JP6778026B2 - Whitening agents and whitening foods and drinks containing 4'-demethylnobiletin as an active ingredient - Google Patents

Description

The present invention relates to whitening cosmetics, external preparations, internal preparations, and foods and drinks containing 4'-demethylnobiletin as an active ingredient.

Skin stains on the face and hands gradually progress with age due to exposure to ultraviolet rays for many years. Many people have worries about age spots because they look old. Especially in the case of women, the quality of life (QOL) may be impaired, such as refraining from appearing in public because they care about their appearance. Most of the spots that increase with age are senile pigment spots.

Drugs containing L-cysteine and vitamin C are the mainstream as oral preparations for age spots, but the main effect is to promote metabolism, which is a very mild effect. As for external preparations, quasi-drugs containing kojic acid and arbutin are often used, but these also do not have a strong inhibitory effect on melanin production on melanin-producing cells (see Patent Document 1 and Non-Patent Document 1). ).
In addition to these, compounds and plant extracts that suppress melanin production have been reported (see Patent Documents 2 and 3), but no drug that actually has a sufficient effect of improving stains in humans has been found.

Japanese Patent Application Laid-Open No. 60-016906 Japanese Unexamined Patent Publication No. 2011-246353 Japanese Unexamined Patent Publication No. 2011-046683

Yamazaki Y, Kawano Y, Chem.Pharm.Bull., 58 (11) 1536-1540 (2010)

An object of the present invention is to solve the above-mentioned problems and to develop an internal preparation, an external preparation, a cosmetic and a food or drink having an excellent stain-improving effect.

Nobiletin, which is a polymethoxyflavonoid, is a flavonoid peculiar to citrus fruits, but in recent years, various physiological actions such as cancer prevention, aging suppression, and anti-arteriosclerosis have come to be known. The present inventors convert nobiletin, which is the main component, into 4'-demethylnobiletin (see [Chemical formula 1] below) by fermenting with a specific type of aspergillus using the peel of nobiletin containing a large amount of nobiletin. Clarified. The present inventors have also found that 4'-demethylnobiletin has an excellent memory-improving effect (see Japanese Patent No. 5667651).

As a result of repeated studies on the functionality of 4'-demethylnobiletin, the present inventors have found that it exhibits a remarkable melanin production inhibitory effect on human-derived melanin-producing cells. Furthermore, a stain improving effect was obtained in humans.

That is, the present invention according to claim 1 relates to an oral preparation for suppressing melanin production containing 4'-demethylnobiletin as an active ingredient.
The present invention according to claim 2 relates to a food or drink for suppressing melanin production containing 4'-demethylnobiletin as an active ingredient.
The present invention according to claim 3 relates to an oral preparation for whitening containing 4'-demethylnobiletin as an active ingredient.
The present invention according to claim 4 relates to a food or drink for whitening containing 4'-demethylnobiletin as an active ingredient.

The present invention relates to functional foods and drinks and pharmaceuticals (senile pigment spots, freckles, chloasma, etc.) containing safe 4'-demethylnobiletin derived from foods obtained from fermented aspergillus of citrus peel as an active ingredient. It is possible to provide whitening cosmetics (effective against spots).

It is a figure which shows the melanin production inhibitory action of 4'-demethylnobiletin isolate. The bar graph shows the results of the negative control (without addition), kojic acid 500 μM, arbutin 500 μM, 4'-demethylnobiletin isolate 20 μM, and nobiletin isolate 20 μM from the left. The vertical axis shows the amount of melanin produced (%) with the control (without additives) as 100%. Bars indicate standard deviation. It is a figure which shows the effect of the 4'-demethylnobiletin combination preparation for improving spot skin on humans. In the figure, white indicates improvement, gray indicates maintenance, and black indicates progress (deterioration). It is a figure which shows the effect of the L-cysteine / vitamin C preparation for improving spot skin on humans. In the figure, white indicates improvement, gray indicates maintenance, and black indicates progress (deterioration).

Hereinafter, the present invention will be described in detail.
The present invention relates to a melanin production inhibitor and a whitening agent containing 4'-demethylnobiletin as an active ingredient, and foods and drinks used for these purposes.
In addition, the present invention provides cosmetics, quasi-drugs (external preparations), pharmaceuticals and foods and drinks that are effective against spots such as senile pigment spots, freckles and chloasma containing 4'-demethylnobiletin as an active ingredient. Regarding.

[4'-demethylnobiletin]
Although 4'-demethylnobiletin (see [Chemical Formula 1]) is not commercially available, nobiletin-containing citrus fruits, especially fruit skins, were used as synthetic products or by the method of Japanese Patent No. 5675651 described above. A pure 4'-demethylnobiletin product (isolated) or a 4'-demethylnobiletin-containing composition obtained by fermentation of Jiuqu can be used. However, the method of Patent No. 5675651, which utilizes the biological conversion of nobiletin by fermentation of Jiuqu, is preferable because it is simpler and cheaper.

4'-demethylnobiletin is also one of the metabolites produced after nobiletin is absorbed in the body. Citrus peel is used as a raw material for sweets such as marmalade and sugar boiled, and mandarin orange (Citrus reticulata), which has a high nobiletin content, has many years of eating experience as a chimpi, and 4'-demethylnobiletin and its composition. Is very safe.

The method for producing 4'-demethylnobiletin and the composition containing the same described in Japanese Patent No. 5675651 will be described below.

[Fermentation raw material]
The raw material for fermentation of aspergillus is the'fruit'of citrus fruits containing nobiletin, which is a polymethoxyflavonoid (whole fruit including peel, juice, pulp, seeds, etc.), but in particular, the content of nobiletin and the effectiveness of waste From the viewpoint of utilization, it is desirable to use'pericarp'.
Further, as the type of citrus fruits, any varieties and strains (for example, ponkan, shikuwasha, tangerine, tachibana, etc.) can be used as long as they are nobiletin-containing citrus fruits.
As the fermentation raw material, those containing other parts of the plant body of citrus fruits (for example, leaves, buds, stems, flowers, etc.) may be used, but those not containing these in terms of the content of nobiletin. Is desirable.

As the citrus fruits, it is preferable to use harvested / collected raw ones or washed ones with water, but dried, frozen, long-term stored ones and the like can also be used.
The citrus fruits may be used as they are, but it is desirable to perform any treatment of chopping, slicing, or crushing.
The process involves a wide range of actions, such as chopping citrus fruits into small pieces, chopping them into small pieces, crushing them, crushing them, and powdering them. Preferably, it can be carried out by making a large piece of about 1 to several cm.
Furthermore, extracts (extracts, dried products) obtained by extracting nobiletin from these fermentation raw materials in advance, or those isolated as pure nobiletin can also be used.
It is preferable that these fermentation raw materials are heat-treated to sterilize various germs in the raw materials before the fermentation of Jiuqu, which will be described later.

[Jiuqu fermentation]
Aspergillus kawachii (Aspergillus kawachii), Aspergillus awamori (Aspergillus awamori), Aspergillus niger (Aspergillus niger), Aspergillus oryzae (Aspergillus oryzae), Aspergillus soya (Aspergillus soya) , Aspergillus saitoi, Aspergillus usamii, Aspergillus filamentous fungus (also known as Aspergillus), and the like can be used. Further, these may be mixed and used.
Of the aspergillus, preferably Aspergillus kawachii, Aspergillus awamori, Aspergillus oryzae, Aspergillus niger, and 4'-demethylnoviletin are used. It can be obtained with a high content rate.

As a method of inoculating the fermented raw material with the aspergillus, spores of the aspergillus can be directly sprinkled on the fermented raw material and attached. In addition, a medium obtained by pre-fermenting the aspergillus by liquid culture may be inoculated so as to spread over the entire fermentation raw material.
As the microbial fermentation conditions for inoculating the aspergillus into the fermentation raw material, it is desirable to carry out under aerobic conditions. Therefore, for example, a container having a bottomed cylindrical bottom and a wide bottom and a shallow depth is preferable.
It is advisable to spread the fermentation raw material evenly on the bottom of such a container so that the contact area with air becomes large.

The fermentation temperature is preferably 10 to 40 ° C, more preferably 20 to 40 ° C, still more preferably 25 to 32 ° C, as conditions suitable for the growth of the aspergillus. In addition, as a condition suitable for the growth of the aspergillus, it is preferable to ferment in a dark place. In addition, it is preferable that the raw material contains sufficient water.
The fermentation period for microbial fermentation to obtain a large amount of 4'-demethylnobiletin is preferably 2 to 21 days, more preferably 3 to 14 days, and even more preferably 4 to 12 days.
When this fermentation period is less than 2 days, sufficient 4'-demethylnobiletin cannot be obtained because the microbial fermentation by the aspergillus is hardly progressing. On the contrary, if it exceeds 21 days, the decomposition of 4'-demethylnobiletin produced by microbial conversion proceeds, and the preferable aroma derived from citrus fruits disappears.

Further, in the fermentation of Jiuqu, nobiletin is demethylated by an enzyme secreted from Jiuqu and converted into 4'-demethylnobiletin.
Therefore, instead of performing the fermentation of Jiuqu, a solution is extracted from the Jiuqu or the fermented product obtained after fermentation to obtain an enzyme solution containing an enzyme that demethylates nobiletin, and the enzyme is used to carry out an enzymatic reaction with the raw material. It is also possible to obtain 4'-demethylnoviletin by obtaining the reaction product.
Specifically, the enzymatic reaction can be carried out by recovering the water-dissolved product from the fermented product after the fermentation of Jiuqu and using it as a crude enzyme solution.

By performing the aspergillus fermentation of the present invention, nobiletin, which is a polymethoxyflavonoid contained in the citrus raw material, is all converted to 4'-demethyl nobiletin.
Specifically, by fermenting the citrus raw material with aspergillus, 4'-demethylnobiletin has a high content of about 0.5 to 1.5% by mass (specifically, about 1% by mass) per dry weight. A rate of fermented aspergillus can be obtained.
Therefore, the fermented aspergillus fermented product obtained here can be processed as it is or processed (for example, fragmented, crushed, powdered, dried, etc.) to provide the agent and functionality of the present invention. It can be used as an active ingredient in foods and drinks and whitening cosmetics.

[Solution extraction]
In view of purity, in the production of the drug, functional food and drink, and whitening cosmetic of the present invention, it is desirable to obtain an extract by performing solution extraction from the fermented product obtained after the fermentation of Jiuqu. ..
The solution extraction step can be performed directly on the fermented aspergillus, but it is obtained after the fermented aspergillus is further subjected to any treatment such as fragmentation, crushing, crushing, and powdering. It is desirable to do it for fermented foods.

As the solvent used in the solution extraction step, water, a buffer solution, an organic solvent, or a water-containing solvent thereof can be used. Examples of the organic solvent include lower fatty alcohols such as ethanol, methanol, isopropanol and butanol, acetone, ethyl acetate, chloroform and the like.
Among these solvents, water, ethanol or hydrous ethanol is particularly preferable in terms of extraction efficiency, ease of handling and safety.
Further, in particular, by performing the extraction with ethanol having a final concentration of 55% or more, preferably a final concentration of 60% or more, and more preferably 80% or more, elution of polysaccharides as impurities can be suppressed. '-Preferably because it can improve the extraction efficiency of demethylnobiletin.
As the extraction conditions, the solvent is added in an amount of 1 to 50 times, preferably 2 to 15 times (both by mass ratio) to the raw material (preferably fragmented product), and the temperature is 0 ° C. to the boiling point of the solvent. Extraction is possible by immersion or shaking under conditions, preferably at room temperature to below the boiling point of the solvent, for 5 minutes to 1 month, preferably 20 minutes to 1 week.

The obtained extract can be made into a concentrated dry product by freeze-drying or drying using an evaporator or the like.
Further, the solution extraction step can be performed a plurality of times with a plurality of different solvents. In particular, when the first extraction is performed with water or a low-concentration hydrous alcohol, the extraction efficiency of 4'-demethylnobiletin can be improved by performing the extraction with ethanol having a specific concentration or higher. it can.
The extract (extract or concentrated dry matter) obtained as described above can be used as it is as an active ingredient of the drug, functional food or drink, and whitening cosmetic of the present invention.

〔purification〕
In addition, the purity can be further increased by performing a purification step on these.
As a purification step, high purification can be performed by liquid-liquid separation extraction or column purification using silica gel, chemically modified silica gel, activated carbon, a synthetic adsorption resin carrier or the like. An example of suitable purification conditions is shown below.
First, a porous synthetic adsorption resin in which the ethanol-removed solution of the extract (specifically, the extract that has undergone ethanol extraction) is equilibrated with water (specifically, Diaion HP-20 [manufactured by Mitsubishi Chemical Corporation]) Serve in the column of. Then, after removing the water-eluting component, the liquid eluted with 39 to 41% ethanol (specifically, 40% ethanol) is further removed. Next, by recovering the components eluted with 44 to 46% ethanol (specifically, 45% ethanol), a highly purified 4'-demethylnobiletin-containing composition can be obtained.
By performing extraction and purification under the suitable conditions described above, a composition containing a high amount of 4'-demethylnobiletin having a purity of 80% or more can be obtained.

