Dissertation - Ningapi.ning.com/files/BZNY8QvGZuYkUls3AUwEcs0TeMM-w6... · 2017-05-28 · Dissertation Submitted to KLE University, Belgaum, KarnatakaSubmitted to KLE University,

I

““DDEESSIIGGNN AANNDD EEVVAALLUUAATTIIOONN OOFF ‘‘TTAABBLLEETT IINN

CCAAPPSSUULLEE DDEEVVIICCEE’’-- PPUULLSSAATTIILLEE DDRRUUGG

DDEELLIIVVEERRYY SSYYSSTTEEMM FFOORR TTHHEE TTRREEAATTMMEENNTT OOFF

NNOOCCTTUURRNNAALL AASSTTHHMMAA””

Dissertation

Submitted to KLE University, Belgaum, KarnatakaSubmitted to KLE University, Belgaum, KarnatakaSubmitted to KLE University, Belgaum, KarnatakaSubmitted to KLE University, Belgaum, Karnataka In partial fulfillment of the requirement for the degree ofIn partial fulfillment of the requirement for the degree ofIn partial fulfillment of the requirement for the degree ofIn partial fulfillment of the requirement for the degree of

MMMaaasssttteeerrr ooofff PPPhhhaaarrrmmmaaacccyyy

IIInnn

PPPhhhaaarrrmmmaaaccceeeuuutttiiicccsss

By

MR. JATIN A. POPAT B.Pharm

Under the guidance of

DR. BASAVARAJ K.NANJWADE M.Pharm, Ph.D

DEPARTMENT OF PHARMACEUTICS, JN MEDICAL COLLEGE,

BELGAUM-590010, KARNATAKA, INDIA

MAYMAYMAYMAY----2010201020102010

II

KKLLEE UUNNIIVVEERRSSIITTYY,, BBEELLGGAAUUMM,, KKAARRNNAATTAAKKAA

Declaration by the Candidate

II hheerreebbyy ddeeccllaarree tthhaatt tthhiiss ddiisssseerrttaattiioonn eennttiittlleedd

““DDEESSIIGGNN AANNDD EEVVAALLUUAATTIIOONN OOFF ‘‘TTAABBLLEETT IINN CCAAPPSSUULLEE

DDEEVVIICCEE’’-- PPUULLSSAATTIILLEE DDRRUUGG DDEELLIIVVEERRYY SSYYSSTTEEMM FFOORR TTHHEE

TTRREEAATTMMEENNTT OOFF NNOOCCTTUURRNNAALL AASSTTHHMMAA”” iiss aa bboonnaaffiiddee aanndd

ggeennuuiinnee rreesseeaarrcchh wwoorrkk ccaarrrriieedd oouutt bbyy mmee uunnddeerr tthhee

gguuiiddaannccee ooff Dr. BASAVARAJ K. NANJWADE PPrrooffeessssoorr,,

DDeeppaarrttmmeenntt ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,,

BBeellggaauumm.

DDaattee::

PPllaaccee:: BBeellggaauumm..

MMrr.. JJAATTIINN AA.. PPOOPPAATT BB..PPhhaarrmm

DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,,

JJNN MMeeddiiccaall CCoolllleeggee,,

BBeellggaauumm –– 559900 001100,,

KKaarrnnaattaakkaa..

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III

IV


Certificate by the Guide




TTRREEAATTMMEENNTT OOFF NNOOCCTTUURRNNAALL AASSTTHHMMAA”” iiss aa bboonnaaffiiddee

rreesseeaarrcchh wwoorrkk ddoonnee bbyy MMRR.. JJAATTIINN AA.. PPOOPPAATT iinn ppaarrttiiaall

ffuullffiillllmmeenntt ooff tthhee rreeqquuiirreemmeenntt ffoorr tthhee ddeeggrreeee ooff MMaasstteerr

ooff PPhhaarrmmaaccyy iinn PPhhaarrmmaacceeuuttiiccss..

DDaattee::


DDrr.. BB..KK.. NNAANNJJWWAADDEEMM..PPhhaarrmm,,PPhh.. DD

PPrrooffeessssoorr,, DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,,




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V


Certificate by the Co-Guide




TTRREEAATTMMEENNTT OOFF NNOOCCTTUURRNNAALL AASSTTHHMMAA”” iiss aa bboonnaaffiiddee

rreesseeaarrcchh wwoorrkk ddoonnee bbyy MMRR.. JJAATTIINN AA.. PPOOPPAATT iinn ppaarrttiiaall

ffuullffiillllmmeenntt ooff tthhee rreeqquuiirreemmeenntt ffoorr tthhee ddeeggrreeee ooff MMaasstteerr

ooff PPhhaarrmmaaccyy iinn PPhhaarrmmaacceeuuttiiccss..

DDaattee::

MMrr.. JJIIGGAARR PPAATTEELL

DDiirreeccttoorr,, LLiinnccoollnn PPhhaarrmmaacceeuuttiiccaall LLttdd..

KKhhaattrraajj,, DDiisstt::GGaannddhhiinnaaggaarr,,

GGuujjaarraatt..

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PPllaaccee::

VII


Endorsement By The HOD, Principal/ Head

of The Institution

This is to certify that the dissertation entitled “DESIGN

AND EVALUATION OF ‘TABLET IN CAPSULE DEVICE’-

PULSATILE DRUG DELIVERY SYSTEM FOR THE TREATMENT

OF NOCTURNAL ASTHMA” is a bonafide research work done

by Mr. JATIN A. POPAT in partial fulfillment of the

requirement for the degree of Master of Pharmacy in

Pharmaceutics, under the guidance of DDrr.. BB.. KK.. NNAANNJJWWAADDEE,,

Professor, Department of Pharmaceutics, JN Medical

College, Belgaum.

DDaattee::


DDRR.. VV.. DD.. PPAATTIILL MMDD,, DDCCHH

PPrriinncciippaall,,




MMRRSS.. RR.. SS.. MMAASSAARREEDDDDYY MM..PPHHAARRMM

AAssssoocciiaattee PPrrooffeessssoorr && HHeeaadd,,



BBeellggaauumm –– 559900 001100..

KKaarrnnaattaakkaa

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DDaattee::


VIII


Copyright Declaration by the Candidate

II hheerreebbyy ddeeccllaarree tthhaatt tthhee KKLLEE UUnniivveerrssiittyy,, BBeellggaauumm,,

KKaarrnnaattaakkaa sshhaallll hhaavvee tthhee rriigghhttss ttoo pprreesseerrvvee,, uussee aanndd

ddiisssseemmiinnaattee tthhiiss ddiisssseerrttaattiioonn//tthheessiiss iinn pprriinntt oorr

eelleeccttrroonniicc ffoorrmmaatt ffoorr aaccaaddeemmiicc//rreesseeaarrcchh ppuurrppoossee..

DDaattee::


MMrr.. JJAATTIINN AA.. PPOOPPAATTBB..PPhhaarrmm





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IX

© J.N. Medical College, KLE University, Belgaum, Karnataka

AAffffeeccttiioonnaatteellyy DDeeddiiccaatteedd

TToo

MMyy BBeelloovveedd PPaarreennttss

EEsstteeeemmeedd GGuuiiddee

VIII

Acknowledgement TTTTTTTThhhhhhhheeeeeeee AAAAAAAAllllllllmmmmmmmmiiiiiiiigggggggghhhhhhhhttttttttyyyyyyyy,,,,,,,, IIIIIIII aaaaaaaammmmmmmm tttttttthhhhhhhhaaaaaaaannnnnnnnkkkkkkkkffffffffuuuuuuuullllllll aaaaaaaannnnnnnndddddddd ggggggggrrrrrrrraaaaaaaatttttttteeeeeeeeffffffffuuuuuuuullllllll ttttttttoooooooo yyyyyyyyoooooooouuuuuuuu ffffffffoooooooorrrrrrrr ccccccccoooooooonnnnnnnnssssssssttttttttaaaaaaaannnnnnnntttttttt ssssssssuuuuuuuuppppppppppppppppoooooooorrrrrrrrtttttttt nnnnnnnnooooooootttttttt oooooooonnnnnnnnllllllllyyyyyyyy ffffffffoooooooorrrrrrrr mmmmmmmmyyyyyyyy

pppppppprrrrrrrroooooooojjjjjjjjeeeeeeeecccccccctttttttt bbbbbbbbuuuuuuuutttttttt ffffffffoooooooorrrrrrrr aaaaaaaallllllllllllllll tttttttthhhhhhhheeeeeeee aaaaaaaacccccccchhhhhhhhiiiiiiiieeeeeeeevvvvvvvveeeeeeeemmmmmmmmeeeeeeeennnnnnnnttttttttssssssss iiiiiiiinnnnnnnn mmmmmmmmyyyyyyyy lllllllliiiiiiiiffffffffeeeeeeee........ IIIIIIII bbbbbbbboooooooowwwwwwww ddddddddoooooooowwwwwwwwnnnnnnnn ttttttttoooooooo yyyyyyyyoooooooouuuuuuuu wwwwwwwwiiiiiiiitttttttthhhhhhhh bbbbbbbbooooooootttttttthhhhhhhh tttttttthhhhhhhheeeeeeee hhhhhhhhaaaaaaaannnnnnnnddddddddssssssss ffffffffoooooooollllllllddddddddeeeeeeeedddddddd........

WWWWWWWWoooooooorrrrrrrrddddddddssssssss sssssssseeeeeeeeeeeeeeeemmmmmmmm ttttttttoooooooo bbbbbbbbeeeeeeee ttttttttoooooooooooooooo ssssssssmmmmmmmmaaaaaaaallllllllllllllll ffffffffoooooooorrrrrrrr eeeeeeeexxxxxxxxpppppppprrrrrrrreeeeeeeessssssssssssssssiiiiiiiinnnnnnnngggggggg mmmmmmmmyyyyyyyy tttttttthhhhhhhhaaaaaaaannnnnnnnkkkkkkkkssssssss ttttttttoooooooo tttttttthhhhhhhheeeeeeee ffffffffoooooooolllllllllllllllloooooooowwwwwwwwiiiiiiiinnnnnnnngggggggg ppppppppeeeeeeeerrrrrrrrssssssssoooooooonnnnnnnnssssssss........

IIIIIIIItttttttt iiiiiiiissssssss wwwwwwwwiiiiiiiitttttttthhhhhhhh ffffffffaaaaaaaatttttttthhhhhhhhoooooooommmmmmmmlllllllleeeeeeeessssssssssssssss ggggggggrrrrrrrraaaaaaaattttttttiiiiiiiittttttttuuuuuuuuddddddddeeeeeeee tttttttthhhhhhhhaaaaaaaatttttttt eeeeeeeexxxxxxxxpppppppprrrrrrrreeeeeeeesssssssssssssssseeeeeeeessssssss mmmmmmmmyyyyyyyy bbbbbbbbeeeeeeeennnnnnnneeeeeeeevvvvvvvvoooooooolllllllleeeeeeeennnnnnnntttttttt tttttttthhhhhhhhaaaaaaaannnnnnnnkkkkkkkkssssssss ttttttttoooooooo mmmmmmmmyyyyyyyy rrrrrrrreeeeeeeevvvvvvvveeeeeeeerrrrrrrreeeeeeeennnnnnnntttttttt

tttttttteeeeeeeeaaaaaaaacccccccchhhhhhhheeeeeeeerrrrrrrr aaaaaaaannnnnnnndddddddd gggggggguuuuuuuuiiiiiiiiddddddddeeeeeeee,,,,,,,, DDDDDDDDrrrrrrrr........ BBBBBBBBaaaaaaaassssssssaaaaaaaavvvvvvvvaaaaaaaarrrrrrrraaaaaaaajjjjjjjj KKKKKKKK........ NNNNNNNNaaaaaaaannnnnnnnjjjjjjjjwwwwwwwwaaaaaaaaddddddddeeeeeeee,,,,,,,, PPPPPPPPrrrrrrrrooooooooffffffffeeeeeeeessssssssssssssssoooooooorrrrrrrr,,,,,,,, DDDDDDDDeeeeeeeepppppppptttttttt........ ooooooooffffffff PPPPPPPPhhhhhhhhaaaaaaaarrrrrrrrmmmmmmmmaaaaaaaacccccccceeeeeeeeuuuuuuuuttttttttiiiiiiiiccccccccssssssss,,,,,,,, KKKKKKKKLLLLLLLLEEEEEEEE

UUUUUUUUnnnnnnnniiiiiiiivvvvvvvveeeeeeeerrrrrrrrssssssssiiiiiiiittttttttyyyyyyyy,,,,,,,, BBBBBBBBeeeeeeeellllllllggggggggaaaaaaaauuuuuuuummmmmmmm........ IIIIIIII aaaaaaaammmmmmmm iiiiiiiinnnnnnnnddddddddeeeeeeeebbbbbbbbtttttttteeeeeeeedddddddd ttttttttoooooooo hhhhhhhhiiiiiiiimmmmmmmm ffffffffoooooooorrrrrrrr hhhhhhhhiiiiiiiissssssss gggggggguuuuuuuuiiiiiiiiddddddddaaaaaaaannnnnnnncccccccceeeeeeee tttttttthhhhhhhhrrrrrrrroooooooouuuuuuuugggggggghhhhhhhhoooooooouuuuuuuutttttttt mmmmmmmmyyyyyyyy pppppppprrrrrrrroooooooojjjjjjjjeeeeeeeecccccccctttttttt........ HHHHHHHHiiiiiiiissssssss kkkkkkkkiiiiiiiinnnnnnnndddddddd

ssssssssuuuuuuuuppppppppppppppppoooooooorrrrrrrrtttttttt hhhhhhhhaaaaaaaassssssss bbbbbbbbeeeeeeeeeeeeeeeennnnnnnn vvvvvvvvaaaaaaaalllllllluuuuuuuuaaaaaaaabbbbbbbblllllllleeeeeeee ffffffffoooooooorrrrrrrr ccccccccoooooooommmmmmmmpppppppplllllllleeeeeeeettttttttiiiiiiiioooooooonnnnnnnn ooooooooffffffff mmmmmmmmyyyyyyyy pppppppprrrrrrrroooooooojjjjjjjjeeeeeeeecccccccctttttttt........ IIIIIIIItttttttt iiiiiiiissssssss aaaaaaaa ggggggggrrrrrrrreeeeeeeeaaaaaaaatttttttt hhhhhhhhoooooooonnnnnnnnoooooooouuuuuuuurrrrrrrr ttttttttoooooooo bbbbbbbbeeeeeeee hhhhhhhhiiiiiiiissssssss ssssssssttttttttuuuuuuuuddddddddeeeeeeeennnnnnnntttttttt........

IIIIIIII aaaaaaaammmmmmmm tttttttthhhhhhhhaaaaaaaannnnnnnnkkkkkkkkffffffffuuuuuuuullllllll ttttttttoooooooo mmmmmmmmyyyyyyyy ccccccccoooooooo--------gggggggguuuuuuuuiiiiiiiiddddddddeeeeeeee MMMMMMMMrrrrrrrr........ JJJJJJJJiiiiiiiiggggggggaaaaaaaarrrrrrrr PPPPPPPPaaaaaaaatttttttteeeeeeeellllllll,,,,,,,, MMMMMMMM........DDDDDDDD........ LLLLLLLLiiiiiiiinnnnnnnnccccccccoooooooollllllllnnnnnnnn PPPPPPPPhhhhhhhhaaaaaaaarrrrrrrrmmmmmmmmaaaaaaaacccccccceeeeeeeeuuuuuuuuttttttttiiiiiiiiccccccccaaaaaaaallllllllssssssss LLLLLLLLttttttttdddddddd................ HHHHHHHHeeeeeeee

hhhhhhhhaaaaaaaassssssss hhhhhhhheeeeeeeellllllllppppppppeeeeeeeedddddddd mmmmmmmmeeeeeeee rrrrrrrroooooooouuuuuuuunnnnnnnndddddddd tttttttthhhhhhhheeeeeeee cccccccclllllllloooooooocccccccckkkkkkkk ffffffffoooooooorrrrrrrr mmmmmmmmyyyyyyyy pppppppprrrrrrrroooooooojjjjjjjjeeeeeeeecccccccctttttttt........ IIIIIIII aaaaaaaammmmmmmm tttttttthhhhhhhhaaaaaaaannnnnnnnkkkkkkkkffffffffuuuuuuuullllllll ttttttttoooooooo hhhhhhhhiiiiiiiimmmmmmmm ffffffffoooooooorrrrrrrr pppppppprrrrrrrroooooooovvvvvvvviiiiiiiiddddddddiiiiiiiinnnnnnnngggggggg mmmmmmmmeeeeeeee aaaaaaaallllllllllllllll tttttttthhhhhhhheeeeeeee

ffffffffaaaaaaaacccccccciiiiiiiilllllllliiiiiiiittttttttiiiiiiiieeeeeeeessssssss ffffffffoooooooorrrrrrrr mmmmmmmmyyyyyyyy pppppppprrrrrrrroooooooojjjjjjjjeeeeeeeecccccccctttttttt wwwwwwwwoooooooorrrrrrrrkkkkkkkk........

IIIIIIII aaaaaaaammmmmmmm bbbbbbbbeeeeeeeehhhhhhhhoooooooollllllllddddddddeeeeeeeennnnnnnn ttttttttoooooooo DDDDDDDDrrrrrrrr........ VVVVVVVV........ DDDDDDDD........ PPPPPPPPaaaaaaaattttttttiiiiiiiillllllll,,,,,,,, PPPPPPPPrrrrrrrriiiiiiiinnnnnnnncccccccciiiiiiiippppppppaaaaaaaallllllll,,,,,,,, JJJJJJJJNNNNNNNN MMMMMMMMeeeeeeeeddddddddiiiiiiiiccccccccaaaaaaaallllllll CCCCCCCCoooooooolllllllllllllllleeeeeeeeggggggggeeeeeeee aaaaaaaannnnnnnndddddddd DDDDDDDDrrrrrrrr........ FFFFFFFF........VVVVVVVV........ MMMMMMMMaaaaaaaannnnnnnnvvvvvvvviiiiiiii,,,,,,,,

PPPPPPPPrrrrrrrriiiiiiiinnnnnnnncccccccciiiiiiiippppppppaaaaaaaallllllll,,,,,,,, CCCCCCCCoooooooolllllllllllllllleeeeeeeeggggggggeeeeeeee ooooooooffffffff PPPPPPPPhhhhhhhhaaaaaaaarrrrrrrrmmmmmmmmaaaaaaaaccccccccyyyyyyyy,,,,,,,, KKKKKKKKLLLLLLLLEEEEEEEE UUUUUUUUnnnnnnnniiiiiiiivvvvvvvveeeeeeeerrrrrrrrssssssssiiiiiiiittttttttyyyyyyyy,,,,,,,, BBBBBBBBeeeeeeeellllllllggggggggaaaaaaaauuuuuuuummmmmmmm,,,,,,,, ffffffffoooooooorrrrrrrr pppppppprrrrrrrroooooooovvvvvvvviiiiiiiiddddddddiiiiiiiinnnnnnnngggggggg aaaaaaaa cccccccclllllllleeeeeeeeaaaaaaaannnnnnnn aaaaaaaannnnnnnndddddddd hhhhhhhheeeeeeeeaaaaaaaalllllllltttttttthhhhhhhhyyyyyyyy

eeeeeeeennnnnnnnvvvvvvvviiiiiiiirrrrrrrroooooooonnnnnnnnmmmmmmmmeeeeeeeennnnnnnntttttttt ffffffffoooooooorrrrrrrr ssssssssttttttttuuuuuuuuddddddddyyyyyyyyiiiiiiiinnnnnnnngggggggg iiiiiiiinnnnnnnn tttttttthhhhhhhhiiiiiiiissssssss iiiiiiiinnnnnnnnssssssssttttttttiiiiiiiittttttttuuuuuuuutttttttteeeeeeee........

IIIIIIII eeeeeeeexxxxxxxxpppppppprrrrrrrreeeeeeeessssssssssssssss mmmmmmmmyyyyyyyy ddddddddeeeeeeeeeeeeeeeepppppppp ggggggggrrrrrrrraaaaaaaattttttttiiiiiiiittttttttuuuuuuuuddddddddeeeeeeee ttttttttoooooooo PPPPPPPPrrrrrrrrooooooooffffffff........ TTTTTTTTaaaaaaaarrrrrrrraaaaaaaannnnnnnnaaaaaaaalllllllllllllllliiiiiiii,,,,,,,, MMMMMMMMrrrrrrrrssssssss........ RRRRRRRR........SSSSSSSS........ MMMMMMMMaaaaaaaassssssssaaaaaaaarrrrrrrreeeeeeeeddddddddddddddddyyyyyyyy aaaaaaaannnnnnnndddddddd tttttttthhhhhhhheeeeeeee eeeeeeeennnnnnnnttttttttiiiiiiiirrrrrrrreeeeeeee ssssssssttttttttaaaaaaaaffffffffffffffff

ooooooooffffffff KKKKKKKKLLLLLLLLEEEEEEEE UUUUUUUUnnnnnnnniiiiiiiivvvvvvvveeeeeeeerrrrrrrrssssssssiiiiiiiittttttttyyyyyyyy ffffffffoooooooorrrrrrrr tttttttthhhhhhhheeeeeeeeiiiiiiiirrrrrrrr kkkkkkkkiiiiiiiinnnnnnnndddddddd ssssssssuuuuuuuuppppppppppppppppoooooooorrrrrrrrtttttttt aaaaaaaannnnnnnndddddddd ccccccccoooooooo--------ooooooooppppppppeeeeeeeerrrrrrrraaaaaaaattttttttiiiiiiiioooooooonnnnnnnn tttttttthhhhhhhhrrrrrrrroooooooouuuuuuuugggggggghhhhhhhhoooooooouuuuuuuutttttttt mmmmmmmmyyyyyyyy aaaaaaaaccccccccaaaaaaaaddddddddeeeeeeeemmmmmmmmyyyyyyyy ssssssssttttttttaaaaaaaayyyyyyyy iiiiiiiinnnnnnnn

BBBBBBBBeeeeeeeellllllllggggggggaaaaaaaauuuuuuuummmmmmmm........

IIIIIIII aaaaaaaacccccccckkkkkkkknnnnnnnnoooooooowwwwwwwwlllllllleeeeeeeeddddddddggggggggeeeeeeee tttttttthhhhhhhheeeeeeee ccccccccooooooooooooooooppppppppeeeeeeeerrrrrrrraaaaaaaattttttttiiiiiiiioooooooonnnnnnnn aaaaaaaannnnnnnndddddddd hhhhhhhheeeeeeeellllllllpppppppp ooooooooffffffff MMMMMMMMrrrrrrrr........ SSSSSSSShhhhhhhhaaaaaaaarrrrrrrrdddddddduuuuuuuullllllll,,,,,,,, MMMMMMMMrrrrrrrr........ NNNNNNNNiiiiiiiillllllllaaaaaaaayyyyyyyy,,,,,,,, MMMMMMMMrrrrrrrr........ HHHHHHHHiiiiiiiimmmmmmmmaaaaaaaannnnnnnnsssssssshhhhhhhhuuuuuuuu,,,,,,,, MMMMMMMMrrrrrrrr........

