Drug Targeting Systems

• An important point to remember is that while rate-controlled systems can deliver the drug at a
predetermined rate, they are generally unable to control the fate of the drug, once it enters the body.

• Drug targeting systems are used to achieve site-specific drug delivery.

• Site-specific drug delivery is desirable in therapeutics, in order to improve:

• drug safety, as toxic side-effects caused by drug action at non-target sites are
minimized;
• drug efficacy, as the drug is concentrated at the site of action rather than being
dispersed throughout the body;
• patient compliance, as increased safety and efficacy should make therapy more
acceptable and thus improve compliance
• In its simplest form, drug targeting can • Sophisticated drug targeting technology is also
be achieved by the local administration available, particularly for oral and parenteral
of the therapeutic compound; this delivery.
strategy is feasible even with
conventional dosage forms. • However, technology is not yet advanced
sufficiently for the design of “magic bullet” drug
delivery systems, proposed by Paul Ehrlich at the
• For example, if the site for desired turn of the 20th century, in which the drug is
drug action is the skin, the medication precisely targeted to its exact site of action.
may be applied in ointment, lotion, or
cream form, directly on the desired site. • For oral delivery, systems are available to
achieve site-specific delivery within the
• Direct injection of an anti- gastrointestinal tract; for example, targeting the
inflammatory agent into a joint is drug to the small intestine, colon, or gut
another example of site-specific lymphatics.
delivery which is achievable without
having recourse to a highly specialized • Drug delivery systems available for targeted oral
drug delivery and targeting system. delivery include those that use enteric coatings,
prodrugs, osmotic pumps, colloidal carriers and
hydrogels.
• Technologies for targeted drug delivery are most advanced for parenteral administration. Such
technologies are concerned with delivering drugs to specific targets in the body and also to
protect drugs from degradation and premature elimination.
• They include the use of:
• soluble carriers, such as monoclonal antibodies, dextrans, soluble synthetic polymers;
• particulate carriers, such as liposomes, micro- and nano-particles, microspheres;
• target-specific recognition moieties, such as monoclonal antibodies, carbohydrates and
lectins.
• Recent advances in biological and chemical sciences have led to the development of various
“Smart” technologies to ensure more effective drug delivery and targeting of drugs to
specific sites within the body. Such approaches include the use of:
• antibody-directed enzyme/prodrug therapy (ADEPT);
• virus-directed prodrug/enzyme therapy (VDEPT);
• chemical drug delivery systems.
 • There also exist certain specialized routes and modes of drug delivery, like the liposomal
delivery, prodrug delivery, Beaded Delivery, Antibody-Drug Conjugates and Coated
Implantable Devices.

Prodrugs

• Prodrugs are inactive (or less active) • For example, levodopa is absorbed from the
GI tract and crosses to blood-brain barrier to
precursors that are metabolized to
get converted to the active metabolite,
(more) active metabolites.
dopamine, which, by itself, cannot cross the
barrier.
• In most cases, prodrugs have an
advantage over the active metabolite in • Another example is famciclovir, which is a
that they have better pharmacokinetic prodrug of penciclovir, and has better
properties. bioavailability than its active metabolite.
• The molecule with the most potent form • These latent groups are used in a transient manner to
does not always have the desired change the properties of the parent drug to achieve a
physicochemical properties needed for specific function, e.g., alter (permeability,
drug dissolution and/or absorption. solubility, or stability).
• In fact, of all the pharmaceutically active
ingredients, 43% are sparingly water • After the prodrug has achieved its goal, the
soluble or insoluble in water. functional group is removed in the body (enzymatic
cleavage or hydrolysis) and the parent compound is
released to elicit its pharmacological action.
• 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.
• Ideal prodrugs should have no The prodrug approach has been used for one or
pharmacological activity against a more of the following reasons:
particular target but should be able to be
metabolically transformed into a A. To change half-life.
compound with the desired activity. B. To cross a biological barrier.
C. To increase retention time.
• Prodrugs are of two types;
D. To target a specific site.
type I (intracellular bioactivation) and
type II (extracellular bioactivation).
A- To change half-life: B- To cross a biological barrier:

