JP6288759B2 - Transglutaminase activator - Google Patents
Transglutaminase activator Download PDFInfo
- Publication number
- JP6288759B2 JP6288759B2 JP2013178621A JP2013178621A JP6288759B2 JP 6288759 B2 JP6288759 B2 JP 6288759B2 JP 2013178621 A JP2013178621 A JP 2013178621A JP 2013178621 A JP2013178621 A JP 2013178621A JP 6288759 B2 JP6288759 B2 JP 6288759B2
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- extract
- skin
- sunflower
- agent
- improving agent
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Description
本発明はトランスグルタミナーゼ活性化剤、セラミド産生促進剤、及びインボルクリン発現促進剤に関する。 The present invention relates to a transglutaminase activator, a ceramide production promoter, and an involucrin expression promoter.
表皮の角質層は、体内の水分の蒸散や外界からの刺激や異物侵入を防ぐバリア機能を担っている。角質層は角質細胞と細胞間脂質から構成され、角質細胞はコーニファイドエンベロープ(cornified envelope)と呼ばれる細胞膜様構造体で包まれている。コーニファイドエンベロープは、安定な角質細胞構造の構築に寄与しており、皮膚のバリア機能維持にとって重要な構造である。コーニファイドエンベロープは、角層の基底層にあるケラチノサイトが角化するとともに、角化に必要なタンパク質であるインボルクリン(本明細書において、「IVL」ともいう)やロリクリン等が合成され、次いでそれらのタンパク質がトランスグルタミナーゼの活性化により架橋されることで形成される。インボルクリンの発現・合成やトランスグルタミナーゼの活性は、コーニファイドエンベロープの正常な形成と表皮の正常な角化、ひいては皮膚の保湿機能の維持・改善にとって重要である。この点について、インボルクリンの発現促進及びトランスグルタミナーゼの活性化が、皮膚の正常な角化、バリア機能改善、及び肌荒れ改善につながることが報告されている(例えば、非特許文献1及び2、並びに特許文献1及び2参照)。 The stratum corneum of the epidermis has a barrier function to prevent transpiration of moisture in the body, irritation from the outside world, and entry of foreign substances. The stratum corneum is composed of corneocytes and intercellular lipids, and the corneocytes are encapsulated in a cell membrane-like structure called a cornified envelope. The cornified envelope contributes to the construction of a stable keratinocyte structure and is an important structure for maintaining the barrier function of the skin. The cornified keratinocytes in the cornified basal layer are keratinized, and involucrin (also referred to as “IVL” in this specification), loricrin, and the like are synthesized in the cornified envelope. Proteins are formed by cross-linking by activation of transglutaminase. The expression and synthesis of involucrin and the activity of transglutaminase are important for the normal formation of the cornified envelope, the normal keratinization of the epidermis, and the maintenance and improvement of the skin moisturizing function. In this regard, it has been reported that involucrin expression promotion and transglutaminase activation lead to normal skin keratinization, barrier function improvement, and rough skin improvement (for example, Non-Patent Documents 1 and 2 and Patents). Reference 1 and 2).
また、スフィンゴ脂質の一つであるセラミドは、生体全体の中では微量しか存在しない脂質である。しかし、皮膚の最も外側の層である角層中において、セラミドは脂質の約半分を占め、皮膚の保湿機構、バリア機構に重要な役割を果たしている。このセラミドは表皮細胞中において産生、分泌された後に角層の細胞間においてラメラ構造を構築することにより機能する。しかし、乾燥肌、荒れ肌、アトピー性皮膚炎、老人性乾皮症、乾癬等の皮膚疾患においては、セラミドの健全な代謝が妨げられ、角層中のセラミド量が減少し、皮膚の保湿能の低下や表皮の角化不全、バリア能の低下等を引き起こしていることが数多く報告されている(非特許文献3参照)。セラミドの産生を促進する物質には、動物細胞の増殖抑制、分化誘導、アポトーシスを誘導するなどの効果が期待でき、ひいては炎症性疾患、悪性腫瘍など、細胞の増殖あるいは分化の異常に起因する疾患に対する治療効果が期待できると考えられている(非特許文献4参照)。さらに、セラミドには、骨吸収抑制作用、骨強化作用、歯槽骨減少抑制作用があり、骨粗鬆症、骨折、腰痛、リウマチなどの骨関節疾患の予防及び改善に有用であること(特許文献3参照)、歯周病の予防に効果があること(特許文献4参照)、セラミドには、毛髪のハリ、コシの付与及び感触改善作用があることも報告されている(特許文献5参照)。
このようにセラミドには種々の効能が期待できることもあり、セラミドの産出を促進しうる物質の探求が望まれている。
In addition, ceramide, which is one of the sphingolipids, is a lipid that exists only in a trace amount in the entire living body. However, in the stratum corneum, the outermost layer of the skin, ceramide occupies about half of the lipid and plays an important role in the skin moisturizing and barrier mechanisms. This ceramide functions by constructing a lamellar structure between cells in the stratum corneum after being produced and secreted in epidermal cells. However, in skin diseases such as dry skin, rough skin, atopic dermatitis, senile psoriasis and psoriasis, the healthy metabolism of ceramide is hindered, the amount of ceramide in the stratum corneum is reduced, and the skin's moisture retention ability is reduced. It has been reported many that it causes a decrease, keratinization failure of the epidermis, a decrease in barrier ability, etc. (see Non-Patent Document 3). Substances that promote ceramide production can be expected to have effects such as suppression of animal cell proliferation, induction of differentiation, and induction of apoptosis. As a result, diseases caused by abnormal cell proliferation or differentiation such as inflammatory diseases and malignant tumors. It is thought that the therapeutic effect with respect to can be expected (refer nonpatent literature 4). Furthermore, ceramide has a bone resorption inhibitory action, a bone strengthening action, and an alveolar bone loss inhibitory action, and is useful for the prevention and improvement of osteoarthritis such as osteoporosis, fracture, low back pain, rheumatism (see Patent Document 3). It has also been reported that ceramide has an effect in preventing periodontal disease (see Patent Document 4), and that ceramide has an effect of imparting firmness and stiffness to the hair and improving touch (see Patent Document 5).
Thus, ceramide can be expected to have various effects, and there is a demand for a substance that can promote the production of ceramide.
また、インボルクリン等の角化関連タンパク質は毛髪形成にも関与することが知られている。例えば、毛髪毛根部における遺伝子発現解析の結果、くせ毛形質者ではインボルクリン遺伝子の発現量が有意に増加していること、及びインボルクリン遺伝子の発現量を増加させる物質がくせ毛や縮毛の促進剤又はウェーブ化促進剤となりうることが報告されている(特許文献6参照)。 In addition, keratin-related proteins such as involucrin are known to be involved in hair formation. For example, as a result of gene expression analysis in hair roots, the expression level of the involucrin gene is significantly increased in those with comb hair, and a substance that increases the expression level of the involucrin gene is a promoter or wave of comb hair or curly hair. It has been reported that it can be a chemical accelerator (see Patent Document 6).
キツネノマゴ(Acanthaceae)科ハグロソウ(Peristrophe)属に属する植物の1種であるハグロソウ(Peristrophe japonica)について、その抽出物の生理活性としては、メラニン生成の抑制効果及びドーパオキシダーゼ活性の抑制効果を有すること等が知られている(例えば、特許文献7参照)。しかし、ハグロソウの抽出物がトランスグルタミナーゼを活性化し、セラミドの産生、及びインボルクリンの発現を促進し、皮膚のバリア機能や保湿機能の維持又は改善、肌荒れの予防又は改善、並びに毛髪のくせ毛化、縮毛、ウェーブ化に有用であることはこれまで知られていなかった。 As for the physiological activity of the extract of Peristrophe japonica , one of the plants belonging to the genus Peristrophe belonging to the family Acanthaceae, it has an inhibitory effect on melanin production and an inhibitory effect on dopa oxidase activity, etc. Is known (see, for example, Patent Document 7). However, the extract of gypsophila activates transglutaminase, promotes the production of ceramide and the expression of involucrin, maintains or improves the barrier function and moisturizing function of the skin, prevents or improves rough skin, and makes the hair become bruised and shrunk. It has not been known so far to be useful for hair and wave formation.
本発明は、トランスグルタミナーゼを活性化し、皮膚のバリア機能や保湿機能の維持又は改善、肌荒れの予防又は改善に有用な、トランスグルタミナーゼ活性化剤の提供を課題とする。
また、本発明は、セラミドの産生を促進し、皮膚のバリア機能や保湿機能の維持又は改善、肌荒れの予防又は改善などに有用な、セラミド産生促進剤の提供を課題とする。
さらに、本発明は、インボルクリンの発現を促進し、皮膚のバリア機能や保湿機能の維持又は改善、肌荒れの予防又は改善、並びに毛髪のくせ毛化、縮毛、ウェーブ化に有用な、インボルクリン発現促進剤の提供を課題とする。
An object of the present invention is to provide a transglutaminase activator that activates transglutaminase and is useful for maintaining or improving the skin barrier function and moisturizing function, and preventing or improving rough skin.
Another object of the present invention is to provide a ceramide production promoter that promotes the production of ceramide and is useful for maintaining or improving the skin barrier function and moisturizing function, preventing or improving rough skin, and the like.
Furthermore, the present invention is an involucrin expression promoter that promotes the expression of involucrin, and is useful for maintaining or improving the skin barrier function and moisturizing function, preventing or improving rough skin, as well as hair combing, curling, and waving. The issue is to provide
本発明者等は上記課題に鑑み鋭意検討を行った結果、ハグロソウの抽出物が、トランスグルタミナーゼを活性化すること、セラミドの産生を促進すること、及びインボルクリンの発現を促進することを見出した。本発明はこれらの知見に基づいて完成されたものである。 As a result of intensive studies in view of the above-mentioned problems, the present inventors have found that an extract of Agrobacterium activates transglutaminase, promotes ceramide production, and promotes involucrin expression. The present invention has been completed based on these findings.
本発明は、ハグロソウの抽出物を有効成分とする、トランスグルタミナーゼ活性化剤に関する。
また、本発明は、ハグロソウの抽出物を有効成分とする、セラミド産生促進剤に関する。
また、本発明は、ハグロソウの抽出物を有効成分とする、インボルクリン発現促進剤に関する。
また、本発明は、ハグロソウの抽出物を有効成分とする、表皮角化改善剤に関する。
また、本発明は、ハグロソウの抽出物を有効成分とする、皮膚保湿機能改善剤に関する。
また、本発明は、ハグロソウの抽出物を有効成分とする、皮膚バリア機能改善剤に関する。
また、本発明は、ハグロソウの抽出物を有効成分とする、肌荒れ予防又は改善剤に関する。
さらに、本発明は、ハグロソウの抽出物を有効成分とする、くせ毛化剤に関する。
TECHNICAL FIELD The present invention relates to a transglutaminase activator comprising an extract of agglomerated as an active ingredient.
Moreover, this invention relates to the ceramide production promoter which uses the extract of a sunflower as an active ingredient.
