Ulllted States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,948,430
`
`Zcrbc ct al.
`
`[45] Date of Patent:
`
`Scp. 7, 1999
`
`US00594-8430A
`
`................................. .. 427/3
`7/1993 Pins et al.
`5,229,164
`9/1994 Heibertet al.
`........................... 424/435
`5,346,201
`
`.................... .. 424/435
`5/1995 Nrnomrya et al.
`5,413, /92
`.. 424/435
`5,472,704 12/1995 Santus et al.
`
`..................... .. 424/435
`5,700,478 12/1997 B1cga]sk1 ct al.
`,
`. ,,
`,
`,
`,
`,
`,
`,
`,
`.
`,
`EOREIGN PAl l:Nl DOLUMENIS
`1 263 312
`11/1989 Canada .
`0 219 762
`4/1987 European Pat. Off.
`0 381 194
`8/1990 European Pat. Off.
`O 200 508 10/1991
`European Pat. Off.
`0 452 446
`10/1991
`European Pat. Off.
`2 449 865
`4/1976 Germany .
`.
`V
`—
`~ /
`~
`Wsma 21221
`
`.
`.
`.
`.
`
`.
`Primary EW’"i””—5h‘}P K R059
`Attorney, Agent, or Fzrm—Wenderoth, Lind & Ponack,
`L.L.p.
`
`V
`ABSTRACT
`I57I
`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 fil111 is coated and dried utilizing
`existing coating technology and exhibits instant Wettability
`'
`'
`'
`followed by rapid dissolution/disintegration upon adminis-
`“anon 1“ the °”‘1°aV"y'
`
`12 Claims, N0 Drawings
`
`[54
`
`VVATER SOLUBLE FIL]\I FOR ORAL
`
`VVETTABILITY
`
`US
`
`Inventors: Horst Georg Zerbe) Green Pond;
`Jian-Hwa Guo, Sparta; Anthony
`Selim)’ Boontont all of Ni
`
`[73 Assignee: LTS Lohmann Therapie-Systeme
`GmbH, Neuwied, Germany
`
`t
`APPI‘ N0“ 08/904507
`1»
`Foreign Application Priority Data
`
`[21
`r22
`[30
`
`Nov. 11, 1996
`
`[DE]
`
`Germany ........................... 196 46 392
`
`[51
`
`Int. CL5 ........................... .. A61F 7/02, A61K 13/00;
`A61K 9/70; A61L 15/16
`.................................. .. 424/435
`[52 U.S. Cl.
`[58
`Field Of Search ......................................... .. 424/435
`_
`References Clted
`Utst PATENT DOCUMENTS
`
`[56
`
`424/:22
`..
`“ :3:/,3;
`424/435
`424/435
`................ .. 424/435
`
`
`
`6/:1977 MI0d0Z°nfC° Ct a1~
`4,029,757
`C1
`.................... ..
`iaggiggg 2/3; ¥I."fd°‘°“‘°° “I ‘*1’
`4:876:092 10:19:39 Mizobuchietal.
`.
`4,900,552
`2/1990 Sanvordeker et aI.
`5,047,244
`9/1991 Sanvordeker et al.
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05024342
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`5,948,430
`
`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 film 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. U.S.
`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 furned silica. An optional
`water-insoluble film can be added to provide a non-adhering
`surface. In WO 91/06270,
`the same authors disclose a
`trilaminate film 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
`inflexibility of the support layer by introducing soft film
`supports. EP 0 200 508 B1 and EP 0 381 194 B1 disclose the
`use of polyethylene filnis, polyvinyl acetate, etliylene-vinyl
`acetate copolymers, metal foils, laminates of cloth or paper
`and a plastic film and similar materials as soft film 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 polyelefines such as polyethylene, polypropylene,
`polyesters, PVC, and non—woven fabrics as soft support
`materials.
`
`leave the patient with a
`these devices still
`However,
`considerable amount of residue from the water-insoluble
`support film thereby still causing a feeling of discomfort.
`The obvious solution to overcome tis problem was to
`develop mucoadhesive films which completely disintegrate,
`or even completely dissolve in the saliva. Fuchs and Hil-
`mann (DE 24 49 865.5) prepared homogeneous, water-
`soluble filnis intended for bueeal adrninistration of hor-
`mones. They proposed the use of water-soluble cellulose-
`derivatives,
`like hydroxyethyl cellulose, hydroxypropyl
`cellulose, or methyl hydroxypropyl cellulose, as film 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 film
`forming agents, which upon application to the oral cavity
`slowly disintegrate, thereby releasing an active ingredient
`incorporated in the film. The same polymers can also be used
`to prepare films which are intended for dental cleansing, as
`described in EP 0 452 466 B1.
