) are placed
in elastic polymeric envelope type system (C).
The polymeric envelope is permeable to drug
and fluids.
This system gets swollen in gastric fluid and
integrity is retained by elastic polymeric
envelope and drug is released in controlled
manner.
March 22, 2013 DrLDP 41

42. Swelling systems
ii) Tiny pills in matrix
Tiny pills containing drug are incorporated into
hydrogel matrix and coated with wax to give
strength to wall. It works by plugging pylorus
sphincter. It keeps the stomach in fed state and
thus delays house keeper waves which comes in
fasted state.
After administration, it achieves high volume and
tiny pills are released slowly out from matrix and
gives GR to drug.
i) The dosage from side-view
ii) The cross-sectional view which
comprises of A) Waxy wall
B) Hydrogel Matrix
March 22, 2013 DrLDP 42
C) Tiny pills

43. b) Unfolding
systems a capsule
It is (A) containing 2
i) Obstructing means reservoirs (C) attached together
with hydrophilic/hydrophobic strips
(B). The flexible strips get enlarge
and get sufficient strength and
becomes rigid to achieve gastro
retention.
March 22, 2013 DrLDP 43

44. b) Unfolding
systems
ii) Multilayer films Gelatin band/Strip (C)
It consists of one erodible
polymeric film containing
drug (A) which is adhered
on another non-erodible
carrier polymeric film (B) .
This bilayer sheet is folded Before
and gelatin bands/strips (C)
are used to maintain
folded. The system is
placed in capsule. After
In stomach, capsule and
gelatin band dissolves to
give unfolded system.
Drug (A)
March 22, 2013 Drug Erodible Polymer film (B)
DrLDP 44

45. b) Unfolding
systems
ii) Multilayer films
Intec Pharma Drug Delivery
system produced by Virtual Point
March 22, 2013 DrLDP 45

46. iii) Geometric configurations
iv) Recaptacle means
March 22, 2013 DrLDP 46

47. C) BIO/MUCO-ADHESIVE
SYSTEMS
Drug is incorporated with
bio /muco adhesive agents,
enabling the device to
adhere to stomach wall,
thus resisting gastric
emptying.
The mucus on the walls of
stomach is in a state of
constant renewal, resulting
in unpredictable
adherence.
March 22, 2013 Hence, this approach is not
DrLDP 47

48. Bio-Muco-Adhesive
March 22, 2013 DrLDP 48

49. D) HIGH DENSITY
SYSTEMS- SEDIMENTATION
Density greater than stomach
content i.e. 1.004 g/cm3.
When the patient is upright,
small high-density pellets sink
to the bottom of stomach
where they are entrapped in
the folds of antrum & thus
withstand peristaltic motion of
stomach.
Prepared by coating or mixing
drug with heavy (>3g/cm3) inert
material like BaSO4, ZnO, iron
powder, TiO2.
March 22, 2013 DrLDP 49

50. E) RAFT FORMING
SYSTEMS
RAFT (Continuous viscous gel layer)
Raft forming system
contains alginates &
alkaline bicarbonates
or carbonates.
Upon reaction with the
gastric acid, causes
the bubbles to form &
thus enables floating.
Generally used for
antacids.
March 22, 2013 DrLDP 50

51. Factors affecting the
performance of
GRDDS
Formulation factors Idiosyncratic factors
• Density of DF • Food intake, nature
<1 for floating of food, caloric
• Size of DF content & frequency.
> size of DF, > • Effect of gender,
GR time posture, age, sleep &
disease state.
March 22, 2013 DrLDP 51

52. Evaluation of GRDDS
In-vitro evaluation
1) For floating systems
2) For swelling systems
3) Penetration rate
4) Dissolution
March 22, 2013 DrLDP 52

53. 1) For floating system
• Buoyancy lag time : Time taken by DF to float on top of
the dissolution medium.
• Floating time : Time for which DF continuously floats on
the dissolution medium.
• Specific gravity/ density
• Resultant weight : Density changes with change in
F resultant – Fgrav as Df.g.V – Ds.g.V = (Df – Ds).g.V = (Df –
= Fbuoy weight = a function of time.
M/V).g.V,
F=Resultant weight of object, Df=Density of Fluid, Ds=Density
of object, g=Gravitational force, M=Mass of dosage form,
V=Volume of DF
March 22, 2013 DrLDP 53