• Drugs with unbalanced hydrophilic or

• Half-life is defined as the time hydrophobic properties will not effectively
required by the biological system for cross the biological barriers.
removing 50 % of administered drug.
• Drugs with very short half-life may • Attachment of functional groups can change
not be therapeutically beneficial the properties of the parent drug and allow
unless this characteristic is improved. the prodrug to cross the barrier.
• 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.
C- To increase retention time: D- To target a specific site:

• Connecting specialized functional groups

• When intended for a part of the body that have site-specific affinity (peptide,
with high tissue turnover rate, such antibody, etc.) can allow the parent drug to
as stinteinal mucosa, a drug linked be delivered to the targeted area of the
to a (muco-adhesive polymer) can body to produce site specific therapeutic
increase adhesion to the site and action.
increase bioavailability of a drug
that has low residence time.
 Beaded Delivery Antibody-Drug Conjugates
• The beaded delivery pattern consists of • The conjugates of antibody and drug (ADC)
several minute beads composed of are commonly used in oncotherapy, where
polystyrene-like inert substances. an anticancer drug is tagged with an
antibody with the help of a linker.
• These beads are overlaid with the active
substance and encased within delivery • The antibody is specific against a particular
capsules. protein expressed only on cancerous cells.
• The delivery is usually made to be acid- • Thus, ADCs are very specific and bind only
sensitive, thus releasing the drug on to these cancerous cells so that the normal
exposure to gastric acid. tissues are spared of the toxicity.
• Drug levels become dependent on the • Classical examples include;
amount of gastric acidity in the stomach. - trastuzumab emtansine (for HER-2-positive
• For example, tolterodine has been breast cancer treatment) and
administered via beaded delivery. - gemtuzumab ozogamicin (for AML).
Coated Implantable Devices

• Drug-eluting stents (DES) can be • These agents conventionally block

peripheral or coronary stent devices cell proliferation, thus prevent the
that release drugs at a slow and risk of restenosis in the coronary
sustained pace. circulation.

• These stents classically have three • However, stents are associated

parts; with the risk of stent thrombosis.
a platform, a drug and a polymer
coating that binds the drug to the • Another class of implantable
platform. devices:
is the hormonal intrauterine
devices (IUDs), which are used as
• Common drugs used as stents include contraceptive devices.
sirolimus and paclitaxel.
What Are the Four Drug Delivery Methods?
• Another important factor in medication delivery is the amount of time it takes for a
drug to be released into the body.
• Drug delivery can be modified and controlled by different properties, so there are several
methods of drug transfer that can occur.

• Immediate Release: The dosage form that is • Site-Specific Release: The dosage form that offers
designed to give a rapid and complete targeted delivery of a drug directly to the location
release of the drug. where it is administered.

• Non-Immediate Release: The dosage form • Sustained Release: The dosage form that releases a
encompassing drugs that do not fully release drug continuously at a slow or controlled rate over a
upon administration. prolonged period of time.

• These and other delivery methods could enhance the performance of specific drugs by increasing the
effectiveness, safety, and patient compliance that surrounds the drug, which can ultimately lead to
better patient outcomes.
 Rate-Controlled Release in Drug Delivery Systems

Drug release from a delivery system can be zero-order, variable or bioresponsive.

Zero-order drug release is an ideal way to improve the therapeutic effect and avoid the
side effects of the drug.
- The drug is released from the carrier at a constant rate;
therefore, the drug concentration–time profile is flat.
Advantages of Controlled release drug delivery Disadvantages of using such delivery
systems includes: systems includes:

1. The frequency of drug administration is 1. Poor in vitro – in vivo correlation is

reduced. observed.
2. Patient compliance can be improved. 2. Possibility of dose dumping due to food,
3. The drug administration is more convenient. physiologic or formulation variables or
chewing or grinding of oral formulations
4. There is better control of drug absorption. by the patient and thus, increased risk of
5. The total amount of drug administration can toxicity.
be reduced. 3. Retrieval of drug is difficult in case of
6. Safety margin of high potency drugs can be toxicity, poisoning or hypersensitivity
reactions.
increased.
7. Treatment efficacy is improved. 4. Increased cost of manufacturing.
8. Bioavailability of drugs is improved. 5. More rapid development of tolerance and
counseling.
9. Reduction in health care cost by improved
therapy and shorter treatment period.
• Although there are hundreds of commercial products based on controlling drug release
rate from delivery systems, there are in fact only a small number of mechanisms by
which drug release rate is controlled:

