Package and preserving method for reduced coenzyme q10

Abstract

The present specification discloses a reduced coenzyme Q10 product which does not require the formulation of reduced coenzyme Q10 and in which the oxidation of reduced coenzyme Q10 is suppressed. Also, the present specification discloses a method for preserving reduced coenzyme Q10, which can inhibit the oxidation of reduced coenzyme Q10 without requiring the formulation of reduced coenzyme Q10.　One or more embodiments of the present invention relates to a package comprising a reduced coenzyme Q10 and a container for packing the reduced coenzyme Q10, wherein the relative humidity of the gas phase inside the container is 50% or more. Also, one or more embodiments of the present invention relates to a method for preserving reduced coenzyme Q10, the method comprising a preserving step for preserving the reduced coenzyme Q10 in a gas phase having a relative humidity of 50% or more.

Description

Reduced coenzyme Q10 packaging and storage method

[0001] One or more embodiments of the present invention relate to packaging and storage methods for reduced coenzyme Q10.

[0002] Coenzyme Q is an essential component widely distributed in living organisms, from bacteria to mammals, and is known as a component of the mitochondrial electron transport chain in 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.

[0003] 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.

[0004] Reduced coenzyme Q10 is easily oxidized, which results in high storage costs and limits the range of application of the product form.

[0005] A general method for obtaining reduced coenzyme Q10 has already been disclosed (Patent Document 1). Meanwhile, Patent Document 2 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" or "QH Form II crystal") is much more stable than conventional reduced coenzyme Q10 (hereinafter referred to as "reduced coenzyme Q10 Form I crystal" or "QH Form I crystal") and also has other superior physical properties.

[0006] Patent Document 3 describes a method for producing reduced coenzyme Q10, in which a coenzyme Q10-cyclodextrin inclusion complex (CoQ10-CD inclusion complex) is mixed with an antioxidant and then stored in an atmosphere at 10 to 100°C and 0 to 100% humidity to produce a reduced CoQ10-CD inclusion complex. Patent Document 3 also describes that when a mixture of CoQ10 that is not a CD inclusion complex and an antioxidant is stored under conditions of 60°C and 75% humidity, a low rate of reduced CoQ10 is produced, whereas when a mixture of the CoQ10-CD inclusion complex and an antioxidant is stored under the same conditions, a large amount of reduced CoQ10 is produced.

[0007] Patent Document 4, Patent Document 5 and Patent Document 6 disclose a particulate composition, in which reduced coenzyme Q10 has high oxidation stability and high bioabsorbability, and in which an oily component containing reduced coenzyme Q10 or an oily component containing reduced coenzyme Q10 and a lipophilic antioxidant forms domains and polydisperses in a matrix containing a water-soluble excipient or a matrix containing a water-soluble excipient and a water-soluble ascorbic acid, and a stabilization method for this particulate composition is described, characterized in that the particulate composition is placed in an environment with a relative humidity of 90% or less.Examples of water-soluble excipients include gum arabic and gelatin.

[0008] Patent Document 7 describes a reduced coenzyme Q10 solid preparation as a preparation for protecting reduced coenzyme Q10 from oxidation, which is a solid composition containing reduced coenzyme Q10 coated with at least one coating medium selected from an oil-soluble coating medium and a water-soluble coating medium, and describes a method characterized by placing this preparation in an environment adjusted to a relative humidity of 75% or less. Examples of oil-soluble coating mediums include shellac and zein. Examples of water-soluble coating mediums include gelatin, sugar, gum arabic, pullulan, cellulose derivatives, and yeast cell walls.

[0009] Patent Document 8 describes a method for preserving reduced coenzyme Q10, which comprises producing or obtaining capsules containing reduced coenzyme Q10 and controlling the environment surrounding the capsules to a relative humidity of 0% to 60%. Gelatin and the like are exemplified as materials for the capsules.

[0010] It is known that protein coatings such as gelatin increase their oxygen permeability under high humidity conditions, resulting in a decrease in gas barrier properties. For example, Non-Patent Document 1 describes that the oxygen permeability of a gelatin film that does not contain glycerin increases 10 times when the relative humidity increases by 20%. Non-Patent Document 2 states that "with an increase in water activity and relative humidity, the oxygen permeability decreases by 10 to 10 ５ For example, the oxygen permeability of a collagen film is 6.6 x 10 when the water activity is 0. －１９ gm －１ s －１ Pa －１ However, when the water activity is 0.93, the value is 13.68 x 10 －１５ gm －１ s －１ Pa －１ Non-Patent Document 3 states that "When the amount of plasticizer, temperature, and relative humidity increase, the oxygen and water vapor transmission rates of protein films generally increase."

[0011] Patent Documents 4 to 8 all relate to technologies for improving the oxidation stability of QH by coating it with a coating of a gas barrier material such as gelatin, gum arabic, or shellac. Patent Documents 4 to 8 describe that QH is stabilized when a QH preparation coated with a gas barrier coating such as gelatin is stored at a relative humidity of a predetermined value or less. As described above, in light of the publicly known information that gas barrier coatings made of proteins such as gelatin increase in oxygen permeability under high humidity conditions, it can be understood that Patent Documents 4 to 8 reduce the oxygen permeability of the gas barrier coating and suppress the oxidation of QH by keeping the relative humidity at a predetermined value or less.

[0012] It is known that the stability of organic compounds generally decreases with increasing relative humidity (Non-Patent Documents 4 and 5).

[0013] Patent Document 9 describes the discovery of a cocrystal containing reduced coenzyme Q10 and a compound such as 3,4-dihydroxybenzoic acid as a further form of reduced coenzyme Q10. Patent Document 10 also describes the formation of a cocrystal between reduced coenzyme Q10 and nicotinamide. Although the oxidative stability of reduced coenzyme Q10 may be improved by cocrystallizing reduced coenzyme Q10 with one or more other compounds, it is still not possible to completely protect reduced coenzyme Q10 from oxidation.

[0014] Japanese Patent Publication No. 10-109933 International Publication No. WO2012 / 176842 Japanese Patent Publication No. 2010-126492 International Publication No. WO2007 / 148798 International Publication No. WO2008 / 129980 Japanese Patent Publication No. 2009-149584 International Publication No. WO2006 / 075502 Japanese Patent Publication No. 2006-206583 International Publication No. WO2019 / 162429 Chinese Patent Application Publication No. 113024362A

[0015] Soft Gelatin Capsules II: Oxygen Permeability Study of Capsule Shells, Hom FS, Veresh SA, and Ebert WR, Journal of Pharmaceutical Sciences, 1975, 64(5):851-857Handbook of Encapsulation and Controlled Release, CRC Press, 2016, Edited by Munmaya Mishra, p.818Protein-Based Films and Coatings (Book), CRC press, 2002, edited by Aristippos Gennadios, CHAPTER 1 (by John M Korochta), p.12Evaluating Stability of Vitamin C in Fortified Formula Using Water Activity and Glass Transition, Sablani SS, Al-Belushi K, Al-Marhubi I, and Al-Belushi R, International Journal of Food Properties, 2007, 10(1):61-71Preformulation Studies of a Prodrug of Δ9-Tetrahydrocannabinol, Thumma S, Majumdar S, ElSohly MA, Gul W, and Repka MA, 2008, AAPS Pharm Sci Tech, 9(3):982-990

[0016] Patent Documents 3 to 8 disclose reduced coenzyme Q10 (QH) products that can prevent oxidation of QH and enable stable storage. However, all of these documents require QH to be formulated with specific ingredients, which limits the uses of QH.

