TW201717986A - 腎素－血管張力素系抑制用組成物 - Google Patents
腎素－血管張力素系抑制用組成物 Download PDFInfo
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- TW201717986A TW201717986A TW105120787A TW105120787A TW201717986A TW 201717986 A TW201717986 A TW 201717986A TW 105120787 A TW105120787 A TW 105120787A TW 105120787 A TW105120787 A TW 105120787A TW 201717986 A TW201717986 A TW 201717986A
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
本發明之課題為提供腎素-血管張力素系抑制用組成物、用以抑制腎素-血管張力素系的該組成物之使用、及抑制腎素-血管張力素系之方法。其解決手段為發現了特定之環狀二肽或其鹽，具有腎素-血管張力素系之抑制作用。本發明為提供可供血壓上昇抑制等之有效且新穎的手段。
Description
本發明係關於腎素(renin)-血管張力素(angiotensin)系抑制用組成物。更詳細而言，係關於以胺基酸為構成單位之特定環狀二肽或其鹽作為有效成分的腎素-血管張力素系抑制用組成物、用以抑制腎素-血管張力素系之特定環狀二肽或其鹽的使用、及抑制腎素-血管張力素系之方法。
腎素-血管張力素系，係關於在生體中之血壓調節作用或體液．電解質之體內恆定性維持，已知與高血壓症之發病高度相關。腎素-血管張力素系中，具有末梢毛細血管收縮作用，刺激交感神經及腎上腺而促進兒茶酚胺之放出的血管張力素II，係顯示高的血壓上昇作用。血管張力素II亦會促進腎上腺皮質激素之醛固酮的分泌，因此亦藉由鈉之再吸收促進及循環血流量之增大的機制，使血壓上昇。
存在於血管內皮細胞膜等之血管張力素轉換酵素(亦稱為血管張力素I轉換酵素)，於血管張力素II之
產生而言，係擔當重要角色。因此，阻礙血管張力素轉換酵素之活性的卡特普(captopril)或伊那拉普利(enalapril)等，以往即利用作為高血壓治療藥。血管張力素轉換酵素除了產生血管張力素II以外，亦具有使具備血管擴張作用之舒緩激肽(bradykinin)分解的作用，因此血管張力素轉換酵素阻礙劑，亦可藉由舒緩激肽分解阻礙作用之機制，來期待血壓下降作用。
關於血管張力素轉換酵素之阻礙，已知來自食品蛋白質之直鏈狀胜肽亦為有用。其血管張力素轉換酵素阻礙作用或其所伴隨的血壓上昇抑制作用，至今為止已有多數報告，例如添加芝麻胜肽(白胺酸-纈胺酸-酪胺酸(LVY))等作為相關成分之特定保健用食品已有多數實用化(非專利文獻1)。
來自食品蛋白質之胜肽當中，鍵結有二個胺基酸之「二肽」亦作為功能性物質而受到矚目。二肽係能夠附加單質胺基酸所沒有的物理、化學性質或嶄新功能，被期待作為具有單質胺基酸以上之應用範圍者。關於血管張力素轉換酵素之阻礙，至今為止揭示了來自魚貝類之特定直鏈狀二肽為有用(專利文獻1)。
於腎素-血管張力素系之抑制而言，除了抑制血管張力素II之產生以外，阻礙血管張力素II對血管張力素II受體之結合亦為有用。血管張力素II受體係存在有AT-1與AT-2的2種次型。其中AT-1係分布於血管平滑肌、肺、肝臟、腎臟、腎上腺、卵巢、脾臟、腦等，與
血管收縮或動脈硬化相關。
於阻礙血管張力素II對其受體之結合方面，已有使用血管張力素II受體(AT-1)拮抗劑，其特別有效於腎素依賴性之高血壓治療，具有優良之臟器保護效果。以往所使用之藥劑，可列舉洛沙坦(Losartan)、坎地沙坦(Candesartan)、纈沙坦(Valsartan)、替米沙坦(Telmisartan)、奧美沙坦(Olmesartan)、艾比沙坦(Irbesartan)等。又，關於胜肽，係揭示了丙胺酸-白胺酸-脯胺酸-甲硫胺酸(ALPM)之四肽為有用(專利文獻2)。
近年來，血管張力素II受體(AT-1)拮抗藥，於大規模臨床試驗中被證明不僅具有血壓調節作用，亦具備腦中風、心肌梗塞、心猝發等心血管事件之發病抑制或蛋白尿減少等之腎保護效果。又，關於血管張力素轉換酵素阻礙藥，亦被證明有臟器保護作用。
如上所述，腎素-血管張力素系之抑制，以往即使用各種醫藥品，另一方面，有擔憂該等之副作用者。關於此，可認為來自食品蛋白質之直鏈狀胜肽為有效。但是，直鏈狀二肽因極性基之胺基與羧基露出於末端，因此存在有缺乏脂溶性的問題點。因此，直鏈狀二肽係有不易以高濃度對植物油或橄欖油、魚油、米胚芽油等油性基材混合的情況。又，直鏈狀二肽可能因分泌於消化道之羧基胜肽酶或胺基胜肽酶等之各種胜肽酶的作用，而被分解為游離胺基酸(非專利文獻2)，因此特性，亦可認為對體內之吸收性會變低。由以上觀點，可認為於效果高之腎素-
血管張力素系抑制劑當中，亦期望副作用更少、亦可應用於油性基材、進而對體內之吸收性亦優良者。
[專利文獻1]日本特開2003-24012號公報
[專利文獻2]日本特開2005-350443號公報
[非專利文獻1]功能性蛋白質．胜肽與生體利用、建吊社、第19頁
[非專利文獻2]J Biochem., Aug;94(2) : 619-22 (1983)
本發明之課題為提供安全性高、於製劑化之使用性優良、進而可期待對體內之高吸收性的腎素-血管張力素系抑制用組成物。又，本發明之課題，為提供用於抑制腎素-血管張力素系的該組成物之使用、及抑制腎素-血管張力素系之方法等。
本發明者等人對於上述課題努力探討的結果，著眼於環狀二肽之利用。環狀二肽，為存在於直鏈狀
二肽之末端的胺基與羧基藉由脫水縮合所生成之具有環狀構造之二肽，近年來其各種生理活性受到矚目。本發明者等人對於由天然胺基酸之組合所成之達100種以上的多數之環狀二肽進行努力探討，由其中首次發現特定環狀二肽具有血管張力素轉換酵素阻礙作用及/或血管張力素II受體拮抗作用。基於該見解，本發明者等人完成了本發明。
亦即，本發明係關於以下者，但不限定於此等。
(1)一種腎素-血管張力素系抑制用組成物，其係含有以胺基酸為構成單位之環狀二肽或其鹽作為有效成分的腎素-血管張力素系抑制用組成物，其中前述環狀二肽或其鹽，為包含選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、
環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上者。
(2)如(1)之腎素-血管張力素系抑制用組成物，其係具有血管張力素轉換酵素阻礙作用，且環狀二肽或其鹽，為包含選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-
Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、及環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕所成之群的1者或2者以上者。
(3)如(1)之腎素-血管張力素系抑制用組成物，其係具有血管張力素II受體拮抗作用，且環狀二肽或其鹽，為包含選自由環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-
Trp)〕、環纈胺醯纈胺酸〔Cyclo(Val-Val)〕、及環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕所成之群的1者或2者以上者。
(4)如(1)~(3)中任一項之腎素-血管張力素系抑制用組成物，其係血壓上昇抑制用、血壓下降用、腎功能保護用、或腦中風或心疾病之預防或改善用。
(5)如(1)~(4)中任一項之腎素-血管張力素系抑制用組成物，其中環狀二肽或其鹽為由來自動植物之胜肽所得到者。
(6)如(1)~(5)中任一項之腎素-血管張力素系抑制用組成物，其係附有藉由抑制腎素-血管張力素系所發揮之功能的標示。
(7)如(6)之腎素-血管張力素系抑制用組成物，其中功能的標示，為選自由「期待血壓降低」、「抑制血壓上昇」、「緩和血壓上昇」、「預防高血壓症」、「有用於高血壓症之改善」、「保護腎功能」、及「改善腎功能」所成之群者。
(8)如(1)~(7)中任一項之腎素-血管張力素系抑制用組成物，其中前述組成物為藥劑。
(9)一種以胺基酸為構成單位之環狀二肽或其鹽之使用，其係使用於抑制腎素-血管張力素系，其中，前述環狀二肽或其鹽，為包含選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、
環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸
〔Cyclo(Val-Val)〕所成之群的1者或2者以上者。
(10)一種抑制腎素-血管張力素系之方法，其係使用以胺基酸為構成單位之環狀二肽或其鹽作為有效成分，其中前述環狀二肽或其鹽，為包含選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯
纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上者。
依照本發明，可提供具有腎素-血管張力素系之優良抑制效果的組成物。又，本發明之組成物具有血管張力素轉換酵素阻礙作用及/或血管張力素II受體拮抗作用，因此亦有用於作為血管張力素轉換酵素阻礙用組成物及/或血管張力素II受體拮抗用組成物。此外，若利用本發明之組成物，對於列舉為代謝症候群診斷之次要項目的高血壓，可得到血壓下降作用，進一步地，係有亦得到腦中風、心肌梗塞、心猝發等心血管事件之發病抑制、或蛋白尿減少等之腎保護效果的可能性。
本發明之組成物中作為有效成分而含有的環狀二肽或其鹽，由於亦於來自食品蛋白質之胜肽的熱處理物中含有，因此可認為安全性高，副作用相較於以往的醫藥品而言為極少。又，環狀二肽相較於直鏈狀二肽而言，親油性優良，對油性基材之高濃度填充亦充分可能。因此，本發明之組成物，可說於製劑化之使用性優良。進一
步地，環狀二肽富於脂溶性，且並非僅以單純胜肽鍵所構成之二肽，因此可認為對分泌於消化道之各種胜肽分解酵素的作用具有耐性，亦可期待高的消化道吸收性。
[圖1]圖1為顯示各種二肽經口投與後的血漿中濃度之圖。
本說明書中，「腎素-血管張力素系」，係指基於腎素及血管張力素原(angiotensinogen)之作用，而主管血壓調節之系統。腎素為由腎臟所分泌之蛋白質分解酵素，以血管張力素原為基質，對其作用，而生成血管張力素I。該血管張力素I藉由血管張力素轉換酵素(本說明書中亦稱為「血管張力素I轉換酵素」)之作用而變化為血管張力素II，該血管張力素II會造成血壓上昇。
本說明書中，「腎素-血管張力素系抑制」，意指為了抑制血壓上昇、降低血壓、保護腎功能、或預防或改善腦中風或心疾病，而抑制上述腎素-血管張力素系。該「抑制」係包含腎素-血管張力素系之抑制所相關之各種因子的一切作用機轉。其一具體例子，可列舉血管
張力素轉換酵素之阻礙。血管張力素轉換酵素之阻礙活性，可遵照公知之方法測定，例如，將對合成基質Hippuryl-His-Leu作用而得到之馬尿酸以乙酸乙酯溶劑萃取後，濃縮乾燥，並藉由再溶解而測定228nm之吸光度來算出。又，血管張力素轉換酵素之阻礙活性，亦可使用市售之套組等來測定。
腎素-血管張力素系抑制之別的具體例子，可列舉阻礙血管張力素II對血管張力素II受體(AT-1或AT-2)之結合。阻礙血管張力素II對其受體之結合，可使用具有血管張力素II受體拮抗作用(亦即，與血管張力素II拮抗，來阻礙血管張力素II對血管張力素II受體之結合的作用)之物質來處理。關於血管張力素II受體拮抗作用，可遵照公知之方法評估，例如，可使用表現血管張力素II受體之細胞，測定添加血管張力素II時的細胞內鈣離子濃度之變化，並比較試樣存在時與不存在時之測定值來評估。更具體而言，相對於試樣不存在時的測定值而言，試樣存在時的測定值越低(亦即，細胞內鈣離子濃度之變化越小)，可評估為血管張力素II受體拮抗作用越大。
本說明書中，「環狀二肽」，係指以胺基酸為構成單位為特徵，且藉由胺基酸之胺基與羧基進行脫水縮合所生成之具有二酮哌嗪構造的環狀二肽者。因此，環狀二肽，
係與鏈狀之二肽有所區別。再者，本說明書中，係有將環狀二肽或其鹽單純一併稱為環狀二肽的情況。又，本說明書中，若環狀二肽之胺基酸構成為相同，則該等之記載順序係何者為先均可，例如，〔Cyclo(Met-Arg)〕與〔Cyclo(Arg-Met)〕為表示相同之環狀二肽者。
環狀二肽中，二個胺基酸之末端部分係透過醯胺鍵而鍵結(亦即，環狀二肽，具有胺基末端與羧基末端藉由醯胺鍵鍵結所形成的環狀構造)，因此具有相較於分子末端部分露出有極性基之羧基或胺基的直鏈狀二肽(特別是由同種之胺基酸組成所構成之直鏈狀二肽)而言，環狀二肽脂溶性較高的特徵。因此，環狀二肽相較於直鏈狀之二肽而言，消化道穿透性或膜穿透性較優良。此由過去報告之使用大鼠反轉腸道的化合物穿透試驗之結果亦可明顯得知(J.Pharmacol,1998,50：167-172)。又，環狀二肽，由於其特異性構造，可認為對各種胜肽酶之耐性亦會提高。
本發明中作為有效成分所含有之環狀二肽或其鹽，為選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺
酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上者。環狀二肽或其鹽之數目並無特別限定，但本發明中，較佳為以由上述環狀二肽或其鹽中選擇之2者以上作為有效成分。
本發明中，由血管張力素轉換酵素阻礙效果
之觀點而言，作為有效成分所含有之環狀二肽或其鹽，較佳為選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、及環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕所成之群的1者或2者以上者；更佳為以由前述環狀二肽或其鹽中選擇之3者以上為有效成分。又，前述環狀二肽或其鹽當中，尤佳為選自由環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、及環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕所成之群的1者或2者以上；更佳為環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、及/或環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕。
又，本發明中，由血管張力素II受體拮抗效果之觀點而言，作為有效成分所含有之環狀二肽或其鹽，較佳為選自由環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺
醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、環纈胺醯纈胺酸〔Cyclo(Val-Val)〕、及環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕所成之群的1者或2者以上者；更佳為以由前述環狀二肽或其鹽中選擇之3者以上為有效成分。又，前述環狀二肽或其鹽當中，尤佳為選自由環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環纈胺醯纈胺酸〔Cyclo(Val-Val)〕、及環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕所成之群的1者或2者以上；更佳為環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、及/或環纈胺醯纈胺酸〔Cyclo(Val-Val)〕。
本說明書中，「環狀二肽之鹽」，係指前述環狀二肽之藥理上所容許的任意之鹽(包含無機鹽及有機鹽)，例如，可列舉前述環狀二肽之鈉鹽、鉀鹽、鈣鹽、鎂鹽、銨鹽、鹽酸鹽、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、富馬酸鹽、丙酸鹽、甲酸鹽、安息香酸鹽、苦味酸鹽、苯磺酸鹽、三氟乙酸鹽等)等，但不限定於此等。環狀二肽之鹽，可藉由該領域中公知之任意方法，經所屬技術領域中具有通常知識者容易地配製。
本發明中使用之環狀二肽，可遵照該領域中公知之方法來配製。例如，可藉由化學合成法或酵素法、微生物發酵法來製造，可藉由將直鏈狀胜肽脫水及環化來合成，亦可遵照日本特開2003-252896號公報或Journal of Peptide Science,10,737-737,2004記載之方法來配製。例如，藉由將對含有來自動植物之蛋白質的原料實施酵素處理或熱處理而得到之來自動植物之胜肽，進一步予以高溫加熱處理，可得到含有豐富之環狀二肽的來自動植物之胜肽熱處理物。由此等觀點，本發明中使用之環狀二肽或其鹽，可為化學或生物合成者、或亦可為由來自動植物之胜肽所得到者。
本說明書中之「來自動植物之胜肽」並無特殊限定，例如可使用大豆胜肽、茶胜肽、麥芽胜肽、乳胜肽、胎盤
胜肽、膠原蛋白胜肽等。可由含有來自動植物之蛋白質或蛋白質的原料配製來自動植物之胜肽來使用、亦可使用市售品。
本說明書中所稱之「大豆胜肽」，係指藉由對大豆蛋白質實施酵素處理或熱處理，使蛋白質低分子化而得到之低分子胜肽。作為原料之大豆(學名：Glycine max)可不限制品種或產地等來使用，亦可使用粉碎品等之加工品階段者。
本說明書中所稱之「茶胜肽」，係指藉由對茶(包含茶葉或茶渣)萃取物實施酵素處理或熱處理，使蛋白質低分子化而得到之來自茶之低分子胜肽。作為萃取原料之茶葉，可使用萃取使用茶樹(學名：Camellia sinensis)所製造之茶葉的葉、莖等而能夠飲用之部位。又，其形態亦不限制為大葉、粉狀等。關於茶葉之收穫期，亦可配合所期望之香味來適當選擇。
本說明書中所稱之「麥芽胜肽」，係指藉由對由麥芽或其粉碎物所得到之萃取物實施酵素處理或熱處理，將蛋白質低分子化而得到之來自麥芽之低分子胜肽。作為原料
之麥芽胜肽，可不限制品種或產地等來使用，但特別適宜使用使大麥種子發芽之大麥麥芽。本說明書中，亦有將大麥麥芽單純表述為「麥芽」者。
本說明書中所稱之「乳胜肽」，係指將天然之來自乳的成分之乳蛋白質分解為至少鍵結有數個胺基酸的分子者。更具體而言，可列舉藉由將乳清(乳清蛋白質)或酪蛋白等之乳蛋白質以蛋白酶等之酵素水解，並使將之過濾而得的濾液經殺菌及/或濃縮並乾燥所得到之乳清胜肽、酪蛋白胜肽等。
胎盤係指哺乳類之胎盤，由於其優良的功能性，近年來使用作為健康食品、化妝品、醫藥品素材。本說明書中，「胎盤胜肽」，係指將胎盤藉由酵素處理、或亞臨界處理而予以可溶化、低分子化者。又，雖與本來的意義不同，但由植物之胎座所得到之萃取物，作為具有與來自胎盤之胎盤同等之生理學效果者而被利用於健康食品、化妝品等，此等係稱為植物胎盤。本說明書中，「胎盤胜肽」亦包含對植物胎盤實施酵素處理、或亞臨界處理等，而予以可溶化、低分子化者。
本說明書中所稱之「膠原蛋白胜肽」係指藉由將膠原蛋白或其粉碎物實施酵素處理或熱處理，將膠原蛋白低分子化而得到之低分子胜肽。膠原蛋白為動物之結締組織的主要蛋白質，其係於包含人類之哺乳類身體中最大量含有的蛋白質。
如上所述，藉由將來自動植物之胜肽予以高溫加熱處理，可得到含有豐富之環狀二肽的來自動植物之胜肽熱處理物。本說明書中，「高溫加熱處理」，意指於100℃以上之溫度且超過大氣壓之壓力下處理一定時間。作為高溫高壓處理裝置，可配合條件來使用耐壓性萃取裝置或壓力鍋、熱壓釜等。
高溫加熱處理之溫度，只要係100℃以上則無特殊限定，較佳為100℃~170℃、更佳為110℃~150℃、又更佳為120℃~140℃。再者，當使用耐壓性萃取裝置作為加熱裝置時，該溫度係表示測定萃取管柱之出口溫度之值，當使用熱壓釜作為加熱裝置時，該溫度係表示測定壓力容器內之中心溫度的溫度之值。
高溫加熱處理之壓力，只要係超過大氣壓之壓力則無特殊限定，較佳為0.101MPa~0.79MPa、更佳為0.101MPa~0.60MPa、又更佳為0.101MPa~0.48MPa。
高溫加熱處理時間，只要可得到含有環狀二肽之處理物，則無特殊限定，較佳為15分~600分左
右、更佳為30分~500分左右、又更佳為60分~300分左右。
又，來自動植物之胜肽的高溫加熱處理條件，只要可得到含有環狀二肽之處理物，則無特殊限定，較佳為[溫度：壓力：時間]為[100℃~170℃：0.101MPa~0.79MPa：15分~600分]、更佳為[110℃~150℃：0.101MPa~0.60MPa：30分~500分]、又更佳為[120℃~140℃：0.101MPa~0.48MPa：60分~300分]。
再者，亦可對所得到之來自動植物之胜肽熱處理物，依期望進行過濾、離心分離、濃縮、超微過濾、冷凍乾燥、粉末化等之處理。又，來自動植物之胜肽熱處理物中的特定環狀二肽若不滿足所期望之含量，對於不足之特定環狀二肽，亦可使用其他來自動植物之胜肽或市售品、合成品來適當追加。
本發明之一態樣，為以特定環狀二肽或其鹽為有效成分之腎素-血管張力素系抑制用組成物。
本發明之腎素-血管張力素系抑制用組成物，為含有選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺
醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上之環狀二肽或其鹽作為有效成分者。本發明之腎素-血管
張力素系抑制用組成物中所含有的環狀二肽或其鹽之數目並無特別限定，但本發明中，較佳為含有由上述環狀二肽或其鹽中選擇之3者以上。
本發明之腎素-血管張力素系抑制用組成物，就血管張力素轉換酵素阻礙效果之觀點而言，為含有選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、及環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕所成之群的1者或2者以上之環狀二肽或其鹽作為有效成分者。本發明之組成物，較佳為含有由前述環狀二肽或其鹽中選擇之3者以上作為有效成分者。前述環狀二肽或其鹽當中，尤佳為選自由環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、及環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕所成之群的1者或2者以上；更佳為環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、及/或環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕。
又，本發明之腎素-血管張力素系抑制用組成
物，由血管張力素II受體拮抗效果之觀點而言，為含有選自由環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、環纈胺醯纈胺酸〔Cyclo(Val-Val)〕、及環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕所成之群的1者或2者以上之環狀二肽或其鹽作為有效成分者。本發明之組成物，較佳為含有由前述環狀二肽或其鹽中選擇之3者以上作為有效成分者。前述環狀二肽或其
鹽當中，尤佳為選自由環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環纈胺醯纈胺酸〔Cyclo(Val-Val)〕、及環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕所成之群的1者或2者以上；更佳為環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、及/或環纈胺醯纈胺酸〔Cyclo(Val-Val)〕。
本發明之腎素-血管張力素系抑制用組成物中之環狀二肽或其鹽之含量，只要係考慮其投與形態、投與方法等，而可得到本發明所期望之效果的量即可，並無特殊限定。例如，使用來自動植物之胜肽作為原料時，本發明之組成物中之環狀二肽或其鹽的含量總量，為1.0×10ppm/Brix以上、較佳為1.0×102ppm/Brix以上，且係5.0×103ppm/Brix以下，較佳為3.0×103ppm/Brix以下。又，本發明之腎素-血管張力素系抑制用組成物中之環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門
冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、環纈胺醯纈胺酸〔Cyclo(Val-Val)〕、或各自所對應之鹽的含量，係1.0ppm/Brix以上、較佳為1.0×10ppm/Brix以上，且係5.0×103ppm/Brix以下，較佳為3.0×103ppm/Brix以下。前述之含量，於使用合成品或精製品之環狀二肽或其鹽的情況時亦可適用。本發明中，環狀二肽或其鹽之含量，如上所述，係以每單位Brix(布里度)之量表示。本說明書中，「每單位Brix之量」，意指以相當於20℃之蔗糖溶液(僅含有蔗糖作為溶質之水溶液)的質量百分率之值所規定的
量。再者，若無特別指明，本說明書中所用之「ppm」，意指重量/容量(w/v)之ppm，1.0ppm/Brix係溶劑之比重為1時，換算為0.1mg/mL，換算為0.01重量%者。
環狀二肽或其鹽之含量，可遵照公知之方法測定。例如，可藉由使用LC-MS/MS或糖度計測定。
如上所述，「腎素-血管張力素系」，係指基於腎素及血管張力素原之作用來調節血壓之系統。該系統與各種因子相關，其中之一可列舉血管張力素轉換酵素。血管張力素轉換酵素係存在於肺毛細血管等，具有將血管張力素I轉換為血管張力素II之作用。藉此所轉換之血管張力素II，係結合於存在於腎上腺皮質的受體，促進自腎上腺皮質合成及分泌醛固酮。藉由該醛固酮之作用，促進於腎集合管之鈉的再吸收，藉此增加體液量，造成昇壓作用。因此，血管張力素轉換酵素之阻礙，有助於抑制血管張力素II之產生，藉此可得到血壓上昇抑制作用或血壓下降作用。
又，腎素-血管張力素系所相關的因子中，與上述內容相關地，可列舉血管張力素II及血管張力素II受體(AT-1或AT-2)。如上所述，血管張力素II結合於血管張力素II受體，促進醛固酮之合成及分泌，結果造成昇壓作用。因此，阻礙血管張力素II對血管張力素II受體之結合，係有助於抑制醛固酮之合成及分泌，藉此可得
到血壓上昇抑制作用或血壓下降作用。阻礙血管張力素II對其受體之結合，可使用具有血管張力素II受體拮抗作用(亦即，與血管張力素II拮抗，以阻礙血管張力素II對血管張力素II受體之結合的作用)之物質來處理。
本發明之腎素-血管張力素系抑制用組成物，可依照其形態，於環狀二肽或其鹽之外，含有任意之添加劑、通常所使用之任意成分。此等添加劑及/或成分之例子，可列舉維生素E、維生素C等之維生素類、礦物質類、營養成分、香料等之生理活性成分，此外可列舉於製劑化時摻合之賦形劑、結合劑、乳化劑、繃緊劑(等張劑)、緩衝劑、溶解輔助劑、防腐劑、安定化劑、抗氧化劑、著色劑、凝固劑、或包覆劑等，但不限定於此等。
本發明之腎素-血管張力素系抑制用組成物，其特徵為含有前述環狀二肽或其鹽作為有效成分，該有效成分可有助於腎素-血管張力素系之抑制效果。腎素-血管張力素系之抑制，係包含血管張力素轉換酵素之阻礙或血管張力素II對其受體(AT-1或AT-2)之結合阻礙，前述環狀二肽或其鹽，如後述實施例亦有顯示者，具有血管張力素轉換酵素之阻礙作用或血管張力素II受體之拮抗作用。因此，本發明之一態樣，為含有特定之環狀二肽或其鹽作為
有效成分之腎素-血管張力素系抑制用組成物，且為具有血管張力素轉換酵素阻礙作用之前述組成物。又，本發明之另一態樣，為含有特定之環狀二肽或其鹽作為有效成分之腎素-血管張力素系抑制用組成物，且為具有血管張力素II受體(AT-1或AT-2)拮抗作用之前述組成物。基於此等作用，本發明之腎素-血管張力素系抑制用組成物，亦可成為血管張力素轉換酵素阻礙用組成物及/或血管張力素II受體(AT-1或AT-2)拮抗用組成物。
又，本發明之組成物中所含有的前述環狀二肽或其鹽，可通過腎素-血管張力素系之抑制，來進行血壓上昇抑制、血壓下降、腎功能保護、及腦中風或心疾病之預防或改善。因此，本發明之又另一態樣，為含有特定之環狀二肽或其鹽作為有效成分之腎素-血管張力素系抑制用組成物，且係血壓上昇抑制用、血壓下降用、腎功能保護用、或腦中風或心疾病之預防或改善用之前述組成物。基於此等用途，本發明之腎素-血管張力素系抑制用組成物，亦可成為血壓上昇抑制用組成物、血壓下降用組成物、腎功能保護用組成物、或腦中風或心疾病之預防或改善用組成物。
又，本發明之組成物，與血壓上昇相關地，亦有用於高血壓症等之治療及/或預防。再者，腦中風當中係包含腦梗塞、腦出血、蜘蛛膜下出血等，心疾病當中係包含狹心症、心肌梗塞、心肥大、心衰竭等。
本發明之腎素-血管張力素系抑制用組成物，
例如可於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、崩解劑、或潤滑劑等，遵照公知之方法，製劑為錠劑、顆粒劑、散劑、粉末劑、或膠囊劑等之固形劑、或一般液劑、懸浮劑、或乳劑等之液劑等。此等組成物可直接與水等一起服用。又，可配製為可容易摻合之形態(例如粉末形態或顆粒形態)後，例如作為醫藥品之原材料使用。
本發明之腎素-血管張力素系抑制用組成物，作為一例，能夠以藥劑之形態提供，但不限定於本形態。可將該藥劑直接以組成物的形態、或亦可以含有該藥劑之組成物的形態提供。本發明之組成物，可列舉醫藥組成物、飲食品組成物、食品組成物、飲料組成物、化妝用組成物等，但不限定於此等。作為食品組成物之非限定的例子，可列舉功能性食品、健康輔助食品、營養功能食品、特別用途食品、特定保健用食品、營養輔助食品、食物療法用食品、健康食品、補給品(supplement)、食品添加劑等。
本發明之腎素-血管張力素系抑制用組成物，係治療用途(醫療用途)或非治療用途(非醫療用途)均可適用。具體而言，可列舉作為醫藥品、醫藥部外品及化妝料等或藥事法上雖不屬於此等，但有明示或暗示地訴求抑制血壓上昇效果、緩和血壓上昇效果、高血壓症之預防效果、或高血壓症之改善效果等的組成物之使用。
本發明於另一方面，係關於附有藉由抑制腎素-血管張力素系所發揮之功能的標示之前述腎素-血管張力素系抑制用組成物。如此之標示或功能性標示並無特殊限定，可列舉例如「期待血壓降低」、「抑制血壓上昇」、「緩和血壓上昇」、「預防高血壓症」、「有用於高血壓症之改善」、「保護腎功能」、「改善腎功能」等；或者可視為與此等相同之標示或功能性標示。本說明書中，如該標示及功能性標示般的標示，可附於組成物本身、亦可附於組成物之容器或包裝上。
本發明之腎素-血管張力素系抑制用組成物，能夠依其形態以適當之方法攝取。只要係本發明之環狀二肽或其鹽可於循環血中移動者，則攝取方法並無特殊限定。例如，可為錠劑、包覆錠劑、顆粒劑、散劑、或膠囊劑等之經口用固形製劑；內服液劑、或糖漿劑等之經口用液體製劑；注射劑、外用劑、栓劑、或經皮吸收劑等之非經口用製劑等之形態，但不限定於此等。再者，本說明書中，「攝取」係作為包含攝取、服用、或飲用等之全部態樣者來使用。
本發明之腎素-血管張力素系抑制用組成物之適用量，係依照其形態、投與方法、使用目的及投與對象之患者或患病動物之年齡、體重、症狀而適時設定，並非一定。本發明之組成物之有效人類攝取量並非一定，例如，以其有效成分之環狀二肽或其鹽的重量計，體重50kg之人類每一日，較佳為10mg以上、更佳為100mg以
上。又，投與亦可於所期望之投與量範圍內，於1日內單次或分為數次進行。投與期間亦為任意。再者，本發明之組成物之有效人類攝取量，係指於人類顯示有效之效果的本發明之腎素-血管張力素系抑制用組成物之攝取量，該組成物中所含有的環狀二肽之種類並無特殊限定。
本發明之腎素-血管張力素系抑制用組成物之適用對象，較佳為人類，但亦可為牛、馬、山羊等之家畜動物；狗、貓、兔子等之寵物動物、或小鼠、大鼠、天竺鼠、猴子等之實驗動物。
本發明之一態樣，為以胺基酸為構成單位之特定環狀二肽或其鹽之用於腎素-血管張力素系抑制之使用。較佳為，選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環
離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上之環狀二肽或其鹽之用於腎素-血管張力素系抑制之使用。更佳為，含有由前述環狀二肽或其鹽中選擇之3者以上者之用於腎素-血管張力素系抑制之使用。
本發明之使用，係包含例如用以阻礙血管張力素轉換酵素、用以阻礙血管張力素II對其受體(AT-1或AT-2)之結合、及/或用以抑制血壓上昇的前述環狀二肽或其鹽之使用，但不限定於此等。又，該使用係於人類或非人類動物之使用，可為治療上的使用亦可為非治療的使
用。此處，「非治療的」，係指不包含醫療行為，亦即，不包含治療所致之對人體的處理行為之概念。
本發明之一態樣，為使用以胺基酸為構成單位之環狀二肽或其鹽作為有效成分的抑制腎素-血管張力素系之方法。該方法較佳為包含使用選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、
環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上之環狀二肽或其鹽作為有效成分的抑制腎素-血管張力素系之方法。更佳為包含使用含有由前述環狀二肽或其鹽中選擇之3者以上者作為有效成分的抑制腎素-血管張力素系之方法。
關於該方法之其他態樣，為包含對以腎素-血管張力素系之抑制為必要的對象，以特定之環狀二肽或其鹽為有效成分來投與治療有效量的抑制腎素-血管張力素系之方法。較佳為包含以選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、
環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上之環狀二肽或其鹽為有效成分，來投與治療有效量的抑制腎素-血管張力素系之方法。更佳為包含以含有由前述環狀二肽或其鹽中選擇之3者以上者為有效成分，來投與治療有效量的抑制腎素-血管張力素系之方法。
上述方法中，以腎素-血管張力素系之抑制為必要的對象，係與本發明之腎素-血管張力素系抑制用組成物之前述適用對象相同。又，本說明書中，治療有效量係指將本發明之腎素-血管張力素系抑制用組成物投與至上述對象時，相較於未投與之對象而言，腎素-血管張力素系被抑制的量。具體的有效量，係依投與形態、投與方法、使用目的及對象之年齡、體重、症狀等而適時設定，並非一定。
本發明之方法中，亦可以成為前述治療有效量的方式，將前述特定之環狀二肽或其鹽直接、或以含有特定之環狀二肽或其鹽的組成物的形態來進行投與。
依照本發明之方法，可不產生副作用地，來抑制腎素-血管張力素系。
以下，藉由實施例以更詳細說明本發明，但並非藉此限定本發明之範圍。所屬技術領域中具有通常知識者，可將本發明之方法作各種變更、修飾來使用，此等亦包含於本發明之範圍中。
調查了環狀二肽試樣對血管張力素I轉換酵素活性之阻礙效果。具體而言，對於化學合成之環狀二肽試樣，使用ACE Kit-WST((股)同仁化學研究所)，遵照該套組附屬
的說明書測定各種環狀二肽之血管張力素I轉換酵素阻礙活性。環狀二肽係針對50μM及500μM之各濃度進行探討，作為使用下述式1所算出之血管張力素I轉換酵素的殘存活性，來評估其阻礙活性。控制組係使用添加蒸餾水來取代環狀二肽水溶液者。
殘存活性(%)=(環狀二肽添加群之450nm吸光度/控制組之450nm吸光度)×100
各種環狀二肽之評估結果係示於下述表1。
由上述結果，明顯可知表1所示之環狀二肽均具有血管張力素I轉換酵素之阻礙活性。
為了調查環狀二肽試樣於血管張力素II受體之拮抗作用(亦即，血管張力素II對血管張力素II受體之結合阻礙作用)，實施對血管張力素II受體之結合分析。具體而言，係使用表現人類重組血管張力素II 1型受體(AT-1)之HEK-293細胞，對其添加3nM之血管張力素II與各種濃度之化學合成的環狀二肽試樣，測定鈣離子流入所致之細胞內鈣離子濃度的變化。再者，細胞內鈣離子濃度係藉由螢光光度分析來定量。
關於被驗環狀二肽之拮抗作用，係以未添加環狀二肽時的反應率(細胞內鈣離子濃度之變化)為100%，評估對其添加環狀二肽時的反應率(%)。其結果示於表2。
由上述結果，明顯可知表2所示之環狀二肽均具有於血管張力素II受體之拮抗作用(亦即，血管張力素II對血管張力素II受體之結合阻礙作用)。
將具有腎素-血管張力素系抑制作用之環狀二肽的一種即Cyclo(Tyr-Gly)10mg/kg對小鼠經口投與後，測定血漿中濃度，確認血中動態。作為比較對象，一併探討投與以體重每1kg之重量計為等量之直鏈二肽Tyr-Gly(10mg/kg)後之血中動態。
由日本CLEA公司購入BALB/c小鼠(雄性、6週齡)，馴化約1週後供試驗。將Cyclo(Tyr-Gly)(神戶天然物化學公司)或直鏈二肽Tyr-Gly(BACHEM公司)溶解於蒸餾水，以投與量成為10mg/kg的方式使用注射器及醫用引流管分別對各別的小鼠個體經口投與。一定時間後由腹部大靜脈回收血液，使用添加有肝素鋰及血漿分離劑之採血容器(Capiject、Terumo公司)快速取得血漿。將所取得之血漿當中之20μL，依序與添加有內部標準物質之溶液10μL、水10μL、及乙腈80μL混合，進行攪拌及離心分離(15,000rpm、10℃、4℃)，去除蛋白質。再者，作為內部標準物質，Cyclo(Tyr-Gly)時為使用華法林、直鏈Tyr-Gly時為使用苯妥英。將離心後之上清液於氮氣流下蒸發乾燥，以乙腈15%水溶液再溶解，進行LC-MS/MS分析(質譜分析裝置：API5000、AB Sciex公司)。LC-MS/MS分析係由以下分析條件實施。定量解析係利用使用空白血漿試樣與標準品水溶液所製成之檢量線數據來實施，得到投與後各時間之血漿中濃度(ng/mL)。其結果示於圖1。圖中之各時刻的血漿中濃度之值為表示(平均值)±(標準誤
差)(n=4)。
移動相係使用以下溶劑，並應用下述梯度條件。
流速：0.2mL/分
分析時間：Cyclo(Tyr-Gly)：15分/樣品
直鏈Tyr-Gly：13分/樣品
管柱：Cadenza CD-C18 150(mm)×2(mm)，粒子徑3μm
A相：0.1%甲酸水溶液
B相：甲醇
(梯度條件)
測定模式：Cyclo(Tyr-Gly)：MRM negative
直鏈Tyr-Gly：MRM positive
Q1/Q3：219>113(Cyclo(Tyr-Gly))
239>136(直鏈Tyr-Gly)
由上述結果，明顯可知環狀二肽Cyclo(Tyr-
