Controlled drug delivery systems

Prepared by : Dr. Tejas J. Patel

Associate Professor
Department of Pharmaceutics
SNLPCP,Umrakh.
 INTRODUCTION
• Science of controlled release was first originated
from the development of oral sustained release
products in the 1940s and early 1950s.

• First of all, the controlled release of marine

antifoulants (the 1950s) and controlled release of
fertilizer (1970s) were formulated which had only
a single application in the soul science.

• Over the past 30 years as the complication

involves in marketing of new drug increased and
various advantages recognized of Controlled drug
delivery system, the greater attention is being
paid in this field.
• Today the oral controlled drug delivery system
becomes major drug delivery systems mainly drugs
having high water solubility and short biological
half-life.

• Other than oral, various routes like Transdermal,

ocular, vaginal & parenteral route use for controlled
release of various drugs.

• Controlled release drug delivery systems provide

uniform concentration of drug to absorption site
and thus allows maintenance of plasma
concentration within therapeutic range which
minimizes not only the side effects but also the
frequency of administration.
 Modified Release Oral Drug Delivery System

Controlled Release Delayed Release

Sustained Extended Prolonged

release release release
 DEFINITIONS
• Controlled release : The dosage form in which
the drug is released in a planned, predictable and
slower than conventional dosage form.

• Delayed release : This is a specific type of

modified release dosage form that releases the
drug at a particular time. E.g. Enteric coated tablet.

• Sustained release : This is a specific type of

modified release dosage form that allows at least a
two-fold reduction in the dosage frequency
compared to conventional drug delivery system
• Extended release : Pharmaceutical dosage
forms that release the drug slower than normal
manner at predetermined rate and necessarily
reduce the dosage frequency by two folds.

• Prolonged release : They are designed to

release the drug slowly and to provide a
continuous supply of drug over an extended
period. They prevent very rapid absorption of
the drug, which could result in extremely high
peak plasma drug concentration.
 ADVANTAGES
• Increased patient compliance. .
• Reduced dosing frequency.
• Maintenance of drug levels within a desired range.
• Minimization or elimination of local or systemic
side effects.
• Improvement in bioavailability of some drugs.
• Minimal drug accumulation on chronic usage.
• Improve efficiency of treatment.
• Reduction in Health care cost .
• Constant level of drug conc. in blood plasma.
• Night time dosing can be avoided.
 DISADVANTAGES
• Delay in onset of drug action.
• Possibility of dose dumping.
• Increased potential for first pass metabolism.
• Poor in vitro-in vivo correlation.
• Greater dependence on GI residence time.
• Possibility of less accurate dose adjustment.
• Cost per unit dose is higher when compared with
conventional doses.
• Not all drugs are suitable for formulating into
Extended release dosage form.
• Drugs which are having very short half-life (<1
hour) e.g.: Penicillin, Furosemide are poor
candidates for SR formulations.
APPROACHES TO DESIGN CONTROL
RELEASE FORMULATION
Depending upon the manner of drug release
CRDDS are classified as follows:

1) Continuous release systems.

2) Delayed transit and continuous release

systems.

3) Delayed release systems :

1) Continuous release systems: These
systems release the drug continuously for
prolonged period of time along the entire
length of GIT with normal transit time.
Different systems under this class are:

A) Dissolution controlled release systems.

B) Diffusion controlled release systems.
C) Dissolution & Diffusion controlled release
systems.
D) Ion exchange resin drug complex.
E) Osmotic pressure controlled systems.
A) Dissolution controlled release systems.
• A drug with a slow dissolution rate is inherently sustained
and for those drugs with high water solubility, one can
decrease dissolution through appropriate salt or derivative
formation.
• These systems are most commonly employed in the production
of enteric coated dosage forms.
• To protect the stomach from the effects of drugs such as
Aspirin, a coating that dissolves in natural or alkaline media is
used.
• This inhibits release of drug from the dosage form until it
reaches the higher pH of the intestine.
• Dissolution controlled release can be obtained by slowing the
dissolution rate of a drug in the GI medium, incorporating the
drug in an insoluble polymer and coating drug particles or
granules with polymeric materials of varying thickness.
• The rate of dissolution can be expressed as following
dm/dt= ADS/h
• The dissolution system is of two types:

a) Matrix Dissolution Controlled Systems:

