Classifications

• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/18—Antioxidants, e.g. antiradicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D77/00—Packages formed by enclosing articles or materials in preformed containers, e.g. boxes, cartons, sacks or bags
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
  • B65D81/18—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents providing specific environment for contents, e.g. temperature above or below ambient
  • B65D81/22—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents providing specific environment for contents, e.g. temperature above or below ambient in moist conditions or immersed in liquids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C46/00—Preparation of quinones
  • C07C46/10—Separation; Purification; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C50/00—Quinones
  • C07C50/02—Quinones with monocyclic quinoid structure
  • C07C50/06—Quinones with monocyclic quinoid structure with unsaturation outside the quinoid structure
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3

Definitions

• One or more embodiments of the present invention relate to reduced coenzyme Q10 packages and storage methods.
• Coenzyme Q is an essential component that is widely distributed in living organisms, from bacteria to mammals, and is known as a component of the mitochondrial electron transport system in cells in living organisms.
• coenzyme Q10 which has 10 repeating structures in the side chain of coenzyme Q, is the main component, and about 40 to 90% of the coenzyme exists in vivo as a reduced form.
• Physiological actions of coenzyme Q include activation of energy production by mitochondrial activation, activation of cardiac function, stabilization of cell membranes, and protection of cells by antioxidant action.
• QH reduced coenzyme Q10
• Patent Document 1 A general method for obtaining reduced coenzyme Q10 has already been disclosed (Patent Document 1).
• Patent Document 2 describes that crystal polymorphism is observed in reduced coenzyme Q10. or "QH Form II type crystal" is much more stable than conventional reduced coenzyme Q10 (hereinafter, this crystal is referred to as "Form I type crystal of reduced coenzyme Q10" or "QH Form I type crystal"), Other physical properties are also reported to be excellent.
• Patent Document 3 as a method for producing reduced coenzyme Q10, after mixing a coenzyme Q10-cyclodextrin clathrate (CoQ10-CD clathrate) with an antioxidant, the A method for producing a reduced CoQ10-CD clathrate by storing in a 100% atmosphere is described.
• Patent Document 3 when a mixture of CoQ10, which is not a CD clathrate, and an antioxidant is stored at 60° C. and a humidity of 75%, the production ratio of reduced CoQ10 is low, whereas CoQ10-CD clathrate and It is described that when a mixture with an antioxidant was stored under the same conditions, a large amount of reduced CoQ10 was produced.
• Patent Documents 4, 5, and 6 a matrix containing a water-soluble excipient or a water-soluble excipient and water-soluble ascorbic is used as reduced coenzyme Q10 having high oxidation stability and high bioabsorbability.
• water-soluble excipients include gum arabic and gelatin.
• Patent Document 7 as a formulation for protecting reduced coenzyme Q10 from oxidation, a solid composition containing reduced coenzyme Q10 is coated with at least one type of coating selected from an oil-soluble coating medium and a water-soluble coating medium.
• a solid preparation of reduced coenzyme Q10 coated with a medium is described, and a method is described in which the preparation is placed in an environment adjusted to a relative humidity of 75% or less.
• Shellac and zein are exemplified as oil-soluble coating media.
• Gelatine, sugar, gum arabic, pullulan, cellulose derivatives and yeast cell walls are exemplified as aqueous coating media.
• Patent Document 8 a capsule containing reduced coenzyme Q10 is manufactured or obtained, and the environment surrounding the capsule is controlled to a relative humidity of 0% or more and 60% or less.
• the storage method for Q10 is described.
• Gelatin and the like are exemplified as the material of the capsule.
• Non-Patent Document 1 describes that the oxygen permeability of a gelatin film containing no glycerin increases tenfold when the relative humidity increases by 20%.
• Non-Patent Document 2 "Oxygen permeability tends to increase by 10 to 105 times as water activity and relative humidity increase.
• the oxygen permeability of a collagen film is 6 when the water activity is 0. .6 ⁇ 10 ⁇ 19 gm ⁇ 1 s ⁇ 1 Pa ⁇ 1 , but becomes 13.68 ⁇ 10 ⁇ 15 gm ⁇ 1 s ⁇ 1 Pa ⁇ 1 when the water activity is 0.93.”
• Non-Patent Document 3 describes that "in general, when the amount of plasticizer, temperature, and relative humidity increase, the oxygen and water vapor permeability of the protein film increases.”
