Manufacturing method of granulated material

Abstract

To provide a method for manufacturing hardly water-soluble flavonoid-containing granulated product having excellent dissolubility of hardly water-soluble flavonoid into water.SOLUTION: A method for manufacturing granulated product containing hardly water-soluble flavonoid includes the following processes (1) and (2): (1) a process of preparing binding liquid containing hardly water-soluble flavonoid (A) which has solubility into water at 25°C of 2 mg / mL or less, ethanol (B) and water (C), and a mass ratio [(B) / (A)] between the hardly water-soluble flavonoid (A) and ethanol (B) is 1.0 to 8.0; and (2) a process of spraying the binding liquid prepared in the process (1) onto powder including filler (D) to granulate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a granulated material containing a poorly water-soluble flavonoid. [Background technology]

[0002] Flavonoids are a general term for compounds with a C6-C3-C6 carbon skeleton in which two phenyl groups are bonded via three carbon atoms. They are naturally found in the flowers, leaves, roots, stems, fruits, etc. of plants. Numerous reports have been published on the physiological effects of flavonoids on the body, and many foods for specified health uses and foods with functional claims that contain flavonoids are on the market. However, many flavonoids themselves are poorly water-soluble, and have various problems, such as low bioabsorbability, poor handling properties, and residual residue when used in instant beverages. Therefore, techniques for improving the solubility of poorly water-soluble flavonoids in water have been investigated, and for example, a method of mixing naringin with α-glucosylhesperidin and β-monoglucosylhesperetin (Patent Document 1), a method of dispersing nobiletin in an amorphous state in a water-soluble carrier to form a solid dispersion, and the like have been reported.

[0003] On the other hand, the fluidized bed granulation method is a granulation method in which a binder liquid is sprayed onto the powder while fluidizing the powder with a large amount of air, and is widely used in the processing of powders for beverages and foods and powders of active pharmaceutical ingredients for the purpose of improving the solubility and dispersibility of the powder (e.g., Patent Documents 3 and 4). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2007-39419 A [Patent Document 2] JP 2019-167336 A [Patent Document 3] JP 2006-325491 A [Patent Document 4] Special Publication No. 2006-502194 Summary of the Invention [Problem to be solved by the invention]

[0005] However, conventional fluidized bed granulation methods did not sufficiently improve the solubility of poorly water-soluble flavonoids in water, and some of the granulated material remained undissolved when dissolved in water, so a technology to further improve solubility was needed. Therefore, an object of the present invention is to provide a method for producing a granulated product containing a poorly water-soluble flavonoid, which has excellent solubility in water of a poorly water-soluble flavonoid. [Means for solving the problem]

[0006] The present inventors have conducted intensive research in light of the above-mentioned problems and have found that by preparing a binding liquid containing a poorly water-soluble flavonoid and ethanol in a specific mass ratio, and then spraying the prepared binding liquid onto a powder containing an excipient to granulate, a granulated product can be obtained in which the solubility of the poorly water-soluble flavonoid in water is improved, and that such a granulated product is easily soluble in water and the formation of a precipitate when dissolved in water can be suppressed.

[0007] That is, the present invention relates to a method for producing a pharmaceutical composition comprising the following steps (1) and (2): (1) preparing a binding solution containing a poorly water-soluble flavonoid (A) having a solubility in water of 2 mg / mL or less at 25° C., ethanol (B) and water (C), in which the mass ratio of the poorly water-soluble flavonoid (A) to the ethanol (B) [(B) / (A)] is 1.0 to 8.0; (2) A step of spraying the binding liquid prepared in the step (1) onto a powder containing an excipient (D) to granulate the powder. The present invention provides a method for producing a granulated material containing a poorly water-soluble flavonoid, comprising: Effect of the Invention

