JP2000178185A - Oral mucous membrane-adhering type sustained release tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an oral mucous membrane-adhering type sustained release tablet containing xylitol and/or erythritol suitable for the application in the oral cavity, for the purpose of an oral cavity hygiene, the prevention and treatment of a disease in the oral cavity, and further a sustained release of a systemic medicine, adhering to the oral mucous membrane, excellent in releasing property, also capable of sustaining its effect for a sufficient period of time and having a good use feeling. SOLUTION: This sustained release tablet has an adhesive layer to an oral mucous membrane and a non-adhesive layer, in which the adhesive layer contains xylitol and/or erythritol and 60-95 wt.% polyvinylpyrrolidone having >=300,000 mean molecular weight. Also, the sustained release tablet has the adhesive layer to the oral mucous membrane and the non-adhesive layer, in which the non-adhesive layer contains xylitol and/or erythritol and 2-70 wt.% polyvinylpyrrolidone having <=100,000 mean molecular weight.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to xylitol and / or erythritol suitable for oral application for the purpose of oral hygiene, prevention and treatment of oral diseases, and continuous administration of systemic drugs. The present invention relates to an oral mucosa-adhered sustained-release tablet having an adhesive layer and a non-adhesive layer, which contains an adhesive layer and a non-adhesive layer, which adhere to the oral mucosa, have excellent release properties, can maintain the effect for a sufficient time, and have a good feeling in use.

[0002]

2. Description of the Related Art Conventionally, various dosage forms have been tried as sustained-release preparations for treating or preventing various diseases by administering a drug into the oral cavity.
Among them, the conventional liquid preparations, sustained-release preparations of ointments, etc. are washed into saliva and adhere to the oral mucosa, the amount of retention is not enough,
Therefore, the sustained release is low. Therefore, insolubility and oiliness have to be increased in order to further increase the adhesiveness, and the feeling of use such as taste and foreign-body sensation is poor. In addition, lozenges, sublingual tablets, etc.
If the foreign body feels or melts and becomes small, the patient often inevitably chews them and swallows them, and none of them can achieve sustained release of the target drug. Furthermore, the use of licking has the disadvantage of causing problems in interpersonal relationships.

On the other hand, tablets and film preparations have been tried as oral mucosa-adhered sustained-release preparations for the purpose of adhering to the oral mucosa and releasing the drug for a long time.
Film preparations are generally the most suitable as oral mucosa-adhesive preparations in terms of foreign body sensation, but they must be kept at a low rate for sustained-release preparations because they are inevitably thinner and require less drug dosage in terms of manufacturing. There is. Therefore, as a drug, it can only be applied to a strong drug exhibiting an effect in a very small amount, or to a very limited narrow site such as stomatitis. Therefore, in order to prevent bad breath, prevent tooth decay, gingivitis, periodontal illness such as periodontitis, oral diseases such as pharyngitis, and systemic diseases, the dosage from the film preparation is also considered from the viewpoint of production. It is essential that the oral mucosa-adhesive sustained-release tablet can increase the amount of the drug.

However, tablets generally have a strong foreign body sensation and are hard, and conventional oral mucosa-attached sustained-release tablets have to be reduced in size in order to compensate for their disadvantages. As a result, it was necessary to increase the content of polymers such as water-insoluble and other excipients generally used for forming tablets. In addition, the release rate has to be slowed for such long-term sustained release, and it takes time to reach the effective concentration of the drug. Therefore, there is a limitation that the drug is applied to a strong drug which shows an effect in a small amount. Further, the powdery and high-molecular viscous sensation in the mouth, foreign body sensation due to insoluble components, poor taste, etc. were exhibited, and the feeling of use was poor, making it difficult to withstand long-term use.

[0005] Formulations for oral administration and long-term retention include:
Since the taste of the oral cavity and the sensation to the foreign substance are extremely sharp, the sense of use, such as the lack of taste and foreign substance sensation and the refreshing of the oral cavity, are extremely important. In addition, oral mucosa-attached sustained release tablets stay in the oral cavity for a long time, so in the formulation design, it is necessary to avoid the factors that induce dental caries, but in order to make tablets, lactose, starch, A cariogenic excipient such as dextrin had to be used.

On the other hand, xylitol and erythritol have good and moderate sweetness, high solubility in water,
Since it has an excellent taste quality such as having a cool feeling by absorbing heat when dissolved, it is used for internal tablets such as quick dissolve tablets, granules and troches. In addition, these are non-cariogenic sweet substances that do not become substrates for various bacteria existing in the oral cavity. In addition, xylitol has been found to have caries-preventing effects such as suppression of acid production from oral bacteria by ingestion of sucrose, promotion of dental remineralization, and inhibition of oral bacterial metabolism. In recent years, dental associations in Finland, Sweden, Norway, Iceland, the United Kingdom, the Netherlands, and Belgium have promoted the use of xylitol in confectionery and food products. It is used.

However, conventionally, oral mucosa-attached sustained-release tablets are considered to be unsuitable because of their excessively high solubility and poor moldability. Only examples in the category of sugar alcohols as excipients are given.

[0008] The present invention has been made in view of the above circumstances, and a sustained release tablet for oral mucosa adherence has a long residence time, has a good feeling in use, can withstand a long use, and has a long-term retention. It is an object of the present invention to provide an improved sustained-release oral mucosa-adhesive tablet comprising a safe adhesive layer and a non-adhesive layer that do not induce dental caries.

[0009]

Means for Solving the Problems and Embodiments of the Invention The present inventor first gave xylitol and / or erythritol to an oral mucosa-adhered sustained-release tablet having an adhesive layer to the oral mucosa and a non-adhesive layer. By containing it, it stays for a sufficient time, and it does not collapse or peel off from the adhesive layer, has a good feeling of use, withstands long-term use, and has a safe oral cavity without the possibility of inducing dental caries. A mucoadhesive sustained release tablet was proposed (Japanese Patent Application No. 10-181606).

[0010] When the oral mucosa-adhered sustained-release tablet containing xylitol and / or erythritol is applied to the oral cavity, the saliva in the oral cavity causes the polymer in the adhesive layer to absorb and swell the water and exhibit adhesiveness. As a result, the tablet is fixed to the mucous membrane, and the non-adhesive layer gradually dissolves from the surface to exhibit sustained release. Finally, after the non-adhesive layer is completely dissolved and disappears, the adhered and swollen adhesive layer completely absorbs water, remains as an ointment, and then dissolves and disappears. In order to prevent bad breath and apply to oral diseases such as alveolar pyorrhea, until the adhesive layer has completely disappeared, there is no foreign substance feeling or stickiness due to swelling or ointment, no off-taste, It is hoped that is good.

