JPH0696518B2 - Oral formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to an oral preparation which is applied to the moist mucous membrane and the tooth surface of the oral cavity and exerts a local effect over a long period of time at the application site.

[Conventional technology]

2. Description of the Related Art Conventionally, various topical agents have been administered as ointments or liquids in the dental and oral area for the prevention and treatment of diseases in the oral cavity such as alveolar pyorrhea and inflammation. like this,
The greatest obstacle to the administration of a drug to the mucous membrane of the oral cavity is that the drug is washed away in a short time due to the secretion of saliva or eating and drinking, and it is difficult to sufficiently develop the drug.

In addition, it is rarely done to cover and protect the damaged part in the oral cavity because there is no effective oral bandage, but saliva is constantly secreted in the oral cavity as described above and food and drink enter. Therefore, there is a major obstacle to the realization of the coating protection.

Recently, various proposals have been made in order to overcome these obstacles and effectively administer a drug to oral diseases. Among them, those having a concept relatively close to that of the oral preparation of the present invention is an oral mucoadhesive preparation containing a water-soluble polymer substance as an adhesive component. The water-soluble polymer substance varies in degree depending on its type, but when it absorbs a small amount of water, it becomes a viscous aqueous solution or gel and exhibits adhesiveness. Utilizing this property, paste (Japanese Patent Publication No. 56-27491), sponge (Japanese Patent Publication No. 56-25211), tablet (Japanese Patent Publication No. 58-7605), sheet (Japanese Patent Publication No. (16676, JP 59-186913)
Various oral mucoadhesive formulations have been devised.

[Problems to be solved by the invention]

Although the above-mentioned various preparations have considerably improved adhesion and the like as compared with conventional liquid agents or ointments, they are still insufficient. That is, in a paste-like or sponge-like preparation, since these do not have sufficient physical strength, they are removed by stretching or rubbing the mucous membrane during conversation, and do not have long-term adhesion persistence. .
In particular, in a pasty preparation, it is difficult to administer the intended drug amount accurately. Further, since the tablet-shaped preparation itself is rigid, it is difficult to apply it to all parts of the oral mucosa having a complicated shape. Therefore, it is difficult to administer the drug to a desired site. The sheet-shaped formulation is
Although it does not have the drawbacks of the above-mentioned tablet-like preparation, it has the drawback that it does not adhere to the mucosa for a sufficient time for administration of the drug, and it does not yet have satisfactory performance. .

In general, the oral preparation is intended to be applied to the diseased part or damaged part of the oral cavity to administer the drug and to cover and protect those parts, and it is difficult to adhere due to bleeding from the damaged part. To the mucous membrane in the oral cavity, an adhesive force capable of strongly adhering and an adhesive sustaining force capable of adhering over a long period of time are required. However, none of the above-mentioned conventional oral preparations have such characteristics, and it is the actual situation that sufficient effects cannot be obtained. Needless to say, the adhesive tape such as a bandage used for the outer skin does not have adhesiveness to the moist surface such as the mucous membrane of the oral cavity, and therefore cannot be diverted to the oral preparation.

The present invention has been made in view of such circumstances, and has a strong adhesive force, long-term adhesive continuity, and flexibility that can be applied to any part of the oral mucosa or tooth surface, and further to that part. It is intended to provide an oral preparation capable of sufficiently administering a drug.

[Means for solving problems]

In order to achieve the above-mentioned object, the present invention comprises a formulation consisting of a film-like adherent alone containing a topical drug, or an integrated product of the film-like adherent and a flexible film-like support, and the above-mentioned film-like adherent. A formulation containing a topical drug in at least one of a body and a film-like support, wherein the film-like adherent is in a compatible state with at least one of a polycarboxylic acid and a polycarboxylic acid anhydride and a vinyl acetate polymer. The first gist is an intraoral preparation composed of a flexible film-like material having a flexible film-like structure, and at least one of a polycarboxylic acid and a polycarboxylic acid anhydride and a vinyl acetate polymer are in a compatible state. A second gist is an oral preparation in which a salt having a neutralizing action is contained in a simple film-like body.

Water-soluble polymeric substances such as polycarboxylic acids and polycarboxylic acid anhydrides have shape-retaining properties by themselves, and invent a strong adhesive property in the state of absorbing a small amount of water, but immediately absorb excessive water. Then, the viscosity is lowered and the particles are disintegrated to become substantially dissolved in water to lose the adhesiveness. In addition, since dissolved polycarboxylic acid is acidic, it gives strong irritation when it comes into contact with a sensitive damaged part of the oral mucosa and causes deterioration of the damaged part.

The present inventors make use of the strong adhesive force of water-soluble polymer substances such as polycarboxylic acid and polycarboxylic acid anhydride at the time of such water absorption, and effectively utilize this for oral preparations. A series of studies were conducted to make water-soluble polymeric substances water-insoluble for the purpose of improving adhesion loss during excessive absorption of water and improving irritation to damaged areas in the oral cavity.
As a result, the polycarboxylic acid and polycarboxylic acid anhydride are compatible with the vinyl acetate polymer, and when both are made compatible, the polycarboxylic acid and polycarboxylic acid anhydride are substantially insolubilized in water. It is realized in an enhanced state without impairing the strong adhesiveness at the time of absorbing water, and it does not disintegrate in the wet state even if it is formed into a thin flexible film by containing a local drug in the compatible material of both. When it exhibits a strong adhesive force for a long time and contains a salt (salt or base) having a neutralizing effect on the polycarboxylic acid or polycarboxylic anhydride in the above-mentioned compatible material, the mucous membrane in the oral cavity It has been found that it becomes possible to almost eliminate irritation to the damaged part. Therefore, the oral preparation of the present invention is flexible and can be applied to any mucosal site in the oral cavity, and not only can the drug be sufficiently administered to that site, but also to the damaged site, etc. Even when applied, a sufficient amount of drug can be administered without giving a strong irritation to the damaged area and causing deterioration of the damaged area.
Moreover, it has a characteristic that the above-mentioned stuck state lasts for an extremely long time. The administration of the drug as described above can be realized not only by using a flexible film (film-like adherent) composed of the above-mentioned compatible material, but also by incorporating a topical drug into the film-like support that supports it. You can

A flexible film made of a compatible material of at least one of the above-mentioned polycarboxylic acid and polycarboxylic anhydride (hereinafter collectively referred to as "polycarboxylic acids") and a vinyl acetate polymer has an adhesive property when dried. However, it has an epoch-making characteristic that it exhibits strong adhesiveness when absorbing water and its state hardly changes even when immersed in water. Such characteristics are exhibited only when the polycarboxylic acid and the vinyl acetate polymer are in a compatible state, and do not appear when they are not in a compatible state.

The term "compatible state" as used herein means a state in which polycarboxylic acids and a vinyl acetate polymer are homogeneously dissolved without phase separation to form independent small regions. When the polycarboxylic acids and the vinyl acetate polymer are in a compatible state, they exhibit properties that cannot be predicted from the properties of the mixture in the phase-separated state. That is, the film in the phase-separated state is cloudy, whereas the film in the compatible state has high transparency, and independent small regions cannot be recognized even by observation with an optical microscope. Also, in the state of being immersed in water,
The phase-separated film elutes polycarboxylic acids and collapses as a whole, but the compatible film only swells uniformly, and the elution of polycarboxylic acids is extremely small, and the polycarboxylic acids are substantially insolubilized. ing. By utilizing the insolubilization of the polycarboxylic acids, the compatibility of the polycarboxylic acids with the vinyl acetate polymer can be investigated.

