TW202014104A - External secretagogue - Google Patents

Abstract

The present invention addresses the problem of providing, for the purpose of symptomatic improvement of dry skin, dry eye, dry mouth, etc., an external secretagogue that promotes external secretions in a comprehensive manner and that can be utilized as a food composition, and more specifically, providing an agent that increases the moisture content of the horny cell layer, a saliva secretagogue, and a tear fluid secretagogue. Provided is an external secretagogue including a compound represented by a general formula (1) as an effective component. More specifically, provided is an agent that increases the moisture content in the horny cell layer, a saliva secretagogue, or a tear fluid secretagogue. (In general formula (1): R1-R4, R6 and R7 each denote a hydrogen atom or the like; R5 denotes a hydroxyl group or the like; and * denotes an asymmetric carbon atom.).

Description

Exocrine promoter

The invention relates to an exocrine promoter. In more detail, the present invention relates to an agent for increasing the water content of the stratum corneum, an agent for promoting saliva secretion, and an agent for promoting secretion of tear fluid.

The term "exocrine" refers to secretion that occurs directly on the body surface or in the lumen of the body through gland cells or through a catheter. As a representative example of exocrine, saliva is known. In addition, secretion of nasal mucosa and respiratory tract mucosa, stomach and intestine secretion, vaginal secretion, sweat and the like can be cited. Examples of diseases accompanying the exocrine disorders include dry mouth (dry mouth), dry nose (dry nose), and dry eye (dry eye) , Dry skin (dry skin), vaginal dryness (dry vagina) (vaginal xerosis) and other dry symptoms; chronic pancreatitis, chronic gastritis, chronic bronchitis caused by the reduction of exocrine.

Dry skin can be judged by the amount of water in the stratum corneum. Therefore, if the moisture content of the stratum corneum is increased, the skin dryness can be improved. As an agent for increasing the amount of water in the stratum corneum, a technique using pine bark extract, hyaluronic acid (hyaluronic acid) and ceramide (ceramide) as active ingredients has been proposed (for example, refer to Patent Document 1); Technology of extract of Justicia procumbens) as an active ingredient (for example, refer to Patent Document 2).

In addition, there are 50 million consumers who feel distressed by dry eyes or dry mouth. Dry eyes can be judged by the amount of tears secreted. In addition, dry mouth can be judged by the amount of saliva secretion. Therefore, if you increase the amount of tears or saliva, you can improve dry eyes or dry mouth. In order to increase both tear secretion and saliva secretion, a technique of using a peptide derivative having activation of protease-activated receptors 2 (PAR-2) as an active ingredient (for example, refer to Patent Document 3); or a technique using fatty acid derivatives as an active ingredient (for example, refer to Patent Document 4). [Prior Art Literature] [Patent Literature]

Patent Document 1: Japanese Patent Laid-Open No. 2015-86160 Patent Document 2: Japanese Patent Laid-Open No. 2014-62090 Patent Document 3: Japanese Patent Special Publication No. 2005-538961 Patent Document 4: Japanese Patent Special Publication No. 2003-504397

[Problems to be solved by the invention] However, in order to improve symptoms such as dry skin, dry eyes, or dry mouth, a technique for promoting exocrines in general is desired. In addition, these symptoms are general symptoms that occur in daily life, so it is expected that they can be improved without relying on a doctor or drugs.

An object of the present invention is to provide an exocrine enhancer that can promote exocrine in general and can be used as a food composition in order to improve symptoms such as dry skin, dry eyes, or dry mouth, and more specifically, to provide an increase in moisture content of the stratum corneum Agents, salivary secretion promoters, and tear secretion promoters. [Means to solve the problem]

（所述通式（1）中，R¹ 表示氫原子、羥基、或甲氧基。R² 表示氫原子、羥基、或甲氧基。R³ 表示氫原子、或羥基。R⁴ 表示氫原子、或-C₆ H₁₁ O₅ 基。R⁵ 表示羥基、或甲氧基。R⁶ 表示氫原子、或-C₆ H₁₁ O₅ 基。R⁷ 表示氫原子、或羥基。其中，R⁴ 及R⁶ 中的一者為-C₆ H₁₁ O₅ 基。*表示不對稱碳原子） [2] 如所述[1]所述的外分泌促進劑，其中，所述通式（1）中，作為R⁴ 及R⁶ 中的至少一者而表示的-C₆ H₁₁ O₅ 基為具有四氫吡喃骨架的基團。 [3] 如所述[1]或[2]所述的外分泌促進劑，其中，所述通式（1）中，作為R⁴ 及R⁶ 中的至少一者而表示的-C₆ H₁₁ O₅ 基為具有4個羥基的基團。 [4] 如所述[1]至[3]中任一項所述的外分泌促進劑，其進而含有下述通式（2）所表示的化合物所表示的化合物，所述通式（2）所表示的化合物相對於所述通式（1）所表示的化合物的比率（通式（2）所表示的化合物/通式（1）所表示的化合物）為0.001～1。 [化2]

