Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~` . '. ,3' !':J^.~M C~ Irl ~ ?.~T-~ EP.~TME~I`r N~ 3il,~ P. ~/39
1113l~
The pr~sent inv~ntion relates to an i~p~oved arl~cle and ~h~d
for medica~ion delivery or more particularly to ~n i:lpxsved dru~
xelease art~ cle suitable ~o~ d~live~i~g a m63~icaale~lt directl~
in~o the p~riodt~ntal poe~cet o a patierlt. ~t is ~nown i~
art to deliver actiYe ag~nts t~ the per~odon~l pock~t ~or
pe~iodont~l therapy ~r ira~ ion ,ed;~ction. ~ n thi~ regard i'c
is known ~o incorpor~te antib~ct~ l or ~sti~ ~a~o~y
m~rial lnto ~hin, monolithic s~ri~ fo:r in~er~:ion intv th~
p~rio~ontal poa~c~t. In ~e in~nc~, d.ixect appllca~c~on o~
medical~ion to an afPec:t~d a~a is r~or~ d~sirable ~h~ ys
t~ea~nt ;ria inge~tion. Syste~ic tr~3~2n~ u~ually involv~
drug of hig~r dose than i6 n2c~s~ary co~pare~ loc~l
appl i~at~on. rrhis situation c~n ~e sigrli~ica1~t ~ p~ nt~ wlth
allergic t~ndenci~ r ~id~ e~ct~ to the r~air~d activ~a a~nt7
Al~o, 5y~t:~31ie: th~r~py proYid~ hi~h ~re~t~t do~3 wh~c:h
~'Ct nua1:~ guicltly and ~11U8t~ ep~ated ov4æy ~ hour~
Periodont~l s rlp~ are know~ an~ are advanta~30~s n~:e th~y c:an ~:
}~æ positione~ d~ re~'cly on th~ a:~e~l~ed area thus provldi~ a ~ .
rel~ti~rely hi~h do~e o~ a~C:tiYB ~gent ar~ec!l ~ a ~all r~gio~
with lit~l@ actisr~ ag~nt b~ trar~3~err~d to ~h~3 r~t o~
pa~i~nt's body. The ~trip, once irl~erted ~y a ~nt~l
pro~ io~ l, provid~ ~ continuou~ ~p~ SioII o~ the ~c~
ag~nt ~ r a num~er o~ day~. It ha~ ~en A pro~lerr in ~he art to
~ilor the d~ge r~lea~ to th~ p~rtl~ular ~ ge~ to be
... .. .
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33 '::J~ ? ~ )hr~l`d ~JE?.~ThEl.~r N~. 303~ P 5/39
~ed. ~o~rn mc~nolithic periodontal strips so~eti~e~ exhau~t ~e
a¢tive ingre ient prem~turely. In this regard, A~dy, M., at al
~ , J. P~riodontolD ~1982)
'Jol. 52, PS~ 633-69~ hows ~nd e~a3.uate~ m~nol$t~ic acryli~
strip~ ~or dn~ ~elive~y ~ Xi~a~;hi , K., et, al , ~S~
pe~,Qdo~ o~k~t, J~ Periodos~ol. P~es. (1990) Vol. ~S, pg$. l-~i
sho~d~ a mc1no~i~ic perio~ontal in~r~ co:mpri in~i ofloxaci~ ;~n~
hyd~oxypropylceliulo~ . Lindhe , J ., et ~ 4~USY~
, J.
Clinical Per$odontology ~1~79~ Vol. 6~ pgs 141-1~9 show~
p~riodor~tal a~inistra~ lon of te~racyclin~ ~ia hollow ~ r~.
U~S. patent 4,975,271 show~ ~he pl~ ent of a che~otAerap~ul:i~
~ent ~nto the per~Lodon~al poc3cet ~ogeth~3r with ~ ~kin
r~'zior~ an~. U.S~ pat~n~ 4,9~5,Z62 s~ows t:~ 104al
ad~n~ni~r~ion o~ drug r-oJl~in~ng ~e~s andl tapes t~ l~h~
EP app~ca~ion 0 43~ 474 Al ehows treat~nt ~ ~he o~l c~ y
with po~yl~kide/glycolide de~ s.. IJ.S. pat~nt ~I,g81,6~3 sh~
a c:~mpo~ ioal ha~ring a poly~er ad~ix~d with a th~r~peu~içally
active ~ngr~ t. Tl~ x~ur~ 1~ c:~a81: into a ~heet, ~ d a~
i~ox~ed into s~rips ~or pla~ n~ in~o th¢ periodor,~l po~kls~.
~o-lay6~red l~minat~d ~ilms are showrl with ïay~rs 4~ r4~t
poly~er~ h~Ying dlssimil~r solu~ iti~, a~d, 2ach lay~r Ar~
ac~ ingrodiqnt. A thre~ laye~d st~uct~ is not c~nsidered
where ~ c~ er laye~ h~s an actiYe in~redient in ~ixtur~ wi~h a
`.' ~ ,, : ',
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Ge . ~ 3~ I G~A~ Lû.4r- F.~r~ P~rt~ E`~T ~. g l32 ? ~'39
. .
