Barrier function enhancing agent and transepithelial electrical resistance increasing agent

Abstract

To discover, from among safe natural products, a substance having a barrier function enhancing action or a transepithelial electrical resistance increasing action to provide a barrier function enhancing agent and a transepithelial electrical resistance increasing agent containing the discovered substance as an active ingredient.SOLUTION: The present invention provides a barrier function enhancing agent and a transepithelial electrical resistance increasing agent, containing at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extracts as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a barrier function enhancer and an agent for increasing transepithelial electrical resistance. [Background technology]

[0002] One of the structures that separate the inside and outside of a living body is epithelial tissue composed of epithelial cells. Epithelial tissue has a barrier function that controls the permeation of substances, which creates an internal environment in the living body that is different from the outside world. Such a barrier function is mainly formed by adhesion between cells, and one such adhesion is tight junctions (hereinafter sometimes referred to as "TJ"). TJ is an intercellular adhesion structure that not only brings adjacent epithelial cells into close contact with each other, but also controls the permeation of substances by sealing the gap between cells. Proteins such as claudins, occludins, ZO-1, and ZO-2 that constitute TJ are thought to form the skeleton of the TJ strand and control the barrier function of TJ (see Non-Patent Document 1). If the expression of these proteins is reduced, for example, in the digestive tract, food allergens, pathogenic microorganisms, etc. will invade the body, which is thought to be a factor in inflammatory bowel disease and various infectious diseases. In addition, if the function of TJ in the skin is reduced, it is thought to be a factor in skin symptoms such as dry skin, rough skin, atopic dermatitis, and various infectious diseases.

[0003] When histamine in mast cells is released outside the cells, the released histamine causes an inflammatory reaction, and allergic diseases and inflammatory diseases are aggravated. In recent years, a mechanism has been known in which histamine inhibits epidermal keratinocyte differentiation and contributes to the impairment of the barrier function in the skin (see Non-Patent Document 2). Therefore, it is considered that the improvement of the impairment of the skin barrier function caused by histamine stimulation can strengthen the barrier function in the epithelial tissue, and prevent or improve inflammatory bowel disease, food allergy, various infectious diseases, etc. in the digestive tract, while preventing or improving skin symptoms such as dry skin, rough skin, atopic dermatitis, and various infectious diseases in the epidermis.

[0004] In epithelial cells, TJs limit the permeation of ions between the luminal side and the basement membrane side, resulting in trans-epithelial electric resistance (TER). Therefore, when the barrier function of epithelial cells is impaired, TER also decreases. Therefore, it is believed that by increasing TER, the barrier function can be restored and diseases caused by impaired barrier function can be prevented or improved. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Journal of the Japanese Society of Cosmetic Science, 2007, vol.31, pp.296-301 [Non-Patent Document 2] Gschwandtner M et al., Allergy, January 2013, vol.68(1), pp.37-47 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to find substances having a barrier function enhancing effect or a transepithelial electrical resistance increasing effect from among highly safe natural products, and to provide barrier function enhancing agents and transepithelial electrical resistance increasing agents that contain these substances as active ingredients. [Means for solving the problem]

[0007] In order to solve the above problems, the barrier function enhancer and transepithelial electrical resistance increasing agent of the present invention contains at least one active ingredient selected from the group consisting of glycyrrhizic acid and its derivatives, glycyrrhetinic acid and its derivatives, and licorice extract. The glycyrrhizic acid derivative may be dipotassium glycyrrhizinate. Effect of the Invention

[0008] According to the present invention, it is possible to provide a barrier function enhancer and a transepithelial electrical resistance increasing agent which have an excellent barrier function enhancing effect or transepithelial electrical resistance increasing effect and are highly safe. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] An embodiment of the present invention will now be described in detail. Both the barrier function enhancer and the transepithelial electrical resistance increasing agent of this embodiment contain at least one active ingredient selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract.

