United States Patent [19]
`Zerbe et al.
`
`[54] WATER SOLUBLE FILM FOR ORAL
`ADMINISTRATION WITH INSTANT
`WETTABILITY
`
`[75] Inventors: Horst Georg Zerbe, Green Pond;
`J ian-HWa Guo, Sparta; Anthony
`Serino, Boonton, all of NJ.
`
`[73] Assignee: LTS Lohmann Therapie-Systeme
`GmbH, NeuWied, Germany
`
`[21] Appl. No.1 08/904,607
`[22]
`Filed:
`Aug. 1, 1997
`[30]
`Foreign Application Priority Data
`
`US005948430A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,948,430
`Sep. 7, 1999
`
`5,229,164
`5,346,701
`5,413,792
`
`7/1993 Pins et al. ................................. .. 427/3
`9/1994 Heiber et al.
`. 424/435
`5/1995 Ninomiya et al.
`424/435
`
`5,472,704 12/1995 Santus et al. . . . . . . .
`. . . .. 424/435
`5,700,478 12/1997 Biegajski et al. ..................... .. 424/435
`
`FOREIGN PATENT DOCUMENTS
`
`1 263 312 11/1989
`Canada .
`0 219 762 4/1987
`European Pat. Off. .
`0 381 194 8/1990
`European Pat. Off. .
`0 200 508 10/1991
`European Pat. Off. .
`0 452 446 10/1991
`European Pat. Off. .
`2 449 865
`4/1976 Germany .
`3 630 603 3/1988 Germany .
`WO91/06270 5/1991 WIPO .
`
`Nov. 11, 1996 [DE]
`
`Germany ......................... .. 196 46 392
`
`[51]
`
`Int. Cl.6 ........................... .. A61F 7/02; A61K 13/00;
`A61K 9/70; A61L 15/16
`[52] US. Cl. ............................................................ .. 424/435
`[58] Field of Search ............................................. .. 424/435
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6/1977 MlodoZeniec et al. ................. .. 424/27
`4,029,757
`6/1977 MlodoZeniec et al. ..
`.. 424/27
`4,029,758
`6/1977 Reif .............................. .. 424/27
`4,031,200
`4,876,092 10/1989 MiZobuchi et al.
`424/435
`4,900,552
`2/1990 Sanvordeker et al.
`424/435
`5,047,244
`9/1991 Sanvordeker et al. ................ .. 424/435
`
`Primary Examiner—Shep K. Rose
`Attorney, Agent, or Firm—Wenderoth, Lind & Ponack,
`L.L.P.
`
`[57]
`
`ABSTRACT
`
`A composition containing therapeutic agents and/or breath
`freshening agents for use in the oral cavity is disclosed. The
`carrier comprises Water-soluble polymers in combination
`With certain ingredients and provides a therapeutic and/or
`cosmetic effect. The ?lm is coated and dried utilizing
`existing coating technology and exhibits instant Wettability
`folloWed by rapid dissolution/disintegration upon adminis
`tration in the oral cavity.
`
`12 Claims, No Drawings
`
`TEVA EXHIBIT 1027
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`1
`WATER SOLUBLE FILM FOR ORAL
`ADMINISTRATION WITH INSTANT
`WETTABILITY
`
`BACKGROUND OF THE INVENTION
`A composition containing therapeutic agents and/or
`breath freshening agents for use in the oral cavity is dis
`closed. The carrier comprises Water-soluble polymers in
`combination With certain ingredients and provides a thera
`peutic and/or cosmetic effect. The ?lm is coated and dried
`utilizing existing coating technology and exhibits instant
`Wettability folloWed by rapid dissolution/disintegration
`upon administration in the oral cavity.
`Mucoadhesive dosage forms for application to the oral
`cavity Which are designed to deliver therapeutic and/or
`cosmetic agents to the oral mucosa are knoWn in the art. US.
