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`Moreover, the pharmaceutically active agents may be sprayed and congealed with
`
`fully hydrogenated oils or waxes considered safe for human consumption and are relatively
`
`stable. Useful, but non-limiting, pharmaceutically acceptable oils include mineral oil, peanut
`
`oil, soybean oil, sunflower oil, com oil, olive oil, hard palm oil and rapeseed oil.
`
`Furthermore, crown ether compounds, such as cyclodextrins, are also useful for
`
`coating the pharmaceutically active agents. The pharmaceutically active agents are taste
`
`masked with crown ethers through entrapment or coaccervation methods. Useful
`
`cyclodextrins are commercially available under the trade name ofTrappsol® from CTD, Inc.
`
`5
`
`10
`
`Pharmaceutically active agents may be taste masked with the above-described taste(cid:173)
`
`masking agents by a variety of techniques. The techniques coat the pharmaceutically active
`
`agents or portions of the pharmaceutically active agents with taste masking agents to avoid
`
`the unpleasant taste effects, such as bitterness, often associates with the pharmaceutically
`
`15
`
`active agents or drugs. Useful coating techniques include, but are not limited to, fluidized
`
`bed coating, spray congealing coating, agglomeration or granulation coating, entrapment
`
`coating, coaccervation coating, infusion coating, spin coating, ion exchange coating and the
`
`like.
`
`20
`
`The fluidized bed coating method is commonly used in pharmaceutical industries for
`
`taste masking pharmaceutically active agents. Fluidized bed coaters achieve fluidization of
`
`the pharmaceutically active agents by introducing a continuous stream of process gas into a
`
`chamber. The coating material is deposited onto the suspended agent as it passes through the
`
`spray path of the coating material. The coated agents is dried. A relative low water solubility
`
`25
`
`polymer is typically used to coat the active particles' surface. Minimum limits on particle
`
`sizes are about 100 to 120 microns. Smaller particle sizes are difficult to achieve due to
`
`process limitation and product loss. Water insoluble pharmaceutically active agents may be
`
`suitable coated with water soluble taste masking agents with this method.
`
`30
`
`In the spray congealing method both the pharmaceutically active agents and the
`
`coating materials are sprayed simultaneously into a chamber supplied with process gas to
`
`create a uniformly coated active. This method typically involves the coating of the actives
`
`with material that could be melted at reasonable temperatures, for example fatty materials or
`
`polymers such as certain Eudragit® polymers. The mix of materials are sprayed through a
`
`16
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`fine nozzle and cooled through a temperature-control air stream or a cold surface.
`
`Consideration of mixture temperature is important. The melting temperature of the coating
`
`agent selected should not exceed a degradation temperature of the pharmaceutically active
`
`agent.
`
`5
`
`fu the agglomeration or granulation method, the pharmaceutically active agents are
`
`~mixed with the taste-masking agents and a solvent by mechanical means or by spray drying.
`
`The solvent is gradually removed by vacuum or heating, or both. Particles are then
`
`agglomerated. The agglomerated particles are not typically coated entirely with the taste
`
`10 masking agent and some bitterness may result accordingly. The bitterness, however, may be
`
`further reduced by incorporating such coated particles in the films of the present invention.
`
`fu typical entrapment coating methods, certain compounds having specific properties
`
`that can trap pharmaceutically active agents into its molecule cages must first be selected.
`
`15
`
`Compounds, like certain specifically made starches and crown ether type molecules, such as
`
`' cyclodextrins and zeolites, are useful with this method. The compounds and the agents are
`
`entrapped by ionic attraction. The entrapped agents are then precipitated from solution.
`
`The coaccervation coating method uses two polymers with opposite charges in
`
`20
`
`solution. When the solution is neutralized an insoluble matrix will precipitate from solution
`
`and trap the pharmaceutically active agents therein. Examples include interactions of gum
`
`arabic and gelatin solutions and interactions of cyclodextrins and protein solutions.