DDDDDDDDhhhhhhhhaaaaaaaavvvvvvvvaaaaaaaallllllll,,,,,,,, MMMMMMMMrrrrrrrr........ DDDDDDDDiiiiiiiippppppppaaaaaaaakkkkkkkk,,,,,,,, MMMMMMMMrrrrrrrr........ HHHHHHHHiiiiiiiirrrrrrrreeeeeeeennnnnnnn,,,,,,,, MMMMMMMMrrrrrrrr........ NNNNNNNNiiiiiiiikkkkkkkkhhhhhhhhiiiiiiiillllllll,,,,,,,, MMMMMMMMrrrrrrrr........ SSSSSSSSaaaaaaaannnnnnnnjjjjjjjjeeeeeeeeeeeeeeeevvvvvvvv,,,,,,,, MMMMMMMMrrrrrrrr........ YYYYYYYYooooooooggggggggeeeeeeeesssssssshhhhhhhh,,,,,,,, MMMMMMMMrrrrrrrrssssssss........ MMMMMMMMoooooooonnnnnnnniiiiiiiikkkkkkkkaaaaaaaa aaaaaaaannnnnnnndddddddd aaaaaaaallllllllllllllll

wwwwwwwwoooooooorrrrrrrrkkkkkkkkeeeeeeeerrrrrrrrssssssss ooooooooffffffff FFFFFFFF&&&&&&&&DDDDDDDD ddddddddeeeeeeeeppppppppaaaaaaaarrrrrrrrttttttttmmmmmmmmeeeeeeeennnnnnnntttttttt ffffffffoooooooorrrrrrrr tttttttthhhhhhhheeeeeeeeiiiiiiiirrrrrrrr ssssssssuuuuuuuuppppppppppppppppoooooooorrrrrrrrtttttttt,,,,,,,, gggggggguuuuuuuuiiiiiiiiddddddddaaaaaaaannnnnnnncccccccceeeeeeee,,,,,,,, vvvvvvvvaaaaaaaalllllllluuuuuuuuaaaaaaaabbbbbbbblllllllleeeeeeee ssssssssuuuuuuuuggggggggggggggggeeeeeeeessssssssttttttttiiiiiiiioooooooonnnnnnnn,,,,,,,, ccccccccoooooooonnnnnnnnssssssssttttttttrrrrrrrruuuuuuuuccccccccttttttttiiiiiiiivvvvvvvveeeeeeee

ccccccccrrrrrrrriiiiiiiittttttttiiiiiiiicccccccciiiiiiiissssssssmmmmmmmm aaaaaaaannnnnnnndddddddd hhhhhhhheeeeeeeellllllllpppppppp ffffffffrrrrrrrroooooooommmmmmmm tttttttthhhhhhhheeeeeeee bbbbbbbbeeeeeeeeggggggggiiiiiiiinnnnnnnnnnnnnnnniiiiiiiinnnnnnnngggggggg ooooooooffffffff tttttttthhhhhhhheeeeeeee wwwwwwwwoooooooorrrrrrrrkkkkkkkk ttttttttiiiiiiiillllllllllllllll tttttttthhhhhhhheeeeeeee ccccccccoooooooommmmmmmmpppppppplllllllleeeeeeeettttttttiiiiiiiioooooooonnnnnnnn ooooooooffffffff iiiiiiiitttttttt........

IIIIIIII aaaaaaaammmmmmmm ggggggggrrrrrrrraaaaaaaatttttttteeeeeeeeffffffffuuuuuuuullllllll ttttttttoooooooo mmmmmmmmyyyyyyyy BBBBBBBB........ PPPPPPPPhhhhhhhhaaaaaaaarrrrrrrrmmmmmmmm lllllllleeeeeeeeccccccccttttttttuuuuuuuurrrrrrrreeeeeeeerrrrrrrrssssssss DDDDDDDDrrrrrrrr........ HHHHHHHH........MMMMMMMM........ TTTTTTTTaaaaaaaannnnnnnnkkkkkkkk,,,,,,,, DDDDDDDDrrrrrrrr........ MMMMMMMMaaaaaaaannnnnnnniiiiiiiisssssssshhhhhhhh RRRRRRRRaaaaaaaacccccccchhhhhhhhcccccccchhhhhhhhhhhhhhhh aaaaaaaannnnnnnndddddddd

MMMMMMMMrrrrrrrr........ DDDDDDDDaaaaaaaarrrrrrrrsssssssshhhhhhhhaaaaaaaannnnnnnn PPPPPPPPaaaaaaaarrrrrrrreeeeeeeekkkkkkkkhhhhhhhh ffffffffoooooooorrrrrrrr tttttttthhhhhhhheeeeeeeeiiiiiiiirrrrrrrr mmmmmmmmoooooooorrrrrrrraaaaaaaallllllll ssssssssuuuuuuuuppppppppppppppppoooooooorrrrrrrrtttttttt........

IIIIIIII aaaaaaaammmmmmmm tttttttthhhhhhhhaaaaaaaannnnnnnnkkkkkkkkffffffffuuuuuuuullllllll ttttttttoooooooo mmmmmmmmyyyyyyyy ccccccccoooooooo--------ttttttttrrrrrrrraaaaaaaaiiiiiiiinnnnnnnneeeeeeeeeeeeeeeessssssss AAAAAAAAnnnnnnnnkkkkkkkkiiiiiiiitttttttt,,,,,,,, PPPPPPPPrrrrrrrraaaaaaaajjjjjjjjeeeeeeeesssssssshhhhhhhh,,,,,,,, RRRRRRRRaaaaaaaakkkkkkkkeeeeeeeesssssssshhhhhhhh,,,,,,,, PPPPPPPPiiiiiiiiyyyyyyyyuuuuuuuusssssssshhhhhhhh,,,,,,,, HHHHHHHHaaaaaaaarrrrrrrreeeeeeeesssssssshhhhhhhh,,,,,,,, aaaaaaaannnnnnnndddddddd DDDDDDDDaaaaaaaarrrrrrrrsssssssshhhhhhhhaaaaaaaannnnnnnnaaaaaaaa

ffffffffoooooooorrrrrrrr tttttttthhhhhhhheeeeeeeeiiiiiiiirrrrrrrr ssssssssuuuuuuuuppppppppppppppppoooooooorrrrrrrrtttttttt dddddddduuuuuuuurrrrrrrriiiiiiiinnnnnnnngggggggg mmmmmmmmyyyyyyyy pppppppprrrrrrrroooooooojjjjjjjjeeeeeeeecccccccctttttttt........

IX

IIIIIIII aaaaaaaammmmmmmm tttttttthhhhhhhhaaaaaaaannnnnnnnkkkkkkkkffffffffuuuuuuuullllllll ttttttttoooooooo mmmmmmmmyyyyyyyy bbbbbbbbaaaaaaaattttttttcccccccchhhhhhhh mmmmmmmmaaaaaaaatttttttteeeeeeeessssssss SSSSSSSSuuuuuuuussssssssmmmmmmmmiiiiiiiitttttttthhhhhhhhaaaaaaaa,,,,,,,, KKKKKKKKiiiiiiiirrrrrrrraaaaaaaannnnnnnn,,,,,,,, RRRRRRRRuuuuuuuucccccccchhhhhhhhaaaaaaaa,,,,,,,, AAAAAAAAnnnnnnnnuuuuuuuu,,,,,,,, AAAAAAAAmmmmmmmmoooooooollllllll,,,,,,,, BBBBBBBBhhhhhhhhuuuuuuuusssssssshhhhhhhhaaaaaaaannnnnnnn,,,,,,,, RRRRRRRRaaaaaaaajjjjjjjjeeeeeeeesssssssshhhhhhhh,,,,,,,,

VVVVVVVViiiiiiiisssssssshhhhhhhhwwwwwwwwaaaaaaaassssssss,,,,,,,, DDDDDDDDhhhhhhhhaaaaaaaavvvvvvvvaaaaaaaallllllll,,,,,,,, PPPPPPPPrrrrrrrraaaaaaaattttttttiiiiiiiinnnnnnnn,,,,,,,, KKKKKKKKuuuuuuuunnnnnnnnaaaaaaaallllllll,,,,,,,, KKKKKKKKeeeeeeeemmmmmmmmyyyyyyyy,,,,,,,, VVVVVVVViiiiiiiisssssssshhhhhhhhaaaaaaaallllllll,,,,,,,, SSSSSSSSaaaaaaaaggggggggaaaaaaaarrrrrrrr aaaaaaaannnnnnnndddddddd DDDDDDDDiiiiiiiivvvvvvvvyyyyyyyyaaaaaaaannnnnnnnsssssssshhhhhhhhuuuuuuuu,,,,,,,, ffffffffoooooooorrrrrrrr tttttttthhhhhhhheeeeeeeeiiiiiiiirrrrrrrr iiiiiiiinnnnnnnnvvvvvvvvaaaaaaaalllllllluuuuuuuuaaaaaaaabbbbbbbblllllllleeeeeeee

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PPooppaatt

X

LIST OF ABBREVIATIONS

γ - Gamma

% - Percentage

%C.D.R. - Percentage Cumulative Drug Realease

0C - Degree centigrade

CFU - colony Forming Unit

CSDDS - Colon Specific Drug Delivery System

EC - Ethyl Cellulose

FT-IR - Fourier Transformed-Infrared Specroscopy

GIT - Gastro Intestinal Tract

HPMC - Hydroxy Propyl Methyl Cellulose

hrs - Hours

mg - Miligram

ml - Mililiter

RH - Relative Humidity

t1/2 - Elimiantion half life

TCES - Time Controlled Explosion System

ug, mcg - Micrograms

um - Micrometer

UV - Ultra Violet

XI

ABSTRACT

The present study aimed at preparing a novel time dependent pulsed release

system containing ‘Tablet-in-Capsule’ for the programmed release of salbutamol

sulphate for the treatment of nocturnal asthma. The core tablets of salbutamol

sulphate were prepared using wet granulation containing a superdisintegrant. Physical

characterization of tablet and powder blends used to form the core tablet was under

taken using a range of experimental technique. Eudragit S100 and Eudragit L100

were used as pH dependent polymers for coating the core tablet which were filled in

to the capsule. The ratio of Eudragit S100 and Eudragit L100 and the coating level

was optimized using 32 full factorial designs. Factors studied in design were

percentage of Eudragit S100 in combination with Eudragit L100 and the effect of

coating level on In-vitro drug release. Dissolution studies of ‘Tablet-in-Capsule’

device in media with different pH (1.2, 5.5, 6.8 and 7.4) showed that drug release in

colon could be modulated by optimizing the concentration of Eudragit L100: Eudragit

S100 (1:2). The study showed that, lag time prior to drug release was highly affected

by the coating level. The dissolution data reveled that the level of coating and the ratio

of polymers are very important to achieve a optimum formulation. The In-vitro

release from optimized formulation was found to be independent of paddle speed. The

gamma scintigraphic study pointed out the capability of the system to release drug in

lower parts of GIT after a programmed lag time for nocturnal asthma. Stability study

of the optimized formulation indicates no significant difference in release profile after

a period of one month.

Key words: salbutamol sulphate, Nocturnal asthma, pH dependent drug delivery

sytem, ‘Tablet-in-Capsule’.

XII

CONTENTS

SL. NO.

TITLE PAGE NO.

1. INTRODUCTION 1-33

2. RESEARCH OBJECTIVE 34-37

3. REVIEW OF LITERATURE 38-71

4. MATERIAL & METHODOLOGY 72-92

5. RESULTS AND DISCUSSION 93-133

6. CONCLUSION 134-135

7. SUMMARY 136-137

8 BIBLIOGRAPHY 138-146

9 ANNEXURE

XIII

LIST OF TABLES

TABLE

NO. TITLE

PAGE

NO.

1. Circadian rhythm and the manifestation of clinical diseases 2

2. Drug that have been developed or are under development as

chronotherapies

13

3. Various pharmaceutical approaches to colon targeted drug

delivery systems.

15

4. Summary of anatomical and physiological features of small

intestine and colon

17

5. Drug metabolizing enzymes in the colon that catalyze

reactions

19

6. The transit time of dosage form in GIT. 20

7. Summary of colon-specific drug delivery strategies. 27

8. Interaction with other medicaments and other forms of

interaction

42

9. List of material used 72

10. List of equipment used 73

11. Effect of Carr’s Index and Hausner’s Ratio on flow property 76

12. Effect of Angle of repose (ф) on Flow property 77

13. Drug excipients compatibility study 78

14. Pharmacokinetics parameters of salbutmaol sulphate 80

15. Composition of first pulse tablets of Salbutamol sulphate 81

16. Composition of second pulse tablets of Salbutamol sulphate 81

17. Composition of Coating solution 86

18. Composition of coating solution 87

19. 32 Full Factorial Design Layout 89

XIV

TABLE

NO. TITLE

PAGE

NO.

20. Formula of Factorial batches 89

21. Result of Preformulation study of Salbutamol Sulphate 103

22. Result of Drug excipients compatibility study After 1 month

at 40ºC±2°C / 75%RH± 5 % RH

114

23. Standard calibration curve of Salbutamol Sulphate in 0.1 N

HCL

115

24. Standard calibration curve of salbutmaol sulphate in pH 5.5

Phosphate buffer

116

25. Standard calibration curve of Salbutamol Sulphate in pH 6.8

phosphate buffer

117


Phosphate buffer

118

27. Pre-compression evaluation of the prepared granules 119

28. Post-compression evaluation of the prepared Tablets 119

29. In-vitro drug release study of tablets coated with Eudragit

S100

120

30. In-vitro drug release study of tablets coated with Eudragit

L100: Eudragit S100

121

31. Effect of Independent variable on dependent variable by 32

full factorial design of Salbutamol Sulphate for Pulsatile

Release

122

32. In-vitro drug release study of factorial batches 123

33. Summary of regression analysis of Salbutamol Sulphate tablet

for Pulsatile release

126

34. In-vitro drug release study of ‘Tablet in Capsule’ device 129

35. In-vitro drug release study of ‘Tablet in Capsule’ device with

different rotational speed

130

36. In-vitro drug release study of ‘Tablet in Capsule’ device for

stability testing

133

XV

LIST OF FIGURES

FIGURE

NO. TITLE

PAGE

NO.

1. Drug release profile of pulsatile drug delivery system 1

2. 24-hr clock diagram of the peak time of selected human

circadian rhythm with reference to the day-night cycle 3

3. Possible causes of morning increase in the incidence of

coronary event 4

4. Classification of pulsatile drug delivery system 6

5. Drug release mechanism from PORT system 8

6. Anatomy of the colon 16

7. Schematic diagram of Tablet in Capsule device 28

8. Pathophysiolofy of asthma 30

9. Diurnal variations in lung function in healthy and asthmatic

subjects. 31

10. FT-IR Spectra of pure Salbutamol sulphate 102

11. FT-IR Spectra of Salbutamol sulphate + Eudragit S 100 104

12. FT-IR Spectra of Salbutamol sulphate + Eudragit L-100 105

13. FT-IR Spectra of Salbutamol sulphate + Starch 106

14. FT-IR Spectra of Salbutamol sulphate + Lactose 107

15. FT-IR Spectra of Salbutamol sulphate + PVP K30 108

16. FT-IR Spectra of Salbutamol sulphate + Magnesium stearate 109

17. FT-IR Spectra of Salbutamol sulphate + Aerosil 110

18. FT-IR Spectra of Salbutamol sulphate + S.S.G. 111

19. FT-IR Spectra of Salbutamol sulphate + Lactose + Starch 112

20. FT-IR Spectra of whole formulation 113

XVI

FIGURE

NO. TITLE

PAGE

NO.

21. Standard calibration curve of Salbutamol Sulphate in 0.1 N

HCL 115


Phosphate buffer 116

23. Standard calibration curve of Salbutamol Sulphate in pH 6.8

phosphate buffer 117


Phosphate buffer 118

25. In-vitro drug release profile of tablets coated with Eudragit

S100 120

26. In-vitro drug release profile of tablets coated with Eudragit

L100: Eudragit S100 121

27. In-vitro drug release profile of factorial batches F7 to F9 124



30. In-vitro drug release profile of ‘Tablet in Capsule’ device 129

31. In-vitro drug release profile of ‘Tablet in Capsule’ device with

different rotational speed 130

32. In-vitro drug release study of ‘Tablet in Capsule’ device for

stability testing 133

Chapter – 1 Introduction

Department of Pharmaceutics, KLE University, Belgaum 1

INTRODUCTION

Introduction to pulsatile drug delivery system: 1, 2

Oral controlled drug delivery systems represent the most popular form of

controlled drug delivery systems for the obvious advantages of oral route of drug

administration. Such systems release the drug with constant or variable release rates.

These dosage forms offer many advantages, such as nearly constant drug level at the

site of action, prevention of peak-valley fluctuations, reduction in dose of drug,

reduced dosage frequency, avoidance of side effects, and improved patient

compliance

However, there are certain conditions for which such a release pattern is not

suitable. These conditions demand release of drug after a lag time. In other words, it is

required that the drug should not be released at all during the initial phase of dosage

form administration. Such a release pattern is known as pulsatile release.

A pulsatile drug delivery system is characterized by a lag time that is an interval of

no drug release followed by rapid drug release.

FigureNo. 1: Drug release profile of pulsatile drug delivery system 1,2

A: Ideal sigmoidal release B & C: Delayed release after initial lag time



The first pulsed delivery formulation that released the active substance at a

precisely defined time point was developed in the early 1990s. In this context, the aim

of the research was to achieve a so-called sigmoidal release pattern (pattern A in

Figure). The characteristic feature of the formulation was a defined lag time followed

by a drug pulse with the enclosed active quantity being released at once. Thus, the

major challenge in the development of pulsatile drug delivery system is to achieve a

rapid drug release after the lag time. Often, the drug is released over an extended

period of time (patterns B & C in Figure). This following reviews the various pulsatile

drug delivery systems that are reported.

Table No. 1: Circadian rhythm and the manifestation of clinical diseases 3,4 Disease or syndrome Circadian rhythmicity

Allergic Rhinitis Worse in the morning/upon rising

Intraocular Pressure

(IOP)

In glaucoma patients IOP peaks at 4 AM and has a trough

in the afternoon, opposite that of people with normal IOP

Asthma Exacerbation more common during the sleep period

Hormone Secretion Growth hormone and melatonin are produced at night;

testosterone and cortisol in the early morning hours

Blood Coagulation Even with constant heparin infusion rate, thromboplastin

time and risk of bleeding vary significantly during the

day

Rheumatoid Arthritis Symptoms are most intense upon awakening

Osteoarthritis Symptoms worse in the middle/later portion of the day

Angina Pectoris Chest pain and ECG changes more common in early

morning

Myocardial Infraction Incidence higher in the early morning

Stroke Incidence higher in the morning

Sudden cardiac death Incidence higher in the morning after awakening

Peptic ulcer disease Worse in late evening and early morning hours

Seasonal Affective

Disorder (SAD)

Affects 1% to 3% of adults; increased sleep and appetite

are well-known phenomena in winter



In chronopharmacotherapy (timed drug therapy) drug administration is

synchronized with biological rhythms to produce maximal therapeutic effect and

minimum harm for the patient. By basing drug delivery on circadian patterns of

diseases drug effect can be optimized and side effects can be reduced. If symptoms

occur at daytime a conventional dosage form can be administered just prior the

symptoms are worsening. If symptoms of a disease became worse during the night or

in the early morning the timing of drug administration and nature of the drug delivery

system need careful consideration.4,5

Figure No. 2: 24-hr clock diagram of the peak time of selected human circadian

rhythm with reference to the day-night cycle 4,5

Control release systems for 12 or 24 hr drug release are not suitable for

diseases, which follow circadian variation. In that condition there is requirement for

time or pulsatile drug delivery system.



Figure No. 3: Possible causes of morning increase in the incidence of

coronary event

4

Advantages: 1, 2

� Many body functions that follow circadian rhythm. A number of hormones

like rennin, aldosterone, and cortisol show daily fluctuations in their blood

levels. Circadian effects are also observed in case of pH and acid secretion in

stomach, gastric emptying, and gastro-intestinal blood transfusion.

• Diseases like bronchial asthma, myocardial infarction, angina pectoris,

rheumatic disease, ulcer, and hypertension display time dependence. Sharp

increase in asthmatic attacks during early morning hours. Such a condition

demands considerations of diurnal progress of the disease rather than

maintaining constant plasma drug level. A drug delivery system administered

at bedtime, but releasing drug well after the time of administration (during

AM Circadian Patterns Supply/Demand Ratio

↑ Physical Activity Increased Myocardial Demand

↑ Environmental Stimuli ↑ Blood Pressure

↑Sympathetic Cardiac Activity ↑ Contractility

↑Catecholamines ↑ Heart rate

↑ Cortisol

↑Platelet Aggerability Decreased Supply

↑Vascular Receptor Sensitivity ↑ Coronary Tone

↓ Vessel Caliber

Lower Threshold

For:

Ischemia

Infraction

Sudden Death

Hypertension

Stroke



morning hours), would be ideal in this case. It is true for preventing heart

attacks in the middle of the night and the morning stiffness typical of people

suffering from arthritis.

• Drugs that produce biological tolerance demand for a system that will prevent

their continuous presence at the biophase, as this tends to reduce their

therapeutic effect.

• The lag time is essential for the drugs that undergo degradation in gastric

acidic medium (e.g., peptide drugs) irritate the gastric mucosa or induce

nausea and vomiting. These conditions can be satisfactorily handled by enteric

coating, and in this sense, enteric coating can be considered as a pulsatile drug

delivery system.

• Targeting a drug to distal organs of gastro-intestinal tract (GIT) like the colon

requires that the drug release be prevented in the upper two-third portion of

the GIT.

• The drugs that undergo extensive first-pass metabolism (β-blockers) and those

that are characterized by idiosyncratic pharmacokinetics or

pharmacodynamics resulting in reduced bioavailability, altered

drug/metabolite ratios, altered steady state levels of drug and metabolite, and

potential food-drug interactions require delayed release of the drug to the

extent possible.

Classification of pulsatile drug delivery systems: 1, 2

Pulsatile drug delivery systems (PDDS) can be classified in site-specific and

time-controlled systems. Drug release from site-specific systems depends on the

environment in the gastro intestinal track, e.g., on pH, presence of enzymes, and the

pressure in the gastro intestinal track. In contrast, time-controlled DDS are



independent of the biological environment. The drug release is controlled only by the

system. Time-controlled pulsatile delivery has been achieved mainly with drug-

containing cores, which are covered with release-controlling layers.

Single unit system:

Capsular system:

Different single-unit capsular pulsatile drug delivery systems have been

developed. A general architecture of such systems consists of an insoluble capsule

body housing a drug and a plug. The plug is removed after a predetermined lag time

owing to swelling, erosion, or dissolution.

Figure No. 4: Classification of pulsatile drug delivery system 1,2

The Pulsincap® system is an example of such a system that is made up of a

water-insoluble capsule body filled with drug formulation. The body is closed at the

PPuullssaattiillee DDrruugg DDeelliivveerryy SSyysstteemm

Time Controlled System Site Specific System

Single unit system Multiple unit system

Tablet

E.g. Time clock system

Chronotropic system

Capsule

E.g.: Pulsincap system

Port system

Pellets

E.g. Time-Controlled Explosion

System

Permeability Controlled System



open end with a swellable hydrogel plug. Upon contact with dissolution medium or

gastro-intestinal fluids, the plug swells, pushing itself out of the capsule after a lag

time. This is followed by a rapid drug release. Manipulating the dimension and the

position of the plug can control the lag time. For water-insoluble drugs, a rapid release

can be ensured by inclusion of effervescent agents or disintegrants. The plug material

consists of insoluble but permeable and swellable polymers (e.g., polymethacrylates),

erodible compressed polymers (e.g., hydroxypropylmethyl cellulose, polyvinyl

alcohol, polyethylene oxide), congealed melted polymers (e.g., saturated

polyglycolated glycerides, glyceryl monooleate), and enzymatically controlled

erodible polymer (e.g., pectin). These formulations were well tolerated in animals and

healthy Volunteers, and there were no reports of gastro-intestinal irritation. However,

there was a potential problem of variable gastric residence time, which was overcome

by enteric coating the system to allow its dissolution only in the higher pH region of

small intestine. 1, 2, 6-8

The Port® System 1,2,9

consists of a gelatin capsule coated with a

semipermeable membrane (eg, cellulose acetate) housing an insoluble plug (eg,

lipidic) and an osmotically active agent along with the drug formulation (Figure No.

5). When in contact with the aqueous medium, water diffuses across the

semipermeable membrane, resulting in increased inner pressure that ejects the plug

after a lag time. Coating thickness controls the lag time. The system showed good

correlation in lag times of in-vitro and in-vivo experiments in humans. The system

was proposed to deliver methylphenidate for the treatment of attention deficit

hyperactivity disorder (ADHD) in school-age children. Such a system avoids a second

daily dose that otherwise would have been administered by a nurse during school

hours.



Figure No. 5: Drug release mechanism from PORT system 9

Tablets system:

Most of the pulsatile drug delivery systems are reservoir devices coated with a

barrier layer. This barrier erodes or dissolves after a specific lag period, and the drug



is subsequently released rapidly. The lag time depends on the thickness of the coating

layer.

The Time Clock® system consists of a solid dosage form coated with lipidic barriers

containing carnauba wax and bees wax along with surfactants, such as

polyoxyethylene sorbitan monooleate. This coat erodes or emulsifies in the aqueous

environment in a time proportional to the thickness of the film, and the core is then

available for dispersion. In a study with human Volunteers, it was shown that the lag

time was independent of gastric residence time, and the hydrophobic film re-

dispersion did not appear to be influenced by the presence of intestinal enzymes or

mechanical action of stomach or gastro-intestinal pH. The lag time increased with

increasing coating thickness. Such systems are better suited for water-soluble drugs.

The major advantage of this system is its ease of manufacturing without any need of

special equipment. However, such lipid-based systems may have high in-vivo

variability (e.g., food effects).

The possible problems of erosion-controlled systems include a premature drug

release when the penetrating water dissolves the drug, which diffuses out through the

barrier layers, and sustained release after the lag phase when the barrier layer is not

eroded or dissolved completely, thereby retarding the drug release.