54. 2) For swelling system
i) Swelling Index: dimensional changes are
measured in terms of increase in tablet thickness /
diameter with time.
ii) Water uptake/Weight gain:
Water uptake= Wu= (Wt –
Wo).100/Wo,
Wt = weight of dosage form at
time t,
iii) Penetration
Wo = initial weight of dosage
form
rate:
March 22, 2013 DrLDP 54

55. Swelling system
Continuous monitoring of Penetration rate
BALANCE HEATER
March 22, 2013 DrLDP 55

56. In-vitro dissolution
HEATER
Modified Rossett-
Rice Test
March 22, 2013 DrLDP 56

57. In-vivo evaluation
• Radiology
∀ γ-Scintigraphy
• Gastroscopy
• Magnetic Marker Monitoring
• Ultrasonography
• 13C Octanoic Acid Breath
Test
March 22, 2013 DrLDP 57

58. Demerits…
- GRDDS is not preferred for drugs which are
unstable at acidic pH, insoluble drugs &
drugs causing gastric irritation.
- For floating, high level of fluid in stomach is
required. Sleeping condition is not favorable
for the better results as DF may swept
away.
- Food is an important factor . Presence of
food delays emptying time of DF. So
presence of food is preferable.
- Adhesive systems can not prevail longer due
to high turn-over rate of mucus layer and
presence of soluble mucin.
- For swelling systems, it is necessary that it
should not exit before appropriate swelling.
March 22, 2013 DrLDP 58

59. Conclusions
• In the field of GR, there are many
obstacles that need to be overcome in
order to able to claim true gastric
retention.
• Considering the advantages for improved
delivery of drugs, some mfgers have
undertaken the herculious task of
developing such devices, some with
success and some with failure ended due
to un-predictability of GIT.
• However, the scientists are as close as
ever been to seeing a greater transition
of GR devices from a developmental level
to the manufacturing & commercial.
March 22, 2013 DrLDP 59

60. Marketed
Products
Brand Drug (dose) Company
Name
Levodopa (100 mg),
Madopar® Roche, USA
Benserazide (25 mg)
Hoffman LaRoche,
Valrelease® Diazepam (15 mg)
USA
Liquid Al(OH)3 + MgCO3 GlaxoSmithKlein,
Gaviscon® India
Topalkan® Pierre Fabre Drug,
Al – Mg antacid
Liquid France
Conviron® Ferrous sulfate Ranbaxy, India
Cifran OD® Ciprofloxacin (1 g) Ranbaxy, India
Cytotec®
March 22, 2013 Misoprostal (100/200µg)
DrLDP Pharmacia, USA 60

61. References
• 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, Khalid Shah, Progresses in
Gastro-retentive drug delivery system-A report. Business briefing,
Pharmtech 2003, 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.
• S. T. Prajapati, L. D. Patel, D. M. Patel, Formulation and In vitro Evaluation
of floating Matrix Tablets of domperidone: Influence of Combination of
Hydrophilic and Hydrophobic Matrix Formers, J. Pharmacy and Chemistry,
Vol. 2, Issue 1, 54-59, January-March 2008.
• S. T. Prajapati, L. D. Patel, D. M. Patel, Gastric floating matrix tablets:
Design and optimization using combination of polymers, Acta
Pharmaceutica, 58 (2), 221-229, 2008.
• Tejas B. Patel, L. D. Patel, Timir B. Patel, Kirit A. Patel, Tushar R. Patel,
Sunil H. Makwana, Design and Development of gastric Floating drug
delivery system Using Factorial Design, Pharma Buzz, Vol. 3, No. 6, 21-27,
June 2008.
March 22, 2013 DrLDP 61

62. THANK YOU
ALL
for your participation!
Dr. L. D. Patel
Sr. Lecturer, L.M. College of Pharmacy, Ahmedabad
March 22, 2013 DrLDP 62
(Gujarat)

63. BEST
WISHES…. L. D. Patel
Dr.
Principal & Professor
SAL Institute of
Pharmacy, Ahmedabad
(Gujarat)
Dr. L. D. Patel
Dean & Professor
Faculty of Pharmacy,
D.D. University, Nadiad –
387001 (Gujarat)
March 22, 2013 DrLDP 63

64. QUESTIONS - -
Lachoo College of
Pharmacy, Jodhpur on 7 th
June 2012
DR. L.D. PATEL
DIRECTOR & PROFESSOR
C.U. SHAH COLLEGE OF PHARMACY &
RESEARCH
March 22, 2013 DrLDP 64
WADHWAN-363030, DIST: SURENDRANAGAR