Reduced coenzyme q10 crystal-containing composition and method for improving stability of reduced coenzyme q10 crystals

Abstract

One purpose of the present invention is to provide a reduced coenzyme Q10 crystal-containing composition that has a high melting point, and has improved thermal stability and oxidation stability. Another purpose of the present invention is to provide a method for improving the stability of reduced coenzyme Q10 crystals. This reduced coenzyme Q10 crystal-containing composition contains reduced coenzyme Q10 crystals and ethanol, wherein the weight ratio of the ethanol to the reduced coenzyme Q10 crystals is 1×10–7 to 1×10–3.

Description

Composition containing reduced coenzyme Q10 crystals, and method for improving the stability of reduced coenzyme Q10 crystals.

[0001] The present invention relates to a composition containing reduced coenzyme Q10 crystals, and to a method for improving the stability of reduced coenzyme Q10 crystals.

[0002] Coenzyme Q is an essential component widely distributed in living organisms, from bacteria to mammals, and is known as a component of the mitochondrial electron transport chain in cells. In humans, coenzyme Q10, which has a repeating structure of 10 side chains, is the main component, and in the body, 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 (often referred to as "QX" in this specification), but in recent years, reduced coenzyme Q10 (often referred to as "QH" in this specification), which exhibits higher oral absorption than oxidized coenzyme Q10, has also appeared on the market and is being used.

[0004] Patent Document 1 discloses that QH exhibits polymorphism, and that a specific crystal form in this polymorphism (hereinafter referred to as "Form II crystal") is significantly more stable than conventional QH crystals (hereinafter referred to as "Form I crystal"), and therefore is less susceptible to oxidation and has a higher melting point compared to Form I crystals.

[0005] However, the Form II crystal of reduced coenzyme Q10 described in Patent Document 1 (often referred to as "QH Form II crystal" in this specification) is often heated during processing when applied to hard capsules, tablets, or food products. Therefore, it was desired to further increase the melting point in order to improve thermal stability. At the same time, further improvement of oxidative stability was also still desired.

[0006] International Publication No. 2012 / 176842

[0007] Therefore, in view of the above-mentioned conventional situation and problems, the present invention aims to provide a reduced coenzyme Q10 crystal-containing composition (often referred to herein as "QH crystal-containing composition") that has a high melting point and improved thermal stability and oxidative stability. The present invention also aims to provide a method for improving the stability of reduced coenzyme Q10 crystals (often referred to herein as "QH crystals").

[0008] To solve the above problems, the inventors obtained QH Form II crystals using various manufacturing methods and confirmed the physical properties of each crystal. As a result, it became clear that QH Form II crystals obtained by crystallization while ethanol was evaporated showed higher oxidation stability and a higher melting point compared to QH Form II crystals obtained by the conventional ethanol crystallization method. Further detailed investigation of the differences between the two revealed that the amount of residual ethanol mixed as an impurity in the QH Form II crystals obtained by solid-phase transition was less than that in the QH Form II crystals obtained by ethanol crystallization.

[0009] Therefore, the inventors combined QH crystals and ethanol, and further adjusted the weight ratio of both components to a specific range, and found that the melting point and thermal stability of the QH crystal-containing composition could be made higher than that of conventional QH crystals, thus completing the present invention. Furthermore, they found that the composition exhibits higher oxidation stability than conventional QH crystals, thus completing the invention. In other words, the gist of the present invention is as follows: (1) A composition containing QH crystals and ethanol, wherein the weight ratio of ethanol to QH crystals is 1 × 10⁻⁶ －７ ~1 x 10 －３A QH crystal-containing composition, wherein (2) the QH crystal-containing composition according to (1), further comprising oxidized coenzyme Q10 and / or water. (3) the QH crystal-containing composition according to (1) or (2), further comprising QX and / or water, wherein the weight ratio of water to the QH crystal is 0.0001 to 0.001. (4) the QH crystal-containing composition according to any one of (1) to (3), wherein the ethanol content in the QH crystal-containing composition is 0.1 to 1000 ppm. (5) the QH crystal-containing composition according to any one of (1) to (4), wherein the QH crystal content in the QH crystal-containing composition is 95% by weight or more. (6) the QH crystal-containing composition according to any one of (1) to (5), wherein the melting point is 53.5 ± 0.5°C. (7) The QH crystal-containing composition according to (5) or (6), wherein the QH crystal is a Form II type crystal. (8) The QH crystal-containing composition according to any one of (1) to (7), further comprising an antioxidant. (9) The QH crystal-containing composition according to any one of (1) to (8), further comprising an emulsifier. (10) The QH crystal-containing composition according to any one of (1) to (9), which is granular. (11) A food product comprising the QH crystal-containing composition according to any one of (1) to (10). (12) A method for improving the stability of QH crystals, comprising the step of coexisting the QH crystals and ethanol in a composition, wherein the weight ratio of ethanol to the QH crystals in the composition is 1 × 10 －７ ~1 x 10 －３ The method is as described herein. This specification includes the disclosures of Japanese Patent Application No. 2025-026423, which forms the basis of the priority claim of this application.

[0010] The QH crystal-containing composition of the present invention has a higher melting point than conventional QH crystals and exhibits high thermal stability and oxidation stability. Furthermore, the stability of the QH crystal can be enhanced by the method of the present invention.

[0011] This graph shows the ratio of QH to the total amount of coenzyme Q10 contained in the QH crystal-containing compositions of Production Example 1 and Example 1 when stored in a constant temperature bath at 40°C and 75% RH (Relative Humidity).

[0012] The present invention will be described in detail below based on embodiments. <Reduced Coenzyme Q10 Crystal-Containing Composition (QH Crystal-Containing Composition)> The QH crystal-containing composition of the present invention contains QH crystals and ethanol as essential components, and the weight ratio of ethanol to the QH crystals is 1 × 10 －７ ~1 x 10 －３ It is characterized by being such.

[0013] <Reduced Coenzyme Q10 (QH)> In one embodiment of the present invention, the composition contains reduced coenzyme Q10 as an essential component. "Reduced coenzyme Q10 (QH)" is a reduced form of coenzyme Q10, also known as ubiquinol, and refers to an active form of coenzyme Q10 that can act directly in living organisms.

[0014] QH can be obtained by known methods, such as synthesis, fermentation, and extraction from natural products, and by combining these with reduction reactions as needed. Preferably, it can be obtained by reducing existing high-purity coenzyme Q10 or other QX, or a mixture of QX and QH, with a common reducing agent, such as sodium hyposulfite, sodium borohydride, or ascorbic acid.

