JP2014162761A - BLOOD apoCI CONCENTRATION REDUCER - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide materials which can reduce blood apoCI concentrations by ingestion.SOLUTION: An oral blood apoCI (apolipoprotein CI) concentration reducer comprises, as an active ingredient, at least one selected from the group consisting of gabexate mesilate, alacepril, crotamiton, tiopronin, sorbic acid, N,N-dimethylacetamide, cycloserine, sebacic acid diisopropyl, isosorbide dinitrate, licinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate.

Description

  The present invention relates to a blood apoCI concentration lowering agent.

  The skin covers the outermost layer of the living body, forms a boundary with the outside world, and has a barrier function essential for life support such as prevention of entry of outside substances and prevention of moisture evaporation. Known to induce dry skin, atopic dermatitis, skin roughness, etc. if the skin barrier function is impaired by ultraviolet rays, surfactants, drying, mechanical irritation, active oxygen, residual chlorine in tap water, etc. Yes.

  Conventionally, as means for improving the skin barrier function and moisturizing function, transdermal administration of lotions and creams containing oil and moisturizing ingredients is generally used. More recently, attempts have been made to control skin function by controlling body fluid components through ingestion of oral formulations. Patent Document 1 describes that a composition for oral administration containing a syrup improving agent comprising a bile acid such as cholic acid or a salt thereof obtains a skin beautifying effect, an atopic dermatitis therapeutic effect, and a dermatitis group therapeutic effect. Has been. Non-Patent Document 1 and Patent Documents 2 to 3 describe that the moisture retention function of skin is improved by oral intake of ceramide, hyaluronic acid, collagen, or chondroitin sulfate.

  Apolipoprotein CI (hereinafter apoCI) is known as a protein that constitutes lipoprotein in blood. In apoCI overexpressing mice, it is known that the levels of total cholesterol, triglycerides and free fatty acids in blood increase (Non-patent Document 2). On the other hand, when apoCI is overexpressed locally in the skin, it has been reported that abnormal skin, increased transdermal water transpiration (TEWL), and atopic dermatitis-like symptoms occur (Non-Patent Documents 3 to 5). . However, no attempt has been made so far to connect blood apoCI concentration with skin function. In addition, it has not been known so far that skin function can be controlled by a compound that regulates the apoCI concentration in blood.

Japanese Patent Laid-Open No. 10-114665 JP 2002-356432 A JP 2009-073775 A

Fragrance Journal 123 (1), 81 (1995) J. Clin. Invest., 101 (1), 145-152 (1998) J. Lipid Res., 48, 1353-1361 (2007) J. Invest. Dermatol., 128 (5), 1165-1172 (2008) B. J. Dermatol., 160, 54-61 (2009)

  The present invention relates to a material that can reduce apoCI concentration in blood by ingestion and thereby improve skin functions such as skin barrier function and skin moisturizing function.

  The present inventors investigated the relationship between skin functions such as a skin barrier function and a skin moisturizing function and various blood protein concentrations, and found that the concentration of apoCI in the blood affects the skin function. The inventor further searched for a substance that can reduce the apoCI concentration in blood when ingested orally and found that the substance can be used as an agent for improving oral skin function.

That is, the present invention relates to gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, And an oral blood apoCI concentration-reducing agent comprising at least one selected from the group consisting of sodium deoxycholate as an active ingredient.
The present invention also includes gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, And an oral skin function improving agent comprising at least one selected from the group consisting of sodium deoxycholate as an active ingredient.
The present invention also includes gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, And prevention or improvement of rough skin due to dryness or chemical substances, prevention or improvement of skin aging, prevention of skin deterioration, for oral administration or ingestion, comprising as an active ingredient at least one selected from the group consisting of sodium deoxycholate Alternatively, the present invention provides an agent for improvement, prevention or improvement of atopic dermatitis, or prevention or improvement of various diseases caused by a decrease in the immune function of the epidermis.

