Solid composition including antioxidant and crystal particles containing reduced coenzyme q

Abstract

The present invention addresses the problem of providing a solid composition that has high oxidation stability and high oral absorbability, and a simple method for producing the same.　Provided is a solid composition comprising an antioxidant and crystal particles which contain reduced coenzyme Q and which have a median diameter of 50 um or less.

Description

A solid composition containing crystalline particles with reduced coenzyme Q and an antioxidant.

[0001] The present invention relates to crystalline particles containing reduced coenzyme Q and a solid composition containing an antioxidant, and a method for producing the same.

[0002] Coenzyme Q is an essential component widely distributed in living organisms, from bacteria to mammals, and is known as a component of the electron transport chain in mitochondria within cells. In humans, coenzyme Q10, which has 10 repeating side chains, is the main component, and in living organisms, approximately 40-90% usually exists in the reduced form. The physiological effects of coenzyme Q include activation of energy production through mitochondrial activation, activation of cardiac function, stabilization of cell membranes, and protective effects on cells through antioxidant activity.

[0003] Most coenzyme Q10 currently manufactured and sold is oxidized coenzyme Q10. However, in recent years, reduced coenzyme Q10 (sometimes referred to as "QH" in this specification), which exhibits higher oral absorption (absorption in the intestines) compared to oxidized coenzyme Q10, has also appeared on the market and is being used.

[0004] Reduced coenzyme Q10 is easily oxidized, resulting in high storage costs and limited applicability to various product forms. In particular, there is a demand for a solid composition containing reduced coenzyme Q10 that exhibits excellent oxidative stability and can be applied in forms such as granules, hard capsules, and tablets.

[0005] Patent Document 1 reports that a solid composition containing reduced coenzyme Q10 can be stabilized by coating it with a coating medium such as shellac, gelatin, or gum arabic.

[0006] Patent Document 2 reports a particulate composition in which an oily component containing reduced coenzyme Q10 forms domains and is polydispersed in a matrix containing a water-soluble excipient and water-soluble ascorbic acid derivatives.

[0007] International Public Release WO2006 / 075502 International Public Release WO2008 / 129980

[0008] However, conventionally reported solid compositions containing reduced coenzyme Q10 have complicated manufacturing methods, and there was room for further improvement regarding the oxidative stability of reduced coenzyme Q10.

[0009] The production of the solid composition described in Patent Document 1 requires a step of spraying a coating medium solution and a step of drying it thereafter. Furthermore, the production of the particulate composition described in Patent Document 2 requires a step of preparing an oil-in-water emulsion with an aqueous solution of a water-soluble excipient such as gum arabic and an oily component containing reduced coenzyme Q10, and a step of removing water from the emulsion droplets by spray drying or heating in oil to form particles.

[0010] When imparting gas barrier properties to a solid composition containing reduced coenzyme Q10 using a coating medium such as a water-soluble excipient, complete coating of the solid composition is required, leading to various problems such as limited manufacturing methods, increased costs, larger solid composition size, or reduced reduced coenzyme Q10 content. Furthermore, the reduced coenzyme Q10-containing solid composition produced by the above method is unsuitable as a raw material for further formulation, such as tableting, because it cracks under pressure and loses its gas barrier properties.

[0011] As mentioned above, since reduced coenzyme Q is absorbed into the body and exerts physiological effects, it is required to have both improved oxidative stability and high oral absorption.

[0012] Generally, improving oral absorption requires high efficiency of exposure to the external environment, while improving oxidative stability requires increasing the efficiency of blocking exposure to the external environment. In other words, improving oxidative stability and improving oral absorption are in a trade-off relationship, and achieving both simultaneously has been difficult.

[0013] The object of the present invention is to provide a solid composition having high oxidative stability and high oral absorption, and a simple method for producing the same.

[0014] First, it was confirmed that when the crystal particles of reduced coenzyme Q are made finer, the oxidative stability usually decreases. Furthermore, as a result of intensive research conducted by the inventors to solve the above problem, it was found that by compounding with an antioxidant in a solid state, using finer crystal particles compared to using larger crystal particles not only improves oral absorption but also improves oxidative stability.

[0015] The present invention is based on the aforementioned novel findings and provides the following: [1] A solid composition comprising crystalline particles containing reduced coenzyme Q and an antioxidant, wherein the median diameter of the crystalline particles is 50 μm or less. [2] The solid composition according to [1], wherein the content ratio of the crystalline particles in the solid composition is 35% by weight or more. [3] The solid composition according to [1] or [2], wherein the content ratio of the oil and fat component in the solid composition is less than 50% by weight. [4] The solid composition according to [3], wherein the oil and fat is a triglyceride. [5] The solid composition according to any one of [1] to [4], wherein the content ratio of the antioxidant in the solid composition is more than 10% by weight and 65% by weight or less. [6] The solid composition according to any one of [1] to [5], wherein the antioxidant is ascorbic acid and / or a salt thereof. [7] The solid composition according to any one of [1] to [6], wherein the reduced coenzyme Q is reduced coenzyme Q9, reduced coenzyme Q10 and / or reduced coenzyme Q11. [8] The solid composition according to any one of [1] to [7], wherein the crystalline particles comprise Form II crystals. [9] The solid composition according to any one of [1] to [8], further comprising an emulsifier.

[10] The solid composition according to any one of [1] to [9], further comprising a binder.

[11] The solid composition according to any one of [1] to

[10] , wherein the median diameter of the crystalline particles is 13 μm or less. [12-1] A method for producing a molded article containing crystalline particles having improved oxidative stability, comprising the steps of: preparing a combination of crystalline particles having a median diameter of 50 μm or less and an antioxidant; mixing and / or compounding the crystalline particles having reduced coenzyme Q and the antioxidant; and molding the mixed and / or compounded composition into a desired shape. [12-2] A method for producing a molded article containing crystalline particles having improved oxidative stability, comprising the steps of: mixing and / or compounding crystalline particles having a median diameter of 50 μm or less and an antioxidant; and molding the mixed and / or compounded composition into a desired shape.[13-1] A method for improving the oxidative stability of crystalline particles containing reduced coenzyme Q, comprising the steps of: preparing a combination of crystalline particles containing reduced coenzyme Q having a median diameter of 50 μm or less and an antioxidant; mixing and / or compounding the crystalline particles containing reduced coenzyme Q and the antioxidant; and preparing a solid composition comprising the mixed and / or compounded crystalline particles and antioxidant. [13-2] A method for improving the oxidative stability of crystalline particles containing reduced coenzyme Q, comprising the steps of: mixing and / or compounding crystalline particles containing reduced coenzyme Q having a median diameter of 50 μm or less and an antioxidant; and preparing a solid composition comprising the mixed and / or compounded crystalline particles and antioxidant. This specification encompasses the disclosures of Japanese Patent Application No. 2025-052454, which forms the basis of the priority of this application.

[0016] The solid composition of the present invention provides a reduced coenzyme Q composition with improved oxidative stability and oral absorption.

[0017] According to the manufacturing method of the present invention, the solid composition of the present invention can be provided.

[0018] This graph shows the oxidative stability results for Reference Example 1 and Examples 1-4. Figure 2 shows the bioabsorbability of the solid composition of Comparative Example 6 and the solid composition of Example 11. In Figure 2, "AUC (relative value)" is the value standardized with the AUC of the solid composition of Comparative Example 6 set to 1, and the error bars show the standard deviation.

[0019] The present invention will be described in detail below.

[0020] <Reduced Coenzyme Q> As mentioned above, "Coenzyme Q" is an essential component widely distributed in living organisms, from bacteria to mammals. In humans, the main component is coenzyme Q10, which has 10 repeating structures in its side chain. However, in this specification, the number of repeating structures in the side chain of coenzyme Q is not limited as long as it is 2 or more. The number of repeating structures in the side chain of coenzyme Q is, for example, 8 to 12, preferably 9 to 11, and more preferably 10.

[0021] Furthermore, coenzyme Q can be oxidized or reduced. In this specification, the number of repeating structures in the side chain of oxidized coenzyme Q is, for example, 8 to 12, and examples include oxidized coenzyme Q8, oxidized coenzyme Q9, oxidized coenzyme Q10, oxidized coenzyme Q11, and oxidized coenzyme Q12. Oxidized coenzyme Q is preferably oxidized coenzyme Q9, oxidized coenzyme Q10, or oxidized coenzyme Q11, and more preferably oxidized coenzyme Q10. In this specification, the number of repeating structures in the side chain of reduced coenzyme Q is, for example, 8 to 12, and examples include reduced coenzyme Q8, reduced coenzyme Q9, reduced coenzyme Q10, reduced coenzyme Q11, and reduced coenzyme Q12. Reduced coenzyme Q is preferably reduced coenzyme Q9, reduced coenzyme Q10, or reduced coenzyme Q11, and more preferably reduced coenzyme Q10.

[0022] In this specification, reduced coenzyme Q may contain oxidized coenzyme Q as long as it is the main component. Here, "main component" means, for example, 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, particularly preferably 95% by weight or more, and especially preferably 98% by weight or more. The above percentage is the ratio of reduced coenzyme Q to the total amount of coenzyme Q.

[0023] <Crystal Particles> In the present invention, the solid composition includes crystal particles containing reduced coenzyme Q. "Crystal particles" refers to solid particles having a crystalline structure in at least a portion of it, and "crystal particles containing reduced coenzyme Q" refers to crystal particles containing at least one type of reduced coenzyme Q.

[0024] The crystal particles may contain only one type of reduced coenzyme Q, or they may contain multiple types of reduced coenzyme Q. Examples of multiple types include two or more reduced coenzyme Q with different side chain lengths, such as reduced coenzyme Q9 and reduced coenzyme Q10, or, as will be described in detail later, two or more crystalline polymorphs of reduced coenzyme Q with the same side chain length (for example, reduced coenzyme Q10), or combinations thereof.

[0025] Furthermore, when multiple reduced coenzymes Q with different side chain lengths are included, it is preferable that the main component of reduced coenzyme Q is reduced coenzyme Q10. It is preferable that 50% or more by weight of reduced coenzyme Q is reduced coenzyme Q10, and more preferably 60% or more by weight, 70% or more by weight, 80% or more by weight, 90% or more by weight, 95% or more by weight, or 98% or more by weight.

[0026] Furthermore, the crystalline particles may contain one or more components other than reduced coenzyme Q. The specific components in this case are not particularly limited and include, for example, oxidized coenzyme Q, derivatives of reduced coenzyme Q (including metabolites, degradation products, biosynthetic intermediates, etc.), ascorbic acids, nicotinamides (nicotinamide, nicotinamide mononucleotide, nicotinamide riboside, nicotinamide adenine dinucleotide or their reduced forms, etc.), salts thereof, or combinations thereof.

[0027] When components other than reduced coenzyme Q are included, it is generally preferable that reduced coenzyme Q is the main component of the crystal particles, and reduced coenzyme Q (or the total amount if multiple types are included) is usually 50% by weight or more, preferably 60% by weight or more, more preferably 70% by weight or more, even more preferably 80% by weight or more, even more preferably 90% by weight or more, even more preferably 95% by weight or more, and particularly preferably 98% by weight or more of the crystal particles.

[0028] Furthermore, components other than the reduced coenzyme Q may be included in the crystal particles in a manner that forms a cocrystal with the reduced coenzyme Q. When included in a manner that forms a cocrystal, the reduced coenzyme Q does not have to be the main component in the crystal particles.

[0029] The solid composition of the present invention contains a plurality of the above-mentioned crystalline particles, but the composition of each crystalline particle (the type of reduced coenzyme Q included, components other than reduced coenzyme Q, and their content) may be the same or different.

[0030] When the solid composition of the present invention contains multiple types of crystalline particles with different compositions, the proportion of crystalline particles of a particular composition is not particularly limited. However, for example, when the composition of the present invention is used on humans, considering that coenzyme Q10 is the main component of coenzyme Q in humans, it is preferable that there are many crystalline particles containing reduced coenzyme Q10, and it is also preferable that each individual crystalline particle contains a large amount of reduced coenzyme Q10. For example, when the solid composition of the present invention contains crystalline particles containing reduced coenzyme Q10 (containing as a main component or consisting of), the amount of crystalline particles containing reduced coenzyme Q10 can be, for example, 20 parts by weight or more, more preferably 50 parts by weight or more, more preferably 80 parts by weight or more, even more preferably 90 parts by weight or more, and particularly preferably 95 parts by weight or more, per 100 parts by weight of crystalline particles containing reduced coenzyme Q.

