JPS6345829B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to an oral bandage that is applied to moist mucous membranes in the oral cavity to prevent the outflow of drugs administered to the oral mucosa, cover and protect damaged areas of the oral mucosa, and the production thereof. It is about law. [Prior Art] Conventionally, various drugs have been administered in the form of ointments and liquids for oral diseases such as alveolar pyorrhea and inflammation. In addition to these topical therapeutic drugs, focusing on the fact that the mucous membrane absorbs drugs relatively well compared to the outer skin, systemic drugs such as hormones that are difficult to absorb by oral administration can also be used in the oral cavity. Administration through the mucous membrane has been attempted. The biggest obstacle to administering drugs through the oral mucosa is that the drugs are washed away in a short time by saliva secretion and eating and drinking, making it difficult to develop sufficient medicinal efficacy. be. In addition, covering and protecting damaged areas in the oral cavity is rarely done as there are no effective oral bandages, but as mentioned above, saliva is constantly secreted in the oral cavity, and food and drinks also enter the oral cavity. Therefore, there are major obstacles to realizing such coating protection. Recently, various proposals have been made in an attempt to overcome these obstacles and effectively administer drugs for oral diseases. Among these, there are oral mucoadhesive preparations containing a water-soluble polymeric substance as an adhesive component, which are relatively similar in concept to the intraoral bandage of the present invention. When a water-soluble polymer substance absorbs a small amount of water to different degrees depending on its type, it becomes a viscous aqueous solution or gel and exhibits adhesive properties. Utilizing this property, paste-like (Special Publication No. 56-27491) and sponge-like (Special Publication No. 56-27491)
56-25211), tablet form (Special Publication No. 1983-
Various oral mucosal-adhesive preparations have been devised, such as those in the form of sheets (Japanese Patent Publication No. 16676/1976, Japanese Patent Application Laid-open No. 186913/1983). [Problems to be solved by the invention] However, each of the above-mentioned preparations merely adheres to the oral mucosa and administers the internal medicine;
It is sufficient that the adhesion is strong enough to administer the internal drug, and it is sufficient that it remains attached to the mucous membrane for a long enough time to administer the drug.
It does not have the strong adhesion and long-term adhesion that are required for intraoral bandages. That is,
Oral bandages are applied to diseased or damaged areas in the oral cavity to prevent the medication administered there from escaping and to protect those areas. It is required to have strong adhesion ability even to the oral mucosa, which is difficult to adhere to, and adhesion sustainability ability to adhere for a long time. Due to its nature, the above-mentioned oral mucoadhesive preparation does not have both the adhesion force and the adhesion persistence required for an oral bandage, as described above, and therefore, the base of the preparation cannot be used intraorally. Even if it is used as a bandage, it cannot achieve the above-mentioned characteristics required for an intraoral bandage. Of course, adhesive tapes such as plasters used for external skins cannot be used as intraoral bandages because they do not have adhesion to wet surfaces such as the oral mucosa. Intraoral bandages are applied to diseased areas in the oral cavity to prevent the administration of drugs from being washed away and to protect the area, so as mentioned above, they are required to have strong adhesion and long-lasting adhesion. In addition, it must be flexible enough to be applied to any part of the oral mucosa, which has a complex shape, and must be safe enough to avoid irritating the injured area and worsening the wound. . However, the reality is that nothing with such characteristics exists. The present invention was developed in view of the above circumstances, and has strong adhesion, long-term adhesion ability, flexibility that allows it to be applied to any part of the oral mucosa, and stimulation to the damaged area to prevent scratches. The object of the present invention is to provide an intraoral bandage and a method for producing the same that are safe and do not deteriorate the oral cavity. [Means for Solving the Problems] In order to achieve the above object, the present invention provides an intraoral dressing consisting of a film-like adhesive alone or an integrated film-like adhesive and a flexible film-like support. In the film-like adhered body, at least one of the polycarboxylic acid and the polycarboxylic anhydride is in a compatible state with the vinyl acetate homopolymer, and the film-like adhered body is in a state where the vinyl acetate homopolymer is in a compatible state with respect to the polycarboxylic acid or the polycarboxylic anhydride. The first aspect is an intraoral bandage composed of a flexible non-sponge-like film-like material containing salts having a soothing effect, and at least one of polycarboxylic acid and polycarboxylic anhydride and vinyl acetate alone. a step of dissolving the polymer in a common solvent for both, and preparing a solution containing salts having a neutralizing effect on polycarboxylic acid or polycarboxylic anhydride; and a step of forming the solution into a film. The second gist is a method for manufacturing an intraoral bandage having the following features. Water-soluble