(12) United States Patent (cid:9)
`United States Patent
`Bess et al. (cid:9)
`Bess et a].
`
`(12)
`
`(10) Patent No.: (cid:9)
`(10) Patent N0.:
`(45) Date of Patent: (cid:9)
`(45) Date of Patent:
`
`US 7,067,116 B1
`US 7,067,116 B1
`*Jun. 27, 2006
`*Jun. 27, 2006
`
`11111111111111101111111111!11111611111111111111111111111111110111111
`
`US007067116B1
`
`(54) FAST DISSOLVING ORALLY CONSUMABLE
`(54) FAST DISSOLVING ORALLY CONSUMABLE
`SOLID FILM CONTAINING A TASTE
`SOLID FILM CONTAINING A TASTE
`MASKING AGENT AND
`MASKING AGENT AND
`PHARMACEUTICALLY ACTIVE AGENT AT
`PHARMACEUTICALLY ACTIVE AGENT AT
`WEIGHT RATIO OF 1:3 TO 3:1
`WEIGHT RATIO 0F 13 T0 31
`
`-
`
`-
`
`,
`,
`.
`(75) Inventors: William S. Bess, Edison, NJ (US);
`(75) Inventors: William S. Bess,.Ed1son, NJ (U S);
`Neema Kulkarni, Randolph, NJ (US);
`Neema Klllkarfll, Randolph, NJ (Us);
`Suhas H. Ambike, West Hill (CA);
`Suhas H-Amblke, WPSt H111 (CA);
`Michael P. Ramsay, Ajax (CA)
`Michael P. Ramsay, Ajax (CA)
`
`(73) Assignee: Warner-Lambert Company LLC,
`(73) Assignee: Warner-Lambert Company LLC,
`Morris Plains, NJ (US)
`Morris Plains, NJ (US)
`
`( * ) Notice:
`( * )
`Notice:
`
`Subject to any disclaimer, the term of this
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`This patent is subject to a terminal dis-
`Claimer
`claimer.
`'
`
`_
`(21) Appl. No.: 09/535,005
`(21) Appl. No.. 09/535,005
`.
`(22) Filed: (cid:9)
`(22) F1led:
`
`Mar. 23, 2000
`Mar. 23, 2000
`
`Int. Cl.
`(51)
`(51) Int- Cl-
`(2006.01)
`A61K 9/14 (cid:9)
`(2006-01)
`A61K 9/14
`(2006.01)
`A61K 31/74 (cid:9)
`(2006.01)
`A61K 31/74
`(2006.01)
`A61K 31/785 (cid:9)
`(2006.01)
`A61K 31/785
`(52) U.S. Cl. (cid:9)
` 424/78.1; 424/78.11; 424/78.12;
`(52) us. Cl. ............. .. 424/78.1; 424/78.11; 424/78.12;
`424/483; 424/23
`424/483; 424/23
`_
`_
`_
`(58) Field of Classification Search (cid:9)
` 514/23,
`(58) Field of Classi?cation Search ................ .. 514/23,
`514/54, 289, 850; 424/9, 78.1, 78 (cid:9) 11, 78.12,
`514/54, 289, 850; 424/9, 78.1, 78.11, 78.12,
`424/483
`424/483
`See application file for complete search history.
`See application ?le for complete search history.
`
`(56)
`(56)
`
`References Cited
`References Cited
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`
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`5,980,882 A 11/1999 Eichman
`$1
`If‘;
`gin ettali
`6,001,392 A
`12/1999 Wen et al.
`6,552,024 B1
`4/2003 Chen et al.
`6,596,298 B1 *
`7/2003 Leung et a1. ............. .. 424/435
`6,596,298 Bl* 7/2003 Leung et al. (cid:9)
` 424/435
`2003/0008008 Al
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`2003/0008008 A1
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`2003/0206942 A1
`110003 Kulkami et a1‘
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`2003/0211136 A1 11/2003 Kulkami et a1.
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`7/2004 Leung et al.
