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World Journal of Pharmaceutical Research
Bhatt et al.
World Journal of Pharmaceutical
SJIFResearch
Impact Factor 5.990
Volume 4, Issue 8, 871-882.
Review Article
ISSN 2277– 7105
ORAL SUSTAINED RELEASE DRUG DELIVERY SYSTEM: A
CONCISE REVIEW
Kamal Bhatt*, Divya juyal, Shivani kala and Meenakshi mehra
Himalayan Institute of Pharmacy & Research, Dehradun, 248001(Uttarakhand).
Article Received on
06 June 2015,
Revised on 29 June 2015,
Accepted on 19 July 2015
ABSTRACT
Oral drug delivery system is the most preferred any convenient option
as the oral route provide maximum active surface area among all drug
delivery system. Pharmaceutical reinvention and research are
increasingly focusing on delivery system, which enhance desirable
*Correspondence for
therapeutic objectives while minimizing side effect in the recent years,
Author
focus on the development of oral controlled release drug delivery
Kamal Bhatt
system has increased. The principal goal of sustained release dosage
Department of
Pharmaceutical
Science,Himalayan
form is the improvement of drug therapy assessed by the relationship
between advantages and disadvantages of the use of sustained release
Institute of Pharmacy &
system. Sustained release dosages forms are designed to release a drug
Research, Dehradun,
at a predetermined rate by maintaining a constant drug level for a
248001(Uttarakhand).
specific period of time with minimum side effect.
KEYWORDS: Pharmaceutical Reinvention, Sustained Release Dosage and Formulation
Methods, Factors Influcing, Factors Governing The Design of Sustained Release Dosage
Form.
INTRODUCTION
The drug delivery systems that are designed to achieve a prolonged therapeutic effect by
continuously releasing medication over an extended period of time after administration of
single dose of drug,[1] probably the earliest work in the area of sustained drug delivery dosage
forms can be traced to the 1938 patent of Israel Lipowski. This work involved coated pallets
for prolonged release of drug and was presumably forerunner to the development of the
coated particle approach to sustained drug delivery that introduced in the early 1950s. Ideally,
a drug should arrive rapidly at the site of action (receptor) in the optimum concentration,
remain for the desired time, be excluded from other sites, and be rapidly removed from the
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site when indicated i.e. the basic goal of the therapy is to achieve steady state blood level that
is therapeutically effective and non-toxic for an extended period of time. Generally, the time
course of a dosage form (pharmacokinetics) in man is considered to be controlled by the
chemical structure of the drug. Decreasing the rate of absorption and/ or changing the dosage
form provide a useful adjunct. When it is feasible or desirable to modify the drug compound
on a molecular level, often sought is a product that will require less frequent administration to
obtain the required biologic activity time profile; for example, a tablet that has the same
clinical effect when administered every twelve hours. In another instance, it may be desirable
to decrease the absorption rate in order to obtain a more acceptable clinical response.[2]
During the last two decades there has been remarkable increase in interest in sustained release
drug delivery system. This has been due to various factor viz. the prohibitive cost of
developing new drug entities, expiration of existing international patents, discovery of new
polymeric materials suitable for prolonging the drug release, and the improvement in
therapeutic efficiency and safety achieved by these delivery systems. Now-a-days the
technology of sustained release is also applied for veterinary products. These systems also
provide a slow release of drug over an extended period of time and also can provide some
control, whether this be of a temporal or spatial nature, or both, of drug release in the body.[3]
MERITS OF SUSTAINED RELEASE DOSAGE FORM[4, 5, 6, 7]
1. Decreased local and systemic side effects:
Reduced Gastrointestinal Irritation.
2. Better drug utilization:
Reduction in total amount of drug used.
Minimum drug accumulation on chronic dosing.
3. Improved efficiency in treatment:
Optimized therapy.
Less reduction in drug activity with chronic use.
4. Improved patient compliance:
Less frequent dosing
Reduced night-time dosing
5. Economical to the health care providers and the Patients
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DEMERITS OF CONVENTIONAL RELEASE DOSAGE FORM
1. If the drug has short half-life, it has to be administered frequently, so there are chances of
Missing the dose.
2. If the drug is not taken at periodic interval, peak valley plasma concentration time profile
Obtained is not steady.
3. The fluctuations of drug plasma level that occurs during conventional release may
producer Overmedication.