Further, when salts having a neutralizing effect on polycarboxylic acids are added, the mixed state thereof hardly affects the adhesiveness. Therefore, the salts may be in a compatible state or in a coarse mixed state in which powder is dispersed. Further, as described above, if it is a mixture of only polycarboxylic acid and vinyl acetate polymer, it is possible to clearly observe the compatible state, but in the mixture containing salts having a neutralizing effect, the difference Becomes unclear. That is, in the case of a mixture of only polycarboxylic acids and vinyl acetate polymer, the film in the phase-separated state becomes cloudy, while the film in the compatible state has high transparency, but has a neutralizing effect. In the case of a mixture containing salts, there is no regulation on the mixed state of the salts, so even if the polycarboxylic acids and the vinyl acetate polymer are in a compatible state, if the salts are in a coarse mixed state, the film still becomes cloudy. To do. As described above, it may not always be possible to determine the mixed state of the polycarboxylic acid and the vinyl acetate polymer by visual observation or observation with an optical microscope.

However, as described above, the present inventors have found that when the polycarboxylic acids and the vinyl acetate polymer are in a compatible state, the water solubility of the polycarboxylic acid, which should be water-soluble, is significantly limited, and even in water. It has been found that even if it is soaked for a long time, it swells uniformly and does not collapse. This property was observed with and without the neutralizing salt.

Utilizing this property, the compatibility of polycarboxylic acids and vinyl acetate polymer can be investigated. Further, it can be said that this determination method is appropriate considering that the oral preparation of the present invention can adhere to the oral viscosity over a long period of time because the water solubility of the polycarboxylic acids is limited.

In the present invention, the compatibility state of the polycarboxylic acid and the vinyl acetate polymer is to be investigated from the elution amount of the polycarboxylic acid, and the compatibility state in the present invention specifically means the following dissolution rate measurement method. The dissolution rate of polycarboxylic acids thus obtained is 40% by weight (hereinafter abbreviated as “%”) or less in a mixed state, and in the case of an oral preparation containing salts having a neutralizing action, salts Since elution also occurs, the term refers to the case of a mixed state in which the elution rate determined by the following measurement method is 50% or less.

<Elution rate measuring method: When salt is not contained> A film (film-like adhered material) composed of polycarboxylic acids and a vinyl acetate polymer is crushed at 0 ° C or less and weighed. Put this in a mesh bag and
After soaking in purified water at 0 ° C. or more at 20 ° C. for 1 hour in a stationary state, the adhered body is taken out together with the bag, and the amount of polycarboxylic acids eluted in the purified water is determined by a method such as neutralization titration. This is divided by the blending amount of polycarboxylic acids in the film to calculate the dissolution rate.

<Elution rate measurement method: In the case of containing salts> The same operation as described above is performed on a film containing salts having a neutralizing action (film-like adherent). The amount of the polycarboxylic acids and salts having a neutralizing action eluted in the purified water by this operation is determined by, for example, reducing the weight of the adherent by immersion. The dissolution rate is calculated by dividing this by the sum of the compounding amounts of the polycarboxylic acids and the salts having a neutralizing action in the film.

The oral preparation of the present invention is a film-like adherent (base material), which is a flexible film which does not exhibit adhesiveness when dried and exhibits adhesiveness only when absorbing water, as described above. Since it does not have adhesiveness when it is dry, it can be stored as it is without any special storage mode,
At the time of use, it is simply pressed against the mucous membrane in the oral cavity or the tooth surface to absorb moisture such as saliva on the mucous membrane or moisture in the mucous membrane, rapidly exhibit adhesiveness, and strongly adhere to the mucous membrane or tooth surface.
Therefore, it strongly adheres to the intraoral disease site or damaged area where it is difficult to adhere due to the administered drug or bleeding, etc., and exerts drug administration or wound covering protection action. This adhered state lasts for a remarkably long time, which is a major feature of the present invention. Such a long-term adhesion persistence is realized only when the polycarboxylic acid and the vinyl acetate polymer are in a compatible state in the film-like adherent as described above.

The generation mechanism of this adhesion persistence is not clear, but under compatible conditions, polycarboxylic acids provide adhesion to wet mucous membranes and vinyl acetate polymer provides water resistance. It is considered that the adhesion persistence of is expressed. The mixed state of the salts having a neutralizing effect on the polycarboxylic acids does not affect the adhesiveness, but the characteristics of the salt itself have a delicate influence on the adhesiveness and the like. For example, polyvalent metal salts such as zinc oxide and calcium oxide have the function of reducing adhesion and increasing water resistance, but monovalent metal salts such as sodium acetate and
Monovalent bases such as sodium hydroxide and triethanolamine act to increase the adhesion and reduce the water resistance.

As described above, since the oral preparation of the present invention has long-term adhesion persistence, it retains the absorption of the administered drug for a long time in the oral disease site, and significantly improves the absorption rate for healing. It is possible to speed up the recovery of the damaged oral cavity by maintaining the coating protection for a long time.

Also, when using by sticking to the damaged part of the oral mucosa,
By performing the neutralization treatment with the above salts, the irritation by the eluting polycarboxylic acids is prevented, so that it is possible to avoid the situation that the damaged part is adversely deteriorated due to the sticking of the oral preparation. . Moreover, the film-like adherent is composed of a substantially water-insoluble flexible film in which polycarboxylic acids and a vinyl acetate polymer are in a compatible state, and the water-soluble polymer substance is simply used as it is. Since it is not a substance, it exhibits long-term adhesion persistence in a very thin state. That is, when the water-soluble polymer substance is used as it is, if it is made too thin, it will not be thinned because it will be rapidly dissolved by saliva in a short time and the adhesive property will be rapidly lost. Will have a thickness of. However, in this way, the feeling of foreign matter at the time of use is increased, and at the same time, the flexibility of the oral preparation is impaired. The film-like adherent, which is the base material of the oral preparation of the present invention, exhibits a strong adhesive force for a long time in a very thin state, so that it is not necessary to make the thickness thick, and a feeling of foreign matter due to an excessive thickness is caused. It does not make you feel. As described above, the oral preparation of the present invention is composed of a film-like adhered body as a base material with a thin and flexible film.

The oral preparation of the present invention comprises, for example, a polycarboxylic acid and a vinyl acetate polymer, which are dissolved in a solvent common to both, and a topical drug is added to the solvent, which is then quickly cast and dried to obtain a film. It can be produced by forming a sheet-like adherent.

On the other hand, the oral preparation of the present invention containing a salt having a neutralizing action, for example, polycarboxylic acids and vinyl acetate polymer, dissolved in a solvent common to both, after containing a topical drug, Further, it can be produced by blending a salt having a neutralizing effect on polycarboxylic acids, rapidly casting and drying the mixture to form a film-like adherent.
The above-mentioned salt may be compounded by dissolving the salt in the solution or by dispersing a powdery one. According to both the above-mentioned manufacturing methods, there is an advantage that a very thin film-like body can be easily formed.

The topical drug contained in the oral preparation is a polycarboxylic acid and a vinyl acetate polymer, and the topical drug contained in the oral lumber is a polycarboxylic acid and a vinyl acetate polymer in a compatible state. It may be contained in any one of the film-like adherent and the film-like support that supports it, and there is no particular limitation on the method of inclusion. For example, as described above, a topical drug is blended in a solution of polycarboxylic acid and vinyl acetate polymer dissolved in a common solvent as it is or in a solution state, and this is rapidly cast and dried to obtain a film. It can be contained in the form of an adherent. When the film-shaped support contains a drug, a method of kneading with the resin for the support, a method of mixing in a solution state, a method of adsorption and impregnation and the like can be mentioned.

