SUSTAINED AND CONTROLLED

DRUG DELIVERY SYSTEM

Presented By: Ms. Sukanya Patil Guided By: Dr. Sheela Yadav
Semester I (F. Y. M. Pharmacy) Associate Professor
Department of Pharmaceutics Department of Pharmaceutics

H. K. College of Pharmacy, Oshiwara- 400102

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CONTENT:
 Definition of Sustained Release
(SR) and Controlled Release (CR)
Drug Delivery System (DDS)
 Comparison of drug release profile
 Advantages and disadvantages
 Drug selection (Formulation
approaches)
 Types of Polymers
 Classification of CR/SR DDS
 Recent Approaches
 Marketed Formulations
 References
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Controlled Release DDS:
Controlled drug delivery is that type
of system which release the medicaments from
the dosage form at a predetermined specified
rate locally or systemically for a specified period
of time.

Sustained Release DDS:

Sustained drug delivery is that type
of system which achieve prolonged therapeutic
effect by continuously releasing medication over
an extended period of time after administration of
single dose.

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DRUG RELEASE PROFILE :

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ADVANTAGES:
 Enhance patient compliance and
convenience.
 Reduction in dosing frequency.
 Reduced fluctuations in circulating drug
levels.
 More uniform effect.
 Maximum utilization of drug enabling
reduction in total amount of dose.
 Minimize or eliminates local side effects.
 Minimize or eliminates systemic side effects.
 Minimize drug accumulation with chronic
dosing.
 Product life-cycle extension
 Market expansion
 Patent extension
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 DISADVANTAGES:
 When immediate change during the therapy or if
any significant adverse effect is noted and
prompt termination of therapy is needed is not
facilitated.
 More costly process and equipment.
 Less flexibility in adjusting dosage regimen as
this is fixed by design of dosage form.
 Reduced drug absorption may delay onset of
action. The effect of food on drug absorption.
 In case of accidental failure of the product
effective antidote may be difficult to employ.
 Drugs which are acted upon by enzymes in
intestine undergo significant enzymatic
breakdown as drug remains in body for longer
time.
 Risk of dose dumping, leading to toxicity.
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DRUG SELECTION:
The biopharmaceutical evaluation of a drug for potential use in
SR/ CR DDS requires knowledge of absorption mechanism of
the drug form the gastrointestinal (GI) tract, the general
absorbability, the drug’s molecular weight, pKa, solubility at
different pH, apparent partition coefficient, absorption,
distribution, metabolism, safety margin, side effect, disease
state and biological half-life/duration of action.

The above mentioned factors are broadly classified into 2

types:
PHYSICOCHEMICAL FACTORS BIOLOGICAL FACTORS
a. Aqueous solubility a. Absorption
b. Partition coefficient (P [O/W]) b. Distribution
c. Drug pKa and ionization at c. Metabolism
physiological pH d. Biological half life
d. Drug stability e. Therapeutic Index
e. Molecular weight and f. Side effect
diffusivity g. Disease state
f. Protein binding
g. Dose size.
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( I ) PHYSICOCHEMICAL FACTORS:-
(A) AQUEOUS SOLUBILITY:
Most of the drugs are weak acids or weak bases. Drugs with
low water solubility will be difficult to incorporate into extended
release mechanism. For a drug with high solubility and rapid
dissolution rate, it is often quite difficult to retard its dissolution
rate. A drug of high water solubility can dissolve in water or GI
fluid readily and tends to release its dosage form in a burst and
thus is absorbed quickly leading to a sharp increase in the
blood drug concentration compared to less soluble drug. It is
often difficult to incorporate a highly water-soluble drug in the
dosage form and retard the drug release, especially when the
dose is high. The pH-dependent solubility, particularly in the
physiological pH range, would be another problem for SR
formulation because of the variation in the pH throughout the GI
tract and variation in the dissolution rate. The
biopharmaceutical classification system allows estimation of the
likely contribution of three major factors which affect the oral
absorption.
• Solubility
• Dissolution 8
(B) PARTITION COEFFICIENT :
The partition coefficient is defined
as the fraction of drug in an oil
phase to that of an adjacent
aqueous phase. Partition
coefficient influences not only the
permeation of the drug across the
biological membranes but also
diffusion across the rate controlling membrane or matrix
between the time when a drug is administered, and when it is
eliminated from the body, it must diffuse through a variety of
biological membranes that act primarily as lipid-like barriers. A
major criterion in evaluation of the ability of a drug to
penetrate these lipid membranes (i.e., its membrane
permeability) in its apparent oil or water partition coefficient
defined as,
K= Co/Cw
The relationship between tissue permeation and partition
coefficient for the drug is generally defined by the Hansch
correlation, which describe a parabolic relationship between
the logarithm of its partition coefficient. 9
(C) DRUG PKA AND IONIZATION AT
PHYSIOLOGICAL PH
Drugs existing largely in an ionized form are poor candidates.
Absorption of the unionized drugs is well whereas permeation
of ionized drug is negligible because the absorption rate of the
ionized drug is 3-4 times less than that of the unionized drug.
The pKa range for an acidic drug whose ionization is pH
sensitive is around 3.0-7.5 and pKa range for a 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%
(D) DRUG STABILITY
Drugs undergo both acid/base hydrolysis and enzymatic
degradation when administered orally. Drugs that are unstable
in gastric pH can be developed as slow release dosage form
and drug release can be delayed until the dosage form reaches
the intestine. Drugs that undergo gut wall metabolism and show
instability in the small intestine are not suitable. In such case,
the drug can be modified chemically to form prodrugs, which
may possess different physicochemical properties or a different
route of administration should be chosen. 10
(E) MOLECULAR WEIGHT AND DIFFUSIVITY
Diffusivity is defined as the ability of a drug to diffuse through
the membrane. Diffusivity depends on size and shape of the
cavities of the membrane. The diffusion co-efficient of
intermediate drug molecular weight is 100-400 Daltons; through
flexible polymer range is 10-6 – 10-9 cm2 /seconds. Molecular
size or weight is indirectly proportional to the diffusivity. Drugs
with larger molecular size are a poor candidate for oral CR/SR
system.

(F) PROTEIN BINDING

It is well-known that many drugs bind to plasma proteins with
concomitant influence on the duration of drug action. Since
blood proteins are, the most re-circulated part and not
eliminated, drug protein binding can serve as the depot for drug
producing a prolonged release profile, especially if a high
degree of drug binding occurs. The drug interaction and the
period of binding with mucin-like protein also influence the rate
and extent of oral absorption.
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(G) DOSE SIZE
For orally administered systems, there is an upper limit to the
bulk size of the dose to be administered. In general, a single
dose of 0.5-1.0 gm is considered maximal for a conventional
dosage form. This also holds for CR/SR dosage forms.
Those compounds that require large dosing size can
sometimes be given in multiple amounts or formulated into
liquid systems. Another consideration is the margin of safety
involved in the administration of large amounts of a drug with
narrow therapeutic range.

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( II ) BIOLOGICAL FACTORS:-
(A) ABSORPTION
The constant blood or tissue concentration of drug can be
obtained through uniform and consistent release as well as
absorption of the drug. Apparently the release of the drug
from the system is the rate limiting step, where rapid
absorption relative to the drug release is always expected,
i.e., Kr << Ka. If we assume the transit time of dosage forms
in the absorptive areas of GI tract is about 8-12 hrs, the
maximum half-life for absorption should be approximately 3-4
hrs. Otherwise, the dosage form will pass out of absorptive
regions before drug release is complete. Therefore, the
compounds with lower absorption rate constants are poor
candidates. Some possible reasons for the low extent of
absorption are poor water solubility, small partition co-
efficient, protein binding, acid hydrolysis and metabolism or
site specific or dose-dependent absorption. Drugs which
metabolizes extensively are not suitable. Drugs that are
metabolized before absorption, either in the lumen or the
tissues of the intestine, can show decreased bioavailability
from these systems. 13
(B) DISTRIBUTION
The distribution of drug molecules into the tissue and cells
can be the primary factor in particularly drug elimination
kinetics. Since it not only lowers the concentration of
circulating drug, but it also can be rate limiting in its
equilibrium with blood and extravascular tissue. The
distribution includes the binding of the drug to the tissues
and blood proteins. Protein-bound drugs molecules are
considered as inactive and unable to permeate biological
membranes, and a high degree of protein binding provides
prolonged therapeutic action. The apparent volume of
distribution is one of the important parameters of the drugs
that describes the magnitude of distribution as well as
protein binding within the body. The apparent volume of
distribution is the proportionality constant of the plasma
concentration of the drug to the total drug amount in the
body. Thus for the design of sustain or control release
products, one must have information of the disposition of
drug.

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(C) METABOLISM
Metabolism of the drug is either an inactivation of an active
drug or conversion of an inactive drug to an active
metabolite. Metabolism of the drug occurs in a variety of
tissues, which are containing more enzymes. Drugs that are
significantly metabolized before absorption, either in the
lumen or tissue of the intestine, can show decreased
bioavailability from slower-releasing dosage forms. Most
intestinal wall enzyme systems are saturable. As the drug is
released at a slower rate to these regions, less total drug is
presented to the enzymatic process during a specific period,
allowing more complete conversion of the drug to its
metabolites. The formulation of these enzymatically
susceptible compounds as prodrugs is another viable
solution. Drugs that are capable of either inducing or
inhibiting enzyme synthesis, they are the poor candidate
due to difficulty in maintaining uniform blood levels. Drugs
possessing variation in bioavailability due to the first-pass
effect or intestinal metabolism are not suitable.

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(D) BIOLOGICAL HALF LIFE
The usual goal of an oral sustained-release or controlled-
release product is to maintain therapeutic blood levels over
an extended period. The duration of action significantly
influences the design of the system and it is dependent on
the biological half-life. Factors influencing the biological half-
life of a drug include its elimination, metabolism and
distribution patterns. Drugs with short half-lives required
frequent dosing to minimize fluctuations in the blood levels.
These dosage forms would appear very desirable for such
drugs. For a given steady state drug concentration, the zero-
order rate of release of a drug from its dosage form is directly
proportional to its rate of elimination. Thus drug with very
short half-lives require faster rate of release, for a modest
duration of time while dosage form requires large dosage. In
general, drugs with half-lives shorter than 2 hrs are poor
candidates. Compounds with long half-lives, more than 8 hrs,
are also generally not used in extending forms, since there
effect is already sustained.

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(E) THERAPEUTIC INDEX
Margin of safety of a drug can be described by considering
therapeutic index, which is the ration of median toxic dose
and median effective dose.

Therapeutic index = TD50/ED50

A drug is considered to be relatively safe with therapeutic

index more than 10 i.e., larger the ratio the more safely is the
drug. Margin of the safety of the drugs determined on the
basis of therapeutic index is the range of plasma
concentration in which the drug is considered to the safe and
therapeutically effective. The drugs with narrow therapeutic
indices the release pattern should be more precise to
maintain the plasma concentration within the narrow
therapeutic and safety range.

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(F) SIDE EFFECT
The side effects of the some drugs are mainly developed due
to fluctuation in the plasma concentrations. The incidences of
side effects can be minimized by controlling the concentration
within therapeutic range at any given time. These drug
delivery is the most widely used to incidences of the GI (local)
side effects rather than a systemic side effect of the drug. The
drug properties which induce local or systemic side effect can
be circumvented or modified by their incorporation in a
suitable delivery system that employs a specific controlled
release mechanism.

(G) DISEASE STATE

Disease state and circadian rhythm are not drug properties,
but they are equally important as drug properties in
considering a suitable drug.
For example:-
• Aspirin SR for rheumatoid arthritis

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POLYMERS USED:
Since the structural and physicochemical characteristics
of the polymer are decisive in the drug release
mechanism, some will be more suitable than others,
depending on the aim pursued and the drug desired.

POLYMERS

HYDROPHILIC
HYDROPHILIC HYDROPHOBIC

NON-
CELLULOSIC
CELLULOSIC

Apart from these two types, waxes and insoluble

polymers are also used.
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CLASSIFICATION OF CR/ SR DDS
(1) Diffusion Controlled System
(2) Dissolution Controlled System
(3) Diffusion and Dissolution Controlled System
(4) Water Penetration Controlled System
(5) Methods using Ion Exchange
(6) Chemically Controlled Release Systems
(7) pH- Dependent Formulations
(8) Hydrogels
(9) Altered Density Formulations
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(1) DIFFUSION CONTROLLED SYSTEM
Basically diffusion process shows the movement of drug
molecules from a region of a higher concentration to one of
lower concentration. The flux of the drug J (in amount / area
-time), across a membrane in the direction of decreasing
concentration is given by Fick’s law.

 J= - D dc/dx

Where, D = diffusion coefficient in area/ time dc/dx =

change of concentration 'c' with distance ‘x’

Diffusion systems are characterized by release rate of

drug is dependent on its diffusion through inert water
insoluble membrane barrier. There are basically two types
of diffusion devices.
(A) RESERVOIR TYPE
(B) MATRIX TYPE
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(A) RESERVOIR TYPE
In the system, a water insoluble polymeric material
encloses a core of drug, which controls release rate. 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 polymers commonly used
in such devices are Ethyl cellulose and Poly-vinyl acetate.
The rate of drug released (dm/dt) can be calculated using
the following equation.

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(B) MATRIX TYPE
A solid drug is homogenously 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 solid
dissolution.
Advantages: Easier to produce than reservoir or
encapsulated devices, can deliver high molecular weight
compounds.
Disadvantages: Cannot provide zero order release, removal
of remaining matrix is necessary for implanted system.
 

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(2) DISSOLUTION CONTROLLED SYSTEM
Drugs having high aqueous solubility and dissolution rate,
shows challenge in controlling their dissolution rate.
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 limiting step for
dissolution of a drug is the diffusion across the aqueous
boundary layer. The solubility of the drug provides the
source of energy for drug release, which is countered by
the stagnant-fluid diffusional boundary layer. The rate of
dissolution (dm/dt) can be approximated by

Divided into two types:

(A) ENCAPSULATION
(B) MATRIX TYPE
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(A) ENCAPSULATION
The drug particles are
coated or encapsulated
by microencapsulation
techniques with slowly
dissolving materials like
cellulose, poly ethylene
glycols,
polymethacrylates,
waxes etc. the
dissolution rate of coat
depends upon the
solubility and thickness
of the coating. Those
with the thinnest layers
will provide the initial
dose. The maintenance
of drug levels at late
times will be achieved
from those with thicker
coating.
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(B) MATRIX TYPE
In matrix systems the drug is homogeneously
dispersed throughout a rate controlling medium. They
employ waxes such as beeswax, carnauba wax,
hydrogenated castor oil etc, which control drug
dissolution 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. The drug release is often
first order from such matrices. The wax embedded
drug is generally prepared by dispersing the drug in
molten wax and solidifying and granulating the same.

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(3) DISSOLUTION AND DIFFUSION
CONTROLLED SYSTEM
The drug core is enclosed in a partially soluble membrane.
Pores are thus created due to dissolution of parts of the
membrane which permit entry of aqueous medium into the
core and hence drug dissolution and diffusion of dissolved
drug out of the system. An example of obtaining such a
coating is using a mixture of ethyl cellulose with poly vinyl
pyrrolidine or methylcellulose.

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(4) WATER PENETRATION CONTROLLED
SYSTEM
In water penetration controlled delivery systems, rate
control is obtained by the penetration of water into the
system. They are

(A)SWELLING CONTROLLED SYSTEMS

(B)OSMOTICALLY CONTROLLED RELEASE SYTEMS

(A) SWELLING CONTROLLED SYSTEMS

Swelling controlled release systems are initially dry and
when placed in the body absorbs water or other body
fluids and swells. Swelling increases the aqueous
solvent content within the formulation as well as the
polymer mesh size, enabling the drug to diffuse through
the swollen network into the external environment.

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(B) OSMOTICALLY CONTROLLED SYSTEMS
These systems are fabricated by encapsulating an
osmotic drug core containing an osmotically active drug
(or a combination of an osmotically inactive drug with an
osmotically active salt eg NaCl) within a semi permeable
membrane made from biocompatible polymer, e.g.
cellulose acetate. A gradient of osmotic pressure is they
created, under which the drug solutes are continuously
pumped out of tablet through small delivery orifice in
tablet coating over a prolonged period of time through
the delivery orifice. This type of drug system dispenses
drug solutes continuously at a zero order rate. Release
of drug is independent on the environment of the system.

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(5) METHODS USING ION EXCHANGE
This system is designed to provide the controlled
release of an ionic or ionizable drug. It is prepared
by first absorbing an ionized drug onto the ion-
exchange resin granules such as codeine base with
Amberlite, and then after filtration from the alcoholic
medium, coating the drug resin complex granules
with a water permeable polymer, e.g. a modified
copolymer of polyacrylic and methacrylic ester, and
then spray drying the coated granules to produce
the polymer coated drug resin preparation. The
drug is released by exchanging with appropriately
charged ions in the GIT. The drug is then diffuse out
of the resin.

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Resin + - drug - + X - Resin + - X - + drug -
Where X- are ions in the GI tract
 The rate of diffusion control by: the area of
diffusion, diffusion path length and rigidity of resin.
 Thus, drug release depends on the ionic
environment (pH, electrolyte conc.) and the
properties of resin.

 Advantage - for those drugs which are highly

susceptible to degradation by enzymatic processes
since it offers a protective mechanism by
temporarily altering the substrate.

 Limitation - The release rate is proportional to the

conc. of the ions present in the vicinity of
administration site. So variable diet, water intake &
intestinal contents affects the release rate of drug.
They are mainly of 2 types –
cation exchange and anion exchange resin
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 They are mainly of 2 types - cation exchange and anion
exchange resin.

(A) CATIONIC DRUGS

A cationic drug forms a complex with an anionic ion-
exchange resin e.g. a resin with a SO - group. In the GI
tract Hydronium ion (H+) in the gastrointestinal fluid
penetrates the system and activity the release of cationic
drug from the drug resin complex.
H+ + Resin – SO3 - Drug + Resin – SO3 - H+ + Drug +

(B) ANIONIC DRUGS

An anionic drug forms a complex with a cationic ion
exchange resin, e.g. a resin with a [N (CH ) +] group. In the
GI tract, the Chloride ion (Cl-) in the gastrointestinal fluid
penetrates the system and activates the release of anionic
drug from the drug resin complex.

Cl- + Resin – [N (CH ) +] - Drug- Resin-[N (CH ) +] - Cl- + Drug-

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(6) CHEMICALLY CONTROLLED RELEASE
SYSTEMS
Chemically controlled release systems are the systems that
change their chemical structure, when exposed to biological
fluid. Mostly, biodegradable polymers are designed to degrade
as a result of hydrolysis of the polymer chains into biologically
safe and progressively smaller moieties. It is of two types and
they are Erodible systems and Pendent chain system.
(A) ERODIBLE SYSTEMS
In erodible systems, the mechanism of drug release occurs by
erosion. Erosion may be two types and they are
Bulk Erosion process polymer degradation may occur through
bulk hydrolysis.
When the polymer is exposed to water hydrolysis occurs.
Hydrolysis degrades the large polymers into smaller
biocompatible compounds.
These small compound diffuse out of the matrix through the
voids caused by swelling.
Loss of the small compounds accelerates the formation of
voids thus the exit of drug molecules.
e.g. poly lactide, polyglycolic acid. 33
Surface Erosion process Polymers like polyorthoesters and
polyanhydrides etc occurs degradation only at the surface of
the polymer, resulting in a release rate that is proportional to the
surface area of the delivery system.
When the polymer is exposed to water hydrolysis occurs
Hydrolysis degrades the large polymers into smaller
biocompatible compounds
These small compound diffuse from the interface of the
polymer
Loss of the small compounds leads to drug loss Note these
polymers do not swell.
e.g polyanhydrides

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(B) PENDENT CHAIN SYSTEMS
Pendent chain systems consist of linear homo or
copolymers with the drug attached to the backbone
chains. The drug is released from the polymer by
hydrolysis or enzymatic degradation of the linkages. Zero
order can be obtained and the cleavage of the drug is the
rate controlling mechanism. Example for polymers used in
pendent chain systems like n-(2- hydroxy
propyl)methacrylamide etc.

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(7) PH DEPENDENT FORMULATIONS
The gastrointestinal tract present some unusual features
for the oral route of drug administration with relatively
brief transit time through the gastrointestinal tract, which
constraint the length of prolongation, further the chemical
environment throughout the length of gastrointestinal tract
is constraint on dosage form design. Since most drugs
are either weak acids or weak bases, the release from
sustained release formulations is pH dependent.
However, buffers such as salts of amino acids, citric acid,
phthalic acid phosphoric acid or tartaric acid can be
added to the formulation, to help to maintain a constant
pH thereby rendering pH independent drug release. A
buffered controlled release formulation is prepared by
mixing a basic or acidic drug with one or more buffering
agent, granulating with appropriate pharmaceutical
excipients and coating with gastrointestinal fluid
permeable film forming polymer. When gastrointestinal
fluid permeates through the membrane, the buffering
agents adjust the fluid inside to suitable constant pH
thereby rendering a constant rate of drug.
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(7) HYDROGELS
Hydrogels are water swollen three dimensional structures
composed of primarily hydrophilic polymers. They are
insoluble because of chemical or physical cross-links.
The physical cross-links include crystallites,
entanglements or weak associations like hydrogen bonds
or vander waals forces. These crosslinks provide the
physical integrity and network structure. Hydrogels
provide desirable protection of labile drugs, peptides and
proteins.
(8) ALTERED DENSITY FORMULATIONS
Several approaches have been developed to prolong the
residence time of drug delivery system in the
gastrointestinal tract like High density approach and Low
density approach.

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RECENT APPROACHES
 Ocular topical depot preparation.
 Cancer treatment.
 Use of controlled drug delivery vehicle.
 Externally controlled microchips.
 Use of bacterial nanocellulose (BNC).
 Used in scaffolds.

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MARKETED FORMULATIONS

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