Granule manufacturing method

Abstract

To provide a method for producing granules that can produce granules having high intraoral solubility from a water-soluble powder material at high yield.SOLUTION: A method for producing granules includes a step of performing wet-granulation using a water-soluble powder material and an ethanol-containing binding liquid. In the method, following components: (A) a cellulose derivative and (B) an organic acid having one or more carboxy groups in each molecule are used in a mode selected from the following (i)-(iii): (i) at least one of the water-soluble powder material and the binding liquid containing the component (A) and the component (B); (ii) the water-soluble powder material containing the component (A) and the binding liquid containing the component (B); and (iii) the water-soluble powder material containing the component (B) and the binding liquid containing the component (A), in such a manner that the mass ratio between the component (A) and the component (B) [(B) / (A)] is 0.3 to 10 in the produced granules.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing granules.

Background Art

[0002] As dosage forms of oral solid preparations in the fields of pharmaceuticals, foods, etc., for example, tablets, capsules, granules, and powders are known. Among them, granules are useful as a dosage form that is easy to ingest even for the elderly, children, and patients with weak swallowing ability because they dissolve in saliva when held in the mouth and can be ingested without water. However, if the water solubility of the granules is low, there is also a problem that there is a foreign body sensation in the mouth and the eating feeling is poor.

[0003] Conventionally, as a method for producing granular foods with good water solubility and dispersibility, for example, an ethanol aqueous solution having an ethanol / water mixing volume ratio of 5 / 5 to 9.5 / 0.5 is added to a powder food or powder enzyme containing 3% by weight or more and 99.5% by weight or less of dextrin and granulated (Patent Document 1). In addition, a step of adding a 70% ethanol aqueous solution to a powder mixture containing a plant extract, a sugar alcohol, and starch and kneading, and a step of extruding and granulating the kneaded powder mixture are performed, and by setting the water content of the kneaded powder mixture to be more than 5.1% by weight and less than 8.9% by weight, it is reported that granules that can be immediately dissolved in the mouth, are difficult to feel bitter, and can be easily taken without water can be produced (Patent Document 2).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] When producing granules from water-soluble powder raw materials by wet granulation, ethanol or the like is usually used as a binding agent, as described in the above prior art documents. However, the inventors' research has shown that there is room for improvement in terms of yield, and that when water is used as a binding agent, granules with excellent oral solubility cannot be obtained. Therefore, the inventors investigated how to produce granules with excellent oral solubility and found that cellulose derivatives such as hydroxypropyl methylcellulose are effective in improving oral solubility. However, they discovered that when using ethanol or the like together with cellulose derivatives during wet granulation of water-soluble powder raw materials, the cellulose derivatives are insoluble in ethanol or the like, making it difficult for them to become granules while remaining in powder form, resulting in a decrease in yield during manufacturing. The object of the present invention is to provide a method for producing granules that have excellent oral solubility from water-soluble powder raw materials and can be manufactured with high yield. [Means for solving the problem]

[0006] In view of the above problems, the inventors have conducted extensive research and have found that when wet granulation of water-soluble powder raw materials, (A) a cellulose derivative and (B) an organic acid having one or more carboxyl groups in its molecule (hereinafter also simply referred to as "organic acid") are used in the presence of ethanol or the like, and are included in a specific proportion in the granules, thereby enabling the production of granules with excellent oral solubility in a high yield.

[0007] In other words, the present invention provides the following [1] to [7]. [1] A method for producing granules, comprising a step of wet granulation using a water-soluble powder raw material and a binding solution containing ethanol, The following ingredients; (A) Cellulose derivatives, and (B) Organic acids having one or more carboxyl groups in the molecule (i)~(iii) below; (i) At least one of the water-soluble powder raw material and the binding liquid contains component (A) and component (B). (ii) The water-soluble powder raw material contains component (A), and the binding solution contains component (B). (iii) The water-soluble powder raw material contains component (B), and the binding solution contains component (A). In any one embodiment selected from the above, and used in a proportion such that the mass ratio of component (A) to component (B) [(B) / (A)] is 0.3 to 10 in the granules produced, A method for producing granules. [2] A method for producing granules according to [1], wherein the content of component (A) is 0.1 to 10% by mass. [3] A method for producing granules according to [1] or [2], wherein the content of component (B) is 0.1 to 10% by mass. [4] A method for producing granules according to any one of [1] to [3], wherein component (A) is one or more selected from alkylcellulose, hydroxyalkylcellulose, and hydroxyalkylalkylcellulose. [5] A method for producing granules according to any one of [1] to [4], wherein component (B) is an organic acid having two or more carboxyl groups in its molecule. [6] The method for producing granules according to [5], wherein the organic acid having two or more carboxyl groups in the molecule is one or more selected from malic acid, tartaric acid, and citric acid. [7] A method for producing granules according to any one of [1] to [6] above, wherein the wet granulation is fluid bed granulation or extrusion granulation. [Effects of the Invention]

[0008] According to the present invention, granules with excellent oral solubility can be produced from water-soluble powder raw materials with a high yield. [Modes for carrying out the invention]

[0009] The present invention provides a method for producing granules, comprising a step of wet granulation using a water-soluble powder raw material and a binding solution containing ethanol, characterized in that, during wet granulation, (A) a cellulose derivative and (B) an organic acid are used in coexistence with the binding solution and in a specific proportion within the granules. First, the materials used in the manufacturing method of this invention will be described.

[0010] <(A) Cellulose derivatives> In this specification, "cellulose derivative" refers to cellulose having substituents, and does not include cellulose itself without substituents. A cellulose derivative does not require that all hydrogen atoms of the hydroxyl groups in the monomer unit (glucose) be substituted with substituents; it is sufficient if some of the hydrogen atoms of the hydroxyl groups are substituted with substituents. The number of substituents in the monomer unit is usually 1 to 5, preferably 1 to 3, and more preferably 1 or 2.

[0011] (A) Examples of cellulose derivatives include hydroxyalkylalkylcellulose, alkylcellulose, hydroxyalkylcellulose, carboxyalkylcellulose, carboxycellulose, or salts thereof. (A) One or more cellulose derivatives may be used.

[0012] Examples of salts include metal salts, acid addition salts, and salts with bases. Examples of metal salts include salts with monovalent metals (e.g., sodium, potassium) and salts with divalent metals (e.g., calcium, magnesium). Examples of acid addition salts include salts with inorganic acids (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid) and salts with organic acids (e.g., acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, monomethyl sulfate). Examples of salts with bases include salts with inorganic bases (e.g., ammonia) and salts with organic bases (e.g., ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, triethanolamine). Among these, metal salts are preferred.

[0013] In alkyl cellulose, hydroxyalkyl cellulose, and carboxyalkyl cellulose, the alkyl may be linear or branched, preferably having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. When there are two or more alkyl groups, they may be the same or different.

[0014] Hydroxyalkylalkyl cellulose is a cellulose having both hydroxyalkyl and alkyl groups, and examples thereof include hydroxymethylmethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose (HPMC), and hydroxybutylmethyl cellulose.

[0015] Examples of alkyl cellulose include methyl cellulose (MC), ethyl cellulose (EC), propyl cellulose, butyl cellulose, pentyl cellulose, and hexyl cellulose.

[0016] Examples of hydroxyalkyl cellulose include hydroxymethyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxybutyl cellulose, hydroxypentyl cellulose, and hydroxyhexyl cellulose.

[0017] Examples of carboxyalkyl cellulose include carboxymethyl cellulose (CMC), carboxyethyl cellulose, carboxypropyl cellulose, carboxybutyl cellulose, carboxypentyl cellulose, and carboxyhexyl cellulose.

[0018] Among them, as the (A) cellulose derivative, one or more selected from alkyl cellulose, hydroxyalkyl cellulose, and hydroxyalkylalkyl cellulose are preferable in terms of excellent yield and solubility in the oral cavity, one or more selected from hydroxyalkylalkyl cellulose and alkyl cellulose are more preferable, and hydroxyalkylalkyl cellulose is even more preferable.

[0019] (A) The amount of cellulose derivative used in the granules is preferably 0.1% by mass or more, more preferably 0.5% by mass, even more preferably 1% by mass or more, even more preferably 1.5% by mass or more, especially preferably 2% by mass or more, and also preferably 10% by mass or less, more preferably 9.5% by mass or less, even more preferably 9% by mass or less, even more preferably 8.5% by mass or less, and especially preferably 8% by mass or less. Furthermore, the amount of cellulose derivative used in the granules is preferably 0.1 to 10% by mass, more preferably 0.5 to 9.5% by mass, even more preferably 1 to 9% by mass, even more preferably 1.5 to 8.5% by mass. Especially preferably 2 to 8% by mass.

