EP 0 200 508 81
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`Description
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`This invention relates to an oral bandage that can be adhered to the oral mucosa to prevent a drug
`administered to the oral mucosa from running out and to cover or protect the affected part of the oral
`5 mucosa, and to oral preparations comprising such a bandage having incorporated therein a topical drug.
`In the field of dental and oral surgery, various topical preparations in the form of ointments or solutions
`have hitherto been administered to the oral mucosa for prophylaxis and therapy of oral diseases, such as
`periodontal disease, stomatitis, etc. The most serious problem in administering drugs to the oral mucosa is
`that the drug runs away in a short time by salivary secretion or through eating or drinking, thereby failing to
`fully exert its medical effects.
`On the other hand, protection of the affected part in the oral cavity has scarcely been conducted
`because no effective oral bandage has been developed. As mentioned above, the continuous salivary
`secretion and taking of foods and drinks constitute an insuperable barrier to the protection of the oral
`mucosa.
`In recent years, many proposals have been made in an attempt to effectively administer a drug to the
`mucosa of the oral cavity, so as to overcome the above-described problems. Among them, proposals
`relevant to the present invention relate to preparations adhesive to the oral mucosa, which contain water(cid:173)
`soluble high-molecular substances as an adhesive. When water-soluble high-molecular substances absorb a
`small amount of water, they become a viscous aqueous solution or gel having adhesion, though varying in
`20 extent with their kind. Making use of this property, various preparations adhesive to the oral mucosa have
`been proposed, including pastes as disclosed in Japanese Patent Publication No. 27491/81, sponges as
`disclosed in Japanese Patent Publication No. 25211/81, tablets as disclosed in Japanese Patent Publication
`No. 7605/83, sheets as disclosed in Japanese Patent Publication No. 16676/69 and Japanese Patent
`Application (OPI) No. 186913/84 (the term "OPI" has herein used means "unexamined published applica-
`tion").
`However, these conventional preparations only are intended to have enough adhesion to allow them to
`remain in position for a period of time enough to administer the drug to the mucosa. In other words, these
`preparations do not possess strong adhesion for an extended period of time as required for an oral
`bandage. On the contrary, an oral bandage is intended to prevent running-off of the administered drug or to
`30 provide protection by adhesion to the affected or injured part of the oral cavity. Therefore, it is required to
`have strong and long-lasting adhesion to the oral mucosa which may be less adherable due to the
`administered drug or stomatorrhagia. Since both adhesive strength and duration of adhesion of the
`aforesaid conventional preparations adhesive to the oral mucosa are not so high as demanded for an oral
`bandage, application of bases used in these preparations to an oral bandage can never satisfy the above-
`35 described requirements of an oral bandage. The conventional adhesive tapes which are intended to be
`applied to the skin cannot be, of course, used as an oral bandage because they have no adhesion to a wet
`surface such as oral mucosa.
`Japanese Patent Application (OPI) No.186913/84 is directed to an invention that four components of
`gelatin or agar, gluten, carboxyviny! polymer, and vinyl acetate resin or gum are essential. It is therefore
`40 apparent that the cited reference differs from the present application in which a homogeneous state is
`maintained by a two component system.
`In the JPA document a water-soluble material and a water-insoluble material are mixed together with
`water in such a manner that a water content is 0.5-20 w!w%. From this fact, it is apparent that a
`homogeneous state cannot be obtained.
`Even if a base material having such a state is adhered to the oral mucosa, water at the adhering portion
`is not absorbed uniformly with respect to the base material, resulting in an ununiform absorption, and as a
`result, the system of the base material tends to break, and its adhesion is not maintained for a long period
`of time.
`On the other hand, in the homogeneous state as in the present invention, absorption of water from the
`50 adhering portion is uniformly conducted over the whole base material. Consequently, it is difficult to
`proceed breakage of the system, and the adhesion is sufficiently maintained over a long period of time.
`An oral bandage is required to have not only strong and long-lasting adhesion to the oral mucosa as
`described above but also softn~ss sufficient to be adhered to any desired site of complicated shape in the
`oral mucosa and, in addition, safety from worsening of the injury due to irritation. However, an oral bandage
`55 having such performance characteristics has not yet been developed.
`The present invention is intended to meet the above-described situations.
