(12)
`
`United States Patent
`Bess et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,067,116 B1
`*Jun. 27, 2006
`
`US007067116B1
`
`(54) FAST DISSOLVING ORALLY CONSUMABLE
`SOLID FILM CONTAINING A TASTE
`MASKING AGENT AND
`PHARMACEUTICALLY ACTIVE AGENT AT
`WEIGHT RATIO 0F 13 T0 31
`
`-
`
`-
`
`5,700,478 A 12/1997 Biegajski et a1.
`5,948,430 A
`9/1999 Zerbe et a1.
`5,980,882 A 11/1999 Eichman
`$1
`If‘;
`gin ettali
`6,596,298 B1 *
`7/2003 Leung et a1. ............. .. 424/435
`
`en e a .
`
`,
`
`,
`
`,
`,
`.
`(75) Inventors: William S. Bess,.Ed1son, NJ (U S);
`Neema Klllkarfll, Randolph, NJ (Us);
`Suhas H-Amblke, WPSt H111 (CA);
`Michael P. Ramsay, Ajax (CA)
`
`(73) Assignee: Warner-Lambert Company LLC,
`Morris Plains, NJ (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`Claimer
`'
`
`_
`(21) Appl. No.. 09/535,005
`.
`(22) F1led:
`
`Mar. 23, 2000
`
`(51) Int- Cl-
`(2006-01)
`A61K 9/14
`(2006.01)
`A61K 31/74
`(2006.01)
`A61K 31/785
`(52) us. Cl. ............. .. 424/78.1; 424/78.11; 424/78.12;
`424/483; 424/23
`
`_
`_
`_
`(58) Field of Classi?cation Search ................ .. 514/23,
`514/54, 289, 850; 424/9, 78.1, 78.11, 78.12,
`424/483
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5/1969 Russell
`3,444,858 A
`1/1979 Fuchs et a1.
`4,136,145 A
`4/1980 SturZenegger et 31.
`4,197,289 A
`9/1980 Raghunathan
`4,221,778 A
`4,562,020 A 12/1985 Hijiya et a1.
`4,623,394 A ll/l986 Nakamura et a1.
`4,713,243 A * 12/1987 Schiraldi et a1. .......... .. 424/676
`4,762,709 A
`8/1988 Sheumaker
`4,788,055 A ll/l988 Fischer et a1.
`4,820,506 A
`4/1989 Kleinberg et 31.
`4,925,670 A
`5/1990 Schmidt
`4,927,636 A
`5/1990 Hijiya et a1.
`4,996,047 A
`2/1991 Kelleher et a1.
`5,023,082 A
`6/1991 Friedman et a1.
`5,047,244 A
`9/ 1991 Sanvordeker et a1.
`5,354,551 A 10/1994 Schmidt
`5,411,945 A
`5/1995 Ozaki et a1.
`5,456,745 A 10/1995 Roreger et a1.
`5,518,902 A
`5/1996 Ozaki et a1.
`5,529,783 A
`6/1996 Burke et a1.
`5,629,003 A
`5/1997 Horstmann et a1.
`
`l/2003 Leung et a1.
`2003/0008008 A1
`110003 Kulkami et a1‘
`2003/0206942 A1
`2003/0211136 A1 11/2003 Kulkami et a1.
`2004/0136922 A1
`7/2004 Leung et a1.
`
`CA
`CA
`EP
`EP
`EP
`GB
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`W0
`WO
`WO
`W0
`W0
`W0
`WO
`
`FOREIGN PATENT DOCUMENTS
`1313620
`2/1993
`2234282
`4/1998
`0225615
`6/1987
`0 256 611 A1
`2/1988
`0438147
`7/1991
`2055575
`3/1981
`63059855
`3/1988
`63250318
`10/1988
`63250319
`10/1988
`63280014
`ll/l988
`63296655
`12/1988
`63310817
`l2/l988
`63310818
`12/1988
`5001198
`H1993
`41602
`6/1993
`5236885
`9/1993
`10179045
`12/1996
`2642354
`5/1997
`9124512
`5/1997
`‘VG-9841867 A1
`3/1998
`WO-98/20862 Al
`5/1998
`WO9826763
`6/1998
`WO9826780
`@1998
`WO9855079
`12/1998
`W0 9917753
`4/1999
`0042992
`7/2000
`
`OTHER PUBLICATIONS
`Shih, Frederick E, “Edible Films from Rice Protein Con
`centrate and Pullulan,” from Cereal Chemistry, vol. 73, No.
