.. ~.:~:::'.)._.);;:
`
`f:._=_::-
`
`::':.=·::
`
`SIOCKHOLMSMASSAN
`
`:IRocEEDINGS
`ji)
`
`.. f,
`:I"'')"~
`q;_?- ;:-' ._.
`~,.·,~+.~ .
`;c::Jtf j; ;=:fii~
`~~~:1/.;;J?~:=~~~~>.·{~~
`'STOCKHOLM
`
`SYlnl)O~J um: Tun<~ 16 • 19. 1997
`exhibit: )u!;f.17- 1'.1. 1<>97
`STOCKHrlLMSMii.SSAN'
`~;Mck l1olm .!nternat!mrn! l';1in
`'Wor.kshops:
`ja!'le .lS. l 'i9/
`~l<cr;Hllfl Hutci aml
`Gt:md Hntd
`Jnrw :r.: ... l 9~)7
`STOCKllOLM$MA~SAN
`Sfodiboim rntt~rna;.i.onf<! Patrs
`
`'it:d itV th!~
`.,.,.,.,Jed Rdease Sn<'.icty. h1<'..
`lnt't Symp. Ctmt"•l.
`. "" ~. "fat~.I'., l'J; (.l!J\17)
`l02l..fl17S
`
`Program Chairs:
`Koarl-lkik l'alk
`?\.5ll'il Hassl.~ AH, l :SA
`l'eruo Okaoo
`·fr,ky:1 \Vr.:n1cn's ·M,.:'dk.al Cnllq~e. Triva~t
`
`DRL - EXHIBIT 1022
`DRL001
`
`

`
`· Pubfished by
`
`The Controlled Release Society, Inc.
`1020 Milwaukee Avenue
`Suite 335
`.
`Oee1ileld, IL 60015 USA
`
`First 1~ilion, 1997
`
`Gopyrighfil:) 1997 by The Cc;nlrol!ed Release Society, lnc.
`
`AU rights resi:;r.-ed. No part of this publication may be repr:oduc~d, stared in a reirieval
`systam, er transrnitted in any form or by any means, eleofronic( mechanica!, photocopy:ng,
`recording, or othe1w!se, without tho priClr permission of the pubilsher.
`
`ISSN 1022·0'! 78
`
`Printed in iho USf\
`
`q~i~1Mdg~ Scf6fltifir: Abstracts
`Ch:emica! Abstrnds
`"E>.·cerpta Medica
`
`;}{:· ~:.:;:.-.
`Controffed Aelease Society: assti/r~ no respohsibltlfy
`abstracts not }1Vaiiable at fjme qf;fjri_n'Jing.
`.
`
`::~~@!L.:
`~m~posi11m and Workshop Sci.entif'k
`· "":: '(~onuuittec
`
`!~lJhtih>le Ail. B;i!>
`)f~~~; \\:vt1)r.ur~ Ct.:fudk:a; Co.Ut;~. Jaj.jftn
`
`IE::~::""' CO•~• '"'
`
`~~f:t'!;·~l(nn<. liSA
`
`(1:tn~·Mkhad Ld::. t;:.:.kt:.1~t>= ur g~:nhn<l. C:~rl!"l'AO.f
`
`!J~f>s l·!':ttn::;.;;~;.~. t~l]P"..iXh~ l!r1!\:'<'r:-:ar. Swt'deu
`
`~~.:h .. ·.:..t ~~t·)~ t..:fJk·::~t:.y c;f AJtcht£~n, USA
`
`M?.r}' ~·~~nhaU, ~m:.:.h~<~~t !?.t:~.:;.:.!ln'h hv-;! .. [}.~!\
`
`1Zr11 ~·Uitcf. :\b~1~t (;1i'lor;;:;>'1e~. ~JS:'\
`
`S.t.'.!W Uuiv .. ~!'8i~~ U~.6•
`
`C<llb> Met1n. f;nivt~~'81~~· al'~ Notrfn8ham. J~ui-~nd. t:K
`i ):X.:.rr:l O"Hae1rn. {~'lircn C<!rf.•.>t"t..ao11, tJS:1
`
`f.kbn!'~~ Umt't '.i")i:.y ui i~c:~:<'m. i..·,r~cl
`
`~ ;ndr 1~~>J. ?,1<')tl~u.:~:...;. !)Sf,
`
`!Jhl\~f~!h~· cf t:uih.. 1.:s.A
`
`1 ):ntclti ~~ugJ)·:im!l. t=nh~.::~~w 11! ':'ok~·v, l'~(!a.-;;_
`
`l'nivr.rsu,)' ol t:\.Oh, l!SA
`
`I VJ<:!»<" Xntl!(. lfo!•<dt}' ;;f Wchl&"ll· l3SA
`
`!!
