Solid composition and method for producing same

Abstract

Provided is a solid composition that makes it possible to improve the water solubility of a crystalline organic compound that is sparingly water soluble. The solid composition according to an embodiment of the present invention comprises: an amorphized product of a crystalline organic compound that is sparingly water soluble; a sucrose fatty acid ester having a monoester content of at least 85 mass%; and a water-soluble polymer.

Description

Solid composition and method for producing the same

[0001] SUMMARY OF THE INVENTION Embodiments of the present invention relate to solid compositions and methods for making same.

[0002] Polyphenols are known to have antioxidant properties that prevent arteriosclerosis, cerebral infarction, etc. Carotenoids, retinoids, and steroids are also known to have physiological effects such as antioxidant properties. Therefore, they are expected to be used in the medical field, such as in pharmaceuticals, and in the food field, such as in food additives.

[0003] However, many of these compounds are poorly water-soluble and are poorly absorbed by the body when orally ingested. To improve absorption in the digestive tract, it is necessary to increase their solubility in water. One known method for achieving this is to convert crystalline poorly water-soluble organic compounds from a crystalline state into an amorphous form.

[0004] For example, Patent Document 1 discloses a solid composition containing an amorphous, poorly water-soluble polyphenol, a hydrophilic polymer, and a nonionic surfactant. It also describes the use of polyvinylpyrrolidone as the hydrophilic polymer and a sucrose fatty acid ester having an HLB value of 10 or more as the nonionic surfactant.

[0005] International Publication No. 2017 / 061627

[0006] An object of an embodiment of the present invention is to provide a solid composition that can improve the solubility of a crystalline, poorly water-soluble organic compound in water.

[0007] The present invention includes the following embodiments. [1] A solid composition containing an amorphous body obtained by amorphizing a crystalline poorly water-soluble organic compound, a sucrose fatty acid ester having a monoester ratio of 85% by mass or more, and a water-soluble polymer. [2] The solid composition according to [1], wherein the poorly water-soluble organic compound is at least one selected from the group consisting of flavonoids, phenylpropanoids, stilbenoids, phenolic acids, carotenoids, retinoids, steroids, alkaloids, ceramides, and limonoids. [3] The solid composition according to [1], wherein the poorly water-soluble organic compound is at least one selected from the group consisting of flavanones, flavonols, lignans, coumarins, stilbenoids, phenolic acids, xanthophylls, retinoids, phytosterols, alkaloids, glucosylceramides, and limonoids. [4] The solid composition according to any one of [1] to [3], wherein the mass ratio of the sucrose fatty acid ester to the amorphous body is 0.2 to 30. [5] The solid composition according to any one of [1] to [4], wherein the mass ratio of the water-soluble polymer to the amorphous body is 0.2 to 30. [6] The solid composition according to any one of [1] to [5], wherein the mass ratio of the water-soluble polymer to the sucrose fatty acid ester is 0.1 to 10. [7] The solid composition according to any one of [1] to [6], wherein the water-soluble polymer comprises at least one selected from the group consisting of cellulose ether, cellulose ester, N-vinyl lactam homopolymer, N-vinyl lactam copolymer, polyalkylene glycol, polyalkylene oxide, and poly(meth)acrylate. [8] An oral composition comprising the solid composition according to any one of [1] to [7]. [9] A method for producing a solid composition, comprising dissolving a crystalline poorly water-soluble organic compound, a sucrose fatty acid ester having a monoester ratio of 85% by mass or more, and a water-soluble polymer in a solvent to obtain a solution, and removing the solvent from the solution.

[0008] The solid composition according to the embodiment of the present invention can improve the solubility of poorly water-soluble organic compounds in water.

[0009] XRD chart of the solid composition of Example 1 XRD chart of the solid composition of Comparative Example 1 XRD chart of the solid composition of Example 3 XRD chart of the solid composition of Comparative Example 3 XRD chart of the solid composition of Example 5 XRD chart of the solid composition of Comparative Example 5 XRD chart of the solid composition of Example 7 XRD chart of the solid composition of Comparative Example 7 XRD chart of the solid composition of Example 8 XRD chart of the solid composition of Comparative Example 9

[0010] The solid composition according to this embodiment contains (A) an amorphous substance obtained by amorphizing a crystalline poorly water-soluble organic compound, (B) a sucrose fatty acid ester, and (C) a water-soluble polymer.

[0011] [Amorphous Form (A)] The amorphous form of component (A) is a crystalline poorly water-soluble organic compound that has been made amorphous, i.e., an organic compound that is originally poorly soluble in water (including cases where it is insoluble) because it is crystalline, and is made amorphous, and is also referred to as an amorphous poorly water-soluble organic compound. Here, the solubility (maximum solubility concentration) of the crystalline poorly water-soluble organic compound (in the state before being made amorphous) in pure water at 25°C is 1 mg / mL or less, or may be 100 μg / mL or less, 10 μg / mL or less, or 1 μg / mL or less.