`3, 1996, pp. 406-409.
`
`(Continued)
`Primary ExamineriElli Peselev
`(74) Attorney, Agent, or FirmiBarry H. Jacobsen; Evan J.
`Federrnan
`
`(57)
`
`ABSTRACT
`
`Physiologically acceptable ?lms, including edible ?lms, are
`disclosed. The ?lms include a Water soluble ?lm-forming
`polymer, such as pullulan, and a taste masked pharmaceu
`tically active agent, such as dextromethorphan. The taste
`masking agent is preferably a sulfonated polymer ion
`exchange resin comprising polystyrene cross-linked With
`divinylbenzene, such as AMBERLITE. Methods for produc
`ing the ?lms are also disclosed.
`
`33 Claims, N0 Drawings
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 7,067,116 B1
`Page 2
`
`OTHER PUBLICATIONS
`
`Krochta, John M. and De Mulder-Johnston, Catherine,
`“Edible and Biodegradable Polymer Films: Challenges and
`Opportunities,” from Food Technology, VOl. 51, No. 2, Feb.
`1997, pp. 60-74.
`Patent Abstracts of Japan for patent document JP-62
`135417, Publication Date: Jun. 18, 1987.
`
`Patent Abstracts of Japan for patent document JP-02
`059513, Publication
`Date:
`Feb.
`28,
`1990, and
`XP-002129504, an English translation of Japanese Patent
`No. 41602-1993.
`
`* cited by examiner
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 7,067,116 B1
`
`1
`FAST DISSOLVING ORALLY CONSUMABLE
`SOLID FILM CONTAINING A TASTE
`MASKING AGENT AND
`PHARMACEUTICALLY ACTIVE AGENT AT
`WEIGHT RATIO OF 1:3 TO 3:1
`
`2
`dissolving orally consumable ?lms containing an ion
`exchange resin to mask the taste of a pharmaceutically
`active agent therein.
`All references cited herein are incorporated herein by
`reference in their entireties.
`
`FIELD OF THE INVENTION
`
`SUMMARY OF THE INVENTION
`
`This invention relates to fast dissolving orally consumable
`?lms containing an agent to mask the taste of a pharmaceu
`tically active agent therein, and more speci?cally to such
`?lms containing an ion exchange resin as the taste masking
`agent.
`
`BACKGROUND OF THE INVENTION
`
`It has been knoWn to administer pharmaceutically active
`agents in an edible ?lm vehicle.
`For example, W0 99/ 17753 discloses rapidly dissolving
`?lms for delivery of drugs to be adsorbed in the digestive
`tract.
`WO 98/26780 discloses a ?at, foil, paper or Wafer type
`presentation for the application and release of active sub
`stances in the buccal cavity. The speci?c active ingredient
`disclosed in WO 98/26780 is buprenorphine.
`WO 98/20862 discloses a ?lm for use in the oral cavity
`that can contain a cosmetic or pharmaceutical active sub
`stance.
`WO 98/26763 discloses a ?at, foil, paper or Wafer like
`presentation for release of active substances into the buccal
`cavity. The particular active disclosed is apomorphine.
`US. patent application Ser. No. 09/395,104 also discloses
`the delivery of pharmaceutical agents in a edible ?lm
`vehicle.
`US. Pat. No. 5,411,945 to OZaki et al. discloses a pullulan
`binder and products produced thereWith, including edible
`?lms (Example B-2). The products can include a variety of
`ingredients in addition to pullulan, such as other polysac
`charides, antibacterial agents, ?avor-imparting agents and
`pharmaceutically active substances (column 4, lines 5415).
`US. Pat. No. 3,784,390 Hijiya et al. discloses pullulan
`?lms and their use in coating and packing materials for
`foods, pharmaceuticals and other oxygen sensitive materi
`als. All of the examples in this patent teach mixing pullulan
`in hot Water.
`It has also been knoWn to combine ion exchange resins
`With pharmaceutically active agents to provide sustained
`release formulations.
`For example, US. Pat. No. 6,001,392 to Wen et al.
`discloses a controlled-release syrup suspension for oral
`administration containing dextromethorphan adsorbed to a
`polystyrene sulfonate ion exchange resin. Pharmaceutical
`?lms are not disclosed.