As a result of further study on the demand of this point, the present inventor surprisingly found that polyvinylpyrrolidone having an average molecular weight of 300,000 or more was used in combination with xylitol and / or erythritol in the adhesive layer in a specific amount. There is no swelling during use by the adhesive layer, and the viscosity of saliva does not increase too much, there is no discomfort or unpleasant taste, and it adheres for a sufficient time as a preventive or therapeutic agent for oral diseases, after dissolution and disappearance of the non-adhesive layer Found that the adhesive layer quickly disappeared, so that the feeling of use was good and that it could be used for a long time.

[0012] It is also desired that the above-mentioned oral mucosa-adhered sustained-release tablet should further increase the release initiation speed immediately after it is adhered to the oral mucosa, and better control the release property immediately after administration.

The present inventor has also studied the need for this point. As a result, surprisingly, a specific amount of polyvinylpyrrolidone having an average molecular weight of 100,000 or less is added to and contained in the non-adhesive layer together with xylitol and / or erythritol. Also has good release properties from the beginning, the viscosity of saliva in the mouth does not rise too much during use, and it stays for a sufficient time,
It was found that the feeling of use was good and that it could be used for a long time.
In addition, they have found that the incorporation of a water-soluble sucrose fatty acid ester therein can further control the releasability from the initial stage, and have accomplished the present invention.

Accordingly, the present invention provides a sustained-release tablet having an adhesive layer and a non-adhesive layer for the oral mucosa, wherein the adhesive layer contains xylitol and / or erythritol and has an average molecular weight of 300,000 or more. The oral mucosa-adhered sustained-release tablet characterized in that the adhesive layer contains 60 to 95% by weight of polyvinylpyrrolidone.

The present invention also provides a sustained-release tablet having an adhesive layer and a non-adhesive layer for the oral mucosa, wherein the non-adhesive layer contains xylitol and / or erythritol and has an average molecular weight of 100,000. An oral mucosa-adhered sustained-release tablet comprising the following polyvinylpyrrolidone in an amount of 2 to 70% by weight in a non-adhesive layer.

Hereinafter, the present invention will be described in more detail. The sustained-release tablet for oral mucosa according to the present invention comprises xylitol and / or
Or a tablet containing an erythritol-containing adhesive layer and a non-adhesive layer to the oral mucosa.

In this case, the adhesive layer for the oral mucosa of the sustained-release tablet of the present invention for oral mucosa adheres to the wet surface of the oral cavity, absorbs water, swells, and exhibits a polymer exhibiting adhesiveness to the mucous membrane. It is contained as an adhesive component and is intended to fix and hold the tablet on the oral mucosa. On the other hand, the non-adhesive layer for the oral mucosa does not adhere even when it comes into contact with the wet surface of the oral cavity,
It gradually dissolves and disappears by sustained release of components.

The xylitol and / or erythritol used in the present invention may be in a crystalline form, but is more preferably a fine powder. By making it into a fine powder, the compressed tablet does not disintegrate when applied to the oral cavity and dissolves. It becomes easy to stay. In this case, the average particle size of xylitol or erythritol is preferably 500 μm or less, particularly preferably 50 μm or less.

Here, in the first sustained-release tablet for oral mucosa adhesion of the present invention, the adhesive layer contains xylitol and / or erythritol and polyvinylpyrrolidone having an average molecular weight of 300,000 or more. .

The amount of xylitol and / or erythritol in the adhesive layer is 5 to 40% (% by weight,
The same applies hereinafter), and particularly preferably 10 to 35%.
If the amount is too small, the cooling sensation may be reduced and the usability may be inferior. If the amount is too large, the adhesiveness may be reduced.

The first sustained-release preparation of the present invention uses polyvinylpyrrolidone having an average molecular weight of 300,000 or more, preferably 300,000 to 2,000,000, and more preferably 300,000 to 1.5 million as an adhesive component. As a result, sufficient mucoadhesiveness is exhibited, and after the non-adhesive layer has disappeared, it disappears promptly, does not cause off-flavor or discomfort, and in combination with the above xylitol and / or erythritol, the entire tablet disappears Unusual feeling such as swelling with saliva to form an ointment after the non-adhesive layer dissolves and disappears, and a sticky feeling such as increased viscosity of saliva and bad taste. There is no danger of causing

The amount of the polyvinylpyrrolidone having an average molecular weight of 300,000 or more in the pressure-sensitive adhesive layer is from 60 to 95%, particularly from 65 to 90%, from the viewpoint of effectively exhibiting the above-mentioned effects.
It is. If the amount is too small, the tackiness becomes insufficient,
If it is too large, the amount of xylitol and / or erythritol decreases, and the effect of imparting a comfortable cooling feeling to the adhesion site decreases.

The pressure-sensitive adhesive layer may contain other water-soluble polymers described below in a range (0 to 20%, particularly 0 to 10%) which does not impair the effects of the present invention. Further, the adhesive layer may contain excipients, binders, lubricants, coloring agents, flavoring agents, flavors, surfactants, sweeteners, preservatives, pharmacologically active ingredients, and the like, which will be described later.

In the first sustained-release preparation of the present invention, the non-adhesive layer preferably contains xylitol and / or erythritol, and the content thereof is 20 to 9 in the non-adhesive layer.
It is preferably 5%, particularly preferably 30 to 90%. If the content is too small, a sufficient release of the pharmacologically active ingredient may not be obtained in some cases. If the content is too large, the release may be too fast to obtain a sustained release.

As described above, xylitol and / or
Alternatively, it is preferable to contain erythritol. In tablets using xylitol and / or erythritol,
It has an appropriate softness to the contact mucous membrane, has a little foreign body sensation, has a cooling sensation, has a moderate and good sweetness, and has a shape without peeling or collapsing of the non-adhesive layer from the adhesive layer during oral application. Dissolve gradually from the surface of the non-adhesive layer while keeping
Since it disappears, sustained release can be achieved and long-term retention can be obtained.

In addition, in the case of a single-layered adhesive tablet, if importance is attached to the oral mucosa, it adheres to both surfaces of the administered site, giving a sense of incongruity and cannot be applied for a long time. Because of the inability to do so, they cannot stay for a long time.