Representative examples of the above polycarboxylic acids include acrylic acid polymers, methacrylic acid polymers, and maleic anhydride polymers, which can be used alone or in combination. Specific examples of the acrylic acid polymer include acrylic acid homopolymers, acrylates such as butyl acrylate and 2-ethylhexyl acrylate, and methacrylates such as methyl methacrylate and vinyl acetate. Examples thereof include copolymers with vinyl monomers and polymers such as carboxyvinyl polymers. Further, specific examples of the methacrylic acid polymer include, in addition to the methacrylic acid homopolymer, the same copolymers as in the case of the acrylic acid polymer, and specific examples of the maleic anhydride polymer include methyl vinyl ether. And the like.

It goes without saying that the compounds exemplified in the above specific examples can be used not only individually but also as a mixture. Among these polycarboxylic acids, in the polycarboxylic acid,
COOH group is 20% or more, in the polycarboxylic anhydride, -CO-
It is preferable for the effect that the O-CO- group content is 16% or more.

A typical example of the vinyl acetate polymer is a vinyl acetate homopolymer. In addition to this, a vinyl acetate homopolymer and a vinyl monomer copolymer such as an acrylic ester and a vinyl acetate homopolymer are partially saponified. Partially saponified compounds are also included. These can be used alone or in combination. The average molecular weight (viscosity average molecular weight) of these is preferably 60,000 or more. Average molecular weight is 6
If it is less than 0000, the water resistance of the above film-like adherent is lowered, and it is difficult to obtain the desired effect. However,
This is not the case when the apparent molecular weight is increased due to intermolecular crosslinking or the like.

Salts having a neutralizing effect on polycarboxylic acids,
Not only salts but also bases are included, and typical examples thereof include salts of metals and weak acids, metal oxides, metal hydroxides, amines, and mixtures thereof. Specific examples of salts of metals and weak acids include sodium, potassium,
Examples thereof include salts of calcium, magnesium and the like with carboxylic acids such as acetic acid, lactic acid and citric acid, and specific examples of metal oxides include zinc oxide, calcium oxide and magnesium oxide. Specific examples of metal hydroxides include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like, and specific examples of amines include triethanolamine, diisopropanolamine and the like. To be The compounds specifically exemplified above can be used alone or in combination. The preferable blending amount of such salts greatly varies depending on the type of salt or base. When a polyvalent metal salt is used, the amount of the polycarboxylic acid in the film-like adherent is 0.2 to
It is preferable to add 0.8 equivalent, and when the amount is less than 0.2 equivalent, the effect of reducing irritation to the damaged part (damaged mucous membrane) becomes insufficient, and when the amount exceeds 0.8 equivalent, it becomes difficult to obtain sufficient adhesion persistence. When using a monovalent metal salt or a monovalent base, it is preferable to add 0.03 to 0.2 equivalent to the polycarboxylic acid in the film-like adherent, and if the amount is less than 0.03 equivalent. This is because the effect of reducing irritation to the damaged part becomes insufficient, and when the amount exceeds 0.2 equivalent weight, the water resistance of the film-like adhered material decreases and it becomes difficult to obtain sufficient adhesion.

The common solvent for the polycarboxylic acids and the vinyl acetate polymer is a lower alcohol such as methanol or ethanol, and a mixture thereof with an organic solvent such as soluble acetone or ethyl acetate, the lower alcohol being the main component. Examples thereof include those described above, or the above mixture or a mixture obtained by further adding water to a lower alcohol. Regarding the above-mentioned solvent, it is preferable to limit the content of the organic solvent such as acetone and ethyl acetate to 30% or less. This is because if it exceeds 30%, it becomes difficult to dissolve the polycarboxylic acids.
Regarding the above solvents, it is preferable to limit the content of water to 30% or less. This is because if the water content exceeds 30%, it tends to be difficult to dissolve the vinyl acetate polymer.

In the case of producing an oral preparation as described above,
The mixing ratio of the polycarboxylic acid and the vinyl acetate polymer is
It is preferable to regulate the A value obtained by the following formula so that it falls within the range of 15 to 45.

As the A value increases, the adhesive force of the film-like adherent to the mucous membrane or the tooth surface increases, but the adhesion persistence tends to decrease, and conversely, the smaller the A value, the smaller the adhesive force. The adhesion persistence tends to increase. And
When the A value is less than 15, it becomes difficult to obtain sufficient adhesive force, and when it exceeds 45, it becomes difficult to obtain sufficient adhesion durability. Therefore, it is preferable to regulate the mixing ratio of the polycarboxylic acid and the vinyl acetate polymer so that the A value is within the range of 15 to 45. The case where polyacrylic acid is used as the polycarboxylic acid will be described as an example. When the proportion of polyacrylic acid in the film-like adherent is in the range of 24 to 72%, the A value falls within the above range. Therefore, favorable results can be obtained.

Further, when the above-mentioned polycarboxylic acids and vinyl acetate polymer are dissolved in a common solvent, it is necessary to take care so that both are sufficiently dissolved. In this case, the concentration of the polymeric substance such as polycarboxylic acid and vinyl acetate polymer is not particularly limited, but if the concentration of the polymeric substance becomes too high, the solution viscosity becomes large, and the casting film is Since it tends to be difficult to form the polymer, it is preferable that the concentration of the polymer substance does not exceed 40%.

The solution of polycarboxylic acids and vinyl acetate polymer dissolved in a solution containing a topical drug, or a solution containing a salt for neutralization in the solution is cast into a dry film, and the following procedure is applied. Can be done by That is, after casting the above solution on a suitable film such as polyethylene laminated paper which has been subjected to a peeling treatment, it is dried quickly by using a high temperature air bath or a vacuum dryer such as a dryer or a drying tower. It can be performed by forming a film. The proper drying time or temperature is
It depends on the composition of the common solvent, the solid content concentration in the solution, the casting thickness, the degree of decompression during drying, etc.
It is preferable to dry at a temperature of 1 to 120 ° C. for about 1 to 20 minutes.

In this way a very thin film-like deposit is obtained. This film-shaped adherent contains a topical drug and can be directly used as the oral preparation of the present invention. In this case, the thickness of the film-like adherent can be adjusted by controlling the casting amount and the like, and is preferably regulated within the range of 5 to 100 μm. This is because if the thickness is less than 5 μm, it becomes difficult to develop sufficient adhesive properties, and if it exceeds 100 μm, a feeling of foreign matter in the mouth is likely to appear when used, and the flexibility of the film-like adhered body tends to be impaired.

As described above, the film-like adherent is in a state in which the polycarboxylic acids and the vinyl acetate polymer are not simply mixed but the two are in a compatible state, and the polycarboxylic acids are substantially insolubilized. Therefore, even if it is in a very thin state as described above, it does not disintegrate by absorbing water, exerts a strong adhesive force over a long period of time, and the contained drug is administered over a long period of time. Since this is flexible, it can be easily deformed and attached along its shape simply by pressing it against the mucous membrane in the oral cavity.

The topical drug may be a solid or a liquid at room temperature, and may be any that can be dissolved or dispersed in the film-like adherent and the film-like support that supports the same.

