JP5694315B2 - Whitening food and oral preparation containing Zedelon or Zedelon related substances as active ingredients - Google Patents

Description

  The present invention relates to a food having a whitening effect, containing zederone or a zederone-related substance as an active ingredient, and an oral administration agent such as an oral liquid.

  Conventionally, various external preparations for whitening that improve skin color blackness, spots, freckles and the like have been provided. Arbutin, kojic acid, ascorbic acid and derivatives thereof, glutathione, colloidal sulfur and the like are used as well-known substances as whitening ingredients to be blended as an active ingredient of the whitening agent. In recent years, 4-MSK (4-methoxy Salicylic acid potassium salt), lucinol (registered trademark), magnolignan (registered trademark), ellagic acid, linoleic acid, and the like are used as active ingredients of commercially available whitening agents.

  In addition to these compounds, various animal and plant extracts such as rumbling extract, scallop extract, chamomile extract, mulberry white skin extract, placenta extract, and seaweed extract are also used as active ingredients for whitening topical preparations. .

  However, among the components contained in these animal and plant extracts, few have been identified as to which component has a whitening effect. So far, it has only been known that arbutin in a walnut extract has a whitening effect, and in recent years, a condensed tannin-type substance having a specific structure has been whitened from a Jatoba extract, which has a known whitening effect. It is only disclosed that it has an effect | action (refer patent document 1). On the other hand, it is also true that various whitening components have been found from plant extracts whose whitening effect is not known (see, for example, Patent Document 2).

  Zederone represented by the following structural formula is not only found in gadgets (Non-Patent Document 1) but also in gadgets (Non-Patent Document 1) since its existence was confirmed in gadgets (Curcuma zedoaria Roscoe (Zingiberaceae)) Related plants of the genus Turmeric, such as C. phaeocaulis and turmeric (Curcuma longa [syn. C. domestica]: also known as autumn turmeric), spring turmeric (Curcuma aromatica Salisb) (Chloranthus serratus (Chloranthaceae)) and many others have been reported (see, for example, non-patent documents 2 to 4).

  In addition to the whitening effect, the gadget extract and the turmeric extract have an antiallergic action (see Patent Documents 3 to 6), a slimming action (see Patent Document 7), and a hair growth promoting action (Patent Document) 8), blood circulation promoting action (see Patent Document 9), skin aging and wrinkle-preventing action (see Patent Document 10), and various other pharmacological actions have been reported.

  However, it has been confirmed by the applicant of the present application that autumn turmeric, which is a plant belonging to the turmeric genus, has no whitening effect (see Patent Document 11). However, it was not limited, and it was not considered that Zedron was the essence of the whitening component.

  Furthermore, various studies have been conducted on the mechanism of whitening action, and various mechanisms of action have been found. For example, it has been found that the c-kit gene is involved in the production of melanin, and in Patent Document 11 mentioned above, 50% (v / v) ethanol extract of gadget suppresses the expression of the c-kit gene. It is disclosed that a whitening effect is exhibited. However, even if the suppression of c-kit gene expression is found as a mechanism of action of the gadget extract, any substance contained in the gadget extract is involved in the suppression of c-kit gene expression as described above. It is unclear whether or not

  In addition, the extract was strong in bitterness and was resistant to administration as an oral administration agent such as food or oral liquid.

  On the other hand, when referring to zederone as a substance, zederone has antibacterial activity (see Non-Patent Document 5), and has an action to prevent liver damage induced by D-GalN / LPS (see Non-Patent Document 6). ) Is only known. Further, in Patent Document 3, a gadget extract containing zederone promotes skin activation, and in Patent Document 11, an essential oil component of gadget containing zederone promotes the detoxification function, diuretic action, and cardiotonic action of the liver. In the above-mentioned patent document 12, it is described that terpenes such as zederone exhibit an anti-lifestyle-related disease action, and each patent document discloses zederone. It is not clarified that directly shows these effects.

  In addition, furanodienone contained in gadget is known as a substance having anti-inflammatory activity (see Non-Patent Document 7), and a component isolated from gadget has an action of suppressing stress ulcer and is a substance having anti-ulcer activity. Furanodienone is known (see Non-Patent Document 8).

  Moreover, furanodienone and cruzelenone, which are zederone-related substances, are known as substances having antimicrobial action, antibacterial effect, and antiviral effect (see Patent Document 13).

  As described above, there has been no report on the whitening action of zederone or zederone-related substances so far, and the fact is that little is known about the whitening component in the extract.

  Under such a technical background, the present inventors have sought a whitening component that can be administered orally differently. That is, ascorbic acid is easily oxidized and unstable, and various derivatives are used. However, as a cosmetic ingredient that touches human skin, a natural product-derived ingredient is preferable. Glutathione and colloidal sulfur have the disadvantage of producing a characteristic odor and precipitation. Animal and plant extracts and seaweed extracts have problems such as insufficient effects and inconsistent quality. Since kojic acid, arbutin and ellagic acid having a phenol group may cause coloring in the presence of an alkali or metal ions, there is a problem in formulation that maintenance of the stability must be considered. In addition, the sesquiterpene lactones described in Patent Document 2 often have a characteristic odor, and it is known that oily compounds are not stable, and it is difficult to stably add them to products. It was. Furthermore, the ganj extract has a strong bitter taste and it is difficult to take an effective amount orally. As described above, each of the whitening components so far has certain drawbacks.

Japanese Patent No. 3650245 Japanese Patent Laid-Open No. 2005-2050 JP-A-2-209804 Japanese Patent Laid-Open No. 61-291524 JP-A-62-108822 JP 09-208480 A Japanese Patent Laid-Open No. 11-193240 Japanese Patent Laid-Open No. 2002-20242 JP 2002-249435 A JP 2005-194246 A JP 2006-246752 A JP 2007-129920 A JP 2000-119188 A

Hiroshi Hikino et al., Chemical Pharmaceutical Bulletin (1968), 16 (6), 1081-1087. Yu-Chi Hou et al., Chinese Pharmaceutical Journal (Taipei) (1997), 49 (2), 119-125. Jun Kawabata et.al., Agricultural and Biological Chemistry (1985), 49 (5), 1479-1485. Minh Giang Phan et al., Tap Chi Hoa Hoc (2000), 38 (4), 96-99. Minh Giang Phan et al., Tap Chi Hoa Hoc (2000), 38 (1), 91-94. Hisashi Matsuda, Chemical Pharmaceutical Bulletin (2001), 49 (12), 1558-1566. H. Makabe et al., Natural Product Research, Part B: Bioactive Natural Products (2006), 20 (7), 680-685. Kazuo Watanabe et al., Yakugaku Zasshi (1986), 106 (12), 1137-1142.