[0008] According to the present invention, it is possible to provide a granulated product containing a poorly water-soluble flavonoid in which the poorly water-soluble flavonoid has high solubility in water and in which the formation of precipitates upon dissolution in water is suppressed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The method for producing a granulated material containing a poorly water-soluble flavonoid of the present invention comprises the following steps (1) and (2): (1) preparing a binding solution containing a poorly water-soluble flavonoid (A) having a solubility in water of 2 mg / mL or less at 25° C., ethanol (B) and water (C), in which the mass ratio of the poorly water-soluble flavonoid (A) to the ethanol (B) [(B) / (A)] is 1.0 to 8.0; (2) A step of spraying the binding liquid prepared in the step (1) onto a powder containing an excipient (D) to granulate the powder.

[0010] [Step (1)] This step is a step of preparing a binding solution containing a poorly water-soluble flavonoid (A) having a solubility in water of 2 mg / mL or less at 25°C, ethanol (B) and water (C), in which the mass ratio of the poorly water-soluble flavonoid (A) to ethanol (B) [(B) / (A)] is 1.0 to 8.0. As used herein, the term "poorly water-soluble flavonoid" refers to a flavonoid having a solubility in water at 25°C of 2 mg / mL or less. In the present invention, even when a poorly water-soluble flavonoid is used, from the viewpoint of being able to provide a poorly water-soluble flavonoid-containing granulated product in which the generation of precipitates upon dissolution in water is suppressed, the present invention is preferably applicable to flavonoids having a solubility in water at 25° C. of preferably 1.5 mg / mL or less, more preferably 1.0 mg / mL or less, and even more preferably 0.5 mg / mL or less. Here, the solubility represents the number of milligrams of solute dissolved in 1 mL of solution, and is expressed in mg / mL.

[0011] Poorly water-soluble flavonoids are classified into flavones, flavonols, isoflavones, flavans, flavanols, flavanones, flavanonols, chalcones, anthocyanidins, etc. based on the structure of the C3 portion (C ring) of the C6-C3-C6 carbon skeleton and the bonding mode of the hydroxyl group. Specifically, flavones such as sudachitin, lingenin, prunin, astragalin, kaempferol, apiin, apigenin, nobiletin, and tangeretin; flavonols such as quercetin, fisetin, rutin, quercitrin, isoquercitrin, myricitrin, and myricetin; isoflavones such as soy isoflavones, daidzein, daidzin, glycitein, glycitin, genistein, and genistin; hesperidin, neohesperetin, and hesperetin. Examples of such anthocyanidins include flavanones such as chin, naringin (naringin), and naringenin; flavanonols such as dihydroquercetin and dihydrokaempferol; and anthocyanidins such as delphinidin, delphin, nasunin, peonidin, peonin, petunin, peonidin, malvidin, malvin, enin, cyanidin, leucocyanidin, cyanin, chrysanthemin, keracyanin, idein, mecocyanin, pelargonidin, and callistephin. These may be used alone or in combination of two or more. This also includes hydrates of poorly water-soluble flavonoids when they exist. In addition, poorly water-soluble flavonoids include not only aglycones but also glycosides in which sugar is bound to the aglycone. For example, hesperidin is a glycoside in which rutinose (L-rhamnosyl-(α1→6)-D-glucose) is beta-bound to hesperetin, and naringin is a glycoside in which neohesperidose (L-rhamnosyl-(α1→2)-D-glucose) is bound to naringenin. In the present invention, from the viewpoint of being able to provide a poorly water-soluble flavonoid-containing granulated product in which the generation of precipitates upon dissolution in water is suppressed, the poorly water-soluble flavonoid is preferably one or more types selected from the group consisting of flavones, flavonols and flavanones, more preferably one or more types selected from the group consisting of nobiletin, tangeretin, quercetin, rutin, hesperidin and naringin, even more preferably hesperidin, naringin or a combination thereof, and even more preferably naringin.

