1199-4P
`
`PATENT
`
`THIN FILM WITH NON-SELF-AGGREGATING
`
`UNIFORM HETEROGENEITY
`
`FIELD OF THE INVENTION
`The invention relates to rapidly dissolving films and methods of their preparation.
`
`[0001]
`
`The films may also contain an active ingredient that is evenly distributed throughout the film.
`The even or uniform distribution is achieved through a controlled drying process that reduces
`aggregation or conglomeration of the components in the film.
`
`BACKGROUND OF THE RELATED TECHNOLOGY
`
`[0002]
`
`Active ingredients such as drugs or pharmaceuticals, may be prepared in a tablet
`
`form to allow for accurate and consistent dosing. However, this form of preparing and
`dispensing medications has many disadvantages including that a large proportion of adjuvants
`
`that must be added to obtain a size able to be handled, that a larger medication form requires
`additional storage space, that dispensing includes counting the tablets which has a tendency for
`
`inaccuracy. In addition, many persons, around 28%, have difficulty swallowing tablets.
`
`Difficulty swallowing tablets is particularly an issue where tablets such as controlled release
`
`drugs may not be crushed to allow for an easier administration of the drug, e.g. mixing the
`crushed tablet with food.
`
`[0003)
`
`Some have proposed that films may be used to carry active ingredients such as
`
`drugs, pharmaceuticals, and the like. However, historically films have suffered from a number
`
`of unfavorable characteristics that have not allowed them to be used in practice.
`
`[0004]
`
`Films that incorporate a pharmaceutically active ingredient are disclosed in U.S.
`
`Patent No. 4, 136,145 to Fuchs, et al. C'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, however, examination of films made in accordance with the process disclosed in Fuchs
`
`reveals that such films suffer from the aggregation or conglomeration of particles, i.e., self(cid:173)
`
`aggregation, making them inherently non-uniform. This result is believed to be related to Fuchs'
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`TEVA EXHIBIT 1010
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`

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`process which uses relatively long drying times, thereby permitting intramolecular attractive
`
`forces, conventional forces and the like to encourage such agglomeration. When large dosages
`
`are involved, there is a need to be especially attentive to ensuring an adequate amount of the
`active is present in the delivery vehicle. For example, where a large amount of active is used, a
`
`small change in the dimensions of the film would lead to a large difference in the amount of
`active per film. 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.
`
`[0005]
`
`The problems of self-aggregation leading to non-uniformity of a film, were
`
`addressed in U.S. Patent 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 is especially
`
`important in the pharmaceutical area. Schmidt abandoned the idea that a mono-layer film may
`provide an accurate dosage form and instead attempted to solve this problem by forming a multi(cid:173)
`
`layered film. Not only does Schmidt fail to provide a uniformly distributed film, he proposed a
`multi-step process that is not practical for commercial use.
`
`[0006]
`
`Two other U.S. Patents directly addressed the problems that Fuchs had regarding
`
`that the uniformity of films was affected by the self-aggregation of particles that occurred during
`
`the drying of the film. In an attempt to overcome non-uniformity, U.S. Patent 5,629,003 to
`
`Horstmann et al. and U.S. Patent 5,948,430 to Zerbe et al. added gel formers and polyhydric
`alcohols respectively, to increase the viscosity of the film before it is dry in an effort to reduce
`
`aggregation of the components in the film. Both of these methods have the disadvantage of
`requiring additional components which translates to additional cost 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 aggregation of the
`
`active and other adjuvant. Such processes also run the risk of exposing the active, i.e., a drug, or
`vitamin C, or other components to prolonged exposure to moisture and elevated temperatures
`which may render it ineffective or even harmful.
`
`2
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`

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`(0007]
`
`Therefore, there is a need for compositions which can be forward into film
`
`products, which use a minimal number of materials or components, and which provide a
`
`substantially non-self-aggregating uniform heterogeneity throughout the area of the films.
`Desirably, such films are produced through a selection of polymer that will provide a desired
`
`viscosity, a specific film-forming process such as reverse roll coating, and a controlled, and
`desirably rapid, drying process which serves to maintain the uniform distribution of non-self(cid:173)
`
`aggregating components without the necessary addition of gel formers or polyhydric alcohols
`
`which are required in the products and for the processes of Horstmann and Zerbe.