`Accordingly, an object of this invention is to provide an oral bandage having high adhesive strength for
`a prolonged period of time and softness with which to adhere to desired site of the oral mucosa or teeth.
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`2
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`DRL - EXHIBIT 1007
`DRL2201
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`

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`EP 0 200 508 81
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`5
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`10
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`Another object of this invention is to provide an oral preparation adhesive to the oral mucosa by which
`an active ingredient can be surely and effectively administered to the oral mucosa.
`According to the invention we provide an oral bandage comprising a soft adhesive film consisting of a
`mixture of (a) an acrylic acid polymer, methacrylic acid polymer and/or maleic anhydride polymer and (b) a
`vinyl acetate polymer, the polymers (a) and (b) being uniformly dissolved in each other without regions of
`phase separation, so as to be substantially water-insolubilized; and optionally a basic substance capable of
`neutralizing said polymers (a) and an oral preparation comprising such an oral bandage having incorporated
`therein a topical drug.
`.
`The term "compatible state" as herein used means such a state that the polymers (a) and (b)
`(hereinafter simply referred to as "polycarboxylic acids") and the vinyl acetate polymer (hereinafter referred
`to as polyvinyl acetate) are uniformly dissolved in each other without forming small individual regions due to
`phase separation.
`Water-soluble high-molecular compounds, such as polycarboxylic acids and polycarboxylic acid anhy(cid:173)
`drides have per se a shape-retention property. When they absorb a small amount of water, they exhibit
`15 strong adhesiveness but soon take up excess water to cause reduction in viscosity and degradation, thus
`resulting in losing their adhesiveness by being substantially dissolved in water. Moreover, since polycarbox(cid:173)
`ylic acids in a dissolved state are acidic, they heavily irritate the sensitive injured part of the oral mucosa to
`cause worsening of the condition.
`The present inventors have conducted extensive investigations on water-insolubilization of the above-
`20 described water-soluble high-molecular compounds, such as polycarboxylic acids, polycarboxylic acid
`anhydrides, etc., aiming at effective utilization of these compounds exhibiting excellent adhesion upon
`absorption of water as an oral bandage, while eliminating the above-described disadvantages, i.e., loss of
`adhesion due to over-absorption of water and irritation of the injured part. As a result, it has now been found
`that polycarboxylic acids and polyvinyl acetate are compatible with each other, and mixing of these two
`25 components in a compatible state substantially realizes water-insolubilization of the polycarboxylic acids
`without impairing the strong adhesion upon water absorption. Therefore, even if such a compatible mixture
`of the two components is shaped into a thin and soft film, it can exert strong adhesion for an extended
`period of time without undergoing degradation due to water absorption in a wet state.
`It has further been found that incorporation of a basic substance {salt or base) capable of neutralizing
`the polycarboxylic acids into the above-described compatible mixture can further relieve the irritation on the
`injured part of the oral mucosa.
`It has furthermore been found that incorporation of topical drugs into adhesive film and/or film support
`comprising the above-described compatible mixture can provide film-like oral preparations retaining the
`strong adhesion, by which the drug can be surely, simply and effectively administered to the oral mucosa,
`thus permitting prevention and treatment of oral diseases.
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`In the accompanying drawing:
`
`The graph is a characteristic curve of (dissolved amount)/(total dissolved amount) of a drug, over a
`40 period of time.
`A soft film comprising a compatible mixture of the polycarboxylic acids and polyvinyl acetate according
`to the present invention does not show adhesion in a dry state but comes to exhibit strong adhesion upon
`water absorption, such adhesion being substantially unchangeable even when immersed in water. Such a
`characteristic can first be manifested when the polycarboxylic acids and polyvinyl acetate are in a
`45 compatible state, not appearing when they are not in a compatible state.
`As described above, the mixture of the polycarboxylic acids and polyvinyl acetate in a compatible state
`exhibit characteristics unpredictable from those of a mixture in a phase-separated state. More specifically, a
`film in a phase-separated state is turbid, whereas a film in a compatible state has such a high transparency
`that no independent small region is observed under an optical microscope. Further, when immersed in .