The Chronotropic® system consists of a drug-containing core coated by

hydrophilic swellable hydroxypropylmethyl cellulose (HPMC), which is responsible

for a lag phase in the onset of release (10)

. In addition, through the application of an

outer gastric-resistant enteric film, the variability in gastric emptying time can be

overcome, and a colon-specific release can be obtained, relying on the relative

reproducibility of small intestinal transit time. The lag time is controlled by the

thickness and the viscosity grades of HPMC. The cores containing Antipyrine as the



model drug were prepared by tabletting and retarding, and enteric coats were applied

in a fluidized bed coater. The in-vitro release curves displayed a lag phase preceding

drug release, and the in-vivo pharmacokinetic data showed a lag time prior to presence

of detectable amounts of drug in saliva. Both in-vitro and in-vivo lag times correlate

well with the applied amount of the hydrophilic retarding polymer. The system is

suitable for both tablets and capsules.

Multiparticulate systems:

Multiparticualte systems (e.g., pellets) offer various advantages over single-

unit systems. These include no risk of dose dumping, flexibility of blending units with

different release patterns, and reproducible and short gastric residence time. But the

drug-carrying capacity of multiparticulate systems is lower due to presence of higher

quantity of excipients. Such systems are invariably a reservoir type with either

rupturable or altered permeability coating.

Pulsatile system based on rupturable coating:

Time-Controlled Explosion System (Fujisawa Pharmaceutical Co., Ltd.): This

is a multiparticulate system in which drug is coated on non-pareil sugar seeds

followed by a swellable layer and an insoluble top layer. The swelling agents used

include superdisintegrants like sodium carboxymethyl cellulose, sodium starch

glycollate, L-hydroxypropyl cellulose, polymers like polyvinyl acetate, polyacrylic

acid, polyethylene glycol, etc. Alternatively, an effervescent system comprising a

mixture of tartaric acid and sodium bicarbonate may also be used. Upon ingress of

water, the swellable layer expands, resulting in rupture of film with subsequent rapid

drug release. The release is independent of environmental factors like pH and drug

solubility. Varying coating thickness or adding high amounts of lipophilic plasticizer

in the outermost layer can vary the lag time. A rapid release after the lag phase was



achieved with increased concentration of osmotic agent. In-vivo studies of time-

controlled explosion system (TCES) with an in-vitro lag time of three hr showed

appearance of drug in blood after 3 hr, and maximum blood levels after 5 hr.

Osmotic-based rupturable coating systems:

Permeability Controlled System: This system is based on a combination of

osmotic and swelling effects. The core containing the drug, a low bulk density solid

and/or liquid lipid material (e.g., mineral oil) and a disintegrant were prepared. This

core was then coated with cellulose acetate. Upon immersion in aqueous medium,

water penetrates the core displacing lipid material. After the depletion of lipid

material, internal pressure increases until a critical stress is reached, which results in

rupture of coating.

Another system is based on a capsule or tablet composed of a large number of

pellets consisting of two or more pellets or parts (i.e., populations). Each pellet has a

core that contains the therapeutic drug and a water-soluble osmotic agent. Water-

permeable, water-insoluble polymer film encloses each core. A hydrophobic, water-

insoluble agent that alters permeability (e.g., a fatty acid, wax, or a salt of fatty acid)

is incorporated into the polymer film. The rate of water influx and drug efflux causes

the film coating of each population to differ from any other pellet coating in the

dosage form. The osmotic agents dissolve in the water causing the pellets to swell,

thereby regulating the rate of drug diffusion. The effect of each pellet population

releasing its drug content sequentially provides a series of pulses of drug from a single

dosage form. The coating thickness can be varied amongst the pellets. This system

was used for the delivery of antihypertensive drug, diltiazem.

Schultz and Kleinebudde reported the use of osmotically active agents that do

not undergo swelling. The pellet cores consisted of drug and sodium chloride. These



were coated with a semipermeable cellulose acetate polymer. This polymer is

selectively permeable to water and is impermeable to the drug. The lag time increased

with increase in the coating thickness and with higher amounts of talc or lipophilic

plasticizer in the coating. The sodium chloride facilitated the desired fast release of

drug. In absence of sodium chloride, a sustained release was obtained after the lag

time due to a lower degree of core swelling that resulted in generation of small

fissures.

Pulsatile delivery by change in membrane permeability:

The permeability and water uptake of acrylic polymers with quaternary

ammonium groups can be influenced by the presence of different counter-ions in the

medium. Several delivery systems based on this ion exchange have been developed.

Eudragit RS 30D is reported to be a polymer of choice for this purpose. It typically

contains positively polarized quaternary ammonium group in the polymer side chain,

which is always accompanied by negative hydrochloride counter-ions. The

ammonium group being hydrophilic facilitates the interaction of polymer with water,

thereby changing its permeability and allowing water to permeate the active core in a

controlled manner. This property is essential to achieve a precisely defined lag time.

The cores were prepared using theophylline as model drug and sodium acetate. These

pellets were coated using Eudragit RS 30D (10% to 40% weight gain) in four

different layer thicknesses. A correlation between film thickness and lag time was

observed. It was found that even a small amount of sodium acetate in the pellet core

had a dramatic effect on the drug permeability of the Eudragit film. After the lag time,

interaction between the acetate and polymer increases the permeability of the coating

so significantly that the entire active dose is liberated within a few minutes. The lag



time increases with increasing thickness of the coat, but the release of the drug was

found to be independent of this thickness.

Table No. 2: Drug that have been developed or are under development as

chronotherapies 4

CLASS DRUGS

Cardiovascular drugs Verapamil, Propranolol, Diltiazem, Nifedipine, Enalapril

Antiasthmatic drugs Methylprednisolone, Prednisolone, Albuterol, terbutaline,

Theophylline

Anticancer drugs Cisplatine, Oxaliplatine, Doxorubicin, 5- fluorouracil, Folinic

acid, Methotrexate, Mercaptopurine

Non steroidal anti-

inflammatory drugs

Ibuprofen, Ketoprofen, Indomethacine, Tenoxicam,

Acetylsalicylic acid

Anti ulcer drugs Cimetidine, Ranitidine, Famotidine, Pirenzipine, Omeprazole

Anticholesterolemic

drugs

Simvastatin, Lovastatin

Others Vitamin D3, Diazepam, Haloperidol

Introduction to oral colon-specific drug delivery system:

The oral route is considered to be most convenient for administration of drugs

to patients. Oral administration of conventional dosage forms normally dissolves in

the stomach fluid or intestinal fluid and absorb from these regions of the

gastrointestinal tract (GIT) depends upon the physicochemical properties of the drug.

It is a serious drawback in conditions where localized delivery of the drugs in the

colon is required or in conditions where a drug needs to be protected from the hostile

environment of upper GIT. Dosage forms that deliver drugs into the colon rather than

upper GIT offers number of advantages. Oral delivery of drugs to the colon is



valuable in the treatment of diseases of colon (ulcerative colitis, Crohn’s disease,

carcinomas and infections) whereby high local concentration can be achieved while

minimizing side effects that occur because of release of drugs in the upper GIT or

unnecessary systemic absorption. The colon is rich in lymphoid tissue. Uptake of

antigens into the mast cells of the colonic mucosa produces rapid local production of

antibodies and this helps in efficient vaccine delivery. The colon is attracting interest

as a site where poorly absorbed drug molecule may have an improved bioavailability.

This region of the colon is recognized as having a somewhat less hostile environment

with less diversity and intensity of activity than the stomach and small intestine.

Additionally, the colon has a longer retention time and appears highly responsive to

agents that enhance the absorption of poorly absorbed drugs. Apart from retarding or

targeting dosage forms, a reliable colonic drug delivery could also be an important

starting position for the colonic absorption of perorally applied, undigested,

unchanged and fully active peptide drugs. As the large intestine is relatively free of

peptidases such special delivery systems will have a fair chance to get their drug

sufficiently absorbed after peroral application. The simplest method for targeting of

drugs to the colon is to obtain slower release rates or longer release periods by the

application of thicker layers of conventional enteric coatings or extremely slow

releasing matrices1.

Various pharmaceutical approaches that can be exploited for the development of

colon targeted drug delivery systems are summarized in Table No. 311



Table No. 3: various pharmaceutical approaches to colon targeted drug delivery

systems.2, 3

No Approaches BBaassiicc ffeeaattuurree

1. CCoovvaalleenntt lliinnkkaaggee ooff aa ddrruugg wwiitthh aa ccaarrrriieerr 1.1 Azo conjugates The drug is conjugated via an azo bond.

1.2 Cyclodextrins conjugates The drug is conjugated with Cyclodextrins.

1.3 Glycoside conjugates The drug is conjugated with Glycoside.

1.4 Glucuronate conjugates The drug is conjugated with Glucuronate.

1.5 Dextran conjugates The drug is conjugated with Dextran.

1.6 Polypeptide conjugates The drug is conjugated with Poly (aspartic

acid).

1.7 Polymeric conjugates The drug is conjugated with polymer.

2 Approaches to deliver the intact molecule to the colon 2.1 Coating with polymer

2.1.1 Coating with pH sensitive polymers Formulation coated with enteric polymers

releases drug when pH move towards

alkaline range

2.1.2 Coating with biodegradable

polymers

Drug is released following degradation of

the polymer due to the reaction of colonic

bacteria

2.2 Embedding in matrices

2.2.1 Embedding in biodegradable

matrices and hydrogel

The embedded drug in polysaccharide

matrices is released by swelling and by the

biodegradable action of polysaccharide

2.2.2 Embedding in pH sensitive matrices Degradation of the pH sensitive polymer in

the GIT releases the embedded drug

2.3 Time release system Once the multicoated Formulation passes

the stomach, the drug is released after a lag

time of 3-5 hr that is equivalent to small

intestinal transit time

2.4 Redox sensitive polymer Drug Formulated with Azo polymer and

disulfide polymers that selectively respond

to the Redox potential of the colon provides

colonic delivery

2.5 Bioadhesive system Selectively provide adhesion to colonic

mucosa may release drug in the colon

2.6 Coating with microparticles Drug is linked with microparticles

2.7 Osmotic controlled drug delivery Drug is released through semi permeable

membrane



Factors affecting in the design of colon-specific drug delivery system:

Anatomy and physiology of colon:

The large intestine extends from the distal end of the ileum to the anus.

Human large intestine is about 1.5 m long (Table No. 4) 15. The colon is upper five

feet of the large intestine and mainly situated in the abdomen. The colon is a

cylindrical tube that is lined by moist, soft pink lining called mucosa; the pathway is

called the lumen and is approximately 2-3 inches in diameter. The cecum forms the

first part

Figure No. 6: Anatomy of the colon

of the colon and leads to the right colon or the ascending colon (just under the liver)

followed by the transverse colon, the descending colon, sigmoid colon, rectum and

the anal canal (Figure No. 6) 14

. The physiology of the proximal and distal colon

differs in several respects that can have an effect on drug absorption at each site. The

physical properties of the luminal content of the colon also change, from liquid in the

cecum to semisolid in the distal colon. The major functions of the colon are (1) the

consolidation of the intestinal contents into feaces by the absorption of the water and

electrolytes and to store the feaces until excretion. The absorptive capacity is very

high, each day about 2000 ml of fluid enters the colon through the ileocecal valve



from which more than 90% of the fluid is absorbed. (2) Creation of a suitable

environment for the growth of colonic microorganisms such as Bacteroides,

Eubacterium, and Enterobacteriaceae; (3) expulsion of the contents of the colon at a

suitable time; and (4) absorption of water and Na+ from the lumen, concentrating the

fecal content, and secretion of K+ and (HCO3

-) 18.

Table No. 4: Summary of anatomical and physiological

features of small intestine and colon

RReeggiioonn ooff ggaassttrrooiinntteessttiinnaall ttrraacctt Characteristics

Length (cm)

EEnnttiirree ggaassttrrooiinntteessttiinnaall ttrraacctt 500-700

SSmmaallll iinntteessttiinnee Duodenam 20-30

Jejunam 150-200

Ileum 200-350

LLaarrggee iinntteessttiinnee Cecum 6-7

Ascending colon 20

Transverse colon 45

Descending colon 30

Sigmoid colon 40

Rectum 12

Anal canal 3

Internal diameter

Small intestine 3-4

Large intestine 6

pH

Stomoch

Fasted 1.5-3

Fed 2-5

SSmmaallll iinntteessttiinnee 3-4

Duodenam(fasted) 6.1

Duodenam(fed) 5.4

Ileum 7-8

Large intestine

Cecum and coln 5.5-7.7

Rectum 7



pH in the colon:

The pH of the gastrointestinal tract is subject to both inter and intra subject

variations. Diet, diseased state, and food intake influence the pH of the

gastrointestinal fluid. The change in pH along the gastrointestinal tract has been used

as a means for targeted colon drug delivery 16.

There is a pH gradient in the gastrointestinal tract with value ranging from 1.2

in the stomach through 6.6 in the proximal small intestine to a peak of about 7.5 in the

distal small intestine (Table No. 2). The pH difference between the stomach and small

intestine has historically been exploited to deliver the drug to the small intestine by

way of pH sensitive enteric coatings. There is a fall in pH on the entry into the colon

due to the presence of short chain fatty acids arising from bacterial fermentation of

polysaccharides. For example lactose is fermented by colonic bacteria to produce

large amounts of lactic acid resulting in drop in the pH to about 5.0 21.

Colonic micro flora and their enzymes:

Intestinal enzymes are used to trigger drug release in various parts of the GIT.

Usually, these enzymes are derived from gut microflora residing in high numbers in

the colon. These enzymes are used to degrade coatings/matrices as well as to break

bonds between an inert carrier and an active agent (i.e., release of a drug from a

prodrug). Over 400 distinct bacterial species have been found, 20-30% of which are

of the genus Bacteroides7. The upper region of the GIT has very small number of

bacteria and predominantly consists of Gram-positive facultative bacteria. The

concentration of bacteria in the human colon is 1011- 10

12 CFU/ml. The most

important anaerobic bacteria are Bacteroides, Bifidobacterium, Eubacterium,

Peptococcus, Peptostreptococcus, Ruminococcus. Summary of the most important

metabolic reaction carried out by intestinal bacteria are given in Table No. 517



Table No. 5: Drug metabolizing enzymes in the colon that catalyze reactions

Transit of material in the colon:

Gastric emptying of dosage forms is highly variable and depends primarily on

whether the subject is fed or fasted and on the properties of the dosage form such as

size and density. The arrival of an oral dosage form at the colon is determined by the

rate of gastric emptying and the small intestinal transit time. The transit times of

small oral dosage forms in GI tract are given in Table No. 6.

Enzymes Microorganism Metabolic reaction

catalyzed

Nitroreductase E. coli, Bacteroids Reduce aromatic and

heterocyclic nitro

compounds

Azoreductase Clostridia, Lactobacilli, E.

Coli

Reductive cleavage of azo

compounds

N-Oxide

reductase,

sulfoxide

reductase

E. coli Reduce N-Oxides and

sulfoxides

Hydrogenase Clostridia, Lactobacilli Reduce carbonyl groups and

aliphatic double bonds

Esterases and

amidases

E. coli, P. vulgaris, B.

subtilis, B. mycoides

Cleavage of esters or

amidases of carboxylic acids

Glucosidase Clostridia, Eubacteria Cleavage of β-glycosidases

of alcohols and phenols

Glucuronidase E. coli, A. aerogenes Cleavage of β-

glucuronidases of alcohols

and phenols



TThhee mmoovveemmeenntt ooff mmaatteerriiaallss tthhrroouugghh tthhee ccoolloonn iiss ssllooww

aanndd tteennddss ttoo bbee hhiigghhllyy vvaarriiaabbllee aanndd iinnfflluueenncceedd bbyy aa

nnuummbbeerr ooff ffaaccttoorrss ssuucchh aass ddiieett,, ddiieettaarryy ffiibbeerr ccoonntteenntt,,

mmoobbiilliittyy,, ssttrreessss,, ddiisseeaassee,, aanndd ddrruuggss..

IInn hheeaalltthhyy yyoouunngg aanndd aadduulltt mmaalleess,, ddoossaaggee ffoorrmmss

ssuucchh aass ccaappssuulleess aanndd ttaabblleettss ppaassss tthhrroouugghh tthhee ccoolloonn iinn

aapppprrooxxiimmaatteellyy 2200--3300 hhoouurrss,, aalltthhoouugghh tthhee ttrraannssiitt ttiimmee ooff

aa ffeeww hhoouurrss ttoo mmoorree tthhaann 22 ddaayyss ccaann ooccccuurr.. DDiisseeaasseess

aaffffeeccttiinngg ccoolloonniicc ttrraannssiitt hhaavvee iimmppoorrttaanntt iimmpplliiccaattiioonnss ffoorr

ddrruugg ddeelliivveerryy:: ddiiaarrrrhhooeeaa iinnccrreeaasseess ccoolloonniicc ttrraannssiitt aanndd

ccoonnssttiippaattiioonn ddeeccrreeaasseess iitt.. HHoowweevveerr,, iinn mmoosstt ddiisseeaassee

ccoonnddiittiioonnss,, ttrraannssiitt ttiimmee aappppeeaarrss ttoo rreemmaaiinn rreeaassoonnaabbllyy

ccoonnssttaanntt..



Table No. 6: The transit time of dosage form in GIT.

Approaches to colonic drug delivery via oral route:

Prodrug:

Prodrug is pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or

enzymatic transformation in vivo to release the active drug. For colonic delivery of drugs, prodrugs are designed to

undergo minimal absorption and hydrolysis in the tracts of the upper GIT and undergo enzymatic hydrolysis in the

colon, there by releasing the active drug moiety from the carrier.

A number of other linkages susceptible to bacterial hydrolysis specifically in the colon have been prepared

where the drug is attached to hydrophilic moieties like amino acid, glucuronic acid, glucose, galactose, cellulose, coating

materials over drug cores etc.

Polysaccharides are used as glucuronic prodrugs, which are specifically

degraded by colonic glucuronidases(18)

, and glycosidic prodrugs, which are

specifically degraded by colonic glycosidases. Back in 1942 it was realized that

sulphasalazine given for the treatment of rheumatoid arthritis was also useful in

patients with inflammatory bowel disease (IBD). Furthermore, Khan et al., 1977

found that the active moiety effective in IBD was 5-amino- 3 salicylic acid (5-ASA)

and sulphapyridine (SP) only acted as a carrier. The high site specificity of prodrugs

clearly indicates the involvement of the colon for the prodrug to drug conversion.

AAnnttii-- iinnffllaammmmaattoorryy gglluuccooccoorrttiiccooiiddss ddoo nnoott ppoosssseessss

ccaarrbbooxxyylliicc aacciidd ggrroouuppss aanndd mmuusstt bbee cchheemmiiccaallllyy

Organ Transit time (hr)

Stomach <1 (Fasting)

>3 (Fed)

Small intestine 3-4

Large intestine 20-30



ttrraannssffoorrmmeedd iinn oorrddeerr ttoo rreeaacctt wwiitthh ddeexxttrraann..

DDeexxaammeetthhaassoonnee aanndd mmeetthhyyll pprreeddnniissoolloonnee wweerree aattttaacchheedd

ttoo ddeexxttrraann uussiinngg ssuucccciinniicc aacciidd aass aa ssppaacceerr aanndd tthhee

rreessuullttaanntt pprrooddrruugg wweerree iinnccuubbaatteedd wwiitthh rraatt GGIITT ccoonntteennttss,,

bbuutt wweerree rraappiiddllyy ddeeggrraaddeedd iinn ccaaeeccaall aanndd ccoolloonniicc

ccoonntteennttss.. TThhiiss iilllluussttrraatteess tthhee uusseeffuullnneessss ooff tthhee

ccoonnjjuuggaatteess ffoorr sseelleeccttiivvee ddeelliivveerryy ooff gglluuccooccoorrttiiccooiiddss ttoo

tthhee llaarrggee iinntteessttiinnee..

pH responsive delivery :

The pH-dependent systems exploit the generally accepted view that pH of the

human GIT increases progressively from the stomach (pH 1-2 which increases to 4

during digestion), small intestine (pH 6-7) at the site of digestion and it increases to 7-

8 in the distal ileum. The coating of pH-sensitive polymers to the tablets, capsules or

pellets provide delayed release and protect the active drug from gastric fluid. The

polymers used for colon targeting, however, should be able to withstand the lower pH

values of the stomach and of the proximal part of the small intestine and also be able

to disintegrate at the neutral of slightly alkaline pH of the terminal ileum and

preferably at the ileocecal junction. Widely used polymers are methacrylic resins

(Eudragit), which are available in water-soluble and water-insoluble forms. Eudragit

L and S are copolymers of methacrylic acid and methyl methacrylate. Colon targeted

drug delivery systems based on methacrylic resins has described for insulin,



prednisolone, quinolones, salsalazine, cyclosporine, beclomethasone dipropionate and

naproxane20.

In fact, the pH in the distal small intestine is usually around 7.5, while the pH

in the proximal colon is closer to 6.0. These delivery systems therefore have a

tendency to release their drug load prior to reaching the colon. To overcome the

problem of premature drug release, a copolymer of methacrylic acid,

methylmethacrylate and ethylmethacrylate (Eudragit FS), which dissolve at a slower

rate and at a higher threshold pH (7-7.5), has been developed recently 21.

Time responsive delivery:

Time-dependent delivery has also been proposed as a means of targeting the colon.

Time dependent systems release their drug load after a preprogrammed time delay. To

attain colonic release, the lag time should equate the time taken for the system to

reach the colon. This time is difficult to predict in advance, although a lag time of five

hours is usually considered sufficient, given that small intestine transit time is

reported to be relatively constant at three to four hours. A number of systems have

been developed based on this principle, with one of the earliest being the somewhat

complex Pulsincap device 21.

Bacteria responsive delivery:

The bioenvironment inside the human GIT is characterized by the presence of

complex micro flora especially the colon that is rich in microorganisms that are

involved in the process of reduction of dietary component or other materials. Drugs

that are coated with the polymers, which are showing degradability due to the



influence of colonic micro- Organisms, can be exploited in designing drugs for colon

targeting.

Polysaccharides offer an alternative substrate for the bacterial enzymes present in the

colon. Many of these polymers are already used as excipients in drug formulations or

are constituents of the human diet and are therefore generally regarded as safe. A

large number of polysaccharides have already been studied for their potential as

colon-specific drug carrier systems, such as chitosan, pectin, chondroitin sulphate,

cyclodextrin, dextrans, guar gum, inulin, amylose, sodium alginate and locust bean

gum 22.

Evaluation of Colon-Specific Drug Delivery System 23, 24, 25

A successful colon-specific drug delivery system is one that remains intact in

the physiological environment of stomach and small intestine, but releases the drug in

the colon. Different in-vitro and in-vivo methods are used to evaluate the colonic drug

delivery systems.

In-vitro methods:

In-vitro dissolution testing is important in the development of solid dosage

forms. It provides decisive information on formulation selection, the critical

processing variables, in-vitro/in-vivo correlation and quality assurance during clinical

manufacturing. In order to provide this information, dissolution testing should be

conducted in physiochemical and hydrodynamically defined conditions to simulate

the environment that the dosage form encounters in the GI tract. Conventional

dissolution testing proposed in USP appears unable to discriminate drug mechanisms.

For in-vitro evaluation of colon-specific drug delivery systems, the ideal dissolution



testing should closely mimic the in-vivo conditions with regard to pH, bacteria, types

of enzymes enzymatic activity, fluid volume and mixing intensity. Apparently, such

dissolution specifications will be very difficult, if possible at all, to be standardized

and validated. Nonetheless, several dissolution methodologies were reported in the

literature for the testing of CSDDS.

Dissolution testing of colon delivery systems with the conventional basket

method has usually been conducted in different buffers for different periods of time to

simulate the GI tract pH and transit time that the colon-specific delivery system might

encounter in-vivo. The ability of the coats/carriers to remain intact in the

physiological environment of the stomach and small intestine is generally assessed by

conduction drug release studies in 0.1N HCL for 2 hours (mean gastric emptying

time) and in pH 7.4 Sorensen’s phosphate buffer for 3 hours (mean small intestinal

transit time) using USP dissolution rate test apparatus or flow through dissolution

apparatus. For example, Takeuchi et al. assessed the dissolution of spray-dried lactose

composite particles containing alginate-chitosan complex as compression coating in

pH 1.2 and 6.8 buffers. Despite the simplicity and convenience, conventional

dissolution testing primarily provides essential information on the processing

specifications of a colon-specific delivery system rather than on the validity of the

system design. For those delivery systems triggered by bacteria in the colon, the

conventional dissolution testing appears unlikely to be predictive of in-vivo

performance. Additional factors that make conventional dissolution testing of colon-

specific drug delivery systems less predictive of its in-vivo performance are scarcity

of fluid and reduced motility in the colon.