`
`.;·:·:·:· .. , .. ;·:·:·:· .. ....J:.~-...... · .. .':":·:::..;:·:::.;::.~.::..:· ... ~·:-·-~·· ............ -··
`
`.·.·.·.
`
`. .............
`
`•.•.•,•.:--.·..:
`
`Hi
`
`···~···~~ ............... ~ .................. ~~~· .. ······· ..... ,,
`
`s
`(~
`I
`E
`N
`T
`I
`F
`I c
`p
`R
`()
`G
`R
`A
`M
`c
`0
`M
`M
`I
`T
`T
`E
`E
`
`DRL - EXHIBIT 1022
`DRL002
`
`

`
`A
`I.J
`L
`A
`B .
`
`l 996~1 tJ97 Officers of the Cont.rolled Release Society, Inc.
`Vi~ President.
`'P'n•sident
`tfsWJ.ei.i S.:.~ui
`Uwts•»~ Kl»•cl
`Phrnr:P:-··~1ffi\'tt~i~r uf Mar!.m:~
`;'{c;~hi t:nlrf:t"j~t.r
`~'l~a.i;. <«rnzm;<
`·n·.lkyu .. Jnpau
`
`Pa.st P:reloidc:nt
`Jlnd"d' ~·p~d'
`i;,;i<-r.r~:f~ <~C Bf;, h
`s:,it l,..'lks: c:ty. t !"r
`U!S,\
`
`t•residcut Elect
`Rtm>fd A. Sir!llll
`IJs-;;:n~:s:tt:~ n( C1llifv1 nt<c
`S~h F:ra:rid."~<$. CA
`t:s.~
`
`Sdcnti:(k Sccrc.tary
`R4i~l"t tjurur
`l.hti~'<'"l'SU? {·~£ l)t~~~·*
`(~.~t~(l\I., S(vit{c.1"iami.
`
`Treasurer
`U•11. lkat\\h>n.t'q>l"'S
`i?.i.c:s.~l T:c.~!H"l~. foe.
`!ri<lia64Q<>li<, IN
`l'SA
`
`0 u
`T
`c
`R .
`s
`
`Admini~"tr.athrc Staff of the (Amh~oUed Releast• Sodety, foe.
`
`Ex1,1cutivc Dirocoor
`!'.I. :Juifltlt fl<"""'"''
`r.<l:l Ad1t;~ii,;("•ll<~ l:lt:arlq1ia1 t'"~
`\020 ,~fll"""'k" .~ .. .., .. SHI""-' 3 H
`°'"'riid:i. ll. 60015 USA
`Y.Jmw~~ {:S47J .~OS·.?·071
`r:.-sx.
`t~~11) ~ns. /01~
`t.·r:V'!?.t:1 :,:.1:l:;.:1~d~.t>.:.J;
`£..m:ln~
`~i • .£\A;"\"V: htt;f.'W<~':t'l.~ . .;r..;c'1.1.1mhdq.(•fg/
`
`1;unr1,can ·Man<ti;ct"
`l>aphne f,. ftuu>r
`.~~h<>•1 <:f l'harmacy
`;;1d<~s,;:~ ~,{ G1:u~~·~
`~~). ~U,ti E. t\ri.:-.c-n::(::~
`CJ.?.'! .. ? J t (Y}:x:~:a 4 $wtt~!':r!mt.::
`Pl>:>~<~ .... ~~):: ( +·<. l ; I./. 7~l1 i>JJ•J
`{: -m:?t\ J.>-'>r.t..c.,;.t...;.my@yh::u·:":'! .<tt"~K< . :-..:..
`
`I
`I
`
`l • i
`
`t
`~
`l
`• I
`I
`I
`I
`f
`t
`I
`I
`
`.f.'inanctn.l lfani,gcr
`!fl<i!K<tt C, .IW""'t'"''
`G'Ol&~~ &utilo!,. TX US.0~
`
`Bmtrd of Governors
`M"rl:. .Jt..;< Ai<>.u~"
`Slumtt&n~b
`t&lfo 11'~,rul,,1~-•I
`S•t~rl ( '•ul.r
`"''"'illlm lfu~ruft
`M'.ll'°"t'<> I hvd>4lt>
`s.,.,tt lkrll!t:
`l•"'"'Paul M~rt!
