GASTRO RETENTIVE DRUG DELIVERY SYSTEM (GRDDS)

Gastro retentive drug delivery system which includes, principles concepts, advantages and disadvantages of GRDDS, Modulation of GI transit time, Approaches to extend GI transit, Buccal drug delivery systems, Principle of muco adhesion, advantages and disadvantages of GRDDS, Mechanism of drug permeation, Methods of formulation and its evaluations.

1. Masters of pharmacy, Pharmaceutical technology (Pharmaceutics)
Subject- Drug delivery system (MPH-102T)
Lesion no- 3, Gastro Retentive Drug Delivery System By- Drx JAYESH M.RAJPUT
Points:-
1) GRDDS Principle and Introduction:-
Conventional oral drug delivery system (DDS) is complicated by limited gastric residence tie (GRT).
Rapid Gastro intestinal (GI) transit can prevent complete drug release in absorption zone and reduce
the efficacy of the administered dose since the majority of drugs are absorbed in stomach or the
upper part of small intestine. To overcome these limitations, various approaches have been
proposed to increase gastric residence of drug delivery systems in the upper part of GIT includes
gastro retentive drug delivery system (GRDDS). Among the GRDDS, floating drug delivery system
(FDDS) have been the most commonly used.
Gastro retentive drug delivery is one of the site specific delivery of the drugs at stomach. It is
obtained by retaining dosage form into stomach and drug is being released at sustained manner to
specific site either in stomach or intestine.

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 intestinal tract physiology:-
Anatomically the stomach is divided into 3 regions:-
 Fundus
 Body and
 Pylorus

2. pH environment in different parts of GIT:-
Stomach- 1.5 to 3.5
Duodenum- 5 to 7
Jejunum- 6 to 7
Ileum- 6.0 to 7.5
Colon- 5.5 to 7.0
Rectum- 7

3. 2) Advantages:-
 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 stomach, for
example treatment of peptic ulcer disease
 Bio-availability can be improved
 Reduced frequency of dosing with improved patient compliance
 Minimize the fluctuation of drug concentrations
 Site specific drug delivery
 Enhances the pharmacological effects
 Improved drug absorption
 Enhanced bioavailability
 Reduced dose frequency
 Controlled drug delivery of drug
 Site specific drug delivery
 The principle of HBS can be used for any particular medicament or class of medicament.
 The HBS formulations are not restricted to medicaments, which are principally absorbed from the
stomach. Since it has been found that these are equally efficacious with medicaments which are
absorbed from the intestine e.g. Chlorpheniramine maleate
 The HBS are advantageous for drugs absorbed through the stomach e.g. ferrous salts and for drugs
meant for local action in the stomach and treatment of peptic ulcer disease e.g. antacids.

4.  The efficacy of the medicaments administered utilizing the sustained release principle of HBS has
been found to be independent of the site of absorption of the particular medicaments
 Administration of a prolonged release floating dosage form tablet or capsule will result in
dissolution of the drug in gastric fluid. After emptying of the stomach contents, the dissolve drug
available for absorption in the small intestine. It is therefore expected that a drug will be fully
absorbed from the floating dosage form if it remains in solution form even at alkaline pH of the
intestine.
 When there is vigorous intestinal movement and a short transit time as might occur in certain type
of diarrhea, poor absorption is expected under such circumstances it may be advantageous to keep
the drug in floating condition in stomach to get a relatively better response
 Gastric retention will provide advantages such as the delivery of drugs with narrow absorption
windows in the small intestinal region.
 Many drugs categorized as once-a-day delivery have been demonstrated to have suboptimal
absorption due to dependence on the transit time of the dosage form, making traditional extended
release development challenging. Therefore, a system designed for longer gastric retention will
extend the time within which drug absorption can occur in the small intestine
 Certain types of drugs can benefit from using gastro retentive devices. These include:
• Drugs acting locally in the stomach;
• Drugs those are primarily absorbed in the stomach;
• Drugs those are poorly soluble at an alkaline pH;
• Drugs with a narrow window of absorption;
• Drugs absorbed rapidly from the GI tract; and
• Drugs those degrade in the colon

3) Disadvantages:-
 There are certain situations where gastric retention is not desirable. Aspirin and nonsteroidal
anti-inflammatory drugs are known to cause gastric lesions, and slow release of such drugs in
the stomach is unwanted
 Thus, drugs that may irritate the stomach lining or are unstable in its acidic environment should
not be formulated in gastroretentive systems.
 Furthermore, other drugs, such as isosorbide dinitrate, that are absorbed equally well
throughout the GI tract will not benefit from incorporation into a gastric retention system.
 The drug substances that are unsuitable 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.

