modification of drug

7/26/2019 modification of drug

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http://www.animationfactory.com/animations/nature/rainbow/a2d1a/http://www.animationfactory.com/animations/nature/rainbow/a2d1a/


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Introduction

Mechanisms of controlled release Intelligent controlled release DDS Examples Recent advances References
http://www.animationfactory.com/animations/animals/bears/4f1bf/


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Introduction:

Fluctuating plasma level in conventional DF.

Development of CR ,SR, TR Etc.
http://www.animationfactory.com/animations/animals/bears/4f328/


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Targeted delivery

It has goal ofdelivering the drug to

specific cell types,tissues or organs.


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Controlled release

Assigned to release theDRUat

a !REDE"ERMI#EDRate.


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Modulated release

Release of drug at a varia$leratecontrolled by

Environmental conditions,Biofeedback,

Sensor input External control device.


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Sustained release (SR)

In SR%Drug release is affected $yExternal environment.

& Release is slo' thanconventional D(.

In )R% Release is dependant on thedesign of dosage form.


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DRUG RELEASE MDULATI!

AD*A#"AES

DISAD*A#"AES

DRUS U#SUI"A+E (-R )R


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Di""erent controlled release syste#s

Time of release

Cumulative

release

Burst like release

Pulsatile release

Diffusion controlled release

Zero order (linear) release

Lag followed by

Burst release


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$ACTRS G%ER!I!G T&E DESIG! $ CRDSAGE $RMS

I. Drug related

II. +iological

III.!hysiological

I*. !harmacoinetic

*. !harmacological


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$ACTRS G%ER!I!G T&E DESIG! $ CR

DSAGE $RMS

a'ueous soluility

rotein indingdrug staility

#olecular si*e

artition coe""icient

Drug relatedDrug related


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DSAGE $RMS

absorption

side effects

margin of safety

elimination

distribution

duration of action

disease state Biological


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DSAGE $RMS

Physiological

prolonged drug absorption

GI blood flow

ariability on GI

emptying ! motility


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DSAGE $RMS

Pharmacokinetic

first pass metabolism

ariability of urinary p"

effect on drug elimination

dose dumping


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DSAGE $RMS

Pharmacological

changes in drug effectupon multiple dosing

Sensitivity / tolerance


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+ASIC ,RI!CI,LES $ CR

DI((USI-#

S0EI#

+I-DERADA+E or+I-ER-DI+E


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Schematic depiction of variousclasses of controlled release system

)ontrolledrelease system 0ater penetration controlled

S'elling

)hemically controlled

Erodi$le

1ydrogel

DiffusionS'ellingEnvironmental

Ion exchange resin

anioncation

)hemically

Diffusion

Reservoir and monolithic

Matrix

ReservoirDissolution

Encapsulation Matrix

Diffusion and Dissolution

osmotically

Drug lined

polymer


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DI$$USI! C!TRLLED S-STEMS

MONOLITHIC-MATRIX !T"M

Drug+

polymer


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M!L T& C.MATR / S-STEMS Materials used as retardants in #atri0 talet

"or#ulations :.MA"RI2)1ARA)"ERIS"I)S

MA"ERIA

Insoluble, inertmatrix

PolyethylenePolyvinyl chlorideEthylcellulose

Insoluble,erodable

Carnauba wax

Polyethylene glycol

Castor wax

hydrophilic

Methyl cellulose

Carboxypolymethylene

Sodium alginate

H#MC


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O$al s%stem

RESER*-IR S3S"EMSRESER*-IR S3S"EMS


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RESER*-IR S3S"EMS(irst layer-f the drugcrystals

!olymerphase

Diffusionlayer


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DI$$USI! C!TRLLED S-STEMS

Reservoir system

Achievement of 4ero orderis easy

Degrada$le reservoirsystems may $e difficult todesign

Rupture can result indangerous dose dumping Drug inactivation $y contact

'ith the polymeric matrixcan $e avoided

Matrixsystem

o Achievement of 4ero orderis difficult

Suita$lefor $othdegrada$le 5 non&degrada$le systems

#o dangerof dose dumping #ot all drugs can $e $lended

'ith a given polymericmatrix


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Phase I outer membrane layers

Phase II reservoir matrix material

)-M+I#ED RESER*-IR&M-#-I"1I)

S3S"EMS

Outer membrane layer (phase I)

Dispersed agent in polymer matrix

(phase II)


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)-M+I#ED RESER*-IR&M-#-I"1I)

S3S"EMS

#onolithic

#atri$ (phase

II)

%uter membrane

(phase I)

&gent

loaded

#atri$layer

&gent

depleted

#atri$layer

Initially the release rate of diffusionthrough the phase 6 ,as the time progress,a layer depleted from the active agent isgenerated in phase 66 reservoir materialimmediately ad7acent to the mem$rane

layer.


