chapter 9: solid oral modified-release dosage forms and drug delivery systems
TRANSCRIPT
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Embedding drug in Slowly Eroding orHydrophilic Matrix System
The drug substance is combined and made intogranules with an excipient material that slowlyerodes in body fluids, progressively releasing the
drug for absorption.
Hydrophilic cellulose polymers
- commonly used as excipient base in tablet
matrix systems
- Hydroxypropyl methylcellulose (HPMC)
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Embedding Drug in Inert
Plastic MatrixThe drug is granulated with an inertplastic material such as polyethylene,
polyvinyl acetate, or polymethacrylate,and the granulation is compressed intotablets.
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Complex Formation
Form complexes that may be soluble in bodyfluids, depending on the pH of theenvironment.
The slow dissolution rate provides extendedrelease of the drug.
Salts of Tannic acid, Tannates, provide thisquality in a variety of products.
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Ion Exchange Resins
The release of the drug depends on the pHand electrolyte concentration in thegastrointestinal tract.
Release is greater in the acidity of thestomach than in the less acidic environmentof the small intestine.
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Osmotic Pump
The system is composed of a core tabletsurrounded by a semipermeable coating havinga 0.4mm diameter hole produced by laser beam.
The core tablet has 2 layers, one containing thedrug and the other containing a polymericosmotic agent.
The system is designed such that only a fewdrops of water are drawn into the tablet everyhour.
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Repeat Action Tablets
Prepared so that an initial dose of drug isreleased immediately and a second dosefollows later.
In general, the drug from the inner core isexposed to body fluids and released 4 to 6hours after administration.
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Delayed Release Oral
Dosage FormsRelease of a drug that may be
intentionally delayed until it reachesthe intestines for several reasons.
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Properties of Enteric
Coated TabletspH dependentBreaks down in the less acidic environment of
the intestine.
Time dependent
Enzyme dependent
Erodes by moisture over time duringgastrointestinal transit.
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USP REQUIREMENTSAND FDA GUIDANCE
FOR MODIFIED-RELEASE DOSAGE
FORMS
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Drug Release
Test for drug release for ER and delayed-releasearticles: dissolution form the dosage unit againstelapsed time
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Example
Aspirin Extended-Release tablet
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Uniformity of Dosage
UnitsUniformity of dosage units may be
demonstrated by either of two methods:
weight variations or contentuniformity
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In Vitro-In vivo
CorrelationsCritical to the development of oral extended-releaseproducts
Important throughout product development ,clinicalevaluation submission of an application for FDAapproval for marketing, & during post approval forany proposed formulation or manufacturing changes
it provides guidance to sponsors of new drug
applications and abbreviated new drug applicationsand abbreviated new drug applications for extendedrelease of oral products
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IVIVC provides methods of:
Developing an IVIVC and evaluating itspredictability
Using an IVIVC to establish dissolutionspecifications
Applying an IVIVC as a surrogate for in vitro-in vivo bioequivalence during the approvalprocess or during post approval for certainformulation or manufacturing changes
f
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3 Categories of IVIVCsinclude in the document
Level A
the relationship between the entire in vitro
dissolution and release time course and theentire in vivo response time course
Example: the time course of plasma drugconcentration or
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Level B
predictive mathematical model of therelationship between summary parametersthat characterize in vitro and in vivo timecourses
Example: models that relate the mean invivo dissolution time to the mean in vitrodissolution time
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Level C
a predictive mathematical model of therelationship between the amountdissolved in vitro at a particular timeand a summary parameter that
characterizes the time in vivo timecourse or area under the curve
the level of IVIVCs may be useful in the
early stages of formulationdevelopment when pilot formulationsare being selected
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MOST COMMON PROCESS FORDEVELOPING IVIVC MODEL (LEVEL A)
Develop formulations with different release rates ora single release rate if dissolution is independent ofcondition
Obtain in vitro dissolution profiles and in vivo plasmaconcentration profiles for these formulations
Estimate the in vivo absorption or dissolution time
course for each formulation and subject usingappropriate mathematical approaches
CRITERIA IN DEVELOPMENT APPLICABLE
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CRITERIA IN DEVELOPMENT APPLICABLETO THE DEVELOPMENT OF IVIVCS ARE
THE FOLLOWING:
in determining in vitro dissolution, USPdissolution apparatus; type I (basket) or type II(paddle) is preferred, although type III
(reciprocating cylinder) or type IV (flow-throughcell) may be applicable in some substances
aqueous medium with a pH not exceeding 6.8 is
preferred as the medium for dissolution studies.For poorly soluble drugs, a surfactant may beadded
CRITERIA IN DEVELOPMENT APPLICABLE
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CRITERIA IN DEVELOPMENT APPLICABLETO THE DEVELOPMENT OF IVIVCS ARE
THE FOLLOWING:
The dissolution profiles of at least 12individual dosage units from each lot shouldbe determined
for vivo studies, human subjects are used inthe fasted state unless the drug is not welltolerated, in which case the studies may be
conducted in the fed state. Acceptable datasets have been shown to be generated withuse of 6 to 36 human subjects
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Crossover studies are preferred, but parallelstudies or cross-study analysis may beacceptable using a common referencetreatment product, such as an intravenoussolution, an aqueous oral solution, or animmediate-release product
CRITERIA IN DEVELOPMENT APPLICABLETO THE DEVELOPMENT OF IVIVCS ARE
THE FOLLOWING:
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LABELING
They must be specific for the monographarticle
Aspirin delayed-release tablets must statethat the tablets are enteric coated
Capsules must indicate whether the product
is intended for dosage every 12 to 24 hoursand state which in vitro drug release test theproduct complies
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CLINICALCONSIDERATIONS IN
THE USE OF ORALMODIFIED-RELEASE
DOSAGE FORMS
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Not to be used interchangeably orconcomitantly with immediate-release formsof the same drug
patients using a modified release productshould not be changed into immediaterelease without consideration to the blood
concentration
patients should not be changed to anotherextended-release product unless there is
assurance of equivalent bioavailability
Different product can result in a marketedshift in the patients drug blood level because
of differences in drug release characteristics
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Modified release tablets and capsules should
not be crushed or chewedPatients if fed through the nasogastric tubemay receive modified- release medications
Non-erodible plastic matrix shells andosmotic tablets remain intact throughoutgastrointestinal transit and the empty shellsor ghosts from osmotic tablets may be seen
in the stool
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