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Gastroretentive Dosage Forms
Selected Topics in
Pharmaceutical Technology
Gastroretentive Dosage Forms
• Drugs can have poor bioavailability after peroral
administration due to slow dissolution, poor permeation
and/or degradation in the gastrointestinal (GI) tract.
• The poor bioavailability of some of these drugs may be
due to their narrow absorption window (NAW) at the
upper part of the gastrointestinal tract.
• The proximal part of the small intestine exhibits good
absorption properties (including high surface area (villi)
larger gaps between the tight junctions, and dense active
transporters).
• Despite the extensive absorption properties of the
duodenum and jejunum, the extent of absorption at
these sites is limited because the passage through this
region is rapid.
Gastroretentive Dosage Forms
• Enhancing the gastric residence time (GRT) of a NAW
drug may significantly improve the net extent of its
absorption.
Gastroretentive Dosage Forms
• Extended release DDS possessing gastric retention
properties may be potentially useful as the retention of
oral dosage forms in the upper GIT causes prolonged
contact time of drug with the GI mucosa, leading to:
– Higher bioavailability, and hence therapeutic efficacy
– Reduced time intervals for drug administration
– Potentially reduced dose size and thus improved
patient compliance
Gastroretentive Dosage Forms
Drug Candidates for Gastric Retention
• Gastroretentive DDSs exhibiting controlled drug release
are significantly important for drugs which are:
– Acting locally in the stomach (e.g. antibiotics against
Helicobacter Pylori, antacids and misoprostol)
– Absorbed incompletely due to a relatively narrow window of
absorption in the GIT, such as cyclosporin, ciprofloxacin,
furosemide, L-DOPA and riboflavin.
– Unstable in the intestinal or colonic environment such as
captopril
– Exhibit low solubility at high pH values such as verapamil HCl,
diazepam and chlordiazepoxide
Gastroretentive Dosage Forms
Drug Candidates for Gastric Retention
• Gastroretentive DDS, on the other hand, are not suitable
for drugs:
– That may cause gastric lesions, e.g., non-steroidal antiinflammatory agents
– Drug substances that are unstable in the strong acidic
environment of the stomach.
– In addition, gastroretentive systems do not offer significant
advantages over conventional dosage forms for drugs which are
absorbed throughout the gastrointestinal tract.
Approaches to Gastric Retention
• The most important parameters affecting gastric
emptying and, hence, the gastric retention time of oral
dosage forms include:
– 1. Density, size and shape of the device.
– 2. Concomitant ingestion of food and its nature, caloric content
and frequency of intake.
– 3. Simultaneous administration of drugs with impact on
gastrointestinal transit time; for example, drugs acting as
anticholinergic agents (e.g. atropine, propantheline), opiates
(e.g. codeine) and prokinetic agents (e.g. metoclopramide,
cisapride).
– 4. Biological factors such as gender, posture, age, sleep, body
mass index, physical activity and disease states (e.g. diabetes,
Crohn's disease).
Gastroretentive Dosage Forms
• The main approaches that have been examined for
gastroretentive drug delivery include:
– low density of the GRDF that causes buoyancy above
gastric fluid
– high density which retains within folds the dosage
form (DF) in the body of the stomach that is
anatomically lower than the pyloric sphincter
– concomitant administration of drugs or excipients
which slow the motility of the gastrointestinal tract
– bioadhesion to gastric mucosa
– swelling to a large size which prevents emptying of
the DF through the pyloric sphincter
APPROACHES TO ACHIEVE GASTRIC
RETENTION
Bioadhesive drug delivery
systems
• It involves the use of bioadhesive polymers that can
adhere to the epithelial surface of the GIT.
• A bioadhesive can be defined as a substance with the
ability to interact with biological materials and is capable
of being retained on the biological substrate for a period
of time.
Bioadhesive drug delivery
systems
• Bioadhesive polymers are usually macromolecular,
hydrophilic gelling substances with numerous hydrogenbond forming groups (carboxyl, hydroxyl, amide and
sulfate groups):
– polyacrylic acids (Carbapol), sodium carboxymethyl cellulose
(CMC), sodium alginate and carrageenan.
• Anionic polymers have been found to have better binding
capacity than neutral or cationic polymers.
