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`24th lntetnationaJ. Symposium on
`~~ftllled Release of r~~ii':;\ Bmact1ve Materials
`~~lf'~~:,
`·
`t :·,?-< June ·15-19, 1997
`STOCKHOLMSMASSAN
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`Sym1ln1'i Utn! J"und6 • l<). 1997
`exhibit: Jui;d 7- 19, 1997
`STOCt;H!ltA1SMi\S--<;AN
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`Program Cbalrs:
`Kosrl-fa1k l'alk
`Astt';l Hassl.~ /\l;I, USA
`l'eruo Okano
`Tt»ky~·s \'V,;~u1~ri·s "Medk;;l (~tlkgc, Jr.pa~t
`
`DRL - EXHIBIT 1023
`DRL001
`
`

`
`·Published by
`
`The Controlled Release Society, Inc.
`1ow Milwaukee Avenue
`.
`Suit~335
`Oee1iield. IL 6o615 USA
`
`First ;~ilion, 1997
`
`•
`, •
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`~
`wmn~~~}~~F
`~lb~nimosmm and Workshop Sc1.ent1fk
`~i.•m Conuuittec
`.:e&i~~·
`gJt )\filfifit<>le A'!. B.'i!>
`~·lit~~ V;<>,,•)u's Mcdit~! c.,ur.;~. i<>•~"
`!!·ill:"'":,lty uf foutf«rt• Co!ilbrn:: •. ;;sA
`
`C.opyright~' 1997 by The CC)nlroUed Release Society, Inc.
`
`Ali rights reserved. No part of this publication may be reproduc~d. stored in a retrieval
`system, or transrnilted in ar1y form or by any means, electronlc,:mechanicaJ, photocopy;ng,
`recording, ()( othe1w!se, without the prior permission Oi ttie pubiisher.
`
`ISSN 1022·0178
`
`Rrinted in iho USA
`
`' , ,
`
`%@'N#iue t:nh:ersit.y. (JSA
`::!;1:i~~(f11:nu<. l:SA
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`::::~~~fiµ;~~-l~r.g::.o::-:ln, Astra Orac-() AB. Swt:.!e:n
`.... lll~.:·;t~iv<..-rni:y Hf }i<)t!IUY.h••,,.,, l'.>1~•nJ. t::K
`
`~ li!bstracts in this book are listedjn tl'}6:folia~ii;lg:
`¢~mbricig~ Sci(fofific Abstracts
`ifoJmica! Ab.."ltrotls
`eJ<"cerpta Medica
`
`.
`
`·~'.
`
`The Controffed Releas& Society_ essq~:~ ~o ,;;;hsibl1itY
`t,~t abstracts not ~wallable at time. Qf prin1mg.
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`TEVA EXHIBIT 1023
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`l ~l96-1 tJ97 Officers of the Controlled Release Society, Inc.
`Prl."sldeut
`Vice? Pl'csident.
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`DRL - EXHIBIT 1023
`DRL003
`
`

`
`' sec~
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`purpos~ of vafa!atini; :he !.heore;icn!
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`width of the b-:ihis (introduced 10 cm into
`th>.: d\Jooem1r.:i) is im!i-:.e;ed in the fig~re.
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`f~t that tbe bolus wB~ inttochi.~ed I 0 Cltl
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`rind theuretka! predinlons for tl:-e c~ of
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`near the exp;:rim~nt~l cs1lm1i\c. Tht) g.100
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`i;ssuming an i:.pithelial pem1r-.ih!lity d
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`
`REJ<'ERENCES
`l. Knydiyyeh, S.L. Bitar, K.M.,
`Bikhazi., A.B. J. Pharm. Sci., 79. 494
`(1990).
`2. Adscn. A.. Rai:b, T 1 • Burton, P.S ..
`Barsuhn. C.L., Hilge~. A.R .. .c\udus,
`K.L., Ho. N.f. J. Pha.rm. Sci., 83.
`1529 {1994).
`3 . Brenner, H., Edwards, D.A.