[0012] Specific examples of the poorly water-soluble organic compound in this embodiment include: (A1) polyphenols: for example, flavanones (e.g., hesperetin, nobiletin, sudachitin, narirutin, naringin, naringenin, and hesperidin), flavonols (e.g., myricetin, quercetin, tiliroside, silibinin, rutin, isoquercitrin, galangin, kaempferol, fisetin, and hyperoside), and flavones (e.g., luteolin, apigenin, baicalein, chrysin, 5,7-dimethoxyflavone, diosmin, diosmetin, and flavoxate). Flavonoids such as flavanols (e.g., catechin, epicatechin, theaflavin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, procyanidins), isoflavones (e.g., genistein, daidzein, equol, puerarin, ipriflavone), anthocyanidins (e.g., cyanidin, delphinidin, malvidin, pelargonidin, peonidin), proanthocyanidins, and oligomeric proanthocyanidins (OPCs); phenylpropanoids such as lignans (e.g., sesamin, sesamolin, sesamol, sesaminol) and coumarins (e.g., auraptene, umbelliferone, coumestrol); stilbenoids such as resveratrol; phenolic acids such as chlorogenic acid, hydroxycinnamic acids (e.g., caffeic acid), hydroxybenzoic acids (e.g., gallic acid, ellagic acid), and rosmarinic acid;(A2) Carotenoids: For example, xanthophylls (for example, astaxanthin, lutein, β-cryptoxanthin, zeaxanthin, neoxanthin), carotenes (for example, β-carotene, lycopene), (A3) Retinoids: For example, retinoic acid, retinol, retinal, adapalene, tamibarotene, (A4) Steroids: For example, phytosterols (for example, β-sitosterol, stigmasterol, campesterol, brassicasterol, 7-ergostenol, isofucosterol, 7-stigmasterol, avenasterol, diosgenin, ginsenoside), vitamin D (for example, ergocalciferol, cholecalciferol), (A5) Alkaloids: For example, phytosterols (for example, β-sitosterol, stigmasterol, campesterol, brassicasterol, 7-ergostenol, isofucosterol, 7-stigmasterol, avenasterol, diosgenin, ginsenoside), vitamin D (for example, ergocalciferol, cholecalciferol), (A6) Alkaloids: For example, hydroxybenzoates (for example, hydroxybenzoates), ... Examples include berberine, morphine, and capsaicinoid; (A6) ceramides, such as glucosylceramide, human ceramide, and synthetic ceramide; and (A7) limonoids, such as limonin and azadirachtin. These may be used alone or in combination of two or more. In this specification, the terms "polyphenol," "carotenoid," "retinoid," "steroid," "alkaloid," "ceramide," and "limonoid" are used to encompass derivatives such as aglycones, acetylated products, fatty acid esterified products, amidated products, malonylated products, methylated products, polymers, condensates, salts, and glycosides.

[0013] Among these, the poorly water-soluble organic compound is preferably at least one selected from the group consisting of flavonoids, phenylpropanoids, stilbenoids, phenolic acids, carotenoids, retinoids, steroids, alkaloids, ceramides, and limonoids. More preferably, the poorly water-soluble organic compound is at least one selected from the group consisting of flavanones, flavonols, lignans, coumarins, stilbenoids, phenolic acids, xanthophylls, retinoids, phytosterols, alkaloids, glucosylceramides, and limonoids. More preferably, the poorly water-soluble organic compound is at least one selected from the group consisting of flavanones, flavonols, lignans, xanthophylls, and phytosterols, and even more preferably at least one selected from the group consisting of hesperetin, myricetin, sesamin, astaxanthin, and β-sitosterol.

[0014] The solid composition of this embodiment contains an amorphous body obtained by amorphizing the poorly water-soluble organic compound. The amorphous state of the poorly water-soluble organic compound can be confirmed by the absence of a clear diffraction peak in X-ray diffraction (XRD). The solid composition may contain a crystalline poorly water-soluble organic compound in addition to the amorphous body. However, it is preferable that the amount of the crystalline poorly water-soluble organic compound is as small as possible, and it is preferable that the solid composition contains substantially no or no crystalline poorly water-soluble organic compound.

[0015] The content of the amorphous body in the solid composition is not particularly limited, but is preferably 1 to 50% by mass, more preferably 3 to 40% by mass, more preferably 4 to 40% by mass, more preferably 5 to 30% by mass, and even more preferably 6 to 20% by mass.

[0016] [(B) Sucrose Fatty Acid Ester] In this embodiment, a sucrose fatty acid ester having a monoester ratio of 85% by mass or more is used as component (B). Sucrose fatty acid esters are formed by esterifying a fatty acid to a hydroxy group of sucrose. One sucrose molecule has eight hydroxy groups, and the ester ranges from monoester to octaester depending on the number of ester-linked fatty acids. In this embodiment, a sucrose fatty acid ester is used in which the ratio of monoesters, in which a fatty acid is bonded to one hydroxy group, is 85% by mass or more relative to 100% by mass of the sucrose fatty acid ester. While typical sucrose fatty acid esters have a monoester ratio of 80% by mass or less, a sucrose fatty acid ester having a high monoester ratio of 85% by mass or more is used in this embodiment. This improves the solubility of poorly water-soluble organic compounds in water.

[0017] The proportion of monoesters in the sucrose fatty acid ester is preferably 90% by mass or more, more preferably 95% by mass or more, even more preferably 97% by mass or more, still more preferably 99% by mass or more, and may be 100% by mass. Therefore, the proportion of diesters or higher esters is preferably 10% by mass or less, more preferably 5% by mass or less, even more preferably 3% by mass or less, and still more preferably 1% by mass or less.

