2. WHAT IS GRDDS???
Gastroretentive 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.
3. NEED FOR GRDDS…???
Oral drug delivery system Sustained drug delivery systems
These drug delivery systems suffer from mainly two adversities:
short gastric retention time(GRT) and
unpredictable short gastric emptying time (GET)
which can result in incomplete drug release from the dosage form in the
absorption zone (stomach or upper part of small intestine) leading to
diminished efficacy of administered dose.
To formulate a site-specific orally administered controlled release dosage
form, it is desirable to achieve a prolong gastric residence time by the
drug delivery. Prolonged gastric retention time (GRT) in the stomach
could be advantageous for local action e.g. treatment of peptic ulcer, etc.
4. POTENTIAL DRUG CANDIDATES FOR
GASTRORETENTIVE DRUG DELIVERY
SYSTEMS
1. Drugs acting locally in the stomach(active in stomach)
e.g. Antacids and drugs for H. Pylori viz., Misoprostol
2. Drugs that are primarily absorbed in the stomach
e.g. Amoxicillin
3. Drugs that are poorly soluble at alkaline pH
e.g. Furosemide, Diazepam, Verapamil, etc.
4. Drugs with a narrow window of absorption
e.g. Cyclosporine, Methotrexate, Levodopa, etc.
5. Drugs which are absorbed rapidly from the GI tract.
e.g. Metronidazole, tetracycline.
6. Drugs that degrade in the colon.
e.g. Ranitidine, Metformin HCl.
7. Drugs that disturb normal colonic microbes
e.g. antibiotics against Helicobacter pylori.
5. 1] DRUGS THAT HAVE VERY LIMITED ACID
SOLUBILITY
PHENYTOIN ETC.
2) DRUGS THAT SUFFER INSTABILITY IN THE
GASTRIC ENVIRONMENT E.G.
ERYTHROMYCIN ETC.
3) DRUGS INTENDED FOR SELECTIVE
RELEASE IN THE COLON
5-AMINO SALICYLIC ACID AND
CORTICOSTEROIDS
ETC.
FACTORS AFFECTING THE
GASTRORETENTIVE SYSTEM.
1. DENSITY.
2. SIZE.
3. SHAPE OF DOSAGE FORM.
4. SINGLE OR MULTIPLE UNIT FORMULATION.
5. FED OR UNFED STATE.
6. 7. NATURE OF MEAL 8. FREQUENCY OF FEED 9. GENDER. 10. AGE.
11. POSTURE. 12.CONCOMITANT DRUG. 13. BIOLOGICAL FACTORS.
APPROACHES TO GASTRIC RETENTION
7.
8. PHYSIOLOGY OF THE STOMACH
The stomach is an organ with a capacity for storage and
mixing. The antrum region is responsible for the mixing and
grinding of gastric contents.
Under fasting conditions, the stomach is a collapsed bag with
a residual volume of approximately 50ml and contains a small
amount of gastric fluid (pH 1–3) and air.
9. REQUIREMENTS FOR GASTRIC
RETENTION
The dosage form must satisfy certain requirements:
Able to withstand the forces caused by peristaltic waves in the
stomach and the constant contractions and grinding and
churning mechanisms.
Resist premature gastric emptying.
Device should be removed from the stomach with ease.
APPROACHES TO ACHIEVE GASTRIC
RETENTION
Floating drug delivery systems
10. The major requirements for floating drug delivery system are:
• Release contents slowly to serve as a
reservoir.
• Maintain specific gravity lower than gastric contents
(1.004 – 1.01 gm/cm3).
• Form a cohesive gel barrier.
The inherent low density can be provided by the
entrapment of air (e.g. hollow chambers) or by the incorporation
of low density materials (e.g. fatty materials or oils, or foam
powder.
Multiple-unit floating system preferred over Single-unit dosage
because of dose dumping.
11. Multiple-unit floating system:
Air compartment multiple-unit system hollow microspheres
(microballoons)
Microparticles.
Based on the mechanism of buoyancy two distinctly different
technologies, i.e. non-effervescent and effervescent systems
have been utilized in the development of floating drug delivery
system.
Non-effervescent Systems
Prepared from gel-forming or highly swellable cellulose type
hydrocolloids, polysaccharides or matrix forming polymers like
polyacrylate, polycarbonate, polystyrene and polymethacrylate.
12. The air trapped by the swollen polymer confers buoyancy to these
dosage forms.
Excipients used are HPMC, polyacrylates, polyvinyl acetate,
carbopol, agar, sodium alginate, calcium chloride, polyethylene
oxide and polycarbonates.
