Solid composition containing co-crystal of reduced coenzyme q10

Abstract

The present specification discloses a means for suppressing a decrease in reduced coenzyme Q10 due to oxidation during the storage of a solid composition containing a co-crystal of reduced coenzyme Q10.　One or more embodiments of the present invention relate to a solid composition containing a co-crystal of reduced coenzyme Q10, an emulsifying agent, and an antioxidant. One or more other embodiments of the present invention relate to a method for producing a granular solid composition containing a co-crystal of reduced coenzyme Q10, an emulsifying agent, an antioxidant, and a binding agent, the method comprising granulating a mixture including the co-crystal of reduced coenzyme Q10, the emulsifying agent, the antioxidant, the binding agent, and a liquid binder.

Description

Solid composition containing cocrystal of reduced coenzyme Q10

[0001] One or more embodiments of the present invention relate to a solid composition containing a co-crystal of reduced coenzyme Q10.

[0002] One or more other embodiments of the present invention relate to a method for producing a granular solid composition containing a co-crystal of reduced coenzyme Q10.

[0003] Coenzyme Q is an essential component widely distributed in living organisms, from bacteria to mammals, and is known as a component of the mitochondrial electron transport chain in living cells. In humans, the main component is coenzyme Q10, which has 10 repeating side chains of coenzyme Q, and in living organisms, approximately 40 to 90% of it is usually present in the reduced form. The physiological effects of coenzyme Q include activating energy production by activating mitochondria, activating cardiac function, stabilizing cell membranes, and protecting cells through its antioxidant properties.

[0004] Most of the coenzyme Q10 currently manufactured and sold is oxidized coenzyme Q10, but in recent years, reduced coenzyme Q10 (hereinafter sometimes referred to as "QH"), which shows higher oral absorbability than oxidized coenzyme Q10, has also appeared on the market and is being used.

[0005] Reduced coenzyme Q10 is easily oxidized, which results in high storage costs and limits the range of applicable product forms. In particular, there is a demand for a solid composition containing reduced coenzyme Q10 that is applicable in the form of granules, hard capsules, tablets, etc. and has excellent oxidation stability.

[0006] Patent Document 1 reports that a solid composition containing reduced coenzyme Q10 can be stabilized by coating the solid composition with a coating medium such as shellac, gelatin, or gum arabic.

[0007] Patent Document 2 reports a particulate composition in which an oily component containing reduced coenzyme Q10 forms domains and is polydispersed in a matrix containing a water-soluble excipient and a water-soluble ascorbic acid.

[0008] Patent Document 3 describes that reduced coenzyme Q10 exhibits crystalline polymorphism, and reports that the newly emerged crystalline form (hereinafter referred to as "reduced coenzyme Q10 Form II crystal," "QH Form II crystal," or "Form II crystal") is much more stable than conventional reduced coenzyme Q10 (hereinafter referred to as "reduced coenzyme Q10 Form I crystal," "QH Form I crystal," or "Form I crystal") and also has other superior physical properties.

[0009] Patent Document 4 describes a reduced coenzyme Q10 composition that is solid at room temperature, such as a powder, and has good oxidation stability, is suitable for inexpensive and simple formulation to meet market demands, and is a composition that is solid at 25°C and contains reduced coenzyme Q10, an organic acid, and a carbonate containing sodium cations and / or calcium cations, and describes that reduced coenzyme Q10 is preferably in the form of Form II crystals. Patent Document 4 also describes that in order to improve the oxidation stability of reduced coenzyme Q10 in the composition, it is essential to add a carbonate containing sodium cations and / or calcium cations.

[0010] Furthermore, Patent Document 5 describes that reduced coenzyme Q10 can form a cocrystal with nicotinamide, and that the cocrystal exhibits higher oxidation stability than conventional crystals of reduced coenzyme Q10.

[0011] On the other hand, Patent Document 6 describes a novel granule that can adsorb and solidify a large amount of a poorly soluble functional substance while having excellent solubility in water of the functional substance, the granule comprising a carrier containing porous calcium silicate, a functional substance and a nonionic surfactant adsorbed on the carrier, and a binder, wherein the functional substance is at least one selected from the group consisting of a poorly soluble liquid, a low-melting and poorly soluble solid, and a herbal extract containing a poorly soluble active ingredient. Patent Document 5 cites coenzyme Q10 as a specific example of the functional substance.

[0012] Patent Document 7 discloses a method for producing a granular product containing an emulsifier by tumbling granulation, but it also describes that when granulation is carried out using an emulsifier with a melting point lower than 25°C, i.e., an emulsifier that is liquid at room temperature, the granulated material becomes lumpy, and the desired granulated product cannot often be obtained.

[0013] International Publication WO2006 / 075502 International Publication WO2008 / 129980 International Publication WO2012 / 176842 International Publication WO2015 / 122531 Chinese Publication CN113024362A JP2010-189337A JP60-221078A

[0014] However, the production methods for the previously reported solid compositions containing reduced coenzyme Q10 are complicated, and there is still room for improvement in the oxidation stability of reduced coenzyme Q10.

[0015] The production of the solid composition of Patent Document 1 requires a step of spraying a coating medium solution and a subsequent drying step, while the production of the particulate composition of Patent Document 2 requires a step of preparing an oil-in-water emulsion from an aqueous solution of a water-soluble excipient such as gum arabic and an oily component containing reduced coenzyme Q10, and a step of removing moisture from the emulsion composition droplets by spray drying or heating in oil to form particles.

