(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`
`International Bureau
`
`(43) International Publication Date
`17 April 2003 (17.04.2003)
`
`PCT
`
`(10) International Publication Number
`W 0 03/030883 A1
`
`(51) International Patent Classificationlz
`9/00, 9/16
`
`A61K 9/70,
`
`(21) International Application Number:
`
`PCT/USO2/32594
`
`(22) International Filing Date: 11 October 2002 (11.10.2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/328,868
`10/074,272
`60/386,937
`60/414,276
`
`12 October 2001 (12.10.2001)
`14 February 2002 (14.02.2002)
`7 June 2002 (07.06.2002)
`27 September 2002 (27.09.2002)
`
`US
`US
`US
`US
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`
`GM: HR: HU: ID: IL: IN: IS: JP: KE: KG: KR KR: KZ: LC:
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK,
`SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA,
`ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES: FT: FR: GB: GR: IE: IT: LU: MC: NL: PT: SE: SK:
`TR): OAPI Pate“t (BF: 131 CE CG: CL CM: GA: GN: GQ:
`GW: ML: MR: NE: SN: TD: TG)«
`
`Declaration under Rule 4.17:
`
`(71) Applicant (for all designated States except US): KOS- i ofinventorship (Rule 4:] 70")» for US only
`MOS PHARMA [US/US] ; 1142 Walker Road, Great Falls,
`VA 22066 (US).
`
`Published:
`7 with international search report
`
`(72) Inventors; and
`(75) Inventors/Applicants(for US only): FUISZ, Richard, C.
`[US/US]; 1287 Ballentrae Farm Road, McLean, VA 22101
`(US). YANG, Robert, K. [US/US]; 138—10 Franklin Av—
`enue, Apt. 2C, Flushing, NY 11355 (US). MYERS, Gary,
`L. [US/US]; 908 C01faX Avenue, Kingsport, TN 37660
`(US).
`
`7 before the expiration of the time limit for amending the
`claims and ’0 be republished in the event of receipt of
`amendments
`
`For two-letter codes and other abbreviations, refer to the ”Guid-
`ance Notes on Codes andAbbreviations ” appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`(74) Agents: SCOLA, Daniel, A., Jr.; Hoffmann & Baron,
`LLP, 6900 Jericho Turnpike, Syosset, NY 11791 et al.
`(US).
`
`3A1
`
`00 (54) Title: UNIFORM FILMS FOR RAPID DISSOLVE DOSAGE FORM INCORPORATING TASTE—MASKING COMPOSI—
`go TIONS
`
`030 (57) Abstract: A thin film drug delivery composition includes (1) a flowable water—soluble film forming matrix; (11) a particulate
`
`\ bioeffecting agent uniformly stationed therein; and (iii) a taste—masking agent coated or intimately associated with the particulate to
`provide taste—masking of the bioeffecting agent. The combined particulate and taste—masking agent have a particle size of 200 mi—
`crons or less and the flowable water—soluble film forming matrix is capable of being dried without loss of uniformity in the stationing
`O of the particulate bioeffecting agent therein. The combined particulate and taste—masking agent have a particle size of 150 microns
`or less, for example 100 microns or less. Moreover, the flowable water—soluble film forming matrix is formable into a dry film of
`less than about 380 microns in thickness, for example less than about 250 microns in thickness.
`
`Page 1
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`BDSI EXHIBIT 1031
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`Page 1
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`

`

`W0 03/030883
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`PCT/US02/32594
`
`UNIFORM FILMS FOR RAPID DISSOLVE DOSAGE FORM INCORPORATING TASTE—MASKING
`COMPOSITIONS
`
`FIELD OF THE INVENTION
`
`The present invention relates to compositions and methods for the preparation and use
`
`of a uniform rapid dissolve dosage form in the form of a film that includes a pharmaceutically
`
`‘ active or bioeffecting agent and a taste-masking agent for masking the taste of the
`
`pharmaceutically active agent.
