Pharlec.report (1)

8/22/2019 Pharlec.report (1)

1/72

Solid Oral Modified-releaseDosage Forms and Drug

Delivery Systems

Solid Oral Modified-releaseDosage Forms and Drug

Delivery Systems

Solid oral modified-release dosage formsand drug delivery systemsSolid oral modified-release dosage formsand drug delivery systems


2/72

DefinitionDefinition

Products provide eitherdelayed or extendedrelease of drugs.Most products are

orally administered

Products provide eitherdelayed or extendedrelease of drugs.Most products are

orally administered

Some other modifdosage forms, incluocular, parenteral,subdermal, and vag

products.

Some other modifdosage forms, incluocular, parenteral,subdermal, and vag

products.


3/72

Rationale for extended releasepharmaceuticalsRationale for extended releasepharmaceuticals

Extended-release productsprovide an immediaterelease of drug thatpromptly produces thedesired therapeutic effect,followed by gradual release

of additional amounts ofdrug to maintain this effectover a predetermined period

Extended-release productsprovide an immediaterelease of drug thatpromptly produces thedesired therapeutic effect,followed by gradual release

of additional amounts ofdrug to maintain this effectover a predetermined period


4/72

Extended releaseExtended release

Allows reduction indosing frequency fromthe necessitated by aconvention dosage

form, such as solution,or an immediaterelease dosage form

Allows reduction indosing frequency fromthe necessitated by aconvention dosage

form, such as solution,or an immediaterelease dosage form


5/72

Rationale for extended releasepharmaceuticalsRationale for extended releasepharmaceuticals

Extended releasetablets & capsules =take once or twicedaily

Conventional forms =3 to 4 times daily toachieve same TE

Extended releasetablets & capsules =take once or twicedaily

Conventional forms =3 to 4 times daily toachieve same TE

For nonoral ratecdrug delivery sysdrug release pattranges in duratiohours for mosttransdermal pat

months for the evaginal ring inse

For nonoral ratecdrug delivery sysdrug release pattranges in duratiohours for mosttransdermal pat

months for the evaginal ring inse


6/72

Multiple daily dosingMultiple daily dosing

Inconvenient for thepatient and can result inmissed doses, made-updoses, andnoncompliance with theregimen

When doses are notadministered onschedule, the resultingpeaks and valleys reflectthe optimum drug therapy

Inconvenient for thepatient and can result inmissed doses, made-updoses, andnoncompliance with theregimen

When doses are notadministered onschedule, the resultingpeaks and valleys reflectthe optimum drug therapy


7/72

Extended-release dosage formsadvantage over conventional formsExtended-release dosage formsadvantage over conventional forms

Less fluctuation in drug blood levels Frequency reduction in dosing Enhanced convenience and compliance

Reduction in adverse side effectsReduction in overall health care costs

Less fluctuation in drug blood levels Frequency reduction in dosing Enhanced convenience and compliance

Reduction in adverse side effectsReduction in overall health care costs


8/72

Disadvantage of extended-release dformsDisadvantage of extended-release dforms

Loss of flexibilityRisk of sudden and total drug releaseDose dumping due to a failure of technolog

Loss of flexibilityRisk of sudden and total drug releaseDose dumping due to a failure of technolog


9/72

TerminologiesTerminologies

Sustained Release(SR)

Sustained Action (SA) Extended Release (ER) Long Acting (LA)

Controlled Release(CR)

Sustained Release(SR)

Sustained Action (SA) Extended Release (ER) Long Acting (LA)

Controlled Release(CR)

Prolonged Rel(PR)

Timed release

Prolonged Rel(PR)

Timed release


10/72

Terms and abbreviations used for exrelease dosage formsTerms and abbreviations used for exrelease dosage forms

SR (sustained release) SR (sustained release) SA (sustained SA (sustained


11/72


PA (prolonged action) PA (prolonged action)

CR (controlledrelease)

CR (controlledrelease)


12/72


LA (long acting)

LA (long acting)

ER (extended

ER (extended


13/72


TR (timed releas TR (timed releas


14/72

Delayed-release dosage formDelayed-release dosage form

Designed to release thedrug at a time otherthan promptly afteradministration

Time based or based on

the influence ofenvironmentalconditions (e.g.gastrointestinal pH)

