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`It has also been observed that certain polymers which when used alone would
`
`ordinarily require a plasticizer to achieve a flexible film, can be combined without a
`
`plasticizer and yet achieve flexible films. For example, HPMC and HPC when used in
`
`combination provide a flexible, strong film with the appropriate plasticity and elasticity for
`
`5 manufacturing and storage. No' additional plasticizer or polyalcohol is needed for flexibility.
`
`Controlled Release Films
`
`The term "controlled release" is intended to mean the release of active at a pre(cid:173)
`
`selected or desired rate. This rate will vary depending upon the application. Desirable rates
`
`10
`
`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. Pulsed drug releases are also contemplated.
`
`The polymers that are chosen for the films of the present invention may also be
`
`15
`
`chosen to allow for controlled disintegration ofthe 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
`
`20
`
`soluble film matrix to achieve the controlled release property of the active inside the digestive
`
`system upon consumption.
`
`Films that provide a controlled release of the active are particularly useful for buccal,
`
`gingival, sublingual and vaginal applications. The films of the present invention are
`
`25
`
`particularly useful where mucosal membranes or mucosal fluid is present due to their ability
`
`to readily wet and adhere to these areas.
`
`The convenience of administering a single dose of a medication which releases active
`
`ingredients in a controlled fashion over an extended period of time as opposed to the
`
`30
`
`administration of a number of single doses at regular intervals has long been recognized in
`
`the 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
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`addition to those well-known for controlled release tablets. For example, thin films are
`
`difficult to inadvertently aspirate and provide an increased patient compliance because they
`
`need not be swallowed like a tablet. Moreover, certain embodiments ofthe inventive films
`
`are designed to adhere to the buccal cavity and tongue, where they controllably dissolve.
`
`5
`
`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.
`
`The actives employed in the present invention may be incorporated into the film
`
`compositions of the present invention in a controlled release form. For example, particles of
`
`10
`
`drug may be coated with polymers such as ethyl cellulose or polymethacrylate, commercially
`
`available under brand names such as Aquacoat ECD and Eudragit E-1 00, respectively.
`
`Solutions of drug may also be absorbed on such polymer materials and incorporated into the
`
`inventive film compositions. Other components such as fats and waxes, as well as
`
`sweeteners and/or flavors may also be employed in such controlled release compositions.
`
`15
`
`The actives may be taste-masked prior to incorporation into the film composition, as
`
`set forth in co-pending PCT application titled, Uniform Films For Rapid Dissolve Dosage
`
`Form Incorporating Taste-Masking Compositions, (based on U.S. Provisional Application
`
`No. Express Mail Label No.: EU552991605 US ofthe same title, filed September 27, 2003,
`
`20
`
`attorney docket No. 1199-15P) the entire subject matter ofwhich is incorporated by reference
`
`herein.
`
`Actives
`
`When an active is introduced to the film, the amount of active per unit area is
`
`25
`
`determined by the uniform distribution of the 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
`
`30 medicament, i.e. a drug.
`
`The active components that may be incorporated into the films of the present
`
`invention include, without limitation pharmaceutical and cosmetic actives, drugs,
`
`medicaments, antigens or allergens such as ragweed pollen, spores, microorganisms, seeds,
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`mouthwash components, flavors, fragrances, enzymes, preservatives, sweetening agents,
`
`colorants, spices, vitamins and combinations thereof.
`
`A wide variety of medicaments, bioactive active substances and pharmaceutical
`
`5
`
`compositions may be included in the dosage forms of the present invention. Examples of
`
`useful drugs include ace-inhibitors, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti(cid:173)
`
`cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic
`
`agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti(cid:173)
`
`inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-
`
`10
`
`thyroid preparations, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid
`
`preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations,
`
`systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents,
`
`anti-rheumatic agents, appetite stimulants, biological response modifiers, blood modifiers,
`
`bone metabolism regulators, cardiovascular agents, central nervous system stimulates,
`
`15
`
`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,
`
`20
`
`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,
`
`25
`
`peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors,
`
`migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti(cid:173)
`
`coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants,
`
`neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid
`
`preparations, diuretics, anti-spasmodics, terine relaxants, anti-obesity drugs, erythropoietic
`
`30
`
`drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs,
`
`and combinations thereof.
