USOO7666337B2
`
`(12) United States Patent
`(10) Patent No.:
`US 7,666,337 B2
`
`Yang et al.
`(45) Date of Patent:
`Feb. 23, 2010
`
`(54) POLYETHYLENE OXIDE-BASED FILMS AND
`DRUG DELIVERY SYSTEMS MADE
`THEREFROM
`
`(75)
`
`Inventors: Robert K. Yang; Flushing; NY (US);
`Richard C. Fuisz; McLean; VA (US);
`Gary L. Myers; Kingsport; TN (US);
`Joseph M. Fuisz; McLean; VA (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 619 days.
`
`(21)
`
`Appl. No.: 10/856,176
`
`(22)
`
`Filed:
`
`May 28, 2004
`
`(65)
`
`(63)
`
`Prior Publication Data
`
`US 2005/0037055 A1
`
`Feb. 17; 2005
`
`Related US. Application Data
`
`Continuation-in-part of application No. 10/768,809,
`filed on Jan. 30; 2004; now Pat. No. 7,357,891; and a
`continuation-in-part of application No. PCT/USO2/
`32575; filed on Oct. 11; 2002; and a continuation-in-
`part ofapplication No. PCT/USO2/32594; filed on Oct.
`1 1; 2002; and a continuation-in-part ofapplication No.
`PCT/USO2/32542; 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.
`
`Int. Cl.
`
`(51)
`
`(52) U.S.C1.
`
`.................. 264/172.19; 264/212; 264/234;
`264/319; 264/344
`(58) Field of Classification Search ....................... None
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`307,537 A
`
`11/1884 Foulks
`
`(Continued)
`FOREIGN PATENT DOCUMENTS
`
`DE
`
`2432925 B2
`
`1/1976
`
`(Continued)
`OTHER PUBLICATIONS
`
`XP-002298105; Polyethylenglykole; Internet: www.r0empp.com;
`Sep. 20, 2004.
`
`(Continued)
`
`Primary ExamineriEdmund H. Lee
`(74) Attorney, Agent, or FirmiHoffmann & Baron; LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to the film products and methods oftheir
`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 pro-
`cess that maintains the required uniformity of the film. The
`films contain a polymer component; which includes polyeth-
`ylene oxide optionally blended with hydrophilic cellulosic
`polymers. Desirably; the films 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 film.
`
`329C 39/14
`
`(2006.01)
`
`30 Claims, 34 Drawing Sheets
`
`
`
`Page 1
`
`BDSI EXHIBIT 1033
`
`Page 1
`
`

`

`US 7,666,337 B2
`
`Page 2
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`US. PATENT DOCUMENTS
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`
`Page 2
`
`

`

`US 7,666,337 B2
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`
`EP
`EP
`EP
`EP
`EP
`
`EP
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`
`W0
`W0
`W0
`W0
`W0
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`
`0 514 691 A2
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`
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`
`* cited by examiner
`
`Page 3
`
`Page 3
`
`

`

`US. Patent
`
`Feb. 23, 2010
`
`Sheet 1 of 34
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`US 7,666,337 B2
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`US 7,666,337 B2
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`1
`POLYETHYLENE OXIDE-BASED FILMS AND
`DRUG DELIVERY SYSTEMS MADE
`THEREFROM
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims the benefit of US. Provisional
`Application No. 60/473,902, filed May 28, 2003 and is a
`continuation-in-part of US. application Ser. No. 10/768,809,
`filed Jan. 30, 2004 now US. Pat. No. 7,357,891,which claims
`benefit to US. Provisional Application No. 60/443,741 filed
`Jan. 30, 2003 and is a continuation-in-part of:
`(a) PCT/USO2/32575 filed Oct. 11, 2002, which claims
`priority to: (1) US. application Ser. No. 10/074,272, filed
`Feb. 14, 2002 which claims benefit to US. Provisional Appli-
`cation No. 60/328,868, filed Oct. 12, 2001 and (2) US. Pro-
`visional Application No. 60/386,937, filed Jun. 7, 2002;
`(b) PCT/USO2/32594, filed Oct. 11, 2002, which claims
`priority to: (1) US. Provisional Application No. 60/414,276,
`filed Sep. 27, 2002, (2) US. application Ser. No. 10/074,272,
`filed Feb. 14, 2002, which claims benefit to US. Provisional
`Application No. 60/328,868, filed Oct. 12, 2001 and (3) US.
`Provisional Application No. 60/386,937, filed Jun. 7, 2002;
`and
`
`(c) PCT/US/02/32542, filed Oct. 11, 2002, which claims
`priority to: (1) US. Provisional Application No. 60/371,940,
`filedApr. 11, 2002, (2) US. application Ser. No. 10/074,272,
`filed Feb. 14, 2002, which claims benefit to US. Provisional
`Application No. 60/328,868, filed Oct. 12, 2001 and (3) US.
`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
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`the like. However, historically films and the process of mak-
`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 US. 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 insufficient amount of active for the recommended
`
`treatment. Failure to achieve a high degree of accuracy with
`respect to the amount of active ingredient in the cut film can
`be harmful to the patient. For this reason, dosage forms
`formed by processes such as Fuchs, would not likely meet the
`stringent standards of governmental or regulatory agencies,
`such as the US. 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 US. 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 US. 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, US. Pat. No. 5,629,003 to Horstmann et al.
`and US. 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
`drying in an effort to reduce aggregation ofthe components in
`the film. These methods have the disadvantage of requiring
`additional components, which translates to additional cost
`
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`US 7,666,337 B2
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`3
`and manufacturing steps. Furthermore, both methods employ
`the use the conventional time-consuming drying methods
`such as a high-temperature air-bath using a drying oven,
`drying tunnel, vacuum drier, or other such drying equipment.
`The long length of drying time aids in promoting the 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-
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`erwise be occupied by the film composition. None of the
`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 Horstmann 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.
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to rapid-dissolve film
`products containing at
`least one water-soluble polymer
`including polyethylene oxide alone or in combination with a
`hydrophilic cellulosic polymer, wherein the film product is
`free of added plasticizers.
`Another embodiment of the rapid-dissolve film product
`includes at least one water-soluble polymer containing about
`20% to 100% by weight polyethylene oxide, about 0% to 80%
`by weight hydroxypropylmethyl cellulose, and about 0% to
`80% by weight hydroxypropyl cellulose; an active compo-
`nent; sucralose; precipitated calcium carbonate;
`at least one flavoring; simethicone; water; and at least one
`colorant, wherein the film product is free of added plas-
`ticizers, surfactants, and polyalcohols.
`invention is
`Yet another embodiment of the present
`directed to an edible water-soluble delivery system in the
`form ofa film composition, which contains at least one water-
`soluble polymer comprising polyethylene oxide alone or in
`combination with a polymer selected from the group consist-
`ing of hydroxypropylmethyl cellulose and hydroxypropyl
`cellulose, wherein the edible water-soluble delivery system is
`essentially free of organic solvents, plasticizers, surfactants,
`and polyalcohols.
`The present invention is also directed to processes for
`making a film having a substantially uniform distribution of
`components, including the steps of: (a) combining at least one
`water-soluble polymer comprising polyethylene oxide alone
`or in combination with a hydrophilic cellulosic polymer, a
`solvent, and an active component to form a matrix with a
`uniform distribution of the components; (b) forming a film
`from the matrix; and (c) drying the film, wherein the film is
`free of added plasticizers.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows a side view of a package containing a unit
`dosage film of the present invention.
`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.
`
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`US 7,666,337 B2
`
`5
`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 photomicrographic representation of a film
`containing fat coated particles dried by the inventive drying
`process.
`FIG. 22 is a photomicrographic representation of a film
`containing fat coated particles dried by the inventive drying
`process.
`FIG. 23 is a photomicrographic representation of a film
`containing fat coated particles dried by the inventive drying
`process.
`FIG. 24 is a photomicrographic representation of a film
`containing fat coated particles dried by the inventive drying
`process.
`FIG. 25 is a photomicrographic representation of a film
`containing fat coated particles dried by the inventive drying
`process.
`FIG. 26 is a photomicrographic representation of fat coated
`particles not in film, heated for 9 minutes at 80° C.
`FIG. 27 is a photomicrographic representation of fat coated
`particles not in film, heated for 9 minutes at 80° C.
`FIG. 28 is a photomicrographic representation of fat coated
`particles at room temperature prior to processing.
`FIG. 29 is a photomicrographic representation of fat coated
`particles at room temperature prior to processing.
`FIG. 30 is a photomicrographic representation of fat coated
`particles at room temperature prior to processing.
`FIG. 31 is a photomicrographic representation of fat coated
`particles at room temperature prior to processing.
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`FIG. 32 is a graphical representation of a microarray on the
`blood of a human after ingestion by the human of a film ofthe
`present invention containing a bovine derived protein.
`FIG. 33 is a graphical representation of the temperature
`differential between the inside and outside of a film of the
`
`present invention during drying.
`FIG. 34 is a graphical representation of the temperature
`differential between the inside and outside of a film of the
`
`present invention during drying.
`FIG. 35 is a schematic representation of a continuously-
`linked zone drying apparatus in accordance with the present
`invention.
`
`FIG. 36 is a schematic representation of a separate zone
`drying apparatus in accordance with the present invention.
`FIG. 37 is a schematic representation of a extrusion device
`for use in producing films of the present invention.
`FIG. 38 provides a table of various compositions of the
`invention, as well as certain properties.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`For the purposes ofthe present invention the term non- self-
`aggregating uniform heterogeneity refers to the ability of the
`films of the present invention, which are formed from one or
`more components in addition to a polar solvent, to provide a
`substantially reduced occurrence of, i.e. little or no, aggrega-
`tion or conglomeration of components within the film as is
`normally experienced when films are formed by conventional
`drying methods such as a high-temperature air-bath using a
`drying oven, drying tunnel, vacuum drier, or other such dry-
`ing equipment. The term heterogeneity, as used in the present
`invention, includes films that will incorporate a single com-
`ponent, such as a polymer, as well as combinations of com-
`ponents, such as a polymer and an active. Uniform heteroge-
`neity includes the substantial absence of aggregates or
`conglomerates as is common in conventional mixing and heat
`drying methods used to form films.
`Furthermore, the films of the present invention have a
`substantially uniform thickness, which is also not provided by
`the use ofconventional drying methods used for drying water-
`based polymer systems. The absence of a uniform thickness
`detrimentally affects uniformity of component distribution
`throughout the area of a given film.
`The film products of the present invention are produced by
`a combination of a properly selected polymer and a polar
`solvent, optionally including an active ingredient as well as
`other fillers known in the art. These films provide a non-self-
`aggregating uniform heterogeneity of the compon