• Diffusion-controlled release mechanisms

• Dissolution-controlled release mechanisms
• Osmosis-controlled release mechanisms
• Mechanical-controlled release mechanisms
• Bio-responsive controlled release mechanisms
 Diffusion-controlled release

• In this case, the drug must diffuse through either a polymeric membrane or polymeric
or lipid matrix, in order to be released.

• Diffusion-controlled devices can be divided into two types:

1. Matrix system
2. Reservoir system
• Reservoir devices: • Matrix (also described as monolith) devices:

in which the drug is distributed throughout a

in which the drug is surrounded by a
continuous phase composed of polymer or
rate-controlling polymer membrane
lipid.
(which can be non-porous, or
microporous).
Diffusion-controlled reservoir devices
• The rate of diffusion of drug molecules • If the drug concentration gradient
through the membrane follows Fick’s remains constant, for example where
Law and is thus dependent on: solid drug particles are present and
constant dissolution maintains the
- The partition and diffusion coefficient of concentration of the drug in solution, the
the drug in the membrane. rate of drug release does not vary with
- The available surface area. time and zero order controlled release is
- The membrane thickness. attained.
- and the drug concentration gradient.

Examples of Diffusion-controlled reservoir

devices are used in a wide variety of routes
including those shown
 Diffusion-controlled matrix devices
• A drug dissolved in a matrix system • This increased diffusion time results in a
is also known as a monolithic decrease in the release rate from the device with
solution, whereas a drug dispersed time.
in a matrix system is referred to as a • Generally the rate of release is found to
monolithic dispersion.
decrease in proportion to the square root of
time.
• Regardless of a drug’s physical state
in the polymeric matrix, such • However, the decrease in drug release rate can
devices do not usually provide be compensated for by designing systems of
zero-order drug release special geometry, which provide an increasing
properties. This is because as the surface area over time.
drug molecules at the surface of the
Examples of diffusion-controlled matrix devices in drug
device are released, those in the
delivery
centre of the device have to migrate
longer distances to be released,
which takes a longer time.
 Dissolution-controlled release

• In dissolution-controlled drug release devices, drug release is controlled

by controlling the dissolution rate of an employed polymer.

• As for diffusion-controlled release, dissolution-controlled devices

can be divided into:

• Reservoir devices: • Matrix devices:

- in which the drug is surrounded - in which the drug is distributed

by a polymeric membrane which throughout a polymeric matrix, which
retains the drug. dissolves with time, thereby releasing
- After a certain period of time the the drug.
polymeric membrane dissolves,
thereby releasing the drug;
• Since the dissolution of polymeric
• In general, synthetic water-soluble polymers
materials is the key to this
mechanism, the polymers used tend to be widely used for oral-controlled release
must be water soluble and/or dosage forms.
degradable in water. • Biodegradable polymers tend to be used for
injectable, or implantable, drug delivery systems.
• The choice of a particular polymer
for a particular controlled release
dosage form depends on various
factors such as the dissolution
mechanism, delivery period,
delivery route, the drug etc.
 Dissolution-controlled reservoir devices

• In dissolution-controlled reservoir
devices, • Drug cores can be coated with
polymers of different coating
thickness, so that drug release can be
• The drug release is controlled by the
thickness and/or the dissolution rate of delayed for certain periods,
the polymer membrane surrounding the for example 1, 3, 6 and 12 h after
drug core. administration.
• Once the coating polymer dissolves, the
drug is available for dissolution and
absorption.
• Such systems are often used for sustained
release oral drug delivery.
• The coated drug particles can be placed in a capsule, or
compressed into tablets.
• By using a dosage form incorporating a spectrum of different
coating thicknesses, the overall drug release from the dosage
form (as a whole, rather than from the individual
microparticles) can adjust to give zero-order drug release.
• Spansule, Sequel and SODAS capsules are examples of
dissolution-controlled reservoir devices for oral drug delivery
of various drugs.
 Dissolution-controlled matrix devices