`
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`
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`
`,
`
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`CA
`CA
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`EP
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`GB
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`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`WO
`W0
`WO
`WO
`WO
`WO
`W0
`WO
`W0
`WO
`W0
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`1313620
`2/1993
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`6/1993
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`9/1993
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`10179045
`12/1996
`2642354
`5/1997
`2642354
`5/1997
`9124512
`5/1997
`9124512
`5/1997
`WO-98/11867 Al
`3/1998
`‘VG-9841867 A1
`3/1998
`WO-98/20862 Al
`5/1998
`WO-98/20862 Al
`5/1998
`W09826763
`6/1998
`WO9826763
`6/1998
`WO9826780
`@1998
`W09826780
`6/1998
`WO9855079
`12/1998
`W09855079
`12/1998
`W0 9917753
`4/1999
`WO 9917753
`4/1999
`0042992
`7/2000
`0042992
`7/2000
`
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`Shih, Frederick F., "Edible Films from Rice Protein Con-
`Shih, Frederick E, “Edible Films
`from Rice Protein Con
`centrate and Pullulan," from Cereal Chemistry, vol. 73, No.
`centrate and Pullulan,” from Cereal Chemistry, vol. 73, No.
`3, 1996, pp. 406-409.
`3, 1996, pp. 406-409.
`
`(Continued)
`(Continued)
`Primary ExamineriElli Peselev
`Primary Examiner (cid:9) Elli Peselev
`(74) Attorney, Agent, or Firm (cid:9) Barry H. Jacobsen; Evan J.
`(74) Attorney, Agent, or FirmiBarry H. Jacobsen; Evan J.
`Federman
`Federrnan
`
`(57)
`(57) (cid:9)
`
`ABSTRACT
`ABSTRACT
`
`Physiologically acceptable ?lms, including edible ?lms, are
`Physiologically acceptable films, including edible films, are
`disclosed. The films include a water soluble film-forming
`disclosed. The ?lms include a Water soluble ?lm-forming
`polymer, such as pullulan, and a taste masked pharmaceu-
`polymer, such as pullulan, and a taste masked pharmaceu
`tically active agent, such as dextromethorphan. The taste
`tically active agent, such as dextromethorphan. The taste
`masking agent is preferably a sulfonated polymer ion
`masking agent is preferably a sulfonated polymer ion
`exchange resin comprising polystyrene cross-linked With
`exchange resin comprising polystyrene cross-linked with
`divinylbenzene, such as AMBERLITE. Methods for produc-
`divinylbenzene, such as AMBERLITE. Methods for produc
`ing the films are also disclosed.
`ing the ?lms are also disclosed.
`
`33 Claims, No Drawings
`33 Claims, N0 Drawings
`
`Par Pharm., Inc., et al.
`Exhibit 1019
`Page 001
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`US 7,067,116 B1
`US 7,067,116 B1
`Page 2
`Page 2
`
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`
`Krochta, John M. and De Mulder-Johnston, Catherine,
`Krochta, John M. and De Mulder-Johnston, Catherine,
`“Edible and Biodegradable Polymer Films: Challenges and
`"Edible and Biodegradable Polymer Films: Challenges and
`Opportunities,” from Food Technology, VOl. 51, No. 2, Feb.
`Opportunities," from Food Technology, vol. 51, No. 2, Feb.
`1997, pp. 60-74.
`1997, pp. 60-74.
`Patent Abstracts of Japan for patent document JP-62
`Patent Abstracts of Japan for patent document JP-62-
`135417, Publication Date: Jun. 18, 1987.
`135417, Publication Date: Jun. 18, 1987.
`
`Patent Abstracts of Japan for patent document JP-02
`Patent Abstracts of Japan for patent document JP-02-
`059513, Publication
`Date:
`Feb.
`28,
`1990, and
`059513, Publication Date: Feb. 28, 1990, and
`XP-002129504, an English translation of Japanese Patent
`XP-002129504, an English translation of Japanese Patent
`No. 41602-1993.
`No. 41602-1993.
`
`* cited by examiner
`* cited by examiner
`
`Par Pharm., Inc., et al.
