JP2005336194A - Method for stabilizing reduced coenzyme q10 - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for stabilizing reduced coenzyme Q10 which is useful in foods with nutrient function claims, foods for specific health uses, and the like, to provide a method for preserving the same, and so on, and to provide a process for efficiently obtaining the reduced coenzyme Q10 with good qualities by an industrially adequate method. <P>SOLUTION: This method for stabilizing the reduced coenzyme Q10, comprising allowing the reduced coenzyme Q10 and an ascorbic acid compound to coexist, is characterized by performing the coexistence in the presence of a monohydric or dihydric alcohol and/or a water-soluble solvent except the alcohol and using the monohydric or dihydric alcohol and/or the water-soluble solvent except the alcohol in an amount of ≥5 wt.% in the total mixture. A reduced coenzyme Q10-containing composition is characterized by comprising a reduced coenzyme Q10, an ascorbic acid compound, and a monohydric or dihydric alcohol and/or a water-soluble solvent except the alcohol, and using the monohydric or dihydric alcohol and/or the water-soluble solvent except the alcohol in an amount of ≥5 wt.% in the total mixture. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention is a method of stabilizing reduced coenzyme Q _10, storage method using the same, and the isolation (crystallization) method and compositions. Further relates to a method for producing reduced coenzyme Q _10. Reduced coenzyme Q _10, already show a high oral absorbability compared with oxidized coenzyme Q ₁₀ which is used as a food or the like, excellent food, food with nutrient function claims, food for specified health use, nutritional supplement, nutritional It is a compound useful as an animal drug, beverage, feed, cosmetics, pharmaceutical, therapeutic agent, prophylactic agent and the like.

Widely oxidized coenzyme Q ₁₀ is a benzoquinone derivative distributed in the living world, the vitamin-like function which is also known as vitamin Q, rejuvenating the body as a nutrient source for returning the weakened cell activity in healthy ingredients It is. On the other hand, reduced coenzyme Q ₁₀ is a two-electron reduction of oxidized coenzyme Q _10, whereas the oxidized coenzyme Q ₁₀ is an orange crystal, reduced coenzyme Q ₁₀ is a white crystalline . Reduced coenzyme Q ₁₀ and oxidized coenzyme Q _10, anti-mitochondrial, lysosomal, golgi, microsomes, peroxisomes, or the like localized cell membrane, ATP production activation as constituents of the electron transport system in vivo It is an indispensable substance for maintaining the functions of living organisms that are known to be involved in oxidation and membrane stabilization.

Reduced coenzyme Q ₁₀ is readily oxidized to oxidized coenzyme Q ₁₀ by molecular oxygen. In industrial scale production, storage and handling, it is extremely difficult to completely remove or block oxygen, and the time required for individual operations is considerably longer than in lab scale production. the oxygen remaining, the greater adverse effects such as reduced coenzyme Q ₁₀ is oxidized to oxidized coenzyme Q _10. Thus, although it is difficult to obtain crystals of high quality reduced coenzyme Q ₁₀ in an industrial scale, for example, even when producing reduced coenzyme Q ₁₀ of high quality, food, food with nutrient function claims, Specified health foods, nutrients, nutritional supplements, animal drugs, beverages, feeds, cosmetics, pharmaceuticals, therapeutic drugs, preventive drugs, etc., or when processed into their materials and compositions and / or stored after processing in that, the oxidation stability of the reduced coenzyme Q ₁₀ is a very important issue. Even during the above processing and storage, it is extremely difficult to completely remove or block oxygen, and the remaining or mixed oxygen has a great adverse effect especially on heating during processing and storage over a long period of time. Oxidation protection in the above manufacturing, storage, handling, processing and storage is extremely important. Oxidized coenzyme _{Q 10} as a byproduct by the oxidation of the reduced coenzyme _{Q 10,} reduced the yield of reduced coenzyme _{Q 10,} also oxidized coenzyme _{Q 10} from reduced coenzyme _{Q 10} because of the separation is difficult, as an impurity in reduced coenzyme Q ₁₀ as a product, or lower the purity, such as the crystal becomes as yellowish, or giving an uncomfortable feeling to the consumer or customer problem Is generated.

Reduced coenzyme Q ₁₀ is, for example, synthetic, fermentation, after obtaining coenzyme Q ₁₀ by a conventionally known method such as extraction from natural products, the reduced coenzyme Q ₁₀ divided in the effluent by chromatography It is known that it can be obtained by a method of concentrating (Patent Document 1). In this case, the oxidized coenzyme Q ₁₀ which is present as impurities in the reduced coenzyme Q _10, using sodium borohydride, a general reducing agent such as sodium dithionite (sodium hydrosulfite) after reduction, it may be followed by concentration by chromatography, also, reduced coenzyme Q _10, can also be obtained by method of reacting the above-mentioned reducing agent to an existing highly pure coenzyme Q _10, the public It is described in the publication. Moreover, the method of using zinc as a reducing agent is also known (nonpatent literature 1). However, the preparation of reduced coenzyme Q ₁₀ are not necessarily satisfactory. For example, a method using chromatography is complicated to use on an industrial scale, and the reducing agent is used on an industrial scale, or a food, a nutritional functional food, a food for specified health use, a nutritional supplement. agents, nutrients, animal drugs, drinks, feeds, cosmetics, pharmaceuticals, therapeutic agents, when producing reduced coenzyme Q ₁₀ used in prophylactics such as generation of gas (hydrogen, sulfur dioxide, etc.), odor, safety , there is a process, such as handling difficulty of the problem after use, to not always preferable, after obtaining a fraction of coenzyme Q ₁₀ by chromatography, obtaining reduced coenzyme Q ₁₀ using the above reducing agent The method of moving further away from the preferred industrial process. The complexity of the process and post-treatment causes deterioration of quality due to oxidation by molecular oxygen described later.

Moreover, reduced coenzyme Q ₁₀ obtained by the above methods as a so isolated from instability to molecular oxygen of reduced coenzyme Q _10, it is not always easy to isolate in highly pure state, for example, , low purity crystal containing impurities, including oxidized coenzyme Q _10, is often obtained as a semi-solid or oil. Thus, in the reduction reaction, any oxidized coenzyme Q _10, or even to obtain a most contained no reaction mixture of reduced coenzyme Q _10, to obtain the crystals of reduced coenzyme Q ₁₀ of high quality It is extremely difficult.

As described above, stabilizing the reduced coenzyme Q ₁₀ , that is, protecting it from oxidation, is a very important issue. However, since the reduced coenzyme Q ₁₀ is not commercially available until now, the reduced coenzyme Q ₁₀ is not available. studies on the method and the like for holding the enzyme Q ₁₀ stably has not been few. Only Patent Document 2 describing a composition in which a reducing agent coexists and a method for producing the same is recognized.
Patent Document 2 discloses various reducing agents such as vitamin Cs (that is, ascorbic acids such as ascorbic acid, ascorbic acid palmitic acid ester, ascorbic acid stearic acid ester) and vitamin E as more preferable reducing agents that can be used in foods and the like. It discloses a method of producing reduced coenzyme Q ₁₀ by reduction using the agent. Furthermore, a composition comprising reduced coenzyme Q ₁₀ , a reducing agent, and a surfactant or vegetable oil or a mixture thereof, and a composition for oral administration in which the above composition is formulated into a gelatin capsule or tablet further, as a method for obtaining the above composition, a method of preparing in situ using oxidized coenzyme Q ₁₀ and a reducing agent are proposed.

The above compositions and their methods of preparation are complex-cumbersome, it multiple roles in the composition (i.e., reaction field for the reduction of oxidized coenzyme Q ₁₀ to reduced coenzyme Q ₁₀ in the first a it will be the composition and, presumably because that reduced coenzyme Q ₁₀ expect is also a composition for stably held) in the second. In other words, it is enabling a very in special circumstances, the reduction of oxidized coenzyme Q ₁₀ to reduced coenzyme Q _10, reduced coenzyme Q ₁₀ obtained can be held stably. However, this method is a method of reducing such surfactants and vegetable oils with high boiling components and fat-soluble component, after the reduction reaction, the reduced coenzyme Q ₁₀ is very difficult to isolate, stabilization of the The use of the method as well as the composition is substantially limited to direct use for food and the like. The method, only in the reaction mixture may hold reduced coenzyme _{Q 10} in pure state, it is in situ preparation.

In the composition described in Patent Document 2, as a solvent, for example, 0.25 to 50% by weight of an organic solvent such as glycerol, 1,2-propanediol (propylene glycol) or other polyhydric alcohol or ethanol, preferably It is described that 1 to 25 wt%, more preferably 1.5 to 15-20 wt%, can be included if desired. However, the polyhydric alcohol and ethanol are not essential components, and in the examples of the specification, a composition not containing them is described in Example 2, and in Example 4, glycerin or propylene glycol is added as 1. In the composition containing 63% by weight, Examples 1 and 3, only compositions containing 4% by weight and 3.55% by weight of glycerin are described.

As a result of preliminary studies on the stabilization of reduced coenzyme Q _{10 by} the present inventors, vitamin Cs have a stabilizing effect, but vitamin E has no stabilizing effect, and vitamin Cs It has been found that the stabilizing effect when using together with trihydric or higher alcohol such as glycerin is very poor.
The aforementioned Patent Document 2, no detailed description of the quality and stabilizing effect, etc. of reduced coenzyme Q ₁₀ contained in the composition, vitamin C and a monohydric and / or dihydric alcohol combinations, especially 1 There is no disclosure that the combination with a monohydric alcohol exhibits an extremely excellent stabilizing effect. Furthermore, the present invention relates to a crystallization method, composition, handling, and storage (including long-term stable storage at a temperature at which it can usually be encountered) utilizing the stabilizing effect of the combination of vitamin C and mono- and / or dihydric alcohol. There is no description.

Thus, by reducing oxidized coenzyme Q ₁₀ to produce a reduced coenzyme Q _10, in the method of storing stably, the conventional methods were not always satisfactory. Under such circumstances, there has been a demand for the development of a highly versatile stabilization method that overcomes the above problems, a storage method using the same, an isolation (crystallization) method, and a composition. In addition to obtaining reduced coenzyme Q ₁₀ of high quality as the reaction mixture, such as may be suitably obtained as crystals, it was also desired to develop the easy production method used in a variety of applications.
JP-A-10-109933 WO01 / 52822A1 Journal of Leveled Compounds, Vol. 6, 1970, 66-75.

In view of the above, a simple and preferred method of stabilizing reduced coenzyme Q _10, storage method using the same, and to provide an isolated (crystallization) method and compositions. Furthermore, an object of the present invention is to provide a method for producing reduced coenzyme Q ₁₀ in versatility using the above stabilization method.

The present inventors believe that if an excellent stabilization method can be established, the stabilization method can be suitably used as a storage method, a method for isolation (crystallization, production), or a composition. It came. Therefore, as a result of earnest research,
(1) Reduced coenzyme Q ₁₀ in the presence of citric acid and / or ascorbic acid, are suitably protected from oxidation with molecular oxygen. In particular, it is suitably protected in the presence of monovalent or divalent alcohols and / or water-soluble solvents other than alcohols.
(2) reduced coenzyme Q ₁₀ by crystallizing in the presence of citric acid and / or ascorbic acid, is shifted to a crystalline state in a state in which by-product of the oxidized coenzyme Q ₁₀ is minimized, it can be obtained as high-quality reduced coenzyme Q ₁₀ crystal. In particular, crystallization can be suitably performed in the presence of a monovalent or divalent alcohol and / or a water-soluble solvent other than the alcohol.
(3) After the oxidized coenzyme Q ₁₀ was converted by reduction with ascorbic acid to a reduced coenzyme Q _10, the generated reduced coenzyme Q ₁₀ by subsequently crystallized in the presence of ascorbic acid it can by-product oxidized coenzyme Q ₁₀ is shifted to a crystalline state in a minimized state, obtained as a high-quality reduced coenzyme Q ₁₀ crystal. In particular, it can be suitably carried out in the presence of ascorbic acids, monovalent or divalent alcohols and / or water-soluble organic solvents other than alcohols.
As a result, the present invention has been completed.

That is, the present invention relates to a method for stabilizing reduced coenzyme Q _10, characterized in the reduced coenzyme Q ₁₀ to coexist with citric acid.
Further, the present invention provides a method of stabilizing reduced coenzyme Q ₁₀ by coexistence of reduced coenzyme Q ₁₀ and ascorbic acid, a mono- or dihydric alcohol and / or alcohol the coexisting Stabilization of reduced coenzyme Q ₁₀ characterized in that it is carried out in the presence of a water-soluble solvent other than 1 and is monovalent or divalent alcohol and / or water-soluble solvent other than alcohol is 5% by weight or more in the total mixture It also relates to the conversion method.
Furthermore, the present invention relates to reduced coenzyme Q _10, in the crystallization method of reduced coenzyme Q _10, characterized in that crystallized in a solvent containing citric acid and / or ascorbic acids.
Furthermore, the present invention reduces the oxidized coenzyme Q ₁₀ using ascorbic acid to convert it into reduced coenzyme Q ₁₀ , and then produces the reduced coenzyme Q ₁₀ in the presence of citric acid and / or ascorbic acid. It relates to a process for the production of reduced coenzyme Q ₁₀ crystal, characterized by subsequently crystallized under.

The invention also relates to a storage method of reduced coenzyme Q ₁₀ for storing the method reduced coenzyme Q ₁₀ stabilized by at 50 ° C. or less.
The present invention is further characterized by containing a reduced coenzyme Q ₁₀ and citric acids, also relates to a reduced coenzyme Q ₁₀ containing composition. The present invention also includes reduced coenzyme Q ₁₀ , ascorbic acids, monovalent or divalent alcohol and / or a water-soluble solvent other than alcohol, and monovalent or divalent alcohol and / or wherein the water-soluble solvent other than alcohols is 5 wt% or more in the total composition, also relates to a reduced coenzyme Q ₁₀ containing composition.
According to the present invention, using the easily reagent handling safety, also depending on the purpose and application, the solvent used can also be suitably selected, isolated and further derivatization of reduced coenzyme Q ₁₀ The method is widely used because it is suitable for use as a composition for foods, medicines, and the like.
Hereinafter, the present invention will be described in detail.

In the practice of the present invention, reduced coenzyme Q to suppress the oxidation of the oxidized coenzyme Q ₁₀ from ₁₀ to stabilize reduced coenzyme Q _10, or reduced coenzyme Q ₁₀ and for storage stability Furthermore, citric acids and / or ascorbic acids are used to obtain high-quality reduced coenzyme Q ₁₀ crystals.
Citric acids are not particularly limited, and citric acid, citrate esters such as isopropyl citrate, ethyl citrate, butyl citrate, and glyceride citrate, and salts such as sodium citrate and potassium citrate are included. Can do. In particular, citric acid, isopropyl citrate, and citrate glyceride are preferable. The method for stabilizing reduced coenzyme Q ₁₀ of the present invention, storage method, in the crystallization method and compositions may, depending on its purpose and application, free to choose the citric acid. These citric acids may be used alone or in combination. It can be used in combination with ascorbic acids described later.

The ascorbic acid is not particularly limited, and for example, not only ascorbic acid but also rhamno-ascorbic acid, arabo-ascorbic acid, gluco-ascorbic acid, fuco-ascorbic acid, glucohepto-ascorbic acid, xyllo-ascorbic acid, galacto- Examples include those similar to ascorbic acid such as ascorbic acid, gulo-ascorbic acid, allo-ascorbic acid, erythro-ascorbic acid, and 6-desoxyascorbic acid, and may be esters or salts thereof. These may be L-form, D-form, or racemate. Specifically, for example, L-ascorbic acid, L-ascorbic acid palmitic acid ester, L-ascorbic acid stearic acid ester, L-ascorbic acid 2-palmitic acid ester, L-ascorbic acid sodium, L-ascorbic acid calcium, D -Arabo-ascorbic acid etc. can be mentioned. In reduced coenzyme method for producing an enzyme Q ₁₀ crystal of the present invention, when it can be used both preferably the ascorbic acid, considering the generated reduced coenzyme Q ₁₀ the ease of separation of the like, the Of these ascorbic acid-related compounds, those having particularly high water solubility are preferably used. Most preferably, from the viewpoint of availability, price, etc., free forms such as L-ascorbic acid and D-arabo-ascorbic acid are used. is there. The method for stabilizing reduced coenzyme Q ₁₀ of the present invention, storage method, in the crystallization method and compositions may, depending on its purpose and application, free to choose the ascorbic acids. These ascorbic acids may be used alone or in combination. It can be used in combination with the aforementioned citric acids.

The method for stabilizing reduced coenzyme Q ₁₀ of the present invention, storage method, the citric acid in any of these crystallization methods and compositions and / or ascorbic acid can be used. In the reduced coenzyme method for producing an enzyme Q ₁₀ crystal of the present invention, the above ascorbic acids particularly preferably used. If necessary, citric acids may be used in combination.
Reduced coenzyme Q ₁₀ in the form of contacting mode to coexist with citric acid and / or ascorbic acids, i.e. reduced coenzyme Q ₁₀ and citric acid and / or ascorbic acids is not particularly limited, for example, reduced coenzyme when the enzyme Q ₁₀ and citric acid and / or ascorbic acid is present as both a solid phase, if at least one of citric acid in a liquid phase containing reduced coenzyme Q ₁₀ and / or ascorbic acid is present as a solid phase, If reduced coenzyme Q ₁₀ in a liquid phase containing at least one of citric acid and / or ascorbic acid is present as a solid phase, reduced coenzyme Q ₁₀ and citric acid and / or ascorbic acid are both in the liquid phase It may be present or present in the liquid phase. The liquid phase may be uniform or non-uniform (consisting of a plurality of different liquid phases), but is preferably uniform. Needless to say, a high contact efficiency between reduced coenzyme Q ₁₀ and citric acid and / or ascorbic acid system is suitable for oxidation protection, in particular, reduced coenzyme Q ₁₀ and citric acid and / or ascorbic acids It is preferable that both are in the liquid phase or exist in the liquid phase, and the liquid phase is preferably uniform. Needless to say, the liquid phase containing reduced coenzyme Q _10, may be a solution of reduced coenzyme Q _10, or may be a melt of reduced coenzyme Q _10.

Solvents that can be used in the present invention are not particularly limited, and are hydrocarbons, fatty acid esters, ethers, alcohols, fatty acids, ketones, nitrogen compounds (including nitriles and amides), sulfur compounds. And water. These solvents can also be used as a mixture of any two or more.
Although it does not restrict | limit especially as hydrocarbons, For example, an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon etc. can be mentioned. In particular, an aliphatic hydrocarbon and an aromatic hydrocarbon are preferable, and an aliphatic hydrocarbon is particularly preferable.

The aliphatic hydrocarbon is not particularly limited regardless of whether it is cyclic or non-cyclic, or saturated or unsaturated, but in general, a saturated hydrocarbon is preferably used. Usually, those having 3 to 20 carbon atoms, particularly 5 to 12 carbon atoms, especially 5 to 8 carbon atoms are preferably used. Specific examples include propane, butane, isobutane, pentane, 2-methylbutane, hexane, 2-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, heptane, heptane isomers (for example, 2- Methylhexane, 3-methylhexane, 2,3-dimethylpentane, 2,4-dimethylpentane), octane, 2,2,3-trimethylpentane, isooctane, nonane, 2,2,5-trimethylhexane, decane, dodecane 2-pentene, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, p-menthane, cyclohexene, etc. it can. Pentane, 2-methylbutane, hexane, 2-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, heptane, heptane isomers (eg, 2-methylhexane, 3-methylhexane, 2,3-dimethyl) Pentane, 2,4-dimethylpentane), octane, 2,2,3-trimethylpentane, isooctane, nonane, 2,2,5-trimethylhexane, decane, dodecane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, Ethylcyclohexane, p-menthane and the like are preferable, and in particular, pentane, 2-methylbutane, hexane, 2-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, heptane, heptane isomers (for example, 2-methyl Hexane, 3-methylhexane, 2,3- Methyl pentane, 2,4-dimethyl pentane), octane, 2,2,3-trimethylpentane, isooctane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane and the like are preferable. In general, not only heptanes and heptanes but also heterogeneous heptanes such as methylcyclohexane having 7 carbon atoms and a mixture thereof are preferably used. Usually, pentane having 5 carbon atoms (for example, pentane), hexanes having 6 carbons (for example, hexane, cyclohexane, etc.), heptanes having 7 carbon atoms (for example, heptane, methylcyclohexane, etc.) are preferably used. Are most preferably heptanes (eg, heptane, methylcyclohexane, etc.), with heptane being particularly preferred.

Although it does not restrict | limit especially as an aromatic hydrocarbon, Usually, a C6-C20, especially C6-C12, especially C7-C10 thing is used suitably. Specific examples include, for example, benzene, toluene, xylene, o-xylene, m-xylene, p-xylene, ethylbenzene, cumene, mesitylene, tetralin, butylbenzene, p-cymene, cyclohexylbenzene, diethylbenzene, pentylbenzene, dipentylbenzene. , Dodecylbenzene, styrene and the like. Toluene, xylene, o-xylene, m-xylene, p-xylene, ethylbenzene, cumene, mesitylene, tetralin, butylbenzene, p-cymene, cyclohexylbenzene, diethylbenzene, pentylbenzene and the like are preferable, and in particular, toluene, xylene, o- Xylene, m-xylene, p-xylene, cumene, tetralin and the like are preferable. Most preferred is cumene.

The halogenated hydrocarbon is not particularly limited regardless of whether it is cyclic or non-cyclic, or saturated or unsaturated. In general, a non-cyclic hydrocarbon is preferably used. Usually, chlorinated hydrocarbons and fluorinated hydrocarbons are preferable, and chlorinated hydrocarbons are particularly preferable. Those having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, especially 1 to 2 carbon atoms are preferably used. Specific examples include, for example, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,1,2 -Tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, hexachloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, trichloroethylene, tetrachloroethylene, 1,2-dichloropropane, 1,2,3- Examples thereof include trichloropropane, chlorobenzene, 1,1,1,2-tetrafluoroethane and the like. Dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, trichloroethylene, Chlorobenzene, 1,1,1,2-tetrafluoroethane and the like are preferable, and dichloromethane, chloroform, 1,2-dichloroethylene, trichloroethylene, chlorobenzene, 1,1,1,2-tetrafluoroethane and the like are particularly preferable.

Although it does not restrict | limit especially as fatty acid esters, For example, propionate ester, acetate ester, formate ester etc. can be mentioned. In particular, acetate ester and formate ester are preferable, and acetate ester is particularly preferable. Although not particularly limited, generally, as an ester group, an alkyl ester or aralkyl ester having 1 to 8 carbon atoms, preferably an alkyl ester having 1 to 6 carbon atoms, more preferably an alkyl ester having 1 to 4 carbon atoms is preferably used. . Specific examples of the propionic acid ester include, for example, methyl propionate, ethyl propionate, butyl propionate, isopentyl propionate, and the like. Specific examples of the acetate ester include, for example, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, pentyl acetate, isopentyl acetate, sec-hexyl acetate, cyclohexyl acetate, benzyl acetate and the like. Can be mentioned. Methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, pentyl acetate, isopentyl acetate, sec-hexyl acetate, cyclohexyl acetate, and the like are preferable. Most preferred are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate and the like, with ethyl acetate being particularly preferred. Specific examples of the formate ester include methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, isobutyl formate, sec-butyl formate, pentyl formate and the like. Methyl formate, ethyl formate, propyl formate, butyl formate, isobutyl formate, pentyl formate and the like are preferable. Most preferred is ethyl formate.

Ethers are not particularly limited, regardless of whether they are cyclic or non-cyclic, and whether saturated or unsaturated. In general, saturated ethers are preferably used. Usually, those having 3 to 20 carbon atoms, particularly 4 to 12 carbon atoms, especially 4 to 8 carbon atoms are preferably used. Specific examples include, for example, diethyl ether, methyl tert-butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dihexyl ether, ethyl vinyl ether, butyl vinyl ether, anisole, phenetole, butyl phenyl ether, methoxy toluene, dioxane, furan, 2 -Methylfuran, tetrahydrofuran, tetrahydropyran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dibutyl ether and the like can be mentioned. Diethyl ether, methyl tert-butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dihexyl ether, anisole, phenetol, butyl phenyl ether, methoxytoluene, dioxane, 2-methylfuran, tetrahydrofuran, tetrahydropyran, ethylene glycol dimethyl ether, ethylene glycol Diethyl ether, ethylene glycol dibutyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether and the like are preferable, and particularly diethyl ether, methyl tert-butyl ether, anisole, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether and the like. preferable. Most preferred are diethyl ether, methyl tert-butyl ether, anisole, dioxane, tetrahydrofuran and the like, with dioxane and tetrahydrofuran being particularly preferred.

The nitriles are not particularly limited regardless of whether they are cyclic or non-cyclic, and whether saturated or unsaturated. In general, saturated ones are preferably used. Usually, those having 2 to 20 carbon atoms, particularly 2 to 12 carbon atoms, especially 2 to 8 carbon atoms are preferably used.
Specific examples include, for example, acetonitrile, propionitrile, malononitrile, butyronitrile, isobutyronitrile, succinonitrile, valeronitrile, glutaronitrile, hexanenitrile, heptyl cyanide, octyl cyanide, undecane nitrile, dodecane nitrile, tridecane. Nitrile, pentadecane nitrile, stearonitrile, chloroacetonitrile, bromoacetonitrile, chloropropionitrile, bromopropionitrile, methoxyacetonitrile, methyl cyanoacetate, ethyl cyanoacetate, tolunitrile, benzonitrile, chlorobenzonitrile, bromobenzonitrile, cyano Benzoic acid, nitrobenzonitrile, anisonitrile, phthalonitrile, bromotolunitrile, methyl cyanobenzoate, methoxybenzene Zonitrile, acetylbenzonitrile, naphthonitrile, biphenylcarbonitrile, phenylpropionitrile, phenylbutyronitrile, methylphenylacetonitrile, diphenylacetonitrile, naphthylacetonitrile, nitrophenylacetonitrile, chlorobenzyl cyanide, cyclopropanecarbonitrile, cyclohexanecarbonitrile, Examples include cycloheptanecarbonitrile, phenylcyclohexanecarbonitrile, tolylcyclohexanecarbonitrile and the like. Of these, acetonitrile is preferable.

The alcohol is not particularly limited regardless of whether it is cyclic or non-cyclic, and whether saturated or unsaturated. In general, a saturated alcohol is preferably used. Usually, a monohydric alcohol having 1 to 20 carbon atoms, particularly 1 to 12 carbon atoms, especially 1 to 6 carbon atoms, and especially 1 to 5 carbon atoms is preferable, and a dihydric alcohol having 2 to 5 carbon atoms is preferable. Specific examples of these alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3 -Pentanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl- 2-pentanol, 2-ethyl-1-butanol, 1-heptanol, 2-heptanol, 3-heptanol, 1-octanol, 2-octanol, 2-ethyl-1-hexanol, 1-nonanol, 1-decanol, 1 -Undecanol, 1-Dodecano , Allyl alcohol, propargyl alcohol, benzyl alcohol, cyclohexanol, 1-methylcyclohexanol, 2-methylcyclohexanol, 3-methylcyclohexanol, 4-methylcyclohexanol, 2-methoxyethanol, 2-ethoxyethanol, 2- ( Methoxymethoxy) ethanol, 2-isoproxyethanol, 2-butoxyethanol, 2- (isopentyloxy) ethanol, 2- (hexyloxy) ethanol, furfuryl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, Triethylene glycol monomethyl ether, 1-methoxy-2-propanol, 1-ethoxy-2-propanol, dip Pyrene glycol monomethyl ether, dipropylene glycol monoethyl ether, tripropylene glycol monomethyl ether, 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3- Butanediol, 1,4-butanediol, 2,3-butanediol, 1,5-pentanediol, 2-butene-1,4-diol, 2-methyl-2,4-pentanediol, 2-ethyl-1 , 3-hexanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol and the like.

As monohydric alcohol, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3-pentanol, 2 -Methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl-2-pentanol, 2-ethyl-1-butanol, 1-heptanol, 2-heptanol, 3-heptanol, 1-octanol, 2-octanol, 2-ethyl-1-hexanol, 1-nonanol, 1-decanol, 1-undecanol, 1- Dodecanol, benzyl alcohol , Cyclohexanol, 1-methylcyclohexanol, 2-methylcyclohexanol, 3-methylcyclohexanol, 4-methylcyclohexanol, 2-methoxyethanol, 2-ethoxyethanol, 2- (methoxymethoxy) ethanol and the like are particularly preferable. Methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol , Isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl-2-pentanol, 2-ethyl-1 Butanol, cyclohexanol and the like are preferable, and methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3- Pentanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol and the like are preferable. Most preferred are methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-methyl-1-butanol, isopentyl alcohol, etc., among which methanol, ethanol, 1 -Propanol and 2-propanol are preferable, and ethanol is particularly preferable.

Examples of the dihydric alcohol include 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 2-butene-1,4-diol, 2-methyl-2,4-pentanediol, 2- Ethyl-1,3-hexanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol and the like are preferable, and 1,2-propanediol and polyethylene glycol are most preferable.
When citric acids are used, trihydric alcohols can also be preferably used. As the trivalent alcohol, glycerin is preferable.

Examples of fatty acids include formic acid, acetic acid, propionic acid, oleic acid, linoleic acid, and linolenic acid, but formic acid and acetic acid are preferred, and acetic acid is most preferred.
The ketones are not particularly limited, and those having 3 to 6 carbon atoms are preferably used. Specific examples include, for example, acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, and the like. Particularly, acetone and methyl ethyl ketone are preferable, and acetone is most preferable.
Examples of nitrogen compounds include nitromethane, triethylamine, pyridine, formamide, N-methylformamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
Examples of sulfur compounds include dimethyl sulfoxide and sulfolane.

Of the above-mentioned solvents, hydrocarbons, fatty acid esters, ethers or nitriles, preferably water-soluble ethers or nitriles (for example, tetrahydrofuran, dioxane, acetonitrile, etc.) are solvents having a high oxidation protection effect. since, subsidize a stabilizing effect of the reduced coenzyme Q ₁₀ by citric acid and / or ascorbic acid, it can contribute to byproduct inhibition of oxidized coenzyme Q _10.
Among the above solvents, monovalent or divalent alcohols and / or water-soluble solvents other than alcohols (preferably water-soluble organic solvents) exhibit a remarkable oxidation protection effect by ascorbic acids and / or citric acids. The effects of the invention are maximized. When using ascorbic acid, coexistence with monohydric or dihydric alcohol and / or water-soluble solvent other than alcohol (preferably water-soluble organic solvent) is effective, especially coexistence with monohydric alcohol. It is effective.

Specific examples of the monovalent or divalent alcohol include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2- Pentanol, 3-pentanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl-2-pentanol, 2-ethyl-1-butanol, 1-heptanol, 2-heptanol, 3-heptanol, 1-octanol, 2-octanol, 2-ethyl-1-hexanol, 1-nonanol, 3 , 5,5-trimethyl-1-hexanol, 1-de 1-undecanol, 1-dodecanol, allyl alcohol, propargyl alcohol, benzyl alcohol, cyclohexanol, 1-methylcyclohexanol, 2-methylcyclohexanol, 3-methylcyclohexanol, 4-methylcyclohexanol, benzyl alcohol, 2 -Methoxyethanol, 2-ethoxyethanol, 2- (methoxymethoxy) ethanol, 2-isoproxyethanol, 2-butoxyethanol, 2- (isopentyloxy) ethanol, 2- (hexyloxy) ethanol, furfuryl alcohol, diethylene glycol Monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, triethylene glycol monomethyl ether, 1- Toxi-2-propanol, 1-ethoxy-2-propanol, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, tripropylene glycol monomethyl ether, 1,2-ethanediol, 1,2-propanediol, 1,3 -Propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 1,5-pentanediol, 2-butene-1,4-diol, 2 -Methyl-2,4-pentanediol, 2-ethyl-1,3-hexanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol and the like. As monohydric alcohol, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3-pentanol, 2 -Methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl-2-pentanol, 2-ethyl-1-butanol, 1-heptanol, 2-heptanol, 3-heptanol, 1-octanol, 2-octanol, 2-ethyl-1-hexanol, 1-nonanol, 1-decanol, 1-undecanol, 1- Dodecanol, benzyl alcohol , Cyclohexanol, 1-methylcyclohexanol, 2-methylcyclohexanol, 3-methylcyclohexanol, 4-methylcyclohexanol, 2-methoxyethanol, 2-ethoxyethanol, 2- (methoxymethoxy) ethanol and the like are particularly preferable. Methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol , Isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl-2-pentanol, 2-ethyl-1 Butanol, cyclohexanol and the like are preferable, and methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3- Pentanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol and the like are preferable. Most preferred are methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-methyl-1-butanol, isopentyl alcohol, etc., among which methanol, ethanol, 1 -Propanol and 2-propanol are preferable, and ethanol is particularly preferable. Examples of the dihydric alcohol include 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 2-butene-1,4-diol, 2-methyl-2,4-pentanediol, 2- Ethyl-1,3-hexanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol and the like are preferable, and 1,2-propanediol and polyethylene glycol are most preferable.

Examples of the water-soluble solvent other than alcohol include ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitrogen compounds such as acetonitrile and dimethylformamide, and water. Preferred are tetrahydrofuran and acetone, and more preferred is acetone.

Of these, ethanol, 1,2-propanediol, polyethylene glycol (preferably polyethylene glycol having a molecular weight of 300 to 1000) and the like are particularly suitable for use in food, medicine, and the like. Needless to say, a mixture of these can also be suitably used.
The amount of the solvent described above is not particularly limited as long as it is an amount that can produce a desired effect or ability to be expected (that is, an effective amount). 5% by weight or more, preferably 10% by weight or more, more preferably 20% by weight or more, particularly preferably 30% by weight or more, especially 40% by weight or more, especially 50% by weight or more, and more than 50% by weight.

In particular, in the case of ascorbic acids, the amount of the solvent used is preferably 60% by weight or more, more preferably 70% by weight or more, and still more preferably 80% by weight or more.
Further, from the viewpoint of maximizing the effects of citric acids and / or ascorbic acids, a simple composition is preferable, and it is preferable that substantially no vegetable oil and / or surfactant is contained.

First, a method of stabilizing reduced coenzyme Q _10, described preservation method.
The amount of citric acid and / or ascorbic acid to be used in the present invention may be, for example, an amount that can produce an expected suitable effect or ability (that is, an effective amount). enzyme Q ₁₀ may be an effective amount which can protect from being oxidized to oxidized coenzyme Q _10. Therefore, more on the type of citric acid and / or ascorbic acid, is not particularly limited, usually, reduced coenzyme Q ₁₀ 0.1 parts by weight or more relative to 100 parts by weight, preferably 1 part by weight or more, more Preferably it is 10 weight part or more. When the solvent is mixed, although it depends on the type of citric acid or ascorbic acid, it is usually 0.01 parts by weight or more, preferably 0.1 parts by weight or more, more preferably 1 part by weight with respect to 100 parts by weight of the solvent. It is better to use more than one part.
Oxidation protective effect of reduced coenzyme Q ₁₀ in a solvent, because there is further increase tendency in highly concentrated solutions of reduced coenzyme Q _10, is not particularly limited, reduced coenzyme Q relative to 100 parts by weight of solvent Usually 1 part by weight or more as _10, preferably handled at a concentration of at least 2 parts by weight, or, when stored would be more effective.

In carrying out the stabilization method of the present invention, the temperature is not particularly limited, but is usually 50 ° C. or lower, preferably 40 ° C. or lower, more preferably 30 ° C. or lower in order to maximize the stabilizing effect.
Therefore, the by stabilizing method stabilized reduced coenzyme Q ₁₀ to 50 ° C. or less, contained in preferably 40 ° C. or less, even this aspect of the present invention to store more preferably at 30 ° C. or less.
As described above, according to the present invention, the use of the citric acid and / or ascorbic acid, reduced coenzyme Q ₁₀ is preferably protected from oxidation by molecular oxygen, it can be stabilized. Therefore, extraction, washing with water, concentrated, to can also be carried out suitably in case of an operation such as column chromatography, further reduced coenzyme Q ₁₀ can be stably stored.

Next, the crystallization method of the present invention will be described. The present invention is crystallized reduced coenzyme Q ₁₀ in a solvent containing citric acid and / or ascorbic acids.
Reduced coenzyme Q ₁₀ is used for the crystallization, for example, synthetic, fermentation can be obtained by a conventionally known method such as extraction from natural products. Preferably, it is obtained by reducing oxidized coenzyme Q ₁₀ contained in reduced coenzyme Q ₁₀ or oxidized coenzyme Q ₁₀ , and more preferably the reduction of the present invention described later. It was obtained using the reaction.

Crystallization method of the present invention is applicable also reduced coenzyme Q ₁₀ containing a relatively large amount of oxidized coenzyme Q _10, reduced coenzyme high purity prepared by the reduction method to be described later enzyme Q ₁₀ It is particularly effective against. In the present invention, obtained by a conventionally known method, or purified doubles as the removal of impurities contained in the reaction liquid or extract containing reduced coenzyme Q ₁₀ produced by reduction method to be described later Crystallization is particularly effective. Thereby, coexisting impurities, in particular, similar compounds having a structure that is not always easy to remove (specifically, reduced coenzyme Q ₉ , reduced coenzyme Q ₈ , reduced coenzyme Q ₇₎ Etc.) can be removed in the mother liquor. Needless to say, the purification crystallization for repurified reduced coenzyme Q ₁₀ crystal, it is very effective as recrystallization.

Crystallization of reduced coenzyme Q _10, cooling, concentration, solvent substitution, the general crystallization operations such as the use of a poor solvent, used alone, or may be appropriately combined and implemented. In particular, a cooling operation (cooling crystallization) is preferably used or used in combination.
The amount of citric acid and / or ascorbic acid to be used in the present invention may be, for example, an amount that can produce an expected suitable effect or ability (that is, an effective amount). enzyme Q ₁₀ may be an effective amount which can protect from being oxidized to oxidized coenzyme Q _10. In general, more on the type of citric acid and / or ascorbic acid, is not particularly limited, usually, reduced coenzyme Q ₁₀ 0.1 parts by weight or more relative to 100 parts by weight, preferably 1 part by weight or more More preferably, it is 10 parts by weight or more, usually 0.01 parts by weight or more, preferably 0.1 parts by weight or more with respect to 100 parts by weight of the solvent. The upper limit is not particularly limited, but is usually 10 parts by weight or less, preferably 5 parts by weight or less, more preferably 1 part by weight or less in consideration of economy.

Crystallization of reduced coenzyme Q ₁₀ is preferably carried out under forced flow. In order to suppress the formation of supersaturation, to smoothly nucleate and grow crystals, or from the viewpoint of high quality, the required power for stirring per unit volume is usually about 0.01 kW / m ³ or more, preferably about 0.1 kW / ^{m 3} or more, more preferably about 0.3 kW / ^{m 3} or more flow is preferred. The forced flow is usually given by the rotation of a stirring blade, but it is not always necessary to use the stirring blade as long as the flow is obtained. For example, a method by circulating liquid may be used.
In crystallization, it is preferable to add seed crystals in order to suppress the formation of supersaturation and to smoothly nucleate and grow crystals.

Crystallization temperature of the reduced coenzyme Q ₁₀ (the cooling temperature during crystallization) is different based also on the type and method of crystallizing a crystallization solvent, can not be defined uniformly, for example, preferably 25 ° C. or less, more It is preferably 20 ° C. or lower, especially 15 ° C. or lower, especially 10 ° C. or lower. The lower limit is the solidification temperature of the system. Usually, it can implement suitably at about 0-25 degreeC.
Resulting minimize contamination of various impurities into reduced coenzyme Q _10, or purpose of obtaining a slurry having good properties, it is possible to control the crystallization of the crystalline per unit time during crystallization . The preferred amount of crystallization per unit time is, for example, not more than the rate at which about 50% of the total amount of crystallization per unit time is crystallized (ie, a maximum of 50% amount / hour), preferably per unit time. About 25% of the total crystallization is below the rate of crystallization (ie up to 25% / hour). The cooling rate in the cooling crystallization is usually about 40 ° C./hour or less, preferably about 20 ° C./hour or less.

Oxidation protective effect of reduced coenzyme Q ₁₀ in a solvent, because there is further increase tendency in highly concentrated solutions of reduced coenzyme Q _10, is not particularly limited, reduced coenzyme Q relative to 100 parts by weight of solvent ₁₀ generally 1 part by weight or more as will preferably more effective is crystallized at a concentration at least 2 parts by weight. The upper limit of the concentration of crystallization is different depending on the type and the crystallization method of crystallizing solvent, can not be defined uniformly, for example, as a reduced coenzyme Q ₁₀ to the crystallization solvent 100 parts by weight of at crystallization finished, preferably Is about 15 parts by weight or less, more preferably about 13 parts by weight or less, especially about 10 parts by weight or less. Usually, about 5 to 10 parts by weight can be preferably carried out.

Crystals of reduced coenzyme Q ₁₀ obtained in this way, preferably, for example, centrifugation, pressure filtration, solid-liquid separation by filtration under reduced pressure or the like, performs a cake washed if necessary, as a wet product Can be acquired. Further, the wet body is charged into a vacuum dryer (vacuum dryer) whose inside is replaced with an inert gas, dried under reduced pressure, and can be obtained as a dry body, and preferably obtained as a dry body.

Solvents that can be used in the crystallization method include the above-mentioned hydrocarbons, fatty acid esters, ethers, alcohols, fatty acids, ketones, nitrogen compounds (including nitriles and amides), and sulfur compounds. As mentioned above, the solvent that can be most preferably used is a monovalent or divalent alcohol and / or a water-soluble solvent other than alcohol. Particularly preferred solvents are methanol, ethanol, 1-propanol, 2-propanol, acetone, methyl ethyl ketone, or water, or mixtures thereof, especially ethanol, acetone, or mixtures thereof.
Monovalent or divalent alcohol or ketone, preferably monovalent or divalent alcohol or water-soluble ketone (specifically, methanol, ethanol, 1-propanol, 2-propanol, acetone, methyl ethyl ketone, preferably ethanol, in the case of using acetone or the like) can be obtained crystals of good slurry properties and crystallinity properties reduced coenzyme Q _10.

Further, to obtain a higher yield advantageously reduces the solubility of reduced coenzyme Q _10, improving the slurry properties, and in particular, it should be noted, improved solid-liquid separability of the (filterability) increased In particular, it is preferable that a small amount of water is present in a monovalent or divalent alcohol and / or a water-soluble organic solvent other than alcohol. Since the ratio of monovalent or divalent alcohol and / or water-soluble organic solvent other than alcohol and water varies depending on the type of solvent, it cannot be uniformly defined, and substantially the above monovalent or divalent alcohol and / or alcohol. Although it will not restrict | limit especially if it is a solvent which has water-soluble organic solvents other than as a main component, Preferably, the ratio of the said monovalent | monohydric or dihydric alcohol and / or water-soluble organic solvents other than alcohol with respect to 100 weight part of total solvents, Usually, the lower limit is about 90 parts by weight, preferably about 91 parts by weight, more preferably about 92 parts by weight, especially about 93 parts by weight, and the upper limit is about 99.5 parts by weight, preferably about 99 parts by weight. Preferably it is about 98 parts by weight, especially about 97 parts by weight. Usually, it is most suitably carried out at about 93 to 97 parts by weight.

Oxidation protective effect of reduced coenzyme Q ₁₀ in a solvent, because there is further increase tendency in highly concentrated solutions of reduced coenzyme Q _10, is not particularly limited, reduced coenzyme Q relative to 100 parts by weight of solvent It would be more effective to crystallize at a concentration of usually ₁₀ parts by weight or more, preferably 2 parts by weight or more.
According to the present invention, shifts the reduced coenzyme Q _10, by crystallizing in the presence of ascorbic acids and / or citric acid, side reactions undesirable oxygen in the crystalline state in a minimized state are allowed, it is possible to obtain high yields of high quality reduced coenzyme Q ₁₀ crystal.
Is reduced coenzyme Q ₁₀ crystal obtained by the crystallization method of the present invention, an extremely high quality, the weight ratio of reduced coenzyme Q _{10 /} oxidized coenzyme Q _10, 98/2 or more, preferably 99 / 1 or more can be expected.

Next, a method for manufacturing the reduced coenzyme Q _10. In the present invention, after conversion to reduced coenzyme Q ₁₀ to oxidized coenzyme Q ₁₀ and reduced with ascorbic acid, the generated reduced coenzyme Q ₁₀ in the presence of citric acid and / or ascorbic acid Crystallization is then continued (direct isolation method (one-pot method)). Here, “continuous crystallization” means that the reaction solution obtained by the reduction reaction is crystallized without additional operations such as extraction and washing. This simplifies and minimizes the operation and minimizes oxidation from molecular oxygen.
First, the reduction reaction will be described. In the present invention, the aforementioned ascorbic acids are used as the reducing agent.

The amount of the above ascorbic acids to be used is not particularly limited, and may be, for example, an amount (that is, an effective amount) that can produce a suitable effect and ability to be expected. Specifically, oxidized coenzyme Q ₁₀ the may be an effective amount which can be converted into reduced coenzyme Q _10. In general, for oxidized coenzyme Q _10, usually 1-fold molar amount or more, preferably 1.2-fold molar amount or more. The upper limit is not particularly limited, but is usually 10-fold molar amount, preferably 5-fold molar amount, more preferably 3-fold molar amount in consideration of economy.
Although citric acids do not act as a reducing agent, citric acids can be added from the time of the reduction reaction from the viewpoint of the stabilizing effect during the subsequent crystallization.

Reduction using the ascorbic acids, reduced coenzyme reaction accelerator in the production of the enzyme Q ₁₀ (e.g., reduction of the reaction temperature, shorten the reaction time) added with reaction promoting effect of a basic substance or bisulfite or the like as It can be carried out in the presence of an agent.
The basic substance is not particularly limited, and for example, any inorganic compound or organic compound can be used. Although it does not restrict | limit especially as said inorganic compound, For example, the hydroxide of metal (preferably alkali metal, alkaline-earth metal, etc.), carbonate, hydrogencarbonate, ammonia, etc. can be mentioned. Typical examples thereof include, for example, alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as sodium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, and alkaline earth metal carbonates such as magnesium carbonate. Etc. Although it does not restrict | limit especially as said organic compound, For example, amines, such as a triethylamine, etc. can be mentioned. Among the above basic substances, weak basic substances such as inorganic compounds such as carbonates, hydrogen carbonates and ammonia of metals (preferably alkali metals and alkaline earth metals); organic compounds such as amines such as triethylamine ( A weak base or a weak alkali) can be particularly preferably used. Most preferred is the inorganic compound, and more preferred is the weakly basic inorganic compound.

Moreover, as a hydrogen sulfite, alkali metal hydrogen sulfites, such as sodium hydrogen sulfite, can be mentioned as a suitable thing, for example.
The amount of the additive is not particularly limited as long as it is an amount (effective amount) that can exhibit the expected effect of promoting the reaction, but in general, with respect to ascorbic acids in consideration of economy. Usually, it is 20 times mole amount or less, preferably 10 times mole amount or less, more preferably 5 times mole amount or less, especially 2 times mole or less. The lower limit is not particularly limited, but is usually 0.01-fold mol amount or more, preferably 0.05-fold mol amount or more, more preferably 0.1-fold mol amount or more, particularly 0.2-fold mol amount or more.

The reduction reaction described in the present invention is preferably carried out under forced flow. As power required for stirring per unit volume, typically from about 0.01 kW / ^{m 3} or more, preferably about 0.1 kW / ^{m 3} or more, more preferably about 0.3 kW / ^{m 3} or more flow is preferred. The forced flow is usually given by the rotation of a stirring blade, but it is not always necessary to use the stirring blade as long as the flow is obtained. For example, a method by circulating liquid may be used.
The reduction temperature is usually 30 ° C. or higher, preferably 40 ° C. or higher, more preferably 50 ° C. or higher. The upper limit is the boiling point of the system. Usually, about 30-150 degreeC, Preferably it is about 40-120 degreeC, More preferably, it can implement suitably at about 50-100 degreeC.

The reaction concentration is not particularly limited, but generally it is usually about 1 part by weight or more, preferably 3 parts by weight or more, more preferably 10 parts by weight or more, especially as the weight of oxidized coenzyme Q ₁₀ with respect to 100 parts by weight of the solvent. 15 parts by weight or more. The upper limit is not particularly limited, but is usually about 60 parts by weight, preferably 50 parts by weight, more preferably 40 parts by weight, especially 30 parts by weight. In general, it can be suitably carried out at about 2 to 30 parts by weight, preferably about 5 to 30 parts by weight, more preferably about 10 to 30 parts by weight.
The reduction reaction varies depending on the type and amount of the reducing agent and cannot be defined uniformly, but it can usually be completed within 48 hours, preferably within 24 hours, more preferably within 10 hours, especially within 5 hours.

After the reduction reaction in the above method, the above-described crystallization is performed from the reaction solution. In this case, in crystallization, the effective amount of citric acid and / or ascorbic acid described in the above crystallization method may be present in the system, and these are added ascorbic acid (and citric acid) added during the reduction reaction. It may be. It is preferable that ascorbic acids added during the reduction reaction remain and coexist during crystallization. A preferred embodiment of the crystallization method in the method for producing the reduced coenzyme Q ₁₀ also are those described in the crystallization methods described above.

Solvents that can be used in the above production method include the hydrocarbons, fatty acid esters, ethers, alcohols, fatty acids, ketones, nitrogen compounds (including nitriles and amides), sulfur compounds, Although water etc. can be mentioned, As mentioned above, the solvent which can be used most suitably is a monovalent or divalent alcohol and / or a water-soluble solvent other than alcohol. Particularly preferred solvents are methanol, ethanol, 1-propanol, 2-propanol, acetone, methyl ethyl ketone, or water, or mixtures thereof, especially ethanol, acetone, water, or mixtures thereof.
Monovalent or divalent alcohol or ketone, preferably monovalent or divalent alcohol or water-soluble ketone (specifically, methanol, ethanol, 1-propanol, 2-propanol, acetone, methyl ethyl ketone, preferably ethanol, in the case of using acetone or the like) can be obtained crystals of good slurry properties and crystallinity properties reduced coenzyme Q _10.

Further, to obtain a higher yield advantageously reduces the solubility of reduced coenzyme Q _10, improving the slurry properties, and in particular, it should be noted, improved solid-liquid separability of the (filterability) increased From the viewpoint of achieving this, it is preferable that a small amount of water be present in the monovalent or divalent alcohol and / or a water-soluble organic solvent other than alcohol during crystallization. Since the ratio of monovalent or divalent alcohol and / or water-soluble organic solvent other than alcohol and water varies depending on the type of solvent, it cannot be uniformly defined, and substantially the above monovalent or divalent alcohol and / or alcohol. Although it will not restrict | limit especially if it is a solvent which has water-soluble organic solvents other than as a main component, Preferably, the ratio of the said monovalent | monohydric or dihydric alcohol and / or water-soluble organic solvents other than alcohol with respect to 100 weight part of total solvents, Usually, the lower limit is about 90 parts by weight, preferably about 91 parts by weight, more preferably about 92 parts by weight, especially about 93 parts by weight, and the upper limit is about 99.5 parts by weight, preferably about 99 parts by weight. Preferably it is about 98 parts by weight, especially about 97 parts by weight. Usually, it is most suitably carried out at about 93 to 97 parts by weight.

Oxidation protective effect of reduced coenzyme Q ₁₀ in a solvent, because there is further increase tendency in highly concentrated solutions of reduced coenzyme Q _10, is not particularly limited, reduced coenzyme Q relative to 100 parts by weight of solvent It would be more effective to crystallize at a concentration of usually ₁₀ parts by weight or more, preferably 2 parts by weight or more.
The production method of the present invention, very high quality, i.e., reduced coenzyme _{Q 10} / weight ratio of oxidized coenzyme _{Q 10} is 98/2 or more, preferably reduced coenzyme _{Q 10} crystals over 99/1 It can be obtained easily and stably.
The manufacturing method described above, the reduced coenzyme Q ₁₀ containing oxidized coenzyme Q _10, which is also very effective as a purification method for enhancing the weight ratio of reduced coenzyme Q _10.

Next, the composition of the present invention will be described. One of the compositions of the present invention containing reduced coenzyme Q ₁₀ and citric acid, which is a reduced coenzyme Q ₁₀ containing composition. In the composition of the present invention, the aforementioned hydrocarbons, fatty acid esters, ethers, alcohols, fatty acids, ketones, nitrogen compounds (including nitriles and amides), sulfur compounds, water, etc. Although it can be used as a solvent, the above-mentioned monovalent or divalent alcohol and / or a water-soluble solvent other than alcohol (preferably a water-soluble organic solvent) is particularly preferable.
In addition, another one of the compositions in the present invention contains reduced coenzyme Q ₁₀ , ascorbic acid, and a monovalent or divalent alcohol and / or a water-soluble organic solvent other than alcohol, valence or divalent alcohols and / or water-soluble organic solvent other than alcohol is 5 wt% or more in the total composition is a reduced coenzyme Q ₁₀ containing composition.

In the composition of the present invention, ascorbic acids and citric acids can be used in combination.
The amount of citric acid and / or ascorbic acid to be used in the present invention may be, for example, an amount that can produce an expected suitable effect or ability (that is, an effective amount). enzyme Q ₁₀ may be an effective amount which can protect from being oxidized to oxidized coenzyme Q _10. In general, more on the type of citric acid and / or ascorbic acid, is not particularly limited, usually, reduced coenzyme Q ₁₀ 0.1 parts by weight or more relative to 100 parts by weight, preferably 1 part by weight or more More preferably, it is 10 parts by weight or more, and usually 0.01 parts by weight or more, preferably 0.1 parts by weight or more with respect to 100 parts by weight of the solvent. The upper limit is not particularly limited, but is usually 10 parts by weight or less, preferably 5 parts by weight or less, more preferably 1 part by weight or less in consideration of economy.
Examples of the solvent that can be used in the composition of the present invention include the hydrocarbons, fatty acid esters, ethers, alcohols, fatty acids, ketones, nitrogen compounds (including nitriles and amides), and sulfur compounds. The solvent that can be most suitably used is a monovalent or divalent alcohol and / or a water-soluble solvent other than alcohol, as described above.
In the composition of the present invention, a suitable solvent can be selected and used according to the purpose and application. For example, the reduced coenzyme Q ₁₀ is isolated, or, in terms of utilizing the reaction mixture obtained to a further derivatization (next reaction), boiling point usually 0.99 ° C. or less, preferably those of 100 ° C. or less It is particularly preferred to use it. In addition, when used for food, medicine, etc., ethanol, 1,2-propanediol, polyethylene glycol (preferably polyethylene glycol having a molecular weight of 300 to 1000) and the like are suitable.

The amount of the above-mentioned monovalent or divalent alcohol and / or water-soluble solvent other than alcohol (preferably a water-soluble organic solvent) is generally generally 5% by weight or more, for example, in the whole composition, preferably Is 10% by weight or more, more preferably 20% by weight or more, particularly preferably 30% by weight or more, especially 40% by weight or more, especially 50% by weight or more, and more than 50% by weight. In particular, in the case of ascorbic acids, the amount of the solvent used is preferably 60% by weight or more, more preferably 70% by weight or more, and still more preferably 80% by weight or more. When the composition of the present invention is used for edible, medicinal, preferably edible, medicinal oral administration, for example, the lower limit, usually 5% by weight, preferably 10% by weight, and more. Preferably 20% by weight, particularly preferably 30% by weight, especially 40% by weight, especially 50% by weight, upper limit, usually 99% by weight, preferably 95% by weight, more preferably 90% by weight, particularly preferably 85% by weight, Particularly preferred is 80% by weight, especially 70% by weight.
Reduced coenzyme Q _10, also served as the reaction mixture obtained by the production method of the present invention may, or may be obtained by external addition. For external addition, for example, those isolated from the above reaction mixture or separately synthesized and isolated can be used.

When the reaction mixture is used, there is a merit that it is simple. On the other hand, there is a concern that a by-product or the like generated during the reduction reaction is not necessarily suitable for the body and may be entrained in the composition. From this viewpoint, the reduced coenzyme Q _10, rather than utilizing the above reaction mixture, it is more preferable to use those externally added.
Needless to say, in the compositions of the present invention, it does not interfere with the coexistence of other active substances other than reduced coenzyme Q _10. Examples of other active substances include amino acids, vitamins, minerals, polyphenols, organic acids, saccharides, peptides, proteins, and the like.

The composition of the present invention can be used as it is, but it can be preferably used after further processing into oral dosage forms such as capsules (hard capsules, soft capsules), tablets, syrups and beverages, creams, suppositories, kneads. It can also be used by further processing into a form for brushing teeth. Particularly preferred are capsules, especially soft capsules. The capsule base material is not particularly limited, and includes gelatin derived from cow bone, cow skin, pig skin, fish skin, and other base materials (for example, seaweeds such as carrageenan and alginic acid that can be used as food additives). It is also possible to use a thickening stabilizer such as a derived product, a plant seed derived product such as locust bean gum or guar gum, or a production agent containing celluloses.

The method for stabilizing reduced coenzyme Q ₁₀ of the present invention, storage method, crystallization method and production method, by be carried out under deoxygenated atmosphere, it is possible to increase the antioxidant effect. The composition of the present invention is preferably prepared or stored in a deoxygenated atmosphere. The deoxygenated atmosphere can be achieved by substitution with an inert gas, reduced pressure, boiling, or a combination thereof. It is preferable to use at least substitution with an inert gas, that is, an inert gas atmosphere. Examples of the inert gas include nitrogen gas, helium gas, argon gas, hydrogen gas, carbon dioxide gas, and the like, preferably nitrogen gas.

In the stabilization method and the composition described above, after storage for a predetermined period, the reduced coenzyme Q ₁₀ is reduced to a reduced coenzyme Q ₁₀ / (reduced coenzyme Q ₁₀ + oxidized coenzyme Q ₁₀ ) weight ratio. 90% by weight or more, preferably 95% by weight or more can be expected. The storage period is, for example, 1 day or more, preferably 1 week or more, more preferably 1 month or more, especially 6 months or more, especially 1 year or more, especially 2 years or more.

According to the present invention, using the easily reagent handling safety, also depending on the purpose and application, the solvent used can also be suitably selected, isolated and further derivatization of reduced coenzyme Q ₁₀ The method is widely used because it is suitable for use as an edible or pharmaceutical composition or an oral dosage form, and thus has great advantages.

The present invention, which has the constitution described hereinabove, convenient and preferred method of stabilizing reduced coenzyme Q _10, storage method using the same, it is possible to provide an isolated (crystallization) method and compositions. Furthermore, the production method of reduced coenzyme Q ₁₀ in versatility using the above stabilization method can also be provided. To stabilize reduced coenzyme Q _10, it can be further stored stably. Further, in a manner suitable for production on an industrial scale, it is also possible to obtain a reduced coenzyme Q ₁₀ of high quality easily and efficiently.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.
Further, the purity of reduced coenzyme Q ₁₀ in the embodiment, reduced coenzyme weight ratio of enzyme Q ₁₀ and oxidized coenzyme Q ₁₀ has been determined by the following HPLC analysis, the obtained reduced coenzyme Q ₁₀ purity is not intended to define the limits of the purity in the present invention, Similarly, also the proportion of reduced coenzyme Q ₁₀ in the weight ratio of reduced coenzyme Q ₁₀ and oxidized coenzyme Q _10, The upper limit is not specified.

(HPLC analysis conditions)
Column: SYMMETRY C18 (manufactured by Waters) 250 mm (length) 4.6 mm (inner diameter), mobile phase; C ₂ H ₅ OH: CH ₃ OH = 4: 3 (v: v), detection wavelength: 210 nm, flow rate: 1 ml / min, reduced coenzyme retention time of the enzyme _{Q 10; 9.1min,} retention time of oxidized coenzyme _{Q 10; 13.3min.}

Example 1
In 1000 g of ethanol, 100 g of oxidized coenzyme Q ₁₀ (containing 0.40% oxidized coenzyme Q ₉ and purity 99.4%) and 60 g of L-ascorbic acid were added and stirred at 78 ° C. Then, a reduction reaction was performed. After 30 hours, the mixture was cooled to 50 ° C., and 400 g of ethanol was added while maintaining the same temperature. While this ethanol solution was agitated (the reduced coenzyme _{Q 10} 100 g (including the reduced coenzyme _{Q 9} 0.40% content)) (stirring power requirement 0.3 kW / ^{m 3),} of 10 ° C. / Time It cooled to 2 degreeC with the cooling rate, and obtained the white slurry. The obtained slurry was filtered under reduced pressure, and the wet crystals were washed with cold ethanol, cold water, and cold ethanol in this order (the temperature of the cold solvent used for washing was 2 ° C.), and the wet crystals were further dried under reduced pressure (20-40). ° C., by 1～30MmHg), white dry crystals 95 g (reduced coenzyme _{Q 9} 0.21% content, removal rate 48%) was obtained (Yusugata yield 95 mol%). All operations except for drying under reduced pressure were performed in a nitrogen atmosphere. The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 99.5 / 0.5, and the purity of reduced coenzyme Q ₁₀ was 99.2%.

(Example 2)
The oxidized coenzyme _{Q 10} of 100g was dissolved in heptane 1000g at 25 ° C.. While stirring the above oxidized coenzyme Q ₁₀ heptane solution (required stirring power 0.3 kW / m ³ ), an aqueous solution in which 100 g of sodium hyposulfite (purity 75% or more) as a reducing agent was dissolved in 1000 ml of water was used. The solution was gradually added to the solution and subjected to a reduction reaction at 25 ° C. and pH 4-6. After 2 hours, the aqueous phase was removed from the reaction solution, and the heptane phase was washed 6 times with 1000 g of degassed saturated brine. All the above operations were performed in a nitrogen atmosphere. The heptane solution was solvent replaced under reduced pressure, reduced coenzyme Q ₁₀ relative to 100 parts by weight of ethanol was adjusted to an ethanol solution of 1 part by weight.
Dispense the ethanol solution min, ascorbic acids listed in Table 1 so that (10 parts by weight per 100 parts by weight of reduced coenzyme Q ₁₀₎ 0.1 parts by weight per 100 parts by weight of ethanol Or each citric acid was added and it stirred in air at 25 degreeC. After 24 hours, showing the weight ratio of reduced coenzyme Q _{10 /} oxidized coenzyme Q ₁₀ in ethanol solution in Table 1. For comparison, the results in the case of no addition are also shown.

(Reference Example 1)
The ethanol solution was adjusted in the same manner as in Example 2, 0.1 parts by weight of antioxidant in Table 2 relative to 100 parts by weight of ethanol (10 parts by weight per 100 parts by weight of reduced coenzyme Q ₁₀ ) And stirred in air at 25 ° C. After 24 hours, showing the weight ratio of reduced coenzyme Q _{10 /} oxidized coenzyme Q ₁₀ in ethanol solution in Table 2.

(Example 3)
Using reduced coenzyme Q ₁₀ crystal obtained in Example 1, reduced coenzyme Q ₁₀ relative to 100 parts by weight of ethanol was adjusted to an ethanol solution of 5 parts by weight. The ethanol solution was added L- ascorbic acid such that (20 parts by weight per 100 parts by weight of reduced coenzyme _{Q 10)} 1 part by weight relative to 100 parts by weight of the solvent, 50 ° C., air Stir in. Table 3 shows the weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the solution and the residual ratio of L-ascorbic acid after 50 hours. For comparison, reduced coenzyme Q _{10 and,,} are also shown results with L- ascorbic acid each alone. These results, L- stabilizing effect of reduced coenzyme Q ₁₀ by the presence of ascorbic acid is oxidized coenzyme Q ₁₀ to produce a stabilized based on the reduction effect of L- ascorbic acid by air oxidation It was suggested that it is not.

(Example 4)
Relative to 100 parts by weight of ethanol, reduced coenzyme Q ₁₀ crystal 1 part by weight obtained in Example 1, was added ascorbic acid 1 part by weight described in Table 4, 45 ° C., and stirred in air. The weight ratio of reduced coenzyme _{Q 10} / oxidized coenzyme _{Q 10} after 24 hours is shown in Table 4. For comparison, the results in the case of no addition are also shown.

(Comparative Example 1)
Relative to glycerin 100 parts by weight of reduced coenzyme Q ₁₀ crystal 1 part by weight obtained in Example 1, was added ascorbic acid 1 part by weight described in Table 5, 45 ° C., and stirred in air. The weight ratio of reduced coenzyme _{Q 10} / oxidized coenzyme _{Q 10} after 24 hours is shown in Table 5. For comparison, the results in the case of no addition are also shown.

(Example 5)
In 1000 g of ethanol, 100 g of oxidized coenzyme Q ₁₀ (containing 0.40% oxidized coenzyme Q ₉ and purity 99.4%) and 60 g of L-ascorbic acid were added and stirred at 78 ° C. Then, a reduction reaction was performed. After 30 hours, the mixture was cooled to 50 ° C., and 330 g of ethanol and 70 g of water were added while maintaining the same temperature. While this ethanol solution was agitated (the reduced coenzyme _{Q 10} 100 g (including the reduced coenzyme _{Q 9} 0.40% content)) (stirring power requirement 0.3 kW / ^{m 3),} of 10 ° C. / Time It cooled to 2 degreeC with the cooling rate, and obtained the white slurry. The slurry showed very good fluidity as compared with Example 1, and could be easily discharged from the crystallization vessel. The obtained slurry was filtered under reduced pressure, and the wet crystals were washed with cold ethanol, cold water, and cold ethanol in this order (the temperature of the cold solvent used for washing was 2 ° C.), and the wet crystals were further dried under reduced pressure (20-40). ° C., by 1～30MmHg), white dry crystals 97 g (reduced coenzyme _{Q 9} 0.24% content, removal rate 41%) was obtained (Yusugata yield 97 mol%). All operations except for drying under reduced pressure were performed in a nitrogen atmosphere. The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 99.5 / 0.5, and the purity of reduced coenzyme Q ₁₀ was 99.2%.

(Example 6)
In 1000 g of ethanol, 100 g of oxidized coenzyme Q ₁₀ (purity 99.4%), 60 g of L-ascorbic acid and 30 g of sodium hydrogen carbonate were added, and the mixture was stirred at 78 ° C. to carry out a reduction reaction. After 3 hours, the mixture was cooled to 50 ° C., and 330 g of ethanol and 70 g of water were added while maintaining the same temperature. While this ethanol solution was stirred (stirring power requirement 0.3 kW / m ^3), and cooled to 2 ℃ at a cooling rate of 10 ° C. / time, to give a white slurry. The slurry showed very good fluidity as compared with Example 1, and could be easily discharged from the crystallization vessel. The obtained slurry was filtered under reduced pressure, and the wet crystals were washed with cold ethanol, cold water, and cold ethanol in this order (the temperature of the cold solvent used for washing was 2 ° C.), and the wet crystals were further dried under reduced pressure (20-40). C., 1-30 mmHg) to obtain 97 g of white dry crystals (solid yield 97 mol%). All operations except for drying under reduced pressure were performed in a nitrogen atmosphere. The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 99.5 / 0.5, and the purity of reduced coenzyme Q ₁₀ was 99.2%.

(Example 7)
In 1000 g of acetone, 100 g of oxidized coenzyme Q ₁₀ (containing 0.40% oxidized coenzyme Q ₉ and purity 99.4%), 60 g of L-ascorbic acid, 30 g of sodium bicarbonate were added, The mixture was stirred at 50 ° C. to carry out a reduction reaction. After 45 hours, 400 g of acetone was added while maintaining the same temperature. While this acetone solution was stirred (reduced coenzyme _{Q 10} 100 g (reduced coenzyme _{Q 9} and containing 0.40% content)) (stirring power requirement 0.3 kW / ^{m 3),} of 10 ° C. / Time It cooled to 2 degreeC with the cooling rate, and obtained the white slurry. The obtained slurry was filtered under reduced pressure, and the wet crystals were washed with cold acetone, cold water and cold acetone in this order (the temperature of the cold solvent used for washing was 2 ° C.), and the wet crystals were further dried under reduced pressure (20-40 ° C. by 1～30MmHg), white dry crystals 93 g (reduced coenzyme _{Q 9} 0.23% content, removal rate 42%) was obtained (Yusugata yield 93 mol%). All operations except for drying under reduced pressure were performed in a nitrogen atmosphere. The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 99.6 / 0.4, and the purity of reduced coenzyme Q ₁₀ was 99.3%.

(Example 8)
Purity 98.4% of oxidized coenzyme _{Q 10} using (oxidized coenzyme _{Q 9} 1.0%, the oxidized coenzyme _{Q 8} 0.30% and, an oxidized coenzyme _{Q 7} 0 except that a .04% content), the reduction reaction, ethanol, addition of water in exactly the same conditions as in example 5 to prepare a water-containing ethanol solution of reduced coenzyme Q ₁₀ of 50 ° C. (reduction type coenzyme _{Q 9} 1.00%, reduced coenzyme _{Q 8} 0.30%, and, containing reduced coenzyme _{Q 7} 0.04%). While the aqueous ethanol solution was stirred (required stirring power: 0.3 kw / m ³ ), it was cooled to 2 ° C. at a cooling rate of 3 ° C./hour to precipitate crystals. The slurry showed very good fluidity as compared with Example 1, and could be easily discharged from the crystallization vessel. All the above operations were performed under a nitrogen atmosphere. The obtained slurry was filtered under reduced pressure, and the wet crystals were washed with cold ethanol, cold water and cold ethanol in this order (the temperature of the cold solvent used for washing was 2 ° C.), and the wet crystals were further dried under reduced pressure (20 to 40 ° C. , 1～30MmHg by) that white dry crystals 95 g (reduced coenzyme _{Q 9} 0.52% content, removal rate 48%, reduced coenzyme _{Q 8} and reduced coenzyme _{Q 7} does not detect ) Was obtained (yield 97 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 99.5 / 0.5, and the purity of reduced coenzyme Q ₁₀ was 98.9%.

Example 9
100 g of oxidized coenzyme Q ₁₀ (purity 99.4%) was dissolved in 1000 g of heptane at 25 ° C. While the oxidized coenzyme _{Q 10} heptane solution was stirred (stirring power requirement 0.3 kW / ^{m 3),} sodium hyposulfite (or 75% pure) as a reducing agent aqueous solution obtained 100g dissolved in water 1000ml above heptane The solution was gradually added to the solution and subjected to a reduction reaction at 25 ° C. and pH 4-6. After 2 hours, the aqueous phase was removed from the reaction solution, and the heptane phase was washed 6 times with 1000 g of degassed saturated brine. All the above operations were performed in a nitrogen atmosphere. The heptane phase was solvent replaced under reduced pressure, reduced coenzyme Q ₁₀ relative to 100 parts by weight of ethanol to obtain a 50 ° C. ethanol solution of 7 parts by weight. (0.7 parts by weight per 100 parts by weight of ethanol, 10 parts by weight per 100 parts by weight of reduced coenzyme _{Q 10)} 10 g citric acid isopropyl this ethanol solution was added, stirred (stirring required in air The slurry was cooled to 2 ° C. with a power of 0.3 kW / m ³ ) to obtain a white slurry. The obtained slurry was filtered under reduced pressure, the wet crystals were washed with cold ethanol, cold water, and cold ethanol in this order (the temperature of the cold solvent used for washing was 2 ° C.), and the wet crystals were dried under reduced pressure (20-40 ° C., 1 ˜30 mmHg), 95 g of white dry crystals were obtained (yield 95 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 99.4 / 0.6, and the purity of reduced coenzyme Q ₁₀ was 99.1%.

(Example 10)
In the same manner as in Example 9, a heptane solution of reduced coenzyme Q ₁₀ (purity 99.4%) was obtained. The heptane solution was solvent replaced under reduced pressure, and reduced coenzyme Q ₁₀ relative to 100 parts by weight of ethanol to obtain a 50 ° C. ethanol solution of 7 parts by weight. (0.7 parts by weight per 100 parts by weight of ethanol, based on 100 parts by weight of reduced coenzyme _{Q 10} 10 parts by weight) 10 g of L- ascorbyl stearate to this ethanol solution was added, stirring in air A white slurry was obtained by cooling to 2 ° C. while stirring (power required for stirring 0.3 kW / m ³ ). The obtained slurry was filtered under reduced pressure, the wet crystals were washed with cold ethanol, cold water, and cold ethanol in this order (the temperature of the cold solvent used for washing was 2 ° C.), and the wet crystals were dried under reduced pressure (20-40 ° C., 1 ˜30 mmHg), 95 g of white dry crystals were obtained (yield 95 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 99.4 / 0.6, and the purity of reduced coenzyme Q ₁₀ was 99.1%.

(Example 11)
During crystallization, L-(0.07 parts by weight per 100 parts by weight of ethanol, 1 part by weight per 100 parts by weight of reduced coenzyme _{Q 10)} ascorbyl stearate to 1g all examples except for the addition of 10 was performed to obtain 95 g of white dry crystals (yield 95 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 98.5 / 1.5, and the purity of reduced coenzyme Q ₁₀ was 98.2%.

(Comparative Example 2)
In the crystallization, everything was carried out in the same manner as in Example 10 except that L-ascorbic acid stearate was not added to obtain 95 g of white dry crystals (yield 95 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained crystal was 96.4 / 3.6, and the purity of reduced coenzyme Q ₁₀ was 96.1%.

Example 12
Ground crystals 2g of a reduced coenzyme Q ₁₀ obtained in Example 9 in a mortar with ascorbic acids or citric acid 0.2g were listed in Table 6, it was mixed. 25 ° C., the weight ratio of reduced coenzyme Q _{10 /} oxidized coenzyme Q ₁₀ after being left 4 days in air is shown in Table 2. For comparison, the results in the case of no addition are also shown.

(Example 13)
Polyethylene glycol was heated to 50 ° C., the crystals and L- ascorbic acid of reduced coenzyme Q ₁₀ obtained in Example 1 was added to the polyethylene glycol at the same temperature by conventional methods of gelatin consisting of the following components A soft capsule formulation was obtained.
Reduced coenzyme Q ₁₀ 60 parts by weight L-ascorbic acid 100 parts by weight Polyethylene glycol 1000 parts by weight

(Example 14)
Polyethylene glycol was heated to 50 ° C., was added crystals of reduced coenzyme Q ₁₀ obtained in Example 1, the L- ascorbic acid and ethanol polyethylene glycol at the same temperature, consisting of the following components by a conventional method A soft capsule formulation of carrageenan was obtained.
Reduced coenzyme Q ₁₀ 30 parts by weight L-ascorbic acid 1 part by weight Polyethylene glycol 950 parts by weight Ethanol 50 parts by weight

(Example 15)
Polyethylene glycol was heated to 50 ° C., was added crystals of citric acid of reduced coenzyme Q ₁₀ obtained in Example 1 polyethylene glycol at the same temperature, soft capsule formulation of gelatin consisting of the following components by a conventional method Got.
Reduced coenzyme Q ₁₀ 60 parts by weight Citric acid 10 parts by weight Polyethylene glycol 1000 parts by weight

The present invention, which has the constitution described hereinabove, convenient and preferred method of stabilizing reduced coenzyme Q _10, storage method using the same, it is possible to provide an isolated (crystallization) method and compositions. Furthermore, the production method of reduced coenzyme Q ₁₀ in versatility using the above stabilization method can also be provided. To stabilize reduced coenzyme Q _10, it can be further stored stably. Further, in a manner suitable for production on an industrial scale, it is also possible to obtain a reduced coenzyme Q ₁₀ of high quality easily and efficiently.

Claims (22)

A method of stabilizing reduced coenzyme Q ₁₀ by coexistence of reduced coenzyme Q ₁₀ and ascorbic acid, the presence of a monovalent or divalent alcohols and / or water-soluble solvent other than alcohols performed in the presence, monovalent or divalent alcohols and / or water-soluble solvent other than alcohols stabilization method of reduced coenzyme Q _10, characterized in that it is the total mixture 5 wt% or more. Ascorbic acids are ascorbic acid, rhamno-ascorbic acid, arabo-ascorbic acid, gluco-ascorbic acid, fuco-ascorbic acid, glucocohepto-ascorbic acid, xylo-ascorbic acid, galacto-ascorbic acid, gulo-ascorbic acid, allo-ascorbic acid, The stabilization method according to claim 1, wherein the stabilization method is at least one selected from the group consisting of acids, erythro-ascorbic acid, 6-desoxyascorbic acid, esters thereof and salts thereof. The stabilization method according to claim 1 or 2, wherein ascorbic acids are present in an amount of 0.1 parts by weight or more with respect to 100 parts by weight of the reduced coenzyme Q ₁₀ . A liquid phase containing reduced coenzyme Q _10, the stabilization method according to claim 1, ascorbic acid is present as a solid phase. The liquid phase containing the ascorbic acid, the stabilization method according to claim 1 is reduced coenzyme Q ₁₀ exists as a solid phase. Stabilization method according to claim 1, reduced coenzyme Q ₁₀ and ascorbic acid is present or is both in the liquid phase are both liquid phases. The stabilization method according to any one of claims 4 to 6, wherein the liquid phase is a homogeneous phase. The stabilization method according to any one of claims 4 to 7, wherein the solvent present in the liquid phase is at least one selected from the group consisting of ethanol, 1,2-propanediol and polyethylene glycol. The stabilization method according to any one of claims 1 to 8, wherein citric acids are present together with ascorbic acids. The storage method of reduced coenzyme Q ₁₀ to store the stabilized reduced coenzyme by a method according to any of claims 1 to 9 at 50 ° C. or less. The storage method according to claim _{10, wherein} the reduced coenzyme Q10 is stored in a deoxygenated atmosphere. A reduced coenzyme Q ₁₀ , ascorbic acid, and a monovalent or divalent alcohol and / or a water-soluble solvent other than alcohol, and a monovalent or divalent alcohol and / or a water-soluble solvent other than alcohol characterized in that is at least 5% by weight in the total composition, reduced coenzyme Q ₁₀ containing composition. Ascorbic acids include ascorbic acid, rhamno-ascorbic acid, arabo-ascorbic acid, gluco-ascorbic acid, fuco-ascorbic acid, glucocohepto-ascorbic acid, xyllo-ascorbic acid, galacto-ascorbic acid, gulo-ascorbic acid, allo-ascorbic acid, acid, erythro-ascorbic acid, 6-desoxy-ascorbic acid, their esters, and claim 12 reduced coenzyme Q ₁₀ containing composition, wherein at least one selected from the group consisting of salts thereof. To reduced coenzyme Q _{10 100} parts by weight, claim 12 or 13 reduced coenzyme Q ₁₀ containing composition, wherein the containing ascorbic acid 0.1 parts by weight or more. As a solvent, ethanol, 2-propanediol and reduced coenzyme Q _{10-containing} composition according to any one of claims 12 to 14 further comprising at least one selected from the group consisting of polyethylene glycol. Reduced coenzyme Q ₁₀ containing composition according to any one of claims 12 to 15, further containing citric acid with ascorbic acid. Reduced coenzyme Q _10, reduced coenzyme Q ₁₀ containing composition according to any one of claims 12-16 in which an externally added. Besides reduced coenzyme Q _10, reduced coenzyme Q ₁₀ containing composition according to any one of claims 12 to 17 which further contains other active substances. The composition according to any one of claims 12 to 18, which has been processed into an oral dosage form. 20. A composition according to claim 19, wherein the form is a capsule. The composition according to claim 20, wherein the capsule is a soft capsule. The composition according to any one of claims 12 to 21, which is prepared or stored in a deoxygenated atmosphere.