JP6116869B2 - Oral UV resistance improver - Google Patents

Description

  The present invention relates to an oral ultraviolet resistance improver that improves the ultraviolet resistance of skin by oral ingestion.

  In recent years, a decrease in the ozone layer has become a factor, and skin damage due to ultraviolet rays has become a problem. For example, chronic UV exposure may cause erythema and edema of the skin, wrinkles, sagging, spots and freckles appear significantly, skin elasticity decreases, skin darkening, yellowing increases A decrease in the amount of keratin water is induced.

  Conventionally, as means for improving damage to the skin due to ultraviolet rays, so-called sunscreens containing ultraviolet scattering agents and ultraviolet absorbers have been mainly used, and whitening agents having a melanin production inhibitory effect and the like have been mainly used. However, most of these are expected to have an effect obtained when used as a skin external preparation.

  However, in recent years, from an approach based on holistic skin control, it is considered ideal to create a body resistant to ultraviolet rays, and attempts have been made to improve the resistance of skin to ultraviolet rays by ingestion. For example, when Lactobacillus sp is orally ingested, the skin barrier function damage caused by UV irradiation is suppressed (Patent Document 1), and when carotenoids are mixed with elastin or ceramide, they are induced by UV. It has been reported that the erythema of the skin which can be effectively suppressed (patent document 2).

On the other hand, hesperidin is used in foods, pharmaceuticals, cosmetics and the like as vitamin P having physiological actions such as strengthening of capillaries, prevention of bleeding, and blood pressure adjustment, and as a yellow colorant, antioxidant and the like. Methyl hesperidin is obtained by methylating such hesperidin and solubilizing it in water. In Japan, it is also designated as a pharmaceutical additive and a food additive. Hesperidin methyl chalcone is blended in cosmetics for the purpose of antioxidants and the like. In addition, skin cosmetics using a combination of methyl hesperidin, an ascorbic acid derivative and an organic acid salt have an effect of preventing skin inflammation caused by ultraviolet rays and an effect of preventing / suppressing inflammatory pigmentation (Patent Document 3), It has been reported that cosmetics formulated with a combination of diisopropylamine dichloroacetate have a whitening effect (Patent Document 4). In addition, α-glycosyl hesperidin has been reported to have a melanin lowering effect and a skin lightness lowering suppressing effect when orally administered (Patent Document 5).
Recently, the present applicant has reported that when methyl hesperidin is orally ingested, it has an effect of improving the resistance of skin to ultraviolet rays (Patent Document 6).

  On the other hand, it is known that tocopherols have an antioxidant action, suppress peroxidation of biological membrane lipids, and have a peripheral vasodilatory action. In addition, it has been reported that glycosides and maltosides of tocopherol have a melanin production-inhibiting action and can be used by being blended into a skin whitening external preparation (Patent Document 7).

  However, it has not been known so far what effect it has on skin damage caused by ultraviolet rays when it is taken orally in combination with methyl hesperidin and tocopherols.

JP 2008-179601 A JP 2004-229611 A JP-A-11-199468 JP-A-11-171756 JP 2009-7336 A JP 2011-105714 A JP 2000-128762 A

  The present invention relates to providing an oral ultraviolet resistance improver that can increase the skin's resistance to ultraviolet rays and reduce or suppress skin damage caused by exposure to ultraviolet rays by oral ingestion.

  The present inventors examined an orally ingestible material that improves the ultraviolet resistance of the skin. As a result, the combination of methyl hesperidin and tocopherol or a derivative thereof or a salt thereof (hereinafter also referred to as “tocopherols”) was orally administered. When ingested, it was found that the onset of skin erythema, pigmentation, epidermis thickening, decrease in stratum corneum water content, etc. caused by UV exposure could be significantly suppressed, and this was useful as an oral UV resistance improver.

  That is, the present invention relates to an oral ultraviolet resistance improver comprising a combination of methyl hesperidin or a salt thereof and tocopherol or a derivative thereof or a salt thereof.

  The ultraviolet resistance improver of the present invention is, for example, skin inflammation such as erythema and edema caused by exposure to ultraviolet rays on the skin, formation of wrinkles and sagging, formation of spots and freckles, reduction of skin elasticity, pigment It is effective for reducing or suppressing various skin damages such as so-called skin aging or skin deterioration such as deposition, darkening of the skin, increased yellowing, decreased skin barrier function, and decreased stratum corneum function.

  The methyl hesperidin used in the ultraviolet resistance improver of the present invention is obtained by methylating hesperidin and solubilizing it in water. Such methyl hesperidin is known to mainly include chalcone type compounds (A) and flavanone type compounds (B), and examples of the constituents thereof include those having the structures shown below.

  (In the formula, R represents a hydrogen atom or a methyl group.)

  Here, methyl hesperidin as a pharmaceutical additive and a food additive is mainly handled as a mixture of the compounds (C) and (D).

  (In the formula, Gl represents a glucose residue, Rh represents a rhamnose residue, and Gl-2 represents the 2-position of the glucose residue (including C3-position), and Rh-2 represents Represents the second position of the rhamnose residue.)

  Hesperidin methyl chalcone as a cosmetic raw material is handled as a compound represented by (E).

  (In the formula, R represents a hydrogen atom or a methyl group.)

The methyl hesperidin used in the ultraviolet resistance improver of the present invention may contain both the chalcone type compound (A) and flavanone type compound (B) shown above, or only one of them. But it ’s okay.
Further, in the case of a composition mainly containing a large amount of chalcone type compound, it may be called hesperidin methyl chalcone, but this is also the same.

  In the present invention, more preferred methyl hesperidin is methyl hesperidin (mainly a mixture of compound (C) and compound (D)) used as a pharmaceutical additive and food additive, and hesperidin used as a cosmetic raw material. And methyl chalcone (compound (E)).

Methyl hesperidin is a known method, for example, hesperidin produced from citrus peel is dissolved in an aqueous sodium hydroxide solution, a corresponding amount of dimethyl sulfate is allowed to act on the alkaline solution, and the reaction solution is neutralized with sulfuric acid. -It can be manufactured by extracting with butyl alcohol, distilling off the solvent and then recrystallizing with isopropyl alcohol (Sakibuka, Nippon Kagaku Kagaku, 79, 733-6 (1958)), but the manufacturing method is limited to this It is not a thing.
In addition, commercially available products (for example, those that are distributed as pharmaceutical additives, food additives, and cosmetic raw materials, or “methyl hesperidin” (Tokyo Kasei Kogyo Co., Ltd.), “hesperidin methyl chalcone” (Sigma), etc.) It can also be purchased and used.

In the tocopherol or a derivative thereof or a salt thereof (“tocopherols”) of the present invention, examples of the tocopherol include d-α-tocopherol, dl-α-tocopherol, etc. Examples of the tocopherol derivative include, for example, an ester derivative of tocopherol, For example, d-α-tocopherol succinate, dl-α-tocopherol succinate, d-α-tocopherol acetate or dl-α-tocopherol acetate, d-α-tocopherol nicotinate, dl-α-tocopherol nicotinate, phosphoric acid Examples include d-α-tocopherol (d-α-tocopherol phosphate ester), dl-α-tocopherol phosphate (dl-α-tocopherol phosphate ester), and the like.
Moreover, as a salt of tocopherol or its derivative (s), a calcium salt, sodium salt, etc. are mentioned, for example.

  Tocopherol or a derivative thereof or a salt thereof is preferably d-α-tocopherol, d-α-tocopherol acetate, d-α-tocopherol succinate, d-α-tocopherol phosphate sodium salt, d-α. -Tocopherol succinic acid ester calcium salt etc. are mentioned.

  In the ultraviolet resistance improver of the present invention, in addition to the above-mentioned tocopherols, ascorbic acid or a derivative thereof or a salt thereof (also referred to as “ascorbic acid”), and riboflavin or a derivative thereof or a salt thereof (“riboflavin”) Vitamins selected from the group consisting of ascorbic acid and riboflavin are more preferably used in combination.

Ascorbic acid derivatives include, for example, ester derivatives and glycosides of ascorbic acid. Specifically, ascorbic acid (mono, di or tri) stearate, ascorbic acid (mono, di or tri) palmitate, ascorbine Examples include acid (mono, di or tri) oleate, ascorbic acid (mono, di or tri) phosphate ester, ascorbic acid-2-sulfuric acid, ascorbic acid-2-glucoside and the like.
As the ascorbic acid, any of d-form that is erythorbic acid (isoascorbic acid), l-form that is vitamin C, and dl-form can be used.
Examples of ascorbic acid or a derivative thereof or a salt thereof include calcium salt, sodium salt, magnesium salt and the like.

  As ascorbic acid or a derivative thereof or a salt thereof, L-ascorbic acid, calcium L-ascorbate, sodium L-ascorbate, L-ascorbic acid phosphate, magnesium ascorbate phosphate, ascorbine Acid phosphate sodium salt, ascorbic acid sulfate sodium salt, erythorbic acid, calcium erythorbate, sodium erythorbate, erythorbic acid phosphate, magnesium erythorbate phosphate, magnesium erythorbate phosphate, sodium erythorbate Examples include ester sodium salts.

Examples of riboflavin derivatives include flavin mononucleotide, flavin adenine dinucleotide, riboflavin tetrabutyrate, riboflavin butyrate, riboflavin phosphate (riboflavin phosphate ester), and the like.
Examples of the salt of riboflavin or a derivative thereof include sodium salt.
Preferred examples of riboflavin or a derivative thereof or a salt thereof include riboflavin butyrate and sodium riboflavin phosphate (riboflavin phosphate sodium salt).

  Such tocopherols, ascorbic acids and riboflavins are widely commercially available and can be easily obtained. Moreover, the vitamin main ingredient formulation which mix | blended vitamins containing tocopherols, ascorbic acids, and riboflavin is also marketed, and such a formulation can also be utilized as it is.

  Oral ultraviolet resistance improver comprising a combination of methyl hesperidin or a salt thereof of the present invention and tocopherols, as a compounding agent, even if each effective amount is formulated into one dosage form at an appropriate compounding ratio, Moreover, the kit which enabled it to use separately what separately formulated the chemical | medical agent containing each effective amount separately at intervals.

  The ratio of the combination of methyl hesperidin or a salt thereof and tocopherols in the oral ultraviolet resistance improver of the present invention can be appropriately selected, and is, for example, 1: 0.001 to 100, preferably 1: 0.01. -10. Further, when combining ascorbic acid and riboflavin, the ratio of methyl hesperidin or a salt thereof, tocopherols, ascorbic acid, and riboflavin is, for example, 1: 0.001 to 100: 0.001 to 100: 0. 001 to 10, preferably 1: 0.01 to 10: 0.01 to 10: 0.01 to 1.

As shown in the examples below, when the mice are orally ingested in combination with ascorbic acids and riboflavins in addition to methyl hesperidin and tocopherols, or methyl hesperidin and tocopherols, onset of skin erythema due to the ultraviolet rays Is significantly suppressed, the effect exceeds the addition of the effects obtained when methyl hesperidin and tocopherols, or methyl hesperidin and the vitamins (tocopherols, ascorbic acid and riboflavin) are each administered alone, It can be said that this is a synergistic effect.
That is, the combined use of methyl hesperidin and tocopherols can be used to increase the resistance of the skin against ultraviolet rays, that is, can be used as an ultraviolet resistance improver, and also produces the ultraviolet resistance improver. Can be used for. The use can be in humans or non-human animals, or specimens derived therefrom, and can be either therapeutic or non-therapeutic. Here, “non-therapeutic” means a concept that does not include medical practice, that is, a concept that does not include a method for operating, treating, or diagnosing a person, more specifically, a doctor or a person who has received instructions from a doctor It is a concept that does not include a method for performing surgery, treatment, or diagnosis on the subject.
Therefore, the oral ultraviolet resistance improver of the present invention improves the resistance to ultraviolet rays and induces skin inflammation such as erythema and edema of the skin, formation of wrinkles and sagging, formation of spots and freckles induced by ultraviolet exposure. Oral to reduce or suppress skin disorders such as skin aging or skin deterioration such as skin elasticity reduction, pigmentation, skin blackening, yellowing increase, skin barrier function reduction, stratum corneum function reduction It is useful as a medicine, quasi-drug, supplement or food, or as a material or preparation for blending into these.

  The pharmaceutical, quasi-drug or supplement dosage form containing methyl hesperidin and tocopherols may be either a solid formulation or a liquid formulation. Specifically, tablets, coated tablets, capsules, granules, powders, Examples include powders, sustained-release preparations, suspensions, emulsions, internal liquids, dragees, pills, fine granules, syrups, elixirs and the like.

  A pharmaceutically acceptable carrier can be added to the above preparation. Such carriers include, for example, excipients, binders, disintegrants, lubricants, diluents, osmotic pressure regulators, fluidity promoters, absorption aids, pH adjusters, emulsifiers, preservatives, stabilization. Agent, antioxidant, colorant, UV absorber, wetting agent, thickener, brightener, activity enhancer, anti-inflammatory agent, bactericidal agent, flavoring agent, flavoring agent, extender, surfactant, dispersant, Buffering agents, preservatives, fixing agents, fragrances, coating agents and the like can be mentioned. Moreover, a well-known medicinal component can also be suitably mix | blended with the said formulation. Examples of such components include various vitamins other than vitamins B, C and E, amino acids and peptides and derivatives thereof, nucleic acids and derivatives thereof, saccharides and derivatives thereof, carotenoids, soybean isoflavones, catechins, chlorogenic acid and the like. And other antioxidants.

The content of methyl hesperidin in the preparation is usually 0.001% by mass or more, preferably 0.01% by mass or more, and 90% by mass or less, preferably 60% by mass or less, based on the total mass of the formulation. For example, 0.001-90 mass%, Preferably 0.01-60 mass% is mentioned.
Further, the content of tocopherols is 0.001% by mass or more, preferably 0.01% by mass or more, and 90% by mass or less, preferably 60% by mass or less, based on the total mass of the preparation. For example, 0.001-90 mass%, Preferably 0.01-60 mass% is mentioned.
Further, when ascorbic acid and / or riboflavin is contained in addition to tocopherols, the content of ascorbic acid or riboflavin is 0.001% by mass or more, preferably 0 as the ascorbic acid or riboflavin, respectively. 0.01 mass% or more, and 90 mass% or less, preferably 60 mass% or less. For example, 0.001-90 mass%, Preferably 0.01-60 mass% is mentioned.
In particular, when three types of ascorbic acid and riboflavin are used in addition to tocopherols, tocopherols are 0.001% by mass to 90% by mass and ascorbic acids are 0.001% by mass to 90% in the total mass of the preparation. Preferably, the riboflavin content is 0.001% to 30% by mass, and in this case, methyl hesperidin is preferably 0.001% to 90% by mass of the total mass of the preparation.

  In addition to general foods and drinks, the above-mentioned food containing methyl hesperidin and tocopherols is caused by ultraviolet rays, erythema and edema of the skin, formation of wrinkles and sagging, formation of spots and freckles, reduced skin elasticity, Beauty food with the concept of reducing or suppressing skin damage such as pigmentation, darkening of the skin, increased yellowing, reduced skin barrier function, reduced stratum corneum function, etc. Functional foods such as foods for the sick, functional foods for nutrition, or foods for specified health use are included.

  The form of the food product can be solid, semi-solid or liquid. Examples of food include confectionery such as breads, noodles, cookies, jelly, dairy products, frozen foods, instant foods, processed starch products, processed meat products, other processed foods, coffee beverages, soups, Examples include seasonings, dietary supplements, and the like, and raw materials thereof. Further, like the above-mentioned preparation for oral administration, it may be in tablet form, pill form, capsule form, liquid form, syrup form, powder form, granule form and the like.

Such foods include any food and drink materials, solvents, softeners, oils, emulsifiers, preservatives, fragrances, stabilizers, colorants, ultraviolet absorbers, antioxidants, moisturizers, thickeners, sticking agents. , A dispersant, a wetting agent, and the like can be mixed and prepared as appropriate.
Various vitamins other than vitamins B, C and E, amino acids and peptides and derivatives thereof, nucleic acids and derivatives thereof, saccharides and derivatives thereof, carotenoids, soybean isoflavones, catechins, antioxidant components such as chlorogenic acid, etc. It can mix | blend suitably.

The content of methyl hesperidin in the above food or drink varies depending on the use form, but is usually 0.0001% by mass or more, preferably 0.001%, and 50% by mass or less, preferably 10% by mass or less. It is. For example, 0.0001% -50 mass%, Preferably 0.001-10 mass% is mentioned. The content of tocopherols is 0.0001% by mass or more, preferably 0.001% by mass or more, and 50% by mass or less, preferably 10% by mass or less, based on the total mass of the preparation. For example, 0.0001-50 mass%, Preferably 0.001-10 mass% is mentioned.
Further, in the case of containing ascorbic acid and / or riboflavin in addition to tocopherols, the content of ascorbic acid or riboflavin is 0.0001% by mass or more of the total mass of the preparation as ascorbic acid or riboflavin, respectively, preferably 0.001% by mass or more and 50% by mass or less, preferably 10% by mass or less. For example, 0.0001-50 mass%, Preferably 0.001-10 mass% is mentioned. In particular, when three types of tocopherols, ascorbic acids and riboflavins are used, in the total mass of the preparation, tocopherols are 0.0001% by mass to 50% by mass, ascorbic acids are 0.0001% by mass to 50% by mass, Riboflavin is preferably 0.0001 mass% or more and 10 mass% or less, and in this case, methyl hesperidin is preferably 0.0001 mass% or more and 50 mass% or less of the total mass of the preparation.

When the combination of methyl hesperidin and tocopherols of the present invention is used as a pharmaceutical or in combination with a pharmaceutical, the dosage may vary according to the patient's condition, body weight, sex, age or other factors, The daily dose per adult is usually 0.01 g or more, preferably 0.05 g or more, and 10 g or less, preferably 5 g or less as methyl hesperidin. The tocopherols are 0.01 g or more, preferably 0.05 g or more, and 10 g or less, preferably 3 g or less.
Moreover, when further ascorbic acid and / or riboflavin is mix | blended, it is preferable that they are 0.01 g or more and 10 g or less as ascorbic acid, and 0.01 g or more and 5 g or less as riboflavin.
Moreover, although the said formulation can be administered according to arbitrary administration schedules, it is preferable to divide once to several times a day, and to administer continuously for several weeks to several months.
The subject of administration or ingestion is not particularly limited as long as it is an animal that needs or desires it, but skin damage induced by UV exposure, such as erythema of the skin, decreased skin elasticity, pigmentation And a human who needs or desires to reduce or suppress a decrease in skin barrier function or a decrease in stratum corneum function.

Regarding the above-described embodiment, the following aspects are further disclosed in the present invention.
<1> An oral ultraviolet resistance improver comprising a combination of methyl hesperidin or a salt thereof and tocopherol or a derivative thereof or a salt thereof.
<2> Use of a combination of methyl hesperidin or a salt thereof and tocopherol or a derivative thereof or a salt thereof for producing an oral ultraviolet resistance improver.
<3> A combination of methyl hesperidin or a salt thereof for use in improving oral ultraviolet resistance and tocopherol or a derivative thereof or a salt thereof.
<4> A method for improving oral ultraviolet resistance, comprising administering or ingesting an effective amount of a combination of methyl hesperidin or a salt thereof and tocopherol or a derivative thereof or a salt thereof.
<5> In the above items <1> to <4>, the tocopherol or a derivative thereof or a salt thereof is d-α-tocopherol acetate.
<6> In the above items <1> to <4>, ascorbic acid or a derivative thereof or a salt thereof, and a vitamin selected from riboflavin, a derivative thereof, or a salt thereof are further combined.
<7> In the above item <6>, ascorbic acid or a derivative thereof or a salt thereof is ascorbic acid or a salt thereof.
<8> In the above item <6>, the riboflavin or a derivative thereof or a salt thereof is riboflavin butyrate.
<9> In the above items <1> to <8>, the improvement in oral ultraviolet resistance is to reduce or suppress skin damage induced by ultraviolet exposure.
<10> In the above item <9>, the skin disorder induced by exposure to ultraviolet rays is skin inflammation or skin aging.
<11> In the above item <9>, in the skin disorder induced by ultraviolet exposure, the skin disorder induced by ultraviolet exposure is erythema of skin, decreased skin elasticity, pigmentation, decreased skin barrier function and It is 1 or more types chosen from the fall of a stratum corneum function.
<12> In the above item <3>, the use is a non-therapeutic use.
<16> In <4>, the method is a non-therapeutic method.
<17> In the above item <4>, the subject to be administered or ingested is a skin disorder induced by exposure to ultraviolet rays, such as erythema of the skin, decreased skin elasticity, pigmentation, decreased skin barrier function or decreased horny layer function. An animal, preferably a human, in need or desired to reduce or suppress the above.
<18> In the above <1> to <17>, the daily dose per adult when orally administering methyl hesperidin or a salt thereof and tocopherol or a derivative thereof or a salt thereof is 0.001 g as methyl hesperidin Or more, preferably 0.05 g or more, and 10 g or less, preferably 5 g or less. As tocopherol or a derivative thereof or a salt thereof, 0.01 g or more, preferably 0.05 g or more, and 10 g or less, preferably 3 g or less. It is.

Example 1 Erythema inhibitory effect and epidermal thickening inhibitory effect by UVB irradiation when a combination formulation of methyl hesperidin and tocopherol is orally administered (1) Method Hairless mouse HR-1 (female, 8 weeks old, n = 10) (Japan) SLC) was preliminarily raised for one week, and then divided into a control group, a methyl hesperidin administration group (methyl hesperidin: used as an additive), a tocopherol administration group, and a methyl hesperidin + tocopherol administration group.
During the test period, feed and water were freely consumed, and the animals were raised under conditions of a temperature of 23 ± 1 ° C., a humidity of 50 ± 1%, and a lighting time of 7:00 to 19:00. The methyl hesperidin administration group is methyl hesperidin (Alps Yakuhin Kogyo) 50 mg / kg body weight, the tocopherol administration group is d-α-tocopherol acetate (Sigma) 40 mg / kg body weight, the methyl hesperidin + tocopherol administration group is the methyl hesperidin administration group Each combination of d-α-tocopherol acetate administration groups was prepared so that the dosage was 0.1 mL / 10 g body weight, and was administered by oral gavage once a day for 2 weeks using a stomach tube in the form of an emulsion. did. In the control group, these drugs were removed, and an emulsion was prepared and similarly administered orally.
Two weeks after oral administration, under pentobarbital anesthesia, a 1.5 cm × 1.0 cm site was set close to the back of the mouse so as to be bilaterally symmetric, with a UVB irradiation dose of 1 mW / cm ² , Irradiation was for 0 second (0 mJ) and 40 seconds (40 mJ), respectively. Evaluate the extent of erythema 48 hours after irradiation (-; no response, ± (minimal erythema); mild or partial erythema, +; clear erythema, ++; erythema and edema, +++; erythema) Skin color (a ^* value) was measured using an edema and blisters) and a spectroscopic color difference meter SE-6000 (Nippon Denshoku Industries Co., Ltd.). The a ^* value is an index representing the redness of the skin color, that is, the intensity of erythema, and the larger the a ^* value, the more the skin changes to red, that is, erythema occurs. For each group, the site of 0 mJ (unirradiated site) was subtracted from the site of 40 mJ (irradiated site) and expressed by Δa ^* value (mean ± standard deviation).
Immediately thereafter, the blood was sacrificed by blood sampling, the UVB non-irradiated site and the irradiated site skin were collected, HE-stained specimens were prepared, and the skin thickness was observed with a microscope. For the skin thickness, the average value of the skin thickness at any 50 locations per tissue was defined as the skin thickness of the tissue (mean ± standard deviation).

(2) Results 1) Erythema inhibitory effect The results are shown in Table 1 (Δa * value) and Table 2 (visual evaluation).
Methyl hesperidin, in combination with tocopherol, was confirmed to have an effect of enhancing erythema formation from the results of skin color (a * value) and erythema visual score.

2) Skin thickening inhibitory effect The results are shown in Table 3 (skin thickness).
Microscopic observation confirmed that the epidermis was thickened by UVB irradiation. It has been clarified that the combination of methyl hesperidin and tocopherol enhances the inhibitory effect of methyl hesperidin on the epidermal thickening caused by UVB irradiation.

Example 2 Erythema inhibitory effect and epidermal thickening inhibitory effect by UVB irradiation when a combination formulation of methyl hesperidin and vitamins (tocopherol, ascorbic acid, riboflavin) is orally administered (1) Method Hairless mouse HR-1 (female, 8 Weekly age, n = 7-8) (Japan SLC) pre-bred for 1 week, then control group, methyl hesperidin administration group (methyl hesperidin: used as an additive), vitamins (tocopherol, ascorbic acid, riboflavin) ) Divided into administration group, methyl hesperidin + vitamins administration group.
During the test period, feed and water were freely consumed, and the animals were raised under conditions of a temperature of 23 ± 1 ° C., a humidity of 50 ± 1%, and a lighting time of 7:00 to 19:00. The methyl hesperidin administration group is methyl hesperidin (Alps Yakuhin Kogyo Co., Ltd.) 50 mg / kg body weight, the vitamin administration group is d-α-tocopherol acetate (Sigma) 20 mg / kg body weight, L (+)-sodium ascorbate (Pure Wako) Yakuhin Kogyo Co., Ltd.) 66.6 mg / kg body weight, tetrabutyrate riboflavin (Wako Pure Chemical Industries) 0.8 mg / kg body weight, methyl hesperidin + vitamins administration group is the above-mentioned methyl hesperidin administration group and vitamin administration group Each combination was prepared to a dosage of 0.1 mL / 10 g body weight, and was orally administered by gavage once a day for 2 weeks using a stomach tube in the form of an emulsion. In the control group, these drugs were removed, and an emulsion was prepared and similarly administered orally.
Two weeks after oral administration, under pentobarbital anesthesia, a 1.5 cm × 1.0 cm site was set close to the back of the mouse so as to be bilaterally symmetric, with a UVB irradiation dose of 1 mW / cm ² , Irradiation was for 0 second (0 mJ) and 40 seconds (40 mJ), respectively. Evaluate the extent of erythema 48 hours after irradiation (-; no response, ± (minimal erythema); mild or partial erythema, +; clear erythema, ++; erythema and edema, +++; erythema) Skin color (a ^* value) was measured using an edema and blister) and a spectroscopic color difference meter SE-6000 (Nippon Denshoku Industries Co., Ltd.). The a ^* value is an index representing the redness of the skin color, that is, the intensity of erythema, and the larger the a ^* value, the more the skin changes to red, that is, erythema occurs. For each group, the site of 0 mJ (unirradiated site) was subtracted from the site of 40 mJ (irradiated site) and expressed by Δa ^* value (mean ± standard deviation).
Immediately after that, after sacrifice by cardiac blood sampling, the UVB non-irradiated part and the skin of the irradiated part were collected, HE-stained specimens were prepared, and the epidermis thickness was observed with a microscope. For the skin thickness, the average value of the skin thickness at any 50 locations per tissue was defined as the skin thickness of the tissue (mean ± standard deviation).

(2) Results 1) Erythema inhibitory effect The results are shown in Table 4 (Δa ^* value) and Table 5 (visual evaluation).
Methyl hesperidin, in combination with vitamins containing ascorbic acid, was confirmed to have an effect of enhancing erythema formation from the results of skin color (a ^* value) and erythema visual score.

2) Skin thickening inhibitory effect The results are shown in Table 6 (skin thickness).
Microscopic observation confirmed that the epidermis was thickened by UVB irradiation. It has been clarified that the combination of methyl hesperidin and vitamins enhances the inhibitory effect of methyl hesperidin on the epidermal thickening caused by UVB irradiation.

Claims (8)

Methyl hesperidin or a salt thereof and tocopherol or d-α-tocopherol succinate, dl-α-tocopherol succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, d-α-tocopherol nicotinate, dl nicotinate dl An oral ultraviolet resistance improver comprising a derivative of tocopherol selected from α-tocopherol, d-α-tocopherol phosphate, and dl-α-tocopherol phosphate , or a salt thereof.   The oral ultraviolet resistance improving agent according to claim 1, wherein the tocopherol or a derivative thereof or a salt thereof is d-α-tocopherol acetate. Further, ascorbic acid or ascorbic acid stearate, ascorbyl palmitate, ascorbic acid oleate, ascorbyl phosphate ester, ascorbic acid-2-sulfate, and derivatives of ascorbic acid selected from ascorbic acid 2-glucoside or a salt thereof and riboflavin or flavin mononucleotide, flavin adenine dinucleotide, riboflavin tetrabutylate late, riboflavin butyrate, and derivatives of riboflavin selected from riboflavin phosphate, or their formed by combining salt or we vitamins selected claim 1 or 2. The oral ultraviolet resistance improver according to 2.   The oral ultraviolet resistance improver according to claim 3, wherein the ascorbic acid or a derivative thereof or a salt thereof is ascorbic acid or a salt thereof.   The oral ultraviolet resistance improver according to claim 3 or 4, wherein the riboflavin or a derivative thereof or a salt thereof is riboflavin butyrate.   The oral ultraviolet resistance improver according to any one of claims 1 to 5, which reduces or suppresses skin damage induced by ultraviolet exposure.   The oral ultraviolet resistance improver according to claim 6, wherein the skin disorder induced by exposure to ultraviolet rays is skin inflammation or skin aging.   7. The oral ultraviolet resistance according to claim 6, wherein the skin damage induced by exposure to ultraviolet rays is at least one selected from erythema of the skin, decreased skin elasticity, pigmentation, decreased skin barrier function and decreased stratum corneum function. Improver.