[0018] The ratio of monoesters in sucrose fatty acid esters can be determined by analyzing the ester distribution of the sucrose fatty acid esters by GPC (gel permeation chromatography), and is calculated as the ratio of the peak area derived from monoesters to the total peak area. The GPC analysis conditions are as follows:

[0019] <GPC conditions> Apparatus: "LC-6A" manufactured by Shimadzu Corporation Column: "Megapak GEL201" manufactured by JASCO Corporation Solvent: THF Flow rate: 3 mL / min Sample concentration: 6% by mass / volume Sample injection amount: 50 μL Column temperature: 25° C.

[0020] The sucrose fatty acid ester preferably contains a fatty acid having 12 to 22 carbon atoms as a constituent fatty acid. That is, as the fatty acid constituting the sucrose fatty acid ester, a saturated or unsaturated, linear or branched fatty acid having 12 to 22 carbon atoms is preferably used, and one or more of these fatty acids can be used in combination. The constituent fatty acid preferably contains a fatty acid having 12 to 22 carbon atoms as a main component, more preferably a fatty acid having 14 to 18 carbon atoms, and even more preferably a fatty acid having 16 to 18 carbon atoms as a main component. Here, "mainly containing" means that the fatty acid accounts for 50% by mass or more of 100% by mass of the constituent fatty acids, more preferably 70% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and may even be 100% by mass.

[0021] The constituent fatty acids of the sucrose fatty acid ester are preferably saturated fatty acids, and more preferably straight-chain saturated fatty acids. In a preferred embodiment, the constituent fatty acids are mainly composed of stearic acid, and a mixture of stearic acid and palmitic acid is preferably used.

[0022] The HLB value of the sucrose fatty acid ester is not particularly limited, and may be 10 or more, 13 or more, or 16 or more.

[0023] [(C) Water-Soluble Polymer] The water-soluble polymer of component (C) is a natural or synthetic polymer that is soluble in water. The solubility of the water-soluble polymer in pure water at 25°C (maximum solubility concentration) is preferably 0.001% by mass or more, more preferably 0.1% by mass or more, and may be 1% by mass or more.

[0024] Specific examples of water-soluble polymers include: homopolymers and copolymers of N-vinyl lactams such as polyvinylpyrrolidone (PVP), copovidone (i.e., a copolymer of N-vinylpyrrolidone and vinyl acetate), and a copolymer of N-vinylpyrrolidone and vinyl propionate; cellulose ethers such as alkylcelluloses (e.g., methylcellulose, ethylcellulose), hydroxyalkylcelluloses (e.g., hydroxypropylcellulose (HPC)), and hydroxyalkylalkylcelluloses (e.g., hydroxypropylmethylcellulose (HPMC), hydroxyethylmethylcellulose (HEMC)); cellulose esters such as cellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose succinate, and hydroxypropylmethylcellulose acetate succinate (HPMCAS); polyalkylene glycols (PAGs) having a structure corresponding to a polymer of alkylene glycol having 2 to 4 carbon atoms, such as polyethylene glycol (PEG) and polypropylene glycol (PPG); - polyalkylene oxides (PAO) such as polyethylene oxide (PEO), polypropylene oxide (PPO), copolymers of ethylene oxide and propylene oxide; - poly(meth)acrylates such as methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), alkyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, alkyl methacrylate / methacrylic acid copolymer, alkyl methacrylate / methyl methacrylate copolymer, alkyl methacrylate / methacryloyloxyethyltrimethylammonium chloride copolymer; - polyvinyl caprolactam / polyvinyl acetate / polyethylene glycol graft copolymer; - polyacrylamide; - polyvinyl alcohol; - starch and derivatives thereof such as starch, modified starch, modified starch, etc.; - Dextrin and its derivatives such as dextrin, modified dextrin, and processed dextrin;and oligosaccharides and polysaccharides such as carrageenan, galactomannan, xanthan gum, and gum arabic. These may be used alone or in combination of two or more. Note that polyalkylene glycols and polyalkylene oxides are compounds having essentially the same structure, with the former having an average molecular weight of up to about 20,000, and the latter known to those skilled in the art as having a larger molecular weight.

[0025] Among these, the water-soluble polymer is preferably at least one (C1) selected from the group consisting of cellulose ether, cellulose ester, N-vinyl lactam homopolymer, N-vinyl lactam copolymer, polyalkylene glycol, polyalkylene oxide, and poly(meth)acrylate, and more preferably at least one (C2) selected from the group consisting of cellulose ether, cellulose ester, N-vinyl lactam homopolymer, and N-vinyl lactam copolymer. In this case, 100% by mass of the water-soluble polymer preferably contains 70 to 100% by mass of the at least one (C1) or (C2), more preferably 80 to 100% by mass, more preferably 90 to 100% by mass, and even more preferably 95 to 100% by mass.

[0026] In one embodiment, the water-soluble polymer preferably comprises at least one (C3) selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyethylene glycol, and more preferably comprises hydroxypropyl cellulose (C4). 100% by mass of the water-soluble polymer preferably comprises 70 to 100% by mass, more preferably 80 to 100% by mass, more preferably 90 to 100% by mass, and even more preferably 95 to 100% by mass of the at least one (C3) or hydroxypropyl cellulose (C4).

[0027] The molecular weight of the water-soluble polymer is not particularly limited, and may be, for example, a weight average molecular weight (Mw) of 1,000 to 600,000, 1,000 to 100,000, 5,000 to 80,000, or 10,000 to 60,000. Here, the weight average molecular weight (Mw) is a value measured by a GPC method.