- As the drug is homogeneously dispersed throughout

the rate controlling medium, this system also called as
monolith system.
• It is very common and employs waxes such as
beeswax, carnauba wax which control the drug
release rate by controlling the rate of dissolution
fluid penetration into the matrix by altering the
porosity of tablet, decreasing its wettability or by
itself getting dissolved at a slower rate.

b) Reservoir Dissolution Controlled Systems:

- In this type, the drug particles are coated or
encapsulated by one of the several
microencapsulation techniques with slowly
dissolving materials like cellulose and
polyethylene glycol.
 - This dissolution rate of coat depends upon the
solubility and thickness of the coating.
B) Diffusion controlled release systems.
• Diffusion process shows the movement of drug molecules
from a region of a higher concentration to one of lower
concentration.
• The diffusion system is of two types:

a) Matrix Diffusion Controlled Systems:

• This system is defined as a well-mixed composite of one
or more drugs with gelling agent i.e. hydrophilic
polymers.

• Matrix systems are widely used for sustaining the release

rate.

• It is the release system which prolongs and controls the

release of the drug that is dissolved or dispersed.
• A solid drug is dispersed in an insoluble matrix and the rate
of release of drug is dependent on the rate of drug diffusion
and not on the rate of dissolution.

There are three types of diffusion matrix system

· Hydrophobic matrix system
· Hydrophilic matrix system
· Fat-wax matrix system
b) Reservoir Diffusion Controlled Systems:

• In this system, a water insoluble polymeric material like

Ethyl cellulose or Polymethacrylate covers a core of drug.

• Drug will partition into the membrane and exchange with

the fluid surrounding the particle or tablet.

• Additional drug will enter the polymer, diffuse to the

periphery and exchange with the surrounding media.

• The drug release takes place by diffusion mechanism.

• The polymer can be applied by coating and

microencapsulation technique.

• The disadvantage of reservoir devices over matrix diffusion

controlled system is a chance of sudden drug dumping.
C) Dissolution and diffusion controlled release
systems.

• In such system, the drug core is

encased in a partially
soluble membrane.
• Pores are thus created due to
dissolution of parts of the
membrane .
• It Permit entry of aqueous
medium into the core & drug
dissolution
• Diffusion of dissolved drug
out of the system.
• E.g. Ethyl cellulose & PVP
Mixture dissolves in water
& create pores of insoluble ethyl
cellulose membrane.
D) Ion exchange resin drug complex.

• Ion exchange resins are cross-linked water-

insoluble polymers carrying ionisable functional
groups .
• The resins have been used in various
pharmaceutical applications, primarily for taste
masking and controlled release systems.
• In tablet formulations, ion exchange resins have
been used as disintegrants, because of their swelling
ability.
• It forms irreversible complex with ionisable drugs
upon prolonged exposure of the drug to the resin.
• A resin bound drug is removed when appropriate
ions are in contact with ion-exchanged groups.
• The area and length of diffusion pathway and the
amount of cross-linked polymer in the resin moiety
governs the rate of drug release.
 Strong Acid

Cation-
Exchange
Resin
Weak Acid

Ion-Exchange
Resin
Strong Base

Anion-Exchange
Resin

Weak Base
• IER are insoluble polymers that contain acidic and basic
functional groups have the ability to exchange counter-ions
within aqueous solutions surrounding them.

• Application of IER :
1) Taste Masking
2) Eliminating Polymorphism
3) Improving the dissolution of poorly soluble drugs
4) Improving Stability
5) Improving physical Characteristics
6) Some Drug delivery of IER include:
- Oral Drug Delivery.
- Nasal Drug Delivery.
- Transdermal Drug Delivery.
- Ophthalmic Drug Delivery.
E) Osmotic pressure controlled systems.
• In this method, the release controlling factor that must be
optimized is the osmotic pressure gradient between inside
the compartment and the external environment.

• The simplest and most predictable way to achieve a constant

osmotic pressure is to maintain a saturated solution of
osmotic agent in the compartment.

