JP2019196340A - Inclusion composite of sesaminol and cyclodextrin and its production method - Google Patents
Inclusion composite of sesaminol and cyclodextrin and its production method Download PDFInfo
- Publication number
- JP2019196340A JP2019196340A JP2018091707A JP2018091707A JP2019196340A JP 2019196340 A JP2019196340 A JP 2019196340A JP 2018091707 A JP2018091707 A JP 2018091707A JP 2018091707 A JP2018091707 A JP 2018091707A JP 2019196340 A JP2019196340 A JP 2019196340A
- Authority
- JP
- Japan
- Prior art keywords
- sesaminol
- inclusion complex
- sesaminols
- sml
- water
- 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.)
- Granted
Links
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- KQRXQIPRDKVZPW-ISZNXKAUSA-N sesaminol Chemical compound C1=C2OCOC2=CC([C@H]2OC[C@H]3[C@@H]2CO[C@@H]3C2=CC=3OCOC=3C=C2O)=C1 KQRXQIPRDKVZPW-ISZNXKAUSA-N 0.000 title claims abstract description 112
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- 239000002131 composite material Substances 0.000 title abstract 4
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title description 72
- 229920000858 Cyclodextrin Polymers 0.000 title description 56
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- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- ZCLAHGAZPPEVDX-MQHGYYCBSA-N panose Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@@H](O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O)O[C@@H]1CO[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 ZCLAHGAZPPEVDX-MQHGYYCBSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000021067 refined food Nutrition 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 235000014102 seafood Nutrition 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@H](CO)O[C@@H](O[C@@H]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Chemical & Material Sciences (AREA)
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Abstract
Description
本発明は、難水溶性リグナン類であるセサミノール類がシクロデキストリン類で包接されている包接複合体及びその製造方法に関する。更に詳しくは、セサミノール類がシクロデキストリン類で包接された水溶性の改善された包接複合体及びその製造方法に関する。また、本発明は、前記包接複合体を含有する食品、医薬品又は医薬部外品に関する。 The present invention relates to an inclusion complex in which sesaminols, which are poorly water-soluble lignans, are included in cyclodextrins, and a method for producing the same. More specifically, the present invention relates to a water-soluble inclusion complex in which sesaminols are included in cyclodextrins and a method for producing the same. In addition, the present invention relates to a food, drug or quasi drug containing the inclusion complex.
ゴマに含まれるリグナンの一種であるセサミノール（ＳＭＬ、CAS No.: 74061-79-3）は、様々な生理活性（抗酸化活性、抗動脈硬化作用、抗がん作用など）を有すること、また、既に健康促進成分として市販されているセサミン（CAS No.: 607-80-7）より強い抗酸化作用を示すことが知られており（非特許文献１）、その効果が非常に期待されている物質である。 Sesaminol (SML, CAS No .: 74061-79-3), a kind of lignan contained in sesame, has various physiological activities (antioxidant activity, anti-atherosclerotic effect, anti-cancer effect, etc.) In addition, it is known to exhibit a stronger antioxidant action than sesamin (CAS No .: 607-80-7) already marketed as a health promoting ingredient (Non-patent Document 1), and its effect is highly expected. It is a substance.
セサミノールは、ゴマ種子中では三つのグルコースがフェノール性水酸基に結合したセサミノールトリグルコシド（2,6-O-di(β-D-グルコピラノシル)-β-D-グルコピラノシルセサミノール、ＳＴＧ、CAS No.: 157469-83-5）という配糖体として存在し、ゴマ油の製造の過程で排出される搾りかすの中に多量に含まれている。セサミノールの活性は配糖体の状態では発揮されず、アグリコンであるセサミノールに加水分解される必要があるが、この糖鎖は難分解性であり、これまでその作用を持つ酵素は見出されていなかった。しかし、東北大学の中山らはＳＴＧを加水分解する酵素（Paenibacillus sp由来のSTG加水分解β-グルコシダーゼ、ＰＳＴＧ）を発見し（特許文献１、非特許文献２）、セサミノールの供給に関しては大きな進展があった。 In sesame seed, sesaminol triglucoside (2,6-O-di (β-D-glucopyranosyl) -β-D-glucopyranosyl sesaminol, STG) in which three glucoses are bonded to a phenolic hydroxyl group in sesame seeds. , CAS No .: 157469-83-5) and is contained in a large amount in the pomace discharged in the process of producing sesame oil. The activity of sesaminol is not exerted in the state of glycosides, and it needs to be hydrolyzed to sesaminol, an aglycone, but this sugar chain is hardly degradable, and thus an enzyme with its action has been found so far. Was not. However, Nakayama et al., Tohoku University, discovered an enzyme that hydrolyzes STG (an STG-hydrolyzing β-glucosidase derived from Paenibacillus sp, PSTG) (Patent Document 1, Non-Patent Document 2), and made significant progress in the supply of sesaminol. was there.
前記酵素はＳＴＧの糖鎖末端のグルコース単位が一つ外れたセサミノールジグルコシド（2-O-(β-D-グルコピラノシル)-β-D-グルコピラノシルセサミノール、２−ＳＤＧ、CAS No.: 157469-82-4及び6-O-(β-D-グルコピラノシル)-β-D-グルコピラノシルセサミノール、６−ＳＤＧ、CAS No.: 474431-66-8）や糖鎖末端のグルコース単位が二つ外れたセサミノールモノグルコシド（β-D-グルコピラノシルセサミノール、ＳＭＧ、CAS No.: 153512-13-1）を経由し、最終的にセサミノールを生成する。ＳＴＧ、２−及び６−ＳＤＧはある程度水への溶解性を持っているが、糖鎖が短くなるにしたがい、急速にその溶解性は低下し、ｐＨ７、２５℃におけるセサミノールの溶解度は１．７μｍｏｌ/Ｌ（０．６３μｇ/ｍＬ）と予想されている（Advanced Chemistry Development (ACD/Labs) Software V11.02 ((c)1994-2016 ACD/Labs)を用いて算出）。この値はセサミンの溶解度の予想値１．２μｍｏｌ/Ｌ（０．４３μｇ/ｍＬ、Advanced Chemistry Development (ACD/Labs) Software V11.02 ((c) 1994-2016 ACD/Labs)を用いて算出）を少し上回るが、難水溶性であることには変わりない。このように、セサミノールの医薬品や機能性食品としての活用を考える際に、難水溶性であることは、消化管からの低い吸収性を示す可能性が高い。また、不用意に何かしらの方法で溶解性を高め、分子分散状態にすると、セサミノールの活性の一つが抗酸化作用に基づくことから、酸化を受けやすくなり製剤としての寿命が短縮する可能性がある。 The enzyme is Sesaminol diglucoside (2-O- (β-D-glucopyranosyl) -β-D-glucopyranosyl sesaminol, 2-SDG, CAS No .: 157469-82-4 and 6-O- (β-D-glucopyranosyl) -β-D-glucopyranosyl sesaminol, 6-SDG, CAS No .: 474431-66-8) and sugar chain terminal Sesaminol is finally produced via sesaminol monoglucoside (β-D-glucopyranosyl sesaminol, SMG, CAS No .: 153512-13-1) with two glucose units off. STG, 2- and 6-SDG have a certain degree of solubility in water, but as the sugar chain becomes shorter, the solubility decreases rapidly, and the solubility of sesaminol at pH 7 and 25 ° C. is 1. 7 μmol / L (0.63 μg / mL) is predicted (calculated using Advanced Chemistry Development (ACD / Labs) Software V11.02 ( (c) 1994-2016 ACD / Labs)). This value is the expected value of sesamin solubility 1.2 μmol / L (0.43 μg / mL, calculated using Advanced Chemistry Development (ACD / Labs) Software V11.02 ( (c) 1994-2016 ACD / Labs)) Slightly higher, but still water-insoluble. Thus, when considering the use of sesaminol as a pharmaceutical or functional food, it is highly possible that it is poorly water-soluble, indicating low absorbability from the digestive tract. In addition, if the solubility is inadvertently increased in some way and is in a molecularly dispersed state, one of the activities of sesaminol is based on an antioxidant action, which may lead to oxidation and shorten the life of the preparation. is there.
また、保存時、更には低温時において、わずかに溶けたセサミノールが、沈殿、凝集する不安定さがあり、ましてや、それらを高濃度に水に溶解させようとしても、低い飽和溶解度のため、沈殿、凝集としての外観的性状を示す傾向がある。
また、水溶性タイプの製品として、医薬品、化粧材、各種加工食品、飲料として、単体又は他のものと混合するとき、無色透明な水性液体製剤としての性状が、外観上強く望まれる。
In addition, at the time of storage, even at low temperatures, there is instability that slightly dissolved sesaminol precipitates and agglomerates, and even if you try to dissolve them in water at a high concentration, because of low saturation solubility, There is a tendency to show appearance properties as precipitation and aggregation.
Moreover, when it mixes with a simple substance or another thing as a water-soluble type product as a pharmaceutical, a cosmetic material, various processed foods, and a drink, the property as a colorless and transparent aqueous liquid formulation is strongly desired on the external appearance.
以上のように、産業的利用という観点では、セサミノールの大量工業的抽出技術は、既に機能製品として広く流通しているセサミンに比べ遅れているため、水への溶解度向上に関しては、あまり注目されてこなかった。 As described above, from the viewpoint of industrial use, the mass industrial extraction technology of sesaminol lags behind that of sesamin, which is already widely distributed as a functional product, so much attention has been paid to improving the solubility in water. I did not come.
例えば、セサミン類が有する生理活性を顕著に高めた物質として、セサミン類と、該セサミン類を包接するシクロデキストリンなどのホスト化合物とからなる包接複合体が知られている（特許文献２）。シクロデキストリン（以下、ＣＤともいう）は、６個以上のグルコピラノース単位がα−１,４結合により環状に結合した底の抜けたバケツ状の分子であり、グルコピラノース単位が６、７、８個からなるα−ＣＤ（CAS No.: 10016-20-3）、β-ＣＤ（CAS No.: 7585-39-9）、γ−ＣＤ（CAS No.: 17465-86-0）及びこれらの修飾体が知られている。しかしながら、特許文献２には、水への溶解性の性状に関しては触れられていない。
また、エマルションを利用したセサミノールの製剤化が報告されている（非特許文献３）。これらの方法では油状の液体にセサミノールを溶解させているが、油状液体の粘性や酸化などの点で、油状の液体に特有の問題があり、その取り扱いは煩雑である。また、セサミノールを乳化する場合、その調製には特殊な装置が必要となる。
このように、先行技術において、セサミノール類の水性液体製剤への含有においては、種々の工夫がなされているものの、水性液体製剤への溶解性の向上は十分とはいえなかった。
For example, an inclusion complex composed of sesamin and a host compound such as cyclodextrin that encloses the sesamin is known as a substance that significantly increases the physiological activity of sesamin (Patent Document 2). Cyclodextrin (hereinafter also referred to as CD) is a bucket-like molecule in which 6 or more glucopyranose units are cyclically bonded by α-1,4 bonds, and glucopyranose units are 6, 7, 8 Α-CD (CAS No .: 10016-20-3), β-CD (CAS No .: 7585-39-9), γ-CD (CAS No .: 17465-86-0) and these Modified forms are known. However, Patent Document 2 does not mention the property of solubility in water.
In addition, the preparation of sesaminol using an emulsion has been reported (Non-patent Document 3). In these methods, sesaminol is dissolved in an oily liquid, but there are problems specific to the oily liquid in terms of the viscosity and oxidation of the oily liquid, and the handling thereof is complicated. Moreover, when emulsifying sesaminol, a special apparatus is required for its preparation.
As described above, in the prior art, various improvements have been made to contain sesaminols in aqueous liquid preparations, but improvement in solubility in aqueous liquid preparations has not been sufficient.
本発明の課題は、難水溶性のセサミノール類の水溶性を顕著に改善したセサミノール類含有包接複合体及びその製造方法を提供することである。また、本発明の他の課題は、前記セサミノール類含有包接複合体を含む食品、医薬品又は医薬部外品を提供することにある。 It is an object of the present invention to provide a sesaminol-containing inclusion complex and a method for producing the same, in which the water-solubility of slightly water-soluble sesaminols is remarkably improved. Another object of the present invention is to provide a food, drug or quasi-drug containing the sesaminol-containing inclusion complex.
セサミノールに関しては、セサミノール配糖体からの、工業的生産技術が、確立されておらず、機能性食品素材としても、高価で、しかも入手が難しいこともあり、難水溶性セサミノールの生理的活用などの産業的利用の観点での、水への溶解度の向上の検討及びＣＤによる包接の試みはこれまでところほとんど知られていない。
そこで、本発明者らは、上記課題を解決するために、難水溶性リグナン類とＣＤ類による包接複合体を形成し、定性的かつ定量的な基礎的評価検討を行った。
まず、包接複合体であることを1H-NMR解析にて検証し、次に水への溶解性の評価を、凝集・沈殿の有無、無色・透明度の観点から網羅的に評価することにより、セサミノール類と分岐型β−ＣＤ又は化学修飾型β−ＣＤとからなる包接複合体がα−、β−及びγ−ＣＤとの包接複合体と比べてより顕著な水溶性を示すことを見出し、本発明を完成するに至った。
Regarding sesaminol, industrial production technology from sesaminol glycosides has not been established, and it is expensive and difficult to obtain as a functional food material. Until now, few studies have been made on the examination of improving solubility in water and inclusion by CD from the viewpoint of industrial use such as general use.
In order to solve the above problems, the present inventors formed an inclusion complex of poorly water-soluble lignans and CDs, and conducted qualitative and quantitative basic evaluation studies.
First, it is verified by 1 H-NMR analysis that it is an inclusion complex, and then the water solubility is evaluated comprehensively from the viewpoint of the presence or absence of aggregation / precipitation, colorlessness, and transparency. , Inclusion complexes composed of sesaminols and branched β-CD or chemically modified β-CD exhibit more remarkable water solubility than inclusion complexes of α-, β-, and γ-CD As a result, the present invention has been completed.
すなわち、本発明は、
［１］セサミノール類と、該セサミノール類を包接した分岐型ＣＤ又は化学修飾型ＣＤとからなる包接複合体、
［２］セサミノール類が、セサミノール、セサミノールモノグルコシド及びセサミノールジグルコシドからなる群より選ばれる少なくとも一つである前記［１］に記載の包接複合体、
［３］分岐型ＣＤが分岐型β−ＣＤであり、化学修飾型ＣＤが化学修飾型β−ＣＤである前記［１］または［２］に記載の包接複合体、
［４］分岐型β−ＣＤがグルコシル−β−ＣＤ（Ｇ１−β−ＣＤ）又はマルトシル−β−ＣＤ（Ｇ２−β−ＣＤ）である前記［３］に記載の包接複合体、
［５］化学修飾型β−ＣＤがメチル化β−ＣＤ（Ｍ−β−ＣＤ）又は２−ヒドロキシプロピル−β−ＣＤ（ＨＰ−β−ＣＤ）である前記［３］に記載の包接複合体、
［６］前記［１］〜［５］のいずれかに記載の包接複合体を含有する食品、医薬品又は医薬部外品、
［７］セサミノール類を溶解させた高濃度のエタノール水溶液と化学修飾型ＣＤとを混合して攪拌する工程、及び得られた混合溶液中の溶媒を留去し乾燥する工程を含んでいることを特徴とする、セサミノール類と、該セサミノール類を包接した化学修飾型ＣＤとからなる包接複合体の製造方法
に関する。
That is, the present invention
[1] an inclusion complex comprising sesaminols and a branched CD or a chemically modified CD containing the sesaminols,
[2] The inclusion complex according to [1], wherein the sesaminols are at least one selected from the group consisting of sesaminol, sesaminol monoglucoside and sesaminol diglucoside,
[3] The inclusion complex according to [1] or [2], wherein the branched CD is branched β-CD, and the chemically modified CD is chemically modified β-CD,
[4] The inclusion complex according to [3], wherein the branched β-CD is glucosyl-β-CD (G1-β-CD) or maltosyl-β-CD (G2-β-CD),
[5] The inclusion complex according to [3], wherein the chemically modified β-CD is methylated β-CD (M-β-CD) or 2-hydroxypropyl-β-CD (HP-β-CD). body,
[6] A food, pharmaceutical or quasi drug containing the inclusion complex according to any one of [1] to [5],
[7] It includes a step of mixing and stirring a high-concentration ethanol aqueous solution in which sesaminols are dissolved and chemically modified CD, and a step of distilling off the solvent in the obtained mixed solution and drying it. The present invention relates to a method for producing an inclusion complex comprising sesaminols and a chemically modified CD containing the sesaminols.
本発明の包接複合体は、セサミノール類の水溶性が顕著に改善された包接複合体であるため、水難溶性であったセサミノール類の用途を飛躍的に拡大することができる。例えば、本発明の包接複合体を無色で澄明な水性液体製剤としての活用が可能となり、また粉体化することにより、錠剤や顆粒剤などの調製の際に使用が容易な製剤原体としての供給が可能となる。
以上のように、本発明の包接複合体を用いることで、難溶性であるためこれまで開発が進んでいないかったセサミノール類を含有する食品、医薬品、医薬部外品などを提供することができる。
Since the inclusion complex of the present invention is an inclusion complex in which the water-solubility of sesaminols is remarkably improved, the use of sesaminols that are poorly water-soluble can be dramatically expanded. For example, the inclusion complex of the present invention can be used as a colorless and clear aqueous liquid preparation, and by making it into a powder, it can be used as a drug substance that can be easily used in the preparation of tablets and granules. Can be supplied.
As described above, by using the inclusion complex of the present invention, it is possible to provide foods, pharmaceuticals, quasi-drugs, and the like containing sesaminols that have not been developed so far because they are poorly soluble. Can do.
以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
１．包接複合体
本発明の包接複合体は、セサミノール類と、該セサミノール類を包接した分岐型ＣＤ又は化学修飾型ＣＤとからなることを特徴とする。
1. Inclusion Complex The inclusion complex of the present invention is characterized by comprising sesaminols and a branched CD or a chemically modified CD containing the sesaminols.
〔セサミノール類〕
本発明で使用するセサミノール類とは、水への溶解性が低い難水溶性リグナン類の一種であり、例えば、セサミノール、セサミノールモノグルコシド、セサミノールジグルコシドなどが挙げられる。
セサミノールは、以下の化学構造：
[Sesaminols]
The sesaminols used in the present invention are one kind of poorly water-soluble lignans having low solubility in water, and examples thereof include sesaminol, sesaminol monoglucoside, sesaminol diglucoside and the like.
Sesaminol has the following chemical structure:
を有する化合物である。
セサミノールモノグルコシドは、β−Ｄ−グルコシルセサミノールともいわれ、セサミノールの水酸基部分にグルコース１個がグリコシド結合した配糖体である。
セサミノールジグルコシドは、２−Ｏ−（β−Ｄ−D-グルコシル)−β−Ｄ−グルコシルセサミノールともいわれ、セサミノールの水酸基部分にグルコース２個がグリコシド結合した配糖体である。
本発明の包接複合体において、セサミノール、セサミノールモノグルコシド及びセサミノールジグルコシドは、それぞれ単独で、又は混合して使用することができる。また、セサミノール類としては、例えば、ゴマ油から、公知の方法で、工業的に抽出されたものであってもよく、その形態や製造方法など何ら制限されるものではない。
It is a compound which has this.
Sesaminol monoglucoside is also called β-D-glucosyl sesaminol and is a glycoside in which one glucose is glycosidically bonded to the hydroxyl portion of sesaminol.
Sesaminol diglucoside is also called 2-O- (β-D-D-glucosyl) -β-D-glucosyl sesaminol, and is a glycoside in which two glucoses are glycoside-bonded to the hydroxyl portion of sesaminol.
In the inclusion complex of the present invention, sesaminol, sesaminol monoglucoside and sesaminol diglucoside can be used alone or in combination. Moreover, as sesaminols, for example, it may be industrially extracted from sesame oil by a known method, and its form and production method are not limited at all.
〔分岐型ＣＤ又は化学修飾型ＣＤ〕
本発明で用いる分岐型ＣＤ及び化学修飾型ＣＤは、ＣＤを基本骨格とする化合物である。
[Branched CD or chemically modified CD]
The branched CD and chemically modified CD used in the present invention are compounds having CD as a basic skeleton.
シクロデキストリン（ＣＤ）とは、６個以上のグルコース単位がα−１,４結合により環状に結合した非還元性の環状オリゴ糖であり、６個のグルコース単位からなるα−ＣＤ、７個のグルコース単位からなるβ−ＣＤ、８個のグルコース単位からなるγ−ＣＤ、９個以上のグルコース単位からなる大環状ＣＤ類が挙げられる。これらのＣＤはいずれも、複数のグルコース単位で構成された環状の中心部に空洞部を有する構造を備えた化合物である。
また、前記α−ＣＤ、β−ＣＤ及びγ−ＣＤは、天然型ＣＤともよばれており、デンプンなどのα−グルカンをシクロデキストリングルカノトランスフェラーゼ（EC 2.4.1.19）などにより処理した際に、鎖状糖とともに生成される環状のオリゴ糖である。
９個以上のグルコース単位からなる大環状ＣＤ類については、トウモロコシや馬鈴薯などから得られるデンプンを、Paenibacillus maceransなどの細菌類が生産するシクロデキストリン合成酵素（Cyclodextrin glucanotransferase、CGTase）により処理して生産される市販のＣＤ粉飴から単離・精製することにより得ることができる。また、高重合度の酵素合成アミロースを、CGTase、馬鈴薯由来のＤ−酵素、Thermus aquaticus由来アミロマルターゼ（Amylomaltase）及びその変異酵素、グリコーゲン脱分枝酵素（Glycogen debranching enzyme）などにより処理して得られるＣＤ類の混合物（CGTaseを用いた場合は６個以上のグルコース単位、Ｄ−酵素を用いた場合は１６個以上のグルコース単位、アミロマルターゼを用いた場合は２２個以上のグルコース単位、グリコーゲン脱分枝酵素を用いた場合は１１個以上のグルコース単位からなるＣＤ類の混合物）から単離・精製することにより得ることができる。さらに、２２〜５０個のグルコース単位からなる大環状ＣＤ類の混合物は、江崎グリコ株式会社が生産し、和光純薬工業株式会社が販売する「シクロアミロース」から単離・精製することも可能である。
Cyclodextrin (CD) is a non-reducing cyclic oligosaccharide in which 6 or more glucose units are cyclically bonded by α-1,4 bonds, and α-CD consisting of 6 glucose units, Examples include β-CD composed of glucose units, γ-CD composed of 8 glucose units, and macrocyclic CDs composed of 9 or more glucose units. Each of these CDs is a compound having a structure having a hollow portion in an annular central portion composed of a plurality of glucose units.
In addition, the α-CD, β-CD and γ-CD are also called natural CDs, and when α-glucan such as starch is treated with cyclodextrin glucanotransferase (EC 2.4.1.19) or the like, the chain It is a cyclic oligosaccharide produced together with a saccharide.
Macrocyclic CDs consisting of 9 or more glucose units are produced by treating starch obtained from corn or potato with cyclodextrin synthase (Cyclodextrin glucanotransferase, CGTase) produced by bacteria such as Paenibacillus macerans. It can be obtained by isolation and purification from commercially available CD powder cake. In addition, enzyme-synthesized amylose having a high degree of polymerization is obtained by treating with CGTase, potato-derived D-enzyme, Thermus aquaticus-derived amylomaltase and its mutant enzyme, glycogen debranching enzyme, etc. Mixture of CDs (6 or more glucose units when CGTase is used, 16 or more glucose units when D-enzyme is used, 22 or more glucose units when amylomaltase is used, glycogen defragmentation) When a branch enzyme is used, it can be obtained by isolation and purification from a mixture of CDs consisting of 11 or more glucose units. Furthermore, a mixture of macrocyclic CDs consisting of 22-50 glucose units can be isolated and purified from “cycloamylose” produced by Ezaki Glico Co., Ltd. and sold by Wako Pure Chemical Industries, Ltd. is there.
分岐型ＣＤは、天然型ＣＤ又は大環状ＣＤ類に対して、グルコースなどの糖分子が、直接α−１，６結合した構造を有する。
修飾に使用される糖分子の種類としては、１グルコース単位からなるグルコース、２グルコース単位からなるマルトース、３グルコース単位からなるマルトトリオースやパノースが挙げられる。またグルコース単位以外の糖を含むマンノースやガラクトースなども分岐鎖に使用される。さらにこれらの糖がＣＤ分子の１個のグルコース単位に導入されたモノ置換体のみならず、２個以上のグルコース単位に導入された多置換体も存在する。
中でも、セサミノール類の水溶性を改善する観点から、天然型ＣＤに対して分岐化したものが好ましく、β−ＣＤに対してグルコシル化（グルコシル−β−ＣＤ（Ｇ１−β−ＣＤ））及びマルトシル化（マルトシル−β−ＣＤ（Ｇ２−β−ＣＤ））されたものがより好ましい。
前記分岐型ＣＤとしては、例えば、市販品を使用することができる。また、市販されていない分岐型ＣＤに関しては、目的とする分岐型ＣＤの構成要素であるＣＤと鎖状糖の高濃度試料を、α−１，６結合の切断酵素であるプルラナーゼなどで処理することにより調製し、これを単離・精製することにより得ることができる。
また、後述のように、本発明の包接複合体を食品、医薬品又は医薬部外品に使用する場合には、本発明の包接複合体を構成する分岐型ＣＤの種類は、１種であってもよいし、２種以上を混合したものでもよい。
中でも、溶解性に優れる観点から、分岐型ＣＤとしては、Ｇ1−β−ＣＤとＧ２−β−ＣＤが好ましい。
The branched CD has a structure in which a sugar molecule such as glucose is directly α-1,6 linked to a natural CD or a macrocyclic CD.
Examples of the sugar molecule used for the modification include glucose consisting of 1 glucose unit, maltose consisting of 2 glucose units, maltotriose and panose consisting of 3 glucose units. In addition, mannose and galactose containing sugars other than glucose units are also used for the branched chain. Furthermore, there exist not only mono-substituted products in which these sugars are introduced into one glucose unit of a CD molecule, but also poly-substituted products in which two or more glucose units are introduced.
Among these, from the viewpoint of improving the water solubility of sesaminols, those branched from natural CD are preferred, and β-CD is glycosylated (glucosyl-β-CD (G1-β-CD)) and Those that have been maltosylated (maltosyl-β-CD (G2-β-CD)) are more preferred.
As the branched CD, for example, a commercially available product can be used. For branched CDs that are not commercially available, a high-concentration sample of CD and chain sugar, which are the components of the target branched CD, is treated with pullulanase, which is an α-1,6-linked cleavage enzyme. Can be obtained by isolation and purification.
As will be described later, when the inclusion complex of the present invention is used for foods, pharmaceuticals or quasi drugs, there is only one kind of the branched CD constituting the inclusion complex of the present invention. It may be present or a mixture of two or more.
Among these, G1-β-CD and G2-β-CD are preferable as the branched CD from the viewpoint of excellent solubility.
化学修飾型ＣＤは、天然型ＣＤ又は大環状ＣＤ類の水酸基が有機基により一部置換された誘導体である。
置換されるＣＤの位置及び数については、特に限定はない。
前記有機基としては、メチル基（メチル化）、プロピル基（プロピル化）などが挙げられる。
化学修飾型ＣＤとしては、例えば、メチル化β−ＣＤ（Ｍ−β−ＣＤ）、２−ヒドロキシプロピル−β−ＣＤ（ＨＰ−β−ＣＤ）などが挙げられるが、セサミノール類の水溶性を改善する観点から、Ｍ−β−ＣＤ、ＨＰ−β−ＣＤが好ましい。
前記化学修飾型ＣＤとしては、例えば、市販品を使用することができる。
また、後述のように、本発明の包接複合体を食品、医薬品又は医薬部外品に使用する場合には、本発明の包接複合体を構成する化学修飾型ＣＤは、１種であってもよいし、２種以上を混合したものでもよい。
Chemically modified CD is a derivative in which the hydroxyl group of natural CD or macrocyclic CD is partially substituted with an organic group.
There is no particular limitation on the position and number of CDs to be replaced.
Examples of the organic group include a methyl group (methylated) and a propyl group (propylated).
Examples of the chemically modified CD include methylated β-CD (M-β-CD), 2-hydroxypropyl-β-CD (HP-β-CD), and the like. From the viewpoint of improvement, M-β-CD and HP-β-CD are preferable.
As the chemically modified CD, for example, a commercially available product can be used.
As will be described later, when the inclusion complex of the present invention is used for foods, pharmaceuticals or quasi drugs, there is only one chemically modified CD constituting the inclusion complex of the present invention. It may be a mixture of two or more.
〔包接複合体〕
本発明において、「包接複合体」とは、前記セサミノール類（ゲスト分子）が、ＣＤ（ホスト分子）の空洞中に少なくとも部分的にそれ自体挿入されて、いわゆる包接された状態となっている複合体を意味する。前記包接複合体におけるセサミノール類の状態については、ゲスト分子単体、ＣＤ単体並びに包接複合体のＮＭＲの化学シフトの比較により判別することができる。
[Inclusion complex]
In the present invention, the “inclusion complex” means that the sesaminols (guest molecules) are at least partially inserted into a cavity of a CD (host molecule) and become a so-called inclusion state. Means a complex. The state of sesaminols in the inclusion complex can be determined by comparing NMR chemical shifts of the guest molecule alone, the CD alone and the inclusion complex.
本発明において、水溶性の評価は、非常に高い難水溶性を示すセサミノール類に関しては、セサミノール類含有水溶液中への、ＣＤ類の添加による外観目視評価により行うことができる。すなわち、水中にセサミノール類とＣＤ類とが共存したとき、懸濁液の形成、澄明な溶液と沈殿物のへの分離、更には、完全に溶解した澄明な溶液状態になることにより、確認することができる。 In the present invention, the evaluation of water solubility can be carried out by visual appearance evaluation of a sesaminol-containing aqueous solution with respect to sesaminols exhibiting very low water solubility by adding CDs. That is, when sesaminols and CDs coexist in water, it is confirmed by the formation of a suspension, separation into a clear solution and a precipitate, and a completely dissolved clear solution state. can do.
２．包接複合体の製造方法
本発明の包接複合体は、セサミノール類とＣＤ類とを相互作用させ、包接複合体を形成させることにより調製する。
例えば、セサミノール類およびＣＤ類に対して可溶性のある溶媒（例えば、重水）中においてセサミノール類およびＣＤ類を混合して撹拌することで両者を相互作用させ、包接複合体を形成させることができる。
中でも、化学修飾型ＣＤを用いた包接複合体の場合、効率よく製造する観点から、高濃度のエタノール水溶液と化学修飾型ＣＤとを混合して攪拌することで包接複合体を製造することもできる。
2. Method for Producing Inclusion Complex The inclusion complex of the present invention is prepared by allowing sesaminols and CDs to interact to form an inclusion complex.
For example, by mixing and stirring sesaminols and CDs in a solvent that is soluble in sesaminols and CDs (for example, heavy water), both of them interact to form an inclusion complex. Can do.
In particular, in the case of an inclusion complex using a chemically modified CD, from the viewpoint of efficient production, an inclusion complex is produced by mixing and stirring a highly concentrated aqueous ethanol solution and a chemically modified CD. You can also.
前記混合において混合されるセサミノール類とＣＤ類との量比についても、特に限定はないが、セサミノール類／ＣＤ類の比率（モル比）が１／１〜１／５０であればよい。
前記セサミノール類については、セサミノール、セサミノールモノグルコシド及びセサミノールジグルコシドのいずれか単独であってもよいし、２種を混合したものでもよい。
ＣＤ類である分岐型ＣＤや化学修飾型ＣＤの種類は、１種であってもよいし、２種以上を混合したものでもよい。
The amount ratio of sesaminols and CDs mixed in the mixing is not particularly limited, but the ratio (molar ratio) of sesaminols / CDs may be 1/1 to 1/50.
The sesaminols may be any of sesaminol, sesaminol monoglucoside, and sesaminol diglucoside, or may be a mixture of two.
The type of the branched CD or the chemically modified CD that is a CD may be one type or a mixture of two or more types.
また、前記混合において使用する前記高濃度のエタノール水溶液とは、仕込み量のセサミノール類を完全に溶解させるのに必要なエタノール濃度をいう。前記濃度は、セサミノール類と化学修飾型ＣＤとを効率よく溶解させる観点から、５０％以上が好ましく、８５％〜９５％がより好ましい。
前記エタノール水溶液中のエタノールと水との比率については、特に限定はないが、セサミノール類と化学修飾型ＣＤとを効率よく溶解させる観点から、エタノール／水の比率（容量比）が５０／５０〜９５/５が好ましく、８５／１５〜９５／５がより好ましい。
Further, the high-concentration ethanol aqueous solution used in the mixing means an ethanol concentration necessary for completely dissolving the charged amount of sesaminols. The concentration is preferably 50% or more, more preferably 85% to 95%, from the viewpoint of efficiently dissolving sesaminols and chemically modified CD.
The ratio of ethanol and water in the aqueous ethanol solution is not particularly limited, but from the viewpoint of efficiently dissolving sesaminols and chemically modified CD, the ethanol / water ratio (volume ratio) is 50/50. -95/5 are preferable and 85 / 15-95 / 5 are more preferable.
なお、前記混合における温度は、特に限定はなく、常温の範囲であればよい。
前記混合における撹拌の速度についても特に限定はない。
また、前記混合は、撹拌している混合溶液の状態が澄明になった時点で終了すればよい。なお、澄明とは、混合溶液を入れている容器の内側表面が、目視にて、にごりなく見える状態をいう。
In addition, the temperature in the said mixing does not have limitation in particular, What is necessary is just the range of normal temperature.
There is no particular limitation on the stirring speed in the mixing.
Further, the mixing may be terminated when the state of the stirred mixed solution becomes clear. The term “clear” refers to a state in which the inner surface of the container in which the mixed solution is placed can be seen with no sight.
前記のようにして得られた混合溶液中には、包接複合体が形成されているため、混合溶液をそのまま水性液体製剤として用いることができる。 Since the inclusion complex is formed in the mixed solution obtained as described above, the mixed solution can be used as it is as an aqueous liquid preparation.
また、前記混合溶液を乾燥処理することで、固体状の包接複合体としてもよい。
例えば、前記混合溶液中の溶媒を留去し乾燥する工程（乾燥工程）を経て固形状の包接複合体を製造することができる。
Moreover, it is good also as a solid inclusion complex by drying the said mixed solution.
For example, a solid inclusion complex can be produced through a process (drying process) in which the solvent in the mixed solution is distilled off and dried.
前記乾燥工程において、得られた混合溶液中に含まれるエタノール、重水、水などの溶媒を留去する手段としては、減圧乾燥、凍結乾燥、噴霧乾燥（スプレードライ）などが挙げられるが、特に限定はない。
例えば、留去手段として噴霧乾燥（スプレードライ）を用いた場合、その乾燥条件としては、水-エタノール系溶媒の共沸点である７８．１５℃以上などに調整していればよい。
In the drying step, examples of means for distilling off the solvent such as ethanol, heavy water, and water contained in the obtained mixed solution include reduced-pressure drying, freeze-drying, and spray drying (spray drying). There is no.
For example, when spray drying (spray drying) is used as the distillation means, the drying conditions may be adjusted to 78.15 ° C. or higher, which is the azeotropic point of the water-ethanol solvent.
以上のようにして得られた固体状の包接複合体は、粉砕処理に供することで、粉末状にしたり、さらには、固形状の包接複合体を再度水又はエタノール水溶液に溶解して水性液剤として用いることもできる。 The solid inclusion complex obtained as described above is subjected to a pulverization treatment to form a powder, or further, the solid inclusion complex is dissolved in water or an aqueous ethanol solution again to form an aqueous solution. It can also be used as a liquid agent.
以上のようにして得られる本発明の包接複合体は、水溶性に優れたものであるため、食品、医薬品及び医薬部外品に配合して使用することができる。このような食品、医薬品及び医薬部外品は、セサミノール類に由来する機能性作用を有する食品、医薬品又は医薬部外品となる。 Since the inclusion complex of the present invention obtained as described above is excellent in water solubility, it can be used in foods, pharmaceuticals and quasi drugs. Such foods, pharmaceuticals and quasi drugs are foods, pharmaceuticals or quasi drugs having a functional action derived from sesaminols.
前記食品としては、例えば、飲料、アルコール飲料、ゼリー、菓子等、どのような形態でもよく、菓子類の中でも、その容量等から保存や携帯性に優れた、ハードキャンディ、ソフトキャンディ、グミキャンディ、タブレット等にすることができる。なお、食品には、機能性食品、健康食品、健康志向食品等も含まれる。 As the food, for example, any form such as beverage, alcoholic beverage, jelly, confectionery, etc., among confectionery, hard candy, soft candy, gummy candy, which is excellent in storage and portability due to its capacity, etc. It can be a tablet or the like. The food includes functional food, health food, health-oriented food, and the like.
また、前記食品には、ヒトが食べる食品だけでなく、例えば、非ヒト動物、例えば、ラット、マウス、モルモット、ウサギ、ヒツジ、ブタ、ウシ、ウマ、ネコ、イヌ、サル、チンパンジー等の哺乳類、鳥類、両生類、爬虫類等の治療剤又は飼料に配合してもよい。飼料としては、例えばヒツジ、ブタ、ウシ、ウマ、ニワトリ等に用いる家畜用飼料、ウサギ、ラット、マウス等に用いる小動物用飼料、ウナギ、タイ、ハマチ、エビ等に用いる魚介類用飼料、イヌ、ネコ、小鳥、リス等に用いるペットフードが挙げられる。 In addition to the foods eaten by humans, the food includes, for example, non-human animals such as rats, mice, guinea pigs, rabbits, sheep, pigs, cows, horses, cats, dogs, monkeys, chimpanzees, and other mammals, You may mix | blend with therapeutic agents or feed, such as birds, amphibians, and reptiles. As feed, for example, feed for livestock used for sheep, pigs, cattle, horses, chickens, etc., feed for small animals used for rabbits, rats, mice, etc., feed for seafood used for eels, Thailand, hamachi, shrimp, etc., dogs, Pet foods used for cats, small birds, squirrels, etc.
前記医薬品としては、散剤、錠剤、丸剤、カプセル剤、顆粒剤等の固形製剤、懸濁剤、乳剤等の液剤、ゲル剤等が挙げられる。錠剤、丸剤、顆粒剤、顆粒を含有するカプセル剤等の顆粒は、必要により、ショ糖等の糖類、マルチトール等の糖アルコールで糖衣を施したり、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース等でコーティングを施したりしてもよいし、胃溶性若しくは腸溶性物質のフィルムで被覆してもよい。また、製剤の溶解性を向上させるために、前記の製剤に公知の可溶化処理を施すこともできる。常法に基づいて、前記液剤を注射剤又は点滴剤に配合して使用してもよい。 Examples of the pharmaceuticals include solid preparations such as powders, tablets, pills, capsules and granules, liquids such as suspensions and emulsions, and gels. If necessary, granules such as tablets, pills, granules, capsules containing granules can be sugar-coated with sugars such as sucrose, sugar alcohols such as maltitol, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. Or may be coated with a film of gastric or enteric material. Moreover, in order to improve the solubility of a formulation, the said formulation can also be given a known solubilization process. Based on a conventional method, the liquid preparation may be used in an injection or infusion.
医薬部外品としては、口腔に用いられる医薬部外品、例えば、歯磨き、マウスウォッシュ、マウスリンス、ドリンク剤が挙げられる。 Examples of quasi-drugs include quasi-drugs used in the oral cavity, such as toothpaste, mouthwash, mouth rinse, and drink.
本発明の包接複合体を用いて食品、医薬品又は医薬部外品を調製する場合、本発明の効果が損なわれない範囲内で食品、医薬品又は医薬部外品に通常用いられる成分を適宜任意に配合することができる。
例えば、食品の場合には、水、アルコール、澱粉質、蛋白質、繊維質、糖質、脂質、ビタミン、ミネラル、着香料、着色料、甘味料、調味料、安定剤、防腐剤のような食品に通常配合される原料又は素材と組み合わせることができる。
医薬品や医薬部外品の場合には、主剤、基材、界面活性剤、起泡剤、湿潤剤、増粘剤、透明剤、着香料、着色料、安定剤、防腐剤、殺菌剤等に組み合わせ、常法に基づいて、液状などの最終形態等にすることができる。
When preparing foods, pharmaceuticals or quasi drugs using the inclusion complex of the present invention, the components usually used in foods, pharmaceuticals or quasi drugs are arbitrarily selected as long as the effects of the present invention are not impaired. Can be blended.
For example, in the case of food, food such as water, alcohol, starch, protein, fiber, carbohydrate, lipid, vitamin, mineral, flavoring, coloring, sweetener, seasoning, stabilizer, preservative Can be combined with raw materials or materials usually blended in
In the case of pharmaceuticals and quasi-drugs, the main ingredients, base materials, surfactants, foaming agents, wetting agents, thickeners, clearing agents, flavoring agents, coloring agents, stabilizers, preservatives, bactericides, etc. A final form such as a liquid can be obtained based on a combination or a conventional method.
また、本発明の包接複合体を食品に添加する場合には、セサミノールの１日当たりの必要摂取量や最大許容量の範囲内になるように添加することが好ましい。 Moreover, when adding the inclusion complex of this invention to a foodstuff, it is preferable to add so that it may become in the range of the required intake per day and the maximum allowable amount of sesaminol.
本発明の包接複合体を医薬用途で使用する場合、例えば、その摂取量は、所望の改善、治療又は予防効果が得られるような量であれば特に制限されず、通常、薬剤の態様、患者の年齢、性別、体質その他の条件、疾患の種類並びにその程度等に応じて適宜選択される。１日当たり約０．１ｍｇ〜１，０００ｍｇ程度とするのがよく、これを１日に１〜４回に分けて摂取することができる。 When the inclusion complex of the present invention is used for pharmaceutical purposes, for example, the amount of intake thereof is not particularly limited as long as the desired improvement, treatment or prevention effect can be obtained. It is appropriately selected according to the age, sex, constitution and other conditions of the patient, the type and degree of disease. About 0.1 mg to about 1,000 mg per day is preferable, and this can be taken in 1 to 4 times a day.
本発明の新規化合物を医薬部外品に添加する場合には、該医薬部外品中に、セサミノールの１日当たりの必要摂取量や最大許容量の範囲内になるように添加するのが好ましい。 When the novel compound of the present invention is added to a quasi-drug, it is preferably added to the quasi-drug so that the daily intake or maximum allowable amount of sesaminol is within the range. .
以下、本発明を実施例に基づいて更に詳細に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to these.
（実験例１：重水中におけるセサミノール及びその配糖体とα−、β−、γ−ＣＤ間の相互作用）
α−、β−及びγ−ＣＤでは、包接複合体を形成すると、空洞内に位置するグルコース単位の３及び５位のプロトンの化学シフト値が高磁場シフトすることが一般的に知られている。又３位のプロトンは空洞の広い口側（２級水酸基側）に、５位のプロトンは狭い口側（１級水酸基側）に存在するため、その高磁場シフトの大きさから、ゲストの空洞内の存在位置をおおまかに推定することができる。そこで、セサミノールとその配糖体（ＳＴＧ、２−ＳＤＧ及び６−ＳＤＧ）とα−、β−及びγ−ＣＤ間の相互作用を１Ｈ−ＮＭＲを用いて確認し、最適なＣＤの探索を行った。
(Experimental example 1: Interaction between sesaminol and its glycoside and α-, β-, and γ-CD in heavy water)
In α-, β-, and γ-CD, it is generally known that when an inclusion complex is formed, the chemical shift values of protons at the 3rd and 5th positions of the glucose unit located in the cavity are shifted by a high magnetic field. Yes. The proton at the 3rd position is located on the wide mouth side (secondary hydroxyl group side) and the proton at the 5th position is located on the narrow mouth side (primary hydroxyl group side). It is possible to roughly estimate the location of the inside. Therefore, the interaction between sesaminol and its glycosides (STG, 2-SDG and 6-SDG) and α-, β-, and γ-CD was confirmed using 1 H-NMR, and the search for the optimal CD was made. Went.
セサミノール及びその配糖体が９．３８ｍｇとなるようにエタノール水溶液を秤取し、溶媒を留去した。この残渣（ＳＭＬ：１６．９ｍｍｏｌ、２−及び６−ＳＤＧ：９．０ｍｍｏｌ、ＳＴＧ：７．３ｍｍｏｌ）に等モル量のα−、β−及びγ−ＣＤを添加し、１．５ｍＬの重水を加え、超音波処理後、２５℃の恒温振とう槽で一晩撹拌した。この調製した試料を目視で観察後、遠心分離し、上清を０．４５μｍのメンブランフィルターで濾過した溶液を１Ｈ−ＮＭＲに供した。（測定装置：JNM-ECA-600II、テトラメチルシラン（Tetramethylsilane）を使用した外部標準法、測定温度３０℃） The aqueous ethanol solution was weighed so that sesaminol and its glycosides were 9.38 mg, and the solvent was distilled off. To this residue (SML: 16.9 mmol, 2- and 6-SDG: 9.0 mmol, STG: 7.3 mmol) equimolar amounts of α-, β- and γ-CD were added, and 1.5 mL of heavy water was added. In addition, after sonication, the mixture was stirred overnight in a constant temperature shaking bath at 25 ° C. The prepared sample was visually observed and then centrifuged, and a solution obtained by filtering the supernatant with a 0.45 μm membrane filter was subjected to 1 H-NMR. (Measuring device: JNM-ECA-600II, external standard method using tetramethylsilane, measuring temperature 30 ° C.)
[溶解状態]
図１左側にＳＴＧのＣＤ無添加、α−、β−及びγ−ＣＤ添加試料、図１右側に６−ＳＤＧのＣＤ無添加、α−、β−及びγ−ＣＤ添加試料を示した。この写真像で分かるように、ＳＴＧ及び６−ＳＤＧは、９．３８ｍｇ/１．５ｍＬ（６．２５ｍｇ/ｍＬ）の濃度ではＣＤ無添加試料においても澄明な溶液となった。又これにＣＤを共存させても澄明なままであった。一方、図２左側に２−ＳＤＧのＣＤ無添加、α−、β−及びγ−ＣＤ添加試料を示した。ＣＤ無添加試料では沈降性のある白色固体が沈殿した。これにα−ＣＤを添加すると、白色の懸濁液となった。β−ＣＤ添加系では沈降性の白色固体が生成したが、その体積はＣＤ無添加と比較して減少していた。γ−ＣＤ添加系では澄明な溶液が得られた。図２右側にＳＭＬのＣＤ無添加、α−、β−及びγ−ＣＤ添加試料を示した。ＣＤ無添加試料では器壁に付着したままＳＭＬが存在した。これにα−ＣＤを添加しても変化はほとんど見られなかった。β−及びγ−ＣＤ添加系では、白濁液が形成され、白色の固体が沈殿した。
[Dissolved state]
The left side of FIG. 1 shows STG CD-free and α-, β-, and γ-CD added samples, and the right side of FIG. 1 shows 6-SDG-free CD, α-, β-, and γ-CD added samples. As can be seen from this photographic image, STG and 6-SDG became clear solutions even in the CD-free sample at a concentration of 9.38 mg / 1.5 mL (6.25 mg / mL). Moreover, even if CD was coexisted with this, it remained clear. On the other hand, 2-SDG CD-free, α-, β-, and γ-CD added samples are shown on the left side of FIG. In the CD-free sample, a white solid with sedimentation was precipitated. When α-CD was added thereto, a white suspension was formed. In the β-CD addition system, a sedimentary white solid was produced, but its volume was reduced as compared with the case where CD was not added. In the γ-CD addition system, a clear solution was obtained. On the right side of FIG. 2, SML-free samples, α-, β-, and γ-CD added samples are shown. In the CD-free sample, SML was present while adhering to the vessel wall. Even when α-CD was added thereto, almost no change was observed. In the β- and γ-CD addition system, a cloudy liquid was formed and a white solid precipitated.
「１Ｈ−ＮＭＲ」
図３に上段からα-ＣＤのみ、α−ＣＤ/ＳＴＧ系、α−ＣＤ/６−ＳＤＧ系、α−ＣＤ/２−ＳＤＧ系、α−ＣＤ/ＳＭＬ系の１Ｈ−ＮＭＲスペクトルを示した。α−ＣＤ添加系では、３．７７ｐｐｍ付近に観測される３位のプロトンに由来するトリプレットシグナル及び３．７付近に観測される５位のプロトンに由来するシグナルがＳＴＧと６−ＳＤＧでは高磁場シフトしているが、２−ＳＤＧとＳＭＬでは化学シフトの変化が認められない。又４．８４ｐｐｍ付近に観測される１位のプロトンに由来するダブレットシグナルは３位のシフト変化よりも小さい。この結果から、α−ＣＤはＳＭＬと相互作用することは可能であるが、その強さは低いものと考えられる。そのため、α−ＣＤの環構造に変化は起きにくく、１位のプロトンのシフトが小さかったものと考えられる。
"1 H-NMR"
FIG. 3 shows the 1 H-NMR spectra of α-CD alone, α-CD / STG system, α-CD / 6-SDG system, α-CD / 2-SDG system, and α-CD / SML system from the top. . In the α-CD addition system, a triplet signal derived from the 3rd-position proton observed near 3.77 ppm and a signal derived from the 5th-position proton observed near 3.7 are high magnetic fields in STG and 6-SDG. Although there is a shift, no change in chemical shift is observed in 2-SDG and SML. Moreover, the doublet signal derived from the proton at the 1st position observed in the vicinity of 4.84 ppm is smaller than the shift change at the 3rd position. From this result, it is considered that α-CD can interact with SML, but its strength is low. Therefore, it is considered that the change in the α-CD ring structure hardly occurs, and the proton shift at the 1-position was small.
図４に上段からβ−ＣＤのみ、β−ＣＤ/ＳＴＧ系、β−ＣＤ/６−ＳＤＧ系、β−ＣＤ/２−ＳＤＧ系、β−ＣＤ/ＳＭＬ系の１Ｈ−ＮＭＲスペクトルを示した。β−ＣＤ添加系では、３、５及び１位のプロトンが大きくシフトしており、かなり強固な包接複合体を形成していると考えられる。又、α−及びγ−ＣＤ添加系ではＳＭＬ由来のシグナルが観測できず、測定試料中のSML濃度が１Ｈ−ＮＭＲの検出感度より低い状態であったが、β−ＣＤ添加系では弱いながらもシグナルが観測可能であったことから、ＳＭＬの溶解度の改善にはβ−ＣＤが最も寄与することが確認された。 FIG. 4 shows 1 H-NMR spectra of only β-CD, β-CD / STG system, β-CD / 6-SDG system, β-CD / 2-SDG system, and β-CD / SML system from the upper stage. . In the β-CD addition system, protons at positions 3, 5 and 1 are greatly shifted, and it is considered that a fairly strong inclusion complex is formed. In addition, in the α- and γ-CD added systems, no signal derived from SML was observed, and the SML concentration in the measurement sample was lower than the detection sensitivity of 1 H-NMR, but the β-CD added system was weak. Since the signal was observable, it was confirmed that β-CD contributed most to the improvement of the solubility of SML.
図５に上段からγ−ＣＤのみ、γ−ＣＤ/ＳＴＧ系、γ−ＣＤ/６−ＳＤＧ系、γ−ＣＤ/２−ＳＤＧ系、γ−ＣＤ/ＳＭＬ系の１Ｈ−ＮＭＲスペクトルを示した。γ−ＣＤ添加系では、ＳＴＧ、２−及び６−ＳＤＧでは３、５及び１位のプロトンが大きくシフトしており、強く相互作用していると考えられる。しかし、ＳＭＬではＣＤ由来の化学シフトに変化は認められず、またＳＭＬ由来のシグナルが観測できなかったことから、γ−ＣＤはＳＭＬとは相互作用が非常に低い可能性が示唆された。 FIG. 5 shows 1 H-NMR spectra of only γ-CD, γ-CD / STG system, γ-CD / 6-SDG system, γ-CD / 2-SDG system, and γ-CD / SML system from the top. . In the γ-CD addition system, the protons at positions 3, 5, and 1 are greatly shifted in STG, 2- and 6-SDG, and it is considered that they interact strongly. However, no change was observed in the chemical shift derived from CD in SML, and no signal derived from SML could be observed, suggesting that γ-CD may have a very low interaction with SML.
（実施例１：水溶性β−ＣＤ類を使用したＳＭＬの可溶化）
実験例１の結果から、α−、β−及びγ−ＣＤのうち、β−ＣＤが最も強くＳＭＬと包接複合体を形成していると考えられ、又ＳＭＬの水溶性を改善可能であることが明らかになった。
しかし、β−ＣＤは使用した３種のＣＤ類の中で一番溶解度が低く（２５℃における溶解度（ｍｇ/ｍＬ）：α−ＣＤ；１４５、β−ＣＤ；１８．５、γ−ＣＤ；２３２）、得られる包接複合体が飽和溶解度を持つため、結晶性の固体を生成することがしばしばある（溶解度相図においてＢＳ型をとなる系）。ＳＭＬ/β−ＣＤでは実験例１で調製した試料において、白色の固体が沈殿していることから、β−ＣＤはＳＭＬの溶解度を改善できるが限界があること、又飽和溶解度の包接複合体水溶液を冷却した場合、結晶性の沈殿が生じる可能性高い。このため、β−ＣＤの水溶性を高めた誘導体を用いたＳＭＬの可溶化を検討した。
(Example 1: Solubilization of SML using water-soluble β-CDs)
From the results of Experimental Example 1, among α-, β-, and γ-CD, β-CD is considered to form the strongest inclusion complex with SML, and the water solubility of SML can be improved. It became clear.
However, β-CD has the lowest solubility among the three CDs used (solubility at 25 ° C. (mg / mL): α-CD; 145, β-CD; 18.5, γ-CD; 232), since the resulting inclusion complex has a saturated solubility, it often produces a crystalline solid (a system that becomes BS type in the solubility phase diagram). In SML / β-CD, a white solid is precipitated in the sample prepared in Experimental Example 1. Therefore, β-CD can improve the solubility of SML, but there is a limit, and the inclusion complex of saturated solubility. When the aqueous solution is cooled, crystalline precipitation is likely to occur. For this reason, the solubilization of SML using derivatives with enhanced water solubility of β-CD was examined.
使用したβ−ＣＤ誘導体は、糖転移酵素によりβ−ＣＤの１個のグルコース単位の６位の水酸基にα−１,６結合を介してグルコース又はマルトースを結合させたグルコシル（Glucosyl）−β−ＣＤ（Ｇ１−β−ＣＤ、CAS No.: 92517-02-7）とマルトシル（Maltosyl）−β−ＣＤ（Ｇ２−β−ＣＤ、CAS No.: 104723-60-6）の２種の分岐ＣＤ類、及び化学反応により７個存在するグルコース単位の２、３及び６位の水酸基をランダムにメチル化又は２−ヒドロキシプロピル化したメチル（Methyl）−β−ＣＤ（Ｍ−β−ＣＤ）と２−ヒドロキシプロピル（Hydroxypropyl）−β−ＣＤ（ＨＰ−β−ＣＤ）の２種の化学修飾型ＣＤ類、計４種類のβ−ＣＤ誘導体である。
ＳＭＬが約２ｍｇ（５．４μｍｏｌ）となるように試験管にエタノール水溶液を秤取し、溶媒を留去した。この残渣に１５ｍＭのＣＤ水溶液（軽水）１ｍＬを加え、撹拌と超音波処理後、２５℃の恒温振とう槽で一晩撹拌し、溶解の状況を目視で確認した。
The β-CD derivative used was glucosyl-β-, in which glucose or maltose was bonded to the 6-position hydroxyl group of one glucose unit of β-CD via an α-1,6 bond by glycosyltransferase. Two types of branched CDs: CD (G1-β-CD, CAS No .: 92517-02-7) and Maltosyl-β-CD (G2-β-CD, CAS No .: 104723-60-6) Methyl-β-CD (M-β-CD) and 2 obtained by random methylation or 2-hydroxypropylation of hydroxyl groups at positions 2, 3, and 6 of 7 glucose units present by chemical reaction -Hydroxypropyl-β-CD (HP-β-CD), two chemically modified CDs, a total of four β-CD derivatives.
The aqueous ethanol solution was weighed into a test tube so that the SML was about 2 mg (5.4 μmol), and the solvent was distilled off. 1 mL of a 15 mM CD aqueous solution (light water) was added to the residue, and after stirring and sonication, the residue was stirred overnight in a constant temperature shaking bath at 25 ° C., and the state of dissolution was visually confirmed.
[溶解状態]
図６に、分岐型β−ＣＤ（左側：Ｇ１−β−ＣＤ、右側：Ｇ２−β−ＣＤ）の振とう後のＳＭＬの溶解状態を示した。両試料とも試験管の底に白色のＳＭＬが残留しており、ＳＭＬに対して約３倍量の分岐型ＣＤを共存させてもＳＭＬの溶解はできなかった。一方、図７に示した化学修飾型ＣＤ（左側：Ｍ−β−ＣＤ、右側：ＨＰ−β−ＣＤ）では、両試料とも澄明な水溶液を与え、ＳＭＬを完全に溶解させることができた。
[Dissolved state]
FIG. 6 shows the dissolution state of SML after shaking of branched β-CD (left side: G1-β-CD, right side: G2-β-CD). In both samples, white SML remained at the bottom of the test tube, and SML could not be dissolved even when about 3 times the amount of branched CD was present in the SML. On the other hand, with the chemically modified CD (left side: M-β-CD, right side: HP-β-CD) shown in FIG. 7, both samples gave clear aqueous solutions and SML could be completely dissolved.
（実施例２：エタノールを溶解助剤とした化学修飾型β−ＣＤ類を使用した水溶性ＳＭＬ/β−ＣＤ包接複合体の調製）
α−、β−、γ−ＣＤ及び分岐型ＣＤは高濃度のエタノール水溶液では、その溶解性が純水にくらべ低下する。一方、Ｍ−β−ＣＤやＨＰ−β−ＣＤは９５％エタノール水溶液中でも１５ｍＭの溶液は容易に作製可能である。一般に、包接複合体の形成は、ゲスト分子とホスト分子の両者が分子分散状態にある系ではその平衡は非常に速やかに完結する。もしこのような方法で包接複合体を調製できれば、固体のＳＭＬからＳＭＬ分子をＣＤ類が引き剥がす（可溶化）ために必要な振とう時間（平衡到達時間）を省略することができ、調製作業の簡略化につながる。このため、ＳＭＬ（２ｍｇ）を溶解した９５％エタノール水溶液１ｍＬに、Ｍ−β−ＣＤ又はＨＰ−β−ＣＤ（約２０ｍｇ）を添加した溶液（物質量比は実施例１と同じ）をボルテックスミキサーによる簡単な混合後、溶媒を留去した際に残る残渣（包接複合体）の精製水への溶解性を確認した。
(Example 2: Preparation of water-soluble SML / β-CD inclusion complex using chemically modified β-CDs with ethanol as a dissolution aid)
The solubility of α-, β-, γ-CD, and branched CD is lower in a high concentration ethanol aqueous solution than in pure water. On the other hand, a 15 mM solution of M-β-CD and HP-β-CD can be easily prepared even in a 95% ethanol aqueous solution. In general, the formation of an inclusion complex is completed very quickly in a system in which both a guest molecule and a host molecule are in a molecularly dispersed state. If the inclusion complex can be prepared by such a method, the shaking time (equilibration time) required for the CDs to peel (solubilize) the SML molecules from the solid SML can be omitted. It leads to simplification of work. For this reason, a vortex mixer was prepared by adding M-β-CD or HP-β-CD (approximately 20 mg) to 1 mL of 95% ethanol aqueous solution in which SML (2 mg) was dissolved (substance ratio is the same as in Example 1). After simple mixing, the solubility of the residue (inclusion complex) remaining when the solvent was distilled off in purified water was confirmed.
図８は、残渣に１ｍＬの精製水を加え、室温でのボルテックスミキサーによる混合後の溶解状態を示しており、左からＭ−β−ＣＤ添加系、ＨＰ−β−ＣＤ添加系、ＣＤ無添加系の試料である。ＣＤ無添加系ではＳＭＬが器壁に固着して溶解しなかったが、Ｍ−β−ＣＤ及びＨＰ−β−ＣＤ添加系では２ｍｇ/ｍＬのＳＭＬ水溶液を容易に調製可能であり、エタノール水溶液のようなＳＭＬと化学修飾型ＣＤの両者が溶解する溶液中で包接複合体を形成させることは、水溶性ＳＭＬの調製にとって非常に有用であることが明らかとなった。 FIG. 8 shows a dissolved state after adding 1 mL of purified water to the residue and mixing with a vortex mixer at room temperature. From the left, M-β-CD added system, HP-β-CD added system, CD not added It is a sample of the system. In the CD-free system, SML adhered to the vessel wall and did not dissolve, but in the system with M-β-CD and HP-β-CD, a 2 mg / mL SML aqueous solution can be easily prepared. It has been found that forming an inclusion complex in a solution in which both SML and chemically modified CD are dissolved is very useful for the preparation of water-soluble SML.
実施例１及び２の結果から、Advanced Chemistry Development (ACD/Labs) Softwareで予測されたＳＭＬの水への溶解度（６．３×１０−４ｍｇ/ｍＬ）をもとに考えると、Ｍ−β−ＣＤやＨＰ−β−ＣＤとの包接複合体形成により、ＳＭＬの溶解度は約３，０００倍向上することがわかった。 From the results of Examples 1 and 2, considering the solubility of SML in water (6.3 × 10 −4 mg / mL) predicted by Advanced Chemistry Development (ACD / Labs) Software, M-β It was found that the solubility of SML was improved by about 3,000 times by the inclusion complex formation with -CD and HP-β-CD.
（実施例３：ＳＭＬ/ＣＤ包接複合体の高水溶性固体の調製）
高い水溶性を持つSML/ＣＤ包接複合体の水溶液の調製は成功したが、水中では一般的に分解などの化学反応が起きやすいため、長期のＳＭＬ/ＣＤ包接複合体の保存を考えると、高い水溶性を維持したままの固体の包接複合体を調製することは重要性がある。又、錠剤や散剤などの固形製剤への配合を考えるとき、固体の包接複合体は製剤原体として、有用である。そこで、高い水溶性を持つＳＭＬ/Ｍ−β−ＣＤ添加系及びＳＭＬ/ＨＰ−β−ＣＤ添加系の粉体化を試みた。
(Example 3: Preparation of highly water-soluble solid of SML / CD inclusion complex)
Although preparation of an aqueous solution of SML / CD inclusion complex with high water solubility was successful, chemical reactions such as decomposition generally occur easily in water, so considering long-term storage of SML / CD inclusion complex It is important to prepare a solid inclusion complex that remains highly water soluble. When considering compounding into a solid preparation such as a tablet or powder, the solid inclusion complex is useful as a drug substance. Therefore, an attempt was made to powderize the SML / M-β-CD addition system and the SML / HP-β-CD addition system having high water solubility.
調製方法は実施例２と同じで、仕込み量を２倍にした系、すなわちＳＭＬ（４ｍｇ）を溶解した９５％エタノール水溶液２ｍＬに、Ｍ−β−ＣＤ又はＨＰ−β−ＣＤ（約４０ｍｇ）を添加した溶液（物質量比は実施例１と同じ）をボルテックスミキサーによる簡単な混合後、溶媒を留去した際に残る残渣（包接複合体）を精製水へ溶解し、これを凍結乾燥により固体化した。 The preparation method was the same as in Example 2, and M-β-CD or HP-β-CD (about 40 mg) was added to 2 mL of a 95% ethanol aqueous solution in which SML (4 mg) was dissolved. After the added solution (substance ratio is the same as in Example 1) with a vortex mixer, the residue (inclusion complex) remaining when the solvent is distilled off is dissolved in purified water, and this is freeze-dried. Solidified.
図９に凍結乾燥処理により得られたＳＭＬ/Ｍ−β−ＣＤ及びＳＭＬ/ＨＰ−β−ＣＤの凍結乾燥品を示した。この凍結乾燥品は開封状態で室内に保存していても吸湿による潮解は認められなかった。一方、２ｍＬの精製水を添加し、ボルテックスミキサーによる撹拌を行うだけで、容易に澄明な水溶液となった。包接複合体の固体化は凍結乾燥法だけではなく、噴霧乾燥法でも実施可能である。本法に寄れば、溶解補助剤であるエタノール水溶液にＳＭＬとＭ−β−ＣＤ又はＨＰ−β−ＣＤを溶解し、混合した試料について噴霧乾燥処理を施すだけで包接複合体の固体が調製可能であり、さらに有効であることがわかる。 FIG. 9 shows lyophilized products of SML / M-β-CD and SML / HP-β-CD obtained by lyophilization. The freeze-dried product was not deliquescent due to moisture absorption even when stored indoors in an opened state. On the other hand, a clear aqueous solution was easily obtained simply by adding 2 mL of purified water and stirring with a vortex mixer. The inclusion complex can be solidified not only by freeze-drying but also by spray-drying. According to this method, the inclusion complex solid is prepared simply by dissolving SML and M-β-CD or HP-β-CD in an aqueous ethanol solution, which is a solubilizing agent, and spray-drying the mixed sample. It turns out that it is possible and more effective.
（実施例４：低温下におけるＳＭＬ/Ｍ−β−ＣＤ及びＳＭＬ/ＨＰ−β−ＣＤの溶解性）
室温において溶解度に近い濃度を持つ水溶液を、冷蔵庫などの低温条件下に保存すると、固体の析出が観測される場合がある。そこで、１ｍＬの精製水中にＳＭＬを２ｍｇ含む種々の配合比のＳＭＬ/Ｍ−β−ＣＤ系及びＳＭＬ/ＨＰ−β−ＣＤ系の水系試料を調製し、低温下での析出及びその可逆性並びに安定に存在するための各ＣＤの必要量を確認した。
表１は、Ｍ−β−ＣＤ及びＨＰ−β−ＣＤの４種の配合比における、室温（ＲＴ）及び冷蔵庫中（約４℃）における溶解状態を示したものである。○は澄明な溶液となったことを示しており、×は油状あるいは固体が析出したことを示している。又４℃で保存した試料をＲＴに保存した際の状態変化を矢印右側に示した。
(Example 4: Solubility of SML / M-β-CD and SML / HP-β-CD at low temperature)
When an aqueous solution having a concentration close to solubility at room temperature is stored under low temperature conditions such as a refrigerator, solid precipitation may be observed. Therefore, SML / M-β-CD and SML / HP-β-CD aqueous samples having various blending ratios containing 2 mg of SML in 1 mL of purified water were prepared, precipitation at low temperature and reversibility thereof, and The required amount of each CD to exist stably was confirmed.
Table 1 shows the dissolution state at room temperature (RT) and in a refrigerator (about 4 ° C.) at four blending ratios of M-β-CD and HP-β-CD. ○ indicates a clear solution, and x indicates that an oil or solid is precipitated. The change in state when a sample stored at 4 ° C. is stored in RT is shown on the right side of the arrow.
表１は、ＲＴ及び４℃において、ＳＭＬを可溶化するために必要なＭ−β−ＣＤ及びＨＰ−β−ＣＤの物質量比と析出物の温度による溶解性を示したものである。 Table 1 shows the M-β-CD and HP-β-CD material amount ratio necessary for solubilizing SML at RT and 4 ° C., and the solubility depending on the temperature of the precipitate.
ＳＭＬ/Ｍ−β−ＣＤ系では、ＳＭＬに対して２倍量のＭ−β−ＣＤが存在する系ではＲＴでも４℃でも澄明な溶液が作製できた。一方、ＳＭＬ/ＨＰ−β−ＣＤ系では、ＲＴではＳＭＬ/Ｍ−β−ＣＤ系と同様に澄明な溶液が作製できたが、４℃においてはＳＭＬに対して２倍量のＨＰ−β−ＣＤが存在する系では析出が認められた。しかし、この析出はＲＴに保管することにより消失し、澄明な溶液に戻ることから、この析出は可逆的であると考えられた。３倍量のＨＰ−β−ＣＤが存在する系ではＲＴでも４℃でも澄明な溶液が作製できた。 In the SML / M-β-CD system, a clear solution could be prepared at both RT and 4 ° C. in a system where M-β-CD twice the amount of SML was present. On the other hand, in the SML / HP-β-CD system, a clear solution could be prepared in RT as in the SML / M-β-CD system, but at 4 ° C., twice the amount of HP-β- Precipitation was observed in the system where CD was present. However, this precipitation disappeared upon storage at RT and returned to a clear solution, which was considered to be reversible. In a system containing 3 times the amount of HP-β-CD, a clear solution could be prepared at both RT and 4 ° C.
以上のように、分岐型ＣＤ又は化学修飾型ＣＤを用いた本発明の包接複合体は、セサミノール類単独に比べて溶解性が顕著に高くなることから、難溶性のセサミノール類をそのまま経口で摂取した場合と比べると、体内吸収性は顕著に高くなると予測される。 As described above, the inclusion complex of the present invention using a branched CD or a chemically modified CD has significantly higher solubility than sesaminols alone, so that hardly soluble sesaminols are used as they are. It is expected that the absorbability in the body will be remarkably higher than when taken orally.
Claims (7)
Characterized in that it comprises a step of mixing and stirring a high-concentration ethanol aqueous solution in which sesaminols are dissolved and chemically modified CD, and a step of distilling off the solvent in the obtained mixed solution and drying it. A method for producing an inclusion complex comprising sesaminols and a chemically modified CD containing the sesaminols.
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