`50 water, the polycarboxylic acids is dissolved out from the film in a phase-separated state, resulting in
`degradation as a whole; while the film in a compatible state only undergoes uniform swelling with very little
`elution of the polycarboxylic acids into water, which indicates that the polycarboxylic acids is substantially
`water-insolubilized. The compatible state (compatibility) of the polycarboxylic acids and polyvinyl acetate
`can be determined by making use of insolubilization of the polycarboxylic acids.
`When a basic substance capable of neutralizing polycarboxylic acids is mixed with the above-described
`compatible mixture, the state of its mixing has no substantial influence on the adhesion property. Therefore,
`the basic substance may be mixed either in a compatible state or in a coarse dispersion.
`Compatibility between the polycarboxylic acids and polyvinyl acetate can be clearly observed if the
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`3
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`DRL - EXHIBIT 1007
`DRL2202
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`

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`EP 0 200 508 81
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`10
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`mixture consists of only these two components as mentioned above. However, differrences in compatibility
`become unclear in those mixtures containing a basic substance having a neutralizing effect. In other words,
`in a mixture containing a basic substance, the mixing state of the basic substance being not restricted, even
`if the polycarboxylic acids and polyvinyl acetate are in a compatible state, the basic substance, if being
`5 mixed in a coarse dispersion, makes the film turbid. Thus, the mixing state of the polycarboxylic acids and
`polyvinyl acetate cannot always be observed visually or under an optical microscope.
`Nevertheless, as described above, it has been confirmed that water-solubility of polycarboxylic acids
`can be markedly inhibited in a compatible mixture with polyvinyl acetate and that such a compatible mixture
`is uniformly swollen without degradation even when immersed in water for a considerably long period of
`time. This property can be recognized irrespective of whether a basic substance having a neutralizing effect
`be present or not.
`Accordingly, this property can be made use of in determination of compatibility between polycarboxylic
`acids and polyvinyl acetate. This method of determination can be regarded reasonable from the fact that
`the oral bandage according to the present invention can be adhered to the oral mucosa for a long period of
`time owing to the limited water-solubility of the polycarboxylic acids.
`In the present invention, the compatibility between polycarboxylic acids and polyvinyl acetate is
`determined from the amount of dissolved polycarboxylic acids. That is, the compatible state as herein
`referred to specifically means that the dissolution ratio of polycarboxylic acids as obtained by the following
`method is 40% by weight or less. In the case of an oral bandage containing a salt having a neutralizing
`20 effect, it means that the dissolution ratio of polycarboxylic acids as obtained by the following method is
`50% by weight or less, taking into account dissolving of the salt.
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`Method of determing Dissolution Ratio:
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`A film comprising polycarboxylic acids and polyvinyl acetate is ground and weighed. The ground
`sample is put in a mesh bag and left to stand still in 300 times or more the weight of pure water at 20 • C
`for one hour. The bag is then taken out, and the amount of polycarboxylic acids dissolved out into the water
`is determined by neutralization titration or the like technique. This value is divided by the amount of the
`polycarboxylic acids initially contained in the film to obtain the dissolution ratio.
`In the case when the film contains a basic substance, the dissolution ratio is obtained in the same
`manner as above except that the bag after the immersion is weighed to obtain the total amount of dissolved
`polycarboxylic acids and dissolved salt from, for example, weight reduction and this value is divided by the
`sum of the polycarboxylic acids and the basic substance initially contained in the film to obtain the
`dissolution ratio.
`Since the oral bandage in accordance with the present invention comprises a soft film which is not
`adhesive in a dry state but shows adhesion only upon absorption of water, it can be stored as such without
`requiring any special storage conditions. On use, the oral bandage is stuck onto the oral mucosa whereupon
`it absorbs saliva or moisture of the mucous membrane to rapidly exerts strong adhesion to the mucous
`membrane. Thus, it firmly adheres to the affected part or injured part of the oral cavity that is less
`40 adherable due to the drug administered, stomatorrhagia, and the like. This adhesion lasts for a markedly
`prolonged period of time, which is a well-marked characteristic of the present invention. Such adhesion of
`long duration can first be attained by the adhesive film comprising the polycarboxylic acids and polyvinyl
`acetate in a compatible state as set forth above.
`The mechanism accounting for the long-lasting adhesion is not clear, but it is believed that the
`45 polycarboxylic acids contributes to adhesiveness to the wet mucosa and the polyvinyl acetate contributes to
`water resistance in a compatible mixture thereof, thus functioning together to give adhesion of long duration.
`The mixing state of the basic substance capable of neutralizing polycarboxylic acids has no influence
`on the adhesion, but the kind of the basic substance to be used exerts delicate influences on the adhesion
`and the like. For example, polyvalent metal salts, e.g., zinc oxide, calcium oxide, etc., function to reduce
`50 adhesion and to enhance water resistance, while monovalent metal salts, e.g., sodium acetate, etc., or a
`monovalent base, e.g., sodium hydroxide, triethanolamine, etc., functions to reduce water resistance and to
`enhance adhesion.
`As described above, since the oral bandage in accordance with the present invention has adhesion of
`long duration, it can prevent the drug administered to the affected part of the oral cavity from running off to
`55 accelerate healing with a remarkably increased absorption of the drug and also give protection to the
`injured part of the oral cavity for a long period of time to expedite recovery.
`Further, since the irritation due to eluted polycarboxylic acids can be reduced by adding a basic
`substance having a neutralizing effect to the adhesive film, a situation wherein the injured part of the oral
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`DRL - EXHIBIT 1007
`DRL2203
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`

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`20
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`30
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`EP 0 200 508 81
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`5
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`5
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`10
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`15
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`cavity becomes worse due to application of the oral bandage can be avoided.
`In addition, the adhesive film according to the present invention is not merely composed of a water(cid:173)
`soluble high-molecular substance but comprises a substantially water-insoluble soft film, in which polycar(cid:173)
`boxylic acids and polyvinyl acetate exist in a compatible state. Therefore, adhesion of long duration can be
`produced in a very thin film. In other words, too a thin film solely made of a water-soluble high-molecular
`substance is readily dissolved out in saliva in a short time to rapidly lose its adhesiveness so that a film
`made of such a material should have a considerably large thickness. However, a thick film produces a
`feeling foreign to the applied part and also reduces softness of the oral bandage. On the contrary, the oral
`bandage of the present invention does not require such a large thickness, thus giving no uncomfortable
`feeling.
`The oral bandage according to the present invention can be produced by, for example, dissolving
`polycarboxylic acids and polyvinyl acetate in a solvent common to both and rapidly flow-casting the solution
`in a thin film, followed by drying.
`The oral bandage containing a basic substance having a neutralizing effect according to the present
`invention can be produced by, for example, dissolving polycarboxylic acids and polyvinyl acetate in a
`solvent common to both, adding a basic substance capable of neutralizing the polycarboxylic acids to the
`solution, and rapidly flow-casting the mixture in a thin film, followed by drying. Incorporation of the basic
`substance may be carried out by dissolving in the solution or by dispersing a powderous basic substance in
`the solution. The above-described flow casting method is advantageous to easily produce a very thin film.
`In the present invention, a topical drug can be incorporated into the oral bandage of the invention to
`obtain oral preparations. The method of incorporation is not particularly restricted, and usually comprises
`adding the topical drug directly or in the form of a solution to the solution of polycarboxylic acids and
`polyvinyl acetate, rapidly casting the composition in a thin film and drying. the acrylic polymers include an
`acrylic acid homopolymer and copolymers of acrylic acid and acrylic esters, e.g., butyl acrylate, 2-
`25 ethylhexyl acrylate,
`methacrylic esters, e.g., methyl methacrylate,
`or vinyl monomers, e.g., vinyl acetate, and copolymers, e.g., carboxyvinyl polymer. Examples of the
`methacrylic polymers include a methacrylic acid homopolymer and copolymers of methacrylic acid and
`comonomers as enumerated for the acrylic polymers. Specific examples of the maleic anhydride polymers
`include copolymers of maleic anhydride and methyl vinyl ether,
`These compounds can be used either individually or in combination of two or more thereof. It is
`preferable that these Polycarboxylic acids contain 20% by weight or more of a -COOH group in case of
`methacrylic polymers or 16% by weight or more or a -C0-0-CO- group in case of maleic anhydride
`polymers.
`The vinyl acetate polymer which can be used in the present invention typically includes a vinyl acetate
`homopolymer. In addition, copolymers of vinyl acetate and vinyl monomers, e.g., acrylic esters, and partial
`saponification products of a vinyl acetate homopolymer may also be employed. These vinyl acetate
`polymers may be used either individually or in combinations of two or more thereof. The polyvinyl acetate
`preferably has an average molecular weight (viscosity-average molecular weight) of not less than 60,000.