To overcome limitation of conventional dissolution testing for evaluating the

performance of CSDDS triggered by colon-specific bacteria, animal caecal contents



including rats, rabbits, pigs, have been utilized as alternative dissolution medium.

Because of the similarity of human and rodent colonic microflora, predominantly

comprising Bifidobacterium, bacteroides and Lactobacillus, rat caecal contents were

more commonly used in the dissolution studies.

In-vivo methods:

When the system design is conceived and prototype formulation with

acceptable In-vivo characteristics is obtained, In-vivo studies are usually conducted to

evaluate the site specificity of drug release and to obtain relevant pharmacokinetics

information of the delivery system. In-vivo bioavailability tests in human beings are

important in developing controlled-release drug delivery systems. From the results of

bioavailability test, sites of drug liberation In-vivo can be determined, if the

formulation has been administered to the subjects in the fasting state.

Animal models:

Different animal models are used for evaluating in-vivo performance of

CSDDS. Guinea pigs were used to evaluate CSDDS from a glucoside prodrug of

dexamethasone. Other animal models used for the In-vivo evaluation of colon-specific

drug delivery systems include the rat and the pig. Although animal models have

obvious advantages in assessing colon-specific drug delivery drug delivery systems,

human subjects are increasingly utilized for evaluation of this type of delivery

systems with visualization techniques such as γ-scintigraphy imaging.

γ-scintigraphy:

With growing complexity in the design of novel drug delivery systems and

associated fabrication process, it is critical to understand the In-vivo performance of

those delivery systems and demonstrate that the system functions In-vivo in



accordance with the proposed rationale. γ-scintigraphy is an imaging modality, which

enables the In-vivo performance of drug delivery systems to be visualized under

normal physiological conditions in a non-invasive manner. Since first employed to

investigate the functionality of tablets and capsules In-vivo more than two decades

ago, γ-scintigraphy has become an established technique and extensively used to

monitor the performance of novel drug delivery systems within human GI tract.

Through γ-scintigraphy imaging, the following information regarding the

performance of CSDDS within human GI tract can be obtained: the location as a

function of time, the time and location of both; initial and complete system

disintegration, the extent of dispersion, the colon arrival time, stomach residence and

small intestine transit times. It can also provide information about regional

permeability in the colon. Information about gastrointestinal transit and the release

behavior of dosage forms can be obtained by combining pharmacokinetic studies and

gammascintigraphic studies (pharmacoscintigraphy). Good correlations between

appearance of a drug in plasma and observed disintegration times have been recorded.

In effence, γ-scintigraphy evaluation of a CSDDS provides “proof of concept”.

i.e. visualization of system disintegration event and ascertainment of disintegration

location in the GI tract. Mechanistically, In-vivo functioning of CSDDSs involves the

interaction between the gut physiologies. Thus, it appears that the precise mechanism

responsible for the disintegration of a CSDDS cannot be determined with γ-

scintigraphy imaging.

Table No. 7: Summary of colon-specific drug delivery strategies.26, 24

Design strategy Drug release

triggering-

mechanisms

Advantages Disadvantages

Prodrugs Cleavage of the Able to achieve site It will be



linkage bond between

drug and carrier via

reduction and

hydrolysis by

enzymes from colon

bacteria. Typical

enzymes include

azoreductase,

glycosidase, and

glucuronidase

specificity. considered as a new

chemical entity

from regulatory

perspective. So far

this approach has

been primarily

constricted to

actives related to

the treatment of

IBD.

pH-dependent

systems

Combination of

polymers with pH-

dependent solubility

to take advantage of

the pH change along

the GI tract.

Formulation well

protected in the

stomach.

Unpredictable site-

specificity of drug

release because of

inter-/intra subject

variation and

similarity of pH

between small

intestine and the

colon.

Time-dependent

systems

The onset of drug

release is aligned

with positioning the

delivery system in

the colon by

incorporating a time

factor simulating the

system transit in

upper GIT.

Small intestine

transit time fairly

consistent

Substantial

variation in gastric

retention times

makes it

complicated in

predicting the

accurate location of

drug release.

Microflora

activated system

Primarily

fermentation of non-

starch

polysaccharides by

colon anaerobic

bacteria. The

polysaccharides are

incorporated into the

delivery system via

film-coating and

matrix formation.

Good site

specificity with pro

drugs and

polysaccharides

Diet and disease

can affect colonic

microflora;

enzymatic

degradation may be

excessively slow.

Introduction to Tablet-in-capsule: 27, 28

Based on the concept that a formulation given once a time daily, a two-pulse

drug release system proposed for oral administration can be designed, for achieving



the selective delivery of drugs at appropriate time, which is a chronopharmaceutical

approach for the better treatment of disease with circadian rhythms. This novel system

is a so-called “tablets in capsule device.” The designed capsule device consists of an

impermeable capsule body and a soluble cap. The multi-layered tablets formulation

prepared is filled within the capsule body and sealed with the water-soluble cap.

A two tablet system in capsule, one of which serves to give first pulse to

provide a loading dose and second tablet after a lag time of 4 to 5 hrs gives the second

pulse. Both tablets are inserted into an impermeable capsule body with a water-

soluble cap. On reaching body fluid, the cap dissolved and the first pulse released,

following which the modulating barrier swelling and eroded which cause a lag phase

preceding the onset of release of the second pulse. The modulating barrier of the bi-

layered tablet performs the same role. Lag time can be successfully controlled by

adjusting the ratio of barrier materials in the coating.

Figure No. 7: Schematic diagram of Tablet in Capsule device

Nocturnal asthma



Asthma is a common chronic inflammatory disease of the airways,

characterized by hyperresponsiveness to a variety of stimuli. It may be classified as

mild intermittent or mild, moderat, or severe persistent. 29

Asthma affects 14 to 15 million persons in the United States. An estimated 4.8

million children have asthma, which makes it the most common chronic disease of

childhood. With the increased understanding of the role inflammation plays in asthma

and the addition of new pharmacologic agents, the management of this disease has

improved.

Pathophysiology of asthma:

Airway inflammation is the primary problem in asthma. An initial event in

asthma appears to be the release of inflammatory mediators (e.g., histamine, tryptase,

leukotrienes and prostaglandins) triggered by exposure by exposure to allergens,

irritants, cold air or exercise. The mediators are released from bronchial mast cells,

alveolar macrophages, T lymphocytes and epithelial cells. Some mediators directly

cause acute brochoconstriction, termed the “early-phase asthmatic response.” The

inflammatory mediators also direct the activation of eosinophils and neutrophils, and

their migration to the airways, where they cause injury. This is so-called “late-phase

asthmatic response” results in epithelial damage, airway edema, mucus hypersecretion

and hyperresponsiveness of bronchial smooth muscle (Figure No. 8). Varying airflow

obstruction leads to recurrent episodes of wheezing, breathlessness, chest tightness

and cough.29



FigureNo. 8: pathophysiolofy of asthma: according to the current view, several inflammatory cells

interact in a complex manner and release multiple inflammatory mediators that act on various target

cells in the airways to produce the characteristic pathophysiology of asthma.

It has been recognized that asthma is worse in night. One of the earliest

observations of a day-night pattern in asthma was made by Aurelianus Caelius in the

5th century A.D. in the 1880s, Slater wrote that “sleep favors asthma......spasm of the

bronchial tubes is prone to occur during the insensibility and lethargy of sleep than

during the waking hours.”

NOCTURNAL ASTHMA is defined as a variable nighttime exacerbation of

the underlying asthma condition associated with increase in symptoms and need for

medication, increased airway responsiveness, and/or worsening of lung function.

Approximately two-thirds of asthmatics suffer from nighttime symptoms. Lung

function (e.g., peak expiratory flow rate or FEV1) is usually highest at 4 PM and

lowest at 4 AM.



Figure No. 9: Diurnal variations in lung function in healthy (top curve) and asthmatic (bottom curve)

subjects. PEFR = peak expiratory flow rate; FEV 1 = forced volume in one second.

The mechanisms of nocturnal asthma are intimately related to circadian

rhythms, which influence inflammatory cells and mediators, hormone levels and

cholinergic tone. Patients with nocturnal asthma symptoms may have greater

nighttime activation of inflammatory cells and mediators, lower levels of epinephrine

and increased vagal tone. In addition, underlying differences in the glucocorticoid

receptor and β-receptors in these patients may diminish their ability to respond to

therapy. While sleep appears to play a role in the pathophysiology of nocturnal

asthma, it is not essential to it.

Management of Nocturnal Asthma: chronotherapy 30

Chronotherapeutics is the synchronization of medication levels in time with

reference to need, taking into account biologic rhythms in the pathophysiology of

medical conditions, and/or rhythmodependencies in patient tolerance for given

chemical interventions. It is based on importance of biologic rhythms in the

pathophysiology of medical conditions and uses the timing of medication to provide

P

E

F

R

O

r

F

E

V

1



maximal efficacy and minimal toxicity. Available therapy includes inhaled and oral

corticosteroids, sustained release salbutamol sulphate, long-acting β-agonists,

leukotriene-modifying agents and anticholinergic medication.

Three chronotherapies have been proposed: 31

• Inhaled corticosteroids administered at 5:30 PM rather than 8 AM.

• Time-release Theophylline formulation (Theo-24) dose ingested at 3 PM

• Β2 agonists administered at 3 PM rather than 8 AM.

A chronotherapeutic approach to Nocturnal asthma: 30

AM 3 PM 6-7 PM Qhs

LA-β-Agonist Oral SR-Salbutamol

Sulphate

Corticosteroid

Leukotriene modifier

LA-β-agonist

Anti-cholinergic

QHS=at bedtime; LA=long acting; SR=sustained release

Certain SR formulations of Salbutamol Sulphate can be administered so that a

rising blood level of the drug occurs when airway obstruction is increasing, while

adverse effects are reduced. For this purpose, SR Salbutamol sulphate is administered

once daily, in the evening, for the management of nocturnal asthma. Another aspect of

Salbutamol sulphate therapy is how it can work in conjunction with inhaled

corticosteroids as part of a chronotherapeutic regimen. This interaction is important,

since inhaled corticosteroid therapy used in patients with moderate to severe asthma

failed to control a significant percentage of nocturnal asthmatic symptoms.



Classification of Anti-asthamatic drugs 32

1. Bronchodialators

a) Sympathomimetics : Adrenaline, Ephedrine, Salbutamol, terbutaline

b)Methyl Xanthines: Theophylline, Aminophylline

c) Anticholinergics: Atropine, Methonitrate, Ipratropium bromide

2. Mast cells Stabilizers Sodium Cromoglycate, Ketotifen

3. Corticosteroids

a) Sytemic Hydrocortisone, Prednisolone

b) Inhalation Beclomethasone dipropionate

4. Miscellaneous

Antihistamines Mepyramine

Chapter 2 Research Objective


RESERCH OBJECTIVE

The rational of this study is to design and evaluate an oral site-specific,

pulsatile drug delivery system containing Salbutamol Sulphate, which can be targeted

to colon in a pH and time dependent manner, to modulate the drug level in synchrony

with the circadian rhythm of nocturnal asthma. In the present research work, we have

attempted to develop a novel dosage form by using a chronopharmaceutical approach.

A pulsatile ‘Tablet in Capsule’ dosage form, taken at bed time with a programmed

start of drug release early in morning hours, can prevent a sharp increase in the

incidence of asthmatic attacks, during the early morning hours (nocturnal asthma), a

time when the risk of asthmatic attacks is the greatest.

Salbutamol Sulphate is selected as a model drug for following reasons:

ϒ It is mainly used for the relief from several diseases including asthma,

bronchitis, apnoea and other respiratory tract infection.

ϒ Salbutamol Sulphate may be useful in the treatment of nocturnal asthma when

administered at specific times in relation to onset of symptoms.

ϒ It represents an appropriate and effective therapeutic option for patients with

wide range of asthmatic symptoms and is popularly prescribed.

ϒ It is having shorter biological half-life which varies from 1.6-4 hrs, can be

used as sustained release product. Salbutamol Sulphate is having narrow

“therapeutic window”, so can be used as a controlled release product.

ϒ Colonic absorption of Salbutamol Sulphate could prevent unwanted systemic

side effect and subsequently a lower dose of life saving drug may be sufficient

to treat nocturnal asthma.



A pulsatile, chronopharmaceutical drug delivery system of Salbutamol sulphate

was developed for the following reasons.

To synchronize drug delivery to the circardian rhythm of asthma.

Overlapping of drug release characteristic with onset of pharmacological

symptoms make the drug delivery system ideal for chronotherapy of

asthma.

To prolong therapeutic effect by continuously releasing the medication

over as extended period of time after administration of single dose.

To delay the releases of drug hence control the onset of drug action.

To minimize the frequency of drug administered at bed time.

Improved therapy can be provided as the drug exerts its action at a time

when it is needed most and dose related side effect could be minimized.

Patient convenience and compliance could be achieved.

OBJECTIVES OF THE STUDY:

To design and characterize an oral, pulsatile drug delivery system of

Salbutamol Sulphate intended to approximate the chronobiology of asthma, proposed

for colonic targeting. It is a chronopharmaceutical approach for the better treatment of

nocturnal asthma.

Based on the concept that a formulation on leaving the stomach, arrives at the

ileocaecal junction in about 5 to 6 hours after administration and difference in pH

throughout GIT, a time and pH dependent pulsatile drug delivery system was

designed.

This novel system is a so-called “Tablets in Capsule device” The designed

capsule device consists of an impermeable capsule body and a soluble cap. The two



tablets formulation prepared is filled within the capsule body and sealed with the

water-soluble cap.

A two tablet system in capsule, one of which serves to give first pulse to

provide a loading dose and second tablet after a lag time of 4 to 5 hrs gives the second

pulse. Both tablets are inserted into an impermeable capsule body with a water-

soluble cap. On reaching body fluid, the cap dissolved and the first pulse released,

following which the modulating barrier erodes which cause a lag phase preceding the

onset of release of the second pulse. The modulating barrier of the bi-layered tablet

performs the same role. Lag time can be successfully controlled by adjusting the ratio

of the barrier materials in the coating.

PLAN OF RESEARCH WORK

Preformulation studies:

§ Selection of polymers and its combination suitavle for the pulsatile drug

delivery system.

§ Drug-excipient compatibility study.

§ Preparation of standard graph of Salbutamol Sulphate using

spectrophotometric methods.

Experimental designing for formulation and evaluation of salbutamol Sulphate

Tablet in capsule device:

§ Preparation of Salbutamol sulphate tablet (1. First pulse dose and 2. Second

pulse dose after lag time)

§ Determination of physicochemical parameter of prepared granules and tablets.

§ Optimization of best coating ration/concentration of coating polymers for

second pulse tablet.

§ In-vitro dissolution profile of second pulse release tablet.



Development of Tablet in Capsule device:

§ Filling of tablet i.e. first pulse and second pulse tablet in “0” size capsule.

§ Evaluation of the dosage forms for their physicochemical parameters, drug

content, In-vitro release rate and in-vivo gamma scintigraphic studies.

§ Stability studies to assess shelf life of the developed drug delivery system.

Chapter – 3 Review of Literature


REVIEW OF LITERATURE

DRUG PROFILE:

SALBUTAMOL SULPHATE:

Various Specification of Salbutamol Sulphate 33-36

Generic name: Salbutamol sulphate

CAS: 18559-94-9

Synonym: Albuterol sulphate

Structure:

Chemical name: (RS)-1-(4- hydroxy – 3 hydroxy – Methyl Phenyl) – 2 –

(tertbutylamino) ethanol sulphate

Empirical Formula: (C13H21NO3)2 • H2SO4

Molecular Weight: 576.7 g/mol

FDA Drug Class: Antiasthmatics/Bronchodilators; Antihypertensive

Generic Class : ß-2 adrenergic bronchodilator

Medicine Classification: Prescription Medicine

Description: A white or almost white, crystalline powder, odorless.



Solubility: Freely soluble in water, slightly soluble in ethanol (95 %)

and in ether; Very slightly soluble in dichloromethane.

Equivalent: 1mg of Salbutamol Sulphate is approximately equivalent to

830 ug of Salbutamol

pKa: 9.3

Melting point: 157-158 oC (with decomposition)

Storage Condition: Stored in well closed, light resistant container.

Pharmacological Properties 34, 35, 39

Salbutamol is a selective β2 adrenoceptor agonist. At therapeutic doses it acts

on the β2 adrenoceptors of bronchial muscle, with little or no action on the β2

adrenoceptors of the heart. It is suitable for the management and prevention of attack

in asthma.

Pharmacodynamic Properties:

Mechanism of action:

The mechanism of the antiasthmatic action of short acting β-adrenergic

receptor agonists is undoubtedly linked to the direct relaxation of airway smooth

muscle and consequent bronchodilation. Stimulating these receptors leads to

activation of adenyl cyclase, increase in cellular cyclic AMP, and consequent

reduction of muscle tone. β2-adrenergic receptors agonists also have been shown to

increase the conductance of potassium channels in airway muscle cells leading to

membrane hyperpolarisation and relaxation. This occurs, in part, by mechanism

independent of adenylyl cyclase activity and cyclic AMP production.



Pharmacokinetic Properties 37-39

Salbutamol is well absorbed from the gastrointestinal tract and undergoes

considerable first-pass metabolism. The major metabolite is sulphate conjugate, which

is inactive. Salbutamol administered intravenously has a half-life of 2 to 4 hours and

is cleared partly renally and partly by metabolism to the inactive 4'-0- sulphate

(phenolic sulphate) which is also excreted primarily in the urine. Peak plasma

concentration after a single oral dose of 4 mg salbutamol is reported to range from 10

to 16.9 microgram per liter. After ingestion of slow release prepration, peak plasma

levels are seen at 5-6 hour and lower than after same dose of conventional formulation

(2-3 h); however, the areas under the curves of plasma concentration versus time are

similar, indicating equivalent bioavailability of the two formulations. The

bioavailability of orally administered salbutamol is about 85%.The proportion of

circulating drug that is protein bound is approximately 10%. The mean volume of

distribution calculated from the data of Fairfax and others is 3.4 +0.6 liter per kg.

Pre-clinical safety data

In common with other potent selective β2 receptor agonists, salbutamol has

been shown to be teratogenic in mice when given subcutaneously. In a reproductive

study, 9.3% of fetuses are found to have cleft palate, at 2.5mg/kg, 4 times the

maximum human oral dose. In rats, treatment at the levels of 0.5, 2.32, 10.75 and

50mg/kg/day orally throughout pregnancy resulted in no significant fetal

abnormalities. The only toxic effect was an increase in neonatal mortality at the

highest dose level as the result of lack of maternal care. A reproductive study in

rabbits revealed cranial malformations in 37% of fetuses at 50mg/kg/day, 78 times the

maximum human oral dose.



Side effects of Salbutamol Sulphate

� The side effects of Salbutamol generally result from the drugs action on

muscles such as cramps or tremors. Other side effects come from the drugs

action on beta1 adrenoceptors in cardiac muscle (500 times less binding than

beta 2) generally causing vasodilatation with resulting effect on blood pressure

and the heart.

� More common side effects include: Aggression, agitation, cough, diarrhoea,

dizziness, excitement, general bodily discomfort, headache, heartburn,

increased appetite, increased blood pressure, indigestion, irritability, laboured

breathing, light-headedness, muscle cramps, nausea, nervousness, nightmares,

nosebleed, over activity, palpitations, rapid heartbeat, rash, ringing in the ears,

shakiness, sleeplessness, stomach ache, stuffy nose, throat irritation, tooth

discoloration, tremors, vomiting, wheezing, worsening bronchospasm.

� Less common side effects include: Chest pain or discomfort, difficulty

urinating, drowsiness, dry mouth and throat, flushing, high blood pressure,

muscle spasm, restlessness, sweating, unusual taste, vertigo, weakness.

� Rare side effects following the use of inhaled salbutamol include: Hoarseness,

skin rash or hives, hypokalemia, myocardial insufficiency, heart failure,

angina-pectoris, hypertension, severe cardiovascular disease, diabetes-

mellitus, maternal-thyrotoxicosis.

Posology of Salbutamol sulphate

Salbutamol has the duration of action of 4 to 6 hours in most patients. As there

may be adverse effects associated with excessive dosing, the dosage or frequency of

administration should only be increased on medical advice.



Adults:- The usual effective dose of salbutamol is 4 milligrams three or four

times per day. Some patients obtain adequate relief with 2 milligrams

salbutamol three or four times daily.

Children:- 2-6 years :1-2mg salbutamol three or four times daily.

6-12 years:2mg salbutamol three or four times daily.

Over 12 years: 2-4mg salbutamol three or four times daily

Overdose:

The preferred antidote for overdosage with salbutamol is a cardioselective β-

blocking agent. However, β-blocking agents should be used with caution in patients

with a history of bronchospasm.Hypokalaemia may occur following overdose with

salbutamol. Serum potassium levels should be monitored.

Contra-indications:

Salbutamol is contra-indicated in patients with a history of hypersensitivity to

any of its components. Although intravenous salbutamol and occasionally salbutamol

tablets are used in the management of premature labour, uncomplicated by conditions

such as placenta praevia, ante-partum haemorrhage or toxaemia of pregnancy,

salbutamol presentations should not be used for threatened abortion.

Table No. 8 Interaction with other medicaments and other forms of interaction

Drug interaction

Beta-blockers Severe bronchospasm may be produced in

asthmatic patients taking Salbutamol

Digoxin Salbutamol may decrease serum digoxin

levels.

Diuretics ECG changes and hypokalemia

associated with these diuretics may

worsen with co administration of

Salbutamol.



The adverse drug reaction associated with the salbutamol sulphate are listed as below.

Cardiovascular Palpitation, tachycardia, elevated B.P.,

chest tightness, angina.

CNS (central nervous system) Tremor, Dizziness, hyperactivity,

nervousness, drowsiness, headache,

insomnia, weakness, restlessness.

EENT Dry mouth, throat infection

Gastro intestinal Nausea, womiting, heartburn, diarrhea.

GU Urinary retention

Respiratory Cough, bronchospasm, wheezing,

dyspnea.

other Flushing, sweating, anorexiaa, unusual

sensory changes.

Pregnancy and lactation:

Administration of medicines during pregnancy should only be considered if

the expected benefit to the mother is greater than any possible risk to the fetus.

Because no consistent pattern of defects can be discerned, and baseline rate for

congenital anomalies is 2-3%, a relationship with salbutamol use cannot be

established. As salbutamol is probably secreted in breast milk, its use in nursing

mothers is not recommended unless the expected benefits outweigh any potential risk.

It is not known whether salbutamol in breast milk has a harmful effect on the neonate.

Market preparations: 33, 39

1. Oral form:

Ventolin Tablets (2 mg; 4 mg) – Glaxo wellcome, USA

Volmax Tablets (4 mg; 8 mg) – Muro, USA

Ventolin Syrup (2 mg/5 ml) - Glaxo wellcome, USA

Ventrolin Capsule ER (4mg, 8mg) - GSK, India

Asthalin SA 4mg tablets – Cipla, India



2. Parentral form:

Ventolin Injection – Allen and Hanbury’s, UK

Ventolin Intravenous Infusion – Allen and Hanbury’s, UK

3. Inhalation form:

Ventolin Aerosol Inhalation (90mcg/actuation) – Glaxo wellcome, USA

Ventolin Rotacaps (200 mcg) – Glaxo wellcome, USA.

REVIEW OF WORK DONE ON SALBUTAMOL SULPHATE:

Samanta M.K. et al., developed pulsincap like system with salbutamol

suphate as drug that release drug in colon. Body was coated with ethyl cellulose and

plug made by gelatin. Microcapsule of salbutamol sulphate was made using eudragit

by emulsion solvent evaporation methods. The in-vitro dissolution result indicated

that the onset of drug release was after 7 to 8 hours of the experiment stated and

revealed its better sustaining efficacy over a period of 24 hr. thus this pulsincap

dosage form of salbutamol sulphate may be used or colon specific drug delivery.