2 1 / 1 3 ~
polymer, and where ~he polymer app~ars on outer lay~rs withc~ut ~
d.rug ¢o~ponerlt. U.5. pat~nts 4,9~0,552 ancl rJ.S. 5/047f244 show a
muLtilayered ~rilayer lamina~e film ~or ~rug delivery. Be~ure
use, pro~cti~e layers are s~ripp~d o~ and the useful s~ru¢'cu~e
is a ~e~ic~tion conta~ g layer which d~e5 not hav~ a coYering,
an 1~50~ e b~rrier l~yer and an ~dhesil~ la~r which allo~s
adhesi~ to t~e inxide of a pa~lent ' ~ cheek~ This stnactur~ i5
not bio-erodi~le. U,S. Pa~ent 4,8~9,720 show~ a dosage rele~s~
structure for oral rather than peria~ontal cld~inistration. The
desig~ ha~ an adhesive layar, barrier layer and drug containing
lay~r. A drug relea6e cont~olling layer surround~ th~ edg~a at
its sid~ 'chus ~loclsi2lg dr~g emiss~on out of ~ side e~ge~.
U,.S. pat0J3~ 3,854,o,80 shows a drug releas~ ~ys~e~D where a ~ug
c~s~tainLng ao~position is en. apau~ted wi~hin ~ pe~lymerio
~rane an~l the drug per~ ate~ thr~ugh th~ polyffler~ Dbra~ne
~v~3r ti~ UPlik~ the pr~sent inv~tion, thB sid~s of the
structure ar~ no~ opsn and the pol~nneri~ ~e~br~n~
~p~ci~i6ally b~ nGn-so~ a~d ~oA-erod~ble ~y b~dy ~luid~
UOS. pat~nt 5, 0~4, ~67 s~ow~ a d0~rio~ for drug ad~inis~ra~io~
wi~hin the! perisdon~cal p~aXe'c. This sh~ws a non-l~yered,
m~nolithic stxu~tur~ U.S~ patent ~,517,173 s3how~ a mu~ou~
~mbr~n~ adh~rin~ having ~ drug contair~ lay~r, wa~r
~oLu~12 l~yer and ~ non-wE~t~ ~ol~le layer to di~che~g~3 dr~gs
into the mouth on ~ releas~ basis. Jap~e~;e pat~
JP4059723 ~howe an adh~si~e ~ilm ~omprisirlg a w~ter soluhla, dr~y
, ....
f ' ,. ~ ' ~ , . ' , :
,,. :
~e 3 ~c3 :~6.~ L~'.TF ~ r!rr~ IE.il~ N~l 8CG" P. ,~3S
-
cont~ining p~ sriG layer and a dnlg controlli rlg layer on one Dr
bot~ si~es of i~.
It ha~ been found that one can improv~ ttpon thç~se pri~r
in~rentions by pro~ ing a ~r1p which gives a continuou~ d~e2 o~
actiYe ag-en~, whi.ch i~ slowly re~eased over an extended peri~d o~
~i~e, u~ually 7~10 d~ys. rrhe ~tr~ctur~ a¢cording to thi~;
i~ven'cion ha a drug con~aining l.ay~r wh~ ch is a mixt,lr~ o~ a
drug and a hio-erDdlble polymer~ ThiS layer is covered 017 it~
kop a~d bottoza s~ aces~ but no'c on its sid~, by a bio-~rodible
polymer layer. 'rh~re are no int~r~e~liary l~yer~ su--h a .
adh~siv~s or plastic fil~s. on6~ plac4~d in th~ pe~iodont~
~so~k~t o~ a patient, a dose of acti~e agent clif~uses olat o~
uno~ared sid~3~ o~ th~ dr~g ~orl~ai~ing layer. O~r~r 'ci
balanc~ is prc~id~d ~i:o th~ patien~ by di~fu~iiot~ ~ ~h~ d~u~
throu~ ~e ~op and J~otto~ layar~.
A~ diBtlngui~h~d ~ pri3~ art periodor.tal d~ug d~ltYery SyAt~
which ini~ally xele~ a ~ior portio3l ~r "burst'~ of 'che d~ug,
~.g. 70-~05 ~ a~e oP ~:h~ d~ug, ~n ~ 24-4~ ~olar5 a~r
insertion, th~ periodontal do~ag~ o~ ~he pr~n~ en~i~n
pr~v~de~ a continuous, slow r~le~se of t~e dru~y, rel0a~:ing only
about ~0-30~c o:~ ~h~ in th# Xlrs~ 24 4~ hour a~tex i;t~o~ion
into ~he p~riodont~l po~k~'c. I~rge ini~iaï bur~'cs o~ r~
cc~ id~re~ t~ Pe dl~Ld~ar~ta5~0u as depletic~n o~ the drag m~
:, .-.~ - ,
3~ 3 ~C ' 1 :i36A~ ~L~.4-E ?~EN- DE.~A~ N`.~ !ltl. ~032 ?. ~ 9
,, ,
h ~ 1 ~ i 3 ~
occur b~fore the full period fc~r t~eat:~ent has ~xpired wi~hou~
~ul~illmzr~ treatma~n~ objecti~es.
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!~ 16h~i ~5LI,AI`r Ph~ iEm~ TI~ENI N~. 83'~ P- 3~9
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Figure 1 shOW5 ~ s~he~atic r~pre~antation of a three layered
periodontal st~ip ac:cording o tlla in~r~ntion.
~ .
Figura 2 ~ho~s a ~c~ema~ic r~pre~entation o~ a n~nolithic
p~riodontal s~rip a~cordin~ to the prior art and Which was
ubject~d ~o co~apara~ive t~stinS3.
i?i~u~e 3 ShOU6 a comp~riso~ of 'ch~ release of metr~nid~ole,
~etra~yalins~, ~lur~iprof~n and chlorhexidin ~ro~ tralayer
lalain~te s:hips.