`Pat. No. 5,047,244 describes a mucoadhesive carrier alloW
`ing the controlled release of a therapeutic agent via the
`mucosal tissue comprising an anhydrous but hydratable
`polymer matrix and amorphous fumed silica. An optional
`Water-insoluble ?lm can be added to provide a non-adhering
`surface. In WO 91/06270, the same authors disclose a
`trilaminate ?lm suitable for prolonged delivery of an active
`ingredient in the oral cavity.
`In a similar Way, US. Pat. No. 4,876,092 discloses a
`sheet-shaped adhesive preparation comprising an adhesive
`layer containing certain Water-soluble and Water-insoluble
`polymers and a Water-insoluble carrier Which can adhere to
`the oral mucosa thereby releasing an active agent to the oral
`cavity. All the devices so far cited are not completely Water
`soluble and Will stay in the oral cavity even after the
`therapeutic goal has been achieved leaving the patient With
`a certain discomfort in the mouth resulting mainly from the
`support layer Which leaves an insoluble residue in the
`mouth.
`A number of attempts have been made to reduce the
`adverse feeling in he oral cavity caused by the rigidity and
`in?exibility of the support layer by introducing soft ?lm
`supports. EP 0 200 508 B1 and EP 0 381 194 B1 disclose the
`use of polyethylene ?lms, polyvinyl acetate, ethylene-vinyl
`acetate copolymers, metal foils, laminates of cloth or paper
`and a plastic ?lm and similar materials as soft ?lm supports,
`Whereby synthetic resins like polyethylene, vinyl acetate
`homopolymers, and ethylene-vinyl acetate are the preferred
`materials. In a similar Way, CA 1 263 312 discloses the use
`of polyole?nes such as polyethylene, polypropylene,
`polyesters, PVC, and non-Woven fabrics as soft support
`materials.
`HoWever, these devices still leave the patient With a
`considerable amount of residue from the Water-insoluble
`support ?lm thereby still causing a feeling of discomfort.
`The obvious solution to overcome tis problem Was to
`develop mucoadhesive ?lms Which completely disintegrate,
`or even completely dissolve in the saliva. Fuchs and Hil
`mann (DE 24 49 865.5) prepared homogeneous, Water
`soluble ?lms intended for buccal administration of hor
`mones. They proposed the use of Water-soluble cellulose
`derivatives, like hydroxyethyl cellulose, hydroxypropyl
`cellulose, or methyl hydroxypropyl cellulose, as ?lm form
`ing agents.
`Both DE 36 30 603 and EP 0 219 762 disclose the use of
`sWellable polymers such as gelatine or corn starch as ?lm
`forming agents, Which upon application to the oral cavity
`sloWly disintegrate, thereby releasing an active ingredient
`incorporated in the ?lm. The same polymers can also be used
`to prepare ?lms Which are intended for dental cleansing, as
`described in EP 0 452 466 B1.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`5,948,430
`
`2
`These preparations still create an adverse feeling in the
`mouth Which is mainly caused by their initial rigidity and
`delayed softening. Thus, there has still been a demand for a
`composition for use in the oral cavity Which meets the
`requirement of providing a pleasant feeling in the mouth.
`The present invention discloses methods and compositions
`that are capable of avoiding an adverse feeling by providing
`the ?lm Which is intended for application to the oral mucosa
`With instant Wettability, While achieving adequate tensile
`strength in the free ?lm to alloW for easy coating,
`converting, and packaging of a consumer-friendly product.