`
`fu the infusion method pharmaceutically active agents and flavors or sweeteners are
`
`25
`
`dissolved and infused into a polymer matrix to form a dry powder. fu spin coating methods,
`
`pharmaceutically active agents are combined with sugars or fats and spun into coated
`
`particles. Details ofthe method are disclosed in U.S. Patent No. 5,028,632, the contents of
`
`which is incorporated herein by reference. fu ion exchange coating, ionic bonding of
`
`pharmaceutically active agents to ion exchange resins masks the tastes of the agents.
`
`30
`
`Extrusion and spheronization methods may also be used of taste-masking
`
`pharmaceutically active particulates. Ratios ofactive(s) and polymer(s) (such as, starch,
`
`cellulose, gum and/or combinations thereof) are first mixed and thicken by adding a small
`
`amount of water. The thickened mixture is then extruded through a single or double nozzle
`
`17
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`screw. Small spherical particles are formed by a Marumerization® process. Desirable
`
`particle sizes are obtained through process control and particulate sieving.
`
`Lyophilization (Freeze-Drying) methods may also be used with the practice of the
`
`5
`
`present invention A combination ofpolymer(s) (such as, starch, gum, cellulose and/or
`
`combinations thereof) with active(s) are mixed and dissolved (or dispersed) in aqueous
`
`medium. This mixture is then freeze-dried on a pre-form su]Jstrate. Desirable particles sizes
`
`can be obtained by process control and product sieving.
`
`10
`
`In some instances, taste-masking may amount to the addition of two components
`
`together, neither of which are particularly pleasing to the taste, but which, due to their
`
`chemical makeup, counteract each other or allow for a third substance or more of one of the
`
`substances to be added without a concomitant reduction in pleasantness of the taste.
`
`15
`
`The edible water-soluble delivery system of the present invention further includes one
`
`or more members selected from antifoaming agents, plasticizing agents, surfactants,
`
`emulsifying agents, thickening agents, binding agents, cooling agents, saliva-stimulating
`
`agents, sweetening agents, antimicrobial agents, antigens and combinations thereof.
`
`20
`
`In one aspect of the present invention, a drug delivery composition includes (i) a
`
`flowable water-soluble film 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-
`
`25
`
`soluble film forming matrix is capable of being dried without loss of uniformity in the
`
`stationing of the particulate bioeffecting agent therein.
`
`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, such
`
`30
`
`particles may be spherical, substantially spherical, or non-spherical, such as irregularly
`
`shaped particles or ellipsoidally shaped particles. Ellipsoidally shaped particles or ellipsoids
`
`are desirable because of their ability to maintain uniformity in the film forming matrix as they
`
`tend to settle to a lesser degree as compared to spherical particles. Furthermore, the flowable
`
`18
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`water-soluble film forming matrix is formable into a dry film ofless than about 380 microns
`
`in thickness, for example less than about 250 microns in thickness.
`
`Desirably, taste-masking agent is a thin film coating over portions of the bioeffecting
`
`5
`
`agent. Useful taste-masking agents include polymeric materials. Water-soluble polymers are
`
`also useful. Desirably, the water-soluble polymers have an average molecular weight of
`
`equal to or greater than about 40,000. Furthermore, water-soluble polymer may be acrylic
`
`polymers, cellulosic polymers, and combinations thereof Additionally, vinyl polymers,
`
`crown ethers, hydrogenated oils and waxes, and combinations thereof may also be used as
`
`10
`
`taste-masking agents.