[0020] <(B) Organic acids having one or more carboxyl groups in the molecule> (B) The organic acid is not particularly limited as long as it is commonly used in the food industry. (B) The organic acid may have an ethylenically unsaturated group or may be in the form of a salt. Note that one or more of (B) organic acids may be used. (B) Examples of organic acids include monobasic organic acids, dibasic organic acids, tribasic organic acids, or salts thereof. Examples of monobasic organic acids include formic acid, acetic acid, propionic acid, butanoic acid, valeric acid, lactic acid, and gluconic acid. Examples of dibasic organic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, malic acid, and tartaric acid. Examples of tribasic organic acids include citric acid and aconitic acid. Examples of salts include metal salts, and specific examples are the same as those described above.

[0021] In particular, as for (B) organic acid, from the viewpoint of improving yield and oral solubility, organic acids having two or more carboxyl groups in the molecule are preferred, more preferably one or more selected from dibasic organic acids and tribasic organic acids, even more preferably one or more selected from malic acid, tartaric acid and citric acid, and even more preferably one or more selected from malic acid and tartaric acid. When the water-soluble powder raw material contains plant extracts, among malic acid and tartaric acid, malic acid is preferred from the viewpoint of taste.

[0022] (B) From the viewpoint of improving yield, the amount of organic acid used in the granules is preferably 0.1% by mass or more, more preferably 0.5% by mass, even more preferably 1% by mass or more, even more preferably 1.5% by mass or more, and especially preferably 2% by mass or more. From the viewpoint of improving oral solubility, it is preferably 10% by mass or less, more preferably 8% by mass or less, even more preferably 6% by mass or less, even more preferably 4% by mass or less, and especially preferably 3% by mass or less. Furthermore, (B) the amount of organic acid used in the granules is preferably 0.1 to 10% by mass, more preferably 0.5 to 8% by mass, even more preferably 1 to 6% by mass, even more preferably 1.5 to 4% by mass, and especially preferably 2 to 3% by mass.

[0023] The ratio of (A) cellulose derivative to (B) organic acid used is 0.3 to 10 as the mass ratio [(B) / (A)] in the granules produced, but from the viewpoint of improving yield, 0.35 or higher is preferred, 0.4 or higher is more preferred, 0.45 or higher is even more preferred, and 0.5 or higher is even more preferred. From the viewpoint of improving oral solubility, 8 or lower is preferred, 6 or lower is more preferred, 5 or lower is even more preferred, and 3 or lower is even more preferred. The mass ratio [(B) / (A)] is preferably 0.35 to 8, more preferably 0.4 to 6, even more preferably 0.45 to 5, and even more preferably 0.5 to 3.

[0024] <Water-soluble powder raw material> In this specification, "water-soluble powder raw material" refers to a solid raw material from which granules are to be produced, and which is soluble in water at room temperature. From the viewpoint of handling, the form of such solid raw material is preferably powder. The median diameter of the water-soluble powder raw material is not particularly limited as long as it is smaller than the granules, since the granules according to the present invention are aggregates of the water-soluble powder raw material. Here, in this specification, "median diameter" refers to the particle diameter (D50) corresponding to a frequency of 50% in the cumulative distribution based on volume. The particle size distribution can be measured using a dynamic light scattering particle size distribution analyzer.

[0025] The water-soluble powder raw materials are not particularly limited as long as they are soluble in water and commonly used in the food industry. Examples include water-soluble excipients and plant extracts.

[0026] [Water-soluble excipients] The water-soluble excipients are not particularly limited as long as they are commonly used in the food industry, but examples include sugar alcohols and water-soluble dextrins. One or more water-soluble excipients can be used, and from the viewpoint of improving yield and oral solubility, it is preferable to use sugar alcohols and water-soluble dextrins in combination.

[0027] (Sugar alcohol) Examples of sugar alcohols include monosaccharide alcohols, disaccharide alcohols, and trisaccharide or higher alcohols. One or more sugar alcohols can be used. Examples of monosaccharide alcohols include erythritol, xylitol (pentitol), sorbitol, mannitol (hexitol), etc. Examples of disaccharide alcohols include maltitol (reduced maltose), lactitol (reduced lactose), reduced palatinose (isomalto), trehalose, and palatinose. Examples of trisaccharide or greater alcohols include maltotriitol, isomalttriitol, and panitol. In particular, from the viewpoint of oral solubility, hygroscopicity, and handling during extrusion granulation, one or more selected from monosaccharide alcohols and disaccharide alcohols are preferred, with disaccharide alcohols being more preferred, and maltitol (reduced maltose) being preferred.

[0028] The amount of sugar alcohol used can be set as appropriate, but from the viewpoint of improving oral solubility, it is preferable that the amount in the granules be 10% by mass or more, more preferably 15% by mass or more, and even more preferably 20% by mass or more. Furthermore, from the viewpoint of improving yield, it is preferable that the amount is 97% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less. The amount of sugar alcohol used in the granules is preferably 10 to 97% by mass, more preferably 15 to 80% by mass, and even more preferably 20 to 70% by mass.

[0029] (Water-soluble dextrin) In this specification, "water-soluble dextrin" refers to a substance obtained by decomposing raw starch with enzymes or acids, which is suitable for use in edible water. One or more water-soluble dextrins may be used. Dextrose equivalent (DE value) is generally used as an indicator to understand the degree of decomposition of raw starch. However, the DE value of the water-soluble dextrin used in this invention is preferably 2 to 30, more preferably 2 to 13, and even more preferably 2 to 5, in order to easily enjoy the effects of this invention. The DE value can be analyzed by commonly known methods for measuring dextrose, such as the Wilstetter-Schudel method. Furthermore, water-soluble dextrin has a molecular structure in which sugars are polymerized by glycosidic bonds, but the glycosidic bonds may be chain-like, cyclic, or a mixture of these. Examples of sugar bonding methods include α-1,4 bonds, α-1,6 bonds, β-1,2 bonds, β-1,3 bonds, β-1,4 bonds, and β-1,6 bonds, and a single bonding method or two or more bonding methods may be used. Furthermore, starches extracted from plants may be used as long as they are soluble in water. Examples of starches extracted from plants include cornstarch, wheat starch, rice starch, potato starch, sweet potato starch, and tapioca starch. Starches extracted from plants may be purified using known methods if necessary.

[0030] The amount of water-soluble dextrin used can be set as appropriate, but from the viewpoint of improving yield and oral solubility, it is preferable that the amount in the granules be 4% by mass or more, more preferably 7% by mass or more, even more preferably 10% by mass or more, and also preferable that it be 50% by mass or less, more preferably 45% by mass or less, and even more preferably 40% by mass or less. The amount of water-soluble dextrin used in the granules is preferably 4 to 50% by mass, more preferably 7 to 45% by mass, and even more preferably 10 to 40% by mass.

[0031] The ratio of sugar alcohol to water-soluble dextrin used, expressed as a mass ratio [water-soluble dextrin / sugar alcohol] in the manufactured granules, is preferably 0.1 or higher, preferably 0.3 or higher, from the viewpoint of improving yield, and preferably 1 or lower, more preferably 0.7 or lower, from the viewpoint of improving oral solubility. The mass ratio [dextrin / sugar alcohol] is preferably 0.1 to 1, and more preferably 0.3 to 0.7.

[0032] (Plant extract) In this specification, "plant extract" means an extract obtained by water from part or all of a plant. The extraction method is not particularly limited, and known extraction methods may be used. The extract obtained from the plant may be filtered, purified, dried, etc., as necessary.

[0033] The plant extracts are not particularly limited as long as they are extracts from edible plants, but examples include extracts from coffee beans, tea, rosemary, asparagus, turmeric, zedoary, soybeans, cocoa, long pepper, and ginkgo leaves. Furthermore, plant extracts that have undergone known decomposition treatments (decomposition by heat or pressure, decomposition by acid or alkali, decomposition by enzymes, etc.) can also be used. One or more plant extracts may be used.

[0034] You can use either roasted or green coffee beans. Examples of tea varieties include C. sinensis var. sinensis (including the Yabukita variety), C. sinensis var. assamica, and tea leaves selected from their hybrids (Camellia sinensis). Tea leaves can be classified into unfermented tea, semi-fermented tea, and fermented tea depending on the processing method. Tea leaves may be used individually or in combination of two or more types. There are no particular restrictions on the tea variety or harvesting time, and the tea leaves may be roasted. Examples of unfermented teas include green tea leaves such as sencha, deep-steamed sencha, hojicha, bancha, gyokuro, kabusecha, tencha, kamairicha, stem tea, twig tea, and bud tea. Examples of semi-fermented teas include oolong tea leaves such as Tieguanyin, Sezhong, Huangjin Gui, and Wuyi rock tea. Examples of fermented teas include black tea leaves such as Darjeeling, Assam, and Sri Lanka. In particular, extracts of one or more plants selected from the group consisting of coffee beans, tea, and rosemary are preferred because they allow for easier enjoyment of the effects of the present invention.

[0035] The amount of plant extract used can be set as appropriate, but from the viewpoint of containing an effective amount of plant extract for nutritional improvement, it is preferable that the solid content in the granules be 10% by mass or more, more preferably 20% by mass or more, and even more preferably 30% by mass or more. Furthermore, from the viewpoint of improving yield and oral solubility, it is preferable that it be 80% by mass or less, more preferably 70% by mass or less, and even more preferably 60% by mass or less. The amount of plant extract used in the granules is preferably 10 to 80% by mass, more preferably 20 to 70% by mass, and even more preferably 30 to 60% by mass, as solid content. Hereinafter, "solid content" in this specification refers to the residue obtained by drying the sample in an electric constant-temperature dryer at 105°C for 3 hours and removing volatile substances.

[0036] (others) Other water-soluble powder raw materials are not particularly limited as long as they are components that are acceptable in final products such as food and beverages and pharmaceuticals and are orally ingestible, but examples include sweeteners, vitamins, minerals, antioxidants, lubricants, and flavorings. One or more of these other water-soluble powder raw materials can be used. The amount of other water-soluble powder raw materials used can be appropriately set within a range that does not impair the purpose of the present invention.

[0037] Examples of sweeteners include monosaccharides, disaccharides, oligosaccharides, isomerized sugars, and high-intensity sweeteners. Examples of monosaccharides include glucose, fructose, and galactose, and examples of disaccharides include maltose, lactose, and sucrose. Examples of oligosaccharides include maltooligosaccharides, fructooligosaccharides, and galactooligosaccharides, and examples of isomerized sugars include glucose-fructose syrup and fructose-glucose syrup. Examples of high-intensity sweeteners include acesulfame K, aspartame, stevia, sucralose, and thaumatin. Examples of lubricants include sucrose fatty acid esters, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, hydrogenated oil, polyethylene glycol, silicon dioxide, and fine silicon dioxide.

[0038] <Binding liquid> The binding solution may contain components other than ethanol; for example, ethanol or an aqueous solution of ethanol can be used. The ethanol used is not particularly limited as long as it is suitable for use in food products. For example, anhydrous ethanol with a purity of 99.5% or higher, as specified in the Japanese Pharmacopoeia, can be used. Furthermore, the ethanol aqueous solution can be, for example, an aqueous solution obtained by diluting ethanol with water. In this case, the mixing ratio of water to ethanol is not particularly limited, but it is preferable that there is an excess of ethanol. For example, the volume ratio of water / ethanol in the ethanol aqueous solution is preferably 1 / 99 to 40 / 60, more preferably 2 / 98 to 35 / 65, and even more preferably 3 / 97 to 30 / 70. The ethanol aqueous solution may be a commercially available ethanol preparation, such as 95% ethanol, or alcohol. The alcohol is not particularly limited as long as it is used for food purposes, but for example, it may be produced by the alcoholic fermentation of natural raw materials containing starch or sugars by yeast, or may contain these components. Liquids containing ethanol can be used, such as alcoholic beverages like sake, shochu, wine, whiskey, and brandy, and fermented seasonings like mirin.

[0039] Next, the method for producing the granules of the present invention will be described. <Wet granulation> In this invention, granules are produced by wet granulation. Wet granulation can employ known methods, such as fluidized bed granulation, extrusion granulation, agitation granulation, and tumbling granulation. Wet granulation may be carried out by combining two or more granulation methods, or by performing one granulation method two or more times. The atmosphere may also be replaced with an inert gas such as nitrogen during granulation. Among these, as wet granulation methods, fluid bed granulation or extrusion granulation is preferred from the viewpoint of improving yield and oral solubility.

[0040] In the present invention, when wet granulation of water-soluble powder raw materials, (A) a cellulose derivative and (B) an organic acid are used in the proportions described above, in the presence of the binder solution. The following (i) to (iii) are examples of how the three components (A) a cellulose derivative, (B) an organic acid, and a binder solution can be present together. (i) At least one of the water-soluble powder raw material and the binder solution contains (A) a cellulose derivative and (B) an organic acid (ii) The water-soluble powder raw material contains (A) a cellulose derivative, and the binding solution contains (B) an organic acid. (iii) A water-soluble powder raw material and (B) an organic acid, and the binding solution contains (A) a cellulose derivative.