• Patent Documents 4 to 8 all relate to techniques for improving oxidation stability by coating QH with a coating of gas barrier materials such as gelatin, gum arabic and shellac.
• Patent Documents 4 to 8 describe that QH is stabilized when a QH preparation coated with a gas-barrier film such as gelatin is stored at a relative humidity below a predetermined value.
• Patent Documents 4 to 8 disclose gas barrier properties by setting the relative humidity to a predetermined value or less. It can be understood that the oxygen permeability of the film is reduced and the oxidation of QH is suppressed.
• Non-Patent Documents 4 and 5 It is known that the stability of organic compounds generally decreases as the relative humidity increases.
• Patent Document 9 describes that a co-crystal containing reduced coenzyme Q10 and a compound such as 3,4-dihydroxybenzoic acid was found as a further form of reduced coenzyme Q10.
• Patent Document 10 describes that reduced coenzyme Q10 and nicotinamide form a co-crystal. Co-crystallization of reduced coenzyme Q10 and one or more other compounds may improve the oxidation stability of reduced coenzyme Q10. Can not.
• Patent Documents 3 to 8 disclose QH products that prevent oxidation of reduced coenzyme Q10 (QH) and can be stored stably.
• QH reduced coenzyme Q10
• Patent Documents 3 to 8 the applications of QH are limited because they all require formulation of QH with specific ingredients.
• one or more embodiments of the present invention provide QH products with reduced oxidation of QH that do not require formulation of QH.
• One or more embodiments of the present invention also provide methods of preserving QH that can inhibit oxidation of QH without requiring formulation of QH.
• the reduced coenzyme Q10 is a Form I crystal of reduced coenzyme Q10, a Form II crystal of reduced coenzyme Q10, a co-crystal consisting of reduced coenzyme Q10 and one or more other compounds, or a reduced coenzyme.
• the package according to (1) which is one or more selected from an amorphous solid of enzyme Q10 and a composition in which reduced coenzyme Q10 is dissolved in a solvent and/or a fat-soluble medium.
• a method for storing reduced coenzyme Q10 comprising: A method comprising a storage step of storing the reduced coenzyme Q10 in a gas phase at a relative humidity of 50% or higher.
• the reduced coenzyme Q10 is a Form I crystal of reduced coenzyme Q10, a Form II crystal of reduced coenzyme Q10, a co-crystal consisting of reduced coenzyme Q10 and one or more other compounds, or a reduced coenzyme.
• the method according to (10) wherein one or more selected from an amorphous solid of enzyme Q10 and a composition in which reduced coenzyme Q10 is dissolved in a solvent and/or a fat-soluble medium.
• the storage step includes the reduced coenzyme Q10; and and a container for packing the reduced coenzyme Q10, Preserving a package in which the relative humidity of the gas phase inside the container is 50% or more, (10) or the method according to (11). (13) further comprising water inside the container; The water is mixed with the reduced coenzyme Q10, arranged in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10. ing, The method according to (12).
• (14) further comprising one or more other ingredients inside said container;
• the other component is mixed with the reduced coenzyme Q10, arranged in contact with the phase containing the reduced coenzyme Q10, or separated from the reduced coenzyme Q10 is placed,
• the water activity at 25° C. of the contents containing the reduced coenzyme Q10 and the other components in the container is 0.50 or more.
• (15) further comprising a substance that releases water to the interior of said container;
• the substance is mixed with the reduced coenzyme Q10, arranged in contact with a phase containing the reduced coenzyme Q10, or arranged separately from the reduced coenzyme Q10. ing, (12)
• (16) further comprising a package preparation step of preparing the package by packing the reduced coenzyme Q10 in the container under a gas phase with a relative humidity of 50% or more; (12) The method according to any one of (15).
• (18) the reduced coenzyme Q10 is not a clathrate of reduced coenzyme Q10 with cyclodextrin; (10) The method according to any one of (17).
• the reduced coenzyme Q10 is not reduced coenzyme Q10 dispersed in a matrix containing a water-soluble excipient in the particulate composition; (10) The method according to any one of (18). (20) the reduced coenzyme Q10 is not the reduced coenzyme Q10 coated with a coating medium in the solid preparation; (10) The method according to any one of (19). (21) the reduced coenzyme Q10 is not a reduced coenzyme Q10 capsule, (10) The method according to any one of (20).
• This specification includes the disclosure contents of Japanese Patent Application Nos. 2021-210581, 2021-210585, 2022-152287, and 2022-152297, which are the basis of priority of the present application.