`
`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;
`
`ethyl cellulose; hydroxyl methyl cellulose; hydroxyethyl cellulose; hydroxypropyl cellulose;
`
`15
`
`hydroxypropylmethyl cellulose; hydroxymethylpropyl cellulose; gum arabic; xanthan gum;
`
`tragacanth; acacia; carageenan; guar gum; locust bean gum; pectin; alginates; gelatinized,
`
`modified or unmodified starch, including tapioca starch, rice starch, com 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,
`
`20
`
`gluten, soy protein, soy protein isolate, and whey protein; whey protein isolate; casein; levin;
`
`collagen; chitin; chitosin; polydextrose and combinations thereof
`
`The bioeffecting agent may be present in amounts of up to about 0.1% to about 60%
`
`by weight ofthe total composition. Useful bioeffecting agents include, but are not limited to,
`
`25
`
`antimicrobial agents, non-steroidal anti-inflammatory drugs, anti-tussives, decongestants,
`
`antihistamines, expectorants, anti-diarrheals, Hz antagonists, proton pump inhibitors, general
`
`non-selective CNS depressants, general non-selective CNS stimulants, selective CNS
`
`functional modifiers, anti-parkinsonism drugs, narcotics, analgesics, erectile dysfunction
`
`therapies, anti-pyretics, psychopharmacological drugs and combinations thereof. The
`
`30
`
`delivery vehicle composition may further include an organoleptic agent.
`
`In another aspect of the present invention, a drug delivery vehicle includes (i) a water(cid:173)
`
`soluble film matrix; and (ii) a particulate bioeffecting agent uniformly suspended within the
`
`matrix and having associated with it a taste-masking agent. The uniformity is determined by
`
`19
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`the presence of no 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
`
`5 microns.
`
`Useful taste-masking agents include water-soluble polymers. Desirably, the water(cid:173)
`
`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
`
`10
`
`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.
`
`In another aspect of the present invention, a drug delivery vehicle includes a dry
`
`15 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
`
`having an average molecular weight of equal to or greater than about 40,000 are also useful.
`
`20 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,
`
`the size of the particles are about 200 microns or less. Desirably, the film has a thickness of
`
`25
`
`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
`
`30 water-soluble polymer; and (ii) a pharmaceutically active particle having a pharmaceutically
`
`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
`
`20
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`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 of200 microns or
`
`less. Desirably, the film has a thiclmess of less than about 380 microns. The drug delivery
`
`5
`
`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
`
`10
`
`pharmaceutically active agent and a taste-masking agent. The active particle has a particle
`
`size of less than about 200 microns. Desirably, the thickness ofthe film is less than about
`
`380 microns.
`
`In another aspect of the present invention, a drug delivery vehicle includes a dry
`
`15 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
`
`20
`
`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-
`
`60% by weight of the particle. Desirably, the taste-masking agent is present in the amount of
`
`about 25-35% by weight of the particle.
`
`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 and an organoleptic agent. The active particle is taste-masked
`
`30 with a taste-masking agent. Useful organoleptic agents include flavors, sweeteners and
`
`combinations thereof.
`
`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
`
`21
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`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.
`
`5
`
`In another aspect of the present invention, a method of preparing a thin film drug
`
`delivery vehicle is provided. The method includes the steps of (a) providing a
`pharmaceutically active agent I 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
`
`10
`
`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 of providing 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.
`
`15
`
`The drying includes applying heat to the bottom of the carrier surface. Moreover, the
`
`drying may include applying microwave energy to the film. Such microwave drying is useful
`
`because drying initiates in the middle portions of the film. The present invention, however, is
`
`not limited to these drying methods. Any drying method may suitably be used as long as the
`
`20
`
`drying does not initiate at the top surface of the casted mixture. Such top surface drying does
`
`not typically provide desirable film uniformity.
`
`Useful methods for providing the pharmaceutically active agent with the taste(cid:173)
`
`masking agent include fluidized bed coating, spray congealing coating, agglomeration or
`
`25
`
`granulation coating, entrapment coating, coaccervation coating, infusion coating, spin
`
`coating, ion exchange coating the taste masking agent onto portions of the pharmaceutically
`
`active agent.
