Gastro-retentive
Drug Delivery System
Session Objectives
By the end of this session, students will be able to:
• Explain various gastro-retentive strategies
for drug absorption
• Elaborate various factors to be considered in
the design of GRDDS
• Explain the significance of various processes
involved in preformulation of GRDDS
• Formulate a suitable gastro-retentive dosage
form based on the need and drug characteristics
Limitations of GRDDS
Retention
in the stomach is not desirable for drugs that cause gastric lesions (e.g. Non-
steroidal anti-inflammatory drugs NSAIDs).
Drugs
that are degraded in acidic environment of stomach (e.g. Insulin).
Drugs
that undergo a significant first-pass metabolism (e.g. Nifedipine).
Drugs
that have very limited acid solubility (e.g. Phenytoin).
A tube about nine meters long that runs through the middle
of the body from the mouth to the anus and includes;
throat (pharynx),
esophagus,
stomach,
small
intestine
–
duodenu
–
jejunum
–
ileum
Large
intestine.
Approaches
Approaches
Floating
drug delivery systems
Mucoadhesive
system
Swellable
Systems
High
density systems.
Floating
DDS
These
are low density systems.
Have
ability to float over gastric contents.
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).
Eased
from the system at desired rate.
Techniques for floatation
Effervescent
Volatile
liquid containing systems
Gas
generating systems
Non-Effervescent
Colloidal
gel barrier systems
Alginate
beads
Hollow
Microspheres
Microporous
Compartment System
1. Effervescent systems
Gas generating systems
Effervescence
is there.
Utilizes
effervescent reactions between carbonate/bicarbonate salts and citric/tartaric
acid.
CO2
is released in presence of H2O.
When
tablet is put in beaker it will sink
2NaHCO3+C4H6O6
à C4H4Na2O6+2CO2+2H2O
With
production of gas it rises up and floats.
Volatile liquid
containing systems
Incorporates
an inflatable chamber, which contains a liquid
e.g. ether, cyclopentane, that gasifies at body temperature
to cause the inflatation of the chamber
in the stomach.
The
device may also consist of a bioerodible plug made up of PVA, 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.
These
systems are very less used as the gas generating systems are safer.
2. Non-effervescent systems
q This
type of system, after swallowing, swells unrestrained via imbibition of gastric
fluid to an extent that it prevents their exit from the stomach.
q One
of the formulation methods of such dosage forms involves the mixing of the drug
with a gel, which swells in contact with gastric fluid after oral
administration.
a) Colloidal gel
barrier systems
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.
e.g.HEC,
HPMC, NaCMC.
On
coming in contact with gastric fluids forms a viscous core.
Incorporates
H2O and entraps air.
Density
of system falls below 1gm/cm3. Then it starts floating
The air trapped by the swollen polymer confers buoyancy to
these dosage forms.
Excipients used most commonly in these systems include
1. Hydroxypropyl
methyl cellulose (HPMC)
2. Polyacrylate
polymers
3. Polyvinyl
acetate
4. Carbopol
5. Agar
6. Sodium
alginate
7. Calcium
chloride
8. Polyethylene
oxide
9. Polycarbonates
b). Microporous membrane
systems
Based
on the encapsulation of drug reservoir inside a Microporous 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.
c) Alginate Beads
Spherical
beads of approximately 2.5 mm in diameter can be prepared by dropping a sodium
alginate solution in to aqueous solutions of calcium chloride, causing precipitation
of calcium alginate.
Sodium
alginate+ Calcium chloride à
Calcium alginate+ NaCl
The
beads are then separated snap and frozen in liquid nitrogen, and freeze dried
at -40°C for 24 hours, leading to the formation of porous system.
Maintain
a floating force of over 12 hours.
d) Hollow microspheres
Microballoons
/ hollow microspheres loaded with drugs are prepared by simple solvent
evaporation method.
Commonly
used polymers to develop these systems are polycarbonate, cellulose acetate, calcium
alginate, Eudragit S, agar and pectin etc.
These
systems have capacity to float on acidic dissolution media containing
surfactant for about 12 hours invitro.
Mucoadhesive systems
Involves
the use of bioadhesive polymers, which can adhere to the epithelial surface in
the stomach.
Dosage form can stick to mucosal surface by following mechanisms:
- The
wetting theory - The
diffusion theory - The
absorption theory - The
electron theory
Swellable Systems
A
dosage form in the stomach will withstand gastric transit if it bigger than
pyloric sphincter, but should be small enough to be swallowed.
These
systems swells many times its original size.
Cross
linking should be optimum highly cross linked don’t swell.
Chitosan,
HPMC, sodium starch glycolate, carbopol are used.
Diclofenac,
Ciprofloxacin, Furosemide are reported with these systems.
These have density greater than that of gastric fluids (1.4g/cc).
Above 1.6g/cc is preferable, tend to
withstand peristaltic movements
of stomach.
Zinc oxide, Iron oxide, Titanium dioxide,
barium sulfate are used as inert heavy core.
Osmotic Drug Delivery System
Osmosis
• Osmosis
can be defined as the net movement of water across a selectively permeable
membrane driven by a difference in osmotic pressure across the membrane.
• It
is driven by a difference in solute concentrations across the membrane that
allows passage of water, but rejects most solute molecules or ions.
• Osmotic
pressure is the pressure which, if applied to the more concentrated solution,
would prevent transport of water across the semipermeable membrane.
Osmotic Drug Delivery
System
Osmotically
controlled drug delivery systems utilize osmotic pressure for controlled
delivery of active agent.
Osmotic
pressure: It is colligative property of solution in which a
non-volatile solute is dissolved in a volatile solvent.
It has no water chamber, and the device is activated by
water imbibed from the surrounding environment.
The pump is activated when it is swallowed or implanted in
the body.
This pump consists of a rigid housing, and the semipermeable
membrane is supported on a perforated frame.
It has a salt chamber containing a fluid solution with
excess solid salt. Recent modification in Higuchi-Leeper pump accommodated
pulsatile drug delivery.
Further simplified variant of Rose-Nelson pump was
developed by Higuchi and Theeuwes
Mechanism of drug release
It involves osmosis
of gastrointestinal fluid across the semi permeable membrane at a controlled
rate.
Dissolution of drug
& osmotic agent to produce a saturated drug solution within a tablet core.
As the no. of
molecules in solution increases, the osmotic pressure within a tablet core
increases.
Outer coating (semi
permeable membrane) is rigid.
Therefore to reduce
the osmotic pressure within the tablet, saturated drug solution is emitted from
a tablet core through orifice.
The major
formulation components of a typical osmotic delivery system include:
- Drug
- Osmotic agents
- Semi permeable membrane
Osmotic agents
Osmotic components
usually are ionic compounds consisting of either inorganic salts or hydrophilic
polymers.
These materials
maintain a concentration gradient across the membrane.
They also generate a
driving force for the uptake of water and assist in maintaining drug uniformity
in the hydrated formulation.
Osmotic pressure of saturated solution of common
pharmaceutical solutes
|
Compound or Mixture |
Osmotic pressure (atm) |
|
Sodium chloride |
356 |
|
Fructose |
355 |
|
Potassium chloride |
245 |
|
Sucrose |
150 |
|
Dextrose |
82 |
|
Potassium sulphate |
39 |
|
Mannitol |
38 |
|
Sodium phosphate tribasic |
36 |
Semi permeable
membrane
Semi permeable
membrane has important role in controlling drug release.
Membrane must meet several performance
criteria-:
1.
Polymer
must exhibit sufficient wet strength and water permeability so as to attain
water flux rate in the desired range.
2.
Reflection
coefficient (leakage of solute through membrane) should approach the limiting
value of 1.
3.
Membrane
should be biocompatible.
e.g. Cellulose
esters like cellulose acetate, cellulose acetate butyrate, cellulose triacetate
and ethyl cellulose and Eudragits.
Wicking agents -:
– It has ability to draw water in to the
porous network of a delivery device
– E.g. colloidal silicon dioxide, kaolin,
titanium dioxide, SLS, low molecular weight (PVP).
Pore forming agents -:
– These agents are
particularly used in the pumps developed for poorly water soluble drugs and in
the development of controlled porosity osmotic pumps.
– These pore forming
agents cause the formation of micro porous membrane.
– alkaline metal
salts such as sodium chloride, sodium bromide, potassium chloride, potassium
sulfate, potassium phosphate, etc.
Classification of ODDS
• Implantable osmotic pump.
• Oral osmotic pump.
Implantable systems
further classified as-:
- For experimental use
- For human use
Oral osmotic pump.
These systems can be
further classified as-:
Single chamber
osmotic system:
– Elementary osmotic pump
Multi-chamber
osmotic systems:
– Push-pull osmotic pump
Miscellaneous:
– Controlled
porosity osmotic pumps
– Osmotic bursting
osmotic pump
– Effervescent
activity-based osmotic systems
– OROS- CT,- L-OROS
Single chamber osmotic system
Elementary osmotic
pump -:
It consist of an osmotic
core containing drug & if required osmotic agent, which is coated with semi
permeable membrane.
When core imbibes
water osmotically at a controlled rate through semi permeable membrane, forming
a saturated drug solution.
The system delivers,
via orifice, saturated drug solution.
Factors
affecting drug release rate
• Orifice
size
• Solubility
• Osmotic
Pressure
Orifice size
The size of the
orifice must be larger than a minimum size (600µ), to minimize hydrostatic
pressure.
This is necessary
step in achieving zero order drug release.
The size of the
orifice must be smaller than a maximum size (1 mm) , to minimize diffusional
contribution to delivery rate.
Solubility
The release rate
depends on the solubility of the solute inside the drug delivery system.
Therefore, drugs
should have sufficient solubility to be delivered by osmotic delivery.
Various solubility modifying approaches include:
– Use of swellable polymers
– Use of wicking agents
– Use of effervescent mixtures
– Use of cyclodextrin
derivatives
– Use of alternative salt form
Advantages
• There is no requirement for the system to
disintegrate for the release of drug to occur.
• Delivery of drugs takes place in solution
form, which is ready for absorption.
• Delivery rate is independent of pH and
outside agitation.
• The in vivo delivery rate of drug is expected
to be same as that in vitro.
• Due to its zero order release profile it is
used in early stages of drug research, such as drug screening, animal
toxicology.
Limitations
• Special
equipment is required for making an orifice in the system.
• If the
coating process is not well controlled there is a risk of film defects, which
results in dose dumping.
• Residence
time of the system in the body varies with the gastric motility and food
intake.
• It may
cause irritation or ulcer due to release of saturated solution of drug.
Elementary osmotic pump
|
Brand Name |
API |
|
Efidac 24 |
Chlorpheniramine |
|
Acutrim |
Phenylpropanolamine |
|
Sudafed 24 |
Pseudoephedrine |
Push-pull osmotic systems
|
Brand Name |
API |
|
Ditropan XL ® |
Oxybutynin chloride |
|
Procardia XL® |
Nifedipine |
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