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`10
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`15
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`20
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`25
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`BACKGROUND OF RELATED TECHNOLOGY
`
`While active ingredients such as pharmaceutical preparations may be included in a
`
`tablet or similar form to provide an accurate and consistent dose, including medicaments in
`
`such a form has several disadvantages in both the administration and preparation of the drug.
`
`Moreover, in such oral dosage forms, such as tablets or emulsions, pharmaceuticals have
`
`been coated to provide control release or taste—masking. Particle sizes of particulate
`
`pharmaceuticals are not critical in such dosage forms and generally large particle sizes, i.e.,
`
`greater than 200 microns have been used.
`
`There have been several attempts to provide an alternate dosage form, such as a film
`
`that would include a pharmaceutical active. However, such attempts have not been
`
`successful in providing a film that incorporates a drug with sufficient uniformity to provide
`
`accurate dosing.
`
`Films that incorporate a pharmaceutically active ingredient are disclosed in expired
`
`US. Patent No. 4,136,145 to Fuchs, et a1. ("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,
`
`30
`
`vaginal, nasal and ear areas.
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`Examination of films made in accordance with the process disclosed in Fuchs,
`
`however, reveals that such fihns 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 specifically disclosed likely include the use of
`
`relatively 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 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 governmental or agency
`
`standards relating to the variation of active in dosage forms. Currently, by law, 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.
`
`Moreover, the problems of self-aggregation leading to non-uniformity of a film can
`
`result in an unpleasant tasting fihn when the film contains an unpleasant tasting
`
`pharmaceutical agent. Agglomerates of unpleasant tasting pharmaceutical agents may not be
`
`adequately masked by flavoring agents and sweeteners that are simply mixed into a film
`
`because the non—uniformity of the agglomerates may result in segregation of the unpleasant
`
`tasting agents from the flavoring agents and sweeteners. Fuchs merely mixes flavors and
`
`sweeteners into a film forming mix and fails to address the problem of aggregation or
`
`segregation of these materials.
`
`Similarly, W0 00/42,992 also discloses the use of taste-modifying agents in a film
`
`dosage form. This international application also merely mixes taste-modifying agents into
`
`the film-forming mix without recognizing the problem of separation or aggregation of the
`
`taste-modifying agents from the unpleasant tasting pharmaceutical agents.
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`Furthermore, WO 01/70,194 discloses the use of ion exchange resins to for covalently
`
`binding pharmaceutical agents thereto. The resins have particle sizes from 20 microns to 200
`
`microns and are described as being taste masking agents. The ion exchange resins are
`
`described as being bound with pharmaceutical agents and being mixed into consumerable
`
`films having thicknesses from 7 to 11 mils, or 180 microns to 280 microns. Such ion
`
`exchange resins, however, have limitations in the binding of pharmaceutical agents to the ion
`
`exchange resins, making the process for producing taste-masked comsumerable films
`
`complicated and expensive. Moreover, the use of ion exchange resins, which are water
`
`10
`
`insoluble, limits the selection of useful pharmaceutical agents in water soluble films to only
`
`certain water soluble pharmaceutical agents that can covalently bond to the ionic resin.
`
`Therefore, there is a need for a rapid dissolve dosage form, presented as a uniform
`
`film that addresses and corrects the problems associated with non-uniformity of a drug in film
`
`15
`
`such as agglomeration or separation of particles within the film and the unpleasant tasting
`
`effects of the same. Moreover, there is a need for taste-masked, pharmaceutically active
`
`agents suitably contained within such a uniform film.
`I
`
`SUMMARY OF THE INVENTION
`
`20
`
`The present invention seeks to attain low adjuvant content, high taste—masked
`
`pharmaceutical active content films which have enhanced flexibility, structural integrity and
`
`uniformity. The present invention also provides for a unique method of producing the
`
`inventive compositions such that the compositional components are evenly distributed
`
`throughout the film. This process is described in detail in co-pending US. Patent Application
`
`25
`
`No. 10/074,272, entitled “Thin Film with Non-Self—Aggregating Uniform Heterogeneity and
`
`Drug Delivery Systems Made Therefiom”, the subject matter of which is herein incorporated
`
`by its entirety.