This system can be further divided into the sub-types:
Hydrodynamically balanced systems:
Sheth and Tossounian
DRUG + GEL- FORMING HYDROCOLLOID= BUOYANT
Single-unit dosage for contains one or more gel-forming
hydrophilic polymers.
Excipients:
13. HPMC
HEC
HPC
NaCMC
Polycarbophil,
Polyacrylate, Polystyrene,
agar, carrageenans or alginic acid.
POLYMER+DRUGS
The capsule shell dissolves in contact with water and
mixture swells to form a gelatinous barrier, which
imparts buoyancy to dosage form in gastric juice for
a long period. Incorporation of fatty excipients
gives low-density formulations reducing the
erosion.
14. MICROSPHERES
Microballoons / Hollow microspheres loaded with drugs
prepared by solvent evaporation or solvent diffusion /
evaporation methods.
Polymers used polycarbonate, cellulose acetate, calcium
alginate, agar, and low methoxylated pectin etc. Buoyancy
and drug release depends on quantity of polymers, plasticizer
polymer and solvents used.
The microballoons floated continuously over the surface of an
acidic dissolution media containing surfactant for >12 hours.
Are the best because they combine the advantages of
multiple-unit system and good floating.
15. ALGINATE BEADS
Talukdar and Fassihi
Recently developed a multiple-unit floating system based on
cross-linked beads. They were made by using Ca2+
and low methoxylated pectin (anionic
polysaccharide) or Ca2+ low methoxylated pectin
and sodium alginate. These beads system can maintain a
floating force for over 12 hrs. These beads improve gastric
retention time (GRT) more than 5.5 hours.
16. MICROPOROUS COMPARTMENT
SYSTEMS
Based on the principle of the encapsulation of a drug reservoir
inside a microporous compartment with pores along its top and
bottom walls.
Gastric fluid enters through the aperture, dissolves the drug and
causes the dissolved drug for continuous transport across the
intestine for drug absorption.
EFFEREVESENT GAS GENERATIONG
SYSTEM
Floatability can be achieved by generation of gas
bubbles(Carbon dioxide) These buoyant systems utilize
matrices prepared with swellable polymers such as
polysaccharides (e.g. chitosan), effervescent components (e.g.
sodium bicarbonate, citric acid or tartaric acid, sodium alginate
and sodium bicarbonate.
17. Multiple unit floating dosage forms generate gas (carbon
dioxide) when ingested, floating mini capsules with a core of
sodium bicarbonate, lactose and polyvinyl pyrrolidone (PVP)
coated with hydroxypropyl methylcellulose (HPMC), and floating
system based on ion exchange resin technology etc.
18. BIOADHESIVE OR MUCOADHESIVE
SYSTEMS
Delivery device within the human to enhance drug absorption in
a site-specific manner.
bio adhesive polymers used which adhere to the epithelial
surface in the stomach & improves the prolongation of gastric
retention.
These mechanisms are:
1) The wetting theory 2) The diffusion theory
3) The absorption theory 4) The electron theory
Materials commonly used for bioadhesion are poly
acrylic acid, chitosan, cholestyramine, sodium
alginate, hydroxypropyl methylcellulose (HPMC),
sucralfate, tragacanth, dextrin, polyethylene glycol and polylactic
acids etc.
19. EXPANDABLE OR UNFOLDABLE
SYSTEMS
A dosage form will withstand gastric transit
bigger than pyloric sphincter
and must be small enough to be
swallowed, and must not cause gastric obstruction
Gastroretentivity is improved by:
combination of substantial dimension with high rigidity
of dosage form to withstand peristalsis and
mechanical contractility of the stomach.
20. SUPER POROUS HYDROGELS
In this approach to improve gastric retention time (GRT) super
porous hydrogels of average pore 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 and are intended to have sufficient
mechanical strength to withstand pressure by gastric contraction.
MAGNETIC SYSTEMS
Enhances the gastric retention time (GRT) based on the simple
principle that the dosage form contains a small internal magnet,
and a magnet placed on the abdomen over the position of the
stomach.
21. ADVANTAGES OF GASTRORETENTIVE
DRUG DELIVERY SYSTEM.
Improves patient compliance e.g. Furosemide
Enhanced bioavailability.
Increased Gastric retention time.
Enhanced absorption of drugs which solubilise only in stomach.
Drug releases in controlled manner for prolonged period e.g. b-lactams.
Site-specific drug delivery to stomach can be achieved.
Superior to single unit floating dosage -- no risk of dose dumping.
Avoids gastric irritation.
Better therapeutic effect of short half-life drugs can be achieved.
22. IN-VIVO EVALUATION
a) Radiology
b) Scintigraphy
c) Gastroscopy
d) Magnetic Marker Monitoring
e) Ultrasonography
f) 13C Octanoic Acid Breath Test
