CN115768739A - Aqueous solution containing stilbene compound and superoxide generation inhibitor containing stilbene compound - Google Patents
Aqueous solution containing stilbene compound and superoxide generation inhibitor containing stilbene compound Download PDFInfo
- Publication number
- CN115768739A CN115768739A CN202180044521.5A CN202180044521A CN115768739A CN 115768739 A CN115768739 A CN 115768739A CN 202180044521 A CN202180044521 A CN 202180044521A CN 115768739 A CN115768739 A CN 115768739A
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- Prior art keywords
- aqueous solution
- stilbene compound
- hydrogen atom
- compound
- formula
- Prior art date
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- -1 stilbene compound Chemical class 0.000 title claims abstract description 154
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- 235000021286 stilbenes Nutrition 0.000 title claims abstract description 147
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 title claims abstract description 36
- 239000003112 inhibitor Substances 0.000 title claims abstract description 16
- 150000002211 flavins Chemical class 0.000 claims abstract description 71
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 39
- 229930182470 glycoside Natural products 0.000 claims abstract description 34
- 150000002338 glycosides Chemical class 0.000 claims abstract description 31
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- 102100033220 Xanthine oxidase Human genes 0.000 claims abstract description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 8
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/72—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by liquid-liquid treatment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
- C07D475/14—Benz [g] pteridines, e.g. riboflavin
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
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Abstract
The present invention provides an aqueous solution in which a stilbene compound (A) and a flavin derivative (B) selected from riboflavin, FMN and FAD are dissolved in an amount of 0.3 to 200mM, wherein the stilbene compound (A) is a compound represented by the following formula (1) or a glycoside thereof. Thereby, an aqueous solution containing the stilbene compound at a high concentration can be provided. In addition, an inhibitor of superoxide production catalyzed by xanthine oxidase can be provided. In the formula (1), R 1 、R 2 And R 3 Each independently is a hydrogen atom or a methyl group, and X is a hydrogen atom, a hydroxyl group or a methoxy group.
Description
Technical Field
The present invention relates to an aqueous solution comprising a stilbene compound and a water solubility enhancer for the stilbene compound. Also disclosed are a composition containing a stilbene compound which is excellent in water solubility and a method for producing the same. In addition, it relates to an efficient extraction process of stilbene compounds. Furthermore, relates to superoxide generation inhibitors comprising stilbene compounds.
Background
Grape juice is known to contain polyphenols as active ingredients. Among the functional compounds contained in the wine known from French Parado, resveratrol is known. Resveratrol has effects of prolonging life, anti-aging, anti-hyperglycemia, anti-hyperuricemia, high LDL blood disease, anti-hypertension, anti-inflammation, and ameliorating obesity, diabetes, etc., and an effect of preventing alzheimer's disease has also been reported (see non-patent documents 1 to 4). Grape pericarp contains resveratrol glycoside (Piceid), but grape juice contains only a very small amount of Piceid, so that it is difficult to supply a large amount of glycoside from the juice. For example, an example of the composition of a commercially available grape concentrate reduced to 100% juice is shown below, and contains only 0.02mM of piceid.
Water: 86.9 +/-2.5 g/dL;
glucose: 5.87 +/-0.21 g/dL;
fructose: 5.76 plus or minus 0.05g/dL;
piceid (piceid): 0.00068g/dL (0.02 mM);
polyphenols (calculated as gallic acid): 0.088g/dL.
As a source of resveratrol, resveratrol contained in an extract of a leaf, stem or seed of grape can be used. However, resveratrol is very insoluble in water due to its hydrophobic nature, and has a solubility of only 0.19mM in water at 20 ℃ (see Table 2 in the specification of this application). In the above-mentioned non-patent documents 1 to 4 in which physiological activities of resveratrol have been reported, a considerable amount (50 to 3000 mg/day) of resveratrol is taken in order to exhibit the physiological activities thereof. Therefore, in order to sufficiently exhibit the effect, a large amount of intake of 0.2mmol or more is required for 1 day. For example, in the case of use as a supplement, it is necessary to prepare a beverage containing resveratrol at a high concentration in order to be efficiently ingested.
In order to produce a resveratrol-containing beverage which can be absorbed by living bodies, methods of converting to a glycoside, clathrating with cyclodextrin, adding alcohol to an aqueous solution, and the like have been attempted (see non-patent documents 5 and 6). However, efficient glycosylation of resveratrol by biocatalysis has not been reported. Further, no method has been reported for obtaining a high-concentration aqueous solution by inclusion of a cyclodextrin compound with resveratrol. Furthermore, the solubility of resveratrol in an aqueous solution containing ethanol is not so great when the ethanol content is low (see fig. 3 in the present specification). Therefore, much resveratrol cannot be dissolved in a low alcohol content wine, and it is desirable to dissolve resveratrol in a non-alcoholic beverage if health is concerned.
Xanthine Oxidase (XO) is an enzyme that catalyzes a reaction in a living body in which hypoxanthine is oxidized to produce xanthine, and catalyzes a reaction in which xanthine is oxidized to produce uric acid. Therefore, the effect of inhibiting xanthine oxidase is effective for the treatment of hyperuricemia or gout. For example, alkyl gallate is effectively described in non-patent document 7 as a xanthine oxidase inhibitor. Oxidation from hypoxanthine to xanthine, reaction of uric acid, and oxygen (O) 2 ) Is reduced to superoxide (O) 2 － H) and hydrogen peroxide (H) 2 O 2 ) The reaction of (c) proceeds in a so-called ping-pong mechanism. Excessive production of Reactive Oxygen Species (ROS) such as superoxide and hydrogen peroxide may cause oxidative stress including the production of lipid peroxides, and may adversely affect health and the food industry (see non-patent document 8).
Documents of the prior art
Non-patent document
Non-patent document 1: szkudelski T, szkudelska K.Resveratro and diabetes from animal to human students Biochim Biophys acta.2015;1852 (6) 1145 to 1154. Non-patent document 2: pasineti GM, wang J, ho L, zhao W, dubner l.rolls of resurratrol and other graft-derived polyphenoles in Alzheimer's disease presence and treatment. Biochim biophysis acta.2015;1852 (6):1202-1208.
Non-patent document 3: khodabandehloo H, seyyedebrarimi S, efahani EN, razi F, meshkani R.Reservation deletion deletions in sections with glucose changing the circulating CD14+ CD16+ monocytes and infilamations cells in properties with type 2 diabetes; 54:40-51.
Non-patent document 4: okang Tian Wuyan, xiaoxiyouli flower, dan Yuanhao, yiokang aromatic, isomerization of stilbene compounds, and stilbene Naturasiaceae.2009 from Polygonum cuspidatum (Polygonum cuspidatum); 14:17-21.
Non-patent document 5: shimoda K, kubota N, hamada H. Synthesis of revolute glycosides by plant glucosyltransferase and cyclodextrine glucosyltransferase and the air neuroprotective activity. Nat.prod.Commun.2015;10 (6):995-6.
Non-patent document 6: szkudelska K, deniziak M, ros P, gwozodz K, szkudelski t. Resuveratrol allevialis ethanol-induced hormonal and metabolic disorders in the rate. Physical. Res.2017;66:135-145.
Non-patent document 7: masuoka N, nihei K, kubo I, xanthene oxidase inhibitor activity of alkyl gallates, mol. 50,725 to 731 non-patent document 8: rattan Tian Zhi, reactive oxygen species, lipid peroxides, mechanisms for the generation and scavenging of free radicals and their biological effects, YAKUGAKU ZASSHI 2002;122 (3):203-218
Disclosure of Invention
Technical problem to be solved by the invention
The present invention has been made to solve the above-mentioned problems, and an object thereof is to provide an aqueous solution containing a stilbene compound at a high concentration. It is also an object of the present invention to provide a water-solubility enhancer capable of enhancing the solubility of a stilbene compound having low solubility in water. It is also an object of the present invention to provide a composition comprising a stilbene compound and having good water solubility and a suitable production method thereof. It is also an object of the present invention to provide a process for the efficient extraction of stilbene compounds using water. Further, it is also an object of the present invention to provide an inhibitor of superoxide generation catalyzed by xanthine oxidase comprising the above stilbene compounds or aqueous solutions and compositions containing the above stilbene compounds.
Technical solution for solving technical problem
The above-mentioned technical problem is solved by providing an aqueous solution in which 0.3 to 200mM of a stilbene compound (A) and 0.3 to 200mM of a flavin derivative (B) are dissolved, wherein the stilbene compound (A) is a compound represented by the following formula (1) or a glycoside or polymer thereof, and the flavin derivative (B) is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.
[ in the formula (1), R 1 、R 2 And R 3 Each independently is a hydrogen atom or a methyl group, and X is a hydrogen atom, a hydroxyl group or a methoxy group.]
[ in the formula (2), n is 0,1 or 2. When n is 0 or 1, Y is a hydrogen atom. When n is 2, Y is a group represented by the following formula (3). ]
In this case, the stilbene compound (a) is preferably at least 1 selected from resveratrol, piceatannol, rhapontigenin, isorhapontigenin, pterostilbene and pinostilbene, and glycosides and polymers thereof. It is also preferable that the molar ratio (B/A) of the flavin derivative (B) to the stilbene compound (A) is from 0.5 to 50. The pH of the aqueous solution is preferably 1.5 to 6. Further, it is also preferable that the concentration of ethanol in the solvent is less than 20% by volume.
In addition, the aqueous solution containing the pH adjuster (C) selected from the group consisting of carboxylic acids having 2 to 6 carbon atoms, ascorbic acid and glycosides thereof is a preferred embodiment. A preferred embodiment of the present invention is an inhibitor of superoxide generation catalyzed by xanthine oxidase, comprising the above aqueous solution. In addition, a preferred embodiment of the present invention is a beverage or cosmetic comprising the aqueous solution.
The above technical problem can also be solved by providing a water solubility enhancer for enhancing the solubility of a stilbene compound (a) in water, which comprises a flavin derivative (B) wherein the stilbene compound (a) is a compound represented by the above formula (1) or a glycoside or polymer thereof, and the flavin derivative (B) is a compound represented by the above formula (2) or a pharmaceutically acceptable salt thereof.
The above-mentioned technical problem can also be solved by providing a composition in a form selected from the group consisting of a powder, a granule, a tablet and a paste, the composition comprising a stilbene compound (a) which is a compound represented by the above formula (1) or a glycoside or polymer thereof and a flavin derivative (B) which is a compound represented by the above formula (2) or a pharmaceutically acceptable salt thereof, wherein the molar ratio (B/a) of the flavin derivative (B) to the stilbene compound (a) is 0.5 to 50. In this case, the composition preferably further comprises a pH adjuster (C) selected from carboxylic acids having 2 to 6 carbon atoms, ascorbic acid and glycosides thereof.
Further, a method for producing the composition is preferable, wherein an aqueous solution in which the stilbene compound (a) and the flavin derivative (B) are dissolved is prepared, and then water is removed. A preferred embodiment of the present invention is an inhibitor of superoxide generation catalyzed by xanthine oxidase comprising the above composition.
The above-mentioned technical problem can also be solved by providing a method for extracting a stilbene compound (a) which comprises bringing a plant material containing the stilbene compound (a) or a crude extract obtained by extracting the plant material with an organic solvent into contact with an aqueous solution in which a flavin derivative (B) is dissolved, wherein the stilbene compound (a) is a compound represented by the above formula (1) or a glycoside or polymer thereof, and the flavin derivative (B) is a compound represented by the above formula (2) or a pharmaceutically acceptable salt thereof, and extracting the stilbene compound (a) from the plant material or the crude extract.
The above-mentioned technical problem can also be solved by providing an inhibitor of superoxide generation catalyzed by xanthine oxidase, which comprises a stilbene compound (a) as an active ingredient, wherein the stilbene compound (a) is a compound represented by the above formula (1) or a glycoside or polymer thereof. In a preferred embodiment, in formula (1), R 1 、R 2 、R 3 And X is a hydrogen atom. In another preferred embodiment, in the formula (1), R is 1 And R 2 Is a hydrogen atom, R 3 Is a hydrogen atom or a methyl group, and X is a hydroxyl group.
ADVANTAGEOUS EFFECTS OF INVENTION
The aqueous solution of the present invention contains a stilbene compound such as resveratrol dissolved in a high concentration, and the stilbene compound can be efficiently taken in a small amount. Since it is dissolved in water, it is excellent in absorption performance in a living body after ingestion. In addition, the aqueous solution of the present invention can dissolve the stilbene compound at a high concentration without adding an organic solvent such as ethanol. Furthermore, the flavin derivative contained in the aqueous solution of the present invention can also be used as vitamin B 2 And metabolites thereof exert useful effects on organisms. Therefore, the aqueous solution of the present invention is useful as a beverage or a cosmetic. In addition, by using the water solubility enhancer of the present invention, the solubility of the stilbene compound in water can be greatly enhanced.
The composition of the present invention has a form such as powder, granule, tablet or paste, and is excellent in solubility in water and absorbability in the living body. Therefore, the composition of the present invention is useful as a supplement or the like. In addition, according to the extraction method of the present invention, even if an organic solvent is not used, the stilbene compound can be efficiently extracted by water.
Further, the above stilbene compound, the above aqueous solution containing the above stilbene compound, and the above composition containing the above stilbene compound can inhibit the production of superoxide catalyzed by xanthine oxidase.
Drawings
Fig. 1 is a graph showing the change in solubility of a stilbene compound in water when the concentration of FMN is changed in example 1.
Fig. 2 is a graph showing the change in solubility of resveratrol in an aqueous solution when concentrations of FMN and FAD in the aqueous solution were changed in example 2.
Fig. 3 is a graph showing the change in solubility of resveratrol in an aqueous solution when the concentration of ethanol in the aqueous solution was changed in reference example 1.
FIG. 4 is a graph comparing the absorption spectrum (dotted line) of an aqueous solution containing 10mM piceatannol and 10mM FMN with the absorption spectrum (solid line) of an aqueous solution containing only 10mM FMN in example 5.
FIG. 5 is a graph comparing the absorption spectrum (dotted line) of an aqueous solution containing 0.01mM of piceatannol and 0.01mM of FMN with the absorption spectrum (solid line) of an aqueous solution containing only 0.01mM of FMN in example 5.
Fig. 6 is a graph showing pH when the acetic acid concentration of an aqueous solution containing resveratrol, FMN and acetic acid was changed in example 8.
FIG. 7 is a graph showing pH values when the concentration ratio of FMN and various acids was changed in reference example 2.
Fig. 8 is a diagram showing a part of the horizontal axis of fig. 7 enlarged.
Fig. 9 is a graph showing the dissolution rate in water of a mixed powder 1 obtained by mixing a resveratrol powder and an FMN powder and a mixed powder 2 obtained by drying an aqueous solution of a resveratrol and FMN mixture in comparative example 9.
FIG. 10 is a graph showing the change in superoxide eliminating activity when the concentration of the stilbene compound is changed in example 14.
Detailed Description
The present invention is an aqueous solution in which 0.3 to 200mM of a stilbene compound (A) and 0.3 to 200mM of a flavin derivative (B) are dissolved, wherein the stilbene compound (A) is a compound represented by the following formula (1) or a glycoside or polymer thereof, and the flavin derivative (B) is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof. The stilbene compound (a) is hydrophobic and therefore has low solubility in water, but the solubility of the stilbene compound (a) can be greatly improved by dissolving the stilbene compound (a) together with the flavin derivative (B).
First, the stilbene compound (A) will be described. The stilbene compound (A) is a compound represented by the following formula (1) or a glycoside or polymer thereof.
R in the formula (1) 1 、R 2 And R 3 Each independently a hydrogen atom or a methyl group. From the viewpoint of water solubility, R is preferred 1 、R 2 And R 3 1 or more of them are hydrogen atoms, more preferably 2 or more are hydrogen atoms, and still more preferably 3 are all hydrogen atoms. X in the formula (1) is a hydrogen atom, a hydroxyl group or a methoxy group.
The stilbene compound (A) may be a glycoside of the compound represented by the formula (1). In this case, the sugar chain is bonded to the hydroxyl group contained in the compound represented by the formula (1). The sugar chain may be a monosaccharide or a polysaccharide. When the sugar chain is long, the water solubility of the stilbene compound (A) is improved, and the stilbene compound (A) has sufficient water solubility even when the flavin derivative (B) is not used in many cases. Therefore, the meaning of the present invention is large in the case where the sugar chain is a monosaccharide or a disaccharide, particularly in the case of a monosaccharide. The sugar forming the sugar chain is not particularly limited, and examples thereof include glucose, β -glufose and the like, but glucose is preferable. Preferred is a glucoside to which 1 molecule of diol is bonded. In addition, a part of the hydroxyl groups of the stilbene compound (A) may form a salt, but it is preferable that the pH of the aqueous solution is kept in a small amount within a range of less than 7. Preferred specific examples of the stilbene compound (A) are shown in Table 1 together with the structure thereof.
[ Table 1]
| Stilbene compounds (A) | R 1 | R 2 | R 3 | X |
| Resveratrol | H | H | H | H |
| New glycoside of spruce | H | Glc | H | H |
| Resveratrol-4' -glucoside | H | H | Glc | H |
| Piceatannol | H | H | H | OH |
| Rheum emodin | H | H | CH 3 | OH |
| Radix et rhizoma RheiVegetable extract | H | H | H | OCH 3 |
| Pinostilbene | H | CH 3 | H | H |
| Pterostilbene | CH 3 | CH 3 | H | H |
Resveratrol is a stilbene compound having 3 hydroxyl groups, and is an important compound in terms of physiological activity. The resveratrol contains piceid (resveratrol-3-glucoside) and resveratrol-4' -glucoside as the substances obtained by combining 1 hydroxyl of resveratrol with glucose (Glc). X is a hydroxyl group and piceatannol having 4 hydroxyl groups in total. The rhapontigenin and isorhapontigenin are substances in which 1 of 4 hydroxyl groups of piceatannol is changed into methoxyl group, and substances in which 1 or 2 of the hydroxyl groups of resveratrol is changed into methoxyl group are pinostilbene and pterostilbene. These compounds are reported to be physiologically active, respectively.
Further, the stilbene compound (A) may be a polymer of the compound represented by the formula (1). The polymer may be a polymer in which molecules of the compound represented by formula (1) are simply bonded to each other, a polymer in which molecules are dehydrogenated, or a polymer in which molecules are dehydrated. Particularly preferred is a polymer obtained by dehydrogenating and bonding. The polymer may be a dimer or a polymer of a trimer or more, but a dimer is preferable. Examples of the resveratrol multimer include epsilon-viniferin (formula (4) below), delta-viniferin, a dehydrodimer such as gnestin C, a dehydrotrimer such as alpha-viniferin, and a dehydrotetramer such as hopapeprenol.
Next, the flavin derivative (B) will be explained. The flavin derivative (B) is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.
In the formula (2), n is 0,1 or 2, Y is a hydrogen atom when n is 0 or 1, and Y is a group represented by the following formula (3) when n is 2. The compound in which n is 0 and Y is hydrogen atom is riboflavin (vitamin B) 2 ). The compound in which n is 1 and Y is a hydrogen atom is Flavin Mononucleotide (FMN). Further, a compound in which n is 2 and Y is a group represented by the following formula (3) is Flavin Adenine Dinucleotide (FAD). Riboflavin is a water-soluble vitamin and is desirably ingested continuously for the purpose of maintaining health. Further, since there is substantially no problem of excessive intake, it is a compound which is preferably dissolved in the aqueous solution of the present invention. Both FMN and FAD are metabolites from riboflavin, and are useful and safe compounds as well as riboflavin.
The flavin derivative (B) may also be a pharmaceutically acceptable salt. The type of the salt is not particularly limited as long as it is a pharmaceutically acceptable salt. Among them, it is preferable that at least a part of the phosphoric acid units contained in the compound represented by the formula (2) form a salt with a cation when n is 1 or 2. The cation species in this case is not particularly limited, and examples thereof include sodium, potassium, magnesium, calcium, zinc, and ammonium.
Used in the inventionThe flavin derivative (B) may be riboflavin (vitamin B) 2 ) Any one of Flavin Mononucleotide (FMN) and Flavin Adenine Dinucleotide (FAD), but FMN and FAD are preferable from the viewpoint of effectively improving the solubility of the stilbene compound (a). As shown in the example (fig. 2), the same number of moles of FMN and FAD are able to dissolve the same degree of amount of stilbene compound (a). Therefore, if comparing the molecular weights of FMN and FAD, FMN that can improve solubility with less quality is more preferable.
The concentration of the stilbene compound (A) dissolved in the aqueous solution of the present invention is 0.3 to 200mM. The concentration of the stilbene compound (A) is preferably 1mM or more, more preferably 2mM or more, still more preferably 5mM or more, and particularly preferably 10mM or more. Dissolving more of the stilbene compound (A) enables the stilbene compound (A) to be efficiently taken up by drinking a smaller amount of the aqueous solution. In addition, when used as a cosmetic, it can be absorbed more effectively from the skin. Depending on the type of stilbene compound (A), it may not be dissolved up to 200mM, and in such a case, the saturation concentration in the aqueous solution is an upper limit.
The concentration of the flavin derivative (B) dissolved in the aqueous solution of the present invention is 0.3 to 200mM. The concentration of the flavin derivative (B) is preferably 2mM or more, more preferably 5mM or more, still more preferably 10mM or more, and particularly preferably 15mM or more. More flavin derivative (B) is dissolved, more stilbene compound (a) can be dissolved. Depending on the type of flavin derivative (B), the maximum saturation concentration may be the upper limit in some cases, since the flavin derivative (B) may not be dissolved in a concentration of up to 200mM.
As shown in example 1 (FIG. 1), the solubility of the stilbene compound (A) increases substantially in proportion to the concentration of the flavin derivative (B). The number of molecules of the flavin derivative (B) required for dissolving 1 molecule of the stilbene compound (A) varies depending on the kind of the stilbene compound (A). The stilbene compound (A) having higher water solubility than the polymer can be dissolved by a smaller number of molecules of the flavin derivative (B). The number of molecules of the flavin derivative (B) required for dissolving the stilbene compound (A) 1 molecule is less than 1 molecule, piceatannol, rhapontigenin and isorhapontigenin are about 1 molecule, resveratrol is about 4 molecules and pterostilbene is about 6 molecules. Though epsilon-viniferin, which is a dehydrodimer of resveratrol, is not originally highly water-soluble, the water solubility is greatly improved by a small amount of flavin derivative (B).
As shown in example 5, in the absorption spectrum of the stilbene compound in the aqueous solution, the absorption maxima were shifted in a dark color by adding FMN. Therefore, in the aqueous solution of the present invention, it is considered that molecules of the stilbene compound (A) and molecules of the flavin derivative (B) are associated at a prescribed ratio. Further, the disappearance of the association was confirmed from example 5 (comparison between fig. 4 and fig. 5) by diluting the aqueous solution. Therefore, the association of the aromatic ring of the stilbene compound (A) with the aromatic ring of the flavin derivative (B) by pi-pi interaction is an association by a relatively weak force, and it is considered that dissociation occurs by dilution.
In the aqueous solution of the present invention, the molar ratio (B/A) of the flavin derivative (B) to the stilbene compound (A) is preferably 0.2 to 50. The molar ratio (B/a) is more preferably 0.5 or more, and still more preferably 0.8 or more. In the case where the stilbene compound (a) is resveratrol, the molar ratio (B/a) is preferably 2 or more, more preferably 3 or more. Since the flavin derivative (B) hardly has a problem due to excessive uptake, it does not matter whether the flavin derivative (B) is dissolved in a larger number of molecules than the number of molecules necessary for association.
The pH of the aqueous solution of the present invention is preferably 1.5 to 6. As shown in example 7 (table 4), when an aqueous solution having a pH of 7 or more is prepared, the amount of the stilbene compound (a) decreases and is easily changed to another compound. The pH is more preferably 5.5 or less, and still more preferably 5 or less. On the other hand, if the pH is too low, the sourness is too strong when used as a beverage, and the irritation to the skin is too strong when used as a cosmetic, so the pH is more preferably 2.5 or more, and still more preferably 3 or more. In addition, if a product to be diluted with water by a consumer and used as a beverage or a cosmetic is considered, the pH of the aqueous solution of the present invention is more preferably 1.5 or more, and still more preferably 2 or more.
The method for adjusting the pH of the aqueous solution of the present invention to 1.5 to 6 is not particularly limited. Preferably, a pharmaceutically acceptable acid is added as the pH adjuster (C). Suitable acids for use as the pH adjuster (C) include carboxylic acids having 2 to 6 carbon atoms, ascorbic acid, and glycosides thereof. Examples of the carboxylic acid having 2 to 6 carbon atoms include acetic acid, citric acid, lactic acid, tartaric acid, succinic acid, malic acid, glutamic acid, gluconic acid, and the like. Among them, citric acid and acetic acid are preferable in view of taste. Ascorbic acid and its glycoside are also preferable because they can provide an antioxidant effect. Examples of the glycoside of ascorbic acid include ascorbic acid 2-glucoside.
The molar ratio (C/B) of the pH adjuster (C) to the flavin derivative (B) is preferably 0.2 to 50. If the molar ratio (C/B) is too small, the pH is not sufficiently lowered. Therefore, the molar ratio (C/B) is more preferably 0.3 or more, and still more preferably 0.5 or more. On the other hand, if the molar ratio (C/B) is too large, the sour taste becomes strong, and the irritation to the skin becomes strong. Therefore, the molar ratio (C/B) is more preferably 10 or less, still more preferably 5 or less, and particularly preferably 2 or less.
The aqueous solution of the present invention may contain components other than the stilbene compound (A), the flavin derivative (B) and the pH adjustor (C). Various ingredients used in beverages or cosmetics may be blended as necessary. Among them, the concentration of ethanol in the solvent is preferably less than 20 vol%. As shown in reference example 1 (fig. 3), the solubility of the stilbene compound (a) when a mixed solvent of water and ethanol is used is greatly increased after the ethanol content exceeds 20 vol%. Therefore, when the concentration of ethanol in the solvent is less than 20% by volume, the flavin derivative (B) is incorporated in a large sense. The concentration of ethanol in the solvent is more preferably 5% by volume or less, still more preferably 1% by volume or less, and particularly preferably 0.05% by volume or less. If the aqueous solution of the present invention is used, a beverage free of alcohol can be provided.
The use of the aqueous solution of the present invention is not particularly limited, and beverages and cosmetics are suitable. Since a large amount of the stilbene compound (a) is dissolved in water, the stilbene compound (a) is excellent in absorbability in organisms. In the case of beverages, they are rapidly absorbed from the intestinal tract, and in the case of cosmetics, they are easily absorbed from the skin. The beverage can be made into nonalcoholic beverage, and alcoholic beverage with low alcohol content less than 20%. Particularly suitable for use as a supplement beverage. As cosmetic, cosmetic water or lotion can be prepared. In addition, the composition can be made into medicinal products such as dripping liquid.
As shown in example 6 and example 7 (table 4), the aqueous solution of the present invention containing the stilbene compound (a) and the flavin derivative (B) may decrease the amount of the stilbene compound (a) by irradiation with light. On the other hand, in the case where the stilbene compound (A) is contained alone without containing the flavin derivative (B), the decrease in the amount of the stilbene compound (A) due to light irradiation can be suppressed. Therefore, it is considered that the photostability of the stilbene compound (A) is lowered by the association with the flavin derivative (B). Therefore, the aqueous solution of the present invention is preferably stored protected from light. As described above, it is preferable that the aqueous solution of the present invention is maintained at pH 1.5 to 6 in terms of stability. Therefore, in the case of storing the aqueous solution of the present invention, a package in which the aqueous solution is stored in a light-shielding state at a pH of 1.5 to 6 and the aqueous solution is stored in a container capable of being stored in a light-shielding state is desirable as a preferred embodiment.
As described above, by incorporating the flavin derivative (B), the solubility of the stilbene compound (A) in water is improved. Accordingly, the technical problem of the present invention can also be solved by providing a water-solubility enhancer comprising a flavin derivative (B) for enhancing the solubility of the stilbene compound (a) in water.
Another embodiment of the present invention is a composition in a form selected from the group consisting of a powder, a granule, a tablet and a paste, the composition comprising a stilbene compound (a) and a flavin derivative (B), wherein the molar ratio (B/a) of the flavin derivative (B) to the stilbene compound (a) is 0.5 to 50. Such a composition is useful as a raw material for obtaining the above aqueous solution, and the stilbene compound (a) is easily absorbed by a living body even when it is taken or applied as it is. In this case, the preferred molar ratio (B/A) is as described in the above description of the aqueous solution. Further, it is also preferable that the aqueous solution further contains a pH adjuster (C) selected from carboxylic acids having 2 to 6 carbon atoms, ascorbic acid and glycosides thereof. The preferred molar ratio (C/B) is as described above in the description of the aqueous solution.
The composition of the present invention may be in a form substantially free of water, such as a powder, a granule or a tablet, or in a form in which the stilbene compound (a) is dispersed as a particle in a high-viscosity liquid without being completely dissolved in water, such as a paste. These compositions may contain components other than the stilbene compound (A), the flavin derivative (B), the pH adjuster (C) and water as required. Even in the composition of the present invention, as shown in example 6, in a state where water is hardly present, the stilbene compound (A) is slightly decreased by light irradiation. Therefore, the composition of the present invention is also preferably stored in the dark like the aqueous solution of the present invention. In addition, a package in which the composition is contained in a container that can be protected from light is a preferred embodiment. The use of the composition of the present invention is not particularly limited, and the composition can be used as a health food or a supplement. In addition, the composition can be made into a pharmaceutical product in the form of a capsule, a tablet, or the like.
The method for producing the composition of the present invention is not particularly limited, and the powder of the stilbene compound (a) and the powder of the flavin derivative (B) may be simply mixed together with other components as necessary. However, from the viewpoint of the dissolution rate in water, it is preferable to prepare an aqueous solution in which the stilbene compound (a) and the flavin derivative (B) are dissolved in advance and then remove the water contained therein to produce the composition of the present invention. As shown in example 9 (fig. 9), the powder of the composition obtained by forming an association of the stilbene compound (a) and the flavin derivative (B) in advance and then drying the association is particularly higher in the dissolution rate in water than the powder obtained by simply mixing the powder of the stilbene compound (a) and the powder of the flavin derivative (B). Therefore, the time required for preparing an aqueous solution by dissolving the composition in water can be shortened, and thus the consumer can easily prepare an aqueous solution. In addition, the absorption rate and absorption rate of the composition when taken directly into the body can be improved.
Another embodiment of the present invention is a method for extracting a stilbene compound (a), wherein a plant material containing the stilbene compound (a) or a crude extract obtained by extracting the plant material with an organic solvent is brought into contact with an aqueous solution in which a flavin derivative (B) is dissolved, and the stilbene compound (a) is extracted from the plant material or the crude extract to the aqueous solution. The aqueous solution in which the flavin derivative (B) is dissolved can dissolve a larger amount of the stilbene compound (a) than water, and therefore the stilbene compound (a) can be efficiently extracted using the aqueous solution. The concentration of the flavin derivative (B) dissolved in the aqueous solution is 0.3 to 200mM. The concentration of the flavin derivative (B) is preferably 2mM or more, more preferably 5mM or more, still more preferably 10mM or more, and particularly preferably 15mM or more.
In extracting hydrophobic active ingredients from plant materials, organic solvents are often used as extraction solvents. However, from the viewpoint of environmental protection, it is desirable not to use an organic solvent as the extraction solvent in order not to volatilize the organic solvent to the surroundings. In addition, even in the case of use in beverages or cosmetics, it is desirable not to use an organic solvent in the extraction process. On the other hand, if an aqueous solution in which the flavin derivative (B) is dissolved is used, the stilbene compound (a) can be efficiently extracted without using an organic solvent. Furthermore, only the stilbene compound (a) capable of associating with the flavin derivative (B) can be selectively extracted, and therefore the stilbene compound (a) having a high purity can be obtained. In addition, the obtained aqueous solution containing the stilbene compound (a) and flavin derivative (B) can be used as it is as a raw material for beverages or cosmetics. Furthermore, when the stilbene compound (a) is extracted from a crude extract obtained by extracting a plant material with an organic solvent or the like in advance, with an aqueous solution containing the flavin derivative (B), the stilbene compound (a) having a high purity can be obtained.
Further, an inhibitor of superoxide generation catalyzed by xanthine oxidase, which comprises as an active ingredient a stilbene compound (a) which is a compound represented by the above formula (1) or a glycoside or polymer thereof, is also an embodiment of the present invention. These compounds inhibit the reaction of producing superoxide more strongly than the reaction of producing uric acid from xanthine using xanthine oxidase as a catalyst. This is the first time to report compounds that specifically inhibit superoxide production catalyzed by xanthine oxidase.
In this case, in the formula (1), R is preferably 1 、R 2 、R 3 And X is a hydrogen atom. That is, it is a preferred embodiment that the stilbene compound (a) is resveratrol or a glycoside or polymer thereof. Resveratrol and its derivatives are considered to be particularly useful as physiologically active substances.
In this case, R in the above formula (1) is also preferable 1 And R 2 Is a hydrogen atom, R 3 Is a hydrogen atom or a methyl group, and X is a hydroxyl group. That is, the stilbene compound (a) is rheum officinale or piceatannol, or a glycoside or polymer thereof is a preferable embodiment. These compounds strongly inhibit both the reaction of xanthine oxidase as a catalyst to produce uric acid from xanthine and the reaction of xanthine oxidase to produce superoxide. The rhapontigenin particularly strongly inhibits the reaction of producing uric acid from xanthine with xanthine oxidase as a catalyst. On the other hand, piceatannol inhibits the reaction of xanthine oxidase as a catalyst to produce uric acid from xanthine, and also accelerates the reaction of oxygen to produce hydrogen peroxide, thereby inhibiting the production of superoxide more strongly than rhapontigenin.
Further, an inhibitor of superoxide generation catalyzed by xanthine oxidase, which comprises the above aqueous solution in which the stilbene compound (a) and the flavin derivative (B) are dissolved, is a preferred embodiment. Further, an inhibitor of superoxide generation catalyzed by xanthine oxidase, which comprises a composition comprising a form selected from the group consisting of powder, granule, tablet and paste, which comprises the stilbene compound (a) and the flavin derivative (B), is also a preferred embodiment.
Examples
Example 1 (solubility in aqueous FMN solution)
Flavin Mononucleotide (FMN) was dissolved in purified water at 20 ℃ to prepare aqueous solutions having concentrations of 2.5, 5,10, 20, 25,50 and 100mM (mmol/L), respectively. FMN used herein is a sodium salt of a compound in which n is 1 and Y is a hydrogen atom in the compound of formula (2), and 1 mole of the phosphate group contained in FMN is neutralized with about 1 mole of sodium ion. The pH of the 20mM aqueous solution of FMN was 5.8. In addition, the concentration of the saturated aqueous solution of FMN at 20 ℃ was 173mM. The same applies to FMN used in other embodiments described below.
Resveratrol powder manufactured by Tokyo chemical industry Co., ltd was put into pure water and FMN aqueous solution of each concentration, and the mixture was dissolved by irradiating with ultrasonic waves for 30 minutes. After standing for 1 hour, the undissolved powder was centrifuged to remove precipitates, and the supernatant was separated and then the resveratrol concentration was measured. In the measurement, the supernatant was diluted with 0.1M sodium citrate buffer (pH 4.0), and the difference spectrum with respect to an aqueous FMN solution of the same concentration was measured to calculate the solubility (mM) of resveratrol in the aqueous solution from the absorbance of the 317nm absorption peak (molar absorptivity. Epsilon.: 29,000). The solubilities obtained are summarized in Table 2 and shown in the graph of FIG. 1.
Piceid (manufactured by LKTlab: absorption maxima 319nm,. Epsilon. =30,500), piceatannol (manufactured by BLDpharm: absorption maxima 324nm,. Epsilon. =27,200), rhapontigenin (manufactured by Tokyo Kasei Co., ltd.: absorption maxima 324nm,. Epsilon. =28,900), isorhapontigenin (manufactured by Tokyo Kasei Co., ltd.: absorption maxima 324nm,. Epsilon. =29,300), pterostilbene (manufactured by BLDpharm: absorption maxima 317nm,. Epsilon. =29,200) and epsilon-viniferin (manufactured by Fuji film and Wako pure drugs: absorption maxima 322nm,. Epsilon. =25,500) were measured for absorbance at each wavelength in the same manner as the above-mentioned resveratrol, and solubility was obtained. The measurement results are summarized in Table 2 and shown in the graph of FIG. 1.
[ Table 2]
As can be seen from Table 2 and FIG. 1, the solubilities of piceid, rhapontigenin and isorhapontigenin in pure water were 1.19 to 2.73mM, but the solubilities were much higher than those in pure water by dissolving them in FMN aqueous solution. Since the solubility of these stilbene compounds increased linearly almost in proportion to the concentration of FMN at 1:1, it was found that 1 molecule of FMN was required to dissolve 1 molecule of these stilbene compounds. Therefore, it is assumed that these stilbene compounds associate with FMN in a ratio of 1 to 1 in aqueous solution.
On the other hand, in the case of dissolving resveratrol having a solubility of 0.19mM in pure water in an FMN aqueous solution, the solubility of resveratrol increases substantially linearly in proportion to the concentration of FMN, but in order to dissolve 1 molecule of resveratrol, about 4 molecules of FMN are required. Therefore, it is assumed that resveratrol is dissolved in water while being surrounded by about 4 molecules of FMN.
In the case of less soluble pterostilbene (0.09 mM) in pure water, more molecules of FMN are needed to dissolve 1 molecule than resveratrol. On the other hand, in the case of piceatannol (8.34 mM) and ε -viniferin (3.83 mM) having high solubility in pure water, FMN required for dissolving 1 molecule was 1 molecule or less.
Example 2 (solubility in aqueous FAD solution)
Flavin Adenine Dinucleotide (FAD) was dissolved in pure water at 20 ℃ to prepare aqueous solutions having concentrations of 5,10 and 20mM, respectively. FAD used herein is a sodium salt of a compound in which n is 2 and Y is a group represented by formula (3) in the compound of formula (2), and a diphosphate group contained in FAD is neutralized with about 2 moles of sodium ions. The concentration of the saturated aqueous solution of FMN at 20 ℃ was 324mM.
Pure water and FAD aqueous solutions of various concentrations were dissolved in resveratrol powder in the same manner as in example 1, and the solubility of resveratrol was measured. The solubility of resveratrol in the obtained aqueous FAD solution is summarized in table 3 and fig. 2 together with the solubility of resveratrol in the aqueous FMN solution obtained in example 1.
[ Table 3]
As is clear from table 3 and fig. 2, both the FMN aqueous solution and the FAD aqueous solution can dissolve resveratrol in the same molar number as long as the molar concentrations are the same. Thus, it is believed that both FMN and FAD act in the same way on the resveratrol molecule, contributing to its water solubility.
Example 3 (solubility in aqueous Riboflavin solution)
A saturated aqueous solution of riboflavin was prepared with a solubility of 0.43mM. The riboflavin is a compound represented by the formula (2) wherein n is 0 and Y is a hydrogen atom. The saturated aqueous solution of riboflavin was dissolved in the resveratrol powder and the solubility of resveratrol was measured in the same manner as in example 1. As a result, resveratrol at 0.45mM was dissolved and the solubility in pure water (0.19 mM) was more than twice as high.
Reference example 1 (solubility in ethanol aqueous solution)
Ethanol was added to pure water to prepare aqueous ethanol solutions having concentrations of 5,10, 20, 30 and 40 vol%, respectively. With respect to pure water and ethanol aqueous solutions of respective concentrations, the resveratrol powder was dissolved and the solubility of resveratrol was measured in the same manner as in example 1. The solubility (mM) of resveratrol at each ethanol concentration was 0.19. + -. 0.03 (pure water), 0.25. + -. 0.02 (5 vol%), 0.37. + -. 0.02 (10 vol%), 1.30. + -. 0.30 (20 vol%), 7.38. + -. 1.10 (30 vol%), 32.9. + -. 3.0 (40 vol%). The solubility versus ethanol concentration is shown in the graph of fig. 3.
As can be seen from fig. 3, the solubility of resveratrol increased as the ethanol concentration increased. However, the solubility of resveratrol having an ethanol concentration of about 20 vol% is not so high, and the solubility rapidly increases with 30 vol% and 40 vol%. The solubility changes with the change in the polarity of the solvent, and the linear increase in the solubility of the stilbene compound in proportion to the concentration of the flavin derivative is greatly different from that of the stilbene compound.
Example 4 preparation of Mixed powder of stilbene Compound and FMN
An aqueous solution comprising a stilbene compound (resveratrol, piceid or piceatannol) and FMN is prepared. At this time, referring to the results of example 1 (table 2), FMN was added in an amount required for complete dissolution of each stilbene compound in water. That is, FMN was added in an amount of 4 times the number of moles of resveratrol, 1.5 times the number of moles of piceid, and 1 time the number of moles of piceatannol.
Specifically, 1mmol (228 mg) of resveratrol was completely dissolved in an aqueous solution obtained by dissolving 4mmol (1913 mg) of FMN in 200mL of water. In addition, 2mmol (780 mg) of piceid was completely dissolved in an aqueous solution prepared by dissolving 3mmol (1436 mg) of FMN in 150mL of water. In addition, 1mmol (244 mg) of piceatannol was completely dissolved in an aqueous solution prepared by dissolving 1mmol (479 mg) of FMN in 100mL of water. The aqueous solution thus obtained was dried under reduced pressure to obtain a mixed powder containing resveratrol and FMN at a molar ratio of 1:4, a mixed powder containing piceid and FMN at a molar ratio of 2:3, and a mixed powder containing piceatannol and FMN at a molar ratio of 1:1, respectively. The mass of each mixed powder containing 1 mol of FMN was 535g, 738g, and 723g, respectively.
Example 5 (Spectrum of Mixed aqueous solution of stilbene Compound and FMN)
When the mixed powder of the stilbene compound and FMN obtained in example 4 was dissolved in water, all the powders showed red-orange color. Since the aqueous FMN solution of the same concentration containing no stilbene compound showed yellow color, it was found that the color tone was changed by containing the stilbene compound. In order to quantitatively grasp this phenomenon, the absorption spectrum of each aqueous solution was measured.
The mixed powder of piceatannol and FMN obtained in example 4 was dissolved in pure water at a concentration of 7.23mg/mL to prepare an aqueous solution containing piceatannol and FMN each at 10 mM. The visible light absorption spectrum of the obtained aqueous solution was measured with a glass cuvette having an optical path length of 0.1mm, and the spectrum of the aqueous solution of the mixture of piceatannol and FMN was obtained (dotted line in fig. 4). The spectrum of an aqueous solution containing only 10mM FMN is also shown in FIG. 4 by a solid line. The absorption coefficients ε of the absorption maxima of the mixed aqueous solution were 27,800 (331 nm), 6,490 (377 nm), 8,330 (449 nm) and 2,020 (510 nm), respectively. It is presumed that the appearance of weak absorption near 510nm causes a change in hue from yellow to reddish orange. The absorption band decreases if diluted with water. The mixed aqueous solution was diluted 100 times with pure water, and the FMN concentration was 0.01mM, and the resulting spectrum (dotted line in FIG. 5) was measured with a cuvette having an optical path length of 10mM, and the sum of the spectrum of piceatannol alone and the spectrum of FMN alone was almost the same.
The mixed powder of spruce neoside and FMN obtained in example 4 was dissolved in pure water at a concentration of 7.38mg/mL to prepare an aqueous solution containing 6.7mM of spruce neoside and 10mM of FMN. The absorption coefficients ε of the absorption maxima were 21,100 (328 nm), 6,900 (380 nm), 8,730 (449 nm) and 1,700 (510 nm), respectively, as a result of the spectroscopic measurement in the same manner as described above. In addition, the mixed powder of resveratrol and FMN obtained in example 4 was dissolved in pure water at a concentration of 5.35mg/mL to prepare an aqueous solution containing resveratrol 2.5mM and FMN 10 mM. The absorption coefficients ε of the absorption maxima were 10,100 (336 nm), 8,070 (376 nm), 9,920 (448 nm) and 730 (510 nm), respectively, as a result of spectral measurement.
It is known that the absorption maxima in the absorption spectrum of stilbene compounds are shifted in a dark color by the addition of FMN. In addition, since absorption at 510nm is observed in an aqueous solution containing a stilbene compound and FMN, it is considered that a complex of the two compounds is formed in the aqueous solution. Since the complex produced in an aqueous solution of high concentration is reduced by dilution, it is presumed that the stilbene compound and FMN associate in an aqueous solution by a relatively weak pi-pi interaction generated therebetween.
Example 6 stability of a mixture of resveratrol and FMN
The mixed powder of resveratrol and FMN obtained in example 4 was placed in a transparent glass bottle, and after being stored at room temperature (20 ℃) under a fluorescent lamp for 30 days, the absorbance was measured, and as a result, the amount of decrease in resveratrol contained in the mixed powder was only 3.6 ± 1.5%. This mixed powder was dissolved in pure water at a concentration of 5.35mg/mL to prepare an aqueous solution containing 2.5mM of resveratrol and 10mM of FMN. The obtained aqueous solution was stored in a transparent glass bottle at room temperature (20 ℃) under a fluorescent lamp for 5 days, and when the amount of resveratrol was measured, a decrease of 25.6% was observed. On the other hand, if a brown glass bottle was placed in place of the transparent glass bottle and stored under the same conditions, the amount of resveratrol decreased by only 3.4% even after 17 days. In addition, the above aqueous solution was diluted to 100 times with pure water to prepare an aqueous solution containing resveratrol 0.025mM and FMN 0.1 mM. The diluted aqueous solution was allowed to stand at 20 ℃ for 1 day without being shielded from light, whereby the absorbance (317 nm) of resveratrol was significantly reduced and the amount of residual resveratrol was half or less. If light is shielded, the decrease in the absorbance of resveratrol is suppressed.
Example 7 (Effect of light and pH on Mixed aqueous solutions of resveratrol and FMN)
100mM sodium citrate buffer as a buffer of pH4, 100mM sodium phosphate buffer as buffers of pH6 and pH7, and 40mM sodium phosphate buffer as a buffer of pH8 were prepared, respectively. To 0.6mL of a saturated (0.19 mM) aqueous resveratrol solution, the above buffers each having pH4, 6, 7 and 8 were added to make the total amount to be 3.00mL, and mixed to obtain 4 kinds of aqueous solutions. In addition, to 0.03mL of an aqueous solution containing 2.5mM of resveratrol and 10mM of FMN, the above-mentioned respective buffers were also added to make the total amount to be 3.00mL, and mixed to obtain 4 kinds of aqueous solutions. The aqueous solution thus obtained was placed in a cuvette for measurement made of quartz glass. The resulting aqueous solutions were irradiated with light at 20 ℃ or allowed to stand for 1 hour under dark conditions, and then the absorbance at 317nm was measured. The light source in this case was a fluorescent lamp, and light was emitted through the container at a position of about 2m directly below 2 fluorescent lamps of 2250 lumens. The reduction rate (%) of the resveratrol amount was calculated from the absorbance thus obtained. The results are summarized in Table 4.
[ Table 4]
As shown in table 4, it was found that resveratrol in a diluted aqueous solution prepared by dissolving a mixed powder of resveratrol and FMN in water is unstable to light. This is presumably because FMN is included. In addition, it is also known that if the pH is increased, the pH gradually becomes unstable. Therefore, it is found that when an aqueous solution containing resveratrol and FMN is stored, it is desirable to keep the aqueous solution acidic and protected from light.
Example 8 (pH of aqueous solution comprising resveratrol, FMN and acetic acid)
To an aqueous solution containing 5mM resveratrol and 20mM FMN, acetic acid was added so that the ratio of the number of moles of acetic acid to the number of moles of FMN (acetic acid/FMN) became 0, 0.25, 0.5, 1, 2, 5,10, 25,50 and 100, to prepare an aqueous solution, and their pH was measured. In addition, aqueous solutions from each of which resveratrol was removed were prepared, and their pH was also measured. The results are shown in fig. 6. The pH of an aqueous solution containing resveratrol and FMN can be adjusted to a desired value by adjusting the amount of acetic acid to be incorporated. The presence or absence of resveratrol does not have a large influence on the pH of the aqueous solution, but it is considered that this is due to the large pKa value of the stilbene compound (a). In this way, by adding an appropriate amount of acid, the pH is lowered to ensure stability of the stilbene compound (a) and a mixture having a moderate sour taste can be obtained.
Reference example 2 (pH of aqueous solution containing FMN and acid)
An aqueous solution was prepared by adding an acid (acetic acid, citric acid, lactic acid, ascorbic acid) to a 20mM FMN aqueous solution so that the ratio of the number of moles of the acid to the number of moles of FMN (acid/FMN) was 0, 0.25, 0.5, 1, 2, 5,10, 25,50, and 100, and the pH thereof was measured. The results are summarized in fig. 7 and 8. The pH of the aqueous solution can be adjusted to a desired value between 1.5 and 6 by adjusting the kind and the mixing ratio of the acid.
Example 9 (dissolution speed of the mixed powder in Water)
114mg (0.5 mmol) of resveratrol powder and 957mg (2 mmol) of FMN powder were mixed together and mixed in an agate mortar to prepare mixed powder 1. On the other hand, mixed powder 2 obtained by drying the mixed aqueous solution of resveratrol and FMN in example 4 was prepared. About 0.2mg of any of mixed powder 1 and mixed powder 2 was added to 3mL of 0.1M citric acid buffer (pH 4.0), and immediately stirred slowly, the absorbance at 317, 374 and 445nm was measured every 3 minutes, and stirring and measurement were repeated until after 33 minutes. 317nm is the absorption peak from resveratrol, 374nm and 445nm are the absorption peaks from FMN. The amount of dissolved resveratrol was calculated from the absorbance at 317nm and is shown in FIG. 9. As shown in fig. 9, a method of preparing a mixed aqueous solution in advance and then drying the mixed aqueous solution, instead of merely mixing the powder, can obtain a powder having a higher dissolution rate. Further, the taste of the mixture powder of resveratrol, FMN and citric acid has a moderate sour taste, and the mixture powder of resveratrol and FMN is substantially tasteless.
Example 10 extraction of resveratrol
Commercially available crude extract powder obtained by extracting grapes or the like with an organic solvent and drying is used. The crude extract powder contained resveratrol in an amount of about 10% by mass. To 100mL of the crude extract powder, 10mL of an aqueous solution or pure water described below was added, and the mixture was extracted by ultrasonic irradiation for 30 minutes. After standing, the insoluble fraction was centrifuged to obtain a supernatant as an extract. The solubility of resveratrol was calculated from the absorbance at 317nm obtained by diluting the obtained extract with a 0.1M citric acid buffer solution (pH 4.0). The recovery rate of resveratrol thus obtained was 9.2% when pure water was used as the extract, 84% when 25mM FMN aqueous solution was used, and 96% when 50 vol% ethanol aqueous solution was used. From this result, it was found that by using an aqueous FMN solution, the extract can be efficiently extracted as an aqueous solution without using an organic solvent.
Example 11 (test for uric acid production)
Xanthine Oxidase (XO) enzyme solution (EC 1.1.3.22, gradeIV) was purchased from Sigma-Aldrich. A10 mM sample solution was prepared by dissolving the stilbene compound in DMSO. A mixture (2.88 mL) was prepared by adding 0 to 200. Mu.M of a DMSO solution of a xanthine and stilbene compound (0 to 0.03 mL) to a 40mM sodium carbonate buffer solution (pH 10) containing 0.1mM EDTA. To the mixture solution at 25 ℃ was added 0.12mL of XO enzyme solution (0.04 units), and the reaction was started, and the absorbance at 293nm (maximum absorption value in the ultraviolet region of uric acid) was measured for 60 seconds. Control experiments were performed by replacing the sample solution with DMSO. The reaction rate was determined from the linear increase in absorbance. The inhibition constant Ki (. Mu.M) of uric acid production reaction by the stilbene compound and the 50% inhibition concentration IC at a xanthine concentration of 200. Mu.M were determined 50 (. Mu.M), the results are shown in Table 5. In addition, in order to confirm the absorption by the stilbene compound at 293nm, the uric acid can be quantified only when the concentration of the stilbene compound is less than 0.1 mM.
Each measurement was performed 3 times or more in each experiment. The analysis was performed with Sigma plot 2001 (SPSS Inc., chicago, IL.). Inhibition patterns and reaction rate theory were analyzed using Enzyme Kinetics modules 1.1 (SPSS Inc.) attached to Sigma plot 2001. These methods are also used in the following examples 12 to 14.
[ Table 5]
| Stilbene compounds | Ki(μM) | IC 50 (μM) |
| Resveratrol | 7.7±0.7 | 34±4 |
| Resveratrol-3-glucoside | － | >50 |
| Resveratrol-4' -glucoside | 7.0±0.8 | 25±4 |
| Resveratrol-3-oligosaccharide glycoside | － | >50 |
| Pterostilbene | － | >50 |
| Piceatannol | 6.7±1.6 | 15±5 |
| Rheum emodin | 3.5±0.2 | 7.9±0.5 |
| Yidan pillEmodin from leaves | 96±2 | 161±11 |
As shown in Table 5, resveratrol-4' -glucoside, piceatannol, rhapontigenin and isorhapontigenin only calculated the inhibition constant Ki and not the other inhibition constants, so the assay inhibited uric acid production by competitive inhibition. This competitive inhibition is expected from the slow oxidation reaction of xanthine and the fast reduction reaction of oxygen. Slave IC 50 Of these, rhapontigenin has particularly strong inhibitory activity against uric acid production.
Example 12 (test for superoxide production)
A sample solution (0.06 mL) obtained by dissolving 0 to 200. Mu.M of xanthine, 0.03mL of 0.5% bovine serum albumin, 0.03mL of 2.5mM nitroblue tetrazolium, and 10mM of stilbene compound in DMSO was added to a 40mM sodium carbonate buffer solution (pH 10) containing 0.1mM EDTA to prepare a mixed solution (2.88 mL). To the mixture at 25 ℃ was added 0.12mL of XO enzyme solution (0.04 units) to start the reaction, and the absorbance at 560nm was measured for 60 seconds. Control experiments were performed by replacing the sample solution with DMSO. The reaction rate was determined from the linear increase in absorbance. The above reaction is for the detection of unstable superoxide (O) 2 － At pH 10. Superoxide reduces and converts nitro blue tetrazolium into blue formazan (with an absorption maximum of 560 nm), so that quantitative detection is carried out on the blue formazan. When the concentration of xanthine is varied from 0 to 200. Mu.M, the production of superoxide is inhibited by stilbene compounds. The results are summarized in Table 6.
[ Table 6]
| Stilbene compounds | Ki(μM) | K'i(μM) | IC 50 (μM) |
| Resveratrol | 7.1±1.0 | － | 21±3 |
| Resveratrol-3-glucoside | 19±2 | － | 49±1 |
| Resveratrol-4' -glucoside | 5.0±0.1 | － | 11±2 |
| Resveratrol-3-oligosaccharide glycoside | 121±19 | － | 323±20 |
| Pterostilbene | 43±5 | － | 124±16 |
| Piceatannol | 2.2±0.1 | 21.1±1.0 | 4.5±0.4 |
| Rheum emodin | 2.4±0.2 | － | 5.0±0.2 |
| Isorhapontigenin | 36±3 | － | 99±8 |
As shown in table 6, the stilbene compounds other than piceatannol only calculated the inhibition constant Ki, and not the other inhibition constants, so the analysis inhibited superoxide generation by competitive inhibition. On the other hand, analysis further calculates that piceatannol with inhibition constant K' i inhibits superoxide generation by mixed (mixed) inhibition. Slave IC 50 Of these, piceatannol has a particularly strong superoxide generation inhibitory activity. These stilbene compounds strongly inhibit superoxide generation through uric acid generation, thus indicating that stilbene compounds bind to FAD sites within Xanthine Oxidase (XO).
Example 13 (DPPH scavenging Activity)
The method for scavenging DPPH (2,2-diphenyl-1-picrylhydrazine) as a stable free radical is the method described in Blois, M.S. (1958), antibiotic degrees by the use of stable free radical medicine, nature,181, 1199-1200. In addition, DPPH activity shows the nature of electron-donating or hydrogen atoms (Zhang, r., kang, k.a., pia, m.j., lee, k.h., jang, h.s., park, m.j., kim, b.j., kim, j.s., kim, y.s., ryu, s.y., hyun, j.w. (2007)). After 1.0mL of 100mM acetic acid buffer (pH 5.5), 1.87mL of ethanol and 0.1mL of 3mM ethanol solution of DPPH were added to the test tube, 0.03mL of a sample solution of 10mM stilbene compound in DMSO was added, and the reaction was carried out at 25 ℃ for 20 minutes. Meanwhile, the absorbance at 517nm (DPPH,. Epsilon. = 8.32X 10) was measured 3 ). Control experiments were performed with the sample solution replaced with DMSO. Measurement for 20 pointsThe decrease in absorbance of the bell counts the number of molecules of DPPH scavenging 1 molecule of the stilbene compound as the scavenging activity. The initial rate of the clearing reaction was determined from the decrease in absorbance after sample addition (Masuoka, n., isobe, t., kubo, i. (2006). Anisoxidates from Rabdosia japonica. The results are summarized in Table 7.
[ Table 7]
As shown in table 7, resveratrol and its glycosides, and pterostilbene showed as weak scavenging activity as alkenylphenols. On the other hand, piceatannol, danesenbergine and isodanesenbergine showed the same degree of strong activity. However, if the initial rate of the scavenging activity of these compounds is determined, the initial rate of piceatannol is faster than the other 2 compounds. This indicates that piceatannol is capable of reducing the XO molecule (see Hille, R., & Massey, V. (1981) students on the oxidative half-reaction of xanthine oxidase. J. Biol. Chem.256,9090-9095 and Masuoka, N., kubo, I (2018) Characterisation of the xanthine oxidase inhibitor activity of alk (en) yl phenols and related compounds. Phytochemistry (2018) 155, 100-106). Wherein the food additive with antioxidant effect has DPPH scavenging activity of dodecyl gallate of 7.32 + -0.04.
Example 14 (superoxide scavenging Activity)
Superoxide (O) 2 － Produced non-enzymatically in The PMS-NADH system (Nishikimi, M., rao, N.A., yagi, K. (1972) The occucurence of superoxide reaction in The reaction of reduced phenazine process and molecular oxygen. Biochem. Biophys. Commun.46, 849-854). A mixture (2.97 mL) of 2.82mL of 40mM sodium carbonate buffer (pH 10) containing 0.1mM EDTA, 0.03mL of 0.5% bovine serum albumin aqueous solution, 0.03mL of 2.5mM nitroblue tetrazolium aqueous solution, 0.06mL of a sample solution obtained by dissolving 10mM stilbene compound in DMSO, and 0.03mL of 7.8mM NADH aqueous solution was prepared. To the mixture at 25 ℃ was added a 115. Mu.M aqueous solution of PMS (phenazine methosulfate)0.03mL, the reaction was started, and the absorbance at 560nm was measured for 60 seconds. Superoxide is scavenged (eliminated) in reaction with stilbene compounds. Unreacted superoxide radical reacts with nitro blue tetrazole to become blue (formazan), and thus the amount of the blue is quantified. Control experiments were performed with the sample solution replaced with DMSO. The reaction rate was determined from the linear increase in absorbance, and the scavenging activity was determined by the following equation. The scavenging activity of the stilbene compounds is shown in FIG. 10.
Scavenging activity (%) = [1- (sample speed)/(control speed) ] × 100
In the radical scavenging reaction, superoxide (O) 2 － ·) is reacted with a stilbene compound in a molar ratio of 1:1. Among these stilbene compounds, piceatannol is abnormally high in activity. Even with caffeic acid (IC) 50 =51 μ M) or gallic acid (IC) 50 =29 μ M) IC of piceatannol 50 The value (9.0. + -. 2.0. Mu.M) was also significantly small, indicating that piceatannol is a strong scavenger. This scavenging activity may be related to the stronger stabilization of piceatannol free radical by the long conjugated enediol structure of piceatannol.
Claims (17)
1. An aqueous solution characterized by:
0.3 to 200mM of a stilbene compound (A) represented by the following formula (1) or a glycoside or multimer thereof and 0.3 to 200mM of a flavin derivative (B) represented by the following formula (2) or a pharmaceutically acceptable salt thereof are dissolved,
in the formula (1), R 1 、R 2 And R 3 Each independently is a hydrogen atom or a methyl group, X is a hydrogen atom, a hydroxyl group or a methoxy group,
in the formula (2), when n is 0,1 or 2,n is 0 or 1, Y is a hydrogen atom, and when n is 2, Y is a group represented by the following formula (3),
2. the aqueous solution of claim 1, wherein:
the stilbene compound (A) is at least 1 selected from resveratrol, piceatannol, rhapontigenin, isorhapontigenin, pterostilbene and pinostilbene and their glucoside and polymer.
3. The aqueous solution of claim 1 or 2, wherein:
the molar ratio (B/A) of the flavin derivative (B) to the stilbene compound (A) is 0.5 to 50.
4. The aqueous solution of any one of claims 1 to 3, wherein:
the pH value is 1.5-6.
5. The aqueous solution of any one of claims 1 to 4, wherein:
further comprises a pH adjuster (C) selected from carboxylic acids having 2 to 6 carbon atoms, ascorbic acid and glycosides thereof.
6. The aqueous solution of any one of claims 1 to 5, wherein:
the concentration of ethanol in the solvent is less than 20% by volume.
7. An inhibitor of superoxide production catalyzed by xanthine oxidase, comprising:
comprising the aqueous solution of any one of claims 1 to 6.
8. A beverage or cosmetic product characterized by:
comprising the aqueous solution of claims 1 to 6.
9. A water solubility enhancer characterized by:
for increasing the solubility of the stilbene compound (A) in water, the water solubility enhancer comprising a flavin derivative (B),
the stilbene compound (A) is a compound represented by the following formula (1) or a glycoside or polymer thereof,
the flavin derivative (B) is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof,
in the formula (1), R 1 、R 2 And R 3 Each independently is a hydrogen atom or a methyl group, X is a hydrogen atom, a hydroxyl group or a methoxy group,
in the formula (2), when n is 0,1 or 2,n is 0 or 1, Y is a hydrogen atom, and when n is 2, Y is a group represented by the following formula (3),
10. a composition in a form selected from the group consisting of a powder, a granule, a tablet, and a paste, wherein:
comprises a stilbene compound (A) and a flavin derivative (B), wherein the stilbene compound (A) is a compound represented by the following formula (1) or a glycoside or polymer thereof, the flavin derivative (B) is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof, the molar ratio (B/A) of the flavin derivative (B) to the stilbene compound (A) is from 0.5 to 50,
in the formula (1), R 1 、R 2 And R 3 Each independently is a hydrogen atom or a methyl group, X is a hydrogen atom, a hydroxyl group or a methoxy group,
in the formula (2), when n is 0,1 or 2,n is 0 or 1, Y is a hydrogen atom, and when n is 2, Y is a group represented by the following formula (3),
11. the composition of claim 10, wherein:
further comprises a pH adjuster (C) selected from carboxylic acids having 2 to 6 carbon atoms, ascorbic acid and glycosides thereof.
12. An inhibitor of superoxide production catalyzed by xanthine oxidase, comprising:
comprising the composition of claim 10 or 11.
13. A method for producing a composition according to any one of claims 10 to 12, characterized in that:
after preparing an aqueous solution in which the stilbene compound (A) and the flavin derivative (B) are dissolved, water is removed.
14. A method for extracting a stilbene compound (A), which is characterized by comprising the following steps:
contacting a plant material containing a stilbene compound (A) or a crude extract obtained by extracting the plant material with an organic solvent with an aqueous solution in which a flavin derivative (B) is dissolved, and extracting the stilbene compound (A) from the plant material or the crude extract into the aqueous solution, the stilbene compound (A) being a compound represented by the following formula (1) or a glycoside or multimer thereof, the flavin derivative (B) being a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof,
in the formula (1), R 1 、R 2 And R 3 Each independently is a hydrogen atom or a methyl group, X is a hydrogen atom, a hydroxyl group or a methoxy group,
in the formula (2), when n is 0,1 or 2,n is 0 or 1, Y is a hydrogen atom, and when n is 2, Y is a group represented by the following formula (3),
15. an inhibitor of superoxide generation catalyzed by xanthine oxidase, comprising a stilbene compound (A) as an active ingredient, wherein the stilbene compound (A) is a compound represented by the following formula (1) or a glycoside or polymer thereof,
in the formula (1), R 1 、R 2 And R 3 Each independently is a hydrogen atom or a methyl group, and X is a hydrogen atom, a hydroxyl group or a methoxy group.
16. The inhibitor of claim 15, wherein:
in the formula (1), R 1 、R 2 、R 3 And X is a hydrogen atom.
17. The inhibitor of claim 15, wherein:
in the formula (1), R 1 And R 2 Is a hydrogen atom, R 3 Is a hydrogen atom or a methyl group, and X is a hydroxyl group.
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| PCT/JP2021/015889 WO2021261062A1 (en) | 2020-06-22 | 2021-04-19 | Aqueous solution containing stilbene compound, and superoxide generation inhibitor comprising stilbene compound |
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| CN101669938A (en) * | 2008-09-11 | 2010-03-17 | 上海体育科学研究所 | Nutrient composition for eliminating exercise-induced fatigue |
| CN102652760A (en) * | 2012-04-18 | 2012-09-05 | 陶宁 | Tumor preventing compound preparation for improving immunity, replenishing blood and resisting oxidation |
| US9561175B1 (en) * | 2014-01-22 | 2017-02-07 | Pete D. Menegan | Deodorant health systems |
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| WO2019202508A1 (en) * | 2018-04-16 | 2019-10-24 | S&R Farmaceutici S.P.A. | Mixture of resveratrol supported on metal hydroxide and non-supported pure resveratrol for treating female fertility |
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- 2021-04-19 JP JP2021558778A patent/JP7082845B2/en active Active
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| CN101669938A (en) * | 2008-09-11 | 2010-03-17 | 上海体育科学研究所 | Nutrient composition for eliminating exercise-induced fatigue |
| CN102652760A (en) * | 2012-04-18 | 2012-09-05 | 陶宁 | Tumor preventing compound preparation for improving immunity, replenishing blood and resisting oxidation |
| US9561175B1 (en) * | 2014-01-22 | 2017-02-07 | Pete D. Menegan | Deodorant health systems |
| CN107212423A (en) * | 2017-05-16 | 2017-09-29 | 柳州放心源农业有限公司 | A kind of hypertension nutraceutical |
| WO2019202508A1 (en) * | 2018-04-16 | 2019-10-24 | S&R Farmaceutici S.P.A. | Mixture of resveratrol supported on metal hydroxide and non-supported pure resveratrol for treating female fertility |
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| JPWO2021261062A1 (en) | 2021-12-30 |
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| CN115768739B (en) | 2024-03-01 |
| JP2022117993A (en) | 2022-08-12 |
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