`
`DESCRIPTION OF THE INVENTION
`
`The present invention contemplates a rapidly dissolving
`?lm Which can be adhered to the oral cavity thereby releas
`ing a pharmaceutically or cosmetically active agent, said
`?lm comprising Water-soluble polymers, one or more
`polyalcohols, and one or ore pharmaceutically or cosmeti
`cally active ingredients. Optionally, he formulation may
`contain a combination of certain plasticiZers or surfactants,
`colorants, sWeetening agent, ?avors, ?avor enhancers, or
`other excipients commonly used to modify the taste of
`formulations intended for application to the oral cavity. The
`resulting ?lm is characteriZed by an instant Wettability
`Which causes the ?lm to soften immediately after application
`to the mucosal tissue thus preventing the patient from
`experiencing any prolonged adverse feeling in the mouth,
`and a tensile strength suitable for normal coating, cutting,
`slitting, and packaging operations.
`The mucoadhesive ?lm of the present invention contains
`as essential components a Water-soluble polymer or a com
`bination of Water-soluble polymers, one or more plasticiZers
`or surfactants, one or more polyalcohols, and a pharmaceu
`tically or cosmetically active ingredient.
`The polymers used for the mucoadhesive ?lm include
`polymers Which are hydrophilic and/or Water-dispersible.
`Preferred polymers are Water-soluble cellulose-derivatives.
`Hydroxypropylmethyl cellulose, hydroxyethyl cellulose, or
`hydroxypropyl cellulose, either alone, or mixtures thereof,
`are particularly preferred. Other optional polymers, Without
`limiting the invention, include polyvinyl pyrrolidone, car
`boxymethyl cellulose, polyvinyl alcohol, sodium alginate,
`polyethylene glycol, natural gums like xanthane gum,
`tragacantha, guar gum, acacia gum, arabic gum, Water
`dispersible polyacrylates like polyacrylic acid, methyl
`methacrylate copolymer, carboxyvinyl copolymers. The
`concentration of the Water-soluble polymer in the ?nal ?lm
`can vary betWeen 20 and 75% (W/W), preferably betWeen 50
`and 75% (W/W).
`The surfactants used for the mucoadhesive ?lm may be
`one or more nonionic surfactants. When a combination of
`surfactants is used, the ?rst component may be a polyoxy
`ethylene sorbitan fatty acid ester or a ot-hydro-uu
`hydroxypoly (oxyethylene)poly(oxypropylene)poly
`(oxyethylene) block copolymer, While the second
`component may be a polyoxyethylene alkyl ether or a
`polyoxyethylene castor oil derivative. Preferably the HLB
`value of the polyoxyethylene sorbitan fatty acid ester should
`be betWeen 10 and 20, Whereby a range of 13 to 17 is
`particularly preferred. The ot-hydro-uu-hydroxypoly
`(oxyethylene)poly(oxypropylene) poly(oxyethylene) block
`copolymer should contain at lest 35 oxypropylene-units,
`preferably not less than 50 oxyproplene-units.
`The polyoxyethylene alkyl ether should have an HLB
`value betWeen 10 and 20, Whereby an HLB value of not less
`than 15 is preferred. The polyoxyethylene castor oil deriva
`
`TEVA EXHIBIT 1027
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`5,948,430
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`3
`tive has to have an HLB value of 14—16. In order to achieve
`the desired instant Wettability, the ratio betWeen the ?rst and
`second component of the binary surfactant mixture should
`be kept Within 1:10 and 1:1, more preferably betWeen 1:5
`and 1:3. The total concentration of surfactants in the ?nal
`?lm depends on the properties of the other ingredients, but
`usually has to stay betWeen 0.1 and 5% (W/W). The polyal
`cohol is used to achieve the desired level of softness of the
`?lm. Examples of polyalcohols include glycerol, polyeth
`lene glycol, propylene glycol, glycerol monoesters With fatty
`acids or other pharmaceutically used polyalcohols. The
`concentration of the polyalcohol in the dry ?lm usually
`ranges betWeen 0.1 and 5% (W/W).
`The ?lm is Well suited for the delivery of a Wide range of
`pharmaceutically active ingredients via the mucous mem
`branes of a patient particularly the buccal mucosa. Thera
`peutic agents Which exhibit absorption problems due to
`solubility limitations, degradation in the gasto-intestinal
`tract, or extensive metabolism are particularly Well suited.