`Macmtr:ll\~J'Ort Pr<:cessc~. Bo$tiln:
`Butterworth·Hcmemar. (i9'J'.)).
`4. Swi!. B,. B11tycky, R., Lcip<'ld, H.,
`Milstein, S., F..dw;;rd$, D. Subm.i•tod
`(1997}.
`5. Dn-);sman, J.'B., Bass, P., Ri;,;chel.
`W,A., Friend, D.R., R.ihin~teiu, A ..
`Ziv, E. J. Pb11m;. Sci., 82, 857
`(1993).
`6. Ifowe!")I, C.Y. J. hd. Endo<.·rin. 6, 21
`(199J.}.
`
`. ~Z~·
`
`:: r..··. t~:~ .J::; ~ .~f~Y C3;::<~L~} . :~·:n4r.t .?'!~~e: . . ::~: :%n
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`W1\ l'ER SOUJIH.E Fll.M. FOR ORAL .\.H!l.HMSTR.\ TION
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`.lii!ll·Hwa I;,,.,• a.thl U1w$I l~rlic'
`
`'Aqu:.lon llivi,;,,,., Ucncuks Inc,, $1)1) U~rculcs JM., Wi!111i11i;wn, DE 1!1808-1599
`'LTS Cc>rtl .. 21 H1~1.trl"'..-><1 lk. W~1 Cahh<cll. NJ 07006
`
`ph<1rrr1aceuUcaJly 01 r--csrne1~::ally active
`:igcnl, said iiim compr:G:ng wa1<1r-r.olub!e
`polymers. a combinafo:\ cl certain
`si;rfa;,1a.'ll!;, cne •Jr m•Jre po;yalcoho!s. anct
`ona er morn pt•1mr:o;;outica!ly tir
`cc1::'11<:tk:aJ1y act:-:a lngrntlim1ts. Oµtlonti.ily.
`th~ !crr:1L1ir:t:or. .,.,,,y <:<:>:'ltain col:m1flt:; .
`sweatening agef'~t$. flavors~ i~avor
`entmnee1:>. or cthc;r exc:pisnts comrnr.r.I}•
`us!ld to mod~y the ;aste rJf fonn-.sla;ion;,
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`cut :nto p:e:;!Js o! a shape ar:d size \hill
`meet the requirements ot tt:e specific
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`containers.
`
`Experimental
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`Mt.;C08dhtis•vt; do:;~;g~ forrrm fo:'
`~r>tk::a!itt:~ to ihe o~~= C.3\'tly which ar~
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`:tt;U u:j'd~d to o<ovtU!3 a fo--;n-ctdh&rino
`·S<Jr!ace. They ali.o disdo;:.r:d a :ril;,'l'irm1e
`: ... 1~r:'.\ ~~j;mcle fo: prctw.(JeC dt:lHvery ~~far:
`t <tclk<l ingred1em in the oral ;.;av:ly (2i. i:'l .,
`}$jr.1iiar ~'~Y. Mlrn111,c.hi, HI al. (3) dbcioscd a
`}#.;ee!-sMpecJ eidh·JSi'-'e pmparatior,
`~rnpt!s:ng at; a~hss:ve layer con1eini:'lU
`qei;;Jin .vater-su;uule an~ writer-inso!ut;!!
`-poiyrnE:rs and a wate;-msoiuble carr:ar
`'::,~tii::h cm., aC1!1e1c 10 the oral mucos<:
`~fo;£rety ~!easing ur. ac:tivl1 agv111 to the om!
`~~~~vity. A n~n)hor of ~ttompt~t have t;~en
`·. :rtla~ to r~1duc1;; tl'a <:dver:;.1 !E>eting in Ille
`«al c;a·,:;y caustid by the rr,1idily ar:d
`, l::tllexibillly of ~~•to supp~;1 !a)'ar by
`·;wro.jucing soil lil:l: ~".lppr;:ts(·H>) .