When it administered in the evening, it may prevent nocturnal attack of asthma and

there by may reduced the unexpected mortality rate.6

Ahuja et. al. prepared a time dependent pulsed release system consisting of an

effervescent core containing Salbutamol Sulphate surrounded by consecutive layers of

swelling and rupturable polymers. The cores were prepared by direct compassion

using microcrystalline cellulose and effervescent agents and were coated sequentially

with inner swelling layer containing hydrocolloid, HPMC and outer rupturable layer

having Eudragit RL/RS. Effects of processing ad formulative parameter on the



performance of various systems were studied. The study showed lag time of

Salbutamol Sulphate decreased by increasing the inner swelling layer and increased

by increasing the rupturing layer. 40

Bhalla et. al., reported the sustained release formula of Salbutamol Sulphate

tablet achieved by use of wax and acrylic resin matrices. It was concluded that

Eudragit RS 100 and RL 100 (Acrylic resin polymers) used possess pH dependant

release pattern and had better stability than wax based matrices. 41

Vyas et al., developed an oral osmotic system which can deliver theophylline

and salbutamol sulphate simultaneously for extended period of time was developed

and characterized in a view to reduce the problems associated with the multidrug

therapy of asthma. Simple controlled porosity osmotic pump contained both drugs (in

freely soluble form) did not provide satisfactory extended release of theophylline. A

modified two-layered, push–pull osmotic system was developed by using the basic

designs of various oral osmotic pumps, such as controlled porosity osmotic pump

(CPOP), elementary osmotic pump (EOP) and push–pull osmotic pump (PPOP).

Scanning electron microscopy of cellulose acetate coating membrane after dissolution

revealed that 25% (w/w) of sorbitol can be used as an optimized concentration of pore

forming agent with 25% (w/w) of plasticizer, which was kept constant. Formulations

were initially developed for theophylline and the release was optimized by using two

different soluble forms of theophylline with varying amount of hydrophilic polymer

mixture in upper layer and polyethylene oxide (expandable hydrogel) in lower layer.

Further, the release of salbutamol sulphate was optimized by keeping the drug in

upper or lower layer or both layers. In vitro release studies showed satisfactory

controlled release profiles of both drugs. The release profiles of both drug statistically

compared with respective marketed controlled release formulations. An optimized



system was selected to study the effect of concentration of pore forming agent and

orifice diameter on the release of both drugs.42

Sayed H et al., utilized ion exchange resin for the sustained release of

Salbutamol Sulphate. Effect of drug concentration and resin forms on the loading

capacity of resins and drug release patterns were tested. Results showed that release

rates were too high to get sustained release property. However on microencapsulation

with cabufucon A coatings showed sustained release rates.43

Bahnja et al., microencapsulated Salbutamol Sulphate using Eudragit RS 100.

Dissolution studies were performed on different size of microcapsules. Data analysis

showed that Higuchi Mechanism predominates over first and zero order release

mechanism. The diffusion co-efficient was decreases as the diameter of the

microcapsule decreases.44

Amperiadou et al., prepared Microcapsules of salbutamol sulphate with ethyl

cellulose were prepared using an emulsion-solvent evaporation technique and by the

use of two different stirrer types, propeller and magnet. Different amounts of drug

were added in order to obtain various drugs to polymer ratios. They evaluated

physical properties, loading efficiency and dissolution rate depended on the emulsion-

solvent evaporation technique and on the drug to polymer ratio using Tween-80 as a

dispersing agent. They further investigated the type of drug release mechanism taking

place, the dissolution data were plotted according to the four different kinetic models.

In vitro dissolution studies showed that first-order and square-root of time (Higuchi

model) release characteristics were exhibited.45

Bogin et al., investigated the use of a pulsed-released albuterol in ten patients

with nocturnal symptoms of asthma. In a randomized, double-blind, placebo-



controlled, crossover designed study; they tested the use of 8 mg of pulsed-release

albuterol sulphate (Proventil Repetabs) vs. placebo. The pulsed-release albuterol

significantly blunted the overnight drop in FEy,, improved peak flow readings in the

morning, and decreased subjective awakenings from sleep. They also concluded that

pulsed-released albuterol is an effective therapeutic option in patients with nocturnal

asthma.46

POLYMER DATA: 47, 48

Polymethacrylates:

Synonym: Eudragit; Methacrylic acid

Non-proprietary Names:

NF: Methacrylic acid copolymer; Polymeric methacrylates

Chemical Name:

Copolymers synthesized from dimethyl aminoethyl methacrylate and other

neutral methacrylic esters.

Functional category:

Film former and tablet binder.

Density: 12.5; 0.825g/cm3



Structural Formula:

CH2

C

O

OC

CH2

C

O

OC

CH2

C

O

OC

C

O

OC

CH2

R1R3R3 R1

R2 R2R4 R4

Type S and Type L

R1 = - CH3 R3 = -CH3

R2 = -H R4 = CH3

Molecular Weight: ≥100,000 and approximately 135,000

CAS Registry Number: None

Description:

Polymethacrylates are film coatings and matrix structures based on polymeric

methacrylates.They are synthetic cationic and anionic polymers of

dimethylaminoethylmethacrylates, methacrylic ratios.

Type L (easily soluble in intestinal fluid) is 50% methacrylic acid and Type S

(barely soluble in intestinal fluid) is 30% methacrylic acid; both are anionic polymers

of methacrylic acid and methacrylic acid esters in different ratios available as 12.5%

solution in isopropanol without plasticizer (L 12.5, S 12.5); and as 12.5% ready to use

solution in isopropanol with 1.25% dibutylphthalate as plasticizer (L 12.5p, S 12.5p);

colorless, with the characteristic odor of the solvent.



Solubility:

1g of Eudragit L100 0r Eudragit S100 dissolves in 7g methanol, ethanol, in

aqueous isopropyl alcohol and acetone, as well as in 1 N sodium hydroxide to give

clear to slightly cloudy solutions. Eudragit L100 and Eudragit S100 are practically

insoluble in ethyl acetate, methylene chloride, petroleum ether and water.

Viscosity:

Eudragit L100=18mm2/s

Eudragit S100= 29mm2/s

Acid value:

Eudragit L100=316mgKOH/gDS

Eudragit S 100=190mgKOH/gDS

Incompatibilities:

Incompatibilities occur with acid and/or alkaline conditions depending upon

which polymer is being used.

Stability and storage condition:

Dry powder forms appear to be stable at room temperature. Dispersions are

stable for about 1 yr after manufacturing and stored at room temperature in tight

containers protect against moisture.

Safety:

Acute toxicity studies have been performed in rats, rabbits and dogs. No toxic

effects were observed. Chronic toxicity studies were performed in rats over a period

of 3 months. No significant changes were found in the animal organs.



Application in pharmaceutical formulation or technology:

Eudragit S 100 and eudragit L100 are employed as film coating agents

resistant to gastric fluid with solubility above pH 6.0 and Ph 7.0 respectively, for

enteric coating of formulations.

Comments:

For spray coating, the lacquer solutions and dispersions must be thinned with

suitable solvents. Suitable solvents are ethanol, methanol, isopropyl alcohol, diethyl

ether, acetone, mehtylene chloride and water. Suitable plasticizer are glyceryl

triacetate, pthalic acid esters, polyethylene glycols, triacetin, dibutyl phthalate and

citric acid esters.

REVIEW OF WORK DONE ON POLYMERS:

Shivakumar et al., formulated oral controlled onset system of meloxicam that

match chronobiology. The multiparticulate system comprising of drug loaded non

pareil seed coated with Eudragit S-100 was designed utilized powder layering

technique in a conventional coating pan. In-vitro dissolution studies of the coated

pellets shows that pellet with lower coat weight (>10%) controlled the drug release

below 6 pH but fail to controlled the release at higher pH 7 followed by rapid release.

Since meloxicam is a drug which exhibits a pH dependent solubility, a coating weight

of 12% weight gain was sufficient to minimized the effectively target the drug to the

colon.49

Prasad et al., evaluated oral formulations of Gentamycin containing labrasol

in beagle dogs. The past work done on the gentamicin (GM) was a polarized water-

soluble compound having very poor intestinal membrane permeability resulting in



low oral bioavailability. Labrasol was found to improve the intestinal absorption of

GM in rats. In the present study, GM formulations containing labrasol were evaluated

in beagle dogs after filling into hydroxypropylmethyl cellulose (HPMC) capsules

wrapped with Eudragit L100 (Eud L) and Eudragit S100 (Eud S) films. The results of

the in vitro drug release studies could not differentiate between two kinds of enteric

capsules and among the three kinds of GM formulations. Oral administration of GM

solution at a dose of 50.0 mg per dog of GM and 0.60 ml per dog of labrasol has

resulted in Cmax values of 2.38 ± 0.50_g/ml and 2.30±0.42_g/ml with Eudragit L100

and Eudragit S100 capsules, respectively. The AUC values obtained were also higher

at 4.35±1.31_g h/ml and 5.34±0.95_g h/ml with Eud L and Eud S capsules,

respectively. Formulation of GM as a suspension in labrasol has resulted in the

decrease of Cmax values by two to four times and AUC values by >2.5 times

compared to the solution formulation. The above results indicate that solution

formulation was better over the suspension. An absorbent, synthetic sponge was used

to Absorb GM solution formulation and encapsulated with Eudragit L and Eudragit S

capsules. The Cmax and AUC values obtained with sponge formulation were higher

than those of suspension formulations but were lower than solution formulations.

There was no significant difference in the extent of GM absorption between Eudragit

L and Eudragit S capsules used for encapsulating GM formulations.50

Akhghari et al., studied stastical optimization of indomethacin pellets coated

with pH-dependent methacrylic polymers for possible colonic drug delivery. The

effect of two factors (ratio of Eudragit S100 and Eudragit L100 and the coating level)

on indomethacin release from pellets was studied in order to optimize coating

formulations for colonic delivery. Coating formulations were designed based on the

full factorial design. Two independent variables were the ratio of Eudragit S100:



Eudragit L100 (1:4, 1:1 and 1:0) and the level of coating (10%, 15% and 20%, w/w),

respectively. Polymers were coated onto the pellets containing 20% (w/w)

indomethacin, using a fluidized bed coating apparatus. Dissolution test was carried

out in media with different pH (1.2, 6.5, 6.8 and 7.2). The dissolution data revealed

that the level of coating and the ratio of polymers are very important to achieve

optimum formulation. Using responses and resulted statistical equations, optimum

formulation consisted of Eudragit S100:L100 in 4:1 ratio and the level of coating

(20%) was predicted.. The results of this study revealed that factorial design is a

suitable tool for optimization of coating formulations to achieve colon delivery. It was

shown that coating formulation consisted of Eudragit S100: Eudragit L100 in 4:1 ratio

at 20% coating level has potential for colonic delivery of indomethacin loaded pellets.

The optimized formulation produced dissolution profiles that were close to predicted

values.51

Sinha V.R. et al., studied the comparison of the usual entering coating

polymers viz. Eudragit, a cellulose acetate phthalate with shellac and ethyl cellulose,

as carriers for colon specific drug delivery. Lactose based indomethacin tablets were

prepared. These were coated with one of the coating polymers to a varying coat

thickness. Comparative dissolution data revealed that, of all the various polymers and

coat thicknesses used, a 3% (m/m) coat of shellac was most suitable for colonic drug

delivery. It retarded drug release by 3–4 h (the usual small intestinal transit time) in

simulated small intestinal fluid, where after a rapid drug release was observed. 52

Chan W.A. et al., coated the freeze-dried beads Eudragit S100 in an aqueous

phase using a fluidised-bed spray coater. The release profile of the drug was measured

in two solutions, both designed to mimic the environment in the human intestine.

These are a phosphate buffer, frequently used for this purpose and a physiological salt



solution (Hank’s pH 7.4) which resembles the pH and ion concentration in the fluid of

the small intestine. From the results obtained, it was found that the drug release rate in

the phosphate buffer was significantly faster than that in Hank’s solution. This effect

was even more pronounced when the coating thickness was increased. 53

Khan M.Z.I et al., studied Manipulation of drug release using Eudragit L100-

55 and Eudragit S100 combinations. Mesalazine containing tablets were coated using

various combinations of two methacrylic acid copolymers, Eudragit L100-55 and

Eudragit S100, by spraying from aqueous systems. The Eudragit L100-55–Eudragit

S100 combinations (w/w) studied were 1:0, 4:1, 3:2, 1:1, 2:3, 1:4, 1:5 and 0:1. The

coated tablets were tested in vitro for their suitability for pH dependent colon targeted

oral drug delivery. Dissolution studies performed on the mesalazine tablets further

confirmed that the release profiles of the drug could be manipulated by changing the

Eudragit L100-55 and Eudragit S100 ratios within the pH range of 5.5 to 7.0 in which

the individual polymers are sol respectively, and a coating formulation consisting of a

combination of the two copolymers can overcome the issue of high gastrointestinal

(GI) pH variability among individuals. The results also demonstrated that a

combination of Eudragit L100-55 and Eudragit S100 can be successfully used from

aqueous system to coat tablets for colon targeted delivery of drugs and the

formulation can be adjusted to deliver drug at any other desirable site of the intestinal

region of the GI tract on the basis of pH variability. For colon targeted delivery of

drugs the proposed combination system is superior to tablets coated with either

Eudragit L100-55 or Eudragit S100 alone. 54

Siepmann J. et al., studied physicochemical characterization and drug release

patterns of blends of enteric and GIT-insoluble polymers used for film coating. A

broad range of drug release patterns from coated pellets could be achieved by varying



the GIT-insoluble:enteric polymer blend ratio. With increasing relative amounts of

Eudragit L, the release rates in both media significantly increased. The increase at low

pH could be attributed to an increase in water uptake, as observed with thin films.

Interestingly, only partial Eudragit L leaching occurred in phosphate buffer pH 7.4

even at high enteric polymer contents, indicating that the GIT-insoluble polymer

effectively hindered the dissolution of the entrapped Eudragit L. At high pH, both

polymer leaching and polymer swelling contributed to the control of drug release. The

determined apparent drug diffusion coefficients take the two effects adequately into

account. 55

Shimono N. et al., studied Chitosan dispersed system for colon-specific drug

delivery. A chitosan dispersed system (CDS), which was composed of active

ingredient reservoir and the outer drug release regulating layer dispersing chitosan

powder in hydrophobic polymer, was newly developed for colon-specific drug

delivery. An aminoalkyl methacrylate copolymer RS (Eudragit† RS) was selected as a

hydrophobic polymer because it is hardly dissolved in acidic medium in which easily

dissolves chitosan. In order to obtain the bi-functional releasing characteristics, i.e.

time dependent and site specific, capsules containing the active ingredient (Drug

Capsules) were coated by the chitosan dispersed hydrophobic polymer, resulting in

CDS Capsules. It was found that the release rate could be controlled by changing the

thickness of the layer. 56

Gang et al., investigated Time- and pH-dependent colon-specific drug

delivery systems (CDDS) for orally administered diclofenac sodium (DS) and 5-

aminosalicylic acid (5-ASA), respectively. DS tablets and 5-ASA pellets were coated

by ethylcellulose (EC) and methacrylic acid copolymers (Eudragit® L100 and S100),

respectively. The in vitro release behavior of the DS coated tablets and 5-ASA coated



pellets were examined, and then in vivo absorption kinetics of DS coated tablets in

dogs were further studied. Two types of CDDS, prepared herein by means of the

regular coating technique, are able to achieve site-specific drug delivery targeting at

colon following oral administration, and provide a promising strategy to control drug

release targeting the desired lower gastrointestinal region.57

EXCIPIENTS DATA: 47

Starch:

Nonproprietary Names:

BP: Maize starch

USPNF: Corn starch

JP: Corn starch

Synonyms:

Amido; amidon; amilo; amylum

Chemical Name:

Starch

Empirical Formula and Molecular Weight: (C6H10O5)n and 50 000–160 000



Structural Formula:

Functional Category:

Glidant; tablet and capsule diluent; tablet and capsule disintegrant; tablet

binder

Description:

Starch occurs as an odorless and tasteless, fine, white-colored powder

comprising very small spherical or ovoid granules whose size and shape are

characteristic for each botanical variety.

Stability and Storage Conditions:

Dry, unheated starch is stable if protected from high humidity. When used as a

diluent or disintegrant in solid-dosage forms, starch is considered to be inert under

normal storage conditions. However, heated starch solutions or pastes are physically

unstable and are readily attacked by microorganisms to form a wide variety of starch

derivatives and modified starches that have unique physical properties.

Applications in Pharmaceutical Formulation or Technology:

Starch is used as an excipient primarily in oral solid-dosage formulations

where it is utilized as a binder, diluent, and disintegrant. In tablet formulations,

freshly prepared starch paste is used at a concentration of 5–25% w/w in tablet

granulations as a binder. Starch is one of the most commonly used tablet disintegrants

at concentrations of 3–15%W/w.



SODIUM STARCH GLYCOLATE:

Nonproprietary Names

NF: sodium starch glycolate

BP: sodium starch glycolate

Synonyms:

Sodium carboxy, methyl starch, explotab, primojel


USP: Tablet disintegrant

Others: Tablet and capsule disintegrant

Chemical names:

Starch carboxyl methyl ether, sodium salt

Description:

White to offwhite, odourless, tateless, free flowing powder microscopic: oval

or spherical granules, 30-100µm in diameter with some less spherical granules

ranging from 10-35 µm in diameter.

Typical properties:

Density: 1.5 gm/cm3

Bulk volume: 1.4 gm/cm3; sodium chloride: 5% (Max); viscosity [ 2% solution,

Brookfield : 25cps (max) ]



Solubility: at 2% W/V, it disperses in cold water and settles in the form of a highly

form a highly saturated layer. Insoluble in organic solvents.

Stability and storage conditions:

Stable, store in a well closed container to protect it from wide variations in

humidity and temperature that may cause caking. It has long shelf life stability.

Incompatibilities:

No citation found.

Application in pharmaceutical formulations or technology:

It is used in tablet/capsule as disintegrant (wet granulation or direct

compression) with concentration range 2-10 %.

MAGNESIUM STEARATE:

Non- proprietary Name:

NF: Magnesium Stearate

BP: Magnesium Stearate

Synonyms:

Metallic stearic, Magnesium salt.


Tablet and capsule lubricant



Chemical Names:

Octadecanoic acid; Magnesium salt; magnesium Stearate.

Structurla Formula:

Emperical Formula:

C36H70MgO4

Molecular Weight:

591.3

Description:

It is a fine, white, precipitated, or milled, impalpabale powder of low bulk

density, having a faint characteristic odour and taste. The powder is greasy to touch

and readily adheres to the skin.

Typical properties:

Solubility

Practically insoluble in ethanol, ethanol(95%), ether and water, slightly

soluble in benzene and warm ethanol(95%)




Stable, non-self polymerizable. Store in a cool, dry place in a well closed

container.

Incompatibilities:

Incompatible with strong acids, alkalies, iron salts and with strong oxidizing

material.

Applications in Pharmaceuticals Formulation or Technology:

Tablet and capsule lubricant, glidant and antiadherent in the concentration

range of 0.25-2.0%.

POVIDONE:


BP: Povidone

JP: Povidone

PhEur: Povidonum

USP: Povidone

Synonyms:

Kollidon; Plasdone

Chemical Name:

1- Ethenyl-2-pyrrolidinone homopolymer



Empirical Formula:

(C6H9NO) n

Molecular Weight:

50, 000

Structural Formula:


Disintegrant; dissolution aid; suspending agent; tablet binder

Description:

Povidone occurs as a fine, white to creamy-white colored, odorless or almost

odorless, hygroscopic powder. Povidones with K-values equal to or lower than 30 are

manufactured by Spray-drying and occur as spheres.

Method of Manufacture:

Povidone is manufactured by the Reppe process. Acetylene and formaldehyde

are reacted in the presence of a highly active copper acetylide catalyst to form

butynediol, which is hydrogenated to butanediol and then cyclodehydrogenated to

form butyrolactone. Pyrrolidone is produced by reacting butyrolactone with ammonia.

This is followed by a vinylation reaction in which pyrrolidone and acetylene are



reacted under pressure. The monomer, vinylpyrrolidone, is then polymerized in the

presence of a combination of catalysts to produce povidone.

Typical Properties:

Density

1.180 g/cm 3

Melting point

Softens at 150°C.

Solubility

Freely soluble in acids, chloroform, ethanol (95%), ketones, methanol, and

water; practically insoluble in ether, hydrocarbons, and mineral oil.

Incompatibilities:

Povidone is compatible in solution with a wide range of inorganic salts,

natural and synthetic resins, and other chemicals. It forms molecular adducts in

solution with sulfathiazole, sodium salicylate, salicylic acid, phenobarbital, tannin,

and other compounds.


Povidone darkens to some extent on heating at 150°C, with a reduction in

aqueous solubility. It is stable to a short cycle of heat exposure around 110–130°C;

steam sterilization of an aqueous solution does not alter its properties. Aqueous

solutions are susceptible to mold growth and consequently require the addition of

suitable preservatives. Povidone may be stored under ordinary conditions without



undergoing decomposition or degradation. However, since the powder is hygroscopic,

it should be stored in an airtight container in a cool, dry place.

Application in Pharmaceutical Formulation and Technology:

Although povidone is used in a variety of pharmaceutical formulations, it is

primarily used in solid-dosage forms. In tableting, povidone solutions are used as

binders in wet-granulation processes. Povidone is also added to powder blends in the

dry form and granulated in situ by the addition of water, alcohol, or hydroalcoholic

solutions. Povidone is used as a solubilizer in oral and parenteral formulations and has

been shown to enhance dissolution of poorly soluble drugs from solid-dosage forms.

Povidone solutions may also be used as coating agents.

Lactose:


Tablet and capsule diluent

Chemical Names:

4-O- β-D galactopyranosyl-α-D-glucocpyranose,

4-( β-D-galactosido)-D-glucose.

Emperical formula:

C22H22O11

Description:

White to off white crystalline particles or powder, odorless and slightly sweet

tasting.



Typical properties:

Solubility:

Freely soluble in water, practically insoluble in chloroform, ethanol and ether.


Under humid conditions (80%RH and above) mold growth may occur. It

should be stored in a well closed container in a cool, dry place.

Incompatibilities:

A millard type condensation reaction is likely to occur between lactose and

compounds with a primary amine group to form brown coloured products.

Applications in pharmaceutical formulation or technology:

As a filler or diluent in tablets (wet granulation and direct compression) and

capsules, in lyophilized products and infant fed formulas.

AEROSIL:


BP: Colloidal anhydrous silica

USPNF: Colloidal silicon dioxide

Synonyms:

Colloidal silica; fumed silica; light anhydrous silicic acid; silicic anhydride;

silicon dioxide fumed.



Chemical Name:

Silica

Empirical Formula and Molecular Weight:

SiO2 and 60.08


Adsorbent; anticaking agent; emulsion stabilizer; glidant; suspending agent;

tablet disintegrant; thermal stabilizer; viscosity-increasing agent.

Description:

Aerosil is submicroscopic fumed silica with a particle size of about 15 nm. It

is a light, loose, bluish-white-colored, odorless, tasteless, nongritty amorphous

powder.


Aerosil is hygroscopic but adsorbs large quantities of water without

Liquefying. Colloidal silicon dioxide powder should be stored in a well-closed

container.

Applications in Pharmaceutical Formulation or Technology:

Aerosil is also used to stabilize emulsions and as a thixotropic thickening and

suspending agent in gels and semisolid preparations. Colloidal silicon dioxide is also

used as a tablet disintegrant and as an adsorbent dispersing agent for liquids in

powders.



REVIEW OF WORK DONE ON PULSATILE DRUG DELIVERY SYSTEM:

Mastiholimath V.S. et al., formulated and investigated of an oral colon

specific, pulsatile device to achieve time and/or site specific release of theophylline,

based on chrono pharmaceutical consideration. The basic design consists of an

insoluble hard gelatin capsule body, filled with Eudragit microcapsules of

theophylline and sealed with a hydrogel plug. The entire device was enteric coated, so

that the variability in gastric emptying time can be over come and a colon-specific

release can be achieved. The theophylline microcapsules were prepared in four

batches, with Eudragit L-100 and S-100 (1:2) by varying drug to polymer ratio and

evaluated for the particle size, drug content and in vitro release profile and from the

obtained results; one better formulation was selected for further fabrication of

pulsatile capsule. Different hydrogel polymers were used as plugs, to maintain a

suitable lag period and it was found that the drug release was controlled by the

proportion of polymers used. In vitro release studies of pulsatile device revealed that,

increasing the hydrophilic polymer content resulted in delayed release of theophylline

from microcapsules. The gamma scintigraphic study pointed out the capability of the

system to release drug in lower parts of GIT after a programmed lag time for

nocturnal asthma. Programmable pulsatile, colon-specific release has been achieved

from a capsule device over a 2–24 h period, consistent with the demands of chrono

therapeutic drug delivery. 58

Janugade BU et al., developed an oral press-coated tablet by direct

compression and wet granulation methods to achieve the predetermined lag time. This

press-coated tablet containing montelukast sodium in the inner core was formulated

with an outer barrier layer by different compositions of hydrophobic polymer

ethylcellulose and hydrophilic polymer low-substituted hydroxypropylcellulose. The



effect of formulation composition on the barrier layer comprising both hydrophobic

and hydrophilic excipients on the lag time of drug release was investigated. It was

observed that lag time decreases with increasing concentration of low-substituted

hydroxypropylcellulose. Press coated tablets coated by dry mixing and by wet

granulation showed variations in lag time. As compared to dry mixed blend method

wet granulation method gives less lag time.59

Zhu et al., studied a programmed drug delivery from a novel system, which

contains a water-soluble cap, impermeable capsule body, and two multi-layered

tablets. Types of materials for the modulating barrier and its weight can significantly

affect the lag time. Sodium alginate and hydroxy-propyl methyl cellulose (HPMC E5)

were chose as the candidate modulating barrier material. Through adjusting ratio of

sodium alginate and lactose, lag time was controllable between the first two pulsatile

releases. Linear relationship was observed between the ratio and the lag time.

