3. In 1952, Beecham introduced the first
sustained release formulation that was able to
control the drug release kinetics and achieve
12-hour efficacy
The goal in designing sustained release drug
delivery system is to reduce the frequency of
the dosing, reducing the dose & providing
uniform drug delivery.
Hydrophilic polymer matrix is widely used for
formulating an Sustained dosage form.
4. DRUG DELIVERY SYSTEMS
The term “ drug delivery systems’’ refer to the
technology utilized to present the drug to the
desired body site for drug release and
absorption.
Definition: drug delivery system that achieved
prolong therapeutic effect by continuously
releasing medication or drug over an extended
period of time after administration a single
dose.
5. Sustained release tablets are generally taken
once or twice a day during a course of
treatment whereas in conventional dosage
forms there is need to take 3-4 times dosage in
a day to achieve the same therapeutic action .
Sustained release formulation maintains a
uniform blood level of drug with better patient
compliance as well as increased efficacy of
drug
6. Rational or Reasons for developing of SRDDS.
I. Formulation of SRDDS minimizes dosing
frequency and sustained release provides
availability of a drug at action site throughout
the treatment to improve clinical efficiency of a
drug molecule.
II. To reduce cost of treatment by reducing
number of dosage requirement.
III. To minimize toxicity due to overdose which is
often in conventional dosage from.
IV. To enhance the activity duration of a drug
possessing short half-life.
7. The conventional dosage forms release their active
ingredients into an absorption pool immediately.
This is illustrated in the following simple kinetic scheme.
The absorption pool represents a solution of the drug at the
site of absorption,
Kr, Ka and Ke - first order rate-constant for drug release ,
absorption and overall elimination respectively. Immediate
drug release from a conventional dosage form implies that
Kr>>>>Ka. For non-immediate release dosage forms,
Kr<<<Ka i.e. the release of drug from the dosage form is the
rate limiting step.
The drug release from the dosage form should follows zero-
order kinetics, as shown by the following equation:
Kr° = Rate In = Rate Out = Ke.Cd.Vd
Where,
Kr°: Zero-order rate constant for drug release-Amount/time
Ke: First-order rate constant for overall drug elimination-time
Cd: Desired drug level in the body – Amount/volume
Vd: Volume space in which the drug is distributed in litter
8. sustained release formulation follows First
order kinetics.
Conc. of drug release is not same throughout.
9. Improve patient convenience and compliance
due to less frequent drug administration.
Reduction in fluctuation in steady state level
and therefore better control of disease
condition.
Maximum utilization of drug enabling
reduction in total amount of dose
administration.
Reduction in health care cost through improve
theraphy,shorter treatment period.
Less frequency of dosing and reduction in
personnel time to dispense, administer
monitor patients.
10. Reduction in total drug usage when compared
with conventional therapy.
Reduction in drug accumulation with chronic
therapy.
Reduction in drug toxicity (local/systemic)
Economical to the health care providers and the
patient
11. Delay in onset of drug action.
Possibility of dose dumping in the case of a
poor formulation strategy.
Cost per unit dose is higher when compared
with conventional doses.
Not all drugs are suitable for formulating into
SR dosage form.
Retrieval of drug is difficult in case of toxicity,
poisoning (or) hypersentivity reactions.
12. Two types of factors involved
I. Physicochemical factor
II. Biological Factor
I. Physicochemical factor
Aqueous Solubility
The drug of good aqueous solubility and pH independent
solubility are most desirable candidate for SRDDS.
Poor aqueous solubility possess oral bioavailability
problem and drug which having extreme aqueous
solubility are unsuitable for sustained release because
it is difficult task to control the release of drug from the
dosage form.
13. Partition coefficient
Also called as distribution coefficient; the bioavailability of a
drug is greatly influenced by the partition coefficient, as the
biological membrane is lipophilic in nature transport of drug
across the membrane is depends upon the partition coefficient
of the drug.
The drugs having low partition coefficient are considered as
poor candidate for the sustained release formulation in the
aqueous phase.
Drug Stability
SRDDS is designed to control release of a drug over the length
of the gastrointestinal tract (GIT); hence high stability of
drug in GI environment is required.
14. Protein Binding
Proteins binding of drug play a key role in its
therapeutic.
Pharmacological activity of a drug depends on
unbound concentration of a drug rather than
total concentration. The drugs which bound to
some extent of a plasma and tissue proteins
enhances the biological half-life of a drug.
Release of such drug extended over a period of
time and therefore no need to develop
extended release drug delivery for this type of
drug.
15. Drug pKa and Ionization at Physiological pH
If the unionized drug is absorbed and permeation
of ionized drug is negligible, but the rate of
absorption is 3 to 4 times is less than that of the
unionized drug. Since the drug shall be
unionized at the site to an extent 0.1 to 5%.
