JP2004196781A - Water-soluble composition containing coenzyme q10 - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a water-soluble composition containing coenzyme Q<SB>10</SB>, free from the deposition, precipitation or flotation of the coenzyme Q<SB>10</SB>formulated in a high concentration without using a dissolution medium such as oil-and-fat, keeping a homogeneous and stable dissolved (solubilized) state, having excellent acid resistance, salt resistance and heat resistance necessary as an additive for pharmaceuticals, food products, drink products, cosmetics and feeds and having remarkably improved absorbability in the body, and provide a method for the production of the composition. <P>SOLUTION: This water-soluble composition containing coenzyme Q<SB>10</SB>is composed of (A) 5-40 mass% coenzyme Q<SB>10</SB>, (B) 5-30 mass% monoester of a polyglycerol having an average polymerization degree of 10 and an 18C fatty acid, (C) 1-18 mass% mono-, di-, tri- or penta-ester of a polyglycerol having an average polymerization degree of 3-6 and an 18C fatty acid, (D) water and optionally (E) 10-80 mass% solubilizing assistant. The composition has an average particle diameter of ≤110 nm. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

The present invention, water-soluble composition containing a coenzyme Q _10, and a production method thereof, and pharmaceutical containing the water-soluble composition, food and drink, cosmetic and related feed. In particular, coenzyme Q ₁₀ can be contained at high concentrations, long-term storage and coenzyme Q ₁₀ also precipitation, or the like, not precipitated or floated, excellent storage stability, and absorbability in fasting obtained The present invention relates to a water-soluble composition having excellent absorbability. Further, the present invention is excellent in heat resistance required at the time of addition, acid resistance, medicine containing excellent coenzyme Q ₁₀ in salt tolerance, food, cosmetics, it relates feed.

Coenzyme Q ₁₀ is 2,3-dimethoxy-5-methyl-6-polyprenyl-1,4-ubiquinones which isoprene units in the side chain are present in 10 higher animals benzoquinone (structural formula C ₅₉ H ₉₀ O _4, a molecular weight 863.4), which is one of coenzyme Q, known as ubidecarenone or coenzyme Q _10. As its physical properties, it is known as an orange-yellow crystal and a fat-soluble substance having a melting point of about 49 ° C. Coenzyme Q ₁₀ not only has a biological activity as a coenzyme, known as vitamin-like substance having an action of improving the oxygen utilization efficiency. Coenzyme Q ₁₀ is essential to the production of adenosine triphosphate in the mitochondria, heart disease by improving immune function, hypertension, rheumatic valve disease, efficacy, etc. for inflammation of the alveolar have been reported. It is also used for congestive heart failure, cerebrovascular disorder, side effects prevention of anticancer drugs (prevention of heart damage due to adriamycin), recovery from fatigue, energy activation, antioxidation against active oxygen in vivo, and the like. Further, it is expected to be effective as an external preparation for skin for preventing aging. Thus coenzyme Q ₁₀ has a high physiological activity, and and considered highly safe substance present in the body.

Recently these circumstances, with respect to coenzyme Q _10, various techniques have been disclosed.
For example, in Patent Document 1, a non-ionic surfactant such as polyethylene glycol and hydrogenated castor oil polyoxyethylene- (20) -ether is used and a high pressure homogenizer (500 to 550 kg / cm ² ) of a Manton-Gaulin type is used. A processed fat emulsion is disclosed.
Patent Document 2 discloses an emulsion for intravenous injection which is treated with a vegetable oil such as soybean oil and a phospholipid surfactant such as phosphatidylcholine and has a particle size of 0.5 to 300 µm.
Further, Patent Document 3, using 12.5-13.5 fold amount of coenzyme Q ₁₀ and decaglyceryl point pen Tao rate as an oily solvent, a diacyl mono capric of coenzyme Q ₁₀ as a stabilizer 0.4 to 1.6 There is disclosed a self-emulsifying soft capsule drug which is mixed in a double amount. Patent Literature 4 discloses a fat emulsion contained in a fat emulsion having a specific particle size (0.5 μm or less) using a phospholipid surfactant such as vegetable oil or lecithin as an intravenously administrable emulsion. Have been.
Patent Document 5, using ubiquinone as a crystalline drug, adipic acid, dissolved in an oil component such as soybean oil in a supersaturated state, using a polyoxyalkylene-based, polyglycerin fatty acid ester, tween-based surfactants, An emulsified composition such as a medicinal product having good absorbability, which is prepared by preparing an O / W type microemulsion and added to another O / W type microemulsion, is disclosed.
Patent Document 6 discloses a composition in which ubiquinone is dissolved in fats and oils, emulsified using a fat globule membrane in mammalian milk, and particles having a specific particle size (1 to 5 μm) are fractionated to improve absorbability. ing.
Patent Document 7 discloses that ubiquinone is added as a fat-soluble substance, and polyglycerin fatty acid ester, glycerophospholipid, as well as a polyhydric alcohol and water are added as emulsifiers, and the mixture is stirred and then homogenized at a high pressure of 500 to 2000 kg / cm ^2. An aqueous solution of a fat-soluble substance characterized by the following is disclosed.

Coenzyme Q ₁₀ fatty emulsion of Patent Document 1 has a problem that poor when the grain size is greater clarity.
Furthermore, intravenous emulsion of Patent Document 2 has low content of coenzyme Q _10, storage stability is poor problem when a high concentration. Since the self-emulsifying soft capsules chemical obtained in Patent Document 3 needs a 12.7 to 15.1-fold and a large excess of active agent to Coenzyme Q _10, the flavor and the active agent daily dietary allowance of there is a problem that intake of coenzyme Q ₁₀ is less restricted in relation.
Patent Document 2, Patent Document 4 and Patent Document 6, is disclosed for intravenous emulsion or parenteral administration preparations, in this technique, is used to always dissolving coenzyme Q ₁₀ in oil, further There are problems such as a large particle size and poor transparency. In addition, there are problems such as poor heat resistance, acid resistance, and salt resistance required in the production of food and drink.
Patent Literature 5 discloses a lotion having excellent storage stability at low temperatures. However, with this technique, the transparency becomes poor and the sedimentation occurs as the liquid temperature decreases. In addition, there are problems such as poor heat resistance, acid resistance, and salt resistance that are required.
Patent Literature 7 discloses an oil-in-water microemulsion applicable to various kinds of oily substances. This technique has problems such as acid resistance, salt resistance, and poor heat resistance under various conditions.
Patent Literature 8 discloses a solubilizing solution in which an oily component is composed of a fatty acid ester of polyglycerin, water, and a food additive. This solubilization solution has problems such as poor transparency and stability.

The water-soluble composition containing a coenzyme Q _10,
(1) Small particle size and excellent transparency
(2) a high concentration without the need for oil-based component for dissolving or dispersing the coenzyme Q _10,
(3) excellent in texture and taste,
(4) Special conditions, complicated processes, etc. are not required during manufacturing.
(5) Excellent acid and heat resistance and salt heat resistance required for addition to various foods.
Etc. are required.

However, Coenzyme Q ₁₀ is insoluble in water, light and heat, has high simultaneously crystallinity to be unstable to alkali, accompanied by difficulty in formulation by general emulsion. Also, once even when the emulsified composition was prepared, separation by recrystallization of coenzyme Q _10, precipitation, precipitation or floating is liable to occur. Furthermore, in order to obtain a sufficient effect of coenzyme Q _10, it is necessary to increase the concentration of coenzyme Q ₁₀ of the water-soluble composition, difficulty solution of for such poorly soluble and highly crystalline It is.
Further, the coenzyme Q ₁₀ food products, when added to cosmetics, without the need for oil-based components commonly used, further properties are required in formulating these, transparency, acid resistance, salt tolerance , heat resistance are both excellent, good emulsion stability, storage stability, and the lysate has been demanded that the coenzyme Q ₁₀ may contain a high concentration. Moreover, Coenzyme Q ₁₀ is also low absorbable in vivo, was also determined for the improvement of the absorbent.

JP-A-60-199814 JP-A-61-56124 JP-A-62-67019 JP-A-62-123113 JP-A-63-150221 JP 05-78240A JP 2000-212066 A JP-A-9-168369

Accordingly, an object of the present invention, deposition be stored coenzyme Q ₁₀ obtained by blending a high concentration without using a dissolution medium of oils and fats is a long period of time, without causing precipitation or floating, stable water-soluble homogeneous ( (Solubilized) state, and is excellent in texture, taste, acid resistance, salt resistance, heat resistance required when added to medicines, foods and drinks, cosmetics, feeds, and absorbable in vivo. It was significantly improved, to provide a water-soluble composition and a production method containing coenzyme Q _10. Also, by blending the composition, coenzyme Q ₁₀ is deposited, precipitation, without or floating, pharmaceutical having excellent transparency, food and drink, cosmetic and feed, as well as to provide the method of administration It is in.

The present inventors have intensively studied the results for the above problems solved, if the formation of oil-in-water emulsion using a specific two surfactants, solubilizing condition better retention of high concentrations of coenzyme Q ₁₀ The present invention has been found to improve the bioabsorbability and to complete the present invention. That is, the present invention provides the following [1] to [8].
[1] (A) 5 to 40% by mass of coenzyme Q ₁₀ , (B) 5 to 30% by mass of monoester of polyglycerin having an average degree of polymerization of 10 and a fatty acid having 18 carbon atoms, (C) having an average degree of polymerization of 3 to 6 A water-soluble composition comprising 1 to 18% by mass of a mono-, di-, tri- or pentaester of polyglycerin and a fatty acid having 18 carbon atoms, and (D) water, and having an average particle diameter of 110 nm or less. object,
[2] The water-soluble composition according to the above 1, wherein the fatty acid of the component (B) is stearic acid, oleic acid or linoleic acid, and the fatty acid of the component (C) is stearic acid, oleic acid or linoleic acid.
[3] The water-soluble composition according to [1] or [2], further comprising (E) 10 to 80% by mass of a solubilizing aid,
[4] The water-soluble composition according to the above [3], wherein the solubilizing aid is a gum, a saccharide, or a polyhydric alcohol.
[5] The mass ratio of component (A) / {(B) + (C)} is 1/5 to 0.7, and the mass ratio of component (B) / (C) is 1 / 0.2 to 0.2. 1, the water-soluble composition according to any one of the above [1] to [4],

[6] Next step:
(I) heating and dissolving components (B), (C) and (D), and optionally component (E);
(II) Add component (A) and mix, then (III) homogenize with a homomixer at a peripheral speed of 750 m / min or more with a stirring blade, and / or (IV) homogenize machine. [1] to [5], wherein the homogenization treatment is performed at a homogenization pressure of 98 MPa (1,000 kg / cm ² ) or more, and the average particle size is reduced to 110 nm or less by the above steps. process for producing a water-soluble composition containing a coenzyme Q ₁₀ according to any one of,
[7] The production method according to [6], wherein step (III) or (IV) is repeated, or step (III) is performed, and then step (IV) is performed.

[8] the [1] to a medicament comprising a water-soluble composition containing a coenzyme Q ₁₀ according to any one of [5], food products, cosmetics and feed

Water-soluble composition containing a coenzyme Q ₁₀ of the present invention is excellent in storage stability, long period of time without coenzyme Q ₁₀ is precipitated even when stored, it is possible to maintain the homogeneous and stable state. It also has excellent acid resistance, salt resistance, and heat resistance, and can stably maintain its water-solubilized state even when blended with medicines, foods and drinks, cosmetics, feeds, and additives commonly used in these. Furthermore, it is stable against heat treatment and can be subjected to high-temperature sterilization or sterilization.
The water-soluble composition of the present invention is the absorbent is markedly improved coenzyme Q _10, it is possible to particularly ingest coenzyme Q ₁₀ in an amount sufficient even fasting.
Water-soluble composition of the present invention may be ingested directly, pharmaceutical, food or drink, by incorporating in the production of such cosmetic and feed, it is possible to feed efficiently coenzyme Q ₁₀ in an amount sufficient . In particular, frail elderly, dysphagia, nutrition, etc. postoperative, even for people have difficulty ingesting solid, it is possible to reliably supply the coenzyme Q _10.

Water-soluble composition containing a coenzyme Q ₁₀ of the present invention, (A) coenzyme Q ₁₀ 5 to 40 wt%, (B) an average polymerization degree of 10 of monoester 5 to 30 mass polyglycerol and 18 carbon atoms in the fatty acid %, (C) 1 to 18% by mass of mono-, di-, tri- or pentaester of polyglycerin having an average degree of polymerization of 3 to 6 and a fatty acid having 18 carbon atoms, and (D) water, and optionally (E) a solubilizing aid. It is characterized by comprising 10 to 80% by mass and having an average particle size of 110 nm or less, preferably 80 nm or less, more preferably 60 nm or less.

Component (A)
Coenzyme Q ₁₀ is ubiquinone 10 as ubidecarenone or coenzyme UQ ₁₀ etc., it is described in the Japanese Pharmacopoeia. Coenzyme Q ₁₀ used in the present invention may be those extracted from animal heart such as cows, synthetic methods, include those obtained by fermentation. In particular, as commercially available products, food ingredients coenzyme Q ₁₀ (Nisshin Pharma Co., Ltd., trade name), Kaneka Coenzyme Q ₁₀ (Kaneka Co., Ltd., trade name), CoEnzyme Q ₁₀ (Asahi Kasei (Ltd. ), Product name) and the like. When used, the purity and the like are not particularly limited, but the water-soluble composition of the present invention is applied to beverages, foods, and cosmetics including medicines, various supplements, and the like. It is desirable that the quality of the product, such as its content and its content, be sufficiently controlled.
The amount of coenzyme Q ₁₀ to the water-soluble composition, 5 to 40 wt%, preferably from 7 to 30 wt%, more preferably 9-25 wt%.
Amount of coenzyme Q ₁₀ is, if less than 5 wt%, since the amount of the water soluble composition to obtain the aimed effects increases undesirably. Amount of coenzyme Q ₁₀ is, if more than 40 wt%, the to retain the solubilized state of the coenzyme Q ₁₀ of the water-soluble composition stably becomes difficult, undesirably.

Component (B)
The blending amount of the component (B), that is, the polyglycerol having an average degree of polymerization of 10 and the monoester of a fatty acid having 18 carbon atoms is 5 to 30% by mass, but 5 to 25% by mass from the viewpoint of emulsion stability and flavor. Preferably it is 7-20 mass%.
The constituent fatty acid of component (B) is not particularly limited as long as it is a fatty acid having 18 carbon atoms, but stearic acid, oleic acid, linoleic acid and the like are preferable.
Accordingly, the monoester of the component (B) is not particularly limited, but decaglycerin monostearate, decaglycerin monooleate, decaglycerin monolinoleate and the like are preferable. Also, a mixture of these can be used.
Such monoesters of polyglycerin and a fatty acid having 18 carbon atoms are commercially available, for example, Sunsoft Q-18S and Q-17S (trade names, manufactured by Taiyo Kagaku Co., Ltd.), Poem J-0381 (Manufactured by Riken Vitamin Co., Ltd.), SY Glister MO-750, FRL-1 (manufactured by Sakamoto Pharmaceutical Co., Ltd., trade name), O-15D (manufactured by Mitsubishi Chemical Foods Co., Ltd., trade name) ) And the like.
The purity of the monoester of polyglycerin and a fatty acid having 18 carbon atoms is not particularly limited, but may include some diesters and triesters in addition to the polyglycerin fatty acid monoester having an average degree of polymerization of 10 due to the nature of production. Is also good.

Component (C)
Component (C), that is, the blending amount of polyglycerin having an average degree of polymerization of 3 to 6 and mono-, di-, tri- or pentaester of a fatty acid having 18 carbon atoms is 1 to 18% by mass. To 2 to 18% by mass, more preferably 3 to 9% by mass.
The constituent fatty acid of the component (C) is not particularly limited as long as it has 18 carbon atoms, but stearic acid, oleic acid, linoleic acid and the like are preferable.
Examples of the polyglycerol ester having an average polymerization degree of 3 to 6 include triglycerin, tetraglycerin, pentaglycerin, monoesters, diesters, triesters and pentaesters of hexaglycerin and a fatty acid having 18 carbon atoms. Particularly preferred is pentaglycerin monoester.
Here, the glycerin portion is polyglycerin having an average degree of polymerization of 3 to 6, and may be a mixture thereof.
Specific examples of mono-, di-, tri- or pentaesters of polyglycerin and fatty acids of component (C) include tri-, tetra-, penta- or hexaglycerin mono-, di-, tri- or pentastearate; Hexaglycerin mono, di, tri or pentaolate; tri, tetra, penta or hexaglycerin mono, di, tri or pentalinoleate; and mixtures thereof can also be used.
Such polyglycerin and a fatty acid ester having 18 carbon atoms are commercially available, for example, SY Glyster MS-310, TS-310, MO-310, PO-310, MS-500, and PS-500. MO-500, PO-500 (trade name, manufactured by Sakamoto Pharmaceutical Co., Ltd.), Sunsoft Q-18F, Q-17F, A-181C, A-171C, A181E, A171E And A-173E and A-173E (trade names, manufactured by Taiyo Kagaku Co., Ltd.), Poem J-4581 (trade name, manufactured by Riken Vitamin Co., Ltd.) and the like.
Further, the purity of the polyglycerol fatty acid ester having an average degree of polymerization of 3 to 6 is not particularly limited, but may include a plurality of esters due to the properties of production.
The surfactants of the components (B) and (C) are not necessarily required to be highly purified by distillation or the like, and may be a reaction mixture.

  In the water-soluble composition of the present invention, the blending ratio (mass ratio) of component (A) / {(B) + (C)} is 1/5 to 0.7, and component (B) / (C) Is more preferably from 1 / 0.2 to 1 from the viewpoint of obtaining a stable water-soluble composition.

Component (D)
The component (D), ie, water, is not particularly limited as long as it is water that can be blended in medicine, food and drink, cosmetics, and feed. For example, purified water such as ion-exchanged water and distilled water, tap water, natural water, and alkali Ion water and the like. This may be water alone or water to which food additives have been added. Food additives include vitamins, surfactants, stabilizers, seasonings, acids and salts, and the like.

Component (E)
The solubilizer component (E), gum or sugar alcohol has an action of stabilizing solubilized state of coenzyme Q _10, and saccharides like. Specifically, for example, gums such as gum arabic, xanthan gum, tragacanth gum, guar gum, gellan gum, locust bean gum; polyhydric alcohols such as ethylene glycol, propylene glycol, glycerin, erythritol; maltitol, reduced starch syrup, lactitol, Monosaccharides and disaccharides such as palatinit, sorbitol, mannitol, glucose fructose sugar and lactose; polysaccharides such as dextrin; These solubilizing aids can be used alone or in combination of two or more. Preferably, it is a reducing saccharide such as glucose fructose liquid sugar in terms of sweetness, and gum such as gum arabic in terms of flavor.
The amount of the solubilizing aid added is 10 to 80% by mass, preferably 10 to 70% by mass, and more preferably 15 to 60% by mass. Amount of the amount of the solubilizer is more than 80 wt% Coenzyme Q ₁₀ and solubilizing agent is decreased, intake hardly effect the desired obtained that, also stable water-soluble composition of Coenzyme Q ₁₀ is It is difficult to obtain, which is not preferable.

  In the present invention, in addition to the polyglycerin fatty acid monoester of the component (B) and the polyglycerin fatty acid mono, di, tri or pentaester of the component (C), other interfaces may be used as long as the effects of the present invention are not impaired. Activators may be used alone or in combination of two or more. Specific examples of these surfactants include polyglycerin fatty acid esters other than the component (B) and the component (C), organic acid monoglycerides, glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene. Sorbitan fatty acid ester (polysorbate), propylene glycol fatty acid ester, lecithin, enzymatically degraded lecithin, saponin, sterol, cholic acid, deoxycholic acid, yucca extract, cationic surfactant, anionic surfactant, amphoteric surfactant And nonionic surfactants other than those described above.

Next, a method for producing the water-soluble composition of the present invention will be described.
The production method of the present invention comprises the following steps (I) to (II), then (III) and / or (IV).
Step (I): A predetermined amount of the above components (B), (C) and (D), and optionally component (E) is weighed out and heated and dissolved. For example, it is preferable to stir in a hot water bath at 60 to 80 ° C. with a three-one motor and to heat and dissolve.
Step (II); component (A), i.e., added to and mixed with coenzyme Q _10.
Step (III): Using a homomixer, homogenization treatment is performed with a shearing force at a peripheral speed of the stirring blade of 750 m / min or more.
Step (IV): Using a homogenizer, a homogenizing treatment is performed at a homogenizing pressure of 98 MPa (1,000 kg / cm ² ) or more.

By the above steps, the average particle diameter of coenzyme Q ₁₀ (oil-in-water emulsion containing coenzyme Q ₁₀ ) in the water-soluble composition of the present invention becomes 110 nm or less, more preferably 80 nm or less, further preferably 60 nm or less. To do.
When the average particle diameter of coenzyme Q ₁₀ is more than 110 nm, storage stability of the aqueous composition, it is insufficient absorption and transparency to the living body, can not be obtained in which the effect object of the present invention.
Furthermore, in order to improve more the absorption into the living body of coenzyme Q ₁₀ is preferably set to 60nm or less.

Examples of the homomixer used in the homogenization treatment in the step (III) include TK homomixer (trade name, manufactured by Tokushu Kika Kogyo Co., Ltd.) and Clearmix (trade name, manufactured by M Technique Co., Ltd.). Examples of the homogenization method include a method of giving a high shearing force at a peripheral speed of the stirring blade of 750 m / min or more, preferably 1000 m / min or more, more preferably 1500 m / min or more.
Examples of the high-pressure homogenizer used in the homogenization treatment of the step (IV) include, for example, a homogenizer such as a microfluidizer (trade name, manufactured by Mizuho Industry Co., Ltd.) and an Ultimizer (trade name, manufactured by Sugino Machine Co., Ltd.). processor. Examples of the homogenization method, 98MPa (1,000kg / cm ²⁾ or more, more preferably 150MPa (1531kg / cm ²⁾ or more, more preferably 200MPa (2039kg / cm ²⁾ or more high shear Is given.
Repeated homogenization step (III) or (IV) alone, or by performing step (III) and (IV) is continuously, to obtain a water-soluble composition of Coenzyme Q ₁₀ with a uniform liquid it can. The water-soluble composition of Coenzyme Q ₁₀ in order to further stabilize finer, it is preferable to perform the homogenization treatment more than once.
In addition, in addition to the homogenizer described above, a homogenizer such as a nanomizer and an ultrasonic emulsifier, and various homomixers such as an azimuth mixer and an ultra mixer can be used for the homogenization treatment.
As a method for producing a water-soluble composition of Coenzyme Q ₁₀ of the present invention is a natural emulsification method, a phase inversion emulsification method, liquid crystal emulsion, gel emulsification method, and the D-phase emulsification method and PIT emulsification method or the like can also be utilized. Further, these methods may be combined with a mechanical emulsification method such as the homogenization treatment.

Incidentally, Coenzyme Q ₁₀ is because it is an oil component, optionally, fat that can be used in foods, may lipids, be blended with other oily components, and the like.
Here, examples of fats and oils that can be used for foods and the like include fats and oils or synthetic oils made from animals, plants, and microorganisms. Specifically, lard, beef tallow, chicken oil, whale oil, tuna oil, sardine oil, mackerel oil, saury oil, skipjack oil, herring oil, liver oil, soybean oil, cottonseed oil, safflower oil, rice oil, corn oil, Rapeseed oil, palm oil, perilla oil, perilla oil, sesame oil, cocoa butter, peanut oil, coconut oil, evening primrose oil, borage oil, milk fat, butter, etc., and oils and fats containing synthetic triglycerides such as medium chain fatty acid triglycerides, etc. Can be
Examples of lipids include specific gravity regulators such as glycosylceramide, octacosanol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phytosterol, lycopene, beta-carotene, lutein, and SAIB (sucrose acetate / isobutyrate). Can be
Other oily components include fat-soluble vitamins, oil-soluble flavors, hydrocarbons and the like. Specific examples of the fat-soluble vitamins include fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, vitamin K, and vitamin P. Similarly, specific examples of the oil-soluble flavor include menthol, orange oil, lemon oil, yuzu oil, essential oil, and the like.
Furthermore, examples of the hydrocarbons include squalene, squalane, lanolin, liquid paraffin, and the like.
Especially the amount of fats, lipids, other oily components such as the above, is not particularly limited so can be used as it is coenzyme Q ₁₀ in the present invention, in the case of normal use is preferably 0.1 to 20 mass%.

Water-soluble composition containing a coenzyme Q ₁₀ of the present invention, it may be used as an oil-in-water emulsions, for example, it can be used as a dry powder by removing the water by spray drying method or the like. In this case, when the dry powder was added to an aqueous liquid such as water is the aqueous solution containing Coenzyme Q ₁₀ was dissolved rapidly. When the powder is taken or ingested, the powder is dissolved in the water in the living body and becomes an aqueous solution.

Water-soluble composition of the present invention may be ingested as it is, it can be used as a blending material for adding coenzyme Q ₁₀ in a variety of foods. The use is not particularly limited, and can be applied to all kinds of foods and drinks.
Foods containing the water-soluble composition of the present invention include, for example, drinks such as soft drinks, sports drinks, carbonated drinks, drinks, etc .; noodles such as udon and spaghetti, okonomiyaki, bread, biscuits, candy, and jelly.・ Confectionery; processed dairy products such as yogurt and ham; seasonings such as miso, sauce, liquid soup, sauce and dressing; processed foods such as tofu and noodles; processed fats and oils such as margarine, fat spread and shortening. . Furthermore, powdered foods such as powdered beverages and powdered soups from their shapes; health foods made into capsules, tablets, powders, granules, etc .; other medicines, quasi-drugs, special-use foods, foods for specified health use, nutrition Examples of functional foods and animal feeds include administration to enhance animal nutrition, such as mixing with water at the time of drinking.

Beverages Beverages containing a water-soluble composition of Coenzyme Q ₁₀ of the present invention, including sodium chloride, salts and minerals such as iron, acidulants, sweeteners, alcohols, vitamins, at least one from among flavors and fruit juices Examples include soft drinks, sports drinks, fruit juice drinks, lactic acid bacteria drinks, alcoholic drinks, vitamin / mineral drinks, drinks and the like. Further, there may be mentioned processed milk, soy milk, a beverage for improving the constitution, a beverage combined with a natural material which can be expected to have a physiological effect, and the like.

From the viewpoint of convenience of ingestion, the use of beverages such as soft drinks and drinks is preferred. Such beverages can be easily drunk anywhere, and are reliably supplied to those who have difficulty in taking solids such as the frail elderly, dysphagia, and postoperative nutritional supplementation. Furthermore, an improvement in the in vivo utilization rate is also expected.
When these uses, the amount of coenzyme Q ₁₀ is not particularly limited, for example, in the product, it is desirable 0.001 mass%.

  Examples of cosmetics containing the water-soluble composition of the present invention include O / W type lotions, O / W type creams, viscous microemulsion essences, and O / W type essences. In addition, the cosmetics of the present invention are usually used in the technical field, and additives such as an antioxidant, an ultraviolet ray blocking agent, a horny layer peeling agent, a surfactant, a fragrance, a coloring matter, a preservative, and a pH adjusting agent. , A chelating agent and the like can be appropriately compounded. INDUSTRIAL APPLICABILITY The cosmetic of the present invention can be used for prevention of skin aging and prevention and improvement of skin roughness.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
The measuring method and evaluation method used are shown below.
1. Method for Measuring Average Particle Size The average particle size of the sample was measured by using a submicron particle size distribution analyzer (model: N4SD, manufactured by Beckman Coulter, Inc.) for the dispersed particles.

2. Water-soluble composition of Coenzyme Q ₁₀ in acid-resistance test of citric acid in purified water adjusted to pH 3 or less was added 1%, subjected liquid temperature in a water bath of the composition containing the acidic aqueous solution was reaches raised to 85 ° C. Heat treatment was performed for 30 minutes from the time point. The acidic aqueous solution containing these compositions was allowed to cool at room temperature, and the acid resistance and heat resistance were evaluated based on the average particle diameter after one day.

3. Salt tolerance and heat resistance test saline was added to purified water containing 5% of a water-soluble composition of Coenzyme Q ₁₀ 1%, over the composition containing saline hot water, from the time the liquid temperature was allowed reach the 85 ° C. Heat treatment was performed for 30 minutes. The saline containing these compositions was allowed to cool at room temperature, and the acid resistance and heat resistance were evaluated based on the average particle size after one day.

Example 1
12% by mass of decaglycerin monooleate, 5% by mass of pentaglycerin triolate and 78% by mass of water were heated and completely dissolved to obtain an aqueous phase. 5% by mass of Coenzyme Q ₁₀ (trade name of Nisshin Pharma Co., Ltd., food material Coenzyme Q ₁₀ ) was gradually added to the aqueous phase with stirring, and then 150 MPa (1531 kg / cm ²⁾ with a high-pressure homogenizer. The homogenization treatment was performed under the pressure of (1) to obtain a uniform aqueous composition. This sample was evaluated by the above-described method.
Table 1 shows the composition of the water-soluble composition and the results. The unit of the numbers in the table is nm, and the symbol ○ indicates that the composition is within ± 10 nm when the particle size of the composition is less than 100 nm, and within ± 10% when the particle size of the composition is 100 nm or more. The symbol 良好 is within ± 20 nm when the particle size of the composition is less than 100 nm, and within ± 20% when the particle size of the composition is 100 nm or more. , The stability is poor, and the change exceeds the above range.

Example 2
9.5% by mass of decaglycerin monooleate, 6.5% by mass of pentaglycerin monooleate, 24% by mass of water, and 50% by mass of fructose-fructose mixed liquid sugar were heated and completely dissolved to obtain an aqueous phase. 10% by mass of Coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, and then treated for 15 minutes using a homomixer at a peripheral speed of the blade of 1500 m / min, followed by a high-pressure homogenizer. Homogenization treatment was performed at a pressure of 200 MPa (2039 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Example 3
9.5% by mass of decaglycerin monooleate, 6.5% by mass of pentaglycerin monooleate, 18% by mass of water, and 52% by mass of fructose-fructose mixed liquid sugar were heated and completely dissolved to obtain an aqueous phase. 10% by mass of coenzyme Q ₁₀ previously mixed and dissolved and 4% by mass of palm oil were gradually added to the above aqueous phase while stirring, and then the peripheral speed of the wing was 1500 m / min using a homomixer. The mixture was treated for 15 minutes under the same conditions, and further homogenized with a high-pressure homogenizer at a pressure of 200 MPa (2039 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Example 4
9.5% by mass of decaglycerin monooleate, 4% by mass of pentaglycerin monooleate, 2% by mass of citrate monoglyceride, 55.5% by mass of water, 19% by mass of gum arabic are completely dissolved by heating, and the aqueous phase And 10% by mass of Coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, and then treated with a homomixer at a peripheral speed of the wing of 1800 m / min for 60 minutes to obtain a uniform aqueous composition. I got something. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Example 5
13.5% by mass of decaglycerin monooleate, 6.5% by mass of hexaglycerin monooleate, 31% by mass of water, and 30% by mass of reduced starch saccharified product were heated and completely dissolved to obtain an aqueous phase. 15% by mass of coenzyme Q ₁₀ and 4% by mass of SAIB previously mixed and dissolved in the oil phase were gradually added to the aqueous phase with stirring, and then the peripheral speed of the blade was 1500 m / min using a homomixer. For 15 minutes, and further homogenized with a high-pressure homogenizer at a pressure of 245 MPa (2500 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Example 6
13.5% by mass of decaglycerin monooleate, 6.5% by mass of tetraglycerin monooleate, 31% by mass of water, and 30% by mass of reduced starch saccharified product were completely dissolved by heating to obtain an aqueous phase. 15% by mass of coenzyme Q ₁₀ previously mixed and dissolved and 4% by mass of SAIB were gradually added to the aqueous phase as an oil phase while stirring, and then the peripheral speed of the wing was 1500 m / min using a homomixer. The mixture was treated for 20 minutes under the same conditions, and further homogenized with a high-pressure homogenizer at a pressure of 245 MPa (2500 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Example 7
12.5% by mass of decaglycerin monooleate, 8.5% by mass of pentaglycerin monooleate, 19% by mass of water, and 30% by mass of fructose-fructose mixed liquid sugar were heated and completely dissolved to obtain an aqueous phase. 30% by mass of Coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, then homogenized with a high-pressure homogenizer at a pressure of 150 MPa (1531 kg / cm ² ), and further homogenized at a pressure of 200 MPa (2039 kg / 2039 kg / cm ² ). The homogenization treatment was performed twice at a pressure of ² cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Comparative Example 1
A uniform aqueous composition was obtained in the same manner as in Example 1, except that decaglycerin monooleate was 12% by mass and pentaglycerin monooleate was 5% by mass, and decaglycerin monooleate was 17% by mass. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Comparative Example 2
A uniform aqueous composition was obtained by performing the same process as in Example 1, except that 12% by mass of decaglycerin monooleate and 5% by mass of pentaglycerin monooleate were replaced by 17% by mass of decaglycerin monostearate. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Comparative Example 3
3% by mass of decaglycerin monooleate, 0.5% by mass of pentaglycerin monooleate, 34.5% by mass of water, and 52% by mass of fructose-fructose mixed liquid sugar were heated and completely dissolved to obtain an aqueous phase. 10% by mass of Coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, and then treated with a homomixer at a peripheral speed of the blade of 1500 m / min for 15 minutes, followed by a high-pressure homogenizer. At 200 MPa (2039 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 1.

Comparative Example 4
40% by mass of decaglycerin monooleate, 20% by mass of pentaglycerin monooleate, and 30% by mass of water were heated and completely dissolved to obtain an aqueous phase. 10% by mass of Coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, and then treated with a homomixer at a peripheral speed of the blade of 1500 m / min for 15 minutes, followed by a high-pressure homogenizer. , The homogenization treatment was performed at a pressure of 200 MPa (2039 kg / cm ² ), but the viscosity of the composition was so large that an aqueous composition could not be obtained.

From the above results, Comparative Example 1 in which the solubilizing agent was solubilized only with decaglycerin monooleate and Comparative Example 2 having a particle diameter of 110 nm or more were slightly inferior in stability in acid resistance / heat resistance, salt resistance / heat resistance. .
Comparative Example 3 in which the amount of decaglycerin monooleate of the component (B) and the amount of pentaglycerin monooleate of the component (C) is smaller than the range of the specified amount of the present invention has a large particle size, acid resistance, heat resistance, and salt resistance. Poor stability in heat resistance.
Comparative Example 4 in which the compounding amount of decaglycerin monooleate of the component (B) and pentaglycerin monooleate of the component (C) is larger than the specified range of the present invention cannot be obtained as a stable water-soluble composition.
On the other hand, it can be seen that Examples 1 to 7 of the present invention are stable, water-soluble compositions having excellent acid resistance / heat resistance, salt resistance / heat resistance, and a stable particle diameter of 110 nm or less.

Example 8
16% by mass of decaglycerin monostearate, 4% by mass of pentaglycerin monostearate, 20% by mass of water, and 50% by mass of fructose-fructose mixed liquid sugar were completely dissolved by heating to form an aqueous phase. 10% by mass of Coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, and then treated for 15 minutes using a homomixer at a peripheral speed of the blade of 1500 m / min, followed by a high-pressure homogenizer. Homogenization treatment was performed at a pressure of 200 MPa (2039 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 2.

Example 9
16% by mass of decaglycerin monooleate, 4% by mass of pentaglycerin monostearate, 20% by mass of water, and 50% by mass of fructose-fructose mixed liquid sugar were completely dissolved by heating to form an aqueous phase. 10% by mass of Coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, and then treated for 15 minutes using a homomixer at a peripheral speed of the blade of 1500 m / min, followed by a high-pressure homogenizer. Homogenization treatment was performed at a pressure of 200 MPa (2039 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 2.

Example 10
8% by mass of decaglycerin monostearate, 8% by mass of decaglycerin monolinoleate, 4% by mass of pentaglycerin monostearate, 20% by mass of water, 46% by mass of fructose-fructose mixed liquid sugar are heated and completely dissolved. The aqueous phase was used. 10% by mass of coenzyme Q ₁₀ previously mixed and dissolved and 4% by mass of palm oil were gradually added to the above aqueous phase while stirring, and then the peripheral speed of the wing was 1500 m / min using a homomixer. The mixture was treated for 15 minutes under the same conditions, and further homogenized with a high-pressure homogenizer at a pressure of 200 MPa (2039 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 2.

Example 11
8% by mass of decaglycerin monooleate, 8% by mass of decaglycerin monolinolate, 4% by mass of pentaglycerin monooleate, 20% by mass of water, 46% by mass of fructose fructose mixed liquid sugar are heated and completely dissolved, and the aqueous phase is dissolved. Department. 10% by mass of Coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, and then treated for 15 minutes using a homomixer at a peripheral speed of the blade of 1500 m / min, followed by a high-pressure homogenizer. Homogenization treatment was performed at a pressure of 200 MPa (2039 kg / cm ² ) to obtain a uniform aqueous composition. This sample was evaluated in the same manner as in Example 1. The composition and the results are shown in Table 2.

  From the above results, Examples 8 to 11 in which one or both of the oleic acid ester of the component (B) and the component (C) were replaced with another fatty acid ester having 18 carbon atoms or a mixture thereof also had a particle diameter of 110 nm. The following water-soluble composition was obtained, and it was found that both acid resistance and heat resistance, salt resistance and heat resistance were excellent and stable.

Example 12
0.3% by weight of the water-soluble composition of the above Examples 2 and 3, 15% by weight of fructose-fructose mixed liquid sugar, 7% by weight of granulated sugar, 4% by weight of grapefruit 1/5 concentrated juice, 0.3% by weight of citric acid, A beverage consisting of 0.2% by mass of sodium citrate, 0.2% by mass of grapefruit flavor and 73% by mass of water was prepared, filled in a 100 ml bottle, and sterilized at 85 ° C. for 30 minutes.
Also not observed at all separation of coenzyme Q ₁₀ after sterilization, were able to drink without problems.

Comparative Example 5
9 parts by mass of tetraglycerin monostearate, 6 parts by mass of decaglycerin monostearate, 5 parts by mass of glycerin, and 70 parts by mass of water were heated and completely dissolved to obtain an aqueous phase. 10 parts by mass of coenzyme Q ₁₀ as an oil phase was gradually added to the aqueous phase with stirring, and then treated for 5 minutes using a homomixer to obtain a dispersion of coenzyme Q ₁₀ having an average particle size of 380 nm. . The emulsified state immediately after the production was good, but after 2 weeks, a part of the upper part was separated.

Comparative Example 6 coenzyme Q emulsion powder Coenzyme Q ₁₀ 100 g containing ₁₀ heated and dissolved, then added to sucrose fatty acid ester 200g was dissolved by heating in advance 60 ° C., and emulsified. Further, the mixture was passed through a high-pressure homogenizer (H-11 type, manufactured by Sanwa Kikai Co., Ltd.), and an excipient mixture consisting of lactose (1,000 g) and starch (700 g) was fluidized by a fluidized bed granulator (FLO-MINI, manufactured by Freund Corporation). This liquid was sprayed under the hot condition to obtain an orange-yellow powder-granular composition. When the resulting powder composition 1g is put into water of 100 g, promptly dispersed and dissolved, coenzyme Q ₁₀ dispersion of pale yellow was obtained. 50% particle diameter as measured Coenzyme Q ₁₀ dispersed particle size of this dispersion was 2.62Myuemu.

Soft capsules Coenzyme Q ₁₀ 60 g containing Comparative Example 7 coenzyme Q _10, soybean oil 240 g, glycerin fatty acid ester (Coconad MT) 300 g was dissolved with heating, and cooled to around confirmed after 25 ° C. The dissolution of coenzyme Q ₁₀ at 60 ° C. Thus, a capsule filling liquid was obtained. Then, using conventional techniques, soft capsules containing 30 mg of Coenzyme Q ₁₀ per packet were obtained.

Comparative test 1
Using Example 2 and the water-soluble composition obtained in Comparative Example 5, it was compared absorbable coenzyme Q ₁₀ by animal experiments.
<Animal absorption experiment>
Two groups of three beagle dogs (male) were fasted from 5 p.m. on the day before the administration, and the coenzyme Q ₁₀ lysate obtained in Example 2 and the coenzyme Q obtained in Comparative Example 5 were used. Each of the ₁₀ dispersions was packaged in a hard capsule so as to give a dose of 90 mg / dog per animal, and was single-forcedly administered. Up to 24 hours after administration, examined the transition of coenzyme Q ₁₀ concentration in plasma was collected on a regular basis blood. Table 3 shows the results.
<Measurement Method of coenzyme Q ₁₀ concentration in plasma>
The measurement was performed using HPLC under the following conditions. Incidentally, in the serum, because coenzyme Q ₁₀ of the oxidized and reduced forms present, the addition of iron oxide and oxidized in the sample was determined by HPLC.
<HPLC conditions>
Column: Nucleosil 5C18, 4.6 mmφ × 25 cm,
Mobile phase; ethanol / acetonitrile (= 60/40 volume ratio),
Flow rate; 1 ml / min,
Detector: UV spectrophotometer, detection wavelength: 275 nm.

Note: Cmax (ng / ml): maximum blood concentration tmax (hrs): time to reach maximum blood concentration AUC (0 → 24) (ng · hr / ml): under blood drug concentration-time curve area

From the above results, when the water-soluble composition having a small particle size obtained in Example 2 was ingested, the in vivo absorbability was significantly higher than that of the dispersion of Comparative Example 5. Previously in the normal fasted, was considered to be poor absorption of coenzyme Q _10, it is understood that the absorbent and using a small particle size Coenzyme Q ₁₀ water-soluble composition is remarkably improved.

Comparative test 2 Absorption test in fasted intake Absorption test in fasted intake by oral administration of three subjects each for the aqueous composition of Example 2, the emulsified powder composition of Comparative example 6, and the soft capsule of Comparative example 7. Was done.
And 21 time after fasting the day before, was the route administration of 60mg per person coenzyme Q ₁₀ in the next day morning at 8 o'clock fasting conditions. Oral administration was performed. After administration to measure the blood concentration of coenzyme Q ₁₀ by collecting blood after 2,4,6,8,12,24 hours.
The measurement was performed using HPLC under the following conditions. In addition, since oxidized and reduced forms of coenzyme Q10 are present in the serum, both were measured and their sum was determined. Column: Nhdeosil5C18 4.6 mm * 25 cm
Mobile phase: ethanol: acetonitrile (55:45)
Flow rate: 1 m1 / min Detector: UV spectrophotometer 275 nm

As a result, in the emulsified powder composition of Comparative Example 6 and the soft capsule of Comparative Example 7, the increase in blood concentration after administration was very small and hardly absorbed, whereas the water-soluble composition of Example 2 was fasted. oral administration and coenzyme Q ₁₀ to reliably and high density even when it was found to be absorbed into the body in. The findings so far, but the absorption of long as coenzyme Q ₁₀ is not taken with meals has been considered not obtained, by ingesting the water-soluble composition of the present invention, the absorbent can be remarkably improved even in fasting It was confirmed that. These results are shown in FIG.

Comparative Test 3 Absorption Test after Ingestion After Meal The aqueous composition of Example 2, the emulsified powder composition of Comparative Example 6, and the soft capsule of Comparative Example 7 were subjected to oral administration by oral administration by three subjects, respectively. Was.
The meal was completed by 22:00 the day before, blood was collected the next morning, breakfast was taken, and within 10 minutes, 60 mg of coenzyme Q ₁₀ was orally administered. After administration to measure the blood concentration of coenzyme Q ₁₀ by collecting blood after 2,4,6,8,12,24 hours. The blood concentration was measured in the same manner as in Comparative Test 2.

  As a result, the blood concentration of the emulsified powder composition of Comparative Example 6 and the soft capsule of Comparative Example 7 began to increase 2 hours after ingestion, whereas the blood concentration of the aqueous composition of Example 2 immediately after ingestion. It was found that the rise of the amount of absorption was very fast as compared with the comparative example. This indicates that the water-soluble composition of the present invention has very excellent absorbability. These results are shown in FIG.

It is a graph showing the absorption of coenzyme Q ₁₀ in the fasting ingestion. Is a graph showing the absorption of coenzyme Q ₁₀ in the postprandial upon ingestion.

Claims (11)

(A) 5 to 40% by mass of coenzyme Q ₁₀ , (B) 5 to 30% by mass of polyglycerin having an average degree of polymerization of 10 and a monoester of a fatty acid having 18 carbon atoms, (C) polyglycerin having an average degree of polymerization of 3 to 6; A water-soluble composition comprising 1 to 18% by mass of a mono-, di-, tri- or pentaester of a fatty acid having 18 carbon atoms and (D) water, and having an average particle diameter of 110 nm or less.   The water-soluble composition according to claim 1, wherein the fatty acid of the component (B) is stearic acid, oleic acid or linoleic acid, and the fatty acid of the component (C) is stearic acid, oleic acid or linoleic acid.   The water-soluble composition according to claim 1 or 2, further comprising (E) a solubilizing aid of 10 to 80% by mass.   The water-soluble composition according to claim 3, wherein the solubilizing aid is a gum, a saccharide, or a polyhydric alcohol.   The mass ratio of component (A) / {(B) + (C)} is 1/5 to 0.7, and the mass ratio of component (B) / (C) is 1 / 0.2 to 1. The water-soluble composition according to any one of claims 1 to 4. Next steps:
(I) heating and dissolving components (B), (C) and (D), and optionally component (E);
(II) Add component (A) and mix, then (III) homogenize with a homomixer at a peripheral speed of 750 m / min or more with a stirring blade, and / or (IV) homogenize machine. The method according to any one of claims 1 to 5, wherein the homogenization treatment is performed by using a homogenization pressure of 98 MPa (1,000 kg / cm ² ) or more, and the average particle diameter is reduced to 110 nm or less by the above-described process. method for producing a water-soluble composition containing a coenzyme Q ₁₀ according to item 1.   7. The method according to claim 6, wherein step (III) or (IV) is repeated, or step (III) is performed, and then step (IV) is performed. Medicament comprising a water-soluble composition containing a coenzyme Q ₁₀ according to any one of claims 1 to 5. Food products comprising a water-soluble composition containing a coenzyme Q ₁₀ according to any one of claims 1 to 5. Cosmetic comprising a water-soluble composition containing a coenzyme Q ₁₀ according to any one of claims 1 to 5. Feed containing water-soluble composition containing a coenzyme Q ₁₀ according to any one of claims 1 to 5.

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