The amount of the topical drug contained in the oral preparation varies depending on the type of drug, but usually 0.0001-35%, preferably 0.0002-
20%. Further, in order to administer the drug to the oral mucosa in a positive drop, it is preferable to localize the drug on the side of the film-like adherent, and it may be localized on the side of the film-like support in the treatment of bad breath and the like.

Examples of the topical drug used in the present invention include a) adrenocortical hormone triamcinolone acetonide, dexamethasone, betamethasone, prednisolone, fluocinolone, hydrocortisone, beclomethasone, and salts thereof.

b) anti-inflammatory agents flurbiprofen, ibuprofen, diclofenac, indomethacin, bendazac, flufenamic acid,
Bufuexamatu, cyclosporin, kridanak, glycyrrhizin, ketoprofen, piroxicam, pranoprofen, benzydamine, ibuprofenpiconol, etofenamate, lysozyme, chymotrypsin,
Epidihydrocholesterin, hinokitiol, α-amylase, azulene, chlorophyllin, cromoglycic acid,
Tranilast, seratiopeptidase, pronase, glucanase, shikon extract, etc., and salts thereof.

c) Fungicide acrinol, cetylpyridinium, chlorhexidine, domifuene, iodo, monensin, sanguinarine,
Metronidazole, decalinium, tetracycline,
Minocycline, ofloxacin, penicillin, doxycycline, oxytetracycline, cefatrizine, nystatin, clingmycin, fradiomycin sulfate, and their salts.

d) Analgesics Ethyl aminobenzoate, camphor, eugenol, dibucaine, phenol, menthol, creosote, diphenhydramine, lidocaine, tetracaine, procaine, cocaine, piperocaine, mepivacaine, promoxine, deiclonine, guaiacol, and the like. salt.

e) hemostatic agent tranexamic acid, ε-aminocaproic acid, alginic acid,
Bioflavonoid, vitamin C, thrombin, oxidized cellulose, cetraxate, epinephrine, ferric chloride,
Fibrinogen, carbazochrome, adrenochrome,
Etc, and their salts.

f) vasodilator inositol hexanicotinate, cyclanderate,
Cinnarizine, tolazoline, acetylcholine, and their salts.

g) Tissue repairing agent Sorcoserine, proglumide, sucralfate, gefarnate, nicomethate citrate, glutamine, aceglutamide aluminum, ethylcysteine, chitin,
Vitamin E nicotinate, ubidecarenone, etc., and salts thereof.

h) Antiviral agents such as acyclovir, idoxuridine, vitarabine, amantadine, and salts thereof.

i) Bone metabolizer Vitamin Ds, endotoxin, hydroxyapatite, collagen, cataboline, 2-chloroadenosine, nocardia, calcitriol, alveolar bone prostaglandins, alveolar bone osteoclast activating factor, alveolar bone accessory Thyroid hormone, alveolar calcitonin, etc., and their salts.

j) Astringent tannin, tannic acid, zinc fluoride, sodium fluoride, strontium fluoride, potassium nitrate, tin fluoride, potassium aluminum sulfate, berberine, bismuths, strontium chloride, aluminum lactate, and salts thereof.

And so on.

As described above, the oral preparation of the present invention can be composed of only the film-like adherent, but it can also be composed by combining this with a flexible film-like support.

Explaining the production method of this combination, this combination produces a film-like adherent as described above, and prepares a flexible film separately prepared by a usual method such as thermocompression bonding or using an adhesive. Which can be produced by laminating to a sheet-like support, and which is used for producing a sheet-like adherent, is cast on a flexible film-like support to produce a film-like adherent and a flexible film-like support. It can also be manufactured by performing the same bonding with. In the latter case, there is an advantage that the thermocompression bonding and the bonding work become unnecessary and the manufacturing can be simplified.

As the flexible film-like support, it is preferable to use a substantially water-impermeable support. Typical examples thereof include plastic films such as polyethylene, vinyl acetate resin, ethylene-vinyl acetate copolymer, polyvinyl chloride, and polyurethane, metal foils such as aluminum foil and tin foil, cloth and paper, and plastic films. Laminated film and the like. Among them, polyethylene, vinyl acetate resin, ethylene-
It is preferable to use a plastic film such as a vinyl acetate copolymer. It is preferable to use such a film-shaped support having a thickness of 10 to 100 μm from the viewpoints of handling and not giving a feeling of foreign matter at the time of use. The integrated product preferably has a thickness regulated within the range of 30 to 150 μm. That is, if the thickness is less than 30 μm, the handling and operability are deteriorated, and if the thickness exceeds 150 μm, a feeling of foreign matter tends to be given during use.

The oral preparation obtained by integrating the film-like adherent and the flexible film-like support as described above is strongly adhered to the oral mucosa by the action of the film-like adherent,
It develops long-term adhesion sustainability, but by integrating the above flexible film-shaped support, the strength of the preparation increases and it becomes easier to use. The effect of preventing foreign matter from adhering is further obtained. Then, by using a substantially water-impermeable material as the flexible film-like material, it is possible to further obtain the effect of preventing the intrusion of water from the back surface and achieving the extension of the adhesion duration. .

In addition, it is free to add a coloring agent, a flavoring agent, a softening agent or the like to the film-like adherent or the film-like support of the oral preparation of the present invention as long as the adhesiveness or the pharmacological effect is not impaired. For example, when both the adherent and the support are colorless, blending a colorant into one of the adherents and the support provides the advantage that the front and back of the preparation are clear and easy to use.

As described above, the film-like support used in the present invention is composed of a film-like adherent because the compatibilized material of the polycarboxylic acid and the vinyl acetate polymer is formed into a flexible thin film. Both of this and the one in which this and a flexible film-shaped support are integrated are highly flexible, and when attached to the oral cavity, they absorb the moisture in the oral cavity and further soften. Therefore, it easily fits to any part of the oral cavity and exhibits a strong adhesive force and a long-lasting adhesive force. This adhesion was measured by using a cross-linked collagen film swollen with water as a substitute for the mucous membrane in the oral cavity (180
As a result of (peeling force), a value of 25 to 2000 g / 25 cm width is shown. If the adhesive strength is less than 25 g / 2.5 cm width, it becomes difficult to adhere to the oral mucosa for a long time, and if it exceeds 200 g / 2.5 cm width, the mucous membrane tends to be easily damaged when peeled from the oral mucosa. Is recognized. Therefore, in consideration of these, it can be said that the product of the present invention exerts the optimum adhesive force.

However, the above-mentioned adhesive force varies depending on the type of adherend to be targeted, and the adhesive force is sufficiently expressed on the mucous membrane, mucous membrane-like surface such as outer skin, cross-linked collagen film, or tooth surface, and The adhesive strength is not impaired at all even when the product of the present invention is applied to an adherend and then put into water. However, it exhibits almost no adhesion to plastics, cellophane, etc., and even if it exhibits adhesion, it is weak and disappears rapidly when immersed in water. This property is extremely convenient for the storage of the product of the present invention, and even if it absorbs water during storage, it does not adhere to the packaging material, storage case, etc., so that no special moisture-proof packaging is required. Further, it is not necessary to cut the oral preparation into small pieces and store them, and even if they are formed into a tape and wound on a roll, they can be stored without causing adhesion. Further, although it can be stored in the naked state as it is, if there is a risk of contamination, it may be stored by adhering a paper or plastic protective film to the adhered surface.

