INDEX

Sr. no chapter Page

no
1 Abstract 1
2 Introduction 4
3 Overview o the ora! "ucosa 7
3.1 Structure 8
3.2 Per"eabi!it# 9
3.3 Environ"ent 11
4 $outes o drug absorption 12
5 %ucca! "ucosa as site or drug de!iver#
s#ste"
14
6
E&peri"enta! "ethodo!og# to
investigate bucca! drug per"eation
20
6.1 In vitro 'ethods 21
6.2 In vivo 'ethods 22
6.3 E&peri"enta! Ani"a! Species 23
7 %ucca! drug de!iver# s#ste" 24
8 (onc!usion 35
9 $eerences 37
()AP*E$+1
ABSTRACT
1. A%S*$A(*
Within the oral mucoal ca!it"# the $uccal re%ion o&&er an attracti!e route o&
a'minitration &or "temic 'ru% 'eli!er".
The mucoa ha a rich $loo' u((l" an' it i relati!el" (ermea$le. )t i the o$*ecti!e
o& thi article to re!ie+ $uccal 'ru% 'eli!er" $" 'icuin% the tructure an'
en!ironment o& the oral mucoa an' the e,(erimental metho' ue' in aein%
$uccal 'ru% (ermeation-a$or(tion.
Buccal 'oa%e &orm +ill alo $e re!ie+e' +ith an em(hai on $ioa'hei!e
(ol"meric $ae' 'eli!er" "tem


()AP*E$+2
IN*$OD,(*ION
2. Introduction
Amon%t the !ariou route o& 'ru% 'eli!er"# oral route i (erha( the mot (re&erre'
to the (atient an' the clinician ali.e. /o+e!er# (er oral a'minitration o& 'ru% ha
'ia'!anta%e uch a he(atic &irt (a meta$olim an' en0"matic 'e%ra'ation +ithin
the 1) tract# that (rohi$it oral a'minitration o& certain clae o& 'ru% e(eciall"
(e(ti'e an' (rotein. Cone2uentl"# other a$or(ti!e mucoa are coni'ere' a
(otential ite &or 'ru% a'minitration. Tranmucoal route o& 'ru% 'eli!er" 3i.e.# the
mucoal linin% o& the naal# rectal# !a%inal# ocular# an' oral ca!it"4 o&&er 'itinct
a'!anta%e o!er (eroral a'minitration &or "temic 'ru% 'eli!er". Thee a'!anta%e
inclu'e (oi$le $"(a o& &irt (a e&&ect# a!oi'ance o& (re"temic elimination
+ithin the 1) tract# an'# 'e(en'in% on the (articular 'ru%# a $etter en0"matic &lora &or
'ru% a$or(tion.
The naal ca!it" a a ite &or "temic 'ru% 'eli!er" ha $een in!eti%ate' $" man"
reearch %rou(
157
an' the route ha alrea'" reache' commercial tatu +ith e!eral
'ru% inclu'in% 6/R/
8#9
an' calcitonin
10512
. /o+e!er# the (otential irritation an' the
irre!eri$le 'ama%e to the ciliar" action o& the naal ca!it" &rom chronic a((lication
o& naal 'oa%e &orm# a +ell a the lar%e intra5 an' inter5u$*ect !aria$ilit" in mucu
ecretion in the naal mucoa# coul' i%ni&icantl" a&&ect 'ru% a$or(tion &rom thi ite.
7!en thou%h the rectal# !a%inal# an' ocular mucoa all o&&er certain a'!anta%e# the
(oor (atient acce(ta$ilit" aociate' +ith thee ite ren'er them reer!e' &or local
a((lication rather than "temic 'ru% a'minitration. The oral ca!it"# on the other
han'# i hi%hl" acce(ta$le $" (atient# the mucoa i relati!el" (ermea$le +ith a rich
$loo' u((l"# it i ro$ut an' ho+ hort reco!er" time a&ter tre or 'ama%e 3135
154# an' the !irtual lac. o& 6an%erhan cell 3164 ma.e the oral mucoa tolerant to
(otential aller%en. 8urthermore# oral tranmucoal 'ru% 'eli!er" $"(ae &irt (a
e&&ect an' a!oi' (re5"temic elimination in the 1) tract. Thee &actor ma.e the oral
mucoal ca!it" a !er" attracti!e an' &eai$le ite &or "temic 'ru% 'eli!er".
Within the oral mucoal ca!it"# 'eli!er" o& 'ru% i clai&ie' into three cate%orie9 3i4
u$lin%ual 'eli!er"# +hich i "temic 'eli!er" o& 'ru% throu%h the mucoal
mem$rane linin% the &loor o& the mouth# 3ii4 $uccal 'eli!er"# +hich i 'ru%
a'minitration throu%h the mucoal mem$rane linin% the chee. 3$uccal mucoa4#
an' 3iii4 local 'eli!er"# +hich i 'ru% 'eli!er" into the oral ca!it".
()AP*E$+3
O-E$-IE. O/ *)E O$A0
',(OSA
3.1 STR:CT:R7
3.2 PERMEABILITY
3.3 7;<)R=;>7;T
3. O-E$-IE. O/ *)E O$A0 ',(OSA
3.1 S*$,(*,$E
The oral mucoa i com(oe' o& an outermot la"er o& trati&ie' 2uamou e(ithelium
38i%ure14. Belo+ thi lie a $aement mem$rane# a lamina (ro(ria &ollo+e' $" the
u$mucoa a the innermot la"er. The e(ithelium i imilar to trati&ie' 2uamou
e(ithelia &oun' in the ret o& the $o'" in that it ha a mitoticall" acti!e $aal cell la"er#
a'!ancin% throu%h a num$er o& 'i&&erentiatin% interme'iate la"er to the u(er&icial
la"er# +here cell are he' &rom the ur&ace o& the e(ithelium
17
. The e(ithelium o& the
$uccal mucoa i a$out 40550 cell la"er thic.# +hile that o& the u$lin%ual e(ithelium
contain ome+hat &e+er. The e(ithelial cell increae in i0e an' $ecome &latter a
the" tra!el &rom the $aal la"er to the u(er&icial la"er.
The turno!er time &or the $uccal e(ithelium ha $een etimate' at 556 'a" 3184# an'
thi i (ro$a$l" re(reentati!e o& the oral mucoa a a +hole. The oral mucoal
thic.ne !arie 'e(en'in% on the ite9 the $uccal mucoa meaure at 5005800 ?m#
+hile the mucoal thic.ne o& the har' an' o&t (alate# the &loor o& the mouth# the
!entral ton%ue# an' the %in%i!ae meaure at a$out 1005200 ?m. The com(oition o&
the e(ithelium alo !arie 'e(en'in% on the ite in the oral ca!it". The mucoa o&
area u$*ect to mechanical tre 3the %in%i!ae an' har' (alate4 i .eratini0e' imilar
to the e(i'ermi. The mucoa o& the o&t (alate# the u$lin%ual# an' the $uccal re%ion#
ho+e!er# are not .eratini0e'
18
.
The .eratini0e' e(ithelia contain neutral li(i' li.e cerami'e an' ac"lcerami'e
+hich ha!e $een aociate' +ith the $arrier &unction. Thee e(ithelia are relati!el"
im(ermea$le to +ater. )n contrat# non5.eratini0e' e(ithelia# uch a the &loor o& the
mouth an' the $uccal e(ithelia# 'o not contain ac"lcerami'e an' onl" ha!e mall
amount o& cerami'e
19521
. The" alo contain mall amount o& neutral $ut (olar li(i'#
mainl" choleterol ul&ate an' %luco"l cerami'e. Thee e(ithelia ha!e $een &oun' to
$e coni'era$l" more (ermea$le than +ater than .eratini0e' e(ithelia
18520
.
