Solid composition and method for producing same

Abstract

Provided is a solid composition having a property such that the solubility of a crystalline poorly-water-soluble organic compound in water can be improved. A solid composition according to an embodiment contains; a solid dispersion in which a crystalline poorly-water-soluble organic compound is dispersed in an amorphized state in a water-soluble polymer that serves as an inert carrier; and a sucrose fatty acid ester which has a monoester content ratio of 85 mass% or more. In the solid composition, the solid dispersion and the sucrose fatty acid ester are contained in a mixed state.

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 comprising a mixture of a solid dispersion in which a crystalline poorly water-soluble organic compound is dispersed in an amorphous state in a water-soluble polymer, using the water-soluble polymer as an inert carrier, and a sucrose fatty acid ester having a monoester ratio of 85% by mass or more. [2] The solid composition according to [1], wherein the poorly water-soluble organic compound is at least one selected from the group consisting of curcuminoids, 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 curcuminoids, 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 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. [5] The solid composition according to any one of [1] to [4], wherein the mass ratio of the sucrose fatty acid ester to the poorly water-soluble organic compound 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 mass ratio of the sucrose fatty acid ester to the solid dispersion is 0.1 to 3. [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: obtaining a solid dispersion using a crystalline poorly water-soluble organic compound and a water-soluble polymer, in which the poorly water-soluble organic compound is dispersed in an amorphous state in the water-soluble polymer; and mixing the solid dispersion with a sucrose fatty acid ester having a monoester ratio of 85 mass% or more.

[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 Comparative Example 1 XRD chart of the solid composition of Comparative Example 2 XRD chart of the solid composition of Comparative Example 4 XRD chart of the solid composition of Comparative Example 6 XRD chart of the solid composition of Comparative Example 7 XRD chart of the solid composition of Comparative Example 8 XRD chart of the solid composition of Comparative Example 9 XRD chart of the solid composition of Comparative Example 11 XRD chart of the solid composition of Comparative Example 12 XRD chart of the solid composition of Comparative Example 16 XRD chart of the powder before addition of the sucrose fatty acid ester in Example 7 (powder obtained by passing through a sieve after drying under reduced pressure)

[0010] The solid composition according to this embodiment contains a mixture of a solid dispersion in which a crystalline poorly water-soluble organic compound is dispersed in an amorphous state in a water-soluble polymer, with the water-soluble polymer serving as an inert carrier, and a sucrose fatty acid ester having a monoester ratio of 85% by mass or more. Therefore, the solid composition according to this embodiment contains (A) an amorphous crystalline poorly water-soluble organic compound, (B) a sucrose fatty acid ester, and (C) a water-soluble polymer.

[0011] [(A) Amorphized Poorly Water-Soluble Organic Compound] Component (A) is a crystalline poorly water-soluble organic compound that has been amorphized, i.e., an organic compound that is originally poorly soluble in water (including cases where it is insoluble) because it is crystalline, and is therefore amorphized, 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 amorphization) 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 may be 1 μg / mL or less.

[0012] Specific examples of the poorly water-soluble organic compound in this embodiment include: (A1) curcuminoids: for example, curcumin, demethoxycurcumin, bisdemethoxycurcumin, and tetrahydrocurcumin; (A2) polyphenols: for example, flavanones (for example, hesperetin, nobiletin, sudachitin, narirutin, naringin, naringenin, and hesperidin); flavonols (for example, myricetin, quercetin, tiliroside, silibinin, rutin, isoquercitrin, galangin, kaempferol, fisetin, and hyperoside); and flavones (for example, 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;(A3) Carotenoids: For example, xanthophylls (for example, astaxanthin, lutein, β-cryptoxanthin, zeaxanthin, neoxanthin), carotenes (for example, β-carotene, lycopene), (A4) Retinoids: For example, retinoic acid, retinol, retinal, adapalene, tamibarotene, (A5) 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), (A6) Alkaloids: Examples include berberine, morphine, and capsaicinoid; (A7) ceramides, such as glucosylceramide, human ceramide, and synthetic ceramide; and (A8) limonoids, such as limonin and azadirachtin. These may be used alone or in combination of two or more. In this specification, the terms "curcuminoid," "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 curcuminoids, 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 curcuminoids, 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 curcuminoids, flavanones, flavonols, and xanthophylls, and even more preferably at least one selected from the group consisting of curcumin, hesperetin, myricetin, and astaxanthin.

[0014] The solid composition of this embodiment contains an amorphous 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 poorly water-soluble organic compound. 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 poorly water-soluble organic compound in the solid composition is not particularly limited, but is preferably 1 to 50 mass %, more preferably 3 to 40 mass %, more preferably 4 to 40 mass %, more preferably 5 to 30 mass %, and even more preferably 6 to 20 mass %.

[0016] [(B) Sucrose Fatty Acid Ester] Component (B) is a sucrose fatty acid ester having a monoester ratio of 85% by mass or more. 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 having a larger molecular weight, as known to those skilled in the art.

[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 at least one (C4) selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Alternatively, the water-soluble polymer may comprise at least one (C5) selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate. 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), (C4), or (C5) polymer.