F~ 4 ~how3E; ~ co~parison of the r~lea~e of m~troni~azol~ ~co;~
a monolithio chip and a trila~inatf~ chip.
Fi~ur~ 5 ~o~r8 ~ren d~y rel~s~ stlldy r~ults . o~ tro~iidazole
and ~l~r~ipror'@n ir~ a ~ril~y~r l~Eina~e c:hip~
~igure 6 i~ow~ ex~e~2d~d ~etronid~zole ~t~ldy r2:~iulti5 ~ro
acxyl i.~ Ghlp ~ . Xudr~q~it ~ 4 o
Fiqur~ ~ i3how~ the l Plea~e of ~a~tronid~zole ~ro~ chips li~in~
wi~h d$~ ent druy rollt~nts wi~hin ~acn lay~x.
,r,, ~. .
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~l. 3. Igc~ 1LG4TE i~rEN~ D~r.~ . 8Qr;2 ? 13~39
3.'~
l~e in~ention provide~ a periodontal do~ agf~ fo~ ~uita~le ~or
d~liv0ry os~ an ac~iv~ ingredi~ into a pe~io~ontal pocket which
c~ e~:
a.) an ~c~ve in5~redient cont~ining lay~r havin~ top an:l botto~
~ur;~c~s, ~n~ sidf~ edge~ a~ourld ~he periph~ thereo~ wher~i~
s~id sid~ ~dg~ are suJ:~tanti~lly ~ree o~ applie~ cov~rin~s: s~d
layex co~pri i~g arl ad~i~tur~ o~ ac~-ve in~r~dient and a
phy~iologi~ally ~c~eptable, drug dl~fusible polymer ~o~po~;ition
~hi ch is bio-erodible in the environment o~ t~e periodQnta41
pooke~: and
~.) a poly~ric Layer pa~itioned dlrec~ly orl ~ac:il o~ said tup and
bo~t~aa sur~ac~s~ in t~e ab~ o~ i~te~nedi~ry laye~
poly~ y~r c~pri~ing a phy~tologically ac~eptal:~le, blo~
~rodibl~, polym~r c~po~itlon c:apable o~ di~fu~ng an a~kiv~
in~red~nt th~x~3th~0u~h ~o~ the ac~ciYe ingrodisnt cont~in~
lay~ie ~h~n th~ dos~ge ~or~ i5 ~o~ on~ in a ~asriodo~ta3~ p4c3~t.
Tb~ iMrention al~o p~ovid~ a z~ hod l~or ~eli~ery ~f ~n aeti~re
diE!In~ to a p~riodont~l pock~t which compri~e~
i~ p~oYidln~ a ~xiodont~l do~ g~ fo~ suitabl~ c~pri~ing
a.) an ac:tiYe Lngr~di~nt ~Qntaining l~y~r h~ g ~op and bo~t~
~ur~aaes, and ~ide ~d~2~ around ~h~ p~iph~ h~r~s~ ~her~in
~aid ~ dg~e~ ~r~ sub~Pcanti~lly f~ae D:e aplpli~d ~ov~ri~ 5Zllld
lsyer c~ prisiny an a~sl~cture o~ actlve ir~re~llant ~nd ~
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j - ~ . 3 ~ 9 ~ .M ^~ G.A'~ ?A'EN~ D~ ~.d~"'2~ ~ N3. ~C ;'2 r~
-- 2 . ~
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phy~iologic~lly acceptable, drug dit~usibl~ pol~er compositior
whicA is bio-ero~ible irl the ~n~rir :7nment o~ t~e perio~ontal
pocket: and
b. ) a polymeric lay~ar position~d dire~tly o~ each o~ 6aid top and
hottt~ ur~ces in th~ b~en~e of intermedi~ry lQye~s, said
polyPeric la~er compri~lng a p~y~i~logis:ally ac: epta~l~, b~
~ro~i~le, polym~3r c~mposi~ion capak)lo Df d~ffu~ing ~n ac~ive
ingr~di~3n~ ~h~r~thrcugh ~ro~ ~he acti~e i~edi~nt containing
laye~ ~h~n the do~e fon~l is positi~n~d ir~ a periodor~ta.L pock~t:
a~ld
iil p~iti~ning the periodon~:al dosage Corm in a perio~olltal
pock~t: and
causing the dif~usion of p~rt of the aGt~ Ye i~ isnt
di~ect~y ~n~ he p~io~ontal pocke~ via th~ sid~ e~g~ o~
a~t~ i~t contalning laye~; a~d t~erea~t~r
i~) causins~ tho diS~u~io3~ ~f ~SI addî~ional par:~ o~ th~ actlv~
ing;~di~n~ into thQ p~riodontal po~3s2t t~ro~h th~ top and ~ott~
AurSac~ ~nd throu~h tho polys~erlc lay~
In u~e th~ d~uçr is firs~ ~elea~ed fro~ th~ si~e~ o~ the
multil~y~r chip~ There~ter, ~o b~ rol~ r4s~ top or
bo~to~ l~yers o the chip, t~n~ drug ~us~ s~ dif~us~ through
~mp~y polym~ric layers wher~y the re~a~ o~ d:~g r~rDm t~e
chip 1~ m~intained in a slow, ~onti~uou~ m~nn~r with 'che ~b~
o~ any inltial bu~s~ of th~a drug.