`)~~wr,v<1r, lhr3$0 cf,1vii:13s $tiH lci.;va tll'3
`{~tienl with a o::r.sidNabli- ar.-1ount oi
`resfr3ue fro:r1 Iha wt:;er·!n!'.Oiuli!o St.;ppoit
`!!Im 1.!:ereby sl!I: ·:;ai;!-:nn il !er:l!ng of
`~"dlsc.orn!1~rt. T?'lF. ;.)bv:cu$ so:rniotl !c
`~~~er-c~n1e tt1iv p~~.:>bi0:m WESS io dovclop
`:fff'ff:J(:YX:ld~H·t~iv.'l Wtr1S wr1fr;J1 ,~on:pfatc1ty
`t <.Jisiinegmte, or e-:Ea corn;Jlatel)' d':.-$<Jhm 10
`; tt\E: salrm
`
`The •n-..1xacthssive lilm of the presefli
`i11ve~1t•rJn oor;;ains as ti!\AAoti:l.! c::!mponvr.tt.
`u wute!·sd.utJle; ;.io:ym~r or a comb11~,1;ion of
`;;o"at0r-sok1bicl pol~lffH3rs. ~.i co:-r~bhaticr. ot
`s11rfiil.::trm1.s. ::!ne or morn poirui;;chols, and
`a ;:ha1maceulir.a!ty or cosmetical!y uCl:•e
`ingrOOie:-t~ Tha ;!O:y?r.em issoo tcr the
`m;;coaf.lhes:ve filrn incluoo po!y~El<t> wnfr:r.
`am hydrophi!ic ar;d watar-<lispt;l>T.:bie. Ths
`::n:nbiriurn:n of s1.:rlactan1s used lcr ;he
`rn<«.Mdhil'~'"'~ !iim is u mixtwe of nonio•ilc
`s1:!fact.1r.:S. The. amount of cru~ to be
`ir.corpo:t1ted ir:!<; t.•m mrr. :mper:iJs or1 me
`kind oi drug ;,r.d 's w;iJ:1H;.1 bt:tw~~en O.G 1
`and 20°1~ (wlw). Cos:'\~t'~tic~Hy aGlivn ng~nts
`ma·i i:1clt:<Je brn~th frt'shr:r.ing <:crnpo!Jnd!;
`.. ::: 'ft:•J P=''..1Set't ir~vant;vn ~;.}nft;-l:1·:p;3tas;:
`:~;:·r~tci~ dissol\': ng mm vvh!C?'J can na ad~~: t:d
`hi<e :r.er:i:lu:. o:he:' Ha\•crs tu fr<'!.fJrar:~!?s
`t~ U:B c:-u: : .. ~avn'{ t?'1€=¢b}' :t~:t:asing a
`com=tl01'1f v-sad to: <'ta! hYfJisne. rtn'1!cr
`:'~-.:<:t<:. :"!~ ·. ~ttt;.:..c-r.~ ·~J .'s;. tc:<·~~t ~a ~'.: .. 1•: :%i;
`t.:-r=-.;!'oUt:1 fee:! ~$~~ ::;!.:~"i· ;:i:· ..
`
`··:·.i;.
`
`··············-····
`
`DRL - EXHIBIT 1023
`DRL004
`
`

`
`I 500?
`
`i 5~03
`
`W aier Soluble: Polyca1ions for ( 'out rolled Delivery Systems
`
`NAndini Kooar 8lld Clw!rng-ju Kim
`
`SchooloEPhannacy, Temple University, Philadelphia, PA 19140
`In this study, we present the zero-order
`re~se kinetics of water soluble anionic drugs from
`erodible, drug/polycationic, matrices (tablets) usmg
`poly(trimetbylaminoethyl methacrylate chloride -co(cid:173)
`methacrylm) (PTMAEMC/MMA):
`
`·[CH:· ·).-[-CH,
`:-0
`-CH.i
`
`~H-' ~'
`
`·},.·
`=O
`-(CH,hN" (CRJ,
`er
`
`dissoluuon/disintegration upon
`ndminlstration In the oral cavity.
`
`References
`
`(11 Sanvordeker, D.R. and Leung, S-H. S.
