This document discusses sustained release dosage forms. It begins by introducing the goals of sustained release therapy, which are to achieve steady blood levels of a drug for an extended period of time to maximize drug availability and control effects. It then covers sustained release classifications and advantages over conventional therapy. The key approaches to sustained release are drug modifications or dosage form modifications. Drug modifications involve complexing, adsorbates or prodrugs, while dosage form modifications use embedded matrices, barriers or multilayered tablets to control drug release. Product evaluation involves in vitro dissolution testing and in vivo studies to validate designs.

1. 5. Sustained Release Dosage
Forms
Berhanemeskel W.G, Asst. Prof.
Department of Pharmaceutics
School of Pharmacy
College of Medicine and Health Sciences
University of Gondar
May 2009
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2. Outline
5.1. Introduction
5.2. Theory and Design
5.3. Implementation of Design
5.4. Practical Formulation
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3. 5.1. Introduction
The basic goals of therapy is
1. To achieve a steady-state blood or tissue level
that is therapeutically effective and nontoxic for
an extended period of time.
– This objective can be accomplished by maximizing
drug availability. This can be done by increasing the
drug absorption.
2. To optimize dosage form design so that a
measure of control of the therapeutic effect is
achieved
3. Maximizing drug availability
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4. Objectives of drug delivery
The two aspects most important to drug
delivery.
1. Spatial Placement:- relates to targeting a
drug to a specific organ or tissue.
2. Temporal Placement:- refers to the
controlling the rate of the drug delivery to
the target tissues.
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5. Convention Drug therapy
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6. Convention Drug therapy (2)
 Convention drug therapy is of short duration
of action.
 This is due to the inability of conventional
dosage forms to control temporal delivery.
 If an attempt is made to maintain drug blood
levels in the therapeutic range for longer
period of time
 For e.g. By increasing the dose, then toxic level
may be produced at early times.
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7. Problems with conventional drug
therapy
• If the dosing intervals is not appropriate for
the biological half life of the drug, large
“peaks” and “valleys” in drug blood level may
results.
• The drug blood level may not be within the
therapeutics range at sufficiently early time.
• Patient noncompliance with multiple dosing
regimen.
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8. Sustained Release
• The conventional dosage forms
– Dosage form -> Absorption pool -> Target pool
– The rate of absorption is rate limiting step
• Sustained Release
– Dosage form -> Target pool -> -
– The release of the drug from the dosage from is
rate limiting step.
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9. Classification
• No immediate –release delivery systems may
classified as follows:-
– Delayed release
– Sustained release
• Controlled
• Prolonged
– Site specific release
– Receptor release
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10. • Delayed release:- system uses repetitive
intermitted dosing of a drug from one or more
immediate release units incorporated in a
single dosage form.
• Sustained Release:- includes any drug delivery
system that achieves slow release of drug over
and extended period of time.
• Site specific:- targeting the drug effectively to
a certain biological location.
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11. Potential advantages of sustained release
• Avoid patient compliance problem
• Employ less total drug
– Minimizing or eliminate local side effects.
– Minimizing or eliminate systemic side effects.
– Minimize drug accumulation.
• Improve the efficiency of the treatment
– Cure or control condition more promptly
– Reduce the fluctuation in drug level.
– Improves bioavailability
• Economy
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12. Limitations of SRDFs
• Prompt termination of the medication is
difficult (e.g. if there is technological failure)
• Less flexibility in adjusting dosage regimen
(already fixed)- SRDF is designed for normal
population
• Economic factors (expensive)
• Not all drugs are amenable for SRDFs
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13. Unsuitable Characteristics of drugs for per
oral SRDF
• Drugs not effectively absorbed in the lower
intestine
• Short biologic half life (<1hr)
• Long biological half life (>12hrs)
• Drugs with low therapeutic indices
• Precise dosage titrated to individual patients is
required
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14. Requirements for SRDF
 Must know pharmacokinetics of the dosage
form
 Blood level is well correlated with
pharmacologic effect
 Therapeutic dosage range
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15. 5.2. Theory and Design
Pharmacokinetic models
MD LD
DF
LDi
Kr
TM
Absorption site Body compartment
Central blood
Peripheral tissues
Ka Ke
Where
• TM - the time starts to release maintenance dose (MD)
• Kr- rate constant of release
• MD- maintenance dose
• LD- loading dose 15

