(12) United States Patent
`Leung et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,596,298 B2
`*Jul. 22, 2003
`
`US006596298B2
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`(54)
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`(75)
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`FAST DISSOLVING ORALLY COMSUMABLE
`FILMS
`
`(56)
`
`References Cited
`
`Inventors: Sau-Hung Spence Leung, Parsippany,
`NJ (US); Robert S. Leone, FanWood,
`NJ (US); Lori D. Kumar, Skillman, NJ
`(Us)
`Assignee: Warner-Lambert Company, Morris
`Plains, NJ (US)
`
`Notice:
`
`This patent issued on a continued pros
`ecution application ?led under 37 CFR
`1.53(d), and is subject to the tWenty year
`patent term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`Appl. No.: 09/395,104
`Filed:
`Sep. 14, 1999
`
`Prior Publication Data
`
`US 2003/0054034 A1 Mar. 20, 2003
`
`Related US. Application Data
`Provisional application No. 60/101,798, ?led on Sep. 25,
`1998.
`
`Int. Cl.7 .......................... .. A61K 7/24; A61K 9/70;
`A61M 37/00
`US. Cl. ......................... .. 424/435; 424/49; 424/55;
`424/405; 424/407; 424/410; 424/439; 424/441;
`424/443; 424/444
`Field of Search ............................... .. 424/404, 434,
`424/435, 405, 407, 410, 443, 439, 441,
`444, 49, 55
`
`U.S. PATENT DOCUMENTS
`
`3,444,858 A
`
`5/1969 Russell
`
`(List continued on neXt page.)
`
`FOREIGN PATENT DOCUMENTS
`
`CA
`EP
`
`1313620
`0161681
`
`2/1993
`11/1985
`
`(List continued on neXt page.)
`
`OTHER PUBLICATIONS
`
`Shih, Frederick E; “Edible ?lms from rice protein concen
`trate and pullulan.”; Cereal Chemistry, vol. 73, No. 3, 1996;
`pp 406—409.
`Edible Films Solve Problems; Food Technology; vol. 51,
`No. 2; Feb. 1997; pp. 60—74.
`
`Primary Examiner—Thurman K. Page
`(74) Attorney, Agent, or Firm—Evan J. Federman; Darryl
`C. Little
`
`(57)
`
`ABSTRACT
`
`Physiologically acceptable ?lms, including edible ?lms, are
`disclosed. The ?lms include a Water soluble ?lm-forming
`polymer such as pullulan. Edible ?lms are disclosed that
`include pullulan and antimicrobially effective amounts of
`the essential oils thymol, methyl salicylate, eucalyptol and
`menthol. The edible ?lms are effective at killing the plaque
`producing germs that cause dental plaque, gingivitis and bad
`breath. The ?lm can also contain pharmaceutically active
`agents. Methods for producing the ?lms are also disclosed.
`
`20 Claims, 2 Drawing Sheets
`
`DRL - EXHIBIT 1020
`DRL001
`
`

`
`US 6,596,298 B2
`Page 2
`
`US. PATENT DOCUMENTS
`
`4/1974 Pospischil et a1. .......... .. 424/28
`3,803,300 A
`4/1980 ShurZenegger et 81.
`4,197,289 A
`4,562,020 A * 12/1985 Hijiya et a1. ................ .. 264/39
`
`
`
`
`
`4,623,394 A 11/1986 Nakamura et a1. 4,820,506 A 4/1989 Kleinberg et a1. ........... .. 426/3
`
`5/1990 Schmidt
`4,925,670 A
`5/1990 Hijiya et a1.
`4,927,636 A
`6/1991 Friedman et a1. ......... .. 424/426
`5,023,082 A
`9/1991 Sanvordeker et 81.
`5,047,244 A
`5,284,659 A * 2/1994 Churukuri et a1. ........ .. 424/441
`5,354,551 A 10/1994 Schmidt
`5,411,945 A
`5/1995 Ozaki et 81.
`5,518,902 A
`5/1996 Ozaki et 81.
