Controlled release drug delivery system

INTRODUCTION
• Every drug molecule needs a delivery system to carry the drug to
the site of action upon administration to the patient.
• Delivery of the drugs can be achieved using various types of dosage
forms including {tablets, capsules, creams, ointments, liquids,
aerosols, injections, and suppositories}.
• Most of these conventional drug delivery systems are known to
provide immediate release of the drug with little or no control over
delivery rate.
• To achieve and maintain therapeutically effective plasma
concentrations, several doses are needed daily, which may cause
significant fluctuations in plasma levels.

INTRODUCTION
• Because of these fluctuations in drug plasma levels, the drug level
could fall below the minimum effective concentration (MEC) or
exceed the minimum toxic concentration (MTC).
• Such fluctuations result in unwanted side effects or lack of intended
therapeutic benefit to the patient.
• Sustained-release and controlled-release drug delivery systems
can reduce the undesired fluctuations of drug levels, thus
diminishing side effects while improving the therapeutic outcome of
the drug.

INTRODUCTION
• The terms sustained release and controlled release refer to two
different types of drug delivery systems, although they are often
used interchangeably:
1. Sustained-release dosage forms are systems that prolong the
duration of the action by slowing the release of the drug,
usually at the cost of delayed onset and its pharmacological
action.
2. 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.

CONTROLLED RELEASE DRUG DELIVERY SYSTEM
Design and development of controlled/sustained release delivery
systems have been used to prolong the proprietary status of drug
products.
A typical example is modifying an existing drug product that
requires several doses a day to a single daily dosing to maintain
the dominance over generic competition.

A. Advantages of controlled release drug delivery systems include:
I. Delivery of a drug to the required site.
II. Maintenance of drug levels within a desired range.
III. Reduced side effects.
IV. Fewer administrations.
V. Improved patient compliance.
B. Disadvantages of using such delivery systems include:
I. Possible toxicity of the materials used.
II. Dose dumping.
III. Requirement of surgical procedures to implant or remove the system.
IV. Higher manufacturing costs.

 For some drugs, controlled delivery is necessary, since immediate
release dosage forms cannot achieve the desired pharmacological
action.
 These include:
1. Highly water soluble drugs that need slower release and longer
duration of action.
2. Highly lipophilic drugs that require enhancement of solubility to
achieve therapeutic level.
3. Short half-life drugs that require repeated administration.
4. Drugs with nonspecific action that require the delivery to target sites.

• An ideal drug delivery system
should deliver precise amounts
of a drug at a preprogrammed
rate to achieve a drug level
necessary for treatment of the
disease.
• For most drugs that show a
clear relationship between
concentration and response, the
drug concentration will be
maintained within the
therapeutic range, when the
drug is released by zero-order
rate.

• In order to design a controlled release delivery system, many factors
must be considered such as:
i. Physicochemical properties of the drug.
ii. Route of drug administration.
iii. Pharmacological and biological effects.

PHYSICOCHEMICAL PROPERTIES OF DRUG
• Physicochemical properties play a major role in biological
effectiveness of a drug such as:
i. Solubility.
ii. Stability.
iii. Lipophilicity.
iv. Molecular interactions.
• Solubility is a measure of the amount of solute that can be dissolved
in the solvent.

• For a drug to be absorbed, it must first dissolve in the
physiological fluids of the body at a reasonably fast dissolution
rate.
• Drug molecules with very low aqueous solubility often have lower
bioavailability because of the limited amount of dissolved drug at
the site of absorption.
• In general, drugs with lower than (10 mg/mL) in aqueous solutions
are expected to exhibit low and erratic oral bioavailability.

• Once the drug is administered, biological fluids that are in direct
contact with a drug molecule may influence the stability of the
drug.
• Drugs may be susceptible to both chemical and enzymatic
degradation, which results in a loss of activity of the drug.
• Drugs with poor acidic stability, when coated with enteric coating
materials, will bypass the acidic stomach and release the drug at a
lower portion of the gastrointestinal (GI) tract.
• Drugs can also be protected from enzymatic cleavage by
modifying the chemical structure to form prodrugs.

