United States Patent [19]
`Kuroya et al.
`
`||||||lllllllllllllllllllllllllllllllIHIIIlllllllllIllllllllllllllllllllll
`5,166,233
`Nov. 24, 1992
`
`US005166233A
`[11] Patent Number:
`[45] Date of Patent:
`
`[54] FILM APPLICABLE TO ORAL MUCOSA
`AND DRUG PREPARATION COMPRISING
`THE SAME
`[75] Inventors: Takamasa Kuroya; Yuichi Inoue, both
`of Osaka, Japan
`[73] Assignees: Nitto Denko Corporation; Sunstar
`K.K., both of Osaka, Japan
`[21] Appl. No.: 473,069
`[22] Filed:
`Ja.n.31, 1990
`[30]
`Foreign Application Priority Data
`Jan. 31, 1989 [JP]
`Japan .................................. .. 1-23306
`
`[51] Int. Cl.5 .......................... .. C08J 3/21; COSL U023
`[52] U.S. Cl. ...................................
`524/37; 524/42;
`524/43; 524/44; 427/2; 427/3
`[58] Field of Search ..................... .. 524/ 37, 42, 43, 44;
`427/2, 3
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,524,828 8/1970 Keithly ............................... .. 524/44
`
`FOREIGN PATENT DOCUMENTS
`0106107 4/1984 European Pat. Off. .
`0200508 12/1986 European Pat. Off. .
`
`0241179 10/1987 European Pat. Off. .
`0275550 7/1988 European Pat. Off. .
`1068786 11/1959 Fed. Rep. of Germany .
`
`OTHER PUBLICATIONS
`Chemical Abstracts, vol. 83, Mar. 1975, p. 373, Abstract
`No. 103302t.
`Chemical Abstracts, vol. 99, No. 22', Nov. 1983, p. 349,
`Abstract No. 1814202.
`Primary Examiner-—Nathan ‘M. Nutter
`Assistant Examiner—Jeffrey Culpeper Mullis
`Attorney, Agent, or Firm—-Sughrue, Mion, Zinn,
`Macpeak & Seas
`
`[57]
`.
`ABSTRACT
`A soft ?lm applicable to the oral mucosa and a drug
`preparation comprising said film are disclosed, the ?lm
`comprising a homogeneous mixture comprising a vinyl
`acetate homopolymer, an acrylic acid polymer, and a
`cellulose derivative capable of being dissolved in or
`swollen with water and a lower alcohol. The ?lm or
`preparation is less causative of an adverse feeling on
`application to the oral mucosa, excellent in shape reten
`tion on water absorption, and adhesive to the oral mu
`cosa for an extended period of time.
`
`9 Claims, 1 Drawing Sheet
`
`TEVA EXHIBIT 1022
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US. Patent
`
`Nov. 24, 1992
`
`5,166,233
`
`Hm
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`O)
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`a ..
`
`E
`
`TlME(h)
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`O o I
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`(D O I
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`07 O I
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`N o I
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`0
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`O
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`
`
`
`. RATE OF TRIAMCINOLONE ACETONIDE RELEASE (0/0)
`
`
`
`
`
`TEVA EXHIBIT 1022
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

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`1
`
`FILM APPLICABLE TO ORAL MUCOSA AND
`DRUG PREPARATION COMPRISING THE SAME
`
`5
`
`5,166,233
`2
`though slowly releasing a drug, have a thickness as
`large as 1.3 to 3 mm and lack softness, still involving the
`problem of an adverse feeling on use. The preparations
`for application to the oral mucosa comprising a water
`soluble ?lm containing a drug have softness and thereby
`cause a reduced adverse feeling in the oral cavity. How
`ever, since the ?lm base is water-soluble, it is easily
`dissolved in saliva or water contents in the oral cavity
`and is, therefore, poor in duration of efficacy. The bases
`comprising a mixture of a water-soluble substance and a
`water-insoluble substance are soft and less causative of
`an adverse feeling upon use. Also, they take time to
`disappear in the oral cavity and are thus expected to
`have a longer duration of pharmaceutical effects as
`compared with bases comprising a water-soluble sub
`stance alone. These bases nevertheless exhibit adhesion
`only for 2 to 10 hours at the longest.
`Hence, an intraoral preparation satisfying all the
`three requirements, i.e., freedom from an adverse feel
`ing in the oral cavity on use, excellent shape retention
`on water absorption, and long-term adhesion to the wet
`oral mucosa, has not yet been developed.
