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MODIFIED RELEASE
DOSAGE FORM
by
A. S. Adebayo, PhD
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Introduction
Modified release dosage forms are
drug delivery systems (DDS) which, by
vi r tue of formulat ion and productdesign, provide drug release in a
modified form dist inct f rom that of
the convent ional dosage forms.Drug release can either be delayed or
extended in nature.
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Delayed-release p roduc ts
Usually enteric coated tablets
or capsulesdesigned to pass
through the stomach unal tered
to release their medicat ion
w ithin the intest inal tract .
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Extended-release produc ts
Designed to release their medication in
controlled manner, at pre-determined
rate, durat ion and locat ionin thebody to achieve and maintain
op t imum therapeut ic b lood levelsof
drug.
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Rationale for extended release
pharmaceuticals Drugs that are not inherently long lasting require
multiple daily dosing to achieve the desiredtherapeutic effects.
Multiple daily dosing is often inconvenient and canresult in missed doses, made-up doses and patientnon-compliant with therapeutic regimen.
Blood levels of drugs from conventional immediate-release dosage forms taken more than once dailyfollowing definite schedule usually demonstratesequential peaks and troughs (valleys) associatedwith each dose.
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Rationale for extended release
pharmaceuticals
Extended release tablets or capsules arecommonly taken only once or twice dailycompared with the conventional dosing of 2 to 4times daily
Products are designed to provide an immediate release ofdrugwhich promptly produces the desired therapy, followed bygradual and continual release of additional amounts of drug tomaintain this effect over a predetermined period of time.
The need for night dosing of drugs may beeliminated
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Advantages of Extended-release
Dosage Form s over Convent ional
Forms
Reduction in drug blood level fluctuations
Reduction in frequency of dosing
Enhanced patient compliance
Reduction in incidence of adverse side effects
Reduction in overall healthcare costs.
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Terminology
The following terms have been applied to
extended or sustained drug delivery
systems:
Controlled-release Extended release (ER)
Sustained-release (SR)
Timed-release (TR)
Long-acting (LA)
Prolonged-action (PA), and
Sustained-action (SA)
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Extended-release dosage forms
The US FDA defines ER dosage form
as:
one that al lows areduc t ion in dos ing
frequencyto that presented by a
convent ional dosageform such as a
so lut ion or an immediate releasedosage forms.
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Delayed-release
These are dosage forms designed
to release the drug ata t ime o ther
than prom pt lyafter adm inistration .
The delay may betime-basedor
based on the inf luence ofenvi ronmental cond i tionssuch as
g .i. pH, enzyme, pressure, etc
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Repeat action
These are dosage forms usually
containing 2 sing le dosesof
medication, one forimmediate and thesecond fordelayed release e.g. bi-
layered tablets.
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Targeted release
Drug release that is d irected
towards isolat ing or concentrat ing a
drug in a body region , t issue, or si tefor abso rpt ion or d rug act ion
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Extended-release Oral
Dosage Form s
The general properties of drugs best suited for ERproduct design are:
They exhibit neither very slow nor very fast rates ofabsorption and excretion
They are uniformly absorbed from the g.i.t.
They are administered in relatively small doses.
They possess a good margin of safety i.e. TherapeuticIndex (TI)
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Technology of ER Dosage
Forms
ER Coated Beads, Granu les orMicrospheres
Granules of drug may be coated with lipid
materials such as beeswax, carnuba wax,glyceryl monostearate, cetyl alcohol, etc.
Careful blending of coated and un-
coated granules and with coatings ofdifferent thicknesses will provide drugrelease of desired characteristics.
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COMMERCIAL EXAMPLES
Toprol-XL (metoprolol succinate) tabs.
(Astra);
Indocin SR (indomethacin capsules
(Merck);
Compazine (prochloperazine) Spansule
Capsules (SmithKline Beecham)
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Technology of ER Dosage Forms -
Multitablet system
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Technology of ER Dosage
Forms
Embedding drug in slowly eroding or
hydrophilic matrix system The design
comprises of the drug substance plusexcipient material that slowly erodes in body
fluids thereby progressively releasing the
drug for absorption
E.g. Quinidex Quinine SO4 tablets (Robins);
Oramorph SR Morphine SO4 tabs. Roxane
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Technology of ER Dosage Forms:
ER Microencapsulated Drug
Microencapsulation is a process by which solids,
liquid and semi-solid substances may be
encapsulated into microscopic size particles
through the formation of thin coating ofwall
material around the substance.
Different rate of dru g release can be ob tained
by changing the co re to wal l rat io, the type of
polymer coat and the method ofmicroencapsulat ion.
E.g . K-DurMicroburst Release System (KCl)
tabs. (Key)
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Technology of ER Dosage
Forms: Osmotic pump device
This consists of a core tablet surrounded bya semi-permeable membrane coating with a0.4 mm diameter hole produced by laser
beam.
The core tablet has 2 layers, one containingthe drug (the active layer) and the other
containing the polymeric osmotic agent (thepush layer). E.g. Glucotrol XL (glipizide) tablets (Pfizer)
Covera HS (verapamil HCl) tabs. (Searle)
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Other methods
Embedding drug in an inert plasticmatrix e.g. Desoxyn
(methamphetamine HCl) tabs (Abbott);Procanbid (procainamide HCl tabs.(Parke-Davis)
Complex formation
Ion exchange resins
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K inet ics o f Drug release
Drug release from conventional dosage
forms, like the other processes of ADME,
are governed by the first-order kinetics
model.
In First-order model, drug release is
dependent on the amount of drug availablefor release and therefore the rate of
release decl ines exponent ial ly w ith t ime.
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Kinetics of Drug release
Extended release dosage forms are
governed by zero-order kinetics in which the
rate of release is independent of amountof drug remaining in the dosage form.
Therefore a constant amount of drug will be
released over time from extended releasedosage forms
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Assignments (Due Feb. 4, 2010)
Identify 3 controlled release formulation excipients,giving chemical and commercial names
What is the kinetic mechanism of drug releasefollowed by Osmotic controlled delivery devices?
Using a suitable graph, illustrate the profile thatwould be observed in the following scenarios:
Burst release at peal plasma level
Design failure leading to Dose dumping
Design failure leading to drug being withheld
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THANK YOU FOR YOUR ATTENTION
MODIFIED RELEASE
DOSAGE FORM