JP5159117B2 - Method for producing coenzyme Q10 particles containing reduced coenzyme Q10 - Google Patents

Description

The present invention relates to a process for producing coenzyme Q ₁₀ particles containing reduced coenzyme Q _10. Reduced coenzyme Q ₁₀ shows a comparison with a high oral absorbability and oxidized coenzyme Q _10, excellent, food, food with nutrient function claims, food for specified health use, nutritional supplement, nutritional, animal drug, drink These compounds are useful as feeds, cosmetics, pharmaceuticals, therapeutic agents, preventive agents, and the like.

Widely oxidized coenzyme Q ₁₀ is a benzoquinone derivative which is known to be distributed in the living world, the is also called vitamin Q from vitamin-like function, nutrient return the weakened cell activity in healthy It is a component that rejuvenates the body. 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, 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). However, reduced coenzyme Q ₁₀ thus obtained can not necessarily acquire a high purity state, for example, low-purity crystals or oil containing impurities, including oxidized coenzyme Q _10, half It is easy to obtain as a solid.

The present inventors have intensive studies results, establishing a method for obtaining reduced coenzyme Q ₁₀ of high quality, have filed a patent application (Patent Document 2-5). However, in the method described in Patent Document 2, the crystal is fine, the properties of the slurry and the crystal are poor, the crystallization concentration is difficult to increase, it is difficult to stir, it is difficult to remove from the crystallization can, the filterability is poor, and the crystal is separated. There is a problem of productivity and operability such that it takes time, and the bulk specific gravity is small, leading to an increase in the size and number of packaging containers. In the method described in Patent Document 3, the problem mentioned in Patent Document 2 is somewhat improved, but it is not sufficient. In addition, the method described in Patent Document 4 has a problem that a granulated body of about several centimeters that easily causes scaling on a stirring blade and a can wall is generated, and the particle size distribution is very wide. Furthermore, in the method described in Patent Document 5, although the particle size distribution is relatively narrow, depending on conditions, a granulated body of about several μm is obtained, or a granulated body of more than several mm is obtained, It is difficult to prepare an appropriate particle size. Moreover, a comparatively hard granulated body may be obtained.

When the particle diameter of the obtained granulated body or crystal is too small, too large, or when the granulated body or crystal is hard regardless of the size of the particle diameter, each has a problem. When the particle size is small, physical properties such as the fluidity of the granulated body or crystals are poor, and handling is difficult. On the other hand, if the granule has a large particle size or is hard, food, nutritional functional food, food for specified health use, nutritional supplement, nutritional supplement, animal medicine, beverage, feed, cosmetics, pharmaceutical, therapeutic drug When processed into a preventive agent or the like, a granulated body having a large particle size may remain and not have the required quality. For example, when processing the food applications, deviation occurs is also contemplated that not be uniform in the distribution of the reduced coenzyme Q _10. In addition, if an attempt is made to process a tablet, capsule, or the like for uses such as pharmaceuticals, functional nutritional foods, and foods for specified health use, it may be impossible to make a preparation due to the influence of hardness and particle size.
JP-A-10-109933 WO03 / 006408 publication WO03 / 006409 WO03 / 006411 publication JP 2003-089669 A

In view of the above, the present invention improves powder physical properties such as fluidity, and food, nutritional functional food, food for specified health use, nutritional supplement, nutritional supplement, animal medicine, beverage, feed, cosmetics, pharmaceutical, therapeutic agent, for obtaining coenzyme Q ₁₀ granular material containing reduced coenzyme Q ₁₀ with workable suitable hardness and particle diameter prophylactic etc., manufacturing method suitable for manufacturing on an industrial scale The purpose is to provide.

The present inventors have made intensive studies to solve the above problems, the coenzyme Q ₁₀ containing reduced coenzyme Q _10, the solution was dissolved at a particular concentration in a water-soluble organic solvent, by adding in a mixed solvent of a water-soluble organic solvent and water, for example, about 100 to 1000 [mu] m, granulated form of the coenzyme Q ₁₀ with an appropriate particle size is found to result.

That is, the present invention
And coenzyme _Q 10 30 to 80 wt% containing reduced coenzyme _{Q 10,} coenzyme _{Q 10} solution consisting of 70 to 20% by weight of a water-soluble organic solvent (A),
In an aqueous solution (B) of a water-soluble organic solvent at 25 ° C. or lower,
A method for producing coenzyme Q ₁₀ particles, characterized by comprising:
It is.

According to the method of the present invention, reduced coenzyme Q ₁₀ particles or reduced coenzyme Q having uniform and appropriate hardness and particle size without causing scaling to a stirring blade or a can wall. Coenzyme Q ₁₀ particles containing ₁₀ can be produced.

  Hereinafter, the present invention will be described in detail.

In the method for producing coenzyme _{Q 10} particles of the present invention (granules), consisting of coenzyme _Q 10 30 to 80 wt% and a water-soluble organic solvents 70 to 20 wt% containing reduced coenzyme _{Q 10} coenzyme the enzyme Q ₁₀ solution (a), in 25 ° C. solution of the following water-soluble organic solvent (B), is characterized by adding.

In the production method of the present invention, coenzyme Q ₁₀ containing at least reduced coenzyme Q ₁₀ is of interest. In that case, coenzyme Q ₁₀ is reduced coenzyme Q ₁₀ alone may also be a mixture of oxidized coenzyme Q ₁₀ and reduced coenzyme Q _10. For the mixtures, the ratio to the total amount of coenzyme Q ₁₀ reduced coenzyme Q ₁₀ (i.e., the total amount of reduced coenzyme Q ₁₀ and oxidized coenzyme Q ₁₀₎ is not particularly limited, for example, 10 % By weight, usually 30% by weight or more, preferably 50% by weight or more, more preferably 70% by weight or more, especially 90% by weight or more, especially 96% by weight or more. Although an upper limit is 100 weight% and is not specifically limited, Usually, it is 99.9 weight% or less. If the ratio of oxidized coenzyme Q ₁₀ in coenzyme Q ₁₀ is high, the solubility is lowered to the water-soluble organic solvent, comprising coenzyme Q ₁₀ solution (A) is difficult to prepare a high concentration tends because there is, in the manufacturing method of the present invention, it is preferable that a high proportion of reduced coenzyme Q ₁₀ in coenzyme Q _10. Hereinafter, in the present specification, when “coenzyme Q ₁₀ ” is described, when reduced coenzyme Q _{10 is used} alone, reduced coenzyme Q ₁₀ itself is referred to as oxidized coenzyme Q ₁₀ and reduced coenzyme Q _{10. When} it is a mixture with _10, it means the whole mixture.

Reduced coenzyme Q ₁₀ used in the present invention or coenzyme Q ₁₀ containing reduced coenzyme Q _10, can, for example, synthetic, fermentation can be obtained by a conventionally known method such as extraction from natural products . Preferably, a mixture of existing highly pure coenzyme Q _10, etc. oxidized coenzyme Q ₁₀ or oxidized coenzyme Q ₁₀ and reduced coenzyme Q _10,, common reducing agents, e.g., sodium hydrosulfite ( Sodium hyposulfite), sodium borohydride, ascorbic acid, and the like (including those having a reduced concentration), and more preferably existing high-purity coenzyme Q. It is obtained by reducing oxidized coenzyme Q ₁₀ such as ₁₀ or a mixture of oxidized coenzyme Q ₁₀ and reduced coenzyme Q ₁₀ using ascorbic acids.

  In the production method of the present invention, the following two types of solutions are used.

(A) and coenzyme _Q 10 30 to 80 wt% containing reduced coenzyme _{Q 10,} and a coenzyme _{Q 10} solution (B) a water-soluble organic solvent and water consisting of 70 to 20% by weight of a water-soluble organic solvent The aqueous solution of the mixed water-soluble organic solvent The water-soluble organic solvent used in the coenzyme Q ₁₀ solution (A) and the aqueous solution of the water-soluble organic solvent (B) is not particularly limited, but the solubility in water is usually about 50 w. / W% or more, preferably about 60 w / w% or more, more preferably about 70 w / w% or more, particularly preferably about 80 w / w% or more. Needless to say, a water-soluble organic solvent in which the water-soluble organic solvent and water can be mixed at an arbitrary ratio is most preferable.

  Examples of such water-soluble organic solvents include alcohols, ketones, nitriles, and cyclic ethers.

  The alcohols are not particularly limited regardless of whether they are cyclic or non-cyclic, and are saturated or unsaturated. In general, saturated alcohols are preferably used. Usually, a monohydric alcohol having 1 to 6 carbon atoms, particularly 1 to 5 carbon atoms, particularly 1 to 3 carbon atoms is preferred, a dihydric alcohol having 2 to 5 carbon atoms is preferred, and a trihydric alcohol having 3 carbon atoms is preferred. preferable.

  Examples of the monovalent alcohol include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, and 3-pen. Tanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl-2- Examples include pentanol, 2-ethyl-1-butanol, allyl alcohol, propargyl alcohol, and cyclohexanol. Among them, preferably, 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, more preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol. , 2- Tertanol, 3-pentanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, more preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-methyl-1-butanol, and isopentyl alcohol.

  Examples of the divalent alcohol include 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, , 3-butanediol, 1,5-pentanediol and the like. 1,2-ethanediol, 1,2-propanediol and 1,3-propanediol are preferable, and 1,2-ethanediol is more preferable.

  Glycerin or the like can be suitably used as the trivalent alcohol.

  Among the alcohols, methanol, ethanol, 1-propanol, and 2-propanol, which are monovalent alcohols, are particularly preferable, and ethanol is most preferable.

  The ketones are not particularly limited, and those having 3 to 6 carbon atoms are preferably used. Specific examples thereof include acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, and the like, preferably acetone and methyl ethyl ketone, and most preferably acetone.

  The nitriles are not particularly limited regardless of whether they are cyclic or non-cyclic, and are saturated or unsaturated. In general, saturated ones are preferably used. Usually, those having 2 to 8 carbon atoms, particularly 2 to 6 carbon atoms, especially 2 to 4 carbon atoms are preferably used.

  Specific examples thereof include, for example, acetonitrile, propionitrile, malononitrile, butyronitrile, isobutyronitrile, succinonitrile, valeronitrile, glutaronitrile, hexanenitrile, heptyl cyanide, octyl cyanide, chloroacetonitrile, bromoacetonitrile, chloro Propionitrile, bromopropionitrile, methoxyacetonitrile, methyl cyanoacetate, ethyl cyanoacetate, tolunitrile, benzonitrile, chlorobenzonitrile, bromobenzonitrile, cyanobenzoic acid, nitrobenzonitrile, anisonitrile, phthalonitrile, bromotolunitrile , Methyl cyanobenzoate, methoxybenzonitrile, acetylbenzonitrile and the like. Among them, preferably acetonitrile, propionitrile, succinonitrile, butyronitrile, isobutyronitrile, valeronitrile, methyl cyanoacetate, ethyl cyanoacetate, benzonitrile, tolunitrile, chloropropionitrile, more preferably , Acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and most preferably acetonitrile.

  The cyclic ethers are not particularly limited regardless of whether they are saturated or unsaturated, but generally saturated ones are preferably used. Usually, those having a cyclic ether skeleton of 3 to 6 members, preferably 5 to 6 members are suitably used.

  Specific examples thereof include 1,2-epoxybutane, dioxane, trioxane, furan, 2-methylfuran, tetrahydrofuran, tetrahydropyran, furfuryl alcohol, tetrahydrofurfuryl alcohol, and the like. Preferred are dioxane, trioxane, tetrahydrofuran, and tetrahydropyran, and most preferred are tetrahydrofuran and dioxane.

  Among the water-soluble organic solvents, it is particularly preferable to use a solvent that is acceptable for the production of foods, pharmaceuticals, and the like.

Needless to say, two or more water-soluble organic solvents may be used in combination. The water-soluble organic solvent used in the coenzyme Q ₁₀ solution (A) and the water-soluble organic solvent used in the aqueous solution (B) of the water-soluble organic solvent are industrially preferable, but are different. There is no problem. In at least one of the coenzyme Q ₁₀ solution (A) and the water-soluble organic solvent in an aqueous solution (B), it is preferable to select alcohols as the water-soluble organic solvent, coenzyme Q ₁₀ solution (A) and the water-soluble organic It is more preferable to select alcohols in both the aqueous solution (B) of the solvent.

Concentration of coenzyme _{Q 10} in coenzyme _{Q 10} solution (A) is based on the weight of the total solution, 30 wt% or more, is required to be 80 wt% or less. Coenzyme When Q ₁₀ concentration of coenzyme Q ₁₀ in a solution (A) is less than 30 wt% will become granulated particles diameter of several μm~ several tens μm approximately obtained and fine, the normal crystallization A similar slurry is formed. On the other hand, when the concentration of coenzyme Q ₁₀ in coenzyme Q ₁₀ solution (A) is higher than 80 wt%, or obtained 1mm greater than large particles, easily obtained hard particles as not collapse or To do. Concentration of coenzyme _{Q 10} in coenzyme _{Q 10} solution (A) is preferably about 35% or more, particularly at preferably about 40% or more, and preferably about 75% or less, particularly preferably more than about 70% It is. In the present invention, by the concentration of coenzyme Q ₁₀ in coenzyme Q ₁₀ solution (A) within the above range, it is possible to produce a reduced coenzyme Q ₁₀ particles having a preferred particle size and firmness.

Is not particularly restricted but a process of preparing the coenzyme Q ₁₀ solution (A), coenzyme Q ₁₀ and a water-soluble organic solvent containing the reduced coenzyme Q ₁₀ for the preparation by mixing and dissolving the above concentration range Although but a general, after dissolving coenzyme Q ₁₀ containing a large amount of oxidized coenzyme Q ₁₀ or oxidized coenzyme Q _10, water-soluble organic solvent, an oxidized coenzyme to implement the reduction reaction the Q ₁₀ may be used for what it was converted to reduced coenzyme Q _10. Moreover, coenzyme Q ₁₀ solution used in the production method of the present invention (A) is made of a coenzyme Q ₁₀ and a water-soluble organic solvent containing the reduced coenzyme Q _10, the granules formed Other components may be included in an amount that does not interfere with the above.

  In the production method of the present invention, the mixing ratio of the water-soluble organic solvent and water in the aqueous solution (B) of the water-soluble organic solvent is not particularly limited. However, when the concentration of the water-soluble organic solvent in the aqueous solution (B) of the water-soluble organic solvent is low, the amount of scaling to the can wall and the stirring shaft is slightly increased, and large particles exceeding several mm are obtained. On the other hand, when the concentration of the water-soluble organic solvent is high, the particle size of the granulated material to be precipitated tends to be small, and the powder physical properties such as fluidity of the resulting granulated material tend to be somewhat worse. is there. From this viewpoint, the concentration of the water-soluble organic solvent in the aqueous solution (B) of the water-soluble organic solvent is preferably in the range of about 60 to 95% by weight, but more preferably about 65% by weight from the viewpoint of obtaining an appropriate particle size. % Or more, more preferably about 70% by weight or more, more preferably about 90% by weight or less, and still more preferably about 85% by weight or less. In addition, the aqueous solution (B) of the water-soluble organic solvent may contain a small amount of other water-soluble components as long as the granule formation is not hindered.

In the present invention, the coenzyme Q ₁₀ solution (A), by adding to the aqueous solution (B) of the water-soluble organic solvent, to produce coenzyme Q ₁₀ particles. Adding the coenzyme Q ₁₀ solution (A) in an aqueous solution of a water-soluble organic solvent (B), that is, the granulation step will be described below.

The temperature of the coenzyme Q ₁₀ solution (A) in the granulation step, it is sufficient coenzyme Q ₁₀ is dissolved in a water-soluble organic solvent at a predetermined concentration, varies depending on the kind and amount of the water-soluble organic solvent used Therefore, although not particularly limited, the temperature of the coenzyme Q ₁₀ solution upon addition (a) is preferably from about 40 ° C. or more, more preferably about 45 ° C. or more, and less preferably about 70 ° C., and more preferably Is about 60 ° C. or less.

The temperature of the aqueous solution of the water-soluble organic solvent in the granulating step (B), water-soluble organic solvent of the type and amount of the water-soluble organic solvent of coenzyme Q ₁₀ solution (A), aqueous solution of a water-soluble organic solvent (B) Although it depends on the type and the like, it must be in the range of 25 ° C. or lower. From the viewpoint of suppressing the production of fine particles and increasing the yield, the temperature is preferably as low as possible, and more preferably about 20 ° C. or less. The lower limit of the temperature in the granulation step is the solidification temperature of the system, but is preferably −10 ° C. or higher, more preferably about −5 ° C. or higher, and particularly preferably about 0 ° C. or higher.

The addition of coenzyme Q ₁₀ solution in the granulation step (A) (dropwise) is not particularly limited as method, an aqueous solution of a water-soluble organic solvent (B) adding coenzyme Q ₁₀ solution (A) from the top of the (dropping) may be, by introducing nozzle into the aqueous solution of a water-soluble organic solvent (B), coenzyme Q ₁₀ solution (a) may be added directly to the water-soluble organic solvent of the aqueous solution (B). However, from the viewpoint of suppressing the generation of fine particles, preferably from the top of an aqueous solution of a water-soluble organic solvent (B) to add coenzyme Q ₁₀ solution (A) (dropwise).

Depending on the conditions such as the temperature of the granulation tank, dropwise and simultaneously solidified coenzyme Q ₁₀ solution (A) (Granulation) but may proceed, there is no particular problem even if the.

The granulation step is usually preferably carried out under forced flow. Usually, the required power for stirring per unit volume is preferably about 0.01 kW / m ³ or more, more preferably about 0.1 kW / m ³ , although it depends on the particle size of the target coenzyme Q ₁₀ particles. As mentioned above, it implements on the conditions of about 0.3 kW / m < ³ > or more more preferably. 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 using a method of circulating liquid may be considered.

Addition of granulation step when the coenzyme Q ₁₀ solution (A) (dropping) rate is not particularly limited, for example, the total amount is added in a unit time (1 hour) per coenzyme Q ₁₀ solution (A) (dropwise ) it is preferable to be less than the speed (100% weight / time) is, more preferably, the rate (50% weight to about 50% weight per unit of time coenzyme _{Q 10} solution (a) is added (dropwise) / hour) or less, more preferably, the rate of about 25% weight per unit of time coenzyme _{Q 10} solution (a) is added (dropwise) (25% weight / hour) or less.

Concentration of coenzyme Q ₁₀ for the entire system in the granulation step is not particularly limited, in general, at the time had been added coenzyme Q ₁₀ solution (A) in an aqueous solution of a water-soluble organic solvent (B) total as the concentration of coenzyme Q ₁₀ for the composition (sum of i.e. coenzyme Q ₁₀ solution (a) and the water-soluble organic solvent in an aqueous solution (B)), preferably from about 50 wt% or less, more preferably less than about 40 wt% More preferably, the content is adjusted to about 30% by weight or less. The lower limit of the concentration of coenzyme Q ₁₀ for the entire system is not particularly limited, from the viewpoint of productivity, the concentration of coenzyme Q ₁₀ is usually about 1 wt% or more, preferably about 2 wt% or more .

Granulating step when the granulation system the weight ratio of the water-soluble organic solvent and water in (a mixture of an aqueous solution of a water-soluble organic solvent (B) is added and the coenzyme Q ₁₀ solution (A)) is not particularly limited, concrete The concentration of the water-soluble organic solvent in the whole grain system is preferably in the range of about 60 to 95% by weight, more preferably about 65% by weight or more, further preferably about 70% by weight or more, and more preferably about 90% by weight. % By weight or less, more preferably about 85% by weight or less. During the granulation step, by adding coenzyme Q ₁₀ solution (A) in an aqueous solution of a water-soluble organic solvent (B), the concentration of the water-soluble organic solvent for granulation system increases, but still a within the above preferred ranges so that, in advance, it may be determined a water-soluble organic solvent concentration of ratio or a water-soluble organic solvent in an aqueous solution of coenzyme Q ₁₀ solutions (a) and the water-soluble organic solvent in an aqueous solution (B) (B) In order to keep the weight ratio of the granulated water-soluble organic solvent and water constant, water may be added separately during granulation.

  On the other hand, when fine particles of about several tens of μm or less are produced during granulation, a water-soluble organic solvent may be added to the system at the end of granulation to dissolve the produced fine particles. When there is much, it is preferable to add a water-soluble organic solvent.

The thus obtained coenzyme Q ₁₀ particles (granulated material) are preferably subjected to solid-liquid separation by, for example, centrifugation, pressure filtration, vacuum filtration, etc., and cake washing is performed as necessary. It can be obtained as a dry body by drying under reduced pressure (vacuum drying), and is preferably obtained as a dry body.

  Moreover, in order to make a particle diameter more uniform, the obtained granule may be classified using a sieve or the like, if necessary.

Since reduced coenzyme Q ₁₀ is readily oxidized by atmospheric oxygen, a series of operations in the production process of the present invention is preferably carried out under an oxygen 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.

With the production method of the present invention, it is a method suitable for production on an industrial scale, and has a uniform and appropriate particle size of about 100 to 1000 μm without causing scaling to a stirring blade or can wall, food, food with nutrient function claims, food for specified health use, nutritional supplement, nutritional, animal drug, drink, feed, cosmetics, pharmaceuticals, therapeutic agents, the workable firmness in prophylactic etc., the reduced coenzyme Q ₁₀ Coenzyme Q ₁₀ particles can be produced.

Hereinafter, the present invention will be described in more detail with reference to production examples and examples, but the present invention is not limited thereto. Incidentally, oxidized coenzyme Q ₁₀ used in the following examples, were used those manufactured by Kaneka Corporation (purity 99.5%). Further, the purity of the oxidized coenzyme _{Q 10} and reduced coenzyme _{Q 10,} the ratio of reduced coenzyme _{Q 10} / oxidized coenzyme _{Q 10} (weight ratio) was determined by the following HPLC analysis.

(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 and 60 g of L-ascorbic acid were added and stirred at 78 ° C. to carry out a reduction reaction. After 30 hours, the mixture was cooled to 50 ° C., and 1000 g of hexane and 1000 g of degassed water were added while maintaining the same temperature. After cooling to 25 ° C., the aqueous phase was removed, and further washed with 1000 g of deaerated saturated brine 1000 times to remove the aqueous phase. All the above operations were performed under a nitrogen atmosphere. From this hexane solution, hexane was distilled off at 48 ° C. under reduced pressure to obtain an oily reduced coenzyme Q ₁₀ (about 100 g). To the resulting reduced coenzyme _{Q 10,} the ethanol 100g added and dissolved at 50 ° C.. The reduced coenzyme Q ₁₀ / ethanol solution is dropped into 1000 g of 80 wt% ethanol aqueous solution at 2 ° C. in a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ³ . gave a coenzyme _{Q 10} granule. The granulated product was filtered under reduced pressure, further 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 further dried under reduced pressure (20-40 ° C., 1-30 mmHg). by to yield a white coenzyme _{Q 10} granules 97 g (Yusugata yield 97 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ of the obtained granule was 99.5 / 0.5, and the purity of reduced coenzyme Q ₁₀ was 99.2%. Moreover, 90% of the obtained granulated material was granular having a diameter of about 200 to 700 μm, and it was hard enough to be easily broken by pressing with a finger.

(Example 2)
The aqueous ethanol solution to be used, except for changing the intended concentration of 70 wt%, by performing the reduction and granulation in all the same manner as in Example 1 to obtain a granulated body 98g of coenzyme Q ₁₀ (Yes Appearance yield 98 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ of the obtained granule was 99.5 / 0.5, and the purity of reduced coenzyme Q ₁₀ was 99.2%. Moreover, 85% of the obtained granulated body was a granule having a diameter of about 300 to 1000 μm, and it was hard enough to be easily broken by pressing with a finger.

(Example 3)
Except that the aqueous ethanol solution used was changed to one having a concentration of 90% by weight, 97 g of granulated body of coenzyme Q10 was obtained by performing reduction and granulation in the same manner as in Example 1 (solid) Yield 97 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ of the obtained granule was 99.5 / 0.5, and the purity of reduced coenzyme Q ₁₀ was 99.2%. Further, 80% of the obtained granulated body was a granule having a diameter of about 100 to 500 μm, and it was hard enough to be easily broken by pressing with a finger.

(Comparative Example 1)
In 1000 g of ethanol, 100 g of oxidized coenzyme Q ₁₀ and 60 g of L-ascorbic acid were added and stirred at 78 ° C. to carry out a reduction reaction. After 30 hours, the mixture was cooled to 50 ° C., and 1000 g of hexane and 1000 g of degassed water were added while maintaining the same temperature. After cooling to 25 ° C., the aqueous phase was removed, and further washed with 1000 g of deaerated saturated brine 1000 times to remove the aqueous phase. All the above operations were performed under a nitrogen atmosphere. From this hexane solution, 48 ° C., distilling off hexane under reduced pressure to give reduced coenzyme Q ₁₀ oil. This oily substance was dropped into 1000 g of a 50 wt% ethanol aqueous solution at 2 ° C. under a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ^3, thereby reducing reduced coenzyme Q. ₁₀ was crystallized. The obtained crystals were 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 further dried under reduced pressure (20 to 40 ° C., 1 to 30 mmHg) to obtain 93 g of white dry crystals (solid yield 93 mol%). About 90% of the obtained crystals are granular having a diameter of about 1.5 to 2 mm, and the weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ is 99.5 / 0.5. the purity of the Q ₁₀ was 99.2%, and hardness is do not readily collapse simply pressing with a finger.

Example 4
10 g of the crystals (reduced coenzyme Q ₁₀ 99.2%) obtained in Comparative Example 1 were dissolved in 10 g of acetone at 50 ° C. By dropping this coenzyme Q ₁₀ / acetone solution into 100 g of a 70 wt% acetone aqueous solution at 2 ° C. in a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ³ . to obtain a coenzyme _{Q 10} granulation body. The granulated product was filtered under reduced pressure and dried under reduced pressure (20 to 40 ° C., 1 to 30 mmHg) to obtain 9.8 g of white coenzyme Q ₁₀ granulated product (solid yield: 98 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ of the obtained granule was 99.4 / 0.6, and the purity of reduced coenzyme Q ₁₀ was 99.1%. Moreover, 60% of the obtained granulated body was a granule having a diameter of about 100 to 400 μm, and it was hard enough to be easily broken by pressing with a finger.

(Example 5)
10 g of the crystals (reduced coenzyme Q ₁₀ 99.2%) obtained in Comparative Example 1 were dissolved in 10 g of ethanol at 50 ° C. By dropping this coenzyme Q ₁₀ / ethanol solution into 100 g of 80 wt% ethanol aqueous solution at 2 ° C. in a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ³ , It was obtained coenzyme _{Q 10} granulation body. The granulated product was filtered under reduced pressure and dried under reduced pressure (20 to 40 ° C., 1 to 30 mmHg) to obtain 9.8 g of white coenzyme Q ₁₀ granulated product (solid yield: 98 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ of the obtained granule was 99.4 / 0.6, and the purity of reduced coenzyme Q ₁₀ was 99.1%. In addition, 90% of the obtained granulated body was granular having a diameter of about 100 to 600 μm, and it was hard enough to be easily broken by pressing with a finger.

(Example 6)
10 g of the crystals (reduced coenzyme Q ₁₀ 99.2%) obtained in Comparative Example 1 were dissolved in 10 g of acetone at 50 ° C. By dropping this coenzyme Q ₁₀ / acetone solution into 100 g of an aqueous 85 wt% ethanol solution at 2 ° C. in a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ³ . to obtain a coenzyme _{Q 10} granulation body. The granulated product was filtered under reduced pressure and dried under reduced pressure (20 to 40 ° C., 1 to 30 mmHg) to obtain 9.8 g of white coenzyme Q ₁₀ granulated product (solid yield: 98 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ of the obtained granule was 99.4 / 0.6, and the purity of reduced coenzyme Q ₁₀ was 99.1%. In addition, 90% of the obtained granulated body was granular having a diameter of about 100 to 600 μm, and it was hard enough to be easily broken by pressing with a finger.

(Example 7)
5 g of oxidized coenzyme Q _{10 and} 5 g of the crystals obtained in Comparative Example 1 (reduced coenzyme Q ₁₀ 99.2%) were dissolved in 10 g of ethanol at 60 ° C. By dropping this coenzyme Q ₁₀ / ethanol solution into 500 g of an aqueous 85 wt% ethanol solution at 2 ° C. in a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ³ , It was obtained coenzyme _{Q 10} granulation body. The granulated product was filtered under reduced pressure and dried under reduced pressure (20 to 40 ° C., 1 to 30 mmHg) to obtain 9.8 g of a yellow coenzyme Q ₁₀ granulated product (solid yield 98 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained granule was 49.4 / 50.6. Moreover, 70% of the obtained granulated body was a granule having a diameter of about 100 to 600 μm, and it was hard enough to be easily broken by pressing with a finger.

(Example 8)
4.5 g of oxidized coenzyme Q ₁₀ and 0.5 g of the crystals obtained in Comparative Example 1 (reduced coenzyme Q ₁₀ 99.2%) were dissolved in 10 g of ethanol at 60 ° C. By dropping this coenzyme Q ₁₀ / ethanol solution into 500 g of an aqueous 85 wt% ethanol solution at 2 ° C. in a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ³ , It was obtained coenzyme _{Q 10} granulation body. The granulated body was filtered under reduced pressure, vacuum drying (20 to 40 ° C., 1～30MmHg) by to afford the coenzyme _{Q 10} granules 9.8g orange (Yusugata 98 mole% yield). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q _{10 in} the obtained granule was 9.7 / 90.3. Further, 70% of the obtained granulated body was granular having a diameter of about 100 to 700 μm, and it was hard enough to be easily broken by pressing with a finger.

(Comparative Example 2)
₁₀ g of oxidized coenzyme Q ₁₀ was dissolved in 130 g of ethanol at 50 ° C. When this oxidized coenzyme Q ₁₀ / ethanol solution was dropped into 200 g of an 80 wt% ethanol aqueous solution at 2 ° C. in a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ³ . , crystal of oxidized coenzyme Q ₁₀ was obtained. The crystals were filtered under reduced pressure, vacuum drying (20 to 40 ° C., 1～30MmHg) by to afford the oxidized coenzyme _{Q 10} crystal 9.8g orange (Yusugata 98 mole% yield). In addition, 90% of the obtained crystals were very fine crystals having a diameter of about 10 μm.

Example 9
10 g of the crystals (reduced coenzyme Q ₁₀ 99.2%) obtained in Comparative Example 1 were dissolved in 2.5 g of ethanol at 60 ° C. By dropping this coenzyme Q ₁₀ / ethanol solution into 200 g of 85 wt% ethanol aqueous solution at 2 ° C. in a nitrogen atmosphere over 1 hour while stirring at a required power of stirring of 0.3 kW / m ³ , It was obtained coenzyme _{Q 10} granulation body. The granulated product was filtered under reduced pressure and dried under reduced pressure (20 to 40 ° C., 1 to 30 mmHg) to obtain 9.8 g of white coenzyme Q ₁₀ granulated product (solid yield: 98 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ of the obtained granule was 99.4 / 0.6, and the purity of reduced coenzyme Q ₁₀ was 99.1%. In addition, 90% of the obtained granulated material was granular having a diameter of about 100 to 700 μm, and it was hard enough to be easily broken by pressing with a finger.

(Example 10)
10 g of the crystals (reduced coenzyme Q ₁₀ 99.2%) obtained in Comparative Example 1 were dissolved in 23 g of ethanol at 50 ° C. By dropping the coenzyme Q ₁₀ / ethanol solution into 200 g of a 75 wt% ethanol aqueous solution at 2 ° C. in a nitrogen atmosphere over 2 hours while stirring at a required power of stirring of 0.3 kW / m ³ , It was obtained coenzyme _{Q 10} granulation body. The granulated product was filtered under reduced pressure and dried under reduced pressure (20 to 40 ° C., 1 to 30 mmHg) to obtain 9.8 g of white coenzyme Q ₁₀ granulated product (solid yield: 98 mol%). The weight ratio of reduced coenzyme Q ₁₀ / oxidized coenzyme Q ₁₀ of the obtained granule was 99.4 / 0.6, and the purity of reduced coenzyme Q ₁₀ was 99.1%. Further, 70% of the obtained granulated body was granular having a diameter of about 100 to 400 μm, and it was hard enough to be easily broken by pressing with a finger.

Claims (8)

And coenzyme Q ₁₀ 30 to 80 wt% containing reduced coenzyme Q _10, coenzyme Q ₁₀ solution consisting of 70 to 20% by weight of a water-soluble organic solvent (A),
In an aqueous solution (B) of a water-soluble organic solvent at 25 ° C. or lower,
A method for producing coenzyme Q ₁₀ particles , comprising:
The water-soluble organic solvent used for the coenzyme Q ₁₀ solution (A) is ethanol and / or acetone, and the water-soluble organic solvent used for the aqueous solution (B) of the water-soluble organic solvent is ethanol and / or acetone. Method for producing enzyme Q ₁₀ particles .   The method according to claim 1, wherein the aqueous solution (B) of the water-soluble organic solvent is an aqueous solution of the water-soluble organic solvent having a concentration of 60 to 95% by weight. The method according to claim 1 or 2, wherein the aqueous solution (B) of the water-soluble organic solvent is an ethanol aqueous solution having a concentration of 80 to 95% by weight . Water-soluble organic solvent used in the coenzyme Q ₁₀ solution (A) and water-soluble organic solvent in an aqueous solution (B) are both ethanol, coenzyme Q ₁₀ according to any one of claims 1 to 3 Particle production method . The process according to coenzyme Q ₁₀ is, any one of claims 1 to 4, which is a coenzyme Q ₁₀ containing 10 wt% or more of reduced coenzyme Q ₁₀ containing reduced coenzyme Q ₁₀ . When adding coenzyme Q ₁₀ solution (A) in an aqueous solution of a water-soluble organic solvent (B), claim added under forced flow of 0.01 kW / m ³ or more as a power required for stirring per unit volume 1 6. The production method according to any one of 5 above. Complement addition rate of the enzyme Q ₁₀ solution (A) The production method according to any one of claims 1 to 6 or less to 100% weight / time of coenzyme Q ₁₀ solution (A). The process according to any one of claims 1 to 7 carried out under deoxygenated atmosphere.