Transcript File

SALMAN BIN ABDUL AZIZ UNIVERSITY
COLLEGE OF PHARMACY
PHARMACEUTICSIV
(PHT 414 )
DESIGN OF SUSTAINED RELEASE
DOSAGE FORMS
Dr. Shahid Jamil
4/2/2016
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DEFINITIONS:SRF’s describes the slow release of a drug
substance from a dosage form to maintain
therapeutic response for extended period (812hrs)of time. Time depends on the dosage form.
In oral form it is in hours, and in parenteral’s it is
in days and months. Ex: Aspirin SR, Dextrim SR.
Controlled release dosage form: In this the rate or
speed at which the drug is released is controlled.
Ex: Adalat CR (Nifidipine), Dynacirc CR
(Isradipine.)

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Flow diagram of immediate release (multiple dose tablet and
capsules), controlled release (zero order) and sustained
release.
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The goal of SRDF’s is to obtain Zero order release from the
dosage form.
Zero order release is a release which is independent of the 
amount of drug present in the dosage form.
Usually SRDF’s do not follow zero order release but they 
try to mimic zero order release by releasing the drug in a
slow first order fashion.
Pharmacological action is seen as long as the drug is in 
therapeutic range, problems occur when drug
concentration is above/below therapeutic range.
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 With many drugs, the basic goal of therapy is to achieve a
steady-state blood or tissue level that is therapeutically
effective and nontoxic for an extended period of time.
 The design of proper dosage regimens is an important
element in accomplishing this goal.
 Dosage regimen: the frequency of administration of drug in a
particular dose is called as dosage regimen
 A basic objective in dosage form design is to optimize the
delivery of medication so as to achieve a measure of control of
the therapeutic effect in the face of uncertain fluctuations in
the in vivo environment in which drug release takes place.
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 This is usually accomplished by maximizing drug
availability, i.e., by attempting to attain a
maximum rate and extent of drug absorption.
 control of drug action through formulation also
implies controlling bioavailability to reduce drug
absorption rates.
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The Sustained Release Concept
 Sustained release, sustained action, prolonged
action, controlled release, extended action, timed
release, depot, and repository dosage forms are
terms used to identify 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 a
single dose.
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 In the case of inject able dosage forms, this period may vary
from days to months.
 In the case of orally administered forms, this period is
measured in hours and critically depends on the residence time
of the dosage form in the gastrointestinal (GI) tract.
 The term "controlled release" has become associated with
those systems from which therapeutic agents may be
automatically delivered at predefined rates over a long period
of time.
 Products of this type have been formulated for oral, inject able,
and topical use, and include inserts for placement in body
cavities as well.
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 Before proceeding with the design of a sustained
release form of an appropriate drug, the formulator
 Should have an understanding of the pharmacokinetics of
the candidate.
 Should be assured that pharmacologic effect can be
correlated with drug blood levels.
 Should be knowledgeable about the therapeutic dosage
range, including the minimum effective and maximum safe
doses.
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Design (Theory)
 To establish a procedure for designing
sustained release dosage forms, it is useful to
examine the properties of drug blood-leveltime profiles characteristic of multiple dosing
therapy of immediate release forms.
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 Figure 1 shows typical profiles observed after administration of equal
doses of a drug using different dosage schedules: every 8 hours (curve A),
every 3 hours (curve B), and every 2 hours (curve C).
FIG 1. Multiple patterns of dosage that characterize non-sustained peroral
administration of a drug with a biologic half-life of 3 hr and a half-life for absorption
of 20 min. Dosage intervals are: A, 8 hr; B, 3 hr; C, 2 hr; and D, 3 hr (loading dose is
twice the maintenance dose). E, Constant rate intravenous infusion.
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 Where:
 t: is the dosing interval,
 t1/2: is the biologic half-life.
 If t = t1/2,
Di = 2Dm.
 Selection of the proper dose and dosage interval
is a prerequisite to obtaining a drug level pattern
that will remain in the therapeutic range.
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 Elimination of drug level oscillations can be achieved by
administration of drug through constant-rate intravenous
infusion.
 Curve E in Figure 1 represents an example whereby the infusion
rate was chosen to achieve the same average drug level as a 3hour dosage interval for the specific case illustrated.
 The objective in formulating a sustained release dosage form is
to be able to provide a similar blood level pattern for up to 12
hours after oral administration of the drug.
 To design an efficacious sustained release dosage form, one
must have a thorough knowledge of the pharmacokinetics of the
drug chosen for this formulation.
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Figure 2 shows a general pharmacokinetic model
of an ideal sustained release dosage form.
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 Measurements of drug blood level are assumed to
correlate with therapeutic effect and drug kinetics
are assumed to be adequately approximated by a
one-body-compartment model.
 That is, drug distribution is sufficiently rapid so that
a steady state is immediately attained between the
central and peripheral compartments, i.e., the
blood-tissue transfer rate constants, k12 and k21, are
large.
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 Under the foregoing circumstances, the drug
kinetics can
parameters:
be
characterized
by
three
 The elimination rate constant (ke) or biologic half-life
(t1/2 = 0.693/ke)
 The absorption rate constant (ka).
 The apparent distribution volume (Vd), which defines
the apparent body space in which drug is distributed.
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 For
the
two-body
compartment
representation of drug kinetics, Vc is the
volume of the central compartment,
including both blood and any body water in
which drug is rapidly perfused.
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 The specific parameters that must be taken into
account in optimizing sustained release dosage form
designs, is shown in Figure 2 at the absorption site are:
 The loading or immediately available portion of the dose (Di).
 The maintenance or slowly available portion of the dose (Dm).
 The time (Tm) at which release of maintenance dose begins
(i.e., the delay time between release of Di and Dm).
 The specific rate of release (kr) of the maintenance dose.
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Figure 3 shows the form of the body drug level
time profile that characterizes an ideal peroral
sustained release dosage form after a single
administration.
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 Tp is the peak time.
 h is the total time after administration in which the
drug is effectively absorbed.
 Cp is the average drug level to be maintained
constantly for a period of time equal to (h - Tp)
hours; it is also the peak blood level observed after
administration of a loading dose.
 The portion of the area under the blood level curve
contributed by the loading and maintenance doses
is indicated on the diagram.
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 To obtain a constant drug level, the rate of
drug absorption must be made equal to its
rate of elimination.
 Consequently, drug must be provided by the
dosage form at a rate such that the drug
concentration becomes constant at the
absorption site.
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