[0016] When a coating medium such as a water-soluble excipient is used to impart gas barrier properties to a solid composition containing reduced coenzyme Q10, the solid composition must be completely coated, which causes various problems, such as limited production methods, high costs, a large solid composition, or a reduced content of reduced coenzyme Q10. Furthermore, the reduced coenzyme Q10-containing solid composition produced by the above method cracks when pressure is applied, causing it to lose its gas barrier properties, making it unsuitable as a raw material for further formulation, such as tableting.

[0017] The present inventors have investigated the Form II crystal of reduced coenzyme Q10 of Patent Document 3 and the cocrystal of reduced coenzyme Q10 of Patent Document 5, and have found that although these exhibit higher oxidation stability than conventional reduced coenzyme Q10 crystals, further stabilization is desired for application in hard capsules or tablet forms. Furthermore, the compositions of Patent Documents 4 and 6 also have room for further improvement in the stabilization effect of reduced enzyme Q10, and the essential requirement of carbonate or porous calcium silicate limits their applications.

[0018] The present specification discloses a means capable of suppressing the reduction of reduced coenzyme Q10 due to oxidation during storage of a solid composition containing reduced coenzyme Q10.

[0019] The present inventors have newly discovered that in a solid composition containing a co-crystal of reduced coenzyme Q10 together with an emulsifier and an antioxidant, for example, a solid composition obtained by granulating a co-crystal of reduced coenzyme Q10 and a solid antioxidant in the presence of a specific emulsifier by a pressure granulation method or a fluidized bed granulation method, the reduction of reduced coenzyme Q10 due to oxidation during storage is suppressed, and have completed the following aspects of the present invention: (1) A solid composition containing a co-crystal of reduced coenzyme Q10, an emulsifier, and an antioxidant. (2) The solid composition according to (1) above, wherein the emulsifier is a liquid, sol, gel, or soft solid emulsifier at 50°C. (3) The solid composition according to (1) or (2), wherein the emulsifier is one or more selected from monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol, and an ester compound of a fatty acid which may have a substituent, and lecithin. (4) The solid composition according to any of (1) to (3), wherein the content of the emulsifier in the solid composition is 1% by weight or more and 99% by weight or less. (5) The solid composition according to any of (1) to (4), wherein the antioxidant is one or more selected from ascorbic acid, ascorbate, erythorbic acid, and erythorbate. (6) The solid composition according to any of (1) to (5), wherein the co-crystal of reduced coenzyme Q10 is a co-crystal of reduced coenzyme Q10 and a benzoic acid or a co-crystal of reduced coenzyme Q10 and nicotinamide. (7) The solid composition according to any one of (1) to (6) above, wherein 70% by weight or more of the reduced coenzyme Q10 contained in the solid composition is contained in a co-crystal state with the reduced coenzyme Q10. (8) The solid composition according to any one of (1) to (7) above, wherein the residual rate of reduced coenzyme Q10 after storing the solid composition in an open state in an environment of 40°C and 75 HR% for 30 days is 93% or more. (9) The solid composition according to any one of (1) to (8) above, further comprising a binder. (10) The solid composition according to (9) above, which is a granular solid composition.(11) The solid composition according to any one of (1) to (10) above, which does not contain a carbonate containing sodium cations and / or calcium cations. (12) The solid composition according to any one of (1) to (11) above, which does not contain porous calcium silicate. (13) A method for producing a granular solid composition containing a co-crystal of reduced coenzyme Q10, an emulsifier, an antioxidant, and a binder, the method comprising granulating a mixture containing a co-crystal of reduced coenzyme Q10, an emulsifier, an antioxidant, a binder, and a liquid binder. (14) The method according to (13) above, wherein the granulation is carried out by extrusion granulation, agitation granulation, or fluidized bed granulation. This specification incorporates the disclosure of Japanese Patent Application No. 2023-148348, from which the present application claims priority.

[0020] According to one or more embodiments of the solid composition of the present invention, the decrease of reduced coenzyme Q10 due to oxidation during storage is suppressed.

[0021] According to the method according to one or more other embodiments of the present invention, a granular solid composition containing a co-crystal of reduced coenzyme Q10 and having excellent storage stability can be produced.

[0022] Furthermore, according to the method according to one or more embodiments of the present invention, a granular solid composition containing a co-crystal of reduced coenzyme Q10 and having excellent handleability can be produced with good yield.

[0023] The present invention will be described in detail below.

[0024] <Reduced Coenzyme Q10> In this specification, reduced coenzyme Q10 may contain oxidized coenzyme Q10 as a part of itself, as long as it is mainly composed of reduced coenzyme Q10. Here, the term "main component" means that it is contained in an amount of, for example, 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, particularly preferably 95% by weight or more, and particularly preferably 98% by weight or more. The aforementioned ratio is the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10.

[0025] As described above, reduced coenzyme Q10 exists in two crystalline polymorphs, Form I and Form II. Specifically, Form I crystals are crystalline forms of reduced coenzyme Q10 that have a melting point of around 48°C and exhibit characteristic peaks at diffraction angles (2θ±0.2°) of 3.1°, 18.7°, 19.0°, 20.2°, and 23.0° in powder X-ray (Cu-Kα) diffraction, while Form II crystals are crystalline forms of reduced coenzyme Q10 that have a melting point of around 52°C and exhibit characteristic peaks at diffraction angles (2θ±0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° in powder X-ray (Cu-Kα) diffraction.

[0026] <Co-crystal of reduced coenzyme Q10> As used herein, a co-crystal refers to a crystalline solid in which two or more different non-ionized compounds are arranged alternately in space to form a crystal lattice.

[0027] A co-crystal of reduced coenzyme Q10 refers to a co-crystal in which one compound is reduced coenzyme Q10.

[0028] In the case of a co-crystal of reduced coenzyme Q10, examples of other compounds that form co-crystals with reduced coenzyme Q10 include polyphenols, benzoic acids, carboxylic acids, nitrogen-containing heterocyclic compounds, and amino acids.

[0029] The polyphenols are not particularly limited, but examples thereof include catechin, epigallocatechin, tannin, rutin, isoflavone, resveratrol, curcumin, luteolin, naringenin, etc. Preferred are catechin, resveratrol, luteolin, naringenin, etc.

[0030] The benzoic acids are not particularly limited, and examples thereof include benzoic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, etc. Preferred are benzoic acid, 3-hydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, etc.

[0031] The carboxylic acids are not particularly limited, but examples thereof include tartaric acid, malonic acid, succinic acid, malic acid, fumaric acid, stearic acid, palmitic acid, ferulic acid, and caffeic acid.

[0032] The nitrogen-containing heterocyclic compound is not particularly limited, but examples thereof include piperazine, pipecolic acid, nicotinic acid, nicotinamide, isonicotinamide, saccharin, etc. Nicotinamide is preferred.

[0033] The amino acids may be in the D- or L-form, or in a racemic form, and are not particularly limited, but examples thereof include glycine, alanine, arginine, leucine, isoleucine, lysine, valine, cysteine, histidine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, aspartic acid, glutamic acid, N-methylglycine, γ-aminobutyric acid, proline, betaine, carnitine, etc. Preferred are lysine, valine, N-methylglycine, γ-aminobutyric acid, proline, betaine, etc.

[0034] As the co-crystal of reduced coenzyme Q10, a co-crystal of reduced coenzyme Q10 with the above-mentioned benzoic acids and a co-crystal of reduced coenzyme Q10 with nicotinamide are preferred, and a co-crystal of reduced coenzyme Q10 with nicotinamide is particularly preferred.

[0035] One or more embodiments of the present invention are characterized by using a co-crystal of reduced coenzyme Q10. By forming a solid composition containing the co-crystal of reduced coenzyme Q10 together with an emulsifier and an antioxidant, the oxidative stability of reduced coenzyme Q10 can be further enhanced compared to the co-crystal.

[0036] <Emulsifier> In the present specification, the type of emulsifier is not limited. For example, an emulsifier having an HLB of 1 or more and 17 or less, preferably 2 or more and 16 or less, can be used. Two or more types of emulsifiers may be used in combination.

[0037] From the viewpoint of the oxidation inhibitory effect on reduced coenzyme Q10, among the above emulsifiers, emulsifiers that are not in powder or flake form are preferred. Examples of emulsifiers that are not in powder or flake form include emulsifiers that are liquid, sol-like, gel-like, 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 the emulsifier, emulsifiers that have the above properties at 50°C are preferred, and emulsifiers that have the above properties at 25°C are most preferred.

[0038] Examples of emulsifiers that are not powdery or flaky include emulsifiers whose melting onset temperature, measured with a differential scanning calorimeter (DSC) at a temperature rise rate of 1°C / min or more and 20°C / min or less, is 50°C or less, preferably 40°C or less, and more preferably 25°C or less.

[0039] From another perspective, examples of the emulsifier include those having a viscosity, measured using a Brookfield viscometer at a rotation speed of 10 rpm and a sample temperature of 50° C., of 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 the viscosity is not particularly limited as long as it is greater than 0 mPa·s, but is more preferably 1 mPa·s or more, more preferably 5 mPa·s or more, and most preferably 10 mPa·s or more.

[0040] In one or more embodiments of the present invention, even when an emulsifier that is not powder or flake-like as described above is used, contrary to the suggestions of Patent Document 6 and the like, the handleability (discharge from a granulation device, mesh passability, transportability, etc.) of the resulting granular solid composition is maintained well, and a granular solid composition can be obtained that combines the oxidative stability of the reduced coenzyme Q10 contained therein with ease of handling.

[0041] Specific examples of the emulsifier include one or more selected from the group consisting of monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol, ester compounds of a fatty acid which may have a substituent, and lecithin.

[0042] The number of glycerin units in polyglycerin may be 2 or more, and preferably 2 to 10. Examples include diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, and decaglycerin.

[0043] The number of oxyethylene units in polyoxyethylene sorbitan may be 2 or more, preferably 10 or more and 30 or less, and more preferably 15 or more and 25 or less.

[0044] The number of propylene glycol units in the polypropylene glycol may be 2 or more, and preferably 2 or more and 10 or less.

[0045] The number of ethylene glycol units in the polyethylene glycol may be 2 or more, and preferably 2 or more and 10 or less.

[0046] Examples of fatty acids which may have a substituent include linear or branched monovalent or divalent fatty acids having from 4 to 24 carbon atoms. Examples of the substituent include a hydroxyl group and an acetoxy group. The number of substituents is preferably two or less. Specific examples of fatty acids which may have a substituent include lauric acid, oleic acid, caprylic acid, stearic acid, behenic acid, ricinoleic acid, succinic acid, and diacetyltartaric acid.

[0047] In the ester compound of the polyol and the fatty acid, the number of fatty acids bonded to one molecule of the polyol is not particularly limited, and can be adjusted appropriately depending on the HLB of the target emulsifier.

[0048] From the viewpoint of inhibiting oxidation of reduced coenzyme Q10, the number of bonds of the 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 more preferably 1.

[0049] Specific examples of the ester compounds of the polyols and the fatty acids include diglycerol monooleate, monoglycerol monocaprylate, diglycerol monocaprylate, decaglycerol pentaoleate, tetraglycerol pentaoleate, pentaglycerol trioleate, decaglycerol monolaurate, hexaglycerol monocaprylate, hexaglycerol monooleate, pentaglycerol monostearate, tetraglycerol tristearate, decaglycerol monobehenate, mono-diglycerol monostearate, monoglycerol monooleate, glycerol monostearate succinate, and monoglycerol succinate. Examples include serine, glyceryl diacetyltartarate monostearate, propylene glycol monooleate, sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, monoglyceryl monolaurate, diglyceryl monolaurate, diglyceryl monomyristate, tetraglyceryl pentastearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, condensed pentaglyceryl ricinoleate, sucrose stearate, sucrose erucate, and sucrose oleate.

[0050] From the viewpoint of inhibiting oxidation of reduced coenzyme Q10, the fatty acid in the ester compound of the polyol and 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, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosatetraenoic acid, adrenic acid, bosseopentaenoic acid, eicosapentaenoic acid, osbondo acid, sardine acid, tetracosapentaenoic acid, docosahexaenoic acid, herring acid, ricinoleic acid, and condensed ricinoleic acid, of which oleic acid, condensed ricinoleic acid, linoleic acid, and erucic acid are more preferred, and oleic acid is particularly preferred.

[0051] From another viewpoint of inhibiting oxidation of reduced coenzyme Q10, the ester compound of the polyol and the fatty acid is more preferably a glycerin fatty acid ester or polyglycerin fatty acid ester that satisfies any one of the following: 1) a glycerin fatty acid ester or polyglycerin fatty acid ester containing an ester of a fatty acid having 8 or less carbon atoms, 2) a polyglycerin fatty acid ester containing an ester of a fatty acid having 9 to 14 carbon atoms and having 2 or more glycerin units, and 3) a polyglycerin fatty acid ester containing an ester of a fatty acid having 15 to 18 carbon atoms and having 5 or more glycerin units. In this case, the fatty acid may be a saturated fatty acid or an unsaturated fatty acid.

[0052] Specific examples of the ester compounds of the polyol and the unsaturated fatty acid include monoglycerol monooleate, monoglycerol mono-dioleate, monoglycerol dioleate, monoglycerol mono-dioleate, diglycerol monooleate, diglycerol monodioleate, diglycerol dioleate, diglycerol trioleate, triglycerol monooleate, triglycerol dioleate, triglycerol trioleate, triglycerol tetraoleate, tetraglycerol monooleate, tetraglycerol dioleate, and triglycerol tetraoleate. 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, Heptaolein Hexaglycerin, Decaglycerin Monooleate, Decaglycerin Dioleate, Decaglycerin Trioleate, Decaglycerin Tetraoleate, Decaglycerin Pentaoleate, Decaglycerin Hexaoleate, Decaglycerin Heptaoleate, Decaglycerin Octaoleate, Decaglycerin Nonaoleate, Decaglycerin Decaoleate, Decaglycerin Dodecaoleate, Diacetoglycerin Monooleate, Glycerin Monooleate Lactate, Glycerin Monooleate Succinate, Glycerin Monooleate Citrate, Diacetoglycerin Glyceryl monooleate, sucrose oleate, propylene glycol monooleate, sorbitan monooleate, sorbitan dioleate, sorbitan trioleate, polyoxyethylene sorbitan monooleate, phosphatidylcholine monooleate monopalmitate, phosphatidylcholine dilinoleate, monoglyceryl monoerucate, monoglyceryl mono-dierucate, monoglyceryl dierucate, monoglyceryl monoerucate, diglyceryl monoerucate, diglyceryl monoerucate, diglyceryl monodierucate, diglyceryl dierucate,Diglyceryl Trierucate, Triglyceryl Monoerucate, Triglyceryl Dierucate, Triglyceryl Trierucate, Triglyceryl Tetraerucate, Tetraglyceryl Monoerucate, Tetraglyceryl Dierucate, Tetraglyceryl Trierucate, Tetraglyceryl Tetraerucate, Tetraglyceryl Pentaerucate, Pentaglyceryl Monoerucate, Pentaglyceryl Dierucate, Pentaglyceryl Trierucate, Pentaglyceryl Tetraerucate Pentaglycerin, Pentaglycerin Pentaerucate, Pentaglycerin Hexaerucate, Hexaglycerin Monoerucate, Hexaglycerin Dierucate, Hexaglycerin Trierucate, Hexaglycerin Tetraerucate, Hexaglycerin Pentaerucate, Hexaglycerin Heptaerucate, Decaglycerin Monoerucate, Decaglycerin Dierucate, Decaglycerin Trierucate, Decaglycerin Tetraerucate Glycerin, Decaglycerin Pentaerucate, Decaglycerin Hexaerucate, Decaglycerin Heptaerucate, Decaglycerin Octaerucate, Decaglycerin Nonaerucate, Decaglycerin Decaerucate, Decaglycerin Dodecaerucate, Diacetoglycerin Monoerucate, Glycerin Monoerucate Lactate, Glycerin Monoerucate Succinate, Glycerin Monoerucate Citrate, Glycerin Monoerucate Diacetyltartarate, Sucrose Ester Examples of the esters of glyceryl esters include glyceryl esters of carboxylic acid, propylene glycol monoerucate, sorbitan monoerucate, sorbitan dierucate, sorbitan trierucate, condensed monoglycerol ricinoleate, condensed diglycerol ricinoleate, condensed triglycerol ricinoleate, condensed tetraglycerol ricinoleate, condensed pentaglycerol ricinoleate, condensed hexaglycerol ricinoleate, condensed heptaglycerol ricinoleate, and condensed decaglycerol ricinoleate.

[0053] Specific examples of the ester compounds of the polyol and the unsaturated fatty acid include monoglycerol monooleate, monoglycerol mono-dioleate, monoglycerol dioleate, monoglycerol mono-dioleate, diglycerol monooleate, diglycerol monodioleate, diglycerol dioleate, diglycerol trioleate, triglycerol monooleate, triglycerol dioleate, triglycerol trioleate, triglycerol tetraoleate, and tetraglycerol monooleate. Serine, Tetraglyceryl Dioleate, Tetraglyceryl Trioleate, Tetraglyceryl Tetraoleate, Tetraglyceryl Pentaoleate, Pentaglyceryl Monooleate, Pentaglyceryl Dioleate, Pentaglyceryl Trioleate, Pentaglyceryl Tetraoleate, Pentaglyceryl Pentaoleate, Pentaglyceryl Hexaoleate, Hexaglyceryl Monooleate, Hexaglyceryl Dioleate, Hexaglyceryl Trioleate, Hexaglyceryl Tetraoleate Serine, Hexaglycerin Pentaoleate, Hexaglycerin Hexaoleate, Heptaglycerin Heptaoleate, Decaglycerin Monooleate, Decaglycerin Dioleate, Decaglycerin Trioleate, Decaglycerin Tetraoleate, Decaglycerin Pentaoleate, Decaglycerin Hexaoleate, Decaglycerin Heptaoleate, Decaglycerin Octaoleate, Decaglycerin Nonaoleate, Decaglycerin Decaoleate, Decaglycerin Dodecaoleate, Decaglycerin Monooleate Diacetoglycerol oleate, glycerol monooleate lactate, glycerol monooleate succinate, glycerol monooleate citrate, glycerol monooleate diacetyltartarate, sucrose oleate, propylene glycol monooleate, sorbitan monooleate, sorbitan dioleate, sorbitan trioleate, polyoxyethylene sorbitan monooleate, and phosphatidylcholine monopalmitate are preferred, and diglycerol monooleate is particularly preferred.

[0054] From the viewpoint of inhibiting oxidation of reduced coenzyme Q10, polyoxyethylene sorbitan fatty acid esters are also preferred as the ester compounds of the polyols and the fatty acids.

[0055] Specific examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monostearate.

[0056] When a solid composition containing an emulsifier is used in combination with an oily ingredient (e.g., vegetable oil, essential oil, animal fat, fish oil, fat-soluble active ingredient, etc.), the emulsifier contained in the solid composition preferably has an HLB of less than 10.0, more preferably less than 8.0, and particularly preferably less than 6.0. By using an ester of a polyol and an unsaturated fatty acid having an HLB of less than 6.0 as an emulsifier, reduced coenzyme Q10 in the solid composition can be stably preserved even under conditions of less than 50% relative humidity, where pharmaceuticals and foods are often stored, and this is preferred.

[0057] Specific examples of the ester of a polyol and an unsaturated fatty acid having an HLB of less than 6.0 include monoglycerol monooleate, monoglycerol mono-dioleate, monoglycerol dioleate, monoglycerol mono-dioleate, tetraglycerol pentaoleate, hexaglycerol pentaoleate, decaglycerol pentaoleate, decaglycerol decaoleate, sorbitan monooleate, sorbitan trioleate, propylene glycol monooleate, monoglycerol monooleate citrate, sucrose oleate, decaglycerol erucate, and sucrose erucate.

[0058] Examples of lecithin include soybean lecithin, egg yolk lecithin, and enzymatically decomposed soybean lecithin.

[0059] It is particularly preferable to use an emulsifier that is acceptable for food, cosmetics, and / or pharmaceuticals.

[0060] <Antioxidant> In the present specification, the type of antioxidant is not limited. Two or more antioxidants may be used in combination. Specific examples of antioxidants that are preferably solid at room temperature include one or more selected from ascorbic acid, ascorbate salts, erythorbic acid, and erythorbate salts.

[0061] The counter ions of ascorbate and erythorbate are not limited, but can each independently be one or more metal salts selected from sodium salts, potassium salts, calcium salts, and magnesium salts.

[0062] It is particularly preferable to use antioxidants that are acceptable for use as foods or pharmaceuticals. As the antioxidant, ascorbic acid salts are preferred, and one or more selected from sodium ascorbate and calcium ascorbate are particularly preferred.

[0063] The solid composition disclosed herein preferably further comprises a binder, which can be used to bind together the ingredients, including the co-crystal of reduced coenzyme Q10, the emulsifier, and the antioxidant, to form a granular solid composition.

[0064] 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.

[0065] Examples of celluloses include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, crystalline cellulose, cellulose powder, methyl cellulose, ethyl cellulose, and salts thereof. Particularly preferred binders are one or more selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose.

[0066] Examples of starches include wheat starch, potato starch, sweet potato starch, corn starch, dextrin, hydroxypropyl starch, starch acetate, oxidized starch, starch octenyl succinate or a salt thereof, and partially pregelatinized starch.

[0067] It is particularly preferable to use a binder that is acceptable for food or pharmaceutical use.

[0068] Solid Composition One or more embodiments of the present invention relate to a solid composition containing a co-crystal of reduced coenzyme Q10, an emulsifier, and an antioxidant.

[0069] The solid composition of this embodiment is suitable for long-term storage, for example, for periods of 3 months or more, because the reduction of reduced coenzyme Q10 due to oxidation is suppressed even when stored in contact with air. The storage temperature of the solid composition can be, for example, 0°C to 45°C, preferably 0°C to 40°C, and more preferably 5°C to 25°C. Under temperatures of 25°C or less, the solid composition of this embodiment can maintain 90% or more by weight of the initial amount of reduced coenzyme Q10 for a long period of 20 months or more. To provide this solid composition at an affordable price, it is preferable that the reduced coenzyme Q10 can be maintained in an amount of 90% or more by weight, more preferably 95% or more by weight, and most preferably 97% or more by weight of the initial amount of reduced coenzyme Q10 for 3 months at 25°C in a closed system packed with silica gel, or for 1 month at 40°C in a closed system packed with silica gel.

[0070] Alternatively, when the solid composition is stored in an open state for 30 days under more severe conditions such as an accelerated test, for example, under an environment of 40°C and 75% RH, the residual rate of reduced coenzyme Q10 (QH residual rate) is usually 93% or more, preferably 94% or more, 95% or more, 96% or more, or 97% or more.

[0071] The solid composition according to this embodiment is a solid composition at 25°C. The solid composition according to this embodiment may be in any shape, such as granules, powder, or flakes, but is preferably granular. The granular shape may be any shape formed by bonding primary particles of materials containing a cocrystal of reduced coenzyme Q10, an emulsifier, and an antioxidant through a granulation operation, and includes granules. The dimensions of the granular solid composition are not limited, but may be, for example, granules with a longest diameter of 0.20 mm or more and 2.0 mm or less.

[0072] The solid composition according to this embodiment can be produced in high yield and has good handling properties, even when a liquid, sol, gel, or soft solid emulsifier is used as the emulsifier. For example, in the case of a solid composition produced by agitation granulation, the transmittance through a mesh with an opening of 710 μm is 50% or more, preferably 60% or more, more preferably 70% or more, more preferably 80% or more, and particularly preferably 90% or more. The size of the mesh opening is usually adjusted depending on the expected particle size, but in the case of granules obtained by extrusion granulation, a mesh with an opening of 3.0 mm or the like can be used.

[0073] Furthermore, the solid composition according to this embodiment contains a co-crystal of reduced coenzyme Q10 in a crystalline state. The crystallinity of the co-crystal (the proportion of the total amount of reduced coenzyme Q10 present as a co-crystal in the solid composition) is usually 50% or more, preferably 70% or more, more preferably 90% or more, and particularly preferably 95% or more. The crystallinity of the co-crystal contained in the solid composition can be calculated by measuring the heat of fusion of crystals by DSC analysis, and using the theoretical heat of fusion calculated from the content of the co-crystal in the solid composition and the measured heat of fusion data according to the following formula: Crystallinity (%) = (measured heat of fusion / theoretical heat of fusion) × 100

[0074] Furthermore, in the solid composition according to this embodiment, the cocrystal of reduced coenzyme Q10 does not need to be completely coated with a gas barrier material, and therefore the coating will not break even when pressure is applied, preventing the oxidation stability from being impaired, and the solid composition can be applied to a wide range of formulations, such as tableting by tableting.

[0075] In the solid composition according to this embodiment, the blending ratio of each component can be adjusted so as to suppress oxidation of reduced coenzyme Q10.

[0076] The solid composition according to this embodiment more preferably contains, for example, 1 part by weight or more and 9,900 parts by weight or less of an antioxidant per 100 parts by weight of a co-crystal of reduced coenzyme Q10. The lower limit of the content of the antioxidant per 100 parts by weight of a co-crystal of reduced coenzyme Q10 is preferably 20 parts by weight or more, more preferably 50 parts by weight or more, and more preferably 80 parts by weight or more. The upper limit of the content of the antioxidant per 100 parts by weight of a co-crystal of reduced coenzyme Q10 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, and more preferably 120 parts by weight or less.

[0077] The solid composition according to this embodiment more preferably contains, for example, 1 part by weight or more and 9,900 parts by weight or less of an emulsifier per 100 parts by weight of a co-crystal of reduced coenzyme Q10. The lower limit of the content of the emulsifier per 100 parts by weight of a co-crystal of reduced coenzyme Q10 is preferably 3 parts by weight or more, more preferably 5 parts by weight or more, and more preferably 8 parts by weight or more. The upper limit of the content of the emulsifier per 100 parts by weight of a co-crystal of reduced coenzyme Q10 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.

[0078] The lower limit of the content of the cocrystal of reduced coenzyme Q10 in the solid composition according to this embodiment 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, and the upper limit of the content is, for example, 90% by weight or less, preferably 80% by weight or less, more preferably 70% by weight or less, more preferably 60% by weight or less. In the solid composition according to this embodiment, the cocrystal of reduced coenzyme Q10 does not need to be completely covered with a gas barrier material, so the content of the cocrystal, and therefore the content of reduced coenzyme Q10, can be increased, and the content of the cocrystal of reduced coenzyme Q10 can be, for example, 45% or more, 50% or more, 55% or more, 60% or more, 70% or more, or 80% or more.

[0079] The lower limit of the content of the antioxidant in the solid composition according to this embodiment is, for example, 1% by weight or more, preferably 10% by weight or more, more preferably 20% by weight or more, and more preferably 30% by weight or more, and the upper limit of the content is, for example, 99% by weight or less, preferably 90% by weight or less, preferably 80% by weight or less, more preferably 70% by weight or less, and more preferably 60% by weight or less.

[0080] The content of the emulsifier in the solid composition according to this embodiment is not particularly limited, but the lower limit of the emulsifier content is, for example, 0.5% by weight or more, preferably 1% by weight or more, and more preferably 3% by weight or more, and the upper limit of the content is, for example, 99% by weight or less, preferably 50% by weight or less, more preferably 30% by weight or less, more preferably 25% by weight or less, more preferably 20% by weight or less, more preferably 15% by weight or less, and more preferably 10% by weight or less. When using an emulsifier in a form other than powder or flake, for example, one or more emulsifiers selected from liquid, sol, gel, and soft solid forms, it is usually difficult to obtain a solid composition with good handleability in high yield. However, if the content of the emulsifier in the solid composition according to this embodiment is, for example, 50% by weight or less, preferably 30% by weight or less, and more preferably 25% by weight or less, it is possible to obtain a solid composition with good handleability in high yield.

[0081] When the solid composition according to this embodiment contains a binder, the lower limit of the binder content in the solid composition is, for example, 1% by weight or more, preferably 5% by weight or more, and more preferably 8% by weight or more, and the upper limit of the binder content is, for example, 20% by weight or less, preferably 15% by weight or less, and more preferably 10% by weight.

[0082] The solid composition according to this embodiment more preferably contains, 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 of a binder per 100 parts by weight of the co-crystal of reduced coenzyme Q10. The solid composition also contains, 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, and even more preferably 30 parts by weight or less of an antioxidant per 100 parts by weight of the co-crystal of reduced coenzyme Q10.

[0083] The solid composition according to this embodiment may further contain other ingredients such as excipients, etc. The other ingredients are preferably ingredients that are acceptable as foods or pharmaceuticals.

[0084] The solid composition according to this embodiment preferably does 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., 0.65-hydrate, monohydrate, 1.5-hydrate, hexahydrate, etc.).

[0085] The solid composition according to this embodiment preferably does not contain porous calcium silicate, and examples of porous calcium silicate include calcium silicate having 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 of 300 to 550 ml / 100 g.

[0086] <Method for producing granular solid composition> Another one or more embodiments of the present invention relate to a method for producing a granular solid composition containing a co-crystal of reduced coenzyme Q10, an emulsifier, an antioxidant, and a binder, the method comprising granulating a mixture containing a co-crystal of reduced coenzyme Q10, an emulsifier, an antioxidant, a binder, and a liquid binder.

[0087] According to the method of this embodiment, a co-crystal of reduced coenzyme Q10 and a solid antioxidant are granulated in the presence of an emulsifier (preferably a liquid to sol, gel, or soft solid emulsifier), thereby making it possible to produce a granular solid composition having the above-mentioned characteristics of high storage stability at low cost and simply.

[0088] The granulation method can be appropriately selected, for example, extrusion granulation, stirring granulation, tumbling granulation (rotational granulation), dry granulation, compression granulation, powder bonding, fluidized bed granulation, coacervation, spray drying, cold spray, evaporation, and liquid hardening. The granulation method is preferably a granulation method that applies pressure (for example, extrusion granulation, stirring granulation, tumbling granulation, dry granulation, compression granulation, powder bonding, etc.) or fluidized bed granulation, more preferably extrusion granulation, stirring granulation, or fluidized bed granulation, and particularly preferably extrusion granulation or stirring granulation.

[0089] In the method according to this embodiment, reduced coenzyme Q10 crystals are not completely dissolved or melted during the granulation process, but are mixed and granulated while basically maintaining the crystalline state.

[0090] The components of the mixture to be granulated other than the liquid binder may be a powder mixture, and the characteristics of each component of the mixture other than the liquid binder are the same as those described for each component contained in the solid composition according to one or more embodiments of the present invention.

[0091] Examples of the liquid binder include water, ethanol, etc. Alternatively, the liquid binder may be prepared by dissolving the above-mentioned binder in a liquid such as water or ethanol. Water is particularly preferred as the liquid binder.

[0092] Granulation can be carried out under suitable conditions so as to obtain granular solid composition having a size suitable for the intended use.

[0093] The method according to the present embodiment preferably further comprises a drying step in which the granulated solid composition is dried after granulation to remove volatile components derived from the raw material components and the liquid binder. If necessary, the granular solid composition having the desired particle size can be separated and recovered by sieving or the like.

[0094] One or more embodiments of the present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. The HPLC measurement conditions in the examples and comparative examples are as follows.

[0095] (Method for evaluating oxidative stability) The weight ratio of reduced coenzyme Q10 to total coenzyme Q10 (i.e., reduced coenzyme Q10 / (oxidized coenzyme Q10+reduced coenzyme Q10)) is defined as the "QH ratio." The QH ratio was determined by the HPLC analysis described below. Furthermore, in evaluating oxidative stability, the QH ratio at the end of the evaluation, when the QH ratio at the start of the evaluation was taken as 100, was defined as the "QH residual rate," and the QH residual rate calculated from the following formula was used as a measure of oxidative stability. QH residual rate (%) = 100 × QH ratio at the end of the evaluation / QH ratio at the start of the evaluation

[0096] (HPLC measurement conditions) Column: SYMMETRY C １８ (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

[0097] (Preparation Example of Co-Crystal) A co-crystal of reduced coenzyme Q10 and nicotinamide (hereinafter also referred to as reduced coenzyme Q10-nicotinamide co-crystal) was prepared as follows, according to the examples described in WO2023 / 120552.

[0098] 4.33 g of QH Form I crystals and 1.22 g of nicotinamide were added to 7.85 g of ethanol, and the mixture was heated to 50 ° C., thereby completely dissolving the QH Form I crystals and nicotinamide. This solution was cooled, and the resulting white slurry was dried under reduced pressure to obtain a cocrystal consisting of QH and nicotinamide. The melting point of the resulting cocrystal was measured using a differential scanning calorimeter (DSC200, Hitachi, heating rate: 1 ° C. / min), and a peak was confirmed at a temperature different from the melting point of the QH Form I crystals used as raw materials (48 ° C.) and the melting point of nicotinamide (127 ° C.). Reduced coenzyme Q10 (trade name: Kaneka QH) manufactured by Kaneka Corporation was used as reduced coenzyme Q10 Form I crystals (QH Form I crystals).

[0099] Comparative Example 1 1.0 g of Form I crystals of reduced coenzyme Q10, 1.0 g of sodium ascorbate, 0.2 g of hydroxypropyl cellulose, and 0.2 g of diglycerol monooleate (Sunsoft Q-17D, manufactured by Taiyo Kagaku Co., Ltd., HLB value 7.5) were mixed, and 0.09 mL of water was added and kneaded. The resulting kneaded mixture was extrusion-granulated using a 1.2 mm diameter screen and dried to obtain a granular solid composition (granules). 1 g of the resulting granular solid composition was stored in an open state in an environment of 25°C and 60% RH for 30 days, and the QH residual rate was evaluated.

[0100] The residual rate of QH was 52.0%, and the granular solid composition prepared using Form I crystals of reduced coenzyme Q10 had insufficient oxidation stability of reduced coenzyme Q10.

[0101] (Comparative Example 2) Reduced coenzyme Q10 and nicotinamide cocrystal were weighed out in 1 g into each of two 30 ml glass vials (operation environment: 28°C, 50 RH%). These vials were stored for 30 days under an environment of 40°C and 75 RH%, with one open and the other sealed with a screw cap (sealed sealing conditions), and the residual rate of reduced coenzyme Q10 was evaluated.

[0102] Example 1: 1 g of reduced coenzyme Q10 / nicotinamide cocrystal, 1 g of sodium ascorbate, 0.2 g of hydroxypropyl cellulose, and 0.2 g of diglycerol monooleate (Sunsoft Q-17D, HLB value 7.5) were mixed, and water was added and kneaded. The resulting kneaded mixture was extrusion granulated using a 1.2 mm diameter screen and dried to obtain a granular solid composition. As in Comparative Example 2, 1 g of the resulting granular solid composition was weighed into two 30 ml glass vials and stored in an open and sealed state at 40°C and 75% RH for 30 days, and the residual rate of reduced coenzyme Q10 was evaluated.

[0103] The results of Comparative Example 2 and Example 1 are shown in Table 1.

[0104] From the above results, it was confirmed that although reduced coenzyme Q10 / nicotinamide cocrystals have higher stability than Form I crystals of reduced coenzyme Q10, further stabilization is required for use in various dosage forms, and that oxidative stability can be greatly improved by forming them into the solid composition of the present invention.

[0105] Although the present embodiment has been described in detail above, the specific configuration is not limited to this embodiment, and any design changes that do not deviate from the gist of the present disclosure are also included in the present disclosure. All publications, patents, and patent applications cited in this specification are incorporated herein by reference in their entirety.

Claims

1. A solid composition comprising a cocrystal of reduced coenzyme Q10, an emulsifier and an antioxidant.

2. The solid composition according to claim 1, wherein the emulsifier is a liquid, sol, gel, or soft solid emulsifier at 50°C.

3. The solid composition according to claim 1 or 2, wherein the emulsifier is one or more selected from an ester compound of a polyol selected from monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol and polyethylene glycol with a fatty acid which may have a substituent, and lecithin.

4. The solid composition according to any one of claims 1 to 3, wherein the content of the emulsifier in the solid composition is 1% by weight or more and 99% by weight or less.

5. The solid composition according to any one of claims 1 to 4, wherein the antioxidant is one or more selected from ascorbic acid, an ascorbate salt, erythorbic acid, and an erythorbate salt.

6. The solid composition according to any one of claims 1 to 5, wherein the cocrystal of reduced coenzyme Q10 is a cocrystal of reduced coenzyme Q10 and a benzoic acid or a cocrystal of reduced coenzyme Q10 and nicotinamide.

7. A solid composition according to any one of claims 1 to 6, wherein 70% by weight or more of the reduced coenzyme Q10 contained in the solid composition is contained in a co-crystalline state of the reduced coenzyme Q10.

8. A solid composition according to any one of claims 1 to 7, in which the residual rate of reduced coenzyme Q10 is 93% or more after the solid composition is stored in an open state in an environment of 40°C and 75 HR% for 30 days.

9. The solid composition according to any one of claims 1 to 8, further comprising a binder.

10. The solid composition of claim 9 which is a granular solid composition.

11. A solid composition according to any one of claims 1 to 10, which does not contain carbonates containing sodium and / or calcium cations.

12. A solid composition according to any one of claims 1 to 11, which does not contain porous calcium silicate.

13. A method for producing a granular solid composition containing a co-crystal of reduced coenzyme Q10, an emulsifier, an antioxidant and a binder, the method comprising granulating a mixture containing a co-crystal of reduced coenzyme Q10, an emulsifier, an antioxidant, a binder and a liquid binder.

14. The method according to claim 13, wherein the granulation is carried out by extrusion granulation, stirring granulation or fluidized bed granulation.

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