`
`1f: f>l~ ($k;\nf)
`lllithkc.n llMl<'M
`ll>'m.~ ~hl>:lor
`llJ>btrr Sp:U'k<
`·vukhi $u~tynma
`'l'l•<.l.Uuir l'. l<»"<'l<l.bn
`C.lrr111 W!l<-.»t
`
`lllt~;~,~!~:: .. : :::.-. ·.::::: :::::. ·. ·.::::: :::~~'.:~;2;
`
`iil~~$i~''.::::: ":: """ "". "" ·."" """::"""::::""::: .. -~t.~~
`
`· · · ....
`
`.. . ..•. . .. .... ... , .19 ·J:i
`'t»m<.>phoretk Deliver;
`1~. ~hd Oli,g-.u1uck .... tidc-; . .. ........ • •.. .. .. • . ~ .. 3,3-.4S
`J'flnd;>le.< •ml
`)l-·fyug Ddivcry I .. ...... . ...... . ....•... . . 4~-M
`'i~'l.'Otar Drut, f.>tHwry . .... . .... • .
`. . . . 65-80
`~t-98
`
`Paper ll
`101-414
`2{JJ-J6J
`20!·20&
`1~)<).2J:>
`t!<i·221
`
`?.?4·']J2
`233~2:10
`~.4!·249
`
`.'fl- ! !2
`
`2~).25(;
`
`> fJdJ.\'<~ty Sin:.t.eg.k .. ~ tlx· ~.-fu;;<,:\;;J
`.
`... . .............. .. .... .. .. . .... . lt3-li'I
`18, 1997 ..•.••.•. . .. .. . ... .. • .. • ... • .... . 121.1-197
`·& Pr.fr:tiples a:1d
`. ·fl>< .Or:.>£ Deli v~~)' H . ....... .
`rl Vr:t<,l'fMry App!ic,t·i<)ll~ <>f
`~~~~ t~~le·a~c. .. .. ... . . .. ...... .. ... .
`
`. .. l2.0-LJS
`
`. '.l ~6-150
`
`257-16i
`J(J/-J<kl
`
`.l(ll.~08
`
`~(Y~·'.'ll~
`
`. l~i· 1'·0
`
`~11·'12 1
`
`lals & l><iuciplcs ar.d
`~oo~ for Dru~· f)divcry ill ... ... . .. . ... . ... ..... .. l!;1~l7~
`•-"M D<:lh•cry .. . .. .. . .. .. . .. .. • .. .
`. .... . ...... l7S'-I ~6
`. ·;:·'~rvm -<>n RrtHt'::<;$>h: :,n<i
`~1:;Drug tJeu .. ·ery ~tra:!cgi~s... . ...... . .
`. .... • ...... l87-lS>7
`· Ju11c rv. J ;;97 •... •...•. . .• •••• •.•...•••.••••••. i91S-2.24
`$~skm; Bt:y<>:W l.\p,'l:X"t.:Y~~s .. J.,jp~d:\ a~
`~~(~m'S iu D:-ug Ddl'<;~ry Syo,'!~~m"
`S~t'')::.km· -~tt:-.. !t.?~,ihi~ A~~r~nhum-
`. ....... .. .. . 2t'iS·21 .. ;
`. U."R; R:~rc .".;>r<!<h:;rn<c•!S . • • . . . . . . . .
`..~r,:o~iun'\ t>n l)rug l)¢hve:..;.• t•."' ~he U!",!:~ . . . .
`. .. __ .. . z;S·.!!:4
`i'L .... . .. ..... .. .... , .... . . .. ... .. ... .. ... . 225. H)c(.3
`K1 , ... .............. , ....... , ........ .......... .. ns-64(}
`. . tt3..Mx-;
`.. .. . . .. . . . . ...... . . ... 1q;-..1.!n
`
`. .. .... •. .... ;<;a~~~n
`
`. .. . • .. .. . •• .. • .... . 44) .. (>:f!
`. .... . , . .. . . , , .. , , . ,Ml·l05l
`.64~ ··6~··;
`. -~'~5.~:1t
`
`.. .. . ' ' .... .. ~?.5 ~7-~~~
`)u:!~ ·!"<t\~L\h':':t~h.~:. Dr~~t r:~H~1:':rJ· ................ , ....... 7-Vi·74!-).
`. . . 749-SoV
`'fo;.i;cri::>:
`. . . . .
`• . . . . .
`..... ·.·. ~~fot~.:..ic..L\. & f;!b~dJ.iJN a~:::
`
`-~~f~i!q'.J~~ ~-~r.r~':': .r~~".\''.:~;: : : ·. '. '. ·,, ............... :1ii~~L11f:i~
`~M'fndtx .. ,. .... , ... ., ......... , .... ... .... . . W57-JOi.1
`
`32;-~:;:;o
`Hl-H·l
`
`~35·3-~{;
`./01·414
`
`4~1l~t()~
`
`40iHUY
`4l() .. !l_$
`5001.6$87
`Jf}fl} ... };1f,.,
`$(>'.H-5c¥i4
`5W:-Yt :_;
`
`5200.5/.99
`(i(l!}!-(0$8!
