Presentation on GRDDS

1. {
Gastro Retentive Drug
Delivery System

2. Successful functioning of an oral CRDDS is
determined by:
i. Physicochemical properties of drug – aq.
solubility, permeability, pH solubility profile
ii. Pharmacokinetic profile the drug
iii. Interaction with anatomy and physiology of
GIT – transit time
Introduction

3. Dosage form Transit time (hr)
Stomach Small intestine Total
Tablets 2.7 ± 1.5 3.1 ± 0.4 5.8
Pellets 1.2 ± 1.3 3.4 ± 1 4.6
Capsules 0.8 ± 1.2 3.2 ± 0.8 4.0
Oral solution 0.3 ± 0.07 4.1 ± 0.5 4.4
Transit time of different dosage forms through GIT

4.  Not all drugs get uniformly absorbed throughout the GIT.
 Some drugs show absorption variability
 Such drugs have an “absorption window” - region from where
absorption primarily occurs
 There can be various reasons for presence of such a window.
Absorption window
Absorption window in
stomach or upper small
intestine
IDEAL CANDIDATES

5. Absorption window
Physicochemical
pH dependent solubility
eg. Basic drugs
pH dependent stability
eg. captopril
Enzymatic degradation
eg. levodopa
Physiological
Mechanism of absorption
eg. furosemide
Microbial degradation eg.
leuprolide
Biochemical
Intestinal metabolic
enzymes eg. cyclosporin
P glycoproteins eg. ACE
inhibitors

7. •e.g. 5- Fluorouracil, anti Helicobacter
pylori drugs, misoprostol
Acting locally in the
stomach
•e.g. ranitidine hydrochloride,
atenolol, furosemide, riboflavin
Primarily absorbed
in the stomach or
upper parts of the
small intestine
•e.g. verapamil, propranolol,
quinidine, metoprolol
Poorly soluble at an
alkaline pH (pH
dependent solubility)
GRDDS are preferred for drugs

8. •e.g. sulphonamides, penicillins,
amino- glycosides, tetracyclines
Narrow window
of absorption
•e.g. ranitidine hydrochloride,
captopril
Unstable in colonic
environment (pH
dependent
stability)
•e.g. leuprolide
Enzymatic
degradation in
intestine

9. Drugs given as enteric coated systems.
Drugs intended for selective release in the colon
e.g. 5-aminosalicylic acid and corticosteroids.
Drugs that have very limited acid solubility e.g.
phenytoin.
Drugs that suffer instability in the gastric
environment e.g. erythromycin
Drugs unsuitable for GRDDS

10.  The stomach is a J- shaped dilated portion of the alimentary tract
 Its volume is 1.5 L in adults and after food has emptied a
“collapsed” state is obtained with a resting volume of only 25-
30mL
 The stomach is anatomically divided into 3 parts:-
1) Fundus.
2) Body.
3) Antrum.
Anatomy of stomach

11.  The proximal stomach, made up of fundus and body serves as a
reservoir for ingested material
 The distal stomach is made up of antrum and pylorus
 The antrum serves as major site for mixing actions and acts as a
pump for gastric emptying by propelling actions
 The fasting gastric pH is usually steady and approximately 2
 Food neutralizes gastric acid thus increasing the pH up to 6.5

12.  After meal ingestion is complete the pH rapidly falls back below
5 and then drastically declines to fasting state values over a
period of a few hrs
 The pylorus is an anatomical sphincter situated between the
terminal portion of the antrum and the duodenum. The pyloric
sphincter has a diameter of 12.8 ± 0.7mm in humans
 It acts as a sieve as well as a mechanical stricture to the passage of
large particles

13.  The contractile motility of the stomach causes
the food to breakdown into small particles.
 The contractions results in mixing of the food
particles with the gastric juices and consequent
emptying of the gastric contents.
 The gastric emptying occurs during fasting and
fed states but pattern of GI motility differs
distinctly in the 2 states.
Gastric motility and gastric
emptying