`
`SUMMARY OF THE JNVENTION
`
`[0008]
`
`In one aspect of the present invention, there is provided a film product that is
`
`formed by combining a polymer and a polar solvent, forming the combination into a film, and
`rapidly drying the film in order to maintain a non-self-aggregating uniform heterogeneity. The
`polar solvent may be water, a polar organic solvent, or a combination thereof An active
`ingredient may be added to the polymer and water combination prior to the drying step.
`Alternatively, or in addition to rapidly drying the film, the polymer may be selected in order to
`
`provide a viscosity that maintains the non-self-aggregating uniform heterogeneity. Reverse roll
`
`coating technique may also be used to form the film.
`
`[0009]
`
`In another aspect of the invention, there is a process for preparing a film with a
`substantially uniform distribution of components. The process includes the steps of combining a
`
`polymer component and water to form a uniformly distributed matrix. This matrix is then
`
`formed into a film and fed onto a surface having top and bottom sides where the bottom side is in
`
`substantially uniform contact with a water bath controlled at a temperature sufficient to dry the
`
`film. The matrix from which the film is formed may also include an active ingredient. Also,
`either alternatively, or in addition to rapidly drying the film, the polymer may be selected in
`
`order to provide a viscosity that maintains the non-self-aggregating uniform heterogeneity.
`Reverse roll coating technique may also be used to form the film.
`
`[0010]
`
`A further aspect of the present invention is method of orally administering an
`
`active including the steps of:
`
`3
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`TEVA EXHIBIT 1010
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`

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`(a)
`
`preparing a film by the steps of:
`
`(i)
`
`combining a polymer, an active component, and water to form a material
`
`with a non-self-aggregating uniform heterogeneity;
`
`(ii)
`
`forming the material into a film; and
`
`(iii)
`
`drying the film in a sufficiently rapid time to maintain the non-self(cid:173)
`
`aggregating uniform heterogeneity; and
`
`(b)
`
`introducing the film to the oral cavity of a mammal.
`
`[0011]
`
`An even further aspect ofthe present invention is method of introducing an active
`
`component to liquid including the steps of:
`
`(a)
`
`preparing a film by the steps of:
`
`(i)
`
`combining a polymer, an active component, and water to form a material
`
`with a non-self-aggregating uniform heterogeneity;
`
`(ii)
`
`forming the material into a film; and
`
`(iii)
`
`drying the film in a sufficiently rapid time to maintain the non-self(cid:173)
`
`aggregating uniform heterogeneity; and
`
`(b)
`
`(c)
`
`placing the film into a liquid; and
`
`allowing the film to dissolve.
`
`[0012]
`
`A still further aspect of the present invention provides a dosage form for the
`
`administration of an active including:
`
`(a)
`
`a first layer including a film formed by the steps of:
`
`(i)
`
`combining a polymer, an active component, and water to form a
`
`material with a non-self-aggregating uniform heterogeneity;
`
`(ii)
`
`forming said material into a film; and
`
`(iii)
`
`drying said film in a sufficiently rapid time to maintain said non-
`
`self-aggregating uniform heterogeneity; and
`
`(b)
`
`a substantially non-water soluble second layer.
`
`[0013]
`
`Another aspect of the present invention provides a method of preparing a dosage
`
`form for the administration of an active including the steps of:
`
`4
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`TEVA EXHIBIT 1010
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`

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`(a)
`
`preparing a film by the steps of:
`(i)
`
`combining a polymer, an active component, and water to form a material
`
`(ii)
`(iii)
`
`with a non-self-aggregating uniform heterogeneity;
`
`forming the material into a film; and
`
`drying the film in a sufficiently rapid time to maintain the non-self(cid:173)
`
`aggregating uniform heterogeneity; and
`
`(b)
`
`applying the film to a substantially non-water soluble support.