`5,629,003 A
`5/1997 Horstmann et 81.
`5,700,478 A * 12/1997 Biegajski et a1. ......... .. 424/434
`5,741,510 A
`4/1998 Rolfet a1. .
`.. 424/448
`5,948,430 A * 9/1999 Zerbe et a1. ..
`424/435
`
`FOREIGN PATENT DOCUMENTS
`
`5};
`EP
`EP
`EP
`EP
`
`ggggg
`gggfggg
`M997
`0750905
`2/1997
`0781546
`0 781 546 A1 * 7/1997
`0803243
`10/1997
`
`JP
`JP
`JP
`JP
`
`JP
`
`JP
`
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`62072609
`62135417
`63059855
`63250318
`
`63296655
`
`63310817
`
`63310818
`04321619
`5001198
`541602
`5236885
`101790451
`2642354
`9124512
`W0 9303649
`W0 9731621
`W0-98/11867
`W0 9820862
`W0 9826763
`W0 9826780
`W0 9855079
`W0 9917753
`
`4/1987
`6/1987
`3/1988
`“V1988
`
`12/1988
`
`12 1988
`/
`12/1988
`11/1992
`1/1993
`6/1993
`9/1993
`12/1996
`5/1997
`5/1997
`3/1993
`9/1997
`3/1998
`5/1998
`6/1998
`671998
`12/1998
`4/1999
`
`* cited by examiner
`
`DRL - EXHIBIT 1020
`DRL002
`
`

`
`U.S. Patent
`
`Jul. 22, 2003
`
`Sheet 1 0f 2
`
`US 6,596,298 B2
`
`DRL - EXHIBIT 1020
`DRL003
`
`

`
`U.S. Patent
`
`Jul. 22, 2003
`
`Sheet 2 0f 2
`
`US 6,596,298 B2
`
`DRL - EXHIBIT 1020
`DRL004
`
`

`
`US 6,596,298 B2
`
`1
`FAST DISSOLVING ORALLY COMSUMABLE
`FILMS
`
`This application claims the bene?t of Provisional Appli
`cation No. 60/101,798, ?led Sep. 25, 1998.
`
`FIELD OF THE INVENTION
`
`This invention relates to fast dissolving orally consumable
`?lms. The ?lms are used to deliver breath deodoriZing
`agents, antimicrobial agents and salivary stimulants to the
`oral cavity. The ?lms can also be used to deliver pharma
`ceutically active agents.
`
`BACKGROUND OF THE INVENTION
`
`In a more perfect World, people Would thoroughly cleanse
`their mouths after each meal as part of their routine oral
`hygienic practices. Unfortunately, several factors conspire to
`prevent Widespread compliance With this basic requirement
`of a good oral cleaning regimen.
`Oral cleansing can be dif?cult or inconvenient at times,
`depending on the nature of the cleansing and the situation in
`Which the cleansing must occur. Brushing, ?ossing, cleaning
`your tongue and gargling using a variety of devices and
`compositions Well-suited for the privacy of one’s home are
`common oral care practices. HoWever, the devices and
`compositions used in oral cleansing practices are less con
`venient to use aWay from home, Where bathroom facilities
`might be scarce, unavailable or unsanitary.
`As brushing, ?ossing, cleaning your tongue and gargling
`in public are not considered to be socially acceptable behav
`iors in many, if not all cultures, a variety of less obtrusive
`oral cleansing products have been developed. These include
`breath-freshening gums and loZenges. Although gums and
`loZenges have been formulated to achieve a variety of
`bene?cial effects, they are not alWays socially acceptable.
`For example, gum is expressly banned from certain
`institutions, such as schools as Well as in certain countries,
`such as Singapore. Gums and mints are used over extended
`periods of time, and they require an amount of sucking or
`cheWing action on the part of the consumer, Which can be
`distracting, tedious and undesirable.
`Another portable oral cleansing product is a mouthspray.
`Like a mouthWash, a mouthspray can provide the consumer
`With a quick burst of strong breath-freshening action, Which
`might be overWhelming in an extended-consumption prod
`uct like gum or loZenges. On the other hand, mouthsprays
`are obtrusive. Spraying a mouthspray typically generates a
`noise, Which undesirably draWs the attention of the public to
`the consumer. Moreover, mouthsprays are typically pack
`aged in relatively expensive and complex metal canisters,
`Which can clog in use and are not environmentally friendly.
`Furthermore, misdirecting the spray not only Wastes the
`product, but can result in irritated eyes, a sticky face and/or
`stained clothing.
`It has been proposed to use an edible ?lm as a vehicle for
`unobtrusively delivering breath-freshening agents. See JP
`5-236885. This Japanese patent application does not,
`hoWever, teach the inclusion of antimicrobial agents in the
`?lm, using the ?lm to decrease the amount of undesirable
`bacteria Within the oral cavity, or stimulating saliva.
`Furthermore, this patent application does not disclose
`employing its ?lm for purposes other than breath freshening
`or Within cavities other than the mouth.
`U.S. Pat. No. 5,518,902 to OZaki et al. (Hayashibara)
`discloses high pullulan content products, such as edible
`
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`2
`?lms, dentifrices and pharmaceuticals (column 3, lines
`44—5 6 and Example B-8). The products can include a variety
`of ingredients in addition to pullulan, such as other
`polysaccharides, polyhydric alcohols, antiseptics and ?avor
`imparting agents (column 4, line 58 to column 5, line 11).
`None of the essential oils, such as thymol, eucalyptol,
`methyl salicylate or menthol, are mentioned as suitable
`ingredients.
`U.S. Pat. No. 5,411,945 to OZaki et al. (Hayashibara)
`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 polysaccharides, antibacterial agents, ?avor
`imparting agents and pharmaceutically active substances
`(column 4, lines 5—15). None of the essential oils are
`mentioned as suitable ingredients.
`U.S. Pat. No. 4,851,394 to Kubodera discloses
`glucomannan/polyhydric alcohol edible ?lms, Which can
`comprise pullulan (column 3, line 59 to column 4, line 21).
`The ?lms are contrasted With existing pullulan-based ?lms,
`Which are said to lack resistance to Water (column 1, lines
`40—44). None of the essential oils are mentioned as suitable
`ingredients.
`U.S. 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.
`U.S. Pat. No. 4,623,394 Nakamura et al. discloses a
`gradually disintegrable molded article that can be a ?lm
`made With pullulan. The articles contain a particular
`heteromannan, Which can be locust bean gum.
`U.S. Pat. No. 4,562,020 Hijiya et al. discloses a process
`for producing a self-supporting ?lm of a glucan, Which can
`be pullulan.
`Japanese Patent Document J P5 -1198 discloses ?lms made
`of polyvinyl alcohol and at least one of carrageenan, Water
`soluble cellulose alpha-starch and Water-soluble polysaccha
`rides.
`W0 99/ 17753 discloses rapidly dissolving ?lms for deliv
`ery 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.
`Despite the existence of rapidly dissolving orally con
`sumable ?lms in the prior art, there is still room for
`improvement in such ?lms, and in processes for making
`them.
`All references cited herein are incorporated herein by
`reference in their entireties.
`
`SUMMARY OF THE INVENTION
`The invention provides a physiologically acceptable ?lm,
`Which is particularly Well adapted to adhere to and rapidly
`dissolve in the mouth of a consumer. In a ?rst embodiment
`of the invention, the ?lm delivers at least one oral care agent,
`such as antimicrobial agents and salivary stimulants. The
`antimicrobial agents are effective against germs that cause
`
`DRL - EXHIBIT 1020
`DRL005
`
`

`
`US 6,596,298 B2
`
`3
`halitosis, dental plaque, and gingivitis. The salivary stimu
`lants are effective against the condition known as xerostomia
`or dry mouth. Additionally, the oral care ?lms are a breath
`freshener effective against oral malodor. The ?lm former
`used to make the ?lms according to the present invention
`entraps the oral care agents in the oral cavity to provide
`extended ef?cacy.
`In a second embodiment of the invention, the rapidly
`dissolvable ?lm acts as a vehicle for administering a phar
`maceutically active agent orally, through a mucous mem
`brane or an open Wound of a patient.
`The invention is also directed to a method for producing
`a supple, non-self-adhering ?lm especially suitable for oral
`delivery. The method comprises mixing a ?lm forming agent
`and at least one stabiliZing agent to provide a ?lm-forming
`mixture; dissolving Water-soluble ingredients in Water to
`provide an aqueous solution; 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 emulsi?ed gel; casting the uniform gel on
`a substrate; and drying the cast gel to provide a ?lm.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a photograph of an agar plate spread With
`Streptococcus mutans, ATCC 25175, and exposed to a ?lm
`according to the present invention that contains 0.391 mg of
`essential oils.
`FIG. 2 is a photograph of an agar plate spread With
`Streptococcus mutans, ATCC 25175, and exposed to drops
`of an essential oil mixture containing 0.391 mg of essential
`oils per drop.
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`Description of Oral Care Film Compositions
`The ?rst embodiment of the invention is a physiologically
`acceptable ?lm that is particularly Well adapted to adhere to
`and dissolve in a mouth of a consumer to deliver an
`antimicrobial agent that kills germs that cause halitosis,
`dental plaque and gingivitis. Thus, the ?lm can be an
`effective tool in the prevention and treatment of halitosis,
`dental plaque accumulation, dental tartar accumulation and
`gingivitis. This ?lm preferably comprises pullulan, thymol,
`methyl salicylate, eucalyptol and menthol.
`LISTERINE® brand mouthWash is, perhaps, the most
`Well-knoWn example of an antiseptic oral composition that
`has proven effective in killing microbes in the oral cavity
`that are responsible for plaque, gingivitis and bad breath.
`LISTERINE® brand mouthWash achieves its antimicrobial
`effect through a combination of essential oils that penetrate
`and kill the microorganisms. These essential oils include
`precisely balanced amounts of thymol, methyl salicylate,
`menthol and eucalyptol (hereinafter “the essential oils”) in a
`hydro alcoholic solution. Many bad breath bacteria live in
`pits or ?ssure on the surface of the tongue. Listerine®
`Antiseptic mouthWash reduces bad breath because of high
`concentrations of antimicrobial agents in a liquid medium
`that can easily penetrate into these pits and ?ssures. This
`Would not be possible With a solid dosage form containing
`loW amounts of these antimicrobial ingredients. HoWever,
`the preferred consumable ?lm of the invention captures a
`signi?cant portion of the hygienic bene?ts and the consumer
`appeal of LISTERINE® brand mouthWash, in a more por
`table and unobtrusively consumed form.
`
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`4
`It Was a signi?cant challenge to maintain the essential oil
`interaction and relatively high oil content of LISTERINE®
`brand mouthWash in a ?lm. HoWever, the inventors have
`overcome this challenge in providing the ?lm of the inven
`tion.
`Afurther aspect of this invention is that While the amounts
`of LISTERINE® essential oils are relatively high for incor
`poration in a ?lm, the ?lm according to the present invention
`still delivers a loWer total amount of essential oils per unit
`dose When compared to that of LISTERINE® mouthWash.
`Yet the ?lm suprisingly provides antimicrobial efficacy in
`the oral cavity. The inventors theoriZe that the preferred ?lm
`forming ingredient, pullulan, forms a thin layer on the oral
`surfaces entrapping the small amount of essential oils Which
`are capable of penetrating into the pits and ?ssures of the
`oral cavity to provide sustained antimicrobial ef?cacy.
`Although the inventors are presently unaWare of any other
`breath-freshening consumable ?lm that provides antimicro
`bial ef?cacy, they are aWare of a consumable ?lm disclosed
`in JP 5-236885, Which is said to possess breath-freshening
`activity, but is not described as possessing any ingredients
`having signi?cant antimicrobial activity. Moreover, JP
`5-236885 teaches that its ?lm should contain ?avor and
`extract in amounts of 5 to 7 Wt %, With the ?avor being
`added as an oil (the essential oils are not disclosed), Whereas
`the ?lm of the invention preferably has an oil content of at
`least about 10 Wt %, more preferably about 15 Wt % to about
`30 Wt %, most preferably about 15 Wt % to about 25 Wt %.
`Except as otherWise noted in the examples, the amounts of
`oils and other ingredients in the ?lm are Wt % after the ?lm
`formulation has been dried to create the ?lm.
`The amounts of the speci?c essential oils used in the ?lm
`compositions can vary as long as they are in amounts
`suf?cient to provide antimicrobial ef?cacy. Generally the
`amount of thymol, methyl salicylate and eucalyptol is from
`about 0.01 to about 4 Wt % of the ?lm composition,
`preferably about 0.50 to about 3.0 Wt % and even more
`preferably from about 0.70 to about 2.0 Wt % of the ?lm.
`Menthol can be added from about 0.01 to about 15 Wt % of
`the composition, preferably about 2.0 to about 10 Wt % and
`even more preferably from about 3 to about 9 Wt % of the
`?lm. The amounts added can be readily determined to those
`skilled in the art and can exceed these amounts as long as the
`total oil content does not create sticking or other processing
`problems. In certain embodiments, the essential oils are
`combined in amounts synergistically effective to kill the
`plaque-producing germs that cause dental plaque, gingivitis
`and bad breath.
`A major dif?culty in formulating a ?lm having such a
`relatively high oil content is that simply increasing the
`amount of oil in the ?lm Without determining the precise
`proportions of the many other ingredients typically results in
`a ?lm that is too moist and therefore dif?cult to handle or
`process. The inventors have discovered hoW to provide a
`high oil content ?lm that is moist enough so that it is not
`brittle, but is not so moist that it feels undesirably slimy or
`signi?cantly adheres to adjacent ?lms. Thus, a non-self
`adhering ?lm according to the invention can be stored in
`contact With another such ?lm (e.g., in a stack), or can be
`Wound about itself (e.g., around a spool), Without having to
`place a non-stick agent (e.g., a plastic ?lm, paper or other
`support) betWeen adjacent portions of ?lm.
`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,
`
`DRL - EXHIBIT 1020
`DRL006
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`US 6,596,298 B2
`
`5
`carboxymethyl cellulose, polyvinyl alcohol, sodium
`alginate, 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,
`collagen, gelatin, Zein, gluten, soy protein isolate, Whey
`protein isolate, casein and mixtures thereof. Apreferred ?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.
`The ?lm of the invention preferably comprises pullulan as
`a ?lm-forming agent and the essential oils as antimicrobial/
`?avoring agents, and can further comprise Water, additional
`antimicrobial agents, additional ?lm-forming agents, plasti
`ciZing agents, additional ?avoring agents, sulfur precipitat
`ing agents, saliva stimulating agents, cooling agents,
`surfactants, stabiliZing agents, emulsifying agents, thicken
`ing agents, binding agents, coloring agents, sWeeteners,
`fragrances, and the like.
`Due to the relatively high oil content in the oral care ?lm,
`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 the
`?lm With a plasticiZing agent other than glycerin, Which is
`also a humectant, and With a sWeetener other than sorbitol,
`Which is a mild humectant.
`Sulfur precipitating agents that reduce oral malodor can
`also be added to the oral care ?lms according to the present
`invention. These agents bind With, and inactivate, the vola
`tile sulfur compounds that cause a large percentage of oral
`malodor. Sulfur precipitating agents useful in the present
`invention include metal salts such as copper salts and Zinc
`salts. Preferred salts include copper gluconate, Zinc citrate
`and Zinc gluconate. The amount of sulfur precipitating agent
`is from about 0.01 to about 2 Wt %, preferably about 0.15 Wt
`% to about 1.5 Wt %, even more preferably about 0.25 Wt %
`to about 1.0 Wt % of the ?lm.
`Saliva stimulating agents can also be added to the oral
`care ?lms according to the present invention. Useful saliva
`stimulating agents are those disclosed in US. Pat. No.
`4,820,506, Which is incorporated by reference herein in its
`entirety. 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 %,
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`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.
`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
`monosaccharides, 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-oxathiaZine-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-aspartyl-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 chlori
`nated 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 B-E beloW dued to the sWeeteners’
`
`DRL - EXHIBIT 1020
`DRL007
`
`

`
`US 6,596,298 B2
`
`10
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`15
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`20
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`25
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`30
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`35
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`known sweetening ability. In contrast, the sweeteners
`described in categories B-E 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
`synthetic fruit ?avors such as vanilla, chocolate, coffee,
`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 63—258, 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-dodecenal (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
`
`40
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`45
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`50
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`55
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`60
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`65
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`8
`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
`sulfobenZylamino) diphenyl-methylene]-[1-N-ethyl-N-p
`sulfonium benZyl)-2,5-cyclo-hexadienimine]. A full recita
`tion of all FD&C and D&C dyes and their corresponding
`chemical structures may be found in the Kirk-Othmer Ency
`clopedia of Chemical Technology, Volume 5, Pages
`857—884, which text is accordingly incorporated herein by
`reference.
`
`Antimicrobial Efficacy of Oral Care Films
`
`The preferred embodiment of the oral care ?lm compo
`sition according to the present invention contains the essen
`tial oils used in Listerine® mouthwash to provide antimi
`crobial ef?cacy. The ?lms are shaped and siZed to be placed
`in the oral cavity. The ?lm adheres to a surface in the mouth,
`usually the roof of the mouth or the tongue, and quickly
`dissolves. The amount of essential oils in one individual ?lm
`that is a preferred siZe for placing in the mouth is signi?
`cantly lower than that in the recommended amount, 20 ml,
`of Listerine® mouthwash.
`In a preferred formula according to the present invention,
`the amount of thymol and eucalyptol in the ?lm is about 70
`times less than in the mouthwash. The amount of methyl
`salicylate in the ?lm is about 46 times less than in the
`mouthwash. The amount of menthol in the ?lm is about 2.8
`times less than in the mouthwash. These ?gures are based on
`comparing a 20 ml dose of liquid mouthwash with a 0.0358
`gram ?lm.
`The inventors have unexpectedly found that the ?lm
`provides sustained antimicrobial ef?cacy at these low
`amounts of oils. The inventors believe that the ef?cacy of the
`essential oils is enhanced by the creation of a layer of
`pullulan in the oral cavity that holds the essential oils. This
`is unexpected because pullulan is water-soluble and the ?lm
`dissolves very quickly.
`The extended antimicrobial activity is shown in the fol
`lowing experiments.
`The purpose of these experiments was to determine the
`antibacterial ef?cacy of an application of a breath ?lm on
`tongue malodor microorganisms thirty, sixty or ninety min
`utes after use. The thirty minute study also tested the ef?cacy
`of using two ?lms. Subjects’ baseline oral malodor micro
`bial recoverable counts were determined by plating the
`microorganisms recovered from a tongue swab on a selec
`tive agar medium. The test product was dispensed and
`subjects dissolved one or two breath ?lms on their tongue.
`Subjects remained on the premises and returned for a second
`tongue swab thirty, sixty or ninety minutes after placement
`of the test product on their tongue. After a forty-eight hour
`washout period, subjects returned for a no treatment control.
`The thirty minute single ?lm use group showed a reduc
`tion in mean log malodor microbial counts compared to the
`control group. The data was borderline statistically signi?
`cant (p=0.052). The difference between the one ?lm group
`and the no treatment control group represented a 42.7%
`reduction in malodor microbial colony counts.
`Statistically signi?cant malodor microbial reduction was
`also observed with the two ?lm use group. A 79.6% reduc
`tion in malodor microbial colony counts was obtained
`(p<0.001).
`Statistical