*he structure o "ucosa
11
3.2 PE$'EA%I0I*2
The oral mucoa in %eneral i a ome +hat lea." e(ithelia interme'iate $et+een that
o& the e(i'ermi an' intetinal mucoa. )t i etimate' that the (ermea$ilit" o& the
$uccal mucoa i 454000 time %reater than that o& the .in
22
. A in'icati!e $" the
+i'e ran%e in thi re(orte' !alue# there are coni'era$le 'i&&erence in (ermea$ilit"
$et+een 'i&&erent re%ion o& the oral ca!it" $ecaue o& the 'i!ere tructure an'
&unction o& the 'i&&erent oral mucoa. )n %eneral# the (ermea$ilitie o& the oral
mucoa 'ecreae in the or'er o& u$lin%ual %reater than $uccal# an' $uccal %reater
than (alatal
18
. Thi ran. or'er i $ae' on the relati!e thic.ne an' 'e%ree o&
.eratini0ation o& thee tiue# +ith the u$lin%ual mucoa $ein% relati!el" thin an'
non5.eratini0e'# the $uccal thic.er an' non5.eratini0e'.
)t i currentl" $elie!e' that the (ermea$ilit" $arrier in the oral mucoa i a reult o&
intercellular material 'eri!e' &rom the o5calle' @mem$rane coatin% %ranuleA 3>C14
23
. When cell %o throu%h 'i&&erentiation# >C1 tart &ormin% an' at the a(ical cell
ur&ace the" &ue +ith the (lama mem$rane an' their content are 'ichar%e' into
the intercellular (ace at the u((er one thir' o& the e(ithelium. Thi $arrier e,it in
the outermot 200?m o& the u(er&icial la"er. Bermeation tu'ie ha!e $een (er&orme'
uin% a num$er o& !er" lar%e molecular +ei%ht tracer# uch a horera'ih (ero,i'ae
24
an' lanthanum nitrate
25
. When a((lie' to the outer ur&ace o& the e(ithelium# thee
tracer (enetrate onl" throu%h outermot la"er or t+o o& cell. When a((lie' to the
u$mucoal ur&ace# the" (ermeate u( to# $ut not into# the outermot cell la"er o& the
e(ithelium. Accor'in% to thee reult# it eem a((arent that &lattene' ur&ace cell
la"er (reent the main $arrier to (ermeation# +hile the more io'iametric cell la"er
are relati!el" (ermea$le. )n $oth .eratini0e' an' non5.eratini0e' e(ithelia# the limit o&
(enetration coinci'e' +ith the le!el +here the >C1 coul' $e een a'*acent to the
u(er&icial (lama mem$rane o& the e(ithelial cell. Since the ame reult +a
o$taine' in $oth .eratini0e' an' non5.eratini0e' e(ithelia# .eratini0ation $" itel& i
not e,(ecte' to (la" a i%ni&icant role in the $arrier &unction 3244. The com(onent o&
the >C1 in .eratini0e' an' non5.eratini0e' e(ithelia are 'i&&erent# ho+e!er 3194.
The >C1 o& .eratini0e' e(ithelium are com(oe' o& lamellar li(i' tac.# +herea
the non5.eratini0e' e(ithelium contain >C1 that are non5lamellar. The >C1 li(i'
o& .eratini0e' e(ithelia inclu'e (hin%om"elin# %luco"lcerami'e# cerami'e# an'
other non(olar li(i'# ho+e!er &or non5.eratini0e' e(ithelia# the ma*or >C1 li(i'
com(onent are choleterol eter# choleterol# an' %l"co(hin%oli(i' 3194. Ai'e
&rom the >C1# the $aement mem$rane ma" (reent ome reitance to (ermeation
a +ell# ho+e!er the outer e(ithelium i till coni'ere' to $e the rate limitin% te( to
mucoal (enetration. The tructure o& the $aement mem$rane i not 'ene enou%h to
e,clu'e e!en relati!el" lar%e molecule.
3.3 EN-I$ON'EN*
The cell o& the oral e(ithelia are urroun'e' $" an intercellular %roun' u$tance#
mucu# the (rinci(le com(onent o& +hich are com(le,e ma'e u( o& (rotein an'
car$oh"'rate. Thee com(le,e ma" $e &ree o& aociation or ome ma"$e attache'
to certain re%ion on the cell ur&ace. Thi matri, ma" actuall" (la" a role in cell5cell
a'heion# a +ell a actin% a a lu$ricant# allo+in% cell to mo!e relati!e to one
another 3264. Alon% the ame line# the mucu i alo $elie!e' to (la" a role in
$ioa'heion o& mucoa'hei!e 'ru% 'eli!er" "tem 3274. )n trati&ie' 2uamou
e(ithelia &oun' ele+here in the $o'"# mucu i "nthei0e' $" (eciali0e' mucu
ecretin% cell li.e the %o$let cell# ho+e!er in the oral mucoa# mucu i ecrete' $"
the ma*or an' minor ali!ar" %lan' a (art o& ali!a 326# 284. :( to 70C o& the total
mucin &oun' in ali!a i contri$ute' $" the minor ali!ar" %lan' 326# 284. At
(h"iolo%ical (/ the mucu net+or. carrie a ne%ati!e char%e 3'ue to the ialic aci'
an' ul&ate rei'ue4 +hich ma" (la" a role in mucoa'heion. At thi (/ mucu can
&orm a tron%l" cohei!e %el tructure that +ill $in' to the e(ithelial cell ur&ace a a
%elatinou la"er 3174. Another &eature o& the en!ironment o& the oral ca!it" i the
(reence o& ali!a (ro'uce' $" the ali!ar" %lan'. Sali!a i the (rotecti!e &lui' &or all
tiue o& the oral ca!it". )t (rotect the o&t tiue &rom a$raion $" rou%h material
an' &rom chemical. )t allo+ &or the continuou mineraliation o& the tooth enamel
a&ter eru(tion an' hel( in remineraliation o& the enamel in the earl" ta%e o& 'ental
carie 3294. Sali!a i an a2ueou &lui' +ith 1C or%anic an' inor%anic material. The
ma*or 'eterminant o& the ali!ar" com(oition i the &lo+ rate +hich in turn 'e(en'
u(on three &actor9 the time o& 'a"# the t"(e o& timulu# an' the 'e%ree o& timulation
326# 284. The ali!ar" (/ ran%e &rom 5.5 to 7 'e(en'in% on the &lo+ rate. At hi%h
&lo+ rate# the o'ium an' $icar$onate concentration increae lea'in% to an increae
in the (/. The 'ail" ali!ar" !olume i $et+een 0.5 to 2 liter an' it i thi amount o&
&lui' that i a!aila$le to h"'rate oral mucoal 'oa%e &orm. A main reaon $ehin' the
election o& h"'ro(hilic (ol"meric matrice a !ehicle &or oral tranmucoal 'ru%
'eli!er" "tem i thi +ater rich en!ironment o& the oral ca!it".
()AP*E$+3
%,((A0 $O,*S O/ D$,4
A%SO$P*ION
3. %,((A0 $O,*ES O/ D$,4 A%SO$P*ION
The are t+o (ermeation (ath+a" &or (ai!e 'ru% tran(ort acro the oral mucoa9
(aracellular an' trancellular route. Bermeant can ue thee t+o route
imultaneoul"# $ut one route i uuall" (re&erre' o!er the other 'e(en'in% on the
(h"icochemical (ro(ertie o& the 'i&&uant. Since the intercellular (ace an'
c"to(lam are h"'ro(hilic in character# li(o(hilic com(oun' +oul' ha!e lo+
olu$ilitie in thi en!ironment. The cell mem$rane# ho+e!er# i rather li(o(hilic in
nature an' h"'ro(hilic olute +ill ha!e 'i&&icult" (ermeatin% throu%h the cell
mem$rane 'ue to a lo+ (artition coe&&icient.