16. In pharmacokinetic model of peroral SRDF
• Measurement of drug blood level are
assumed to correlate with therapeutic effect
• Drug kinetics are assumed to adequately
approx. by a one body compartment model
• Drug distribution is sufficiently rapid so that a
steady state is immediately attained between
the central and peripheral compartment
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17. Blood level time profile (Ideal SRDFs)
MSL
MEL
Cp
Loading Dose
Maintenance Dose
Tp Time h
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18. Theoretical treatment of SRDFs
• A system in which drug is released by
– Zero order or
– First order with or with out LD
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19. 5.3. Implementation of design
Basically there are two approaches
1. Based on drug modification
2. Based on dosage form modification
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20. Approaches based on drug
modifications
• Are methods based on modification of the
physical and or chemical properties of the drug
• The physicochemical properties of a drug may be
altered through
1. Drug - complex formation
2. Drug – adsorbate preparation
3. Prodrug synthesis
• These techniques are possible only with drug
moieties containing appropriate functional
groups (e.g. acidic or basic)
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21. Advantages
• The approach to sustained release is
independent of the dosage form design
• Thus, drugs modified may be formulated as
liquid, suspensions, capsules or tablets
• Loading doses of unmodified drug may be
incorporated in formulations that are
ordinarily formulated to release both
unmodified and modified drugs without
significant delay
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22. Mechanisms of SR based on drug modification
Drug complex
DC solid DC solution D
Drug-Adsorbate
AD solid D
Prodrug
PD solid PD solution PD plasma D
Dissolution Dissociation Absorption
Desorption Absorption
Dissolution
Absorption Metabolism
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23. Approaches based on dosage form modification
• Formulations based on modification of the physicochemical
properties of these dosage forms can be classed into three
product types:
1. Encapsulated slow release beads or granules
2. Tabletted mixed or slow release granulations
3. Slow release (core) tablets
• Fabrication of tablets allows for direct incorporation of loading
doses by
– Multilayered or
– Press coated tablets
• Encapsulated sustained release dosage forms have two specific
advantages over core tablet designs
– Undisintegrated tablets may remain in the stomach for extended periods
of time but not in encapsulated SR
– There is statistical assurance of drug release with encapsulated forms
since release of drug by a significant fraction from the granules is highly
probable 23

24. Mechanisms in retarding drug release
• Two general principles are involved in
retarding drug release from most
practical SR formulations involving
dosage for modification
1. Embedded matrix
2. Barrier principles
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25. Embedded Matrix
• Drug is dispersed in a matrix of retardant material
which may be encapsulated in particulate form or
compressed in to tablets.
• Release is controlled by a combination of several
physical processes.
• These includes:
1. Permeation of the matrix by water
2. Leaching (extraction or diffusion) of drug from the
matrix
3. Erosion of matrix material
• Matrices may be prepared from insoluble or
erodible materials
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26. Diffusion in Porous Systems
Swellable Hydrogel Systems
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27. Barrier Method
• It implies that a layer of retardant material is
imposed between a drug and the elution
medium.
• Drug release results
1. From diffusion of drug through the barrier
2. Permeation of the barrier by moisture or
3. Erosion of the barrier
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28. C
D Where
A – drug diffusion through
Barrier
B- Permeation of barrier by
elution media followed by
drug diffusion
C- Erosion of barrier and
release drug
D – Rupture of barrier as a
result of permeation of
elusion media
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29. Product Evaluation and Testing
1. In vitro measurement of drug availability
• Dissolution testing methods
2. In vivo measurement of drug availability
• Validation of SR products designs can be
achieved only by in vivo testing
• Basic objective is to establish the bioequivalence
of the product for which a controlled release
claim is to be made with conventional dosage
forms of formulated drug
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