Designed to release thedrug at a time otherthan promptly afteradministration

Time based or based on

the influence ofenvironmentalconditions (e.g.gastrointestinal pH)


15/72

Repeat actionRepeat action

Contain two singledoses of medication,one for immediaterelease and the

second for delayedrelease

Contain two singledoses of medication,one for immediaterelease and the

second for delayedrelease


16/72

Targeted releaseTargeted release

Directed toward isolating or concentrating in a body region, tissue, or site of absorptiofor drug action

Directed toward isolating or concentrating in a body region, tissue, or site of absorptiofor drug action

E t d d R l O l D FE t d d R l O l D F


17/72

Extended Release Oral Dosage Form(Successful ER Product)Extended Release Oral Dosage Form(Successful ER Product)

1. Release from dosage forms at a predetermrate2. Dissolve in GT3. Maintain sufficient GT residence time4. Be absorbed at a rate that will replace the

amount of drug being metabolized and ex

1. Release from dosage forms at a predetermrate2. Dissolve in GT3. Maintain sufficient GT residence time4. Be absorbed at a rate that will replace the

amount of drug being metabolized and ex


18/72

Characteristics of Extended release-formsCharacteristics of Extended release-forms

They exhibit neither very slow nor very fast rabsorption and excretion

They are uniformly absorbed from thegastrointestinal tract

They exhibit neither very slow nor very fast rabsorption and excretion

They are uniformly absorbed from thegastrointestinal tract


19/72

Characteristics of Extended release-formsCharacteristics of Extended release-forms

They are administered in relatively small do They possess a good margin of safety They are used in the treatment of chronic r

than acute conditions

They are administered in relatively small do They possess a good margin of safety They are used in the treatment of chronic r

than acute conditions


20/72

Mechanism of Drug ActionMechanism of Drug Action

Affecting the rate at which the drug is releafrom the dosage form

By slowing the transit time of the dosage fothrough the gastrointestinal tract

Affecting the rate at which the drug is releafrom the dosage form

By slowing the transit time of the dosage fothrough the gastrointestinal tract


21/72

EXTENDED-RELEASE TECHNOLOGFOR ORAL DOSAGE FORMSEXTENDED-RELEASE TECHNOLOGFOR ORAL DOSAGE FORMS


22/72

Basis of Drug ReleaseBasis of Drug Release

Modifying drug dissolution by controlling accbiologic fluids to the drug through the use of coatings

Controlling drug diffusion rates from dosage f

Chemical reaction or interaction between the substance or its pharmaceutical barrier andspecific biological fluids

Modifying drug dissolution by controlling accbiologic fluids to the drug through the use of coatings

Controlling drug diffusion rates from dosage f

Chemical reaction or interaction between the substance or its pharmaceutical barrier andspecific biological fluids


23/72

Coated beads, Granules, and microsCoated beads, Granules, and micros

Using conventional plancoating or air suspensioncoating, a solution of thedrug substance is placedon small intact nonparent

seeds or beads made up ofsugar and stand or onmicrocrystalline cellulosesphere

Using conventional plancoating or air suspensioncoating, a solution of thedrug substance is placedon small intact nonparent

seeds or beads made up ofsugar and stand or onmicrocrystalline cellulosesphere

Nonpareil seeds (425 to 850Nonpareil seeds (425 to 850


24/72

Coated beads, Granules, and microsCoated beads, Granules, and micros

Microcrystallinecellulose1. More durable during

production than

sugar-based cores2. 170-600 m

Microcrystallinecellulose1. More durable during

production than

sugar-based cores2. 170-600 m

Lipid materials used to coatLipid materials used to coat


25/72

Lipid materials used to coatgranulesLipid materials used to coatgranules

Beeswax

Beeswax

Glyceryl Monos

Glyceryl Monos



26/72


Cellulosic material(ethyl cellulose)

Cellulosic material(ethyl cellulose)

Cetyl alcCetyl alc



27/72


Carnauba waxCarnauba wax



28/72


Aqueous coating systemseliminate the hazards andenvironmental concernsassociated with organicsolventbased systems

The thicker the coat, themore resistant topenetration and the moredelayed will be drugrelease and dissolution.

Aqueous coating systemseliminate the hazards andenvironmental concernsassociated with organicsolventbased systems

The thicker the coat, themore resistant topenetration and the moredelayed will be drugrelease and dissolution.


