United States Patent
`US 7,067,116 Bl
`(10) Patent No.:
`(12)
`Bess et al.
`(45) Date of Patent:
`*Jun. 27, 2006
`
`
`US007067116B1
`
`12/1997 Biegajski etal.
`5,700,478 A
`9/1999 Zerbe et al.
`5,948,430 A
`11/1999 Bichman
`5,980,882 A
`4/3003 Chen ata
`0383.04 BL
`Ha
`nen et al.
`dye
`............. 424/435
`6,596,298 BL™ 7/2003 Leung et al.
`2003/0008008 Al
`1/2003 Leunget al.
`5003/0206942 Al
`11/2003 Kulkamietal.
`2003/0211136 Al
`11/2003 Kulkamiet al.
`2004/0136922 Al
`7/2004 Leungetal.
`;
`_
` FOREIGN PATENT DOCUMENTS
`
`
`(54)
`
`(75)
`
`FAST DISSOLVING ORALLY CONSUMABLE
`SOLID FILM CONTAINING A TASTE
`MASKING AGENT AND
`PHARMACEUTICALLY ACTIVE AGENT AT
`.
`.
`WEIGHT RATIO OF1:3 TO 3:1
`—
`.
`-
`ys
`.
`Inventors: William S. Bess, Edison, NJ (US);
`Neema Kulkarni, Randolph, NJ (US);
`Suhas H. Ambike, West Hill (CA);
`Michael P. Ramsay, Ajax (CA)
`
`(73) Assignee: Warner-Lambert Company LLC,
`Morris Plains, N.J (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`US.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`,
`
`(21) Appl. No.: 09/535,005
`,
`“og.
`
`CA
`CA
`EP
`FP
`EP
`GB
`JP
`
`JP
`JP
`JP
`JP
`1.
`JP
`
`1313620
`793428?
`0225615
`0 256 611 Al
`0438147
`2055575
`63059855
`
`63250318
`63250319
`63280014
`63296655
`63310815
`63310818
`
`
`
`2/1993
`4/1998
`6/1987
`2/1988
`7/1991
`3/1981
`3/1988
`
`10/1988
`10/1988
`11/1988
`12/1988
`1b108s
`12/1988
`
`6/1993
`9/1993
`12/1996
`5/1997
`5/1997
`3/1998
`S190
`5/
`
`1908
`4/1999
`7/2000
`
`(31)
`
`.
`Int. Cl.
`(2006.01)
`AGIK 9/14
`(2006.01)
`AGIK 31/74
`(2006.01)
`A6LK 31/785
`(52) US. Ch ccc. 424/781; 424/78.11; 424/78.12;
`sous ains
`..
`1 age
`ms
`
`41602
`JP
`5236885
`JP
`10179045
`Je
`2642354
`JP
`9124512
`JP
`WO-98/11867 Al
`WO
`WO Wook: AL
`é
`53
`
`514/54, 289, 850; 424/9, 78.1, 78.11, 78.12,
`424/483,
`See application file for complete search history.
`
`wo
`wo
`WO
`
`W09855079
`WO 9917753
`0042992
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`............ 424/676
`
`5/1969 Russell
`3,444,858 A
`1/1979 Fuchs et al.
`4,136,145 A
`4/1980 Sturzeneggeret al.
`4,197,289 A
`9/1980 Raghunathan
`4,221,778 A
`12/1985. Hijiya etal.
`4,562,020 A
`11/1986 Nakamuraet al.
`4,623,394 A
`4,713,243 A * 12/1987 Schiraldi et al.
`4,762,709 A
`8/1988 Sheumaker
`4,788,055 A
`11/1988 Fischer et al.
`4,820,506 A
`4/1989 Kleinberg et al.
`4,925,670 A
`5/1990) Schmidt
`4,927,636 A
`5/1990 Hijiyaet al.
`4,996,047 A
`2/1991 Kelleher etal.
`§,023,082 A
`6/1991 Friedman et al.
`§,047,244 A
`9/1991 Sanvordekeret al.
`5,354,551 A
`10/1994 Schmidt
`S5A1L.945 A
`5/1995 Ovaki et al.
`5,456,745 A
`10/1995 Roregeretal.
`5,518,902 A
`§/1996 Ozaki etal.
