(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2005/0037055 A1
`Feb. 17, 2005
`(43) Pub. Date:
`Yang et al.
`
`US 2005003 7055A1
`
`(54) POLYETHYLENE OXIDE-BASED FILMS
`AND DRUG DELIVERY SYSTEMS MADE
`THEREFROM
`
`(75)
`
`Inventors: Robert K. Yang, Flushing, NY (US);
`Richard C. Fuisz, McLean, VA (US);
`Gary L. Myers, Kingsport, TN (US);
`Joseph M. Fuisz, Washington, DC (US)
`
`Correspondence Address:
`HOFFMANN & BARON, LLP
`6900 JERICHO TURNPIKE
`SYOSSET, NY 11791 (US)
`
`Assignee: MonoSolRX LLC.
`
`Appl. No.:
`
`10/856,176
`
`Filed:
`
`May 28, 2004
`
`Related U.S. Application Data
`
`Continuation-in-part of application No. 10/768,809,
`filed on Jan. 30, 2004, and which is a continuation-
`in-part of application No. l’C'l‘/US02/32575, filed on
`Oct. 11, 2002, and which is a continuation-in-part of
`application No. PCT/US02/32594, filed on Oct. 11,
`2002, and which is a continuation-in-part of applica-
`tion No. PCT/US02/32542, filed on Oct. 11, 2002.
`
`(60) Provisional application No. 60/473,902, filed on May
`28, 2003. Provisional application No. 60/443,741,
`filed on Jan. 30, 2003. Provisional application No.
`60/371,940, filed on Apr. 11, 2002.
`
`(30)
`
`Foreign Application Priority Data
`
`Sep. 27, 2002
`
`(US) ................................. .. EU552991707
`
`Publication Classification
`
`Int. Cl.7 ........................... .. B29C 47/00, A61K 9/70
`(51)
`(52) U.S.Cl.
`....................................... ..424/443,264/176.1
`
`(57)
`
`ABSTRACT
`
`The invention relates to the film products and methods of
`their preparation that demonstrate a non—self—aggregating
`uniform heterogeneity. Desirably, the films disintegrate in
`water and may be formed by a controlled drying process, or
`other process that maintains the required uniformity of the
`film. The films contain a polymer component, which
`includes polyethylene oxide optionally blended with hydro-
`philic ccllulosic polymcrs. Desirably, the films also contain
`a pharmaceutical and/or cosmetic active agent with no more
`than a 10% variance of the active agent pharmaceutical
`and/or cosmetic active agent per unit area of the film.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019101
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 1 of 34
`
`US 2005/0037055 A1
`
`70
`/ 74
`
`FIG. 5
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019102
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 2 of 34
`
`US 2005/0037055 A1
`
`wavavuimq
`nlaflnflafinl-
`
`FIG. 6
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019103
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 3 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019104
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 4 of 34
`
`US 2005/0037055 A1
`
`0 2 9I
`
`\ BU
`
`)
`
`SEC7'/ONB
`
`SECTIONA
`
`\ $
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019105
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 5 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019106
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 6 of 34
`
`US 2005/0037055 A1
`
`E
`H
`mm
`xmEoANvo
`TM.VC.NA.SUSLABTUECAMRAHPmET
`.HX.
`
`mm
`
`RBP_TEVA05019107
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`RBP_TEVA05019108
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`RBP_TEVA05019109
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 9 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019110
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`RBP_TEVA05019111
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`RBP_TEVA05019112
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 12 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019113
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`RBP_TEVA05019114
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 14 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019115
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 15 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019116
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 16 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019117
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 17 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019118
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 18 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019119
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 19 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019120
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 20 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019121
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 21 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019122
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 22 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019123
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 23 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019124
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 24 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019125
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 25 of 34
`
`US 2005/0037055 A1
`
`E
`H
`mm
`xmEoANvo
`TM.VC.NA.SUSLABTUECAMRAHPmET
`.HX.
`
`mm
`
`RBP_TEVA05019126
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005
`
`of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019127
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 27 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019128
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005
`
`Sheet 28 of 34
`
`US 2005/0037055 A1
`
`88¢_.
`
`E5am.23.5_3.<z§_%.__E§o§.s.2_
`
`
`
`.U®03UC_D._m0:“m0«mop:.IDn_<0OwU®N__wE._OZ
`
`mm.0_n_
`
`
`
`§_§_§___=53£5583...3E28$8:3.2.__m..m_._288.3%
`
`
`age.»£335¢__m.um:28_._..__§§__=53m=_EE8$._.%a.x_v_s_§2e%__._=efim=_eEa8.
`
`
`(M21) Jd5‘zooo'NaIsK
`
`0_VN}:l9HW3U!LUU1“O3°f ZOLOH
`
`E
`H
`mm
`xmEoANvo
`TM.VC.NA.SUSLABTUECAMRAHPmET
`.HX.
`
`mm
`
`RBP_TEVA05019129
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 29 of 34
`
`US 2005/0037055 A1
`
`’\
`9..
`CL
`EI\
`
`5-B‘
`C)
`c:
`
`
`
`EL +ov£/vTEMP(c)
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019130
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 30 of 34
`
`US 2005/0037055 A1
`
`—I—OVENTEMP(C)
`
`"\
`8,
`
`Q EI
`
`x
`
`Lu
`on
`C)
`vx
`o.
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019131
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 31 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019132
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 32 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019133
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`Patent Application Publication Feb. 17, 2005 Sheet 33 of 34
`
`US 2005/0037055 A1
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019134
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`lbuPn0.naCHPPAtneLluaP
`
`50027:1b.eFn0..ua.01.
`
`Sheet 34 of 34
`
`US 2005/0037055 A1
`
`% %
`
`-
`
`'\
`
`SE
`
`
`
`.56£§.§\§.s$.58m=.§oEE3.3.38Qm_..Esm.a&.smug.u8§e.§§_EowEEu
`.33.3SE53a&\_.§%=&Va%§___gmsxxom.
`
`M.
`
`
`
` .S.3e15:3isfiggs§§3.$25St.&:32:.§._.§%8=e&&.
`
`
`
`2we§§%..:.33
`
`Hax2&5
`
`E2:3E.»%.N8%9%..5E.Q§§"I"§.-
`
`www
`
`HHEE
`
`mm.o_n_
`
`V
`
`M.
`
`
`
`32%NN£human.‘E:3E83.3§.§Em..¥a$.E.
`
`3%8Raev2.393.3.§..:3%93$.3...._.‘slag3.QCIII.aS.3:E58.‘§_$..:_s..&.a.39‘3.589%En93$EatIIIII
`
`3......e$-3%E...g:gm
`3ésii§§.59%Q.5
`
`.2E3...3...3Eco.aEu.‘3.RN$3.»34»9%8.EIIIE.géllfilgI‘.
`
`&E%§.2ha.‘N
`
`.T
`
`%S4—
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019135
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 2005/0037055 A1
`
`Feb. 17, 2005
`
`POLYETHYLENE OXIDE-BASED FILMS AND
`DRUG DELIVERY SYSTEMS MADE THEREFROM
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims the benefit of U.S. Provi-
`sional Application No. 60/473,902, filed May 28, 2003 and
`is a continuation-in-part of PCT/US02/32575 filed Oct. 11,
`2002, wl1icl1 claims priority to U.S. application Ser. No.
`10/074,272, filed Feb. 14, 2002 which claims priority to U.S.
`Provisional Application No. 60/328,868, filed Oct. 12, 2001
`and U.S. Provisional Application No. 60/386,937, filed Jun.
`7, 2002; PCT/US02/32594,
`filed Oct. 11, 2002, which
`claims priority to U.S. Provisional Application No. 60/414,
`276, filed Sep. 27, 2002, U.S. application Ser. No. 10/074,
`272, filed Feb. 14, 2002, which claims priority to U.S.