5. 4) Modulation of GI transit time:-
What is GI transit time?
Gastrointestinal transit time is the time it takes for food or drug to leave stomach and travel through
intestines. The transit time for the mouth to anus varies person to person and also depending upon
object ingested and physiological condition of the tract. A study shows transit time for an indigestible
object vary from 8-62 hours. 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. It takes varying amounts of time for food to pass
through the different areas of your intestinal tract, which includes the stomach, small intestine and
large intestine.
Successful modulation of GI transit time of drug delivery involves study of following sections:-
 Anatomy of GI tract
 GI tract is a group of organs joined in a long tube which is divided into several sections,
each of that fulfills a specific function
 The tract begins with oral cavity, follows pharynx, esophagus, stomach, small intestine
and large intestine ending with rectum to anus part
 GI with muscular walls comprising four different layers
1. Inner mucosa
2. Sub mucosa
3. Muscularis externa
4. Serosa
 Stomach serves the most primarily mixing area and a reservoir that secretes
pepsinogen, gastric lipase, hydrochloric acid, and the intrinsic factor
 This section of the GI tract is normally impermeable for absorption of most materials
into the blood except water, ions, alcohol, and certain drugs such as aspirin
 It follows small intestine, the major digestive and absorptive site of the GI tract,
providing an extended surface area by the circular folds of about 10 mm height
through the microvilli on the absorptive cells of the mucosa
 The last part of the GI tract is the large intestine extending from the ileum to the anus
with 1.5 M long and 6.35 cm in diameter serving mainly the fecal storage and water
absorptive roles.

6.  Dynamics of GI tract
 GI tract is always in a state of continuous motility mainly there are 2 types of motility
patterns:-
1. Digestive mode
2. Interdigestive mode
 This mode consists of four distinct phases
1. Period of no contraction
2. Period of intermittent contractions
3. Period of regular contractions at maximal frequency
4. Period of transition between phase 3 and phase 1
 Average duration of these 4 phases is 90-120 minutes, this can be influenced under
disease states
 Phase 3 serves a role of clearing all indigestible materials from stomach and intestine
 Controlled-release GIDDS are intended to prolong GI retention so the system must be
designed as such that it must be capable of resisting PHASE 3
 Bioadhesive properties able the system to adhere mucosal membrane strongly to
withstand shear produced during this stages
 The secretions of stomach, pancreas, liver, large and small intestine provide mechanical
and chemical means required for PHASE 3 in fasting conditions.
 GI transit
 GI transit is most limiting factor in development of controlled release GIDDS and GI
transit depend upon whether the person is fasted or fed state
 The physical state of DDS, either a solid or liquid also influences GI transit
A. Fasted state
o The gastric empting of liquids in fasted state is function of volume
administered, for small volume (<100ml) liquid emptied on onset of
PHASE 2 and for larger volume (>150ml) their empting is irrespective of
phase activity
o The fasted state emptying of liquid is independent of presence of any
indigestible solid in stomach and is suggested DDS should be administered
with small volume of liquid for prolongation GI emptying time.
o Emptying of solid is function of their size small size (<1mm) can be
emptied with liquid solids of 2 mm or more done not empty until arrival of
phase 3
o During phase 1 contractions are minimum no or little movement of liquid or
solid in phase 2 and 3 movement become progressively faster, segregation
of liquid and solid also seen, liquid migrates during phase 2 and 3
o During fasted state relative motion between the dosage form in small
intestine and luminal fluid content is observed, continue shear forces and
constant fluid movement around dosage form may lead to difference
between in vivo and in vitro bioavailability of drug release.
B. Feed state
o Feeding the Fundus of stomach expand to accommodate food without an
appreciable increase in intragastric pressure
o Solids emptied at a faster rate than solids are their emptying controlled by
feedback mechanism from duodenum and ileum

7. o Solids are not emptied in feed state until they ground to 2mm or less in size,
since grinding and mixing take place in antral area dosage form tend to
reside in this are if large
o Gastric secretions also start following ingestion of food depend upon nature
and volume of ingested food, the volume emptied is replaced by gastric
secretions and thus gastric secretions and thus gastric volume remains
constant for 1
st
four hours of gastric emptying
o In small intestine contents move faster in fed state, the intestinal transit time
regardless of nature is around 3-4 hours
o Non-disintegrating tablets and capsule stay for 2-6 hour and disintegration
re emptied with the food.
 Ileocecal junction
 This serves mainly to ensure the unidirectional flow of luminal contents from small to
large intestine
 Ileocecal junction is point along the course of the gastrointestinal tract where the small
intestine (ileum) ends as it opens into the cecal portion of the large intestine.
 Colon and gut flora
 Gut flora is the complex community of microorganisms that live in the digestive tracts of
humans and other animals, including insects.
 Reactions are carried out in gut flora enzymatic cleavage i.e., glycosidase these metabolic
processes lead to metabolism of drug and applied to colon TDDS