• The ability of a drug to partition into a lipid phase can be evaluated
by the distribution of drug between lipid and water phase at
equilibrium.
• A distribution constant, the partition coefficient K, is commonly
used to describe the equilibrium of drug concentrations in two
phases.
• The partition coefficient of a drug reflects the permeability of the
drug through the biological membrane and/or the polymer
membrane.
• Commonly, the partition coefficient is determined by equilibrating
the drug in a saturated mixture of octanol (lipid phase) and water.

• Drugs with a high partition coefficient can easily penetrate
biological membranes, as they are made of lipid bilayers, but are
unable to proceed further because of a higher affinity to the
membrane than the aqueous surroundings.
• Drugs with a low partition coefficient can easily move around the
aqueous areas of the body, but will not cross the biological
membranes easily.

ORAL ROUT OF ADMINISTRATION
The oral route is most widely utilized route because of its ease of
administration and the large surface area of the GI tract (200 m2).
The presence of microvilli makes this the largest absorptive surface
of the body (4500 m2).

ORAL ROUT OF ADMINISTRATION
The challenges of oral administration are:
1) Short GI transit time.
2) Extreme acidic ph.
3) Abundant presence of digestive enzymes.
4) First-pass metabolism in the liver.
Several products were designed to prolong the retention time of a
drug in the gastrointestinal tract.
A hydro dynamically balanced drug-delivery system (HBS) is
designed to prolong gastric residence time of the drug.
This dosage form is also called floating capsules or tablets because
of this characteristic.

PARENTERAL ROUT OF ADMINISTRATION
Another commonly used route for drug delivery is parenteral
administration.
The routes used for parenteral therapy include:
i. Intradermal.
ii. Subcutaneous.
iii. Intravenous.
iv. Intracardiac.
v. Intramuscular.
vi. Intraarterial.
vii. Intrasynovial.

PARENTERAL ROUT OF ADMINISTRATION
Parenteral administrations offer immediate response, in such
situations as cardiac arrest or shock, and good bioavailability for
drugs that undergo degradation by digestive enzymes in the GI tract.
The disadvantages of parenteral administrations are difficulty of
administration, requirement of sterile conditions, and cost of
manufacturing.

TRANSDERMAL ROUT OF ADMINISTRATION
Skin, with surface area of 2m2, is a commonly used route for drug
delivery.
Advantages of the transdermal route include:
I. Avoidance of the first-pass effect.
II. Potential of multiday therapy with a single application.
III. Rapid termination of drug effects.
IV. Easy application of medication in an emergency.

TRANSDERMAL ROUT OF ADMINISTRATION
The limitations are:
I. Skin irritation and/or sensitization.
II. Variation of intra and inter individual percutaneous absorption
efficiency.
III. The limited time that the patch can remain affixed.
IV. Higher cost.

PHARMACOLOGICAL AND BIOLOGICAL EFFECTS
Pharmacological and biological effects are important in the design
of the drug delivery systems.
Biological factors, such as {age, weight, gender, ethnicity,
physiological processes, and disease state} , will change the
pharmacokinetics and pharmacodynamics of a drug.
For example:
1- Dosing newborn infants requires caution because of their
immature hepatic function and higher water content in the body.
2- Geriatric patients may suffer from reduced sensitivity of certain
receptors that may lead to insensitivity to certain drugs.

PHARMACOLOGICAL AND BIOLOGICAL EFFECTS
3- It has been found that different ethnic groups respond to drugs
differently.
Ex: Diuretics and calcium channel blockers are recommended as
first-line therapy in hypertensive Black patients, while beta
blockers work better for Caucasian patients.
4- Pathological changes may influence the distribution and
bioavailability of the drug by altering the physiological process.
Ex: Decrease kidney and/or liver functions will affect the
clearance of many drugs.

TYPES OF CONTROLLED RELEASE DRUG DELIVERY SYSTEM
1. PRODRUG.
2. DIFFUSION-CONTROLLED DELIVERY SYSTEMS.
3. DISSOLUTION/COATING-CONTROLLED DELIVERY
SYSTEMS.
4. BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS.
5. OSMOTIC PUMP.
6. ION EXCHANGE RESINS.
7. HYDRO DYNAMICALLY BALANCED DELIVERY SYSTEMS.
8. NEW MACROMOLECULAR DELIVERY APPROACHES.