[0028] The K value of the water-soluble polymer is not particularly limited, and is, for example, preferably 5 to 100, more preferably 10 to 70, even more preferably 15 to 50, and even more preferably 15 to 35. The K value represents the molecular weight measured by the Fikentscher method, and can be determined by a known measurement method and the following Fikentscher equation: K value = {[300ClogZ + (C + 1.5ClogZ) ２ ] １／２ +1.5ClogZ-C} / (0.15C+0.003C ２ In the formula, C represents the concentration of the sample (mass %). Z represents the relative viscosity (ηrel) of a solution of concentration C. The relative viscosity ηrel can be obtained from the following formula: ηrel = (flow time of the solution) ÷ (flow time of water)

[0029] In one embodiment, a hydroxyalkyl cellulose such as HPC may be used as the water-soluble polymer. In this case, the hydroxyalkyl cellulose preferably has a viscosity (20°C) of 0.1 to 10,000 mPa·s when prepared as a 2% by mass aqueous solution, more preferably 0.3 to 5,000 mPa·s, more preferably 0.3 to 3,000 mPa·s, more preferably 0.3 to 1,000 mPa·s, more preferably 0.5 to 500 mPa·s, more preferably 0.8 to 100 mPa·s, more preferably 1 to 20 mPa·s, more preferably 1.2 to 10 mPa·s, more preferably 1.5 to 8 mPa·s, and more preferably 1.8 to 4 mPa·s. The viscosity is measured in accordance with the rotational viscometer method of the 9th edition of the Japanese Standards of Food Additives.

[0030] The hydroxyalkyl cellulose has a weight average molecular weight (Mw) of 1,000 to 600,000, more preferably 2,000 to 500,000, more preferably 3,000 to 400,000, more preferably 5,000 to 300,000, more preferably 10,000 to 200,000, more preferably 15,000 to 150,000, more preferably 20,000 to 100,000, more preferably 25,000 to 80,000, and more preferably 30,000 to 50,000. Here, the weight average molecular weight (Mw) is a value measured by the GPC method.

[0031] In addition, the degree of substitution of hydroxyalkoxy groups (hydroxypropoxy groups in the case of HPC) in hydroxyalkyl cellulose is preferably 5 to 99% by mass, more preferably 10 to 95% by mass, more preferably 15 to 90% by mass, and more preferably 20 to 85% by mass. Here, the degree of substitution is measured by a method based on the gas chromatographic measurement method described for hydroxypropyl cellulose in the 9th edition of the Japanese Standards of Food Additives.

[0032] [Solid Composition] In the solid composition according to this embodiment, the poorly water-soluble organic compound is contained in an amorphous state due to the water-soluble polymer. In one embodiment, the water-soluble polymer may penetrate between the molecules of the poorly water-soluble organic compound together with the emulsifier sucrose fatty acid ester, disrupting the crystallinity of the poorly water-soluble organic compound and causing it to become amorphous. The poorly water-soluble organic compound thus amorphized is dispersed at the molecular level in the inert carrier water-soluble polymer. Therefore, in one embodiment, the solid composition is a solid dispersion. Generally, in a solid dispersion, the poorly water-soluble drug is amorphized, and the solid poorly water-soluble drug in an amorphous state is dispersed at the molecular level in the inert carrier, making it easily soluble in water. In particular, in this embodiment, the solubility of the poorly water-soluble organic compound in water can be improved by using a sucrose fatty acid ester in combination with the water-soluble polymer.

[0033] The solid composition according to this embodiment is solid at room temperature (25° C.), and more specifically, remains solid even when left at room temperature for 5 hours or more.

[0034] In the solid composition, the mass ratio (B) / (A), which is the ratio of the mass of the sucrose fatty acid ester (B) to the mass of the amorphous form of the poorly water-soluble organic compound (A), is preferably 0.2 to 30, more preferably 0.5 to 20, even more preferably 1.0 to 15, even more preferably 1.5 to 12, even more preferably 2.0 to 10, even more preferably 2.5 to 8.0, and even more preferably 3.0 to 6.0.

[0035] In the solid composition, the mass ratio (C) / (A), which is the ratio of the mass of the water-soluble polymer (C) to the mass of the amorphous form of the poorly water-soluble organic compound (A), is preferably 0.2 to 30, more preferably 0.5 to 25, even more preferably 1.0 to 20, even more preferably 2.0 to 15, even more preferably 3.0 to 12, even more preferably 3.5 to 10, and even more preferably 4.0 to 9.0.

[0036] In the solid composition, the mass ratio (C) / (B), which is the ratio of the mass of the water-soluble polymer (C) to the mass of the sucrose fatty acid ester (B), is preferably 0.1 to 10, more preferably 0.2 to 8.0, more preferably 0.3 to 5.0, even more preferably 0.5 to 4.0, still more preferably 1.0 to 3.0, and may be 1.0 to 2.5.

[0037] The solid composition according to this embodiment may contain other components in addition to the above components (A) to (C). The other components are not particularly limited and include, for example, excipients, binders, fillers, lubricants, extenders, disintegrants, surfactants, seasonings, and flavors.

[0038] In one embodiment, the solid composition may contain an excipient such as sugar, sugar alcohol, starch, dextrin, or crystalline cellulose. The incorporation of an excipient can further improve the solubility in water. The excipient is preferably incorporated into the solid composition by powder mixing with the solid dispersion containing the above components (A) to (C).

[0039] Specific examples of the sugars and / or sugar alcohols include lactose, sucrose, glucose, maltose, xylose, trehalose, mannitol, sorbitol, xylitol, erythritol, maltitol, etc., and any one of these may be used alone or in combination of two or more.