In particular, the product of the present invention containing a salt for neutralization in the film-like adherent does not cause deterioration of the damaged part by stimulating the damaged part with the acid of the eluted polycarboxylic acid when applied to the site of the intraoral damage or the like. It is highly safe. That is, even if the salts for neutralization are removed from such a film-like adherent, it can be used without any problem on the skin of shaving guinea pigs, the eye mucous membrane of rabbits, the oral mucosa of healthy persons, etc. Yes, almost no irritation was observed. However, irritation is observed when this is affixed to the injured skin produced by peeling the stratum corneum from the shaved guinea pig skin using an adhesive tape. On the other hand, those containing salts for neutralization showed almost no irritation when applied to the damaged skin. Needless to say, irritation to normal mucosa was not observed.

Further, the oral preparation of the present invention, the polycarboxylic acids constituting the film-like adherent are substantially insolubilized,
Even if it is immersed in water, it swells only and never collapses by absorbing water, and it has high water resistance. Therefore, when the above-mentioned preparation is applied to the mucous membrane of the oral cavity, it retains the adhesive force for a long time (generally 3 or 4 hours),
It is also possible to attach it all day and night.

〔The invention's effect〕

The buccal preparation of the present invention is composed of a thin flexible film which is a substantially water-insoluble state of a compatible material of a polycarboxylic acid and a vinyl acetate polymer, and the action of this film. Develops a stronger adhesive force and strongly adheres to the mucous membrane in the oral cavity, and the state is maintained for a long time. As a result, it is possible to obtain a remarkable effect in absorbing a proper amount of the administered drug to the site of oral disease and covering and protecting the damaged site. Moreover, the above-mentioned oral preparation is flexible and deforms and adheres along the membrane surface of the oral mucosa by simply pressing it at the time of use, and can be applied to any part of the oral mucosa or the tooth surface. .

In particular, the oral preparation of the present invention containing salts for neutralization is irritating to the damaged site because it is neutralized even when a trace amount of polycarboxylic acids is to be eluted when it is used by adhering to the damaged site. It has an extremely practical effect that it can be used safely without being deteriorated by giving As described above, the oral preparation of the present invention strongly adheres to the oral mucosa and maintains the state for a long time, so that the topical drug can be sufficiently administered to the application site and a sufficient pharmacological effect is exhibited. Can be made. Moreover, as described above, the oral preparation of the present invention has an advantage of being extremely easy to handle because it is attached to the wet surface of the affected area for a long time.

Next, examples will be described together with comparative examples.

Example 1 A carboxyvinyl polymer was used as the polycarboxylic acid, and 5 parts by weight (hereinafter abbreviated as “part”) and 5 parts of the vinyl acetate resin (1500) were added to 90 parts of methanol, which is a common solvent for both. Pour, mix and dissolve to make a uniform solution,
To this, mepivacaine corresponding to 5% of the solid content in the solution was mixed. Next, this solution was cast on a paper separator, dried, and peeled to form a film-like adherent having a thickness of 30 μm. It was found that the A-value of this film-like adherent was 31.3, and the elution rate of polycarboxylic acids, which was an indicator of the compatibility state, was 9%, indicating the compatibility state. Then, the above film-like adherent was thermocompression-bonded to an aluminum foil having a thickness of 15 μm to obtain an oral preparation.

[Comparative Example 1] 5 parts of vinyl acetate resin (1500) was dissolved in 20 parts of toluene, and 5 parts of carboxyvinyl polymer powder insoluble in toluene was added thereto and sufficiently stirred and mixed to uniformly disperse a suspension, In the same manner as above, mepivacaine was mixed with 5% of the solid content of the suspension. Next, this was cast and dried on a paper separator, then thermocompression-bonded and peeled off to form a film-like adherent having a thickness of 30 μm. The A value of this product is shown in Example 1.
However, the elution rate of polycarboxylic acids was 67%, and it was found that the carboxyvinyl polymer and the vinyl acetate resin were in a phase-separated state. Next, the above film-shaped adherent was thermocompression-bonded to an aluminum foil having a thickness of 15 μm in the same manner as in Example 1 to obtain an oral preparation.

[Comparative Example 2] 5 parts of carboxyvinyl polymer was dissolved in 45 parts of purified water, and 5 parts of vinyl acetate resin (1500) was added to toluene.
It was dissolved in 20 parts and then both solutions were mixed. Next, this was stirred for 3 minutes at 5000 rpm using a small stirrer (small disper) to obtain a suspension, and 5% of mepivacaine was mixed therein. The resulting suspension was cast on a paper separator, dried, and peeled off to form a film-like adherent having a thickness of 30 μm.
The A value of this product was the same as in Example 1, but the elution rate of polycarboxylic acids was 79%, and it was found that the carboxyvinyl polymer and the vinyl acetate resin were in a phase-separated state. Next, the above-mentioned film-like adhered body was used in Example 1
In the same manner as above, an oral preparation was obtained by thermocompression bonding to an aluminum foil having a thickness of 15 μm.

Next, with respect to the oral preparations obtained in the above Examples and Comparative Examples, the solubility of the film-like adherent and the elution rate of polycarboxylic acids were measured. The results are shown in Table 1.

As is clear from Table 1, the film-like adherent of Example 1 is in a good compatibility state with the polycarboxylic acids and the vinyl acetate polymer, unlike those of Comparative Examples 1 and 2. . In particular, as a result of measuring the elution rate of polycarboxylic acids, in Comparative Examples 1 and 2, most of the polycarboxylic acids that are adhesive components elute by 1 hour after the immersion.
In Example 1, the polycarboxylic acids were hardly eluted by the immersion in water, and the elution rate was 9% 1 hour after the immersion, which was 12% after 4 hours.
%, But only increased by 3% (however, the elution rate did not increase after 4 hours and leveled off). From this, it can be seen that the elution of polycarboxylic acids is almost completed because most of the total elution amount is eluted during the first hour. This is shown in the drawing.

In addition, an adhesion test was conducted on the oral preparations obtained in the above Examples and Comparative Examples, and the 180 ° peel force was measured. The results are shown in Table 2.

As is clear from Table 2, the samples of Comparative Examples 1 and 2 peeled off early in the adhesion test, and even in the 180 ° peeling test, they could not be measured at 30 minutes of immersion in water. On the other hand, the intraoral preparations of Examples had extremely excellent results in the adhesiveness test, and also in the 180 ° peel test, the peel force after immersion in water for 4 hours was still 80% of the initial value, which is extremely high. It can be seen that the strong adhesive force can be maintained for a long time.

Example 2 A 10% methanol solution of carboxyvinyl polymer (CVP) and a 10% methanol solution of vinyl acetate resin (PVAc2500) were mixed at a ratio of (CVP) / (PVAc) = 5/5, and this was mixed with paper. A film-like adherent having a thickness of 20 μm (see A in Table 3) was prepared by casting, drying and peeling on a separator. Next, a vinyl acetate resin (2500) containing 2% of cetylpyridinium chloride and 3% of 1-menthol was added.
An oral preparation was obtained by thermocompression bonding with a film having a thickness of 50 μm.

Regarding the obtained oral preparation, the dissolution rate of the polycarboxylic acid after immersing the film-like adherent in water for 1 hour was determined in Example 1.
In the same manner as in Example 1, an adhesiveness test (immersion time in water: 10 minutes) was performed in the same manner as in Example 1 to measure the adhesiveness, and in the same manner as in Example 1, the 180 ° peeling force was measured. The results are shown in Table 3.