[5] 如所述[1]至[4]中任一項所述的外分泌促進劑，其中，每日攝取量為0.001 mg～1000 mg，攝取3天以上。 [6] 如所述[1]至[5]中任一項所述的外分泌促進劑，其為角質層水分量增加劑、唾液分泌促進劑、或淚液分泌促進劑。 [7] 一種外分泌促進用食品組成物，其包含如所述[1]至[6]中任一項所述的外分泌促進劑。 [發明的效果]The inventors of the present invention conducted intensive studies on the above-mentioned problems, and as a result, they found that the problems can be solved by using a compound represented by a specific chemical formula as an active ingredient, thereby completing the present invention. In addition, it has been found that by continuously ingesting the active ingredient, the symptom effect is improved. That is, the present inventors provide the following [1] to [7]. [1] An exocrine promoter comprising a compound represented by the following general formula (1) as an active ingredient. [Chemical 1]

(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 group. R ⁵ represents a hydroxyl group or a methoxy group. R ⁶ represents a hydrogen atom or a -C ₆ H ₁₁ O ₅ group. R ⁷ represents a hydrogen atom or a hydroxyl group. Among them, R ⁴ And one of R ⁶ is a -C ₆ H ₁₁ O ₅ group. * represents an asymmetric carbon atom) [2] The exocrine promoter described in [1] above, in which the 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 a tetrahydropyran skeleton. [3] The exocrine promoter according to [1] or [2], wherein in the general formula (1), -C ₆ H ₁₁ represented as at least one of R ⁴ and R ⁶ The O ₅ group is a group having 4 hydroxyl groups. [4] The exocrine promoter according to any one of the above [1] to [3], which further contains a compound represented by a compound represented by the following general formula (2), the general formula (2) The ratio of the compound represented 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 0.001 to 1. [Chem 2]

[5] The exocrine promoter according to any one of [1] to [4], wherein the daily intake is 0.001 mg to 1000 mg, and the intake is more than 3 days. [6] The exocrine promoting agent according to any one of the above [1] to [5], which is an agent for increasing the amount of water in the stratum corneum, a salivary secretion promoting agent, or a tear secretion promoting agent. [7] An exocrine-promoting food composition comprising the exocrine-promoting agent according to any one of [1] to [6]. [Effect of invention]

According to the present invention, in order to improve symptoms such as dry skin, dry eyes, or dry mouth, an exocrine promoter that can promote exocrine in general and can be used as a food composition can be provided. In more detail, an agent for increasing the amount of cuticle moisture can be provided , Saliva secretion promoter, and tear secretion promoter.

Hereinafter, the present invention will be described in detail in conjunction with its preferred embodiments.

[1. Active ingredients] In more detail, the exocrine promoter of the present invention includes the compound represented by the general formula (1) as a common active ingredient in the stratum corneum water content increasing agent, saliva secretion promoting agent, and tear secretion promoting agent.

[Chemical 3]

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 a -C ₆ H ₁₁ O ₅ group. R ⁵ represents a hydroxyl group or a methoxy group. R ⁶ represents a hydrogen atom or a —C ₆ H ₁₁ O ₅ group. R ⁷ represents a hydrogen atom or a hydroxyl group. Among them, one of R ⁴ and R ⁶ is a -C ₆ H ₁₁ O ₅ group. * Indicates an asymmetric carbon atom.