[0012] The poorly water-soluble flavonoid can be obtained by chemical synthesis or by extraction and purification from plants containing poorly water-soluble flavonoids. Commercially available products can also be used. The purity of the poorly water-soluble flavonoid is not particularly limited, and it is sufficient that the poorly water-soluble flavonoid has a purity that allows it to exhibit the desired pharmacological effect when made into a granulated product, for example.

[0013] The content of the poorly water-soluble flavonoid (A) in the binding liquid is preferably 5% by mass or more, more preferably 7% by mass or more, and even more preferably 9% by mass or more from the viewpoint of improving the production efficiency of the granulated product, and is preferably 30% by mass or less, more preferably 25% by mass or less, and even more preferably 14% by mass or less from the viewpoint of improving the fluidity of the poorly water-soluble flavonoid (A) in the binding liquid and improving the solubility of the finally obtained granulated product.

[0014] In the present invention, the ethanol (B) that can be used may be absolute ethanol or the like. The content of ethanol (B) in the binding solution is preferably 25% by mass or more, more preferably 40% by mass or more, and even more preferably 43% by mass or more, from the viewpoint of improving the fluidity of the poorly water-soluble flavonoid (A) in the binding solution and improving the solubility of the finally obtained granulated product, and is preferably 70% by mass or less, more preferably 65% ​​by mass or less, and even more preferably 55% by mass or less, from the viewpoint of improving the production efficiency of the granulated product.

[0015] In the binding solution, the mass ratio of the water-insoluble flavonoid (A) to ethanol (B) [(B) / (A)] is 1.0 to 8.0, but from the viewpoint of improving the fluidity of the water-insoluble flavonoid (A) in the binding solution and improving the solubility of the finally obtained granulated product, it is 1.0 or more, preferably 2.0 or more, and more preferably 3.0 or more, and from the viewpoint of improving the production efficiency of the granulated product, it is 8.0 or less, preferably 6.0 or less, and more preferably 5.0 or less.

[0016] In the present invention, the water (C) may be any of distilled water, ion-exchanged water, deaerated water, tap water, well water, etc. The content of water (C) in the binding liquid is preferably 10% by mass or more, more preferably 20% by mass or more, from the viewpoint of improving the fluidity of the poorly water-soluble flavonoid (A) in the binding liquid and improving the solubility of the finally obtained granulated product, and is preferably 70% by mass or less, more preferably 55% by mass or less, and even more preferably 48% by mass or less, from the viewpoint of improving the production efficiency of the granulated product.

[0017] In the binding solution, the mass ratio of the total amount of ethanol (B) and water (C) to the water-insoluble flavonoid (A) [((B)+(C)) / (A)] is preferably 1 or more, more preferably 2 or more, and even more preferably 5 or more, from the viewpoint of improving the fluidity of the water-insoluble flavonoid (A) in the binding solution and improving the solubility of the finally obtained granulated product, and is preferably 20 or less, more preferably 16 or less, and even more preferably 12 or less, from the viewpoint of improving the production efficiency of the granulated product.

[0018] In the binding solution, the ethanol concentration [[(B) / {(B)+(C)}]×100] is preferably 10% by mass or more, more preferably 30% by mass or more, and even more preferably 48% by mass or more, from the viewpoints of improving the fluidity of the poorly water-soluble flavonoid (A) in the binding solution and improving the solubility of the finally obtained granulated product, and of improving the production efficiency of the granulated product, and is preferably 90% by mass or less, more preferably 60% by mass or less, from the viewpoints of safety in the production process of the granulated product and preventing ethanol from remaining in the finally obtained granulated product.

[0019] In this step, in order to dissolve the poorly water-soluble flavonoid (A), it is preferable to first dissolve the poorly water-soluble flavonoid (A) in ethanol (B) and then mix it with water (C) to prepare a binding solution. If necessary, it may be heated.