`
`In one aspect of the present invention, a drug delivery composition includes (i) a
`
`30
`
`flowable water—soluble fihn forming matrix; (ii) a particulate bioeffecting agent uniformly
`
`stationed therein; and (iii) a taste-masking agent coated or intimately associated with the
`
`particulate to provide taste-masking of the bioeffecting agent. The combined particulate and
`
`taste-masking agent have a particle size of 200 microns or less, and the flowable water-
`
`soluble film forming matrix is capable of being dried without loss of uniformity in the
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`PCT/US02/32594
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`stationing of the particulate bioeffecting agent therein. The importance of such particle sizes
`has not been recognized in the prior art, especially in prior art dosage forms, such as tablets
`and emulsions. Moreover, the importance ofparticle size is heightened in orally ingestible
`thin films, where uniformity is also ofparticular importance, and the prior art has failed to
`recognize such critically important features.
`
`Desirably, the size of the combined particulate and taste-masking agent have a
`particle size of 150 microns or less, for example 100 microns or less. Moreover, the flowable
`water-soluble film forming matrix is forrnable into a dry film of less than about 380 microns
`in thickness, for example less than about 250 microns in thickness. Desirably, such particle
`sizes are contained within these dry films. In other words the dry films of the present
`invention desirably have smooth surfaces free of exposed agents that could impart grittiness
`or maldistribution ofthe active. Thus, in one aspect ofthe invention there is provided a film
`vehicle which contains a uniform distribution of actives, as defined herein, being suitably free
`of particles which accumulate on the film surface when dried.
`
`Desirably, taste-masking agent is a thin film coating over portions ofthe bioeffecting
`agent. Useful taste-masking agents include polymeric materials. Water-soluble polymers are
`also useful. Desirably, the water—soluble polymer has an average molecular weight of equal
`to or greater than about 40,000. Furthermore, water—soluble polymers may be acrylic
`polymers, cellulosic polymers, and combinations thereof. Additionally, vinyl polymers,
`crown ethers, hydrogenated oils and waxes, and combinations thereofmay also be used as
`taste-masking agents.
`
`5
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`10
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`15
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`20
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`25
`
`The matrix may be a cellulosic material; a gum; a protein; a starch; a glucan; and
`combinations thereof; such as but not limited to carboxymethyl cellulose; methyl cellulose;
`hydroxyl methyl cellulose; hydroxyethyl cellulose; hydroxypropyl cellulose;
`hydroxypropylmethyl cellulose; hydroxymethylpropyl cellulose; gum arabic; xanthan gum;
`tragacanth; acacia; carageenan; guar gum; locust bean gum; pectin; alginates; gelatinized,
`30 modified or unmodified starch, including tapioca starch, rice starch, corn starch, potato
`starch, and wheat starch; polyvinyl alcohol; polyacrylic acid; polyvinyl pyrrolidone;
`poly(meth)acrylate; poly(meth)copolymers; dextrin; dextran; proteins, such as, gelatin, zein,
`gluten, soy protein, soy protein isolate, and whey protein; whey protein isolate; casein; levin;
`collagen; chitin; chitosin; polydextrose and combinations thereof.
`
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`PCT/US02/32594
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`The bioeffecting agent may be present in amounts of up to about 0.1% to about 60%
`
`by weight of the total composition. Useful bioeffecting agents include, but are not limited to,
`antimicrobial agents, non—steroidal anti-inflammatory drugs, anti-tussives, decongestants,
`
`antihistamines, expectorants, anti-diarrheals, H2 antagonists, proton pump inhibitors, general
`
`non—selective CNS depressants, general non-selective CNS stimulants, selective CNS
`
`functional modifiers, anti-parkinsonism drugs, narcotics, analgesics, anti-pyretics,
`
`psychopharrnacological drugs and combinations thereof. The delivery vehicle composition
`
`may further include an organoleptic agent.
`
`In another aspect of the present invention, a drug delivery vehicle includes (i) a water-
`
`soluble fihn matrix; and (ii) a particulate bioeffecting agent unifome suspended within the
`
`matrix and having associated with it a taste-masking agent. The uniformity is determined by
`the presence ofno more than a 10% by weight of drug variance throughout the matrix.