`Provisional Application No. 60/328,868, filed Oct. 12, 2001
`and U.S. Provisional Application No. 60/386,937, filed Jun.
`7, 2002; and PCT/US02/32542, filed Oct. 11, 2002, which
`claims priority to U.S. Provisional Application No. 60/371,
`940, filed Apr. 11, 2002, U.S. application Ser. No. 10/074,
`272, filed Feb. 14, 2002, which claims priority to U.S.
`Provisional Application No. 60/328,868, filed Oct. 12, 2001
`and U.S. Provisional Application No. 60/386,937, filed Jun.
`7, 2002.
`
`FIELD OF THE INVENTION
`
`[0002] The invention relates to rapidly dissolving films
`and methods of their preparation. The films contain a
`polymer component, which includes polyethylene oxide
`optionally blended with cellulosic polymers. The films may
`also contain an active ingredient that is evenly distributed
`throughout the film. The even or uniform distribution is
`achieved by controlling one or more parameters, and par-
`ticularly the elimination of air pockets prior to and during
`film formation and the use of a drying process that reduces
`aggregation or conglomeration of the components in the film
`as it forms into a solid structure.
`
`BACKGROUND OF THE RELATED
`TECHNOLOGY
`
`[0003] Active ingredients, such as drugs or pharmaceuti-
`cals, may be prepared in a tablet form to allow for accurate
`and consistent dosing. However, this form of preparing and
`dispensing medications has many disadvantages including
`that a large proportion of adjuvants that must be added to
`obtain a size able to be handled, that a larger medication
`form requires additional storage space, and that dispensing
`includes counting the tablets which has a tendency for
`inaccuracy. In addition, many persons, estimated to be as
`much as 28% of the population, have difficulty swallowing
`tablets. While tablets may be broken into smaller pieces or
`even crushed as a means of overcoming swallowing diffi-
`culties, this is not a suitable solution for many tablet or pill
`forms. For example, crushing or destroying the tablet or pill
`form to facilitate ingestion, alone or in admixture with food,
`may also destroy the controlled release properties.
`
`[0004] As an alternative to tablets and pills, films may be
`used to carry active ingredients such as drugs, pharmaceu-
`ticals, and the like. However, historically films and the
`process of making drug delivery systems therefrom have
`suffered from a number of unfavorable characteristics that
`
`have not allowed them to be used in practice.
`
`[0005] Films that incorporate a pharmaceutically active
`ingredient are disclosed in expired U.S. Pat. No. 4,136,145
`to Fuchs, et al. (“Fuchs”). These films may be formed into
`a sheet, dried and then cut into individual doses. The Fuchs
`disclosure alleges the fabrication of a uniform film, which
`includes the combination of water-soluble polymers, surfac-
`tants,
`flavors, sweeteners, plasticizers and drugs. These
`allegedly flexible films are disclosed as being useful for oral,
`topical or enteral use. Examples of specific uses disclosed by
`Fuchs include application of the films to mucosal membrane
`areas of the body, including the mouth, rectal, vaginal, nasal
`and ear areas.
`
`[0006] Examination of films made in accordance with the
`process disclosed in Fuchs, however, reveals that such films
`suffer from the aggregation or conglomeration of particles,
`i.e., self—aggregation, making them inherently 11on-uniform.
`This result can be attributed to Fuchs’ process parameters,
`which although not disclosed likely include the use of
`relatively long drying times, thereby facilitating intermo-
`lecular attractive forces, convection forces, air flow and the
`like to form such agglomeration.
`
`[0007] The formation of agglomerates randomly distrib-
`utes the film components and any active present as well.
`When large dosages are involved, a small change in the
`dimensions of the film would lead to a large difference in the
`amount of active per film. If such films were to include low
`dosages of active, it is possible that portions of the film may
`be substantially devoid of any active. Since sheets of film are
`usually cut into unit doses, certain doses may therefore be
`devoid of or contain an insufficient amount of active for the
`
`recommended treatment. Failure to achieve a high degree of
`accuracy with respect to the amount of active ingredient in
`the cut film can be harmful to the patient. For this reason,
`dosage forms formed by processes such as Fuchs, would not
`likely meet
`the stringent standards of governmental or
`regulatory agencies, such as the U.S. Federal Drug Admin-
`istration (“FDA”), relating to the variation of active in
`dosage forms. Currently, as required by various world
`regulatory authorities, dosage forms may not vary more than
`10% in the amount of active present. When applied to
`dosage units based on films, this virtually mandates that
`uniformity in the film be present.
`
`[0008] The problems of self—aggregation leading to non-
`uniformity of a film were addressed in U.S. Pat. No. 4,849,
`246 to Schmidt (“Schmidt”). Schmidt specifically pointed
`out that the methods disclosed by Fuchs did not provide a
`uniform film and recognized that that the creation of a
`non-uniform film necessarily prevents accurate dosing,
`which as discussed above is especially important in the
`pharmaceutical area. Schmidt abandoned the idea that a
`mono-layer film, such as described by Fuchs, may provide
`an accurate dosage form and instead attempted to solve this
`problem by forming a multi-layered film. Moreover, his
`process is a multi-step process that adds expense and com-
`plexity and is not practical for commercial use.
`
`[0009] Other U.S. patents directly addressed the problems
`of particle self—aggregation and non-uniformity inherent in
`conventional film forming techniques. In one attempt
`to
`overcome non-uniformity, U.S. Pat. No. 5,629,003 to Horst-
`mann et al. and U.S. Pat. No. 5,948,430 to Zerbe et al.
`incorporated additional
`ingredients,
`i.e. gel formers and
`polyhydric alcohols respectively, to increase the viscosity of
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019136
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 2005/0037055 Al
`
`Feb. 17, 2005
`
`the film prior to drying in an efiort to reduce aggregation of
`the components in the film. These methods have the disad-
`vantage of requiring additional components, which trans-
`lates to additional cost and manufacturing steps. Further-
`more, both methods employ the use the conventional time-
`consuming drying methods such as a high-temperature air-
`bath using a drying oven, drying tunnel, vacuum drier, or
`other such drying equipment. The long length of drying time
`aids in promoting the aggregation of the active and other
`adjuvant, notwithstanding the use of viscosity modifiers.
`Such processes also run the risk of exposing the active, i.e.,
`a drug, or vitamin C, or other components to prolonged
`exposure to moisture and elevated temperatures, which may
`render it ineffective or even harmful.
`
`In addition to the concerns associated with degra-
`[0010]
`dation of an active during extended exposure to moisture,
`the conventional drying methods themselves are unable to
`provide uniform films. The length of heat exposure during
`conventional processing, often referred to as the “heat
`history”, and the manner in which such heat is applied, have
`a direct effect on the formation and morphology of the
`resultant film product. Uniformity is particularly difficult to
`achieve via conventional drying methods where a relatively
`hicker film, which is well-suited for the incorporation of a
`drug active,
`is desired.
`'lhicker uniform films are more
`difficult to achieve because the surfaces of the film and the
`'nner portions of the film do not experience the same
`external conditions simultaneously during drying. Thus,
`observation of relatively thick films made from such con-
`ventional processing shows a non-uniform structure caused
`3y convection and intermolecular forces and requires greater
`han 10% moisture to remain flexible. The amount of free
`moisture can often interfere over time with the drug leading
`o potency issues and therefore inconsistency in the final
`aroduct.
`
`[0011] Conventional drying methods generally include the
`use of forced hot air using a drying oven, drying tunnel, and
`he like. The difficulty in achieving a uniform film is directly
`elated to the rheological properties and the process of water
`evaporation in the film-forming composition. When the
`surface of an aqueous polymer solution is contacted with a
`1igh temperature air current, such as a film-forming com-
`aosition passing through a hot air oven, the surface water is
`immediately evaporated forming a polymer film or skin on
`he surface. This seals the remainder of the aqueous film-
`orming composition beneath the surface, forming a barrier
`hrough which the remaining water must force itself as it is
`evaporated in order to achieve a dried film. As the tempera-
`ure outside the film continues to increase, water Vapor
`Jressure builds up under the surface of the film, stretching
`he surface of the film, and ultimately ripping the film
`surface open allowing the water vapor to escape. As soon as
`he water vapor has escaped,
`the polymer film surface
`reforms, and this process is repeated, until
`the film is
`completely dried. The result of the repeated destruction and
`reformation of the film surface is observed as a “ripple
`elfect” which produces an uneven, and therefore non-uni-
`form film. Frequently, depending on the polymer, a surface
`will seal so tightly that the remaining water is difficult to
`remove, leading to very long drying times, higher tempera-
`tures, and higher energy costs.
`
`[0012] Other factors, such as mixing techniques, also play
`a role in the manufacture of a pharmaceutical film suitable
`
`for commercialization and regulatory approval. Air can be
`trapped in the composition during the mixing process or
`later during the film making process, which can leave voids
`in the film product as the moisture evaporates during the
`drying stage. The film frequently collapse around the voids
`resulting in an uneven film surface and therefore, non-
`uniformity of the final film product. Uniformity is still
`affected even if the voids in the film caused by air bubbles
`do not collapse. This situation also provides a non-uniform
`film in that the spaces, which are not uniformly distributed,
`are occupying area that would otherwise be occupied by the
`film composition. None of the above-mentioned patents
`either addresses or proposes a solution to the problems
`caused by air that has been introduced to the film.
`
`[0013] Therefore, there is a need for methods and com-
`positions for film products, which use a minimal number of
`materials or components, and which provide a substantially
`non—self—aggregating uniform heterogeneity throughout the
`area of the films. Desirably, such films are produced through
`a selection of a polymer or combination of polymers that
`will provide a desired viscosity, a film-forming process such
`as reverse roll coating, and a controlled, and desirably rapid,
`drying process which serves to maintain the uniform distri-
`bution of non-self-aggregated components without the nec-
`essary addition of gel formers or polyhydric alcohols and the
`like which appear to be required in the products and for the
`processes of prior patents, such as the aforementioned
`IIorstmann and Zerbe patents. Desirably, the films will also
`incorporate compositions and methods of manufacture that
`substantially reduce or eliminate air in the film,
`thereby
`promoting uniformity in the final film product.
`
`SUMMARY OF THE INVENTION
`
`[0014] The present invention is directed to rapid-dissolve
`film products containing at least one water-sol11ble polymer
`including polyethylene oxide alone or in combination with
`a hydrophilic cellulosic polymer, wherein the film product is
`free of added plasticizers.
`
`[0015] Another embodiment of the rapid-dissolve film
`product includes at least one water-soluble polymer con-
`taining about 20% to 100% by weight polyethylene oxide,
`about 0% to 80% by weight hydroxypropylmethyl cellulose,
`and about 0% to 80% by weight hydroxypropyl cellulose; an
`active component; sucralose; precipitated calcium carbon-
`ate;
`
`at least one flavoring, simethieone, water, and
`[0016]
`at least one colorant, wherein the film product is free
`of added plasticizers, surfactants, and polyalcohols.
`
`[0017] Yet another embodiment of the present invention is
`directed to an edible water-soluble delivery system in the
`form of a film composition, which contains at least one
`water-soluble polymer comprising polyethylene oxide alone
`or in combination with a polymer selected from the group
`consisting of hydroxypropylmethyl cellulose and hydrox-
`ypropyl cellulose, wherein the edible water-soluble delivery
`system is essentially free of organic solvents, plasticizers,
`surfactants, and polyalcohols.
`
`[0018] The present invention is also directed to processes
`for making a film having a substantially uniform distribution
`of components, including the steps of: (a) combining at least
`one water-soluble polymer comprising polyethylene oxide
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019137
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 2005/0037055 A1
`
`Feb. 17, 2005
`
`alone or in combination with a hydrophilic cellulosic poly-
`mer, a solvent, and an active component to form a matrix
`with a uniform distribution of the components; (b) forming
`a film from the matrix; and (c) drying the film, wherein the
`film is free of added plasticizers.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0019] FIG. 1 shows a side View of a package containing
`a unit dosage film of the present invention.
`
`[0020] FIG. 2 shows a top View of two adjacently coupled
`packages containing individual unit dosage forms of the
`present invention, separated by a tearable perforation.
`
`[0021] FIG. 3 shows a side View of the adj acently coupled
`packages of FIG. 2 arranged in a stacked configuration.
`
`[0022] FIG. 4 shows a perspective view of a dispenser for
`dispensing the packaged unit dosage forms, dispenser con-
`taining the packaged unit dosage forms in a stacked eon-
`figuration.
`
`[0023] FIG. 5 is a schematic view of a roll of coupled unit
`dose packages of the present invention.
`
`[0024] FIG. 6 is a schematic View of an apparatus suitable
`for preparation of a pre-mix, addition of an active, and
`subsequent formation of the film.
`
`[0025] FIG. 7 is a schematic view of an apparatus suitable
`for drying the films of the present invention.
`
`[0039] FIG. 21 is a p iotomicrograp 11C re aresentation of a
`film containing fat coated particles driec by the inven ive
`drying process.
`
`[0040] FIG. 22 is a p iotomicrograp 11C re aresentation of a
`film containing fat coated particles driec by the inven ive
`drying process.
`
`[0041] FIG. 23 is a p iotomicrograp 11C re aresentation of a
`film containing fat coated particles driec by the inven ive
`drying process.
`
`[0042] FIG. 24 is a p iotomicrograp 11C re aresentation of a
`film containing fat coated particles driec by the inven ive
`drying process.
`
`[0043] FIG. 25 is a p iotomicrograp 11C re wresentation of a
`film containing fat coated particles driec by the inven ive
`drying process.
`
`[0044] FIG. 26 is a photomicrographic representation of
`fat coated particles not in film, heated fo 9 minutes at 80°
`C.
`
`[0045] FIG. 27 is a photomicrographic representation of
`fat coated particles not in film, heated for 9 minutes at 80°
`C.
`
`[0046] FIG. 28 is a photomicrographic representation of
`fat coated particles at room temperature prior to processing.
`
`[0047] FIG. 29 is a photomicrographic representation of
`fat coated particles at room temperature prior to processing.
`
`[0026] FIG. 8 is a sequential representation of the drying
`process of the present invention.
`
`[0048] FIG. 30 is a photomicrographic representation of
`fat coated particles at room temperature prior to processing.
`
`[0027] FIG. 9 is a photographic representation of a film
`dried by conven ional drying processes.
`
`[0028] FIG. 10 is a photographic representation of a film
`dried by conven ional drying processes.
`
`[0029] FIG. 11 is a photographic representation of a film
`dried by conven ional drying processes.
`
`[0030] FIG. 12 is a photographic representation of a film
`dried by conven ional drying processes.
`
`[0031] FIG. 13 is a photographic representation of a film
`dried by conven ional drying processes.
`
`[0032] FIG. 14 is a photographic representation of a film
`dried by conven ional drying processes.
`
`[0033] FIG. 15 is a photographic representation of a film
`dried by conven ional drying processes.
`
`[0034] FIG. 16 is a photographic representation of a film
`dried by conven ional drying processes.
`
`[0035] FIG. 17 is a photographic representation of a film
`dried by the inventive drying process.
`
`[0036] FIG. 18 is a photomicrographic representation of a
`film containing fat coated particles dried by the inventive
`drying process.
`
`[0037] FIG. 19 is a photomicrographic representation of a
`film containing fat coated particles dried by the inventive
`drying process.
`
`[0038] FIG. 20 is a photomicrographic representation of a
`film containing fat coated particles dried by the inventive
`drying process.
`
`[0049] FIG. 31 is a photomicrographic representation of
`fat coated particles at room temperature prior to processing.
`
`[0050] FIG. 32 is a graphical representation of a microar-
`ray on the blood of a human after ingestion by the human of
`a film of the present invention containing a bovine derived
`protein.
`
`[0051] FIG. 33 is a graphical representation of the tem-
`perature differential between the inside and outside of a film
`of the present invention during drying.
`
`[0052] FIG. 34 is a graphical representation of the tem-
`perature differential between the inside and outside of a film
`of the present invention during drying.
`
`[0053] FIG. 35 is a schematic representation of a continu-
`ously-linked zone drying apparatus in accordance with the
`present invention.
`
`[0054] FIG. 36 is a schematic representation of a separate
`zone drying apparatus in accordance with the present inven-
`tion.
`
`[0055] FIG. 37 is a schematic representation of a extru-
`sion deviee for use in producing films of the present inven-
`tion.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0056] For the purposes of the present invention the term
`non-self-aggregating uniform heterogeneity refers to the
`ability of the films of the present invention, which are
`formed from one or more components in addition to a polar
`solvent, to provide a substantially reduced occurrence of, i.e.
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019138
`
`TEVA EXHIBIT 1006
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 2005/0037055 A1
`
`Feb. 17, 2005
`
`little or no, aggregation or conglomeration of components
`within the film as is normally experienced when films are
`formed by conventional drying methods such as a high-
`temperature air-bath using a drying oven, drying tunnel,
`vacuum drier, or other such drying equipment. The term
`heterogeneity, as used in the present
`invention,
`includes
`films that will incorporate a single component, such as a
`polymer, as well as combinations of components, such as a
`polymer and an active. Uniform heterogeneity includes the
`substantial absence of aggregates or conglomerates as is
`common in conventional mixing and heat drying methods
`used to form films.
`
`the films of the present invention
`[0057] Furthermore,
`lave a substantially uniform thickness, which is also not
`arovided by the use of conventional drying methods used for
`drying water—based polymer systems. The absence of a
`uniform thickness detrimentally alfects uniformity of com-
`aonent distribution throughout the area of a given film.
`
`invention are
`[0058] The film products of the present
`Jroduced by a combination of a properly selected polymer
`and a polar solvent, optionally including an active ingredient
`as well as other fillers known in the art. These films provide
`a non-self-aggregating uniform heterogeneity of the com-
`Jonents within them by utilizing a selected casting or
`deposition method and a
`controlled drying process.
`Examples of controlled drying processes include, but are not
`imited to, the use ofthe apparatus disclosed in U.S. Pat. No.
`4,631,837 to Magoon (“Magoon”), herein incorporated by
`reference, as well as hot air impingement across the bottom
`substrate and bottom heating plates. Another drying tech-
`nique for obtaining the films of the present
`invention is
`controlled radiation drying, in the absence of uncontrolled
`air currents, such as infrared and radio frequency radiation
`(i.e. microwaves).
`
`[0059] The objective of the drying process is to provide a
`method of drying the films that avoids complications, such
`as the noted “rippling” effect,
`that are associated with
`conventional drying methods and which initially dry the
`upper surface of the film,
`trapping moisture inside.
`In
`conventional oven drying methods, as the moisture trapped
`inside subsequently evaporates, the top surface is altered by
`Jeing ripped open and then reformed. These complications
`are avoided by the present invention, and a uniform film is
`arovided by drying the bottom surface of the film first or
`otherwise preventing the formation of polymer film forma-
`ion (skin) on the top surface of the film prior to drying the
`dept