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

In the general formula (1), at least one of R ⁴ and R ⁶ is a -C ₆ H ₁₁ O ₅ group, and preferably R ⁶ is a -C ₆ H ₁₁ O ₅ group. In addition, the -C ₆ H ₁₁ O ₅ group is preferably a group having a tetrahydropyran skeleton, more preferably a group having 4 hydroxyl groups, and further preferably a group represented by the following formula (3). It is considered that at least one of R ⁴ and R ⁶ is a C-glycoside of -C ₆ H ₁₁ O ₅ group. Compared with O-glycoside, the glycoside portion is more difficult to cut in the intestine, and in the state where the glycoside is bonded Circulate in the blood. In addition, it is known that the O-glycoside of the formula (1) has antioxidant capacity, and it is considered that it strongly exhibits this effect by becoming a C-glycoside.

[Chemical 4]

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

[Chem 5]

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, still more preferably 0.1 mg or more, and still more preferably 0.2 mg or more. If it is 0.001 mg or more, in order to improve the symptoms of dry skin, dry eyes or dry mouth, it can promote exocrines in a comprehensive manner. On the other hand, the upper limit is preferably 1000 mg or less, more preferably 100 mg or less, further preferably 50 mg or less, and still more preferably 10 mg or less. If it is 1000 mg or less, bitterness can be suppressed, so it can be preferably used as a food composition. The daily intake of the compound represented by the general formula (1) is preferably 0.001 mg to 1000 mg, more preferably 0.05 mg to 100 mg, further preferably 0.1 mg to 50 mg, and still more preferably 0.2 mg to 10 mg .

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, and still more preferably 7 days or more. In the examples described later, when the compound represented by the general formula (1) is continuously ingested, the cuticle moisture content, saliva volume, and tear meniscus height are improved, and it is expected that the skin is dry and the eyes Improvement of symptoms such as dryness or dry mouth. In addition, the compound represented by general formula (1) may be used alone as an active ingredient, or two or more kinds may be used in combination.

[2. Exocrine promoters, horny layer moisture increase agents, saliva secretion promoters, tear secretion promoters] The exocrine promoter of the present invention, more specifically, an agent for increasing the amount of cuticle moisture, an agent for promoting saliva secretion, an agent for promoting secretion of tears (hereinafter, also collectively and only described as "preparation") The indicated compound serves as an active ingredient. In view of the effectiveness, the exocrine promoter of the present invention, in more detail, the cuticle moisture increasing agent, saliva secretion promoting agent, tear secretion promoting agent can be expected to be used as a skin dryness improving agent, mouth dryness improving agent, eye Drying improver.

The exocrine promoting agent of the present invention, more specifically, the stratum corneum water content increasing agent, saliva secretion promoting agent, tear secretion promoting agent preferably contains the compound represented by the compound represented by the following general formula (2) as the above Additives for active ingredients. In the case where the compound represented by the general formula (2) is included as an adjuvant for the 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. If the range of the ratio is within the above 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 still more preferably 0.1 or less. In addition, the lower limit value is preferably 0.002 or more, more preferably 0.01 or more, and still more preferably 0.04 or more. Furthermore, in the case where the compound represented by the general formula (2) is included as an adjunct to the active ingredient, if the ratio exceeds 1, the compound represented by the general formula (1) may be significantly reduced as an effective ingredient Effect.

[化6]

The formulation 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 any route of oral (eg, intraoral, sublingual), non-oral (eg, eye drops, intravenous, intramuscular, subcutaneous, transdermal, nasal, and pulmonary). Among these routes, the less invasive route is preferred, and the oral route is more preferred.

Examples of the form in the case of oral ingestion (oral administration) include powder, fine granules, granules, capsules, sachets, tablets, bolus, and lozenge. Etc. solid forms; aqueous solutions, extracts, suspensions, syrups, elixirs, emulsions, dispersions and other liquid forms; semi-liquid, cream, paste ) Shape and other forms. Among them, it is preferably in the form of a powder or a concentrate in a capsule, that is, a pill; as in the case of drinking powdered tea, in the form of a powder that can be ingested after being put in or dissolved in a liquid such as water or hot water; freeze-dried (freeze drying) granular forms such as granules; chewable forms such as tablets ingestion (administration).

Examples of forms for parenteral administration include eye drops for liquids such as aqueous solutions, extracts, suspensions, emulsions, and dispersions; ophthalmic agents such as semi-liquid forms, pastes, and pastes; and aqueous solutions. Intravenous injections, intramuscular injections or subcutaneous injections of liquids such as extracts, suspensions, emulsions, dispersions, etc.; transdermal administration of liquids such as aqueous solutions, extracts, suspensions, emulsions, dispersions; aqueous solutions, extractions Liquids, suspensions, emulsions, dispersions and other liquids, powders, fine particles and other forms of nasal administration or transpulmonary administration.