• In this case, drug release is controlled • For example, Zoladex subcutaneous

by dissolution of the matrix. implant comprises a bulk-eroding,
• Since the size of the matrix decreases poly(lactide-co-glycolide) (PLGA)
as the dissolution process continues, matrix system for the delivery of
the amount of drug released also goserelin (gonadorelin analog).
decreases with time.
• The decrease in drug release can be • PLGA polymers are also widely used in
compensated in part by constructing a the fabrication of dissolution controlled
non-linear concentration profile in the microspheres for parenteral
polymer matrix. administration, e.g. Lupron Depot for the
delivery of goserelin.
• This strategy is used in the oral dosage
form, Adalat tab, where the core of
the dissolution matrix contains more • Microparticulates made of proteins, in
drug than the outer layer. particular albumin, are also widely used
in the preparation of injectable drug
• Matrix dissolution devices are widely carriers.
used in parenteral therapy.
 Osmosis-controlled drug release

• Osmosis is defined as the movement of • Device and formulation

water through a semi-permeable parameters can be controlled so
membrane into a solution. that drug release is zero order.
• The movement of water results in an
increase in pressure in the solution and • An important consideration is that
the excess pressure is known as the osmotic-controlled devices require
osmotic pressure. only osmotic pressure to be
• Osmotic pressure can used to pump out effective, thus such devices
a drug at a constant rate from the operate essentially independently
delivery system. of the environment.
• 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 • The main advantage of the
molecule is mixed with an osmotic agent osmotic pump system is that
in the core of the device. constant release rate can be
• For drugs that are highly or poorly water achieved,
soluble, a two compartment push-pull since it relies simply on the
bilayer system has been developed, in passage of water into the system,
which the drug core is separated from and the human body is made up of
the push compartment. 70% water.

• Hence, in vitro drug release rate is

often consistent with the in vivo
release profile.
• For oral delivery, • The DUROS implant pump is a modified
changes in pH or ionic strength in version of the Alzet pumps and was developed
the gastrointestinal tract will not specifically for the controlled delivery of
affect the drug release rate. peptides and proteins.

• Osmotic mini-pumps,

• In parenteral therapy, the - such as the Oros osmotic pump (osmotic-

subcutaneously implantable, osmotic controlled release oral delivery system), are
mini-pumps developed by the Alza also available for controlled release via the oral
Corp. are used widely in route;
experimental animal studies. commercial products include, Procardia XL
(nifedipine) and Efidac 24 (pseudoephedrine
for congestion; chlorpheniramine for allergy).
 Mechanical-controlled drug release
• Mechanically driven pumps are common • Ideally, a pump
tools for the intravenous administration of
drugs in the hospital setting. - should deliver the drug at the prescribed rate(s) for
extended periods of time and thus, should incorporate
a wide range of delivery rates, ensure accurate,
• They allow physicians and patients to precise and stable delivery, contain reliable pump and
precisely control the infusion rate (dosing electrical components and finally, provide a simple
rate) of a drug. means to monitor pump status and performance.
• Externally programmable pumps can
facilitate: - A pump should also be convenient for the patient and
thus, should ideally be reasonably small in size and
• zero-order controlled drug release; inconspicuous, have a long reservoir life and be easy
• intermittent drug release (are usually to program.
initially guided by the terminal
pharmacokinetic half life and are dependent on - The biocompatibility of the device surface is also an
drug formulation). important issue for consideration.
- Other safety concerns include danger of overdosage,
drug leakage and pump blockage.
 Bio-responsive controlled drug release

• Bio-responsive controlled drug • The change in pH caused by the

delivery systems modulate drug biotransformation of the substrate by the
release in response to changes in the enzyme thereby causes a change in
external environment. permeability of a pH-sensitive polymeric
• For example, drug release may be system in response to the specific
controlled by the way in which pH or biomolecule.
ionic strength affects the swell ability
of a polymeric delivery system. • Such systems may be used to modulate the
• More sophisticated systems release of drug through a controlled
incorporate specific enzymes which feedback mechanism.
causes changes in localized pH or
increases in localized concentrations
of specific substrates such as glucose.