.,
3 ~gc. ~I ~,Al~ !,G.4~E ~ EN~ '2.'~ N~ ~CC~ ?. 1~/~3
2 ~ 3 ~l 3 S
In the prac~ice of the present i~v2ntion, one prQpares an ~tiYe
ing~e~ient cor~taininS1 poly~ layer, whic:h il3 broadly c:~po~d
o~ a drug co~p~n~nt, a physiolo~ic~lly ~cc~pta~le, bio-er~dibl~
polymer, an~l ~pti~nally, ~ut pre~0rably a physiologically
a~cep~a~l~ pl ticizer. This ac~itre in~redient c:ontaining layHr
h~ as 4 in Figu~e 1. ~ithin the cDnt~;ct o~ this in~e~tion,
a~ di~tin~uish~d ~rola biodeç~ran3~ y which is a chemic~
degradatlon o~ a poly~er into a dl~eren~ c4~pound og r~uc~d
molQcular ~r~ight, ~ erodi~ y means 2 cl~an~ of a physic. 1
s~a1t~3 o~ a co~pound rAther t3~2~n che~ical changæ~ Witllin t:h2
cc~nt~xt o~ this invention, a dn~ d~ sibl~ poly~er oo~po~it~o~
i~ on~ ~rhioh is capa~7 f~ of ~ f~u~;~g an A~ ins2~3slient
therlathrou~. ~hese poly~r ~n. ~ctive ingrædierll: co~apon~nt~
blend~d in a ~401vent c3mpo~ition, for3~d into a ~he
dried. Oll to~ n ~chis a~tiv~ ~ngredien~ on~ininy layer 4 i~
appli~d ~ ~eeon~ polymeri~ l~y~ær 2 ~hich ~l~o c~ prl~uæ~ a
phy~iolc~gi~lly ac~ep ~ ,. bio-ersdible, an~ option~lly, ~t
pre~rably a phy~iologi~ally a6c~;abl~ p}~:ici~e~, ~ho~0
inqredi~t~ ar~ b~end~d in a sc~ 'c e~po~it1~n, ~atedl ln
m o~ e3~ ~il~ Oll ~ho actl-te ingr@!dien~ G~nt~niXig lay~
~nd dried. Anoll;her ~uch pol~ri~ lay~ 6 i ~imilarly ~D~Il~d
~n tho oth~r si~ o~ the ~c~ ingr~di~nt <:on~aininç~ layer ~ ~o
form t~e thr~ 2no~b~r~d L~min~te con~truction ~how~ i~ Figur~L 1.
Sl:r~p~ vr ta~ s O~ thi~ uctu~e may b~ cut ou~ to khe de~irq~d
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3` ~ C3 :J7.~ LC.~.T~ P..~ T nE~.~F'~l~E`~ N~.~Ou P 13i39
o : :
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?~ e and ~;h~pe. Importan~ly, ~he side ~f th~ aG~iv~ ~ompon~r~t
~-Dnt~iniS~g lay~r 4 are ~no~ c:overed in anr way ~o tha~ wh~ the
s~ructu2~ is placad in a periodontal poekel~ ct~e c~mpon~nt
can d'2~u~ out of ~h~ sid~ of tl~e a~iv~ component c~ntai~in~
layer 4, a~ ShD~ by ~he ~rows in Fi~ure 1.
Physi~lQgically acceptable~, bio-~rodl~lp, poly~ers non-
~*~lu~iYely include copoly~ers of acrylic acid, ~othacrylie ac~d
an~ r e~3k~rs t~ereo~, such ~s F~ethyl acrylat~m~'ChaCryliC a~$~
copoly~er, ~thyl methasrylate~th~ryli~ acid copoly2e~, and
ph~balatQ contæining poly~ in~luding cQllu~ a~etat~
p~thalat~, p~lyv~nyl ace~te ph~ha~a~e and hydroxy p~opyl ~t~yl
ce~lul w ~ ph~alate.
Th~ poly~r~ 116~d abo~e ~n be pre~ar~ so a~ to hav¢ ~ d~r~d
~olubi~lty i~ ~e pe~iodontal ~n~iron~n~ ~y, for exa~pla,
ad~u~tin~ t~ d~gre~ oP po~ymeri~atlon. Accordin~ly~ ~ poly~r
~ailo~d to ~rod~ a~c the p~ o~ the p~riodontal podc~ a~n
d~termined a~ d~ired ~y sel~c~ing a ~ le poly~er fro~ th~
aho~e~ t~d poly~er~ or ~y ~l~nding ~wo ~r ~e of th~
poly~e~s~
Th~ ~ost pr~ferred polymers ~re ~tl~yl~e~ac:ryla~e~methaç/cyli~
aaid cop41y~er~ ha~ing th~ tr~de~ark d~ nat~orl Eud~agit ~lOO
and Eudra~it LlOO slraila~l~ com~r~iaLly ~ro~ ~oh~ ~ Hi~ sa Such
copol~ r h~ve ~h0 stru~ur~l fo~la.
., . , ~
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~?~;. 3. ISs~ 38~ CiL~A~E P,~.?EN? D-~ !? NQ. 80~2 ~ I~,/3
r-
' .L ~ 7'3
:"
13 1~3
C~2--I CH2--C--_,
COOH COOC:~3 n ~ :~
"
wh~re n is s~l~cl~ed ~o pro~ide a m@an mole~:ular weigh~ in th~ ~
~nge o~ ~r4m about 1~5,000 ~o abou~ 150,00C~ Eudra~i~ S~DQ ha~ :
hn ac~d ~c ~stcr ra~io o~ abou~c 2: l and Eudragit L~ao h~r5 an ~c:id
to e~ r ratio a~ abo~t l:1.
