JPWO2019208435A1 - Exocrine promoter - Google Patents

Abstract

An exocrine secretagogue that comprehensively promotes exocrine secretion and can be used as a food composition for the purpose of improving symptoms of dry skin, dry eye, dry mouth, etc., more specifically, a stratum corneum water content increasing agent, saliva secretion. It is an object to provide a promoter and a tear secretion promoter, and an exocrine secretagogue containing a compound represented by the following general formula (1) as an active ingredient, more specifically, a stratum corneum water content increasing agent, saliva. It is a secretagogue or a saliva secretagogue. (In the general formula (1), R1 to R4, R6 and R7 represent hydrogen atoms and the like. R5 represents a hydroxyl group and the like. * Indicates an asymmetric carbon atom and the like.

Description

The present invention relates to an exocrine promoter. More specifically, the present invention relates to a stratum corneum water content increasing agent, a saliva secretion promoting agent, and a tear secretion promoting agent.

Exocrine secretion refers to secretion that is secreted directly by gland cells or into the body surface or lumen through a conduit or the like. Saliva is known as a typical example of exocrine secretion, and other examples include secretion of nasal mucosa and respiratory tract mucosa, gastric and intestinal secretion, vaginal secretion, and sweat. Diseases associated with such exocrine disorders include dry mouth (xerostomia), dry nose (xerostomia), dry eye (dry eye), dry skin (dry skin), dry skin (dry vagina), etc. Dry symptoms; chronic pancreatitis, chronic gastrointestinal inflammation, chronic bronchitis, etc. due to decreased exocrine secretion.

Dry skin can be judged by the water content of the stratum corneum. Therefore, increasing the water content of the stratum corneum can improve dry skin.
A technique using pine bark extract, hyaluronic acid and ceramide as active ingredients as an agent for increasing the water content of the stratum corneum (see, for example, Patent Document 1) and a technique using an extract of foxtail as an active ingredient (see, for example, Patent Document 2). ) Has been proposed.

In addition, it is estimated that 50 million consumers suffer from dry eye and dry mouth. Dry eye can be determined by the amount of tear secretion. In addition, dry mouth can be judged by the amount of saliva secretion. Therefore, increasing tear secretion and saliva secretion can improve dry eye and dry mouth.
For the purpose of increasing both tear secretion and saliva secretion, a technique using a peptide derivative having a PAR-2 activating action as an active ingredient (see, for example, Patent Document 3) and a technique using a fatty acid derivative as an active ingredient have been proposed. (See, for example, Patent Document 4).

Japanese Unexamined Patent Publication No. 2015-86160 Japanese Unexamined Patent Publication No. 2014-62090 Special Table 2005-538961 Special Table 2003-504397

However, for the purpose of improving symptoms of dry skin, dry eye, dry mouth, etc., a technique for comprehensively promoting exocrine gland is desired. Moreover, since these symptoms are universal symptoms that occur in daily life, those that can be improved without relying on doctors or medicines are desired.

An object of the present invention is an exocrine enhancer that comprehensively promotes exocrine secretion and can be used as a food composition for the purpose of improving symptoms of dry skin, dry eye, dry mouth, etc., more specifically, stratum corneum water. To provide a dose-increasing agent, a saliva secretion-promoting agent, and a tear secretion-promoting agent.

（前記一般式（１）中、Ｒ^１は、水素原子、水酸基、又はメトキシ基を示す。Ｒ^２は、水素原子、水酸基、又はメトキシ基を示す。Ｒ^３は、水素原子、又は水酸基を示す。Ｒ^４は、水素原子、又は−Ｃ_６Ｈ_１１Ｏ_５基を示す。Ｒ^５は、水酸基、又はメトキシ基を示す。Ｒ^６は、水素原子、又は−Ｃ_６Ｈ_１１Ｏ_５基を示す。Ｒ^７は、水素原子、又は水酸基を示す。但し、Ｒ^４及びＲ^６の一方は、−Ｃ_６Ｈ_１１Ｏ_５基である。＊は、不斉炭素原子を示す。）
〔２〕前記一般式（１）中、Ｒ^４及びＲ^６の少なくとも一方として表される−Ｃ_６Ｈ_１１Ｏ_５基が、テトラヒドロピラン骨格を有する基である上記〔１〕に記載の外分泌促進剤。
〔３〕前記一般式（１）中、Ｒ^４及びＲ^６の少なくとも一方として表される−Ｃ_６Ｈ_１１Ｏ_５基が、４つの水酸基を有する基である上記〔１〕又は〔２〕に記載の外分泌促進剤。
〔４〕下記一般式（２）で表される化合物で表される化合物をさらに含有し、前記一般式（１）で表される化合物に対する前記一般式（２）で表される化合物の比率（一般式（２）で表される化合物／一般式（１）で表される化合物）が、０．００１〜１である上記〔１〕〜〔３〕のいずれかに記載の外分泌促進剤。