  The present invention has been made in view of the above-described background art, and an object of the present invention is to provide a whitening food and an oral administration agent that have a high whitening effect and can be easily taken.

As a result of diligent efforts under the above-mentioned background art, the present inventors have found that a group of substances has an excellent whitening effect, starting with a gadget extract, and the substances themselves have no bitterness, The present invention has been completed by finding that it is suitable for oral intake. That is, the present invention [1]
Formula (1):
{Where,
R ¹ is H or C _1-3 alkyl;
R ² and R ³ are independently H, OH or C _1-3 alkyl;
Or R ² and R ³ together become = 0,
R ⁴ is H or C _1-3 alkyl;
X and Y are represented by formula (2):
[Where:
symbol:
Represents a single bond or a double bond;
R ⁵ is H or C _1-3 alkyl;
R ⁶ is H, OH or C _1-3 alkyl;
R ⁷ and R ⁸ are independently H or C _1-3 alkyl, or R ⁵ and either R ⁷ or R ⁸ are not present when bond (1) is a double bond. Or R ⁶ and R ⁷ together form -O-
R ⁹ is H or C _1-3 alkyl;
R ¹⁰ is H or C _1-3 alkyl, or R ¹⁰ is not present when the bond (2) is a double bond].
Or formula (3):
[Where:
R ¹¹ is linear or branched C _1-5 alkyl or linear or branched C _1-5 alkenyl,
R ¹² is linear or branched C _1-5 alkyl or linear or branched C _1-5 alkenyl;
R ¹³ is H or C _1-3 alkyl] to form a divalent group represented by
A food for whitening and an orally-administered agent containing one or more isolated substances represented by the formula:
[2]
The substance has the formula (1):
{Where,
R ¹ is methyl;
R ² and R ³ are independently H or OH, or R ² and R ³ together are ═O,
R ⁴ is H;
X and Y are represented by formula (2):
[Where symbol:
Represents a single bond or a double bond;
R ⁵ is H or absent,
R ⁶ is H or OH;
R ⁷ and R ⁸ are independently H or methyl, or when bond (1) is a double bond, R ⁵ and either R ⁷ or R ⁸ are not present, or R ⁶ and R ⁷ together form -O-
R ⁹ is methyl;
R ¹⁰ is H, or R ¹⁰ is not present when the bond (2) is a double bond].
Or formula (3):
[Where:
R ¹¹ is isopropenyl;
R ¹² is ethenyl;
R ¹³ is methyl] to form a divalent group represented by
The food for whitening and the oral administration agent according to the above [1], which are one or more substances represented by the formula:
[3]
The substance is represented by formula (4):
Zedelon represented by formula (5):
Furanodienone represented by formula (6):
Cruzelenone represented by formula (7):
Hydrogenated zederone represented by the formula (8):

The whitening food and the oral administration agent according to the above [1], which are one or more substances selected from the group consisting of hydrogenated furanodienone represented by:
[4]
The whitening agent according to any one of the above [1] to [3], comprising about 0.1 to 30% by mass of the substance as an active ingredient as a total amount of one or more substances. Foods and oral preparations;
[5]
The whitening food and oral administration agent according to any one of [1] to [4], wherein the total dose of one or more substances is administered at a daily dose of about 2 mg to 100 mg / day;
[6]
A natural product extract containing one or more substances selected from the group consisting of zederone, furanodienone and cruzelenone as an active ingredient, and one or more substances selected from the group consisting of zederone, furanodienone and cruelenone The food for whitening and the oral administration agent according to any one of [1] to [5], which does not contain
[7]
Liquid, jelly, gummi, syrup, dry syrup, tablet, powder, granule, fine granule, chewable preparation, orally disintegrating powder, orally disintegrating granule, orally disintegrating fine granule or orally disintegrating tablet The whitening food and the oral administration agent according to any one of the above [1] to [6], which are dosage forms selected from the group consisting of:

  ADVANTAGE OF THE INVENTION According to this invention, the food which has a high whitening effect and is easy to take orally, and the agent for internal use are provided. Therefore, in the past, in order to enhance the effect, although it was required to blend the ganj extract at a high concentration, it could not be blended at a certain concentration or more due to its bitterness. The present invention provides a food product that can be taken orally with an effective amount of an active ingredient without being affected by the above, and an agent for oral use.

In addition to the above substances whose whitening effect has been confirmed in the present invention, hydrogenated cruzelenone and the following compounds are known, but according to the present invention, these compounds are also expected to have a whitening effect by oral administration. .

It is a flowchart which shows the fraction by a liquid-liquid distribution from a gajutsu extract powder (A). It is the photograph which shows the melanin production inhibitory effect by the liquid-partition distribution of gorgeous extract powder (A), (a) is a control, (b) is arbutin, (c) is gudget extract powder (A), The hexane fractions (B) and (e) are the results of the ethyl acetate fraction (C), and (f) are the results of the water fraction (D). It is a chromatogram by preparative thin layer chromatography. It is a chromatogram of each fraction obtained by preparative thin layer chromatography. It is a photograph which shows the melanin production inhibitory effect of the fraction obtained by preparative thin layer chromatography, (a) is a control, (b) is arbutin, (c) is a gadget extract powder (A), (d) Is the hexane fraction (B), (e) is sample B-1 (band S1), (f) is sample B-2 (band S2), (g) is sample B-3 (bands S3 to S5), ( h) is the result of sample B-4 (bands S6 to S8). It is an ultraviolet absorption spectrum of a purified melanin production inhibitor (Zedron). It is the chart by IR of the refined melanin production inhibitory substance (Zederon). 2 is a mass spectrum of a purified melanin production inhibitor (Zederon). ^{1 is} a ¹ H-NMR spectrum of a purified melanin production inhibitor (Zederon). It is a ¹³ C-NMR spectrum of a purified melanin production inhibitory substance (Zedelon). It is an HPLC chart of a fraction eluted with hexane-ethyl acetate (8: 2) of ganjyu extract powder (A). It is an ultraviolet absorption spectrum of a purified melanin production inhibitor (furanodienone). It is the chart by IR of the refined melanin production inhibitory substance (furanodienone). It is an ultraviolet absorption spectrum of the purified melanin production inhibitory substance (cruzelenone). It is the chart by IR of the refined melanin production inhibitory substance (Cruzelenone). It is an ultraviolet absorption spectrum of the produced | generated melanin production inhibitory substance (hydrogenated zederone). It is an ultraviolet absorption spectrum of the produced | generated melanin production inhibitory substance (hydrogenated furanodienone). It is a photograph which shows the melanin production inhibitory effect by the product of manufacture example 1, Comprising: (a) is a control, (b) is arbutin, (c) is a gadget extract powder (A), (d) is a result of manufacture example 1. It is.

