JP5324755B2 - Particulate composition and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a particulate composition capable of stabilizing, for a long time, a fat-soluble active component unstable to oxygen, light, acid, base and/or radical and the like, especially a fat-soluble active component expectable to be useful in the fields of food, functional nutritive food, specified health food, nutritious supplement, nutrient, animal drug, drink, feed, cosmetics, pharmaceuticals, therapeutic agent, preventive, etc., and having low stability and a method for producing the composition. <P>SOLUTION: As a result of intensive investigation for solving the above problems, the inventors have accomplished the invention by finding out that a particulate composition containing a water-soluble excipient and a fat-soluble active component, wherein the true specific gravity of the water-soluble excipient component is &ge;1.25 under the condition of the water-content of the particulate composition of &le;3 wt.% and the sphericity of the particulate composition is &ge;0.9, can stabilize an unstable fat-soluble active component for a long time, and finding a method for producing the particulate composition. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a particulate composition and a method for producing the same. More specifically, the present invention relates to a particulate composition capable of stabilizing a fat-soluble active ingredient unstable to oxygen, light, acid / base and / or radical over a long period of time, and a method for producing the same.

  In recent years, in the fields of foods, functional foods, pharmaceuticals, cosmetics, and the like, development of useful components that express effective functions in living bodies has been promoted for various purposes. However, some of these useful components are decomposed by the action of oxygen in the atmosphere, light (ultraviolet rays, visible rays, infrared rays), coexistence of acids and bases, or active substances such as radicals. There are a lot of low substances. For example, coenzyme Q10, which is known as a functional food material and a pharmaceutical, has low stability to light, oxygen, redox substances, and the like. In particular, its reduced form, reduced coenzyme Q10, is It is easily oxidized to oxygen and is converted to oxidized coenzyme Q10. In addition to this, as a functional substance that is decomposed by oxygen in the atmosphere, for example, highly unsaturated fatty acids represented by docosahexaenoic acid, eicosapentaenoic acid, α-linolenic acid, beef tallow, pork fat, fish oil, rapeseed oil, Natural animal and vegetable oils and fats such as palm oil, soybean oil and sesame oil, and hardened oils, transesterified oils, wintering oils and the like, and natural or synthetic additives such as tocopherols can be used. Also in the field of fragrances, the compounds that make up fragrances have different volatility and stability depending on their molecular weight, functional group, and molecular structure, so there are issues with persistence and stability after processing into final products. It has become.

  The technology for stabilizing fat-soluble components represented by these, which are represented by low stability (hereinafter referred to as fat-soluble active components), has been studied for a long time. A typical example is given. In general, fat-soluble active ingredients are made into powder oils by emulsifying an unstable fat-soluble active ingredient in an aqueous solution containing a water-soluble excipient and spray-drying the resulting oil-in-water emulsion composition. It is used (for example, Patent Document 1 and Non-Patent Document 1).

  However, the polynuclear microencapsulated powdered oil particles obtained by these methods usually have an irregular particle shape and tend to have a small particle size, and the stability of the fat-soluble active ingredient is compared with that before microencapsulation. Although greatly improved, it is not completely satisfactory in terms of ensuring long-term stability at a level that can withstand practical use. In recent years, a fluidized bed layering granulation method has been proposed for the purpose of eliminating the above-mentioned deficiencies of powder obtained by spray drying (Patent Document 2). In this method, fine powdered fats and oils obtained by the spray drying method are coated with an emulsion of fat-soluble active ingredients in a fluidized bed to obtain powdered fats and oils having a relatively high sphericity and a large particle size. ing. However, for example, as long as the literature is viewed, the form of the generated particles is still not spherical, and there is no mention of the effect of improving the stability of the fat-soluble active ingredient.

  On the other hand, spray cooler methods, in-liquid curing methods, freeze-drying-pulverization methods, and the like are known as methods for obtaining polynuclear microencapsulated powders and fats by methods other than spray drying. The spray cooler method and the submerged curing method are an oil-in-water emulsion composition obtained by emulsifying a fat-soluble active ingredient in an aqueous solution containing gelatin or other excipient that reversibly changes sol-gel due to temperature change. This is a technique in which an object is gelled and solidified at a low temperature, and the gel-like particles containing water thus obtained are dried at a low temperature below the gelation temperature (Patent Document 3). Polynuclear microencapsulated powdered fats and oils obtained by this method have better particle shape than powdered fats and oils obtained by spray drying, but it is essential to use excipients having gelling properties such as gelatin. It has the disadvantage that the choice of excipient components aimed at stabilizing soluble active ingredients is extremely narrow. In addition, in the freeze-drying-pulverization method, the form of the particles obtained is inevitably distorted, and depending on the pulverization position, the fat-soluble active ingredient is exposed to the particle surface. It is hard to say that it is satisfactory.

Furthermore, a seamless encapsulation technique using a double nozzle is known as a technique for stabilizing a fat-soluble active ingredient for obtaining a mononuclear type microcapsule instead of a multinuclear type (Patent Document 4). In this method, an unstable fat-soluble active ingredient can be positioned in the vicinity of the center of the microcapsule, so that the capsule film thickness can be made thicker than that of the multinuclear capsule, thereby improving the stability of the microcapsule. You can expect to get a capsule. However, even in this method, like the above-described spray cooler method and submerged hardening method, it is essential to use an excipient such as gelatin having a gelling property, and the particle size in terms of stable capsule production. Is preferably in the range of about 1.5 mm or more, for example, the choice of excipient components aimed at stabilizing fat-soluble active ingredients becomes extremely narrow, or it becomes difficult to produce a particulate composition of 1000 μm or less, etc. , Not satisfactory.
JP 7-313055 A JP2003-24001 JP 2006-089381 A JP 2003-325638 A Biosci. Biotechnol. Biochem. 66, p1829-1834, 2002

  In order to solve the above problems, the present invention provides a fat-soluble active ingredient that is unstable to oxygen, light, acid / base and / or radicals, among others, food, nutritional functional food, food for specified health use, Particulate form that can stabilize long-term stable fat-soluble active ingredients that can be expected to be useful in the fields of nutritional supplements, nutritional supplements, animal drugs, beverages, feeds, cosmetics, pharmaceuticals, therapeutic drugs, preventive drugs, etc. It is an object to propose a composition and a method for producing the composition.

  As a result of intensive studies to solve the above problems, the present inventors have obtained a particulate composition containing a water-soluble excipient and a fat-soluble active ingredient, and the true specific gravity of the water-soluble excipient component is high, and A particulate composition having a high sphericity of the particulate composition can stabilize an unstable fat-soluble active ingredient over a long period of time, and a manufacturing method for obtaining such a particulate composition has been found, and the present invention has been completed. It came to do.

That is, the present invention provides the following:
[1] A particulate composition containing a water-soluble excipient and a fat-soluble active ingredient, wherein the true specific gravity of the water-soluble excipient ingredient is 3 wt% or less. A particulate composition having a particle composition of 1.25 or more and a sphericity of the particulate composition of 0.9 or more.
[2] The particulate composition according to [1], wherein the volume average particle diameter is 50 to 1000 μm.
[3] An oily component (A) containing 5 to 100% by weight of a fat-soluble active ingredient is formed into a domain and polydispersed in a matrix composed of a water-soluble excipient [1] ] Or the particulate composition of [2].
[4] The particulate composition according to [3], wherein the domain formed by the oil component (A) has a volume average particle diameter of 0.01 to 10 μm.
[5] The particulate composition according to any one of [1] to [4], wherein the fat-soluble active ingredient is a fat-soluble active ingredient unstable to oxygen, light, acid / base, and / or radical.
[6] The particulate composition according to any one of [1] to [4], wherein the fat-soluble active ingredient is reduced coenzyme Q10, oxidized coenzyme Q10, highly unsaturated fatty acid, or a mixture thereof.
[7] The particulate composition according to any one of [1] to [4], wherein the fat-soluble active ingredient is a fragrance.
[8] The particulate composition according to any one of [1] to [4], wherein the fat-soluble active ingredient is a physiologically active substance.
[9] The particle according to any one of [1] to [8], 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.
[10] The particulate composition according to any one of [1] to [9], wherein 20 to 100% by weight of the water-soluble excipient component is gum arabic.
[11] The surfactant (C) is at least one selected from the group consisting of glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, lecithins, and saponins, [9] or [9] 10] The particulate composition.
[12] The particulate composition according to [9] or [10], wherein the sugar is at least one selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and sugar alcohols.
[13] The particulate composition according to any one of [1] to [12], wherein the particulate composition contains 0.1 to 20% by weight of a reducing agent.
[14] The particulate composition according to [13], wherein the reducing agent is at least one selected from the group consisting of fat-soluble ascorbic acids, water-soluble ascorbic acids, tocopherols and polyphenols.
[15] The particulate composition according to [13], wherein the reducing agent is L-ascorbic acid and / or D-arabo-ascorbic acid.
[16] The particulate composition according to any one of [1] to [15], characterized by containing 0.01 to 30% by weight of water.
[17] The particulate composition according to any one of [1] to [16], wherein the content of the fat-soluble active ingredient in the particulate composition is in the range of 1 to 70% by weight.
[18] Any of [1] to [17], wherein the retention rate of the fat-soluble active ingredient in the particulate composition after storage for 30 days under light-shielding conditions at 40 ° C. in the air is 90% by weight or more. The particulate composition.
[19] After an oil-in-water emulsion composition prepared from an aqueous solution containing a water-soluble excipient and an oily component (A) containing a fat-soluble active ingredient is dispersed or suspended in the oily component (B) [3] Particulate composition [20] obtained by removing water in the emulsified composition in the oil component (B) [20] As the oil component (B), fat 5 The particulate composition according to [19], wherein an oily component comprising ˜100% by weight and surfactant (D) 0 to 95% by weight is used.
[21] The particulate composition according to [20], wherein lecithins are used as the surfactant (D).
[22] The particulate composition according to any one of [19] to [21], which is obtained by removing moisture until the moisture content in the particulate composition is 10% by weight or less.
[23] A food, beverage, cosmetic or pharmaceutical comprising the particulate composition according to any one of [1] to [22].
[24] A food, beverage, cosmetic or pharmaceutical product comprising the particulate composition of any one of [1] to [22] dissolved in an aqueous medium.
[25] A soft capsule, a hard capsule, a tablet or a chewable agent comprising the particulate composition according to any one of [1] to [22] and / or a pulverized powder thereof.

  The present invention relates to fat-soluble active ingredients that are unstable to oxygen, light, acids / bases and / or radicals, among others, foods, nutritional functional foods, foods for specified health use, nutritional supplements, nutrients, animals A particulate composition that can be expected to be useful in the fields of medicines, beverages, feeds, cosmetics, pharmaceuticals, therapeutics, preventives, etc. but has low stability, and a method for producing the same provide.

  First, the particulate composition of the present invention will be described. The particulate composition of the present invention is a particulate composition containing a water-soluble excipient and a fat-soluble active ingredient, and water-soluble shaping under conditions where the moisture content of the particulate composition is 3% by weight or less It is a particulate composition in which the true specific gravity of the agent component is 1.25 or more and the sphericity of the particulate composition is 0.9 or more.

  The fat-soluble active ingredient that can be contained in the particulate composition of the present invention is not particularly limited as long as it is a fat-soluble or sparingly water-soluble useful ingredient, but it can be used for oxygen, light, acid / base and / or radical, etc. A fat-soluble active ingredient having a problem in stability is preferable in that the effect of the present invention can be exhibited. Examples of such fat-soluble active ingredients include coenzymes Q such as reduced coenzyme Q10 and oxidized coenzyme Q10; highly unsaturated fatty acids such as docosahexaenoic acid, eicosapentaenoic acid and α-linolenic acid; Natural fats and oils such as pork fat, fish oil, rapeseed oil, palm oil, soybean oil, sesame oil and the like, and oils and fats thereof such as hardened oil, transesterified oil, and wintering oil, as well as perfumes and various physiologically active substances are equivalent. . As fragrances, specifically, citrus essential oils such as orange, lemon, lime and grapefruit; flower essential oils; plant essential oils such as peppermint oil, spearmint oil and spice oil; cola nuts, coffee, vanilla, cocoa, black tea, green tea, oolong tea Extracts of pulverized products such as spices, herbs, knots, dried sardines, oleoresins, essences and recovered incense; orange juice, lemon, lime, grapefruit juice, etc .; beef extract, pork extract, chicken extract Animal extracts such as scallop extract and crab extract; plant extracts such as garlic extract, onion extract and celery extract; synthetic fragrance compounds, blended fragrance compositions and any mixtures thereof. Bioactive substances include fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, vitamin K, tocotrienol and their derivatives; licorice, turmeric, perilla, clove, cinnamon, ginger, lemongrass, peppermint, dokudami, yokuinin , Rice bran, cornflower, fennel, wolfberry, salamander, nasturtium, san yak, salamander, kinkaran, amacha eel, Sakuhakuyo, bald eagle, parsley, onion, nutmeg, wild rice, gluten feed, konjac powder, paprika, horseradish, lemon, Hydrophobic extracts obtained by extracting plants such as chili, sesame seeds, spearmint, or high vegetables and their processed products using organic solvents such as ethanol, acetone, hexane and the like (polyphenols, Pens etc.), carotenes such as α-carotene, β-carotene, γ-carotene, δ-carotene, ε-carotene, lycopene, lutein, zeaxanthin, canthaxanthin, fucoxanthin, anthaxanthin, violaxanthin, astaxanthin, xanthophylls, and Their derivatives and the like can be exemplified.

  Among these, usefulness can be expected especially in the fields of food, functional nutrition food, food for specified health use, nutritional supplement, nutritional supplement, animal medicine, beverage, feed, cosmetics, pharmaceuticals, therapeutic drugs, preventive drugs, etc. It is more preferable for the purpose of the present invention that the instability with respect to oxygen, light, acid / base, and / or radicals is a problem, and a representative example thereof is reduced coenzyme Q10. A preferred example is given.

  Reduced coenzyme Q10 is a compound represented by the following formula (1).

(Where n = 10)
As described above, coenzyme Q10 has a reduced form and an oxidized form. In the present invention, in particular, when reduced coenzyme Q10 is targeted as coenzyme Q10, its instability to oxidation has jumped. It is preferable because it can be improved. In this case, the reduced coenzyme Q10 may be reduced type alone or may be coenzyme Q10 which is a mixture of oxidized coenzyme Q10 and reduced coenzyme Q10. 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.

As described in JP-A-10-109933, the reduced coenzyme Q10 is obtained by, for example, oxidizing coenzyme Q10 and reduced coenzyme by a conventionally known method such as synthesis, fermentation, extraction from a natural product, or the like. After obtaining coenzyme Q10, which is a mixture of Q10, it can be produced by, for example, a method of concentrating reduced coenzyme Q10 in the effluent using chromatography. 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 also 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, etc., and obtained by reduction, more preferably, existing high-purity oxidized coenzyme Q10, or oxidized coenzyme Q10 and reduced coenzyme Q10 Is obtained by reducing coenzyme Q10, which is a mixture of the above, with ascorbic acids.
In the present invention, the unstable fat-soluble active ingredient as described above can be stabilized by using a particulate composition together with a water-soluble excipient. The water-soluble excipient component that can be used in the present invention is not particularly limited, but is at least one selected from the group consisting of a water-soluble polymer, a surfactant (C), a sugar, and a yeast cell wall. It is preferable. In the present invention, these water-soluble polymers, surfactants (C), sugars, yeast cell walls and other water-soluble excipients are arbitrarily combined, and the composition is adjusted so that “water content is 3% described later”. The condition that the true specific gravity of the water-soluble excipient component is 1.25 or more under the condition of weight or less can be satisfied. 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, gelatin, agar, starch, pectin, gati gum, 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), higher fatty acid sugar esters, 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, gati gum, agar, starch, pectin, carrageenan, casein, dried egg white, curdlan, alginic acids, soybean polysaccharide, pullulan, celluloses, xanthan gum, carmellose salt, polyvinylpyrrolidone, etc. are more preferable. Most preferably, gum arabic can be used. In the present invention, when gum arabic is used alone or in combination with other excipient components as a water-soluble excipient component, the fat-soluble active ingredient can be stabilized over a long period of time. . In this case, the amount of gum arabic used in the water-soluble excipient component is preferably in the range of 20 to 100% by weight, more preferably in the range of 30 to 90% by weight, and particularly preferably in the range of 40 to 80% by weight.
The surfactant (C) 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, sucrose fatty acid esters, Examples include 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 18, preferably 6 to 12 carbon atoms.
Examples of the sorbitan fatty acid esters include those obtained by esterifying one or more hydroxyl groups of sorbitans with a fatty acid having 6 to 18, preferably 6 to 12 carbon atoms.
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.

  In the surfactant (C), a hydrophilic surfactant is particularly preferable for achieving the object of the present invention. For example, HLB is 4 or more, usually HLB is 6 or more, preferably HLB is Eight or more surfactants can be suitably 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 ricinoleate, pentaglycerin condensed ricinoleate, hexaglycerin condensed ricinoleate, 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.

  The sugar that can be used as a component of the water-soluble excipient is not particularly limited as long as it is acceptable for foods. For example, monosaccharides such as glucose, fructose, galactose, arabinose, xylose, mannose; maltose, sucrose, Disaccharides such as lactose; oligosaccharides such as fructooligosaccharide, soybean oligosaccharide, galactooligosaccharide, xylooligosaccharide, and cyclodextrin; sugar alcohols such as sorbitol, maltitol, erythritol, lactitol, and xylitol;

  Examples of the yeast cell wall that can be used as a component of the water-soluble excipient include brewer's yeast cell walls.

  In the particulate composition of the present invention, the true specific gravity of the water-soluble excipient component under the condition that the moisture content of the particulate composition is 3% by weight or less needs to be 1.25 or more. A more preferable range of the true specific gravity of the water-soluble excipient component under the condition where the water content is 3% by weight or less is 1.27 or more, and most preferably 1.30 or more. The reason why “under the condition that the water content is 3% by weight or less” is because the true specific gravity of the water-soluble excipient varies depending on the water content. In addition, “under the condition that the water content is 3% by weight or less” means that the true specific gravity value set anywhere in the range of 0 to 3% by weight of the water content is satisfied, and the water content is 3% by weight or less. It is not necessary to satisfy the true specific gravity value set under all the conditions. When the true specific gravity of the water-soluble excipient component under the condition where the water content is 3% by weight or less is less than 1.25, the water-soluble shaping effective in terms of imparting oxidative stability, for the reason described later, Even when the agent component is used, the stability of the fat-soluble active ingredient after microencapsulation is lowered. On the other hand, the upper limit value of the true specific gravity of the water-soluble excipient component under the condition that the water content is 3% by weight or less is not particularly limited as long as the object of the present invention can be achieved. is there.

  The true specific gravity can be measured by a known measuring method such as a liquid phase substitution method or a gas phase substitution method. The measuring method of “true specific gravity of water-soluble excipient under the condition that the water content is 3% by weight or less” in the present invention is in accordance with the examples described later. In order to calculate the moisture content of the particulate composition, the value of the absolute dry weight of the particulate composition after completely removing moisture is required. In the present invention, in a thermogravimetric analyzer, when the heating is continued at 120 ° C., the weight at which weight loss is not observed for 1 minute or more is defined as the absolute dry weight (water content 0%), and the water content of the particulate composition is determined. calculate. The true specific gravity of the water-soluble excipient can be converted from the density of the oily component (A) contained in the particulate composition and the content (% by weight) by calculation.

  In the present invention, the true specific gravity of the entire particulate composition is not particularly limited because it is affected by the specific gravity of the fat-soluble active ingredient and the content ratio of the water-soluble excipient in the particulate composition. When reduced coenzyme Q10 is contained as an active ingredient in an amount of about 15 to 30% by weight in the particulate composition, it is usually 1.1 or more, preferably 1.2 or more.

Further, the sphericity of the particulate composition of the present invention needs to be 0.9 or more, preferably 0.95 or more, and more preferably 0.96 or more. When the sphericity of the particulate composition is smaller than 0.9, the stabilizing effect of the fat-soluble active ingredient is lowered for the reason described later. Note that the sphericity of the particulate composition was measured by photographing the target 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, the volume average particle diameter of the particulate composition of the present invention is preferably 50 to 1000 μm, more preferably 70 to 750 μm, and most preferably 100 to 500 μm. When the volume average particle diameter of the particulate composition is smaller than 50 μm, the total surface area per unit weight of the particulate composition is increased, and the stabilizing action of the fat-soluble active ingredient may be reduced. The upper limit of the volume average particle diameter of the particulate composition is not particularly limited as long as the object of the present invention can be achieved, but is preferably about 1000 μm, which is a level that enables handling as a so-called powder. The volume average particle size of the particulate composition of the present invention can be measured, for example, in an ethanol solvent using a commercially available laser diffraction / scattering type particle size distribution analyzer.

  In the particulate composition of the present invention, the oil component (A) containing a fat-soluble active ingredient is polydispersed by forming a domain in a matrix mainly composed of a water-soluble excipient. preferable. The term “main component” as used herein means that the matrix is formed of at least 80% by weight or more, preferably 90% by weight or more of a water-soluble excipient. In addition, the oil component (A) in this case may be (a) a fat-soluble active ingredient alone or a mixture of two or more fat-soluble active ingredients, or (b) a fat-soluble active ingredient, It may be a mixture of fats and oils and / or surfactant (E).

  The fat and oil component (component of the oily component (A)) that can be added to the fat-soluble active ingredient is not particularly limited as long as the object can be achieved. For example, natural fats and oils from animals and plants may be used. Fats and oils and processed oils and fats may be used. More preferably, it is acceptable for foods, cosmetics or pharmaceuticals. 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, egoma oil, cottonseed oil, sunflower seed oil, kapok oil, evening primrose oil, shea fat, monkey fat, cacao butter, sesame oil, safflower oil, olive oil, etc. Animal fats and oils include, for example, pork fat, milk fat, fish oil, beef tallow and the like, and oils and fats processed by fractionation, hydrogenation, transesterification, etc. (for example, hardened oil) Can do. 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 oil and fat components, vegetable oils, synthetic oils and processed oils and fats are preferable from the viewpoints of ease of handling and odor. 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 (E) include glycerin fatty acid esters, polyglycerin esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, lecithins, and the like. Activators are preferred, but are not limited to these.

  Examples of such glycerin fatty acid esters include monoglycerides and diglycerides in which the fatty acid has 6 to 18 carbon atoms, preferably 6 to 12 carbon atoms. Examples of the polyglycerin esters include polyglycerin mainly composed of polyglycerin having a degree of polymerization of 2 to 10, and one or more hydroxyl groups of polyglycerin each having 6 to 18, preferably 6 to 12 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 18 carbon atoms, preferably 6 to 12 carbon atoms. Examples of sorbitan fatty acid esters include those obtained by esterifying one or more hydroxyl groups of sorbitans with a fatty acid having 6 to 18, preferably 6 to 12 carbon atoms. Examples of the propylene glycol fatty acid esters include monoglycerides and diglycerides in which the fatty acid has 6 to 18 carbon atoms, preferably 6 to 12 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 surfactants (E), fats that are unstable with respect to oxygen, light, acids / bases and / or radicals, etc., which have good compatibility with fat-soluble active ingredients or are the object of the present invention In view of obtaining a particulate composition capable of stabilizing a soluble active ingredient over a long period of time, a lipophilic surfactant is preferable, and for example, a surfactant having an HLB of 10 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 ester such as ester with fatty acid of formula 6-22, and polyglycerin condensed lysi such as ester of polyglycerin with average polymerization degree of 2-10 and polyricinoleic acid with condensation degree of 2-4 Glycerin fatty acid esters such as oleic acid esters; Propylene glycol fatty acid esters such as propylene glycol monostearic acid ester, propylene glycol monooleic acid ester, and propylene glycol monolauric acid ester; sorbitan distearic acid ester, sorbitan tristearic acid ester, sorbitan A sorbitan fatty acid ester such as sesquioleate, sorbitan dioleate, and sorbitan trioleate; and one or a mixture of two or more selected from lecithins such as soybean lecithin, egg yolk lecithin, and enzymatically decomposed lecithin Can be mentioned. 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, monoglycerine 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) and polyglycerin condensed ricinoleate ( Particularly, it is one or a mixture of two or more kinds selected from 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 ester (particularly monoester). Glycerin fatty acid Acid ester, monoglycerin coconut palm oil acetate), and specific examples include 50% acetylated monoglycerol monostearate, fully acetylated coconut monoglyceride, soybean lecithin, egg yolk lecithin, and enzymatically degraded lecithin . 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 solid fats and oils, fatty acids and ester derivatives thereof can be contained in the oil-based component (A) according to various purposes.

Examples of the solid fat include food waxes such as beeswax, mole, cadilla wax, rice bran wax, carmauba wax, and snow wax.
Examples of the fatty acid and its ester derivative 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.

  In the present invention, the ratio of the fat-soluble active ingredient in the oil component (A) is preferably in the range of 5 to 100% by weight. From such a viewpoint, the oil component (A) contains 5 to 100% by weight of a fat-soluble active ingredient, 0 to 95% by weight of fat and oil, and 0 to 95% by weight of a surfactant (E). Preferably, it consists of 25 to 100% by weight of fat-soluble active ingredient, 0 to 75% by weight of fat and oil, and 0 to 75% by weight of surfactant (E), more preferably 50 to 100% by weight of fat. Most preferably, it consists of a soluble active ingredient, 0 to 50% by weight of fat and oil, and 0 to 50% by weight of surfactant (E). When the fat-soluble active ingredient in the oil-based component (A) is less than 5% by weight, the content of the fat-soluble active ingredient in the finally obtained particulate composition is reduced, for example, a predetermined amount of fat-soluble When an active ingredient is orally administered, it is necessary to ingest a large amount of a particulate composition.

  In the particulate composition of the present invention, the oil component (A) is formed when the oil component (A) containing the fat-soluble active ingredient is polydispersed in the matrix mainly composed of the water-soluble excipient. The volume average particle diameter of the domain is not particularly limited as long as the object of the present invention can be achieved, but is preferably in the range of 0.01 to 10 μm, more preferably in the range of 0.01 to 5 μm. The most preferable range is 0.01 to 3 μm. When the volume average particle diameter of the domain formed by the oil-based component (A) containing the fat-soluble active ingredient is larger than 10 μm, for example, when the particulate composition is taken orally, the oral absorbability tends to decrease. . On the other hand, the lower limit of the average particle diameter of the domain formed by the oil-based component (A) containing the fat-soluble active ingredient is not particularly limited, but if it is smaller than 0.01 μm, the stability of the emulsified droplets during the production process It tends to be difficult to maintain the sex.

  In addition, the volume average particle diameter of the domain formed by the oil-based component (A) containing the fat-soluble active ingredient can be obtained by image analysis from an electron microscope image of the fracture surface of the particle composition that is hemispherically broken. it can.

Furthermore, in the present invention, when a component unstable to oxygen is used as the fat-soluble active ingredient, the lipid-soluble active ingredient can be oxidized and stabilized by including a reducing agent in the particulate composition of the present invention. The property can be further improved.
Reducing agents that can be used in that case include fat-soluble reducing agents such as tocopherols, polyphenols, and extracts containing these in addition to fat-soluble ascorbic acids such as palmitate and ascorbic acid stearate; And water-soluble ascorbic acids which are reducing agents. In the present invention, when a fat-soluble reducing agent is used, it is most convenient and preferable to add it to the oil component (A). When a water-soluble reducing agent is used, it is convenient and preferable to use it by adding and dissolving it in an aqueous excipient solution in which a water-soluble excipient is dissolved.

  Among these, a preferable reducing agent is a water-soluble reducing agent, and in particular, when water-soluble ascorbic acids are used, in the particulate composition of the present invention, particularly the stability of the fat-soluble active ingredient unstable to oxidation. Is more preferable because it can be effectively improved. Examples of the water-soluble ascorbic acid that can be used in the present invention include not only ascorbic acid but also rhamo-ascorbic acid, arabo-ascorbic acid, gluco-ascorbic acid, fuco-ascorbic acid, glucohepto-ascorbic acid, xylo-ascorbic acid Acids, galacto-ascorbic acid, gulo-ascorbic acid, allo-ascorbic acid, erythro-ascorbic acid, those similar to ascorbic acid such as 6-desoxyascorbic acid, and salts thereof are preferred. These may be L-form, D-form, or racemate. Specific examples include L-ascorbic acid, sodium L-ascorbate, calcium L-ascorbate, and D-arabo-ascorbic acid. Among these, L-ascorbic acid and D-arabo-ascorbic acid can be more preferably used in terms of stabilization of a fat-soluble active ingredient unstable to oxygen, which is an object of the present invention. Needless to say, these water-soluble ascorbic acids may be used alone or in combination.

  The amount of the reducing agent used is not particularly limited in achieving the object of the present invention, but it is usually preferable to contain 0.1 to 20% by weight of the reducing agent in the particulate composition. The content is more preferably 0.1 to 15% by weight, and most preferably 0.5 to 10% by weight. In addition, since the particulate composition of the present invention can impart a very high stabilizing effect to the fat-soluble active ingredient than the powdered fat obtained by the conventional production method, it is not always necessary to use a reducing agent. A higher effect can be expected by adding 0.1% by weight or more. On the other hand, the upper limit of the amount of reducing agent used is not limited as long as the object of the present invention can be achieved, but is usually 20% by weight.

  In the present invention, particularly when a reducing agent is contained, even if water is present in the particulate composition, a higher stabilizing effect of the fat-soluble active ingredient is realized compared to the conventional powdered fat composition. can do. From such a viewpoint, the particulate composition of the present invention may contain 0.01 to 30% by weight of water, and the preferable water content is 0.1 to 20% by weight, more preferably 0. The range is from 1 to 15% by weight, but is not limited as long as the object of the present invention can be achieved. In the present invention, particularly when the above-mentioned water-soluble reducing agent is used, there is a tendency that a higher stabilizing effect of the fat-soluble active ingredient tends to be obtained particularly when water is contained in the particulate composition. .

  The content of the fat-soluble active ingredient 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. The most preferable range is as follows. When the content of the fat-soluble active ingredient in the particulate composition is less than 1% by weight, for example, it is necessary to take a large amount of the particulate composition when orally administering a predetermined amount of the fat-soluble active ingredient It becomes. On the other hand, the upper limit of the content of the fat-soluble active ingredient in the particulate composition is not particularly limited as long as the object of the present invention can be achieved, but usually 70% by weight or less is preferable. When the content of the fat-soluble active ingredient in the particulate composition is more than 70% by weight, it tends to be difficult to maintain high stability for various purposes.

  In addition, to the particulate composition of the present invention, various additives that can be used for various purposes and active ingredients other than fat-soluble active ingredients are added according to the respective purposes in food, cosmetics, and pharmaceutical applications. be able to.

  For example, in addition to the above compounds, excipients such as crystalline cellulose, calcium phosphate, calcium sulfate, calcium citrate, calcium carbonate, sodium hydrogen carbonate, dextrin, crystalline cellulose, carboxymethyl cellulose, tragacanth, alginic acid and other disintegrants, talc, Lubricants such as magnesium stearate, 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 Anti-aggregation agents such as silicic acid and hydrous silica dioxide, absorption accelerators such as higher alcohols and higher fatty acids, solubilizers such as fumaric acid, succinic acid and malic acid, benzoic acid, sodium benzoate, paraoxybenzoic acid Stabilizers such as ethyl and beeswax It can gel.

  In the particulate composition of the present invention, the retention rate (%) of the fat-soluble active ingredient after being stored for 30 days under light-shielding conditions at 40 ° C. in air (ratio to the weight of the first fat-soluble active ingredient) is 90 It is preferably at least weight percent, more preferably at least 95% weight, and particularly preferably at least 98% weight. The humidity in the storage atmosphere is not particularly limited, but is usually about 90% or less relative humidity, preferably about 75% or less, more preferably about 60% or less, and particularly preferably about 40% or less relative humidity. .

  Next, the preferable manufacturing method of the particulate composition 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 of the present invention preferably comprises an oil-in-water emulsion composition prepared from an oily component (A) containing a fat-soluble active ingredient and an aqueous solution containing a water-soluble excipient, and an oily component (B). After being dispersed or suspended therein, it can be produced by a method of removing water in the emulsified composition in the oil component (B).

  In the above production method, the water-soluble excipient is used in the form of an aqueous solution dissolved in water, and the concentration thereof is not particularly limited, but it is handled at a concentration such that the viscosity of the aqueous solution does not exceed 1 Poise, It is preferable in securing liquid transfer properties. 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 method, the oil-based component (A) containing the fat-soluble active ingredient is prepared at room temperature when the fat-soluble active ingredient is liquid, and the fat-soluble active ingredient is in a crystalline or amorphous state (liquid) at room temperature. If it is not in the state, use the one that has been heated and melted above the melting point of the fat-soluble active ingredient as it is, or add fat or surfactant (E) or a mixture thereof to the fat-soluble active ingredient, and visually That are mixed so as to be uniform can be used. Specific examples and preferred examples of each component of the oil component (A) at this time are the same as those described in the description of the particulate composition.

  Next, in the production method of the present invention, an oil-in-water emulsion composition is prepared from an aqueous solution containing the oil component (A) and a water-soluble excipient. As the method for preparing the oil-in-water emulsion composition, for example, the oil component (A) is added to the aqueous water-soluble excipient solution, and preferably at a temperature equal to or higher than the melting point of the fat-soluble active component, a high-pressure homogenizer, etc. It is most convenient and preferable to adjust by finely dispersing and emulsifying the oily component (A) to a desired average particle size using a known emulsifying device.

  In the production method of the present invention, the emulsion particle size of the oil component (A) of the oil-in-water emulsion composition is preferably in the range of 0.01 to 3 μm, and preferably in the range of 0.01 to 2 μm. More preferably, it is the range of 0.01-1.5 micrometers. The emulsified particle size of the oil-in-water emulsion composition correlates with the average particle size of the domain formed by the oil-based component (A) containing the fat-soluble active ingredient in the obtained particulate composition, so that the emulsified particle size is When it is larger than 3 μm, for example, when the particulate composition is orally ingested, the oral absorbability tends to decrease. On the other hand, the lower limit of the emulsified particle diameter is not particularly limited, but when it is smaller than 0.01 μm, it tends to be difficult to maintain the stability of the emulsified droplets during the production process. By controlling the particle size of the emulsified droplets in this step, the domain particle size in the obtained particulate composition can be controlled.

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

  In the production method of the present invention, the step of preparing the oil-in-water emulsion composition from the oily component (A) and the aqueous solution of the water-soluble excipient is more than the melting point of the fat-soluble active component contained in the oily component (A). It is preferable to carry out at a high temperature, usually in the range of 50 to 100 ° C. Although the upper limit of the temperature in an emulsification process changes with specifications of an apparatus, 120 degrees C or less is preferable normally.

  In the production method of the present invention, the above oil-in-water emulsion composition is further mixed with another oil component (B), and the oil-in-water emulsion composition is added to the oil component (B) so as to obtain a desired particle size. To make an O / W / O type emulsion. In the above mixing operation, for example, it is simplest and preferable to add the oil-in-water emulsion composition to the oil component (B) that has been heated to 50 ° C. or higher in advance, but is not limited thereto. . Adjustment of the suspended particle size of the oil-in-water emulsion composition in the oil component (B) can be achieved by applying shear to the mixed solution such as stirring. The suspended particle size in the oil-based component (B) of the oil-in-water emulsion composition is not particularly limited as long as a particulate composition having a target particle size (for example, 50 to 1000 μm) is obtained after removing water, but usually, It is preferable to adjust to the range of 60-1200 micrometers. The temperature of the oil component (B) when preparing the mixed solution is usually preferably in the range of 50 to 150 ° 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 emulsion composition and oil-based component (B) in the manufacturing method of this invention, In the whole liquid mixture of an oil-in-water emulsion composition and oil-based component (B) The weight% of the oil-in-water emulsion composition is preferably 1 to 70% by weight, more preferably 10 to 60% by weight, and most preferably 15 to 55% by weight. When the amount of 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 amount of 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 added to the oil component (B). It tends to be difficult to suspend.

  The oil component (B) in the production method of the present invention is not particularly limited as long as it is a fat that can suspend the oil-in-water emulsion composition, and may be, for example, a natural fat from animals or plants. Fats and oils and processed oils and fats may be used. 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 and odor. 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.

  In the production method of the present invention, for the purpose of ensuring the dispersion stability of the oil-in-water emulsion composition droplets dispersed in the oil component (B), a surfactant is contained in the oil component (B) as necessary. (D) can be added. 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 (D) 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 dramatically improved.

  Although there is no restriction | limiting in particular in content of surfactant (D) in oil-based component (B), surfactant (D) is a composition of oil-based component (B) with respect to 5-99.99 weight% of fats and oils. It is preferable to arbitrarily adjust so that the amount falls within the range of 0.01 to 95% by weight. When the addition amount of the surfactant (D) is less than 0.01% by weight, the effect of suppressing aggregation between droplets of the oil-in-water emulsion composition during drying tends to be difficult to obtain. However, in some cases, the surfactant (D) may not be used and 100% by weight of the oil or fat can be used as the oil component (B).

The surfactant (D) 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, polyglycerin esters, Examples include sucrose fatty acid esters, sorbitan fatty acid esters, and lecithins. 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 18 carbon atoms, preferably 12 to 18 carbon atoms.

Examples of the polyglycerin esters include polyglycerin mainly composed of polyglycerin having a degree of polymerization of 2 to 10, and one or more hydroxyl groups of polyglycerin each having 6 to 18, preferably 12 to 18 carbon atoms. What esterified fatty acid is mentioned.
Examples of sucrose fatty acid esters include those obtained by esterifying one or more hydroxyl groups of sucrose with fatty acids having 6 to 18 carbon atoms, preferably 12 to 18 carbon atoms, as sorbitan fatty acid esters. One or more of the hydroxyl groups may be esterified with a fatty acid having 6 to 18, preferably 12 to 18 carbon atoms.

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

  Among the above surfactants (D), in the production method of the present invention, monoglycerin monostearin is specifically exemplified from the viewpoint that aggregation between the oil-in-water emulsion composition droplets during drying can be efficiently suppressed. Monoglycerin monofatty acids such as acid esters, monoglycerin monooleates, monoglycerin monomyristates, monoglycerin monocaprylate, monoglycerin monolaurate, monoglycerin monobehenate, monoglycerin monoerucate Esters; monoglycerol distearate, monoglycerol dioleate, monoglycerol dicaprylate, monoglycerol dilaurate, etc .; monoglycerol stearate citrate, Monoglycerol fatty acid organics such as glycerol stearic acid acetate, monoglycerol palm hardened oil acetate, monoglycerol stearic acid succinate, monoglycerol caprylic acid succinate, monoglycerol stearate lactate, monoglycerol stearate diacetyl tartaric acid ester 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. Monoglycerin fatty acid ester; polyglycerin fatty acid ester such as an ester of polyglycerin having an average degree of polymerization of 2 to 10 and a fatty acid having 6 to 22 carbon atoms, and an average degree of polymerization Glycerin fatty acid esters such as polyglycerin condensed ricinoleic acid ester such as ester of -10 polyglycerin and polyricinoleic acid having a condensation degree of 2 to 4; propylene glycol monostearate, propylene glycol monooleate, and propylene glycol Propylene glycol fatty acid esters such as monolaurate; sorbitan fatty acid esters such as sorbitan distearate, sorbitan tristearate, sorbitan sesquioleate, sorbitan dioleate, and sorbitan trioleate; and soy lecithin , One or a mixture of two or more selected from lecithins such as egg yolk lecithin and enzymatically decomposed lecithin. 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 monoglycerin monofatty acid ester, monoglycerin di 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 fatty acid having 6 to 22 carbon atoms) Ester), polyglycerin condensed ricinoleic acid ester (especially ester of polyglycerin having an average polymerization degree of 2 to 10 and polyricinoleic acid having a degree of condensation of 2 to 4), soybean lecithin, egg yolk lecithin, and enzymatically decomposed lecithin One kind or It is a mixture of two or more, more preferably monoglycerin fatty acid organic acid ester (especially monoglycerin fatty acid acetate ester, monoglycerin coconut palm oil acetate ester), and as a specific example, 50% acetylated product of monoglycerin monostearate ester , A fully acetylated product of coconut oil monoglyceride, soybean lecithin, egg yolk lecithin, or one or a mixture of two or more enzyme-decomposed lecithins. Among these, lecithins such as soybean lecithin, egg yolk lecithin, and enzyme-decomposed lecithin can be more suitably used for achieving the above object.

  In the production method of the present invention, after the O / W / O type emulsion is obtained, water is removed from the oil-in-water emulsion composition suspended in the oil component (B). 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.

  In the production method of the present invention, the time required for removing water from the oil-in-water emulsion composition droplets is not particularly limited, but is preferably 5 seconds to 24 hours, more preferably 10 seconds to 12 hours, most preferably It is in the range of 15 seconds to 6 hours. When the time required for removing water is less than 5 seconds, the water is rapidly evaporated from the oil-in-water emulsion composition droplets, so that a particulate composition having a distorted particle shape and a low sphericity can be easily obtained. Therefore, it is not preferable. On the other hand, when the time required for removing moisture is longer than 24 hours, there is no particular limitation as long as the object of the present invention can be achieved, but productivity tends to decrease.

  Incidentally, the removal of water in the production method 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 recovery in the form of particles is possible. It is sufficient if it is in a state. The residual water content is usually preferably 10% by weight or less, more preferably 5% by weight or less, and most preferably 3% by weight or less of the weight of the recovered particles.

  In the above production method, the method for recovering the particulate composition after removing water is not particularly limited, but after removing the oil component (B) by solid-liquid separation, the obtained particle composition is washed with an organic solvent or the like. It is most convenient and preferable to remove most of the oil component (B) and further remove the organic solvent and moisture by drying and collect it as a powder.

  Examples of the organic solvent for washing the oil component (B) include, but are not limited to, ethanol, methanol, isopropanol, acetone, hexane, ethyl acetate, and tetrahydrofuran. Examples of the method for drying the organic solvent include, but are not limited to, vacuum drying, heat drying, air drying, fluid drying, and the like. 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.

  In the production method of the present invention, each oil-in-water emulsified composition droplet suspended in a substantially spherical shape in the oil component (B) gradually removes moisture while maintaining a spherical shape. To do. Accordingly, the sphericity of the resulting particles is necessarily very high. Further, the particle size of the obtained particles can be arbitrarily set within the scope of the present invention by adjusting the droplet size of the oil-in-water emulsion composition suspended in the oil component (B), for example, by the stirring strength. Can be adjusted. That is, by these operations, the total surface area per unit weight of the obtained particulate composition can be made extremely small as compared with the spray drying method.

  Conventionally, as a multinuclear type microcapsule encapsulating a fat-soluble active ingredient having a water-soluble excipient as a capsule wall, a powdery fat composition produced by a production method typified by a spray drying method is widely known. Such a powdery oil / fat composition is a particulate composition in which a fat-soluble active ingredient is encapsulated in a polydisperse form in a water-soluble excipient matrix as in the present invention. In the conventional spray drying method, an oil-soluble active ingredient is emulsified in an aqueous solution in which a water-soluble excipient is dissolved, and the resulting oil-in-water emulsion composition is formed into droplets, for example, in hot air at 150 to 200 ° C. Sprayed and dried to perform microencapsulation. In the drying process, the water evaporates in a few seconds from the oil-in-water emulsion composition droplets, so there is a large hole in the center, the particle shape becomes irregular, and the particle surface becomes rough and rough. Such a phenomenon is induced. Further, in order to suppress a decrease in yield due to adhesion to the champ etc., it is preferable to set the spray droplet diameter as small as possible and complete the drying in a short time. In the case of normal production, the volume average particle of the obtained dry particles The diameter is about 5 to 30 μm. That is, the powdered fats and oils obtained by the spray drying method have a feature that the total surface area per unit weight of the recovered particles is extremely large because the particle diameter is small and the shape is irregular.

  On the other hand, for example, when considering the stability to oxidation of powdered fats and oils containing fat-soluble active ingredients that are unstable to oxygen in the atmosphere, the physical oxygen molecule shielding effect of the water-soluble excipient capsule wall is You can easily imagine what is important. In general, in the diffusion phenomenon of gas (assuming oxygen molecules) into a solid substance (assuming water-soluble excipient components), the surface area of the solid substance, the concentration difference between the gas outside and inside the solid substance, and the solid substance It is known to be a function of density. To further explain each factor, (I) the larger the surface area of the solid substance (capsule wall), the more parts that are in direct contact with the external gas, and the higher the probability that the gas will enter the solid substance. (II) The higher the gas concentration difference between the inside and outside of the solid material, the easier it is for the gas to penetrate into the solid material due to the concentration gradient. (III) The higher the density of the solid material, the fewer voids the gas molecules can move. The diffusion rate decreases.

  When these factors are applied to the oxidation stability of powdered fats and oils containing fat-soluble active ingredients that are unstable to oxygen, (I) shows that the larger the particle size of the particulate composition is, the higher the sphericity is. For stability, (II) should be stored in an atmosphere with low oxygen concentration, and for (III), the density of solid substance (water-soluble excipient), that is, the true specific gravity should be as high as possible. Are respectively important in terms of ensuring oxidation stability.

Based on the above concept, the potential for the oxidative stability of powdered fats and oils obtained by conventional production methods will be described subsequently. As described above, since the polynuclear microcapsule powder oil and fat composition produced by the spray drying method has a small particle diameter and an irregular shape, the oxidation stability is lowered due to the reason (I).
On the other hand, the polynuclear microcapsule powder oil-fat composition obtained by the spray cooler method or the submerged curing method can adjust the particle size to an arbitrary size, and the particle shape represented by sphericity is relatively good. However, it is essential to use gelatin as the water-soluble excipient, and the true specific gravity of the water-soluble excipient component in the obtained microcapsules is not high, and is usually lower than 1.25. In the spray cooler method or the submerged hardening method, moisture is gradually removed from gelatin in a gel state formed by cooling at low temperatures to produce dry particles. However, gelatin in a gel state is in a state in which physical crosslinks are formed between high molecular weight gelatin molecular chains, and in the drying process, the degree of freedom at the molecular level of the excipient component is limited. The true specific gravity of the particulate composition mainly composed of gelatin obtained by the cooler method or the submerged hardening method is low, and it is estimated that the stabilization effect of the fat-soluble active ingredient to be included is inferior in the above (III). The

  The particulate composition of the present invention surpasses the limitations of the prior art, especially for the first time in the item of true specific gravity of (III) above, and thereby to oxygen, light, acid / base and / or radical, etc. Long-term stability of an unstable fat-soluble active ingredient can be realized. In particular, in the production method of the present invention, the excipient component in the droplets of the oil-in-water emulsion composition suspended in the oil component (B) is gradually dried, that is, accompanied with a decrease in water content. Thus, a time delay is provided to form a more stable and dense packing state (a high true specific gravity can be realized). In particular, when gum arabic or the like that is not in a gel state is used as an excipient component, the excipient component polymer chain can freely form a more stable and dense packing state in the drying process. On the other hand, in the case of the spray drying method or the layering granulation method, the water is evaporated at once from the oil-in-water emulsion composition droplet sprayed in the high temperature gas phase within a few seconds (about 1 to 3 seconds). Therefore, it is presumed that the excipient component does not have time to form a dense packing state, that is, solidifies in a sparse packing state (a state with a low true specific gravity). The true specific gravity of the water-soluble excipient is considered to be due to the difference in the packing state of the water-soluble excipient component due to the difference in the drying conditions.

  From the above, the particulate composition of the present invention satisfies the condition that “the true specific gravity of the water-soluble excipient under the condition that the water content is 3% by weight or less” is 1.25 or more, and “the sphericity is By satisfying the condition of “0.9 or more”, it is possible to show a remarkable stabilization effect not found in conventional powdered oils and fats.

  Next, the stabilization method and handling method of the particulate composition of the present invention will be described.

  The stabilization described in the present specification indicates that the fat-soluble active ingredient in the particulate composition is inhibited from being decomposed by oxygen, light, acid / base, and / or radical. 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, classification, packaging, packing, storage, storage, and transport. Storage is preferred.

  The upper limit of the temperature in the method for stabilizing and handling the particulate composition of the present invention is usually about 100 ° C. or lower, preferably about 80 ° C. or lower, more preferably about 60 ° C. or lower, more preferably about 40 ° C. or lower, Particularly preferably, it can be carried out 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 addition, when water-soluble ascorbic acids are used as the reducing agent in the particulate composition of the present invention, the influence of humidity in the storage atmosphere can be reduced. 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 fat-soluble active ingredient 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%.

Retention rate (%) of the fat-soluble active ingredient in the particulate composition after storage for 30 days under the light-shielding condition at 40 ° C. in the preferred embodiment, where the humidity in the storage atmosphere is adjusted as described above. 90% by weight or more, more preferably 95% by weight or more, still more preferably 98% by weight or more, and most preferably 99% by weight or more.
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 dry inert gas) 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.

  Further, in order to maximize the effects of the present invention, from the viewpoint of the stability of the fat-soluble active ingredient, when the fat-soluble active ingredient is unstable with respect to oxygen, naturally, the particle composition of the present invention Manufacture and storage of the product are preferably performed in an inert gas atmosphere, for example, in an inert gas atmosphere such as nitrogen gas, helium gas, and argon gas.

  In addition, the particulate composition obtained by this invention can be handled using a glass bottle, a plastic bottle, a plastic bag, an aluminum laminated bag, etc., for example, can be packaged and packed. In the above handling, for example, packaging, packaging, examples of materials include materials such as glass, high density polyethylene, medium density polyethylene, low density polyethylene, polyethylene terephthalate, polyvinyl alcohol, polypropylene, polyvinyl chloride, polyvinylidene chloride, A material obtained by laminating a metal film such as aluminum on the polyethylene, polyethylene terephthalate, or the like can also be suitably used. In addition, when a material having a relatively low gas barrier property and moisture resistance such as polyethylene is used, it is preferable that the outer bag is packaged or packed in a double or more manner with a material excellent in gas barrier property and moisture resistance such as an aluminum laminate. . 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 material. After packaging and packing, it can be transported and stored in steel drums, resin drums, fiber drums, cardboard, etc. as necessary. Needless to say, moisture-proofing agents such as silica gel, calcium chloride, and synthetic zeolite can be enclosed.

  In the present invention, the particulate composition of the present invention is mixed slurry suspended in the oil component (F), and this is filled in a soft capsule such as gelatin, so that the fat-soluble active ingredient is higher. It is possible to make a soft capsule preparation that can realize stability and high oral absorbability.

  Conventionally, for example, as a soft capsule preparation containing reduced coenzyme Q10 having poor oxidation stability, reduced coenzyme Q10 powder is dispersed or dissolved in a slurry form in an oily component mainly composed of vegetable oil and / or surfactant. A preparation in which a gelatin soft capsule is filled with the above composition is known. However, in this preparation, the invasion of oxygen from the outside is physically shielded only by the gelatin capsule wall, and the reduced coenzyme Q10 filled after the preparation is in particular under humidified conditions. Oxidation tends to progress gradually.

  On the other hand, in the present invention, reduced coenzyme Q10 is used as a fat-soluble active ingredient to form a particulate composition containing reduced coenzyme Q10, and this is a mixed slurry suspended in the oily component (F). In a soft capsule formulation obtained by filling a soft capsule such as gelatin with a reduced coenzyme Q10, not only the gelatin capsule wall but also a water-soluble excipient wall having a true specific gravity of 1.25 or more is used in combination. It is possible to physically shield the entry of oxygen from the outside with the film, and it is possible to obtain a preparation with better stability.

  In addition, the soft capsule formulation of the present invention also tends to exhibit higher oral absorbability than conventional soft capsule formulations in terms of oral absorbability. This is because the particulate composition of the present invention is broken down in the stomach or intestine, and the oil component (A) constituting the domain maintains a fine particle size that is advantageous for absorption into the digestive tract. It is presumed to be due to release into the body.

  Examples of the oil component (F) used in the above soft capsule preparations include rapeseed oil, safflower oil, vegetable oils such as medium chain fatty acids, lecithins, enzymatically decomposed lecithins, food emulsifiers such as (poly) glycerin fatty acid esters, Solid fats such as beeswax and the like can be used alone or in a mixture of two or more, but are not limited thereto, and are arbitrarily set so that the oral absorbability of the particulate composition of the present invention is good it can.

Further, in the present invention, gelatin is used as the powder obtained by mixing the particulate composition of the present invention as it is or with a general preparation component, or as a slurry suspended in the oil component (F). It is possible to obtain a hard capsule preparation capable of realizing high stability and high oral absorption by filling in a hard capsule.
Usually, for example, as a hard capsule preparation containing reduced coenzyme Q10, a preparation obtained by filling a hard capsule such as gelatin with a powder composition containing reduced coenzyme Q10 powder is assumed. However, in this preparation, similarly to the soft capsule preparation, only the gelatin capsule wall physically shields the entry of oxygen from the outside, and the reduced coenzyme Q10 filled even after preparation is prepared. Can be easily oxidized.

  On the other hand, for example, in a hard capsule formulation obtained by filling a hard capsule such as gelatin with the particulate composition of the present invention using reduced coenzyme Q10 as a fat-soluble active ingredient, reduced coenzyme Q10 is a gelatin capsule. In addition to the wall, it is possible to physically shield the entry of oxygen from the outside with a double film combined with a water-soluble excipient wall with a true specific gravity of 1.25 or more, and it has better oxidation stability A reduced coenzyme Q10 preparation can be obtained.

  In addition, in the hard capsule preparation of the present invention, in terms of oral absorption, when the particulate composition of the present invention disintegrates compared to the hard capsule preparation filled with a powder of an oily active ingredient having a volume average particle diameter of usually about 10 μm. Furthermore, since the oily component (A) constituting the domain is released into the living body while maintaining a fine particle size that is advantageous for absorption into the digestive tract, it tends to exhibit good oral absorption. .

  In the present invention, the particulate composition of the present invention can be processed into a tablet or chewable agent together with any excipient powder such as lactose. Usually, for example, as a tablet or chewable agent containing reduced coenzyme Q10, a preparation obtained by processing a powder composition containing reduced coenzyme Q10 powder by tableting or the like is assumed. However, in this preparation, naked reduced coenzyme Q10 powder is dispersed and distributed in an excipient powder such as lactose, and the stability against oxidation is inevitably at a low level. However, the tablet or chewable agent obtained by processing the particulate composition of the present invention is covered with a water-soluble excipient wall having a true specific gravity of 1.25 or more, and physical entry of oxygen from the outside is prevented. Thus, it is possible to obtain a preparation having better oxidation stability. Of course, the tablet or chewable preparation of the present invention can be coated with a sugar coating or the like, if necessary. Also, in terms of oral absorbability, a good preparation is obtained due to the same effect as the soft capsule and the hard capsule.

  In addition, in the soft capsule, the hard capsule, the tablet, and the chewable agent containing the above-described particulate composition of the present invention, the particulate composition may be crushed by shearing or pressure during the preparation processing. However, even in such a case, the stabilizing effect of the fat-soluble component unstable to oxygen, light, acid / base and / or radical of the particulate composition of the present invention is not extremely impaired. In the preparation of soft capsules, hard capsules, tablets, chewable agents and the like containing the particulate composition of the present invention, the pulverized product of the particulate composition of the present invention may be contained.

  Further, the particulate composition of the present invention can be widely used in the food field such as a powder seasoning widely used in curry roux, gum, jelly, yogurt, instant noodles and the like in a powder state. Moreover, it can be widely used as an additive to functional foods and pharmaceuticals as the above-mentioned preparations, and further to cosmetics and sunscreens.

  Furthermore, in the particulate composition of the present invention, an emulsion in which the oily component (A) obtained by dissolving the particulate composition in an aqueous medium is finely dispersed in an aqueous medium, a food such as jelly and yogurt, Alternatively, it can be added to beverages, cosmetics, medicines and the like.

  In addition, the particulate composition of the present invention includes foods (general foods, nutritional functional foods, foods for specified health use, nutritional supplements, nutrients), animal drugs, beverages, feeds, cosmetics, pharmaceuticals, other than those exemplified above. It can be used extensively in applications such as therapeutic agents, preventive agents and the like, or processing them into raw materials and compositions.

  EXAMPLES Next, although this invention is demonstrated further in detail based on an Example, this invention is not limited only to this Example. In the following Examples and Comparative Examples, reduced coenzyme Q10 that is unstable against oxygen in the atmosphere was used as a model substance as a fat-soluble active ingredient. Reduced coenzyme Q10 was prepared according to the following production 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 particulate compositions obtained in Examples, Comparative Examples, and Reference Examples was obtained by analyzing images obtained by electron microscope observation of the particles after collection using image analysis software (WinROOF Ver. 3.30). It was obtained from the ratio of the diameter of a circle having the same area and the diameter of a circumscribed minimum circle. In the analysis, 20 samples were analyzed and the average value was obtained.

(Storage stability)
The particulate compositions obtained in Examples and Comparative Examples were stored at 40 ° C. in air under light-shielding conditions for 30 days, and the retention rate (%) of the fat-soluble active ingredient before and after storage was calculated according to the following formula 1. did.

Retention rate (%) = (purity of fat-soluble active ingredient after storage
/ Purity of fat-soluble active ingredient before storage) × 100 (Formula 1)
(Measurement of true specific gravity)
The true specific gravity of the particulate compositions obtained in Examples, Comparative Examples, and Reference Examples was measured by a liquid phase replacement method. In the liquid phase substitution method, measurement was performed using AUTO TRUE DENSER MAT-7000 (manufactured by Seishin Enterprise Co., Ltd.) under conditions of dry ethanol solvent and 25 ± 2 ° C.

(Density of reduced coenzyme Q10)
Reduced coenzyme Q10 dissolved by heating at 60 ° C. was diluted in a 20 cc volumetric flask in an atmosphere at 60 ° C., and the weight of reduced coenzyme Q10 in a liquid state was measured. From the obtained weight value, the density of reduced coenzyme Q10 in a liquid state was calculated and found to be 0.925 g / cm ³ . Reduced coenzyme Q10 required for calculating the true specific gravity of the water-soluble excipient component under the condition that the water content of the particulate composition in the particulate compositions obtained in Examples and Comparative Examples is 3% by weight or less As the density, the above value was used as a representative value.

(The true specific gravity of the water-soluble excipient component under the condition that the water content of the particulate composition is 3% by weight or less)
The particulate compositions obtained in Examples, Comparative Examples, and Reference Examples were heated at 100 ° C. for 2 hours to adjust the moisture content (volatile content) of the particulate compositions to 3% by weight or less. In addition, the moisture content is measured using a thermogravimetric analyzer (TG / DTA220 manufactured by Seiko Instruments Inc.) when the heating is continued at 120 ° C. and the weight at which weight loss is not observed for 1 minute or more is measured as the absolute dry weight W ₁ ( It was calculated according to the following formula 2 from the weight W ₂ before the measurement.

Water content (% by weight) = 100 × [(W ₂ −W ₁ ) / W ₁ ] (Formula 2)
The true specific gravity of the particulate composition whose water content was adjusted to 3% by weight or less was measured under the above conditions to obtain the true specific gravity d of each particulate composition. The true specific gravity of the water-soluble excipient component is the true specific gravity d of the particulate composition, the density of the oil component (A) (0.925 g / cm ³ when the oil component (A) is reduced coenzyme Q10 alone) From the content c (% by weight) of the oil component (A) in the particulate composition, calculation was performed according to the following formula 3.

True specific gravity of water-soluble excipient component = [d − {(c / 100) × 0.925}]
/ [(100-c) / 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 110 g of distilled water, 60 g of gum arabic (manufactured by Ina Food Industry Co., Ltd .; gum arabic A) was dissolved at 60 ° C. to prepare a water-soluble excipient aqueous solution. This aqueous solution was kept at 60 ° C., 25.6 g of reduced coenzyme Q10 powder obtained in the above production example was added and melted as an oil component (A), and then TK homomixer Mark II (manufactured by PRIMIX Corporation). The mixture was emulsified at 10,000 rpm for 30 minutes to obtain an oil-in-water emulsion composition. The emulsion particle size of reduced coenzyme Q10 in the oil-in-water emulsion composition was about 1 μm. 75 g of the oil-in-water emulsion composition obtained here was heated to 90 ° C. in advance, 100 g of MCT (manufactured by Riken Vitamin Co., Ltd .; Actor M-2) and paste lecithin (ADM Far East Co., Ltd.) Yelkin TS) was added to the oil component (B) consisting of 1 g, and the stirring rotation speed was adjusted so that the particle diameter of the oil-in-water emulsion composition suspension droplets was about 300 μm. While the stirring at the same stirring number is continued, the temperature of the suspension is adjusted to 105 ° C., whereby the removal of water from the oil-in-water emulsion composition suspension droplets proceeds, and the majority of the time is about 30 minutes. Of water evaporated. 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 500 g of ethanol and then dried at 50 ° C. A particulate composition containing Q10 was obtained.

  The resulting granular composition had a sphericity of 0.97, a volume average particle size of about 250 μm, and a true specific gravity of the particulate composition under a condition where the water content was 3% by weight or less, calculated to be 1.24. The true specific gravity of the soluble excipient component was 1.37. In addition, the retention rate of reduced coenzyme Q10 after storage for 30 hours at 40 ° C. in air and under light-shielding conditions was 99.0%.

  In FIG. 1, the scanning electron microscope (Hitachi S-4800) photograph of the external appearance of the obtained particulate composition was shown. FIG. 2 shows a scanning electron micrograph after the particulate composition was broken and immersed in hexane to dissolve and remove reduced coenzyme Q10 (oil component (A)). 1 and 2, it can be seen that the particulate composition of the present invention has an extremely high sphericity, and the oil component (A) is dispersed in a water-soluble matrix by forming fine and clear domains. .

(Example 2)
In 110 g of distilled water, 60 g of gum arabic (manufactured by Ina Food Industry Co., Ltd .; gum arabic A) and 10 g of sucrose (general reagent of Wako Pure Chemical Industries) were dissolved at 60 ° C. to prepare a water-soluble excipient aqueous solution. This aqueous solution was kept at 60 ° C., 30 g of reduced coenzyme Q10 powder obtained in the above production example was added and melted as an oil component (A), and then rotated 10,000 times with a TK homomixer Mark II (manufactured by Primics Co., Ltd.). × Emulsified for 30 minutes to obtain an oil-in-water emulsion composition. The emulsion particle size of reduced coenzyme Q10 in the oil-in-water emulsion composition was about 1 μm. 75 g of the oil-in-water emulsion composition obtained here was heated to 90 ° C. in advance, 100 g of MCT (manufactured by Riken Vitamin Co., Ltd .; Actor M-2) and paste lecithin (ADM Far East Co., Ltd.) Yelkin TS) was added to the oil component (B) consisting of 1 g, and the stirring rotation speed was adjusted so that the particle diameter of the oil-in-water emulsion composition suspension droplets was about 300 μm. While the stirring at the same stirring number is continued, the temperature of the suspension is adjusted to 105 ° C., whereby the removal of water from the oil-in-water emulsion composition suspension droplets proceeds, and the majority of the time is about 30 minutes. Of water evaporated. 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 500 g of ethanol and then dried at 50 ° C. A particulate composition containing Q10 was obtained.

  The obtained granular composition had a sphericity of 0.97, a volume average particle size of about 250 μm, and a true specific gravity of the particulate composition under the conditions of a water content of 3% by weight or less, calculated as 1.30. The true specific gravity of the soluble excipient component was 1.46. In addition, the retention rate of reduced coenzyme Q10 after storage for 30 hours at 40 ° C. in air and under light-shielding conditions was 99.5%.

(Example 3)
20 g of gelatin (manufactured by Nitta Gelatin Co., Ltd .; APH-250) was dissolved in 180 g of distilled water at 60 ° C. to prepare a water-soluble excipient aqueous solution. This aqueous solution was kept at 60 ° C., and 8.6 g of reduced coenzyme Q10 powder obtained in the above production example was added and melted as an oil component (A), and then TK homomixer Mark II (manufactured by Primix Co., Ltd.). The mixture was emulsified at 10,000 rpm for 30 minutes to obtain an oil-in-water emulsion composition. The emulsion particle size of reduced coenzyme Q10 in the oil-in-water emulsion composition was about 1 μm. 75 g of the oil-in-water emulsion composition obtained here was heated to 90 ° C. in advance, 100 g of MCT (manufactured by Riken Vitamin Co., Ltd .; Actor M-2) and paste lecithin (ADM Far East Co., Ltd.) Yelkin TS) was added to the oil component (B) consisting of 1 g, and the stirring rotation speed was adjusted so that the particle diameter of the oil-in-water emulsion composition suspension droplets was about 300 μm. While the stirring at the same stirring number is continued, the temperature of the suspension is adjusted to 105 ° C., whereby the removal of water from the oil-in-water emulsion composition suspension droplets proceeds, and the majority of the time is about 30 minutes. Of water evaporated. 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 500 g of ethanol and then dried at 50 ° C. A particulate composition containing Q10 was obtained.

  The resulting granular composition had a sphericity of 0.97, a volume average particle diameter of about 250 μm, and a true specific gravity of the particulate composition under a condition where the water content was 3% by weight or less, calculated to be 1.17. The true specific gravity of the soluble excipient component was 1.28. In addition, the retention rate of reduced coenzyme Q10 after storage for 30 hours under the light-shielding condition in the air at 40 ° C. was about 94%.

Example 4
The particulate composition obtained in Example 1 was classified using a sieve having openings of 45 μm and 90 μm to obtain a particulate composition having a volume average particle diameter of about 75 μm.

  The resulting granular composition had a sphericity of 0.97, a true specific gravity of the particulate composition under a condition where the water content was 3% by weight or less, and a calculated true specific gravity of the water-soluble excipient component. Was 1.37. In addition, the retention rate of reduced coenzyme Q10 after storage for 30 hours under the light-shielding condition in the air at 40 ° C. was 95%.

(Comparative Example 1)
In 110 g of distilled water, 60 g of gum arabic (manufactured by Ina Food Industry Co., Ltd .; gum arabic A) was dissolved at 60 ° C. to prepare a water-soluble excipient aqueous solution. This aqueous solution was kept at 60 ° C., 25.6 g of reduced coenzyme Q10 powder obtained in the above production example was added and melted, and then emulsified with TK homomixer Mark II (manufactured by Primics Co., Ltd.) for 10,000 rotations × 30 minutes. As a result, an oil-in-water emulsion composition was obtained. The emulsion particle size of reduced coenzyme Q10 in the oil-in-water emulsion composition was about 1 μm. The oil-in-water emulsified composition obtained here is spray-dried using a spray dryer (manufactured by Nihon Büch Co., Ltd .; B-290) at a temperature of hot air of 200 ° C. to form a particulate form containing reduced coenzyme Q10. A composition was obtained.

  The resulting granular composition had a sphericity of 0.87, a volume average particle diameter of about 15 μm, and a true specific gravity of the particulate composition under the condition of a moisture content of 3% by weight or less, calculated as 1.24. The true specific gravity of the soluble excipient component was 1.37. In addition, the retention rate of reduced coenzyme Q10 after storage for 30 hours under the light-shielding condition in the air at 40 ° C. was about 70%.

(Comparative Example 2)
20 g of gelatin (manufactured by Nitta Gelatin Co., Ltd .; APH-250) was dissolved in 180 g of distilled water at 60 ° C. to prepare a water-soluble excipient aqueous solution. This aqueous solution was kept at 60 ° C., and 8.6 g of reduced coenzyme Q10 powder obtained in the above production example was added and melted, followed by emulsification with TK homomixer Mark II (manufactured by Primics Co., Ltd.) for 10,000 rotations × 30 minutes. As a result, an oil-in-water emulsion composition was obtained. The emulsion particle size of reduced coenzyme Q10 in the oil-in-water emulsion composition was about 1 μm. The oil-in-water emulsified composition obtained here is spray-dried using a spray dryer (manufactured by Nihon Büch Co., Ltd .; B-290) at a temperature of hot air of 200 ° C. to form a particulate form containing reduced coenzyme Q10. A composition was obtained.

  The obtained granular composition had a sphericity of 0.83, a volume average particle diameter of about 10 μm, and a true specific gravity of the particulate composition under the condition of a water content of 3% by weight or less, calculated 1.05. The true specific gravity of the soluble excipient component was 1.10. In addition, the retention rate of reduced coenzyme Q10 after storage for 30 hours at 40 ° C. in air and under light-shielding conditions was about 60%.

(Comparative Example 3)
20 g of gelatin (manufactured by Nitta Gelatin Co., Ltd .; APH-250) was dissolved in 180 g of distilled water at 60 ° C. to prepare a water-soluble excipient aqueous solution. This aqueous solution was kept at 60 ° C., and 8.6 g of reduced coenzyme Q10 powder obtained in the above production example was added and melted, followed by emulsification with TK homomixer Mark II (manufactured by Primics Co., Ltd.) for 10,000 rotations × 30 minutes. As a result, an oil-in-water emulsion composition was obtained. The emulsion particle size of reduced coenzyme Q10 in the oil-in-water emulsion composition was about 1 μm. 75 g of the oil-in-water emulsion composition obtained here was heated to 60 ° C. in advance, 100 g of MCT (manufactured by Riken Vitamin Co., Ltd .; Actor M-2) and paste lecithin (ADM Far East Co., Ltd.) Yelkin TS) was added to the oil component (B) consisting of 1 g, and the stirring rotation speed was adjusted so that the particle diameter of the oil-in-water emulsion composition suspension droplets was about 400 μm. While the stirring at the same stirring number was continued, the temperature of the suspension was cooled to 5 ° C., whereby the oil-in-water emulsion composition suspension droplets gelled to form gel-like particles. Thereafter, the oily component (B) is carefully filtered by solid-liquid separation, and after washing the oily component (B) adhering to the particles with about 500 g of ethanol, a drying operation is carried out in a 25 ° C drying desiccator, Furthermore, after the powder could be handled sufficiently, it was dried overnight at 60 ° C. to remove most of the water, and a particulate composition containing reduced coenzyme Q10 was obtained.
The obtained granular composition had a sphericity of 0.97, a volume average particle diameter of about 350 μm, and a water composition with a water content of 3% by weight or less, and the true specific gravity of the particulate composition was 1.13. The true specific gravity of the soluble excipient component was 1.22. In addition, the retention rate of reduced coenzyme Q10 after storage for 30 hours under light-shielding conditions at 40 ° C. in air was about 78%.

(Reference Example 1)
In 110 g of distilled water, 60 g of gum arabic (manufactured by Ina Food Industry Co., Ltd .; gum arabic A) was dissolved at 60 ° C. to prepare a water-soluble excipient aqueous solution. 100 g of MCT (manufactured by Riken Vitamin Co., Ltd .; Actor M-2) and paste lecithin (A / D) were prepared by heating 75 g of the aqueous water-soluble excipient solution without adding the oil component (A). -M Far East Co., Ltd .; Yelkin TS) was added to an oil component (B) consisting of 1 g, and the stirring rotation speed was adjusted so that the particle diameter of the aqueous excipient suspension droplets was about 300 μm. Adjusting the temperature of the suspension to 105 ° C. while continuing stirring at the same number of stirrings, the removal of water from the excipient aqueous solution suspension droplets progressed, and most of the water in about 30 minutes. Evaporated. Thereafter, according to a conventional method, the oily component (B) is separated by solid-liquid separation, the oily component (B) adhering to the particles is washed with about 500 g of ethanol, and then dried at 50 ° C. A particulate composition consisting only of the agent was obtained.

  The specific gravity under the condition that the water content of the obtained particulate composition was 3% by weight or less was 1.32.

(Reference Example 2)
20 g of gelatin (manufactured by Nitta Gelatin Co., Ltd .; APH-250) was dissolved in 180 g of distilled water at 60 ° C. to prepare a water-soluble excipient aqueous solution. Without adding oil component (A), 75 g of this water-soluble excipient aqueous solution was heated to 90 ° C. in advance, 100 g of MCT (manufactured by Riken Vitamin Co., Ltd .; Actor M-2) and paste lecithin (A.D. M Far East Co., Ltd .; YelkinTS) was added to 1 g of the oil component (B), and the stirring rotation speed was adjusted so that the particle diameter of the aqueous solution suspension droplets was about 400 μm. Adjusting the temperature of the suspension to 105 ° C. while continuing stirring at the same number of stirrings, the removal of water from the excipient aqueous solution suspension droplets progressed, and most of the water in about 30 minutes. Evaporated. Thereafter, according to a conventional method, the oily component (B) is separated by solid-liquid separation, the oily component (B) adhering to the particles is washed with about 500 g of ethanol, and then dried at 50 ° C. A particulate composition consisting only of the agent was obtained.

  The specific gravity under the condition that the water content of the obtained particulate composition was 3% by weight or less was 1.32.

(Reference Example 3)
In 110 g of distilled water, 60 g of gum arabic (manufactured by Ina Food Industry Co., Ltd .; gum arabic A) was dissolved at 60 ° C. to prepare a water-soluble excipient aqueous solution. 75 g of the aqueous water-soluble excipient solution is spray-dried using a spray dryer (manufactured by Nihon Büch Co., Ltd .; B-290) at a temperature of hot air of 200 ° C. to form a particulate composition consisting only of the water-soluble excipient. Got.
The true specific gravity under the condition that the water content of the obtained particulate composition was 3% by weight or less was 1.12.

(Reference Example 4)
20 g of gelatin (manufactured by Nitta Gelatin Co., Ltd .; APH-250) was dissolved in 180 g of distilled water at 60 ° C. to prepare a water-soluble excipient aqueous solution. 75 g of the aqueous water-soluble excipient solution is spray-dried using a spray dryer (manufactured by Nihon Büch Co., Ltd .; B-290) at a temperature of hot air of 200 ° C. to form a particulate composition consisting only of the water-soluble excipient. Got.

  The true specific gravity under the condition that the water content of the obtained particulate composition was 3% by weight or less was 0.47.

(Reference Example 5)
20 g of gelatin (manufactured by Nitta Gelatin Co., Ltd .; APH-250) was dissolved in 180 g of distilled water at 60 ° C. to prepare a water-soluble excipient aqueous solution. 75 g of the water-soluble excipient aqueous solution was heated to 60 ° C. in advance, 100 g of MCT (manufactured by Riken Vitamin Co., Ltd .; Actor M-2) and paste lecithin (manufactured by ADM Far East Co., Ltd .; YelkinTS) ) The oily component (B) consisting of 1 g was added, and the stirring rotation speed was adjusted so that the particle diameter of the aqueous excipient solution suspension droplets was about 400 μm. While the stirring at the same stirring number was continued, the temperature of the suspension was cooled to 5 ° C., whereby the excipient aqueous solution suspension droplets gelled to form gel-like particles. Thereafter, the oily component (B) is carefully filtered by solid-liquid separation, and after washing the oily component (B) adhering to the particles with about 500 g of ethanol, a drying operation is carried out in a 25 ° C drying desiccator, Furthermore, after the powder could be handled sufficiently, it was dried overnight at 60 ° C. to remove most of the water, and a particulate composition containing reduced coenzyme Q10 was obtained.

  The true specific gravity was 1.16 under conditions where the water content of the obtained particulate composition was 3% by weight or less.

  The composition, production method, sphericity, volume average particle diameter, and water content of the particulate composition obtained in Examples, Comparative Examples, and Reference Examples were 3% by weight or less. Table 1 shows the true specific gravity of the excipient components and the retention rate of reduced coenzyme Q10 after 30-hour storage at 40 ° C. in air and under light-shielding conditions.

  From Table 1, the true specific gravity of the water-soluble excipient component under the condition that the water content of the particulate composition of the present invention is 3% by weight or less is 1.25 or more, and the sphericity of the particulate composition is 0.00. Only the particulate compositions (Examples 1 to 4) satisfying all the conditions of 9 or more and the volume average particle diameter of 50 to 1000 μm are reduced to a reduced amount after storage for 30 hours under light shielding conditions at 40 ° C. in air. It can be seen that the retention rate of enzyme Q10 can be 90% by weight or more.

  Specifically, the particulate compositions (Comparative Examples 1 and 2) prepared by a spray drying method with a small particle size and low sphericity may have a water-soluble excipient component true specific gravity of 1.25 or more. The stabilizing effect of the fat-soluble active ingredient is at a very low level. In addition, the particulate composition prepared by the submerged curing method (Comparative Example 3) satisfying the conditions of the particulate composition of the present invention in terms of sphericity and particle diameter has a true specific gravity of the water-soluble excipient component. Since it is much smaller than 1.25, it can confirm that the stabilization effect of a fat-soluble active ingredient is a low level. That is, in order to realize the stabilization effect of the fat-soluble active ingredient at a very high level, which is a target of the present invention, it is necessary to satisfy the conditions described in claim 1. Moreover, it turns out that such a particulate composition can be created only with the preferable manufacturing method of this invention.

  Regarding the superiority of the preferred production method of the present invention, in particular, a clear advantage over other production methods from the comparison of the true specific gravity of the water-soluble excipient component not containing the oily component (A) (Reference Examples 1 to 5). Sex can be confirmed.

The scanning electron micrograph of the external appearance of the particulate composition obtained in Example 1. 2 is a scanning electron micrograph of a fracture surface of the particulate composition obtained in Example 1. FIG.

Claims (25)

A particulate composition containing a water-soluble excipient and a fat-soluble active ingredient, and gum arabic alone or a combination of gum arabic and other water-soluble excipient ingredients use is the moisture content of the particulate composition is 3 true specific gravity of the water-soluble excipient component in weight percent of conditions than 1.30, and sphericity of the particulate composition is 0.9 or more particles Composition.   The particulate composition according to claim 1, wherein the volume average particle diameter is 50 to 1000 µm. The oil-based component (A) containing 5 to 100% by weight of a fat-soluble active ingredient is formed into a domain and polydispersed in a matrix mainly composed of a water-soluble excipient. 3. The particulate composition according to 1 or 2.   The particulate composition of Claim 3 whose volume average particle diameter of the domain which an oil-based component (A) forms is 0.01-10 micrometers.   The particulate composition according to any one of claims 1 to 4, wherein the fat-soluble active ingredient is a fat-soluble active ingredient that is unstable with respect to oxygen, light, acid / base and / or radical.   The particulate composition according to any one of claims 1 to 4, wherein the fat-soluble active ingredient is reduced coenzyme Q10, oxidized coenzyme Q10, highly unsaturated fatty acid, or a mixture thereof.   The particulate composition according to any one of claims 1 to 4, wherein the fat-soluble active ingredient is a fragrance. The particulate composition according to any one of claims 1 to 4, wherein the fat-soluble active ingredient is a physiologically active substance. The other water-soluble excipient is one or more selected from the group consisting of a water-soluble polymer other than gum arabic , a surfactant (C), a sugar, and a yeast cell wall. 2. The particulate composition according to item 1.   The particulate composition according to any one of claims 1 to 9, wherein 20 to 100% by weight of the water-soluble excipient component is gum arabic. Surfactant (C), glycerin fatty acid ester, sucrose fatty acid esters, sorbitan fatty acid esters, at least one selected from lecithin Contact and saponin or Ranaru group, particulate composition according to claim 9 or 10 object. Sugars, monosaccharides, disaccharides, oligosaccharides, and at least one selected from sugar alcohols or Ranaru group, particulate composition according to claim 9 or 10.   The particulate composition according to any one of claims 1 to 12, wherein the particulate composition contains 0.1 to 20% by weight of a reducing agent. The particulate composition according to claim 13, wherein the reducing agent is at least one selected from the group consisting of fat-soluble ascorbic acid , water-soluble ascorbic acid , tocopherol and polyphenol.   14. The particulate composition according to claim 13, wherein the reducing agent is L-ascorbic acid and / or D-arabo-ascorbic acid. The particulate composition according to any one of claims 1 to 15, characterized by containing 0.01 to 30% by weight of water. The particulate composition according to any one of claims 1 to 16, wherein the content of the fat-soluble active ingredient in the particulate composition is in the range of 1 to 70% by weight.   The retention rate of the fat-soluble active ingredient in the particulate composition after storage for 30 days under light-shielding conditions at 40 ° C in the air is 90% by weight or more. Particulate composition. An oil-in-water emulsion composition prepared from an aqueous solution containing a water-soluble excipient and an oily component (A) containing a fat-soluble active ingredient is dispersed or suspended in the oily component (B), and then 80 ° C. The particulate composition according to claim 3 or 4, wherein the particulate composition is obtained by heating to remove water in the emulsion composition in the oil component (B).   The particulate composition according to claim 19, wherein an oily component comprising 5 to 100% by weight of fat and oil and 0 to 95% by weight of a surfactant (D) is used as the oily component (B). The particulate composition according to claim 20, wherein lecithin is used as the surfactant (D). The particulate composition according to any one of claims 19 to 21, which is obtained by removing moisture until the moisture content in the particulate composition is 10% by weight or less.   A food, beverage, cosmetic, or pharmaceutical comprising the particulate composition according to any one of claims 1 to 22.   A food, beverage, cosmetic or pharmaceutical product comprising the particulate composition according to any one of claims 1 to 22 dissolved in an aqueous medium. A soft capsule, a hard capsule, a tablet or a chewable agent comprising the particulate composition according to any one of claims 1 to 22 and / or a pulverized powder thereof.