• Reduced coenzyme Q10 in the package and method according to one or more embodiments of the present invention means that as long as the main component is reduced coenzyme Q10, it partially contains oxidized coenzyme Q10. good too.
• the main component is, 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, still more preferably 90% by weight or more, particularly preferably 95% by weight. Above, it means that the content is more than 98% by weight.
• the ratio is the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10.
• reduced coenzyme Q10 has two crystal polymorphs, Form I and Form II. Specifically, the melting point is around 48° C., and the diffraction angles (2 ⁇ 0.2°) are 3.1°, 18.7°, 19.0°, and 20° in powder X-ray (Cu—K ⁇ ) diffraction.
• the crystal form of reduced coenzyme Q10 showing characteristic peaks at .2° and 23.0° is Form I type crystal, and has a melting point of around 52°C.
• Reduced coenzyme Q10 showing characteristic peaks at angles (2 ⁇ 0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0° and 33.3° is a Form II crystal.
• reduced coenzyme Q10 includes QH Form I type crystals, QH Form II type crystals, co-crystals composed of QH and one or more other compounds, amorphous solids of QH, and QH.
• QH can be used one or more selected from compositions in which 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, oils and fats, essential oils, and propylene glycol fatty acid esters.
• the fat-soluble medium is not particularly limited as long as it is a substance capable of dissolving QH.
• a composition in which QH is dissolved in a solvent and/or a fat-soluble medium may be a liquid composition or a solid composition under the temperature conditions at which the package is used or stored, but is preferably is a liquid composition.
• the one or more other compounds contained in the co-crystal composed of QH and one or more other compounds are not particularly limited as long as they are compounds capable of forming a co-crystal with QH. Examples include benzoic acid and derivatives thereof. organic carboxylic acids, including resorcinol, benzyl alcohol, organic alcohols including phenol and its derivatives, urea, nicotinamide, and the like.
• the other one or more compounds may be one or more, and may be one or two or more, preferably one to three compounds.
• the alcohols are not particularly limited, regardless of whether they are cyclic or non-cyclic, and whether they are saturated or unsaturated. Generally, those having 1 to 20 carbon atoms are mentioned, preferably 1 to 12 carbon atoms, more preferably 1 to 5 carbon atoms, particularly preferably 1 to 4 carbon atoms, and among these, monohydric alcohols are preferred. Most preferably, it is a monohydric alcohol having 2 carbon atoms. Dihydric alcohols having 2 to 5 carbon atoms, preferably 2 to 4 carbon atoms, more preferably 3 carbon atoms, and trihydric alcohols having 3 carbon atoms are also suitably used.
• Monohydric alcohols include, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, 3-pen Tanol, 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, 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
• 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 and the like can be mentioned.
• Preferred are 1,2-ethanediol, 1,2-propanediol, 1,3-butanediol and 1,3-propanediol, and most preferred is 1,2-propanediol.
• glycerin As the trihydric alcohol, glycerin or the like can be suitably used.
• the hydrocarbons are not particularly limited, but may include, for example, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, and the like. Aliphatic hydrocarbons and aromatic hydrocarbons are particularly preferred, and aliphatic hydrocarbons are particularly preferred.
• the aliphatic hydrocarbon is not particularly limited regardless of whether it is cyclic or non-cyclic, and whether it is saturated or unsaturated, but non-cyclic aliphatic hydrocarbons are particularly preferably used. Further, those having 3 to 20 carbon atoms, preferably 5 to 12 carbon atoms are usually used.
• 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, dodecane and the like.
• the ketones are not particularly limited regardless of whether they are cyclic or non-cyclic, saturated or unsaturated. Specific examples include acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, acetophenone, 4-methoxyphenylacetone, paramethylacetophenone, methyl ⁇ -naphthyl ketone and the like, preferably acetone, acetophenone, They are 4-methoxyphenylacetone, paramethylacetophenone, and methyl ethyl ketone.
• the terpenes are not particularly limited, and any of hemiterpene, monoterpene, sesquiterpene, diterpene, sesterterpene, and triterpene can be suitably used. Among them, from the viewpoint of solubility in QH, hemiterpene, monoterpene and sesquiterpene are more preferable, monoterpene and sesquiterpene are particularly preferable, and monoterpene is most preferable.