`
`Examples of medicating active ingredients contemplated for use in the present
`
`invention include antacids, H2-antagonists, and analgesics. For example, antacid dosages can
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`be prepared using the ingredients calcium carbonate alone or in combination with magnesium
`
`hydroxide, and/or aluminum hydroxide. Moreover, antacids can be used in combination with
`
`H2-antagonists.
`
`5
`
`Analgesics include opiates and opiate derivatives, such as oxycodone (available as
`
`Oxycontin®), ibuprofen, aspirin, acetaminophen, and combinations thereof that may
`
`optionally include caffeine.
`
`Other preferred drugs for other preferred active ingredients for use in the present
`
`10
`
`invention include anti-diarrheals such as immodium AD, anti-histamines, anti-tussives,
`
`decongestants, vitamins, and breath fresheners. Common drugs used alone or in combination
`
`for colds, pain, fever, cough, congestion, runny nose and allergies, such as acetaminophen,
`
`chlorpheniramine maleate, dextromethorphan, pseudoephedrine HCl and diphenhydramine
`
`may be included in the film compositions of the present invention.
`
`15
`
`Also contemplated for use herein are anxiolytics such as alprazolam (available as
`
`Xanax®); anti-psychotics such as clozopin (available as Clozaril®) and haloperidol
`
`(available as Haldol®); non-steroidal anti-inflammatories (NSAID's) such as dicyclofenacs
`
`(available as Voltaren®) and etodolac (available as Lodine®), anti-histamines such as
`
`20
`
`loratadine (available as Claritin®), astemizole (available as Hismanal™), nabumetone
`
`(available as Relafen®), and Clemastine (available as Tavist®); anti-emetics such as
`
`granisetron hydrochloride (available as Kytril®) and nabilone (available as Cesamet™);
`
`bronchodilators such as Bentolin®, albuterol sulfate (available as Proventil®); anti(cid:173)
`
`depressants such as fluoxetine hydrochloride (available as Prozac®), sertraline hydrochloride
`
`25
`
`(available as Zoloft®), and paroxtine hydrochloride (available as Paxil®); anti-migraines
`
`such as Imigra®, ACE-inhibitors such as enalaprilat (available as Vasotec®), captopril
`
`(available as Capoten®) and lisinopril (available as Zestril®); anti-Alzheimer's agents, such
`
`as nicergoline; and CaH-antagonists such as nifedipine (available as Procardia® and
`
`Adalat®), and verapamil hydrochloride (available as Calan®).
`
`30
`
`Erectile dysfunction therapies include, but are not limited to, drugs for facilitating
`
`blood flow to the penis, and for effecting autonomic nervous activities, such as increasing
`
`parasympathetic (cholinergic) and decreasing sympathetic (adrenersic) activities. Useful
`
`non-limiting drugs include sildenafils, such as Viagra®, tadalafils, such as Cialis®,
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`vardenafils, apomorphines, such as Uprima®, yohimbine hydrochlorides such as
`
`Aphrodyne®, and alprostadils such as Caveiject®.
`
`The popular H2-antagonists which are contemplated for use in the present invention
`
`5
`
`include cimetidine, ranitidine hydrochloride, famotidine, nizatidien, ebrotidine, mifentidine,
`
`roxatidine, pisatidine and aceroxatidine.
`
`Active antacid ingredients include, but are not limited to, the following: aluminum
`
`hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate,
`
`10
`
`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
`
`15
`
`solids, aluminum mono-ordibasic calcium phosphate, tricalcium phosphate, potassium
`
`bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicates, tartaric acids
`
`and salts.
