GRDDS-Modulation to GI transit time,Approach to extend GI transit time, Presented by RESHMA V MOHAN

1. GRDDS-MODULATION TO GI
TRANSIT TIME,APPROACH TO
EXTEND GI TRANSIT TIME
PRESENTED BY :
RESHMA V MOHAN
M PHARM FIRST YEAR
PHARMACEUTICS
DPS,CPAS,PUTHUPPALLY
1

2. INTRODUCTION
 Gastro retentive drug delivery is an approach to
prolong gastric residence time, thereby targeting site-
specific drug release in the upper gastrointestinal
tract (GIT) for local or systemic effects.
 Gastro retentive systems can remain in the gastric
region for several hours and hence significantly
prolong the gastric residence time of drugs.
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3. Gastro retention helps to provide better
availability of new products with new
therapeutic possibilities and substantial
benefits for patients.
Prolonged gastric retention
improves bioavailability
reduces drug waste and
improves solubility
3

4. Gastrointestinal Transit
 Gastrointestinal transit is the time it takes for food to leave your
stomach and travel through your intestines.
 Many factors can affect transit time, including your diet, medications,
prior surgeries, gender, level of physical activity and stress level, as
well as any chronic or acute illnesses that affect your gastrointestinal
tract.
 The transit time of a gastrointestinal drug delivery system along the GI
tract is the most limiting physiological factor in the development of a
controlled-release GRDDS, it is targeted to once-a-day medication.
 Factors influence the transit time of GIT:
1. Motility pattern: whether the person is in a fasted or fed state.
2. The physical state of DDS: either a solid or a liquid
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5. MODULATION OF GI TRANSIT TIME
 The transit time for the mouth to the anus varies from one person
to another. It also depends upon the physical properties of the
object ingested and the physiological conditions of the alimentary
canal.
PHYSIOLOGY OF STOMACH
ANATOMY:
 The stomach is an organ with a capacity for storage and mixing.
 Anatomically the stomach is divided into three regions:
1. fundus
2.body
3.antrum( pylorus)
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6.  The proximal part made of fundus and body acts as a reservoir for
undigested materials.
 The antrum is the main site for mixing motions and acts as a pump for
gastric emptying propelling actions.
Under fasting conditions the stomach is a collapsed bag with a
residual volume 50ml and contains a small amount of gastric
fluid(pH1-3) and air.
• There are two main secreations:
1. mucus
2. acid
Produced by specialized cells in the stomach lining.
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7.  The stomach is an expanded section of the digestive tube
between the oesophagus and small intestine.
 The wall of the stomach is structurally similar to the other
parts of the digestive tube.
 In the empty state, the stomach is contacted and its mucosa
and sub mucosa are thrown up into distinct folds called rugae.
 There are 4 major types of secretary epithelial cells that cover
the surface of the stomach and extend down into gastric pits
and glands:
Mucous cells, Parietal cells, Chief cells, G cells.
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8.  The contraction of gastric smooth muscle serves two basic functions:
1. Ingested food is crushed, ground, mixed and liquefying to form chyme.
2. Chyme is forced through the pyloric canal into the small intestine, a
process called gastric emptying.
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9. DYNAMICS
 The gastrointestinal tract is always in a state of continuous
motility.
 There are 2 modes of motility pattern:
1. The digestive mode
2. The inter digestive mode
 Involved in the digestion of food.
 Inter digestive GI motility is characterized by a cyclic pattern
that originates in the foregut and propagates to the terminal
ileum and consists of four distinct phases:
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10. During the fasting state an inter digestive series of electrical events take
place which cycle both through stomach and intestine every 2-3 hrs, which is
called as inter digestive myoelectric cycle or migrating myoelectric cycle
(MMC).
Which is further divided into 4 phases:
1.Phase I
2.Phase II
3.Phase III
4.Phase IV
Schematic representation of inter digestive motility
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11.  Phase I: Basic phase, last from 30-60 minutes with rare contractions.
 Phase II: Pre-burst phase, last for 20-40 minutes with intermittent action potential and
contractions.
 Phase III: Burst phase, last for 10-20minutes which includes intense and regular
contractions for short period.
 Phase IV: last for 0-5 minutes and occurs between phase 2 and 1of 2 consecutive cycles.
 A complete cycle of these four phases has an average duration of 90-120 min in both
human and dog.
 Phase III has a housekeeping role and serves to clear all indigestible materials from the
stomach and the small intestine.
 Consequently, any controlled-release gastrointestinal drug delivery system designed to
stay during the fasted state should be capable of resisting the housekeeping action of
phase III if one intends to prolong the GI retention time.
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12. ILEOCECAL JUNCTION
 This serves mainly to ensure the unidirectional flow of the luminal contents from
the small to the large intestine.
COLON AND GUT FLORA
 The high water absorption capacity of the colon, the colonic contents are
considerably viscous and their mixing is not efficient.
 The availability of most drugs to the absorptive membrane is low.
 The human colon has over 400 distinct species of bacteria as resident flora, a
possible population of up to 1010 bacteria per gram of colonic content.
 Reactions carried out by gut flora are azoreduction and enzymatic cleavage.
 These metabolic processes may be responsible for the metabolism of many drugs
and may also be applied to colon-targeted drug delivery.
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13. GI MUCUS
 Mucus is continuously secreted by specialized goblet cells located
throughout the GI tract.
 Fresh mucus on the mucosal surface is very thick and becomes diluted
and less viscous as it nears the lumen. Its thickness varies depending
the region of the GI tract.
 Primary function of mucus: protection of the surface mucosal cells
from gastric acid and peptidase as well as a barrier to antigens,
bacteria, and virus.
 It also act as a lubricant to assist the passage of solids.
 The presence of mucus on the GI tract has presented an opportunity to
prolong transit time by application of bio(mucus)adhesive polymer
technology.
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14. APPROACHES TO EXTEND GASTRIC
TRANSIT TIME
Prolonged gastric retention time in the stomach could
be advantageous for local action in the upper part of
the small intestine
Eg : Treatment of peptic ulcer
In the few decades several stomach specific and gastro
retentive approaches being designed and developed
including,
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15. 15