Actlv~ ingredi~nt inc:lu~ ~ny ~her~peuti~ material su~ ta~l~a ~Eor
t~a~ant of p~ricdo~.; al ~onditions. I~e~ n~n~ JLu~ ly
~nt:lu~3 g~rmici~al, antl~ robi2~1, antl~in~ ato~y, oollag~ ;o
in~hi~ltir~g, ~nd pl~que solta~ilizin~ ~g~ ts. ~x~pl~s i~cl~
gor~ici~3~, ~uoh ~ chlorh~xidin~ çFlyc~ryl ~ o~id~a, ph~nol,
benza~ko~ s chlo~id~, c~ylpyxidiniu~ chl~rid~, and ~ae~ lik~;
antimic:srob~al ag~r,t~ a~ mpic~llin, t6!~tra~yc1 in~,
b~nzyl~oni¢i~linf a~ damy~, ce~ lexin, ~rythro~yci~, -
c~l~ra~ nicol, s~nguin~3:ia, m~tronidazol~, dox~ycline,
~in~yclin~ t~iclo~aLn~ rofloxacil~, ofl~xa&irl a~ th~ liket
anti~ lcory ~ag~nl:~ssr sur~:l a~ ibuproe~, ind~m~t~Ac:in,
k~t~pr~n, m~na~ic ac:id, an~ip~rinei lur~ipro~n,
dni~410ne, d~ ~ason~, 'cri~cinolon~ onid~, an~l h~
like~3 pla~qUI3 ~slubilizin~ ~snt~, such a~ ran~se, prO~ 8
3 and th~ an~ coll~g@!n~ hi~$tor~ ob~i~d ~E~a~ll
12
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r~; 3 1~I.S~ .`L~A'E ?.~'E-~. 3~ G~ 15,~33
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th13 extr~ ion o~ c~d~ drugs, s~ch as ga~ir-cate~hu. T~ ~o~t
pr~rre~ active in~redients are ~etronidazole, tetracycline,
chlorh~xidir~e and f l urbiprof en ~
Pla~tic~zers non-exclu~i~.rely inslude glycerin, propylelle ~lycol,
ca~tor oil ~n~ dibutyl phthalate. Th~ laye~ ay irlclude ons o~
:~ore o:e phar~aceu'cically a~eptabl~ 3?rRserva~i~es, p~I regula~ing
~gents, base materlals for preparinq film or ~intment, l~ica~t~
a~d~or st:~bilizers~.
T~2 ~t~e in~dien~, polyr~e:r ~nd plasti~.,ize~ are pre$eraJ:1y
co~ined Yia a ~olution including a Bo~V~1: SUr~l a~ dE~ior~
~ter~ ac$to~ et~anol an~ is~pr~p?mol~ Th?s acl:iYe is~ en~
~on~aini~ layer ~ay ~ prepar~d by ~ixin~ on~ or D~o~e ~ctlv~
edl~n~; ~ith a polymer a~d/or p~ticiz~r a~d ~on~ing ~o
re~u~t~nt mi~re i~to ~ ho~og~eo~ solid ~aterial in ~ o~n
of ~ilm, sh~t or bar 1~ e~ting or uazltinq on~o ~ s~ tx~to ~ith
d~yit~ . ~h~ ps: ly~or l~ye~ cozopos~ti~n is ~ riLy
fo2med by castirl~, c~ting or lamislatln~ onto on~ 3 o~ th~s
~ot~e i~5~r6~ contai~ing lay~r wi~ quen~ ~ryiny, i~
n~ ary. T~ is th~n r~pea~ed o~ t~l3 ot:h~r sid~ o~ tho a~t~
ing~e3di~nt con ainin~ layer to ~ e ~s~ber~ L
constructl4n. Th2 ~olid t:ompo~ition o~ ~h~ re~lo~ ~n ~ ~or~
o~ h~3t or bar can loe prep~r~ in d~er~nt ~ize3.
¢ont~Qrli~nt ~ize~ y b~ frPm about ~.3 mm to ab4ut 0.~ ~ in
o~rerall thickre ~, ~rom Ab~4Ut 1 ~ to a~out 4 W~ in o-,r~icall
r)~l 3 1~ .3~ A~E ?.~TE~ D~.rA~T~ G~2 ~. 16~3~
2 ~ 3 ~
wid~, and ~rom about 1 mm to abou~ 10 mm i~ o~erall lerl~:h.
~e ac~ 3 in~redient conta'ning layer m~y lb~ fr~m about 0.~ m~
to about ~ . 4 ~ in thick~es~, from a~ut 1 ~n to about 4 ~ in
width, and ~ bou~ 7 ~ ~o about 10 mm in lengt~ Eac~
poly~eric layer ~y b~ ~ro~ about 0~1 ~ to about 0. 3 mm in
tbicJule~Q, fr~ al~out 1 ~ to about 4 m~ idth, and fro~ ~out
7 ~m to a~otlt 10 mm in length. EIowever, ~h~s~ dim~nsions ar~ nc1t
critic~l and arly com~nien~ size or shalpP- m~y be made dependlng
o~ sev~ral ~a~tor~, such as sev~rlty of the di~ea~e, and th~
~ridt~ and depth o~ ~he locu~ to be applied.. I'hs structur~ o~ the
iAven~ion i8 Applied to ~he periods~ntal poc~et ~y insertion.
T~ ac~iY~ in~re~i&nt comp~nent is p~e~exably p~es~nt in 'cha
actlve in~r~d~ent contRl~ing laye~ ln an amount o~ f~om ~o~t
1 % to about 2~ % 1~ w~ight ~ the dry lay~. A ~re pr~od
rang~ ro~ a~out 5 9~ ~o about ~ 0 % ar~ p~e~ra~ly ~ro~o
about 10 % t~ ~bout 15 S~,
~he bis-erod~10 poly~r ~ ponont is pr~rably pr~ent in t,h~
acti~re ingredient contair,irlg laye~ in an a~ouslt c~ fr~ about
65 % to about 99 ~ by weig~t o~ th2 d~ yor. A ~or2 pre~rr~
Iange i5 ~ro3l1 a~ou~ 7~ ~ to abollt ~ d lao~t prQ~erably ~rom
about 7 5 $ ~o aboul~ ~ 5 96 .
Tha plasticizer ingr~di~n~ co~apor~ent 1~ pre~erably p~sen~ in the!
aative ingr~di~ corltaining l~y~ ~ w~n ~ i5 u~ed, in ~n
1~
. _ . . . _
- .. .
` '
'',
e~ 3 !3C3 ~ k'.d v~lLrT~rE ~A~ D~?A~M`~ No 80l~1~ P ~7/~0
~,7~ ': `
.i amount ~ gro~ about 5 % to a~out 20 % by ~eight o~ the dry
layer . A more pr~rred ran~ is ~ roD ~out 10 ~ to abou~ 20 96
an~ ~,ost preferably fro~ a3aou~ 10 ~ to about 15 %.
i
io-e~odibl~ poly~Der componeTIt i~ pre~e~ably prçs~nt ia~ the
~olym~ric lay~r in an amount o~ fro~n a~out 65 % to about loO ~c by
w~i~ht o~ the dry layer. A ~r~ pref~rred rang~ i8 ~ out 70
to a~ou~ 9D ~ ~2d most prefer~bly ~rDm abou~ 75 % to ~bout
~5~ .
~he pl~ zer ~ngr0~ient component is pref~r~bly pre~ in
~oiy~eric layer, wh~ one is used, in a~ aDIount of ~n a~ou~
o i~ to about 20 % ~y weight o~ th8 dry lay~. A mora~ pr~P~ d
ra~ m about l~ ~ ~o about 20 ~ and mo6~ pre~ ly
ab~u~ 10 % ~ out 15 ~.
solv~n'c colD}aon~n~ m~y b~ u~e~ ny c~ ni~nt a~ unt
~or:~ing the lay~red ~t~u~ur~ and whi~h c~ s~ ~aently b~
tarltially r~DIo~ed. ~ o~r o~ the abo~e ~ention~d op~onell
in~redient~; are preserl~ in ~inor a~unts . E~ch or s i . poly~ic
layers ar~d ~aid ac~iv~ in~redi@nl; ~n~ainlng laye~ is ero~ t
a p~ no~lly pr~æe~t in a perio~cn'cal po ket, i~e. in ~ao r~g~
o~ ~ro~ ~b~lt 6~0 t~ a~ollt ~.0, and particul~rly ~ro~ about 7.0
to al~ 7 . Jl
~1 . 3.~. 3. !9~ lSA.J '~L~A~E ~AIEN~ DE~ RTI~E.'~Tn~ 0 ~r;~, p, IG/3C
., .
2 ~ 3 i~
-1 :
ThQ ~ollowin~ non-limitin~ ~xa~ple se~ves to illuætrate the
ir~vs~t~tio~.
A. ~
T~ polyme~ use~ in this exampl~ W2~5 Eudragit Sloo.
~iz~
~h~ plas'tic~zer was dibutyl phthalate.
~1~ ,
Th~ aa~cive ingredi~n~s used includ~d ant~mi~ro~i31 ag~nts
D~et~onidazol~ tracycli~e, chlorh~axidir~e and ~ iprofen, a
non-~tero~-d~î anti-in~la~at~ry agent.
~8~
~h~ solvgat~ u~d fo~ the poly~ solution wer~3 ~ 50:SO a~tan~:
i~oprop~nol mixtur~.
T~3 a~tt~r~3 in~rf~dlerlt was inoorpor~te~ in t~ polym~r 301lJ~ion in
whi~ had ~e~n di~olv~d tne dibutyl phthalate pla~ticizer asad
wa~ mixed u~tll ~ ti~r~ ingredier~ eith~r dl~i~olYed in
solutlon or wa uni~Qrmly ~i persed~ The re~ultant po~ymer
slutiorl had th~ ~ollowing coDlpoei~icTn
-`-C 3. I~C~ C~G.~E ~A'`EN~ n.ri~'~2``,'D ~3. ~Ci2 ? 19~33
,
Solvent 5~
Acti~e irl~redien~ 10
Eudr8git S100 25
~ibutyl phthaLate 15
50~ ,pn~_
A backir~ m~rane wa~s ~ped 'co a ~al sheet with the ext~
side up. Poly~er solution prep~red in B. was ~pli~d 'tD thiE!
lu~ran~. A me~allic bar with ~ wire coill3d around ig havt~g
wi~e~ thickne~ o~ 0 ~ 51 mi~ron~ was pulled down the ~acXi~g
~br~n~ reat~ng a:~ ~v~n a~d thiC:k, ~i~ lay~ on
ran~ whic:h W~; a~lo~e~ ~o air dr}~. 5'o prep~re addition~
l~ye~, thls R't~ W2~5 r3peat~d for la~inat~ on *op of ~ i~irst
lay~r. me ~Rt layer co~tainiD~ th~ a~iY~ ingredient wa~
but n~ co~pl~t~ly dry (u~ually a~ul: 15 ~0 minu~) wh~
additional lay~rs wç~re app~ le~ which didl no~ CD~lt~in ac~
ing~d~elnt~ The ~otal thic3cnes~ o the t~ilay~r la2l1inate w~
0~ The thicXn~s~ o~ ~e la:~in~ chip ~ a~r~ing
chl~rh~xidi~ wa~ 0. 31 m~. ~he la~inat~d æh~ t w~re cut in~o
lxl.cm sgua~ wi~h ~ sc~lp~l and 1 ~PI te~pla~ ts ~orm ~hlp~ ~or
evAluation og drug rele~s~.