The present invention provides a whitening food and an orally-administered agent containing zederone or a zederone-related substance as an active ingredient.
The food and the oral preparation of the present invention comprise a group of substances having a gelmacron-like skeleton as active ingredients. As described above, these active ingredients used in the present invention are known as ingredients contained in plants belonging to the ginger family, including gadgets. Substances used as active ingredients in the present invention include those produced by hydrogenating natural ingredients isolated from plants belonging to the ginger family.

  The substance contained in the oral administration agent of the present invention has no bitterness and is easy to ingest as shown in the following examples, and exhibits a high whitening effect.

  A group of substances contained as an active ingredient in the food and the oral preparation of the present invention are each part of the roots, stems, leaves, etc. of whole vegetation (Curcuma zedoaria Roscoe (Zingiberaceae): also known as purple turmeric), or preferably the rhizomes. Extracted with various organic solvents and purified by using activated carbon, styrene-divinylbenzene synthetic adsorbent (for example, Mitsubishi Kasei Co., Ltd .: HP-20), octadecylsilylated silica gel or silica gel. At this time, as the extraction solvent, water, methanol, a lower alcohol having about 1 to 4 carbon atoms such as ethanol or an aqueous solution thereof, ketones such as acetone or methyl ethyl ketone, esters such as methyl acetate, ethyl acetate, butyl acetate, One type or two or more types of solvents selected from various saturated and unsaturated hydrocarbons such as n-pentane, n-hexane, cyclohexane, benzene, and toluene, regardless of whether they are linear or branched, can be used. These solvents are properly used, for example, polar solvents are preferably used rather than nonpolar solvents for extraction from plants, and then fractionation can be performed by lowering the polarity. Moreover, the hydrogenated substance contained as an active ingredient in the foodstuff and oral administration agent of this invention can be obtained by hydrogenating the obtained compound according to a well-known method.

  However, the substance used as an active ingredient in the present invention does not necessarily have to be purified to a single pure substance. As described in the following examples, extraction, adsorption, liquid-liquid distribution, crystallization using various solvents By relatively high concentration, for example, 60% (w / w), 65% or more, 70% or more, 75% or more, preferably 80% or more, more preferably 85%. More preferably, it is obtained as a crude product containing a substance having a purity of 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, most preferably 99.5% or more. It is also possible.

A group of substances contained as an active ingredient in the oral administration agent of the present invention includes the formula (4):
Zedelon represented by formula (5):

Furanodienone represented by formula (6):

Cruzelenone represented by formula (7):

Hydrogenated zederone represented by formula (8):

And preferred compounds are zederone, furanodienone and cruzelenone, and most preferred is zederone.
In addition to the methods described in the present specification, these substances may be synthesized by known methods or commercially available.

In one form, a group of substances contained as an active ingredient in the food and oral preparation of the present invention are:
(1) Prepare a garnet extract by immersing the dried cucumber (Curcuma zedoaria) in a solvent.
(2) Distilling off the solvent of the ganj extract under reduced pressure,
(3) The produced crystal content can be washed with a small amount of solvent, and then (4) the obtained crystal content can be obtained by a recrystallization process from the solvent.

In another form, a group of substances contained as an active ingredient in the food and oral administration of the present invention,
(1) A dried extract of gadget is soaked in a solvent to prepare a gadget extract,
(2) Distilling off the solvent of the ganj extract under reduced pressure,
(3) Dissolving the dried product thus obtained in a solvent and performing fractionation by column chromatography using silica gel as a filler, and then (4) crystallizing the solvent distillate of the fraction from the solvent. It can obtain by the manufacturing method containing.

In another form, a group of substances contained as an active ingredient in the food and oral administration of the present invention,
(1) A dried extract of gadget is soaked in a solvent to prepare a gadget extract,
(2) Add activated carbon to the ganj extract and stir,
(3) The mixture is filtered, the residue is washed with a solvent, and then (4) a melanin production inhibitor is extracted from the washed residue with a solvent.

Furthermore, in another form, a group of substances contained as an active ingredient in the food and oral administration of the present invention,
(1) A dried extract of gadget is soaked in a solvent to prepare a gadget extract,
(2) It is subjected to liquid-liquid distribution between a non-aqueous solvent and a hydrophilic solvent,
(3) A non-aqueous solvent layer is subjected to column chromatography, the solvent of the objective fraction is dried under reduced pressure, and then (4) obtained by a production method including a step of recrystallization from a non-aqueous solvent. Can do.

  In a preferred form, the group of materials is about 1:50 to about 1: 3 (volume ratio), preferably about 1:10 to about 1: 4 (volume ratio) of ganjut: solvent bath ratio, about The reaction is carried out by stirring, Soxhlet extraction or standing for about 2 hours to about 14 days, preferably about 7 days, from 10 ° C. to the boiling point of the extraction solvent, preferably from room temperature to about 10 ° C. lower than the boiling point of the solvent.

  In a preferred embodiment, the solvent used for operations such as extraction, adsorption, liquid partitioning, crystallization, and chromatography mobile phase is water, methanol, ethanol, 30-95% (v / v) aqueous methanol solution or aqueous ethanol solution, Hexane or ethyl acetate, and these solvents can be used alone or in combination.

In a preferred form, the chromatography conditions are as follows.
Column: Chemcobond 5-ODS-W (6.0 x 150 (6A)) (Chemco Corporation)
Mobile phase: 75% (v / v) aqueous methanol column temperature: 55 ° C
Flow rate: 1.0mL / min
Injection volume: 10μL
Monitor: UV 280nm Absorbance

In a preferred form, zederone contained as an active ingredient in the food and oral preparation of the present invention is:
(1) Soaked dried radish rhizomes in ethyl acetate and allowed to stand at room temperature for extraction.
(2) The extract was filtered through a filter (ADVANTEC No.131), the solvent was distilled off under reduced pressure,
(3) The dried product was subjected to column chromatography (same as the above analysis conditions) with silica gel as a packing material using a mixed liquid of hexane and ethyl acetate (volume ratio 7: 3) as the mobile phase, and the wavelength was 210 nm. Perform fractionation using ultraviolet absorption as an index,
(4) Collect the fraction in which absorption was observed, and distill off the solvent under reduced pressure.
(5) Recrystallize the distillate using hexane, and then (6) After dissolving in a 50% aqueous ethanol solution at a concentration of about 1%, recrystallize at room temperature to obtain zederone. Can be obtained.

In a preferred form, furanodienone contained as an active ingredient in the food and oral preparation of the present invention,
(1) Concentrate the dried ganj rhizome by refluxing with hexane,
(2) The dried product obtained by distilling the collected extract under reduced pressure was dissolved in a small amount of hexane,
(3) Apply to a silica column and elute sequentially with hexane, hexane: ethyl acetate (volume ratio 9: 1), hexane: ethyl acetate (volume ratio 8: 2),
(4) Collect the fraction eluted with hexane: ethyl acetate (volume ratio 8: 2), and then (5) dissolve in a small amount of 75% (v / v) aqueous methanol solution and apply to an ODS column. It can be obtained by a production method including a step of fractionating to obtain furanodienone.

