1. CRDDS & Polymers.pptx

Controlled drug delivery systems
Prepared by :
Akshay.p.sanklrcha
Assistant Professor.

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
release
Extended
release
Prolonged
release

DEFINITIONS
• Controlled release :A controlled drug delivery system is one that delivers the
drug at a controlled rate for specified period of time .the release rate was
preplanned or predetermined and reproducible kinetics' for predetermined
period .follow zero order kinetics'
• Delayed release : This is a specific type of modified release dosage form that
releases the drug at a particular timeand particular position. 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 : it allow for the drug to be released over prolonged time
periods.

• 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.
• Product life-cycle extension
• Product differentiation
• Market expansion , Patent extension

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.
• Stability problems
• Increased risk of toxicity
• 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.

Rational of controlled drug delivery systems
•The basic rationale of a controlled release drug delivery system is to optimize
the biopharmaceutics, pharmacokinetics, and pharmacodynamics properties of
a drug in such a way that its utility is maximized through reduction in side
effects and cure or control of disease condition in the shortest possible time by
using smallest quantity of drug, administered by most suitable route.
• The immediate release drug delivery system lacks some features like dose
maintenance, controlled release rate and site targeting.
• An ideal drug delivery system should deliver the drug at a rate dictated by the
need of body over a specified period of treatment.
•The main reason for creating a new dosage form is controlled release dosage
from is to provide a site specific action at desired rate for a prolonged
duration and increase drug absorption and bioavailability

“Ideal” Drug Delivery System
• Inert
• Biocompatible
• Mechanically strong
• Comfortable for the patient
• Capable of achieving high drug loading
• Readily processable
• Safe from accidental release
• Simple to administer and remove
• Easy to fabricate and sterilize
• Free of leachable impurities
1
3

Selection of drug candidates
To be a successful extended-release product, the drug must be released
from the dosage form at a predetermined rate, dissolved in the
gastrointestinal fluids, maintained at sufficient gastrointestinal residence
time, and absorbed at a rate that will replace the amount of drug being
metabolized and excreted.
•Short elimination half-life
• Long elimination half-life
• Narrow therapeutic index
• Poor absorption trough GIT
•Low or slow absorption
•Extensive first pass metabolism effect
•Less protein binding
•The drug not affected by ph and enzymes.
•The solubility of drugs
•No of dose
•Potency of drug

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 :

systems: These
1) Continuous
systems release
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
microencapsulation techniques
the several
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.

Ion-Exchange
Resin
Cation-Exchange
Resin
Anion-Exchange
Resin
Weak Base
Strong Base
Weak Acid
Strong Acid

•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.

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
colours
different

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
indications
drugs meant for
which requires
chronic
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

1. CRDDS & Polymers.pptx

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