JP6110138B2 - Skin disorder protective treatment - Google Patents
Skin disorder protective treatment Download PDFInfo
- Publication number
- JP6110138B2 JP6110138B2 JP2012288405A JP2012288405A JP6110138B2 JP 6110138 B2 JP6110138 B2 JP 6110138B2 JP 2012288405 A JP2012288405 A JP 2012288405A JP 2012288405 A JP2012288405 A JP 2012288405A JP 6110138 B2 JP6110138 B2 JP 6110138B2
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- skin
- dhe
- increased
- oral
- sunburn
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Description
本発明は、14-デヒドロエルゴステロール(14-DHE)又は14-DHE含有麹菌発酵エキスを有効成分として含有する皮膚障害防護治療剤に関する。 The present invention relates to an agent for protecting and treating skin disorders containing 14-dehydroergosterol (14-DHE) or 14-DHE-containing gonococcal fermented extract as an active ingredient.
本発明はまた、有効量の上記皮膚障害防護治療剤を含有する、医薬組成物、飲食品若しくは飼料添加物、動物飼料又は化粧組成物に関する。 The present invention also relates to a pharmaceutical composition, food / beverage product or feed additive, animal feed or cosmetic composition containing an effective amount of the above-mentioned skin disorder protective treatment.
麹菌発酵産物には、以下の特許文献1〜8に記載されるように、皮膚等に対して生物活性を有する種々の物質が含有されていることが知られている。 As described in the following Patent Documents 1 to 8, it is known that the koji mold fermentation product contains various substances having biological activity on the skin and the like.
特許文献1には、米麹を乾燥粉末化して得られた乾燥麹を、皮膚に対して保湿、保護作用を有する有効成分として含有する化粧料が記載されている。 Patent Document 1 describes a cosmetic containing dry koji obtained by dry-powdering rice koji as an active ingredient having a moisturizing and protecting action on the skin.
特許文献2には、麹菌及び種麹粉末からなる皮膚調整用基礎化粧料が記載されており、麹菌が生成するコウジ酸が、肌の新陳代謝を活発にし、肌に潤いを与える作用、紫外線によるメラニン色素の生成の抑制作用、シミの抑制作用などを有することが記載されている。
特許文献3には、2-0-(β-D-グルコピラノシル)アスコルビン酸、その塩若しくはエステルと、麹菌若しくはその処理物とを含有する外用組成物が記載されている。このアスコルビン酸誘導体は、強い抗酸化作用を有している。麹菌若しくはその処理物は、皮膚浸透性を改善する効果を有すると記載されている。
特許文献4には、麹菌発酵粕由来のスフィンゴ脂質が記載されており、それを構成するセラミド類のなかに保湿の役割を有するものが含まれていることが記載されている。 Patent Document 4 describes sphingolipids derived from koji mold fermented koji, and describes that ceramides constituting the same include those having a moisturizing role.
特許文献5〜7には、米麹菌発酵抽出物を必須成分とする、美白、日焼け止め又は老化防止のための組成物が記載されている。生理活性物質の抽出は、麹菌発酵米を水で抽出することによって行われている。
特許文献8には、これは本願と同じ出願人による出願であるが、穀類植物由来材料の麹菌発酵物又はその処理物のなかで14-DHEを有効成分として含有するものを免疫調節剤として使用することや、14-DHEを被験体の細胞と接触させることによる制御性樹状細胞や制御性T細胞の製造方法が記載されている。また、14-DHEは、麹菌発酵物をエタノール抽出した画分に含まれることが記載されている。
In
皮膚用のその他の薬効成分として、日焼け等により生じる皮膚の黒化や炎症、色素沈着により生ずるシミ、ソバカス等を防止するための、カラミン、アスコルビン酸類、グルタチオン、コロイドイオウ、ハイドロキノン、シンナミックアルデヒド等の物質や、抗酸化、肌荒れ改善、皮膚老化防止、細胞賦活の他、切創やひげそり後の傷の治療、ひび、あかぎれ、ただれ、痔疾、火傷などの改善等の創傷治療のための、アスタキサンチン、アラントイン、アロエ抽出物、人参抽出物、シコン抽出物、胎盤抽出物、牛血液除蛋白物、発酵代謝物等の薬効成分が知られている(特許文献9及び10)。
Other medicinal ingredients for skin include calamine, ascorbic acids, glutathione, colloidal sulfur, hydroquinone, cinnamic aldehyde, etc. to prevent skin darkening and inflammation caused by sunburn, etc., spots, freckles caused by pigmentation, etc. Astaxanthin for the treatment of wounds such as anti-oxidants, anti-oxidation, improvement of rough skin, prevention of skin aging, cell activation, treatment of wounds after cut and shaving, improvement of cracks, scratches, sores, hemorrhoids, burns, etc. Medicinal components such as allantoin, aloe extract, carrot extract, sicon extract, placenta extract, bovine blood deprotein, fermented metabolite are known (
本発明の目的は、新規な効果を有する皮膚障害防護治療剤を提供することである。 The object of the present invention is to provide a skin disorder protective treatment having a novel effect.
1.発明の概要
本発明は、要約すると、以下の特徴を有する。
(1) 14-デヒドロエルゴステロール(14-DHE)を有効成分として含有する、皮膚障害防護治療剤。
(2) 有効成分としての14-DHEを含有する麹菌発酵エキスを含有する、皮膚障害防護治療剤。
(3) アスタキサンチンをさらに含有する、上記(1)又は(2)に記載の皮膚障害防護治療剤。
(4) 麹菌発酵エキスが、穀類植物種子由来の材料を黒麹菌又は白麹菌で発酵させて得られる14-DHE含有発酵エキスである、上記(2)に記載の皮膚障害防護治療剤。
(5) 麹菌発酵エキスが、麹菌発酵物をエタノールで抽出することを含む方法で得られるものである、上記(2)〜(4)のいずれかに記載の皮膚障害防護治療剤。
(6) 14-DHEが、0.0001重量%以上100重量%未満の量で含有する、上記(1)〜(5)のいずれかに記載の皮膚障害防護治療剤。
(7) 皮膚炎症を防護又は治療する作用を有する、上記(1)〜(6)のいずれかに記載の皮膚障害防護治療剤。
(8) 経口投与剤型又は皮膚投与剤型である、上記(1)〜(7)のいずれかに記載の皮膚障害防護治療剤。
(9) 上記(1)〜(8)のいずれかに記載の皮膚障害防護治療剤を有効量で含有する医薬組成物。
(10) 上記(1)〜(8)のいずれかに記載の皮膚障害防護治療剤を有効量で含有する食品添加物。
(11) 上記(1)〜(8)のいずれかに記載の皮膚障害防護治療剤を有効量で含有するサプリメント。
(12) 上記(1)〜(8)のいずれかに記載の皮膚障害防護治療剤又は上記(10)に記載の食品添加物を皮膚障害防護治療有効量で含有する飲食品。
(13) 上記(1)〜(8)のいずれかに記載の皮膚障害防護治療剤を有効量で含有する動物飼料添加物若しくは動物飼料。
(14) 上記(1)〜(8)のいずれかに記載の皮膚障害防護治療剤を有効量で含有する化粧組成物。
1. SUMMARY OF THE INVENTION In summary, the present invention has the following features.
(1) A skin disorder protective treatment comprising 14-dehydroergosterol (14-DHE) as an active ingredient.
(2) A skin disorder protective therapeutic agent comprising a koji mold fermented extract containing 14-DHE as an active ingredient.
(3) The skin disorder protective treatment agent according to (1) or (2), further comprising astaxanthin.
(4) The skin disorder protective treatment agent according to (2) above, wherein the koji mold extract is a 14-DHE-containing fermented extract obtained by fermenting a cereal plant seed-derived material with black koji mold or white koji mold.
(5) The skin disorder protective therapeutic agent according to any one of (2) to (4) above, wherein the koji mold extract is obtained by a method comprising extracting a koji mold fermented product with ethanol.
(6) The skin disorder protective treatment agent according to any one of (1) to (5) above, wherein 14-DHE is contained in an amount of 0.0001% by weight or more and less than 100% by weight.
(7) The skin disorder protective treatment agent according to any one of the above (1) to (6), which has an action of protecting or treating skin inflammation.
(8) The skin disorder protective treatment agent according to any one of the above (1) to (7), which is an oral dosage form or a skin dosage form.
(9) A pharmaceutical composition comprising an effective amount of the skin disorder protective treatment agent according to any one of (1) to (8) above.
(10) A food additive containing an effective amount of the dermatological protection agent according to any one of (1) to (8) above.
(11) A supplement containing an effective amount of the agent for protecting against skin damage according to any one of (1) to (8) above.
(12) A food or drink containing the skin disorder protective treatment agent according to any one of (1) to (8) or the food additive according to (10) in an effective amount for skin disorder protection treatment.
(13) An animal feed additive or an animal feed containing an effective amount of the skin disorder protective agent according to any one of (1) to (8) above.
(14) A cosmetic composition containing an effective amount of the dermatological disorder protective therapeutic agent according to any one of (1) to (8) above.
2.定義
本明細書で使用する用語は、以下の定義を包含する。
「皮膚障害防護治療」とは、ヒトを含む哺乳動物における皮膚障害の防護又は治療を意味し、主要な皮膚障害には、疾病としての紫外線や放射線照射による急性、慢性の皮膚炎症、皮膚障害、皮膚肥厚化に加えて、日常的にみられる肌荒れ、日焼け、角質化などの皮膚障害が含まれる。
2. Definitions The terms used in this specification include the following definitions.
“Skin damage protection treatment” means protection or treatment of skin damage in mammals including humans. Major skin disorders include acute and chronic skin inflammation, skin damage caused by ultraviolet rays or radiation as a disease, In addition to thickening of the skin, skin disorders such as daily rough skin, sunburn, and keratinization are included.
「エキス」とは、麹菌発酵物を、エタノールなどの、14-DHEの抽出を容易にする有機溶媒等によって抽出して得られる、14-DHE含有抽出液又はその14-DHE含有処理物を意味し、この処理物は、抽出液の濃縮、乾燥、クロマトグラフィー処理などの処理により得られる、14-DHE含有処理物であり、好ましくは14-DHEに富む処理物、例えば処理物あたり14-DHEを0.1重量%以上、5〜30重量%又はそれ以上、或いは50重量%以上、含有する処理物である。 “Extract” means a 14-DHE-containing extract or a 14-DHE-containing treated product obtained by extracting a koji mold fermented product with an organic solvent that facilitates the extraction of 14-DHE, such as ethanol. However, this processed product is a 14-DHE-containing processed product obtained by a process such as concentration of an extract, drying, chromatography, etc., preferably a processed product rich in 14-DHE, for example, 14-DHE per processed product. Is a processed product containing 0.1 wt% or more, 5 to 30 wt% or more, or 50 wt% or more.
「サプリメント」とは、皮膚障害防護治療効果を有する栄養補助食品を指す。
「哺乳動物」とは、ヒトを含む哺乳動物を指し、ヒト以外の動物の例は、皮膚障害を起こし易い動物、例えばイヌ、ネコ、げっ歯類、ウサギ目などのペット動物、ウシ、ウマ、ブタなどの家畜である。このような動物には、皮膚障害や疾患の治療中の動物に加えて、皮膚障害予防中の健常動物、専門医の治療を必要としない程度の軽い皮膚障害をもつ動物などが含まれる。
“Supplement” refers to a dietary supplement that has a protective effect on skin disorders.
“Mammal” refers to mammals including humans, and examples of non-human animals include animals that are prone to skin disorders, such as pet animals such as dogs, cats, rodents, and rabbit eyes, cows, horses, Domestic animals such as pigs. Such animals include, in addition to animals undergoing treatment for skin disorders and diseases, healthy animals during prevention of skin disorders, and animals having mild skin disorders that do not require treatment by specialists.
本発明は、14-DHEや14-DHE含有麹菌発酵エキスに、炎症時の皮膚における水分保持作用、抗炎症作用などの効果があることを見出したことに基づいており、疾病としての紫外線や放射線照射あるいは加齢による急性、慢性の皮膚炎症、皮膚障害、皮膚肥厚化に加えて、日常的にみられる肌荒れ、日焼け、角質化などの皮膚障害に対する防護治療効果を提供する。 The present invention is based on the finding that 14-DHE and 14-DHE-containing gonococcal fermented extract have effects such as water retention action and anti-inflammatory action on the skin during inflammation. In addition to acute and chronic skin inflammation, skin damage, and skin thickening due to irradiation or aging, it provides protective treatment effects against skin disorders such as daily rough skin, sunburn, and keratinization.
本発明の皮膚障害防護治療剤は、14-DHE又は14-DHE含有麹菌発酵エキスを有効成分として含有することを特徴とし、その改善効果は、化粧品等に使用されるアスタキサンチンと同等以上の効果を有しており、14-DHEは、皮膚において、水分保持、水分蒸散抑制、紅斑抑制、皮膚炎症抑制などの効果を有するため、ヒトを含む哺乳動物における皮膚の恒常性維持、障害予防、障害改善などを含む皮膚障害防護治療のために有用である。 The skin disorder protective treatment agent of the present invention is characterized by containing 14-DHE or 14-DHE-containing gonococcal fermented extract as an active ingredient, and the improvement effect thereof is equivalent to or better than astaxanthin used in cosmetics and the like. 14-DHE has effects such as retention of moisture, suppression of transpiration, suppression of erythema, and suppression of skin inflammation in the skin. Therefore, maintenance of skin homeostasis, prevention of injury and improvement of injury in mammals including humans. It is useful for skin damage protection treatment including.
本発明をさらに詳細に説明する。
1.皮膚障害防護治療剤
本発明は、14-デヒドロエルゴステロール(14-DHE)を有効成分として含有する、皮膚障害防護治療剤を提供する。
The present invention will be described in further detail.
1. The skin disorder protective treatment agent The present invention provides a skin disorder protective therapeutic agent containing 14-dehydroergosterol (14-DHE) as an active ingredient.
本明細書で使用する「皮膚障害防護治療」は、上記の定義のとおり、ヒトを含む哺乳動物における皮膚障害の防護又は治療を意味し、主要な皮膚障害には、疾病としての紫外線や放射線照射あるいは加齢による急性、慢性の皮膚炎症、皮膚障害、皮膚肥厚化に加えて、日常的にみられる肌荒れ、日焼け、角質化などの皮膚障害が含まれる。 As used herein, “skin injury protective treatment” means the protection or treatment of skin injury in mammals including humans, as defined above. Major skin disorders include ultraviolet rays and radiation as diseases. Or, in addition to aging acute and chronic skin inflammation, skin disorders, and skin thickening, skin disorders such as daily rough skin, sunburn, and keratinization are included.
14-DHEは、後述の実施例で証明されるように、皮膚において、水分保持、水分蒸散抑制、紅斑抑制、皮膚炎症抑制などの効果を有するため、ヒトを含む哺乳動物における皮膚の恒常性維持、障害予防、障害改善などを含む皮膚障害防護治療のために有用である。 14-DHE has effects such as moisture retention, moisture transpiration suppression, erythema suppression, and skin inflammation suppression in the skin, as demonstrated in the examples described later, so that skin homeostasis is maintained in mammals including humans. It is useful for protective treatment of skin disorders including prevention, improvement of disorders, etc.
14-DHEは、1951年にアスペルギルス・ニガーにおいて見出され(Barton, DHR., and Bruun, T., J. Chem. Soc., 2728-2733 (1951))、2009年にキウイフルーツ果皮の一成分として再発見されたが(Fiorentino, A.ら, J. Agric. Food Chem., 57:4148-4155 (2009))、その生物活性については、本出願と同じ出願人である特許文献8で、14-DHEが免疫調節作用を有するという生物活性が報告されるまでは報告されていなかった。
14-DHEは、例えば麹菌による穀類植物由来材料発酵物から得ることができる。
14-DHE was found in Aspergillus niger in 1951 (Barton, DHR., And Bruun, T., J. Chem. Soc., 2728-2733 (1951)). Although it was rediscovered as an ingredient (Fiorentino, A. et al., J. Agric. Food Chem., 57: 4148-4155 (2009)), its biological activity is described in
14-DHE can be obtained, for example, from a cereal plant-derived material fermented product by Aspergillus.
例えば、特許文献8に記載のように、黒麹菌(秋田今野社:黒麹マイルド(アスペルギルス・アワモリ))を用いて、培養温度30℃、培養日数3日、水分量55%の固体培養条件下で小麦フスマ麹菌発酵物を調製し、得られた発酵物をさらにエタノール抽出、さらにヘキサン抽出に供し、発酵物の凍結乾燥物100gから抽出物3gを取得することができる。得られた抽出物を200mg/mLとなるようにヘキサンに溶解し、ヘキサンでコンディショニングしたMega Bond Elute SI(20g)(Varian社製)に、1本あたり3mLアプライし、続いて60mLのヘキサンでカラムを洗浄し、60mLの酢酸エチルで溶出して、カラム吸着物を回収することができる。得られた溶出液をエバポレーターで乾固し、3gのヘキサン抽出物から、2.8gのS1カラム吸着物を得ることができる。得られたS1カラム吸着物を、200mg/mLとなるようにヘキサン/エタノール(80/20;v/v)に溶解し、UK-Silica(10×250mm)(インタクト社製)を用いた高速液体クロマトグラフィー(ヘキサン/イソプロパノール=98/2)にかけ、保持時間18〜19分の画分を分取し、濃縮乾固し、これをさらにヘキサン/エタノール(20/80;v/v)に溶解し、Develosil C30-UG-5(10×250mm)(野村化学社製)を用いた高速液体クロマトグラフィー(アセトニトリル/イソプロパノール=99/1)にかけ、保持時間32.5〜33.5分の画分を分取する。この画分に14-DHEが含まれる。14-DHEは、以下の構造式及び物理化学的特性を有する。
(構造式)
For example, as described in
(Structural formula)
(物理化学的特性)
(1)分子量:394.32275(高分解能APCI-Orbitrap法による観測値:m/z 395.33057(M+H)+)
(2)分子式:C28H42O(精密分子量:394.323565)
(3)溶剤に対する溶解性:水に不溶、エタノールに難溶、クロロホルムに易溶
(4)紫外部吸収スペクトル(MeCN):391nm
(5) 1H-NMR(CD3OD)ppm: 6.15 (1H, m), 5.75 (1H, m), 5.65 (1H, dd, J = 2.2, 5.9 Hz), 5.27 (1H, dd, J = 7.0, 15.1 Hz), 5.21 (1H, dd, J = 7.9, 15.1 Hz), 3.64 (1H, m), 2.51 (1H, ddd, J = 2.2, 5.1, 10.6 Hz), 2.30 (1H, m), 2.20 (1H, m), 2.20 (1H, dd, J = 3.2, 7.8 Hz), 2.06 (1H, m), 2.05 (1H, m), 1.94 (1H, m), 1.90 (1H, m), 1.87 (2H, m), 1.87 (1H, ddd, J = 3.2, 7.0, 7.3 Hz), 1.71 (1H, m), 1.59 (1H, m), 1.57 (1H, m), 1.45 (1H, m), 1.45 (1H, ddd, J = 3.2, 6.3, 6.5 Hz), 1.30 (1H, m), 1.05 (3H, d, J = 6.8 Hz ), 0.93 (3H, d, J = 7.3 Hz), 0.92 (3H, s,), 0.89 (3H, s), 0.85 (3H, d, J = 6.5 Hz), 0.83 (3H, d, J = 6.3 Hz).
(6) 13C-NMR(CD3OD)ppm:149.2 (s), 143.0 (s), 135.4 (s), 132.2 (s), 132.0 (s), 120.5 (s), 120.4 (s), 117.4 (s), 70.4 (s), 58.1 (s), 46.3 (s), 45.4 (s), 42.8 (s), 41.0 (s), 39.0 (s), 38.9 (s), 37.8 (s), 37.0 (s), 36.0 (s), 33.1 (s), 32.0 (s), 21.1 (s), 19.9 (s), 19.7 (s), 19.6 (s), 17.6 (s), 16.8 (s), 14.5 (s).
(Physicochemical properties)
(1) Molecular weight: 394.32275 (observed by high resolution APCI-Orbitrap method: m / z 395.33057 (M + H) +)
(2) Molecular formula: C28H42O (precision molecular weight: 394.323565)
(3) Solubility in solvents: Insoluble in water, hardly soluble in ethanol, easily soluble in chloroform
(4) UV absorption spectrum (MeCN): 391 nm
(5) 1 H-NMR (CD 3 OD) ppm: 6.15 (1H, m), 5.75 (1H, m), 5.65 (1H, dd, J = 2.2, 5.9 Hz), 5.27 (1H, dd, J = 7.0, 15.1 Hz), 5.21 (1H, dd, J = 7.9, 15.1 Hz), 3.64 (1H, m), 2.51 (1H, ddd, J = 2.2, 5.1, 10.6 Hz), 2.30 (1H, m), 2.20 (1H, m), 2.20 (1H, dd, J = 3.2, 7.8 Hz), 2.06 (1H, m), 2.05 (1H, m), 1.94 (1H, m), 1.90 (1H, m), 1.87 (2H, m), 1.87 (1H, ddd, J = 3.2, 7.0, 7.3 Hz), 1.71 (1H, m), 1.59 (1H, m), 1.57 (1H, m), 1.45 (1H, m), 1.45 (1H, ddd, J = 3.2, 6.3, 6.5 Hz), 1.30 (1H, m), 1.05 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 7.3 Hz), 0.92 (3H , s,), 0.89 (3H, s), 0.85 (3H, d, J = 6.5 Hz), 0.83 (3H, d, J = 6.3 Hz).
(6) 13 C-NMR (CD 3 OD) ppm: 149.2 (s), 143.0 (s), 135.4 (s), 132.2 (s), 132.0 (s), 120.5 (s), 120.4 (s), 117.4 (s), 70.4 (s), 58.1 (s), 46.3 (s), 45.4 (s), 42.8 (s), 41.0 (s), 39.0 (s), 38.9 (s), 37.8 (s), 37.0 (s), 36.0 (s), 33.1 (s), 32.0 (s), 21.1 (s), 19.9 (s), 19.7 (s), 19.6 (s), 17.6 (s), 16.8 (s), 14.5 (s).
本発明の皮膚障害防護治療剤に含まれる14-DHEは、精製14-DHE、粗製14-DHE又は14-DHE含有物質のいずれであってもよい。14-DHE含有物質の例は、有効成分としての14-DHEを含有する麹菌発酵エキスである。 The 14-DHE contained in the therapeutic agent for protecting skin disorders of the present invention may be any of purified 14-DHE, crude 14-DHE, or 14-DHE-containing substance. An example of a 14-DHE-containing substance is a koji mold fermented extract containing 14-DHE as an active ingredient.
そのような麹菌発酵エキスは、例えば以下のような、穀類植物種子由来の材料を麹菌で発酵させて得られる14-DHE含有麹菌発酵エキスである。 Such a koji mold fermented extract is a 14-DHE-containing koji mold fermented extract obtained by, for example, fermenting a cereal plant seed-derived material with koji mold as follows.
好ましい穀類植物としては、植物分類表においてイネ科に分類されるすべての植物が挙げられる。具体的には、イネ、オオムギ、コムギ、ライムギ、アワ、ヒエ、トウモロコシ等が例示されるが、これらに限定されるものではない。このうち、イネ、オオムギ、コムギ及びライムギが好ましく、コムギが特に好ましい。 Preferred cereal plants include all plants that are classified as Gramineae in the plant taxonomy. Specific examples include, but are not limited to, rice, barley, wheat, rye, millet, millet and corn. Of these, rice, barley, wheat and rye are preferred, and wheat is particularly preferred.
穀類植物由来材料は、穀類植物の種子に由来する材料であり、典型的には、穀類植物の種子全体、又はその一部分である。好ましくは、種子の外皮を含む材料であり、例えば、穀類種子全粒粉、穀類植物のフスマ、米糠などが挙げられる。特に好ましい穀類植物由来材料は、穀類植物のフスマ、最も好ましくは小麦フスマである。穀類植物のフスマは、穀類植物種子の粉砕又は搗精により得られる種子の外側の部分を回収することで得ることができる。 A cereal plant-derived material is a material derived from the seeds of a cereal plant and is typically the whole seed of a cereal plant or a part thereof. Preferably, it is a material containing a seed shell, and examples thereof include whole grains of grain seeds, bran of cereal plants, and rice bran. A particularly preferred cereal plant-derived material is a cereal plant bran, most preferably wheat bran. The bran of the cereal plant can be obtained by recovering the outer part of the seed obtained by grinding or milling the cereal plant seeds.
麹菌は、穀類植物由来材料を発酵させて14-DHEを産生することができれば特に限定されないが、好ましくは、黒麹(アスペルギルス・アワモリ、アスペルギルス・ニガー)、黄麹(アスペルギルス・オリゼー)、紅麹(モナスカス・アンカ)、醤油用麹菌(アスペルギルス・ソーヤ)、白麹(アスペルギルス・カワチ)、テンペ菌(リゾプス・オリゴスポラス)などである。好ましくは、麹菌はアスペルギルス属糸状菌であり、最も好ましくは黒麹菌である。好ましい麹菌は、狭義の黒麹菌であるアスペルギルス・アワモリ及びアスペルギルス・ニガー、狭義には白麹菌と称されるアスペルギルス・カワチ、並びにこれらの菌種から誘導された亜種を含む。これらの麹菌の種麹は、秋田今野社、樋口もやし社、日本醸造工業社などから入手することができる。 The koji mold is not particularly limited as long as it can ferment a cereal plant-derived material to produce 14-DHE, but preferably black koji (Aspergillus awamori, Aspergillus niger), twilight (Aspergillus oryzae), red yeast rice (Monascus anca), koji mold for soy sauce (Aspergillus soja), white birch (Aspergillus kawachi), tempeh fungus (Rhizopus oligosporus) and the like. Preferably, the koji mold is an Aspergillus filamentous fungus, most preferably a black koji mold. Preferred Neisseria gonorrhoeae include Aspergillus awamori and Aspergillus niger which are black gonococci in the narrow sense, Aspergillus kawachi, which is narrowly referred to as white gonococcus, and subspecies derived from these species. These koji molds can be obtained from Akita Imano Co., Higuchi Moyashi Co., Nippon Brewing Industry Co., etc.
発酵は、原料に麹菌を接種して培養する当業者に公知の方法を用いて行うことができる。そのような方法としては、例えば、蓋麹法、箱麹法、床麹法、機械麹法などを挙げることができる。 Fermentation can be carried out using methods known to those skilled in the art of inoculating and culturing koji molds as raw materials. As such a method, for example, a lid culling method, a box culling method, a floor culling method, a mechanical culling method and the like can be exemplified.
種麹の添加量は、水を加えて処理(例えば、オートクレーブ、蒸煮など)された穀類植物由来材料に対して、好ましくは0.005〜5重量%、より好ましくは0.01〜1重量%、さらに好ましくは0.05〜0.5重量%、最も好ましくは0.1重量%である。発酵温度は、使用する麹によっても若干異なるが、一般的には20℃〜50℃、好ましくは22℃〜45℃、より好ましくは30℃〜40℃である。発酵時間は、例えば、24時間〜14日間、好ましくは48時間〜10日間、より好ましくは72時間〜7日間である。発酵中に、一定時間ごと(例えば24時間ごと)に手入れ(塊になった麹をほぐす作業)を行うのが好ましい。発酵時の湿度は、当業者であれば、麹菌の種類に応じて適切に調節することができる。例えば、発酵中、相対湿度を80%以上に維持する。又は、発酵初期には相対湿度を高く(例えば90%以上)保ち、発酵後期(例えば、麹菌接種後24時間以降)は相対湿度を若干下げて(例えば75%以上)、発酵を行う。発酵方法の詳細については、例えば、発酵ハンドブック((財)バイオインダストリー協会 発酵と代謝研究会編、東京、日本、2001年)などに記載されている。 The amount of seed meal added is preferably 0.005 to 5% by weight, more preferably 0.01 to 1% by weight, and still more preferably, based on the cereal plant-derived material treated by adding water (eg, autoclave, steaming, etc.) 0.05 to 0.5% by weight, most preferably 0.1% by weight. The fermentation temperature varies slightly depending on the koji used, but is generally 20 ° C to 50 ° C, preferably 22 ° C to 45 ° C, more preferably 30 ° C to 40 ° C. The fermentation time is, for example, 24 hours to 14 days, preferably 48 hours to 10 days, more preferably 72 hours to 7 days. During fermentation, it is preferable to carry out care (work for loosening the lump that becomes a lump) at regular intervals (for example, every 24 hours). A person skilled in the art can appropriately adjust the humidity during fermentation according to the type of koji mold. For example, the relative humidity is maintained at 80% or higher during fermentation. Alternatively, the relative humidity is kept high (for example, 90% or more) in the early stage of fermentation, and the relative humidity is slightly lowered (for example, 75% or more) in the late stage of fermentation (for example, 24 hours or more after inoculation with koji mold). The details of the fermentation method are described in, for example, the Fermentation Handbook (Edited by the Bioindustry Association, Fermentation and Metabolism Study Group, Tokyo, Japan, 2001).
麹菌発酵エキスは、穀類植物由来材料麹菌発酵物から溶媒抽出により取得することができる。抽出方法としては、例えば、有機溶媒抽出、超臨界流体抽出法、加温加圧抽出法などが挙げられる。溶媒抽出は当業者に公知の一般的な手法を用いて行うことができる。溶媒抽出に用いる有機溶媒として、限定するものではないが、エタノール、メタノール、n‐プロパノール、イソプロパノール、酢酸メチル、酢酸エチル、ヘキサン、ヘプタンなどを用いることができる。好ましい有機溶媒は、エタノール、メタノール、酢酸エチル、及びヘキサンである。これらの有機溶媒は2種類以上を混合して用いてもよく、また2種類以上の有機溶媒を用いた2段階以上の溶媒抽出工程を行なってもよい。具体的には、溶媒抽出は、例えば、凍結乾燥により乾燥させた発酵材料を粉砕し、これに有機溶媒を添加し、20〜50℃、好ましくは25〜45℃にて撹拌しながら超音波処理を施して行うことができる。添加する溶媒の量は、発酵材料の重量の1〜50倍、好ましくは2〜40倍、より好ましくは10〜30倍である。抽出時間は、10分間〜24時間、好ましくは15分間〜1時間、より好ましくは20〜50分間である。その後、濾過や遠心分離などにより濾液を回収し、残渣に含まれる不溶性画分を取り除き、例えば減圧蒸発により濾液から有機溶媒画分(すなわち、抽出画分)を濃縮し、流体又は乾燥形態で抽出物を得ることができる。また、有機溶媒抽出後の不溶性画分について有機溶媒による抽出を繰り返すことにより、第1回目の有機溶媒抽出後の残渣から有機溶媒画分をさらに取得することもできる。また、溶媒抽出に続いてさらに別の溶媒を用いた分画を行ってもよい。例えば、溶媒抽出により得られた有機溶媒画分に、溶媒抽出に用いたものと同じか又は異なる第2の有機溶媒を添加し、これに、第2の有機溶媒とは混和しない第3の有機溶媒を添加して抽出し、第3の有機溶媒に溶解性の画分を得ることができる。 The koji mold fermented extract can be obtained from the cereal plant-derived material koji mold fermented product by solvent extraction. Examples of the extraction method include organic solvent extraction, supercritical fluid extraction method, warming pressure extraction method and the like. Solvent extraction can be performed using general techniques known to those skilled in the art. Although it does not limit as an organic solvent used for solvent extraction, ethanol, methanol, n-propanol, isopropanol, methyl acetate, ethyl acetate, hexane, heptane, etc. can be used. Preferred organic solvents are ethanol, methanol, ethyl acetate, and hexane. Two or more kinds of these organic solvents may be used as a mixture, or two or more steps of solvent extraction using two or more kinds of organic solvents may be performed. Specifically, for solvent extraction, for example, fermented material dried by freeze-drying is pulverized, an organic solvent is added thereto, and sonication is performed with stirring at 20 to 50 ° C., preferably 25 to 45 ° C. Can be performed. The amount of the solvent to be added is 1 to 50 times, preferably 2 to 40 times, more preferably 10 to 30 times the weight of the fermentation material. The extraction time is 10 minutes to 24 hours, preferably 15 minutes to 1 hour, more preferably 20 to 50 minutes. The filtrate is then collected by filtration, centrifugation, etc., and the insoluble fraction contained in the residue is removed. For example, the organic solvent fraction (ie, the extract fraction) is concentrated from the filtrate by evaporation under reduced pressure, and extracted in a fluid or dry form. You can get things. Further, the organic solvent fraction can be further obtained from the residue after the first organic solvent extraction by repeating extraction with the organic solvent for the insoluble fraction after the organic solvent extraction. Further, fractionation using another solvent may be performed following the solvent extraction. For example, a second organic solvent that is the same as or different from that used for solvent extraction is added to the organic solvent fraction obtained by solvent extraction, and a third organic solvent that is not miscible with the second organic solvent is added thereto. A solvent can be added for extraction to obtain a fraction soluble in the third organic solvent.
有機溶媒画分に存在する物質をさらに精製してもよく、この場合、公知の分離、精製法を適当に組み合わせて行うことができる。例えば、液‐液分配、有機溶媒沈澱、各種カラムクロマトグラフィー(例えばHPLC、シリカゲルクロマトグラフィー、分子篩クロマトグラフィー、イオン交換クロマトグラフィー、逆相クロマトグラフィーなど)、結晶化などを使用することができる。 The substance present in the organic solvent fraction may be further purified. In this case, known separation and purification methods can be combined appropriately. For example, liquid-liquid partition, organic solvent precipitation, various column chromatography (for example, HPLC, silica gel chromatography, molecular sieve chromatography, ion exchange chromatography, reverse phase chromatography, etc.), crystallization, etc. can be used.
好ましくは、麹菌による穀類植物由来材料発酵物又はその処理物は、発酵後に、エタノール抽出によりエタノール溶解画分を分離することにより得られたエタノール画分である。必要に応じて、エタノール抽出の後、さらにヘキサン分画によりヘキサン溶解画分を分離してもよい。 Preferably, the fermented cereal plant-derived material or its treated product by Aspergillus is an ethanol fraction obtained by separating an ethanol-soluble fraction by ethanol extraction after fermentation. If necessary, the hexane-soluble fraction may be further separated by hexane fraction after ethanol extraction.
本発明の皮膚障害防護治療剤には、14-DHEが、皮膚障害防護治療剤中に0.0001〜100重量%未満、例えば0.001〜90重量%、0.01〜70重量%又は0.05〜50重量%、好ましくは、0.1〜10重量%の含量で含まれうるが、皮膚障害防護治療作用を発揮する限り、その量は特に制限されないものとする。 In the skin injury protective treatment agent of the present invention, 14-DHE is 0.0001 to less than 100% by weight, for example 0.001 to 90% by weight, 0.01 to 70% by weight, or 0.05 to 50% by weight, preferably in the skin injury protective treatment agent. May be contained in a content of 0.1 to 10% by weight, but the amount thereof is not particularly limited as long as it exhibits a protective action against skin disorders.
本発明の皮膚障害防護治療剤は、経口投与剤型又は皮膚投与剤型のいずれであっても皮膚障害防護治療効果を有する。経口投与剤型は、錠剤、顆粒剤、粉末剤、カプセル剤、溶液剤、懸濁化剤、乳濁化剤、ゲル化剤などの経口投与に適するいずれの剤型も選択可能である。また、皮膚投与剤型は、軟膏、ローション、乳液、クリーム、ゲルなどの皮膚投与に適したいずれの剤型も選択可能である。これらの投与剤型は、14-DHEの有効成分の他に、担体、賦形剤、希釈剤、結合剤、崩壊剤、滑沢剤、乳化剤、増量剤、着色剤、香味剤、甘味料、安定化剤、保存料などの添加剤を含有させることができる。 The skin disorder protective treatment agent of the present invention has a skin disorder protective treatment effect regardless of whether it is an oral dosage form or a skin dosage form. As the oral dosage form, any dosage form suitable for oral administration such as tablets, granules, powders, capsules, solutions, suspending agents, emulsifying agents, gelling agents and the like can be selected. As the dermal administration dosage form, any dosage form suitable for dermal administration such as ointment, lotion, emulsion, cream, gel and the like can be selected. These dosage forms include carriers, excipients, diluents, binders, disintegrants, lubricants, emulsifiers, bulking agents, coloring agents, flavoring agents, sweeteners, in addition to the active ingredients of 14-DHE. Additives such as stabilizers and preservatives can be included.
本発明の皮膚障害防護治療剤は、14-DHEの他に、アスタキサンチンをさらに含有してもよい。 The skin disorder protective treatment agent of the present invention may further contain astaxanthin in addition to 14-DHE.
アスタキサンチンは、抗酸化効果、酸化防止効果、抗炎症効果、皮膚老化防止効果、美白効果などの生物活性を有しており、オキアミ、サケ、マス、福寿草、赤色酵母等を、アセトン、エーテル、クロロホルム、アルコール(エタノール、メタノール等)等の有機溶媒で抽出し、カラムクロマトグラフィーや高速液体クロマトグラフィー(HPLC)等で処理することによって調製することができる(日本特許第4564471号公報、特開平2-49091号公報、特開平5-155736号公報、等)。皮膚障害防護治療剤中のアスタキサンチンの含量は、好ましくは14-DHEとの間で相乗的効果又は相加的効果が得られるような量であり、例えば0.0001〜3重量%であるが、この範囲に制限されないものとする。 Astaxanthin has biological activities such as antioxidant effect, antioxidant effect, anti-inflammatory effect, skin aging preventive effect, whitening effect, etc., and krill, salmon, trout, fujusakusa, red yeast, etc., acetone, ether, chloroform And can be prepared by extraction with an organic solvent such as alcohol (ethanol, methanol, etc.) and treatment with column chromatography, high performance liquid chromatography (HPLC), or the like (Japanese Patent No. 4456471, JP-A-2- No. 49091, JP-A-5-155736, etc.). The content of astaxanthin in the dermatological protective agent is preferably such an amount that a synergistic or additive effect is obtained with 14-DHE, for example 0.0001 to 3% by weight. It is not limited to.
2.医薬組成物
本発明はさらに、本発明の皮膚障害防護治療剤を有効量で含有する医薬組成物を提供する。
2. Pharmaceutical Composition The present invention further provides a pharmaceutical composition comprising an effective amount of the skin disorder protective agent of the present invention.
医薬組成物は、経口投与剤型及び皮膚投与剤型(外用剤)の剤型であることが好ましい。 The pharmaceutical composition is preferably an oral dosage form or a dermal dosage form (external preparation).
経口投与剤型には、有効成分である皮膚障害防護治療剤(14-DHE又は14-DHE含有麹菌発酵エキス)を製薬上許容される担体、賦形剤又は希釈剤と共に、液剤、懸濁剤、散剤、顆粒剤、錠剤、カプセル剤、丸剤、糖衣錠、ゲル剤などの投与形態に製剤化しうる。皮膚投与剤型には、外皮用剤、塗布剤、貼付剤などの投与形態が含まれ、有効成分である皮膚障害防護治療剤(14-DHE又は14-DHE含有麹菌発酵エキス)を製薬上許容される担体、賦形剤又は希釈剤と共に、軟膏剤、ローション剤、乳液剤、クリーム剤、ゲル剤、チック剤、エアゾール剤、パッチ剤、ハップ剤などの投与形態に製剤化しうる。 For oral dosage forms, the active ingredient skin damage protective treatment agent (14-DHE or 14-DHE-containing gonococcal fermented extract) together with pharmaceutically acceptable carriers, excipients or diluents, solutions and suspensions , Powders, granules, tablets, capsules, pills, dragees, gels and the like. Dermal dosage forms include administration forms such as skin preparations, coatings, patches, etc., and pharmaceutically acceptable dermatological protection agents (14-DHE or 14-DHE-containing gonococcal fermented extract) that are active ingredients Along with such carriers, excipients or diluents, it can be formulated into dosage forms such as ointments, lotions, emulsions, creams, gels, tics, aerosols, patches, and haps.
皮膚障害防護治療剤の含有量は、医薬組成物の単回投与剤型あたり、14-DHEの重量で換算して10ng〜100mg、好ましくは10μg〜10mgであるが、この範囲に限定されないものとする。 The content of the skin injury protective treatment agent is 10 ng to 100 mg, preferably 10 μg to 10 mg in terms of the weight of 14-DHE per single dosage form of the pharmaceutical composition, but is not limited to this range. To do.
製薬上許容される担体、賦形剤又は希釈剤としては、限定するものではないが、乳糖、ショ糖、ブドウ糖などの糖類、デンプン、ゼラチン、アラビアゴム、ステアリン酸マグネシウム、タルク、炭酸カルシウム、硫酸カルシウム等の無機物、結晶セルロース、蒸留水、精製水、エタノール、グリセロール、ゴマ油、ダイズ油、コーン油、オリーブ油、綿実油、菜種油などの植物油、ゼラチン、ポリアルキレングリコールなどの、医薬分野で一般的に使用されている担体、賦形剤又は希釈剤を例示することができる。また、医薬組成物には、担体、賦形剤又は希釈剤の他に、結合剤、滑沢剤、分散剤、懸濁剤、乳化剤、緩衝剤、抗酸化剤、保存料、皮膚浸透剤、増量剤(充填剤)、着色剤、湿潤化剤などの添加剤を使用することができる。ここで、皮膚浸透剤としては、例えば、エチルアルコール、イソプロピルアルコール、オクチルフェニルポリエチレングリコール、オレイン酸、ポリエチレングリコール400、プロピレングリコール、N-デシルメチルスルホキシド、脂肪酸エステル、例えば、イソプロピルミリステート、メチルラウレート、グリセロールモノオレエート、プロピレングリコールモノオレエートなどが挙げられる。その他の添加剤の例は、Reminton, The Science and Practice of Pharmacy, 19th 版, Mack Publishing Company, 1995に記載されている。
Pharmaceutically acceptable carriers, excipients or diluents include, but are not limited to, sugars such as lactose, sucrose, glucose, starch, gelatin, gum arabic, magnesium stearate, talc, calcium carbonate, sulfuric acid Commonly used in the pharmaceutical field, such as minerals such as calcium, crystalline cellulose, distilled water, purified water, ethanol, glycerol, sesame oil, soybean oil, corn oil, olive oil, cottonseed oil, rapeseed oil and other vegetable oils, gelatin and polyalkylene glycol Examples of carriers, excipients or diluents that have been used can be given. In addition to carriers, excipients or diluents, pharmaceutical compositions include binders, lubricants, dispersants, suspending agents, emulsifiers, buffers, antioxidants, preservatives, skin penetration agents, Additives such as extenders (fillers), colorants, wetting agents and the like can be used. Here, as the skin penetrant, for example, ethyl alcohol, isopropyl alcohol, octylphenyl polyethylene glycol, oleic acid,
皮膚障害防護治療効果をもつことが知られている他の医薬品と混合又は併用することも可能である。そのような医薬品として、例えばアスタキサンチン、ステロイド剤、アズノール剤等を挙げることができる。 It is also possible to mix or use in combination with other pharmaceuticals known to have a skin disorder protective treatment effect. As such pharmaceuticals, for example, astaxanthin, steroids, azunol agents and the like can be mentioned.
医薬組成物は、経口投与の場合、例えば1日1〜3回服用し、皮膚投与の場合、例えば1日1〜3回皮膚に塗布する。 The pharmaceutical composition is taken, for example, 1 to 3 times a day for oral administration, and applied to the skin, for example, 1 to 3 times a day for skin administration.
3.食品添加物又は飼料添加物
本発明はさらに、上記の本発明の皮膚障害防護治療剤を有効量で含有する、食品添加物、動物飼料添加物、又はサプリメントを提供する。
3. Food additive or feed additive The present invention further provides a food additive, animal feed additive, or supplement containing the above-mentioned skin disorder protective treatment agent of the present invention in an effective amount.
本明細書中、有効量とは、ヒトを含む哺乳動物において、皮膚障害防護治療効果を発揮しうる用量を指す。本発明の皮膚障害防護治療のための主要な皮膚障害には、疾病としての紫外線や放射線照射による急性、慢性の皮膚炎症、皮膚障害、皮膚肥厚化に加えて、日常的にみられる肌荒れ、日焼け、角質化が含まれ、有効成分である14-DHEは、皮膚において、水分保持、水分蒸散抑制、紅斑抑制、皮膚炎症抑制などの効果を有するため、ヒトを含む哺乳動物における皮膚の恒常性維持、障害予防、障害改善などを含む皮膚障害防護治療を可能にする。 In the present specification, an effective amount refers to a dose that can exert a skin damage protective treatment effect in mammals including humans. The major skin disorders for skin disorder protection treatment of the present invention include acute and chronic skin inflammation, skin disorders, and skin thickening caused by ultraviolet rays and radiation as diseases, as well as daily rough skin and sunburn. 14-DHE, which contains keratinization and is an active ingredient, has effects such as retention of moisture, suppression of transpiration, suppression of erythema, and suppression of skin inflammation in the skin, thus maintaining skin homeostasis in mammals including humans. Protective treatments for skin disorders including prevention, improvement, etc.
食品添加物又は動物飼料添加物は、14-DHEを含有しないか、或いは有効量の14-DHEを含有しない、食品又は動物飼料中に添加することによって、ヒトを含む哺乳動物において皮膚障害防護治療効果を発揮しうるようにする添加物である。 A food additive or animal feed additive does not contain 14-DHE, or does not contain an effective amount of 14-DHE, and is added to food or animal feed to protect against skin disorders in mammals including humans. It is an additive that makes it possible to exert an effect.
サプリメントは栄養補助食品であるが、本発明の場合、経口摂取によって皮膚障害防護治療効果をもたらす14-DHEを有効成分として含有することを特徴としている。 The supplement is a dietary supplement, but in the case of the present invention, it is characterized in that it contains 14-DHE as an active ingredient, which provides a skin disorder protection treatment effect by oral intake.
本発明の皮膚障害防護治療剤は、経口投与や摂食によって皮膚障害防護治療をもたらすことが可能であるため、上記のように経口投与剤型に製剤化しうる。本発明の添加物やサプリメントは、製剤化された皮膚障害防護治療剤の他に、他の成分、例えば各種ビタミン類、アミノ酸類、食物繊維、ミネラル、香料、着色料、酸化防止剤、酵素類、果汁液、等を適量含有しうる。これらの他の成分の含有量は、14-DHEの皮膚障害防護治療効果を損なわない限り制限されないものとする。 Since the skin injury protective treatment agent of the present invention can provide skin injury protection treatment by oral administration or feeding, it can be formulated into an oral dosage form as described above. The additives and supplements of the present invention include other ingredients such as various vitamins, amino acids, dietary fibers, minerals, fragrances, coloring agents, antioxidants, enzymes, in addition to the formulated skin disorder protective treatment. , Fruit juice, and the like. The content of these other components is not limited as long as it does not impair the skin damage protective effect of 14-DHE.
4.飲食品
本発明はさらに、本発明の皮膚障害防護治療剤又は食品添加物を皮膚障害防護治療有効量で含有する飲食品を提供する。
4). Food / Beverage Product The present invention further provides a food / beverage product containing the skin disorder protective treatment agent or food additive of the present invention in an effective amount for skin disorder protective treatment.
本発明の皮膚障害防護治療剤又は食品添加物を飲食品に配合してあらゆる食品形態に加工することが可能である。その配合量は、14-DHEの皮膚障害防護治療効果を発揮しうる量である。例えば1回の飲食あたり、14-DHEの重量に換算して10ng〜100mg、好ましくは10μg〜10mgであるが、この範囲に限定されないものとする。 It is possible to mix | blend the skin disorder protection therapeutic agent or food additive of this invention with food-drinks, and to process it into all food forms. The compounding amount is an amount capable of exerting an effect of 14-DHE for protecting against skin disorders. For example, it is 10 ng to 100 mg, preferably 10 μg to 10 mg, in terms of the weight of 14-DHE per food and drink, but is not limited to this range.
飲食品の例としては、限定するものではないが、錠剤形、粉末状、顆粒状、カプセル状、ゼリー状等の固体形態もしくは半固体形態の、或いはドリンク剤等の液体形態の、機能性食品、健康食品又は特定保健用食品(トクホ)、パン類、菓子類、クッキー、ビスケット、チューインガム、シリアルバー、等の穀類加工品、牛乳、ヨーグルト、アイスクリーム、チーズ等の乳製品類、炭酸飲料、清涼飲料、果汁入り飲料(オレンジジュース、リンゴジュース、グレープフルーツジュースなどの果汁入り飲料)、スポーツドリンク、茶、紅茶、コーヒー等の飲料、ソース、ドレッシング、調味料、惣菜、加工食品、等が挙げられる。 Examples of foods and drinks include, but are not limited to, functional foods in solid form or semi-solid form such as tablet form, powder form, granule form, capsule form, jelly form, or liquid form such as drinks. , Health foods or foods for specified health use (tokuho), breads, confectionery, cookies, biscuits, chewing gum, cereal bars, and other cereal products, milk, yogurt, ice cream, cheese and other dairy products, carbonated drinks, Soft drinks, fruit drinks (fruit juice drinks such as orange juice, apple juice, grapefruit juice), sports drinks, tea, tea, coffee drinks, sauces, dressings, seasonings, prepared dishes, processed foods, etc. .
機能性食品、健康食品又は特定保健用食品(トクホ)においては、有効成分である14-DHE又は14-DHE含有麹菌発酵エキスを、食品において許容される担体、賦形剤又は希釈剤と混合し、さらに適宜、添加剤を加えて製造されうる。担体、賦形剤又は希釈剤としては、限定するものではないが、乳糖、ショ糖、ブドウ糖などの糖類、デンプン、デキストロース、米粉、炭酸カルシウム、硫酸カルシウム、リン酸カルシウム等の無機物、結晶セルロース、蒸留水、精製水、ゴマ油、ダイズ油、コーン油、オリーブ油、綿実油、菜種油などの植物油、ステアリン酸マグネシウム、ステアリン酸、クロスカルメロースナトリウム、デンプングリコール酸ナトリウム、マルトデキストリン、クロスポピドン、植物ガム、メチルセルロース、ポビドン、カルボキシメチルセルロース、チクル、エステルガムなどを例示することができる。また、添加剤として、例えば、結合剤、光沢剤(シェラック、パラフィンワックスなど)、分散剤、懸濁剤、乳化剤(ダイズレシチン、グリセリン脂肪酸エステルなど)、緩衝剤、抗酸化剤(ビタミンC、ビタミンEなど)、保存料(ソルビン酸、安息香酸ナトリウムなど)、防かび剤(オルトフェニルフェノール、チアベンダゾールなど)、pH調整剤(塩酸、水酸化カリウムなど)、酸味料(クエン酸、乳酸、リンゴ酸など)、甘味料(ショ糖、アスパルテーム、キシリトール、ステビアなど)、調味料(グルタミン酸ナトリウム、イノシン酸二ナトリウムなど)、着色料(クチナシ色素、食用緑色3号、食用黄色4号など)、増粘安定剤(ペクチン、カラギーナン、カルボキシメチルセルロース、アセチル化アジピン酸架橋デンプン、アルギン酸塩など)、香料(オレンジ香料、バニリン、アセト酢酸エチル、アニスアルデヒド、アミルアルコール、アミルシンナムアルデヒド、蟻酸イソアミル、蟻酸ゲラニル、酢酸シクロヘキシル、シトロネロールなど)などを、適宜、含有させることができる。 For functional foods, health foods or foods for specified health use (Tokuho), 14-DHE or 14-DHE-containing gonococcal fermented extract as an active ingredient is mixed with a carrier, excipient or diluent acceptable in foods. Furthermore, it can be produced by adding additives as appropriate. Carriers, excipients or diluents include, but are not limited to, sugars such as lactose, sucrose and glucose, starch, dextrose, rice flour, calcium carbonate, calcium sulfate, calcium phosphate and other inorganic substances, crystalline cellulose, distilled water , Refined water, sesame oil, soybean oil, corn oil, olive oil, cottonseed oil, rapeseed oil, etc., magnesium stearate, stearic acid, croscarmellose sodium, sodium starch glycolate, maltodextrin, crospovidone, vegetable gum, methylcellulose, povidone , Carboxymethylcellulose, chicle, ester gum and the like. Examples of additives include binders, brighteners (shellac, paraffin wax, etc.), dispersants, suspensions, emulsifiers (soy lecithin, glycerin fatty acid esters, etc.), buffers, antioxidants (vitamin C, vitamins). E), preservatives (sorbic acid, sodium benzoate, etc.), fungicides (such as orthophenylphenol, thiabendazole), pH adjusters (hydrochloric acid, potassium hydroxide, etc.), acidulants (citric acid, lactic acid, malic acid) Etc.), sweeteners (sucrose, aspartame, xylitol, stevia, etc.), seasonings (sodium glutamate, disodium inosinate, etc.), colorants (such as gardenia pigment, edible green No. 3, edible yellow No. 4), thickening Stabilizers (pectin, carrageenan, carboxymethylcellulose, acetylated adipic acid cross-linked starch, algin Salt, etc.), flavoring (orange flavor, vanillin, ethyl acetoacetate, anisaldehyde, amyl alcohol, amyl cinnamaldehyde, isoamyl formate, formic acid, geranyl, cyclohexyl acetate, etc. citronellol) and, as appropriate, may be contained.
5.動物飼料
本発明はさらに、皮膚障害防護治療剤又は動物飼料添加物を皮膚障害防護治療有効量で含有する動物飼料を提供する。
5. Animal feed The present invention further provides an animal feed containing an effective amount of the skin disorder protective treatment agent or animal feed additive in an effective amount.
好ましい飼料は、ペットフード、好ましくはイヌ、ネコ、げっ歯類又はウサギ目用のペットフードである。 A preferred feed is a pet food, preferably a pet food for dogs, cats, rodents or rabbit eyes.
本発明の皮膚障害防護治療剤又は食品添加物を動物飼料に配合してあらゆる飼料形態に加工することが可能である。その配合量は、14-DHEの皮膚障害防護治療効果を発揮しうる量である。例えば1回の食餌あたり、14-DHEの重量に換算して10ng〜100mg、好ましくは10μg〜10mgであるが、この範囲に限定されないものとする。 It is possible to mix the skin disorder protecting agent or food additive of the present invention into animal feed and process it into any feed form. The compounding amount is an amount capable of exerting an effect of 14-DHE for protecting against skin disorders. For example, it is 10 ng to 100 mg, preferably 10 μg to 10 mg in terms of the weight of 14-DHE per one meal, but is not limited to this range.
有効性成分である14-DHE又は14-DHE含有麹菌発酵エキスを、動物飼料において許容される担体、賦形剤又は希釈剤と混合し、或いは調理した肉類(チキン、ビーフ、等)と混合し、さらに適宜、添加剤を加えて製造されうる。担体、賦形剤又は希釈剤としては、限定するものではないが、乳糖、ショ糖、ブドウ糖などの糖類、デンプン、炭酸カルシウム、硫酸カルシウム、リン酸第二鉄、硫酸亜鉛、塩化ナトリウム、塩化カリウム、硫酸マグネシウム等の無機物、結晶セルロース、蒸留水、精製水、ゴマ油、ダイズ油、コーン油、オリーブ油、綿実油、菜種油等の植物油などを例示することができる。また、添加剤として、例えば、結合剤、滑沢剤、分散剤、懸濁剤、乳化剤、緩衝剤、抗酸化剤、保存料などを含有させることができる。 14-DHE or 14-DHE-containing gonococcal fermented extract as an active ingredient is mixed with an acceptable carrier, excipient or diluent in animal feed, or mixed with cooked meat (chicken, beef, etc.) Furthermore, it can be produced by adding additives as appropriate. Carriers, excipients or diluents include, but are not limited to, sugars such as lactose, sucrose, glucose, starch, calcium carbonate, calcium sulfate, ferric phosphate, zinc sulfate, sodium chloride, potassium chloride And inorganic substances such as magnesium sulfate, crystalline cellulose, distilled water, purified water, sesame oil, soybean oil, corn oil, olive oil, cottonseed oil, rapeseed oil, and other vegetable oils. Moreover, as an additive, a binder, a lubricant, a dispersing agent, a suspending agent, an emulsifier, a buffering agent, an antioxidant, a preservative, etc. can be contained, for example.
通常、動物飼料には、主成分として、炭水化物源及び/又はタンパク源が含まれ、これに、副成分として、ビタミン類、アミノ酸類、ミネラル、調理野菜、酵素(例えば、α−アミラーゼやフィターゼ)などが含まれる。 Usually, animal feed contains a carbohydrate source and / or a protein source as main components, and vitamins, amino acids, minerals, cooked vegetables, enzymes (for example, α-amylase and phytase) as auxiliary components. Etc. are included.
炭水化物源は、主に穀類である。穀類は、少なくとも25重量%、好ましくは少なくとも30重量%の割合で含有させることができる。穀類の例は、コムギ、トウモロコシ、ライムギ、オオムギ、オートムギ、マイロ、キャッサバ、イネ、穀類のフスマ、或いはそれらの混合物、であり、それらを粉砕したものや調理したものを使用できる。 The carbohydrate source is mainly cereals. Cereals can be included in a proportion of at least 25% by weight, preferably at least 30% by weight. Examples of cereals are wheat, corn, rye, barley, oats, milo, cassava, rice, cereal bran, or mixtures thereof, which can be crushed or cooked.
タンパク源は、例えば、魚肉、鶏肉、牛肉などの動物タンパク質、ダイズなどの植物タンパク質などである。タンパク質としては、通常調理したものか、或いは乾燥粉末としたもの、などが使用できる。タンパク質源は、通常、飼料に対し約50%以下で含有させることができる。 Examples of the protein source include animal proteins such as fish, chicken and beef, and plant proteins such as soybean. Proteins that are usually cooked or dried powder can be used. The protein source can usually be contained at about 50% or less based on the feed.
本発明はさらに、上記の動物飼料又は医薬組成物をペット動物あるいは家畜に投与して皮膚炎症を予防又は改善することを含む、ペット動物あるいは家畜での皮膚障害防護治療のための方法を提供する。 The present invention further provides a method for skin injury protection treatment in a pet animal or livestock, comprising administering the above animal feed or pharmaceutical composition to a pet animal or livestock to prevent or ameliorate skin inflammation. .
好ましいペット動物は、イヌ、ネコ、げっ歯類、或いはウサギ目である。また好ましい家畜はウシ、ウマ、またはブタである。これらの動物は、アレルギー性の皮膚炎症を基とする皮膚障害を起こすことがあるため、本発明の動物飼料を与えることによって、皮膚障害の防護や治療に効果的である。このような動物には、皮膚障害予防中の健常動物、専門医の治療を必要としない程度の軽い皮膚障害をもつ動物、皮膚疾患の治療中の動物などが含まれる。 Preferred pet animals are dogs, cats, rodents, or rabbit eyes. The preferred livestock is a cow, horse or pig. Since these animals may cause skin disorders based on allergic skin inflammation, the animal feed of the present invention is effective in protecting and treating skin disorders. Such animals include healthy animals during the prevention of skin disorders, animals with mild skin disorders that do not require treatment by specialists, animals under treatment of skin diseases, and the like.
6.化粧組成物
本発明はさらに、本発明の皮膚障害防護治療剤を有効量で含有する化粧組成物を提供する。
6). Cosmetic Composition The present invention further provides a cosmetic composition containing an effective amount of the skin disorder protective agent of the present invention.
化粧組成物は、溶液剤、分散剤、懸濁剤、乳剤、微粉剤、ミクロ粒子剤、ナノ粒子剤、軟膏剤、ゲル剤、泡剤、スプレー剤、ワイプなどの種々の形態をとることができる。例えば、クリーム、ローション、ボディローション、ミルク、スプレー、エアゾールムース、フォーム、パウダー、ゲル、ファウンデーション、ヘアリキド、ヘアトニック、ヘアカラー、シェービングフォーム、アフターシェビングローション、オーデコロン、口紅、化粧水、日焼け止め(サンスクリーン)などの化粧品分野で通常使用しうるあらゆる形態に調製できる。 Cosmetic compositions can take various forms such as solutions, dispersions, suspensions, emulsions, fine powders, microparticles, nanoparticles, ointments, gels, foams, sprays, wipes, and the like. it can. For example, cream, lotion, body lotion, milk, spray, aerosol mousse, foam, powder, gel, foundation, hair liquid, hair tonic, hair color, shaving foam, after-shave lotion, cologne, lipstick, lotion, sunscreen ( It can be prepared in any form that can be normally used in the cosmetic field such as sunscreen.
化粧組成物には、化粧品分野で承認されている担体や添加剤を含有させることができる。担体は、該組成物の基剤となるものであり、例えば、脂肪物質、油、水、有機溶媒、シリコーン、油脂、ロウ、脂肪酸、脂肪酸エステル、精製水、エチルアルコール、タルク、カオリン、酸化チタン、合成ポリマー(アクリル系合成ポリマーなど)、天然高分子(結晶セルロースなど)などが挙げられる。 The cosmetic composition may contain carriers and additives approved in the cosmetic field. The carrier is a base of the composition, for example, a fatty substance, oil, water, organic solvent, silicone, fat, wax, fatty acid, fatty acid ester, purified water, ethyl alcohol, talc, kaolin, titanium oxide , Synthetic polymers (such as acrylic synthetic polymers), and natural polymers (such as crystalline cellulose).
皮膚障害防護治療剤の含有量は、化粧組成物1回使用あたり、14-DHEの重量で換算して10ng〜100mg、好ましくは10μg〜10mgであるが、この範囲に限定されないものとする。 The content of the skin disorder protective treatment agent is 10 ng to 100 mg, preferably 10 μg to 10 mg in terms of the weight of 14-DHE per use of the cosmetic composition, but is not limited to this range.
化粧組成物を構成する成分は、14-DHE及び14-DHE含有麹菌発酵エキスを除いて、化粧品分野で通常使用される化粧品基材から選択されうる。 The components constituting the cosmetic composition can be selected from cosmetic base materials commonly used in the cosmetic field, except for 14-DHE and 14-DHE-containing koji mold fermented extract.
化粧品添加剤として、例えば、保存剤、抗酸化剤、増粘剤、軟化剤、乳化剤、消泡剤、保湿剤、香料、界面活性剤、増量剤、キレート剤、合成ポリマー、噴射剤、緩衝剤、色素、着色剤、顔料、光安定剤、抗菌剤、香料、美白剤などが挙げられる。 Cosmetic additives such as preservatives, antioxidants, thickeners, softeners, emulsifiers, antifoaming agents, moisturizers, fragrances, surfactants, extenders, chelating agents, synthetic polymers, propellants, buffers , Dyes, colorants, pigments, light stabilizers, antibacterial agents, fragrances, whitening agents and the like.
例えば、保存剤の例には、サリチル酸ナトリウム、パラベン、ブチルパラベンなどが含まれる。界面活性剤の例には、ポリソルベート、ヤシ脂肪酸、ラウリルベタイン、レシチンなどが含まれる。抗酸化剤の例には、アスコルビン酸、トコフェロール、白金ナノコロイド、セラミドなどが含まれる。香料の例には、植物精油、人工香料、香水、メントール、レモン油、ローズ水などが含まれる。保湿剤の例には、グリセリン、ジグリセリン、ポリエチレングリコール、尿素、及びプロピレングリコール、乳酸ナトリウム、ヒアルロン酸、ラクトフェリン、リジン、リンゴエキス、加水分解コラーゲン、ポリグルタミン酸などが含まれる。増粘剤の例には、カラギーナン、カルボキシビニルポリマーなどが含まれる。キレート剤の例には、クエン酸などが含まれる。抗菌剤の例には、抗菌性オリゴペプチドなどが含まれる。その他に、ビタミン類(トコフェロール、酢酸トコフェロール、アスコルビン酸、アスコルビルリン酸、ビタミンQ、D、およびK、レチノール、レチナール、レチノイン酸、酢酸レチノール、パルミチン酸レチノールなど)、カロチノド類(β−カロテン、リコペン、アスタキサンチンなど)、アミノ酸類(メチオニン、システイン、トリプトファン、フェニルアラニン、チロシン、フェノールなど)、ポリフェノール類、セラミド類などの成分を、適宜、化粧組成物に含有させることができる。 For example, examples of preservatives include sodium salicylate, paraben, butyl paraben, and the like. Examples of the surfactant include polysorbate, coconut fatty acid, lauryl betaine, lecithin and the like. Examples of the antioxidant include ascorbic acid, tocopherol, platinum nanocolloid, ceramide and the like. Examples of the fragrance include plant essential oil, artificial fragrance, perfume, menthol, lemon oil, rose water and the like. Examples of the humectant include glycerin, diglycerin, polyethylene glycol, urea, and propylene glycol, sodium lactate, hyaluronic acid, lactoferrin, lysine, apple extract, hydrolyzed collagen, polyglutamic acid, and the like. Examples of thickeners include carrageenan, carboxyvinyl polymer and the like. Examples of chelating agents include citric acid and the like. Examples of antibacterial agents include antibacterial oligopeptides and the like. In addition, vitamins (tocopherol, tocopherol acetate, ascorbic acid, ascorbyl phosphate, vitamins Q, D and K, retinol, retinal, retinoic acid, retinol acetate, retinol palmitate, etc.), carotinodos (β-carotene, lycopene) , Astaxanthin, etc.), amino acids (methionine, cysteine, tryptophan, phenylalanine, tyrosine, phenol, etc.), polyphenols, ceramides and the like can be appropriately contained in the cosmetic composition.
有効成分である14-DHE及び14-DHE含有麹菌発酵エキスを化粧組成物に含有させることにより、化粧効果に加えて、肌荒れの改善、日焼け等による皮膚炎症の改善、などの皮膚障害防護治療効果を化粧組成物に付与することができる。 By including 14-DHE and 14-DHE-containing gonococcal fermented extract, which are active ingredients, in the cosmetic composition, in addition to cosmetic effects, skin damage protection treatment effects such as improvement of rough skin, improvement of skin inflammation due to sunburn, etc. Can be added to the cosmetic composition.
以下の実施例を参照しながら、本発明をさらに具体的に説明するが、しかし、本発明の範囲は、それらの実施例によって制限されることを意図していない。 The present invention will be described more specifically with reference to the following examples, but the scope of the present invention is not intended to be limited by these examples.
[実施例1]
この実施例では、14-DHEを含有する様な麹菌発酵物由来の抽出エキスについて、紫外線照射皮膚障害モデルに対して、強制経口投与によるin vivoでの効果を検討した。
[Example 1]
In this Example, the in vivo effect of oral gavage administration was examined for an extract derived from Aspergillus oryzae fermented product containing 14-DHE against an ultraviolet irradiation skin injury model.
<実験方法>
(1)麹菌醗酵エキスの調製
小麦フスマに黒麹菌を生やした醗酵物(秋田今野商店の黒麹マイルドを麹蓋1cm盛りで加水して72時間培養したもの)を凍結乾燥して、ミキサーにて細粉した。細粉した醗酵物1g当たり6mLになるようエタノール(Wako)を添加し、超音波処理(SHIBATA)を37℃で15分間施した。超音波処理後、3,000rpm、10分間遠心処理をした上清をメンブレン濾過して回収した。残渣にエタノールによる超音波抽出を加え、抽出作業を計3回行った。回収したエタノール抽出物をエバポレーターにて乾固したものを14-DHEを含有する麹菌醗酵エキスサンプルとした。なお、麹菌発酵エキスサンプル1mgあたりに1μgの14-DHEが含まれることを確認した。
<Experiment method>
(1) Preparation of koji mold fermented extract Fermented with black koji mold on wheat bran (Akita Imano Shoten's black koji milder was cultivated for 72 hours with a 1 cm pouch cover) and dried in a mixer Fine powder. Ethanol (Wako) was added to 6 mL per 1 g of the finely ground fermentation product, and sonication (SHIBATA) was performed at 37 ° C. for 15 minutes. After sonication, the supernatant obtained by centrifugation at 3,000 rpm for 10 minutes was collected by membrane filtration. Ultrasonic extraction with ethanol was added to the residue, and extraction was performed three times in total. The collected ethanol extract was dried by an evaporator and used as a koji mold fermentation extract sample containing 14-DHE. It was confirmed that 1 μg of 14-DHE was contained per 1 mg of the koji mold extract sample.
(2)強制経口投与による、皮膚障害防護作用
へアレスマウス(HOS:HR-1,4週齢,雄)に、(1)で調製した麹エキスサンプルをコーン油で10mg/mLに希釈したものを麹菌醗酵エキス投与液とし、100μL(1mg/匹/day、1μg 14-DHE相当)を2週間胃内投与した(1群7匹)。最終投与の翌日に紫外線の単回照射(UV-B、線量90mJ/cm2相当)を行った。光源にはSAN-EIのUVF-204Sを用いた。照射日を基準として3日目における皮膚水分量をCorneometer CM825(Courage & Khazaka)、皮膚水分蒸散量をTewameter TM300(Courage & Khazaka)、および紅斑値をMexameter MX18(Courage & Khazaka)にて測定し、MPA5(Courage & Khazaka)で解析した。その後、マウスを安楽死させて、背部試験部位皮膚を摘出した。皮膚の一部は10%中性ホルマリン緩衝液にて固定を行い、パラフィン切片を作製し、H&E染色を行った。また、残りの一部はLysis緩衝液にて組織溶解液を作製し、その上清のサイトカインを測定した。ELISAキットはMouse TNF-α Ready-SET-Go!(eBioscience)、Mouse IL-6 Ready-SET-Go!(eBioscience)を用いた。また、コーン油のみを投与した対照群(5匹)とコーン油のみを投与しかつ紫外線照射を行わない非照射群(5匹)を設けた。
(2) Skin damage protective effect by oral gavage: Hairless mice (HOS: HR-1, 4 weeks old, male) diluted with corn oil to 10 mg / mL of cocoon extract sample prepared in (1) Was used as an administration solution for koji mold and 100 μL (1 mg / animal / day, equivalent to 1 μg 14-DHE) was intragastrically administered for 2 weeks (7 animals per group). The day after the last administration, a single irradiation of ultraviolet rays (UV-B, equivalent to a dose of 90 mJ / cm 2 ) was performed. SAN-EI UVF-204S was used as the light source. Measure skin moisture on
<結果>
図1に示すように、一般的に皮膚にUV-Bが照射されると水分量の低下、水分蒸散量の上昇、および紅斑値の上昇が誘導されることが報告されているが、麹菌醗酵エキスを摂取することで皮膚水分量の低下、皮膚水分蒸散量の上昇、および紅斑値の上昇を有意に抑制した。
<Result>
As shown in Figure 1, it has been reported that UV-B irradiation on the skin generally induces a decrease in water content, an increase in water transpiration, and an increase in erythema value. Ingestion of the extract significantly suppressed the decrease in skin water content, the increase in skin water transpiration, and the increase in erythema value.
図2に示すように、麹菌醗酵エキスの摂取でUV-B照射で誘導された炎症性サイトカインであるTNF-αおよびIL-6の産生が減少傾向であった。 As shown in FIG. 2, the production of TNF-α and IL-6, which are inflammatory cytokines induced by UV-B irradiation upon ingestion of the Neisseria gonorrhoeae fermentation extract, tended to decrease.
図3に示した通り、麹菌醗酵エキスの摂取でUV-B照射による表皮部分(矢印の部分)の肥厚化を有意に抑制した。 As shown in FIG. 3, the thickening of the epidermis part (arrow part) by UV-B irradiation was significantly suppressed by ingestion of the koji mold fermentation extract.
以上のことより、14-DHEを含有する麹菌醗酵エキスを経口摂取することにより、紫外線照射によって起こる皮膚障害に対する防護治療効果を示すことが判明した。 From the above, it has been found that oral ingestion of the koji mold fermentation extract containing 14-DHE exhibits a protective treatment effect against skin damage caused by ultraviolet irradiation.
[実施例2]
麹菌発酵物から単離精製した14-DHEについて、紫外線照射皮膚障害モデルに対して、混餌投与によるin vivoでの効果を検討した。
[Example 2]
14-DHE isolated and purified from Aspergillus oryzae fermented products was examined for the effects of dietary administration in vivo on UV-irradiated skin damage models.
<実験方法>
(1)14-DHEの単離精製
Aspergillus kawachii (NBRC4308株)を600mLスケールで前培養(malt extract broth, 25℃, 120rpm)した。続いて、600mLの前培養液4本を、200L培養槽を用いて100Lのジャーファーメンターで250rpm、25±1℃で10日間培養した。菌体を回収し、イソプロパノールで抽出した後、シリカゲルカラムで粗精製を行ない、ODSカラムにて精製して14-DHEを得た。エバポレーターにて乾固したものを14-DHEサンプルとした。Develosil C30-UG-3 (4.6mm i.d. ×150mm, 3μm) を備えた分析用HPLC 島津LC10-ADVP(移動相A: アセトニトリル(99), 移動相B: 2-プロパノール(1), 流速: 1.0 mL/min, カラム温度: 40℃, UV波長320nm)において、14-DHEが保持時間12.23分にシングルピークとして検出されることを確認した。
<Experiment method>
(1) Isolation and purification of 14-DHE
Aspergillus kawachii (NBRC4308 strain) was precultured (malt extract broth, 25 ° C., 120 rpm) on a 600 mL scale. Subsequently, 4 600 mL precultures were cultured in a 100 L jar fermenter using a 200 L culture tank at 250 rpm and 25 ± 1 ° C. for 10 days. The cells were collected and extracted with isopropanol, and then roughly purified with a silica gel column and purified with an ODS column to obtain 14-DHE. A 14-DHE sample was obtained by drying with an evaporator. Analytical HPLC Shimadzu LC10-ADVP with Develosil C30-UG-3 (4.6mm id × 150mm, 3μm) (mobile phase A: acetonitrile (99), mobile phase B: 2-propanol (1), flow rate: 1.0 mL / min, column temperature: 40 ° C., UV wavelength: 320 nm) 14-DHE was detected as a single peak at a retention time of 12.23 minutes.
(2)14-DHE混餌投与による、皮膚障害防護作用
へアレスマウス(HOS:HR-1,4週齢,雄)に、(1)で調製した14-DHEサンプルを予め2週間混餌(10μg/匹/day 相当)にて自由に摂取させた(1群6匹)。最終投与の翌日に紫外線の単回照射(UV-B、線量90mJ/cm2相当)を行い、照射日を基準として3日目における皮膚水分量、皮膚水分蒸散量、および紅斑値を測定した。その後、マウスを安楽死させて、背部試験部位皮膚を摘出した。皮膚の一部は10%中性ホルマリン緩衝液にて固定を行い、パラフィン切片を作製しH&E染色を行った。また、被験物質を摂取させない対照群(6匹)、被験物質を摂取させずかつ紫外線照射を行わない非照射群(6匹)を設けた。
(2) Skin damage protection by 14-DHE mixed administration Hairless mice (HOS: HR-1, 4 weeks old, male) were previously mixed with the 14-DHE sample prepared in (1) for 2 weeks (10 μg / Per day / equivalent)) (6 animals per group). The day after the last administration, a single irradiation of ultraviolet rays (UV-B, equivalent to a dose of 90 mJ / cm 2 ) was performed, and the skin moisture content, skin moisture transpiration amount, and erythema value on the third day were measured based on the irradiation date. Thereafter, the mice were euthanized and the dorsal test site skin was removed. A part of the skin was fixed with 10% neutral formalin buffer, and a paraffin section was prepared and subjected to H & E staining. In addition, a control group (6 animals) in which the test substance was not ingested and a non-irradiation group (6 animals) in which the test substance was not ingested and ultraviolet irradiation was not performed were provided.
<結果>
図4に示すように、一般的に皮膚にUV-Bが照射されると水分量の低下、水分蒸散量の上昇、および紅斑値の上昇が誘導されることが報告されているが、14-DHEを混餌摂取させることで皮膚水分量の低下および水分蒸散量の上昇、および紅斑値の上昇を抑制する傾向にあった。
図5に示すように、14-DHEを混餌摂取させることでUV-B照射による表皮部分の肥厚化を有意に抑制した。
<Result>
As shown in Figure 4, it has been reported that UV-B irradiation on the skin generally induces a decrease in water content, an increase in water transpiration, and an increase in erythema value. Ingestion of DHE tended to suppress a decrease in skin water content, an increase in water transpiration, and an increase in erythema value.
As shown in FIG. 5, thickening of the epidermis part by UV-B irradiation was significantly suppressed by ingesting 14-DHE.
以上のことより、14-DHE単体を経口摂取することにより、紫外線照射による皮膚障害に対する防護治療効果を示すことが判明した。 From the above, it was found that oral intake of 14-DHE alone has a protective treatment effect against skin damage caused by ultraviolet irradiation.
[実施例3]
単離精製した14-DHEについて、紫外線照射皮膚障害モデルに対して、皮膚への直接塗布によるin vivoでの効果を検討した。化粧料成分として高い効果があるとされるアスタキサンチンおよび14-DHE類似抗炎症性物質のエルゴステロールと比較検討を行なった。
[Example 3]
For the isolated and purified 14-DHE, we examined the in vivo effects of direct application to the skin against UV irradiation skin damage models. A comparative study was conducted with astaxanthin and 14-DHE-like anti-inflammatory substance ergosterol, which is said to be highly effective as a cosmetic ingredient.
<実験方法>
(1)14-DHE塗布による、皮膚障害防護作用
実験には日本SLC社より購入したヘアレスマウス(HOS:HR-1,5週齢,雌)を用いた。
実施例2で調製した14-DHEサンプルをエタノールで1mg/mLに調製し、50μL(50μg/匹/day相当)をヘアレスマウスの背部試験部位皮膚(8cm2)に1日1回、7日間の塗布を行った。アスタキサンチン(Wako)およびエルゴステロール(Wako)についても同濃度で行なった。最終塗布の翌日に紫外線の単回照射(UV-B、線量90mJ/cm2相当)を行い、照射3日後に皮膚水分量、皮膚水分蒸散量、および紅斑値を測定した。その後、マウスを安楽死させて、背部試験部位皮膚を摘出した。皮膚は10 %中性ホルマリン緩衝液にて固定を行い、パラフィン切片を作製し、H&E染色を行った(1群7匹)。エタノールのみを塗布した対照群(5匹)、エタノールのみを塗布しかつ紫外線照射を行わない非照射群(7匹)、比較対照のアスタキサンチン塗布群(7匹)、および14-DHE類似抗炎症性物質のエルゴステロール塗布群(6匹)を設けた。
<Experiment method>
(1) Skin damage protective effect by application of 14-DHE Hairless mice (HOS: HR-1, 5 weeks old, female) purchased from Japan SLC were used for experiments.
The 14-DHE sample prepared in Example 2 was adjusted to 1 mg / mL with ethanol, and 50 μL (equivalent to 50 μg / animal / day) was applied to the skin of the back test site (8 cm 2 ) of hairless mice once a day for 7 days. Application was performed. Astaxanthin (Wako) and ergosterol (Wako) were also performed at the same concentration. The day after the final application, a single irradiation of ultraviolet light (UV-B, equivalent to a dose of 90 mJ / cm 2 ) was performed, and the skin moisture content, skin moisture transpiration rate, and erythema value were measured 3 days after the irradiation. Thereafter, the mice were euthanized and the dorsal test site skin was removed. The skin was fixed with 10% neutral formalin buffer solution, paraffin sections were prepared, and H & E staining was performed (7 per group). Control group (5 animals) applied only with ethanol, non-irradiated group (7 animals) applied only with ethanol and not irradiated with ultraviolet rays, astaxanthin application group (7 animals) for comparison, and 14-DHE-like anti-inflammatory properties An ergosterol application group (6 animals) of the substance was provided.
(2) 14-DHE塗布による、皮膚炎症防護作用
実験には日本SLC社より購入したヘアレスマウス(HOS:HR-1,5週齢,雌)を用いた。
実施例2で調製した14-DHEサンプルをエタノールで1mg/mLに調製し、50 μL(50 μg/匹/day 相当)をヘアレスマウスの背部試験部位皮膚(8cm2)に1日1回、7日間の塗布を行った。アスタキサンチンおよびエルゴステロールについても同濃度で行なった。最終塗布の翌日に紫外線の単回照射(UV-B、線量90mJ/cm2相当)を行い、照射1日後にマウスを安楽死させて、背部試験部位皮膚を摘出した。皮膚は一部10%中性ホルマリン緩衝液にて固定を行った後、凍結切片を作製し、myeloperoxidase(MPO)の免疫組織化学染色を行った。また、残りの一部はRNAを抽出し、リアルタイムPCRで炎症性サイトカインの遺伝子発現を解析した。total RNAは RNAeasy Mini Kit(QIAGEN)およびQiashredderを用いて精製した。total RNAからcDNAをiScript cDNA Synthesis Kit(Bio-Rad)を用いて合成した。SYBR Premix Ex Taq(Perfect Real Time)(TaKaRa)を用いてLightCycler480(Roche)によりRT-PCRを行い、各種サンプルのGAPDH、TNF-αの発現解析を実施した(1群5匹)。プライマーは、GAPDH:5’-AACGACCCCTTCATTGAC-3’(順方向)(配列番号1)、5’-TCCACGACATACTCAGCAC- 3’(逆方向)(配列番号2)、TNF-α:5’-TGCCTATGTCTCAGCCTCTTC-3’(順方向)(配列番号3)、5’- GAGGCCATTTGGGAACTTCT-3’(逆方向)(配列番号4)を使用して行なった。エタノールのみを塗布した対照群(5匹)、エタノールのみを塗布しかつ紫外線照射を行わない非照射群(5匹)、比較対照のアスタキサンチン塗布群(5匹)、および14-DHE類似抗炎症性物質のエルゴステロール塗布群(5匹)を設けた。
(2) Skin inflammation protective effect by 14-DHE application Hairless mice (HOS: HR-1, 5 weeks old, female) purchased from Japan SLC were used for the experiment.
The 14-DHE sample prepared in Example 2 was prepared to 1 mg / mL with ethanol, and 50 μL (equivalent to 50 μg / animal / day) was applied to the skin of the back test site (8 cm 2 ) of hairless mice once a day. Daily application was performed. Astaxanthin and ergosterol were also used at the same concentration. The day after the final application, UV irradiation was performed once (UV-B, equivalent to a dose of 90 mJ / cm 2 ). One day after irradiation, the mouse was euthanized, and the skin on the back test site was removed. The skin was partially fixed with 10% neutral formalin buffer, and then frozen sections were prepared and immunohistochemical staining for myeloperoxidase (MPO) was performed. In addition, RNA was extracted from the remaining part, and gene expression of inflammatory cytokines was analyzed by real-time PCR. Total RNA was purified using RNAeasy Mini Kit (QIAGEN) and Qiashredder. cDNA was synthesized from total RNA using iScript cDNA Synthesis Kit (Bio-Rad). RT-PCR was performed by LightCycler480 (Roche) using SYBR Premix Ex Taq (Perfect Real Time) (TaKaRa), and expression analysis of GAPDH and TNF-α of various samples was performed (5 per group). Primers are GAPDH: 5'-AACGACCCCTTCATTGAC-3 '(forward direction) (SEQ ID NO: 1), 5'-TCCACGACATACTCAGCAC-3' (reverse direction) (SEQ ID NO: 2), TNF-α: 5'-TGCCTATGTCTCAGCCTCTTC-3 ' (Forward direction) (SEQ ID NO: 3), 5′-GAGGCCATTTGGGAACTTCT-3 ′ (reverse direction) (SEQ ID NO: 4) was used. Control group (5 animals) applied only with ethanol, non-irradiated group (5 animals) applied only with ethanol and not irradiated with ultraviolet rays, astaxanthin application group (5 animals) for comparison, and 14-DHE-like anti-inflammatory properties An ergosterol application group (5 animals) of the substance was provided.
<結果>
図6に示すように、一般的にUV-Bが照射されると照射部位の水分量の低下、水分蒸散量の上昇、および紅斑値の上昇が誘導されることが報告されているが、14-DHEの塗布により皮膚水分量の低下および紅斑値の上昇を有意に抑制した。また、皮膚水分蒸散量の上昇を抑制する傾向があった。
<Result>
As shown in FIG. 6, it has been reported that irradiation with UV-B generally induces a decrease in water content, an increase in water transpiration, and an increase in erythema value. -DHE application significantly reduced skin moisture and erythema levels. Moreover, there was a tendency to suppress an increase in skin moisture transpiration.
図7に示すように、14-DHEの塗布によりUV-B照射による表皮部分の肥厚化を有意に抑制した。 As shown in FIG. 7, the application of 14-DHE significantly suppressed thickening of the epidermis due to UV-B irradiation.
図8に示すように、14-DHEの塗布によりUV-B照射による皮膚への好中球(MPO+細胞)の浸潤数が有意に抑制された。 As shown in FIG. 8, the number of infiltrating neutrophils (MPO + cells) into the skin by UV-B irradiation was significantly suppressed by application of 14-DHE.
図9に示すように、14-DHEの塗布により、UV-Bにより誘導される炎症性サイトカインであるTNF-αのメッセージレベルでの発現が有意に抑制された。 As shown in FIG. 9, the application of 14-DHE significantly suppressed the expression of TNF-α, an inflammatory cytokine induced by UV-B, at the message level.
以上のことより、14-DHE単体を皮膚に直接塗布することにより、紫外線照射によって起こる炎症を抑制することで皮膚障害防護治療効果を示すことが判明した。さらにその効果はアスタキサンチンと同等以上であった。 Based on the above, it was found that 14-DHE alone was applied directly to the skin, thereby suppressing the inflammation caused by ultraviolet irradiation and exhibiting a skin disorder protective treatment effect. Furthermore, the effect was equal to or greater than that of astaxanthin.
本発明の皮膚障害防護治療剤は、14-デヒドロエルゴステロール(14-DHE)又は14-DHE含有麹菌発酵エキスを有効成分として含有することを特徴とし、既に化粧品等に使用されるアスタキサンチンと同等以上の効果を有している。14-DHEは、皮膚において、水分保持、水分蒸散抑制、紅斑抑制、皮膚炎症抑制などの効果を有するため、ヒトを含む哺乳動物における皮膚の恒常性維持、障害予防、障害改善などを含む皮膚障害防護治療のために利用可能である。 The skin disorder protective treatment agent of the present invention is characterized by containing 14-dehydroergosterol (14-DHE) or 14-DHE-containing gonococcal fermented extract as an active ingredient, and is at least equivalent to astaxanthin already used in cosmetics and the like It has the effect of. Since 14-DHE has effects such as moisture retention, moisture transpiration suppression, erythema suppression, and skin inflammation suppression in skin, skin disorders including maintenance of skin homeostasis, prevention of injury, and improvement of injury in mammals including humans Available for protective treatment.
配列番号1〜4:プライマー Sequence number 1-4: Primer
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