Gly)相較於直鏈二肽Tyr-Gly而言，於同等之投與量時，達到遠較高之血漿中濃度。即使假定環狀二肽與直鏈二肽於試驗管等級之試驗(in vitro試驗)中的腎素-血管張力素系抑制作用之強度為同等，環狀二肽亦基於其良好的血中動態，與直鏈二肽比較，而有於動物或人類中可期待強力的腎素-血管張力素系抑制作用之可能性。
本發明為提供含有特定之環狀二肽或其鹽作為有效成分的腎素-血管張力素系抑制用組成物者。本發明為提供可供血壓上昇抑制等之安全且有效的新穎手段者，因此產業上之利用性高。
Claims (10)
- 一種腎素-血管張力素系抑制用組成物，其係含有以胺基酸為構成單位之環狀二肽或其鹽作為有效成分的腎素-血管張力素系抑制用組成物，其中前述環狀二肽或其鹽，為包含選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯 酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上者。
- 如請求項1之腎素-血管張力素系抑制用組成物，其係具有血管張力素轉換酵素阻礙作用，且環狀二肽或其鹽，為包含選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、及環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕所成之群的1者或2者以上者。
- 如請求項1之腎素-血管張力素系抑制用組成物，其 係具有血管張力素II受體拮抗作用，且環狀二肽或其鹽，為包含選自由環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、環纈胺醯纈胺酸〔Cyclo(Val-Val)〕、及環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕所成之群的1者或2者以上者。
- 如請求項1~3中任一項之腎素-血管張力素系抑制 用組成物，其係血壓上昇抑制用、血壓下降用、腎功能保護用、或腦中風或心疾病之預防或改善用。
- 如請求項1~4中任一項之腎素-血管張力素系抑制用組成物，其中環狀二肽或其鹽為由來自動植物之胜肽所得到者。
- 如請求項1~5中任一項之腎素-血管張力素系抑制用組成物，其係附有藉由抑制腎素-血管張力素系所發揮之功能的標示。
- 如請求項6之腎素-血管張力素系抑制用組成物，其中功能的標示，為選自由「期待血壓降低」、「抑制血壓上昇」、「緩和血壓上昇」、「預防高血壓症」、「有用於高血壓症之改善」、「保護腎功能」、及「改善腎功能」所成之群者。
- 如請求項1~7中任一項之腎素-血管張力素系抑制用組成物，其中前述組成物為藥劑。
- 一種以胺基酸為構成單位之環狀二肽或其鹽之使用，其係使用於抑制腎素-血管張力素系，且前述環狀二肽或其鹽，為包含選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離 胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上者。
- 一種抑制腎素-血管張力素系之方法，其係使用以 胺基酸為構成單位之環狀二肽或其鹽作為有效成分，且前述環狀二肽或其鹽，為包含選自由環天門冬胺醯苯丙胺酸〔Cyclo(Asp-Phe)〕、環麩胺醯苯丙胺酸〔Cyclo(Glu-Phe)〕、環丙胺醯離胺酸〔Cyclo(Ala-Lys)〕、環麩胺醯酪胺酸〔Cyclo(Glu-Tyr)〕、環天門冬胺醯離胺酸〔Cyclo(Asp-Lys)〕、環異白胺醯離胺酸〔Cyclo(Ile-Lys)〕、環麩胺醯組胺酸〔Cyclo(Glu-His)〕、環色胺醯天門冬醯胺〔Cyclo(Trp-Asn)〕、環離胺醯離胺酸〔Cyclo(Lys-Lys)〕、環纈胺醯絲胺酸〔Cyclo(Val-Ser)〕、環異白胺醯絲胺酸〔Cyclo(Ile-Ser)〕、環精胺醯酪胺酸〔Cyclo(Arg-Tyr)〕、環精胺醯苯丙胺酸〔Cyclo(Arg-Phe)〕、環離胺醯苯丙胺酸〔Cyclo(Lys-Phe)〕、環天門冬醯胺醯離胺酸〔Cyclo(Asn-Lys)〕、環離胺醯纈胺酸〔Cyclo(Lys-Val)〕、環絲胺醯酪胺酸〔Cyclo(Ser-Tyr)〕、環天門冬胺醯麩胺酸〔Cyclo(Asp-Glu)〕、環組胺醯異白胺酸〔Cyclo(His-Ile)〕、環丙胺醯麩胺酸〔Cyclo(Ala-Glu)〕、環纈胺醯甘胺酸〔Cyclo(Val-Gly)〕、環丙胺醯白胺酸〔Cyclo(Ala-Leu)〕、環異白胺醯脯胺酸〔Cyclo(Ile-Pro)〕、環麩胺醯纈胺酸〔Cyclo(Glu-Val)〕、環丙胺醯酪胺酸〔Cyclo(Ala-Tyr)〕、環甘胺醯酪胺酸〔Cyclo(Gly-Tyr)〕、環麩醯胺醯苯丙胺酸〔Cyclo(Gln-Phe)〕、環蘇胺醯纈胺酸〔Cyclo(Thr-Val)〕、環天門冬胺醯纈胺酸〔Cyclo(Asp-Val)〕、環甲 硫胺醯精胺酸〔Cyclo(Met-Arg)〕、環天門冬胺醯白胺酸〔Cyclo(Asp-Leu)〕、環異白胺醯蘇胺酸〔Cyclo(Ile-Thr)〕、環丙胺醯甲硫胺酸〔Cyclo(Ala-Met)〕、環離胺醯脯胺酸〔Cyclo(Lys-Pro)〕、環絲胺醯色胺酸〔Cyclo(Ser-Trp)〕、環白胺醯色胺酸〔Cyclo(Leu-Trp)〕、及環纈胺醯纈胺酸〔Cyclo(Val-Val)〕所成之群的1者或2者以上者。
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