4. Poor patient compliance
PARAMETERS FOR DRUG TO BE FORMULATED IN SUSTAINED RELEASE
DOSAGE FORM
Physicochemical parameters for the drug selection
There are some physiochemical parameters for drug selection to be formulated in sustained
release dosage form which mainly includes the knowledge on the absorption mechanism of
the drug from the gastro intestinal tract, its general absorbability, the drug molecular weight,
solubility at different PH and apparent partition coefficient as shown in table 1.[10-12]
Parameter
Molecular weight/size
Solubility
Apparent partition coefficient
Absorption mechanism
Diffusion
From all GI segments
Preferred value
< 1000 Daltons
> 0.1 mg/ml for pH 1 to pH 7.8
High
Diffusion
General absorbability
Release
Pharmacokinetic parameter for drug selection
The pharmacokinetic evaluation requires knowledge on a drug’s elimination half-life, total
clearance, absolute bioavailability, possible first-pass effect, and the desired steady
concentrations for peak and trough. Table.2.[12]
Parameter
Elimination half life
Total clearance
Elimination rate constant
Apparent volume of distribution Vd
Intrinsic absorption rate
Therapeutic concentration Cssav
Absolute bioavailability
Toxic concentration
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Preferred value
Preferably between 0.5 and 8
Should not be dose dependent
Required for design
The larger Vd and MEC, the larger will be the required dose size.
Must be greater than release rate
The lower Cssav and smaller Vd, the loss among of drug required
Should be 75% or more
Apart the values of MTC and MEC, safer the dosage form. Also
suitable for drugs with very short half-life.
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Design and Formulation of Oral Sustained Release Drug Delivery System
Sustained (zero-order) drug release has been attempted to be achieved, by following classes
of Sustained drug delivery system.
A) Diffusion sustained system.
i) Reservoir type.
ii) Matrix type
B) Dissolution sustained system.
i) Reservoir type.
ii) Matrix type
C) Methods using Ion-exchange.
D) Methods using osmotic pressure.
E) PH independent formulations.
F) Altered density formulations
A) Diffusion sustained system[13, 14, 15, and 16]
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.
D = diffusion coefficient in area/ time
dc /dx = change of concentration 'c' with distance 'x'
(i)Reservoir type
In the system, a water insoluble polymeric material encases 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.
Figure 1. Schematic representation of a reservoir diffusional device.
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ii) Matrix type
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 solid dissolution. Higuchi has derived the
appropriate equation for drug release for this system,
Fig2: Schematic representation of diffusion sustained drug release: matrix system.
Q = D / T [2 A – Cs] Cst ½
Where;
Q = weight in grams of drug released per unit area of surface at time t
D = Diffusion coefficient of drug in the release medium
= porosity of the matrix
Cs = solubility of drug in release medium
T= Tortuosity of the matrix
A = concentration of drug in the tablet, as gm/ ml
B) Dissolution sustained systems[15, 16]
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 the stomach from the effects of drugs such as Aspirin,
i) Reservoir type
Drug is coated with a given thickness coating, which is slowly dissolved in the contents of
gastrointestinal tract. The maintenance of drug levels at late times will be achieved from
those with thicker coating. This is the principle of the spansule capsule. Cellulose nitrate
phthalate was
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Synthesized and used as an enteric coating agent for acetyl salicylic acid tablets.
ii) Matrix type
The more common types of dissolution sustained dosage form as shown in figure 3. It can be
either a drug impregnated sphere or a drug impregnated tablet, which will be subjected to
slow erosion.
Two types of dissolution- sustained pulsed delivery systems:
A) Single bead– type device with alternating drug and rate-controlling layer
B) Beads containing drug with differing thickness of dissolving
Figure 3. Two types of dissolution-controlled delivery system
C) Methods using lon Exchange[14, 15, 17, 18]
It is based on the formation of drug resin complex formed when a ionic solution is kept in
contact with ionic resins. The drug from this complex gets exchanged in gastrointestinal tract
and released with excess of Na+ and Cl- present in gastrointestinal tract.
Figure 4. Ion exchange system
+
-
-
Resin - drug + X
resin
+
-
=
resin- -
=
X- + drug –
Conversely,
Resin- - drug+ + Y+
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Y+ + drug+
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D) Methods using osmotic pressure[15, 19, 20, 21]
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. These types of system are also known as
oros, which follows the mechanism of osmotic pressure where the drug is released at constant
zero order rate. The reservoir is made up of the drug and osmotic agent like mannitol or KCl,
which is surrounded by semi permeable membrane. These systems generally appear in two
different forms. The first contains the drug as a solid core together with electrolyte, which is
dissolved by the incoming water. The electrolyte provides the high osmotic pressure
difference. The second system contains the drug in solution in an impermeable membrane
within the device.