[3. Food composition for exocrine promotion] The preparation of the present invention can also be directly ingested (administered). In addition, the preparation of the present invention can also be used to impart to foods, drinks, functional foods, and compositions selected from tear secretion promoting effect, eye fatigue prevention/improving effect, and eye regulating power reduction prevention/improving effect, saliva volume increasing effect , And at least one additive in the group consisting of the effect of increasing the amount of tear fluid.

The food, drink, functional food, and composition that can be prepared by using the formulation of the present invention as an additive are not particularly limited. For example, beverages (cool drinks, carbonated drinks, nutritious drinks, powder drinks, fruit drinks, milk drinks, jelly drinks, etc.), cakes (cookies, cakes, gum), candy (candy) ), tablet, gummies, buns, yolk, pudding, jelly, ice cream, sherbet, etc.), processed aquatic products (fish cake, cylindrical fish cake, fish meat) Potato cakes, etc.), processed livestock products (hamburger, ham, sausage, wienerwurst), cheese, butter, yogurt, fresh cream, margarine , Fermented milk, etc.), soup (powder soup, liquid soup, etc.), staple foods (rice, noodles (dry noodles, raw noodles), bread, cereals, etc.), seasonings (mayonnaise), ghee (Shortening), dressing, sauce, sauce, soy sauce, etc.).

In addition, the preparation of the present invention can also be used as, for example, an internal composition or a pharmaceutical composition included as an active ingredient in a composition for promoting tear secretion, for preventing or improving eye fatigue, or for preventing or improving eye accommodation. use.

The formulation or composition of the present invention may also contain any commonly used auxiliary ingredients for manufacturing solid dosage forms or liquid dosage forms, such as excipients, disintegrating agents, diluents, buffers, perfumes, colorants, flavoring agents, adhesives At least one of agents, surfactants, tackifiers, lubricants, suspending agents, preservatives, antioxidants, etc.

Examples of the excipients include celluloses such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, crystalline cellulose, ethyl cellulose, and low-substituted hydroxypropyl cellulose, and the like. Pharmacologically allowed derivatives; polyvinyl pyrrolidone, partially saponified polyvinyl alcohol and other synthetic polymers; gelatin, arabic gum powder, polytriglucose (pullulan), agar (agar), seaweed Acid, sodium alginate, xanthan gum and other polysaccharides; corn starch, potato starch, alpha starch, hydroxypropyl starch and other pharmacologically acceptable derivatives; lactose, fructose, glucose, White sugar, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, reduced palatinose, powdered reduced maltose Sugars, maltitol, brown sugar glucose liquid sugar and other sugars and sugar alcohols; light silicic anhydride, particulate silica, titanium oxide, aluminum hydroxide gel and other inorganic excipients.

Examples of the disintegrant include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and carboxyl group. Methyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, hydroxypropyl starch, partially alpha starch.

Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin, and dextrin (dextrin) ), starch, alpha starch.

Examples of lubricants include calcium stearate, magnesium stearate, sucrose fatty acid esters, light silicic anhydride, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid.

Examples of flavoring agents include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, acesulfame potassium, thaumatin, and sucralose. ), fructose and other sweetener preparations; citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid or these salts and other acidic materials.

Examples of antioxidants include ascorbic acid, ascorbyl palmitate, propyl gallate, dibutyl hydroxy toluene (BHT), butylated hydroxyanisole (BHA), and edible food. A mixture of propyl gallate and citric acid, hydroquinone, tertiary butyl hydroquinone, disaccharide trehalose, natural tocopherol compounds, long-chain esters of gallic acid (C8 ~ C22), such as Lauryl sub-acid, Irganox compounds available from Ciba Specialty Chemicals (shares), citric acid and/or isopropyl citrate, 4,5-di Hydroxy m-benzenesulfonic acid/sodium salt, dimethoxyphenol, catechol, methoxyphenol, carotenoids, furans, amino acids.