 GI mucus
 Mucus is continuously secreted by goblet cells located throughout GIT
 Fresh mucous is very thick and becomes diluted and less thick near lumen, thickness varies
upon various region in GIT
 Main function is to protect surface mucosal cell from gastric acid as well as barrier to
antigens bacteria and virus
 Chemical composition Is network of glycoproteins
 Presence of mucus in GIT presented opportunity to prolong transit time by application of
bio (muco) adhesive polymers.

8. Candidates for GRDDS:-
 Drugs acting locally in the stomach E.g. antacids
 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
 Drugs with variable bioavailability
 Drugs with less half life


Advantages of low density approach OR floating drug delivery:-

9. Drugs those are:-
 Primarily absorbed in the stomach
 Poorly soluble at an alkaline pH
 Narrow window of absorption
 Degrade in colon
 When there is a vigorous intestinal movement and a short transit time as might occur in
certain type of diarrhea, poor absorption is expected. Under such circumstances it may be
advantageous to keep the drug in floating condition in stomach to get a relatively better
response.
Disadvantages of low density approach
 Not feasible for those drugs that have solubility OR stability problem in GIT
 Require high level of fluid in stomach
 The drugs that may irritate the stomach lining OR are unstable in acidic environment
 The dosage form should be administered with a full glass of water (200-250 ml)


Disadvantages of swelling system:-

10.  The dosage form must maintain a size larger than pyloric sphincter
 The dosage form must resist premature gastric emptying

Bio/ Muco adhesive polymers
 Chitosan
 Polyacrylic acid
 Carbopol 934p, 971p, 980
 Sodium alginate
 HPMC k4m, k15m, k100m
 Hydroxy propyl cellulose (HPC)
 Cholestyramine
Problem of muco-adhesive system:-
 Rapid removal of mucus
 We are not sure whether the DF will adhere to the mucus or epithelial cell layer
 DF may adhere to esophagus resulting in drug induced injuries

Diluents such as:-

11.  Barium sulphate (density=4.9)
 Zinc oxide
 Titanium dioxide
 Iron powder
Must be used to manufacture such high-density formulations.
Problems with high density approach:-
 Higher amount of drug require
 The dosage form must stand with peristaltic movement of stomach
5) Approaches to extend GI transit:-
Several approaches have been attempted in the preparation of gastro-retentive drug delivery
systems. These include floating systems, swell able and expandable systems, high density systems,
Bioadhesive systems, altered shape systems, gel forming solution or suspension systems and sachet
systems. Various approaches have been followed to encourage gastric retention of an oral dosage
form. Floating systems have low bulk density so that they can float on the gastric juice in the
stomach. The problem arises when the stomach is completely emptied of gastric fluid. In such a
situation, there is nothing to float on. Floating systems can be based on the following.
Hydrodynamically balanced systems (HBS) – incorporated buoyant materials enable the device to
float
*Effervescent systems – gas-generating materials such as sodium bicarbonates or other carbonate
salts are incorporated. These materials react with gastric acid and produce carbon dioxide, which
entraps in the colloidal matrix and allows them to float
*Low-density systems -- have a density lower than that of the gastric fluid so they are buoyant;
*Bioadhesive or mucoadhesive systems – these systems permit a given drug delivery system
(DDS) to be incorporated with bio/mucoadhesive agents, enabling the device to adhere to the
stomach (or other GI) 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.
*High-density Systems - sedimentation has been employed as a retention mechanism for pellets
that are small enough to be retained in the rugae or folds of the stomach body near the pyloric
region, which is the part of the organ with the lowest position in an upright posture. Dense pellets
(approximately 3g/cm3 ) trapped in rugae also tend to withstand the peristaltic movements of the
stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours,
depending more on density than on diameter of the pellets, although many conflicting reports
stating otherwise also abound in literature. Commonly used Excipients are barium sulphate, zinc
oxide, titanium dioxide and iron powder, etc. These materials increase density by up to 1.5–2.4
g/cm3 . However, no successful high density system has made it to the market
Large Single- unit Dosage Forms - these dosage forms are larger than the pyloric opening and so
are retained in the stomach. There are some drawbacks associated with this approach. Permanent
retention of rigid large-sized single-unit forms can cause bowel obstruction, intestinal adhesion and
gastroplasty