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DISSLUTI! C!TRLLED RELEASE S-STEMS

"'o classes8Encapsulation dissolutioncontrolMatrix dissolution control


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MatrixMatrix dissolution controldissolution control

#embrane controlled#embrane controlled Polymer erosion controlledPolymer erosion controlled

drug

membrane


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DI((USI-# 5 DISS-U"I-#DI((USI-# 5 DISS-U"I-#)-#"R-ED S3S"EMS)-#"R-ED S3S"EMS

Release rate is dependenton surface area

diffusion coefficient ofdrug though pore incoating

conc. of drug in

dissolution media.

membrane

drug


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1ATER ,E!ETRATI! C!TRLLED S-STEMS

rate control is o$tained $ypenetration of 'ater into the

system. classified into 9 parts.

s'elling controlled systems

osmotically controlledsystems


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C&EMICALL- C!TRLLED S-STEMS

delivery systems that change theirchemical structure , 'hen exposed to

$iological milieu "his system include $iodegrada$le

polymer that degrade 'ithin $ody as aresult of natural $iological process,eliminating the need to remove thedelivery system after exhausting ofactive agent from system


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C&EMICALL- C!TRLLED S-STEMS

"he polymer degradation $y 9 'ays8

+ul erosion surface erosion


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*E%+#IS* &- P&")*ER ER&SI

Type IA clea!age of cross lin"s

Type I# disintegration of $ater soluble polymer bac"bone


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MEC&A!ISM $ ,L-MER ERSI!Type II %ater insoluble macromolecules are con!erted into

$ater soluble compounds by hydrolysis& ioni'ation or

protonation of a pendent group.

hydrolysis

Ionizationprotonation

Water insoluble molecules Water soluble molecules


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*E%+#IS* &- P&")*ER ER&SI

"ype III%erosion mechanisim

Water insoluble molecules Water soluble molecules

Hydrolytic

cleavage


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*E%+#IS* &- (R$ RE"ESE $ioactive covalently lined topolymer $ac$one , scission of

the $ondsconnecting the drug topolymer $ac$one.


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List o" iodegradale oly#er

!olylactides

!oly

!olyanhydrides.!olyorthoesters.


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+)(R&$E"S

1ydrogels are 'aters'ollenthree dimensionalstructures composed ofprimarily hydrophilicpolymers.

&-DRGELS


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&-DRGELS

)lassification8&6= Diffusion controlled release

/ reservoir

/ matrix

9= )hemically controlled release/ biodegradable polymers

/ covalently linked drug 0 polymer

>= S'elling controlled release?= Environmentally responsive hydrogelsystems

&-DRGELS


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S1elling controlled release consists of drug dispersion 1ithin glassy

polymer matrix. !hen the system comes incontact 1ith biofluids, it starts s1elling.

Drug releaseGlassy

polymer

Sollen gel

ater

&-DRGELS


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Environmentally responsive hydrogelsystems

T&e c&anges in net'o$( st$uctu$e in$esponse to e)te$nal envi$onment a$e

$eve$si*lein natu$e.

T

pH pH

T!

!


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"ype of hydrogel"ype of hydrogel

Super porous hydrogel p+ sensitive hydrogel

'emperature sensitive hydrogel $lucose sensitive system #eutral hydrogel

&ral insulin hydrogel


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Super porous hydrogelSuper porous hydrogel

Mainly for speedys'elling

)arried out $ymaing very fineparticle of dried

hydrogel havingshort diffusion pathlength

Electronic microscopic fig of super poroushydrogel


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Recent application of super porousRecent application of super porousgel in drug deliverygel in drug delivery

DE*E-!ME#" -( AS"RI)

RE"E#"I-# DE*I)ES

Development of fast dissolving ta$let

Development per oral peptide deliverysystem


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I-#&E2)1A#E RESI#I-#&E2)1A#E RESI# 2ero order release obtained

kinetics (rug release depends only onthe ionic environment of the resinscontaining drug

3 types./ cation exchange resin 0 anionexchange resin.


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)A"I-# E2)1A#E RESI# 8&)A"I-# E2)1A#E RESI# 8&

Synthesi4ed by copolymeri4ation of divinylben4ene 0 styrene.

CH

CH

CH"

CH"

CH CH"

diinyl benene

styrene

CH

S#$

H

CH" CH CH"

CH

CH

S#$

H

CH" CH"

CH CH"

CH

CH

S#$

H

CH"

CH

S#$

H

CH"

CH

CH

CH"CH"

CH"

CH CHCH

S#$

HCH

CH


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Anion exchange resinAnion exchange resin is prepared $y

chloromethylation of$en4ene rings of three

dimensional styrene&divinyl $en4ene copolymernet'or leading toinsertion of %)19)l groups

5 forms strong anionexchange resin.