`Without limiting the invention, examples of the therapeutic
`agents include hypnotics, sedatives, antiepileptics, aWaken
`ing agents, psychoneurotropic agents, neuromuscular block
`ing agents, antispasmodic agents, antihistaminics,
`antiallergics, cardiotonics, antiarrhythmics diuretics,
`hypotensives, vasopressors, antitussive expectorants, thy
`roid hormones, sexual hormones, antidiabetics, antitumor
`agents, antibiotics and chemotherapeutics, and narcotics.
`The amount of drug to be incorporated into the ?lm depends
`on the kind of drug and is usually betWeen 0.01 and 20%
`(W/W), but it can be higher if necessary to achieve the desired
`effect.
`Cosmetically active agents may include breath freshening
`compounds like menthol other ?avors or fragrances com
`monly used for oral hygiene, and/or actives used for dental
`and/or oral cleansing like quarternary ammonium bases. The
`effect of ?avors may be enhanced using ?avor enhancers like
`tartaric acid, citric acid vanillin, or the like. Colorants Which
`may optionally be mixed in the ?lm must be safe in terms of
`toxicity and should be accepted by the Food And Drug
`Administration for use in cosmetics.
`The mucoadhesive ?lm according to the present invention
`can be prepared as folloWs: The polyalcohol, surfactants,
`plasticiZers, and possible other ingredients except the Water
`soluble or Water-dispersible polymer(s) are dissolved in a
`sufficient amount of a solvent Which is compatible With
`them. Examples of compatible solvents include Water, alco
`hols or mixtures thereof. After a clear solution has been
`formed, the Water-dispersible polymer or mixture of Water
`dispersible polymers is sloWly added With stirring, and heat
`if necessary, until a clear and homogeneous solution has
`been formed, folloWed by the addition of active ingredients
`and ?avors. The solution is coated onto a suitable carrier
`material and dried to form a ?lm. The carrier material must
`have a surface tension Which alloWs the polymer solution to
`spread evenly across the intended coating Width Without
`soaking in to form a destructive bond betWeen the tWo.
`Examples of suitable materials include non-siliconiZed poly
`ethylene terephthalate ?lm, non-siliconiZed kraft paper,
`polyethylene-impregnated kraft paper, or non-siliconiZed
`polyethylene ?lm.
`The coating of the solution onto the carrier material can
`be performed using any conventional coating equipment. A
`more preferred coating technique Wold involve a knife-over
`roll coating head.
`The thickness of the resulting ?lm depends on the con
`centration of solids in the coating solution and on the gap of
`
`55
`
`60
`
`65
`
`4
`the coating head and can vary betWeen 5 sand 200 pm.
`Drying of the ?lm is carried out in a high-temperature
`air-bath using a drying oven, drying tunnel, vacuum drier, or
`any other suitable drying equipment, Which does not
`adversely affect the active ingredient(s) or ?avor of the ?lm.
`In order to reliably avoid an adverse feeling in the mouth, a
`dry ?lm thickness of 70 pm should not be exceeded.
`For better ease of use, the dry ?lm can be cut into pieces
`of suitable siZe and shape and packed in to a suitable
`container.
`The invention Will noW be explained more speci?cally
`With reference to the folloWing examples, Which are given
`for illustration of this invention and are not intended to be
`limiting thereof.
