JPWO2008026310A1 - Trehalose-containing oral mucosa protective agent - Google Patents

Abstract

An object of the present invention is to provide an oral mucosal protective agent for protecting the mucous membrane in the oral cavity from dry stimulation. The above-mentioned problem is basically solved by an oral mucosa protective agent containing trehalose as an active ingredient in an effective amount. As demonstrated by the examples, according to the oral mucosa protective agent of the present invention, it is possible to effectively prevent the situation where the oral cavity dries. The situation where it is damaged by the stimulus can be prevented. [Selection figure] None

Description

  The present invention relates to an oral mucosal protective agent for protecting the mucous membrane in the oral cavity containing trehalose as an active ingredient. More specifically, the present invention relates to a protective agent for oral mucosa, which is effective as a therapeutic or prophylactic agent for xerostomia or dry mice, which protects tissues from drought stimulation with trehalose.

  Since saliva contains various bacteria, in oral surgery such as implant placement, treatment is generally performed while aspirating saliva. Therefore, during the operation, the oral cavity including the wound is dry. In other words, the oral mucosa is damaged by oxidative stress due to dryness caused by exposure to air. Therefore, a mucosal protective agent for protecting the mucous membrane in the oral cavity from drying during the treatment is desired.

  Also, in daily life, when salivary secretion decreases, the self-cleaning action decreases and the mucosal lubrication action decreases, so that the oral cavity dries, causing various symptoms such as mucosal damage, the occurrence of dental caries and periodontal disease. Will occur. In particular, dryness in the oral cavity is caused by diseases such as Siegren's syndrome and rheumatism, side effects caused by drugs and radiotherapy, decreased saliva due to aging, and mouth breathing. Therefore, a therapeutic or prophylactic agent for xerostomia or dry mouth is desired.

  Dry mucous membranes are vulnerable to physical irritation. Therefore, for patients using dentures (dentures), trauma ulcers may be caused by the damage caused by the dentures when the oral cavity is dry. Therefore, an agent that prevents dryness in the oral cavity is desired particularly for patients who use dentures.

  Patent No. 3,418,423 (Patent Document 1) relates to a pharmaceutical composition for transmucosal administration, and claim 1 includes “containing trehalose, ointment, cream, gel cream, lotion, aerosol, liquid, An invention consisting of “a pharmaceutical composition for transmucosal administration, characterized in that it is a dosage form selected from the group consisting of suppositories” is described. That is, claim 1 of Japanese Patent No. 3,418,423 includes “a pharmaceutical composition for transmucosal administration containing trehalose and being a liquid”. However, the invention disclosed in the publication is intended to alleviate irritation when a hormone is administered from the nasal cavity, and is not intended for oral administration. Trehalose is incorporated in a pharmaceutical composition for transmucosal administration (paragraph 0006 of the same publication), and trehalose is not a physiologically active substance (paragraph 0010 of the publication).

  Japanese Patent Application Laid-Open No. 2002-308783 (Patent Document 2) discloses that trehalose is used as a saccharide for “a pharmaceutical composition for preventing or treating skin or mucosal diseases” (claim 3, paragraph 0007). However, “the mechanism of action of sugars is to adjust the state of water in the composition of extracellular fluid or intercellular fluid, to supply monosaccharides that can become cytoplasmic energy such as glucose and fructose, and It is thought to be due to delaying the oxidative degradation of the intercellular fluid due to the reducing properties "(paragraph 0007). That is, in this publication, saccharides are considered to be an energy source, and there is no example using trehalose.

  JP-A-61-100512 (Patent Document 3) relates to “skin moisturizing composition and method”, which treats dry skin by topical application of a skin moisturizing composition containing an effective amount of trehalose. And / or found that skin dryness can be suppressed. "(Page 2, right lower column, lines 4 to 7). Japanese Patent Application Laid-Open No. 61-100512 discloses that trehalose is used only to prevent skin dryness. That is, trehalose has been suggested to prevent skin dryness, but there is no description or suggestion that it can protect the mucous membranes in the oral cavity from dryness.

  Japanese Patent No. 2,896,211 (Patent Document 4) relates to an edible composition for treating xerostomia containing xylitol as an active ingredient. However, the gazette in the publication basically prevents the oral cavity from drying by stimulating the secretion of saliva with a gum. In addition, xylitol, which is a sugar alcohol, and trehalose, which is a disaccharide, have completely different molecular structures and completely different physical properties except that they are sweeteners.

Japanese Patent No. 3,418,423 JP 2002-308783 A JP-A-61-100512 Japanese Patent No. 2,896,211

  An object of the present invention is to provide an oral mucosa protective agent for protecting the mucous membrane in the oral cavity from dry stimulation. Another object of the present invention is to provide an oral mucosa protective agent that is excellent in taste.

  An object of the present invention is to provide an oral mucosal protective agent for protecting the mucous membrane in the oral cavity from dry stimulation during treatment.

  An object of the present invention is to provide a therapeutic or prophylactic agent for xerostomia or dry mouth.

  An object of this invention is to provide the therapeutic agent or preventive agent of the traumatic ulcer by dentures.

  The present invention basically relates to an oral mucosa protective agent containing an effective amount of trehalose as an active ingredient. As demonstrated by the examples described later, according to the oral mucosal protective agent of the present invention, it is possible to effectively prevent a situation in which the oral cavity dries, so that the treated part and the surrounding mucous membrane are particularly dried during the treatment. This is based on the knowledge that damage caused by dry stimulation caused by can be prevented.

  According to the present invention, an agent containing an effective amount of trehalose as an active ingredient can effectively prevent a situation in which the oral cavity dries, so that it can effectively prevent suffering from xerostomia or dry mouth, It is based on the knowledge that it is effective in treating dry mouth or dry mice by moisturizing the mouth of patients suffering from dry mouth or dry mice. Since the oral mucosa protective agent of the present invention uses, for example, trehalose as an active ingredient, it can provide an oral mucosa protective agent with excellent taste.

  That is, the present invention basically relates to an oral mucosa protective agent for protecting the mucous membrane in the oral cavity containing trehalose or a pharmaceutically acceptable solvate thereof as an active ingredient. Trehalose plays a role in place of water in tissues or cells, and even when water is lost from tissues or cells, it is considered to protect cells from damage caused by drying.

  A preferred embodiment of the oral mucosa protective agent of the present invention is the above-described oral mucosa protective agent containing a thickener, and pullulan is preferred as the thickener. That is, because it contains a thickener, it can increase the adhesion of trehalose, which is an active ingredient, to the oral mucosa, increase the concentration of trehalose that stays in the mucosa, and lengthen the time that trehalose stays in the mucosa. . A preferred embodiment of the oral mucosa protective agent of the present invention is the oral mucosa protective agent described above containing a wetting agent, and since it contains a wetting agent, it is possible to prevent rapid transpiration of moisture against drying by abrupt air or the like. , It can reduce the changes in the oral mucosa, help trehalose penetrate into the mucosa, and lengthen the time that trehalose stays in the mucosa. A preferred embodiment of the oral mucosa protective agent of the present invention is the oral mucosa protective agent according to any one of the above, which contains an antioxidant. A preferred embodiment of the oral mucosa protective agent of the present invention is the oral mucosa protective agent according to any one of the above, containing an antibacterial agent.

  In a preferred embodiment of the oral mucosa protective agent of the present invention, the oral mucosa protective agent is a liquid agent, and the pH of the liquid agent is 5.7 to 8.5 (5.7 to 8.5, the same shall apply hereinafter). .) The oral mucosa protective agent according to any one of the above. The pH of the aqueous trehalose solution (30% aqueous solution) is 4.5 to 6.5. When the pH is 5.5 or lower, the enamel that protects the tooth surface generally melts and causes caries. Trehalose has low acid production in the oral cavity and does not produce insoluble glucan that contributes to caries. Trehalose also suppresses the adhesion of sugar-derived insoluble glucan by about 60%. Therefore, although there is little risk of progression of caries due to trehalose, since the agent of the present invention is also intended to be used without irritating the oral cavity with water or the like after administration, the dental caries will progress in the oral cavity. In order to prevent such a situation, it is preferable to set the acidity as described above.

  Preferred embodiments of the oral mucosa protective agent of the present invention include “menthol, anethole, peppermint oil, spearmint oil, methyl salicylate, eugenol, eucalyptol, limonene cetylpyridinium chloride, chlorhexidine gluconate, triclosan, isopropylmethylphenol, dipotassium glycyrrhizinate. Oral mucosa protection according to any one of the above, containing one or more compounds selected from the group consisting of sodium azulenesulfonate, decalinium chloride, lysozyme chloride, hinokitiol, sodium lauroyl sarcosine, lactoferrin, and paraben It is an agent. That is, the oral mucosal protective agent of the present invention preferably contains a fragrance component, a bactericidal agent, a saliva component (enzyme, glycoprotein), an anti-inflammatory agent or an antifungal agent, and the like, and the fragrance is adjusted.