Drugs existing largely in ionized form are poor
candidates for oral SR drug delivery system.
16. II. Biological Factor
Absorption
To maintain the constant uniform blood or tissue level of
drug ,it must be uniformly released from the sustained
release system & then uniformly absorbed in the body.
Since the purpose of forming a SR product is to place
control on the delivery system,
it is necessary that the rate of release is much slower than
the rate of absorption. If we assume that the transit
time of most drugs in the absorptive areas of the GI
tract is about 8-12 hours, the maximum half-life for
absorption should be approximately 3-4 hours;
otherwise, the device will pass out of the potential
absorptive regions before drug release is complete.
17. Thus corresponds to a minimum apparent absorption rate
constant of 0.17-0.23 h-1 to give 80-95% over this time
period. Hence, it assumes that the absorption of the
drug should occur at a relatively uniform rate over the
entire length of small intestine.
For many compounds this is not true. If a drug is
absorbed by active transport or transport is limited to a
specific region of intestine, SR preparation may be
disadvantageous to absorption.
One method to provide sustaining mechanisms of
delivery for compounds tries to maintain them within
the stomach. This allows slow release of the drug,
which then travels to the absorptive site. These
methods have been developed as a consequence of the
observation that co-administration results in sustaining
effect.
18. Distribution
Drugs with high apparent volume of
distribution, which influence the rate of
elimination of the drug, are poor for oral SR
drug delivery system e.g. Chloroquine.
Metabolism
The metabolic conversion of a drug is to be
considered before converting into another
form. Since as long as the location, rate, and
extent of metabolism are known a successful
sustain release product can be developed.
19. Drugs those are significantly metabolized before absorption,
either in the lumen or the tissue of the intestine, can show
decreased bioavailability from slower-releasing dosage form.
Half-life of Drug
The drug having short biological half-life between <5 but drugs
is soluble in water. The drugs should have larger therapeutic window
absorbed in GIT. The usual goal of an oral SR product is to
maintain therapeutic blood levels over an extended period of time.
To achieve this, drug must enter the circulation at approximately
the same rate at which it is eliminated.
The elimination rate is quantitatively described by the half-life
(t1/2).
Each drug has its own characteristic elimination rate,
which is the sum of all elimination processes, including metabolism,
urinary excretion and all over processes that permanently remove
drug from the blood stream.
20. Margin of safety
As we know that larger the value of
therapeutic index safer is the drug. Drugs with
less therapeutic index usually poor candidate
for formulation of oral S.R drug delivery
system.
TD= median toxic dose
median effective dose
TD50/ED50
21. Diffusion is rate limiting
Diffusion is driving force where the movement of drug
molecules occurs from high concentration in the tablet
to lower concentration in gastro intestinal fluids.
This movement depends on surface area exposed to
gastric fluid, diffusion pathway, drug concentration
gradient and diffusion coefficient of the system.
In practice we can follow either of the two methods,
I. The drug particles are coated with polymer of defined
thickness so as the portion of drug slowly diffuse
through the polymer to maintain constant drug level in
Blood .
22. II. The drug is formulated in an insoluble matrix;
the gastric fluid penetrates the dosage form
and dissolves the medicament and release the
drug through diffusion.
23. Dissolution is rate limiting
The drugs with poor water solubility (BCS class 2 and
4) are inherently sustained release forms.
While for water-soluble drugs, it’s possible to
incorporate a water insoluble carrier to
reduce dissolution of the drug particles are coated with
this type of materials e.g. Polyethylene Glycol. One
may skip the use of disintegrating agent to promote
delayed release.
24. Osmotic pressure is rate limiting
Osmosis is a phenomenon in which the flow of
liquid occurs from lower concentration to high
concentration through a semi permeable
membrane which allows transfer of liquid only.
The whole drug is coated with a semi permeable
membrane with a hole on one end of tablet made
by a laser beam.
The gastric fluid penetrates through the
membrane, solubilizes the drug and increases the
internal pressure which pumps the drug solution
out of the aperture and releases the drug
environment.
The delivery rate is constant provided that the
excess of drug present inside the tablet. But, it
declines to zero.
25. Release is controlled by ion exchange
Ion exchangers are water insoluble resinous
materials containing salt forming anionic or
cationic groups. While manufacturing, the drug
solution is mixed with resin and dried to form
beads which are tableted .
The drug release depends upon high concentration
of charged ions in gastro intestinal tract where, the
drug molecules are exchanged and diffused out of
the resin into the surrounding fluid. This
mechanism relies upon the environment of resin
and not pH or enzyme on absorption site
26. Reference
N.K. Jain –Controlled and sustained & novel
drug delivery.
Novel Study in Sustained Release Drug
Delivery System: A Review article by
Rakesh Roshan Mali*, Vaishali Goel, Sparsh
Gupta