`
`10
`
`15
`
`30
`
`L»’J\
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 film which is intended for application to the oral mucosa
`with instant wettability, while achieving adequate tensile
`strength in the free film to allow for easy coating,
`converting, and packaging of a consumer—friendly product.
`DESCRIPTION OF THE INVENTION
`
`The present invention contemplates a rapidly dissolving
`film which can be adhered to the oral cavity thereby releas-
`ing a pharmaceutically or cosmetically active agent, said
`film 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, flavors, flavor enhancers, or
`other excipients commonly used to modify the taste of
`formulations intended for application to the oral cavity. The
`resulting film is characterized by an instant wettability
`which causes the film 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 film 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 film include
`polymers which are hydrophilic and/or water-dispersible.
`Preferred polymers are water-soluble cellulose-derivatives.
`Hydroxypropylmethyl cellulose, hydroxyethyl cellulose, or
`hydroxyprepyl cellulose, either alone, or mixtures thereof,
`are particularly preferred. Other optional polyrners, 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, arabie gum, water-
`dispersible polyacrylates like polyacrylic acid, methyl-
`methacrylate copolymer, carboxyvinyl copolymers. The
`concentration of the water-soluble polymer in the final film
`can vary between 20 and 75 % (W/W), preferably between 50
`and 75% (w/w).
`The surfactants used for the mucoadhesive film may be
`one or more rioriionie surfactants. When a combination of
`surfactants is used, the first component may be a polyoxy-
`ethylene sorbitan fatty acid ester or
`a 0.-hydro-up
`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 or-hydro-u)-hydroxypoly
`(oxyethylene)p0ly(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 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05024343
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`5,948,430
`
`3
`tive has to have an HLB value of 14-16. In order to achieve
`the desired instant wettability, the ratio between the first and
`second component of the binary surfactant mixture should
`be kept within 1:10 and 1:1, n1ore preferably between 1:5
`and 1:3. The total concentration of surfactants in the final
`film depends on the properties of the other ingredients, b11t
`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
`film. 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 film usually
`ranges between 0.1 and 5% (w/w).
`The film 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,
`hypotensivcs, vasoprcssors, antitussivc cxpcctorants,
`thy-
`roid hormones, sexual hormones, antidiabetics, antitumor
`agents, antibiotics and chemotherapeutics, and narcotics.
`The amount of drug to be incorporated into the film 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 flavors 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 flavors may be enhanced using flavor enhancers like
`tartaric acid, citric acid vanillin, or the like. Colorants which
`may optionally be mixed in the film must be safe in terms of
`toxicity and should be accepted by the Food And Drug
`Administration for use in cosmetics.
`
`The mucoadhesive film 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 flavors. The solution is coated onto a suitable carrier
`material and dried to form a film. 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 film, non-siliconized kraft paper,
`polyethylene-impregnated kraft paper, or non-siliconized
`polyethylene film.
`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 film depends on the con-
`centration of solids in the coating solution and on the gap of
`
`10
`
`15
`
`30
`
`L»’J\
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`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`the coating head and can vary between 5 sand 200 ,um.
`Drying of the film 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 fiavor of the film.
`In order to reliably avoid an adverse feeling in the mouth, a
`dry film thickness of 70 ,um should not be exceeded.
`For better ease of use, the dry film can be cut into pieces
`of suitable size and shape and packed in to a suitable
`container.
`
`The invention will now be explained more specifically
`with reference to the following examples, which are given
`for illustration of this invention and are not intended to be
`limiting thereof.
`
`EXAMPLE 1
`
`l5 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 flavor, 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
`film thickness between 20 and 50 gm. The drying ten1pera-
`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 film. The result-
`ing film is peeled off the carrier web and cut into pieces of
`a shape and size suitable for the intended use.
`
`EXAMPLE 2
`
`3 0
`D sorbitol 1.5 g Kollidon 30 (supplier: BASF), 5 g
`glycerol, 5 g propylene glycol, 5 g polyethylene glycol, 4 g
`polysorbate 80 (Tween 80), 8 g Brij 35, 12 g peppermint
`llavor, 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 film 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 flavor, 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 film 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 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05024344
`
`TEVA EXHIBIT 1020
`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 flavor followed by a
`solution/suspension of 27.13 g aspartanie, 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 film 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 flavor 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 film 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 film 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 flavoring agent
`said film being one which rapidly softens and completely
`disintegrates in the oral environment and having a dry film
`thickness which is suitable for application into the month
`without causing adverse feeling the mouth.
`2. A monolayer film according to claim 1 wherein the dry
`film thickness is about 70 gm.
`3. A monolayer film 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 polyalcoliol is between
`0.1 and 5% (W/W) and the amount of pharniaceutically active
`ingredient is between 0.01 and 20% (w/w).
`4. A monolayer film according to claim 1, wherein the
`water-soluble polymer is selected from the group consisting
`
`6
`of hydroxypropylmethyl cellulose, liydroxyetliyl cellulose,
`hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxym-
`ethyl cellulose polyvinyl alcohol sodium alginate, polyeth-
`ylene glycol, xanthane gun], tragacantha guai’ gui11, acacia
`gym, arabic gum, polyacrylic acid, methylmethacrylate
`copolymer carboxyvinyl polymer and copolymers and mix-
`tures thereof.
`5. A monolayer film according to claim 1, wherein the
`concentration of the water-soluble polymer in the dry film
`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 film according to claim 1 containing a
`polyalcohol and at least one surfactant.
`8. A monolayer film according to claim 1, wherein the
`surfactant is a polyoxyethylene sorbitan fatty acid ester, a
`CL-hydroxy-oohydroxypoly-(oxyethylene)poly
`(oxypropylene)poly(ox}/propylene) block copolylmer, a
`polyoxyethylene alkyl ether or a polyoxyethylene castor oil
`derivative or a mixture thereof.
`9. A monolayer film according to claim 1, comprising
`sorbitol and/or polyvinylpyrrolidone together with water-
`soluble cellulose-derivative polymer.
`10. A monolayer film 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 film 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 film according to claim 1 in a shape
`suitable for application into the i11outl1.
`*
`*
`=l<
`*
`*
`
`10
`
`15
`
`30
`
`L»’J\
`
`40
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05024345
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`(12) REEXAMINATION CERTIFICATE (4745111)
`United States Patent
`US 5,948,430 C1
`Zerbe et al.
`(45) Certificate Issued:
`Mar. 4, 2003
`
`(10) Number:
`
`USOO5948430C1
`
`(54) VVATER SOLUBLE FILM FOR ORAL
`ADMINISTRATION WITH INSTANT
`VVETTABILITY
`
`(75)
`
`Inventors: Horst Georg Zerbe, Green Pond, NJ
`(US); Jian-Hwa Guo, Sparta, NJ (US);
`Anthony Serino, Hoonton, N.l (US)
`
`(73) Assignee: LTS Lohmann Therapie-Systeme
`GmbH, Neuwied (DE)
`
`Reexamination Request:
`No. 90/005,887, Dec. 11, 2000
`
`Reexamination Certificate for:
`Patent No.2
`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. CL7 ......................... .. A61F 7/02, A61K 13/00;
`A61K 9/70; A61L 15/16
`..................................................... .. 424/435
`(52) U.S. Cl.
`(58) Field of Search ........................................ .. 424/435
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,713,239 A
`5,402,749 A
`FOREIGN PATENT DOCUMENTS
`
`12/1987 Bubuiun et ul.
`10/1995 Rencher et al.
`
`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
`W0 92/15289
`
`12/1987
`3/1988
`7/1997
`2/1986
`6/1993
`9/1993
`5/1991
`9/1992
`
`OTHER PU HI .I(IAI‘I()NS
`
`I-Iagers Handbuch der Pharm azeutischen Praxis, EV. Rrnch-
`hausen (publisher), Vol. 2, p. 849, Springer—Verlag, Berlin
`(1991) (English translation).
`l-lollinger
`Drug Delivery Systems, V.V. Ranade and M.A.
`(eds.), 62-66, CRC Press, Boca Raton, Fla (1996).
`C.D. Ebert et al., Journal of Controlled Release, Vol. 28, p.
`37-44 (1994).
`Database CA PLUS on STN, AN 19962193234, abstract of
`JP—6l—0305l6 (1986).
`Patent Abstracts of Japan, abstract of JP 61—030516 (1986).
`Y.W. Chien, Novel Drug Delivery Systems, Second Edition,
`p. 171—173, Marcel Dekker Inc., New York (1992).
`
`Primary Examir1er—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 film is coated and dried utilizing
`existing coating technology and exhibits instant Wettahility
`followed by rapid dissolution/disintegration upon adminis-
`tration in the oral cavity.
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05024346
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 5,948,430 Cl
`
`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 patem_
`AS A RESULT OF REEXAMINATION’ IT HAS BEEN
`DETERMINED THAT:
`
`The patenmbihty of Claims 3, 7 and 10 is Confirmed
`
`2
`copolynier, a polyoxyethylene alkyl ether or a polyoXyeth-
`ylene castor oil derivative or a mixture thereof.
`
`5
`
`9. Anionolayei’ filni according to claim [1] J3, coiiiprising
`sorbitol and/or polyvinylpyrrolidone together with water-
`soliible celliilose-derivative polymer.
