JP7569153B2 - Oral skin barrier function improver - Google Patents

Description

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

The skin, which constitutes the outermost layer of the human body, is responsible for important physiological functions such as thermoregulation, prevention of excessive water loss, sensory input via mechanoreceptors, immune defense, and endocrine secretion (vitamin D production). Among these, the skin's most important function is to provide 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 keratinocytes containing filamentous keratin. The stratum corneum acts as a permeability barrier to slow transepidermal evaporative water loss in a dry external environment. The stratum corneum is a multilayered tissue of flat anucleated keratinocytes, which are embedded in highly ordered lipid lamellae composed of ceramides, free fatty acids, and cholesterol. The localization of these highly hydrophobic lipids in the extracellular domain of the stratum corneum inhibits the outward movement of water. In addition, natural moisturizing factors such as organic acids, free amino acids, and inorganic ions are present in the stratum corneum. Abnormalities in the stratum corneum associated with alterations in epidermal differentiation and lipid composition result in a breakdown of the skin barrier leading to the invasion of environmental allergens, immune responses, and inflammation in atopic dermatitis. Therefore, maintaining an intact skin barrier is of paramount importance.
A common method for maintaining the skin barrier is to apply cosmetics or medicated cosmetics transdermally, but in recent years, the importance of orally ingesting appropriate nutrients has also been pointed out (Non-Patent Document 1).

In recent years, attention has been focused on the effect of psychological stress on skin properties. It has been pointed out that psychological stress may affect skin barrier function through the hypothalamic-pituitary-adrenal (HPA) axis and the locus coeruleus norepinephrine sympathetic adrenal medulla system in the central nervous system, and the intracutaneous HPA axis and the release of mediators from peripheral sensory and autonomic nerves in the periphery (Non-Patent Document 2). Abnormalities in skin barrier function are prominent in patients with atopic dermatitis, psoriasis, and other similar skin conditions, and it has been reported that sympathetic nerve activity is elevated compared to healthy subjects (Non-Patent Documents 3 and 4). Furthermore, it has been revealed that parasympathetic nerve activity obtained by heart rate variability analysis in healthy subjects shows a negative correlation with transepidermal water loss (TEWL), and sympathetic nerve activity shows a positive correlation with transepidermal water loss (Non-Patent Document 5). This suggests that autonomic nerve function and 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 walls of plants. Ferulic acid and dihydroferulic acid play a role in joining lignin and polysaccharides in the lignocellulose of the cell wall. It has been reported that ferulic acid has various physiological effects such as antioxidant, antitumor, blood glucose lowering, hypertension improvement, brain function improvement, and autonomic nerve function improvement (for example, Patent Document 1). It has also been reported that ferulic acid applied to human skin suppresses inflammatory reactions caused by UV irradiation and has a photoprotective effect (Non-Patent Document 4). Ferulic acid suppresses the activation of TRPV4 (Patent Document 2), but on the other hand, it has been reported that activation of TRPV4 promotes the formation of tight junctions in keratinocytes and enhances skin barrier function (Patent Document 3). From these prior documents, it has been speculated that ferulic acid reduces skin barrier function, and there have been no reports to date on the effect of oral intake of this substance on skin barrier function.

JP 2002-145765 A JP 2014-24805 A JP 2016-130230 A

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 Venereol. 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 improver.

In light of the above problems, the present inventors conducted extensive research and discovered that oral intake of ferulic acid or a salt thereof improves skin barrier function.

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

According to the present invention, by orally taking ferulic acid or a salt thereof, it is possible to enhance the skin barrier function and prevent or improve skin diseases caused by abnormalities in the barrier function of the stratum corneum.

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 C10H10O4 and has} the following structure:

Ferulic acid can be obtained by chemical synthesis or by extraction and purification from natural products containing ferulic acid, such as rice (rice bran, rice germ), wheat, rye, barley, coffee, apple, artichoke, peanut, orange, pineapple, etc. Also, commercially available reagents can be used.
Ferulic acid or a salt thereof has stereoisomers, and in the present invention, a pure stereoisomer or a mixture thereof can be used.

The salt of ferulic acid is preferably a pharma- ceutically acceptable salt. Examples of such salts include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with inorganic bases such as ammonium salts; salts with basic amino acids such as arginine, lysine, histidine, and ornithine; and salts with organic bases such as monoethanolamine, diethanolamine, and triethanolamine. Of these, salts with alkali metals or alkaline earth metals are preferred.

As shown in the Examples below, oral ingestion of ferulic acid reduced transepidermal water loss, which means that ferulic acid or a salt thereof has the effect of improving the skin barrier function.
Therefore, ferulic acid or a salt thereof can be a skin barrier function improver and can be used to improve the skin barrier function, and can also be used to produce a skin barrier function improver.
Here, the former "use" may be administration or ingestion to humans or non-human animals, and may be therapeutic or non-therapeutic use. Note that "non-therapeutic" is a concept that does not include medical procedures, i.e., a concept that does not include a method of surgery, treatment, or diagnosis of humans, more specifically, a concept that does not include a method of surgery, treatment, or diagnosis performed by a physician or a person under the instruction of a physician.

In the present invention, the "skin barrier function" refers to the function of preventing evaporation of moisture from the inside of the skin and the function of preventing the intrusion of substances from the outside into the skin. In the present invention, the function of preventing evaporation of moisture from the inside of the skin (moisture permeation barrier function) is suitable for improving the function.
"Improving skin barrier function" also includes the concepts of strengthening, preventing, inhibiting, or maintaining the deterioration, destruction, or breakdown of skin barrier function.
Oral ingestion of ferulic acid or a salt thereof improves the skin barrier function, thereby making it possible to prevent or improve skin diseases caused by abnormalities in the barrier function of the stratum corneum. Here, "prevention" refers to preventing or delaying the onset of a disease or symptom in an individual, or reducing the risk of an individual developing a disease or symptom. "Improvement" refers to improving a symptom or condition, preventing, suppressing or delaying the worsening of a symptom or condition, or reversing, preventing, suppressing or delaying the progression of a symptom or condition.

The oral skin barrier function improver of the present invention may be a drug, quasi-drug, supplement or food for improving skin barrier function itself, or it may be a material or preparation used by being incorporated into the drug, quasi-drug, or food.
The food in question is based on the concept of improving skin barrier function and includes functional foods, foods for specified health uses, supplements, etc. that are labeled as such when necessary. These foods are permitted to have functional claims and can be distinguished from general foods.

The pharmaceutical (including quasi-drugs) is a pharmaceutical for improving the skin barrier function and contains ferulic acid or its salt as an active ingredient for improving the skin barrier function. Furthermore, the pharmaceutical may contain a pharma- ceutical acceptable carrier, or other active ingredients, pharmacological ingredients, etc., as necessary, so long as the function of the active ingredient is not lost.

The dosage form of the pharmaceutical product (including quasi-drugs) may be an orally administrable dosage form, such as oral solid preparations such as tablets (including chewable tablets), capsules, granules, powders, and lozenges, and oral liquid preparations such as oral liquids and syrups. Preparations of these dosage forms may be prepared according to standard methods by appropriately combining ferulic acid or a salt thereof with a pharma- ceutically acceptable carrier (e.g., excipient, binder, bulking agent, disintegrant, surfactant, lubricant, dispersant, buffer, preservative, flavoring agent, fragrance, coating agent, diluent, etc.), other medicinal ingredients, etc.

The food is 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 food may be in a solid, semi-solid or liquid form (e.g., a beverage). Examples of the food include beverages such as soft drinks, tea drinks, coffee drinks, fruit juice drinks, carbonated drinks, jelly drinks, near water, jellies, wafers, biscuits, bread, noodles, sausages, and other foods and beverages, nutritional foods, and ingredients thereof. Alternatively, the food may be a supplement in the form of an oral preparation such as a tablet, capsule, granule, powder, liquid, or syrup.

The food can be prepared according to a standard method by appropriately combining ferulic acid or a salt thereof with any food ingredient, or other active ingredient, or additive acceptable for food (e.g., solvent, softener, oil, emulsifier, preservative, acidulant, sweetener, bittering agent, pH adjuster, stabilizer, colorant, ultraviolet absorber, antioxidant, moisturizer, thickener, adhesive, dispersant, flow improver, wetting agent, aromatic, seasoning, flavor adjuster), etc.

The content of ferulic acid or its salt in the above-mentioned medicines, quasi-drugs, or foods may vary depending on their dosage form or shape. For example, the content in ferulic acid equivalent is preferably 0.01% by mass or more, more preferably 1% by mass or more, and even more preferably 5% by mass or more, and is preferably 90% by mass or less, more preferably 70% by mass or less, and even more preferably 30% by mass or less.

In the present invention, the dosage and administration schedule 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 dosage of ferulic acid or a salt thereof according to the present invention (in terms of ferulic acid) is, for example, preferably 5 mg or more, more preferably 10 mg or more, even more preferably 50 mg or more, even more preferably 100 mg or more per day for an adult (60 kg), and is preferably 1000 mg or less, more preferably 500 mg or less, even more preferably 300 mg or less.
In the present invention, the above-mentioned dose is preferably divided into one, two, or three or more times a day and orally administered or ingested. More preferably, the above-mentioned dose of ferulic acid or its salt is orally administered or ingested once a day. The administration or ingestion period is not particularly limited, but is preferably continuous, more preferably one week or more, and even more preferably two weeks or more. The timing of administration or ingestion is preferably between after dinner and going to bed, and more preferably within one hour before going to bed.

In a preferred embodiment of the present invention, the above-mentioned daily dose of ferulic acid or a salt thereof is orally administered or ingested to a human in need of improved skin barrier function.

Test Example 1
1. Subjects The experiment was conducted in accordance with the ethical guidelines for clinical research and the ethical principles set out in the Declaration of Helsinki, with the approval of the Research Ethics Committee of Kao Corporation. Sixteen healthy Japanese males aged 35 to 50 years were recruited as subjects. The exclusion criteria were as follows:
Exclusion criteria: smoking habit, prevalence of serious illnesses (e.g. hypertension, heart disease, kidney disease, diabetes, etc.), poor physical condition, ongoing treatment requiring medication, taking sleeping pills.

2. Study design The test items used were capsules containing ferulic acid (FA) derived from rice germ (67 mg/capsule as ferulic acid, 11.6% by mass) and placebo capsules. The placebo capsules did not contain ferulic acid. Ferulic acid can be analyzed by any commonly known analytical method, such as HPLC, that is appropriate for the condition of the sample (see J. Agric. Food Chem. 2002; 50: 5735-5741, J. Nutr. 2007; 137: 2196-2201).

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

3. Statistical analysis Data were expressed as mean ± standard deviation (SD). SPSS statistics version 26 (IBM, Armonk, NY, USA) was used. Comparisons between baseline measurements and measurements after 2 weeks of continuous intake within the same group were performed using paired t-tests. Comparisons of changes were performed using Student's t-tests. The significance level was set at 5%.

4. Results The results are shown in Figure 1. The transepidermal water loss (g/ ^m2 /hr) in 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 (p=0.089), while in the ferulic acid intake group, the transepidermal water loss significantly decreased from 6.1±1.1 to 4.8±1.0 (p=0.004). The change in the transepidermal water loss in the placebo group was 0.5±0.7, and the change in the transepidermal water loss in the ferulic acid intake group was -1.3±0.9. The change in the transepidermal water loss was significantly different between the two groups (p<0.01). These results indicate that continuous oral intake of ferulic acid for 2 weeks improves the skin barrier function.

Claims (4)

An oral skin barrier function enhancer containing ferulic acid or a salt thereof as an active ingredient, wherein the skin barrier function is a function of preventing evaporation of moisture from inside the skin . The oral skin barrier function improver according to claim 1 , which is orally administered or ingested in an amount of 5 to 1000 mg per day for an adult as ferulic acid. The present invention provides an oral food for improving skin barrier function, which contains ferulic acid or a salt thereof as an active ingredient, and the skin barrier function is a function for preventing evaporation of moisture from inside the skin . The food for improving skin barrier function according to claim 3 , wherein ferulic acid is orally ingested in an amount of 5 to 1000 mg per day by an adult.