[0017] Therefore, one or more embodiments of the present invention provide a QH product in which the oxidation of QH is suppressed without the need for formulation of QH. Also, one or more embodiments of the present invention provide a method for preserving QH, which can suppress the oxidation of QH without the need for formulation of QH.

[0018] As described above, organic compounds generally have lower stability as the relative humidity increases. However, the present inventors have made the unexpected discovery that QH has higher oxidation stability as the relative humidity increases, and have completed the following aspects of the present invention.

[0019] (1) A package comprising reduced coenzyme Q10 and a container for packaging the reduced coenzyme Q10, wherein the relative humidity of the gas phase inside the container is 50% or higher. (2) The package according to (1), wherein the reduced coenzyme Q10 is one or more selected from Form I crystals of reduced coenzyme Q10, Form II crystals of reduced coenzyme Q10, a co-crystal consisting of reduced coenzyme Q10 and one or more other compounds, an amorphous solid of reduced coenzyme Q10, and a composition in which reduced coenzyme Q10 is dissolved in a solvent and / or a fat-soluble medium. (3) The package according to (1) or (2), further comprising water inside the container, wherein the water is mixed with the reduced coenzyme Q10, is arranged so as to be in contact with the phase containing the reduced coenzyme Q10, or is arranged separately from the reduced coenzyme Q10. (4) The package according to any one of (1) to (3), further comprising one or more other ingredients inside the container, wherein the other ingredients are mixed with the reduced coenzyme Q10, arranged so as to be in contact with the phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10, and the water activity of the contents of the container containing the reduced coenzyme Q10 and the other ingredients at 25°C is 0.50 or higher. (5) The package according to any one of (1) to (4), further comprising a substance that releases water inside the container, wherein the substance is mixed with the reduced coenzyme Q10, arranged so as to be in contact with the phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10. (6) The package according to any one of (1) to (5), wherein the reduced coenzyme Q10 is not an inclusion complex of reduced coenzyme Q10 with cyclodextrin. (7) The package according to any one of (1) to (6), wherein the reduced coenzyme Q10 is not reduced coenzyme Q10 dispersed in a matrix containing a water-soluble excipient in a particulate composition. (8) The package according to any one of (1) to (7), wherein the reduced coenzyme Q10 is not reduced coenzyme Q10 coated with a coating medium in a solid formulation. (9) The package according to any one of (1) to (8), wherein the reduced coenzyme Q10 is not a capsule of reduced coenzyme Q10.

[0020] (10) A method for storing reduced coenzyme Q10, comprising a storage step of storing the reduced coenzyme Q10 in a gas phase at a relative humidity of 50% or more. (11) The method according to (10), wherein the reduced coenzyme Q10 is one or more selected from Form I crystals of reduced coenzyme Q10, Form II crystals of reduced coenzyme Q10, co-crystals of reduced coenzyme Q10 and one or more other compounds, amorphous solids of reduced coenzyme Q10, and compositions in which reduced coenzyme Q10 is dissolved in a solvent and / or a fat-soluble medium. (12) The method according to (10) or (11), wherein the storage step comprises storing the reduced coenzyme Q10 and a container for packaging the reduced coenzyme Q10, wherein the relative humidity of the gas phase inside the container is 50% or more. (13) The method according to (12), further comprising: water contained in the container, wherein the water is mixed with the reduced coenzyme Q10, is placed in contact with the phase containing the reduced coenzyme Q10, or is placed separately from the reduced coenzyme Q10. (14) The method according to (12) or (13), further comprising: one or more other components contained in the container, wherein the other components are mixed with the reduced coenzyme Q10, are placed in contact with the phase containing the reduced coenzyme Q10, or are placed separately from the reduced coenzyme Q10, and the water activity of the contents of the container containing the reduced coenzyme Q10 and the other components is 0.50 or more at 25°C. (15) The method according to any one of (12) to (14), further comprising a substance that releases water into the interior of the container, wherein the substance is mixed with the reduced coenzyme Q10, arranged to be in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10. (16) The method according to any one of (12) to (15), further comprising a package preparation step of packaging the reduced coenzyme Q10 in the container in a gas phase with a relative humidity of 50% or more to produce the package. (17) The method according to any one of (12) to (15), further comprising a package preparation step of packaging the reduced coenzyme Q10 in the container and filling the container with a gas phase with a relative humidity of 50% or more to produce the package.(18) The method according to any one of (10) to (17), wherein the reduced coenzyme Q10 is not an inclusion complex of reduced coenzyme Q10 with cyclodextrin. (19) The method according to any one of (10) to (18), wherein the reduced coenzyme Q10 is not reduced coenzyme Q10 dispersed in a matrix containing a water-soluble excipient in a particulate composition. (20) The method according to any one of (10) to (19), wherein the reduced coenzyme Q10 is not reduced coenzyme Q10 coated with a coating medium in a solid formulation. (21) The method according to any one of (10) to (20), wherein the reduced coenzyme Q10 is not a capsule of reduced coenzyme Q10. This specification includes the disclosures of Japanese Patent Application Nos. 2021-210581, 2021-210585, 2022-152287, and 2022-152297, from which this application claims priority.

[0021] According to one or more of the packages and methods disclosed herein, reduced coenzyme Q10 (QH) can be prevented from being oxidized and can be stably stored.

[0022] The present invention will be described in detail below.

[0023] <Reduced Coenzyme Q10> In the packaging and method according to one or more embodiments of the present invention, "reduced coenzyme Q10" refers to reduced coenzyme Q10 as long as it is the main component, and may also contain oxidized coenzyme Q10 as a part of it. Here, "main component" means, for example, 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, particularly preferably 95% by weight or more, and especially preferably 98% by weight or more. Here, the aforementioned ratio refers to the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10.

[0024] As mentioned above, reduced coenzyme Q10 exists in two types of crystalline polymorphism, 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.

