Method for preserving solid composition that contains form ii type crystals of reduced coenzyme q10, and packing that contains said solid composition

Abstract

The present description discloses a means for suppressing a decrease, through oxidation, of the reduced coenzyme Q10 when a solid composition containing the reduced coenzyme Q10 is preserved.　One or more embodiments of the present invention relate to a method for preserving a solid composition that contains form II type crystals of the reduced coenzyme Q10, an emulsifier that has an HLB of at least 6.0, and an antioxidant, wherein the method includes preserving the solid composition in a gas phase with a relative humidity of less than 50%. Another one or more embodiments of the present invention relate to a packing that comprises: a solid composition that contains form II type crystals of the reduced coenzyme Q10, an emulsifier that has an HLB of at least 6.0, and an antioxidant; a gas phase with a relative humidity of less than 50%; and a container that encapsulates the solid composition and the gas phase.

Description

Method for storing a solid composition containing Form II crystals of reduced coenzyme Q10 and a package containing the solid composition

[0001] One or more embodiments of the present invention relate to a method for preserving a solid composition containing Form II crystals of reduced coenzyme Q10.

[0002] One or more other embodiments of the present invention relate to a package containing a solid composition containing Form II crystals of reduced coenzyme Q10.

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

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

[0005] Reduced coenzyme Q10 is easily oxidized, which results in high storage costs and limits the range of application of the product form.

[0006] Patent Document 1 describes that reduced coenzyme Q10 exhibits crystalline polymorphism, and reports that the newly emerged crystalline form (hereinafter referred to as "reduced coenzyme Q10 Form II crystal," "QH Form II crystal," or "Form II crystal") is much more stable than conventional reduced coenzyme Q10 (hereinafter referred to as "reduced coenzyme Q10 Form I crystal," "QH Form I crystal," or "Form I crystal") and also has other superior physical properties.

[0007] Patent Document 2 describes a reduced coenzyme Q10 composition that is solid at room temperature, such as a powder, and has good oxidation stability, is suitable for inexpensive and simple formulation to meet market demands, and is a composition that is solid at 25°C and contains reduced coenzyme Q10, an organic acid, and a carbonate containing sodium cations and / or calcium cations, and describes that reduced coenzyme Q10 is preferably in the form of Form II crystals. Patent Document 2 also describes that in order to improve the oxidation stability of reduced coenzyme Q10 in the composition, it is essential to add a carbonate containing sodium cations and / or calcium cations.

[0008] On the other hand, Patent Document 3 describes a particulate composition as a composition containing reduced coenzyme Q10 that is stable against oxidation, in which the oily component (A) containing reduced coenzyme Q10 and lipophilic antioxidant forms domains and polydisperses in a matrix that is mainly composed of a water-soluble excipient.Patent Document 3 further describes that the water-soluble excipient can contain surfactant, and the surfactant is preferably hydrophilic, for example, HLB is 4 or more, usually HLB is 6 or more, preferably HLB is 8 or more; and the oily component (A) preferably further contains a lipophilic surfactant, for example, HLB is 10 or less, preferably 8 or less, more preferably 6 or less, and even more preferably 5 or less surfactant can be used.Patent Document 3 also describes that in the particulate composition, reduced coenzyme Q10 is preferably not in a crystalline state, but in an amorphous or melt state, and preferably 10% by weight or more, more preferably 20% by weight or more, more preferably 50% by weight or more, even more preferably 70% by weight or more, particularly preferably 80% by weight or more.

[0009] International Publication WO2012 / 176842 International Publication WO2015 / 122531 Japanese Patent Application Laid-Open No. 2009-149584

[0010] As described above, various methods for preventing the oxidation of reduced coenzyme Q10 have been developed. However, the invention described in Patent Document 2 requires the incorporation of a specific component, a carbonate containing sodium cations and / or calcium cations, to stabilize reduced coenzyme Q10, and the invention described in Patent Document 3 requires the formulation of reduced coenzyme Q10 in a specific form, which limits the form and use of the reduced coenzyme Q10-containing composition. Therefore, there is still a need for new methods for preventing the oxidation of reduced coenzyme Q10.

[0011] Therefore, this specification discloses a new means for suppressing the decrease of reduced coenzyme Q10 due to oxidation during storage of a solid composition containing reduced coenzyme Q10.

