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
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
• • 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
  • A61K47/30—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
  • A61K47/30—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
  • A61K47/38—Cellulose; Derivatives thereof
• • 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
  • B65D81/24—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants
• • 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
  • B65D81/24—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants
  • B65D81/26—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants with provision for draining away, or absorbing, or removing by ventilation, fluids, e.g. exuded by contents; Applications of corrosion inhibitors or desiccators
• • 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.
• QH Form II type crystal or “Form II type crystal”
• Form I type crystal of reduced coenzyme Q10 is a conventional reduced coenzyme Q10 (hereinafter referred to as “Form I type crystal of reduced coenzyme Q10”, “QH Form I type crystal” or “Form I It is reported to be much more stable than "type crystals”) and have excellent other physical properties.
• 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.
• a QH preparation coated with a gas-barrier film such as gelatin is stored at a relative humidity below a predetermined value.
• QH formulations coated with gas barrier coatings during storage It can be understood that the oxygen permeability of the gas barrier film is reduced and the oxidation of QH is suppressed by setting the relative humidity of the gas barrier film to a predetermined value or less.
• 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 use of QH is limited because it requires formulation such as clathration, coating, granular composition, or encapsulation of QH with a specific component.
• one or more embodiments of the present invention provide a package of QH that does not require formulation, is suppressed in oxidation, and can be stored stably.
• One or more embodiments of the present invention also provide a method of preserving QH that does not require formulation and can inhibit oxidation.
• the present inventors have found that conventional forms of QH (QHFormI type crystals and QHFormI type crystals and QHFormI type crystals and QHFormI type crystals and The inventors have found that it has properties different from those of QH dissolved in fats and oils, and completed the following embodiments of the present invention.
• the reduced coenzyme Q10 includes at least one of a Form II type crystal and a co-crystal composed of reduced coenzyme Q10 and one or more other compounds,
• the package wherein the gas phase inside the container is a gas phase with a relative humidity of 45% or less.
• 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 0.45 or less.
• a method for storing reduced coenzyme Q10 comprising:
• the reduced coenzyme Q10 includes at least one of a Form II type crystal and a co-crystal composed of reduced coenzyme Q10 and one or more other compounds,
• a method comprising a storage step of storing the reduced coenzyme Q10 in a gas phase at a relative humidity of 45% or less.
• the storage step includes the reduced coenzyme Q10; and and a container for packing the reduced coenzyme Q10, Preserving a package in which the gas phase inside the container is a gas phase with a relative humidity of 45% or less, The method as described in (4).
• reduced coenzyme Q10 (QH) to be accommodated is enclosed or coated with other components, or is made into a formulation such as a capsule to block oxygen. Even if not, the QH can be stably stored without being oxidized.
• 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.
• the reduced coenzyme Q10 (QH) contained or stored in the package at least one of a QH Form II type crystal and a co-crystal consisting of QH and one or more other compounds is used.
• the ratio of the total amount of the QH Form II crystal and the co-crystal composed of QH and one or more other compounds to the total amount of QH is not particularly limited, but is, for example, 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, or more. It is preferably 80% by weight or more, more preferably 90% by weight or more, particularly preferably 95% by weight or more, particularly preferably 98% by weight or more, and most preferably 100% by weight.
• the forms include QH Form I crystals, QH amorphous solids, and QH melts. and one or more selected from QH dissolved in a solvent or a fat-soluble medium, one or more selected from QH Form I crystals and QH amorphous solids are preferred, and QH Form I crystals are particularly preferred.
• 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 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 consist of non-preformulated QH, the QH can be used in a wide variety of applications. Therefore, it is preferable.
• the QH to be housed in the package and the QH to be stored are preformulated QH (e.g., inclusion complex of QH with cyclodextrin, dispersed in a matrix containing a water-soluble excipient in the particulate composition QH coated with a coating medium in a solid formulation, or capsules of QH).
• preformulated QH e.g., inclusion complex of QH with cyclodextrin, dispersed in a matrix containing a water-soluble excipient in the particulate composition QH coated with a coating medium in a solid formulation, or capsules of QH.
• 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 the QH and can be sealed together with the gas phase.
• the 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 QH includes at least one of a Form II type crystal and a co-crystal consisting of QH and one or more other compounds,
• the gas phase inside the container has a relative humidity of 45% or less.