[0020] In addition to the above components, the binding liquid may contain additives such as excipients, surfactants, sweeteners, acidulants, flavorings, colorants, preservatives, binders, disintegrants, etc., within the range that does not impair the effects of the present invention. The content of the additives can be appropriately set within the range that does not impair the object of the present invention.

[0021] [Step (2)] This step is a step of spraying the binder liquid prepared in the step (1) onto a powder containing an excipient (D) to granulate the powder. The granulation method in this step includes a wet granulation method, but from the viewpoint of improving the solubility of the granulated product and improving the production efficiency of the granulated product, it is preferable to use a fluidized bed granulation method. In the present invention, the poorly water-soluble flavonoid (A) is dissolved in a binder liquid in advance, and the binder liquid is sprayed onto a powder containing an excipient (D). This is believed to reduce crystallization of the poorly water-soluble flavonoid (A) when the powder is granulated, and improve the solubility of the granulated product obtained as a final product.

[0022] The excipient (D) may be an organic excipient or an inorganic excipient. Examples of the organic excipient include sugars such as lactose, starches (including starch hydrolysates), cyclodextrin, sucrose, maltose, glucose, and crystalline cellulose, and sugar alcohols such as maltitol, erythritol, xylitol, sorbitol, mannitol, lactitol, trehalose, and reduced palatinose. Examples of the inorganic excipient include sodium chloride, aluminum silicate, calcium silicate, silicon dioxide, light anhydrous silicic acid, calcium sulfate, and calcium hydrogen phosphate. Among them, from the viewpoint of improving the fluidity of the poorly water-soluble flavonoid (A) in the binding solution and improving the solubility of the finally obtained granulated product, organic excipients are preferred, and monosaccharides, disaccharides, starches, and sugar alcohols are more preferred, and starch hydrolysates and sugar alcohols are even more preferred, and maltitol, erythritol, and xylitol are even more preferred, and maltitol is even more preferred. These may be used alone or in combination. The sugar alcohol may be either anhydrous or hydrated.

[0023] The content of the excipient (D) in the powder can be appropriately set within a range that does not impair the object of the present invention. When the powder contains maltitol as the excipient (D), the content of maltitol in the powder is preferably 10% by mass or more, more preferably 15% by mass or more, and even more preferably 20% by mass or more from the viewpoint of improving the fluidity of the poorly water-soluble flavonoid (A) in the binding liquid and improving the solubility of the finally obtained granulated product, and is preferably 60% by mass or less, more preferably 50% by mass or less from the viewpoint of suppressing unpleasant sticking to the mouth when the granulated product is dissolved in water.

[0024] In addition to the excipient (D), the powder may contain additives such as surfactants, sweeteners, acidulants, flavorings, colorants, preservatives, binders, disintegrants, etc., within the range that does not impair the effects of the present invention. The content of the additives can be appropriately set within the range that does not impair the object of the present invention.

[0025] In the fluidized bed granulation method, it is preferable to form a fluidized bed of the powder part containing the excipient (D) by air flow, spray the binding liquid prepared in the above step (1) into the layer, and granulate the particles by adhering and agglomerating them by liquid bridging. The amount of the binding liquid prepared in step (1) to be sprayed is preferably 10 parts by mass or more, more preferably 25 parts by mass or more, per 100 parts by mass of the powder containing excipient (D) from the viewpoint of the meltability and water dispersibility of the granulated product, and is preferably 90 parts by mass or less, more preferably 80 parts by mass or less, and even more preferably 50 parts by mass or less, from the viewpoint of improving the production efficiency of the granulated product.

[0026] From the viewpoint of flavor, the temperature during fluidized bed granulation is preferably 90° C. or lower. In addition, the spray rate is preferably 2 to 8 mL / min, more preferably 3 to 7 mL / min, and even more preferably 4 to 5 mL / min, from the viewpoint of improving the fluidity of the poorly water-soluble flavonoid (A) in the binding liquid and improving the solubility of the final granulated product. Moreover, the spray pressure is preferably 0.09 to 0.3 MPa, more preferably 0.11 to 0.20 MPa, from the viewpoint of improving the production efficiency of the granulated product. After the fluidized bed granulation, the mixture may be dried and, if necessary, sized. The drying step may be carried out simultaneously with the granulation step.

[0027] The granulated product containing the poorly water-soluble flavonoid of the present invention thus obtained ("granulated product containing poorly water-soluble flavonoid") has excellent solubility of the poorly water-soluble flavonoid in water. Therefore, as shown in the Examples below, when dissolved in water, no residue remains and the occurrence of precipitates is suppressed. Therefore, the poorly water-soluble flavonoid-containing granulated product of the present invention is expected to have improved handleability and improved absorbability of the poorly water-soluble flavonoid after oral ingestion, and is expected to exhibit high functional properties of the poorly water-soluble flavonoid.

[0028] The content of the poorly water-soluble flavonoid (A) in the poorly water-soluble flavonoid-containing granulated product of the present invention is preferably 1% by mass or more, more preferably 2% by mass or more, and even more preferably 3% by mass or more, from the viewpoint of improving the physiological effect when the granulated product is taken, and is preferably 25% by mass or less, more preferably 15% by mass or less, and even more preferably 10% by mass or less, from the viewpoint of improving the solubility of the granulated product.

[0029] The content of the excipient (D) in the water-insoluble flavonoid-containing granulated product of the present invention is preferably 50% by mass or more, more preferably 70% by mass or more, and even more preferably 85% by mass or more, from the viewpoint of improving the fluidity of the water-insoluble flavonoid (A) in the granulated product and improving the solubility of the granulated product, and is preferably 98% by mass or less, more preferably 96% by mass or less, from the viewpoint of suppressing unpleasant sticking to the mouth when the granulated product is dissolved in water.

[0030] When the water-insoluble flavonoid-containing granulated product contains maltitol as an excipient (D), the content of maltitol in the granulated product is preferably 10% by mass or more, more preferably 15% by mass or more, and even more preferably 21% by mass or more, from the viewpoint of improving the fluidity of the water-insoluble flavonoid (A) in the binding liquid and improving the solubility of the granulated product, and is preferably 60% by mass or less, more preferably 50% by mass or less, from the viewpoint of suppressing unpleasant sticking to the mouth when the granulated product is dissolved in water.

[0031] In the water-insoluble flavonoid-containing granulated product of the present invention, the mass ratio of the water-insoluble flavonoid (A) to the excipient (D) [(A) / (D)] is preferably 0.015 or more, more preferably 0.02 or more, and even more preferably 0.04 or more, from the viewpoint of improving the physiological effect when the granulated product is taken, and is preferably 0.3 or less, more preferably 0.2 or less, and even more preferably 0.15 or less, from the viewpoint of improving the solubility of the granulated product.

[0032] In the water-insoluble flavonoid-containing granulated product of the present invention, when the granulated product contains maltitol as an excipient (D), the mass ratio of the water-insoluble flavonoid (A) to maltitol [(A) / maltitol] is preferably 0.01 or more, more preferably 0.05 or more, and even more preferably 0.07 or more, from the viewpoint of improving the physiological effect when the granulated product is taken, and is preferably 0.5 or less, more preferably 0.4 or less, and even more preferably 0.3 or less, from the viewpoint of improving the solubility of the granulated product.

[0033] The poorly water-soluble flavonoid-containing granulated product of the present invention can be used in various foods and beverages, medicines, quasi-drugs, cosmetics, etc. In particular, due to its high solubility in water, it is useful for use in products that are dissolved in an aqueous solvent when used, for example, instant drinks that are diluted and dissolved in an aqueous solvent for drinking. EXAMPLES

[0034] [Analysis of Naringin and Hesperidin] Naringin and hesperidin were analyzed by filtering the sample solution with a filter (0.45 μm) and measuring by the gradient method at a column temperature of 40°C using a high-performance liquid chromatograph (model CBM-20A, Shimadzu Corporation) equipped with an octadecyl group-introducing packed column for liquid chromatography (L-column 2ODS 4.6 mmφ×250 mm: Chemicals Evaluation and Research Institute, Japan). The mobile phase A solution was distilled water, B solution was acetonitrile, and C solution was a distilled water solution containing 0.5% acetic acid. The flow rate was 1 mL / min, the sample solution injection amount was 10 μL, and the UV detector wavelength was 285 nm. The gradient conditions were as follows: Concentration gradient conditions (volume%) Time Mobile phase A Mobile phase B Mobile phase C 0.0 minutes 75% 15% 10% 40.0 minutes 50% 30% 20% The sample injection volume is 10 μL, and detection is performed by quantification based on absorbance at a wavelength of 285 nm.

[0035] [Evaluation of water solubility] The granules (25°C) were weighed out into a 200mL transparent plastic cup so that the amount of poorly water-soluble flavonoid was 100mg, and 170mL of water (25°C) was added thereto, and the mixture was stirred 30 times with a spatula to mix the granules and water uniformly. After 30 minutes of mixing, the state of precipitation in the water was visually observed. If no precipitate was observed, it was marked as "○", if some precipitate was observed, it was marked as "△", Cases where a precipitate was observed were marked "X." Cases where the granulation operation itself could not be carried out due to reasons such as low fluidity of the binding liquid were not evaluated.

[0036] [Evaluation of cup precipitation amount of poorly water-soluble flavonoids] The granules (25°C) were weighed out into a transparent plastic cup with a capacity of 200 mL so that the amount of poorly water-soluble flavonoid was 100 mg, and 170 mL of water (25°C) was added thereto, and then the mixture was stirred 30 times with a spatula to mix the granules and water uniformly. After 30 minutes of mixing, the liquid in the cup was removed, the precipitate remaining in the cup was redissolved, and the amount of poorly water-soluble flavonoid in the precipitate was analyzed to measure the amount of poorly water-soluble flavonoid precipitated in the cup. The evaluation was performed in terms of the amount of poorly water-soluble flavonoid in the precipitate relative to 100 mg of the weighed poorly water-soluble flavonoid. The method for analyzing the amount of poorly water-soluble flavonoid can be the same as that described above for naringin and hesperidin.

[0037] [Raw materials] Naringin: Naringin, Seikodo Ishida Shoten Co., Ltd., purity 97% or more Hesperidin: Hesperidin Wako Grade 1, Fujifilm Wako Pure Chemical Industries, purity 95% or more Maltitol: Amalti MR-50, Mitsubishi Corporation Foodtech Co., Ltd. Non-cyclic dextrin (MW=17000): Sandec #100, dextrose equivalent (DE) 2-5, Sanwa Starch Co., Ltd. Cyclodextrin 1: γ-CD, CAVAMAX W7, Wacker Chemical Cyclodextrin 2: γ-CD, CAVAMAX W8, Wacker Chemical

[0038] Examples 1 to 5 and Comparative Examples 4 to 5 A binding solution was prepared by completely dissolving naringin in 99.5% ethanol in the composition shown in Table 1, and adding tap water so that the ethanol concentration became the concentration shown in Table 1. In Comparative Example 4, naringin was added to tap water in the composition shown in Table 1 to prepare a binding solution. On the other hand, the powders shown in Table 1 were mixed and charged into a fluidized bed granulator (FLOW COATER FL-LABO manufactured by Freund Corporation, the same applies below) so that the final weight of the powder was 200 g. Next, the binding liquid was added to the fluidized bed granulator with an intake air temperature of 70° C. and an intake air volume of 0.3 m 3 / min, spray rate of about 4 mL / min, spray pressure of 0.18 MPa, spray amount of 93 g (Example 1), 72 g (Examples 2-3), or 145 g (Examples 4-5) was sprayed onto the powder in the powder section, granulated, and then the air volume was 0.3 m 3 The mixture was dried at a rate of 1 / min until the exhaust temperature reached 42°C, and then sieved through a sieve with 1 mm openings to prepare granules. The granulated products obtained in Examples 1 to 5 were subjected to an [evaluation of water solubility]. The granulation time in step (2) in each Example was also measured. Furthermore, an [evaluation of the cup precipitation amount of poorly water-soluble flavonoid] was performed for Example 1. The results are shown in Table 1. Note that in Comparative Examples 4 to 5, the fluidity of the binding liquid was extremely low, and the granulation operation itself could not be carried out.

[0039] Comparative Examples 1 to 3 The powders shown in Table 1 were mixed and charged into a fluidized bed granulator so that the powder had a final weight of 200 g. Then, tap water or an aqueous ethanol solution was added to the fluidized bed granulator at an intake temperature of 80°C and an intake air volume of 0.3 m 3 / min, spray speed approx. 4mL / min, spray pressure 0.18MPa, spray amount 72g, spray onto powder in powder section, granulate, air volume 0.3m 3 The mixture was dried at a rate of 1 / min until the exhaust temperature reached 42°C, and then sieved through a sieve with 1 mm openings to prepare granules. The granules obtained in Comparative Examples 1 to 3 were evaluated for water solubility. Furthermore, the amount of water-insoluble flavonoid precipitated in the cup was evaluated for Comparative Example 1. The results are shown in Table 1.

[0040] [Table 1]

[0041] As shown in Table 1, a binding solution containing a poorly water-soluble flavonoid and ethanol in a specific mass ratio was prepared, and then the prepared binding solution was sprayed onto a powder containing an excipient and subjected to fluidized bed granulation. It was confirmed that a granulated product in which the poorly water-soluble flavonoid is highly soluble in water was obtained, and that no residue was left undissolved when dissolved in water, and the occurrence of precipitation was suppressed. In contrast, in the granules of Comparative Examples 1 to 3, the poorly water-soluble flavonoid had low solubility in water, and when dissolved in water, the flavonoid remained undissolved and precipitates were observed.

Claims

1. The following steps (1) and (2): (1) preparing a binding solution containing a poorly water-soluble flavonoid (A) having a solubility in water of 2 mg / mL or less at 25° C., ethanol (B) and water (C), wherein the mass ratio of the poorly water-soluble flavonoid (A) to the ethanol (B) [(B) / (A)] is 1.0 to 8.0; (2) A step of spraying the binding liquid prepared in the step (1) onto a powder containing an excipient (D) to granulate the powder. The method for producing a granulated product containing a poorly water-soluble flavonoid, comprising the steps of:

2. The method for producing a granulated material containing a poorly water-soluble flavonoid according to claim 1, wherein the amount of the binder liquid sprayed is 10 to 90 parts by mass per 100 parts by mass of the powder containing the excipient (D).

3. The method for producing a granulated material containing a poorly water-soluble flavonoid according to claim 1 or 2, wherein the excipient (D) contains a sugar alcohol.

4. The method for producing a granulated product containing a poorly water-soluble flavonoid according to any one of claims 1 to 3, wherein the poorly water-soluble flavonoid (A) having a solubility in water at 25°C of 2 mg / mL or less is naringin.

5. The method for producing a granulated product containing the water-insoluble flavonoid according to any one of claims 1 to 4, wherein the concentration of the water-insoluble flavonoid (A) having a solubility in water at 25 ° C. of 2 mg / mL or less in the binding liquid is 5 to 30 mass %.

6. The method for producing a granulated product containing a poorly water-soluble flavonoid according to any one of claims 1 to 5, wherein the granulation method in the step (2) is a fluidized bed granulation method.

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