Formulation and drug incorporation:
Several approaches have been investigated for the
incorporation of drug into mucoadhesive polymers onto
and/or in cores (maultiparticlute system, such as pellets,
granules and microcapsules)
1 Coating: An immediate release core is coated with the
mucoadhesive polymer. In this case, the duration of
retention is controlled by the dissolution rate of the
polymer. Cross-linking can retard this, however, it also
reduce the rate of hydration, which negatively affect
mucoadhesion. Dose dumping (premature drug release)
can result when the coat separate.
2 Matrix type: The drug is dispersed in a matrix of the
mucoadhesive polymer.
3 Hybrid: Matrix coated with a polymer.
Bioadhesive drug delivery
systems
• The proposed mechanism of bioadhesion is the
formation of hydrogen – and electrostatic bonding at the
mucus-polymer boundary.
• Rapid hydration in contact with the muco-epithelial
surface appears to favor adhesion.
Size-increasing drug delivery systems
• Another approach to retaining a pharmaceutical dosage
form in the stomach is by increasing its size above the
diameter of the pylorus .
• However, owing to significant inter-individual variations,
the cut-off size cannot be determined exactly.
• Roughly, the dosage forms should be larger than 13 mm,
Size-increasing drug delivery systems
• In order to facilitate swallowing, it is highly desirable to
design dosage forms with an initially small size that —
once in the stomach — significantly increase in size.
• The expanded state should be achieved rapidly in order
to prevent premature emptying through the pylorus.
• Conversely, the systems should also guarantee their
clearance from the stomach after predetermined time
intervals to avoid accumulation upon multiple
administrations.
• In addition, the dosage form should have no effect on
gastric motility or emptying process.
Size-increasing drug delivery systems
• Deshpande et al. (Deshpande et al., 1997a; Deshpande et al.,
1997b) developed a controlled-release gastric retention system
composed of:
– a swellable core, which consisted of the drug, chlorphenamine maleate or
riboflavin 5′ phosphate, and the expanding agents crosslinked polyvinyl
pyrrolidone (PVP), Carbopol 934P and calcium carbonate.
– The tablet core was coated with a permeable coating, consisting of blends of
Eudragit RL® 30 D and NE 30 D in different ratios.
• The tablets swelled to 2- 4 times their original volume, while
releasing the drug in a controlled manner.
• The optimal ratio of Eudragit® RL 30 D: NE 30 D was found to be
70: 30, which was optimum for sufficient elasticity to withstand the
pressure of expansion during the initial swelling phase, and allowing
the breakdown of the tablet following release of the drug.
Floating drug delivery systems
• Drug delivery systems that float immediately upon
contact with gastric fluids present promising approaches
for increasing the bioavailability of drugs with absorption
windows in the upper small intestine.
• However, immediate floating can only be achieved if the
density of the device is low at the very beginning.
• Devices with an initially high density (which decreases
with time) first settle down in the stomach and, thus,
undergo the risk of premature emptying.
• Inherent low density can, for example, be provided by
the entrapment of air or by the (additional) incorporation
of low-density materials (e.g. fatty substances or oils, or
foam powder).
Hydrodynamically Balanced System
 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 slowly
and facilitate floating by achieving
density lower than 1.
 The coating forms a viscous
barrier, and the inner polymer
slowly gets hydrated as well,
facilitating the controlled drug
release by controlling solvent into
the tablet penetration and drug
diffusion
•
The polymers used in this system
includes
hydroxypropylmethylcellulose,hydroxy
ethylcellulose, hydroxypropylcellulose,
sodium carboxymethylcellulose, agar,
carrageenans, and alginic acid.
Effervescent matrix
This system can be made as
tablets, pellets or granules.
These buoyant systems utilize
matrices prepared with
swellable polymers like
methocel, polysaccharides like
chitosan, effervescent
components like sodium
bicarbonate, citric acid and
tartaric acid. As sodium
bicarbonate reacts with HCl in
the stomach or incorporated
citric acid and or tartaric acid
CO2 is released and entrapped
in the gelling polymer, which
causes rapid floating as the
gas has low density
High density drug delivery systems
• These devices use their weight as a retention
mechanism.
• When the density of the system is larger than that of the
gastric juice (~1.004 g/cm³), the device settles down to
the bottom of the stomach, and remains located below
the pylorus.
• This could be accomplished by including a heavy inert
material such as zinc oxide, titanium dioxide, iron
powder or barium sulphate into the drug containing core
pellets or coating drug containing pellets with it.
• These materials increase density by up to 1.5–2.4 g/cm3