JP2012006895A - Melanin production promoter - Google Patents
Melanin production promoter Download PDFInfo
- Publication number
- JP2012006895A JP2012006895A JP2010146931A JP2010146931A JP2012006895A JP 2012006895 A JP2012006895 A JP 2012006895A JP 2010146931 A JP2010146931 A JP 2010146931A JP 2010146931 A JP2010146931 A JP 2010146931A JP 2012006895 A JP2012006895 A JP 2012006895A
- Authority
- JP
- Japan
- Prior art keywords
- group
- melanin production
- fisetin
- compound
- acetyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000008099 melanin synthesis Effects 0.000 title claims abstract description 81
- XHEFDIBZLJXQHF-UHFFFAOYSA-N fisetin Chemical compound C=1C(O)=CC=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 XHEFDIBZLJXQHF-UHFFFAOYSA-N 0.000 claims abstract description 91
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 235000011990 fisetin Nutrition 0.000 claims abstract description 53
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 42
- DANYIYRPLHHOCZ-UHFFFAOYSA-N 5,7-dihydroxy-4'-methoxyflavone Chemical compound C1=CC(OC)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 DANYIYRPLHHOCZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 235000009962 acacetin Nutrition 0.000 claims abstract description 12
- 229960001876 diosmetin Drugs 0.000 claims abstract description 11
- HUOOMAOYXQFIDQ-UHFFFAOYSA-N isoginkgetin Chemical compound C1=CC(OC)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C(C=3C(=CC=C(C=3)C=3OC4=CC(O)=CC(O)=C4C(=O)C=3)OC)=C2O1 HUOOMAOYXQFIDQ-UHFFFAOYSA-N 0.000 claims abstract description 8
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- MBNGWHIJMBWFHU-UHFFFAOYSA-N diosmetin Chemical compound C1=C(O)C(OC)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 MBNGWHIJMBWFHU-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 62
- 125000000217 alkyl group Chemical group 0.000 claims description 31
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- SQFSKOYWJBQGKQ-UHFFFAOYSA-N kaempferide Chemical compound C1=CC(OC)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 SQFSKOYWJBQGKQ-UHFFFAOYSA-N 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000004423 acyloxy group Chemical group 0.000 claims description 13
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
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Abstract
Description
本発明は、メラニンの産生を促進することで、毛髪の黒色化を図って白髪を予防または改善したり、また肌の褐色化(タンニング)を促して白斑病の治療や太陽光(日光)暴露等によらなくても日焼け効果が得られるメラニン産生促進剤に関する。 The present invention promotes the production of melanin, thereby preventing or improving white hair by promoting blackening of the hair, or promoting browning (tanning) of the skin to treat white spot disease or exposure to sunlight (sunlight) It is related with the melanin production promoter which can obtain a sunburn effect even if it does not depend on etc.
毛髪の色を決定するメラニン色素は、毛母細胞上部に存在するメラノサイト(メラニン合成細胞)内のメラノソームでチロシンから生合成され、毛髪に供給される。白髪は、老化やストレス等により、例えば、メラノサイトやメラノソームの減少、あるいはこれら細胞や器官の異常によるチロシナーゼの量や活性の低下、メラノソームの輸送阻害等が関与すると考えられているが、未だその全容は明らかになっていない。 The melanin pigment that determines the color of hair is biosynthesized from tyrosine by melanosomes in melanocytes (melanin synthesizing cells) existing on the upper part of the hair matrix cells and supplied to the hair. Gray hair is thought to be involved in aging, stress, etc., including, for example, a decrease in melanocytes and melanosomes, a decrease in the amount and activity of tyrosinase due to abnormalities in these cells and organs, and inhibition of melanosome transport. Is not clear.
また、白斑とはメラニン色素をつくる細胞であるメラノサイトが消失するか、あるいはその機能が低下してメラニン色素の生成が減少する皮膚疾患である。メラノサイトの消失あるいは機能低下は先天的な場合もあるが後天的に起こることもある。先天的なものには、白斑性母斑、脱色素性色素失調症、部分的白皮症などがあり、一方、後天的なものには尋常性白斑、外傷あるいは炎症後の白斑などが挙げられる。これらの中でも尋常性白斑が最も多く発症するが原因はいずれも不明である。従って治療法としては、日光照射、紫外線照射等の光線療法、ステロイドホルモンの内服、外用等が挙げられるが有効なものがなく、安全性についても問題があるのが現状である。 Vitiligo is a skin disease in which melanocytes, which are cells that produce melanin pigments, disappear or the function of the cells decreases and the production of melanin pigments decreases. Melanocyte loss or loss of function may be congenital or acquired. Congenital ones include vitiligo nevus, depigmentation dyschromia, partial albinism, while acquired ones include common vitiligo, vitiligo after trauma or inflammation. Of these, vulgaris occurs most frequently, but the cause is unknown. Therefore, as a treatment method, there are phototherapy such as sunlight irradiation and ultraviolet irradiation, oral administration of steroid hormones, external use, etc., but there is no effective method, and there is a problem with safety.
白髪防止や白髪改善のような抗白髪作用を有するもの、あるいはメラノサイトを改善し、メラニン産生を促進するための技術としては、植物抽出液を有効成分とする物質が種々提案されている(例えば、特許文献1、特許文献2、特許文献3及び特許文献4を参照)。しかし、これらの抽出物等では、その有効性や安全性の面で満足する結果が得られていないのが現状である。
Various substances having plant extract as an active ingredient have been proposed as a technique for preventing white hair and improving anti-white hair, or as a technique for improving melanocytes and promoting melanin production (for example, (See
また、野菜や果実などの植物に広く存在しているフラボノイドに関しては、ルテオリン、ケルセチン、アピゲニン、ケンフェロール及びアメントフラボンにメラニン産生促進効果があることが報告されている(特許文献5〜7を参照)。
In addition, regarding flavonoids widely present in plants such as vegetables and fruits, it has been reported that luteolin, quercetin, apigenin, kaempferol and amentoflavone have a melanin production promoting effect (
しかしながら、未だ充分満足できる効果を有する物質はなく、また、白髪の発生機序等の複雑さを考えれば、優れたメラニン産生を促進する有効成分が望まれている。 However, there is still no substance having a sufficiently satisfactory effect, and an active ingredient that promotes excellent melanin production is desired in view of complexity such as the mechanism of generation of gray hair.
本発明は、優れたメラニン産生促進効果を有する化合物を有効成分とするメラニン産生促進剤を提供することを目的とする。また本発明は、当該メラニン産生促進剤を有効成分とする白髪予防または改善剤を提供することを目的とする。さらに本発明は、局所的あるいは汎発的に皮膚のメラニン合成能が低下して白色部位が斑点状に発生する白斑病の治療剤として、また太陽光暴露等によらないで日焼け効果が得られる日焼け用化粧料として有用なタンニング促進剤を提供することを目的とする。 An object of this invention is to provide the melanin production promoter which uses the compound which has the outstanding melanin production promotion effect as an active ingredient. Another object of the present invention is to provide an agent for preventing or improving white hair comprising the melanin production promoter as an active ingredient. Furthermore, the present invention provides a tanning effect as a therapeutic agent for white spot disease in which the skin melanin synthesizing ability is locally or generally reduced and the white part is spotted, and is not dependent on sunlight exposure. An object is to provide a tanning accelerator useful as a tanning cosmetic.
本発明者らは、上記課題を解決するために種々検討していたところ、下記一般式(1)で示されるR1に低級アルキル基、特にメチル基を有する化合物又は代謝によりメチル基を有することになる化合物に優れたメラニン産生促進作用があることを見いだし、本発明を完成するに至った。 The inventors of the present invention have made various studies in order to solve the above-mentioned problems. As a result, R 1 represented by the following general formula (1) has a lower alkyl group, particularly a compound having a methyl group, or a methyl group by metabolism. It was found that the resulting compound has an excellent melanin production promoting action, and the present invention has been completed.
すなわち、本発明には下記の態様が含まれる。 That is, the present invention includes the following aspects.
(I)メラニン産生促進剤
(I-1)下記一般式(1)で示される化合物群から選択される少なくとも1種の化合物を有効成分とするメラニン産生促進剤:
(I) Melanin production promoter (I-1 ) Melanin production promoter containing as an active ingredient at least one compound selected from the group of compounds represented by the following general formula (1):
(式中、R1は炭素数1〜4の低級アルキル基または水素原子;R3及びR4は、同一又は異なって、水素原子、水酸基又はアシルオキシ基;R5は炭素数1〜4の低級アルキル基、水素原子又はアシル基;R2は水素原子、水酸基、アシルオキシ基又は下記一般式(2)で示される基: Wherein R 1 is a lower alkyl group having 1 to 4 carbon atoms or a hydrogen atom; R 3 and R 4 are the same or different and are a hydrogen atom, a hydroxyl group or an acyloxy group; R 5 is a lower group having 1 to 4 carbon atoms. An alkyl group, a hydrogen atom or an acyl group; R 2 is a hydrogen atom, a hydroxyl group, an acyloxy group or a group represented by the following general formula (2):
[式中、R6及びR7は、同一又は異なって、炭素数1〜4の低級アルキル基又は水素原子;・は一般式(1)で示される化合物との結合部位を意味する。]
を意味する。但し、R1が水素原子であるとき、R2及びR3は水酸基で、R4及びR5は水素原子である。)
[Wherein, R 6 and R 7 are the same or different and each represents a lower alkyl group having 1 to 4 carbon atoms or a hydrogen atom; · means a bonding site with the compound represented by the general formula (1). ]
Means. However, when R 1 is a hydrogen atom, R 2 and R 3 are hydroxyl groups, and R 4 and R 5 are hydrogen atoms. )
(I-2)一般式(1)においてR1、R5、R6及びR7で示される低級アルキル基はメチル基またはエチル基であり、R5で示されるアシル基及びR2〜R4で示されるアシルオキシ基中のアシル基はアセチル基である、(I-1)に記載するメラニン産生促進剤。 (I-2) In the general formula (1), the lower alkyl group represented by R 1 , R 5 , R 6 and R 7 is a methyl group or an ethyl group, and the acyl group represented by R 5 and R 2 to R 4 The melanin production promoter according to (I-1), wherein the acyl group in the acyloxy group represented by is an acetyl group.
(I-3)一般式(1)で示される化合物が、プラトール(Pratol)、アカセチン(Acacetin)、ケンフェライド(Kaempferide)、フィセチン(Fisetin)、4’-O-メチルフィセチン(4’-O-Methylfisetin)、4’-O-エチルフィセチン(4’-O-Ethylfisetin)、ジオスメチン(Diosmetin)、3,3’,7-O-アセチル-4’-O-メチルフィセチン(3,3’,7-O-Acetyl-4’-O-Methylfisetin)、3’,5,7-O-アセチル-ジオスメチン(3’,5,7-O-Acetyl-Diosmetin)、イソギンクゲチン(Isoginkgetin)及びシアドピチシン(Sciadopitysin)からなる群から選択されるいずれか少なくとも一種である(I-1)または(I-2)に記載するメラニン産生促進剤。 (I-3) The compound represented by the general formula (1) is selected from the group consisting of Pratol, Acacetin, Kaempferide, Fisetin, 4'-O-methylfisetin (4'-O- Methylfisetin), 4'-O-Ethylfisetin (4'-O-Ethylfisetin), Diosmetin, 3,3 ', 7-O-acetyl-4'-O-methylfisetin (3,3', 7-O-Acetyl-4'-O-Methylfisetin), 3 ', 5,7-O-acetyl-diosmethin (3', 5,7-O-Acetyl-Diosmetin), isoginkgetin and Sciadopitysin The melanin production promoter described in (I-1) or (I-2), which is at least one selected from the group consisting of:
(II)白髪予防または改善剤
(II-1)(I-1)乃至(I-3)のいずれかに記載するメラニン産生促進剤を有効成分とする白髪予防または改善剤。
(II) White hair preventing or improving agent (II-1) A white hair preventing or improving agent comprising as an active ingredient the melanin production promoter described in any one of (I-1) to (I-3).
(II-2)頭皮頭髪用組成物または経口組成物である(II-1)に記載する白髪予防または改善剤。 (II-2) The white hair preventing or improving agent according to (II-1), which is a composition for scalp and hair or an oral composition.
(II-3)白髪予防用の化粧料または医薬部外品である(II-1)または(II-2)に記載する白髪予防または改善剤。 (II-3) The white hair prevention or improvement agent described in (II-1) or (II-2), which is a cosmetic or quasi-drug for white hair prevention.
(II-4)白髪予防または治療用の医薬品である(II-1)または(II-2)に記載する白髪予防または改善剤。 (II-4) The agent for preventing or improving white hair described in (II-1) or (II-2), which is a pharmaceutical product for preventing or treating white hair.
(II-5)白髪予防用の食品である(II-1)または(II-2)に記載する白髪予防または改善剤。 (II-5) The agent for preventing or improving white hair described in (II-1) or (II-2), which is a food for preventing white hair.
(III)タンニング促進剤
(III-1)(I-1)乃至(I-3)のいずれかに記載するメラニン産生促進剤を有効成分とするタンニング促進剤。
(III) Tanning accelerator (III-1) A tanning accelerator comprising as an active ingredient the melanin production promoter described in any one of (I-1) to (I-3).
(III-2)皮膚外用組成物または経口組成物である(III-1)に記載するタンニング促進剤。 (III-2) The tanning promoter according to (III-1), which is a composition for external use on the skin or an oral composition.
(III-3)日焼け用の化粧料または医薬部外品である(III-1)または(III-2)に記載するタンニング促進剤。 (III-3) Tanning accelerator according to (III-1) or (III-2), which is a tanning cosmetic or quasi-drug.
(III-4)日焼け用の食品である(III-1)または(III-2)に記載するタンニング促進剤。 (III-4) Tanning accelerator according to (III-1) or (III-2), which is a food for sunburn.
(III-5)白斑病改善または治療用の医薬品、化粧料または医薬部外品である(III-1)または(III-2)に記載するタンニング促進剤。 (III-5) The tanning promoter described in (III-1) or (III-2), which is a pharmaceutical, cosmetic or quasi drug for improving or treating white spot disease.
(III-6)白斑病改善用の食品である(III-1)または(III-2)に記載するタンニング促進剤。 (III-6) The tanning promoter according to (III-1) or (III-2), which is a food for improving white spot disease.
本発明のメラニン生成促進剤は、メラニン産生細胞に作用してメラニン生成を顕著に促進する作用に優れているため、皮膚や毛髪の色調改善や褐色〜黒色化(タンニング化)に有効に使用することができる。このため、本発明のメラニン生成促進剤を有効成分とする頭皮頭髪用組成物または経口組成物は白髪予防または改善剤として、また皮膚外用組成物または経口組成物は、白斑病治療効果や日焼け効果を発揮するタンニング促進剤として提供することができる。 The melanin production promoter of the present invention is effective in improving the color tone of skin and hair and browning to blackening (tanning) because it has an excellent effect of significantly promoting melanin production by acting on melanin producing cells. be able to. Therefore, the scalp scalp hair composition or oral composition containing the melanin production promoter of the present invention as an active ingredient is used as a white hair preventing or improving agent, and the skin external composition or oral composition is used for the treatment of white spot disease or sunburn effect. Can be provided as a tanning accelerator.
(I)メラニン産生促進剤
本発明のメラニン産生促進剤は、下記一般式(1)で示される化合物群から選択される少なくとも1種の化合物(以下、一般式(1)で示される化合物を単に「化合物(1)」ともいう。)を有効成分とすることを特徴とする:
(I) Melanin Production Promoter The melanin production promoter of the present invention is simply at least one compound selected from the group of compounds represented by the following general formula (1) (hereinafter simply referred to as a compound represented by the general formula (1)). (Also referred to as “compound (1)”) as an active ingredient:
ここで、R1は炭素数1〜4の低級アルキル基又は水素原子である。炭素数1〜4の低級アルキル基としては、具体的にはメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、s−ブチル基、及びt−ブチル基を挙げることができる。好ましくは炭素数1〜3の低級アルキル基であり、より好ましくは炭素数1〜2の低級アルキル基であり、特に好ましくはメチル基である。 Here, R 1 is a lower alkyl group having 1 to 4 carbon atoms or a hydrogen atom. Specific examples of the lower alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, and t-butyl group. A lower alkyl group having 1 to 3 carbon atoms is preferable, a lower alkyl group having 1 to 2 carbon atoms is more preferable, and a methyl group is particularly preferable.
R3及びR4は、同一又は異なって、水素原子、水酸基又はアシルオキシ基を意味する。アシルオキシ基として、好ましくはアシル基としてアセチル基を有するアセチルオキシ基を挙げることができる。 R 3 and R 4 are the same or different and each represents a hydrogen atom, a hydroxyl group or an acyloxy group. Preferred examples of the acyloxy group include acetyloxy groups having an acetyl group as the acyl group.
R5は、炭素数1〜4の低級アルキル基、水素原子又はアシル基を意味する。ここでいう炭素数1〜4の低級アルキル基にも上記で列記したアルキル基が包含される。好ましくは炭素数1〜3の低級アルキル基であり、より好ましくは炭素数1〜2の低級アルキル基であり、特に好ましくはメチル基である。アシル基として、好ましくはアセチル基を挙げることができる。 R 5 means a lower alkyl group having 1 to 4 carbon atoms, a hydrogen atom or an acyl group. The alkyl groups listed above are also included in the lower alkyl group having 1 to 4 carbon atoms. A lower alkyl group having 1 to 3 carbon atoms is preferable, a lower alkyl group having 1 to 2 carbon atoms is more preferable, and a methyl group is particularly preferable. The acyl group is preferably an acetyl group.
R2は、水素原子、水酸基、アシルオキシ基又は下記一般式(2)で示される基を意味する。 R 2 means a hydrogen atom, a hydroxyl group, an acyloxy group, or a group represented by the following general formula (2).
[式中、R6及びR7は、同一又は異なって、炭素数1〜4の低級アルキル基又は水素原子;・は一般式(1)で示される化合物との結合部位を意味する。]。 [Wherein, R 6 and R 7 are the same or different and each represents a lower alkyl group having 1 to 4 carbon atoms or a hydrogen atom; · means a bonding site with the compound represented by the general formula (1). ].
なお、R6及びR7で示される「炭素数1〜4の低級アルキル基」にも上記で列記したアルキル基が包含される。好ましくは炭素数1〜3の低級アルキル基であり、より好ましくは炭素数1〜2の低級アルキル基であり、特に好ましくはメチル基である。アシルオキシ基として、好ましくはアシル基としてアセチル基を有するアセチルオキシ基を挙げることができる。 The “lower alkyl group having 1 to 4 carbon atoms” represented by R 6 and R 7 also includes the alkyl groups listed above. A lower alkyl group having 1 to 3 carbon atoms is preferable, a lower alkyl group having 1 to 2 carbon atoms is more preferable, and a methyl group is particularly preferable. Preferred examples of the acyloxy group include acetyloxy groups having an acetyl group as the acyl group.
本発明の化合物(1)には、R1が低級アルキル基、R2及びR5がいずれも水素原子、R3及びR4が、同一又は異なって水素原子又は水酸基であるフラボン及びフラボノールが含まれる。当該化合物(1)としては、具体的にプラトール(Pratol)[R1=CH3、R2=H、R3=H、R4=H、R5=H]、アカセチン(Acacetin)[R1=CH3、R2=H、R3=H、R4=OH、R5=H]、ケンフェライド(Kaempferide)[R1=CH3、R2=H、R3=OH、R4=OH、R5=H]が含まれる。 The compound (1) of the present invention includes flavones and flavonols in which R 1 is a lower alkyl group, R 2 and R 5 are both hydrogen atoms, and R 3 and R 4 are the same or different and are hydrogen atoms or hydroxyl groups. It is. Specific examples of the compound (1) include: Pratol [R 1 = CH 3 , R 2 = H, R 3 = H, R 4 = H, R 5 = H], Acacetin [R 1 = CH 3 , R 2 = H, R 3 = H, R 4 = OH, R 5 = H], Kaempferide [R 1 = CH 3 , R 2 = H, R 3 = OH, R 4 = OH , R 5 = H].
また本発明の化合物(1)には、R1が低級アルキル基、R2が水酸基またはアシルオキシ基、R3が水素原子、水酸基又はアシルオキシ基、R4が水素原子、水酸基またはアシルオキシ基、R5が水素原子またはアシル基であるフラボン及びフラボノールが含まれる。当該化合物(1)としては、具体的にジオスメチン(Diosmetin)[R1=CH3、R2=OH、R3=H、R4=OH、R5=H]、3’,5,7-O-アセチル−ジオスメチン(3’,5,7-O-Acetyl-Diosmetin)[R1=CH3、R2=OAc、R3=H、R4=OAc、R5=Ac]、4’-O-メチルフィセチン(4’-O-Methylfisetin)[R1=CH3、R2=OH、R3=OH、R4=H、R5=H]、4’-O-エチルフィセチン(4’-O-Ethylfisetin)[R1=C2H5、R2=OH、R3=OH、R4=H、R5=H]、3,3’,7-O-アセチル-4’-O-メチルフィセチン(3,3’,7-O-Acetyl-4’-O-Methylfisetin)[R1=CH3、R2=OAc、R3=OAc、R4=H、R5=Ac]が含まれる。また、本発明の化合物(1)には、代謝により、R1に低級アルキル基を有する4’-O-メチルフィセチンや4’-O-エチルフィセチンになる化合物となる化合物も含まれ、かかる化合物としてはフィセチン(Fisetin)[R1=H、R2=OH、R3=OH、R4=H、R5=H]を挙げることができる。
In the compound (1) of the present invention, R 1 is a lower alkyl group, R 2 is a hydroxyl group or an acyloxy group, R 3 is a hydrogen atom, a hydroxyl group or an acyloxy group, R 4 is a hydrogen atom, a hydroxyl group or an acyloxy group, R 5 Flavones and flavonols in which is a hydrogen atom or an acyl group. Specific examples of the compound (1) include diosmetin [R 1 = CH 3 , R 2 = OH, R 3 = H, R 4 = OH, R 5 = H], 3 ', 5,7- O-acetyl-diosmethine (3 ′, 5,7-O-Acetyl-Diosmetin) [R 1 = CH 3 , R 2 = OAc, R 3 = H, R 4 = OAc, R 5 = Ac], 4'- 4′-O-Methylfisetin [R 1 = CH 3 , R 2 = OH, R 3 = OH, R 4 = H, R 5 = H], 4'-O-Methylfisetin ( 4'-O-Ethylfisetin) [R 1 = C 2
さらに、本発明の化合物(1)には、R1が低級アルキル基、R3が水素原子、R4が水酸基、R5が水素原子または低級アルキル基、R2が一般式(2)で示される基であるフラボンが含まれる。当該化合物(1)としては、具体的にイソギンクゲチン(Isoginkgetin)[R1=CH3、R2=一般式(2)(R6=CH3、R7=H)、R3=H、R4=OH、R5=H]、シアドピチシン(Sciadopitysin)[R1=CH3、R2=一般式(2)(R6=CH3、R7=H)、R3=H、R4=OH、R5=CH3]が含まれる。 Further, in the compound (1) of the present invention, R 1 is a lower alkyl group, R 3 is a hydrogen atom, R 4 is a hydroxyl group, R 5 is a hydrogen atom or a lower alkyl group, and R 2 is represented by the general formula (2). Flavones, which are groups to be included. Specific examples of the compound (1) include isoginkgetin [R 1 = CH 3 , R 2 = general formula (2) (R 6 = CH 3 , R 7 = H), R 3 = H, R 4 = OH, R 5 = H], Sciadopitysin [R 1 = CH 3 , R 2 = general formula (2) (R 6 = CH 3 , R 7 = H), R 3 = H, R 4 = OH , R 5 = CH 3 ].
本発明の化合物(1)は、種々の植物から単離、精製された植物由来のものであってもよいし、また公知の方法で合成された合成品であってもよい。かかる植物としては、例えばコウヤマキ(Sciadopitys verticillata)を挙げることができる。例えば、本発明の化合物(1)に含まれるイソギンクゲチン及びシアドピチシンは、実施例に記載するように当該コウヤマキから抽出・精製することができる。本発明の化合物(1)のうち、プラトール、アカセチン、ケンフェライド、フィセチン、ジオスメチンはいずれも商業的に入手することができる。例えば、アカセチンはSIGMA社から、プラトール、ケンフェライド、ジオスメチンはEXTRSYNTHESE S.A. 社から、またフィセチンは和光純薬(株)からそれぞれ入手することができる。 The compound (1) of the present invention may be derived from a plant isolated and purified from various plants, or may be a synthetic product synthesized by a known method. An example of such a plant is Koyamaki (Sciadopitys verticillata). For example, the sea anemone getin and cyanadopiticin contained in the compound (1) of the present invention can be extracted and purified from the cedar tree as described in Examples. Of the compound (1) of the present invention, all of plateol, acacetin, kaempferide, fisetin and diosmethine can be obtained commercially. For example, acacetin can be obtained from SIGMA, platol, kaempferide and diosmethine can be obtained from EXTRSYNTHESE S.A., and fisetin can be obtained from Wako Pure Chemical Industries, Ltd.
ちなみに、プラトールの合成方法は「Dao, Tran Thanh; Chi, Yeon Sook; Kim, Jeongsoo; Kim, Hyun Pyo; Kim, Sanghee; Park, Haeil, Bioorganic & Medicinal Chemistry Letters 14(5), 1165-1167 (2004)」に、アカセチンの合成方法は「Seijas, Julio A.; Vazquez-Tato, M. Pilar; Carballido-Reboredo, Raquel. Journal of Organic Chemistry, 70(7), 2855-2858 (2005)」に、ケンフェライドの合成方法は「Wadher, S. J.; Tapas, A. R.; Yeole, P. G., International Journal of Chemical Sciences, 4(4), 761-766 (2006)」により、公知になっている。また、ジオスメチンは、ジオスメチン配糖体を加水分解することによって調製することができ、かかる方法は「Matsuda, Hisashi; Morikawa, Toshio; Toguchida, Iwao; Yoshikawa, Masayuki. Chemical & Pharmaceutical Bulletin, 50(6), 788-795 (2002)」に記載されている。 By the way, the synthesis method of platol is `` Dao, Tran Thanh; Chi, Yeon Sook; Kim, Jeongsoo; Kim, Hyun Pyo; Kim, Sanghee; Park, Haeil, Bioorganic & Medicinal Chemistry Letters 14 (5), 1165-1167 (2004 ) '', The synthesis method of acacetin is described in `` Seijas, Julio A .; Vazquez-Tato, M. Pilar; Carballido-Reboredo, Raquel. Journal of Organic Chemistry, 70 (7), 2855-2858 (2005) ''. The synthesis method is known from “Wadher, SJ; Tapas, AR; Yeole, PG, International Journal of Chemical Sciences, 4 (4), 761-766 (2006)”. In addition, diosmethine can be prepared by hydrolyzing diosmethine glycoside, such a method is described in “Matsuda, Hisashi; Morikawa, Toshio; Toguchida, Iwao; Yoshikawa, Masayuki. Chemical & Pharmaceutical Bulletin, 50 (6) , 788-795 (2002).
また、4’-O-メチルフィセチンは、「Hosny, Mohammed; Dhar, Kajari; Rosazza, John P. N., Journal of Natural Products 64(4), 462-465 (2001)」に記載する方法で製造することができるほか、4’-O-メチルフィセチン及び4’-O-エチルフィセチンは、フィセチンを原料としてそれぞれ製造例2及び3に記載する方法に従って製造することができる。 4′-O-methylfisetin should be produced by the method described in “Hosny, Mohammed; Dhar, Kajari; Rosazza, John PN, Journal of Natural Products 64 (4), 462-465 (2001)”. In addition, 4′-O-methyl fisetin and 4′-O-ethyl fisetin can be produced according to the methods described in Production Examples 2 and 3, respectively, using fisetin as a raw material.
さらに3’,5,7-O-アセチル−ジオスメチンは、ジオスメチンを原料として製造例4に記載する方法に従って製造することができ、3,3’,7-O-アセチル-4’-O-メチルフィセチンは4’-O-メチルフィセチンを原料として製造例5に記載する方法に従って製造することができる。 Furthermore, 3 ′, 5,7-O-acetyl-diosmethine can be produced according to the method described in Production Example 4 using diosmethine as a raw material, and 3,3 ′, 7-O-acetyl-4′-O-methyl is produced. Fisetin can be produced according to the method described in Production Example 5 using 4′-O-methylfisetin as a raw material.
本発明のメラニン産生促進剤は、一般式(1)に示される化合物の少なくとも1種を含むものであればよく、任意に選択される2種以上を組み合わせて含むものであってもよい。本発明のメラニン産生促進剤中に含まれる化合物(1)の配合割合としては、メラニン産生促進作用を発揮する限り特に制限されず、例えば0.0003重量%(3ppm)〜100重量%の範囲から適宜選択することができる。 The melanin production promoter of this invention should just contain at least 1 sort (s) of the compound shown by General formula (1), and may contain it combining 2 or more types selected arbitrarily. The blending ratio of the compound (1) contained in the melanin production promoter of the present invention is not particularly limited as long as the melanin production promoting action is exhibited, and for example, from the range of 0.0003 wt% (3 ppm) to 100 wt%. It can be selected appropriately.
後述するように、本発明のメラニン産生促進剤は、それ単独で、または頭皮頭髪用の基剤またはその他の成分を配合して、頭皮頭髪用組成物(白髪予防または治療剤:医薬品、医薬部外品、化粧料が含まれる)として使用することができる。また、本発明のメラニン産生促進剤は、それ単独で、または皮膚外用剤の基剤またはその他の成分を配合して、皮膚外用組成物(タンニング促進剤:医薬品、医薬部外品、化粧料が含まれる)として使用することができる。さらに本発明のメラニン産生促進剤は、それ単独で、または経口摂取可能な基剤またはその他の成分を配合して、経口組成物(白髪予防または治療剤、タンニング促進剤:経口医薬品、医薬部外品及び食品が含まれる。但し、好ましくは経口医薬品である)として使用することができる。 As will be described later, the melanin production promoter of the present invention is a composition for scalp and hair (a white hair preventive or therapeutic agent: pharmaceuticals, pharmaceuticals) alone or in combination with a base for scalp and hair or other ingredients. It can be used as external products and cosmetics). In addition, the melanin production promoter of the present invention can be used alone or in combination with a base for skin external preparations or other components to prepare a composition for external use on skin (tanning promoter: pharmaceuticals, quasi drugs, cosmetics). Included). Furthermore, the melanin production promoter of the present invention is an oral composition (white hair prevention or treatment agent, tanning promoter: oral medicine, quasi-drug), alone or in combination with an ingestible base or other ingredients. Products and foods, although preferably oral drugs).
(II)白髪予防または改善剤
本発明の白髪予防または改善剤は、前述する本発明のメラニン産生促進剤を有効成分とするものである。当該白髪予防または治療剤は、メラニン産生促進剤に含まれる化合物(1)のメラニン産生促進作用に基づいて、毛髪の黒色化を促進して、白髪を予防したり白髪を改善することができる。
(II) Preventing or improving white hair The preventive or improving agent for white hair of the present invention comprises the above-described melanin production promoter of the present invention as an active ingredient. The agent for preventing or treating gray hair can promote the blackening of hair based on the melanin production promoting action of the compound (1) contained in the melanin production promoter, thereby preventing or improving white hair.
本発明の白髪予防または改善剤に配合するメラニン産生促進剤の配合割合としては、白髪予防または改善作用を発揮する限り特に制限されないが、有効成分である化合物(1)の量に換算して、通常0.0003重量%(3ppm)〜80重量%程度を挙げることができる。好ましくは0.0003〜70重量%、さらに好ましくは0.003〜50重量%である。 The blending ratio of the melanin production promoter to be blended with the gray hair preventing or improving agent of the present invention is not particularly limited as long as it exhibits the white hair preventing or improving action, but in terms of the amount of compound (1) as an active ingredient, Usually, about 0.0003 weight% (3 ppm)-about 80 weight% can be mentioned. Preferably it is 0.0003 to 70 weight%, More preferably, it is 0.003 to 50 weight%.
本発明の白髪予防または改善剤は、頭皮頭髪に適用される頭皮頭髪用組成物(外用医薬品、医薬部外品、化粧料が含まれる)として調製及び供給することができるし、また経口的に摂取して用いられる経口組成物(経口医薬品、医薬部外品、食品が含まれる)として調製及び供給することもできる。 The agent for preventing or improving gray hair of the present invention can be prepared and supplied as a composition for scalp and hair (including external medicines, quasi-drugs, and cosmetics) applied to scalp and hair, orally. It can also be prepared and supplied as an oral composition (including oral drugs, quasi-drugs, and foods) to be taken and used.
頭皮頭髪用組成物の調製には、医薬品、医薬部外品または化粧料などの用途に応じて、各分野で許容される希釈剤(溶剤を含む)、界面活性剤(アニオン性界面活性剤、非イオン性界面活性剤、カチオン性界面活性剤、両性界面活性剤)、油脂剤、保湿剤、増粘剤、皮膜形成剤、防腐剤、酸化防止剤、金属イオン封鎖剤、紫外線防止剤、pH調整剤、その他の活性物質、色剤、香料等を、目的とする剤型に応じて適宜使用することができる。 For the preparation of the scalp and hair composition, depending on the use of pharmaceuticals, quasi drugs or cosmetics, diluents (including solvents) and surfactants (anionic surfactants, Nonionic surfactants, cationic surfactants, amphoteric surfactants), fats and oils, moisturizers, thickeners, film forming agents, preservatives, antioxidants, sequestering agents, UV inhibitors, pH Conditioners, other active substances, colorants, fragrances and the like can be appropriately used depending on the intended dosage form.
その他の活性物質としては、塩化カプロニウム、センブリエキス、アセチルコリン誘導体等の血管拡張剤、セリン、メチオニン等のアミノ酸類、ビタミンB6、ビタミンEおよびその誘導体、ビオチン等のビタミン類、パントテン酸およびその誘導体、グリチルリチン酸およびその誘導体、ニコチン酸ベンジルなどのニコチン酸エステル類、セファランチン等の皮膚機能亢進剤およびエストラジオール等の女性ホルモン剤等、ならびにこれらの混合物が挙げられる。さらに、例えばヒノキチオール、ヘキサクロロフェン、ベンザルコニウムクロリド、セチルピリジニウムクロリド、ウンデシレン酸、トリクロロカルバニリドおよびビチオノール等の抗菌剤、メントール等の清涼剤、サリチル酸、亜鉛およびその誘導体、乳酸およびそのアルキルエステル等の活性物質、クエン酸等の有機酸類、アルギニン等のアミノ酸類も、本発明の組成物に添加することができる。 Other active substances include vasodilators such as capronium chloride, assembly extract, acetylcholine derivatives, amino acids such as serine and methionine, vitamin B 6 , vitamin E and its derivatives, vitamins such as biotin, pantothenic acid and its derivatives Glycyrrhizic acid and derivatives thereof, nicotinic acid esters such as benzyl nicotinate, skin function enhancing agents such as cephalanthin and female hormone agents such as estradiol, and mixtures thereof. Furthermore, for example, antibacterial agents such as hinokitiol, hexachlorophene, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarbanilide and bithionol, refreshing agents such as menthol, salicylic acid, zinc and derivatives thereof, lactic acid and alkyl esters thereof, etc. Active substances, organic acids such as citric acid, and amino acids such as arginine can also be added to the composition of the present invention.
頭皮頭髪用組成物の形態は、液状、乳液、軟膏、クリーム、フォーム及びゲルなどの頭皮または頭髪に適用できる性状のものであればいずれでもよく、一般的にヘアローション、ヘアセットローション、ヘアクリーム、ヘアジェル、ヘアフォーム、ヘアシャンプー、ヘアリンス、ヘアトニック、ヘアリキッド、スカルプトリートメント、エアゾールスプレー、等と称される製品形態をとることができる。 The composition for scalp and hair may be any form that can be applied to the scalp or hair, such as liquid, emulsion, ointment, cream, foam and gel, and is generally a hair lotion, hair set lotion, hair cream. Product forms called hair gels, hair foams, hair shampoos, hair rinses, hair tonics, hair liquids, scalp treatments, aerosol sprays, and the like.
これらの製品形態を有する本発明の白髪予防または改善剤は、有効成分である化合物(1)の用量が、1日1回当りとして1.5〜120mg/体重60kg、好ましくは3〜90mg/体重60kgとなるように頭皮または頭髪に施用することができる。 The agent for preventing or improving gray hair according to the present invention having these product forms has a dose of compound (1) as an active ingredient of 1.5 to 120 mg / body weight 60 kg, preferably 3 to 90 mg / body weight per day. It can be applied to the scalp or hair so as to be 60 kg.
経口組成物の調製には、経口医薬品または食品などの用途に応じて、各分野で許容される賦形剤、結合剤、湿潤剤、増粘剤、滑沢剤、酸化防止剤、その他の活性物質、色剤、香料等を、目的とする剤型に応じて適宜使用することができる。 For the preparation of oral compositions, depending on the use such as oral pharmaceuticals or foods, excipients, binders, wetting agents, thickeners, lubricants, antioxidants and other activities that are acceptable in each field Substances, colorants, fragrances and the like can be appropriately used depending on the intended dosage form.
経口組成物の形態は、丸剤、顆粒剤、カプセル剤、トローチ剤、液状(ドリンクを含む)、シロップ状、クリーム状などの経口的に摂取できる形態であればいずれでもよい。食品としては、飲料や飴やガムなどの形状に調製することもできるが、丸剤、顆粒剤、カプセル剤、トローチ剤、または液剤などの製剤形態を有するサプリメントとして調製することもできる。 The oral composition may be in any form that can be taken orally, such as pills, granules, capsules, troches, liquids (including drinks), syrups, and creams. As food, it can be prepared in the form of beverages, strawberries, gums, etc., but it can also be prepared as a supplement having a pharmaceutical form such as pills, granules, capsules, troches, or liquids.
これらの製品形態を有する本発明の白髪予防または改善剤は、有効成分である化合物(1)の用量が、1日1回当り1.5〜120mg/体重60kg、好ましくは3〜90mg/体重60kgとなるように経口摂取することができる。 In the agent for preventing or improving gray hair according to the present invention having these product forms, the dose of compound (1) as the active ingredient is 1.5 to 120 mg / 60 kg body weight, preferably 3 to 90 mg / 60 kg body weight per day. Can be taken orally.
(III)タンニング促進剤
本発明のタンニング促進剤は、前述する本発明のメラニン産生促進剤を有効成分とするものである。当該タンニング促進剤は、メラニン産生促進剤に含まれる化合物(1)のメラニン産生促進作用に基づいて、皮膚の褐色化を促進して、白斑病を治療若しくは改善したり、また効率的に日焼け効果を発揮することができる。
(III) Tanning accelerator The tanning accelerator of the present invention comprises the above-described melanin production promoter of the present invention as an active ingredient. The tanning promoter promotes browning of the skin based on the melanin production promoting action of the compound (1) contained in the melanin production promoter, treats or improves white spot disease, and efficiently tans. Can be demonstrated.