[0040] The amount of the excipient is not particularly limited, and may be, for example, 10 to 500 parts by mass, 50 to 400 parts by mass, or 100 to 300 parts by mass relative to 100 parts by mass of the total amount of (A) to (C).

[0041] The form of the solid composition is not particularly limited, and it may be in the form of a powder, or in the form of granules obtained by granulating the powder, and may take the form of various solid preparations.

[0042] [Method for Producing Solid Composition] The method for producing the solid composition according to this embodiment is not particularly limited. In one embodiment, the method for producing the solid composition includes the following steps: (1) dissolving a crystalline poorly water-soluble organic compound, a sucrose fatty acid ester having a monoester ratio of 85% by mass or more, and a water-soluble polymer in a solvent to obtain a solution; and (2) removing the solvent from the obtained solution.

[0043] In step (1), the solvent used is not particularly limited and is a solvent capable of dissolving the poorly water-soluble organic compound, the sucrose fatty acid ester, and the water-soluble polymer. Specific examples of the solvent include alcohols such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, and 2-butanol; ketones such as methyl ethyl ketone and acetone; acetate esters such as ethyl acetate and methyl acetate; ethers such as diethyl ether; alkanes such as propane, butane, and hexane; polyhydric alcohols such as propylene glycol and glycerin; chlorinated hydrocarbons such as dichloromethane, chloroform, and dichloroethane; and organic solvents such as cyclohexane. Mixtures of any one or more of these organic solvents may also be used. Mixtures of these organic solvents with water may also be used.

[0044] In step (1), the poorly water-soluble organic compound, sucrose fatty acid ester, and water-soluble polymer are dissolved in the solvent while heating. The poorly water-soluble organic compound and sucrose fatty acid ester may be dissolved in the solvent first, and then the water-soluble polymer may be added and dissolved; the order of dissolution is not important. The dissolution is preferably carried out by stirring or applying ultrasonic vibrations using an ultrasonic device. The temperature at which the solvent is heated is not particularly limited, and is preferably, for example, 60 to 90°C.

[0045] The concentration of each component in the solution prepared in step (1) is not particularly limited. For example, the concentration of the poorly water-soluble organic compound may be 0.1 to 5% by mass, or 0.2 to 3% by mass. The concentrations of the sucrose fatty acid ester and the water-soluble polymer may be set depending on the mass ratios (B) / (A), (C) / (A), and (C) / (B) of the components in the solid composition to be produced.

[0046] In one embodiment, when astaxanthin is used as the poorly water-soluble organic compound, the astaxanthin may be isomerized by aging it in an organic solvent.

[0047] In step (2), the solvent is removed from the solution obtained in step (1) to obtain a solid composition. The method for removing the solvent is not particularly limited, and examples thereof include vacuum drying, spray drying, freeze drying, heat drying, and natural drying. After removing the solvent, a pulverization treatment may be performed.

[0048] [Uses of the solid composition] The solid composition according to this embodiment is suitable for use in pharmaceuticals, quasi-drugs, health foods (e.g., foods for specified health uses, foods with nutrient functions, foods with functional claims, etc.), health foods, nutritional supplements, foods such as supplements, pet foods, cosmetics, etc. Preferably, it is used as an oral preparation. That is, an oral composition according to a preferred embodiment contains the above solid composition.

[0049] The oral composition may consist solely of the solid composition, or may contain, in addition to the solid composition, other food materials, other active ingredients, and / or additives, etc. Examples of additives include excipients, binders, fillers, lubricants, extenders, disintegrants, surfactants, seasonings, fragrances, and colorants.

[0050] The form of the oral composition is not particularly limited, and examples thereof include tablets, granules, powders, fine granules, granules, pills, and capsules.

[0051] The solid composition according to this embodiment has excellent solubility in water of poorly water-soluble organic compounds, and is therefore expected to exhibit high elution of poorly water-soluble organic compounds into body fluids when orally administered or ingested, thereby enabling efficient ingestion of poorly water-soluble organic compounds.

[0052] The present invention will be explained in more detail below based on examples and comparative examples, but the present invention is not limited thereto.

[0053] Details of the ingredients in Tables 1 and 2 are as follows: HPT: Hesperetin, manufactured by Fujifilm Wako Chemical Co., Ltd., purchased from Fujifilm Wako Pure Chemical Industries, Ltd. MIR: Myricetin, manufactured by Combi-Blocks, 3,3',4',5,5',7-Hexahydroxyflavone, purchased from Fujifilm Wako Pure Chemical Industries, Ltd., product code QA-0360 SES: Sesamin, manufactured by Combi-Blocks, (1S,3aR,4S,6aR)-1,4-bis(Benzo[d][1,3]dioxol-5-yl)tetrahydro-1H,3H-furo[3,4-c]furan, purchased from Fujifilm Wako Pure Chemical Industries, Ltd., product code QG-3906 AST: Astaxanthin, manufactured by Combi-Blocks, Beta-Carotene-4,4'-dione, purchased from Fujifilm Wako Pure Chemical Industries, Ltd., product code QA-1399 β-SIT: β-Sitosterol, manufactured by MP Biomedicals, Inc., β-Sitosterol, practical grade, purchased from Fujifilm Wako Pure Chemical Industries, Ltd., product code 102886

[0054] SE-SS: "DK Ester SS" manufactured by Daiichi Kogyo Seiyaku Co., Ltd., a sucrose fatty acid ester whose main constituent fatty acid is stearic acid having 18 carbon atoms. The ratio of monoester is 99% by mass, and the ratio of the remaining diester and triester is 1% by mass. HLB = 19

[0055] HPC: Hydroxypropyl cellulose "CELNY SSL" manufactured by Nippon Soda Co., Ltd. (viscosity 2.0 to 2.9 mPa·s (20°C, 2% by mass aqueous solution), weight average molecular weight 40,000)

[0056] Examples 1 and 2 and Comparative Examples 1 and 2 A total of 40 g of (A) hesperetin (HPT) as a water-insoluble organic compound, (B) sucrose fatty acid ester, (C) hydroxypropyl cellulose (HPC) as a water-soluble polymer, and solvent were prepared according to the formulations (parts by mass) shown in Tables 1 and 2. The hesperetin, sucrose fatty acid ester, and solvent were placed in a 50 mL screw tube. The tube was then subjected to two steps: (1) a heating treatment in which the screw tube was immersed in a 75°C water bath for 4 minutes, and (2) an ultrasonic treatment in which the screw tube was immersed in a 20-50°C bath using a compact ultrasonicator (Yamato Scientific Co., Ltd., "BRANSON 2210") for 4 minutes (selecting "SET SONICS min" and turning ON the device). Steps (1) and (2) were repeated until the hesperetin and sucrose fatty acid ester were completely dissolved.

[0057] While stirring the resulting solution with a rotor, HPC was added and stirred until dissolved. If it did not dissolve, it was dissolved by ultrasonic treatment at 20 to 40°C. Next, the solvent was distilled off using an evaporator. The treatment using the evaporator was carried out by reducing the pressure to 160 hPa at 75°C and distilling off the solvent until it was almost completely removed, then continuing at 60 to 90 hPa for 10 to 50 minutes, and then at 3 to 20 hPa for another 10 to 50 minutes. The solid material adhering to the wall of the eggplant flask was scraped off with a spatula, and the solid material was pulverized in an agate mortar to obtain the solid compositions of Examples 1 and 2 and Comparative Example 2. In Comparative Example 1, hesperetin powder was used as the solid composition as is.

[0058] [Examples 3, 4 and Comparative Examples 3, 4] Except for changing hesperetin to myricetin (MIR), the solid compositions of Examples 3, 4 and Comparative Example 4 were obtained in the same manner as in Examples 1, 2 and Comparative Example 2. In Comparative Example 3, the powder of myricetin was used as a solid composition as it was.

[0059] Examples 5 and 6 and Comparative Examples 5 and 6: (A) Sesamin (SES) as a water-insoluble organic compound, (B) Sucrose fatty acid ester, (C) HPC as a water-soluble polymer, and solvent were prepared in a total amount of 40 g according to the formulations (parts by mass) shown in Tables 1 and 2 below. The sucrose fatty acid ester and solvent were placed in a 50 mL screw tube, and while stirring with a rotor, HPC was added and stirred until dissolved. Sesamin was then added, and (1) the screw tube was immersed in a 75°C water bath for 4 minutes, followed by (2) ultrasonic treatment for 4 minutes by immersing the screw tube in a small ultrasonic device (Yamato Scientific Co., Ltd., "BRANSON 2210") at 20-50°C (select "SET SONICS min" on the device and turn it ON). Steps (1) and (2) were repeated until the sesamin was completely dissolved.

[0060] The solvent was then removed using an evaporator. The treatment using the evaporator was carried out by reducing the pressure at 75°C until the solvent was almost completely removed, then continuing at 60-90 hPa for 10-50 minutes, and then at 3-20 hPa for 10-50 minutes. The solid matter adhering to the wall of the recovery flask was scraped off with a spatula, and the solid matter was pulverized in an agate mortar to obtain the solid compositions of Examples 5 and 6 and Comparative Example 6. In Comparative Example 5, the sesamin powder was used as the solid composition as is.

[0061] [Example 7 and Comparative Examples 7 and 8] Chloroform was placed in a medium bottle so that the astaxanthin concentration was 0.5% by mass, and the solution was treated in a water bath at 60°C for 4 hours, then aged at room temperature for 3 nights, and further treated in a water bath at 60°C for 1 hour to dissolve and isomerize the astaxanthin, thereby obtaining a chloroform solution of astaxanthin.

[0062] 40 g of the above astaxanthin chloroform solution was distilled under reduced pressure at 55°C until the solvent was almost completely removed, and then dried at 60 to 90 hPa for 30 minutes and then at 3 to 20 hPa for 30 minutes to obtain a solid. The obtained solid was pulverized in an agate mortar to obtain the solid composition of Comparative Example 7.

[0063] While stirring 80 g of the above astaxanthin chloroform solution with a rotor, 1.6 g of HPC was added and stirred until dissolved, yielding a chloroform solution containing astaxanthin and HPC. The resulting solution was divided into two equal parts, and one part was distilled under reduced pressure at 55 ° C until the solvent was almost completely removed, followed by drying at 60 to 90 hPa for 30 minutes and then at 3 to 20 hPa for 30 minutes to obtain a solid. The resulting solid was pulverized in an agate mortar to obtain the solid composition of Comparative Example 8.

[0064] 0.8 g of sucrose fatty acid ester was added to another chloroform solution containing astaxanthin and HPC and stirred until dissolved. The resulting solution was distilled under reduced pressure at 55°C until the solvent was almost completely removed, and then dried at 60 to 90 hPa for 30 minutes and then at 3 to 20 hPa for 30 minutes to obtain a solid. The resulting solid was pulverized in an agate mortar to obtain the solid composition of Example 7.

[0065] [Examples 8 and 9 and Comparative Examples 9 and 10] Except for changing hesperetin to β-sitosterol (β-SIT), the solid compositions of Examples 8 and 9 and Comparative Example 10 were obtained in the same manner as in Examples 1 and 2 and Comparative Example 2. In Comparative Example 9, β-sitosterol powder was used as the solid composition as it was.

[0066] The obtained solid compositions were subjected to X-ray diffraction (XRD) to evaluate amorphization. Furthermore, dissolution tests 1 and 2 were conducted to evaluate the solubility in water. Regarding these evaluation results, "-" in Tables 1 and 2 indicates that the evaluation was not performed. The evaluation methods were as follows.

[0067] [Amorphization Evaluation: XRD] An XRD chart of the solid composition was obtained using a RINT Ultima III horizontal goniometer (D / teX-25) manufactured by Rigaku Corporation. The XRD measurement conditions were focusing method, X-ray: Cu / 40 kV / 40 mA, scanning range: 3.0° to 50.0°, scanning axis: 2θ / θ. The amorphization of the poorly water-soluble organic compound was evaluated from the obtained XRD chart according to the following criteria: A: No crystalline peaks specific to poorly water-soluble organic compounds (amorphous state) B: Crystalline peaks specific to poorly water-soluble organic compounds (including crystalline)

[0068] [Dissolution Test 1: Dissolution Amount 1] (In the Case of Hesperetin) An "NTR-6600AST" manufactured by Toyama Sangyo Co., Ltd. was used as a dissolution tester. 900 mL of ion-exchanged water was charged into the vessel, and the vessel was stirred overnight at a water temperature of 37°C ± 0.2°C for degassing. A gelatin capsule ("HF Capsule" manufactured by Matsuya Co., Ltd.) filled with 8 mg of solid composition in terms of hesperetin was placed in a sinker and placed in the vessel. After a predetermined time, the vessel was sampled through a 100 μm filter and filtered with a 0.45 μm membrane filter. Tests were conducted for predetermined times of 60 minutes, 120 minutes, and 240 minutes. The filtrate was diluted 2-fold with ethanol and filtered with a 0.20 μm membrane filter, and hesperetin was quantified by HPLC. Two tests were conducted for each solid composition, and the average was calculated. The average was rounded to two decimal places to determine the dissolution amount. The 100 μm filter used was a "porous prefilter Poro Filter 30" manufactured by Toyama Sangyo Co., Ltd. (filter material: ultra-high molecular weight polyethylene, mesh size: 100 μm). The 0.45 μm membrane filter used was a "25HP045AN" manufactured by Advantec Co., Ltd. (filter material: hydrophilic PTFE, mesh size: 0.45 μm). The 0.20 μm membrane filter used was a "13HP020AN" manufactured by Advantec Co., Ltd. (filter material: hydrophilic PTFE, mesh size: 0.20 μm). The HPLC conditions were: column: octadecylsilyl column, mobile phase: a mixture of acetonitrile and 10 mM ammonium acetate aqueous solution, wavelength: 289 nm.

[0069] (In the case of myricetin) The amount of solid composition filled into gelatin capsule is 8 mg in terms of myricetin.In addition, the mobile phase of HPLC conditions is a mixture of methanol / 10 mM ammonium acetate aqueous solution, and wavelength: 371 nm.Otherwise, the same as in the case of hesperetin, the elution amount is calculated.

[0070] [Elution Test 2: Elution Amount 2] (In the Case of Astaxanthin) A 50 mL screw tube was charged with 0.4 mg of solid composition (equivalent to astaxanthin) and 45 mL of ion-exchanged water. The screw tube was inverted 10 times every 30 minutes to mix, and then allowed to stand at 25°C for 120 minutes, after which it was filtered through a 0.45 μm membrane filter. The filtrate was diluted 2-fold with ethanol and filtered through a 0.20 μm membrane filter, and the area value of astaxanthin was calculated by HPLC. The 0.45 μm and 0.20 μm membrane filters were the same as those used for hesperetin. HPLC conditions were: column: octadecylsilyl column, mobile phase: acetonitrile / 10 mM ammonium acetate aqueous solution mixture, wavelength: 470 nm.

[0071]

[0072]

[0073] In Comparative Example 1, in which hesperetin powder was used as a solid composition, a peak specific to hesperetin was observed in the XRD chart as shown in Figure 2. Therefore, the hesperetin was in a crystalline state, and as shown in Table 2, it had poor solubility in water in dissolution test 1.

[0074] In contrast, in Example 1, a solid composition was prepared using hesperetin together with sucrose fatty acid ester SE-SS and HPC. As shown in FIG. 1 , the XRD chart of the solid composition of Example 1 did not show any peaks specific to hesperetin, indicating that the hesperetin was in an amorphous state. Therefore, in Example 1, a solid dispersion containing amorphous hesperetin was obtained. As shown in Table 1, in Dissolution Test 1, Example 1 had improved solubility in water compared to Comparative Example 1. In Example 2, in which the amount of HPC was increased compared to Example 1, hesperetin was made amorphous in the same way as in Example 1, and its solubility in water was even more significantly improved than in Example 1.

[0075] In Comparative Example 2, a solid composition was prepared using HPC without using sucrose fatty acid ester SE-SS. In this case, as shown in Table 2, hesperetin was amorphized, but its solubility in water was comparable to that of Comparative Example 1 and inferior to that of Examples 1 and 2.

[0076] In Comparative Example 3, in which myricetin powder was used as a solid composition, there was a peak specific to myricetin in the XRD chart as shown in FIG. 4. Therefore, myricetin was in a crystalline state, and as shown in Table 2, it was poor in solubility in water in dissolution test 1. In contrast, in the solid compositions of Examples 3 and 4, as shown in FIG. 3 and Table 1, there was no peak specific to myricetin in the XRD chart, myricetin was in an amorphous state, and a solid dispersion containing amorphous myricetin was obtained. In Examples 3 and 4, the solubility in water was improved compared to Comparative Example 3 in dissolution test 1. On the other hand, in Comparative Example 4, although myricetin was amorphized, its solubility in water was comparable to that of Comparative Example 3 and was inferior to that of Examples 3 and 4.

[0077] In Comparative Example 5, in which sesamin powder was used as a solid composition, a peak specific to sesamin was observed in the XRD chart, as shown in Figure 6. In contrast, the solid compositions of Examples 5 and 6 did not have a peak specific to sesamin in the XRD chart, as shown in Figure 5 and Table 1, and the sesamin was in an amorphous state, and therefore were solid dispersions containing amorphous sesamin. On the other hand, in Comparative Example 6, the solid composition was prepared using HPC without using a sucrose fatty acid ester, and in this case, the sesamin was insufficiently amorphized, as shown in Table 2.

[0078] In Comparative Example 7, in which a powder of astaxanthin isomerized by aging in chloroform was used as a solid composition, a peak specific to isomerized astaxanthin was observed in the XRD chart as shown in FIG. 8. Therefore, the isomerized astaxanthin was in a crystalline state, and as shown in Table 2, its solubility in water was poor in dissolution test 2. In contrast, the solid composition of Example 7 did not have a peak specific to isomerized astaxanthin in the XRD chart as shown in FIG. 7, indicating that the isomerized astaxanthin was in an amorphous state. Therefore, it was a solid dispersion containing amorphous astaxanthin. As shown in Table 1, Example 7 had improved water solubility compared to Comparative Example 7 in dissolution test 2. On the other hand, in Comparative Example 8, a solid composition was prepared using HPC without using a sucrose fatty acid ester. In this case, although the isomerized astaxanthin was amorphized as shown in Table 1, its water solubility was poor compared to Example 7.

[0079] In Comparative Example 9, in which β-sitosterol powder was directly used as a solid composition, a peak specific to β-sitosterol was observed in the XRD chart as shown in Figure 10. In contrast, the solid compositions of Examples 8 and 9 did not have a peak specific to β-sitosterol in the XRD chart as shown in Figure 9 and Table 1, and the β-sitosterol was in an amorphous state, and therefore were solid dispersions containing amorphous β-sitosterol. On the other hand, in Comparative Example 10, a solid composition was prepared using HPC without using a sucrose fatty acid ester, and in this case, the β-sitosterol was insufficiently amorphized as shown in Table 2.

[0080] The various numerical ranges described in this specification can be arbitrarily combined with their respective upper and lower limit values, and all such combinations are considered to be preferred numerical ranges described in this specification. Furthermore, a numerical range described as "X to Y" means from X to Y.

[0081] Although several embodiments of the present invention have been described above, these embodiments are presented as examples and are not intended to limit the scope of the invention. These embodiments can be implemented in various other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their omissions, substitutions, modifications, etc. are included within the scope and spirit of the invention, as well as within the scope of the invention described in the claims and their equivalents.

Claims

1. A solid composition comprising an amorphous body obtained by amorphizing a crystalline poorly water-soluble organic compound, a sucrose fatty acid ester having a monoester ratio of 85% by mass or more, and a water-soluble polymer.

2. The solid composition according to claim 1, wherein the poorly water-soluble organic compound is at least one selected from the group consisting of flavonoids, phenylpropanoids, stilbenoids, phenolic acids, carotenoids, retinoids, steroids, alkaloids, ceramides, and limonoids.

3. The solid composition according to claim 1, wherein the poorly water-soluble organic compound is at least one selected from the group consisting of flavanones, flavonols, lignans, coumarins, stilbenoids, phenolic acids, xanthophylls, retinoids, phytosterols, alkaloids, glucosylceramides, and limonoids.

4. The solid composition according to claim 1, wherein the mass ratio of the sucrose fatty acid ester to the amorphous body is 0.2 to 30.

5. The solid composition according to claim 1, wherein the mass ratio of said water-soluble polymer to said amorphous body is 0.2 to 30.

6. The solid composition according to claim 1, wherein the mass ratio of the water-soluble polymer to the sucrose fatty acid ester is 0.1 to 10.

7. The solid composition of claim 1, wherein the water-soluble polymer comprises at least one selected from the group consisting of cellulose ethers, cellulose esters, homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, polyalkylene glycols, polyalkylene oxides, and poly(meth)acrylates.

8. An oral composition comprising the solid composition of any one of claims 1 to 7.

9. A method for producing a solid composition, comprising: dissolving a crystalline, poorly water-soluble organic compound, a sucrose fatty acid ester having a monoester ratio of 85% by mass or more, and a water-soluble polymer in a solvent to obtain a solution; and removing the solvent from the solution.

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