`§,529,783 A
`6/1996 Burkeetal.
`5,629,003 A
`5/1997 Horstmann et al.
`
`
`
`OTHER PUBLICATIONS
`Shih, Frederick F., “Edible Films from Rice Protein Con-
`centrate and Pullulan,” from Cereal Chemistry, vol. 73, No.
`3, 1996, pp. 406-409.
`
`(Continued)
`
`
`Primary Examiner—Elli Peselev
`(74) Attorney, Agent, or Firm—Barry H. Jacobsen; EvanJ.
`Federman
`
`(57)
`
`ABSTRACT
`
`Physiologically acceptable films, including edible films, are
`disclosed. The films include a water soluble film-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 asAMBERLITE. Methodsfor produc-
`ing the films are also disclosed,
`
`33 Claims, No Drawings
`
`Dr. Reddy's - EX1019
`Page 1
`
`Dr. Reddy's - EX1019
`Page 1
`
`

`

`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
`
`Page 2
`
`Page 2
`
`

`

`US 7,067,116 Bl
`
`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 films 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 inventionrelates to fast dissolving orally consumable
`films containing an agent to mask the taste of a pharmaceu-
`tically active agent therein, and more specifically to such
`films containing an ion exchangeresin as the taste masking
`agent.
`
`BACKGROUND OF THE INVENTION
`
`It has been known to administer pharmaceutically active
`agents in an edible film vehicle.
`For example, WO 99/17753 discloses rapidly dissolving
`films for delivery of drugs to be adsorbed in the digestive
`tract.
`
`WO 98/26780 discloses a flat, foil, paper or wafer type
`presentation for the application and release ofactive sub-
`stances in the buccal cavity. The specific active ingredient
`disclosed in WO 98/26780 is buprenorphine.
`WO 98/20862 discloses a film for use in the oral cavity
`that can contain a cosmetic or pharmaceutical active sub-
`stance.
`
`WO 98/26763 discloses a flat, foil, paper or wafer like
`presentation for release of active substances into the buccal
`cavity. The particular active disclosed is apomorphine.
`U.S. patent application Ser. No. 09/395,104 also discloses
`the delivery of pharmaceutical agents in a edible film
`vehicle.
`
`U.S. Pat. No. 5,411,945 to Ozaki etal. discloses a pullulan
`binder and products produced therewith, including edible
`films (Example B-2). The products can include a variety of
`ingredients in addition to pullulan, such as other polysac-
`charides, antibacterial agents, flavor-imparting agents and
`pharmaceutically active substances (column4, lines 5-15).
`U.S. Pat. No. 3,784,390 Hijiya et al. discloses pullulan
`films 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.
`
`30
`
`35
`
`40
`
`45
`
`It has also been known to combine ion exchange resins
`with pharmaceutically active agents to provide sustained
`release formulations.
`For example, U.S. 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
`films are not disclosed.
`
`55
`
`U.S. 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
`degradationof 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 films 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 film.
`Accordingly, an object of this invention is to provide fast
`
`The invention provides a consumable film adapted to
`adhere to and dissolve in a mouth of a consumer, wherein the
`film 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
`film of the invention, comprising:
`dissolving water-soluble ingredients in water to provide
`an aqueous solution;
`mixing at least one water soluble film former and at least
`one stabilizing agent to provide a film-forming mixture;
`combining the film-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 uniformgel;
`casting the uniform gel on a substrate; and
`drying the cast gel to provide the film.
