JP2007176835A5 - - Google Patents
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- JP2007176835A5 JP2007176835A5 JP2005375332A JP2005375332A JP2007176835A5 JP 2007176835 A5 JP2007176835 A5 JP 2007176835A5 JP 2005375332 A JP2005375332 A JP 2005375332A JP 2005375332 A JP2005375332 A JP 2005375332A JP 2007176835 A5 JP2007176835 A5 JP 2007176835A5
- Authority
- JP
- Japan
- Prior art keywords
- skin
- extract
- external preparation
- purified product
- preparation
- 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.)
- Pending
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- 210000003491 Skin Anatomy 0.000 claims description 54
- 238000002360 preparation method Methods 0.000 claims description 48
- 239000000284 extract Substances 0.000 claims description 44
- 210000002510 Keratinocytes Anatomy 0.000 claims description 28
- 239000012264 purified product Substances 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 241000218657 Picea Species 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 11
- 239000002798 polar solvent Substances 0.000 claims description 11
- 230000004625 regulation of water loss via skin Effects 0.000 claims description 10
- 239000011575 calcium Substances 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 claims description 7
- 240000003472 Citrus aurantium Species 0.000 claims description 7
- 229940025878 Hesperidin Drugs 0.000 claims description 7
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- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 claims description 7
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
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- 229910001424 calcium ion Inorganic materials 0.000 description 5
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- 238000011084 recovery Methods 0.000 description 4
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- 229960003237 betaine Drugs 0.000 description 3
- 235000020971 citrus fruits Nutrition 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 235000010417 guar gum Nutrition 0.000 description 3
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- 229920002101 Chitin Polymers 0.000 description 2
- 241000207199 Citrus Species 0.000 description 2
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- 235000016646 Citrus taiwanica Nutrition 0.000 description 2
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- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N Palmitic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene (PE) Substances 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
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- 239000002280 amphoteric surfactant Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- 239000003240 coconut oil Substances 0.000 description 2
- 235000019864 coconut oil Nutrition 0.000 description 2
- 235000019414 erythritol Nutrition 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- QUEDXNHFTDJVIY-WENCSYSZSA-N gamma-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@](CCC[C@@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-WENCSYSZSA-N 0.000 description 2
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
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- MAKUBRYLFHZREJ-JWBQXVCJSA-M sodium;(2S,3S,4R,5R,6R)-3-[(2S,3R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylate Chemical compound [Na+].CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@H](O)[C@H]1O MAKUBRYLFHZREJ-JWBQXVCJSA-M 0.000 description 2
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Description
本発明は、皮膚外用剤とその製造方法に関し、詳しくは皮膚バリア機能を向上させる皮膚外用剤とその製造方法に関する。
The present invention relates to a method of manufacturing the skin Hadagaiyo agent, details and its manufacturing how skin external agent for improving skin barrier function.
本発明は、この様な状況下為されたものであり、皮膚そのもののバリア機能を向上させる手段を提供することを課題とした。
The present invention has been made under such circumstances, and an object of the present invention is to provide means for improving the barrier function of the skin itself.
この様な状況に鑑みて、本発明者らは、皮膚そのもののバリア機能を向上させる皮膚外用剤を簡便に得る手段を求めて鋭意研究努力を重ねた結果、表皮角化細胞をカルシウムイオンを０．１〜０．２ｍＭ含有する液体培地で０．１〜１２μｍの微細孔を有する支持体上にコンフルエントになるまで培養し、しかる後に、カルシウムイオンを１〜２ｍＭ含有する液体培地で培養することにより、皮膚バリア機能を簡便に評価できる表皮角化細胞層膜が得られること、またこの表皮角化細胞層膜に、ミカン科ミカン属ダイダイの果皮（トウヒ）を極性溶媒で抽出して得られた抽出物、もしくは該抽出物を更に分画、精製して得られた分画精製物を、前記表皮角化細胞層膜の存する液体培地中に含有せしめることにより、表皮角化細胞層膜のバリア機能が向上すること、更にこの抽出物を皮膚外用剤に含有せしめることにより、簡便に皮膚そのもののバリア機能を向上させる皮膚外用剤が得られることなどを見出し、本発明を完成させた。すなわち、本発明は、以下に示す通りである。
In view of such a situation, the present inventors have intensively studied for a means for easily obtaining an external preparation for skin that improves the barrier function of the skin itself. As a result, the epidermis keratinocytes have 0 calcium ions. By culturing on a support having 0.1 to 12 μm micropores in a liquid medium containing 1 to 0.2 mM until confluent, and then culturing in a liquid medium containing 1 to 2 mM calcium ions , and this epidermal keratinocytes layer membrane can be conveniently evaluated skin barrier function is obtained, also in the epidermal keratinocytes layer film, obtained by extracting citrus family citrus aurantium peels the (spruce) in a polar solvent extracts, or further fractionated the extracts, fractions purified product obtained by purifying, by incorporating in the liquid medium residing of the epidermal keratinocytes layer membranes, epidermal keratinocytes layer film barrier The ability is improved, and further by incorporating the extract to the skin external preparation, conveniently found such that the external skin preparation for improving the barrier function of the skin itself is obtained, to complete the present invention. That is, the present invention is as follows.