Moreover, this invention relates to the involucrin expression promoter which uses the extract of a sunflower as an active ingredient.
In addition, the present invention relates to an epidermis keratinization improving agent comprising an extract of Amaranthus as an active ingredient.
Moreover, this invention relates to the skin moisturizing function improving agent which uses the extract of a sunflower as an active ingredient.
Moreover, this invention relates to the skin barrier function improving agent which uses the extract of a sunflower as an active ingredient.
Moreover, this invention relates to the rough skin prevention or improvement agent which uses the extract of a sunflower as an active ingredient.
Furthermore, the present invention relates to a combing hair agent containing an extract of Amaranthus as an active ingredient.
本発明のトランスグルタミナーゼ活性化剤は、トランスグルタミナーゼを活性化し、皮膚のバリア機能や保湿機能の維持又は改善、肌荒れの予防又は改善に有用である。
本発明のセラミド産生促進剤は、セラミドの産生を促進し、皮膚のバリア機能や保湿機能の維持又は改善、肌荒れの予防又は改善などに有用である。
本発明のインボルクリン発現促進剤は、インボルクリンの発現を促進し、皮膚のバリア機能維持又は改善、肌荒れの予防又は改善や毛髪のくせ毛化、縮毛、ウェーブ化に有用である。
The transglutaminase activator of the present invention activates transglutaminase and is useful for maintaining or improving the skin barrier function and moisturizing function, and preventing or improving rough skin.
The ceramide production promoter of the present invention promotes the production of ceramide and is useful for maintaining or improving the barrier function and moisturizing function of skin, preventing or improving rough skin, and the like.
The involucrin expression promoter of the present invention promotes the expression of involucrin, and is useful for maintaining or improving the barrier function of skin, preventing or improving rough skin, and combing hair, curly hair, and making waves.
本明細書において、「改善」とは、疾患、症状又は状態の好転、疾患、症状又は状態の悪化の防止又は遅延、あるいは疾患、症状又は状態の進行の逆転、防止又は遅延をいう。
また、本明細書において、「非治療的」とは、医療行為、すなわち治療による人体への処置行為を含まない概念である。
また、本明細書において、「予防」とは、個体における疾患若しくは症状の発症の防止又は遅延、あるいは個体の疾患若しくは症状の発症の危険性を低下させることをいう。
さらに、本明細書において、「肌荒れ」とは、皮膚の保湿力が低下して皮膚の水分が奪われ、皮膚表面に落屑や皮膚のひび割れが認められる状態又は皮膚表面粗さが大きくなるような状態をいう。このような状態の皮膚を「あれ肌」又は「ドライスキン」ともいう。
In the present specification, “improvement” refers to improvement of a disease, symptom or condition, prevention or delay of deterioration of the disease, symptom or condition, or reversal, prevention or delay of progression of the disease, symptom or condition.
Further, in the present specification, “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by therapy.
In the present specification, “prevention” means prevention or delay of the onset of a disease or symptom in an individual, or reduction of the risk of onset of a disease or symptom in an individual.
Furthermore, in this specification, “rough skin” means that the moisture retention capacity of the skin is reduced and the moisture of the skin is taken away, and the skin surface is crushed or cracked, or the skin surface roughness is increased. State. Skin in such a state is also referred to as “that skin” or “dry skin”.
本発明のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、及びインボルクリン発現促進剤は、ハグロソウの抽出物を有効成分とする。後述の実施例で実証するように、ハグロソウの抽出物は、トランスグルタミナーゼ活性化効果、セラミドの産生促進効果、及びインボルクリン発現促進効果を有する。
また、本発明の表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、及び肌荒れ予防又は改善剤も、ハグロソウの抽出物を有効成分とする。前述のように、トランスグルタミナーゼの活性化、セラミドの産生促進、及びインボルクリンの発現促進は、表皮の角化改善や皮膚の保湿機能の改善、皮膚のバリア機能維持、及び肌荒れの予防又は改善に非常に重要である。したがって、トランスグルタミナーゼ活性化効果、セラミドの産生促進効果、及びインボルクリン発現促進効果を有するハグロソウの抽出物を、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、及び肌荒れ予防又は改善剤の有効成分とすることができる。
また、前述のように、セラミドは細胞の増殖、分化、アポトーシス等の制御に関係する。そのため、セラミドの産生を促進するハグロソウの抽出物は、動物細胞の増殖抑制、分化誘導、アポトーシスの誘導等により、炎症性疾患、悪性腫瘍など、細胞の増殖あるいは分化の異常に起因する疾患を予防又は治療するための医薬品、医薬部外品等に有用である。また、ハグロソウの抽出物は、骨粗鬆症、骨折、腰痛、リウマチなどの骨関節疾患の予防又は改善、歯周病の予防又は改善のための医薬品、医薬部外品等にも使用しうる。さらに、ハグロソウの抽出物は、毛髪にハリ・コシを付与したり毛髪の感触を改善するための医薬部外品、化粧品等の用途にも有用である。
さらに、前述のように、インボルクリン遺伝子の発現量を増加させる物質がくせ毛や縮毛の促進剤又はウェーブ化促進剤となりうる。したがって、インボルクリン発現促進効果を有するハグロソウの抽出物を、くせ毛化剤の有効成分とすることができる。なお、本明細書において「くせ毛化」とは、毛髪のくせ毛や縮毛の促進、ウェーブ化の促進を包含するものである。
The transglutaminase activator, the ceramide production promoter, and the involucrin expression promoter of the present invention contain an extract of sunflower as an active ingredient. As demonstrated in the examples described later, the extract of sunflower has a transglutaminase activation effect, a ceramide production promoting effect, and an involucrin expression promoting effect.
In addition, the epidermis keratinization improving agent, skin moisturizing function improving agent, skin barrier function improving agent, and rough skin preventing or improving agent of the present invention also have an extract of hazelnut as an active ingredient. As mentioned above, activation of transglutaminase, promotion of ceramide production, and promotion of involucrin expression are very effective in improving keratinization of the epidermis and skin moisturizing function, maintaining the barrier function of skin, and preventing or improving rough skin. Is important to. Therefore, an extract of angiosperm having transglutaminase activation effect, ceramide production promotion effect, and involucrin expression promotion effect is used as an epidermis keratinization improving agent, skin moisturizing function improving agent, skin barrier function improving agent, and rough skin prevention or improvement. It can be an active ingredient of an agent.
As described above, ceramide is involved in the control of cell proliferation, differentiation, apoptosis, and the like. For this reason, the extract of Agrobacterium that promotes ceramide production prevents diseases caused by abnormal cell growth or differentiation, such as inflammatory diseases and malignant tumors, by suppressing the growth of animal cells, inducing differentiation, and inducing apoptosis. Or it is useful for the pharmaceutical for treatment, a quasi-drug, etc. Moreover, the extract of the sunflower can be used for prevention or improvement of osteoarthritis such as osteoporosis, bone fracture, low back pain, rheumatism, pharmaceuticals for preventing or improving periodontal disease, quasi drugs, and the like. Furthermore, the extract of gypsophila is also useful for applications such as quasi-drugs and cosmetics for imparting firmness and stiffness to the hair and improving the feel of the hair.
Furthermore, as described above, a substance that increases the expression level of the involucrin gene can be a promoter for comb hair and curly hair or a promoter for wave formation. Therefore, the extract of the sunflower which has the effect of promoting the expression of involucrin can be used as an active ingredient of the hair-cutting agent. In the present specification, “combination” includes the promotion of comb hair and curly hair and the promotion of wave formation.
本明細書における「ハグロソウ」は、キツネノマゴ科ハグロソウ属の植物である。
ハグロソウ抽出物の製造には、ハグロソウの任意の部分が使用可能であり、全草、根、塊根、根茎、幹、枝、茎、葉(葉身、葉柄等)、樹皮、樹液、樹脂、花(花弁、子房等)、果実(成熟果実、未熟果実等)、種子等を用いることができる。また、これらの部位を複数組み合わせて用いてもよい。なかでも、本発明に用いるハグロソウの抽出物は、ハグロソウの全草の抽出物であることが好ましい。
In the present specification, the term “Annelina” refers to a plant belonging to the genus Amaranthaceae.
Any part of the plant can be used for the production of the plant extract, including whole grass, root, tuberous root, rhizome, trunk, branch, stem, leaf (leaf blade, petiole, etc.), bark, sap, resin, flower (Petals, ovaries, etc.), fruits (mature fruits, immature fruits, etc.), seeds and the like can be used. A combination of these parts may also be used. Especially, it is preferable that the extract of the sunflower used for this invention is the extract of the whole plant of a sunflower.
本発明に用いるハグロソウの抽出物は、植物抽出等に用いられる通常の抽出方法により得ることができる。抽出方法は適宜設定することができ、上記植物を常温又は加温下にて抽出するか又はソックスレー抽出器等の抽出器具を用いて抽出することにより得ることが好ましい。
ハグロソウの抽出物の調製には、ハグロソウをそのまま又は乾燥粉砕して用いることができる。また、ハグロソウの水蒸気蒸留物又は圧搾物を用いることもでき、これらは精油等より精製したものを用いることもでき、また市販品を利用することもできる。ハグロソウ、又はその水蒸気蒸留物若しくは圧搾物は、いずれかを単独で、又は2種以上を組み合わせて使用してもよい。
The extract of the sunflower used in the present invention can be obtained by an ordinary extraction method used for plant extraction or the like. The extraction method can be appropriately set, and is preferably obtained by extracting the plant at room temperature or under heating or using an extraction tool such as a Soxhlet extractor.
For the preparation of the extract of the sunflower, the sunflower can be used as it is or after being dried and ground. Moreover, a steam-distilled product or a pressed product of the sunflower can be used, and these can be purified from essential oils or the like, or commercially available products can also be used. You may use the sunflower, or its steam distillate or compressed product, alone or in combination of two or more.
ハグロソウの抽出物の調製に用いる抽出溶媒は適宜選択することができ、植物成分の抽出に通常用いられるもの、例えば水;メタノール、エタノール、プロパノール、ブタノール等のアルコール類;エチレングリコール、プロピレングリコール、1,2-ブチレングリコール、1,3-ブチレングリコール、1,4-ブチレングリコール、2,3-ブチレングリコール等の多価アルコール類;アセトン、メチルエチルケトン等のケトン類;酢酸メチル、酢酸エチル等のエステル類;テトラヒドロフラン、ジエチルエーテル等の鎖状及び環状エーテル類;ポリエチレングリコール等のポリエーテル類;ジクロロメタン、ジクロロエタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類;ヘキサン、シクロヘキサン、石油エーテル等の炭化水素類;ベンゼン、トルエン等の芳香族炭化水素類;ピリジン類;超臨界二酸化炭素;油脂、ワックス、その他オイル等が挙げられる。これらは単独で用いてもよいし、2種以上を組み合わせて用いてもよい。なかでも、水、エタノール、及びエタノール水溶液が好ましく、エタノール水溶液がより好ましく、アルコール含有率が30体積%以上のエタノール水溶液がさらに好ましく、アルコール含有率が40体積%以上のエタノール水溶液が特に好ましい。また、抽出に際して酸やアルカリなどを添加し、抽出溶媒のpHを調整してもよい。 The extraction solvent used for the preparation of the extract of the sunflower can be selected as appropriate, and those usually used for the extraction of plant components, such as water; alcohols such as methanol, ethanol, propanol, butanol; ethylene glycol, propylene glycol, 1 Polyhydric alcohols such as 1,2-butylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, 2,3-butylene glycol; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate Chain and cyclic ethers such as tetrahydrofuran and diethyl ether; polyethers such as polyethylene glycol; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; hydrocarbons such as hexane, cyclohexane and petroleum ether Benzene, torr Aromatic hydrocarbons such as ene; pyridines; supercritical carbon dioxide; fats and oils, waxes, and other oils. These may be used alone or in combination of two or more. Among these, water, ethanol, and an aqueous ethanol solution are preferable, an aqueous ethanol solution is more preferable, an aqueous ethanol solution having an alcohol content of 30% by volume or more is more preferable, and an aqueous ethanol solution having an alcohol content of 40% by volume or more is particularly preferable. Further, acid or alkali may be added during extraction to adjust the pH of the extraction solvent.