`M~.I; ·6fflt
`cwH;uo
`
`<::2a~ ·62 , 1
`~~H·i~~{}:·
`C:4et.,~4M
`
`·~.~;f .f,j;j"j
`
`T
`A
`B
`IJ
`E
`
`0
`F
`c
`0
`N
`T
`E
`N
`T
`s
`
`-------------·- .
`
`IV
`
`........
`
`-=::·rr·· ·.~-.· .. -..-.:~·:·::::::;·
`
`......... · ............ ·.· . .-..
`
`DRL - EXHIBIT 1022
`DRL003
`
`

`
`i Sil·.~
`
`t S<l·•t'
`
`pre.iiclion i~ obt-:dned apoi; ns.~umir.~ an
`cp~the fol penni!ability of 6x Hr' cmts.
`
`f l~~~~ .... _ ...................... ~~~·; .. j
`
`Wt\ n:R 1'0LUnJ ,[. FH.!t.'1 FOR ORAL .\JJ!l.HN!Sl'lt\.TJO~
`
`Ji.in·tl<va Goo' wttl H<ws.i J;~''"''
`
`'Aq1mlu11 l)ivhi...,, llt•·mtcs Inc., SIJO lltrcule.s lM~ Wilmi11gto11, Hf.; 1<1808- 1599
`' l,TS Ct>q1 .. 21 Ht'"'~'''"•""" lls .. W-.,,;, Cahlwl'U, NJ 07006
`
`purpo$~ of validating !he l.hr:K>r<:;ical
`appt'-ia:::I\. The ex~eil pe<ik l<v,;atioa anil
`width of the biihis (i11tr0<h1ced 10 cm into
`th>! d\lodet11Jr.l) is fodi.;,e;ed in the figure.
`The pr.ak of the bobs is euctiy JO cm
`beyond the distance r7 .,, from the
`e.111rauce t<> the duodenm:n, re.l1cctir:tr, the
`foe; th:ll the bolus wa~ introdm~ed IO cm
`into ;he small intesti.Ile, AlsiJ, the width of
`the ptal: corre~ponds 10 tltt lhec-retkal
`expectation ( .J 15 * t } .
`Theoretical ~ennn co1lccntrntio11s
`were l!():llparod with experimental &-:a in
`various cases. Figu1·e 2 sh<)WS
`11
`comparison betv.llell e:tpcrimemal data
`ruid t~retical predktions for the l'l!SC of
`ibuprofrn, admlni~IK.red ocnlly in b.uman~
`(5). To1aJ predic!OO absorption is 5 l % .
`near the exp.mmcntal estimate. Tht' &,1<)(\
`match of the lliita is <lbt&incd upon
`l!SS!Aming an ~pithdi31 pe:mu~'-'tl!lity nf
`7.8xto-<I emfs ..
`
`'-
`
`i
`
`::r-······-;.-;~:.-~·~:··· .. ·-···:~:,:_:.····1
`_ ;
`I
`l
`1- i
`'.
`,'/
`. I ,
`"-·
`,
`1-1· I
`-, ·
`i •*
`'
`i
`'·-l i
`: ~
`-~f
`"co ~f ;: ..
`
`;
`.. t..,..,.,...... .......... _ .. ...................... , •••• - - -••••••••••••••• :
`P"
`'
`...
`-
`.,.,.
`- . ._ ._-
`·
`, ,. .
`_..
`., ••
`
`f;g. Z Cumpuison o! .. pe<imt=l (l:)mbol}
`;111d !"«di-:1t<l (S<llid c:.:n·e} itn.m <Of>~<,,lt'4!i<>n
`pn>fil•• fc:
`ibi<profcn
`folh>wmg oral
`Bdministr.~tiuu w hc-!'r:&:::~
`
`Fip.ure 3 show~ 11 comparison
`bew.ee:n exP<":rinietl!nl data and lllelltetic:il
`prerlictioos fer tt~ case ()f GH.RP .. J.
`adm.inist~red Mally in f\umam; (61.
`Tlaioretic.:il nb!>-:ilui.: bit)evaihibi!itv is
`approximiltely O. l %. The 1heoreilcal
`
`:
`i
`
`' ·
`·'~.
`~"
`~ '-.'
`
`'-, . . ,_
`
`!]
`,.