  ADVANTAGE OF THE INVENTION According to this invention, the raw material which can reduce the apoCI density | concentration in blood by oral administration or ingestion is provided. Moreover, according to this invention, the raw material which can improve skin functions, such as a skin barrier function and a skin moisturizing function, is provided by oral administration or ingestion.

Transdermal water transpiration (TEWL) value (A) and low blood apoCI concentration (B) in the skin low barrier group and the high barrier group. *: P <0.05, ***: p <0.001. Relative apoCI concentration in blood in the test substance administration group. Transdermal water transpiration (TEWL) value (A) and blood relative apoCI concentration (B) in mice treated with sodium deoxycholate. **: p <0.01.

  As used herein, “non-therapeutic” does not include medical practice, that is, does not include methods for operating, treating or diagnosing humans. It is a concept that does not include a method for the recipient to perform surgery, treatment or diagnosis on humans.

  As used herein, “improvement” of a disease, symptom or condition refers to improvement of the disease, symptom or condition, prevention or delay of deterioration of the disease, symptom or condition, prevention or delay of progression of the disease, symptom or condition, or Recovery from a disease, symptom, or condition.

  As used herein, “prevention” refers to preventing or delaying the onset of a disease, symptom or condition in an individual, or reducing the risk of developing an individual's disease, symptom or condition.

  In the present specification, “improvement of skin function” includes improvement of various skin functions including skin moisturizing function, skin barrier function and epidermal immune function. In a more specific example, an increase in the amount of moisture retained in the skin or a decrease in the amount of transdermal moisture transpiration is an example of an improvement in skin function, and is included in the “improvement of skin function” herein. .

  The transdermal moisture transpiration (TEWL) value is known as an index of the skin barrier function and moisturizing function (HY. Jeon, JK Kim, WG Kim SJ Lee, Skin Pharmacol Physiol 2009, 22: 137-141). When the TEWL value is high, it means that the skin has lost the barrier function and the amount of water is decreasing. Conversely, when the TEWL value is low, the skin retains the high barrier function and the moisturizing function is improved. Represents that. Furthermore, the skin barrier function and moisturizing function state may be various skin function states such as epidermal immune function, rough skin state, skin aging state, skin deterioration state, atopic dermatitis state, and epidermis. This reflects the state of various diseases caused by a decrease in immune function. Therefore, the TEWL value also indicates the good or bad state of the immune function of the epidermis, the good or bad state of rough skin, the good or bad state of skin aging, the good or bad state of skin deterioration, the state of atopic dermatitis It can be an indicator of the goodness or badness of the disease and the goodness or badness of various disease states resulting from a decrease in the immune function of the epidermis.

  The present inventors have found that the blood apoCI concentration of an individual increases or decreases in parallel with respect to the TEWL value that is an index of various skin functions described above. As shown in FIG. 1, the blood apoCI concentration is high in the group with a high TEWL value, while the blood apoCI concentration is low in the group with a low TEWL value. The blood apoCI concentration measured from the group with a low TEWL value is significantly lower than the blood apoCI concentration measured from the group with a high TEWL value. Therefore, the blood apoCI concentration can be an index that reflects the skin barrier function and moisturizing function as well as the TEWL value. As a result, like the TEWL value, the immune function of the epidermis, the state of rough skin, the state of skin aging, It can also be an index reflecting various skin functions such as the state of skin deterioration, the state of atopic dermatitis, the state of various diseases caused by a decrease in the immune function of the epidermis. That is, the skin function of the individual is reflected in the blood apoCI concentration. Individuals with low apoCI concentration in blood have high skin barrier function, moisturizing function, and immune function of epidermis, and rough skin due to dryness and chemical substances, skin aging, skin deterioration, atopic dermatitis, or epidermis It is an individual in which various diseases resulting from a decrease in immune function are prevented or improved.

  Therefore, a substance capable of lowering the apoCI concentration in blood improves skin functions such as skin barrier function and moisturizing function, and prevents and / or prevents rough skin due to dryness or chemical substances, skin aging, skin deterioration, etc. It is a substance that can improve and further improve the immune function of the epidermis to prevent and / or improve various diseases caused by atopic dermatitis and a decrease in the immune function of the epidermis.