`us patent 5,04'7,244, 1991.
`(2) Sanvordekot. D.R. and lenug, S-H. S.
`WO patent 91/06270, 1991.
`(3) MizobiK:hi, T., Ohji. A., Sakoh. S. ilnd
`Mugururna. Y. US Patent 4,876.092, 1989
`(4) Kuroya, T. and Inoue, Y. European
`Patent 0·381 -194·81. 1990.
`(5i Blank, R G., Mody, D.S.. Kenny, R.J.
`and Aveson. M.C. US Patent 4.946,684,
`1990.
`(6) Inoue, T., Maeda, K. and Eguchi. Y.
`Patont 5,206,010, 1993.
`
`.S::1"1
`
`lB
`~16
`g>12
`~10
`(ii 8
`.!!1 6
`-~ 4
`~ 2
`0
`
`nc1rv,3s used for der1tal and/or oral
`cloansing like quartemary ammonium
`bases. The mucoadhesive film according to
`the present invention can be prepared as
`follows: The active ingredient. surfactants.
`pclyillcohol. and pcsslble other Ingredients
`except the water-dispersible polymer are
`dissolved in a sufficient amount of a solvent
`which is C-011'.patible to them. After a clear
`sol:Jlion has been formed, the water·
`dispersible polymer or mixivru of wa1er·
`dispersible polymers is slowly added ur.der
`stirring until a clear and homogeneous
`solution has been formed. The solution is
`coated cnlo a suitable carrier matena.1 an:!
`dr:ed to form a film. The carrier material
`must have a surface tonsion wt1ich allows
`;he polymer solution to be sprGad ovenly
`across the intended coating width. The
`coating o1 thB solution onto the carrier
`material can be performed using any
`ccnvent!ooal coming equipment
`TI1e 1l!ms with desired thickness were
`cut er puncherj out tor the disintegration
`and tensile wenyth tests. The tensile
`strength of the films was assessed using
`Erichsen (Model 474. A. M. E1ictisen
`GrnbH, GerrnMy) and was expressed as
`the maximum force (N) (Figure 1 ). A 25-c:m"
`film was placed in the peri dish which was
`filled with deionized waler, and the time for
`the film to totally disintegrate was recorded
`(Figure 2). TI1e decreaso of lnhigration time
`ot formulations A to E was accompanied by
`the decrease of tensile force of the
`formuia1ions. This correlation indkated that
`the choice of the most optlrr.al formll!ation
`coold t>e ~ecided by using either the tensile
`st:engt!1 or the disintegration test.
`
`Conclusion
`
`A rumposi1ion containing therapeutic
`agents am.tior breath hestu.ming agents for
`UM in the oral cavity is disclosed. TM
`carrier romptiSlls wat11r-soluble polymers in
`mrnbiM\it)(l with etlrtaln 1ngtedret\ls r:ind
`provides n thernpeufin and/or cosmetic
`eflect. l"he film is c:oated and dried utilizing
`existing coaUng technotogy and O)'hiblts
`!nstant wettability tol!owed by rapid
`~1..;c.C!~~. ~r.:. · 1 ·'?•tt~Co::tr~l.?.al. ~ia~c~. :bttt. ~2'1 l,lfJ}
`c,.;~t·oncc ~elus~ s~detr ~r.~
`
`·228·
`
`Formula1ions
`
`Figure 2: Tho disintegrntior. lime
`of polymer films.
`
`:ion
`Drug delivery systems using iou ex.cllange
`are one of the oldest processes { l j.
`:rcially available ioo exchange resins are
`on highly cross-linked poly(styrme/divinyl
`>) (sulfonated ar.ui quatem1zed) or cross-linked
`. :thacrylic acid). Highly crO'Ss·linked gel type
`·:{negligible swellinB) si!lllificantly s~in the
`~· of a drug in the gel matrix, "'hid! yields JI
`. .l kinetie!. ..,,;th a tailing.
`rt S=tly.