[0031] As mentioned above, there are two crystalline polymorphs of reduced coenzyme Q10: Form I and Form II. Specifically, Form I crystals of reduced coenzyme Q10 have a melting point of around 48°C and exhibit characteristic peaks at diffraction angles (2θ±0.2°) of 3.1°, 18.7°, 19.0°, 20.2°, and 23.0° in powder X-ray (Cu-Kα) diffraction. Form II crystals of reduced coenzyme Q10 have a melting point of around 52°C and exhibit characteristic peaks at diffraction angles (2θ±0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° in powder X-ray (Cu-Kα) diffraction. In the present invention, the reduced coenzyme Q10 may be a Form I crystal, a Form II crystal, or a combination thereof.

[0032] In one or more embodiments of the present invention, the reduced coenzyme Q10 (QH) is characterized by using Form II crystals of reduced coenzyme Q10 (QH). Since QH Form II crystals have high stability against oxidation, solid compositions containing QH Form II crystals together with an emulsifier and an antioxidant have excellent storage stability.

[0033] The QHForm II crystal may consist of Form II crystals, or it may be a QH crystal or crystalline solid with Form II crystals as the main component. Here, "main component" means that Form II crystals make up, for example, 50% by weight or more, preferably 60% by weight or more, more preferably 80% by weight or more, more preferably 90% by weight or more, most preferably 95% by weight or more, and most preferably 98% by weight or more, relative to the total amount of QH.

[0034] It is known that crystalline particles containing reduced coenzyme Q10 and other components exhibit increased oxidative stability of reduced coenzyme Q10 when the other components include specific compounds (e.g., nicotinamides). Therefore, from the viewpoint of oxidative stability, the solid composition preferably includes crystalline particles containing reduced coenzyme Q10 and other components. The proportion of crystalline particles containing reduced coenzyme Q10 and other components (containing as a main component or consisting of) is not particularly limited, but for 100 parts by weight of crystalline particles containing reduced coenzyme Q, the solid composition contains, for example, 50 parts by weight or more, preferably 60 parts by weight or more, more preferably 70 parts by weight or more, more preferably 80 parts by weight or more, particularly preferably 90 parts by weight or more, and most preferably 95 parts by weight or more. According to the solid composition of the present invention, excellent oxidative stability is exhibited even when the crystalline particles do not contain other components. Therefore, in one embodiment, the solid composition contains crystalline particles containing reduced coenzyme Q10 and other components in a certain proportion or less, or does not contain crystalline particles containing reduced coenzyme Q10 and other components. In this case, the proportion of crystalline particles containing reduced coenzyme Q10 and other components (containing as a main component or consisting of) is not particularly limited, but the amount of crystalline particles containing reduced coenzyme Q10 and other components can be, for example, 95 parts by weight or less, 90 parts by weight or less, 80 parts by weight or less, 70 parts by weight or less, 50 parts by weight or less, 40 parts by weight or less, 30 parts by weight or less, 20 parts by weight or less, 10 parts by weight or less, 5 parts by weight or less, 1 part by weight or less, etc., per 100 parts by weight of crystalline particles containing reduced coenzyme Q.

[0035] QH Form II crystal is a crystalline polymorph that exhibits high oxidative stability even when it contains no other components. Therefore, when oxidative stability, cost, and QH content are considered comprehensively, the crystal particles preferably comprise QH Form II crystals. The proportion of crystal particles containing (comprising as a main component or consisting of) QH Form II crystals is not particularly limited, but based on 100 parts by weight of crystal particles containing reduced coenzyme Q, the amount of crystal particles containing (comprising as a main component or consisting of) QH Form II crystals is, for example, 50 parts by weight or more, preferably 60 parts by weight or more, more preferably 70 parts by weight or more, still more preferably 80 parts by weight or more, particularly preferably 90 parts by weight or more, and most preferably 95 parts by weight or more.

[0036] QH Form I crystal is the most easily produced crystal, and its cost is low since it is commercially available. Therefore, from the viewpoint of cost, the crystal particles preferably comprise QH Form I crystals. The proportion of crystal particles containing (comprising as a main component or consisting of) QH Form I crystals is not particularly limited, but based on 100 parts by weight of crystal particles containing reduced coenzyme Q, the amount of crystal particles containing (comprising as a main component or consisting of) QH Form I crystals is, for example, 50 parts by weight or more, preferably 60 parts by weight or more, more preferably 70 parts by weight or more, still more preferably 80 parts by weight or more, particularly preferably 90 parts by weight or more, and most preferably 95 parts by weight or more.

[0037] The median diameter of the crystalline particles containing the reduced coenzyme Q in the solid composition of the present invention is 50 μm or less. In this specification, the median diameter refers to the median diameter calculated based on volume in the particle size distribution. The specific median diameter of the crystalline particles containing the reduced coenzyme Q is not particularly limited, as long as it is 50 μm or less. For example, the particle size can be 46 μm or less, 45 μm or less, preferably 40 μm or less, 35 μm or less, more preferably 30 μm or less, 29 μm or less, more preferably 25 μm or less, 24 μm or less, 20 μm or less, more preferably 17 μm or less, 15 μm or less, 14 μm or less, 13 μm or less, 12.5 μm or less, 12.4 μm or less, 12.3 μm or less, 12 μm or less, 11 μm or less, 10 μm or less, particularly preferably 5 μm or less, 4.5 μm or less, 4.4 μm or less, 4 μm or less, 3 μm or less, 2 μm or less, 1 μm or less, most preferably 0.5 μm or less, 0.4 μm or less, 0.35 μm or less, etc. Furthermore, from the viewpoint of handling, for example, the median diameter may be 0.001 μm or more, 0.005 μm or more, preferably 0.01 μm or more, 0.05 μm or more, 0.1 μm or more, more preferably 0.3 μm or more, 0.35 μm or more, and particularly preferably 1 μm or more, 2 μm or more, 3 μm or more, 4 μm or more, 4.4 μm or more, 4.5 μm or more, 5 μm or more, 10 μm or more, 11 μm or more, 11.5 μm or more, 12 μm or more, 12.3 μm or more, 12.4 μm or more, 12.5 μm or more, 13 μm or more, 14 μm or more, 15 μm or more, 16 μm or more, 17 μm or more, 20 μm or more, 21 μm or more, 23 μm or more, 24 μm or more, etc. The specific range of the median diameter is not particularly limited, but for example, 0.001 μm to 46 μm, 0.005 μm to 45 μm, 0.01 μm to 40 μm, 0.05 μm to 35 μm, 0.1 μm to 40 μm, 0.1 μm to 35 μm, 0.1 μm to 30 μm, 0.1 μm to 29 μm, 0.1 μm to 25 μm, 0.1 μm to 24 μm, 0.1 μm to 2 0 μm, 0.1 μm to 17 μm, 0.1 μm to 15 μm, 0.1 μm to 14 μm, 0.1 μm to 13 μm, 0.1 μm to 12.5 μm, 0.1 μm to 12.4 μm, 0 .1 μm to 12.3 μm, 0.1 μm to 12 μm, 0.1 μm to 10 μm, 0.1 μm to 9 μm, 0.1 μm to 8 μm, 0.1 μm to 7 μm,0.1μm~6μm, 0.1μm~5μm, 0.1μm~4.5μm, 0.1μm~4.4μm, 0.1μm~4μm, 0.1μm~3μm, 0.1μm~2μm, 0.1μm~1μm, 0.1μm~0.5μm, 0.3μm~40μm, 0.3μm~35μm, 0.3μm~ 30μm, 0.3μm~29μm, 0.3μm~25μm, 0.3μm~24μm, 0.3μm~20μm, 0.3μm~17μm, 0.3μm~15μm, 0.3μm~14μm, 0.3μm~13μm, 0.3μm~12.5μm, 0.3μm~12.4μm, 0.3μm ~12.3μm, 0.3μm~12μm, 0.3μm~11μm, 0.3μm~10μm, 0.3μm~9μm, 0.3μm~8μm, 0.3μm~7μm, 0.3μm~6μm, 0.3μm~5μm, 0.3μm~4.5μm, 0.3μm~4.4μm, 0.3μm~4μm ,0.3μm~3μm,0.3μm~2μm,0.3μm~1μm,0.3μm~0.5μm,0.35μm~25μm,1μm~40μm,1μm~35μm,1μm~30μm,1μm~29μm,1μm~25μm,1μm~24μm,1μm~20μm,1μm~17 μm, 1μm~15μm, 1μm~14μm, 1μm~13μm, 1μm~12.5μm, 1μm~12.4μm, 1μm~12.3μm, 1μm~12μm, 1μm~11μm, 1μm~10μm, 1μm~μm, 1μm~8μm, 1μm~6μm, 1μm~5μm, 1μm ~4.5μm, 1μm~4.4μm, 1μm~4μm, 1μm~3μm, 1μm~2μm, 2μm~20μm, 3μm~17μm, 4μm~40μm, 4μm~35μm, 4μm~30μm, 4μm~29μm, 4μm~25μm, 4μm~24μm, 4μm~200μm, 4μm m~17μm、4μ~~15μm、4μ~~14μm、4μ~13μm、4μ~~12.5μm、4μ~~12.4μm、4μ~~1 .3μm、4.4μm~40μm、4...~35μm、4...~3..、4...~29. 4μm~24μm, 4.4μm~20μm, 4.4μm~17μm, 4.4μm~15μm, 4.4μm~14μm, 4.4μm~13μm, 4.4μm~12.5μm, 4.4μm~12.4μm, 4.4μm~12.3μm, 4.5μm~40μm, 4.5μm~35μm,4.5μm~30μm、4.5μm~29μm、4.5μm~25μm、4.5μm~24μm - . μm、5μm~24μm、5μm~20μm、5μm~11μm、5μm~15μm、5μm~14μm、5μm~13μm、5μm - 10μm~29μm、10μm~25μm、10μm~24μm、10μ~~20μm、10μ~17μm、10μ~15μm、 10μm~14μm、10m~13--、10-~12.5-10-~12.1-10-~12.3- - - μ~12.4μm、11.~12.3μm、11.5μm~40.、11.5μm~35μm、11.5~31. . . m、11.5μm~12.3μm、12.~45μm、12.3μ~~40μm m、13μm~45μm、14μm~40m、15m~35mm、16m~~30mm、11m~29mm、20~~30 m、21μ~30μm、23μ~30μm、24μ~~45μm、0.005μ~12μm、0.01μ~~11μm、0.05μ~10μm、0.01μ~0.4μ~~0.35μ~ etc.

[0038] The determination may be made based on the proportion of particles having a particle size equal to or less than a certain value. For example, the proportion of particles of 68 µm or less may be 60% or more, 65% or more, 70% or more, 71% or more, 72% or more, 75% or more, 80% or more, 85% or more, 90% or more, 92% or more, 94% or more, based on volume, among the crystal particles containing reduced coenzyme Q contained in the solid composition.

[0039] The method for measuring the median diameter of crystal particles is not particularly limited. Typically, when the solid composition according to the present embodiment is added to water, the crystal particles are separated from other components, and thus the median diameter can be measured, for example, by measuring the particle size distribution of such separated crystal particles.

[0040] <Antioxidant> The type of antioxidant is not limited in the present specification. Typically, the antioxidant is solid at ordinary temperature. Two or more antioxidants may be used in combination. Specific examples of antioxidants include ascorbic acids. Examples of ascorbic acids include, but are not particularly limited to, ascorbic acid, erythorbic acid, derivatives thereof (e.g., ascorbic acid fatty acid esters, ascorbic acid glycosides, ascorbic acid peptides, etc.) or salts thereof.

[0041] The counterion of the salt of an antioxidant (ascorbate, erythorbate, etc.) is not limited, and each counterion can independently be one or more metal salts selected from sodium salts, potassium salts, calcium salts, zinc salts and magnesium salts.

[0042] It is particularly preferable to use an antioxidant acceptable for foods, cosmetics or pharmaceuticals as the antioxidant. The antioxidant is preferably one or more selected from the group consisting of ascorbic acid, ascorbate, erythorbic acid and erythorbate, and sodium ascorbate and / or sodium erythorbate is particularly preferable.

[0043] The shape is not particularly limited. For example, it may be granular, powdery, or flaky, may be sol, gel or soft solid, and may be liquid, viscous liquid, sticky liquid, or paste.

[0044] <Emulsifiers> The solid compositions described herein may further contain emulsifiers. The type of emulsifier described herein is not limited as long as the crystals are not completely lost (for example, the degree of crystallinity does not deviate from the range described below). For example, emulsifiers with an HLB of 1 to 17, preferably 2 to 16, can be used. Two or more emulsifiers may be used in combination.