Through adjusting the ratio of HPMC E5/lactose, lag time between the second and the

third pulse can be successfully modulated. In further studies, drug release rate of the

second pulsatile dose can be improved by adding a separating layer between the third

and the modulating barrier layer in the three-layered tablet. To evaluate contribution

of bulking agent to drug release rate, lactose, sodium chloride, and effervescent blend

were investigated. No superiority was found using sodium chloride and effervescent

blend. However, lactose favored it. The results reveal that programmed drug delivery

to achieve pulsatile drug release for three times daily can be obtained from these

tablets in capsule system by systemic formulation approach.60

Efentakis et al., investigated a novel oral pulsatile drug delivery system based

on a core-in-cup dry coated tablet, where the core tablet surrounded on the bottom and

circumference wall with inactive material, is proposed. The system consists of three



different parts, a core tablet, containing the active ingredient, an impermeable outer

shell, and a top cover layer-barrier of a soluble polymer. The core contained either

diclofenac sodium or ketoprofen as model drugs. The impermeable coating cup

consisted of cellulose acetate propionate and the top cover layer of hydrophilic

swellable materials, such as polyethylene oxide, sodium alginate or sodium

carboxymethyl cellulose. The effect of the core, the polymer characteristics and

quantity at the top cover layer, on the lag time and drug release was investigated. The

results show that the system release of the drug after a certain lag time generally due

to the erosion of the top cover layer. The quantity of the material, its characteristics

and the drug solubility was found to modify lag time and drug release.61

Gohel et al., studied a programmed drug delivery from hard gelatin capsules

containing a hydrophilic plug (HPMC or guar gum). The significance of factors such

as type of plug (powder or tablet), plug thickness and the formulation of fill material

on the release pattern of diltiazem HCl, a model drug, was investigated. A linear

relationship was observed between weight of HPMC K15M and log % drug released

at 4 h from the capsules containing the plug in powder form. In order to accelerate the

drug release after a lag time of 4 h, addition of an effervescent blend, NaHCO3 and

citric acid, in the capsules was found to be essential. The plugs of HPMC in tablet

form, with or without water soluble adjuvant (NaCl or lactose) were used for

obtaining immediate drug release after the lag time. The results indicate that the drug

release was also dependant on the type of swellable hydrophilic agent (HPMC or guar

gum) and molecular weight of HPMC (K15M or 20 cPs). The results reveal that

programmed drug delivery can be obtained from hard gelatin capsules by systemic

formulation approach.63



Ying-huan Li et al., developed a multifunctional an multiple unit system,

which contains versatile mini tablet in a hard gelatin capsule, as Rapid- release Mini-

tablets (RMTs), Sustained-release Mini-tablets (SMTs), Pulsetile Mini-tablets (PMTs)

and Delayed onset Sustained-release Mini tablets (DSMTs), each with various lag

time of release.63

Gazzaniga et al., evaluated an oral system (ChronotopicE) designed to

achieve time and/or site-specific release. The system consists in a drug-containing

core, coated by a hydrophilic swellable polymer. For this study, tablets prepared cores

containing antipyrine as the model drug and both the retarding and enteric coatings

were applied in fluid bed. The in vivo testing performed on healthy volunteers,

determine the antipyrine salivary concentration. The obtained results showed the

capability of the system in delaying drug release for a programmable period of time

and the possibility of exploiting such delay to attain colon-targeted delivery according

to a time-dependent approach.64

Ying et al., developed theophylline pulsatile release tablets consisting of fast

swelling core with water insoluble ethyl cellulose. Effect of coating material, amount

of the plasticizer, subcoating, the type of the disintegrant, and coating level on drug

release profile were investigated. They concluded that ethyl cellulose was the best

candidate polymer for pulsatile release tablets. Rupture time increased with increasing

the amount of the plasticizer, but 15% plasticizer provided the best release profiles.

The lag time of tablets containing different disintegrants increased in the following

order: Ac-Di-sl < sodium starch glycolate < lowsubstituted hydroxypropyl cellulose <

crospovidone. A mathematical model was presented to predict the lag time prior to

rupture and it correlate with experimental data.65



Yang et al., designed dry-coated tablet with optimal lag time to simulate the

dosing time of drug administration according to the physiological needs. The

formulations containing different weight ratios of coarse/fine particles of EC powders

or 167.5 µm EC powder/ excipients in the upper layer of the outer shell to influence

the release behavior of diclofenac sodium from dry-coated tablet were also explored.

The results indicate that diclofenac sodium released from all the dry-coated tablets

exhibited an initial lag period, followed by a stage of rapid drug release. Its lag time

might be freely modulated, depending on the amount of EC powder added. Once

different excipients were respectively incorporated into the upper layer of the outer

shell, different release mechanisms were observed as follows: time-controlled

explosion for Explotab, disruption for Avicel and spray-dried lactose, erosion for

dibasic calcium phosphate anhydrate, and sigmoidal profile for hydroxypropyl

methylcellulose.66

Bodmeier et al., developed and evaluated a rupturable pulsatile drug delivery

system based on soft gelatin capsules with or without a swelling layer and an external

water-insoluble but -permeable polymer coating, which released the drug after a lag

time. Croscarmellose sodium (Ac-Di-Sol) as swelling agent and ethyl cellulose (EC)

and cellulose acetate propionate (CAPr), rupturing agent and therefore more complete

drug release than the flexible polymer coating, Eudragit RS. The lag time of the

release system increased with higher polymer coating levels with an increasing

amount of the intermediate swelling layer. Soft gelatin capsule-based systems showed

shorter lag times compared to hard gelatin capsules because of the higher

hardness/filling state of the soft gelatin capsules.67

Bodmeier et al., studied variable affecting the performance based drug

delivery system with pulsatile drug release they filled capsules with lactose, MCC,



Aerosil, and then coated with swellable layer of Ac-di-sol and ruptureable layer of

ethyl cellulose. They evaluate disintegrating time of swelling layer, lag time for

release of content form capsules, weight uniformity of coating. They concluded that

capsule to capsule uniformity in both coating layers, which affect the lag time and

optimize by deceasing batch size, increasing pan speed. Full filled hard gelatin

capsules had short lag time than half filled hard gelatin capsules. Lag time was stable

over 240 days period in stability study. 68

Krishnaiah YSR et al., reviewed γ scintigraphy: an imaging technique for

non invasive in- vivo evaluation of oral dosage forms. These article reviews the radio

nuclitides used in γ scintigraphy, the various imagining device and their

applications.69

Ishibashi T et al., performed scintigraphic evaluation of a new capsule type

colon specific drug delivery system in healthy volunteers. The human data validates

the designed concept behind the release mechanisms, in that capsule disintegration

and hence the drug release, did not start until 5 hours after gastric emptying,

irrespective of whether the product was administered to fated or fed subjects.70

Chapter 4 Material and Methodology


MATERIAL AND METHODOLOGY

MATERIAL USED:

Table No.: 9. List of Material used

Sr No. Material Manufacturer

1 Salbutamol Sulphate Jayco chemical industries

2 Eudragit S-100 Molychem, Mumbai.

3 Eudragit L-100 Molychem, Mumbai.

4 Hydrochloric acid S. D. Finechem Ltd., Mumbai

5 Isopropyl alcohol Ranchem Ltd.

6 Acetone Ranchem Ltd.

7 Magnesium stearate Vasa Pharmachem P. Ltd., Ahmedabad

8 Mannitol Shandong Tianli Pharmaceutical Co Ltd.

9 Lactose monohydrate B.P. S.D. Fine Chem Ltd, Mumbai

10 Micro crystalline cellulose Gujarat Microwax Pvt. Ltd.

11 Polyvinyl pyrrolidone NaNHang Industrial Co. Ltd.

12 Sodium starch glycolate FMC Biopolymers

13 Potassium dihydrogen phosphate

Ranbaxy Fine Chemicals Ltd., Navi Mumbai

14 Sodium hydroxide pellets Ranbaxy Fine Chemicals Ltd., Navi Mumbai

15 Aerosil Gujarat Ambuja Export Ltd.

16 Talcum powder Gujarat Microwax Pvt. Ltd.



EQUIPMENT OR INSTRUMENTS USED:

Table No.: 10. List of equipments and instruments used

Sr No. List of Instrument Manufacturer

1 Coating machine Avon Engineering Works, Mumbai.

2 Double rotary tablet compression machine (CMB4-35 station) Cadmach Machinery Co Ltd., Ahmedabad

3 Digital weighing balance (BT 124 S) (120 g)

Sartorius Biotech (India) Pvt. Ltd., Bangalore

4 Digital weighing balance (6 Kg) Elder Instruments Pvt. Ltd.

5 Dissolution automated sampling system Labindia Instruments Pvt. Ltd., Thane

6 Dissolution test system (8000) Labindia Instruments Pvt. Ltd., Thane

7 Fluidized bed dryer Avon Engineering Works, Mumbai.

8 Friability test apparatus EF-2 (USP) Electrolab, Mumbai.

9 FTIR (8400 S) Shimadzu Corporation, Kyoto, Japan

10 Hardness tester Ketan Dial Hardness Tester

11 Hot air oven Ambika Eng. Works, Ahmedabad

12 Hot plate (EHP 200 TC) Electron Equipment Co

13 Moisture analyzer (HB43-S) Mettler Toledo, Switzerland.

14 Octagonal blender Avon Engineering Works, Mumbai.

15 pH meter Labindia Instruments Pvt. Ltd., Thane

16 Rapid mixer granulator Avon Engineering Works, Mumbai.

17 Scanning electron microscope Philips XL 30 ESEM TMP + EDAX



18 Stability chamber (106 Model) EIE Instruments Pvt. Ltd.

19 Tap density tester ((USP) (ETD-1020) Electrolab, Mumabai.

20 Thickness gauge Absolute Digimatic

21 UV spectrophotometer (1800) Shimadzu Corporation, Kyoto, Japan

22 Vibratory sifter Avon Engineering Works, Mumbai.

Introduction

Nocturnal asthma, a condition prevalent in two-thirds of the asthmatics, is

defined as a variable night time exacerbation of the underlying asthma condition

associated with increase in symptoms and need for the medication, increased airway

responsiveness and worsening of lung function. Symptoms typically occur between

midnight and 8 a.m., especially around 4 a.m. It is inconvenient to take the medication

at midnight.

Thus, present study attempts to design and evaluate a chronomodulated drug

delivery system of salbutamol sulphate, a selective β2 receptor agonist for the

treatment of nocturnal asthma using a novel technique “Tablet in Capsule” device.

The system can be used for daily programmed drug delivery and eliminate mid-night

medication, thereby increasing patient compliance.

Preformulation Studies: 71

Preformulation testing is the first step in the rationale development of dosage

forms of a drug substance. It can be defined as an investigation of physical and

chemical properties of a drug substance alone and when combined with excipients.

The overall objective of preformulation testing is to generate information useful to the



formulator in developing stable and bioavailable dosage forms, which can be mass-

produced.

Following preformulation studies were performed…

PREFORMULATION STUDIES OF PURE DRUG:

Identification of pure drug:

Identification of Salbutamol Sulphate was carried out by Infrared Absorption

Spectroscopy.

Melting point determination:

Melting point of Salbutamol Sulphate was determined by Open capillary

Method.

Bulk Density:

a) Loose Bulk Density: Accurately weighed 5 g of drug (M), which was previously

passed through 20 # sieve, was transferred in 50 ml graduated cylinder. The powder in

the cylinder was leveled without compacting, and the unsettled apparent volume (V0)

was noted. The apparent bulk density (gm/ml) was calculated by the following

formula

Bulk density = Weight of powder / Bulk volume …………….. (1)

b) Tapped bulk density: Accurately weighed 5g of drug, which was previously

passed through 20 # sieve, was transferred in 50 ml graduated cylinder. Then the

cylinder containing the sample was mechanically tapped by raising the cylinder and

allowing it to drop under its own weight using mechanically tapped density tester that

provides a fixed drop of 14± 2 mm at a nominal rate of 300 drops per minute. The

cylinder was tapped 500 times initially and the tapped volume (V1) was measured to

the nearest graduated units, the tapping was repeated an additional 750 times and the

tapped volume (V2) was measured to the nearest graduated units. If the difference



between two volumes is less than 2% then the final volume (V2). The tapped bulk

density in gm/ml was calculated by the following formula:

Tapped Density = Weight of powder / Tapped volume ………….. (2)

5.3.4 Carr’s Index

The Compressibility Index of the powder blend was determined by Carr’s

compressibility index. It is a simple test to evaluate the BD and TD of a powder and

the rate at which it is packed down. The formula for Carr’s Index is as below:

Carr’s Index (%) = [(TD-BD) x100]/TD ………….. (3)

5.3.5 Hausner’s Ratio

The Hausner’s ratio is a number that is correlated to the flowability of a powder

or granular material.

Hausner’s Ratio = TD / BD ……………. (4)

Table No. 11: Effect of Carr’s Index and Hausner’s Ratio on flow property

Carr’s Index (%) Flow Character Hausner’s Ratio

< 10 Excellent 1.00–1.11

11–15 Good 1.12–1.18

16–20 Fair 1.19–1.25

21–25 Passable 1.26–1.34

26–31 Poor 1.35–1.45

32–37 Very poor 1.46–1.59

>38 Very, very poor >1.60

Angle of repose

The angle of repose of API powder was determined by the funnel method. The

accurately weight powder blend were taken in the funnel. The height of the funnel

was adjusted in such a way the tip of the funnel just touched the apex of the powder

blend. The powder blend was allowed to flow through the funnel freely on to the



surface. The diameter of the powder cone was measured and angle of repose was

calculated using the following equation.

tan θθθθ = h/r …………….(5)

Where, h and r are the height and radius of the powder cone respectively.

Table No. 12: Effect of Angle of repose (ф) on Flow property

Angle of Repose (Ф) Type of Flow

< 20 Excellent

20-30 Good

30-34 Passable

>35 Very poor

Particle Size Analysis

Particle size of drug was determined by Malvern particle size analyzer.

D (10, 13.42), D (50, 55.32), D (90, 149.21).

Drug - excipient Compatibility Studies: 73

A successful formulation of a stable and effective solid dosage form depends

on careful selection of excipients that are added to facilitate administration, promote

the consistent release and bioavailability of the drug and protect it from degradation.

If the excipients are new and not been used in formulation containing the active

substance, the compatibility studies are of paramount importance.

Compatibility of salbutamol sulphate with the respective polymers that is

Eudragit L100 and S100, individual excipients and physical mixture of main

formulation was established by Infrared Absorption Spectral Analysis (FTIR). Any

changes in the chemical composition after combining with the excipients were

investigated with IR spectral analysis.



Table No. 13: Drug excipients compatibility study

Drug + Excipient Ratio

25ºCº±2°C /

60%RH± 5 %

RH

40ºC±2°C /

75%RH± 5 %

RH

Drug 1 4 Weeks 4 Weeks

Drug : Lactose 1:1 4 Weeks 4 Weeks

Drug : Starch 1:1 4 Weeks 4 Weeks

Drug: P.V.P. K-30 1:0.25 4 Weeks 4 Weeks

Drug : Mg Stearate 1:1 4 Weeks 4 Weeks

Drug : Aerosil 1:1 4 Weeks 4 Weeks

Drug+ Lactose + starch Proportional

Mixture 4 Weeks 4 Weeks

Drug + Lactose + Starch +

P.V.P. K-30 + Mg. Stearate+

Aerosil

Proportional

Mixture 4 Weeks 4 Weeks

Drug : Eudragit S100 1:0.25 4 Weeks 4 Weeks

Drug : Eudragit L100 1:0.25 4 Weeks 4 Weeks

Analytical Method:

Standard Calibration curve of Salbutamol Sulphate:

Calibration curve of Salbutamol Sulphate was taken in four different media

i.e. in pH 1.2, 5.5, 6.8, and pH 7.4 phosphate buffer media.

Ø Preparation of solution:

Preparation of 0.1 N HCl solution:

0.1M HCl was prepared by diluting 8.5 ml of concentrated Hydrochloric acid

to 1000 ml distilled water.

Preparation of 6.8 pH phosphate buffer solution:

27.22g of monobasic potassium phosphate was weighed and diluted up to

1000 ml to get stock solution of monobasic potassium phosphate. 8g Sodium



hydroxide was weighed and diluted up to 1000ml to get 0.2M sodium hydroxide

solution. 50 ml of the monobasic potassium phosphate solution was taken from the

stock solution in a 200-mL volumetric flask and 22.4 ml of sodium hydroxide solution

from stock solution of 0.2M sodium hydroxide solution was added and then water was

used to make up the volume.



1000 ml to get stock solution of monobasic potassium phosphate. 8g Sodium


solution.50 ml of the monobasic potassium phosphate solution from stock solution

was taken in a 200-mL volumetric flask and 22.4 ml of sodium hydroxide solution

from stock solution of 0.2M sodium hydroxide solution was added to it. The

remaining volume was made up with water.



1000 ml to get stock solution of monobasic potassium phosphate. 8g of Sodium


solution.

50 ml of the monobasic potassium phosphate solution from stock solution was

taken in a 200-mL volumetric flask, and 39.1 ml of sodium hydroxide solution from

stock solution of 0.2M sodium hydroxide solution was added, the remaining volume

was made up with water.

Standard (Stock) solution:

The stock solution was prepared by adding 10 mg of drug in 100ml with

respective buffer. From this solution serial dilution were performed to prepare 10-100



µg/ml of drug concentration were made using respective buffer solutions. All samples

were analyzed by UV spectrophotometer by measuring the absorbance at 276 nm.

Calculation of First pulse Dose

The pharmacokinetic parameters of Salbutamol Sulphate were utilized for the

calculation of theoretical drug release profile for pulsatile release dosage form. The

immediate release part of salbutamol sulphate was calculated using following

equation.

F

VdCssFPD

×= (1)

Where Css is steady-state plasma concentration, Vd is volume of distribution, and F is

fractional bioavailability. The total dose of salbutmaol sulphate required for pulsatile

release release profile was calculated using following equation.

(2)

Where, t is time up to which controlled release is required and t½ is half-life drug

TTaabbllee NNoo::----1144 PPhhaarrmmaaccookkiinneettiicc ppaarraammeetteerrss ooff SSaallbbuuttaammooll SSuullpphhaattee

Bioavailability

Steady State concentration (µµµµg/ml)

Volume of distribution (lit/kg)

Half life (hour)

Clearance (ml/min)

85% 9.5-16 0.21 2 – 2.5 1.2

Preparation of core tablets:

The core tablets (average weight 70 mg) of salbutamol sulphate were prepared

by wet granulation technique using PVP-K30 and Starch solution as binders. The

composition of core tablets is given in Table 5.1 and Table 5.2. Lactose was used as a

diluent and SSG (2mg) was added to obtain a fast disintegrating tablet.

Dose = FPD {1 + (0.693 x t/t1/2)}



Table: No. 15: Composition of first pulse tablets of salbutamol sulphate

Ingredients Quantity (mg/tablet)

Salbutamol sulphate 2.4

Lactose 35.4

Starch (intragranular) 25.2

Starch (binder solution) 3.5

Pvpk-30 (binder solution) 0.5

Magnesium stearate 1

Aerosil 1

Sodium Starch Glycolate 1

Total weight 70

Table: No. 16: Composition of second pulse tablets of salbutamol sulphate

Ingredients Quantity (mg/tablet)

Salbutamol sulphate 4.8

Lactose 33

Starch (intragranular) 25.2

Starch (binder solution) 3.5

PVPK-30 (binder solution) 0.5

Magnesium stearate 1

Aerosil 1

Sodium Starch Glycolate 2

Total weight 70

Procedure:

1. Starch paste containing PVPK-30 was used as a binder solution.

2. PVPK-30 was dissolved in required quantity of water.

3. Starch paste was prepared by dispersing starch in boiling water.

4. Solution obtained in step-2 was added in starch paste and mixed thoroughly.



5. Salbutamol, lactose, and starch were passed through the 40 # sieve and thoroughly

mixed then granulated using PVP-K30 and starch solution as the binder.

6. The granules so obtained were dried at 60 °C for 2 hr in the oven.

7. Dried granules were passed through 20 # sieve and the fines were separated using

40 # sieve to obtain 20-40 # granules.

8. SSG and Aerosil were passed through 40 # sieve and mixed with dried granules.

9. These granules were lubricated with magnesium stearate. The lubricated granules

were compressed into tablets using Minipress Tablet Compression Machine.

(Rimek minipress-11 MT, Karnavati Engineering Ltd., Ahmedabad, India).

10. Weight variation, hardness, friability, and disintegration test were performed for

the core tablets.

Evaluation of core tablets:

Precompressional Studies: 71

Angle of repose:

The angle of repose of blend was determined by the funnel method. The

accurately weight blend was taken in the funnel. The height of the funnel was

adjusted in such a way that the tip of the funnel just touched the apex of the blend.

The blend was allowed to flow through the funnel freely on to the surface. The

diameter of the powder cone was measured and angle of repose was calculated using

the following equation.

tan θθθθ = h/r

Where, h and r are the height and radius of the powder cone.



Bulk density and Tapped Density:

Both loose bulk density (LBD) and tapped bulk density (TBD) were

determined. A quantity of 2 gm of blend from each formula, previously shaken to

break any agglomerates formed, was introduced in to 10 ml measuring cylinder. After

that the initial volume was noted and the cylinder was allowed to fall under its own

weight on to a hard surface from the height of 2.5 cm at second intervals. Tapping

was continued until no further change in volume was noted. LBD and TDB were

calculated using the following equations.

LBD= Weight of the Granules/Untapped Volume of the packing

TBD=Weight of the Granules/Tapped Volume of the packing

Compressibility Index:

The Compressibility Index of the blend was determined by Carr’s

compressibility index. It is a simple test to evaluate the LBD and TBD of a powder

and the rate at which it packed down. The formula for Carr’s Index is as below:

Carr’s Index (%) = [(TBD-LBD) x100]/TBD

Hausner’s Ratio:

Hausner’s Ratio was determined by Following Equation:

Hausner’s Ratio = Tapped Density / Bulk Density

Post-compressional Studies:

Shape and appearance: 71

Tablets were examined under a lens for the shape of the tablet, and color was

observed by keeping the tablets in light.



Uniformity of thickness: 71

Thickness and diameter of both core tablets and coated tablets were measured

using a calibrated dial calipers. Three tablets of each formulation were picked

randomly and dimensions determined. It is expressed in mm and standard deviation

was also calculated.

Weight variation test: 71

To study weight variation 20 tablets of each pulse dose formulation were

weighed separately using a Sartorius electronic balance and the test was performed

according to the official method.

Hardness test: 71

Hardness indicates the ability of a tablet to withstand mechanical shocks while

handling. Hardness of core tablets was determined using a validated dial type

hardness tester. It is expressed in kg/cm2. Three tablets were randomly picked from

each batch and analyzed for hardness. The mean and standard deviation were also

calculated.

Friability test: 71

For each pulse dose tablet formulation, the friability of 6 tablets was

determined using the Roche friabilator (Camp-bell Electronics, Mumbai, India).

Friability can be determined by following equation:

Tablet dosage forms assay: 73

Tablet containing 4.8 mg of drug was dissolved in 100 ml of simulated gastric

fluid (SGF) pH 1.2. The drug was allowed to dissolve in the solvent, the solution was

filtered, and 1ml of filtrate was suitably diluted with simulated gastric fluid pH 1.2

and analyzed spectrophotometrically at 276 nm. The amount of Salbutamol sulphate



was estimated by using standard calibration curve of the drug. Drug content studies

were carried out in triplicate for each batch of formulation.

In-vitro Disintegration test for first pulse tablet: 73

Tablet disintegration was carried by placing one tablet in each tube of the

basket and top portion of the each tube was closed with disc and run the apparatus

containing pH 1.2 SGF (simulated gastric fluid) maintained at 37±20C as the

immersion liquid. The assembly was raised and lowered between 30 cycles per

minute. The time taken for complete disintegration of the tablet with no palpable mass

remaining in the apparatus was measured and recorded. The experiment was carried

out in triplicate.