29/72

Multitablet systemMultitablet system

Small spheroid compressed tablets 3 to 4 mm in dimay be prepared to have varying drug releasecharacteristics

Each capsule may contain 8 to 10 minitablets , somuncoated for immediate release and others coated extended drug release

Small spheroid compressed tablets 3 to 4 mm in dimay be prepared to have varying drug releasecharacteristics

Each capsule may contain 8 to 10 minitablets , somuncoated for immediate release and others coated extended drug release


30/72

Microencapsulated drugMicroencapsulated drug

Microencapsulationis aprocess by whichsolids, liquids, or evengases may beenclosed inmicroscopic particles

by formation of thincoatings of wallmaterial around thesubstance

Microencapsulationis aprocess by whichsolids, liquids, or evengases may beenclosed inmicroscopic particles

by formation of thincoatings of wallmaterial around thesubstance

Gelatinis a comwall-forming mand synthetic psuch as polyvinalcohol, ethyl ce

polyvinyl chloriother materialsmay be used

Gelatinis a comwall-forming mand synthetic psuch as polyvinalcohol, ethyl ce

polyvinyl chloriother materialsmay be used


31/72

Encapsulation processEncapsulation process

1.

Dissolving the wall material2. Encapsulated material is added to the mixturethoroughly stirred

3. A solution to second material is added (e.g. a4. The final dry microcapsules are free-flowing

discrete particles of coated material5. Wall material constitute into 2 % to 20% of the

particle weight

1.

Dissolving the wall material2. Encapsulated material is added to the mixturethoroughly stirred

3. A solution to second material is added (e.g. a4. The final dry microcapsules are free-flowing

discrete particles of coated material5. Wall material constitute into 2 % to 20% of the

particle weight


32/72

Advantage of MicroencapsulatAdvantage of Microencapsulat

administered dose of a drug is subdivided small units that are spread over a large aregastrointestinal tract, which may enhanceabsorption by diminishing local drug conce

administered dose of a drug is subdivided small units that are spread over a large aregastrointestinal tract, which may enhanceabsorption by diminishing local drug conce

Embedding Drug in Slowly Eroding orEmbedding Drug in Slowly Eroding or


33/72

Embedding Drug in Slowly Eroding orHydrophilic Matrix SystemEmbedding Drug in Slowly Eroding orHydrophilic Matrix System

drug substance iscombined and madeinto granules with anexcipient material thatslowly erodes in bodyfluids, progressivelyreleasing the drug forabsorption

drug substance iscombined and madeinto granules with anexcipient material thatslowly erodes in bodyfluids, progressivelyreleasing the drug forabsorption

Hydrophiliccepolymersarcommonly uthe excipientablet matrix

Hydrophiliccepolymersarcommonly uthe excipientablet matrix

Effectiveness of the Hydrophilic maEffectiveness of the Hydrophilic ma


34/72

Effectiveness of the Hydrophilic mabased on:Effectiveness of the Hydrophilic mabased on:

1.

Successive process of hydration on the psurface2. Gel formation on the polymers surface3. Tablet erosion

4. Subsequent and continuous release of dr

1.

Successive process of hydration on the psurface2. Gel formation on the polymers surface3. Tablet erosion

4. Subsequent and continuous release of dr


35/72

Hydroxypropyl Methy Cellulose (HMHydroxypropyl Methy Cellulose (HM

a free-flowing powder; commonly usedto provide the hydrophilic matrix A successful hydrophilic system must

contain the following:1. polymer must form a gelatinous layer

rapidly enough to protect the inner

core of the tablet from disintegratingtoo rapidly after ingestion2. 20% of HPMC results in satisfactory

rates of release for an extended-release tablet formulation

a free-flowing powder; commonly usedto provide the hydrophilic matrix A successful hydrophilic system must

contain the following:1. polymer must form a gelatinous layer

rapidly enough to protect the inner

core of the tablet from disintegratingtoo rapidly after ingestion2. 20% of HPMC results in satisfactory

rates of release for an extended-release tablet formulation

Manufacturers may prepare two-laManufacturers may prepare two-la


36/72

Manufacturers may prepare two latabletsManufacturers may prepare two latablets

one layer containing the uncombined drug immediate release the other layer having the drug embedded

hydrophilic matrix for extended release.

one layer containing the uncombined drug immediate release the other layer having the drug embedded

hydrophilic matrix for extended release.