Figure 5. Diagrammatic representation of two types of osmotically controlled system
E) pH– Independent formulations[16, 22]
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 sustained
release formulations 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 release.
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F) Altered density formulations[23, 24, 25, 26]
It is reasonable to expect that unless a delivery system remains in the vicinity of the
absorption site until most, if not all of its drug contents is released, it would have limited
utility. To this end, several approaches have been developed to prolong the residence time of
drug delivery system in the gastrointestinal tract. Globular shells which have density lower
than that of gastric fluid used as a carrier of drug for sustained release purpose.
High density approach: In this approach the density of the pellets should be more than that
of normal stomach content and should therefore, be at least 1-4gm/cm3. In preparing such
formulation drug can be coated on a heavy core or mixed with heavy inert materials such as
barium sulfate titanium dioxide iron powder and zinc oxide. Globular shells which have
density lower than that of gastric fluid used as a carrier of drug for sustained release purpose.
The undercoated shell is then coated by mixture of drug with polymer such as ethyl cellulose
and hydroxypropyl cellulose. Thus the final product floats on the gastric fluid for a prolonged
period, while slow releasing drug.
FACTORS GOVERNING THE DESIGN OF SUSTAINED RELEASE DOSAGE
FORM
Aqueous solubility
A drug of high water solubility can dissolve in water or gastrointestinal 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. Diffusion or
dissolution will be depend on the solubility of drug in aqueous system. So the lower limit for
the solubility of drug to be formulate in release system has been reported to be
0.1mg/ml.[27,28]
Half life
The half-life of a drug is an index of its residence time in the body. If the drug has short half
(less than two hrs.) life, the dosage form require large quantity of drug. If drug have
eliminated half-life more than eight hrs. are sufficient sustained in the body. This ideally the
drug for sustained release should have half-life of three to four hours.[29, 30]
Therapeutic index
Drug have low therapeutic index are not suitable for sustained release drug delivery. If the
system fails in the body, dose dumping may occur, which leads toxicity.[31]
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T.I. (therapeutic index)=TD50/ED50
Longer the value of T.I. the safer is the drug. Drug is considered to be safer if its T.I. value is
greater than 10.[32]
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 SRDDS.[33]
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 SR drug delivery system.[34]
Diffusibility
In many control or sustained release system drug must diffuse through plyometric membrane
or matrix. The ability of a drug to diffuse through plyometric membrane or matrix called
diffusibility (diffusibility coefficient D), is a function of its molecular weight (molecular
size). [35]
LogD=-Svlog u + kv =-SM log M+km
Where,
V=molecular volume
M=molecular weight
Sv, Sm, kv, km=constant
For drug with a molecular weight greater than 500 Dalton, the diffusion coefficient in many
polymer are frequently so small that they are difficulty to quantify (i.e. less than 1012cm2/sec).thus high molecular weight drugs should be slow release in extend release using
diffusion through plyometric membrane.[36]
Duration of action
Duration of action is the time period for which the blood levels remains above the MEC and
below MSC levels. Drug acting for long duration are unsuitable candidates for formulation in
to SR/CR forms.tisue binding, partition coefficient, half-life, metabolism, irreversible binding
to cells are some parameters which are responsible for long duration of action of drug.[37]
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Partition coefficient
Partition coefficient is defined as the fraction of drug in an oil phase to that of an adjust
aqueous phase. Drug that have higher partition coefficient that means very oil soluble and
drug that have lower partition coefficient that means low lipid solubility.in both the cases that
type of dosage form are not suitable for sustained release preparation.[38]
K = C0 / C w
Where,
C0
=
equilibrium concentration of all forms of the drug in an organic phase at equilibrium
Cw = equilibrium concentration at all forms in an aqueous phase.
CONCLUSION
Sustained release system include any drug delivery system that achieve slow release of drug
over extend time and maintain therapeutic concentration of drug. If it is unsuccessful
maintain the concentration of drug but maintain the time period. It is considered prolong
release system. The above discussion concludes that the matrix or coating system are helpful
for formulating sustained release drug delivery system by various approaches. And discussed
about the types and formulating factors that are necessary to know before the formulating
drug as sustained release.
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