Preparation of coating solution:

Coating solution was made using different ratios of material like Eudragit

L100 and Eudragit S100.. Required quantity of polymers were dissolved in mixture of

solvents and stirred on magnetic stirrer to get homogeneous coating solution. Diethyl

Phthalate was added in above solution as plasticizer (1%w/v). After getting

homogeneous coating solution; coating was done on tablets.

Parameter Value

Inlet Air Temperature 40-450C

Exhaust Temperature 30-350C

Bed Temperature 380C

Atomization (bar) 2

Spray rate (gm/min) 10

Pan RPM 10



Percentage weight gain calculated by following equation1:

Percentage Weight Gain = [(Wt-Wo)/Wo]*100

Where,

Wt = Weight of table after coating

Wo = initial weight of tablet

Trials of Coating with Eudragit S100:

Coating was done using Eudragit S100. Three formulations were formulated

by varying the weight gain on tablet upon coating. The coated tablets were evaluated

for In-vitro drug release profile.

Table No. 17: Composition of Coating solution

In-vitro drug release studies of tablets coated with Eudragit S100: 74

Drug release studies of coated tablets were carried out using a USP XXIII

dissolution rate test apparatus (Apparatus 2, 100 rpm, 37 °C) for 2 hr in 0.1 M HCl

(900 ml) as the average gastric emptying time is about 2 hr. Then the dissolution

medium was replaced with pH-5.5 phosphate buffer (900 ml) for 1hr and then in pH

6.8 phosphate buffer (900 ml) for 2 hr as the average small intestinal transit time is

about 3 hr. After 5 hr, the dissolution medium was replaced with pH 7.4 phosphate

buffer (900 ml) and tested for drug release up to complete drug release. At the end of

the time period 10 ml of the samples were taken and analyzed for Salbutamol

Ingredients F1 F2 F3

Eudragit S100 25 25 25

Diethyl Pthalate 3 3 3

Acetone 250 250 250

Isopropyl Alcohol 250 250 250

% coating 8 10 12

Quantity in gms



Sulphate content. A 10 ml Volume of fresh and filtered dissolution medium was

added to make the Volume after each sample withdrawal. Sample was analyzed using

UV spectrophotometer at 276 nm.

Trials of coating with Combination of Eudragit L100 and Eudragit S100

Coating was done using Eudragit S100 and Eudragit L100 in combination.

Three formulations were formulated by varying the weight gain on tablet upon

coating. The coated tablets were evaluated for In-vitro drug release profile.

Table No. 18: Composition of coating solution

In-vitro drug release studies of coated tablet of Salbutamol Sulphate with

Eudragit L100 and Eudragit S100: 74








Ingredients F4 F5 F6

Eudragit L100 15 15 15

Eudragit S100 15 15 15

Diethyl Phthalate 3 3 3

Acetone 250 250 250

Isopropyl Alcohol 250 250 250

% coating 8 10 12

Quantity in gms




Sulphate content. A 10 ml Volume of fresh and filtered dissolution medium was

added to make the Volume after each sample withdrawal. Sample was analyzed using

UV spectrophotometer at 276 nm.

Optimization by using 32 full factorial designs: 51

In the present study, a 32 full factorial design was employed to study the effect

of independent variables, i.e. Ratio of Eudragit L100: Eudragit S100 (X1) and %

Coating (X2) on dependent variables, % drug release at Q5 & Q6. A statistical model

(see equation) incorporating interactive and polynomial terms was utilized to evaluate

the responses.

Y = b0 + b1X1+b2X2 + b12X1X2 + b11X12 + b22X2

2

Where, Y is the dependent variables, b0 is the arithmetic mean response of the

nine runs, and b1 is the estimated coefficient for the factor X1. The main effects (X1

and X2) represent the average result of changing one factor at a time from its low to

high value. The interaction terms (X1X2) show how the response changes when two

factors are simultaneously changed. The polynomial terms (X12 and X2

2) are included

to investigate non-linearity. The results indicate that all the dependent variables are

strongly dependent on the selected independent variables as they show a wide

variation among the nine batches (F7 to F15). The fitted equations (Full model)

relating the responses, i.e., % drug release at Q5 & Q6 are shown in Table 5.6. The

polynomial equation can be used to draw conclusions after considering the magnitude

of coefficient and the mathematical sign it carries, i.e. positive or negative. The high

values of correlation coefficient (Table No:--17) for the dependent variables indicate a

good fit. The equation may be used to obtain estimate of the response because small

error of variance was noticed in the replicates.



Table No. 19: 32 Full Factorial Design Layout

Batch No. Independent variables

X1 X2

F7 -1 -1

F8 -1 0

F9 -1 1

F10 0 -1

F11 0 0

F12 0 1

F13 1 -1

F14 1 0

F15 1 1

Concentration of Independent variable

Level Ratio of Eudragit L100: S100 % Coating

-1 1:1 12

0 1:2 15

1 1:3 18

Table No. 20: Formula of Factorial batches

Ingredients F7 F8 F9 F10 F11 F12 F13 F14 F15

Eudragit L100 15 15 15 15 15 15 15 15 15

Eudragit S100 15 15 15 30 30 30 45 45 45

Diethyl Phthalate 3 3 3 3 3 3 3 3 3

Acetone 250 250 250 250 250 250 250 250 250

Isopropyl Alcohol 250 250 250 250 250 250 250 250 250

% coating 12 15 18 12 15 18 12 15 18

Quantity in gms



In-vitro release studies of factorial batches: 74









Sulphate content. A 10 ml volume of fresh and filtered dissolution medium was added

to make the volume after each sample withdrawal. Sample was analyzed using UV

spectrophotometer at 276 nm.

Preparation of “Tablet in Capsule” device:

Tablet in capsule device was formed by filling size “0” capsule with two tablets, one

of each pulse, i.e., one for first pulse release and other for second pulse release.

Evaluation of “Tablet in Capsule” device:

In-vitro drug release studies of device: 74

Conducting in vitro drug release studies assessed the “Tablet in capsule”

device of Salbutamol to release the drug in two pulses with immediate first pulse as

loading dose and remaining second pulse after the required lag time. Drug release

studies were carried out using a USP XXIII dissolution rate test apparatus (Apparatus

2, 100 rpm, 37 °C) for 2 hr in 0.1 M HCl (900 ml) as the average gastric emptying

time is about 2 hr. Then the dissolution medium was replaced with pH-5.5 phosphate

buffer (900 ml) for 1hr and then in pH 6.8 phosphate buffer (900 ml) for 2 hr as the

average small intestinal transit time is about 3 hr. After 5 hr, the dissolution medium



was replaced with pH 7.4 phosphate buffer (900 ml) and tested for drug release up to

complete drug release. At the end of the time period 10 ml of the samples were taken

and analyzed for salbutamol sulphate content. A 10 ml volume of fresh and filtered

dissolution medium was added to make the volume after each sample withdrawal.

Sample was analyzed using UV spectrophotometer at 276 nm.

Effect of paddle speed on the lag time and release characteristics: 40

Devices were subjected to in-vitro dissolution study at different paddle speed

(50, 75 and 100 rpm). Other conditions remained as described above. Effect of paddle

speed on release behavior and lag time was observed and analyzed using a

spectrophotrometer10

In-vivo Gamma-Scintigraphic Studies: 58, 69, 70

Rabbit was used for scintigraphy study. The radio labeled capsule was

administered and then rabbit was immobilized and seated comfortably in the rabbit

cage. The rabbit had small sealed source of 0.06MBq 99mT firmly taped to the skin at

the position of its shoulder joint and hip joint on the same side, which was depicted as

an anatomical reference marker. The source was also used for repositioning when the

images were taken. Scintiscans were taken after 30 min, 2 hrs, 4 hrs and after 5.5 hrs.

Stability study of “Tablet in Capsule” device: 75

Reproduced large scale batch F 16 was placed for stability study at 40˚C/75%

RH for 1 month. Sample was collected at every 10 days interval and evaluated for In-

vitro drug release study in 0.1N HCl, pH 5.5, pH 6.8 and pH 7.4 Phosphate buffer

solutions, USP- II paddle apparatus, 50rpm.



Plate No.: 1. Core Tablets

Plate No.: 2. Coated Tablets

Plate No.: 3. “Tablet-in-Capsule Device”

Chapter – 5 Results and Discussion


RESULTS AND DISCUSSION

PREFORMULATION STUDIES OF PURE DRUG:

Identification of Drug:

The IR spectrum of pure drug (Figure No.10) was found to be similar to the

reference standard IR spectrum of Salbutamol Sulphate given in British

pharmacopoeia.

Melting point determination

Melting point of salbutamol sulphate was found to be in the range of 158°C to

160°C with decomposition as reported in pharmacopoeia, thus indicating purity of the

drug sample.

Other preformulation studies

Data obtained from the preformulation studies of the pure drug are shown in

Table No.21 from the results it can be concluded that inherent flow properties of the

pure drug is poor. So, it requires modifying its flow properties in order to obtain the

tablets having uniform weight.

Drug - excipient Compatibility Studies:

Compatibility studies of pure drug Salbutamol sulphate with polymers and

other excipients were carried out prior to the preparation of tablets. I.R spectra of pure

drug salbutamol sulphate, and that of with polymers and other ingredients were

obtained, which are shown in figure No.11 to 20. All the characteristic peaks of

Salbutamol sulphate were present in spectra thus indicating compatibility between

drug and excipients. It shows that there was no significant change in the chemical

integrity of the drug. The results of compatibility study are shown in Table No.22.



Analytical Method

Table No.23 to Table No.26 shows the absorbance reading of salbutamol

sulphate standard solution containing 10 – 100 µg/ml of drug in pH 1.2, phosphate

buffer pH 5.5, pH 6.8 and pH 7.4 at the maximum wavelength of 276 nm.

Figure No.21 to Figure No.24 shows the standard calibration curve for

salbutamol sulphate with slope, intercept and regression co-efficient. The calculations

of drug contents and in-vitro drug release study are based on this standard curve.

Calculation of First pulse Dose

From the equation the dose of first pulse tablet was found to be 2.4 mg and

total dose was found to be 6 mg of salbutamol sulphate.

EVALUATION OF CORE TABLETS:

Precompressional parameters:

Granules of all the formulations were subjected for various precompressional

evaluation such as angle of repose, bulk and tapped density, compressibility index and

Hausner’s Ratio.

Results of all the pre-compression parameters performed on the granules for

batch T1 and T2 are shown in Table No.27.

The result of angle of repose was found to be 28.36 and 27.36 for batch T1

and T2 respectively. Compressibility index was found to be 13.84 and 13.95 for batch

T1 and T2. The results of Hausner’s ratios were found to be 1.15 and 1.13

respectively for batch T1 and T2. The results of angle of repose (<30) indicate good

flow properties of the powder based on Table No.12. This was further supported by

lower compressibility index values. Generally, compressibility index values up to

15% results in good to excellent flow properties.



Post-compressional parameters:

All the tablet formulations were subjected for evaluation according to various

official specifications and other parameters. Shape, thickness, hardness, friability,

weight variation, tablet dosage form assay and in vitro disintegration time.

Shape and appearance:

Formulations prepared were randomly picked from each batch examined

under lens for shape and in presence of light for color. Tablets showed standard

concave surfaces with circular shape. Tablets were white in color.

Uniformity of thickness:

Thickness of the tablets was measured using calibrated dial calipers by picking

three tablets randomly from all the batches. The results of thickness for tablets are

shown in Table No. 28. The mean thickness of tablets (n=3) of batch T1 and T2 were

2.8±0.1mm. The standard deviation values indicated that all the formulations were

within the range.

Weight variation test:

The weight variation of both the formulations is shown in Table No.28. All the

tablets passed the weight variation test, i.e., average percentage weight variation was

found within the pharmacopoeial limits of ±10%.

Hardness test:

Hardness or crushing strength of the tablets of both the formulation was found

to be 3.0±0.28 for batch T1 and 3.5±0.5 for batch T2. The mean hardness test results

are tabulated in Table No.28.



The low standard deviation values indicated that the hardness of all the

formulations was almost uniform and the tablets possess good mechanical strength

with sufficient hardness.

Friability test:

Friability values for batch T1 and T2 were found 0.56 and 0.42% respectively.

The obtained results were found to be well within the approved range (<1%) in all the

designed formulations. That indicated tablets possess good mechanical strength. The

results are tabulated in Table No.28.

Tablet dosage form assay:

Tablet dosage form assay for both the formulations was carried out. Three

replicates of each test were carried out. The average value and standard deviations

were calculated. In assay of both the formulation, the tablets of batch T1 and T2

showed 98.17±0.33% and 98.56±0.30%drug content respectively. The results are

tabulated in Table No.28.

The results were within the limit (90% to 110%) specified in pharmacopoeia. The

cumulative percentage drug released from each tablet in the in-vitro release studies

was based on the average drug content present in the tablet.

In-vitro disintegration time of first pulse tablet:

In-vitro disintegration time for T1formulations was found to be 2.5±0.25

minutes. The formulation showed the in–vitro DT within the limit specified in

pharmacopoeia.



Trials of Coating with Eudragit S100:

The In-vitro release studies were carried out using – XXIII dissolution

assembly. Cumulative % drug release after 7 hrs was found to be 79.14%, 75.29% and

79.16% for formulation F1, F2 and F3 respectively. The release before completion of

lag time was found to be 36.49%, 30.16% and 25.74% for formulation F1, F2 and F3

respectively. The results clearly indicate that, tablet coated with Eudragit S100 alone

failed to achieve a lag time, required burst effect after completion of lag time and

therefore release profile was not desirable. So further study was planned by using

some combination of Eudragit S100 and Eudragit L100 in different concentration.

The results obtained in the in-vitro drug release study are tabulated in Table

No. 29. The cumulative percentage release of salbutamol sulphate as a function of

time for all the formulations are shown in Figure No.25.

Trials of coating with Combination of Eudragit L100 and Eudragit S100:

The In-vitro release studies were carried out using – XXIII dissolution

assembly. Cumulative % drug release after 7 hrs was found to be 82.62%, 81.16% and

84.15% for formulation F4, F5 and F6 respectively. The release before completion of

lag time was found to be 36.49%, 37.19% and 33.33% for formulation F1, F2 and F3

respectively.

The results obtained in the In-vitro drug release study are tabulated in Table

No.30. The cumulative percentage of salbutamol sulpahte released as a function of

time for all the formulations are shown in Figure No.26.

Coating of tablets with Eudragit L100: Eudragit S100 in combination showed

the lag time of nearly 5 hrs before burst effect. From the result, concluded that the

combination of Eudragit L100: Eudragit S100 can be successfully utilized to create



desire release profile similar to the targeted release profile in future study. On the

basis of the preliminary trials in the present investigation a 32 full factorial design was

applied to study the effect of independent variables, i.e. ratio of Eudragit L100:

Eudragit S100 (X1) and % coating of tablets (X2) on dependent variables like, % drug

release at Q5 & Q6.

Effect of Independent variables on dependent variables by 32 full factorial design

of Salbutamol sulphate for Pulsatile Release:

The factorial batches were prepared by using independent variables like ratio

of Eudragit S100: Eudragit L100 and % coating and to check its effect on dependent

variables like Q5 and Q6 which are tabulated in Table No.31.

Factorial batches of Salbutamol Sulphate for pulsatile release were evaluated

for the In-vitro drug release and by its regression analysis. The results obtained in the

in-vitro drug release study are tabulated in Table No.32. The cumulative percentage of

salbutamol sulpahte released for all the formulations (F7 to F15) are shown in Figure

No.27 to Figure No.29. The effect of the individual polymer and combination of the

polymers was studied. The summary of regression analysis for pulsatile release tablet

shown in Table No.33.

The result of regression analysis showed that all the co-efficient bear a

different sign, which indicate that both the Independent variables shows significant

effect on dependent variables.

Drug release at 5th hr (Q5) gives correlation co-efficient 0.97736071. The P

value for variable X1 and X2 were 0.002 and 0.0380 respectively (P<0.05), it indicate

that both variables shows significant effect on drug release and combination co-



efficient was negative but the P value was not less than 0.05, which indicates that

combination of independent variable does not show significant effect at 5th hr.

Q5 =22.28 - 0.0816X1 – 0.0285X2 – 0.00767X1X2 – 0.0491X12 – 0.0069X2

2 …… (9)

Drug release at 6th hrs (Q6) has less linearity compared to Q5 with correlation

co-efficient 0.76426095. The P value for variable X1 and X2 were 0.56 and 0.18

(P<0.05), it indicate that both variables does not show significant effect on the drug

release at 6h, also the combination co-efficient was negative but the P value was not

less than 0.05 so, we say that the combination of independent variable does not give

the significant effect at 6h release. The co-efficient of X1 and X2 were negative

indicating that when concentration of both the variable increases than drug release

decreases.

Q6 = 77.99 – 0.0107X1 – 0.0282X2 – 0.0073X1X2 – 0.0604X12 – 0.0372X2

2 …. (10)

The Q5 and Q6 for all the batches F7 to F15 varied from 33.33 % to 12.79% and

87.77% to 71% with correlation coefficient as 0.9773 and 0.7643 respectively.

Formulation F15 showed the least drug release at Q5 with only 12% drug release but it

failed to completely release the drug at second pulse with only 71% drug release.

Formulation F11 showed 17.23% drug release at Q5 but it showed maximum release

at Q6 with 87.77% drug release and hence on this basis it was considered as best

formulation.

The response surface plot was plotted against X variable, Y variable and Z

variable. X variable taken as ratio of Eudragit S100:L100, Y variable taken as %

coating and Z variable considered as drug release at 5th and 6th hour as shown in Plot

No. 1 and Plot No. 2.



Preparation of “Tablet in Capsule” device:

Each part of the novel system can be prepared separately and fabricated in

the final step. Whole dosage form “Tablets in capsule” was formulated by filling a

first pulse tablet and a second pulse tablets in an empty “0” size capsule shell and

evaluated for the in-vitro drug release, effect of paddle speed on lag time and release

characteristic, stability, and in-vivo Gamma scintigraphic studies.

Evaluation of “Tablet in Capsule” device:

In-vitro drug release studies of device:

The best promising formulation F16 was selected for the study of in vitro drug

release profile. The 100% drug released from the first pulse tablet within 15 minutes

and 87.77% drug released after a completion of lag time. Drug released before lag

completion of lag time was found to be 17.23%.

The results obtained in the In-vitro drug release study are tabulated in Table

No.34. The cumulative percentage of salbutamol sulpahte released from “Tablet-in –

Capsule” device as a function of time for all the formulations F16 is shown in Figure

No.30.

The drug release profile showed sigmoidal release pattern which is considered

to be an ideal for the pulsatile drug delivery system.

Effect of paddle speed on the lag time and release characteristics:

Drug release from the device, need to be independent of agitational intensity

of the release media. In order to verify effect of agitational intensity, the dissolution

studies were conducted at three different rpm (75, 100, and 150). Formulation F16

was considered for this study. Dissolution studies were carried out using USP- Type II



dissolution apparatus and results are given in the Table No. 35 and release profile of

F16 is plotted as shown in the Figure No. 31. The cumulative percentages of drug

released from the device were found to be 92.74, 94.15 and 95.74% respectively for

50, 75, and 100 rpm. A perusal to Figure 30 showed there was no drastic change in

release profiles.

No significant difference in drug release was observed for release study in

under different rotational speed. This shows an advantage for the system, as it predicts

no change in the performance of the system as increased gastric motility.

In-vivo Gamma-Scintigraphic Studies

Gamma scintigraphy, a noninvasive technique, is a reliable tool for evaluating

the In-vivo performance of dosage form in the different regions of GIT. Plat no. 4 to 7

showes the scinti scans taken on the rabbit during gamma scintigraphic studies.

Stability study of “Tablet in Capsule” device:

The stability study was carried out at 40°C/75% RH for formulation F16 up to

30 days. At every 10 days time interval, the devices were analyzed for drug content

uniformity and In-vitro drug release. The results of accelerated stability study are

tabulated in Table No.36 and release profile of F16 after stability study is plotted as

shown in the Figure No.32.

The results of accelerated stability study showed that there was no change in

the formulation after one month. In-vitro drug release study showed that after 10, 20

and 30 days; values obtained were 95.62%, 94.84% and 93.62% respectively. The

drug release throughout 7 hours obtained within range of targeted release profile.

After 1 month accelerated stability study the assay result was stable.

Chapter – 5 R

esult and Discussion

Departm

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aceutics, KLE University, B

elgaum 102

Figure No. 10: FT-IR Spectra of pure Salbutamol sulphate

750900105012001350150016501800195021002400270030003300360039001/cm

0

10

20

30

40

50

60

70

80

90

%T

3481.6

33464.2

73446.9

13377.4

7

3275.2

4

3144.0

73117.0

73097.7

83080.4

22983.9

82947.3

32933.8

3

2777.5

9

2690.7

92650.2

8

2559.6

2

2457.3

92422.6

72349.3

82316.5

8

1635.6

91616.4

0

1508.3

81489.1

01471.7

41446.6

61437.0

21394.5

81361.7

91330.9

31311.6

4

1246.0

6

1203.6

2

1139.9

7 1091.7

51062.8

11043.5

2 1030.0

2

979.8

7 947.0

8916.2

2

881.5

0

840.9

9

790.8

4771.5

5748.4

1 732.9

7713.6

9675.1

1

SALBUTAMOL SULPHATE PDDS

Chapter – 5 R


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Table No. 21: Result of Preformulation study of Salbutamol Sulphate

Drug Angle of Repose (0)

Loose Bulk Density (g/ml)

Tapped Bulk Density (g/ml)

Carr’s Index (%) Hausner’s Ratio

Drug 27.34 0.375 0.516 30 1.37

Chapter – 5 R


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Figure No. 11: FT-IR Spectra of Salbutamol sulphate + Eudragit S 100

7509001050120013501500 16501800195021002400270030003300360039001/cm

0

10

20

30

40

50

60

70

80

90

100

110

120

%T

3269.453257.883248.23

3136.363120.93

3103.57

2982.052953.12

2775.66

2729.372690.792669.572654.142559.62

2482.47

2457.39

2360.95

2349.38

1732.13

1616.40

1506.461489.101467.88

1438.94

1394.58

1377.22

1361.791330.93

1311.64

1246.061195.911132.25

1114.89

1085.961080.17

1060.88

1031.95

1012.66

977.94

947.08916.22

881.50

839.06

792.77

767.69 748.41

731.05

SALBUTAMOL+EUDRAGIT S-100

Chapter – 5 R


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elgaum 105

Figure No. 12: FT-IR Spectra of Salbutamol sulphate + Eudragit L-100

75090010501200135015001650180019502100240027003000 3300360039001/cm

0

10

20

30

40

50

60

70

80

90

100

110

120

130

%T

3149.863144.073126.71

3101.64

2983.982972.402953.12

2783.372775.66

2721.652692.722667.642656.07

2582.77

2559.62

2482.47

2457.39

2360.95

2322.37

1732.131716.70

1616.40

1506.46

1489.101465.951438.94

1394.58

1377.22

1361.791330.93

1309.71

1244.131193.981132.251114.89

1085.96

1060.88

1031.95

1012.66

977.94

947.08916.22

881.50

839.06

790.84

773.48 748.41

731.05 719.47

SALBUTAMOL+EUDRAGIT L-100

Chapter – 5 R


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elgaum 106

750900105012001350150016501800195021002400270030003300360039001/cm

0

7.5

15

22.5

30

37.5

45

52.5

60

67.5

75

82.5

90

%T

3566.5

0

3466.2

03446.9

13377.4

73335.0

33257.8

83163.3

63153.7

23140.2

23126.7

13068.8

53024.4

82972.4

02933.8

32889.4

62862.4

62781.4

42727.4

42694.6

52688.8

62559.6

22482.4

72457.3

92422.6

72362.8

82341.6

62333.9

4

1635.6

91616.4

0

1506.4

6

1456.3

01438.9

4

1394.5

8

1361.7

91330.9

31311.6

4

1244.1

3

1197.8

3

1134.1

81112.9

61084.0

31058.9

61030.0

21010.7

3989.5

2

939.3

6916.2

2

862.2

1839.0

6

771.5

5

721.4

0

STARCH PDDS

Figure No. 13: FT-IR Spectra of Salbutamol sulphate + Starch

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Figure No. 14: FT-IR Spectra of Salbutamol sulphate + Lactose

750900105012001350150016501800195021002400270030003300360039001/cm

0

10

20

30

40

50

60

70

80

90

100

%T

3524.0

63479.7

03466.2

0

3271.3

8

3171.0

83151.7

93117.0

73088.1

42980.1

22933.8

32901.0

42872.1

02781.4

42729.3

72694.6

52673.4

32586.6

32559.6

22482.4

72457.3

92422.6

72359.0

22341.6

62330.0

9 1616.4

0

1506.4

6 1489.1

01467.8

81438.9

4

1394.5

81377.2

21361.7

91338.6

41309.7

1

1259.5

61244.1

3

1203.6

2 1166.9

71134.1

81114.8

91085.9

61060.8

81031.9

5

987.5

9977.9

4947.0

8916.2

2898.8

6877.6

4839.0

6

771.5

5748.4

1

711.7

6

669.3

2

LACTOSE PDDS

Chapter – 5 R


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Figure No. 15: FT-IR Spectra of Salbutamol sulphate + PVP K30

750900105012001350150016501800195021002400270030003300360039001/cm

0

10

20

30

40

50

60

70

80

90

100

%T

3481.6

3

3250.1

63153.7

23138.2

93099.7

13086.2

12982.0

52970.4

82949.2

62933.8

32781.4

42723.5

82690.7

9

2559.6

2

2457.3

92420.7

42357.0

9 2341.6

6

1616.4

0

1506.4

6 1489.1

01467.8

81438.9

4

1394.5

81377.2

21361.7

91330.9

31311.6

4

1244.1

3

1205.5

5

1132.2

51114.8

91085.9

6 1060.8

81035.8

11010.7

3977.9

4

947.0

8916.2

2

839.0

6

771.5

5748.4

1

P.V.P.K-30 PDDS

Chapter – 5 R


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Figure No. 16: FT-IR Spectra of Salbutamol sulphate + Magnesium stearate

750900 10501200 13501500 16501800 195021002400270030003300360039001/cm

0

10

20

30

40

50

60

70

80

90

100 %T

3524.063479.703466.20

3271.383171.083151.79

3117.07

3088.14

2980.122933.83

2901.042872.10

2781.44

2729.372694.652673.43

2586.63

2559.62

2482.472457.39

2422.67

2359.02

2341.66

2330.09

1616.40

1506.46

1489.10

1467.881438.94

1394.581377.22

1361.791338.64

1309.71

1259.56

1244.131203.62

1166.97

1134.181114.89

1085.96

1060.88

1031.95

987.59 977.94

947.08

916.22

898.86877.64

839.06771.55

748.41

711.76 669.32

MG. STEARATE

Chapter – 5 R


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elgaum 110

Figure No. 17: FT-IR Spectra of Salbutamol sulphate + Aerosil

750900105012001350150016501800195021002400270030003300360039001/cm

0

10

20

30

40

50

60

70

80

90

100

110

120

%T

3273.3

1

3151.7

93144.0

73124.7

93084.2

82983.9

82974.3

32949.2

62933.8

32787.2

32777.5

92723.5

82692.7

22584.7

02559.6

2

2457.3

92420.7

42362.8

82341.6

6

1616.4

0

1508.3

81489.1

01465.9

51438.9

41394.5

81379.1

51361.7

91330.9

31309.7

1

1238.3

4

1195.9

1

1114.8

91087.8

91062.8

11033.8

8

977.9

4

947.0

8916.2

2

839.0

6

794.7

0773.4

8748.4

1

AEROSIL PDDS

Chapter – 5 R


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elgaum 111

Figure No. 18: FT-IR Spectra of Salbutamol sulphate + S.S.G.