`SUMMARY OF THE INVENTION
`An object of this invention is to provide a ?lm appli
`cable to the oral mucosa, which is less causative of an
`adverse feeling in the oral cavity on use, excellent in
`shape retention on water absorption, and adhesive to
`the oral mucosa for an extended time.
`Another object of this invention is to provide a prepa
`ration applicable to the oral mucosa which comprises
`the above-described ?lm and a drug as an active ingre
`dient.
`'
`Other objects and effects of the present invention will
`be apparent from the following description.
`The inventors have conducted a series of studies
`about a base which is less causative of an adverse feeling
`on application to the oral cavity, excellent in shape
`retention on water absorption, and adhesive to the oral
`mucosa for an extended period of time. As a result, it
`has been found that a ?lm applicable to the oral mucosa
`satisfying all these requirements is obtained by using a
`homogeneous mixture comprising (A) a vinyl acetate
`homopolymer, (B) an acrylic acid polymer, and (C) a
`cellulose derivative capable of being dissolved in or
`swollen with water and a lower alcohol (hereinafter
`simply referred to as cellulose derivative), thus reaching
`the present invention.
`The present invention relates to a soft adhesive ?lm
`applicable to the oral mucosa comprising a homogene
`ous mixture comprising (A) a vinyl acetate homopoly
`mer, (B) an acrylic acid polymer, and (C) a cellulose
`derivative capable of being dissolved in or swollen with
`water and a lower alcohol.
`The present invention further relates to a composite
`?lm applicable to the oral mucosa comprising the
`above-described soft adhesive film having laminated on
`one side thereof a soft water-insoluble support ?lm.
`The present invention still further relates to a prepa
`ration comprising the above-described soft adhesive
`?lm containing a topical drug.
`
`BACKGROUND OF THE INVENTION
`A. Field of the Invention
`This invention relates to a ?lm which is applied to the
`wet mucosa of the oral cavity and a preparation com
`prising the same, which are useful to maintain a long
`term intraoral administration of a drug.
`B. Description of the Related Art
`Known dosage forms for intraoral administration of
`drugs include solutions, ointments, troches, buccal tab
`lets, sublingual tablets, etc. Recently, slow-releasing
`intraoral tablets of track-?eld type which are less causa
`tive of an adverse feeling in the oral cavity (as described
`in JP-A-55-59-09, JP-A-58-154547, and JP-A-SS
`154548, the term “J P-A” as used herein means an “unex
`amined published Japanese patent application”) and
`slow-releasing Nifedipine tablets of track-?eld type
`applied to the oral mucosa (as described in JP-A-6l
`15829 and JP-A-6l-17510) have been proposed. For the
`purpose of further reducing an adverse feeling in the
`oral cavity, medical bandage using, as a base, a water
`25
`soluble high polymer which exhibits adhesion when
`dissolved or gelled with water (as described in J P-A-60
`142927), preparations applicable to the oral mucosa
`comprising a water-soluble ?lm having incorporated
`thereinto a steroid or non-steroid agent (as described in
`JP-A-6l-280423), and sheet preparations comprising a
`support sheet having thereon a drug, gelatin, agar, glu
`ten, a carboxyvinyl polymer, a polyhydric alcohol, a
`gum, and a wax as essential components (as described in
`JP-A-6l-8S3l5) have also been proposed.
`More recently, there have been proposed bases for
`application to the oral mucosa which comprise a mix
`ture of a water-soluble substance and a water-insoluble
`substance; for example, intraoral bandage composed by
`a soft ?lm in which at least one of a polycarboxylic acid
`and a polycarboxylic acid anhydride, and a vinyl ace
`tate polymer are mixed in a compatible state as dis
`closed in JP-A-6l-249472 and JP—A-61-249473; a base
`comprising a water-insoluble or sparingly water-soluble
`support having thereon an adhesive layer containing an
`acrylic acid polymer which exhibits adhesion when
`45
`dissolved in or swollen with water and a water-insolu
`ble cellulose derivative as disclosed in JP-A-63-160649;
`a composite for application to the oral mucosa compris
`~ ing a surface layer containing ethyl cellulose and a vi
`nyl-pyrrolidone polymer or copolymer having thereon
`an adhesive layer as disclosed in JP-A-63-17l564 and
`JP—A-63-171565; and an adhesive composition contain
`ing a vinylpyrrolidone polymer or copolymer, at least
`one of hydroxyethyl cellulose and hydroxypropyl cellu
`lose, and a water-retaining softener as disclosed in JP
`A-63-174660.