• This technology provides zero order release used for

hydrophilic drugs. Drug may be osmotically active or
combine with osmotically active salt eg. NaCl.

• Osmotic pressure is the hydrostatic pressure produced by a

solution in a space divided by a semi permeable membrane
due to difference in concentration of solutes.
• Osmosis is the diffusion of fluid through a semi
permeable membrane from a solution with a low solute
concentration to a solution with a higher solute
concentration until there is an equal concentration of
fluid on both sides of the membrane.
• A semi permeable membrane is placed around a
tablet, particle or drug solution that allows
transport of water into the tablet with eventual
pumping of drug solution out of the tablet through a
small delivery aperture in tablet coating.

• The osmotic systems are classified in major two

types, i.e. type-A and type-B. In type-A system, the
core contains both, the drug and electrolytes. The
electrolytes provide osmotic pressure and maintain
the rate of drug release.

• In type-B system, the drug solution is present in a

semi permeable membrane surrounded by the
electrolytes.
 2) Delayed transit and continuous release
systems:

❑ These systems are designed to prolong release of drug

with increased residence time in GIT.
❑ Such dosage forms are designed to remain in the
stomach.
❑ The drug present in such systems should be stable at
gastric pH.
❑ This class includes following systems
· Altered density systems
· Mucoadhesive systems
· Size based systems
 3) Delayed release systems :

❑ These systems are fabricated to release the drug only at

specific site in the GIT.
❑ The drugs contained in such system are those that are :
· Destroyed in stomach or by intestinal enzymes.
· Known to cause gastric irritation
· Absorbed from specific site in intestine, or
exert local effect at specific GI site.

• The two types of delayed release systems are

· Intestinal release systems
· Colonic release systems.
FACTORS INFLUENSING ON CRDDS
A) Physicochemical Factor:

1)Dose size :
• In general, a single dose of 0.5-1.0 gm is considered
maximal for a conventional dosage form. This also hold
for sustained release dosage form.

• Drugs with single oral dose larger than 1g are poor

candidates for oral sustained release products.

• Compound that require larger dose size can sometimes

be given in multiple amounts or formulated into liquid
systems.
2) Aqueous solubility:
• The aqueous solubility of drug is an extremely important
consideration in its biological performance as well as in
its incorporation into controlled drug delivery system.

• Aqueous solubility of drug exercises its control on the

absorption process in two ways i) By influence on the
dissolution rate of compound, ii) By its effect on the
ability of the drug to penetrate tissues.

• Finally drugs which are having low aqueous solubility

generally suffer from low oral bioavailability easy to
convert in slow release form.

• Compounds with very high aqueous solubility are

sometime difficult to convert slow release dosage forms.
3) Drug pKa and ionization at physiological pH :
• Drugs existing largely in ionized form are poor candidates
for oral controlled release drug delivery system.

• Absorption of the unionized drugs are well for control

release, whereas permeation of ionized drug is negligible
because the absorption rate of ionized drug is 3-4 times less
than that of the unionized drug.

• The pKa range for acidic drug whose ionization is pH

sensitive is around 3.0-7.5 and pKa range for basic drug
whose ionization is pH sensitive is around 7.0-11.0 are ideal
for optimum positive absorption.

• Drug shall be unionized at the site to an extent 0.1-5.0% .

4) Partition Coefficient :
• In the time span between drug administration and its
elimination from body, the drug must cross a variety of
membranes .

• Drugs with low partition coefficient easily permeate through

biological membrane however for further functions aqueous
solubility is required.

• Drugs with extremely high partition coefficient will either

readily penetrate into membrane producing an
accumulation in body tissue with subsequent slow
elimination.
5) Stability :
• Drugs that are unstable in gastric pH can be developed
as slow release dosage form and drug release can be
delayed till the dosage form reaches the intestine.

• Drugs that undergo gut wall metabolism and show

instability in small intestine are not suitable for oral
controlled drug delivery system.
FACTOR INFLUENCING ON CRDDS
B) Biological Factor:

• The absorption behaviour of a drug can affect its

suitability as an extended release product.

• The aim of formulating controlled release product is to

place a control on the delivery system .