`·~;
`'fi
`·Ii
`·r
`'
`-! .... ··:::···":.;."·";;;""';!;::::...:;;· .... ;;. .. ···:;;. .... ·.::. .......
`
`I
`
`.... .
`
`fi;i. 3 C()m;><<ri'"" of ~.~peri•~~fal isyrt,\-·~n
`.-~~ pttdkt~ tsclid ("'¥.:\'~} Smit1'°i ''1>t>Cc:.:.t.'"8ti-On
`for GH.RJ>-1
`;>t<>filcs
`following oral
`adrr,m1stnn!<>n '" hu-n$
`
`The fl!'Oposed ther,retkal model cnr.
`hl:i used to predict tlic ab><irhe;J systcmi::
`com:.entnitions of thcr3peuti~s nmgin,~
`from ~m:ill liphophlk molet,ule-.s t:;
`rr.acromalecu!~$.
`
`RJ~JlERENCES
`L Kreydiyyeh, S.L. Bitar, K..M.,
`Bil<hazi, A.B. J. Phorm. Sd., 79. 494
`(1990).
`2. Adson. A.. R&ul>. T 1 , Burton, P.S ..
`B<irsuhn. C.L., Hilgel'8, A.R .. Am1us,
`K.L., l:b. N,f. J. Phann. Sti., 83.
`1529 {1994).
`3 .. Brenner, H., F.dw;;rds, D.A.
`Mncmtran~p;irt P.-ncesses. Bc>sto::a;
`ButterM!!th-Hcmemar. (19'J}).
`4. Smil. B., Batycky, R., Leipold, H ..
`Mih;tein, S., Edwards, f>. Suhmi;tcd
`(1997),
`5. Dl't'ssou1n, J.'!J., 8a5s, P .. Ril~~hel,
`W,A., F~ienrl, D.R., Rubm~teit~, A.,
`Ziv, F... l. Phami. Sci., 82, 857
`(1993).
`6. fs<>wcr.;, C. Y. J. Pt:<l. fuitk.'<·rin. (), 21
`(199'.I}.
`
`. M1,;CC$db;,srvll d~·s.1w- formo; tor
`... J:applicantu~ to the Oiai c.3\1fty which are
`;;::i\f:!·~~:~~~~ ;~~~;~,~~ :;;:1~~:~~~~~~~~0:.$
`,,,,.,,\:~l'\OW!'l ir. th'3· ari. Silnv:ndeke; ar:rj L~w1n
`\ {;) descr:!:>ad c. mucom~hr,;;;;;n caniur
`;a;10\'lir.g tiM c::maoliad mlease ct a
`... tterapeutic ;;ge~it ;;ia ths 1r::JOO$al !ff.we
`f~;,,pri!lir.g <:n :?.:'ltiydr(>us but hy'1rat..1b!e
`U?::lymar main>: an:i arno1pi10;.is furn<><-1
`~~~Ji~a. Ar: opt$cr.at WH!<H·!nsohP..;te fihn {.i!n
`~~ha a:$d&d to 9rovid9 a 11,~r.·<stih(:tm9
`;'svrtace They al~o tlisdoscd a :ril:imirmle
`]~m ~tm:~cfe k~: prctonrJe~ d~Hv0ty cf ar:
`~ii!cli~ll :ngrediern in tt;e ora1 c<ivlty (2). :n ,1
`/~riilar ~my. Mir.:-.b1~chl, HI al. (3} <Ji~ciosed a
`{~'if.!til·stieped adh<".mi;,0 pr<iparatior;
`:~~tn;>r:s:s;g af~ adhBs:ve lay~r con1a;nif!U
`\®tl;lit~ w~leMwiul>l<l anct wr.ter·ir.so!ut;i?
`{p¢!~mers arid a wallii·insoi.,ble cart:!lr
`i@\)\t,i::h wr. Mt'l<?fO to ltie oral IYIUC()S?.
`·· 'M6E>roty :"t:i<?il.Sing ur. aclhll• agv•tl to \he ore!
`!~~vity. A n:;rnher tif attempt~; ha\le t;oe!l
`::rtia'-"' l'-1 re-Juce tt;E> ?.d~er;,,'3 !er:!ing :n !he
`:pral t-a·,:;y cav&11d by the r.qidlly and
`:;~9Unxillilily of ~ht' suppo;1 :ayar h)'
`fotfc;d1,;cing <><Jf\ Iii:'!; s;ippr;:ts(·Hi).
`J~(iwev~r. !has<O> dnvi<:Gs $!iii Jt .. uva tt•'.l
`i~lienl wilt: a «~Jr.siderabli- ar.1out~t r;:
`t~sidt1e fr<:><n the Wff!l~·l!l!'">O!uh!o s1,;pµo1t
`thereby s11;: C<J•;sino n !er:t!ng o!