[0015] QH exists in two crystalline polymorphs: Form I and Form II. Specifically, Form I crystals of QH 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°, or 23.0° in powder X-ray (Cu-Kα) diffraction. Form II crystals 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°, or 33.3° in powder X-ray (Cu-Kα) diffraction. Furthermore, QH exists as cocrystals with other compounds. Other compounds that may be included as cocrystals of QH include, for example, derivatives of QH (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. In the present invention, the QH crystal may contain any of these.

[0016] In this specification, "reduced coenzyme Q10 Form I crystal" (often referred to as "QH Form I crystal" in this specification) means a QH crystal or QH crystalline solid exhibiting Form I polymorphism.

[0017] In this specification, "reduced coenzyme Q10 Form II crystal (QH Form II crystal)" refers to a QH crystal or QH crystalline solid exhibiting Form II polymorphism.

[0018] In this specification, "reduced coenzyme Q10 crystal (QH crystal)" refers to a crystalline form of reduced coenzyme Q10, and includes QH Form I crystals, QH Form II crystals, and cocrystals of reduced coenzyme Q10 with other compounds.

[0019] In one embodiment of the present invention, a QH Form II crystal, which has a higher melting point than a QH Form I crystal, is preferably used as the QH crystal because it also has higher thermal stability and oxidation stability.

[0020] In this specification, "reduced coenzyme Q10 crystal-containing composition (QH crystal-containing composition)" refers to a composition containing at least ethanol in addition to QH crystals. It may also contain QX crystals, water (described later), or other substances.

[0021] In the QH crystal-containing composition according to one embodiment of the present invention, the lower limit of the QH crystal content (weight of QH crystals / total composition weight) in the composition consisting of QH crystals and ethanol is not particularly limited, but for example, it may be 55% by weight or more, preferably 75% by weight or more, more preferably 90% by weight or more, and particularly preferably 95% by weight or more. Similarly, the upper limit is not particularly limited, but for example, it may be 99% by weight or less, preferably 98% by weight or less, and more preferably 97% by weight or less. That is, the QH crystal content in the composition can be in the range of 55 to 99% by weight, preferably 75 to 98% by weight, more preferably 90 to 97% by weight, and particularly preferably 95 to 97% by weight.

[0022] Furthermore, in the QH crystal-containing composition according to one embodiment of the present invention, if it contains other substances other than the QH crystals and ethanol described later, the lower limit of the QH crystal content in the composition (weight of QH crystals / total composition weight) is not particularly limited, but for example, it may be 0.1% by weight or more, preferably 0.5% by weight or more, more preferably 1% by weight or more, particularly preferably 2% by weight or more, and even more preferably 5% by weight or more. Similarly, the upper limit is not particularly limited, but for example, it may be 90% by weight or less, preferably 85% by weight or less, and more preferably 80% by weight or less. In other words, the QH crystal content in the composition when it contains other substances other than the QH crystals and ethanol can be in the range of 0.1 to 90% by weight, preferably 0.5 to 85% by weight, more preferably 1 to 80% by weight, particularly preferably 2 to 80% by weight, and most preferably 5 to 80% by weight.

[0023] In a QH crystal-containing composition according to one embodiment of the present invention, the content of QH Form II crystals relative to the QH crystals in the composition (weight of QH Form II crystals / weight of QH crystals) is not particularly limited, but may be, for example, 50% by weight or more, 60% by weight or more, 70% by weight or more, 75% by weight or more, 80% by weight or more, 85% by weight or more, 90% by weight or more, 95% by weight or more, 98% by weight or more, 99% by weight or more, or 100%.

[0024] <Ethanol> In one embodiment of the present invention, the composition contains ethanol as an essential component. By adjusting the ethanol content relative to the QH crystals in the composition, the thermal stability of the QH crystals can be increased, and at the same time, the oxidative stability can be increased. The ethanol content in the composition may be adjusted by adding a predetermined amount of ethanol to the QH crystals, or by subjecting a mixture of QH crystals and ethanol to a volatilization process such as heating to volatilize the ethanol.

[0025] In the QH crystal-containing composition according to an embodiment of the present invention, the ethanol content in the composition (ethanol weight / total composition weight) is not particularly limited and varies depending on the form of the composition, but is 0.1 ppm or more, preferably 0.5 ppm or more, more preferably 1.0 ppm or more, and particularly preferably 1.5 ppm or more. The upper limit is not particularly limited, but is 1000 ppm or less, preferably 500 ppm or less, more preferably 200 ppm or less, and particularly preferably 100 ppm or less. That is, the ethanol content in the composition can be in the range of 0.1 to 1000 ppm, preferably 0.5 to 500 ppm, more preferably 1.0 to 200 ppm, and particularly preferably 1.5 to 100 ppm. The ethanol weight in the composition can be measured by GC (gas chromatography). The measurement conditions of GC are exemplified by the following conditions. (GC measurement conditions) Apparatus: Shimadzu GC-2014 Column: Gas Chrompak 54 60 / 80 mesh 2 m × 3 mm Carrier gas: Nitrogen gas Flow rate: 1 = 150 kPa Temperature: Column oven 180°C Injector 180°C Detector 200°C Detection method: FID

[0026] Furthermore, in the QH crystal-containing composition of the present invention, the weight ratio of ethanol to QH crystal (ethanol weight / QH crystal weight) may be within the range of 1×10 －７ to 1×10 －３ . Preferably, it may be within the range of 5×10 －７ to 5×10 －４ , and more preferably within the range of 1×10 －６ to －４ －４ . When the weight ratio is outside the above range, the melting point may not be high, and the thermal stability may not be improved, or the oxidation stability may not be improved.

[0027] <Other Ingredients> (Oxidized Coenzyme Q10: QX) In one embodiment of the present invention, the QH crystal-containing composition may also contain oxidized coenzyme Q10. "Oxidized coenzyme Q10" (QX) refers to the oxidized form of coenzyme Q10, also known as ubiquinone.

[0028] In one embodiment of the present invention, the content of QH (weight of QH / (weight of QH + weight of QX)) relative to the content of QH and QX in the composition is not particularly limited, but for example, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 96% or more, 96% or more. It may be % or more, 96.6% or more, 96.7% or more, 96.8% or more, 96.9% or more, 97% or more, 97.5% or more, 97.6% or more, 97.7% or more, 97.8% or more, 97.9% or more, 98% or more, 98.5% or more, 98.6% or more, 98.7% or more, 98.8% or more, 98.9% or more, 99% or more, 99.1% or more, 99.2% or more, 99.3% or more, etc.

[0029] (Water) In one embodiment of the present invention, the QH crystal-containing composition can contain water. The lower limit of the water content (water weight / total composition weight) in the composition is not particularly limited and varies depending on the form of the composition, but it may be 0.01% by weight or more, preferably 0.012% by weight or more, more preferably 0.015% by weight or more, and particularly preferably 0.02% by weight or more. The upper limit is also not particularly limited, but it may be 0.1% by weight or less, preferably 0.09% by weight or less, more preferably 0.08% by weight or less, and particularly preferably 0.07% by weight or less. That is, the water content in the composition can be in the range of 0.01 to 0.1% by weight, preferably 0.012 to 0.09% by weight, more preferably 0.015 to 0.08% by weight, and particularly preferably 0.02 to 0.07% by weight. The water weight in the composition can be measured by the Karl Fischer method. The water content in the composition may be adjusted by adding a predetermined amount of water to the QH crystal, or may be adjusted by evaporating water by subjecting a mixture of the QH crystal, ethanol, and water to a drying process or the like. The measurement conditions in the Karl Fischer method are exemplified by the following conditions. (Karl Fischer measurement conditions) Apparatus: Mitsubishi CA-06 Reagent: Anolyte Aquamicron AX Catholyte Aquamicron CXu

[0030] Further, in the QH crystal-containing composition of the present invention, the weight ratio of water to the QH crystal (water weight / QH crystal weight) is not particularly limited, but for example, it may be within the range of 0.0001 to 0.001, preferably within the range of 0.00012 to 0.0009, more preferably within the range of 0.00015 to 0.0008, and still more preferably within the range of 0.0002 to 0.0007.

[0031] In one embodiment of the present invention, the composition can further contain an antioxidant. The type of the antioxidant is not particularly limited, and two or more antioxidants may be used in combination. Specific examples of the antioxidant include, for example, one or more selected from ascorbic acid, ascorbate, erythorbic acid, and erythorbate.

[0032] The counterions of ascorbate and erythorbate are not limited, but may be one or more metal salts independently selected from sodium, potassium, calcium, and magnesium salts.

[0033] It is particularly preferable to use antioxidants that are acceptable as food or pharmaceuticals. As antioxidants, ascorbic acid salts are preferred, and one or more selected from sodium ascorbate and calcium ascorbate are particularly preferred.

[0034] In one embodiment of the present invention, the content of the antioxidant in the composition is not particularly limited and can be adjusted as appropriate to suppress the oxidation of the QH crystals. For example, the composition contains, for example, 1 to 9900 parts by weight of antioxidant per 100 parts by weight of QH crystals. The lower limit of the antioxidant content per 100 parts by weight of QH crystals is preferably 20 parts by weight or more, more preferably 50 parts by weight or more, and more preferably 80 parts by weight or more. The upper limit of the antioxidant content per 100 parts by weight of QH crystals is preferably 5000 parts by weight or less, more preferably 1000 parts by weight or less, more preferably 500 parts by weight or less, more preferably 200 parts by weight or less, and more preferably 120 parts by weight or less. That is, the antioxidant content per 100 parts by weight of QH crystals can be in the range of 20 to 5000 parts by weight, preferably 50 to 1000 parts by weight, more preferably 80 to 500 parts by weight, more preferably 80 to 200 parts by weight, and more preferably 80 to 120 parts by weight.

[0035] In one embodiment of the present invention, an emulsifier can be further contained in the composition. The type of the emulsifier is not particularly limited, and two or more kinds of emulsifiers may be used in combination. As the emulsifier, for example, an emulsifier having an HLB (Hydrophile-Lipophile Balance) of 1 or more and 17 or less, preferably 2 or more and 16 or less can be used, and two or more kinds of emulsifiers may be used in combination. Specific examples of the emulsifier include one or more emulsifiers selected from the group consisting of glycerin fatty acid ester, sucrose fatty acid ester, retinol fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, and polysorbate.

[0036] From the viewpoint of the oxidation inhibitory effect on QH crystals, among the above emulsifiers, an emulsifier that is not powdery or flaky is preferable. The "emulsifier that is not powdery or flaky" includes, for example, an emulsifier that is liquid, sol-like, gel-like, or soft solid, and an emulsifier that is liquid, viscous liquid, sticky liquid, paste, pellet, wax-like mass, wax, soft solid, or semi-solid is more preferable. As the emulsifier, an emulsifier having the above properties at 50°C is preferable, and an emulsifier having the above properties at 25°C is most preferable.

[0037] Examples of the emulsifier that is not powdery or flaky include an emulsifier having a melting start point measured by setting the heating rate of a differential scanning calorimeter (DSC) to 1°C / min or more and 20°C / min or less and having a melting start point of 50°C or less, preferably 40°C or less, more preferably 25°C or less.

[0038] From another viewpoint, an emulsifier having a viscosity of, 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 when measured at a rotation speed of 10 rpm and a sample temperature of 50°C using a B-type viscometer can be mentioned. The lower limit of the viscosity is not particularly limited as long as it is greater than 0 mPa·s, but it is more preferably 1 mPa·s or more, more preferably 5 mPa·s or more, and most preferably 10 mPa·s or more.

[0039] Specific examples of such 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.

[0040] In polyglycerin, the number of glycerin units is two or more, preferably two to ten. Examples include diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, and decaglycerin.

[0041] In polyoxyethylene sorbitan, the number of oxyethylene units is two or more, preferably 10 to 30, and more preferably 15 to 25.

[0042] In polypropylene glycol, the number of propylene glycol units is 2 or more, preferably 2 to 10.

[0043] In polyethylene glycol, the number of ethylene glycol units is 2 or more, preferably 2 to 10.

[0044] 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.

[0045] 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.

[0046] From the viewpoint of suppressing oxidation of QH crystals, the number of fatty acids bonded to one polyol molecule should 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, or more preferably 1.

[0047] 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 Examples include serine, glyceryl monostearate diacetyl tartrate, propylene glycol monooleate, sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, monoglyceryl monolaurate, diglyceryl monolaurate, diglyceryl monomyristate, tetraglyceryl pentastearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, pentagricerine condensed ricinoleate, sucrose stearate, sucrose erucate, and sucrose oleate.

[0048] From the viewpoint of suppressing oxidation of QH crystals, it is more preferable that the fatty acid in the ester compound of the polyol and the fatty acid is an unsaturated 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.

[0049] From another viewpoint of inhibiting oxidation of QH crystals, 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 may be either a saturated fatty acid or an unsaturated fatty acid.

[0050] 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 Decaglycerin, pentaerucate pentaglycerin, hexaerucate pentaglycerin, monoerucate hexaglycerin, dierucate hexaglycerin, trierucate hexaglycerin, tetraerucate hexaglycerin, pentaerucate hexaglycerin, hexaerucate hexaglycerin, heptaercate hexaglycerin, monoerucate decaglycerin, dierucate decaglycerin, trierucate decaglycerin, tetraerucate decaglycerin Glycerin, 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 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, and decaglycerin condensed ricinoleate.

[0051] From the viewpoint of suppressing oxidation of QH crystals, polyoxyethylene sorbitan fatty acid esters are also preferably used as the ester compound of the polyol and the fatty acid.

[0052] Specific examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monostearate.

[0053] When the composition of this embodiment, which contains an emulsifier, is used in combination with an oily component (e.g., vegetable oil, essential oil, animal fat, fish oil, and lipid-soluble active ingredient), the HLB of the emulsifier contained in the composition of this embodiment is preferably 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 10.0 as an emulsifier is preferable because it allows for stable storage of the QH crystals in the composition even under conditions of relative humidity (RH) of less than 50%, which are often the conditions under which pharmaceuticals and foods are stored.

[0054] Specific examples of esters of the polyol with an HLB of less than 10.0 and an unsaturated fatty acid 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, and sucrose erucate ester.

[0055] Examples of lecithin include soy lecithin, egg yolk lecithin, and enzymatically hydrolyzed soy lecithin.

[0056] It is particularly preferable to use an emulsifier that is acceptable for use in food, cosmetics, and / or pharmaceuticals.

[0057] In one embodiment of the present invention, the emulsifier content is, for example, 1 part by weight or more and 9900 parts by weight or less per 100 parts by weight of reduced coenzyme Q10 crystals. The lower limit of the emulsifier content per 100 parts by weight of QH crystals is not limited, but for example, preferably 3 parts by weight or more, more preferably 5 parts by weight or more, and more preferably 8 parts by weight or more. The upper limit of the emulsifier content per 100 parts by weight of QH crystals is also not limited, but for example, preferably 5000 parts by weight or less, more preferably 1000 parts by weight or less, more preferably 500 parts by weight or less, more preferably 200 parts by weight or less, more preferably 150 parts by weight or less, more preferably 100 parts by weight or less, more preferably 50 parts by weight or less, and more preferably 30 parts by weight or less. In other words, with respect to 100 parts by weight of QH crystals, the amount of emulsifier can be in the range of 3 to 5,000 parts by weight, preferably 5 to 1,000 parts by weight, more preferably 8 to 500 parts by weight, more preferably 8 to 200 parts by weight, more preferably 8 to 150 parts by weight, more preferably 8 to 100 parts by weight, more preferably 8 to 50 parts by weight, and more preferably 8 to 30 parts by weight.

[0058] In one embodiment of the present invention, the composition may further contain a binder. The binder can be used to bind the QH crystals and ethanol, as well as the aforementioned antioxidants, emulsifiers, and other components, to form the composition into granules.

[0059] The type of binder is not particularly limited, and one type 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.

[0060] Examples of celluloses include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, crystalline cellulose, cellulose powder, methylcellulose, ethylcellulose, and salts thereof. Particularly preferred binders are one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose.

[0061] Examples of starches include wheat starch, potato starch, sweet potato starch, corn starch, dextrin, hydroxypropyl starch, acetate starch, oxidized starch, and partially pregelatinized starch.

[0062] It is particularly preferable to use a binder that is acceptable as a food or pharmaceutical product.

[0063] In one embodiment of the present invention, the content of the binder (weight of binder / total weight of composition) is not particularly limited and varies depending on the form of the composition, but may be, for example, 1% by weight or more, preferably 5% by weight or more, more preferably 8% by weight or more in the whole composition, and the upper limit of the content may be, for example, 20% by weight or less, preferably 15% by weight or less, more preferably 10% by weight or less. That is, the content of the binder in the composition can be in the range of 1 to 20% by weight, preferably 5 to 15% by weight, more preferably 8 to 10% by weight.

[0064] Furthermore, the binder contains, for example, 1 part by weight or more, preferably 3 parts by weight or more, more preferably 5 parts by weight or more, and more preferably 8 parts by weight or more, per 100 parts by weight of QH crystals.

[0065] In one embodiment of the present invention, the composition may further contain emulsifying starch. Emulsifying starch is a type of modified starch that has been given emulsifying ability by introducing lipophilic groups into hydrophilic starch. It possesses both viscosity adjustment and emulsifying functions, and by including it in the composition of the present invention, the bioabsorption of coenzyme Q10 can be enhanced. Although not bound by theory, it is presumed that the reason for the improved absorption of coenzyme Q10 is that the composition of the present invention gels in the body due to the inclusion of emulsifying starch, thereby allowing coenzyme Q10 to remain in the body for a longer period of time. The emulsifying starch used in this embodiment is not particularly limited as long as it is edible and has emulsifying properties. Examples include natural starch esterified with alkyl-added carboxylic acid or its salts, or esterified starches that have been partially hydrolyzed while retaining their emulsifying properties to produce dextrins. Specifically, examples include sodium octenyl succinate starch, hydroxypropyl starch, and oxypropanol starch. Among these, sodium octenyl succinate starch is particularly preferred because of its excellent ability to enhance the bioavailability of coenzyme Q10. While both α- and β-type emulsifying starches are applicable, the α-type is preferred. Even the β-type can be gelatinized before use.

[0066] In one embodiment of the present invention, the weight ratio of the emulsifying starch to the QH crystals (weight of emulsifying starch / weight of QH crystals) is not particularly limited, but may be in the range of 1.0 to 10.0, preferably in the range of 1.0 to 5.0.

[0067] Other substances included in the QH crystal-containing composition of the present invention are not particularly limited, but examples include excipients, disintegrants, lubricants, dyes, anti-aggregation agents, absorption enhancers, solubilizers, stabilizers, fragrances, oils and fats, surfactants, higher fatty acids, and active ingredients other than coenzyme Q10.

[0068] The QH crystals contained in the composition of the present invention exhibit a melting point of 53.5 ± 0.5°C, which is a higher temperature range than the melting point of conventional QH Form I crystals (48°C) and QH Form II crystals (52°C). Here, the melting point of the QH crystals can be measured using a differential scanning calorimeter (DSC). Here, "melting point" refers to the peak top temperature of the endothermic peak associated with the melting of the QH crystals detected when the heating rate is 1°C / min. The following conditions are examples of DSC measurement conditions: (DSC measurement conditions) Apparatus: DSC6220 manufactured by SII Nanotechnology Sample container: Aluminum pan & cover (SSC000C008) Heating rate: 1°C / min Sample amount: 5 ± 2 mg

[0069] Thus, the QH crystals contained in the composition of the present invention, when coexisting with ethanol in a specific weight ratio, exhibit a higher melting point than conventional QH crystals, and are expected to be thermally stable and highly oxidatively stable.

[0070] Furthermore, the form of the composition according to the present invention is not particularly limited and can be appropriately selected as needed. Specifically, examples include oral preparations such as tablets, powders, chewable tablets, pills, capsules, granules, fine granules, sustained-release preparations, suspensions, emulsions, syrups, and elixirs, or parenteral preparations such as injections, suppositories, topical preparations, and patches. Since QH has excellent oral absorption, the form of an oral preparation is particularly preferred. Moreover, since the QH crystal-containing composition according to the present invention has a higher melting point, higher thermal stability, and greater oxidative stability than conventional QH crystals, it is preferable that it be a granular composition that has undergone formulation processing requiring heating. The granular composition will be described in detail below.

[0071] The form of the granular QH crystal-containing composition according to the present invention is not particularly limited, and examples include granular, tablet, and capsule forms.

[0072] "Granular" means any form formed by the bonding of primary particles of a material containing QH crystals, ethanol, and optionally antioxidants or emulsifiers, through a granulation process. The dimensions of the granular composition are not limited, but for example, the granules should have a longest diameter of 0.20 mm or more and 2.0 mm or less.

[0073] "Tablet-shaped" refers to any shape molded primarily for tablet use, and its shape and size are not particularly limited. Examples of tablet shapes include round, oval, triangular, and square shapes. In the case of a round shape, the diameter may be 7 to 16 mm, preferably 13 to 16 mm, and the thickness may be 4 to 8 mm, preferably 5 to 7 mm. The weight per tablet of the tablet-shaped composition may be, for example, 200 to 1600 mg, preferably 900 to 1200 mg. The shape of the tablet can be appropriately changed, for example, by the shape of the punch and die used when molding in a tablet press, or by the shape of the mold.

[0074] "Capsule form" refers to a form in which a powdered or granular QH crystal-containing composition is enclosed in an oral capsule.

[0075] One embodiment of the present invention is a food product containing the QH crystal-containing composition. The food product is not particularly limited, but can be used as an additive to, for example, beverages such as milk drinks, soft drinks, sports drinks, nutritional drinks, beauty drinks, and liquid nutritional supplements; confectionery such as chewing gum, chocolate, candy, jelly, cakes, biscuits, and crackers; frozen desserts such as ice cream and frozen desserts; noodles such as udon, Chinese noodles, spaghetti, and instant noodles; processed fish products such as kamaboko, chikuwa, and hanbara; seasonings such as dressings, mayonnaise, and sauces; and bread, ham, porridge, rice, soup, various retort foods, and various frozen foods. The food product containing the coenzyme Q10 crystal-containing composition according to the present invention can be used in applications such as so-called health foods, supplements, functional foods, functional foods, nutritional supplements, foods for specified health uses, nutritional functional foods, nursing care foods, smile care foods, chewing and swallowing aid foods, concentrated liquid foods, and foods for sick people. Needless to say, it can also be used in other food forms. Furthermore, it can also be used in pet food and livestock feed.

[0076] <Method for Producing a QH Crystal-Containing Composition> Next, the method for producing the QH crystal-containing composition of the present invention will be described. In one embodiment of the present invention, the QH crystal-containing composition can be produced by separating a solid composition containing QH crystals and ethanol from a solution containing QH and ethanol. When separating the solid composition, a composition with high thermal stability and oxidative stability can be obtained by controlling the mixing ratio of each component in the solution and the conditions of the separation process so that the weight ratio of QH crystals and ethanol in the composition is within a specific range.

[0077] In one embodiment, the step of separating the composition from the solution can be carried out by adding a seed crystal of QH to a solution containing QH and ethanol, and then cooling it. This allows the composition containing QH crystals and ethanol to precipitate.

[0078] The solution containing QH and ethanol may be a homogeneous solution in which QH is dissolved in ethanol, or it may be a slurry in which some QH remains undissolved, but a homogeneous solution is preferred. In addition, the solution may contain various compounds other than the above-mentioned QH and ethanol.

[0079] Furthermore, the QH used in the above solution can be crystalline or amorphous, and its crystalline polymorphism is not a concern. Therefore, either the conventionally known QH Form I crystal or QH Form II crystal can be used. In addition, since its purity can be increased during crystal precipitation, QH containing impurities or unrefined / crudely refined QH is also acceptable. Moreover, the extract of QH obtained by conventionally known methods, or the reaction solution containing QH obtained from QX by known reduction methods, can be used as is, or, if necessary, purified and / or solvent-substituted, as the solution in the separation step.

[0080] In this embodiment, the solution containing QH and ethanol may also contain other organic solvents besides ethanol. Examples of such organic solvents include alcohols other than ethanol, hydrocarbons, fatty acid esters, and nitrogen compounds. In order to improve conditions that affect crystal precipitation, such as the solubility of each component including QH, crystal precipitation concentration, yield, slurry properties, and crystal properties, two or more solvents may be mixed in appropriate proportions according to the characteristics of each solvent.

[0081] The concentration of QH in the ethanol-containing solution can be adjusted as appropriate and is not particularly limited. For example, a QH concentration of 80% by weight or less, preferably 70% by weight or less, more preferably 60% by weight or less, even more preferably 50% by weight or less, and particularly preferably 40% by weight or less. Furthermore, from the viewpoint of production efficiency, it is preferable to adjust the QH concentration in the solution to a somewhat high concentration, for example, 1% by weight or more is preferable, even more preferably 5% by weight or more, and particularly preferably 10% by weight or more. That is, the QH concentration in the ethanol-containing solution can be in the range of 1 to 80% by weight, preferably 5 to 70% by weight, more preferably 10 to 60% by weight, even more preferably 10 to 50% by weight, and particularly preferably 10 to 40% by weight.

[0082] The solution used in the step of adding seed crystals to precipitate crystals may be a supersaturated solution in which QH is dissolved at a concentration equal to or greater than the saturation concentration of QH in the range of 32 to 43°C. Such a supersaturated solution can be prepared by heating the raw material mixture containing ethanol and QH to a temperature of 42°C or higher, 45°C or higher, more preferably 49°C or higher, even more preferably 70°C or lower, and particularly preferably 55°C or lower to dissolve QH, and then cooling the heated solution to a temperature lower than the heating temperature and in the range of 32 to 43°C.

[0083] If the solution does not contain any organic solvent other than ethanol, the concentration of QH in the solution is preferably 5% by weight or more, particularly preferably 10% by weight or more, preferably 50% by weight or less, more preferably 40% by weight or less, more preferably 25% by weight or less, and particularly preferably 20% by weight or less. That is, the concentration of QH in the ethanol-containing solution can be in the range of 5 to 50% by weight, preferably 10 to 40% by weight, more preferably 10 to 25% by weight, and even more preferably 10 to 20% by weight. When the concentration is within the above range, a supersaturated solution of QH is easily prepared, and crystals are easily precipitated by adding seed crystals.

[0084] In this embodiment, a mixture for the crystal precipitation step is prepared by adding QH crystals as seed crystals to the solution containing QH and ethanol. The amount of QH crystals added as seed crystals (seed crystal amount) is not particularly limited, but is preferably 0.1 to 30% by weight, more preferably 0.5 to 20% by weight, and particularly preferably 0.8 to 5% by weight relative to the amount of QH in the solution before the addition of seed crystals. The QH crystals used as seed crystals preferably contain QH Form II crystals, but may also contain QH Form I crystals or amorphous crystals. The QH Form II crystals should preferably have a high purity, for example, 50% by weight or more, preferably 75% by weight or more, more preferably 80% by weight or more, and more preferably 90% by weight or more.

[0085] Furthermore, in this embodiment, it is preferable that the temperature of the solution when adding the seed crystal is in the range of 32 to 43°C. More preferably, the temperature of the solution when adding the seed crystal should be 35°C or higher, and particularly preferably 38°C or higher. Also, it is preferable that the upper limit be 41°C or lower. If the temperature of the solution when adding the seed crystal exceeds 43°C, the added seed crystal may dissolve and crystals may not precipitate. Also, if a seed crystal is added to a solution at a temperature below 32°C, the proportion of crystals in the precipitated QH may be low, or crystals may not precipitate at all.

[0086] Next, one or more preferred embodiments of the crystal precipitation step in which QH crystals are precipitated in the mixed solution will be described. The temperature of the crystal precipitation step after seed crystal addition is not particularly limited as long as the temperature of the solution at the time of seed crystal addition is within the above range, but for example, it includes maintaining the temperature of the mixed solution preferably at 32°C or higher, more preferably in the range of 32 to 43°C, for a period of 1 hour or more after the addition of the seed crystal. The lower limit of the time for which the mixed solution is maintained in the above temperature range is not particularly limited, but 1 hour or more is preferred, 2 hours or more is preferred, 4 hours or more is more preferred, and 10 hours or more is particularly preferred. The upper limit of the time for which the mixed solution is maintained in the above temperature range is not particularly limited, but sufficient effect can be obtained in about 24 hours. In this case, for example, a constant temperature between 32 and 43°C may be maintained, or for example, in cooling crystallization, the mixed solution may be gradually cooled to 32°C after the addition of the seed crystal. Alternatively, the temperature may be maintained at 32 to 43°C throughout the crystal precipitation step, or the temperature may be maintained at 32 to 43°C for, for example, 1 hour or more, and then cooled.

[0087] The upper limit of the endpoint temperature of the crystal precipitation process is not particularly limited, but from the viewpoint of increasing the recovery amount, it is preferably carried out at 40°C or lower, more preferably at 35°C or lower, and especially at 30°C or lower. The lower limit is the solidification temperature of the system, which is preferably 0°C or higher, more preferably at 10°C or higher.

[0088] In the crystal precipitation process, it is preferable to control the amount of crystals precipitated per unit time to control the formation of supersaturation. The amount of precipitation per unit time should be, for example, less than or equal to the rate at which approximately 50% of the total precipitated amount per unit time precipitates (i.e., a maximum of 50% / hour), and preferably less than or equal to the rate at which 25% of the total precipitated amount per unit time precipitates (i.e., a maximum of 25% / hour).

[0089] In one embodiment of the present invention, the crystal precipitation step includes a step of gradually lowering the temperature of the mixed liquid, i.e., a cooling crystallization step. In cooling crystallization, the solubility of QH in the liquid phase is reduced by cooling the mixed liquid, thereby promoting crystallization. The step of cooling the mixed liquid is performed, for example, immediately after the above step of maintaining the mixed liquid at a temperature of 32°C or higher for a certain period of time to precipitate crystals that can precipitate at this temperature. "Decreasing the temperature of the mixed liquid over time" includes continuously lowering the temperature of the mixed liquid over time, lowering it in stages, or a combination thereof. When the temperature of the mixed liquid is decreased over time, the cooling rate is not particularly limited, but for example, it is a cooling rate such that the temperature decrease per hour is 30°C or less, preferably 20°C or less, more preferably 15°C or less, more preferably 10°C or less, more preferably 5°C or less, more preferably 1°C or more, and more preferably 2°C or more. The cooling rate when the temperature of the mixed liquid is decreased over time may be constant or may vary. In particular, if the cooling rate increases continuously or stepwise as the temperature of the mixture decreases, that is, if the rate of temperature decrease per hour increases, then QH, whose remaining amount in the liquid phase decreases as the temperature of the mixture decreases, can be efficiently crystallized. For example, until the mixture reaches 25°C, the mixture is cooled at a rate of preferably 5°C or less, more preferably 3°C or less, in terms of the rate of temperature decrease per hour. Subsequently, in the step of further cooling the mixture to a temperature below 25°C, the cooling can be performed at a rate of preferably 6°C or more, more preferably 8°C or more, in terms of the rate of temperature decrease per hour. In one embodiment of the present invention, the endpoint temperature reached by decreasing the temperature of the mixture over time is preferably 25°C or less, more preferably 20°C or less, more preferably 10°C or less, more preferably 7°C or less, and more preferably 5°C or less. The lower limit of the endpoint temperature is the solidification temperature of the mixture system, which is preferably 0°C or higher, more preferably 3°C or higher.

[0090] Crystal precipitation is preferably carried out while forcibly flowing the mixed solution after seed crystal addition. To suppress the formation of supersaturation and to ensure smooth nucleation and crystal growth, or from the viewpoint of improving quality, the required stirring power per unit volume is typically about 0.01 kW / m³. ３ Preferably, the above is 0.03 kW / m². ３ More preferably, 0.1 kW / m ３ More preferably 0.3 kW / m ３ It is preferable to provide the above-described flow to the mixture. The above-described forced flow is usually provided by the rotation of an agitator, but if the above flow can be obtained, it is not necessarily required to use an agitator, and methods such as circulating the mixture may be used.

[0091] In the manufacturing method of the present invention, the step of separating the solid composition containing QH and ethanol from the solution is not particularly limited, and in addition to the above-mentioned cooling crystallization, methods such as poor solvent crystallization and concentration crystallization can be used. Cooling crystallization, or a method combining cooling crystallization with other crystallization methods, is preferred. "Poor solvent crystallization" is a method of reducing the solubility by mixing a poor solvent with the above-mentioned mixture and crystallizing QH. Here, "poor solvent" refers to a solvent that hardly dissolves QH or does not dissolve it at all. It is preferable that the poor solvent is mutually soluble with the organic solvent used in the solution containing QH, etc.

[0092] Methods for mixing with a poor solvent include adding the poor solvent to the solution, or adding the solution to the poor solvent. Other crystallization methods to be combined with cooling crystallization include, in addition to the poor solvent crystallization described above, concentration crystallization, for example, in which crystals are precipitated by concentrating the solution.

[0093] A solid composition containing QH crystals and ethanol can be obtained by the above method. The obtained solid composition can be recovered by a solid-liquid separation and drying process, for example, by a conventionally known method. For example, pressure filtration and centrifugal filtration can be used for solid-liquid separation. In addition, the crystals or crystalline solids after drying can be recovered by crushing and classifying (sieving) as needed.

[0094] In the recovered composition, the ethanol content was high, and the weight ratio of ethanol to QH crystals was 1 × 10⁻⁶. －７ ~1 x 10 －３ If it falls outside this range, it can be subjected to a further volatilization step to evaporate the ethanol.

[0095] One method for volatilizing ethanol is heating the composition. Heating may be carried out while shearing the composition by stirring or other means. The heating temperature should be as high as possible without completely melting the QH crystals in the composition, for example, within the range of 45 to 50°C. The heating time is not particularly limited, but for example, it may be 30 to 60 hours, and the heating may also be carried out under reduced pressure. The pressure when reduced pressure is applied should be 4 to 60 kPa. Furthermore, volatilization treatments such as crushing, reduced-pressure drying, or vacuum drying may be performed before and / or after the heating.

[0096] Furthermore, each step in the manufacturing method of the present invention, specifically the mixed liquid formation step, crystal precipitation step, recovery step such as solid-liquid separation and drying, and the subsequent volatilization step described above, is preferably carried out under a deoxygenated atmosphere. A deoxygenated atmosphere can be achieved by replacing the atmosphere with an inert gas, reducing the pressure, boiling, or a combination thereof. At a minimum, it is preferable to replace the atmosphere with an inert gas, i.e., to use an inert gas atmosphere. Examples of the inert gas include nitrogen gas, helium gas, argon gas, and carbon dioxide gas, with nitrogen gas being preferred.

[0097] Whether the resulting composition containing QH crystals and ethanol contains QH Form I or QH Form II crystals can be confirmed by the diffraction angle (2θ ± 0.2°) in powder X-ray (Cu-Kα) diffraction.

[0098] The composition obtained by separating QH crystals and ethanol from the solution can be used by conventionally known methods, depending on the form, such as powder, granules, tablets, or hard capsules.

[0099] A powdered QH crystal-containing composition can be produced, for example, by mixing a composition containing QH crystals and ethanol as powdered raw materials with substances such as antioxidants, emulsifiers, binders, and excipients as needed.

[0100] Furthermore, granular QH crystal-containing compositions can be manufactured, for example, by mixing a composition containing QH crystals and ethanol as powder raw materials with a binder and, if necessary, substances such as antioxidants and emulsifiers, adding water to the mixture, granulating, drying, classifying, and grinding.

[0101] Furthermore, the QH crystal-containing tablet composition can be manufactured by compressing the aforementioned powder or granular QH crystal-containing composition into tablets using a conventional method.

[0102] A hard capsule containing QH crystals can be manufactured by filling a hard capsule with the aforementioned powder or granular QH crystal-containing composition using a conventional method.

[0103] The granulation method is not particularly limited, but can be appropriately selected from methods such as extrusion granulation, agitation granulation, tumbling granulation (rotary granulation), dry granulation, compression granulation, powder bonding, fluidized bed granulation, coacervation, spray drying, cold spray, evaporation, and liquid curing. The granulation method is preferably carried out by a granulation method that applies pressure (e.g., extrusion granulation, agitation granulation, tumbling granulation, dry granulation, compression granulation, powder bonding, etc.) or fluidized bed granulation, more preferably by extrusion granulation, agitation granulation, or fluidized bed granulation, and particularly preferably by extrusion granulation or agitation granulation.

[0104] In this embodiment, the QH crystals are not completely dissolved or melted during the granulation process, and are mixed and granulated while essentially maintaining their crystalline state.

[0105] The components of the mixture to be granulated, other than the liquid binder, may be in powder form. The characteristics of each component of the mixture other than the liquid binder are as described above.

[0106] Examples of liquid binders include water or ethanol. Alternatively, the aforementioned binder may be dissolved in water or ethanol to form a liquid binder. Water is particularly preferred as the liquid binder.

[0107] Granulation can be carried out by setting appropriate conditions to obtain a solid composition having dimensions suitable for the intended use.

[0108] Preferably, the process further includes a drying step in which the solid QH composition after granulation is dried to 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 other means.

[0109] The QH composition for tablets can be manufactured by compressing a powder composition or a granular composition obtained through processes such as granulation and drying, but the method of compression is not particularly limited. For example, methods such as direct compression, semi-direct compression, dry granular compression, and wet granular compression can be appropriately selected. The method of compression is preferably carried out by direct compression or semi-direct compression, with direct compression being more preferable.

[0110] <Method for improving the stability of QH crystals> One embodiment of the present invention relates to a method for improving the stability of QH crystals. The method is characterized by including a step of coexisting QH crystals and ethanol in a specific weight ratio.

[0111] In this specification, "improved stability" means that the melting point of the target QH crystal is higher than that of conventional QH crystals, thereby improving thermal stability, or that the target QH crystal is less susceptible to oxidation, thereby improving oxidation stability.

[0112] Here, the oxidation stability of QH crystals can be determined by storing the QH crystals under oxidation conditions, measuring the QH content and QX content in the composition during storage using high-performance liquid chromatography (HPLC), and calculating the ratio of QH to the total amount of coenzyme Q10 contained in the composition (QH ratio). Examples of high-performance liquid chromatography (HPLC) conditions include the following: (HPLC measurement conditions) Column: AS12S05-1546WT (YMC) 150 mm × 4.6 mm Mobile phase: C ２ H ３ N:CH ３ OH = 1:9 (v:v) Detection wavelength: 290 nm Flow rate: 1 ml / min

[0113] The method for coexisting QH crystals and ethanol is as described above in the section on <QH crystal-containing composition>.

[0114] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0115] (Manufacturing Example 1) After purging the inside of a 300 mL reaction flask (made of heat-resistant glass) with nitrogen, 4 g of QH Form I crystals (manufactured by Kaneka Corporation; QH content 99.7%, ethanol content 20 ppm) and 96 g of ethanol were added, and the mixture was heated to 40°C while stirring until completely dissolved. After cooling this solution to 30°C at a cooling rate of 10°C / hour, 0.4 g of QH Form II crystals (manufactured by Kaneka Corporation) were added as seed crystals. After holding at 30°C for 24 hours, the mixture was immediately filtered and dried to obtain a QH crystal-containing composition. Analysis of the composition by DSC showed that when heated at a rate of 1°C / min, an endothermic peak indicating melting was observed at 52.0°C. That is, the melting point of this composition was 52.0°C. Furthermore, analysis by powder X-ray diffraction showed that the QH crystals in the obtained composition exhibited a Form II type diffraction pattern. The composition contains 97.7% by weight of QH crystals, 2822 ppm of ethanol, and 0.18% by weight of water. The weight ratio of ethanol to QH crystals is 2.9 × 10⁻⁶. －３ That was the case.

[0116] (Example 1) 675 kg of QH Form I crystals used in Production Example 1 and 7 kg of a QH crystal-containing composition prepared in the same manner as in Production Example 1 were placed in a reaction vessel equipped with anchor blades and a heating device. The mixture was stirred for 40 hours at a temperature of 45-50°C while the pressure inside the reaction vessel was reduced to 4 kPa using a vacuum pump. Subsequently, the composition in the reaction vessel was crushed with a crusher, and the ethanol was further evaporated by holding the pressure at 4 kPa for 40 hours to obtain a QH crystal-containing composition. Analysis of the composition by DSC revealed an endothermic peak indicating melting at 53.5°C when the temperature was increased at a rate of 1°C / min. That is, the melting point of this composition was 53.5°C, which was higher than that of the QH Form II crystals obtained in Production Example 1. Furthermore, analysis by powder X-ray diffraction showed that the QH crystals in the obtained composition exhibited a Form II type diffraction pattern. The composition contains 99.4% by weight of QH crystals, 5 ppm of ethanol, and 0.02% by weight of water. The weight ratio of ethanol to QH crystals is 5.0 × 10⁻⁶. －６ That was the case.

[0117] (Example 2) The QH crystal-containing compositions prepared in Production Example 1 and Example 1 were stored in a constant temperature bath at 40°C and 75% RH. The QH content and QX content in the stored compositions were measured by high-performance liquid chromatography (HPLC) under the following conditions, and the ratio of QH to the total amount of coenzyme Q10 contained in the composition (QH ratio) was calculated. The results are shown in Figure 1. (HPLC measurement conditions) Column: AS12S05-1546WT (YMC) 150 mm × 4.6 mm Mobile phase: C ２ H ３ N:CH ３ OH = 1:9 (v:v) Detection wavelength: 290 nm Flow rate: 1 ml / min

[0118] QH ratio (%) = QH content / (QX content + QH content)

[0119] As shown in Figure 1, the QH ratio of the QH crystal-containing composition prepared in Example 1 was higher than that of the QH crystal-containing composition prepared in Production Example 1, indicating high oxidation stability. All publications, patents, and patent applications cited herein are incorporated herein by direct reference.

Claims

1. Contains reduced coenzyme Q10 crystals and ethanol, wherein the weight ratio of ethanol to the reduced coenzyme Q10 crystals is 1 × 10⁻⁶ －７ ~1 x 10 －３ A composition containing reduced coenzyme Q10 crystals.

2. The reduced coenzyme Q10 crystal-containing composition according to claim 1, further comprising oxidized coenzyme Q10 and / or water.

3. The reduced coenzyme Q10 crystal-containing composition according to claim 2, wherein the weight ratio of water to the reduced coenzyme Q10 crystal is 0.0001 to 0.

001.

4. The reduced coenzyme Q10 crystal-containing composition according to claim 1 or 2, wherein the ethanol content in the reduced coenzyme Q10 crystal-containing composition is 0.1 to 1000 ppm.

5. The reduced coenzyme Q10 crystal-containing composition according to claim 1, wherein the content of the reduced coenzyme Q10 crystals in the reduced coenzyme Q10 crystal-containing composition is 95% by weight or more.

6. The reduced coenzyme Q10 crystal-containing composition according to claim 5, wherein the melting point is 53.5 ± 0.5°C.

7. The reduced coenzyme Q10 crystal-containing composition according to claim 5 or 6, wherein the reduced coenzyme Q10 crystal is a Form II type crystal.

8. The reduced coenzyme Q10 crystal-containing composition according to claim 1 or 2, further comprising an antioxidant.

9. The reduced coenzyme Q10 crystal-containing composition according to claim 1 or 2, further comprising an emulsifier.

10. A granular composition containing reduced coenzyme Q10 crystals according to claim 1 or 2.

11. A food product comprising the reduced coenzyme Q10 crystal-containing composition according to claim 1 or 2.

12. A method for improving the stability of reduced coenzyme Q10 crystals, comprising the step of coexisting the reduced coenzyme Q10 crystals and ethanol in a composition, wherein the weight ratio of ethanol to the reduced coenzyme Q10 crystals in the composition is 1 × 10⁻⁶ －７ ~1 x 10 －３ The method described above.

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