In a preferred form, cruzelenone contained as an active ingredient in the food and oral preparation of the present invention is:
(1) Concentrate the dried ganj rhizome by refluxing with hexane,
(2) The dried product obtained by distilling the collected extract under reduced pressure was dissolved in a small amount of hexane,
(3) Apply to a silica column and elute sequentially with hexane, hexane: ethyl acetate (volume ratio 9: 1), hexane: ethyl acetate (volume ratio 8: 2),
(4) Collect the fraction eluted with hexane: ethyl acetate (volume ratio 8: 2), and then (5) dissolve in a small amount of 75% (v / v) aqueous methanol solution and apply to an ODS column. It can be obtained by a production method including a step of fractionating to obtain cruzelenone.

In a preferred form, hydrogenated zederone contained as an active ingredient in the food and oral administration of the present invention is:
(1) Dissolve zederone obtained by the above production method in 99.5% (v / v) ethanol,
(2) Add 5% Pd-alumina and perform hydrogenation reaction using hydrogen bag, then (3) Perform filtration after completion of the reaction, and distill off the solvent of the filtrate under reduced pressure to obtain hydrogenated zederone. It can be obtained by a production method including steps.

In a preferred form, the hydrogenated furanodienone included as an active ingredient in the food and oral preparation of the present invention is:
(1) Furanodienone obtained by the above production method or the like is dissolved in 99.5% (v / v) ethanol,
(2) Add 5% Pd-alumina and conduct hydrogenation reaction using hydrogen bag, then (3) Perform filtration after completion of the reaction, and distill off the filtrate solvent under reduced pressure to obtain hydrogenated furanodienone. It can be obtained by a production method including steps.

In a preferred form, the hydrogenated cruzelenone contained as an active ingredient in the food and oral preparation of the present invention is:
(1) Dissolve kruzelenone obtained by the above-mentioned production method in 99.5% (v / v) ethanol,
(2) Add 5% Pd-alumina and perform hydrogenation reaction using hydrogen bag, then (3) Perform filtration after completion of the reaction, and distill off the solvent of the filtrate under reduced pressure to obtain hydrogenated cruzelenone. It can be obtained by a production method including steps.

  In the food for whitening and the oral administration agent of the present invention, the total amount of one or more substances is about 0.1 to 30% by mass, preferably about 0.2 to 20% by mass with respect to the whole agent. %, About 0.2 to 15% by weight, more preferably about 0.3 to 10% by weight of the above substances are included as active ingredients.

  In addition, the whitening food and the oral administration agent of the present invention are preferably about 2 to 100 mg / day, about 3 to 100 mg / day, and about 5 to 100 mg / day as the total dose of one or more substances. About 7-100 mg / day, about 10-100 mg / day, more preferably about 3-80 mg / day, about 5-80 mg / day, about 7-80 mg / day, about 10-80 mg / day, about 3 70 mg / day, about 5-70 mg / day, about 7-70 mg / day, about 10-70 mg / day, about 3-60 mg / day, about 5-60 mg / day, about 7-60 mg / day, about 10-60 mg / Day, most preferably at a daily dose of about 8-50 mg / day, about 9-50 mg / day, about 10-50 mg / day.

The food for whitening of the present invention includes all foods and drinks other than those classified as quasi-drugs or drugs prescribed in the Pharmaceutical Affairs Law.
On the other hand, the oral administration agent for whitening of the present invention is not particularly limited as long as it is a dosage form that can be administered orally classified as a quasi-drug or a pharmaceutical specified in the Pharmaceutical Affairs Law, but it is a liquid agent, a jelly agent, a gummi agent. , Syrup, dry syrup, tablet, powder, granule, fine granule, chewable preparation, orally disintegrating powder, orally disintegrating granule, orally disintegrating fine granule or orally disintegrating tablet Can do. The liquid preparation includes suspensions and internal liquids. More preferably, since it does not require water at the time of taking, it can be administered without being affected by time and place, jelly, gummi, chewable preparation, orally disintegrating powder, orally disintegrating granules, orally disintegrating fine particles A granule or an orally disintegrating tablet is mentioned. From the standpoint of adjusting the dose according to the patient, liquids, syrups, dry syrups, powders, granules, fine granules, orally disintegrating powders, orally disintegrating granules, orally disintegrating fine granules, etc. preferable. From the viewpoint of easy administration to patients who have difficulty swallowing, the elderly, and children, liquids, syrups, jellies, gummi, dry syrups, powders, granules, fine granules, chewable preparations, oral disintegration Preference is given to mold powders, orally disintegrating granules, orally disintegrating fine granules, orally disintegrating tablets and the like.

  In addition to the above, in the food and the oral administration agent of the present invention, non-toxic and inert additives usually used in the food or pharmaceutical field can be added. These additives include those that do not substantially affect the effects of the present invention and are generally added as additives to foods and pharmaceuticals. For example, excipients such as D-mannitol, xylitol, sorbitol, erythritol, maltitol, reduced starch saccharified, reduced palatinose, talc, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, crystalline cellulose, stearic acid, stearin Lubricants such as magnesium oxide, calcium stearate, sodium stearyl fumarate, fluidizing agents such as light anhydrous silicic acid, disintegrants such as carboxymethylcellulose calcium and low-substituted hydroxymethylcellulose, hydroxypropylcellulose, hypromellose (hydroxypropylmethylcellulose) , Povidone (polyvinylpyrrolidone), gelatin, methylcellulose, gum arabic powder, polyvinyl alcohol, alkylhydroxyethylcellulose, etc. Agents, coloring agents such as yellow ferric oxide, sweeteners, flavoring agents, adsorbents, preservatives, stabilizers, wetting agents, antistatic agents, pH adjusters, polysorbates (for example, polysorbate 80) Agents, starches such as corn starch, solvents such as water, suspending agents and the like. In particular, in the case of oral solid preparations that can be taken without water, such as dry syrup, orally disintegrating powder, orally disintegrating granules, orally disintegrating fine granules, orally disintegrating tablets, by adding a water-soluble excipient Disintegration and solubility in the oral cavity are improved, and administration is easier.

  Examples of water-soluble excipients include sorbitol, D-mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, or erythritol. Can be used. Preferable water-soluble excipients include D-mannitol, xylitol or erythritol, and more preferably D-mannitol or erythritol.