本発明のタンニング促進剤に配合するメラニン産生促進剤の配合割合としては、タンニング促進作用(皮膚の褐色化を促進する作用)を発揮する限り特に制限されないが、有効成分である化合物(1)の量に換算して、通常0.0003重量%(3ppm)〜80重量%程度を挙げることができる。好ましくは0.0003〜70重量%、さらに好ましくは0.003〜50重量%である。 The blending ratio of the melanin production promoter to be blended with the tanning promoter of the present invention is not particularly limited as long as it exhibits a tanning promoting action (an action to promote browning of the skin), but the compound (1) which is an active ingredient In terms of the amount, usually about 0.0003 wt% (3 ppm) to about 80 wt% can be mentioned. Preferably it is 0.0003 to 70 weight%, More preferably, it is 0.003 to 50 weight%.
本発明のタンニング促進剤は、皮膚に適用される皮膚外用組成物(外用医薬品、医薬部外品、化粧料が含まれる)として調製及び供給することができるし、また経口的に摂取して用いられる経口組成物(経口医薬品、医薬部外品、食品が含まれる)として調製及び供給することもできる。 The tanning accelerator of the present invention can be prepared and supplied as a composition for external use on skin (including external medicines, quasi drugs, and cosmetics), and can be taken orally. And can be prepared and supplied as an oral composition (including oral drugs, quasi drugs, and foods).
皮膚外用組成物の調製には、外用医薬品、医薬部外品または化粧料などの用途に応じて、各分野で許容される希釈剤、界面活性剤(アニオン性界面活性剤、非イオン性界面活性剤、カチオン性界面活性剤、両性界面活性剤)、油脂剤、保湿剤、増粘剤、溶剤、収レン剤、防腐剤、酸化防止剤、金属イオン封鎖剤、紫外線防止剤、紫外線散乱剤、その他の活性物質、色剤、香料等を、目的とする剤型に応じて適宜使用することができる。具体的な成分については、制限されないが、(II)において説明したものを同様に用いることができる。なお、収レン剤及び紫外線散乱剤についても、特に制限されず、通常、皮膚外用組成物に使用される慣用成分を用いることができる。 For the preparation of a composition for external application to the skin, depending on the application such as topical pharmaceuticals, quasi-drugs or cosmetics, diluents, surfactants (anionic surfactants, nonionic surfactants) that are acceptable in each field Agents, cationic surfactants, amphoteric surfactants), fats and oils, moisturizers, thickeners, solvents, encapsulating agents, preservatives, antioxidants, sequestering agents, UV inhibitors, UV scattering agents, Other active substances, colorants, fragrances and the like can be appropriately used depending on the intended dosage form. Although it does not restrict | limit about a specific component, What was demonstrated in (II) can be used similarly. The collecting agent and the ultraviolet light scattering agent are not particularly limited, and commonly used components that are usually used in an external composition for skin can be used.
皮膚外用組成物の形態は、液状、乳液、軟膏、クリーム、フォーム、貼付剤及びゲルなど、皮膚に外用適用できる性状のものであればいずれでもよく、一般的に皮膚用ローション、皮膚用乳液、皮膚用ゲル剤、皮膚用軟膏、化粧水、メイクアップクリーム、乳液状ファンデーション、エアゾールスプレー、スプレーフォーム等と称される製品形態をとることができる。 The form of the external composition for skin may be any form such as liquid, emulsion, ointment, cream, foam, patch and gel, as long as it has a property that can be applied externally to the skin. Generally, a lotion for skin, an emulsion for skin, Product forms called skin gels, skin ointments, lotions, makeup creams, emulsion foundations, aerosol sprays, spray foams and the like can be used.
これらの製品形態を有する本発明のタンニング促進剤は、有効成分である化合物(1)の用量が、1日1回当り1.5〜120mg/体重60kg、好ましくは3〜90mg/体重60kgとなるように頭皮または頭髪に施用することができる。 In the tanning promoter of the present invention having these product forms, the dose of the active ingredient compound (1) is 1.5 to 120 mg / 60 kg body weight, preferably 3 to 90 mg / 60 kg body weight per day. Can be applied to scalp or hair.
経口組成物の調製には、経口医薬品または食品などの用途に応じて、各分野で許容される賦形剤、結合剤、滑沢剤、崩壊剤、湿潤剤、増粘剤、香味剤、安定剤、吸収助剤、酸化防止剤、その他の活性物質、色剤、香料等を、目的とする剤型に応じて適宜使用することができる。特に制限されないが、賦形剤としては、例えば、トウモロコシデンプン、バレイショデンプン、砂糖、ショ糖、乳糖、マンニトール、ソルビトール、エリスリトール、タルク、カオリン、硫酸カルシウム、炭酸マグネシウム、炭酸カルシウム、軽質無水ケイ酸、システイン、結晶セルロースなどを挙げることができる。また結合剤としては、例えば、デンプン、α−デンプン、ショ糖、デキストリン、ヒドロキシプロピルスターチ、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ゼラチン、結晶セルロース、エチルセルロース、セルロース高分子、アクリル酸系高分子、アラビアゴム、ポリビニルアルコール、マクロゴール、プルランなどを挙げることができる。また、滑沢剤としては、例えば、ロウ類、水素添加植物油、ショ糖脂肪酸エステル、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸アルミニウム、ポリエチレングリコール、硬化ヒマシ油、タルクなどを挙げることができる。また崩壊剤としては、例えば、デンプン、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロース、低置換度ヒドロキシメチルセルロース、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルメロースカルシウム、架橋化ポリビニルピロリドンなどを挙げることができる。 For the preparation of oral compositions, depending on the application such as oral pharmaceuticals or foods, excipients, binders, lubricants, disintegrants, wetting agents, thickeners, flavoring agents, stable agents that are acceptable in each field Agents, absorption aids, antioxidants, other active substances, colorants, fragrances and the like can be appropriately used depending on the intended dosage form. Although not particularly limited, examples of the excipient include corn starch, potato starch, sugar, sucrose, lactose, mannitol, sorbitol, erythritol, talc, kaolin, calcium sulfate, magnesium carbonate, calcium carbonate, light anhydrous silicic acid, Examples include cysteine and crystalline cellulose. Examples of the binder include starch, α-starch, sucrose, dextrin, hydroxypropyl starch, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, crystalline cellulose, ethylcellulose, Examples thereof include cellulose polymers, acrylic acid polymers, gum arabic, polyvinyl alcohol, macrogol, and pullulan. Examples of the lubricant include waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol, hydrogenated castor oil, and talc. Examples of the disintegrant include starch, sodium carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose, low-substituted hydroxymethylcellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, and crosslinked polyvinylpyrrolidone. be able to.
その他、湿潤剤、増粘剤、香味剤、安定剤、吸収助剤、酸化防止剤、その他の活性物質、色剤、香料等についても、特に制限されず、通常、医薬品や食品などの経口組成物に使用される慣用成分を用いることができる。 In addition, wetting agents, thickeners, flavoring agents, stabilizers, absorption aids, antioxidants, other active substances, coloring agents, fragrances, etc. are not particularly limited, and are usually oral compositions such as pharmaceuticals and foods. Conventional components used in products can be used.
経口組成物の形態は、丸剤、顆粒剤、カプセル剤、トローチ剤、液状(ドリンクを含む)、シロップ状、クリーム状などの経口的に摂取できる形態であればいずれでもよい。食品としては、飲料や飴やガムなどの形状に調製することもできるが、丸剤、顆粒剤、カプセル剤、トローチ剤、または液剤などの製剤形態を有するサプリメントとして調製することもできる。 The oral composition may be in any form that can be taken orally, such as pills, granules, capsules, troches, liquids (including drinks), syrups, and creams. As food, it can be prepared in the form of beverages, strawberries, gums, etc., but it can also be prepared as a supplement having a pharmaceutical form such as pills, granules, capsules, troches, or liquids.
これらの製品形態を有する本発明のタンニング促進剤は、有効成分である化合物(1)の用量が、1日1回当り1.5〜120mg/体重60kg、好ましくは3〜90mg/体重60kgとなるように経口摂取することができる。 In the tanning promoter of the present invention having these product forms, the dose of the active ingredient compound (1) is 1.5 to 120 mg / 60 kg body weight, preferably 3 to 90 mg / 60 kg body weight per day. Can be taken orally.
以下、実験例及び処方例を挙げて、本発明をより詳細に説明する。但し、本発明の範囲は、これらによって何ら限定されるものでない。 Hereinafter, the present invention will be described in more detail with reference to experimental examples and formulation examples. However, the scope of the present invention is not limited by these.
製造例1 イソギンクゲチンとシアドピチシンの抽出及び精製
乾燥コウヤマキ葉(926g)を細かく切り刻み乳鉢ですりつぶし粉末とした。その粉末を3000ml容三角フラスコ2つに、それぞれ450gずつ入れ、室温中48時間メタノール(3L)で3回抽出した。得られたメタノール抽出液に水を加え、90容量% メタノールにして、90%メタノール液:Hexane=7:1で4回分液した。90%メタノール層は水と沈殿物の混合液(水層)になるまで、減圧濃縮し、この混合液を酢酸エチルで3回分液した(H2O: 酢酸エチル=1:1)。分液後、水層、不溶物、及び酢酸エチル層を濃縮し重量を量った(水層:約111.1g、不溶物:約62.2g、酢酸エチル層:約54.5g)。酢酸エチル層(約54.5g)のうち29.7gをSiO2column chromatography(メタノール: CHCl3=95:5)を用いて分離し、各フラクションを薄層クロマト(TLC)で、確認し、Sciadopitysinを含むフラクション(Sciadopitysin含有フラクション)をまとめて減圧濃縮しSciadopitysin含有フラクションの11.9gを得た。このフラクションのうち7.8gを、SiO2分取薄層クロマトグラフィー(PLC; 展開溶媒メタノール:CHCl3:トルエン=95:5:1)で分離しSciadopitysin 2.2gを得た。このうち0.27gを酢酸エチルに溶かし、そこに、Hexaneを加えることで、沈殿を生じさせる結晶化を行い、黄色結晶0.2gを得た。
Production Example 1 Extraction and purification of sea anemone getin and cyanadopiticin Dry Koyamaki leaves (926 g) were finely chopped into a powder in a mortar. 450 g each of the powder was placed in two 3000 ml Erlenmeyer flasks and extracted three times with methanol (3 L) for 48 hours at room temperature. Water was added to the obtained methanol extract to make 90 volume% methanol, and the mixture was separated 4 times with 90% methanol solution: Hexane = 7: 1. The 90% methanol layer was concentrated under reduced pressure until it became a mixture of water and precipitate (aqueous layer), and the mixture was partitioned three times with ethyl acetate (H 2 O: ethyl acetate = 1: 1). After separation, the aqueous layer, insoluble matter, and ethyl acetate layer were concentrated and weighed (aqueous layer: about 111.1 g, insoluble matter: about 62.2 g, ethyl acetate layer: about 54.5 g). 29.7g of the ethyl acetate layer (about 54.5g) was separated using SiO 2 column chromatography (methanol: CHCl 3 = 95: 5), and each fraction was confirmed by thin layer chromatography (TLC) and contained Sciadopitysin. Fractions (Sciadopitysin-containing fraction) were combined and concentrated under reduced pressure to obtain 11.9 g of a Sciadopitysin-containing fraction. 7.8 g of this fraction was separated by SiO 2 preparative thin layer chromatography (PLC; developing solvent methanol: CHCl 3 : toluene = 95: 5: 1) to obtain 2.2 g of Sciadopitysin. Of this, 0.27 g was dissolved in ethyl acetate, and hexane was added thereto to perform crystallization to cause precipitation, thereby obtaining 0.2 g of yellow crystals.
かかる黄色結晶を、下記条件のLC-MSに供し、イソギンクゲチン及びシアドピチシンに相当する画分をそれぞれ単離し、得られた各化合物を1H-NMR (400 MHz, DMSO-d6, 25 ℃)で分析し、構造確認した。 The yellow crystals are subjected to LC-MS under the following conditions, and the fractions corresponding to isoginkgetin and cyanadopiticin are isolated, and each obtained compound is analyzed by 1 H-NMR (400 MHz, DMSO-d6, 25 ° C.). And the structure was confirmed.
<LC-MS条件>
Column: Inertsil ODS-3 (2.1 x 50 mm),
Eluant: 0.1% HCOOH CH3CN/H2O=30/70-80/20 (60 min),
Detection: UV 254 nm,
Temperature: 40 ℃。
<LC-MS conditions>
Column: Inertsil ODS-3 (2.1 x 50 mm),
Eluant: 0.1% HCOOH CH 3 CN / H 2 O = 30 / 70-80 / 20 (60 min),
Detection: UV 254 nm,
Temperature: 40 ° C.
製造例2 4’-O-メチルフィセチンの製造Production Example 2 Production of 4'-O-methylfisetin
Fisetin (122.4 mg, 4.3×10-4 mol)をN,N-dimethylformamide (10 mL)に溶解し、K2CO3 (71.7 mg, 5.1×10-4 mol)とMeI (26.4μL, 4.3×10-4)を加え、室温で一晩撹拌しながら反応させた。反応液を減圧濃縮後、酢酸エチルに溶解し、その酢酸エチル相を飽和食塩水で洗浄した。酢酸エチル相をMgSO4で乾燥させ、減圧溜去し粗生成物を得た。これを液体クロマトグラフィー(JAIGEL GS-320、展開溶媒:MeOH) および薄層クロマトグラフィー (PLC plate 20×20 cmsilica gel 60 F254, 1mm, 展開溶媒 : CHCl3 /MeOH)で精製後、凍結乾燥し、黄色粉末状の4’-O-メチルフィセチンを得た(5.9 mg, 5.3 %)。
Fisetin (122.4 mg, 4.3 × 10 -4 mol) is dissolved in N, N-dimethylformamide (10 mL), and K 2 CO 3 (71.7 mg, 5.1 × 10 -4 mol) and MeI (26.4 μL, 4.3 × 10 -4 ) was added and allowed to react at room temperature with stirring overnight. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and the ethyl acetate phase was washed with saturated brine. The ethyl acetate phase was dried over MgSO 4 and distilled under reduced pressure to obtain a crude product. This was purified by liquid chromatography (JAIGEL GS-320, developing solvent: MeOH) and thin layer chromatography (
製造例3 4’-O-エチルフィセチンの製造Production Example 3 Production of 4'-O-ethylfisetin
Fisetin (93.5 mg, 3.3×10-4 mol)をN,N-dimethylformamide (7 mL)に溶解し、K2CO3 (55.8 mg, 4.0×10-4 mol)とCH3CH2I (26.0μL, 3.3×10-4)を加え、室温で一晩撹拌しながら反応させた。反応液を減圧濃縮後、酢酸エチルに溶解し、その酢酸エチル相を飽和食塩水で洗浄した。酢酸エチル相をMgSO4で乾燥させ、減圧溜去し粗生成物を得た。これを液体クロマトグラフィー(JAIGEL GS-320、展開溶媒:MeOH)で精製後、凍結乾燥し、黄色粉末状の4’-O-Ethylfisetinを得た(4.6 mg, 4.5 %)。 Fisetin (93.5 mg, 3.3 × 10 -4 mol) is dissolved in N, N-dimethylformamide (7 mL) and K 2 CO 3 (55.8 mg, 4.0 × 10 -4 mol) and CH 3 CH 2 I (26.0 μL) , 3.3 × 10 −4 ) was added and the reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and the ethyl acetate phase was washed with saturated brine. The ethyl acetate phase was dried over MgSO 4 and distilled under reduced pressure to obtain a crude product. This was purified by liquid chromatography (JAIGEL GS-320, developing solvent: MeOH) and then lyophilized to obtain 4′-O-Ethylfisetin in the form of a yellow powder (4.6 mg, 4.5%).
製造例4 3’,5,7-O-アセチルジオスメチンの製造Production Example 4 Production of 3 ', 5,7-O-acetyldiosmethine
Diosmetin (11.0 mg, 3.7×10-5 mol)をN,N-dimethylformamide (500μL)に溶解し、無水酢酸(500μL, 5.3×10-3 mol)と数滴のトリエチルアミンを加え、室温で1時間撹拌しながら反応させた。反応液を減圧濃縮後、酢酸エチルに溶解し、その酢酸エチル相を飽和食塩水で洗浄した。酢酸エチル相をMgSO4で乾燥させ、減圧溜去した。これを凍結乾燥し、黄色粉末状のDiosmetinのアセチル化体(3’,5,7-O-アセチルジオスメチン)を得た(9.0 mg, 57.7 %)。 Dissolve Diosmetin (11.0 mg, 3.7 × 10 -5 mol) in N, N-dimethylformamide (500 μL), add acetic anhydride (500 μL, 5.3 × 10 -3 mol) and a few drops of triethylamine, and stir at room temperature for 1 hour While reacting. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and the ethyl acetate phase was washed with saturated brine. The ethyl acetate phase was dried over MgSO 4 and evaporated in vacuo. This was freeze-dried to obtain an acetylated form (3 ′, 5,7-O-acetyldiosmethine) of Diosmetin (9.0 mg, 57.7%) as a yellow powder.
製造例5 3,3’,7-O-アセチル-4’-O-メチルフィセチンの製造Production Example 5 Production of 3,3 ', 7-O-acetyl-4'-O-methylfisetin
4’-O-Methylfisetin (6.3 mg, 2.1×10-5 mol)に無水酢酸(500μL, 5.3×10-3mol)と数滴のトリエチルアミンを加え、室温で3時間反応させた。反応液を酢酸エチルに溶解し、その酢酸エチル相を飽和食塩水で洗浄した。窒素気流下で酢酸エチル相を溜去し、黄色油状の4’-O-Methylfisetinのアセチル化体を得た(2.5 mg, 27.9 %)。 Acetic anhydride (500 μL, 5.3 × 10 −3 mol) and a few drops of triethylamine were added to 4′-O-Methylfisetin (6.3 mg, 2.1 × 10 −5 mol) and reacted at room temperature for 3 hours. The reaction solution was dissolved in ethyl acetate, and the ethyl acetate phase was washed with saturated brine. The ethyl acetate phase was distilled off under a stream of nitrogen to obtain a yellow oily 4'-O-Methylfisetin acetylated product (2.5 mg, 27.9%).
実験例1 メラニン産生促進効果の評価
(1)試験方法
下記に示す各種フラボノイド類(表1参照)を用いて、メラニン産生促進効果を評価した。具体的には、マウス由来のB16メラノーマ細胞(入手先:JCRB0202:B16メラノーマ:医薬基盤研究所)を各種フラボノイドを含む培地で培養した後、細胞中のメラニン量(pg/細胞)を測定し、各種フラボノイド類のメラニン産生促進作用を比較した。なお、コントロール試験として、各種フラボノイドの添加に代えて、当該フラボノイドを溶解する溶媒として用いたDMSO液を添加したものについても同様に、B16メラノーマ細胞に含まれるメラニンの量(pg/細胞)を測定した。
Experimental Example 1 Evaluation of melanin production promoting effect
(1) Test method The melanin production promoting effect was evaluated using various flavonoids shown below (see Table 1). Specifically, after culturing mouse-derived B16 melanoma cells (source: JCRB0202: B16 melanoma: Institute of Pharmaceutical Sciences) in a medium containing various flavonoids, the amount of melanin (pg / cell) in the cells was measured, The melanin production promoting action of various flavonoids was compared. As a control test, the amount of melanin contained in B16 melanoma cells (pg / cell) was also measured in the same manner in the case of adding DMSO solution used as a solvent for dissolving the flavonoids instead of adding various flavonoids. did.
(1-1)被験化合物
<本発明対象化合物>
プラトール(EXTRSYNTHESE S.A. 社から入手)
アカセチン(SIGMA社から入手)
ケンフェライド(EXTRSYNTHESE S.A. 社から入手)
ジオスメチン(EXTRSYNTHESE S.A. 社から入手)
3’,5,7-O-アセチル-ジオスメチン(製造例4参照)
フィセチン(和光純薬工業(株)から入手)
4’-O-メチルフィセチン(製造例2参照)
4’-O-エチルフィセチン(製造例3参照)
3,3’,7-O-アセチル-4’-O-メチルフィセチン(製造例5参照)
イソギンクゲチン(製造例1参照)
シアドピチシン(製造例1参照)。
(1-1) Test compound <target compound of the present invention>
Plateol (obtained from EXTRSYNTHESE SA)
Acacetin (obtained from SIGMA)
Kenferide (obtained from EXTRSYNTHESE SA)
Diosmethine (available from EXTRSYNTHESE SA)
3 ', 5,7-O-acetyl-diosmethine (see Production Example 4)
Fisetin (obtained from Wako Pure Chemical Industries, Ltd.)
4'-O-methylfisetin (see Production Example 2)
4'-O-ethyl fisetin (see Production Example 3)
3,3 ', 7-O-acetyl-4'-O-methylfisetin (see Production Example 5)
Sea anemone gettin (see Production Example 1)
Siadoticin (see Production Example 1).
<比較化合物>
ケルセチン(東京化成工業(株)から入手)
イソラムネチン(EXTRSYNTHESE S.A. 社から入手)
ルテオリン(EXTRSYNTHESE S.A. 社から入手)
アピゲニン(EXTRSYNTHESE S.A. 社から入手)
ケンフェロール(EXTRSYNTHESE S.A. 社から入手)
アメントフラボン(SIGMA社から入手)。
<Comparative compound>
Quercetin (obtained from Tokyo Chemical Industry Co., Ltd.)
Isoramnetin (obtained from EXTRSYNTHESE SA)
Luteolin (obtained from EXTRSYNTHESE SA)
Apigenin (obtained from EXTRSYNTHESE SA)
Kaempferol (obtained from EXTRSYNTHESE SA)
Amentoflavone (obtained from SIGMA).
(1-2)細胞の培養方法
培地は、10%(v/v)牛胎児血清を含むダルベッコ改変イーグル培地/高グルコースを使用した。12ウェルマイクロプレートの各ウェル1mlの培地に、B16メラノーマ細胞を1×104個/ウェルずつ播種した。B16メラノーマ細胞を37℃、5%CO2条件下で3日間培養した後、培地を、10μM濃度の各種フラボノイド(アメントフラボン、イソギンクゲチン、シアドピチシンは5μM)を含有する培地に交換し、さらに上記同条件で4日間培養を行った。
(1-2) Cell culture method Dulbecco's modified Eagle medium / high glucose containing 10% (v / v) fetal calf serum was used as the medium. B16 melanoma cells were seeded at 1 × 10 4 cells / well in 1 ml of each well of a 12-well microplate. After culturing B16 melanoma cells under conditions of 37 ° C. and 5% CO 2 for 3 days, the medium was replaced with a medium containing various flavonoids having a concentration of 10 μM (ammentoflavone, isogingetgetin, and siadopiticin were 5 μM), and the same as above. Culture was performed for 4 days under the conditions.
(1-3)細胞中のメラニンの定量
上記のように培養した細胞を、ダルベッコのりん酸緩衝液で洗浄し、0.02%EDTAを含む0.25%トリプシン溶液を加え剥離した。剥離した細胞に適量の培地を加え、細胞浮遊液を作り、血球計算盤にて細胞数を測定し、1ウェルあたりの細胞数を算出した。
(1-3) Quantification of Melanin in Cells The cells cultured as described above were washed with Dulbecco's phosphate buffer, and detached by adding a 0.25% trypsin solution containing 0.02% EDTA. An appropriate amount of medium was added to the detached cells to prepare a cell suspension, the number of cells was measured with a hemocytometer, and the number of cells per well was calculated.
細胞数を測定した後、1000rpmで10分間遠心分離し、得られた細胞ペレットをダルベッコのりん酸緩衝液で洗浄した。さらに遠心分離により細胞ペレットを回収し、風乾させた後、1NのNaOH水溶液を200μl加え、加温および超音波処理により細胞とメラニンを溶解した。その後、得られた細胞溶解液を96ウェルマイクロプレートに移しマイクロプレートリーダーにて吸光度(415nm)を測定し、既知量の合成メラニン(Melanin;シグマ アルドリッチ ジャパン社製)により作成した検量線を用いて、計算により1細胞に含まれるメラニン量(pg/細胞)を決定した。 After measuring the number of cells, it was centrifuged at 1000 rpm for 10 minutes, and the resulting cell pellet was washed with Dulbecco's phosphate buffer. Further, the cell pellet was collected by centrifugation and air-dried, and then 200 μl of 1N NaOH aqueous solution was added, and the cells and melanin were dissolved by heating and sonication. Thereafter, the obtained cell lysate was transferred to a 96-well microplate, the absorbance (415 nm) was measured with a microplate reader, and a calibration curve prepared with a known amount of synthetic melanin (Melanin; manufactured by Sigma Aldrich Japan) was used. The amount of melanin contained in one cell (pg / cell) was determined by calculation.
また、遠心分離後の細胞ペレットの褐色〜黒色度の程度を目視で観察し、これからメラニンの産生量を以下の基準で評価した。 Moreover, the degree of brown to blackness of the cell pellet after centrifugation was visually observed, and the production amount of melanin was evaluated based on the following criteria.
+++:メラニンの産生量が非常に多い
++:メラニンの産生量が多い
+:メラニンの産生量が少ない
−:メラニンの産生がほとんどない。
++: Very high melanin production ++: High melanin production +: Low melanin production-: Little melanin production
(2)結果
各種フラボノイドで処理した細胞のメラニン含量(pg/細胞)と、黒色度を目視判定した結果を表1及び図1に示す。
(2) Results Table 1 and FIG. 1 show the results of visual determination of melanin content (pg / cell) and blackness of cells treated with various flavonoids.
アカセチンとアピゲニンは、一般式(1)で示す化合物の置換基のうち、R1のみが異なり(アカセチン:CH3、アピゲニン:H)、他の置換基は共に同一の置換基(R2=H、R3=H、R4=OH、R5=H)を有する化合物である。表1及び図1に示すように、アカセチンはアピゲニンよりも2倍以上も高いメラニン産生量を示した。 Acacetin and apigenin differ only in R 1 among the substituents of the compound represented by the general formula (1) (acacetin: CH 3 , apigenin: H), and the other substituents are both the same substituent (R 2 = H , R 3 = H, R 4 = OH, R 5 = H). As shown in Table 1 and FIG. 1, acetetine showed a melanin production amount that was more than twice as high as apigenin.
ケンフェライドとケンフェロールも、同様に、一般式(1)で示す化合物の置換基のうち、R1のみが異なり(ケンフェライド:CH3、ケンフェロール:H)、他の置換基は共に同一の置換基(R2=H、R3=OH、R4=OH、R5=H)を有する化合物である。表1及び図1に示すように、ケンフェライドはケンフェロールよりも3倍以上も高いメラニン産生量を示した。 Similarly, kaempferide and kaempferol are different in the substituent of the compound represented by the general formula (1) only in R 1 (kaempride: CH 3 , kaempferol: H), and the other substituents are the same substituent. (R 2 = H, R 3 = OH, R 4 = OH, R 5 = H). As shown in Table 1 and FIG. 1, kaempferide showed a melanin production amount three times higher than kaempferol.
さらに、ジオスメチンとルテオリンも、同様に、一般式(1)で示す化合物の置換基のうち、R1のみが異なり(ジオスメチン:CH3、ルテオリン:H)、他の置換基は共に同一の置換基(R2=OH、R3=H、R4=OH、R5=H)を有する化合物である。表1及び図1に示すように、ジオスメチンはルテオリンよりも2倍以上も高いメラニン産生量を示した。 Furthermore, diosmethine and luteolin also differ in the substituent of the compound represented by the general formula (1) only in R 1 (diosmethine: CH 3 , luteolin: H), and other substituents are the same substituents. (R 2 = OH, R 3 = H, R 4 = OH, R 5 = H). As shown in Table 1 and FIG. 1, diosmethine exhibited a melanin production amount that was twice or more higher than luteolin.
また、同様の構造活性相関が合成化合物にも言えて、4’-O-メチルフィセチンや4’-O-エチルフィセチンとフィセチンも、同様に、一般式(1)で示す化合物の置換基のうち、R1のみが異なり(4’-O-メチルフィセチン:CH3、4’-O-エチルフィセチン:C2H5、フィセチン:H)、他の置換基は共に同一の置換基(R2=OH、R3=OH、R4=H、R5=H)を有する化合物である。表1及び図1に示すように、4’-O-メチルフィセチンや4’-O-エチルフィセチンはフィセチンよりも高いメラニン産生量を示した。 In addition, the same structure-activity relationship can be applied to synthetic compounds, and 4′-O-methylfisetin and 4′-O-ethylfisetin and fisetin are similarly substituted on the compound represented by the general formula (1). Among them, only R 1 is different (4′-O-methylfisetin: CH 3 , 4′-O-ethylfisetin: C 2 H 5 , fisetin: H), and all other substituents are the same substituents. (R 2 = OH, R 3 = OH, R 4 = H, R 5 = H). As shown in Table 1 and FIG. 1, 4′-O-methyl fisetin and 4′-O-ethyl fisetin showed higher melanin production than fisetin.
これらのことから、R1基を水素原子からCH3基を始めとする低級アルキル基に置換してなる化合物(1)は、顕著に優れたメラニン産生促進作用を発揮することが判明した。 From these results, it was found that the compound (1) obtained by substituting the R 1 group with a lower alkyl group such as a CH 3 group from a hydrogen atom exhibits a remarkably excellent melanin production promoting action.
また同様に、R1基がCH3基ではなく水素原子であるケルセチン、イソラムネチン及びアメントフラボンはいずれもメラニン産生量が少ないのに対して、R1基がCH3基であるプラトール、ジオスメチン及びそのアセチル体(3’,5,7-O-アセチル-ジオスメチン)、イソギンクゲチン、シアドピチシン、並びにR1基が低級アルキル基で置換されたフィセチン(4’-O-メチルフィセチン、4’-O-エチルフィセチン)及びそのアセチル体(3’5,7-O-アセチル-4’-O-メチルフィセチン)は、優れたメラニン産生促進作用を発揮することが確認された。 Similarly, quercetin R 1 group is a hydrogen atom instead of a CH 3 group, whereas little isorhamnetin and amentoflavone Any melanin production amount, Puratoru R 1 groups are CH 3 groups, diosmetin and Its acetylated form (3 ', 5,7-O-acetyl-diosmethine), isoginkgetin, cyanadopiticin, and fisetin (4'-O-methylfisetin, 4'-O-) in which R 1 group is substituted with a lower alkyl group Ethyl fisetin) and its acetylated form (3′5,7-O-acetyl-4′-O-methyl fisetin) were confirmed to exhibit an excellent melanin production promoting action.
以上のことから、一般式(1)で示されるR1にメチル基やエチル基等のアルキル基を有する化合物は、顕著に優れたメラニン産生作用を発揮することが認められた。 From the above, it was confirmed that the compound having an alkyl group such as a methyl group or an ethyl group in R 1 represented by the general formula (1) exhibits a remarkably excellent melanin producing action.
実験例2 メラニン産生促進効果試験:マウス等を用いた摂食試験
(1)実験方法
背部の一部を剃毛したAyマウス(日本SLCから購入、4.5週齢)の二匹のうち、一方のマウスに0.5 % フィセチンを含むMF粉餌(オリエンタル酵母製)を4日間自由に食べさせた(フィセチン含有飼料給餌マウス)。対照試験として、他方のマウスにはフィセチンを含まないMF粉餌(オリエンタル酵母製)を4日間自由に食べさせた(対照マウス)。
Experimental Example 2 Melanin production promoting effect test: Eating test using mice
(1) Experimental method Among two Ay mice (purchased from Japan SLC, 4.5 weeks old) with a portion of the back shaved, 4 mice were fed with MF powder containing 0.5% fisetin (made by Oriental Yeast). They were allowed to eat freely for days (Fisetin-containing feed-fed mice). As a control test, the other mouse was allowed to freely eat MF powder diet (oriental yeast) containing no fisetin for 4 days (control mouse).
(2)実験結果
図2の(A)に給餌前の剃毛したAyマウスの背部を写した画像を、(B)に給餌後、毛が生えそろったAyマウスの背部を写した画像を、それぞれ示す。各図において左側のマウスはフィセチン含有飼料給餌マウスであり、右側のマウスは対照マウスである。この結果からわかるように、フィセチンの投与により明らかに毛髪の黒色化(メラニン産生増加)が確認された。なお、フィセチン含有飼料給餌マウスの糞中には、R1=CH3を有する化合物(4’-O-メチルフィセチン)(フィセチンのR1=CH3化代謝物)が多く含まれていることが確認された(実験例3参照)。
(2) Experimental results An image of the back of a shaved Ay mouse before feeding is shown in (A) of FIG. 2, and an image of the back of an Ay mouse with full hair after feeding is shown in (B). Each is shown. In each figure, the left mouse is a fisetin-containing feed-fed mouse, and the right mouse is a control mouse. As can be seen from the results, the administration of fisetin clearly confirmed the blackening of hair (increased melanin production). The feces of fisetin-containing feed-fed mice contain a large amount of a compound having R 1 = CH 3 (4'-O-methylfisetin) (R 1 = CH 3 metabolite of fisetin). Was confirmed (see Experimental Example 3).
フィセチンは一般式(1)においてR1基として水素原子を有する化合物であり、実験例1で好適な化合物(1)として示した「R1=CH3」を有する化合物に入らない。しかし、上記で示すように、フィセチンを経口投与したマウスでメラニン産生促進作用を示し、しかもその糞中にはR1=CH3化代謝物(4’-O-メチルフィセチン)が多く含まれていた。またB16細胞に対して、フィセチンのメラニン産生促進活性は弱いものの、そのR1=CH3化体(4’-O-メチルフィセチン)のメラニン産生促進活性は強かった。これらのことから、フィセチンは生体内でメチル化されて活性本体(R1=CH3化体、4’-O-メチルフィセチン)となり、作用していると考えられる。つまり、フィセチンは4’-O-メチルフィセチンの前駆体(プロドラッグ)として機能すると考えられる。 Fisetin is a compound having a hydrogen atom as the R 1 group in the general formula (1), and does not enter the compound having “R 1 = CH 3 ” shown as a suitable compound (1) in Experimental Example 1. However, as shown above, mice that have been orally administered fisetin show a melanin production promoting action, and the feces are rich in R 1 = CH 3 metabolites (4′-O-methylfisetin). It was. The relative B16 cells, although melanin production promoting activity of fisetin is weak, the R 1 = CH 3 embodying (4'-O-Mechirufisechin) melanin production promoting activity was stronger. From these facts, it is considered that fisetin is methylated in vivo to become an active main body (R 1 = CH 3 trimer, 4′-O-methyl fisetin) and acts. In other words, fisetin is considered to function as a precursor (prodrug) of 4′-O-methylfisetin.
実験例3 フィセチン含有飼料給仕マウスの糞中代謝物の分析
(1)実験方法
マウスに1 % フィセチンを含む餌を5日間自由に食べさせ、その期間の糞を回収した。水と酢酸エチル混合液(水:酢酸エチル= 1 : 1)40 mLを回収した糞3.0 gに加え、4℃で一晩撹拌した。その後、8000 rpm、10 min遠心分離し、酢酸エチル相を回収した。回収した酢酸エチル相を窒素気流下、溶媒を溜去し、これを下記条件の高性能液体クロマトグラフ質量分析計(LCMS)で分析した。
Experimental Example 3 Analysis of fecal metabolites of fisetin-containing feed-fed mice
(1) Experimental method Mice were allowed to freely eat a diet containing 1% fisetin for 5 days, and feces during that period were collected. 40 mL of a mixed solution of water and ethyl acetate (water: ethyl acetate = 1: 1) was added to the recovered feces (3.0 g), and the mixture was stirred at 4 ° C. overnight. Thereafter, the mixture was centrifuged at 8000 rpm for 10 min to recover the ethyl acetate phase. The collected ethyl acetate phase was distilled off the solvent under a nitrogen stream, and this was analyzed with a high performance liquid chromatograph mass spectrometer (LCMS) under the following conditions.
<LCMS条件>
カラム:C18(Waters)
カラム温度:30℃
検出波長:255 nm
流速:0.2 mL / min
溶媒:0.1 % ギ酸アセトニトリル‐水(20 % - 100 %、25 min)。
<LCMS conditions>
Column: C 18 (Waters)
Column temperature: 30 ° C
Detection wavelength: 255 nm
Flow rate: 0.2 mL / min
Solvent: 0.1% acetonitrile formate-water (20% -100%, 25 min).
(2)実験結果
結果を図3に示す。結果からわかるように、糞中にはフィセチンの他、その代謝物として一般式(1)においてR1基としてメチル基を有する4’-O-メチルフィセチンが含まれていた。このことから、フィセチンは体内で代謝して4’-O-メチルフィセチンとなること、つまりフィセチンは4’-O-メチルフィセチンの前駆体(プロドラッグ)であると考えられる。
(2) Results of the experiment are shown in FIG. As can be seen from the results, feces contained 4′-O-methylfisetin having a methyl group as the R 1 group in general formula (1) as a metabolite in addition to fisetin. This suggests that fisetin is metabolized in the body to 4'-O-methylfisetin, that is, fisetin is a precursor (prodrug) of 4'-O-methylfisetin.
以下に、本発明のメラニン産生促進剤を含有する処方例を示す。なお、下記処方例に記載する「メラニン産生促進剤」とは、実験例1でメラニン産生促進作用が確認された各化合物(プラトール、アカセチン、ケンフェライド、ジオスメチン、3’,5,7-O-アセチル-ジオスメチン、フィセチン、4’-O-メチルフィセチン、4’-O-エチルフィセチン、3,3’,7-O-アセチル-4’-O-メチルフィセチン、イソギンクゲチン、及びシアドピチシン)、並びにコウヤマキ抽出物のそれぞれを意味する。 Below, the formulation example containing the melanin production promoter of this invention is shown. The “melanin production promoter” described in the following formulation examples refers to each compound (platol, acacetin, kaempferide, diosmethine, 3 ′, 5,7-O-acetyl) that was confirmed to promote melanin production in Experimental Example 1. -Diosmethine, fisetin, 4'-O-methyl fisetin, 4'-O-ethyl fisetin, 3,3 ', 7-O-acetyl-4'-O-methyl fisetin, isoginkgetin, and siadoticine), and It means each of Kouyamaki extract.
また使用したコウヤマキ抽出物は、下記の方法で調製したコウヤマキ葉の抽出物であり、イソギンクゲチンとシアドピチシンを合計して0.01〜50重量%含むものである。 Moreover, the used Koyamaki extract is an extract of Koyamaki leaf prepared by the following method, and contains 0.01 to 50% by weight of total sea anemone getin and cyanadopiticin.
<コウヤマキ抽出物の調製>
乾燥コウヤマキ葉(1kg)を粉末とし、その粉末を室温中48時間メタノール(3L)で2回抽出した。得られたメタノール抽出液に水を加え、90容量% メタノール溶液にして、これをHexaneで4回洗浄した。その後、洗浄済みの90容量% メタノール層をクロロホルムで3回抽出し、ここで得られたクロロホルム層(下層)をエバポレーターで濃縮した。その濃縮残渣をエタノールに溶かし濃縮する工程を繰り返し、残留するクロロホルムとメタノールを除き、得られた濃縮残渣をコウヤマキ抽出物とした。
<Preparation of Kouyamaki extract>
Dried Koyamaki leaves (1 kg) were powdered, and the powder was extracted twice with methanol (3 L) for 48 hours at room temperature. Water was added to the obtained methanol extract to make a 90% by volume methanol solution, which was washed 4 times with Hexane. Thereafter, the washed 90 volume% methanol layer was extracted three times with chloroform, and the chloroform layer (lower layer) obtained here was concentrated with an evaporator. The process of dissolving the concentrated residue in ethanol and concentrating was repeated, the remaining chloroform and methanol were removed, and the obtained concentrated residue was used as Kouyamaki extract.
処方例1 皮膚用ローション
(1)エタノール[溶剤] 30.0(%)
(2)ヒドロキシエチルセルロース[増粘剤] 1.0
(3)メラニン産生促進剤 0.05
(4)パラオキシ安息香酸メチル[防腐剤] 0.1
(5)水 全量を100とする量
製法:
(1)〜(5)を混合し均一とする。
Formulation Example 1 Skin Lotion
(1) Ethanol [solvent] 30.0 (%)
(2) Hydroxyethylcellulose [Thickener] 1.0
(3) Melanin production promoter 0.05
(4) Methyl paraoxybenzoate [preservative] 0.1
(5) Amount in which the total amount of water is 100 Manufacturing method:
Mix (1) to (5) to make uniform.
処方例2 皮膚用乳剤
(1)ステアリン酸[油脂剤] 0.2(%)
(2)セタノール[油脂剤] 1.5
(3)ワセリン [油脂剤] 3.0
(4)流動パラフィン[油脂剤] 7.0
(5)ポリオキシエチレン(10EO)セチルエーテル[界面活性剤] 2.5
(6)メラニン産生促進剤 0.3
(7)グリセリン [保湿剤] 5.0
(8)パラオキシ安息香酸メチル[防腐剤] 0.1
(9)トリエタノールアミン[pH調整剤] 1.0
(10)香料 0.1
(11)水 全量を100とする量
製法:
(1)〜(5)の油相成分に(6)を混合して約80℃に加熱する。一方(7)〜(9)、(11)の水相成分を混合、加熱して均一とし、約80℃とする。この水相成分に前記油相成分を撹拌しながら徐々に添加して乳化・混合し、冷却後40℃で(10)を添加し、混合する。
Formulation Example 2 Skin Emulsion
(1) Stearic acid [oil and fat agent] 0.2 (%)
(2) Cetanol [grease] 1.5
(3) Petrolatum [Oil and fat] 3.0
(4) Liquid paraffin [grease] 7.0
(5) Polyoxyethylene (10EO) cetyl ether [surfactant] 2.5
(6) Melanin production promoter 0.3
(7) Glycerin [Humectant] 5.0
(8) Methyl paraoxybenzoate [preservative] 0.1
(9) Triethanolamine [pH adjuster] 1.0
(10) Fragrance 0.1
(11) Amount in which the total amount of water is 100 Manufacturing method:
(6) is mixed with the oil phase components (1) to (5) and heated to about 80 ° C. On the other hand, the aqueous phase components (7) to (9) and (11) are mixed and heated to be uniform to about 80 ° C. The oil phase component is gradually added to the aqueous phase component with stirring and emulsified and mixed. After cooling, (10) is added at 40 ° C. and mixed.
処方例3 皮膚用ゲル剤
(1)カルボキシビニルポリマー[増粘剤] 0.5(%)
(2)プロピレングリコール[保湿剤] 10.0
(3)パラオキシ安息香酸メチル[防腐剤] 0.1
(4)メラニン産生促進剤 0.01
(5)水酸化カリウム[pH調整剤] 0.1
(6)水 全量を100とする量
製法:
(6)に(1)を均一にした後、(2)〜(4)を添加して、次いで(5)を加えて増粘させ、均一に混合する。
Formulation Example 3 Skin Gel
(1) Carboxyvinyl polymer [Thickener] 0.5 (%)
(2) Propylene glycol [humectant] 10.0
(3) Methyl paraoxybenzoate [preservative] 0.1
(4) Melanin production promoter 0.01
(5) Potassium hydroxide [pH adjuster] 0.1
(6) Amount in which the total amount of water is 100 Manufacturing method:
After (1) is made uniform in (6), (2) to (4) are added, and then (5) is added to increase the viscosity and mix uniformly.
処方例4 皮膚用軟膏
(1)ミツロウ[油脂剤] 6.0(%)
(2)セトステアリルアルコール[油脂剤] 5.0
(3)吸着精製ラノリン[油脂剤] 5.0
(4)スクワラン [油脂剤] 30.0
(5)親油型モノオレイン酸グリセリル[界面活性剤] 2.0
(6)親油型モノステアリン酸グリセリル[界面活性剤] 5.0
(7)メラニン産生促進剤 0.1
(8)ジプロピレングリコール [保湿剤] 5.0
(9)パラオキシ安息香酸メチル [防腐剤] 0.1
(10)水 全量を100とする量
製法:
(1)〜(6)の油相成分に(7)メラニン産生剤を混合して約75℃に加熱する。一方、(8)〜(10)の水相成分を混合、溶解して約75℃に加熱する。ついで、上記水相成分に油相成分を添加してホモミキサーで均一に乳化・撹拌し、冷却する。
Formulation Example 4 Skin Ointment
(1) Beeswax [grease] 6.0 (%)
(2) cetostearyl alcohol [grease] 5.0
(3) Adsorption refined lanolin [oil and fat agent] 5.0
(4) Squalane [Oil and fat] 30.0
(5) Lipophilic glyceryl monooleate [surfactant] 2.0
(6) Lipophilic glyceryl monostearate [surfactant] 5.0
(7) Melanin production promoter 0.1
(8) Dipropylene glycol [Humectant] 5.0
(9) Methyl paraoxybenzoate [Preservative] 0.1
(10) Amount of water with a total amount of 100 Manufacturing method:
(7) Melanin producing agent is mixed with the oil phase components (1) to (6) and heated to about 75 ° C. On the other hand, the aqueous phase components (8) to (10) are mixed, dissolved, and heated to about 75 ° C. Next, the oil phase component is added to the aqueous phase component, and the mixture is uniformly emulsified and stirred with a homomixer and cooled.
処方例5 ヘアローション
(1)エタノール[溶剤] 90.0(%)
(2)酢酸トコフェロール[油脂剤] 0.5
(3)プロピレングリコール[保湿剤] 2.0
(4)メラニン産生促進剤 1.0
(5)水 全量を100とする量
製法:
(1)に(2)〜(5)を順次添加して均一に混合する。
Formulation Example 5 Hair Lotion
(1) Ethanol [solvent] 90.0 (%)
(2) Tocopherol acetate [grease] 0.5
(3) Propylene glycol [humectant] 2.0
(4) Melanin production promoter 1.0
(5) Amount in which the total amount of water is 100 Manufacturing method:
(2) to (5) are sequentially added to (1) and mixed uniformly.
処方例6 ヘアセットローション
(1)エタノール[溶剤] 30.0(%)
(2)アクリル樹脂アルカノールアミン液(40%)[皮膜形成剤] 5.0
(3)パラオキシ安息香酸メチル[防腐剤] 0.1
(4)ポリオキシエチレン変性シリコーン[油脂剤] 0.5
(5)グリセリン[保湿剤] 2.0
(6)ヒアルロン酸ナトリウム(1%)[保湿剤] 1.0
(7)メラニン産生促進剤 0.05
(8)水 全量を100とする量
製法:
(1)に(2)〜(8)を加えて均一に溶解する。
Formulation Example 6 Hair Set Lotion
(1) Ethanol [solvent] 30.0 (%)
(2) Acrylic resin alkanolamine liquid (40%) [film forming agent] 5.0
(3) Methyl paraoxybenzoate [preservative] 0.1
(4) Polyoxyethylene-modified silicone [grease] 0.5
(5) Glycerin [humectant] 2.0
(6) Sodium hyaluronate (1%) [humectant] 1.0
(7) Melanin production promoter 0.05
(8) Amount in which the total amount of water is 100 Manufacturing method:
Add (2) to (8) to (1) and dissolve uniformly.
処方例7 ヘアクリーム
(1)セタノール[油脂剤] 2.0(%)
(2)ベヘニルアルコール[油脂剤] 2.0
(3)パルミチン酸イソプロピル[油脂剤] 5.0
(4)自己乳化型モノステアリン酸プロピレングリコール[界面活性剤]1.0
(5)メラニン産生促進剤 0.3
(6)グリセリン[保湿剤] 5.0
(7)1,3−ブチレングリコール[保湿剤] 3.0
(8)エチレンジアミン四酢酸二ナトリウム[金属イオン封鎖剤] 0.1
(9)水 全量を100とする量
製法:
(1)〜(4)の油相成分に(5)を混合して約80℃に加熱する。一方、(6)〜(9)の水相成分を混合,溶解して約80℃に加熱する。ついで、前記水相成分に油相成分を添加して、ホモミキサーで均一に乳化・撹拌し、冷却する。
Formulation Example 7 Hair Cream
(1) Cetanol [Oil and fat] 2.0 (%)
(2) Behenyl alcohol [grease] 2.0
(3) Isopropyl palmitate [grease] 5.0
(4) Self-emulsifying type propylene glycol monostearate [surfactant] 1.0
(5) Melanin production promoter 0.3
(6) Glycerin [humectant] 5.0
(7) 1,3-butylene glycol [humectant] 3.0
(8) Ethylenediaminetetraacetic acid disodium [metal ion sequestering agent] 0.1
(9) Amount of water in which the total amount is 100 Manufacturing method:
(5) is mixed with the oil phase components (1) to (4) and heated to about 80 ° C. On the other hand, the aqueous phase components (6) to (9) are mixed and dissolved and heated to about 80 ° C. Next, an oil phase component is added to the aqueous phase component, and the mixture is uniformly emulsified and stirred with a homomixer and cooled.
処方例8 ヘアジェル
(1)カルボキシビニルポリマー[増粘剤] 0.7(%)
(2)グリセリン[保湿剤] 5.0
(3)ポリビニルピロリドン[皮膜形成剤] 2.0
(4)エタノール[溶剤] 10.0
(5)メラニン産生促進剤 0.01
(6)水酸化ナトリウム[pH調整剤] 0.2
(7)水 全量を100とする量
製法:
(7)に(1)〜(5)を順次添加し、均一に溶解する。前記溶解物に(6)を添加し、中和増粘させ、混合し均一にする。
Formulation Example 8 Hair Gel
(1) Carboxyvinyl polymer [Thickener] 0.7 (%)
(2) Glycerin [humectant] 5.0
(3) Polyvinylpyrrolidone [film forming agent] 2.0
(4) Ethanol [solvent] 10.0
(5) Melanin production promoter 0.01
(6) Sodium hydroxide [pH adjuster] 0.2
(7) Water in which the total amount is 100 Manufacturing method:
(1) to (5) are sequentially added to (7) and dissolved uniformly. (6) is added to the lysate, neutralized and thickened, and mixed to make uniform.
処方例9 ヘアフォーム(原液処方)
(1)塩化ジメチルジアルキルアンモニウム・アクリルアミド共重合体[皮膜形成剤]
3.0(%)
(2)ポリオキシエチレン(50EO)硬化ヒマシ油[界面活性剤] 1.0
(3)ジメチルシリコン[油脂剤] 3.0
(4)プロピレングリコール[保湿剤] 7.0
(5)エタノール[溶剤] 15.0
(6)メラニン産生促進剤 0.01
(7)水 全量を100とする量
(充填処方)
上記の原液 90.0
DME/液化石油ガス(LPG)(95/5) 10.0
製法:
(1)〜(7)の成分を混合し、原液を調製する。充填は缶に原液を充填し、バルブ等装着後、DME/液化石油ガス(LPG)を充填する。
Formulation Example 9 Hair Foam (stock solution formulation)
(1) Dimethyldialkylammonium chloride / acrylamide copolymer [film-forming agent]
3.0 (%)
(2) Polyoxyethylene (50EO) hydrogenated castor oil [surfactant] 1.0
(3) Dimethyl silicon [grease] 3.0
(4) Propylene glycol [humectant] 7.0
(5) Ethanol [solvent] 15.0
(6) Melanin production promoter 0.01
(7) Amount with 100% water
(Filling formula)
The above stock solution 90.0
DME / liquefied petroleum gas (LPG) (95/5) 10.0
Manufacturing method:
The ingredients (1) to (7) are mixed to prepare a stock solution. For filling, the stock solution is filled in a can, and after mounting a valve or the like, DME / liquefied petroleum gas (LPG) is filled.
