TWI445528B - The use of arachidonic acid as a constituent fatty acid triglyceride for the manufacture of a pharmaceutical composition and a food product for preventing or ameliorating a symptom or a disease caused by aging of the blood vessel caused by a decrease in blood vessel elasticity, The manufacturing method - Google Patents
The use of arachidonic acid as a constituent fatty acid triglyceride for the manufacture of a pharmaceutical composition and a food product for preventing or ameliorating a symptom or a disease caused by aging of the blood vessel caused by a decrease in blood vessel elasticity, The manufacturing method Download PDFInfo
- Publication number
- TWI445528B TWI445528B TW093132969A TW93132969A TWI445528B TW I445528 B TWI445528 B TW I445528B TW 093132969 A TW093132969 A TW 093132969A TW 93132969 A TW93132969 A TW 93132969A TW I445528 B TWI445528 B TW I445528B
- Authority
- TW
- Taiwan
- Prior art keywords
- arachidonic acid
- acid
- fatty acid
- triglyceride
- blood vessel
- Prior art date
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- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 title claims description 297
- 235000021342 arachidonic acid Nutrition 0.000 title claims description 150
- 229940114079 arachidonic acid Drugs 0.000 title claims description 150
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- 235000014113 dietary fatty acids Nutrition 0.000 title claims description 71
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- 150000004665 fatty acids Chemical class 0.000 title claims description 71
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Classifications
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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Description
本發明係有關以含有花生四烯酸或以花生四烯酸為構成脂肪酸之化合物為主要成分;對於血管老化所引起之症狀或疾病,具有預防或改善作用之組成物,與對於血管老化所引起之症狀或疾病,具有預防或改善作用之飲食品,以及其製造方法。更詳細而言,有關花生四烯酸,花生四烯酸之醇酯,花生四烯酸作為構成脂肪酸之三酸甘油酯,再加上選自磷脂質之群至少一種作為有效成分,具有對於血管彈性之降低,動脈硬化,例如對於缺血性臟疾病(心筋梗塞、狹心症)或腦中風(腦出血、腦梗塞)具有預防或改善作用之組成物,與具有預防或改善作用之飲食品,以及其製造方法。
近年來,隨著醫療的進步,快速趨向高齡化社會。隨着動脈硬化病患人數亦增加。根據「2000年度版厚生白書」及「腦梗塞性老人對策檢討報告書」,在於2000年度的動脈硬化病患人數為150~160萬人,而65歲以上的動脈硬化病患14人中就有1人。因而臆測2030年病患人數,穩定增加為10人中有1人。動脈硬化大致可分為粥狀動脈硬化、中膜鈣硬化、細動脈硬化等三種。
臨床上以粥狀動脈硬化最為重要,其好發部位為從大
動脈到四肢之動脈,冠狀動脈,腦底部動脈等。動脈硬化隨著病情進行,可發現有缺血性心臟疾病、包括頸動脈狹窄在內之腦梗塞、閉塞性動脈硬化症之症狀,致妨礙日常生活或社會生活。粥狀動脈硬化之危險因子除高膽固醇血症外,雖尚有年齡之增加,高血壓,糖尿病,抽菸,冠狀動脈疾病之家族病史,低HDL-膽固醇血症等,但其對於促進粥狀動脈硬化之機制,認為係多種之因子複合所成之結果(藥局54,2245-2249,2003)。
從此種觀點言,對應於推測動脈硬化疾病之危險因子,而通常施用之高脂血症治療藥,高血壓治療藥,糖尿病治療藥等之原發性預防治療,與對應於缺血性心臟疾病或腦梗塞等狀,所投藥之抗血小板藥,ACE抑制藥,β遮斷藥,抗凝固藥,腦保護藥等之繼發性預防治療(藥局54,2287-2303,2003)。但其幾乎都在於抑制腦部形成血栓之抗血小板凝集藥或抗凝血酶藥;抑制腦缺血所引起的細胞障礙之腦保護藥;或引起動脈硬化的危險因子的高脂血症之高脂血症治療藥;對於高血壓的降壓劑等對症療法,而對於改善隨着血管老化引起的變化之藥劑,未被注意之情形。
動脈硬化性疾病與血管息息相關。該血管細胞膜所構成之磷脂質為高度不飽和脂肪酸,其以花生四烯酸,25碳5烯酸及26碳6烯酸作為構成脂肪酸而結合為主。但該等高度不飽和脂肪酸在動物體內無法重新(de novo)合成,須直接或間接(如為花生四烯酸時,其前驅物為亞油酸;如為25碳
5烯酸及26碳6烯酸時,其前驅物為α-亞麻酸)從飲食品攝取。迄今含有亞油酸或α-亞麻酸之高度不飽和脂肪酸,具有降低血中膽固醇之作用,同時被認為具有動脈硬化預防效果而備受期待及注目(食糧、營養、健康,72-78,1991)。
但另一方面,n-6系高度不飽和脂肪酸之亞油酸攝取過多,亦有使動脈硬化反而惡化之報告(臨床營養87,254-259,1995);而對於預防動脈硬化有效的n-3系高度不飽和脂肪酸之α-亞麻酸,25碳5烯酸及26碳6烯酸,反而被積極攝取使用。而且在於醫藥品使用上,對於高脂血症及閉塞性動脈硬化症的治療藥,雖己有25碳5烯酸乙基酯上市銷售,但其機制並非作用於血管細胞膜,而是以膽固醇降低作用為基礎。
非專利文獻1 2000年度厚生白皮書
非專利文獻2 藥局54,2245-2249,2003
非專利文獻3 藥局54,2287-2303,2003
非專利文獻4 食糧、營養、健康,72-78,1991
非專利文獻5 臨床營養87,254-259,1995
因此,由於預防血管老化,維持血管本身的彈性,改善或預防血管老化所引起之症狀或疾病,另強烈期望能開發對食品具有良好適應性且副作用低之化合物。
因此本發明等,係提供以花生四烯酸或以花生四烯酸
為構成脂肪酸之化合物作為有效成分,而對於血管老化所引起於之症狀或疾病,具有預防或改善作用之組成物,與血管老化所引起之症狀或疾病,具有預防或改善作用之飲食品,以及其製造方法。
更詳細而言,提供花生四烯酸,花生四烯酸之醇酯,花生四烯酸作為構成脂肪酸之三酸甘油酯,另加上選自磷脂質之群至少一種作為有效成分,具有對於血管彈性之降低,動脈硬化,例如缺血性心臟疾病(心筋梗塞、狹心症)或腦中風(腦出、腦梗塞)具有預防或改善作用之組成物,與具有預防或改善作用之飲食品,以及其製造方法。
本發明人等為要解明以花生四烯酸或以花生四烯酸為構成脂肪酸之化合物作為有效成分,對於血管老化所引起之症狀或疾病,具有預防或改善效果為目的,經努力研究結果,令人驚奇者,以20個月齡以上之老齡老鼠,供為血管弛緩之確認試驗,得以解明本發明的有效成分之效果。
再者,以微生物所生產的含有花生四烯酸20%以上之三酸甘油酯,得以工業生產化成功,因而可供為本發明的效果試驗而明白其效果。
再者,根據酵素法製成在於1,3-位有中鏈脂肪酸,而2-位有花生四烯酸結合的含有三酸甘油酯之油脂,因而可大量供為本發明的效果試驗而解明其效果。
因而根據本發明提供以花生四烯酸或以花生四烯酸為構成脂肪酸之化合物作為主要成分,對於血管老化所引起之症狀或疾病,具有預防或改善作用之組成物,與對於血
管老化所引起之症狀或疾病,具有預防或改善作用之飲食品,及其製造方法。更詳細而言,可提供有關花生四烯酸,花生四烯酸之醇酯,以花生四烯酸作為構成脂肪酸之甘油三酸酯,加上選自磷脂質之群至少一種作為有效成分,具有對於血管彈性之降低,動脈硬化,例如對於缺血性心臟疾病(心筋梗塞、狹心症)或腦中風(腦出血、腦梗塞)具有預防或改善作用之組成物,與具有預防或改善作用之飲食品,以及其製造方法,故對生活於現代社會之人類,特別有貢獻。
第1圖係以老齡老鼠的血管實施活體外試驗中,乙醯膽鹼濃度與血管弛緩率之關係所表示之曲線。
第2圖係含有花生四烯酸飼料的效果影響於老齡老鼠的胸部大動脈中之花生四烯酸含量所表示之曲線。
第3圖係老齡老鼠血管中之花生四烯酸含量與血管弛緩率的關係所表示之曲線。
本發明係有關以花生四烯酸或以花生四烯酸為構成脂肪酸之化合物作為主要成分;對血管老化所引起之症狀或疾病,具有預防或改善作用之組成物,與對血管老化所引起之症狀或疾病,具有預防或改善作用之飲食品,及其製造方法。
血管老化所引起之症狀或疾病,雖可舉例如血管彈性
之降低,動脈硬化【例如缺血性臟疾病(心筋梗塞、狹心症)或腦中風(腦出血、腦梗塞)】,但並非僅限定於該等疾病,由於血管老化所引起之症狀或疾病,均包含在內。
P.Ghosh等報告對於12~14週齡雌性老鼠,從交配前10天起至出產後21天為止,給與高脂肪性飼料(混合20%油脂),在其離乳後,恢復為一般性飼料(混合3%油脂),雖再將其飼養至23週齡,與交配後第10天起至出產後第21天期間,給與一般性飼料比較,結果其由於乙醯膽鹼所引起之弛緩反應(血管彈性的指標)較小(J.Physiol.533,815-822,2001)。
再者,從父母代飼養高脂肪性飼料群所生的老鼠血管之磷脂質中的脂肪酸組成,在於離乳後雖飼以一般性飼料,與父母代飼養一般性飼料所生產之老鼠比較,花生四烯酸量顯然減少。但從一般性飼料中,僅含有花生四烯酸0.13%之事實,而根據傳統上認知而言,花生四烯酸的效果是不能期待的。
本發明人等,著眼於隨著老鼠年齡增加,顯示有血管弛緩之降低情形,因而顛覆了傳統上之認知,發現花生四烯酸的效果,得以完成本發明。
本發明之有效成分為花生四烯酸,因此可利用以花生四烯酸為構成脂肪酸之化合物。以花生四烯酸為構成脂肪酸之化合物有花生四烯酸塩,可舉例如鈣塩,鈉塩等。另,花生四烯酸的低級醇酯,可舉例如花生四烯酸甲基酯,花生四烯酸乙基酯等。另,以花生四烯酸為構成脂肪酸之三
酸甘油酯,磷脂質,及糖脂質等均可利用。另,本發明並非僅限定上述所舉例者,以花生四烯酸為構成脂肪酸之所有化合物,均可利用。
考慮到對於適用於食品時,花生四烯酸以三酸甘油酯或磷脂質之形態,特以三酸甘油酯之形態最為理想。在於自然界含有花生四烯酸之三酸甘油酯(與構成脂肪酸之一部分或全部,皆為含有花生四烯酸之三酸甘油酯同義)之供給源幾乎不存在,由於本發明人等以含有花生四烯酸作為構成脂肪酸之三酸甘油酯,在工業上成為可充分利用,而對20個月齡以上的老齡老鼠之血管弛緩效果得以評價,因而首先解明本發明的有效成分之效果,確定了對於血管老化所引起之症狀或疾病,具有預防或改善效果。
由於本發明中,本發明之有效成分為構成脂肪酸之一部分或全部,係含有花生四烯酸為三酸甘油酯之三酸甘油酯(含有花生四烯酸之三酸甘油酯)均可使用。而含有花生四烯酸之三酸甘油酯,其構成三酸甘油酯之全脂肪酸中,花生四烯酸有20%重量(w/w)%以上之比例,而以30重量%為佳,較佳為40重量%以上之油脂(甘油三酸酯),為適用於食品的最期望之形態。因此,在本發明中,由具有生產含有花生四烯酸之油脂(甘油三酸酯)能力之微生物,培養所得者均可使用。
微生物具有生產含有花生四烯酸之油脂(三酸甘油酯)能力者,可舉例如屬於Mortierella屬、Conidiobolus屬、Pythium屬、Phytophthora屬、Penicillium屬、Cladosporium
屬、Mucor屬、Fusarium屬、Aspergillus屬、Rhodotorula屬、Entomophthora屬、Echinosporangium屬、Saprolegnia屬等微生物。
Mortierella屬Mortierella亞屬所屬之微生物中,可舉例如Mortierella elongata,Mortierella exigua,Mortierella hygrophilla,Mortierella alpina。具體而言可舉例如Mortierella elongata IF08570,Mortierella exigua IF08571,Mortierella hygrophilla IF05941,Mortierella alpina IF08568,ATCC16266,ATCC32221,ATCC42430,CBS219.35,CBS224.37,CBS250.53,CBS343.66,CBS527.72,CBS529.72,CBS608.70,CBS.68等菌株。
該等菌株可自大阪市財團法人醱酵研究所(IFO),美國Aerican Type Culture Collection(ATCC)及Centrralbureau voor Schimmelcultures(CBS)等機關不受任何限制取得。另本發明的研究團隊,從土壤分離所得之菌株Mortierella elongata SAM0219(微工研菌寄第8703號)(微工研菌寄第1239號)亦可使用。
本發明使用之菌株培養時,將該菌株之胞子,菌絲,或預先培養所得之前培養液,接種培養於液體培養基或固體培養基。液體培養基時,其碳源雖通常使用葡萄糖,果糖,木糖,蔗糖,麥芽糖,可溶性澱粉,糖蜜,甘油,甘露糖醇等,任何一種均可使用,並未限定於僅用該等物質。
氮源使用蛋白腖,酵母萃取物,麥芽萃取物,肉萃取物,酪蛋白氨基酸,玉米澱粉廢液(Corn steep liquor),黃
豆蛋白,脫脂黃豆,棉籽餅等天然氮源之外,尿素等有機氮源,以及硝酸鉀,硝酸銨等亦可使用。其他因應必要可使用磷酸塩,硫酸鎂,硫酸鐵,硫酸銅等無機塩,硫酸銨等無機氮源,以及維他命等供為微量營養供給源。該等培養基成分,在於不為害微生物的發育之濃度範圍,並未特予限制。在實用上,通常碳源為0.1~40重量%,而以1~25重量%之濃度為佳。初期的氮源添加量為0.1~10重量%,而以0.1~6重量%為佳,亦可在培養過程中連續添加氮源。
再者,可由控制培養基碳源濃度,將含有花生四烯酸45重量(w/w)%以上之油脂(甘油三酸脂)作為本發明之有效成分。培養期中,培養第2~4天為止係菌體增殖期,培養第2~4天以後為油脂蓄積期。初期的碳源濃度為1~8重量%,而以1~4重量%之濃度為佳;僅於菌體增殖期及油脂蓄積期的初期培養,逐次增添碳源,而逐次增添的碳源總量和為2~20重量%,而以5~15重量%為佳。另,在於菌體增殖期及油脂蓄積期之間,碳源之逐次增加量,因應初期培養的氮源濃度之添加,通常在於培養第7天以後,而以培養第6天為佳,較佳者為培養第4天以後,由於使培養基中之碳源濃度漸趨於0,因而可獲得含有花生四烯酸45重量%以上之油脂(三酸甘油酯),可作為本發明之有效成分。
花生四烯酸生產菌的培養溫度,雖依使用之微生物不同而設定,通常為5~40℃,而以20~30℃為佳;或培養於20~30℃菌體增殖後,續培養於5~20℃,亦可生產不飽和
脂肪酸。根據此種溫度管理,可提高生成脂肪酸中的高度不飽和脂肪酸之比例。培養基之pH為4~10,而以pH5~9為佳,採用通氣攪拌培養,振盪培養或靜置培養。培養期間通常為2~30天,以5~20天之間為佳,較佳者為5~15天。
再者,對於花生四烯酸之油脂(三酸甘油酯)中,提高其花生四烯酸的比例之方法,除控制培養基碳源濃度外,對於含有花生四烯酸之油脂,進行選擇性之加水分解,亦可獲得含有高度花生四烯酸之油脂。該加水分解所使用之脂酶,由於對三酸甘油酯缺乏位置特異性,因此加水分解隨著雙重結合數之比例降低,故高度不飽和脂肪酸以外的脂肪酸之酯結合被加水分解。因此,在於所產生PUFA的部分三酸甘油酯之間,發生酯交換反應,成為高度不飽和脂肪酸提高之三酸甘油酯【「Enhancement of Archidonic:Selective Hydrolysis of a Single-Cell Oil from Mortierella with Candida cylindracea Lipase」;J.Am.Oil Chem.Soc 72,1323-1327(1998)】。
誠如上述,含有花生四烯酸之油脂,經加水分解得到之高度含有花生四烯酸之油脂(三酸甘油酯),可作為本發明之有效成分。本發明之含有花生四烯酸的油脂(甘油三酸酯)之全脂肪酸,對於花生四烯酸之比例,雖以排除其他的脂肪酸之影響為目的而期望使用較高比例者,但並非僅限定於高比例,實際在適用於食品上,有時花生四烯酸之絕對量,可能會成為問題;雖是含有10重量%以上花生四烯酸之油脂(甘油三酸酯),實質上亦可使用。
再者,在本發明中以上的花生四烯酸之油脂(三酸甘油構成脂肪酸的一部分或全部為花生四烯酸之三酸甘油酯,在於1,3-位有鏈脂肪酸,而於2-位有花生四烯酸結合之三酸甘油酯可供使用。另,在於1,3-位有中鏈脂肪酸,而於2-位有花生四烯酸結合之三酸甘油酯為5摩耳%以上,而以10摩耳%以上為佳,較佳者20摩耳%以上,最佳者可使用含有30摩耳%以上之油脂(三酸甘油酯)。在於上述三酸甘油酯的1,3-位結合之中鏈脂肪酸,可利用選自具有碳數6~12個之脂肪酸。具有碳數6~12個之脂肪酸,可舉例如辛酸或癸酸等。特以1,3-辛酸-2-花生四烯酸-甘油(1,3-Capryloyl-2-Arachidonoyl-glycerol)(以後簡稱「8A8」)為佳。
該等在於1,3-位有中鏈脂肪酸,而於2-位有花生四烯酸結合之三酸甘油酯,係最適於高齡者為對象之油脂(三酸甘油酯)。通常攝取油脂(三酸甘油酯),進入小腸中,雖受胰臟油酶之加水分解,該胰臟油酶具有1,3-位特異性,故三酸甘油酯之1,3-位被切斷成2分子之游離脂肪酸,同時生成1分子之2-單醯基甘油(2-MG)。由於該2-MG對於膽汁酸溶解性極高而吸收性良好,據說通常以2-位脂肪酸之吸收性較高。
另,2-MG溶解膽汁酸時,具有類似界面活性劑之作用,故可提高游離脂肪酸之吸收作用。其次,游離酸與2-MG,與膽固醇或磷脂質等同時,生合成膽汁酸複合微胞,被吸收於小腸上皮細胞,引起再合成三甘油脂),最後成為
乳糜微粒(chylomicrons)而放出。不過,該胰臟油酶的脂肪酸特性具有高飽和脂肪酸,花生四烯酸不易切斷之特徵。另有問題在於胰臟油酶活性,隨年齡增加降低低,故對易於血管老化所引起之症狀或疾病之高齡者而言,在於1,3-位有鏈脂肪酸,而於2-位有花生四烯酸之結合三酸甘油酯,成為最適用之油脂(三酸甘油酯)。
1,3-位有中鏈脂肪酸,而於2-位有花生四烯酸結合之三酸甘油酯,其具體的製法之一,係含有花生四烯酸之油脂(三酸甘油酯)與中鏈脂肪酸的存在下,以僅作用於三酸甘油酯的1,3-位的酯結合之脂酶作用加以而製造。原料之油脂(三酸甘油酯)係以花生四烯酸為構成脂肪酸之三酸甘油酯,而相對於構成三酸甘油酯之全脂肪酸,其花生四烯酸之比例高時,由於未反應油脂(僅有原料之三酸甘油酯與1,3-位的脂肪酸中之一側,成為中鏈脂肪酸之三酸甘油酯)增加,而為防止反應收率降低起見,通常的酵素反應溫度20~30℃,提高為30~50℃,而以40~50℃為佳。
對於三酸甘油酯的1,3-位之酯結合,具有特異性作用之油酶,可舉例如Rhizopus屬、Rhizomucor屬、Aspergillus屬等之微生物所產生,及豚胰臟油酶等。對於相關之油酶,亦可使用市面上銷售者。雖可舉例如Rhizopus delemar之油酶(田邊製藥股份公司製Talipase),Rhizomucor miehei之油酶(Nodisk,Lipozyme)。Aspergillus niger之油酶(天野製藥股份公司油酶A)等,但並未僅限定使用該等酵素,只要具有對1,3-位特異性的油酶,均可使用。
上述油酶的使用形態,係以提高反應效率為目的,其溫度為30℃以上,為要使適溫為以40℃以上為佳,與附加酵素的耐熱性為目的起見,以使用固定化的固定化載體之油酶為最高期望。固定化載體係多孔性樹脂,具有孔徑約100Å以上之離子交換樹脂載體,可舉例如Dowex MARTHON WBA等。但並未限定僅使用該等固定化載體,只要可附加耐熱性之固定化載體,均可使用。
對於固定化載體1,懸浮於1,3-位特異性油酶水溶液5~20倍重量中,而對於懸浮液以2~5倍量之冷甲苯(例如-8℃),邊攪拌緩慢加入,使之形成沈澱。在減壓下乾燥,該沈澱物可調製成固定化酵素。另更簡便的方法,係相對於固定化載體1,將0.05~0.4倍量的1,3-位特異性的油酶,溶解於最小量限的水,邊攪拌與固定化載體混合,可在減壓下乾燥調製成固定化酵素。根據該操作雖約有90%油酶,可被載體固定化成載體,但在此情形下,酯交換活性完全未顯示,而在加有水1-10重量(w/w)%之基質中,宜在添加水1-3重量(w/w)%之基質中,經前處理,則固定化酵素可發揮至最有效率之活性化,可供用於製造。
依酵素的種類,在於本反應系所添加之水分量極為重要,不含水時,酯交換難於進行;另,水分量多時引起加水分解,甘油酯之回收率降低(引起加水分解,則生成二酸甘油酯及甘油一酸酯)。此種由於使用因前處理而活性化之固定化酵素,在本反應系中添加之水分量,失去其重要性,故在完全不含水之系統中,亦可引起效率良好之酯交換反
應。另由於酵素劑種類之選擇,亦可省略前處理。
誠如所述,使用具有耐熱性之固定化酵素,提高了酵素反應溫度,在於1,3-位特異性油酶,雖含有反應性低的花生四烯酸之油脂(三酸甘油酯),亦不會使之降低反應效率,反而在於1,3-位有中鏈脂肪酸,而於2-位有花生四烯酸結合之三酸甘油酯(8A8),可有效率地製成。
有關血管老化所引起之症狀及疾病,具有預防或改善作用的飲食品之製法,以花生四烯酸及/或以花生四烯酸為構成脂肪酸之化合物,單獨或實質性不含花生四烯酸,或有含有花生四烯酸,但僅能與少量飲食品原料混合。此處所指之少量,意即飲食品原料雖含有花生四烯酸,而與其混合之食品組成物,雖經人食用攝取,仍然未達後述本發明的花生四烯酸1天攝取量之量。
特別是構成脂肪酸一部分或全部為花生四烯酸之三酸甘油酯時,有關油脂(三酸甘油酯)之用途具有無限之可能性,可作為食品,飲料,化粧品,醫藥品的原料。然而,有關其使用目的,使用量並不受任何之限制。
例如作為食品組成物可舉例如一般食品之外,機能性食品,培養補助食品,特定保健用食品,早產兒用調製乳,乳嬰用調製乳,孕婦用食品或老人用食品等。含有油脂之食品例,可舉例如肉類,魚類,或堅果等含有本身具有的油脂之天然食品;在湯汁等調理食品中添加油脂之食品;甜甜圈等之載熱體所使用油脂的食品;奶油等油脂食品;餅乾等加工裝飾所噴霧或塗抹的油脂之食品等。另,對於
不含油脂之,農產食品,醱酵食品,畜產食品,水產食品或飲料中亦可添加。另,不管機能性食品,醫藥品的形態,例如成為經腸管營養劑,粉末,顆粒,含劑,內服液,懸浮液,乳濁液,糖漿等之加工形態亦可。
再者,本發明的組成物除本發明之有效成分外,通常在於飲食品,醫藥品或準醫藥品(例如藥用牙膏)中,所用之各種載體或添加物亦可含有。特別對於本發明之有效成分,期望含有抗氧化為目的之抗氧化劑。抗氧化劑可舉例如生育酚類,黃酮衍生物,甜茶內酯類,麴酸(kojic acid),沒食子酸衍生物,兒茶酸類,款冬酸(butterbur acid)。棉子酚,吡嗪衍生物,芝麻酚,碘愈木醇,愈瘡木酸,p-香豆酸,去甲二氫愈瘡木酸(Nordihydro-guaiaretic acid),固醇類,萜烯類,核酸鹼類(nucleic acid bases),類胡蘿蔔素類,木聚糖類等天然抗氧化劑,以及抗壞血酸,棕櫚酸酯(Palmitc acid ester),抗壞血酸硬脂酸酯,丁基羥基茴香醚(BHA),丁基羥基甲苯(BHT),1-t-丁基輥醇(TBHQ),4-羥基甲基-2,6-雙-t-丁基苯酚(HMBP)等所代表之合成抗氧化劑。
生育酚類可舉例如α-生育酚,β-生育酚,γ-生育酚,δ-生育酚,ε-生育酚,ζ-生育酚,η-生育酚及生育酚酯(醋酸生育酚等);另有類似化合物之生育三烯醇。另,類胡蘿蔔素類可舉例如β-胡蘿蔔素,角黃素(Canthaxanthin),蝦黃素等。
本發明的組成物除本發明之有效成分外,載體可舉例
如各種載體,增充劑,稀釋劑,增量劑,分散劑,賦形劑,結合劑溶劑(例如水,乙醇,植物油),溶解補助劑,緩衝劑,溶解促進劑,膠化劑,懸濁化劑,小麥粉,米粉,澱粉,玉米澱粉,多糖類,乳蛋白質,膠原,米油,卵磷脂等。添加劑雖可舉例如維他命類,甘味料,有機酸,着色劑,香料,抗潮濕劑(Anti-moisturizing),纖維,電解質,礦物質,營養素,抗氧化劑,保存劑,芳香劑,濕潤劑(Humictants),天然食品萃取物,蔬菜萃取物等,並未限定僅使用該等添加劑。
花生四烯酸及花生四烯酸所構成脂肪酸之化合物,其主藥效成分在於花生四烯酸。據報告(脂質營養學4,78-82,1995)花生四烯酸從食物之一天攝取量,關東地區為0.14g,關西地區為0.19~0.20;有關高齡者對油脂攝取量之降低,從胰臟油酶活性降低點等因素考量,有必要攝取相當量或更多量之花生四烯酸。因此,本發明花生四烯酸及花生四烯酸所構成脂肪酸之化合物,成人(例如體重為60kg)一天攝取量,換算成花生四烯酸為0.001g-20g,而以0.01-10g為佳,較佳者為0.05-5g,最佳為0.1-2g。
本發明的有效成分實際上適用為飲食品時,食品所混合之花生四烯酸的絕對量極為重要。但是,飲食品所混合之絕對量,由於亦隨著混合飲食品攝取量而變化,故以含有構成脂肪酸一部分或全部為花生四烯酸的三酸甘油酯之三酸甘油酯混合於食品時,混合花生四烯酸為0.001重量%以上,而以0.01重量%以上為佳,較佳者為0.1重量%以上。
另,將在1,3-位有中鏈脂肪酸,而於2-位有花生四烯酸結合之三酸甘油酯,混合於飲食品時為0.0003重量%以上,而以0.003重量%以上為佳,較佳者0.03重量%以上。
本發明之組成物供為醫藥品使用時,在製劑技術領域中所慣用的方法,例如可根據日本藥局方所記載的方法,或比照該方法製造。
本發明之組成物供為醫藥品使用時,組成物中有效成分之分配量,以可達成本發明目的之範圍內,未特予限制,適當地調整混合比例即可使用。
本發明之組成物供為醫藥品使用時,期望以投藥劑量單位之形態來給藥,特別以口服投藥為佳。本發明的組成物投藥量,雖依年齡,體重,症狀,投藥次數等而異,例如成人(以60kg為準)以本發明的花生四烯酸及/或以花生四烯酸為構成脂肪酸之化合物,一天需要量換算為花生四烯酸量,通常約為0.001g-20g,而以01g-10g為佳,較佳為0.05g-5g,最佳為0.1g-2g,分成一天1-3次投藥為宜。
在於構成血管細胞膜之磷脂質中,結合有高度不飽和酸脂肪酸,其以花生四烯酸,25碳5烯酸與26碳6烯酸為構成脂肪酸結合為主;當考慮到平衡問題時,所期望者係以25碳5烯酸及/或26碳6烯酸組合列成者。
然而,在於花生四烯酸與26碳6烯酸組合,所期望者係以花生四烯酸/25碳5烯酸及/或26碳6烯酸之比,在於.25~8範圍內之飲食品。
其次,對於本發明舉述實施例加以詳細說明。但本發
明不受此等實施例所限制。
以花生
四烯酸為構成脂肪酸的
三酸甘油酯之製法
使用花生四烯酸生產菌之Mortierella alpina CBS754.68。含有葡萄糖1.8%,脫脂黃豆粉3.1%,黃豆油0.1%,KH2PO4 0.3%,Na2SO4 0.1%,CaCl2、2HH2O 0.05%,及MgCl2、6H2O之培養基6KL,置入於10KL培養槽中,初期PH調整為6.0。菌種接種於前述培養基液30KL,在於溫度26℃,通氣量360m3/h,槽內壓200kPa的條件下,進行通氣攪拌培養8天。另,調整攪拌數以溶解氧濃度可維持於10~15ppm範圍。另,葡萄糖濃度到第4天為止,以連續添加之方法將培養基中之葡萄糖濃度,維持於1~2.5%範圍,此後維持於0.5~1%(前述%意為重量(W/V)%)。
培養結束後,過濾,乾燥以回收含有以花生四烯酸為構成脂肪酸的三酸甘油酯之菌體,從所得的菌體以己烷萃取獲得油脂,經食用油脂精製工程(脫膠,脫酸,脫臭,脫色),得到含有花生四烯酸之三酸甘油酯(構成脂肪酸一部分或全部,為含有花生四烯酸的三酸甘油酯之三酸甘油酯)150kg。所得的油脂(三酸甘油酯)經酙甲基酯化,將得到脂肪酸甲基酯,以氣相層析法分析結果,在全脂肪酸中花生四烯酸所佔的比例為40.84%。
再者,棕櫚酸,硬脂酸,油酸,亞油酸,γ-亞麻酸,雙高-γ-亞麻酸(Dihomo-γ-linolenic acid)等,各分別含有11.63%,7.45%,7.73%,9.14%,2.23%,3.27%。
另,前述含有花生四烯酸之油脂(三酸甘油酯)(SUNTGA40S)經乙基酯化,從含有花生四烯酸乙基酯40%之脂肪酸油脂混合物,以規定方法的高速液相層析法,分離、精製99%花生四烯酸甲基酯。
在於1,3-位有中鏈脂肪酸,而於2-位有花生四烯酸結合之三酸甘油酯(8A8),製造含有5%以上之三酸甘油酯
離子交換樹脂載體(Dowex MARATHON WBA:Dow Chemical.)100g,懸浮於Rhizopus delemar油酶水溶液(Talipase粉末12.5%:田邊製藥股份公司)80ml,以冷甲苯(-80℃)240ml攪拌,在減壓下乾燥獲得固定化油酶。
其次,在參考例1所得的含有40%花生四烯酸酯之三酸甘油酯(SUNTGA40S)80g,辛酸160g,前述固定化油酶12g,水4.8ml,在於30℃、48小時,邊攪拌(130rpm)使之反應。反應結束後,去除反應液,得到活性化之固定化酵素。
其次,將固定化酵素(Rhizopus delemar油酶,載體:Dowex MARATHON WBR)10g,充填於附有套管之玻璃管柱(1.8 x 12.5cm,容量31.8ml),將參考例得到的SUNTGA40S與辛酸,將1:2混合的反應油脂,以一定的流速(40ml/h)通過管柱,經連續反應獲得反應油脂400g。另,管柱溫度為40~41℃。從所得的反應油脂中未反應的辛酸與游離脂肪酸,以分子蒸餾去除,經食用油脂精製工程(脫膠,脫酸,脫臭,脫色),得到含有8A8之油酯(三酸甘油酯)。
然後,以氣相層析法及高速液相層析法,調查所得的
含有8A8油脂(三酸甘油酯)中8A8之比例為31.6%(另,8P8,808,8L8,8G8,8D8之比例,各分別為0.6,7.9,15.1,5.2,4.8%。在於三酸甘油酯的2-位結合之脂肪酸P,O,L,G,D分別表示棕櫚酸,油酸,γ-亞油酸,雙高-γ-亞麻酸。8P8為1,3-capryloyl-2-Palmitolein-glycerol;808為1,3-capryloyl-2-oleoyl-glyerol,8L8為1,3-capryloyl-2-linoleoyl-glcerol,8G8為1,3-capryloyl-2-γ-linolenoyl-glycerol,8D8為1,3-capryloyl-2-dihomo-γ-linolenoyl-glycerol)。另,從所得的含有8A8油脂(三酸甘油酯),以規定方法的高速液相層析法,分離、精製得到96摩耳%之8A8。
依據乙醯膽鹼血管弛緩反應試驗對於SUNTGA40S之評價
以參考例1所調製的花生四烯酸為構成脂肪酸之三酸甘油酯{含有花生四烯酸油脂(SUNTGA40S)},以老鼠調查乙醯膽鹼對於血管弛緩反應之影響。以老齡老鼠為實驗群,分成19個月齡雄性Fischer系老鼠15隻作為對照飼料群(8隻:OC群)與SUNTGA40S混合飼料群(7隻:OA群)之2群,分別投給與第1表所示的對照飼料與SUNTGA40S混合飼料。然而,以年青老鼠作為對照群,1個月齡雄性Fischer系老鼠10隻,給與第1表之對照飼料(10隻:YC群)
每隻老鼠的攝取量約為20g,每隻老鼠一天SUNTGA40S的攝取量為100mg。參考例1調製的含有花生四烯酸油脂(SUNTGA40S)所結合之全脂肪酸中,由於含有40%為花生四烯酸,故老鼠每隻一天攝取花生四烯酸量為40mg。該40mg換算為人類的攝取量相當於133mg/60kg/天。
飼養至第3個月(老齡老鼠時為22個月齡,年青老鼠時為4個月齡)開刀摘出胸部大動脈,部分供為活體外之血管弛緩反應試驗,殘餘的血管供為脂肪酸組成分析之用。血管弛緩反應試驗,將慎重摘出而未傷及血管內皮之胸部大動脈製成血管環,以脫羥腎上腺素引起前收縮後,測定以乙醯膽鹼10-9~10-6M濃度引起之弛緩反應。該項結果與年青老鼠比較結果,老齡老鼠的血管弛緩反應明顯下降,但由於攝取含有花生四烯酸油脂,老齡老鼠之血管弛緩反應獲得改善(第1圖)。
其次,從摘出的胸部大動脈以Folch法萃取全脂質。萃取的脂質與乙醇共沸去除水分後,以10%塩酸-甲醇作成
之脂肪酸甲基酯,以氣相層析法分析脂肪酸組成。該項結果與年青老鼠比較,接近老齡老鼠的血管單位重量,所含之花生四烯酸量明顯下降,但由於攝取含有花生四烯酸油脂,接近老齡老鼠之血管單位重量,所含之花生四烯酸量增加(第2圖)。另,對於接近老齡老鼠胸部大動脈單位重量,所含之花生四烯酸量,求其與乙醯膽鹼10-7M引起之血管弛緩率之關聯性,結果認為其與花生四烯酸含量之間,顯示有意義之高度關聯(R=0.92)(第3圖)。誠如上述,由於攝取含有花生四烯酸油脂,因而初顯其具有可改善血管弛緩之能力,或血管內皮細胞之機能,而其效果係來自花生四烯酸,首先獲得解明。
依據乙醯膽鹼血管弛緩反應試驗對於8A8(96摩耳%)之評價
以參考例2調製的1,3-位有中鏈脂肪酸,而於2-位結合有花生四烯酸之三酸甘油酯(8A8),以老鼠調查對於乙醯膽鹼血管弛緩之影響。以老齡老鼠為實驗群,分成19個月齡雄性Fischer系老鼠15隻作為對照飼料群(8隻:OC群)與8A8混合飼料群(7隻:OB群)之2群,分別給與第2表所示的對照飼料與8A8混合飼料。另以年青老鼠作為對照群,將第2表之對照飼料給與1個月齡雄性Fischer系老鼠10隻(10隻:YC群)。另,混合於8A8混合飼料之8A8,係使用參考例2得96摩耳%之8A8。
每隻老鼠的攝取量約為20g,由於8A8的分子量為628.7,故實驗食料對於8A8混合飼料群的老鼠,設計成每隻一天花生四烯酸攝取量為40mg。該40mg換算為人類攝取量相當於133mg/60kg/天。
飼養至第3個月(老齡老鼠時為22個月齡,年輕老鼠時為4個月齡)開刀摘出胸部大動脈,部分供為活體外之血管弛緩反應試驗,殘餘的血管供為脂肪酸組成分析用。血管弛緩反應試驗,將慎重摘出不傷及血管內皮之胸部大動脈製成作血管環,以脫羥腎上腺素引起前收縮後,測定以乙醯膽鹼10-9~10-6M濃度引起之弛緩反應。
該結果依乙醯膽鹼10-7M濃度引起之平均弛緩率,以攝取對照飼料的年青老鼠為80.5%,攝取對照飼料的老齡老鼠為52.3%,攝取8A8混合飼料的老齡老鼠為62.7.5%,故老齡老鼠由於攝取8A8,其血管弛緩反應獲得改善。
混合花生四烯酸為構成脂肪酸的油脂(三酸甘油酯)膠
囊之調製
明膠100重量分,與食品添加級甘油35重量分,加水於50~60℃溶解,調製成粘度2000cp的明膠被膜。然後將參考例1所得含有花生四烯酸油脂(三酸甘油酯),與維他命E油0.05重量%混合,調製成內容物1。參考例2所得的含有32摩耳%的8A8油脂(三酸甘油酯),與維他命E油0.05重量%混合,調製成內容物2。
其次,參考例1所得含有花生四烯酸油脂(三酸甘油酯)50重量%,與魚油(鮪魚油:全脂肪酸中25碳5烯酸與26碳6烯酸所佔的比例,分別為5.1%及26.5%)50重量%混合,混合維他命E油0.05重量%調製成內容物3。含有花生四烯酸油脂(三酸甘油酯)80重量%,與魚油(鮪魚油:全脂肪酸中25碳5烯酸與26碳6烯酸所佔的比例,分別為5.1%及26.5%)20重量%混合,混合維他命E油0.05重量%,調製成內容物4。參考例1所得99%花生四烯酸甲基酯,混合維他命E油0.05重量%調製成內容物5。使用該等內容物1~5,依照通常方法進行膠囊之成形及乾燥,製成1粒含有200mg內容物之軟膠囊。
供用為脂肪輸液劑
參考例2所得的含有32% 8A8的油脂(三酸甘油酯)400g,加入精製蛋卵磷脂48g,油酸20g,甘油100g及0.1N苛性鈉40ml,以均質器打散後,加入注射用蒸餾水調成4L。以高壓噴霧式乳化機將其乳化調製成脂質乳液。該脂質乳
液各分裝200ml於塑膠製袋後,在121℃ 20分鐘高壓蒸氣滅菌處理供用為脂肪輸液劑。
供用為果汁
β-環糊精2g添加20%甲醇水溶液20ml,邊以攪拌器攪拌,加入參考例1所得含有花生四烯酸之三酸甘油酯(調有維他命E油0.05重量%)100mg,在50℃培養2小時。在室溫冷却(約1小時後)後,在於4℃持續攪拌,培養10小時。生成的沈澱以遠心分離回收,以n-乙烷清洗後凍結乾燥,得到含有花生四烯酸中含有三酸甘油酯之環糊精包合化合物1.8g。該粉末1g均勻混合於果汁10L,調製成含有花生四烯酸中含有三酸甘油酯之果汁。
第1圖係以老齡老鼠的血管實施活體外試驗中,乙醯膽鹼濃度與血管弛緩率之關係所表示之曲線。
第2圖係含有花生四烯酸飼料的效果影響於老齡老鼠的胸部大動脈中之花生四烯酸含量所表示之曲線。
第3圖係老齡老鼠血管中之花生四烯酸含量與血管弛緩率的關係所表示之曲線。
Claims (17)
- 一種以花生四烯酸為構成脂肪酸之三酸甘油酯用於製造用於預防或改善因血管彈力性降低造成之血管老化所引起之症狀或疾病之醫藥組成物的用途,該因血管彈力性降低造成之血管老化所引起之症狀或疾病係選自於由血管彈力性降低、動脈硬化、缺血性心臟疾病及腦中風所構成之群組,且該以花生四烯酸為構成脂肪酸之三酸甘油酯含有5%以上,在1,3-位處結合中鏈脂肪酸,並於2-位處結合前述花生四烯酸。
- 如申請專利範圍第1項之用途,其中前述以花生四烯酸為構成脂肪酸之三酸甘油酯中,花生四烯酸佔三酸甘油酯之全脂肪酸之比例為20%以上。
- 如申請專利範圍第1項之用途,其中前述以花生四烯酸為構成脂肪酸之三酸甘油酯係由從屬於Mortierella屬,Conidiobolus屬,Pythium屬,Phytophthora屬,Penicillium屬,Cladosporium屬,Mucor屬,Fusarium屬,Aspergillus屬,Rhodotorula屬,Entomophthora屬,Echinosporangium屬,或Saprolegnia屬之微生物中萃取出來者。
- 如申請專利範圍第1項之用途,其中前述中鏈脂肪酸係選自於具有碳數6至12個之脂肪酸。
- 如申請專利範圍第1項之用途,其中前述缺血性心臟疾病為心肌梗塞及/或狹心症。
- 如申請專利範圍第1項之用途,其中前述腦中風為腦出血及/或腦梗塞。
- 一種以花生四烯酸為構成脂肪酸之三酸甘油酯用於製造用於預防或改善因血管彈力性降低造成之血管老化所引起之症狀或疾病之飲食品的用途,該因血管彈力性降低造成之血管老化所引起之症狀或疾病係選自於由血管彈力性降低、動脈硬化、缺血性心臟疾病及腦中風所構成之群組,且該以花生四烯酸為構成脂肪酸之三酸甘油酯含有5%以上,在1,3-位處結合中鏈脂肪酸,並於2-位處結合前述花生四烯酸。
- 如申請專利範圍第7項之用途,其中前述以花生四烯酸為構成脂肪酸之三酸甘油酯中,花生四烯酸佔三酸甘油酯之全脂肪酸之比例為20%以上。
- 如申請專利範圍第7項之用途,其中前述以花生四烯酸為構成脂肪酸之三酸甘油酯係由從屬於Mortierella屬,Conidiobolus屬,Pythium屬,Phytophthora屬,Penicillium屬,Cladosporium屬,Mucor屬,Fusarium屬,Aspergillus屬,Rhodotorula屬,Entomophthora屬,Echinosporangium屬,或Saprolegnia屬之微生物中萃取出來者。
- 如申請專利範圍第7項之用途,其中前述中鏈脂肪酸係選自於具有碳數6至12個之脂肪酸。
- 如申請專利範圍第7至10項中任一項之用途,其中前述飲食品為機能性食品、營養補助食品、特定保健用食品或老人用食品。
- 如申請專利範圍第7項之用途,其中前述缺血性心臟疾病為心肌梗塞及/或狹心症。
- 如申請專利範圍第7項之用途,其中前述腦中風為腦出血及/或腦梗塞。
- 一種以花生四烯酸為構成脂肪酸之三酸甘油酯用於製造對於因血管彈力性降低造成之血管老化所引起之症狀或疾病具有預防或改善作用的飲食品的用途,該因血管彈力性降低造成之血管老化所引起之症狀或疾病係選自於由血管彈力性降低、動脈硬化、缺血性心臟疾病及腦中風所構成之群組,且該飲食品係在以花生四烯酸為構成脂肪酸之三酸甘油酯,與25碳5烯酸及/或與26碳6烯酸之組合中,花生四烯酸/25碳5烯酸及/或與26碳6烯酸之比在0.25~8之範圍者。
- 一種在1,3-位結合中鏈脂肪酸,並於2-位結合花生四烯酸之三酸甘油酯用於製造對於因血管彈力性降低造成之血管老化所引起之症狀或疾病具有預防或改善作用的飲食品的用途,該因血管彈力性降低造成之血管老化所引起之症狀或疾病係選自於由血管彈力性降低、動脈硬化、缺血性心臟疾病及腦中風所構成之群組,且該飲食品係含有0.001重量%以上,在1,3-位結合中鏈脂肪酸,並於2-位結合花生四烯酸之三酸甘油酯。
- 如申請專利範圍第15項之用途,其中前述中鏈脂肪酸係選自於具有碳數6~12個之脂肪酸。
- 一種製造飲食品的方法,係對於因血管彈力性降低造成之血管老化所引起之症狀或疾病具有預防或改善作用之飲食品的製造方法,該因血管彈力性降低造成之血管 老化所引起之症狀或疾病係選自於由血管彈力性降低、動脈硬化、缺血性心臟疾病及腦中風所構成之群組,該方法之特徵係將以花生四烯酸為構成脂肪酸之三酸甘油酯單獨地混合、或者與實質上不含有花生四烯酸或即使含有花生四烯酸亦為少量之飲食品原料混合,且該以花生四烯酸為構成脂肪酸之三酸甘油酯含有5%以上,在1,3-位處結合中鏈脂肪酸,並於2-位處結合前述花生四烯酸。
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JP2003369147A JP4522075B2 (ja) | 2003-10-29 | 2003-10-29 | 血管の老化に起因する症状あるいは疾患の予防又は改善作用を有する組成物 |
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TW093132969A TWI445528B (zh) | 2003-10-29 | 2004-10-29 | The use of arachidonic acid as a constituent fatty acid triglyceride for the manufacture of a pharmaceutical composition and a food product for preventing or ameliorating a symptom or a disease caused by aging of the blood vessel caused by a decrease in blood vessel elasticity, The manufacturing method |
TW102125771A TWI503117B (zh) | 2003-10-29 | 2004-10-29 | A pharmaceutical composition and a food and medicine for preventing or ameliorating a symptom or a disease caused by aging of the blood vessel caused by a decrease in blood vessel elasticity, a method for producing the same, and arachidonic acid and / or arachidonic acid The use of fatty acid compounds for the manufacture of drugs (2) |
TW104113281A TW201529067A (zh) | 2003-10-29 | 2004-10-29 | 用於預防或改善因血管彈力性降低造成之血管老化所引起之症狀或疾病之醫藥組成物及飲食品、該飲食品的製造方法、以及花生四烯酸及/或以花生四烯酸爲構成脂肪酸之化合物用於製造藥物的用途(三) |
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TW102125771A TWI503117B (zh) | 2003-10-29 | 2004-10-29 | A pharmaceutical composition and a food and medicine for preventing or ameliorating a symptom or a disease caused by aging of the blood vessel caused by a decrease in blood vessel elasticity, a method for producing the same, and arachidonic acid and / or arachidonic acid The use of fatty acid compounds for the manufacture of drugs (2) |
TW104113281A TW201529067A (zh) | 2003-10-29 | 2004-10-29 | 用於預防或改善因血管彈力性降低造成之血管老化所引起之症狀或疾病之醫藥組成物及飲食品、該飲食品的製造方法、以及花生四烯酸及/或以花生四烯酸爲構成脂肪酸之化合物用於製造藥物的用途(三) |
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EP (1) | EP1679068A4 (zh) |
JP (1) | JP4522075B2 (zh) |
KR (1) | KR101245364B1 (zh) |
CN (1) | CN1723016B (zh) |
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EP1542670B2 (en) * | 2002-09-24 | 2023-07-05 | Suntory Holdings Limited | Composition containing arachidonic acid alone or in combination with docosahexaenoic acid for enhancing cognitive abilities in adults |
JP2006083136A (ja) * | 2004-09-17 | 2006-03-30 | Suntory Ltd | ストレスに起因する脳機能の低下およびそれに伴う症状あるいは疾患の予防又は改善作用を有する組成物 |
JP4993852B2 (ja) | 2004-09-17 | 2012-08-08 | サントリーホールディングス株式会社 | ストレスに起因する行動異常を伴う症状あるいは疾患の予防又は改善作用を有する組成物 |
JP5697293B2 (ja) * | 2005-06-30 | 2015-04-08 | サントリーホールディングス株式会社 | 器質的脳障害に起因する高次脳機能の低下に対する改善作用を有する組成物 |
JP5967855B2 (ja) | 2005-06-30 | 2016-08-10 | サントリーホールディングス株式会社 | 日中活動量の低下および/又はうつ症状の改善作用を有する組成物 |
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WO2024047483A1 (en) * | 2022-08-29 | 2024-03-07 | Fundação Calouste Gulbenkian | Arachidonic acid for preventing or decreasing post-operative bleeding |
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- 2004-10-28 CN CN200480001751XA patent/CN1723016B/zh active Active
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AU2004283610A1 (en) | 2005-05-06 |
EP1679068A1 (en) | 2006-07-12 |
AU2004283610B2 (en) | 2011-02-03 |
WO2005039559A1 (ja) | 2005-05-06 |
TW201529067A (zh) | 2015-08-01 |
TW201350112A (zh) | 2013-12-16 |
TW200522939A (en) | 2005-07-16 |
JP4522075B2 (ja) | 2010-08-11 |
JP2005132758A (ja) | 2005-05-26 |
KR20060113360A (ko) | 2006-11-02 |
US20060088573A1 (en) | 2006-04-27 |
CA2512133A1 (en) | 2005-05-06 |
CN1723016A (zh) | 2006-01-18 |
EP1679068A4 (en) | 2010-09-29 |
TWI503117B (zh) | 2015-10-11 |
CN1723016B (zh) | 2012-04-04 |
CA2512133C (en) | 2013-10-01 |
KR101245364B1 (ko) | 2013-03-19 |
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