TWI531382B - 皮膚膠原蛋白產生促進劑 - Google Patents
皮膚膠原蛋白產生促進劑 Download PDFInfo
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- TWI531382B TWI531382B TW101104239A TW101104239A TWI531382B TW I531382 B TWI531382 B TW I531382B TW 101104239 A TW101104239 A TW 101104239A TW 101104239 A TW101104239 A TW 101104239A TW I531382 B TWI531382 B TW I531382B
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- tgf
- skin
- collagen production
- less
- skin collagen
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Description
本發明係關於一種對於防止粗糙、皺紋、彈性下降等之皮膚劣化為有用的皮膚膠原蛋白產生促進劑、皮膚膠原蛋白產生促進用飲食品及皮膚膠原蛋白產生促進用化妝品。更詳細而言,本發明係關於一種皮膚膠原蛋白產生促進劑,將轉型生長因子貝他(TGF-β)及/或將TGF-β以蛋白質分解酵素分解而得到的TGF-β分解物作為有效成分。
近年來關於皮膚劣化之機制的研究有所進展,巨觀上作為皮膚之乾燥感或肌膚粗糙的原因,係因為老化導致的新陳代謝之衰減,除此以外亦確認與太陽光(紫外線)、乾燥、氧化等之因子的作用有複雜的關連。根據該等因子導致的作用,明顯可知作為真皮之最主要的基質成分之膠原蛋白纖維會顯著地減少。由膠原蛋白纖維保持的皮膚緊緻或彈性此類之保持張力的機構若因為紫外線等之因子的作用而被破壞的話,皮膚會成為增加皺紋或鬆弛的狀態。又,膠原蛋白可在其分子中保持水分,因此,對於將皮膚保持於濕潤的狀態亦有幫助,故外在因子導致膠原蛋白被破壞時,肌膚會乾燥且成為粗糙的狀態。根據前述情事,吾人希望有一種藉由促進作為真皮層之主要的成分之一的膠原蛋白之生合成,可防止皮膚之皺紋或鬆弛,而且在安全性方面也沒有問題的皮膚膠原蛋白產生促進劑。
轉型生長因子貝他(TGF-β)為存在於哺乳類動物之乳汁中的生長因子之一種。在TGF-β家族中,存在有5種的子類型,且藉由雙硫鍵而形成約25kDa之二聚物的蛋白質。具有調節細胞增殖或生合成、分化、細胞死亡之促進.抑制的作用。TGF-β之有用
的作用,係確認有動物細胞之分化誘導作用(專利文獻1)。又,有人報導在皮膚中的纖維母細胞的生長因子(非專利文獻1)。
專利文獻1:日本特開2004-254674號公報
非專利文獻1:J.Dermatol.Sci.,vol.24(Supple),p.70,2000
本發明的目的在於提供一種於安全性方面沒有問題的皮膚膠原蛋白產生促進劑。又,本發明的目的在於提供一種摻合如前述的物質之皮膚膠原蛋白產生促進用飲食品及皮膚膠原蛋白產生促進用化妝品。
本案發明人等為了解決該等問題,廣泛地針對食品材料所包含之展現皮膚膠原蛋白產生促進作用的物質,認真進行研究時,發現TGF-β或是分解該TGF-β而得到的TGF-β分解物可增加皮膚的膠原蛋白量,進而達成本發明。
詳言之,本發明包含以下態樣。
(1)一種皮膚膠原蛋白產生促進劑,係將TGF-β及/或TGF-β分解物作為有效成分。
(2)如(1)記載之皮膚膠原蛋白產生促進劑,其中,該TGF-β分解物係將TGF-β以蛋白質分解酵素分解而得到。
(3)如(2)記載之皮膚膠原蛋白產生促進劑,其中,該蛋白質分
解酵素係選自於胰蛋白酶、胰酶、胰凝乳蛋白酶、胃蛋白酶、木瓜蛋白酶、激肽釋放酶(kallikrein)、組織蛋白酶、嗜熱菌蛋白酶、V8蛋白酶中之任一種以上。
(4)如(1)~(3)中任一項記載之皮膚膠原蛋白產生促進劑,其中,該TGF-β分解物的平均分子量為500以上、8000以下。
(5)一種皮膚膠原蛋白產生促進用飲食品,係摻合如(1)~(4)中任一項記載之TGF-β及/或TGF-β分解物。
(6)一種皮膚膠原蛋白產生促進用化妝品,係摻合如(1)~(4)中任一項記載之TGF-β及/或TGF-β分解物。
(7)一種膚質之改善方法,係利用經口攝取或塗佈該TGF-β及/或該TGF-β分解物。
(8)一種膚質之改善方法,係利用每1天經口攝取該TGF-β及/或該TGF-β分解物10μg以上、或是塗佈該TGF-β及/或該TGF-β分解物使其為0.001~2重量%。
(9)一種皮膚膠原蛋白產生促進方法,係包含投予TGF-β及/或TGF-β分解物。
(10)如(9)記載之皮膚膠原蛋白產生促進方法,其中,該TGF-β分解物係將TGF-β以蛋白質分解酵素分解而得到。
(11)如(10)記載之皮膚膠原蛋白產生促進方法,其中,該蛋白質分解酵素係選自於胰蛋白酶、胰酶、胰凝乳蛋白酶、胃蛋白酶、木爪蛋白酶、激肽釋放酶、組織蛋白酶、嗜熱菌蛋白酶、V8蛋白酶中之任一種以上。
(12)如(9)~(11)中任一項記載之皮膚膠原蛋白產生促進方法,其中,該TGF-β分解物的平均分子量為500以上、8000以下。
(13)一種皮膚劣化防止或改善方法,係包含投予TGF-β及/或TGF-β分解物。
(14)如(13)記載之皮膚劣化防止或改善方法,其中,該TGF-β分解物係將TGF-β以蛋白質分解酵素分解而得到。
(15)如(14)記載之皮膚劣化防止或改善方法,其中,該蛋白質分解酵素係選自於胰蛋白酶、胰酶、胰凝乳蛋白酶、胃蛋白酶、
木瓜蛋白酶、激肽釋放酶、組織蛋白酶、嗜熱菌蛋白酶、V8蛋白酶中之任一種以上。
(16)如(13)~(15)中任一項記載之皮膚劣化防止或改善方法,其中,該TGF-β分解物的平均分子量為500以上、8000以下。
(17)一種皮膚劣化防止或是改善劑,係將TGF-β及/或TGF-β分解物作為有效成分。
(18)如(17)記載之皮膚劣化防止或是改善劑,其中,該TGF-β分解物係將TGF-β以蛋白質分解酵素分解而得到。
(19)如(18)記載之皮膚劣化防止或是改善劑,其中,該蛋白質分解酵素係選自於胰蛋白酶、胰酶、胰凝乳蛋白酶、胃蛋白酶、木瓜蛋白酶、激肽釋放酶(kallikrein)、組織蛋白酶、嗜熱菌蛋白酶、V8蛋白酶中之任一種以上。
(20)如(17)~(19)中任一項記載之皮膚劣化防止或是改善劑,其中,該TGF-β分解物的平均分子量為500以上、8000以下。
(21)一種皮膚劣化防止或改善用飲食品,係摻合如(17)~(20)中任一項記載之TGF-β及/或TGF-β分解物。
(22)一種皮膚劣化防止或改善用化妝品,係摻合如(17)~(20)中任一項記載之TGF-β及/或TGF-β分解物。
(23)一種純粹為美容目的之膚質的改善方法,係利用經口攝取或塗佈該TGF-β及/或該TGF-β分解物。
(24)一種純粹為美容目的之膚質的改善方法,係利用每1天經口攝取該TGF-β及/或該TGF-β分解物10μg以上、或是塗佈該TGF-β及/或該TGF-β分解物使其為0.001~2重量%。
根據本發明,可提供一種將TGF-β及/或TGF-β分解物作為有效成分的皮膚膠原蛋白產生促進劑、皮膚膠原蛋白產生促進用飲食品及皮膚膠原蛋白產生促進用化妝品。本發明的皮膚膠原蛋白產生促進劑、皮膚膠原蛋白產生促進用飲食品及皮膚膠原蛋白產生促進用化妝品,具有促進皮膚之膠原蛋白產生的作用,對於皮
膚之皺紋或鬆弛、乾燥感或肌膚粗糙之預防或治療為有用。
本發明之皮膚膠原蛋白產生促進劑的特徵在於:將TGF-β及/或將TGF-β以胃蛋白酶或胰酶等之蛋白質分解酵素分解而得到的TGF-β分解物作為有效成分。本發明的TGF-β無論是來自何者均可使用。例如,來自人與牛的TGF-β,其基因序列已經明瞭,可利用基因重組生產,但本發明中,亦可使用藉由基因工程手法生產的TGF-β。又,TGF-β較大量地包含於牛初乳中,亦可為自乳汁中回收者。再者,TGF-β亦可自細胞培養的培養液中回收,也可使用來自於如前述的細胞者。例如,關於來自於乳的TGF-β,可根據公知的方法(例如,參照J.Protein Chem.,vol.10,p565-575,1991)而製造,藉由從生乳或奶粉、脫脂乳、還原乳或是其他加工乳,適當組合加熱處理、加鹽處理、乙醇處理、離子交換層析或膠體過濾層析等之各種層析處理、以及超過濾處理而進行,可得到TGF-β。
TGF-β分解物,亦可使用將TGF-β以胰蛋白酶、胰酶、胰凝乳蛋白酶、胃蛋白酶、木瓜蛋白酶、激肽釋放酶、組織蛋白酶、嗜熱菌蛋白酶、V8蛋白酶等之蛋白質分解酵素限定分解成平均分子量8,000以下的胜肽混合物。
但是,平均分子量的下限為500以上較為理想。例如,TGF-β分解物的平均分子量為500以上8000以下、1500以上8000以下、2500以上8000以下、3500以上8000以下、4500以上8000以下、5500以上8000以下、6500以上8000以下、7500以上8000以下、500以上7500以下、1500以上7500以下、2500以上7500以下、3500以上7500以下、4500以上7500以下、5500以上7500以下、6500以上7500以下、500以上6500以下、1500以上6500以下、2500以上6500以下、3500以上6500以下、4500以上6500以下、
5500以上6500以下、500以上5500以下、1500以上5500以下、2500以上5500以下、3500以上5500以下、4500以上5500以下、500以上4500以下、1500以上4500以下、2500以上4500以下、3500以上4500以下、500以上3500以下、1500以上3500以下、2500以上3500以下、500以上2500以下、1500以上2500以下、或是500以上1500以下。
本發明的皮膚膠原蛋白產生促進劑,藉由經口投予或塗佈而發揮皮膚膠原蛋白產生促進效果。在經口投予本發明的皮膚膠原蛋白產生促進劑時,亦可將作為有效成分的TGF-β或TGF-β分解物維持原本的狀態而使用,但也可根據常法,製劑化為粉劑、顆粒劑、錠劑、膠囊劑、飲用劑等之口服劑而使用。在本發明中,粉劑、顆粒劑、錠劑、膠囊劑等之口服劑,例如,係使用澱粉、乳糖、白糖、甘露醇、羧甲基纖維素、玉米澱粉、無機鹽類等之賦形劑,藉由常法而進行製劑化。該種類的製劑中,除該賦形劑以外,亦可適當使用黏結劑、崩解劑、界面活性劑、潤滑劑、流動性促進劑、著色料、香料等之醫藥品添加物。更具體而言,作為黏結劑,例如,可舉出澱粉、糊精、***膠、明膠、羥丙澱粉、羧甲基纖維素鈉、甲基纖維素、結晶纖維素、乙基纖維素、聚乙烯吡咯烷酮。又,作為崩解劑,例如,可舉出澱粉、羥丙澱粉、羧甲基纖維素、羧甲基纖維素鈉、交聯羧甲基纖維素鈉、結晶纖維素等。作為界面活性劑,可舉出大豆卵磷脂、蔗糖脂肪酸酯等;作為潤滑劑,可舉出滑石、蠟、蔗糖脂肪酸酯、氫化植物油等;作為流動性促進劑,可舉出無水矽酸、乾燥氫氧化鋁、矽酸鎂等。
再者,也可將該等之TGF-β或TGF-β分解物維持原樣或製劑化後,摻合至營養劑或飲食品等。又,與維他命C等之自以往據認為具有有效產生膠原蛋白的作用之成分一起摻合TGF-β或TGF-β分解物的話,可期待更進一步之皮膚膠原蛋白產生促進作用。再者,由於TGF-β或TGF-β分解物對於熱比較穩定,故可將
包含TGF-β或TGF-β分解物的原料在如通常實施的條件加熱殺菌。
在塗佈本發明的皮膚膠原蛋白產生促進劑時,根據其使用目的,可藉由摻合於通常使用之公知的成分而調製成液劑、固體製劑、半固體製劑等之各種劑型,較理想之組成物可舉出軟膏、凝膠、乳霜、噴霧劑、貼附劑、乳液、粉末等。例如,藉由將本發明的皮膚膠原蛋白產生促進劑混合於凡士林等之碳氫化物、硬脂醇、肉豆蔻酸異丙酯等之高級脂肪酸低級烷基酯、羊毛脂等之動物性油脂、甘油等之多元醇、甘油脂肪酸酯、單硬脂酸、聚乙二醇等之界面活性劑、無機鹽、蠟、樹脂、水、以及視需要混合於對羥基苯甲酸甲酯、對羥基苯甲酸丁酯等之保存劑,可製造皮膚膠原蛋白產生促進用化妝品或醫藥品。
本發明的皮膚膠原蛋白產生促進劑利用經口投予的有效量,根據其製造形態、投予方法、使用目的、以及應用該皮膚膠原蛋白產生促進劑的患者之年齡、體重、病狀而適當規定,雖不一定,但若根據使用大鼠的動物實驗之結果,可得知為了展現皮膚膠原蛋白產生促進作用,若大鼠體重每1kg攝取10μg以上的TGF-β及/或TGF-β分解物,可期待其效果。因此,根據外插法時,通常成人每一人一天攝取10μg以上的TGF-β及/或TGF-β分解物的話,可期待其效果,故只要可確保該TGF-β及/或TGF-β分解物需要量而摻合於飲食品,或者,作為醫藥投予即可。再者,投予視需要亦可分成一天數次而進行。
本發明的皮膚膠原蛋白產生促進劑利用塗佈的有效量,根據劑型而不同,但將應用的組成物總量作為基準,較理想之樣態為使TGF-β及/或TGF-β分解物為0.001~2重量%而摻合。但是,如沐浴劑在使用時稀釋者,更可增加摻合量。
以下舉實施例及試驗例而詳細地說明本發明,但該等僅單純例示本發明的實施態樣,本發明並非限定於該等。
將填充有S瓊脂糖凝膠(S-Sepharose)3,000g的管柱以去離子水充分清洗,通入脫脂乳10,000L,且以去離子水充分清洗後,以0.1~1.0M之氯化鈉的直線濃度梯度溶離。然後,將包含TGF-β的溶離分離物再度以苯基S瓊脂糖凝膠疏水性管柱層析分離。並且,將該分離物採用HPLC系統以C4及C8逆相層析、膠體過濾層析依序處理,得到412mg的TGF-β(分離物A)。再者,如前述進行而得到的TGF-β,可直接作為皮膚膠原蛋白產生促進劑使用。
使實施例1所得到的分離物A25mg懸浮於水100ml中,加入胰酶使最終濃度為1%,並於37℃進行5分鐘至6小時的酵素處理。然後,在90℃加熱處理5分鐘,使酵素失活後,進行冷凍乾燥,得到TGF-β分解物24mg(分離物B、C、D)。再者,如前述而得到的TGF-β分解物之平均分子量,B為約8,000,C為約500,D為約300。分離物B、C可直接作為皮膚膠原蛋白產生促進劑使用。
對於實施例1所得到的分離物A及實施例2所得到的分離物B至D,藉由利用大鼠的動物實驗而調查膠原蛋白產生促進作用。將7週齡之威斯特(Wistar)系雄性大鼠分成生理食鹽水投予群組(控制群組)、大鼠體重每1kg投予實施例1所得到的分離物A 10μg的群組(A-1群組)、大鼠體重每1kg投予實施例1所得到的分離物A 100μg的群組(A-2群組)、大鼠體重每1kg投予實施例2所得到的分離物B至D 10μg的群組(B-1~D-1群組)、大鼠體重每1kg
投予實施例2所得到的分離物B至D 100μg的群組(B-2~D-2群組)之9個試驗群組(n=6),且每天1次各別以胃管經口投予並飼育10週。關於皮膚的膠原蛋白量,將大鼠的真皮依照林尼(Nimni)等人的方法(參照Arch.Biochem.Biophys.,292頁,1967年)處理後,測定包含於可溶性分離物的羥脯胺酸量。羥脯胺酸,為僅包含於膠原蛋白之特殊的胺基酸,佔構成膠原蛋白的全部胺基酸之約10%,故可推定膠原蛋白量(參照淺野隆司等人,Bio Industory,12頁,2001年)。其結果示於表1。
該結果為10週後的可溶性分離物中羥脯胺酸量,相較於控制群組,全部的試驗群組均顯示顯著的高值。由此可知:TGF-β及平均分子量為500以上8000以下的TGF-β分解物有皮膚膠原蛋白產生促進作用,表示作為皮膚膠原蛋白產生促進劑有用。又,可知:該皮膚膠原蛋白產生促進作用於大鼠體重每1kg投予TGF-β或TGF-β分解物最低10μg的情況中可確認。
對於實施例1所得到的分離物A及實施例2所得到的分離物B,藉由利用正常人纖維母細胞株[從白人女性的皮膚採取的CCD45SK(ATCCRL 1506)]的實驗而調查皮膚膠原蛋白產生促進
作用。使用含10容量%之胎牛血清(以下簡稱為FBS)之改進的伊格爾培養基(modified Eagle medium,MEM、10-101、大日本製藥公司製),將正常人纖維母細胞株以4×104個/井/0.4ml而接種於24井培養盤,在5%二氧化碳、飽和水蒸氣下,於37℃培養24小時後,更換為含0.6容量%之FBS的MEM培養基。然後,使實施例1所得到的分離物A及實施例2所得到的分離物B以0.1容量%而添加至各井(n=6),且於培養24小時後,添加β-胺丙腈50μg/ml、氚-L-脯胺酸1μCi/ml,並培養24小時而得到培養液。將利用如前述方式而得到的培養液,依照韋伯斯特(Webster)等人的方法(參照Analytical Biochemistry,220頁,1979年)分離膠原蛋白分離物,並測定被吸收至膠原蛋白分離物的放射能。再者,作為對照,不添加TGF-β及TGF-β分解物而進行同樣的試驗。其結果示於表2。
根據前述,相較於未添加TGF-β及TGF-β分解物的群組(對照),添加TGF-β及TGF-β分解物後的群組均展現2倍以上的膠原蛋白產生促進能力。因此可知:TGF-β及TGF-β分解物會作用於皮膚纖維母細胞,有促進膠原蛋白產生的作用,且表示作為皮膚膠原蛋白產生促進劑有用。
利用常法製造表3所示之摻合的皮膚膠原蛋白產生促進用飲料。製造的飲料風味良好,即令於常溫保存1年風味也不會變差,且沒有沉澱等之問題。
利用常法製作表4所示之摻合的麵糰(dough),且於成形後,進行烘培而製造皮膚膠原蛋白產生促進用餅乾。
利用常法製造表5所示之摻合的皮膚膠原蛋白產生促進劑。
利用常法製造表6所示之摻合的化妝水。
利用常法製造表7所示之摻合的乳霜。
使用實施例6所得到的化妝水及實施例7所得到的乳霜,進行實際使用試驗。作為比較品,除了TGF-β及TGF-β分解物以外,係使用與實施例6及7相同的摻合物。將確認有臉部之鬆弛或小細紋之具有乾燥肌膚的成人女性20人,每10人各別隨機地分成2個群組(E、F群組),而且,將確認手部肌膚粗糙之女性20人,每10人各別隨機地分成2個群組(G、H群組),在E群組的臉部塗佈本發明品的化妝水2g,在F群組的臉部塗佈比較品的化妝水2g,在G群組的手指塗佈本發明品的乳霜2g,在H群組的手指塗佈比較品的乳霜2g,1天2次各與通常之使用狀態同樣地塗佈10天。其結果示於表8。
根據表8,可明確得知在使用實施例品6之化妝水、實施例品7之乳霜的E群組、G群組中,相較於使用比較品之化妝水、乳霜的F群組、H群組,特別是對於乾燥感或肌膚粗糙展現顯著的改善效果。
Claims (2)
- 一種轉型生長因子β分解物的用途,係於製造預防或治療皮膚之皺紋、鬆弛、乾燥感、肌膚粗糙之皮膚膠原蛋白產生促進劑時使用將轉型生長因子β以胰酶分解而得之平均分子量為500以上、8000以下的轉型生長因子β分解物,且該轉型生長因子β分解物係利用經口攝取。
- 如申請專利範圍第1項之轉型生長因子β分解物之用途,係利用每1天經口攝取該轉型生長因子β分解物10μg以上。
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