Classifications

• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
• • 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
  • 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

Definitions

• One or more embodiments of the present invention relate to a method for preserving reduced coenzyme Q10, a method for inhibiting oxidation of reduced coenzyme Q10, and a liquid composition containing reduced coenzyme Q10.
• 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 Documents 3, 4, and 5, for example, are examples of documents that disclose techniques for suppressing the oxidation of reduced coenzyme Q10 and stably preserving it.
• reduced coenzyme Q10 having high oxidation stability and high bioabsorbability
• a particulate composition in which an oily component containing reduced coenzyme Q10 or an oily component containing reduced coenzyme Q10 and a lipophilic antioxidant forms domains and is polydispersed is described, and the particles
• a method for stabilizing a particulate composition is described, which comprises exposing the particulate composition to an ambient relative humidity of 90% or less.
• water-soluble excipients include gum arabic and gelatin.
• Patent Documents 3 to 5 are all techniques for improving oxidation stability by covering QH with a film of gas barrier material such as gum arabic and gelatin.
• Non-Patent Documents 1 and 2 It is known that the stability of organic compounds generally decreases as the relative humidity increases.
• Coenzyme Q10 (coenzyme Q10) is a hydrophobic compound. Techniques for solubilizing coenzyme Q10 in water have been conventionally developed in order to incorporate coenzyme Q10 into aqueous liquid compositions such as beverages.
• Patent Document 6 describes a water-soluble composition in which coenzyme Q10 is water-soluble by emulsification.
• Patent Document 7 describes a coenzyme Q10-containing liquid composition obtained by dispersing and emulsifying it in an aqueous liquid containing a water-soluble substance consisting of starch octenylsuccinate and dextrin and glycerin.
• Patent Document 8 describes an emulsified composition in which coenzyme Q10 is emulsified in water together with a medium-chain triglyceride, a surfactant and a polyhydric alcohol.
• Patent Document 9 describes a coenzyme Q-containing water-soluble composition comprising coenzyme Q, a hydrophilic polyglycerol fatty acid ester, a lipophilic sucrose fatty acid ester, and an aqueous phase component.
• Patent Document 10 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. Moreover, Patent Document 11 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 5 disclose QH products that prevent oxidation of reduced coenzyme Q10 (QH) and can be stored stably. However, in Patent Documents 3 to 5, the applications of QH are limited because they all require formulation of QH with specific ingredients.
• Patent Documents 6 to 9 disclose liquid compositions in which coenzyme Q10 is solubilized in water using a surfactant or the like. However, since the solubilized coenzyme Q10 cannot be recovered as a solid again, the uses of coenzyme Q10 are limited. In addition, the solubilization techniques and liquid compositions described in Patent Documents 6 to 9 are aimed at improving the absorbability of (oxidized) coenzyme Q10, and do not consider the oxidation stability of QH at all.
• one or more embodiments of the present invention provide a method for preserving QH that can inhibit oxidation of QH without requiring formulation of QH, a method for inhibiting oxidation of QH, and a liquid composition comprising QH. I will provide a.
• a method for storing reduced coenzyme Q10 comprising: A method comprising storing a composition comprising solid reduced coenzyme Q10 and water.
• the solid reduced coenzyme Q10 is a Form I crystal of reduced coenzyme Q10, a Form II crystal of reduced coenzyme Q10, a co-crystal composed of reduced coenzyme Q10 and one or more other compounds; and one or more selected from amorphous solids of reduced coenzyme Q10, (1)
• the composition is a liquid composition containing the solid reduced coenzyme Q10 in water, or a solid composition containing the solid reduced coenzyme Q10 wetted with water; The method according to (1) or (2).
• a method for suppressing oxidation of reduced coenzyme Q10 comprising: A method comprising storing a composition comprising solid reduced coenzyme Q10 and water.
• the solid reduced coenzyme Q10 is a Form I crystal of reduced coenzyme Q10, a Form II crystal of reduced coenzyme Q10, a co-crystal composed of reduced coenzyme Q10 and one or more other compounds; and one or more selected from amorphous solids of reduced coenzyme Q10, (4) The method described in (4).
• the composition is a liquid composition containing the solid reduced coenzyme Q10 in water, or a solid composition containing the solid reduced coenzyme Q10 wetted with water. (4) or the method according to (5).