[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 (% by mass), and the K value of PVP in the following examples was measured at a sample concentration of 1% by 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] In one embodiment, hydroxypropylmethylcellulose phthalate (HPMCP) may be used as the water-soluble polymer. In this case, the HPMCP preferably has a viscosity (viscosity at 20°C of a solution obtained by dissolving 10 g of HPMCP in 90 g of a methanol / dichloromethane mixture (1:1) (mass ratio)) of 10 to 200 mPa·s, more preferably 20 to 100 mPa·s, and even more preferably 30 to 50 mPa·s, as measured by the measurement method described in the 18th Edition of the Japanese Pharmacopoeia, "Hypromellose Phthalate."

[0033] Furthermore, the weight average molecular weight Mw of HPMCP measured by SEC-MALS (size exclusion chromatography-multi-angle light scattering) is preferably 10,000 to 200,000, more preferably 20,000 to 100,000, and even more preferably 30,000 to 60,000.

[0034] The conditions for the SEC-MALS method for HPMCP are as follows: Column: Shodex OHpak SB-806MHQ manufactured by Resonaq Co., Ltd. Eluent: 0.10 mol / L acetate buffer / DMF = 9 / 1 (v / v) mixture (acetate buffer was prepared using sodium acetate, acetic acid, and sodium chloride) Flow rate: 1.0 mL / min Sample concentration: 0.1 w / v% Injection volume: 0.1 mL Detector: DAWN manufactured by Wyatt Technology, Shodex RI-71 manufactured by Resonaq Co., Ltd.

[0035] Furthermore, the amount of carboxybenzoyl groups in HPMCP, as measured by the method described in the 18th Edition of the Japanese Pharmacopoeia, "Hypromellose Phthalate," is preferably 1 to 60%, more preferably 10 to 50%, and even more preferably 20 to 40%.

[0036] In one embodiment, hydroxypropylmethylcellulose acetate succinate (HPMCAS) may be used as the water-soluble polymer. In this case, the viscosity of HPMCAS measured at 20°C of a solution obtained by adding 2 g of HPMCAS to a dilute sodium hydroxide solution to make 100 g is preferably 1 to 200 mPa·s, more preferably 1 to 50 mPa·s, and even more preferably 1 to 10 mPa·s, as determined by the measurement method described in the Japanese Pharmacopoeia, 18th Edition, "Hypromellose acetate succinate."

[0037] Furthermore, the weight average molecular weight Mw of HPMCAS measured by SEC-MALS is preferably 1,000 to 200,000, more preferably 5,000 to 100,000, and even more preferably 10,000 to 30,000.

[0038] Here, the Mw of HPMCAS is a value calculated by measuring the Mw of its backbone, hypromellose (HPMC), by the SEC-MALS method under the following conditions to determine the degree of polymerization, and then multiplying the degree of polymerization by the monomer molecular weight calculated from the degree of HPMCAS substitution. Column: Shodex OHpak SB-806MHQ manufactured by Resonac Co., Ltd. Eluent: aqueous solution of sodium hydroxide, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate Flow rate: 1.0 mL / min Sample concentration: 0.2 w / v% Injection volume: 0.1 mL Detector: DAWN manufactured by Wyatt Technology, Shodex RI-71 manufactured by Resonac Co., Ltd.

[0039] Furthermore, HPMCAS preferably has a methoxy group content of 10 to 40%, more preferably 20 to 30%, as measured by the method described in the Japanese Pharmacopoeia, 18th Edition, "Hypromellose Acetate Succinate." The hydroxypropoxy group content is preferably 1 to 20%, more preferably 3 to 10%. The acetyl group content is preferably 1 to 30%, more preferably 5 to 15%. The succinyl group content is preferably 1 to 30%, more preferably 5 to 15%.

[0040] [Solid Composition] In the solid composition according to this embodiment, the poorly water-soluble organic compound as component (A) and the water-soluble polymer as component (C) constitute a solid dispersion (D), and the solid dispersion (D) and the sucrose fatty acid ester as component (B) are contained in a state of being mixed by powder-to-powder mixing. That is, a powder of the solid dispersion (D) containing components (A) and (C) is mixed with a powder of component (B).

[0041] A solid dispersion is a molecular dispersion of a poorly water-soluble organic compound in a water-soluble polymer, which serves as an inert carrier. The water-soluble polymer penetrates between the molecules of the poorly water-soluble organic compound, disrupting the crystallinity of the poorly water-soluble organic compound and rendering the poorly water-soluble organic compound amorphous. Generally, in a solid dispersion, a poorly water-soluble drug is rendered amorphous, and the amorphous solid poorly water-soluble drug is dispersed in an inert carrier at a molecular level, making it easily soluble in water. In particular, in this embodiment, the specific sucrose fatty acid ester is powder-mixed with the solid dispersion by post-mixing, thereby significantly improving the solubility of the poorly water-soluble organic compound in water.

[0042] 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.

[0043] 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 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.

[0044] 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 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.

[0045] 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.

[0046] In the solid composition, the mass ratio (B) / (D), which is the ratio of the mass of the sucrose fatty acid ester (B) to the mass of the solid dispersion (D), is preferably 0.1 to 3, more preferably 0.2 to 2, and even more preferably 0.3 to 1.0.

[0047] 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.

[0048] 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 (D) solid dispersion and (B) sucrose fatty acid ester.

[0049] 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.

[0050] 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).

[0051] 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.

[0052] [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) obtaining a solid dispersion using a crystalline poorly water-soluble organic compound and a water-soluble polymer, in which the poorly water-soluble organic compound is dispersed in an amorphous state in the water-soluble polymer, and (2) mixing the obtained solid dispersion with a sucrose fatty acid ester having a monoester ratio of 85% by mass or more.