• It is essential that the rate of release is much slower than

the rate of absorption.
 1) Biological Half Life :
• The half-life of a drug is an index of its residence time in
the body. If the drug has short half life (less than 2
hours) the dosage form may contain a prohibitively
large quantity of the drug.

• On the other hand, drug with elimination half-life of 8

hours or more are sufficiently controlled in the body,
when administered in conventional dosage from and
controlled release drug delivery system is generally not
necessary in such cases.

• Ideally, the drug should have half-life of 3-4 hours for

formulation of drug delivery system.
2) Therapeutic index :
• Drugs with low therapeutic index are unsuitable for
incorporation in controlled release formulations.

• If the system fails in the body, dose dumping may occur,

which leads to toxicity.

3) Absorption window :
• Certain drugs when administered orally are absorbed only
from a specific part of gastrointestinal tract.

• This part is referred to as the ‘absorption window’. These

candidates are also not suitable for CRDDS.
4) Plasma concentration response relationship :
• Generally, plasma drug concentration is more responsible
for pharmacological activity rather than dose.

• But the drug having pharmacological activity independent

of plasma concentrations, are poor candidate for oral CR
drug delivery system.

5) Concentration dependency on transfer of drug:

• Transfer of drug from one compartment to other, if
follows zero order kinetic process then such drugs are
poor candidate for oral control release delivery system.

• It should be of first order kinetics.

 EVALUATION OF CRDDS
• Check relative bioavailability following a single dose.
• Check relative bioavailability following a multiple
dose.
• Effect of food on drug absorption.
• Dose proportionality.
• Single dose bioequivalence study
• In vitro- In vivo correlation
• Pharmacokinetic / Pharmacodynamic relation ship.
• Unit dosage strength proportionality.
POLYMER USED IN CRDDS
INTRODUCTION OF POLYMER
❑ The word “polymer” means “many parts.” A
polymer is a large molecule made up of many
small repeating units.
❑ Polymers are considered to be a subset of
macromolecules. Macromolecule refers to any
large molecule.
❑ A monomer is a small molecule that combines
with other molecules of the same or different
types to form a polymer.
❑ Because of their unique properties , polymers
are used in pharmaceuticals.
CLASSIFICATION OF POLYMER
1) Hydrophilic Polymers: Hydroxyl propyl methyl
cellulose (HPMC), hydroxyl propyl cellulose(HPC),
hydroxyl ethyl cellulose (HEC), Xanthan gum, Sodium
alginate, poly(ethylene oxide), and cross linked
homopolymers and co-polymers of acrylic acid.
2) Hydrophobic Polymers: Includes waxes and water
insoluble polymers in their formulation
Waxes: Carnauba wax, bees wax, candelilla wax, micro
crystalline wax, ozokerite wax, paraffin waxes and low
molecular weight polyethylene.
Insoluble polymers: Ammoniomethacrylate co-
polymers (Eudragit RL100, PO, RS100), ethyl cellulose,
cellulose acetate butyrate, cellulose acetate propionate
and latex dispersion of meth acrylic ester copolymers.
PROPERTIES OF POLYMER
• Low Density.
• Low coefficient of friction.
• Good corrosion resistance.
• Good mould ability.
• Excellent surface finish can be obtained.
• Economical.
• Poor tensile strength.
• Low mechanical properties.
• Poor temperature resistance.
• Can be produced transparent or in different
colours
 ADVANTAGES OF POLYMER
The three key advantages that polymeric drug
delivery products can offer are:

• Localized delivery of drug: The delivery

system can be implanted directly at the site where
drug action is needed and hence systemic exposure
of the drug can be reduced.
• This becomes especially important for toxic drugs,
which produce various systemic side effects (such
as the chemotherapeutic drugs).
• Sustained delivery of drug: The drug
encapsulated is released over extended periods
and hence eliminates the need for multiple
doses.
• This feature can improve patient compliance
especially for drugs meant for chronic
indications which requires frequent
administrations.
• Stabilization of the drug: The incorporated
polymer can protect the drug from physiological
environment of GIT and hence improve its
stability in-vivo.
GENERAL MECHANISM OF DRUG
RELEASE FROM POLYMER
Three primary mechanism for drug release ,
namely:
• Diffusion :
• Degradation:
- Enzymatic Degradation
- Hydrolysis
- Combination
• Water penetration(Swelling):

