chapter 9: solid oral modified-release dosage forms and drug delivery systems

7/29/2019 Chapter 9: Solid Oral Modified-release Dosage Forms and Drug Delivery Systems

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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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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


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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chapter 9: solid oral modified-release dosage forms and drug delivery systems

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