`However, none of these known intraoral preparations
`or bases satis?es both duration of adhesion and freedom
`from an adverse feeling in the oral cavity on use. For
`example, since solutions, ointments or the like prepara
`60
`tions easily run away with saliva or other water content,
`it is dif?cult to maintain ef?cacy for a long time with
`these preparations. Troches, which are large tablets
`prepared by punching a mixture of a drug and a base,
`e.g., saccharides, cause a considerable adverse feeling.
`Buccal tablets and sublingual tablets are generally de
`signed for rapid mucosal absorption of drugs and are,
`therefore, of short duration. The track-?eld type tablets,
`
`65
`
`55
`
`BRIEF DESCRIPTION OF THE DRAWING
`FIG. 1 illustrates the relationship of the rate of Tri
`amcinolone Acetonide release to the time.
`
`TEVA EXHIBIT 1022
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`3/7 to 6/4. A weight ratio of vinyl acetate homopoly
`DETAILED DESCRIPTION OF THE
`mer (A) to the sum of acrylic acid polymer (B) and
`INVENTION
`cellulose derivative (C) (A/(B+C)) preferably ranges
`When the soft adhesive ?lm according to the present
`from 2/ 8 to 8/2. To ensure further long-term adhesion
`invention is applied to, for example, the fore gingiva of
`to the oral mucosa, the weight ratio B/C more prefera
`the upper jaw, the adhesive ?lm base absorbs saliva and
`bly ranges from 4/6 to 6/4.
`Thus, the working time of the preparation in the oral
`a water content in the oral cavity to exhibit adhesion to
`cavity, which partly depends on the duration of adhe
`the oral mucosa. The adhesiveness is retained for a long
`period of time because of the excellent shape retention.
`sion, can be appropriately controlled by varying the
`Since the ?lm base is homogeneous and soft, it is tightly
`ratio of vinyl acetate homopolymer (A), acrylic acid
`polymer (B), and cellulose derivative (C).
`adhered to the oral mucosa without causing an adverse
`feeling during application. The terminology “homoge
`If desired, the adhesive film of the present invention
`nous” as used herein means that the vinyl acetate homo
`may further contain a salt or a base. That is, since the
`polymer, the acrylic acid polymer and the cellulose
`film comprising only the above-described components
`derivative in the mixture are homogeneously mixed
`assumes acidity attributed to the acrylic acid polymer, it
`under optical microscopic observation and that each of
`sometimes gives a slight irritation to excitable parts,
`these components does not exist solely in parts.
`such as an injured part. Where such an irritation due to
`The ?lm according to the present invention is ob
`acidicity gives rise to troubles, incorporation of a salt or
`tained using a homogeneous mixture of a vinyl acetate
`base having a neutralizing effect can substantially re
`homopolymer, an acrylic acid polymer, and a speci?c
`move the irritation to the injured part.
`cellulose derivative. A two-component mixture com
`, Examples of the salts and bases include salts of metals
`prising only the vinyl acetate homopolymer and the
`and weak acids, e.g., a salt of an alkali metal (e.g., so
`acrylic acid polymer forms a homogenous soft ?lm but
`dium and potassium) and a carboxylic acid (e.g., acetic
`acid, lactic acid, and citric acid); metal hydroxides, e.g.,
`is swollen with saliva or other water content in the oral
`sodium hydroxide and potassium hydroxide; amines,
`cavity and is inferior in shape retention on application
`e.g., triethanolamine and diisopropanol amine; and mix
`to the oral mucosa. Further, a two-component mixture
`comprising only the acrylic acid polymer and the cellu
`tures thereof. A salt of an alkali metal (e.g., sodium and
`lose derivative forms a homogeneous soft ?lm but does
`potassium) and a carboxylic acid (e. g., acetic acid, lactic
`not withstand long-term use in the oral cavity because
`acid, and citric acid) is preferably used. The amount of
`of water-solubility of these components. Furthermore, a
`the salt or base to be incorporated widely varies de
`two-component mixture comprising only the vinyl ace
`pending on its kind. For example, a monovalent metal
`tate homopolymer and the cellulose derivative hardly
`salt is preferably used in an amount of from 0.03 to 0.2
`equivalent to the acrylic acid polymer. Amounts less
`forms a homogeneous and soft ?lm.