In addition to xylitol and / or erythritol, the non-adhesive layer may have water-soluble polymers, such as water-soluble polymers, such as Polyacrylic acid, pharmaceutically acceptable salts thereof such as carboxyvinyl polymer or sodium polyacrylate, or acrylic acid as a main component,
Acrylic acid copolymers obtained by further copolymerizing methacrylic acid and the like, polyacrylic esters such as polyhydroxyethyl acrylate, hydrophilic vinyl polymers such as polyvinyl alcohol; methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl Hydrophilic cellulose derivatives such as methylcellulose, carboxymethylcellulose or salts thereof; alginic acid or salts thereof, polysaccharides such as tragacanth gum, xanthan gum, carrageenan, tamarind gum, gellan gum, pullulan or derivatives thereof; collagen, gelatin or derivatives thereof, and average molecular weight 100,000 or less polyvinylpyrrolidone or the like may be blended. However, the compounding amount is 0 to 80%, more preferably 0 to 7%.
0%, more preferably 0 to 50%. If the amount is too large, the solubility is low and the release hardly occurs. In addition, the viscosity of the saliva is increased due to the dissolved polymer, the feeling of use is deteriorated, and a sufficient cooling effect is not obtained. When the above polymer is blended in the non-adhesive layer, the kind and amount of the polymer are selected so that the adhesive layer adheres to the oral mucosa when applied in the oral cavity, and the non-adhesive layer does not adhere.

The non-adhesive layer may further contain an excipient, a binder, a lubricant, a coloring agent, a flavoring agent, a fragrance, a surfactant, a sweetener, a preservative, a pharmacologically active ingredient, if necessary. May be blended. Furthermore, the non-adhesive layer can be a multilayer of two or more layers. When the non-adhesive layer is a multilayer, xylitol and / or erythritol may be blended in any of the layers.

Next, in the second sustained-release preparation of the present invention, the non-adhesive layer contains xylitol and / or erythritol and contains polyvinylpyrrolidone having an average molecular weight of 100,000 or less.

In this case, the content of xylitol and / or erythritol in the non-adhesive layer is 20 to 95.
%, Particularly preferably 30 to 90%. The reason is as described above.

The non-adhesive layer has an average molecular weight of 100,000 or less, preferably 2000 to 100,000, more preferably 50 to 100,000.
Polyvinylpyrrolidone in an amount of from 100,000 to 80,000 is contained, thereby giving a good initial release property and giving a good feeling of use without inconvenience such as increasing the viscosity of saliva in the mouth during use. It should be noted that no effect on the initial release property is recognized with polyvinylpyrrolidone or other water-soluble polymers having an average molecular weight exceeding 100,000.

The amount of the polyvinylpyrrolidone having an average molecular weight of 100,000 or less in the non-adhesive layer is 2 to 70%, particularly 2 to 50%. When the amount is too small, there is no effect on the initial release property, and when the amount is too large, the release property is reduced and sufficient sustained release property cannot be obtained. In addition, the viscosity of saliva increases during use, and the feeling of use decreases.

The other components that can be incorporated in the non-adhesive layer are the same as those in the non-adhesive layer of the first sustained-release preparation. If necessary, besides polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose or a salt thereof, alginic acid or a salt thereof, tragacanth gum, xanthan gum, carrageenan, tamarind gum, gellan gum, pullulan and the like Saccharides or derivatives thereof, collagen, water-soluble polymers such as gelatin or derivatives thereof, in addition to powder properties and moldability required for compression tableting, to further impart sustained release, swelling,
You may mix | blend in the range which does not affect a feeling of use, such as a feeling of strangeness by stickiness. However, the amount is 0-20
%, More preferably 0 to 15%. If it is more than 20%, the viscosity of saliva is increased due to swelling or dissolved polymer, and the feeling of use is deteriorated, which is not preferable.

When a water-soluble nonionic surfactant is contained in the non-adhesive layer, the initial release property is further improved, and the effect of controlling the release property is produced, whereby the sustained release property is obtained. The content of the non-adhesive layer is preferably 2 to 30%. If the content in the non-adhesive layer is small, the effect on the initial release property is not recognized, and if it is too large, the dissolution rate is too high, or the composition may disintegrate, so that the sustained release property may not be obtained. Examples of the water-soluble nonionic surfactant include water-soluble sucrose fatty acid ester, lactose fatty acid ester, lactitol fatty acid ester, maltitol fatty acid ester, monoglyceride stearate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monostearate. , Polyoxyethylene (40,
60,80,100 mol) hydrogenated castor oil, polyoxyethylene alkyl ether, polymer of ethylene oxide and propylene oxide and polyethylene oxide such as polyoxyethylene polyoxypropylene monolauryl ester, fatty acid, fatty alcohol, polyhydric alcohol and polypropylene Condensation products with oxides, alkylol amides and the like can be mentioned. Among them, a water-soluble sucrose fatty acid ester is preferably used in terms of taste, tablet moldability and the like.

Examples of the polymer as an adhesive component forming the second sustained-release preparation include pharmaceutically acceptable salts thereof such as polyacrylic acid, carboxyvinyl polymer and sodium polyacrylate. Or a copolymer of acrylic acid containing acrylic acid as a main component and further copolymerized with methacrylic acid, etc., polyacrylates such as polyhydroxyethyl acrylate, and hydrophilic vinyl polymers such as polyvinyl alcohol and polyvinylpyrrolidone. A hydrophilic cellulose derivative such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or a salt thereof;
Polysaccharides or derivatives thereof such as alginic acid or a salt thereof, tragacanth gum, xanthan gum, carrageenan, tamarind gum, gellan gum, pullulan;
Gelatin or a derivative thereof is exemplified. Among these polymers, sodium polyacrylate is suitably used in terms of mucoadhesiveness, tastelessness, and safety, and polyvinylpyrrolidone having an average molecular weight of 300,000 or more is also preferable. These polymers may be used alone or in admixture of two or more in the pressure-sensitive adhesive layer.
-100%, more preferably 5-100%. If the amount is small, the adhesiveness will not be exhibited. In addition, the molecular weight of these polymers is preferably as large as possible among the types of each polymer because the adhesiveness becomes strong.

The adhesive layer may contain xylitol and / or erythritol, if necessary. In this case, the content of xylitol and / or erythritol is 0 to 70%, preferably 0 to 60%. If the amount is too large, adhesion to the oral mucosa cannot be obtained.

In the adhesive layer, excipients, binders, lubricants, coloring agents, flavoring agents, flavors, surfactants, sweeteners,
Preservatives, pharmacologically active ingredients, and the like can be added, as in the first sustained-release preparation.

The sustained-release tablet for oral mucosa adherence of the present invention includes:
As described above, the purpose thereof, depending on the type of the composition, the adhesive layer, the non-adhesive layer, a known excipient, a binder, a lubricant, a coloring agent, a flavoring agent, a fragrance, a surfactant, Appropriate components such as sweeteners, preservatives, and pharmacologically active ingredients can be blended.