Although it does not specifically limit as a compounding quantity of the water-soluble excipient | filler in the foodstuff and oral administration agent of this invention, Usually, 15 to 75% (w / w), Preferably it can be set to 25 to 50% (w / w).
The compounding amount of additives other than the above-mentioned water-soluble excipient is not particularly limited, and an amount known per se can be appropriately selected according to the dosage form.

  The production method of the food and oral preparation of the present invention is not particularly limited and includes known methods. In the case of a solid preparation, for example, as a granulation method, extrusion granulation method, crushing granulation method, dry method Consolidation granulation method, fluidized bed granulation method, tumbling granulation method, rolling fluidized bed granulation method, high speed stirring granulation method, kneading granulation method, etc. Examples thereof include a granule compression method and a direct compression method.

  Next, 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 these examples. In addition, unless otherwise indicated, a compounding quantity represents the mass%.

[Extraction and fraction purification from gadgets]
In extraction and purification of the melanin production inhibitor according to the present invention from gadgets, first, fractionation operation was performed by the method shown in FIG. 1, and the whitening action was examined for each fraction. The whitening action was performed by examining the melanin production inhibitory action as shown below. The gadgets obtained from Shinwa Bussan Co., Ltd. were used.

  1800 mL of 50% (v / v) aqueous ethanol solution was added to 300 g of dried radish (Curcuma zedoaria Roscoe (Zingiberaceae)) and left at room temperature for 5 days. Then, it filtered and 1600 mL extract was obtained. The extract was concentrated under reduced pressure to obtain 7.5 g of a dried product (Gadju extract powder (A)). 1 g of the dried product was dissolved in a small amount of 50% (v / v) ethanol aqueous solution and then poured into a separatory funnel. Further, water and hexane (1: 1 by volume) were added and shaken well. I put it. The lower aqueous layer was taken out, and the upper hexane layer was separated into another flask. The taken out aqueous layer was returned to the separatory funnel again, almost the same volume of hexane as the aqueous layer was added, and the same operation was repeated twice more. Next, the aqueous layer was returned again to the separatory funnel, and a liquid separation operation was performed by adding approximately the same volume of ethyl acetate as the aqueous layer. The upper ethyl acetate layer was collected, the taken-out aqueous layer was returned to the separatory funnel, ethyl acetate having the same volume as the aqueous layer was added again, and the same operation was repeated twice more. The collected hexane layer, ethyl acetate layer, and the remaining aqueous layer were concentrated under reduced pressure, and used as samples for the melanin production inhibition test (samples (A) to (D)).

(Melanin production inhibition test)
As a melanin production inhibition test, a test using a three-dimensional cultured skin model and a test using the amount of melanin and protein produced at that time as indices were performed.
The melanin production inhibition test was performed using a commercially available three-dimensional cultured skin model (MEL-300 kit Asian donor: Kurabo Industries). According to the method of using the kit, a MEL-300 skin model cup is set in each well of a 6-well plate and warmed in a 37 ° C. incubator (EPI-100: SCF reaches a final concentration of 10 ng / mL when the medium is added) Aseptically, 5 mL each was put into a skin model cup. 100 μL of each sample solution was added directly into the skin model cup, and the 6-well plate containing the skin model cup was placed in an incubator (37 ° C., 5% CO ₂ , humidified state) and cultured for 14 days. Every two days, the medium was replaced with a new medium, and each time 100 μL of the solution of each sample was added to the skin model cup. In addition, PBS (-) for cell culture was used for preparation of the solution of each sample.

  After culturing, the MEL-300 skin model cup was washed 3 times with PBS (−), the cell part was detached and placed in a 1.5 mL Eppendorf tube, 0.5 mL of 2 mol / L-NaOH was added, and at room temperature. Left overnight. After boiling for 15 minutes, 250 μL of each sample was transferred to a 96-well plate, and melanin was quantified at 405 nm.

  Furthermore, 40 μL of the sample for quantifying melanin after boiling was transferred to a 96-well plate, and 200 μL of BCA reagent (trade name: Takara Bio Inc.) for protein quantification was placed in each well and incubated at 37 ° C. for 30 minutes. Thereafter, the absorbance at 540 nm was measured.

  A similar test was performed using PBS (-) as a control and arbutin-PBS (-) solution (2.0% (w / v)) as a positive control. Relative ratio) and protein amount (relative ratio) were calculated, and the degree of inhibition of melanin production was examined. The results are shown in Table 1. Moreover, the photograph which shows the result of the three-dimensional cultured skin model at that time is shown in FIG.

(Fractionation purification by TLC)
From the results of Table 1 and FIG. 2, it was found that the hexane extract fraction shown in FIG. 1B showed the strongest melanin production suppression degree (FIG. 2D). Therefore, this fraction was further purified using preparative TLC (preparative thin layer chromatography).

  After the solvent was distilled off from the hexane extraction layer, the concentrate was dissolved in a small amount of hexane, and mixed with hexane and ethyl acetate in a preparative thin layer plate (silica gel 60 / F254, Merck, thickness 2 mm). Fractionation was performed using (volume ratio 7: 3) as a developing solvent. Detection was performed visually and with a UV lamp having a wavelength of 254/366 nm. The result is shown in FIG. As shown in FIG. 3, three distinct bands (S1 to S3), two bands (S5, S7) that were observed slightly, and one band (S8) tailed from the origin were observed. Therefore, as shown in the figure, it was fractionated into 8 bands (band S1 to band S8). Each fractionated band was scraped and extracted with ethyl acetate, and then ethyl acetate was distilled off to obtain each fraction component.

  Next, the fractionation status of the fraction components was confirmed by TLC. A small amount of each fraction concentrate was dissolved again in a small amount of hexane, and then developed with the above developing solvent using a thin layer plate (silica gel 60 / F254, thickness 0.2 mm (Merck)). The result is shown in FIG. The lanes in which the hexane solutions of bands S1, S2, S3,... S7, S8 are spotted in order from the left are shown. As a result, a single spot was detected in band S2 (detection by iodine).

(Melanin production inhibition test)
Next, the fractionated sample was subjected to a melanin production inhibition test. In the test, based on the results of this TLC, each band was used as a sample (sample B-1 and sample B-2) for bands S1 and S2, respectively, and for bands S3 to S5 and bands S6 to S8, the bands Were used as samples (Sample B-3 and Sample B-4), respectively. Table 2 shows the results of the degree of inhibition of melanin production determined from the amount of melanin and the amount of protein. In addition, as a reference, tests were also conducted on the gadget extract powder (A) and the hexane layer concentrate (B). As a result, the fraction of sample B-2 from which a single spot was obtained showed the strongest degree of inhibition of melanin production. Moreover, the photograph which shows the result of the three-dimensional cultured skin model at this time is shown in FIG.