`
`[0014]
`
`In still another aspect of the present invention there is provided another method of
`
`administering an active including the steps of:
`
`(a)
`
`preparing dosage form by the steps of:
`
`(i)
`
`combining a polymer, an active component, and water to form a material
`
`(ii)
`(iii)
`
`with a non-self-aggregating uniform heterogeneity;
`
`forming the material into a film;
`
`drying the film in a sufficiently rapid time to maintain the non-self(cid:173)
`
`aggregating uniform heterogeneity; and
`
`(iv)
`
`applying the film to a substantially non-water soluble support;
`
`(b)
`
`(c)
`
`removing the film from said support; and
`
`applying the film to the oral cavity of a mammal.
`
`[0015]
`
`Another aspect of the invention provides a film product formed by the steps of:
`
`(a)
`
`combining a polymer and a liquid carrier to form a material with a non-self-
`
`aggregating uniform heterogeneity;
`
`(b)
`
`(c)
`
`forming said material into a film; and
`
`removing said liquid carrier, for example, by evaporative methods or by
`
`permitting volatilization to occur at selected temperatures, from said film in a manner to
`
`maintain said non-self-aggregating uniform heterogeneity.
`
`[0016]
`
`Also provided is a process for making a film having a substantially uniform
`
`distribution of components comprising:
`
`5
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`TEVA EXHIBIT 1010
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`

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`(a)
`
`combining a polymer component and liquid carrier to form a matrix with a
`
`uniform distribution of said components;
`
`(b)
`
`(c)
`
`forming a film from said matrix; and
`
`removing said liquid carrier, for example, by evaporative methods or by
`
`permitting volatilization to occur at selected temperatures, from said film in a manner to
`
`maintain said uniform distribution.
`
`[0017]
`
`A still further aspect of the present invention provides process for making a film
`
`having a substantially uniform distribution of components comprising:
`
`(a)
`
`combining a polymer component and a polar solvent to form a matrix with a
`
`uniform distribution of said components, said polymer selected to provide a viscosity sufficient
`
`to maintain said uniform distribution; and
`
`(b)
`
`forming a film from said matrix.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0018]
`
`For the purposes of the present invention the term non-self-aggregating uniform
`
`heterogeneity refers to the ability of the films of the present invention which are formed from
`
`one or more components in addition to a polar solvent to provide a substantially reduced
`
`occurrence of aggregation or conglomeration of components within the film as is normally
`
`experienced when films are formed by conventional drying methods such as a high-temperature
`
`air-bath using a drying oven, drying tunnel, vacuum drier, or other such drying equipment.
`
`[0019]
`
`The film products ofthe present invention are produced by a combination of a
`
`properly selectecl 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 components within them by utilizing a selected casting method and a
`
`controlled drying processes. Examples of controlled drying processes include, but are not
`
`limited to, the use of the apparatus disclosed in U.S. Patent No. 4,631,837 to Magoon
`
`("Magoon"), herein incorporated by reference. Desirably, the drying of the film will occur
`
`within about ten minutes or fewer, or more desirably within about five minutes or fewer.
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`6
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`TEVA EXHIBIT 1010
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`

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`[0020]
`
`The product~ and processes of the present invention rely on the interaction among
`
`various steps of the production of the films in order to provide films that substantially reduce the
`
`self-aggregation of the components within the films. Specifically, these steps include the
`
`particular method used to form the film, the viscosity of the film forming composition and the
`
`method of drying the film. More particularly, a greater viscosity of components in the mixture is
`
`important when the active is not soluble in the selected polar solvent in order to prevent the
`
`active from settling out initially. However, the viscosity must not be too great as to prevent the
`
`method of casting, desirably reverse roll coating which provides a film of substantially consistent
`
`thickness. While the viscosity and casting method are important in the first steps of forming the
`
`film to promote uniformity, the method of drying is also important. Although the viscosity
`
`assists uniformity initially, a rapid drying process ensures that the uniformity will be maintained
`
`until the film is dry.