（１） ミカン科ミカン属ダイダイの果皮（トウヒ）を極性溶媒で抽出して得られた抽出物、もしくは該抽出物を分画、精製して得られた分画精製物を皮膚外用剤に含有させる皮膚外用剤の製造方法において、表皮角化細胞をカルシウムを０．１〜０．２ｍＭ含有する液体培地で０．１〜１２μｍの微細孔を有する支持体上でコンフルエントになるまで培養し、しかる後、カルシウムイオンを１〜２ｍＭ含有する液体培地で培養して得られる表皮角化細胞層膜を、前記抽出物又は分画精製物で処理した場合に、該表皮角化細胞層膜の物質透過性を抑制する作用を有することを確認し、該作用を有する抽出物又は分画精製物を皮膚外用剤に含有せしめることを特徴とする、皮膚外用剤の製造方法。
（２） 前記極性溶媒が含水エタノール又は含水１，３−ブタンジオールであることを特
徴とする、（１）に記載の皮膚外用剤の製造方法。
（３） 前記分画精製物が、前記抽出物から極性溶媒を除去し、しかる後に酢酸エチルと水を加え、液−液抽出し、酢酸エチル層を取り、該酢酸エチル層の溶媒を除去して得られたものであることを特徴とする、（１）又は（２）に記載の皮膚外用剤の製造方法。
（４） 前記表皮角化細胞がヒト由来のものであることを特徴とする、（１）〜（３）何れか1つに記載の皮膚外用剤の製造方法。
（５） 未処理の表皮角化細胞層膜に比して、ＴＥＲ（Transepithelial Electrical Resistance）値が１０％以上増加する場合、前記皮膚外用剤が、前記表皮角化細胞層膜の物質透過性を抑制する作用を有するとすることを特徴とする、（１）〜（４）何れか1つに記載の皮膚外用剤の製造方法。
（６） 前記皮膚外用剤が、皮膚バリア機能改善用であることを特徴とする（１）〜（５）何れか1つに記載の皮膚外用剤の製造方法。
（７） ミカン科ミカン属ダイダイの果皮を極性溶媒で抽出して得られた抽出物、もしくは該抽出物を分画、精製して得られた分画精製物を、含有するヘスペリジンの量を指標として、皮膚バリア機能を向上させるのに充分な量で配合することを特徴とする、皮膚外用剤。
（８） 前記抽出物又は分画精製物中のヘスペリジン含有量が０．０５〜０．１質量％となるように５０％エタノール水溶液を添加して調整したものを０．０１〜１質量％含有することを特徴とする、（７）に記載の皮膚外用剤。
(1) Contains an extract obtained by extracting the peel (spruce) of the mandarin orange mandarin genus with a polar solvent , or a fraction purified product obtained by fractionating and purifying the extract as a skin external preparation. In the method for producing an external preparation for skin , epidermal keratinocytes are cultured in a liquid medium containing 0.1 to 0.2 mM of calcium until it becomes confluent on a support having 0.1 to 12 μm micropores. after, when the epidermal keratinocytes layer film obtained by culturing in a liquid medium 1~2mM containing calcium ions, and treated with the extract or fraction purified product, material permeability of the epidermis keratinocyte layer film confirmed to have an effect of suppressing sex, it characterized by allowed to contain an extract or fractionated purified product having a the acting external preparation for skin, producing how the skin external preparation.
(2), wherein the polar solvent medium is a water-containing ethanol or water-containing 1,3-butanediol, prepared how the skin external preparation as described in (1).
(3) the fraction purified product is, the polar solvent is removed from the extract, whereafter ethyl acetate and water were added to the liquid - liquid extraction to take ethyl acetate layer, the solvent was removed in acetic acid ethyl layer characterized in that it was collected using, (1) or manufacture how the skin external preparation as described in (2).
(4), wherein the epidermal keratinocytes are of human origin, (1) - (3) producing how the skin external preparation according to any one.
(5) When the TER (Transepithelial Electrical Resistance) value is increased by 10% or more as compared with an untreated epidermal keratinocyte layer membrane, the external preparation for skin has a substance permeability of the epidermal keratinocyte layer membrane. The method for producing an external preparation for skin according to any one of (1) to (4), which has an inhibitory action.
(6) The method for producing an external preparation for skin according to any one of (1) to (5), wherein the external preparation for skin is used for improving a skin barrier function.
(7) The amount of hesperidin contained in the extract obtained by extracting the peel of the citrus fruit genus Daidai with a polar solvent, or the fraction purified product obtained by fractionating and purifying the extract as, wherein the blending in an amount sufficient to improve the skin barrier function, the skin external preparation.
(8) the extract or 0.01 to 1 mass what Hesuperiji emissions containing chromatic amount of fraction purified product in was adjusted by addition of 50% aqueous ethanol solution such that 0.05 to 0.1 mass% The skin external preparation as described in (7) characterized by containing%.