`The vinyl acetate homopolymer which can be used in
`than 0.03 equivalent produce insufficient effects to re
`the present invention is not particularly limited, and any
`duce the irritation of an injured part. If the amount
`known vinyl acetate homopolymer (as disclosed, e.g, in
`exceeds 0.2 equivalent, water resistance of the adhesive
`S. Imoto, Plastic Zairyo Koza (Lectures on Plastic Mate
`?lm tends to be reduced, failing to attain suf?cient adhe
`rials) Vol. 14 Vinyl Acetate Resins, published by Nikkan
`sion to the oral mucosa.
`Kogyo Press, Japan, on May 15, 1970) can be used as
`The ?lm applicable to the oral mucosa according to
`such either alone or in combination thereof. The weight
`the present invention can be obtained as follows. A
`average molecular weight of the vinyl acetate homopol
`vinyl acetate homopolymer, an acrylic acid polymer,
`ymer is preferably from 40,000 to 200,000.
`and a cellulose derivative are dissolved in a solvent
`Examples of the acrylic acid polymer which can be
`commonly compatible to them to form a ?lm-forming
`used in the present invention include an acrylic acid
`composition. The composition is cast on a releasable
`homopolymer; copolymers of acrylic acid and vinyl
`liner and dried to form a ?lm.
`monomers, such as acrylic esters (e.g., butyl acrylate
`Examples of the solvent commonly compatible to the
`and 2-ethylhexyl acrylate), methacrylic esters (e.g.,
`?lm-forming components include an alcohol and a wa
`methyl methacrylate), and vinyl acetate; and other pol
`ter-alcohol mixed solvent. Taking solubility of the cel
`ymers, e.g., a carboxyvinyl polymer. Among these, an
`lulose derivative into consideration, lower alcohols,
`acrylic acid polymer having a carboxyl group content
`e.g., methanol and ethanol, are exempli?ed as the alco
`of 20% by weight or more is preferred. These polymers
`hol. The water content in the mixed solvent is prefera
`bly not more than 30% by weight. If it exceeds 30% by
`may be used either alone or in combinations thereof.
`weight, the vinyl acetate homopolymer tends to be
`The cellulose derivative which can be used in the
`present invention must be capable of being dissolved in
`hardly dissolved.
`'
`or swollen with water and a lower alcohol. Examples of
`Examples of the releasable liner on which the ?lm
`55
`the cellulose derivative include methyl cellulose, ethyl
`‘forming composition is cast includes a release-treated
`cellulose, hydroxyethyl cellulose, hydroxypropyl cellu
`polyethylene laminated paper, a polyethylene ?lm, and
`lose, and hydroxypropylmethyl cellulose. The degree
`a silicone-treated polyethylene terephthalate ?lm.
`of substitution of the cellulose derivative is preferably
`Drying of the cast ?lm can be carried out in a high
`from 0.1 to 3, and more preferably from 1.0 to 2.5.
`temperature air bath using a drying oven or a drying
`Hydroxypropyl cellulose having a degree of substitu
`tower, and a vacuum drier.
`tion of from 1.3 to 2.0 is most preferred. These cellulose
`Thickness of the film can be adjusted by controlling
`the amount of the composition cast and is preferably in
`derivatives may be used either alone or as a mixture of
`the range of from 5 to 500 pm. From the standpoint of
`two or more thereof.
`A weight ratio of acrylic acid polymer (B) to cellu
`?lm strength and a feeling on use, a thickness of from 10
`lose derivative (C) (B/C) preferably ranges from l/ 9 to
`to 100 pm is more preferred.
`9/1. To ensure further long-term adhesion to the oral
`The ?lm applicable to the oral mucosa according to
`the present invention basically comprises a homogene
`mucosa, the weight ratio B/C preferably ranges from
`
`60
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`40
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`45
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`65
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`TEVA EXHIBIT 1022
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`

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`35
`
`5
`ous and soft adhesive ?lm which is obtained from a
`vinyl acetate homopolymer, an acrylic acid polymer,
`and a cellulose derivative as described above. If desired,
`a water-insoluble support may be provided on the adhe
`sive ?lm to endow the preparation with improved shape
`retention on water absorption.