[0045] From the viewpoint of inhibiting oxidation of reduced coenzyme Q10, emulsifiers that are not in powder or flake form are preferred among the above emulsifiers. Examples of emulsifiers that are not in powder or flake form include liquids, sols, gels, or soft solids, and emulsifiers that are liquids, viscous liquids, pastes, pellets, waxy masses, waxes, soft solids, or semi-solids are more preferred. As for the emulsifier, an emulsifier having the above properties at 50°C is preferred, and an emulsifier having the above properties at 25°C is most preferred.

[0046] Examples of emulsifiers that are not in powder or flake form include emulsifiers whose melting point, as measured by setting the heating rate of a differential scanning calorimeter (DSC) to 1°C / min or more and 20°C / min or less, is 50°C or lower, preferably 40°C or lower, and more preferably 25°C or lower.

[0047] From another perspective, examples of emulsifiers include those whose viscosity, when measured using a B-type viscometer at a rotation speed of 10 rpm and a sample temperature of 50°C, is, for example, 150,000 mPa·s or less, preferably 100,000 mPa·s or less, 50,000 mPa·s or less, more preferably 30,000 mPa·s or less, and most preferably 25,000 mPa·s or less. The lower limit of viscosity is not particularly limited as long as it is greater than 0 mPa·s, but more preferably 1 mPa·s or more, more preferably 5 mPa·s or more, and most preferably 10 mPa·s or more.

[0048] Specific examples of emulsifiers include ester compounds of polyols selected from monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol, and fatty acids which may have substituents, as well as one or more selected from lecithin.

[0049] In polyglycerin, the number of glycerin units is two or more, preferably two to ten. Examples include diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, and decaglycerin.

[0050] In polyoxyethylene sorbitan, the number of oxyethylene units is 2 or more, preferably 10 to 30, and more preferably 15 to 25.

[0051] In polypropylene glycol, the number of propylene glycol units is 2 or more, preferably 2 to 10.

[0052] In polyethylene glycol, the number of ethylene glycol units is 2 or more, preferably 2 to 10.

[0053] Examples of fatty acids that may have substituents include linear or branched monovalent or divalent fatty acids having 4 to 24 carbon atoms. Examples of substituents include hydroxyl groups and acetoxy groups. It is preferable that the number of substituents be two or less. Specific examples of fatty acids that may have substituents include lauric acid, oleic acid, caprylic acid, stearic acid, behenic acid, ricinoleic acid, succinic acid, and diacetyltartaric acid.

[0054] In the ester compound of the polyol and the fatty acid, the number of fatty acid molecules bonded to one polyol molecule is not particularly limited and can be appropriately adjusted according to the HLB of the desired emulsifier.

[0055] From the viewpoint of inhibiting the oxidation of reduced coenzyme Q10, the number of fatty acids bound to one polyol molecule can be, for example, 12 or less, preferably 10 or less, more preferably 7 or less, more preferably 6 or less, more preferably 5 or less, more preferably 3 or less, more preferably 2 or less, and more preferably 1.

[0056] Specific examples of ester compounds of the polyol and the fatty acid include: diglyceryl monooleate, monoglyceryl monocaprylate, diglyceryl monocaprylate, decaglyceryl pentaoleate, tetraglyceryl pentaoleate, pentaglyceryl trioleate, decaglyceryl monolaurate, hexaglyceryl monocaprylate, hexaglyceryl monooleate, pentaglyceryl monostearate, tetraglyceryl tristearate, decaglyceryl monobehenate, mono- and diglyceryl monostearate, monoglyceryl monooleate, glyceryl monostearate succinate, monoglyceryl succinate, glyceryl monostearate diacetyltartarate, propylene glycol monooleate, mono Examples include sorbitan leate, sorbitan monostearate, sorbitan tristearate, monoglyceryl monolaurate, diglyceryl monolaurate, diglyceryl monomyristate, tetraglyceryl pentastearate, monoglyceride stearin succinate, monoglyceride oleic acid citrate, monoglyceride stearin citrate, monoglyceride stearin diacetyltartrate, monoglyceride laurine acetate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, pentagricerin condensed ricinoleate, sucrose stearate, sucrose erucate, and sucrose oleate.

[0057] From the viewpoint of inhibiting the oxidation of reduced coenzyme Q10, an unsaturated fatty acid is more preferable in the ester compound of the polyol and the fatty acid. Examples of the unsaturated fatty acids include crotonic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, α-linolenic acid, γ-linolenic acid, pinolenic acid, α-eleostearic acid, β-eleostearic acid, meadic acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosatetraenoic acid, adrenaline, boseopentaenoic acid, eicosapentaenoic acid, osbondic acid, sardic acid, tetracosapentaenoic acid, docosahexaenoic acid, herringic acid, ricinoleic acid, and condensed ricinoleic acid, with oleic acid, condensed ricinoleic acid, linoleic acid, and erucic acid being more preferred, and oleic acid being particularly preferred.

[0058] From another viewpoint of inhibiting the oxidation of reduced coenzyme Q10, the ester compound of the polyol and the fatty acid is more preferably a glycerin fatty acid ester or polyglycerin fatty acid ester that satisfies any of the following: 1) a glycerin fatty acid ester or polyglycerin fatty acid ester containing an ester of a fatty acid with 8 or fewer carbon atoms; 2) a polyglycerin fatty acid ester containing an ester of a fatty acid with 9 to 14 carbon atoms and having 2 or more glycerin units; and 3) a polyglycerin fatty acid ester containing an ester of a fatty acid with 15 to 18 carbon atoms and having 5 or more glycerin units. In this case, the fatty acid can be a saturated fatty acid or an unsaturated fatty acid.

[0059] Specific examples of ester compounds of the polyol and the unsaturated fatty acid include monoglycerin monooleate, mono-dioleate monoglycerin, dioleate monoglycerin, mono-diglycerin monooleate, diglycerin mono-dioleate, diglycerin dioleate, diglycerin trioleate, triglycerin monooleate, triglycerin dioleate, triglycerin trioleate, triglycerin tetraoleate, tetraglycerin monooleate, tetraglycerin dioleate, and trioleate. Tetraglycerin ioate, tetraglycerin tetraoleate, tetraglycerin pentaoleate, pentaglycerin monooleate, pentaglycerin dioleate, pentaglycerin trioleate, pentaglycerin tetraoleate, pentaglycerin pentaoleate, pentaglycerin hexaoleate, hexaglycerin monooleate, hexaglycerin dioleate, hexaglycerin trioleate, hexaglycerin tetraoleate, hexaglycerin pentaoleate, hexaglycerin hexaoleate, heptaolein Hexaglycerin acid, decaglycerin monooleate, decaglycerin dioleate, decaglycerin trioleate, decaglycerin tetraoleate, decaglycerin pentaoleate, decaglycerin hexaoleate, decaglycerin heptaoleate, decaglycerin octaoleate, decaglycerin nonaoleate, decaglycerin decaoleate, decaglycerin dodecaoleate, diacetoglycerin monooleate, glycerin monooleate lactate, glycerin monooleate succinate, glycerin monooleate citrate, diacetoglycerin Glyceryl monooleate tartrate, sucrose oleate ester, propylene glycol monooleate, sorbitan monooleate, sorbitan dioleate, sorbitan trioleate, polyoxyethylene sorbitan monooleate, phosphatidylcholine monopalmitate, phosphatidylcholine dilinoleate, monoglyceryl monoerucate, monoglyceryl mono-dierucate, monoglyceryl dierucate, mono-diglyceryl monoerucate, monoglyceryl mono-dierucate, diglyceryl dierucateDiglyceryl trierucate, triglyceryl monoerucate, triglyceryl dielucate, triglyceryl trierucate, triglyceryl tetraerucate, tetraglyceryl monoerucate, tetraglyceryl dielucate, tetraglyceryl trierucate, tetraglyceryl tetraerucate, tetraglyceryl pentaerucate, pentaglyceryl monoerucate, pentaglyceryl dielucate, pentaglyceryl trierucate, tetraglyceryl tetraerucate Pentaglycerin, Pentaglycerin pentaerucate, Pentaglycerin hexaerucate, Hexaglycerin monoerucate, Hexaglycerin dierucate, Hexaglycerin trierucate, Hexaglycerin tetraerucate, Hexaglycerin pentaerucate, Hexaglycerin hexaerucate, Hexaglycerin heptaerucate, Decaglycerin monoerucate, Decaglycerin dierucate, Decaglycerin trierucate, Decaglycerin tetraerucate Decaglycerin, Decaglyceryl Pentaerucate, Decaglyceryl Hexaerucate, Decaglyceryl Heptaerucate, Decaglyceryl Octaerucate, Decaglyceryl Nonaerucate, Decaglyceryl Decaerucate, Decaglyceryl Dodecaerucate, Diacetoglyceryl Monoerucate, Glyceryl Monoerucate Lactate, Glyceryl Monoerucate Succinate, Glyceryl Monoerucate Citrate, Glyceryl Monoerucate Diacetyltartrate, Sucrose Examples include ferrous acid esters, propylene glycol monoerucate, sorbitan monoerucate, sorbitan dielucate, sorbitan trierucate, monoglycerin condensed ricinoleate, diglycerin condensed ricinoleate, triglycerin condensed ricinoleate, tetraglycerin condensed ricinoleate, pentaglycerin condensed ricinoleate, hexaglycerin condensed ricinoleate, heptaglycerin condensed ricinoleate, decaglycerin condensed ricinoleate, etc.

[0060] Specific examples of ester compounds of the polyol and the unsaturated fatty acid include monoglycerin monooleate, mono-dioleate monoglycerin, dioleate monoglycerin, mono-diglycerin monooleate, diglycerin mono-dioleate, diglycerin dioleate, diglycerin trioleate, mono-triglycerin monooleate, triglycerin dioleate, triglycerin trioleate, tetraoleate triglycerin, and mono-tetraglycerin monooleate. Serine, tetraglyceryl dioleate, tetraglyceryl trioleate, tetraglyceryl tetraoleate, tetraglyceryl pentaoleate, pentaglyceryl monooleate, pentaglyceryl dioleate, pentaglyceryl trioleate, pentaglyceryl tetraoleate, pentaglyceryl pentaoleate, pentaglyceryl hexaoleate, hexaglyceryl monooleate, hexaglyceryl dioleate, hexaglyceryl trioleate, hexaglyceryl tetraoleate Serine, hexaglycerin pentaoleate, hexaglycerin hexaoleate, hexaglycerin heptaoleate, decaglycerin monooleate, decaglycerin dioleate, decaglycerin trioleate, decaglycerin tetraoleate, decaglycerin pentaoleate, decaglycerin hexaoleate, decaglycerin heptaoleate, decaglycerin octaoleate, decaglycerin nonaoleate, decaglycerin decaoleate, decaglycerin dodecaoleate, mono Diacetoglycerin oleate, glyceryl monooleate lactate, glyceryl monooleate succinate, glyceryl monooleate citrate, glyceryl monooleate diacetyltartrate, sucrose oleate ester, propylene glycol monooleate, sorbitan monooleate, sorbitan dioleate, sorbitan trioleate, polyoxyethylene sorbitan monooleate, and phosphatidylcholine monopalmitate are preferred, with diglyceryl monooleate being particularly preferred.

[0061] From the viewpoint of inhibiting the oxidation of reduced coenzyme Q10, polyoxyethylene sorbitan fatty acid esters are also preferred as the ester compound of the polyol and the fatty acid.

[0062] Specific examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monostearate.

[0063] When a solid composition containing an emulsifier is used in combination with an oily component (e.g., vegetable oil, essential oil, animal fat, fish oil, lipid-soluble active ingredient, etc.), the preferred HLB of the emulsifier contained in the solid composition is less than 10.0, more preferably less than 8.0, and particularly preferably less than 6.0. Using an ester of the polyol and an unsaturated fatty acid with an HLB of less than 6.0 as an emulsifier is preferable because it allows for the stable preservation of reduced coenzyme Q10 in the solid composition even under conditions of relative humidity of 50% or higher, which are often the conditions under which cosmetics and food products are stored.