[0025] In one or more embodiments of the present invention, reduced coenzyme Q10 (QH) can be one or more selected from QH Form I crystals, QH Form II crystals, cocrystals of QH and one or more other compounds, amorphous solids of QH, and compositions in which QH is dissolved in a solvent and / or a fat-soluble medium. The solvent is not particularly limited as long as it can dissolve QH. Examples of the solvent include alcohols, hydrocarbons, ketones, terpenes, fats and oils, essential oils, and propylene glycol fatty acid esters. The fat-soluble medium is not particularly limited as long as it can dissolve QH. Examples of fat-soluble media include fatty acids, emulsifiers, fat-soluble vitamins, and vitamin derivatives. The composition in which QH is dissolved in a solvent and / or a fat-soluble medium may be a liquid or solid composition under the temperature conditions under which the package is used or stored, but is preferably a liquid composition.

[0026] The one or more other compounds contained in the cocrystal consisting of QH and the one or more other compounds are not particularly limited as long as they are compounds capable of forming a cocrystal with QH, and examples thereof include organic carboxylic acids including benzoic acid and derivatives thereof, resorcinol, benzyl alcohol, organic alcohols including phenol and derivatives thereof, urea, and nicotinamide. The one or more other compounds may be one or more types, and may be one or more types, or two or more types, and preferably 1 to 3 types of compounds.

[0027] The alcohols are not particularly limited and may be cyclic or acyclic, saturated or unsaturated. Examples include alcohols having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 5 carbon atoms, and particularly preferably 1 to 4 carbon atoms. Among these, monohydric alcohols are preferred. Monohydric alcohols having 2 carbon atoms are most preferred. Dihydric alcohols having 2 to 5 carbon atoms, preferably 2 to 4 carbon atoms, and even more preferably 3 carbon atoms, and trihydric alcohols having 3 carbon atoms are also suitable.

[0028] Examples of monohydric alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 3-methyl-2-butanol, neopentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl-2-pentanol, 2-ethyl-1-butanol, 1-heptanol, Examples of the alcohol include 2-heptanol, 3-heptanol, 1-octanol, 2-octanol, 2-ethyl-1-hexanol, 1-nonanol, 1-decanol, 1-undecanol, 1-dodecanol, allyl alcohol, propargyl alcohol, benzyl alcohol, cyclohexanol, 1-methylcyclohexanol, 2-methylcyclohexanol, 3-methylcyclohexanol, 4-methylcyclohexanol, cinnamyl alcohol, phenol, and α-methylbenzyl alcohol, and ethanol is the most preferred.

[0029] Examples of dihydric alcohols include 1,2-ethanediol, 1,2-propanediol (propylene glycol), 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 1,5-pentanediol, etc. Preferred are 1,2-ethanediol, 1,2-propanediol, 1,3-butanediol, and 1,3-propanediol, and most preferred is 1,2-propanediol.

[0030] As the trihydric alcohol, glycerin or the like can be suitably used.

[0031] The hydrocarbons are not particularly limited, but examples thereof include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, etc. In particular, aliphatic hydrocarbons and aromatic hydrocarbons are preferred, and aliphatic hydrocarbons are particularly preferred.

[0032] The aliphatic hydrocarbon may be cyclic or acyclic, saturated or unsaturated, and is not particularly limited, but acyclic aliphatic hydrocarbons are particularly preferred, usually having 3 to 20 carbon atoms, preferably 5 to 12 carbon atoms.

[0033] Specific examples include propane, butane, isobutane, pentane, 2-methylbutane, cyclopentane, 2-pentene, hexane, 2-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, methylcyclopentane, cyclohexane, 1-hexene, cyclohexene, heptane, 2-methylhexane, 3-methylhexane, 2,3-dimethylpentane, 2,4-dimethylpentane, methylcyclohexane, 1-heptene, octane, 2,2,3-trimethylpentane, isooctane, ethylcyclohexane, 1-octene, nonane, 2,2,5-trimethylhexane, 1-nonene, decane, 1-decene, p-menthane, undecane, and dodecane.

[0034] The ketones are not particularly limited and may be cyclic or acyclic, saturated or unsaturated. Specific examples include acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, acetophenone, 4-methoxyphenylacetone, paramethylacetophenone, and methyl β-naphthyl ketone, and are preferably acetone, acetophenone, 4-methoxyphenylacetone, paramethylacetophenone, or methyl ethyl ketone.

[0035] The terpenes are not particularly limited, and any of hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, and triterpenes can be suitably used. Among them, from the viewpoint of solubility in QH, hemiterpenes, monoterpenes, and sesquiterpenes are more preferred, monoterpenes and sesquiterpenes are particularly preferred, and monoterpenes are most preferred.

[0036] Specific examples of terpenes include prenol, 3-methyl-3-buten-2-ol, tiglic acid, angelic acid, senicioic acid, isovaleric acid, alloocimene, β-bourbonene, δ-cadinene, dehydro-p-cymene, menthol, dl-limonene, d-limonene, l-limonene, p-cymene, α-pinene, valencene, myrcene, bisabolene, carene, caryophyllene, terpinene, phytol, cis-3,7-dimethyl-1,3,6-octatriene, δ-elenium, Mene, β-elemene, α-farnesene, β-farnesene, farnesene, germacrene D, β-guaiene, longifolene, β-ocimene, α-phellandrene, pinocampone, sabinene, terpinolene, thujopsene, α-copaene, hydrogenated limonene dimer, isocaryophyllene, pinene dimer, dipentene dimer, dipentene trimer, geraniol, citral, citronellal, citronellol, 1,8-cineole, hydroxycitronella ol, linalool, cosmen, nerol, myrcenol, lavandulol, ipsedienol, neral, geranial, perylene, rosifuran, geranilic acid, thioterpineol, α-terpineol, β-terpineol, γ-terpineol, δ-terpineol, carveol, terpine, perillaldehyde, perilla alcohol, carvone, ascaridole, anethole, thujone, thujanol, α-ionone, β-ionone, γ-ionone, farnesol, nerol Examples of terpenes include dl-sinensal, α-sinensal, β-sinensal, bisabol, squalene, citronelloxyacetaldehyde, myrtenal, perillaldehyde, 2-p-cymenol, 2-ethoxy-p-cymene, carbenol, 4-carbomethanesulfonyl acetate, carvyl propionate, caryophyllene alcohol, caryophyllene alcohol acetate, 1,4-cineole, eugenol, d-selinene, thymol, d-camphene, linalool acetate, etc. Terpenes are most preferably dl-limonene and d-limonene.

[0037] The oils and fats may be natural oils and fats derived from animals and plants, or may be synthetic or processed oils and fats. Examples of vegetable oils and fats include coconut oil, palm oil, palm kernel oil, linseed oil, camellia oil, brown rice germ oil, rapeseed oil, rice oil, peanut oil, corn oil, wheat germ oil, soybean oil, perilla oil, cottonseed oil, sunflower seed oil, kapok oil, evening primrose oil, shea butter, monkey fat, cocoa butter, sesame oil, safflower oil, olive oil, avocado oil, poppy seed oil, and burdock oil. Examples of animal oils and fats include lard, milk fat, fish oil, and beef tallow. Furthermore, examples of oils and fats (e.g., hardened oils) obtained by processing these oils and fats through fractionation, hydrogenation, transesterification, and the like may also be used. Needless to say, medium-chain triglycerides (MCTs), partial glycerides of fatty acids, and the like may also be used. Mixtures of these may also be used.

[0038] The medium-chain fatty acid triglyceride is not particularly limited, but examples thereof include triglycerides in which the number of carbon atoms in each fatty acid is 6 to 12, preferably 8 to 12.

[0039] The essential oil is not particularly limited, but is preferably an essential oil containing terpenes, and examples thereof include orange oil, capsicum oil, mustard oil, garlic oil, caraway oil, clove oil, cinnamon oil, cocoa extract, coffee bean extract, ginger oil, spearmint oil, celery seed oil, thyme oil, onion oil, nutmeg oil, parsley seed oil, peppermint oil, vanilla extract, funnel oil, pennyroyal oil, peppermint oil, eucalyptus oil, lemon oil, rose oil, rosemary oil, almond oil, ajowan oil, anise oil, amyris oil, angelica root oil, ambrette seed oil, estragon oil, origanum oil, orris root oil, olibanum oil, cassia oil, cascarilla oil, cananga oil, chamomile oil, calamus oil, cardamom oil, carrot seed oil, and kimchi oil. Examples of suitable oils include tuberous root oil, cumin oil, grapefruit oil, cinnamon leaf oil, cade oil, pepper oil, costus root oil, cognac oil, copaiba oil, coriander oil, perilla oil, musk oil, juniper berry oil, star anise oil, sage oil, savory oil, geranium oil, tangerine oil, dill oil, angelica oil, tolu balsam oil, basil oil, birch oil, patchouli oil, palmarosa oil, pimento oil, petitgrain oil, bay leaf oil, bergamot oil, Peru balsam oil, benzoin resin, bois de rose oil, hops oil, boronia absolute, marjolan oil, mandarin oil, myrtle oil, yuzu fragrance, lime oil, lavender oil, roux oil, lemongrass oil, letionine, lovage oil, laurel leaf oil, and wormwood oil.

[0040] The propylene glycol fatty acid ester is not particularly limited, and examples thereof include propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monocaprate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol dilaurate, propylene glycol monomyristate, propylene glycol dimyristate, propylene glycol monopalmitate, propylene glycol dipalmitate, propylene glycol monostearate, propylene glycol distearate, propylene glycol monoisostearate, propylene glycol diisostearate, propylene glycol monooleate, propylene glycol dioleate, propylene glycol monolinoleate, propylene glycol dilinoleate, propylene glycol monolinolenate, and propylene glycol dilinolenate. In addition to the above, propylene glycol difatty acid esters in which the two fatty acid residues are different may also be used.

[0041] Examples of the fatty acids include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, and linolenic acid.

[0042] Examples of the emulsifier include glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyglycerin condensed ricinoleic acid esters, polyoxyethylene sorbitan fatty acid esters, saponins, and phospholipids.

[0043] The phospholipid is not particularly limited, and examples thereof include lecithins such as egg yolk lecithin and purified soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, dicetylphosphate, stearylamine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositolamine, cardiolipin, ceramide phosphorylethanolamine, ceramide phosphorylglycerol, and mixtures thereof. Phospholipids that have been processed by hydrogenation, enzymatic hydrolysis, etc. (hydrogenated lecithin and lysolecithin) can also be used.

[0044] Examples of the fat-soluble vitamins include vitamin E, vitamin A, vitamin D, and vitamin K.

[0045] Examples of the derivatives of vitamins include derivatives of the fat-soluble vitamins and fat-soluble derivatives of water-soluble vitamins, such as vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin, pantothenic acid, folic acid, and biotin.

[0046] The QH contained in the package according to one or more embodiments of the present invention and the QH preserved by the method according to one or more embodiments of the present invention do not need to be preformulated. The QH contained in the package according to one or more embodiments of the present invention and the QH preserved by the method according to one or more embodiments of the present invention are preferably non-preformulated QH, such as QH Form I crystals, QH Form II crystals, cocrystals of QH and one or more other compounds, amorphous solids of QH, and compositions in which QH is dissolved in a solvent and / or a lipid-soluble medium, because this allows the QH, for example, the QH contained in the package and the QH preserved by the method, to be used in a wide range of applications. More preferably, the QH is not preformulated QH (e.g., a cyclodextrin inclusion complex of QH, QH dispersed in a matrix containing a water-soluble excipient in a particulate composition, QH coated with a coating medium in a solid dosage form, or a capsule of QH).

[0047] The water-soluble excipient may be, for example, one or more selected from the group consisting of a water-soluble polymer, a surfactant, a sugar, and a yeast cell wall.

[0048] The coating medium may be, for example, an oil-soluble coating medium or a water-soluble coating medium. The oil-soluble coating medium may be, for example, a sugar ester of a higher fatty acid, shellac, a cellulose derivative, a fatty acid and its ester derivative, a fat or oil, zein, etc. The water-soluble coating medium may be, for example, gelatin, sugar, gum arabic, a sugar ester of a higher fatty acid, tragacanth, pectin, pullulan, alginic acid, dried egg white, milk, curdlan, a cellulose derivative, casein, a casein compound, starch, a yeast cell wall, etc.

[0049] The capsule agent is, for example, QH encapsulated as a soft capsule, hard capsule, microcapsule, etc. Examples of materials for the capsule agent include gelatin derived from cattle bone, cattle hide, pigskin, fish skin, etc.; seaweed-derived products such as carrageenan and alginic acid that can be used as food additives; plant seed-derived products such as locust bean gum and guar gum; manufacturing agents containing cellulose; and starches such as wheat starch, potato starch, sweet potato starch, corn starch, and dextrin.

[0050] <Container> A package according to one or more embodiments of the present invention includes a container for packaging the QH. The container is not particularly limited as long as it can contain the QH and be sealed together with the gas phase. The container may be, for example, a glass container, metal container, resin container, wooden container, or bag that can contain the QH and be sealed together with the gas phase.

[0051] <Packaging> A packaging according to one or more embodiments of the present invention includes a QH and a container for packaging the QH, and is characterized in that the relative humidity of the gas phase inside the container is 50% or higher.

[0052] <Storage Method> A method for storing reduced coenzyme Q10 (QH) according to one or more embodiments of the present invention is characterized by comprising a storage step of storing the QH in a gas phase at a relative humidity of 50% or more.

[0053] It is generally believed that general organic compounds, especially pharmaceutical compounds, are stable under low humidity conditions. However, QH has an unexpected property of exhibiting higher oxidation stability under conditions of higher relative humidity. The packaging and method according to the present embodiment can suppress the oxidation of QH and enable stable storage of QH.

[0054] By storing the package according to this embodiment, and by using the method for storing QH according to this embodiment, oxidation of QH is suppressed, and QH is stored stably.

[0055] Since the production costs of QH in the form of QH Form II crystal, a co-crystal of QH and one or more other compounds, and a composition in which QH is dissolved in a solvent and / or a fat-soluble medium are high, a QH residual rate (see Examples for definition) of 85% or more after storage is required in order to provide QH in these forms at an appropriate price. The package and the QH storage method according to this embodiment are preferable because they can ensure that the QH residual rate of QH in the form of QH Form II crystal, a co-crystal of QH and one or more other compounds, or a composition in which QH is dissolved in a solvent and / or a fat-soluble medium after storage is 85% or more.

[0056] Although QH in the form of QHForm I crystals can be produced at low cost, it is susceptible to oxidation, and therefore, in order to provide this form of QH at an appropriate price, it is required that the QH residual rate after storage (see Examples for definition) be 40% or more. According to the package and the QH storage method of this embodiment, when QH is in the form of QHForm I crystals, the QH residual rate of QH after storage can be made 40% or more, which is preferable.

[0057] In the package according to this embodiment and the method according to this embodiment, the relative humidity of the gas phase is preferably 53% or more, more preferably 60% or more, even more preferably 70% or more, even more preferably 75% or more, even more preferably 80% or more, even more preferably 85% or more, and particularly preferably 90% or more. In particular, when QH is Form I crystal, the relative humidity is preferably 53% or more, more preferably 60% or more, even more preferably 70% or more, even more preferably 75% or more, even more preferably 80% or more, even more preferably 85% or more, and particularly preferably 90% or more. When QH is other than Form I crystal, the relative humidity of the gas phase is preferably 53% or more, more preferably 60% or more, especially preferably 70% or more, and most preferably 75% or more.

[0058] The gas phase in the package according to this embodiment may have the above-mentioned relative humidity when measured at the temperature of the environment in which the package is intended to be used (transported, stored, etc.). The temperature and the temperature in the storage step in the method according to this embodiment are, for example, temperatures of -25°C or higher and 50°C or lower, preferably temperatures of -20°C or higher, -10°C or higher, 0°C or higher, 4°C or higher, 10°C or higher, 15°C or higher, 20°C or higher, or 25°C or higher, and preferably temperatures of 45°C or lower or 40°C or lower. Specifically, the temperature may be 25°C or 40°C.

[0059] In the method according to this embodiment, the period for storing the QH is not particularly limited as long as it is the period from production until the product is used, and can be adjusted appropriately depending on storage conditions such as temperature, but is preferably 3 days or more, 1 week or more, or 2 weeks or more, and can be, for example, 5 years or less, usually 3 years or less, preferably 2 years or less, more preferably 1 year or less, even more preferably 6 months or less, even more preferably 8 weeks or less, and most preferably 6 weeks or less, 5 weeks or less, or 4 weeks or less.

[0060] The gas phase can be air. Compared with a package containing a gas phase of an inert gas such as nitrogen, a package containing air as a gas phase is preferred because it can be manufactured at low cost. Furthermore, compared with a method using a gas phase of an inert gas such as nitrogen, a method using air as a gas phase is preferred because it can be implemented at low cost.

[0061] The method for producing the package according to this embodiment includes a method including a step of placing QH in the container and sealing it in a gas phase with a relative humidity of 50% or more, or a method including a step of placing QH in the container and a step of filling the inside of the container with a gas phase with a relative humidity of 50% or more and sealing it.

[0062] In the package according to this embodiment, the relative humidity of the gas phase can be made 50% or more by further packing a component that makes the relative humidity of the gas phase 50% or more in the container.

[0063] One aspect of the packaging body according to this embodiment is characterized in that the container further contains water, and the water is mixed with the QH or is arranged separately from the QH.

[0064] A more preferred aspect of the method for preserving QH according to one or more embodiments of the present invention is that the preservation step comprises preserving a package comprising the QH and a container for packaging the QH, wherein the relative humidity of the gas phase inside the container is 50% or more.

[0065] According to this aspect, by adjusting the relative humidity of the gas phase in the container to 50% or more, it is possible to store the QH in a gas phase with a relative humidity of 50% or more.

[0066] The relative humidity of the gas phase in the container is preferably 53% or more, more preferably 60% or more, even more preferably 70% or more, even more preferably 75% or more, even more preferably 80% or more, even more preferably 85% or more, and particularly preferably 90% or more. In particular, when QH is Form I crystal, it is preferably 53% or more, more preferably 60% or more, even more preferably 70% or more, even more preferably 75% or more, even more preferably 80% or more, even more preferably 85% or more, and particularly preferably 90% or more. When QH is other than Form I crystal, the relative humidity of the gas phase is preferably 53% or more, more preferably 60% or more, particularly preferably 70% or more, and most preferably 75% or more.

[0067] The container is not particularly limited as long as it can contain QH and be sealed together with the gas phase. The container may be, for example, one of those described above in the section <Container>.

[0068] The method according to this aspect, which includes storing the package in the preservation step, may further include a package preparation step, which may include a step of placing the QH in the container and sealing it in a gas phase with a relative humidity of 50% or more, or a step of packaging the QH in the container and filling the container with a gas phase with a relative humidity of 50% or more to prepare the package.

[0069] The package can also have a gas phase with a relative humidity of 50% or more by further packaging a component in the container that can set the gas phase with a relative humidity of 50% or more.

[0070] One embodiment of the package is characterized in that the container further contains water, and the water is mixed with the QH and arranged to be in contact with a phase containing reduced coenzyme Q10, or arranged separately from the QH.

[0071] In this embodiment of the package, i.e., the package further contains water inside the container, and the water is mixed with the QH, arranged in contact with the phase containing reduced coenzyme Q10, or arranged separately from the QH, the relative humidity of the gas phase is 50% or more due to water vapor evaporated from the liquid water present inside the container. In this embodiment, "water" refers to water present in liquid form. The liquid water present inside the container does not need to be pure water, but may be present as an aqueous solution. The aqueous solution may be a salt solution in which an inorganic salt is dissolved in water to adjust the water activity to less than 1.0. Alternatively, the liquid water may be water releasably supported on a porous carrier such as paper.

[0072] QH is insoluble in water. Examples of water mixed with QH include a dispersion of QH in water and wet crystals of QH.

[0073] The water arranged to be in contact with the phase containing reduced coenzyme Q10 includes water in contact with a solution in which QH is dissolved in a water-immiscible solvent and / or a fat-soluble medium, etc. Examples of the contact state include a state in which the water and the QH solution are layered, or a state in which the water and the QH solution form a water-in-oil or oil-in-water emulsion.

[0074] The water placed separately from the QH refers to water placed in the container so as not to come into contact with the QH. In this case, the QH in the package can be used without drying out after opening, which is preferable.

[0075] Another aspect of the package is characterized in that the container further contains one or more other ingredients, which are mixed with the QH, arranged in contact with a phase containing the QH, or arranged separately from the QH, and the water activity of the contents of the container, including the QH and the other ingredients, at 25°C is 0.50 or more.

[0076] The water activity of the contents can be measured by a conventional method. When a package containing contents with a water activity value of A (a number between 0 and 1) at a predetermined temperature is held at a predetermined temperature until it reaches equilibrium, the relative humidity of the gas phase in the container is A x 100 (%). Therefore, if the water activity of the contents is 0.50 or higher, the relative humidity of the gas phase in the container will be 50% or higher.

[0077] In this embodiment, the water activity of the content at 25°C is preferably 0.53 or more, more preferably 0.60 or more, even more preferably 0.70 or more, even more preferably 0.75 or more, even more preferably 0.80 or more, even more preferably 0.85 or more, and particularly preferably 0.90 or more. In particular, when QH is Form I crystal, the water activity is preferably 0.53 or more, more preferably 0.60 or more, even more preferably 0.70 or more, even more preferably 0.75 or more, even more preferably 0.80 or more, even more preferably 0.85 or more, and particularly preferably 0.90 or more. When QH is other than Form I crystal, the water activity is preferably 0.53 or more, more preferably 0.60 or more, particularly preferably 0.70 or more, and most preferably 0.75 or more.

[0078] In this embodiment, the "one or more other ingredients" may be any ingredient that is used in combination with QH, such as ingredients that are acceptable as foods, cosmetics, or pharmaceuticals.

[0079] When the other component is mixed with QH, the mixture of the other component and QH can be a composition acceptable for use as a food, cosmetic, or pharmaceutical. The mixture of the other component and QH may be a homogeneous mixture of QH and the other component, or a heterogeneous mixture of QH and the other component. A homogeneous mixture refers to a mixture containing QH and the other component, in which the concentration distribution of QH is homogeneous or substantially homogeneous throughout the mixture. A homogeneous mixture can be obtained, for example, by thoroughly mixing QH and the other component. A heterogeneous mixture refers to a mixture containing QH and the other component, in which the concentration distribution of QH is uneven rather than homogeneous. A heterogeneous mixture can be obtained, for example, by adding QH to one or more other components, such as a food material.

[0080] "A phase containing QH" refers to a phase consisting of QH or a homogeneous phase containing QH, such as one or more selected from QH Form I crystals, QH Form II crystals, cocrystals consisting of QH and one or more other compounds, amorphous solids of QH, and compositions in which QH is dissolved in a solvent and / or a fat-soluble medium. An example of a state in which the other component is arranged so as to be in contact with the phase containing QH is a state in which the other component and the phase containing QH are laminated. In this aspect, the other component forms a phase that can be in contact with the phase containing QH without mixing. An example of an embodiment in which the other component is arranged so as to be in contact with the phase containing QH is a laminate of the phase containing QH and the other component, or a state in which one of the phase containing QH and the other component is supported on the other. A further example of an embodiment in which the other component is arranged to contact the QH-containing phase includes a first phase (an example of the QH-containing phase) consisting of a composition in which QH is dissolved in a solvent and / or a fat-soluble medium, and a second phase (an example of the other component) consisting of water or an aqueous solution that is immiscible with the first phase and the second phase, with one of the first and second phases laminated on the other. Another example of an embodiment in which the other component is arranged to contact the QH-containing phase includes a first phase (an example of the QH-containing phase) consisting of particles containing QH, and a second phase (an example of the other component) consisting of one or more other components in a matrix, with the first phase supported on the second phase. Another example of an embodiment in which the other component is arranged to contact the QH-containing phase includes a first phase (an example of the QH-containing phase) consisting of particles containing QH, and a second phase (an example of the other component) consisting of a substance that releases water, with the first phase and the second phase arranged to contact each other.

[0081] The other components arranged separately from the QH refer to the other components arranged in the container so as not to come into contact with the QH. In this case, the QH in the package can be used directly after opening, which is preferable.

[0082] Another aspect of the packaging is characterized in that it further contains a substance that releases water into the interior of the container, and the substance is mixed with the QH, placed in contact with a phase containing the QH, or placed separately from the QH.

[0083] The water-releasing substance is a substance that slowly releases water vapor. By packaging the water-releasing substance, the relative humidity of the gas phase inside the container during the storage step is set to 50% or more, preferably 53% or more, more preferably 60% or more, more preferably 70% or more, more preferably 75% or more, more preferably 80% or more, more preferably 85% or more, and particularly preferably 90% or more.

[0084] The "phase containing QH" refers to a phase consisting of QH or a homogeneous phase containing QH, such as one or more selected from QH Form I crystal, QH Form II crystal, a co-crystal consisting of QH and one or more other compounds, an amorphous solid of QH, and a composition in which QH is dissolved in a solvent and / or a fat-soluble medium. An example of a state in which the water-releasing substance is arranged so as to be in contact with the phase containing QH is a state in which the water-releasing substance and the phase containing QH are layered.

[0085] The water-releasing substance arranged separately from the QH refers to the water-releasing substance arranged in the container so as not to come into contact with the QH. In this case, the QH in the package can be used directly after opening, which is preferable.

[0086] 1. [Regarding Raw Materials] The present invention will be described in more detail in the following examples, but the present invention is not limited to these examples. In the examples, reduced coenzyme Q10 manufactured by Kaneka Corporation (trade name: Kaneka QH) was used as reduced coenzyme Q10 Form I crystals (QH Form I crystals).

[0087] 2. [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 using the following formula was used as a measure of oxidative stability.

[0088] QH remaining rate (%) = 100 x QH ratio at the end of evaluation / QH ratio at the start of evaluation

[0089] (HPLC analysis conditions) Column: SYMMETRY C18 (manufactured by Waters) 250 mm (length) 4.6 mm (inner diameter) Mobile phase: C ２ H ５ OH:CH ３ OH = 4:3 (v:v) Detection wavelength: 210 nm Flow rate: 1 ml / min

[0090] 3. [Method for producing reduced coenzyme Q10 Form II crystals (QHForm II crystals)] 89 g of QHForm I crystals was added to 611 g of ethanol and heated to 50 ° C. to completely dissolve the QHForm I crystals. The solution was cooled, and when it reached 36 ° C., 1.8 g of reduced coenzyme Q10 Form II crystals prepared according to the description of Patent Document 2 were added as seed crystals. The solution was cooled to 33.5 ° C. over 7 hours, then cooled to 25 ° C. at a rate of 1 ° C. / hour, and further cooled to 1 ° C. at a rate of 10 ° C. / hour to obtain a white slurry. The resulting slurry was filtered under reduced pressure to obtain wet crystals, which were washed with cold ethanol and further dried under reduced pressure to obtain QHForm II crystals.

[0091] 4. [Method for Adjusting Humidity in Package] <Method for Adjusting Humidity Using Saturated Salt Aqueous Solution> Approximately 50 ml of saturated aqueous solution was prepared for each of the salts shown in Table 1. By using an excess amount of the salt relative to its solubility, the solid salt remained in the solution, preventing changes in the salt concentration of the aqueous solution due to moisture absorption. For each salt, the saturated aqueous solution containing the solid salt was divided and placed into two 90 mm diameter Petri dishes, and these Petri dishes were placed in a polycarbonate jar (internal volume 7000 ml) to prepare packages 4-(1) to 4-(6).

[0092]

[0093] 5. Storage of QHForm II Crystals in a Humidity-Controlled Atmosphere [Example 1 and Reference Example 1] 0.2 g of QHForm II crystals was packed in an open state into packages 4-(1) to 4-(6) in Table 1 above and sealed. The saturated salt solution and QHForm II crystals were placed separately within the package. The packages (4-(1) to 4-(6)) containing the QHForm II crystals were stored at 40°C or 25°C for 4 weeks, and the QH residual rate was determined. The relative humidity within 4-(1) to 4-(6) was also determined according to Greenspan, J Res NBS A Phys Ch, 1977. The QH residual rate and the relative humidity within the package are shown in Table 2.

[0094]

[0095] From Table 2, it was found that QHForm II crystals can be kept stable if stored under conditions of a relative humidity of 50% or higher.

[0096] [Example 2] In a chamber adjusted to a relative humidity of 85%, 0.1 g of the QHForm II crystal obtained above was placed in an aluminum laminate bag (volume approximately 1000 ml) and sealed to prepare a package containing QHForm II crystal. After storing the package at 25 ° C for 4 weeks, the QH residual rate was determined. The relative humidity and QH residual rate in the package are shown in Table 3.

[0097]

[0098] Table 3 reveals that reduced coenzyme Q10 can be kept stable by adjusting the relative humidity of the environment in which the package is produced, i.e., the relative humidity of the gas phase enclosed in the package, to 50% or more.

[0099] Example 3: 3 g of water was placed in a glass bottle (volume 33 ml). 0.1 g of the QHForm II crystal obtained above was placed in the glass bottle using aluminum foil to prevent contact with the water, and the glass bottle was sealed. This package was stored for 4 weeks under conditions of 40°C and 75% relative humidity, and the QH residual rate was determined.

[0100] [Example 4] 3 g of commercially available bread was placed in a glass bottle (volume 33 ml). 0.1 g of the QHForm II crystals obtained above was placed in contact with the bread in the glass bottle, and the glass bottle was sealed. This package was stored under conditions of 40 ° C and 75% relative humidity for 4 weeks, and then the QH residual rate was determined.

[0101] The results obtained in Examples 3 and 4 are summarized in Table 4.

[0102]

[0103] Table 4 and Example 1 reveal that when water and / or substances containing water are present in the package, the packed QHForm II type crystal can be kept very stable regardless of whether or not it comes into contact with the water and / or substances containing water.

[0104] 6. Storage of reduced coenzyme Q10 dissolved in MCT oil under a humidity-controlled atmosphere [Example 5 and Reference Example 2] Packages 6-(1) to 6-(4) were prepared using the salts shown in Table 5 instead of the salts shown in Table 1. Furthermore, packages were prepared in the same manner as in Example 1, except that 3 g of an MCT (medium-chain fatty acid triglyceride) solution containing 3.3% (w / w) reduced coenzyme Q10 was used instead of 0.2 g of QH Form II crystals. After storing these packages at 40°C for 2 weeks, the QH residual rate was determined in the same manner as in Example 1. The QH residual rate and the relative humidity inside the packages are shown in Table 6.

[0105]

[0106]

[0107] Table 6 reveals that under conditions of a relative humidity of 50% or higher, the QH residual rate is high, that is, the reduced coenzyme Q10 present in the MCT solution is kept stable.

[0108] Example 6: 3 g of a 0.04% aqueous solution of hexaglycerin monolaurate was placed in a glass bottle (volume 33 ml) and layered with 1.5 g of MCT containing 3.3% (w / w) reduced coenzyme Q10. The water activity of the composition consisting of 3 g of a 0.04% aqueous solution of hexaglycerin monolaurate and 1.5 g of MCT containing 3.3% (w / w) reduced coenzyme Q10 at 25°C was 0.98. The glass bottle was sealed and stored at 25°C and 60% relative humidity for 4 weeks. The QH residual rate was measured and found to be 96.2%.

[0109] Example 6 revealed that reduced coenzyme Q10 present in the MCT solution remains stable even when the layer of the MCT solution containing reduced coenzyme Q10 is in contact with water.

[0110] 7. Storage of QHForm I Crystal in a Humidity-Controlled Environment [Example 7 and Reference Example 3] Packages 7-(1) to 7-(8) were prepared using the salts shown in Table 7 instead of the salts shown in Table 1. In addition, a package similar to that of Example 1 was prepared, except that QHForm I crystal was used instead of QHForm II crystal. After storing this package at 40°C for 2 weeks, the QH residual rate was determined in the same manner as in Example 1. The QH residual rate and the relative humidity inside the package are shown in Table 8.

[0111]

[0112]

[0113] From Table 8, it was found that under conditions of a relative humidity of 50% or more, the QH residual rate was high, i.e., the QHForm I crystals were kept stable. Furthermore, in the case of QHForm I crystals, a tendency for the stability to increase as the relative humidity increased was observed.

[0114] [Example 8] Tissue paper containing about 20 g of water and 0.2 g of QHForm I crystals were placed in an aluminum laminated bag (volume: about 1000 ml) so as not to come into contact with each other, and the bag was sealed. This package was stored at 40°C and a relative humidity of 75% for 2 weeks, and then the residual rate of QH was determined.

[0115] [Example 9] 0.1 g of QHForm I crystals was placed in a glass bottle (volume 33 ml) containing 3 g of water using aluminum foil to prevent contact with the water, and the glass bottle was sealed. This package was stored for 2 weeks under conditions of 40°C and a relative humidity of 75%, and then the QH residual rate was determined.

[0116] [Example 10] 3 g of commercially available bread was placed in a glass bottle (volume 33 ml), and 0.1 g of QHForm I crystals was placed in contact with the bread in the glass bottle, and the glass bottle was sealed. This package was stored under conditions of 40 ° C and 75% relative humidity for 2 weeks, and then the QH residual rate was determined.

[0117] Example 11 0.1 g of QHForm I crystals was placed in a glass bottle (volume 33 ml). The water or aqueous solution shown in Table 9 was placed in the glass bottle in the amount shown in Table 9, and mixed with the QHForm I crystals. The glass bottle was sealed and stored at 40°C and a relative humidity of 75% for 2 weeks, after which the residual QH rate was determined.

[0118]

[0119] The results obtained in Examples 8 to 11 are summarized in Table 10.

[0120]

[0121] [Example 12] 3 g of commercially available bread was placed in a glass bottle (volume 33 ml). 0.1 g of QHForm I crystals was placed in contact with the bread in the glass bottle, and the glass bottle was sealed. This package was stored for 4 weeks under conditions of 25 ° C and 60% relative humidity, and then the QH residual rate was determined. The water activity at 25 ° C of the composition consisting of 3 g of bread and 0.1 g of QHForm I crystals was 0.95.

[0122] Example 13 0.1 g of QHForm I crystals was placed in a glass bottle (volume 33 ml). The aqueous solutions shown in Table 11 were placed in the glass bottle in the amounts shown in Table 11 and mixed with the QHForm I crystals. The glass bottle was sealed and stored at 25°C and 60% relative humidity for 4 weeks, after which the QH residual rate was determined.

[0123]

[0124] Reference Example 4 0.2 g of QHForm I crystals was packed in an open state and sealed in a package 7-(1) shown in Table 7. The package with an internal relative humidity of 11% was stored at 25°C for 4 weeks, and then the QH residual rate was determined in the same manner as in Example 1.

[0125] The results obtained in Examples 12, 13, and Reference Example 4 are summarized in Table 12.

[0126]

[0127] Tables 10, 8, and 12 reveal that when water and / or substances containing water are present in the package, the packed QHForm I type crystal can be kept very stable regardless of whether or not it comes into contact with the water and / or substances containing water.

[0128] 8. [Method for producing a cocrystal consisting of reduced coenzyme Q10 and nicotinamide] 4.33 g of QHForm I crystals and 1.22 g of nicotinamide were added to 7.85 g of ethanol, and the mixture was heated to 50°C, completely dissolving the QHForm I crystals and nicotinamide. The 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 observed at a temperature different from the melting point of the QHForm I crystals used as raw materials (48°C) and the melting point of nicotinamide (127°C).

[0129] [Example 14 and Reference Example 5] 0.2 g of a cocrystal consisting of QH and nicotinamide was packed in an open state into the packages 4-(1) and 4-(2) in Table 1 above and then sealed. The saturated salt solution and the cocrystal were placed separately within the package. The packages (4-(1) and 4-(2)) containing the cocrystal were stored at 40°C for 2 weeks, and then the QH residual rate was determined. In addition, the relative humidity within 4-(1) and 4-(2) was determined according to Greenspan, J Res NBS A Phys Ch, 1977. The QH residual rate and the relative humidity within the package are shown in Table 13.

[0130]

[0131] Table 13 reveals that under conditions of relative humidity of 50% or higher, the QH residual rate is high, that is, the QH present in the cocrystal consisting of QH and nicotinamide is stably maintained.

[0132] The examples show that reduced coenzyme Q10 is stable regardless of whether it is a Form I crystal, a Form II crystal, or a co-crystal consisting of reduced coenzyme Q10 and one or more other compounds, and that non-crystalline reduced coenzyme Q10 present in solution is also stable.

[0133] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0134] 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 the numerical ranges can be arbitrarily combined to define a preferred range, the upper limits of the numerical ranges can be arbitrarily combined to define a preferred range, and the lower limits of the numerical ranges can be arbitrarily combined to define a preferred range. Furthermore, in this application, numerical ranges expressed using the symbol "to" include the numerical values ​​written before and after the symbol "to" as the upper and lower limits, respectively.

[0135] Throughout this specification, singular terms should be understood to include the plural concept unless otherwise stated. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise stated.

[0136] Although the present embodiment has been described in detail above, the specific configuration is not limited to this embodiment, and even if there are design changes within the scope that do not deviate from the gist of this disclosure, they are included in this disclosure.

Claims

1. Reduced coenzyme Q10, A container for packaging the reduced coenzyme Q10; Including, A package in which the relative humidity of the gas phase inside the container is 50% or more.

2. The reduced coenzyme Q10 is one or more selected from Form I crystals of reduced coenzyme Q10, Form II crystals of reduced coenzyme Q10, cocrystals consisting of reduced coenzyme Q10 and one or more other compounds, amorphous solids of reduced coenzyme Q10, and compositions in which reduced coenzyme Q10 is dissolved in a solvent and / or a fat-soluble medium. The package of claim 1.

3. Further comprising water within the container; The water is mixed with the reduced coenzyme Q10, arranged to be in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10. The package according to claim 1 or 2.

4. further comprising one or more other ingredients within said container; The other component is mixed with the reduced coenzyme Q10, arranged so as to be in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10; The water activity of the contents of the container, which contain reduced coenzyme Q10 and the other ingredients, at 25°C is 0.50 or more. The package according to claim 1 or 2.

5. further comprising a substance that releases water into the interior of the container; The substance is mixed with the reduced coenzyme Q10, arranged to be in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10. The package according to claim 1 or 2.

6. A method for preserving reduced coenzyme Q10, comprising: A method comprising a storage step of storing the reduced coenzyme Q10 in a gas phase with a relative humidity of 50% or more.

7. The reduced coenzyme Q10 is one or more selected from Form I crystals of reduced coenzyme Q10, Form II crystals of reduced coenzyme Q10, cocrystals consisting of reduced coenzyme Q10 and one or more other compounds, amorphous solids of reduced coenzyme Q10, and compositions in which reduced coenzyme Q10 is dissolved in a solvent and / or a fat-soluble medium. The method of claim 6.

8. The preservation step comprises: The reduced coenzyme Q10, A container for packaging the reduced coenzyme Q10; Including, A package in which the relative humidity of the gas phase inside the container is 50% or more. including storing 8. The method according to claim 6 or 7.

9. Further comprising water within the container; The water is mixed with the reduced coenzyme Q10, arranged to be in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10. The method of claim 8.

10. further comprising one or more other ingredients within said container; The other component is mixed with the reduced coenzyme Q10, arranged so as to be in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10; The water activity of the contents of the container, which contain reduced coenzyme Q10 and the other ingredients, at 25°C is 0.50 or more. The method of claim 8.

11. further comprising a substance that releases water into the interior of the container; The substance is mixed with the reduced coenzyme Q10, arranged to be in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10. The method of claim 8.

12. The method further includes a package preparation step of packaging the reduced coenzyme Q10 in the container in a gas phase with a relative humidity of 50% or more to prepare the package; The method of claim 8.

13. The method further includes a package preparation step of packaging the reduced coenzyme Q10 in the container and filling the inside of the container with a gas phase having a relative humidity of 50% or more to prepare the package. The method of claim 8.