本発明の皮膚外用剤の製造方法は、ミカン科ミカン属ダイダイの果皮（トウヒ）を極性溶媒で抽出して得られた抽出物、もしくは該抽出物を更に分画、精製して得られた分画精製物を皮膚外用剤に含有させる皮膚外用剤の製造方法において、表皮角化細胞をカルシウムを０．１〜０．２ｍＭ含有する液体培地で０．１〜１２μｍの微細孔を有する支持体上でコンフルエントになるまで培養し、しかる後、カルシウムイオンを１〜２ｍＭ含有する液体培地で培養して得られる表皮角化細胞層膜を、前記抽出物又は分画精製物で処理した場合に、該表皮角化細胞層膜の物質透過性を抑制する作用を有することを確認し、該作用を有する該抽出物又は分画精製物を皮膚外用剤に含有せしめることを特徴とする。
Producing how the skin external preparation of the present invention was obtained Rutaceae Citrus aurantium peels the (spruce) extract obtained by extraction with a polar solvent, or further fractionated extract, purified In the method for producing a skin external preparation containing the fractionated purified product in the skin external preparation, a support having 0.1 to 12 μm fine pores in a liquid medium containing 0.1 to 0.2 mM calcium as epidermal keratinocytes were cultured to confluence on, thereafter, when the epidermal keratinocytes layer film obtained by culturing calcium ions in a liquid medium containing 1-2 mM, was treated with the extract or fraction purified product, It is confirmed that the substance has an action of suppressing substance permeability of the epidermal keratinocyte layer membrane, and the extract or fraction purified product having the action is contained in an external preparation for skin.
前記、ミカン科ミカン属ダイダイの果皮（トウヒ）の抽出物の製造に用いる溶媒としては極性溶媒が挙げられ、水、エタノールやイソプロパノール等のアルコール類、アセトン、メチルエチルケトン等のケトン類、アセトニトリルなどのニトリル類、ジエチルエーテルやテトラヒドロフラン等のエーテル類、酢酸エチルや蟻酸メチル等のエステル類、１，３−ブタンジオール、プロピレングリコール等の多価アルコール類が好ましく例示できる。これらは単独でも複数を混合して用いても良い。抽出に際しては、植物体乃至はその加工物１質量部に対して、１〜１０質量部の溶媒を加え、室温であれば数日間、沸点付近の温度であれば数時間、所望により攪拌を加え、浸漬すればよい。浸漬後、所望により濾過などで不溶物を除去し、必要に応じて溶媒除去などを行い用いることができる。更に、こ
れらを液−液抽出、イオン交換樹脂やシリカゲルを担体としたクロマトグラフィーなどを用いて分画精製物とすることもできる。
Wherein, as the solvent medium used in the preparation of the extract of citrus family Citrus aurantium peel (spruce) include polar Solvent, water, alcohols such as ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, acetonitrile, etc. Preferred examples include nitriles of the above, ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate and methyl formate, and polyhydric alcohols such as 1,3-butanediol and propylene glycol. These may be used alone or in combination. At the time of extraction, the plant body or its workpiece 1 part by mass, addition of Solvent 1 to 10 parts by weight, for several days if room temperature for several hours if the temperature around the boiling point, stirring if desired In addition, it may be immersed. After soaking, the insoluble matter can be removed by filtration or the like, if necessary, and the solvent can be removed if necessary. Further, these liquid - liquid extraction can also be a fractionated purified product by using a chromatography using ion exchange resin or silica gel as carrier.
かくして得られた抽出物又は分画精製物は表皮角化細胞をカルシウムを０．１〜０．２ｍＭ含有する液体培地で０．１〜１２μｍの微細孔を有する支持体上でコンフルエントになるまで培養し、しかる後、カルシウムイオンを１〜２ｍＭ含有する液体培地で培養し、さらに前記抽出物又は分画精製物を含有する、或いは含有しない液体培地で培養して得られる表皮角化細胞層膜を用い、それぞれの細胞層膜で隔てられた二室のチャンバーの一室に指標物質を充填し、被検物質の他室への移動の程度が、前記抽出物又は分画精製物の有無において、前記抽出物又は分画精製物を含有する培養液で培養した細胞層膜における物質の透過性の抑制作用を有する分画を求め、かかる作用が皮膚外用剤への配合において十分に効果を奏するとは、この作用が１０％以上の抑制作用を示すことであり、かかる濃度を決定し、皮膚外用剤への配合量が決定される。０．１〜１２μｍの微細孔を有する支持体としては、コーニング社やミリポア社より、ポリエチレンテレフタレート製、ポリカーボネート製、コラーゲン処理ポリテトタフルオロエチレン製の膜が市販されているので、これらを購入して使用することができ、好ましい。これらを用いた測定方法に関しては以下に一例を示す。
The extract or fraction-purified product thus obtained is cultured until the epidermal keratinocytes are confluent on a support having 0.1 to 12 μm micropores in a liquid medium containing 0.1 to 0.2 mM calcium. Then, an epidermal keratinocyte layer membrane obtained by culturing in a liquid medium containing 1 to 2 mM of calcium ions and further culturing in a liquid medium containing or not containing the extract or fractionated purified product. Used, filling one chamber of two chambers separated by each cell layer membrane with an indicator substance, the degree of movement of the test substance to the other chamber in the presence or absence of the extract or fraction purified product , Obtaining a fraction having an action of suppressing the permeability of a substance in a cell layer membrane cultured in a culture solution containing the extract or the fraction-purified product , and such action is sufficiently effective in blending into an external preparation for skin This work There is to show an inhibitory effect of 10% or more, and determine such concentrations, the amount of the skin external preparation is determined. The support having fine pores of 0.1～12Myuemu, from Corning Inc. and Millipore, polyethyleneterephthalate off tallates made, polycarbonate, since collagen treated poly Tet data fluoroethylene made of film is commercially available, purchased them Can be used. An example of the measurement method using these is shown below.
＜表皮角化細胞層膜を介しての物質の移動の抑制による皮膚バリア機能の測定＞
凍結正常ヒト表皮角化細胞（ＮＨＥＫ）（倉敷紡績株式会社製）を解凍し、０．１５ｍＭ−Ｃａ含有培養液（Ｈｕｍｅｄｉａ−ＫＧ２；倉敷紡績株式会社製）にて、３７℃、５０％二酸化炭素雰囲気下で培養した。この正常ヒト表皮角化細胞（ＮＨＥＫ）をMillicell Tissue Culture Plate（ミリポア社製）にコーニング社製トランスウェル（直径１２ｍｍ、ポリエチレンテレフタレート０．４μｍポア）をセットし、上層０．５ｍｌ、下層０．５ｍｌの前記培養液を入れ、２×１０ 5 ／ｃｍ 2 で播種し、さらに７２時間培養した。
コンフルエントになったことを確認し、１．４５ｍＭ−Ｃａ含有−Ｈｕｍｅｄｉａ−ＫＧ２培地に交換し、その後９６時間培養した。その後、被検試料である抽出物を含有する培養液に交換して、培養を継続し、１日後、２日後、３日後にＴＥＲ（Transepithelial Electrical Resistance）値（Ωｍ 2 ）を測定する。被検試料含有培養液の添加時のＴＥＲ値に対する、一定時間後のＴＥＲ値を測定することによって、前記阻害濃度が決定される。
この様な阻害濃度は簡易的にヘスペリジンの含有量によって推定できる。これはトウヒ中に含まれる皮膚バリア機能を向上させる作用を有する成分がヘスペリジンと類似した溶出挙動を示すためである。前記の皮膚外用剤への配合において十分に皮膚バリア機能を向上しうる抽出物又は分画精製物としては、ヘスペリジンの含有量が０．０５〜０．１質量％のものが好ましく例示できる。かかる抽出物又は分画精製物を、０．０１〜１質量％、好ましくは０．０５〜０．５質量％含有せしめることにより、皮膚バリア機能を向上せしめる皮膚外用剤とすることができる。
<Measurement of skin barrier function by inhibiting movement of substance through epidermal keratinocyte layer membrane>
Frozen normal human epidermal keratinocytes (NHEK) (manufactured by Kurashiki Boseki Co., Ltd.) are thawed and cultured at 37 ° C. and 50% carbon dioxide in a 0.15 mM-Ca-containing culture solution (Humdia-KG2; Kurashiki Boseki Co., Ltd.). Cultured under atmosphere. The normal human epidermal keratinocytes (NHEK) were set on a Millicell Tissue Culture Plate (Millipore) and Corning Transwell (diameter 12 mm, polyethylene terephthalate 0.4 μm pore), upper layer 0.5 ml, lower layer 0.5 ml. Of the above culture solution was added, seeded at 2 × 10 5 / cm 2 , and further cultured for 72 hours.
After confirming that the cells were confluent, the medium was replaced with 1.45 mM-Ca-containing-Humdia-KG2 medium, and then cultured for 96 hours. Then exchanged with a culture medium containing extract is a test sample, the culture was continued, after one day, after two days, measured TER (Transepithe l ial Electrical Resistance) values (Omega m 2) after 3 days . The inhibitory concentration is determined by measuring the TER value after a certain time with respect to the TER value at the time of adding the test sample-containing culture solution.
Such an inhibitory concentration can be easily estimated by the content of hesperidin. This is because a component having an action of improving the skin barrier function contained in spruce shows an elution behavior similar to that of hesperidin. Preferred examples of the extract or fraction purified product that can sufficiently improve the skin barrier function in the above-mentioned external preparation for skin include those having a hesperidin content of 0.05 to 0.1% by mass. By containing 0.01 to 1% by mass, preferably 0.05 to 0.5% by mass of the extract or the fraction-purified product , a skin external preparation that improves the skin barrier function can be obtained.
前記測定において、１０％以上の抵抗値の増加が認められる場合に、本発明の皮膚外用剤に含有させるのに適切な抽出物又は分画精製物の濃度であると判断した。この時、被検試料の力価が一定になるように抽出物又は分画精製物を水、５０％エタノール水溶液、５０％１，３−ブタンジオールなどで希釈して配合することもできる。
In the measurement, when an increase in resistance value of 10% or more was observed, it was determined that the concentration of the extract or fraction purified product was appropriate for inclusion in the external preparation for skin of the present invention. At this time, the extract or fraction- purified product can be diluted with water, 50% ethanol aqueous solution, 50% 1,3-butanediol or the like so that the titer of the test sample becomes constant.
本発明の皮膚外用剤に於いては、前記のミカン科ミカン属ダイダイの果皮（トウヒ）の抽出物又は分画精製物以外に、通常化粧料や皮膚外用医薬で使用される任意成分を含有することが出来る。この様な任意成分としては、例えば、マカデミアナッツ油、アボガド油、トウモロコシ油、オリーブ油、ナタネ油、ゴマ油、ヒマシ油、サフラワー油、綿実油、ホホバ油、ヤシ油、パーム油、液状ラノリン、硬化ヤシ油、硬化油、モクロウ、硬化ヒマシ油、ミツロウ、キャンデリラロウ、カルナウバロウ、イボタロウ、ラノリン、還元ラノリン、硬質ラノリン、ホホバロウ等のオイル、ワックス類、流動パラフィン、スクワラン、プリスタン、オゾケライト、パラフィン、セレシン、ワセリン、マイクロクリスタリンワックス等の炭化水素類、オレイン酸、イソステアリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、ベヘン酸、ウンデシレン酸等の高級脂肪酸類、セチルアルコール、ステアリルアルコール、イソステアリルアルコール、ベヘニルアルコール、オクチルドデカノール、ミリスチルアルコール、セトステアリルアルコール等の高級アルコール等、イソオクタン酸セチル、ミリスチン酸イソプロピル、イソステアリン酸ヘキシルデシル、アジピン酸ジイソプロピル、セバチン酸ジ−２−エチルヘキシル、乳酸セチル、リンゴ酸ジイソステアリル、ジ−２−エチルヘキサン酸エチレングリコール、ジカプリン酸ネオペンチルグリコール、ジ−２−ヘプチルウンデカン酸グリセリン、トリ−２−エチルヘキサン酸グリセリン、トリ−２−エチルヘキサン酸トリメチロールプロパン、トリイソステアリン酸トリメチロールプロパン、テトラ−２−エチルヘキサン酸ペンタンエリトリット等の合成エステル油類、ジメチルポリシロキサン、メチルフェニルポリシロキサン、ジフェニルポリシロキサン等の鎖状ポリシロキサン、オクタメチルシクロテトラシロキサン、デカメチルシクロペンタシロキサン、ドデカメチルシクロヘキサンシロキサン等の環状ポリシロキサン、アミノ変性ポリシロキサン、ポリエーテル変性ポリシロキサン、アルキル変性ポリシロキサン、フッ素変性ポリシロキサン等の変性ポリシロキサン等のシリコーン油等の油剤類、脂肪酸セッケン（ラウリン酸ナトリウム、パルミチン酸ナトリウム等）、ラウリル硫酸カリウム、アルキル硫酸トリエタノールアミンエーテル等のアニオン界面活性剤類、塩化ステアリルトリメチルアンモニウム、塩化ベンザルコニウム、ラウリルアミンオキサイド等のカチオン界面活性剤類、イミダゾリン系両性界面活性剤（２−ココイル−２−イミダゾリニウムヒドロキサイド−１−カルボキシエチロキシ２ナトリウム塩等）、ベタイン系界面活性剤（アルキルベタイン、アミドベタイン、スルホベタイン等）、アシルメチルタウリン等の両性界面活性剤類、ソルビタン脂肪酸エステル類（ソルビタンモノステアレート、セスキオレイン酸ソルビタン等）、グリセリン脂肪酸類（モノステアリン酸グリセリン等）、プロピレングリコール脂肪酸エステル類（モノステアリン酸プ
ロピレングリコール等）、硬化ヒマシ油誘導体、グリセリンアルキルエーテル、ＰＯＥソルビタン脂肪酸エステル類（ＰＯＥソルビタンモノオレエート、モノステアリン酸ポリオキエチレンソルビタン等）、ＰＯＥソルビット脂肪酸エステル類（ＰＯＥ−ソルビットモノラウレート等）、ＰＯＥグリセリン脂肪酸エステル類（ＰＯＥ−グリセリンモノイソステアレート等）、ＰＯＥ脂肪酸エステル類（ポリエチレングリコールモノオレート、ＰＯＥジステアレート等）、ＰＯＥアルキルエーテル類（ＰＯＥ２−オクチルドデシルエーテル等）、ＰＯＥアルキルフェニルエーテル類（ＰＯＥノニルフェニルエーテル等）、プルロニック型類、ＰＯＥ・ＰＯＰアルキルエーテル類（ＰＯＥ・ＰＯＰ２−デシルテトラデシルエーテル等）、テトロニック類、ＰＯＥヒマシ油・硬化ヒマシ油誘導体（ＰＯＥヒマシ油、ＰＯＥ硬化ヒマシ油等）、ショ糖脂肪酸エステル、アルキルグルコシド等の非イオン界面活性剤類、ポリエチレングリコール、グリセリン、１，３−ブタンジオール、エリスリトール、ソルビトール、キシリトール、マルチトール、プロピレングリコール、ジプロピレングリコール、ジグリセリン、イソプレングリコール、１，２−ペンタンジオール、２，４−ヘキシレングリコール、１，２−ヘキサンジオール、１，２−オクタンジオール等の多価アルコール類、ピロリドンカルボン酸ナトリウム、乳酸、乳酸ナトリウム等の保湿成分類、グアガム、クインスシード、カラギーナン、ガラクタン、アラビアガム、ペクチン、マンナン、デンプン、キサンタンガム、カードラン、メチルセルロース、ヒドロキシエチルセルロース、カルボキシメチルセルロース、メチルヒドロキシプロピルセルロース、コンドロイチン硫酸、デルマタン硫酸、グリコーゲン、ヘパラン硫酸、ヒアルロン酸、ヒアルロン酸ナトリウム、トラガントガム、ケラタン硫酸、コンドロイチン、ムコイチン硫酸、ヒドロキシエチルグアガム、カルボキシメチルグアガム、デキストラン、ケラト硫酸，ローカストビーンガム，サクシノグルカン，カロニン酸，キチン，キトサン、カルボキシメチルキチン、寒天、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、ポリアクリル酸ナトリウム、ポリエチレングリコール、ベントナイト等の増粘剤、表面を処理されていても良い、マイカ、タルク、カオリン、合成雲母、炭酸カルシウム、炭酸マグネシウム、無水ケイ酸（シリカ）、酸化アルミニウム、硫酸バリウム等の粉体類、表面を処理されていても良い、ベンガラ、黄酸化鉄、黒酸化鉄、酸化コバルト、群青、紺青、酸化チタン、酸化亜鉛の無機顔料類、表面を処理されていても良い、雲母チタン、魚燐箔、オキシ塩化ビスマス等のパール剤類、レーキ化されていても良い赤色２０２号、赤色２２８号、赤色２２６号、黄色４号、青色４０４号、黄色５号、赤色５０５号、赤色２３０号、赤色２２３号、橙色２０１号、赤色２１３号、黄色２０４号、黄色２０３号、青色１号、緑色２０１号、紫色２０１号、赤色２０４号等の有機色素類、ポリエチレン末、ポリメタクリル酸メチル、ナイロン粉末、オルガノポリシロキサンエラストマー等の有機粉体類、パラアミノ安息香酸系紫外線吸収剤、アントラニル酸系紫外線吸収剤、サリチル酸系紫外線吸収剤、桂皮酸系紫外線吸収剤、ベンゾフェノン系紫外線吸収剤、糖系紫外線吸収剤、２−（２’−ヒドロキシ−５’−ｔ−オクチルフェニル)ベンゾトリアゾール、４−メトキシ−４’−ｔ−ブチルジベンゾイルメタン等の紫外線吸収剤類、エタノール、イソプロパノール等の低級アルコール類、ビタミンＡ又はその誘導体、ビタミンＢ 6 塩酸塩，ビタミンＢ 6 トリパルミテート，ビタミンＢ 6 ジオクタノエート，ビタミンＢ 2 又はその誘導体，ビタミンＢ 12 ，ビタミンＢ 15 又はその誘導体等のビタミンＢ類、α−トコフェロール，β−トコフェロール，γ−トコフェロール，ビタミンＥアセテート等のビタミンＥ類、ビタミンＤ類、ビタミンＨ、パントテン酸、パンテチン、ピロロキノリンキノン等のビタミン類、フェノキシエタノール等の抗菌剤などが好ましく例示できる。これらを常法に従って処理することにより、本発明の皮膚外用剤は製造することが出来る。
The external preparation for skin of the present invention contains optional components usually used in cosmetics and external preparations for skin, in addition to the above-mentioned extract of the citrus mandarin genus perilla (spruce) or purified fraction. I can do it. Examples of such optional ingredients include macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, and hardened coconut oil. Oils such as hardened oil, mole, hardened castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, waxes, liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum , Hydrocarbons such as microcrystalline wax, higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid, cetyl alcohol, stearyl alcohol, isostearyl Alcohol, behenyl alcohol, octyldodecanol, higher