[Determination of structure of melanin inhibitor]
As shown in Table 2, the fraction of band S2 showed the strongest inhibition of melanin production, and a single spot could be confirmed in detection by ultraviolet absorption and detection by iodine, so melanin present in this fraction The structure of the production inhibitor was determined. Structure determination is based on analysis by ultraviolet absorption spectrum (solvent: hexane), infrared absorption analysis (IR), mass spectrometry, ¹ H-NMR (solvent: CDCl ₃ ) and ¹³ C-NMR (solvent: CDCl ₃ ). went. The results are as follows, and charts according to each analysis are shown in FIGS. The assignment by NMR is shown in Table 3. From these results, the produced melanin production inhibitor was identified as zederone. As can be seen from Table 2, the degree of inhibition of melanin production of this substance shows almost the same effect at a concentration of about 1/400 of the arbutin concentration as compared with arbutin which has been considered to have a whitening effect so far. The action is about 400 times stronger than arbutin.

Properties: White crystalline solid UV absorption: Maximum absorption wavelength (λmax) 281nm
Mass spectrometry: 246 (m / e)
Infrared absorption spectrum (cm ^-1 ): 1662,1523,1427,1400,1232,1066,1020,929,881,863.

[Confirmation of stability]
A solution obtained by dissolving 100 mg of zederone obtained in the above method in 200 mL of 50% (v / v) aqueous ethanol solution was added at a high temperature (60 ° C.), and 0.5 mol / L-NaOH was added to this solution to give a final concentration of 0.125 mol. / L-NaOH and 0.5 mol / L-HCl added to a final concentration of 0.125 mol / L-HCl were stored at room temperature to confirm stability. Moreover, what stored the ethanol solution same as the above at 4 degreeC was used for control. Stability was measured by performing high performance liquid chromatography under the following conditions and determining the residual ratio from the percentage by peak area. In addition, the sample solution preserve | saved alkali and acid was measured after neutralization, respectively.

(Analysis conditions)
Column: Chemcobond 5-ODS-W (6.0 x 150 (6A)) (Chemco Corporation)
Mobile phase: Methanol Column temperature: 55 ° C
Flow rate: 1.0mL / min
Injection volume: 10μL
Monitor: UV 280nm Absorbance

  The results are shown in Table 4. It is well known that phenolic compounds such as arbutin and ellagic acid brown in the alkaline region, but no change was observed in zederone. In addition, although a slight decrease was observed in the acidic range, it was found that it is stable even in alkaline and high temperature conditions, and zederone can be blended in a composition under various physical conditions. It became clear that it can be used in.

[Example 2]

Next, a group of substances contained in the food and oral preparation of the present invention was prepared according to the following production method.
[Production Example 1] 1 kg of dried rhizomes of Zederon gudget (Curcuma zedoaria) was immersed in 6 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), the solvent was distilled off from the filtrate under reduced pressure, and the mixture was left in a cool dark place. The produced crystal was separated and washed with a small amount of hexane. Furthermore, the obtained crystal was recrystallized with hexane to obtain 300 mg of Zedelon (purity of about 95%). The purity was determined by operating under the above liquid chromatography conditions. The zederone obtained in Example 1 was used as a standard product, and zederone was quantified from the peak height ratio at a detection wavelength of 220 nm (the same applies to Production Example 2).

[Production Example 2] 1 kg of dried Zedelon radish was dipped in 6 L of ethyl acetate and allowed to stand at room temperature for 4 days for extraction. The extract was filtered through a filter (ADVANTEC No.131), the solvent was distilled off from the filtrate under reduced pressure, and the mobile layer was then mixed with silica gel using a mixture of hexane and ethyl acetate (volume ratio 7: 3). Purification by column chromatography (same as the above analysis conditions) using as a filler. Fractionation was performed with a fraction collector, and fractionation was performed using ultraviolet absorption at a wavelength of 280 nm measured for each fraction as an index. The solvent distillate of the fraction in which absorption was observed was recrystallized using hexane to obtain 2200 mg of white crystals (zederone content of 2000 mg).

[Production Example 3] 350 g of dried furanodienone rhizome was refluxed with 1750 mL of hexane for 3 hours. The solvent was filtered off and concentrated. 1750 mL of hexane was added to the residue and refluxed, and the same operation was repeated. The collected extract was distilled off under reduced pressure to obtain 3.12 g of a dried solid product. Dissolve it in a small amount of hexane (about 20 mL), filter the insoluble matter, apply it to a silica column (BW300 (Fuji Silysia), φ = 20 mm, h = 200 mm), hexane, hexane: ethyl acetate (volume ratio) 9: 1) and hexane: ethyl acetate (volume ratio 8: 2) were eluted sequentially with 100 mL each. The fraction eluted with hexane: ethyl acetate (volume ratio 8: 2) was collected, and the solvent was distilled off to obtain a yield of 0.484 g. Next, it was dissolved in a small amount of 75% (v / v) aqueous methanol solution and applied to a column under the following conditions. Fractions were collected using a fraction collector, and each fraction was analyzed using liquid chromatography under the following conditions. Fractions having only a partial peak corresponding to * 1 in the chart of FIG. 11 were collected, and the solvent was distilled off. 0.10 g (yield 0.028%) of a white crystalline solid was obtained. The structure of the melanin production inhibitor existing in this fraction was determined. The structure was determined based on analysis by ultraviolet absorption spectrum (solvent: hexane), infrared absorption analysis (IR), and ¹ H-NMR (solvent: CDCl ₃ ), and the following physical properties were obtained. Charts by ultraviolet absorption and infrared absorption analysis are shown in FIGS.
It was found that the melanin production inhibitor obtained from these physical properties was furanodienone.

Column: Chemcobond 5-ODS-W (6.0 × 150 (6A)) (Chemco Corporation)
Mobile phase: methanol: water = 75:25 (v: v)
Column temperature: 55 ° C
Flow rate: 1.0mL / min
Injection volume: 10 μL
Detection wavelength: 280nm

Ultraviolet absorption: Maximum absorption wavelength (λmax): None Infrared absorption spectrum (cm ^-1 ): 1644, 1523, 1375, 1270, 1240, 1105, 1020,931
¹ H-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).

[Production Example 4] Cruzelenone Further, fractions having only a partial peak corresponding to * 2 in the chart of FIG. 11 were collected and the solvent was distilled off to obtain 0.07 g (yield 0.02%) of a transparent oily liquid. It was. The structure of the melanin production inhibitor existing in this fraction was determined. The structure was determined based on analysis by ultraviolet absorption spectrum (solvent: hexane), infrared absorption analysis (IR), and ¹ H-NMR (solvent: CDCl ₃ ), and the following physical properties were obtained. Charts by ultraviolet absorption and infrared absorption analysis are shown in FIGS.
It was found that the melanin production inhibitor obtained from these physical property values was cruzelenone.

Ultraviolet absorption: maximum absorption wavelength (λmax): 272 nm
Infrared absorption spectrum (cm ^-1 ): 1675,1562,1427,1257,1070,997
¹ 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).

[Production Example 5] Hydrogenated Zedron 500 mg of Zedelon obtained in Production Example 2 was dissolved in 100 mL of 99.5% (v / v) ethanol, 100 mg of 5% Pd-alumina was added, and hydrogenation reaction was performed using a hydrogen bag. went. The reaction was carried out at room temperature for 15 hours. Filtration was performed after completion of the reaction, and the solvent of the filtrate was distilled off under reduced pressure to obtain 500 mg of a white crystalline solid. The structure of the melanin production inhibitor existing in this fraction was determined. The structure was determined based on analysis by ultraviolet absorption spectrum (solvent: hexane) and ¹ H-NMR (solvent: CDCl ₃ ), and the following physical property values were obtained. A chart obtained by ultraviolet absorption analysis is shown in FIG.
The melanin production inhibitor obtained from these physical properties was found to be hydrogenated zederone.

Ultraviolet absorption: maximum absorption wavelength (λmax): 287 nm
¹ H-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), 1.776 (1H, d), 4.199 (1H, d).

[Production Example 6] Hydrogenated Furanodienone 500 mg of furanodienone obtained in Production Example 3 was dissolved in 100 mL of 99.5% ethanol, 100 mg of 5% Pd-alumina was added, and a hydrogenation reaction was performed using a hydrogen bag. The reaction was carried out at room temperature for 15 hours. Filtration was performed after completion of the reaction, and the solvent of the filtrate was distilled off under reduced pressure to obtain 500 mg of a white crystalline solid. The structure of the melanin production inhibitor existing in this fraction was determined. The structure was determined based on analysis by ultraviolet absorption spectrum (solvent: hexane) and ¹ H-NMR (solvent: CDCl ₃ ), and the following physical property values were obtained. A chart obtained by ultraviolet absorption analysis is shown in FIG.
The melanin production inhibitor obtained from these physical properties was found to be hydrogenated furanodienone.

Ultraviolet absorption: Maximum absorption wavelength (λmax): None
¹ H-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).

[Inhibition test of melanin production using human melanocytes]
(Human melanocyte culture)
Human melanocytes (NHEM (Moderately), Kurabo Corp.) are seeded at 2.5 × 10 ⁴ per well in a 12-well plate containing 1000 μL of Medium 254 medium (containing growth factor HMGS-2), and the next day stem cells are placed in the medium. Growth factors (SCF, final concentration 10 ng / mL) and test samples were added after 4 hours. It was incubated at 37 ° C., the medium was changed after 3 days, SCF (final concentration 10 ng / mL) was added again, a test sample was added 4 hours later, and incubated at 37 ° C. for 7 days. Thereafter, the amount of melanin and the amount of protein were measured according to the following method.

(Quantification of melanin)
The medium in the well was removed, and the cells were washed 3 times with 500 μL of PBS (−), and then PBS (−) was completely removed. 400 μL of 2 mol / L-NaOH was added to the washed cells to lyse the cells, and the cells were shaken for 30 minutes to prepare a cell lysate. Each cell lysate was transferred to a 1.5 mL Eppendorf tube, heated with boiling water for 10 minutes, and stirred vigorously with a Voltex mixer. 350 μL of this was transferred to a 96-well, and the absorbance was measured at 405 nm.

(Quantification of protein)
40 μL of the cell lysate obtained above was mixed with 200 μL of BCA solution and incubated at 37 ° C. for 30 minutes, and then the absorbance was measured at 540 nm.

  Inhibition of melanin production using the above-described quantification of melanin and protein as indicators for zederone, furanodienone, cruzelenone, hydrogenated zederone and hydrogenated furanodienone obtained in [Production Example 1] and [Production Example 3] to [Production Example 6] A test was conducted. Table 5 shows the amount of melanin and protein by each component. The zederone, furanodienone, cruzelenone, hydrogenated zederone, and hydrogenated furanodienone obtained in [Production Example 1] and [Production Example 3] to [Production Example 6] are almost the same as zederone isolated by thin-layer chromatography. Moreover, the melanin production inhibitory effect beyond it was recognized.

  Zederone, furanodienone, cruzelenone, hydrogenated zederone and hydrogenated furanodienone are all less toxic to cells than arbutin, which is known to have a whitening effect, and have been confirmed to show a whitening effect at very low concentrations. It was.

  Similarly to the above-described (melanin production inhibition test), a melanin production inhibition test was performed on the zederone obtained in [Production Example 1] using a three-dimensional skin culture model. The results are shown in Table 6 and FIG. The zederone obtained in [Production Example 1] was found to have almost the same inhibitory effect on melanin production as zederone isolated by thin layer chromatography.

[Whitening effect test by oral administration]
Preparation of Zedelon 10 kg of dried rhizomes of curduma (Curcuma zedoaria) were immersed in 60 L of hexane and extracted by leaving at room temperature for 7 days. The extract was filtered through a filter (ADVANTEC No. 131), the solvent was distilled off from the filtrate under reduced pressure, and the mixture was left in a cool dark place. The produced crystal was separated and washed with a small amount of hexane. Further, the obtained crystal was recrystallized with hexane to obtain 3 g of zederone. 3 g of crystals obtained by recrystallization with hexane were added to 200 mL of a 50% ethanol solution, dissolved by heating, and the insoluble matter was filtered through a filter (ADVANTEC No. 131). The filtrate was allowed to stand at room temperature and recrystallized to obtain 2.1 g of crystals, which were used as an active ingredient of an orally administered agent.

Preparation of Oral Administration Agent for Whitening 2 g of obtained Zedelone was evenly dispersed in 98 g of dextrin to prepare an oral administration agent. 250 mg of the prepared oral preparation was dispensed into commercially available cellulose capsules and used for the test as a group for administration of 10 mg per two.
Moreover, 0.2 g of zederone was evenly dispersed in 98.8 g of dextrin to prepare an oral administration agent. 250 mg of the prepared oral preparation was dispensed into commercially available cellulose capsules and used in the test for the 1 mg administration group per two.

