CONTROLLED RELEASE

DELIVERY SYSTEM
GROUP1
INTRODUCTION
› Controlled release dosage forms delivers a constant supply of the
active ingredient, usually at a zero-order rate by continuously
releasing for a certain period of time the amount of drug equivalent
to that eliminated by the body.
› Controlled release drug systems are more sophisticated than just
simply delaying the release rate and are designed to deliver the
drug at specific release rates within a predetermined time period.
› The terms sustained release and controlled release are usually used
interchangeably.
› Examples of controlled release dosage forms are: injections,
transdermal patch, tablets, capsules, suspensions etc.
› The Blood level time profile of controlled- The blood level profile of immediate versus
release and sustained-release dosage form controlled release
Factors To Consider In Design Of Controlled
Release Delivery System
1. Physiochemical properties of drug such as solubility, stability,
lipophilicity and molecular interactions.
2. Route of drug administration
3. Pharmacological effects
4. Biological effects such as age, weight, gender, ethnicity,
physiological processes and disease state.
Biological factors could change the pharmacokinetics and
pharmacodynamics of drug.
ADVANTAGES
1. Therapeutic advantage
2. Reduction in adverse side effects eg. Aspirin CR has been
showed to produce less gastric bleeding and improvement
to tolerability.
3. Patient comfort and compliance
4. Reduction in healthcare cost
5. Used to prolong the proprietary status of drug products
6. Avoid night time dosing
DISADVANTAGES
1. Some drugs such as riboflavin and ferrous sulphate are more
efficiently absorbed in particular regions of the GIT and
therefore controlled-release tablets are not very useful
because they release the drug throughout the intestinal tract.
2. Dose dumping
3. Less flexibility in accurate does adjustment
4. Increased potential for first pass clearance eg. Potassium
chloride CR tablets
5. Patient variation
Differences between controlled release
and sustained release
TYPES OF CONTROLLED RELEASE DELIVERY
SYSTEM
1. Prodrug
2. Diffusion-controlled delivery system
3. Dissolution/coating controlled system
4. Biodegradable/erodible delivery system
5. Osmotic pump
6. ion exchange resins
7. Hydro dynamically balanced delivery system
8. New macromolecular delivery approaches
PRODRUG
A. To change half-life:
• Drugs with very short half-life may not be therapeutically beneficial unless this characteristic is improved.
• Attaching the drug to a polymer as part of a pendent will enhance its half-life.
• Modification of the drug to protect the site of degradation or metabolism is another method to achieve longer
half-life.
B. To cross a biological barrier:
• Drugs with unbalanced hydrophilic or hydrophobic properties will not effectively cross the biological barriers.
• Attachment of functional groups can change the properties of the parent drug and allow the prodrug to cross
the barrier.
C. To increase retention time:
• When intended for a part of the body with high tissue turnover rate, such as intestinal mucosa, a drug linked to
a muco-adhesive polymer can increase adhesion to the site and increase bioavailability of a drug that has low
residence time.
D. To target a specific site:
• Connecting specialized functional groups that have site-specific affinity (peptide, antibody, etc.) Can allow the
parent drug to be delivered to the targeted area of the body to produce site specific therapeutic action.
DIFFUSION CONTROLLED DELIVERY SYSTEM
• According to the diffusion principle, controlled-release drug delivery
systems can be designed as a reservoir system or a matrix system.
• Drugs released from both reservoir and matrix type devices follow the
principle of diffusion, but they show two different release patterns.
In a reservoir system, if the active agent is in a saturated state, the
driving force is kept constant until it is no longer saturated.
For matrix systems, because of the changing thickness of the depletion
zone, release kinetics is a function of the square root of time.
• A typical reservoir system for transdermal delivery consists of a backing
layer, a rate-limiting membrane, a protective liner, and a reservoir
compartment. The drug is enclosed within the reservoir compartment and
released through a rate-controlling polymer membrane.
Transdermal patch picture
IMAGE OF DIFFUSION-CONTROLLED DELIVERY
SYSTEMS
DISSOLUTION/COATING-CONTROLLED DELIVERY
SYSTEMS
Controlled release of drug from delivery systems can also be designed by enclosing the drug in a
polymer shell or coating.
• After the dissolution or erosion of the coating, drug molecules become available for absorption.
• Release of drug at a predetermined time is accomplished by controlling the thickness of coating.
• In this systems, drug molecules are enclosed in beads of varying thickness to control the time and
amount of drug release. Coating-controlled delivery systems can also be designed to prevent the
degradation of the drug in the acidic environment of the stomach, which can reach as low as pH
(1.0).
• Such systems are generally referred as enteric-coated systems.
• In addition, enteric coating also protects the stomach from ulceration caused by drug agents.
