Oral preparation for improving minimal erythema dose

Abstract

[Problem] The problem of the present invention is to suppress the occurrence of erythema caused by ultraviolet irradiation, by using glutathione. [Solution] According to the present invention, by orally ingesting glutathione at a low dose of 100 mg / day or less, the numerical value of the ultraviolet irradiation level (minimum erythema dose: MED) necessary for the occurrence of erythema can be improved, and the occurrence of erythema due to ultraviolet irradiation can be suppressed. According to the present invention, the tolerance to ultraviolet exposure can be improved, and pigmentation can be suppressed.

Description

Oral agent for improving the minimal erythema dose

[0001] The present invention relates to a glutathione-containing composition that is suitably used for improving the minimum erythema dose due to ultraviolet radiation, and a method for improving the minimum erythema dose using the composition.

[0002] Although the mechanisms of skin pigmentation, age spots, and freckles are still unclear, it is believed that hormonal abnormalities and ultraviolet light stimulation cause the formation of melanin pigment, which then deposits in the skin. Tyrosinase is an enzyme that catalyzes the oxidation of tyrosine or dopa, and by inhibiting the activity of tyrosinase, the production of melanin pigment is suppressed. Tyrosinase inhibitors are used as whitening agents for cosmetics and as browning inhibitors for foods.

[0003] Glutathione is a tripeptide composed of the amino acids cysteine, glutamic acid, and glycine, and is known to improve the liver's detoxification function. Glutathione intake is known to improve non-alcoholic fatty liver disease. It also functions as a rich flavor substance, and is used in food ingredients and pharmaceuticals.

[0004] Furthermore, when glutathione is orally ingested, the typical dosage is 100 mg / day to 300 mg / day, and Non-Patent Document 1 reports that taking 250 mg or more increased blood glutathione levels by 17% after six months. Non-Patent Document 2 examines the effect of taking 500 mg / day for four weeks on melanin in the skin.

[0005] Furthermore, methods have been reported in which glutathione is combined with other materials to improve skin conditions. Patent Document 1 reports that tyrosinase activity is inhibited by α-lipoic acid and reduced glutathione.

[0006] However, there have been no reports on the redness (erythema) that occurs on the skin due to ultraviolet irradiation, and a method for suppressing erythema caused by ultraviolet irradiation has been desired.

[0007] JP 2009-51768 A

[0008] Richie JP Jr, Nichenametla S, Neidig W, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. 2015;54(2):251-263.Arjinpathana, Nutthavuth, Glutathione as an oral whitening agent: A randomized, double-blind, placebo-controlled study. Journal of Dermatological Treatment 2012;23(2): 97-102

[0009] An object of the present invention is to suppress the formation of erythema caused by ultraviolet irradiation by glutathione.

[0010] As a result of intensive research into solving the above-mentioned problems, the inventors discovered that oral administration of low doses of glutathione can suppress the occurrence of erythema caused by ultraviolet irradiation and improve the minimum erythema dose value, thereby completing the present invention.

[0011] That is, the present invention relates to the following first to fifth aspects. First, an oral preparation for improving the minimal erythema level of skin, which contains glutathione as an active ingredient. Second, the first oral preparation for improving the minimal erythema level of skin, which contains 100 mg or less of glutathione. Third, the first or second oral preparation for improving the minimal erythema level of skin, in which the glutathione is glutathione contained in yeast extract. Fourth, a method for improving the minimal erythema level of skin, which involves orally ingesting 100 mg or less of glutathione per day. Fifth, the method for improving the minimal erythema level of skin according to claim 4, in which the glutathione is glutathione contained in yeast extract.

[0012] According to the present invention, oral administration of a low dose of glutathione of 100 mg / day or less can suppress the occurrence of erythema caused by ultraviolet radiation, and by increasing the amount of ultraviolet radiation required to cause erythema (minimum erythema dose), tolerance to ultraviolet radiation exposure can be improved.

[0013] In the present invention, erythema refers to redness of the skin caused by UV irradiation. The UV irradiation dose required to cause erythema is called the minimal erythema dose (MED), and an increase in the MED value indicates a higher UV irradiation dose required to cause erythema. An increase in the MED value due to glutathione intake indicates that glutathione suppresses the occurrence of erythema caused by UV irradiation.

[0014] The ultraviolet rays that can suppress the occurrence of erythema with glutathione refer to electromagnetic waves in the wavelength range of 10 to 400 nm, and more preferably electromagnetic waves in the wavelength range of 280 to 320 nm.

[0015] The MED is measured using a solar simulator in the following manner. Twelve test areas are set on the subject's back. The first test area, which has the weakest irradiation intensity, is set to 11.57 mJ / cm^2. The second adjacent test area is increased by 15% from the first test area. Similarly, the irradiation intensity of the nth test area is set to 15% higher than the (n-1)th test area, and the irradiation intensity up to the 12th test area is set. The 12th test area, which has the strongest irradiation intensity, is set to 53.87 mJ / cm^2. The UV exposure time is 38 seconds. One day after UV exposure using the solar simulator, a physician visually checks the UV-exposed areas for the presence or absence of erythema. Of the test areas where erythema was observed, the irradiation intensity of the weakest test area is designated as the subject's MED.

[0016] Since skin erythema is caused by pigmentation, the degree of pigmentation can be evaluated using the L* value. The higher the L* value, the more suppressed the pigmentation, i.e., the more suppressed the erythema. This L* value can be measured using a spectrophotometer. The L* value is the difference between the L* value of the exposed and non-exposed areas after 7 days of exposure to ultraviolet light at an intensity 1.5 times the subject's MED.

[0017] Glutathione in the present invention refers to reduced glutathione, oxidized glutathione, or a mixture thereof. Reduced glutathione refers to a tripeptide having the structure γ-L-Glu-L-Cys-Gly, and oxidized glutathione is formed by two molecules of reduced glutathione bound together via an S—S bond. The form of glutathione may be any as long as it contains glutathione as an active ingredient.

[0018] The glutathione of the present invention is not particularly limited as long as it is obtained by a method that allows it to be used as a pharmaceutical or food. Typically, it can be obtained from microorganisms such as yeast (JP 59-151894 A), produced by synthesis using enzymes (JP 2020-72 A), or produced by chemical synthesis (Bull. Chem., Soc. Jpn., 1980, Vol. 53, p. 2529). The glutathione used in the present invention is not limited. Glutathione and oxidized glutathione can also be purchased, and purchased products may be used as long as they are usable as foods, pharmaceuticals, etc.

[0019] The glutathione content in the composition of the present invention is arbitrary, but it is preferable that the content in the composition is 100 mg or less so that the daily intake is 100 mg or less. Furthermore, when the composition of the present invention is in the form of a tablet, for example, the content per tablet may be 100 mg, or, for example, the content per tablet may be 20 mg, and the composition of the present invention may be equivalent to five tablets. The same applies to granules, liquids, etc.

[0020] The glutathione used in the glutathione-containing composition of the present invention may be in any form, including purified, crude, or mixed, as long as it contains glutathione. The mixture may be an extract containing glutathione, such as yeast extract. Examples of yeast containing glutathione include "Hithion Cobo MG" (Mitsubishi Corporation Life Sciences), and examples of yeast extract containing glutathione include "Hithion Extract YH" (Mitsubishi Corporation Life Sciences).

[0021] In the present invention, the glutathione content in a mixture such as yeast extract is measured using high performance liquid chromatography (HPLC). The measurement conditions are as follows: Column: Mightysil RP-18GP (Kanto Chemical) 4.6 mm-150 cm; Mobile phase: 5% diammonium hydrogen phosphate (adjusted to pH 3.2 with phosphoric acid); Measurement wavelength: 210 nm. Furthermore, the total glutathione, which includes GSH and GSSG, is quantified according to the Tietze method (Analytical Biochemistry, Vol. 27, p. 502, 1969). Note that the glutathione content in the present invention refers to the total glutathione content, including both reduced and oxidized forms.

[0022] In the present invention, glutathione is effective even if it is a purified product when taken in small doses, but glutathione-containing yeast extract is even better. As the yeast extract, it is particularly preferable to use a yeast extract with a high glutathione content. Particularly preferred is a yeast extract containing 8% by weight or more of glutathione, more preferably a yeast extract containing 10% by weight or more. Particularly preferred is an enzyme extract containing 15% by weight or more of glutathione.

[0023] The composition of the present invention can contain other substances as long as they do not impair the effects of the present invention.Additions that can be made include excipients used in common supplements, feeds, and pharmaceuticals, various vitamin preparations, inorganic substances such as calcium, magnesium, iron, and zinc, organic acids such as lactic acid, citric acid, and malic acid, proteins, lactic acid bacteria extracts, polyphenols, and organic substances such as plant extracts.In addition, acidulants, sweeteners, flavorings, stabilizers, and the like that are commonly added to foods can also be added.

[0024] The method of administering the product of the present invention is not particularly limited, and examples thereof include oral administration and parenteral administration such as intravenous, intraperitoneal, or subcutaneous administration. Specifically, the product may be administered in any of oral forms such as tablets, powders, granules, pills, suspensions, emulsions, infusions / decoctions, capsules, syrups, liquids, elixirs, extracts, tinctures, and liquid extracts, or parenteral forms such as injections, drip infusions, creams, and suppositories. Conventional methods can be used to prepare these tablets, and there are no limitations to the present invention.

[0025] The dosage of the present invention is effective even at low doses. When administered to humans, the intake amount and frequency of administration vary depending on the dosage form, the age and weight of the recipient, etc., but an adult should ingest 100 mg or less of glutathione per day. Typically, 10 mg to 100 mg, preferably 20 mg to 80 mg, and particularly preferably 30 mg to 50 mg, is ingested once or several times a day. When using a yeast extract containing glutathione, the glutathione content in the yeast extract is measured, and the intake amount is adjusted to achieve the dose specified in this paragraph.

[0026] The composition of the present invention can be ingested not only as a pharmaceutical product but also as a functional food or nutritional supplement, in which case it may be ingested in the amount described above.

[0027] The method for improving the minimum erythema dose of the present invention can be determined by determining how much the MED irradiation intensity is improved by taking glutathione using the glutathione intake method described above.

[0028] Similarly, the L* value improvement method of the present invention can be determined by irradiating the skin with ultraviolet light at an irradiation intensity 1.5 times the MED and measuring the difference in L value between the irradiated and non-irradiated areas 7 days later.

[0029] The present invention will be specifically explained below using examples, but the present invention is not limited to these examples.

[0030] <Test method> A randomized, placebo-controlled, double-blind, parallel-group comparative intervention study was conducted on healthy adults aged 30 to 59 years, in which the test food was ingested for five weeks to examine the effect on the occurrence of erythema caused by ultraviolet radiation.

[0031] <Test Food> Yeast extract A is a yeast extract containing 15% by weight of glutathione, and the glutathione content in test food A is 40 mg. Maltitol (manufactured by Mitsubishi Corporation Life Sciences) was used as the control food, so the glutathione content in the control food was 0 mg.

[0032] <Exam period> March to April 2023.

[0033] <Dosage> The test food group orally ingested test food A, with the daily intake of each ingredient being 40 mg of glutathione. The placebo group orally ingested a control food, with the ingredients other than glutathione being the same as test food A.

[0034] <MED Measurement> MED (minimal erythema dose) was measured as follows. Twelve test plots were set up on the subject's back. The first test plot, which had the weakest irradiation intensity, was set at 11.57 mJ / cm^2. The second test plot, which was adjacent to the first test plot, was set at 15% higher than the first test plot. Similarly, the irradiation intensity for the nth test plot was set at 15% higher than the (n-1)th test plot, and the 12th test plot, which had the strongest irradiation intensity, was set at 53.87 mJ / cm^2. UV irradiation (wavelength: 290-320 nm) was performed using a solar simulator. The UV irradiation time was 38 seconds. One day after UV irradiation, a physician visually confirmed the presence or absence of erythema. The irradiation intensity of the test plot with the weakest irradiation intensity among the test plots where erythema was observed was used as the subject's MED (pre-ingestion MED) before ingestion of test food A or the control food. After the MED measurement, subjects began taking test food A or the control food. 28 days after the start of intake, MED was measured as described above and used as the MED after ingestion of test food A or the control food (MED after ingestion). Intake of test food A or the control food continued for 36 days after ingestion. The mean and standard error of MED for each group consuming test food A (test food group) or the control food (placebo group) were calculated, and significance was tested using the Wilcoxon signed-rank test. Furthermore, the change in MED before and after ingestion for each group was calculated, and significance was tested using the Mann-Whitney U test.

[0035] <MED Measurement Results> The higher the MED value, the stronger the UV irradiation intensity required to produce erythema. The MED measurement results are shown in Table 1 as mean ± standard error. The MED after ingestion was 37.29 ± 1.06 for the test food group and 34.25 ± 0.99 for the placebo group. However, no significant difference was observed between the two groups before ingestion. Furthermore, when comparing the MED of the test food group before and after ingestion, the difference was significant (p < 0.001), but no significant difference was observed in the MED of the placebo group before and after ingestion (p > 0.1). Furthermore, when comparing the change in MED between the groups before and after ingestion, the difference was significant (p < 0.05).

[0036]

[0037] <L* Value Measurement Test> Each subject was irradiated with ultraviolet light (wavelength: 290-320 nm) at an intensity 1.5 times the pre-ingestion MED measured in the MED measurement test. Seven days after irradiation, the L* value of the irradiated area was measured using a spectrophotometer (CM-26d; Konica Minolta Japan, Inc.). Simultaneously, the L* value of the non-irradiated area was also measured. Furthermore, 28 days after the start of ingestion of test food A or the control food, UV irradiation was performed at an intensity 1.5 times the pre-ingestion MED, as described above, and the L* value of the irradiated area (post-ingestion L* value) was measured 7 days later. Simultaneously, the L* value of the non-irradiated area was also measured. The difference between the L* values ​​of the irradiated and non-irradiated areas measured simultaneously was calculated as the ΔL* value of the subject, and the ΔL* values ​​before and after ingestion of test food A or the control food were calculated. The difference between the ΔL* value before ingestion and the ΔL* value after ingestion was defined as the change in ΔL* value. A paired t-test was used to test for significance of the ΔL* values ​​before and after ingestion of test food A or the control food within each group. In addition, an unpaired t-test was used to test for significance of the change in ΔL* values ​​between groups.

[0038] <Measurement Results of ΔL* Values> The L* value indicates the degree of pigmentation due to UV exposure, with a higher value indicating greater pigmentation inhibition. The L* value results are shown in Table 2. First, a comparison of the L* values ​​before and after ingestion of the test food revealed a significant improvement (p<0.001). On the other hand, no improvement in L* values ​​was observed in the control food intake group. Furthermore, a comparison of the change in L* value between groups revealed that the test food group had a significantly improved L* value compared to the placebo group (p<0.001). Furthermore, the L* values ​​before and after ingestion were calculated by subtracting the L* value of the non-irradiated area from the L* value of the irradiated area to obtain the ΔL* value, and the change in ΔL* value before and after ingestion was calculated from the L* values ​​of each group. A larger change in ΔL* value indicates greater inhibition of pigmentation. The ΔL* value for the test food group was 1.003, while the ΔL* value for the placebo group was -0.510, and the difference was significant (p<0.001).

[0039]

[0040] These results suggest that taking low doses of glutathione can increase the amount of UV rays required for erythema to occur, and by suppressing pigmentation, it can also suppress the occurrence of erythema caused by UV exposure.

Claims

1. An oral preparation for improving minimal erythema on the skin, containing glutathione as an active ingredient.

2. An oral preparation for improving minimal erythema of the skin according to claim 1, having a glutathione content of 100 mg or less.

3. An oral preparation for improving the minimal erythema level of the skin according to claim 1 or 2, wherein the glutathione is glutathione contained in yeast extract.

4. A method for improving minimal skin erythema by orally taking glutathione at a dose of 100 mg / day or less.

5. The method for improving the minimal erythema level of the skin according to claim 4, wherein the glutathione is glutathione contained in yeast extract.

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