37/72

Three-layer tabletsThree-layer tablets

outer layers containing the drug for immedrelease Some commercial tablets are prepared wit

inner core containing the extended-release

of drug and an outer shell enclosing the cocontaining drug for immediate release

outer layers containing the drug for immedrelease Some commercial tablets are prepared wit

inner core containing the extended-release

of drug and an outer shell enclosing the cocontaining drug for immediate release


38/72

Embedding Drug in Inert Plastic MaEmbedding Drug in Inert Plastic Ma

drug is granulated with an inert plastic materiaas polyethylene, polyvinyl acetate, orpolymethacrylate , and the granulation is compinto tablets

slowly released from the inert plastic matrix by

diffusion retains its shape during leaching of the drug anduring its passage through the alimentary tract

drug is granulated with an inert plastic materiaas polyethylene, polyvinyl acetate, orpolymethacrylate , and the granulation is compinto tablets

slowly released from the inert plastic matrix by

diffusion retains its shape during leaching of the drug anduring its passage through the alimentary tract


39/72

Embedding Drug in Inert Plastic MaEmbedding Drug in Inert Plastic Ma

Gradumet

Gradumet


40/72

Complex FormationComplex Formation

Form complexes thatmay be only slowlysoluble in body fluids,depending on the pHof the environment

slow dissolution rate

Form complexes thatmay be only slowlysoluble in body fluids,depending on the pHof the environment

slow dissolution rate

Rynatan- Salts of taacid, tannates , provthis quality in a varieof proprietary produ

Rynatan- Salts of taacid, tannates , provthis quality in a varieof proprietary produ


41/72

Ion exchange resinsIon exchange resins

A solution of a cationic drug may be passed through a co

containing an ion exchange resin, forming a complex by treplacement of hydrogen atoms

release of the drug depends on the pH and electrolyte conthe gastrointestinal tract

release is greater in the acidity of the stomach than in theenvironment of the small intestine

hydrocodone polistirex and chlorpheniramine polistirex s(Tussionex Pennkinetic Extended Release Suspension phentermine resin capsules (Ionamin Capsules [CellTec

A solution of a cationic drug may be passed through a co

containing an ion exchange resin, forming a complex by treplacement of hydrogen atoms

release of the drug depends on the pH and electrolyte conthe gastrointestinal tract

release is greater in the acidity of the stomach than in theenvironment of the small intestine

hydrocodone polistirex and chlorpheniramine polistirex s(Tussionex Pennkinetic Extended Release Suspension phentermine resin capsules (Ionamin Capsules [CellTec


42/72

Mechanism of ion exchange reMechanism of ion exchange re

In the Stomach1. Drug resinate + HCl acidic resin + drughydrochloride

2. Resin Salt + HCl resin chloride + acidic

drug

In the Stomach1. Drug resinate + HCl acidic resin + drughydrochloride

2. Resin Salt + HCl resin chloride + acidic

drug


43/72

Mechanism of ion exchange reMechanism of ion exchange re

In the Intestine

1. Drug resinate + NaCl sodium resinate

+ drug hydrochloride

2. Resin Salt + NaCl resin chloride

+ sodium salt of drug release is extended over 12 hours by ionic exch

In the Intestine

1. Drug resinate + NaCl sodium resinate

+ drug hydrochloride

2. Resin Salt + NaCl resin chloride

+ sodium salt of drug release is extended over 12 hours by ionic exch


44/72


45/72

Osmotic pumpOsmotic pump

The pioneer oral osmotic

pump drug deliverysystem is the Oros systemdeveloped by Alza

composed of a core tabletsurrounded by asemipermeable

membrane coating havinga 0.4 mm diameter holeproduced by laser beam(e.g. Acutrim)

The pioneer oral osmotic

pump drug deliverysystem is the Oros systemdeveloped by Alza

composed of a core tabletsurrounded by asemipermeable

membrane coating havinga 0.4 mm diameter holeproduced by laser beam(e.g. Acutrim)

core tablet halayers, one cothe drug (the alayer) and the containing a

polymeric osmagent (the pus

core tablet halayers, one cothe drug (the alayer) and the containing a

polymeric osmagent (the pus


46/72

Osmotic pumpOsmotic pump

The system isdesigned such thatonly a few drops ofwater are drawn intothe tablet each hour