  As shown in Examples below, the compounds described in Table 1 below were orally administered to reduce the apoCI concentration in the blood of an individual (FIG. 2). These substances can be used to reduce apoCI levels in the blood by oral administration. Moreover, orally administering the compound of Table 1 reduced the apoCI density | concentration in blood, and the TEWL value fell (FIG. 3). That is, by orally administering the compounds shown in Table 1, skin functions such as skin barrier function and moisturizing function are improved through reduction of blood apoCI concentration. Further, skin deterioration and the like can be prevented and / or improved, and the immune function of the epidermis can be further improved to prevent and / or improve various diseases caused by atopic dermatitis and a decrease in the immune function of the epidermis.

  The substances listed in Table 1 are substances conventionally administered orally as pharmaceuticals and pharmaceutical additives. However, it has not been known that oral administration of these compounds has the effect of reducing blood apoCI concentration and thereby improving skin function.

  Accordingly, the present invention provides an oral blood apoCI concentration-reducing agent comprising at least one selected from the group consisting of the compounds described in Table 1 as an active ingredient. The oral blood apoCI concentration lowering agent is an oral agent for lowering blood apoCI concentration. Moreover, this invention provides the oral skin function improving agent which uses as an active ingredient at least 1 selected from the group which consists of a compound of Table 1. Examples of the skin function improving agent include a skin barrier function improving agent and a skin moisturizing function improving agent. Furthermore, the present invention provides an active ingredient containing at least one selected from the group consisting of the compounds listed in Table 1 for the prevention of rough skin due to dryness or chemical substances, skin aging, skin deterioration, etc. The present invention provides an agent for improving / reducing various diseases caused by atopic dermatitis or a decrease in the immune function of the epidermis. In one embodiment, the agent consists essentially of at least one selected from the group consisting of the substances listed in Table 1.

  In another embodiment of the present invention, the compounds listed in Table 1 can be used orally administered alone or in any combination to reduce apoCI levels in the blood. Alternatively, the compounds listed in Table 1 can be used orally administered alone or in any combination to improve skin function. Examples of the improvement of the skin function include an improvement of a skin barrier function and a moisturizing function. Alternatively, the compounds shown in Table 1 may be used alone or in any combination to prevent and / or ameliorate skin roughness, skin aging, skin deterioration, etc. due to dryness or chemical substances by oral administration or ingestion. It can be used to improve or prevent and / or improve various diseases caused by atopic dermatitis or a decrease in the immune function of the epidermis. The use may be for use in a human or non-human mammal and may be for therapeutic or non-therapeutic use. Non-therapeutic uses include preventing skin dryness for cosmetic or aesthetic purposes, improving skin moisturizing function, or preventing and / or improving rough skin, skin aging, and skin deterioration. The use of the compounds listed in Table 1 may be mentioned.

  In yet another aspect of the present invention, the compounds listed in Table 1 can be used alone or in any combination for the manufacture of an oral blood apoCI concentration-reducing agent. In yet another embodiment, the compounds listed in Table 1 can be used alone or in any combination for the production of an oral skin function improving agent. Examples of the skin function improving agent include a skin barrier function improving agent and a skin moisturizing function improving agent. Or, for oral administration or ingestion, prevention and / or amelioration of rough skin due to dryness or chemical substances, skin aging, skin deterioration, etc., epidermal immune function improver, or atopic dermatitis or decrease in immune function of epidermis It can be used for the prevention of various diseases caused by the above and / or the production of an ameliorating agent. In one embodiment, the effect of the agent is provided by a reduction in blood apoCI concentration.

  The compounds listed in Table 1 also prevent skin roughness such as dryness or chemical substances, skin aging, skin deterioration, etc. to improve skin functions such as improvement of skin barrier function and moisturizing function due to lowering of apoCI concentration in blood And / or an oral preparation intended to improve or improve the immune function of the epidermis and to prevent and / or improve various diseases caused by atopic dermatitis and a decrease in the immune function of the epidermis, for example, It is used for the production of oral preparations such as pharmaceuticals, quasi-drugs, foods and drinks, and feeds, and may be an active ingredient having the effect. The above-mentioned medicine, quasi drug, food and drink, feed and the like can be produced or used for human or non-human mammals. Such pharmaceuticals, quasi drugs, foods and drinks, feeds and the like are also within the scope of the present invention.

  The said pharmaceutical or quasi-drug contains the compound of Table 1 as an active ingredient. The pharmaceutical or quasi drug can be administered in any oral dosage form. Dosage forms for oral administration include, for example, solid dosage forms such as tablets, coated tablets, granules, powders, capsules, and liquid dosage forms such as elixirs, syrups and suspensions.

  The above-mentioned food and drink or feed is used for the reduction of blood apoCI concentration, improvement of skin function such as improvement of skin barrier function and moisturizing function, and prevention and / or improvement of rough skin due to drying and chemical substances, prevention of skin aging and To prevent and / or improve various diseases caused by // improvement, prevention and / or improvement of skin deterioration, improvement of the epidermal immune function, or atopic dermatitis or reduction of the immune function of the epidermis It may be a food / beverage product, a functional food / beverage product, a sick / beverage food / beverage product, a specific health food / beverage product, a pet food or the like displayed as necessary. In addition, food / beverage products, functional food / beverage products, food / beverage products for the sick, and food / beverage products for specified health use that have the above functions displayed as necessary are food / beverage products for which function display is permitted, and general function indications It is distinguished from foods and drinks without food. The types and forms of the food and drink and feed are not particularly limited.

  The medicine, quasi-drug, food / beverage product or feed can contain any of the compounds listed in Table 1 alone or in combination, and the compound described in Table 1 loses the effect of reducing the apoCI concentration in blood. Unless otherwise specified, other active ingredients, pharmacological ingredients, nutritional ingredients, and the like may be contained. Furthermore, you may contain the additive which can be used for a pharmacologically acceptable carrier and food-drinks. Such carriers and additives include excipients, coating agents, binders, extenders, disintegrating agents, lubricants, diluents, osmotic pressure adjusting agents, pH adjusting agents, dispersants, emulsifiers, preservatives, stabilizers. , Antioxidants, colorants, ultraviolet absorbers, humectants, thickeners, activity enhancers, anti-inflammatory agents, bactericides, solvents, softeners, fragrances, flavoring agents, flavoring agents and the like. The said pharmaceutical, quasi-drug, food-drinks, or feed can be manufactured by a conventional method combining these components.

  The content of the compound described in Table 1 in the pharmaceutical or quasi-drug is 0.0001% by mass or more, preferably 0.001% by mass or more, and 100% by mass or less, preferably as the total amount of the compound. Is 50% by mass or less, or 0.0001 to 100% by mass, preferably 0.001 to 50% by mass. Moreover, content of the compound of Table 1 in the said food-drinks or feed is 0.0001 mass% or more as a total amount of the said compound, Preferably it is 0.001 mass% or more, and 50 mass% or less, Preferably Is 20% by mass or less, or 0.0001 to 50% by mass, preferably 0.001 to 20% by mass.

  In still another aspect of the present invention, there is provided a method for lowering apoCI concentration in blood comprising orally administering or ingesting at least one selected from the group consisting of the compounds listed in Table 1 to a subject. Alternatively, a method for improving skin function is provided, which comprises orally administering or ingesting at least one selected from the group consisting of the compounds described in Table 1 to a subject. Examples of the improvement of the skin function include an improvement of a skin barrier function and a moisturizing function. Alternatively, or at least one selected from the group consisting of the compounds described in Table 1 is orally administered or ingested to the subject to prevent skin dryness, skin aging, skin aging, skin deterioration, etc. Alternatively, an improvement method, a method for improving the immune function of the epidermis, or a method for preventing and / or improving various diseases caused by atopic dermatitis or a decrease in the immune function of the epidermis is provided.

