Method for producing stable crystals of reduced coenzyme q

Abstract

The present invention addresses the problem of providing a method for producing form-II crystals of reduced coenzyme Q10 without using an organic solvent.　This method for producing stable crystals of reduced coenzyme Q includes a warming step in which a composition comprising an emulsifier and reduced coenzyme Q having two or more, different crystal forms is kept warm.

Description

Method for producing stable reduced coenzyme Q crystals

[0001] The present invention relates to a method for producing stable reduced coenzyme Q crystals, a method for producing a composition comprising stable reduced coenzyme Q crystals and an emulsifier, and a method for producing a pharmaceutical, a cosmetic, a food or a beverage, and the like.

[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 system in cells in vivo. It is known that coenzyme Q functions as a transfer component in the electron transport system by repeating oxidation and reduction in mitochondria, and reduced coenzyme Q has an antioxidant effect. In humans, coenzyme Q10, whose side chain has 10 repeating units, is the main component of coenzyme Q, and usually about 40 to 90% of coenzyme Q exists in a reduced form in vivo. Physiological effects of coenzyme Q include activation of energy production via mitochondrial activation effect, activation of cardiac function, cell membrane stabilization effect, and cytoprotective effect via antioxidant effect, and the like.

[0003] Most of the coenzyme Q10 currently produced and sold is in oxidized form, but in recent years, reduced coenzyme Q10, which exhibits higher oral absorbability than oxidized coenzyme Q10, has also appeared on the market and come into use.

[0004] Patent Document 1 describes that a polymorphic phenomenon is observed in reduced coenzyme Q10, and the newly emerged crystal form (hereinafter, this crystal is referred to as "Form II crystal of reduced coenzyme Q10", "QH Form II crystal" or "Form II crystal") is disclosed to be much more stable than conventional reduced coenzyme Q10 (hereinafter, this crystal is referred to as "Form I crystal of reduced coenzyme Q10", "QH Form I crystal" or "Form I crystal") and excellent in other physical properties.

[0005] Regarding specific methods for producing Form II crystals, Patent Document 1 discloses a production method based on crystallization. The crystallization method is a method for forming Form II crystals by slowly precipitating reduced coenzyme Q10 in a solution. Patent Document 1 also describes a crystal transition method that applies heat and shear force.

[0006] Patent Document 2 describes a method for causing a Form I crystal to undergo a polymorphic transformation into a Form II crystal by adding a seed crystal made of Form II crystal and an organic solvent to a Form I crystal and heating it in a wet crystalline state.

[0007] WO2012 / 176842WO2020 / 067275

[0008] The objective is to provide a simple method for producing Form II crystals of reduced coenzyme Q10 without using organic solvents.

[0009] Among the conventional methods for producing Form II crystals of reduced coenzyme Q10, the crystallization method has the problem of low production efficiency because it takes a long time for crystal formation. Furthermore, methods based on heat and shear force are complicated. All of the above methods have a very narrow range of parameter control, and many challenges remain for industrialization. Regarding polymorphic transition methods using organic solvents, a step is required to remove the organic solvent from the Form II crystals obtained by this method, which presents the problem that they cannot be directly added to food products.

[0010] To solve the problems of conventional methods, the inventors have discovered a method for inducing a polymorphic transformation of Form I crystals to Form II crystals in a composition containing Form II crystals as seed crystals. The inventors have found that the polymorphic transformation from Form I crystals to Form II crystals in the composition proceeds efficiently when the granules contain an emulsifier. This method can easily induce a polymorphic transformation to Form II crystals without requiring complicated steps such as crystallization. Furthermore, since it does not involve the use of organic solvents, it has the advantage that the polymorphic transformed Form II crystals can be directly added to food products, etc.

[0011] The present invention is based on the above findings and provides the following: (1) A method for producing stable reduced coenzyme Q crystals, comprising a heating step of heating a composition comprising reduced coenzyme Q containing two or more different crystal forms and an emulsifier. (2) The method according to (1), comprising a mixing / compounding step of mixing and / or compounding the reduced coenzyme Q containing the two or more different crystal forms with an emulsifier before the heating step. (3) The method according to (2), wherein each of the two or more different crystal forms subjected to the mixing / compounding step is 0.1% by weight or more of the total amount of coenzyme Q. (4) The method according to any one of (1) to (3), wherein the composition is heated at 30°C to 50°C during the heating step. (5) The method according to any one of (1) to (4), wherein the composition is heated for a cumulative total of 12 hours or more during the heating step. (6) The method of (2) or (3), wherein the compounding comprises pressurization and / or kneading; or the method of (4) or (5) by reference to (2) or (3). (7) The method of (6), wherein the mixing / compounding step comprises pressurizing a mixture containing reduced coenzyme Q and an emulsifier by dry granulation, tableting, or powder bonding. (8) The method of (2) or (3), or the method of (4) or (5) by reference to (2) or (3); or the method of (6) or (7), wherein the mixing / compounding step comprises granulating a mixture containing reduced coenzyme Q and an emulsifier by wet granulation. (9) The method of (8), wherein the wet granulation method is selected from the group consisting of agitation granulation, extrusion granulation, fluid bed granulation, spray granulation, rolling granulation, cold spray, evaporation, and liquid curing. (10) The method according to any one of (1) to (9), wherein the emulsifier is in liquid, sol, gel, or soft solid form.(11) The method according to any one of (1) to (10), wherein the emulsifier is a polyol fatty acid ester having at least one of the following characteristics (i) to (iv): (i) comprising an ester of an unsaturated fatty acid; (ii) being a polyoxyethylene sorbitan fatty acid ester; (iii) being a (poly)glycerin fatty acid ester having at least one of the following characteristics (a) to (d): (a) comprising an ester of a fatty acid having 8 or fewer carbon atoms; (b) comprising an ester of a fatty acid having 2 or more glycerin units and 9 to 14 carbon atoms; (c) comprising an ester of a fatty acid having 5 or more glycerin units and 15 to 18 carbon atoms; (d) comprising an ester of an unsaturated fatty acid; (iv) comprising an ester of a saturated fatty acid having 14 or fewer carbon atoms, and excluding polyoxyethylene sorbitan fatty acid esters and (poly)glycerin fatty acid esters. (12) The method according to (11), wherein the emulsifier has at least the characteristic of (iii) above. (13) The method according to (12), wherein the emulsifier is diglyceryl monooleate. (14) The method according to (11), wherein the emulsifier has at least the characteristics of (ii). (15) The method according to (11), wherein the emulsifier is a propylene glycol fatty acid ester. (16) The method according to (11), wherein the emulsifier is an organic acid monoglyceride. (17) The method according to any one of (1) to (16), wherein the two or more different crystal forms include reduced coenzyme Q crystals obtained by reducing oxidized coenzyme Q in the presence of an emulsifier. (18) The method according to (17), wherein the reduction is carried out using one or more reducing agents selected from the group consisting of ascorbic acids, ascorbic acid salts, erythorbic acid salts, and erythorbic acid salts. (19) A method for producing stable reduced coenzyme Q crystals, comprising a transfer step of transferring unstable reduced coenzyme Q crystals to stable reduced coenzyme Q crystals in the presence of an emulsifier. (20) The method according to (19), wherein the emulsifier used in the transfer step is in the form of a liquid, sol, gel, or soft solid.(21) The method according to (19) or (20), wherein the emulsifier is a polyol fatty acid ester having at least one of the following characteristics (i) to (iv): (i) comprising an ester of an unsaturated fatty acid; (ii) being a polyoxyethylene sorbitan fatty acid ester; (iii) being a (poly)glycerin fatty acid ester having at least one of the following characteristics (a) to (d): (a) comprising an ester of a fatty acid having 8 or fewer carbon atoms; (b) comprising an ester of a fatty acid having 2 or more glycerin units and 9 to 14 carbon atoms; (c) comprising an ester of a fatty acid having 5 or more glycerin units and 15 to 18 carbon atoms; (d) comprising an ester of an unsaturated fatty acid; (iv) comprising an ester of a saturated fatty acid having 14 or fewer carbon atoms, and excluding polyoxyethylene sorbitan fatty acid esters and (poly)glycerin fatty acid esters. (22) The method according to (21), wherein the emulsifier has at least the characteristic of (iii) above. (23) The method according to (22), wherein the emulsifier is diglyceryl monooleate. (24) The method according to (21), wherein the emulsifier has at least the characteristics of (ii) above. (25) The method according to (21), wherein the emulsifier is a propylene glycol fatty acid ester. (26) The method according to (21), wherein the emulsifier is an organic acid monoglyceride. (27) The method according to any one of (19) to (26), wherein in the transfer step, an unstable reduced coenzyme Q crystal is transferred to a stable reduced coenzyme Q crystal at 30°C to 50°C. (28) The method according to any one of (19) to (27), wherein in the transfer step, the transfer is carried out for a cumulative total of 12 hours or more. (29) The method according to any one of (19) to (28), wherein the transfer step is carried out under humidity conditions of 60% RH or higher. (30) A method for producing stable reduced coenzyme Q crystals, comprising a removal step of removing an emulsifier from stable reduced coenzyme Q crystals obtained by any of the methods in (1) to (29). (31) A method for producing a composition comprising stable reduced coenzyme Q crystals and an emulsifier, comprising a transfer step of transferring the crystal form of the unstable reduced coenzyme Q crystals to a stable crystal form using the stable reduced coenzyme Q crystals as a seed crystal in the composition comprising stable reduced coenzyme Q crystals, unstable reduced coenzyme Q crystals, and an emulsifier.(32) The method according to (31), wherein the stable reduced coenzyme Q crystal has higher oxidative stability than the unstable reduced coenzyme Q crystal. (33) A method for producing a pharmaceutical, cosmetic, food or beverage containing a stable reduced coenzyme Q crystal using a composition produced by the method according to (31) or (32). This specification includes the disclosures of Japanese Patent Application No. 2025-039472, which forms the basis of the priority of this application.

[0012] The present invention provides a method for producing stable reduced coenzyme Q crystals without using organic solvents.

[0013] Figure 1 shows the results of DSC measurements performed on samples in Example A after 7 days and 31 days of storage. Figure 2 shows the XRD measurement results for Examples H to L, where the QHFormII ratio was 100% after 7 days of storage.

[0014] 1. Method for Producing Stable Reduced Coenzyme Q 1-1. Overview The first aspect of the present invention is a method for producing stable reduced coenzyme Q crystals (in this specification, this may be referred to as "a method for producing stable reduced coenzyme Q crystals"). In one embodiment, the method for producing stable reduced coenzyme Q crystals of the present invention includes a heat retention step, which can improve the stability of reduced coenzyme Q. In a further embodiment, the method for producing stable reduced coenzyme Q crystals of the present invention includes a mixing / compounding step and a heat retention step, which can improve the stability of reduced coenzyme Q. In another embodiment, the method for producing stable reduced coenzyme Q crystals of the present invention includes a transfer step, which can transfer unstable reduced coenzyme Q crystals to stable reduced coenzyme Q crystals.

[0015] 1-2. Definitions of Terms The terms frequently used in this specification are defined below.

