TW201143804A - Skin-whitening food and oral administration agent containing zederone or zederone-related substances as active ingredients - Google Patents

Abstract

The present invention provides an oral administration agent featuring higher skin-whitening effect and easy absorption. Specifically, the present invention provides a whitening oral administration agent containing active ingredients of hydride and a group of substances having a specific germacrone like skeleton purified from one or more kinds of curcuma extract. The oral administration agent of this invention contains zederone, curcuma cyclic dienone, curcuma furanone, hydrogenated curcuma epoxy ketone, and hydrogenated curcuma cyclic dienone as active ingredients. Substances prepared from curcuma extract have no bitter taste.

Description

201143804 VI. Description of the Invention: [Technical Field] The present invention relates to a food containing a whitening effect, an oral administration liquid, and the like, which are related to a substance containing an oxime epoxy ketone or an oxime epoxy ketone as an active ingredient. Agent. [Prior Art] Various external preparations for whitening which have improved skin tone, black or chloasma, freckles and the like have been provided. Among the whitening ingredients formulated as active ingredients of whitening agents, arbutin or k0jic acid, ascorbic acid and derivatives thereof, glutathi〇ne, gum Colloidal sulfur or the like has been used as a well-known substance. In recent years, 4-MSK (4-methoxysulfate salicylic acid, 4_meth〇xy salicylic acid) or Rucinol (registered trademark), Magn〇lignan (registered trademark), ellagic acid or linoleic acid (Hn〇leie add) is used as an active ingredient of a commercially available external preparation for whitening. In addition to the above compounds, bear grape leaf extract or zedoary turmeric extract 'chamomile extract, mulberry extract, placenta extract and other animal and plant extracts, extract (four) as an active ingredient of whitening agent. However, there is little indication that which component of the components contained in the extracts of such animals and plants exerts a whitening effect. So far, only the bearberry bitter extract of the bear grape leaf extract has been known to have a whitening effect. In recent years, it has only revealed that the condensed acid type substance of the special structure of the lycium bean extract of the Wubai effect has Whitening effect (refer to the patent literature). On the other hand, various whitening ingredients are also found in the plant extracts of the unknown whitening effect, which is also the fact 148987.doc 201143804 (for example, refer to Patent Document 2). Since the ketone (Zetjerone) has confirmed its existence in the request (Curcuma zedoaria R〇scoe (Zingiberaceae, Zingiberaceae): alias Gong Jiangqi) (Non-Patent Document 1), it has been reported many times that the dysentery oxy ketone is not only It is found in sputum, and it is also found in the genus Ginger as its related plant, for example, C. phaeocau 丨丨 5 or Curcuma l〇nga [syn cd〇mestica] : an alias of autumn turmeric, Curcula aromatica Salisb, and Chloranthus serratus (Chl〇ranthaceae) and the like (see, for example, Non-Patent Documents 2 to 4).

There are many reports that the extracts of zedoary turmeric and turmeric extracts exhibit an anti-allergic effect (see Patent Document 3 to 6) or have a squatting effect (see Patent Document 7), in addition to exhibiting a whitening effect. Hair growth promoting action (refer to Patent Document 8), and having blood circulation promoting effect (refer to the special

In the literature 9), λ has anti-aging effects or acts as an enemy (refer to various pharmacological effects. 駄Q ΐ人,, ” π 1 and milk heart 畺 yellow has a whitening effect (refer to patent document ii), and even Similarly, the plant extracts of epoxy ketones do not all exert whitening effect. 148987.doc 201143804 It is not considered that the ketone epoxy ketone is the essence of whitening ingredients. Furthermore, the industry has conducted various studies on the mechanism of whitening effect and found various mechanisms of action. For example, it was found that the c_kit gene is involved in the production of melanin as disclosed in the above-mentioned Patent Document 11, and the 5% of the genus (the ethanol extract exerts a whitening effect by suppressing the expression of the e-kit gene, even if c- is found as described above) The inhibition of the performance of the kit gene acts as a mechanism of action of the extract of zedoary turmerics. However, it is not clear what kind of substance contained in the extract is involved in the inhibition of the expression of the c-kit gene as described above. There is resistance to the administration of an oral administration agent such as a food or an oral liquid. Another aspect 'refers to the substance as a substance for the epoxy ketone, only the box is known. Epoxy ketone has antibacterial activity (refer to Non-Patent Document 5) and has a role in preventing liver disease induced by D-GalN/LPS (D-galactosamine/lip lactic acid) (refer to Non-Patent Literature) 6) β, in the above-mentioned Patent Document 3, it is described that the lightly-drawn substance including the epoxidized ketone is capable of promoting skin activation, and the above-mentioned patent document discloses an essential oil containing zedoary ketoxime. The component exhibits a detoxification function promoting action and a diuretic action of the liver, a cardiotonic action, a blood cholesterol action, and the like. ^ Patent Document 12, which describes a bismuth oxime oxime, etc. (4)

It is now!! It is resistant to lifestyle-related diseases. However, it is not explicitly stated in any of the patent documents; it is directly linked to the table (iv). Further, as the substance f having an anti-inflammatory activity, it is known that the component 2 contained in the sputum contained in the sputum (see Non-Patent Document 7) and the component 1 which is detached from the box has a pressure-cracking action as an anti-ulcer activity. It is known that there is money I48987.doc 201143804 Circumcision bismuth (see Non-Patent Document 8). Further, as a substance having an antibacterial action, an antibacterial or an antiviral effect, it is used as an epoxide-related substance f. Planting a cyclodextrin furanone (refer to Patent Document 13). I have not yet seen a report on the use of epoxy ketones or the preparation of epoxy oxime-related substances in ancient & The actual situation is that there is almost no knowledge of the whitening ingredients in the extract of Rhizoma Curcumae. In the technical background of the present invention, the present inventors have been seeking a whitening ingredient that can be administered orally by different sputums. Ascorbic acid is easily oxidized and unstable. At present, each (4) organism is used, but as a component of a cosmetic material that comes into contact with human skin, it is preferable to use a component derived from a natural product. The glutathione or the gum has a characteristic odor or a temple. Disadvantages. , the effects of substances and seaweed extracts are insufficient, or the quality is unstable. Money, bear fruit with age base _ and Turkey I have the possibility of causing coloration in the presence of metal ions or ions, so it is not allowed The problem of the formulation which maintains its stability is not considered. Further, the sesqui canenolactones disclosed in the above Patent Document 2 are known to have a characteristic odor, and the stability of the oily compound is not good, so that it is difficult to stably mix them. Further, 'the extract of the zedoary turmeric extract is strong and it is difficult to orally ingest an effective amount. As described above, the whitening ingredients have a certain disadvantage. [Prior Art Document] [Patent Document] [Patent Document 1] Japanese Patent Publication No. 3650245 [Patent Document 2] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. [Patent Document 5] Japanese Patent Laid-Open Publication No. SHO-62-108822 (Patent Document 6) Japanese Patent Laid-Open Publication No. Hei 09-208480 (Patent Document 7) Japanese Laid-Open Patent Publication No. 2002-242435 [Patent Document No. JP-A-2002-249435] [Patent Document 10] Japanese Patent Laid-Open No. 2005-1 94246 [Patent Document 11] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. 2007-129920 (Patent Document No. JP-A-2007-129920) [Patent Document 13] Japanese Patent Laid-Open Publication No. 2000-1 191 88 [Non-Patent Document] [Non-Patent Document 1] Hiroshi Hikino et al., Chemical Pharmaceutical Bulletin (1968), 16(6), 1081-1087. [Non-Patent Document 2] Yu-Chi Hou et al·, Chinese Pharmaceutical

Journal (Taipei) (1997), 49(2), 119-125. [Non-Patent Document 3] Jun Kawabata et. al., Agricultural and Biological Chemistry (1985), 49(5), 1479-1485. [Non-Patent Document 4] Minh Giang Phan et al., Tap Chi Hoa Hoc (2000), 38(4), 96-99. [Non-Patent Document 5] Minh Giang Phan et al., Tap Chi Hoa Hoc (2000), 38(1), 91-94. [Non-Patent Document 6] Hisashi Matsuda, Chemical Pharmaceutical

Bulletin (2001), 49(12), 1558-1566. 148987.doc 201143804 [Non-Patent Document 7] H. Makabe et al., Natural Product Research,