`Examples of the water-insoluble support includes a
`?lm of a synthetic resin, e. g., polyethylene, a vinyl
`acetate homopolymer, an ethylene-vinyl acetate co
`polymer, polyvinyl chloride, and polyurethane; a metal
`foil, e.g., an aluminum foil and a tin foil; and a laminate
`?lm comprising cloth or paper and a synthetic resin
`?lm. From the viewpoint of safety and a feeling on use,
`it is preferable to use a ?lm of a synthetic resin, e.g.,
`polyethylene, a vinyl acetate homopolymer, and an
`ethylene-vinyl acetate copolymer as a support. In order
`to assure ease in handling and to avoid giving an-ad
`verse feeling on use, the water-insoluble support prefer
`ably has a thickness of from 10 to 100 um. ‘
`The above-described composite ?lm can be obtained
`by, for example, hot pressing the adhesive ?lm and the
`water-insoluble support ?lm. Alternatively, the com
`posite ?lm can be obtained by casting the above
`described ?lm-forming composition on the water
`insoluble support followed by drying.
`The thus obtained ?lm or composite ?lm according
`to the present invention, when applied to the wet oral
`mucosa, absorbs water contents and is swollen with the
`water contents to exhibit excellent adhesion and shape
`retention for an extended time without causing an ad
`verse feeling while protecting the site. The ?lm is thus
`applicable to an affected part in the oral cavity as ban
`dage. Where a drug is used in_combination, the drug can
`be prevented from running off due to saliva, etc., and an
`administration of the drug to the affected part can be
`maintained in a stable manner.
`The preparation applicable to the oral mucosa ac
`cording to the present invention is prepared by incorpo
`rating a topical drug into the adhesive ?lm. The prepa
`ration can be used for the treatment of an affected part
`in the oral cavity.
`Topical drugs which can be used in the preparation of
`the invention may be either solid or liquid at room
`temperature, and any topical drug which can be dis
`solved or dispersed in the soft adhesive ?lm can be
`employed. The method for dissolving or dispersing the
`topical drugs in the soft adhesive ?lm is not particularly
`limited. For example, the vinyl acetate homopolymer,
`the acrylic acid polymer and the cellulose derivative are
`dissolved in a solvent which is compatible to these com
`ponents, and the topical drug is separately dissolved or
`dispersed in the same solvent. The resulting solutions
`(or solution and dispersion) are mixed with each other
`to form a ?lm-forming composition, and the ?lm-form
`ing composition is then cast on a releasable liner fol
`lowed by drying so as to form the preparation.
`Examples of the topical drugs include glucocorti
`coids, e.g., Triamcinolone Acetonide, Dexamethasone,
`Betamethasone, Prednisolone, Fluocinolone, Hydro
`cortisone, Beclomethasone, etc. and salts thereof; anti
`in?ammatory agents, e.g., Flurbiprofen, Ibuprofen,
`Diclofenac, Indomethacin, Bendazac, Flufenamic Acid,
`Bufexamac, Cyclosporins, Clidanac, Glycyrrhizin,
`Ketoprofen, Piroxicam, Pranoprofen, Benzydamine,
`Ibuprofen Piconol, Etofenamate, Lysozyme, Chymo
`trypsin, Epidihydrocholesterin, Hinokitiol, cit-Amylase,
`Azulene, Chlorophyllin, Cromoglicic Acid, Tranilast,
`Serrapeptase, Pronase, Glucanase, Lithospermz' Radix
`
`5,166,233
`6
`extract, etc. and salts thereof; bactericides, e. g., Acrinol,
`Cetylpyridinium, Chlorhexidine, Domiphen, Iodine,
`Monensin, Sanguinarine, Metronidazole, Dequalinium,
`Thetracycline, Minocycline, O?oxacin, Penicillin, Oxy
`cycline, Oxytetracycline, Cefatrizine, Nystatin, Clinda
`mycin, Fradiomycin Sulfate, etc. and salts thereof; anal
`gesics, e.g., Ethyl Aminobenzoate, Camphor, Eugenol,
`Dibucaine, Phenol, Menthol, Creosote, Diphenhydra
`mine, Lidocaine, Tetracaine, Procaine, Cocaine,
`Piperocainum, Mepivacaine, Bromoxine, Guaiacol, etc.
`and salts thereof; hemostatics, e.g., Tranexamic Acid,
`B-Aminocaproic Acid, Alginic Acid, Bio?avonoid,
`Vitamin C, Thrombin, Oxidized Cellulose, Cetraxate,
`Epinephrine, Ferric Chloride, Fibrinogen, Carbazo
`chrome, etc. and salts thereof; vasodilators, e.g., Inosi
`tol Hexanicotinate, Cyclandelate, Cinnarizine, Tolazo
`line., Acetylcholine, etc. and salts thereof; tissue repair
`ing agents, e. g., Solcoseryl, Proglumide, Sucralfate,
`Nicametate, Gefarnate, Glutamine, Aceglutamide Alu
`minum, Ethylcysteine, Chitin, Vitamin E Nicotinate,
`Ubidecarenone, etc. and salts thereof; antiviral agents,
`e.g., Aciclovir, Idoxuridine, Amantadine, etc. and salts
`thereof; bone metabolic agents, e.g., Vitamin D, Endo
`toxin, Hydroxyapatite, Collagen, Cataboline, 2
`Chloroadenosine, Mecardia, Calcitriol, prostaglandins
`for the alveolar bone, parathyroid hormone for the
`alveolar bone, Calcitonin for the alveolar bone, etc. and
`salts thereof; and astringents, e.g., Tannin, Tannic Acid,
`zinc bromide, sodium ?uoride, strontium ?uoride, po
`tassium nitrate, tin ?uoride, aluminum potassium sul
`fate, Berberine, bismuth derivatives, strontium ?uoride,
`aluminum lactate, etc. and salts thereof.
`The amount ‘of the topical drug to be incorporated
`into the adhesive ?lm depends on the kind of the drug
`and is generally selected from 0.001 to 40% by weight,
`preferably from 0.002 to 20% by weight, based on the
`?lm in view of the pharmacological effects and adhe
`sion to the oral mucosa.
`The preparation applicable to the oral mucosa ac
`cording to the present invention is less causative of an
`adverse feeling on use, excellent in shape retention on
`water absorption, and adhesive to the oral mucosa for
`an extended period of time, thereby maintaining a stable
`administration of a topical drug.
`As described above, the ?lm or preparation applica
`ble to the oral mucosa of the present invention which
`comprises a soft adhesive ?lm prepared from a homoge
`neous mixture of a vinyl acetate homopolymer, an
`acrylic acid polymer, and a speci?c cellulose derivative
`is soft, less causative of an adverse feeling in the oral
`cavity on use and excellent in shape retention on water
`absorption. Further, the ?lm or preparation exhibits
`close adhesion to the oral mucosa for a long period of
`time. Furthermore, because of the homogeneity and
`softness, the ?lm or preparation can be deformed in
`perfect accord with the shape of the oral mucosa simply
`by lightly pressing and adhered close to the mucosa.
`The present invention is now illustrated in greater
`detail by way of the following Examples, but it should
`be understood that the'present invention is not deemed
`to be limited thereto. In these examples, all the parts,
`percents and ratios are by weight unless otherwise spec
`i?ed.
`
`40
`
`45
`
`60
`
`65
`
`EXAMPLE 1
`Five parts of a vinyl acetate homopolymer (weight
`average molecular weight: 172,000), 3 parts of a carbox
`yvinyl polymer (carboxyl group content: 58-63% by
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`weight) (as the acrylic acid polymer), 2 parts of hydrox
`ypropyl cellulose (viscosity: 6.0—l0.0 cp (2%-aqueous
`solution at 20° C.)) (as the cellulose derivative) were
`added to 90-parts of a 1/9 water/methanol mixture as a
`common solvent to form a ?lm-forming composition.
`The composition was cast over a silicone-release paper,
`dried, and stripped off to obtain a 30 pm thick adhesive
`?lm.
`
`COMPARATIVE EXAMPLE 1
`Five parts of a vinyl acetate homopolymer (weight
`average molecular weight: 172,000) and 5 parts of a
`hydroxypropyl cellulose (viscosity: 6.0—l0.0 cp (2%
`aqueous solution at 20° C.)) (as the cellulose derivative)
`were added to 90 parts of a l/ 9 water/ methanol mixture
`as a common solvent to form a ?lm-forming composi
`tion. The composition was cast over a silicone-release
`paper, dried, and stripped off to obtain a 30 pm thick
`?lm.
`Each of the ?lms prepared in Example 1 and Compar
`ative Example 1 was observed under an optical micro
`scope. The three components constituting the ?lm of
`Example 1 were found homogeneously mixed together,
`and each of them did not exist solely in parts, whereas
`the two components constituting the ?lm of Compara
`tive Example 1 were not homogeneously mixed and
`each of them solely existed in parts.