`
`[0021)
`
`The film products are generally formed by combining a properly selected polymer
`
`and polar solvent, as well as any active ingredient or filler as desired. Desirably, the solvent
`
`content of the combination is at least about 30% by weight of the total combination. The matrix
`
`formed by this combination is formed into a film, desirably by roll coating, and then dried,
`
`desirably by a rapid drying process to maintain the uniformity of the film, more specifically, a
`
`non-self-aggregating uniform heterogeneity. The resulting film will desirably contain less than
`
`about 6% by weight solvent, more desirably less than about 4% by weight solvent, or most
`
`desirably less than about 2% by weight solvent. The solvent may be water, a polar organic
`
`solvent such as ethanol, isopropanol, acetone, methylene chloride, or any combination thereof
`
`Film-Forming Polymers
`
`[0022]
`
`The polymer may be water soluble, water insoluble, or a combination of one or
`
`more either water soluble or water insoluble polymers. The polymer may include cellulose or a
`
`cellulose derivative. Specific examples of useful water soluble polymers include, but are not
`
`limited to, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
`
`polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium aginate, polyethylene
`
`glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,
`
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`TEVA EXHIBIT 1010
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`methylmethacrylate copolymer, carboxyvinyl copolymers, starch, and combinations thereof
`
`Specific examples of useful water insoluble polymers include, but are not limited to, ethyl
`
`cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl
`
`cellulose phthalate and combinations thereof
`
`[0023]
`
`Other polymers useful for incorporation into the films of the present invention
`
`include biodegradable polymers, copolymers, block polymers and combinations thereof Among
`the known useful polymers or polymer classes which meet the above criteria are: poly(glycolic
`
`acid) (PGA), poly(lactic acid) (PLA), polydioxanoes, polyoxalates, poly( a-esters),
`
`polyanhydrides, polyacetates, polycaprolactones, poly( orthoesters ), polyamino acids,
`
`polyaminocarbonates, polyurethanes, poly carbonates, , polyamides, poly( alkyl cyanoacrylates ),
`and mixtures and copolymers thereof Additional useful polymers include, stereopolymers of L(cid:173)
`and D-lactic acid, copolymers ofbis(p-carboxyphenoxy) propane acid and sebacic acid, sebacic
`acid copolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolic
`
`acid)/polyethyleneglycol copolymers, copolymers of polyurethane and (poly(lactic acid),
`
`copolymers of polyurethane and poly(lactic acid), copolymers of a-amino acids, copolymers of
`
`a-amino acids and caproic acid, copolymers of a-benzyl glutamate and polyethylene glycol,
`copolymers of succinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates and
`mixtures thereof Binary and ternary systems are contemplated.
`
`[0024]
`
`Other specific polymers useful include those marketed under the Medisorb and
`
`Biodel trademarks. The Medisorb materials are marketed by the Dupont Company of
`
`Wilmington, Delaware and are generically identified as a "lactide/glycolide co-polymer"
`containing "propanoic acid, 2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid."
`
`Four such polymers include lactide/glycolide IOOL, believed to be 100% lactide having a melting
`point within the range of338°-347°F (170°-l75°C); lactide/glycolide lOOL, believed to be 100%
`
`glycolide having a melting point within the range of 437°-455°F (225°-235°C); lactide/glycolide
`
`85/15, believed to be 85% lactide and 15% glycolide with a melting point within the range of
`338°-347°F (170°-175° C); and lactide/glycolide 50/50, believed to be a copolymer of 50%
`lactide and 50% glycolide with a melting point within the range of338°-347°F (170°-175°C).
`
`8
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`

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`[0025]
`
`The Biodel materials represent a family of various polyanhydrides which differ
`
`chemically.
`
`[0026]
`
`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. For example, if the active
`
`or other components are not soluble in the selected solvent, a polymer that will provide a greater
`
`viscosity is desired to assist in maintaining uniformity. On the other hand, if the components are
`
`soluble in the solvent, a polymer that provides a lower viscosity may be preferred.
`
`Controlled Release Films
`
`[0027]
`
`The term "controlled release" is intended to mean the release of active at a pre-
`selected or desired rate. This rate will vary depending upon the application. Desirable rates
`
`include fast or immediate release profiles as well as delayed, sustained or sequential release.
`Combinations of release patterns, such as initial spiked release followed by lower levels of
`sustained release of active are contemplated.
