(12) Ulllted States Patent
`Yang et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,017,150 B2
`Sep. 13, 2011
`
`US008017150B2
`
`(54) POLYETHYLENE OXIDE-BASED FILMS AND
`DRUG DELIVERY SYSTEMS MADE
`THEREFROM
`
`(75) Inventors: Robert K. Yang, Flushing, NY (US);
`-
`-
`.
`glcharEC1\;IF“lsZ’I<MCLean’
`)’
`(
`any -
`yefs’ mgSPOI't’
`Joseph M. FlllSZ, washlngton, DC (US)
`
`(73) Assignee: MonoSol RX, LLC, Portage, IN (US)
`
`( * ) Notice:
`
`Subject' to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 364 days.
`
`.
`(21) APPI'NO" 12/107’389
`.
`_
`(22) Flled-
`
`APr-221 2008
`
`(65)
`
`Prior Publication Data
`
`US 2008/0260809 A1
`
`001. 23, 2008
`
`Related US. Application Data
`_
`_
`
`_
`
`_
`
`_
`
`(60) Division of application No. 10/856,176, ?led on May
`28, 2004, noW Pat. No. 7,666,337, Which is a
`continuation-in-part
`of
`application
`No.
`PCT/US02/032575, ?led on Oct. 11, 2.002, and a
`contmuatron-m-part
`of
`application
`No.
`PCT/US02/32594, ?led on Oct. 11, 2002, and a
`continuation-in-part
`of
`application
`No.
`PCT/US02/ 32542, ?led on Oct. 11, 2002.
`(60) Provisional application No. 60/473,902, ?led on May
`28, 2003, provisional application No. 60/414,276,
`?led on Sep. 27, 2002, provisional application No.
`60/371,940, ?led on Apr. 11, 2002.
`
`(51) Int- 0-
`(2006.01)
`A61K 9/14
`(52) U.S.Cl. ...... .. 424/484;424/486;424/488;424/434;
`424/435
`
`(58) Field of Classi?cation Search ................ .. 424/434,
`424/435, 436, 443, 484
`See application ?le for complete search history.
`
`(56)
`
`References Cited
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`OTHER PUBLICATIONS
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`Flick, E~,Water-$<>1ub1eResinsiAnlndustrial Guide, 1991101191
`Ed.) William Andrew Publishing/Noyes, pp. 389-391 .*
`
`(Continued)
`
`Primary Examiner * Gina C Yu
`(74) Attorney, Agenz, or Firm i Hoffmann & Baron, LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to the ?lm products and methods of their
`preparation that demonstrate a non-self-aggregating uniform
`heterogeneity. Desirably, the ?lms disintegrate in Water and
`may be formed by a controlled drying process, or other pro
`cess that maintains the required uniformity of the ?lm. The
`?lms contain a polymer component, Which includes polyeth
`ylene oxide optionally blended With hydrophilic cellulosic
`polymers. Desirably, the ?lms also contain a pharmaceutical
`and/or cosmetic active agent With no more than a 10% vari
`ance of the active agent pharmaceutical and/ or cosmetic
`active agent per unit area of the ?lm.
`
`18 Claims, 34 Drawing Sheets
`
`TEVA EXHIBIT 1001
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 8,017,150 B2
`Page 2
`
`US. PATENT DOCUMENTS
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`’
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`DE
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`WO
`WO
`WO
`WO
`
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`0259749 B1
`7/1988
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`0452446 B1
`11/1992
`0514691 B1
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`0598606 A1
`6/2001
`1110546 A1
`5/1991
`9105540
`9/1992
`9215289
`2/1995
`9505416
`7/1995
`9518046
`9/1997
`9731621
`4/2000
`0018365
`7/2000
`0042992
`9/2001
`0170194 A1
`0191721 A2 12/2001
`03030882 A1
`4/2003
`03030883 A1
`4/2003
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`2008011194 A2
`V2008
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`OTHER PUBLICATIONS
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`.
`.
`.
`Repka et .31.; In?uence of V1tam1n E. TPGS on the propert1es of
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`* cited by examiner
`
`TEVA EXHIBIT 1001
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`

`
`US. Patent
`
`Sep. 13, 2011
`
`Sheet 1 0134
`
`US 8,017,150 B2
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`70
`l/ 74
`
`12
`
`14
`
`FIG. 1
`
`10
`
`70J
`
`FIG. 5
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`TEVA EXHIBIT 1001
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`

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`US. Patent
`
`Sep. 13, 2011
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`Sheet 2 0134
`
`US 8,017,150 B2
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`20
`
`f_/
`
`24
`
`54'
`
`36
`40
`
`0
`
`/\-/ 48
`
`TEVA EXHIBIT 1001
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`

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`US. Patent
`
`Sep. 13, 2011
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`Sheet 3 0134
`
`US 8,017,150 B2
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`44
`
`42
`
`sol-L172 i ‘Tl-:60
`
`21‘ /5IL
`A \56
`
`54\
`
`W50
`
`~52
`
`FIG. 7
`
`TEVA EXHIBIT 1001
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`

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`US. Patent
`
`Sep. 13, 2011
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`Sheet 4 0134
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`US 8,017,150 B2
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`
`9 29C 0mm.
`
`
`
`m 292 umw,
`
`w .01
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`TEVA EXHIBIT 1001
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`US. Patent
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`Sep. 13, 2011
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`Sheet 5 0134
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`US 8,017,150 B2
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`1052.
`
`FIG. 9
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`TEVA EXHIBIT 1001
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`US. Patent
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`Sep. 13, 2011
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`Sheet 6 0134
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`US 8,017,150 B2
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`
`FIG. 10
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`US. Patent
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`Sep. 13, 2011
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`US 8,017,150 B2
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`FIG. 11
`
`100
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`US. Patent
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`Sep. 13, 2011
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`Sheet 8 0134
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`US 8,017,150 B2
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`Sheet 9 0134
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`US 8,017,150 B2
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`
`100
`
`FIG. 13
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`
`FIG. 14
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`100
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`FIG. 15
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`US 8,017,150 B2
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`//
`
`710
`
`FIG. 16
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`FIG. 17
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`FIG. 18
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`FIG. 19
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`FIG. 20
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`FIG. 21
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`FIG. 22
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`U.S. Patent
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`US 8,017,150 B2
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`FIG. 23
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`FIG. 24
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`FIG. 25
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`U.S. Patent
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`US 8,017,150 B2
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`FIG. 26
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`U.S. Patent
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`Sheet 23 of 34
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`US 8,017,150 B2
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`FIG. 27
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`TEVA EXHIBIT 1001
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`U.S. Patent
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`Sheet 24 of 34
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`FIG. 28
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`FIG. 29
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`Sheet 26 of 34
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`US 8,017,150 B2
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`FIG. 30
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`US 8,017,150 B2
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`FIG. 31
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`U.S. Patent
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`8SU
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`7
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`2B
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`mI1,mmGE
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`M.88?Emmom_9:3“mos.._._on_<oB8~__m_Eoz
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`1mmM2.,_V3M.1Bmm
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`TEVA EXHIBIT 1001
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`

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`U.S. Patent
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`Sep. 13, 2011
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`Sheet 29 of 34
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`US 8,017,150 B2
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`Sep. 13, 2011
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`Sheet 31 of 34
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`TEVA EXHIBIT 1001
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`U.S. Patent
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`Sep. 13, 2011
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`Sheet 32 of 34
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`U.S. Patent
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`Sep. 13, 2011
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`Sheet 33 of 34
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`U.S. Patent
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`Sep. 13, 2011
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`Sheet 34 of 34
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`US 8,017,150 B2
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`US 8,017,150 B2
`
`1
`POLYETHYLENE OXIDE-BASED FILMS AND
`DRUG DELIVERY SYSTEMS MADE
`THEREFROM
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional ofU.S. application Ser. No.
`10/856,176, filed May 28, 2004, which claims the benefit of
`U.S. Provisional Application No. 60/473,902, filed May 28,
`2003 and which is a continuation-in-part of PCT/US02/
`32575 filed Oct. 11, 2002, which 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. ProvisionalApplicationNo.
`60/386,937, filed Jun. 7, 2002; PCT/US02/32594, filed Oct.
`11, 2002, which claims priority to U.S. Provisional Applica-
`tionNo. 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
`
`The invention relates to rapidly dissolving films and meth-
`ods of their preparation. The films contain a polymer compo-
`nent, 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 control-
`ling one or more parameters, and particularly the elimination
`of air pockets prior to and during film formation and the use
`of a drying process that reduces aggregation or conglomera-
`tion of the components in the film as it forms into a solid
`structure.
`
`BACKGROUND OF THE RELATED
`TECHNOLOGY
`
`Active ingredients, such as drugs or pharmaceuticals, may
`be prepared in a tablet form to allow for accurate and consis-
`tent 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 count-
`ing the tablets which has a tendency for inaccuracy. In addi-
`tion, 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 difiiculties, 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 con-
`trolled release properties.
`As an alternative to tablets and pills, films may be used to
`carry active ingredients such as drugs, pharmaceuticals, and
`the like. However, historically films and the process of mak-
`
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`ing drug delivery systems therefrom have suffered from a
`number of unfavorable characteristics that have not allowed
`
`them to be used in practice.
`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, surfactants, 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.
`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 non-uniform. This
`result can be attributed to Fuchs’ process parameters, which
`although not disclosed likely include the use ofrelatively long
`drying times, thereby facilitating intermolecular attractive
`forces, convection forces, air flow and the like to form such
`agglomeration.
`The formation of agglomerates randomly distributes the
`film components and any active present as well. When large
`dosages are involved, a small change in the dimensions ofthe
`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 con-
`tain an insufiicient 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 Administration (“FDA”), relat-
`ing 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.
`The problems of self-aggregation leading to non-unifor-
`mity ofa 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 pro-
`cess that adds expense and complexity and is not practical for
`commercial use.
`
`Other U.S. patents directly addressed the problems of par-
`ticle self-aggregation and non-uniformity inherent in conven-
`tional film forming techniques. In one attempt to overcome
`non-uniformity, U.S. Pat. No. 5,629,003 to Horstmarm et al.
`and U.S. Pat. No. 5,948,430 to Zerbe et al. incorporated
`additional ingredients, i.e. gel formers and polyhydric alco-
`hols respectively, to increase the viscosity of the film prior to
`driving in an effort to reduce aggregation of the components
`in the film. These methods have the disadvantage ofrequiring
`additional components, which translates to additional cost
`and manufacturing steps. Furthermore, both methods employ
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`US 8,017,150 B2
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`3
`the use the conventional time-consuming drying methods
`such as a high-temperature air-bath using a drying oven,
`drying turmel, vacuum drier, or other such drying equipment.
`The long length of drying time aids in promoting the aggre-
`gation 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 com-
`ponents to prolonged exposure to moisture and elevated tem-
`peratures, which may render it ineffective or even harmful.
`In addition to the concerns associated with degradation of
`an active during extended exposure to moisture, the conven-
`tional drying methods themselves are unable to provide uni-
`form 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 conven-
`tional drying methods where a relatively thicker film, which is
`well-suited for the incorporation of a drug active, is desired.
`Thicker uniform films are more difficult to achieve because
`
`the surfaces of the film and the inner portions of the film do
`not experience the same external conditions simultaneously
`during drying. Thus, observation of relatively thick films
`made from such conventional processing shows a non-uni-
`form structure caused by convection and intermolecular
`forces and requires greater than 10% moisture to remain
`flexible. The amount of free moisture can often interfere over
`
`time with the drug leading to potency issues and therefore
`inconsistency in the final product.
`Conventional drying methods generally include the use of
`forced hot air using a drying oven, drying tunnel, and the like.
`The difficulty in achieving a uniform film is directly related to
`the rheological properties and the process of water evapora-
`tion in the film-forming composition. When the surface of an
`aqueous polymer solution is contacted with a high tempera-
`ture air current, such as a film-forming composition passing
`through a hot air oven, the surface water is immediately
`evaporated forming a polymer film or skin on the surface.
`This seals the remainder of the aqueous film-forming com-
`position beneath the surface, forming a barrier through which
`the remaining water must force itself as it is evaporated in
`order to achieve a dried film. As the temperature outside the
`film continues to increase, water vapor pressure builds up
`under the surface ofthe film, stretching the surface ofthe film,
`and ultimately ripping the film surface open allowing the
`water vapor to escape. As soon as the 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 effect” which produces an uneven, and
`therefore non-uniform 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 temperatures, and higher energy costs.
`Other factors, such as mixing techniques, also play a role in
`the manufacture of a pharmaceutical film suitable for com-
`mercialization 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 prod-
`uct 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 ofthe 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 oth-
`erwise be occupied by the film composition. None of the
`
`4
`
`above-mentioned patents either addresses or proposes a solu-
`tion to the problems caused by air that has been introduced to
`the film.
`Therefore, there is a need for methods and compositions
`for film products, which use a minimal number ofmaterials or
`components, and which provide a substantially non-self-ag-
`gregating 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 distribution ofnon-self-
`aggregated components without the necessary 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 Horstmarm and Zerbe
`patents. Desirably, the films will also incorporate composi-
`tions and methods ofmanufacture that substantially reduce or
`eliminate air in the film, thereby promoting uniformity in the
`final film product.
`
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`
`SUMMARY OF THE INVENTION
`
`Some embodiments of the present invention provide a
`mucosally-adhesive water-soluble film product, which
`includes:
`
`25
`
`an analgesic opiate pharmaceutical active; and
`at least one water-soluble polymer component including
`polyethylene oxide in combination with a hydrophilic cellu-
`losic polymer;
`wherein:
`
`the water-soluble polymer component includes greater
`than 75% polyethylene oxide and up to 25% hydrophilic
`cellulosic polymer;
`the polyethylene oxide includes one or more low molecular
`weight polyethylene oxides and one or more higher molecu-
`lar weight polyethylene oxides, the molecular weight of the
`low molecular weight polyethylene oxide being in the range
`100,000 to 300,000 and the molecular weight of the higher
`molecular weight polyethylene oxide being in the range 600,
`000 to 900,000; and
`the polyethylene oxide of low molecular weight is about
`60% or more in the polymer component.
`Another embodiment of the present invention provides a
`mucosally-adhesive water-soluble film product, which
`includes:
`
`an analgesic opiate pharmaceutical active; and
`at least one water-soluble polymer component including
`polyethylene oxide in combination with a hydrophilic cellu-
`losic polymer;
`wherein:
`
`the water-soluble polymer component includes the hydro-
`philic cellulosic polymer in a ratio of up to about 4:1 with the
`polyethylene oxide;
`the polyethylene oxide includes one or more low molecular
`weight polyethylene oxides and one or more higher molecu-
`lar weight polyethylene oxides, the molecular weight of the
`low molecular weight polyethylene oxide being in the range
`100,000 to 300,000 and the molecular weight of the higher
`molecular weight polyethylene oxide being in the range 600,
`000 to 900,000; and
`the polyethylene oxide of low molecular weight is about
`60% or more in the polymer component.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
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`FIG. 1 shows a side view of a package containing a unit
`dosage film of the present invention.
`
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`US 8,017,150 B2
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`5
`FIG. 2 shows a top View of two adjacently coupled pack-
`ages containing individual unit dosage forms of the present
`invention, separated by a tearable perforation.
`FIG. 3 shows a side View of the adjacently coupled pack-
`ages of FIG. 2 arranged in a stacked configuration.
`FIG. 4 shows a perspective view of a dispenser for dispens-
`ing the packaged unit dosage forms, dispenser containing the
`packaged unit dosage forms in a stacked configuration.
`FIG. 5 is a schematic view of a roll of coupled unit dose
`packages of the present invention.
`FIG. 6 is a schematic view of an apparatus suitable for
`preparation of a pre-mix, addition of an active, and subse-
`quent formation of the film.
`FIG. 7 is a schematic view of an apparatus suitable for
`drying the films of the present invention.
`FIG. 8 is a sequential representation of the drying process
`of the present invention.
`FIG. 9 is a photographic representation of a film dried by
`conventional drying processes.
`FIG. 10 is a photographic representation of a film dried by
`conventional drying processes.
`FIG. 11 is a photographic representation of a film dried by
`conventional drying processes.
`FIG. 12 is a photographic representation of a film dried by
`conventional drying processes.
`FIG. 13 is a photographic representation of a film dried by
`conventional drying processes.
`FIG. 14 is a photographic representation of a film dried by
`conventional drying processes.
`FIG. 15 is a photographic representation of a film dried by
`conventional drying processes.
`FIG. 16 is a photographic representation of a film dried by
`conventional drying processes.
`FIG. 17 is a photographic representation of a film dried by
`the inventive drying process.
`FIG. 18 is a photomicrographic representation of a film
`containing fat coated particles dried by the inventive drying
`process.
`FIG. 19 is a photomicrographic representation of a film
`containing fat coated particles dried by the inventive drying
`process.
`FIG. 20 is a photomicrographic representation of a film
`containing fat coated particles dried by the inventive drying
`process.
`FIG. 21 is a photomic