CA2111136A1

CA2111136A1 - Polymeric bio-erodible delivery system for the periodontal pocket

Info

Publication number: CA2111136A1
Application number: CA 2111136
Authority: CA
Inventors: Rohinton Toddywala
Original assignee: Individual
Current assignee: Colgate Palmolive Co
Priority date: 1992-12-11
Filing date: 1993-12-10
Publication date: 1994-06-12
Also published as: GB9325292D0; GB2274586A; FR2699076A1; AU664504B2; AU5233693A; DE4342842A1; GB2274586B

Abstract

Abstract A periodontal dosage form and method for delivery of a drug ingredient into a periodontal pocket. It is comprised of a drug containing layer having top and bottom surfaces, and side edges around its periphery where the side edges are substantially free of applied coverings. Directly on the top and bottom surfaces of the drug containing layer are polymeric layers comprising a physiologically acceptable, bio-erodible polymer composition capable of diffusing a drug through it from the drug containing layer when the dosage form is positioned in a periodontal pocket. In use, the patient receives an initial dosage via the side edges of the drug containing layer.
Prolonged administration is achieved through slow diffusion through the polymeric covering layers.

Description

~` . '. ,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 ... .. .

,',' ' .
,!,, ~ ~ , : ~ : ' ',; ' : ' ::'- , 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 `.' ~ ,, : ', .. . '. . . " ' '' ~ ' ' ' ' 1 ' ,"~ ' .,.' .'. .

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.

.- .

.,; .. ~ ~.~ , :

!~ 16h~i ~5LI,AI`r Ph~ iEm~ TI~ENI N~. 83'~ P- 3~9 ."

,, 'i 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,, ~. .

~i' ''"'- ~"

~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 ~

. ,, ,: . ... . :

j - ~ . 3 ~ 9 ~ .M ^~ G.A'~ ?A'EN~ D~ ~.d~"'2~ ~ N3. ~C ;'2 r~
-- 2 . ~

~, :
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 :: . , . :. :
..

3` ~ C3 :J7.~ LC.~.T~ P..~ T nE~.~F'~l~E`~ N~.~Ou P 13i39 o : :

., .

?~ 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.

., . , ~

, ~ , . . . ~ ~ . -~ , , ~?~;. 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 .

,'`~'. "' '' ' . ' ' .

r~; 3 1~I.S~ .`L~A'E ?.~'E-~. 3~ G~ 15,~33 , " ' ~ 1 ? i '~ ~
j 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~ .

.. ....... ..

- :

~ . , .. , ~ .

Claims

1. A periodontal dosage form suitable for delivery of an active ingredient into a periodontal pocket which comprises:
a.) an active ingredient containing layer having top and bottom surfaces, and side edges around the periphery thereof wherein said side edges are substantially free of applied coverings; said layer comprising an admixture of the active ingredient and a physiologically acceptable, drug diffusible polymer composition bio-erodible in the environment of the periodontal pocket; and b.) a polymeric layer positioned directly on each of said top and bottom surfaces in the absence of intermediary layers, said polymeric layer comprising a physiologically acceptable, bio-erodible, polymer composition capable of diffusing an active ingredient therethrough from the active ingredient containing layer when the dosage form is positioned in a periodontal pocket.

2. The dosage form of claim 1 wherein said active ingredient is selected from the group consisting of germicidal, antimicrobial, anti-inflammatory, collagenase inhibiting, and plaque solubilizing agents.

3. The dosage form of claim 1 wherein said active ingredient is selected from the group consisting of metronidazole, tetracycline, chlorhexidine, flurbiprofen, glyceryl iodide, phenol, benzalkonium chloride, cetylpyridinium chloride, ampicillin, tetracycline, benzylpenicillin, clin?amycin, cefalexin, erthromycin, chloramphheniicol, sanguinaria, doxycycline, minocycline, triclosan, ciprofloxan, ofloxacin, ibuprofen, indomethacin, ketoprofen, mefenamic acid, antipyrine, prednisolone, dexamethasone, triamcinolone acetonide, prostaglandin, dextranase, protease, amylase and gambir-catechu.

4. The dosage form of claim 1 wherein said physiologically acceptable, bio-erodible, polymer compostion is selected from the group consisting of copolymers of acrylic acid, methacrylic acid and/or esters thereof, and phthalate containing polymers.

5. The dosage form of claim 4 wherein the polymer composition is a methyl methacrylate/methacrylic acid copolymer.

6. The dosage form of claim 1 wherein each of said polymeric layers is formed on said top and bottom surfaces of said active ingredient containing layer by coating, lamination or casting.

7. The dosage form of claim 1 wherein each of said polymeric layers and said active ingredient containing layer is erodible at a pH in the range of from about 6.0 to about 8Ø

8. The dosage form of claim 1 wherein each of said polymeric layers and said active ingredient containing layer is erodible at a pH in the range of from about 7.0 to about 7.4.

9. The dosage form of claim 1 wherein at least one of the active ingredient containing layer and the polymeric layer further comprises a physiologically acceptable plasticizer.

10. The dosage form of claim 1 wherein at least one of said active ingredient containing layer and said polymeric layers further comprises a physiologically acceptable, bio-erodible, plasticizer selected from the group consisting of glycerin, propylene glycol, castor oil and dibutyl phtalate.

11. The dosage form of claim 10 wherein the plasticizer is dibutyl phthalate.

12. The dosage form of claim 1 wherein the active ingredient containing layer comprises:
a) from about 1 % to about 20 % by weight of the layer of an active ingredient; and b) from about 65 % to about 95 % by weight of the layer of a physiologically acceptable, bio-erodible polymer; and c) from about 5 % to about 20 % by weight of the layer of a physiologically acceptable plasticizer.

13. The dosage form of claim 1 wherein the active ingredient containing layer comprises:

a) from about 10 % to about 15 % by weight of the layer of an active ingredient; and b) from about 75 % to about 85 % by weight of the layer of a physiologically acceptable, bio-erodible, polymer; and c) from about 10 % to about 15 % by weight of the layer of a physiologically acceptable plasticizer.

14. The dosage form of claim 1 wherein the polymeric layer comprises a) from about 65 % to about 100 % by weight of the layer of a physiologically acceptable, bio-erodible, non-biodegradable polymer; and b) from about 0 % to about 20 % by weight of the layer of a physiologically acceptable plasticizer.

15. The dosage form of claim 1 wherein at least one of said active ingredient containing layer and said polymeric layers further comprises one or more of components selected from the group consisting of pharmaceutically acceptabale preservatives, pH
regulating agents, ointments lubricants, solvents and stabilizers.

16. A method for delivery of an active ingredient into a periodontal pocket which comprises i) providing a periodontal dosage form suitable comprising a.) an active ingredient containing layer having top and bottom surfaces, and side edges around the periphery thereof wherein said side edges are substantially free of applied coverings; said layer comprising an admixture of the active ingredient and a physiologically acceptable, drug diffusible polymer composition bio-erodible in the environment of the periodontal pocket; and b.) a polymeric layer positioned directly on each of said top and bottom surfaces in the absence of intermediary layers, said polymeric layer comprising a physiologically acceptable, bio-erodible, polymer composition capable of diffusing an active ingredient therethrough from the active ingredient containing layer when the dosage form is positioned in a periodontal pocket;
and ii) positioning the periodontal dosage form in a periodontal pocket; and iii) causing the diffusion of part of the active ingredient directly into the periodontal pocket via the side edges of the active ingredient containing layer; and thereafter iv) causing the diffusion of an additional part of the active ingredient directly into the periodontal pocket through the top and bottom surfaces and through the polymeric layers.

17. The method of claim 16 wherein said active ingredient is selected from the group consisting of germicidal, antimicrobial, anti-inflammatory, collagenase inhibiting and plaque solubilizing agents.

18. The method of claim 16 wherein said active ingredient is selcted from the group consisting of metronidazole, tetracycline, chlorhexidine, flurbiprofen, glyceryl iodide, phenol, benzalkonium chloride, cetylpyridinium chloride, ampicillin, tetracycline, benzylpenicillin, clindamycin, cefalexin, erythromycin, chloramphenicol, sanguinaria, doxycycline, minocycline, triclosan, ciprofloxan, ofloxacin, ibuprofen, indomethacin, ketoprofen, mefenamic acid, antipyrine, prednisolone, dexamethasone, triamcinolone acetonide, dextranase, protease, amylase and gambir-catechu.

19. The method of claim 16 wherein said physiologically acceptable, bio-erodible, polymer composition is selected from the group consisting of copolymers of acrylic acid, methacrylic acid and/or esters thereof and phthalate containing polymers.

20. The method of claim 19 wherein the polymer composition is a methyl methacrylate/methacrylic acid copolymer.

21. The method of claim 16 wherein each of said polymeric layers is formed on said top and bottom surfaces of said active ingredient containing layer by coating, lamination or casting.

22. The method of calim 16 wherein each of said polymeric layers and said active ingredient containing layer is erodible at a pH
in the range of from about 6.0 to about 8Ø

23. The method of claim 16 wherein each of said polymeric layers and said active ingredient containing layer is erodible at a pH
in the range of from about 7.0 to about 7.4.

24. The method of claim 16 wherein at least one of the active ingredient containing layer and the polymeric layer further comprises a physiologically acceptable plasticizer.

25. The method of claim 16 wherein at least one of said active ingredient containing layer and said polymeric layers further comprises a physiologically acceptable, bio-erodible, plasticizer is selected from the group consisting of glycerin, propylene glycol, castor oil and dibutyl phthalaate.

26. The method of claim 16 wherein the active ingredient containing layer comprises:
a) from about 1 % to about 20 % by weight of the layer of an active ingredient; and b) from about 65 % to about 95 % by weight of the layer of a physiologically acceptable, bio-erodible, polymer; and c) from about 5 % to about 20 % by weight of the layer of a physiologically acceptable plasticizer.

27. The method of claim 16 wherein the active ingredient containing layer comprises:
a) from about 10 % to about 15 % by weight of the layer of an active ingredient; and b) from about 75 % to about 85 % by weight of the layer of a physiologically acceptable, bio-erodible, polymer; and c) from about 10 % to about 15 % by weight of the layer of a physiologically acceptable plasticizer.

28. The method of claim 16 wherein the polymeric layer comprises a) from about 65 % to about 100 % by weight of the layer of a physiologically acceptable, bio-erodible polymer; and b) from about 0 % to about 20 % by weight of the layer of a physiologically acceptable plasticizer.

29. The method of claim 16 wherein at least one of said active ingredient containing layer and said polymeric layers further comprises one or more of components selected from the group consisting of pharmaceutically acceptabale preservatives, pH
regulating agents, ointments, lubricants, solvents and stabilizers.