抽出条件も通常の条件を適用でき、例えばハグロソウを0℃以上100℃以下で0.5時間以上30日間以下浸漬又は加熱還流すればよい。抽出効率を上げる為、併せて攪拌を行ったり、溶媒中でホモジナイズ処理を行ってもよい。用いる抽出溶媒の量は、ハグロソウの重量に対して1倍量以上(好ましくは5倍量以上)100倍量以下(好ましくは50倍量、より好ましくは40倍量以下)である。 As extraction conditions, normal conditions can be applied. For example, the sunflower can be immersed or heated to reflux at 0 ° C. to 100 ° C. for 0.5 hours to 30 days. In order to increase the extraction efficiency, stirring may be performed together or homogenization treatment may be performed in a solvent. The amount of the extraction solvent to be used is not less than 1 time (preferably not less than 5 times) and not more than 100 times (preferably not more than 50 times, more preferably not more than 40 times) the weight of the sunflower.
本発明において、ハグロソウの抽出物をそのまま用いてもよいし、さらに適当な分離手段、例えばゲル濾過、クロマトグラフィー、精密蒸留等により活性の高い画分を分画して用いることもできる。また、得られたハグロソウの抽出物を希釈、濃縮又は凍結乾燥した後、粉末又はペースト状に調製して用いることもできる。また、前記方法により得られた抽出物を、前記抽出溶媒とは異なる溶媒で転溶して用いることもできる。
本発明において抽出物とは、前記のような抽出方法で得られた各種溶剤抽出液、その希釈液、その濃縮液、その精製画分、その乾燥末又はその転溶液を含むものである。
In the present invention, the extract of sunflower can be used as it is, or a fraction having high activity can be fractionated and used by an appropriate separation means such as gel filtration, chromatography, precision distillation or the like. Moreover, after diluting, concentrating, or freeze-drying the extract of the obtained sunflower, it can also be prepared and used for powder or paste form. In addition, the extract obtained by the above method can be used by being dissolved in a solvent different from the extraction solvent.
In the present invention, the extract includes various solvent extracts obtained by the extraction method as described above, diluted solutions thereof, concentrated solutions thereof, purified fractions thereof, dried powders thereof or transferred solutions thereof.
本発明のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ抑制又は改善剤、及びくせ毛化剤の形態は適宜選択することができ、例えば、医薬組成物、化粧料組成物若しくは食品組成物とするか、又はこれらに含有させることができる。 The forms of transglutaminase activator, ceramide production promoter, involucrin expression promoter, epidermis keratinization improver, skin moisturizing function improver, skin barrier function improver, skin roughness inhibitor or improver, and hair growth agent of the present invention are: For example, it can be a pharmaceutical composition, a cosmetic composition or a food composition, or can be contained in these.
医薬組成物を調製する場合は、通常、前記有効成分と好ましくは薬学的に許容される担体を含む製剤として調製する。薬学的に許容される担体とは、一般的に、前記有効成分とは反応しない、不活性の、無毒の、固体又は液体の、増量剤、希釈剤又はカプセル化材料等をいい、例えば、水、エタノール、ポリオール類(例えば、プロピレングリコール、ブチレングリコール、グリセリン、及びポリエチレングリコール等)、適切なそれらの混合物、植物性油などの溶媒又は分散媒体などが挙げられる。 When preparing a pharmaceutical composition, it is usually prepared as a preparation containing the active ingredient and preferably a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier generally refers to an inert, non-toxic, solid or liquid, bulking agent, diluent or encapsulating material that does not react with the active ingredient, eg, water. , Ethanol, polyols (for example, propylene glycol, butylene glycol, glycerin, and polyethylene glycol), suitable mixtures thereof, solvents or dispersion media such as vegetable oils, and the like.
医薬組成物は、経口により、非経口により、例えば、口腔内に、皮膚に、皮下に、粘膜に、静脈内に、動脈内に、筋肉内に、腹腔内に、膣内に、肺に、脳内に、眼に、及び鼻腔内に投与される。経口投与製剤としては、錠剤、顆粒剤、細粒剤、散剤、カプセル剤、チュアブル剤、ペレット剤、シロップ剤、液剤、懸濁剤及び吸入剤などが挙げられる。非経口投与製剤としては、坐剤、保持型浣腸剤、点滴剤、点眼剤、点鼻剤、ペッサリー剤、注射剤、口腔洗浄剤並びに軟膏、クリーム剤、ゲル剤、制御放出パッチ剤及び貼付剤などの皮膚外用剤などが挙げられる。医薬組成物は、徐放性皮下インプラントの形態で、又は標的送達系(例えば、モノクローナル抗体、ベクター送達、イオン注入、ポリマーマトリックス、リポソーム及びミクロスフェア)の形態で、非経口で投与してもよい。 The pharmaceutical composition is orally, parenterally, e.g., in the oral cavity, in the skin, subcutaneously, in the mucosa, intravenously, in the artery, in the muscle, in the abdominal cavity, in the vagina, in the lungs. Administered intracerebrally, ocularly and intranasally. Examples of the preparation for oral administration include tablets, granules, fine granules, powders, capsules, chewables, pellets, syrups, solutions, suspensions and inhalants. As parenteral preparations, suppositories, retention enemas, drops, eye drops, nasal drops, pessaries, injections, mouth washes, ointments, creams, gels, controlled release patches and patches Skin external preparations, and the like. The pharmaceutical compositions may be administered parenterally in the form of sustained release subcutaneous implants or in the form of targeted delivery systems (eg, monoclonal antibodies, vector delivery, ion implantation, polymer matrices, liposomes and microspheres). .
医薬組成物はさらに医薬分野において慣用の添加剤を含んでいてもよい。そのような添加剤には、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、抗酸化剤、着色剤、矯味剤などがあり、必要に応じて使用できる。長時間作用できるように徐放化するためには、既知の遅延剤等でコーティングすることもできる。賦形剤としては、例えば、カルボキシメチルセルロースナトリウム、寒天、軽質無水ケイ酸、ゼラチン、結晶セルロース、ソルビトール、タルク、デキストリン、デンプン、乳糖、白糖、ブドウ糖、メタ珪酸アルミン酸マグネシウム、リン酸水素カルシウム等が使用できる。結合剤としては、例えば、アラビアゴム、アルギン酸ナトリウム、エチルセルロース、カゼインナトリウム、カルボキシメチルセルロースナトリウム、寒天、精製水、ゼラチン、デンプン、トラガント、乳糖等が挙げられる。崩壊剤としては、例えば、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、カルボキシメチルセルロースカルシウム、結晶セルロース、デンプン、ヒドロキシプロピルスターチ等が挙げられる。滑沢剤としては、例えば、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、タルク、硬化油、ショ糖脂肪酸エステル、ロウ類等が挙げられる。抗酸化剤としては、トコフェロール、没食子酸エステル、ジブチルヒドロキシトルエン(BHT)、ブチルヒドロキシアニソール(BHA)、アスコルビン酸等が挙げられる。必要に応じてその他の添加剤や薬剤、例えば制酸剤(炭酸水素ナトリウム、炭酸マグネシウム、沈降炭酸カルシウム、合成ヒドロタルサイト等)、胃粘膜保護剤(合成ケイ酸アルミニウム、スクラルファート、銅クロロフィリンナトリウム等)を加えてもよい。 The pharmaceutical composition may further contain additives conventionally used in the pharmaceutical field. Such additives include, for example, excipients, binders, disintegrants, lubricants, antioxidants, colorants, flavoring agents, and the like, and can be used as necessary. In order to achieve sustained release so that it can act for a long time, it can also be coated with a known retarder or the like. Examples of excipients include sodium carboxymethylcellulose, agar, light anhydrous silicic acid, gelatin, crystalline cellulose, sorbitol, talc, dextrin, starch, lactose, sucrose, glucose, magnesium metasilicate magnesium phosphate, calcium hydrogen phosphate, etc. Can be used. Examples of the binder include gum arabic, sodium alginate, ethyl cellulose, sodium caseinate, sodium carboxymethyl cellulose, agar, purified water, gelatin, starch, tragacanth, and lactose. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, crystalline cellulose, starch, hydroxypropyl starch and the like. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, hydrogenated oil, sucrose fatty acid ester, waxes and the like. Examples of the antioxidant include tocopherol, gallic acid ester, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid and the like. Other additives and drugs as required, such as antacids (sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, synthetic hydrotalcite, etc.), gastric mucosa protective agents (synthetic aluminum silicate, sucralfate, copper chlorophyllin sodium, etc.) ) May be added.
化粧料組成物を調製する場合、その形態は適宜選択することができ、溶液、乳液、粉末、水−油二層系、水−油−粉末三層系、ゲル、タブレット等の固形、エアゾール、ミスト、カプセル及びシート等任意の形態とすることができる。また、化粧料組成物の製品形態も任意であり、例えば、洗顔料、メーク落とし、化粧水、美容液、パック、乳液、クリーム及びサンスクリーン等のスキンケア化粧料、ファンデーション、化粧下地、口紅、アイシャドー、アイライナー、マスカラ、アイブロー、頬紅及びネイルエナメル等のメイクアップ化粧料、ヘアシャンプー、ヘアリンス、整髪料、染毛料及び育毛剤等の毛髪化粧料、石鹸、ボディソープ、デオドラント化粧料及び浴用剤等のボディ洗浄料、歯磨剤及び洗口剤等の口腔化粧料、香水等の芳香化粧料等が挙げられる。また、この化粧料は、日本の薬事法上、化粧品もしくは医薬部外品のどちらに属しても良い。 When preparing a cosmetic composition, the form thereof can be selected as appropriate, such as solution, emulsion, powder, water-oil two-layer system, water-oil-powder three-layer system, gel, tablet and other solids, aerosol, It can be in any form such as mist, capsule, and sheet. In addition, the product form of the cosmetic composition is also arbitrary. For example, skin care cosmetics such as face wash, makeup remover, lotion, cosmetic liquid, pack, milky lotion, cream and sunscreen, foundation, makeup base, lipstick, eye Makeup cosmetics such as shadow, eyeliner, mascara, eyebrow, blusher and nail enamel, hair cosmetics such as hair shampoo, hair rinse, hair styling, hair dye and hair restorer, soap, body soap, deodorant cosmetic and bath preparation And other body cleansing agents, oral cosmetics such as dentifrices and mouthwashes, and aromatic cosmetics such as perfumes. Moreover, this cosmetic may belong to either cosmetics or quasi-drugs in accordance with Japanese Pharmaceutical Affairs Law.
化粧料組成物は、化粧品、医薬部外品及び医薬品等に慣用される他の成分、例えば、粉末成分、液体油脂、固体油脂、ロウ、炭化水素、高級脂肪酸、高級アルコール、エステル、シリコーン、アニオン界面活性剤、カチオン界面活性剤、両性界面活性剤、非イオン界面活性剤、保湿剤、水溶性高分子、増粘剤、皮膜剤、紫外線吸収剤、金属イオン封鎖剤、低級アルコール、多価アルコール、糖、アミノ酸、有機アミン、高分子エマルジョン、pH調整剤、皮膚栄養剤、ビタミン、酸化防止剤、酸化防止助剤、香料、水等を必要に応じて配合し、常法により製造することができる。
その他の化粧料組成物に配合可能な成分としては、例えば、防腐剤(エチルパラベン、ブチルパラベン等)、消炎剤(例えば、グリチルリチン酸誘導体、グリチルレチン酸誘導体、サリチル酸誘導体、ヒノキチオール、酸化亜鉛、アラントイン等)、美白剤(例えば、アスコルビン酸及びその誘導体、胎盤抽出物、ユキノシタ抽出物、アルブチン等)、各種抽出物(例えば、オウバク、オウレン、シコン、シャクヤク、センブリ、バーチ、セージ、ビワ、ニンジン、アロエ、ゼニアオイ、アイリス、ブドウ、ヨクイニン、ヘチマ、ユリ、サフラン、センキュウ、ショウキュウ、オトギリソウ、オノニス、ニンニク、トウガラシ、チンピ、トウキ、海藻等)、賦活剤(例えば、ローヤルゼリー、感光素、コレステロール誘導体等)、血行促進剤(例えば、ノニル酸ワレニルアミド、ニコチン酸ベンジルエステル、ニコチン酸β−ブトキシエチルエステル、カプサイシン、ジンゲロン、カンタリスチンキ、イクタモール、タンニン酸、α−ボルネオール、ニコチン酸トコフェロール、イノシトールヘキサニコチネート、シクランデレート、シンナリジン、トラゾリン、アセチルコリン、ベラパミル、セファランチン、γ−オリザノール等)、抗脂漏剤(例えば、硫黄、チアントール等)、抗炎症剤(例えば、トラネキサム酸、チオタウリン、ヒポタウリン等)及び殺菌剤(例えば、トリクロサン、塩化セチルピリジニウム、チモール類、塩化ベンザルコニウム等)等が挙げられる。
The cosmetic composition includes other components commonly used in cosmetics, quasi drugs and pharmaceuticals, such as powder components, liquid fats and oils, solid fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, silicones, anions. Surfactant, cationic surfactant, amphoteric surfactant, nonionic surfactant, humectant, water-soluble polymer, thickener, film agent, UV absorber, sequestering agent, lower alcohol, polyhydric alcohol , Sugar, amino acids, organic amines, polymer emulsions, pH adjusters, skin nutrients, vitamins, antioxidants, antioxidant auxiliaries, fragrances, water, etc. may be blended as necessary and manufactured by conventional methods. it can.
Examples of other components that can be incorporated into the cosmetic composition include preservatives (ethyl paraben, butyl paraben, etc.), anti-inflammatory agents (eg, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc. ), Whitening agents (for example, ascorbic acid and its derivatives, placenta extract, saxifrage extract, arbutin, etc.), various extracts (for example, buckwheat, auren, shikon, peonies, assembly, birch, sage, loquat, carrot, aloe , Mallow, iris, grape, yokuinin, loofah, lily, saffron, senkyu, ginger, hypericum, onionis, garlic, capsicum, chimpi, red snapper, seaweed, etc.), activator (eg royal jelly, photosensitizer, cholesterol derivative, etc.) , Blood circulation promoter For example, nonyl acid valenylamide, nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, gingerone, cantalis tincture, ictamol, tannic acid, α-borneol, nicotinic acid tocopherol, inositol hexanicotinate, cyclandrate, cinnarizine , Trazoline, acetylcholine, verapamil, cephalanthin, γ-oryzanol, etc.), antiseborrheic agents (eg, sulfur, thianthol, etc.), anti-inflammatory agents (eg, tranexamic acid, thiotaurine, hypotaurine, etc.) and fungicides (eg, triclosan, Cetylpyridinium chloride, thymols, benzalkonium chloride, etc.).
前記医薬組成物及び化粧料組成物は、口腔用組成物、外用組成物、内服組成物などの形態で適用することができ、皮膚外用組成物の形態で用いることが好ましい。
皮膚外用組成物の形態で使用する場合、ハグロソウ抽出物の他に、通常の皮膚外用組成物に用いられる成分、例えば界面活性剤、油性物質、高分子化合物、防腐剤、各種の薬効成分、紛体、紫外線吸収剤、色素、香料、乳化安定剤、pH調整剤等を適宜配合できる。薬効成分としては、表皮角化改善剤や皮膚保湿機能改善剤の場合は、例えば、ビタミンD3、スフィンゴシン誘導体、オレアノール酸、クロフィブリン酸、オレイエタノールアミドが挙げられる。
The pharmaceutical composition and cosmetic composition can be applied in the form of an oral composition, an external composition, an internal use composition, etc., and is preferably used in the form of a skin external composition.
When used in the form of a composition for external use on the skin, in addition to the extract of gypsophila, components used in normal composition for external use on the skin, such as surfactants, oily substances, polymer compounds, preservatives, various medicinal ingredients, powders UV absorbers, dyes, fragrances, emulsion stabilizers, pH adjusters, and the like can be appropriately blended. As a medicinal component, in the case of an epidermis keratinization improving agent or a skin moisturizing function improving agent, for example, vitamin D3, a sphingosine derivative, oleanolic acid, clofibric acid, oleethanolamide may be mentioned.
食品組成物を調製する場合、その形態は適宜選択することができ、飲料も包含される。一般食品の他に、表皮の角化改善又は皮膚の保湿機能やバリア機能改善・維持等、トランスグルタミナーゼの活性化、セラミドの産生促進、及びインボルクリンの発現促進のいずれかにより治療、予防又は改善しうる疾患又は状態の治療、予防又は改善等をコンセプトとしてその旨を表示した飲食品、すなわち、健康食品、機能性食品、病者用食品及び特定保健用食品なども包含される。健康食品、機能性食品、病者用食品及び特定保健用食品は、具体的には、細粒剤、錠剤、顆粒剤、散剤、カプセル剤、シロップ剤、液剤、流動食等の各種製剤形態として使用することができ、これら製剤のために使用することができる。製剤形態の食品組成物は、医薬製剤と同様に製造することができ、前記有効成分と、食品として許容できる担体、例えば適当な賦形剤(例えば、でん粉、加工でん粉、乳糖、ブドウ糖、水等)等とを混合した後、慣用の手段を用いて製造することができる。さらに、食品組成物は、スープ類、ジュース類、乳飲料、茶飲料、コーヒー飲料、ココア飲料、ゼリー状飲料などの液状食品組成物、プリン、ヨーグルトなどの半固形食品組成物、パン類、うどんなどの麺類、クッキー、チョコレート、キャンディ、ガム、せんべいなどの菓子類、ふりかけ、バター、ジャムなどのスプレッド類等の形態もとりうる。また、食品には、飼料も含まれる。 When preparing a food composition, the form can be selected as appropriate, and beverages are also included. In addition to general foods, treatment, prevention, or improvement can be achieved by either keratinization of the epidermis or improvement / maintenance of skin moisturizing and barrier functions, activation of transglutaminase, promotion of ceramide production, and promotion of involucrin Also included are foods and drinks that indicate the concept of treatment, prevention or improvement of possible diseases or conditions, that is, health foods, functional foods, foods for the sick, foods for specified health use, and the like. Health foods, functional foods, foods for patients and foods for specified health use are specifically formulated in various forms such as fine granules, tablets, granules, powders, capsules, syrups, liquids, and liquid foods. Can be used for these formulations. A food composition in the form of a preparation can be produced in the same manner as a pharmaceutical preparation. The active ingredient and a carrier acceptable as a food, for example, an appropriate excipient (eg, starch, processed starch, lactose, glucose, water, etc.) ) And the like, and then can be produced using conventional means. In addition, food compositions include soups, juices, milk beverages, tea beverages, coffee beverages, cocoa beverages, jelly-like beverages and other liquid food compositions, pudding, yogurt and other semi-solid food compositions, breads, udon Such as noodles such as cookies, chocolate, candy, gum, rice crackers and the like, spreads such as sprinkles, butter, jam and the like. The food also includes feed.
食品組成物には、種々の食品添加物、例えば、酸化防止剤、香料、各種エステル類、有機酸類、有機酸塩類、無機酸類、無機酸塩類、無機塩類、色素類、乳化剤、保存料、調味料、甘味料、酸味料、果汁エキス類、野菜エキス類、花蜜エキス類、pH調整剤、品質安定剤などの添加剤を単独、あるいは併用して配合してもよい。 Food compositions include various food additives such as antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, seasonings Additives such as additives, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, and quality stabilizers may be used alone or in combination.
本発明のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤の投与対象は、好ましくは温血脊椎動物であり、より好ましくは哺乳動物である。本明細書において哺乳動物は、例えば、ヒト、並びにサル、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタなどの非ヒト哺乳動物が挙げられる。本発明のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤は、ヒト、サルなどの霊長類、特にヒトへの投与に好適である。
本発明に用いる前記抽出物、並びに本発明のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤は、表皮の角化不全の予防若しくは治療、皮膚の保湿、皮膚バリア機能の改善、肌荒れの予防若しくは改善、又は毛髪のくせ毛化を所望する対象者に適用することができる。前記抽出物又は剤は、必要な条件下(好ましくは、湿度が低く乾燥した条件下)で適用するのが好ましい。また、前記抽出物又は剤は、皮膚、頭皮又は毛髪に適用するのが好ましい。
Administration target of transglutaminase activator, ceramide production promoter, involucrin expression promoter, epidermis keratinization improver, skin moisturizing function improver, skin barrier function improver, skin roughening preventive or improver, or hair growth agent of the present invention Is preferably a warm-blooded vertebrate, more preferably a mammal. As used herein, mammals include, for example, humans and non-human mammals such as monkeys, mice, rats, rabbits, dogs, cats, cows, horses, and pigs. Transglutaminase activator, ceramide production promoter, involucrin expression promoter, epidermis keratinization improver, skin moisturizing function improver, skin barrier function improver, rough skin preventive or improver, or hair growth agent of the present invention is human. Suitable for administration to primates such as monkeys, especially humans.
The extract used in the present invention, and the transglutaminase activator, ceramide production promoter, involucrin expression promoter, epidermal keratinization improver, skin moisturizing function improver, skin barrier function improver, rough skin prevention or improvement of the present invention The agent or combing agent can be applied to a subject who wants to prevent or treat keratinization failure of the epidermis, moisturize the skin, improve the skin barrier function, prevent or improve rough skin, or make the hair comb. . The extract or agent is preferably applied under necessary conditions (preferably under low humidity and dry conditions). The extract or agent is preferably applied to the skin, scalp or hair.
本発明のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤における前記有効成分の投与量は、個体の状態、体重、性別、年齢、素材の活性、投与又は摂取経路、投与又は摂取スケジュール、製剤形態又はその他の要因により適宜決定することができる。例えば、前記有効成分の質量に基づき、1日あたり、体重1kgあたり、好ましくは0.001mg以上、1g以下、又は好ましくは0.001〜1mgである。また、前記有効成分は、1日1回〜数回に分け、又は任意の期間及び間隔で摂取・投与され得る。 The above-mentioned effects in the transglutaminase activator, ceramide production promoter, involucrin expression promoter, epidermis keratinization improver, skin moisturizing function improver, skin barrier function improver, rough skin preventive or ameliorate agent, or combing agent of the invention The dosage of the components can be appropriately determined according to the individual's condition, body weight, sex, age, material activity, administration or intake route, administration or intake schedule, formulation form, or other factors. For example, based on the mass of the active ingredient, it is preferably 0.001 mg or more, 1 g or less, or preferably 0.001 to 1 mg per kg of body weight per day. The active ingredient can be taken or administered once a day to several times a day, or at an arbitrary period and interval.
本発明のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤における前記有効成分の含有量は、上記投与量を達成するように適宜決定できる。例えば、本発明のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤において、前記有効成分の含有量は、0.00001質量%以上が好ましく、0.0001質量%以上がより好ましく、0.0005質量%以上がさらに好ましく、20質量%以下が好ましく、10質量%以下がより好ましく、5質量%以下がさらに好ましく、0.00001〜20質量%が好ましく、0.0001〜10質量%がより好ましく、0.0005〜5質量%がさらに好ましい。 The above-mentioned effects in the transglutaminase activator, ceramide production promoter, involucrin expression promoter, epidermis keratinization improver, skin moisturizing function improver, skin barrier function improver, rough skin preventive or ameliorate agent, or combing agent of the invention The content of the components can be appropriately determined so as to achieve the above dose. For example, in the transglutaminase activator, ceramide production promoter, involucrin expression promoter, epidermis keratinization improving agent, skin moisturizing function improving agent, skin barrier function improving agent, skin roughening preventing or improving agent, or hair growth agent of the present invention. The content of the active ingredient is preferably 0.00001% by mass or more, more preferably 0.0001% by mass or more, further preferably 0.0005% by mass or more, preferably 20% by mass or less, more preferably 10% by mass or less, and 5% by mass. The following is more preferable, 0.00001 to 20% by mass is preferable, 0.0001 to 10% by mass is more preferable, and 0.0005 to 5% by mass is further preferable.
上述した実施形態に関し、本発明はさらに以下のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防又は改善剤、くせ毛化剤、製造方法、方法及び使用を開示する。 In relation to the above-described embodiment, the present invention further includes the following transglutaminase activator, ceramide production promoter, involucrin expression promoter, epidermis keratinization improving agent, skin moisturizing function improving agent, skin barrier function improving agent, rough skin prevention or improvement. Disclosed are agents, combing agents, manufacturing methods, methods and uses.
<1>ハグロソウの抽出物を有効成分とする、トランスグルタミナーゼ活性化剤。
<2>ハグロソウの抽出物を有効成分とする、セラミド産生促進剤。
<3>ハグロソウの抽出物を有効成分とする、インボルクリン発現促進剤。
<4>ハグロソウの抽出物を有効成分とする、表皮角化改善剤。
<5>ハグロソウの抽出物を有効成分とする、皮膚保湿機能改善剤。
<6>ハグロソウの抽出物を有効成分とする、皮膚バリア機能改善剤。
<7>ハグロソウの抽出物を有効成分とする、肌荒れ予防又は改善剤。
<8>ハグロソウの抽出物を有効成分とする、くせ毛化剤。
<1> A transglutaminase activator comprising an extract of agglomerates as an active ingredient.
<2> A ceramide production promoter comprising an extract of agglomerates as an active ingredient.
<3> An involucrin expression promoter, comprising an extract of Amaranthus as an active ingredient.
<4> An epidermis keratinization improving agent comprising an extract of agglomerates as an active ingredient.
<5> A skin moisturizing function-improving agent comprising an extract of agglomerates as an active ingredient.
<6> A skin barrier function-improving agent comprising an extract of agglomerates as an active ingredient.
<7> An agent for preventing or improving rough skin, comprising an extract of agglomerates as an active ingredient.
<8> A combing hair agent, comprising an extract of agglomerates as an active ingredient.
<9>前記ハグロソウの抽出物がハグロソウの全草の抽出物である、前記<1>〜<8>のいずれか1項に記載のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤。
<10>前記ハグロソウの抽出物が、エタノール水溶液(好ましくは、アルコール含有率が30体積%以上(より好ましくは40体積%以上)のエタノール水溶液)を抽出溶媒としてハグロソウを抽出して得られた、前記<1>〜<9>のいずれか1項に記載のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤。
<11>前記有効成分の含有量が、0.00001質量%以上(好ましくは0.0001質量%以上、より好ましくは0.0005質量%以上)20質量%以下(好ましくは10質量%以下、より好ましくは5質量%以下)である、前記<1>〜<10>のいずれか1項に記載のトランスグルタミナーゼ活性化剤、セラミド産生促進剤、インボルクリン発現促進剤、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤。
<9> The transglutaminase activator, the ceramide production promoter, or the involucrin expression promoter according to any one of <1> to <8>, wherein the extract of the sunflower is an extract of whole plant of sunflower , An epidermis keratinization improving agent, a skin moisturizing function improving agent, a skin barrier function improving agent, a rough skin preventing or improving agent, or a combing hair agent.
<10> The extract of the sunflower is obtained by extracting the sunflower using an aqueous ethanol solution (preferably an ethanol aqueous solution having an alcohol content of 30% by volume or more (more preferably 40% by volume or more)) as an extraction solvent. Transglutaminase activator according to any one of <1> to <9>, ceramide production promoter, involucrin expression promoter, epidermis keratinization improver, skin moisturizing function improver, skin barrier function improver, An agent for preventing or improving rough skin, or a combing hair agent.
<11> The content of the active ingredient is 0.00001% by mass or more (preferably 0.0001% by mass or more, more preferably 0.0005% by mass or more), 20% by mass or less (preferably 10% by mass or less, more preferably 5% by mass or less). The transglutaminase activator according to any one of <1> to <10>, a ceramide production promoter, an involucrin expression promoter, an epidermal keratinization improving agent, a skin moisturizing function improving agent, and a skin barrier A function improving agent, a rough skin preventing or improving agent, or a wrinkling agent.
<12>トランスグルタミナーゼ活性化剤、セラミド産生促進剤又はインボルクリン発現促進剤としての、ハグロソウの抽出物の使用。
<13>トランスグルタミナーゼ活性化剤、セラミド産生促進剤又はインボルクリン発現促進剤の製造のための、ハグロソウの抽出物の使用。
<14>ハグロソウの抽出物を、トランスグルタミナーゼ活性化剤、セラミド産生促進剤又はインボルクリン発現促進剤として使用する方法。
<15>ハグロソウの抽出物を用いる、トランスグルタミナーゼ活性化方法、セラミド産生促進方法又はインボルクリン発現促進方法。
<16>前記抽出物を表皮の角化不全の予防若しくは治療、皮膚の保湿、皮膚バリア機能の改善、肌荒れの予防若しくは改善、又は毛髪のくせ毛化を所望する対象者に適用する、前記<15>項記載の方法。
<17>前記抽出物の適用が必要な条件下(好ましくは、湿度が低く乾燥した条件下)で前記抽出物を適用する、前記<15>又は<16>項記載の方法。
<18>前記抽出物を皮膚、頭皮又は毛髪に適用する、前記<15>〜<17>のいずれか1項記載の方法。
<19>前記ハグロソウの抽出物がハグロソウの全草の抽出物である、前記<12>〜<18>のいずれか1項に記載の使用又は方法。
<20>前記ハグロソウの抽出物が、エタノール水溶液(好ましくは、アルコール含有率が30体積%以上(より好ましくは40体積%以上)のエタノール水溶液)を抽出溶媒としてハグロソウを抽出して得られた、前記<12>〜<19>のいずれか1項に記載の使用又は方法。
<21>トランスグルタミナーゼ活性化剤、セラミド産生促進剤又はインボルクリン発現促進剤におけるハグロソウの抽出物の含有量が、0.00001質量%以上(好ましくは0.0001質量%以上、より好ましくは0.0005質量%以上)20質量%以下(好ましくは10質量%以下、より好ましくは5質量%以下)である、前記<12>〜<20>のいずれか1項に記載の使用又は方法。
<12> Use of an extract of Agrobacterium as a transglutaminase activator, a ceramide production promoter or an involucrin expression promoter.
<13> Use of an extract of sunflower for the production of a transglutaminase activator, a ceramide production promoter or an involucrin expression promoter.
<14> A method of using an extract of Amaranthus as a transglutaminase activator, a ceramide production promoter or an involucrin expression promoter.
<15> A method for activating transglutaminase, a method for promoting ceramide production, or a method for promoting involucrin expression, which uses an extract of Amaranthus.
<16> The above extract is applied to a subject who desires prevention or treatment of keratinization failure of the epidermis, skin moisturization, improvement of skin barrier function, prevention or improvement of rough skin, or hair combing, <15> The method described in the item>.
<17> The method according to <15> or <16>, wherein the extract is applied under conditions that require application of the extract (preferably under dry conditions with low humidity).
<18> The method according to any one of <15> to <17>, wherein the extract is applied to skin, scalp or hair.
<19> The use or method according to any one of <12> to <18>, wherein the extract of the sunflower is an extract of the whole plant of sunflower.
<20> The extract of the sunflower is obtained by extracting the sunflower using an ethanol aqueous solution (preferably an ethanol aqueous solution having an alcohol content of 30% by volume or more (more preferably 40% by volume or more)) as an extraction solvent. The use or method according to any one of <12> to <19>.
<21> Transglutaminase activator, ceramide production promoter or involucrin expression promoter, the content of the extract of trichomes is 0.00001 mass% or more (preferably 0.0001 mass% or more, more preferably 0.0005 mass% or more) 20 mass % Or less (preferably 10% by mass or less, more preferably 5% by mass or less). The use or method according to any one of <12> to <20>.
<22>表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤としての、ハグロソウの抽出物の使用。
<23>表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤の製造のための、ハグロソウの抽出物の使用。
<24>ハグロソウの抽出物を、表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤として使用する方法。
<25>ハグロソウの抽出物を適用する、表皮角化改善方法、皮膚保湿機能改善方法、皮膚バリア機能改善方法、肌荒れ予防若しくは改善方法、又はくせ毛化方法。
<26>前記抽出物を表皮の角化不全の予防若しくは治療、皮膚の保湿、皮膚バリア機能の改善、肌荒れの予防若しくは改善、又は毛髪のくせ毛化を所望する対象者に適用する、前記<24>又は<25>項記載の方法。
<27>前記抽出物の適用が必要な条件下(好ましくは、湿度が低く乾燥した条件下)で前記抽出物を適用する、前記<24>〜<26>のいずれか1項記載の方法。
<28>前記抽出物を皮膚、頭皮又は毛髪に適用する、前記<24>〜<27>のいずれか1項記載の方法。
<29>皮膚の表皮角化不全の予防若しくは治療方法、皮膚保湿機能改善方法、皮膚バリア機能改善方法、肌荒れ予防若しくは改善方法、又はくせ毛化方法のために用いる、ハグロソウの抽出物。
<30>皮膚の表皮角化不全の予防若しくは治療薬、皮膚保湿機能改善薬、皮膚バリア機能改善薬、肌荒れ予防若しくは改善薬、又はくせ毛化薬の製造のための、ハグロソウの抽出物の使用。
<31>皮膚の表皮角化不全、皮膚保湿機能、皮膚バリア機能、肌荒れ、又はくせ毛化の非治療的な処置方法のために用いる、ハグロソウの抽出物の使用。
<32>ハグロソウの抽出物を医薬組成物又は化粧料組成物の形態で適用する、前記<31>項記載の使用。
<33>ハグロソウの抽出物を外用組成物の形態で適用する、前記<32>項記載の使用。
<34>ハグロソウの抽出物を食品又は飲料の形態で適用する、前記<31>項記載の使用。
<35>前記ハグロソウの抽出物がハグロソウの全草の抽出物である、前記<22>〜<34>のいずれか1項に記載の使用又は方法。
<36>前記ハグロソウの抽出物が、エタノール水溶液(好ましくは、アルコール含有率が30体積%以上(より好ましくは40体積%以上)のエタノール水溶液)を抽出溶媒としてハグロソウを抽出して得られた、前記<22>〜<35>のいずれか1項に記載の使用又は方法。
<37>前記表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、肌荒れ予防若しくは改善剤、又はくせ毛化剤における、ハグロソウの抽出物の含有量が、0.00001質量%以上(好ましくは0.0001質量%以上、より好ましくは0.0005質量%以上)20質量%以下(好ましくは10質量%以下、より好ましくは5質量%以下)である、前記<22>〜<36>のいずれか1項に記載の使用又は方法。
<22> Use of an extract of agglomerated as a skin keratinization improving agent, a skin moisturizing function improving agent, a skin barrier function improving agent, a rough skin preventing or improving agent, or a wrinkling agent.
<23> Use of an extract of agglomerated for production of an epidermis keratinization improving agent, a skin moisturizing function improving agent, a skin barrier function improving agent, a rough skin preventing or improving agent, or a hair-cutting agent.
<24> A method of using an extract of agglomerated as an epidermis keratinization improving agent, a skin moisturizing function improving agent, a skin barrier function improving agent, a rough skin preventing or improving agent, or a wrinkling agent.
<25> A method for improving skin keratinization, a method for improving skin moisturizing function, a method for improving skin barrier function, a method for preventing or improving rough skin, or a method for combing hair, which comprises applying an extract of Amaranthus.
<26> Applying the extract to a subject who desires prevention or treatment of keratinization failure of the epidermis, skin moisturization, improvement of skin barrier function, prevention or improvement of rough skin, or hair combing, <24 > Or <25>.
<27> The method according to any one of <24> to <26>, wherein the extract is applied under conditions that require application of the extract (preferably under dry conditions with low humidity).
<28> The method according to any one of <24> to <27>, wherein the extract is applied to skin, scalp or hair.
<29> An extract of Amaranthus used for a method for preventing or treating skin epikeratinization failure, a method for improving skin moisturizing function, a method for improving skin barrier function, a method for preventing or improving rough skin, or a method for combing hair.
<30> Use of an extract of Amaranthus for the manufacture of a prophylactic or therapeutic agent for skin keratinization failure, a skin moisturizing function improving agent, a skin barrier function improving agent, a rough skin preventing or improving agent, or a combing hair fixative.
<31> Use of an extract of sunflower that is used for a non-therapeutic treatment method for skin keratinization failure, skin moisturizing function, skin barrier function, rough skin, or comb hair.
<32> The use according to <31> above, wherein the extract of Amaranthus is applied in the form of a pharmaceutical composition or a cosmetic composition.
<33> The use according to <32> above, wherein the extract of sunflower is applied in the form of a composition for external use.
<34> The use according to <31> above, wherein the extract of sunflower is applied in the form of food or beverage.
<35> The use or method according to any one of <22> to <34>, wherein the extract of the sunflower is an extract of the whole plant of sunflower.
<36> The extract of the sunflower is obtained by extracting the sunflower using an ethanol aqueous solution (preferably an ethanol aqueous solution having an alcohol content of 30% by volume or more (more preferably 40% by volume or more)) as an extraction solvent. The use or method according to any one of <22> to <35>.
<37> The content of the extract of the sunflower in the epidermis keratinization improving agent, the skin moisturizing function improving agent, the skin barrier function improving agent, the rough skin preventing or improving agent, or the shading agent is 0.00001% by mass or more (preferably Any one of the above <22> to <36>, wherein 0.0001% by mass or more, more preferably 0.0005% by mass or more) is 20% by mass or less (preferably 10% by mass or less, more preferably 5% by mass or less). Use or method as described.
以下、本発明を実施例に基づきさらに詳細に説明するが、本発明はこれに限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.
調製例1
ハグロソウの全草(新和物産社製)10gを細切し、30体積%エタノール水溶液100mLを加え、室温・静置条件下で7日間抽出を行った。その後、濾過して、ハグロソウ抽出物61mLを得た。得られた抽出物について、蒸発残分を算出したところ、蒸発残分は1.10%(w/v)であった。これを30体積%エタノール水溶液で希釈し、1.0%(w/v)(エキス固形分)抽出物を調製した。
<蒸発残分の算出>
ハグロソウ抽出物1mLを乾燥機(DRY Thermo Unit DTU-1C(商品名、TAITEC CORPORATION社製))を用いて105℃で6時間乾燥させたところ、乾燥物11.0mgが得られた。この抽出物の蒸発残分を、11.0/1000×100=1.10%(w/v)と算出した。なお、下記の調製例においても、各抽出物の蒸発残分は同様にして算出されたものである。
Preparation Example 1
10 g of whole plant of sunflower (manufactured by Shinwa Bussan Co., Ltd.) was shredded, 100 mL of a 30% by volume aqueous ethanol solution was added, and extraction was carried out for 7 days under room temperature and standing conditions. Thereafter, filtration was performed to obtain 61 mL of an extract of nematode. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 1.10% (w / v). This was diluted with a 30% by volume ethanol aqueous solution to prepare a 1.0% (w / v) (extract solid content) extract.
<Calculation of evaporation residue>
When 1 mL of the extract of sunflower was dried at 105 ° C. for 6 hours using a dryer (DRY Thermo Unit DTU-1C (trade name, manufactured by TAITEC CORPORATION)), 11.0 mg of a dried product was obtained. The evaporation residue of this extract was calculated as 11.0 / 1000 × 100 = 1.10% (w / v). In the following preparation examples, the evaporation residue of each extract is calculated in the same manner.
調製例2
調製例1と同様の条件で50体積%エタノール水溶液を使用して抽出を行った。その後、濾過して、ハグロソウ抽出物58mLを得た。得られた抽出物について、蒸発残分を算出したところ、蒸発残分は0.92%(w/v)であった。これを濃縮した後、50体積%エタノール水溶液で1.0%(w/v)(エキス固形分)抽出物を調製した。
Preparation Example 2
Extraction was performed using a 50% by volume ethanol aqueous solution under the same conditions as in Preparation Example 1. Thereafter, filtration was performed to obtain 58 mL of an extract of nematode. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 0.92% (w / v). After concentrating this, 1.0% (w / v) (extract solid content) extract was prepared with 50 volume% ethanol aqueous solution.
調製例3
調製例1と同様の条件で60体積%エタノール水溶液を使用して抽出を行った。その後、濾過して、ハグロソウ抽出物58mLを得た。得られた抽出物について、蒸発残分を算出したところ、蒸発残分は0.79%(w/v)であった。これを濃縮した後、60体積%エタノール水溶液で1.0%(w/v)(エキス固形分)抽出物を調製した。
Preparation Example 3
Extraction was performed using a 60% by volume aqueous ethanol solution under the same conditions as in Preparation Example 1. Thereafter, filtration was performed to obtain 58 mL of an extract of nematode. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 0.79% (w / v). After concentration, 1.0% (w / v) (extract solid content) extract was prepared with 60% by volume ethanol aqueous solution.
調製例4
調製例1と同様の条件で70体積%エタノール水溶液を使用して抽出を行った。その後、濾過して、ハグロソウ抽出物60mLを得た。得られた抽出物について、蒸発残分を算出したところ、蒸発残分は0.70%(w/v)であった。これを濃縮した後、70体積%エタノール水溶液で1.0%(w/v)(エキス固形分)抽出物を調製した。
Preparation Example 4
Extraction was performed using a 70 vol% aqueous ethanol solution under the same conditions as in Preparation Example 1. Thereafter, filtration was performed to obtain 60 mL of an extract of nematode. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 0.70% (w / v). After concentrating this, 1.0% (w / v) (extract solid content) extract was prepared with 70 volume% ethanol aqueous solution.
調製例5
調製例1と同様の条件で80体積%エタノール水溶液を使用して抽出を行った。その後、濾過して、ハグロソウ抽出物55mLを得た。得られた抽出物について、蒸発残分を算出したところ、蒸発残分は0.60%(w/v)であった。これを濃縮した後、80体積%エタノール水溶液で1.0%(w/v)(エキス固形分)抽出物を調製した。
Preparation Example 5
Extraction was performed using an 80% by volume aqueous ethanol solution under the same conditions as in Preparation Example 1. Thereafter, filtration was performed to obtain 55 mL of an extract of nebula. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 0.60% (w / v). After concentrating this, 1.0% (w / v) (extract solid content) extract was prepared with 80 volume% ethanol aqueous solution.
調製例6
調製例1と同様の条件で90体積%エタノール水溶液を使用して抽出を行った。その後、濾過して、ハグロソウ抽出物53mLを得た。得られた抽出物について、蒸発残分を算出したところ、蒸発残分は0.36%(w/v)であった。これを濃縮乾固させた後、90体積%エタノール水溶液で1.0%(w/v)(エキス固形分)抽出物を調製した。
Preparation Example 6
Extraction was performed using a 90 volume% aqueous ethanol solution under the same conditions as in Preparation Example 1. Thereafter, filtration was performed to obtain 53 mL of the extract of nebula. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 0.36% (w / v). This was concentrated to dryness, and then 1.0% (w / v) (extract solid content) extract was prepared with 90% by volume ethanol aqueous solution.
調製例7
調製例1と同様の条件で99.5体積%エタノール水溶液を使用して抽出を行った。その後、濾過して、ハグロソウ抽出物52mLを得た。得られた抽出物について、蒸発残分を算出したところ、蒸発残分は0.17%(w/v)であった。これを濃縮乾固させた後、99.5体積%エタノール水溶液で1.0%(w/v)(エキス固形分)抽出物を調製した。
Preparation Example 7
Extraction was performed using a 99.5% by volume aqueous ethanol solution under the same conditions as in Preparation Example 1. Thereafter, filtration was performed to obtain 52 mL of an extract of nebula. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 0.17% (w / v). This was concentrated to dryness, and then an extract of 1.0% (w / v) (extract solid content) was prepared with a 99.5% by volume ethanol aqueous solution.
調製例8
ハグロソウの全草(親和物産社製)600gを細切し、99.5体積%エタノール水溶液6000mLを加え、室温・静置条件下で7日間抽出を行った。その後、濾過して、ハグロソウ抽出物4504mLを得た。得られた抽出物4000mLにヘキサン2000mLを加え撹拌した後、さらに水6000mLを加えた。これを液液分配した後、下層8367mLを抜出した。得られた抽出液2500mLに1,3-ブチレングリコール1000mLを加え、エバポレータにて濃縮し、エタノール及び水を除去した。これに水1500mLを加えた後、5℃、4日間の条件で澱出しした。濾過により不溶物を除去した後、得られた濾液2403Lに40体積%1,3-ブチレングリコール水溶液を加え、抽出物3266mLを調製した。得られた抽出物について蒸発残分を算出したところ、蒸発残分は0.02%(w/v)であった。
Preparation Example 8
600 g of whole plant of sunflower (manufactured by Affinity Products Co., Ltd.) was chopped, 6000 mL of a 99.5% by volume ethanol aqueous solution was added, and extraction was performed for 7 days under room temperature and standing conditions. Thereafter, filtration was performed to obtain 4504 mL of the extract of nebula. After 2,000 mL of hexane was added to 4000 mL of the resulting extract and stirred, 6000 mL of water was further added. After liquid-liquid partitioning, 8367 mL of the lower layer was extracted. 1000 mL of 1,3-butylene glycol was added to 2500 mL of the obtained extract and concentrated with an evaporator to remove ethanol and water. After adding 1500 mL of water to this, it was starched at 5 ° C. for 4 days. After removing insolubles by filtration, 40 volume% 1,3-butylene glycol aqueous solution was added to 2403 L of the obtained filtrate to prepare 3266 mL of an extract. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 0.02% (w / v).
試験例1 トランスグルタミナーゼ活性の測定
12穴プレートにヒト表皮角化細胞株HEKn(KURABO社製)を4×104個/ウェルにて播種し、培養した。培地には、市販のクラボウ社製EpiLife-KG2を用いた。37℃、5%CO2条件下で一日培養後、増殖因子(BPE、EGF)を含まない培地に交換し、製造例1〜8で調製したハグロソウ抽出物を最終濃度が表1に示す値となるように、それぞれ添加した。また、ハグロソウ抽出物のかわりに、コントロールとして抽出溶媒である50体積%エタノールを最終濃度0.1%(v/v)で、ポジティブ・コントロールとしてCaCl2を最終濃度1.5mMで、それぞれ添加した。なお、CaCl2には角化を促す作用が知られており、ポジティブ・コントロールとして用いた。これらはいずれも更に37℃で3日間培養した。
培養終了後、培養液を除去し、PBS(−)で2回洗浄し、150μLの抽出緩衝液(0.5mM EDTA、1%TritonX-100、Protease inhibitorsを含む10mM Tris-HCl buffer、pH7.4)でセルスクレーパーを用い細胞を回収し、超音波処理による細胞破砕液を得た。遠心分離操作(15,000rpm、10分)によって得られた上清をライセートとして評価に用いた。Transglutaminase Colorimetric Microassay Kit(商品名)によりメーカーの使用説明書に従って、酵素活性を測定した。タンパク質濃度はBCA Protein Assay Kit(商品名、Thermo Scientific社製)を用いてメーカーの使用説明書に従って、定量した。
Test Example 1 Measurement of transglutaminase activity Human epidermal keratinocyte cell line HEKn (manufactured by KURABO) was seeded at 4 × 10 4 cells / well in a 12-well plate and cultured. As the medium, commercially available EpiLife-KG2 manufactured by Kurabo Industries was used. After culturing at 37 ° C. and 5% CO 2 for one day, the medium was replaced with a medium not containing growth factors (BPE, EGF), and the final concentration of the extract of the sunflower extract prepared in Production Examples 1 to 8 was shown in Table 1. Each was added so that Further, instead of the extract of sunflower, 50% by volume ethanol as an extraction solvent was added at a final concentration of 0.1% (v / v) as a control, and CaCl 2 was added as a positive control at a final concentration of 1.5 mM. . CaCl 2 is known to promote keratinization and was used as a positive control. All of these were further cultured at 37 ° C. for 3 days.
After completion of the culture, the culture solution was removed, washed twice with PBS (−), and 150 μL of extraction buffer (10 mM Tris-HCl buffer, pH 7.4 containing 0.5 mM EDTA, 1% TritonX-100, and protease inhibitors). The cells were collected using a cell scraper to obtain a cell disruption solution by ultrasonic treatment. The supernatant obtained by centrifugation (15,000 rpm, 10 minutes) was used for evaluation as a lysate. Enzyme activity was measured using Transglutaminase Colorimetric Microassay Kit (trade name) according to the manufacturer's instructions. The protein concentration was quantified using BCA Protein Assay Kit (trade name, manufactured by Thermo Scientific) according to the manufacturer's instructions.
評価結果を表1に示す。各抽出物サンプルのトランスグルタミナーゼ活性は、50体積%エタノールを添加したコントロールのトランスグルタミナーゼ活性を1とした場合の相対値で示した。 The evaluation results are shown in Table 1. The transglutaminase activity of each extract sample was shown as a relative value when the transglutaminase activity of the control to which 50% by volume of ethanol was added was 1.
表1から明らかなように、ハグロソウ抽出物を添加した系ではトランスグルタミナーゼ活性がポジティブ・コントロールと同程度或いはそれ以上に大きく上昇していた。
さらに、トランスグルタミナーゼ活性は皮膚のバリア機能維持、保湿機能の維持又は改善、及び肌荒れの予防又は改善に関係し、トランスグルタミナーゼを活性化することで、表皮の角化不全の防止や皮膚の保湿機能の改善、及び肌荒れの予防又は改善などが可能となる。したがって、トランスグルタミナーゼ活性化効果を有するハグロソウの抽出物を表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、及び肌荒れ予防又は改善剤の有効成分とすることができる。
As is apparent from Table 1, in the system to which the extract of sunflower was added, the transglutaminase activity was greatly increased to the same level or more than that of the positive control.
Furthermore, transglutaminase activity is related to maintenance of skin barrier function, maintenance or improvement of moisturizing function, and prevention or improvement of rough skin, and activation of transglutaminase prevents keratinization failure of the epidermis and moisturizing function of skin. Improvement and prevention or improvement of rough skin are possible. Therefore, the extract of the sunflower which has a transglutaminase activation effect can be used as an active ingredient of an epidermis keratinization improving agent, a skin moisturizing function improving agent, a skin barrier function improving agent, and a rough skin prevention or improving agent.
試験例2 セラミド産生促進効果の検証
培養プレートを用い、培養液(商品名:EpiLife-KG2、KURABO社製)中にて、正常ヒト表皮角化細胞(商品名:NHEK(F)、KURABO社製)を37℃、5%CO2で培養した。
その後、培養液を上皮成長因子などの増殖因子を除いたEpiLife-KG2に換え、調製例2で調製したハグロソウ抽出物を、濃度が固形分換算で1w/v%となるように調整したものを、0.1%量添加した。また、ハグロソウ抽出物のかわりに、コントロールとして抽出溶媒である50体積%エタノールを最終濃度0.1%v/vで、ポジティブ・コントロールとして下記に示すように調製したユーカリ(Eucalyptus globulus)抽出物を表2に示す最終濃度となるように、それぞれ添加した。なお、ユーカリ抽出物にはセラミドの産生を促す作用が知られており、ポジティブ・コントロールとして用いた。
3日間培養した後、各々の細胞を1wellごと回収した。
Test Example 2 Verification of ceramide production promotion effect Normal human epidermal keratinocytes (trade name: NHEK (F), manufactured by KURABO) in a culture solution (trade name: EpiLife-KG2, manufactured by KURABO) using a culture plate ) At 37 ° C. and 5% CO 2 .
Thereafter, the culture solution was changed to EpiLife-KG2 from which growth factors such as epidermal growth factor were removed, and the extract of the sunflower prepared in Preparation Example 2 was adjusted so that the concentration was 1 w / v% in terms of solid content. 0.1% amount was added. Also, instead of an extract of sunflower, Eucalyptus globulus extract prepared as shown below as a positive control with 50% by volume of ethanol as a control at a final concentration of 0.1% v / v. The final concentrations shown in Table 2 were added respectively. Eucalyptus extract is known to have an effect of promoting ceramide production and was used as a positive control.
After culturing for 3 days, each cell was collected together with 1 well.
回収した細胞からBligh and Dyer法により脂質を抽出した有機相をガラス管に移し、窒素乾固した後、クロロホルム、メタノールで再溶解し、脂質サンプルとした。
また、脂質を抽出した後の細胞に0.1N NaOH、1%SDS水溶液を加え、60℃で2時間加熱することにより、タンパク質を可溶化し、室温まで冷却した後2N HClを加えて中和し、タンパク量をBCA法により定量した。
The organic phase from which the lipid was extracted from the collected cells by the Bligh and Dyer method was transferred to a glass tube, solidified with nitrogen, and then redissolved with chloroform and methanol to obtain a lipid sample.
In addition, 0.1N NaOH, 1% SDS aqueous solution is added to the cells after lipid extraction, and the protein is solubilized by heating at 60 ° C. for 2 hours, cooled to room temperature, and then neutralized by adding 2N HCl. The amount of protein was quantified by the BCA method.
調製した脂質サンプルを薄膜クロマトグラフィー(TLC)でクロロホルム:メタノール:酢酸=190:9:1で2回水平展開した。硫酸銅液をスプレーで噴霧し、ホットプレートで焼き付けセラミドを検出し、セラミド量とした。なお、セラミド量は、50体積%エタノールを添加したときのセラミド量を1とし、相対値で示した。
結果を表2に示す。
The prepared lipid sample was horizontally developed by thin film chromatography (TLC) twice with chloroform: methanol: acetic acid = 190: 9: 1. The copper sulfate solution was sprayed and sprayed with a hot plate to detect ceramide, and the amount was determined. The amount of ceramide was expressed as a relative value, assuming that the amount of ceramide when ethanol of 50% by volume was added was 1.
The results are shown in Table 2.
(参考例)
ユーカリノキ(Eucalyptus globules Labillardiere、新和物産社製)の葉40gを細切し、50体積%エタノール400mLを加え、室温・静置条件下で7日間抽出を行った。その後、濾過して、ユーカリ抽出物291mLを得た。得られた抽出物について蒸発残分を算出したところ、蒸発残分は3.16%(w/v)であった。これを50体積%エタノール水溶液で希釈して、1.0%(w/v)抽出物を調製した。
(Reference example)
40 g of Eucalyptus globules Labillardiere (manufactured by Shinwa Bussan) was cut into small pieces , 400 mL of 50% by volume ethanol was added, and extraction was performed for 7 days under room temperature and standing conditions. Then, it filtered and 291 mL of eucalyptus extracts were obtained. When the evaporation residue was calculated for the obtained extract, the evaporation residue was 3.16% (w / v). This was diluted with a 50% by volume aqueous ethanol solution to prepare a 1.0% (w / v) extract.
表2から明らかなように、ハグロソウ抽出物を添加した系ではコントロールの系に比べてセラミド産出量の上昇が認められた。したがって、ハグロソウ抽出物を有効成分とする本発明のセラミド産生促進剤は、セラミド産生を促進することができることがわかる。
さらに、セラミドは皮膚のバリア機能維持、保湿機能の維持又は改善、及び肌荒れの予防又は改善に関係し、セラミドの産生を促進することで、表皮の角化不全の防止や皮膚の保湿機能の改善、及び肌荒れの予防又は改善などが可能となる。したがって、セラミドの産生促進効果を有するハグロソウの抽出物を表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、及び肌荒れ予防又は改善剤の有効成分とすることができる。
As is clear from Table 2, the ceramide output was increased in the system to which the extract of sunflower was added compared to the control system. Therefore, it turns out that the ceramide production promoter of this invention which uses an extract of hagrose as an active ingredient can promote ceramide production.
Furthermore, ceramide is related to maintaining or improving the skin barrier function, moisturizing function, and preventing or improving rough skin, and promotes the production of ceramide, thereby preventing keratinization failure of the epidermis and improving skin moisturizing function. , And prevention or improvement of rough skin are possible. Therefore, an extract of trichomes having an effect of promoting production of ceramide can be used as an active ingredient of an epidermis keratinization improving agent, a skin moisturizing function improving agent, a skin barrier function improving agent, and a rough skin preventing or improving agent.
試験例3 インボルクリン発現量の評価
(1)細胞培養
ヒト表皮角化細胞株HaCaTは、DMEM(ギブコ社製)に、非働化した10%ウシ胎児血清、1%ペニシリン−ストレプトマイシン(ギブコ社製)を添加した培地で37℃、5%CO2条件下で培養した。
Test Example 3 Evaluation of Involucrin Expression Level (1) Cell Culture The human epidermal keratinocyte cell line HaCaT was prepared by inactivating 10% fetal bovine serum, 1% penicillin-streptomycin (manufactured by Gibco) into DMEM (manufactured by Gibco). The cultured medium was cultured under the conditions of 37 ° C. and 5% CO 2 .
(2)IVL発現の評価
1次スクリーニングにはInvolucrin ELISA Assay Kit BT-650(商品名、BTI製)を一部プロトコルを改変して使用した。詳細なプロトコルを以下に示す。
24穴プレートにHaCaT細胞を5×104個/ウェルにて播種し、培養した。翌日、調製例2で調製した固形分換算で1.0%(w/v)となったハグロソウ抽出物を表3に示す最終濃度含む培地に交換して更に24時間培養した。また、ハグロソウ抽出物のかわりに、コントロールとして抽出溶媒である50体積%エタノールを最終濃度0.5%v/v含む培地に交換してさらに24時間培養したものを用いた。抽出物の添加から24時間後、細胞をPBS(−)で2回洗浄し、20mM Tris-HCl(pH:7.5)・2mM EDTAにComplete Mini Protease Inhibitor Cocktail(商品名、Roche社製)を含む抽出緩衝液400μLを細胞に添加した。Protease Inhibitor Cocktailは抽出緩衝液10mLに対して1粒加えた。この抽出緩衝液存在下でセルスクレーパーにより、細胞を剥離・回収した後、ソニケーターによる超音波処理を行った。この溶液を遠心して回収した上清をライセートとして評価に用いた。
ライセートの総タンパク質濃度はBCA Protein Assay Kit(商品名、Thermo Scientific社製)を用いてメーカーの使用説明書に従って、定量した。96穴プレートの1ウェルに対し、3μgの総タンパク質量となるようにライセートをbuffer B(2mM EDTA、5g/L Tween 20、2.5g/L Gelatin in PBS)で希釈し、96穴プレートに添加した後、抗IVL抗体(キット付属品、希釈率1/300)を加えて4℃で一晩1次抗体反応を行った。また、別の96穴プレート(ナルジェヌンク製、469078)にヒトIVLタンパク質(キット付属品)を1ng/wellずつ添加し、縮合剤であるEDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide、関東化学株式会社製)10μg/wellと共に、4℃で一晩抗原の吸着を行った。翌日、抗原を吸着させたプレートの溶液を吸引除去し、100μLの0.1M NH4Clを添加して30分間室温で反応させた。反応後、distilled H2O(ギブコ社製)で4回、buffer Bで1回洗浄し、前日の1次抗体反応液100μLを添加して30分間室温で反応させた。この反応の後、buffer Bで5回洗浄し、キット付属の抗ウサギ-AP Conjugate抗体(希釈率1/2000)を添加して室温で1時間反応させた。反応後、buffer Bで4回、buffer D(1mM MgCl2・6H2O in 0.05M carbonate/bicarbonate(シグマ社製、商品名:C3041-50CAP)で1回洗浄し、p-nitrophenylphosphate(1mg/mL in buffer D、シグマ社製)溶液を100μL添加して発色反応を行った。発色が確認された後、405nmの吸光度を測定し、IVL量を定量した。
評価結果を表3に示す。抽出物サンプルのIVL量は、50%エタノールを添加したコントロールのIVL量を1とした場合の相対値で示した。
(2) Evaluation of IVL expression For the primary screening, Involucrin ELISA Assay Kit BT-650 (trade name, manufactured by BTI) was used with a partly modified protocol. The detailed protocol is shown below.
In a 24-well plate, HaCaT cells were seeded at 5 × 10 4 cells / well and cultured. On the next day, the extract of the sunflower extract that was 1.0% (w / v) in terms of solid content prepared in Preparation Example 2 was replaced with a medium containing the final concentration shown in Table 3, and further cultured for 24 hours. In addition, instead of the extract of sunflower, a culture medium in which 50% ethanol as an extraction solvent was replaced with a medium containing a final concentration of 0.5% v / v and cultured for 24 hours was used as a control. Twenty-four hours after the addition of the extract, the cells were washed twice with PBS (−), and Complete Mini Protease Inhibitor Cocktail (trade name, manufactured by Roche) was added to 20 mM Tris-HCl (pH: 7.5) · 2 mM EDTA. 400 μL of the extraction buffer containing was added to the cells. One Protease Inhibitor Cocktail was added to 10 mL of extraction buffer. Cells were detached and collected with a cell scraper in the presence of this extraction buffer, and then sonicated with a sonicator. The supernatant collected by centrifugation of this solution was used as an lysate for evaluation.
The total protein concentration of the lysate was quantified using BCA Protein Assay Kit (trade name, manufactured by Thermo Scientific) according to the manufacturer's instructions. Dilute lysate with buffer B (2 mM EDTA, 5 g / L Tween 20, 2.5 g / L Gelatin in PBS) to a total well of 3 μg per well of a 96-well plate and add to 96-well plate Then, an anti-IVL antibody (kit accessory, dilution ratio 1/300) was added, and a primary antibody reaction was performed overnight at 4 ° C. Also, human IVL protein (kit accessory) was added to each 96-well plate (Nalgenunk, 469078) by 1 ng / well, and EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, a condensing agent, Kanto The antigen was adsorbed overnight at 4 ° C. together with 10 μg / well manufactured by Chemical Co., Ltd. On the next day, the solution of the plate on which the antigen was adsorbed was removed by suction, 100 μL of 0.1 M NH 4 Cl was added, and the mixture was reacted at room temperature for 30 minutes. After the reaction, it was washed four times with distilled H 2 O (manufactured by Gibco) and once with buffer B, and 100 μL of the primary antibody reaction solution of the previous day was added and allowed to react at room temperature for 30 minutes. After this reaction, it was washed 5 times with buffer B, anti-rabbit-AP Conjugate antibody (dilution ratio 1/2000) attached to the kit was added, and allowed to react at room temperature for 1 hour. After the reaction, it was washed once with buffer B and once with buffer D (1 mM MgCl 2 .6H 2 O in 0.05M carbonate / bicarbonate (manufactured by Sigma, product name: C3041-50CAP), and p-nitrophenylphosphate (1 mg / mg). Color development reaction was performed by adding 100 μL of a solution in mL in buffer D (manufactured by Sigma) After confirming the color development, the absorbance at 405 nm was measured to quantify the amount of IVL.
The evaluation results are shown in Table 3. The IVL amount of the extract sample was shown as a relative value when the IVL amount of the control to which 50% ethanol was added was 1.
表3から明らかなように、ハグロソウ抽出物を添加した系ではインボルクリンの発現量が増加していた。
さらに、インボルクリンの発現は皮膚のバリア機能維持、保湿機能の維持又は改善、及び肌荒れの予防又は改善に関係し、インボルクリンの発現を促進することで、表皮の角化不全の防止や皮膚の保湿機能の改善、及び肌荒れの予防又は改善などが可能となる。また、インボルクリン遺伝子の発現量を増加させる物質がくせ毛や縮毛の促進剤又はウェーブ化促進剤となりうる。したがって、インボルクリン発現促進効果を有するハグロソウの抽出物を表皮角化改善剤、皮膚保湿機能改善剤、皮膚バリア機能改善剤、及び肌荒れ予防又は改善剤及びくせ毛化剤の有効成分とすることができる。
As is apparent from Table 3, the expression level of involucrin was increased in the system to which the extract of sunflower was added.
Furthermore, the expression of involucrin is related to the maintenance and improvement of the skin barrier function, the moisturizing function, and the prevention or improvement of rough skin, and by promoting the expression of involucrin, the prevention of epikeratosis and the moisturizing function of the skin. Improvement and prevention or improvement of rough skin are possible. In addition, a substance that increases the expression level of the involucrin gene can be a comb hair or curly hair promoter or a wave promoter. Therefore, the extract of the sunflower which has an involucrin expression promoting effect can be used as an active ingredient of an epidermis keratinization improving agent, a skin moisturizing function improving agent, a skin barrier function improving agent, and a rough skin prevention or improving agent and a hair growth agent.
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