CH

Cl! %CH$&$'+CH

"

CH"

CH CH"

CHCH

" CH"CH CH

"

CH

CH"

CH"

CH

CH

CH"CH" CH"CH CH

CHCH

CH"'+%CH

$&$Cl!

CH

CH"'+%CH

$&$Cl!

CH

CH"'+%CH

$&$Cl!

CH

CH"'+%CH

$&$Cl!

CH


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I!TELLIGE!T C!TRLLED RELEASE DRUG DELI%ER-

S-STEMS:.

Provide the bioactive in responseto the physiological need 0 should

5sense6 the changes 0 manipulatethe drug release in response toexternal stimuli like heat,ultrasound, magnetic field, p+and7or conc. of specificmolecules.


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(!

)ASSI(I)A"I-#8)ASSI(I)A"I-#8

pulsatile systems responsive systems

systems utilizing

chelation

systems utilizing

enzymessystems utilizing

antibodies

I#'E""I$E#'%'R&""E(

RE"ESE S)S'E*S

electically regulated

ultrasonically modulated

magnetically modulated

photoresponsive

Glucose sensitive

inflammation responsive

thermosensitive

pH sensitive

urea responsive

glucose responsive


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,ULSATILE S-STEMS :.

Magnetically modulated systems+-

*o applied

field+ield turn on Drug release

E E E


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RESPSI8E S)S'E*SRESPSI8E S)S'E*S lucose sensitive polymers8&

Glucose in Glycosylated insulin out

Polymer membrane

Glycosylated insulin

glucose

)oncavalin ASepharose 4B bead

)*S#'SI,* S-ST*.S)*S#'SI,* S-ST*.S


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,lucose sensitive pol%me$s

+-

insulin

microcapsule

Polymer & Polymer B

release

glucose

)*S#'SI,* S-ST*.S)*S#'SI,* S-ST*.S

S)S'E*S 'I"I2I#$ E#2)*ES


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a $ea $esponsive /elive$%

s%stems Urea is converted into #1?1)->5#1?-1 $y the action of urease that increases the p1.

"ydrogel prepared by immobiliing

urease

In cross,linked boine serum albumin

*,hy$yl half ester with dispersed drug



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S)S'E*S 'I"I2I#$ E#2)*ES * ,lucose $esponsive insulin

/elive$% +-

"his system utili4es en4yme&glucoseoxidase 'hich converts glucose intogluconic acid.

lucose @ -9 gluconic acid @ 19-

G

G

G

G

H')"

H')"

H')"

H')"

H')"

H')"

Glu#/

G

')"

')"

')"

')"

')"

')"

Glu#/

Glu#/

G ')"

')"

')"

')"

')"

')"

Glu#/

Glu#/

G

G

G


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S)S'E*S 'I"I2I#$ E#2)*ES * lucose responsive insulin delivery 8&

G#D G#D

H##C C##H

insulin

G#D G#D

!##C C##!

insulin

glucose

insulin


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An insulin $ese$voi$0li(e aregular syringe=

A small $attery operated pump A computer chipfor control )om$ination 'ith lucose

sensors

E0a#les(

Insulin pump,luco

'atch


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Recent in"or#ation

Polymer therapeuticscovers natural or synthetic polymers,

1hich have either inherent therapeutic potential orcarry covalently bonded drugs. 'he covalently bonded drugs have to be released atthe desired tissue or cell type. Polymeric therapeutics aree.g.

polymeric drugs,polymer/protein con9ugates,polymer/(# complexes,polymer/drug con9ugates or

polymeric micelles.


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)hemo mechanical polymer drug)hemo mechanical polymer drugdelivery systemdelivery system

)hemomechanical polymers, developed $y!rofessor 1ans&org Schneider and his team

at the University of Saarland, ermany, havegreatly improved functionality compared toexisting expanding / contracting materialsused to perform $iomedical functions, and

could $e used in applications such asactuators, implants,drug release systemsanddrug screening.

! l l d d


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!e2 oly#er enales near *ero order drug

release

)avilin "Md

1ighly porous polymer micro$ead


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Advance tec3nologies in #odi"ied release

"ro# dosage "or#

"IMERxMASRx0 )-SRxsystems

!rocise:comprised of a compression coated

core; (rug (elivery Systems Based on$eometric %onfiguration

Ringcap 'echnology tablets


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Advance tec3nologies in #odi"ied

release "ro# dosage "or#

Smartrix system multiple layered tab.

#ovel Erosion/%ontrolled &ral (eliverySystem"heriform'echnology novel method offabrication based on three dimensional

printing, a solid freeform fabricationtechnology/ implantsAccudeptechnology layered capsules


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Advance tec3nologies in #odi"ied release

"ro# dosage "or#

"hreeformtechnology ,/ Meltrextechnology melt extrusion process

Dissocu$es,IDDtechnology insoluble drugdelivery technology

Bydis oral fast dissolving dosage form. -rasolv0 Durasolv efficient technologies

for production of orally disintegratingtablets.


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Re"erences:.

S.!.*yas, R.C.Char, )ontrolled drug delivery& concepts 5advances., 6&, 6FG

.S.+aner, Modern !harmaceutics, >rd edition, G )hien 3.0., #ovel fundamentals, developmental concepts,

$iomedical assessments. Ro$inson 5 ee, controlled drug delivery8 fundamentals and

applications, 9nd edition. Donald .0ise, 1and$oo of !harmaceutical controlled

release technology, ??>. !raveen "yle , drug delivery devices8 fundamentals and

applications, Marcel Deer, >9F&>F>, >GF&>H9. ames S'ar$ric, ames ). +oylan, Encyclopedia of

!harmaceutical "echnology, Marcel Deer, III, 9H9, 9G&>66.


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Re"erences:.

Remington8 "he Science and !ractice of !harmacy, 6thedition, 6FF&6FG

eon achman, "he "heory and !ractice of Industrial!harmacy, third edition, ?>. '''.minimed.com '''.gluco'atch.com "aludar M. M. , Cinget R., S'elling and drug release

$ehaviour of xanthan gum matrix ta$lets, Int. A. !harm.69E%G9. Al&Shamhani A. and Duncan R. Int. A. !harm.

699


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Re"erences(!

iannos S., Dinh S. and +erner +. A. !harm. Sci. H?.

1eller . and "rescony !.*. A. !harm. Sci. FH H9


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Re"erences:.

oseph R. Ro$inson, Sustained release and controlledrelease drug delivery systems, volume F,Marcel Deer.

R.E. #otari, A. !harm. Sci.,F9, HF = ..(lynn, S.1. 3alo'sy and ".. Roseman, A. !harm.

Sci.,F>, ?G


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Re"erences:.

"heeu'es (. Elementary osmotic pump. !harm Sci.6GKF?86HG&66.

Bentner M, Ror S, 1immelstein C. "he controlled porosityosmotic pump. )ontrolled Rel. 6HK689F&9H9.

S'anson DR, +arclay ++, 0ong !S, "heeu'es (. #ifedipinegastrointestinal therapeutic systems. Am Med. 6HGKH>&.

)arrigan !, +ates "R. +iopharmaceutics of drug administeredin lipid& containing dosage forms, part I8 I a$sorption ofgriseofulvin from an oil&in&'ater emulsion in the rat. !harmSci. 6G>KF986?GG.

#oguchi ", "aahashi ), Cimura ", Muranishi S, Se4ai 1.Mechanism of the intestinal a$sorption of drugs from oil&in&'ater emulsions. )hem !harm +ull. 6GK9>8GG. F.)onstantinides !!. ipid microemulsions for improving drugdissolution and oral a$sorption8 physical and $iopharmaceuticalaspects. !harm Res. 6K6986F.


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Re"erences:.0ichterle -, im, D. 1ydrophilic gels for $iological use. #ature.6FK6H866G&66H.)hen , +levins 0E, !ar 1, !ar C. astric retention properties

of superporous hydrogel composites. )ontrolled Rel. 9KF?8>&6.Shala$y 0S0, +levins 0E, !ar C. In vitro and in vivo studies ofen4yme&digesti$le hydrogels for oral drug delivery. )ontrolledRel. 69K686>6&6??.Shala$y 0S0, +levins 0E, !ar C. "he use of ultrasound imagingand fluoroscopic imaging to study gastric retention of en4yme&digesti$le hydrogels. +iomaterials. 69K6>89H&9F.Dre's . Luest of "omorro's Medicines. #e' 3or, #38Springer&*erlagK #e' 3orK 6.Doroosh (A, +orchard , Rafiee&"ehrani M, *erhoef ),unginger 1E. Evaluation of superporous hydrogel


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Re"erences:.

Doroosh (A, *erhoef ), +orchard , Rafiee&"ehrani M, unginger 1E.Development and characteri4ation of a novel peroral peptide drug deliverysystem. )ontrolled Rel. 96KG68>G&>6H.

Doroosh (A, *erhoef ), Am$ragts M1), Rafiee&"ehrani M, +orchard, unginger 1E. !eroral delivery systems $ased on superporous hydrogelpolymers8 release characteristics for the peptide drugs $userelin,octreotide, and insulin. !harm Sci.

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modification of drug