  A preferred embodiment of the oral mucosa protective agent of the present invention is a spray solution (agent that sprays a drug solution toward a target site), a solution for spraying or vaporizing administration, a mouthwash, a mouthwash, a foam aerosol, a perfusate, or The oral mucosa protective agent according to any one of the above, which is an infusion pack containing solution. That is, the oral mucosa protective agent of the present invention can be made into a dosage form suitable for the purpose such as the target disease.

  A preferred embodiment of the oral mucosa protective agent of the present invention relates to the oral mucosa protective agent according to any one of the above, which is a therapeutic agent or prophylactic agent for xerostomia or a therapeutic agent or prophylactic agent for dry mice. That is, according to the oral mucosal protective agent of the present invention, it is possible to effectively prevent a situation in which the oral cavity dries. Therefore, it is possible to effectively prevent xerostomia or dry mouth, and to prevent dry mouth or dry mouth. Moisturizes the mouth of patients affected by mice and is effective in treating xerostomia or dry mice.

  The present invention also provides the use of trehalose for producing an oral mucosa protective agent. The present invention also includes a step of administering an oral mucosal protective agent containing an effective amount of trehalose to a subject, particularly a method for protecting the oral mucosa during treatment, a method for treating xerostomia or dry mouth, and xerostomia Also provided is a method for preventing illness or dry mice.

  ADVANTAGE OF THE INVENTION According to this invention, the oral mucosa protective agent for protecting the mucous membrane in an oral cavity from dry irritation can be provided. Since the oral mucosa protective agent of the present invention uses, for example, trehalose as an active ingredient, it can provide an oral mucosa protective agent with excellent taste.

  ADVANTAGE OF THE INVENTION According to this invention, the oral mucosa protective agent for protecting the mucous membrane in an oral cavity from the dry stimulus during a treatment can be provided.

  According to the present invention, a therapeutic or prophylactic agent for dry mouth or dry mice can be provided.

  ADVANTAGE OF THE INVENTION According to this invention, the therapeutic agent or preventive agent of the traumatic ulcer by dentures can be provided.

  The present invention basically relates to an oral mucosa protective agent containing an effective amount of trehalose or a pharmaceutically acceptable solvate thereof as an active ingredient. “Oral mucosa protective agent” means an agent that specifically protects the mucous membrane in the oral cavity from dry irritation. Since the oral mucosa protective agent of the present invention uses, for example, trehalose as an active ingredient, it can provide an oral mucosa protective agent with excellent taste.

  “Trehalose” means a non-reducing disaccharide in which two molecules of glucose are linked by 1,1. As trehalose, any trehalose such as hydrous crystal trehalose, anhydrous crystal trehalose, trehalose-containing sugar, α, α-trehalose (narrowly defined trehalose), α, β-trehalose (neotrehalose), β, β-trehalose (isotrehalose), etc. It can also be used. Among these, α, α-trehalose (α-D-glucopyranosyl α-D glycopyranoside) hydrated crystal trehalose or anhydrous crystal trehalose is preferable. Trehalose is known, and is described in, for example, Japanese Patent No. 3,515,456, “Process for preparing trehalose-containing hydrate by adding anhydrous crystalline trehalose and / or amorphous anhydrous trehalose to hydrated product, And a method of producing a trehalose-containing powder composition characterized by including a step of drying the prepared trehalose-containing hydrated product.

  “The pharmaceutically acceptable solvate” means a solvate of trehalose. A solvate of trehalose is trehalose dihydrate. In the present invention, it is expected that the tissue is protected from dry irritation and the like. However, an agent using trehalose dihydrate is preferable because it has a preferable tissue protecting ability. Examples of solvates include hydrates. Further, the compound of the present invention may absorb moisture, adhere to adsorbed water, or become a hydrate by being left in the atmosphere or recrystallized. The case where such a solvate is formed is also included in “the solvate”.

  “Active ingredient” means an ingredient having a function of protecting the mucous membrane in the oral cavity from dry irritation. In the present invention, trehalose is an active ingredient. However, active ingredients other than trehalose may be included as appropriate.

  “Effective amount” means the amount of trehalose effective to protect mucosal tissue and the like from drying irritation. Trehalose is generally contained in foods mainly as sweet additives, stabilizers, texture-improving agents and the like. Trehalose may also be added as a stabilizer in medicine. In the oral mucosal protective agent of the present invention, trehalose is used as a liquid agent for preventing tissue drying, and therefore it is preferable to add more trehalose than when it is added as a stabilizer in medicine. What is necessary is just to adjust suitably the weight of the trehalose contained in an oral mucosa protective agent according to a use. The trehalose content in the oral mucosa protective agent is 0.5 to 25% by weight, preferably 3 to 15% by weight. On the other hand, if the trehalose content is too high, the oral mucosal protective agent may feel extremely sweet, but the content of trehalose contained in the oral mucosal protective agent is 20% by weight in order to effectively prevent dry irritation. It may be ˜80 wt% or 25 wt% ˜50 wt%. However, if the oral mucosa protective agent is diluted with a solvent when used, the concentration may be adjusted as appropriate according to the degree of thinning.

  A preferred embodiment of the oral mucosa protective agent of the present invention relates to the oral mucosa protective agent according to any one of the above, which is a therapeutic agent or prophylactic agent for xerostomia or a therapeutic agent or prophylactic agent for dry mice. That is, according to the oral mucosal protective agent of the present invention, it is possible to effectively prevent a situation in which the oral cavity dries. Therefore, it is possible to effectively prevent the patient from suffering from xerostomia or dry mice. Moisturizes the mouth of patients affected by mice and is effective in treating xerostomia or dry mice.

  When the trehalose of the present invention is used as the above-mentioned therapeutic agent or prophylactic agent, it may be administered per se or in admixture with a pharmacologically acceptable carrier. Such an agent can be produced by a known method. Examples of the agent using the compound of the present invention include a spray, a liquid for spray administration, a liquid for vaporization administration, a mouthwash, a mouthwash, a foam aerosol, a perfusate, or an infusion pack. Here, the spray is an agent stored in a spray container and administered in a spray form. The liquid agent for spray administration is an agent that is contained in a container that is physically separated from the spray administration device, and is sprayed after being brought into a state suitable for spraying in the spray unit as necessary. The liquid agent for vaporization administration is an agent that is contained in a container that is physically separated from the vaporization administration unit, vaporized as necessary, and administered from the vaporization administration unit. The mouthwash means gargle and the like, but the mouthwash of the present invention may be discharged after washing the inside of the oral cavity, preventing drying in the oral cavity or moistening the oral cavity. It can be swallowed after being let down. In general, a cleaning agent is one that is discharged after the oral cavity has been cleaned. On the other hand, since the cleaning agent of the present invention basically contains only a compound having high biocompatibility, there is no problem even if it is swallowed. Therefore, a psychologically superior cleaning agent can be provided. An gargle is a liquid that is expelled after rinsing in the mouth. As a prophylactic or therapeutic agent for xerostomia or dry mouth, a liquid agent containing an effective amount of trehalose, particularly a liquid agent and a spray agent are preferable.

The agent of the present invention may appropriately contain a thickener, a wetting agent, a pH adjuster and the like. That is, a preferred embodiment of the oral mucosa protective agent of the present invention is the oral mucosa protective agent described above containing a thickener. As the thickener, a known pharmaceutically acceptable thickener can be appropriately used. As thickeners, “polysaccharides such as pullulan, guar gum, lambda carrageenan, tragacanth gum, pectin, mannan, methylcellulose, methylhydroxypropylcellulose, ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) , Carboxymethylcellulose, carboxymethylethylcellulose or salts thereof, crystalline cellulose, cellulose acetate, cellulose acetate phthalate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, powdered cellulose, etc., gum arabic , Galactan, agar, quince seed, wheat starch, rice starch, corn Si starch, potato starch, curdlan, xanthan gum, succinoglucan, dextran, hyaluronic acid, albumin, casein, collagen, gelatin, fibroin, carboxymethyl starch and its salts, croscarmellose and its salts, pregelatinized starch, partial alpha Starch, carboxymethyl starch, dextrin, methyl starch, sodium alginate, propylene glycol alginate, sodium chondroitin sulfate, sodium hyaluronate, carboxyvinyl polymer, sodium polyacrylate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, polyvinyl pyrrolidone, methacrylic Acid-ethyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, meta At least one selected from the group consisting of ethyl crylate / methacrylated trimethylammonium ethyl copolymer, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, hydrous silicon dioxide, light silicic anhydride, colloidal alumina, bentonite and laponite Species or two or more compounds. That is, because it contains a thickener, it can increase the adhesion of trehalose, which is an active ingredient, to the oral mucosa, increase the concentration of trehalose that stays in the mucosa, and lengthen the time that trehalose stays in the mucosa. . Of the above compounds, pullulan is preferred. This is because pullulan has the above-described action, has good compatibility with trehalose, and has the action of drastically enhancing the effect of protecting trehalose from drying stimulation, as demonstrated by the examples described later. For example, pullulan powder having an average molecular weight of 100,000 (trade name “Pullan PF-10”) and pullulan powder having an average molecular weight of 200,000 (trade names “Pullan PF-20” and “Pullan PI-20”) are commercially available. Yes. Any of these may be used. That is, the number average molecular weight of pullulan is 50,000 to 400,000 (50,000 to 400,000, the same applies hereinafter), preferably 150,000 to 250,000.

  The content of the thickener may be 5 to 100 parts by weight when trehalose is 100 parts by weight, may be 10 to 80 parts by weight, and more preferably 20 to 50 parts by weight. preferable. When using an oral mucosa protective agent as a liquid or spray, the viewpoint of securing an appropriate viscosity and obtaining good adhesion to mucosal tissues and the prevention of deterioration in jetting properties due to gel formation and jelly formation Therefore, the content in the liquid composition may be determined.

  A humectant is a compound added to moisten and moisturize tissue. Examples of the wetting agent include mucin, glycerin, propylene glycol, sorbitol, polyethylene glycol, and the like. As the wetting agent, one having excellent biocompatibility is desired. And since mucin is a moisturizer and moisturizer contained in saliva, it can be said to be physiologically desirable. Glycerin is preferable in terms of taste and safety. When the trehalose is 100 parts by weight, the content of the wetting agent is 5 to 100 parts by weight, and may be 10 to 80 parts by weight, and more preferably 20 to 60 parts by weight.

  Antioxidants are compounds that prevent tissue mucous membranes from being oxidized by oxygen in the air. As the oral mucosa protective agent of the present invention, those capable of reducing oxidative stimulation are preferable. Therefore, when the oral mucosa protective agent contains an antioxidant, it is possible to reduce oxidative stimulation and effectively prevent the liquid agent itself from being oxidized and deteriorated. As an antioxidant in the oral mucosa protective agent of the present invention, an ascorbic acid derivative is exemplified. As such an antioxidant, one having excellent stability and low irritation is desirable. From such a viewpoint, ascorbic acid glycoside is particularly preferable. The antioxidant should be contained in the oral mucosa protective agent in an amount generally contained in the liquid preparation.

An antibacterial agent means an antibacterial compound. In the oral cavity, about 1 × 10 ¹¹ bacteria are present in 1 gram of tissue. And there are countless pathogens in those bacteria, and when these pathogens enter the living body, the living body will be damaged. On the other hand, saliva contains substances having antibacterial action, such as lactoferrin and lysozyme, which inhibits the increase of bacteria. Therefore, as the antibacterial agent, lactoferrin or lysozyme that is contained in saliva and excellent in biocompatibility is preferable. In addition, lactoferrin has a function of binding to ferric ions in the oral cavity. Since ferric ions are necessary components for the growth of bacteria, oral mucosal protective agents containing lactoferrin induce a deficiency of ferric ions in the oral cavity, thereby It is thought that growth can be inhibited. On the other hand, lysozyme acts on the bacterial cell wall to break down the cell wall. And when the cell wall is broken down, the cells begin to lyse and eventually kill the bacteria. Therefore, an oral mucosal protective agent containing lysozyme is preferable because it can break down cell walls of cells and kill bacteria. As the antibacterial agent, a known disinfectant may be included, and specific examples include isopropylmethylphenol, shoji oil, thymol, chlorhexidine hydrochloride, cetylpyridinium chloride and the like. These antibacterial agents are preferably contained in an amount effective for exerting an antibacterial action.

  A preferred embodiment of the oral mucosa protective agent of the present invention is the oral mucosa protective agent according to any one of the above, wherein the oral mucosa protective agent is a liquid agent, and the pH of the liquid agent is 5.7 to 8.5. The pH of the aqueous trehalose solution (30% aqueous solution) is 4.5 to 6.5. When the pH is 5.5 or lower, the enamel that protects the tooth surface generally melts and causes caries. Trehalose has low acid production in the oral cavity and does not produce insoluble glucan that contributes to caries. Trehalose also suppresses the adhesion of sugar-derived insoluble glucan by about 60%. Therefore, although there is little risk of progression of caries due to trehalose, since the agent of the present invention is also intended to be used without irritating the oral cavity with water or the like after administration, the dental caries will progress in the oral cavity. In order to prevent such a situation, it is preferable to set the acidity as described above. In order to adjust the pH, an alkaline pH adjusting agent or an acidic pH adjusting agent may be appropriately added. As an alkaline agent, “sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, calcium lactate, disodium succinate, sodium malate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate And one or more compounds selected from the group consisting of As an acid agent, one or more selected from the group consisting of “acetic acid, citric acid, tartaric acid, propionic acid, hydrochloric acid, fumaric acid, adipic acid, benzoic acid, malic acid, phosphoric acid, lactic acid, gluconic acid” Compounds.

  Examples of the pharmacologically acceptable carrier include sterilized water, purified water, distilled water, sterilized organic solvent, aqueous starch, artificial saliva, physiological saline, alcohol, oil, and starch.

  The oral mucosa protective agent may contain those appropriately selected from preservatives and flavoring agents. Preferred embodiments of the oral mucosa protective agent of the present invention include “menthol, anethole, peppermint oil, spearmint oil, methyl salicylate, eugenol, eucalyptol, limonene cetylpyridinium chloride, chlorhexidine gluconate, triclosan, isopropylmethylphenol, dipotassium glycyrrhizinate. Oral mucosa protection according to any one of the above, containing one or more compounds selected from the group consisting of sodium azulenesulfonate, decalinium chloride, lysozyme chloride, hinokitiol, sodium lauroyl sarcosine, lactoferrin, and paraben It is an agent. That is, the oral mucosal protective agent of the present invention preferably contains a fragrance component, a bactericidal agent, a saliva component (enzyme, glycoprotein), an anti-inflammatory agent or an antifungal agent, and the like, and the fragrance is adjusted.

  Examples of preservatives include paraoxybenzoates such as methyl paraben and propyl paraben, alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol, phenols such as benzalkonium chloride, phenol and cresol, thimerosal, Examples include dehydroacetic acid and sorbic acid. Examples of the flavoring agent include sweeteners, acidulants, and fragrances. Diluents include sterilized water, sterilized organic solvents, aqueous starch, artificial saliva, and physiological saline.

The agent of the present invention can be produced according to a known method using the compound of the present invention or the pharmaceutical composition of the present invention. The liquid can be obtained by using the compound of the present invention or the pharmaceutical composition of the present invention and mixing with sterilized water, sterilized organic solvent, aqueous starch, artificial saliva, physiological saline or the like.
The gum-like oral mucosa protective agent can be produced according to a known gum production method.

  What is necessary is just to adjust the usage-amount of the compound of this invention suitably according to a symptom, age, sex, administration method, etc. In the case of intraoral surgery such as implant placement, surgery may be performed after rinsing the mouth with the 5 ml to 100 ml oral mucosa protective agent of the present invention. In addition, a liquid or spray oral mucosa protective agent may be appropriately administered to the affected area and surrounding mucosa. As a prophylactic or therapeutic agent for xerostomia or dry mouth, the mouth may be rinsed with 1 to 100 ml of liquid oral mucosal protective agent. What is necessary is just to administer the frequency | count of administration 1 time-several times per day according to a symptom, for example.

  In the present invention, xerostomia or dryness in which an oral mucosal protective agent for protecting the mucous membrane in the oral cavity containing trehalose or a pharmaceutically acceptable solvate as an active ingredient is administered to a subject to be treated. A method of treating a mouse is also provided. In this treatment method, the oral mucosa protective agent can be appropriately used in various patterns described so far.

  The present invention also provides use (especially as a main component) of trehalose or a pharmaceutically acceptable solvate thereof for producing a prophylactic or therapeutic agent for dry mouth or dry mouth. To do.

  Hereinafter, the present invention will be specifically described with reference to examples. The present invention can be appropriately modified within the scope obvious to those skilled in the art from the following examples, and is not limited to the following examples.

  10 g of trehalose (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) and 4 g of pullulan (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) were dissolved in sterile purified water (manufactured by Hikari Pharmaceutical Co., Ltd.). A 0.2 mol / l sodium bicarbonate aqueous solution was used to adjust the acidity of the solution to pH 7.4, and sterile purified water (manufactured by Hikari Pharmaceutical Co., Ltd.) was added to make 100 g. Filtration was performed using a filter having a pore diameter of 0.22 micrometers to obtain an oral mucosa protective agent. Sodium bicarbonate was a Japanese pharmacopoeia product.

  10 g of trehalose (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), 4 g of pullulan (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) and 5 g of concentrated glycerin were dissolved in sterilized purified water (manufactured by Hikari Pharmaceutical Co., Ltd.). A 0.01 mol / l sodium bicarbonate aqueous solution was used to adjust the acidity of the solution to pH 7.4, and sterile purified water (manufactured by Hikari Pharmaceutical Co., Ltd.) was added to make 100 g. Filtration was performed using a filter having a pore diameter of 0.22 micrometers to obtain an oral mucosa protective agent. Concentrated glycerin and sodium bicarbonate were Japanese Pharmacopoeia.

  20 g of trehalose (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.), 4 g of pullulan (manufactured by Hayashibara Biochemical Laboratories Co., Ltd.) and 2 g of concentrated glycerin were dissolved in sterilized purified water (manufactured by Hikari Pharmaceutical Co., Ltd.). The acidity of the solution was adjusted to pH 7.4 using 0.03 g of 0.01 mol / l sodium hydrogen carbonate aqueous solution, and sterilized purified water (manufactured by Hikari Pharmaceutical Co., Ltd.) was added to make 100 g. Filtration was performed using a filter having a pore diameter of 0.22 micrometers to obtain an oral mucosa protective agent. Concentrated glycerin and sodium bicarbonate were Japanese Pharmacopoeia.

  As a comparative example for the target experiment in the following experiment, an aqueous solution having a sodium bicarbonate concentration of 0.2 mol / l using “sterilized purified water (manufactured by Hikari Pharmaceutical Co., Ltd.)” was obtained. “Sterilized purified water (manufactured by Hikari Pharmaceutical Co., Ltd.)” was adjusted to pH 7.4 using an aqueous sodium solution to obtain 100 g of an aqueous sodium bicarbonate solution having a pH of 7.4. In addition, Japanese pharmacopoeia was used for sodium bicarbonate.

Dry protection performance evaluation-Moisture transition on the back of the tongue-
The oral mucosa protective solutions obtained in Example 1, Example 2 and Comparative Example were evaluated using 4 subjects. The evaluation procedure is as follows.

  Procedure 1. Place a roll pat on the buccal side of the maxillary second molar, which is the opening of the salivary gland, and the mandibular yard, and use the solution of Example 1 and Example 2 or the reference solution as a control as the palate, left and right buccal mucosa, Spray was applied to four places on the back of the tongue (1.2 g in total) to moisten the oral cavity.

Procedure 2. A bite block was placed on the right molar part, an intra-oral vacuum was placed on the left mandibular corner of the mandible, and suction was performed to generate airflow in the oral cavity, which was then dried by air. After 5 minutes, the oral vacuum was removed.

Procedure 3. After that, the salivary duct was attached, the tip of the tongue was attached to the lower gum, and the mouth was kept open for 5 minutes.

  Regarding the “moisture transition on the tongue back surface”, the moisture content on the tongue back surface was measured using an oral moisture meter (Mucus (registered trademark) Life) before the start of treatment, after step 2 and after step 3. The obtained results are shown in Table 1.

  From Table 1, it can be seen that the transition of moisture on the back surface of the tongue is remarkably reduced in the dry environment of the comparative example. When Example 1 or Example 2 is compared with the comparative example, it can be seen that the example can more effectively prevent the mucous membrane from drying than the comparative example. There was no great difference between Example 1 and Example 2 in the persistence of wetness in the oral cavity, and Example 2 was slightly better. In addition, the sweet taste of Example 1 was weaker than that of Example 2, and Test B gave an unclear taste. In addition, Example 3 had a strong sweet taste, and many people preferred Example 2.

Dry protection performance evaluation-Observation of filamentous nipple-
Dry protection performance was evaluated by examining changes in the oral mucosa protective solution obtained in Example 2 and the comparative example by visual observation of the filiform nipple with a digital camera using 5 subjects. The evaluation procedure was as follows.
Procedure 1. Place a roll pat on the buccal side of the maxillary second molar, which is the opening of the salivary gland, and the mandibular yard. (1.2g in total) and moistened the oral cavity.

  Procedure 2. A bite block was placed on the right molar part, an intra-oral vacuum was placed on the left mandibular corner of the lower jaw, and suction was performed to create an air flow in the oral cavity, which was then dried by air. After 5 minutes, the oral vacuum was removed.

  Procedure 3. After that, the salivary duct was attached, the tip of the tongue was attached to the lower gum, and the mouth was kept open for 5 minutes.

Before starting observation of the filiform papilla, after step 2 and after step 3, the state of the filiform papilla was observed with a digital camera under visible light (Microskin Scope Co., Ltd.).

  When the comparative example was administered, a significant change in the state was observed, particularly in the three nipples of the test subjects, and the appearance of whitening and narrowing was observed. The degree of change increased with time. On the other hand, no significant change was observed in the condition of the filiform papilla before spraying, after 5 minutes, and after 10 minutes for the subjects administered the oral mucosa protective agent of Example 2, confirming the mucosal protective effect. It was.

Before starting observation of the wrinkled nipple, after step 2 and after step 3, the size of the wrinkled nipple is photographed with a reference (marker) using a digital camera (Micro Skin Scope, Inc.) under visible light. From the image, the major axis and minor axis were measured, and the equivalent area of the ellipse was calculated. The results are shown in Table 2.

  Table 2 shows the change in the area ratio after 5 minutes and 10 minutes when the area of the nipple nipple before spraying is 1.000. The fungiform nipple is dried by air, and the liquid of the example causes a slight atrophy and a small area, but there is no significant difference before and after spraying, before and after spraying, and after 5 and 10 minutes. It was not recognized, and suppression of contraction was observed. In the reference examples, clear atrophy was observed after 5 and 10 minutes, and there was a significant difference between before and after spraying, before and after spraying, after 10 and after 5 and 10 minutes, and dried by air. It contracted by. After 10 minutes, it shrank to 0.505 before spraying.

  After 5 minutes, natural drying, which is a mild dry environment, was carried out for 5 minutes (after 10 minutes), but some subjects in the examples showed a recovery not seen in the comparative examples. The mucosal protective effect was clarified by the drying of the liquid of the example by air during oral treatment. Similarly, it was revealed that the present invention is useful for protecting the oral mucosa from dryness in the oral cavity due to mouth breathing, saliva reduction, and the like. In addition, the components of the oral mucosa protective solution of Example 1 and Example 2 are highly safe, are composed of components that can be swallowed, and do not need to be spit out or swallowed with water or the like, so that the effect is sustained.

  Since the oral mucosa protective agent is effective during dental surgery and as a therapeutic or preventive agent for xerostomia or dry mouth, it can be suitably used in the pharmaceutical industry.

Claims (10)

  An oral mucosa protective agent for protecting the oral mucosa containing trehalose or a pharmaceutically acceptable solvate thereof as an active ingredient.   The oral mucosa protective agent according to claim 1, comprising a thickener.   The oral mucosa protective agent according to claim 1 containing pullulan.   2. The oral mucosa protective agent according to claim 1, comprising a wetting agent.   2. The oral mucosal protective agent according to claim 1, comprising an antioxidant.   2. The oral mucosa protective agent according to claim 1, comprising an antibacterial agent.   The oral mucosa protective agent according to claim 1, wherein the oral mucosa protective agent is a liquid, and the pH of the liquid is 5.7 to 8.5.   “Menthol, anethole, peppermint oil, spearmint oil, methyl salicylate, eugenol, eucalyptol, limonene cetylpyridinium chloride, chlorhexidine gluconate, triclosan, isopropylmethylphenol, dipotassium glycyrrhizinate, sodium azulenesulfonate, decalinium chloride, lysozyme chloride, The oral mucosa protective agent according to claim 1, comprising one or more compounds selected from the group consisting of hinokitiol, sodium lauroyl sarcosine, lactoferrin, and paraben.   The oral mucosa protective agent according to claim 1, which is a spray liquid, a liquid for spraying or vaporizing administration, a mouthwash, a mouthwash, a foamy aerosol, a perfusate or an infusion pack containing liquid.   The oral mucosa protective agent according to claim 1, which is a therapeutic agent or preventive agent for xerostomia, or a therapeutic agent or prophylactic agent for dry mice.