polymer substances such as polycarboxylic acids and polycarboxylic anhydrides have shape retention properties and exhibit strong adhesion when they absorb a small amount of water, but they quickly absorb excessive water. As a result, the viscosity decreases and collapses, becoming substantially dissolved in water and losing its adhesive properties. Moreover, the dissolved polycarboxylic acid is acidic and strongly irritates the injured area of the sensitive oral mucosa, causing deterioration of the injured area. The present inventors took advantage of the strong adhesion of water-soluble polymeric substances such as polycarboxylic acids and polycarboxylic anhydrides when they absorb water, and in order to effectively utilize this for intraoral bandages, we aim to eliminate their defects. A series of studies were conducted with the aim of improving the loss of adhesion caused by excessive water absorption and the irritation to oral lesions. As a result, polycarboxylic acid, polycarboxylic anhydride, and vinyl acetate homopolymer are compatible, and when they are made compatible, the polycarboxylic acid and polycarboxylic anhydride become substantially water-insoluble. but,
This has been realized in a state where the strong adhesion when water is absorbed is not impaired, but rather enhanced, and even when a compatible mixture of the two is formed into a thin, flexible film, it does not disintegrate upon absorption of water in a wet state and exhibits strong adhesion for a long time. Furthermore, when the above-mentioned compatible solution contains salts (including both salts and bases) that have a neutralizing effect on polycarboxylic acids or polycarboxylic anhydrides, irritation to the damaged area of the oral mucosa can be reduced. We discovered that it can be eliminated and arrived at this invention. A non-sponge-like flexible film made of a compatible solution of at least one of polycarboxylic acid and polycarboxylic anhydride (hereinafter collectively referred to as "polycarboxylic acids") and vinyl acetate homopolymer as described above is dried. Although it sometimes has no adhesive properties, it exhibits a strong adhesive force when it absorbs water, and its state hardly changes even when immersed in water, which is an epoch-making property. Such properties are only developed when the polycarboxylic acids and the vinyl acetate homopolymer are in a compatible state, and are not developed unless they are in a compatible state. Note that the mixing state of salts that have a neutralizing effect on polycarboxylic acids has little effect on the above-mentioned adhesion. These salts may be in a compatible state with the polycarboxylic acids and vinyl acetate homopolymer, or may be in a coarsely mixed state such that the powder is dispersed. Here, the term "compatible state" refers to a state in which polycarboxylic acids and vinyl acetate homopolymer, etc., are uniformly dissolved without phase separation to form independent small regions. When polycarboxylic acids and vinyl acetate homopolymer are in a compatible state, they exhibit properties that are not expected from the properties of a mixture in a phase-separated state. The difference in these properties is that if it is a mixture of only polycarboxylic acids and vinyl acetate homopolymer,
Although it is possible to clearly observe the difference, in a mixture that also contains salts having a neutralizing effect, such as the adhered body of the present invention, the difference becomes unclear. In other words, if it is a mixture of only polycarboxylic acids and vinyl acetate polymer, the phase-separated film will be cloudy, and the compatible film will be highly transparent. In mixtures containing salts, there are no regulations regarding the mixing state of salts, so even if polycarboxylic acids and vinyl acetate homopolymer are in a compatible state, if the salts are in a roughly mixed state, the film will still become cloudy. It is something. As described above, it may not always be possible to determine the mixed state of the polycarboxylic acid and the vinyl acetate homopolymer by visual observation or observation using an optical microscope. However, as already mentioned, the present inventors found that when polycarboxylic acids and vinyl acetate homopolymer are in a compatible state, the water solubility of the polycarboxylic acids, which should be water-soluble, is significantly limited. It has been found that even when immersed in water for a considerable period of time, it swells homogeneously and does not disintegrate. This property was observed regardless of the presence or absence of neutralizing salts. Utilizing this property, the state of compatibility between polycarboxylic acids and vinyl acetate homopolymer can be investigated. Furthermore, considering that the intraoral bandage of the present invention can adhere to the oral mucosa for a long time due to the limited water solubility of polycarboxylic acids, this discrimination method can be said to be appropriate. In this invention, the compatibility state of polycarboxylic acids and vinyl acetate homopolymer is investigated from the elution amount of polycarboxylic acids. Specifically, the compatibility state in this invention is determined by the elution rate measurement method described below. Refers to a mixed state in which the elution rate determined by the method is 50% by weight (hereinafter abbreviated as "%") or less. <Method for Measuring Elution Rate> A film (film-like adherent) consisting of polycarboxylic acids, vinyl acetate homopolymer, and salts having a neutralizing effect is pulverized at 0° C. or lower and weighed.
Put this in a mesh bag and calculate the weight of the attached body.