[Example 3] Methyl vinyl ether-maleic anhydride alternating copolymer 4
Parts and 6 parts of vinyl acetate resin (1000) were dissolved in 90 parts of methanol, and then shikon extract corresponding to 0.3% of the solid content was added thereto. This was cast on a paper separator, dried at 80 ° C. and peeled off to obtain a film-like adherent having a thickness of 60 μm. Next, add this to vinyl acetate resin (20
It was thermocompression-bonded with a 30 μm thick film of (00) to obtain an oral preparation. In this case, the A value was 23.0, and the elution rate after immersion in water for 1 hour was 12%.

The oral preparation thus obtained was cut into a circle with a diameter of 10 mm, and the time until it was actually applied to the palate mucosa of 10 panelists and peeled off was measured. As a result, the average peeling time was 4.0 hours.

Example 4 6 parts of polyacrylic acid (5000) and 14 parts of partially saponified polyvinyl acetate (saponification degree: 20 mol%, 1500) were dissolved in 80 parts of methanol, and chlorhexidine hydrochloride was added to the solid content. 2% was added. Next, this was cast on a paper separator, dried at 80 ° C. and peeled off to obtain an oral preparation containing only a film-like adherent having a thickness of 100 μm. A of this thing
The value was 37.5, and the elution rate of polycarboxylic acids after soaking in water for 1 hour was 37%.

The oral preparation obtained in this way has a long diameter of 20 mm and a short diameter of 7 mm.
Was cut into an oval shape, adhered to the gingival mucosa of 10 panelists, and the time until peeling was measured. As a result, the average peeling time was 7.6 hours.

Example 5 4 parts of carboxyvinyl polymer and vinyl acetate resin (
2000) 6 parts was dissolved in isopropanol, 0.2% of solid content of prednisolone was added thereto, 2 parts of titanium oxide as a coloring agent was further added, and the mixture was sufficiently stirred and mixed, and cast on a paper separator. Then dried at 90 ° C and peeled off for thickness
A 40 μm film-like adherent was obtained. This product has an A value of 25
The elution rate of polycarboxylic acids after immersion in water for 1 hour was 6%. On the other hand, vinyl acetate resin (
2000) 0.1% edible red No. 3 aluminum lake was added to 100 parts of a 20% ethyl acetate solution, mixed thoroughly with stirring, cast on a paper separator, dried at 180 ° C, peeled, and formed into a film with a thickness of 30 μm. I made an adherent.

The oral preparation thus obtained was cut into a circle having a diameter of 20 mm, and the preparation was attached to the buccal mucosa of 10 panelists and the time until peeling was measured. As a result, the average peeling time was 5.6 hours.

Example 6 3 parts of carboxyvinyl polymer, 2 parts of methyl vinyl ether maleic anhydride copolymer and 5 parts of polyvinyl acetate polymer (2000) were dissolved in 90 parts of methanol to prepare a mixed solution, and azulene sulfone was added thereto. Sodium acid was added at 0.5% solids. Next, this was cast on a paper separator, dried at 60 ° C. and peeled off to obtain a film-like adherent having a thickness of 20 μm. This product has an A value of 30.3 and is 1 in water.
The elution rate of the polycarboxylic acids after the time immersion was 10%.

Next, the above film-like adherent was thermocompression-bonded at 100 ° C. to a polyvinyl acetate (1500) film having a thickness of 30 μm, which is a film-like support, to obtain an oral preparation.

The oral preparation thus obtained was cut into a circle having a diameter of 10 mm, and the preparation was attached to the gingival mucosa of 10 panelists and the time until peeling was measured. As a result, the time until peeling was 5.4 hours on average.

Example 7 4.7 parts of carboxyvinyl polymer and vinyl acetate resin (
1500) 4.7 parts and 90 parts methanol which is a common solvent for both
Then, 0.6 part of diisopropanolamine was added and mixed and dissolved to form a uniform solution, to which triamcinolone acetonide was added at 0.05% of the solid content. Next, this solvent was cast on polyethylene laminated paper and dried in a dryer at 80 ° C. for 8 minutes to form a film-like adherent having a thickness of 30 μm. It was found that the A-value of this film-like adherent was 31, and the elution rate of polycarboxylic acids, which was an index of the compatibility state, was 12%, indicating that the film-like adhered body was in the compatibility state. Then, the above film-like adherent was thermocompression-bonded to a film of vinyl acetate resin (2000) having a thickness of 40 μm at 100 ° C. to obtain an oral preparation.

[Example 8] In place of triamcinolone acetonide, dipotassium glycyrrhizinate was added at 1.0% of the solid content. An oral preparation was obtained in the same manner as in Example 7 except for the above.

[Example 9] In place of triamcinolone acetonide, fradiomycin sulfate was added at 1.0% of solid content and hydrocortisone acetate was added at 0.5% of solid content. An oral preparation was obtained in the same manner as in Example 7 except for the above.

[Example 10] In place of triamcinolone acetonide, 10.0% of solid content of ethyl aminobenzoate was added. Otherwise, Example 7
An oral preparation was obtained in the same manner as.

Example 11 In place of triamcinolone acetonide, tocopherol nicotinate was added in an amount of 2.0% of solid content and cetylpyridinium chloride was added in an amount of 0.2% of solid content. An oral preparation was obtained in the same manner as in Example 7 except for the above.

[Comparative Example 3] 4.7 parts of vinyl acetate resin (1500) and 0.6 part of diisopropanolamine were dissolved in 30 parts of toluene, and 5 parts of toluene-insoluble carboxyvinyl polymer powder was added thereto and sufficiently stirred and mixed to uniformly disperse. Make a suspension,
To this, triamcinolone acetonide was added at 0.05% solids. Next, this was cast on polyethylene laminated paper and dried in a dryer at 100 ° C for 10 minutes to give a thickness of 40μ.
m film-like adherend was produced. The A value of this product was the same as that of Example 7, but the elution rate as an index of the compatible state was 72%, and it was found that the carboxyvinyl polymer and the vinyl acetate resin were in a phase separated state. Next,
The above film-like adhered body was made to have a thickness of 40 μm as in Example 7.
The above-mentioned vinyl acetate resin film was heat-pressed at 100 ° C. to obtain an oral preparation.

[Comparative Example 4] 4.7 parts of carboxyvinyl polymer and 0.6 parts of diisopropanolamine were dissolved in 4.5 parts of purified water, 4.7 parts of vinyl acetate resin (1500) was dissolved in 30 parts of toluene, and then both solutions were mixed, To this, triamcinolone acetonide was added at 0.05% solids. Next, this was stirred for 5 minutes at 5000 rpm using a small stirrer (small disper) to obtain a suspension. The obtained suspension was cast on polyethylene laminated paper, dried in a dryer at 100 ° C. for 10 minutes, and peeled off to form a film-like adherent having a thickness of 40 μm. The A value of this product was the same as that of Example 7, but the elution rate, which is an index of the compatible state, was 77%, and it was found that the carboxyvinyl polymer and the vinyl acetate resin were in a phase separated state. Next, the film-like adherent was applied to a vinyl acetate resin film having a thickness of 40 μm in the same manner as in Example 7.
An oral preparation was obtained by thermocompression bonding at 0 ° C.

Next, with respect to the oral preparations obtained in Example 7 and Comparative Examples 3 and 4, the adhesiveness of the oral preparation and the 180 ° peeling force were measured, and a practical test was conducted. The results are shown in Table 4.