[0010] Glycyrrhizic acid derivatives include, for example, glycyrrhizic acid (C 42 H 62 O 16 ) with an alkali. Examples of glycyrrhizinic acid derivatives include dipotassium glycyrrhizinate, trisodium glycyrrhizinate, and monoammonium glycyrrhizinate, and dipotassium glycyrrhizinate is preferably used.

[0011] Dipotassium glycyrrhizinate can be obtained by reacting glycyrrhizic acid with potassium hydroxide (KOH) or the like. 42 H 62 O 16 ) can be obtained by isolating and purifying from a plant extract containing glycyrrhizinic acid. The plant extract containing glycyrrhizinic acid includes an extract obtained by using a plant containing glycyrrhizinic acid as an extraction raw material, a diluted or concentrated solution of the extract, a dried product obtained by drying the extract, or any of these roughly purified or purified products.

[0012] The glycyrrhetinic acid derivatives can be synthesized by known methods. Examples of the glycyrrhetinic acid derivatives include stearyl glycyrrhetinate, disodium succinyl glycyrrhetinate, and glycyrrhetinyl stearate. For example, stearyl glycyrrhetinate can be obtained by isolating and purifying glycyrrhetinic acid from a plant extract containing glycyrrhetinic acid, and hydrolyzing the glycyrrhetinic acid obtained by this isolation and purification using an aqueous solution of an acid (hydrochloric acid, sulfuric acid, etc.) to obtain glycyrrhetinic acid (C 30 H 46 O4) and then subjecting the glycyrrhetinic acid to an esterification reaction with stearyl alcohol.

[0013] The plant extract containing glycyrrhizic acid can be obtained by a method generally used for extracting plants. Examples of plants containing glycyrrhizic acid include licorice.

[0014] Licorice is a perennial herb belonging to the genus Glycyrrhiza in the family Fabaceae. Examples of licorice include Glychyrrhiza glabra, Glychyrrhiza inflata, Glychyrrhiza uralensis, Glychyrrhiza aspera, Glychyrrhiza eurycarpa, Glychyrrhiza pallidiflora, Glychyrrhiza yunnanensis, Glychyrrhiza lepidota, Glychyrrhiza echinata, and Glychyrrhiza acanthocarpa. Of these, any type of licorice may be used as the extraction raw material, but it is particularly preferable to use Glychyrrhiza glabra as the extraction raw material.

[0015] Examples of licorice parts that can be used as extraction raw materials include above-ground parts such as leaves, branches, bark, trunks, stems, fruits, and flowers, as well as roots and mixtures of these parts, with the roots being preferred.

[0016] A plant extract containing glycyrrhizic acid can be obtained by drying the extraction raw material, pulverizing it directly or using a crusher, and extracting it with an extraction solvent. Drying can be done in the sun or using a commonly used dryer. It can also be used as an extraction raw material after pretreatment such as degreasing with a non-polar solvent such as hexane. By performing pretreatment such as degreasing, the plant can be efficiently extracted with a polar solvent.

[0017] As the extraction solvent, it is preferable to use a polar solvent, such as water or a hydrophilic organic solvent, which is preferably used alone or in combination of two or more at room temperature or at a temperature below the boiling point of the solvent.

[0018] Water that can be used as an extraction solvent includes pure water, tap water, well water, mineral water, hot spring water, spring water, fresh water, etc., as well as water that has been subjected to various treatments. Treatments that can be applied to water include, for example, purification, heating, sterilization, filtration, ion exchange, osmotic pressure adjustment, buffering, etc. Therefore, water that can be used as an extraction solvent in this embodiment also includes purified water, hot water, ion-exchanged water, physiological saline, phosphate buffer, phosphate buffered physiological saline, etc.

[0019] Examples of hydrophilic organic solvents that can be used as the extraction solvent include lower aliphatic alcohols having 1 to 5 carbon atoms, such as methanol, ethanol, propyl alcohol, and isopropyl alcohol; lower aliphatic ketones, such as acetone and methyl ethyl ketone; and polyhydric alcohols having 2 to 5 carbon atoms, such as 1,3-butylene glycol, propylene glycol, and glycerin.

[0020] When using a mixture of two or more polar solvents as an extraction solvent, the mixing ratio can be adjusted appropriately. For example, when using a mixture of water and a lower aliphatic alcohol, it is preferable to mix 1-90 parts by volume of the lower aliphatic alcohol with 10 parts by volume of water, when using a mixture of water and a lower aliphatic ketone, it is preferable to mix 1-40 parts by volume of the lower aliphatic ketone with 10 parts by volume of water, when using a mixture of water and a polyhydric alcohol, it is preferable to mix 10-90 parts by volume of the polyhydric alcohol with 10 parts by volume of water.

[0021] The extraction process is not particularly limited as long as the soluble components contained in the extraction raw material can be dissolved in the extraction solvent, and can be performed according to a conventional method. For example, the extraction raw material is immersed in an extraction solvent of 5 to 15 times the amount (mass ratio) of the extraction raw material, and the soluble components are extracted at room temperature or under reflux heating, and then the extraction residue is removed by filtration to obtain an extract. The solvent is distilled off from the obtained extract to obtain a paste-like concentrate, and the concentrate is further dried to obtain a dry product.

[0022] The method for isolating and purifying glycyrrhizinic acid from the extract obtained as above, the concentrate of the extract, or the dried product of the extract is not particularly limited, and can be performed by a conventional method. For example, the plant extract can be subjected to column chromatography using a porous material such as silica gel or alumina, or a porous resin such as styrene-divinylbenzene copolymer or polymethacrylate, and eluted with water and alcohol in this order, to obtain glycyrrhizinic acid as a fraction eluted with alcohol.

[0023] Examples of alcohols that can be used as an eluent in column chromatography include lower aliphatic alcohols having 1 to 5 carbon atoms, such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, and aqueous solutions thereof, but are not limited to these.

[0024] Furthermore, the alcohol fraction obtained by column chromatography may be purified using any organic compound purification means, such as reverse phase silica gel chromatography using ODS, recrystallization, liquid-liquid countercurrent extraction, or column chromatography using an ion exchange resin.

[0025] The glycyrrhizinic acid thus obtained can be reacted with an alkali such as potassium hydroxide (KOH) in a conventional manner to obtain a glycyrrhizinic acid derivative such as dipotassium glycyrrhizinate.

[0026] In addition, glycyrrhetic acid can be obtained by hydrolyzing the glycyrrhizinic acid using an aqueous solution of an acid (hydrochloric acid, sulfuric acid, etc.) in a conventional manner, and glycyrrhetinic acid derivatives such as stearyl glycyrrhetinate can be obtained by esterifying the glycyrrhetinic acid with stearyl alcohol.

[0027] As will be apparent from the examples described later, the glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract obtained as described above have a barrier function enhancing effect and a transepithelial electrical resistance increasing effect, and in particular have an effect of improving barrier function disorders caused by histamine stimulation, and therefore can be used as active ingredients of barrier function enhancing agents and transepithelial electrical resistance increasing agents by utilizing these effects.

[0028] The barrier function enhancer or transepithelial electrical resistance increasing agent of the present embodiment may consist of at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract, or may be a formulation of at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract.

[0029] At least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract can be formulated into any dosage form such as powder, granules, tablets, liquid, etc., according to a conventional method using a pharma- ceutically acceptable carrier such as dextrin, cyclodextrin, and other optional auxiliary agents. In this case, for example, excipients, binders, disintegrants, lubricants, stabilizers, flavorings, and odorants can be used as auxiliary agents. At least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract can be used by blending with other compositions (e.g., skin cosmetics, etc.), and can also be used as ointments, external liquids, patches, etc.

[0030] In addition, the barrier function enhancer or transepithelial electrical resistance increasing agent of this embodiment can be used as an active ingredient by blending it with other natural extracts having a barrier function enhancing effect or a transepithelial electrical resistance increasing effect, if necessary.

[0031] The method of administration of the barrier function enhancer or transepithelial electrical resistance increasing agent of this embodiment generally includes transdermal administration, oral administration, etc., but a method suitable for prevention, treatment, etc. may be appropriately selected depending on the type of disease. The dosage of the barrier function enhancer or transepithelial electrical resistance increasing agent of this embodiment may also be appropriately increased or decreased depending on the type and severity of the disease, individual differences between patients, administration method, administration period, etc.

[0032] The barrier function enhancer or transepithelial electrical resistance increasing agent of the present embodiment enhances the barrier function in epithelial tissue through the barrier function enhancing effect or transepithelial electrical resistance increasing effect of at least one active ingredient selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract, and is effective in treating inflammatory bowel disease, food allergies, various infectious diseases transmitted through the digestive tract, and the like; dry skin, rough skin, atopic dermatitis, sensitive skin, skin aging symptoms, psoriasis, acne (including hidradenitis suppurativa), burns, The agent can prevent, treat or improve skin conditions and various infectious diseases, such as diaper rash, Netherton syndrome, actinic keratosis, dermatomycosis, dermatosis, ectodermal dysplasia, contact dermatitis, dermatitis, seborrheic dermatitis, ichthyosis vulgaris, and infections from the oral cavity and respiratory tract; allergic rhinitis, asthma, irritable bowel syndrome, systemic autoimmune diseases (rheumatoid arthritis, lupus erythematosus, etc.), allergies (food allergies, hay fever, etc.), lifestyle-related diseases (obesity, type 1 or type 2 diabetes, hypertension, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), arteriosclerosis, etc.). However, the barrier function enhancer or transepithelial electrical resistance increasing agent of the present embodiment can be used for all applications in which it is meaningful to exert a barrier function enhancing effect or a transepithelial electrical resistance increasing effect, in addition to the above applications.

[0033] In addition, the barrier function enhancer or transepithelial electrical resistance increasing agent of the present embodiment has an excellent barrier function enhancing effect or transepithelial electrical resistance increasing effect, and is therefore suitable for incorporation into, for example, a skin external preparation or an oral composition. In this case, at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetic acid, glycyrrhetic acid derivatives, and licorice extract may be directly incorporated, or a barrier function enhancer or transepithelial electrical resistance increasing agent formulated from at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetic acid, glycyrrhetic acid derivatives, and licorice extract may be incorporated.

[0034] Here, topical skin preparations are not limited to specific classifications and include a wide range of skin cosmetics, quasi-drugs, medicines, etc. that are used percutaneously. Specific examples include ointments, creams, milky lotions, beauty serums, lotions, packs, foundations, lip balms, bath additives, hair tonics, hair lotions, soaps, body shampoos, etc.

[0035] The amount of at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract in the topical skin preparation can be adjusted appropriately depending on the type of topical skin preparation, but a suitable blending ratio is 0.0001 to 10 mass%, and a particularly suitable blending ratio is 0.001 to 1 mass%.

[0036] The oral composition refers to a composition that is unlikely to cause harm to human health and is taken orally or by administration through the digestive tract in normal social life, and is not limited to administrative classifications such as food, medicine, and quasi-drug. Therefore, the "oral composition" in this embodiment broadly includes general food, feed, health food, health functional food (specified health food, nutrient functional food, functional food), quasi-drug, medicine, etc. that are taken orally. The oral composition in this embodiment is preferably an oral composition that can display the favorable effect of at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract on the oral composition or its packaging, and is particularly preferably a health functional food (specified health food, nutrient functional food, functional food), quasi-drug, or medicine.

[0037] The amount of at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract in the oral composition can be appropriately changed considering the purpose of use, symptoms, sex, etc., but it is preferable to make the daily intake of the extract about 1 to 1000 mg for an adult considering the general intake of the oral composition to be added. When the oral composition to be added is in the form of granules, tablets, or capsules, the amount of at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid derivatives, glycyrrhetinic acid, glycyrrhetinic acid derivatives, and licorice extract is usually 0.0001 to 10% by mass, preferably 0.001 to 1% by mass, based on the oral composition to be added.

[0038] Furthermore, since the barrier function enhancer or transepithelial electrical resistance increasing agent of this embodiment has an excellent barrier function enhancing effect or transepithelial electrical resistance increasing effect, in particular the effect of improving barrier function disorders caused by histamine stimulation, it can also be suitably used as a reagent for research on the mechanisms of these actions.

[0039] In addition, the barrier function enhancer or transepithelial electrical resistance increasing agent of this embodiment is preferably applied to humans, but can also be applied to animals other than humans as long as the respective functional effects are exerted. EXAMPLES

[0040] The present invention will be described in more detail below with reference to test examples, but the present invention is not limited to the following test examples. In the following test examples, dipotassium glycyrrhizinate (manufactured by Maruzen Pharmaceutical Co., Ltd.) was used as a test sample.

[0041] [Test Example 1] Skin barrier function enhancement test (electrical resistance value TER measurement and permeability evaluation using FITC-Dex) Human normal neonatal skin epidermal keratinocytes (NHEK) were cultured in human normal neonatal epidermal keratinocyte medium (KGM) and then harvested by trypsinization. The harvested cells were 2.2 × 10 5After diluting with KGM to a cell density of 10000 cells / mL, 0.5 mL of each sample was seeded in the upper layer of a 12-well Transwell (Corning, diameter 12 mm, 0.4 μm pores) and 1.5 mL of KGM was added to the lower layer and cultured for 3 days. After the culture was completed, 0.5 mL of the test sample (see Table 1 for sample concentration) dissolved in KGM containing 1.5 mmol / L CaCl2 was added to the upper layer of each well, and 1.5 mL of KGM containing 1.5 mmol / L CaCl2 was added to the lower layer of each well and cultured for 4 days to induce tight junction formation. Electrical resistance (TER) was measured using a Millicell-ERS resistance measurement system (Millipore) at the time of addition of the test sample and at 24 hours, 48 ​​hours, 72 hours, and 96 hours after the addition of the test sample, and the barrier formation promotion rate (%) of the test sample compared to the control was calculated using the following formula. The results are shown in Table 1.

[0042] Barrier formation promotion rate (%) = A / B x 100 In the formula, A represents "TER when a test sample is added" and B represents "TER when a test sample is not added."

[0043] After the TER measurement, the upper and lower layers were washed with PBS(-), and 0.5 mL of FITC-Dextran 4000-conjugate (FITC-Dex, Sigma) dissolved in HBSS(-) to a concentration of 1 mg / mL was added to the upper layer, and 1 mL of HBSS(-) was added to the lower layer, and the cells were cultured at 37°C for 90 minutes. After the culture was completed, 200 μL was taken from each lower layer, and the fluorescence intensity was measured at an excitation wavelength of 485 nm and a fluorescence wavelength of 545 nm. The amount of FITC-Dex that had permeated from the upper layer to the lower layer was calculated based on the calibration curve, and the permeation inhibition rate (%) of the test sample compared to the control was calculated using the following formula. The results are shown in Table 2.

[0044] Transmission suppression rate (%)=(1-A / B)×100 In the formula, A represents the "permeation amount when a test sample is added" and B represents the "permeation amount when no test sample is added."

[0045] [Table 1]

[0046] [Table 2]

[0047] As shown in Tables 1 and 2, it was confirmed that dipotassium glycyrrhizinate has excellent effects of enhancing the skin barrier function and increasing transepithelial electrical resistance.

[0048] [Test Example 2] Test of the skin barrier function enhancement effect by histamine stimulation (electrical resistance value TER measurement and permeability evaluation by FITC-Dex) Human normal neonatal skin epidermal keratinocytes (NHEK) were cultured in human normal neonatal epidermal keratinocyte medium (KGM) and then harvested by trypsinization. The harvested cells were 2.2 × 10 5 After diluting with KGM to a cell density of 1000 cells / mL, 0.5 mL of the cells were seeded in the upper layer of a 12-well Transwell (Corning, diameter 12 mm, 0.4 μm pores) at 0.5 mL per well, and 1.5 mL of KGM was added to the lower layer and cultured for 3 days. After the culture was completed, 0.5 mL of the test sample (see Table 3 for sample concentration) dissolved in KGM containing 1000 μmol / L histamine and 1.5 mmol / L CaCl2 was added to the upper layer of each well, and 1.5 mL of KGM containing 1000 μmol / L histamine and 1.5 mmol / L CaCl2 was added to the lower layer of each well, and the cells were cultured for 4 days to induce tight junction formation. The electrical resistance (TER) was measured using a Millicell-ERS resistance measurement system (Millipore) at the time of adding the test sample, and at 24 hours, 48 ​​hours, 72 hours, and 96 hours after adding the test sample, and the barrier formation promotion rate (%) of the test sample compared to the control was calculated using the following formula. The results are shown in Table 3.

[0049] Barrier formation promotion rate (%) = A / B x 100 In the formula, A represents "TER when a test sample is added" and B represents "TER when a test sample is not added."

[0050] After the TER measurement, the upper and lower layers were washed with PBS(-), and 0.5 mL of FITC-Dextran 4000-conjugate (FITC-Dex, Sigma) dissolved in HBSS(-) to a concentration of 1 mg / mL was added to the upper layer, and 1 mL of HBSS(-) was added to the lower layer, and the cells were cultured at 37°C for 90 minutes. After the culture was completed, 200 μL was taken from each lower layer, and the fluorescence intensity was measured at an excitation wavelength of 485 nm and a fluorescence wavelength of 545 nm. The amount of FITC-Dex that had permeated from the upper layer to the lower layer was calculated based on the calibration curve, and the permeation inhibition rate (%) of the test sample compared to the control was calculated using the following formula. The results are shown in Table 4.

[0051] Transmission suppression rate (%)=(1-A / B)×100 In the formula, A represents the "permeation amount when a test sample is added" and B represents the "permeation amount when no test sample is added."

[0052] [Table 3]

[0053] [Table 4]

[0054] As shown in Tables 3 and 4, it was confirmed that dipotassium glycyrrhizinate has an excellent effect of improving the skin barrier function disorder caused by histamine stimulation. [Industrial Applicability]

[0055] The barrier function enhancer and transepithelial electrical resistance increasing agent of this embodiment can greatly contribute to enhancing the barrier function in epithelial tissue (prevention, treatment, or amelioration of inflammatory bowel disease, food allergies, various infectious diseases transmitted through the digestive tract, etc.; prevention, treatment, or amelioration of skin conditions such as dry skin, rough skin, and atopic dermatitis, and various infectious diseases, etc.).

Claims

1. A barrier function enhancer comprising as an active ingredient at least one member selected from the group consisting of glycyrrhizinic acid and its derivatives, glycyrrhetinic acid and its derivatives, and licorice extract.

2. 2. The barrier function enhancer according to claim 1, wherein the derivative of glycyrrhizinic acid is dipotassium glycyrrhizinate.

3. 3. The barrier function enhancer according to claim 1 or 2, which has the effect of improving skin barrier function disorders caused by histamine stimulation.

4. A transepithelial electrical resistance increasing agent, comprising at least one active ingredient selected from the group consisting of glycyrrhizic acid and its derivatives, glycyrrhetinic acid and its derivatives, and licorice extract.

5. The transepithelial electrical resistance increasing agent according to claim 4, characterized in that the derivative of glycyrrhizinic acid is dipotassium glycyrrhizinate.

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