`Exhibit 1019
`Page 002
`
`

`

`US 7,067,116 B1
`US 7,067,116 B1
`
`1
`1
`FAST DISSOLVING ORALLY CONSUMABLE
`FAST DISSOLVING ORALLY CONSUMABLE
`SOLID FILM CONTAINING A TASTE
`SOLID FILM CONTAINING A TASTE
`MASKING AGENT AND
`MASKING AGENT AND
`PHARMACEUTICALLY ACTIVE AGENT AT
`PHARMACEUTICALLY ACTIVE AGENT AT
`WEIGHT RATIO OF 1:3 TO 3:1
`WEIGHT RATIO OF 1:3 TO 3:1
`
`2
`2
`dissolving orally consumable ?lms containing an ion
`dissolving orally consumable films containing an ion
`exchange resin to mask the taste of a pharmaceutically
`exchange resin to mask the taste of a pharmaceutically
`active agent therein.
`active agent therein.
`All references cited herein are incorporated herein by
`All references cited herein are incorporated herein by
`reference in their entireties.
`5 reference in their entireties.
`
`FIELD OF THE INVENTION
`FIELD OF THE INVENTION
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`
`This invention relates to fast dissolving orally consumable
`This invention relates to fast dissolving orally consumable
`films containing an agent to mask the taste of a pharmaceu-
`?lms containing an agent to mask the taste of a pharmaceu
`tically active agent therein, and more speci?cally to such
`tically active agent therein, and more specifically to such
`films containing an ion exchange resin as the taste masking
`?lms containing an ion exchange resin as the taste masking
`agent.
`agent.
`
`10
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`
`15
`
`20
`
`25
`25
`
`35
`35
`
`40
`40
`
`It has been knoWn to administer pharmaceutically active
`It has been known to administer pharmaceutically active
`agents in an edible film vehicle.
`agents in an edible ?lm vehicle.
`For example, W0 99/ 17753 discloses rapidly dissolving
`For example, WO 99/17753 discloses rapidly dissolving
`?lms for delivery of drugs to be adsorbed in the digestive
`films for delivery of drugs to be adsorbed in the digestive
`tract.
`tract.
`WO 98/26780 discloses a flat, foil, paper or wafer type
`WO 98/26780 discloses a ?at, foil, paper or Wafer type
`presentation for the application and release of active sub
`presentation for the application and release of active sub-
`stances in
`the buccal cavity.
`The speci?c active ingredient
`stances in the buccal cavity. The specific active ingredient
`disclosed in WO 98/26780 is buprenorphine.
`disclosed in WO 98/26780 is buprenorphine.
`WO 98/20862 discloses a film for use in the oral cavity
`WO 98/20862 discloses a ?lm for use in the oral cavity
`that can contain a cosmetic or pharmaceutical active sub-
`that can contain a cosmetic or pharmaceutical active sub
`stance.
`stance.
`WO 98/26763 discloses a flat, foil, paper or wafer like 3o
`WO 98/26763 discloses a ?at, foil, paper or Wafer like
`30
`presentation for release of active substances into the buccal
`presentation for release of active substances into the buccal
`cavity. The particular active disclosed is apomorphine.
`cavity. The particular active disclosed is apomorphine.
`U.S. patent application Ser. No. 09/395,104 also discloses
`US. patent application Ser. No. 09/395,104 also discloses
`the delivery of pharmaceutical agents in a edible film
`the delivery of pharmaceutical agents in a edible ?lm
`vehicle.
`vehicle.
`U.S. Pat. No. 5,411,945 to Ozaki et al. discloses a pullulan
`US. Pat. No. 5,411,945 to OZaki et al. discloses a pullulan
`binder and products produced thereWith, including edible
`binder and products produced therewith, including edible
`films (Example B-2). The products can include a variety of
`?lms (Example B-2). The products can include a variety of
`ingredients in addition to pullulan, such as other polysac-
`ingredients in addition to pullulan, such as other polysac
`charides, antibacterial agents, ?avor-imparting agents and
`charides, antibacterial agents, flavor-imparting agents and
`pharmaceutically active substances (column 4, lines 5415).
`pharmaceutically active substances (column 4, lines 5-15).
`U.S. Pat. No. 3,784,390 Hijiya et al. discloses pullulan
`US. Pat. No. 3,784,390 Hijiya et al. discloses pullulan
`films and their use in coating and packing materials for
`?lms and their use in coating and packing materials for
`foods, pharmaceuticals and other oxygen sensitive materi-
`foods, pharmaceuticals and other oxygen sensitive materi
`als. All of the examples in this patent teach mixing pullulan
`als. All of the examples in this patent teach mixing pullulan
`in hot water.
`in hot Water.
`It has also been known to combine ion exchange resins
`It has also been knoWn to combine ion exchange resins
`With pharmaceutically active agents to provide sustained
`with pharmaceutically active agents to provide sustained
`release formulations.
`release formulations.
`For example, U.S. Pat. No. 6,001,392 to Wen et al.
`For example, US. Pat. No. 6,001,392 to Wen et al.
`discloses a controlled-release syrup suspension for oral
`discloses a controlled-release syrup suspension for oral
`administration containing dextromethorphan adsorbed to a
`administration containing dextromethorphan adsorbed to a
`polystyrene sulfonate ion exchange resin. Pharmaceutical
`polystyrene sulfonate ion exchange resin. Pharmaceutical
`films are not disclosed.
`?lms are not disclosed.
`U.S. Pat. No. 5,980,882 to Eichman discloses a method
`US. Pat. No. 5,980,882 to Eichman discloses a method
`for improving the stability of a pharmaceutical composition
`for improving the stability of a pharmaceutical composition
`that contains a drug-resin complex, comprising adding a
`that contains a drug-resin complex, comprising adding a
`chelating agent in an amount effective to reduce the rate of
`chelating agent in an amount effective to reduce the rate of
`degradation of the drug in the drug-resin complex. Although
`degradation of the drug in the drug-resin complex. Although
`Eichman teaches that complexing a drug with an ion
`Eichman teaches that complexing a drug With an ion
`exchange resin can mask the taste of the drug. Pharmaceu-
`exchange resin can mask the taste of the drug. Pharmaceu
`tical films are not disclosed.
`tical ?lms are not disclosed.
`The inventors are not aware of any suggestion in the
`The inventors are not aWare of any suggestion in the
`published art that ion exchange resins can act as taste 65
`published art that ion exchange resins can act as taste
`65
`masking agents in a fast dissolving orally consumable ?lm.
`masking agents in a fast dissolving orally consumable film.
`Accordingly, an object of this invention is to provide fast
`Accordingly, an object of this invention is to provide fast
`
`45
`45
`
`50
`50
`
`55
`55
`
`60
`60
`
`The invention provides a consumable ?lm adapted to
`The invention provides a consumable film adapted to
`adhere to and dissolve in a mouth of a consumer, wherein the
`adhere to and dissolve in a mouth of a consumer, Wherein the
`film comprises at least one water soluble polymer, at least
`?lm comprises at least one Water soluble polymer, at least
`one pharmaceutically active agent and at least one taste
`one pharmaceutically active agent and at least one taste
`masking agent.
`masking agent.
`Also provided is a method for preparing the consumable
`Also provided is a method for preparing the consumable
`?lm of the invention, comprising:
`film of the invention, comprising:
`dissolving Water-soluble ingredients in Water to provide
`dissolving water-soluble ingredients in water to provide
`an aqueous solution;
`an aqueous solution;
`mixing at least one water soluble film former and at least
`mixing at least one Water soluble ?lm former and at least
`one stabiliZing agent to provide a ?lm-forming mixture;
`one stabilizing agent to provide a film-forming mixture;
`combining the ?lm-forming mixture and the aqueous
`combining the film-forming mixture and the aqueous
`solution to provide a hydrated polymer gel;
`solution to provide a hydrated polymer gel;
`mixing oils to form an oil mixture;
`mixing oils to form an oil mixture;
`adding the oil mixture to the hydrated polymer gel and
`adding the oil mixture to the hydrated polymer gel and
`mixing to provide a uniform gel;
`mixing to provide a uniform gel;
`casting the uniform gel on a substrate; and
`casting the uniform gel on a substrate; and
`drying the cast gel to provide the ?lm.
`drying the cast gel to provide the film.