There&ore# the intercellular (ace (oe a the ma*or $arrier to (ermeation o&
li(o(hilic com(oun' an' the cell mem$rane act a the ma*or tran(ort $arrier &or
h"'ro(hilic com(oun'. Since the oral e(ithelium i trati&ie'# olute (ermeation ma"
in!ol!e a com$ination o& thee t+o route. The route that (re'ominate# ho+e!er# i
%enerall" the one that (ro!i'e the leat amount o& hin'rance to (aa%e.

()AP*E$+5
%,((A0 ',(OSA AS A SI*E
/O$ D$,4 DE0I-E$2
5. %,((A0 ',(OSA AS A SI*E /O$ D$,4 DE0I-E$2
A tate' a$o!e in ection )# there are three 'i&&erent cate%orie o& 'ru% 'eli!er"
+ithin the oral ca!it" 3i.e.# u$lin%ual# $uccal# an' local 'ru% 'eli!er"4. Selectin% one
o!er another i mainl" $ae' on anatomical an' (ermea$ilit" 'i&&erence that e,it
amon% the !ariou oral mucoal ite. The u$lin%ual mucoa i relati!el" (ermea$le#
%i!in% ra(i' a$or(tion an' acce(ta$le $ioa!aila$ilitie o& man" 'ru%# an' i
con!enient# accei$le# an' %enerall" +ell acce(te' 3184. The u$lin%ual route i $"
&ar the mot +i'el" tu'ie' o& thee route. Su$lin%ual 'oa%e &orm are o& t+o
'i&&erent 'ei%n# thoe com(oe' o& ra(i'l" 'iinte%ratin% ta$let# an' thoe
conitin% o& o&t %elatin ca(ule &ille' +ith li2ui' 'ru%. Such "tem create a !er"
hi%h 'ru% concentration in the u$lin%ual re%ion $e&ore the" are "temicall"
a$or$e' acro the mucoa. The $uccal mucoa i coni'era$l" le (ermea$le than
the u$lin%ual area# an' i %enerall" not a$le to (ro!i'e the ra(i' a$or(tion an' %oo'
$ioa!aila$ilitie een +ith u$lin%ual a'minitration. 6ocal 'eli!er" to tiue o& the
oral ca!it" ha a num$er o& a((lication# inclu'in% the treatment o& toothache 3304#
(erio'ontal 'ieae 331# 324# $acterial an' &un%al in&ection 3334# a(hthou an' 'ental
tomatiti 3344# an' in &acilitatin% tooth mo!ement +ith (rota%lan'in 3354.
7!en thou%h the u$lin%ual mucoa i relati!el" more (ermea$le than the $uccal
mucoa# it i not uita$le &or an oral tranmucoal 'eli!er" "tem. The u$lin%ual
re%ion lac. an e,(ane o& mooth mucle or immo$ile mucoa an' i contantl"
+ahe' $" a coni'era$le amount o& ali!a ma.in% it 'i&&icult &or 'e!ice (lacement.
Becaue o& the hi%h (ermea$ilit" an' the rich $loo' u((l"# the u$lin%ual route i
ca(a$le o& (ro'ucin% a ra(i' onet o& action ma.in% it a((ro(riate &or 'ru% +ith hort
'eli!er" (erio' re2uirement +ith in&re2uent 'oin% re%imen. Due to t+o im(ortant
'i&&erence $et+een the u$lin%ual mucoa an' the $uccal mucoa# the latter i a more
(re&erre' route &or "temic tranmucoal 'ru% 'eli!er" 318# 234. 8irt 'i&&erence
$ein% in the (ermea$ilit" characteritic o& the re%ion# +here the $uccal mucoa i le
(ermea$le an' i thu not a$le to %i!e a ra(i' onet o& a$or(tion 3i.e.# more uita$le
&or a utaine' releae &ormulation4. Secon' $ein% that# the $uccal mucoa ha an
e,(ane o& mooth mucle an' relati!el" immo$ile mucoa +hich ma.e it a more
'eira$le re%ion &or retenti!e "tem ue' &or oral tranmucoal 'ru% 'eli!er". Thu
the $uccal mucoa i more &itte' &or utaine' 'eli!er" a((lication# 'eli!er" o& le
(ermea$le molecule# an' (erha( (e(ti'e 'ru%.
Similar to an" other mucoal mem$rane# the $uccal mucoa a a ite &or 'ru% 'eli!er"
ha limitation a +ell. =ne o& the ma*or 'ia'!anta%e aociate' +ith $uccal 'ru%
'eli!er" i the lo+ &lu, +hich reult in lo+ 'ru% $ioa!aila$ilit". <ariou com(oun'
ha!e $een in!eti%ate' &or their ue a $uccal (enetration enhancer in or'er to
increae the &lu, o& 'ru% throu%h the mucoa 3Ta$le 14. Since the $uccal e(ithelium
i imilar in tructure to other trati&ie' e(ithelia o& the $o'"# enhancer ue' to
im(ro!e 'ru% (ermeation in other a$or(ti!e mucoa ha!e $een ho+n to +or. in
im(ro!in% $uccal 'ru% (enetration 3364. Dru% in!eti%ate' &or $uccal 'eli!er" uin%
!ariou (ermeation-a$or(tion enhancer ran%e in $oth molecular +ei%ht an'
(h"icochemical (ro(ertie. Small molecule uch a $ut"ric aci' an' $utanol 3374#
ioni0a$le lo+ molecular +ei%ht 'ru% uch a ac"clo!ir 338# 394# (ro(ranolol 3404#
an' alic"lic aci' 3414# lar%e molecular +ei%ht h"'ro(hilic (ol"mer uch a 'e,tran
3424# an' a !ariet" o& (e(ti'e inclu'in% octreoti'e 3434# leutini0in% hormone
releain% hormone 36/R/4 3444# inulin 3364# an' a5inter&eron 3454 ha!e all $een
tu'ie'.
A erie o& tu'ie 342# 46# 474 on $uccal (ermeation o& $uerelin an' &luorecein
iothioc"anate 38)TC4 la$elle' 'e,tran re(orte' the enhancin% e&&ect o& 'i5 an' tri5
h"'ro," $ile alt on $uccal (enetration. Their reult ho+e' that in the (reence o&
the $ile alt# the (ermea$ilit" o& (orcine $uccal mucoa to 8)TC increae' $" a 1005
200 &ol' com(are' to 8)TC alone. The mechanim o& (enetration enhancement o&
8)TC5la$elle' 'e,tran $" o'ium %l"cocholate 3S1C4 +a ho+n to $e concentration
'e(en'ent 3474. Belo+ 10 m> S1C# $uccal (ermeation +a increae' $" increain%
the intercellular tran(ort an' at 10 m> an' hi%her concentration $" o(enin% u( a
trancellular route. 1an'hi an' Ro$inon
3414 in!eti%ate' the mechanim o& (enetration enhancement o& tran$uccal 'eli!er"
o& alic"lic aci'. The" ue' o'ium 'eo,"cholate an' o'ium laur"l ul&ate a
(enetration enhancer# $oth o& +hich +ere &oun' to increae the (ermea$ilit" o&
alic"lic aci' acro ra$$it $uccal mucoa. Their reult alo u((orte' that the
u(er&icial la"er an' (rotein 'omain o& the e(ithelium ma" $e re(oni$le &or
maintainin% the $arrier &unction o& the $uccal mucoa.