The system isdesigned such thatonly a few drops ofwater are drawn intothe tablet each hour

function of thedepends on anosmotic gradibetween the cof the two-lay

and the fluid ingastrointestin

function of thedepends on anosmotic gradibetween the cof the two-lay

and the fluid ingastrointestin

l b l d bl b l d b


47/72

Drug release may be altered byDrug release may be altered by

Changing the surfacearea

ThicknessComposition of the

membrane and/or

diameter of the drugrelease orifice

Changing the surfacearea

ThicknessComposition of the

membrane and/or

diameter of the drugrelease orifice

l i ff d bl i ff d b


48/72

Release rate is not affected by:Release rate is not affected by:

Gastrointestinal acidity or alkanity Fed conditionsGT motility

Gastrointestinal acidity or alkanity Fed conditionsGT motility

(GITS)(GITS)


49/72

(GITS)(GITS)

1. is employed in the manufacture of Glucotrol extended release tablets and Procardia XL exrelease tablets

2. Another example of the osmotic system is thecontrolled-onset extended release (COER [Ssystem used in Covera-HS Tablets, in whicdrug is released 4 to 5 hours after tablet ing

1. is employed in the manufacture of Glucotrol extended release tablets and Procardia XL exrelease tablets

2. Another example of the osmotic system is thecontrolled-onset extended release (COER [Ssystem used in Covera-HS Tablets, in whicdrug is released 4 to 5 hours after tablet ing

R i blR i bl


50/72

Repeat action tabletsRepeat action tablets

Initial dose of drug isreleased immediatelyand a second dosefollows later

released 4 to 6 hoursafter administration

Initial dose of drug isreleased immediatelyand a second dosefollows later

released 4 to 6 hoursafter administration

Example: Repe Example: Repe

They are best suited for tchronic conditions requiridosing Low dosage and fairly raabsorption and excretion

They are best suited for tchronic conditions requiridosing Low dosage and fairly raabsorption and excretion

D l d l d fD l d l d f


51/72

Delayed-release dosage formsDelayed-release dosage forms

release of a drug from an

oral dosage form may beintentionally delayed untilit reaches the intestinesfor several reasons

protect a drug destroyedby gastric fluids

release of a drug from an

oral dosage form may beintentionally delayed untilit reaches the intestinesfor several reasons

