JP2009149584A - Reduced coenzyme q10-containing particulate composition and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To propose a reduced coenzyme Q10-containing particulate composition that exhibits both high oxidation stability and high bioabsorbability in the fields of foods, nutrient functional foods, foods for specific health care, nutritional supplements, nutrients, animal drugs, drink, fodder, cosmetics, pharmaceuticals, therapeutic agents, prophylactic agents, and the like, its manufacturing method and its stabilization method. <P>SOLUTION: A particulate composition comprising a matrix mainly composed of a water-soluble excipient and, polydispersed by forming domains therein, an oily component containing a reduced coenzyme Q10 and a lipophilic antioxidant is found to be a composition that exhibits both high oxidation stability and high oral absorbability. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a particulate composition containing reduced coenzyme Q10 and a method for producing the same. More specifically, the present invention realizes a particulate composition containing reduced coenzyme Q10 having both high oxidative stability and high oral absorbability, a method for producing the same, and high oxidative stability and high oral absorbability. The present invention relates to a preparation form.

  Coenzyme Q is an essential component widely distributed in living organisms from bacteria to mammals. In humans, it is known that the side chain of coenzyme Q has 10 repeating structures and coenzyme Q10 is the main component. Coenzyme Q10 is a physiological component that exists as a constituent component of the mitochondrial electron transport system in cells in the living body, and plays a role as a transport component in the electron transport system by repeating oxidation and reduction in the living body. .

  Coenzyme Q10 is known to exhibit energy production, membrane stabilization and antioxidant activity in living bodies, and its usefulness is wide. Coenzyme Q10 has an oxidized type and a reduced type, and it is known that about 40 to 90% is usually present in reduced form in vivo. Among the coenzymes Q10, oxidized coenzyme Q10 (also known as ubiquinone or ubidecalenone) is used for pharmaceutical use as a congestive heart failure drug, and for non-medical use as well as vitamins. Widely used as an agent.

  On the other hand, reduced coenzyme Q10 exhibits higher oral absorbability than oxidized coenzyme Q10, and food, nutritional functional food, food for specified health use, nutritional supplement, nutritional supplement, animal drug, beverage, feed, cosmetics, It is an excellent compound that is effective as a pharmaceutical, therapeutic, prophylactic and the like. However, reduced coenzyme Q10 is easily oxidized to oxidized coenzyme Q10 by molecular oxygen, and reduced coenzyme Q10 is converted into food, nutritional functional food, food for specified health use, nutritional supplement, nutritional supplement, animal drug, Stabilization of beverages, feeds, cosmetics, pharmaceuticals, therapeutic drugs, preventive drugs, etc. or their materials and compositions and / or handling after processing remains an important issue. During the above handling, it is extremely difficult to completely remove or block oxygen. Especially in heating during processing and long-term storage, the remaining or mixed oxygen has a great adverse effect, and the quality such as by-product of oxidized coenzyme Q10. Directly related to the problem of the surface.

  Thus, maintaining the reduced coenzyme Q10 stably (protecting from oxidation) is a very important issue, but research on a method and a composition for stably holding the reduced coenzyme Q10 up to now. There has been little done. There are a few examples describing the stabilization method in which a reducing agent coexists, a storage method and its composition (Patent Document 1: WO 03/32967) and an example of stabilizing reduced coenzyme Q10 in fats and oils. (Patent Document 2: WO 03/62182).

  Patent Document 1 discloses a method for stabilizing reduced coenzyme Q10 by coexisting reduced coenzyme Q10 and ascorbic acids in the presence of a monovalent or divalent alcohol and / or a water-soluble solvent other than alcohol. A storage method and the above composition are disclosed. However, in the method described in Patent Document 1, there is a problem that usable solvents are limited.

  In Patent Document 2, as a method for protecting reduced coenzyme Q10 from oxidation, reduced coenzyme Q10 is composed mainly of fats and oils (however, excluding olive oil) and / or polyol, and reduced type. A method for stabilizing reduced coenzyme Q10 is disclosed, which is characterized in that the composition does not substantially inhibit the stabilization of coenzyme Q10. In the above-described stabilization method, the stability of reduced coenzyme Q10 is stabilized. Sometimes sex is not enough.

In Patent Document 3 (WO01 / 52822),
1) Reduced coenzyme Q10, an amount of reducing agent effective to suppress oxidation of reduced coenzyme Q10 to oxidized coenzyme Q10, and dissolving the reduced coenzyme Q10 and the reducing agent A composition comprising an effective amount of a surfactant or vegetable oil or a mixture thereof, and optionally a solvent,
2) A composition for oral administration in which the above composition is formulated into a gelatin capsule or tablet;
3) A method for preparing the above-described composition containing reduced coenzyme Q10 in situ using oxidized coenzyme Q10 and a reducing agent is disclosed.

  However, although Patent Document 3 describes the production method or composition, the quality of reduced coenzyme Q10 contained in the composition (for example, the weight of reduced coenzyme Q10 and oxidized coenzyme Q10) Ratio) and the like, and although there is a description that the reduced coenzyme Q10 is stabilized, there is no detailed description about the stabilizing effect, etc., and there is no example, and how much stabilization It is not clear whether or not

  Furthermore, the compositions described in Patent Documents 1 to 3 are limited to liquid compositions, but the liquid compositions are quality control in terms of transportation and hygiene compared to solid particulate compositions. There is a problem that becomes more difficult.

  There is also a prior document that discloses the addition of a water-soluble reducing agent such as ascorbic acid to a composition containing reduced coenzyme Q10 (Patent Document 4: WO05 / 097091). Since Q10 is fat-soluble, it is not only limited to use in a solvent (for example, ethanol) system that dissolves both, but it is also a liquid composition.

Under such circumstances, there has been a demand for a reduced coenzyme Q10-containing composition that is a particulate composition and is stable against oxidation.
WO03 / 32967 WO03 / 062182 WO01 / 52822 WO05 / 097091

  In order to provide a solution to the above points, the present invention is in the fields of foods, nutritional functional foods, foods for specified health use, nutritional supplements, nutrients, animal drugs, beverages, feeds, cosmetics, pharmaceuticals, therapeutic drugs, preventive drugs, etc. An object of the present invention is to propose a particulate composition containing reduced coenzyme Q10 having both high oxidative stability and high oral absorbability, a method for producing the same, and a preparation form for realizing high oxidative stability .

  As a result of intensive studies to solve the above problems, the present inventors have found that an oily component containing reduced coenzyme Q10 and a lipophilic antioxidant forms a domain in a matrix composed of a water-soluble excipient. The polydispersed particulate composition is a composition having both high oxidative stability and high oral absorbability, and a manufacturing method and a preparation form for obtaining such a particulate composition are found. The invention has been completed.

That is, the present invention provides the following:
[1] A particulate composition in which an oily component (A) containing reduced coenzyme Q10 and a lipophilic antioxidant forms a domain and is polydispersed in a matrix mainly composed of a water-soluble excipient. object.
[2] The particulate composition according to [1], wherein the lipophilic antioxidant is an ascorbic acid fatty acid ester.
[3] The particulate composition according to [1] or [2], wherein the sphericity is 0.8 or more.
[4] The particulate composition according to any one of [1] to [3], wherein 10% by weight or more of the reduced coenzyme Q10 in the particulate composition is not in a crystalline state.
[5] The particulate composition according to any one of [1] to [4], wherein the oily component (A) is polydispersed by forming 5 or more domains.
[6] Any of [1] to [5], wherein the ratio of the reduced coenzyme Q10 and the lipophilic antioxidant in the particulate composition is in the range of 100: 1 to 1: 5 by weight. A particulate composition as described in 1.
[7] In any one of [1] to [6], the water-soluble excipient is one or more selected from the group consisting of a water-soluble polymer, a surfactant (C), a sugar, and a yeast cell wall. The particulate composition described.
[8] The water-soluble polymer is gum arabic, gelatin, agar, starch, pectin, carrageenan, casein, dried egg white, curdlan, alginic acid, soybean polysaccharide, pullulan, celluloses, xanthan gum, carmellose salt, and polyvinylpyrrolidone. The particulate composition according to [7], which is one or more selected from the group consisting of:
[9] The particulate composition according to [7], wherein the sugar is at least one selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, sugar alcohols, and polysaccharides.
[10] The oily component (A) containing reduced coenzyme Q10 is 5 to 99.95% by weight of coenzyme Q10, 0.05 to 95% by weight of a lipophilic antioxidant, 0 to 94.95% by weight. The particulate composition according to any one of [1] to [9], comprising 1% oil and fat, and 0 to 94.95% by weight surfactant (D).
[11] The particulate composition according to any one of [1] to [10], wherein the content of reduced coenzyme Q10 in the particulate composition is 1 to 70% by weight.
[12] The particulate composition according to any one of [1] to [11], wherein the volume average particle diameter is 1 to 1000 μm.
[13] The particulate composition according to any one of [1] to [12], wherein an average particle diameter of a domain formed by the oily component (A) containing reduced coenzyme Q10 is 0.01 to 50 μm. .
[14] The retention rate of reduced coenzyme Q10 in the particulate composition after storage for 30 days under light-shielding conditions at 40 ° C., 75% relative humidity is 80% by weight or more [1] to [13] A particulate composition according to any one of the above.
[15] A capsule, tablet, chewable tablet, food, beverage or cosmetic obtained by processing the particulate composition according to any one of [1] to [14].
[16] The particulate composition described in any one of [1] to [14] or the capsule, tablet, chewable tablet, food, beverage or cosmetic according to [15] A method for stabilizing a particulate composition or capsule, tablet, chewable tablet, food, beverage or cosmetic containing reduced coenzyme Q10, which is characterized in that
[17] The particulate composition described in any one of [1] to [14] or the capsule, tablet, chewable tablet, food, beverage, or cosmetic described in [15] is made of glass, plastic, and / or Alternatively, a method of stabilizing a particulate composition or capsule, tablet, chewable tablet, food, beverage, or cosmetic containing reduced coenzyme Q10, which is packed and packed with a metal material.
[18] The stabilization method according to [16] or [17], wherein a dampproofing agent is used in combination.
[19] An oil-in-water emulsion composition is prepared from an aqueous solution containing a water-soluble excipient and an oil component (a) containing coenzyme Q10 and a lipophilic antioxidant, and further an oil-in-water emulsion composition The manufacturing method of the particulate composition containing reduced coenzyme Q10 characterized by removing the water | moisture content in it.
[20] The production method according to [19], wherein reduced coenzyme Q10 is used as coenzyme Q10 contained in the oily component (a).
[21] In the process of producing a particulate composition using oxidized coenzyme Q10 or a mixture of oxidized coenzyme Q10 and reduced coenzyme Q10 as coenzyme Q10 contained in the oily component (a), [19] The production method according to [19], wherein at least part of oxidized coenzyme Q10 in coenzyme Q10 is reduced to reduced coenzyme Q10.
[22] The production method according to any one of [19] to [21], wherein the lipophilic antioxidant is an ascorbic acid fatty acid ester.
[23] The oil-in-water emulsion composition is suspended in the oil component (B), and then the water in the oil-in-water emulsion composition is removed in the oil component (B). [19] The production method according to any one of [22].
[24] The production method according to [23], wherein the oil component (B) contains 5 to 99.99% by weight of a fat and oil and 0.01 to 95% by weight of a surfactant (E).
[25] The oil-in-water emulsion composition is spray-dried in a gas phase to remove water in the oil-in-water emulsion composition, according to any one of [19] to [22] Manufacturing method.
[26] The production method according to any one of [19] to [25], wherein the obtained granular composition has a sphericity of 0.8 or more.
[27] The production method according to any one of [19] to [26], wherein 1 to 500 parts by weight of water-insoluble ascorbic acid is used for 100 parts by weight of coenzyme Q10.
[28] The water-soluble excipient is one or more selected from the group consisting of a water-soluble polymer, a surfactant (C), a sugar, and a yeast cell wall, [19] to [27] The manufacturing method as described.
[29] The water-soluble polymer is gum arabic, gelatin, agar, starch, pectin, carrageenan, casein, dried egg white, curdlan, alginic acid, soybean polysaccharide, pullulan, cellulose, xanthan gum, carmellose salt, and polyvinylpyrrolidone. The production method according to [28], which is one or more selected from the group consisting of:
[30] The production method according to [28], wherein the sugar is at least one selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, sugar alcohols, and polysaccharides.
[31] The oil component (a) containing coenzyme Q10 is 5 to 99.95% by weight of coenzyme Q10, 0.05 to 95% by weight of lipophilic antioxidant, 0 to 94.95% by weight. The production method according to any one of [19] to [30], comprising an oil and fat and 0 to 94.95% by weight of a surfactant (D).

  The present invention provides a particulate composition containing reduced coenzyme Q10 having high oxidative stability, a method for producing the same, and a preparation form for realizing high oxidative stability and high oral absorption. The particulate composition containing the reduced coenzyme Q10 of the present invention is particularly excellent in oxidative stability under high humidity such as a relative humidity of 75%.

  First, the particulate composition of the present invention will be described. The particulate composition of the present invention is polydispersed by forming a domain of oily component (A) containing reduced coenzyme Q10 and a lipophilic antioxidant in a matrix mainly composed of a water-soluble excipient. It is the particulate composition characterized by having carried out.

  The reduced coenzyme Q10 contained in the granular particle composition of the present invention is represented by the following formula (1).

As described above, coenzyme Q10 has a reduced form and an oxidized form, and the particulate composition of the present invention contains reduced coenzyme Q10 among the coenzyme Q10. It is a composition. The reduced coenzyme Q10 contained in the particulate composition of the present invention may be reduced type alone or coenzyme Q10 which is a mixture of oxidized coenzyme Q10 and reduced coenzyme Q10. good. When the particulate composition of the present invention contains both reduced coenzyme Q10 and oxidized coenzyme Q10, the reduced coenzyme Q10 is the total amount of coenzyme Q10 (that is, reduced coenzyme Q10 and oxidized coenzyme). The ratio of the total amount of enzyme Q10) is not particularly limited, but is, for example, about 20% by weight or more, usually about 40% by weight or more, preferably about 60% by weight or more, more preferably about 80% by weight or more, especially about 90%. % By weight, above all about 96% by weight. The upper limit is 100% by weight and is not particularly limited, but is usually about 99.9% by weight or less. In the present specification, when simply described as “coenzyme Q10”, unless otherwise specified, a mixture of oxidized coenzyme Q10 and reduced coenzyme Q10 is shown. When the enzyme Q10 is present alone (or used alone), when used, it may mean reduced coenzyme Q10 alone or oxidized coenzyme Q10 alone, respectively.

  The reduced coenzyme Q10 contained in the particulate composition of the present invention may be derived from the reduced coenzyme Q10 used as a raw material when preparing the particulate composition, or the particulate composition The oxidized coenzyme Q10 used as a raw material (or part thereof) for preparing a product may be reduced coenzyme Q10 reduced in the production process. When reduced coenzyme Q10 is used as a raw material when preparing the particulate composition of the present invention, the reduced coenzyme Q10 is synthesized, for example, as described in JP-A-10-109933. After obtaining coenzyme Q10 which is a mixture of oxidized coenzyme Q10 and reduced coenzyme Q10 by a conventionally known method such as fermentation or extraction from natural products, the reduced form in the effluent is obtained using chromatography. It can be produced by a method of concentrating the coenzyme Q10 section. In this case, the oxidized coenzyme Q10 contained in the coenzyme Q10 is reduced using a general reducing agent such as sodium borohydride, sodium dithionite (sodium hyposulfite), and then chromatographed. Concentration by may be performed. Reduced coenzyme Q10 can be obtained by allowing the above reducing agent to act on existing high-purity oxidized coenzyme Q10.

  Preferably, the existing high-purity oxidized coenzyme Q10 or coenzyme Q10, which is a mixture of oxidized coenzyme Q10 and reduced coenzyme Q10, is replaced with a common reducing agent such as hydrosulfite sodium (sodium hyposulfite ), Sodium borohydride, ascorbic acid, and the like, and obtained by reduction in a large amount of solvent such as ethanol. More preferably, the existing high-purity oxidized coenzyme Q10 or oxidized coenzyme is used. It is obtained by reducing coenzyme Q10, which is a mixture of enzyme Q10 and reduced coenzyme Q10, using ascorbic acids.

  The lipophilic antioxidant to be contained (or used) in the particulate composition of the present invention is not particularly limited as long as it is lipophilic (oil-soluble) and has antioxidant ability, food or medicine, etc. Ascorbyl fatty acid such as ascorbyl palmitate, ascorbyl tetraisopalmitate, ascorbyl isopalmitate, ascorbyl stearate, ascorbyl diisopalmitate, ascorbyl dibutyrate, ascorbyl tetrahexyl decanoate, etc. In addition to esters, vitamin A, tocopherol, tocotrienol, hydrophobic flavonoids, lycopene, lutein, astaxanthin, zeaxanthin, cryptoxanthin, canthaxanthin, fucoxanthin, violaxanthin and the like can be mentioned. Among these, ascorbic acid fatty acid esters and the like are preferable, and among them, ascorbyl palmitate and ascorbyl stearate are more preferably used from the viewpoints of availability, safety, food experience, and the like. Further, these ascorbic acid fatty esters may be L-form, D-form, or racemate. Needless to say, a plurality of these lipophilic antioxidants may be used in combination.

  The content of the lipophilic antioxidant in the particulate composition of the present invention is not particularly limited as long as it is effective in stabilizing the oxidation of reduced coenzyme Q10 present in the particulate composition, The weight ratio of the content of the reduced coenzyme Q10 and the lipophilic antioxidant in the particulate composition is preferably in the range of 100: 1 to 1: 5, and more preferably 20: 1 to 1: 3. Is more preferably 10: 1 to 1: 2.5, particularly preferably 5: 1 to 1: 2.

  The matrix in the particulate composition of the present invention is a so-called excipient component that is necessary for holding the oil component (A) in the particulate composition and shaping the particle shape. The water-soluble excipient that is the main component of the matrix of the particulate composition of the present invention is not particularly limited, but is selected from the group consisting of water-soluble polymers, surfactants (C), saccharides, and yeast cell walls. It is preferable that they are 1 type, or those mixtures. The water-soluble excipient is not particularly limited as long as it is acceptable for food, cosmetics, and pharmaceutical use, but is preferably acceptable for food.

  Examples of the water-soluble polymer include gum arabic, gati gum, gelatin, agar, starch, pectin, carrageenan, casein, casein compound, dried egg white, curdlan, alginic acids, soybean polysaccharides, pullulan, celluloses, xanthan gum, Carmellose salts (such as carmellose sodium or carmellose calcium), sugar esters of higher fatty acids, tragacanth, milk, etc., water-soluble polymers based on amino acids or / and sugars, or polyvinylpyrrolidone alone Or it can use as a 2 or more types of mixture. Among them, gum arabic, gelatin, agar, starch, pectin, carrageenan, casein, dried egg white, curdlan, alginic acids, soy polysaccharides, pullulan, celluloses, xanthan gum, carmellose salt, and polyvinylpyrrolidone are preferable. Gum arabic, gelatin, and soybean polysaccharide are more preferably used from the viewpoint of obtaining a particulate composition having both handleability or high oxidative stability and high bioabsorbability, which is the object of the present invention.

  The surfactant (C) is not particularly limited as long as it is acceptable for foods, cosmetics, and pharmaceuticals, but is particularly preferably acceptable for foods. For example, glycerin fatty acid esters, sucrose fatty acid esters, Examples include sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, lecithins, and saponins. Needless to say, in the present invention, these can be used alone or as a mixture of two or more.

  Examples of the glycerin fatty acid esters include monoglycerin fatty acid organic acid esters, polyglycerin fatty acid esters, polyglycerin condensed ricinoleic acid esters, and the like. Examples of monoglycerin fatty acid organic acid esters include monoglycerin stearic acid citrate, monoglycerin stearic acid acetate, monoglycerin stearic acid succinic acid ester, monoglycerin caprylic acid succinic acid ester, monoglycerin stearic acid lactate, mono Examples thereof include glyceryl stearic acid diacetyl tartaric acid ester. As polyglycerol fatty acid ester, the average polymerization degree of polyglycerol is 2-10, for example, and a constituent fatty acid is a C6-C22 fatty acid. Examples of the polyglycerol condensed ricinoleic acid ester include those having an average degree of polymerization of polyglycerol of 2 to 10 and an average degree of condensation of polyricinoleic acid (average of the number of condensation of ricinoleic acid) of 2 to 4.

Examples of the sucrose fatty acid esters include those obtained by esterifying one or more hydroxyl groups of sucrose with fatty acids having 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms.
Examples of the sorbitan fatty acid esters include those obtained by esterifying one or more hydroxyl groups of sorbitans with fatty acids having 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms.

  As the polyoxyethylene sorbitan fatty acid esters, at least one hydroxyl group of sorbitans is substituted with a polyoxyethylene chain, and at least one of the existing hydroxyl groups has 6 to 22 carbon atoms, preferably What was esterified with the fatty acid of 6-18 is mentioned.

  Examples of the lecithins include egg yolk lecithin, purified soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, dicetylphosphate, stearylamine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositolamine, cardiolipin, ceramide phosphorylethanolamine, Examples thereof include ceramide phosphorylglycerol and a mixture thereof.

  Examples of the saponins include Enjusaponin, Quillaja Saponin, Soy Saponin, Yucca Saponin and the like.

  Among the above surfactants (C), a particulate composition that can stably emulsify an oily component containing reduced coenzyme Q10, and has high oxygen stability and high bioabsorbability, which are the objects of the present invention. From the viewpoint of obtaining a product, the surfactant (C) is preferably a hydrophilic surfactant, for example, a surfactant having an HLB of 4 or more, usually an HLB of 6 or more, preferably an HLB of 8 or more. Can be used. Specific examples of such surfactants include monoglycerol fatty acid organic acid esters such as monoglycerol stearic acid citrate and monoglycerol stearate diacetyltartaric acid; triglycerol monolaurate and triglycerol monomyristate , Triglycerol monooleate, triglycerol monostearate, pentaglycerol monomyristate, pentaglycerol trimyristate, pentaglycerol monooleate, pentaglycerol trioleate, pentaglycerol monostearate, Pentaglycerin tristearate, pentaglycerin monostearate, hexaglycerin monocaprylate, hexa Glycerin dicaprylate, hexaglycerol monolaurate, hexaglycerol monomyristate, hexaglycerol monooleate, hexaglycerol monostearate, decaglycerol monolaurate, decaglycerol monomyristate, decaglycerol monooleate Esters, polyglycerin fatty acid esters such as decaglycerin monopalmitate, decaglycerin monostearate, decaglycerin distearate; tetraglycerin condensed ricinoleic acid ester, pentaglycerin condensed ricinoleic acid ester, hexaglycerin condensed ricinoleic acid ester, di Polyglycerin condensed ricinolein such as glycerin condensed ricinoleate Esters; sorbitan fatty acid esters such as sorbitan monostearate and sorbitan monooleate; sucrose fatty acid esters such as sucrose palmitate and sucrose stearate; soybean lecithin, egg yolk lecithin, enzymatically decomposed lecithin, etc. Lecithins; saponins such as Enjusaponin, Quillaja Saponin, Soy Saponin, Yucca Saponin and the like.

  In the present invention, the surfactant (C) is preferably used in combination with other water-soluble excipients.

  The sugar is not particularly limited as long as it is acceptable for food. Examples thereof include monosaccharides such as glucose, fructose, galactose, arabinose, xylose, and mannose; disaccharides such as maltose, sucrose, and lactose; fructo-oligosaccharide, soybean Oligosaccharides such as oligosaccharide, galactooligosaccharide, and xylooligosaccharide; sugar alcohols such as sorbitol, maltitol, erythritol, lactitol, and xylitol; polysaccharides such as dextrin; and the like can be preferably used.

  The dextrin may be any decomposition product of starch, and any of low molecular dextrins and high molecular dextrins can be suitably used, and is not particularly limited. However, from the viewpoint of solubility in the aqueous layer, the dextrose equivalent (DE) is usually 40 or less, preferably 35 or less, more preferably 30 or less, and usually 1 or more, preferably 2 or more, more preferably Five or more dextrins can be preferably used. Also, the dextrin may be maltodextrin, cyclodextrin, cluster dextrin or the like.

  Examples of the yeast cell wall include a cell wall of brewer's yeast.

  In the present invention, it is preferable to use a combination of a water-soluble polymer and a sugar as the water-soluble excipient, and gum arabic is selected as the water-soluble polymer, and sucrose and / or dextrin is selected as the sugar. It is particularly preferable to combine them. When the water-soluble polymer and saccharide are used in combination, the weight ratio of the water-soluble polymer and saccharide is not particularly limited, but the ratio of the water-soluble polymer to the total amount of saccharide is usually 25% by weight. Or more, preferably 40% by weight or more, more preferably 50% by weight or more, particularly preferably 60% by weight or more, and usually 99% or less, preferably 95% by weight or less, more preferably 90% by weight or less, particularly Preferably it is 85 weight% or less.

  The oil component (A) containing reduced coenzyme Q10 and a lipophilic antioxidant that forms the domain part of the particulate composition of the present invention includes (1) reduced coenzyme Q10 or coenzyme Q10 (reduced Type coenzyme Q10 and oxidized coenzyme Q10) and a lipophilic antioxidant alone, or (2) reduced coenzyme Q10 or coenzyme Q10 and lipophilic antioxidant, What mixed fats and oils and / or surfactant (D) may be used. Any of these oil components (A) is preferably an oil component that can be visually mixed uniformly when heated and melted at 50 ° C. or higher. From the viewpoint of increasing the content of reduced coenzyme Q10 in the oil component (A), the above (1) is preferable.

  The oil / fat used when the oil / fat component (A) is (2) is not particularly limited, and may be, for example, a natural oil / fat from animals or plants, or a synthetic oil / processed oil / fat. More preferably, it is acceptable for food, cosmetics or medicine. For example, as vegetable oils and fats, for example, palm oil, palm oil, palm kernel oil, linseed oil, camellia oil, brown rice germ oil, rapeseed oil, rice oil, peanut oil, corn oil, wheat germ oil, soybean oil, sesame oil, Examples include cottonseed oil, sunflower seed oil, kapok oil, evening primrose oil, shea fat, monkey fat, cacao fat, sesame oil, safflower oil, olive oil, etc. Examples of animal fats include pork fat, milk fat, fish oil, beef tallow Furthermore, the fats and oils (for example, hardened oil) which processed these by fractionation, hydrogenation, transesterification, etc. can also be mentioned. Needless to say, medium chain fatty acid triglycerides (MCT) may also be used. Moreover, you may use these mixtures. Examples of the medium-chain fatty acid triglyceride include triglycerides in which the fatty acid has 6 to 12 carbon atoms, preferably 8 to 12 carbon atoms.

  Of the above oils and fats, vegetable oils, synthetic oils and processed oils and fats are preferable from the viewpoint of ease of handling, odor, and the like. Examples include coconut oil, palm oil, palm kernel oil, rapeseed oil, rice oil, soybean oil, cottonseed oil, safflower oil, olive oil, MCT, and the like.

  Examples of the surfactant (D) used when the oil and fat component (A) is (2) include glycerin fatty acid esters, polyglycerin esters, sucrose fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene. Examples include sorbitan fatty acid esters, propylene glycol fatty acid esters, and lecithin. Among them, fat-soluble surfactants are preferable, but are not limited thereto.

  Examples of such glycerin fatty acid esters include monoglycerides and diglycerides in which the fatty acid has 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms. Examples of the polyglycerin esters include polyglycerin mainly composed of polyglycerin having a polymerization degree of 2 to 10, and one or more hydroxyl groups of polyglycerin each having 6 to 22, preferably 6 to 18 carbon atoms. What esterified fatty acid is mentioned. Examples of the sucrose fatty acid esters include those obtained by esterifying one or more hydroxyl groups of sucrose with a fatty acid having 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms. Examples of sorbitan fatty acid esters include those obtained by esterifying one or more hydroxyl groups of sorbitans with fatty acids having 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms. As polyoxyethylene sorbitan fatty acid esters, at least one hydroxyl group of sorbitans is substituted with a polyoxyethylene chain, and at least one of the existing hydroxyl groups has 6 to 22 carbon atoms, preferably 6 Those esterified with ˜18 fatty acids. Examples of the propylene glycol fatty acid esters include monoglycerides and diglycerides in which the fatty acid has 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms. Examples of lecithin include egg yolk lecithin, purified soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, dicetylphosphate, stearylamine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositolamine, cardiolipin, ceramide phosphorylethanolamine, ceramide Examples include phosphorylglycerol and mixtures thereof.

  Among the above surfactants (D), particles exhibiting good compatibility with reduced coenzyme Q10 and lipophilic antioxidant, or particles having both high oxidative stability and high bioabsorbability, which is the object of the present invention In view of obtaining a composition, a lipophilic surfactant is preferable. For example, a surfactant having an HLB of 10 or less, preferably 8 or less, more preferably 6 or less, and even more preferably 5 or less can be used. Specific examples of such surfactants include monoglycerol monostearate, monoglycerol monooleate, monoglycerol monomyristate, monoglycerol monocaprylate, monoglycerol monolaurate, monoglycerol monobe Monoglycerin monofatty acid esters such as heminate and monoglycerin monoerucate; monoglycerin difatty acids such as monoglyceryl distearate, monoglycerin dioleate, monoglycerin dicaprylate and monoglycerin dilaurate Esters: monoglycerin stearic acid citrate, monoglycerin stearic acid acetate, monoglycerin coconut palm oil acetate, monoglycerin steer Monoglycerin fatty acid organic acid esters such as succinic acid succinate, monoglyceryl caprylic succinate, monoglyceryl stearic acid lactic acid ester, monoglyceryl stearic acid diacetyltartaric acid ester; monoglycerin beef tallow oil fatty acid ester, monoglycerin rapeseed oil Monoglycerin fatty acid ester obtained by using various fats and oils such as fatty acid ester, monoglycerin soybean hardened oil fatty acid ester, monoglycerin cottonseed oil fatty acid ester, monoglycerin safflower oil fatty acid ester; polyglycerin having an average polymerization degree of 2 to 10 and carbon Polyglycerin fatty acid esters such as esters with 6 to 22, preferably 6 to 18 fatty acids, and esters of polyglycerin having an average degree of polymerization of 2 to 10 and polyricinoleic acid having a degree of condensation of 2 to 4 Glycerin fatty acid esters such as glycerin condensed ricinoleate; propylene glycol fatty acid esters such as propylene glycol monostearate, propylene glycol monooleate, and propylene glycol monolaurate; sorbitan distearate, sorbitan tristearate Sorbitan fatty acid esters such as sorbitan sesquioleate, sorbitan dioleate, and sorbitan trioleate; polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate Esters, polyoxyethylene sorbitan monooleate, etc. Examples thereof include polyoxyethylene sorbitan fatty acid esters; and one or a mixture of two or more selected from lecithins such as soybean lecithin, egg yolk lecithin, and enzymatically decomposed lecithin. Among them, preferably one or a mixture of two or more selected from glycerin fatty acid esters and / or lecithins, more preferably monoglycerin monofatty acid ester, monoglycerin difatty acid ester, monoglycerin fatty acid organic acid ester (particularly Monoglycerin fatty acid acetate, monoglycerin coconut palm oil acetate), polyglycerin fatty acid ester (especially ester of polyglycerin having an average polymerization degree of 2 to 10 and fatty acid having 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms) and poly One or a mixture of two or more selected from glycerin-condensed ricinoleic acid ester (especially an ester of polyglycerin having an average degree of polymerization of 2 to 10 and polyricinoleic acid having a degree of condensation of 2 to 4, more preferably monoglycerin fatty acid Organic acid esters (especially monoglycerides) Specific examples include 50% acetylated monoglycerol monostearate, fully acetylated monoglyceride monoglyceride, soybean lecithin, egg yolk lecithin, and enzymatically decomposed lecithin. Can be mentioned. These lipophilic polyhydric alcohol fatty acid esters can be used alone or in admixture of two or more.

  In addition to the above, in the present invention, oil-soluble components (A) such as waxes, fatty acids and ester derivatives thereof can be contained in the oil-based component (A) according to various purposes.

  Examples of the waxes include food waxes such as beeswax, mole, cadilla wax, rice bran wax, carmauba wax, and snow wax.

  Examples of the fatty acid and ester derivatives thereof include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, behenic acid and esters thereof such as methyl ester and ethyl ester thereof. However, it is not limited to these.

  The composition of the oil component (A) containing the reduced coenzyme Q10 in the particulate composition of the present invention is not particularly limited, but the content of reduced coenzyme Q10 in the particulate composition is maintained high. From the viewpoint, the content of coenzyme Q10 in the oily component (A) is usually 5% by weight or more, preferably 20% by weight or more, more preferably 40% by weight or more, still more preferably 50% by weight or more, particularly preferably. Is 60% by weight or more, and since it is necessary to contain some lipophilic antioxidant necessary for oxidation inhibition, 99.95% by weight or less is preferable, and 90% by weight or less is more preferable. The content of the lipophilic antioxidant in the oil component (A) is usually 0.05% by weight or more, preferably 1% by weight or more, and more preferably 5% by weight from the viewpoint of inhibiting oxidation of the reduced coenzyme Q10. % Or more, more preferably 10% by weight or more, and from the viewpoint of securing the content of reduced coenzyme Q10 to some extent, it is usually 95% by weight or less, preferably 80% by weight or less, more preferably 60% by weight or less, More preferably, it is 50 weight% or less.

  The oil content in the oil component (A) is usually 94.95% by weight or less, preferably 79% by weight or less, more preferably 55% by weight or less, and particularly preferably 40% by weight or less. It is also possible to contain 0% by weight, ie no fats and oils. The content of the surfactant (D) in the oil component (A) is usually 94.95% by weight or less, preferably 79% by weight or less, more preferably 55% by weight or less, particularly preferably 40% by weight. The lower limit is 0% by weight, that is, it is possible to contain no surfactant (D). That is, the composition of the oil component (A) is 5 to 99.95% by weight of coenzyme Q10, 0.05 to 95% by weight of lipophilic antioxidant, 0 to 94.95% by weight of fat and oil, 0 to It preferably contains 94.95% by weight of surfactant (D), 20-90% by weight of coenzyme Q10, 1-80% by weight of lipophilic antioxidant, 0-79% by weight of fats and oils. More preferably 0 to 79% by weight of surfactant (D), 40 to 90% by weight of coenzyme Q10, 5 to 60% by weight of lipophilic antioxidant, 0 to 55% by weight. More preferably, 0 to 55% by weight of surfactant (D), 50 to 90% by weight of coenzyme Q10, 10 to 50% by weight of lipophilic antioxidant, 0 to 55% It is particularly preferable to contain 0% to 55% by weight of a fat and oil and 0 to 55% by weight of a surfactant (D). 60-90% by weight of coenzyme Q10,10~40 wt% of a lipophilic antioxidant, and most preferably consisting of 0 to 30 wt% fat, and 0-30% by weight of a surfactant (D). When the content of the coenzyme Q10 in the oil component (A) is less than 5% by weight, the content of the reduced coenzyme Q10 contained in the particulate composition is also reduced as a result. When orally administering the reduced coenzyme Q10, it is necessary to ingest a large amount of the particulate composition. Needless to say, the coenzyme Q10 as the component of the oil component (A) may be reduced coenzyme Q10 alone or a mixture of reduced coenzyme Q10 and oxidized coenzyme Q10. In the case of a mixture of Q10 and oxidized coenzyme Q10, the ratio of reduced coenzyme Q10 in coenzyme Q10 is preferably higher.

  The average particle diameter of the domain formed by the oil component (A) in the particulate composition of the present invention is not particularly limited as long as the object of the present invention can be achieved, but may be in the range of 0.01 to 50 μm. Preferably, it is in the range of 0.01 to 20 μm, and most preferably in the range of 0.01 to 10 μm. When the average particle size of the domain formed by the oil component (A) is larger than 50 μm, the oral absorbability of the reduced coenzyme Q10 in the particulate composition tends to decrease. On the other hand, when the average particle size of the domain formed by the oil component (A) is smaller than 0.01 μm, it tends to be difficult to maintain the stability of the emulsified droplets in the production process.

  In addition, the average particle diameter of the domain formed by the oil component (A) can be obtained by image analysis from an electron microscope image of the fractured surface obtained by breaking the particle composition into a hemispherical shape.

  In the particulate composition of the present invention, the number of domains of the oil component (A) containing the reduced coenzyme Q10 and the lipophilic antioxidant dispersed in the matrix mainly composed of a water-soluble excipient. It is preferable to increase the number of domains. For example, it is preferable that 5 or more domains are formed and polydispersed. When the number of domains in the matrix composed of the water-soluble excipient is less than 5, the content of reduced coenzyme Q10 in the finally obtained powdery composition is reduced, and a predetermined amount of reduction is achieved. When orally administering type coenzyme Q10, it is necessary to ingest a large amount of the particle composition.

  The content of reduced coenzyme Q10 in the particulate composition of the present invention is preferably in the range of 1 to 70% by weight, more preferably in the range of 5 to 60% by weight, and 10 to 55% by weight. Most preferably, it is in the range of%. When the content of reduced coenzyme Q10 in the particulate composition is less than 1% by weight, it is necessary to ingest a large amount of the particulate composition when orally administering a predetermined amount of reduced coenzyme Q10. It becomes. On the other hand, the upper limit of the reduced coenzyme Q10 content in the particulate composition is not particularly limited as long as high oxidation stability, which is one of the objects of the present invention, can be imparted, but it is usually preferably 70% by weight or less. When the content of reduced coenzyme Q10 in the particulate composition is more than 70% by weight, it tends to be difficult to maintain high oxidation stability.

  In general, fat-soluble oxidizable active ingredients stabilized by microencapsulation with water-soluble excipients have oxidative stability under conditions where water-soluble excipients absorb moisture, such as in humid conditions. (Y. Minemoto, et al., Food Sci. Technol. Res., 7, 91-93, 2001). However, in the particulate composition of the present invention, moisture is contained in the particulate composition. Even when contained, high oxidative stability of the reduced coenzyme Q10 can be realized. Accordingly, the water content in the particulate composition of the present invention is not particularly limited, and for example, it is possible to contain about 0.01 to 30% by weight of water. The water content in the particulate composition of the present invention is preferably 0.01 to 20% by weight, more preferably 0.01 to 15% by weight. When the water content in the particulate composition in the present invention is more than 30% by weight, it tends to be difficult to obtain a significant effect of improving oxidative stability, but the target oxidative stability can be achieved. This is not the case. On the other hand, the lower limit of the water content in the particulate composition is preferably smaller in view of the oxidation stability of the reduced coenzyme Q10, but is usually 0.01% by weight or more.

  In the particulate composition of the present invention, the sphericity is preferably higher. Specifically, it is preferably 0.8 or more, more preferably 0.85 or more, and 0.9 or more. Most preferred. The higher the sphericity of the particulate composition, the smaller the total surface area per unit weight of the particulate composition, and the less the oxidation reaction caused by oxygen molecules in the air estimated to proceed from the particle surface. Tend to be. On the other hand, when the sphericity of the particulate composition is low, the total surface area per unit weight of the particulate composition increases, and oxygen in the air is estimated to travel from the surface of the particulate composition. It tends to be susceptible to oxidation reaction by molecules, and it tends to be difficult to obtain a particulate composition having high oxygen stability, which is one of the objects of the present invention.

  That is, even in the case of a particulate composition containing reduced coenzyme Q10 having the same composition, the oxidization stability of reduced coenzyme Q10 having high oxygen stability in the particulate composition is greatly affected by the sphericity. Affect. In addition, this preferable sphericity can be easily achieved by adopting a preferable production method (1) described later.

  The sphericity of the particulate composition is determined by taking an image of the subject particulate composition with an electron microscope or the like and using the image analysis software WinROOF Ver. 3.30 or the like can be used to determine the ratio of the diameter of a circle having the same area and the diameter ratio of the circumscribed minimum circle.

  Furthermore, in the particulate composition of the present invention, when the particle diameter is about the same, the smaller the surface roughness (Ra), the better. The smaller the surface roughness (Ra) of the particulate composition, the smaller the total surface area per unit weight of the particulate composition, and the corresponding amount of oxidation by oxygen molecules in the air estimated to proceed from the particle surface. It is thought that it becomes difficult to receive a reaction. On the other hand, when the surface roughness (Ra) of the particulate composition is large, the total surface area per unit weight of the particulate composition increases, and the air is estimated to advance from the particle surface by that amount. It is considered that it tends to be difficult to obtain a particulate composition having high oxygen stability, which is one of the objects of the present invention.

  The surface roughness (Ra) of the particles can be obtained as an arithmetic average surface roughness (Ra) defined by, for example, JIS B 0601-1994. The surface roughness referred to here is considered to have a substantially contradictory relationship with the sphericity, and the higher the sphericity, the smaller the surface roughness tends to be.

  In the particulate composition of the present invention, the reduced coenzyme Q10 in the composition is 10% by weight or more, preferably 20% by weight or more, more preferably 50% by weight or more, and further preferably 70% by weight or more. Preferably, 80% by weight or more is preferably not in a crystalline state, that is, in an amorphous state or in a melt state, and the proportion of the reduced coenzyme Q10 in the amorphous state or molten state in the particulate composition is higher. Is more preferable. Needless to say, 100% of the reduced coenzyme Q10 in the composition, ie. Most preferably, the total amount is not in a crystalline state, that is, in an amorphous state or a melt state. Usually, the reduced coenzyme Q gradually changes to a crystalline state when stored below the melting point. However, in the particulate composition obtained by the preferred production method described below, for example, after production, 25 ° C., air Even after storage for 30 days, 10% by weight or more of the reduced coenzyme Q10 in the composition is not in a crystalline state. Since the reduced coenzyme Q10 is held in the particulate composition in an amorphous state or a melted state, not in a crystalline state, the particulate composition is disintegrated and released in the gastric fluid or intestinal fluid after oral administration. The oil component (A) containing the reduced coenzyme Q10 is also presumed to maintain an amorphous state or a melt state. Usually, the reduced coenzyme Q10 in an amorphous state or in a melt state is more coexisting in the living body or in the particulate composition in the stomach or intestine than the reduced coenzyme Q10 in the crystalline state. As a result, the reduced coenzyme Q10 in an amorphous state or in a melt state is more easily absorbed from the digestive tract than the reduced coenzyme Q10 in the crystalline state, and as a result, The preferred particulate composition of the present invention is considered to have high oral absorption, which is one of its purposes.

  In the particulate composition of the present invention, the oily component (A) containing the reduced coenzyme Q10 and the lipophilic antioxidant is added to form a domain in the water-soluble excipient matrix to be polydispersed. Control the structure. For example, in a preferable production method described later, the oily component (A) in a melt state is confined in a microcapsule surrounded by a water-soluble excipient, and therefore, generation of crystal nuclei of reduced coenzyme Q10 occurs. The probability is greatly reduced, and it is presumed that the amorphous state or the melt state is maintained for a long time after the particles are formed. That is, an oily component (A) containing reduced coenzyme Q10 and a lipophilic antioxidant forms a domain in a matrix composed of a water-soluble excipient, which is the particulate composition of the present invention, to form a polydisperse This structure is considered to be extremely important for the purpose of achieving high oral absorption.

  The volume average particle diameter of the particulate composition of the present invention is not particularly limited as long as the object of the present invention can be achieved, but is usually 1 μm or more, preferably 5 μm or more, more preferably 10 μm from the viewpoint of easy collection as a powder. Above, more preferably 20 μm or more, particularly preferably 30 μm or more, particularly preferably 50 μm or more. The upper limit of the volume average particle diameter is not particularly limited as long as the high stability and high absorbency of the reduced coenzyme Q10 targeted by the present invention can be maintained, but it can be processed into foods, pharmaceuticals, cosmetics and the like. In view of ease, it is usually 5000 μm or less, preferably 3000 μm or less, more preferably 2000 μm or less, further preferably 1000 μm or less, particularly preferably 800 μm or less, and particularly preferably 700 μm or less. That is, the volume average particle size of the particulate composition of the present invention is usually 1 to 5000 μm, preferably 5 to 3000 μm, more preferably 10 to 2000 μm, still more preferably 20 to 1000 μm, particularly preferably 30 to 800 μm, especially Preferably it is 50-700 micrometers. The volume average particle diameter can be measured, for example, using an ethanol solvent in a laser diffraction / scattering type particle size distribution measuring apparatus (manufactured by Nikkiso Co., Ltd .; Microtrack MT3000II).

  In addition, various additives that can be used for various purposes and active ingredients other than coenzyme Q are added to the particulate composition of the present invention in accordance with each purpose. Can do.

  For example, in addition to the above compounds, excipients such as crystalline cellulose, calcium phosphate and calcium sulfate, calcium citrate, calcium carbonate, sodium bicarbonate, crystalline cellulose, carboxymethylcellulose, tragacanth, alginic acid and other disintegrants, talc, stearic acid Lubricants such as magnesium, polyethylene glycol, silica, hydrogenated oil, titanium oxide, food dyes, bengara dyes, safflower dyes, caramel dyes, gardenia dyes, tar dyes, chlorophyll dyes, stearic acid, talc, light anhydrous silicic acid , Aggregation inhibitors such as hydrous silicic acid dioxide, higher alcohols, absorption accelerators such as higher fatty acids, solubilizing aids such as fumaric acid, succinic acid, malic acid, benzoic acid, sodium benzoate, ethyl paraoxybenzoate, List stabilizers such as beeswax That.

  In addition, the active ingredient other than coenzyme Q is not particularly limited as long as it is acceptable for food, cosmetics, or pharmaceutical use. For example, glutathione, L-cysteine, N-acetylcysteine, reduced α-lipoic acid, Ascorbic acid, erythorbic acid and ester derivatives and salts thereof, carotenoids, rutin, hydrophilic flavonoids, L-carnitine and salts thereof (such as tartrate and fumarate), acetyl-L-carnitine, propionyl-L-carnitine, magnesium, Zinc, selenium, manganese, riboflavin, niacinamide, curcuminoid, proanthocyanidins extracted from grape seeds and pine bark, NADH (reduced nicotinamide adenine dinucleotide), NADPH (reduced nicotinamide adenine dinucleotide phosphate), Resverato Le, lingonberry extract, milk thistle extract, can be mentioned highly unsaturated fatty acids obtained by concentrating from fish oil. Preferably, glutathione, L-cysteine, ascorbic acid, erythorbic acid and ester derivatives and salts thereof, hydrophilic flavonoids, and L-carnitine are used. Among these, from the viewpoint of the stability of reduced coenzyme Q10, it is preferable to use an active ingredient having an antioxidative action such as ascorbic acid.

  Needless to say, the various components listed here can be used as a mixture of two or more. These various additives and active ingredients are preferably contained in a matrix containing a water-soluble excipient as a main component if water-soluble, or in an oily component (A) that becomes a domain if fat-soluble. It is not limited to it.

  In the particulate composition of the present invention, the retention rate (%) of reduced coenzyme Q10 after storage for 30 days under light-shielding conditions in air at 40 ° C. and 75% relative humidity (the initial reduced coenzyme Q10 The ratio to the weight is preferably 80% by weight or more, more preferably 85% by weight or more, further preferably 90% by weight or more, and particularly preferably 95% by weight or more. As described above, the particulate composition of the present invention has a high humidity in the storage atmosphere as compared with the case where the water-insoluble ascorbic acid is not contained, and even when the moisture content becomes high due to moisture absorption, for example, relative humidity. Even under the condition of 75%, the reduced coenzyme Q10 can be held more stably.

  In the particulate composition of the present invention, when the particulate composition is disintegrated, the reduced coenzyme Q10 is released in a fine state that is effective for absorption into the digestive tract. It becomes good.

  Next, the preferable manufacturing method of the particulate composition containing reduced coenzyme Q10 of this invention is demonstrated. The particulate composition of the present invention is preferably obtained by the following production method, but the production method is not limited to the following if a similar particulate composition can be obtained by another production method.

The particulate composition containing the reduced coenzyme Q10 of the present invention is preferably
(1) An oil-in-water emulsion composition prepared from an aqueous solution containing a water-soluble excipient and an oily component (a) containing coenzyme Q10 and a lipophilic antioxidant is suspended in the oily component (B). After turbidity, a method of removing water in the oil-in-water emulsion composition in the oil component (B) (hereinafter referred to as production method (1)), or
(2) A method of spray-drying an oil-in-water emulsion composition prepared from an aqueous solution containing a water-soluble excipient and an oily component (a) containing coenzyme Q10 and a lipophilic antioxidant in the gas phase (Hereinafter referred to as production method (2)).

  In the above production methods (1) and (2), the aqueous solution that becomes the aqueous phase of the oil-in-water emulsion composition (hereinafter referred to as “excipient aqueous solution”) is an aqueous solution in which a water-soluble excipient is dissolved in water. It is preferably used in the form, and the concentration is not particularly limited, but it is preferable to handle the solution at a concentration that does not exceed 1 Poise in order to ensure transferability. Specific examples and preferred examples of the water-soluble excipient at this time are the same as those described in the description of the particulate composition.

  In the above production methods (1) and (2), the preparation of the oil component (a) containing coenzyme Q10 and a lipophilic antioxidant is carried out by adding a lipophilic anti-oxidant to coenzyme Q10 melted at 50 ° C. or higher. A method of adding an oxidant and, if necessary, fats and oils and / or surfactant (D) and mixing them by stirring or the like is the simplest and preferable, but is not limited thereto.

  The coenzyme Q10 used for the oil component (a) at this time is not only reduced coenzyme Q10, a mixture of reduced coenzyme Q10 and oxidized coenzyme Q10, but also oxidized coenzyme Q10 alone. It can also be used. In the production method of the present invention, as described later, when oxidized coenzyme Q10 is used alone or when coenzyme Q10 having a low content of reduced coenzyme Q10 is used, oxidized form is used in the production process. By reducing the coenzyme Q10, the reduced coenzyme Q10 ratio in the resulting particulate composition can be increased. Specific examples and preferred examples of the lipophilic antioxidant used for the oil component (a) are the same as those described for the oil component (A) of the particulate composition. The amount of the lipophilic antioxidant used in the production methods (1) and (2) of the present invention is an amount effective for improving the oxidative stability of the reduced coenzyme Q10 in the obtained particulate composition. Although there is no particular limitation as long as it is present, the purpose is to sufficiently improve the stability of the reduced coenzyme Q10 in the obtained particulate composition, and if necessary, the oxidized form contained in the oil component (a) in the production process For the purpose of reducing the coenzyme Q10, from the viewpoint of securing a certain amount of the reduced coenzyme Q10 content in the particulate composition obtained to some extent, with respect to 100 parts by weight of the coenzyme Q10 used for the oil component (a). The amount of the lipophilic antioxidant used is preferably 1 to 500 parts by weight, more preferably 5 to 300 parts by weight, still more preferably 10 to 250 parts by weight, and 20 to 200 parts by weight. In It is particularly preferred.

  Specific examples and preferred examples of other components of the oil component (a), such as fats and oils and surfactant (D), and preferred contents in the oil component (a) are described in the description of the particulate composition. It is the same as the oily component (A).

  Specific examples and preferred examples are the same as those described in the description of the particulate composition.

  Next, in the production methods (1) and (2) of the present invention, an oil-in-water emulsion composition is prepared from an oily component (a) containing the coenzyme Q10 and a lipophilic antioxidant, and an aqueous excipient solution. Prepare. The oil-in-water emulsion composition can be prepared, for example, by adding the oil component (a) prepared at a temperature equal to or higher than the melting point of coenzyme Q10 to the aqueous excipient solution previously heated to 50 ° C. or higher. And the oily component (a) is finely dispersed and emulsified to a desired average particle size using a known emulsifier such as a high-pressure homogenizer. In addition, a coenzyme Q10 powder, a lipophilic antioxidant, and other oil components as necessary are added to an aqueous excipient solution that has been heated to 50 ° C. or higher in advance. In the method of emulsifying after coenzyme Q10 and lipophilic antioxidant and other oily components are melted, or coenzyme Q10 in powder form in an aqueous solution containing a water-soluble excipient and / or 50 Add as a melt melted at ℃ or higher, add lipophilic antioxidant and other oil components as needed, then warm to 50 ℃ or higher to melt coenzyme Q10 and other oil components And then emulsifying again by adding coenzyme Q10 to an aqueous excipient solution that has been heated to 50 ° C. or higher, emulsifying it once, and then adding a lipophilic antioxidant. Methods, etc. can be used, but are not limited to these. .

  In the production method of the present invention, the preferred emulsified particle size of the oil component (a) of the oil-in-water emulsion composition is not particularly limited, but the average particle size of the oil component (a) of the oil-in-water emulsion composition is large. In some cases, the absorptivity of reduced coenzyme Q10 may be lowered, so that it is usually 50 μm or less, preferably 20 μm or less, more preferably 15 μm or less, and particularly preferably 10 μm or less. On the other hand, when the average particle size of the oil component (a) of the oil-in-water emulsion composition is small, an excess of water-soluble excipient is required to maintain the stability of the emulsified droplets in the production process. Since problems such as requiring an excessive load on the emulsifying device occur, it is usually 0.001 μm or more, more preferably 0.05 μm or more, and particularly preferably 0.01 μm or more. In addition, the domain particle diameter in the obtained particulate composition can be controlled by controlling the particle diameter of the emulsified droplets in this step.

  The emulsion particle diameter of the oil component (a) of the oil-in-water emulsion composition can be measured with a commercially available laser diffraction / scattering particle size distribution analyzer.

  In the production methods (1) and (2) of the present invention, the step of preparing the oil-in-water emulsion composition from the oily component (a) and the aqueous excipient solution, and the temperature in the emulsification step are the oil-in-water composition. The temperature is not particularly limited as long as it is at or above the temperature at which the coenzyme Q10 is melted, but is usually 50 ° C or higher, preferably 55 ° C or higher, more preferably 60 ° C or higher. The upper limit is the boiling point of the system and differs depending on the conditions such as pressurization, and the temperature cannot be defined unconditionally. However, in the case of normal pressure conditions, it is usually 100 ° C. or lower, preferably 90 ° C. or lower.

  In the production method (1) of the present invention, the above oil-in-water emulsion composition is further mixed with another oil component (B), and an oil-in-water component is added to the oil component (B) so as to obtain a desired particle size. The type emulsion composition is suspended to obtain an O / W / O type emulsion. In the above mixing operation, for example, it is most convenient and preferable to add the oil-in-water emulsion composition containing coenzyme Q10 to the oil component (B) that has been heated to 50 ° C. or higher in advance. However, the present invention is not limited to this. Adjustment of the suspended particle size of the oil-in-water emulsion composition in the oil component (B) can be achieved by imparting shear to the mixed solution, such as stirring and liquid circulation. The temperature of the oil component (B) at the time of preparing the mixed liquid is usually preferably in the range of 50 to 120 ° C. in order to avoid rapid evaporation of moisture.

  Although there is no restriction | limiting in particular in the mixing ratio of the oil-in-water-type emulsion composition and oil-based component (B) in the manufacturing method (1) of this invention, The liquid mixture of an oil-in-water-type emulsion composition and oil-based component (B) The weight percent of the oil-in-water emulsion composition is preferably 1% by weight or more, more preferably 10% by weight or more, and particularly preferably 15% by weight or more from the viewpoint of production efficiency. preferable. Further, from the viewpoint of suspendability in the oil component (B) of the oil-in-water emulsion composition, it is preferably 70% by weight or less, particularly preferably 60% by weight or less, and 50% by weight or less. Is particularly preferred. Usually, it can be suitably carried out at 1 to 70% by weight, preferably 10 to 60% by weight, more preferably 15 to 50% by weight.

  When the oil-in-water emulsion composition in the mixed liquid of the oil-in-water emulsion composition and the oil component (B) is less than 1% by weight, production efficiency is lowered, which is not preferable. When the oil-in-water emulsion composition in the mixed liquid of the oil-in-water emulsion composition and the oil component (B) is 70% by weight or more, the oil-in-water emulsion composition is suspended in the oil component (B). This tends to be difficult.

  In the production method (1) of the present invention, the water is removed from the oil-in-water emulsion composition suspended in the oil component (B) after the O / W / O emulsion is formed. As a method for removing water from the oil-in-water emulsion composition, for example, the water is evaporated by heating to 80 ° C. or higher, preferably 100 ° C. or higher under atmospheric pressure. Alternatively, a method such as setting the temperature near the boiling point of water under the reduced pressure and evaporating the water may be used, but the method is not limited to these. From the viewpoint of minimizing the operation time, it is preferable to carry out under an arbitrary reduced pressure.

In this invention, the oil-based component (B) in a manufacturing method (1) is a component containing fats and oils and surfactant (E) as needed. The oil component (B) is not particularly limited as long as it can suspend the oil-in-water emulsion composition, and may be, for example, a natural fat from animals or plants, such as a synthetic fat or processed fat. May be. More preferably, it is acceptable for food, cosmetics or medicine. For example, as vegetable fats and oils, for example, palm oil, palm oil, palm kernel oil, linseed oil, camellia oil, brown rice germ oil, rapeseed oil, rice oil, peanut oil, corn oil, wheat germ oil, soybean oil, sesame oil, Examples include cottonseed oil, sunflower seed oil, kapok oil, evening primrose oil, shea fat, monkey fat, cacao fat, sesame oil, safflower oil, olive oil, etc. Examples of animal fats include pork fat, milk fat, fish oil, beef tallow Furthermore, the fats and oils (for example, hardened oil) which processed these by fractionation, hydrogenation, transesterification, etc. can also be mentioned. Needless to say, medium chain fatty acid triglycerides (MCT) may also be used. Moreover, you may use these mixtures.
Examples of the medium-chain fatty acid triglyceride include triglycerides in which the fatty acid has 6 to 12 carbon atoms, preferably 8 to 12 carbon atoms.

  Of the above oils and fats, vegetable oils, synthetic oils and processed oils and fats are preferable from the viewpoint of ease of handling and odor. For example, palm oil, palm oil, palm kernel oil, rapeseed oil, rice oil, soybean oil, cottonseed oil, safflower oil, olive oil, MCT and the like can be raised.

  In the production method (1) of the present invention, the oil component (B) may be an oil or fat alone, but for the purpose of ensuring the dispersion stability of the oil-in-water emulsion composition droplets dispersed in the oil component (B). If necessary, the surfactant (E) can be added to the oil component (B). The droplets of the oil-in-water emulsified composition gradually increase in tackiness as drying progresses, and tend to aggregate between particles. However, when the surfactant (E) is allowed to coexist in the oil component (B), the aggregation between the oil-in-water emulsion composition droplets during drying with increased tackiness is greatly relieved, and as a result, The recovery rate of the particulate composition having a desired volume average particle diameter can be remarkably improved, which is preferable.

  Although there is no restriction | limiting in particular in content of surfactant (E) in oil-based component (B), From viewpoints, such as aggregation suppression between the droplets of the oil-in-water emulsion composition in the middle of drying, oil-based component (B) The weight percent of the surfactant (E) is usually 0.001 wt% or more, preferably 0.005 wt% or more, and more preferably 0.01 wt% or more. Although the upper limit is not particularly limited, it is usually 95% by weight or less, preferably 80% by weight or less, more preferably 60% by weight or less, from the viewpoint of fluidity of the oil component (B), removability of the surfactant (E), and the like. It is.

  The surfactant (E) is not particularly limited as long as it is acceptable for food, cosmetics, and pharmaceutical use, but is particularly preferably acceptable for food, for example, glycerin fatty acid esters, polyglycerin esters, Examples thereof include sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and lecithin. Needless to say, in the present invention, these can be used alone or as a mixture of two or more.

  Examples of glycerin fatty acid esters include monoglycerides and diglycerides in which the fatty acid has 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms.

  Examples of the polyglycerin esters include polyglycerin mainly composed of polyglycerin having a polymerization degree of 2 to 10, and one or more hydroxyl groups of polyglycerin each having 6 to 22, preferably 6 to 18 carbon atoms. What esterified fatty acid is mentioned.

Examples of sucrose fatty acid esters include those obtained by esterifying a fatty acid having 6 to 22 carbon atoms, preferably 6 to 18 carbon atoms, to one or more hydroxyl groups of sucrose. One or more hydroxyl groups may be esterified with a fatty acid having 6 to 22, preferably 6 to 18 carbon atoms.

  As polyoxyethylene sorbitan fatty acid esters, at least one hydroxyl group of sorbitans is substituted with a polyoxyethylene chain, and at least one of the existing hydroxyl groups has 6 to 22 carbon atoms, preferably 6 Those esterified with ˜18 fatty acids.

  Examples of lecithins include egg yolk lecithin, purified soybean lecithin, enzyme-decomposed lecithin, and mixtures thereof.

  Among the above surfactants (E), in the production method (1) of the present invention, specifically, the aggregation between the oil-in-water emulsion composition droplets during drying can be efficiently suppressed, and specifically, Mono, such as glycerol monostearate, monoglycerol monooleate, monoglycerol monomyristate, monoglycerol monocaprylate, monoglycerol monolaurate, monoglycerol monobehenate, monoglycerol monoerucate Glycerin monofatty acid ester; monoglycerin distearate, monoglycerin dioleate, monoglycerin dicaprylate, monoglycerin dilaurate, etc .; monoglycerin stearate citrate ester Monoglycerol such as monoglycerol stearic acid acetate, monoglycerol coconut palm oil acetate, monoglycerol stearic acid succinate, monoglycerol caprylic acid succinate, monoglycerol stearate lactate, monoglycerol stearate diacetyl tartaric acid Fatty acid organic acid ester: Monoglycerin beef tallow fatty acid ester, monoglycerin rapeseed hardened oil fatty acid ester, monoglycerin soybean hardened oil fatty acid ester, monoglycerin cottonseed oil fatty acid ester, monoglycerin safflower oil fatty acid ester, etc. Monoglycerol fatty acid ester obtained; polyglycerol fatty acid ester such as ester of polyglycerol having an average degree of polymerization of 2 to 10 and fatty acid having 6 to 22 carbon atoms, and average Glycerin fatty acid esters such as polyglycerin condensed ricinoleic acid ester such as ester of polyglycerin having a degree of synthesis of 2 to 10 and polyricinoleic acid having a degree of condensation of 2 to 4; propylene glycol monostearate, propylene glycol monooleate, and Propylene glycol fatty acid esters such as propylene glycol monolaurate; sorbitan fatty acid esters such as sorbitan distearate, sorbitan tristearate, sorbitan sesquioleate, sorbitan dioleate, and sorbitan trioleate; poly Oxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbita 1 or a mixture of two or more selected from polyoxyethylene sorbitan fatty acid esters such as styrene monostearate and polyoxyethylene sorbitan monooleate; and lecithins such as soybean lecithin, egg yolk lecithin, and enzymatically decomposed lecithin Can be mentioned. Among them, preferably glycerol fatty acid esters and / or one or a mixture of two or more selected from lecithins such as soybean lecithin, egg yolk lecithin, and enzymatically decomposed lecithin, more preferably monoglycerol monofatty acid ester and monoglycerol diester. Fatty acid ester, monoglycerin fatty acid organic acid ester (especially monoglycerin fatty acid acetate, monoglycerin coconut palm oil acetate), polyglycerin fatty acid ester (especially polyglycerin having an average polymerization degree of 2 to 10 and 6 to 22 carbon atoms, preferably 6-18 fatty acid esters), and polyglycerin condensed ricinoleic acid esters (especially esters of polyglycerin having an average polymerization degree of 2 to 10 and polyricinoleic acid having a condensation degree of 2 to 4), soybean lecithin, egg yolk lecithin, Selected from enzymatically degraded lecithin 1 or a mixture of two or more thereof, more preferably monoglycerin fatty acid organic acid esters (particularly monoglycerin fatty acid acetate, monoglycerin coconut palm oil acetate), and specific examples of monoglycerin monostearate Examples thereof include 50% acetylated product, fully acetylated product of coconut oil monoglyceride, soybean lecithin, egg yolk lecithin, and one or a mixture of two or more of enzymatically degraded lecithin.

  In the production method (1) of the present invention, it is particularly preferable to use MCT as the fat and oil, and egg yolk lecithin, soybean lecithin or enzymatically decomposed lecithin as the surfactant (E) in combination.

  In the production method (1) of the present invention, the time required for removing moisture from the oil-in-water emulsion composition droplets is not particularly limited, but is preferably 1 second to 24 hours, more preferably 3 seconds to 12 hours, Most preferably, it is in the range of 5 seconds to 6 hours. When the time required for removing moisture is less than 1 second, intense foaming may occur due to evaporation of moisture from the oil component (B) at once. On the other hand, when the time required for removing moisture is longer than 24 hours, productivity is lowered.

Incidentally, the removal of water in the production method (1) of the present invention means that even when the water is not completely removed, the drying of the oil-in-water emulsion composition droplets proceeds and the particles are recovered in the form of particles. As long as the state is possible. The water content of the particulate composition is usually preferably 30% by weight or less, more preferably 20% by weight or less, and most preferably 15% by weight or less of the weight of the particles after recovery. Needless to say, the lower limit is 0% by weight, but it is usually 0.01% by weight or more. In the production method (1), the method for recovering the particulate composition after removing the water is not particularly limited. After removing the oil component (B), the obtained particle composition is washed with an organic solvent or the like, and most of the oil component (B) is washed away, and further the organic solvent is removed by drying and recovered as a powder. Is most convenient and preferred.

  The organic solvent for washing the oil component (B) is not particularly limited as long as it is an organic solvent that can dissolve and remove the oil component (B), but it can be used for the production of foods, pharmaceuticals, cosmetics and the like. Is preferred. Examples of such a solvent include, but are not limited to, ethanol, methanol, isopropanol, acetone, hexane, ethyl acetate, tetrahydrofuran, and the like. Among these, when using the particulate composition of the present invention for food applications, it is most preferable to use ethanol. Examples of the method for drying the organic solvent include, but are not limited to, vacuum drying, heat drying, and air drying. In addition, classification operation can also be implemented in order to arrange | position the particulate composition after collection | recovery to a particle diameter desirable as a predetermined | prescribed product.

  On the other hand, in the production method (2) of the present invention, as described above, an oil-in-water emulsion composition prepared from an oily component (a) containing coenzyme Q10 and an aqueous excipient solution is used in the gas phase. The particulate composition of the present invention can be obtained by spray drying. A so-called spray drying method can be used as the spray drying method in the gas phase. The conditions for spray drying can be appropriately selected from the conditions that are usually carried out.

  Of the two types of production methods described above, in production method (1), the individual oil-in-water emulsion composition droplets suspended substantially spherically in the oil component (B) retained a spherical shape. Since moisture removal proceeds in a state, it tends to be easy to obtain a particulate composition having high oxidation stability, high sphericity and small surface roughness (Ra), which is the object of the present invention. This is a preferred production method.

  On the other hand, in the production method (2), particles containing reduced coenzyme Q10 having a nearly spherical shape and a small surface roughness (Ra) can be obtained by appropriately controlling the temperature and residence time during drying. A composition can be made.

  In addition, about manufacturing method (1) and (2) in this invention, of course, in order to suppress the oxidation of reduced coenzyme Q10 in a manufacturing process, each operation can be implemented in a deoxygenated atmosphere.

  In addition, in the production methods (1) and (2) of the present invention, when coenzyme Q10 containing oxidized coenzyme Q10 or oxidized coenzyme Q10 itself is used as a production raw material, By reducing at least a part of oxidized coenzyme Q10 with the lipophilic antioxidant used, the ratio of reduced coenzyme Q10 in the resulting particulate composition can be increased. Examples of the production process in which oxidized coenzyme Q10 is reduced to a lipophilic antioxidant include, for example, a preparation process of the above-described oil-in-water emulsion composition and a process of removing water from the oil-in-water emulsion composition. . However, even in this case, the coenzyme used as a raw material is easy to control the content of reduced coenzyme Q10 in the particulate composition obtained (or the weight ratio of reduced coenzyme Q10 to coenzyme Q10). A higher weight ratio of reduced coenzyme Q10 in Q10 is preferred.

  Next, a stabilization method and a handling method of the particulate composition containing the reduced coenzyme Q10 of the present invention described above will be described.

  The stabilization described in the present specification indicates that reduced coenzyme Q10 is inhibited from being oxidized to oxidized coenzyme Q10. The handling described in the present specification is to maintain or exert the function of an object by applying an external action to the object. Examples of handling can include, but are not limited to, dispensing from a coating machine, packaging, packing, storage, storage, and transport. Storage is preferred.

  In addition, the upper limit of the temperature in the method for stabilizing and handling the particulate composition containing the reduced coenzyme Q10 of the present invention is usually about 100 ° C. or less, preferably about 80 ° C. or less, more preferably about 60 ° C. Hereinafter, it can be carried out more preferably at about 40 ° C. or less, particularly preferably at about 20 ° C. or less. In this case, the lower limit of the temperature is usually about −100 ° C. or higher, preferably about −80 ° C. or higher, more preferably about −60 ° C. or higher, further preferably about −40 ° C. or higher, particularly preferably −20 ° C. or higher. .

  In the matrix of the present invention having a water-soluble excipient as a main component, the oily component (A) containing reduced coenzyme Q10 and a lipophilic antioxidant forms domains and is polydispersed. The composition can reduce the influence of humidity in the storage atmosphere as compared to a particulate composition that does not use a lipophilic antioxidant. However, considering long-term storage stability, the storage atmosphere condition is preferably lower humidity, relative humidity of about 90% or less, preferably about 80% or less, more preferably about about relative humidity. The particulate composition containing the reduced coenzyme Q10 of the present invention can be handled more stably in an environment adjusted to 70% or less, particularly preferably relative humidity of about 60% or less. The lower limit of the relative humidity is 0%.

  That is, the present invention provides a particulate composition containing reduced coenzyme Q10 and a method for stabilizing and handling a preparation containing the composition, wherein the relative humidity is adjusted.

  The environment in which the relative humidity is adjusted is given by dehumidification from the environment or introduction of a dehumidified gas (which may be air, but preferably a dry inert gas such as dry nitrogen) into the environment. The dehumidification is not particularly limited, but can be achieved by freezing moisture, using a dehumidifier, a desiccant (silica gel, calcium chloride, synthetic zeolite, etc.) and the like. Needless to say, the method is not particularly limited as long as an environment in which the relative humidity is adjusted is given.

  In order to maximize the effects of the present invention, the particle composition of the present invention is naturally produced and stored in a deoxygenated atmosphere from the viewpoint of the stability of the reduced coenzyme Q10. For example, it is preferable to carry out in a deoxygenated atmosphere such as an inert gas such as nitrogen gas or argon gas.

  In the present invention, the reduced coenzyme Q10 in the particulate composition is stabilized for a long period of time by packaging and packing the particulate composition of the present invention with a glass, plastic and / or metal material. Can be stored and / or handled.

  Examples of the glass material include soft glass and hard glass. Examples of the plastic material include high density polyethylene, medium density polyethylene, low density polyethylene, polypropylene, polyethylene terephthalate, polyvinyl alcohol, polyvinyl chloride, polyvinylidene chloride, and nylon. Needless to say, films made by laminating the above plastic materials, films made by laminating aluminum etc. on plastic materials such as aluminum laminate, and films made by evaporating aluminum, alumina, silica, etc. on plastic materials are also made of plastic. Included in the material. Examples of the metal material include iron, aluminum, zinc, nickel, cobalt, copper, tin, titanium, chromium, and alloys thereof (stainless steel, brass, etc.). In addition, materials such as enamels that combine glass and metal can be used.

  The above-mentioned material is preferably molded into a bottle, bag, can, drum, box, etc., and the particulate composition of the present invention is packaged and packed. Moreover, it can also be set as PTP packaging, three-side seal packaging, four-side seal packaging, pillow packaging, strip packaging, aluminum molding packaging, stick packaging, etc. using said raw material. When materials with relatively low gas barrier properties and moisture-proof properties such as polyethylene are used, it is preferable to use double or more packaging / packaging. At this time, aluminum laminate, vapor deposited film of aluminum, alumina, silica, etc., glass It is particularly preferable to use a material having relatively high gas barrier properties and moisture resistance such as metal. After packaging and packing, it can be transported and stored in steel drums, resin drums, fiber drums, cardboard, etc. as necessary. Needless to say, a moisture-proofing agent such as silica gel, calcium chloride, or synthetic zeolite may be enclosed.

  Then, the preferable formulation form of the particulate composition containing the reduced coenzyme Q10 of this invention is demonstrated.

  The particulate composition containing reduced coenzyme Q10 obtained in the present invention is a tablet, pill, capsule (hard capsule, soft capsule, microcapsule, etc.), chewable tablet, powder, granule, syrup, drink, etc. It can be processed or used as pharmaceuticals, other foods, cosmetics, etc. as a formulation, and a formulation form for realizing the high oxidative stability and high oral absorbability which are the objects of the present invention can be realized. In addition, the formulation here refers not only to a medicine but also to those belonging to foods and cosmetics and having the above-mentioned form. In formulation, in addition to excipients, disintegrants, lubricants, binders, anti-aggregation agents, absorption promoters, solubilizers, antioxidants, stabilizers, etc., in addition to capsules, oils and fats, lecithin, A surfactant such as lysolecithin can also be used in combination.

The above-mentioned particulate composition of the present invention is made into a mixed slurry suspended in the oil component (F), and the slurry is filled in a soft capsule such as gelatin to achieve high oxidation stability and high oral absorption. It is also possible to make a soft capsule formulation.
Conventionally, as a soft capsule preparation containing reduced coenzyme Q10, a composition in which reduced coenzyme Q10 powder is dispersed or dissolved in a slurry form in an oily component mainly composed of vegetable oil and / or a surfactant is used as a soft capsule. Preparations filled in are known. However, in this preparation, the invasion of oxygen from the outside is physically shielded only by the capsule skin wall, and the reduced coenzyme Q10 is stabilized. When stored under humid conditions, the reduced form is used. The stability of coenzyme Q10 is not sufficient.

  On the other hand, in the soft capsule formulation obtained by filling the mixed slurry in which the particulate composition of the present invention is suspended in the oil component (F) into a soft capsule such as gelatin, the reduced coenzyme Q10 is only in the capsule shell. In addition, it is possible to physically shield the entry of oxygen from the outside with a double film combined with the water-soluble excipient layer, and it becomes possible to obtain a preparation with better oxidation stability. The conceptual diagram is shown in FIG.

Since the particulate composition of the present invention can be stably handled and / or stored even under humid conditions, it is particularly excellent in stability under humid conditions compared to conventional soft capsules.
Moreover, the soft capsule formulation of the present invention also shows higher oral absorbability than the conventional soft capsule formulation in terms of oral absorbability. This is because the particulate composition of the present invention is disintegrated in the stomach or intestine in the presence of fats and oils, and the reduced coenzyme Q10 is released in vivo in a fine state effective for absorption into the digestive tract. It is estimated that this is because of this.

  As the oil component (F) used in the soft capsule formulation, the above-described oil and fat, surfactant (emulsifier), waxes such as beeswax, and the like can be used alone or in a mixture of two or more. Without being limited thereto, other components may be optionally added so that the oral absorbability of reduced coenzyme Q10 in the particulate composition of the present invention is good, and any other active ingredients It may be a mixture. Needless to say, among the oils and fats, surfactants and waxes, those acceptable for foods, pharmaceuticals and the like are preferable.

  Further, in the present invention, the particulate composition of the present invention is used as it is or as a powder obtained by mixing with a general preparation component such as any excipient or lubricant, or the oil component (F). By filling a hard capsule such as gelatin as a slurry suspended therein, it is possible to obtain a hard capsule preparation capable of realizing high oxidation stability and high oral absorption.

Usually, a hard capsule preparation containing reduced coenzyme Q10 is assumed to be a preparation obtained by filling a hard capsule such as gelatin with a powder composition containing reduced coenzyme Q10 powder. However, in this preparation, similarly to the soft capsule preparation, the invasion of oxygen from the outside is only physically shielded only by the capsule shell, and the reduced coenzyme Q10 filled even after the preparation is prepared. Can be easily oxidized.
On the other hand, in a hard capsule preparation obtained by filling a particulate composition containing the reduced coenzyme Q10 of the present invention into a hard capsule such as gelatin, the reduced coenzyme Q10 is not only a capsule shell but also a water-soluble additive. It is possible to physically shield the entry of oxygen from the outside with a double film combined with the shape layer, and to obtain a reduced coenzyme Q10 preparation that is more stable against oxidation.

  Moreover, in the hard capsule preparation of the present invention, the particulate composition of the present invention is disintegrated in terms of oral absorption as compared with the hard capsule preparation filled with the reduced coenzyme Q10 powder usually having a volume average particle diameter of about 10 μm. Since the reduced coenzyme Q10 is released in vivo in a fine state effective for absorption into the digestive tract, oral absorbability is improved.

  Needless to say, other components may be optionally added so that the oral absorbability of the reduced coenzyme Q10 of the present invention is good, or a mixture with any other active ingredient may be used.

  In the present invention, the particulate composition of the present invention can be processed into a tablet or chewable agent together with any excipient, lubricant and the like.

  Usually, as a tablet or chewable agent containing reduced coenzyme Q10, a preparation obtained by processing a composition containing reduced coenzyme Q10 powder by tableting or the like is assumed. However, in this preparation, naked reduced coenzyme Q10 powder is only dispersed and distributed in a composition containing an excipient such as lactose and a lubricant such as magnesium stearate and crystalline cellulose. Since the reduced coenzyme Q10 cannot be prevented from oxidation, the oxidation stability is inevitably at a low level. However, the tablet or chewable agent obtained by processing the particulate composition containing reduced coenzyme Q10 of the present invention is a water-soluble excipient matrix in which reduced coenzyme Q10 contains water-soluble ascorbic acid. Therefore, it is possible to physically block the invasion of oxygen from the outside, and to obtain a reduced coenzyme Q10 preparation that is more stable against oxidation. Needless to say, other components may be optionally added so as to improve the oral absorbability of the particulate composition of the present invention, or a mixture with any other active ingredient may be used. Needless to say, other components may be optionally added so that the oral absorbability of the reduced coenzyme Q10 of the present invention is good, or a mixture with any other active ingredient may be used. In addition, the tablet or chewable preparation of the present invention can be coated with sugar coating or the like, if necessary.

  In addition, from the viewpoint of the stability of the particulate composition containing reduced coenzyme Q10, the above preparation is also handled or stored in an environment in which the relative humidity is adjusted as described above, and / or When handling or storing, it is a preferable aspect to perform the packaging as described above.

  Furthermore, the particulate composition of the present invention can be used for foods such as jelly and yogurt, beverages, cosmetics, etc. containing reduced coenzyme Q10 as it is or dissolved in water. In each production process of these foods, beverages or cosmetics, in some cases, the particulate composition of the present invention is disintegrated in water, and the oil component containing the reduced coenzyme Q10 in the domain portion has a volume average particle size of 0. It becomes fine particles of 01 to 50 μm and is dispersed in the product. Thus, by using the particulate composition of the present invention, reduced coenzyme Q10 can be stored in a product while it can be stored in a state of good oxidation stability until immediately before production of the product. Not only can it be in a finely dispersed state with a very small particle size, but a reduced coenzyme Q10-containing emulsion composition can be obtained under mild stirring conditions without using a large-scale emulsifying device.

  The particulate composition of the present invention includes the above-mentioned forms and other forms, foods (general foods, nutritional functional foods, foods for specified health use, nutritional supplements, nutritional agents), animal drugs, beverages, feeds, It can be used extensively in applications such as cosmetics, pharmaceuticals, therapeutic agents, prophylactic agents, etc., or processing into raw materials and compositions thereof.

  EXAMPLES Next, although this invention is demonstrated further in detail based on an Example, this invention is not limited only to this Example.

(Purity of reduced coenzyme Q10)
The purity of reduced coenzyme Q10 and the weight ratio (%) of reduced coenzyme Q10 were determined by the following HPLC analysis (weight ratio (%) = reduced coenzyme Q10 / (oxidized coenzyme Q10 + reduced coenzyme Q10). ) × 100). The HPLC analysis conditions are described below.

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 0.0 ml / min, retention time of reduced coenzyme Q10; 9.1 min, retention time of oxidized coenzyme Q10; 13.3 min.

(Sphericity)
The sphericity of the obtained particulate composition is determined by analyzing the image obtained by electron microscope observation of the recovered particles with image analysis software (WinROOF Ver. 3.30), and the diameter and circumscribing of a circle having the same area. It was calculated from the diameter ratio of the smallest circle. In the analysis, 20 samples were analyzed and the average value was obtained.

(Crystallinity)
The crystallinity of reduced coenzyme Q10 in the obtained particulate composition was determined by analyzing the following DSC (differential scanning calorimeter [EXSTAR6000 manufactured by Seiko Denshi Kogyo Co., Ltd.]) after storage at 25 ° C. in air for 30 days. Determined by doing. After storing the particulate compositions obtained in Examples and Comparative Examples under the above-mentioned predetermined conditions, 10 mg of them are taken into an aluminum pan and heated from 15 ° C. to 70 ° C. at a temperature rising rate of 5 ° C./min. The heat of crystal melting at that time was measured. The degree of crystallinity was calculated according to the following formula 3 from the theoretical heat of fusion obtained from the content of reduced coenzyme Q10 in the particulate composition and the data of heat of fusion measured by DSC.

Crystallinity (%) = (Measured heat of fusion / Theoretical heat of heat) × 100 (Formula 3)
(Production example)
In 1000 g of ethanol, 100 g of oxidized coenzyme Q10 crystal (manufactured by Kaneka Corporation) 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 400 g of ethanol and 100 g of water were added while maintaining the same temperature. While stirring this ethanol solution, it was cooled to 2 ° C. at a cooling rate of 10 ° C./hour, washed in this order with cold ethanol and cold water, and the resulting wet crystals were dried under reduced pressure to obtain 95 g of white dry crystals. Obtained (solid yield 95 mol%). All operations except for drying under reduced pressure were performed in a nitrogen atmosphere. The purity of the obtained crystal was 99.1%, and the weight ratio (%) of reduced coenzyme Q10 to the total amount of coenzyme Q was 99.0%.
Example 1
In 104.9 g of distilled water, 56.5 g of gum arabic (manufactured by Colloid Naturel; Instant Gum AA), 7.5 g of lysolecithin (manufactured by Cargill; Emultop IP), ascorbyl palmitate (manufactured by Wako Pure Chemical Industries, Ltd.) 6.0 g and 30 g of reduced coenzyme Q10 powder obtained in the above production example were added, heated to 60 ° C. and dissolved, and then rotated 10,000 times with a TK homomixer Mark II (manufactured by Primics Co., Ltd.) The mixture was emulsified for 20 minutes to obtain an oil-in-water emulsion composition. The emulsified particle diameter of the oil component containing reduced coenzyme Q10 in the oil-in-water emulsion composition was about 1000 nm. 204.4 g of the oil-in-water emulsion composition obtained here was heated to 90 ° C. in advance, 400 g of MCT (manufactured by Riken Vitamin Co., Ltd .; Actor M-2) and a surfactant (paste lecithin: AD M Far East Co., Ltd .; Yelkin TS) was added to 2 g of the oil component (B), and the stirring rotation speed was adjusted so that the particle diameter of the oil-in-water emulsion composition suspension droplets was about 200 μm. While stirring at the same number of stirring, stirring at 90 ° C. for 60 minutes under reduced pressure conditions (about 200 torr), further stirring at 120 ° C. for 60 minutes under reduced pressure conditions to completely remove moisture and form particles. went.

  Thereafter, according to a conventional method, the oily component (B) is separated by solid-liquid separation, and the oily component (B) adhering to the particles is washed with about 180 g of ethanol, followed by vacuum drying at 40 ° C. for 6 hours. And a particulate composition containing reduced coenzyme Q10 was obtained.

  The sphericity of the obtained particulate composition is 0.8 or more, and the retention rate of reduced coenzyme Q10 after storing the particulate composition at 40 ° C., relative humidity of 75%, and under light-shielding conditions for 30 days is , 98.1%. Further, the crystallinity of reduced coenzyme Q10 in the particulate composition measured by DSC is less than 90%, and 10% by weight or more of reduced coenzyme Q10 in an amorphous state or a melt state. Contained.

  When the appearance of the obtained particulate composition was observed with a scanning electron microscope (S-4800, manufactured by Hitachi, Ltd.), it was found that it had a very beautiful spherical shape as shown in FIG.

(Example 2)
115.3 g of distilled water, 62.1 g of gum arabic (manufactured by Colloidal Naturel; Instant Gum AA), 1.9 g of diglycerin monooleate (manufactured by Riken Vitamin; Poem DO-100V), ascorbyl palmitate (Japanese) Koyo Pure Chemical Industries, Ltd.) 6.0 g and reduced coenzyme Q10 powder 30 g obtained in the above production example were used in the same manner as in Example 1 except that an oil-in-water emulsion composition was prepared. A particulate composition containing coenzyme Q10 was obtained. The sphericity of the obtained particulate composition is 0.8 or more, and the retention rate of reduced coenzyme Q10 after storing the particulate composition at 40 ° C., relative humidity of 75%, and under light-shielding conditions for 30 days is 98.0%.

(Comparative Example 1)
The white dried crystals of reduced coenzyme Q10 obtained in Production Example were pulverized in a mortar to obtain reduced coenzyme Q10 powder. The retention of reduced coenzyme Q10 in the obtained reduced coenzyme Q10 powder after storage for 30 days under the conditions of 40 ° C., relative humidity of 75% and light shielding was 28%.

(Comparative Example 2)
116 g of distilled water, 62.5 g of gum arabic (manufactured by Colloid Naturel; Instant Gum AA), 7.5 g of lysolecithin (manufactured by Cargill; Emultop IP), and reduced coenzyme Q10 powder obtained in the above production example A particulate composition containing reduced coenzyme Q10 was obtained in the same manner as in Example 1 except that 30 g was used and an oil-in-water emulsion composition was prepared without using ascorbyl palmitate. The sphericity of the obtained particulate composition is 0.8 or more, and the retention rate of reduced coenzyme Q10 after storing the particulate composition at 40 ° C., relative humidity of 75%, and under light-shielding conditions for 30 days is 78.8%.

(Example 3: Soft capsule)
The particulate composition containing reduced coenzyme Q10 obtained in Example 1 above is added to a mixture of safflower oil and beeswax to form a slurry, which is then encapsulated in a conventional manner, from the following ingredients: A gelatin soft capsule preparation was obtained.

Particulate composition containing reduced coenzyme Q10 30 parts by weight Safflower oil 65 parts by weight Beeswax 5 parts by weight (Example 4: hard capsule)
The particulate composition containing reduced coenzyme Q10 obtained in Example 1 was encapsulated in a hard capsule by a conventional method to obtain a hard capsule formulation.

(Example 5: Tablet)
After mixing the particulate composition containing reduced coenzyme Q10 obtained in Example 1 above with crystalline cellulose (Avicel), magnesium stearate is further mixed, and tablets comprising the following components are prepared by a conventional method. Obtained. The appearance of the obtained tablets was beautiful and no tableting problems were observed, and there were no troubles such as sticking (drug adhesion to the mortar surface) during production.

Particulate composition containing reduced coenzyme Q10 50 parts by weight Crystalline cellulose 50 parts by weight Magnesium stearate 1 part by weight

From the examples and comparative examples, the particulate composition of the present invention is a reduction contained in the particulate composition by incorporating a water-insoluble ascorbic acid into a matrix mainly composed of a water-soluble excipient. It can be seen that the oxidation stability of the type coenzyme Q10 is improved. Furthermore, it can be seen that high oxidation stability is maintained even under humid conditions.

The scanning electron micrograph of the external appearance of the particulate composition obtained in Example 1.

Claims (31)

  A particulate composition in which an oily component (A) containing reduced coenzyme Q10 and a lipophilic antioxidant is formed into a domain and polydispersed in a matrix mainly composed of a water-soluble excipient.   The particulate composition according to claim 1, wherein the lipophilic antioxidant is an ascorbic acid fatty acid ester.   The particulate composition according to claim 1 or 2, wherein the sphericity is 0.8 or more.   The particulate composition according to any one of claims 1 to 3, wherein 10% by weight or more of the reduced coenzyme Q10 in the particulate composition is not in a crystalline state.   The particulate composition according to any one of claims 1 to 4, wherein the oil component (A) is polydispersed by forming 5 or more domains.   The ratio of the reduced coenzyme Q10 and the lipophilic antioxidant in the particulate composition is in the range of 100: 1 to 1: 5 by weight, according to any one of claims 1 to 5. Particulate composition.   The particle according to any one of claims 1 to 6, wherein the water-soluble excipient is at least one selected from the group consisting of a water-soluble polymer, a surfactant (C), a sugar, and a yeast cell wall. Composition.   The group in which the water-soluble polymer is gum arabic, gelatin, agar, starch, pectin, carrageenan, casein, dried egg white, curdlan, alginic acids, soybean polysaccharide, pullulan, celluloses, xanthan gum, carmellose salt, and polyvinylpyrrolidone The particulate composition according to claim 7, wherein the particulate composition is one or more selected from the above.   The particulate composition according to claim 7, wherein the sugar is at least one selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, sugar alcohols, and polysaccharides.   The oily component (A) containing reduced coenzyme Q10 is 5 to 99.95% by weight of coenzyme Q10, 0.05 to 95% by weight of lipophilic antioxidant, and 0 to 94.95% by weight of fat and oil. The particulate composition according to any one of claims 1 to 9, comprising 0 and 94.95% by weight of a surfactant (D).   The particulate composition according to any one of claims 1 to 10, wherein the content of reduced coenzyme Q10 in the particulate composition is 1 to 70% by weight.   The particulate composition according to any one of claims 1 to 11, wherein the volume average particle diameter is 1 to 1000 µm.   The particulate composition according to any one of claims 1 to 12, wherein an average particle diameter of a domain formed by the oil component (A) containing reduced coenzyme Q10 is 0.01 to 50 µm.   The retention rate of reduced coenzyme Q10 in the particulate composition after storage for 30 days under light-shielding conditions at 40 ° C, relative humidity 75% is 80% by weight or more. The particulate composition.   Capsules, tablets, chewable tablets, foods, beverages, or cosmetics obtained by processing the particulate composition according to any one of claims 1 to 14.   The particulate composition according to any one of claims 1 to 14 or the capsule, tablet, chewable tablet, food, beverage or cosmetic according to claim 15 in an environment having a relative humidity of 90% or less. A method for stabilizing a particulate composition or capsule, tablet, chewable tablet, food, beverage or cosmetic containing reduced coenzyme Q10,   The particulate composition according to any one of claims 1 to 14 or the capsule, tablet, chewable tablet, food, beverage or cosmetic according to claim 15, which is made of glass, plastic and / or metal. A method of stabilizing a particulate composition or capsule containing reduced coenzyme Q10, a tablet, a chewable tablet, a food, a beverage, or a cosmetic, characterized by packaging and packing with a manufactured material.   The stabilization method according to claim 16 or 17, wherein a moisture-proof agent is used in combination.   An oil-in-water emulsion composition is prepared from an aqueous solution containing a water-soluble excipient and an oily component (a) containing coenzyme Q10 and a lipophilic antioxidant, and water in the oil-in-water emulsion composition A process for producing a particulate composition containing reduced coenzyme Q10, wherein   The production method according to claim 19, wherein reduced coenzyme Q10 is used as coenzyme Q10 contained in oil component (a).   In the process of producing a particulate composition using oxidized coenzyme Q10 or a mixture of oxidized coenzyme Q10 and reduced coenzyme Q10 as coenzyme Q10 contained in oil component (a), coenzyme Q10 The production method according to claim 19, wherein at least a part of the oxidized coenzyme Q10 is reduced to reduced coenzyme Q10.   The production method according to any one of claims 19 to 21, wherein the lipophilic antioxidant is an ascorbic acid fatty acid ester.   The oil-in-water emulsion composition is suspended in the oil component (B), and then water in the oil-in-water emulsion composition is removed in the oil component (B). The manufacturing method according to any one of 22 above.   24. The production method according to claim 23, wherein the oil component (B) contains 5 to 99.99% by weight of fat and oil and 0.01 to 95% by weight of the surfactant (E).   The production method according to any one of claims 19 to 22, wherein water in the oil-in-water emulsion composition is removed by spray drying the oil-in-water emulsion composition in a gas phase. .   The manufacturing method of any one of Claims 19-25 whose sphericity of the particulate composition obtained is 0.8 or more.   27. The production method according to any one of claims 19 to 26, wherein 1 to 500 parts by weight of water-insoluble ascorbic acid is used for 100 parts by weight of coenzyme Q10.   28. The production according to any one of claims 19 to 27, wherein the water-soluble excipient is at least one selected from the group consisting of a water-soluble polymer, a surfactant (C), a sugar, and a yeast cell wall. Method.   The group in which the water-soluble polymer is gum arabic, gelatin, agar, starch, pectin, carrageenan, casein, dried egg white, curdlan, alginic acids, soybean polysaccharide, pullulan, celluloses, xanthan gum, carmellose salt, and polyvinylpyrrolidone The production method according to claim 28, wherein the production method is at least one selected from the group consisting of   The production method according to claim 28, wherein the sugar is at least one selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, sugar alcohols, and polysaccharides.   Oily component (a) containing coenzyme Q10 is 5 to 99.95% by weight coenzyme Q10, 0.05 to 95% by weight lipophilic antioxidant, 0 to 94.95% by weight fat and oil, and The manufacturing method of any one of Claims 19-30 containing 0-94.95 weight% of surfactant (D).