`US. Pat. No. 5,980,882 to Eichman discloses a method
`for improving the stability of a pharmaceutical composition
`that contains a drug-resin complex, comprising adding a
`chelating agent in an amount effective to reduce the rate of
`degradation of the drug in the drug-resin complex. Although
`Eichman teaches that complexing a drug With an ion
`exchange resin can mask the taste of the drug. Pharmaceu
`tical ?lms are not disclosed.
`The inventors are not aWare of any suggestion in the
`published art that ion exchange resins can act as taste
`masking agents in a fast dissolving orally consumable ?lm.
`Accordingly, an object of this invention is to provide fast
`
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`60
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`65
`
`The invention provides a consumable ?lm adapted to
`adhere to and dissolve in a mouth of a consumer, Wherein the
`?lm comprises at least one Water soluble polymer, at least
`one pharmaceutically active agent and at least one taste
`masking agent.
`Also provided is a method for preparing the consumable
`?lm of the invention, comprising:
`dissolving Water-soluble ingredients in Water to provide
`an aqueous solution;
`mixing at least one Water soluble ?lm former and at least
`one stabiliZing agent to provide a ?lm-forming mixture;
`combining the ?lm-forming mixture and the aqueous
`solution to provide a hydrated polymer gel;
`mixing oils to form an oil mixture;
`adding the oil mixture to the hydrated polymer gel and
`mixing to provide a uniform gel;
`casting the uniform gel on a substrate; and
`drying the cast gel to provide the ?lm.
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`The invention provides a physiologically acceptable ?lm
`that is particularly Well adapted to adhere to and dissolve in
`a mouth of a consumer to deliver a pharmaceutically active
`agent. Preferred ?lms according to the invention comprise a
`pharmaceutically active agent, an ion exchange resin, a
`?lm-forming agent, and at least one of the folloWing addi
`tional ingredients: Water, antimicrobial agents, plasticiZing
`agents, ?avoring agents, saliva stimulating agents, cooling
`agents, surfactants, stabiliZing agents, emulsifying agents,
`thickening agents, binding agents, coloring agents, sWeet
`eners, fragrances, triglycerides, preservatives, polyethylene
`oxides, propylene glycol, and the like.
`The expression “physiologically acceptable” as used
`herein is intended to encompass compounds, Which upon
`administration to a patient, are adequately tolerated Without
`causing undue negative side effects. The expression encom
`passes edible compounds.
`The expression “pharmaceutically active agents” as used
`herein is intended to encompass agents other than foods,
`Which promote a structural and/or functional change in
`and/or on bodies to Which they have been administered.
`These agents are not particularly limited; hoWever, they
`should be physiologically acceptable and compatible With
`the ?lm. Suitable pharmaceutically active agents include,
`but are not limited to:
`A. antimicrobial agents, such as triclosan, cetyl pyridium
`chloride, domiphen bromide, quaternary ammonium salts,
`Zinc compounds, sanguinarine, ?uorides, alexidine, octoni
`dine, EDTA, and the like;
`B. non-steroidal anti-in?ammatory drugs, such as aspirin,
`acetaminophen, ibuprofen, ketoprofen, di?unisal, fenopro
`fen calcium, naproxen, tolmetin sodium, indomethacin, and
`the like;
`C. anti-tussives, such as benZonatate, caramiphen edisy
`late, menthol, dextromethorphan hydrobromide, chlophedi
`anol hydrochloride, and the like;
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 7,067,116 B1
`
`3
`D. decongestants, such as pseudoephedrine hydrochlo
`ride, phenylepherine, phenylpropanolamine, pseudoephe
`drine sulfate, and the like;
`E. anti-histamines, such as brompheniramine maleate,
`chlorpheniramine maleate, carbinoxamine maleate, clemas
`tine fumarate, dexchlorpheniramine maleate, diphenhy
`dramine hydrochloride, diphenylpyraline hydrochloride,
`aZatadine meleate, diphenhydramine citrate, doxylamine
`succinate, promethaZine hydrochloride, pyrilamine maleate,
`tripelennamine citrate, triprolidine hydrochloride, acrivas
`tine, loratadine, brompheniramine, dexbrompheniramine,
`and the like;
`F. expectorants, such as guaifenesin, ipecac, potassium
`iodide, terpin hydrate, and the like;
`G. anti-diarrheals, such a loperamide, and the like;
`H. H2-antagonists, such as famotidine, ranitidine, and the
`like;
`I. proton pump inhibitors, such as omepraZole, lansopra
`Zole, and the like;
`J. general nonselective CNS depressants, such as aliphatic
`alcohols, barbiturates and the like;
`K. general nonselective CNS stimulants such as ca?feine,
`nicotine, strychnine, picrotoxin, pentylenetetraZol and the
`like;
`L. drugs that selectively modify CNS function, such as
`phenyhydantoin, phenobarbital, primidone, carbamaZepine,
`ethosuximide, methsuximide, phensuximide, trimethadione,
`diaZepam, benZodiaZepines, phenacemide, pheneturide,
`acetaZolamide, sulthiame, bromide, and the like;
`M. antiparkinsonism drugs such as levodopa, amantadine
`and the like;
`N. narcotic-analgesics such as morphine, heroin, hydro
`morphone, metopon, oxymorphone, levorphanol, codeine,
`hydrocodone, xycodone, nalorphine, naloxone, naltrexone
`and the like;
`0. analgesic-antipyretics such as salycilates, phenylbuta
`Zone, indomethacin, phenacetin and the like; and
`P. psychopharmacological drugs such as chlorpromaZine,
`methotrimepraZine, haloperidol, cloZapine, reserpine, imi
`pramine, tranylcypromine, phenelZine, lithium and the like.