`
`DETAILED DESCRIPTION OF PREFERRED
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`EMBODIMENTS
`
`The invention provides a physiologically acceptable ?lm
`The invention provides a physiologically acceptable film
`that is particularly well adapted to adhere to and dissolve in
`that is particularly Well adapted to adhere to and dissolve in
`a mouth of a consumer to deliver a pharmaceutically active
`a mouth of a consumer to deliver a pharmaceutically active
`agent. Preferred films according to the invention comprise a
`agent. Preferred ?lms according to the invention comprise a
`pharmaceutically active agent, an ion exchange resin, a
`pharmaceutically active agent, an ion exchange resin, a
`film-forming agent, and at least one of the following addi-
`?lm-forming agent, and at least one of the folloWing addi
`tional ingredients: Water, antimicrobial agents, plasticiZing
`tional ingredients: water, antimicrobial agents, plasticizing
`agents, ?avoring agents, saliva stimulating agents, cooling
`agents, flavoring agents, saliva stimulating agents, cooling
`agents, surfactants, stabiliZing agents, emulsifying agents,
`agents, surfactants, stabilizing agents, emulsifying agents,
`thickening agents, binding agents, coloring agents, sWeet
`thickening agents, binding agents, coloring agents, sweet-
`eners, fragrances, triglycerides, preservatives, polyethylene
`eners, fragrances, triglycerides, preservatives, polyethylene
`oxides, propylene glycol, and the like.
`oxides, propylene glycol, and the like.
`The expression “physiologically acceptable” as used
`The expression "physiologically acceptable" as used
`herein is intended to encompass compounds, which upon
`herein is intended to encompass compounds, Which upon
`administration to a patient, are adequately tolerated without
`administration to a patient, are adequately tolerated Without
`causing undue negative side effects. The expression encom
`causing undue negative side effects. The expression encom-
`passes edible compounds.
`passes edible compounds.
`The expression “pharmaceutically active agents” as used
`The expression "pharmaceutically active agents" as used
`herein is intended to encompass agents other than foods,
`herein is intended to encompass agents other than foods,
`which promote a structural and/or functional change in
`Which promote a structural and/or functional change in
`and/or on bodies to which they have been administered.
`and/or on bodies to Which they have been administered.
`These agents are not particularly limited; however, they
`These agents are not particularly limited; hoWever, they
`should be physiologically acceptable and compatible With
`should be physiologically acceptable and compatible with
`the ?lm. Suitable pharmaceutically active agents include,
`the film. Suitable pharmaceutically active agents include,
`but are not limited to:
`but are not limited to:
`A. antimicrobial agents, such as triclosan, cetyl pyridium
`A. antimicrobial agents, such as triclosan, cetyl pyridium
`chloride, domiphen bromide, quaternary ammonium salts,
`chloride, domiphen bromide, quaternary ammonium salts,
`Zinc compounds, sanguinarine, ?uorides, alexidine, octoni
`zinc compounds, sanguinarine, fluorides, alexidine, octoni-
`dine, EDTA, and the like;
`dine, EDTA, and the like;
`B. non-steroidal anti-in?ammatory drugs, such as aspirin,
`B. non-steroidal anti-inflammatory drugs, such as aspirin,
`acetaminophen, ibuprofen, ketoprofen, di?unisal, fenopro
`acetaminophen, ibuprofen, ketoprofen, diflunisal, fenopro-
`fen calcium, naproxen, tolmetin sodium, indomethacin, and
`fen calcium, naproxen, tolmetin sodium, indomethacin, and
`the like;
`the like;
`C. anti-tussives, such as benzonatate, caramiphen edisy-
`C. anti-tussives, such as benZonatate, caramiphen edisy
`late, menthol, dextromethorphan hydrobromide, chlophedi
`late, menthol, dextromethorphan hydrobromide, chlophedi-
`anol hydrochloride, and the like;
`anol hydrochloride, and the like;
`
`Par Pharm., Inc., et al.