[0012] The present inventors have newly discovered that in a solid composition containing Form II crystals of reduced coenzyme Q10 together with an emulsifier and an antioxidant, the decrease in reduced coenzyme Q10 due to oxidation during storage is suppressed, and have completed the following forms of the present invention.

[0013] (1) A method for storing a solid composition containing Form II crystals of reduced coenzyme Q10, an emulsifier having an HLB of 6.0 or more, and an antioxidant, the method comprising storing the solid composition in a gas phase having a relative humidity of less than 50%. (2) The method according to (1), wherein the gas phase is air. (3) The method according to (1) or (2), wherein the emulsifier is one or more selected from the group consisting of monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol, and an ester compound of a fatty acid which may have a substituent, and lecithin. (4) The method according to any one of (1) to (3), wherein the antioxidant is one or more selected from the group consisting of ascorbic acid, ascorbate, erythorbic acid, and erythorbate. (5) The method according to any one of (1) to (4), wherein the solid composition contains 1 part by weight or more and 9,900 parts by weight or less of the emulsifier per 100 parts by weight of the crystals. (6) The method according to any one of (1) to (5), wherein the content of the emulsifier in the solid composition is 1% by weight or more and 99% by weight or less. (7) The method according to any one of (1) to (6), wherein the solid composition further contains a binder. (8) The method according to (7), wherein the binder is one or more selected from hydroxypropyl cellulose and hydroxypropyl methylcellulose. (9) The method according to (7) or (8), wherein the solid composition is a granular solid composition. (10) The method according to any one of (1) to (9), wherein the solid composition does not contain a carbonate salt containing sodium cations and / or calcium cations. (11) The method according to any one of (1) to (10), wherein the solid composition is not a composition in which an oily component containing reduced coenzyme Q10 and a lipophilic antioxidant forms domains and is polydispersed in a matrix containing a water-soluble excipient. (12) A package comprising: a solid composition containing Form II crystals of reduced coenzyme Q10, an emulsifier having an HLB of 6.0 or more, and an antioxidant; a gas phase having a relative humidity of less than 50%; and a container for enclosing the solid composition and the gas phase. (13) The package according to (12), wherein the gas phase is air.(14) The package according to (12) or (13), wherein the emulsifier is one or more selected from monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol, and an ester compound of a fatty acid which may have a substituent, and lecithin. (15) The package according to any of (12) to (14), wherein the antioxidant is one or more selected from ascorbic acid, ascorbate, erythorbic acid, and erythorbate. (16) The package according to any of (12) to (15), wherein the solid composition contains 1 part by weight or more and 9,900 parts by weight or less of the emulsifier per 100 parts by weight of the crystals. (17) The package according to any of (12) to (16), wherein the content of the emulsifier in the solid composition is 1% by weight or more and 99% by weight or less. (18) The package according to any one of (12) to (17), wherein the solid composition further comprises a binder. (19) The package according to (18), wherein the binder is one or more selected from hydroxypropyl cellulose and hydroxypropyl methylcellulose. (20) The package according to (18) or (19), wherein the solid composition is a granular solid composition. (21) The package according to any one of (12) to (20), wherein the solid composition does not contain a carbonate salt containing sodium cations and / or calcium cations. (22) The package according to any one of (12) to (21), wherein the solid composition is not a composition in which an oily component containing reduced coenzyme Q10 and a lipophilic antioxidant forms domains and is polydispersed in a matrix containing a water-soluble excipient. This specification incorporates the disclosure of Japanese Patent Application No. 2022-042288, from which the present application claims priority.

[0014] The method according to one or more embodiments of the present invention inhibits the reduction of reduced coenzyme Q10 due to oxidation during storage of a solid composition containing Form II crystals of reduced coenzyme Q10.

[0015] The packaging according to one or more other embodiments of the present invention inhibits the reduction of reduced coenzyme Q10 due to oxidation during storage of a solid mixture containing Form II crystals of reduced coenzyme Q10.

[0016] The present invention will be described in detail below.

[0017] <Reduced Coenzyme Q10> In this specification, reduced coenzyme Q10 may contain oxidized coenzyme Q10 as a part of itself, as long as it is mainly composed of reduced coenzyme Q10. Here, the term "main component" means that it is contained in an amount of, for example, 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, particularly preferably 95% by weight or more, and particularly preferably 98% by weight or more. The aforementioned ratio is the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10.