`_
`_
`_
`11' A mqnolayer 11.131 accgrdmg [0 Clalm [1] 13’ Wherem
`the ‘iosmetlcany acnve agent 15 Selected from the group
`10 :01‘lS1Stl1‘lg ofda[br:<|:2;th frejlhetping compound, af favjor oi
`ragrance use
`or
`or or
`ygiene, an agent or
`enta
`and/or oral cleansing and IIl1XI1lI‘CS thereof.
`
`.
`.
`12. A [molecular] monolayer film according to claim [1]
`15 13, in a shape suitable for application into the mouth.
`
`Claim 1 is Cancelled.
`
`Claims 2, 4-6, 8-9, and 11-12 are determined to be
`patentable as amended.
`
`NCW claims
`patentable.
`
`are added and d€I€I'IIll[1€d
`
`[0 be
`
`20
`
`7
`-5
`
`13. A monolayer film formed from a mucoadhesive com-
`position which comprises
`t1)tl7 1571570775 Wt1757‘-50lllbl5 P01)’77757’;
`b) a surfactant alone or in combination with at least one
`member selected from the group consisting of a poly-
`alcghgl and a plasticizgy; or [1 pglyalcghgl and a
`plasticizer;
`c at least one cosmetic or harmaceutical in redient,
`.
`_
`.
`P
`8
`and
`2. A nionolayer film according to claim [1] 13, wliereni
`£0 a flamfing agent
`the dry film thickness is about 70 am.
`$5,114 film ’’“’’3 one which Wipidly Softens and, Completely
`4. A monolayer film according to [1] 13, wherein the
`ojl§lZtcgrat£:;.l7 the Ofalblmvuionmclnf a.”d hiwmg; dry fill?
`water-soluble polymer is selected from the group consisting
`Elsdfiglgi f:e]l:,0’:ga51p[fll:a’:L1Z’;[;l”[0 [18 mow”
`of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, 30
`.
`.
`’
`.
`hydroxypropyl cellulose, polyvinyl pyrrolidone, carboXym-
`14/1 mafwlayer film according 10 Clabm 13» Where” the
`ethyl cellulose, polyvinyl alcohol, sodium alginate, polyeth-
`E_0’;‘7Cem’:an0”h0f Wa[‘3r'50llfble Polymer 15 bémlfell 20 and
`ylene glycol, Xanthane gum, tragacantha giiar gum, acacia
`/5£ri0$_((;V/IV)», I
`€‘Z'0’1C€m‘W1[l0".0f5l"'fa§'{a7t
`1; ]5:TV‘:e”l 01
`[gym] gum, arabic gum, polyacrylic acid, mcthy1mcthacry—
`late copolymer carboxyvinyl polymer and copolymers and 35 an ‘
`" (w/w)) I '0 C0”'C‘?"'mm0" Ofpoyl C" '0' ‘S grlvggn
`mixtures thereof.
`0.1 and 5% (w/w) and the amount of pharmaceutically
`active ingredient is between 0.0] and 20% (w/w).
`f5~[A 72701710163787‘flilm 670007157713: 70 Claim 13; C077Wm”8 (1
`I70 W C0 0 0” at east 0”? 5”" acmm
`16. A monolayer film according to claim 13, wherein the
`pharmaceutically active ingredient
`is selected from the
`group consisting of a hypnotic, a sedative, an antiepileptic,
`071 awn/wning 08977’; apyschomwatropic agent, 0 7’1€’1“‘0'
`muscular‘ blocking agent, an antispasmodic agent, an
`45 antihistaminic, an antiallergic, a cardiolunic, an
`antiarrhythmic, a diuretic, a hypotensive, a vasopressor; an
`a71lif14SSiV€‘
`€>v’P€‘CF07‘W1E
`0 F/1)’7‘0id /107‘m071€;
`61 Sexual
`/1077710776, 6771 fifllidiabelici 61” 1/mllT“m07’ 086712 4171 film-bl'0Tl‘C;
`£1 Ché3m0l‘h€7’a17€llIiC,
`and L1 7’l£17‘C0liC.
`
`5. A monolayer film according to claim [1] 13, wherein
`the concentration of the Water-soluble polymer in the dry
`filni lies between 20 and 75% (w/w),
`
`40
`
`6, A [composition] monolayer filni according to claim [1]
`13, wherein the polyalcohol is selected from the group
`consisting of glycerol, polyethylene glycol, propylene gly.
`col, and glycerol inonoegteig with fatty acids.
`
`8. A nionolayer film according to claim [1] 13, wherein
`the surfactant is a polyoxyethylene sorbitan fatty acid ester,
`a
`[CL-hydroxy-uihydroXypoly-(oXyethylene)poly(oXypropy-
`lene)poly(oXypropylene)]
`oL-hydroxy-Lo-hydrox)y2oly-(0uy-
`ethylene)poly(oxypropylene)poly(oxyethylene)
`block
`
`50
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05024347
`
`TEVA EXHIBIT 1020
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC