JP5583422B2 - Crocetin composition - Google Patents
Crocetin composition Download PDFInfo
- Publication number
- JP5583422B2 JP5583422B2 JP2010028419A JP2010028419A JP5583422B2 JP 5583422 B2 JP5583422 B2 JP 5583422B2 JP 2010028419 A JP2010028419 A JP 2010028419A JP 2010028419 A JP2010028419 A JP 2010028419A JP 5583422 B2 JP5583422 B2 JP 5583422B2
- Authority
- JP
- Japan
- Prior art keywords
- crocetin
- ciscrocetin
- singlet oxygen
- transcrocetin
- composition
- 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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- PANKHBYNKQNAHN-MQQNZMFNSA-N crocetin Chemical compound OC(=O)C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)C(O)=O PANKHBYNKQNAHN-MQQNZMFNSA-N 0.000 title claims description 72
- PANKHBYNKQNAHN-JTBLXSOISA-N Crocetin Natural products OC(=O)C(\C)=C/C=C/C(/C)=C\C=C\C=C(\C)/C=C/C=C(/C)C(O)=O PANKHBYNKQNAHN-JTBLXSOISA-N 0.000 title claims description 48
- PANKHBYNKQNAHN-JUMCEFIXSA-N carotenoid dicarboxylic acid Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C(=O)O)C=CC=C(/C)C(=O)O PANKHBYNKQNAHN-JUMCEFIXSA-N 0.000 title claims description 48
- 239000000203 mixture Substances 0.000 title claims description 33
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 27
- 229950004497 transcrocetin Drugs 0.000 claims description 24
- 229940123973 Oxygen scavenger Drugs 0.000 claims description 8
- 235000013305 food Nutrition 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 9
- 230000002000 scavenging effect Effects 0.000 description 9
- 238000004435 EPR spectroscopy Methods 0.000 description 8
- -1 etc.) Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 7
- 239000012452 mother liquor Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 5
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229940087168 alpha tocopherol Drugs 0.000 description 3
- 235000021466 carotenoid Nutrition 0.000 description 3
- 150000001747 carotenoids Chemical class 0.000 description 3
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- 244000215068 Acacia senegal Species 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical compound CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
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- 208000002177 Cataract Diseases 0.000 description 2
- SEBIKDIMAPSUBY-ARYZWOCPSA-N Crocin Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)OC(=O)C(C)=CC=CC(C)=C\C=C\C=C(/C)\C=C\C=C(C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1)O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SEBIKDIMAPSUBY-ARYZWOCPSA-N 0.000 description 2
- SEBIKDIMAPSUBY-JAUCNNNOSA-N Crocin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C(=O)OC1OC(COC2OC(CO)C(O)C(O)C2O)C(O)C(O)C1O)C=CC=C(/C)C(=O)OC3OC(COC4OC(CO)C(O)C(O)C4O)C(O)C(O)C3O SEBIKDIMAPSUBY-JAUCNNNOSA-N 0.000 description 2
- 244000111489 Gardenia augusta Species 0.000 description 2
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- 229920000084 Gum arabic Polymers 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
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- 235000011187 glycerol Nutrition 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
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- PJVXUVWGSCCGHT-ZPYZYFCMSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;(3s,4r,5r)-1,3,4,5,6-pentahydroxyhexan-2-one Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO PJVXUVWGSCCGHT-ZPYZYFCMSA-N 0.000 description 1
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- VDVUCLWJZJHFAV-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidin-4-ol Chemical compound CC1(C)CC(O)CC(C)(C)N1 VDVUCLWJZJHFAV-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
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- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
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- 229920002261 Corn starch Polymers 0.000 description 1
- 244000124209 Crocus sativus Species 0.000 description 1
- 235000015655 Crocus sativus Nutrition 0.000 description 1
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Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、クロセチンを含有する組成物に関する。 The present invention relates to a composition containing crocetin.
近年、活性酸素の一種である一重項酸素(1O2)が老化や様々な疾患・障害に関与することが注目されている。例えば、目や皮膚のように太陽光に直接曝される部位では一重項酸素が発生し易く、こうして発生した一重項酸素が白内障や加齢黄斑変性、皮膚の老化などの原因になると考えられている。そこで、このような疾患等の予防を目的として、コエンザイムQ10、D−システノール酸、トコフェノールその他の一重項酸素の消去能を有する物質を利用することが従来検討されている。 In recent years, attention has been focused on singlet oxygen ( 1 O 2 ), which is a kind of active oxygen, being involved in aging and various diseases and disorders. For example, singlet oxygen is likely to be generated in parts such as eyes and skin that are directly exposed to sunlight, and the singlet oxygen thus generated is considered to cause cataracts, age-related macular degeneration, skin aging, etc. Yes. Thus, for the purpose of preventing such diseases and the like, the use of coenzyme Q10, D-cystenoic acid, tocophenol and other substances having the ability to scavenge singlet oxygen has been studied.
一方、カロテノイドの一種であり、クチナシの果実やサフランの雌しべなどから抽出されたクロシンを加水分解して得られるクロセチンも一重項酸素の消去能を発揮することが知られている(特許文献1参照)。しかし、従来のクロセチンは、一重項酸素の消去能の程度において必ずしも満足できるものではなかった。 On the other hand, it is a kind of carotenoid, and crocetin obtained by hydrolyzing crocin extracted from gardenia fruit or saffron pistil is also known to exhibit singlet oxygen scavenging ability (see Patent Document 1). ). However, the conventional crocetin is not always satisfactory in terms of the singlet oxygen scavenging ability.
本発明は、一重項酸素の消去能がさらに改善されたクロセチンの組成物を提供することを課題とする。 An object of the present invention is to provide a composition of crocetin with further improved singlet oxygen scavenging ability.
本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、13−シスクロセチンの含有量の割合が一定の範囲内に含まれるように調製したクロセチン組成物に顕著な一重項酸素消去能を見出し、本発明を完成した。
即ち、本発明は、
[1].下記式(1)
As a result of intensive studies to solve the above problems, the present inventors have found that crocetin compositions prepared so that the proportion of the 13-ciscrocetin content falls within a certain range are prominent singlet oxygen. The erasing ability was found and the present invention was completed.
That is, the present invention
[1]. Following formula (1)
で表される13−シスクロセチン及び下記式(2) 13-ciscrocetin represented by the following formula (2)
で表されるトランスクロセチンを含有する組成物であって、13−シスクロセチン及びトランスクロセチンの含有量の合計中、13−シスクロセチンの含有量の割合が3〜10%であるクロセチン組成物、及び A composition containing transcrocetin represented by the formula: wherein the ratio of the content of 13-ciscrocetin is 3 to 10% in the total content of 13-ciscrocetin and transcrocetin; and
[2].[1]に記載のクロセチン組成物を有効成分とする一重項酸素消去剤、
を提供するものである。
[2]. A singlet oxygen scavenger comprising the crocetin composition according to [1] as an active ingredient,
Is to provide.
本発明のクロセチン組成物は、優れた一重項酸素消去能を有する。
本発明のクロセチン組成物は、一重項酸素消去剤として、一重項酸素が関与する各種障害又は疾患の予防に利用し得る。
The crocetin composition of the present invention has excellent singlet oxygen scavenging ability.
The crocetin composition of the present invention can be used as a singlet oxygen scavenger for the prevention of various disorders or diseases involving singlet oxygen.
本発明でいうところのクロセチンとは、下記式(1)で表される13−シスクロセチン(分子量328.40)、下記式(2)で表されるトランスクロセチン(分子量328.40)及びこれらの異性体のすべてをいう。 Crocetin in the present invention refers to 13-ciscrocetin (molecular weight 328.40) represented by the following formula (1), transcrocetin (molecular weight 328.40) represented by the following formula (2), and these Refers to all isomers.
このクロセチンは、通常、アカネ科クチナシ(Gardenia augusta MERRIL var. grandiflora HORT.,Gardenia jasminoides ELLIS)の果実などに含まれるカロテノイド系の黄色色素であるクロシン(クロセチンのジゲンチオビオースエステル)を加水分解することにより得られる。また、クロセチンは市販されており、市販品を使用することもできる。 This crocetin is usually a carotenoid yellow pigment, crocin (a digentiobiose ester of crocetin), which is a carotenoid yellow pigment contained in the fruits of Rubiaceae (Gardenia augusta MERILIL var. Grandiflora HORT., Gardenia jasminoides ELLIS). Can be obtained. Moreover, crocetin is marketed and a commercial item can also be used.
本発明のクロセチン組成物は、上記13−シスクロセチン及びトランスクロセチンを含有する組成物であって、13−シスクロセチン及びトランスクロセチンの含有量の合計中、13−シスクロセチンの含有量の割合(以下「13−シスクロセチン量」という)が好ましくは約3〜10%、より好ましくは約4〜9.5%、更に好ましくは約5〜9%のものである。 The crocetin composition of the present invention is a composition containing the 13-cis crocetin and trans crocetin described above, and the ratio of the content of 13-cis crocetin in the total content of 13-cis crocetin and trans crocetin (below) "13-ciscrocetin amount") is preferably about 3 to 10%, more preferably about 4 to 9.5%, and still more preferably about 5 to 9%.
このようなクロセチン組成物を製造する方法に特に制限はなく、例えば、常法により製造されたクロセチンを水で洗浄した後、エタノール水溶液で更に洗浄し、該エタノール水溶液に可溶の成分を除くことにより、13−シスクロセチン量が約3〜10%の範囲に含まれるように精製する方法、或いは常法により製造されたクロセチンから、13−シスクロセチン及びトランスクロセチンをそれぞれ分離した後に、13−シスクロセチン量が約3〜10%の範囲に含まれるようにこれらを配合した組成物を調製する方法などが挙げられる。この内、後者の方法において、クロセチンから13−シスクロセチン及びトランスクロセチンそれぞれを分離して調製するため、例えば以下の方法を用いることができる。 There is no particular limitation on the method for producing such a crocetin composition. For example, after washing crocetin produced by a conventional method with water, further washing with an aqueous ethanol solution to remove components soluble in the aqueous ethanol solution. After separating 13-ciscrocetin and transcrocetin from crocetin produced by a method for purification so that the amount of 13-ciscrocetin is contained in the range of about 3 to 10%, or crocetin produced by a conventional method, Examples thereof include a method of preparing a composition in which these are blended so that the amount of crocetin is included in the range of about 3 to 10%. Among these, in the latter method, since 13-ciscrocetin and transcrocetin are separately prepared from crocetin, for example, the following method can be used.
[13−シスクロセチンの調製方法]
常法により製造されたクロセチンにジメチルホルムアミドを加え、約50〜90℃で加温・溶解する。得られた不溶物をろ過し、ろ液を約1〜30℃で3〜9日間静置する。次に生成したトランスクロセチンの結晶を含む母液をろ過し、得られたろ液を濃縮して静置する工程を1〜5回繰り返し行う(ろ過・濃縮・静置工程)。該工程では、濃縮は、ロータリーエバポレーターを用いて約70〜90℃、約0.5〜3kPaの条件で行うことが好ましく、静置は、約9〜11℃で3〜9日間行うことが好ましい。次に、ろ過・濃縮・静置工程により生成したトランスクロセチンの結晶を含む母液をろ過し、得られたろ液を濃縮する工程を1〜5回繰り返し行う(ろ過・濃縮工程)。該工程では、濃縮は、ロータリーエバポレーターを用いて約70〜90℃、約0.5〜3kPaの条件で行うことが好ましい。また、該工程では、濃縮により得られた濃縮液にメタノールを加え、超音波洗浄器により洗浄処理しても良い。続いて、ろ過・濃縮工程により得られた濃縮液をメタノールに溶解し、得られた溶解液を自体公知の分取HPLCシステムに供給して13−シスクロセチンを分取することにより、13−シスクロセチンが調製される。
[Method for preparing 13-ciscrocetin]
Dimethylformamide is added to crocetin produced by a conventional method, and heated and dissolved at about 50 to 90 ° C. The obtained insoluble matter is filtered, and the filtrate is allowed to stand at about 1 to 30 ° C. for 3 to 9 days. Next, the mother liquor containing the produced transcrocetin crystals is filtered, and the step of concentrating the obtained filtrate and allowing to stand still is repeated 1 to 5 times (filtration, concentration, and standing step). In this step, concentration is preferably performed using a rotary evaporator at about 70 to 90 ° C. and about 0.5 to 3 kPa, and standing is preferably performed at about 9 to 11 ° C. for 3 to 9 days. . Next, the mother liquor containing transcrocetin crystals produced by the filtration / concentration / standing step is filtered, and the step of concentrating the obtained filtrate is repeated 1 to 5 times (filtration / concentration step). In this step, the concentration is preferably performed using a rotary evaporator under conditions of about 70 to 90 ° C. and about 0.5 to 3 kPa. In this step, methanol may be added to the concentrated solution obtained by concentration, and washing may be performed with an ultrasonic cleaner. Subsequently, the concentrate obtained by the filtration / concentration step is dissolved in methanol, and the resulting solution is supplied to a well-known preparative HPLC system to separate 13-ciscrocetin. Crocetin is prepared.
[トランスクロセチンの調製方法]
常法により製造されたクロセチンにジメチルホルムアミドを加え、約50〜90℃で加温・溶解する。得られた不溶物をろ過し、ろ液を約1〜30℃で3〜9日間静置する。次に生成したトランスクロセチンの結晶を含む母液をろ過器でろ過し、該ろ過器に残った結晶をメタノールで洗浄し、更に約30〜80℃で乾燥することによりトランスクロセチンが調製される。
[Method for preparing transcrocetin]
Dimethylformamide is added to crocetin produced by a conventional method, and heated and dissolved at about 50 to 90 ° C. The obtained insoluble matter is filtered, and the filtrate is allowed to stand at about 1 to 30 ° C. for 3 to 9 days. Next, the mother liquor containing the transcrocetin crystals produced is filtered with a filter, the crystals remaining in the filter are washed with methanol, and further dried at about 30 to 80 ° C. to prepare transcrocetin.
本発明のクロセチン組成物における13−シスクロセチン量は、クロセチン組成物をHPLCで分析した場合の、HPLCクロマトグラムにおけるトランスクロセチンのピークの面積と、13−シスクロセチンのピークの面積とから求められる。
ここで、本発明のクロセチン組成物についての13−シスクロセチン量は、下記の方法により測定される。
The amount of 13-ciscrocetin in the crocetin composition of the present invention is determined from the peak area of transcrocetin and the peak area of 13-ciscrocetin in the HPLC chromatogram when the crocetin composition is analyzed by HPLC.
Here, the amount of 13-ciscrocetin for the crocetin composition of the present invention is measured by the following method.
[13−シスクロセチン量測定法]
1)試料約6mgを精密に量り、ジメチルスルホキシド(DMSO)5mLに溶かし、メタノールを加えて正確に50mLとする。
2)その液を0.45μmのメンブレンフィルターでろ過した液を試験溶液とする。
3)試験溶液10μLをHPLCに注入し、エンパワークロマトグラフィーマネージャーにより、トランスクロセチンに対応する保持時間7分付近のピーク及び13−シスクロセチンに対応する13分付近のピークの面積を各々測定し、次式により13−シスクロセチン量(%)を算出する。
[13-ciscrocetin content measurement method]
1) About 6 mg of a sample is accurately weighed and dissolved in 5 mL of dimethyl sulfoxide (DMSO), and methanol is added to make exactly 50 mL.
2) A solution obtained by filtering the solution through a 0.45 μm membrane filter is used as a test solution.
3) 10 μL of the test solution was injected into the HPLC, and the area of the peak around 7 minutes corresponding to transcrocetin and the peak around 13 minutes corresponding to 13-ciscrocetin was respectively measured by Empower Chromatography Manager. The 13-ciscrocetin amount (%) is calculated according to the formula.
上記HPLCの分析システム及び分析条件を以下に示す。 The HPLC analysis system and analysis conditions are shown below.
<HPLC分析システム>
2695セパレーションモジュール(日本ウォーターズ社製)
2996フォトダイオードアレイ検出器(日本ウォーターズ社製)
エンパワークロマトグラフィーマネージャー(日本ウォーターズ社製)
<HPLC分析条件>
カラム:Wakosil 5C18(内径4.6mm、長さ150mm)(和光純薬工業社製)
移動相:0.1%TFA水溶液−0.1%TFAメタノール(25:75)
流速:1mL/min
検出:430nm
カラム温度:40℃
<HPLC analysis system>
2695 separation module (manufactured by Nippon Waters)
2996 Photodiode Array Detector (Nippon Waters)
Empower Chromatography Manager (Nippon Waters)
<HPLC analysis conditions>
Column: Wakosil 5C18 (inner diameter 4.6 mm, length 150 mm) (manufactured by Wako Pure Chemical Industries, Ltd.)
Mobile phase: 0.1% TFA aqueous solution-0.1% TFA methanol (25:75)
Flow rate: 1 mL / min
Detection: 430nm
Column temperature: 40 ° C
本発明のクロセチン組成物は、該クロセチン組成物をそのまま、あるいは医薬品添加物、食品添加物及び食品素材などを適宜配合し、常法に従い、例えば液剤(例えばドリンク剤など)、散剤、顆粒剤、錠剤、マイクロカプセル、ソフトカプセル、ハードカプセル、油脂組成物、O/W型乳化液、W/O型乳化液または可溶化液などの形状の製剤として製造され得る。 The crocetin composition of the present invention is prepared by mixing the crocetin composition as it is or appropriately with a pharmaceutical additive, a food additive, a food material, etc., according to a conventional method, for example, a liquid (for example, a drink), a powder, a granule, It can be produced as a preparation in the form of a tablet, microcapsule, soft capsule, hard capsule, oil / fat composition, O / W emulsion, W / O emulsion or solubilized solution.
上記製剤の製造に用いられる医薬品添加物、食品添加物及び食品素材としては、例えば賦形剤(乳糖、デキストリン、コーンスターチ、結晶セルロースなど)、滑沢剤(ステアリン酸マグネシウム、ショ糖脂肪酸エステル、グリセリン脂肪酸エステルなど)、崩壊剤(カルボキシメチルセルロースカルシウム、無水リン酸水素カルシウム、炭酸カルシウムなど)、結合剤(デンプン糊液、ヒドロキシプロピルセルロース液、アラビアガム液など)、溶解補助剤(アラビアガム、ポリソルベート80など)、甘味料(砂糖、果糖ブドウ糖液糖、ハチミツ、アスパルテームなど)、着色料(β−カロテン、食用タール色素、リボフラビンなど)、保存料(ソルビン酸、パラオキシ安息香酸メチル、亜硫酸ナトリウムなど)、増粘剤(アルギン酸ナトリウム、カルボキシメチルセルロースナトリウム、ポリアクリル酸ナトリウムなど)、酸化防止剤(BHT、BHA、アスコルビン酸、トコフェロールなど)、香料(ハッカ、ストロベリー香料など)、酸味料(クエン酸、乳酸、DL−リンゴ酸など)、調味料(DL−アラニン、5´−イノシン酸ナトリウム、L−グルタミン酸ナトリウムなど)、乳化剤(グリセリン脂肪酸エステル、ショ糖脂肪酸エステルなど)、pH調整剤(クエン酸、クエン酸三ナトリウムなど)、ビタミン類、ミネラル類、アミノ酸類などが挙げられる。これらは1種のみ用いてもよく2種以上を使用してもよい。製剤中のクロセチン組成物の含有量は特に限定されないが、通常最終製剤に対して、約0.001〜99質量%である。 Examples of pharmaceutical additives, food additives and food materials used in the preparation of the above preparations include excipients (lactose, dextrin, corn starch, crystalline cellulose, etc.), lubricants (magnesium stearate, sucrose fatty acid ester, glycerin). Fatty acid esters, etc.), disintegrating agents (carboxymethylcellulose calcium, anhydrous calcium hydrogen phosphate, calcium carbonate, etc.), binders (starch glue solution, hydroxypropyl cellulose solution, gum arabic solution, etc.), solubilizers (gum arabic, polysorbate 80) Etc.), sweeteners (sugar, fructose glucose liquid sugar, honey, aspartame, etc.), coloring agents (β-carotene, edible tar dye, riboflavin, etc.), preservatives (sorbic acid, methyl parahydroxybenzoate, sodium sulfite, etc.), Thickener (Nalginate Sodium, sodium carboxymethylcellulose, sodium polyacrylate, etc.), antioxidants (BHT, BHA, ascorbic acid, tocopherols, etc.), flavors (mint, strawberry flavors, etc.), acidulants (citric acid, lactic acid, DL-malic acid, etc.) ), Seasoning (DL-alanine, sodium 5'-inosinate, sodium L-glutamate, etc.), emulsifier (glycerin fatty acid ester, sucrose fatty acid ester, etc.), pH adjuster (citric acid, trisodium citrate, etc.), Vitamins, minerals, amino acids and the like can be mentioned. These may be used alone or in combination of two or more. Although content of the crocetin composition in a formulation is not specifically limited, Usually, it is about 0.001-99 mass% with respect to a final formulation.
更に、本発明のクロセチン組成物は、飲食品の形態をとることが可能である。該飲食品としては、例えば清涼飲料、ドロップ、キャンディ、チューインガム、チョコレート、グミ、ヨーグルト、アイスクリーム、プリン、ゼリー菓子、クッキーなどが挙げられる。 Furthermore, the crocetin composition of this invention can take the form of food-drinks. Examples of the food and drink include soft drinks, drops, candy, chewing gum, chocolate, gummy, yogurt, ice cream, pudding, jelly confectionery, and cookies.
本発明のクロセチン組成物は、一重項酸素消去能に優れているため、該クロセチン組成物を有効成分とする一重項酸素消去剤として利用し得る。該一重項酸素消去剤の摂取により、一重項酸素が関与する様々な障害又は疾患(例えば、白内障、加齢黄斑変性症、網膜血管閉塞症など)の予防効果が期待できる。 Since the crocetin composition of the present invention is excellent in singlet oxygen scavenging ability, it can be used as a singlet oxygen scavenger containing the crocetin composition as an active ingredient. The intake of the singlet oxygen scavenger can be expected to prevent various disorders or diseases involving singlet oxygen (for example, cataract, age-related macular degeneration, retinal vascular occlusion, etc.).
本発明の一重項酸素消去剤を経口摂取する場合、成人1日当たりの用量は、有効成分であるクロセチン組成物として、通常約0.1〜500mgの範囲である。この量を、1回〜3回に分けて摂取することが好ましい。但し、実際の用量は、目的や摂取者の状況(性別、年齢、健康状態など)を考慮して決められるべきである。 When the singlet oxygen scavenger of the present invention is taken orally, the daily dose for an adult is usually in the range of about 0.1 to 500 mg as the active ingredient crocetin composition. This amount is preferably taken in 1 to 3 divided doses. However, the actual dose should be determined in consideration of the purpose and the situation of the intaker (gender, age, health status, etc.).
以下に本発明を実施例に基づいてより具体的に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited thereto.
[製造例1]
[トランスクロセチンの調製]
市販のクロセチン(商品名:クロビットP;理研ビタミン社製)20gにジメチルホルムアミド840mLを加え、80℃で加温・溶解した。得られた不溶物を定量ろ紙(No.5C;アドバンテック東洋社製)でろ過し、ろ液を10℃で6日間静置した。
生成したトランスクロセチンの結晶を含む母液をガラスろ過器No.3でろ過し、該ろ過器に残った結晶をメタノール1300mLで洗浄し、更に50℃で真空乾燥してトランスクロセチン約10.5gを得た。このものの13−シスクロセチン量は0.2%であった。
[Production Example 1]
[Preparation of transcrocetin]
840 mL of dimethylformamide was added to 20 g of commercially available crocetin (trade name: clobit P; manufactured by Riken Vitamin Co., Ltd.), and heated and dissolved at 80 ° C. The obtained insoluble matter was filtered with a quantitative filter paper (No. 5C; manufactured by Advantech Toyo Co., Ltd.), and the filtrate was allowed to stand at 10 ° C. for 6 days.
The mother liquor containing the produced transcrocetin crystals was filtered with a glass filter No. 3, and the crystals remaining on the filter were washed with 1300 mL of methanol and further vacuum dried at 50 ° C. to obtain about 10.5 g of transcrocetin. It was. The amount of 13-ciscrocetin of this product was 0.2%.
[製造例2]
[13−シスクロセチンの調製]
市販のクロセチン(商品名:クロビットP;理研ビタミン社製)20gにジメチルホルムアミド840mLを加え、80℃で加温・溶解した。得られた不溶物を定量ろ紙(No.5C;アドバンテック東洋社製)でろ過し、ろ液を10℃で6日間静置した。生成したトランスクロセチンの結晶を含む母液をガラスろ過器No.3でろ過し、得られたろ液の重量が150gになるまでロータリーエバポレーターを用いて約1kPa、約80℃の条件で該ろ液を濃縮し、得られた濃縮液を10℃で6日間静置した。静置後、生成したトランスクロセチンの結晶を含む母液をガラスろ過器No.3でろ過し、得られたろ液の重量が32gになるまでロータリーエバポレーターを用いて約1kPa、約80℃の条件で該ろ液を濃縮し、得られた濃縮液を10℃で6日間静置した。静置後、生成した13−シスクロセチンの結晶を含む母液をガラスろ過器No.3でろ過した。得られたろ液の重量が5.3gになるまでロータリーエバポレーターを用いて約1kPa、約80℃の条件で濃縮した。得られた濃縮液にメタノール40mLを加え、超音波洗浄器により懸濁した後、ガラスろ過器No.3でろ過し、得られたろ液の重量が3.4gになるまでロータリーエバポレーターを用いて約1kPa、約80℃の条件で濃縮した。得られた濃縮物0.256gをメタノール12.8mLに溶解し、下記の分取HPLCシステム及び条件により、保持時間20分付近のピークを分取した。分取した液はロータリーエバポレーターを用いて約40℃、約2kPaの条件で濃縮し、13−シスクロセチン20mgを得た。このものの13−シスクロセチン量は98.7%であった。
[Production Example 2]
[Preparation of 13-ciscrocetin]
840 mL of dimethylformamide was added to 20 g of commercially available crocetin (trade name: clobit P; manufactured by Riken Vitamin Co., Ltd.), and heated and dissolved at 80 ° C. The obtained insoluble matter was filtered with a quantitative filter paper (No. 5C; manufactured by Advantech Toyo Co., Ltd.), and the filtrate was allowed to stand at 10 ° C. for 6 days. The resulting mother liquor containing transcrocetin crystals was filtered with a glass filter No. 3, and the filtrate was concentrated under the conditions of about 1 kPa and about 80 ° C. using a rotary evaporator until the weight of the obtained filtrate reached 150 g. The resulting concentrated solution was allowed to stand at 10 ° C. for 6 days. After standing, the mother liquor containing the transcrocetin crystals produced was filtered through a glass filter No. 3, and the obtained filtrate was used with a rotary evaporator at about 1 kPa and about 80 ° C. until the weight of the filtrate became 32 g. The filtrate was concentrated and the resulting concentrate was allowed to stand at 10 ° C. for 6 days. After standing, the mother liquor containing the produced 13-ciscrocetin crystals was filtered with a glass filter No. 3. The obtained filtrate was concentrated under the conditions of about 1 kPa and about 80 ° C. using a rotary evaporator until the weight of the filtrate became 5.3 g. 40 mL of methanol was added to the obtained concentrated liquid and suspended in an ultrasonic cleaner, followed by filtration with a glass filter No. 3, using a rotary evaporator until the weight of the obtained filtrate was 3.4 g. The solution was concentrated under the conditions of 1 kPa and about 80 ° C. 0.256 g of the resulting concentrate was dissolved in 12.8 mL of methanol, and a peak with a retention time of about 20 minutes was collected using the following preparative HPLC system and conditions. The separated liquid was concentrated using a rotary evaporator under the conditions of about 40 ° C. and about 2 kPa to obtain 20 mg of 13-ciscrocetin. The amount of 13-ciscrocetin of this product was 98.7%.
<分取HPLCシステム>
ポンプ:LC−6AD(島津製作所社製)
検出器:SPD−20A(島津製作所社製)
<分取HPLC条件>
カラム:μBONDASPHERE(内径19mm、長さ150mm)(日本ウォーターズ社製)
カラム温度:室温
移動相:0.05%TFA水溶液−TFAメタノール(20:80)
流速:10mL/min
検出:430nm
<Preparative HPLC system>
Pump: LC-6AD (manufactured by Shimadzu Corporation)
Detector: SPD-20A (manufactured by Shimadzu Corporation)
<Preparative HPLC conditions>
Column: μBONDASPHERE (inner diameter 19 mm, length 150 mm) (manufactured by Nippon Waters)
Column temperature: Room temperature Mobile phase: 0.05% TFA aqueous solution-TFA methanol (20:80)
Flow rate: 10 mL / min
Detection: 430nm
[クロセチン組成物の調製]
製造例1で得たトランスクロセチンを100%DMSO(ジメチルスルホキシド)に溶解し、1mMのトランスクロセチン溶液を調製した。また、製造例2で得た13−シスクロセチンを100%DMSOに溶解し、1mMの13−シスクロセチン溶液を調製した。次にトランスクロセチン溶液及び13−シスクロセチン溶液を表1に示す割合で各々混合し、50.0μLのクロセチン組成物1〜7を調製した。この内、クロセチン組成物4〜6は、本発明に係る実施例であり、クロセチン組成物1〜3及び7はそれらに対する比較例である。
[Preparation of Crocetin Composition]
Transcrocetin obtained in Production Example 1 was dissolved in 100% DMSO (dimethyl sulfoxide) to prepare a 1 mM transcrocetin solution. Further, 13-ciscrocetin obtained in Production Example 2 was dissolved in 100% DMSO to prepare a 1 mM 13-ciscrocetin solution. Next, the trans crocetin solution and the 13-cis crocetin solution were mixed at the ratios shown in Table 1 to prepare 50.0 μL of crocetin compositions 1-7. Among these, crocetin compositions 4 to 6 are examples according to the present invention, and crocetin compositions 1 to 3 and 7 are comparative examples for them.
[試験例]
[一重項酸素消去能の測定]
[Test example]
[Measurement of singlet oxygen scavenging ability]
上述したクロセチン組成物1〜7をサンプル溶液として、以下に示す電子スピン共鳴(ESR)法により一重項酸素消去能を測定した。また、比較のため、一重項酸素消去能を有する物質として公知のα−トコフェロール(製品名:(±)α−トコフェロール;Sigma社製)を100%DMSOに溶解し、α−トコフェロール濃度1mMとした溶液についても同様に測定した。 The singlet oxygen scavenging ability was measured by the electron spin resonance (ESR) method shown below using the crocetin compositions 1 to 7 described above as sample solutions. For comparison, a known α-tocopherol (product name: (±) α-tocopherol; manufactured by Sigma) as a substance having a singlet oxygen scavenging ability was dissolved in 100% DMSO to obtain an α-tocopherol concentration of 1 mM. It measured similarly about the solution.
(1)評価検体の調製
以下の1)〜5)を混合して評価検体を調製した。
1)リン酸緩衝液(pH7.2) 700μL
2)ローズベンガル(50μM) 100μL
3)4−OH−TEMP 100μL
4)サンプル溶液 50μL
5)超純水 50μL
なお、ローズベンガルは、光照射により一重項酸素を発生させるために用いた。また、4−OH−TEMP(2,2,6,6-tetramethyl-4-hydroxyl-piperidine)は、一重項酸素の補足剤として用いた。
(1) Preparation of Evaluation Sample An evaluation sample was prepared by mixing the following 1) to 5).
1) Phosphate buffer solution (pH 7.2) 700 μL
2) Rose Bengal (50 μM) 100 μL
3) 4-OH-TEMP 100 μL
4) Sample solution 50 μL
5) Ultrapure water 50μL
Rose Bengal was used to generate singlet oxygen by light irradiation. 4-OH-TEMP (2,2,6,6-tetramethyl-4-hydroxyl-piperidine) was used as a supplement for singlet oxygen.
(2)ESR装置による測定
(1)で得た評価検体をフラットセルに回収し、このフラットセル内の評価検体に対し光照射(18000lux、5分間)を行った。光照射の直後にこの評価検体をESR装置(型式:JES−RE1X;日本電子社製)に供して以下の条件でESRシグナル強度を測定した。
<ESR測定条件>
Center Field: 335.9mT
Modulation Width: 79μT
Sweep Width: 5.0mT
Time constant: 0.03sec
Seep Time: 1.0min
Gain: 400
(2) Measurement by ESR apparatus The evaluation specimen obtained in (1) was collected in a flat cell, and light irradiation (18000 lux, 5 minutes) was performed on the evaluation specimen in the flat cell. Immediately after the light irradiation, this evaluation specimen was subjected to an ESR apparatus (model: JES-RE1X; manufactured by JEOL Ltd.), and the ESR signal intensity was measured under the following conditions.
<ESR measurement conditions>
Center Field: 335.9mT
Modulation Width: 79μT
Sweep Width: 5.0mT
Time constant: 0.03 sec
Sleep Time: 1.0min
Gain: 400
(3)結果
(1)及び(2)を実施して得られたESRシグナル強度及び次式に基づいて一重項酸素消去率(%)を算出した。結果を表2に示す。
(3) Results The singlet oxygen elimination rate (%) was calculated based on the ESR signal intensity obtained by carrying out (1) and (2) and the following equation. The results are shown in Table 2.
尚、上記式中、S1は、評価検体について測定されたESRシグナル強度であり、S2は、サンプル溶液に替えて5%DMSOを用いて調製した評価検体について測定したときのESRシグナル強度である。 In the above formula, S 1 is the ESR signal intensity measured for the evaluation specimen, and S 2 is the ESR signal intensity measured for the evaluation specimen prepared using 5% DMSO instead of the sample solution. is there.
表2の結果から、13−シスクロセチン量が3〜10%の範囲に含まれる本発明のクロセチン組成物4〜6は、この範囲に含まれないクロセチン組成物1〜3及び7並びにα−トコフェロールに比べて優れた一重項酸素消去能を発揮することが明らかである。また、この結果は、本発明のクロセチン組成物が優れた一重項酸素消去剤として利用可能であることを示すものである。 From the results of Table 2, the crocetin compositions 4 to 6 of the present invention in which the amount of 13-ciscrocetin is included in the range of 3 to 10% are crocetin compositions 1 to 3 and 7 and α-tocopherol not included in this range. It is clear that it exhibits superior singlet oxygen scavenging ability compared to. This result also shows that the crocetin composition of the present invention can be used as an excellent singlet oxygen scavenger.
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