12. Co-administration of gastric- emptying delaying drugs - this concept of simultaneous
administration of a drug to delay gastric emptying together with a therapeutic drug has not received
the favour of clinicians and regulatory agencies because of the questionable benefit-to-risk ratio
associated with these devices. The stomach is a size-filtering system and so it would seem ideally
suited to retaining a DDS that is larger than the pylorus. The drawback is that the DDS is not small
enough to be taken orally if sizes larger than the pylorus are required. Several systems have been
investigated to encourage gastric retention using increasing size of DDS. Systems have been based
on expansion due to gases and swelling due to intake of external liquids
Raft systems incorporate alginate gels – these have a carbonate component and, upon reaction with
gastric acid, bubbles form in the gel, enabling floating of raft on gastric fluid.
6) Factors affecting the gastro-retentive system:-
Various attempts have been made to retain the dosage form in the stomach as a way of increasing
the retention time. These attempts include use of floating dosage forms (gasgenerating systems and
swelling or expanding systems), mucoadhesive systems, highdensity systems, modified shape
systems, gastric-emptying delaying devices and coadministration of gastric-emptying delaying
drugs. Most of these approaches are influenced by a number of factors that affect their
bioavailability and efficacy of the gastro retentive system: • Density – gastric retention time (GRT)
is a function of dosage form buoyancy that is dependent on the density; • Size – dosage form units
with a diameter of more than 7.5 mm are reported to have an increased GRT compared with those
with a diameter of 9.9 mm; • Shape of dosage form – tetrahedron and ring shaped devices with a
flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT
90% to 100% retention at 24 hours compared with other shapes; • Single or multiple unit
formulation – multiple unit formulations show a more predictable release profile and insignificant
impairing of performance due to failure of units, allow co-administration of units with different
release profiles or containing incompatible substances and permit a larger margin of safety against
dosage form failure compared with single unit dosage forms; Fed or unfed state – under fasting
conditions, the GI motility is characterized by periods of strong motor activity or the migrating
myoelectric complex (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested
material from the stomach and, if the timing of administration of the formulation coincides with
that of the 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; • Nature of meal – feeding of indigestible
polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus
decreasing the gastric emptying rate and prolonging drug release; • Caloric content – GRT can be
increased by four to 10 hours with a meal that is high in proteins and fats; • 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; • 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); • Age – elderly people, especially those over
70, have a significantly longer GRT; • Posture – GRT can vary between supine and upright
ambulatory states of the patient; • Concomitant drug administration – anticholinergics like atropine
and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride;
can affect floating time. • Biological factors – diabetes and Crohn’s disease, etc.

13. 7) Buccal drug delivery system:-
Novel drug delivery system (NDDS) is the system where the man searches for new method of
entry of drug in to the body in order to show its activity in the body. The new drug delivery system
that have been developed and developing are the mucoadhesive drug delivery systems, drug
patches, transdermal patches, etc.
The Buccal mucosa lines the inner cheek and buccal formulations are placed in mouth between the
upper gums and cheek to treat local and systemic conditions. It is richly vascularized and more
accessible for the administration and removal of dosage form. Additionally, buccal drug delivery
has highly patient acceptability, compared to other non-oral routes of drug administration.
Extensive first pass metabolism and drug degradation in the harsh gastrointestinal environment can
be administering the drug via buccal route. Drug absorption through buccal mucosa is mainly by
passive diffusion into lipoidal membrane, after absorption, the drug is transported through facial
vein which then drains into the general circulation via jugular vein, by passing the liver and there
by sparing the drug from first pass metabolism. Buccal route provides one of the potential routes
for typically large, hydrophilic and unstable proteins, oligonucleotides and polysaccharides as well
as conventional small drug molecules.
8) Principle of mucoadhesion:-
Mucoadhesive are synthetic or natural polymers which interact with the mucus layer covering the
mucosal epithelial surface and mucin molecules constituting a major part of mucus. Two surfaces
are held together by interfacial forces which may consist of valence forces, inter locking action or
both. Mucoadhesive drug delivery system utilizes the property of bio-adhesion of certain water
soluble polymers which become adhesive on hydration. If adhesive attachment is to a mucous coat
the phenomenon is known as mucoadhesion.