17 ~ ~:
^33 3~r~ '.4"~ -AT~ P.~..T~ N ~,00~ P. 2G~3
~'~ ' .7 ? ~1 r3
D.
The trilayer laalin3ta chip~ prepar~d in C. w~r~3 weighed out and
than plac~d in a vlal . lo ml o f pH 7 ~ 4 phospha e buf ~er were
ad~d ~o ~e ~ial. The vial wa~ ~h n plac~ in a ~ha~ing ~ater
~a~h (4~ t 37~. U3pon compl~t~ dissolut:ior~ of th~
lamin~ted chip, a 1 ~1 ~ple wa~ t~Rnsferred to a
~icrocentri~u~ t~ ampl~ was centri~u~ed at ~000 R~2 rOr
approximatæly 15 r~inutes. 50 ~nicroliter~ of the supern~ta~t
diluted with 95Q ~1 ~ fr~:sh phosphate bu~fer solutiorl. Eit~r
~IPI~C ~or metronid~zole arld flurbiprof~n) or W a say ~or
t~tr3~ycline anâ s::hlorhexidlne) was used to ~Pter~ine ~he
s:oncen~ration of ~he ~tive agent releas~d into ~h~ bu~ared
soluSlorl. All ~tl~di~s w~r~ carried out in ~ipl~c~te.
Th~ ~o~positi~n o~E the la:~ina~d Chip8 and th~ar phy~i~al
pr~ r~ 5Umm~lUr'~ z~d ~ lo t l:elow. ~ r~sult~ o~ a 24
hour ~tudy ~r~ recor~d in t~e ~g.ph o~ Flgur~ 3.
1~
:.. . .
.
i
: . ~ ~ ... ... . .
:. i ,.
)~ . 3. :-~'3 .;'~3.4~1 rjirArE P.~.~ `;T ~E?~.~TI~E`~ No P!0~ P. ~ S
3 (3
~a~
0-10~ onida201e Clear, S~ron~ ancl Elasl:io
Outer La~ar~ ~ 0S Meltronidazole
Nid~le l~yer - 10% 2~etronldAzole
0-10-0% Flu~bipro~n Clear, Strong and Ela~tlc
e~uter ~ye~ % Dru~
Middle ~y~r - 10% Drug
:
0~10-0~6 Tetra~ycline Y~llow, strong ~n~ ~la~tic
Outer ~ye~ 0~ Drug
Middl~ l~yer - 10% Drug
0-10~0% C~lQrh~i~i:ne Wh~ lumps ~ m~rty ~u
Ou~e~ ~ayers ~ O~ Drug
2~iddle L~ 10~ Drug
r~nc~ to F~ure 3 indi~a~ t th~ relea~s~ ~ro~lle o~
mekronidaz~le~ flur~ipr4~n an~ r~cyc~ w~ ilar in
i~ad~cating ~on~inuou~, ~lo~ relea~e o~ the a~tiv~ ingr~ t w~h
the ~eptl~n o~ ~hlorhsxid~e which wa~ ~rrati~ ~or ~he 1~t
two h~urs o~ expQsur~ pocsibly dll~ to di~i ulty i~ dts~ol~v~ç~
chlorh~xidln~ in the poly~r s~lutiort.
1~
-, . . :
. ~
:
~ ^. 3 ; v~3 1 1 3 ~ 1 r J' l.,.~''`t ?AT~F.~ r.EPhRTI~Ei, ~ 032 P. ~2,~39
~ ~ 113f~
Fo~ p~arp6~ses of ~o~p ris~n, a 2 4 hcur atudy follow~ng the
proc~dur~ of ~xampl~ I was repea~e~ with the exceptiorl ~h~t ~he
~ilayer ~ ch~p c~nt~ining O-~O-Og~ ~aetronida~ale o~
Ex~le I ~aa ~o~r~d t~ a monolayer chip o~ e ~a~ ~iclcne~3
~ontaining 1S~ dibutyl phthala~e and lO~ m~ror~ldazol~, T~
re~ults o~ this ~tuây ar~ recor~d in the graph o~ Fi~re 4.
R~r~nc:Q to Fi~ur~ dic~es th~ th~ monolithlo chip rel~a~ed
9C~ of i~s ~aetronidazole conter~t within about g hour wh~areas ir
~h~t s~e p~riod ~f ~ime le~s tha~ 30P~ of t~e m~troniàa~ole ha~
I~@en rel~ed ~0~3 the tr~lay~r lam~na~e.
~2~ ', .
A s~ n ~ay ~udy ~9 p~r~orx~od u~ing 0-10-o~ m~r~nida~6lle ~a~
m~oni~azole in ou~er lay~rs, 10% ~e~ronid2lzol~ th~ mid~l~
layer) a~d o-lo-o~ ~lur~ipro~ 0~6 flu~bipro~ iD t~ro ou~
layer~, 10~ flurbipr~fe~ in the ~idd1~ lay~r3 trilay~-r chi.p~
i~olLo~ang the ~ procedure as in ~a~ple ~:. Th~ res~ o~
thi~ s~udy sre ~eoorded in ~he ~r~ph in Fi~a~e g. Tho re~ul~s ln
th~ ~r3ph in Figure 5 ~how a r~l~ass pr~fil~ o~ ~trsnida~ol~
~lurbipro~n ind~ca~in~ qlow and continuou~ r~l~a~e o~ ~h~
aqt~ e in~r~dil3n~ fro~ the chip olrer ~le ~s~e~ ~ay per~o~, le~
th~n 30~ o~ the a~tl~e ingrédi~n~ bein~ ~e~ ed duri~g ~h~
initia1 24 hour per?od of çhip exp6:)sllren
.,
''' ~ . ~ ', ' , ~
:`
:. : ~ ' '
~, t 33 ', ~A~ A~ PAr~-Fr DE~ ?~lMElilr N`. 30!.`" P. 2~ $
~.1 1, 3~
Th~ pro~edure a~ Exampl~ II w~s repeat~d U5il~g a trilayer O-lO-OS
Dlet:r4nidazoie Eu ragi~ Sloo ~:hip- ~o~ p~arpo~e~ o~ C02llparisc3a7
the pro~edu~e wa~ rep~a~@d ~xC~p~ a sin~l& ~e~ylic chip c~po~d
of a poly~y~ ~ha¢ryL~te~poly~hylm~thacrylzte co-pol~r
~onk~ining ls~ mo~ronidazole wa~ ev~luated. The co~po~taor~ and : ~ ;
physica} p~oper~ s o~ th0 two ~hips are su~arized below:
Drug Cont~3nt PC~ Qr P~as~icizer PhyaiG~l
0~0-0% N~'er~anidazole Eudragl~ D1~utyl B~o-ero~ Chlp~
S100 Ph~C~alate Cl~r, Strong ~1
Elastic
10~ e~r~ d~zolo Pol~ethyl None ~on-biodLe
me~acryl~tef chip~, C~
polyetl~yl - ~tr~g ~nd
Sampl2~ wsre taJslsn durisg the ~r~t 2~ hours and thez~ tak~3 ~nc~ ~
a d~y ~or th~ r~aainde~ o~ ~h~ ren d21y e~epo~l3re. T~0 r~ t~ :
wære r~co~ in tb~ ~ra~ in Fi~ uïts i~dica~
that t~a ~udragi~ ~loO c~1p h~d a ~;iig;ht~t hurst. pha~ up ws~ L2
hou~, a~d then t~e rt~ Q o~ Lonida~ol~ wa2i st~ady. T~
monolil;hle ~eryl$c chip r~ a~ 50% o~ t~ae druç~ hin ;~L ho~
~nd xel~a~ed 90~ o~ t~ drug bri~hin ~ hola~æ. ~a ~5udr~i.t ~
chip on th~ oth~r hand rel~a~d ap~roximately 1~ o~ the ~rug
in ~ gl~6t d~y and ~nly ~5-7 0~ o~ th~ d~q in ~;e~bn daya3
indi cating a ~signi~ica~t redu~:'ciwl o~ th~ ~ur~ pha~e and
~tead~ r~lezlse ~r 7 dar~.
. ~ ,
' . "~ '' ' : -I . ', '
- , : .
: . -. : , ,
3 ~ 3. 19S~ OAY ~ 5A `E PAmEI~ D~ T~ l3 ~;52 ~ ~I, i'
2 ~ 1 3 ~o
~he proc:eclure of ~xampl~ I was repeated with tS~e ~xaeption
0-10-0~ rila~r Eudragit SlOo ~ne~ronid~zole ch~p ~a~ compare~
witA trilay~r ~e~r~nidalzole chip~ in which th~ outer l~yer~ h~
incorpo~at~ed t~erein ~s or 10~ metronidazole.
Th~ co~po~l~icn and physical properties o~ thes~ chip~ are
su~ariz~ b~lo~. .
o-lo~o~ ronid zol~ Tril ~yer ~aips
ou~er ~yers - 0~ ronid~zolç~ s:lear, s~rong and ~las~io
~lddle ~yer ~ 10~ ~e~ronid~zole
5-10-5~ ~orli~azo Trl~y~r Chips~
Outer l~yor~ - 5~ ror~id~zol~ C~3ar, ~t~ong arld Elas~
~ddl~ layer - 10~ M~tr~nid~zole
10-10-1~% Me~ronida~ol~ y~ ~LipS
Out~x l~yer~ - 10~4 ~Se~ron~dazole Clear, Stron~ ~n~l ~lasl:lr:
Isiddl~ Layer - 10% ~fe~.~onidazole
_____
Ii~ . 3 ^c~ Oh'; ~iL'Ar~ P.~ DE~A~ Ei`~ f!. 80~^ P. ~5~9
! j ,
i 3 ~
Th~ m~tronidazole relea~e over a 24 h~ur p~riod ~ro~ th2 chips is
suE~arized in th~ graph of Fi~re ~ . The resul'cs cum~ariz ad in
the ~raph in Figur~ ~ indicate the 5~ 5% and
10-1o-~ssC metronida201e ~ril2~ye~ çhips had ~ r r~lease
pro~iles ~arked ~y a large inltial ~ar~t phas~. Alao the~ c~ips
co~pletely dissolved within 24 hours~ ~y w~y of con~rast, th~ :;
0-10~0% m~t2~0niâazD1~ trilayer chip indicat~d steady rel~ase
through~ut ~he ~4 hour timer p~riod an~ did nol: c~mple~ely
~i~solv~ .
.. ....... ..
- :
~ . ,
.. , ~ .