`The amount of pharmaceutically active agent that can be
`used in the rapidly dissolving ?lms, according to the present
`invention, is dependent upon the dose needed to provide an
`effective amount of the pharmaceutically active agent.
`Examples of doses for speci?c pharmaceutically active
`agents that can be delivered per one strip of rapidly dissolv
`ing oral ?lm are revieWed in Table A.
`
`TABLE A
`
`PHARMACEUTICALLY ACTIVE AGENT
`
`PREFERRED DOSE
`
`Chlorpheniralnine Maleate
`Brompheniralnine Maleate
`Dexchlorpheniralnine
`Dexbrompheniralnine
`Triprolidine Hydrochloride
`Acrivastine
`Azatadine Maleate
`Loratidine
`Phenylephrine Hydrochloride
`Dextromethorphan Hydrobromide
`Ketoprofen
`Sumatriptan Succinate
`Zolmitriptan
`Loperalnide
`Falnotidine
`Nicotine
`Diphenhydramine Hydrochloride
`Pseudoephedrine Hydrochloride
`
`4 mg.
`4 mg.
`2 mg
`2 mg
`2.5 mg
`8 mg
`1 mg
`10 mg
`10 mg
`10430 mg
`12.5425 mg
`35470 mg
`2.5 mg
`2 mg
`10 mg
`2 mg
`12.5425 mg
`30 mg
`
`4
`Ion exchange resins preferred for use in the ?lms of the
`invention are Water-insoluble and consist of a pharmaco
`logically inert organic or inorganic matrix containing
`covalently bound functional groups that are ionic or capable
`of being ioniZed under the appropriate conditions of pH. The
`organic matrix may be synthetic (e.g., polymers or copoly
`mers of acrylic acid, methacrylic acid, sulfonated styrene,
`sulfonated divinylbenZene), or partially synthetic (e.g.,
`modi?ed cellulose and dextrans). The inorganic matrix can
`also be, e.g., silica gel modi?ed by the addition of ionic
`groups. The covalently bound ionic groups may be strongly
`acidic (e.g., sulfonic acid), Weakly acidic (e.g., carboxylic
`acid), strongly basic (e.g., quaternary ammonium), Weakly
`basic (e.g., primary amine), or a combination of acidic and
`basic groups. In general, those types of ion exchangers
`suitable for use in ion exchange chromatography and for
`such applications as deioniZation of Water are suitable for
`use in these controlled release drug preparations. Such ion
`exchangers are described by H. F. Walton in “Principles of
`Ion Exchange” (pp. 3124343). The ion exchange resins
`useful in the present invention have exchange capacities
`beloW about 6 milliequivalents per gram (meq/ g) and pref
`erably beloW about 5.5 meq/g.
`The resin is crosslinked With a crosslinking agent selected
`from difunctional compounds capable of crosslinking poly
`styrenes; these are commonly knoWn in the art. Preferably,
`the crosslinking agent is a divinyl or polyvinyl compound.
`Most preferably the crosslinking agent is divinylbenZene.
`The resin is crosslinked to an extent of about 3 to about 20%,
`preferably about 4 to about 16%, more preferably about 6 to
`about 10%, and most preferably about 8% by Weight based
`on the total resin. The resin is crosslinked With the crosslink
`ing agent by means Well knoWn in the art.
`The siZe of the ion exchange resins should preferably fall
`Within the range of about 20 to about 200 micrometers.