[0053] In step (1), the method for producing the solid dispersion is not particularly limited, and may be, for example, (1-1) a method in which a poorly water-soluble organic compound and a water-soluble polymer are dissolved in a solvent to prepare a solution, and then the solvent is removed from the solution, or (1-2) a method in which a poorly water-soluble organic compound and a water-soluble polymer are thermally melted.

[0054] In the above method (1-1), the solvent used is a solvent capable of dissolving the poorly water-soluble organic compound and the water-soluble polymer, and is not particularly limited. 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.

[0055] In the above method (1-1), the poorly water-soluble organic compound and the water-soluble polymer may be dissolved while heating the solvent. The poorly water-soluble organic compound 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. When dissolving, it is preferable to dissolve the compounds by stirring or by 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.

[0056] In the solution prepared by the method (1-1) above, the concentration of each component is not particularly limited. For example, the concentration of the poorly water-soluble organic compound may be 0.1 to 5 mass %, or 0.2 to 3 mass %. The concentration of each water-soluble polymer may be set depending on the mass ratio (C) / (A) of the above components in the solid composition to be produced.

[0057] 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.

[0058] In the above method (1-1), the method for removing the solvent from the solution is not particularly limited, and examples thereof include vacuum drying, spray drying, freeze drying, heat drying, natural drying, etc. After removing the solvent, a pulverization treatment may be carried out.

[0059] In step (2), the method for mixing the solid dispersion and the sucrose fatty acid ester is not particularly limited as long as it involves mixing powders together without using a solvent.

[0060] [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.

[0061] 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.

[0062] The form of the oral composition is not particularly limited, and examples thereof include tablets, granules, powders, fine granules, granules, pills, and capsules.

[0063] 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.

[0064] The present invention will be explained in more detail below based on examples and comparative examples, but the present invention is not limited thereto.

[0065] Details of the ingredients in Tables 1 to 3 are as follows: CUR: Curcumin, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Wako Special Grade HPT: Hesperetin, manufactured by Fujifilm Wako Chemical Co., Ltd. "Hesperetin", 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 AST: Astaxanthin, manufactured by Combi-Blocks, Beta-Carotene-4,4'-dione, purchased from Fujifilm Wako Pure Chemical Industries, Ltd., product code QA-1399

[0066] 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

[0067] SE-F160: "DK Ester F-160" 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 70% by mass, and the remaining ratio of diester and triester is 30% by mass. HLB = 15

[0068] SE-F50: "DK Ester F-50" 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 monoesters is 30% by mass, and the remaining esters of diesters or higher are 70% by mass. HLB = 6

[0069] PVP: polyvinylpyrrolidone "Eiftact K-30PH" manufactured by Daiichi Kogyo Seiyaku Co., Ltd. (weight average molecular weight 45,000, K value = 30) 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)

[0070] HPMCAS: hydroxypropyl methylcellulose acetate succinate "Shin-Etsu AQOAT AS-MG" manufactured by Shin-Etsu Chemical Co., Ltd. (viscosity 2 to 4 mPa·s (20°C, 2% by mass solution), weight average molecular weight 22,400, 21 to 25% methoxy groups, 5 to 9% hydroxypropoxy groups, 7 to 11% acetyl groups, 10 to 14% succinyl groups). HPMCP: hydroxypropyl methylcellulose phthalate "HPMCP HP-55" manufactured by Shin-Etsu Chemical Co., Ltd. (viscosity 32 to 48 mPa·s (20°C, 10% by mass solution), weight average molecular weight 45,600, 27 to 35% carboxybenzoyl groups).

[0071] Comparative Example 1 Curcumin (CUR) was pulverized in an agate mortar to prepare a powder, which was used as a solid composition of Comparative Example 1.

[0072] Comparative Example 2: (A) curcumin (CUR) as a water-insoluble organic compound, (C) polyvinylpyrrolidone (PVP) as a water-soluble polymer, and a solvent were prepared in a total amount of 40 g according to the formulation (parts by mass) shown in Table 1 below. These were charged into a 50 mL screw tube, and then (1) the screw tube was heated by immersing it in a 75°C water bath for 4 minutes, and (2) the screw tube was sonicated for 4 minutes by immersing it in a bath of a small ultrasonic device (Yamato Scientific Co., Ltd., "BRANSON 2210") at 20 to 50°C (select "SET SONICS min" on the device and turn it ON). Steps (1) and (2) were repeated until all of the curcumin and PVP were dissolved. The solvent was removed from the resulting solution using an evaporator. The treatment with the evaporator was carried out at 75°C, with the pressure reduced from 400 hPa to 160 hPa, and the solvent was removed by distillation until almost all of the solvent was removed, and then the pressure was reduced to 10 to 60 hPa and continued for another 10 to 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 composition of Comparative Example 2. The solid composition of Comparative Example 2 was a solid dispersion, as described below. Note that "(C) Solid Dispersion" in Table 1 refers to the case in which the water-soluble polymer constitutes a part of the solid dispersion (the same applies to Tables 2 to 6).

[0073] Comparative Example 3 One part by mass of curcumin powder (pulverized in an agate mortar), 2 parts by mass of sucrose fatty acid ester SE-SS powder, and 4 parts by mass of PVP powder were mixed on a medicine wrapping paper to obtain a solid composition of Comparative Example 3. Note that "(C) Powder Mixing" in Table 1 refers to the case where a water-soluble polymer was blended into the solid composition by powder mixing (the same applies to Tables 2, and 4 to 6).