`
`Desirably, the drug variance is less than 5% by weight, less than 2% by weight, less than 1%
`
`by weight, or less than 0.5% by weight. Moreover, the particulates have a particle size of 200
`
`microns or less. Furthermore, the film matrix desirably has a thickness of less than about 380
`
`microns. Useful taste-masking agents include water-soluble polymers. Desirably, the water-
`
`soluble polymer has an average molecular weight of equal to or greater than about 40,000.
`
`Non-limiting water-soluble polymers include acrylic polymers, cellulosic polymers, and
`
`combinations thereof. The taste-masking agents may also include vinyl polymers, crown
`
`ethers, hydrogenated oils and waxes, and combinations thereof. The drug delivery vehicle of
`
`claim may further include an organoleptic agent with the bioeffecting agent.
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`10
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`15
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`20
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`25
`
`In another aspect of the present invention, a drug delivery vehicle includes a dry
`
`mucoadhering film having a thickness defined by opposed surfaces. The film includes (i) a
`
`water-soluble polymer; and (ii) a pharmaceutically active particle comprising a
`
`pharmaceutically active agent coated or encapsulated with a water-soluble polymer having an
`
`average molecular weight of equal to or greater than about 25,000. Water-soluble polymers
`
`30
`
`having an average molecular weight of equal to or greater than about 40,000 are also useful.
`
`Useful water-soluble polymers include of acrylic polymers, cellulosic polymers, and
`
`combinations thereof. Desirably, the pharmaceutically active particles are embedded within
`
`the film. Additionally, the film includes sections of substantially equal size and the particles
`
`are distributed in an amount that varies less than about 10% among the sections. Desirably,
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`PCT/US02/32594
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`the size of the particles are about 200 microns or less. Desirably, the film has a thickness of
`
`less than about 380 microns. Moreover, the drug delivery vehicle may further include an
`
`organoleptic agent with the water—soluble polymer.
`
`In another aspect of the present invention, a drug delivery vehicle includes a dry
`
`mucoadhering film having a thickness defined by opposed surfaces. The film includes (i) a
`
`water-soluble polymer; and (ii) a phannaceutically active particle having a pharmaceutically 7
`
`active agent and a taste-masking agent present in the amount of about 15—80% by weight of
`
`the particle. Desirably, the taste-masking agent is present in the amount of about 20-60% by
`
`weight of the particle. More desirably, the taste-masking agent is present in the amount of
`
`about 25—35% by weight of the particle. The pharmaceutically active particle is desirably
`
`embedded within the film, and the film includes sections of substantially equal size Where the
`
`particles are distributed in an amount that varies less than about 10% among the sections.
`
`Useful sizes of the pharmaceutically active particles include particle sizes of 200 microns or
`
`less. Desirably, the film has a thickness of less than about 380 microns. The drug delivery
`
`vehicle may further include an organoleptic agent with the taste-masking agent.
`
`In another aspect of the present invention, a drug delivery vehicle includes a dry
`
`mucoadhering film having a thickness defined by opposed surfaces. The film includes (i) a
`
`water—soluble polymer; and (ii) a pharmaceutically active particle comprising a
`
`pharmaceutically active agent and a taste-masking agent. The active particle has a particle
`
`size of less than about 200 microns. Desirably, the thickness of the film is less than about
`
`380 microns.
`
`In another aspect of the present invention, a drug delivery vehicle includes a dry
`
`mucoadhering film having a thickness defined by opposed surfaces. The film includes (i) a
`
`water-soluble polymer; and (ii) a pharmaceutically active particle comprising a
`
`pharmaceutically active agent and a taste-masking agent. The particle desirably has a particle
`
`size of less than about 200 microns and the taste-masking agent is present in amounts of
`
`about 15-80% by weight of the particle. A particle size of about 150 microns or less is also
`
`useful. Desirably, the particle size of the particle is about 100 microns or less. Desirably, the
`
`thickness of the film is less than about 380 microns, for example, less than about 250
`
`microns. Furthermore, the taste-masking agent may be present in the amount of about 20-
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`60% by weight ofthe particle. Desirably, the taste-masking agent is present in the amount of
`about 25-35% by weight of the particle.
`
`In another aspect of the present invention, a drug delivery vehicle includes a dry
`mucoadhering film having a thickness defined by opposed surfaces. The film includes (i) a
`water-soluble polymer; and (ii) a pharmaceutically active particle comprising a
`pharmaceutically active agent and an organoleptic agent. The active particleis taste-masked ,
`i with a taste-masking agent. Useful organoleptic agents include flavors, sweeteners and
`
`combinations thereof.
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`10
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`15
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`20
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`25
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`30
`
`In another aspect of the present invention, a drug delivery vehicle includes a dry
`mucoadhering film having a thickness defined by opposed surfaces. The film includes (i) a
`water-soluble polymer; and (ii) a pharmaceutically active particle comprising a
`pharmaceutically active agent being taste-masked with a taste-masking composition
`comprising a water-soluble polymer and at least one of a flavor or a sweetener.
`
`In another aspect of the present invention, a method ofpreparing a thin film drug
`delivery vehicle is provided. The method includes the steps of (a) providing a
`pharmaceutically active agent / taste-masking agent complex; (b) combining the complex
`with a water-soluble polymer and a solvent to form a mixture with uniform distribution of the
`complex therein; (c) casting the mixture onto a planar carrier surface to form a thin film on
`the carrier surface; and (d) controllably drying the thin film to form a distribution variance of
`the complex having less than about 10% variance throughout any given area of the thin film.
`The step ofproviding the pharmaceutically active agent with the taste-masking agent includes
`a treatment for coating the taste masking agent onto portions of the pharmaceutically active
`agent. The drying includes applying heat the bottom of the carrier surface. Moreover, the
`drying may include applying microwave energy to the film. Useful methods for providing
`the pharmaceutically active agent with the taste-masking agent include fluidized bed coating,
`spray congealing coating, agglomeration or granulation coating, entrapment coating,
`coaccervation coating, infusion coating, spin coating,ion exchange coating the taste masking
`agent onto portions of the pharmaceutically active agent.
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`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 shows a side View of a package containing a unit dosage film of the present
`
`invention.
`
`Figure 2 shows a top View of two adj acently coupled packages containing individual
`
`unit dosage forms of the present invention, separated by a tearable perforation.
`
`Figure 3 shows a side view of the adj acently coupled packages of Figure 2 arranged in
`
`a stacked configuration.
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`20
`
`Figure 4 shows a perspective View of a dispenser for dispensing the packaged unit
`
`dosage forms, dispenser containing the packaged unit dosage forms in a stacked
`
`configuration.
`
`Figure 5 is a schematic View of a roll of coupled unit dose packages of the present
`
`invention.
`
`Figure 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.
`
`Figure 7 is a schematic view of an apparatus suitable for drying the films of the
`
`present invention.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`25
`
`The present invention provides a pharmaceutical composition in the form of a film for
`
`external or topical administration, including a composition having a uniformly distributed
`
`combination of a polymer, a polar solvent, and a taste-masked pharmaceutically active or
`
`bioeffecting agent. The composition in its dried film form maintains the uniform distribution
`
`of components through the application of controlled bottom drying of the film.
`
`30
`
`Water—soluble polymers useful in the present invention include cellulosic materials,
`
`gums, proteins, starches, and combinations thereof.
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`As used herein the phrase “water soluble polymer” and variants thereof refer to a
`
`polymer that is at least partially soluble in water, and desirably fully or predominantly soluble
`
`in water, or absorbs water. Polymers that absorb water are often referred to as being water
`
`swellable polymers. The materials useful with the present invention may be water soluble or
`
`water swellable at room temperature and other temperatures, such as temperatures exceeding
`
`room temperature. Moreover, the materials may be water soluble or water swellable at
`
`pressures less than atmospheric pressure, Desirably, the water soluble polymers are water
`
`soluble or water swellable having at least 20 percent by weight water uptake. Water
`
`swellable polymers having a 25 or greater percent by weight water uptake are also useful.
`
`Fihns or dosage forms of the present invention formed from such water soluble polymers are
`
`desirably sufficiently water soluble to be dissolvable upon contact with bodily fluids.
`
`Examples of cellulosic materials include, Without limitation, carboxymethyl cellulose,
`
`methyl cellulose, ethyl cellulose, hydroxylmethyl cellulose, hydroxyethyl cellulose,
`
`hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxymethylpropyl cellulose,
`
`and combinations thereof.
`
`Examples of water—soluble gums include gum arabic, xanthan gum, tragacanth,
`
`acacia, carageenan, guar gum, locust bean gum, pectin, alginates and combinations thereof.
`
`Examples of other polymeric materials which may be incorporated include polyvinyl
`
`alcohol, polyacrylic acid, polyvinyl pyrrolidone, poly(meth)acry1ate, poly(meth)copolymers
`
`and combinations thereof.
`
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`15
`
`20
`
`‘25
`
`Useful starches include gelatinized, modified or unmodified starches. The source of
`
`the starches may vary and include pullulan, tapioca, rice, corn, potato, wheat and
`
`combinations thereof.
`
`Usefiil water-soluble protein polymers include gelatin, zein, gluten, soy protein, soy
`
`30
`
`protein isolate, whey protein, whey protein isolate, casein, levin, collagen and combinations
`
`thereof. Additional water-soluble polymers include dextrin, dextran and combinations
`
`thereof, as well as chitin, chitosin and combinations thereof, polydextrose and fructose
`
`oligomers.
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`Although a variety of different polymers may be used, it is desired to select polymers
`
`to provide a desired viscosity of the mixture prior to drying. The polymer plays an important
`
`role in affecting the viscosity of the film. Viscosity is one property of a liquid that controls
`
`the stability of the active in an emulsion, a colloid or a suspension. Generally the viscosity of
`the matrix will vary from about 400 cps to about 100,000 cps, preferably from about 800 cps
`
`to about 60,000 cps, and most preferably from about 1,000 cps to about 40,000 cps.
`
`Desirably, the viscosity of the filrnfforrning matrix,will rapidly increase upon initiation of the,
`
`drying process.
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`10
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`15
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`The edible water—soluble delivery system of the present invention fiirther include
`
`glucans, such as pullulan and elsinan. The ratio of glucan to water soluble polymer is about
`
`40:1 to about 0.1 :5. Glucans are generally desirable materials for edible film because of their
`
`high water solubility, rapid dissolution and excellent mouth-feel.
`
`The edible water-soluble delivery system of the present invention further include an
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`anti-foaming or defoaming agent, such as Simethicone, which is a combination of a
`
`polymethylsiloxane and silicon dioxide. Simethicone acts as either an anti-foaming or
`
`defoaming agent which reduces or eliminates air from the film composition. An anti-foaming
`
`agent will aid in preventing the introduction of air into a composition, while a defoaming
`
`20
`
`agent will aid in removing air from the composition.
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`25
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`30
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`The edible water-soluble delivery system of the present invention further include an
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`active component selected from cosmetic agents, pharmaceutical agents, bioactive agents and
`
`combinations thereof. The active component may be present in any amount effective for the
`
`intended treatment. It is particularly desirable and an advantage of the present invention that
`
`the active component can be included in high loads. For example, the active component may
`
`be present in amounts up to about 60% by weight of the total composition and desirably in
`
`amounts of 0.01% to about 50% by weight of total composition.
`
`The pharrnaceutically or bioeffecting active components that may be incorporated into
`
`the films of the present invention include a wide variety of medicaments and pharmaceutical
`
`compositions. Examples of useful drugs include ace-inhibitors, antianginal drugs, anti—
`
`arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti—convulsants,
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`anti—depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti—histamines,
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`anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-
`
`nauseants, anti-stroke agents, anti-thyroid preparations, anti-turner drugs, anti-viral agents,
`
`acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral
`
`drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-
`
`neoplastics, anti-parkinsonian agents, anti—rheumatic agents, appetite stimulants, biological
`
`response modifiers, blood modifiers, bone metabolism regulators, cardiovascular agents,
`
`central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants,
`
`dietary supplements, dopamine receptor agonists, endometriosis management agents,
`
`enzymes, erectile dysfunction therapies, fertility agents, gastrointestinal agents, homeopathic
`
`remedies, hormones, hypercalcemia and hypocalcemia management agents,
`
`immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments,
`
`muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics,
`
`parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents,
`
`respiratory agents, sedatives, smoking cessation aids, sympatholytics, tremor preparations,
`
`urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics,
`
`appetite suppressants, expectorants, anti-anxiety agents, anti—ulcer agents, anti—inflammatory
`
`substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics,
`
`stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics,
`
`tranquilizers, anti—psychotics, anti—tumor drugs, anti-coagulants, anti—thrombotic drugs,
`
`hypnotics, anti—emetics, anti-nauseants, anti—convulsants, neuromuscular drugs, hyper- and
`
`hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics,
`
`terine relaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants,
`
`mucolytics, DNA and genetic modifying drugs, and combinations thereof.
`
`Erectile dysfunction therapies include, but are not limited to, drugs for facilitating
`
`blood flow to the penis, and for effecting autonomic nervous activities, such as increasing
`
`parasympathetic (cholinergic) and decreasing sympathetic (adrenersic) activities. Useful
`
`non-limiting drugs include sildenafils, such as Viagra®, tadalafils, such as Cialis®,
`
`vardenafils, apomorphines, such as Uprima®, yohimbine hydrochlorides such as
`
`10
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`15
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`20
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`25
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`30
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`Aphrodyne®, and alprostadils such as Caverj ect®.
`
`Examples of medicating active ingredients contemplated for use in the present
`
`invention include antacids, Hz—antagonists, and analgesics. For example, antacid dosages can
`
`be prepared using the ingredients calcium carbonate alone or in combination with magnesium
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`hydroxide, and/0r aluminum hydroxide. Moreover, antacids can be used in combination with
`
`Hz-antagonists.
`
`Analgesics include opiates and opiate derivatives, such as oxycodone (available as
`
`Oxycontin®), ibuprofen, aspirin, acetaminophen, and combinations thereof that may
`
`optionally include caffeine.
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`10
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`15
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`20
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`25
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`30
`
`Other preferred drugs for other preferred active ingredients for use in the present
`
`invention include anti—diarrheals such as immodium AD, anti-histamines, anti—tussives,
`
`decongestants, vitamins, and breath fresheners. Common drugs used alone or in combination
`
`for colds, pain, fever, cough, congestion, runny nose and allergies, such as acetaminophen,
`
`chlorpheniramine maleate, dextromethorphan, pseudoephedrine HCl and diphenhydramine
`
`may be included in the film compositions of the present invention.
`
`Also contemplated for use herein are anxiolytics such as alprazolam (available as
`
`Xanax®); anti-psychotics such as clozopin (available as Clozaril®) and haloperidol
`
`(available as Haldol®); non-steroidal anti-inflammatories (NSAID’S) such as dicyclofenacs
`
`(available as Voltaren®) and etodolac (available as Lodine®), anti-histamines such as
`
`loratadine (available as Claritin®), astemizole (available as HismanalTM), nabumetone
`
`(available as Relafen®), and Clemastine (available as Tavist®); anti-emetics such as
`
`granisetron hydrochloride (available as Kytril®) and nabilone (available as CesametTM);
`
`bronchodilators such as Bentolin®, albuterol sulfate (available as Proventi1®); anti-
`
`depressants such as fluoxetine hydrochloride (available as Prozac®), sertraline hydrochloride
`
`(available as Zoloft®), and paroxtine hydrochloride (available as Paxil®); anti-migraines
`
`such as Imigra®, ACE-inhibitors such as enalaprilat (available as Vasotec®), captopril
`
`(available as Capoten®) and lisinopril (available as Zestri1®); anti-A