[0064] Specific examples of esters of the polyol with an unsaturated fatty acid having an HLB of less than 6.0 include monoglycerin monooleate, mono-dioleate monoglycerin, dioleate monoglycerin, mono-diglycerin monooleate, tetraglycerin pentaoleate, hexaglycerin pentaoleate, decaglycerin pentaoleate, decaglycerin decaoleate, sorbitan monooleate, sorbitan trioleate, propylene glycol monooleate, monoglycerin citrate, sucrose oleate ester, decaglycerin erucate, sucrose erucate ester, succinate monoglyceride stearin, tetraglycerin tristearate, decaglycerin monobehenate, mono-diglycerin monostearate, and sorbitan tristearate.

[0065] It is preferable to use an ester of the polyol and fatty acid with an HLB of 6.0 or higher as an emulsifier in the solid composition, as this allows for stable storage of the reduced coenzyme Q produced in this process even under conditions of relative humidity less than 50%, which are often the conditions under which pharmaceuticals, foods, and supplements are stored. In this case, the HLB of the emulsifier is, for example, 6.0 or higher, preferably 7.0 or higher, and for example, 17 or lower, preferably 16 or lower.

[0066] Specific examples of esters of the polyol with a fatty acid having an HLB of 6.0 or higher include diglyceryl monooleate, monoglyceryl monocaprylate, diglyceryl monocaprylate, pentaglyceryl trioleate, decaglyceryl monolaurate, hexaglyceryl monocaprylate, hexaglyceryl monooleate, pentaglyceryl monostearate, monoglyceryl succinate, glyceryl monostearate diacetyltartarate, diglyceryl monolaurate, diglyceryl monomyristate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, pentaglyceryl condensed ricinoleate, sucrose stearate, sucrose erucate, and sucrose oleate. More preferred examples of ester compounds of the polyol and the fatty acid include diglycerin monooleate, diglycerin monocaprylate, pentaglicerin trioleate, decaglycerin monolaurate, hexaglycerin monocaprylate, hexaglycerin monooleate, pentaglicerin monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, sucrose stearate ester, and sucrose oleate ester. Particularly preferred examples of ester compounds of the polyol and the fatty acid include diglycerin monooleate.

[0067] Examples of lecithin include soy lecithin, egg yolk lecithin, and enzymatically hydrolyzed soy lecithin.

[0068] It is particularly preferable to use an emulsifier that is acceptable for use in food, cosmetics, and / or pharmaceuticals.

[0069] <Binder> The solid compositions disclosed herein may further contain a binder. The binder can be used to bind components such as crystalline particles and antioxidants to form granular solid compositions.

[0070] The type of binder is not limited. One type of binder may be used, or two or more types of binders may be used in combination. Specific examples of binders include one or more selected from celluloses and starches.

[0071] Examples of celluloses include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, crystalline cellulose, cellulose powder, methylcellulose, ethylcellulose, and their salts. Particularly preferred binders are one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose.

[0072] Examples of starches include wheat starch, potato starch, sweet potato starch, corn starch, dextrin, hydroxypropyl starch, starch acetate, oxidized starch, octenyl succinate starch or its salts, and partially pregelatinized starch.

[0073] It is particularly preferable to use a binder that is acceptable as a food or pharmaceutical product.

[0074] <Solid Composition> One or more embodiments of the present invention relate to a solid composition comprising crystalline particles containing a reduced coenzyme Q and an antioxidant.

[0075] The solid composition according to this embodiment is suitable for long-term storage, for example, for a period of three months or more, because the reduction due to oxidation of reduced coenzyme Q is suppressed even when stored under conditions of contact with air. Examples of storage temperatures for the solid composition include 0°C to 45°C, preferably 0°C to 40°C, 4°C to 40°C, 10°C to 40°C, 15°C to 40°C, 20°C to 40°C, 25°C to 40°C, and 30°C to 45°C. When the solid composition of the above embodiment contains Form II crystals of reduced coenzyme Q10, since Form II crystals of reduced coenzyme Q10 have high manufacturing costs, it is preferable that, in order to provide it at an appropriate price, it is possible to maintain an amount of reduced coenzyme Q of 90% by weight or more, more preferably 94% by weight or more, more preferably 94.3% by weight or more, and particularly preferably 94.6% by weight or more of the initial amount, for three months under the conditions of 40°C, a sealed system, and silica gel, or for one month under the conditions of 40°C, a sealed system, and silica gel.

[0076] The solid composition according to this embodiment is a solid composition at 40°C. The solid composition according to this embodiment can be any shape, such as granular, powdery, or flakey, but is preferably granular. Granular means any shape formed by the bonding of crystalline particles containing reduced coenzyme Q and particles of a material containing an antioxidant through a granulation operation, and includes granular form. The dimensions of the granular solid composition are not limited, but for example, it can be granules with a longest diameter of 0.2 mm to 5.0 mm, preferably 0.3 mm to 4.0 mm, 0.4 mm to 3.0 mm, or 0.5 mm to 2.0 mm.

[0077] The solid composition according to this embodiment can be manufactured in high yield and has good handling characteristics, even when an emulsifier in liquid, sol, gel, or soft solid form is used as the emulsifier. For example, in the case of a solid composition manufactured by stirring granulation, it exhibits a transmittance of 50% or more, preferably 60% or more, more preferably 70% or more, more preferably 80% or more, and particularly preferably 90% or more, with respect to a mesh with a mesh opening of 710 μm. The mesh opening size is usually adjusted according to the expected particle size, but in the case of granules obtained by extrusion granulation, a mesh with a mesh opening of 3.0 mm or the like can be used.

[0078] Furthermore, the solid composition according to this embodiment contains reduced coenzyme Q in a crystalline state. The degree of crystallinity of reduced coenzyme Q (the proportion of the total amount of reduced coenzyme Q contained in the solid composition that exists as crystals) is usually 50% or more, preferably 60% or more, more preferably 70% or more, more preferably 80% or more, more preferably 90% or more, and particularly preferably 95% or more.

[0079] The degree of crystallinity of reduced coenzyme Q contained in a solid composition can be calculated using the following formula, based on the theoretical heat of fusion obtained from the content of reduced coenzyme Q in the solid composition, measured by DSC analysis, and the measured heat of fusion data: Degree of crystallinity (%) = (Measured heat of fusion / Theoretical heat of fusion) × 100

[0080] Furthermore, in this embodiment, the solid composition does not require the reduced coenzyme Q10 to be completely coated with a gas barrier material. Therefore, even when pressure is applied, the coating does not break and the oxidative stability is not impaired, and it can be applied to a wide range of formulations, such as tablets formed by compression.

[0081] In the solid composition according to this embodiment, the proportion of each component can be adjusted so as to suppress the oxidation of reduced coenzyme Q.

[0082] The lower limit of the content ratio of crystalline particles containing reduced coenzyme Q in the solid composition according to this embodiment is, for example, 1% by weight, preferably 10% by weight, more preferably 20% by weight, and particularly preferably 30% by weight, 35% by weight, 40% by weight, 41% by weight, 42% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, and 65% by weight, and the upper limit of the content ratio is, for example, 90% by weight, 80% by weight, 70% by weight, 60% by weight, 56% by weight, 55% by weight, 50% by weight, 40% by weight, 30% by weight, 25% by weight, and 20% by weight. Furthermore, the content ratio of reduced coenzyme Q10 in the solid composition according to this embodiment, and the content ratio of Form II crystals and / or Form I crystals of reduced coenzyme Q10, are set to the above values ​​for crystalline particles, specifically, for example, 30% to 90% by weight, 30% to 80% by weight, 30% to 70% by weight, 35% to 90% by weight, 35% to 80% by weight, 35% to 70% by weight, 40% to 90% by weight It can be %, 40% to 80% by weight, 40% to 70% by weight, 45% to 90% by weight, 45% to 80% by weight, 45% to 70% by weight, 50% to 90% by weight, 50% to 80% by weight, 50% to 70% by weight, 55% to 90% by weight, 55% to 80% by weight, 55% to 70% by weight, 60% to 90% by weight, 60% to 80% by weight, or 60% to 70% by weight.

[0083] The lower limit of the content ratio of reduced coenzyme Q in the solid composition according to this embodiment is, for example, 1% by weight, preferably 10% by weight, more preferably 20% by weight, and particularly preferably 25% by weight, 30% by weight, 35% by weight, 40% by weight, 41% by weight, 42% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, and 65% by weight, and the upper limit of the content ratio is, for example, 90% by weight, 80% by weight, 70% by weight, 60% by weight, 56% by weight, 55% by weight, 50% by weight, 40% by weight, 30% by weight, 25% by weight, and 20% by weight.Furthermore, the content ratio of reduced coenzyme Q10 in the solid composition according to this embodiment is, for example, 10% to 90% by weight, 10% to 80% by weight, 10% to 70% by weight, 10% to 60% by weight, 10% to 56% by weight, 10% to 55% by weight, 10% to 50% by weight, 10% to 40% by weight, 10% to 30% by weight, 10% to 25% by weight, 10% to 20% by weight, 25% to 90% by weight, 25% to 80% by weight, 25% to 70% by weight, and 25% by weight. wt% to 60 wt%, 25 wt% to 56 wt%, 25 wt% to 55 wt%, 25 wt% to 50 wt%, 25 wt% to 40 wt%, 30 wt% to 90 wt%, 30 wt% to 80 wt%, 30 wt% to 70 wt%, 30 wt% to 60 wt% , 30% to 56% by weight, 30% to 55% by weight, 30% to 50% by weight, 30% to 40% by weight, 35% to 90% by weight, 35% to 80% by weight, 35% to 70% by weight, 35% to 60% by weight, 35% to 56% by weight Weight%, 35% to 55% by weight, 35% to 50% by weight, 35% to 40% by weight, 40% to 90% by weight, 40% to 80% by weight, 40% to 70% by weight, 40% to 60% by weight, 40% to 56% by weight, 40% by weight ~55wt%, 40wt%~50wt%, 45wt%~90wt%, 45wt%~80wt%, 45wt%~70wt%, 45wt%~60wt%, 45wt%~56wt%, 45wt%~55wt%, 45wt%~50wt%, 50 It can be set to % to 90% by weight, 50% to 80% by weight, 50% to 70% by weight, 50% to 60% by weight, 50% to 56% by weight, 50% to 55% by weight, 55% to 90% by weight, 55% to 80% by weight, 55% to 70% by weight, 55% to 60% by weight, 56% to 90% by weight, 56% to 80% by weight, 56% to 70% by weight, 56% to 60% by weight, 60% to 90% by weight, 60% to 80% by weight, and 60% to 70% by weight.

[0084] The solid composition according to this embodiment more preferably contains, for example, 1 to 9900 parts by weight of antioxidant per 100 parts by weight of reduced coenzyme Q (reduced coenzyme Q10, etc.). The lower limit of the antioxidant content ratio per 100 parts by weight of reduced coenzyme Q (reduced coenzyme Q10, etc.) is preferably 20 parts by weight or more, more preferably 25 parts by weight or more, 30 parts by weight or more, 50 parts by weight or more, 55 parts by weight or more, 60 parts by weight or more, more preferably 80 parts by weight or more, more preferably 100 parts by weight or more, 120 parts by weight or more, 200 parts by weight or more, 500 parts by weight or more, 700 parts by weight or more, and 900 parts by weight or more. The upper limit of the antioxidant content ratio per 100 parts by weight of reduced coenzyme Q (reduced coenzyme Q10, etc.) is preferably 5,000 parts by weight or less, more preferably 1,000 parts by weight or less, 900 parts by weight or less, more preferably 700 parts by weight or less, 500 parts by weight or less, more preferably 200 parts by weight or less, more preferably 120 parts by weight or less, and more preferably 100 parts by weight or less.

[0085] The lower limit of the antioxidant content ratio in the solid composition according to this embodiment is, for example, 1% by weight, preferably 10% by weight (for example, more than 10% by weight), more preferably 20% by weight, 30% by weight, and particularly preferably 33% by weight, 35% by weight, 37% by weight, 38% by weight, 39% by weight, 40% by weight, 41% by weight, 42% by weight, 45% by weight, and 50% by weight, and the upper limit of the content ratio is, for example, 90% by weight, 80% by weight, 75% by weight, 70% by weight, 65% by weight, 60% by weight, 55% by weight, and 50% by weight. Specifically, for example, over 10% by weight and up to 65% by weight, 30% to 90% by weight, 30% to 75% by weight, 30% to 70% by weight, 30% to 65% by weight, 30% to 60% by weight, 30% to 55% by weight, 30% to 50% by weight, 33% to 90% by weight, 33% to 75% by weight, 33% to 70% by weight, 33% to 65% by weight, 33% to 60% by weight, 33% to 55% by weight, 33% to 50% by weight. , 35% to 90% by weight, 35% to 75% by weight, 35% to 70% by weight, 35% to 65% by weight, 35% to 60% by weight, 35% to 55% by weight, 35% to 50% by weight, 37% to 90% by weight %, 37% to 75% by weight, 37% to 70% by weight, 37% to 65% by weight, 37% to 60% by weight, 37% to 55% by weight, 37% to 50% by weight, 38% to 90% by weight, 38% to 75% by weight %, 38% to 70% by weight, 38% to 65% by weight, 38% to 60% by weight, 38% to 55% by weight, 38% to 50% by weight, 39% to 90% by weight, 39% to 75% by weight, 39% to 70% by weight Amount%, 39% to 65% by weight, 39% to 60% by weight, 39% to 55% by weight, 39% to 50% by weight, 40% to 90% by weight, 40% to 75% by weight, 40% to 70% by weight, 40% to 65% by weight It can be expressed as weight %, 40% to 60% by weight, 40% to 55% by weight, 40% to 50% by weight, 45% to 90% by weight, 45% to 75% by weight, 45% to 70% by weight, 45% to 65% by weight, 45% to 60% by weight, 45% to 55% by weight, 45% to 50% by weight, 50% to 90% by weight, 50% to 75% by weight, 50% to 70% by weight, 50% to 65% by weight, or 50% to 60% by weight.

[0086] The total content ratio of reduced coenzyme Q (such as reduced coenzyme Q10) and antioxidant in the solid composition according to this embodiment is, for example, 5% to 100% by weight, preferably 10% to 100% by weight, 20% to 100% by weight, 30% to 100% by weight, more preferably 37% to 100% by weight, 40% to 100% by weight, 50% to 100% by weight, 60% to 100% by weight, and particularly preferably 70% to 100% by weight, 70% to 9% by weight. The percentages are 5% by weight, 70% to 90% by weight, 70% to 85% by weight, 75% to 100% by weight, 75% to 95% by weight, 75% to 90% by weight, 75% to 85% by weight, 80% to 100% by weight, 80% to 95% by weight, 80% to 90% by weight, 80% to 85% by weight, 83% to 100% by weight, 83% to 95% by weight, 83% to 90% by weight, 85% to 100% by weight, 85% to 95% by weight, and 85% to 90% by weight.

[0087] When the solid composition according to this embodiment contains an emulsifier, the content ratio is not particularly limited, but for example, it contains 1 to 9900 parts by weight of emulsifier per 100 parts by weight of reduced coenzyme Q (such as reduced coenzyme Q10). The lower limit of the emulsifier content ratio per 100 parts by weight of reduced coenzyme Q is preferably 3 parts by weight, more preferably 5 parts by weight, more preferably 8 parts by weight, more preferably 10 parts by weight, particularly preferably 15 parts by weight, and most preferably 20 parts by weight. The upper limit of the emulsifier content ratio per 100 parts by weight of reduced coenzyme Q is preferably 5000 parts by weight, more preferably 1000 parts by weight, more preferably 500 parts by weight, more preferably 200 parts by weight, more preferably 150 parts by weight, more preferably 100 parts by weight, more preferably 50 parts by weight, more preferably 30 parts by weight, and more preferably 20 parts by weight.

[0088] If the solid composition according to this embodiment contains an emulsifier, the content ratio is not particularly limited, but the lower limit of the emulsifier content ratio is, for example, 0.1% by weight, 0.2% by weight, 0.5% by weight, preferably 1% by weight, more preferably 3% by weight, more preferably 5% by weight, and more preferably 8% by weight, and the upper limit of the content ratio is, for example, 99% by weight, preferably 50% by weight, more preferably 30% by weight, more preferably 25% by weight, more preferably 20% by weight, more preferably 15% by weight, more preferably 10% by weight, and more preferably 9% by weight.

[0089] If the solid composition according to this embodiment contains a binder, the binder content is not particularly limited, but the solid composition more preferably contains, for example, 1 to 9900 parts by weight of binder per 100 parts by weight of reduced coenzyme Q (such as reduced coenzyme Q10). The lower limit of the binder content ratio per 100 parts by weight of reduced coenzyme Q is preferably 3 parts by weight, more preferably 5 parts by weight, and more preferably 8 parts by weight. The upper limit of the binder content ratio per crystalline particle containing 100 parts by weight of reduced coenzyme Q is preferably 5000 parts by weight, more preferably 1000 parts by weight, more preferably 500 parts by weight, more preferably 200 parts by weight, more preferably 150 parts by weight, more preferably 100 parts by weight, more preferably 50 parts by weight, more preferably 30 parts by weight, and more preferably 20 parts by weight.

[0090] If the solid composition according to this embodiment contains a binder, the binder content ratio is not particularly limited, but the lower limit of the binder content ratio is, for example, 0.5% by weight, preferably 1% by weight, more preferably 3% by weight, more preferably 5% by weight, and more preferably 8% by weight, and the upper limit of the binder content ratio is, for example, 99% by weight, preferably 50% by weight, more preferably 30% by weight, more preferably 25% by weight, more preferably 20% by weight, more preferably 15% by weight, more preferably 10% by weight, and more preferably 9% by weight.

[0091] The solid composition according to this embodiment may further contain other components, such as excipients. The other components are preferably those that are acceptable as food, cosmetic, and / or pharmaceutical ingredients.

[0092] The solid composition according to this embodiment preferably does not contain a carbonate containing sodium cations and / or calcium cations. Examples of carbonates containing sodium cations include sodium carbonate and its hydrates (e.g., monohydrate, heptahydrate, decahydrate, etc.) and sodium bicarbonate. Examples of carbonates containing calcium cations include calcium carbonate and its hydrates (e.g., 0.65hydrate, monohydrate, 1.5hydrate, hexahydrate, etc.).

[0093] The solid composition according to this embodiment preferably does not contain porous calcium silicate. Examples of porous calcium silicate include calcium silicate with an average particle size of 18 to 32 μm, a loose bulk density of 0.07 to 0.15 g / ml, and an oil absorption capacity of 300 to 550 ml / 100 g.

[0094] The solid composition according to this embodiment preferably does not contain 50% by weight or more of oils and fats such as triglycerides. Preferably, the upper limit of the content ratio of oils and fats such as triglycerides is, for example, less than 50% by weight, 49% by weight, 45% by weight, 40% by weight, more preferably 30% by weight, 25% by weight, 20% by weight, 15% by weight, 10% by weight, 5% by weight, 1% by weight, or 0.1% by weight. In this specification, oils and fats refer to compounds in which fatty acids and glycerol are ester-bonded, and which are solid compounds at room temperature (3°C to 30°C). In this specification, oils and fats also include waxes and natural resins, but triglycerides are preferred.

[0095] The solid composition according to this embodiment preferably does not contain 50% by weight or more of water-soluble polymers. Preferably, the upper limit of the water-soluble polymer content is, for example, 45% by weight, 40% by weight, more preferably 30% by weight, 25% by weight, 20% by weight, 15% by weight, 10% by weight, or 9% by weight. Examples of water-soluble polymers include water-soluble polymers mainly composed of amino acids and / or sugars, such as gum arabic, gelatin, agar, pectin, carrageenan, casein, casein compounds, dried egg white, curdlan, alginic acid derivatives, soybean polysaccharides, pullulan, xanthan gum, carmellose salt (carmellose sodium or carmellose calcium, etc.), sugar esters of higher fatty acids, tragacanth, milk, or polyvinylpyrrolidone.

[0096] The shape of the solid composition according to this embodiment is not particularly limited. Examples include granular, powdery, flakey, rod-shaped, plate-shaped, polyhedral, and the like.

[0097] In the case of granular or powdery solid compositions, the sphericity, angle of repose, bulk density, specific surface area, etc., are not particularly limited. In stabilization compositions based on gas barrier properties, it is necessary to increase the sphericity in order to reduce the surface area as much as possible, for example, to 0.8 or higher, which limits processing methods and increases manufacturing costs. On the other hand, the stabilization mechanism of the composition of the present invention is not based on gas barrier properties, and it is preferable because it is not necessary to strictly control the sphericity. The sphericity of the solid composition according to this embodiment (the value obtained by dividing (the surface area of ​​a sphere equivalent to the volume of the particle) by (the surface area of ​​the actual particle)) is, for example, 0.9 or less, 0.89 or less, 0.88 or less, 0.87 or less, 0.86 or less, 0.85 or less, 0.84 or less, 0.83 or less, 0.82 or less, 0.81 or less, 0.8 or less, preferably 0.79 or less, more preferably 0.75 or less, more preferably 0.7 or less, particularly preferably 0.6 or less, and most preferably 0.5 or less. The lower limit of sphericity is not particularly limited, but examples include 0.1, 0.2, 0.3, preferably 0.4, more preferably 0.5, etc.

[0098] The angle of repose of the solid composition according to this embodiment can be, for example, 30° or more, 35° or more, 40° or more, 45° or more, 50° or more, etc. The method for measuring the angle of repose is not particularly limited, but it can be measured, for example, by the method described in JIS R9301-2-2:1999. The bulk density (loose bulk density) of the solid composition according to this embodiment is, for example, 0.7 g / cm³. ３ Below, 0.65g / cm ３ Below, 0.6g / cm ３ Below, 0.55g / cm ３ Below, 0.5g / cm ３ The following are possible. The method for measuring bulk density is not particularly limited, but for example, it can be measured by the method for measuring initial bulk density described in JIS R1628-1997. The specific surface area (surface area per unit mass) of the solid composition according to this embodiment is, for example, 1 cm². ２ / g or more, 2 cm ２ / g or more, 3 cm ２ / g or more, 5 cm ２ / g or more, 7 cm ２ / g or more, 10 cm ２ / g or more, 50 cm ２ / g or more, 100 cm ２ / g or more, etc. The method for measuring the specific surface area is not particularly limited, and for example, measurement can be performed by the measurement method described in JIS Z8830:2013.

[0099] The use of the solid composition of the present invention is not particularly limited. For example, it may be a solid composition for administration to a target animal.

[0100] In this case, the animal species of the target animal is not particularly limited. For example, it may encompass any vertebrate including humans, such as fish (including chondrichthyes and osteichthyes), reptiles, amphibians, birds, mammals, rodents, and primates. Examples of non-human targets include companion animals (tropical fish, frogs, lizards, turtles, small birds such as parakeets, dogs, cats, rabbits, etc.), racehorses, experimental animals (zebrafish, frogs, chickens, mice, rats, guinea pigs, monkeys, etc.), livestock (cattle, horses, sheep, goats, pigs, chickens, ostriches, etc.), cultured fish and crustaceans, and the like. The target animal may be healthy or may be affected by some disease. For example, it may be a solid composition for administration to humans, a solid composition for administration to primates (including non-human primates), a solid composition for administration to mammals (including non-human mammals), and the like.

[0101] <Method for Manufacturing Solid Compositions> Another embodiment of the present invention relates to a method for manufacturing a molded article containing crystalline particles having improved oxidative stability, the method comprising the steps of: preparing a combination of crystalline particles having a median diameter of 50 μm or less and an antioxidant; mixing and / or compounding the crystalline particles having a median diameter of 50 μm or less and the antioxidant; and molding the mixed and / or compounded composition into a desired shape. When using crystalline particles having a median diameter of 50 μm or less, the method includes the steps of mixing and / or compounding the crystalline particles having a median diameter of 50 μm or less and the antioxidant; and molding the mixed and / or compounded composition into a desired shape.

[0102] According to this manufacturing method, the above-mentioned solid composition can be prepared as a molded article.

[0103] According to the method of this embodiment, a solid composition having the above-mentioned characteristics of high storage stability can be produced at low cost and in a simple manner by mixing and / or compounding a reduced coenzyme Q crystal with a solid antioxidant and molding it.

[0104] In the method according to this embodiment, the reduced coenzyme Q crystals are not completely dissolved or melted during the manufacturing process, and are basically mixed, compounded, and molded while maintaining their crystalline state.

[0105] In the process of preparing the combination, a combination is prepared that includes crystalline particles containing reduced coenzyme Q with a median diameter of 50 μm or less and an antioxidant. In the combination in this process, it is sufficient that crystalline particles containing reduced coenzyme Q with a median diameter of 50 μm or less and an antioxidant coexist, and the manner in which they coexist is not particularly limited.

[0106] The preparation method in this process is not particularly limited. For example, it may be prepared by combining crystalline particles containing reduced coenzyme Q with a median diameter of 50 μm or less with an antioxidant, or by combining crystalline particles containing reduced coenzyme Q with a median diameter greater than 50 μm with an antioxidant and then performing a micronization treatment so that the median diameter of the crystalline particles containing reduced coenzyme Q becomes 50 μm or less. The median diameter of the combination in this method is not particularly limited as long as it is 50 μm or less, but for example, the above-mentioned median diameters (e.g., 0.1 μm to 30 μm, 0.3 μm to 25 μm, 0.3 μm to 24 μm, 0.3 μm to 17 μm, 0.3 μm to 13 μm, 0.3 μm to 5 μm, etc.) can be suitably used for the crystalline particles containing reduced coenzyme Q contained in the solid composition of the present invention.

[0107] If this process includes a micronization treatment, the specific method is not limited to any dry grinding method that can micronize crystalline particles containing reduced coenzyme Q while they remain in a solid state. For example, micronization can be achieved by crushing the crystalline particles using a mill, freeze grinding, or a combination thereof. The type of mill used is not particularly limited. Examples include roller mills; jet mills; high-speed rotary grinders such as hammer mills, cutter mills, pin mills, sample mills, turbo mills, and atomizers; container-driven mills such as rotary mills, vibratory mills, and planetary mills; and media-stirring mills such as bead mills, ball mills, and rod mills, or combinations thereof. The conditions for the dry grinding method are not particularly limited. For example, any conditions known in the art can be used.

[0108] The pressure when using the jet mill is not particularly limited. For example, 0.1 MPa to 10 MPa, 0.1 MPa to 5 MPa, 0.1 MPa to 1 MPa, 0.1 MPa to 0.9 MPa, 0.1 MPa to 0.8 MPa, 0.2 MPa to 1 MPa, 0.2 MPa to 0.9 MPa, 0.2 MPa to 0.8 MPa, 0.3 MPa to 1 MPa, 0.3 MPa to 0.9 MPa, 0.3 MPa to 0.8 MPa, 0.3 MPa to 0.7 MPa, 0.4 MPa to 1 MPa, 0.4 MPa to 0.9 MPa. The pressure can be set to 0.4 MPa to 0.8 MPa, 0.4 MPa to 0.7 MPa, 0.5 MPa to 1 MPa, 0.5 MPa to 0.9 MPa, 0.5 MPa to 0.8 MPa, 0.5 MPa to 0.7 MPa, 0.6 MPa to 0.9 MPa, 0.7 MPa to 0.9 MPa, 0.8 MPa to 10 MPa, 0.8 MPa to 5 MPa, 0.8 MPa to 2 MPa, 0.8 MPa to 1 MPa, 0.8 MPa to 0.9 MPa, etc.

[0109] There are no particular limitations on the peripheral speed when using a high-speed rotary crusher. For example, 20m / s to 40m / s, 25m / s to 45m / s, 30m / s to 50m / s, 35m / s to 55m / s, 40m / s to 60m / s m / s, 45m / s to 65m / s, 50m / s to 70m / s, 55m / s to 75m / s, 60m / s to 80m / s, 65m / s to 85 m / s, 70m / s~90m / s, 75m / s~95m / s, 80m / s~100m / s, 85m / s~105m / s, 90m / s~ 110m / s, 95m / s~115m / s, 100m / s~120m / s, 105m / s~125m / s, 110m / s~130m / s , 115m / s to 135m / s, 120m / s to 140m / s, 125m / s to 145m / s, 130m / s to 150m / s, 135 m / s~155m / s, 140m / s~160m / s, 145m / s~165m / s, 150m / s~170m / s, 155m / s~1 75m / s, 160m / s~180m / s, 165m / s~185m / s, 170m / s~190m / s, 175m / s~195m / s, 180m / s to 200m / s, 185m / s to 205m / s, 190m / s to 210m / s, 195m / s to 215m / s, 200 m / s ~ 220m / s, 205m / s ~ 225m / s, 210m / s ~ 230m / s, 215m / s ~ 235m / s, 1m / s ~ 23 5m / s, 1m / s to 60m / s, 1m / s to 20m / s, 2m / s to 8m / s, 3m / s to 7m / s, 4m / s to 6m / s, 1m / s s~80m / s, 1m / s~30m / s, 5m / s~15m / s, 7m / s~13m / s, 9m / s~11m / s, 10m / s~14 m / s, 1m / s to 120m / s, 1m / s to 50m / s, 5m / s to 35m / s, 10m / s to 30m / s, 15m / s to 25m / s , 17m / s~23m / s, 18m / s~22m / s, 19m / s~21m / s, 20m / s~235m / s, 40m / s~200m / s, 50m / s~160m / s, 55m / s~135m / s, 60m / s~120m / s, 63m / s~110m / s, 66m / s~ 90m / s, 68m / s~80m / s, 69m / s~71m / s, 40m / s~235m / s, 60m / s~220m / s, 70m / s s ~ 190m / s, 80m / s ~ 160m / s, 90m / s ~ 130m / s, 95m / s ~ 115m / s, 98m / s ~ 110m / s,It can be set to 99 m / s to 101 m / s, 100 m / s to 235 m / s, 140 m / s to 235 m / s, 170 m / s to 230 m / s, 185 m / s to 215 m / s, 195 m / s to 205 m / s, etc.

[0110] In a container-driven mill or a media stirring mill, the size of the balls or beads used as the medium is not particularly limited. For example, 0.1mm to 100mm, 0.1mm to 50mm, 0.1mm to 20mm, 0.1mm to 10mm, 0.1mm to 6mm, 0.1mm to 5mm, 0 .1mm to 3mm, 0.1mm to 2mm, 0.1mm to 1mm, 0.1mm to 0.5mm, 0.25mm to 100mm, 0.25mm to 50mm, 0.25 mm~20mm, 0.25mm~10mm, 0.25mm~6mm, 0.25mm~5mm, 0.25mm~3mm, 0.25mm~2mm, 0.25mm ~1mm, 0.25mm~0.5mm, 0.5mm~100mm, 0.5mm~50mm, 0.5mm~20mm, 0.5mm~10mm, 0.5mm~6 The dimensions can be mm, 0.5 mm to 5 mm, 0.5 mm to 3 mm, 0.5 mm to 2 mm, 0.5 mm to 1 mm, 1 mm to 100 mm, 1 mm to 50 mm, 1 mm to 20 mm, 1 mm to 10 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 3 mm, 1 mm to 2 mm, 2 mm to 100 mm, 2 mm to 50 mm, 2 mm to 20 mm, 2 mm to 10 mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 3 mm, 3 mm to 100 mm, 3 mm to 50 mm, 3 mm to 20 mm, 3 mm to 10 mm, 3 mm to 6 mm, 3 mm to 5 mm, 5 mm to 100 mm, 5 mm to 50 mm, 5 mm to 20 mm, 5 mm to 10 mm, 5 mm to 6 mm, etc.

[0111] The temperature used when freeze grinding is not particularly limited. For example, it can be -196°C to -80°C, -196°C to -40°C, -196°C to -20°C, -196°C to 0°C, -150°C to -80°C, -150°C to -40°C, -120°C to -80°C, -100°C to -80°C, -100°C to -40°C, -80°C to -40°C, -80°C to -20°C, -80°C to -10°C, -60°C to -40°C, -60°C to -20°C, -40°C to -20°C, -40°C to -10°C, -40°C to -5°C, -30°C to -20°C, -20°C to -10°C, -20°C to -5°C, -10°C to -1°C, etc.

[0112] The mixing and / or compounding step may be performed simultaneously with the preparation of the combined product, or after the preparation of the combined product. When both steps are performed simultaneously, for example, the combined product may be prepared by mixing and / or compounding crystalline particles containing reduced coenzyme Q with a median diameter of 50 μm or less with an antioxidant, or by mixing and / or compounding crystalline particles containing reduced coenzyme Q with a median diameter greater than 50 μm with an antioxidant, and then performing a micronization treatment so that the median diameter of the crystalline particles containing reduced coenzyme Q becomes 50 μm or less. When both steps are performed simultaneously, the mixing and / or compounding step may be performed again after the preparation of the combined product. Furthermore, the mixing and / or compounding step and the step of molding the mixed and / or compounded composition into a desired shape may be performed simultaneously.

[0113] In this method, the specific conditions for mixing the crystalline particles and the antioxidant are as long as the particles of reduced coenzyme Q and the antioxidant are thoroughly mixed. For example, a liquid binder such as water or ethanol may be added to the reduced coenzyme Q and the antioxidant as needed, and then mixing operations such as stirring or flowing may be performed. The method of adding the liquid is not particularly limited. For example, the liquid binder may be added to the reduced coenzyme Q and / or the antioxidant afterward, or vice versa, and one or more components may be added in multiple steps. Preferably, this method does not involve emulsion formation in the mixing and compounding steps described later.

[0114] Examples of liquid binders include water and ethanol. Alternatively, the aforementioned binder may be dissolved in a liquid such as water or ethanol to form a liquid binder. Water is particularly preferred as the liquid binder.

[0115] In this specification, "complexing" means forming a complex containing two or more components. In this process, this refers to forming a complex containing reduced coenzyme Q and an antioxidant. This complex may be a solid composition or a mixture.

[0116] The mixing and / or compounding and / or molding steps preferably include pressurizing and / or kneading. In this specification, "pressurizing" means applying pressure to a level exceeding 1 atmosphere (atmospheric pressure). In this embodiment, the particles of reduced coenzyme Q and antioxidant in the mixture can be pressurized and / or kneaded together.

[0117] In one embodiment, pressurization is performed by granulation. In this case, the mixing and / or compounding process and / or molding process are performed simultaneously.

[0118] The granulation method can be selected as appropriate, but for example, it can be selected from the group consisting of extrusion granulation, stirring granulation, rolling granulation (rotary granulation), dry granulation, tableting, compression granulation, powder bonding, fluidized bed granulation, coacervation, spray granulation, cold spray, evaporation, and liquid curing. The granulation method is preferably carried out by a granulation method that applies pressure (e.g., dry granulation, tableting, wet granulation, powder bonding, etc.) or fluidized bed granulation, and more preferably by wet granulation.

[0119] In this specification, "dry granulation method" refers to a method of obtaining granules by compressing and molding raw material powder, then crushing and classifying it into particles of an appropriate size. The method of compressing the powder raw material is not particularly limited as long as the dry raw material powder can be pressurized, but a method using a tablet press or a roller compressor is preferred.

[0120] In this specification, "tableting" is not particularly limited as long as it can be performed by applying pressure to the raw material and forming it into a predetermined shape, and can be carried out using a tableting device. For example, it can be carried out by filling the die (mold) of the tableting device with raw material and compressing it from above and below with a punch. The tableting device is not particularly limited, and for example, a single-shot tablet press, a rotary tablet press, a tabletop tablet forming machine, etc., can be used.

[0121] In this specification, "powder bonding method" refers to a particle processing technology that combines multiple particles by applying mechanical energy such as impact, shear, or compressive force to a powder layer with a high-speed rotating blade or the like, and by causing particles to collide with each other.

[0122] In one embodiment, the process includes granulating a mixture containing an oxidized coenzyme Q, an emulsifier, and a reducing agent by a wet granulation method.

[0123] In this specification, "wet granulation method" refers to a method of drying a wet granule obtained by dropping or spraying a liquid binder such as water onto a raw material powder and granulating it. The wet granulation method is selected from the group consisting of, for example, the stirring granulation method, the extrusion granulation method, the fluidized bed granulation method, the spray granulation method, the rolling granulation method, the cold spray method, the evaporation method, and the liquid curing method.

[0124] The components of the mixture to be granulated, other than the liquid binder, may be in powder form.

[0125] The amount of liquid binder is not particularly limited, but for example, it can be 0.01 to 100 times, 0.05 to 60 times, 0.05 to 1 time, 0.05 to 0.5 times, 0.05 to 0.25 times, 0.1 to 55 times, 0.1 to 30 times, 0.1 to 20 times, 0.1 to 10 times, 0.1 to 5 times, 0.1 to 1 time, 0.15 times or more than the total weight of the crystal particles and antioxidant. Liquid binders with volumes corresponding to 0.5 times, 0.15 to 0.4 times, 0.15 to 0.35 times, 0.18 to 0.35 times, 0.2 to 0.35 times, 0.33 to 1 time, 0.35 to 1 time, 10 to 100 times, 20 to 100 times, 40 to 100 times, 10 to 60 times, 20 to 60 times, and 40 to 60 times the weight of water can be used.

[0126] Granulation can be carried out by setting appropriate conditions to obtain a solid composition of a size suitable for the intended use.

[0127] The method according to this embodiment preferably further includes a drying step in which the solid composition is dried after granulation to dry and remove volatile components derived from each raw material component and the liquid binder. Furthermore, if necessary, the solid composition having a desired particle size can be separated and recovered by sieving or the like.

[0128] The median diameter of the crystal particles included in the combination of materials according to the method of the present invention is 50 μm or less. Crystal particles with a median diameter of 50 μm or less may already be obtained and used, or crystal particles containing reduced coenzyme Q may be subjected to a micronization treatment. The specific details of the micronization treatment in this case are not particularly limited. For example, the above-described method can be used for the step of preparing the combination. Alternatively, for example, the crystal particles may be made finer by rapidly cooling them during their formation, or by crushing them with a hammer, mill, or the like.

[0129] One or more other embodiments of the present invention relate to a method for improving the oxidative stability of crystalline particles containing reduced coenzyme Q. This method is based on mixing and / or compounding reduced coenzyme Q with an antioxidant in a solid state. Typically, the method includes, for example, the steps of preparing a combination of crystalline particles containing reduced coenzyme Q with a median diameter of 50 μm or less and an antioxidant, mixing and / or compounding the crystalline particles containing reduced coenzyme Q and the antioxidant, and preparing a solid composition containing the mixed and / or compounded crystalline particles and antioxidant. When using crystalline particles containing reduced coenzyme Q with a median diameter of 50 μm or less, the method includes the steps of mixing and / or compounding the crystalline particles containing reduced coenzyme Q with a median diameter of 50 μm or less and an antioxidant, and preparing a solid composition containing the mixed and / or compounded crystalline particles and antioxidant. The specific details of this method are the same as those described above for the method of producing the solid composition. The specific composition of the solid composition prepared by the step of preparing the solid composition is the same as those described above for the solid composition.

[0130] For example, the improved method may include steps of micronizing the reduced coenzyme Q (for example, so that the median diameter is 50 μm or less) and mixing and / or compounding it with an antioxidant in a solid state.

[0131] One or more embodiments of the present invention will be described in more detail below with reference to examples, but the present invention is not limited to these embodiments.

[0132] [Regarding raw materials] In the following examples, reduced coenzyme Q10 (product name: Kaneka QH) manufactured by Kaneka Corporation was used as reduced coenzyme Q10 Form I crystal (QHForm I). Other compounds shown in Table 1 were also used.

[0133]

[0134] [Method for producing reduced coenzyme Q10 Form II crystals (QHFormII)] An ethanol solution containing 8.5% by weight of reduced coenzyme Q10 was heated to 50°C. When the solution was cooled to 36.5°C, reduced coenzyme Q10 Form II crystals, prepared according to the description in Patent Document (WO2012 / 176842), were added as seed crystals. By gradually cooling this solution to 2°C, a white slurry was obtained. The obtained slurry was filtered under reduced pressure to obtain wet crystals, which were washed with cold ethanol and then dried under reduced pressure to obtain reduced coenzyme Q10 Form II crystals (QHFormII).

[0135] [Analysis Method for Reduced Coenzyme Q10 Content (QH Ratio) in the Composition] The weight ratio (%) of reduced coenzyme Q10 to total coenzyme Q10 (i.e., 100 × reduced coenzyme Q10 / (oxidized coenzyme Q10 + reduced coenzyme Q10)) is defined as the "QH ratio". The QH ratio was determined by the following HPLC analysis.

[0136] (HPLC analysis conditions) Column: SYMMETRY C18 (Waters) (Length: 250 mm; Inner diameter: 4.6 mm) Mobile phase: C ２ H ５ OH:CH ３ OH = 4:3 (v:v) Detection wavelength: 210 nm Flow rate: 1 ml / min

[0137] [Method for Evaluating Oxidative Stability] The "QH reduction rate" is defined as the percentage decrease in the QH ratio at the end of the evaluation, with the QH ratio at the start of the evaluation set at 100. The QH reduction rate calculated from the following formula was used as a measure of oxidative stability. QH reduction rate (%) = 100 × (QH ratio at the start of the evaluation - QH ratio at the end of the evaluation) / QH ratio at the start of the evaluation

[0138] [Manufacturing Example 1] The QHFormII before processing is referred to as the sample name "QHFormII_Unground".

[0139] QHFormII_Unground was sieved using a 75 μm mesh sieve, and the particles remaining on the sieve were collected. This sample is referred to as "QHFormII_75 μm Non-Pass".

[0140] QHFormII (unground) was ground using a lab mill (WARING). This sample is referred to as "QHFormII (ground, before sieving)".

[0141] QHFormII (pre-sieving) was sieved using a sieve with a mesh size of 75 μm, and the particles that passed through the sieve were collected. This sample is referred to as "QHFormII_75μm pass".

[0142] QHFormII (pre-sieving) was sieved using a sieve with a mesh size of 53 μm, and the particles that passed through the sieve were collected. This sample is referred to as "QHFormII_53μm pass".

[0143] The particle size distribution of the above samples was measured using a laser diffraction / scattering particle size analyzer (Partica LA-960, manufactured by Horiba, Ltd., wet measurement), and the results are shown in Table 2.

[0144]

[0145] [Manufacturing Example 2] Reduced coenzyme Q10 Form I crystals (QHFormI) (manufactured by Kaneka Corporation) were pulverized using a lab mill, and then sieved using a sieve with a mesh size of 75 μm. The particles that passed through the sieve were collected. This sample was named "QHFormI_75μm pass". The particle size distribution of this sample was measured using a laser diffraction / scattering particle size analyzer (Partica LA-960, manufactured by Horiba, Ltd., wet measurement), and the median diameter (volume basis) was found to be 29 μm.

[0146] QHFormI, which had been heated and melted, was dropped into ice-cold aqueous ethanol to obtain bead-shaped QHFormI particles. The particle size was found to be approximately 4 mm. This sample will be referred to as "QHFormI_4mm".

[0147] The QHFormI slurry obtained by crystallization was filtered using filter paper, and the solvent in the filtrate was removed using an evaporator to obtain fine QHFormI crystals. The particle size distribution of this sample was measured using a dynamic light scattering particle size analyzer (LB-550, Horiba, Ltd., wet measurement), and the median diameter (volume-based) was found to be 314 nm. This sample is referred to as "QHFormI_314nm".

[0148] The particle size distribution of the above samples is summarized in Table 3.

[0149]

[0150] [Reference Example 1-1] A sample that did not pass QHFormII_75μm was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. The QH reduction rate was calculated to be 11.2% when the prepared package was stored in a constant temperature bath at 40°C / 75%RH for 3 months.

[0151] [Reference Example 1-2] A sample of QHFormII_75μm pass was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. The QH reduction rate was calculated to be 13.2% when the prepared package was stored in a constant temperature bath at 40°C / 75%RH for 3 months.

[0152] [Reference Example 2-1] A sample of QHFormI_4mm was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. The QH reduction rate was calculated to be 5.2% when the prepared package was stored in a constant temperature bath at 40°C / 75%RH for two weeks.

[0153] [Reference Example 2-2] A sample of QHFormI with a 75 μm pass was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. The QH reduction rate was calculated to be 69.4% when the prepared package was stored in a constant temperature bath at 40°C / 75% RH for two weeks.

[0154] The results from Reference Examples 1 and 2 showed that the smaller the QH particle size, the greater the QH reduction rate, meaning that oxidative stability decreases. This is thought to be because the increased specific surface area makes it more susceptible to oxidation by oxygen in the air. Generally, reducing particle size improves absorption in the intestines, but these results suggest that there is a trade-off relationship between reducing particle size and maintaining oxidative stability, and that achieving both is difficult.

[0155] [Comparative Example 1] 2.0 g of QHFormII (unground), 2.0 g of ANA, 0.4 g of Q-17D, and 0.4 g of HPC were kneaded in a beaker while adding 1.0 ml of water. The resulting kneaded mixture was extruded and granulated using a 1.2 mmΦ screen and dried to obtain a granular solid composition.

[0156] The prepared solid composition was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. The QH reduction rate was calculated to be 7.1% when the prepared package was stored in a constant temperature bath at 40°C / 75% RH for three months.

[0157] [Example 1] A granular solid composition was obtained in the same manner as in Comparative Example 1, except that QHFormII_ground (before sieving) was used instead of QHFormII_unground.

[0158] When the obtained solid composition was stored in the same manner as in Comparative Example 1, the QH reduction rate was calculated to be 5.9%.

[0159] From the results of Comparative Example 1 and Example 1, an unexpected phenomenon was observed in compositions containing antioxidants: contrary to the case of QH alone, smaller particle sizes actually resulted in higher oxidation stability. In the following examples, the effect of each condition on this phenomenon was tested. The results are summarized in Table 4 and Figure 1.

[0160] [Comparative Example 2] 1.5 g of QHFormII_75 μm non-pass, 1.5 g of ENa, 0.3 g of Q-17D, and 0.3 g of HPMC were kneaded in a beaker while adding 0.56 ml of water. The resulting kneaded mixture was extruded and granulated using a 1.2 mmΦ screen and dried to obtain a granular solid composition.

[0161] The obtained solid composition was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. The QH reduction rate was calculated to be 5.5% when the prepared package was stored in a constant temperature bath at 40°C / 75%RH for one month.

[0162] [Example 2-1] A granular solid composition was obtained in the same manner as in Comparative Example 2, except that QHFormII_75μm pass was used instead of QHFormII_75μm non-pass.

[0163] When the obtained solid composition was stored in the same manner as in Comparative Example 2, the QH reduction rate was calculated to be 5.4%.

[0164] [Example 2-2] A granular solid composition was obtained in the same manner as in Comparative Example 2, except that QHFormII_53μm pass was used instead of QHFormII_75μm non-pass.

[0165] When the obtained solid composition was stored in the same manner as in Comparative Example 2, the QH reduction rate was calculated to be 5.3%.

[0166] [Comparative Example 3] 1.5 g of QHFormII_75 μm non-pass and 1.5 g of ENa were kneaded in a beaker while adding 1.0 ml of water. The resulting kneaded material was extruded and granulated using a 1.2 mmΦ screen and dried to obtain a granular solid composition.

[0167] The obtained solid composition was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. The QH reduction rate was calculated to be 5.8% when the prepared package was stored in a constant temperature bath at 40°C / 75% RH for one month.

[0168] [Example 3] A granular solid composition was obtained in the same manner as in Comparative Example 3, except that QHFormII_75μm pass was used instead of QHFormII_75μm non-pass.

[0169] When the obtained solid composition was stored in the same manner as in Comparative Example 3, the QH reduction rate was calculated to be 5.7%.

[0170] [Comparative Example 4] First, 0.5 g of ANA was dissolved in 80 ml of 67% aqueous ethanol. 1.0 g of QHFormII_75 μm non-pass was dispersed therein, and the solvent was removed using an evaporator while stirring to obtain a granular solid composition.

[0171] The obtained solid composition was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. The QH reduction rate of the prepared package was calculated to be 6.1% when stored in a constant temperature bath at 40°C / 75% RH for one month.

[0172] [Example 4] A granular solid composition was obtained in the same manner as in Comparative Example 4, except that QHFormII_75μm pass was used instead of QHFormII_75μm non-pass.

[0173] When the obtained solid composition was stored in the same manner as in Comparative Example 4, the QH reduction rate was calculated to be 5.6%.

[0174] The results of Reference Example 1 and Examples 1-3 are shown in Table 4 and Figure 1.

[0175] Regardless of the type of antioxidant used (Example 2), the presence or absence of emulsifiers and binders (Example 3), or the method used to prepare the solid composition (Example 4), the phenomenon observed in Example 1, where smaller particle sizes actually resulted in higher oxidation stability, was consistently observed.

[0176]

[0177] [Test Example 1] As an indicator of absorption, the solubility of coenzyme Q10 contained in each composition in artificial intestinal fluid was investigated.

[0178] First, 11.27 g of FeSSIF buffer concentrate (manufactured by Biorelevant) and 127.3 g of water were added to a beaker and stirred with a stirrer. Then, 1.551 g of FeSSIF powder (manufactured by Biorelevant) was added and stirred further until completely dissolved to prepare the artificial intestinal solution. The prepared artificial intestinal solution was dispensed into 10 ml test tubes, and the solid compositions obtained in Comparative Example 3, Example 3, Comparative Example 4, and Example 4 were added to each test tube to a total of 50 mg of coenzyme Q10. After purging the gas phase inside the test tubes with nitrogen, the mixtures were stirred with a stirrer (750 rpm, 37°C, 3 hours). The entire volume of the stirred solution was centrifuged (11,000 × g, 37°C, 10 minutes), and the supernatant was filtered using filter paper to collect the filtrate. The coenzyme Q10 in the recovered filtrate was extracted using hexane, and the coenzyme Q10 content was measured using HPLC to calculate the solubility of coenzyme Q10 in the artificial intestinal fluid.

[0179] The results are shown in Table 5.

[0180]

[0181] The results in Table 5 suggest that the solid composition containing small-particle crystalline particles obtained in the examples had higher solubility of coenzyme Q10 in artificial intestinal fluid and exhibited higher intestinal absorption compared to the solid composition containing large-particle crystalline particles obtained in the comparative examples.

[0182] This suggests that solid compositions containing small-particle crystalline particles and antioxidants can resolve the trade-off between enteric absorption and oxidative stability, resulting in a combination of high enteric absorption and oxidative stability.

[0183] [Comparative Example 5] 0.5 g of QHFormI_4 mm, 0.5 g of ANA, 0.1 g of Q-17D, and 0.1 g of HPC were kneaded in a beaker while adding 0.1 ml of water. The resulting kneaded mixture was dried and then crushed to obtain a granular solid composition.

[0184] [Example 5] A granular solid composition was obtained in the same manner as in Comparative Example 5, except that QHFormI_314nm was used instead of QHFormI_4mm.

[0185] The compositions of Comparative Example 5 and Example 5 were each placed in aluminum laminate bags with silica gel and sealed by heat sealing. The QH reduction rates when the prepared packages were stored in a constant temperature bath at 40°C / 75%RH for two weeks are shown in Table 6, along with the results for Reference Example 2.

[0186]

[0187] The results in Table 6 show that the oxidation stability of small-particle QHFormI is dramatically increased in the presence of ANA. In particular, although QHFormI generally tends to have lower oxidation stability compared to QHFormII, the composition of Example 5, which uses submicron-sized QHFormI, showed the surprising result of exhibiting oxidation stability comparable to that of the composition using QHFormII.

[0188] On the other hand, for bead-shaped QHFormI particles with extremely large particle sizes to enhance physical stability, the results from Reference Example 2-1 and Comparative Example 5 showed the unexpected result that oxidative stability actually decreased in the presence of ANA.

[0189] The results from the above examples demonstrate that by creating a solid composition in which small-particle reduced coenzyme Q10 coexists with an antioxidant, the trade-off between intestinal absorption and oxidative stability can be resolved, and a solid composition possessing both high intestinal absorption and oxidative stability can be produced.

[0190] [Example 6] QHFormII unground and ANA were pre-mixed in a weight ratio of 1:9, totaling 1 kg. The mixture was then co-ground using a jet mill (pressure: 0.8 MPa) to obtain a granular solid composition. No adhesion or blockage of the raw material mixture was observed in the jet mill grinding.

[0191] The granular solid composition from which the particle size distribution of QH was obtained was placed in water and stirred, and the QH was further dispersed using ultrasound, and ANA was dissolved. The particle size distribution of QH in this dispersion was measured using a laser diffraction / scattering particle size analyzer (Partica LA-960, Horiba, Ltd., wet measurement), and the median diameter (volume basis) was 4.4 μm. The particle size distribution measurement was performed while suppressing re-aggregation using the attached internal ultrasound.

[0192] [Test Example 2] The QH reduction rate was calculated when the solid composition obtained in Example 6 was stored for one month in a constant temperature bath at 40°C / 75% RH without being packaged, and it was found to be 0%. Compared to Comparative Example 4 (median diameter of QH crystal: 96 μm, QH reduction rate: 6.1%), it was found that the oxidation stability was significantly improved.

[0193] [Example 7] A granular solid composition was obtained in the same manner as in Example 6, except that 1 kg of unground QHFormII and ANA were pre-mixed in a weight ratio of 1:1. During jet mill grinding, although the ground powder could be recovered immediately after starting, adhesion and blockage of the raw material mixture within the equipment were observed.

[0194] The particle size distribution of QH was measured in the same manner as in Example 6, and the median diameter (volume-based) was found to be 15 μm.

[0195] [Example 8] QHFormII unground and ANA were pre-mixed in a weight ratio of 1:3, totaling 1 kg. The mixture was then co-ground using a ball mill (ball size: 5 mm) to obtain a granular solid composition. No adhesion or blockage of the raw material mixture was observed in the ball mill grinding. The particle size distribution of QH was measured in the same manner as in Example 6, and the median diameter (volume basis) was 24 μm.

[0196] [Example 9] QHFormII unground and ANA were pre-mixed in a weight ratio of 5:3, totaling 1 kg, and then co-ground using a ball mill to obtain a granular solid composition. During ball mill grinding, although the ground powder could be recovered immediately after starting, adhesion and blockage within the equipment due to the raw material mixture were observed. The particle size distribution of QH was measured in the same manner as in Example 6, and the median diameter (volume basis) was 46 μm.

[0197] [Comparative Example 6] QHFormII (median diameter: 66 μm), ANA, HPC, and Q-17D were mixed in a total of 1 kg in a weight ratio of 55:33:7:5. Water was added to the mixture and granulated using a stirring granulator (SPGJ-2TG, manufactured by Dalton Co., Ltd.), and then vacuum-dried to obtain a granular solid composition.

[0198] [Test Example 3] The QH reduction rate was calculated when the solid composition of Example 8 (median diameter of QH crystal: 24 μm) and the solid composition of Comparative Example 6 (median diameter of QH crystal: 66 μm) were stored as they were, without being packaged, under conditions equivalent to 100 days of storage in air at 40°C.

[0199] As a result, the QH reduction rate was 3.6% for the solid composition of Example 8 and 10.0% for the solid composition of Comparative Example 6. It was confirmed that high oxidation stability can be achieved without the inclusion of emulsifiers by refining the crystal particles.

[0200] [Reference Example 3] Wet grinding is known as a more powerful method for finer pulverization. Unground QHFormII was dispersed in 20 times the volume of a 20% ethanol aqueous solution, and wet grinding was attempted using a wet bead mill (bead size: 0.3 mm). As a result, adhesion of the raw material within the equipment was observed. Furthermore, the obtained QH did not maintain a crystalline state, indicating that it is difficult to apply these grinding methods.

[0201] The results from Examples 6 to 9 showed that QHFormII can be micronized in a solid state without complex processes by mixing it with an antioxidant such as ANA and then micronizing it.

[0202] Furthermore, the results from Test Examples 2 and 3 showed that, surprisingly, this method of refinement did not impair oxidative stability, but rather significantly improved it, and that the smaller the median diameter of the crystal grains, the higher the oxidative stability of QH.

[0203] Furthermore, the results from Examples 6 to 9 showed that, for QH, which is difficult to grind due to its low melting point and high adhesion, pre-mixing it with a certain amount or more of an antioxidant such as ANA before grinding significantly improved its handling properties and made grinding easier. It was found that this method makes it possible to produce compositions with both high enteric absorption and oxidative stability very simply.

[0204] [Example 10] Unground QHFormII was freeze-ground (freezing temperature: approximately -80°C). The resulting QH was referred to as the sample name "QHFormII_freeze-ground".

[0205] The particle size distribution of QH was measured in the same manner as in Example 6, and the median diameter (volume-based) was found to be 12.3 μm.

[0206] [Example 11] 300 g of QHFormII freeze-dried, 180 g of ANA, 27 g of Q-17D, and 38 g of HPC were mixed. The resulting mixture was placed in a stirring granulator (SPGJ-2TG, manufactured by Dalton Co., Ltd.) and mixed, then 54 mL of water was added to granulate and the mixture was dried to obtain a granular solid composition.

[0207] This solid composition was placed in an aluminum laminate bag with silica gel and sealed by heat sealing. When the prepared package was stored in a constant temperature bath at 40°C / 75% RH for three months, the QH reduction rate was 3.0%, indicating higher oxidation stability compared to Comparative Example 1 (QH reduction rate: 7.1%).

[0208] [Test Example 4] Table 7 shows the results of measuring the bulk density and angle of repose for the solid composition of Example 11 (median diameter of QH crystal: 12.3 μm) and the solid composition of Comparative Example 6 (median diameter of QH crystal: 66 μm).

[0209]

[0210] However, the results in Table 7 show that although the solid composition of Example 11 contains fine QH crystals which are thought to impair handling properties, it has a bulk density and high fluidity (low angle of repose) equivalent to or better than the solid composition of Comparative Example 6 which contains unground QH crystals with larger particle sizes. From this, it was confirmed that good handling properties can be achieved even when using fine crystalline particles by combining the composition with an antioxidant.

[0211] [Test Example 5] Bioabsorption tests were conducted using the solid compositions of Comparative Example 6 and Example 11. For the bioabsorption tests, samples were filled into rat medication gelatin capsules (TORPAC, size 9 el, filling capacity 0.08 ml) to a dose of 30 mg / kg / capsule as QH. The prepared capsules were force-administered orally to SD rats (male, 8 weeks old, satiety conditions) using a rat capsule dispenser, and immediately afterward, 0.5 ml of distilled water was ingested. Approximately 0.5 ml of blood was collected from the carotid artery of the rats 1, 2, 4, 8, and 24 hours after administration, and the total coenzyme Q10 concentration in the plasma (reduced coenzyme Q10 concentration + oxidized coenzyme Q10 concentration) was measured by HPLC. The experiment was repeated five times for each solid composition.

[0212] Assuming a concentration of 0 at 0 hours after administration, a 24-hour total coenzyme Q10 blood concentration-time curve was created to represent total blood absorption, and the AUC (area under the curve) was calculated.

[0213] Figure 2 shows the results of standardizing the AUC of the solid composition of Comparative Example 6 to 1.

[0214] Figure 2 shows that the solid composition of Example 11 (median diameter of QH crystal: 12.3 μm) exhibits improved absorption compared to the solid composition of Comparative Example 6 (median diameter of QH crystal: 66 μm). This result is consistent with the results of Test Example 1, which tested solubility in artificial intestinal fluid.

[0215] Furthermore, this test example showed that the bioavailability of the solid composition of Example 11 was approximately 2.1 times that of the solid composition of Comparative Example 6. This indicates that the absorption rate is significantly improved by refining the QH crystals.

[0216] The results above demonstrate that by combining micronized reduced coenzyme Q crystals with antioxidants, it is possible to produce an astonishing composition that possesses three properties that are normally incompatible: significantly improved bioavailability, high oxidative stability, and good formulation characteristics (such as tableting and capsule filling properties) and handling. All publications, patents, and patent applications cited herein are incorporated herein by direct reference.

Claims

1. A solid composition comprising crystalline particles containing a reduced coenzyme Q and an antioxidant, wherein the median diameter of the crystalline particles is 50 μm or less.

2. The solid composition according to claim 1, wherein the median diameter of the crystal particles is 13 μm or less.

3. The solid composition according to claim 1, wherein the content ratio of the crystalline particles in the solid composition is 35% by weight or more.

4. The solid composition according to claim 1, wherein the content ratio of oil and fat components in the solid composition is less than 50% by weight.

5. The solid composition according to claim 4, wherein the oil is a triglyceride.

6. The solid composition according to claim 1, wherein the content ratio of the antioxidant in the solid composition is more than 10% by weight and 65% by weight or less.

7. The solid composition according to claim 1, wherein the antioxidant is ascorbic acid and / or a salt thereof.

8. The solid composition according to claim 1, wherein the reduced coenzyme Q is reduced coenzyme Q9, reduced coenzyme Q10 and / or reduced coenzyme Q11.

9. The solid composition according to any one of claims 1 to 8, wherein the crystalline particles include Form II type crystals.

10. The solid composition according to claim 1, further comprising an emulsifier.

11. The solid composition according to claim 1, further comprising a binder.

12. A method for producing a molded article containing crystalline particles having improved oxidative stability, comprising: a step of preparing a combination of crystalline particles having a median diameter of 50 μm or less and an antioxidant; a step of mixing and / or compounding the crystalline particles having the reduced coenzyme Q and the antioxidant; and a step of molding the mixed and / or compounded composition into a desired shape.

13. A method for improving the oxidative stability of crystalline particles containing reduced coenzyme Q, comprising the steps of: preparing a combination of crystalline particles containing reduced coenzyme Q having a median diameter of 50 μm or less and an antioxidant; mixing and / or compounding the crystalline particles containing reduced coenzyme Q and the antioxidant; and preparing a solid composition containing the mixed and / or compounded crystalline particles and antioxidant.

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