• a liquid composition containing solid reduced coenzyme Q10 in water (8)
• the liquid composition according to (7) which contains 10 parts by mass or more of water for 1 part by mass of the solid reduced coenzyme Q10. (9) further comprising a surfactant;
• the liquid composition according to (7) or (8) includes the disclosure contents of Japanese Patent Application Nos. 2021-210678 and 2022-152299, which are the basis of priority of the present application.
• QH reduced coenzyme Q10
• QH can be stably stored while preventing oxidation.
• oxidation of QH can be effectively prevented.
• liquid composition containing QH disclosed in the present specification oxidation of QH can be prevented and stored stably. Furthermore, solid QH can be easily recovered from the liquid composition.
• “Reduced coenzyme Q10” in one or more embodiments of the present invention may partially contain oxidized coenzyme Q10 as long as it contains reduced coenzyme Q10 as a main component.
• 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.
• solid reduced coenzyme Q10 preferably includes Form I crystals of reduced coenzyme Q10, Form II crystals of reduced coenzyme Q10, and reduced coenzyme Q10. and one or more other compounds, and one or more selected from amorphous solids of reduced coenzyme Q10, particularly preferably Form I crystals of reduced coenzyme Q10, and , Form II type crystal of reduced coenzyme Q10.
• the solid reduced coenzyme Q10 may be a solid further containing components other than reduced coenzyme Q10, but is preferably a solid composed of reduced coenzyme Q10.
• 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 solid reduced coenzyme Q10 is preferably particulate solid.
• the size of the solid reduced coenzyme Q10 is not particularly limited. It is preferably 30 ⁇ m or more, and usually 1 mm or less, preferably 0.5 mm or less, and more preferably 0.2 mm or less.
• the average particle size can be measured with a laser diffraction/scattering particle size distribution analyzer.
• the solid reduced coenzyme Q10 (QH) used in one or more embodiments of the present invention need not be formulated in advance.
• solid QH can be easily separated and recovered by methods such as filtration, centrifugation, and drying, so QH can be used for a wide range of purposes after storage. It is preferable because it can be done.
• the solid QH is a pre-formulated QH (e.g., an inclusion complex of QH with cyclodextrin, a QH dispersed in a matrix containing a water-soluble excipient in a particulate composition, a QH in a solid formulation, is not QH coated with a coating medium 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 first embodiment of the present invention comprises: A method for storing QH, comprising: A method comprising storing a composition comprising QH and water in solid form.
• the method according to the present embodiment it is possible to suppress oxidation of QH and stably store QH.
• Common compounds are said to be unstable in the presence of water, and it is important to store them in a dry state.
• the solid QH is one or more selected from QH Form I crystals, QH Form II crystals, co-crystals composed of reduced coenzyme Q10 and one or more other compounds, and amorphous solid QHs. is preferred.
• Form II type crystals of QH and co-crystals composed of reduced coenzyme Q10 and one or more other compounds have high production costs themselves, so the residual rate of QH after storage (see Examples for definition) is 80. % or more is required in order to provide QH of the above form at an appropriate price.
• the QH residual rate of QH after storage is It is preferable because it can be 80% or more.
• the QH in the Form I crystal form of QH can be produced at a low cost, but is susceptible to oxidation. required to provide form QH at a reasonable price.
• the QH residual rate of QH after storage can be 40% or more when QH is in the form of Form I type crystal of QH, which is preferable.
• composition containing solid QH and water in the method according to the present embodiment is not particularly limited as long as it contains solid QH and water, but a liquid composition containing solid QH in water , or a solid composition containing solid QH wetted with water.
• the water may further contain other ingredients such as surfactants and salts.
• a liquid composition containing solid QH in water is, for example, a liquid composition in which solid QH is suspended in water.
• the content of water in the liquid composition is not particularly limited, but water is preferably 10 parts by mass or more, more preferably 30 parts by mass or more, relative to 1 part by mass of solid QH.
• the upper limit of the amount of water is not particularly limited, for example, water can be 10,000 parts by mass or less, 1,000 parts by mass or less, or 100 parts by mass or less with respect to 1 part by mass of solid QH.
• the water is preferably water further containing a surfactant.
• the liquid composition containing a surfactant can stabilize the dispersion of solid QH. Examples of surfactants include polyglycerol fatty acid esters, polyalkylene glycols, alcohols, and alginates.
• the liquid composition may contain other components in addition to water and QH.
• the content of water in the solid composition containing solid QH wetted with water is not particularly limited. Preferably, it is 0.10 parts by mass or more. Although the upper limit of the amount of water is not particularly limited, for example, water can be less than 10 parts by mass, 5 parts by mass or less, 3 parts by mass or less, or 2 parts by mass or less for 1 part by mass of solid QH. .
• the solid composition may contain other components in addition to water and QH.
• the temperature at which the composition is stored in the method according to the present embodiment is, for example, -25°C or higher and 50°C or lower, preferably -20°C or higher, -10°C or higher, 0°C or higher, and 4°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.
• the period for storing the composition 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, further preferably 6 months or less, further preferably 8 weeks It can be less than, most preferably less than 6 weeks, less than 5 weeks or less than 4 weeks.
• the composition can be a package that is housed in a container and sealed in order to prevent volatilization of water.
• the package may contain a gas phase within the container, and the gas phase may 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 according to this embodiment preferably comprises Further comprising recovering QH in solid form from said composition after storage.
• the recovered solid QH can be used for various purposes.
• Methods for recovering solid QH from the composition after storage include methods such as filtration, centrifugation, and drying.
• a second embodiment of the present invention comprises: A method of inhibiting oxidation of QH, comprising: A method comprising storing a composition comprising QH and water in solid form.
• the oxidation of QH can be efficiently suppressed at low cost.
• the characteristics and preferred aspects of each of the solid QH, water, the composition, and the step of storing the composition are as described for the method according to the first embodiment. be.
• the method according to this embodiment preferably comprises Further comprising recovering QH in solid form from said composition after storage.
• the recovered solid QH can be used for various purposes.
• Methods for recovering solid QH from the composition after storage include methods such as filtration, centrifugation, and drying.
• a third embodiment of the present invention is The present invention relates to a liquid composition containing solid reduced coenzyme Q10 in water.
• Oxidation of QH in the form of a liquid composition according to the present embodiment is effectively suppressed. Furthermore, solid QH can be easily recovered from the liquid composition.
• liquid composition according to the present embodiment, the respective features and preferred aspects of solid QH, water, and the liquid composition are as described for the method according to the first embodiment.
• 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 of storing reduced coenzyme Q10 in contact with water [Example 1] 0.1 g of QHForm I type crystal was placed in a glass bottle (volume: 33 ml). Water or an aqueous solution shown in Table 1 was placed in the glass bottle in the amount shown in Table 1 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 1 The results obtained in Example 1 and Comparative Example 1 are summarized and shown in Table 2.
• Example 2 0.1 g of QHForm I type crystal was placed in a glass bottle (volume: 33 ml). Aqueous solutions shown in Table 3 were placed in the above glass bottles in amounts shown in Table 3, 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 2 The results obtained in Example 2 and Comparative Example 2 are summarized and shown in Table 4.
• reduced coenzyme Q10 can be stably maintained in contact with water and/or a substance containing water.
• Reduced coenzyme Q10 was stably maintained when the water and/or substance containing water was 0.1 parts by mass or more relative to reduced coenzyme Q10. Further, the present inventors have found that the water-containing substance can contain a surfactant and stabilizes reduced coenzyme Q10 regardless of the type of surfactant contained. Reduced coenzyme Q10 was kept stable even when the substance containing water was hydrous alcohol.
• Example 3 0.1 g of QHForm II type crystal was placed in a glass bottle (volume: 33 ml). 3 g of a 0.04% hexaglycerin monolaurate aqueous solution was placed in the glass bottle and mixed with the QH Form II type crystals. After the glass bottle was sealed and stored for 4 weeks under the conditions of 40° C. and 75% relative humidity, the residual QH ratio was determined. As a result, the QH residual rate was 83.0%.
• Example 4 0.1 g of QHForm II type crystal was placed in a glass bottle (volume: 33 ml). 3 g of a 0.04% hexaglycerin monolaurate aqueous solution was placed in the glass bottle and mixed with the QH Form II 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. As a result, the QH residual rate was 93.8%.
• 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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