`(12) Patent Application Publication (10) Pub. No.: US 2005/0037055 A1
`(43) Pub. Date:
`Feb. 17, 2005
`Yang et al.
`
`US 20050037055A1
`
`(54) POLYETI-IYLENE 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:
`I-IOFFMANN & BARON, LLP
`6900 JERICHO TURNPIKE
`SYOSSET, NY 11791 (US)
`
`(73) Assignee: M0n0SolRx LLC.
`
`(21) Appl.No.:
`
`10/856,176
`
`(22) Filed:
`
`May 28, 2004
`
`Related U.S. Application Data
`
`(63) Continuation-in-pan of application No. 10/768,809,
`filed on Jan. 30, 2004, and which is a continuation-
`in-part of application No. PCT/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
`
`EU552991707
`
`Publication Classification
`
`Int. Cl.’ ............................. 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 cellulosic polymers. 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.
`
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`Patent Application Publication Feb. 17, 2005 Sheet 1 of 34
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`10
`/ 74
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`72
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`Patent Application Publication Feb. 17, 2005 Sheet 3 of 34
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`US 2005/0037055 A1
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`Patent Application Publication Feb. 17, 2005 Sheet 32 of 34
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`DRL - EXHIBIT 1010
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`DRL035
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`DRL - EXHIBIT 1010
`DRL035
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`US 2005/0037055 A1
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`Feb. 17, 2005
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`POLYETHYLENE OXIDE-BASED FILMS AND
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`DRUG DELIVERY SYSTEMS MADE THEREFROM
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`CROSS-REFERENCE TO RELATED
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`APPLICATIONS
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`[0001] This application claims the benefit of U.S. Provi-
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`sional Application No. 60/473,902, filed May 28, 2003 and
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`is a continuation-in-part of PCT/US02/32575 filed Oct. 11,
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`2002, which claims priority to U.S. application Ser. No.
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`10/074,272, filed Feb. 14, 2002 which claims priority to U.S.
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`Provisional Application No. 60/328,868, filed Oct. 12, 2001
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`and U.S. Provisional Application No. 60/386,937, filed Jun.
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`7, 2002; PCT/US02/32594,
`filed Oct. 11, 2002, which
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`claims priority to U.S. Provisional Application No. 60/414,
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`276, filed Sep. 27, 2002, U.S. application Ser. No. 10/074,
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`272, filed Feb. 14, 2002, which claims priority to U.S.
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`Provisional Application No. 60/328,868, filed Oct. 12, 2001
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`and U.S. Provisional Application No. 60/386,937, filed Jun.
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`7, 2002; and PCT/US02/32542, filed Oct. 11, 2002, which
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`claims priority to U.S. Provisional Application No. 60/371,
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`940, filed Apr. 11, 2002, U.S. application Ser. No. 10/074,
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`272, filed Feb. 14, 2002, which claims priority to U.S.
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`Provisional Application No. 60/328,868, filed Oct. 12, 2001
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`and U.S. Provisional Application No. 60/386,937, filed Jun.
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`7, 2002.
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`FIELD OF THE INVENTION
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`[0002] The invention relates to rapidly dissolving films
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`and methods of their preparation. The films contain a
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`polymer component, which includes polyethylene oxide
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`optionally blended with cellulosic polymers. The films may
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`also contain an active ingredient that is evenly distributed
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`throughout the film. The even or uniform distribution is
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`achieved by controlling one or more parameters, and par-
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`ticularly the elimination of air pockets prior to and during
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`film formation and the use of a drying process that reduces
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`aggregation or conglomeration of the components in the film
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`as it forms into a solid structure.
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`BACKGROUND OF THE RELATED
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`TECHNOLOGY
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`[0003] Active ingredients, such as drugs or pharmaceuti-
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`cals, may be prepared in a tablet form to allow for accurate
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`and consistent dosing. However, this form of preparing and
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`dispensing medications has many disadvantages including
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`that a large proportion of adjuvants that must be added to
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`obtain a size able to be handled, that a larger medication
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`form requires additional storage space, and that dispensing
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`includes counting the tablets which has a tendency for
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`inaccuracy. In addition, many persons, estimated to be as
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`much as 28% of the population, have difficulty swallowing
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`tablets. While tablets may be broken into smaller pieces or
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`even crushed as a means of overcoming swallowing diffi-
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`culties, this is not a suitable solution for many tablet or pill
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`forms. For example, crushing or destroying the tablet or pill
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`form to facilitate ingestion, alone or in admixture with food,
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`may also destroy the controlled release properties.
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`[0004] As an alternative to tablets and pills, films may be
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`used to carry active ingredients such as drugs, pharmaceu-
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`ticals, and the like. However, historically films and the
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`process of making drug delivery systems therefrom have
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`suffered from a number of unfavorable characteristics that
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`have not allowed them to be used in practice.
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`[0005] Films that incorporate a pharmaceutically active
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`ingredient are disclosed in expired U.S. Pat. No. 4,136,145
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`to Fuchs, et al. (“Fuchs”). These films may be formed into
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`a sheet, dried and then cut into individual doses. The Fuchs
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`disclosure alleges the fabrication of a uniform film, which
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`includes the combination of water-soluble polymers, surfac-
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`flavors, sweeteners, plasticizers and drugs. These
`tants,
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`allegedly flexible films are disclosed as being useful for oral,
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`topical or enteral use. Examples of specific uses disclosed by
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`Fuchs include application of the films to mucosal membrane
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`areas of the body, including the mouth, rectal, vaginal, nasal
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`and ear areas.
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`[0006] Examination of films made in accordance with the
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`process disclosed in Fuchs, however, reveals that such films
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`suffer from the aggregation or conglomeration of particles,
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`i.e., self-aggregation, making them inherently non-uniform.
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`This result can be attributed to Fuchs’ process parameters,
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`which although not disclosed likely include the use of
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`relatively long drying times, thereby facilitating intermo-
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`lecular attractive forces, convection forces, air flow and the
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`like to form such agglomeration.
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`[0007] The formation of agglomerates randomly distrib-
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`utes the film components and any active present as well.
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`When large dosages are involved, a small change in the
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`dimensions of the film would lead to a large difference in the
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`amount of active per film. If such films were to include low
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`dosages of active, it is possible that portions of the film may
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`be substantially devoid of any active. Since sheets of film are
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`usually cut into unit doses, certain doses may therefore be
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`devoid of or contain an insufficient amount of active for the
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`recommended treatment. Failure to achieve a high degree of
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`accuracy with respect to the amount of active ingredient in
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`the cut film can be harmful to the patient. For this reason,
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`dosage forms formed by processes such as Fuchs, would not
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`likely meet
`the stringent standards of governmental or
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`regulatory agencies, such as the U.S. Federal Drug Admin-
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`istration (“FDA”), relating to the variation of active in
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`dosage forms. Currently, as required by various world
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`regulatory authorities, dosage forms may not vary more than
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`10% in the amount of active present. When applied to
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`dosage units based on films, this virtually mandates that
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`uniformity in the film be present.
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`[0008] The problems of self-aggregation leading to non-
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`uniformity of a film were addressed in U.S. Pat. No. 4,849,
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`246 to Schmidt (“Schmidt”). Schmidt specifically pointed
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`out that the methods disclosed by Fuchs did not provide a
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`uniform film and recognized that that the creation of a
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`non-uniform film necessarily prevents accurate dosing,
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`which as discussed above is especially important in the
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`pharmaceutical area. Schmidt abandoned the idea that a
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`mono-layer film, such as described by Fuchs, may provide
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`an accurate dosage form and instead attempted to solve this
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`problem by forming a multi-layered film. Moreover, his
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`process is a multi-step process that adds expense and com-
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`plexity and is not practical for commercial use.
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`[0009] Other U.S. patents directly addressed the problems
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`of particle self-aggregation and non-uniformity inherent in
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`conventional film forming techniques. In one attempt to
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`overcome non-uniformity, U.S. Pat. No. 5,629,003 to Horst-
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`mann et al. and U.S. Pat. No. 5,948,430 to Zerbe et al.
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`incorporated additional
`ingredients,
`i.e. gel formers and
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`polyhydric alcohols respectively, to increase the viscosity of
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`DRL - EXHIBIT 1010
`
`DRL036
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`DRL - EXHIBIT 1010
`DRL036
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`US 2005/0037055 A1
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`Feb. 17, 2005
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`the film prior to drying in an effort to reduce aggregation of
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`the components in the film. These methods have the disad-
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`vantage of requiring additional components, which trans-
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`lates to additional cost and manufacturing steps. Further-
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`more, both methods employ the use the conventional time-
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`consuming drying methods such as a high-temperature air-
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`bath using a drying oven, drying tunnel, vacuum drier, or
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`other such drying equipment. The long length of drying time
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`aids in promoting the aggregation of the active and other
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`adjuvant, notwithstanding the use of viscosity modifiers.
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`Such processes also run the risk of exposing the active, i.e.,
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`a drug, or vitamin C, or other components to prolonged
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`exposure to moisture and elevated temperatures, which may
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`render it ineffective or even harmful.
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`[0010]
`In addition to the concerns associated with degra-
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`dation of an active during extended exposure to moisture,
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`the conventional drying methods themselves are unable to
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`provide uniform films. The length of heat exposure during
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`conventional processing, often referred to as the “heat
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`history”, and the manner in which such heat is applied, have
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`a direct effect on the formation and morphology of the
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`resultant film product. Uniformity is particularly difficult to
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`achieve via conventional drying methods where a relatively
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`thicker film, which is well-suited for the incorporation of a
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`drug active,
`is desired. Thicker uniform films are more
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`difficult to achieve because the surfaces of the film and the
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`inner portions of the film do not experience the same
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`external conditions simultaneously during drying. Thus,
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`observation of relatively thick films made from such con-
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`ventional processing shows a non-uniform structure caused
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`by convection and intermolecular forces and requires greater
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`than 10% moisture to remain flexible. The amount of free
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`moisture can often interfere over time with the drug leading
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`to potency issues and therefore inconsistency in the final
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`product.
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`[0011] Conventional drying methods generally include the
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`use of forced hot air using a drying oven, drying tunnel, and
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`the like. The difficulty in achieving a uniform film is directly
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`related to the rheological properties and the process of water
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`evaporation in the film-forming composition. When the
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`surface of an aqueous polymer solution is contacted with a
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`high temperature air current, such as a film-forming com-
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`position passing through a hot air oven, the surface water is
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`immediately evaporated forming a polymer film or skin on
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`the surface. This seals the remainder of the aqueous film-
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`forming composition beneath the surface, forming a barrier
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`through which the remaining water must force itself as it is
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`evaporated in order to achieve a dried film. As the tempera-
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`ture outside the film continues to increase, water vapor
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`pressure builds up under the surface of the film, stretching
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`the surface of the film, and ultimately ripping the film
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`surface open allowing the water vapor to escape. As soon as
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`the water vapor has escaped,
`the polymer film surface
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`reforms, and this process is repeated, until
`the film is
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`completely dried. The result of the repeated destruction and
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`reformation of the film surface is observed as a “ripple
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`effect” which produces an uneven, and therefore non-uni-
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`form film. Frequently, depending on the polymer, a surface
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`will seal so tightly that the remaining water is difficult to
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`remove, leading to very long drying times, higher tempera-
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`tures, and higher energy costs.
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`[0012] Other factors, such as mixing techniques, also play
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`a role in the manufacture of a pharmaceutical film suitable
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`for commercialization and regulatory approval. Air can be
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`trapped in the composition during the mixing process or
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`later during the film making process, which can leave voids
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`in the film product as the moisture evaporates during the
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`drying stage. The film frequently collapse around the voids
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`resulting in an uneven film surface and therefore, non-
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`uniformity of the final film product. Uniformity is still
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`affected even if the voids in the film caused by air bubbles
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`do not collapse. This situation also provides a non-uniform
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`film in that the spaces, which are not uniformly distributed,
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`are occupying area that would otherwise be occupied by the
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`film composition. None of the above-mentioned patents
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`either addresses or proposes a solution to the problems
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`caused by air that has been introduced to the film.
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`[0013] Therefore, there is a need for methods and com-
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`positions for film products, which use a minimal number of
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`materials or components, and which provide a substantially
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`non-self-aggregating uniform heterogeneity throughout the
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`area of the films. Desirably, such films are produced through
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`a selection of a polymer or combination of polymers that
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`will provide a desired viscosity, a film-forming process such
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`as reverse roll coating, and a controlled, and desirably rapid,
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`drying process which serves to maintain the uniform distri-
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`bution of non-self-aggregated components without the nec-
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`essary addition of gel formers or polyhydric alcohols and the
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`like which appear to be required in the products and for the
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`processes of prior patents, such as the aforementioned
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`Horstmann and Zerbe patents. Desirably, the films will also
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`incorporate compositions and methods of manufacture that
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`substantially reduce or eliminate air in the film, thereby
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`promoting uniformity in the final film product.
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`SUMMARY OF THE INVENTION
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`[0014] The present invention is directed to rapid-dissolve
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`film products containing at least one water-soluble polymer
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`including polyethylene oxide alone or in combination with
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`a hydrophilic cellulosic polymer, wherein the film product is
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`free of added plasticizers.
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`[0015] Another embodiment of the rapid-dissolve film
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`product includes at least one water-soluble polymer con-
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`taining about 20% to 100% by weight polyethylene oxide,
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`about 0% to 80% by weight hydroxypropylmethyl cellulose,
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`and about 0% to 80% by weight hydroxypropyl cellulose; an
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`active component; sucralose; precipitated calcium carbon-
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`ate;
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`[0016]
`at least one flavoring; simethicone; water; and
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`at least one colorant, wherein the film product is free
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`of added plasticizers, surfactants, and polyalcohols.
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`[0017] Yet another embodiment of the present invention is
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`directed to an edible water-soluble delivery system in the
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`form of a film composition, which contains at least one
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`water-soluble polymer comprising polyethylene oxide alone
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`or in combination with a polymer selected from the group
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`consisting of hydroxypropylmethyl cellulose and hydrox-
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`ypropyl cellulose, wherein the edible water-soluble delivery
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`system is essentially free of organic solvents, plasticizers,
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`surfactants, and polyalcohols.
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`[0018] The present invention is also directed to processes
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`for making a film having a substantially uniform distribution
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`of components, including the steps of: (a) combining at least
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`one water-soluble polymer comprising polyethylene oxide
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`DRL - EXHIBIT 1010
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`DRL037
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`DRL - EXHIBIT 1010
`DRL037
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`US 2005/0037055 A1
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`Feb. 17, 2005
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`alone or in combination with a hydrophilic cellulosic poly-
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`mer, a solvent, and an active component to form a matrix
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`with a uniform distribution of the components; (b) forming
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`a film from the matrix; and (c) drying the film, wherein the
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`film is free of added plasticizers.
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`BRIEF DESCRIPTION OF THE DRAWINGS
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`[0039] FIG. 21 is a photomicrographic representation of a
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`film containing fat coated particles dried by the inventive
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`drying process.
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`[0040] FIG. 22 is a photomicrographic representation of a
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`film containing fat coated particles dried by the inventive
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`drying process.
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`[0041] FIG. 23 is a photomicrographic representation of a
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`film containing fat coated particles dried by the inventive
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`drying process.
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`[0042] FIG. 24 is a photomicrographic representation of a
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`film containing fat coated particles dried by the inventive
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`drying process.
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`[0043] FIG. 25 is a photomicrographic representation of a
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`film containing fat coated particles dried by the inventive
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`drying process.
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`[0044] FIG. 26 is a photomicrographic representation of
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`fat coated particles not in film, heated for 9 minutes at 80°
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`C.
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`[0045] FIG. 27 is a photomicrographic representation of
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`fat coated particles not in film, heated for 9 minutes at 80°
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`C.
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`[0046] FIG. 28 is a photomicrographic representation of
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`fat coated particles at room temperature prior to processing.
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`[0047] FIG. 29 is a photomicrographic representation of
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`fat coated particles at room temperature prior to processing.
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`[0048] FIG. 30 is a photomicrographic representation of
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`fat coated particles at room temperature prior to processing.
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`[0049] FIG. 31 is a photomicrographic representation of
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`fat coated particles at room temperature prior to processing.
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`[0050] FIG. 32 is a graphical representation of a microar-
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`ray on the blood of a human after ingestion by the human of
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`a film of the present invention containing a bovine derived
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`protein.
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`[0051] FIG. 33 is a graphical representation of the tem-
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`perature differential between the inside and outside of a film
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`of the present invention during drying.
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`[0052] FIG. 34 is a graphical representation of the tem-
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`perature differential between the inside and outside of a film
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`of the present invention during drying.
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`[0053] FIG. 35 is a schematic representation of a continu-
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`ously-linked zone drying apparatus in accordance with the
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`present invention.
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`[0054] FIG. 36 is a schematic representation of a separate
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`zone drying apparatus in accordance with the present inven-
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`tion.
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`[0055] FIG. 37 is a schematic representation of a extru-
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`sion device for use in producing films of the present inven-
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`tion.
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`DETAILED DESCRIPTION OF THE
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`INVENTION
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`[0056] For the purposes of the present invention the term
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`non-self-aggregating uniform heterogeneity refers to the
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`ability of the films of the present
`invention, which are
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`formed from one or more components in addition to a polar
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`solvent, to provide a substantially reduced occurrence of, i.e.
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`DRL - EXHIBIT 1010
`
`DRL038
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`[0019] FIG. 1 shows a side view of a package containing
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`a unit dosage film of the present invention.
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`[0020] FIG. 2 shows a top view of two adj acently coupled
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`packages containing individual unit dosage forms of the
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`present invention, separated by a tearable perforation.
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`[0021] FIG. 3 shows a side view of the adj acently coupled
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`packages of FIG. 2 arranged in a stacked configuration.
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`[0022] FIG. 4 shows a perspective view of a dispenser for
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`dispensing the packaged unit dosage forms, dispenser con-
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`taining the packaged unit dosage forms in a stacked con-
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`figuration.
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`[0023] FIG. 5 is a schematic view of a roll of coupled unit
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`dose packages of the present invention.
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`[0024] FIG. 6 is a schematic view of an apparat