`
`EXAMPLE 1
`
`15 g of sorbitol 6 g of glycerol, 0.5 g of polysorbate 80
`(TWeen 80), 2 g of Brij 35, 25 g of lemon mint ?avor, 3 g
`of aspartame, 15 g of 1-menthol, and 3 g of citric acid are
`stirred at 60° C. in a mixture of 250 g Water and 250 g
`ethanol until a clear solution has been formed. To the
`solution, 30 g of hydroxypropylmethyl cellulose are added
`sloWly under stirring until a clear and homogeneous solution
`has been formed. The resulting solution is alloWed to cool to
`room temperature and coated onto a suitable carrier material,
`for example non-siliconiZed, polyethylene-coated kraft
`paper using conventional coating/drying equipment. Coat
`ing gap and Web speed have to be adjustable to achieve a dry
`?lm thickness betWeen 20 and 50 pm. The drying tempera
`ture depends on the length of the drying oven and the Web
`speed and has to be adjusted to remove the solvents
`completely, or almost completely, from the ?lm. The result
`ing ?lm is peeled off the carrier Web and cut into pieces of
`a shape and siZe suitable for the intended use.
`
`EXAMPLE 2
`
`3 g sorbitol 1.5 g Kollidon 30 (supplier: BASE), 5 g
`glycerol, 5 g propylene glycol, 5 g polyethylene glycol, 4 g
`polysorbate 80 (TWeen 80), 8 g Brij 35, 12 g peppermint
`?avor, and 0.8 g aspartame are dissolved in a mixture
`containing 400 g Water and 400 g ethanol at 60° C. under
`stirring. To the clear solution, 28 g hydroxypropylmethyl
`cellulose are added sloWly under stirring. After the polymer
`is completely dissolved, the solution is cooled to room
`temperature and coated onto a suitable carrier Web using the
`coating and drying conditions as described in the previous
`example. The dry ?lm is again out into pieces of suitable siZe
`and shape.
`
`EXAMPLE 3
`
`15 g sorbitol, 22.5 g glycerol, 2.5 g propylene glycol, 2.5
`g Brij 35, 2.5 g poloxamer 407, 3.5 g Cremophor RH 40 9
`g herb mint ?avor, and 0.5 aspartame are dissolved under
`stirring at 60° C. in a mixture containing 250 g Water and
`250 g ethanol. To the clear solution, 75 g hydroxypropyl
`cellulose are added sloWly under continuous stirring. The
`clear solution is again coated and dried under the conditions
`as described in EXAMPLE 1 and the dry ?lm is cut into
`pieces of a shape and siZe suitable for the intended use.
`
`EXAMPLE 4
`
`3.6 g TWeen 80, 3.6 g glycerol, 39 g menthol, and 171 g
`Kollidon 30 are dissolved in a solution of 600 ml Water and
`2800 ml ethanol at ambient temperature With stirring. 247.5
`g hydroxypropylmethyl cellulose is then added sloWly and
`
`TEVA EXHIBIT 1027
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`5,948,430
`
`5
`portionWise at 50—55° C. and stirred until completely dis
`solved. The mixture is then allowed to cool and added in
`succession are 90 g lemon mint ?avor folloWed by a
`solution/suspension of 27.13 g aspartame, 18 g citric acid,
`and 0.17 g FD&C yelloW #5 in 120 ml Water With stirring.
`The clear solution is coated and dried under the conditions
`as described in EXAMPLE and the dry ?lm is cut into pieces
`of a shape and siZe suitable for the intended use.
`
`EXAMPLE 5
`
`165.4 g Kollidon 30 are dissolved in a solution of 720 ml
`Water and 2660 ml ethanol at ambient temperature With
`stirring. 220.5 g hydroxypropylmethyl cellulose is then
`added at 55—60° C. and stirred vigorously until clear and
`homogeneous. The mixture is then alloWed to cool and
`added in succession are 78.75 g ?avor folloWed by a mixture
`of 28.88 g nicotine salicylate and 31.5 g caramel liquid in
`120 ml Water With stirring. The clear, tan-colored solution is
`coated an dried under the conditions as described in
`EXAMPLE 1 and the dry ?lm is cut into pieces of a shape
`and siZe suitable for the intended use so as to deliver a
`nicotine dose betWeen 1—2 mg per piece.