The known excipients used as needed here include, for example, crystalline cellulose, silicic anhydride, mannitol, sorbitol, anhydrous calcium phosphate and the like, and the binders include hydroxypropyl cellulose, carmellose sodium, polyvinyl alcohol, and the like. Polyvinylpyrrolidone, gelatin, tragacanth, sodium alginate, crystalline cellulose, etc., lubricating agents such as magnesium stearate, talc, stearic acid or a salt thereof, sucrose fatty acid ester, etc .;
No., as a flavoring agent such as titanium dioxide, citric acid,
Examples include fumaric acid, tartaric acid, menthol, and various flavors.

Examples of the surfactant include anionic surfactants, nonionic surfactants, amphoteric surfactants, and cationic surfactants. Specific examples include sodium lauryl sulfate, sucrose fatty acid ester, and lactose. Fatty acid ester, lactitol fatty acid ester, maltitol fatty acid ester, stearic acid monoglyceride, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene (10, 20, 40, 60, 80, 100 mol) curing Castor oil, polyoxyethylene alkyl ether, polymer of ethylene oxide and propylene oxide and polyethylene oxide such as polyoxyethylene polyoxypropylene monolauryl ester and fatty acids, fatty alcohols, polyhydric alcohols Condensation products of Lumpur and polypropylene oxide, alkylol amide, 2-alkyl -N- carboxymethyl -N- hydroxyethyl imidazolinium betaine.

Further, sweeteners include sodium saccharin, stevioside, stevia extract, paramethoxycinamic aldehyde, neohesperidyl dihydrochalcone, and perillartin, and preservatives include paraoxybenzoate and sodium benzoate.

The pharmacologically active ingredient further includes oral diseases such as prevention of bad breath, periodontal disease, xerostomia, pharyngeal diseases such as inflammation of the throat, dental diseases such as prevention of dental caries and hyperesthesia, and controlled release. There are pharmacological components for treating systemic diseases that are expected to increase the therapeutic effect.

Examples of pharmacological components for oral diseases, pharyngeal diseases, and dental diseases include copper compounds such as sodium copper chlorophyllin and copper gluconate, bad breath preventing components such as tea polyphenols and flavonoids, cetylpyridinium chloride, and the like.
Chlorhexidine hydrochloride, decalinium chloride, chlorhexidine gluconate, bactericides such as chloromethyl gluconate, isopropyl methylphenol, pharmacologic components for stomatitis such as sicon extract, triamcinolone acetonide, cephalexin, tetracycline hydrochloride, minocycline hydrochloride, pharmacological components for gingivitis such as fradiomycin, Procaine hydrochloride, tetracaine hydrochloride, dibucaine hydrochloride, benzocaine, prostaglandin F2, indomethacin, ibuprofen, lysozyme chloride, dextranase, sodium fluoride, potassium fluoride, ammonium fluoride, stannous fluoride,
Fluoride such as sodium monofluorophosphate, potassium salt of orthophosphoric acid, water-soluble phosphoric acid compound such as sodium salt, allantoin, allantoinchlorohydroxyaluminum, glycyrrhizic acid and its salts, sodium chloride, tranexamic acid, epsilon aminocaproic acid,
Dl-tocopherol acetate, α-bisabolol, azulene, glycyrrhetinic acid, aluminum lactate, strontium chloride, potassium nitrate, berberine, hydroxamic acid and its derivatives, sodium tripolyphosphate, zeolite, dextranase, mutanase, amylase, epidihydrocholesterin, dihydro Cholesterol, trichlorocarbanilide, zinc citrate, soft corn extract,
Oak extract, clove, rosemary, ogre,
Examples include extracts such as safflower, terpenes such as l-menthol, carvone, anethole, limonene, and derivatives thereof.

In this case, particularly when the tablet of the present invention is used as a therapeutic agent for periodontal disease, it is more preferable that at least one of the tablets contains an antibacterial agent. Antibacterial agents include quaternary ammonium compounds such as benzethonium chloride, benzalkonium chloride, decalinium chloride, and cetylpyridinium chloride; bactericides such as chlorhexidines and triclosan; and antibiotics such as minocycline hydrochloride, cephalexin, tetracycline hydrochloride, and fradiomycin. In particular, a quaternary ammonium compound cetylpyridinium chloride is a water-soluble powder, bitter,
The present invention is preferable in that it has little off-taste.

The pharmacological components for treating systemic diseases include antianginal drugs such as nitroglycerin, isosorbide dinitrate and nifedipine; inotropic drugs such as digitalis and digoxin;
Anti-asthmatic drugs such as sodium cromoglycate; antibiotics such as erythromycin; chemotherapeutic drugs such as sulfathiazole and nitrofurazone; antitussive expectorants such as codeine phosphate and isoproterenol hydrochloride; diphenhydramine hydrochloride; chlorpheniramine maleate; Antihistamines and the like. Furthermore, it is applied to pharmacological components such as steroids, non-steroids, sex hormones, antineoplastic drugs, neuropsychiatric diseases, respiratory diseases and the like.

The amounts of these components can be set as usual within a range not to impair the effects of the present invention.

The oral mucosa-adhered sustained-release tablet of the present invention has a moderate soft feel to the contact mucosa, and when applied to the oral cavity, the saliva in the oral cavity causes the polymer in the adhesive layer to absorb moisture. When it swells, especially when it contains xylitol or erythritol, it not only releases the components and cools the affected area, but also develops adhesiveness to immobilize the preparation on mucous membranes. The non-adhesive layer does not adhere to mucous membranes, so there is little foreign body sensation.Slowly dissolving from the surface expresses the release and cooling of the components, while the sustained release effectively releases the drug to the affected area To Moreover, since the non-adhesive layer is not peeled off from the adhesive layer during oral application or disintegrates, it gradually dissolves and disappears from the surface of the non-adhesive layer while maintaining its shape,
It can achieve sustained release and long-term retention. In the case of a single-layer tablet, if the oral mucosal adhesion is emphasized, it adheres to both sides of the administered site, causing a strong sense of discomfort and cannot be applied for a long period of time. Can not.

Finally, after all the non-adhesive layer is dissolved and disappears, the adhered and swollen adhesive layer basically dissolves and disappears. Therefore, it is basically preferable that all the constituents are water-soluble, but from the viewpoint of tableting formability and shape retention in the mouth, poorly water-soluble or insoluble components may be blended.

In the present invention, it is optional to form or coat a more rapidly soluble non-adhesive layer on the non-adhesive layer.

