TWI687235B - 抗老化用皮膚外用劑 - Google Patents
抗老化用皮膚外用劑 Download PDFInfo
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- TWI687235B TWI687235B TW104111960A TW104111960A TWI687235B TW I687235 B TWI687235 B TW I687235B TW 104111960 A TW104111960 A TW 104111960A TW 104111960 A TW104111960 A TW 104111960A TW I687235 B TWI687235 B TW I687235B
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- oxide
- adenosine
- skin
- effect
- phosphate
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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Abstract
本發明之課題係提供一種抗老化用皮膚外用組成物,其係用於預防或改善因增齡、老化造成之皺紋、細紋、鬆弛、斑等之皮膚外觀上之問題,同時維持或亢進皮膚中之阻隔功能。
本發明藉由提供一種抗老化用皮膚外用劑而解決上述課題,該外用劑含有由腺苷(adenosine)N1-氧化物5’-磷酸、其類似物及其鹽選出之一種或兩種以上作為有效成分。
Description
本發明係關於抗老化用皮膚外用劑,詳言之,係關於含有由腺苷(adenosine)N1-氧化物5’-磷酸,其類似物及其鹽選出之一種或兩種以上作為有效成分之抗老化用皮膚外用劑。
想永遠年輕為人類共通普遍的願望,但隨著年齡增加連帶地使人類皮膚產生皺紋、細紋、鬆弛、斑等之變化為人類長期以來所經歷,隨著年齡增加皮膚亦會老化,而於皮膚顯現皺紋、細紋、鬆弛、斑等之外觀上之變化可謂為自然天理,認為無法避免。
不過,近幾年來,隨著關於人類皮膚構造或其新陳代謝之機制的研究進展,已逐漸明瞭隨著年齡增加而於皮膚顯現皺紋、細紋、鬆弛、斑等變化之發生原因或機構。亦即,已充分了解,皮膚係由外側之較薄表皮(上皮組織)與其下層之較厚真皮(結締組織)所構成,表皮係作為身體最外層,保護活體免受外界影響同時防止內部之水
分及營養分漏出至外界,另一方面,真皮主要具有使纖維母細胞、膠原纖維(collagen)、彈性纖維(彈力蛋白)、蛋白聚糖(proteoglycan)等複合以三次元狀擴展之構造的結締組織,擔任使皮膚具有強度、伸展性及彈力性之角色,但一般認為於增齡之同時皮膚之皮脂及水分量減少時,皮膚表面之角質層之保濕力喪失,因乾燥等容易產生細紋或肌膚粗糙。
且,人類之表皮係自外側起由「角質層(角質)」、「顆粒層」、「棘細胞層」、「基底層」所構成,於基底層產生之表皮細胞(角質細胞(keratinocyte))依序朝外側移動而成為角質層,最終剝落。更詳言之,角質細胞在位於表皮最內側之基底層中增生、分化,被推至上層,最終成為位於表皮最外側之角質層(角質),成為垢而脫落。該角質細胞之增生、移動、分化、脫落之一連串過程稱為更新(turnover),角質細胞以一定週期汰新,而使皮膚保持恆穩性,但一般認為隨著增齡肌膚之更新速度變慢,結果,產生皺紋及鬆弛及肌膚粗糙。肌膚之更新速度隨人體部位而異,但健康之10多歲之人類肌膚之更新約為20天,20多歲約28天,30多歲約40天,40多歲約為20多歲之約2倍的約55天,50多歲約為75天(非專利文獻1)。
如上述,一般認為隨著增齡肌膚之更新速度變慢造成皺紋、鬆弛及肌膚粗糙,故而包含自開始在意該等肌膚症狀之30歲前後至50歲前之年齡層之所謂初老
(pre aging)世代之肌膚,欲使其更新速度回到20多歲之正常肌膚之更新速度仍有困難,若能藉由任何手段,使隨著增齡之更新速度減慢恢復,則能有效地改善皺紋及鬆弛及肌膚粗糙(專利文獻1)。基於該觀點,認為可藉由促進角質細胞之增生、移動、分化、脫落之一連串過程之至少一過程而提高更新速度。然而,尚未有實用的解決手段被提供。
角質層為角質細胞多重重疊構成之層,於角質細胞之最外層,存在有守護角質細胞內部之稱為角質肥厚膜(cornified envelope)之由外皮蛋白(involucrin)等各種蛋白質所構成之強固膜。前述角質肥厚膜在皮膚之障蔽功能中扮演重要角色。皮膚之障蔽功能若降低,則因紫外線,尤其是到達至真皮之長波長紫外線A波,會使真皮中存在之膠原、彈力蛋白、透明質酸等受損。且,亦已知皮膚之障蔽功能降低時,會使皮膚乾燥使保濕力降低,並促進皮脂過度分泌誘發大人粉刺,引起更新之混亂。隨著增齡,皮膚之障蔽功能降低,藉此,引起皮膚皺紋、細紋、鬆弛、斑等(參考專利文獻2及3)。
所謂皮膚之障蔽功能為皮膚中之與所謂稱為1次障蔽之皮脂膜功能成對比之稱為2次障蔽之角質層之功能,亦即防止異物自活體外侵入至活體內、或防止過量水自活體內釋出至活體外之功能,以及藉由存在於與角質層鄰接之表皮顆粒層中之稱為緊密連接(tight junction)之細胞間接著構造體而隔開活體之內與外之功能。
且,一般認為真皮中之纖維母細胞與透明質酸因增齡而減少,引起膠原切斷或彈性蛋白變性時,會形成皺紋,使皮膚彈性降低引起鬆弛及肌膚粗糙。具有支配膠原之纖維的角色之纖維的彈性蛋白具有對肌膚賦予張力及彈力之角色,彈性蛋白之減少與皺紋及鬆弛之形成有關(非專利文獻2)。又,膠原分解而成之基質金屬蛋白酶(matrix metalloproteinase)-1已知為皺紋之原因(非專利文獻3)。
又,內皮素(endothelin)-1為促進黑色素細胞之活化及增生之物質,已知為斑的原因。進而,亦已發現自黑色素細胞排出至表皮細胞之黑色素未自表皮細胞被順利排出將成為於肌膚中色素沉澱(斑)或肌膚暗沉之原因(非專利文獻4)。
基於該等研究成果及發現,目前已完成基於科學見解而可合理預防或改善隨著增齡而於人類皮膚顯現皺紋、細紋、鬆弛、斑等之變化之所謂抗老化用之皮膚外用劑之多種提案(例如參考專利文獻4至10),人類已逐步接近想永保年輕之實現。然而,現在所提案之抗老化用之皮膚外用劑不過是追求、實現眾多可能性中之極少一部分之可能性,基於抗老化劑所發揮之不同機制、及使用方便性良好、進而亦包含製造容易性之觀點,現狀依然期望由更多方面之角度提供新穎抗老化用之皮膚外用劑。
[先前技術文獻]
[專利文獻]
[專利文獻1]日本特開2012-056857號公報
[專利文獻2]日本特開2004-091376號公報
[專利文獻3]日本特開2008-007411號公報
[專利文獻4]日本再公表特許第WO2007/011066號公報
[專利文獻5]日本特開2007-291102號公報
[專利文獻6]日本特開2008-169196號公報
[專利文獻7]日本特開2008-255020號公報
[專利文獻8]日本特開2008-260721號公報
[專利文獻9]日本特開2009-040690號公報
[專利文獻10]日本特開2009-249306號公報
[非專利文獻]
[非專利文獻1] Farage等(編者)「Textbook of Aging Skin」,Springer公司發行,2010年
[非專利文獻2]小倉等,「日本化粧品技術者會誌」,第44卷第4號,278至284頁,2010年
[非專利文獻3] Fisher等,「American Journal of Pathology」,第174卷第1號,101至114頁,2009年
[非專利文獻4] Gilchrest等,「Photochemistry and Photobiology」,第63卷第1號,1至10頁,1996年
本發明係鑑於上述以往技術之現狀而完成者,其課題係提供一種用於預防或改善隨著增齡而顯現之人類皮膚之皺紋、細紋、鬆弛、斑等之變化的新穎抗老化用皮膚外用劑者。
本發明人等為解決上述課題而重複積極研究努力之結果,發現腺苷N1-氧化物5’-磷酸、其類似物及其鹽因發揮優異之抗老化效果,亦即、改善更新、維持或亢進皮膚之障蔽功能、增強皮膚之纖聚蛋白(filaggrin)表現、促進皮膚之彈力蛋白產生、抑制皮膚之基質金屬蛋白酶-1產生、或抑制皮膚之內皮素-1產生之效果,而發揮預防或改善隨著增齡之皮膚皺紋、細紋、鬆弛、斑等之抗老化效果,因而完成本發明。
亦即,本發明係藉由提供含有由腺苷N1-氧化物5’-磷酸、其類似物及其鹽選出之一種或兩種以上作為有效成分之抗老化用皮膚外用劑而解決上述課題者。
又,本發明人等發現藉由併用抗壞血酸2-葡萄糖苷、表沒食子兒茶素沒食子酸酯(epigallocatechin gallate)及/或乙二胺四乙酸,能有意義地強化腺苷N1-氧化物5’-磷酸、其類似物及其鹽所發揮之抗老化效果。
依據本發明之抗老化用皮膚外用劑,可改善皮膚之更新、維持或亢進皮膚之障蔽功能、增強皮膚之纖聚蛋白表現、維持或亢進皮膚之彈力蛋白產生、抑制皮膚之基質金屬蛋白酶-1產生、或抑制皮膚之內皮素-1產生,故可有效預防或改善隨著增齡之皮膚皺紋、細紋、鬆弛、斑等。
本發明之皮膚外用劑含有腺苷N1-氧化物5’-磷酸、其類似物及其鹽作為有效成分。該腺苷N1-氧化物5’-磷酸、其類似物及其鹽不管其來源,可為由天然物經純化者,亦可為化學合成者。本發明中所謂腺苷N1-氧化物5’-磷酸之類似物可列舉為例如腺苷N1-氧化物或3’-α-葡萄糖糖基腺苷N1-氧化物、5’-α-葡萄糖糖基腺苷N1-氧化物、腺苷N1-氧化物5’-二磷酸、腺苷N1-氧化物5’-三磷酸等。又,本發明中所謂腺苷N1-氧化物5’-磷酸之鹽可列舉出例如腺苷N1-氧化物5’-磷酸鈉或腺苷N1-氧化物5’-磷酸鉀等。作用效果方面以腺苷N1-氧化物5’-磷酸、腺苷N1-氧化物、3’-α-葡萄糖糖基腺苷N1-氧化物及5’-α-葡萄糖糖基腺苷N1-氧化物較佳,更好為腺苷N1-氧化物5’-磷酸、腺苷N1-氧化物及3’-α-葡萄糖糖基腺苷N1-氧化物,最好為腺苷N1-氧化物5’-磷酸及腺苷N1-氧化物。此外,就光安定性或溶解度方面而言,腺苷N1-氧化物
5’-磷酸比腺苷N1-氧化物更適當。腺苷N1-氧化物5’-磷酸之鹽由於係作為腺苷N1-氧化物5’-磷酸發揮作用,故腺苷N1-氧化物5’-磷酸與其鹽發揮同等效果,但就溶解度方面而言,腺苷N1-氧化物5’-磷酸之鹽比腺苷N1-氧化物5’-磷酸更佳。該等化合物可包含源自製造原料之成分或合成過程中產生之副產物,通常以固體成分換算,以純度95質量%以上較佳,更好為98質量%以上,最好為99質量%以上(只要無特別指明,則本說明書中將質量%僅記為「%」)。
以下,針對本發明之皮膚外用劑具體加以說明。
通常,本發明之皮膚外用劑之情況,由腺苷N1-氧化物5’-磷酸、其類似物及其鹽選出之一種或兩種以上之調配比例一般相對於皮膚外用劑之總質量,宜為0.001至10.0%,更好為0.01至1.0%。該等調配量相對於皮膚外用劑之總質量未達0.001%時,會有無法上述有效成分之作用未充分發揮之情況。相反地,超過10.0%時,由於無法獲得與使用量成比例之效果,故有時並不佳。
本發明所用之腺苷N1-氧化物5’-磷酸、其類似物及其鹽由於其本身發揮更新改善作用、皮膚之障蔽功能之維持或亢進作用、增強皮膚之纖聚蛋白表現、維持或亢進皮膚之彈力蛋白產生、抑制皮膚之基質金屬蛋白酶-1產生、或抑制皮膚之內皮素-1產生之作用,故其單獨可有利地利用作為本發明之皮膚外用組成物之有效成分。又,
亦可隨意併用其他成分。
腺苷N1-氧化物5’-磷酸、其類似物及其鹽所發揮之抗老化效果可藉由與壞血酸2-葡萄糖苷、表沒食子兒茶素沒食子酸酯及/或乙二胺四乙酸併用而有意義地強化,故該等亦可有利地利用作為本發明之皮膚外用組成物之成分。
又,本發明所稱之更新改善意指使由「角質層(角層)」、「顆粒層」、「棘細胞層」及「基底層」構成之成為人類表皮根本之表皮細胞(角質細胞)之增生、移動、分化、脫落之一連串過程(更新)保持在健康狀態。更具體而言,意指使隨著增齡而增長之肌膚更新週期縮短。
依據本發明之含有腺苷N1-氧化物5’-磷酸、其類似物及其鹽作為有效成分之皮膚外用劑,藉由促進角質細胞之分化、增強轉榖醯胺酶(transglutaminase)活性,而促進角質肥化膜產生,改善皮膚之更新,故可有效預防或改善隨著增齡之皮膚皺紋、細紋、鬆弛、斑等。又,該皮膚外用劑由於強化皮膚之緊密連接功能、維持或亢進皮膚障蔽功能、抑制水分釋出,故可有效預防或改善隨著增齡之皮膚細紋、鬆弛等。另外,本發明之皮膚外用劑由於促進能對肌膚賦予張力或彈力之彈力蛋白之產生,且抑制成為皺紋原因之基質金屬蛋白酶-1之產生,故可有效預防或改善皺紋、鬆弛等。此外,本發明之皮膚外用劑由於可抑制內皮素-1之產生,故可有效預防或改善斑等。
且,本發明之皮膚外用劑可依據其具體形態
而調配習知成分。亦即,皮膚外用劑之形態之情況中,通常可在不損及本發明期望效果之範圍內調配可用於皮膚外用劑之成分之一種或兩種以上。例如,只要適當調配油成分、界面活性劑、防腐劑(抗菌劑)、香料、美白劑、保濕劑、增黏劑、抗氧化劑、螯合劑、紫外線吸收‧散射劑、維他命類、胺基酸類、抗炎症劑、血流促進劑、海藻萃取物、收斂劑、抗皺紋劑、細胞賦活劑、抗老化防止劑、育毛‧生毛劑、經皮吸收促進劑、水、醇類、水溶性高分子、pH調整劑、發泡劑、粉體、醫藥品‧準醫藥‧化妝品‧食品用之添加劑、醫藥用‧準醫藥之有效成分等,只要依據常用方法製造皮膚外用劑即可。
具體而言,油成分可例示為澳洲胡桃油、蓖麻油、橄欖油、可可亞油、椿油、椰油、木蠟、荷荷芭油、葡萄籽油、酪梨油等植物油脂類,貂油、蛋黃油等動物油脂類,蜜蠟、鯨蠟、卵磷脂、巴西棕櫚蠟、小燭樹蠟等蠟類,液體石蠟、角鯊烷、微鯨蠟、地蠟、石蠟、凡士林等烴類,癸酸、肉荳蔻酸、棕櫚酸、硬脂酸、山萮酸、綿羊油酸、亞油酸、亞麻酸、月桂酸、肉荳蔻酸、油酸、異硬脂酸等天然及合成脂肪酸類,十六烷醇、硬脂醇、十六烷醇、十八烷醇、月桂醇、癸醇、肉荳蔻醇、鯨醇、膽固醇、植甾醇等天然及合成高級醇類,肉荳蔻酸異丙酯、棕櫚酸異丙酯、肉荳蔻酸十八烷酯、油酸十八烷酯、膽固醇油酸酯等酯類等。
界面活性劑可例示為單月桂酸山梨糖醇酐
酯、單棕櫚酸山梨糖醇酐酯、倍半油酸山梨糖醇酐酯、三油酸山梨糖醇酐酯、單月桂酸聚氧伸乙基山梨糖醇酐酯、單硬脂酸聚氧伸乙基山梨糖醇酐酯、聚乙二醇單油酸酯、聚乙二醇烷酸酯、聚氧伸乙基烷基醚、聚二醇二醚、月桂醯基二乙醇醯胺、脂肪酸異丙醇醯胺、多羥基脂肪酸醚、烷基化多糖、烷基葡糖苷、糖酯等非離子性界面活性劑,親油型甘油單硬脂酸酯、自我乳化型甘油單硬脂酸酯、聚甘油單硬脂酸酯、聚甘油烷酸酯、山梨糖醇酐單油酸酯、聚乙二醇單硬脂酸酯、聚氧伸乙基山梨糖醇酐單油酸酯、聚氧伸乙基鯨基醚、聚氧伸乙基化固醇、聚氧伸乙基化綿羊油、聚氧伸乙基化蜜蠟、聚氧伸乙基硬化蓖麻油等非離子性界面活性劑,硬脂酸鈉、棕櫚酸鉀、鯨基硫酸鈉、月桂基磷酸鈉、棕櫚酸三乙醇胺、聚氧伸乙基月桂基磷酸鈉、N-醯基穀胺酸鈉、棕櫚酸鈉、月桂酸鈉、十二烷基酸鈉、十二烷基硫酸鉀、烷基硫酸三乙醇胺醚、硫酸化蓖麻油(sulfated castor oil)、直鏈十二烷基苯硫酸、聚氧伸乙基硬化蓖麻油馬來酸、醯基甲基牛磺酸等陰離子性界面活性劑,氯化硬脂基二甲基苄基銨、氯化硬脂基三甲基銨、硬脂基三甲基銨氯化物、氯化苯二甲羥銨(benzalkonium chloride)、月桂基胺氧化物等陽離子界面活性劑,鹽酸烷基胺乙基甘胺酸液、卵磷脂等兩性界面活性劑等。
防腐劑(抗菌劑)可例示為苯甲酸及其鹽類、水楊酸及其鹽類、山梨醇酸及其鹽類、脫氫乙酸及其鹽類、以對羥基苯甲酸烷酯為代表之對羥基苯甲酸酯、2,4,4’-三
氯-2’-羥基二苯基醚、3,4,4’-三氯碳醯苯胺、六氯苯酚、氯化苯二甲羥銨、苯氧基乙醇、扁柏醇(hinokitiol)、間苯二酚、乙醇、1,3-丁二醇、感光素201號等。
香料可例示為苯甲醛、苯甲酸苄酯、苯基乙酸、檀香捲、丁香油酚、鈴蘭醛(lilial)、新鈴蘭醛(lyral)、芳樟醇、2-甲基-3-(4-甲基苯基)-丙醛、酮麝香(musk ketone)、桂皮醛、Beltfix()、甲基紫羅蘭酮(methyl ionone)、甲酸香葉酯(geranyl formate)、龍涎酮(Iso E Super)、γ-十一碳烷內酯、水楊酸己酯、水楊酸順式-3-己烯酯、二氫茉莉酮酸甲酯(methyl dihydrojasmonate)、3-巰基丙酸四氫糠酯、2-甲基-3-(3,4-甲二氧基苯基)丙醇(KOVANOL)、香草醛、香莢蘭、天竺葵(geranium)精油、胡薄荷(pennyroyal)精油、樺木(Birch)精油、艾嵩油(armoise oil)等。
美白劑可例示為抗壞血酸或其衍生物及該等之鹽類、烷氧基水楊酸類及其鹽類、氫醌或其配糖體等之氫醌衍生物、胺甲環酸(tranexamic acid)或其衍生物及彼等之鹽類、間苯二酚之衍生物、麴酸或其衍生物及彼等之鹽類、鞣花酸或亞油酸及彼等之鹽類、德國洋甘菊萃取物、四氫類姜黃素、藍草萃取物等。
保濕劑可例示為赤蘚醇、木糖醇、山梨糖醇、麥芽糖醇、甘油、丙二醇、1,3-丁二醇、聚甘油、聚乙二醇、二丙二醇、1,2-戊二醇、異戊二醇等之多元醇類,葡萄糖、麥芽糖、海藻糖之糖質衍生物、糊精、環糊
精、國際公開WO 02/10361號說明書所揭示之具有環{→6)-α-D-吡喃葡萄糖基-(1→3)-α-D-吡喃葡萄糖基-(1→6)-α-D-吡喃葡萄糖基-(1→3)-α-D-吡喃葡萄糖基-(1→}之構造之環狀四糖、日本特開2005-95148號公報所記載之具有環{→6)-α-D-吡喃葡萄糖基-(1→4)-α-D-吡喃葡萄糖基-(1→6)-α-D-吡喃葡萄糖基-(1→4)-α-D-吡喃葡萄糖基-(1→}之構造之環狀四糖、胺基酸、乳酸鈉、吡啶酮羧酸鈉等之天然保濕成分、糖原、刺槐豆膠、木糖葡萄糖、榅桲籽(quince seed)、卡拉膠、果膠、甘露聚糖、卡德蘭膠、環葡聚糖、半乳聚糖、硫酸皮膚素、硫酸角質素、軟骨素、硫酸軟骨素、硫酸黏多糖、硫酸角質、甲殼素、硫酸肝素、透明質酸等之黏多糖類或該等黏多糖類之水解物、絲或膠原等之蛋白質.胜肽或該等之水解物等之水溶性高分子物質、該等之鹽類、二甲基聚矽氧烷、甲基苯基矽氧烷等之聚矽氧類、乳酸菌.益生菌等之培養上清液等。
增黏劑可例示為海藻酸鈉、黃原膠、矽酸鋁、榅桲種子萃取物、阿拉伯膠、羥乙基瓜爾膠、羧甲基瓜爾膠、瓜爾膠、糊精、黃蓍膠、澱粉、普魯蘭多糖、甲殼素、殼聚糖、寒天、纖維素等之天然高分子物質,羥丙基纖維素、甲基羥丙基纖維素、甲基纖維素、羧甲基纖維素、羥乙基纖維素、可溶性澱粉、陽離子化纖維素、羧甲基甲殼素等之半合成高分子物質、羧基乙烯基聚合物、聚乙烯醇、聚乙烯吡啶酮、乙烯醇.乙酸乙烯酯共聚物等之合成高分子物質等。
抗氧化劑可例示為二丁基羥基甲苯、丁基羥基苯甲醚、沒食子酸丙酯、抗壞血酸、維他命E、兒茶素類、類黃酮類或該等之衍生物等。
螯合劑可例示為乙二胺四乙酸二鈉、乙二胺四乙酸鹽、焦磷酸、六偏磷酸、檸檬酸、酒石酸、葡萄糖酸等。
pH調整劑可例示為氫氧化鈉、氫氧化鉀、三乙醇胺、硝基三乙醇、檸檬酸、檸檬酸鈉、硼酸、硼砂、磷酸氫鉀等。
紫外線吸收.散射劑可例示為對胺基苯甲酸系紫外線吸收劑、鄰胺基苯甲酸系紫外線吸收劑、水楊酸系紫外線吸收劑、桂皮酸系紫外線吸收劑、二苯甲酮系紫外線吸收劑、糖系紫外線吸收劑、3-(4’-甲基亞苄基)-d-樟腦、3-亞苄基-d,1-樟腦、尿刊酸(urocanic acid)、尿刊酸乙酯、2-苯基-5-甲基苯并噁唑、2,2’-羥基-5-甲基苯基苯并三唑、2-(2’-羥基-5’-第三辛基苯基)苯并三唑、2-(2’-羥基-5’-甲基苯基)苯并三唑、二苯甲醚基甲烷、4-甲氧基-4’-第三丁基二苯甲醯基甲烷、5-(3,3-二甲基-2-亞降冰片基)-3-戊-2-酮、2-羥基-4-甲氧基二苯甲酮、二甲基對胺基苯甲酸辛酯、對甲氧基桂皮酸乙基己酯、氧化鈦、高嶺土、滑石等。
維他命類可例示為維他命A及其衍生物、維他命B1及其衍生物、維他命B2及其衍生物、維他命B6鹽酸鹽、維他命B6三棕櫚酸鹽、維他命B6二辛酸鹽、
維他命B12、維他命B15及其衍生物等之維他命B類,抗壞血酸及其衍生物、α-生育酚、維他命E乙酸鹽等之維他命E類、維他命D類、維他命H、泛酸、泛硫乙胺(pantethine)、維他命F、維他命K、維他命P及其衍生物、維他命U、阿魏酸(ferulic acid)、γ-穀維素(oryzanol)、α-硫辛酸、乳清酸、輔酶Q10等及該等之衍生物等,亦可為該等之鹽類。
胺基酸類可例示為甘胺酸、丙胺酸、纈胺酸、白胺酸、異白胺酸、絲胺酸、蘇胺酸、苯基丙胺酸、酪胺酸、天冬醯胺、穀胺酸、牛磺酸、色胺酸、胱胺酸、半胱胺酸、甲硫胺酸、脯胺酸、羥基脯胺酸、天門冬胺酸、穀醯胺酸、精胺酸、組胺酸、離胺酸、肉鹼、瓜胺酸及該等之衍生物等,亦可為該等之鹽類。
使用本發明之皮膚外用劑時之形態並未特別限制,例如可以水溶液系、可溶化系、乳化系、粉末分散系、固形棒系、水-油兩層系、水-油-粉末三層系等之各種形態應用本發明之皮膚外用劑。且其具體劑型亦未特別限制,亦非拘束於醫藥品、準醫藥、化妝品等之藥事法上之區別者。本發明之皮膚外用劑可說是作為醫藥品、準醫藥或化妝品應用於皮膚、口唇或頭皮等之外皮及口腔內者,具體而言,可例示為軟膏、乳霜、乳液、乳劑、精華液、凍膏、膠體、貼片、洗髮精、潤絲精、護髮劑、面膜、眼睫毛膏、眼線筆、育毛劑、唇膏(口紅)、唇蜜、粉底、腮紅、眼影、蜜粉、修指甲、肥皂、身體皂、沐浴用劑、牙
粉、潤性牙膏、牙膏、漱口水、藥用牙膏、口中清涼劑、口中清涼膜、漱口液、含嗽藥等。
以下,利用實驗說明本發明。
〈實驗1:腺苷N1-氧化物5’-磷酸及其類似物對正常人類表皮角化細胞之更新之影響〉
角質細胞之增生、移動、分化、脫落之一連串過程稱為更新,角質細胞以一定週期汰新而保持皮膚之恆穩性,但隨著增齡肌膚之更新速度變慢,結果,產生皺紋及鬆弛及肌膚粗糙。因此,認為若能誘發角質細胞分化,則能使更新速度加速,可改善皺紋及鬆弛及肌膚粗糙。因此,本實驗係評價腺苷N1-氧化物5’-磷酸及其類似物之更新促進作用、角質細胞之分化誘發作用、角質肥化膜產生促進作用及轉榖醯胺酶活性增強作用作為指標。又,實驗係依據「Hasegawa等,『Lipids』,第46卷第6號,第529至535頁,2011年」及「Sturniolo等『The Journal of Biological Chemistry』,第278卷第48號,48066至48073頁,2003年」進行。
〈實驗1-1:對角質細胞分化之影響〉
於12孔盤中添加1ml之以含有增生因子之角質細胞用培養基(商品名「EpiLife」,Life Technologies公司製)調製成2.5×104個/ml之濃度而成之正常人類表皮角化細胞,培養至細胞佔孔之底面一半左右之狀態。隨後,將培
養基換成不含增生因子之角質細胞用培養基並培養2天,接著,將培養基分別交換成以表1所示之各濃度添加表1所記載之被驗物質之不含增生因子之角質細胞用培養基並培養3天。又,將不添加被驗物質以外同樣進行培養者作為對照。在顯微鏡下進行細胞形態之觀察,根據以下基準評價角質細胞之分化誘發能。
分數0:無變化
分數1:顯示扁平形態之細胞數為全體之50%以下
分數2:顯示扁平形態之細胞數為全體之50%以上
分數3:細胞幾乎全部呈不規則形態,亦確認一部分有光澤之細胞
分數愈大意指愈促進細胞之分化。實驗進行3次,求出其平均分數。腺苷N1-氧化物5’-磷酸類似物對於角質細胞之分化誘發作用示於表1。
如由表1所了解,未添加被驗物質之對照未發現正常人類表皮角化細胞之形態變化,相對於此,腺苷N1-氧化物5’-磷酸鈉及腺苷N1-氧化物在10μm之濃度下確認到形態變化,在20~40μM下扁平細胞進一步脫核而變小,細胞成為不規則形態,其中亦確認到有光澤之細胞,分化進行中。3’-α-葡萄糖基腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物分別在40~80μM及200~400μM之濃度下確認到形態變化,分別在160μM及800μM下扁平細胞進一步脫核而變小,細胞成為不規則形態,其中亦
確認到有光澤之細胞,分化進行中。另一方面,腺苷在400μM之濃度下,3’-α-葡萄糖基腺苷及5’-α-葡萄糖基腺苷在800μM之濃度下未確認到形態變化。
在試驗之濃度範圍中,於腺苷N1-氧化物5’-磷酸鈉、腺苷N1-氧化物、3’-α-葡萄糖基腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物之任一者均見到角質細胞之分化促進,判知其效果於腺苷N1-氧化物5’-磷酸鈉及腺苷N1-氧化物較強。該等結果表示腺苷N1-氧化物5’-磷酸、其類似物及其鹽由於能促進角質細胞之分化,故可使用作為更新改善劑。
〈實驗1-2:對於角質肥化膜之產生之影響〉
角質肥化膜在皮膚中之障蔽功能中扮演重要角色。皮膚之障蔽功能降低時,引起皮膚之皺紋、細紋、鬆弛、斑等。因此,本實驗係調查腺苷N1-氧化物5’-磷酸及其類似物對角質肥化膜之影響。又,實驗係依據「Hasegawa等,『Lipids』,第46卷第6號,第529至535頁,2011年」進行。
除了以表2所示之各濃度添加表2所記載之被驗物質外,餘與實驗1-1同樣培養正常人類表皮角化細胞。以磷酸緩衝生理食鹽水洗淨培養之正常人類表皮角化細胞1次後,添加0.5ml之磷酸緩衝生理食鹽水並刮取附著於盤上之細胞。於所得細胞懸浮液中添加1/4液量之10%月桂基硫酸鈉溶液並攪拌,在-80℃冷凍。解凍後,進
行離心分離(12000×g,15分鐘),以含有2%月桂基硫酸鈉之磷酸緩衝生理食鹽水洗淨所回收之細胞殘渣1次後,再進行離心分離(12000×g,15分鐘),使回收之細胞殘渣懸浮在含有2%之月桂基硫酸鈉及20mM之二硫蘇糖醇(dithiothreitol)之磷酸緩衝生理食鹽水中。在沸騰水浴中煮沸該細胞殘渣懸浮液1小時後,測定310nm之吸光度作為角質肥化膜產生量。將未添加被驗物質以外進行相同處理者設為對照,將其同樣於310nm之吸光度設為100%,依據下述計算式相對評價角質肥化膜產生量。
計算式:角質肥化膜產生量(相對值%)=(添加被驗物質之樣品之吸光度/對照之吸光度)×100
實驗進行3次,相對於對照進行Dunnett之多重比較檢定。以危險率p<0.01設為有意義差,且以*表示。腺苷N1-氧化物5’-磷酸類似物對於隨著角質細胞分化之角質肥化膜產生之作用示於表2。
如由表2所了解,與未添加被驗物質之對照比較,腺苷N1-氧化物5’-磷酸鈉及腺苷N1-氧化物,在25μM之濃度下使角質肥化膜產生量提高至約180%,確認有意義之角質肥化膜產生促進作用。且,3’-α-葡萄糖基腺苷N1-氧化物在200μM之濃度下確認有意義之角質肥化膜產生促進作用。5’-α-葡萄糖基腺苷N1-氧化物在600μM之濃度下確認有有意義之角質肥化膜產生促進作用。腺苷5’-磷酸在400μM之濃度下確認有促進角質肥化膜產生之傾向。另一方面,腺苷及3’-α-葡萄糖基腺苷分別在400μM及800μm之濃度下均未見到角質肥化膜產生促進作用。
試驗之濃度下,腺苷N1-氧化物5’-磷酸鈉、腺苷N1-氧化物、3’-α-葡萄糖基腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物確認到角質肥化膜之產生促進,判
知其效果腺苷N1-氧化物、腺苷N1-氧化物5’-磷酸鈉及3’-α-葡萄糖基腺苷N1-氧化物較強,最強為腺苷N1-氧化物及腺苷N1-氧化物5’-磷酸鈉。該等結果表示由於腺苷N1-氧化物5’-磷酸、其類似物及其鹽能促進角質肥化膜之形成,故可使用作為更新改善劑。
〈實驗1-3:對轉榖醯胺酶活性之影響〉
轉榖醯胺酶為催化蛋白質交聯之酵素,參與角質肥化膜之形成。因此,藉由增強轉榖醯胺酶活性而促進角質肥化膜之形成,故可預防或改善皮膚之皺紋、細紋、鬆弛、斑等。因此,本實驗係調查腺苷N1-氧化物5’-磷酸及其類似物對轉榖醯胺酶活性之影響。又,實驗係依據「Sturniolo等『The Journal of Biological Chemistry』,第278卷第48號,48066至48073頁,2003年」進行。
除了以表3所示之各濃度添加表3所記載之被驗物質外,餘與實驗1-1同樣培養正常人類表皮角化細胞。對培養之正常人類表皮角化細胞添加100μM之螢光素屍胺(fluorescein cadaverine)且靜置4小時。隨後,以磷酸緩衝生理食鹽水洗淨細胞1次,接著,以冷甲醇固定處理10分鐘使細胞固定。以冷甲醇洗淨細胞3次後,添加磷酸緩衝生理食鹽水。使用細胞成像工作站(Cell Imaging Station)(Molecular Probes公司製)對因轉榖醯胺酶進入到細胞之螢光素屍胺進行解析,以其螢光強度作為轉榖醯胺酶活性。未添加被驗物質以外餘同樣處理者設為
對照,將其螢光強度設為100%,依據下述計算式相對評價轉榖醯胺酶活性。
計算式:轉榖醯胺酶活性(相對值%)=(添加被驗物質之樣品之螢光強度/對照之螢光強度)×100
實驗進行3次,相對於對照進行Dunnett之多重比較檢定。以危險率p<0.01設為有意義差,以*表示。腺苷N1-氧化物5’-磷酸類似物對於參與角質肥化膜之產生之轉榖醯胺酶活性之作用示於表3。
如由表3所了解,與未添加被驗物質之對照比較,腺苷N1-氧化物5’-磷酸鈉及腺苷N1-氧化物在20μM之濃度下之轉榖醯胺酶活性分別提高至約570%及約630%,確認有意義之轉榖醯胺酶活性增強作用。此外,5’-α-葡萄糖基腺苷N1-氧化物在400μm之濃度下確認有意
義的轉榖醯胺酶活性增強作用。3’-α-葡萄糖基腺苷N1-氧化物在100μm之濃度下雖未確認到轉榖醯胺酶活性增強作用,但於5’-α-葡萄糖基腺苷N1-氧化物由於在400μM之濃度下確認到效果,故關於3’-α-葡萄糖基腺苷N1-氧化物認為在更高濃度下使用亦可見到效果。腺苷、腺苷5’-磷酸、3’-α-葡萄糖基腺苷及5’-α-葡萄糖基腺苷在400μM之濃度下均未確認到轉榖醯胺酶活性增強作用。
在試驗濃度下,轉榖醯胺酶活性之增強於腺苷N1-氧化物5’-磷酸鈉、腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物被確認,判知其效果以腺苷N1-氧化物及腺苷N1-氧化物5’-磷酸鈉較強。該等結果表示腺苷N1-氧化物5’-磷酸、其類似物及其鹽具有增強轉榖醯胺酶活性之作用,可使用作為更新改善劑。
〈實驗2:腺苷N1-氧化物5’-磷酸及其類似物對於對源自人類類上皮細胞癌之細胞之緊密連接功能強化作用之影響〉
緊密連接具有防止異物自活體外朝活體內侵入或過量水分自活體內朝活體外釋出之功能。因此,認為藉由強化緊密連接功能,與皮膚障蔽功能之亢進或保濕有關。因此,本實驗係調查腺苷N1-氧化物5’-磷酸及其類似物對緊密連接之影響。又,實驗係依據「Suzuki及Hara『Journal of Nutrition』第139卷第5號,965至974頁,2009年」進行。
將以表4所示之各濃度添加表4所記載之被驗物質之培養基調製成1×105個/ml濃度之源自人類類上皮細胞癌之A-431細胞以各2ml逐次添加於12孔插入杯中,培養自細胞佔據孔之底面全體之狀態為止。將培養液量在插入杯之內側與外側分別一致為2mL,確認水面無變化,以成為最終濃度100μM之方式將作為透過物之模型之螢光色素的螢蝦黃(lucifer yellow)(Life Technologies)添加於插入杯之內側。隨後,測定插入杯之內側與外側各自之培養液中之螢蝦黃之螢光強度,以下述計算式求出外側之螢光強度相對於插入杯之內側與外側之螢光強度之和之比例,作為螢蝦黃之透過率。
計算式:螢蝦黃之透過率(%)={插入杯外側之吸光度/(插入杯內側之吸光度+插入杯外側之吸光度)}×100
未添加被驗物質以外進行同樣處理者作為對照,且將其螢蝦黃之透過率設為100%,依據下述計算式相對評價因緊密連接功能之強化所致之透過率減少。
計算式:螢蝦黃之相對透過率(相對值%)=(添加被驗物質之樣品之透過率/對照之透過率)×100
實驗進行3次,相對於對照進行Dunnett之多重比較檢定。以危險率p<0.01設為有意義差,以*表示。腺苷N1-氧化物5’-磷酸類似物對於源自人類類上皮細胞癌之細胞之緊密連接功能之作用示於表4。
如由表4所了解,與未添加被驗物質之對照比較,腺苷N1-氧化物5’-磷酸鈉在20μM之濃度下之螢蝦黃透過率減少至約60%,確認有意義的緊密連接功能強化作用。且,腺苷N1-氧化物在10~20μM之濃度下確認有意義的緊密連接功能強化作用。再者,腺苷在200~400μM之濃度下確認有意義的緊密連接功能強化作用。然而,3’-α-葡萄糖基腺苷N1-氧化物、5’-α-葡萄糖基腺苷N1-氧化物、腺苷5’-磷酸、3’-α-葡萄糖基腺苷及5’-α-葡萄糖基腺苷在200~400μM之濃度下未確認到緊密連接功能強化作用。
在試驗濃度範圍內,緊密連接功能強化作用,就效果方面而言,可說腺苷N1-氧化物5’-磷酸鈉、腺苷N1-氧化物及腺苷較佳,以腺苷N1-氧化物5’-磷酸鈉
及腺苷N1-氧化物更佳。該等結果可說是由於腺苷N1-氧化物5’-磷酸鈉及腺苷N1-氧化物具有緊密連接功能之強化作用,因此作為皮膚障蔽功能亢進劑及保濕劑為有用。
〈實驗3:腺苷N1-氧化物5’-磷酸鈉於正常人類表皮角化細胞之纖聚蛋白表現增強作用〉
關於皮膚之障蔽功能之形成、或水分保持扮演重要角色之蛋白質之一已知為纖聚蛋白。纖聚蛋白以絲聚蛋白(profilaggrin)在表皮產生,使其分解時成為纖聚蛋白,擔任皮膚之障蔽功能。且纖聚蛋白進而接受分解亦作為天然保濕因子作用。再者,近年來,已指出纖聚蛋白之表現降低與異位性皮膚炎之關聯性(「Osawa等人之『Allergology International』第60卷第1號,1至9頁,2011年」。因此本實驗係調查腺苷N1-氧化物5’-磷酸鈉於正常人類表皮角化細胞之纖聚蛋白表現增強作用。又實驗係依據「Otsuka等『The Journal of Allergy and Clinical Immunology』,第133卷第1號,139至146頁,2014年」進行。
在6孔盤中,以含有增生因子之角質細胞用培養基(商品名「EpiLife」,KURABO公司製)播種為5×104個/孔之濃度之正常人類表皮角化細胞於37℃下培養4天。第4天細胞佔孔之80%時,每隔2天以添加有成為2μM、5μM、10μM之腺苷N1-氧化物5’-磷酸鈉之EpiLife培養基進行培養基更換,再培養4天而誘發纖聚蛋白之表
現。除了使用以成為0.5mM添加氯化鈣之EpiLife培養基替代腺苷N1-氧化物5’-磷酸鈉以外餘同樣培養正常人類表皮角化細胞作為陽性對照。培養4天後,以杜貝克氏(Dulbecco’s)磷酸緩衝生理食鹽水洗淨細胞,添加0.1mL之含蛋白分解酵素阻礙劑之SDS樣品緩衝液(62.5mM Tris-HCl pH6.8,2%SDS,10%甘油,50mM DTT),且使用細胞刮取棒回收細胞。回收之細胞煮沸10分鐘後經超音波破碎,以Pierce BCA蛋白質分析套組(ThermoFisher Scientific公司製)進行蛋白質定量。以規定法將一定量(100μg/道)之樣品供給至SDS-聚丙烯醯胺電泳,隨後轉印於PVDF膜上。
使用Block Ace(DS Pharma Biomedical公司製)將PVDF轉印膜阻斷後,使作為1次抗體之抗小鼠纖聚蛋白抗體(AKH1,Santa Cruz公司製,200倍稀釋)或抗小鼠肌動蛋白抗體(MAB1501,Chemicon International公司製,20,000倍稀釋)反應,接著使作為2次抗體之HRP標記之抗小鼠免疫球蛋白抗體(P0447,Dako公司製,2,000倍稀釋)反應。反應後,使用ECL Plus西方墨點檢測系統(GE Healthcare公司製),於化學發光用薄膜Hyperfilm ECL(GE Healthcare公司製)上檢測區帶(band)。所檢測出之區帶利用圖像解析軟體「Image J」解析並數值化。
以未添加被驗物質者之數據作為對照,將其纖聚蛋白/肌動蛋白之區帶強度比設為100%,以纖聚蛋白/
肌動蛋白之區帶強度比之上升率相對評價纖聚蛋白之表現量。腺苷N1-氧化物5’-磷酸鈉對於正常人類表皮角化細胞中之纖聚蛋白之表現之作用示於表5。
如由表5所明瞭,與未添加被驗物質之對照比較,腺苷N1-氧化物5’-磷酸鈉係添加濃度依存性地使纖聚蛋白之表現量上升,於10μM時,確認到308%之與陽性對照之0.5mM之氯化鈣同等程度之表現上升作用。該等結果係因腺苷N1-氧化物5’-磷酸鈉所致之緊密連接功能強化作用之一部分係透過纖聚蛋白之表現增強作用者,可說是本物質作為皮膚障蔽功能亢進劑及保濕劑為有用。
進而,近幾年來,已指出因皮膚障蔽功能降低而使外來異物透過皮膚侵入,結果變得對於外來過敏原易產生過敏反應而關連到異位性皮膚炎之發病。該實驗結果係顯示經由腺苷N1-氧化物5’-磷酸鈉之纖聚蛋白表現增強作用亦與防止異位性皮膚炎發病有關者。
<實驗4:腺苷N1-氧化物5’-磷酸類似物對於正常人類皮膚纖維母細胞之彈力蛋白產生促進作用之影響>
具有支撐膠原之纖維的角色之纖維的彈力蛋白係發揮對肌膚賦予張力及彈力之作用,引起彈力蛋白變性時,皮膚彈性降低而與皺紋及鬆弛之形成有關。因此,藉由促進彈力蛋白之產生,可預防或改善皺紋及鬆弛。因此,本實驗係調查腺苷N1-氧化物5’-磷酸及其類似物對於彈力蛋白產生之影響。又,實驗係根據「Syedain及Tranquillo,『Journal of Biomechanics』,第44卷第5號,848至855頁,2011年」進行。
將使用含有10%胎牛血清之杜貝克氏改質鷹氏培養基(Dulbecco’s modified Eagle’s medium)調製成3×105個/ml濃度之正常人類皮膚纖維母細胞以各0.5mL添加於24孔盤中,培養1天。使用杜貝克氏磷酸緩衝生理食鹽水洗淨細胞後,進一步以表5所示之各濃度添加有表5所記載之被驗物質之杜貝克氏改質鷹氏培養基培養2天,而誘發彈力蛋白合成。隨後,回收上澄液,以1mL杜貝克氏磷酸緩衝生理食鹽水洗淨細胞後,添加0.1mL之0.25%胰蛋白酶(trypsin)及乙二胺四乙酸並在37℃處理2分鐘,且將細胞自盤剝離。於盤中添加0.5mL之杜貝克氏磷酸緩衝生理食鹽水,將所得細胞懸浮液回收至1.5mL之試管中,進行離心分離(3,000×g,5分鐘),回收剝離之細胞。彈力蛋白之定量係使用彈力蛋白比色定量套組(BIOCOLOR公司製)進行。使用先前回收之培養上澄液使
細胞懸浮,添加0.16mL之1M草酸(套組試藥)於100℃反應1小時,使彈力蛋白可溶化。添加0.66mL之彈力蛋白沉澱劑(套組試藥)上下倒轉混合15分鐘,進行離心分離(10,000×g,10分鐘),使蛋白質沉澱。於沉澱中添加0.5mL染色劑(套組試藥)上下倒轉混合90分鐘,進行離心分離(10,000×g,10分鐘),回收結合有色素之沉澱。隨後,添加0.25mL之色素分離劑(套組試藥)上下倒轉混合1小時,測定490nm之吸光度,算出每孔之彈力蛋白量。使用套組附屬品作成校正線。除外添加被驗物質並進行同樣處理者作為對照,將其之490nm之吸光度設為100%,基於下述計算式,相對評價彈力蛋白產生量。
計算式:彈力蛋白產生量(相對值%)=(添加被驗物質之樣品之吸光度/對照之吸光度)×100
又,為了確認在同條件下之細胞增生,使用含有10%胎牛血清之杜貝克氏改質鷹氏培養基調製成2.5×105個/ml濃度之正常人類皮膚纖維母細胞以各0.1mL添加於96孔微盤中,培養1天。使用杜貝克氏磷酸緩衝生理食鹽水洗淨後,以表5所示之各濃度添加有表5所記載之被驗物質之杜貝克氏改質鷹氏培養基培養2天。去除上澄液後,添加0.2mL之以培養基稀釋10倍之AlamarBlue,在37℃反應2小時,測定螢光強度(激發波長544nm,營光波長590nm),將除了未添加被驗物質以外進行同樣處理之對照的螢光強度設為100%,求出添加
被驗物質時之細胞數變化率。
實驗進行3次,相對於對照進行Dunnett之多重比較檢定。以危險率p<0.01設為有意義差,以*表示。腺苷N1-氧化物5’-磷酸類似物對於正常人類皮膚纖維母細胞之彈力蛋白產生之作用示於表6。
如由表6所明瞭,與未添加被驗物質之對照比較,腺苷N1-氧化物5’-磷酸鈉及腺苷N1-氧化物於10μM之濃度,彈力蛋白產生量提高至約120%,確認有意義的彈力蛋白產生增強作用。且,腺苷5’-磷酸於10~40μM之濃度有增強彈力蛋白產生之傾向,於100μM之濃度,確認有意義的彈力蛋白產生增強作用。又,本實驗系未見到對細胞增生之影響。
在試驗濃度範圍內,彈力蛋白產生促進作用,就效果方面而言,可說腺苷N1-氧化物5’-磷酸鈉、腺苷N1-氧化物及腺苷5’-磷酸較佳,以腺苷N1-氧化物5’-磷酸鈉及腺苷N1-氧化物更佳。該等結果可說是由於腺
苷N1-氧化物5’-磷酸鈉及其類似物的腺苷N1-氧化物具有促進彈力蛋白產生之作用,因此作為抗皺紋劑為有用。
<實驗5:腺苷N1-氧化物5’-磷酸及其類似物對於正常人類皮膚纖維母細胞之基質金屬蛋白酶-1產生之抑制作用的影響>
一般認為膠原蛋白因基質金屬蛋白酶-1而分解,於膠原分解時,形成皺紋,使皮膚彈性降低而引起鬆弛。因此藉由抑制基質金屬蛋白酶-1之產生,可預防或改善皺紋及鬆弛。本實驗係調查腺苷N1-氧化物5’-磷酸及其類似物對於基質金屬蛋白酶-1產生之影響。又,實驗係依據「Fuller等,『Journal of Cosmetic Dermatology』,第5卷第1號,30至38頁,2006年」進行。
將使用含有10%胎牛血清之杜貝克氏改質鷹氏培養基調製成2.5×105個/ml濃度之正常人類皮膚纖維母細胞以各0.1mL添加於96孔微盤中,培養至佔據孔之底面全體之狀態。接著,將培養基更換成無血清培養基培養24小時,進而以表6所示之各濃度添加表6記載之被驗物質並培養24小時。隨後,添加人類IL-1β以始終濃度為1ng/ml,進而培養24小時。接著,使用特異之ELISA套組(R&D系統公司製)檢測培養上澄液中之基質金屬蛋白酶-1,以四甲基聯苯胺顯色後,測定450nm之吸光度。將除了未添加被驗物質以外同樣處理者作為對照,將對照中之培養上澄液中之基質金屬蛋白酶-1設為100%,
利用下述計算式,相對評價基質金屬蛋白酶-1產生量。
計算式:基質金屬蛋白酶-1產生量(相對值%)=(添加被驗物質樣品之吸光度/對照之吸光度)×100
且,細胞數係以細胞數測定套組(染色法)測定,將對照設為100%,求出添加被驗物質時之細胞數變化率。
實驗進行3次,相對於對照進行Dunnett之多重比較檢定。以危險率p<0.01設為有意義差,以*表示。腺苷N1-氧化物5’-磷酸類似物對於正常人類皮膚纖維母細胞之基質金屬蛋白酶-1產生量之作用示於表7。
如由表7所明瞭,與未添加被驗物質之對照比較,腺苷N1-氧化物5’-磷酸鈉於10~20μM之濃度,基質金屬蛋白酶-1產生量減少至約80~30%,確認濃度依存性且有意義的抑制產生之作用。腺苷N1-氧化物於5~20μM之濃度確認到同樣之抑制產生之作用。且,3’-α-葡萄糖基腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物於200~800μM之濃度,確認濃度依存性且有意義的抑制
產生之作用,其效果3’-α-葡萄糖基腺苷N1-氧化物比5’-α-葡萄糖基腺苷N1-氧化物強。腺苷、腺苷5’-磷酸、3’-α-葡萄糖基腺苷及5’-α-葡萄糖基腺苷未確認到有意義之抑制基質金屬蛋白酶-1產生之作用。
在試驗濃度範圍內,基質金屬蛋白酶-1產生之抑制作用,就效果方面而言,可說腺苷N1-氧化物5’-磷酸鈉、腺苷N1-氧化物、3’-α-葡萄糖基腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物較佳,以腺苷N1-氧化物5’-磷酸鈉及腺苷N1-氧化物更佳。該等結果可說是由於腺苷N1-氧化物5’-磷酸鈉、其類似物及其鹽具有抑制基質金屬蛋白酶-1產生之作用,而作為抗皺紋劑為有用。
<實驗6:腺苷N1-氧化物5’-磷酸及其類似物對於正常人類表皮角化細胞之內皮素-1產生之抑制作用的影響>
已知內皮素-1為促進黑色素細胞之活化及增生之物質,為皺紋的原因。再者,亦已知自黑色素細胞排出至表皮細胞之黑色素未自表皮細胞順利排出時將成為色素於肌膚上沉澱(斑)及肌膚暗沉之原因。因此,藉由抑制內皮素-1產生,可預防或改善色素於肌膚上之沉澱(斑)及肌膚暗沉。因此,本實驗係調查腺苷N1-氧化物5’-磷酸及其類似物對於內皮素-1產生之影響。又,實驗係依據「Ishida及Sakaguchi,『Biological & Pharmaceutical Bulletin』,第30卷第5號,928-934頁,2007年」進行。
於96孔微盤中,使用含有增生因子之角質細胞用培養基(商品名「EpiLife」,Life Technologies公司製)使正常人類表皮角化細胞增生至佔據孔之底面全體之狀態後,將培養基換成不含增生因子之角質細胞用培養基並培養2天。隨後,以成為10、20或50μM之方式添加腺苷N1-氧化物5’-磷酸鈉,靜置6小時。以漢氏緩衝液洗淨後,以40mJ/cm2之強度對細胞照射紫外線B波,進而添加含有增生因子之角質細胞用培養基並培養24小時。接著,使用特異之ELISA套組(R&D系統公司製)檢測培養上澄液中之內皮素-1,以四甲基聯苯胺顯色後,測定450nm之吸光度。將除了不添加腺苷N1-氧化物5’-磷酸鈉以外同樣處理者作為對照,將對照之培養上澄液中之內皮素-1產生量設為100%,藉由下述計算式,相對評價內皮素-1產生量。
計算式:內皮素-1產生量(相對值%)=(添加被驗物質樣品之吸光度/對照之吸光度)×100
又,細胞之增生係以亞甲基藍測定,求出將對照設為100%時之添加被驗物質時之細胞數之變化率。
實驗進行3次,相對於對照進行Dunnett之多重比較檢定。以危險率p<0.01設為有意義差,以*表示。腺苷N1-氧化物5’-磷酸鈉對於正常人類表皮角化細胞之內皮素-1產生之作用示於表8。
如由表8所明瞭,與未添加被驗物質之對照比較,腺苷N1-氧化物5’-磷酸鈉於20μM之濃度,有抑制內皮素-1產生之傾向,於50μM之濃度,內皮素-1之產生量減導致約50%,確認有意義的內皮素-1產生之抑制作用。且,在本實驗系統當中,沒有見到對細胞增生有影響。
該結果可說是由於腺苷N1-氧化物5’-磷酸鈉具有抑制內皮素-1產生之作用,故於作為抗斑劑為有用。
<實驗7:表沒食子兒茶素沒食子酸酯與腺苷N1-氧化物5’-磷酸併用對角質細胞分化誘發之影響>
實驗除了以表8及表9所示之各濃度添加各表8及表9記載之被驗物質以外,分別依據實驗1-2及實驗1-3記載之方法進行,調查藉由併用於化妝品中作為抗氧化劑使用之表沒食子兒茶素沒食子酸酯之腺苷N1-氧化物5’-磷酸鈉對於角質肥厚膜產生促進作用及轉穀醯胺酶活性增強作用之影響。除了未添加被驗物質以外同樣處理者作為對照,分別基於下述計算式,求出相對於對照之角質肥厚膜產生量增加率及轉穀醯胺酶活性增加率。
計算式:角質肥厚膜產生量增加率(%)={(添加被驗物
質之樣品之吸光度/對照之吸光度)×100}-100
計算式:轉穀醯胺酶活性增加率(%)={(添加被驗物質之樣品之螢光強度/對照之螢光強度)×100}-100
各結果示於表9及表10(確認到效果之組合的增加率以*表示)。
如由表9及表10所明瞭,15μM之腺苷N1-
氧化物5’-磷酸鈉與1.6~6.5μM之表沒食子兒茶素沒食子酸酯併用時,角質肥化膜產生量增加率及轉穀醯胺酶活性增加率均比分別單獨添加腺苷N1-氧化物5’-磷酸鈉與表沒食子兒茶素沒食子酸酯時之增加率之單純的和更顯著增加。由此,判斷腺苷N1-氧化物5’-磷酸鈉與表沒食子兒茶素沒食子酸酯併用時,對於角質肥化膜產生促進作用及轉穀醯胺酶活性增加作用有相乘效果。且,腺苷N1-氧化物5’-磷酸鈉與表沒食子兒茶素沒食子酸酯之莫耳比較佳在15μM:6.5μM~15μM:1.6μM之範圍,亦即2.3:1~9.4:1。該結果可說是由於於腺苷N1-氧化物5’-磷酸、其類似物及其鹽中調配有表沒食子兒茶素沒食子酸酯之組成物相乘地促進或增強角質肥化膜之產生及轉穀醯胺酶活性,故於作為抗斑劑為有用。
<實驗8:腺苷N1-氧化物5’-磷酸與乙二胺四乙酸併用對緊密連接功能之影響>
實驗中除了以表11所示之各濃度添加表11所記載之被驗物質以外,依據實驗2記載之方法進行,調查藉由與於化妝品中作為保存料使用之乙二胺四乙酸併用之腺苷N1-氧化物5’-磷酸鈉鹽對緊密連接功能強化作用之影響。除了未添加被驗物質以外同樣處理者作為對照,基於下述計算式,求出相對於對照之螢蝦黃之相對透過率之減少率。
計算式:螢蝦黃之相對透過率之減少率(%)=100-
{(添加被驗物質之樣品之透過率/對照之透過率)×100}
結果示於表11(確認到效果之組合之減少率以*表示)。
如由表11所明瞭,作為保存料使用於化妝品之乙二胺四乙酸本身雖顯示減弱緊密連接功能之作用,但併用腺苷N1-氧化物5’-磷酸鈉與乙二胺四乙酸時,確認乙二胺四乙酸之減弱緊密連接功能之作用大幅緩和。且,上述結果可說是若腺苷N1-氧化物5’-磷酸鈉與乙二胺四乙酸之莫耳比至少為10μM:3mM以上,亦即至少1:300以上時,即使存在乙二胺四乙酸,藉由使用腺苷N1-氧化物5’-磷酸鈉,亦可實現充分之緊密連接功能之強化。該結果可說是由於於腺苷N1-氧化物5’-磷酸鈉、其類似物及其鹽中調配有乙二胺四乙酸之組成物對緊密連接功能強化作用顯示有意義之效果,故於作為皮膚障蔽功能亢進劑及保濕劑為有用。
<實驗9:抗壞血酸2-葡萄糖苷與腺苷N1-氧化物5’-
磷酸或其類似物併用對於基質金屬酶-1產生之影響>
實驗中除了以表12所示之各濃度添加表12所記載之被驗物質以外,依據實驗5記載之方法進行,調查藉由與化妝品中作為美白劑使用之抗壞血酸2-葡萄糖苷併用之腺苷N1-氧化物5’-磷酸類似物對抗皺紋之影響。除了未添加被驗物質以外同樣處理者作為對照,基於下述計算式,求出相對於對照之基質金屬蛋白酶-1產生量減少率。
計算式:基質金屬蛋白酶-1產生量減少率(%)=100-{(添加被驗物質之樣品之吸光度/對照之吸光度)×100}
結果示於表12(確認到效果之組合之減少率以*表示)。
如由表12所明瞭,5~10μM之腺苷N1-氧化物5’-磷酸鈉或其類似物的腺苷N1-氧化物與200μM之抗壞血酸2-葡萄糖苷併用時,基質金屬蛋白酶-1產生量減少率比腺苷N1-氧化物5’-磷酸鈉、腺苷N1-氧化物及抗壞血酸2-葡萄糖苷分別單獨使用時之減少率之單純之和更為顯著增加。由此判斷腺苷N1-氧化物5’-磷酸鈉或腺苷N1-氧化物與抗壞血酸2-葡萄糖苷併用時,對於基質金屬蛋白酶-1產生之抑制作用有相乘效果。且腺苷N1-氧化物5’-磷酸鈉或腺苷N1-氧化物與抗壞血酸2-葡萄糖苷之莫耳比較佳在5μM:200μM~10μM:200μM,亦即1:40~1:20。該結果可說是由於調配有腺苷N1-氧化物5’-磷酸、其類似物及其鹽與抗壞血酸2-葡萄糖苷之組成物相乘地抑制基質金
屬蛋白酶-1之產生,故於作為抗皺紋劑為有用。
<實驗10:光對腺苷N1-氧化物5’-磷酸及其類似物之影響>
皮膚外用劑由於推定於其使用時會暴露於光中,因此其中所含之有效成分期望不顯示光毒性,當然期望對光安定。所謂光毒性係於化學物質或其混合物投予後接觸光時,所投予之物質對於皮膚細胞顯現障礙之現象。本實驗係比較腺苷N1-氧化物5’-磷酸與作為其類似物之腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物對光之安定性。
對於表13所記載之被驗物質25mg分別添加調整至各pH之McIlvain緩衝液作成50ml,於試驗根數量之透明玻璃螺旋管瓶(5ml)中分別逐次注入2.0ml。於螢光燈下(約4000Lux,溫度28℃),將分注有各被驗物質之透明玻璃螺旋管瓶橫躺之狀態設置。針對腺苷N1-氧化物5’-磷酸鈉,於實驗開始與其8週後,且針對腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物,係於實驗開始時與自開始起8週內每2週,取出1根分注有各被驗物質之透明玻璃螺旋管瓶,使用HPLC進行分析。實驗進行3次,由實驗開始時之HPLC層析中之相對於被驗物質之峰面積之面積比,基於下述計算式算出各被驗物質之平均殘留率。表13中顯示腺苷N1-氧化物5’-磷酸及其類似物對光之安定性。
計算式:被驗物質之殘留率(%)=(被驗物質之各pH下
經過一訂時間後之平均峰面積/被驗物質之各pH下之實驗開始時之平均峰面積)×100
如由表13所明瞭,腺苷N1-氧化物5’-磷酸鈉於實驗開始8週後,於pH4~9之條件下殘留率約為89~97%,對於光非常安定。另一方面,腺苷N1-氧化物於實驗開始8週後,於pH6~9之條件下殘留率約為25%,對於光不安定。且,5’-α-葡萄糖基腺苷N1-氧化物於實驗開始8週後,於pH6~9之條件下殘留率約為24~34%,於pH4~5之條件下,殘留率約10%,對於光非常不安定。
由於預測在太陽光下與螢光燈照射下相比會更早分解,因此腺苷N1-氧化物5’-磷酸鈉於各種pH條件下與其類似物比較顯示對於光更安定之上述結果顯示腺苷N1-氧化物5’-磷酸作為皮膚外用劑之有效成分更為有用。
又,依據用於評價化學物質及其混合物之安定性之國際上被認可之試驗方法的OECD試驗指南之「TG432:In vitro 3T3 NRU光毒性試驗」進行試驗之結
果,腺苷N1-氧化物5’-磷酸鈉、腺苷N1-氧化物、3’-α-葡萄糖基腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物未見到光毒性。由此,可說含有腺苷N1-氧化物5’-磷酸、其類似物及其鹽之皮膚外用劑為安全者。
以下,列舉實施例進一步詳細說明本發明,但本發明之技術範圍不應解釋為受到該等實施例之任何限制。
[實施例1]
<化妝水>
(調配處方)
將上述調配處方之成分(1)至(4)溶解於純化水
(9)後,緩慢添加將成分(5)至(8)混合而成者並混合,而調製化妝水。本物品由於調配腺苷N1-氧化物5’-磷酸鈉,故為促進皮膚更新優異之化妝水,可使用作為皮膚之障蔽功能之維持或亢進作用、彈力蛋白之維持或亢進作用、抗皺紋作用、抗細紋作用、抗鬆弛作用、抗斑作用均優異之化妝水。且,由於調配1,2-戊二醇,故為防腐效果及保濕性優異之化妝水。
[實施例2]
<乳液>
(調配處方)
將上述成分(1)、(3)、(10)、(11)及純化水(14)混合作成水相。其次,將成分(2)、(5)~(9)、(12)及(13)加熱、混合作為油相。於油相中添加水相,均一混合後,冷卻,添加成分(4)均質混合獲得乳液。本物品由於調配腺苷N1-氧化物5’-磷酸鈉及抗壞血酸2-葡萄糖苷,故為促進皮膚之更新優異之乳液,可使用作為皮膚之障蔽功能之維持或亢進作用、彈力蛋白之維持或亢進作用、抗皺紋作用、抗細紋作用、抗鬆弛作用、抗斑作用均優異之乳液。
[實施例3]
<化妝用乳液>
(調配處方)
依據上述處方,藉由常用方法混合調配成分後,進而添加適量香料製造乳液。本物品由於調配腺苷N1-氧化物5’-磷酸鈉及表沒食子兒茶素沒食子酸酯,因此為促進皮膚更新優異之乳液,可使用作為皮膚之障蔽功能之維持或亢進作用、彈力蛋白之維持或亢進作用、抗皺紋作用、抗細紋作用、抗鬆弛作用、抗斑作用均優異之抗老化用乳液。
[實施例4]
<化妝用乳霜>
(調配處方)
於純化水(14)中添加成分(6)至(9),加溫至60℃,調製水相。另外,混合成分(1)至(5)、(10)至(13),加溫至70℃調製油相,添加至先前調製之水相中。將其依常用方法乳化製造乳霜。本物品由於調配腺苷N1-氧化物5’-磷酸鈉,因此為促進皮膚更新優異之乳霜,且由於調配乙二胺四乙酸二鈉(ethylenediaminetetraacetic disodium),故安定。可使用作為皮膚之障蔽功能之維持或亢進作用、彈力蛋白之維持或亢進作用、抗皺紋作用、抗細紋作用、抗鬆弛作用、抗斑作用均優異且不黏膩之使用感良好之抗老化用化妝乳霜。
[實施例5]
<美容液>
(調配處方)
依據上述處方,藉由常用方法混合調配成分,調製美容液。由於調配腺苷N1-氧化物5’-磷酸鈉,因此本物品為促進皮膚更新優異之美容液,可使用作為皮膚之障蔽功能之維持或亢進作用、彈力蛋白之維持或亢進作用、抗皺紋作用、抗細紋作用、抗鬆弛作用、抗斑作用
均優異,且即使塗佈於皮膚亦無黏膩感之使用感良好之抗老化用美容液。
如以上說明,依據本發明之抗老化皮膚外用劑,可改善皮膚之更新、維持或亢進皮膚之障蔽功能、增強皮膚之纖聚蛋白之表現、維持或亢進皮膚之彈力蛋白之產生、抑制皮膚之基質金屬蛋白酶-1之產生、或抑制皮膚之內皮素-1之產生,因此可有效預防或改善隨著增齡之皮膚皺紋、細紋、鬆弛、斑等。本發明係對本技藝具有巨大貢獻意義之發明。
Claims (5)
- 一種抗老化用皮膚外用劑,其含有:由腺苷N1-氧化物5’-磷酸、其類似物及其鹽選出之一種或兩種以上,與乙二胺四乙酸及/或表沒食子兒茶素沒食子酸酯(epigallocatechin gallate),作為有效成分,且該腺苷N1-氧化物5’-磷酸之類似物係由腺苷N1-氧化物、3’-α-葡萄糖基腺苷N1-氧化物及5’-α-葡萄糖基腺苷N1-氧化物選出之一種或兩種以上。
- 如請求項1之皮膚外用劑,其中進一步含有抗壞血酸2-葡萄糖苷。
- 如請求項1或2之皮膚外用劑,其係作為皮膚阻隔功能亢進劑。
- 如請求項1或2之皮膚外用劑,其係作為抗皺紋劑。
- 如請求項1或2之皮膚外用劑,其係作為抗斑劑。
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