`
`[0028]
`
`The polymers that are chosen for the films of the present invention may also be
`
`chosen to allow for controlled disintegration of the active. This may be achieved by providing a
`
`substantially water insoluble film that incorporates an active that will be released from the film
`over time. This may be accomplished by incorporating a variety of different soluble or insoluble
`
`polymers and may also include biodegradable polymers in combination. Alternatively, coated
`controlled release active particles may be incorporated into a readily soluble film matrix to
`
`achieve the controlled release property of the active inside the digestive system upon
`consumption.
`
`[0029]
`
`Films that provide a controlled release of the active are particularly useful for
`buccal, gingival, and sublingual applications.
`
`[0030]
`
`The convenience of administering a single dose of a medication which releases
`active ingredients in a controlled fashion over an extended period oftime as opposed to the
`
`administration of a number of single doses at regular intervals has long been recognized in the
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`9
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`pharmaceutical arts. The advantage to the patient and clinician in having consistent and uniform
`
`blood levels of medication over an extended period of time are likewise recognized. The
`
`advantages of a variety of sustained release dosage forms are well known. However, the
`preparation of a film that provides the controlled release of an active has advantages in addition
`to those well-known for controlled release tablets. For example, thin films are difficult to
`
`aspirate and provide an increased patient compliance because they need not be swallowed like a
`
`tablet. Furthermore, thin films may not be crushed in the manner of controlled release tablets
`
`which is a problem leading to abuse of drugs such as Oxycontin.
`
`Actives
`[0031]
`
`When an active is introduced to the film the amount of active per area is
`determined by the uniform distribution ofthe film. For example, when the films are cut into
`individual dosage forms, the amount of the active in the dosage form can be known with a great
`
`deal of accuracy. This is achieved because the amount of the active in a given area is
`
`substantially identical to the amount of active in an area of the same dimensions in another part
`
`of the film. The accuracy in dosage is particularly advantageous when the active is a
`medicament, i.e. a drug.
`
`[0032]
`
`The active components that may be incorporated into the films of the present
`invention include, without limitation, medicaments, flavors, fragrances, enzymes, preservatives,
`sweetening agents, colorants, spices, vitamins and combinations thereof
`
`[0033)
`
`A wide variety of medicaments and pharmaceutical compositions may be
`included in the dosage forms ofthe present invention. Examples of useful drugs include ace(cid:173)
`inhibitors, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics,
`anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations,
`
`antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents,
`anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti(cid:173)
`
`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(cid:173)
`
`neoplastics, anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants, biological
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`10
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`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(cid:173)
`thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular
`drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti(cid:173)
`
`spasmodics, terine relaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough
`suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof
`
`[0034]
`
`Examples of active ingredients contemplated for use in the present invention
`include antacids, H2-antagonists, and analgesics. For example, antacid dosages can be prepared
`using the ingredients calcium carbonate alone or in combination with magnesium hydroxide,
`and/or aluminum hydroxide Mor~over, antacids can be used in combination with H2-antagonists.
`
`[0035]
`
`Analgesics include opiates and opiate derivatives, such as Oxycontin, ibuprofen,
`
`aspirin, acetaminophe~ and combinations thereof that may optionally include caffeine.
`
`[0036]
`
`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. Also contemplated for use herein are anxiolytics
`such as Xanax; anti-psychotics such as clozaril and Haldol; non-steroidal anti-inflammatories
`
`(NSAID's) such as Voltaren and Lodine, anti-histamines such as Claritin, Hismanal, Relafen,
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`11
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`

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`and Tavist; anti-emetics such as Kytril and Cesamet; bronchodilators such as Bentolin, Proventil;
`
`anti-depressants such as Prozac, Zoloft, and Paxil; anti-migraines such as Imigra, ACE-inhibitors
`
`such as Vasotec, Capoten and Zestril; anti-Alzheimer's agents, such as Nicergoline; and CaR(cid:173)
`
`antagonists such as Procardia, Adalat, and Calan.
`
`[0037]
`
`The popular Hz-antagonists which are contemplated for use in the present
`
`invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidien, ebrotidine,
`
`mifentidine, roxatidine, pisatidine and aceroxatidine.
