JP2021120358A - Oral skin barrier function improver - Google Patents

Abstract

To provide an ingestible skin barrier function improver.SOLUTION: An oral skin barrier function improver having ferulic acid or a salt thereof as an active ingredient.SELECTED DRAWING: None

Description

The present invention relates to an oral skin barrier function enhancer.

The skin, the outermost organ of the human body, has important physiology such as thermoregulation, prevention of excessive water loss, sensory input via mechanoreceptors, immune defense, and endocrine (production of vitamin D). It has a function. Among them, an important function of the skin is a physical barrier to protect the body from pathogens, chemicals, and solar UV rays. The barrier of the skin is the stratum corneum, which is the outermost layer of the epidermis and consists of 15 to 20 layers of corneocytes containing filamentous keratin. The stratum corneum serves as a permeable barrier that delays transdermal evaporation moisture loss in a dry external environment. The stratum corneum is a multi-layered tissue of flat, non-nucleated corneocytes, composed of corneocytes embedded in a highly ordered lipid lamella composed of ceramide, free fatty acids, and cholesterol. Localization of these highly hydrophobic lipids within the extracellular domain of the stratum corneum suppresses the outward migration of water. Furthermore, natural moisturizing factors such as organic acids, free amino acids, and inorganic ions are present in the stratum corneum. Abnormalities of the stratum corneum associated with epidermal differentiation and changes in lipid composition result in the invasion of environmental allergens in atopic dermatitis, immune response, and disruption of the skin barrier leading to inflammation. Therefore, maintaining a healthy skin barrier is very important.
Percutaneous application of cosmetics and medicated cosmetics is a common method for maintaining the skin barrier, but in recent years it has been pointed out that it is important to take appropriate nutrients orally (non-patents). Patent Document 1).

In recent years, attention has been paid to the effect of psychological stress on skin properties. Psychological stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and the blue-spotted norepinephrine sympathetic adrenal medulla system in the center, and the pathway of mediator release from the intracutaneous HPA axis and peripheral sensory and autonomic nerves in the periphery. Therefore, it has been pointed out that it may affect the skin barrier function (Non-Patent Document 2). Abnormal skin barrier function is prominent in patients with atopic dermatitis, psoriasis, and other similar skin conditions, and sympathetic nerve activity has been reported to be elevated compared to healthy individuals (non-healthy). Patent Documents 3 and 4). Furthermore, it was clarified that the parasympathetic nerve activity obtained by heart rate variability analysis showed a negative correlation with the transepidermal water loss (TEWL) in healthy subjects, and the sympathetic nerve activity showed a positive correlation with the transepidermal water loss. (Non-Patent Document 5). From this, it is considered that the autonomic nerve function and the skin barrier function may be related.

On the other hand, ferulic acid (FA; 4-hydroxy-3-methoxycinnamic acid) is a compound present in the cell wall of plants. Ferulic acid and dihydroferulic acid play a role in binding lignin and polysaccharide in lignocellulosic cell wall. Ferulic acid has been reported to have various physiological actions such as antioxidant, antitumor, blood glucose lowering, hypertension improvement, brain function improvement, and autonomic nerve function improvement (for example, Patent Document 1). Further, it has been reported that ferulic acid applied to human skin suppresses an inflammatory reaction due to UV irradiation and has a photoprotective effect (Non-Patent Document 4). Ferulic acid suppresses the activation of TRPV4 (Patent Document 2), while the activation of TRPV4 promotes the formation of tight junctions in keratinocytes and enhances the skin barrier function (Patent Document 2). 3). From these previous documents, it is speculated that ferulic acid lowers the skin barrier function, and there have been no reports on the effect of oral ingestion of the substance on the skin barrier function.

JP-A-2002-145765 Japanese Unexamined Patent Publication No. 2014-24805 Japanese Unexamined Patent Publication No. 2016-130230

Vollmer DL, West VA, Lephart ED. Enhancing skin health: By oral administration of natural compounds and minerals with implications to the dermal microbiome. Int J Mol Sci. 2018; 19: pii: E3059 Hunter HJ, Momen SE, Kleyn CE. The impact of psychosocial stress on healthy skin. Clin Exp Dermatol. 2015; 40: 540-546 Cicek D, Kandi B, Berilgen MS, et al. Does autonomic dysfunction play a role in atopic dermatitis? Br J Dermatol. 2008; 159: 834-838 Tran BW, Papoiu AD, Russoniello CV, et al. Effect of itch, scratching and mental stress on autonomic nervous system function in atopic dermatitis. Acta Derm Teleol. 2010; 90: 354-361 Nomura T, Yoshida-Amano Y, Yoshida K, et al. Relationships between transepidermal water loss, cutaneous microcirculatory function and autonomic nervous activity. Int J Cosmet Sci. 2017; 39: 275-283

The present invention relates to providing an orally ingestible skin barrier function improving agent.

The present inventor has made a diligent study in view of the above problems and found that oral ingestion of ferulic acid or a salt thereof improves the skin barrier function.

That is, the present invention relates to the following 1) and 2).
1) An oral skin barrier function improving agent containing ferulic acid or a salt thereof as an active ingredient.
2) A food for improving the oral skin barrier function containing ferulic acid or a salt thereof as an active ingredient.

According to the present invention, by ingesting ferulic acid or a salt thereof orally, the skin barrier function can be enhanced, and skin diseases and the like due to abnormalities in the barrier function of the stratum corneum can be prevented or ameliorated.

A graph showing changes in transepidermal water loss (TEWL).

In the present invention, ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a _{cinnamic acid derivative having the molecular formula C 10} H ₁₀ O ₄ and has the following structure.

Ferulic acid can be chemically synthesized or extracted from natural products containing ferulic acid, such as rice (rice bran, rice germ), wheat, rye, barley, coffee, apples, artichokes, peanuts, oranges, pineapples, etc. -It can be obtained by purifying. In addition, commercially available reagents can be used.
There are stereoisomers in ferulic acid or salts thereof, and in the present invention, pure stereoisomers or mixtures thereof can be used.

The salt of ferulic acid is preferably a pharmaceutically acceptable salt. Examples of the salt include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium, and salts with inorganic bases such as ammonium salts; bases such as arginine, lysine, histidine, and ornithine. Salts with sex amino acids; Salts with organic bases such as monoethanolamine, diethanolamine, triethanolamine and the like are used. Of these, salts with alkali metals or alkaline earth metals are preferable.

As shown in Examples below, oral ingestion of ferulic acid reduced transepidermal water loss. That is, ferulic acid or a salt thereof has an action of improving the skin barrier function.
Therefore, ferulic acid or a salt thereof can be a skin barrier function improving agent, can be used for improving the skin barrier function, and can be used for producing a skin barrier function improving agent.
Here, the former "use" can be administration or ingestion to humans or non-human animals, and may be therapeutic or non-therapeutic use. The term "non-therapeutic" means a concept that does not include medical practice, that is, a concept that does not include a method of surgery, treatment, or diagnosis of a human being, and more specifically, a doctor or a person who has been instructed by a doctor to treat a human being. It is a concept that does not include a method of performing surgery, treatment, or diagnosis.

In the present invention, the "skin barrier function" means a function of preventing the evaporation of water from the inside of the skin and a function of preventing the invasion of substances from the outside into the skin. In the present invention, it is suitable for improving the function of preventing the evaporation of water from the inside of the skin (moisture permeation barrier function).
"Improvement of skin barrier function" also includes the concept of strengthening, lowering, destroying or collapsing skin barrier function, preventing or suppressing it, and maintaining it.
By improving the skin barrier function by oral ingestion of ferulic acid or a salt thereof, it is possible to prevent or improve skin diseases and the like due to abnormalities in the barrier function of the stratum corneum. Here, "prevention" means preventing or delaying the onset of a disease or symptom in an individual, or reducing the risk of developing a disease or symptom in an individual. "Improvement" means improvement of a symptom or condition, prevention, suppression or delay of deterioration of the symptom or condition, or reversal, prevention, suppression or delay of progression of the symptom or condition.

The oral skin barrier function improving agent of the present invention may itself be a drug, a quasi drug, a supplement or a food for improving the skin barrier function, or the drug, the quasi drug, or the food. It may be a material or a preparation used in combination.
The foods include foods with functional claims, foods for specified health use, supplements, etc., which have the concept of improving the skin barrier function and are labeled to that effect as necessary. Since these foods are foods for which functional labeling is permitted, they can be distinguished from general foods.

The drug (including quasi-drugs) is a drug for improving the skin barrier function, and contains ferulic acid or a salt thereof as an active ingredient for improving the skin barrier function. Further, the pharmaceutical product may contain a pharmaceutically acceptable carrier, other active ingredient, pharmacological ingredient and the like, if necessary, as long as the function of the active ingredient is not lost.

Dosage forms of the drug (including non-pharmaceutical products) include dosage forms that can be orally administered, for example, oral solid preparations such as tablets (including chewable tablets), capsules, granules, powders, and troches. And oral liquid preparations such as oral liquids and syrups. Formulations of these dosage forms use ferulic acid or salts thereof as pharmaceutically acceptable carriers (eg, excipients, binders, bulking agents, disintegrants, surfactants, lubricants, dispersants, buffers). , Preservatives, flavoring agents, fragrances, coating agents, diluents, etc.), and other medicinal ingredients, etc., can be appropriately combined and prepared according to a conventional method.

The food is a food for improving the skin barrier function, and contains ferulic acid or a salt thereof as an active ingredient for improving the skin barrier function. The form of the food can be solid, semi-solid or liquid (eg beverage). Examples of the food include soft drinks, tea-based beverages, coffee beverages, fruit juice beverages, carbonated beverages, jelly-like beverages, near-water beverages, and foods and drinks such as jelly, wafers, biscuits, bread, noodles, and sausages. Various foods such as goods and nutritional foods, and their raw materials can be mentioned. Alternatively, the food product may be a supplement in the form of an orally administered preparation such as tablets, capsules, granules, powders, liquids and syrups.

The food is ferulic acid or a salt thereof, any food material, or other active ingredient, or food-acceptable additives (eg, solvents, softeners, oils, emulsifiers, preservatives, acidity agents, sweeteners). , Bitterness, pH regulator, stabilizer, colorant, UV absorber, antioxidant, moisturizer, thickener, sticker, dispersant, fluidity improver, wetting agent, fragrance, seasoning, flavor It can be prepared according to a conventional method by appropriately combining it with a regulator) or the like.

The content of ferulic acid or a salt thereof in the above-mentioned pharmaceutical products, quasi-drugs or foods may vary depending on their dosage forms and forms. For example, in terms of ferulic acid equivalent, it is preferably 0.01% by mass or more, more preferably 1% by mass or more, further preferably 5% by mass or more, and preferably 90% by mass or less, more preferably 70% by mass. % Or less, more preferably 30% by mass or less.

In the present invention, the dose and administration plan of ferulic acid or a salt thereof can be appropriately determined by those skilled in the art according to the species, weight, sex, age, condition, or other factors of the subject.
The dose of ferulic acid or a salt thereof (ferulic acid equivalent amount) according to the present invention is, for example, preferably 5 mg or more, more preferably 10 mg or more, still more preferably 10 mg or more per day for one adult (60 kg). It is 50 mg or more, more preferably 100 mg or more, preferably 1000 mg or less, more preferably 500 mg or less, still more preferably 300 mg or less.
In the present invention, it is preferable that the above dose is orally administered or orally ingested, for example, once, twice or three times or more a day. More preferably, the above dose of ferulic acid or a salt thereof is orally administered or orally ingested once a day. The administration or ingestion period is not particularly limited, but is preferably continuous, more preferably 1 week or longer, still more preferably 2 weeks or longer. The timing of administration or ingestion is preferably from after dinner to bedtime, and more preferably within 1 hour before bedtime.

In a preferred embodiment of the present invention, the daily dose of ferulic acid or a salt thereof is orally administered or orally ingested to a human who needs to improve the skin barrier function.

Test Example 1
1. 1. Subjects The experiments were conducted with the approval of the Research Ethics Review Board of Kao Corporation in accordance with the ethical guidelines for clinical research and the ethical principles stipulated in the Declaration of Helsinki. Sixteen healthy Japanese men aged 35 to 50 years were selected as subjects. The exclusion criteria were as follows.
Exclusion criteria: Smoking habits, prevalence of severe illness (eg, high blood pressure, heart disease, kidney disease, diabetes, etc.), poor health, ongoing treatment in need of medication, taking sleeping pills.

2. Test design As test products, capsules containing ferulic acid (FA) derived from rice germ (67 mg / capsule as ferulic acid, mass ratio 11.6%) and placebo capsules were used. Placebo capsules do not contain ferulic acid. The analysis of ferulic acid can be performed by an analysis method suitable for the condition of the measurement sample among the commonly known measurement methods such as HPLC (J. Agric. Food Chem. 2002; 50: 5735-5741). See J. Nutr. 2007; 137: 2196-2201).

A double-blind, placebo-controlled, parallel study was conducted. Subjects were divided into two groups (n = 8 / group) receiving placebo and ferulic acid, respectively. Before going to bed, the subjects ingested three placebo capsules in the placebo group and three capsules containing ferulic acid in the ferulic acid intake group.
The intake period was 2 weeks, and skin properties were measured at the beginning of the 2-week ferulic acid intake period and at the end of the study. Subjects cleaned the inside of the forearm to be examined and then acclimatized in an air-conditioned room for 20 minutes. Transepidermal water loss (TEWL) based on capacitance measurement of the dielectric medium was measured using Tewameter® TM300 (Courage + Khazaka Electronic GmbH, Koln, Germany).

3. 3. Statistical analysis data are expressed as mean ± standard deviation (SD). SPSS statistics version 26 (IBM, Armonk, NY, USA) was used. A pair of t-tests was used to compare baseline measurements with those taken during a two-week continuous ingestion within the same group. In addition, Student's t-test was performed to compare the amount of change. The significance level was set to 5%.

4. Results The results are shown in FIG. The transepidermal water loss (g / m ² / hr) of the placebo group tended to increase from 4.8 ± 1.9 before the 2-week intake period to 5.3 ± 2.4 after the intake period. However, in the ferulic acid intake group, transepidermal water loss significantly decreased from 6.1 ± 1.1 to 4.8 ± 1.0 (p = 0.004). The change in transepidermal water loss in the placebo group was 0.5 ± 0.7, and the change in transepidermal water loss in the ferulic acid intake group was -1.3 ± 0.9. The amount of change in transepidermal water loss was significantly different between the two groups (p <0.01). From the above results, it was shown that the skin barrier function was improved by continuous oral intake of ferulic acid for 2 weeks.

Claims (6)

An oral skin barrier function improving agent containing ferulic acid or a salt thereof as an active ingredient. The oral skin barrier function improving agent according to claim 1, wherein the skin barrier function is a water permeation barrier function. The oral skin barrier function improving agent according to claim 1 or 2, wherein 5 to 1000 mg of ferulic acid is orally administered or orally ingested per day for an adult. A food for improving the oral skin barrier function containing ferulic acid or a salt thereof as an active ingredient. The food for improving the oral skin barrier function according to claim 4, wherein the skin barrier function is a water permeation barrier function. The food for improving the oral skin barrier function according to claim 4 or 5, wherein 5 to 1000 mg of ferulic acid is orally ingested per day for an adult.

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