`
`Uses of Thin Films
`
`30
`
`The thin films of the present invention are well suited for many uses. The high degree
`
`of uniformity of the components of the film makes them particularly well suited for
`
`incorporating pharmaceuticals. Furthermore, the polymers used in construction of the films
`
`may be chosen to allow for a range of disintegration times for the films. A variation or
`
`extension in the time over which a film will disintegrate may achieve control over the rate
`
`22
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`that the active is released, which may allow for a sustained release delivery system. In
`
`addition, the films may be used for the administration of an active to any of several body
`
`surfaces, especially those including mucous membranes, such as oral, anal, vaginal,
`
`ophthalmological, the surface of a wound, either on a skin surface or within a body such as
`
`5
`
`during surgery, and similar surfaces.
`
`The films may be used to orally administer an active. This is accomplished by .
`
`preparing the films as described above and introducing them to the oral cavity of a mammal.
`
`This film may be prepared and adhered to a second or support layer from which it is removed
`
`10
`
`prior to use, i.e. introduction to the oral cavity. An adhesive may be used to attach the film to
`
`the support or backing material which may be any of those known in the art, and is preferably
`
`not water soluble. If an adhesive is used, it will desirably be a food grade adhesive that is
`
`ingestible and does not alter the properties of the active. Mucoadhesive compositions are
`
`particularly useful. The film compositions in many cases serve as mucoadhesives
`
`15
`
`themselves.
`
`The films may be applied under or to the tongue of the mammal. When this is
`
`desired, a specific film shape, corresponding to the shape of the tongue may be preferred.
`
`Therefore the film may be cut to a shape where the side of the film corresponding to the back
`
`20
`
`of the tongue will be longer than the side corresponding to the front of the tongue.
`
`Specifically, the desired shape may be that of a triangle or trapezoid. Desirably, the film will
`
`adhere to the oral cavity preventing it from being ejected from the oral cavity and permitting
`
`more of the active to be introduced to the oral cavity as the film dissolves.
`
`25
`
`Another use for the films of the present invention takes advantage of the films'
`
`tendency to dissolve quickly when introduce to a liquid. An active may be introduced to a
`
`liquid by preparing a film in accordance with the present invention, introducing it to a liquid,
`
`and allowing it to dissolve. This may be used either to prepare a liquid dosage form of an
`
`active, or to flavor a beverage.
`
`30
`
`The films of the present invention are desirably packaged in sealed, air and moisture
`
`resistant packages to protect the active from exposure oxidation, hydrolysis, volatilization
`
`and interaction with the environment. Referring to Figure 1, a packaged pharmaceutical
`
`dosage unit 10, includes each film 12 individually wrapped in a pouch or between foil and/or
`
`23
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`plastic laminate sheets 14. As depicted in Figure 2, the pouches 10, 10' can be linked
`
`together with tearable or perforated joints 16. The pouches 10, 1 O'may be packaged in a roll
`
`as depicted in Figure 5 or stacked as shown in Figure 3 and sold in a dispenser 18 as shown in
`
`';
`
`Figure 4. The dispenser may contain a full supply of the medication typically prescribed for
`
`5
`
`the intended therapy, but due to the thim1ess of the film and package, is smaller and more
`
`, convenient than traditional bottles used for tablets, capsules and liquids. Moreover, the films
`
`of the present invention dissolve instantly upon contact with saliva or mucosal membrane
`
`areas, eliminating the need to wash the dose down with water.
`
`10
`
`Desirably, a series of such unit doses are packaged together in accordance with the
`
`prescribed regimen or treatment, e.g., a 10-90 day supply, depending on the particular
`
`therapy. The individual films can be packaged on a backing and peeled off for use.