Any of these mechanism can occur in a

Controlled drug release system
APPLICATIONS OF POLYMERS FOR
CONTROLLED DRUG DELIVERY SYSTEMS
1. Oral drug delivery system:
• Here, the drug gets released at controlled rate
when administered orally.
• For that several mechanisms are involved.
a) Osmotic pressure controlled GI delivery
system
b) Gel diffusion controlled GI delivery system
c) Mucoadhesive GI delivery system
2. The Ocusert System :
• The delivery of therapeutic agents to the eye for
the treatment of disorders of the eye, (e.g.,
glaucoma), using conventional drug delivery
systems, e.g., drops, ointments, is an inefficient
process.
• The efficiency of ocular drug delivery is improved
through the use of polymeric implants that are
implanted under the lower cul-de-sac of the eye.
• In this system pilocarpine is dispersed within an
alginic acid matrix which is sandwiched between
two layers each composed of poly(ethylene-co-
vinyl acetate).
• It is designed to release either 20 µg/h or 40 µg/h
of a therapeutic agent for a seven day period
following implantation.
3. Transdermal Patches :
• Transdermal drug delivery involves the diffusion
of the drug through the skin and ultimately
absorption into the systemic circulation.
• The drug delivery system is composed of several
layers, namely a metallic backing layer, which is
impermeable to drug diffusion thereby preventing
drug loss, the drug containing reservoir, a rate
controlling membrane and an adhesive layer.
• In the matrix drug is dissolved or dispersed with
solid polymer (acrylate co-polymer).
4. Polyanhydride are used in CDDS because
of their unique property of surface
erosion.

5. Polymers can be used as film coatings to

mask the unpleasant taste of a drug & to
modify drug release characteristics.

6. Polymer used in controlled release

ophthalmic preparations.
e.g. Hyaluronic acid

7. Polymers like all the cellulose derivative

are used as coating materials in solid
dosage form.
8. Polymers like following used as a Binder and
disintegrating agent in solid dosage form.
e.g. Methyl cellulose ,HEC, HEMC, CMC sodium

9. Drug delivery and the treatment of diabetes.

• Here the polymer will act as barrier between blood stream and
insulin.
e.g. Polyacrylamide or N,N di-methyl-amino-ethyl methacrylate

10.Drug delivery of various contraceptives and

hormones:
e.g. Medroxyprogesterone acetate Vaginal contraceptive ring
 Smart polymer
• Smart polymers are composed of polymers that respond
in a dramatic way to very slight changes in the
environment or they may be defined as plastics which
change or react in a certain way according to the
environment.
• They are also known as ‘stimuli-responsive polymers’ or
‘intelligent polymers’ or ‘environmental-sensitive
polymers’.
• The characteristic feature that actually makes these
polymers ‘smart’ is their ability to respond to very slight
• The uniqueness of these materials lies not only
in the fast microscopic changes occurring in
their structure but also these transitions being
reversible.
• The responses are manifested as changes in
one or more of the following-shape, surface
characteristics, solubility, formation of an
intricate molecular assembly, a sol-to-gel
transition and others.
Advantage of Smart Polymer
• Smart polymers are non-thrombogenic,
biocompatible, strong, flexible, tough, easy
to color & mould.
• Maintain stability of the drug, and maintain
drug level in therapeutic window.
• Easy to manufacture.
• Used for blood contacting application.
• They are good transport of nutrients to cells
and products from cell.
• May be easily modified with cell adhesion
ligands.
• They can be injected in vivo as a liquid that
gels at body temperature.
Disadvantage of Smart Polymer
• They can be hard to handle.
• They are usually mechanically weak.
• They are also difficult to load with drugs and
cells and crosslink in vitro as a prefabricated
matrix.
• They may be difficult to sterilize.
Classification of Smart Polymer
• pH sensitive smart polymers
• Temperature sensitive smart polymers
• Polymers with dual stimuli-responsiveness
• Phase sensitive smart polymers
• Light sensitive smart polymers
THANK YOU