〔５〕１日当たりの摂取量が、０．００１〜１０００ｍｇであり、３日間以上摂取する上記〔１〕〜〔４〕のいずれかに記載の外分泌促進剤。
〔６〕角層水分量増加剤、唾液分泌促進剤、又は涙液分泌促進剤である上記〔１〕〜〔５〕のいずれかに記載の外分泌促進剤。
〔７〕上記〔１〕〜〔６〕のいずれかに記載の外分泌促進剤を含む外分泌促進用食品組成物。As a result of diligent studies on the above problems, the present inventors have found that the above problems can be solved by using a compound represented by a specific chemical formula as an active ingredient, and have completed the present invention. It was also found that continuous ingestion of the active ingredient improves the above-mentioned symptomatic effects.
That is, the present inventors provide the following [1] to [7].
[1] An exocrine promoter containing a compound represented by the following general formula (1) as an active ingredient.

(In the general formula (1), R ¹ represents a hydrogen atom, a hydroxyl group, or a methoxy group. R ² represents a hydrogen atom, a hydroxyl group, or a methoxy group. R ³ represents a hydrogen atom or a hydroxyl group. .R ^4, the .R ⁵ represents a hydrogen atom, or _-C 6 _H 11 _{O 5} group, .R ⁶ in which a hydroxyl group or a methoxy group, a hydrogen atom, or _-C 6 _H 11 _{O 5} group . R ⁷ represents a hydrogen atom or a hydroxyl group. However, one of R ⁴ and R ⁶ is -C ₆ H ₁₁ O ₅ groups. * Indicates an asymmetric carbon atom.)
[2] The exocrine promotion according to the above [1], wherein the _{-C 6} H ₁₁ O ₅ group represented as at least one of ^{R 4} and R ^{6 in} the general formula (1) is a group having a tetrahydropyran skeleton. Agent.
[3] In the above general formula (1), the _{-C 6} H ₁₁ O ₅ group represented as at least one of ^{R 4} and R ⁶ is a group having four hydroxyl groups in the above [1] or [2]. The listed exocrine promoters.
[4] The ratio of the compound represented by the general formula (2) to the compound represented by the general formula (1) further containing the compound represented by the compound represented by the following general formula (2). The exocrine promoter according to any one of the above [1] to [3], wherein the compound represented by the general formula (2) / the compound represented by the general formula (1) is 0.001 to 1.

[5] The exocrine secretagogue according to any one of the above [1] to [4], which has a daily intake of 0.001 to 1000 mg and is ingested for 3 days or more.
[6] The exocrine secretagogue according to any one of the above [1] to [5], which is a stratum corneum water content increasing agent, a saliva secretion promoting agent, or a tear secretion promoting agent.
[7] An exocrine-promoting food composition containing the exocrine-promoting agent according to any one of the above [1] to [6].

According to the present invention, an exocrine promoter that comprehensively promotes exocrine secretion and can be used as a food composition for the purpose of improving symptoms of dry skin, dry eye, dry mouth, etc., more specifically, stratum corneum water. A dose-increasing agent, a saliva secretion-promoting agent, and a tear secretion-promoting agent can be provided.

FIG. 1 is a graph showing the results of the evaluation test 1. FIG. 2 is a graph showing the results of the evaluation test 2. FIG. 3 is a graph showing the results of the evaluation test 3. FIG. 4 is a graph showing the results of the evaluation test 4. FIG. 5 is a graph showing the results of the evaluation test 5. FIG. 6 is a graph showing the results of the evaluation test 6. FIG. 7 is a graph showing the results of the evaluation test 7. FIG. 8 is a graph showing the results of the evaluation test 8. FIG. 9 is a graph showing the results of the evaluation test 9. FIG. 10 is a graph showing the results of the evaluation test 10. FIG. 11 is a graph showing the results of the evaluation test 11. FIG. 12 is a graph showing the results of the evaluation test 12.

Hereinafter, the present invention will be described in detail according to the preferred embodiment thereof.

[1. Active ingredient]
The exocrine secretagogue of the present invention, more specifically, the stratum corneum water content increasing agent, the saliva secretion promoting agent, and the tear secretion promoting agent have a compound represented by the general formula (1) as a common active ingredient.