`orn!crt. Thf.' cbv1ous soi\Jlion 1<~
`rcom<l tt1i$ i.1rouioin was io d<>voh;1p
`""·"
`f!'i~("t>;tdhf'"''"'~ li!ms w!'Jd: comp!?.tr;I>'
`:f.Jisimegmle, or El\'t=il cornµletely d!':.'~OI;;<! :n
`l~e s:1lr._..il
`
`::::: < 'ft::.! P:"'!Sent ir:v~r~t:<;r:- \..~ont~:l"'p~3t0s;:
`:jf%)f\!iy d:ssoht:ng fiinl whK;~s can n~ adn~rt:d
`UaJ en:: ;~)Vit~ trie:etJ:>' :e:c::asing ~.,
`
`9h<irrriaceuti1;3Jly or :-;c:imt!\l!',ally act:ve
`;1guil, saicJ lilm compr:Ging wator-rnlubie
`;,rJiy;r.ers. a ccmb:nallo:1 cf certain
`s1;rfm:la..'lls. cne or mr.ire po;yafcohcls. and
`ona ,,r rn:m.i pt:ar:'f:c.;c!lutica!ly (Jr
`cos"~<':licatly ;act:::e ir:gre,Jlilnts. Oµtlon0<.:ty.
`\ht; icrr:1ul11t:on n-:<ry G<>nlmn col(lranlH .
`!;weateriing ager~ts.. flavors\ iiavor
`enhilncer >. or other exc:pients cor.,T:.-:r.ly
`used lo rnotl:fy the iaste rJf fo11n-.da;icn&
`ir:tendN! fi:r nppiicat:or: to 11::.3 oral cav:ty.
`Tl1<.> ~,:1,,;.11iing lilm is chmactori:Led by ar;
`ins1ant w':lll<1.bil1ty which r.nuse$ lhe Iii:'!; ;;i
`soften :nwMdiat<!\' aftilr r.ppiicalk:-n to tne
`mucosul tissue thus ;:;ievem<:1g the patiE>n!
`!m~ e:<p!lriendng any prolonged adv.;rsr
`fe<:>iing ;n I.he mouth.
`''he f:hn is mem:faclurecl using
`cor;ve1,~0N1i coating and dry:ng tr:cm.,:qlie!l,
`cut :nlo p:e::~s ol a shape ai:d size tt"k1t
`:nr::it th!? rnq;;irnmenls 01 !~•e sper,ifir,
`applicatmn, and pa(;kaged into suitable
`oontainei:l.
`
`Experimental
`
`TM :ri-Jcoa:!hasive film o! lh'? ;>r<3seru
`;;wer1t«Jn cori;air.s <ss essentia.! c:;mpor:;ir.ti:
`u Wi.!ler·soiut>w ;io:yme;r ore comtw1,1\io11 of
`wil\N·Sok1bit1 polyfl>i.!rs, a Ct)rr:binet.cr. of
`s1Hfactm11s. nne or morn poivalcoh<>ls, ard
`a pt:arm.:1Cau1icn!ty or ~OHnetical!y a:.:1;;;()
`mgr~'-~te:-!~ lh~ po:ymem IS$ed tcr the
`rm;coadhe$:ve lilm induoo po!ymE>:"S vmir,h
`aro hyd10phi!ic &Pd wat;;r·disp9>'l:>ibia. ·1 !iG
`co.:r.b:rmHcn of st:da~ti?nts used fer :_he
`r.'l<iCO:Jdhil~~"'J !:im is a mixtute cf nor:.io:ik
`swtact.1r.ts. Thr: amount :if d~ug t:; be
`ir:corpor,w~d uw: tho film cmper;tl" on me
`le.ind oi dmg ;ir.d is u: .. 11l!ly bE>!W<len 0 .0 I
`;;:ld 20",;, (wN1). Cos:w:tic.1i!y ~::livr: ,1ge1ils
`ma.:; ::1clt:da breath freshcr.ing wm)ltr.ir.ds
`J1;.~e :r.~r.;!\Oi. o:he: :ta\"C?'$ Ol fr?.grar::?.?$
`corr::1"KY.•I)' i;~aa fo: oral hyrilane. flr:~tor
`
`=':-·.:;~i<:. ~t:~'. , ~~~;.v~r.~~,J · '~~; . B: ~~~t .Y:~~at . . 1• i :~H;
`::-~~:·.~~¢tl~~ ft~l~s·~~ :v:.:~~~~ !:i~ ..
`
`____________________ ................ _ ..