The shape of the tablet may be any of a circle, a flat, a cablet, a bar and a column. Each tablet weighs 0.05 to 1 g, particularly 0.1 to 0.7 g.
g is preferable, especially in the case of a therapeutic agent for periodontal disease, from 0.05 to
0.5 g, especially 0.1 to 0.3 g, is preferred. 0.05
If it is less than g, the duration is too short, and if it is more than 1 g, the required area in the oral cavity may be too large, or the thickness may be large and the feeling of foreign substances may be too strong. In this case, although the ratio of the adhesive layer to the non-adhesive layer is appropriately selected, the former: the latter = 2: 98
It is preferably from 90:10, particularly preferably from 2:98 to 80:20 (weight ratio).

The sustained-release tablet for oral mucosa of the present invention has excellent characteristics as described above, and can be produced, for example, as follows.

Adhesive polymer powder for oral mucosa, and one or more of xylitol and / or erythritol added as needed, flavoring agents, binders, lubricants, excipients, pharmacologically active ingredients, etc. Is thoroughly mixed to form a uniform mixture to form an adhesive layer, while xylitol and / or erythritol, and flavoring agents, binders, lubricants, excipients, pharmacologically active ingredients and the like added as needed. One or two or more are sufficiently mixed to form a uniform mixture to be a non-adhesive layer. Then, an appropriate amount of the uniform mixture to be the non-adhesive layer is placed on an appropriate amount of the uniform mixture to be the adhesive layer, and a method of directly pressing and molding using a punch, a die, and a press, or an appropriate increase of each layer is performed. By a method of press molding through a granulation step, an oral mucosa-adhered sustained-release tablet having two or more layers of an oral mucosa-containing adhesive layer and a non-adhesive layer containing xylitol and / or erythritol can be easily produced. At this time, an appropriate amount of the uniform mixture serving as the adhesive layer is pressed, and then an appropriate amount of the uniform mixture serving as the non-adhesive layer is placed thereon, and the mixture may be pressure-formed using a punch, a die, and a press. .

Usually, it is preferable that the uniform mixture of the respective layers before the pressure molding be a fine powder. By making the powder into a fine powder, the compressed tablet does not disintegrate when applied to the oral cavity and dissolves. Easier to do.

[0054]

According to the first sustained-release tablet of the present invention, the adhesive layer to the oral mucosa contains xylitol and / or erythritol containing polyvinylpyrrolidone having an average molecular weight of 300,000 or more. Continue to feel a pleasant cooling sensation in the affected area after adhering, there is almost no swelling,
The viscosity of saliva increases due to dissolution, and there is no off-taste, after the non-adhesive layer is completely dissolved and disappeared, the adhesive layer dissolves and disappears without expressing discomfort and off-taste such as stickiness and increased viscosity of saliva, In addition, it stays on for a sufficient time, releases it continuously,
The feeling of use is good, for example, a refreshing feeling in the oral cavity continues until the tablet disappears during use.

Further, the second sustained-release tablet of the present invention for oral mucosa is characterized in that the non-adhesive layer contains xylitol and / or erythritol containing polyvinylpyrrolidone having an average molecular weight of 100,000 or less, so that the release from the initial stage is improved. It is good, saliva does not become too viscous during use, it does not become uncomfortable, and it stays for a sufficient time, releases it continuously, keeps feeling cool during that time, good feeling of use such as maintaining a refreshing feeling in the oral cavity .

Further, all tablets do not peel off the non-adhesive layer from the adhesive layer during application to the oral cavity and do not disintegrate, so that they can be used for a long time and may cause dental caries. With no safety, it can be used as a new sustained-release tablet base for oral mucosa. That is, based on the oral mucosa-attached sustained-release tablet of the present invention, further, prevention of bad breath, oral diseases such as periodontal disease, pharyngeal diseases such as inflammation of the throat, caries prevention, dental diseases such as hyperesthesia, By combining a pharmacological component for treating systemic diseases and the like, which is expected to further increase the therapeutic effect due to sustained release, it is possible to administer the drug over a long period of time without causing pain to the patient as ever. And an excellent effect can be expected without any trouble in interpersonal relationships.

[0057]

EXAMPLES Hereinafter, the effects of the present invention will be described specifically with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. In addition, all% in each example are weight%.

Examples 1 to 4 and Comparative Examples 1 to 16 The powders of the respective layers having the following formulations were mixed well to obtain uniform fine powders. 0.05 g of the powder for the adhesive layer was used as a lower layer raw material, and 0.45 g of the powder for a non-adhesive layer was used as an upper layer raw material, and pressed to prepare a disk-shaped two-layer tablet of about 0.5 g having a diameter of 10 mm.

Each of the tablets was administered between the lower buccal mucosa in the oral cavity and the gingiva of the ten subjects, and the adhesive layer side was administered as the gingival surface, and evaluated. The results are shown in Table 1 as average values. Oral mucosa adhesive layer Water-soluble polymer listed in Table 1 Set amount Perfume 2 xylitol Balance 100% Oral mucosal non-adhesive layer Xylitol 60% Flavor 2 Sucrose fatty acid ester 10 hydroxypropylcellulose 28 100%

[0060]

[Table 1] Evaluation criteria: 1 Very bad 2 Bad 3 Somewhat bad 4 Good 5 Very good

The oral mucosa-adhered sustained-release tablet of the present invention shows good adhesion to the oral mucosa, little swelling, no increase in saliva viscosity, foreign body sensation, and off-taste, as shown in Examples 1-4. It is understood that the sample has a low feeling and has a good feeling of use. In addition, the non-adhesive layer does not peel off from the adhesive layer during use and does not collapse and release at once, so it can withstand long-term use,
It has been found that it allows for administration over a suitably long period of time without causing pain to the subject. In addition, since it has safety without fear of inducing dental caries, it is understood that it can be used as a new sustained-release tablet base for oral mucosa for oral diseases.

Example 5 Oral Mucosa Adhesive Layer Xylitol 30% Fragrance 2 Polyvinylpyrrolidone (Molecular Weight 360,000) 68 100% Oral Mucosa Non-Adhesive Layer Xylitol 80% Fragrance 2 Hydroxypropylcellulose 18 100% Same as in Example 1. Then, pressure-molding was performed using 0.1 g of the powder for the adhesive layer as the lower raw material and 0.4 g of the powder for the non-adhesive layer as the upper raw material to obtain about 0.5 g of a two-layer tablet. As a result of administering this into the oral cavity of the subject in the same manner as in Example 1, the results showed that all 10 adhered to the oral mucosa, had little swelling, had little increase in the viscosity of saliva, had a low foreign body sensation, and had a low taste. It had a good feeling of use, and continued to feel cool and moderately good sweetness due to the release of the components, and a refreshing state in the oral cavity was maintained. During this time, the non-adhesive layer stayed without peeling or collapsing from the adhesive layer, and a good feeling of use was maintained until all the components were dissolved and disappeared. Residence time to disappearance averaged about 2.5 hours.