`
`The pharmaceutically active agents employed in the present invention may include
`
`20
`
`allergens or antigens, such as , but not limited to, plant pollens from grasses, trees, or
`
`ragweed; animal danders, which are tiny scales shed from the skin and hair of cats and other
`
`furred animals; insects, such as house dust mites, bees, and wasps; and drugs, such as
`
`penicillin.
`
`25
`
`An anti-oxidant may also be added to the film to prevent the degradation of an active,
`
`especially where the active is photosensitive.
`
`Cosmetic active agents may include breath freshening compounds like menthol, other
`
`flavors or fragrances, especially those used for oral hygiene, as well as actives used in dental
`
`30
`
`and oral cleansing such as quaternary ammonium bases. The effect of flavors may be
`
`enhanced using flavor enhancers like tartaric acid, citric acid, vanillin, or the like.
`
`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
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`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.
`
`Other examples of coloring agents include known azo dyes, organic or inorganic
`
`5
`
`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.
`
`10
`
`Flavors may be chosen from natural and synthetic flavoring liquids. An illustrative
`
`list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils,
`
`liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and
`
`combinations thereof. A non-limiting representative list of examples includes mint oils,
`
`cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences
`
`15
`
`including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or
`
`other fruit flavors.
`
`The films containing flavorings may be added to provide a hot or cold flavored drink
`
`or soup. These flavorings include, without limitation, tea and soup flavorings such as beef
`
`20
`
`and chicken.
`
`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
`
`25
`
`(citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), and 2-
`
`dodecenal (citrus, mandarin), combinations thereof and the like.
`
`The sweeteners may be chosen from the following non-limiting list: glucose (com
`
`syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various
`
`30
`
`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-
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`K), and sodium and calcium salts thereof, and natural intensive sweeteners, such as Lo Han
`
`Kuo. Other sweeteners may also be used.
`
`When the active is combined with the polymer in the solvent, the type of matrix that
`
`5
`
`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, ifthe
`
`components are not soluble, the matrix may be classified as an emulsion, a colloid, or a
`
`suspension.
`
`10 Dosages
`
`The film products of the present invention are capable of accommodating a wide
`
`range of amounts ofthe active ingredient. The films are capable ofproviding 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
`
`15
`
`extremely low. Therefore, depending on the type of active or pharmaceutical composition
`
`that is incorporated into the film, the active amount may be as high as about 300mg, desirably
`
`up to about 150mg or as low as the microgram range, or any amount therebetween.
`
`The film products and methods of the present invention are well suited for high
`
`20
`
`potency, low dosage drugs. This is accomplished through the high degree of uniformity of
`
`the films. Therefore, low dosage drugs, particularly more potent racemic mixtures of actives
`
`are desirable.
`
`Anti-foaming and De-foaming Compositions
`
`25
`
`Anti-foaming and/or de-foaming components may also be used with the films ofthe
`
`present invention. These components aid in the removal of air, such as entrapped air, from
`
`the film-forming compositions. As described above, such entrapped air may lead to non(cid:173)
`
`uniform films. Simethicone is one particularly useful anti-foaming and/or de-foaming agent.
`
`The present invention, however, is not so limited and other anti-foam and/or de-foaming
`
`30
`
`agents may suitable be used.
`
`Simethicone is generally used in the medical field as a treatment for gas or colic in
`
`babies. Simethicone is a mixture of fully methylated linear siloxane polymers containing
`
`repeating units of polydimethylsiloxane which is stabilized with trimethylsiloxy end-blocking
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`unites, and silicon dioxide. It usually contains 90.5-99% polymethylsiloxane and 4-7%
`
`silicon dioxide. The mixture is a gray, translucent, viscous fluid which is insoluble in water.