• Release of the drug from coating controlled delivery systems may depend upon the polymer
used.
• A combination of diffusion and dissolution mechanisms may be required to define the drug
release from such systems.
IMAGE OF DISSOLUTION/COATING-CONTROLLED
DELIVERY SYSTEMS
Tablet coating as a technique for controlling
release
The three types in common use are:
1. Sugar coating
2. Film coating
3. Press coating eg modified acrylates,water insoluble
cellulose(ethyl cellulose)
4. Enteric coating
Controlled Release of Coated Tablet
Controlled Release Capsule
BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS
› Biologically degradable systems contain polymers that degrade
into smaller fragments inside the body to release the drug in a
controlled manner.
› Zero-order release can be achieved in these systems as long
as the surface area or activity of the labile linkage between the
drug and the polymeric backbone are kept constant during
drug release.
OSMOTIC PUMP
› This type of delivery device has a semipermeable membrane that allows a controlled
amount of water to diffuse into the core of the device filled with a hydrophilic
component.
› A water-sensitive component in the core can either dissolve or expand to create
osmotic pressure and push the drug out of the device through a small delivery orifice,
which is drilled to a diameter that correlates to a specific rate.
› In an elementary osmotic pump, the drug molecule is mixed with an osmotic agent in
the core of the device.
› For drugs that are highly or poorly water soluble, a two compartment push-pull bilayer
system has been developed, in which the drug core is separated from the push
compartment.
› The main advantage of the osmotic pump system is that constant release rate can be
achieved, since it relies simply on the passage of water into the system, and the
human body is made up of 70% water.
Osmotic Pump
Release controlled by osmotic pressure
› A semipermeable membrane is plaved around a tablet or drug
particle which allows transport of water into the centre of the
tablet by osmosis
› As a result of increased internal pressure, drug solution is then
pumped out of the tablet through a small hole in the tablet
coating with the use of a laser beam.
› Eg cellulose acetate containing 32% or 38% acetyl content
ION EXCHANGE RESINS
› The ion exchange resin system can be designed by binding drug to the resin.
› After the formation of a drug/resin complex, a drug can be released by an ion
exchange reaction with the presence of counter ions.
› • In this type of delivery system, the nature of the ionizable groups attached
determines the chemical behavior of an ion exchange resin.
› • First-generation ion-exchange drug delivery systems had difficulty controlling the
drug release rate because of a lack of control of exchange ion concentration.
› • The second-generation ion-exchange drug delivery system (Penn kinetic system)
made an improvement by treating the drug-resin complex further with an
impregnating agent such as polyethylene glycol 4000 to retard the swelling in
water.
› • These particles are then coated with a water-permeable polymer such as ethyl
cellulose to act as a rate-controlling barrier to regulate the drug release.
HYDRO DYNAMICALLY BALANCED DRUG
DELIVERY SYSTEMS
› Hydro dynamically balanced drug delivery systems have great
potential as controlled-release drug delivery systems.
› These systems can reside in the stomach for several hours, so
in this way they significantly prolong the gastric residence time
of drugs resulting in improvement of the dissolution as well as
bioavailability of the drugs that are poorly soluble in a high pH
environment.
› These systems are also used for local delivery of drugs to the
stomach and proximal small intestine.
NEW MACROMOLECULAR DELIVERY
APPROACHES -POLYMERIZED LIPOSOMES
› • The advances in biotechnology have introduced many proteins and
other macromolecules that have potential therapeutic applications.
› • These macromolecules bring new challenges to formulation
scientists, since the digestive system is highly effective in metabolizing
these molecules, making oral delivery almost impossible, while
parenteral routes are painful and difficult to administer.
› • A potential carrier for oral delivery of macromolecules is
polymerized liposomes.
› • Liposomes are lipid vesicles that target the drug to selected tissues
by either passive or active mechanisms.
› Another example is the dendrimer-drug conjugates.
Liposomes
Dendrimer Drug Conjugates
Controlled Release in Parenteral Depot
Injections
Formulated by;
1. Use of viscosity builder which increases vehicle viscosity and
reduce diffusion coefficient of drug. Eg. Methyl cellulose, CMC,
polyvinylpyrrolidone.
2. Can be achieved by formation of salts or complexes with low
aqueous solubility.
3. Formation of microspheres which are spherical shaped particles
containing drug in solid or liquid enclosed into polymeric matrix
system. Examples of such polymers are polygalactin, polyacetic
acid.
The release mechanism is diffusion-controlled.
4. Formation of microcapsules with polymers such as nylon,
dipolylactic acid, albumin etc.
• The release mechanism is both dissolution and diffusion.
5. Magnetic microspheres
6. Resealed erythrocytes
7. Use of implants usually via SC route.
• Polymers are also used
• Drug release is by diffusion/dissolution or both.