As is apparent from Table 4, the film-like adherent of Example 7 is in a good compatibility state with the polycarboxylic acids and the vinyl acetate polymer, unlike those of Comparative Examples 3 and 4. . That is, the adhesives of Comparative Examples 3 and 4 peeled off early in the adhesion test, and even in the 180 ° peeling strength test, the adhesion was drastically reduced after 10 minutes of immersion in water. Peeling off early even in a practical application test. On the other hand, the oral preparations of Examples are
The results of the adhesion test are extremely excellent, and also excellent results are obtained both in the 180 ° peeling force test and in the practical application test, showing that the strong adhesion can be maintained for a long time.

Next, in order to clarify the high safety of the oral preparation of the present invention containing a salt for neutralization, a reference example product having a film-like adherent containing no diisopropanolamine is prepared as follows. It was

Carboxy vinyl polymer 5.0 parts Vinyl acetate resin (2000) 5.0 parts Methanol 90.0 parts The above raw materials were stirred and mixed to form a uniform solution, and 10% of solid content of ethyl aminobenzoate was added thereto. This solution was cast on polyethylene laminated paper and dried for 8 minutes at 80 ° C. to obtain a film-like adherent having a thickness of 40 μm. This was thermocompression-bonded to a 40 μm vinyl acetate resin (2000) film at 100 ° C. to obtain an oral preparation.

The irritation of normal and damaged skin of guinea pigs was examined as follows by comparing the buccal preparation obtained in Example 10 with the buccal preparation of the reference example obtained as described above.

The back of Hartley guinea pig females (body weight 300g to 400g) was shaved with an electric clipper and an electric shaver to expose normal skin. Further, application and peeling of the adhesive tape to normal skin was repeated 7 times to remove the stratum corneum and generate damaged skin.

Then, a circular sample having a diameter of 10 mm was cut and immersed in water, and the sample was applied to normal skin and damaged skin, respectively, and then covered with a cotton swab, and further covered with an adhesive tape to carry out the block application. The sample was removed 6 hours after application and the irritation was determined 1 hour and 24 hours after removal.

The judgment of irritation was made in four stages according to the following criteria.

−: No change …… 0 ±: Mild erythema …… 0.5 +: Moderate erythema …… 1 ++: Severe erythema / edema …… 2 And the numerical values of 0, 0.5, 1 and 2 at each stage. Assigned and averaged for irritation. The results are shown in Table 5, and there is no difference when applied to normal skin, but when applied to damaged skin, the product of Example 10 is safe as it does not cause irritation, almost the same as when applied to normal skin. .

[Example 12] Carboxyvinyl polymer 8.0 parts Vinyl acetate resin (1500) 2.0 parts ZnO 3.6 parts Methanol 26.4 parts Each raw material was blended as described above and kneaded to form a uniform blend, and tetracycline hydrochloride was added to this. Was added at 3% solids. This blended bag is cast on polyethylene laminated paper and dried in a dryer at 70 ° C for 15 minutes to obtain a thickness.
A 20 μm film-like adherent was obtained. This product has an A value of 50
It was. Next, this was thermocompression-bonded to a film of a vinyl acetate resin (800) / polybutene mixture (95: 5) having a thickness of 30 μm at 100 ° C. to obtain an oral preparation.

With respect to this sample, the adhesive force was measured and a practical test (adhesion time) was carried out in the same manner as in Example 7, and an irritation test for damaged skin was carried out in the same manner as in Example 10. The measured values were as follows, and were good.

Adhesion force 60 g / 2.5 cm width Adhesion time 186 minutes Stimulation value 0.6 [Example 13] 5% of solid content of strontium chloride was added in place of tetracycline hydrochloride. An oral preparation was obtained in the same manner as in Example 12 except for the above.

Example 14 In place of tetracycline hydrochloride, tranexamic acid was added in an amount of 0.1% of solid content. An oral preparation was obtained in the same manner as in Example 12 except for the above.

The oral preparations obtained in Examples 13 and 14 above were also used in Example 12
Similar to the buccal preparation obtained in 1., it showed good performance in the measurement of adhesive force, practical test (adhesion time), and irritation test for damaged skin.

[Example 15] Carboxyvinyl polymer 3.4 parts Vinyl acetate resin (1000) 8.4 parts Citric acid 3Na 0.2 parts Methanol 71.0 parts Purified water 17.0 parts Each raw material was blended as described above and mixed to form a uniform solution. Then, dexamethasone was added thereto in an amount of 0.1% of solid content. This solution was cast on a polyethylene terephthalate film and dried in an oven at 80 ° C for 15 minutes to obtain a thickness of 60
A film-shaped adherent having a thickness of μm was obtained. The A value of this product was 18. Next, this is 100 μm on aluminum foil with a thickness of 9 μm.
It was thermocompression-bonded at 0 ° C. to obtain an oral preparation.

With respect to this product, adhesion force measurement, practical test (adhesion time), and irritation test for damaged skin were conducted in the same manner as in Example 12. The measured values were as follows, and were good.

Adhesion force 25 g / 2.5 cm width Adhesion time 258 minutes Irritation value 0.3 [Example 16] Instead of dexamethasone, sodium fluoride was added at 5% of the solid content. An oral preparation was obtained in the same manner as in Example 15 except for the above.

Example 17 Instead of dexamethasone, lysozyme chloride was added to a solid content of 0.
5% was added. An oral preparation was obtained in the same manner as in Example 15 except for the above. However, the drying was carried out at room temperature under reduced pressure for 1 hour.

Regarding the oral preparations obtained in Examples 16 and 17, the adhesive strength measurement, the practical test (adhesion time), and the irritation test result on the damaged skin showed almost the same excellent results as those of Example 15. It was

[Example 18] Polyacrylic acid 7.0 parts 20 mol% saponified polyvinyl acetate 3.0 parts ZnO 0.8 part Methanol 89.2 parts Each raw material was blended as described above and mixed to form a uniform solution, on which lidocaine was added. Was added at 5% solids. This solution was cast on a film (thickness 60 μm) of ethylene-vinyl acetate copolymer (vinyl acetate content 28%) at 80 ° C.
Was dried in a dryer for 10 minutes, and integrated with the above film to obtain an oral preparation. The A value of this product was 44.

With respect to this product, adhesion force measurement, practical test (adhesion time), and irritation test for damaged skin were conducted in the same manner as in Example 12. The measured values were as follows, and were good.

Adhesion force 70 g / 2.5 cm width Adhesion time 166 minutes Irritation value 0.5 [Example 19] Carboxy vinyl polymer 4.0 parts Vinyl acetate resin (2000) 6.0 parts Diisopropanolamine 0.7 parts ZnO 1.4 parts Methanol 87.9 parts Each raw material as described above And mixed with each other to form a uniform solution, and 5% of solid content of aluminum lactate was added thereto. This solution is cast on a polyethylene terephthalate film and dried in a dryer at 80 ° C for 15 minutes to obtain a thickness of
A 60 μm film-like adherent was obtained. This product has an A value of 25
It was.

Vinyl acetate resin (2000) 80.0 parts Titanium white 19.5 parts Food dye Aluminum Lake Red No. 3 0.5 parts On the other hand, a 30 μm thick mixture film comprising the above composition is prepared and the film-like adherent is kept at 100 ° C.
Then, it was thermocompression-bonded to obtain an oral preparation.

With respect to this product, the adhesion force measurement, practical test (adhesion time), and irritation test for damaged skin were carried out in the same manner as in Example 12. The measured values were as follows, and were good.