[0016] As mentioned above, "coenzyme Q" is an essential component widely distributed in living organisms, from bacteria to mammals. In humans, coenzyme Q10, which has 10 repeating structures in its side chain, is the main component, but in this specification, the number of repeating structures in the side chain of coenzyme Q is not limited as long as there are two 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.

[0017] 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.

[0018] Crystal polymorphism is observed in reduced coenzyme Q10. The newly appearing crystal form described in Patent Document 1 (hereinafter referred to as "Form II crystal of reduced coenzyme Q10", "QHForm II crystal", or "Form II crystal") is known to be much more stable and superior in other physical properties than conventional reduced coenzyme Q10 (hereinafter referred to as "Form I crystal of reduced coenzyme Q10", "QHForm I crystal", or "Form I crystal"). Specifically, reduced coenzyme Q10 with a melting point of around 48°C exhibits 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, and reduced coenzyme Q10 with a melting point of around 52°C exhibits 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, and this crystal form is called Form II crystal.

[0019] In this specification, "stable reduced coenzyme Q crystal" means a reduced coenzyme Q crystal that has at least high oxidative stability or crystallographic stability. A reduced coenzyme Q crystal that has at least high oxidative stability or crystallographic stability may also have high oxidative stability and crystallographic stability.

[0020] In this specification, the type of "antioxidant" is not limited. Two or more antioxidants may be used in combination. Specific examples of antioxidants include one or more selected from ascorbic acids, ascorbates, erythorbic acids, and erythorbates, which are preferably solid at room temperature. The counterions of ascorbic acids and erythorbates are not limited, but can be one or more metal salts independently selected from sodium salts, potassium salts, calcium salts, zinc salts, and magnesium salts. It is particularly preferable to use antioxidants that are acceptable for use in food, cosmetics, and / or pharmaceuticals. For example, ascorbic acids and erythorbates are preferred, and one or more selected from sodium ascorbate, calcium ascorbate, and sodium erythorbate are particularly preferred.

[0021] In this specification, the type of "binder" is not limited. Two or more binders may be used in combination. Specific examples of binders include one or more selected from celluloses and starches. Examples of celluloses include hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, crystalline cellulose, cellulose powder, methylcellulose, ethylcellulose, and their salts. Particularly preferred binders are one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. Examples of starches include wheat starch, potato starch, sweet potato starch, corn starch, dextrin, hydroxypropyl starch, acetate starch, oxidized starch, octenyl succinate starch or its salts, and partially pregelatinized starch. It is particularly preferable to use a binder that is acceptable as a food or pharmaceutical.

[0022] In this specification, the "granulation" method can be appropriately selected, but examples include extrusion granulation, agitation granulation, tumbling granulation (rotary granulation), dry granulation, tableting, compression granulation, powder bonding, fluidized bed granulation, coacervation, spray granulation, cold spray, evaporation, and liquid curing. Examples of granulation methods that involve pressure include extrusion granulation, agitation granulation, tumbling granulation, dry granulation, tableting, compression granulation, powder bonding, and fluidized bed granulation.

[0023] 1-3. method

[0024] In one embodiment, the method for producing stable reduced coenzyme Q crystals according to this embodiment includes a heat retention step as an essential step and a mixing / compounding step and a removal step as optional steps.

[0025] In further embodiments, the method for producing stable reduced coenzyme Q crystals according to this embodiment includes a mixing / compounding step and a heat retention step as essential steps, and a removal step as a selective step.

[0026] In another embodiment, the method for producing reduced coenzyme Q crystals according to this embodiment includes a transfer step as an essential step and a removal step as a selective step.

[0027] (Mixing / Combining Step) In the method for producing stable reduced coenzyme Q crystals according to this embodiment, the "mixing / combining step" is a step of mixing and / or combining reduced coenzyme Q containing two or more different crystal forms with an emulsifier. This step is an essential step in embodiments of the method for producing stable reduced coenzyme Q crystals according to this embodiment that include a mixing / combining step and a heat retention step. Through this step, reduced coenzyme Q containing two or more different crystal forms can adhere to the emulsifier at least at a particle level. In this specification, "mixing / combining" refers to either compounding or mixing, or both. Also, unless otherwise specified, "composition" is used as a term that includes mixtures.

[0028] In this specification, "compounding" means forming a composition containing multiple components. In this process, this refers to forming a composition containing reduced coenzyme Q containing two or more different crystalline forms, an emulsifier, and optionally other components (e.g., antioxidants, binders, oxidized coenzyme Q, and / or excipients). By compounding reduced coenzyme Q containing two or more different crystalline forms with an emulsifier, the reduced coenzyme Q containing two or more different crystalline forms can adhere to the emulsifier at least at a particle level. In this process, compounding, mixing, or both may be performed.

[0029] Furthermore, when this process involves mixing, the specific conditions for mixing reduced coenzyme Q containing two or more different crystalline forms with an emulsifier are simply those conditions under which the particles of reduced coenzyme Q containing two or more different crystalline forms and the emulsifier are thoroughly mixed. For example, a solvent such as water or ethanol may be added as needed to the reduced coenzyme Q containing two or more different crystalline forms, the emulsifier, and optionally other components (e.g., antioxidants, binders, oxidized coenzyme Q, and / or excipients), and then a mixing operation such as stirring or flowing may be performed. By mixing reduced coenzyme Q containing two or more different crystalline forms with an emulsifier, the reduced coenzyme Q containing two or more different crystalline forms can adhere to the emulsifier at least at a particle level.

[0030] In this specification, "reduced coenzyme Q containing two or more different crystal forms" refers to reduced coenzyme Q containing two or more different crystal forms, in which the number of repeating structures in the side chain is, in principle, the same. Reduced coenzyme Q containing two or more different crystal forms is, for example, reduced coenzyme Q9 containing two or more crystal forms, reduced coenzyme Q10 containing two or more crystal forms, or reduced coenzyme Q11 containing two or more crystal forms, and is preferably reduced coenzyme Q10 containing two or more crystal forms. Examples of reduced coenzyme Q10 containing two or more crystalline forms include reduced coenzyme Q10 containing Form I crystals and Form II crystals, reduced coenzyme Q10 containing reduced coenzyme Q10 crystals and Form I crystals that can be obtained by reducing oxidized coenzyme Q10 in the presence of an emulsifier, and reduced coenzyme Q10 containing reduced coenzyme Q10 crystals and Form II crystals that can be obtained by reducing oxidized coenzyme Q10 in the presence of an emulsifier. More preferably, examples include reduced coenzyme Q10 containing Form I crystals and Form II crystals, and reduced coenzyme Q10 containing reduced coenzyme Q10 crystals and Form II crystals obtained by reducing oxidized coenzyme Q10 in the presence of an emulsifier. For example, if the reduced coenzyme Q containing two or more different crystal forms is reduced coenzyme Q10 containing Form I crystals and Form II crystals, this process results in the formation of highly stable Form II crystals from Form I crystals, thereby improving the stability of the reduced coenzyme Q crystals.

[0031] In the reduced coenzyme Q used in this process, which contains two or more different crystal forms, the proportion of the different crystal forms is not particularly limited. For 100 parts by weight of the first crystal form, the second crystal form may be, for example, 0.1 parts by weight or more and 100,000 parts by weight or less, 1 part by weight or more and 10,000 parts by weight or less, or 1 part by weight or more and 9,900 parts by weight or less. More specifically, for 100 parts by weight of the first crystal form, the proportion of the second crystal form may be, for example, 0.1 parts by weight or more, preferably 0.5 parts by weight or more, more preferably 1 part by weight or more, more preferably 2 parts by weight or more, preferably 5 parts by weight or more, more preferably 10 parts by weight or more, more preferably 20 parts by weight or more, more preferably 30 parts by weight or more, more preferably 40 parts by weight or more, and more preferably 50 parts by weight or more. Furthermore, the ratio of the second crystal form to 100 parts by weight of the first crystal form is, for example, 100,000 parts by weight or less, or 20,000 parts by weight or less, preferably 10,000 parts by weight or less, or 5,000 parts by weight or less, more preferably 2,000 parts by weight or less, or 1,000 parts by weight or less, more preferably 500 parts by weight or less, or 200 parts by weight or less, and particularly preferably 100 parts by weight or less. In this step, in addition to the reduced coenzyme Q containing two or more different crystal forms, reduced or oxidized coenzyme Q with different numbers of repeating structures in the side chain, or oxidized coenzyme Q with the same number of repeating structures in the side chain may also be included.

[0032] In this process, the lower limit of the amount of reduced coenzyme Q containing two or more different crystalline forms relative to the entire reaction system is, for example, 1% by weight or more, preferably 10% by weight or more, more preferably 20% by weight or more, more preferably 30% by weight or more, more preferably 40% by weight or more, more preferably 50% by weight or more, particularly preferably 60% by weight or more, particularly preferably 70% by weight or more, and most preferably 80% by weight or more. The upper limit of the amount used is not particularly limited, but the amount used is, for example, 95% by weight or less or 90% by weight or less.

[0033] Each of the two or more different crystalline forms used in the mixing / compounding process is, for example, 99.9% by weight or less, 99% by weight or less, 95% by weight or less, more preferably 90% by weight or less, 85% by weight or less, and especially preferably 80% by weight or less, relative to the total amount of coenzyme Q.

[0034] Furthermore, each of the two or more different crystalline forms used in the mixing / compounding process is, for example, 0.1% by weight or more, more preferably 1% by weight or more, 5% by weight or more, and particularly preferably 10% by weight or more, or 20% by weight or more, relative to the total amount of coenzyme Q.

[0035] In this specification, the type of "emulsifier" is not limited. For example, an emulsifier with an HLB of 1 to 17, preferably 2 to 16, can be used. Two or more emulsifiers may be used in combination.

[0036] Among the emulsifiers mentioned above, emulsifiers that are not in powder or flake form are preferred. Examples of emulsifiers that are not in powder or flake form include those that are liquid, sol, gel, or soft solid, and emulsifiers that are liquid, viscous liquid, viscous liquid, paste, pellet, waxy mass, wax, soft solid, or semi-solid 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.

[0037] 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.

[0038] 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.

[0039] Specific examples of emulsifiers include one or more selected from ester compounds of a polyol selected from monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol, and a fatty acid which may have a substituent, and lecithin.

[0040] In polyglycerin, the number of glycerin units only needs to be 2 or more, and preferably 2 or more and 10 or less. Examples thereof include diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, and decaglycerin.

[0041] In polyoxyethylene sorbitan, the number of oxyethylene units only needs to be 2 or more, preferably 10 or more and 30 or less, and more preferably 15 or more and 25 or less.

[0042] In polypropylene glycol, the number of propylene glycol units only needs to be 2 or more, and preferably 2 or more and 10 or less.

[0043] In polyethylene glycol, the number of ethylene glycol units only needs to be 2 or more, and preferably 2 or more and 10 or less.

[0044] Examples of the fatty acid which may have a substituent include linear or branched monovalent or divalent fatty acids having 4 to 24 carbon atoms. Examples of the substituent include a hydroxyl group and an acetoxy group. The number of substituents is preferably 2 or less. Specific examples of the fatty acid which may have a substituent include lauric acid, oleic acid, caprylic acid, stearic acid, behenic acid, ricinoleic acid, succinic acid, and diacetyl tartaric acid.

[0045] In the ester compound of the polyol and the fatty acid, the number of bonds of the fatty acid to one molecule of the polyol is not particularly limited, and can be appropriately adjusted according to the HLB of the target emulsifier.

[0046] The number of bonds of said fatty acid per molecule of polyol 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 particularly preferably 1.

[0047] Specific examples of the ester compound of said polyol and said 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-diglyceryl monostearate, monoglyceryl monooleate, glyceryl monostearate succinate, monoglyceryl succinate, glyceryl monostearate diacetyl tartrate, propylene glycol monooleate, sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, monoglyceryl monolaurate, diglyceryl monolaurate, diglyceryl monomyristate, tetraglyceryl pentastearate, polyoxyethylene sorbitan monooleate, stearic monoglyceride succinate, oleic monoglyceride citrate, stearic monoglyceride citrate, stearic monoglyceride diacetyl tartrate, lauric monoglyceride acetate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, pentaglyceryl condensed ricinoleate, sucrose stearate, sucrose erucate, sucrose oleate.

[0048] The ester compound of the polyol and the fatty acid preferably has at least one of the following characteristics (1) to (4): (1) contains an ester of an unsaturated fatty acid; (2) is a polyoxyethylene sorbitan fatty acid ester; (3) is a (poly)glycerol fatty acid ester having at least one of the following characteristics (a) to (d): (a) contains an ester of a fatty acid having 8 or fewer carbon atoms; (b) contains an ester of a fatty acid having 2 or more glycerol units and 9 to 14 carbon atoms; (c) contains an ester of a fatty acid having 5 or more glycerol units and 15 to 18 carbon atoms; (d) contains an ester of an unsaturated fatty acid; (4) contains an ester of a saturated fatty acid having 14 or fewer carbon atoms, and excludes polyoxyethylene sorbitan fatty acid esters and (poly)glycerol fatty acid esters.

[0049] The emulsifier is preferably one that has at least the characteristics of (3) above. For example, the emulsifier is diglyceryl monooleate.

[0050] In the ester compound of the polyol and the fatty acid, the fatty acid is more preferably 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, adrenalineic acid, bosopentaenoic 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.

[0051] 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, triglycerin tetraoleate, tetraglycerin monooleate, tetraglycerin dioleate, and Tetraglycerin tetraoleate, 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, hep Hexaglycerin oleate, 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 diacetomonolaureate, glycerin monooleate lactate, glycerin monooleate succinate Serine, glyceryl monooleate citrate, glyceryl monooleate diacetyl tartrate, sucrose oleate, 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, diglyceryl monoerucateDiglyceryl mono-dielucate, diglyceryl dielucate, diglyceryl trierucate, triglyceryl monoerucate, triglyceryl dielucate, triglyceryl trierucate, triglyceryl tetraerucate, tetraglyceryl monoerucate, tetraglyceryl dielucate, tetraglyceryl trierucate, tetraglyceryl tetraerucate, tetraglyceryl pentaerucate, pentaglyceryl monoerucate, pentaglyceryl dielucate, trie Pentaglycerin tetraerucate, pentaglycerin pentaerucate, pentaglycerin hexaerucate, hexaglycerin monoerucate, hexaglycerin dierucate, hexaglycerin trierucate, hexaglycerin tetraerucate, hexaglycerin pentaerucate, hexaglycerin hexaerucate, hexaglycerin heptaerucate, decaglycerin monoerucate, decaglycerin dierucate, decaglycerin trierucate Ricelin, Decaglyceryl Tetraerucate, 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 Examples include sucrose erucate, 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.

[0052] 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, mono-tetraglycerin dioleate, and tetraglycerin dioleate. Serine, tetraglyceryl trioleate, tetraglyceryl tetraoleate, tetraglyceryl pentaoleate, pentaglycerin monooleate, pentaglycerin dioleate, pentaglycerin trioleate, pentaglycerin tetraoleate, pentaglycerin pentaoleate, pentaglycerin hexaoleate, hexaglycerin monooleate, hexaglycerin dioleate, hexaglycerin trioleate, hexaglycerin tetraoleate, hexaglycerin pentaoleate, hexaglycerin Decaglycerin, hexaglycerin heptaoleate, 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 diacetomonolaureate, glycerin monooleate lactate Phosphorus, glyceryl monooleate succinate, glyceryl monooleate citrate, glyceryl monooleate diacetyl tartrate, sucrose oleate ester, propylene glycol monooleate, sorbitan monooleate, sorbitan dioleate, sorbitan trioleate, polyoxyethylene sorbitan monooleate, propylene glycol monooleate, and phosphatidylcholine monopalmitate monooleate are preferred, with polyoxyethylene sorbitan monooleate and diglyceryl monooleate being particularly preferred.

[0053] Polyoxyethylene sorbitan fatty acid esters are also preferred as ester compounds of the polyol and the fatty acid.

[0054] Specific examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monostearate, with polyoxyethylene sorbitan monooleate being more preferred.

[0055] As the ester compound of the polyol and the fatty acid, propylene glycol fatty acid esters are also preferred.

[0056] Specific examples of the propylene glycol fatty acid ester include propylene glycol monolaurate, propylene glycol monopalmitate, propylene glycol monostearate, propylene glycol monooleate, and propylene glycol monobehenate, with propylene glycol monooleate being more preferred.

[0057] Organic acid monoglycerides are also preferred as ester compounds of the polyol and the fatty acid. Organic acid monoglycerides are compounds in which an organic acid such as acetic acid, lactic acid, citric acid, succinic acid, or tartaric acid is esterified to a monoester of glycerin and a fatty acid.

[0058] Specific examples of the aforementioned organic acid monoglycerides include diacetoglycerin monooleate, glycerin diacetomonolaureate, glycerin monooleate lactate, glycerin monooleate succinate, glycerin monooleate citrate, and glycerin monooleate diacetyltartrate, with glycerin diacetomonolaureate being more preferred.

[0059] When 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.) in this process, the preferred HLB of the emulsifier used in this process is less than 10.0, more preferably less than 8.0, and particularly preferably less than 6.0. Using an ester compound of the polyol and fatty acid with an HLB of less than 6.0 as an emulsifier is preferable because it allows for stable storage of the reduced coenzyme Q produced in this process even under conditions of relative humidity of 50% or higher, which are often the conditions under which food and cosmetics are stored.

[0060] Specific examples of ester compounds of the polyol and fatty acid with 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, glycerin diacetomolaurate, sucrose oleate ester, decaglycerin erucate, and sucrose erucate ester.

[0061] In this process, it is preferable to use an ester compound of the polyol and fatty acid with an HLB of 6.0 or higher as an emulsifier, as this allows for stable storage of the reduced coenzyme Q produced in this process even under conditions of relative humidity below 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.

[0062] Specific examples of ester compounds of the polyol and fatty acid with 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 erucate ester, and sucrose oleate ester. 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, and sucrose oleate ester. Particularly preferred examples of ester compounds of the polyol and the fatty acid include polyoxyethylene sorbitan monooleate, sucrose oleate ester, and diglycerin monooleate.

[0063] Examples of lecithin include soy lecithin, egg yolk lecithin, and enzymatically hydrolyzed soy lecithin.

[0064] It is particularly preferable to use an emulsifier that is acceptable for use in food, cosmetics, and / or pharmaceuticals.

[0065] The amount of emulsifier used in this process is, for example, 1 part by weight or more and 9,900 parts by weight or less per 100 parts by weight of coenzyme Q. The lower limit of the amount of emulsifier used per 100 parts by weight of reduced coenzyme Q containing two or more different crystalline forms is, for example, 1 part by weight or more, preferably 3 parts by weight or more, more preferably 5 parts by weight or more, more preferably 8 parts by weight or more, more preferably 10 parts by weight or more, more preferably 15 parts by weight or more, and particularly preferably 20 parts by weight or more. The upper limit of the amount of emulsifier used per 100 parts by weight of reduced coenzyme Q containing two or more different crystalline forms is preferably 5,000 parts by weight or less, more preferably 1,000 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.

[0066] In the mixing / compounding process of this step, the amount of emulsifier used relative to the entire reaction system is not particularly limited, but the lower limit of the amount of emulsifier used is, for example, 0.5% by weight or more, preferably 1% by weight or more, more preferably 3% by weight or more, more preferably 5% by weight or more, more preferably 8% by weight or more, more preferably 10% by weight or more, particularly preferably 14% by weight or more, and most preferably 20% by weight or more, and the upper limit of the amount used is, for example, 99% by weight or less, preferably 70% by weight or less, more preferably 50% by weight or less, more preferably 40% by weight or less, more preferably 30% by weight or less, and particularly preferably 25% by weight or less.

[0067] This process can be carried out in a reaction system that includes a reduced coenzyme Q containing two or more different crystalline forms, an emulsifier, and an antioxidant.

[0068] When an antioxidant is used in this process, the antioxidant is not particularly limited, and any of the above-mentioned types may be used. For example, the antioxidant includes one or more selected from the group consisting of ascorbic acids, ascorbates, erythorbic acids, and erythorbates. The ascorbic acids may be ascorbic acid esters such as palmitate. More preferably, it is one or more selected from the group consisting of ascorbic acid, ascorbates, erythorbic acid, and erythorbates, more preferably one or more selected from ascorbic acid, sodium ascorbate, calcium ascorbate, erythorbic acid, and sodium erythorbate, and particularly preferably one or more selected from sodium ascorbate, calcium ascorbate, and sodium erythorbate.

[0069] When an antioxidant is used in this process, the antioxidant can be used in a ratio of, for example, 1 part by weight or more, preferably 5 parts by weight or more, more preferably 10 parts by weight or more, more preferably 20 parts by weight or more, and particularly preferably 30 parts by weight or more, per 100 parts by weight of coenzyme Q. Alternatively, the antioxidant can be used in a ratio of, for example, 200 parts by weight or less, preferably 150 parts by weight or less, more preferably 100 parts by weight or less, and particularly preferably 50 parts by weight or less, per 100 parts by weight of coenzyme Q.

[0070] When an antioxidant is used in this process, the lower limit of the amount of antioxidant used relative to the entire reaction system is, for example, 1% by weight or more, preferably 5% by weight or more, more preferably 10% by weight or more, more preferably 15% by weight or more, and particularly preferably 20% by weight or more, and the upper limit of the content is, for example, 70% by weight or less, preferably 50% by weight or less, more preferably 40% by weight or less, and particularly preferably 30% by weight or less.

[0071] Furthermore, this process can be carried out in a reaction system that includes a binder in addition to a reduced coenzyme Q containing two or more different crystalline forms, an emulsifier, and optionally an antioxidant. The binder can be used to bind the reduced coenzyme Q containing two or more different crystalline forms, the emulsifier, and optionally an antioxidant to form a composition or mixture.

[0072] When a binder is used in this process, the binder can be used in a ratio of, 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 coenzyme Q. Alternatively, the binder can be used in a ratio of, for example, 200 parts by weight or less, preferably 150 parts by weight or less, more preferably 100 parts by weight or less, more preferably 50 parts by weight or less, even more preferably 30 parts by weight or less, and most preferably 20 parts by weight or less, per 100 parts by weight of coenzyme Q.

[0073] When a binder is used in this process, the lower limit of the amount of binder used relative to the entire reaction system is, for example, 1% by weight or more, preferably 3% by weight or more, and more preferably 5% by weight or more, and the upper limit of the content is, for example, 20% by weight or less, preferably 15% by weight or less, and more preferably 10% by weight or less.

[0074] For example, in this process, a liquid binder can be used to mix or compound the reduced coenzyme Q containing two or more different crystalline forms with an emulsifier. In this case, components other than the liquid binder used for mixing or compounding in this process may be in powder form. Examples of liquid binders include water, ethanol, and aqueous ethanol. Alternatively, some or all of the emulsifier, the aforementioned antioxidant, and / or the aforementioned binder may be dissolved in a liquid such as water, ethanol, or aqueous ethanol to form a liquid binder; however, since this would complicate the process, it is preferable not to dissolve one or more of the emulsifier, reducing agent, and binder in the liquid, and more preferably not to dissolve two or more of the components in the liquid. Water is particularly preferred as the liquid binder. Furthermore, this process may further include a drying step in which the mixed mixture is dried to remove volatile components derived from each raw material component and the liquid binder.

[0075] In this process, other components such as excipients may be used. Preferably, these other components are those that are acceptable as food, cosmetic, and / or pharmaceutical ingredients.

[0076] The composition or mixture obtained by mixing and / or compounding in this process preferably does not contain organic solvents. In this specification, "organic solvent" is a general term for organic compounds that have the property of dissolving other substances. Examples of organic solvents include alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, nitriles, etc., and examples include methanol, acetone, pentane, hexane, heptane, octane, and toluene. The content of organic solvents in the composition or mixture obtained by mixing and / or compounding in this process is, for example, 5% by weight or less, 4% by weight or less, 3% by weight or less, or 2% by weight or less, and preferably 1% by weight or less, 0.5% by weight or less, 0.1% by weight or less, or 0.01% by weight or less.

[0077] This process can be carried out in the presence of terpenes, oils and fats, or ethanol as a non-toxic solvent, but it is more preferable to carry it out in the absence of such a non-toxic solvent in order to keep the oxidized coenzyme Q in a solid state. Examples of the aforementioned non-harmful solvents include hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, cestaterpenes, and triterpenes and their alcohols or other derivatives; coconut oil, palm oil, palm kernel oil, linseed oil, camellia oil, brown rice germ oil, olive oil, rapeseed oil, rice oil, peanut oil, corn oil, wheat germ oil, soybean oil, perilla oil, cottonseed oil, sunflower seed oil, kapok oil, evening primrose oil, shea butter, sal fat, cocoa butter, sesame oil, safflower oil, avocado oil, poppy oil, burdock seed oil, lard, milk fat, fish oil, beef tallow, medium-chain triglycerides, and oils and fats processed by fractionation, hydrogenation, transesterification, etc.; and ethanol. In this process, the content of the non-harmful solvent in the reaction system for reduction is, for example, 50% by weight or less, preferably 40% by weight or less, more preferably 30% by weight or less, more preferably 20% by weight or less, more preferably 10% by weight or less, more preferably 5% by weight or less, more preferably 3% by weight or less, and particularly preferably 1% by weight or less.

[0078] This process is preferably carried out under conditions that do not contain carbonates 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.).

[0079] Furthermore, this process is preferably carried out under conditions that do 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.

[0080] The composition or mixture obtained by mixing and / or compounding in this process is preferably in a solid state. In this specification, "solid state" means a state other than a liquid state or a gaseous state, for example, a state in which it is not dissolved in a solvent. In the composition or mixture obtained by mixing and / or compounding in this process, it is preferable that at least a portion of each of the two types of crystal forms contained in the reduced coenzyme Q, which contains two or more different crystal forms, is not completely dissolved in the solvent, such as water, in order to avoid the loss of crystal forms due to dissolution. For example, even if a solvent such as water is present, it is sufficient if at least a portion of each of the two types of crystal forms exists as crystals. Therefore, it is permissible for the composition or mixture obtained by mixing and / or compounding in this process to contain a solvent.

[0081] The state in which reduced coenzyme Q is not completely dissolved in the solvent refers to a state in which, of the total amount of reduced coenzyme Q, for example, 10% by weight or more, preferably 30% by weight or more, more preferably 50% by weight or more, more preferably 70% by weight or more, more preferably 80% by weight or more, more preferably 90% by weight or more, particularly preferably 95% by weight or more, and most preferably 98% by weight or more, is present in a solid state.

[0082] The reduced coenzyme Q in solid state is preferably in a crystalline state, and the degree of crystallinity of the reduced coenzyme Q is, for example, 30% or more, preferably 50% or more, more preferably 60% or more, more preferably 70% or more, more preferably 80% or more, particularly preferably 90% or more, and most preferably 95% or more, and it is also preferable that it contains two or more crystalline polymorphs.

[0083] The type of solvent included in the reaction system is not particularly limited as long as it does not completely dissolve the reduced coenzyme Q. However, since the solubility of reduced coenzyme Q is low, water or a polar solvent containing water is preferred, water or aqueous ethanol is more preferred, and water is most preferred.

[0084] If the reaction system in this step contains water, the amount of water in the entire reaction system is not particularly limited, but is, for example, 1% by weight or more, preferably 3% by weight or more, and more preferably 5% by weight or more. As an upper limit, for example, 70% by weight or less, preferably 50% by weight or less, more preferably 40% by weight or less, more preferably 30% by weight or less, more preferably 20% by weight or less, and particularly preferably 10% by weight or less. Note that the reaction in this step will proceed without any particular problems even in a dry state with a water content of less than 1% by weight.

[0085] In this process, components other than the reduced coenzyme Q, which contains two or more different crystalline forms, do not necessarily have to be in a solid state. For example, the emulsifier itself may or may not be in a liquid state, but as mentioned above, it is preferable that it be in a liquid state.

[0086] In one embodiment, the composition or mixture obtained by mixing and / or compounding in this process may be a solid composition or solid mixture. The shape of the solid composition or solid mixture may be any shape, such as granular, powdery, or flakey. Granular means any shape formed by the bonding of particles of a material containing two or more different crystalline forms of reduced coenzyme Q and an emulsifier through a granulation operation or the like, and includes granular form. The dimensions of the granular solid composition are not limited, but for example, it may be granules with a longest diameter of 0.10 mm or more and 5.0 mm or less, preferably granules with a longest diameter of 0.20 mm or more and 2.0 mm or less.

[0087] The above-described solid compositions can efficiently produce stable reduced coenzyme Q crystals and have good handling characteristics, even when using liquid, sol, gel, or soft solid emulsifiers. For example, in the case of solid compositions produced by stirring granulation, 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 is observed 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 an opening of 3.0 mm can be used.

[0088] In one embodiment, the step includes pressurizing and / or kneading a mixture or composition containing reduced coenzyme Q containing two or more different crystalline forms and an emulsifier. In this specification, "pressurizing" means applying pressure to a level exceeding 1 atmosphere (atmospheric pressure). In this embodiment, by pressurizing and / or kneading the particles of reduced coenzyme Q containing two or more different crystalline forms and the emulsifier, it becomes possible to produce stable reduced coenzyme Q based on the promotion of crystal form transition in the heat retention step described later.

[0089] In one embodiment, pressurization is performed on a mixture containing reduced coenzyme Q and an emulsifier, which includes two or more different crystalline forms, based on a dry granulation method, tableting, or powder bonding method.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] In one embodiment, this process involves granulating a mixture containing a reduced coenzyme Q having two or more different crystalline forms and an emulsifier by a wet granulation method.

[0094] In this specification, "wet granulation method" refers to a method of drying a wet granule obtained by dropping or spraying water or a binder solution onto a raw material powder and granulating it. The wet granulation method is selected from the group consisting of, for example, agitation granulation, extrusion granulation, fluidized bed granulation, spray granulation, rolling granulation, cold spray method, evaporation method, and liquid curing method.

[0095] The granulated material obtained by any of the above methods can be in any shape, such as granular, powdery, or flakey. Granular means any shape formed by the bonding of particles of a material containing two or more different crystalline forms of reduced coenzyme Q and an emulsifier through a granulation operation, and also includes granular form. The particle size of the granulated material is not particularly limited, but can be, for example, 0.10 mm or more, preferably 0.2 mm or more, more preferably 0.3 mm or more, more preferably 0.5 mm, and / or, for example, 10.0 mm or less, preferably 2.0 mm or less, preferably 1.5 mm or less, more preferably 1 mm or less, more preferably 0.7 mm or less.

[0096] In one embodiment, the two or more different crystalline forms used for mixing / compounding in this step include reduced coenzyme Q crystals obtained by reducing oxidized coenzyme Q in the presence of an emulsifier. In this embodiment, this reduction can be carried out using any reducing agent. For example, any of the antioxidants exemplified above may be used, such as ascorbic acid, ascorbate, erythorbic acid, and erythorbate. In this embodiment, the emulsifier used for reducing oxidized coenzyme Q is also the same as the example described above. For example, reduced coenzyme Q10 crystals (crystals that are not Form II crystals) obtained by reducing oxidized coenzyme Q10 in the presence of an emulsifier, and Form II crystals of reduced coenzyme Q10 may be used as two or more different crystalline forms used for mixing / compounding in this step. In this case, the reduced coenzyme Q10 crystals obtained by reducing oxidized coenzyme Q10 can undergo polymorphic transformation to Form II crystals using Form II crystals as seed crystals.

[0097] (Insulation step) In the method for producing stable reduced coenzyme Q crystals according to this embodiment, the "insulation step" is a step of keeping a composition containing reduced coenzyme Q with two or more different crystal forms and an emulsifier warm. For example, it is a step of keeping the composition obtained in the mixing / compounding step described above warm. This step is an essential step in some embodiments of the method for producing stable reduced coenzyme Q crystals according to this embodiment.

[0098] In this process, the temperature conditions for maintaining the temperature of the composition obtained in the mixing / compounding process are, for example, 0°C or higher, preferably 20°C or higher, more preferably 25°C or higher, more preferably 30°C or higher, more preferably 35°C or higher, particularly preferably 40°C or higher, most preferably 41°C or higher, and for example, 50°C or lower, more preferably 47°C or lower, particularly preferably 45°C or lower. The temperature conditions for maintaining the temperature in this process do not necessarily need to be constant; for example, the temperature may fluctuate within the above temperature range, or it may fluctuate intermittently to stay within the above temperature range. The method for maintaining the temperature of the composition in this process is not particularly limited; for example, methods using devices such as incubators or water baths are possible. Furthermore, temperature control is not necessarily required when maintaining the temperature at room temperature.

[0099] In this process, the humidity conditions for maintaining the temperature of the composition obtained in the mixing / compounding process are not particularly limited, but are, for example, 40% RH or higher, preferably 50% RH or higher or 60% RH or higher, more preferably 65% ​​RH or higher, more preferably 70% RH or higher, and more preferably 80% RH or higher. The upper limit of the humidity conditions is not particularly limited, but are, for example, 100% RH or lower, preferably 90% RH or lower, more preferably 80% RH or lower, more preferably 70% RH or lower, more preferably 60% RH or lower, more preferably 55% RH or lower, more preferably 50% RH or lower, and more preferably 40% RH or lower. From the viewpoint of the stability of reduced coenzyme Q, higher humidity is preferable. Also, from the viewpoint of moisture absorption of the composition subjected to temperature maintenance, lower humidity is preferable.

[0100] In this process, the incubation time is not limited as long as it is the cumulative time required for the reduced coenzyme Q crystal to undergo sufficient polymorphic transformation. For example, the cumulative time can be 1 hour or more, 2 hours or more, 3 hours or more, 6 hours or more, 12 hours or more, 1 day or more, 3 days or more, 5 days or more, 1 week or more, or 2 weeks or more, preferably 3 weeks or more or 1 month or more, more preferably 2 months or more, 3 months or more, or 6 months or more. There is no particular upper limit to the reaction time, but for example, the cumulative time can be 2 years or less, 1 year or less, or 9 months or less. In this process, a longer reaction time is preferable because the transformation can proceed more effectively. Note that the above cumulative time represents the total incubation time, and even if incubation is performed for a shorter time than the above, it is acceptable as long as the cumulative time of each incubation period is within the above range.

[0101] The conditions for maintaining temperature in this process may be either a closed system or an open system, but a closed system is more preferable. Furthermore, if a closed system is used, it may be low-oxygen or oxygen-free. For example, this process may be carried out in or without an oxygen absorber, but when the temperature maintenance period is long, such as one month or more, and / or when an antioxidant is not used, it is more preferable to carry out the process in the presence of an oxygen absorber and / or in an oxygen-deoxidizing atmosphere. Examples of oxygen absorbers include iron-based and organic types, but iron-based ones are preferred. Examples of oxygen absorbers include powder, granules, tablets, and sheets, but powder is preferred. Powdered oxygen absorbers are preferably packaged in packaging material. An oxygen-deoxidizing atmosphere can be achieved by displacement with an inert gas, reduced pressure, boiling, or a combination thereof. At a minimum, displacement with an inert gas, i.e., using an inert gas atmosphere, is preferable. Examples of the above-mentioned inert gases include nitrogen gas, helium gas, argon gas, hydrogen gas, and carbon dioxide gas, with nitrogen gas and / or carbon dioxide gas being preferred, and nitrogen gas being more preferred.

[0102] (Transfer step) In the method for producing stable reduced coenzyme Q crystals according to this embodiment, the "transfer step" is a step of transferring unstable reduced coenzyme Q crystals to stable reduced coenzyme Q crystals in the presence of an emulsifier. This step is an essential step in embodiments of the method for producing stable reduced coenzyme Q crystals according to this embodiment that include a transfer step.

[0103] In this embodiment, "unstable reduced coenzyme Q crystal" and "stable reduced coenzyme Q crystal" mean that the stability of the "stable reduced coenzyme Q crystal" is at least higher in oxidative stability or crystal stability compared to the "unstable reduced coenzyme Q crystal." An example of a combination of "unstable reduced coenzyme Q crystal" and "stable reduced coenzyme Q crystal" is a combination of Form I crystals and Form II crystals of reduced coenzyme Q10.

[0104] In this specification, "transition" refers to a transition of crystal forms. For example, in coenzyme Q, a transition of crystal forms can occur between two or more different crystal forms, even though the number of repeating structures in the side chain remains the same. A preferred transition is one between two or more polymorphic crystal forms. In polymorphic crystals, a relatively less stable crystal form can transition to a relatively more stable crystal form, using the latter as a seed crystal.

[0105] In this specification, "in the presence of an emulsifier" means that unstable reduced coenzyme Q crystals and stable reduced coenzyme Q crystals constitute a composition or mixture together with the emulsifier. In this composition or mixture, it is preferable that the unstable reduced coenzyme Q crystals and stable reduced coenzyme Q crystals are attached to the emulsifier at least at a particle level.

[0106] The specific conditions for this process can be the same as those for the mixing / compounding process and the heat retention process described above. For example, in this process, the conditions described in the mixing / compounding process above as the amount and ratio of two or more different crystal forms can be applied as the amount and ratio of "unstable reduced coenzyme Q crystals" and "stable reduced coenzyme Q crystals." In addition, in this process, the conditions described in the mixing / compounding process and the heat retention process above can also be applied to the type, properties, and amount of emulsifier used. Furthermore, this process can be carried out in the coexistence of an antioxidant, binder, and / or excipient in addition to the emulsifier, and the conditions described in the mixing / compounding process and the heat retention process above can also be applied to the amount and type of these other components used.

[0107] Furthermore, the transition in this process may be carried out using a composition or mixture containing unstable reduced coenzyme Q crystals and stable reduced coenzyme Q crystals and an emulsifier, which has been pressurized and / or kneaded. Alternatively, the composition or mixture may be pressurized by dry granulation, tableting, or powder bonding. Or, the composition or mixture may be granulated by wet granulation, and the wet granulation method may be selected from the group consisting of agitation granulation, extrusion granulation, fluid bed granulation, spray granulation, rolling granulation, cold spray method, evaporation method, and liquid curing method. The conditions for the above processing method can be the same as those for the mixing / compounding process and the heat retention process described above, so a detailed explanation is omitted here.

[0108] In this process, the temperature conditions for the transition are, for example, 0°C or higher, preferably 20°C or higher, more preferably 25°C or higher, more preferably 30°C or higher, more preferably 35°C or higher, particularly preferably 40°C or higher, most preferably 41°C or higher, and for example, 50°C or lower, more preferably 47°C or lower, particularly preferably 45°C or lower. Note that the temperature conditions in this process do not necessarily need to be kept constant; for example, the temperature may fluctuate within the above temperature range, or the temperature may fluctuate intermittently to stay within the above temperature range.

[0109] The time required for the transfer in this process is not limited as long as it is the cumulative time required for the unstable reduced coenzyme Q crystal to sufficiently transfer to the stable reduced coenzyme Q crystal. For example, the cumulative time can be 1 hour or more, 2 hours or more, 3 hours or more, 6 hours or more, 12 hours or more, 1 day or more, 3 days or more, 5 days or more, 1 week or more, or 2 weeks or more, preferably 3 weeks or more or 1 month or more, more preferably 2 months or more, 3 months or more, or 6 months or more. There is no particular upper limit on the time, but for example, the cumulative time can be 2 years or less, 1 year or less, or 9 months or less. In this process, a longer reaction time is preferable because the transfer can proceed more effectively.

[0110] In this process, the humidity conditions for the transfer are not particularly limited, but are, for example, 40% RH or higher, preferably 50% RH or higher or 60% RH or higher, more preferably 65% ​​RH or higher, more preferably 70% RH or higher, and more preferably 80% RH or higher. The upper limit of the humidity conditions is not particularly limited, but is, for example, 100% RH or lower, preferably 90% RH or lower, more preferably 80% RH or lower, more preferably 70% RH or lower, more preferably 60% RH or lower, more preferably 55% RH or lower, more preferably 50% RH or lower, and more preferably 40% RH or lower. From the viewpoint of the stability of reduced coenzyme Q, higher humidity is preferable. Also, from the viewpoint of moisture absorption of the composition subjected to the transfer, lower humidity is preferable.

[0111] The conditions for the transition in this process may be either a closed system or an open system, but a closed system is more preferable. Furthermore, if a closed system is used, it may be low-oxygen or oxygen-free. For example, this process may be carried out in or without an oxygen scavenger, but if the transition period is long, such as one month or more, and / or if an antioxidant is not used, it is more preferable to carry it out in the presence of an oxygen scavenger and in an oxygen-deoxidizing atmosphere. Examples of oxygen scavengers include iron-based and organic types, but iron-based ones are preferred. Examples of dosage forms include powder, granules, tablets, and sheets, but powder is preferred. Powdered forms are preferably packaged in packaging material. An oxygen-deoxidizing atmosphere can be achieved by displacement with an inert gas, reduced pressure, boiling, or a combination thereof. At a minimum, displacement with an inert gas, i.e., using an inert gas atmosphere, is preferable. Examples of the above-mentioned inert gases include nitrogen gas, helium gas, argon gas, hydrogen gas, and carbon dioxide gas, with nitrogen gas and / or carbon dioxide gas being preferred, and nitrogen gas being more preferred.

[0112] The amount of unstable reduced coenzyme Q crystals converted to stable reduced coenzyme Q crystals in the transfer of this step is not particularly limited, but it is preferable that a larger amount of highly stable reduced coenzyme Q crystals are produced. At the end of the transfer of this step, the ratio of highly stable reduced coenzyme Q to the total amount of reduced coenzyme Q crystals is, for example, 10% by weight or more, or 30% by weight or more, preferably 40% by weight or more, preferably 50% by weight or more, preferably 60% by weight or more, particularly preferably 65% ​​by weight or more, particularly preferably 70% by weight or more, particularly preferably 80% by weight or more, particularly preferably 85% by weight or more, and most preferably 90% by weight or more. Furthermore, the proportion of the unstable reduced coenzyme Q crystals at the starting point of the transfer in this process that are transferred to the highly stable reduced coenzyme Q at the endpoint is, for example, 10% by weight or more, or 30% by weight or more, preferably 40% by weight or more, preferably 50% by weight or more, preferably 60% by weight or more, particularly preferably 65% ​​by weight or more, particularly preferably 70% by weight or more, particularly preferably 80% by weight or more, particularly preferably 85% by weight or more, and most preferably 90% by weight or more.

[0113] If the highly stable reduced coenzyme Q10 crystal in this process is a Form II crystal of reduced coenzyme Q10, and the less stable reduced coenzyme Q10 crystal is a Form I crystal of reduced coenzyme Q10, then the ratio of Form II crystals to 100 parts by weight of Form I crystals at the end of the transition in this process is, for example, 10 parts by weight or more, or 30 parts by weight or more, preferably 50 parts by weight or more, more preferably 100 parts by weight or more, particularly preferably 200 parts by weight or more, particularly preferably 280 parts by weight or more, particularly preferably 400 parts by weight or more, and most preferably 900 parts by weight or more.

[0114] When Form II crystals of reduced coenzyme Q10 are produced by the manufacturing method of this embodiment, it is preferable that the oxidative stability of the produced Form II crystals of reduced coenzyme Q10 is high. After isolating the Form II crystals of reduced coenzyme Q10 produced by the transfer step or heat retention step, etc., of this embodiment from the composition by the method described later and storing them at 40°C / 75% RH for 28 days, the QH remaining percentage is, for example, 85% or more, preferably 90% or more, more preferably 92% or more, particularly preferably 93% or more, and most preferably 93.6% or more.

[0115] When Form II crystals of reduced coenzyme Q10 are produced by the manufacturing method of this embodiment, from the viewpoint of texture in food and cosmetics, it is preferable that the melting point of the produced Form II crystals of reduced coenzyme Q10 be low. When Form II crystals of reduced coenzyme Q10 produced by the transfer step or heat retention step, etc. of this embodiment are isolated from the composition by the method described later and DSC measurement (sample amount 8 ± 1 mg, heating rate 1 °C / min) is performed, the maximum melting point (the point at which the DSC is lowest, i.e., the peak top temperature) is, for example, less than 54.0 °C, preferably less than 53.5 °C, more preferably less than 53.0 °C, more preferably 52.7 °C or lower, particularly preferably 52.5 °C or lower, and most preferably 52.3 °C or lower.

[0116] Form II crystals of reduced coenzyme Q10 produced by the manufacturing method of this embodiment tend to show a relatively high peak intensity at 2.2° in XRD measurements. Specifically, when XRD measurements (reflection method) are performed under the following XRD measurement conditions, the peak intensity at 2.2° tends to be, for example, 0.7 times or more, 0.8 times or more, or 0.85 times or more compared to the peak intensity at 4.3°, and the peak intensity at 2.2° tends to be, for example, 0.6 times or more, 0.7 times or more, 0.8 times or more, or 0.9 times or more compared to the peak intensity at 6.4°. Since these tendencies differ from those of conventional Form II crystals of reduced coenzyme Q10, it can be presumed that Form II crystals of reduced coenzyme Q10 having the above characteristics were produced by the manufacturing method of this embodiment.

[0117] XRD measurement conditions: Equipment: Rigaku MiniFlex II X-rays used: Cu-Kα rays Intensity: 30kV, 15mA Scanning speed: 2° / min Divergence slit: 0.625° Scattering slit: 1.25° Receiving slit: 0.3mm

[0118] (Removal step) In the method for producing stable reduced coenzyme Q crystals according to this embodiment, the "removal step" is a step of removing an emulsifier from the stable reduced coenzyme Q crystals obtained in the above-described heat retention step or transfer step. This step is a selective step.

[0119] In this process, the method for removing the emulsifier is not particularly limited, and any method that can reduce the emulsifier content from the composition, mixture, or granules, etc., containing the stable reduced coenzyme Q crystals and emulsifier obtained in the above-mentioned heat retention step or transfer step is acceptable. For example, methods include adding or spraying a solvent such as water or ethanol onto the composition to dissolve the emulsifier, dispersing the composition in a solvent to dissolve the emulsifier, washing the stable reduced coenzyme Q crystals, or removing the dissolved emulsifier by methods such as decantation or aspiration. In addition, the emulsifier can be preferentially removed using methods such as filtration, centrifugation, membrane separation, or precipitation. When dispersing the composition in a solvent, methods such as dispersing by applying mechanical force, dispersing using media, and / or dispersing using ultrasound can also be used. The type of solvent is not particularly limited as long as it does not completely dissolve the reduced coenzyme Q. However, since the solubility of reduced coenzyme Q is low, water or a polar solvent containing water is preferred, water or aqueous ethanol is more preferred, and aqueous ethanol is most preferred. It is also permissible to use a combination of two or more solvents.

[0120] 1-4. Effects According to the manufacturing method of this embodiment, stable reduced coenzyme Q crystals, such as Form II crystals of reduced coenzyme Q10, can be produced at low cost and in a simple manner in the presence of an emulsifier. Furthermore, unlike conventional methods, according to the manufacturing method of this embodiment, stable reduced coenzyme Q crystals, such as Form II crystals of reduced coenzyme Q10, can be produced without the presence of harmful organic solvents. Therefore, the stable reduced coenzyme Q crystals obtained by this method can be directly added to pharmaceuticals, cosmetics, foods, or beverages. Consequently, there is no need for a step to separate the stable reduced coenzyme Q crystals from the solvent, overcoming the problems of conventional methods such as the cost of separation and the decrease in the yield of stable reduced coenzyme Q crystals. In addition, according to the manufacturing method of this embodiment, Form II crystals of reduced coenzyme Q10, which have relatively high oxidative stability, can be obtained. Conventionally, obtaining Form II crystals of reduced coenzyme Q10, which have relatively high oxidative stability, required complicated methods. However, the manufacturing method of this embodiment makes it possible to obtain these crystals more simply. Furthermore, the manufacturing method of this embodiment makes it possible to produce Form II crystals of reduced coenzyme Q10 that have high oxidative stability and a relatively low melting point. High oxidative stability and a low melting point are usually a trade-off, but the manufacturing method of this embodiment eliminates this trade-off, thereby providing a new option for low-melting-point materials in Form II crystals of reduced coenzyme Q10 with high oxidative stability. For example, in the fields of food and cosmetics, various materials such as oils and fats with different melting points have been developed to modify the texture when ingested or applied, and the present invention can expand the range of materials applicable to food and cosmetics.

[0121] 2. Method for Producing a Composition Containing Stable Reduced Coenzyme Q Crystals and an Emulsifier 2-1. Overview A second aspect of the present invention is a method for producing a composition containing stable reduced coenzyme Q crystals and an emulsifier (in this specification, this may be referred to as "method for producing a composition").

[0122] 2-2. Method The method for producing the composition of this embodiment includes a transfer step as an essential step and a mixing / compounding step and a removal step as optional steps. Each step will be described below.

[0123] (Mixing / Combining Process) In the method for producing the composition of this embodiment, the "mixing / combining process" is a process of mixing and / or combining reduced coenzyme Q, which includes stable reduced coenzyme Q crystals and unstable reduced coenzyme Q crystals, with an emulsifier. The specific conditions of this process are the same as those described in the "mixing / combining process" of the first embodiment, so a detailed explanation is omitted here.

[0124] (Transfer step) In the method for producing the composition according to this embodiment, the "transfer step" is a step in which, in a composition containing stable reduced coenzyme Q crystals, unstable reduced coenzyme Q crystals, and an emulsifier, the crystalline form of the unstable reduced coenzyme Q crystals is transferred to a stable crystalline form using the stable reduced coenzyme Q crystals as a seed crystal. This step is an essential step.

[0125] In this process, the specific types of unstable reduced coenzyme Q crystals and stable reduced coenzyme Q crystals are not particularly limited, as long as the stability of the stable reduced coenzyme Q crystals is higher than that of the unstable reduced coenzyme Q crystals, at least in terms of oxidative stability or crystallographic stability.

[0126] In one embodiment, stable reduced coenzyme Q crystals have higher oxidative stability than unstable reduced coenzyme Q crystals. An example of such a crystal combination is a combination of Form I and Form II crystals of reduced coenzyme Q10.

[0127] Further specific conditions for this process can be based on the conditions for the transition process in the first embodiment, so a detailed explanation is omitted here.

[0128] (Removal Step) In the method for producing the composition of this embodiment, the "removal step" is a step of removing the emulsifier from the stable reduced coenzyme Q crystals obtained in the transfer step described above. This step is a selective step. The specific conditions of this step are the same as those described in the "removal step" in the first embodiment, so a detailed explanation is omitted here.

[0129] 3. Method for manufacturing pharmaceuticals, cosmetics, food or beverages 3-1. Overview The third aspect of the present invention is a method for manufacturing pharmaceuticals, cosmetics, food or beverages (in this specification, it may be referred to as "method for manufacturing pharmaceuticals, etc.").

[0130] 3-2. Method The method for producing pharmaceuticals, etc. according to this embodiment involves producing a stable reduced coenzyme Q crystal using a composition produced by any of the methods described in the second embodiment, or a stable reduced coenzyme Q crystal produced by any of the methods described in the first embodiment. For example, the method for producing pharmaceuticals, etc. according to this embodiment includes a step of adding a composition produced by any of the methods described in the second embodiment, or a stable reduced coenzyme Q crystal produced by any of the methods described in the first embodiment, to a pharmaceutical, cosmetic, food, or beverage during the manufacturing process. Pharmaceuticals, cosmetics, food, or beverages produced by the manufacturing method according to this embodiment are not limited as long as they contain reduced coenzyme Q, and examples include pharmaceuticals, cosmetics, food, or beverages containing reduced coenzyme Q as a main component, or pharmaceuticals, cosmetics, food, or beverages containing reduced coenzyme Q as an auxiliary component.

[0131] Pharmaceuticals, cosmetics, foods, or beverages manufactured by the manufacturing method of this embodiment are not particularly limited. Examples of pharmaceuticals include veterinary drugs, medicinal drugs, therapeutic drugs, and preventive drugs. Examples of foods include nutritional functional foods, foods for specified health uses, foods with functional claims, nutritional supplements, nutritional supplements, confectionery, animal feed, and pet food. Examples of beverages include nutritional supplement beverages.

[0132] Pharmaceuticals, cosmetics, foods, or beverages produced by the manufacturing method of this embodiment may, as necessary, contain excipients, disintegrants, lubricants, binders, antioxidants, colorants, fragrances, sweeteners, acidulants, pH adjusters, anti-coagulation agents, absorption enhancers, solubilizers, stabilizers, viscosity modifiers, oils and fats, surfactants, or other active ingredients other than reduced coenzyme Q, which are permissible for the respective uses of pharmaceuticals, cosmetics, foods, or beverages. Examples of such other active substances include amino acids, vitamins, minerals, polyphenols, organic acids, sugars, peptides, and proteins.

[0133] The present invention will be described in more detail below using examples. However, the technical scope of the present invention is not limited to these examples.

[0134] <1. Raw Materials> In the following examples, reduced coenzyme Q10 manufactured by Kaneka Corporation (product name: Kaneka QH) was used as reduced coenzyme Q10 Form I crystal (QHForm I). In addition, as emulsifiers, Q-17D (compound name: diglycerin monooleate, product name: Sunsoft Q-17D, manufacturer: Taiyo Kagaku Co., Ltd., HLB: 7), O-120V (compound name: polyoxyethylene sorbitan monooleate, product name: Emazol O-120V, manufacturer: Kao Corporation, HLB: 15), O-170 (compound name: sucrose oleate, product name: Ryoto (trademark) sugar ester O-170, manufacturer: Mitsubishi Chemical Corporation, HLB: 1), G-002 (compound name: glycerin diacetomolaurate, product name: Poem (registered trademark) G-0 02. (Manufacturer: Riken Vitamin Co., Ltd., HLB: 2), TF-60 (Compound name: Polyoxyethylene sorbitan monostearate, Product name: Willsurf® TF-60, Manufacturer: NOF Corporation, HLB: 15.7), PO-100V (Compound name: Propylene glycol monooleate, Product name: Rikemar PO-100V, Manufacturer: Riken Vitamin Co., Ltd., HLB: 3.6), and S-570 (Compound name: Sucrose stearate ester, Product name: Ryoto® Sugar Ester S-570, Manufacturer: Mitsubishi Chemical Corporation, HLB: 5) were used.

[0135] <2. 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. The solution was then cooled, and when it reached 36.5°C, reduced coenzyme Q10 Form II crystals prepared according to the description in Patent Document (WO2012 / 176842) were added as seed crystals. This solution was gradually cooled to 2°C to obtain a white slurry. 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 QHFormII.

[0136] <3. Method for Analyzing the QHFormII Ratio> Except for Examples H, I, and J, Comparative Example D, and Examples K and L, DSC measurements were performed under the following conditions. From the height of the endothermic peak of QHFormI (I-Y difference) and the height of the endothermic peak of QHFormII (II-Y difference) obtained by DSC analysis, the ratio of QHFormII was calculated according to the following formula: QHFormII ratio % = 100 × (II-Y difference) / ((I-Y difference) + (II-Y difference)) In Examples H, I, and J, Comparative Example D, and Examples K and L, DSC measurements were performed under the following conditions. From the area value of the endothermic peak of QHFormI (I-area value) and the area value of the endothermic peak of QHFormII (II-area value) obtained by DSC analysis, the ratio of QHFormII was calculated according to the following formula. QHFormII ratio (%) = 100 × (II - area value) / ((I - area value) + (II - area value)) In addition to Examples H, I, and J, Comparative Example D, and Examples K and L, the QHFormII ratio was calculated using the above formula with the area value and it was confirmed that the value was approximately the same as the QHFormII ratio calculated using the formula with the Y difference. The following conditions were used for DSC measurement: Apparatus: DSC200 (Hitachi High-Tech) Sample container: Aluminum pan & cover (GCA-0052) Heating rate: 1℃ / min Sample amount: 4±2 mg

[0137] <4. Evaluation Method by XRD> Powder X-ray diffraction (XRD) analysis was performed under the following conditions. The XRD analysis was performed using the reflection method. (XRD Measurement Conditions) Apparatus: Rigaku MiniFlex II X-rays used: Cu-Kα rays Intensity: 30kV, 15mA Scanning speed: 2° / min Divergence slit: 0.625° Scattering slit: 1.25° Receiving slit: 0.3mm

[0138] <5. Method for Analyzing the 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. (HPLC analysis conditions) Column: SYMMETRY C18 (Waters) 250 mm (length) 4.6 mm (inner diameter) Mobile phase: C ２ H ５ OH:CH ３ OH = 4:3 (v:v) Detection wavelength: 210 nm Flow rate: 1 mL / min

[0139] <6. Evaluation Method for Oxidation Stability> The QH ratio at the end of the evaluation, with the QH ratio at the start of the evaluation set to 100, was defined as the "QH retention rate," and the QH retention rate calculated from the following formula was used as a measure of oxidation stability. QH Retention Rate (%) = 100 × QH Ratio at End of Evaluation / QH Ratio at Start of Evaluation

[0140] <Example A> 2.0 g of QHFormI, 2.0 g of QHFormII, and 1.0 g of Q-17D as an emulsifier were used as raw materials and kneaded while adding water. After drying the resulting composition, it was crushed to obtain a granular solid composition. The obtained composition was placed in an aluminum laminate bag together with an oxygen absorber (Ageless ZJ-15PT), and heat-sealed and sealed. The prepared package was stored in a constant temperature bath at 40°C for 7 days or 31 days, after which the composition was removed. The results of DSC analysis of the removed composition are shown in Figure 1. Analysis of the QHFormII ratio after storage showed that it was 69% after 7 days of storage and 100% after 31 days of storage. Furthermore, XRD analysis of the sample after 31 days of storage showed a peak at a position characteristic of QHFormII as shown in Patent Document 1.

[0141] <Example B> 0.5 g of the sample obtained in Example A after 31 days of storage was placed in a 50 mL centrifuge tube. 40 mL of water was added and vortex suspension was performed, followed by centrifugation (5000 × g, 2 min) and removal of the supernatant. Subsequently, 40 mL of an ethanol aqueous solution containing 20% ​​by weight of ethanol was added and vortex suspension was performed, followed by centrifugation (5000 × g, 2 min) to remove the supernatant, and this procedure was repeated twice. The obtained wet crystals were vacuum dried to obtain dry crystals of QHFormII.

[0142] <Example C> QHForm II obtained by conventional methods according to the above manufacturing method, the composition of Example A after 31 days of storage, and the QHForm II dried crystals of Example B were stored in an open system in a constant temperature bath at 40°C / 75%RH or 25°C / 60%RH for 28 days, and the QH retention rate was examined. The results are shown in Table A.

[0143]

[0144] The results from Example C showed that QHFormII produced in the presence of an emulsifier exhibited significantly higher oxidation stability compared to QHFormII produced by conventional methods.

[0145] <Reference Example A> To obtain QHForm II with high oxidation stability, crystallization of QHForm II was performed according to patent document (WO2024 / 204380). More specifically, during the cooling crystallization process, the temperature was repeatedly lowered and raised under strict temperature control to redissolve and reprecipitate a portion of the precipitated crystals, and then the crystals were completely precipitated by cooling again. The obtained crystals were vacuum dried to obtain QHForm II crystals. When the oxidation stability of the obtained crystals was examined, the QH retention rate after 28 days of storage at 40°C / 75%RH was 91.6%.

[0146] <Example D> QHFormII obtained by conventional methods according to the above manufacturing method, the QHFormII dry crystals of Example B, and the QHFormII of Reference Example A were used as samples, and DSC measurements were performed (sample amount 8 ± 1 mg, heating rate 1 °C / min). The peak top temperature in the DSC measurement results for each sample and the QH retention rate after storage at 40 °C / 75% RH for 28 days are shown in Table B.

[0147]

[0148] As described in WO2024 / 204380, it was generally accepted that QHFormII with a DSC peak top temperature of 53.0°C or higher has high oxidation stability. However, the results in Table B show that the QHFormII obtained in this invention has the characteristic of being extremely stable even though its DSC peak top temperature is less than 53.0°C.

[0149] <Example E> 3.0 g of QHFormI, 3.0 g of QHFormII, and 1.5 g of Q-17D as an emulsifier were mixed using a coffee grinder. The resulting mixture was placed in a tabletop tablet press equipped with an 8 mmΦ mortar and pestle and compressed with a pressure of 10 kN. The resulting tablets were crushed in a mortar to obtain a dry-granulated granular solid composition. The obtained composition was placed in an aluminum laminate bag together with an oxygen absorber (Ageless ZJ-15PT), and heat-sealed and sealed. The prepared packaging was stored in a constant temperature bath at 40°C for 5 days or 28 days, after which the composition was removed. Analysis of the QHFormII ratio after storage showed that it was 74% after 5 days of storage and 100% after 28 days of storage. Furthermore, XRD analysis of the sample after 28 days of storage revealed a peak at a position characteristic of QHFormII.

[0150] <Example F> 2.7 g of QHFormI, 0.9 g of QHFormII, and 0.9 g of Q-17D as an emulsifier were used as raw materials and kneaded while adding water. After drying the resulting composition, it was crushed to obtain a granular solid composition. The obtained composition was placed in an aluminum laminate bag together with an oxygen absorber (Ageless ZJ-15PT), and heat-sealed and sealed. The prepared package was stored in a constant temperature bath at 40°C for 33 days, after which the composition was removed. The QHFormII ratio after storage was 100%. Furthermore, XRD analysis was performed on the stored sample, and a peak characteristic of QHFormII was observed.

[0151] <Comparative Example A> A mixed powder was obtained by mixing 0.15 g of QHFormI and 0.05 g of QHFormII.

[0152] <Comparative Example B> 0.15 g of QHFormI, 0.05 g of QHFormII, and 0.05 g of Q-17D as an emulsifier were used as raw materials and kneaded while adding water. After drying the resulting composition, a granular solid composition was obtained by crushing it.

[0153] <Example G> The composition of Example F, the mixed powder of Comparative Example A, and the composition of Comparative Example B were stored in an open system in a constant temperature bath at 25°C / 60% RH for 28 days, and the QH remaining rate was examined. The results are shown in Table C.

[0154]

[0155] The results in Table C show that by performing a transfer treatment at a certain temperature or higher in the presence of an emulsifier, a composition containing reduced coenzyme Q10 crystals with high oxidative stability can be obtained using reduced coenzyme Q10 crystals with low oxidative stability as a raw material.

[0156] <Example R> 2.0 g of oxidized coenzyme Q10 crystals (product name: Kaneka Coenzyme Q10, manufacturer: Kaneka Corporation), 2.0 g of QHForm II, 1.5 g of sodium ascorbate as a reducing agent, 1.0 g of Q-17D as an emulsifier, and 0.5 g of hydroxypropyl cellulose as a binder were used as raw materials and kneaded in a beaker while adding 0.4 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. The obtained composition was placed in a poly resealable bag, and together with an oxygen absorber (Ageless ZJ-15PT), it was placed in an aluminum laminate bag and heat-sealed. After storing the prepared package in a constant temperature bath at 40°C for one month, the QH ratio in the composition was analyzed by HPLC and found that 87.5% of the oxidized coenzyme Q10 had been converted to reduced coenzyme Q10.

[0157] <Example S> The composition of Example R was thoroughly washed with water and aqueous ethanol and dried to obtain coenzyme Q10 crystals. XRD analysis was performed using the obtained coenzyme Q10 crystals, and a peak was observed at a position characteristic of QHFormII as shown in Patent Document 1.

[0158] The results from Example S showed that by incorporating QHFormII into a composition capable of solid-phase reduction of oxidized coenzyme Q10, oxidized coenzyme Q10 is solid-phase reduced and transferred to QHFormII.

[0159] <Example T> The composition of Example R was stored in an open system in a constant temperature bath at 25°C / 60% RH for 3 months. The QH retention rate after storage was 99.6%.

[0160] <Comparative Example C> 1.0 g of QHFormII, 1.0 g of sodium ascorbate as a reducing agent, 0.2 g of Q-17D as an emulsifier, and 0.2 g of hydroxypropylcellulose as a binder were used as raw materials and kneaded in a beaker while adding water. The resulting kneaded mixture was extruded and granulated using a 1.2 mmΦ screen and dried to obtain a granular solid composition. The obtained composition was stored in an open system in a constant temperature bath at 25°C / 60% RH for 3 months. The QH retention rate after storage was 98.7%.

[0161] The results from Example T and Comparative Example C showed that QHFormII obtained by solid-phase reduction from oxidized coenzyme Q10 crystals and solid-phase transition to QHFormII exhibited higher oxidative stability than QHFormII produced by conventional methods. Utilizing this, it was possible to produce a reduced coenzyme Q10 composition with extremely high oxidative stability using oxidized coenzyme Q10 as a raw material.

[0162] <Example H> 1.0 g of QHFormI, 1.0 g of QHFormII, and 0.86 g of Q-17D as an emulsifier were used as raw materials and kneaded while adding water. After drying the obtained composition, it was crushed to obtain a granular solid composition. The obtained composition was packed into an aluminum laminate bag under deoxygenated conditions and heat-sealed. The prepared package was stored in a constant temperature bath at 30°C for 7 days, after which the composition was removed (Example H-1). Similarly, the prepared package was stored in a constant temperature bath at 35°C for 7 days, after which the composition was removed (Example H-2). When the QHFormII ratio of the removed compositions was analyzed, all samples had a QHFormII ratio of 100%. Furthermore, when XRD analysis was performed on the stored samples, a peak was observed at a position characteristic of QHFormII as shown in Patent Document 1.

[0163] <Example I> A package prepared in the same manner as in Example H was stored in a constant temperature bath at 41°C for one or two days, after which the composition was removed. Analysis of the QHFormII ratio of the removed composition revealed that all samples stored for both periods had a QHFormII ratio of 100%. Furthermore, XRD analysis was performed on the stored samples, and a peak was observed at a position characteristic of QHFormII as shown in Patent Document 1.

[0164] <Example J> 1.0 g of QHForm I, 1.0 g of QHForm II, and 0.5 g of the emulsifier listed in Table D were used as raw materials and kneaded while adding water. After drying the resulting composition, it was crushed to obtain a granular solid composition. The obtained composition was packed into an aluminum laminate bag under deoxygenation conditions and heat-sealed. The prepared package was stored in a constant temperature bath at 40°C for 7 or 28 days, after which the composition was removed and the QHForm II ratio was analyzed. The results are shown in Table D. Furthermore, XRD analysis was performed on a sample showing a QHForm II ratio of 100%, and a peak was observed at a position characteristic of QHForm II as shown in Patent Document 1.

[0165] <Comparative Example D> 1.0 g of QHForm I and 1.0 g of QHForm II were used as raw materials and kneaded while adding water. After drying the resulting composition, it was crushed to obtain a granular solid composition. The obtained composition was packed into an aluminum laminate bag under deoxygenated conditions and heat-sealed and sealed. The prepared package was stored in a constant temperature bath at 40°C for 7 days, and then the composition was removed and the QHForm II ratio was analyzed. The results are shown in Table D.

[0166]

[0167] Table D shows that various emulsifiers promote the transition to QHFormII.

[0168] <Example K> 1.0 g of QHForm I, 1.0 g of QHForm II, and the amount of emulsifier listed in Table E were used as raw materials and kneaded while adding water. After drying the resulting composition, it was crushed to obtain a granular solid composition. The obtained composition was packed into an aluminum laminate bag under deoxygenation conditions and heat-sealed. The prepared package was stored in a constant temperature bath at 40°C for 7 or 28 days, after which the composition was removed and the QHForm II ratio was analyzed. The results are shown in Table E. Furthermore, XRD analysis was performed on a sample showing a QHForm II ratio of 100%, and a peak was observed at a position characteristic of QHForm II as shown in Patent Document 1.

[0169]

[0170] Table E shows that adding an emulsifier of 5% by weight or more is sufficient to promote the transition to QHFormII.

[0171] <Example L> 2.0 g of QHFormI, the amount of QHFormII listed in Table F, and the amount of emulsifier O-120V listed in Table F were used as raw materials and kneaded while adding water. After drying the obtained composition, it was crushed to obtain a granular solid composition. The obtained composition was packed into an aluminum laminate bag under deoxygenation conditions and heat-sealed. The prepared package was stored in a constant temperature bath at 40°C for 7 or 28 days, and then the composition was removed and the QHFormII ratio was analyzed. The results are shown in Table F. Furthermore, XRD analysis was performed on a sample showing a QHFormII ratio of 100%, and a peak was observed at a position characteristic of QHFormII as shown in Patent Document 1.

[0172]

[0173] Table F shows that adding 0.1% by weight or more of QHFormII as seed crystals is sufficient to enable the transfer of QHFormI to QHFormII.

[0174] Figure 2 shows the XRD measurement results (in the range of 2θ = 2 to 7°) for samples in Examples H to L where the QHFormII ratio was 100% after 7 days of storage. Additionally, XRD measurements were performed on samples from Example I that had been stored for 2 days and washed twice with 100 times the amount of pure water. The results are shown as "Example I-2d_Water Washed". For reference, the measurement results for QHFormII and QHFormI are also shown.

[0175] As shown in Figure 2, in the sample where the QHFormII ratio was 100% in the DSC analysis, a peak characteristic of QHFormII was observed. On the other hand, compared to QHFormII, the sample of the example showed a tendency for a relatively higher peak intensity at 2.2°. The peak intensities at 2.2°, 4.3°, and 6.4° (maximum values ​​within the range of ±0.2°) were determined, and the ratio of the peak intensity at 2.2° to the peak intensity at 4.3° or 6.4° was calculated, and the results are shown in Table G.

[0176]

[0177] Table G shows that QHFormII produced by the method of the example tends to have a relatively high peak intensity at 2.2°, and the peak intensity at 2.2° tends to be 0.7 times or more compared to the peak intensity at 4.3° when XRD measurement is performed by the method described above, and the peak intensity at 2.2° tends to be 0.6 times or more compared to the peak intensity at 6.4°.

[0178] The upper and / or lower limits of the numerical ranges described herein can be arbitrarily combined to define a preferred range. For example, the upper and lower limits of a numerical range can be arbitrarily combined to define a preferred range, the upper limits of a numerical range can be arbitrarily combined to define a preferred range, and the lower limits of a numerical range can be arbitrarily combined to define a preferred range. Furthermore, in this application, a numerical range represented using the symbol "~" includes the numerical values ​​written before and after the symbol "~" as the lower and upper limits, respectively.

[0179] Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Therefore, singular articles (for example, "a," "an," and "the" in English) should be understood to include the concept of their plural form unless otherwise specified.

[0180] Although this embodiment has been described in detail above, the specific configuration is not limited to this embodiment, and any design changes that do not depart from the gist of this disclosure are included in this disclosure. All publications, patents and patent applications referenced herein are incorporated herein by direct reference.

Claims

1. A method for producing stable reduced coenzyme Q crystals, comprising a heating step of heating a composition containing reduced coenzyme Q having two or more different crystal forms and an emulsifier.

2. The method according to claim 1, comprising a mixing / compounding step of mixing and / or compounding a reduced coenzyme Q containing two or more different crystalline forms with an emulsifier before the heat retention step.

3. The method according to claim 2, wherein each of the two or more different crystalline forms subjected to the mixing / compounding step is 0.1% by weight or more of the total amount of coenzyme Q.

4. The method according to claim 1, wherein the composition is kept at 30°C to 50°C during the heat retention process.

5. The method according to claim 4, wherein the composition is kept warm for a total of 12 hours or more during the heat retention process.

6. The method according to claim 2, wherein the compounding comprises pressurization and / or kneading.

7. The method according to claim 6, wherein the mixing / compounding step includes pressurizing a mixture containing reduced coenzyme Q and an emulsifier by dry granulation, tableting, or powder bonding.

8. The method according to claim 2, wherein the mixing / compounding step comprises granulating a mixture containing reduced coenzyme Q and an emulsifier by a wet granulation method.

9. The method according to claim 8, wherein the wet granulation method is selected from the group consisting of agitation granulation, extrusion granulation, fluid bed granulation, spray granulation, rolling granulation, cold spray method, evaporation method, and liquid curing method.

10. The method according to claim 1, wherein the emulsifier is in liquid, sol, gel, or soft solid form.

11. The method according to claim 1, wherein the emulsifier is a polyol fatty acid ester having at least one of the following characteristics (1) to (4): (1) comprising an ester of an unsaturated fatty acid; (2) being a polyoxyethylene sorbitan fatty acid ester; (3) being a (poly)glycerin fatty acid ester having at least one of the following characteristics (a) to (d): (a) comprising an ester of a fatty acid having 8 or fewer carbon atoms; (b) comprising an ester of a fatty acid having 2 or more glycerin units and 9 to 14 carbon atoms; (c) comprising an ester of a fatty acid having 5 or more glycerin units and 15 to 18 carbon atoms; (d) comprising an ester of an unsaturated fatty acid; (4) comprising an ester of a saturated fatty acid having 14 or fewer carbon atoms, and excluding polyoxyethylene sorbitan fatty acid esters and (poly)glycerin fatty acid esters.

12. The method according to claim 11, wherein the emulsifier has at least the characteristics of (3) above.

13. The method according to claim 12, wherein the emulsifier is diglyceryl monooleate.

14. The method according to claim 11, wherein the emulsifier has at least the characteristics of (2) above.

15. The method according to claim 11, wherein the emulsifier is a propylene glycol fatty acid ester.

16. The method according to claim 1, wherein the two or more different crystal forms include reduced coenzyme Q crystals obtained by reducing oxidized coenzyme Q in the presence of an emulsifier.

17. The method according to claim 16, wherein the reduction is carried out using one or more reducing agents selected from the group consisting of ascorbic acids, ascorbates, erythorbic acids, and erythorbates.

18. A method for producing stable reduced coenzyme Q crystals, comprising a transfer step of transferring unstable reduced coenzyme Q crystals to stable reduced coenzyme Q crystals in the presence of an emulsifier.

19. The method according to claim 18, wherein the emulsifier used in the transition step is in a liquid state, sol state, gel state, or soft solid state.

20. The method according to claim 18, wherein the emulsifier is a polyol fatty acid ester having at least one of the following characteristics (1) to (4): (1) comprising an ester of an unsaturated fatty acid; (2) being a polyoxyethylene sorbitan fatty acid ester; (3) being a (poly)glycerin fatty acid ester having at least one of the following characteristics (a) to (d): (a) comprising an ester of a fatty acid having 8 or fewer carbon atoms; (b) comprising an ester of a fatty acid having 2 or more glycerin units and 9 to 14 carbon atoms; (c) comprising an ester of a fatty acid having 5 or more glycerin units and 15 to 18 carbon atoms; (d) comprising an ester of an unsaturated fatty acid; (4) comprising an ester of a saturated fatty acid having 14 or fewer carbon atoms, and excluding polyoxyethylene sorbitan fatty acid esters and (poly)glycerin fatty acid esters.

21. The method according to claim 20, wherein the emulsifier has at least the characteristics of (3) above.

22. The method according to claim 21, wherein the emulsifier is diglyceryl monooleate.

23. The method according to claim 20, wherein the emulsifier has at least the characteristics of (2) above.

24. The method according to claim 20, wherein the emulsifier is a propylene glycol fatty acid ester.

25. The method according to claim 18, wherein, in the transfer step, an unstable reduced coenzyme Q crystal is transferred to a stable reduced coenzyme Q crystal at 30°C to 50°C.

26. The method according to claim 25, wherein the transition process is carried out for a cumulative total of 12 hours or more.

27. The method according to claim 18, wherein the transition step is carried out under humidity conditions of 60% RH or higher.

28. A method for producing stable reduced coenzyme Q crystals, comprising a removal step of removing an emulsifier from stable reduced coenzyme Q crystals obtained by the method according to claim 1 or 18.

29. A method for producing a composition comprising a stable reduced coenzyme Q crystal and an emulsifier, the method comprising a transfer step in which the crystalline form of the unstable reduced coenzyme Q crystal is transferred to a stable crystalline form using the stable reduced coenzyme Q crystal as a seed crystal in the composition comprising a stable reduced coenzyme Q crystal, an unstable reduced coenzyme Q crystal, and an emulsifier.

30. The method according to claim 29, wherein the stable reduced coenzyme Q crystal has higher oxidative stability than the unstable reduced coenzyme Q crystal.

31. A method for producing a pharmaceutical, cosmetic, food, or beverage containing a stable reduced coenzyme Q crystal using a composition produced by the method described in claim 29.

Images