JP4633048B2 - 日内リズム正常化組成物 - Google Patents
日内リズム正常化組成物 Download PDFInfo
- Publication number
- JP4633048B2 JP4633048B2 JP2006507691A JP2006507691A JP4633048B2 JP 4633048 B2 JP4633048 B2 JP 4633048B2 JP 2006507691 A JP2006507691 A JP 2006507691A JP 2006507691 A JP2006507691 A JP 2006507691A JP 4633048 B2 JP4633048 B2 JP 4633048B2
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- Prior art keywords
- arachidonic acid
- acid
- triglyceride
- pharmaceutical composition
- fatty acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
両者は外界からの影響因子を可能な限り取り除いた場合、それでもなおリズムが存在するかどうかで見分けることができる。外界から隔離された実験室など環境の周期性の影響が及ばないところではヒトは24時間より長い周期を示す。この周期をフリーラン周期といい、内因性周期又は体内時計と考える(ヒトのフリーラン周期は24.2時間)。
したがって、日内リズムの正常化作用及び/又は概日リズム(生物時計)の同調を促進させ、医薬、さらには食品への適応に優れた副作用の少ない化合物の開発が強く望まれている。
さらに、本発明等は、アラキドン酸を10重量%以上含有するトリグリセリドの微生物による工業生産に成功し、本発明の効果試験に供することが可能となり、該トリグリセリドの効果を明らかにした。
従って本発明は、アラキドン酸及び/又はアラキドン酸を構成脂肪酸とする化合物を有効成分とする、日内リズムの正常化作用及び/又は概日リズム(生物時計)の同調促進作用を有する飲食品及びその製造方法を提供しようとするものである。
本発明の組成物を医薬品として使用する場合、組成物中の有効成分の配分量は、本発明の目的が達成される限り特に限定されず、適宜適当な配合割合で使用が可能である。
アラキドン酸生産菌としてモルティエレラ・アルピナ(Mortierella alpina)を用いた。グルコース1.8%、脱脂大豆粉3.1%、大豆油0.1%、KH2PO4 0.3%、Na2SO4 0.1%、CaCl2・2H2O 0.05%及びMgCl2・6H2O 0.05%を含む培地6kLを、10kL培養槽に調製し、初発pHを6.0に調整した。前培養液30Lを接種し、温度26℃、通気量 360m3/h、槽内圧200kPaの条件で8日間の通気撹拌培養を行った。なお、攪拌数は溶存酸素濃度を10-15ppmを維持するように調整した。さらに、グルコース濃度を4日目までは流加法によって培地中のグルコース濃度が1-2.5%の範囲内となるように、それ以降は0.5-1%を維持した(上記の%は、重量(W/V)%を意味する)。
イオン交換樹脂担体(Dowex MARATHON WBA:ダウケミカル、商標)100gを、Rhizopus delemarリパーゼ12.5%水溶液(タリパーゼ現末:田辺製薬(株))80mlに懸濁し、減圧下で乾燥させて固定化リパーゼを得た。
次に、実施例1で得たアラキドン酸を40重量%含有するトリグリセリド(TGA40S)80g、カプリル酸160g、上記固定化リパーゼ12g、水4.8 mlを30℃で48時間、撹拌(130rpm)しながら反応させた。反応終了後、反応液を取り除き、活性化された固定化リパーゼを得た。
実施例1で調製したアラキドン酸を構成脂肪酸とするトリグリセリド(アラキドン酸含有油脂)の明暗周期の位相変化に及ぼす影響をラットを用いて調べた。
ラットは明期に主に休息(睡眠)し、暗期に活動する習性を持つ。そこで、明暗周期を前後6時間変えることで、新たな明暗周期に同調するまでの日数で同調に対する作用を調べた。なお、同調の評価はラットの日内リズムは1日の運動量を連続的に測定し、明期(休息期)と暗期(活動期)の運動量の経時変化を測定することで調べた。
18ヶ月齢雄性Fischer系ラット20匹を対照飼料群(10匹:OC(18M)群)とアラキドン酸含有油脂配合飼料群(10匹:OA(18M)群)の2群に分け、それぞれの群に、表1に示した対照飼料およびアラキドン酸含有油脂配合飼料を2週間の予備飼育後から与えた。
2ヶ月齢、18ヶ月齢、22ヶ月齢の対照飼料群並びにアラキドン酸含有油脂配合飼料群の明期12時間の運動比率(%)を示した(図1)。アラキドン酸含有油脂の摂取により、老齢(18M及び22M)ラットにおいて明期12時間の運動比率(%)が有意に抑制され、日内リズムが適正化していることが明らかとなった。
24時間暗条件で飼育すると、外部情報(光)が得られなくなるため、ラットは固有の周期(生物時計)で活動する(同調から自由になったという意味でフリーラン、自由継続と呼ぶ)。この自由継続周期を24時間に換算して横軸に示し、概日時刻とすると、その前半の12時間を主観的昼(生物時計で昼の時間と判断しラットは休息する)、後半を主観的夜(生物時計で夜の時間と判断しラットは活動する)と呼ぶ。ラットに光を当てると、その時期によって自由継続リズムの位相が前進したり、後退したりする。実施例において、概日時刻15時に130ルックスの光を30分間照射し位相後退を、概日時刻20時に同様の光を照射し位相前進を調べた。
実施例2で調製した8A8(96モル%)の明暗周期の位相変化に及ぼす影響を実施例3と同様に実施した。
18ヶ月齢雄性Fischer系ラット20匹を対照飼料群(10匹:OC(18M)群)と8A8配合飼料群(10匹:OA(18M)群)の2群に分け、それぞれの群に、表2に示した対照飼料および8A8配合飼料を2週間の予備飼育後から与えた。
ゼラチン100重量部及び食添グリセリン35重量部に水を加え50〜60℃で溶解し、粘度2000cpのゼラチン被膜を調製した。次に実施例1で得たアラキドン酸含有油脂(トリグリセリド)にビタミンE油0.05重量%を混合し、内容物1を調製した。実施例2で得た8A8を32モル%含有する油脂(トリグリセリド)にビタミンE油0.05重量%を配合し、内容物2を調製した。
実施例2で得た8A8を96%含有する油脂(トリグリセリド)400g、精製卵黄レシチン48g、オレイン酸20g、グリセリン100g及び0.1N 苛性ソーダ40mlを加え、ホモジナイザーで分散させたのち、注射用蒸留水を加えて4リットルとする。これを高圧噴霧式乳化機にて乳化し、脂質乳液を調製した。該脂質乳液を200mlずつプラスチック製バッグに分注したのち、121℃、20分間、高圧蒸気滅菌処理して脂肪輸液剤とする。
β-シクロデキストリン2gを20%エタノール水溶液20mlに添加し、ここにスターラーで撹拌しながら、実施例1で得たアラキドン酸含有トリグリセリド(ビタミンEを0.05%配合)100mgを加え、50℃で2時間インキュベートした。室温冷却(約1時間)後、さらに撹拌を続けながら4℃で10時間インキュベートした。生成した沈殿を、遠心分離により回収し、n-ヘキサンで洗浄後、凍結乾燥を行い、アラキドン酸含有トリグリセリドを含有するシクロデキストリン包接化合物1.8gを得た。この粉末1gをジュース10Lに均一に混ぜ合わせ、アラキドン酸含有トリグリセリドを含有するジュースを調製した。
Claims (17)
- アラキドン酸及び/又はアラキドン酸を構成脂肪酸とする化合物を含んで成る、日内リズムの正常化及び/又は概日リズム(生物時計)の同調促進のための医薬組成物。
- アラキドン酸を構成脂肪酸とする化合物が、アラキドン酸のアルコールエステル又は構成脂肪酸の一部もしくは全部がアラキドン酸である、トリグリセリド、リン脂質もしくは糖脂質である請求項1に記載の医薬組成物。
- 構成脂肪酸の一部又は全部がアラキドン酸であるトリグリセリドが、1,3-位に中鎖脂肪酸が、2-位にアラキドン酸が結合したトリグリセリドである請求項2に記載の医薬組成物。
- 中鎖脂肪酸が、炭素数6〜12個を有する脂肪酸から選ばれたものである請求項3に記載の医薬組成物。
- 中鎖脂肪酸が、炭素数8個を有する脂肪酸から選ばれたものである請求項4に記載の医薬組成物。
- 構成脂肪酸の一部又は全部がアラキドン酸であるトリグリセリドを含有するトリグリセリドを含んで成る、日内リズムの正常化及び/又は概日リズム(生物時計)の同調促進のための医薬組成物。
- 構成脂肪酸の一部又は全部がアラキドン酸であるトリグリセリドを含有するトリグリセリドの、アラキドン酸の割合が、トリグリセリドを構成する全脂肪酸に対して10重量%以上であることを特徴とする、請求項6に記載の医薬組成物。
- 構成脂肪酸の一部又は全部がアラキドン酸であるトリグリセリドを含有するトリグリセリドが、モルティエレラ(Mortierella)属に属する微生物から抽出したものである請求項6又は7に記載の医薬組成物。
- 構成脂肪酸の一部又は全部がアラキドン酸であるトリグリセリドを含有するトリグリセリドが、エイコサペンタエン酸を含まない又は含んだとしても1%以下のトリグリセリドである請求項6〜8いずれかに記載の医薬組成物。
- 1,3-位に中鎖脂肪酸が、2-位にアラキドン酸が結合したトリグリセリドを5モル%以上含有するトリグリセリドを含んで成る、日内リズムの正常化作用及び/又は概日リズム(生物時計)の同調促進のための医薬組成物。
- 中鎖脂肪酸が、炭素数6〜12個を有する脂肪酸から選ばれたものである請求項10に記載の医薬組成物。
- 中鎖脂肪酸が、炭素数8個を有する脂肪酸から選ばれたものである請求項11に記載の医薬組成物。
- 日内リズムの乱れに起因する生体リズム障害の予防又は改善作用を有する請求項1〜12記載の医薬組成物。
- 生体リズム障害として、睡眠障害の予防又は改善作用を有する請求項13記載の医薬組成物。
- 生体リズム障害として、概日リズム(生物時計)の同調の遅れに対する障害の予防又は改善作用を有する請求項13記載の医薬組成物。
- 概日リズム(生物時計)の同調の遅れによる時差ボケ、頭痛、耳鳴り、心悸亢進、悪心、腹痛、下痢、判断力・集中力の低下に対する予防又は改善作用を有する請求項15記載の医薬組成物。
- 生体リズム障害として、睡眠相後退症候群に対する予防又は改善作用を有する請求項13記載の医薬組成物。
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JP2003088956 | 2003-03-27 | ||
PCT/JP2004/004318 WO2004084882A1 (en) | 2003-03-27 | 2004-03-26 | Use of arachidonic acid for normalization of infradian rhythm |
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EP (1) | EP1605930B1 (ja) |
JP (1) | JP4633048B2 (ja) |
KR (1) | KR101205516B1 (ja) |
CN (2) | CN1756544B (ja) |
AU (1) | AU2004224513B2 (ja) |
CA (1) | CA2514524C (ja) |
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JP2003048831A (ja) | 2001-08-02 | 2003-02-21 | Suntory Ltd | 脳機能の低下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 |
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 |
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 |
ITMI20060956A1 (it) * | 2006-05-16 | 2007-11-17 | Massimo Ronchetti | Uso di composizioni a base di colina per il trattamento del tinnito |
KR101430214B1 (ko) * | 2006-12-28 | 2014-08-18 | 산토리 홀딩스 가부시키가이샤 | 신경 재생제 |
JP5414192B2 (ja) * | 2007-03-29 | 2014-02-12 | 江崎グリコ株式会社 | 概日リズム調整組成物 |
EP2211881A4 (en) * | 2007-11-01 | 2012-01-04 | Wake Forest University School Of Medicine | COMPOSITIONS AND METHODS FOR PREVENTING AND TREATING DISEASES AFFECTING MAMMALS |
US8343753B2 (en) | 2007-11-01 | 2013-01-01 | Wake Forest University School Of Medicine | Compositions, methods, and kits for polyunsaturated fatty acids from microalgae |
US8178147B2 (en) * | 2008-06-26 | 2012-05-15 | Pepsico, Inc. | Coumalic acid to inhibit non-enzymatic browning in teas |
CA2754952C (en) * | 2009-03-19 | 2018-11-06 | Martek Biosciences Corporation | Thraustochytrids, fatty acid compositions, and methods of making and uses thereof |
JP5576699B2 (ja) * | 2010-04-15 | 2014-08-20 | 花王株式会社 | Gip上昇抑制剤 |
JP5951448B2 (ja) | 2012-05-15 | 2016-07-13 | 国立研究開発法人産業技術総合研究所 | 概日リズム調整剤 |
CN103667068A (zh) | 2012-09-14 | 2014-03-26 | 罗盖特兄弟公司 | 一种由微生物(单细胞真菌高山被孢霉)产生的富含花生四烯酸的油及其制备工艺 |
JP2017214342A (ja) * | 2016-06-02 | 2017-12-07 | 日清オイリオグループ株式会社 | 排尿障害の予防用又は改善用組成物 |
JP6650852B2 (ja) * | 2016-09-14 | 2020-02-19 | マルハニチロ株式会社 | ドコサヘキサエン酸を含有する睡眠の質改善剤 |
CN112423648B (zh) * | 2018-07-18 | 2024-03-22 | 苏州大学 | 一种筛选去同步化指标的方法 |
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US5242941A (en) * | 1990-12-04 | 1993-09-07 | State Of Oregon | Methods of treating circadian rhythm disorders |
US5658767A (en) * | 1991-01-24 | 1997-08-19 | Martek Corporation | Arachidonic acid and methods for the production and use thereof |
PH11992043811B1 (en) * | 1991-01-24 | 2002-08-22 | Martek Corp | Arachidonic acid and methods for the production and use thereof |
GB9617847D0 (en) * | 1996-08-27 | 1996-10-09 | Scotia Holdings Plc | Fatty acid treatment |
FR2762993B1 (fr) | 1997-05-06 | 1999-08-13 | Inst Rech Biolog Sa | Nouvelle utilisation de phospholipides d'origine animale en therapeutique et/ou dietetique |
EP1283038B1 (en) * | 2000-05-16 | 2008-09-03 | Suntory Limited | Compositions normalizing circadian rhythm |
JP2003048831A (ja) * | 2001-08-02 | 2003-02-21 | Suntory Ltd | 脳機能の低下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 |
WO2004028529A1 (en) | 2002-09-24 | 2004-04-08 | Suntory Limited | Composition with effects of decline prevention, improvement or enhancement of normal responses of cognitive abilities of a healthy person |
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AU2004224513A1 (en) | 2004-10-07 |
US9782377B2 (en) | 2017-10-10 |
KR101205516B1 (ko) | 2012-11-28 |
KR20050111611A (ko) | 2005-11-25 |
AU2004224513B2 (en) | 2010-07-01 |
CA2514524A1 (en) | 2004-10-07 |
CA2514524C (en) | 2012-07-10 |
EP1605930B1 (en) | 2020-06-03 |
JP2006521369A (ja) | 2006-09-21 |
TWI367753B (en) | 2012-07-11 |
US20060073187A1 (en) | 2006-04-06 |
CN101843610A (zh) | 2010-09-29 |
CN1756544A (zh) | 2006-04-05 |
WO2004084882A1 (en) | 2004-10-07 |
CN1756544B (zh) | 2011-07-27 |
EP1605930A1 (en) | 2005-12-21 |
TW200507832A (en) | 2005-03-01 |
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