[0018] As described above, reduced coenzyme Q10 exists in two crystalline polymorphs, Form I and Form II. Specifically, Form I crystals are crystalline forms of reduced coenzyme Q10 that have a melting point of around 48°C and exhibit characteristic peaks at diffraction angles (2θ±0.2°) of 3.1°, 18.7°, 19.0°, 20.2°, and 23.0° in powder X-ray (Cu-Kα) diffraction, while Form II crystals are crystalline forms of reduced coenzyme Q10 that have a melting point of around 52°C and exhibit characteristic peaks at diffraction angles (2θ±0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° in powder X-ray (Cu-Kα) diffraction.

[0019] In one or more embodiments of the present invention, reduced coenzyme Q10 (QH) is characterized by using Form II crystals of reduced coenzyme Q10 (QH Form II crystals). Because QH Form II crystals have high stability against oxidation, solid compositions containing QH Form II crystals together with an emulsifier and an antioxidant have excellent storage stability.

[0020] The QH Form II crystal may consist solely of Form II crystal, or may be a QH crystal or crystalline solid containing Form II crystal as the main component, where "main component" means that Form II crystal accounts for preferably 80% by weight or more, more preferably 90% by weight or more, more preferably 95% by weight or more, and most preferably 98% by weight or more of the total amount of QH.

[0021] <Emulsifier> In this specification, an emulsifier having an HLB of 6.0 or more is used, but the type is not limited. Two or more emulsifiers may be used in combination. The HLB of the emulsifier is more preferably 7.0 or more. There is no particular upper limit for the HLB of the emulsifier, but it is preferably 16.0 or less, more preferably 15.5 or less.

[0022] Specific examples of the emulsifier include one or more selected from monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol; ester compounds of a fatty acid which may have a substituent; and lecithin.

[0023] The number of glycerin units in polyglycerin may be 2 or more, and preferably 2 to 10. Examples include diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, and decaglycerin.

[0024] The number of oxyethylene units in polyoxyethylene sorbitan may be 2 or more, preferably 10 or more and 30 or less, and more preferably 15 or more and 25 or less.

[0025] The number of propylene glycol units in the polypropylene glycol may be 2 or more, and preferably 2 or more and 10 or less.

[0026] The number of ethylene glycol units in the polyethylene glycol may be 2 or more, and preferably 2 or more and 10 or less.

[0027] The polyol is particularly preferably one or more selected from monoglycerin, polyglycerin, and sucrose.

[0028] Examples of fatty acids which may have a substituent include linear or branched monovalent or divalent fatty acids having from 4 to 24 carbon atoms. Examples of the substituent include a hydroxyl group and an acetoxy group. The number of substituents is preferably two or less. Specific examples of fatty acids which may have a substituent include lauric acid, oleic acid, caprylic acid, stearic acid, behenic acid, ricinoleic acid, succinic acid, and diacetyltartaric acid, with one or more selected from lauric acid, stearic acid, caprylic acid, oleic acid, and succinic acid being particularly preferred.

[0029] In the ester compound of the polyol and the fatty acid, the number of fatty acids bonded to one molecule of the polyol is not particularly limited, and can be adjusted appropriately depending on the HLB of the target emulsifier.

[0030] Specific examples of the ester compounds of the polyols and the fatty acids include diglycerol monooleate, monoglycerol monocaprylate, diglycerol monocaprylate, decaglycerol pentaoleate, tetraglycerol pentaoleate, pentaglycerol trioleate, decaglycerol monolaurate, hexaglycerol monocaprylate, hexaglycerol monooleate, pentaglycerol monostearate, tetraglycerol tristearate, decaglycerol monobehenate, mono-diglycerol monostearate, monoglycerol monooleate, cocamidopropyl betaine, glycerol diglycerol monooleate ... Examples of the glycerin monostearate include glycerin monostearate, monoglycerin succinate, glycerin diacetyltartaric acid monostearate, propylene glycol monooleate, sorbitan monooleate, sorbitan tristearate, diglycerin monolaurate, diglycerin monomyristate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, condensed pentaglycerin ricinoleate, sucrose stearate, sucrose erucate, and sucrose oleate. More preferred specific examples of the ester compound of the polyol and the fatty acid include diglycerol monooleate, diglycerol monocaprylate, pentaglycerol trioleate, decaglycerol monolaurate, hexaglycerol monocaprylate, hexaglycerol monooleate, pentaglycerol monostearate, glycerol monostearate succinate, and sucrose stearate. A particularly preferred specific example of the ester compound of the polyol and the fatty acid is diglycerol monooleate.