`
`Rheology and Films Properties
`
`15
`
`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, i.e. little or no, aggregation or conglomeration of components within the film
`
`as is normally experienced when films are formed by conventional drying methods such as a
`
`20
`
`high-temperature air-bath using a drying oven, drying tunnel, vacuum drier, or other such
`
`drying equipment. The term heterogeneity, as used in the present invention, includes films
`
`that will incorporate a single component, such as a polymer, as well as combinations of
`
`components, such as a polymer and an active. Uniform heterogeneity includes the substantial
`
`absence of aggregates or conglomerates as is common in conventional mixing and heat
`
`25
`
`drying methods used to form films.
`
`Furthermore, the films of the present invention have a substantially uniform thiclmess,
`
`which is also not provided by the use of conventional drying methods used for drying water(cid:173)
`
`based polymer systems. The absence of a uniform thickness detrimentally affects uniformity
`
`30
`
`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
`
`24
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`heterogeneity of the components within them by utilizing a selected casting or deposition
`
`method and a controlled drying process. Examples of controlled drying processes include,
`
`but are not limited to, the use ofthe apparatus disclosed in U.S. Patent No. 4,631,837 to
`
`Magoon ("Magoon"), herein incorporated by reference, as well as hot air impingement across
`
`5
`
`the bottom substrate and bottom heating plates. Another drying technique for obtaining the
`
`films of the present invention is controlled radiation drying, in the absence of uncontrolled air
`
`currents, such as infrared and radio frequency radiation (i.e. microwaves).
`
`The objective of the drying process is to provide a method of drying the films that
`
`10
`
`avoids complications, such as the noted "rippling" effect, that are associated with
`
`conventional drying methods and which initially dry the upper surface of the film, trapping
`
`moisture inside. In conventional oven drying methods, as the moisture trapped inside
`
`subsequently evaporates, the top surface is altered by being ripped open and then reformed.
`
`These complications are avoided by the present invention, and a uniform film is provided by
`
`15
`
`drying the bottom surface of the film first or otherwise preventing the formation of polymer
`
`film formation (skin) on the top surface of the film prior to drying the depth of the film. This
`
`may be achieved by applying heat to the bottom surface of the film with substantially no top
`
`air flow, or alternatively by the introduction of controlled microwaves to evaporate the water
`
`or other polar solvent within the film, again with substantially no top air flow. Yet
`
`20
`
`alternatively, drying may be achieved by using balanced fluid flow, such as balanced air
`
`flow, where the bottom and top air flows are controlled to provide a uniform film. fu such a
`
`case, the air flow directed at the top of the film should not create a condition which would
`
`cause movement of particles present in the wet film, due to forces generated by the air
`
`currents. Additionally, air currents directed at the bottom of the film should desirably be
`
`25
`
`controlled such that the film does not lift up due to forces from the air. Uncontrolled air
`
`currents, either above or below the film, can create non-uniformity in the final fihn products.
`
`The humidity level of the area surrounding the top surface may also be appropriately adjusted
`
`to prevent premature closure or skinning of the polymer surface.
`
`30
`
`This manner of drying the films provides several advantages. Among these are the
`
`faster drying times and a more uniform surface of the film, as well as uniform distribution of
`
`components for any given area in the film. fu addition, the faster drying time allows viscosity
`
`to quickly build within the film, further encouraging a uniform distribution of components
`
`and decrease in aggregation of components in the final film product. Desirably, the drying of
`
`25
`
`TEVA EXHIBIT 1002
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

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`wo 03/030883
`
`PCTIUS02/32594
`
`the film will occur within about ten minutes or fewer, or more desirably within about five
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`minutes or fewer.
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`The present invention yields exceptionally uniform film products when attention is
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`paid to reducing the aggregation of the compositional components. By avoiding the
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`introduction of and eliminating excessive air in the mixing process, selecting polymers and
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`solvents to provide a controllable viscosity and by drying the fihn in a rapid manner from the
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`bottom up, such films result.