Whitening effect test Eighteen healthy men and women, Zederon 10 mg / day intake group, Zederon 1 mg / day intake group equivalent to the intake as a gadget extract blended in conventional health foods, and a placebo intake group not containing Zederon Were divided into three groups and each was taken once a day. The test was conducted with a double blind. It should be noted that 1 mg / day of zederone, which corresponds to the conventional intake, is considered to be the food with the highest content as food containing zederone, and foods in which the gadget powder itself is taken can be considered, and the average zederone content is about 0 In the range of 0.01 to 0.03%, the intake of zederone by ingestion of 3 g / day of gadget powder was about 0.3 to 1 mg / day, and the maximum was set to correspond to about 1 mg / day.
The whitening effect (increase in skin lightness) was evaluated after 1 and 2 months.
The measurement items were a questionnaire regarding the skin condition and the color difference of the exposed part (cheek part) and the non-exposed part (inner and outer arms). The color difference was measured after acclimatization for 15 minutes in an environment of a temperature of 20 ° C. and a humidity of 30%, measuring six locations in the vicinity of the same part, and obtaining the average value excluding the maximum and minimum values. . The results are shown in Table 7.

As is apparent from Table 7, no significant increase in skin lightness was observed after 2 months in the placebo intake group or in the 1 mg / day intake group of zederone, whereas in the 10 mg / day intake group, the significant skin lightness was observed. An increase was observed.
Therefore, the whitening effect is not achieved by the intake of zederone contained in the food containing the conventional garlic extract, whereas the whitening food and the orally-administered agent of the present invention in which zederone is ingested 10 mg / day is used. It became clear that is played.
In addition, it is necessary to ingest a large amount of powder of 30 g / day in order to ingest 10 mg / day of zederone in which an increase in skin lightness has been observed with a powdered food containing a conventional gadget extract. Ingestion is difficult.

[Taste test of orally administered drugs]
Commercially available gadget powder is 3 g (about 1 teaspoon, about 1 mg of zederone) / day as a guideline, poured with hot water as tea, or with milk, various health teas or juices, etc. Is. Therefore, a dispersion of 3 g of gadget powder in hot water is referred to as Comparative Example 1, a dispersion of milk in Comparative Example 2 is set as Comparative Example 2, and 10 mg of zederone is uniformly dispersed in 3 g of dextrin and dispersed in hot water as Example 1 The dispersed product was designated as Example 2, and 10 men and women were allowed to drink it, and the taste was evaluated. The results are shown in Table 8.

  As is clear from Table 8, the unpurified gadget extract (Comparative Examples 1 and 2) did not give a good evaluation of taste such as bitterness, whereas the zederone purified from the gadget extract was not purified. Despite being higher than the zederone content in it, there was no effect on taste. Therefore, it was shown that the purification of zederone from the extract of gadget makes it possible to be blended into foods and oral preparations that have no bitter taste and can easily take in a large amount of active ingredients.

Formulation Example 1 Tablet Health Food 2 g of purified Zederon, 70 g of dextrin, 90 g of powdered sugar and 10 g of glycerin fatty acid ester were mixed and stirred to prepare uniformly and tableted to obtain health food as a tablet of 200 mg.

Formulation Example 2 Beverage Granules 1 g of purified zederone, 40 g of oligosaccharide, 50 g of sugar and 380 g of dextrin are mixed and stirred to prepare uniformly, granulated by a fluidized bed granulator to obtain a granule for beverage that is 5 g in a package. It was.

Formulation Example 3 Drink Agent 10 mg of purified zederone, 3000 mg of sorbitol, 4500 mg of oligosaccharide, 500 mg of cyclodextrin and 100 mg of ascorbic acid were mixed and dissolved in appropriate amounts of purified water to make 50 mL, thereby obtaining a drink.

Formulation Example 4 Capsule Powder 5 g of purified zederone, 40 g of oligosaccharide and 200 g of dextrin were mixed and stirred to prepare uniformly to obtain a capsule powder of 250 mg per capsule.

  The present invention relates to the field of whitening foods (health foods, etc.) and oral administration agents (quasi-drugs, pharmaceuticals, etc.) that exhibit a high whitening effect and can be easily administered without bitterness.

Claims (6)

Formula (1):
{Where,
R ¹ is H or C _1-3 alkyl;
R ² and R ³ are independently H, OH or C _1-3 alkyl;
Or R ² and R ³ together become = 0,
R ⁴ is H or C _1-3 alkyl;
X and Y are represented by formula (2):
[Where:
symbol:
Represents a single bond or a double bond;
R ⁵ is H or C _1-3 alkyl;
R ⁶ is H, OH or C _1-3 alkyl;
R ⁷ and R ⁸ are independently H or C _1-3 alkyl, or R ⁵ and either R ⁷ or R ⁸ are not present when bond (1) is a double bond. Or R ⁶ and R ⁷ together form -O-
R ⁹ is H or C _1-3 alkyl;
R ¹⁰ is H or C _1-3 alkyl, or R ¹⁰ is not present when the bond (2) is a double bond].
Or formula (3):
[Where:
R ¹¹ is linear or branched C _1-5 alkyl or linear or branched C _1-5 alkenyl,
R ¹² is linear or branched C _1-5 alkyl or linear or branched C _1-5 alkenyl;
R ¹³ is H or C _1-3 alkyl] to form a divalent group represented by
One The oral dosage for whitening comprising two or more isolated substance as an active ingredient represented in. The substance has the formula (1):
{Where,
R ¹ is methyl;
R ² and R ³ are independently H or OH, or R ² and R ³ together are ═O,
R ⁴ is H;
X and Y are represented by formula (2):
[Where symbol:
Represents a single bond or a double bond;
R ⁵ is H or absent,
R ⁶ is H or OH;
R ⁷ and R ⁸ are independently H or methyl, or when bond (1) is a double bond, R ⁵ and either R ⁷ or R ⁸ are not present, or R ⁶ and R ⁷ together form -O-
R ⁹ is methyl;
R ¹⁰ is H, or R ¹⁰ is not present when the bond (2) is a double bond].
Or formula (3):
[Where:
R ¹¹ is isopropenyl;
R ¹² is ethenyl;
R ¹³ is methyl] to form a divalent group represented by
One The oral dosage for whitening according to claim 1, wherein the two or more substances expressed in. The substance is represented by formula (4):
Zedelon represented by formula (5):
Furanodienone represented by formula (6):
Cruzelenone represented by formula (7):
Hydrogenated zederone represented by the formula (8):

Oral dosage for whitening of claim 1 wherein the one or more substances selected from the group consisting of hydrogenated Furanojienon represented in. One or oral for whitening according to any one of claims 1 to 3 comprising two or more of the total amount as in respect to the total agent from 0.1 to 30 wt% of the substance of the substance as an active ingredient Dosage. Oral dosage for whitening according to one or any one of claims 1 is administered 4 in more than one total dose and to 2 Mg～100mg / day daily dose of substance. Liquid, jelly, gummi, syrup, dry syrup, tablet, powder, granule, fine granule, chewable preparation, orally disintegrating powder, orally disintegrating granule, orally disintegrating fine granule or orally disintegrating tablet oral dosage for whitening according to any one of claims 1 to 5 which is a dosage form selected from the group consisting of.