Further, the 4'-demethylnoviretin-containing composition obtained as described above is further subjected to ODS column chromatography (specifically, 45% methanol elution) and thin layer chromatography (TLC) (specifically, hexane / By subjecting to ethanol [7: 3]) and ODS-HPLC (specifically, a mixed solvent of 37% [V / V] acetonitrile / water) and collecting the target peak, a pure product of 4'-demethylnoviretin. Can be isolated.

The 4'-demethylnobiletin obtained as described above is a monodemethyl form of nobiletin with the 4'position demethylated. 4'-demethylnobiletin becomes more polar due to demethylation and is more soluble in alcohol and water than nobiletin.
Further, 4'-demethylnobiletin has an excellent "whitening effect", specifically, a "melanin production inhibitory effect" as compared with nobiletin.

[Drugs / functional foods and drinks]
The above 4'-demethylnobiletin can be used as various raw materials as "compositions directly containing fermented products", "solution extracts", "purified products") and "isolated products" obtained in the above steps. By mixing, it can be used as an active ingredient of drugs and functional foods and drinks.
The "drug" in the present invention includes pharmaceuticals, quasi-drugs, and cosmetics. In addition, the drug or quasi-drug may be in the form of an internal preparation or an external preparation.

The effective intake of 4'-demethylnobiletin when taken orally as an oral preparation or a functional food or drink is 1 mg or more, preferably 5 mg or more per day for an adult weighing 60 kg, thereby senile pigment. It is possible to obtain an excellent improving effect on spots such as spots, freckles, and chloasma. Alternatively, when externally used as a cosmetic or quasi-drug, an external preparation containing 0.001% by mass or more, preferably 0.01% by mass or more of 4'-demethylnobiletin can obtain an excellent stain improving effect.

Therefore, it is expected that the above-mentioned pharmacological action can be obtained by ingesting or applying the drug or functional food or drink of the present invention in a form or ingestion method (number of times, amount) that can secure this required amount. However, it is desirable to appropriately determine the intake amount and application amount according to the target age, body weight, symptoms, intake schedule, formulation form, and the like.

In addition, the content of 4'-demethylnobiletin in drugs and functional foods and drinks may be any as long as it can secure the above-mentioned necessary intake amount, but specifically, 0.001% by mass or more. It can be contained in an amount of preferably 0.01% by mass or more, more preferably 0.1% by mass or more. Further, as the upper limit, 20% by mass or less can be mentioned.

The form of the drug can be, for example, powdery, finely granular, granular, etc. when taken, and in addition to the form of being filled in capsules, the form of a solution dispersed in water, a creamy form, an excipient. It can also be in the form of a tablet obtained by mixing with the above. When used as an external preparation such as a quasi-drug or a cosmetic, it may be in the form of a liquid, gel, cream, ointment or the like.
In addition to 4'-demethylnobiletin or a composition containing the same, the agent of the present invention may contain various carriers, additives, other medicinal ingredients, etc. within the range in which the effects of the present invention are exhibited. ..

In addition, functional foods and drinks may be mixed with various food ingredients and additives to form, for example, biscuits, snacks, gums, chewable tablets, soft drinks, drinks, soups, jellies, candy and the like. Can be done.
The above-mentioned foods and drinks, cosmetics, quasi-drugs, and pharmaceuticals can be used both externally and internally as skin care.

Hereinafter, the present invention will be described with reference to examples, but the scope of the present invention is not limited thereto.

<Example 1> Preparation of 4'-demethylnobiletin-containing composition Nobiletin converter 4'-demethylnobiletin was prepared by fermenting ponkan peel with aspergillus according to the method described in Japanese Patent No. 5675651.
That is, 100 kg of ponkan peel was chopped into small pieces and sterilized by steaming. The obtained ponkan peel was inoculated with Aspergillus awamori (manufactured by Bioc Co., Ltd.) so as to spread throughout. Then, the fermented aspergillus was obtained by aerobically performing (fermentation of aspergillus) in a constant temperature room at 30 ° C. for 5 days.
750 L of water was added to 60 kg of the obtained fermented aspergillus, and the hot water extract was extracted at 100 ° C. for 1 hour, and then the extract obtained by continuous centrifugation was spray-dried to obtain 4'-demethylnobiletin. The containing composition was obtained.

<Example 2> Preparation of 4'-demethylnobiletin isolate 1 kg of the fermented aspergillus fermented product obtained in Example 1 above was crushed and crushed, and 5 L of ethanol was added to extract the extract at room temperature for 3 days. Obtained.
Next, the obtained extract was filtered through a filter paper filter, and the filtrate was concentrated with a rotary evaporator to make 1 L. Then, 5 L of water was added to obtain a water-soluble solution.
The obtained solution was subjected to Diaion HP20 (porous synthetic adsorption resin column) equilibrated with water in advance, the non-adsorbed component was removed with 3 L of water, and then the component eluted with 2 L of 40% ethanol was further removed. .. Then, the component eluted with 2 L of 45% ethanol was recovered, and further concentrated to dryness with an evaporator to obtain a composition having a high content of 4'-demethylnobiletin.

2 g of the 4'-demethylnobiletin high content composition obtained above was dissolved in 20% methanol and subjected to ODS column chromatography (30 g of Wako gel 50C18 packed in a column having an inner diameter of 20 mmφ and a length of 30 cm). The component eluted with 40% methanol was removed to obtain a component eluted with 60% methanol.
Next, the obtained components were subjected to preparative TLC chromatography (silica gel 70PF ₂₅₄ plate Wako, film thickness 0.75 mm, manufactured by Wako Pure Chemical Industries, Ltd.) under the conditions of developing solvent hexane / ethanol 7: 3, and 4'-demethylnobiletin. Fractions containing Nobiletin were collected while checking using a UV lamp.
Then, the obtained fraction was subjected to a preparative HPLC column (TSK GEL ODS, manufactured by Tosoh Corporation, 4.6 mm × 25 cm), and a pure 4'-de was added by a moving layer of 37% (v / v) acetonitrile. Methylnobiletin 20 mg was obtained.

<Example 3> Examination of melanin production inhibitory effect The melanin production inhibitory effect was examined using the 4'-demethylnobiletin isolate obtained in Example 2. Human-derived melanoma cells (HMV-II, DS Pharma Biomedical) were used as melanin-producing cells.
Cells are cultured in DMEM medium containing 10% fetal bovine serum in an incubator at 37 ° C in the presence of 5% CO ₂ , and passaged every 3 to 4 days by 0.25% trypsin treatment containing 0.1% EDTA. went.
Melanoma cells were seeded in 6-well plates (3 × 10 ⁴ cells / well) and 4'-demethylnobiletin isolate (Example 2 product) was added after 1 and 4 days. Nobiletin isolate was added as a comparative control, and kojic acid (sigma) or arbutin (sigma) was added as a positive control in the same manner.
After 7 days, the culture solution was removed, and the intracellular melanin production amount was measured by the alkaline melting method by the method described below. That is, after washing the melanoma cells with phosphate buffered saline, 1 ml of 1N NaOH was added and the cells were allowed to stand at room temperature for 16 hours to lyse the cells. The amount of intracellular melanin was measured by measuring the absorbance at 475 nm, and the melanin production inhibitory effect of the test substance added was evaluated with the value of no addition (negative control) as 100%.

As a result, none of the test subjects affected the cell proliferation of melanocytes. FIG. 1 shows the effect of the 4'-demethylnobiletin isolate on suppressing melanin production.

In FIG. 1, the bar graph shows the results of the negative control (without addition), kojic acid 500 μM, arbutin 500 μM, 4'-demethylnobiletin isolate 20 μM, and nobiletin isolate 20 μM from the left. The vertical axis shows the amount of melanin produced (%) with the control (without additives) as 100%. Bars indicate standard deviation. As shown in FIG. 1, in the results of comparison with pure products, the concentrations of kojic acid and arbutin at 500 μM were 50% and 79%, respectively, as compared with the negative control without addition, whereas 4'- The production of demethylnobiletin and nobiletin isolate was 37% and 83%, respectively, at 20 μM each.
From the above, it was found that 4'-demethylnobiletin clearly exhibits a remarkable melanin production inhibitory effect on kojic acid, arbutin or also nobiletin.

<Example 4> Examination of the effect on human spots (prevention / improvement of pigmentation)
The 4'-demethylnobiletin preparation was orally administered to humans and its effectiveness against human spots was examined.

(1) Preparation of test object Using the 4'-demethylnobiletin-containing composition obtained in Example 1, tablets were prepared according to the following formulation.
As a positive control, a commercially available drug containing L-cysteine and vitamin C was used.

(2) Human test The subjects were men and women aged 40 years or older with spots on the back of their hands, and the administration period was 8 months. Fourteen 4'-demethylnobiletin tablets (4 men and 10 women) took 6 tablets once daily. The daily intake of 4'-demethylnobiletin was 5 mg. On the other hand, 6 people (6 women) who took L-cysteine / vitamin C preparation took 2 tablets after each meal, for a total of 6 tablets. The daily intake of L-cysteine and vitamin C was 240 mg and 1000 mg, respectively.
By comparing the photographs of the backs of the left and right hands taken before the start of the test and at the end of the test 8 months later, the effect of preventing and improving spots was investigated.
The photographs of the backs of the left and right hands before and 8 months after the start showed that the subject information before and after the test was hidden, and 6 third parties who did not attend the test evaluated the degree of improvement in the pigmentation. That is, for the two photographs of the backs of the left and right hands (before and after the test), which one is improving is "no change (maintenance) (0 points)", "slight improvement (1 point)", "improvement (2 points)", A visual judgment was made based on the criteria of "significant improvement (3 points)". In this evaluation, if it was evaluated that the improvement was improved before the start of the test, it means that the stain progressed (worsened) due to the ingestion of the test object, and the improvement was "slightly advanced (-1)". "Points)", improvement is "progress (-2 points)", and improvement is "significant progress (-3 points)". The scores of both the left and right hands were added up, and each subject was evaluated as having no change (maintenance) when the score was ± 0, improving when the score was positive, and progressing when the score was negative.

The results are shown in Table 2, FIG. 2-1 and FIG. 2-2. In FIGS. 2-1 and 2-2, white indicates improvement, gray indicates maintenance, and black indicates progress (deterioration).
As shown in Table 2, when the 4'-demethylnobiletin combination preparation was ingested, the maintenance / improvement rate was 81% on average, whereas when the L-cysteine / vitamin C preparation was ingested, it was taken. The average was 44%, and the 4'-demethylnobiletin preparation clearly had a higher maintenance / improvement effect (whitening effect) than the L-cysteine / vitamin preparation.
As shown in Fig. 2-1 and Fig. 2-2, the rate of improvement was 48% for the 4'-demethylnobiletin combination preparation and 3% for the L-cysteine / vitamin C preparation, and the L-cysteine / vitamin preparation. A remarkable advantage over was recognized.

<Example 5> Prescription example of external preparation Prescription example 1
Cream preparation Olive squalane 30ml
Beeswax 5g
4'-Demethylnobiletin 100 mg containing 1,3-propanediol solution 5 ml
Purified water 15ml

Prescription example 2
Preparation of ointment Olive squalane 30ml
Beeswax 5g
3 drops of tea tree essential oil
4'-Demethylnobiletin 100 mg containing 1,3-propanediol solution 5 ml

Prescription example 3
Lotion preparation Glycerin 7g
4'-Demethylnobiletin 20 mg containing 1,3-propanediol solution 5 ml
86 ml of water
Carbomer 0.1g

Prescription example 4
Preparation of lotion water 200ml
Urea 5g
Glycerin 1ml
1 ml of 1,3-propanediol solution containing 20 mg of 4'-demethylnobiletin

Prescription example 5
Preparation of sunscreen agent Squalene 30ml
Beeswax 5g
Fine particle titanium dioxide 7g
1 ml of 1,3-propanediol solution containing 20 mg of 4'-demethylnobiletin
Purified water 70ml

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide whitening cosmetics, external preparations, internal preparations, and foods and drinks which have a high maintenance / improvement effect by using 4'-demethylnobiletin, which is a highly safe raw material, as an active ingredient.
Therefore, the present invention is expected to be used in the fields of foods and drinks for whitening and beautiful skin, cosmetics, quasi-drugs, and pharmaceuticals. In addition, age spots (senile pigment spots) that gradually progress with aging occur in everyone, and the present invention, which has the effect of improving and preventing them, is the youth of the skin in the modern society that has reached the longevity society. It is expected that there will be a great demand as a material for maintaining the quality.

Claims (4)

An oral preparation for suppressing melanin production containing 4'-demethylnobiletin as an active ingredient. Food and drink for suppressing melanin production containing 4'-demethylnobiletin as an active ingredient. An oral whitening agent containing 4'-demethylnobiletin as an active ingredient. A whitening food and drink containing 4'-demethylnobiletin as an active ingredient.