Part B: Bioactive Natural Products (2006), 20(7), 680-685. [Non-Patent Document 8] Kazuo Watanabe et al., Yakugaku Zasshi (1986), 106(12), 1 137-1 142. [Problem to be Solved by the Invention] The present invention has been made in view of the above background art, and an object of the present invention is to provide a whitening food and oral administration which can exert a high whitening effect and can be easily ingested. Agent. [Technical means for solving the problem] The inventors of the present invention have made great efforts under the above background art, and as a result, it has been found that a group of substances have excellent whitening fruit and found that the substance itself has no bitter taste and is suitable for oral administration. Photographed..., 彳< and completed the invention. That is, the present invention provides: [1] A food for whitening and an oral administration agent, which is an active ingredient of one or two kinds of isolated substances represented by the package, 0-8 (1): 2]

丫

Wherein R1 is 11 or Cw alkyl, 148987.doc 201143804 R2 and R3 are independently Η, 〇H or Cw alkyl, or R2 and R3_ form =〇, R4 is alkyl, X and Y form Divalent group represented by formula (2): [Chemical 3]

[wherein, the symbol: [Chemical 4] represents a single bond or a double bond; R5 is an HSCh alkyl group, R6 is an anthracene, an OHSCw alkyl group, R and R are independently an alkyl group, or when a bond (丨) is a double bond , R5 and R7 or Μ中—there is no, or r, r7 together form _&, R9 is 1{ or Cu-based, R10 is ^Cl.3 alkyl- or when the bond (7) is double-bonded , Ri. Does not exist], or the divalent group shown in formula (3): 148987.doc 201143804 [Chemical 5]

R11

R13 (3) [wherein R is a straight or branched chain (^.5 alkyl or a linear or branched oximeyl group, and R12 is a linear or branched alkyl group or a straight chain or a branched chain) And the oral whitening food according to the above [1], wherein the substance is one or two of the formula (1), wherein R1 is a hydrazine or a Cw alkyl group; Kind of above substances: [Chemistry 6]

Wherein R1 is a fluorenyl group, R2 and R3 are independently hydrazine or OH, or ... and R3 is Η, and X and Υ form a divalent group represented by formula (2): 148987.doc I -10· 201143804 [化7]

[wherein, the symbol: [Chem. 8] represents a single bond or a double bond; R5 is Η, or does not exist, R6 is Η or ΟΗ, R7 and R8 are independently Η or 曱, or when the bond (1) is double In the case of a bond, R5 does not exist with either R7 or R8, or R6 and R7 together form -0-, R9 is methyl, R1Q is Η, or R1Q does not exist when bond (2) is a double bond] Or the divalent group represented by the formula (3): [Chemical 9]

[wherein, R11 is an isopropenyl group, R12 is a vinyl group, 148987.doc •11 - 201143804 R13 is a fluorenyl group]; [3] a whitening food and an oral administration agent according to the above [1], wherein The substance is selected from one or more of the group consisting of: Formula W ·· [10]

The oxime epoxy ketone shown, formula (5): [Chem. 11]

莪 环 环 二烯 、 、, 式 (6): [化 12]

148987.doc 12 (6) 201143804 [Chem. 13]

The hydrogenated oxime epoxy ketone shown and formula (8): [Chem. 14]

(8) The hydrazine hydrazine hydrazide according to any one of the above [1] to [3], wherein the one or more substances are one or two or more substances. The total amount of the substance is about 0. 30% by mass of the substance as a whole component with respect to the whole of the agent; m is the whitening food and the oral administration agent as described in the above items (1) to [4], Wherein, the total amount of the substance or the combination of two or more substances is administered in an amount of about 2 mg to 1 〇〇mg/day; [6] as in any of the above Π] to [5] The whitening administration agent comprises an oral solution selected from the group. The _ species or two of the group consisting of: :: 嗣 嗣 箱 箱 箱 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : Group φ dip per dienone and hydrazine; species or more than two kinds of natural extracts 148987.doc •13· 201143804 [7] The oral administration agent is selected from the group consisting of a liquid agent, a jelly agent, a rubber agent, a syrup, a dry sugar, a lozenge, a powder, a granule, a fine granule, a chewing preparation, an oral disintegrating powder, A dosage form of a group consisting of an orally disintegrating granule, an orally disintegrating granule or an orally disintegrating ingot. [Effects of the Invention] According to the present invention, there is provided a food and an oral administration agent which exhibit a high whitening effect and are easily ingested orally. Therefore, in the past, in order to improve the effect, it has been sought to formulate a high concentration of the extract of Rhizoma Curcumae, but it cannot be formulated at a certain concentration or more due to its bitterness. According to the present invention, it is possible to provide an active ingredient capable of orally ingesting effective i without being affected by it. Bitter-affected foods and oral medications. Further, in the present invention, in addition to the above-mentioned substances which have confirmed the whitening effect, hydroquinone furanone and the following compounds are known, and according to the present invention, these compounds can also be expected to exert a whitening effect by oral administration. [化15]

R=a-H R=a-OH R=j8-OH

Gima ketone r^<Y〇 dehydrogenation II 阙r^<Y°

(+)-Jima 醐 -4,5-epoxide

(+)-Gimerone-4,5-epoxide

13-hydroxy geminone

Gima ketone-1 (10), 4-diepoxide 148987.doc -14- 201143804

Eurasian blood-dandanone furan geranone

Isoprene

莪 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧Dosing agent. The food and the oral administration agent of the present invention have a group substance having a gamma ketone-like skeleton as an active ingredient. As described above, the active ingredients used in the present invention are known as components contained in plants belonging to the family Zingiberaceae, which are represented by the genus Artemisia. The substances used as active ingredients in the present invention: 'also includes A natural component that is isolated from a plant belonging to the family Zingiber is hydrogenated to form a product. As shown in the following examples, the oral administration agent of the present invention contains no bitterness and is easy to ingest, and exhibits a high whitening effect. The group-derived substance as an active ingredient contained in the food and oral administration agent of the present invention can be obtained by the root of the sputum (Cu_a-derived R〇S_(gingeraceae): alias purple turmeric), Stems, leaves and other parts or whole plants, preferably from their roots, using various financial machines (4) for extraction, and using activated carbon, | ethylene-diethyl sulfhydryl synthetic adsorbents (for example, Sanman Chemical company: HP, octadecyl (4) cut or chemical. At this time, as an extraction solvent, can be selected from the following - Ϊ 148987.doc 201143804 two or more solvents: water; sterol, An aqueous solution of a lower alcohol having a carbon number of about 1 to 4 or the like; an ketone such as acetone or mercaptoethyl ketone; an ester of decyl acetate or ethyl acetate or butyl acetate; n-pentane or n-hexane; Cyclohexane, stupid, stupid, etc., regardless of linear, branched, various saturated, unsaturated hydrocarbons, etc. Moreover, these solvents are appropriately used, for example, when extracted from plants, a polar solvent is preferred over a non-polar solvent. Thereafter, the separation can be performed by reducing the polarity. Further, by a known method, The obtained compound is hydrogenated by a lamp to obtain a hydride which is contained as an active ingredient in the food of the present invention and an oral administration agent. However, the substance used as an active ingredient in the present invention does not have to be purified into a single pure substance 'as follows The 'described in the examples' can also be obtained by using various solvents such as extraction, adsorption, liquid-liquid partitioning, crystallization, chromatography separation, etc., to obtain a relatively high concentration, for example, a purity of 6% (w/w). Above, 65% or more, 70% or more, 75% or more, preferably _above' more preferably 85% or more, more preferably 9% by weight or more, 95% or more, more than 97% or more '98°/ The above-mentioned, 99% or more, and preferably 99 5% or more of the crude purified material. The π-investment and the financial-contained as an active ingredient of the present invention include: Formula (4): [Chemistry 16 ]

148987.doc -16* 201143804 莪 环氧 epoxy ketone, formula (5): [Chem. 17] η

[Chem. 18]

The indicated furanosone, formula (7): [Chem. 19]

The hydrogenated oxime epoxy ketone shown and formula (8): [Chem. 20]

(8) 148987.doc -17· 201143804 Hydrogenated hydrazine cycladiene ketone, etc., the preferred compound is 莪 玉 嗣 嗣 莪 莪 莪 莪 莪 莪 莪 莪 莪 莪 莪 莪 莪 莪 : : : : : : : : : : : : : : : : Epoxy These substances can be used in addition to the ones described in this manual. In addition, a synthetic or a commercial product may be used in a form of the present invention by a synthetic method or a commercially available person, and the food of the present invention and the oral administration of a group of substances as an active ingredient may be obtained by a method: The stomach is prepared by the following steps: (1) The dried product of the plant (cTM zedoaria) is immersed in the extract of zedoary turmeric, and the solvent of zedoary turmeric extract is distilled off under reduced pressure. (3) The resulting crystalline component is washed with a small amount of solvent, and then (4) the obtained crystalline component is recrystallized from the solvent. Further, in another embodiment, the food of the present invention and the oral administration agent contained in the oral administration agent are obtained as a final method of the group of substances: (4) The dried product of the sputum is impregnated into the solvent by the production of the following steps (1) Preparing a comparative extract; (7) Distilling the solvent of the extract of Rhizoma Curcumae under reduced pressure; (3) The dried solid is dissolved in a solvent, and the column chromatography is performed by using the gel as a filler. The separation is carried out; then, ",, (4) the solvent-saturated removal of the fraction is crystallized from the solvent. Further, in another embodiment, the present invention is packaged in the oral solution and the oral administration agent. 3 is obtained as a group material method of the active ingredient, and is produced by the following steps: (1) The dried extract of the box is immersed in a solvent to prepare a box extract; 148987.doc • 18· 201143804 (2) Adding activated carbon to the extract of Rhizoma Curcumae and mixing it; (3) filtering the mixture to wash the residue with solvent; then (4) washing the residue from the solvent; extracting the melanin generating agent from the sample. , the food of the invention and the σ-administering agent The group material contained in the active ingredient may be obtained by a manufacturing method comprising the following steps: (1) preparing a zedoary turmeric extract by immersing the dried medicinal material in a solvent; (2) supplying to a non-aqueous solvent _ Liquid-liquid partitioning between hydrophilic solvents; (3) supplying a non-aqueous solvent layer to column chromatography, evaporating the solvent of the target fraction under reduced pressure; and then (4) recrystallizing from a non-aqueous solvent In a preferred embodiment, the preparation of a population of materials is carried out as follows: from about 1 · 50 to about 1: 3 (volume ratio), preferably from about 1: 1 〇 to about! : 4 (volume ratio) The desired dry matter: solvent bath ratio is about 10. (: to the 'solvent point' of the extraction solvent is preferably from room temperature to a temperature lower than the boiling point of the solvent by about 1 o ° C, Soxhlet extraction or standing for about 2 hours to about 14 days, preferably about 7 days. In the preferred form, 'extracting 'adsorption' liquid-liquid distribution, crystallization, and chromatography are equivalent in operation. The solvent used is water, decyl alcohol, ethanol, 30 to 95% (v/v) aqueous solution of sterol or ethanol, and Ethyl acetate vinegar may be used alone or in combination of two or more. In a preferred embodiment, the conditions of the chromatography are as follows: Column: Chemcobond 5-ODS-W (6. 〇xl50 ( 6A)) (Kemco shares 148987.doc • 19·201143804 Ltd.) Mobile phase: 75% (v/v) sterol aqueous column temperature: 55.

Flow rate: 1.0 mL/min Injection volume: 1 〇pL monitor: UV 280 nm absorbance in the rut form, the food and oral administration agent of the present invention can be used as an effective knives It is obtained by the manufacturing method including the following steps: (1) The dried rhizome of the desired stem is immersed in ethyl acetate, and left at room temperature for extraction; (2) using a filter (ADVANTEC No. 131) The extract is filtered, and the filtrate is distilled off under reduced pressure to remove the solvent; (3) The dry solid is supplied to a mixed solution of hexane and ethyl acetate (volume ratio of 7.3) as a mobile phase, and the silicone is used as a filler. The column chromatography (same conditions as the above-mentioned knife analysis) were separated by ultraviolet light absorption at a wavelength of 2 10 nm as an index; μ (4) The area where the absorption was confirmed was collected, and the solvent was distilled off under reduced pressure. (5) re-crystallization of the distillate using hexane; (6) heating and dissolving in an aqueous solution of 5 〇% ethanol at a concentration of about 1%, and then recrystallizing at room temperature to obtain oxime epoxy ketone . In a preferred embodiment, the food of the present invention and the oxime cyclobutadienone contained as an active ingredient in the σ-administering agent can be obtained by a production method comprising the following steps: ^ 148987.doc -20- 201143804 (1) (7) The dried extract of the rhizome of Rhizoma Curcumae is concentrated by refluxing with hexane; (7) The extract collected by the steaming of the museum is decompressed under reduced pressure, and the dried solid matter is dissolved in a small amount of burned; (7) supplied to the column of cerium oxide. , hexane, hexane: ethyl acetate (volume ratio 9.1), hexane: ethyl acetate (volume ratio 8: sequential dissolution of ruthenium (4) to collect hexane: acetic acid (volume ratio of 8: 2) The elution zone; then (5) ♦ is dissolved in a small amount of 75% (v/v) aqueous methanol solution, and then supplied to the ODS s column to 'divide a specific fraction, thereby obtaining a sulfonium ring diene _. In a preferred embodiment, the prosthetic furanone contained as an active ingredient in the food and oral administration agent of the present invention can be obtained by the following steps: (1) The dried stem of the rhizome (2) Distilled under reduced pressure and collected in a small amount of hexane; concentrated under reflux with hexane; Solubility (volume ratio of acetic acid (four) volume ratio of 8:2) sequentially eluted · ^ received m acetic acid B (four) volume ratio 8: 2) elution zone; then (7) dissolved M ^ 75% (v / v) f_ money In the towel column, the specific portion is taken to obtain the 莪^ phase: =: state: 'The food of the invention and the oral administration agent =: oxygen" by including the following steps The production (1) will be carried out in 99.5% (v/v) ethanol using the above-mentioned manufacturing method; the obtained zephyrone ketone is dissolved in 148987.doc • 21 - 201143804 (2) Addition 5. /. The Pd-alumina was subjected to a hydrogenation reaction using a hydrogen gas bag; then (3) filtration was carried out after the completion of the reaction, and the solvent of the liquid was distilled off under reduced pressure to obtain a hydrogenated oxime epoxy ketone. In a preferred embodiment, the hydroquinone cyclodienone contained as an active ingredient in the food and oral administration agent of the present invention can be obtained by a production method comprising the following steps: 0) using the above-described production method or the like The obtained dilute is dissolved in 99.5% (v/v) ethanol; (2) 5% of Pd-alumina is added, hydrogenation is carried out using a hydrogen bag; and then (3) after the reaction is finished, filtering The solvent of the filtrate was distilled off under reduced pressure to obtain a hydroquinone cyclodienone. In a preferred embodiment, the hydrogenated oxime furanone contained as an active ingredient in the food and oral administration agent of the present invention can be obtained by a production method comprising the following steps: (1) Obtained by the above-described production method or the like The equipment is also dissolved in 99.5% (v/v) ethanol; (7) Add 5. /. The Pd_alumina 'hydrogenation is carried out using a hydrogen gas bag; (a) After the end of the reaction, the agent is subjected to a reagent to obtain a hydroquinone furanone. The whitening food of the invention and the investment by σ, with _

The total amount of the above substances is about 0.25 to 20% by mass, preferably about 2 to 15% by mass, more preferably about 0.3%, based on the total amount of the agent (UJM 148987.doc -22·201143804%'. 10% by mass of the above-mentioned substance is used as an active ingredient. Further, the whitening food and the oral administration agent of the present invention are administered in a total amount of one or a combination of two or more substances in the following daily dosage: preferably. It is about 2 to 100 mg/day, about 3 to 1 mg/day, about 5 to ι〇〇_day, about 7 to iOO mg/day, about 10 to 100 mg/day, more preferably about 3 to 8 mg. /day, about 5~80 mg/day, about 7~80 mg/day, about 1〇~8〇mg/day, about 3~7 〇/day, about 5~70 mg/day, about 7~70 mg /day, about 1〇~7〇_day about 3~60 mg/day, about 5~60 mg/day, about 7~6〇mg/day, about 1〇~6〇/day, the best is about 8 to 50 mg / day, about 9 to 5 〇 mg / day, about 1 〇 to 5 〇 claw years. The whitening food of the present invention contains the stipulations on the Medicine Act. Or any food or drink other than the pharmaceutical product. On the other hand, the oral administration agent for whitening of the present invention is only There is no particular limitation on the dosage form that can be administered orally as a quasi-drug or a pharmaceutical product, and can be formulated into a liquid preparation, a jelly, a rubber agent, a syrup, a dry syrup, Lozenges, powders, granules, fine granules, chewable preparations, orally disintegrating powders, orally disintegrating granules, orally disintegrating granules or orally disintegrating tablets, etc. a suspension or an internal liquid. More preferably, a liquid, a jelly, a rubber, a chewing agent, an orally disintegrating powder, which can be administered without being affected by time or place, when water is not taken, Oral disintegrating granules, orally disintegrating granules or orally disintegrating ingots. It is possible to adjust the dosage according to the patient. Lu's is preferably a liquid, syrup, dry syrup, powder, granule, Fine granules 148987.doc -23· 201143804 1 intracavitary granules, orally disintegrating granules, orally disintegrating granules, etc. In addition, it is easy to cast on patients who are difficult to swallow, elderly people, and children. From the point of view, 'preferably liquid agent, sugar destroyer, Glue, rubber dry syrup, powder, granules, fine granules, chewing preparations, disintegrating powder in the mouth, disintegrating granules in the mouth, disintegrating granules in the oral cavity, disintegration in the oral cavity, etc. In addition to the above, the non-toxic and inert additive commonly used in the food or pharmaceutical field may be added to the food and the σ-administered agent of the present invention. The f5 "additives' may not substantially affect the effect of the present invention. Usually added as an additive to foods, pharmaceuticals, etc. Examples thereof include D. mannitol, xylitol, sorbitol 'erythritol, maltitol, reduced temple powder saccharide, and reduced bala gold. Excipients such as sugar (a palatm0se), talc, kaolin, acid-filled acid, sulfuric acid, calcium carbonate, crystalline cellulose; stearic acid, magnesium stearate, stearic acid', stearic acid Lubricants such as steel; fluidizers such as light anhydrous arsenoic acid, slow methyl cellulose, low substitution degree disintegrators such as sulfhydryl cellulose; propyl cellulose, propyl methyl cellulose (4) Job Buweiwei S with (povidone 'polyvinylpyrryl Carbofuran), gelatin, methylcellulose, ala: gelatin, polyvinyl alcohol, alkyl hydroxyethyl cellulose, etc., coloring agent such as chuanxi chrome oxide; sweetener, flavoring, adsorption Surfactant, preservative, stabilizer, wetting agent, antistatic agent, pH adjuster, polysorbate (for example, g sorbitol 8 〇) and other surfactants; corn powder and other moving powder '· water, etc. Solvent; suspending agent, etc. Especially in the case of dry syrup, orally disintegrating powder, orally disintegrating granules, orally disintegrating granules, 148987.doc •24- 201143804 Intraluminal disintegrating tablets, etc. At the time, the force & + & excipients can improve the disintegration and solubility in the sigma cavity, thereby making it easier to administer. • Examples of the water-soluble excipients include sorbitol, D-mannose, alcohol, maltitol, reduced temple powder saccharide, xylitol, reduced balaginose or erythritol. Alternatively, the __ species may be used, or two or more kinds may be used in a suitable ratio. Preferred water-soluble excipients include D-mannitol, xylitol or erythritol, and further preferably D-mannitol or erythritol. The blending amount of the food of the present invention and the water-soluble excipient for oral administration is not particularly limited, and it can be usually 15 to 75% (w/w), preferably 25 to 50% (w/ w). The amount of the additive other than the above water-soluble excipient is not particularly limited, and a known amount can be appropriately selected depending on the dosage form. The method for producing the food and the σ-administered agent of the present invention is not particularly limited. A known method can be used. In the case of a solid preparation, examples of the granulation method include extrusion granulation and crush granulation. Method, dry compaction = particle method, fluidized bed granulation method, rotary granulation method, rotary fluidized bed granulation method, high-speed feeding granulation method, mixed granulation method, etc., when the cavity is disintegrated in the oral cavity, Examples of the wet pellet compression method, the direct compression method, and the like can be mentioned. Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited to the contents of the examples. Furthermore, as long as there is no special explanation, the amount of adjustment indicates quality. /〇. [Examples] 148987.doc •25- 201143804 [Extraction, separation and purification from self-purification] When extracting and purifying the melanogenesis inhibitor of the present invention from the comparison, the separation operation is first performed by the method shown in Fig. 1, and Each district checks the whitening effect. The whitening effect is checked by examining the production inhibition of melanin in the following manner. Further, the sputum system is obtained from the company of Supreme Co., Ltd. and the company. To a dried stem of 300 g of curcuma zed〇aria R〇sc〇e (Zingiberaceae), 18 mL of a 50% (v/v) aqueous solution of ethanol was added and allowed to stand at room temperature for 5 days. Thereafter, filtration was carried out to obtain 16 〇〇 mL of the extract. The extract was concentrated under reduced pressure to give a dry solid, 7 5 g (yield extract (A)). Dissolving the dry solid of ^g in a small amount of a 5% by weight (v/v) aqueous solution of ethanol, and then putting it into a separatory funnel, and further adding water and hexane (in a volume ratio of i: n and fully oscillating) Then, quietly. & mountain a Λ , β 佤 is allowed to stand. Take out the lower layer of water, take the upper layer of hexane 2 to another flask, and return the taken water layer back to the separatory funnel. Add the same volume as the water layer... and repeat the same operation twice. Then, return the water layer to the separatory funnel, and add the same volume of acetic acid B (iv) to the liquid layer. Ethyl acetate (IV), the taken water layer is sent back to the liquid separation leak, and acetic acid (4) is added to the same volume as the water layer again, and the same operation is carried out. The collected burned layer and acetic acid are collected under reduced pressure. B: The remaining part of the water layer is concentrated to produce melanin: material (sample (Α) ~ (D)). Test 4 (melanin production inhibition test) As a melanin production inhibition test, one-dimensional culture skin model 148987 .doc -26- 201143804 The amount of melanin and protein refers to The test of the type 5 test and the test generated at this time. The melanin production inhibition test was carried out using a commercially available three-dimensional culture skin model (MEL-300 kit Asian d_: Kurab.). 'Set the MEL. skin model cup in each well of a 6-well culture plate'. The maintenance medium (EPI_100 ·· when adding the medium, the final concentration reached 10 ng/mL when the medium was warmed with a 37t incubator. The method of adding SCF (Stem CeU Fact〇r, stem cell factor) was added aseptically to each skin model cup, respectively, and the solution of each sample was directly added to the inside of the skin model cup. A 6-well culture plate with a skin model cup was placed in an incubator, 53⁄4 C〇2, humidified state, and cultured for 14 days. The medium was replaced with a new medium every 2 days, and each time the change was made, a solution of each sample was added to the skin model cup. Further, when preparing a solution for each sample, pBS (-) (phosphate buffered saline (-), phosphate buffer (1)) for cell culture was used. After the incubation, the VIEL-300 skin model cup was washed 3 times with PBS(-), and then the cells were partially peeled off and placed in a 5 mL eppendorf tube. 'Add 5 mL of 2 mL. /L-NaOH, left at room temperature overnight. After boiling for 15 minutes, '250 kL of each sample was transferred to a 96-well culture dish' to quantify melanin at 405 nm. Further, 'the boiled melanin quantification sample was transferred to a 96-well culture dish with 40 pL of the sample, and the protein was quantified by BCA (bicinchoninic acid) reagent (trade name: Takara Bio Co., Ltd.) 200 μm. After entering the wells and culturing for 30 minutes at 371, the absorbance at 540 nm was measured at 148987.doc •27·201143804 luminosity. Further, the same test was carried out using PBS (-) as a control and arbutin-PBS (-) solution (2.0 °/〇 (w/v)) as a positive control, and the reference substance was calculated to be 10 The amount of melanin (relative ratio) at 0 o'clock and the amount of protein (relative ratio) were examined for inhibition of melanin production. The results are shown in Table 1. Further, a photograph showing the results of the three-dimensional culture skin model at this time is shown in Fig. 2 . [Table 1] Concentration of melanin amount of protein (%) (%) (%) PBS(-) 100.0 100.0 Arbutin 2.00 54.4 58.3 Rhizoma extract powder (A) 0.05 60.5 80.5 Rhizoma extract powder hexane fraction (B 0.015 51.4 96.4 Ethyl acetate extract powder ethyl acetate fraction (C) 0.025 85.4 93.9 Rhizoma extract powder water fraction (D) 0.05 103.1 97.0 (Separation and purification by TLC (Thin-Layer Chromatography) According to the results of Table 1 and Fig. 2, the hexane extraction fraction shown in (B) of Fig. 1 exhibited the strongest inhibition of melanin production (Fig. 2 (d)). Therefore, the fraction was further purified by preparative TLC (Preparative Thin-Layer Chromatography). After distilling off the solvent from the hexane extraction layer, the concentrate was dissolved in a small amount of hexane, and a thin-layer culture plate (silicone 60_F254, Merck, thickness 2 mm) was prepared for the purpose of hexane and acetic acid. The mixed solution (volume ratio: 7:3) was separated as a developing solvent. The detection was carried out by visual observation and a UV lamp having a wavelength of 254/366 nm. The result is shown in Fig. 3. For example, 148987.doc -28- 201143804, as shown in Figure 3, three bands (S1~S3) are clearly observed, two bands (S5, S7) are observed faintly, and one is gradually reduced from the origin (taiHng). Band (s8). Therefore, as shown in the figure, it is separated into 8 bands (with si to tape S8). Each of the separated belt portions was taken out and extracted with ethyl acetate, and then the acetic acid was distilled off to obtain each separated component. Then, the separation condition was confirmed by TLC on the above separated components. After a small amount of each of the separated concentrates was dissolved again in a small amount of hexane, a thin layer of soil was used. The dish was raised (Shi Xi knee 60.F254, thickness 〇. 2 mm (Merck)), and developed using the above developing solvent. The result is shown in Fig. 4. Fig. 4 shows a lane in which the burned solution of SI, S2, S3, ..., S7, and S8 is sequentially indicated by dots from the left side. As a result, a single point (detection with iodine) was detected in the strip S2. (Melanin Production Inhibition Test) Next, the isolated sample was subjected to a melanin production inhibition test. In the test, based on the result of the TLC, the band s [, the S2 system uses each band as the sample Β-i, the sample B_2, respectively, and the band S3 to S5, and the band system V, D, and 5 are used separately. As a sample (sample B-3, sample B-4). The results of the inhibition of melanin production determined from the amount of the dye and the amount of protein are shown in the table. The test was also carried out on the extract of the extract of zedoary turmeric (4) and the hexane layer. As a result, the table of the sample of the single-point sample Β·2 was obtained, and the degree of inhibition by the melanin produced by the sputum was obtained. A photograph showing the results of the three-dimensional skin model at this time is shown in Fig. 5. ° 148987.doc •29- 201143804 [Table 2] Concentration (% by mass) Melanin amount (%) Protein amount (%) PBS(-) 100.0 100.0 Arbutin 2 54.4 58.3 Rhizoma extract powder (A) 0.05 60.5 80.5 Curcuma Extract powder hexane fraction (B) 0.015 51.4 96.4 Preparation of zedoary turmeric extract powder TLC-Sl(Bl) 0.005 101.8 112.8 Preparation of zedoary turmeric extract powder TLC-S2(B-2) 0.005 47.3 102.2 Preparation of zedoary turmeric powder TLC- S3~5(B-3) 0.003 75.8 101.3 Preparation of extract of zedoary turmeric powder TLC-S6~8(B-4) 0.0045 82.3 103.4 [Structural determination of melanin production inhibitor] As shown in Table 2, the performance of the zone with S2 The strongest melanin production inhibition degree is obtained, and a single point can be confirmed by the detection of ultraviolet light absorption and the detection by iodine, and thus the structure of the melanin production inhibitory substance existing in the area is determined. The structure was determined based on analysis of ultraviolet light absorption spectrum (solvent: burned), infrared absorption analysis (IR), mass spectrometry, 1H-NMR (solvent: CDC13), and 13C-NMR (solvent: CDC13). The results are as follows, and the graphs of the respective analyses are shown in Figs. 6 to 10 . Further, the assignment of NMR is shown in Table 3. Based on these results, it was identified that the melanin production inhibitory substance produced was a sputum oxime. The melanin production inhibition degree of the substance is as understood from Table 2, and the substance exhibits substantially the same concentration as about 1/400 of the concentration of arbutin, as compared with arbutin which has hitherto been considered to have a whitening effect. The effect is therefore considered to have an intensity of about 400 times that of arbutin. ;! 生状: White crystalline solid 148987.doc •30- 201143804 UV absorption: Maximum absorption wavelength 〇max) 281 nm Mass spectrometry analysis: 246 (m/e) Infrared absorption spectrum (crrT1): 1662, 1523, 1427 , 1400, 1232, 1066, 1020, 929, 881, 863.

[Table 3] NMR spectrum position 'H-NMR, 3C-NMR C-1 7.08 s, 1H 138.05 CH C-2 122.23 C C-3 2.15 s, 3H 10.25 ch3 C-4 123.25 C C-5 192.19 c C- 6 3.81 s, 1H 66.53 CH C-7 63.95 C C-8 1.34 s, 3H 15.15 ch3 C-9 1.65, 1.28 m, 2H 37.99 ch2 C-10 2.50, 2.21 m, 2H 24.63 ch2 C-11 5.47 \d, 1H 131.21 CH C-12 131.05 C C-13 1.6 ^3H 15.72 ch3 C-14 3.71 d, 2H ΐΤδδ ch2 C-15 157.08 c [Chem. 21]

[Confirmation of Stability] The solution obtained by the above method is dissolved in 148987.doc -31 - 201143804 50% (v/v) aqueous ethanol solution 200 to obtain a solution at a high temperature ( 6〇〇c) Save the 'again' and add 〇5 m〇l/L-NaOH to the solution to make the final concentration of 0.125 m〇I/L-NaOH solution, and add 〇5 claws to several seven A solution having a final concentration of 0.125 mol/L-HCl was stored at room temperature to confirm the stability. Further, the control product was stored under the same conditions as above for the ethanol solution at 4 C. The stability was measured by a high-performance liquid phase precipitation method under the following conditions, and the residual ratio was determined from the percentage of the peak area. Further, the sample solutions preserved by alkali and acid-storage were separately neutralized and then measured. (Analysis conditions) Column: Chemcobond 5-〇DS-W (6.〇xl50(6A)) (Kemco Co., Ltd.) Mobile phase: Methanol

Column temperature: 55 ° C Flow rate: 1 · 0 mL / min

Injection amount: 10 pL Monitor: UV 280 nm absorbance The results are shown in Table 4. It is well known that bismuth compounds such as arbutin or citric acid produce browning in the test area, but sputum epoxies are not confirmed to change. Moreover, although a slight decrease was observed in the acidic region, it was found to be stable under the conditions of the test region and the high temperature condition, so that it is known that the epoxy resin can be blended in various physical conditions and can be used in various compositions. Use under conditions. 148987.doc -32- 201143804 [Table 4] After 2 days, 5 days later, acidity 88% 82% testability 97% 105% 60°C --1 J02% one 100%

[Example 2J α - human] A group of substances contained in the food of the present invention and an oral administration agent were prepared according to the following production method. [Production Example 1] Curcume ketone ketone The rhizome dried product i kg of Curcuma zedoaria was immersed in hexane and allowed to stand at room temperature for 7 days for extraction. The extract was filtered through a filter (ADVANTEC 13 1), and the filtrate was distilled under reduced pressure to remove the solvent, which was placed in a dark place. The resulting crystalline component was separated and washed with a small amount of 2 calcined. Further, the obtained crystal component is subjected to calcination, and σ aa is used to obtain 300 mg of oxime epoxy ketone (purity is about 95%), and the purity is based on liquid, chromatography, and chromatography. (4) The obtained epoxy ketone was used as a standard, and the weight of the epoxy ketone was determined according to the peak height ratio of the detection wavelength (10) (the same applies to the production example 2). [Production Example 2] oxime epoxy ketone The root canthus dryness i kg was immersed in acetic acid B 6" and allowed to stand at room temperature for 4 days for extraction. The extract was transferred by a transition apparatus (ADVANTEC No U1), and the liquid was evaporated under the solvent. Thereafter, by using a mixture of = burned and ethyl acetate (volume ratio of 7:3) as a filling tube (four) analysis method (same as the above analysis conditions), riding i48987.doc -33- 201143804 The separation system is carried out by using a separate collector and U〇n, and the ultraviolet light absorption of each wavelength of 280 nm is used as ##. The squeegee is separated. The solvent-vapor-removed material of the observed absorption zone is recrystallized to obtain white crystal mass mg ( The epoxy ketone was set to 2000 nig. [Production Example 3] Rhizoma sulphonate 35 〇g of dried rhizome of Rhizoma Curcumae was refluxed for 3 hours with hexane 丨 75 〇 mL. The granules were separated and concentrated. Adding the simmered sputum to the slag, and then repeating the above operation. The distilled extract was distilled under reduced pressure to obtain 3.12 g of dry solids and amp; dissolved in a small amount of hexane ( In the addition of mL), the insoluble components were filtered, and then supplied to a ruthenium dioxide column (BW300 (Fuji Silysia Co., Ltd.), 〇2〇, h=2〇〇), with hexane, hexane: ethyl acetate ( The volume ratio of 9: 丨), hexane: ethyl acetate (volume ratio of 8: 2) was dissolved in 1 〇〇 „11^. The hexane:ethyl acetate (volume ratio 8.2) was dissolved. The solvent was distilled off to obtain a yield of 0.484 g. Then, it was dissolved in a small amount of a 75% (v/v) aqueous methanol solution, and supplied to a column of the following conditions, which was carried out by a fraction c〇llector. For the respective fractions, liquid chromatography was used for the analysis under the following conditions, and the fractions having only the * in the graph corresponding to the graph η were collected. The fraction of the peak, after distilling off the solvent, 'obtained 0.10 g (yield 〇〇 28%) of a white crystalline solid. The structure of the melanin production inhibitory substance present in the fraction was determined. The structure was determined based on ultraviolet absorption spectrum. The analysis (solvent: burned), ^ external absorption analysis (IR, Infrared spectroscopy), h-NMR (solvent. CDC13) was carried out to obtain the following physical properties. Ultraviolet absorption and infrared absorption 148987.doc -34- 201143804 The graphs of the analysis are shown in Figures 12 and 13. Based on these physical properties, it was found that the obtained melanin production inhibitor was a cyclamate I. Column: Chemcobond 5-ODS-W (6_〇xl50(6A)) (Kemco Co., Ltd.) Mobile phase: Methanol: Water = 75: 25 (v: v) Column temperature: 55 ° C Flow rate: 1.0 mL /min Injection amount: 1 〇pL Detection wavelength: 280 nm Ultraviolet absorption: Maximum absorption wavelength (λπιαχ): No infrared absorption spectrum (cm·1): 1644, 1523, 1375, 1270, 1240, 1105, 1020, 931 iH -NMR spectrum: 1.30 (3H, s), 1.99 (3H, s), 2.13 (3H, s)' 1.85-2.49 (4H, m), 3.70 (2H, m), 5.17 (1H, m), 5.81 ( 1H, s), 7.07 (1H, s).

[Manufacturing Example 4] 莪 ·. husband. Further, a ketone was collected, and only a portion having a peak corresponding to *2 in the graph of Fig. 11 was collected. After the solvent was distilled off, a transparent oily liquid of 7 g (yield 0.02%) was obtained. The structure of the melanin production inhibitory substance present in the fraction is determined. The structure was determined based on analysis by ultraviolet light absorption spectrum (solvent: calcination), infrared absorption analysis (IR' Infrared spectroscopy), and 4-NMR (solvent: CDC13), and the following physical properties were obtained. The graphs of ultraviolet absorption and infrared absorption analysis are shown in Fig. 4 and Fig. 15. 148987.doc -35- 201143804 Based on these physical property values, it was found that the obtained melanin production inhibitory substance is a furanone. Ultraviolet absorption: Maximum absorption wavelength (Xmax): 272 nm Infrared absorption spectrum (cm·1) : 1675, 1562, 1427, 1257, 1070, 997 • H-NMR spectrum: 1·222 (3H), 1.658 (3H) , 2_97 (1H, q), 2.262 (3H), 3.166 (1H, d), 3.249 (1H, d), 3.104 (1H), 5.028 (1H, d), 5.029 (1H, d), 5.039 (1H, d), 5.126 (1H, d), 5.729 (1H, d), 7.068 (1H).

[Manufacturing Example 5] Hydrogenated oxime epoxy ketone 5 〇〇mg of the oxime epoxy ketone obtained in Production Example 2 was dissolved in 100 mL of 99.5% (v/v) ethanol, and 5% Pd-alumina 1 〇〇 mg was added. Hydrogenation was carried out using a hydrogen bag. The reaction was carried out at room temperature for 15 hours. After the completion of the reaction, filtration was carried out, and the solvent of the filtrate was distilled off under reduced pressure to obtain 50 g of a white crystalline solid. The structure of the melanin production inhibitor present in the fraction is determined. The structure was determined based on analysis by ultraviolet absorption spectrum (solvent: hexane) and 1H-NMR (solvent: CDC13), and the following physical properties were obtained. A graphical representation of the UV absorption analysis is shown in Figure 16. From the specific property value, it was found that the obtained melanin production inhibitory substance is hydrogenated oxime epoxy ketone. Ultraviolet absorption: Maximum absorption wavelength (Xmax): 287 nm W-NMR spectrum: 2.180 (3H, m), 1.008 (3H, d), 1.059 (3H, d), 7.093 (1H), 1.434 (1H, d) , 1.604 (1H, d), 1.434 (1H, d), 1.653 (1H, d), 1.343 (1H, d), 1.474 (1H, d), 2.995 (1H, d), 2.454 (1H, d), 1.743 (1H, d), 1.657 (1H, d), 2.113 (1H, d), • 36- 148987.doc 201143804 1.776 (1H, d), 4.199 (1H, d).

[Manufacturing Example 6] Hydrogenated hydrazine sulfadienone The 5 〇〇mg of the scorpion ring dilute enthalpy obtained in Example 3 was dissolved in 100 mL of 99.5% ethanol, and 5% of Pd-alumina was added thereto, using hydrogen gas. The bag is subjected to a hydrogenation reaction. The reaction was carried out at room temperature for 15 hours. After completion of the reaction, the solvent of the filtrate was distilled off under reduced pressure to obtain 5 g of a white crystalline solid. The structure of the melanin production inhibitory substance present in the fraction is determined. The structure was determined based on analysis by ultraviolet absorption spectrum (solvent: hexane) and 1H-NMR (solvent · CDC13), and the following physical properties were obtained. A diagram showing the ultraviolet absorption analysis is shown in Fig. 17. From the physical property values, it was found that the obtained melanin production inhibitor was hydrogenated and heavier. UV absorption: maximum absorption wavelength (Xmax): no W-NMR spectrum: 2.167 (3H, m), 0.467 (3H, d), 0.909 (3H, d), 6.594 (1H), 1.440 (1H, d), 1.579 (1H,d), 1.400 (1H,d), 1.779 (1H, d), 1.601 (1H, d), 1.366 (1H, d), 2.808 (1H, d), 2.676 (1H, d), 2.212 (1H, d), 1.884 (1H, d), 4.774 (1H, d), 3.665 (1H, d).

[Melanin production inhibition test using human melanocytes] (culture of human melanocytes) Human melanocytes (NHEM (Normal Human Epidermal Melanocytes) (Moderately, moderate), Kurabo) were used. Medium 254 medium (containing growth factor HMGS-2) 1000 μl per well in a 1000 μί 12-well culture plate, seeded 2.5xl〇4, 148987.doc •37· 201143804 times 曰' Adding stem cell proliferation factor (SCF) to the medium The concentration was 1 〇ng/mL), and then the test sample was added after 4 hours. This was cultured at 37 ° C for '3 days and then changed medium'. SCF (final concentration 1 〇 ng/mL) was added again. Then, the test sample was added after 4 hours, and cultured at 37 ° C for 7 days. Thereafter, the amount of melanin and the amount of protein were measured by the following methods. (Quantification of melanin) The medium in the well was removed. After the cells were washed 3 times with PBS(-)500 pL, PBS(-) was completely removed. Cell lysate was prepared by adding 4 mol/L-NaOH to the washed cells to dissolve the cells and shaking with a shaker for 3 minutes. Transfer each cell lysate to a 5·5 m]L microcentrifuge tube; to; stir water to heat for 1 〇 minutes, and vigorously mix with a Vo hex mixer. The cell lysate was transferred to a 96-well culture dish and the absorbance was measured at 4 〇 5 nm. (Quantification of protein) The cell lysate 4 上述 obtained above and 8 (: eight solution 2 〇〇 # mixed s ' were incubated at 37 C for 30 minutes, and the absorbance was measured at 54 〇 nm. [Manufacture Example 1] And the above-mentioned ephedrine and protein obtained in [Production Example 3] to [Production Example 6], the above-mentioned melanin and protein are obtained by the above-mentioned epoxy ketone, oxime sulfadienone, oxime furanone, hydrogenated oxime epoxy ketone, and hydroquinone cyclodienone. The quantification was a melanin production inhibition test. The melanin and protein amounts of the respective components are shown in Table 5. [Production Example 1] and [Production Example 3] to [Production Example 6] The ketene, the oxime furanone, the hydrazine sulfonate, and the hydrogenated hydrazine ring were confirmed to be approximately the same degree or more than the melanin produced by the thin layer chromatography. Inhibition effect. 148987.doc -38· 201143804 [Table 5] Concentration PBSM Bearberry 0.02% 0.01% 莪 环氧 环氧 0.001 0.001% ~~ 0.0001% 0.00001% 莪 环 环 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1% % ~~' 0.01% 0.001% Hydrogenated oxime epoxy ketone 0.10% 0.01% 0.001% Hydrogen Curcuma ring dienone 0.10% to 0.01%, 0.001%. *

Anthrone, sulphuric acid, and sulphur ketone are weakly known to have whitening effect, and are confirmed by extremely low concentration. Epoxy ketone, cyclamate, and hydrazine oxime Compared with the fruit glycoside, it showed a whitening effect on the cell degree. In the same manner as the above (melanin production inhibition test), the same skin culture model was used, and the [fake test] was obtained in [Production Example 1]. Will, and fruit: I asked for the effect of the ketone on melanin. Table 6 and the figure [Make the oxime obtained in the middle of the oxime is about the same degree of the ring or 丄... by 浔 layer chromatography The melanin production inhibition effect of the sputum. 148987.doc -39- 201143804 [Table 6] Concentration (%) Melanin Content (%) Protein Amount (%) Figure 18: PBS (-) 100.0 100.0 la) Arbutin 2.000 47.8 71.6 lb) Powder (A) 0.050 56.9 107.9 (c) Rheumatine Epoxy Ketone (Manufacturing Example 1) 0.005 47.0 130.5 (d) [Whitening effect test of oral administration agent] Preparation of Curcume Epoxy Ketone The rhizome of Curcuma zedoaria 10 kg of the dried product was immersed in 60 L of hexane and allowed to stand at room temperature for 7 days for extraction. The extract was filtered through a filter (ADVANTEC No. 131), and the filtrate was evaporated under reduced pressure to remove the 'gluten, and then placed in a dark place, and the resulting crystalline component was separated and burned with less than one. Cleaning. Further, the obtained crystalline component was recrystallized using hexane to obtain 3 g of zephyrone. 3 g of the crystal obtained by recrystallization of hexane was added to 2 〇% ethanol solution, and the mixture was heated and dissolved, and then the insoluble component was filtered by a filter (ADVANTEC Ν〇 ΐ 3 1). The filtrate was allowed to stand at room temperature for recrystallization to obtain 2 g of crystals, which was used as an active ingredient of an oral administration agent. Preparation of whitening oral administration agent The obtained medicinal sputum epoxy chest 2 s squirting # from the 八一一 g spoon uniformly dispersed in dextrin 98 g, preparation of oral administration agent. The prepared oral administration agent is dispensed into commercially available cellulose capsules every (four) - two capsules are used as a 1 投 投 投 乂 乂 乂 乂 乂 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 In the case of dextrin 98.8 g, the oral administration agent was prepared. The prepared mashes were dispensed into commercially available cellulose capsules at 148987.doc 201143804 per 250 mg, and each 2 capsules were used as 丨m for testing. ^ ° Whitening effect test 18 healthy males and females were divided into the sputum oximeone 10 mg/day ingestion group, and the sputum oxycodone 1 mg/day ingestion group equivalent to the scutellaria extract prepared in the previous healthy food, And 3 groups of the placebo ingestion group without sputum oxime ketone were taken once a day. The test was performed in a double bmlind manner. Furthermore, regarding the sputum oxy ketone 1 mg/day which is equivalent to the previous intake, it can be considered that the food which is used for the powder itself is the most abundant in the food containing the epoxidized ketone, and the average enthalpy (tetra) oxygen The content of the genus is about 0.01~〇03%, Yishan 43⁄4 τχ·++, t • wrong by the ingestion of zedoary powder 3 g / day, the intake of phlegm and epoxy ketone reaches 〇1 i 堤 j〇·3~1 mg/ In days, the maximum setting is equivalent to approximately 1 mg/day. After 1 month and 2 months, the whitening effect (upper brightness of the skin) was evaluated. The measurement items are a questionnaire on the skin condition and measurement of the color difference between the light-exposed portion (the cheek portion) and the non-light-exposed portion (the inner side and the outer side of the upper arm). The measurement of chromatic aberration is carried out under the environment of 'degree of 2GC and humidity of 3G%, and is adapted to the vicinity of the part of the position of 4 minutes after the 15 minutes, and the average value other than the maximum value and the minimum value of the divisible value is used as the result. . The results are shown in Table 7. 148987.doc -41 - 201143804 [Table 7] 1 month before use Δ1 2 months later Δ2 10 mg group cheek 54.788 55.109 0.321 55.311 0.523 upper arm inner side 64.775 64.757 -0.018 64.801 0.0264 upper arm lateral side 63.584 63.693 0.108 63.713 0.12895 1 mg group Cheek 57.434 57.023 -0.410 57.325 -0.1092 Upper arm inner side 64.825 64.754 -0.071 64.848 0.0222 Upper arm outer side 62.654 62.713 0.058 62.627 -0.0279 0 mg group cheek 55.459 55.259 -0.200 55.502 0.043 Upper arm inner side 64.495 64.501 0.006 64.500 0.0056 Upper arm outer side 62.984 63.003 0.019 62.993 0.0097 △1 : Difference between Δ2 after 1 month and before drinking (L*): The difference between brightness after 2 months and before drinking (L*) is shown in Table 7, placebo ingestion group and sputum ketone 1 mg In the day/day intake group, no significant increase in skin brightness was observed after 2 months, whereas a significant increase in skin brightness was observed in the sputum ketone 1 〇mg/day ingestion group. Therefore, it has been shown that the intake of the oxime ketone contained in the food containing the extract of zedoary turmeric has not been able to exert a whitening effect, whereas the intake of oxime ketene is 10 mg/day. The whitening food and the oral administration agent of the invention can exert a whitening effect. In addition, in order to take in the powdered food of the zedoary sinensis extract previously prepared to increase the brightness of the skin, it is necessary to take a large amount of powder of 30 g/day, which is substantially difficult to achieve daily. Ingestion. [Taste test of oral administration] Commercially available zedoary powder is made into tea by 3 g (about 1 teaspoon, about 1 mg of ketone epoxy ketone)/day. Ingested with cow's milk, various healthy teas or juices. Therefore, the 莪 粉末 powder 148987.doc -42 - 201143804 3 g will be dispersed in hot water as a comparative example ι, dispersed in the milk as a comparative example 2, will make the "epoxyketone mg mean sentence dispersion In the case of 3 g of dextrin and then dispersing in hot water, it was obtained as Example i, and it was dispersed in the milk as Example 2, and it was drinked by 1 male and female, and the taste was evaluated as 4 shells. In Table 8. [Table S]

The number of people who did not feel the bitterness in the table at all was evaluated as shown in Table 8. 'The unpurified zedoary tract extract (the comparison of the bitterness of the sputum and the hook is not well evaluated). Although the content of the purified ketone ketone was higher than that of the unpurified zedofulin extract, it had no effect on the taste. Therefore, it was confirmed that the sputum ring was purified by the sputum extract. Oxy ketone, which can be blended into foods and oral administration agents which have no bitter taste and can easily ingest a large amount of active ingredients. Formulation Example 1 Lozenge Health Foods will be purified 2 g glycone, dextrin 7 g, powder 90 g of granulated sugar and 10 g of glycerin fatty acid are mixed and stirred to prepare a uniform and ingot, and a healthy food as a lozenge of 200 mg is obtained. Formulation Example 2 Beverage granules will be purified 1 g of oxime epoxy ketone, oligosaccharide 4 〇g, granulated sugar 50 g and dextrin 380 g 148987.doc -43- 201143804 Mixing, mixing and modulating evenly. Using a fluidized layer granulator to make granules, obtain 5 g of beverage granules per pack. Formulation Example 3 Drinking Purification of sputum epoxy ketone 1 0 mg, sorbitol 3 〇〇〇 mg, oligosaccharide 45 〇〇 mg, cyclodextrin 500 mg, and ascorbic acid 1 〇 () mg mixed with an appropriate amount of purified water, dissolved into 50 mL 'to obtain a drinking agent. Formulation Example 4 For the capsule powder, 5 g of purified ketone epoxy ketone, 4 〇g of oligosaccharide, and 2 ruthenium ruthenium were mixed and stirred to prepare a capsule powder of 250 mg per capsule. [Industrial Applicable The present invention relates to the field of whitening foods (health foods, etc.) and oral administration agents (quasi-drugs, pharmaceuticals, etc.) which exhibit a high whitening effect and are not easily bitter. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a view showing a self-purchasing extract powder (4) by liquid-liquid distribution. Fig. 2 is a photograph showing a black-skin-inhibition effect of a liquid-liquid distribution of a planting extract powder (4) '(4) is As a result of the control, (b) is bearberry n' (c) is the result of the extract powder (8), (4) is the hexane zone, and '. fruit' (e) is the acetate s zone (C) As a result, (7) is the result of (D). Figure 3 is a chromatogram obtained by preparative thin layer chromatography. Figure 4 is prepared by Layer 4 is also a chromatogram of the valley damage. The melanin I48987.doc -44 - 201143804, which is not obtained by the preparation of the thin layer chromatography, produces a photograph of the inhibitory effect, and (4) is a reference substance. The result of the knot '(4) is the result of the knot of the extract of the plant extract (4), the result of the fruit sound ((1), (the * is the burned area (e) is the sample BU with si), the knot of S2), 〆 Inferior & () is the material B-2 (band. (g) is the result of the sample B_3 (with S3 ~ S5) 4 (with S6 ~ S8). () for the sample B - Figure 6 is purified The melanin production inhibitor has an external light absorption spectrum. Violet (by ketone) Figure 7 is a graph of purified melanin production inhibitor obtained from m. (I "Oxygen," the quality of the sulphuric acid (the oxime epoxy ketone) 1 Η - Figure 8 is the purified melanin production inhibitor spectrum. Figure 9 is the purified melanin production inhibitor NMR Fig. 1 丨3C-NMR spectrum of the purified melanin production inhibitory substance of the lanthanide series, and the oxime-ethyl ruthenium ester of the eucalyptus extract powder (A) (8: 2) HPLC chart of the eluted fraction. Figure 12 is the ultraviolet light absorption spectrum of the purified melanin production inhibitor Γ ν 我 农 农 cyclodextrin ketone. Figure 13 is a purified melanin production inhibitory substance (莪术环二Figure 14 is a graph showing the UV absorption spectrum of the purified melanin production inhibitor (I am a bite). Figure 15 is a purified melanin production inhibitor + | ^ month ( I borrowed turpentone) 148987.doc • 45- 201143804 Figure from IR. Figure 1 shows the UV absorption spectrum of the melanin production inhibitor (hydrogenated oxime). Melanin production inhibitory substance Melanin) The ultraviolet absorption spectrum of the effect of suppressing the generation of

Fig. 8 shows the article of manufacture of the manufacturing example. The photograph '(a) is the reference material λ. The knot of the extract powder (A) 148987.doc -46-

Claims (1)

201143804 VII. Scope of application for patents: 1. A food for whitening and an oral administration agent, which comprises one or two or more kinds of isolated substances represented by formula (1) as an active ingredient. Wherein R1 is an alkyl group, R2 and R3 are independently hydrazine, OH or Cw alkyl, or R2 and R3 together form =0, R4 is a HaCw alkyl group, and X and Y form a formula (2) Divalent base: [Chemical 2] [wherein, the symbol: [Chemical 3] represents a single bond or a double bond; R5 is a 3 alkyl group, 148987.doc 201143804 R6 is Η, 0114 (:, .3 alkyl, independently Η or CM 炫, or When the bond (1) is R5 and R7 or R8 does not exist, or ... together with Han 7 form _〇_, temple, R9 is Η or C|.3 alkyl, R10 is a burnt base, or when the bond (2 ) is a divalent group in which the double enthalpy is in, R does not exist, or the formula (3): [Chemical 4] R11 R13 (3) [wherein R is a linear or branched 2Cl·5 alkyl group or a linear or branched alkenyl group, R12 is a linear or branched alkyl group or a straight chain or a branch. Chain ci5 alkenyl, R 3 is only or Cu alkyl; 2. A food for oral use and an oral administration agent, wherein the substance is one or more of the substances represented by formula U): [Chemical 5] R3 X (1) 148987.doc 201143804 {wherein, R1 is a sulfhydryl group, R and ulmen 3 are independently Η or OH, or R2 and R3 are formed together == 〇R4 is Η, X and Υ form (2) Showing the divalent base: [Chemical 6] R10 [wherein, the symbol: [Chem. 7] represents a single bond or a double bond; r5 is Η, or does not exist, R6 is Η or 〇Η, R7 and R8 are independently Η or 曱, or when the bond (1) When it is a double bond, it does not exist with either R or R8, or R6 and R? together form _〇_, R9 is methyl, R 〇 is ti, or when bond (2) is double bond, r1( ) does not exist], or the divalent group represented by formula (3): 148987.doc 201143804 [Chem. 8] (3), R12 R13 [wherein R11 is an isopropenyl group, R12 is a vinyl group, and R13 is a methyl group]}. 3 · The whitening order of claim 1 σ Β The substance is a substance: $ <夬曰食οσ and oral administration, which are selected from the group consisting of: , , (4): [Chemical 9] 〇 < 0 0 - V ▽ (4) 莪 环氧 epoxy ketone, formula (5): [化 10] Π 148987.doc .4- 201143804 [化11] ο [化 12] [Chem. 13] The hydroquinone cyclodienone is shown. 4_ A food for whitening according to any one of claims 1 to 3, a composition of M a 4 D, which is contained in one or a combination of two or more substances. t, which contains about (U to 30% by mass of the substance as an active ingredient) with respect to the whole of the agent. 5. The whitening food and the oral administration agent according to any one of claims 4 to 4, wherein Or a total of two or more substances administered in a dosage of about 2 mg to 100 mg per day. 148987.doc 201143804 6. In the case of claims 1 to 5, the whitening food for you And an oral administration agent comprising as an active ingredient a seed selected from the group consisting of 莪 衣 衣 氧 S 莪 莪 莪 莪 环 环 环 环 环 莪 莪 莪 莪 莪 莪 莪 莪 莪 莪 莪And does not comprise a natural extract containing one or more than 7-7s A selected from the group consisting of bauxite sn & my xylenone, guanidine cyclodienone and zedofulrone. 7. For the whitening food and oral administration agent of the item 1 to 6, it is a free liquid preparation, a pure earthworm I > agent, a rubber agent, a syrup, a dry syrup, a lozenge, Powder, granules and granules 'intraoral collapse energy ° and chew preparations, oral disintegration type ^ 1 particles, oral disintegration type _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _