20111213 Sublingual Paper

8/19/2019 20111213 Sublingual Paper

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RESEARCH ARTICLE

OPTIMIZATION OF SUBLINGUAL TABLETS OF ZALEPLON

MANNITOL SOLID DISPERSION SYSTEM USING CENTRAL

COMPOSITE DESIGN

Darade Smita *, Kakad Prakash, Narkhede Minal

Dept o Pharma!e"ti!s,

M#$%S Pharma!& Colle'e, Pan!ha(ati, Nasik, Maharashtra, India

*Correspondin' a"thor Email Id) smitadarade+'mail-!om

ABSTRACT

D"e to pres&stemi! meta.olism /aleplon, p&ra0olop&rimidine !lass non.en0odia0epine

h&pnoti!, sho1s 23 4 .ioa(aila.ilit&, hen!e in this st"d& attempt has .een done to de(elop

and optimi0e /aleplon Mannitol solid dispersion !ontanin' s".lin'"al ta.lets .& !entral

!omposite desi'n-S"perdisinte'rants 5 Sodi"m star!h 'l&!olate and Cros!armellose Sodi"m

1ere "sed as independent (aria.les and their ee!t on dependant (aria.les5 1ettin' time and

in-vitro dispersion time 1as st"died- A 6"adrati! model 1as "sed to e(al"ate the main ee!ts

and intera!tion- Intera!tion o independent (aria.les and dependent (aria.les are presented .&

S"ra!e response plots- 7n the .asis o desira.ilit& approa!h optim"m le(el o SS# 2-2 m'

and CCS 8-9: m' 1ere sele!ted as optimi0ed ta.let orm"lation 1hi!h 'i(es the predi!ted

(al"es o 1ettin' time and in-vitro dispersion time :3 se! and :8 se! respe!ti(el&- ;"rther

optimi0ed orm"la ta.let 1as sho1ed 9< 9-+2 se! 1ettin' time and :=< :->8 se! in-vitro

dispersion time in e(al"ation- These o.ser(ed responses 1ere in !lose a!!ord 1ith the

predi!ted (al"es o the optimi0ed orm"lation, there.& demonstratin' the easi.ilit& o the

optimi0ation pro!ed"re in de(elopin' s".lin'"al ta.lets- All the orm"lations sho1ed

hardness in the ran'e 2-= ? 8-= k'@!m : and ria.ilit& not more than 3-+: 4 , the theoreti!al

(al"e o dr"' !ontent 1as o"nd to .e "niorm in ran'es rom +-+3 to 933-8 4 1ith

a(era'e per!enta'e de(iation in a!!epta.le Pharma!opoeial limits-

Keywords: Central !omposite desi'n, 1ettin' time, dispersion time, 0aleplon s".lin'"al

ta.let

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mailto:[email protected]:[email protected]


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INTRODUCTION

Ta.lets that disinte'rate or dissol(e rapidl& in the patient%s mo"th are !on(enient or &o"n'

!hildren, the elderl& and patients 1ith s1allo1in' dii!"lties, and in sit"ations 1here pota.le

li6"ids are not a(aila.le- Sin!e the dr"' !an .e a.sor.ed partiall& or entirel& into the s&stem

!ir!"lation rom .lood (essels in the s".lin'"al m"!osa, the s".lin'"al ro"te .&passes the

hepati! irst pass meta.oli! pro!esses, th"s prod"!in' rapid onset o a!tion- The s".lin'"al

ro"te is appropriate or dr"'s 1ith short deli(er& period re6"irements, or dr"'s 1hi!h are

ina!ti(ated .& irst pass?intestinal or hepati! meta.olism or ina!ti(ated .& the proteol&ti!

en0&mes in the #I tra!t, the hi'hl& (as!"larised oral m"!osa thro"'h 1hi!h dr"'s enter the

s&stemi! !ir!"lation dire!tl&, th"s .&passin' the 'astrointestinal tra!t and the irst pass ee!t

in the li(er-1, , !

/aleplon is a ne1 non.en0odia0epine h&pnoti! a'ent indi!ated or the short5 term

treatment o insomnia- Bork .& intera!tin' 1ith .en0odia0epine re!eptors- 8 Altho"'h

/aleplon is 1ell a.sor.ed, its a.sol"te .ioa(aila.ilit& is approimatel& 234 .e!a"se it

"nder'oes si'nii!ant pres&stemi! meta.olism- It there.& makes it a s"ita.le !andidate or

s".lin'"al dosa'e orm" #,$,%,& The o.e!ti(e o the present in(esti'ation is to anal&0e the ee!t

o orm"lation (aria.les on the properties s"!h as 1ettin' time, dispersion time in the

preparation o /aleplon s".lin'"al ta.lets-

Eperimental desi'ns also !alled desi'ns o eperiments, is an approa!h in the de(elopment

and optimi0ation o dr"' deli(er& de(i!es, .& this method it is easi.le to o.tain the desired

orm"lation as 6"i!kl& as possi.le 1hile a(oidin' "nne!essar& eperiments- The maor

ad(anta'e o this method to de(elop pharma!e"ti!al orm"lation is that the potential a!tors

!o"ld .e st"died sim"ltaneo"sl&, s&stemati!all& and 6"i!kl&- & "sin' desi'n o eperiments,the ee!t o ea!h orm"lation a!tor on ea!h response !an .e e(al"ated and !riti!al a!tors

!an .e identiied .ased on statisti!al anal&sis- Bhen the orm"lation and man"a!t"rin'

pro!ess o a pharma!e"ti!al prod"!t are optimi0ed .& a s&stemati! approa!h s!ale "p and

pro!ess (alidation !an .e (er& ei!ient .e!a"se o the ro."stness o the orm"lation and

man"a!t"rin' pro!ess- In a mit"re eperiments 1hi!h is s"ita.le or pharma!e"ti!al

orm"lations, the independent a!tors are the !omponents o mit"re and the response is

dependant on the relati(e proportions o ea!h in'redient- It in(ol(es !han'in' mit"re

!omposition and eplorin' ho1 s"!h !han'e 1ill ae!t the properties o mit"re- '

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MATERIALS ()d MET*ODS

M(+er(-s

/aleplon 1as s"pplied .& Pre!ise Chemipharma P(t- Ltd- M"m.ai, Mannitol, Sodi"m star!h

'l&!olate, Cros!armellose sodi"m and aerosil p"r!hased rom Resear!h ;ine Chem, M"m.ai-

All other materials 1ere o anal&ti!al 'rade-

Me+.ods

Traditionall& pharma!e"ti!al orm"lations are de(eloped .& !han'in' one (aria.le at a time-

& this method it is dii!"lt to de(elop an optimi0ed orm"lation, as it does not 'i(e an idea

a.o"t the intera!tions amon' the (aria.les- A !entral !omposite desi'n FCCDG is an ee!ti(e

se!ond5order eperimental desi'n asso!iated 1ith minim"m o eperiments to estimate the

inl"en!e o indi(id"al (aria.les Fmain ee!tsG and their se!ond5order ee!ts- ;"rther, this

desi'n has an added ad(anta'e o determinin' the 6"adrati! response s"ra!e, not estima.le

"sin' a a!torial desi'n F;DG at t1o le(els 1/ -Hen!e, a !entral !omposite eperimental desi'n

1ith : a!tors, :le(els and 92 r"ns 1as sele!ted or the optimi0ation st"d&- This desi'n

!onsists o 8 "ll a!torial desi'n points, 8 aial points, and = !enter points11- In this st"d&,

amo"nt o SS# and CCS 1ere !hosen as the independent orm"lation (aria.les- The

dependent (aria.les in!l"ded 1ettin' time FBTG and in vitro dispersion time FDTG- The ee!t

o orm"lation (aria.les on the response (aria.les 1ere stati!all& e(al"ated .& appl&in' one5

1a& AN7$A at 3-3= le(el "sin' Desi'n5Epert FStat Ease, SAG- The desi'n 1as

e(al"ated "sin' a 6"adrati! model, 1hi!h .ears the orm o the e6"ation)

J .3 .9 9 .: : .2 9 : .8 9: .= :

:

Bhere J is the response (aria.le, .3 the !onstant and .9 , .:, .2, .8, .= is the re'ression

!oei!ients and 9, : are the independent (aria.les le(els o 1hi!h 1ere sele!ted rom the

preliminar& eperiments,9 and : stand or the main ee!t 9 : are the intera!tion terms

that sho1s ho1 the response !han'es 1hen t1o a!tors are sim"ltaneo"sl& !han'ed- 9: and

:: are 6"adrati! terms o the independent (aria.les to e(al"ate the nonlinearit&- 1, 11, 1

Eperiments 1ere !arried o"t s&stemati!all& to anal&0e the ee!t o dierent !on!entrations

o disinte'rants on the 1ettin' time and in-vitro dispersion time o the ta.lets, "sin' a

response s"ra!e methodolo'& and to de(elop an optimi0ed orm"lation- As per !omposition

sho1n in Ta.le 9, orm"lations 1ere prepared a!!ordin' to the rotata.le !entral !omposite

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desi'n .& dire!t !ompression 1ith mm p"n!h F#eneral Ma!hiner& Co-, M"m.aiG "sin'

dierent proportions o st"died s"perdisinte'rants, mannitol as a dil"ent, sodi"m sa!!harin as

s1eetenin' a'ent, aerosil 1ith tal! as a lo1 promoter- Man'o la(or 1as "sed as la(orin'

a'ent in ta.let-

E0ALUATION OF TABLETS

*(rd)ess: The !r"shin' stren'th o the ta.lets 1as meas"red "sin' a Pi0er hardness tester-

Three ta.lets rom ea!h orm"lation .at!h 1ere tested randoml& and the a(era'e readin' 1as

noted-1!, 1

Fr(2-+y: ;ria.ilit& test 1as perormed a!!ordin' to I-P- "sin' a Ro!he ;ria.ilator FK"mar

M'- LtdG-Pre(io"sl& 1ei'hed t1ent& ta.lets 1ere rotated at := rpm or o"r min"te- The

1ei'ht loss o the ta.lets ater meas"rement 1as !al!"lated "sin' the ollo1in' orm"la 1!,1

Per!enta'e ria.ilit& Initial 1ei'ht ? ;inal 1ei'ht 933

Initial 1ei'ht

3e4.+ 5(r(+o): Ater !ompression, t1ent& ta.lets rom prepared orm"lations 1ere

sele!ted randoml&, 1ei'hed indi(id"all& and !al!"lated a(era'e 1ei'ht- As per

Pharma!opoeial 1ei'ht (ariation test, the indi(id"al ta.let 1ei'hts are !ompared 1ith their

a(era'e 1ei'ht-1!,1

Co)+e)+ 6)7or8+y: To ass"re "niorm poten!& or ta.lets o lo1 dose dr"'s, !ontent

"niormit& test is perormed- ;rom ea!h orm"lation .at!h, ten ta.lets 1ere randoml&

sampled, po1dered, dissol(ed in methanol and soni!ated or :3 min- The (ol"me 1as make

"p to 933 ml 1ith distilled 1ater- The sol"tion 1as iltered thro"'h Bhatman il ter paper no-

89, s"ita.l& dil"ted and indi(id"all& estimated or the dr"' !ontent, "sin' $5$IS

spe!trophotometerF$5:8=3, Shimad0"G at :23 nm- The mean per!ent dr"' !ontent 1as

!al!"lated as an a(era'e o three determinations-9,9=,:9

3e++)4 +8e: This st"d& is perormed a!!ordin' to pre(io"sl& reported method .& Sindh"

A.raham et al- T1i!e olded tiss"e paper F9:!m93-+=!m G1as pla!ed in ml pH >-

sim"latin' sali(a in Petri dish ha(in' internal diameter !m-A ta.let 1as pla!ed on the paper

and the time taken or !omplete 1ettin' 1as noted- Three ta.lets rom ea!h orm"lation 1ere

randoml& sele!ted and the a(era'e 1ettin' time 1as noted- 1,%

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In-vitro ds9erso) +8e: In vitro dispersion time 1as meas"red a!!ordin' to pre(io"sl&

reported method .& Sindh" A.raham et al- This method 1as perormed .& droppin' a ta.let

in a 93ml meas"rin' !&linder !ontainin' >ml o pH >- sim"latin' sali(a l"id ."er

sol"tion- 1, %

Pre9(r(+o) ()d e5(-6(+o) o7 o9+8ed +(2-e+s 2(+;.


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the ran'e 2-= ? 8-= k'@!m: and ria.ilit& not more than 3-+: 4 , the (al"e o dr"' !ontent 1as

o"nd to .e "niorm in ran'es rom +-+3 to 933-8 4 1ith a(era'e per!enta'e de(iation in

a!!epta.le Pharma!opoeial limits- The per!enta'e de(iation or 1ei'ht (ariation 1as 1ithin

the a!!epta.le Pharma!oepial limits F< +-=4G-

The pol&nomial e6"ation relatin' the responses and the independent (aria.les 1as)

Bettin' time 9>5 2-8 952-9: :53-=3 9:5:-3> 9:3-> :: 55555F:G

Dispersion time:95 2-2> 952-33 :53-+= 9:59-9:3-+ ::55555 F2G

The (al"es o the !oei!ients 95: are related to the ee!t o these (aria.les on the BT

and DT- Coei!ients o more than one, represents intera!tion and sho1s ho1 the response

!han'es 1hen t1o a!tors are sim"ltaneo"sl& !han'ed- Coei!ients o hi'her order terms,

represents 6"adrati! relationship and are in!l"ded to in(esti'ate nonlinearit&- The pol&nomial

e6"ation !an .e "sed to dra1 !on!l"sions ater !onsiderin' the ma'nit"de o ea!h !oei!ient

and the mathemati!al si'n it !arries Fi-e-, positi(e or ne'ati(eG- A ne'ati(e si'n o !oei!ient

or SS#F9G and CCSF:G represents anta'onisti! ee!t o these (aria.les- A positi(e si'n o

the !oei!ient represents in!reasin' BT and DT 1ith 9 and :- The si'nii!an!e o the

dierent orm"lation (aria.les and their intera!tions 1as !ompared "sin' anal&sis o (arian!e

FAN7$AG at a si'nii!an!e le(el o pQ3-3=- The AN7$A res"lts o la!k o it and p"re error

or independant (aria.les pro(ides the mean response and an estimate o p"re eperimental

"n!ertaint&- The pQ3-3= (al"e or independant (aria.les 'i(en in Ta.le 2 s"''ested that the

.oth s"perdisinte'rants ha(e si'nii!ant ee!ts on the 1ettin' and dispersion time-

Co)+o6r 9-o+s: $ario"s RSM !omp"tations or the !"rrent optimi0ation st"d& 1ere

perormed emplo&in' Desi'n Epert Sot1are, T1o ?dimensional F:DG !onto"r plots 1ere

!onstr"!ted .ased on the model pol&nomial "n!tions "sin' Desi'n Epert Sot1are-

Presentation o the data as 'raphs !an help to sho1 the relationship .et1een the independent

and dependent (aria.les- The plot or BT 1as o"nd to .e linear at hi'h le(els o 9 and :

1ith sli'ht !"r(at"re at lo1 le(els o 9 and :- Similar !han'es o.ser(ed 1ith dispersion

time 'raph- It 1as determined rom the !onto"r plot that minim"m (al"es o BT and DT

!o"ld .e o.tained 1ith in!reasin' !on!entrations o an 9 and :-The addition o

disinte'rant to the ta.let is "s"all& ne!essar& to a!hie(e or impro(e the ta.let disinte'ration-

The predi!tion o disinte'ration time o ta.let orm"lations .& mathemati!al model !an .e

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dii!"lt .e!a"se o the n"mero"s parameters inl"en!in' s"!h response- In a!t, the t&pe and

!on!entration o disinte'rant, the disinte'ration me!hanisms Fi-e-, s1ellin' or !apillar&

or!esG, and the !ompression or!e !an ae!t the disinte'ration .eha(ior in dierent 1a&s9+, :3-

Ho1e(er, in this st"d&, this (aria.le sho1ed a satisa!tor& !oei!ient o determination- This

!an .e attri."ted to the lo1er le(el o intera!tion o.ser(ed .et1een independent (aria.les- As

epe!ted, d"e to the 1i!kin' a!tion o disinte'rants the ta.let disinte'ration time 1as

primaril& ae!ted .& the amo"nt o s"perdisinte'rants in the orm"lation 9,9- The SS# and

CCS linear term 1ere the primar& a!tors responsi.le or the de!rease in the ta.let 1ettin'

and dispersion time- This 1as ollo1ed .&, the intera!tion .et1een the : a!tors F9:G and

SS# 6"adrati! term 1hi!h also sho1ed a ne'ati(e ee!t on the response (aria.le that is

de!reasin' 1ettin' time and dispersion time- Ho1e(er, the in!rease o the s"perdisinte'rants

!on!entration res"lted in a ne'ati(e ee!t, de!reasin' the disinte'ration time -The response

s"ra!e plots sho1in' the ee!t o amo"nt o SS# F9G and amo"nt o CCS F:G on the

response BT FJ9G and DT FJ:G are sho1n in ;i'"re 9-

The res"lts in Ta.le = demonstrated a 'ood relationship .et1een predi!ted and eperimental

(al"es, !onirmin' the (alidit& o the model- The hardness o F orm"lation .at!h 1as o"nd

to .e 2F 4- The a(era'e dr"' !ontent

1as o"nd to .e -2= 4 o the theoreti!al (al"e- The per!enta'e de(iation or :3 ta.lets 1as1ithin the a!!epta.le Pharma!oepial limits F< +-=4G- The orm"lation F sho1ed rapid

dissol"tion rate and 2-+= 4 !"m"lati(e dr"' release 1ithin 23 min"tes-

CONCLUSION:

The ee!t o s"perdisinte'rants on 1ettin' time and in -vitro dispersion time o s".lin'"al

ta.lets o /aleplon solid dispersion 1as st"died .& !entral !omposite desi'n FCCDG and

response s"ra!e methodolo'& FRSMG- The st"d& demonstrated that SS# and CCS modiies

the 1ettin' time and in (itro dispersion time- The optim"m orm"la !ontainin' :-== and :-+8

4 F1@1G o SS#, CCS respe!ti(el& sho1ed minim"m 1ettin' time and in (itro dispersion

time- At these !onditions, the ta.let sho1ed a 1ettin' time o 9 F< 9-+2 G se! and dispersion

time o := F8G se!- It 1as o.ser(ed that responses 1ere in !lose a!!ord 1ith the predi!ted

(al"es o optimi0ed orm"lation, there.& demonstratin' the easi.ilit& o the optimi0ation

pro!ed"re in de(elopin' s".lin'"al ta.let orm"lation-

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ACKNO3LEDGEMENT:

The a"thors 1ant to thank Pre!ise Chemipharma P(t- Ltd- M"m.ai or pro(idin' 'it

samples o /aleplon-

REFERENCES:

9G Sindh" A.raham, asa(ara -$, harath S, De(es1aran R, Sharon ;"rtado and

Madha(an $, ;orm"lation and optimi0ation o s".lin'"al ta.lets o Ra.epra0ole

sodi"m, International o"rnal o Pharma!e"ti!al S!ien!es Re(ie1 and Resear!h,

$ol"me =, Iss"e :, Arti!le5393,=35=8, No(em.er ? De!em.er :393-

:G Mona H- A."rahma, Hanan M- EL5Laith&, Jassin El5Said Ham0a, Preparation and In

$itro@In $i(o Chara!teri0ation o Poro"s S".lin'"al Ta.lets Containin' Ternar&

Kneaded Solid S&stem o $inpo!etine 1ith 5C&!lodetrin and H&dro& A!id, S!i

Pharm- ,+) 2>2?2+, :393-

2G $ineet hard1a, $ikesh Sh"kla, Narendra #o&al, MD Salim, PK Sharma,

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rapid a.sorption, and presentation o an indi(id"ali0ed dose administration s&stem,

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!on!epts in administration o dr"'s in ta.lets orms , A!ta ni(ersitatis

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:33=-

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9G att" S-K , Repka M-A, Ma"mdar S, Madh"s"dan R-J- ;orm"lation and e(al"ation

o rapidl& disinte'ratin' eno(erine ta.lets) ee!t o s"perdisinte'rants- Dr"' De( Ind

Pharm-, 22F99G, 9::=52:, No( :33+-

9G S"resh $ K"lkarni, Ranit K"mar P, asa(ara, Somesh1ara Rao ., Ramesh ., Ashok

k"mar P, Ee!t o s"perdisinte'rants on orm"lation o taste masked ast

disinti'ratin' lisinopril ta.lets- Int C"rr Pharm Res, $ol 2, Iss"e9, 9998-

:3G Shan'ra1 R, Mitre(e A, Shah M- A ne1 era o ta.let disinte'rant- Pharm Te!hnol-

J=+, 8)8, 93-

:9G Leon La!hman, Her.ert A- Lie.erman, ose L- Kani', The Theor& and Pra!ti!e o

Ind"strial Pharma!&, 2rd ed-, 233539, 93-

10

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Battu%20SK%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Repka%20MA%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Majumdar%20S%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Madhusudan%20RY%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Battu%20SK%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Repka%20MA%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Majumdar%20S%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Madhusudan%20RY%22%5BAuthor%5D


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TABLES AND FIGURES:

T(2-e 1: Composition o s".lin'"al ta.lets o /aleplon

a 5solid dispersion e6"i(alent to 93 m' /aleplon

IN#REDIENTSFM#G ;9 ;: ;2 ;8 ;= ;+ ; ;99 ;9:

/aleplon5SDa +3 +3 +3 +3 +3 +3 +3 +3 +3

SS# > > 9-+> > 2 93-:8 2

CCS 93-:8 9-+> > > 2 > 2

Sa!!harine sodi"m 2 2 2 2 2 2 2 2 2

Man'o la(or 6 s 6 s 6 s 6 s 6 s 6 s 6 s 6 s 6 s

Tal! : : : : : : : : :

Aerosil 9 9 9 9 9 9 9 9 9

Mannitol => =+-+> >>-:8 >>-:8 >: > =+-+> >: >:

Total 9=3 9=3 9=3 9=3 9=3 9=3 9=3 9=3 9=3

T(2-e : CCD 1ith the responses or 1ettin' time and In-vitro

dispersion time

Parameters ;9 ;: ;2 ;8 ;= ;> ;+ ; ;

Bettin' Time Fse!G

FJ9G

+ 92 := 9 9> :3 93 9=

In vitro dispersion

time Fse!G FJ:G

9: 9 23 :: :9 :8 9= 9+ ::

T(2-e !: S"mmar& o AN7$A res"lts

11


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So"re S"m o

S6"ares

D; Mean

S6"are

;

$al"e

P

$al"e

Pro. U;

Bettin' time

Model :22-32 = 8>->9 -89 3-33=: Si'nii!ant

9 118.03 9 99-32 :2-8 3-339

: ++-8 9 ++-8 9=-+8 3-33=8

9 : 9 9 9 3-:3 3->>>+

9: :-= 9 :-= =- 3-3888

:: 2-: 9 2-: 3->> 3-88:3

Resid"als 28->> + 8-=

La!k o

it

28->> 2 99-==

P"re

error

3-333 8 3-333

Total :>+-> 9:

In-vitro dispersion time

Model 9+-= = 2-=+ -+ 3-33>9 Si'nii!ant

9 3-8= 9 3-8= :3-:+ 3-33:

: +9-: 9 +9-: 9>-93 3-33=9

9 : :-:= 9 :-:= 3-=3 3-=33>

9: :8-8> 9 :8-8> =-8 3-3=9+

:: =-22 9 =-22 9-9 3-293+

Resid"als 29-:2 + 8-8>

La!k o

it

29-:2 2 93-89

P"re

error

3-333 8 3-333

Total ::-3 9:

T(2-e : Composition o optimi0ed orm"lation F;G

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I)4rede)+s ?6()++es


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F46re 1: Response s"ra!e plots sho1in' the ee!t o amo"nt o 9 and : on 1ettin' time

i'- FA, A%G, Dispersion time i'- F, %G

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20111213 Sublingual Paper