After immersing the bag in purified water at 20°C, which is 300 times more concentrated, for 1 hour, remove the adhered material from the bag. Through this operation, the amount of polycarboxylic acids eluted into the purified water and salts having a neutralizing effect are determined by reducing the weight of the adhered body by immersion. The elution rate is calculated by dividing this by the sum of the blended amounts of polycarboxylic acids and neutralizing salts in the film. The oral bandage of the present invention uses a flexible non-sponge-like film as described above that exhibits no adhesive properties when dry and exhibits adhesive force only when water is absorbed, as the film-like adhesive body. Since it does not have adhesive properties when dry, it can be stored as is without any special storage conditions, and when used, simply press it against the mucous membranes in the oral cavity to absorb saliva and moisture from the mucous membranes and quickly become adhesive. It expresses and strongly adheres to mucous membranes. Therefore, it strongly adheres to diseased or damaged areas in the oral cavity, which are difficult to adhere to due to administered drugs or bleeding, and exerts a protective effect to prevent drug leakage and cover wounds. This adhering state lasts for an extremely long time, which is a major feature of the present invention. In this case, although the polycarboxylic acids are substantially insolubilized in the film-like adherent, they are not completely insolubilized, so the polycarboxylic acids are It is conceivable that trace amounts of acids will elute and this will irritate damaged areas, etc. However, the above film-like adherent contains salts that have a neutralizing effect on polycarboxylic acids, and there is a possibility that this will elute. Since certain polycarboxylic acids are neutralized in advance, no irritation is applied to the damaged area, and no problem occurs even if the adhesive remains attached for a long time. As mentioned above, the long-term adhesion of intraoral bandages is only achieved when the polycarboxylic acids and vinyl acetate homopolymer are in a compatible state in the film-like adherent. be. The mechanism by which this persistent adhesion is generated is not clear, but under compatible conditions, the polycarboxylic acids provide adhesion to wet mucous membranes, and the vinyl acetate homopolymer provides water resistance, and the two are in good harmony for a long time. It is thought that it exhibits adhesion persistence over time. Note that the mixing state of salts that have a neutralizing effect on polycarboxylic acids does not affect the adhesion, but their characteristics subtly affect the above-mentioned adhesion. For example, polyvalent metal salts such as zinc oxide and calcium oxide reduce adhesion and increase water resistance, while monovalent metal salts such as sodium acetate, sodium hydroxide, triethanolamine, etc. Monovalent bases act to increase adhesion and reduce water resistance. As described above, the intraoral bandage of the present invention has a long-lasting adhesion ability, and therefore prevents the administered drug from being washed away from the diseased area in the oral cavity for a long time, significantly increases its absorption rate, and promotes healing. In addition, the coating and protection of the injured area in the oral cavity can be maintained for a long time, and the recovery can be accelerated. At this time, the irritation caused by the eluted polycarboxylic acids to the injured area is prevented by the neutralizing effect of the above-mentioned salts, so the situation where the injured area, etc. warps and worsens due to the application of the oral bandage is prevented. They do not invite them. Moreover, the film-like adherent is composed of a substantially water-insoluble, flexible, non-sponge-like film in which polycarboxylic acids and vinyl acetate homopolymer are in a compatible state, and is simply a water-soluble polymeric substance as it is. Because it is not used, it exhibits long-lasting adhesion even in a very thin state. In other words, when using a water-soluble polymer substance as it is, it cannot be made too thin because if it is made too thin, it will rapidly dissolve in saliva and lose its adhesive properties rapidly. This will give it a thickness of . However, in this case, the feeling of a foreign body increases during use, and at the same time, the flexibility of the intraoral bandage is impaired. The film-like adhesive body of the intraoral bandage of the present invention exhibits strong adhesive force over a long period of time in a very thin state, so there is no need to increase the thickness, and there is no feeling of foreign body due to excessive thickness. It is. In the intraoral bandage of the present invention, since the film-like adhesive body is constituted by a thin, flexible, non-sponge-like film, the entire oral bandage is flexible and thin. Therefore, when used, it deforms smoothly and easily adheres to the oral mucosa simply by pressing lightly, and has the advantage that it does not give a foreign body sensation when applied. The oral bandage of the present invention can be produced by, for example, dissolving polycarboxylic acids and vinyl acetate homopolymer in a common solvent for both, and adding salts that have a neutralizing effect to the polycarboxylic acids. It can be manufactured by rapidly casting and drying to form a film-like adherent. The above-mentioned salts may be mixed by dissolving the salts in the above-mentioned solution, or by dispersing the salts in powder form. This manufacturing method has the advantage that a very thin film-like body can be easily formed. Typical examples of the above polycarboxylic acids include acrylic acid polymers, methacrylic acid polymers,
Examples include maleic anhydride polymers, which can be used alone or in combination. Specific examples of the above-mentioned acrylic acid polymers include, in addition to acrylic acid homopolymers, acrylic esters such as butyl acrylate and 2-ethylhexyl acrylate, methacrylic esters such as methyl methacrylate, and vinyl acetate. Examples include copolymers with vinyl monomers and copolymers such as carboxyvinyl polymers. In addition to methacrylic acid homopolymers, specific examples of methacrylic acid polymers include copolymers similar to those of acrylic acid polymers, and specific examples of maleic anhydride polymers include methyl vinyl ether Examples include copolymers with It goes without saying that the compounds exemplified in the above-mentioned specific examples can be used not only alone but also in combination. In these polycarboxylic acids, the polycarboxylic acid contains 20% or more of -COOH groups, and the polycarboxylic anhydride contains 16 -CO-O-CO- groups.
% or more is preferable from the viewpoint of effectiveness. The above vinyl acetate homopolymer is obtained by polymerizing only vinyl acetate monomers. This polymer also includes a partially saponified product obtained by partially saponifying a vinyl acetate homopolymer. It is preferable that these have an average molecular weight (viscosity average molecular weight) of 60,000 or more.
If a polymer having an average molecular weight of less than 60,000 is used, the water resistance of the film-like adherent will decrease, making it difficult to obtain the desired effect. Salts that have a neutralizing effect on polycarboxylic acids include not only salts but also bases. Typical examples include salts of metals and weak acids, metal oxides, metal hydroxides, Examples include amines and mixtures thereof. Specific examples of salts of metals and weak acids include salts of sodium, potassium, calcium, magnesium, etc., and carboxylic acids such as acetic acid, lactic acid, and citric acid. Specific examples of metal oxides include zinc oxide. , calcium oxide, and magnesium oxide. Further, specific examples of metal hydroxides include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, etc., and specific examples of amines include triethanolamine, diisopropanolamine, etc. It will be done. The compounds specifically exemplified above can be used alone or in combination. The preferred amount of such salts varies widely depending on the type of salt or base. When using a polyvalent metal salt, it is preferable to mix it in an amount of 0.2 to 0.8 equivalents to the polycarboxylic acids in the film-like adherent. If the amount is less than 0.2 equivalents, damage to the damaged area (damaged mucous membrane) may occur. If the amount exceeds 0.8 equivalents, it becomes difficult to obtain sufficient adhesion durability. In addition, when using a monovalent metal salt or a monovalent base, it is preferably blended in an amount of 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 area will be insufficient, and if the amount exceeds 0.2 equivalent, the water resistance of the film-like adherent will decrease and it will be difficult to obtain sufficient adhesion. Common solvents for the above polycarboxylic acids and vinyl acetate homopolymer include lower alcohols such as methanol and ethanol, and mixtures of these and soluble organic solvents such as acetone and ethyl acetate, with lower alcohols as the main component. Examples include those in which water is further added and mixed with the above mixtures or lower alcohols. Regarding the above solvents, it is preferable to limit the content of organic solvents such as acetone and ethyl acetate to 30% or less. 30
%, it becomes difficult to dissolve the polycarboxylic acids. Regarding the above solvents, it is preferable to limit the water content to 30% or less. This is because when the water content exceeds 30%, it tends to become difficult to dissolve the vinyl acetate homopolymer. When producing an intraoral bandage as described above, the mixing ratio of polycarboxylic acids and vinyl acetate homopolymer is such that the A value determined by the following formula is
It is preferable to regulate it within the range of 15 to 55.

[Table] 〓 Weight of group 〓 〓 Weight of group 〓
A〓

Claims (1)

[Scope of Claims] 1. An intraoral bandage consisting of a film-like adhesive alone or an integrated film-like adhesive and a flexible film-like support, the film-like adhesive comprising a polycarboxylic acid and a polyanhydride. A flexible non-spongy material in which at least one of the carboxylic acids and a vinyl acetate homopolymer are in a compatible state, and a salt having a neutralizing effect on the polycarboxylic acid or polycarboxylic anhydride is contained. An intraoral bandage characterized by being composed of a film-like body. 2. The intraoral bandage according to claim 1, wherein the salt is at least one of a salt and a base. 3. The intraoral bandage according to claim 1 or 2, wherein the flexible film-like support is a plastic film. 4 At least one of polycarboxylic acid and polycarboxylic anhydride and vinyl acetate homopolymer were dissolved in a common solvent for both, and salts having a neutralizing effect on the polycarboxylic acid or polycarboxylic anhydride were further blended. A method for producing an intraoral bandage, comprising the steps of preparing a solution and forming the solution into a film. 5. The method for producing an intraoral bandage according to claim 4, wherein forming the solution into a film is performed by casting the solution and drying it. 6. The intraoral bandage according to claim 4, wherein the solution is formed into a film on a flexible film support, and the formed film and the flexible film support are integrated. manufacturing method. 7. The method for producing an intraoral bandage according to claim 6, wherein the flexible film-like support is a plastic film.