In the general formula (1), R ¹ represents a hydrogen atom, a hydroxyl group, or a methoxy group. R ² represents a hydrogen atom, a hydroxyl group, or a methoxy group. R ³ represents a hydrogen atom or a hydroxyl group. R ⁴ represents a hydrogen atom or -C ₆ H ₁₁ O ₅ groups. R ⁵ represents a hydroxyl group or a methoxy group. R ⁶ represents a hydrogen atom or -C ₆ H ₁₁ O ₅ groups. R ⁷ represents a hydrogen atom or a hydroxyl group. However, one of ^{R 4} and ^{R 6} _are -C _{6 H} 11 _{O 5} group. * Indicates an asymmetric carbon atom.

In the general formula (1) ^{, examples of R 1 to} R ³ , R ⁵ and R ⁷ include the following combinations (R ¹ , R ² , R ³ , R ⁵ , R ⁷ ). (Hydrogen atom, hydroxyl, hydroxyl, hydroxyl, hydroxyl), (hydrogen, hydroxyl, hydrogen atom, hydroxyl, hydroxyl), (hydrogen atom, methoxy group, hydroxyl, hydroxyl, hydroxyl), (methoxy group, hydroxyl, hydrogen atom, hydroxyl) , Hydrogen atom), (hydrogen atom, methoxy group, hydrogen atom, hydroxyl group, hydroxyl group), (hydrogen atom, hydroxyl group, hydrogen atom, hydroxyl group, hydroxyl group), (hydrogen atom, hydrogen atom, hydrogen atom, hydroxyl group, hydroxyl group), (hydrogen Atomic, hydroxyl, hydrogen atom, methoxy group, hydroxyl group), (hydroxyl, hydroxyl, hydrogen atom, methoxy group, hydroxyl group).
Among ^{these, R 1 ~R 3,} R ⁵ and ^{R 7} is preferably a combination of (a hydroxyl group, a hydroxyl group, a hydrogen atom, a hydroxyl group, a hydroxyl group).

In the general formula (1), at least one of ^{R 4} and R ⁶ _{is preferably -C 6} H ₁₁ O ₅ groups, and R ⁶ is preferably -C ₆ H ₁₁ O _{5 groups.} Further, -C ₆ H ₁₁ O ₅ group, it is preferably a group having a tetrahydropyran skeleton, more preferably a group having 4 hydroxyl groups, a group represented by the following formula (3) Is even more preferable.
In the C-glycoside in which at least one of ^{R 4} and R ⁶ _{is -C 6} H ₁₁ O ₅ , the glycoside is less likely to be cut in the intestine than the O-glycoside, and the glycoside is It is thought that it circulates in the blood while still bound. Further, the O-glycoside of the formula (1) is known to have an antioxidant ability, and it is considered that the effect is strongly exhibited by becoming a C-glycoside.

In the general formula (1), * represents an asymmetric carbon atom. That is, the compound represented by the general formula (1) has the following optical isomers of the (R) -form and the (S) -form. In the present invention, any optical isomer may be used, or a racemate may be used.

The lower limit of the daily intake of the compound represented by the general formula (1) is preferably 0.001 mg or more, more preferably 0.05 mg or more, further preferably 0.1 mg or more, still more preferably 0.2 mg or more. preferable. When it is 0.001 mg or more, exocrine gland can be comprehensively promoted for the purpose of improving symptoms of dry skin, dry eye, dry mouth and the like. On the other hand, the upper limit thereof is preferably 1000 mg or less, more preferably 100 mg or less, further preferably 50 mg or less, still more preferably 10 mg or less. When it is 1000 mg or less, bitterness can be suppressed, so that it can be suitably used as a food composition.
The daily intake of the compound represented by the general formula (1) is preferably 0.001 to 1000 mg, more preferably 0.05 to 100 mg, further preferably 0.1 to 50 mg, and 0.2 to 10 mg. Even more preferable.

The number of days of ingestion of the compound represented by the general formula (1) is preferably 1 day or more, more preferably 3 days or more, still more preferably 7 days or more. In the examples described later, when the compound represented by the general formula (1) is continuously ingested, improvement in the water content of the stratum corneum, the amount of saliva, and the height of the tear meniscus is shown, and dry skin, dry eye, and the like are shown. Improvement of symptom improvement such as dry mouth can be expected.
The compound represented by the general formula (1) may be used alone or in combination of two or more as an active ingredient.

[2. Exocrine secretagogue, stratum corneum water increase agent, saliva secretion promoter, tear secretion promoter]
The exocrine secretagogue of the present invention, more specifically, a stratum corneum water content increasing agent, a saliva secretion promoting agent, and a tear secretion promoting agent (hereinafter, collectively referred to as simply “agents”) are described in the above general formula (1). ) Is the active ingredient.
Considering the above-mentioned effects, the exocrine secretagogue of the present invention, more specifically, the stratum corneum water content increasing agent, the saliva secretion promoting agent, and the tear secretion promoting agent are the skin dryness improving agent and the oral dryness improving agent, respectively. , Can be expected to be used as an eye dryness improving agent.

As the exocrine secretagogue, more specifically, the stratum corneum water content increasing agent, the saliva secretion promoting agent, and the tear secretion promoting agent of the present invention, the compound represented by the compound represented by the following general formula (2) is effective. It is preferably contained as an auxiliary agent for the component.
When the compound represented by the general formula (2) is contained as an auxiliary agent for the above active ingredient, the ratio of the compound represented by the general formula (2) to the compound represented by the general formula (1) (general formula (2). The compound represented by) / the compound represented by the general formula (1) is preferably 0.001 to 1. When the range of the ratio is within such a range, the effect of the present invention can be further improved. The upper limit of the ratio is preferably 0.3 or less, more preferably 0.2 or less, and even more preferably 0.1 or less. The lower limit is preferably 0.002 or more, more preferably 0.01 or more, and even more preferably 0.04 or more. When the compound represented by the general formula (2) is contained as an auxiliary agent for the above active ingredient, when the ratio exceeds 1, the effect of the compound represented by the general formula (1) as an active ingredient is remarkable. May be reduced to.

The route of ingestion (administration) of the agent of the present invention is not particularly limited as long as the desired effect of the present invention can be obtained. For example, it may be oral (eg, intraoral, sublingual) or parenteral (eg, eye drops, intravenous, intramuscular, subcutaneous, transdermal, nasal, transpulmonary). Among these, a less invasive route is preferable, and oral is more preferable.

In the case of oral ingestion (oral administration), for example, solid embodiments such as powder, fine granules, granules, capsules, sachets, tablets, bolus, lozenge; aqueous solution, extract, suspension, syrup, elixir, emulsion, etc. Liquid embodiments such as dispersions; examples include semi-liquid, cream, paste and the like.
Among them, the form of a pill which is a powder or a concentrated solution in a capsule; a powder form which can be ingested after being put in or dissolved in a liquid such as water or hot water in the same manner as drinking powdered tea; freeze-dried granules and the like. Granule form: It is preferable to ingest (administer) in a tablet form such as a chewable form.

In the case of parenteral administration, for example, eye drops such as liquids such as aqueous solutions, extracts, suspensions, emulsions and dispersions; ophthalmic agents such as semi-liquid, cream and paste; aqueous solutions, extracts, Intravenous injections such as liquids such as suspensions, emulsions and dispersions, intramuscular injections or subcutaneous injections; transdermal administrations such as liquids such as aqueous solutions, extracts, suspensions, emulsions and dispersions; aqueous solutions , Extracts, suspensions, emulsions, liquids such as dispersions, powders, fine granules and other nasal and pulmonary agents.

[3. Exocrine promoting food composition]
The agent of the present invention may be ingested (administered) as it is. In addition, the agent of the present invention has a tear secretion promoting action, an eye strain preventing / improving action, an eye accommodation decrease preventing / improving action, a saliva volume increasing action, and tears in foods and drinks, functional foods, and compositions. It can also be used as an additive for imparting at least one action selected from the group consisting of a liquid volume increasing action.

There are no particular restrictions on foods and drinks, functional foods, and compositions in which the agent of the present invention can be blended as an additive. For example, beverages (soft beverages, carbonated beverages, nutritional beverages, powdered beverages, fruit beverages, dairy beverages, jelly beverages, etc.), confectionery (cookies, cakes, gums, candies, tablets, gummy, buns, sheep syrup, pudding, jelly, Ice cream, sherbet, etc.), processed marine products (kamaboko, chikuwa, hampen, etc.), processed livestock products (hamburger, ham, sausage, wiener, cheese, butter, yogurt, fresh cream, margarine, fermented milk, etc.), soup (powder) Examples include soups (like soups, liquid soups, etc.), main foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.), and seasonings (mayonnaise, shortening, dressing, sauces, sauces, soy sauce, etc.).

In addition, the agent of the present invention is included as an active ingredient in a composition for promoting tear secretion, preventing or improving eye strain, or preventing or improving accommodation deterioration of the eye, for example, an internal composition or a pharmaceutical composition. Can also be used as.

The agents or compositions of the present invention are any conventional auxiliary ingredients used to produce solid or liquid dosage forms, such as excipients, disintegrants, diluents, buffers, flavoring agents. , Colorants, flavoring agents, binders, surfactants, thickeners, lubricants, suspending agents, preservatives, antioxidants and the like may be contained.

Excipients include, for example, cellulose such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose and pharmacologically acceptable derivatives thereof; polyvinylpyrrolidone, partially saponified polyvinyl alcohol. Synthetic polymers such as gelatin, gum arabic powder, purulan, agar, alginic acid, sodium alginate, citansangum and other polysaccharides; starch such as corn starch, potato starch, pregelatinized starch, hydroxypropyl starch and its pharmacologically acceptable Derivatives; lactose, fructose, glucose, sucrose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, reduced palatinose, powdered reduced starch sugar syrup, maltitol, brown sugar, sugars such as starch liquid sugar and sugar alcohols; Examples thereof include inorganic excipients such as acid, fine-grained silicon oxide, titanium oxide, and aluminum hydroxide gel.

Examples of the disintegrant include crospovidone, carmellose calcium, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch sodium, croscarmellose sodium, hydroxypropyl starch, and partially pregelatinized starch. ..

Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin, starch and pregelatinized starch.

Examples of the lubricant include calcium stearate, magnesium stearate, sucrose fatty acid ester, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid.

Examples of the flavoring agent include sweetener preparations such as sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose, and fructose; citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or theirs. Examples include acidulants such as salt.

Examples of antioxidants include ascorbic acid, palmitate ascorbic acid, propyl gallate, BHT (dibutylhydroxytoluene), BHA (butylhydroxyanisole), a mixture of propyl gallate and citric acid, hydroquinone, and tertiary butylhydroquinone. , Disaccharide trehalose, natural tocopherol compounds, long-chain esters of propyl gallate (C8-C22), such as dodecyl gallate, irganox compounds available from Ciba Specialty Chemicals, citrate and / or quen. Examples thereof include isopropyl acid acid, 4,5-dihydroxy-m-benzenesulfonic acid / sodium salt, dimethoxyphenol, catechol, methoxyphenol, carotinoid, furans and amino acids.

Colorants include, for example, lycopene base, Benibana red pigment, Kuchinashi yellow pigment, Kuchinashi blue pigment, perilla pigment, red koji pigment, red cabbage pigment, carrot pigment, hibiscus pigment, cacao pigment, spirulina blue pigment, tartrazine pigment and the like. Natural pigments, legal pigments such as Red No. 3, Red No. 104, Red No. 105, Red No. 106, Yellow No. 4, Yellow No. 5, Green No. 3, Blue No. 1, riboflavin, sodium copper chlorophyllin, and titanium dioxide are listed. Be done.

Examples of the flavoring agent include hydrocarbons such as aliphatic hydrocarbons, terpene hydrocarbons, and aromatic hydrocarbons; alcohols such as aliphatic alcohols, terpene alcohols, and aromatic alcohols; aliphatic ethers, aromatic ethers, and the like. Ethers; Aliphatic oxides, terpenic oxides and other oxides; Aliphatic aldehydes, terpene aldehydes, hydrogenated aromatic aldehydes, thioaldehydes, aromatic aldehydes and other aldehydes; Aliphatic ketones, terpene ketones, hydrogen Ketones such as chemical aromatic ketones, aliphatic cyclic ketones, non-benzene aromatic ketones, aromatic ketones; acetals, ketals, phenols, phenol ethers; fatty acids, terpene carboxylic acids, hydrogenated aromatic carboxylics Acids such as acids and aromatic carboxylic acids; Acid amides; Aliphatic lactones, macrocyclic lactones, terpene lactones, hydroaromatic lactones, aromatic lactones and other lactones; aliphatic esters, furan carboxylic acid group esters , Aliphatic cyclic carboxylic acid ester, cyclohexylcarboxylic acid group ester, terpene carboxylic acid ester, aromatic carboxylic acid ester and other esters; Examples thereof include synthetic fragrances such as compounds and fragrances such as natural fragrances from animals and plants.

Hereinafter, the present invention will be described in detail with reference to Examples. The following examples are for the purpose of preferably explaining the present invention, and do not limit the present invention.

The chemical formulas of compounds A to D used in the following examples are shown below. All of the compounds A to D are commercially available products.

(Preparation of tablets)
The preparation method of chewable tablets and placebo tablets used in the following evaluation test is described. Compounds A to D are 0.05 mg to 1 mg, dextrin (Paindex # 2, manufactured by Matsutani Chemical Industry Co., Ltd.) 49 to 49.95 mg (varies according to the amount of compounds A to D, and the total amount is 50 mg), erythritol ( "Erythritol 50M", manufactured by Bussan Food Science Co., Ltd.) 100 mg, crystalline cellulose ("Theoras ST-100", manufactured by Asahi Kasei Co., Ltd.) 90 mg, calcium stearate ("calcium stearate", manufactured by Taihei Chemical Industry Co., Ltd.) 10 mg are uniformly mixed. Tablets were prepared by direct tapping at 12 kN. However, in the case of placebo tablets, compounds A to D are 0 mg, and dextrin is 50 mg instead.

(Evaluation test 1: Improvement evaluation of water content in the stratum corneum 1)
Ten subjects were ingested chewable tablets containing 0.3 mg of compounds A to D alone, chewable tablets containing 0.3 mg each of compounds B and D, and placebo tablets containing no compounds A to D. .. The subject spent in a constant temperature room at 21 ± 2 ° C and 50 ± 5% RH from ingestion to the end of measurement, and the amount of water in the stratum corneum of the inner arm of the right arm before and 120 minutes after ingestion was measured by SKICON-200 (manufactured by IBS). ) Was used for measurement. The water content of the stratum corneum can be obtained by passing a weak electricity to a depth of about 30 μm (mainly the stratum corneum) from the skin surface and measuring the resistance value. However, the blood vessel part shall be excluded. The amount of change in keratin water content before and after 120 minutes of ingestion was calculated. The results of the average value of the amount of change are shown in FIG. 1 and Table 1.

As can be seen from FIG. 1 and Table 1, ingestion of chewable tablets containing 0.3 mg of each of compounds B to D alone increased the water content of the stratum corneum of the subject. In addition, ingestion of chewable tablets containing 0.3 mg each of compounds B and D improved the effect of increasing the water content of the stratum corneum of the subject. On the other hand, the placebo tablet and the chewable tablet containing 0.3 mg of compound A showed almost no effect of increasing the water content of the stratum corneum of the subject.

(Evaluation test 2: Improvement evaluation of water content in the stratum corneum 2)
Ten of the same subjects were ingested chewable tablets containing 0.05 mg to 1 mg of compound D, respectively. They were asked to spend time in the same situation as in Evaluation Test 1, and the water content of the stratum corneum 120 minutes after ingestion was measured by the same method. The amount of change in keratin water content before and after 120 minutes of ingestion was calculated. The results of the average value of the amount of change are shown in FIG. 2 and Table 2.

As can be seen from FIG. 2 and Table 2, ingestion of chewable tablets containing 0.1 mg or more of Compound D was found to improve the effect of improving the water content of the stratum corneum. Further, when the compounding amount of the compound D was increased, the water content of the stratum corneum was also further improved.

(Evaluation test 3: Evaluation of improvement of dry skin)
Ten subjects were ingested chewable tablets and placebo tablets containing 0.3 mg of compound D once a day for one week. Regarding the degree of improvement in skin dryness on the 1st, 3rd, and 7th days after the start of ingestion, the VAS (Visual Analogue Scale) method (Ahlsio B, Britton M, Murray V, Theorell T; 15: 886-890, see 1984.). As for the answers, 100 was set when the dryness of the skin was "extremely improved" compared to before ingestion, 0 was set when "not improved at all", and the degree of improvement of each subject was self-evaluated by the numerical value during that period. The results of the average value of the numerical values are shown in FIG. 3 and Table 3.

As can be seen from FIG. 3 and Table 3, when the chewable tablet containing 0.3 mg of Compound D was ingested, the dry feeling was improved in one day. In addition, it was confirmed that the effect of improving the feeling of dryness was maintained when the tablet was continuously ingested for 3 days or more.

(Evaluation test 4: Improvement evaluation of saliva volume 1)
Ten subjects were ingested chewable tablets containing 0.3 mg of compounds A to D alone, chewable tablets containing 0.3 mg each of compounds B and D, and placebo tablets containing no compounds A to D. .. The subject spent 10 minutes in a resting state before and 120 minutes after ingestion after spending time in a homeothermic chamber at 21 ± 2 ° C. and 50 ± 5% RH from ingestion to the end of measurement. However, oral activity was prohibited from 1 hour before the measurement. The amount of change in saliva volume before and after 120 minutes of ingestion was measured. The results of the average value of the amount of change are shown in FIGS. 4 and 4.

(Evaluation test 5: Improvement evaluation of tear meniscus height 1)
After the test of evaluation test 4, the height of the meniscus of the tear fluid accumulated between the cornea and the lower eyelid under the pupil 2 seconds after the second blink using an optical interference tomography (RS-3000 Advance, manufactured by Nidek). Was measured. However, oral activity was prohibited from 1 hour before the measurement. The amount of change in tear meniscus height before and 120 minutes after ingestion was measured. The results of the average value of the amount of change are shown in FIGS. 5 and 5.

As can be seen from FIGS. 4 and 4, when a chewable tablet containing 0.3 mg of each of Compounds B to D alone was ingested, the saliva volume of the subject increased as compared with placebo and Compound A.
In addition, as can be seen from FIGS. 5 and 5, when the chewable tablets containing 0.3 mg of each of the compounds B to D alone were ingested, the tear meniscus height of the subject increased. In addition, when a chewable tablet containing 0.3 mg each of compounds B and D was ingested, the effect of increasing the tear meniscus of the subject was significantly improved. On the other hand, the placebo tablet and the chewable tablet containing 0.3 mg of compound A did not show the effect of increasing the tear meniscus height.

(Evaluation test 6: Improvement evaluation of saliva volume 2)
The amount of change in saliva volume was measured in the same manner as in Evaluation Test 4 except that the chewable tablets were mixed with 0.05 mg to 1 mg of compound D, respectively. The results of the average value of the amount of change are shown in FIG. 6 and Table 6.

(Evaluation test 7: Improvement evaluation of tear meniscus height 2)
The amount of change in tear meniscus height was measured in the same manner as in Evaluation Test 5 except that the chewable tablets were mixed with 0.05 mg to 1 mg of compound D, respectively. The results of the average value of the amount of change are shown in FIGS. 7 and 7.

As can be seen from FIG. 6 and Table 6, ingestion of chewable tablets containing 0.2 mg or more of Compound D increased the saliva volume of the subjects as compared with placebo.
Further, as can be seen from FIGS. 7 and 7, when a chewable tablet containing 0.05 mg or more of Compound D was ingested, the effect of increasing the tear meniscus height of the subject was observed. In addition, when a chewable tablet containing 0.1 mg or more of Compound D was ingested, a remarkable effect of increasing the tear meniscus height of the subject was observed.

(Evaluation test 8: Evaluation of improvement of dry mouth)
Twelve subjects were ingested chewable tablets and placebo tablets containing 0.3 mg of compound D once a day for one week. On the 1st, 3rd, and 7th days after the start of ingestion, the degree of improvement in xerostomia was evaluated by the VAS (Visual Analogue Scale) method. As for the answers, the case where the dryness in the oral cavity was "extremely improved" was set to 100, and the case where "there was no improvement at all" was set to 0, and the degree of improvement of each subject was self-evaluated by the numerical value during that period. The results of the average value of the numerical values are shown in FIG. 8 and Table 8.

(Evaluation test 9: Evaluation of improvement of dryness of eyes)
Twelve subjects were ingested chewable tablets and placebo tablets containing 0.3 mg of compound D once a day for one week. On the 1st, 3rd, and 7th days after the start of ingestion, the degree of improvement in the feeling of dry eyes was evaluated by the VAS (Visual Analogue Scale) method. As for the answers, the case where the dryness of the eyes was "very improved" was set to 100, and the case where "there was no improvement at all" was set to 0, and the degree of improvement of each subject was self-evaluated by the numerical value during that period. The results of the average value of the numerical values are shown in FIGS. 9 and 9.

As can be seen from FIG. 8 and Table 8, when the chewable tablet containing 0.3 mg of Compound D was ingested, the dry feeling in the oral cavity was improved in one day. In addition, when the tablet was continuously ingested for 3 days or more, a remarkable effect of improving the feeling of dry mouth was confirmed.
Further, as can be seen from FIGS. 9 and 9, when the chewable tablet containing 0.3 mg of Compound D was ingested, the feeling of dryness of the eyes was improved in one day. In addition, when the tablet was continuously ingested for 3 days or more, a remarkable effect of improving the feeling of dry eyes was confirmed.

Examples of prescriptions will be described below.
The compounds (1) to (5) used in the formulation examples are shown in Table 10. In Table 10, R ^{1 to} R ^{7 correspond to R 1 to} R ⁷ of the following general formula (1). -C ₆ H ₁₁ O ₅ groups have a three-dimensional structure represented by the following formula (3).

(Prescription example 1: Tablet)
Compound (1) 0.3 mg
Dextrin 49.7 mg
Erythritol 100 mg
Crystalline cellulose 90 mg
Calcium stearate 10 mg
250 mg in total

(Prescription example 2: Tablet)
Compound (1) 0.3 mg
Compound (2) 0.3 mg
Dextrin 49.4 mg
Erythritol 100 mg
Crystalline cellulose 90 mg
Calcium stearate 10 mg
250 mg in total

(Prescription example 3: Tablet)
Compound (3) 0.3 mg
Compound (4) 0.3 mg
Dextrin 49.4 mg
Erythritol 100 mg
Crystalline cellulose 90 mg
Calcium stearate 10 mg
250 mg in total

(Prescription example 4: Tablet)
Compound (2) 0.3 mg
Compound (5) 0.3 mg
Dextrin 49.4 mg
Erythritol 100 mg
Crystalline cellulose 90 mg
Calcium stearate 10 mg
250 mg in total

(Prescription example 5: Drink)
Compound (3) 0.3 mg
Compound (5) 0.3 mg
Brown sugar Glucose liquid sugar 250 mg
Erythritol 200 mg
Sweetener formulation 1.4 mg
Ascorbic acid 3 mg
Fragrance 12 mg
Lycopene base 8 mg
Purified water Appropriate amount total 10g

The chemical formulas of Compound E used in the following evaluation tests 10 to 12 are shown below. As the compound E, a commercially available product is used.

(Evaluation test 10: Improvement evaluation of water content in the stratum corneum 3)
Ten subjects were ingested chewable tablets containing 0.2 mg of compound D and 0.001 mg to 0.4 mg of compound E, respectively. They were asked to spend time in the same situation as in the evaluation test 1, and the water content of the stratum corneum 120 minutes after ingestion was measured by the same method. The amount of change in keratin water content before and after 120 minutes of ingestion was calculated. The results of the average value of the amount of change are shown in FIGS. 10 and 11.

As can be seen from FIGS. 10 and 11, when a chewable tablet containing 0.2 mg of compound D and 0.001 to 0.2 mg (E / D = 0.005-1) of compound E, respectively, is ingested, the stratum corneum water content is increased. An improvement in the amount improvement effect was observed. On the other hand, when the compound E was 0.4 mg (E / D = 2), it was equivalent to the case where the compound D alone was used.

(Evaluation test 11 :: Improvement evaluation of saliva volume 3)
Ten subjects were ingested chewable tablets containing 0.2 mg of compound D and 0.001 mg to 0.4 mg of compound E, respectively. The amount of change in saliva volume was measured in the same manner as in evaluation test 4. The results of the average value of the amount of change are shown in FIGS. 11 and 12.

As can be seen from FIGS. 11 and 12, when a chewable tablet containing 0.2 mg of compound D and 0.001 mg to 0.2 mg (E / D = 0.005-1) of compound E, respectively, is ingested, the amount of saliva is increased. Improvement of improvement effect was recognized. On the other hand, when the compound E was 0.4 mg (E / D = 2), it was equivalent to the case where the compound D alone was used.

(Evaluation test 12 :: Improvement evaluation of tear meniscus height 3)
Ten subjects were ingested chewable tablets containing 0.2 mg of compound D and 0.001 mg to 0.4 mg of compound E, respectively. The amount of change in the tear meniscus height was measured in the same manner as in the evaluation test 5. The results of the average value of the amount of change are shown in FIGS. 12 and 13.

As can be seen from FIGS. 12 and 13, when a chewable tablet containing 0.2 mg of compound D and 0.001 mg to 0.2 mg (E / D = 0.005-1) of compound E, respectively, is ingested, tear meniscus is ingested. An improvement in the high increase effect was observed. On the other hand, when the compound E was 0.4 mg (E / D = 2), it was equal to or less than the case where the compound D alone was used.

Claims (7)

An exocrine promoter containing a compound represented by the following general formula (1) as an active ingredient.

(In the general formula (1), R ¹ represents a hydrogen atom, a hydroxyl group, or a methoxy group. R ² represents a hydrogen atom, a hydroxyl group, or a methoxy group. R ³ represents a hydrogen atom or a hydroxyl group. .R ^4, the .R ⁵ represents a hydrogen atom, or _-C 6 _H 11 _{O 5} group, .R ⁶ in which a hydroxyl group or a methoxy group, a hydrogen atom, or _-C 6 _H 11 _{O 5} group . R ⁷ represents a hydrogen atom or a hydroxyl group. However, one of R ⁴ and R ⁶ is -C ₆ H ₁₁ O ₅ groups. * Indicates an asymmetric carbon atom.) The exocrine promoter according to claim 1, wherein the _{-C 6} H ₁₁ O ₅ group represented as at least one of ^{R 4} and R ^{6 in} the general formula (1) is a group having a tetrahydropyran skeleton. The exocrine promoter according to claim 1 or 2, wherein the _{-C 6} H ₁₁ O ₅ group represented as at least one of ^{R 4} and R ^{6 in} the general formula (1) is a group having four hydroxyl groups. Further containing a compound represented by the compound represented by the following general formula (2),
The ratio of the compound represented by the general formula (2) to the compound represented by the general formula (1) (the compound represented by the general formula (2) / the compound represented by the general formula (1)) is The exocrine promoter according to any one of claims 1 to 3, which is 0.001 to 1.

The exocrine secretagogue according to any one of claims 1 to 4, wherein the daily intake is 0.001 to 1000 mg, and the intake is taken for 3 days or more. The exocrine secretagogue according to any one of claims 1 to 5, which is a stratum corneum water content increasing agent, a saliva secretion promoting agent, or a tear secretion promoting agent. An exocrine-promoting food composition containing the exocrine-promoting agent according to any one of claims 1 to 6.

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