`
`When dispersed in water, simethicone will spread across the surface, forming a thin
`
`5
`
`film of low surface tension. In this way, simethicone reduces the surface tension of bubbles
`
`air located in the solution, such as foam bubbles, causing their collapse. The function of
`
`simethicone mimics the dual action of oil and alcohol in water. For example, in an oily
`
`solution any trapped air bubbles will ascend to the surface and dissipate more quickly and
`
`easily, because an oily liquid has a lighter density compared to a water solution. On the other
`
`I 0
`
`hand, an alcohol/water mixture is known to lower water density as well as lower the water's
`
`surface tension. So, any air bubbles trapped inside this mixture solution will also be easily
`
`dissipated. Simethicone solution provides both of these advantages. It lowers the surface
`
`energy of any air bubbles that trapped inside the aqueous solution, as well as lowering the
`
`surface tension ofthe aqueous solution. As the result ofthis unique
`
`15
`
`functionality, simethicone has an excellent anti-foaming property that can be used for
`
`physiological processes (anti-gas in stomach) as well as any for external processes that
`
`require the removal of air bubbles from a product.
`
`In order to prevent the formation of air bubbles in the films of the present invention,
`
`20
`
`the mixing step can be performed under vacuum. However, as soon as the mixing step is
`
`completed, and the film solution is returned to the normal atmosphere condition, air will be
`
`re-introduced into or contacted with the mixture. In many cases, tiny air bubbles will be
`
`again trapped inside this polymeric viscous solution. The incorporation of simethicone into
`
`the film-forming composition either substantially reduces or eliminates the formation of air
`
`25
`
`bubbles.
`
`Simethicone may be added to the film-forming mixture as an anti-foaming agent in an
`
`amount from about 0.01 weight percent to about 5.0 weight percent, more desirably from
`
`about 0. 05 weight percent to about 2.5 weight percent, and most desirably from about 0. 1
`
`30 weight percent to about 1.0 weight percent.
`
`Optional Components
`
`A variety of other components and fillers may also be added to the films of the
`
`present invention. These may include, without limitation, surfactants; plasticizers which
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`assist in compatibilizing the components within the mixture; polyalcohols; anti-foaming
`
`agents, such as silicone-containing compounds, which promote a smoother film surface by
`
`releasing oxygen from the film; and thermo-setting gels such as pectin, carageenan, and
`
`gelatin, which help in maintaining the dispersion of components.
`
`5
`
`The variety of additives that can be incorporated into the inventive compositions may
`
`provide a variety of different functions. Examples of classes of additives include excipients,
`
`lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents, fillers,
`
`bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants,
`
`10
`
`plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents,
`
`binders, buffers, absorbents, glidants, adhesives, anti-adherents, acidulants, softeners, resins,
`
`demulcents, solvents, surfactants, emulsifiers, elastomers and mixtures thereof. These
`
`additives may be added with the active ingredient(s).
`
`15
`
`Useful additives include, for example, gelatin, vegetable proteins such as sunflower
`
`protein, soybean proteins, cotton seed proteins, peanut proteins, grape seed proteins, whey
`
`proteins, whey protein isolates, blood proteins, egg proteins, acrylated proteins, water-soluble
`
`polysaccharides such as alginates, carrageenans, guar gum, agar-agar, xanthan gum, gellan
`
`gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragancanth), pectin, water-
`
`20
`
`soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and
`
`hydroxyalkylalkylcelluloses, such as methylcelulose, hydroxymethylcellulose,
`
`hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose,
`
`hydroxypropylmethylcellulose, hydroxybutylrnethylcellulose, cellulose esters and
`
`hydroxyalkylcellulose esters such as cellulose acetate phthalate (CAP),
`
`25
`
`hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses,
`
`carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxyrnethylcellulose
`
`and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acids and
`
`polyacrylic acid esters, polymethacrylic acids and polymethacrylic acid esters,
`
`polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PV AP),
`
`30
`
`polyvinylpyrrolidone (PVP), PVY/vinyl acetate copolymer, and polycrotonic acids; also
`
`suitable are phthalated gelatin, gelatin succinate, crosslinked gelatin, shellac, water soluble
`
`chemical derivatives of starch, cationically modified acrylates and methacrylates possessing,
`
`for example, a tertiary or quaternary amino group, such as the diethylaminoethyl group,
`
`which may be quaternized if desired; and other similar polymers.
`
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`Such extenders may optionally be added in any desired amount desirably within the
`
`range of up to about 80%, desirably about 3% to 50% and more desirably within the range of
`
`3% to 20% based on the weight of all components.
`
`5
`
`Further additives may be inorganic fillers, such as the oxides of magnesium
`
`aluminum, silicon, titanium, etc. desirably in a concentration range of about 0.02% to about
`
`3% by weight and desirably about 0.02% to about 1% based on the weight of all components.
`
`Further examples of additives are plasticizers which include polyalkylene oxides,
`
`10
`
`such as polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, organic
`
`plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or
`
`triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium
`
`diethylsulfosuccinate, triethyl citrate, tributyl citrate, and the like, added in concentrations
`
`ranging from about 0.5% to about 30%, and desirably ranging from about 0.5% to about 20%
`
`15
`
`based on the weight of the polymer.
`
`There may further be added compounds to improve the flow properties of the starch
`
`material such as animal or vegetable fats, desirably in their hydrogenated form, especially
`
`those which are solid at room temperature. These fats desirably have a melting point of 50°C
`or higher. Preferred are tri-glycerides with C 12-, C14-, C16-, C1s-, C20- and C22- fatty acids.
`These fats can be added alone without adding extenders or plasticizers and can be
`
`advantageously added alone or together with mono- and/or di-glycerides or phosphatides,
`
`especially lecithin. The mono- and di-glycerides are desirably derived from the types of fats
`
`described above, i.e. with C12-, C14-, C16-, C1s-, Czo- and Czz- fatty acids.
`
`20
`
`25
`
`The total amounts used of the fats, mono-, di-glycerides and/or lecithins are up to
`
`about 5% and preferably within the range of about 0.5% to about 2% by weight of the total
`
`composition
`
`30
`
`It is further useful to add silicon dioxide, calcium silicate, or titanium dioxide in a
`
`concentration of about 0.02% to about 1% by weight of the total composition. These
`
`compounds act as texturizing agents.
`
`TEVA EXHIBIT 1002
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

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`wo 03/030882
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`33
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`PCT/US02/32575
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`These additives are to be used in amounts sufficient to achieve their intended purpose.
`
`Generally, the combination of certain of these additives will alter the overall release profile of
`
`the active ingredient and can be used to modify, i.e. impede or accelerate the release.
`
`5
`
`Lecithin is one surface active agent for use in the present invention. Lecithin can be
`
`included in the feedstock in an amount of from about 0.25% to about 2.00% by weight.
`
`Other surface active agents, i.e. surfactants, include, but are not limited to, cetyl alcohol,
`
`sodium lauryl sulfate, the Spans™ and Tweens™ which are commercially available from ICI
`
`Americas, Inc. Ethoxylated oils, including ethoxylated castor oils, such as Cremophor® EL
`
`10 which is commercially available from BASF, are also useful. Carbowax™ is yet another
`
`modifier which is very useful in the present invention. Tweens™ or combinations of surface
`
`active agents may be used to achieve the desired hydrophilic-lipophilic balance ("HLB").
`
`The present invention, however, does not require the use of a surfactant and films or film(cid:173)
`
`forming compositions of the present invention may be essentially free of a surfactant while
`
`15
`
`still providing the desirable uniformity features of the present invention.
`
`As additional modifiers which enhance the procedure and product of the present
`
`invention are identified, Applicants intend to include all such additional modifiers within the
`
`scope of the invention claimed herein.
`
`Other ingredients include binders which contribute to the ease of formation and
`
`general quality of the films. Non-limiting examples ofbinders include starches, pregelatinize
`
`starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose,
`
`ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.