Adhesion force 35 g / 2.5 cm width Adhesion time 300 minutes or more Stimulation value 0.4 [Example 20] Carboxy vinyl polymer 3.0 parts Methyl vinyl ether-maleic anhydride alternating copolymer 2.
0 parts Biynyl acetate resin (1500) 4.3 parts Triethanolamine 0.7 parts Methanol 80.0 parts Purified water 10.0 parts Mix each raw material as above, mix them to make a uniform solution, and add dibucaine hydrochloride to it as a solid. 0.5% was added. This solution was cast on polyethylene laminated paper and dried in a drier at 80 ° C. for 10 minutes to obtain a film-like adherent having a thickness of 30 μm. The A value of this product was 33.
Next, add this to a thickness of 30% containing dibucaine hydrochloride.
100 ℃ for film of μm vinyl acetate resin (1500)
Then, it was thermocompression-bonded to obtain an oral preparation.

With respect to this product, adhesion force measurement, practical test (adhesion time), and irritation test for damaged skin were conducted in the same manner as in Example 12. The measured values were as follows, and were good.

Adhesion force 42 g / 2.5 cm width Adhesion time 190 minutes Irritation value 0.4 [Example 21] 2% of solid content of decalinium hydrochloride was added instead of dibucaine hydrochloride. Then, as the vinyl acetate resin film as the film-shaped support, decalinium hydrochloride
The one containing 20% was used. An oral preparation was obtained in the same manner as in Example 20 except for the above.

Example 22 In place of dibucaine hydrochloride, 1α, 24 (R)-(OH) ₂ -vitamin D ₃ was added in an amount of 0.005% of the solid content. Then, the thickness of the film-like adherent was increased to 40 μm, and at the same time, a vinyl acetate resin film having a thickness of 30 μm containing no topical drug was used as a support for the film-like adherent. An oral preparation was obtained in the same manner as in Example 20 except for the above.

Example 23 Instead of 1α, 24 (R)-(OH) ₂ -vitamin D ₃ , 1α,
(OH) - and the Vitamin D ₃ was added 0.005% solids. An oral preparation was obtained in the same manner as in Example 22 except for the above.

It was added 0.001% of Example 24 solid calcitriol instead vitamin D ₃ of Example 22. An oral preparation was obtained in the same manner as in Example 22 except for the above.

The adhesive strength, practical test (adhesion time), and irritation test on damaged skin of the oral preparations obtained in Examples 21 to 24 were almost the same as those in Example 20, and were good.

Next, the effects of the oral preparations obtained in Examples 1 to 24 will be described by taking typical ones.

[Case 1]… Effect on stomatitis Patients with a 5 mm diameter stomatitis on the buccal mucosa at the initial diagnosis (50
(Age, female) the oral preparation prepared in Example 7 was applied three times a day, and the symptoms disappeared on the third day.

[Case 2] ... Effect on abrasion due to brushing The oral preparation prepared in Example 8 was applied to a patient (8 years old, female) having gum damage due to brushing with a toothbrush.
I applied it 3 times a day and gave instructions for blasting, and the symptoms disappeared on the 2nd day.

[Case 3] ... Effect on bad breath Example 2 for a patient (21 years old, female) who came to our hospital with a chief complaint of bad breath
When instructed to apply the buccal preparation prepared in 1) to the lower cervical part twice a day and administered 10 tablets, there was no subjective symptom at the re-examination one week later.

[Case 4] ... Effect on infection prevention of adult periodontitis patient (39 years old, male) with deep periodontal pocket Performed flap operation (Flap Operation) on
The buccal preparation prepared in Example 9 was applied, and a packing agent was applied thereon.

When the pack agent was removed 3 days later, granulation was normal. Therefore, only this oral preparation was administered twice a day for 4 days.
After daily administration, the prognosis was good.

[Case 5] ... Effect on alveolar pyorrhea in a patient with adult periodontitis (45 years old, male) with deep periodontal pocket The intraoral preparation prepared in Example 11 was applied to the above once a day for 4 weeks. In addition, He did not administer anything as a control. As a result, in the Examples, the gingival inflammation index (Gingival Index) was significantly improved from 2 to 1, and the periodontal pocket depth (Pocket Depth) was significantly improved from 5.5 mm to 4.0 mm. On the other hand, almost no improvement was observed on the control side.

[Case 6] ... Effect on hyperesthesia A patient (36 years old, female) who came to our hospital with a chief complaint of hyperalgesia accompanied by severe pain was instructed to apply the oral preparation prepared in Example 13 twice a day to the affected area, and 30 sheets were administered.

Upon reexamination three weeks later, the symptoms had completely healed.

[Case 7] ... Local Ansthetic Effect Patients with Proliferative gingivitis (41
Age, female), the oral preparation prepared in Example 18 was applied to the gingiva before surgery. After that, when Gingivectomy was performed, there was no pain during the operation,
There was no numbness in areas other than the sticking part. The prognosis was good.

[Brief description of drawings]

 The drawing is a characteristic curve diagram of (elution amount) / (total elution amount).

Front page continuation (72) Inventor Shun Tsuyoshi 3-1, Asahi-cho, Takatsuki-shi, Osaka Sunstar Co., Ltd. (72) Inventor Tetsuo Horiuchi 1-2-2 Shimohozumi, Ibaraki-shi, Osaka Nitto Denki Kogyo Co., Ltd. (72) Inventor Yuichi Inoue 1-2-1, Shimohozumi, Ibaraki City, Osaka Prefecture Nitto Electric Industry Co., Ltd.

Claims (7)

[Claims] 1. A preparation comprising a film-like adherent alone containing a topical drug, or an integrated product of the film-like adherent and a flexible film-like support, which comprises the film-like adherent and the film-like support. A formulation containing a topical drug in at least one, wherein the film-like adherent is a flexible film in which at least one of a polycarboxylic acid and a polycarboxylic anhydride is in a compatible state with a vinyl acetate polymer. An intraoral preparation characterized by being constituted by: 2. A mixing ratio of at least one of a polycarboxylic acid and a polycarboxylic acid anhydride and a vinyl acetate polymer is represented by the following formula: The oral preparation according to claim 1, which is in the range of 15 to 45. 3. The flexible film-like material is a film in which at least one of a polycarboxylic acid and a polycarboxylic acid anhydride and a vinyl acetate polymer are dissolved in a common solvent to be in a compatible state. The oral preparation according to item 1. 4. A preparation comprising a film-like adherent alone containing a topical drug, or an integrated product of the film-like adherent and a flexible film-like support, which comprises the film-like adherent and the film-like support. A formulation containing a topical drug in at least one, wherein the film-like adherent is in a compatible state with at least one of a polycarboxylic acid and a polycarboxylic anhydride and a vinyl acetate polymer,
An oral preparation comprising a flexible film containing a salt having a neutralizing effect on the above polycarboxylic acid or polycarboxylic anhydride. 5. A mixing ratio of at least one of polycarboxylic acid and polycarboxylic acid anhydride and a vinyl acetate polymer is represented by the following formula: The oral preparation according to claim 4, which is in the range of 15 to 45. 6. The oral preparation according to claim 4, wherein the salt is at least one of a salt and a base. 7. The flexible film-like material is a film obtained by dissolving at least one of a polycarboxylic acid and a polycarboxylic acid anhydride and a vinyl acetate polymer in a common solvent to obtain a compatible state. The oral preparation according to item 4.