`40 Use of polyvinyl acetate having an average molecular weight less than 60,000 reduces water resistance of
`the adhesive, resulting in failing of the expected effects.
`The basic substance which can be used for neutralizing polycarboxylic acids includes not only salts but
`bases. Typical examples of the salt include salts of metals and weak acids, metal oxides, metal hydroxides,
`amines, and mixtures thereof. Specific examples of the salt of metals and weak acids are salts of sodium,
`45 potassium, calcium, magnesium, etc. and carboxylic acids, e.g., acetic acid, lactic acid, citric acid, etc.
`Specific examples of the metal oxides are zinc oxide, calcium oxide, magnesium oxide, etc. Specific
`examples of the metal hydroxides are sodium hydroxide, potassium hydroxide, calcium hydroxide, magne(cid:173)
`sium hydroxide, etc. Specific examples of the amines are triethanolamine, diisopropanolamine, etc. These
`compounds can be used either alone or in combination. A preferred amount of the basic substance to be
`50 added varies widely depending on the kind thereof. In the case of using a polyvalent metal salt, for
`example, it is preferably added in an amount of from 0.2 to 0.8 equivalent based on the polycarboxylic
`acids. If its amount is less than 0.2 equivalent, the effect to relieve irritation on the injured part of the oral
`mucosa becomes insufficient. If it exceeds 0.8 equivalent, sufficient duration of adhesion can hardly be
`attained. In case of using a monovalent metal salt or a monovalent base, it is preferably added in an amount
`55 of from 0.03 to 0.2 equivalent based on the polycarboxylic acids. Amounts less than 0.03 equivalent reduce
`the effect of relieving irritation on the injured part, and amounts exceeding 0.2 equivalent reduce water
`resistance of the adhesive film, resulting in difficulty in obtaining sufficient adhesion.
`The solvent common to the polycarboxylic acids and polyvinyl acetate includes lower alcohols, such as
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`DRL - EXHIBIT 1007
`DRL2204
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`

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`EP 0 200 508 81
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`methanol, ethanol, etc.; mixed solvents comprising a lower alcohol in a larger proportion and a compatible
`organic solvent, such as acetone, ethyl acetate, etc.; and mixed solvents comprising a lower alcohol or the
`above-described mixed solvent and water. The mixed solvent of a lower alcohol and an organic solvent
`preferably contains not more than 30% by weight of the organic solvent because the organic solvent of
`5 more than 30% by weight makes it difficult to dissolve polycarboxylic acids. The mixed solvent of a lower
`alcohol or a lower alcohol-organic solvent mixed solvent and water preferably contains not more than 30%
`by weight of water because a water content exceeding 30% by weight is liable to make it difficult to
`dissolve the polyvinyl acetate.
`In the preparation of the oral bandage or oral; preparations of the invention, it is preferable that the
`10 polycarboxylic acids to polyvinyl acetate mixing ratio fall within such a range that the value A as obtained
`according to the following formula ranges from 15 to 45:
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`15
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`(Weight of -cooH )
`~(Weight of -co-o-co-)
`A = in Adhesive Film + 4\ in Adhesive Film
`Weight of Polycarboxylic .Acids in Adhesive Film,)x
`(
`+ Weight of Polyvinyl Acetate in Adhesive Film
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`100
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`30
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`As the value A becomes larger, the adhesion to the mucous membrane increases, but the duration of
`20 adhesion tends to decrease. To the contrary, the smaller the value A, the lesser the ahesion, but the
`duration of adhesion tends to increase. If the value A is less than 15, sufficient adhesion is hard to obtain. If
`it exceeds 45, it becomes difficult to obtain sufficient duration of adhesion. Accordingly, the mixing ratio of
`polycarboxylic acids and polyvinyl acetate is preferably adjusted so that the value A falls within a range of
`from 15 to 45. Taking the case of using polyacrylic acid as a polycarboxylic acid for instance, with the
`25 proportion of polyacrylic acid in the adhesive film being between 24 and 72% by weight, the value A falls
`within the above-recited range to obtain good results.