`
`10
`
`25
`
`30
`
`EXAMPLE 2
`A 30 pm thick soft sheet of a vinyl acetate ‘homopoly
`mer (weight average molecular weight: 129,000) was
`laminated as a water-insoluble support on a side of the
`?lm obtained in Example 1 by hot pressing to obtain a
`composite ?lm applicable to the oral mucosa.
`
`35
`
`COMPARATIVE EXAMPLE 2
`Five parts of a vinyl acetate homopolymer (weight
`average molecular weight: 172,000) and 5 parts of a
`carboxyvinyl polymer (carboxyl group content:
`58-63% by weight) (as the acrylic acid polymer) were
`added to 90 parts of a 1/ 9 water/methanol mixture as a
`common solvent to prepare a ?lm-forming composition.
`The composition was cast on a silicone-release paper,
`45
`dried, and stripped off to obtain a 30 pm thick ?lm. A 30
`pm thick soft sheet of a vinyl acetate homopolymer
`(weight average molecular weight: 129,000) as a water
`insoluble support was hot-pressed on the ?lm to obtain
`a composite ?lm.
`
`50
`
`55
`
`COMPARATIVE EXAMPLE 3
`Five parts of a carboxyvinyl polymer (carboxyl
`group content: 53-63% by weight) (as the acrylic acid
`polymer) and 5 parts of hydroxypropyl cellulose (vis
`cosity: 6.0-l0.0 cp (2%-aqueous solution at 20° C.)) (as
`the cellulose derivative) were added to 90 parts of a U9
`water/methanol mixture as a common solvent to pre
`pare a ?lm-forming composition. The composition was
`cast on a silicone~release paper, dried, and stripped off
`60
`to obtain a 30 pm thick ?lm. A30 pm thick soft sheet of
`a vinyl acetate homopolymer (weight average molecu
`lar weight: 129,000) as a water-insoluble support was
`hot-pressed on the ?lm to obtain a composite ?lm.
`Adhesion of each of the composite ?lms prepared in
`65
`Example 2 and Comparative Examples 2 and 3 was
`evaluated according to the following test method (Test
`A), and the results obtained are shown in Table 1 below.
`
`8
`Test A:
`
`A circular specimen of 10 mm in diameter was cut out
`of the composite ?lm. The adhesive layer of the speci
`men was adhered to a water-swollen crosslinked colla
`gen ?lm ?xed on a phenolic resin plate and soaked in
`water at 37° C. under stirring at a constant speed. The
`time required for the ?lm to spontaneously come off the
`collagen ?lm was measured. The measurement was
`conducted on 5 specimens for each sample, and the
`results were averaged.
`TABLE 1
`Comparative
`Example 2
`
`Example 2
`
`Comparative
`Example 3
`
`Time of adhesion
`(min)
`
`422 i 4
`
`162 i 3
`
`28 i 3
`
`EXAMPLE 3
`Five parts of a vinyl acetate homopolymer (weight
`average molecular weight: 129,000), 2 parts of a carbox
`yvinyl polymer (carboxyl group content: 58-63% by
`weight) (as the acrylic acid polymer), 3 parts of hy
`droxypropylmethyl cellulose (degree of substitution:
`1.86-1.90) (as the cellulose derivative), and 0.1 part of
`sodium citrate (as the salt neutralizing the acrylic acid
`polymer) were added to 90 parts of a U9 water/me
`thanol mixture as a common solvent to prepare a ?lm
`forming composition. The composition was cast on a
`silicone-release paper, dried, and stripped off to obtain a
`30 pm thick adhesive ?lm. A 30 pm thick soft sheet of
`a vinyl acetate homopolymer (weight average molecu
`lar weight: 155,000) as a water-insoluble support was
`hot-pressed on the adhesive ?lm to obtain a composite
`?lm applicable to the oral mucosa.
`Shape retention of the composite ?lm of Example 3
`was evaluated according to the following test method
`(Test B), and the results obtained are shown in Table 2
`below.
`
`TEST B
`
`A 1 cm X 2 cm specimen was cut out of the ?lm. The
`adhesive layer of the specimen was applied to the gin
`giva of the upper jaw of each of 10 panel members after
`wiping off the saliva. After the application for 24 hours,
`the adhered area of the ?lm was determined visually.
`During the test, the panel members continued their
`daily life, such as taking foods, drinks, etc.
`TABLE 2
`Time of
`adhesion
`(hour)
`24
`24
`24
`24
`24
`24
`24
`24
`24
`24
`
`Panel member
`A
`B
`C
`D
`E
`F
`G
`H
`I
`J
`Average
`
`Area of
`adhesion
`(%)
`50
`ND
`80
`100
`100
`It!)
`90
`I00
`100
`100
`92
`
`As shown in Table 2, the average area of adhesion
`after the application for 24 hours was 92%.
`
`TEVA EXHIBIT 1022
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`TEST C
`A specimen of 1 cm X 2 em out out of the sample was
`applied to the gingiva of the upper jaw of 10 panel
`members, and the feeling was judged according to the
`following rating system. For comparison, a commer~
`cially available track-?eld type tablet of Sodium Guale
`nate (Azunol ST made by Nippon Shinyaku Co., Ltd.)
`was inserted to the same site, and the feeling was
`judged.
`
`TABLE 3
`
`Panel Member
`
`Example 3
`
`Sample of
`Azunol ST
`
`15
`
`l
`l
`l
`2
`l
`l
`2
`l
`l
`l
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`Rating System:
`1 No adverse feeling
`2 Slight adverse feeling
`3 Adverse feeling
`4 Considerable adverse feeling
`
`3
`3
`4
`4
`4
`3
`4
`4
`4
`3
`
`20
`
`25
`
`From the results of Table 3, the sample of Example 3
`was rated 1.2 in average, while Axunol ST was rated 3.6
`in average. It can thus be seen that the ?lm of Example
`3 causes substantially no adverse feeling in the oral
`cavity on use.
`
`35
`
`45
`
`5,166,233
`9
`10
`drug in the extract was determined by high perfor
`Further, the sample of Example 3 was tested for an
`adverse feeling in the oral cavity on use according to
`mance liquid chromatography. The results obtained
`the following test method (Test C).
`were plotted against time as shown in FIG. 1.
`FIG. 1 reveals that the preparation of Example 4
`keeps adhered to the agar gel, a substitute for the oral
`mucosa, for an extended period of time, releasing the
`active ingredient with time.
`While the invention has been described in detail and
`with reference to speci?c embodiments thereof, it will
`be apparent to one skilled in the art that various changes
`and modi?cations can be made therein without depart
`ing from the spirit and scope thereof.
`What is claimed is:
`1. A ?lm applicable to the' oral mucosa, comprising a
`homogenous mixture comprising
`(a) a vinyl acetate homopolymer,
`(b) an acrylic acid polymer, and
`(c) a cellulose derivative capable of being dissolved in
`or swollen with water and a lower alcohol,
`wherein said ?lm further contains a salt or base
`neutralizing said acrylic acid polymer,
`wherein said salt or base is present in an amount of
`from 0.03 to 0.2 equivalent to said acrylic acid
`polymer,
`wherein said acrylic acid polymer and cellulose deriva
`tive are present at a weight ratio from 1/9 to 9/1, and
`wherein the lower alcohol is methanol or ethanol.
`2. A ?lm as claimed in claim 1, wherein said cellulose
`derivative is selected from the group consisting of
`methyl cellulose, ethyl cellulose, hydroxyethyl cellu
`lose, hydroxypropyl cellulose and hydroxypropyl
`methyl cellulose.
`3_. A ?lm as claimed in claim 1, wherein said acrylic
`acid polymer and cellulose derivative are present at a
`weight ratio of from 3/7 to 6/4.
`4. A ?lm applicable to the oral mucosa, comprising a
`homogenous mixture comprising
`(a) a‘ vinyl acetate homopolymer,
`(b) an acrylic acid polymer, and
`(c) a cellulose derivative capable of being dissolved in
`or swollen with water and a lower alcohol,
`wherein said ?lm further contains a salt or base
`neutralizing said acrylic acid polymer,
`wherein said salt or base is present in an amount of
`from 0.03 to 0.2 equivalent to said acrylic acid
`polymer,
`wherein the weight ratio of said vinyl acetate homopol
`ymer to the sum of said acrylic acid polymer and cellu
`lose derivative is from 2/8 to 8/2, and wherein the
`lower alcohol is a methanol or ethanol.
`5. A ?lm as claimed in claim 4, wherein said acrylic
`acid polymer and cellulose derivative are present at