14.  In the fasting state it is characterized by an inter-digestive series
of electrical events which cycle both through stomach and
intestine every 2 to 3 hrs.
 This is called the inter-digestive myoelectric cycle or migrating
myoelectric cycle (MMC).
 It is generated in the stomach and its aim is to clear the stomach
and small intestine of the ingested debris; swallowed saliva and
sloughed epithelial cells

15. 4 phases
1. Basal phase – lack of secretory or electrical activity or
contractile motions
2. Pre-burst phase – intermittent contractions
3. Burst phase – intense regular contractions, sweeps all
undigested material out – housekeeper wave
4. Transitional phase
Migrating Myoelectric Cycle

17.  In the fed state MMC is delayed, due to presence of food, resulting
in slowdown of gastric emptying rate
 Gastric emptying rate depends on:
i. Nature and caloric content of meal
ii. Posture
iii. Gender
iv. Age
v. Osmolarity
vi. pH of food
vii. Mental stress
viii. Disease state

18. {Approaches to gastroretention
Formulation of
GRDDS

19. Floating systems.
Superporous hydrogels
Swelling and expanding systems
Mucoadhesive & Bioadhesive
systems.
High density systems
Magnetic systems
Ion exchange resins
Osmotic regulated system
Incorporation of passage delaying
food agents
Approaches for gastro retention

20. Difference from Conventional Release
Conventional Release GRDDS
Absorption
window

21. • Non effervescent systems
1. Single unit system
2. Multiple unit systems
• Effervescent systems
1. Single unit system
2. Multiple unit systems
• Raft-forming systems
Floating Systems

22. • They are further classified as:
1. Colloidal gel barrier system (HBS)
2. Microporous compartment system
3. Alginate beads
4. Hollow microspheres (microballoons)
Non-effervescent systems

23. • These systems contain one or more
hydrocolloids and are made into a
single unit along with drug and other
additives.
• When coming in contact with water,
the hydrocolloids at the surface of the
system swell and facilitate floating.
• The coating forms a viscous barrier,
and the inner polymer slowly gets
hydrated as well, facilitating the
controlled drug release. Such systems
are called “hydrodynamically balanced
systems (HBS)”.
Single unit - HBS

24.  The polymers used in this system includes HPMC, HEC,
HPC, Na CMC, agar, carrageenans and alginic acid
 They incorporate a high level of one or more polymers
(20-80%)
 On contact with gastric fluid the hydrocolloid hydrates
and forms a gel barrier around its surface.
 Air is trapped in the swollen polymer to maintain
density < 1 to confer buoyancy.
 The gel barrier will also control the rate of drug release

25. Mechanism of release of Non effervescent DDS

26.  Further classified into:
1. Microporous compartment system
2. Alginate beads
3. Hollow microspheres
Non effervescent systems –
multiple unit

27. Encapsulation of drug reservoir inside a
microporous compartment with apertures along
its top and bottom walls.
Peripheral walls are completely sealed.
The floatation chamber contains entrapped air
which allows the system to float over the gastric
contents.
Gastric fluid enters through the aperture,
dissolves the drug and carries it outside
Microporous compartment
system

28.  Spherical beads can be formed by
dropping sodium alginate solution
in aqueous solution of calcium
chloride forming calcium alginate
beads.
 Beads are then isolated by freeze
drying/ spray drying
Alginate beads

30. Hollow microspheres (microballons), loaded with
ibuprofen in their outer polymer shells were
prepared by a novel emulsion-solvent diffusion
method.
The ehanol:dichloromethane solution of the drug
and an acrylic polymer was poured in to an
agitated aqueous solution of PVA that was
thermally controlled at 40°.
The gas phase generated in dispersed polymer
droplet by evaporation of dichloromethane formed
in internal cavity in microspheres of the polymer
with drug.
The microballons floated continuously over the
surface of acidic dissolution media containing
surfactant for greater than 12 h in vitro.
Hollow microspheres

31.  They are further classified as:
 Volatile liquid containing systems
 Gas generating systems
Effervescent system – single
unit

32.  There are two chambers – inflatable
and deformable
 Inflatable chamber which contains a
volatile liquid eg. Ether, cyclopentane
 They volatalise at body temperature
and cause inflation of the chamber
 Deformable chamber is at the top and
has the drug .
 There is a impermeable, pressure
sensitive movable barrier between the
two chambers
Volatile liquid containing
systems

33.  They utilize effervescent reaction
between carbonate/ bicarbonate salts
and citric/ tartaric acid to liberate
carbon dioxide.
 This CO2 gets trapped in the
gellified hydrocolloid layer, thereby
decreasing its density and aid
floatation.
 Tablets can be single or multi
layered
Gas generating – single unit

34.  Another approach – collapsible spring
 Body consists of non-digestible, acid-resistant and high density
polymer with a gelatin cap
 The lower end of body has an orifice to control drug release

35.  Effervescent granules can be made on same principle as
effervescent tablets
Effervescent systems – multiple
unit

36. Marketed
preparations
of Floating
Drug
Delivery
System.

37. 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, wherein each portion of the liquid
swells, forming a continuous layer called raft.
This raft floats in gastric fluids because of the low bulk density created by the
formation of CO2.
Usually the system contains a gel-forming agent and alkaline bicarbonates or
carbonates responsible for the formation of CO2 to make the system less dense
and more apt to float on the gastric fluids.
Raft forming systems

39. Marketed
formulati
on of the
raft
forming
system.

40. Swellable agents with pore size ranging between 10nm and 10µm, absorption of water
by conventional hydrogel is very slow process and several hours may be needed to reach
as equilibrium state during which premature evacuation of the dosage form may occur.
Superporous hydrogels swell to equilibrium size with in a minute, due to rapid water
uptake by capillary wetting through numerous interconnected open pores.
They swell to large size and are intended to have sufficient mechanical strength to
withstand pressure by the gastric contraction.
This is achieved by co-formulation of a hydrophilic particulate material, Ac-Di-Sol.
Superporous hydrogels

42. These systems include Unfoldable and Swellable
systems.
Unfoldable systems are made of biodegradable
polymers. The concept is to make a carrier, such as a
capsule, incorporating a compressed system which
extends in the stomach.
Caldwell et al. proposed different geometric forms
(tetrahedron, ring or planar membrane [4-lobed, disc
or 4-limbed cross form]) of bioerodible polymer
compressed within a capsule.
Expandable systems

43. Different geometric forms of unfoldable systems

44. Swellable systems are retained because of their mechanical
properties. The swelling is usually results from osmotic
absorption of water.
The dosage form is small enough to be swallowed, and swells in
gastric liquids. The bulk enables gastric retention and maintain
the stomach in fed state, suppressing housekeeper waves.
The whole system is coated by an elastic outer polymeric
membrane which was permeable to both drug and body fluids
and could control the drug release.
The device gradually decreases in volume and rigidity as a
result depletion of drug and expanding agent and/or bioreosion
of polymer layer, enabling its elimination.

45.  The technique involves coating of microcapsules with
bioadhesive polymer, which enables them to adhere to gastric
mucosa (mucin) and remain for longer time period in the
stomach while the active drug is released from the device matrix
Mucoadhesive systems
Examples for Materials commonly
used for bioadhesion are poly(acrylic
acid) (Carbopol®, polycarbophil),
chitosan, Gantrez® (Polymethyl vinyl
ether/maleic anhydride copolymers),
cholestyramine, tragacanth, sodium
alginate

46. They have a density of about 3 g/ml and are
retained in the stomach and are capable of
withstanding its peristaltic movements
Main drawback is technical difficulty to
manufacture such system to get such a high
density
Diluents such as barium sulphate, zinc oxide,
titanium dioxide, iron powder have to be
used.
High density systems

47. This system is based on a simple idea: the
dosage form contains a small internal
magnet, and a magnet placed on the
abdomen over the position of the stomach.
Although these systems seem to work, the
external magnet must be positioned with a
degree of precision that might compromise
patient compliance.
Magnetic systems

48. Ion exchange resins are loaded with bicarbonate and a negatively charged drug is
bound to the resin.
The resultant beads are then encapsulated in a semi-permeable membrane to
overcome the rapid loss of carbon dioxide.
Upon arrival in the acidic environment of the stomach, an exchange of chloride and
bicarbonate ions take place.
As a result of this reaction carbon dioxide is released and trapped in the membrane
thereby carrying beads towards the top of gastric content and producing a floating
layer of resin beads in contrast to the uncoated beads, which will sink quickly
Ion exchange resins

49. It is comprised of an osmotic pressure controlled drug delivery device
and an inflatable floating support in a bioerodible capsule.
In the stomach the capsule quickly disintegrates to release the
intragastric osmotically controlled drug delivery device.
The inflatable support inside forms a deformable hollow polymeric bag
that contains a liquid that gasifies at body temperature to inflate the bag.
The osmotic controlled drug delivery device consists of two components
– drug reservoir compartment and osmotically active compartment
Osmotically regulated systems

51.  Food excipients like fatty acids e.g. salts of
myristic acid change and modify the pattern of
stomach to a fed state, thereby decreasing
gastric emptying rate and permitting
considerable prolongation of release.
 The delay in gastric emptying after meals rich
in fats is largely caused by saturated fatty acids
with chain length of C10-C14.
Incorporation of passage
delaying food agents

52. {
Evaluation of
GRDDS

53. a) Angle of Repose
 The frictional forces in a loose powder or
granules can be measured by angle of repose.
This is the maximum angle possible between
the surface of a pile of powder or granules and
the horizontal plane.
 tan θ = h/r
θ = tan-1 (h/r)
Where, θ = angle of repose
h = height of the heap
r = radius of the heap
Pre-compression parameters

54. b) Compressibility Index
 The flowability of powder can be evaluated by
 comparing the bulk density (ρo) and tapped density (ρt) of
powder and the rate at which it packed down.
 Compressibility index was calculated by

55.  Shape of Tablets
 Tablet Dimensions
 Hardness
 Friability test
 Weight Variation Test
 Tablet Density:
Post-compression
parameters

56.  Buoyancy / Floating Test: The time between introduction of
dosage form and its buoyancy on the simulated gastric fluid and
the time during which the dosage form remain buoyant is
measured.
 The time taken for dosage form to emerge on surface of medium
called Floating Lag Time (FLT) or Buoyancy Lag Time (BLT) and
total duration of time by which dosage form remains buoyant is
called Total Floating Time (TFT).
 In practice, floating time is determined by using the USP
dissolution apparatus containing 900ml of 0.1N HCl as a testing
medium maintained at 37oC.

57.  Swelling Study:
 The swelling behaviour of a dosage form was measured by
studying its weight gain or water uptake.
 The dimensional changes could be measured in terms of the
increase in tablet diameter and/or thickness over time.
 Water uptake was measured in terms of percent weight gain, as
given by the equation.

58.  In vitro drug release studies are usually carried
out in simulated gastric fluid (SGF) or 0.1 N
HCl maintained at 37oC.
 Volume of dissolution medium can range from
100 – 900 ml.
 Tablets have to be held by means of a sinker to
prevent floating
In vitro drug release
studies

59.  Gamma scintigraphy
Evaluation of
gastroretention (in vivo)

60.  Gamma scintigraphy is a technique whereby the transit of a
dosage form through its intended site of delivery can be non-
invasively imaged in vivo via the judicious introduction of an
appropriate short lived gamma emitting radioisotope.
 Attempts have been made to use radioisotope technetium to
study gastro retention ability of the formulation in animals
such as albino rabbits or in humans by gamma scintigraphy
technique.
 Advantage of gamma scintigraphy over other radiological
studies is that it allows visualization over time of the entire
course of transit of a formulation through the digestive tract,
with reasonably low exposure of subjects to radiation.

62. 1. Improved drug absorption, because of increased GRT and
more time spent by the dosage form at its absorption site.
2. Controlled delivery of drugs.
3. Delivery of drugs for local action in the stomach.
4. Minimizing the mucosal irritation due to drugs, by drug
releasing slowly at controlled rate.
5. Treatment of gastrointestinal disorders such as gastro-
esophageal reflux.
6. Simple and conventional equipment for manufacture.
7. Ease of administration and better patient compliance.
8. Site-specific drug delivery.
Advantages of GRDDS

63. 1. GRDDS like FDDS require a sufficiently high level of fluids in
the stomach for the delivery system to float and work
efficiently.
2. GRDDS are not feasible for drugs that have solubility or
stability problems in the gastric fluid.
3. Drugs which have nonspecific, wide absorption sites in the
GIT, drugs that are well absorbed along the entire GIT are not
suitable candidates for GRDDS; e.g. nifedipine.
4. Similarly drugs that undergo significant first-pass metabolism
are not preferred for GRDDS
Limitations of GRDDS

64. {
Drugs used in
GRDDS

66. {
Marketed products

68. {
Example of
GRDDS
formulation
development

69. Plan of work
PREFORMULATION
FORMULATION
DEVELOPMENT
OPTIMISATION
STABILITY STUDIES

70. PREFORMULATION
 Authentication of drug: FTIR, m. p.
 Construction of calibration curve:
I) UV-VIS Spectrophotometry: 0.1N HCl and SGF (pH 1.2)
II) HPLC
 pH solubility profile
 Flow properties of the drug: untapped bulk
density, tapped bulk density, %compressibility,
angle of repose and flow rate.
 Drug-excipient compatibility studies: DSC.
 Forced degradation.

71. PREFORMULATION
RESULTS
 Calibration curves:
 pH solubility profile
Slope Coefficient of
Regression (R2)
UV-VIS Spectrophotometer
0.1 N HCl 0.0347 0.9987
SGF (pH 1.2) 0.0247 0.9969
HPLC
Methanol 44378 0.9991
0
20
40
60
80
100
120
140
160
180
200
0 2 4 6 8 10 12
pH of buffer solutions
Conc
(mg/ml)

72. • Flow properties of drug
Test Result
Untapped bulk density 0.455 gm/mL
Tapped bulk density 0.667 gm/mL
% Compressibility 31.78 %
Angle of Repose 37.56 °
Flow Rate 1 g/60 secs
 Drug-excipient compatibility studies: Drug was
found to have no interaction with HPMC and
EC.
 Forced degradation: The drug degraded in 0.1 N
NaOH and hydrogen peroxide.

73. DSC Thermogram of CAP

74. DSC Thermogram of Cap + EC

75. DSC Thermogram of CAP + HPMC

76. Forced degradation
Concentration: 10 mcg/mL Retention Time: 4.762 mins

77. Concentration: 10 mcg/mL Retention Time: 4.947 mins
Peak Area: 40852.72 [µV.Sec]
Chromatogram of Oxidative Hydrolysis of CAP

78.  Various excipients used for preparation of floating tablets
included the following:
 Diluent: Lactose monohydrate
 Primary polymer: various grades of Hydroxypropyl Methylcellulose
(HPMC)
 Retardant: Ethyl Cellulose (EC)
 Binder: Poly Vinyl Pyrrolidone K-30 (PVP K-30)
 Granulating Fluid: Isopropyl Alcohol (IPA)
 Glidant: Talc
FORMULATION

79. 1) Batches made with primary
polymer

80. 2) Batches made by using alcoholic solution of PVP K-
30 as binder
i) Using 3% solution of PVP K-30 in IPA:

81. ii) Using 5% solution of PVP K-30 in IPA:

82. 3) Batches made by using EC(3%)
in the dry form

83. 4) Batches made by using EC in
alcoholic solution (3 %):

84. EVALUATION
1) Appearance, Hardness, Friability and FLT
- Bad
++ Acceptable
+++ Good

85. 2) In-vitro drug release:
0
20
40
60
80
100
0 5 10 15 20 25
time (hrs)
Drug
Release
(%)
A4
A5
A6
A7
A8
A9
A 10
A 11
A 12 0
20
40
60
80
100
0 5 10 15 20 25
Time (hrs)
Drug
release
(%)
B 1
B 2
B 3
B 4
B 5
B 6
B 7
B 8
B 9
0
20
40
60
80
100
0 5 10 15 20 25
Time (hrs)
Drug
release
(%)
C 1
C 2
C 3
C 4
C 5
C 6
C 7
C 8
C 9
0
20
40
60
80
100
0 5 10 15 20 25
Time (hrs)
Drug
release
(%)
E 1
E 2
E 3
E 4
E 5
E 6
E 7
E 8
E 9
Formulation A 4 - 12 Formulation B 1- 9
Formulation C 1- 9 Formulation E 1- 9

86. OPTIMISATION
 Batch E 9 showed good tablet integrity, appearance, low friability, no
FLT, Floating time of more than 24 hrs and drug release without
initial bursting effect, therefore this formula was optimized. A 32
factorial design was used in the present study.
 FLT, Time for 25 % drug release (T25%) and Time for 80 % drug
release (T80%) were selected as dependent variables.
 The two independent variables at three levels chosen were:
Independent variables +1 0 -1
Amount of HPMC (X1) 400 mg 300 mg 200 mg
Amount of EC (X2) 60 mg 40 mg 20 mg

87. Formulation a3 showed no FLT and T25% & T80% of 2 and 21 hrs respectively.
Therefore a3 as devised as the optimum formulation and was subjected to
stability studies.

88. Test Result
Untapped bulk density 0.222 + 0.05 gm/ml
Tapped bulk density 0.263 + 0.05 gm/ml
% Compressibility 15.58 + 0.5 %
Angle of Repose 14.83 + 0.5 °
Flow Rate 1 g/ 30 secs
Evaluation of optimised
batch
Flow properties of granules ready for compression

89. Parameters Results
Appearance Good
Dimensions Diameter -12.5 mm ± 0.1mm.
Thickness – 5 mm ± 0.1mm
Hardness 3.5 ± 0.5 kg/cm2
Friability 0.459 ± 0.024%
Weight variation Passes
Assay 99.92%
In-vitro buoyancy/ floating lag time 0 secs in 0.1 N HCl
0 secs in SGF
Evaluation of tablets of optimised batch

90. Effect of osmolarity on swelling
behavior
0
20
40
60
80
100
120
140
0 4 8 12 16 20 24
Time (hrs)
%
increase
in
thickness
0.1 N HCl
SGF
iso-osmolar
hypermolar
hypomolar
0
10
20
30
40
50
60
0 4 8 12 16 20 24
Time (hrs)
%
increase
in
diameter
0.1 N HCl
SGF
iso-osmolar
hypermolar
hypomolar
% increase in thickness % increase in diameter.

91. 0.1 N HCl
0
20
40
60
80
100
0 4 8 12 16 20 24
Time (hrs)
Drug
release
(%)
In-vitro drug release

92. 0
20
40
60
80
100
120
0 4 8 12 16 20 24
Time (hrs)
Drug
Release
(%)
0.1 N HCl
SGF
Iso-osmolar
hypermolar
hypomolar
Effect of osmolarity on drug release

93. 0
20
40
60
80
100
120
0 6 12 18 24
Time (hrs)
Drug
release
(%)
pH 1.2
pH 4
pH 6
Effect of pH on drug release

94. 0
2
4
6
8
10
12
0 6 12 18 24
Time (hrs)
Increase
in
weight
(mg)
43.2 % RH
75.3 % RH
97.3 % RH
Moisture absorption studies

95. Effect of pH and osmolarity on
floating behaviour

96. STABILITY STUDIES - Physical parameters of the tablets

97. Drug content of stability batch

98. In-vitro dissolution studies

99.  A non-effervescent floating matrix tablet was developed
using two different grades of HPMC i.e. HPMC-K15MCR
and HPMC-K100MCR. HPMC was selected as it is a
hydrophilic swellable polymer having low density.
Because of freely water soluble nature of CAP it was
necessary to include release retardant in formulation. EC
was selected as retardant due to its hydrophobic nature.
 The developed stable sustained release floating
gastroretentive tablets of CAP were found to have no
FLT, floating time greater than 24 hrs and desired drug
release pattern. Thus the objectives envisaged in this
thesis were fulfilled.
CONCLUSION