`Exhibit 1019
`Page 003
`
`

`

`US 7,067,116 B1
`US 7,067,116 B1
`
`3
`3
`D. decongestants, such as pseudoephedrine hydrochlo
`D. decongestants, such as pseudoephedrine hydrochlo-
`ride, phenylepherine, phenylpropanolamine, pseudoephe
`ride, phenylepherine, phenylpropanolamine, pseudoephe-
`drine sulfate,
`and the like;
`drine sulfate, and the like;
`E. anti-histamines, such as brompheniramine maleate,
`E. anti-histamines, such as brompheniramine maleate,
`chlorpheniramine maleate, carbinoxamine maleate, clemas
`chlorpheniramine maleate, carbinoxamine maleate, clemas-
`tine fumarate, dexchlorpheniramine maleate, diphenhy
`tine fumarate, dexchlorpheniramine maleate, diphenhy-
`dramine hydrochloride, diphenylpyraline hydrochloride,
`dramine hydrochloride, diphenylpyraline hydrochloride,
`aZatadine meleate, diphenhydramine citrate, doxylamine
`azatadine meleate, diphenhydramine citrate, doxylamine
`succinate, promethaZine hydrochloride, pyrilamine maleate,
`succinate, promethazine hydrochloride, pyrilamine maleate,
`tripelennamine citrate, triprolidine hydrochloride, acrivas
`tripelennamine citrate, triprolidine hydrochloride, acrivas-
`tine, loratadine, brompheniramine, dexbrompheniramine,
`tine, loratadine, brompheniramine, dexbrompheniramine,
`and the like;
`and the like;
`F. expectorants, such as guaifenesin, ipecac, potassium
`F. expectorants, such as guaifenesin, ipecac, potassium
`iodide, terpin hydrate, and the like;
`iodide, terpin hydrate, and the like;
`G. anti-diarrheals, such a loperamide, and the like;
`G. anti-diarrheals, such a loperamide, and the like;
`H. H2-antagonists, such as famotidine, ranitidine, and the
`H. H2-antagonists, such as famotidine, ranitidine, and the
`like;
`like;
`I. proton pump inhibitors, such as omepraZole, lansopra
`I. proton pump inhibitors, such as omeprazole, lansopra-
`Zole, and the like;
`zole, and the like;
`J. general nonselective CNS depressants, such as aliphatic
`J. general nonselective CNS depressants, such as aliphatic
`alcohols, barbiturates and the like;
`alcohols, barbiturates and the like;
`K. general nonselective CNS stimulants such as caffeine,
`K. general nonselective CNS stimulants such as ca?feine,
`nicotine, strychnine, picrotoxin, pentylenetetraZol and the
`nicotine, strychnine, picrotoxin, pentylenetetrazol and the
`like;
`like;
`L. drugs that selectively modify CNS function, such as
`L. drugs that selectively modify CNS function, such as
`phenyhydantoin, phenobarbital, primidone, carbamaZepine,
`phenyhydantoin, phenobarbital, primidone, carbamazepine,
`ethosuximide, methsuximide, phensuximide, trimethadione,
`ethosuximide, methsuximide, phensuximide, trimethadione,
`diaZepam, benZodiaZepines, phenacemide, pheneturide,
`diazepam, benzodiazepines, phenacemide, pheneturide,
`acetazolamide, sulthiame, bromide, and the like;
`
`acetaZolamide, sulthiame, bromide,
`and the like;
`M. antiparkinsonism drugs such as levodopa, amantadine
`M. antiparkinsonism drugs such as levodopa, amantadine
`and the like;
`and the like;
`N. narcotic-analgesics such as morphine, heroin, hydro
`N. narcotic-analgesics such as morphine, heroin, hydro-
`morphone, metopon, oxymorphone, levorphanol, codeine,
`morphone, metopon, oxymorphone, levorphanol, codeine,
`hydrocodone, xycodone, nalorphine, naloxone, naltrexone
`hydrocodone, xycodone, nalorphine, naloxone, naltrexone
`and the like;
`and the like;
`0. analgesic-antipyretics such as salycilates, phenylbuta
`0. analgesic-antipyretics such as salycilates, phenylbuta-
`zone, indomethacin, phenacetin and the like; and
`Zone, indomethacin, phenacetin and the like; and
`P. psychopharmacological drugs such as chlorpromaZine,
`P. psychopharmacological drugs such as chlorpromazine,
`methotrimepraZine, haloperidol, cloZapine, reserpine, imi
`methotrimeprazine, haloperidol, clozapine, reserpine, imi-
`pramine, tranylcypromine, phenelZine, lithium and the like.
`pramine, tranylcypromine, phenelzine, lithium and the like.
`The amount of pharmaceutically active agent that can be
`The amount of pharmaceutically active agent that can be
`used in the rapidly dissolving ?lms, according to the present
`used in the rapidly dissolving films, according to the present
`invention, is dependent upon the dose needed to provide an
`invention, is dependent upon the dose needed to provide an
`effective amount of the pharmaceutically active agent.