`
`.. n;.
`
`· l~~·
`
`~~ t.·~ t~~d. t:n t. ~~:.y :;3;q(o-l .~) . r':·:~:~i. ~ .~~ne: .. 2~: :<.:H;
`~~:lttvl!;.f. X4$~<=~:':~ 5~ .. ::e:,.. 1~.c.
`
`DRL - EXHIBIT 1022
`DRL004
`
`

`
`I 500!
`
`nctlves used for de~1tal and/or oral
`cloansirg lli<e quarternary ammoni<.1m
`bases. "'"he muooadhesive film according to
`;he prt!sent invention can be prepared as
`follows: The active ingredient. surfa.ctants,
`pclyalcotiol. and pcsslble 01"er ingredients
`except the water-dispersible polymer are
`dissolved in a svllicient amount of a solvent
`which is compatible to them. After a clear
`solution has benn formed, the water·
`dispersible polymer or mixture of water·
`dispersible polymers is slo .. vly added under
`s1irri'19 untii a clear and homogeneous
`solution has been formed. The solution is
`coa\M cnto a suitable carrier materia.1 an::!
`dr:ed to form a film The carrier material
`must t.ave a surlace tl)nsion wt1id1 allows
`;he polymer solution to be spread ovenly
`across 1he intended coating Width. The
`coating o1 the solution onto the carrier
`material can be performed using any
`ccnvent--00al co.11ing equipment.
`Tiie 'itms with desired thickness were
`c«t or punched out tor the disintegration
`and tensile strength tests. The 1ensile
`strengltl of the tilms was assessed using
`Erichs<:>n (Model 474. A. M. E;richsen
`GrnbH, GerrnMy) and was ex:pressed as
`tho maximum torce (N) (Figurn 1 ). A 25-c:m•
`film was placed in the peri dish which was
`filled wi:h deionized water. and the time for
`the film to totally disintegrate was recorded
`(Figure 2). The decrease of imegration lime
`ot formulations A to E was acccmpanied by
`lhe decrease of lonsife force of the
`formulations. Tnis correlation indicated that
`!he ~hoice ol th'e most optlmal formulation
`could be uecided by using either the tensile
`strength or the disi~1tegralion test.
`
`Conclusion
`
`A ccmposition containing therapeutic
`agents am.1/01 brti.ith heshenin9 ayents for
`t mo in tho oral cavity is disclosed. TM
`carrier compri50s watur-soluble polymers in
`cmnbir:i<1tlon with certain lngredien1s and
`prcvide~ a 11\erilpeulfc and/or cosrnetit:
`effect. The tiJrr. is coaled and dried utilizing
`e xislin tJ coatlng 1echnology <ind a>.'hibits
`instant •.vettabili;y fol!owed by rapld
`
`disso!«tionldisintegration upon
`ndministratiOn in tne oral cavity.
`
`References
`
`(1) SanvOl'deker, D.R. and Leung, S·H . S.
`US patent 5,04'7,244, 1991.
`(2) Sanvordekor. D.R. and lenug, S-H. S.
`WO patent 91/06270, 1991.
`(3) Mizobuchl, T., Ohjl. A.. Sakoh. S. and
`Mugururna. Y. US Patent 4,876,092, t989-
`(4) Kuroya, T. and Inoue, Y. European
`Patent 0-381-194-81. 1990.
`(Si Blank, A.G., Mody, D.S .. Kenny, R.J
`and Aveson. M.C. US Patent 4,946,684,
`1990.
`(6) Inoue, T., Maeda, K. and Eguchi. V. US
`Patont 5,206,010, 1993.
`
`16
`~16
`.c :.:
`g>12
`~ ~o
`q; 8
`~ 6
`·~ 4
`~ ~
`0
`
`Formulations
`
`Figure ?.: The disintegration tim&
`of polymer films.
`
`·?.'.8·
`
`''VU'!~. Ir-:.' l. 5}'1p-.Co~tfG;...?el. $fo~t! .. 11tt r. ~''(l'fi~}
`~;~l·ol1"c Relus~ Siidtt7 !r.t
`
`Ii 5003
`
`W Ater Soluble: Pofyc111ions for Controlled Delivery Systems
`
`!liandini l<onar and ~nit-ju Kim
`
`Scboolof Pbannacy, Temple University, Philadelphia, PA 19140
`In this study. we preseut the rero'9rder
`rcl~se kinetics of water soluble anionic drugs from
`erodibfo, drug/polycationic, matrices (tablets) using
`poly(trimethylam.inoethyl methacryla.te chloride -co(cid:173)
`metb.acrytars) (PTMAEMC/M.1\-11\):
`
`ion
`Dnig delivery systems using ioo ex.Change
`a.re one cf the oldest processes
`[ l j .