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`10
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`The products and processes of the present invention rely on the interaction among
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`various steps of the production of the films in order to provide films that substantially reduce
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`the self-aggregation ofthe components within the films. Specifically, these steps include the
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`particular method used to form the film, making the composition mixture to prevent air
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`bubble inclusions, controlling the viscosity of the film forming composition and the method
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`of drying the film. More particularly, a greater viscosity of components in the mixture is
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`particularly useful when the active is not soluble in the selected polar solvent in order to
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`prevent the active from settling out. However, the viscosity must not be too great as to hinder
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`or prevent the chosen method of casting, which desirably includes reverse roll coating due to
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`its ability to provide a film of substantially consistent thickness.
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`In addition to the viscosity of the film or film-fonning components or matrix, there
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`are other considerations taken into account by the present invention for achieving desirable
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`film uniformity. For example, stable suspensions are achieved which prevent solid (such as
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`drug particles) sedimentation in non-colloidal applications. One approach provided by the
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`25
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`present invention is to balance the density of the particulate (pp) and the liquid phase (PI) and
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`increase the viscosity of the liquid phase (J..L). For an isolated particle, Stokes law relates the
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`tem1inal settling velocity (V o) of a rigid spherical body of radius (r) in a viscous fluid, as
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`follows:
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`At high particle concentrations, however, the local particle concentration will affect
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`the local viscosity and density. The viscosity of the suspension is a strong function of solids
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`volume fraction, and particle-particle and particle-liquid interactions will further hinder
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`settling velocity.
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`26
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`TEVA EXHIBIT 1002
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`

`wo 03/030883
`
`PCTIUS02/32594
`
`Stokian analyses has shown that the incorporation of a third phase, dispersed air or
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`nitrogen, for example, promotes suspension stability. Further, increasing the number of
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`particles leads to a hindered settling effect based on the solids volume fraction. In dilute
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`5
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`particle suspensions, the rate of sedimentation, v, can be expressed as:
`vNo = 1/(1 + K<p)
`where K =a constant, and <pis the volume fraction of the dispersed phase. More particles
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`suspended in the liquid phase results in decreased velocity. Particle geometry is also an
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`important factor since the particle dimensions will affect particle-particle flow interactions.
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`10
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`Similarly, the viscosity of the suspension is dependent on the volume fraction of
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`dispersed solids. For dilute suspensions of non-interaction spherical particles, an expression
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`for the suspension viscosity can be expressed as:
`j..t/1-lo = 1 + 2.5cp
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`where J.!o is the viscosity ofthe continuous phase and cp is the solids volume fraction. At
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`higher volume fractions, the viscosity of the dispersion can be expressed as
`J.!ll-Lo = 1 + 2.5<p + C1 <p2 + C2<p3 + .....
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`where C is a constant.
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`The viscosity of the liquid phase is critical and is desirably modified by customizing
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`the liquid composition to a viscoelastic non-Newtonian fluid with low yield stress values.
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`This is the equivalent of producing a high viscosity continuous phase at rest. Formation of a
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`viscoelastic or a highly structured fluid phase provides additional resistive forces to particle
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`sedimentation. Further, flocculation or aggregation can be controlled minimizing particle(cid:173)
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`particle interactions. The net effect would be the preservation of a homogeneous dispersed
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`phase.
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`The addition ofhydrocolloids to the aqueous phase ofthe suspension increases
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`viscosity, may produce viscoelasticity and can impart stability depending on the type of
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`hydrocolloid, its concentration and the particle composition, geometry, size, and volume
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`fraction. The particle size distribution of the dispersed phase needs to be controlled by
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`selecting the smallest realistic particle size in the high viscosity medium, i.e., <500J.!m. The
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`presence of a slight yield stress or elastic body at low shear rates may also induce permanent
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`stability regardless of the apparent viscosity. The critical particle diameter can be calculated
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`27
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`TEVA EXHIBIT 1002
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`

`wo 03/030883
`
`PCTIUS02/32594
`
`from the yield stress values. h1 the case of isolated spherical particles, the maximum shear
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`stress developed in settling through a medium of given viscosity can be given as
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`'