PRODRUG
• The molecule with the most potent form does not always have the
desired physicochemical properties needed for drug dissolution
and/or absorption.
• In fact, of all the pharmaceutically active ingredients, 43% are
sparingly water soluble or insoluble in water.
• In the prodrug approach for drug delivery, active ingredients are
chemically modified by connecting specialized functional groups
that will be removed in the body after administration, releasing the
parent molecule.
• These latent groups are used in a transient manner to change the
properties of the parent drug to achieve a specific function, e.g.,
alter (permeability, solubility, or stability).

PRODRUG
• After the prodrug has achieved its goal, the functional group is
removed in the body (enzymatic cleavage or hydrolysis) and the
parent compound is released to elicit its pharmacological action.

PRODRUG
• The prodrug approach has been used for one or more of the
following reasons:
A. To change half-life.
B. To cross a biological barrier.
C. To increase retention time.
D. To target a specific site.

PRODRUG
A- To change half-life:
• Half-life is defined as the time required by the biological system for
removing 50 % of administered drug.
• 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.

PRODRUG
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 SYSTEMS
• Diffusion process has been utilized in design of controlled release drug delivery
systems for several decades.
• This process is a consequence of constant thermal motion of molecules, which
results in net movement of molecules from a high concentration region to a low
concentration region.
• The rate of diffusion is dependent on {temperature, size, mass, and viscosity of
the environment}.
• Molecular motion increases as temperature is raised as a result of the higher
average kinetic energy in the system.
 where E = kinetic energy
 k = Boltzmann’s constant
 T = temperature
 m = mass
 v = velocity

• This equation shows that an increase in temperature is exponentially
correlated to velocity (v2).
• Size and mass are also significant factors in the diffusion process.
• At a given temperature, the mass of molecule is inversely proportional to
velocity.
• Larger molecules interact more with the surrounding environment,
causing them to have slower velocity.
• Accordingly, large molecules diffuse much slower than light and small
particles.
• Diffusion is fastest in the gas phase, slower in the liquid phase, and
slowest in the solid phase.

• 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 as
shown.

• 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.

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.
I. The encapsulated particles with thin coatings will dissolve and
release the drug first, while
II. a thicker coating will take longer to dissolve and will release the
drug at later time.

DISSOLUTION/COATING-CONTROLLED DELIVERY SYSTEMS
• 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.

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.

BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS
• Another advantage of biodegradable systems is that:
1) whenformulatedfordepotinjection,surgicalremovalcanbeavoided.
2) Thesenewdeliverysystemscanprotectandstabilizebioactiveagents.
3) enablelong-termadministration.
4) havepotentialfordeliveryofmacromolecules.

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.

OSMOTIC PUMP
• 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
• The release rate of the device can be modified by changing:
1. The amount of osmotic agent.
2. Surface area and thickness of semipermeable membrane.
3. The size of the hole.

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.

ION EXCHANGE RESINS
• 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.
 They allow increased penetration of
the mucus layer and therefore may
increase drug concentration at the
site of action.
 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.

HYDRO DYNAMICALLY BALANCED DRUG DELIVERY SYSTEMS
• Gastro retention property helps to provide better availability of new
products with new therapeutic possibilities and benefits for patients.
• Lots of attempts have been made to develop hydro dynamically balanced
delivery systems, {Swelling, floating, high-density, and muco-adhesive
systems} have been developed to increase gastric retention time of the
dosage forms.
• Various factors may affect the gastric retention time of the drug delivery
systems, such as:
a. Density of dosage form.
b. Gender.
c. Posture.
d. Age.
e. Gastric ph.
f. Size of dosage form.
g. Food intake and nature of food, motility of 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.

“POLYMERIZED LIPOSOMES”
• Advantages of liposomes include:
I. Increased efficacy and therapeutic index.
II. Reduction in toxicity of the encapsulated agent.
III. Increased stability via encapsulation.
• One major weakness of liposomes is the potential leakage of
encapsulated drugs due to the stability of liposome.
• Unlike traditional liposomes, the polymerized liposomes are more
rigid because of cross-linking and allow the polymerized
liposomes to withstand harsh stomach acids and phospholipase.
• This carrier is currently being tested for oral delivery of vaccines.