750900105012001350150016501800195021002400270030003300360039001/cm

0

7.5

15

22.5

30

37.5

45

52.5

60

67.5

75

82.5

%T

3466.2

03446.9

1

3271.3

83244.3

83149.8

63132.5

03120.9

33099.7

13078.4

92982.0

52947.3

32933.8

32783.3

72725.5

12692.7

2 2559.6

2 2457.3

9

2351.3

02322.3

7

1749.4

91734.0

61716.7

0

1616.4

0

1506.4

61489.1

01471.7

41438.9

4

1394.5

81377.2

21361.7

91330.9

31311.6

4

1244.1

3

1199.7

6

1132.2

51112.9

61085.9

6 1060.8

81030.0

21010.7

3977.9

4

947.0

8916.2

2

881.5

0

839.0

6

794.7

0771.5

5746.4

8729.1

2717.5

4

S.S.G PDDS

Chapter – 5 R


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elgaum 112

Figure No. 19: FT-IR Spectra of Salbutamol sulphate + Lactose + Starch

750900105012001350150016501800195021002400270030003300360039001/cm

0

10

20

30

40

50

60

70

80

90

%T

3566.5

03524.0

63466.2

03444.9

83383.2

6

3273.3

13257.8

83180.7

23149.8

63080.4

22978.1

92933.8

32901.0

42885.6

02872.1

02862.4

62783.3

72733.2

22694.6

52671.5

02584.7

02559.6

22482.4

72457.3

92422.6

72362.8

82341.6

6

1616.4

0

1506.4

61489.1

01456.3

01437.0

2

1394.5

8

1361.7

91332.8

61307.7

8

1259.5

61244.1

3

1201.6

9

1134.1

81112.9

61085.9

61074.3

91060.8

81033.8

81004.9

5989.5

2945.1

5916.2

2898.8

6875.7

1839.0

6

771.5

5750.3

3 705.9

7

669.3

2

LACTO-STARCH-SAL PDDS

Chapter – 5 R


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elgaum 113

Figure No. 20: FT-IR Spectra of whole formulation

750900105012001350150016501800195021002400270030003300360039001/cm

0

7.5

15

22.5

30

37.5

45

52.5

60

67.5

75

%T3626.2

93566.5

03524.0

63479.7

03466.2

03446.9

13427.6

23379.4

03331.1

83273.3

13259.8

13161.4

33149.8

63140.2

23128.6

43117.0

73088.1

42980.1

22933.8

32901.0

42879.8

22862.4

62775.6

62692.7

22675.3

62582.7

72559.6

22482.4

72455.4

62420.7

42360.9

52343.5

92146.8

42088.9

82040.7

62017.6

11992.5

31942.3

81923.0

91909.5

91869.0

81844.0

11791.9

31749.4

91734.0

61716.7

01681.9

8

1635.6

91616.4

0

1489.1

01456.3

01438.9

4

1394.5

8

1361.7

91329.0

01311.6

4

1244.1

3

1203.6

2

1132.2

51114.8

91085.9

61060.8

81035.8

11010.7

3989.5

2

945.1

5916.2

2898.8

6875.7

1868.0

0839.0

6

771.5

5746.4

8723.3

3713.6

9

659.6

8

MIX SAMPLE PDDS

Chapter – 5 R


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elgaum 114

Drug + Excipient Initial Observation After 1 month at 40ºC±2°C / 75%RH± 5 %

RH Drug (Salbutamol sulphate) A white to offwhite powder Compatible

Drug + Lactose A white to offwhite powder Compatible

Drug + Starch A white to offwhite powder Compatible

Drug + P.V.P. K-30 A white to offwhite powder Compatible

Drug + Mg. Stearate A white to offwhite powder Compatible

Drug + Aerosil A white to offwhite powder Compatible

Drug + Eudragit S100 A white to offwhite powder Compatible

Drug + Eudragit L100 A white to offwhite powder Compatible

Drug + Mix sample A white to offwhite powder Compatible

Table No. 22: Result of Drug excipients compatibility study After 1 month at 40ºC±2°C / 75%RH± 5 % RH

Chapter – 5 R

esults and Discussion

Departm

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elgaum

115 Table N

o. 23: Standard calibration curve of Salbutamol Sulphate in 0.1 N

HCL

Sr.no Concentration (ug/m

l) Absorbance

Average

Absorbance

1

2 3

1

10 0.055

0.056 0.055

0.055 2

20 0.11

0.11 0.112

0.11 3

30 0.175

0.175 0.177

0.175 4

40 0.23

0.232 0.24

0.232 5

50 0.29

0.29 0.29

0.29 6

60 0.35

0.35 0.35

0.35 7

70 0.41

0.42 0.42

0.42 8

80 0.47

0.47 0.48

0.47 9

90 0.525

0.527 0.526

0.526 10

100 0.586

0.586 0.586

0.586 Absorbance = 0.0059x - 0.0035

Correlation co-efficient R

2 = 0.9999

Figure N

o. 21: Standard calibration curve of Salbutamol Sulphate in 0.1 N

HCL

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Table N

o. 24: Standard calibration curve of salbutmaol sulphate in pH

5.5

Phosphate buffer


l) Absorbance

Average

Absorbance

1

2 3

1 10

0.094 0.094

0.095 0.094

2 20

0.17 0.17

0.17 0.17

3 30

0.243 0.244

0.244 0.244

4 40

0.308 0.309

0.308 0.308

5 50

0.379 0.379

0.379 0.379

6 60

0.448 0.448

0.449 0.448

7 70

0.499 0.499

0.500 0.499

8 80

0.548 0.548

0.549 0.548

9 90

0.578 0.578

0.578 0.578

10 100

0.63 0.64

0.63 0.630

Absorbance = 0.0062x + 0.0326

Regression co-efficient R

2 = 0.9943

Figure N


5.5 Phosphate buffer

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Table N

o. 25: Standard calibration curve of Salbutamol Sulphate in pH

6.8 phosphate buffer


l) Absorbance

Average

Absorbance

1

2 3

1

10 0.075

0.075 0.076

0.075 2

20 0.142

0.143 0.143

00143 3

30 0.208

0.208 0.209

0.208 4

40 0.276

0.276 0.277

0.276 5

50 0.326

0.326 0.327

0.326 6

60 0.395

0.394 0.395

0.395 7

70 0.465

0.465 0.465

0.465 8

80 0.516

0.517 0.516

0.516 9

90 0.576

0.576 0.576

0.576 10

100 0.642

0.642 0.6436

0.642 Absorbance = 0.0063x + 0.0124


2 = 0.9989

Figure N

o. 23: Standard calibration curve of Salbutamol Sulphate in pH

6.8 phosphate buffer

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Table N


7.4

Phosphate buffer

Figure N


7.4 Phosphate buffer


l) Absorbance

Average

Absorbance

1

2 3

1

10 0.065

0.065 0.066

0.065 2

20 0.121

0.121 0.120

0.121 3

30 0.183

0.183 0.183

0.183 4

40 0.24

0.25 0.24

0.24 5

50 0.308

0.309 0.308

0.308 6

60 0.362

0.362 0.362

0.362 7

70 0.424

0.424 0.425

0.424 8

80 0.483

0.483 0.484

0.483 9

90 0.548

0.549 0.548

0.548 10

100 0.604

0.604 0.605

0.604 Absorbance = 0.006x + 0.0015


2 = 0.9998

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Table N

o. 27: Pre-com

pression evaluation of the prepared granules

Batch

T1*

T2*

Angle of R

epose 28.36

27.36

Bulk D

ensity (gm/cc)

0.59 0.62

Tapped density (gm

/cc) 0.78

0.74

Carr’s Index

13.84 13.95

Hausner’s R

atio 1.15

1.12

T1* :- First pulse tablet

T2* :- Second Pulse T

ablet

Table N

o. 28: Post-com

pression evaluation of the prepared Tablets

Batch

T1*

T2*

Uniform

ity of thickness (mm)

2.8 ± 0.1 2.8 ± 0.1

Weight variation (m

g) 70.15 ± 0.64

70.60 ± 0.64

Hardness

3.0 ± 0.28 3.5 ± 0.5

Friability (%

) 0.56

0.42

% Drug C

ontent 98.17 ± 0.33

98.56±0.30

Disintegration T

ime

2.5 ± 0.25 4.5 ± 0.25

T1* :- First pulse tablet

T2* :- Second Pulse T

ablet

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120 Table N

o. 29: In-vitro drug release study of tablets coated with E

udragit S100

Dissolution medium

Time (H

rs)

% Cum

ulative Drug R

elease

F1

F2

F3

0.1 N HCL

1 5.23

0 0

2

12.42 8.19

5.26

5.5 pH buffer

3 19.43

14.84 11.84

6.8 pH buffer

4 27.36

22.16 19.63

5

36.49 30.16

25.74

7.4 PH buffer

6 68.23

62.16 60.36

7

79.14 75.29

79.16

0

10

20

30

40

50

60

70

80

90

01

23

45

67

8

Time

(hrs.)

% C.D.R.

F1

F2

F3

Figure N

o. 25: In-vitro drug release profile of tablets coated with E

udragit S100

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Table N

o. 30: In-vitro drug release study of tablets coated with E

udragit L100:

Eudragit S100

Dissolution medium

Time (hrs)

% Cum

ulative Drug R

elease

F4

F5

F6

0.1 N HCL

1 3.16

0 0

2

14.16 9.46

8.75

5.5 pH buffer

3 22.74

17.64 16.62

6.8 pH buffer

4 28.75

28.16 25.84

5

36.49 37.19

33.33

7.4 PH buffer

6 82.62

82.16 84.15

7

91.52 84.17

82.16

0

10

20

30

40

50

60

70

80

90

10

0

01

23

45

67

8

Time (hrs.)

% C.D.R.

F4F5

F6

Figure N

o. 26: In-vitro drug release profile of tablets coated with E

udragit L100:

Eudragit S100

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Table N

o. 31: Effect of Independent variable on dependent variable by 3

2 full factorial design of Salbutam

ol Sulphate for Pulsatile R

elease

Batch N

o. Independent variable

Dependent variable

X1

X2

Q5

Q6

F6

-1 -1

33.33%

85.55%

F8

-1 0

32.16%

82.40%

F9

-1 +1

31.00%

75.65%

F10

0 -1

24.34%

79.12%

F11

0 0

17.23%

87.77%

F12

0 +1

15.46%

79.16%

F13

+1 -1

18.41%

71.42%

F14

+1 0

16.08%

68.23%

F15

+1 +1

12.79%

66.49%

Independent

Variables

Real V

alue

Low

(-1) Medium

(0) High (+1)

Eudragit S100:

Eudragit L100 (X

1 ) 1:1

1:2 1:3

% Coating (X

2 ) 12

15 18

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Table No. 32: In-vitro drug release study of factorial batches

Dissolution medium Time (hrs) % Cumulative Drug Release

F7 F8 F9 F10 F11 F12 F13 F14 F15

0 0 0 0 0 0 0 0 0 0

0.1 N HCL 1 0 0 0 0 0 0 0 0 0

2 8.75 7.98 5.16 2.35 0 0 0 0 0

5.5 pH buffer 3 16.62 14.13 11.47 10.156 8.74 7.62 6.67 4.54 3.13

6.8 pH buffer 4 25.84 24.1 21.03 18.46 12.86 11.98 11 8.58 5.89

5 33.33 32.16 30.74 24.34 17.23 15.46 18.41 16.08 12.79

7.4 PH buffer 6 85.55 82.4 75.65 79.12 87.77 79.16 71.42 68.23 66.49

7 92.41 91.63 93.75 92.17 95.09 97.43 94.13 91.45 88.114

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0 10 20 30 40 50 60 70 80 90

100

01

23

45

67

8Tim

e (hrs)

% C.D.R.

F7F8

F9

Figure N

o. 27: In-vitro drug release profile of factorial batches F7 to F

9

0

20

40

60

80

100

120

01

23

45

67

8Tim

e (hrs)

%C.D.R.

F10F11

F12

Figure N


12

Chapter – 5 R


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0

10

20

30

40

50

60

70

80

90

10

0

01

23

45

67

8Tim

e (hrs)

%C.D.R.

F13F14

F15

Figure N


15

Chapter – 5 R


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Table N

o. 33: Summary of regression analysis of Salbutam

ol Sulphate tablet for Pulsatile release

Coefficients

b0

b1

b2

b12

b11

b22

R2

Q5

22.28 -0.0816

-0.0285 -0.0076

0.0491 0.0069

0.97736071

Q6

77.99 0.0107

-0.0282 -0.0073

-0.0604 -0.0372

0.76426095

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Plot N

o. 1: surface response curve at 5th hour

Design-Expert® Software

Q5Design points above predicted valueDesign points below predicted value33.33

12.79

X1 = A: Ratio of L:SX2 = B: %

coating

-1.00 -0.50

0.00 0.50

1.00

-1.00

-0.50

0.00

0.50

1.00

10

15

20

25

30

35

Q 5

A: Ratio of L:S B: %

coating

Chapter – 5 R


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128

.

Plot N

o. 2: surface response curve at 6th hour.

Design-Expert® Software

Q6Design points above predicted valueDesign points below predicted value87.77

66.49

X1 = A: Ratio of L:SX2 = B: %

coating

-1.00

-0.50

0.00

0.50

1.00

-1.00

-0.50

0.00

0.50

1.00

65

70

75

80

85

90

Q 6

A: Ratio of L:S B: %

coating

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Table N

o. 34: In-vitro drug release study of ‘Tablet in C

apsule’ device

Dissolution M

edium

Time (hrs)

% Cum

ulative Drug R

elease

First P

ulse Second P

ulse

0

0 0

0.1 N HCL

1 100

0

2

100 0

5.5 pH buffer

3 -

8.74

6.8 pH buffer

4 -

12.86

5

- 17.23

7.4 PH buffer

6 -

87.77

7

- 95.09

-20 0

20

40

60

80

10

0

12

0

01

23

45

67

8

Time (hrs)

% C.D.R.

Series1Series2

Figure N

o. 30: In-vitro drug release profile of ‘Tablet in C

apsule’ device

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Table N


apsule’ device with


Dissolution M

edium

Time (hrs)

Initial % Cum

ulative Drug R

elease

50 RPM

75 RPM

100RPM

0

0 0

0 0

0.1 N HCL

1 33

33 33

33

2 33

33 33

33 5.5 pH

buffer 3

41.74 40.54

41.36 41.74

6.8 pH buffer

4 45.86

43.16 43.95

45.86

5 50.23

49.32 51.49

50.23 7.4 P

H buffer

6 87.77

85.74 86.66

87.77

7 95.74

92.74 94.15

95.74

0

20

40

60

80

10

0

12

0

01

23

45

67

8Tim

e (hrs)

% C.D.R.

Initial50 RPM

75 RPM100RPM

Figure N


apsule’ device with


Chapter – 5 R


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131 In-vivo G

amma-Scintigraphic Studies

Plate N

o. 4: Image taken after 30 m

in

Plate N

o. 5: Image taken after 2 hrs

Chapter – 5 R


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Plate N

o. 6: Image taken after 4 hrs

Plate N

o. 7: Image taken after 5.5 hrs

Chapter – 5 R


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Table N


apsule’ device for stability testing

Dissolution M

edium

Time

(hrs) Initial

% Cum

ulative Drug R

elease

10 days 20 days

30 days

0

0 0

0 0

0.1 N HCL

1 33

33 33

33

2

33 33

33 33

5.5 pH buffer

3 41.74

41.41 40.36

40.1

6.8 pH buffer

4 45.86

45.12 44.92

44.12

5

50.23 50.23

49.56 48.22

7.4 PH buffer

6 87.77

87.77 86.12

85.75

7

95.74 95.62

94.84 93.62

0 20 40 60 80

100

120

01

23

45

67

8

Time (hrs)

%C.D.R.

Initial10 days

20 days30 days

Figure N


apsule’ device for stability testing

Chapter – 6 Conclusion


CONCLUSION

The aim of this study was to explore the feasibility of time and pH dependent

colon specific, pulsatile drug delivery system of salbutamol sulphate to treat the

nocturnal symptoms of asthma. A satisfactory attempt was made to develop new

‘Tablet in Capsule’ device using pH dependent polymers (Eudragit S100 and Eudragit

L100) and evaluated for In vitro characterization studies.

From the results obtained of the executed experiments it can be conclude that:

ü From the above IR Study and physical observation it can be concluded that

there is no significant Drug- Excipient interaction. So we can conclude that

drug and other excipients are compatible with each other.

ü First and second pulse tablets of salbutamol sulpahte were developed to a

satisfactory level, in terms of hardness, thickness, weight variation, In-vitro

disintegration, and content uniformity.

ü Appropriate factorial design and optimization technique can be successfully

used in the development of coating formulations based on Eudragit S100 and

Eudragit L100 to achieve colon delivery.

ü Optimization enabled formulation of Salbutmaol sulphate tablets coated with

combination of pH sensitive polymethacrylates with the desired release

profile. It was shown that coating formulation consisted of Eudragit L100:

Eudragit S100 in ratio of 1:2 at 20% coating level has potential for colonic

delivery of salbutamol sulphate. The optimized formulation showed release

profiles and responses which were close to predicted responses.

ü The release of drug from coated tablet was found to be proportional to the

concentration of the polymer; where the % coating increases lag time

increases.

Chapter – 6 Conclusion


ü On the basis of in-vitro release studies and effective lag time, F11 was selected

as an optimized formulation for designing Tablet-in-capsule device.

ü In-vitro release study was shown in two pulses. First was immediate and

second was after effective lag time. The graph shows sigmoidal release pattern

which was ideal for pulsatile drug delivery system.

ü No significant difference in drug release was observed for drug release study

in different pH or under different rotational speeds. This shows an advantage

for the system, as it predicts no change in the performace of the system at

increased gastric motility.

ü In- vivo test in rabbit, by gamma scintigraphic studies indicated that the

second pulse tablet remained intact in the stomach and intestine and released

upon reaching the colon. Hence it can be concluded that the fabricated device

could be a promising, satisfactory for colon targeting.

ü Accelerated stability studies, proved that the formulation is quite stable.

ü A tablet in capsule device with controllable drug release lag time was

developed. The system can be used for daily programmed drug delivery for

two pulses. The proposed device was manufactured using currently applicable

pharmaceutical technologies and materials recognized as safe. Optimized

coated tablet and rapidly release tablet could be studied and prepared,

respectively, as multi-layered tablets were employed. In the present study,

each part of the novel system can be prepared separately and fabricated in the

final step, which profited industrialization. It can be considered one of the

promising formulation technique for preparing pulsatile drug release system.

Chapter – 7 Summary


SUMMARY

ü Over the past two decades there has been a growing appreciation on the

importance of circadian rhythms on Git physiology and on disease states,

together with the realization of the significance of time-of-day of drug

administration on resultant pharmcodynamic and pharmacokinetics

parameters. The significance of these day-night variation has not been over

looked from the drug delivery perspective and pharmaceutical scientist have

displayed considerable

ü Ingenuity in the development of time delayed drug delivery systems to address

emerging chronotherapeutic formualtuions.

ü The colon is a site where both local and systemic delivery of drugs can take

place. Treatment could be made more effective if it were possible for dugs to

be targeted directly on the colon. Colon-specific systems could also be used in

diseases that have diurnal rhythms. In the present study, attempt was made to

target the drug to the colon, and intentionally delaying the drug absorption

from therapeutic point of view in the treatment of nocturnal asthma, where

peak symptoms are observed in the early morning.

ü Prior to formulation, preformulation studies were carried out in order to

established compatibility between drug and polymers by IR spectroscopy. The

results revealed that the drug and polymers were satisfactorily compatible,

without any significant changes in the chemical nature of the drug.

ü First pulse tablet and second pulse tablets were prepared using wet-granulation

technique and evaluated for various parameters like % drug content, hardness,

thickness, friability and In-vitro disintegration time.

Chapter – 7 Summary


ü Second pulse tablets were coated with Eudragit S100 and Eudragit L100 and

optimization was done using 32 full factorial designs. From the optimization

study it was found that formulation F11 (1:2 ratio of Eudragit L100: Eudragit

S100 with 15% coating) was the best for pulsatile drug delivery system.

ü F11 was found to be optimum formulation and design ‘Tablet-in-Capsule’

with first pulse tablet.

ü From the in-vitro release studies of device, it was observed that with all

formulation, there was absolutely no drug release in simulated gastric fluid

(acidic pH 1.2) for 2 hours. Small amount of drug release was observed in

simulated intenstinal fluid (pH 6.8 phosphate buffer). Burst effect was found

in colonic medium (pH 7.4 phosphate buffer).

ü The polymer used in study are suitable for colon targeting. With the Eudragit

S100 and Eudragit L100 combination, the release was found to be proportional

to its concentration. Increase in the polymer content (% coating and ratio)

resulted in a reduction in release of salbutmol sulphate. The obtained results

showed the capability of the system in delaying drug release for a

programmable period of time and the possibility of exploiting such delay to

attain colon targeting.

ü In- vivo gamma scintigraphic studies revealed that the second pulse tablet

remained intact in the stomach and small intestine and released upon reaching

the colon.

ü From the accelerated stability studies, it was observed that there were no

significant change in the drug content and % release. of drug, therefore the

formulations are quite stable.

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Dissertation - Ningapi.ning.com/files/BZNY8QvGZuYkUls3AUwEcs0TeMM-w6... · 2017-05-28 · Dissertation Submitted to KLE University, Belgaum, KarnatakaSubmitted to KLE University,