alcohol such as myristyl alcohol, cetostearyl alcohol, cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, malic acid Diisostearyl, di-2-ethylhexanoic acid ethylene glycol, dicaprate neopentyl glycol, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, tri Synthetic ester oils such as trimethylolpropane isostearate and pentane erythritol tetra-2-ethylhexanoate, dimethylpolysiloxane, methylphenylpoly Loxane, linear polysiloxane such as diphenylpolysiloxane, cyclic polysiloxane such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexanesiloxane, amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, Oil agents such as silicone oil such as modified polysiloxane such as fluorine-modified polysiloxane, anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine ether of alkyl sulfate, chloride Cationic surfactants such as stearyltrimethylammonium, benzalkonium chloride, laurylamine oxide, imidazoline-based amphoteric surfactants (2-cocoyl-2-imida Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), amphoteric surfactants such as acylmethyltaurine, sorbitan fatty acid esters (sorbitan) Monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (eg, glyceryl monostearate), propylene glycol fatty acid esters (eg, propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid ester Tells (POE-glycerol monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkyl phenyl ethers (POE nonylphenyl) Ethers, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), Nonionic surfactants such as sucrose fatty acid esters and alkyl glucosides, polyethylene glycol, glycerin, 1,3-butanediol, erythritol, sorbitol, xylitol, maltitol, propylene glycol Polyol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexylene glycol, 1,2-hexanediol, 1,2-octanediol and other polyhydric alcohols, pyrrolidone carvone Moisturizing ingredients such as sodium acid, lactic acid, sodium lactate, guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, curdlan, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylhydroxypropylcellulose, chondroitin Sulfuric acid, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, mucoitin sulfate, hydro Xiethyl guar gum, carboxymethyl guar gum, dextran, keratosulfuric acid, locust bean gum, succinoglucan, caronic acid, chitin, chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium polyacrylate, polyethylene Thickeners such as glycol and bentonite, surface may be treated, powders such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicic anhydride (silica), aluminum oxide, barium sulfate Surface may be treated, bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide inorganic pigments, surface may be treated, titanium mica, fish Phosphorous foil, bismuth oxychloride, etc. Red, No. 202, Red 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201 No., Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, and the like, polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer Organic powders such as paraaminobenzoic acid UV absorbers, anthranilic acid UV absorbers, salicylic acid UV absorbers, cinnamic acid UV absorbers, benzophenone UV absorbers, sugar UV absorbers, 2- ( UV absorption such as 2'-hydroxy-5'-t-octylphenyl) benzotriazole, 4-methoxy-4'-t-butyldibenzoylmethane Agents, ethanol, lower alcohols such as isopropanol, vitamin A or its derivatives, vitamin B 6 hydrochloride, vitamin B 6 tripalmitate, vitamin B 6 dioctanoate, vitamin B 2 or derivatives thereof, vitamin B 12, vitamin B 15 Or vitamin B such as derivatives thereof, α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E such as vitamin E acetate, vitamin D, vitamin H, pantothenic acid, panthetin, vitamins such as pyrroloquinoline quinone, Preferred examples include antibacterial agents such as phenoxyethanol. The skin external preparation of this invention can be manufactured by processing these according to a conventional method.
本発明の皮膚外用剤は、前記本発明の製造方法に従って製造されたものであり、前記ミカン科ミカン属ダイダイの果皮（トウヒ）の抽出物又は分画精製物を、表皮角化細胞層膜の透過性を１０％以上抑制するに足る量、好適にはヘスペリジンの含有量が０．０５〜０．１質量％のものを０．０１〜１質量％含有することを特徴としている。この様な透過性の抑制効果について、効果を確認した後に配合されるので、ロット毎の力価の変動が無く、生化学的に安定した皮膚外用剤とすることができる。通常、生薬等の植物体などの抽出物を含有する皮膚外用剤において、有効成分の含有量が生薬等の産地や季節により異なるため、生理化学的効果が大きく異なってしまう場合があったが、本発明の皮膚外用剤では生理学的効果は、生薬等の抽出物を含有する形態においても安定している。
The external preparation for skin of the present invention, the has been produced according to the production method of the present invention, the extract or fraction purified product pericarp (spruce) of the Rutaceae Citrus aurantium, the epidermal keratinocytes layer film An amount sufficient to suppress the permeability by 10% or more , preferably 0.01 to 1% by mass with a hesperidin content of 0.05 to 0.1% by mass . About such an inhibitory effect of permeability, since it is blended after confirming the effect, there is no fluctuation of the titer from lot to lot, and a biochemically stable skin external preparation can be obtained. Usually, in skin external preparations containing extracts such as herbal medicines, etc., because the content of active ingredients varies depending on the production area and season of herbal medicines, etc., the physiochemical effects may vary greatly, In the external preparation for skin of the present invention, the physiological effect is stable even in a form containing an extract such as a herbal medicine.
電流の抵抗値による皮膚バリア機能の測定
凍結正常ヒト表皮角化細胞（ＮＨＥＫ）（倉敷紡績株式会社製）を解凍し、０．１５ｍＭ−Ｃａ含有培養液（Ｈｕｍｅｄｉａ−ＫＧ２；倉敷紡績株式会社製）にて、３７℃、５０％二酸化炭素雰囲気下で培養した。この正常ヒト表皮角化細胞（ＮＨＥＫ）をMillicell Tissue Culture Plate（ミリポア社製）にコーニング社製トランスウェル（直径１２ｍｍ、ポリエチレンテレフタレート０．４μｍポア）をセットし、上層０．５ｍｌ、下層０．５ｍｌの前記培養液を入れ、２×１０ 5 ／ｃｍ 2 で播種し、さらに７２時間培養した。コンフルエントになったことを確認し、１．４５ｍＭ−Ｃａ含有−Ｈｕｍｅｄｉａ−ＫＧ２培地に交換し、その後９６時間培養した。その後、実施例１のトウヒ抽出物を１０-5ｖ／ｖ％となるように培養液中に添加した培養液に交換して、培養を継続し、１日後、２日後、３日後にＴＥＲを測定した。抽出物の添加時のＴＥＲ（Transepithelial Electrical Resistance）値（Ωｍ 2 ）に対する、一定時間後のＴＥＲ値の割合（％）で示した。結果を図１に示す。さらに、前記実施例１において、作製したヘスペリジン含有量の低い比較品１に関しても同様の測定を実施した。結果を図２に示す。
Measurement of skin barrier function by resistance of electric current Frozen normal human epidermal keratinocytes (NHEK) (manufactured by Kurashiki Boseki Co., Ltd.) are thawed, and 0.15 mM-Ca-containing culture solution (Humdia-KG2; Kurashiki Boseki Co., Ltd.) And cultured at 37 ° C. in a 50% carbon dioxide atmosphere. The normal human epidermal keratinocytes (NHEK) were set on a Millicell Tissue Culture Plate (Millipore) and Corning Transwell (diameter 12 mm, polyethylene terephthalate 0.4 μm pore), upper layer 0.5 ml, lower layer 0.5 ml. Of the above culture solution was added, seeded at 2 × 10 5 / cm 2 , and further cultured for 72 hours. After confirming that the cells were confluent, the medium was replaced with 1.45 mM-Ca-containing-Humdia-KG2 medium, and then cultured for 96 hours. Thereafter, the spruce extract of Example 1 was replaced with a culture solution added to the culture solution so as to be 10 −5 v / v%, and the culture was continued. After 1 day, 2 days, and 3 days, TER was changed. It was measured. For extract upon addition TER (Transepithe l ial Electrical Resistance) values (Omega m 2), it is a percentage of the TER value after a predetermined time (%). The results are shown in FIG. Furthermore, in the said Example 1, the same measurement was implemented also about the manufactured comparative product 1 with low hesperidin content. The results are shown in FIG.
下記に示す処方に従って、本発明の皮膚外用剤である乳液を作製した。即ち、（Ａ）の各成分を混合し、８０℃に加熱した。一方、（Ｂ）の各成分を８０℃に加熱した。（Ａ）の混合物に（Ｂ）の混合物を加えて撹拌して乳化させ、更に（Ｃ）を加えて中和し、その後３５℃にまで撹拌、冷却し、実施例３の乳液を作製した。実施例３の乳液において、実施例１のトウヒ抽出物を水に置換した比較例１も作製した。
According to the prescription shown below, the emulsion which is a skin external preparation of this invention was produced. That is, the components (A) were mixed and heated to 80 ° C. On the other hand, each component of (B) was heated to 80 degreeC. The mixture of (B) was added to the mixture of (A) and stirred to emulsify, and further (C) was added to neutralize, and then the mixture was stirred and cooled to 35 ° C. to prepare the emulsion of Example 3 . Comparative Example 1 was also produced in which the spruce extract of Example 1 was replaced with water in the emulsion of Example 3 .
（試験例１）
健常な成人男子５名の上腕内側部に１ｃｍ×１ｃｍの３部位を設定し、未処置部位のＴＥＷＬ値を測定した。次いで、サージカルテープ（３Ｍ社製）により、浸潤液が出るまでテープストリッピングを繰り返し、テープストリッピング直後のＴＥＷＬ値を測定した。ＴＥＷＬ値の測定後、１部位には実施例３のトウヒ抽出物含有乳液、もう一部位には比較例１を塗布し、残りの１部位は何も塗布しないで放置した。このサンプル塗布を１日３回行い、サンプル塗布４８時間後に再度ＴＥＷＬ値を測定し、テープストリッピング直後からのＴＥＷＬの回復状況を評価した。結果を、図３に示す。
(Test Example 1)
Three sites of 1 cm × 1 cm were set on the inner side of the upper arm of five healthy adult males, and the TEWL value of the untreated site was measured. Next, tape stripping was repeated with a surgical tape (manufactured by 3M) until the infiltrating solution was produced, and the TEWL value immediately after the tape stripping was measured. After measuring the TEWL value, the spruce extract-containing emulsion of Example 3 was applied to one site, and Comparative Example 1 was applied to the other part, and the remaining 1 site was left uncoated. This sample application was performed three times a day, and the TEWL value was measured again 48 hours after the sample application, and the recovery state of TEWL immediately after tape stripping was evaluated. The results are shown in FIG.
図３の結果より、テープストリッピング後に、何も塗布しない未処置に対して、比較例１を塗布した部位では、若干の回復の促進が認められたが、トウヒ抽出物を含有した実施例３の乳液においては、損傷されたバリア機能の回復の顕著な促進が認められ、本発明のスクリーニング方法で、バリア能の向上効果の認められたトウヒ抽出物に関して、ヒトの皮膚においても皮膚バリア能の回復効果が認められた。
From the results shown in FIG. 3, in the region where Comparative Example 1 was applied to the non-treated area where nothing was applied after tape stripping, a slight promotion of recovery was observed, but Example 3 containing a spruce extract was observed. In the emulsion, significant improvement in the recovery of damaged barrier function was observed, and the recovery of the skin barrier ability was also observed in human skin with respect to the spruce extract in which the effect of improving the barrier ability was recognized by the screening method of the present invention. The effect was recognized.
Claims (8)
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| JP2008007411A (en) * | 2006-06-27 | 2008-01-17 | Maruzen Pharmaceut Co Ltd | Transglutaminase production promoter and epidermal keratinization-normalizing agent |
| JP2008007412A (en) * | 2006-06-27 | 2008-01-17 | Maruzen Pharmaceut Co Ltd | Involucrin production promoter and epidermal keratinization-normalizing agent |
| JP5275711B2 (en) * | 2008-07-23 | 2013-08-28 | 日本メナード化粧品株式会社 | Keratinocytes differentiated from stem cells and artificial epidermal sheets |
| JP2014091727A (en) * | 2012-11-06 | 2014-05-19 | Fancl Corp | Mif secretion inhibitor |
| JP2020164486A (en) | 2019-03-29 | 2020-10-08 | 丸善製薬株式会社 | Anti-aging agents, antioxidants, anti-inflammatory agents, and whitening agents, as well as cosmetics |
| JP7285504B2 (en) * | 2021-10-14 | 2023-06-02 | 国立大学法人東海国立大学機構 | Scalp condition improving agent and cosmetic containing the same |
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| JPH08208451A (en) * | 1995-02-03 | 1996-08-13 | Kao Corp | Skin-beautifying agent mixed with extract of crude medicine from plant |
| JP4717340B2 (en) * | 1998-03-31 | 2011-07-06 | 株式会社 資生堂 | Laminin 5 production promoter |
| JP4214434B2 (en) * | 1998-11-12 | 2009-01-28 | 東洋紡績株式会社 | Cultured skin, production method and use thereof |
| JP2000212028A (en) * | 1999-01-27 | 2000-08-02 | Pola Chem Ind Inc | Preparation for external use for skin for treatment of stress disorder |
| JP2001131049A (en) * | 1999-11-04 | 2001-05-15 | Lion Corp | Skin preparation for external use |
| JP3953847B2 (en) * | 2002-03-11 | 2007-08-08 | 花王株式会社 | Lipolysis accelerator |
| JP2004000051A (en) * | 2002-05-31 | 2004-01-08 | Ecodevice Co Ltd | Cell culture vessel and method for manufacturing cultured cell |
| JP4787461B2 (en) * | 2003-05-15 | 2011-10-05 | 花王株式会社 | Skin cosmetics |
| JP2005082561A (en) * | 2003-09-10 | 2005-03-31 | B Road:Kk | Cosmetic |
| JP2005137307A (en) * | 2003-11-07 | 2005-06-02 | Japan Science & Technology Agency | Method for evaluating damage to cell and tissue and apparatus for measuring the same damage |
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