`swellable poJyel(lC(rolyte gcl
`rl~~ bave been extensively investigated as drug
`,.,,.,, f · system-. By vatying the ionic pendant
`and the d~r~ of cross·lin.king of the polymer
`the degree of swelling of Charged
`:olytes lllily be ta.ilored Several investig;itors
`iouic and anio111c hydrophobic polymers
`ing of tertiary amine and me<bacrylic acid or
`acid groups, respectively, fur the release of
`..(2-4). Hawevcr, due c.o the pH dependent
`·1if characteristics o£ charged polymers
`·. ~S teltial)' amine or carboxylic acid pet!danl
`it was not feas.ible for these ionic gels to be
`a.s oral cMivery s)'litcms, bccaus~ ·the p.H
`. changes as a ~osage t'onn travels .along the
`. . tesrinal {GI) traCt. · NuJOlll.'l and Kim [5]
`i\xstrated a (pseudo) lmcar rele;ise of water
`~fo drug.s from erodible, drug/resirl complex, gel
`·
`using noncross-linkod poty(sulfopropyl
`<late potaSSl\lm -co- merhyl melhacl)late)
`lMMA). Drug relm~ from drug-PSPMK/
`. , v.i11ch has a dn1g loading of greater tha!l 40
`(;::maintains zero-order release lnnetics for a long
`Id of time because the drug in the matrices is
`i1 to d1~ polymer side diain unril the oomple'< is
`~tlld by incoming c:c.>Wltcr ions. It was fomd Reswts anll D~uuion
`filu'g release was i11depend~~1~ of the pH of tlte
`The cffccl of i<111ic strength on diclofes1ac Nn
`~ffilon medium as long as thti ionic strength was
`from d rvg·PTM.AEl\o;lCiMMA complex
`rel<!llsc
`'"1'1Jan 0. 1 M which is rommonly obsei:wd iiah~
`tablets at pH 7 is shown in Figure I. T;iblew of
`ii#.[6.]. lo addition, tab!&, which are a 'oouu011
`200mg weight we.re fonnulated witlt 20 % dc>1IYOS¢
`led release dos.~gc form wer~ successfully
`a~ a tabk<t binddr. The buffer ccmainoo O O I M
`red. ftom these drugfrcsiu oouylt»~es.
`phosphntc and N3CI tanging from 0.05 M to 0 2 M
`9r~e;.1.,t ·i .s._~ .. cv~tr~' . f.tl .&:''~" -~"e' .. 2(!'i9/}
`(t>\t.r~! lid ,>,,.1°4<_~ ~·3':.:t~!'- J~.
`
`Ex~rimenu1I Methods
`S)'t1Jlr11sls of PTMAEMCIMMA am/ Pr.:parat1"n of
`Drug R ajn<fle Tublt.'t.•
`PTMAEMC/MMA was prepared by the
`free-radical solution pol},llerizaiioo of PTMAfMC
`(40~~} and MMA (60"4>) as reported earlier (1). The
`pol)mer ·w3s dissolwd in de-iooirod water. and a
`drug $0lutil"l was ~ to lhe polymer soWl.ion The
`cou¥l~JU:S vrecipiw.ed in wate( were recovered and
`waslicd sovtral times before being dried. The dried
`drug-~sim1tcs were crushed in a mortar and pest(~ to
`obtain powders. Tablets with drug-resinates and
`dext1ose were fabricated in 9.0 mm diameter die aud
`a flat su1face punch with a Carver press
`Dru(( Rt/east J(inetks Ttsts
`The drug release kinetics ftom drug·resinate
`tablets wcr~ cimcd out in O 01 M phosphate buffer
`c:antammg dit'lbrmt aniounts of NaCl al 37°C by the
`USP basket method ~t 100 rpm. U11less otherwise
`uot~. Drug release was mooitored oo a HP8452A
`diode-array spa;trepho<om<Ur at 250 nm and 290 nm
`fw diclofenac Na and sulfatbiazole Na as model
`drugs, respa;tivdy.
`
`·729-
`
`DRL - EXHIBIT 1023
`DRL005