• terpenes include prenol, 3-methyl-3-buten-2-ol, tiglic acid, angelic acid, senateic acid, isovaleric acid, alloocimene, ⁇ -bourvonene, ⁇ -cadinene, dehydro-p - cymene, menthol, dl-limonene, d-limonene, l-limonene, p-cymene, ⁇ -pinene, valencene, myrcene, bisabolene, carene, caryophyllene, terpinene, phytol, cis-3,7-dimethyl-1,3 , 6-octatriene, ⁇ -elemene, ⁇ -elemene, ⁇ -farnesene, ⁇ -farnesene, farnesene, germacrene D, ⁇ -guayene, longifolene, ⁇ -ocimene, ⁇ -
• the fats and oils may be natural fats and oils from animals and plants, synthetic fats and oils, and processed fats and oils.
• 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, cacao butter, sesame oil, safflower oil, olive oil, avocado oil, poppy seed oil, burdock root oil, etc. can be mentioned.
• Lard, milk fat, fish oil, beef tallow, and the like can be mentioned, and fats and oils (for example, hydrogenated oil) obtained by processing these by fractionation, hydrogenation, transesterification, etc. can also be mentioned.
• fats and oils for example, hydrogenated oil
• MCT medium chain triglycerides
• partial glycerides of fatty acids and the like can also be used. A mixture of these may also be used.
• the medium-chain fatty acid triglyceride is not particularly limited, but includes, for example, triglycerides in which each fatty acid has 6 to 12 carbon atoms, preferably 8 to 12 carbon atoms.
• the essential oil is not particularly limited, it is preferably an essential oil containing terpenes, such as orange oil, capsicum oil, mustard oil, garlic oil, caraway oil, clove oil, cinnamon oil, cocoa extract, and coffee bean extract.
• the propylene glycol fatty acid ester is not particularly limited as a propylene glycol fatty acid ester, but propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monocaprate, propylene glycol dicaprate, propylene glycol monolaurate.
• fatty acids examples include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, and linolenic acid.
• emulsifier examples 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.
• Phospholipids are not particularly limited, but examples include lecithins such as egg yolk lecithin and refined soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, dicetyl phosphate, stearylamine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositolamine, cardiolipin, ceramide phosphorylethanolamine, ceramide phosphorylglycerol, mixtures thereof, and the like.
• Phospholipids (hydrogenated lecithin and lysolecithin) subjected to processing such as hydrogenation and enzymatic decomposition can also be used.
• fat-soluble vitamins examples include vitamin E, vitamin A, vitamin D, vitamin K, and the like.
• Examples of the derivatives of vitamins include derivatives of fat-soluble vitamins and fat-soluble derivatives of water-soluble vitamins.
• examples of water-soluble vitamins include vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin, pantothenic acid, folic acid, biotin and the like.
• the QH to be stored in the package according to one or more embodiments of the present invention and the QH to be stored by the method according to one or more embodiments of the present invention do not need to be formulated in advance.
• the QH in the package according to one or more embodiments of the invention and the QH stored by the method according to one or more embodiments of the invention are not pre-formulated QH, such as QH Form I crystals, QH Form II crystals, QHs and one or more other compounds, an amorphous solid of QH, and QH consisting of only one or more selected from a composition dissolved in a solvent and/or a lipid-soluble medium, QH, for example
• the QHs stored in the package and the QHs stored by the above method can be used for a wide range of purposes, which is preferable.
• the QH is a pre-formulated QH (e.g., an inclusion complex of QH with a cyclodextrin, a QH dispersed in a matrix containing a water-soluble excipient in a particulate composition, a coating medium in a solid formulation). not QH coated with (or capsules of QH).
• a pre-formulated QH e.g., an inclusion complex of QH with a cyclodextrin, a QH dispersed in a matrix containing a water-soluble excipient in a particulate composition, a coating medium in a solid formulation.
• the water-soluble excipient can be, for example, one or more selected from the group consisting of water-soluble polymers, surfactants, sugars, and yeast cell walls.
• the coating medium can be, for example, an oil-soluble coating medium or a water-soluble coating medium.
• the oil-soluble coating medium can be, for example, sugar esters of higher fatty acids, shellac, cellulose derivatives, fatty acids and their ester derivatives, oils and fats, zein and the like.
• Examples of the water-soluble coating medium include gelatin, sugar, gum arabic, sugar esters of higher fatty acids, tragacanth, pectin, pullulan, alginic acid, dried egg white, milk, curdlan, cellulose derivatives, casein, casein compounds, starch, and yeast. It can be a cell wall or the like.