`
`[0038]
`
`Active antacid ingredients include, but are not limited to, the following:
`aluminum hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate,
`dihydroxyaluminum sodium carbonate, bicarbonate, bismuth aluminate, bismuth carbonate,
`bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsilysilate, calcium
`
`carbonate, calcium phosphate, citrate· ion (acid or salt), amino acetic acid, hydrate magnesium
`
`aluminate sulfate, magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium
`glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids,
`
`aluminum mono-ordibasic calcium phosphate, tricalcium phosphate, potassium bicarbonate,
`sodium tartrate, sodium bicarbonate, magnesium aluminosilicates, tartaric acids and salts.
`
`[0039]
`
`Also color additives can be used in preparing the films. Such color additives
`include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external
`
`drug and cosmetic colors (Ext. D&C). These colors are dyes their corresponding lakes, and
`
`certain natural and derived colorants. Lakes are dyes absorbed on aluminum hydroxide.
`
`[0040)
`
`Other examples of coloring agents include known azo dyes, organic or inorganic
`pigments, or coloring agents of natural origin. Inorganic pigments are preferred, such as the
`
`oxides or iron or titanium, these oxides, being added in concentrations ranging from about 0.001
`to about 10%, and preferably about 0.5 to about 3%, based on the weight of all the components.
`
`[0041]
`
`Flavors may be chosen from natural and synthetic flavoring liquids. An
`illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics,
`
`12
`
`HIGHLY CONFIDENTIAL-OUTSIDE COUNSEL EYES ONLY
`
`TEVA EXHIBIT 1010
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and
`combinations thereof A non-limiting representative list of examples includes citrus oils such as
`
`lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape,
`
`strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors.
`
`[0042]
`
`Other useful flavorings include aldehydes and esters such as benzaldehyde
`
`(cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime),
`decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12
`
`(citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), and 2-
`
`dodecenal (citrus, mandarin), combinations thereof and the like.
`
`[0043]
`
`The sweeteners may be chosen from the following non-limiting list: glucose (com
`syrup), dextrose, invert sugar, fructose, and mixtures thereof(when not used as a carrier);
`
`saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame;
`dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside ); chloro derivatives of
`sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also
`
`contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-
`methyl-1-1-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt ( acesulfame-K),
`
`and sodium and calcium salts thereof, and natural intensive sweeteners, such as Lo Han Kuo.
`Other sweeteners may also be used.
`
`[0044]
`
`When the active is combined with the polymer in the solvent, the type of matrix
`
`that is formed depends on the solubilities of the active and the polymer. If the active and/or
`polymer are soluble in the selected solvent, this may form a solution. However, if the
`components are not soluble, the matrix may be classified as an emulsion, a colloid, or a
`suspension.
`
`[0045]
`
`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
`
`13
`
`HIGHLY CONFIDENTIAL-OUTSIDE COUNSEL EYES ONLY
`
`TEVA EXHIBIT 1010
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`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.
`
`The viscosity may be adjusted based on the selected active depending on the
`[0046]
`components within the matrix. For example, if the component is not soluble within the selected
`
`solvent, a proper viscosity may be selected to prevent the component from settling which would
`
`adversely affect the uniformity of the resulting film. The viscosity may be adjusted in different
`
`ways. To increase viscosity the polymer may be chosen of a higher molecular weight,
`
`crosslinkers may be added, such as salts of calcium, sodium and potassium. The viscosity may
`also be adjusted by adjusting the temperature or the adding a viscosity increasing component.
`
`Components that will increase the viscosity or stabilize the emulsion/suspension include higher
`molecular weight polymers and polysaccharides and gums, which include without limitation,
`
`alginate, carrageenan, hydroxypropyl methyl cellulose, locust bean gum, guar gum, xanthan
`
`gum, dextran, gum arabic, gellan gum and combinations thereof
`
`Dosages
`
`[0047]
`The film products of the present invention are capable of accommodating a wide
`range of amounts of the active ingredient. The films are capable of providing an accurate dosage
`
`amount (determined by the size of the film and concentration of the active in the original
`
`polymer/water combination) regardless of whether the required dosage is high or extremely low.
`
`Therefore, depending on the type of active or p