`
`DETAILED DESCRIPTION OF PREFERRED
`
`
`
`EMBODIMENTS
`
`The invention provides a physiologically acceptable film
`that is particularly well adapted to adhere to and dissolve in
`a mouth of a consumerto deliver a pharmaceutically active
`agent. Preferred films according to the invention comprise a
`pharmaceutically active agent, an ion exchange resin, a
`film-forming agent, and at least one of the following addi-
`tional ingredients: water, antimicrobial agents, plasticizing
`agents, flavoring 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 film. Suitable pharmaceutically active agents include,
`but are not limited to:
`
`60
`
`65
`
`A. antimicrobial agents, such astriclosan, cetyl pyridium
`chloride, domiphen bromide, quaternary ammoniumsalts,
`zinc compounds, sanguinarine, fluorides, alexidine, octoni-
`dine, EDTA, and the like;
`B. non-steroidal anti-inflammatory drugs, such as aspirin,
`acetaminophen, ibuprofen, ketoprofen, diflunisal, fenopro-
`fen calcium, naproxen, tolmetin sodium, indomethacin, and
`thelike;
`
`C. anti-tussives, such as benzonatate, caramiphenedisy-
`late, menthol, dextromethorphan hydrobromide, chlophedi-
`anol hydrochloride, and the like;
`
`Page 3
`
`Page 3
`
`

`

`US 7,067,116 Bl
`
`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,
`tripelennaminecitrate, 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. H,-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 2
`alcohols, barbiturates and the like;
`K. general nonselective CNS stimulants suchas caffeine,
`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 thelike;
`N. narcotic-analgesics such as morphine, heroin, hydro-
`morphone, metopon, oxymorphone, levorphanol, codeine,
`hydrocodone, xycodone, nalorphine, naloxone, naltrexone
`and the like;
`O. 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, lithiumand thelike.
`The amount of pharmaceutically active agent that can be
`used in the rapidly dissolving films, 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 specific pharmaceutically active
`agents that can be delivered per one strip ofrapidly dissolv-
`ing oral film are reviewed in Table A.
`
`10
`
`3
`
`35
`
`4
`
`45
`
`PHARMACEUTICALLY ACTIVE AGENT
`
`TABLE A
`
`Chlorpheniramine Maleate
`Brompheniramine Maleate
`Jexchlorpheniramine
`Dexbrompheniramine
`Triprolidine Hydrochloride
`Acrivastine
`Azatadine Maleate
`oratidine
`Phenylephrine Hydrochloride
`Dextromethorphan Hydrobromide
`Ketoprofen
`Sumatriptan Succinate
`Zolmitriptan
`Loperamide
`-amotidine
`Nicotine
`Diphenhydramine Hydrochloride
`-seudoephedrine Hydrochloride
`
`
`
`PREFERRED DOSE
`
`4 meg.
`4 meg.
`2 meg.
`2 mg.
`2.5 mg.
`8 meg.
`1 mg.
`10 mg.
`10 mg.
`10-30 mg.
`12.5-25 mg.
`35-70 mg.
`2.5 mg.
`2 mg.
`10 mg.
`2 mg.
`12.5-25 mg.
`30 meg.
`
`wn
`
`55
`
`60
`
`65
`
`4
`Ion exchange resins preferred for use in the films 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
`ofbeing 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.,
`modified cellulose and dextrans). The inorganic matrix can
`also be, e.g., silica gel modified by the addition ofionic
`groups. The covalently bound ionic groups may bestrongly
`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
`Jon Exchange” (pp. 312-343). 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.
`Theresin is crosslinked with a crosslinking agent selected
`fromdifunctional compounds capable of crosslinking poly-
`styrenes; these are commonly knowninthe art. Preferably,
`the crosslinking agent is a divinyl or polyvinyl] compound.
`Most preferably the crosslinking agent is divinylbenzene.
`The resinis crosslinked to an extent of about 3 to about 20%,
`preferably about 4 to about 16%, morepreferably 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 knownintheart.
`The size of the ion exchangeresins should preferably fall
`within the range of about 20 to about 200 micrometers.
`Particle sizes substantially belowthe lowerlimit are difficult
`to handle in all steps of the processing. Particle sizes
`substantially above the upperlimit, 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 IRP-69 (obtained from Rohm and Haas) and
`Dow 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 ofabout 4.5 to 5.5 meq/g ofdry resin
`(H+-form). Their essential difference is in physical form.
`AMBERLITE IRP-69 comprises irregularly-shaped par-
`ticles with a size range of 47 to 149 micrometers, produced
`by milling the parent, large-sized spheres ofAMBERLITE
`IRP-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 composedof 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 ofdry resin.
`The most preferred resin isAMBERLITE IRP-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., magnesiumtrisilicate.
`See, e.g., U.S. Pat. Nos. 4,650,663 and 4,581,232 to Peters
`et al. Taste can also be masked by polymers, such as
`EUDRAGIT E (Rohmand Haas), and/or cellulosics, such as
`ethylcellulose, and thelike.
`
`Page 4
`
`Page 4
`
`

`

`US 7,067,116 Bl
`
`5
`The film-forming agent used in the films according to the
`present invention can be selected [rom 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 film former
`is pullulan, in amounts ranging from about 0.01 to about 99
`wt %, preferably about 30to about 80 wt %, morepreferably
`from about 45 to about 70 wt %of the film and even more
`
`preferably from about 60 to about 65 wt % ofthe film.
`Unless specified otherwise,
`the term “wt %” as used
`herein with reference to the final product (1.e., the film, as
`opposed to the formulation used to create it), denotes the
`percentage ofthe total dry weight contributed by the subject
`ingredient. This theoretical value candiffer from the experi-
`mental value, because in practice, the film 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 film (and more preferable to have no humectant in the
`film), so as to avoid producing an overly moist, self-
`adhering film. In particular, it is preferred to formulate high
`oil content films 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 films
`according to the present invention. Useful saliva stimulating
`agents are those disclosed in U.S. Pat. No. 4,820,506. Saliva
`stimulating agents include food acids suchas citric, lactic,
`malic, succinic, ascorbic, adipic, fumaric andtartaric acids.
`Preferred food acidsare citric, malic and ascorbic acids. The
`amountofsaliva stimulating agents in the film 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 monomenthy! 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 | to about 5 wt % ofthe film. Other suitable
`surfactants include pluronic acid, sodium lauryl! sulfate, and
`the like.
`
`Preferred stabilizing agents include xanthan gum, locust
`bean gumand carrageenan, in amounts ranging from about
`0 to about 10 wt %, preferably about 0.1 to about 2 wt %of
`the film. 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 film.
`
`2
`
`3
`
`35
`
`4
`
`45
`
`55
`
`6
`
`65
`
`6
`Preferred thickening agents include methylcellulose, car-
`boxy! 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 film.
`Suitable sweeteners that can be included are those well
`
`knownintheart, including bothnaturaland artificial 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 artificial sweeteners such as the soluble
`saccharin salts,
`i.e.. sodium or calcium saccharin salts,
`cyclamate salts, the sodium, ammoniumor calciumsalt of
`3,4-dihydro-6-methy]-1,2,3-oxathiazine-4-one-2,2-dioxide,
`the potassium salt of 3,4-dihydro-6-methy1-1,2,3-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 U.S. Pat.
`No. 3,492,131, L-alpha-aspartyl-N-(2,2,4,4-tetramethy1-3-
`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-(1-cyclohexyen)-alanine, and the like;
`D. water-soluble sweeteners derived from naturally
`occurring water-soluble sweeteners, such as a chlorinated
`derivative ofordinary 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 ofauxiliary sweeteneris
`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 B-E below due to the sweeteners’
`known sweetening ability.
`In contrast,
`the sweeteners
`described in categories B-E are generally used in amounts
`ofabout 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 flavor
`level
`achieved from anyoptional flavor oils used. Of course,
`sweeteners need not be addedtofilms intended for non-oral
`administration.
`
`Theflavorings that can be used include those knownto the
`skilled artisan, such as natural and artificial flavors. These
`flavorings may be chosen from synthetic flavor oils and
`flavoring aromatics, and/or oils, cleo resins and extracts
`derived from plants, leaves, flowers, fruits and so forth, and
`combinations thereof. Representative flavor oils include:
`spearmint oil, cinnamonoil, peppermint oil, clove oil, bay
`oil, thyme oil, cedar leafoil, oi] of nutmeg, oil of sage, and
`oil of bitter almonds. Also useful are artificial, natural or
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`US 7,067,116 Bl
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`7
`flavors such as vanilla, chocolate, coffee,
`synthetic fruit
`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 flavorings can be used individually
`or in admixture. Commonly used flavors include mints such
`as peppermint, artificial vanilla, cinnamon derivatives, and
`various fruit flavors, whether employed individually or in
`admixture. Flavorings such as aldehydes and esters includ-
`ing cinnamy] acetate, cinnamaldehyde, citral, diethylacetal,
`dihydrocarvyl acetate, eugenyl
`formate, p-methylanisole,
`and so forth may also be used, Generally, any flavoring or
`food additive, such as those described in Chemicals Used in
`Food Processing, publication 1274 by the National Academy
`of Sciences, pages 63-258, may be used. Further examples
`ofaldehyde flavorings 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);
`=] o
`ethyl vanillin (vanilla, cream); heliotropine, i.e., piperonal 2
`(vanilla, cream); vanillin (vanilla, cream); alpha-amyl cin-
`namaldehyde (spicy fruity flavors); butyraldehyde (butter,
`cheese); valeraldehyde (butter, cheese); citronellal (modi-
`fies, 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 thelike.
`
`30
`
`The amountof flavoring employed Is normally a matter of
`preference subject to such factors as flavor type, individual
`flavor, and strength desired. Thus, the amount may be varied
`in order to obtain the result desired inthe final 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
`
`35
`
`40
`
`45
`
`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 spectrumof use are preferably 5
`water-soluble, and include FD&C Blue No. 2, whichis the
`disodiumsalt of 5,5-indigotindisulfonic acid. Similarly, the
`dye known as Green No. 3 comprises a triphenylmethane
`dye and is the monosodiumsalt 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 foundin the Kirk-Othmer Encyclopedia of
`Chemical Technology, Volume 5, Pages 857-884, which text
`is accordingly incorporated herein by reference.
`The films can also include a triglyceride. Examples of
`triglycerides include vegetable oils such as corn oil, sun-
`flower oil, peanut oil, olive ol, canola oil, soybean oil and
`mixtures thereof. A preferred triglyceride is olive oil. The
`triglyceride is added to the film 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 film.
`
`55
`
`6
`
`65
`
`8
`The films can include a preservative in amounts from
`about 0.001 wt % to about 5 wit %, preferably from about
`0.01 wt % to about 1 wt % ofthe film. Preferred preserva-
`tives include sodiumbenzoate and potassium sorbate. Other
`suitable preservatives include, but are not limited to, salts of
`edetate (also knownas 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
`
`
`efficacy of the preservative. Methods for evaluating the
`efficacy ofpreservatives in pharmaceutical formulations are
`known to those skilled in the art.
`
`The films 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 fromabout 0.1 wt % to about
`5 wt %, preferably from about 0.2 wt %to about 4.0 wt %
`of the film.
`
`The films canalso include propylene glycol. The propy-
`lene glycol is added in amounts from about | wt %to about
`20 wt %, preferably from about 5 wt %to about 15 wt %of
`the film.
`
`Methods for preparing films according to the invention
`are capable of encapsulating the oil ingredicnts within the
`film-forming matrix and maintaining the integrity of the
`film, even whenthe film contains oils in amounts of 10 wt
`% or more.
`
`In certain methods for preparing films according to the
`invention,
`the film-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 final formulation is preferably produced by mixing the
`film-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
`emulsified.
`In other embodiments,
`the aqueous and film
`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 forma film. The filmis preferably air-dried or
`dried under warm air and cut
`to a desired dimension,
`packaged and stored. The film 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 film-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 ofwater is
`about 40 to 80% of the gel. The resulting hydrated gel is then
`chilled to a temperature ofabout 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.
`
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`US 7,067,116 Bl
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`9
`The water is preferably deionized and the amount of water
`used is about 5 to about 80 wt % ofthe final gel mixture.
`The pharmaceutically active agent is sorbed to the ion
`exchange resin (or other masking agent) without separating
`ion exchanged pharmaceutically active agent from unex-
`changed agent and counter ionsalts.
`Adsorption ofthe pharmaceutically active agent onto the
`ion exchange resin particles to form the pharmaceutically
`active agent/resin complex is a well known technique as
`shown in U.S. Pat. Nos. 2,990,332 and 4,221,778. In gen-
`eral,
`the pharmaceutically active agent
`is mixed with an
`aqueous suspension of the resin, and in less preferred
`embodiments,
`the complex is
`then washed and dried.
`Adsorption of pharmaceutically active agent onto the resin
`may be detected by measuring a change in the pH of the
`reaction medium, or by measuring a change in concentration
`of sodium or pharmaceutically active agent.
`Binding of pharmaceutically active agent to resin can be
`accomplished according to four general reactions.
`In the
`case of a basic pharmaceutically active agent, these are: (a)
`resin (Na-form) plus pharmaceutically active agent (sal