16. 16

17. HIGH DENSITY SYSTEMS
 It is a non-floating drug delivery system
 This approach involves formulation of dosage forms with the density that must
exceed density of normal stomach content 1.004gm/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. These 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. The resultant pellets can be coated with diffusion controlled
membrane .
 These systems have some drawbacks like they are technically difficult to
manufacture with a large amount of drug because the dry material of which it is
made interacts within the gastric fluid to release its drug contents
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18. FLOATING DRUG DELIVERY
SYSTEM(LOW DENSITY SYSTEM)
 FDDS remain afloat above the gastric contents for prolonged periods of
time and provide continuous release of the drug.
 This is one of the most important approaches to achieve gastric
retention to obtain sufficient drug bioavailability.
 Floating drug delivery systems have a bulk density lower than gastric
fluids and thus remain buoyant in the stomach for prolonged period of
time, without affecting the gastric emptying rate.
 The drug is must have sufficient structure to form a cohesive gel barrier.
 It must maintain an overall specific gravity lower than that of gastric
contents (1.004-1.010)
 Large number of floating dosage forms being commercialized and
marketed world-wide
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19. MECHANISM OF FDDS
 FDDS have a bulk density less than gastric fluids and so remain buoyant in
the stomach without affecting the gastric emptying rate for a prolonged
period of time.
F= F buoyancy – F gravity = (Df-Ds) gv
Where, F= total vertical force,
Df= fluid density,
Ds= object density,
V= volume,
g=acceleration due to gravity.
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20. Types of floating drug delivery systems:
Based on the mechanism of buoyancy , two different
technologies have been utilized in the development of FDDS.
 NON-EFFERVESCENT
a)Colloidal gel barrier systems
b)Hollow Microspheres
c) micro porous compartment system
 EFFERVESCENT
a)Volatile liquid containing systems
b)Gas generating systems
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21. NON EFFERVESCENT SYSTEM
 The Non-effervescent FDDS is based on mechanism of
swelling of polymer or bioadhesion to mucosal layer in GI
tract.
 Most commonly used excipients :
 gel forming or highly swellable cellulose type
hydrocolloids, hydrophilic gums, polysaccharides and
matrix forming materials such as
polycarbonate,polyacrylate, polymethacrylate,
polystyrene et
 bioadhesive polymers such as Chitosan
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22. COLLOIDAL GEL BARRIER
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.
eg: HEC, HPMC, Na CMC.
 On coming in contact with gastric fluids forms a viscous
core.
The air trapped by the swollen polymer confers buoyancy to
the dosage form.
Density of system falls below 1gm/cm3. Then it starts
floating.
Two type:
Single layer floating tablet
Bilayer floating tablet
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23. 23

24. Single layer floating tablet Bilayer floating tablet
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25. HOLLOW MICROSPHERES
 Microballoons / hollow microspheres loaded with drugs are
prepared by simple solvent evaporation method/solvent
diffusion method.
 The ethanol/dichloromethane solution of the drug and an
enteric acrylic polymer was poured into unagitated solution of
Poly Vinyl Alcohol (PVA) that was thermally controlled at
40ºC.
 The gas phase is generated in the dispersed polymer droplet
by the evaporation of dichloromethane formed and internal
cavity in the microsphere of the polymer with drug.
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26.  Commonly used polymers to develop these systems are
polycarbonate, cellulose acetate, calcium alginate, Eudragit
S, agar and pectin.
 These systems have capacity to float on acidic dissolution
media containing surfactant for about 12 hours.
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27. MICROPOROUS COMPARTMENT
SYSTEM
 Based on the encapsulation of drug reservoir inside a Micro
porous compartment.
 The peripheral walls of the drug reservoir compartment are
completely sealed to prevent any direct contact of the gastric
mucosal surface with the undissolved drug.
 In stomach the floatation chamber containing entrapped air
causes the delivery system to float over the gastric contents.
 Gastric fluid enters through the apertures, dissolves the drug,
and carries the dissolve drug for absorption.
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28. EFFERVESCENT SYSTEMS
 GAS GENERATING SYSTEMS
1. SINGLE LAYER FLOATING TABLET
2. BILAYER FLOATING TABLET
3. MULTIPLE UNIT TYPE PILLS
4. FLOATING SYSTEM WITH ION EXCHANGE RESINS
 VOLATILE LIQUID/VACCUM SYSTEMS
1. INTRAGASTRIC GASTROINTESTINAL DDS
2. INFLATABLE GASTROINTESTINAL DDS
3.INTRAGASTRIC OSMOTICALLY CONTROLLED DDS
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29. 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.
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30. 1.SINGLE LAYER FLOATING TABLETS
(HBS)
 These are formulated by intimately mixing CO2 generating
agents and the drug within the matrix tablet.
 These having a bulk density lower than the gastric fluids and
therefore remain floating in the stomach unflattering the
gastric emptying rate for a prolonged period.
 The drug is slowly released at the 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 the grt and a better control over
fluctuation in plasma drug concentration
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31. 2.BILAYER FLOATING TABLET
 These are compressed tablet:
 It containing two layer
1) Immediate release layer
2) Sustained release layer
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32. 3.MULTIPLE UNIT FLOATING TABLET
 These system consists of sustained release pills as ‘seeds’
surrounded by double layer.
 The inner layer consists of effervescent agents and the outer
layer is contain swellable membrane layer.
 When the system is immersed in the dissolution medium at
body temperature, it sinks at once and then forms swollen
pills like balloons, which float as they have lower density. The
lower density is due to generation and entrapment of CO2
within the system.
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33. 4.ION EXCHANGE RESIN
 In ion-exchange resin, a multiple-unit type of oral floating
dosage form has been prepared to prolong gastric emptying
time of dosage form.
 The system is composed of beads of drug-resin complex,
which are loaded with bicarbonate ions and coated with
hydrophobic polymer.
 The system is so designed that when the beads reach the
stomach, chloride ions are exchanged with the bicarbonate
and drug ions.
 The generated CO2 is entrapped in the polymeric coated
resins and causes the beads to float.
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34. VOLATILE LIQUID CONTAINING
SYSTEM
 The GRT of a drug delivery system can be sustained by
incorporating an inflatable chamber, which contains liquid eg;
ether, cyclopentane that gasifies at body temperature to cause
inflatation of the chamber in the stomach.
 The device may also consist of a bio erodible plug made up of
Poly vinyl alcohol, Polyethylene, etc. that gradually dissolves
causing the inflatable chamber to release gas and collapse
after a predetermined time to permit the spontaneous ejection
of the inflatable systems from the stomach.
 There systems are very less used as the gas generating systems
are more safe.
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35. VOLATILE LIQUID/VACCUM SYSTEMS:
1. INTRAGASTRIC GASTROINTESTINAL DDS
2. INFLATABLE GASTROINTESTINAL DDS
3.INTRAGASTRIC OSMOTICALLY CONTROLLED DDS
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36. 1.INTRAGASTRIC GASTROINTESTINAL
DDS
 System can be made to float in stomach by floatation chamber, which may
be vaccum or filled with air or a harmless gas.
 This device comprised of a drug reservoir encapsulated in micro porous
compartment having pores on its surface.
 A floating chamber was attached at one surface which gives buoyancy to
entire device. Drug is slowly dissolves out via micro pore.
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37. 2.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.
 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 into the
gastric fluid.
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38. 3.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 intra gastric osmotically controlled drug delivery
device.
Inflatable support forms a deformable hollow polymeric
bag containing liquid that gasifies at body temperature to
inflate the bag.
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39. • Consists of two compartments:
1. Drug reservoir
2. Osmotically active compartment
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40. EXPANDABLE SYSTEMS
1. UNFOLDED SYSTEMS
 Unfolding systems are systems in which are actually of larger
size but they are folded to decrease size and kept in capsules.
 In stomach these systems comes out of capsules and unfolds
to larger size.
 The important factor for unfolding system is shape memory.
 They should have sufficient shape memory such that they
retain their unfolded(expanded) shape in stomach against
gastric motility and not get folded again and escape out till
the desired time interval.
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41. 2. SWELLABLE SYSTEMS
 The swelling is usually results from osmotic absorption of water.
 These are the dosage forms, which after swallowing swells to such an
extent that their exit from the pylorusis prevented, as a result the dosage
form is retained in the stomach for a prolonged period of time.
 On coming in contact with gastric fluid the polymer imbibes water and
swells.
 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.
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42. MAGNETIC SYSTEM
 This approach to enchance the gastric retention time(GRT).
 This is based on the principle that the dosage form contains a small
internal magnet, and a magnet placed on the abdomen over the
position of the stomach can enchance the GRT for a prolonged
period of time.
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43. BIOADHESIVE/MUCOADHESIVE
SYSTEMS
 Mucoadhesive drug delivery systems contain a mucoadhesive polymer
that adheres to the gastric mucosal surface and prolong its gastric
retention in the git. The capability to adhere to the mucus gel layer
makes mucoadhesive polymers very useful exicipients in the GRRDS.
 Natural polymer - sodium alginate, gelatin, guar gum etc
 Semisynthetic polymers - HPMC, carbopol, sodium carboxymethyl
cellulose .
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44. The adhesion of polymers with mucous membrane may be
mediated by hydration, bonding, or receptor mediated.
In hydration mediated adhesion, the hydrophilic polymer become
sticky and mucoadhesive upon hydration.
 Bonding mediated involves mechanical or chemical bonding.
Chemical bonds may involve ionic or covalent bonds or vander
Waal forces between the polymer molecule and the mucous
membrane.
 Receptor mediated adhesion takes place between certain
polymers and specific receptors expressed on gastric cells. The
polymers can be cationic or anionic or neutral
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45. The basis of adhesion is that a dosage form can stick
to the mucosal surface by different mechanisms.
They are:
1) The wetting theory
2) The diffusion theory
3) The absorption theory
4) The electron theory
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46. SUPERPOROUS HYDROGELS
 Super porous hydrogels of average size >100 micro meter, 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 intended to
have sufficient mechanical strength to withstand pressure by gastric
contraction.
46

47. RAFT FORMING SYSTEMS
 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 continous layer called raft.
 This raft floats on gastric fluids because of a low density
created by the formation of CO2. Usually this contains a gel-
forming agent and alkaline bicarbonates or carbonates
responsible for the formation of CO2 to make the system less
dense to float on the gastric fluids.
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48. COMMONLY USED DRUGS IN FORMULATION OF
GASTRORETENTIVE DOSAGES FORMS
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49. REFERENCE
 Yie W Chien,Novel Drug Delivery System,second edition,revised
and expanded,page no:164-177
 Meenakshi Jassal, ujjwal nautiyal, Jyotsana Kundlas, Devendra
singh. A review: Gastroretentive drug delivery system
(grdds).Indian J. Pharm.Biol. Res.2015; 3(1):82-92.
 Pawar Ashish Yaswantrao*, Jadhav Khanderao R. and Nikam
Manasi N. A Raft Forming System: An Novel Approach for
Gastroretention. Int. J. Pure App. Biosci. 3 (4): 178-192 (2015)
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