`We claim:
`1. A monolayer ?lm formed from a mucoadhesive com
`position Which comprises
`at least one Water-soluble polymer; at least one member
`selected from the group consisting of a polyalcohol, a
`surfactant and a plasticiZer; at least one cosmetic or
`pharmaceutically ingredient; and a ?avoring agent
`said ?lm being one Which rapidly softens and completely
`disintegrates in the oral environment and having a dry ?lm
`thickness Which is suitable for application into the month
`Without causing adverse feeling the mouth.
`2. Amonolayer ?lm according to claim 1 Wherein the dry
`?lm thickness is about 70 pm.
`3. A monolayer ?lm according to claim 1 Wherein the
`concentration of Water-soluble polymer is betWeen 20 and
`75% (W/W), the concentration of surfactant is betWeen 0.1
`and 5% (W/W), the concentration of polyalcohol is betWeen
`0.1 and 5% (W/W) and the amount of pharmaceutically active
`ingredient is betWeen 0.01 and 20% (W/W).
`4. A monolayer ?lm according to claim 1, Wherein the
`Water-soluble polymer is selected from the group consisting
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`6
`of hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
`hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxym
`ethyl cellulose polyvinyl alcohol sodium alginate, polyeth
`ylene glycol, xanthane gum, tragacantha guar gum, acacia
`gym, arabic gum, polyacrylic acid, methylmethacrylate
`copolymer carboxyvinyl polymer and copolymers and mix
`tures thereof.
`5. A monolayer ?lm according to claim 1, Wherein the
`concentration of the Water-soluble polymer in the dry ?lm
`lies betWeen 20 and 75% (W/W).
`6. A composition according to claim 1, Wherein the
`polyalcohol is selected from the group consisting of
`glycerol, polyethylene glycol, propylene glycol, and glyc
`erol monoesters With fatty acids.
`7. A monolayer ?lm according to claim 1 containing a
`polyalcohol and at least one surfactant.
`8. A monolayer ?lm according to claim 1, Wherein the
`surfactant is a polyoxyethylene sorbitan fatty acid ester, a
`ot-hydroxy-whydroxypoly-(oxyethylene)poly
`(oxypropylene)poly(oxypropylene) block copolylmer, a
`polyoxyethylene alkyl ether or a polyoxyethylene castor oil
`derivative or a mixture thereof.
`9. A monolayer ?lm according to claim 1, comprising
`sorbitol and/or polyvinylpyrrolidone together With Water
`soluble cellulose-derivative polymer.
`10. A monolayer ?lm according to claim 1, Wherein the
`pharmaceutically active ingredient is selected from the
`group consisting of a hypnotic, a sedative, an antiepileptic,
`an aWakening agent, a pyschoneurotropic agent, a neuro
`muscular blocking agent, an antispasmodic agent, an
`antihistaminic, an antiallergic, a cardiotonic, an
`antiarrhythmic, a diuretic, a hypotensive, a vasopressor, an
`antitussive expectorant, a thyroid hormone, a sexual
`hormone, an antidiabetic, an antitumor agent, an antibiotic,
`a chemotherapeutic, and a narcotic.
`11. A monolayer ?lm according to claim 1, Wherein the
`cosmetically active agent is selected from the group con
`sisting of a breath freshening compound, a favor or fra
`grance used or oral hygiene, an agent for dental and/or oral
`cleansing and mixtures thereof.
`12. A molecular ?lm according to claim 1 in a shape
`suitable for application into the mouth.
`
`*
`
`*
`
`*
`
`*
`
`*
`
`TEVA EXHIBIT 1027
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US005948430C1
`(12) REEXAMINATION CERTIFICATE (4745th)
`United States Patent
`US 5,948,430 (:1
`(10) Number:
`(45) Certi?cate Issued:
`Mar. 4, 2003
`Zerbe et al.