`effective amount of the pharmaceutically active agent.
`Examples of doses for speci?c pharmaceutically active
`Examples of doses for specific pharmaceutically active
`agents that can be delivered per one strip of rapidly dissolv-
`agents that can be delivered per one strip of rapidly dissolv
`ing oral film are reviewed in Table A.
`ing oral ?lm are revieWed in Table A.
`
`TABLE A
`TABLE A
`
`PHARMACEUTICALLY ACTIVE AGENT
`PHARMACEUTICALLY ACTIVE AGENT
`
`PREFERRED DOSE
`PREFERRED DOSE
`
`Chlorpheniralnine Maleate
`Chloipheniramine Maleate
`Brompheniralnine Maleate
`Brompheniramine Maleate
`Dexchlorpheniralnine
`Dexchlorpheniramine
`Dexbrompheniralnine
`Dexbrompheniramine
`Triprolidine Hydrochloride
`Triprolidine Hydrochloride
`Acrivastine
`Acrivastine
`Azatadine Maleate
`Azatadine Maleate
`Loratidine
`Loratidine
`Phenylephrine Hydrochloride
`Phenylephrine Hydrochloride
`Dextromethorphan Hydrobromide
`Dextromethorphan Hydrobromide
`Ketoprofen
`Ketoprofen
`Sumatriptan Succinate
`Sumatriptan Succinate
`Zolmitriptan
`Zolmitriptan
`Loperalnide
`Loperamide
`Famotidine
`Falnotidine
`Nicotine
`Nicotine
`Diphenhydramine Hydrochloride
`Diphenhydramine Hydrochloride
`Pseudoephedrine Hydrochloride
`Pseudoephedrine Hydrochloride
`
`4 mg.
`4 mg.
`4 mg.
`4 mg.
`2 mg
`2 mg.
`2 mg
`2 mg.
`2.5 mg
`2.5 mg.
`8 mg.
`8 mg
`1 mg.
`1 mg
`10 mg.
`10 mg
`10 mg
`10 mg.
`10430 mg
`10-30 mg.
`12.5425 mg
`12.5-25 mg.
`35470 mg
`35-70 mg.
`2.5 mg
`2.5 mg.
`2 mg
`2 mg.
`10 mg.
`10 mg
`2 mg.
`2 mg
`12.5425 mg
`12.5-25 mg.
`30 mg
`30 mg.
`
`4
`4
`Ion exchange resins preferred for use in the ?lms of the
`Ion exchange resins preferred for use in the films of the
`invention are water-insoluble and consist of a pharmaco-
`invention are Water-insoluble and consist of a pharmaco
`logically inert organic or inorganic matrix containing
`logically inert organic or inorganic matrix containing
`covalently bound functional groups that are ionic or capable
`covalently bound functional groups that are ionic or capable
`of being ioniZed under the appropriate conditions of pH. The
`5 (cid:9) of being ionized under the appropriate conditions of pH. The
`organic matrix may be synthetic (e.g., polymers or copoly
`organic matrix may be synthetic (e.g., polymers or copoly-
`mers of acrylic acid, methacrylic acid, sulfonated styrene,
`mers of acrylic acid, methacrylic acid, sulfonated styrene,
`sulfonated divinylbenZene), or partially synthetic (e.g.,
`sulfonated divinylbenzene), or partially synthetic (e.g.,
`modified cellulose and dextrans). The inorganic matrix can
`modi?ed cellulose and dextrans). The inorganic matrix can
`also be, e.g., silica gel modi?ed by the addition of ionic
`10 also be, e.g., silica gel modified by the addition of ionic
`groups. The covalently bound ionic groups may be strongly
`groups. The covalently bound ionic groups may be strongly
`acidic (e.g., sulfonic acid), Weakly acidic (e.g., carboxylic
`acidic (e.g., sulfonic acid), weakly acidic (e.g., carboxylic
`acid), strongly basic (e.g., quaternary ammonium), Weakly
`acid), strongly basic (e.g., quaternary ammonium), weakly
`basic (e.g., primary amine), or a combination of acidic and
`basic (e.g., primary amine), or a combination of acidic and
`basic groups. In general, those types of ion exchangers
`15 basic groups. In general, those types of ion exchangers
`suitable for use in ion exchange chromatography and for
`suitable for use in ion exchange chromatography and for
`such applications as deionization of water are suitable for
`such applications as deioniZation of Water are suitable for
`use in these controlled release drug preparations. Such ion
`use in these controlled release drug preparations. Such ion
`exchangers are described by H. F. Walton in “Principles of
`exchangers are described by H. F. Walton in "Principles of
`Ion Exchange” (pp. 3124343). The ion exchange resins
`20 Ion Exchange" (pp. 312-343). The ion exchange resins
`20
`useful in the present invention have exchange capacities
`useful in the present invention have exchange capacities
`beloW about 6 milliequivalents per gram (meq/ g) and pref
`below about 6 milliequivalents per gram (meq/g) and pref-
`erably beloW about 5.5 meq/g.
`erably below about 5.5 meq/g.
`The resin is crosslinked with a crosslinking agent selected
`The resin is crosslinked With a crosslinking agent selected
`from difunctional compounds capable of crosslinking poly
`25 from difunctional compounds capable of crosslinking poly-
`25
`styrenes; these are commonly knoWn in the art. Preferably,
`styrenes; these are commonly known in the art. Preferably,
`the crosslinking agent is a divinyl or polyvinyl compound.
`the crosslinking agent is a divinyl or polyvinyl compound.
`Most preferably the crosslinking agent is divinylbenZene.
`Most preferably the crosslinking agent is divinylbenzene.
`The resin is crosslinked to an extent of about 3 to about 20%,
`The resin is crosslinked to an extent of about 3 to about 20%,
`30 preferably about 4 to about 16%, more preferably about 6 to
`preferably about 4 to about 16%, more preferably about 6 to
`30
`about 10%, and most preferably about 8% by Weight based
`about 10%, and most preferably about 8% by weight based
`on the total resin. The resin is crosslinked with the crosslink-
`on the total resin. The resin is crosslinked With the crosslink
`ing agent by means well known in the art.
`ing agent by means Well knoWn in the art.
`The siZe of the ion exchange resins should preferably fall
`The size of the ion exchange resins should preferably fall
`35 within the range of about 20 to about 200 micrometers.
`Within the range of about 20 to about 200 micrometers.
`35
`Particle sizes substantially below the lower limit are difficult
`Particle siZes substantially beloW the loWer limit are di?icult
`to handle in all steps of the processing. Particle sizes
`to handle in all steps of the processing. Particle siZes
`substantially above the upper limit, e.g., commercially avail
`substantially above the upper limit, e.g., commercially avail-
`able ion exchange resins having a spherical shape and
`able ion exchange resins having a spherical shape and
`40 diameters up to about 1000 micrometers, are gritty in liquid
`diameters up to about 1000 micrometers, are gritty in liquid
`40
`dosage forms and have a greater tendency to fracture when
`dosage forms and have a greater tendency to fracture When
`subjected to drying-hydrating cycles.
`subjected to drying-hydrating cycles.
`Representative resins useful in this invention include
`Representative resins useful in this invention include
`AMBERLITE IRP-69 (obtained from Rohm and Haas) and
`AMBERLITE lRP-69 (obtained from Rohm and Haas) and
`45 Dow XYS-40010.00 (obtained from The Dow Chemical
`Bow XYS-40010.00 (obtained from The DoW Chemical
`Company). Both are sulfonated polymers composed of
`Company). Both are sulfonated polymers composed of
`polystyrene cross-linked with 8% of divinylbenzene, with an
`polystyrene cross-linked With 8% of divinylbenZene, With an
`ion exchange capacity of about 4.5 to 5.5 meq/g of dry resin
`ion exchange capacity of about 4.5 to 5.5 meq/g of dry resin
`(H+-form). Their essential difference is in physical form.
`(H+-form). Their essential difference is in physical form.
`AMBERLITE lRP-69 comprises irregularly-shaped par
`so AMBERLITE IRP-69 comprises irregularly-shaped par-
`50
`ticles with a size range of 47 to 149 micrometers, produced
`ticles With a siZe range of 47 to 149 micrometers, produced
`by mil