[0074] Example 1 A total of 40 g of (A) curcumin, (B) sucrose fatty acid ester SE-SS, (C) PVP, and solvent were prepared according to the formulation (parts by mass) shown in Table 1. Using the curcumin, PVP, and solvent, a solution was prepared, the solvent was distilled off, and the mixture was pulverized in a mortar in the same manner as in Comparative Example 2. Powder of sucrose fatty acid ester SE-SS was added to the obtained powder, and the mixture was mixed on a medicine wrapping paper to obtain the solid composition of Example 1.

[0075] [Comparative Examples 14 and 15] Solid compositions of Comparative Examples 14 and 15 were obtained in the same manner as in Example 1, except that SE-F160 and SE-F50 were used instead of (B) sucrose fatty acid ester SE-SS according to the formulations (parts by mass) shown in Table 1.

[0076] X-ray diffraction (XRD) was performed to evaluate the amorphization of the solid compositions of Comparative Examples 1 and 2. The evaluation method was as follows. The solid compositions of Example 1 and Comparative Examples 14 and 15 were evaluated in the same manner as Comparative Example 2 because they were prepared by simply powder-mixing a sucrose fatty acid ester with a powder prepared in the same manner as Comparative Example 2. The solid composition of Comparative Example 3 was evaluated in the same manner as Comparative Example 1 because it was prepared by simply powder-mixing a sucrose fatty acid ester and a water-soluble polymer with the solid composition of Comparative Example 1.

[0077] [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)

[0078] The solid compositions of Example 1 and Comparative Examples 1 to 3, 14, and 15 were subjected to a dissolution test to evaluate their solubility in water. The evaluation method was as follows.

[0079] [Dissolution Test: Dissolution Amount] An "NTR-6600AST" dissolution tester manufactured by Toyama Sangyo Co., Ltd. was used. 900 mL of ion-exchanged water was charged into the vessel and stirred overnight at a water temperature of 37°C ± 0.2°C for degassing. Gelatin capsules ("HF Capsules" manufactured by Matsuya Co., Ltd.) filled with 15 mg of solid composition equivalent to curcumin were placed in a sinker and placed in the vessel. After a predetermined time, the vessel was sampled through a 100 μm filter and filtered through a 0.45 μm membrane filter. Tests were conducted at predetermined times of 30 minutes, 60 minutes, 120 minutes, and 240 minutes. The filtrate was diluted 2-fold with ethanol, filtered through a 0.20 μm membrane filter, and the curcumin content was quantified by HPLC. Three 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 methanol and 10 mM ammonium acetate aqueous solution, wavelength: 430 nm.

[0080] The oral absorbability of the solid compositions of Example 1 and Comparative Example 1 was evaluated by animal experiments. The evaluation method was as follows.

[0081] [Evaluation of oral absorbability: animal experiment] A dose of 200 mg / kg of the poorly water-soluble organic compound was orally administered to three male SD rats, and blood samples were taken 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, and 24 hours after administration. The concentration of the poorly water-soluble organic compound in the blood was measured by liquid chromatography mass spectrometry (LC-MS / MS), and the AUC (area under the blood drug concentration-time curve) of the poorly water-soluble organic compound was calculated. The data with the highest AUC from the three rats was used.

[0082] For LC-MS / MS measurement, 20 μL of plasma sample and 80 μL of acetonitrile were suspended in a microtube and deproteinized as a pretreatment. After removing the protein using a centrifuge, the supernatant was centrifuged using a filter (Millipore, Ultrafree-MC, Hydrophilic PTFE membrane, 0.2 μm). This solution was mixed with ultrapure water at a 1:1 (mass ratio) and used as the measurement sample. The LC-MS / MS measurement conditions were as follows: column: octadecylsilyl column, ion source: ESI+, mobile phase: a mixture of methanol and 10 mM ammonium formate aqueous solution.

[0083]

[0084] In Comparative Example 1, the XRD chart showed a peak specific to curcumin as shown in Figure 1. Therefore, the curcumin was in a crystalline state and was not dissolved in water in the dissolution test as shown in Table 1.

[0085] In Comparative Example 2, a solid composition was prepared by using a solution in which curcumin and PVP were dissolved in a solvent and then removing the solvent from the solution. As shown in FIG. 2 , the XRD chart of the solid composition of Comparative Example 2 did not show any peaks specific to curcumin, indicating that the curcumin was in an amorphous state. Therefore, the solid composition of Comparative Example 2 was a solid dispersion containing amorphous curcumin. The solubility of Comparative Example 2 in water was improved compared to Comparative Example 1.

[0086] In Comparative Example 3, curcumin, sucrose fatty acid ester SE-SS, and PVP were mixed in powder form, and simply mixing these three ingredients in powder form did not substantially improve the solubility of curcumin in water.

[0087] In contrast, in Example 1, the sucrose fatty acid ester SE-SS was powder-mixed with the solid dispersion containing curcumin and PVP by post-mixing, and the solubility in water was significantly improved not only compared to Comparative Examples 1 and 3, which were in a crystalline state, but also compared to Comparative Example 2, which was a solid dispersion.

[0088] On the other hand, in Comparative Examples 14 and 15, as in Example 1, sucrose fatty acid ester was mixed in powder form by post-mixing, but since the sucrose fatty acid ester had a low monoester ratio, its solubility in water was inferior to that of Example 1.

[0089] In the evaluation of oral absorbability in animal experiments, the AUC of curcumin was 1 h·ng / mL in Comparative Example 1, whereas it was 212 h·ng / mL in Example 1 in which the sucrose fatty acid ester SE-SS was post-mixed with the solid dispersion, demonstrating excellent absorption efficiency into the body by oral ingestion.

[0090] Comparative Example 4: (A) curcumin (CUR) as a water-insoluble organic compound, (C) hydroxypropyl cellulose (HPC) as a water-soluble polymer, and a solvent were prepared in a total amount of 40 g according to the formulation (parts by mass) shown in Table 2 below. The curcumin and solvent were then placed in a 50 mL screw tube. Subsequently, (1) the screw tube was immersed in a 75°C water bath for 4 minutes to heat it, and (2) the screw tube was immersed in a 20-50°C bath using a compact ultrasonicator (Yamato Scientific Co., Ltd., "BRANSON 2210") for 4 minutes to sonicate it (select "SET SONICS min" and turn it ON). Steps (1) and (2) were repeated until all of the curcumin was dissolved. While stirring the resulting solution with a rotor, HPC was added and stirred until dissolved. The solvent was removed from the resulting solution using an evaporator. The treatment with the evaporator was carried out at 75°C, with the pressure reduced from 400 hPa to 160 hPa, and the solvent was distilled off until almost all of it was gone, and then the pressure was reduced to 10 to 60 hPa and the distillation was continued for another 10 to 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 composition of Comparative Example 4. The solid composition of Comparative Example 4 was a solid dispersion as described below.

[0091] Comparative Example 5 One part by mass of curcumin powder (pulverized in an agate mortar), 4 parts by mass of sucrose fatty acid ester SE-SS powder, and 4 parts by mass of HPC powder were mixed on a medicine wrapping paper to obtain a solid composition of Comparative Example 5.

[0092] Example 2 A total of 40 g of (A) curcumin, (B) sucrose fatty acid ester SE-SS, (C) HPC, and a solvent were prepared according to the formulation (parts by mass) shown in Table 2. Using the curcumin, HPC, and solvent, a solution was prepared, the solvent was distilled off, and the mixture was pulverized in a mortar in the same manner as in Comparative Example 4. Powder of sucrose fatty acid ester SE-SS was added to the obtained powder, and the mixture was mixed on a medicine wrapping paper to obtain the solid composition of Example 2.

[0093] X-ray diffraction (XRD) was performed on the solid composition of Comparative Example 4 to evaluate amorphization. Furthermore, a dissolution test was performed on the solid compositions of Example 2 and Comparative Examples 4 and 5 to evaluate their solubility in water. The evaluation methods were as described above. Regarding the evaluation of amorphization of the solid composition of Example 2, the sucrose fatty acid ester was simply powder-mixed with a powder prepared in the same manner as in Comparative Example 4, and therefore the evaluation was the same as in Comparative Example 4. Regarding the evaluation of amorphization of the solid composition of Comparative Example 3, the sucrose fatty acid ester and the water-soluble polymer were simply powder-mixed with the solid composition of Comparative Example 1, and therefore the evaluation was the same as in Comparative Example 1.

[0094]

[0095] In Comparative Example 4, a solid composition was prepared by using a solution in which curcumin and HPC were dissolved in a solvent and then removing the solvent from the solution. The solid composition of Comparative Example 4 did not exhibit a peak specific to curcumin in the XRD chart, as shown in FIG. 3 , indicating that the curcumin was in an amorphous state. Therefore, the solid composition of Comparative Example 4 was a solid dispersion containing amorphous curcumin. Although Comparative Example 4 was a solid dispersion, the solubility of curcumin in water was poor, as shown in Table 2.

[0096] In Comparative Example 5, curcumin, sucrose fatty acid ester SE-SS, and HPC were mixed in powder form, and simply mixing these three ingredients in powder form did not improve the solubility of curcumin in water.

[0097] In contrast, in Example 2, the sucrose fatty acid ester SE-SS was powder-mixed with the solid dispersion containing curcumin and HPC by post-mixing, and the solubility in water was significantly improved not only compared with Comparative Examples 1 and 5, which were in a crystalline state, but also compared with Comparative Example 4, which was a solid dispersion.

[0098] Comparative Example 6 Hesperetin (HPT) powder was used as the solid composition of Comparative Example 6 as it was.

[0099] Comparative Example 7: (A) hesperetin (HPT) as a water-insoluble organic compound, (C) HPC as a water-soluble polymer, and a solvent were prepared in a total amount of 40 g according to the formulation (parts by mass) shown in Table 3 below. Hesperetin and the solvent were then placed in a 50 mL screw tube. Subsequently, (1) the screw tube was immersed in a 75°C water bath for 4 minutes to heat the mixture, and (2) the screw tube was immersed in a 50°C bath in a compact ultrasonicator (Yamato Scientific Co., Ltd., "BRANSON 2210") for 4 minutes to undergo ultrasonic treatment ("SET SONICS min" was selected and turned ON on the device). Steps (1) and (2) were repeated until all of the hesperetin was dissolved. While stirring the resulting solution with a rotor, HPC was added and stirred until dissolved. The solvent was removed from the resulting solution using an evaporator. The treatment with the evaporator was carried out at 75°C, with the pressure reduced to 160 hPa, and the solvent was distilled off until almost completely removed, followed by further distillation at 60 to 90 hPa for 10 to 50 minutes, and then at 3 to 20 hPa for 10 to 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 composition of Comparative Example 7. The solid composition of Comparative Example 7 was a solid dispersion, as described below.

[0100] Example 3 A total of 40 g of (A) hesperetin, (B) sucrose fatty acid ester SE-SS, (C) HPC, and solvent were prepared according to the formulation (parts by mass) shown in Table 3. Using the hesperetin, HPC, and solvent, a solution was prepared, the solvent was distilled off, and the mixture was pulverized in a mortar in the same manner as in Comparative Example 7. To the obtained powder, sucrose fatty acid ester SE-SS powder was added, and the mixture was mixed on a medicine wrapping paper to obtain the solid composition of Example 3.

[0101] X-ray diffraction (XRD) was performed on the solid compositions of Comparative Examples 6 and 7 to evaluate amorphization. The evaluation method was as described above. Furthermore, a dissolution test was performed on the solid compositions of Example 3 and Comparative Examples 6 and 7 to evaluate their solubility in water. The evaluation method was as follows. Note that the amorphization evaluation of the solid composition of Example 3 was performed in the same manner as in Comparative Example 7, since the sucrose fatty acid ester was simply powder-mixed with a powder prepared in the same manner as in Comparative Example 7.

[0102] [Dissolution test: Dissolution amount] The amount of solid composition filled into gelatin capsules was 8 mg in terms of hesperetin. The mobile phase for HPLC was a mixture of acetonitrile and 10 mM ammonium acetate aqueous solution, and the wavelength was 289 nm. The other conditions were the same as for curcumin, and the dissolution amount was determined.

[0103]

[0104] In Comparative Example 6, a peak specific to hesperetin was present in the XRD chart as shown in Figure 4. Therefore, the hesperetin was in a crystalline state, and as shown in Table 3, it had poor solubility in water in the dissolution test.

[0105] In Comparative Example 7, a solid composition was prepared by using a solution in which hesperetin was dissolved together with HPC in a solvent, and then removing the solvent from the solution. As shown in Figure 5, the solid composition of Comparative Example 7 did not have a peak specific to hesperetin in the XRD chart, and the hesperetin was in an amorphous state. Therefore, the solid composition of Comparative Example 7 was a solid dispersion containing amorphous hesperetin. Although Comparative Example 7 was a solid dispersion, the solubility of hesperetin in water was poor.

[0106] In contrast to this, in Example 3, the sucrose fatty acid ester SE-SS was powder-mixed with the solid dispersion containing hesperetin and HPC by post-mixing, and as a result, the solubility in water was significantly improved not only compared to Comparative Example 6, which was in a crystalline state, but also compared to Comparative Example 7, which was a solid dispersion.

[0107] Comparative Example 8: 1 g of astaxanthin and 199 g of chloroform were placed in a medium bottle, treated in a 60°C water bath for 4 hours, then aged at room temperature for 3 nights, and further treated in a 60°C water bath for 1 hour to dissolve and isomerize the astaxanthin, yielding a chloroform solution of astaxanthin. 80 g of the resulting chloroform solution of astaxanthin was distilled under reduced pressure at 55°C until the solvent was almost completely removed, and then dried at 60-90 hPa for 30 minutes and then at 3-20 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.

[0108] [Comparative Example 9] 80 g of the astaxanthin chloroform solution obtained in Comparative Example 8 was stirred with a rotor, while 1.6 g of (C) HPC was added 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 Comparative Example 9.

[0109] [Comparative Example 10] 1 part by mass of the solid composition obtained in Comparative Example 8 was mixed with 4 parts by mass of sucrose fatty acid ester SE-SS powder and 4 parts by mass of HPC powder on a medicine wrapping paper to obtain a solid composition of Comparative Example 10.

[0110] Example 4 A solid composition of Example 4 was obtained by mixing 5 parts by mass of the solid composition obtained in Comparative Example 9 with 4 parts by mass of sucrose fatty acid ester SE-SS powder on a medicine wrapping paper.

[0111] X-ray diffraction (XRD) was performed to evaluate the amorphization of the solid compositions of Comparative Examples 8 and 9. The evaluation method was as described above. Furthermore, a dissolution test was performed to evaluate the solubility in water of the solid compositions of Example 4 and Comparative Examples 8 to 10. The evaluation method was as follows. Regarding the evaluation of amorphization of the solid composition of Example 4, the sucrose fatty acid ester was simply powder-mixed with a powder prepared in the same manner as in Comparative Example 9, and therefore the evaluation was the same as that of Comparative Example 9. Regarding the evaluation of amorphization of the solid composition of Comparative Example 10, the sucrose fatty acid ester and the water-soluble polymer were simply powder-mixed with the solid composition of Comparative Example 8, and therefore the evaluation was the same as that of Comparative Example 8.

[0112] [Dissolution Test: Dissolution Amount] 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 tube was inverted 10 times every 30 minutes to mix, and then allowed to stand at 25°C for 120 minutes. The filtrate was then 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. The area value of astaxanthin was calculated by HPLC. The 0.45 μm and 0.20 μm membrane filters used were the same as those used for curcumin. The HPLC conditions were: column: octadecylsilyl column; mobile phase: acetonitrile / 10 mM ammonium acetate aqueous solution mixture; wavelength: 470 nm.

[0113]

[0114] In Comparative Example 8, the XRD chart showed a peak specific to isomerized astaxanthin as shown in Figure 6. Therefore, the isomerized astaxanthin was in a crystalline state, and as shown in Table 4, it had poor solubility in water in the elution test.

[0115] In Comparative Example 9, a solid composition was prepared by using a solution in which astaxanthin and HPC were dissolved in a solvent and then removing the solvent from the solution. In the solid composition of Comparative Example 9, as shown in FIG. 7 , there was no peak specific to isomerized astaxanthin in the XRD chart, and the astaxanthin was in an amorphous state. Therefore, the solid composition of Comparative Example 9 was a solid dispersion containing amorphous astaxanthin. In Comparative Example 9, the solubility in water was improved compared to Comparative Example 8.

[0116] In Comparative Example 10, isomerized astaxanthin, sucrose fatty acid ester SE-SS, and HPC were mixed in powder form, and simply mixing these three in powder form did not substantially improve the solubility of astaxanthin in water.

[0117] In contrast, in Example 4, the sucrose fatty acid ester SE-SS was powder-mixed with the solid dispersion containing isomerized astaxanthin and HPC by post-mixing, and the solubility in water was significantly improved not only over Comparative Examples 8 and 10, which were in a crystalline state, but also over Comparative Example 9, which was a solid dispersion.

[0118] [Example 5 and Comparative Examples 11 to 13] The solid compositions of Example 5 and Comparative Example 12 were obtained in the same manner as in Example 3 and Comparative Example 7, respectively, except that hesperetin was replaced with myricetin (MIR). In Comparative Example 11, myricetin powder was used as a solid composition as is. In Comparative Example 13, 1 part by mass of myricetin powder, 4 parts by mass of sucrose fatty acid ester SE-SS powder, and 4 parts by mass of HPC powder were mixed on a medicine wrapping paper to obtain a solid composition.

[0119] X-ray diffraction (XRD) was performed to evaluate the amorphization of the solid compositions of Comparative Examples 11 and 12. The evaluation method was as described above. Furthermore, a dissolution test was performed to evaluate the solubility in water of the solid compositions of Example 5 and Comparative Examples 11 to 13. The evaluation method was as follows. Regarding the evaluation of amorphization of the solid composition of Example 5, the sucrose fatty acid ester was simply powder-mixed with a powder prepared in the same manner as in Comparative Example 12, and therefore the evaluation was the same as that of Comparative Example 12. Regarding the evaluation of amorphization of the solid composition of Comparative Example 13, the sucrose fatty acid ester and the water-soluble polymer were simply powder-mixed with the solid composition of Comparative Example 11, and therefore the evaluation was the same as that of Comparative Example 11.

[0120] [Dissolution test: Dissolution amount] The amount of the solid composition filled into the gelatin capsule was 8 mg in terms of myricetin. The wavelength of the HPLC condition was 371 nm. The other conditions were the same as for curcumin, and the dissolution amount was determined.

[0121]

[0122] In Comparative Example 11, there was a peak specific to myricetin in the XRD chart as shown in Figure 8. Therefore, myricetin was in a crystalline state, and as shown in Table 5, it was poor in solubility in water in the dissolution test.

[0123] In Comparative Example 12, a solid composition was prepared by using a solution in which myricetin was dissolved in a solvent together with HPC, and removing the solvent from the solution. In the solid composition of Comparative Example 12, as shown in Figure 9, there was no peak specific to myricetin in the XRD chart, and myricetin was in an amorphous state. Therefore, the solid composition of Comparative Example 12 was a solid dispersion containing amorphous myricetin. In Comparative Example 12, although it was amorphized, the solubility of myricetin in water was not improved.

[0124] In contrast, in Example 5, by powder-mixing sucrose fatty acid ester SE-SS with a solid dispersion containing myricetin and HPC by post-mixing, the solubility of myricetin in water was significantly improved compared to Comparative Examples 11 and 12. Even in Comparative Example 13, in which myricetin, sucrose fatty acid ester SE-SS, and HPC were simply powder-mixed, the effect of improving the solubility of myricetin in water was observed, but in Example 5, the solubility in water was significantly superior, especially after 240 minutes had elapsed.

[0125] Comparative Example 16 The formulation (parts by mass) is as shown in Table 6 below. 1 part by mass of curcumin (CUR) was placed in a pressure bottle together with 36 parts by mass of acetone and stirred to dissolve. 4 parts by mass of HPMCAS (C) as a water-soluble polymer was added to the resulting solution and dissolved, followed by adding 9 parts by mass of water and stirring. The resulting solution was spray-dried using a spray dryer to distill off the solvent and recover a powder. The resulting powder was dried under reduced pressure. The vacuum drying was performed by applying full pressure using an oil pump for 6 hours. After vacuum drying, the solid composition of Comparative Example 16 was obtained by passing the sieve through a stainless steel sieve with 1.0 mm mesh.

[0126] Comparative Example 17 One part by mass of curcumin powder (pulverized in an agate mortar), 2 parts by mass of sucrose fatty acid ester SE-SS powder, and 4 parts by mass of HPMCAS powder (pulverized in an agate mortar) were mixed on a medicine wrapping paper to obtain a solid composition of Comparative Example 17.

[0127] Example 6 The solid composition of Example 6 was obtained by mixing 5 parts by mass of the solid composition obtained in Comparative Example 16 with 2 parts by mass of sucrose fatty acid ester SE-SS powder on a medicine wrapping paper.

[0128] Example 7 The formulation (parts by mass) is as shown in Table 6 below. 1 part by mass of curcumin (CUR) was placed in a pressure bottle together with 36 parts by mass of acetone and stirred to dissolve. 4 parts by mass of HPMCP (C) as a water-soluble polymer was added to the resulting solution and dissolved, followed by addition of 9 parts by mass of water and stirring. The resulting solution was spray-dried using a spray dryer to remove the solvent and recover the powder. The resulting powder was dried under reduced pressure. The vacuum drying was performed by applying full pressure for 6 hours using an oil pump. After vacuum drying, the powder was passed through a stainless steel sieve with 1.0 mm openings. 5 parts by mass of the resulting powder and 2 parts by mass of sucrose fatty acid ester SE-SS powder were mixed on a medicine wrapping paper to obtain the solid composition of Example 7.

[0129] X-ray diffraction (XRD) was performed to evaluate amorphization for the solid composition of Comparative Example 16 and the powder in Example 7 before the addition of the sucrose fatty acid ester (powder obtained by passing through a sieve after the above-mentioned vacuum drying). The evaluation method was as described above. The solid composition of Example 6 was obtained by simply powder-mixing the sucrose fatty acid ester with a powder prepared in the same manner as in Comparative Example 16, and therefore was evaluated in the same manner as in Comparative Example 16. The solid composition of Comparative Example 17 was obtained by simply powder-mixing the sucrose fatty acid ester and the water-soluble polymer with the solid composition of Comparative Example 1, and therefore was evaluated in the same manner as in Comparative Example 1.

[0130] The solid compositions of Examples 6 and 7 and Comparative Examples 1, 16, and 17 were subjected to a dissolution test to evaluate their solubility in water. The evaluation method was as follows.

[0131] [Dissolution Test: Dissolution Amount] A dissolution tester, "NTR-6600AST" manufactured by Toyama Sangyo Co., Ltd., was used. 900 mL of dissolution test solution 2 (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was charged into the vessel and 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 15 mg of solid composition equivalent to curcumin 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 through a 0.45 μm membrane filter. Tests were conducted for 30, 60, and 120 minutes. The filtrate was diluted 2-fold with ethanol, filtered through a 0.20 μm membrane filter, and the curcumin content was quantified by HPLC. Three 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 the "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 the "25HP045AN" manufactured by Advantec Co., Ltd. (filter material: hydrophilic PTFE, mesh size: 0.45 μm). The 0.20 μm membrane filter used was the "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: 430 nm.

[0132]

[0133] In Comparative Example 16, a solid composition was prepared by using a solution of curcumin and HPMCAS dissolved in a solvent and then removing the solvent from the solution. As shown in FIG. 10 , the XRD chart of the solid composition of Comparative Example 16 did not show any peaks specific to curcumin, indicating that the curcumin was in an amorphous state. Therefore, the solid composition of Comparative Example 16 was a solid dispersion containing amorphous curcumin. As shown in Table 6, Comparative Example 16 had improved solubility in water compared to Comparative Example 1.

[0134] In Comparative Example 17, curcumin, sucrose fatty acid ester SE-SS, and HPMCAS were mixed in powder form, and the solubility of curcumin in water was not improved by simply mixing these three ingredients in powder form.

[0135] In contrast, in Example 6, the sucrose fatty acid ester SE-SS was powder-mixed into the solid dispersion containing curcumin and HPMCAS by post-mixing, and the solubility in water was significantly improved not only compared to Comparative Examples 1 and 17, which were in a crystalline state, but also compared to Comparative Example 16, which was a solid dispersion.

[0136] In Example 7, as shown in FIG. 11 , there was no peak specific to curcumin in the XRD chart of the powder before the addition of the sucrose fatty acid ester. Therefore, it can be seen that the curcumin was in an amorphous state even in Example 7, in which the sucrose fatty acid ester was simply powder-mixed with the powder. In Example 7, the sucrose fatty acid ester SE-SS was powder-mixed with the solid dispersion containing curcumin and HPMCP by post-mixing, thereby significantly improving the solubility in water compared to Comparative Examples 1 and 17. Furthermore, while it is required for oral formulations that the dissolution amount increase as quickly as possible, Example 7 showed a significantly improved dissolution amount at the initial stage compared to Comparative Example 16.

[0137] 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.

[0138] 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, in a mixed state, a solid dispersion in which a crystalline, poorly water-soluble organic compound is dispersed in an amorphous state in a water-soluble polymer, using the water-soluble polymer as an inert carrier, and a sucrose fatty acid ester in which the ratio of monoesters is 85% by mass or more.

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 curcuminoids, 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 curcuminoids, flavanones, flavonols, lignans, coumarins, stilbenoids, phenolic acids, xanthophylls, retinoids, phytosterols, alkaloids, glucosylceramides, and limonoids.

4. The solid composition of claim 1, wherein the water-soluble polymer comprises at least one selected from the group consisting of cellulose ether, cellulose ester, homopolymer of N-vinyl lactam, copolymer of N-vinyl lactam, polyalkylene glycol, polyalkylene oxide, and poly(meth)acrylate.

5. The solid composition according to claim 1, wherein the mass ratio of the sucrose fatty acid ester to the poorly water-soluble organic compound 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 according to claim 1, wherein the mass ratio of the sucrose fatty acid ester to the solid dispersion is 0.1 to 3.

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: obtaining a solid dispersion using a crystalline poorly water-soluble organic compound and a water-soluble polymer, in which the poorly water-soluble organic compound is dispersed in an amorphous state in the water-soluble polymer; and mixing the solid dispersion with a sucrose fatty acid ester having a monoester ratio of 85% by mass or more.

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