protect a drug destroyedby gastric fluids

reduce gastric dcaused by drugparticularly irritthe stomach

facilitategastrointestinafor drugs that aabsorbed from intestines

reduce gastric dcaused by drugparticularly irritthe stomach

facilitategastrointestinafor drugs that aabsorbed from intestines

Example: Enteric CoatedEnseals- Lilly; EcotrinSmithkline

Example: Enteric CoatedEnseals- Lilly; EcotrinSmithkline

Properties of an enteric coating tabl

Properties of an enteric coating tabl


52/72

capsulescapsules

pH dependent breaking down in the less acidic environment of the

intestine time dependent Eroding by moisture over time during gastrointestin

transit enzyme dependent deteriorating as a result of the hydrolysis-catalyzin

of intestinal enzymes

pH dependent breaking down in the less acidic environment of the

intestine time dependent Eroding by moisture over time during gastrointestin

transit enzyme dependent deteriorating as a result of the hydrolysis-catalyzin

of intestinal enzymes

Agents used for enteric coating ofAgents used for enteric coating of


53/72

capsules and tabletscapsules and tablets

ShellacShellac FatsFats FattFatt

Agents used for enteric coating ofAgents used for enteric coating of


54/72

capsules and tabletscapsules and tablets

WaxesWaxes Cellulose acetphthalate

Cellulose acetphthalate

Examples of modified-release tabled l ffi i l i th USP

Examples of modified-release tabled l ffi i l i th USP


55/72

and capsules official in the USPand capsules official in the USP

Delayed release

Aspirin DR tablets

Dirithromycin DR tablet

Doxycycline Hyclate DRcapsules

Erythromycin DR capsulesOxtriphylline Dr tablets

Delayed release

Aspirin DR tablets

Dirithromycin DR tablet

Doxycycline Hyclate DRcapsules

Erythromycin DR capsulesOxtriphylline Dr tablets

Extebded release

Diltiazem ER capsuDisopyramide phos

capsules

Isosorbide dinitratetablets and caps

Propanolol HCL ER

Theophylline ER ca

Extebded release

Diltiazem ER capsuDisopyramide phos

capsules

Isosorbide dinitratetablets and caps

Propanolol HCL ER

Theophylline ER ca

USP REQUIREMENTS AND FDA GUIDANCE FUSP REQUIREMENTS AND FDA GUIDANCE F


56/72

MODIFIEDRELEASE DOSAGE FORMSMODIFIEDRELEASE DOSAGE FORMS

1. Drug release based on drug

dissolution from thedosage unit againstelapsed test time

Example: Aspirin EXcapsules

1. Drug release based on drug

dissolution from thedosage unit againstelapsed test time

Example: Aspirin EXcapsules

Aspirin Dissolution RAspirin Dissolution R

2 Uniformity of dosage units2 Uniformity of dosage units


57/72

2. Uniformity of dosage units2. Uniformity of dosage units

may be demonstrated by either of two methweight variation or content uniformity

may be demonstrated by either of two methweight variation or content uniformity

3 IN VITRO IN VIVO CORRELATION3 IN VITRO IN VIVO CORRELATION


58/72

3. IN VITROIN VIVO CORRELATION3. IN VITROIN VIVO CORRELATION

critical to the

development of oralextended-releaseproducts

It provides guidance tosponsors of new drug

applications andabbreviated new drugapplications for extendedrelease oral products

critical to the

development of oralextended-releaseproducts

It provides guidance tosponsors of new drug

applications andabbreviated new drugapplications for extendedrelease oral products

important throug

product develoclinical evaluasubmission ofapplication forapproval for mand during

postapproval proposed formor manufacturchanges

important throug

product develoclinical evaluasubmission ofapplication forapproval for mand during

postapproval proposed formor manufacturchanges

IVIVC provide methods of:IVIVC provide methods of:


59/72

IVIVC provide methods of:IVIVC provide methods of:

(a) developing anIVIVC and evaluatingits predictability,

(b) using an IVIVC toestablish dissolutionspecifi cations, and

(a) developing anIVIVC and evaluatingits predictability,

(b) using an IVIVC toestablish dissolutionspecifi cations, and

(c) applyingan

a surrogate fbioequivalenit is necessardocumentbioequivalenthe approval or duringpostapprovacertain formumanufacturinchanges

(c) applyingan

a surrogate fbioequivalenit is necessardocumentbioequivalenthe approval or duringpostapprovacertain formumanufacturinchanges

Three categories of IVIVCs are inclui h dThree categories of IVIVCs are inclui h d


60/72

in the document:in the document:

Level A the relationship between the entire in vitro

dissolution and release time course and thentire in vivo response time course

EXAMPLE: the time course of plasma drug

concentration or amount of drug absorbedmost common type of correlation submitte

Level A the relationship between the entire in vitro

dissolution and release time course and thentire in vivo response time course

EXAMPLE: the time course of plasma drug

concentration or amount of drug absorbedmost common type of correlation submitte

Three categories of IVIVCs are incluin the document:Three categories of IVIVCs are incluin the document:


61/72


Level B predictive mathematical model of the relat

between summary parameters that characthe in vitro and in vivo time courses

EXAMPLE: models that relate the mean in vdissolution time to the mean in vivo disstime

Level B predictive mathematical model of the relat

between summary parameters that characthe in vitro and in vivo time courses

EXAMPLE: models that relate the mean in vdissolution time to the mean in vivo disstime

Three categories of IVIVCs are incluin the document:Three categories of IVIVCs are incluin the document:


62/72


LevelC

A predictive mathematical model of the relationship betweamount dissolved in vitro at a particular time (or the time for in vitro dissolution of a fixed percent of the dose, e.g., summary parameter that characterizes the in vivo time comaximum concentration [Cmax] or area under the curve)

The level of IVIVCs may be useful in the early stages of fordevelopment when pilot formulations are being selected

LevelC

A predictive mathematical model of the relationship betweamount dissolved in vitro at a particular time (or the time for in vitro dissolution of a fixed percent of the dose, e.g., summary parameter that characterizes the in vivo time comaximum concentration [Cmax] or area under the curve)

The level of IVIVCs may be useful in the early stages of fordevelopment when pilot formulations are being selected

Most common process for developIVIVC Model (Level A)Most common process for developIVIVC Model (Level A)


63/72

IVIVC Model (Level A)IVIVC Model (Level A)