`Particle siZes substantially beloW the loWer limit are di?icult
`to handle in all steps of the processing. Particle siZes
`substantially above the upper limit, e.g., commercially avail
`able ion exchange resins having a spherical shape and
`diameters up to about 1000 micrometers, are gritty in liquid
`dosage forms and have a greater tendency to fracture When
`subjected to drying-hydrating cycles.
`Representative resins useful in this invention include
`AMBERLITE lRP-69 (obtained from Rohm and Haas) and
`Bow XYS-40010.00 (obtained from The DoW Chemical
`Company). Both are sulfonated polymers composed of
`polystyrene cross-linked With 8% of divinylbenZene, With an
`ion exchange capacity of about 4.5 to 5.5 meq/g of dry resin
`(H+-form). Their essential difference is in physical form.
`AMBERLITE lRP-69 comprises irregularly-shaped par
`ticles With a siZe range of 47 to 149 micrometers, produced
`by milling the parent, large-siZed spheres of AMBERLITE
`lRP-120. The DoW XYS-40010.00 product comprises
`spherical particles With a siZe range of 45 to 150 microme
`ters. Another useful exchange resin, DoW XYS-40013.00, is
`a polymer composed of polystyrene cross-linked With 8% of
`divinylbenZene and functionaliZed With a quaternary ammo
`nium group; its exchange capacity is normally Within the
`range of approximately 3 to 4 meq/g of dry resin.
`The most preferred resin is AMBERLITE lRP-69. HoW
`ever, in less preferred embodiments, the taste masking agent
`need not be an ion exchange resin. In these embodiments,
`the taste masking agent can be, e.g., magnesium trisilicate.
`See, e.g., US. Pat. Nos. 4,650,663 and 4,581,232 to Peters
`et al. Taste can also be masked by polymers, such as
`EUDRAGIT E (Rohm and Haas), and/ or cellulosics, such as
`ethylcellulose, and the like.
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`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 7,067,116 B1
`
`5
`The ?lm-forming agent used in the ?lms according to the
`present invention can be selected from the group consisting
`of pullulan, hydroxypropylmethyl cellulose, hydroxyethyl
`cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone,
`carboxymethyl cellulose, polyvinyl alcohol, sodium algi
`nate, polyethylene glycol, xanthan gum, tragacanth gum,
`guar gum, acacia gum, arabic gum, polyacrylic acid, meth
`ylmethacrylate copolymer, carboxyvinyl polymer, amylose,
`high amylose starch, hydroxypropylated high amylose
`starch, dextrin, pectin, chitin, chitosan, levan, elsinan, col
`lagen, gelatin, Zein, gluten, soy protein isolate, Whey protein
`isolate, casein and mixtures thereof. A preferred ?lm former
`is pullulan, in amounts ranging from about 0.01 to about 99
`Wt %, preferably about 30 to about 80 Wt %, more preferably
`from about 45 to about 70 Wt % of the ?lm and even more
`preferably from about 60 to about 65 Wt % of the ?lm.
`Unless speci?ed otherWise, the term “Wt %” as used
`herein With reference to the ?nal product (i.e., the ?lm, as
`opposed to the formulation used to create it), denotes the
`percentage of the total dry Weight contributed by the subject
`ingredient. This theoretical value can differ from the experi
`mental value, because in practice, the ?lm typically retains
`some of the Water and/or ethanol used in preparation.
`In embodiments containing relatively high oil content, it
`is preferable to avoid substantial amounts of humectant in
`the ?lm (and more preferable to have no humectant in the
`?lm), so as to avoid producing an overly moist, self
`adhering ?lm. In particular, it is preferred to formulate high
`oil content ?lms With a plasticiZing agent other than glyc
`erin, Which is also a humectant, and With a sWeetener other
`than sorbitol, Which is a mild humectant.
`Saliva stimulating agents can also be added to the ?lms
`according to the present invention. Useful saliva stimulating
`agents are those disclosed in US. Pat. No. 4,820,506. Saliva
`stimulating agents include food acids such as citric, lactic,
`malic, succinic, ascorbic, adipic, fumaric and tartaric acids.
`Preferred food acids are citric, malic and ascorbic acids. The
`amount of saliva stimulating agents in the ?lm is from about
`0.01 to about 12 Wt %, preferably about 1 Wt % to about 10
`Wt %, even more preferably about 2.5 Wt % to about 6 Wt %.