  Examples of the subject include human or non-human mammals. These subjects include reduction of blood apoCI concentration, improvement of skin functions such as improvement of skin barrier function and moisturizing function, prevention and / or improvement of skin roughening due to drying and chemical substances, skin aging, skin deterioration, etc. It can be a subject in need of prevention and / or improvement of various diseases caused by improvement in the immune function of the epidermis, or atopic dermatitis or a decrease in the immune function of the epidermis. More specific examples include humans who want to improve rough skin, skin aging, and skin deterioration for beauty or aesthetic purposes, humans who want to improve skin moisturizing function for beauty or aesthetic purposes, or health maintenance purposes. Examples include humans who want to improve the barrier function of the skin or the immune function of the epidermis.

  The above method may be a therapeutic method, or for cosmetic or aesthetic purposes, or for the purpose of maintaining health, preventing dryness of the skin, improving the moisturizing function of the skin, rough skin, or skin aging It may also be a non-therapeutic method for preventing and / or improving skin degradation.

  In the above method, the compounds described in Table 1 may be administered or ingested in an effective amount capable of reducing the apoCI concentration in blood. For example, the effective amount is 1 mg or more, preferably 5 mg or more, more preferably 10 mg or more and 10000 mg or less, preferably 2000 mg or less, more preferably 1000 mg per day for an adult (60 kg) per day as the total amount of the compound. Or 1 mg to 10000 mg, preferably 1 mg to 2000 mg, more preferably 5 mg to 2000 mg, still more preferably 5 mg to 1000 mg, and even more preferably 10 mg to 1000 mg. The effective amount per day can be administered or ingested once a day, or divided into two or three times or more for any period from once to several months. The dose, route, and interval of administration or ingestion can be appropriately set by those skilled in the art in consideration of the subject's species, weight, sex, age, condition, or other factors.

  Alternatively, an effective amount of a compound described in Table 1 is 90% or less, preferably 80% or less, of the blood apoCI concentration of a subject administered or ingested with the compound described in Table 1, compared to a reference value, More preferably, it may be an amount that decreases to 70% or less. The reference value is the mean value of blood apoCI concentration measured from a randomly selected population, the blood apoCI concentration in the subject before administration or intake of the compound described in Table 1, and the compound described in Table 1 Or the mean value of blood apoCI concentration measured from a population that was not ingested, and the like.

  The blood apoCI concentration is apoCI in whole blood collected from a subject or in serum or plasma prepared from the collected blood or in a sample further purified or isolated from the whole blood, serum or plasma. It can be obtained by measuring the concentration. The blood collection method and the method for separating serum or plasma from blood may be performed according to ordinary procedures. The apoCI concentration in blood can be measured by methods such as ELISA, Western blotting, SRM (Selected Reaction Monitoring) analysis using a triple quadrupole mass spectrometer.

  As exemplary embodiments of the present invention, the following compositions, production methods, uses or methods are further disclosed herein. However, the present invention is not limited to these embodiments.

<1> gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and deoxy An oral blood apoCI concentration reducing agent, comprising as an active ingredient at least one selected from the group consisting of sodium cholate.

<2> Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and deoxy An oral skin function-improving agent comprising at least one selected from the group consisting of sodium cholate as an active ingredient.

<3> The skin function improving agent is a skin barrier function improving agent, skin moisturizing function improving agent, or epidermal immune function improving agent, preferably a skin barrier function improving agent or a skin moisturizing function improving agent. 2> The agent described.

<4> Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and deoxy Prevention or amelioration of rough skin due to dryness or chemicals, prevention or amelioration of skin aging, prevention of skin deterioration, for oral administration or ingestion, comprising at least one selected from the group consisting of sodium cholate as an active ingredient Or the improvement agent, the prevention or improvement agent of atopic dermatitis, or the prevention or improvement agent of various diseases resulting from the fall of the immune function of an epidermis.

<5> Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, for producing an oral blood apoCI concentration-reducing agent At least one use selected from the group consisting of cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate.

<6> Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate for producing an oral skin function improving agent At least one selected from the group consisting of succinic acid, adenosine monophosphate, and sodium deoxycholate.

<7> The skin function improving agent is a skin barrier function improving agent, a skin moisturizing function improving agent, or an immune function improving agent for the epidermis, preferably a skin barrier function improving agent or a skin moisturizing function improving agent. 6> Use as described.

<8> Preventive or ameliorating skin roughness caused by dryness or chemical substances for oral administration or ingestion, preventing or improving skin aging, preventing or improving skin deterioration, preventing or improving atopic dermatitis, or Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, nitric acid for producing preventive or ameliorating agent for various diseases caused by decreased immune function of epidermis At least one use selected from the group consisting of isosorbide, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate.

<9> Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril for reducing blood apoCI concentration by oral administration or ingestion , Geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and at least one use selected from the group consisting of sodium deoxycholate.

<10> gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, for improving skin function by oral administration or ingestion, At least one use selected from the group consisting of cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate.

<11> The improvement of the skin function is an improvement of the skin barrier function, an improvement of the skin moisturizing function, or an improvement of the immune function of the epidermis, preferably an improvement of the skin barrier function or an improvement of the skin moisturizing function. > Use as described.

<12> Gabexate mesylate, alaspril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide for preventing or improving dryness or rough skin due to chemical substances, skin aging, or skin deterioration by oral administration or ingestion At least one selected from the group consisting of: cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate.

<13> The use according to any one of <9> to <12>, which is a non-therapeutic use.

<14> Gabexate mesylate, araceryl, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate for use in reducing blood apoCI concentration by oral administration or ingestion, At least one selected from the group consisting of lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate.

<15> Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril for use in improving skin function by oral administration or ingestion, At least one selected from the group consisting of geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate.

<16> The improvement of the skin function is an improvement of the skin barrier function, an improvement of the skin moisturizing function, or an improvement of the immune function of the epidermis, preferably an improvement of the skin barrier function or an improvement of the skin moisturizing function, <15 > Use as described.

<17> Prevention or improvement of dry skin or chemical rough skin by oral administration or ingestion, prevention or improvement of skin aging, prevention or improvement of skin deterioration, prevention or improvement of atopic dermatitis, or immune function of epidermis Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, for use in the prevention or amelioration of various diseases caused by the decrease At least one selected from the group consisting of cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate.

<18> gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and deoxy A method for lowering apoCI concentration in blood, comprising orally administering or ingesting at least one selected from the group consisting of sodium cholate to a human or an animal.

<19> gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and deoxy A method for improving skin function, comprising orally administering or ingesting at least one selected from the group consisting of sodium cholate to a human or an animal.

<20> The improvement of the skin function is an improvement of the skin barrier function, an improvement of the skin moisturizing function, or an improvement of the immune function of the epidermis, preferably an improvement of the skin barrier function or an improvement of the skin moisturizing function, <19 > The method described.

<21> gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and deoxy A method for preventing or ameliorating rough skin caused by dryness or chemical substances, a method for preventing or improving skin aging, comprising orally administering or ingesting at least one selected from the group consisting of sodium cholate to humans or animals, A method for preventing or improving skin deterioration, a method for preventing or improving atopic dermatitis, or a method for preventing or improving various diseases caused by a decrease in the immune function of the epidermis.

<22> The method according to any one of <18> to <21>, which is a non-therapeutic method.

Reference Example 1 Measurement of human transdermal water transpiration and blood apoCI concentration For 326 Japanese women in their 30s and 40s, the transdermal water transpiration (TEWL) value of the upper arm was measured. In order of the measured TEWL values, the top 50 were selected as the high TEWL group (skin low barrier group) and the bottom 50 were selected as the low TEWL group (skin high barrier group), and the apoCI concentration in the serum of each group was quantified. did. 50 μL of human serum was treated using an albumin / IgG removal kit (Calbiochem) according to the attached protocol, and then desalted, concentrated and solvent-replaced. Thereafter, reductive alkylation treatment and trypsin digestion treatment were performed. For quantification, SRM (Selected Reaction Monitoring) analysis was performed using a triple quadrupole mass spectrometer. The peak area value of the apoCI-derived peptide in the sample was determined, the absolute quantitative value was calculated with reference to the calibration curve with the standard peptide, and was used as the apoCI concentration in the serum. FIG. 1 shows TEWL values (A) and serum apoCI concentrations (B) of the selected two groups. In the high skin barrier group with low transdermal moisture transpiration, the serum apoCI concentration was significantly reduced.

Example 1 Measurement of blood apoCI concentration of test substance-administered mice Hairless mice (HR-1, male, 7-9 weeks old) were divided into a test substance-administered group and a control group (each group n = 4), Once a day, the test substance administration group was orally administered with the test substance (compound Nos. 1 to 15 described in Table 1) prepared in an emulsion form, and physiological saline was orally administered to the control group (100 mg / kg body weight). / Day). Two weeks later, blood was collected and the apoCI concentration in the serum was measured. Serum was subjected to reductive alkylation and trypsin digestion. The apoCI concentration in serum was measured by SRM (Selected Reaction Monitoring) analysis using a triple quadrupole mass spectrometer. A certain amount of stable isotope labeled peptide was added as an internal standard in the sample, the peak area value of the apoCI-derived peptide was corrected with the peak area value of the stable isotope labeled peptide, and the area ratio was calculated. The apoCI concentration in the serum of the control group was taken as 100%, and the apoCI concentration in the serum of the test substance administration group was determined as a relative value. FIG. 2 shows the relative apoCI concentration in serum in the test substance administration group.

Example 2 Measurement of transdermal water transpiration and blood apoCI concentration in mice treated with sodium deoxycholate Hairless mice (HR-1, male, 7 weeks old) are administered with sodium deoxycholate administration group and physiological saline. Divided into control groups (each group n = 7), oral administration (100 mg / kg body weight / day) once a day was continued in each group. Two weeks later, the transdermal water transpiration (TEWL) value of the back skin was measured, and the apoCI concentration in the serum was measured. Serum was subjected to reductive alkylation and trypsin digestion. The apoCI concentration was measured by SRM (Selected Reaction Monitoring) analysis using a triple quadrupole mass spectrometer. A certain amount of stable isotope labeled peptide was added as an internal standard in the sample, the peak area value of the apoCI-derived peptide was corrected with the peak area value of the stable isotope labeled peptide, and the area ratio was calculated. The apoCI concentration in the serum of the control group was taken as 100%, and the apoCI concentration in the serum of the sodium deoxycholate administration group was determined as a relative value. The TEWL value of each group and the relative apoCI concentration in serum are shown in FIG. Two weeks after the start of administration, the relative apoCI concentration and the TEWL value were significantly reduced in the sodium deoxycholate administration group compared to the control group.

  From the above results, it is suggested that oral administration of the compounds shown in Table 1 can reduce the TEWL value of the skin through a decrease in blood apoCI concentration and improve skin functions such as moisturizing function and barrier function. It was done.

Claims (4)

  Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate An oral blood apoCI concentration lowering agent, comprising as an active ingredient at least one selected from the group consisting of:   Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate An oral skin function improving agent, comprising as an active ingredient at least one selected from the group consisting of:   The improving agent according to claim 2, wherein the skin function is a skin barrier function or a skin moisturizing function.   Gabexate mesylate, alacepril, crotamiton, thiopronin, sorbic acid, N, N-dimethylacetamide, cycloserine, diisopropyl sebacate, isosorbide nitrate, lisinopril, geraniol, cetraxate hydrochloride, succinic acid, adenosine monophosphate, and sodium deoxycholate Prevention or improvement of rough skin due to dryness or chemical substances, prevention or improvement of skin aging, prevention or improvement of skin deterioration, atopy, for oral administration or ingestion, comprising at least one selected from the group consisting of An agent for preventing or ameliorating dermatitis or preventing or ameliorating various diseases caused by a decrease in the immune function of the epidermis.