• a method for preserving 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 45% or less.
• the present inventors have found that QH Form I type crystals and Q H dissolved in oils and fats, which are conventionally mainly used QH, are unstable under conditions of relative humidity of 45% or less, whereas QH Form II type It has been found that crystals and co-crystals of QH and one or more other compounds have the unexpected property of being stable under conditions of relative humidity of 45% or less. According to the package and method according to the present embodiment, oxidation of at least one of the QH Form II crystal and the co-crystal composed of QH and one or more other compounds can be suppressed, and QH can be stably stored.
• QH Form II type crystals and co-crystals composed of QH and one or more other compounds have high production costs themselves, so it is believed that QH residual ratio after storage (see Examples for definition) is 85% or more. at a reasonable price.
• QH residual ratio after storage is 85% or more. at a reasonable price.
• at least one of the QH Form II crystal and the co-crystal composed of QH and one or more other compounds can have a QH residual rate of 85% or more, which is preferable.
• the relative humidity of the gas phase is 45% or less, preferably 43% or less, more preferably 40% or less, and particularly preferably 38% or less.
• 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 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 45% or less.
• the relative humidity of the gas phase in the container should be 45% or less, preferably 43% or less, more preferably 40% or less, and particularly preferably 38% or less.
• the container is not particularly limited as long as it accommodates the QH and can 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 at least one of a QH Form II crystal and a co-crystal composed of QH and one or more other compounds in the container under a gas phase with a relative humidity of 45% or less, or At least one of a QH Form II crystal and a co-crystal composed of QH and one or more other compounds is packed in the container, and the container is filled with a gas phase having a relative humidity of 45% or less to produce the package. process.
• the relative humidity of the gas phase can be made 45% or less by further packing a component that makes the relative humidity of the gas phase 45% or less in the container.
• One aspect of the package is further comprising one or more other ingredients inside said container; 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 of the contents of the container containing the QH and the other components at 25° C. is 0.45 or less.
• 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 content may be 0.45 or less, preferably 0.43 or less, more preferably 0.40 or less, and particularly preferably 0.38 or less.
• ingredients may be ingredients that are used in combination with QH, and include, for example, ingredients that are acceptable as foods, cosmetics, or pharmaceuticals.
• ingredients that are acceptable as foods, cosmetics, or pharmaceuticals can be suitably used.
• 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 refers to a phase consisting of QH or a homogeneous phase containing QH.
• 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.
• 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.
• a first phase (an example of the phase containing QH) made of particles containing QH and a matrix-like one It includes a second phase (an example of the other component) composed of the above-mentioned other components, and the first phase is supported on the second phase.
• 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 adsorbs water inside the 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 adsorbs water is a substance that adsorbs water vapor in the gas phase inside the container.
• the substance that adsorbs water should have a water activity of 0.45 or less, preferably 0.43 or less, more preferably 0.40 or less, and particularly
• An inorganic salt or an aqueous solution of an inorganic salt is preferably 0.38 or less.
• inorganic salts include calcium chloride and magnesium chloride.
• Other examples of substances that adsorb water include calcium oxide, magnesium oxide, silicon dioxide (such as silica gel), diatomaceous earth, low water activity excipients, and the like.
• Low water activity excipients include celluloses, starches, sugars, and other water-soluble polymeric compounds.
• celluloses examples include crystalline cellulose, cellulose powder, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof.
• starches examples include wheat starch, potato starch, sweet potato starch, corn starch, dextrin, hydroxypropyl starch, starch acetate, oxidized starch, starch octenylsuccinate and salts thereof, and partially pregelatinized starch.
• the dextrin is not particularly limited as long as it is a decomposition product of starch, and both low-molecular-weight dextrin and high-molecular-weight dextrin can be suitably used.
• maltodextrin, cyclodextrin, cluster dextrin, etc. can also be suitably used.
• sugars examples include monosaccharides such as glucose, fructose, galactose, arabinose, xylose and mannose; disaccharides such as maltose, sucrose, lactose and trehalose; oligosaccharides such as fructooligosaccharides, soybean oligosaccharides, galactooligosaccharides and xylooligosaccharides; Examples include sugar alcohols such as sorbitol, maltitol, erythritol, lactitol, and xylitol.
• water-soluble polymer compounds include gum arabic, gelatin, agar, tragacanth, pectin, carrageenan, casein, casein compounds, dried egg white, milk, curdlan, alginates, soybean polysaccharides, pullulan, xanthan gum, locust bean gum. etc. can be exemplified.
• Phase containing QH refers to a phase consisting of QH or a homogeneous phase containing QH.
• a first phase containing QH an example of the phase containing QH
• a substance that adsorbs water is placed in contact with the phase containing QH
• a first phase containing QH an example of the phase containing QH
• a substance that adsorbs water is placed in contact with the phase containing QH
• a first phase containing QH an example of the phase containing QH
• a substance that adsorbs water are and a second phase (an example of the other component)
• the first phase and the second phase are arranged so as to be in contact with each other.
• the water-adsorbing substance arranged separately from the QH refers to the water-adsorbing substance arranged in the container so as not to come into contact with the QH.
• the QH in the package and the QH after storage are preferable because they 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 1 and Comparative Example 1 Store reduced coenzyme Q10 in a humidity-controlled atmosphere [Example 1 and Comparative Example 1] 0.2 g of QHForm II type crystals were packed in an open state to packages 5-(1) to 5-(5) in Table 1 above, and sealed. After storing the packages (5-(1) to 5-(5)) containing the QH Form II type crystals at 40° C. or 25° C. for 4 weeks, the QH residual rate was determined. Also, according to Greenspan, J Res NBS A Phys Ch, 1977, the relative humidity within 5-(1) to 5-(5) was determined. Table 2 shows the QH residual rate and the relative humidity in the package.
• Example 2 In a chamber adjusted to a relative humidity of 10%, 0.1 g of the QHForm II crystal was placed in an aluminum laminate bag (about 1000 ml in volume) and sealed to prepare a package containing the QH Form II crystal. After storing the package at 25° C. for 4 weeks, the QH residual rate was determined. Table 5 shows the relative humidity and QH residual rate in the package.
• Table 5 reveals that QHForm II crystals can be kept stable even by adjusting the relative humidity of the environment in which the package is made, that is, the relative humidity of the gas phase to be enclosed in the package, below 45%. rice field.
• Example 3 0.2 g of QHForm II type crystals and 8 g of silica gel were placed in an aluminum laminate bag (capacity: about 1000 ml) so as not to contact each other, and the aluminum laminate bag was sealed. After storing this package at 40° C. or 25° C. for 4 weeks, the QH residual rate was determined. The relative humidity in the package was maintained at approximately 10% at 40°C and approximately 9% at 25°C. Table 7 shows the relative humidity in the package and the QH residual rate.
• Example 4 The QHFormII type crystals and the respective excipients shown in Table 8 were mixed at a weight ratio of 1:1 to obtain a QHFormII type crystal-containing composition. 0.2 g of the above composition was placed in each glass bottle (volume 33 ml) and sealed. After storing this package under the conditions of 40° C. and 75% relative humidity for 4 weeks, the QH residual rate was determined. In addition, the water activity of the composition at 25° C. was measured and shown in Table 8 together with the QH residual ratio.
• Example 5 QHFormII type crystals and gum arabic dried using a vacuum dryer were mixed at a weight ratio of 1:1 to obtain a QHFormII type crystal-containing composition. 0.03 g of the above composition was placed in a glass bottle (volume 10 ml) and sealed. After storing this package under conditions of 40° C. and 75% relative humidity or 25° C. and 60% relative humidity for 4 weeks, the QH residual ratio was determined. In addition, the water activity of the composition at 25° C. was measured and shown in Table 9 together with the QH residual ratio.
• Example 6 and Comparative Example 2 0.2 g of a co-crystal composed of QH and nicotinamide was packaged in an open state to packages 5-(1) and 5-(5) 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 (5-(1) and 5-(5)) containing the co-crystal at 40° C. for 2 weeks, the QH residual ratio was determined. Also, the relative humidity in 5-(1) and 5-(5) was determined according to Greenspan, J Res NBS A Phys Ch, 1977. Table 10 shows the QH residual rate and the relative humidity in the package.
• reduced coenzyme Q10 containing Form II type crystals and co-crystals consisting of reduced coenzyme Q10 and one or more other compounds are stable, and conventional reduced coenzyme Q10 (Form I type crystals and soluble in fats and oils It exhibited properties different from those of the reduced coenzyme Q10) in the dehydrated state.
• 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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