Example 6 Oral Mucoadhesive Layer Xylitol 10% Fragrance 2 Polyvinylpyrrolidone (Molecular Weight 360,000) 88 100% Oral Mucosal Nonadhesive Layer Xylitol 30% Fragrance 2 D-sorbitol 28 Sucrose Fatty Acid Ester 10 Hydroxypropyl Cellulose 30 100 % In the same manner as in Example 1, 0.25 g of the powder for the adhesive layer was used as the lower raw material, and 0.25 g of the powder for the non-adhesive layer was used as the upper raw material, and pressed to obtain about 0.5 g of a two-layer tablet. Was. As a result of administering this to the oral cavity of the subject in the same manner as in Example 1,
0 people adhere to the oral mucosa and have little swelling,
The increase in the viscosity of saliva was small, the foreign body sensation and off-taste were low, and it had a good feeling of use. By releasing the components, it continued to feel a cooling sensation and a moderately good sweetness, and a refreshing state in the oral cavity was maintained.
During this time, the non-adhesive layer stayed without peeling or collapsing from the adhesive layer, and a good feeling of use was maintained until all the components were dissolved and disappeared. Residence time to disappearance averaged about 3.5 hours.

Example 7 Oral Mucoadhesive Layer Xylitol 28% Fragrance 2 Polyvinylpyrrolidone (Molecular Weight 360,000) 70 100% Oral Mucosa Non-Adhesive Layer Xylitol 95% Fragrance 2 Magnesium Stearate 0.5 Talc 2.5 100% In the same manner as in Example 1, 0.05 g of the powder for the adhesive layer was used as the lower layer raw material, and 0.45 g of the powder for the non-adhesive layer was used as the upper layer raw material, and pressed to obtain about 0.5 g of a two-layer tablet. As a result of administering this to the oral cavity of the subject in the same manner as in Example 1,
0 people adhere to the oral mucosa and have little swelling,
The increase in the viscosity of saliva was small, the foreign body sensation and off-taste were low, and it had a good feeling of use. By releasing the components, it continued to feel a cooling sensation and a moderately good sweetness, and a refreshing state in the oral cavity was maintained.
During this time, the non-adhesive layer stayed without peeling or collapsing from the adhesive layer, and a good feeling of use was maintained until all the components were dissolved and disappeared. Residence time to disappearance averaged about 2 hours.

[Comparative Example 17] Using 0.5 g of the powder for an adhesive layer of Example 5, a single-layer tablet of about 0.5 g was obtained by pressure molding. As a result of administering the compound to the oral cavity of the subject in the same manner as in Example 1, as a result, all 10 persons adhered to both surfaces of the oral mucosal administration site, and had a strong foreign-body sensation, and could not achieve the intended function.

[Example 8] Bad breath inhibitor Oral mucosa adhesive layer Xylitol 30% fragrance 2 Flavonoid 0.95 cetylpyridinium chloride 0.05 polyvinylpyrrolidone (molecular weight 360,000) 67 100% Oral mucosa non-adhesive layer Xylitol 80% fragrance 2 Copper chlorophyllin sodium 8 Flavonoid 0.95 Cetylpyridinium chloride 0.05 Magnesium stearate 0.5 D-sorbitol 8.5 100% In the same manner as in Example 1, 0.1 g of the powder for the adhesive layer was used as the lower layer raw material. The powder for the adhesive layer was subjected to pressure molding using 0.4 g of the upper layer raw material to obtain about 0.5 g of a two-layer tablet. As a result of administering this into the oral cavity of the subject in the same manner as in Example 1, the results showed that all 10 adhered to the oral mucosa, had little swelling, had little increase in the viscosity of saliva, had a low foreign body sensation, and had a low taste. It had a good feeling of use, and continued to feel cool and moderately good sweetness due to the release of components, effectively preventing bad breath in the oral cavity and maintaining a refreshing state. During this time, the non-adhesive layer stayed without peeling or collapsing from the adhesive layer, and a good feeling of use was maintained until all the components were dissolved and disappeared. Residence time to disappearance averaged about 2 hours.

Example 9 Throat Drug Oral Mucoadhesive Layer Xylitol 30% Fragrance 2 Decalinium Chloride 0.1 Dipotassium Glycyrrhizinate 0.4 Chlorpheniramine Maleate 0.6 Lysozyme Chloride 0.4 Polyvinylpyrrolidone (Molecular Weight 360,000) 66.5 100% Non-adhesive layer of oral mucosa Xylitol 80% Fragrance 2 Decalinium chloride 0.1 Dipotassium glycyrrhizinate 0.4 Chlorpheniramine maleate 0.6 Lysozyme chloride 0.4 Sodium azulene sulfonate 0.5 Stearic acid Magnesium 0.5 hydroxypropylcellulose 15.5 100% In the same manner as in Example 1, pressure molding was performed using 0.1 g of the powder for the adhesive layer as the lower raw material and 0.4 g of the powder for the non-adhesive layer as the upper raw material. , About 0.5 g of a two-layer tablet.

Example 10 Drug for Stomatitis Oral Mucoadhesive Layer Xylitol 20% Fragrance 2 Triamcinolone Acetonide 0.025 Magnesium Stearate 0.5 Polyvinylpyrrolidone (Molecular Weight 360,000) 77.475 100% Oral Mucosa Non-Adhesive Layer Xylitol 70% Fragrance 2 Yellow No. 5 Trace amount of magnesium stearate 0.5 Sucrose fatty acid ester 5 hydroxypropylcellulose 22.5 100% In the same manner as in Example 1, 0.1 g of powder for the adhesive layer was used as the lower raw material, and the non-adhesive layer was used. 0.1 g of the powder for use was press-molded as the upper layer raw material to obtain about 0.2 g of a two-layer tablet.

Example 11 Treatment Agent for Periodontal Disease Oral Mucoadhesive Layer Xylitol 30% Fragrance 2 Cetylpyridinium Chloride 0.05 Dipotassium Glycyrrhizinate 0.4 Hinokitiol 0.15 Tocopherol Acetate 0.2 Lysozyme Chloride 0.2 Polyvinyl Pyrrolidone (molecular weight 360,000) 67 100% Non-adhesive layer for oral mucosa Xylitol 80% Flavor 2 Cetylpyridinium chloride 0.05 Dipotassium glycyrrhizinate 0.4 Hinokitiol 0.15 Tocopherol acetate 0.2 Lysozyme chloride 0.2 Magnesium stearate 0 0.5 hydroxypropylcellulose 16.5 100% In the same manner as in Example 1, pressure molding was performed using 0.1 g of the powder for the adhesive layer as the lower layer raw material and 0.4 g of the powder for the non-adhesive layer as the upper layer raw material. 0.5 g of a two-layer tablet was obtained.

[Examples 12 to 16, Comparative Examples 18 to 30]
Using a mixed powder having the following formulation, pressure molding was performed to prepare a disk-shaped bilayer tablet having a diameter of 10 mm and having an adhesive layer and a non-adhesive layer for the oral mucosa. Each tablet was administered between the lower buccal mucosa in the oral cavity and the gingiva of the 10 subjects, and the adhesive layer side was administered as the gingival surface, and evaluated. The results are shown in Table 2 as average values. Oral mucosa adhesive layer Xylitol 70% Fragrance 2 Sodium polyacrylate 28 100% Oral mucosa non-adhesive layer Set amount of water-soluble polymer described in Table 2 Perfume 2 Xylitol Balance 100% Powder of each layer is mixed well and uniform fine powder Body.
The powder for the adhesive layer was formed into a lower layer by using 0.05 g of the powder, and the powder for the non-adhesive layer was formed by using 0.45 g of the upper layer as a pressure material.
5 g of a bilayer tablet were obtained.

[0071]

[Table 2] Evaluation criteria: 1 Very bad 2 Bad 3 Somewhat bad 4 Good 5 Very good

The oral mucosa-adhered sustained-release tablet of the present invention has a lower foreign-body sensation, a better release property immediately after adhering, a good feeling of use, and a sufficient retention time as compared with Examples 12 to 16. , Sustained release, while continuing to feel a cool feeling, the feeling of freshness in the oral cavity is maintained, the feeling of use is better than ever, and the non-adhesive layer peels off from the adhesive layer or collapses during use It can be seen that the drug is not released at a stroke, and therefore can be used for a long time and can be suitably administered for a long time without causing any pain to the subject. In addition, since it has safety without fear of inducing dental caries, it is understood that it can be used as a new oral mucosa-adhesive sustained-release tablet base.

Example 17 Oral Mucosa Adhesive Layer Xylitol 70% Fragrance 2 Sodium Polyacrylate 28 100% Oral Mucosa Non-Adhesive Layer Xylitol 70% Fragrance 2 Water Soluble Sucrose Fatty Acid Ester 10 Polyvinylpyrrolidone (Average Molecular Weight 40,000) 18 100 % In the same manner as in Example 12, pressure molding was performed using 0.05 g of the powder for the adhesive layer as the lower raw material and 0.45 g of the powder for the non-adhesive layer as the upper raw material to obtain about 0.5 g of a two-layer tablet. Was. Example 12
As a result of administering this to the oral cavity of the subject in the same manner as described above, all of the ten subjects had good release properties immediately after being attached to the oral mucosa, felt a refreshing sweetness and cooling feeling, and exhibited a good feeling of use, The sensation of foreign bodies was low, and the release of the components continued to provide a cooling sensation of uniform strength and a moderately good sweetness, and a refreshing state in the oral cavity was maintained. In the meantime, the non-adhesive layer stayed without peeling off or disintegrating from the adhesive layer and dissolved and disappeared. Residence time to disappearance is about 2.
5 hours.

Example 18 Oral Mucosa Adhesive Layer Xylitol 70% Fragrance 2 Sodium Polyacrylate 28 100% Oral Mucosa Non-Adhesive Layer Xylitol 20% D-sorbitol 18 Perfume 2 Water-soluble Sucrose Fatty Acid Ester 10 Polyvinylpyrrolidone (Average Molecular Weight 4 In the same manner as in Example 12, 0.25 g of the powder for the adhesive layer was used as the lower raw material, and 0.25 g of the powder for the non-adhesive layer was used as the upper raw material. A layer tablet was obtained. Example 12
As a result of administering this to the oral cavity of the subject in the same manner as described above, all of the ten subjects had good release properties immediately after being attached to the oral mucosa, felt a refreshing sweetness and cooling feeling, and exhibited a good feeling of use, The sensation of foreign bodies was low, and the release of the components continued to provide a cooling sensation of uniform strength and a moderately good sweetness, and a refreshing state in the oral cavity was maintained. In the meantime, the non-adhesive layer stayed without peeling off or disintegrating from the adhesive layer and dissolved and disappeared. The average residence time before disappearance is about 3.
5 hours.

Comparative Example 31 Oral Mucoadhesive Layer Xylitol 70% Fragrance 2 Sodium Polyacrylate 28 100% Oral Mucosal Non-Adhesive Layer Xylitol 70% Fragrance 2 Water-Soluble Sucrose Fatty Acid Ester 28 100% In the same manner as in Example 12, Pressure-molding was performed using 0.25 g of the powder for the adhesive layer as the lower raw material and 0.25 g of the powder for the non-adhesive layer as the upper raw material to obtain about 0.5 g of a two-layer tablet. Example 12
As a result of administration of this into the oral cavity of the subject in the same manner as described above, no sweetness and cooling sensation were felt immediately after all of the ten subjects had adhered to the oral mucosa, and the cooling sensation was moderate and good after an average of about 10 minutes. The sweetness was felt, and the refreshing state in the mouth continued.
In the meantime, the non-adhesive layer stayed without peeling off or disintegrating from the adhesive layer and dissolved and disappeared. Residence time to disappearance averaged about 1.5 hours. Therefore, the initial release was poor, and the satisfaction in that point was low.

Comparative Example 32 Oral Mucosa Adhesive Layer Xylitol 70% Fragrance 2 Sodium Polyacrylate 28 100% Oral Mucosa Non-Adhesive Layer Xylitol 80% Fragrance 2 Polyvinylpyrrolidone (Molecular Weight 360,000) 18 100% Same as Example 12 Then, 0.25 g of the powder for the adhesive layer was used as the lower layer raw material, and 0.25 g of the powder for the non-adhesive layer was used as the upper layer raw material, and pressed to obtain about 0.5 g of a two-layer tablet. Example 12
As a result of administering this to the oral cavity of the subject in the same manner as above, all of the 10 subjects adhered to the oral mucosa, but also adhered to the buccal mucosa side, the feeling of foreign substances was extremely strong, and the refreshment in the oral cavity was not obtained, Not suitable for prolonged use. Residence time to disappearance averaged about 3.5 hours.