14. 9) Advantages of mucoadhesion:-
 Ease of administration
 Termination of therapy is easy
 Permits localization of drug to the oral cavity for a prolonged period of time
 Can be administered to unconscious patients
 Offers an excellent route, for the systemic delivery of drugs with high first pass metabolism,
thereby offering a greater bioavailability
 A significant reduction in dose can be achieved thereby reducing dose related side effects.
 Drugs which are unstable in the acidic environment are destroyed by enzymatic or alkaline
environment of intestine can be administered by this route
 Drugs which show poor bioavailability via the oral route can be administered conveniently
 The presence of saliva ensures relatively large amount of water for drug dissolution unlike in
case of rectal and transdermal routes
 Systemic absorption is rapid
 This route provides an alternative for the administration of various hormones, narcotic
analgesic, steroids, enzymes, cardiovascular agents. Etc
 The Buccal mucosa is highly perfused with blood vessels and offers a greater permeability
than the skin
10) Disadvantages of mucoadhesion:-
 Drugs, which irritate the oral mucosa, have a bitter or unpleasant taste, odour, can not be
administered by this route
 Drugs, which are unstable at Buccal pH cannot be administered by this route
 Only drugs with small dose requirements can be administered
 Drugs may swallow with saliva and loses the advantages of Buccal route
 Only those drugs, which are absorbed by passive diffusion can be administered by this route
 Eating and drinking may become restricted
Limitations:-
o The mucus is constantly removed from the epithelial surfaces. It will eventually wash out
the dosage form from the site of application
o The mucous turnover rate is different from person to person so fabrication of the dosage
form is difficult
o The adhesion rate of dosage form in the body may not be as per proposed specification
due to disease state, different physiological factors, etc
o The good mucoadhesive polymers that will fulfill all the requirements are less
o Mucoadhesive polymers are poly electrolytes, slight variation in pH, charge of the mucus
changes mucoadhesion property of polymer significantly
o This type of drug delivery system is not suitable for drugs that causes tissue irritation
Uses of Buccal delivery:-
 The oral cavity can be used for local and systemic therapy
 Examples of local therapy would be treatment of oral infections, dental caries, mouth ulcers,
stomatitis, gingivitis, etc

15.  The Buccal route is of particular interest with regard to the systemic delivery of small
molecules that are subjected to first-pass metabolism


Environment of Buccal mucosa:-
 The cells of the oral epithelia are surrounded by an intercellular ground substance,
mucus.
 The oral cavity is marked by the presence of saliva produced by the salivary glands
 Mucus which is secreted by the major and minor salivary glands as part of saliva.

16. 


Design of Buccal dosage form:-
Matrix type: - the buccal patch designed in a matrix configuration contains drug, adhesive, and
additives mixed together. Bi-directional patches release drug in both the mucosa and the mouth.

17. Drug+mucoadhesive matrix
Reserviour type:- the Buccal patch designed in a Reserviour system contains a cavity for the drug
and additives separate from the adhesive, impermeable backing is applied to control the direction
of drug delivery: to reduce patch deformation and disintegration while in the mouth: and to prevent
drug loss.

18. 11) Methods of formulation:-
For Buccal patches/films they are prepared by two methods:-
 Solvent casting method:-
o Here drug and all excipients are weighed and dispersed in the suitable organic solvent
and coated on the release liner
o The organic solvent is allowed to evaporate and after evaporation the thin layer of the
backing material is laminated on the sheet of coated release liner to form laminate
o After that the whole patch is ready to cut into required size (almost 2*2 cm2)
 Direct milling method
o Here, drug and excipients are mixed mechanically by milling or kneading
o After mixing the resultant material is rolled on the release liner till desired thickness is
achieved
o Finally as the previous method, backing material is laminated
o Though there is no difference in the patch performance manufactured by either of the
method but with the SOLVENT method there are chance of residual solvent
o Hence this solvent free method is highly used
o What does backing layer does:-
 Control the direction of drug release
 Also prevent drug losses
 Minimize deformation during handling and transportation
 Reduces the disintegration of device during the application
 Examples:- nitroglycerine patches, fentanyl patches (onsolis)

21. In-Vivo test:-
 Buccal absorption study: assay of drug solution, after mouth gargles
 Perfusion study
 Kinetic study

23. Buccal mucoadhesive dosage forms:-
Type 1
1. Single layer device with multidirectional release
2. Significant drug loss due to swallowing
Type 2
1. Impermeable backing layer is superimposed
2. Preventing drug loss into the oral cavity

24. Type 3
1. Unidirectional release device, drug loss is minimal
2. Achieved by coating every face except contact face
Buccal formulation
Buccal tablets:-
Buccal tablets are small, flat, and oval shaped dosage form. Unlike conventional tablets, buccal
mucoadhesive tablets allow for drinking and speaking without major discomfort. They soften,
adhere to the mucosa, and are retained in position until dissolution and release is complete these
tablets can be applied to different sites in the oral cavity, as well as between the lip and the gum.

26. _______________________THE END____________________________