処方例10 ヘアシャンプー
(1)ポリオキシエチレン(3EO)ラウリルエーテル硫酸トリエタノールアミン(30%)[界面活性剤] 15.0(%)
(2)ラウリル硫酸トリエタノールアミン (30%)[界面活性剤] 5.0
(3)ヤシ油脂肪酸ジエタノールアミド[界面活性剤] 4.0
(4)ラウロイルサルコシントリエタノールアミン[界面活性剤] 4.0
(5)パラオキシ安息香酸メチル[防腐剤] 0.2
(6)エチレンジアミン四酢酸二ナトリウム[金属イオン封鎖剤] 0.3
(7)メラニン産生促進剤 0.1
(8)香料 0.2
(9)水 全量を100とする量
製法:
(9)に(1)〜(8)を順次添加して均一にする。
Formulation Example 10 Hair Shampoo
(1) Polyoxyethylene (3EO) lauryl ether sulfate triethanolamine (30%) [Surfactant] 15.0 (%)
(2) Lauryl sulfate triethanolamine (30%) [Surfactant] 5.0
(3) Palm oil fatty acid diethanolamide [surfactant] 4.0
(4) Lauroyl sarcosine triethanolamine [surfactant] 4.0
(5) Methyl paraoxybenzoate [preservative] 0.2
(6) Ethylenediaminetetraacetic acid disodium [sequestering agent] 0.3
(7) Melanin production promoter 0.1
(8) Fragrance 0.2
(9) Amount of water in which the total amount is 100 Manufacturing method:
(1) to (8) are sequentially added to (9) to make it uniform.
処方例11 ヘアリンス
(1)セチルアルコール[油脂剤] 10.0(%)
(2)ステアリルアルコール[油脂剤] 1.0
(3)オクチルドデカノール[油脂剤] 5.0
(4)パルミチン酸イソプロピル[油脂剤] 1.5
(5)メラニン産生促進剤 0.1
(6)塩化ステアリルトリメチルアンモニウム(30%)[界面活性剤] 3.0
(7)グリセリン[保湿剤] 3.0
(8)水 全量を100とする量
製法:
(1)〜(4)の油相成分に(5)を混合し、約80℃に加熱する。(6)〜(8)の水相成分を混合、均一化し、約80℃に加熱する。油相に水相を添加してホモミキサーで乳化・混合した後、冷却する。
Formulation Example 11 Hair Rinse
(1) Cetyl alcohol [grease] 10.0 (%)
(2) Stearyl alcohol [oil and fat agent] 1.0
(3) Octyldodecanol [grease] 5.0
(4) Isopropyl palmitate [grease] 1.5
(5) Melanin production promoter 0.1
(6) Stearyltrimethylammonium chloride (30%) [Surfactant] 3.0
(7) Glycerin [humectant] 3.0
(8) Amount in which the total amount of water is 100 Manufacturing method:
(5) is mixed with the oil phase components (1) to (4) and heated to about 80 ° C. The aqueous phase components (6) to (8) are mixed, homogenized, and heated to about 80 ° C. The aqueous phase is added to the oil phase, emulsified and mixed with a homomixer, and then cooled.
処方例12 化粧水
(1)エタノール[溶剤] 30.0(%)
(2)グリセリン[保湿剤] 5.0
(3)植物抽出液[収レン剤] 2.0
(4)メラニン産生促進剤 0.05
(5)水 全量を100とする量
製法:
(1)〜(5)を順次添加し、均一にする。
Formulation Example 12 Lotion
(1) Ethanol [solvent] 30.0 (%)
(2) Glycerin [humectant] 5.0
(3) Plant extract [collecting agent] 2.0
(4) Melanin production promoter 0.05
(5) Amount in which the total amount of water is 100 Manufacturing method:
(1) to (5) are sequentially added to make uniform.
処方例13 メイクアップクリーム
(1)ステアリン酸[油脂剤] 7.0(%)
(2)セタノール[油脂剤] 2.0
(3)ホホバ油[油脂剤] 7.5
(4)自己乳化型モノステアリン酸グリセリル[界面活性剤] 2.0
(5)メラニン産生促進剤 0.1
(6)プロピレングリコール[保湿剤] 8.0
(7)水酸化カリウム[pH調整剤] 0.2
(8)酸化チタン[紫外線散乱剤] 1.0
(9)ベンガラ[色剤] 0.1
(10)黄酸化鉄 [色剤] 0.4
(11)香料 0.1
(12)水 全量を100とする量
製法:
(1)〜(4)の油相成分に(5)を混合し約75℃に加熱する。一方(12)に(6)および(7)を混合し、約75℃に加熱・溶解し、これに(8)〜(10)の顔料を添加し、均一に分散させる(水相成分)。この水相成分に前記油相成分を添加し、ホモミキサーにて乳化・撹拌した後冷却し、約40℃で(11)を添加、混合する。
Formulation Example 13 Makeup Cream
(1) Stearic acid [oil and fat agent] 7.0 (%)
(2) Cetanol [grease] 2.0
(3) Jojoba oil [grease] 7.5
(4) Self-emulsifying type glyceryl monostearate [surfactant] 2.0
(5) Melanin production promoter 0.1
(6) Propylene glycol [humectant] 8.0
(7) Potassium hydroxide [pH adjuster] 0.2
(8) Titanium oxide [UV scattering agent] 1.0
(9) Bengala [colorant] 0.1
(10) Yellow iron oxide [Coloring agent] 0.4
(11) Fragrance 0.1
(12) Amount in which the total amount of water is 100 Manufacturing method:
(5) is mixed with the oil phase components (1) to (4) and heated to about 75 ° C. On the other hand, (6) and (7) are mixed with (12), heated and dissolved at about 75 ° C., and the pigments (8) to (10) are added thereto and dispersed uniformly (water phase component). The oil phase component is added to the water phase component, emulsified and stirred with a homomixer, cooled, and (11) is added and mixed at about 40 ° C.
処方例14 乳液状ファンデーション
(1)セタノール[油脂剤] 1.0(%)
(2)ステアリン酸[油脂剤] 2.0
(3)スクワラン[油脂剤] 5.0
(4)ミリスチン酸オクチルドデシル[油脂剤] 5.0
(5)デカステアリン酸デカグリセリル[油脂剤] 8.0
(6)メラニン産生促進剤 0.2
(7)グリセリン[保湿剤] 5.0
(8)水酸化カリウム[pH調整剤] 0.1
(9)パラオキシ安息香酸メチル[防腐剤] 0.1
(10)酸化チタン[紫外線散乱剤] 9.0
(11)タルク[賦形剤] 7.4
(12)ベンガラ[色剤] 0.5
(13)黄酸化鉄[色剤] 1.1
(14)黒酸化鉄[色剤] 0.1
(15)香料 0.1
(16)水 全量を100とする量
製法:
(1)〜(5)の油相成分に(6)を混合し約75℃に加熱して均一とする。一方(16)に(7)〜(9)を混合し、約75℃に加熱・溶解し、これに(10)〜(14)の顔料を添加し、均一に分散させる(水相成分)。この水相成分に前記油相成分を添加し、ホモミキサーで乳化した後冷却し、40℃にて(15)を添加、混合する。
Formulation Example 14 Emulsion Foundation
(1) Cetanol [Oil and fat] 1.0 (%)
(2) Stearic acid [oil and fat agent] 2.0
(3) Squalane [grease] 5.0
(4) Octyldodecyl myristate [Oil agent] 5.0
(5) Decastearic acid decaglyceryl [oil and fat agent] 8.0
(6) Melanin production promoter 0.2
(7) Glycerin [humectant] 5.0
(8) Potassium hydroxide [pH adjuster] 0.1
(9) Methyl paraoxybenzoate [preservative] 0.1
(10) Titanium oxide [UV scattering agent] 9.0
(11) Talc [Excipient] 7.4
(12) Bengala [colorant] 0.5
(13) Yellow iron oxide [colorant] 1.1
(14) Black iron oxide [colorant] 0.1
(15) Fragrance 0.1
(16) Amount of water with a total amount of 100 Manufacturing method:
(6) is mixed with the oil phase components (1) to (5) and heated to about 75 ° C. to make it uniform. On the other hand, (7) to (9) are mixed with (16), heated and dissolved at about 75 ° C., and the pigments (10) to (14) are added thereto and dispersed uniformly (water phase component). The oil phase component is added to the aqueous phase component, emulsified with a homomixer, cooled, and (15) is added and mixed at 40 ° C.
処方例15 錠剤
(1)乳糖[賦形剤] 54.0(mg)
(2)トウモロコシデンプン[賦形剤] 20.0
(3)結晶セルロース[安定剤] 20.0
(4)活性吸収型カルシウム(カキ殻由来)[吸収助剤] 10.0
(5)炭酸マグネシウム[賦形剤] 1.0
(6)メラニン産生促進剤 100.0
(1)〜(6)を上記配合比率で、各成分をよく混合し、この混合物を打錠して錠剤を得る。
Formulation Example 15 Tablet (1) Lactose [Excipient] 54.0 (mg)
(2) Corn starch [excipient] 20.0
(3) Crystalline cellulose [stabilizer] 20.0
(4) Active absorption type calcium (derived from oyster shell) [Absorption aid] 10.0
(5) Magnesium carbonate [excipient] 1.0
(6) Melanin production promoter 100.0
(1) to (6) are mixed at the above-mentioned mixing ratio, and each component is mixed well, and the mixture is tableted to obtain a tablet.
処方例16 カプセル剤
(1)乳糖[香味剤] 60.0(mg)
(2)トウモロコシデンプン[賦形剤] 38.0
(3)炭酸マグネシウム[賦形剤] 2.0
(4)メラニン産生促進剤 300.0
(1)〜(4)を上記配合比率で、よく混合したものを、カプセルに充填してカプセル剤を得る。
Formulation Example 16 Capsule (1) Lactose [flavoring agent] 60.0 (mg)
(2) Corn starch [excipient] 38.0
(3) Magnesium carbonate [excipient] 2.0
(4) Melanin production promoter 300.0
Capsules are obtained by filling well-mixed (1) to (4) with the above blending ratio into capsules.
処方例17 軟カプセル剤
(1)精製大豆油[吸収助剤] 80.0(mg)
(2)トコフェロール[酸化防止剤] 20.0
(3)メラニン産生促進剤 200.0
(1)〜(3)を上記配合比率で、よく混合したものを、カプセルに充填して軟カプセル剤を得る。
Formulation Example 17 Soft capsule (1) Refined soybean oil [absorption aid] 80.0 (mg)
(2) Tocopherol [Antioxidant] 20.0
(3) Melanin production promoter 200.0
A capsule obtained by thoroughly mixing (1) to (3) at the above blending ratio is filled into a capsule to obtain a soft capsule.
Claims (7)
を意味する。但し、R1が水素原子であるとき、R2及びR3は水酸基で、R4及びR5は水素原子である。)。 Melanin production promoter containing as an active ingredient at least one compound selected from the compound group represented by the following general formula (1):
Means. However, when R 1 is a hydrogen atom, R 2 and R 3 are hydroxyl groups, and R 4 and R 5 are hydrogen atoms. ).
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017105777A (en) * | 2015-12-08 | 2017-06-15 | エルジー ハウスホールド アンド ヘルスケア リミテッド | Compositions for improving skin |
CN107586311A (en) * | 2017-07-25 | 2018-01-16 | 贵州维康子帆药业股份有限公司 | The method that the C β D glucosides of robinin 6 are extracted in creeping oxalis |
KR20220078293A (en) * | 2020-12-03 | 2022-06-10 | 제주대학교 산학협력단 | A composition for promoting melanin synthesis comprising chrysoeriol |
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JPH05279225A (en) * | 1992-03-30 | 1993-10-26 | Suntory Ltd | Tanning-stimulating cosmetic composition |
JPH09263534A (en) * | 1996-03-29 | 1997-10-07 | Sunstar Inc | Promoter for melanogenesis |
JP2004002264A (en) * | 2002-04-18 | 2004-01-08 | Tokai Univ | Melanine production-promoting agent and composition of external preparation used for skin containing the same |
JP2007145839A (en) * | 2005-11-24 | 2007-06-14 | Digital Biotech Co Ltd | Composition for preventing and treating recognition functional disorder, containing flavonoid-based compound |
JP2008007452A (en) * | 2006-06-28 | 2008-01-17 | Ajinomoto Co Inc | PANCREAS beta CELL PROTECTANT |
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Publication number | Priority date | Publication date | Assignee | Title |
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JPH05279225A (en) * | 1992-03-30 | 1993-10-26 | Suntory Ltd | Tanning-stimulating cosmetic composition |
JPH09263534A (en) * | 1996-03-29 | 1997-10-07 | Sunstar Inc | Promoter for melanogenesis |
JP2004002264A (en) * | 2002-04-18 | 2004-01-08 | Tokai Univ | Melanine production-promoting agent and composition of external preparation used for skin containing the same |
JP2007145839A (en) * | 2005-11-24 | 2007-06-14 | Digital Biotech Co Ltd | Composition for preventing and treating recognition functional disorder, containing flavonoid-based compound |
JP2008007452A (en) * | 2006-06-28 | 2008-01-17 | Ajinomoto Co Inc | PANCREAS beta CELL PROTECTANT |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2017105777A (en) * | 2015-12-08 | 2017-06-15 | エルジー ハウスホールド アンド ヘルスケア リミテッド | Compositions for improving skin |
CN107586311A (en) * | 2017-07-25 | 2018-01-16 | 贵州维康子帆药业股份有限公司 | The method that the C β D glucosides of robinin 6 are extracted in creeping oxalis |
KR20220078293A (en) * | 2020-12-03 | 2022-06-10 | 제주대학교 산학협력단 | A composition for promoting melanin synthesis comprising chrysoeriol |
KR102506620B1 (en) * | 2020-12-03 | 2023-03-03 | 제주대학교 산학협력단 | A composition for promoting melanin synthesis comprising chrysoeriol |
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