Examples of the coloring agent include lycopene base, safflower red pigment, gardenia yellow pigment, gardenia blue pigment, perilla pigment, red yeast pigment, purple Cabbage pigment, carrot pigment, hibiscus (Hibiscus) pigment, cocoa pigment, spirulina (spirulina) blue pigment, tamarind (tamarind) pigment and other natural pigments; or red No. 3, red No. 104, red No. 105, red No. 106, yellow No. 4, yellow No. 5 , Green No. 3, Blue No. 1 and other legal pigments; riboflavin, sodium chlorophyllin, titanium dioxide.

Examples of fragrance-enhancing agents include hydrocarbons such as aliphatic hydrocarbons, terpene olefins, and aromatic hydrocarbons; alcohols such as aliphatic alcohols, terpene alcohols, and aromatic alcohols; ethers such as aliphatic ethers and aromatic ethers; and fats Oxides such as family oxides and terpene oxides; aliphatic aldehydes, terpene aldehydes, hydrogenated aromatic aldehydes, thioaldehydes, aromatic aldehydes and other aldehydes; aliphatic ketones, terpene ketones, Hydrogenated aromatic ketones, aliphatic cyclic ketones, non-benzene aromatic ketones, aromatic ketones and other ketones; acetals, ketals, phenols, phenol ethers; fatty acids, terpene carboxylic acids, hydrogenated aromatics Acids such as aromatic carboxylic acids and aromatic carboxylic acids; amides; aliphatic lactones, macrocyclic lactones, terpene lactones, hydrogenated aromatic lactones, aromatic lactones and other lactones; aliphatic Esters, furan-based carboxylic acid esters, aliphatic cyclic carboxylic acid esters, cyclohexyl carboxylic acid esters, terpene-based carboxylic acid esters, aromatic carboxylic acid esters, etc.; nitro musk, nitrile , Amines, pyridines, quinolines, pyrrole, indole and other synthetic spices such as nitrogen-containing compounds and natural spices derived from animals or plants and other spices. [Example]

Hereinafter, the present invention will be described in detail by examples. The following embodiments are used to better illustrate the present invention, and do not limit the present invention.

The chemical formulae of compound A to compound D used in the following examples are shown below. In addition, all the compounds A to D used commercially available products.

[化7]

(Preparation of lozenges) The preparation method of the chewable lozenges and placebo lozenges used in the evaluation test described below is described. Dextrin (Pinedex) with 0.05 mg to 1 mg of compound A to compound D and 49 mg to 49.95 mg (variable with the amount of compound A to compound D and set the total amount to 50 mg) (Pinedex)# 2. Made by Matsutani Chemical Industry Co., Ltd., 100 mg of erythritol (“erythritol 50M”, manufactured by Sangyo Food Science Co., Ltd.), 90 mg of crystalline cellulose (“Ceolus ST-100”) , Manufactured by Asahi Kasei Corporation), 10 mg of calcium stearate ("calcium stearate", manufactured by Taiping Chemical Industry Co., Ltd.), uniformly mixed, and directly pressed into tablets at 12 kN to prepare tablets. However, in the case of placebo lozenges, compound A to compound D were set to 0 mg, and instead, dextrin was set to 50 mg.

(Evaluation Test 1: Evaluation of Improvement of Cuticle Moisture 1) 10 subjects were ingested with chewable lozenges separately formulated with 0.3 mg of Compound A to Compound D, chewable lozenges respectively formulated with 0.3 mg of Compound B and Compound D, and those not formulated with Compound A to Compound D Placebo tablets. The subjects spent 21±2°C and 50±5%RH in a constant temperature room from the time of ingestion until the end of the measurement. Before and after 120 minutes of ingestion, the subjects were measured using SKICON-200 (manufactured by IBS) The amount of cuticle moisture in the inner arm of the right arm. The moisture content of the stratum corneum can be obtained by flowing a weak current into the deep part (mainly stratum corneum) about 30 μm from the skin surface and measuring the resistance value. However, the vascular part is excluded. Calculate the amount of change in the water content of the stratum corneum before and 120 minutes after ingestion The results of the average value of the changes are shown in FIG. 1 and Table 1.

[Table 1]

It can be seen from FIG. 1 and Table 1 that if a chewable lozenge prepared separately containing 0.3 mg of Compound B to Compound D is taken, the amount of water in the stratum corneum of the subject increases. In addition, if a chewable lozenge each compounded with 0.3 mg of Compound B and Compound D is ingested, the effect of increasing the moisture content of the stratum corneum of the subject is improved. On the other hand, for placebo tablets and chewable tablets formulated with 0.3 mg of Compound A, almost no increase in the cuticle moisture content of the subjects was found.

(Evaluation Test 2: Evaluation of improvement of cuticle moisture content 2) The 10 subjects were ingested chewable lozenges each compounded with 0.05 mg to 1 mg of Compound D. It was spent under the same conditions as in Evaluation Test 1, and the cuticle moisture content after 120 minutes of ingestion was measured by the same method. Calculate the amount of change in the water content of the stratum corneum before and 120 minutes after ingestion. The results of the average value of the changes are shown in FIG. 2 and Table 2.

[Table 2]

As can be seen from FIG. 2 and Table 2, if a chewable lozenge compounded with 0.1 mg or more of Compound D is ingested, it is found that the effect of improving the moisture content of the stratum corneum is improved. In addition, when the compounding amount of Compound D is increased, the effect of improving the moisture content of the stratum corneum has been further improved.

(Evaluation Test 3: Improvement Evaluation of Dryness of Skin) Ten subjects were ingested once a week with a chewable lozenge and placebo lozenge compounded with 0.3 mg of Compound D. On the 1st, 3rd and 7th day of ingestion, use the Visual Analogue Scale (VAS) method (refer to Ahlsio B, Britton M, Murray) ) V, Theorell T; Disablement and quality of life after stroke (Stroke) 15:886-890, 1984.) to evaluate the improvement of dryness of the skin . Regarding the answer, the case of "very improved" of the dryness of the skin compared to before intake was set to 100, and the case of "totally unimproved" was set to 0, and the improvement value of each subject was evaluated using the median value. Evaluation. The results of the average of the values are shown in Fig. 3 and Table 3.

[table 3]

As can be seen from FIG. 3 and Table 3, if a chewable lozenge compounded with 0.3 mg of Compound D is ingested, the feeling of dryness is improved in one day. In addition, if the tablet is continuously ingested for 3 days or more, it is confirmed that the improvement effect of the dry feeling is maintained.

(Evaluation Test 4: Evaluation of improvement in saliva volume 1) 10 subjects were ingested with chewable lozenges separately formulated with 0.3 mg of Compound A to Compound D, chewable lozenges respectively formulated with 0.3 mg of Compound B and Compound D, and those not formulated with Compound A to Compound D Placebo tablets. The subject spent in a constant temperature room of 21±2°C and 50±5%RH from the time of ingestion until the end of the measurement, and spit out saliva in a quiet state for 10 minutes before and 120 minutes after ingestion. However, oral activity is prohibited from 1 hour before the measurement. The amount of change in saliva volume before ingestion and 120 minutes after ingestion was measured. The results of the average value of the changes are shown in FIG. 4 and Table 4.

[Table 4]

(Evaluation Test 5: Evaluation of improvement of tear meniscus height 1) After the test of Evaluation Test 4, an optical interference tomograph (RS-3000 Advance, manufactured by NIDEK) was used to measure the corneal-lower eyelid interpupillary pupil 2 seconds after 2 blinks. The meniscus height of the accumulated tears. However, oral activity is prohibited from 1 hour before the measurement. The amount of change in the meniscus height of tears before and 120 minutes after ingestion was measured. The results of the average value of the changes are shown in FIG. 5 and Table 5.

[table 5]

It can be seen from FIG. 4 and Table 4 that if a chewable lozenge compounded with 0.3 mg of Compound B to Compound D alone is ingested, the amount of saliva of the subject increases as compared with the placebo or Compound A. In addition, as can be seen from FIG. 5 and Table 5, if chewable lozenges each compounded with 0.3 mg of Compound B to Compound D are ingested, the tear meniscus height of the subject increases. In addition, if a chewable lozenge each compounded with 0.3 mg of Compound B and Compound D was ingested, the effect of increasing the height of the tear meniscus of the subject was significantly improved. On the other hand, for placebo tablets and chewable tablets formulated with 0.3 mg of Compound A, no increase in tear meniscus height was found.

(Evaluation Test 6: Evaluation of improvement in saliva volume 2) With respect to the 10 subjects, 0.05 mg to 1 mg of Compound D was separately formulated for the chewable lozenge, and the amount of change in the amount of saliva was measured in the same manner as in Evaluation Test 4. The results of the average value of the changes are shown in FIG. 6 and Table 6.

[Table 6]

(Evaluation Test 7: Evaluation of improvement of tear meniscus height 2) For the 10 subjects, 0.05 mg to 1 mg of Compound D was prepared for each chewable lozenge, and the amount of change in tear meniscus height was measured in the same manner as in Evaluation Test 5. The results of the average value of the changes are shown in FIG. 7 and Table 7.

[Table 7]

As can be seen from FIG. 6 and Table 6, if a chewable lozenge compounded with 0.2 mg or more of Compound D is ingested, the amount of saliva of the subject increases compared to the placebo. In addition, as can be seen from FIG. 7 and Table 7, if a chewable lozenge compounded with 0.05 mg or more of Compound D is ingested, the effect of increasing the tear meniscus height of the test subject is found. In addition, if a chewable lozenge compounded with 0.1 mg or more of Compound D is ingested, a significant increase effect of the tear meniscus height of the subject is found.

(Evaluation Test 8: Evaluation of improvement of oral dryness) Twelve subjects were ingested once a week a chewable lozenge and placebo lozenge compounded with 0.3 mg of Compound D. On the first day, the third day, and the seventh day of ingestion, the VAS (Visual Analogue Scale) method was used to evaluate the improvement of oral dryness. Regarding the answer, the case of "very improved" dryness in the oral cavity compared to before intake was set to 100, and "completely unimproved" was set to 0, and the intermediate value was used to self-evaluate the improvement degree of each subject . The results of the average of the values are shown in FIG. 8 and Table 8.

[Table 8]

(Evaluation Test 9: Evaluation of improvement in dryness of eyes) Twelve subjects were ingested once a week a chewable lozenge and placebo lozenge compounded with 0.3 mg of Compound D. On the first day, the third day, and the seventh day of ingestion, the VAS (Visual Analogue Scale) method was used to evaluate the improvement in dryness of the eye. Regarding the answer, the case where the dryness of the eyes was "very improved" compared to before ingestion was set to 100, and the "completely unimproved" was set to 0, and the improvement value of each subject was self-assessed using the median value. The results of the average of the values are shown in FIG. 9 and Table 9.

[Table 9]

As can be seen from FIG. 8 and Table 8, if a chewable lozenge compounded with 0.3 mg of Compound D is ingested, the dryness in the oral cavity will be improved in one day. In addition, if the tablets are continuously ingested for more than 3 days, a significant improvement effect of the dryness of the mouth is confirmed. In addition, as can be seen from FIG. 9 and Table 9, if a chewable lozenge formulated with 0.3 mg of Compound D is ingested, the dryness of the eyes is improved in one day. In addition, if the tablet is continuously ingested for more than 3 days, a significant improvement effect of dry eye feel is confirmed.

Recipe examples are described below. In addition, the compound (1)-compound (5) used in the formulation example is shown in Table 10. Table R 10, R ¹ ~ R ⁷ corresponding to the following general formula (1) is ¹ ~ R ^7. The -C ₆ H ₁₁ O ₅ group is a three-dimensional structure represented by the following formula (3).

[Chem 8]

[化9]

[Table 10]

(Formulation Example 1: Lozenges) Compound (1) 0.3 mg Dextrin 49.7 mg 49.7 mg Erythritol 100 mg Crystalline cellulose 90 mg Calcium stearate 10 mg Total 250 mg 250 mg

(Formulation Example 2: Lozenges) Compound (1) 0.3 mg Compound (2) 0.3 mg Dextrin 49.4 mg 49.4 mg Erythritol 100 mg Crystalline cellulose 90 mg Calcium stearate 10 mg Total 250 mg 250 mg

(Formulation Example 3: Lozenges) Compound (3) 0.3 mg Compound (4) 0.3 mg Dextrin 49.4 mg 49.4 mg Erythritol 100 mg Crystalline cellulose 90 mg Calcium stearate 10 mg Total 250 mg 250 mg

(Formulation Example 4: Lozenges) Compound (2) 0.3 mg Compound (5) 0.3 mg Dextrin 49.4 mg 49.4 mg Erythritol 100 mg Crystalline cellulose 90 mg Calcium stearate 10 mg Total 250 mg 250 mg

(Formulation Example 5: Drinks) Compound (3) 0.3 mg Compound (5) 0.3 mg Brown sugar glucose liquid sugar 250 mg Erythritol 200 mg 200 mg Sweetener preparation 1.4 mg 1.4 mg Ascorbic acid 3 mg Spices 12 mg 12 mg Lycopene matrix 8 mg Pure water Appropriate amount Total Total 10 g

The chemical formula of Compound E used in the following Evaluation Test 10 to Evaluation Test 12 is shown below. In addition, as the compound E, a commercially available product was used.

[化10]

(Evaluation Test 10: Evaluation of improvement of cuticle moisture content 3) Ten subjects were ingested with a chewable lozenge compounded with 0.2 mg of Compound D and compounded with 0.001 mg to 0.4 mg of Compound E, respectively. It was spent under the same conditions as in Evaluation Test 1, and the cuticle moisture content after 120 minutes of ingestion was measured by the same method. Calculate the amount of change in the water content of the stratum corneum before and 120 minutes after ingestion. The results of the average value of the changes are shown in FIG. 10 and Table 11.

[Table 11]

It can be seen from Fig. 10 and Table 11 that if ingested chewable lozenges compounded with 0.2 mg of Compound D and compounded with compound E of 0.001 mg to 0.2 mg (E/D=0.005 to 1), the moisture content of the stratum corneum is found The improvement effect is improved. On the other hand, the case where Compound E is 0.4 mg (E/D=2) is equivalent to the case where Compound D alone is used.

(Evaluation Test 11: Evaluation of improvement in saliva volume 3) Ten subjects were ingested with a chewable lozenge compounded with 0.2 mg of Compound D and compounded with 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 changes are shown in FIG. 11 and Table 12.

[Table 12]

As can be seen from FIG. 11 and Table 12, if ingested chewable lozenges formulated with 0.2 mg of Compound D and compounded with 0.001 mg to 0.2 mg (E/D=0.005 to 1), respectively, an improvement in the amount of saliva was found The effect is improved. On the other hand, the case where Compound E is 0.4 mg (E/D=2) is equivalent to the case where Compound D alone is used.

(Evaluation Test 12: Evaluation of improvement of tear meniscus height 3) Ten subjects were ingested with a chewable lozenge compounded with 0.2 mg of Compound D and compounded with 0.001 mg to 0.4 mg of Compound E, respectively. The amount of change in the meniscus height of tears was measured in the same manner as in Evaluation Test 5. The results of the average value of the changes are shown in FIG. 12 and Table 13.

[Table 13]

As can be seen from FIG. 12 and Table 13, if a chewable lozenge compounded with 0.2 mg of compound D and compounded with 0.001 mg to 0.2 mg (E/D=0.005 to 1), the tear meniscus is found The effect of increasing the height is improved. On the other hand, the case where Compound E is 0.4 mg (E/D=2) is equal to or less than the case where Compound D alone is used.

no

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

Claims (7)

An exocrine promoter that uses 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 represents a hydrogen atom , Or -C ₆ H ₁₁ O ₅ group; R ⁵ represents a hydroxyl group or a methoxy group; R ⁶ represents a hydrogen atom, or a -C ₆ H ₁₁ O ₅ group; R ⁷ represents a hydrogen atom or a hydroxyl group; wherein, R ⁴ And one of R ⁶ is -C ₆ H ₁₁ O ₅ group; * represents an asymmetric carbon atom). The exocrine promoter according to item 1 of the patent application scope, wherein in the general formula (1), the -C ₆ H ₁₁ O ₅ group represented as at least one of R ⁴ and R ⁶ has four Hydropyran skeleton group. The exocrine-promoting agent according to item 1 or 2 of the patent application scope, wherein in the general formula (1), -C ₆ H ₁₁ O ₅ represented as at least one of R ⁴ and R ⁶ The group is a group having 4 hydroxyl groups. The exocrine-promoting agent according to any one of claims 1 to 3, which further contains a compound represented by a compound represented by the following general formula (2), and the general formula (2) The ratio of the compound represented 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 0.001 to 1;

. The exocrine promoter according to any one of the first to fourth patent application ranges, wherein the daily intake is 0.001 mg to 1000 mg, and the intake is more than 3 days. The exocrine promoter as described in any one of the first to fifth patent claims, which is a cuticle water content increasing agent, a saliva secretion promoting agent, or a tear secretion promoting agent. An exocrine-promoting food composition comprising the exocrine-promoting agent according to any one of items 1 to 6 of the patent application.

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