`
`20
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`25
`
`Forming the Film
`
`The films of the present invention must be formed into a sheet prior to drying. After
`
`the desired components are combined to form a multi-component matrix, including the
`
`polymer, water, and an active or other components as desired, the combination is formed into
`
`30
`
`a sheet or film, by any method known in the art such as extrusion, coating, spreading, casting
`
`or drawing the multi-component matrix. If a multi-layered film is desired, this may be
`
`accomplished by co-extruding more than one combination of components which may be of
`
`the same or different composition. A multi-layered film may also be achieved by coating,
`
`spreading, or casting a combination onto an already formed film layer.
`
`TEVA EXHIBIT 1002
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

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`wo 03/030882
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`34
`
`PCTIUS02/32575
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`Although a variety of different film-forming techniques may be used, it is desirable to
`
`select a method that will provide a flexible film, such as reverse roll coating. The flexibility
`
`ofthe film allows for the sheets of film to be rolled and transported for storage or prior to
`
`being cut into individual dosage forms. Desirably, the films will also be self-supporting or in
`
`5
`
`other words able to maintain their integrity and structure in the absence of a separate support.
`
`Furthermore, the films of the present invention may be selected of materials that are edible or
`
`ingestible.
`
`Coating or casting methods are particularly useful for the purpose of forming the
`
`10
`
`films of the present invention. Specific examples include reverse roll coating, gravure
`
`coating, immersion or dip coating, metering rod or meyer bar coating, slot die or extrusion
`
`coating, gap or knife over roll coating, air knife coating, curtain coating, or combinations
`
`thereof, especially when a multi-layered film is desired.
`
`15
`
`Roll coating, or more specifically reverse roll coating, is particularly desired when
`
`forming films in accordance with the present invention. This procedure provides excellent
`
`control and uniformity of the resulting films, which is desired in the present invention. In this
`
`procedure, the coating material is measured onto the applicator roller by the precision setting
`
`of the gap between the upper metering roller and the application roller below it. The coating
`
`20
`
`is transferred from the application roller to the substrate as it passes around the support roller
`
`adjacent to the application roller. Both three roll and four roll processes are common.
`
`The gravure coating process relies on an engraved roller running in a coating bath,
`
`which fills the engraved dots or lines of the roller with the coating material. The excess
`
`25
`
`coating on the roller is wiped off by a doctor blade and the coating is then deposited onto the
`
`substrate as it passes between the engraved roller and a pressure roller.
`
`Offset Gravure is common, where the coating is deposited on an intermediate roller
`
`before transfer to the substrate.
`
`30
`
`In the simple process of immersion or dip coating, the substrate is dipped into a bath
`
`of the coating, which is normally of a low viscosity to enable the coating to run back into the
`
`bath as the substrate emerges.
`
`TEVA EXHIBIT 1002
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

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`wo 03/030882
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`35
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`PCT/US02/32575
`
`In the metering rod coating process, an excess of the coating is deposited onto the
`
`substrate as it passes over the bath roller. The wire-wound metering rod, sometimes known
`
`as a Meyer Bar, allows the desired quantity of the coating to remain on the substrate. The
`
`quantity is determined by the diameter of the wire used on the rod.
`
`In the slot die process, the coating is squeezed out by gravity or under pressure
`
`through a slot and onto the substrate. If the coating is 1 00% solids, the process is termed
`
`"Extrusion" and in this case, the line speed is frequently much faster than the speed of the
`
`extrusion. This enables coatings to be considerably thinner than the width of the slot.
`
`5
`
`10
`
`The gap or knife over roll process relies on a coating being applied to the substrate
`
`which then passes through a "gap" between a "knife" and a support roller. As the coating and
`
`substrate pass through, the excess is scraped off.
`
`15
`
`Air knife coating is where the coating is applied to the substrate and the excess is
`
`"blown off' by a powerful jet from the air knife. This procedure is useful for aqueous
`
`coatings.
`
`In the curtain coating process, a bath with a slot in the base allows a continuous
`
`20
`
`curtain of the coating to fall into the gap between two conveyors. The object to be coated is
`
`passed along the conveyor at a controlled speed and so receives the coating on its upper