`Preferred plasticiZing agents include triacetin in amounts
`ranging from about 0 to about 20 Wt %, preferably about 0
`to about 2 Wt %. Other suitable plasticiZing agents include
`monoacetin and diacetin.
`Preferred cooling agents include monomenthyl succinate,
`in amounts ranging from about 0.001 to about 2.0 Wt %,
`preferably about 0.2 to about 0.4 Wt %. A monomenthyl
`succinate containing cooling agent is available from Mane,
`Inc. Other suitable cooling agents include WS3, WS23,
`Ultracool II and the like.
`Preferred surfactants include mono and diglycerides of
`fatty acids and polyoxyethylene sorbitol esters, such as,
`Atmos 300 and Polysorbate 80. The surfactant can be added
`in amounts ranging from about 0.5 to about 15 Wt %,
`preferably about 1 to about 5 Wt % of the ?lm. Other suitable
`surfactants include pluronic acid, sodium lauryl sulfate, and
`the like.
`Preferred stabiliZing agents include xanthan gum, locust
`bean gum and carrageenan, in amounts ranging from about
`0 to about 10 Wt %, preferably about 0.1 to about 2 Wt % of
`the ?lm. Other suitable stabiliZing agents include guar gum
`and the like.
`Preferred emulsifying agents include triethanolamine
`stearate, quaternary ammonium compounds, acacia, gelatin,
`lecithin, bentonite, veegum, and the like, in amounts ranging
`from about 0 to about 5 Wt %, preferably about 0.01 to about
`0.7 Wt % of the ?lm.
`
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`6
`Preferred thickening agents include methylcellulose, car
`boxyl methylcellulose, and the like, in amounts ranging
`from about 0 to about 20 Wt %, preferably about 0.01 to
`about 5 Wt %.
`Preferred binding agents include starch, in amounts rang
`ing from about 0 to about 10 Wt %, preferably about 0.01 to
`about 2 Wt % of the ?lm.
`Suitable sWeeteners that can be included are those Well
`knoWn in the art, including both natural and arti?cial sWeet
`eners. Suitable sWeeteners include, e.g.:
`A. Water-soluble sWeetening agents such as monosaccha
`rides, disaccharides and polysaccharides such as xylose,
`ribose, glucose (dextrose), mannose, galactose, fructose
`(levulose), sucrose (sugar), maltose, invert sugar (a mixture
`of fructose and glucose derived from sucrose), partially
`hydrolyZed starch, corn syrup solids, dihydrochalcones,
`monellin, steviosides, and glycyrrhiZin;
`B. Water-soluble arti?cial sWeeteners such as the soluble
`saccharin salts, i.e., sodium or calcium saccharin salts,
`cyclamate salts, the sodium, ammonium or calcium salt of
`3,4-dihydro-6-methyl-1,2,3-oxathiaZine-4-one-2,2-dioxide,
`the potassium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiaZ
`ine-4-one-2,2-dioxide (acesulfame-K), the free acid form of
`saccharin, and the like;
`C. dipeptide based sWeeteners, such as L-aspartic acid
`derived sWeeteners, such as L-aspartyl-L-phenylalanine
`methyl ester (aspartame) and materials described in US. Pat.
`No. 3,492,131, L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3
`thietanyl)-D-alaninamide hydrate, methyl esters of L-aspar
`tyl-L-phenylglycerin and L-aspartyl-L-2,5,dihydrophenyl
`glycine,
`L-aspartyl-2,5-dihydro-L-phenylalanine,
`L-aspartyl-L-(l-cyclohexyen)-alanine, and the like;
`D. Water-soluble sWeeteners derived from naturally
`occurring Water-soluble sWeeteners, such as a chlorinated
`derivative of ordinary sugar (sucrose), knoWn, for example,
`under the product description of sucralose; and
`E. protein based sWeeteners such as thaumatoccous
`danielli (Thaumatin I and II).
`In general, an effective amount of auxiliary sWeetener is
`utiliZed to provide the level of sWeetness desired for a
`particular composition, and this amount Will vary With the
`sWeetener selected. This amount Will normally be 0.01% to
`about 10% by Weight of the composition When using an
`easily extractable sWeetener. The Water-soluble sWeeteners
`described in category A above, are usually used in amounts
`of about 0.01 to about 10 Wt %, and preferably in amounts
`of about 2 to about 5 Wt %. Some of the sWeeteners in
`category A (e.g., glycyrrhiZin) can be used in amounts set
`forth for categories BiE beloW due to the sWeeteners’
`knoWn sWeetening ability. In contrast, the sWeeteners
`described in categories BiE are generally used in amounts
`of about 0.01 to about 10 Wt %, With about 2 to about 8 Wt
`% being preferred and about 3 to about 6 Wt % being most
`preferred. These amounts may be used to achieve a desired
`level of sWeetness independent from the ?avor level
`achieved from any optional ?avor oils used. Of course,
`sWeeteners need not be added to ?lms intended for non-oral
`administration.