`
`(54) WATER SOLUBLE FILM FOR ORAL
`ADMINISTRATION WITH INSTANT
`WETTABILITY
`
`(75) Inventors: Horst Georg Zerbe, Green Pond, NJ
`(US); Jian-Hwa Guo, Sparta, NJ (US);
`Anthony Serino, Boonton, NJ (US)
`
`(73) Assignee: LTS Lohmann Therapie-Systeme
`GmbH, NeuWied (DE)
`
`Reexamination Request:
`No. 90/005,887, Dec. 11, 2000
`
`Reexamination Certi?cate for:
`Patent No.:
`5,948,430
`Issued:
`Sep. 7, 1999
`Appl. No.:
`08/904,607
`Filed:
`Aug. 1, 1997 08/904,607
`Foreign Application Priority Data
`(30)
`Nov. 11, 1996
`
`(DE) ....................................... .. 196 46 392
`
`(51) Int. Cl.7 ......................... .. A61F 7/02; A61K 13/00;
`A61K 9/70; A61L 15/16
`(52) US. Cl. ..................................................... .. 424/435
`(58) Field of Search ........................................ .. 424/435
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,713,239 A
`5,462,749 A
`
`12/1987 Babaian et a1.
`10/1995 Rencher et 211.
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`
`243925
`
`11/1985
`
`EP
`EP
`EP
`JP
`JP
`JP
`W0
`W0
`
`0 250 187 B1
`0 259 749 B1
`0 781 550 A1
`61-30516
`5-41602
`5-236885
`WO 91/05540
`WO 92/15289
`
`12/1987
`3/1988
`7/1997
`2/1986
`6/1993
`9/1993
`5/1991
`9/1992
`
`OTHER PUBLICATIONS
`
`Hagers Handbuch der PharmaZeutischen Praxis, EV. Bruch
`hausen (publisher), vol. 2, p. 849, Springer—Verlag, Berlin
`(1991) (English translation).
`Drug Delivery Systems, V.V. Ranade and MA. Hollinger
`(eds.), 62—66, CRC Press, Boca Raton, Fla (1996).
`CD. Ebert et al., Journal of Controlled Release, vol. 28, p.
`37—44 (1994).
`Database CA PLUS on STN, AN 1996:193234, abstract of
`JP—61—030516 (1986).
`Patent Abstracts of Japan, abstract of JP 61—0305 16 (1986).
`Y.W. Chien, Novel Drug Delivery Systems, Second Edition,
`p. 171—173, Marcel Dekker Inc., NeW York (1992).
`
`Primary Examiner—Frederick Krass
`
`(57)
`
`ABSTRACT
`
`A composition containing therapeutic agents and/or breath
`freshening agents for use in the oral cavity is disclosed. The
`carrier comprises Water-soluble polymers in combination
`With certain ingredients and provides a therapeutic and/or
`cosmetic effect. The ?lm is coated and dried utilizing
`existing coating technology and exhibits instant Wettability
`followed by rapid dissolution/disintegration upon adminis
`tration in the oral cavity.
`
`TEVA EXHIBIT 1027
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 5,948,430 C1
`
`1
`REEXAMINATION CERTIFICATE
`ISSUED UNDER 35 U.S.C. 307
`
`THE PATENT IS HEREBY AMENDED AS
`INDICATED BELOW.
`
`Matter enclosed in heavy brackets [ ] appeared in the
`patent, but has been deleted and is no longer a part of the
`patent; matter printed in italics indicates additions made
`to the patent.
`
`10
`
`AS A RESULT OF REEXAMINATION, IT HAS BEEN
`DETERMINED THAT:
`
`The patentability of claims 3, 7 and 10 is con?rmed.
`
`Claim 1 is cancelled.
`
`Claims 2, 4—6, 8—9, and 11—12 are determined to be
`patentable as amended.
`
`NeW claims 13—16 are added and determined to be
`patentable.
`
`2. A monolayer ?lm according to claim [1] 13, Wherein
`the dry ?lm thickness is about 70 pm.