“PULMONARY ROUT”
• Pulmonary route is also being
utilized as route for delivery of
macromolecules.
• The lung’s large absorptive surface
area of around 100 m2 makes this
route a promising alternative route
for protein administration.
• Drug particle size is a key parameter to
pulmonarydrugdelivery.
• To reduce the particle size, a
special drying process called
glass stabilization technology was
developed.
• By using this technology, dried
powder particles can be designed
at an optimum size of 1 to 5 μm for
deep lung delivery.

“PULMONARY ROUT”
• Advantages of powder formulation include:
1. Higher stability of peptide and protein for longer shelf life.
2. Lower risk of microbial growth.
3. Higher drug loading compared to liquid formulation.
• Liquid formulations for accurate and reproducible pulmonary
delivery are now made possible by technology which converts
large or small molecules into fine-particle aerosols and deposits
them deep into the lungs.
• The device has a drug chamber that holds the liquid formulation
and upon activation, the pressure will drive the liquid through fine
pores creating the micro size mist for pulmonary delivery.

“TRANSDERMAL NEEDLELESS INJECTION “
• Transdermal needleless injection devices are another candidate for
protein delivery.
• The device propels the drug with a supersonic stream of helium gas.
• When the helium ampule is activated, the gas stream breaks the
membranes that hold the drug.
• The drug particles are picked up by a stream of gas and propelled fast
enough to penetrate the stratum corneum (the rate-limiting barrier of the
skin).
• This delivery device is ideal for painless delivery of vaccine through the
skin to higher drug loading.
• Limitations to this device are the upper threshold of approximately(3 mg)
and temporary permeability change of skin at the site of administration.

• An alternative way to penetrate the skin barrier has been developed
utilizing thin titanium screens with precision micro projections to
physically create pathways through the skin and allow for
transportation of macromolecules.
• Another example of macromolecular delivery is an implantable
osmotic pump designed to deliver protein drugs in a precise
manner for up to 1 year.
• This implantable device uses osmotic pressure to push the drug
formulation out of the device through the delivery orifice.

“SMART SKIN PATCH “
• Drug-delivery systems that can dispense a continuous flow of
therapeutics, without having to rely on the patient to physically
take the drug.
• These systems don't monitor a patient's vitals, this means they can't
be responsive.
• So when a patient needs to take a stronger dose or when they
actually feel pretty good, they still receive the same continuous
flow of whatever drug they're on.
• The scientists have come up with Nature Nanotechnology, dermal
patch that not only dispenses drugs continuously, but also has the
ability to determine when it's time to stop.

• HEAT-ACTIVATED SILICA NANOPARTICLES.
• The patch consists of a 2-inch-long rectangle made of stretchable
nanomaterials.
• The materials contain heat-activated silica nanoparticles that
monitor muscle activity and release therapeutic agents based on a
patient's body temperature.

• This sort of system is ideal for people who suffer from Parkinson's
disease, for instance, because the tremors that accompany the
movement disorder aren't constant.
• When a patient starts to tremble, the patch can pick up on the
motion and release a small amount of the drug it contains.
• The silica nanoparticles are heat-activated so "stretchable heaters"
also embedded into the patch that allow them to control the rate of
drug delivery if needed.

ACTIVAPATCH INTELLIDOSE 2.5 DRUG DELIVERY SYSTEM
Ctivapatch IntelliDose 2.5 Iontophoretic Drug Delivery System is
an intelligent, accurate iontophoresis delivery with Smart Power
LED to provide visual feedback to clinicians and patients.
It is a disposable, single use, non-invasive drug delivery system
that utilizes an intelligent microprocessor to deliver 40 or 80mA
min dosage of a negatively-charged ionic solution.
The self-contained and fully integrated Smart Power system
functions without a charging station or dose controller.
It can be removed and reapplied to complete treatment if
necessary or used for two treatment sites.

ACTIVAPATCH INTELLIDOSE 2.5 DRUG DELIVERY SYSTEM

‫ي‬‫ل‬‫د‬‫ي‬‫ص‬/‫ادل‬‫ع‬‫د‬‫م‬‫ح‬‫م‬
‫ينفعني‬ ‫و‬ ‫به‬ ‫ينفع‬ ‫أن‬ ‫هللا‬ ‫من‬ ‫وأرجوا‬ ‫البحث‬ ‫هذا‬ ‫أتممت‬ ‫وفضله‬ ‫هللا‬ ‫بحمد‬

Controlled release drug delivery system

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