(a) develop formulationswith different release

g., slow, fast, and intermediate) or a single releif dissolution is independent of condition;

(b)obtain in vitro dissolution profi les and in vplasma concentration profi les for these formuand

(c) estimate the in vivo absorptionor dissolutiocourse for each formulation and subject usingappropriate mathematical approaches

(a) develop formulationswith different release

g., slow, fast, and intermediate) or a single releif dissolution is independent of condition;

(b)obtain in vitro dissolution profi les and in vplasma concentration profi les for these formuand

(c) estimate the in vivo absorptionor dissolutiocourse for each formulation and subject usingappropriate mathematical approaches

Criteria in development applicable development of IVIVCS are the folloCriteria in development applicable development of IVIVCS are the follo


64/72

development of IVIVCS are the follodevelopment of IVIVCS are the follo

In determining in vitro dissolution, USP dissol

apparatus, type I (basket) or type II (paddle) isalthough type III (reciprocating cylinder) or typowthrough cell) may be applicable in some ins

An aqueous medium with a pH not exceeding preferred as the medium for dissolution studie

poorly soluble drugs, a surfactant (e.g . 1% sodsulfate) may be added

In determining in vitro dissolution, USP dissol

apparatus, type I (basket) or type II (paddle) isalthough type III (reciprocating cylinder) or typowthrough cell) may be applicable in some ins

An aqueous medium with a pH not exceeding preferred as the medium for dissolution studie

poorly soluble drugs, a surfactant (e.g . 1% sodsulfate) may be added


65/72

The dissolution profiles of at least 12 indiv

dosage units from each lot should be deter For in vivo studies, human subjects are use

fasted state unless the drug is not well tolewhich case the studies may be conducted

state. Acceptable data sets have been showgenerated with use of 6 to 36 human subje

The dissolution profiles of at least 12 indiv

dosage units from each lot should be deter For in vivo studies, human subjects are use

fasted state unless the drug is not well tolewhich case the studies may be conducted

state. Acceptable data sets have been showgenerated with use of 6 to 36 human subje


66/72

Crossover studies are preferred, but paralle

or cross-study analysis may be acceptablecommon reference treatment product, sucintravenous solution, an aqueous oral soluan immediate release product

Crossover studies are preferred, but paralle

or cross-study analysis may be acceptablecommon reference treatment product, sucintravenous solution, an aqueous oral soluan immediate release product

LabelingLabeling


67/72

LabelingLabeling

They must be specific

for the monographarticle

Aspirin DR tabletsmust state that the

tablets are entericcoated

They must be specific

for the monographarticle

Aspirin DR tabletsmust state that the

tablets are entericcoated

Capsules mus

indicate whethproduct is intedosage every hours and sta

in vitro drug retest the producomplies

Capsules mus

indicate whethproduct is intedosage every hours and sta

in vitro drug retest the producomplies

Clinical considerationClinical consideration


68/72


Not to be used

interchangeably orconcomitantly withimmediate-release forms ofthe same drug

Patients using a modified

release product should not be changed into immediaterelease without considerationto the blood concentration

Not to be used

interchangeably orconcomitantly withimmediate-release forms ofthe same drug

Patients using a modified

release product should not be changed into immediaterelease without considerationto the blood concentration

Patients shou

changed to anproduct unlesis assurance oequivalent

bioavailability

Patients shou

changed to anproduct unlesis assurance oequivalent

bioavailability



69/72


Different product can

result in a marketedshift in the patients drugblood level because ofdifferences in drugrelease characteristics

Modified release tabletsand capsules shouldnot be crushed orchewed

Different product can

result in a marketedshift in the patients drugblood level because ofdifferences in drugrelease characteristics

Modified release tabletsand capsules shouldnot be crushed orchewed

Patients if fed thr

nasogastric tubereceive modifiedmedications

Nonerodible plashells and osmotremain intact thr

GT transit and thshells or ghosts osmotic tablets mseen in the stool

Patients if fed thr

nasogastric tubereceive modifiedmedications

Nonerodible plashells and osmotremain intact thr

GT transit and thshells or ghosts osmotic tablets mseen in the stool


70/72


71/72


72/72

Date post:	08-Aug-2018
Category:	Documents
Upload:	chizms1234
View:	213 times
Download:	0 times

Pharlec.report (1)

Documents