`
`25
`
`4. A monolayer ?lm according to [1] 13, Wherein the
`Water-soluble polymer is selected from the group consisting
`of hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
`hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxym
`ethyl cellulose, polyvinyl alcohol, sodium alginate, polyeth
`ylene glycol, xanthane gum, tragacantha guar gum, acacia
`[gym] gum, arabic gum, polyacrylic acid, methylmethacry
`late copolymer carboxyvinyl polymer and copolymers and
`mixtures thereof.
`
`35
`
`5. A monolayer ?lm according to claim [1] 13, Wherein
`the concentration of the Water-soluble polymer in the dry
`?lm lies betWeen 20 and 75% (W/W).
`
`6. A [composition] monolayer ?lm according to claim [1]
`13, Wherein the polyalcohol is selected from the group
`consisting of glycerol, polyethylene glycol, propylene gly
`col, and glycerol monoesters With fatty acids.
`
`45
`
`8. A monolayer ?lm according to claim [1] 13, Wherein
`the surfactant is a polyoxyethylene sorbitan fatty acid ester,
`a [a-hydroxy-whydroxypoly-(oxyethylene)poly(oxypropy
`lene)poly(oxypropylene)] ot-hydroxy-u)-hydroxypoly-(oxy
`ethylene)poly(oxypropylene)poly(oxyethylene)
`block
`
`2
`copolymer, a polyoxyethylene alkyl ether or a polyoxyeth
`ylene castor oil derivative or a mixture thereof.
`
`9. Amonolayer ?lm according to claim [1] 13, comprising
`sorbitol and/or polyvinylpyrrolidone together With Water
`soluble cellulose-derivative polymer.
`
`11. A monolayer ?lm according to claim [1] 13, Wherein
`the cosmetically active agent is selected from the group
`consisting of a breath freshening compound, a favor or
`fragrance used [or] for oral hygiene, an agent for dental
`and/or oral cleansing and mixtures thereof.
`
`12. A [molecular] monolayer ?lm according to claim [1]
`13, in a shape suitable for application into the mouth.
`
`15
`
`13. A monolayer ?lm formed from a mucoadhesive com
`position which comprises
`a) at least one water-soluble polymer;
`b) a surfactant alone or in combination with at least one
`member selected from the group consisting of a poly
`alcohol and a plasticizer; or a polyalcohol and a
`plasticizer,‘
`c) at least one cosmetic or pharmaceutical ingredient;
`and
`ah a ?avoring agent,
`said ?lm being one which rapidly softens and completely
`disintegrates in the oral environment and having dry ?lm
`thickness which is suitable for application into the mouth
`without causing adverse feeling in the mouth.
`14. A monolayer ?lm according to claim 13, wherein the
`concentration of water-soluble polymer is between 20 and
`75% (w/w), the concentration of surfactant is between 0.1
`and 5% (w/w), the concentration of polyalcohol is between
`0.1 and 5% (w/w) and the amount of pharmaceutically
`active ingredient is between 0.01 and 20% (w/w).
`15. A monolayer ?lm according to claim 13, containing a
`polyalcohol and at least one surfactant.
`16. A monolayer ?lm according to claim 13, wherein the
`pharmaceutically active ingredient is selected from the
`group consisting of a hypnotic, a sedative, an antiepileptic,
`an awakening agent, a pyschoneurotropic agent, a neuro
`muscular blocking agent, an antispasmodic agent, an
`antihistaminic, an antiallergic, a cardiotonic, an
`antiarrhythmic, a diuretic, a hypotensive, a vasopressor; an
`antitussive expectorant, a thyroid hormone, a sexual
`hormone, an antidiabetic, an antitumor agent, an antibiotic,
`a chemotherapeutic, and a narcotic.
`
`*
`
`*
`
`*
`
`*
`
`*
`
`TEVA EXHIBIT 1027
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC