TW201600104A - 含有環狀二肽之組成物 - Google Patents
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- TW201600104A TW201600104A TW103144245A TW103144245A TW201600104A TW 201600104 A TW201600104 A TW 201600104A TW 103144245 A TW103144245 A TW 103144245A TW 103144245 A TW103144245 A TW 103144245A TW 201600104 A TW201600104 A TW 201600104A
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Abstract
本發明為將含有選自由環色胺醯基酪胺酸、環甘油基酪胺酸、環脯胺醯基酪胺酸、環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環離胺醯基酪胺酸、環組胺醯基酪胺酸、環丙胺醯基酪胺酸、環麩胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸、環蘇胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環麩醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群的酪胺酸之環狀二肽或其鹽,分別以特定量來含有之含有環狀二肽之組成物。本發明之含有環狀二肽之組成物具有優異之尿酸值降低作用,且有用於例如高尿酸血症或痛風等之預防或治療。
Description
本發明為關於一種含有環狀二肽之組成物。
鍵結兩個胺基酸之「二肽」以作為機能性物質而被注目。二肽能夠附加單體胺基酸所沒有的物理性質或嶄新的機能,並期待被作為具有胺基酸以上之應用範圍者。其中,熟知環狀二肽之二酮哌嗪具有各種生理活性,且預測在醫療.藥理領域中的需要會擴大。
例如,專利文獻1中有報告具有2,5-二酮哌嗪構造之環狀二肽具有抗憂鬱作用或改善學習欲望之作用等。且,非專利文獻1中有記載環狀二肽Cyclo(His-Pro)顯示使體溫降低,使食慾抑制等中樞神經系作用、或抑制泌乳素分泌,促進成長賀爾蒙分泌等像賀爾蒙般的作用等較多的生理活性,且也有報告環狀二肽Cyclo(Leu-Gly)顯示記憶機能改善作用,環狀二肽Cyclo(Asp-Pro)顯示脂肪嗜好性抑制作用。非專利文獻2中有報告一種環狀二肽,其具有抗菌作用或抗氧化作用。
且,非專利文獻3中有記載環狀二肽
Cyclo(Trp-Pro)具有抗癌作用,環狀二肽Cyclo(His-Pro)、Cyclo(Gly-Pro)具有抗菌作用,環狀二肽Cyclo(His-Pro)具有神經保護作用,環狀二肽Cyclo(Gly-Pro)具有記憶機能改善作用,環狀二肽Cyclo(Tyr-Pro)、Cyclo(Phe-Pro)具有作為生物性除草劑之作用。
[專利文獻1]特表2012-517998號公報
[非專利文獻1]Peptides,16(1),151-164(1995)
[非專利文獻2]生物科學與工業,60(7),454-457(2002)
[非專利文獻3]Chemical Reviews,112,3641-3716(2012)
然而,關於環狀二肽上有很多不明的機能。
本發明之課題為提供一種具有優異之尿酸值降低作用且含有環狀二肽的組成物。
本發明為關於下述〔1〕~〔3〕。
〔1〕一種含有環狀二肽之組成物,其係以滿足各個量的範圍之量來含有下述(1)~(19)中之1個或2個以上之含有酪胺酸的環狀二肽或其鹽而成,(1)環色胺醯基酪胺酸或其鹽之含量:0.08×10~0.12×105ppm(2)環甘油基酪胺酸或其鹽之含量:0.80×10~1.30×105ppm(3)環脯胺醯基酪胺酸或其鹽之含量:0.40×10~0.70×105ppm(4)環酪胺醯基甘胺酸或其鹽之含量:0.30×10~0.60×105ppm(5)環酪胺醯基酪胺酸或其鹽之含量:0.10×10~0.30×105ppm(6)環苯丙胺基酪胺酸或其鹽之含量:0.50×10~0.90×105ppm(7)環白胺醯基酪胺酸或其鹽之含量:0.70×10~1.10×105ppm(8)環離胺醯基酪胺酸或其鹽之含量:1.00×10~1.50×105ppm(9)環組胺醯基酪胺酸或其鹽之含量:0.20×10~0.40×105ppm(10)環丙胺醯基酪胺酸或其鹽之含:0.40×10~0.70×105ppm(11)環麩胺醯基酪胺酸或其鹽之含:0.10×10~0.30×105ppm(12)環纈胺醯基酪胺酸或其鹽之含量:0.10×10~
0.30×105ppm(13)環異白胺醯基酪胺酸或其鹽之含量:0.80×10~1.30×105ppm(14)環蘇胺醯基酪胺酸或其鹽之含量:0.50×10~0.90×105ppm(15)環天冬胺醯基酪胺酸或其鹽之含量:0.10×10~0.30×105ppm(16)環天冬醯胺醯基酪胺酸或其鹽之含量:0.50×10~0.90×105ppm(17)環麩醯胺醯基酪胺酸或其鹽之含量:0.30×10~0.50×105ppm(18)環精胺醯基酪胺酸或其鹽之含量:1.00×10~1.60×105ppm(19)環甲硫胺醯基酪胺酸或其鹽之含量:0.10×10~0.20×105ppm。
〔2〕一種含有環狀二肽之組成物,其係以滿足各個量的範圍之量來含有下述(1)~(19)中之1個或2個以上之含有酪胺酸的環狀二肽或其鹽而成,(1)環色胺醯基酪胺酸或其鹽之含量:0.4×10-4~0.7×10mg/100mL(2)環甘油基酪胺酸或其鹽之含量:4.0×10-4~8.0×10mg/100mL(3)環脯胺醯基酪胺酸或其鹽之含量:2.0×10-4~4.0×10mg/100mL
(4)環酪胺醯基甘胺酸或其鹽之含量:2.0×10-4~4.0×10mg/100mL(5)環酪胺醯基酪胺酸或其鹽之含量:0.8×10-4~2.0×10mg/100mL(6)環苯丙胺基酪胺酸或其鹽之含量:3.0×10-4~5.0×10mg/100mL(7)環白胺醯基酪胺酸或其鹽之含量:4.0×10-4~7.0×10mg/100mL(8)環離胺醯基酪胺酸或其鹽之含量:5.0×10-4~9.0×10mg/100mL(9)環組胺醯基酪胺酸或其鹽之含量:1.0×10-4~3.0×10mg/100mL(10)環丙胺醯基酪胺酸或其鹽之含量:2.0×10-4~4.0×10mg/100mL(11)環麩胺醯基酪胺酸或其鹽之含量:1.0×10-4~2.0×10mg/100mL(12)環纈胺醯基酪胺酸或其鹽之含量:1.0×10-4~2.0×10mg/100mL(13)環異白胺醯基酪胺酸或其鹽之含量:4.0×10-4~7.0×10mg/100mL(14)環蘇胺醯基酪胺酸或其鹽之含量:3.0×10-4~5.0×10mg/100mL(15)環天冬胺醯基酪胺酸或其鹽之含量:1.0×10-4~2.0×10mg/100mL
(16)環天冬醯胺醯基酪胺酸或其鹽之含量:3.0×10-4~5.0×10mg/100mL(17)環麩醯胺醯基酪胺酸或其鹽之含量:1.0×10-4~3.0×10mg/100mL(18)環精胺醯基酪胺酸或其鹽之含量:6.0×10-4~1.0×102mg/100mL(19)環甲硫胺醯基酪胺酸或其鹽之含量:0.7×10-4~2.0×10mg/100mL。
〔3〕一種含有環狀二肽之組成物,其係以滿足各個量的範圍之量來含有下述(1)~(19)中之1個或2個以上之含有酪胺酸的環狀二肽或其鹽而成,(1)環色胺醯基酪胺酸或其鹽之含量:0.0008~1.2重量%(2)環甘油基酪胺酸或其鹽之含量:0.008~13重量%(3)環脯胺醯基酪胺酸或其鹽之含量:0.004~7重量%(4)環酪胺醯基甘胺酸或其鹽之含量:0.003~6重量%(5)環酪胺醯基酪胺酸或其鹽之含量:0.001~3重量%(6)環苯丙胺基酪胺酸或其鹽之含量:0.005~9重量%(7)環白胺醯基酪胺酸或其鹽之含量:0.007~11重量%(8)環離胺醯基酪胺酸或其鹽之含量:0.01~15重量%(9)環組胺醯基酪胺酸或其鹽之含量:0.002~4重量%(10)環丙胺醯基酪胺酸或其鹽之含量:0.004~7重量%(11)環麩胺醯基酪胺酸或其鹽之含量:0.001~3重量%(12)環纈胺醯基酪胺酸或其鹽之含量:0.001~3重量%(13)環異白胺醯基酪胺酸或其鹽之含量:0.008~13重量%
(14)環蘇胺醯基酪胺酸或其鹽之含量:0.005~9重量%(15)環天冬胺醯基酪胺酸或其鹽之含量:0.001~3重量%(16)環天冬醯胺醯基酪胺酸或其鹽之含量:0.005~9重量%(17)環麩醯胺醯基酪胺酸或其鹽之含量:0.003~5重量%(18)環精胺醯基酪胺酸或其鹽之含量:0.01~16重量%(19)環甲硫胺醯基酪胺酸或其鹽之含量:0.001~2重量%。
本發明之含有環狀二肽的組成物能夠達到具有優異之尿酸值降低作用這種優異效果。
[圖1]圖1是表示Cyclo(Tyr-Gly)與直鏈二肽之Tyr-Gly、Gly-Tyr、胺基酸之Tyr的黃嘌呤氧化脢阻礙率(%)之圖。
[圖2]圖2是表示探討對高尿酸血症小鼠的含有酪胺酸之環狀二肽的血清尿酸值降低作用結果之圖。
[圖3]圖3是表示探討對高尿酸血症小鼠的含有酪胺酸之環狀二肽隻黃嘌呤氧化脢(XO)活性抑制作用結果之圖。上圖表示肝臟中的XO活性,下圖表示血清中的XO活性之圖。
[圖4]圖4是表示探討對高尿酸血症小鼠之大豆胜肽熱處理物以及大豆胜肽熱處理物中所含有的含有8種Tyr
之環狀二肽混合物之血清尿酸值降低作用結果之圖。
[圖5]圖5表示探討對於高尿酸血症小鼠之大豆胜肽熱處理物之用量所造成的血清尿酸值降低作用結果之圖。
本發明之含有環狀二肽之組成物具有下述特徵:含有選自環色胺醯基酪胺酸〔Cyclo(Trp-Tyr)〕、環甘油基酪胺酸〔Cyclo(Ser-Tyr)〕、環脯胺醯基酪胺酸〔Cyclo(Pro-Tyr)〕、環酪胺醯基甘胺酸〔Cyclo(Tyr-Gly)〕、環酪胺醯基酪胺酸〔Cyclo(Tyr-Tyr)〕、環苯丙胺基酪胺酸〔Cyclo(Phe-Tyr)〕、環白胺醯基酪胺酸〔Cyclo(Leu-Tyr)〕、環離胺醯基酪胺酸〔Cyclo(Lys-Tyr)〕、環組胺醯基酪胺酸〔Cyclo(His-Tyr)〕、環丙胺醯基酪胺酸〔Cyclo(Ala-Tyr)〕、環麩胺醯基酪胺酸〔Cyclo(Glu-Tyr)〕、環纈胺醯基酪胺酸〔Cyclo(Val-Tyr)〕、環異白胺醯基酪胺酸〔Cyclo(Ile-Tyr)〕、環蘇胺醯基酪胺酸〔Cyclo(Thr-Tyr)〕、環天冬胺醯基酪胺酸〔Cyclo(Asp-Tyr)〕、環天冬醯胺醯基酪胺酸〔Cyclo(Asn-Tyr)〕、環麩醯胺醯基酪胺酸〔Cyclo(Gln-Tyr)〕、環精胺醯基酪胺酸〔Cyclo(Arg-Tyr)〕以及環甲硫胺醯基酪胺酸〔Cyclo(Met-Tyr)〕所成之群中的1個或2個以上之環狀二肽或其鹽,該環狀二肽含有酪胺酸,且,該環狀二肽或其鹽之含量為特定量。以對水的溶解性之觀點來看,較佳為含有選自環離胺醯基酪胺酸
〔Cyclo(Lys-Tyr)〕、環異白胺醯基酪胺酸〔Cyclo(Ile-Tyr)〕、環蘇胺醯基酪胺酸〔Cyclo(Thr-Tyr)〕、環天冬胺醯基酪胺酸〔Cyclo(Asp-Tyr)〕、環天冬醯胺醯基酪胺酸〔Cyclo(Asn-Tyr)〕、環麩醯胺醯基酪胺酸〔Cyclo(Gln-Tyr)〕、環精胺醯基酪胺酸〔Cyclo(Arg-Tyr)〕以及環甲硫胺醯基酪胺酸〔Cyclo(Met-Tyr)〕所成之群的1個或2個以上之環狀二肽或其鹽,該環狀二肽或其鹽之含量為特定量者較佳。以下,有時會將前述含有酪胺酸之環狀二肽記載作本發明之環狀二肽或本發明之二酮哌嗪。且,本說明書中,只要環狀二肽中的胺基酸構成相同,此等之記載順序無論何者優先皆無妨,例如Cyclo(Trp-Tyr)與Cyclo(Tyr-Trp)是相同的環狀二肽。
本發明之環狀二肽中,只要構成胺基酸的至少1個是酪胺酸即可,例如將構成的2個胺基酸作為胺基酸A、胺基酸B時,胺基酸A的羧基與胺基酸B的胺基會脫水縮合,且具有胺基酸A的胺基與胺基酸B的羧基脫水縮合後之構造。雖然如此本發明之環狀二肽含有酪胺酸作為構成要素,且雖然詳細理由尚不明朗,例如由後述表1以及表3之對比,考慮具有相同芳香環之含有苯丙胺酸之環狀二肽並無法確認到有黃嘌呤氧化脢阻礙作用後,推測是藉由酪胺酸的酚性羥基來阻礙黃嘌呤氧化脢之活性。惟,此等之推測並非限定於本發明。
本發明之含有環狀二肽的組成物只要含有特定量之前述19個環狀二肽中之1個或2個以上的環狀二
肽或其鹽即可。且,本說明書中,有時將環狀二肽或其鹽統一單純地稱作環狀二肽。
本說明書中,環狀二肽之鹽意指前述環狀二肽之藥理學上所容許之任意的鹽(包含無機鹽以及有機鹽),有舉例如,前述環狀二肽之鈉鹽、鉀鹽、鈣鹽、鎂鹽、銨鹽、氯化氫、硫酸鹽、硝酸鹽、磷酸鹽、有機酸鹽(乙酸鹽、檸檬酸鹽、馬來酸鹽、蘋果酸鹽、草酸鹽、乳酸鹽、琥珀酸鹽、延胡索酸鹽、丙酸鹽、甲酸鹽、苯甲酸鹽、苦味酸鹽、甲苯磺酸鹽等)等。
本發明中所使用之環狀二肽能夠以該領域所習知的方法來調製。例如亦可藉由化學合成方法或酵素法、微生物發酵法來製造,亦可使直鏈胜肽進行脫水.環化反應來合成,也能夠以特開2003-252896號公報或J.Peptide Sci.,10,737-737(2004)中所記載之方法來調製。本發明中,能夠適當地使用將含有大豆胜肽之溶液熱處理後所得之處理物。
將含有大豆胜肽之溶液熱處理後所得之處理物具體來說意指例如能夠將大豆胜肽以20~500mg/mL之濃度溶解於水中,在40~150℃的條件下,加熱5分鐘~120小時所調製。對所得之處理物,亦可依據期望來進行過濾、離心分離、濃縮、超微過濾、冷凍乾燥、粉末化等處理。
環狀二肽之鹽能夠藉由該領域習知的任意方法,並由同領域技術者來輕易調製。
本發明之組成物藉由具有以特定量含有相關之環狀二肽或其鹽之特徵,能夠使該組成物阻礙黃嘌呤氧化脢之活性且抑制尿酸的生成,因此,能夠較適當地使用在需要有尿酸值降低作用之疾病中。因此,作為本發明之組成物,將前述環狀二肽或此等之鹽以本發明所規定的量來調配的組成物包含於本發明之中。
本發明中,作為需要有尿酸值降低作用之疾病,只要是降低血中的尿酸值即能看到治療效果的疾病即可,並無限定。有例示例如高尿酸血症、痛風、痛風石、急性痛風性關節炎、慢性痛風性關節炎、痛風腎、尿道結石、腎機能障礙、關節機能障礙、血管障礙等。
且,本發明之組成物,藉由本發明之環狀二肽或此等之鹽所具有的黃嘌呤氧化脢阻礙作用,在治療或預防上需要有尿酸值降低作用之疾病的症狀改善、預防中非常有用。亦即,本發明之組成物,能夠作為附上以上述疾病之預防或改善為目的之保健機能食品或健康食品,例如,能夠附上用於痛風/高尿酸血症的預防及/或改善之宗旨的表示來提供,且對於血中尿酸值較高者、在意血中尿酸值者、尿酸值較高者、在意尿酸值者、在意嘌呤體者、想預防高尿酸血症者、在意高尿酸血症者、想預防痛風者、在意痛風者等是非常有用的組成物。
本發明之組成物為以特定量含有相關之環狀二肽或其鹽者,依照該組成物的用途,舉出以下的3種型態。且,各型態中的環狀二肽或其鹽之含量能夠以習知的
方法來測定,例如能夠藉由供應至LC-MS/MS來測定。
型態1為含有前述環狀二肽或其鹽之萃取物組成物。萃取物組成物意指例如直接含有對包含前述環狀二肽或該環狀二肽之構成胺基酸的材料進行處理所調製者,或含有將該調製物以習知的方法稀釋或濃縮、醇化者之組成物,並能夠直接將其製劑化,或作為醫藥品、醫藥部外品、或飲食品(健康食品)等原材料來用。
型態1中之各環狀二肽或其鹽的含量如以下所示。
組成物中之含量較佳為0.08×10ppm以上,再較佳為0.08×102ppm以上,更佳為0.16×102ppm以上,較佳為0.12×105ppm以下,再較佳為0.12×104ppm以下,更佳為0.06×104ppm以下。
組成物中之含量較佳為0.80×10ppm以上,再較佳為0.80×102ppm以上,更佳為1.60×102ppm以上,較佳為1.30×105ppm以下,再較佳為1.30×104ppm以下,更佳為0.65×104ppm以下。
組成物中之含量較佳為0.40×10ppm以上,再較佳為0.40×102ppm以上,更佳為0.80×102ppm以上,較佳為0.70×105ppm以下,再較佳為0.70×104ppm以下,更佳為0.35×104ppm以下。
組成物中之含量較佳為0.30×10ppm以上,再較佳為0.30×102ppm以上,更佳為0.60×102ppm以上,較佳為0.60×105ppm以下,再較佳為0.60×104ppm以下,更佳為0.30×104ppm以下。
組成物中之含量較佳為0.10×10ppm以上,再較佳為0.10×102ppm以上,更佳為0.20×102ppm以上,較佳為0.30×105ppm以下,再較佳為0.30×104ppm以下,更佳為0.15×104ppm以下。
組成物中之含量較佳為0.50×10ppm以上,再較佳為0.50×102ppm以上,更佳為1.00×102ppm以上,較佳為0.90×105ppm以下,再較佳為0.90×104ppm以下,更佳為0.45×104ppm以下。
組成物中之含量較佳為0.70×10ppm以上,再較佳為0.70×102ppm以上,更佳為1.40×102ppm以上,較佳為1.10×105ppm以下,再較佳為1.10×104ppm以下,更佳為0.55×104ppm以下。
組成物中之含量較佳為1.00×10ppm以上,再較佳為1.00×102ppm以上,更佳為2.00×102ppm以上,較佳為1.50×105ppm以下,再較佳為1.50×104ppm以下,更佳為0.75×104ppm以下。
組成物中之含量較佳為0.20×10ppm以上,再較佳為0.20×102ppm以上,更佳為0.40×102ppm以上,較佳為0.40×105ppm以下,再較佳為0.40×104ppm以下,更佳為0.20×104ppm以下。
組成物中之含量較佳為0.40×10ppm以上,再較佳為0.40×102ppm以上,更佳為0.80×102ppm以上,較佳為0.70×105ppm以下,再較佳為0.70×104ppm以下,更佳為0.35×104ppm以下。
組成物中之含量較佳為0.10×10ppm以上,再較佳為0.10×102ppm以上,更佳為0.20×102ppm以上,較佳為0.30×105ppm以下,再較佳為0.30×104ppm以下,更佳為0.15×104ppm以下。
組成物中之含量較佳為0.10×10ppm以上,再較佳為0.10×102ppm以上,更佳為0.20×102ppm以上,較佳為0.30×105ppm以下,再較佳為0.30×104ppm以下,更佳為0.15×104ppm以下。
組成物中之含量較佳為0.80×10ppm以上,再較佳為0.80×102ppm以上,更佳為1.60×102ppm以上,較佳為1.30×105ppm以下,再較佳為1.30×104ppm以下,更佳為0.65×104ppm以下。
組成物中之含量較佳為0.50×10ppm以上,再較佳為0.50×102ppm以上,更佳為1.00×102ppm以上,較佳為0.90×105ppm以下,再較佳為0.90×104ppm以下,更佳為0.45×104ppm以下。
組成物中之含量較佳為0.10×10ppm以上,再較佳為0.10×102ppm以上,更佳為0.20×102ppm以上,較佳為0.30×105ppm以下,再較佳為0.30×104ppm以下,更佳為0.15×104ppm以下。
組成物中之含量較佳為0.50×10ppm以上,再較佳為0.50×102ppm以上,更佳為1.00×102ppm以上,較佳為0.90×105ppm以下,再較佳為0.90×104ppm以下,更佳為0.45×104ppm以下。
組成物中之含量較佳為0.30×10ppm以上,再較佳為0.30×102ppm以上,更佳為0.60×102ppm以上,較佳為0.50×105ppm以下,再較佳為0.50×104ppm以下更佳為0.25×104ppm以下。
組成物中之含量較佳為1.00×10ppm以上,再較佳為1.00×102ppm以上,更佳為2.00×102ppm以上,較佳為1.60×105ppm以下,再較佳為1.60×104ppm以下,更佳為0.80×104ppm以下。
組成物中之含量較佳為0.10×10ppm以上,再較佳為0.10×102ppm以上,更佳為0.20×102ppm以上,較佳為0.20×105ppm以下,再較佳為0.20×104ppm以下,更佳為0.10×104ppm以下。
此等中,型態1中之前述環狀二肽或其鹽,只要至少1種成分的含量在前述範圍內,為任何成分皆可,期望較佳為選自環甘油基酪胺酸、環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內,再較佳為選自環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內,更佳為選自環酪胺醯基酪胺酸、環苯丙胺基酪胺酸以及環白胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內,更佳為環酪胺醯基酪胺酸或其鹽之含量在前述範圍內。且,以對水的溶解性之觀點來看,期望較佳為選自環離胺醯基酪胺酸、環異白胺醯基酪胺酸、環蘇胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環麩醯胺醯基酪胺酸、環精胺醯基酪胺酸、以及
環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內。
且,作為滿足前述所舉出的各成分之含量的成分數,期望較佳為1成分以上,再較佳為3成分以上,更佳為7成分以上,更佳為11成分以上。具體來說,例如環酪胺醯基酪胺酸、環苯丙胺基酪胺酸以及環白胺醯基酪胺酸之含量在前述範圍內較佳,環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸以及環甲硫胺醯基酪胺酸之含量在前述範圍內再較佳,環甘油基酪胺酸、環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸之含量在前述範圍內更佳。
型態1中之前述環狀二肽或其鹽的含量,關於各成分如前述所示,但作為環狀二肽或其鹽的總含量較佳為8.0×10ppm以上,再較佳為8.0×102ppm以上,更佳為1.6×103ppm以上,較佳為1.0×106ppm以下,再較佳為1.4×105ppm以下,更佳為0.7×105ppm以下。
且,黃嘌呤氧化脢阻礙作用較高的環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸以及此等之鹽在型態1中的總含量較佳為1.3×10ppm以上,再較佳為1.3×102ppm以上,更佳為2.6×102ppm以上,較佳為
2.3×105ppm以下,再較佳為2.3×104ppm以下,更佳為1.15×104ppm以下。
型態1中的環狀二肽之中,黃嘌呤氧化脢阻礙作用較高的環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸以及此等之鹽所占的合計量比例,以黃嘌呤氧化脢阻礙效果之觀點來看,為5重量%以上較佳,為10重量%以上再較佳,為15重量%以上更佳。且,雖然沒有特別限定其上限,但以可溶化性能之觀點來看,為90重量%以下較佳,為60重量%以下再較佳。
且,環苯丙胺基酪胺酸與環酪胺醯基酪胺酸之重量比〔Cyclo(Tyr-Phe)/Cyclo(Tyr-Tyr)〕,以黃嘌呤氧化脢阻礙效果之觀點來看,為95/5~35/65較佳,90/10~40/60再較佳,90/10~50/50更佳。
且,環苯丙胺基酪胺酸與環酪胺醯基甘胺酸之重量比〔Cyclo(Phe-Tyr)/Cyclo(Tyr-Gly)〕,以黃嘌呤氧化脢阻礙效果之觀點來看,90/10~30/70較佳,90/10~40/60再較佳,90/10~50/50更佳。
型態1之組成物能夠例如在含有前述環狀二肽或其鹽之原料中,依期望添加溶劑、分散劑、乳化劑、緩衝劑、安定劑、賦形劑、結合劑、崩解佐劑、潤滑劑等,並根據習知之方法,製劑化成錠劑、顆粒劑、散劑、粉末劑、膠囊劑等固體劑,或一般的液劑、懸濁劑、乳劑等液劑等。此等之組成物能夠直接與水等一起服用。且,調製成能夠容易調配之形態(例如粉末形態或顆粒形態)
後,能夠作為例如醫藥品、醫藥部外品、或飲食品(健康食品)等原材料來使用。
作為型態1之組成物的具體例,能夠舉出錠劑、顆粒劑、散劑、粉末劑、膠囊劑等固體劑,或液劑、懸濁劑、乳劑等液劑。
型態2為含有前述環狀二肽或其鹽之飲料組成物。飲料組成物意指主要使用在飲用用途之組成物,且型態2中之各環狀二肽或其鹽的含量如以下所述。
組成物中之含量較佳為0.4×10-4mg/100mL以上,再較佳為0.4×10-3mg/100mL以上,更佳為0.8×10-3mg/100mL以上,較佳為0.7×10mg/100mL以下,再較佳為0.7mg/100mL以下,更佳為3.5×10-1mg/100mL以下。
組成物中之含量較佳為4.0×10-4mg/100mL以上,再較佳為4.0×10-3mg/100mL以上,更佳為8.0×10-3mg/100mL以上,較佳為8.0×10mg/100mL以下,再較佳為8.0mg/100mL以下,更佳為4.0mg/100mL以下。
組成物中之含量較佳為2.0×10-4mg/100mL以上,再較佳為2.0×10-3mg/100mL以上,更佳為4.0×10-3mg/100mL以上,較佳為4.0×10mg/100mL以下,再較佳為4.0mg/100mL以下,更佳為2.0mg/100mL以下。
組成物中之含量較佳為2.0×10-4mg/100mL以上,再較佳為2.0×10-3mg/100mL以上,更佳為4.0×10-3mg/100mL以上,較佳為4.0×10mg/100mL以下,再較佳為4.0mg/100mL以下,更佳為2.0mg/100mL以下。
組成物中之含量較佳為0.8×10-4mg/100mL以上,再較佳為0.8×10-3mg/100mL以上,更佳為1.6×10-3mg/100mL以上,較佳為2.0×10mg/100mL以下,再較佳為2.0mg/100mL以下,更佳為1.0mg/100mL以下。
組成物中之含量較佳為3.0×10-4mg/100mL以上,再較佳為3.0×10-3mg/100mL以上,更佳為6.0×10-3mg/100mL以上,較佳為5.0×10mg/100mL以下,再較佳為5.0mg/100mL以下,更佳為2.5mg/100mL以下。
組成物中之含量較佳為4.0×10-4mg/100mL以上,再較佳為4.0×10-3mg/100mL以上,更佳為8.0×10-3mg/100mL以上,較佳為7.0×10mg/100mL以下,再較佳為7.0mg/100mL以下,更佳為3.5mg/100mL以下。
組成物中之含量較佳為5.0×10-4mg/100mL以上,再較佳為5.0×10-3mg/100mL以上,更佳為1.0×10-2mg/100mL以上,較佳為9.0×10mg/100mL以下,再較佳為9.0mg/100mL以下,更佳為4.5mg/100mL以下。
組成物中之含量較佳為1.0×10-4mg/100mL以上,再較佳為1.0×10-3mg/100mL以上,更佳為2.0×10-3mg/100mL以上,較佳為3.0×10mg/100mL以下,再較佳為3.0mg/100mL以下,更佳為1.5mg/100mL以下。
組成物中之含量較佳為2.0×10-4mg/100mL以上,再較佳為2.0×10-3mg/100mL以上,更佳為4.0×10-3mg/100mL以上,較佳為4.0×10mg/100mL以下,再較佳為4.0mg/100mL以下,更佳為2.0mg/100mL以下。
組成物中之含量較佳為1.0×10-4mg/100mL以上,再較佳為1.0×10-3mg/100mL以上,更佳為2.0×10-3mg/100mL以上,較佳為2.0×10mg/100mL以下,再較佳為2.0mg/100mL以下,更佳為1.0mg/100mL以下。
組成物中之含量較佳為1.0×10-4mg/100mL以上,再較佳為1.0×10-3mg/100mL以上,更佳為2.0×10-3mg/100mL以上,較佳為2.0×10mg/100mL以下,再較佳為2.0mg/100mL以下,更佳為1.0mg/100mL以下。
組成物中之含量較佳為4.0×10-4mg/100mL以上,再較佳為4.0×10-3mg/100mL以上,更佳為8.0×10-3mg/100mL以上,較佳為7.0×10mg/100mL以下,再較佳為7.0mg/100mL以下,更佳為3.5mg/100mL以下。
組成物中之含量較佳為3.0×10-4mg/100mL以上,再較佳為3.0×10-3mg/100mL以上,更佳為6.0×10-3mg/100mL以上,較佳為5.0×10mg/100mL以下,再較佳為5.0mg/100mL以下,更佳為2.5mg/100mL以下。
組成物中之含量較佳為1.0×10-4mg/100mL以上,再較佳為1.0×10-3mg/100mL以上,更佳為2.0×10-3mg/100mL以上,較佳為2.0×10mg/100mL以下,再較佳為2.0mg/100mL以下,更佳為1.0mg/100mL以下。
組成物中之含量較佳為3.0×10-4mg/100mL以上,再較佳為3.0×10-3mg/100mL以上,更佳為6.0×10-3mg/100mL以上,較佳為5.0×10mg/100mL以下,再較佳為5.0mg/100mL以下,更佳為2.5mg/100mL以下。
組成物中之含量較佳為1.0×10-4mg/100mL以上,再較佳為1.0×10-3mg/100mL以上,更佳為2.0×10-3mg/100mL以上,較佳為3.0×10mg/100mL以下,再較佳為3.0mg/100mL以下,更佳為1.5mg/100mL以下。
組成物中之含量較佳為6.0×10-4mg/100mL以上,再較佳為6.0×10-3mg/100mL以上,更佳為1.2×10-2mg/100mL以上,較佳為1.0×102mg/100mL以下,再較佳為1.0×10mg/100mL以下,更佳為5.0mg/100mL以下。
組成物中之含量較佳為0.7×10-4mg/100mL以上,再較佳為0.7×10-3mg/100mL以上,更佳為1.4×10-3mg/100mL以上,較佳為2.0×10mg/100mL以下,再較佳為2.0mg/100mL以下,更佳為1.0mg/100mL以下。
此等之中,型態2中之前述環狀二肽或其鹽只要至少1種成分的含量在前述範圍內,為任何成分皆可,期望較佳為選自環甘油基酪胺酸、環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內,再較佳為選自環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內,更佳為選自環酪胺醯基酪胺酸、環苯丙胺基酪胺酸以及環白胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內,更佳為環酪胺醯基酪胺酸或其鹽之含量在前述範圍內。且,以對水之溶解性的觀點來看,期望較佳為選自環離胺醯基酪胺酸、環異白胺醯基酪胺酸、環蘇胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環麩醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二
肽或其鹽之含量在前述範圍內。
且,作為滿足前述所舉出的各成分之含量的成分數,期望較佳為1成分以上,再較佳為3成分以上,更佳為7成分以上,更佳為11成分以上。具體來說,例如環酪胺醯基酪胺酸、環苯丙胺基酪胺酸以及環白胺醯基酪胺酸之含量在前述範圍內較佳,環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸以及環甲硫胺醯基酪胺酸之含量在前述範圍內再較佳,環甘油基酪胺酸、環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸之含量在前述範圍內更佳。
型態2中之前述環狀二肽或其鹽的含量,關於各成分如前述所示,但作為環狀二肽或其鹽的總含量較佳為5.0×10-3mg/100mL以上,再較佳為5.0×10-2mg/100mL以上,更佳為1.0×10-1mg/100mL以上,較佳為8.0×102mg/100mL以下,再較佳為8.0×10mg/100mL以下,更佳為4.0×10mg/100mL以下。
且,黃嘌呤氧化脢阻礙作用較高的環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸以及此等之鹽在型態2中的總含量較佳為7.8×10-4mg/100mL以上,再較佳為7.8×10-3mg/100mL以上,更佳為1.56×10-2
mg/100mL以上,較佳為1.4×10mg/100mL以下,再較佳為1.4mg/100mL以下,更佳為0.7mg/100mL以下。
型態2中之環狀二肽之中,黃嘌呤氧化脢阻礙作用較高的環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸以及此等之鹽所占的合計量之比例,以黃嘌呤氧化脢阻礙效果之觀點來看,為5重量%以上較佳,10重量%以上再較佳,15重量%以上更佳。且,雖然沒有特別限定其上限,但以可溶化性能之觀點來看,為90重量%以下較佳,為60重量%以下再較佳。
且,環苯丙胺基酪胺酸與環酪胺醯基酪胺酸之重量比〔Cyclo(Tyr-Phe)/Cyclo(Tyr-Tyr)〕,以黃嘌呤氧化脢阻礙效果之觀點來看,為95/5~35/65較佳,為90/10~40/60再較佳,為90/10~50/50更佳。
且,環苯丙胺基酪胺酸與環酪胺醯基甘胺酸之重量比〔Cyclo(Phe-Tyr)/Cyclo(Tyr-Gly)〕,以黃嘌呤氧化脢阻礙效果之觀點來看,為90/10~30/70較佳,為90/10~40/60再較佳,為90/10~50/50更佳。
型態2之組成物,例如亦可在調製習知的飲料組成物時,於其原材料中混合特定量的前述環狀二肽或其鹽,再根據習知的飲料組成物之製造方法來調製,或,亦可在已製好的習知飲料組成物中,添加前述環狀二肽或其鹽至前述特定量,再以溶解及/或懸浮來調製。且,習知的飲料組成物亦可為原本就含有前述環狀二肽或其鹽者,本發明的環狀二肽只要成為特定量,即能夠適當地調
配來調製。
作為型態2之組成物的具體例,能舉出烏龍茶飲料、紅茶飲料、綠茶飲料、果汁飲料、蔬菜汁、運動飲料、等張飲料、增強水、礦泉水、舒跑水、咖啡飲料、營養飲料劑、美容飲料劑、無酒精.啤酒風味飲料等非酒精飲料、啤酒、紅酒、清酒、梅酒、氣泡酒、威士忌、白蘭地、燒酒、萊姆酒、琴酒、利口酒類等酒精飲料。且,型態2的組成物中,亦可單獨或併用抗氧化劑、香料、有機酸類、有機酸鹽類、無機酸類、無機酸鹽類、無機鹽類、色素類、乳化劑、保存料、調味料、甜味料、酸味料、膠、油、維他命、胺基酸、果汁萃取物類、野菜萃取物類、pH調整劑、品質安定劑等添加劑來調配。
型態3為含有前述環狀二肽或其鹽之食品組成物。食品組成物意指主要為了正餐或點心之攝取所使用之組成物,型態3中之各環狀二肽或其鹽的含量如以下所述。
組成物中之含量較佳為0.0008重量%以上,再較佳為0.008重量%以上,更佳為0.016重量%以上,較佳為1.2重量%以下,再較佳為0.12重量%以下,更佳為0.06重量%以下。
組成物中之含量較佳為0.008重量%以上,再較佳為0.08重量%以上,更佳為0.16重量%以上,較佳為13重量%以下,再較佳為1.3重量%以下,更佳為0.65重量%以下。
組成物中之含量較佳為0.004重量%以上,再較佳為0.04重量%以上,更佳為0.08重量%以上,較佳為7重量%以下,再較佳為0.7重量%以下,更佳為0.35重量%以下。
組成物中之含量較佳為0.003重量%以上,再較佳為0.03重量%以上,更佳為0.06重量%以上,較佳為6重量%以下,再較佳為0.6重量%以下,更佳為0.3重量%以下。
組成物中之含量較佳為0.001重量%以上,再較佳為0.01重量%以上,更佳為0.02重量%以上,較佳為3重量%以下,再較佳為0.3重量%以下,更佳為0.15重量%以下。
組成物中之含量較佳為0.005重量%以上,再較佳為0.05重量%以上,更佳為0.10重量%以上,較佳為9重量%以下,再較佳為0.9重量%以下,更佳為0.45重量%以下。
組成物中之含量較佳為0.007重量%以上,再較佳為0.07重量%以上,更佳為0.14重量%以上,較佳為11重量%以下,再較佳為1.1重量%以下,更佳為0.55重量%以下。
組成物中之含量較佳為0.01重量%以上,再較佳為0.1重量%以上,更佳為0.2重量%以上,較佳為15重量%以下,再較佳為1.5重量%以下,更佳為0.75重量%以下。
組成物中之含量較佳為0.002重量%以上,再較佳為0.02重量%以上,更佳為0.04重量%以上,較佳為4重量%以下,再較佳為0.4重量%以下,更佳為0.2重量%以下。
組成物中之含量較佳為0.004重量%以上,再較佳為0.04重量%以上,更佳為0.08重量%以上,較佳為7重量%以下,再較佳為0.7重量%以下,更佳為0.35重量%以下。
組成物中之含量較佳為0.001重量%以上,再較佳為0.01重量%以上,更佳為0.02重量%以上,較佳為3重量%以下,再較佳為0.3重量%以下,更佳為0.15重量%以下。
組成物中之含量較佳為0.001重量%以上,再較佳為0.01重量%以上,更佳為0.02重量%以上,較佳為3重量%以下,再較佳為0.3重量%以下,更佳為0.15重量%以下。
組成物中之含量較佳為0.008重量%以上,再較佳為0.08重量%以上,更佳為0.16重量%以上,較佳為13重量%以下,再較佳為1.3重量%以下,更佳為0.65重量%以下。
組成物中之含量較佳為0.005重量%以上,再較佳為0.05重量%以上,更佳為0.10重量%以上,較佳為9重量%以下,再較佳為0.9重量%以下,更佳為0.45重量%以下。
組成物中之含量較佳為0.001重量%以上,再較佳為0.01重量%以上,更佳為0.02重量%以上,較佳為3重量%以下,再較佳為0.3重量%以下,更佳為0.15重量%以下。
組成物中之含量較佳為0.005重量%以上,再較佳為0.05重量%以上,更佳為0.10重量%以上,較佳為9重量%以下,再較佳為0.9重量%以下,更佳為0.45重量%以下。
組成物中之含量較佳為0.003重量%以上,再較佳為0.03重量%以上,更佳為0.06重量%以上,較佳為5重量%以下,再較佳為0.5重量%以下,更佳為0.25重量%以下。
組成物中之含量較佳為0.01重量%以上,再較佳為0.1重量%以上,更佳為0.2重量%以上,較佳為16重量%以下,再較佳為1.6重量%以下,更佳為0.8重量%以下。
組成物中之含量較佳為0.001重量%以上,再較佳為0.01重量%以上,更佳為0.02重量%以上,較佳為2重量%以下,再較佳為0.2重量%以下,更佳為0.1重量%以下。
此等之中,型態3中之前述環狀二肽或其鹽只要至少1個成分的含量在前述範圍內,為任何成分皆可,但期望較佳為選自環甘油基酪胺酸、環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內,再較佳為選自環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內,更佳為選自環酪胺醯基酪胺酸、環苯丙胺基酪胺酸以及環白胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之
含量在前述範圍內,更佳為環酪胺醯基酪胺酸或其鹽之含量在前述範圍內。且,以對水的溶解性之觀點來看,期望較佳為選自環離胺醯基酪胺酸、環異白胺醯基酪胺酸、環蘇胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環麩醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸所成之群中之1個或2個以上的環狀二肽或其鹽之含量在前述範圍內。
且,作為滿足前述所舉出的各成分之含量的成分數,期望較佳為1成分以上,再較佳為3成分以上,更佳為7成分以上,更佳為11成分以上。具體來說例如環酪胺醯基酪胺酸、環苯丙胺基酪胺酸以及環白胺醯基酪胺酸之含量在前述範圍內較佳,環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸以及環甲硫胺醯基酪胺酸之含量在前述範圍內再較佳,環甘油基酪胺酸、環酪胺醯基甘胺酸、環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸、環纈胺醯基酪胺酸、環異白胺醯基酪胺酸、環天冬胺醯基酪胺酸、環天冬醯胺醯基酪胺酸、環精胺醯基酪胺酸以及環甲硫胺醯基酪胺酸之含量在前述範圍內更佳。
型態3中之前述環狀二肽或其鹽的含量,關於各成分如前述所示,但作為環狀二肽或其鹽的總含量,較佳為0.008重量%以上,再較佳為0.08重量%以上,更佳為0.16重量%以上,較佳為100重量%以下,再較佳為
80重量%以下,更佳為60重量%以下。
且,黃嘌呤氧化脢阻礙作用較高之環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸以及此等之鹽在型態3中之總含量較佳為0.013重量%以上,再較佳為0.13重量%以上,更佳為0.26重量%以上,較佳為23重量%以下,再較佳為17.3重量%以下,更佳為11.5重量%以下。
型態3中之環狀二肽之中,黃嘌呤氧化脢阻礙作用較高之環酪胺醯基酪胺酸、環苯丙胺基酪胺酸、環白胺醯基酪胺酸以及此等之鹽所占的合計量之比例,以黃嘌呤氧化脢阻礙效果之觀點來看,為5重量%以上較佳,10重量%以上再較佳,15重量%以上更佳。且,雖然沒有特別限定其上限,但以可溶化性能之觀點來看,為90重量%以下較佳,為60重量%以下再較佳。
且,環苯丙胺基酪胺酸與環酪胺醯基酪胺酸之重量比〔Cyclo(Tyr-Phe)/Cyclo(Tyr-Tyr)〕,以黃嘌呤氧化脢阻礙效果之觀點來看,為95/5~35/65較佳,為90/10~40/60再較佳,為90/10~50/50更佳。
且,環苯丙胺基酪胺酸與環酪胺醯基甘胺酸之重量比〔Cyclo(Phe-Tyr)/Cyclo(Tyr-Gly)〕,以黃嘌呤氧化脢阻礙效果之觀點來看,為90/10~30/70較佳,為90/10~40/60再較佳,為90/10~50/50更佳。
型態3之組成物,例如亦可在調製習知的食品組成物時,於其原材料中混合特定量之前述環狀二肽或
其鹽,再根據習知的食品組成物之製造方法來調製,且,亦可藉由在已製好的習知食品組成物中添加前述環狀二肽或其鹽至前述特定量來調製。且,習知的食品組成物亦可為原本就含有前述環狀二肽或其鹽者,本發明之環狀二肽只要成為特定量,即能夠適當地調配來調製。
作為型態3的組成物之具體例,能夠舉出真空食品、調味料(例如醬汁、湯汁、沙拉醬、美乃滋、奶油)、西點(例如麵包、蛋糕、餅乾、小餅乾等燒烤西點、口香糖、巧克力、糖果)、點心(例如果凍、優格、冰淇淋)。且,飲食品的形態並無特別限定,只要是容易攝取的形態,亦可為固態、粉末、液體、膠體狀、漿狀等之任一者。亦可調配於使用肝臟類、白子、蝦子、沙丁魚、鰹魚等海鮮類等包含較多嘌呤體之食材的料理、餃子、馬鈴薯燉肉、滷肉、漢堡等搭配啤酒風味飲料之料理中來使用。
本發明之組成物能夠以因應其形態之適當的方法來攝取。該攝取方法只要是本發明之環狀二肽或其鹽能夠在血液循環中移行即可,並無特別限定。且,本說明書中,攝取意指用來作為包含攝取、服用或飲用之全型態。
本發明之組成物的攝取量會依照其形態、投予方法、使用目的以及該組成物的攝取對象之患者或罹患疾病之寵物的年齡、體重、症狀而適當地設定,並非一定。例如作為本發明中之本發明環狀二肽或其鹽的有效人
類攝取量,以體重50kg的人類來說,每1天較佳為0.2mg以上,再較佳為2mg以上,更佳為20mg以上,較佳為10g以下,再較佳為5g以下,更佳為2g以下。且,投予為在所期望的投予量範圍內,亦可在1日內以單次或分成數次來進行。投予期間亦為任意。且,於此,本發明之環狀二肽或其鹽的有效人類攝取量意指在人類中表示有效的效果之環狀二肽或其鹽的合計攝取量,且環狀二肽的種類並無特別限定。
本說明書中,本發明之組成物的攝取對象較佳意指必須使血中尿酸值降低之人類,但亦可為牛、馬、羊等家畜動物、狗、貓、兔子等寵物動物、或小鼠、大白鼠、天竺鼠、猴等實驗動物。
以下,示出實施例來具體說明本發明,但本發明並不限定於下述實施例。
環狀二肽為使用神戶天然物化學公司所合成者。黃嘌呤、羧甲基纖維素鈉鹽(CMC-Na)、酪胺酸(Tyr)、甲酸(管柱層析用特製試藥)、甲醇(高性能液相層析儀用)為使用nacalai tesque公司製;異嘌呤醇、氧嗪酸鉀鹽為使用和光純藥公司製;黃嘌呤氧化脢為使用東洋紡公司製;黃嘌呤氧化脢分析試劑組為使用Cayman Chemical Company公司
製;L-Tyrosylglycine為使用Santa Cruz Biotechnology公司製;Glycyl-L-tyrosine為使用Sigma-Aldrich公司製;組織蛋白質萃取試藥(T-PER)、蛋白分解酶抑制劑混合試劑組、Pierce BCA蛋白質定量試劑組、聚苯乙烯製黑色96孔盤為使用Thermo Scientific公司製;肝素鈉鹽為使用持田製藥公司製;普伐他丁鈉鹽為使用SIGMA公司製;大豆胜肽(HINUTE AM)為使用不二製油公司製。
在之後的試驗例中,數據以平均值±標準誤差來表示。統計學的檢定是:在試驗例1中使用Student’s t-test,在其他試驗例中以one-way ANOVA來進行分散分析之後,使用Dunnet’s test來實施多重比較檢定。結果中之「*」為p<0.05,「#」為p<0.1之具有意義的差。且,此等之解析全部使用SPSS for Windows(登錄商標)release 17.0(SPSS公司製)來實施。
針對210種的環狀二肽、直鏈的二肽之Tyr-Gly、Gly-Tyr以及胺基酸Tyr,探討於in vitro中之黃嘌呤氧化脢(XO)阻礙作用。
具體來說,於96孔盤的各個孔中置入溶解於pH7.5的磷酸緩衝液(PBS)之4U/L黃嘌呤氧化脢(XO)75μL,添加5μL之樣本溶液使胜肽或胺基酸相對於
XO最終濃度成為特定濃度,混合5分鐘(胜肽或胺基酸的最終濃度為50~500μM)。之後,添加溶解於PBS之250μM的黃嘌呤溶液20μL,使用分光光度計(Synegy HT,Bio Tek公司製)測定30分鐘後的吸光度。各濃度下的XO阻礙率(%)以下述之計算式算出,求出XO阻礙活性(IC50值)。表1中表示12種類的含有Tyr之環狀二肽之黃嘌呤氧化脢阻礙活性(IC50值),表2表示8種類的含有Tyr之環狀二肽在100Mm中的黃嘌呤氧化脢阻礙率(%),表3表示20種類的含有Phe之環狀二肽的黃嘌呤氧化脢阻礙活性(IC50值)。且,作為陽性對照組為利用習知的尿酸值降低劑之異嘌呤醇(IC50值:12.5μM)。
A:添加酵素且無添加樣本之群在295nm中的吸光度
B:無添加酵素且無添加樣本之群在295nm中的吸光度
C:添加酵素且添加樣本之群在295nm中的吸光度
D:無添加酵素且添加樣本之群在295nm中的吸光度。
由表1、表2可得知,含有Tyr之環狀二肽具有XO阻礙活性,由表3可得知將Tyr置換成Phe後,XO阻礙活性會減弱。
且,針對Cyclo(Tyr-Gly)、直鏈二肽的Tyr-Gly、Gly-Tyr、胺基酸Tyr,也同樣地測定XO阻礙率(%)。將結果表示於圖1。
由圖1可得知藉由環狀化會表現XO阻礙活性,並暗示環狀二肽是相當重要的。
探討高尿酸血症模型動物中,環狀二肽所造成的血清尿酸值之降低作用。
使用動物是自日本Clea公司購入的雄性7週歲之BALBc小鼠,經1週的馴養期間之後,供給於實驗。動物是在具有空調設備的飼養室(溫度23.5±1.0℃,濕度55±10RH%,換氣次數12~15次/小時,照明7:00~19:00/天)中飼養。馴養期間中使其自由地攝取市售飼料(CE-2,日本Clea公司製)以及蒸餾水。
氧嗪酸是藉由阻礙尿酸的代謝酵素之尿酸分解酶,而使血中尿酸值上昇之物質。於此,藉由投予氧嗪酸鉀鹽(PO),來製作高尿酸血症模型動物(參照Planta Med 2009;75:302-306)。於以下的6群進行探討。1)正常群(Normal群,沒有負擔氧嗪酸),
2)PO投予群(PO群,有負擔氧嗪酸),3)PO+異嘌呤醇1mg/kg投予群(PO+AL群),4)PO+Cyclo(Tyr-Gly)10mg/kg投予群(PO+CTG 10群),5)PO+Cyclo(Tyr-Gly)30mg/kg投予群(PO+CTG 30群),6)PO+Cyclo(Tyr-Gly)100mg/kg投予群(PO+CTG 100群),(各群n=6~8)。
有投予PO的全部之群中,以250mg/kg分別於腹腔內投予懸浮於0.5% CMC-Na水溶液之PO,對Normal群分別於腹腔內投予0.5% CMC-Na水溶液。接著,在1小時後,分別對PO+異嘌呤醇投予群以經口投予1mg/kg之異嘌呤醇,分別對PO+Cyclo(Tyr-Gly)投予群以經口投予10、30、100mg/kg之Cyclo(Tyr-Gly),分別對Normal群以經口投予蒸餾水。自PO投予2小時後,於麻醉下以腹部大靜脈進行採血,放血後採取肝臟。採血後的血液於室溫下靜置45分鐘後,以8000rpm進行10分鐘的離心,回收血清。且,血清以及肝臟到實施測定為止是保存在-80℃下。
血清中尿酸值是使用7180臨床分析裝置(日立High-Technologies公司製)來進行測定。將結果表示於圖2。
接下來,將小鼠的肝臟加入包含冰凍過的蛋白分解酶抑制劑混合劑、與EDTA之組織蛋白質萃取試藥(T-PER)的混合物中,均勻化後,以15000rpm,4℃下離心15分鐘,將回收後的上清供給於黃嘌呤氧化脢(XO)活
性之測定。肝臟以及血清中的XO活性是使用黃嘌呤氧化脢分析試劑組、聚苯乙烯製黑色96孔盤來測定。具體來說,添加50μL之XO標準樣本、肝臟樣本、或血清樣本之後,添加50μL之分析用溶液與Detector與HRP以98/1/1(質量比)所混合的分析用混合劑。避光下使其於37℃下反應45分鐘之後,使用分光光度計(Synegy HT,Bio Tek公司製)來測定激發波長為520-550nm、發光波長為585-595nm下的螢光。血清中XO活性是以mU/mL來表示,肝臟中XO活性是用使用Pierce BCA蛋白質定量試劑組所測定之蛋白質濃度的定量結果,並以mU/mg來表示。將結果表示於圖3。
由圖2可得知,Cyclo(Tyr-Gly)具有隨著用量改變的尿酸值降低作用,Cyclo(Tyr-Gly)30、100mg/kg投予群與異嘌呤醇投予群同樣地,對於PO群表示具有有意義差的效果。且,由圖3可得知,Cyclo(Tyr-Gly)100mg/kg投予群與異嘌呤醇1mg/kg投予群同樣地會抑制肝臟以及血清中的黃嘌呤氧化脢活性。
與試驗例2同樣地,使用高尿酸血症模型動物來探討大豆胜肽熱處理物之血清尿酸值的降低作用。具體來說,使用動物與試驗例2同樣地準備以下5群來進行探討。1)正常群(Normal群,沒有負擔氧嗪酸),
2)PO投予群(PO群,有負擔氧嗪酸),3)PO+異嘌呤醇1mg/kg投予群(PO+AL群),4)PO+大豆胜肽熱處理物2g/kg投予群,5)PO+含有8種Tyr之環狀二肽混合物11mg/kg投予群(各群n=6~7)。
對於前述各群,與試驗例2同樣地,進行投予以及採血來測定血清中的尿酸值。將結果表示於圖4。且,環狀二肽8種混合物是使用:用Cyclo(Ser-Tyr)、Cyclo(Tyr-Gly)、Cyclo(Tyr-Tyr)、Cyclo(Phe-Tyr)、Cyclo(Leu-Tyr)、Cyclo(Val-Tyr)、Cyclo(Ile-Tyr)以及Cyclo(Asn-Tyr)之合成品,使其成為大豆胜肽熱處理物中所含有的量來混合、調製者。
且,大豆胜肽之熱處理物是使用:將大豆胜肽(HINUTE AM,不二製油公司製)以200mg/mL之濃度溶解於蒸餾水中,並於132℃下加熱3小時後再凍結乾燥所得者。將大豆胜肽熱處理物之環狀二肽含量供給於LC-MS/MS並根據下述條件來測定。惟,Cyclo(Tyr-Cys)是由於標準品在水溶液中不安定,故無法測定出。將結果表示於表4。
LC裝置 SHIMADZU UFLC XR
管柱 Agilent technologies Zorbax SB-AQ 1.8μm 2.1×150mm
管柱溫度 40℃
移動相 A:0.1%甲酸,B:甲醇之梯度分析
流速 0.2mL/min
注入量 2μL
檢出器 AB Sciex 4000 Q TRAP-Turbo Spray(ESI)-Scheduled MRM(multiple reaction monitoring)
由表4以及圖4可得知大豆胜肽熱處理物含有本發明之環狀二肽,且具有優異之血中尿酸值降低作用。
試驗例4(對於高尿酸血症小鼠之大豆胜肽熱處理物的有效量之探討)
與試驗例3同樣地,使用高尿酸血症模型動物探討大豆胜肽熱處理物之用量所造成的血清尿酸值之降低作用。具體來說,使用動物與試驗例2同樣地準備以下6群來進行探討。1)正常群(Normal群,沒有負擔氧嗪酸),2)PO投予群(PO群,有負擔氧嗪酸),3)PO+異嘌呤醇1mg/kg投予群(PO+AL群),4)PO+大豆胜肽熱處理物200mg/kg投予群,5)PO+大豆胜肽熱處理物400mg/kg投予群,6)PO+大豆胜肽熱處理物800mg/kg投予群(各群n=5~6)。
對於前述各群,與試驗例2同樣地,進行投予以及採血來測定血清中的尿酸值。將結果表示於圖5。
由圖5可得知,藉由以800mg/kg投予大豆胜肽熱處理物,認為對於高尿酸血症模型小鼠之尿酸值為有異意的差,且有效。
本發明之環狀二肽,以來自食品的材料也能夠調製,且為具有能夠輕鬆地服用之安心感的物質之觀點來看,具有與有副作用之虞的異嘌呤醇相異之優點。本發明之環狀二肽會隨著使用量而有相異的作用程度,但觀察到依照其量會有與異嘌呤醇相等或較緩和的尿酸值降低作用。由於尿酸值的降低必須經過長期,且與飲食療法共同
對應,故以日常服用之觀點來看,可以說緩和的作用反而較佳。
以下,例示調配有本發明之環狀二肽或此等之鹽之組成物的具體處方。此等之組成物能夠依照習知的方法來調製。
使用神戶天然物化學公司所合成的環狀二肽,分別將下述表5所示之調配比例的原料溶解於水之後,使用磷酸將pH值調整至3.8,各自適量地添加抗氧化劑、香料、酸味料、甜味料、焦糖色素,儲存約24小時。在這期間,適量地添加碳酸氣體,之後,經過過濾.瓶裝.殺菌(於65℃以上加熱10分鐘)之步驟,得到碳酸飲料。
使用下述表6之調配比例的原料來製作巧克力。將表6之原料置入Hobart攪拌器中,以中速混合3分鐘,進一步經過軋延、混合,得到巧克力團。將此巧克力團以回火處理後,流入模型,冷卻後得到本發明之巧克力。
本發明之含有環狀二肽之組成物由於具有優異之尿酸值降低作用,在例如高尿酸血症或痛風等之預防或治療上是有用的。
Claims (7)
- 一種含有環狀二肽之組成物,以滿足各個量的範圍之量來含有下述(1)~(19)中之1個或2個以上之含有酪胺酸的環狀二肽或其鹽而成,(1)環色胺醯基酪胺酸或其鹽之含量:0.08×10~0.12×105ppm(2)環甘油基酪胺酸或其鹽之含量:0.80×10~1.30×105ppm(3)環脯胺醯基酪胺酸或其鹽之含量:0.40×10~0.70×105ppm(4)環酪胺醯基甘胺酸或其鹽之含量:0.30×10~0.60×105ppm(5)環酪胺醯基酪胺酸或其鹽之含量:0.10×10~0.30×105ppm(6)環苯丙胺基酪胺酸或其鹽之含量:0.50×10~0.90×105ppm(7)環白胺醯基酪胺酸或其鹽之含量:0.70×10~1.10×105ppm(8)環離胺醯基酪胺酸或其鹽之含量:1.00×10~1.50×105ppm(9)環組胺醯基酪胺酸或其鹽之含量:0.20×10~0.40×105ppm(10)環丙胺醯基酪胺酸或其鹽之含量:0.40×10~0.70×105ppm(11)環麩胺醯基酪胺酸或其鹽之含量: 0.10×10~0.30×105ppm(12)環纈胺醯基酪胺酸或其鹽之含量:0.10×10~0.30×105ppm(13)環異白胺醯基酪胺酸或其鹽之含量:0.80×10~1.30×105ppm(14)環蘇胺醯基酪胺酸或其鹽之含量:0.50×10~0.90×105ppm(15)環天冬胺醯基酪胺酸或其鹽之含量:0.10×10~0.30×105ppm(16)環天冬醯胺醯基酪胺酸或其鹽之含量:0.50×10~0.90×105ppm(17)環麩醯胺醯基酪胺酸或其鹽之含量:0.30×10~0.50×105ppm(18)環精胺醯基酪胺酸或其鹽之含量:1.00×10~1.60×105ppm(19)環甲硫胺醯基酪胺酸或其鹽之含量:0.10×10~0.20×105ppm。
- 如請求項1之組成物,其中,含有酪胺酸之環狀二肽或其鹽的總量為8.0×10~1.0×106ppm。
- 一種含有環狀二肽之組成物,其係以滿足各個量的範圍之量來含有下述(1)~(19)中之1個或2個以上之含有酪胺酸的環狀二肽或其鹽而成,(1)環色胺醯基酪胺酸或其鹽之含量:0.4×10-4~0.7×10mg/100mL (2)環甘油基酪胺酸或其鹽之含量:4.0×10-4~8.0×10mg/100mL(3)環脯胺醯基酪胺酸或其鹽之含量:2.0×10-4~4.0×10mg/100mL(4)環酪胺醯基甘胺酸或其鹽之含量:2.0×10-4~4.0×10mg/100mL(5)環酪胺醯基酪胺酸或其鹽之含量:0.8×10-4~2.0×10mg/100mL(6)環苯丙胺基酪胺酸或其鹽之含量:3.0×10-4~5.0×10mg/100mL(7)環白胺醯基酪胺酸或其鹽之含量:4.0×10-4~7.0×10mg/100mL(8)環離胺醯基酪胺酸或其鹽之含量:5.0×10-4~9.0×10mg/100mL(9)環組胺醯基酪胺酸或其鹽之含量:1.0×10-4~3.0×10mg/100mL(10)環丙胺醯基酪胺酸或其鹽之含量:2.0×10-4~4.0×10mg/100mL(11)環麩胺醯基酪胺酸或其鹽之含量:1.0×10-4~2.0×10mg/100mL(12)環纈胺醯基酪胺酸或其鹽之含量:1.0×10-4~2.0×10mg/100mL(13)環異白胺醯基酪胺酸或其鹽之含量:4.0×10-4~7.0×10mg/100mL (14)環蘇胺醯基酪胺酸或其鹽之含量:3.0×10-4~5.0×10mg/100mL(15)環天冬胺醯基酪胺酸或其鹽之含量:1.0×10-4~2.0×10mg/100mL(16)環天冬醯胺醯基酪胺酸或其鹽之含量:3.0×10-4~5.0×10mg/100mL(17)環麩醯胺醯基酪胺酸或其鹽之含量:1.0×10-4~3.0×10mg/100mL(18)環精胺醯基酪胺酸或其鹽之含量:6.0×10-4~1.0×102mg/100mL(19)環甲硫胺醯基酪胺酸或其鹽之含量:0.7×10-4~2.0×10mg/100mL。
- 如請求項3之組成物,其中,含有酪胺酸之環狀二肽或其鹽的總量為5.0×10-3~8.0×102mg/100mL。
- 一種含有環狀二肽之組成物,其係以滿足各個量的範圍之量來含有下述(1)~(19)中之1個或2個以上之含有酪胺酸的環狀二肽或其鹽而成,(1)環色胺醯基酪胺酸或其鹽之含量:0.0008~1.2重量%(2)環甘油基酪胺酸或其鹽之含量:0.008~13重量%(3)環脯胺醯基酪胺酸或其鹽之含量:0.004~7重量%(4)環酪胺醯基甘胺酸或其鹽之含量:0.003~6重量%(5)環酪胺醯基酪胺酸或其鹽之含量:0.001~3重量%(6)環苯丙胺基酪胺酸或其鹽之含量:0.005~9重量%(7)環白胺醯基酪胺酸或其鹽之含量:0.007~11重量% (8)環離胺醯基酪胺酸或其鹽之含量:0.01~15重量%(9)環組胺醯基酪胺酸或其鹽之含量:0.002~4重量%(10)環丙胺醯基酪胺酸或其鹽之含量:0.004~7重量%(11)環麩胺醯基酪胺酸或其鹽之含量:0.001~3重量%(12)環纈胺醯基酪胺酸或其鹽之含量:0.001~3重量%(13)環異白胺醯基酪胺酸或其鹽之含量:0.008~13重量%(14)環蘇胺醯基酪胺酸或其鹽之含量:0.005~9重量%(15)環天冬胺醯基酪胺酸或其鹽之含量:0.001~3重量%(16)環天冬醯胺醯基酪胺酸或其鹽之含量:0.005~9重量%(17)環麩醯胺醯基酪胺酸或其鹽之含量:0.003~5重量%(18)環精胺醯基酪胺酸或其鹽之含量:0.01~16重量%(19)環甲硫胺醯基酪胺酸或其鹽之含量:0.001~2重量%。
- 如請求項5之組成物,其中,含有酪胺酸之環狀二肽或其鹽的總量為0.008~100重量%。
- 如請求項1~6中任一項之組成物,其中,含有含酪胺酸之環狀二肽的組成物為將含有大豆胜肽之溶液熱處理後所得之處理物。
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JP2003252896A (ja) * | 2002-02-26 | 2003-09-10 | Toyohashi University Of Technology | 高温高圧水を用いた環状ペプチドの合成方法 |
JP2006111541A (ja) * | 2004-10-12 | 2006-04-27 | Toyo Shinyaku:Kk | 葛花処理物を含有する経口用肌質改善剤 |
EP2088143A1 (en) * | 2008-01-24 | 2009-08-12 | Commissariat A L'energie Atomique | Novel inhibitors of mycobacterium tuberculosis complex cytochrome P450 CYP121 |
CN102665717B (zh) | 2009-12-25 | 2014-10-29 | 三得利控股株式会社 | 学习积极性改善剂 |
JP6046617B2 (ja) * | 2010-07-15 | 2016-12-21 | 大韓民国農村振興庁Republic Of Korea(Management Rural Development Administration) | 2,5−ジケトピペラジン誘導体を活性成分として含む農業用薬剤 |
JP2013053115A (ja) * | 2011-09-06 | 2013-03-21 | Josho Gakuen | α環状ジペプチドの製造方法 |
JP5456876B1 (ja) * | 2012-12-25 | 2014-04-02 | ゼライス株式会社 | 環状ジペプチドの製造方法 |
JP6669497B2 (ja) * | 2013-06-10 | 2020-03-18 | サントリーホールディングス株式会社 | ジケトピペラジンを含有する植物エキス及びその製造方法 |
-
2014
- 2014-06-20 WO PCT/JP2014/066425 patent/WO2015194035A1/ja active Application Filing
- 2014-12-17 TW TW103144245A patent/TW201600104A/zh unknown
-
2015
- 2015-02-13 AU AU2015275507A patent/AU2015275507A1/en not_active Abandoned
- 2015-02-13 JP JP2016529093A patent/JPWO2015194205A1/ja active Pending
- 2015-02-13 EP EP15810504.9A patent/EP3159353A1/en not_active Withdrawn
- 2015-02-13 WO PCT/JP2015/054015 patent/WO2015194205A1/ja active Application Filing
- 2015-02-13 CN CN201580028275.9A patent/CN106459151A/zh active Pending
- 2015-02-13 US US15/320,098 patent/US20170129919A1/en not_active Abandoned
- 2015-02-13 SG SG11201610090RA patent/SG11201610090RA/en unknown
- 2015-02-13 KR KR1020177001049A patent/KR20170020443A/ko unknown
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JPWO2015194205A1 (ja) | 2017-04-20 |
US20170129919A1 (en) | 2017-05-11 |
SG11201610090RA (en) | 2017-01-27 |
CN106459151A (zh) | 2017-02-22 |
AU2015275507A8 (en) | 2017-01-12 |
WO2015194205A1 (ja) | 2015-12-23 |
WO2015194035A1 (ja) | 2015-12-23 |
EP3159353A1 (en) | 2017-04-26 |
AU2015275507A1 (en) | 2017-01-05 |
KR20170020443A (ko) | 2017-02-22 |
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