`When the polycarboxylic acids and polyvinyl acetate are dissolved in a common solvent, care should
`be taken so as to sufficiently dissolve the both components. On this occasion, concentrations of the
`polycarboxylic acids, polyvinyl acetate, etc. are not particularly limited. However, too a high concentration of
`the high-molecular substance makes the resulting solution highly viscous, and such a viscous solution is
`difficult to flow-cast in a film. Therefore, it is preferable to give care that the concentrations of the high(cid:173)
`molecular substances may not exceed 40% by weight
`In the preparation of the adhesive film according to the present invention, the solution comprising the
`polycarboxylic acids and polyvinyl acetate and, if necessary, a basic substance and/or a topical drug is cast
`35 on an appropriate film, such as polyethylene-laminated paper, having been subjected to releaseability(cid:173)
`imparting treatment, and the casted film is rapidly dried with hot air in a drying oven or a drying tower.
`Suitable time and temperature in drying vary depending on the composition of a common solvent used,
`solid content of the solution, thickness of the cast film, the pressure and the like but, in general, preferably
`range from 60 • to 120 • C in temperature and from 1 to 20 minutes in time under an atmospheric pressure.
`40 A very thin film that can be, as such, used as an oral bandage can be thereby produced. The thickness of
`the resulting film is preferably be adjusted to a range of from 5 to 100 um by controlling the amount of the
`casting solution, and the like. If a film thickness is Jess than 5 JJ.m, it is difficult to obtain sufficient adhesion.
`A film having a thickness exceeding 1 00 um tends to produce a feeling foreign to the mouth and to impair
`softness of the film.
`As described above, the adhesive film in accordance with the present invention comprises a po!ycar-
`boxylic acids and a vinyl acetate polymer not in a merely mixed state but in a compatible state with each
`other, in which the polycarboxylic acids is substantially water-insolubilized. Hence, even being very thin, it
`exerts strong adhesion for an extended period of time without suffering degradation due to water absorption.
`Besides, the film can easily be deformed according to the form of the oral mucosa and adhered thereto
`50 simply by pressing because of its softness.
`The oral bandage and oral preparations according to the present invention may solely comprise the
`adhesive film but may further comprise a soft film support in combination.
`A composite comprising the adhesive film and a support can be produced by laminating the adhesive
`film on a soft film support in a usual manner, such as hot pressing or by the use of an adhesive.
`55 Alternatively, the lamination can be carried out simultaneously with the preparation of the adhesive film by
`casting the film-forming composition on a soft film support, followed by drying. The latter process has an
`advantage over the former in simplifying the production procedure since hot pressing or adhesion with an
`adhesive is unnecessary.
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`45
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`6
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`DRL - EXHIBIT 1007
`DRL2205
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`

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`EP 0 200 508 81
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`5
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`10
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`15
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`20
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`30
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`25
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`The soft film support which can preferably be used in the present invention is substantially imperme(cid:173)
`able to water. Such a support typically includes plastic films, such as polyethylene, polyvinyl acetate resin,
`an ethylene-vinyl acetate copolymer, polyvinyl chloride, polyurethane, etc., metal foils, such as aluminum
`foil, tin foil, etc., laminates of cloth or paper and a plastic film, and the like. Of these, plastic films are
`preferred in view of safety and feeling in use. A preferred thickness of the film support is from 10 to 100
`um in view of handling properties and freedom from a foreign feeling on use. A thickness of the composite
`film, i.e., a total thickness of the adhesive film and the film support, is preferably in the range of from 30 to
`150 um. If it is less than 30 um, handling properties and operation properties are deteriorated. A thickness
`exceeding 150 um is liable to give a foreign feeling on use.
`When the oral bandage of the invention contains a topical drug to obtain an oral preparation as
`described before, the topical drug may be incorporated into the adhesive film and/or the above-described
`film support. In the latter case, incorporation of the drug can be carried out by kneading with a resin
`material for the support, mixing the drug in the form of its solution with a resin material, absorbing onto a
`support, impregnating into a support, or a like method.
`The topical drug which can be used in the present invention may be either solid ·or liquid at room
`temperature as long as it may be incorporated into the adhesive film or the film support by dissolving or
`dispersing.