`rci•lly available ion exchange reoins are
`on highly cross-linked poly(styrene/divinyl
`1e) (sulfooated and quatem1zed) or cross-linked
`acrylic acid). Highly cross-linked gel type
`(negligible swelling) &i1111ificantly sustain the
`1se of a drug in tbe gel matrix, V1hich }~clds .Ji
`~ ~eti.e5 with a tailing.
`swellable polyell'Ctrolytc gcl
`,;;: :,.. Rocanly.
`~~es have been extensively inwstigated as drug
`(t:ty •)1$tem•, By varying the ionic pendant
`s and the degree of cross-finking of the polymer
`:,
`lhe degree of swellmg of Charged
`:olyte• may be tailored Several in\'eSl'igat01s
`~iouic and aniooic hydtopbobic polymers
`. ing of tertiary a.mine· and mt<bacrylic acid or
`.ll~ acid groups, respe(tively, for the release of
`~: (NJ. HoWcvcr, due to 1ho pH dependent
`ch.aracteristi¢S of. chargod polymers
`·, 'g
`· lS terti:uy atnine or carboxylic acid ptl!1dant
`it was not fcas.ible for these iomc gels to be
`as oral ®livery systems, because the pH
`ctuu1ges as a dosage fonn trawls along the
`-IDtestinal (Gn tract. ·NuJOOl3 and Kim [5]
`slcated a (pseudo) linear rele;i~e of water
`~ drugs from erodible, df'lls/re$ilt complex, gel
`· using noncross-linkud poly(snlfopropyl
`:late pot:mium -co- methyi mat11acrylate)
`K/MMA). Drug releare from drug-PSPMK/
`wtuch has a drug loading of greater than 4!)
`, lll<lintains zero-order release ltmetics for a long
`of time because the drug 01 the matrices is
`to die polymer side chain until the comple'.\ is
`·.-<lated by incoming C®ntu ions. It was found
`Results and Discussion
`'j~lug release was indcpendl;'11t of the pH of tile
`The effeci of iunic !>trength on diclofesiac Na
`trom drug-PTMAEMC/MM A complex
`i))lltion medium as long as tho ionic strength was
`release
`·~hban O. l M which is commonly obscrvoo isHh<>
`U!blcts at pH 7 is sho\\11 in Fieure l. Tableis of
`200mg weisht weie formulated with 20 % dc11trose
`· Ill [6}. In addition, tabk-1.s, which are a couuuoo
`as a tablet bindilf. The buffer contained 0 01 M
`release dos.qgc form wer~ successfully
`phosphate and NaCl ranging from 0.05 M to 0 2 M
`red ftom these druefresiu C<JU~ll'.tes.
`?roc~e• hl'l .S~sp.CV~tr·lo ,g!J. I:''"' ·~"e' .. 2(!'<91)
`lo:-.t.r~:ttHt ~·1°4< ~ s~~-::t~y. 1:-.c.
`
`<;:H,
`·[CH,- ·lx-f-CH:-C·tr-
`
`~H3
`~HJ ~~H~hN" {CH.,)_,
`er
`
`E:r.puimenlal Methods
`SynllresJs ef PTMAEMCIMM.4. a11d Preparaffon of
`Drug Rninate Tubld•
`PTMAEMC/MMA was prq>itmd by the
`free-radical solution polymeriutiou of PTMAEMC
`(40%) and MMA (60"4} as reported earlier [7}. The
`polymer was dissolved in de-iooiwd "'-ater, and a
`drug sohrtioo was added to the polymer solution. The
`cornple~ precipitat~ in water were recovered and
`washed 11¢veral times before being dried. The dried
`drug·teSinatcs were cmshad in a mortar and pest!~ to
`obtain powders. Tablets with druR·resinates and
`de:¢rose were fabricated m 9.0 mm diameter die aud
`a flat surface punch with a Carver press
`Drug Re_fe_ase Kirmk-s T~sl$
`The drug relJJase kiuetit'$ ftom drog-resinate
`iablets wcr~ earned out in O 0 l M phosphaie buffer
`eo11tam111g c!iffutcnt amounts of NaCl at 37°C by the
`USP bMket ·mothod at 100 rpm. unless othemise
`noted Drug release was monitor~ oo a HP8452A
`diode-array spectrophotoimur at 250 nm and 290 nm
`!'OT d1clore11ac Na and sulfathiuole Na as model
`drugs, m;pecti,oely.
`
`. 7z g .
`
`DRL - EXHIBIT 1022
`DRL005