[0031] Examples of lecithin include soybean lecithin, egg yolk lecithin, and enzymatically decomposed soybean lecithin.

[0032] It is particularly preferable to use an emulsifier that is acceptable for food, cosmetics, and / or pharmaceuticals.

[0033] <Antioxidant> In the present specification, the type of antioxidant is not limited. Two or more antioxidants may be used in combination. Specific examples of the antioxidant include one or more selected from ascorbic acid, ascorbic acid salts, erythorbic acid, and erythorbic acid salts. It is particularly preferable that the antioxidant does not contain a lipophilic antioxidant (lipophilic antioxidant) such as an ascorbic acid fatty acid ester.

[0034] The counter ions of ascorbate and erythorbate are not limited, but can each independently be one or more metal salts selected from sodium salts, potassium salts, calcium salts, and magnesium salts.

[0035] It is particularly preferred to use an antioxidant that is acceptable as a food or pharmaceutical product, preferably an ascorbate, and particularly preferably one or more selected from sodium ascorbate and calcium ascorbate.

[0036] The solid composition disclosed herein preferably further comprises a binder, which can be used to bind together components including Form II crystals of reduced coenzyme Q10, an emulsifier having an HLB of 6.0 or greater, and an antioxidant to form a granular solid composition.

[0037] The type of binder is not limited. Two or more binders may be used in combination. Specific examples of binders include one or more selected from celluloses and starches.

[0038] Examples of celluloses include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, crystalline cellulose, cellulose powder, methyl cellulose, ethyl cellulose, and salts thereof. Particularly preferred binders are one or more selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose, and more preferably one or more selected from hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

[0039] Examples of starches include wheat starch, potato starch, sweet potato starch, corn starch, dextrin, hydroxypropyl starch, starch acetate, oxidized starch, starch octenyl succinate or a salt thereof, and partially pregelatinized starch.

[0040] It is particularly preferable to use a binder that is acceptable for food or pharmaceutical use.

[0041] <Solid Composition> The solid composition used in one or more embodiments of the present invention contains Form II crystals of reduced coenzyme Q10, an emulsifier having an HLB of 6.0 or more, and an antioxidant.

[0042] When the solid composition is stored in a gas phase with a relative humidity of less than 50%, the reduction of reduced coenzyme Q10 due to oxidation is suppressed, and the solid composition can be stored for a long period of time, for example, for three months or more.

[0043] The solid composition is a solid composition at 25°C. The shape of the solid composition can be any shape, such as granules, powder, flakes, etc., but is preferably granular. The granular shape may be any shape formed by bonding primary particles of materials containing Form II crystals of reduced coenzyme Q10, an emulsifier having an HLB of 6.0 or more, and an antioxidant through a granulation operation, and includes granules. The dimensions of the granular solid composition are not limited, but can be, for example, granules with a longest diameter of 0.20 mm or more and 2.0 mm or less.

[0044] In the solid composition, the blending ratio of each component can be adjusted so as to suppress the oxidation of reduced coenzyme Q10.

[0045] The solid composition more preferably contains, for example, 1 part by weight or more and 9,900 parts by weight or less of an antioxidant per 100 parts by weight of Form II crystals of reduced coenzyme Q10. The lower limit of the content of the antioxidant per 100 parts by weight of Form II crystals of reduced coenzyme Q10 is preferably 20 parts by weight or more, more preferably 50 parts by weight or more, more preferably 80 parts by weight or more. The upper limit of the content of the antioxidant per 100 parts by weight of Form II crystals of reduced coenzyme Q10 is preferably 5,000 parts by weight or less, more preferably 1,000 parts by weight or less, more preferably 500 parts by weight or less, more preferably 200 parts by weight or less, and more preferably 120 parts by weight or less.

[0046] More preferably, the solid composition contains, for example, 1 part by weight or more and 9,900 parts by weight or less of an emulsifier having an HLB of 6.0 or more per 100 parts by weight of Form II crystals of reduced coenzyme Q10. The lower limit of the content of the emulsifier per 100 parts by weight of Form II crystals of reduced coenzyme Q10 is preferably 3 parts by weight or more, more preferably 5 parts by weight or more, more preferably 8 parts by weight or more. The upper limit of the content of the emulsifier per 100 parts by weight of Form II crystals of reduced coenzyme Q10 is preferably 5,000 parts by weight or less, more preferably 1,000 parts by weight or less, more preferably 500 parts by weight or less, more preferably 200 parts by weight or less, more preferably 150 parts by weight or less, more preferably 100 parts by weight or less, more preferably 50 parts by weight or less, more preferably 30 parts by weight or less.

[0047] The lower limit of the content of Form II crystals of reduced coenzyme Q10 in the solid composition is, for example, 1% by weight or more, preferably 10% by weight or more, more preferably 20% by weight or more, more preferably 30% by weight or more, and the upper limit of the content is, for example, 90% by weight or less, preferably 80% by weight or less, more preferably 70% by weight or less, more preferably 60% by weight or less.

[0048] The lower limit of the content of the antioxidant in the solid composition is, for example, 1 wt % or more, preferably 10 wt % or more, more preferably 20 wt % or more, and more preferably 30 wt % or more, and the upper limit of the content is, for example, 99 wt % or less, preferably 90 wt % or less, preferably 80 wt % or less, more preferably 70 wt % or less, and more preferably 60 wt % or less.

[0049] In the solid composition, the lower limit of the content of the emulsifier having an HLB of 6.0 or more is, for example, 0.5% by weight or more, preferably 1% by weight or more, and more preferably 3% by weight or more, and the upper limit of the content is, for example, 99% by weight or less, preferably 50% by weight or less, more preferably 20% by weight or less, more preferably 15% by weight or less, and more preferably 10% by weight or less.

[0050] When the solid composition contains a binder, the lower limit of the binder content in the solid composition is, for example, 1 wt % or more, preferably 5 wt % or more, and more preferably 8 wt % or more, and the upper limit of the binder content is, for example, 20 wt % or less, preferably 15 wt % or less, and more preferably 10 wt %.

[0051] The solid composition more preferably contains, for example, 1 part by weight or more, preferably 3 parts by weight or more, more preferably 5 parts by weight or more, more preferably 8 parts by weight or more of a binder per 100 parts by weight of Form II crystals of reduced coenzyme Q10. Also, the solid composition more preferably contains, for example, 200 parts by weight or less, preferably 150 parts by weight or less, more preferably 100 parts by weight or less, more preferably 50 parts by weight or less, and even more preferably 30 parts by weight or less of an antioxidant per 100 parts by weight of Form II crystals of reduced coenzyme Q10.

[0052] The solid composition may further contain other ingredients such as excipients, which are preferably ingredients that are acceptable as foods or pharmaceuticals.

[0053] The solid composition preferably does not contain carbonates containing sodium cations and / or calcium cations. Examples of carbonates containing sodium cations include sodium carbonate and its hydrates (e.g., monohydrate, heptahydrate, decahydrate, etc.) and sodium bicarbonate. Examples of carbonates containing calcium cations include calcium carbonate and its hydrates (e.g., 0.65-hydrate, monohydrate, 1.5-hydrate, hexahydrate, etc.). By storing the solid composition according to one or more embodiments of the present invention, oxidation of reduced coenzyme Q10 can be inhibited without adding specific components, such as carbonates containing sodium cations and / or calcium cations, to the solid composition.

[0054] The solid composition is preferably not a composition in which an oily component containing reduced coenzyme Q10 and a lipophilic antioxidant forms domains and is polydispersed in a matrix containing a water-soluble excipient. By storing the solid composition by the method according to one or more embodiments of the present invention, oxidation of reduced coenzyme Q10 can be suppressed without requiring the solid composition to have a special multiphase structure.

[0055] <Storage Method> One or more embodiments of the present invention relate to a method for storing a solid composition containing Form II crystals of reduced coenzyme Q10, an emulsifier having an HLB of 6.0 or more, and an antioxidant, the method comprising storing the solid composition in a gas phase with a relative humidity of less than 50%.

[0056] The method according to this embodiment is based on the unexpected finding that when the solid composition is stored in a gas phase with a relative humidity of less than 50%, oxidation of reduced coenzyme Q10 is suppressed compared to when the solid composition is stored in a gas phase with a relative humidity of 50% or more. In a preferred embodiment of the method according to this embodiment, reduced coenzyme Q10 can be maintained in an amount of 90% by weight or more of the initial amount for a long period of time of 2 months or more, even at a high temperature of 40°C. In order to provide this solid composition at an affordable price, it is preferable that reduced coenzyme Q10 can be maintained in an amount of 90% by weight or more, preferably 93% by weight or more, more preferably 95% by weight or more of the initial amount for 2 months at 40°C.

[0057] In the method according to this embodiment, the relative humidity of the gas phase is, for example, less than 50%, preferably 45% or less, more preferably 40% or less, more preferably 30% or less, more preferably 20% or less, more preferably 15% or less, and preferably 1% or more, more preferably 5% or more.

[0058] In the method according to this embodiment, the temperature at which the solid composition is stored may be, for example, −25° C. or higher and 50° C. or lower, preferably −20° C. or higher, −10° C. or higher, 0° C. or higher, 4° C. or higher, 5° C. or higher, 10° C. or higher, 15° C. or higher, or 20° C. or higher, and preferably 45° C. or lower or 40° C. or lower. Specifically, the temperature may be 10° C., 15° C., 25° C., or 40° C. In the method according to this embodiment, the relative humidity of the gas phase is the relative humidity of the gas phase at the storage temperature.

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

[0060] In the method according to this embodiment, the gas phase is preferably air, which is preferable because it can be implemented at lower cost than a method using a gas phase of an inert gas such as nitrogen.

[0061] <Packaging> One or more other embodiments of the present invention relate to a packaging comprising: a solid composition containing Form II crystals of reduced coenzyme Q10, an emulsifier having an HLB of 6.0 or more, and an antioxidant; a gas phase having a relative humidity of less than 50%; and a container enclosing the solid composition and the gas phase.

[0062] The package according to this embodiment is preferable because it suppresses the reduction of reduced coenzyme Q10 due to oxidation during storage.

[0063] The container is not particularly limited as long as it can accommodate the solid composition and can be sealed together with the gas phase. The container may be, for example, a sealable glass container, metal container, resin container, wooden container, or bag.

[0064] In the packaging body according to this embodiment, the relative humidity of the gas phase is, for example, less than 50%, preferably 45% or less, more preferably 40% or less, more preferably 30% or less, more preferably 20% or less, more preferably 15% or less, and preferably 1% or more, more preferably 5% or more.

[0065] In the package according to this embodiment, the relative humidity of the gas phase is the relative humidity of the gas phase at a temperature during storage of the package. The temperature during storage of the package 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, 4° C. or higher, 5° C. or higher, 10° C. or higher, 15° C. or higher, or 20° C. or higher, and preferably 45° C. or lower or 40° C. or lower. Specifically, the temperature may be 10° C., 15° C., 25° C., or 40° C.

[0066] In the packaging body according to the present embodiment, the gas phase is preferably air. Compared to a method using a gas phase of an inert gas such as nitrogen, a method using air as the gas phase is preferable because it can be implemented at low cost.

[0067] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. The HPLC measurement conditions in the following experiments are as follows.

[0068] (Method for evaluating oxidative stability) The weight ratio of reduced coenzyme Q10 to total coenzyme Q10 (i.e., reduced coenzyme Q10 / (oxidized coenzyme Q10+reduced coenzyme Q10)) is defined as the "QH ratio." The QH ratio was determined by the HPLC analysis described below. Furthermore, in evaluating oxidative stability, the QH ratio at the end of the evaluation, when the QH ratio at the start of the evaluation was taken as 100, was defined as the "QH residual rate," and the QH residual rate calculated from the following formula was used as a measure of oxidative stability. QH residual rate (%) = 100 × QH ratio at the end of the evaluation / QH ratio at the start of the evaluation

[0069] (HPLC measurement conditions) Column: SYMMETRY C １８ (Waters) 250 mm (length) 4.6 mm (inner diameter) Mobile phase: C ２ H ５ OH:CH ３ OH = 4:3 (v:v) Detection wavelength: 210 nm Flow rate: 1 ml / min

[0070] Example 1 (Experiment) 1.0 g of Form II crystals of reduced coenzyme Q10, 1.0 g of sodium ascorbate, 0.2 g of hydroxypropyl cellulose, and 0.2 g of an emulsifier (A1 to A9) shown in Table 1 were mixed, and water was added and kneaded. The resulting kneaded mixture was extrusion-granulated using a 1.2 mm diameter screen and dried to obtain a granular solid composition. The resulting granular solid composition was stored for two months in air at a temperature of 40°C and a relative humidity of 75%, and at a temperature of 40°C and a relative humidity of 10%, and the storage stability of reduced coenzyme Q10 was evaluated based on the QH residual rate.

[0071]

[0072] (Results) The QH remaining rate of the granular solid composition after storage at each humidity in the above experiment is shown in the table below.

[0073]

[0074] Example 2: 150 g of Form II crystals of reduced coenzyme Q10, 135 g of finely pulverized sodium ascorbate, and 15 g of diglycerin monooleate (Sunsoft Q-17D) were mixed. The resulting mixture was charged into an agitation granulator (SPGJ-2TG, manufactured by Dalton Co., Ltd.) and mixed. 20 mL of water was added, followed by granulation and drying to obtain a granular solid composition. The resulting granular solid composition was stored for two months in air at a temperature of 40°C and a relative humidity of 75%, and at a temperature of 40°C and a relative humidity of 10%, and the storage stability of reduced coenzyme Q10 was evaluated based on the QH residual rate.

[0075] Example 3: 275 g of Form II crystals of reduced coenzyme Q10, 165 g of finely pulverized sodium ascorbate, 25 g of diglycerol monooleate (Sunsoft Q-17D), and 35 g of hydroxypropyl cellulose were mixed. The resulting mixture was charged into a stirring granulator and mixed, followed by the addition of 15 mL of water for granulation and drying to obtain a granular solid composition. The resulting granular solid composition was stored for two months in air at a temperature of 40°C and a relative humidity of 75%, and at a temperature of 40°C and a relative humidity of 10%, and the storage stability of reduced coenzyme Q10 was evaluated based on the QH residual rate.

[0076] Example 4 326 g of Form II crystals of reduced coenzyme Q10, 149 g of finely pulverized sodium ascorbate, and 25 g of diglycerin monooleate (Sunsoft Q-17D) were mixed. The resulting mixture was charged into a stirring granulator and mixed, followed by the addition of 15 mL of water for granulation and drying to obtain a granular solid composition. The resulting granular solid composition was stored for two months in air at a temperature of 40°C and a relative humidity of 75%, and at a temperature of 40°C and a relative humidity of 10%, and the storage stability of reduced coenzyme Q10 was evaluated based on the QH residual rate.

[0077] The results obtained in Examples 2 to 4 are shown in Table 3.

[0078]

[0079] The results in Tables 2 and 3 show that granular solid compositions containing an antioxidant and an emulsifier with a high HLB value together with Form II crystals of reduced coenzyme Q10 have higher storage stability under low humidity conditions.

[0080] Example 5 (Experiment) Approximately 50 ml of saturated aqueous solution was prepared for each salt listed in Table 4. The salt was used in excess relative to its solubility, allowing the solid salt to remain in solution and preventing changes in the salt concentration of the aqueous solution due to moisture absorption. For each salt, the saturated aqueous solution containing the solid salt was divided into two 90 mm diameter Petri dishes, which were then placed in a polycarbonate jar (7000 ml internal volume) to prepare packages (1) and (2). The relative humidity inside packages (1) and (2) was determined according to Greenspan, J Res NBS A Phys Ch, 1977.

[0081]

[0082] The granular solid compositions of Example 1 A1 and Example 1 A7 were packed in an open state into packages (1) and (2) in Table 4 and then sealed. The saturated salt solution and the granular solid composition were placed separately within the package. The packages containing the granular solid composition were stored at 40°C for 3 months, and then the QH residual rate was determined.

[0083] (Results) The QH residual rates after 3 months of storage at 40°C for Example 5, Example 1 A1 and Example 1 A7 are shown in Tables 5 and 6. In Example 5, the granular solid compositions of Example 1 A1 and Example 1 A7 packed in package (1) were designated "Example 5-(1) A1" and "Example 5-(1) A7", respectively, and the granular solid compositions of Example 1 A1 and Example 1 A7 packed in package (2) were designated "Example 5-(2) A1" and "Example 5-(2) A7", respectively.

[0084]

[0085]

[0086] The results in Tables 5 and 6 show that granular solid compositions containing an antioxidant and an emulsifier with an HLB value of 6.0 or more together with Form II crystals of reduced coenzyme Q10 have higher storage stability under low humidity conditions of less than 50%.

[0087] Reference Example 1 (Experiment) 1.0 g of Form II crystals of reduced coenzyme Q10, 1.0 g of sodium ascorbate, 0.2 g of hydroxypropyl cellulose, and 0.2 g of glycerin monostearate succinate (Poem B-10, manufactured by Riken Vitamin Co., Ltd., HLB value 5) were mixed, and water was added and kneaded. The resulting kneaded mixture was extrusion-granulated using a 1.2 mm diameter screen and dried to obtain a granular solid composition. The resulting granular solid composition was stored for 2 months in air at a temperature of 40°C and a relative humidity of 10%, and the storage stability of reduced coenzyme Q10 was evaluated based on the QH residual rate.

[0088] (Results) The QH residual rate after storage for 2 months under the above low humidity conditions was 90.0%, which was lower than when an emulsifier with an HLB value of 6.0 or higher was used.

[0089] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0090] The upper and / or lower limits of the numerical ranges described herein can be arbitrarily combined to define a preferred range. For example, the upper and lower limits of the numerical ranges can be arbitrarily combined to define a preferred range, the upper limits of the numerical ranges can be arbitrarily combined to define a preferred range, and the lower limits of the numerical ranges can be arbitrarily combined to define a preferred range. Furthermore, in this application, numerical ranges expressed using the symbol "to" include the numerical values ​​written before and after the symbol "to" as the upper and lower limits, respectively.

[0091] Throughout this specification, singular terms should be understood to include the plural concept unless otherwise stated. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise stated.

[0092] Although the present embodiment has been described in detail above, the specific configuration is not limited to this embodiment, and even if there are design changes within the scope that do not deviate from the gist of this disclosure, they are included in this disclosure.

Claims

1. A method for preserving a solid composition containing Form II crystals of reduced coenzyme Q10, an emulsifier having an HLB of 6.0 or higher, and an antioxidant, A method comprising storing the solid composition in a gaseous state with a relative humidity of less than 50%.

2. The method according to claim 1, wherein the gas phase is air.

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

4. The method according to claim 1 or 2, wherein the antioxidant is one or more selected from ascorbic acid, ascorbate, erythorbic acid, and erythorbate.

5. The method according to claim 1 or 2, wherein the solid composition contains 1 to 9900 parts by weight of the emulsifier per 100 parts by weight of the crystal.

6. The method according to claim 1 or 2, wherein the content of the emulsifier in the solid composition is 1% by weight or more and 99% by weight or less.

7. The method according to claim 1 or 2, wherein the solid composition further comprises a binder.

8. The method according to claim 7, wherein the binder is one or more selected from hydroxypropylcellulose and hydroxypropylmethylcellulose.

9. The method according to claim 7, wherein the solid composition is a granular solid composition.

10. The method according to claim 1 or 2, wherein the solid composition does not contain a carbonate containing sodium cations and / or calcium cations.

11. The method according to claim 1 or 2, wherein the solid composition is not a composition in which an oily component containing reduced coenzyme Q10 and a lipophilic antioxidant forms domains and is polydispersed in a matrix containing a water-soluble excipient.

12. A solid composition containing Form II crystals of reduced coenzyme Q10, an emulsifier with an HLB of 6.0 or higher, and an antioxidant. Gas phase with relative humidity less than 50%, and A container for enclosing the solid composition and the gas phase. A packaging body equipped with the following features.

13. The packaging body according to claim 12, wherein the gas phase is air.

14. The packaging body according to claim 12 or 13, wherein the emulsifier is one or more selected from monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol, and an ester compound of a fatty acid which may have a substituent, and lecithin.

15. The packaging according to claim 12 or 13, wherein the antioxidant is one or more selected from ascorbic acid, ascorbate, erythorbic acid, and erythorbate.

16. The packaging body according to claim 12 or 13, wherein the solid composition contains 1 to 9900 parts by weight of the emulsifier per 100 parts by weight of the crystals.

17. The packaging body according to claim 12 or 13, wherein the content of the emulsifier in the solid composition is 1% by weight or more and 99% by weight or less.

18. The packaging according to claim 12 or 13, wherein the solid composition further comprises a binder.

19. The packaging according to claim 18, wherein the binder is one or more selected from hydroxypropylcellulose and hydroxypropylmethylcellulose.

20. The packaging body according to claim 18, wherein the solid composition is a granular solid composition.

21. The packaging according to claim 12 or 13, wherein the solid composition does not contain a carbonate containing sodium cations and / or calcium cations.

22. The packaging according to claim 12 or 13, wherein the solid composition is not a composition in which an oily component containing reduced coenzyme Q10 and a lipophilic antioxidant forms domains and is polydispersed in a matrix containing a water-soluble excipient.