• the capsule is, for example, QH encapsulated with a soft capsule, hard capsule, microcapsule, or the like.
• Materials for the capsule include, for example, gelatin derived from bovine bone, bovine skin, pig skin, fish skin, etc.; seaweed-derived products such as carrageenan and alginic acid that can be used as food additives; locust bean gum, guar gum, etc. Products derived from plant seeds; production agents containing celluloses; starches such as wheat starch, potato starch, sweet potato starch, corn starch, and dextrin.
• a package according to one or more embodiments of the present invention includes a container for packaging QHs.
• the container is not particularly limited as long as it can contain QH and can be sealed together with the gas phase.
• Said container may be, for example, a glass container, a metal container, a resin container, a wooden container or a bag that can contain the QH and be sealed together with the gas phase.
• a package according to one or more embodiments of the present invention comprises: QH and and a container for packaging the QH,
• the gas phase inside the container has a relative humidity of 50% or higher.
• a method for storing reduced coenzyme Q10 (QH) comprises: It is characterized by including a storage step of storing the QH under a gas phase with a relative humidity of 50% or more.
• QH Form II crystals, co-crystals consisting of QH and one or more other compounds, and QH in the form of compositions in which QH is dissolved in a solvent and/or in a lipid-soluble medium have high production costs per se, and are therefore difficult to store.
• a post-QH residual rate (see Examples for definition) of 85% or more is required in order to provide QH in the above form at an appropriate price.
• QH is a QHFormII type crystal, a cocrystal consisting of QH and one or more other compounds, or QH is in a solvent and / or a fat-soluble medium It is preferable because the QH residual rate of the QH after storage when it is in the form of a composition dissolved therein can be 85% or more.
• QH in the form of QHFormI type crystal can be produced at low cost, but is susceptible to oxidation. of QH at an appropriate price.
• the QH residual rate of QH after storage when QH is in the form of QHFormI type crystal can be 40% or more. preferable.
• the relative humidity of the gas phase is preferably 53% or higher, more preferably 60% or higher, still more preferably 70% or higher, further preferably 75% or higher, 80% or more is more preferable, 85% or more is more preferable, and 90% or more is particularly preferable.
• QH is a Form I type crystal
• it is preferably 53% or more, more preferably 60% or more, still more preferably 70% or more, even more preferably 75% or more, still more preferably 80% or more, further preferably 85% or more.
• 90% or more are particularly preferred.
• the relative humidity of the gas phase is preferably 53% or higher, more preferably 60% or higher, particularly preferably 70% or higher, and most preferably 75% or higher.
• the gas phase in the package according to this embodiment may have the above relative humidity when measured at the temperature of the environment in which the package is used (transported, stored, etc.).
• the temperature of the storage step is, for example, a temperature of ⁇ 25° C. or higher and 50° C. or lower, preferably ⁇ 20° C. or higher, ⁇ 10° C. or higher, 0° C. or higher. °C or higher, 10 °C or higher, 15 °C or higher, 20 °C or higher, or 25 °C or higher, preferably 45 °C or lower or 40 °C or lower.
• Said temperature may in particular be 25°C or 40°C.
• the period for storing the QH in the method according to the present embodiment is not particularly limited as long as it is a period from after manufacture to use of the product, and can be appropriately adjusted according to storage conditions such as temperature, but is preferably 3 days or more, 1 week or more, or 2 weeks or more, 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, further preferably 8 weeks or less , most preferably 6 weeks or less, 5 weeks or less or 4 weeks or less.
• the gas phase can be air.
• a package containing air as a gas phase can be manufactured at a lower cost than a package containing a gas phase of an inert gas such as nitrogen, which is preferable.
• the method using air as the gas phase is preferable because it can be carried out at a lower cost than the method using the gas phase of an inert gas such as nitrogen.
• a method for producing a package according to this embodiment or A method including the steps of housing QH in the container, and filling the inside of the container with a gas phase having a relative humidity of 50% or more and sealing the container is exemplified.
• 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.
• the package according to the present embodiment further comprising water inside the container;
• the water is mixed with the QH, or arranged separately from the QH.
• a more preferred aspect of the method for preserving QH according to one or more embodiments of the present invention is
• the storage step includes the QH; and a container for packaging the QH, Preserving the package in which the relative humidity of the gas phase inside the container is 50% or higher.
• the relative humidity of the gas phase in the container is preferably 53% or higher, more preferably 60% or higher, still more preferably 70% or higher, even more preferably 75% or higher, still more preferably 80% or higher, and even more preferably 85% or higher. , 90% or more are particularly preferred.
• QH is a Form I type crystal
• it is preferably 53% or more, more preferably 60% or more, still more preferably 70% or more, even more preferably 75% or more, still more preferably 80% or more, further preferably 85% or more.
• 90% or more are particularly preferred.
• the relative humidity of the gas phase is preferably 53% or higher, more preferably 60% or higher, particularly preferably 70% or higher, and most preferably 75% or higher.
• 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 described in the ⁇ Container> section above.
• the method according to this aspect including storing the package in the storing step may further include a package producing step.
• a package manufacturing process A step of housing and sealing the QH in the container under a gas phase with a relative humidity of 50% or more, or A process of packing the QH in the container and filling the inside of the container with a gas phase having a relative humidity of 50% or more to produce the package is exemplified.
• 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.
• One aspect of the package is further comprising water inside the container;
• the water is mixed with the QH, placed in contact with the phase containing the reduced coenzyme Q10, or placed separately from the QH.
• the package of this aspect i.e., the container, further contains water, and the water is arranged to be in contact with the phase containing the reduced coenzyme Q10 mixed with the QH, or In the package, which is arranged separately from the QH, the relative humidity of the gas phase becomes 50% or more due to the steam evaporated from the liquid water existing inside the container.
• water means water present as a liquid.
• the liquid water present inside the container does not have to be pure water and may be present as an aqueous solution.
• the aqueous solution may be an aqueous salt solution in which an inorganic salt is dissolved in water to adjust the water activity below 1.0.
• the liquid water may be water releasably supported on a porous carrier such as paper.
• QH is water-insoluble.
• the water mixed with QH includes a dispersion liquid in which QH is dispersed in water and a wet crystal of QH.
• the water arranged so as to be in contact with the phase containing the reduced coenzyme Q10 is a solution or the like in which QH is dissolved in a water-immiscible solvent and/or a fat-soluble medium.
• a water-immiscible solvent and/or a fat-soluble medium There is water.
• Examples of contact modes include a state in which water and a QH solution are layered, a state in which water and a QH solution form a water-in-oil or oil-in-water emulsion, and the like.
• the water arranged separately from the QH refers to the water arranged in the container so as not to contact the QH.
• the QH in the package is preferable because it can be used without drying after opening.
• the other component is mixed with the QH, placed in contact with a phase containing the QH, or placed separately from the QH;
• the water activity at 25° C. of the contents containing the QH and the other components in the container is 0.50 or more.
• the water activity of the contents can be measured by a conventional method.
• A a number between 0 and 1
• the gas phase in the container is A ⁇ 100 (%).
• the water activity of the contents at 25° C. is preferably 0.53 or higher, more preferably 0.60 or higher, still more preferably 0.70 or higher, further preferably 0.75 or higher, and 0.80. 0.85 or more is more preferable, and 0.90 or more is particularly preferable.
• QH is a Form I type crystal
• it is preferably 0.53 or more, more preferably 0.60 or more, still more preferably 0.70 or more, still more preferably 0.75 or more, further preferably 0.80 or more, and 0 0.85 or more is more preferable, and 0.90 or more is particularly preferable.
• the water activity is preferably 0.53 or higher, more preferably 0.60 or higher, particularly preferably 0.70 or higher, and most preferably 0.75 or higher.
• ingredients may be ingredients that are used in combination with QH, and include, for example, ingredients that are acceptable as foods, cosmetics, or pharmaceuticals.
• the mixture of the other component and QH can be a composition acceptable as food, cosmetics or pharmaceuticals.
• the mixture of the other component and QH may be a mixture in which QH and the other component are uniformly mixed, or a mixture in which QH and the other component are non-uniformly mixed. good too.
• a uniformly mixed mixture refers to a mixture containing QH and the above-described other components, and having a uniform or substantially uniform concentration distribution of QH throughout the mixture.
• a uniformly mixed mixture can be obtained, for example, by thoroughly mixing QH and the other components.
• the heterogeneously mixed mixture refers to a mixture containing QH and the above-mentioned other components, in which the concentration distribution of the above-mentioned QH is not uniform and is biased.
• a heterogeneously mixed mixture can be obtained, for example, by adding QH to one or more other ingredients, such as food ingredients.
• Phase containing QH means QH Form I type crystals, QH Form II type crystals, co-crystals consisting of QH and one or more other compounds, amorphous solids of QH, and QH in a solvent and/or a lipid-soluble medium. It refers to a phase consisting of or a homogenous phase comprising QHs, such as one or more selected from dissolved compositions.
• the state in which the other component is arranged so as to be in contact with the QH-containing phase is, for example, a state in which the other component and the QH-containing phase are stacked. In this embodiment, the other component forms a phase that is immiscible and contactable with the QH-containing phase.
• An example of an embodiment in which the other component is arranged to be in contact with the QH-containing phase is a stack of the QH-containing phase and the other component, or a QH-containing phase and one of the other components carried on the other.
• the first phase An example of a phase containing the QH
• a second phase an example of the other component
• the first phase and the second phase and the other are laminated.
• a first phase (an example of the phase containing QH) made of particles containing QH
• a second phase (an example of the other component) composed of one or more other components in a matrix form
• the first phase is supported on the second phase.
• a first QH-containing phase (an example of the QH-containing phase) and a water-releasing and a second phase (an example of the other component) containing a substance, wherein the first phase and the second phase are arranged so as to be in contact with each other.
• 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.
• the QH in the package is preferable because it can be used directly after opening.
• Yet another aspect of the package further comprising a substance that releases water into the interior of said container;
• the material is characterized in that it is mixed with the QH, placed in contact with a phase containing the QH, or placed separately from the QH.
• a substance that releases water is a substance that slowly releases water vapor.
• the relative humidity in the gas phase storage process inside the container is 50% or more, preferably 53% or more, more preferably 60% or more, more preferably 70% or more, and more It is preferably 75% or more, more preferably 80% or more, more preferably 85% or more, and particularly preferably 90% or more.
• Phase containing QH means QH Form I type crystals, QH Form II type crystals, co-crystals consisting of QH and one or more other compounds, amorphous solids of QH, and QH in a solvent and/or a lipid-soluble medium. It refers to a phase consisting of or a homogenous phase comprising QHs, such as one or more selected from dissolved compositions.
• the state in which the water-releasing substance is arranged so as to be in contact with the QH-containing phase is, for example, a state in which the water-releasing substance and the QH-containing phase are stacked.
• 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.
• the QH in the package is preferable because it can be used directly after opening.
• reduced coenzyme Q10 (trade name: Kaneka QH) manufactured by Kaneka Corporation was used as reduced coenzyme Q10 Form I type crystal (QH Form I type crystal).
• the weight ratio of reduced coenzyme Q10 to total coenzyme Q10 (that is, reduced coenzyme Q10/(oxidized coenzyme Q10+reduced coenzyme Q10)) is defined as the “QH ratio”.
• the QH ratio was obtained by the following HPLC analysis.
• the QH ratio at the end of the evaluation when the QH ratio at the start of the evaluation is 100 is defined as the “QH residual ratio”, and the QH residual ratio obtained from the following formula is the oxidation stability. was used as a measure of
• QH residual rate (%) 100 ⁇ QH ratio at the end of evaluation / QH ratio at the start of evaluation
• Example 2 In a chamber adjusted to a relative humidity of 85%, 0.1 g of the QHFormII type crystal obtained above was placed in an aluminum laminate bag (capacity: about 1000 ml) and sealed to prepare a package containing the QHFormII type crystal. After storing the package at 25° C. for 4 weeks, the QH residual rate was determined. Table 3 shows the relative humidity in the package and the QH residual rate.
• Example 3 A glass bottle (33 ml volume) was filled with 3 g of water. 0.1 g of the QHForm II type crystal obtained above was placed in the glass bottle using aluminum foil so as not to come into contact with water, and the glass bottle was sealed. After storing this package under the conditions of 40° C. and 75% relative humidity for 4 weeks, the QH residual rate was determined.
• Example 4 3 g of commercially available bread was placed in a glass bottle (volume: 33 ml). 0.1 g of the QH Form II type crystal obtained above was placed in contact with the bread in the glass bottle, and the glass bottle was sealed. After storing this package under the conditions of 40° C. and 75% relative humidity for 4 weeks, the QH residual rate was determined.
• Example 6 Storage of reduced coenzyme Q10 dissolved in MCT oil in a humidity-controlled atmosphere
• Example 5 and Reference Example 2 Using the salts shown in Table 5 instead of the salts shown in Table 1, packages 6-(1) to 6-(4) were produced. Further, 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 QHForm II type crystals. A package was produced. After storing this package at 40° C. for 2 weeks, the QH residual rate was determined in the same manner as in Example 1. Table 6 shows the QH residual rate and the relative humidity inside the package.
• MCT medium chain fatty acid triglyceride
• Example 6 3 g of 0.04% hexaglycerol monolaurate aqueous solution was placed in a glass bottle (volume: 33 ml), and 1.5 g of MCT containing 3.3% (w/w) of reduced coenzyme Q10 was overlaid.
• the water activity at 25° C. of a composition consisting of 3 g of 0.04% hexaglycerol monolaurate aqueous solution and 1.5 g of MCT containing 3.3% (w/w) reduced coenzyme Q10 was 0.98. rice field.
• the glass bottle was hermetically sealed and stored for 4 weeks under conditions of 25° C. and 60% relative humidity, and then the QH residual rate was measured to find that the QH residual rate was 96.2%.
• Example 6 revealed that reduced coenzyme Q10 present in the MCT solution was stably maintained even when the layer of the MCT solution containing reduced coenzyme Q10 was in contact with water.
• Example 8 Tissue paper containing about 20 g of water and 0.2 g of QHForm I type crystals were placed in an aluminum laminate bag (capacity: about 1000 ml) so as not to come into contact with each other and sealed. After storing this package under conditions of 40° C. and relative humidity of 75% for 2 weeks, the QH residual rate was determined.
• Example 9 In a glass bottle (volume: 33 ml) containing 3 g of water, 0.1 g of QHForm I type crystals was placed using aluminum foil so as not to come into contact with water, and the glass bottle was sealed. After storing this package under conditions of 40° C. and relative humidity of 75% for 2 weeks, the QH residual rate was determined.
• Example 10 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 the glass bottle so as to be in contact with the bread, and the glass bottle was sealed. After storing this package under conditions of 40° C. and relative humidity of 75% for 2 weeks, the QH residual rate was determined.
• Example 11 0.1 g of QHForm type I crystals was placed in a glass bottle (volume: 33 ml). Water or an 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 type crystal. After the glass bottle was sealed and stored for 2 weeks under conditions of 40° C. and 75% relative humidity, the residual QH ratio was determined.
• Example 12 3 g of commercially available bread was placed in a glass bottle (volume: 33 ml). 0.1 g of QHForm I type crystals was placed in the glass bottle so as to be in contact with the bread, and the glass bottle was sealed. After storing this package under conditions of 25° C. and 60% relative humidity for 4 weeks, the QH residual rate was determined. The water activity at 25° C. of the composition consisting of 3 g of the above bread and 0.1 g of QHForm type I crystals was 0.95.
• Example 13 0.1 g of QHForm type I crystals was placed in a glass bottle (volume: 33 ml). Aqueous solutions shown in Table 11 were placed in the above glass bottles in amounts shown in Table 11, respectively, and mixed with the above QHForm I type crystals. After the glass bottle was sealed and stored for 4 weeks under conditions of 25° C. and 60% relative humidity, the residual QH ratio was determined.
• Example 14 and Reference Example 5 0.2 g of a co-crystal composed of QH and nicotinamide was packaged in an open state to packages 4-(1) and 4-(2) in Table 1 above, and then sealed. The saturated salt solution and the co-crystal were arranged separately in the package. After storing the packages (4-(1) and 4-(2)) containing the co-crystal at 40° C. for 2 weeks, the QH residual ratio was determined. Also, the relative humidity in 4-(1) and 4-(2) was determined according to Greenspan, J Res NBS A Phys Ch, 1977. Table 13 shows the QH residual rate and the relative humidity in the package.
• reduced coenzyme Q10 is stable regardless of Form I type crystal, Form II type crystal, co-crystal consisting of reduced coenzyme Q10 and one or more other compounds, and is not in a crystalline state existing in solution. Reduced coenzyme Q10 was also stable.
• a preferred range can be defined by arbitrarily combining the upper and lower limits of the numerical range
• a preferred range can be defined by arbitrarily combining the upper limits of the numerical range
• the lower limit of the numerical range Any combination of values can be used to define a preferred range.
• a numerical range represented using the symbol "-" includes the numerical values described before and after the symbol "-" as lower and upper limits, respectively.

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