`Specific examples of the topical drugs to be used in the present invention are adrenal corticosteroids,
`e.g., Triamcinolone acetonide, Dexamethasone, Betamethasone, Prednisolone, Fluocinolone, Hydrocor-
`tisane, Beclomethasone, etc. and salts thereof; anti-inflammatory agents, e.g., Flurbiprofen, Ibuprofen,
`Diclofenac, indomethacin, Bendazac, Flufenamic acid, Bufezamac, Cyclospoline, Clidanac, Glycyrrhizin,
`Ketoprofen, Piroxicam, Pranoprofen, Benzydamine,
`ibuprofenpiconol, Etofenamate,
`Lysozyme,
`Chymotrypsin, Epidihydrocholesterine, Hinokitiol, a-Amylase, Azulene, Chlorophllin, Cromoglic acid,
`Tranilast, Serratiopeptidase, Pronase, Glucanase, Lithospermi Radix extract, etc. and salts thereof; an-
`timicrobial agents, e.g., Acrynol, Cetyl pyridinium, Chlorhexidine, Domifen, Iodine, Monensin, Sanginalfine,
`Metronidazol, Dequalinium, Tetracycline, Minocycline, Ofloxacin, Penicilline, Doxycycline, Oxycycline,
`Cefatrizin, Nystatin, Clindamycin, Fradiomycin, sulfate, etc. and salts thereof; analgesics, e.g., Ethyl
`aminobenziate, Camphor, Eugenol, Dibucaine, Phenol, Menthol, Creosote, Diphenhydramine, Lidocaine,
`Tetracaine, Procaine, Cocaine, Piprocaine, Mepivacaine, Promoxin, Dicronin, Guaiacol, etc. and salts
`thereof; hemostatics, e.g., Tranexamic acid, e-Aminocapronic acid, Alginic acid, Bioflavonoide, Ascorbic
`acid, Thrombin, oxidized Cellulose, Cetraxate, Epinephrine, Ferric chloride, Fibrinogen, Carbazochrome,
`Adrenochrome, etc. and salts thereof; vasodilators, e.g., Inositol hexanicotinate, Cyclanderate, Cinnarizine,
`Tolazoline, Acetylcholine, etc. and salts thereof; agents activaing cellular function, e.g., Solcoseryl, Pro(cid:173)
`glumide, Sucralfate, Gefarnate, Nicametate, Glutamine, Aceglutamide aluminum. Ethylcysteine. Chitin,
`ss Tocopherol nicotinate, Ubidecarenone, etc. and salts thereof; antiviral agents, e.g., Aciclovir, ldoxuridine,
`Betrabin, Amantadine, etc. and salts thereof; agents affecting calcium metabolism, e.g., Vitamin D,
`Endotoxin, Hydroxyapatite, Collagen, Cataboline, 2-Chloroadenosine, Norcardia, Calcitriol, Prostaglandins for
`alveolar bone, Osteoclast activating factors for alveolar bone, Parathormone for alveolar bone, Calcitonine
`for alveolar bone, etc. and salts thereof; astringents, e.g., Tannin, Tanninc acid, Zinc fluoride, Sodium
`fluoride, Strontium fluoride, Potassium nitate, Stannous fluoride, Aluminum potassium sulfate, Berberine,
`Bismuth compounds, Strontium chloride, Aluminum lactate, etc. and salts thereof.
`The amount of these topical drugs to be incorporated in the oral preparation varies depending on the
`kind thereof, but from considerations of pharmacological effects and adhesion to the mucous membrane, it
`usually ranges from 0.0001 to 35% by weight, and preferably from 0.0002 to 20% by weight, based on the
`45 preparation. When positive administration of the drug to the oral mucosa is expected, the drug is preferably
`present in the adhesive film side. In the treatment of bad breath, and the like, it may be prevent in the
`support side.
`The composite film composed of the adhesive film and the support has enhanced strength while
`retaining the excellent adhesion of long duration. As an additional effect, the composite film can present
`50 adhesion of foreign matters, such as foods, onto the back side of the oral bandage or oral preparations.
`Further, use of a substantially water-impermeable support effectively prevents permeation of water through
`the back side to thereby prolong the duration of adhesion.
`The adhesive film or support of the oral bandage or oral preparations according to the present invention
`may further contain other additives, such as coloring matters, flavoring materials, softening agents, and the
`like, as long as they do not impair adhesive