*ab!e 1. 0ist o co"pounds used as ora! "ucosa! per"eation
enhancers
Per"eation Enhancer $eerence6s7
235laur"l ether 3484
A(rotinin 324
A0one 343# 51# 524
Ben0al.onium chlori'e 3534
Cet"l("ri'inium chlori'e 337# 535554
Cet"ltrimeth"lammonium $romi'e 3534
C"clo'e,trin 3454
De,tran ul&ate 3484
6auric aci' 3564
6auric aci'-Bro("lene %l"col 3364
6"o(ho(hati'"lcholine 3494
>enthol 3564
>etho,"alic"late 3484
>eth"loleate 3404
=leic aci' 3404
Bho(hati'"lcholine 3564
Bol"o,"eth"lene 3484
Bol"or$ate 80 337# 45# 544
So'ium 7DTA 32# 43# 484
So'ium %l"cocholate 31# 36# 39# 43# 44# 46# 47# 49# 574
So'ium %l"co'eo,"cholate 336# 41# 42# 44# 465484
So'ium laur"l ul&ate 32# 36# 37# 41# 45# 48# 53# 544
So'ium alic"late 32# 564
So'ium taurocholate 343548# 544
So'ium tauro'eo,"cholate 346# 47# 494
Sul&o,i'e 3364
<ariou al."l %l"coi'e 3504
A num$er o& reearch %rou( 31# 2# 36# 485504 ha!e tu'ie' the &eai$ilit" o& $uccal
mucoal 'eli!er" o& inulin uin% !ariou enhancer in 'i&&erent animal mo'el &or in
!i!o tu'ie. Aun%t et al. 31# 24 +ho ue' o'ium %l"cocholate# o'ium laur"l ul&ate#
o'ium alic"late# o'ium 7DTA 3eth"lene'iamine tetraacetic aci'4# an' a(rotinin on
rat $uccal mucoa notice' an increae in inulin $ioa!aila$ilit" &rom a$out 0.7C
3+ithout enhancer4 to 26527C in the (reence o& o'ium %l"cocholate 35C +-!4 an'
o'ium laur"l ul&ate 35C +-!4.
Similar reult +ere o$taine' uin% 'o% a the animal mo'el &or the in !i!o tu'ie#
+here o'ium 'eo,"cholate an' o'ium %l"cocholate "iel'e' the hi%het
enhancement o& $uccal inulin a$or(tion 3364. Thee tu'ie ha!e all 'emontrate'
the &eai$ilit" o& $uccal 'eli!er" o& a rather lar%e molecular +ei%ht (e(ti'e 'ru% uch
a inulin.
()AP*E$+8
EXPE$I'EN*A0
'E*)ODO0O42 /O$ %,((A0
PE$'EA*ION S*,DIES
8.1 IN+-I*$O 'E*)OD
8.2 IN+-I-O 'E*)OD
8.3 EXPE$I'EN*A0 ANI'A0
SPE(IES
8. EXPE$I'EN*A0 'E*)ODO0O42 /O$ %,((A0
PE$'EA*ION S*,DIES
Be&ore a $uccal 'ru% 'eli!er" "tem can $e &ormulate'# $uccal
a$or(tion-(ermeation tu'ie mut $e con'ucte' to 'etermine the &eai$ilit" o& thi
route o& a'minitration &or the can'i'ate 'ru%. Thee tu'ie in!ol!e metho' that
+oul' e,amine in !itro an'-or in !i!o $uccal (ermeation (ro&ile an' a$or(tion
.inetic o& the 'ru%.
8.1 In vitro 'ethods
At the (reent time# mot o& the in vitro tu'ie e,aminin% 'ru% tran(ort acro
$uccal mucoa ha!e ue' $uccal tiue &rom animal mo'el. Animal are acri&ice'
imme'iatel" $e&ore the tart o& an e,(eriment. Buccal mucoa +ith un'erl"in%
connecti!e tiue i ur%icall" remo!e' &rom the oral ca!it"# the connecti!e tiue i
then care&ull" remo!e' an' the $uccal mucoal mem$rane i iolate'. The mem$rane
are then (lace' an' tore' in ice5col' 34EC4 $u&&er 3uuall" Fre$ $u&&er4 until
mounte' $et+een i'e5$"5i'e 'i&&uion cell &or the in vitro (ermeation e,(eriment.
The mot i%ni&icant 2uetion concernin% the ue o& animal tiue a in vitro mo'el
in thi manner are the !ia$ilit" an' the inte%rit" o& the 'iecte' tiue. /o+ +ell the
'iecte' tiue i (reer!e' i an im(ortant iue +hich +ill 'irectl" a&&ect the reult
an' concluion o& the tu'ie. To 'ate# there are no tan'ar' mean $" +hich the
!ia$ilit" or the inte%rit" o& the 'iecte' tiue can $e aee'. Do+t" et al. 3584
tu'ie' tiue !ia$ilit" $" uin% ATB le!el in ra$$it $uccal mucoa. :in% ATB le!el
a an in'icator &or tiue !ia$ilit" i not necearil" an accurate meaure# ho+e!er.
Do+t" et al. re(orte' a 50C 'ro( in the tiue ATB concentration 'urin% the initial 6
hour o& the e,(eriment +ithout a corre(on'in% 'ro( in tiue (ermea$ilit". De(ite
certain %ra'ual chan%e# the $uccal tiue eem to remain !ia$le &or a rather lon%
(erio' o& time. There&ore# a 'ecreae in ATB le!el 'oe not aure a 'ro( in
(ermea$ilit" characteritic o& the tiue. The mot meanin%&ul metho' to ae
tiue !ia$ilit" i the actual (ermeation e,(eriment itel&# i& the 'ru% (ermea$ilit"
'oe not chan%e 'urin% the time coure o& the tu'" un'er the (eci&ic e,(erimental
con'ition o& (/ an' tem(erature# then the tiue i coni'ere' !ia$le.
Buccal cell culture ha!e alo $een u%%ete' a ue&ul in !itro mo'el &or $uccal
'ru% (ermeation an' meta$olim 325# 595614. /o+e!er# to utili0e thee culture cell
&or $uccal 'ru% tran(ort# the num$er o& 'i&&erentiate' cell la"er an' the li(i'
com(oition o& the $arrier la"er mut $e +ell characteri0e' an' controlle'. Thi ha
not "et $een achie!e' +ith the $uccal cell culture ue' thu &ar.
8.2 In vivo 'ethods
)n !i!o metho' +ere &irt ori%inate' $" Bec.ett an' Tri%% 3624 +ith the o5calle'
$uccal a$or(tion tet. :in% thi metho'# the .inetic o& 'ru% a$or(tion +ere
meaure'. The metho'olo%" in!ol!e the +irlin% o& a 25 ml am(le o& the tet
olution &or u( to 15 minute $" human !olunteer &ollo+e' $" the e,(ulion o& the
olution. The amount o& 'ru% remainin% in the e,(elle' !olume i then 'etermine' in
or'er to ae the amount o& 'ru% a$or$e'. The 'ra+$ac. o& thi metho' inclu'e
ali!ar" 'ilution o& the 'ru%# acci'ental +allo+in% o& a (ortion o& the am(le
olution# an' the ina$ilit" to locali0e the 'ru% olution +ithin a (eci&ic ite 3$uccal#
u$lin%ual# or %in%i!al4 o& the oral ca!it". <ariou mo'i&ication o& the $uccal
a$or(tion tet ha!e $een carrie' out 3635664 correctin% &or ali!ar" 'ilution an'
acci'ental +allo+in%# $ut thee mo'i&ication alo u&&er &rom the ina$ilit" o& ite
locali0ation.
A &eai$le a((roach to achie!e a$or(tion ite locali0ation i to retain the 'ru% on the
$uccal mucoa uin% a $ioa'hei!e "tem 3675694. Bharmaco.inetic (arameter uch
a $ioa!aila$ilit" can then $e calculate' &rom the (lama concentration !. time
(ro&ile. =ther in !i!o metho' inclu'e thoe carrie' out uin% a mall (er&uion
cham$er attache' to the u((er li( o& anetheti0e' 'o% 370# 714. The (er&uion
cham$er i attache' to the tiue $" c"anoacr"late cement. The 'ru% olution i
circulate' throu%h the 'e!ice &or a (re'etermine' (erio' o& time an' am(le &raction
are then collecte' &rom the (er&uion cham$er 3to 'etermine the amount o& 'ru%
remainin% in the cham$er4 an' $loo' am(le are 'ra+n a&ter 0 an' 30 minute 3to
'etermine amount o& 'ru% a$or$e' acro the mucoa4.
8.3. E&peri"enta! Ani"a! Species
Ai'e &rom the (eci&ic metho'olo%" em(lo"e' to tu'" $uccal 'ru%
a$or(tion-(ermeation characteritic# (ecial attention i +arrante' to the choice o&
e,(erimental animal (ecie &or uch e,(eriment. 8or in vivo in!eti%ation# man"
reearcher ha!e ue' mall animal inclu'in% rat 31# 36# 374 an' hamter 351# 54#
724 or (ermea$ilit" tu'ie. /o+e!er# uch choice erioul" limit the !alue o& the
'ata o$taine' ince# unli.e human# mot la$orator" animal ha!e an oral linin% that i
totall" .eratini0e'. The rat ha a $uccal mucoa +ith a !er" thic.# .eratini0e' ur&ace
la"er. The ra$$it i the onl" la$orator" ro'ent that ha non5.eratini0e' mucoal linin%
imilar to human tiue an' ha $een e,teni!el" utili0e' in e,(erimental tu'ie 348#
55# 58# 73# 744. The 'i&&icult" in uin% ra$$it oral mucoa# ho+e!er# i the u''en
tranition to .eratini0e' tiue at the mucoal mar%in ma.in% it har' to iolate the
'eire' non5.eratini0e' re%ion 3214.
The oral mucoa o& lar%er e,(erimental animal that ha $een ue' &or (ermea$ilit"
an' 'ru% 'eli!er" tu'ie inclu'e mon.e" 3754# 'o% 334# 57# 65# 704# an' (i% 342#
47# 765804. Due to the 'i&&icultie aociate' +ith maintenance o& mon.e"# the" are
not !er" (ractical mo'el &or $uccal 'ru% 'eli!er" a((lication. )ntea'# 'o% are
much eaier to maintain an' coni'era$l" le e,(eni!e than mon.e" an' their
$uccal mucoa i non5.eratini0e' an' ha a cloe imilarit" to that o& the human
$uccal mucoa. Bi% alo ha!e non5.eratini0e' $uccal mucoa imilar to that o&
human an' their ine,(eni!e han'lin% an' maintenance cot ma.e them an e2uall"
attracti!e animal mo'el &or $uccal 'ru% 'eli!er" tu'ie.
)n &act# the oral mucoa o& (i% reem$le that o& human more cloel" than an" other
animal in term o& tructure an' com(oition 320# 814. /o+e!er# &or ue in in vivo
tu'ie (i% are not a i'eal a 'o% 'ue to their ra(i' %ro+th +hich ren'er the
animal han'lin% rather 'i&&icult.
>iniature $ree' o& (i% can $e ue' $ut their hi%h cot i a 'eterrent. 8or in !itro
tu'ie thou%h# $ecaue o& ea" a!aila$ilit" an' lo+ cot (orcine tiue i more uite'
a com(are' to 'o% $uccal tiue.


()AP*E$ +9
%,((A0 D$,4 DEI-E$2 S2S*E'S
9. %,((A0 D$,4 DE0I-E$2 S2S*E'S
=ther than the lo+ &lu, aociate' +ith $uccal mucoal 'eli!er"# a ma*or limitation
o& the $uccal route o& a'minitration i the lac. o& 'oa%e &orm retention at the ite o&
a$or(tion. Cone2uentl"# $ioa'hei!e (ol"mer ha!e e,teni!el" $een em(lo"e' in
$uccal 'ru% 'eli!er" "tem. Bioa'hei!e (ol"mer are 'e&ine' a (ol"mer that can
a'here onto a $iolo%ical u$trate. The term mucoa'heion i a((lie' +hen the
u$trate i mucoal tiue 3274.
Bol"mer +hich can a'here to either har' or o&t tiue ha!e $een ue' &or man" "ear
in ur%er" an' 'entitr". Di!ere clae o& (ol"mer ha!e $een in!eti%ate' &or their
(otential ue a mucoa'hei!e.
Thee inclu'e "nthetic (ol"mer uch a monomeric a c"anoacr"late 3824#
(ol"acr"lic aci' 3824# h"'ro,"(ro("l meth"lcelluloe 3174# an' (ol" methacr"late
'eri!ati!e a +ell a naturall" occurrin% (ol"mer uch a h"aluronic aci' 3844 an'
chitoan 3854. =ther "nthetic (ol"mer uch a (ol"urethane# e(o," rein#
(ol"t"rene# an' natural5(ro'uct cement ha!e alo $een e,teni!el" in!eti%ate' 3864.
)n %eneral# 'oa%e &orm 'ei%ne' &or $uccal a'minitration houl' not caue
irritation an' houl' $e mall an' &le,i$le enou%h to $e acce(te' $" the (atient. Thee
re2uirement can $e met $" uin% h"'ro%el. /"'ro%el are h"'ro(hilic matrice that
are ca(a$le o& +ellin% +hen (lace' in a2ueou me'ia 3874. ;ormall"# h"'ro%el are
crolin.e' o that the" +oul' not 'iol!e in the me'ium an' +oul' onl" a$or$
+ater. When 'ru% are loa'e' into thee h"'ro%el# a +ater i a$or$e' into the
matri,# chain rela,ation occur an' 'ru% molecule are releae' throu%h the (ace or
channel +ithin the h"'ro%el net+or.. )n a more $roa' meanin% o& the term#
h"'ro%el +oul' alo inclu'e +ater5olu$le matrice that are ca(a$le o& +ellin% in
a2ueou me'ia# thee inclu'e natural %um an' celluloe 'eri!ati!e. Thee @(eu'o5
h"'ro%elA +ell in&initel" an' the com(onent molecule 'iol!e &rom the ur&ace o&
the matri,.
Dru% releae +oul' then occur throu%h the (ace or channel +ithin the net+or. a
+ell a throu%h the 'iolution an'-or the 'iinte%ration o& the matri,. The ue o&
h"'ro%el a a'hei!e (re(aration &or tranmucoal 'ru% 'eli!er" ha ac2uire'
coni'era$le attention in recent "ear. Ta$le 2 ummari0e the relate' reearch on
mucoa'hei!e (ol"mer an' 'eli!er" "tem.
*ab!e 2. $e!ated research on "ucoadhesive po!#"ers and de!iver#
s#ste"s
%ioadhesive Po!#"er6s7
Studied
Investigation Ob:ectives $eerence
/BC an' CB
Bre&erre' mucoa'hei!e tren%th
on CB# /BC# an' /BC5CB
com$ination
3574
/BC an' CB >eaure' Bioa'hei!e (ro(ert"
uin% moue (eritoneal mem$rane
3884
CB# /BC# B<B# C>C Stu'ie' inter (ol"mer
com(le,ation an' it e&&ect on
$ioa'hei!e tren%th
3894
CB an' /B>C 8ormulation an' e!aluation o&
$uccoa'hei!e controlle' releae
'eli!er" "tem
3904
/BC# /7C# B<B# an' B<A Tete' mucoal a'heion on
(atche +ith t+o5(l" laminate
+ith an im(ermea$le $ac.in% la"er
an' h"'rocolloi' (ol"mer la"er
3914
/BC an' CB :e' /BC5CB (o+'er mi,ture a
(eri(heral $ae &or tron% a'heion
an' /BC5CB &ree0e 'rie' mi,ture
a core $ae
3304
CB# B)B# an' B)B :e' a t+o roll millin% metho' to
(re(are a ne+ $ioa'hei!e (atch
&ormulation
3924
Ganthum %um an' 6ocut
$ean %um
/"'ro%el &ormation $"
com$ination o& natural %um
3934
Chitoan# /BC# C>C# Bectin#
Gantham %um# an'
Bol"car$o(hil
7!aluate mucoa'hei!e (ro(ertie
$" routinel" meaurin% the
'etachment &orce &orm (i%
intetinal mucoa
3854
/"aluronic aci' $en0"l
eter# Bol"car$o(hil# an'
/B>C
7!aluate mucoa'hei!e (ro(ertie 3844
/"'ro,"eth"lcelluloe Dei%n an' "nthei o& a $ila"er
(atch 3(ol"te&5'i.4 &or th"roi'
%lan' 'ia%noi
3944
Bol"car$o(hil Dei%n o& a uni'irectional $uccal
(atch &or oral mucoal 'eli!er" o&
(e(ti'e 'ru%
3704
Bol"3acr"lic aci'4 an'
Bol"3methacr"lic aci'4
S"nthei0e' an' e!aluate'
crolin.e' (ol"mer 'i&&erin% in
char%e 'enitie an'
h"'ro(ho$icit"
3824
;um$er o& Bol"mer
inclu'in% /BC# /B>C# CB#
C>C.
>eaurement o& $ioa'hei!e
(otential an' to 'eri!e meanin%&ul
in&ormation on the tructural
re2uirement &or $ioa'heion
3864
Bol"3acr"lic aci'5co5
acr"lami'e4
A'heion tren%th to the %atric
mucu la"er a a &unction o&
crolin.in% a%ent# 'e%ree o&
+ellin%# an' car$o,"l %rou(
'enit"
3954
Bol"3acr"lic aci'4 7&&ect o& BAA molecular +ei%ht
an' crolin.in% concentration on
+ellin% an' 'ru% releae
characteritic
3964
Bol"3acr"lic aci'5co5meth"l
methacr"late4
7&&ect o& (ol"mer tructural
&eature on mucoa'heion
383# 974
Bol"3acr"lic aci'5co5
$ut"lacr"late4
Relationhi( $et+een tructure
an' a'heion &or mucoa'hei!e
(ol"mer
3164
/7>A co(ol"meri0e' +ith
Bol"me%
H

3(ol"tetrameth"lene %l"col4
Bioa'hei!e $uccal h"'ro%el &or
controlle' releae 'eli!er" o&
$u(renor(hine
3984
C"'ot
H
$" 3> 3$ioa'hei!e
(ol"meric $len' o& CB an'
B)B4
Batch "tem &or $uccal
mucoa'hei!e 'ru% 'eli!er"
369# 994
8ormulation conitin% o&
B<B# CB# an' cet"l("ri'inium
chlori'e 3a ta$ili0er4
De!ice &or oramucoal 'eli!er" o&
6/R/ 5 'e!ice containin% a &at
releae an' a lo+ releae la"er
3444
C>C# Car$o(ol 974B#
Car$o(ol 7G555# Bectin 3lo+
!icoit"4# Chitoan chlori'e#
>ucoa'hei!e %el &or intraoral
'eli!er"
31004
C>C# CB# Bol"eth"lene
o,i'e#
Bol"meth"l!in"lether->aleic
anh"'ri'e 3B>7->A4# an'
Tra%acanth
Buccal mucoa'hei!e 'e!ice &or
controlle' releae antican'i'al
'e!ice 5 C>C ta$let "iel'e' the
hi%het a'hei!e &orce
31014
/B>C an' Bol"car$o(hil
3BC4
Buccal mucoa'hei!e ta$let +ith
o(timum $len' ratio o& 80920 BC to
/B>C "iel'in% the hi%het &orce o&
a'heion
31024
B<B# Bol"3acr"lic aci'4 Tranmucoal controlle' 'eli!er" 3103# 1044
o& ioor$i'e 'initrate
Bol"3acr"lic aci'5co5(ol"
eth"lene%l"col4 co(ol"mer o&
acr"lic aci' an' (ol"
eth"lene%l"col
monometh"lether
monomethacr"alte
To enhance the mucoa'hei!e
(ro(ertie o& BAA &or $uccal
mucoa'hei!e 'ru% 'eli!er"
310551074
Bol" acr"lic aci' an' (ol"
eth"lene %l"col
To enhance mucoa'hei!e
(ro(ertie o& BAA $" inter(ol"mer
com(le,ation throu%h tem(late
(ol"meri0ation
31084
Drum 'rie' +a," mai0e
tarch 3DDW>4# Car$o(ol
974B# an' o'ium
tear"l&umarate
Bioa'hei!e ero'i$le $uccal ta$let
&or (ro%eterone 'eli!er"
31094
Abbreviations9(PICar$o(ol934B#)P(I/"'ro," (ro("l celluloe#P-PIBol"!in"l
("rroli'one4#('(3So'iumcar$o,"meth"lcelluloe4#)P'(3/"'ro,"(ro("lmeth"l
celluloe#
)E(I/"'ro,"eth"lcelluloe#P-AIBol"3!in"lalcohol4#PI%3Bol"3io$ut"lene4#
PIPBol"3io(rene4.
;a%ai et al. 3354 tu'ie' the a((lica$ilit" o& h"'ro,"(ro("l celluloe 3/BC4 a a
mucoa'hei!e a%ent# the" &oun' thi hi%h !icoit" %ra'e material to $e a uita$le
a'hei!e &or to(ical mucu mem$rane. The" re(orte' the com$ination o& /BC an'
car$o(ol 934B 3CB4 to (ro'uce a (re&era$le material &or mucoa'hei!e 'oa%e &orm.
The" e,amine' 'irectl" com(ree' ta$let o& thee (ol"mer $" (lacin% them on an
a%ar %el $e'. /BCta$let ho+e' a li%ht a'heion $ut 'iol!e' eail" on the %el $e'.
=n other ta$let tron% +ollen CB ta$let eeme' too har'. The com$ination o& /BC
an' CB (ro!i'e' the mucoa'heion an' a'e2uate o&tne to (re(are the ta$let. Satoh
et al. 3884 meaure' the $ioa'hei!e (ro(ert" o& ta$let conitin% o& /BC an' CB
uin% moue (eritoneal mem$rane.
The a'hei!e &orce o& the /BC5CB ta$let +a a&&ecte' $" the mi,in% ratio o& /BC
an' CB. The a'heion &orce ho+e' a minimum !alue at the mi,in% ratio o& 392
3/BC9CB4 'ue to the &ormation o& an inter5(ol"mer com(le, $et+een /BC an' CB in
the aci'ic (/ ran%e.
Com(le, &ormation $et+een CB an' /BC eeme' to u((re the interaction $et+een
molecule o& h"'ro%el an' the mucu mem$rane# an' the a'heion &orce +a
there&ore mot re'uce' at a mi,ture ratio o& 194 3/BC-CB4. )nter5(ol"mer
com(le,ation an' it e&&ect on $ioa'hei!e tren%th +a alo tu'ie' $" 1u(ta et al.
3894. The" re(orte' that CB ho+ tron% com(le,ation +ith (ol"3!in"l ("rroli'one4
an' h"'ro,"(ro("l celluloe# $ut !er" little +ith o'ium car$o," meth"l celluloe.
The 'e%ree o& com(le,ation +a hi%her at aci'ic (/ an' 'ecreae' +ith an increae in
(/. Anlar et al. 3904 re(orte' on &ormulation an' e!aluation o& $uccoa'hei!e
controlle' releae "tem &or the 'eli!er" o& mor(hine ul&ate. The" (re(are' ta$let
$" 'irect com(reion o& car$omer an' h"'ro,"(ro("l meth"l celluloe 3/B>C4 an'
&oun' the 'ru% releae $eha!ior to $e non58ic.ian an' alo con&irme' inter(ol"mer
com(le, &ormation $et+een /B>C an' car$omer in aci'ic (/ me'ium.
An'er an' >er.le 3914# 'e!elo(e' an' e!aluate' a'hei!e (atche &or $uccal
a'minitration# conitin% o& t+o5(l" laminate o& an im(ermea$le $ac.in% la"er an'
a h"'rocolloi' (ol"mer la"er containin% the 'ru%. The (ol"mer ue' /BC# /7C#
B<B# an' B<A. The inte%rit" o& the laminate +a $ae' on a'hei!e $on' $et+een
the h"'rocolloi' la"er an' an a%aroe la"er %ra&te' to one i'e o& the $ac.in% la"er
heet. Their +or. ho+e' that amon% the celluloe ether tu'ie' /7C an' /BC
(oee' u(erior mucoal a'heion. )hi'a et al. 3304 utili0e' imilar material in a
li'ocaine 'eli!er" "tem &or toothache. The" ue' an /BC5CB (o+'er mi,ture a a
(eri(heral $ae aimin% at tron% a'heion# $ut an /BC5CB &ree0e5'rie' mi,ture +a
ue' a a core $ae. /BC an' CB &orme' a com(le, 'urin% the &ree0e 'r"in% (roce#
an' thi contri$ute' to the eae o& a'mi,in% $" $loc.a%e o& the &unctional %rou( o&
CB. 1uo 3924 ue' a t+o roll millin% metho' to (re(are a ne+ $ioa'hei!e (ol"mer
(atch &ormulation &or controlle' 'ru% 'eli!er" conitin% o& CB# B)B# an' B)B. )t +a
&oun' that the ur&ace (ro(ertie o& $uccal (atche +ere not onl" 'e(en'ent on the CB
content $ut alo 'e(en'ent on the B)B9B)B ratio. The tron%et (eel tren%th +a
&oun' on $uccal (atche +ith a CB9B)B9B)B ratio o& 50943.7596.25.
Watana$e et al. 3934 re(orte' on h"'ro%el &orme' $" the com$ination o& natural
%um# ,antham %um# an' locut $ean %um# +hich are a((lica$le in $uccal 'eli!er"
"tem. Gantham %um i a natural %um o$taine' throu%h &ermentation o& %lucoe $"
Xanthamonas campestris. 6ocut $ean %um an' ,antham %um alone cannot &orm a
h"'ro%el. /o+e!er# +hen a mi,ture o& thee %um i 'iol!e' in a neutral me'ium at
90EC an' then coole' +ith ice &or 30 min# a clear# tron% h"'ro%el i &orme'. The
mechanim o& %el &ormation +a re(orte' to $e the &ormation o& a three 'imenional
net+or. $" interaction $et+een the 'ou$le heli, tructure o& ,antham %um an' the
trai%ht molecular chain o& locut $ean %um. The %el tren%th o& the h"'ro%el +a
a&&ecte' $" the mi,in% ratio o& the %um# an' the a''ition o& ucroe im(ro!e' the
utaine' releae (ro(ertie o& the h"'ro%el. The h"'ro%el conitin% o& ,antham
%um an' locut $ean %um ho+e' onl" a lo+ mucoa'heion# $ut it can $e a((lie' to a
$uccal 'eli!er" "tem $ecaue o& it a&et"# %el tren%th# utaine' releae (ro(ertie
an' %oo' &eel in the mouth.
An'er et al. 3944 'ei%ne' a $ila"er (atch 3(ol"te&5'i.4 conitin% o& (rotirelin &or
th"roi' %lan' 'ia%noi. The (atch ha' a $ac.in% la"er o& te&lon an' mucoa'hei!e
la"er o& (rotirelin 'i(ere' in h"'ro,"eth"lcelluloe. <eillar' et al. 3704 re(orte' the
ue o& a uni'irectional $uccal (atch +hich conite' o& three la"er9 an im(ermea$le
$ac.in% la"er# a rate limitin% center mem$rane containin% the 'ru%# an' a
mucoa'hei!e la"er containin% $ioa'hei!e (ol"mer (ol"car$o(hil. The $ioa'hei!e
(ol"mer +ell# creatin% a &le,i$le net+or. throu%h +hich 'i&&uion o& 'ru% ta.e
(lace. Thi (atch +a tete' in 'o% $uccal mucoa an' +a ho+n to remain in (lace
&or u( to 17 hour +ithout an" o$!iou 'icom&ort.
ChAn% et al. 3824 "nthei0e' an' e!aluate' a erie o& crolin.e'# +ella$le
(ol"mer o& acr"lic aci' an' methacr"lic aci'# 'i&&erin% in char%e 'enitie an'
h"'ro(ho$icit". The" &oun' that an increae in the num$er o& h"'ro(ho$ic %rou( in
the (ol"mer tructure re'uce' h"'ration +herea the 'enit" o& the (ol"mer +a
una&&ecte'. 8urthermore# (ol"mer o& acr"lic aci' looel" crolin.e' 30.3 C +-+4
+ith 3 'i&&erent a%ent# 'i!in"l %l"col# 2#55'imeth"l51#55he,a'iene# an' 'i!in"l
$en0ene# ho+e' the ame 'e%ree o& $ioa'heion +hile (ol"3methacr"lic aci'4
crolin.e' +ith 'i!in"l $en0ene ho+e' re'uce' $ioa'heion. The mall (ercent o&
crolin.in% a%ent# irre(ecti!e o& (h"icochemical (ro(ertie# 'i' not contri$ute
u$tantiall" to $ioa'heion# +herea the tartin% monomer ha' a lar%e e&&ect. The
e&&ect o& (/ on the $ioa'heion o& (ol"3acr"lic aci'4 crolin.e' +ith 'i!in"l %l"col
+a alo tu'ie' at contant tem(erature# ionic tren%th# an' omolalit". )t +a &oun'
that the (ol"mer ho+e' ma,imum a'heion at (/ 5 an' 6 an' a minimum at (/ 7.
Bar. an' Ro$inon 3864 e,amine' a lar%e num$er o& (ol"mer a to their $ioa'hei!e
(otential an' to 'eri!e meanin%&ul in&ormation on the tructural re2uirement &or
$ioa'heion. The" conclu'e' that char%e' car$o,"late' (ol"anion are %oo' (otential
$ioa'hei!e &or 'ru% 'eli!er". To un'ertan' the role o& the car$o,"l %rou( in
mucoa'heion# acr"lic aci'5acr"lami'e ran'om co(ol"mer JB3AA5co5A>4K +ere
"nthei0e' 3954 an' the a'heion tren%th o& the crolin.e' (ol"mer to the %atric
mucu la"er a a &unction o& (/# initial concentration o& the crolin.in% a%ent# 'e%ree
o& +ellin%# an' car$o,"l %rou( 'enit" +ere e,amine'. 8rom the tu'" on
mucoa'heion o& !ariou B3AA5co5A>4# it +a &oun' that at leat 80C o& the !in"l
%rou( o& the (ol"mer mut (oe car$o,"l %rou( in the (rotonate' &orm. The
'e(en'ence o& mucoa'heion on (/ an' car$o,"l5%rou( 'enit" u%%et that
mucoa'heion occur throu%h h"'ro%en $on'in%. )n a''ition# the 'enit" o& the
crolin.in% a%ent i%ni&icantl" a&&ect mucoa'heion. A the 'enit" o& the
crolin.in% a%ent i lo+ere'# the mucoa'hei!e tren%th increae# althou%h the
'enit" o& car$o,"l %rou( in the tet ur&ace area i re'uce'. )t +a conclu'e' that
&or mucoa'heion to occur# (ol"mer mut ha!e &unctional %rou( that are a$le to
&orm h"'ro%en $on' a$o!e the critical concentration 380C &or !in"l (ol"mer4# an'
the (ol"mer chain houl' $e &le,i$le enou%h to &orm a man" h"'ro%en $on' a
(oi$le. Similar reult +ere achie!e' $" 1arcia51on0ale0 et al. 3964 +ho e!aluate'
the e&&ect o& (ol"3acr"lic aci'4 3BAA4 molecular +ei%ht an' the concentration o&
crolin.in% a%ent 3ucroe4 on +ellin% an' 'ru% 3metoclo(rami'e4 releae
characteritic o& BAA 3car$o(ol4 h"'ro%el. The" re(orte' that $oth &actor an' the
interaction term ha' i%ni&icant e&&ect on h"'ro%el +ellin% an' 'ru% releae. )n
(articular# the" &oun' that increae' ucroe concentration 3hi%h crolin.in% 'enit"4
le' to re'uce' +ellin% an' re'uce' 'ru% releae e&&icienc".
6eun% an' Ro$inon 383# 974 tu'ie' the contri$ution o& anionic (ol"mer tructural
&eature to mucoa'heion uin% 0.2C crolin.e' co(ol"mer o& acr"lic aci' an'
meth"l methacr"late. Their reult ho+e' that the e,(an'e' nature o& $oth the
interactin% mucu an' (ol"mer net+or. in&luence the tren%th o& mucoa'heion.
The" conclu'e' that mucoa'hei!e (ol"mer +ith the 'eire' mucoa'hei!e tren%th
can $e 'ei%ne' $" controllin% the (ercenta%e o& char%e' %rou( an' the
corre(on'in% o(enne o& the net+or..
Bo''e et al. 3164 in!eti%ate' relationhi( $et+een tructure an' a'heion &or
mucoa'hei!e (ol"mer. Their tu'" +a $ae' on an aum(tion that $ioa'heion
houl' (oe t+o (ro(ertie9 3i4 o(timal (olarit" to ma.e ure the (ol"mer i
L+ette'L $" the mucu# an' 3ii4 o(timal &lui'it" to allo+ &or the mutual a'or(tion an'
inter(enetration o& (ol"mer an' mucu to ta.e (lace. The" tu'ie' acr"lic (ol"mer
&ilm# 'ei%ne' &or $uccal 'ru% 'eli!er". The &ilm +ere ma'e either throu%h mi,in%
or co(ol"meri0ation o& (ol" 3$ut"l acr"late4 an' (ol"3acr"lic aci'4. )n $oth cae
ati&actor" mucoa'heion +a &oun' +ithin a ran%e o& com(oition o(timi0e' &or
ur&ace (olarit" an' the &lui'it" o& the (ol"mer &ilm.
)n an attem(t to enhance the intrinic mucoa'hei!e (ro(ertie o& (ol" 3acr"lic aci'4#
Sho*aei an' 6i 310551074 'ei%ne' an' &ormulate' a erie o& no!el co(ol"mer o&
acr"lic aci' an' (ol" eth"lene%l"col monometh"lether monomethacr"late JB3AA5co5
B714K. The a''ition o& B71 into the (ol"mer increae' the (otential &or h"'ro%en
$on' &ormation# ince the lone (air electron o& o,"%en in the re(eat unit 3C/
2
C/
2
=4
o& B71 er!e' a h"'ro%en $on' acce(tor 31074. The ur&ace (ro(ertie o& BAA &or
mucoa'heion +ere alo im(ro!e' $" the B71 incor(oration 31074. :in% thee
co(ol"mer# a (atch 'e!ice +a (re(are' &or $uccal ac"clo!ir 'eli!er" an' the
&eai$ilit" o& uch 'eli!er" +a (ro!en in !itro +ith the incor(oration o& o'ium
%l"cocholate a the (ermeation enhancer 3394.
:in% co(ol"meric h"'ro%el 'ic o& /7>A 3monomer4 an' Bol"me%
H
3macromer4 a
$uccal mucoa'hei!e 'e!ice &or controlle' releae o& $u(renor(hine +a 'e!elo(e'
3984. The h"'ro%el containin% a monomer9macromer ratio o& 80920 3+-+4 "iel'e' the
$et reult $oth in term o& a'heion an' 'ru% releae. The 'e!ice +a a((lie' &or a 3
hour a((lication time an' tea'" tate le!el +ere maintaine' &or the time o&
a((lication. 8ormulation o& another $uccal 'eli!er" "tem +a re(orte' $"
De1ran'e et al. 369# 994 &rom the 3> com(an". The $uccal (atch 'e!ice 3C"'otM 3>
Bharmaceutical# St. Baul# >;4 conit o& a &le,i$le mucoa'hei!e matri, com(oe'
o& a $len' o& (ol"3acr"lic aci'4 3Car$o(ol 934BM B.8. 1oo'rich# Cle!elan'# =/4 an'
(ol"3io$ut"lene4 3<itane,M 7,,on Chemical Com(an"# /outon# TG4. The (atch
'e!ice i uni'irectional +ith a (ol"urethane $ac.in% la"er. The (atch i inten'e' &or
a((lication to the u((er %um an' in !i!o tu'ie in human u$*ect ha!e re!eale'
e&&ecti!e $ioa'hei!e characteritic &or 12 hour o& a((lication 3694. Se!eral
in!eti%ator ha!e re(orte' on the 'e!elo(ment o& TmT 3tranmucoal thera(eutic
"tem4 'e!ice +ith a &iel'5ha(e' $ila"er 'ei%n conitin% o& &at5releae an'
utaine'5releae la"er 344# 103# 1044. The &at releae la"er contain B<B a the
$ioa'hei!e com(onent an' i 'ei%ne' to a'here to the $uccal mucoa an' the
utaine' releae la"er conit o& a mi,ture o& B<B an' (ol"3acr"lic aci'4 an' i
inten'e' to a'here to the %in%i!al mucoa 31034. >ot recentl"# a TmT &ormulation
+a re(orte' &or the $uccal 'eli!er" o& 6/R/ 3luetini0in% hormone releain%
hormone4 3444 +ith reult in'icatin% the &eai$ilit" o& controlle' releae tranmucoal
'eli!er" o& the (e(ti'e 'ru%.
()AP*E$+1
(ON(0,SION


1.(ON(0,SION
The $uccal mucoa o&&er e!eral a'!anta%e &or controlle' 'ru% 'eli!er" &or
e,ten'e' (erio' o& time. The mucoa i +ell u((lie' +ith $oth !acular an'
l"m(hatic 'raina%e an' &irt5(a meta$olim in the li!er an' (re5"temic
elimination in the %atrointetinal tract are a!oi'e'. The area i +ell uite' &or a
retenti!e 'e!ice an' a((ear to $e acce(ta$le to the (atient. With the ri%ht 'oa%e
&orm 'ei%n an' &ormulation# the (ermea$ilit" an' the local en!ironment o& the
mucoa can $e controlle' an' mani(ulate' in or'er to accommo'ate 'ru% (ermeation.
Buccal 'ru% 'eli!er" i a (romiin% area &or continue' reearch +ith the aim o&
"temic 'eli!er" o& orall" ine&&icient 'ru% a +ell a a &eai$le an' attracti!e
alternati!e &or non5in!ai!e 'eli!er" o& (otent (e(ti'e an' (rotein 'ru% molecule.
/o+e!er# the nee' &or a&e an' e&&ecti!e $uccal (ermeation-a$or(tion enhancer i a
crucial com(onent &or a (ro(ecti!e &uture in the area o& $uccal 'ru% 'eli!er".



(hapter+;
$E/E$EN(ES


;. $E/E$EN(ES
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20. /oo%traate# A.N.# <erhoe&# N.C.# Tu.# B.# Bi*(er# A.# !an leen%oe'# 6.A.>.1.#
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21. Wolan"# 1.N.>.# >un0er# N.# Rummelt# A.# an' >er.le# /.B.# Buccal a$or(tion
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22. ;a.ane# S.# Fa.umoto# >.# Oulimatu# F.# an' Chien# O.W.# =ramucoal
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24. Senel# S.# /oo%traate# A.N.# S(ie# 8.# <erhoe&# N.C.# Bo5!an 1eet# A.#
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