Comparative Example 33 Oral Mucosa Adhesive Layer Xylitol 70% Fragrance 2 Sodium Polyacrylate 28 100% Oral Mucosa Non-Adhesive Layer Xylitol 80% Fragrance 2 Hydroxypropyl Cellulose 18 100% Similar to Example 12, Adhesive Layer The lower layer raw material was used as a lower layer raw material, and the non-adhesive layer powder, 0.45 g, as an upper layer raw material, was pressed and molded to obtain about 0.5 g of a two-layer tablet. Example 12
In the same manner as described above, this was administered into the oral cavity of the test subjects. As a result, immediately after adhering to the oral mucosa, the sweet taste and cooling sensation were not felt, the foreign body sensation was strong, and the cooling sensation was greater than after about 10 minutes on average. A moderate and good sweetness was felt, and a refreshing state in the oral cavity was maintained. In the meantime, the non-adhesive layer stayed without peeling off or disintegrating from the adhesive layer and dissolved and disappeared. Residence time to disappearance averaged about 2.5 hours. Therefore, the initial release was poor, and the satisfaction in that point was low.

Example 19 Bad Breath Suppressant Oral Mucosa Adhesive Layer Xylitol 50% Fragrance 2 Flavonoid 0.95 Cetylpyridinium Chloride 0.05 Sodium Polyacrylate 47 100% Oral Mucosa Non-Adhesive Layer Xylitol 70% Fragrance 2 Copper Chlorophyrin Sodium 8 Flavonoid 0.95 Cetylpyridinium chloride 0.05 Magnesium stearate 0.5 Water-soluble sucrose fatty acid ester 8.5 Polyvinylpyrrolidone (average molecular weight 40,000) 10 100% In the same manner as in Example 12, powder for adhesive layer 0 0.1 g was used as a lower layer raw material, and 0.4 g of the non-adhesive layer powder was used as an upper layer raw material to perform pressure molding to obtain about 0.5 g of a two-layer tablet. As a result of administering the compound to the oral cavity of the subject in the same manner as in Example 12, the result was 1
All 0 patients adhere to the oral mucosa, have a low foreign body sensation, have a good release property immediately after adhesion, develop a good feeling of use, and continue to feel cool and moderately good sweetness by releasing the components, Halitosis was effectively prevented and the refreshing state was maintained. In the meantime, the non-adhesive layer stayed without peeling off or disintegrating from the adhesive layer and dissolved and disappeared. Residence time to disappearance averaged about 2.5 hours.

Example 20 Throat Drug Oral Mucoadhesive Layer Xylitol 50% Fragrance 2 Decalinium Chloride 0.1 Dipotassium Glycyrrhizinate 0.4 Chlorpheniramine Maleate 0.6 Lysozyme Chloride 0.4 Sodium Polyacrylate 46. 5 100% non-adhesive layer of oral mucosa xylitol 80% fragrance 2 decalinium chloride 0.1 dipotassium glycyrrhizinate 0.4 chlorpheniramine maleate 0.6 lysozyme chloride 0.4 sodium azulene sulfonate 0.5 magnesium stearate 0. 5 Polyvinylpyrrolidone (average molecular weight 40,000) 15.5 100% In the same manner as in Example 12, 0.1 g of the powder for the adhesive layer was used as the lower raw material, and 0.4 g of the non-adhesive layer powder was used as the upper raw material. The mixture was molded to obtain about 0.5 g of a two-layer tablet.

Example 21 Stomatitis Drug Oral Mucoadhesive Layer Xylitol 50% Fragrance 2 Triamcinolone Acetonide 0.025 Magnesium Stearate 0.5 Sodium Polyacrylate 47.475 100% Oral Mucosa Non-Adhesive Layer Xylitol 70% Fragrance 2 Yellow No. 5 Trace amount of magnesium stearate 0.5 Water-soluble sucrose fatty acid ester 5 Polyvinylpyrrolidone (average molecular weight 40,000) 22.5 100% In the same manner as in Example 12, 0.1 g of the powder for the adhesive layer was used as the lower layer raw material. Then, 0.1 g of the powder for the non-adhesive layer was pressure-formed using the upper layer raw material to obtain about 0.2 g of a two-layer tablet.

Example 22 Periodontal Disease Remedy Oral Mucoadhesive Layer Xylitol 50% Fragrance 2 Cetylpyridinium Chloride 0.05 Dipotassium Glycyrrhizinate 0.4 Hinokitiol 0.15 Tocopherol Acetate 0.2 Lysozyme Chloride 0.2 Poly Sodium acrylate 47 100% Non-adhesive layer for oral mucosa Xylitol 80% Fragrance 2 Cetylpyridinium chloride 0.05 Dipotassium glycyrrhizinate 0.4 Hinokitiol 0.15 Tocopherol acetate 0.2 Lysozyme chloride 0.2 Magnesium stearate 0.5 Sucrose Fatty acid ester 6.5 Polyvinylpyrrolidone (average molecular weight 40,000) 10 100% In the same manner as in Example 12, 0.1 g of the powder for the adhesive layer was used as the lower raw material, and 0.4 g of the non-adhesive layer powder was used as the upper raw material. Formed under pressure, about 0.5g double-layer tablet I got

[Example 23] Angina pectoris Oral mucosa adhesive layer Xylitol 50% Fragrance 2 Isosorbide dinitrate 2 Magnesium stearate 0.5 Sodium polyacrylate 45.5 100% Oral mucosa non-adhesive layer Xylitol 70% Flavor 2 Nitric acid Isosorbide 2 Magnesium stearate 0.5 Polyvinylpyrrolidone (average molecular weight 40,000) 25.5 100% In the same manner as in Example 12, 0.1 g of the powder for the adhesive layer was used as the lower layer raw material, and 0.1% of the powder for the non-adhesive layer was used. 4 g of the upper layer raw material was pressure-molded to obtain about 0.5 g of a two-layer tablet.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA40 AA94 BB22 CC03 CC23 CC31 CC50 DD38 DD68 EE16 EE32 FF31 FF52 FF67 FF70 4C083 AB432 AC131 AC132 AC242 AC692 AC782 AC842 AC932 AD071 AD072 AD092 AD192 AD282 AD472 CC492 AD532 AD662

Claims (2)

[Claims] 1. A sustained-release tablet having an adhesive layer and a non-adhesive layer for the oral mucosa, wherein the adhesive layer contains xylitol and / or erythritol and contains polyvinylpyrrolidone having an average molecular weight of 300,000 or more in the adhesive layer. ~
An oral mucosa-adhered sustained-release tablet characterized by containing 95% by weight. 2. A sustained-release tablet having an adhesive layer and a non-adhesive layer for the oral mucosa, wherein the non-adhesive layer contains xylitol and / or erythritol and contains polyvinylpyrrolidone having an average molecular weight of 100,000 or less. Middle 2
An oral mucosa-adhered sustained-release tablet, characterized in that it contains about 70% by weight.