`The ?avorings that can be used include those knoWn to the
`skilled artisan, such as natural and arti?cial ?avors. These
`?avorings may be chosen from synthetic ?avor oils and
`?avoring aromatics, and/or oils, oleo resins and extracts
`derived from plants, leaves, ?oWers, fruits and so forth, and
`combinations thereof. Representative ?avor oils include:
`spearmint oil, cinnamon oil, peppermint oil, clove oil, bay
`oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and
`oil of bitter almonds. Also useful are arti?cial, natural or
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 7,067,116 B1
`
`7
`synthetic fruit ?avors such as vanilla, chocolate, colfee,
`cocoa and citrus oil, including lemon, orange, grape, lime
`and grapefruit and fruit essences including apple, pear,
`peach, strawberry, raspberry, cherry, plum, pineapple, apri
`cot and so forth. These ?avorings can be used individually
`or in admixture. Commonly used ?avors include mints such
`as peppermint, arti?cial vanilla, cinnamon derivatives, and
`various fruit ?avors, Whether employed individually or in
`admixture. Flavorings such as aldehydes and esters includ
`ing cinnamyl acetate, cinnamaldehyde, citral, diethylacetal,
`dihydrocarvyl acetate, eugenyl formate, p-methylanisole,
`and so forth may also be used. Generally, any ?avoring or
`food additive, such as those described in Chemicals Used in
`Food Processing, publication 1274 by the National Academy
`of Sciences, pages 634258, may be used. Further examples
`of aldehyde ?avorings include, but are not limited to acetal
`dehyde (apple); benZaldehyde (cherry, almond); cinnamic
`aldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime);
`neral, i.e. beta citral (lemon, lime); decanal (orange, lemon);
`ethyl vanillin (vanilla, cream); heliotropine, i.e., piperonal
`(vanilla, cream); vanillin (vanilla, cream); alpha-amyl cin
`namaldehyde (spicy fruity ?avors); butyraldehyde (butter,
`cheese); valeraldehyde (butter, cheese); citronellal (modi
`?es, many types); decanal (citrus fruits); aldehyde C-8
`(citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12
`(citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexenal,
`i.e. trans-2 (berry fruits); tolyl aldehyde (cherry, almond);
`veratraldehyde (vanilla); 2,6-dimethyl-5-heptenal, i.e. mel
`onal (melon); 2-6-dimethyloctanal (green fruit); and 2-dode
`cenal (citrus, mandarin); cherry; grape; mixtures thereof;
`and the like.
`The amount of ?avoring employed is normally a matter of
`preference subject to such factors as ?avor type, individual
`?avor, and strength desired. Thus, the amount may be varied
`in order to obtain the result desired in the ?nal product. Such
`variations are Within the capabilities of those skilled in the
`art Without the need for undue experimentation. In general,
`amounts of about 0.1 to about 30 Wt % are useable With
`amounts of about 2 to about 25 Wt % being preferred and
`amounts from about 8 to about 10 Wt % are more preferred.
`The compositions of this invention can also contain
`coloring agents or colorants. The coloring agents are used in
`amounts effective to produce the desired color. The coloring
`agents useful in the present invention, include pigments such
`as titanium dioxide, Which may be incorporated in amounts
`of up to about 5 Wt %, and preferably less than about 1 Wt
`%. Colorants can also include natural food colors and dyes
`suitable for food, drug and cosmetic applications. These
`colorants are knoWn as FD&C dyes and lakes. The materials
`acceptable for the foregoing spectrum of use are preferably
`Water-soluble, and include FD&C Blue No. 2, Which is the
`disodium salt of 5,5-indigotindisulfonic acid. Similarly, the
`dye knoWn as Green No. 3 comprises a triphenylmethane
`dye and is the monosodium salt of 4-[4-N-ethyl-p-sulfoben
`Zylamino) diphenyl-methylene] - [1 -N-ethyl -N-p - sulfonium
`benZyl)-2,5-cyclo-hexadienimine]. A full recitation of all
`FD&C and D&C dyes and their corresponding chemical
`structures may be found in the Kirk-Othmer Encyclopedia of
`Chemical Technology, Volume 5, Pages 8574884, Which text
`is accordingly incorporated herein by reference.
`The ?lms can also include a triglyceride. Examples of
`triglycerides include vegetable oils such as corn oil, sun
`?oWer oil, peanut oil, olive oil, canola oil, soybean oil and
`mixtures thereof. A preferred triglyceride is olive oil. The
`triglyceride is added to the ?lm in amounts from about 0.1
`Wt % to about 12 Wt %, preferably in a range from about 0.5
`Wt % to about 9 Wt %, of the ?lm.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`The ?lms can include a preservative in amounts from
`about 0.001 Wt % to about 5 Wt %, preferably from about
`0.01 Wt % to about 1 Wt % of the ?lm. Preferred preserva
`tives include sodium benZoate and potassium sorbate. Other
`suitable preservatives include, but are not limited to, salts of
`edetate (also knoWn as salts of ethylenediaminetetraacetic
`acid, or EDTA, such as disodium EDTA) and parabens (e. g.,
`methyl, ethyl, propyl or butyl-hydroxybenZoates, etc.) or
`sorbic acid. The preservatives listed above are exemplary,
`but each preservative must be evaluated on an empirical
`basis, in each formulation, to assure the compatibility and
`e?icacy of the preservative. Methods for evaluating the
`e?icacy of preservatives in pharmaceutical formulations are
`knoWn to those skilled in the art.
`The ?lms can also include a polyethylene oxide com
`pound. The molecular Weight of the polyethylene oxide
`compound ranges from about 50,000 to about 6,000,000. A
`preferred polyethylene oxide compound is N-10 available
`from Union Carbide Corporation. The polyethylene oxide
`compound is added in amounts from about 0.1 Wt % to about
`5 Wt %, preferably from about 0.2 Wt % to about 4.0 Wt %
`of the ?lm.
`The ?lms can also include propylene glycol. The propy
`lene glycol is added in amounts from about 1 Wt % to about
`20 Wt %, preferably from about 5 Wt % to about 15 Wt % of
`the ?lm.
`Methods for preparing ?lms according to the invention
`are capable of encapsulating the oil ingredients Within the
`?lm-forming matrix and maintaining the integrity of the
`?lm, even When the ?lm contains oils in amounts of 10 Wt
`% or more.
`In certain methods for preparing ?lms according to the
`invention, the ?lm-forming ingredients are mixed and
`hydrated With Water separately from the Water- soluble ingre
`dients, Which are mixed in aqueous solution separately from
`the organic ingredients and surfactants. In these methods,
`the ?nal formulation is preferably produced by mixing the
`?lm-forming phase With the aqueous phase, then mixing in
`the organic phase, Which includes surfactants, such as
`Polysorbate 80 and Atmos 300. This mass is mixed until
`emulsi?ed. In other embodiments, the aqueous and ?lm
`forming phases are combined into a single phase by dis
`solving the Water soluble ingredients in the Water and then
`adding the gums to hydrate. The organic phase is then added
`to this single aqueous phase.
`The resulting formulation is cast on a suitable substrate
`and dried to form a ?lm. The ?lm is preferably air-dried or
`dried under Warm air and cut to a desired dimension,
`packaged and stored. The ?lm can contain from about 0.1%
`to about 10 Wt % moisture, preferably from about 3% to
`about 8 Wt % moisture, even more preferably from about 4
`to about 7 Wt % moisture.
`The ?lm-forming phase can include pullulan and stabi
`liZing agents such as xanthan gum, locust bean gum and
`carrageenan. These ingredients are mixed and then hydrated
`in Water for about 30 to about 48 hours to form a gel. The
`Water is preferably heated to a temperature of about 25 to
`about 45° C. to promote hydration. The amount of Water is
`about 40 to 80% of the gel. The resulting hydrated gel is then
`chilled to a temperature of about 20 to about 30° C. for about
`1 to about 48 hours. The Water is preferably deioniZed.
`In preferred embodiments, the aqueous phase includes
`Water heated to a temperature of about 60 to 90° C.,
`preferably 70 to 80° C., and ingredients such as the phar
`maceutically active agent, ion exchange resin (or other
`masking agent), coloring agent, preservative and sWeetener.
`
`TEVA EXHIBIT 1004
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 7,067,116 B1
`
`The Water is preferably deionized and t