[0041] In particular, from the viewpoint of improving yield and oral solubility, the embodiments of (i) or (ii) described above are preferred, the embodiment of (i) is more preferred, and the embodiment in which the water-soluble powder raw material contains (A) a cellulose derivative and (B) an organic acid is even more preferred.

[0042] From the viewpoint of improving yield, the amount of binding solution used is preferably 5 parts by mass or more, more preferably 10 parts by mass or more, and even more preferably 17 parts by mass or more, per 100 parts by mass of total powder. From the viewpoint of improving oral solubility, it is preferably 50 parts by mass or less, more preferably 40 parts by mass or less, and even more preferably 25 parts by mass or less. The amount of binding solution used per 100 parts by mass of total powder is preferably 5 to 50 parts by mass, more preferably 10 to 40 parts by mass, and even more preferably 17 to 25 parts by mass. Here, "total powder amount" refers to the total amount of residue remaining after removing the binding solution from the raw materials for granule production.

[0043] The method for producing granules of the present invention can be appropriately selected depending on the granulation method, but the following method is an example of a preferred embodiment. For example, water-soluble powder raw materials can be produced by subjecting them to a mixing step, a kneading step, a granulation step, and, if necessary, a drying step, a sizing step, and a sieving step.

[0044] 〔mixture〕 First, for example, (A) a cellulose derivative and (B) an organic acid, along with other components such as water-soluble excipients as needed, are mixed. The ratio of (A) the cellulose derivative and (B) the organic acid is as described above. From the viewpoint of handling, the form of the raw materials is preferably solid, and more preferably powder. Any method is acceptable for mixing the raw materials, as long as it can uniformly mix each component of the raw materials. Examples of mixing machines include container mixers, V-type mixers, ribbon mixers, and high-speed agitators (high-speed mixers). The mixing temperature is not particularly limited, but is preferably 10 to 35°C, and more preferably 15 to 25°C. The mixing time is also not particularly limited, but is preferably 0.5 to 5 minutes, and more preferably 1 to 3 minutes.

[0045] [Mixing] Next, the binding solution is added to the mixture and kneaded. A binder may be added to the binding solution as needed. The binder is not particularly limited as long as it is pharmaceutically acceptable, but examples include monosaccharides, disaccharides, polysaccharides, or combinations of two or more of these. The amount of binder added is not particularly limited as long as it allows for granulation.

[0046] [Granulation] Next, the kneaded mixture is granulated. While known methods can be used for granulation, extrusion granulation is preferred because it is easy to obtain granules of the desired particle size and easy to control the particle size. Extrusion granulation is a method of granulation in which a powder, which has been kneaded with a binding solution to impart plasticity, is extruded through a screen with many holes or a die with a predetermined hole diameter using a screw, roller, etc. Examples of granulation machines include horizontal extrusion granulators, front extrusion granulators, dome extrusion granulators, disc pelletizer granulators, ring die granulators, basket granulators, oscillating granulators, and cylinder granulators. Granulation conditions can be set as appropriate, but in order to prevent aspiration during ingestion and to obtain granules with good bulk density and immediate solubility, it is preferable to use extrusion holes with a hole diameter of about 0.5 to 2 mm, and more preferably to use extrusion holes with a hole diameter of 0.8 to 1.2 mm.

[0047] [Drying] The granulated material can be dried using conventional drying methods. Examples of dryers include constant-temperature dryers, forced-air dryers, fluidized bed dryers, vacuum dryers, and vacuum dryers. Drying conditions can be set as appropriate.

[0048] [Grain sorting and sieving] If necessary, the granulated material can be subjected to a sizing process to control the particle size to the desired level. For example, it can be sieved using a sieve with a predetermined pore size, an electric sieve, etc.

[0049] <Product form> The granules according to the present invention are solid at room temperature (20°C ± 15°C) and are preferably used for oral ingestion. Herein, "granules" refers to aggregates of powdered raw materials. The granules according to the present invention typically have a median diameter in the range of 0.5 to 2.0 mm. The moisture content of the granules is usually 5% by mass or less, preferably 4% by mass or less.

[0050] The granules according to the present invention may be provided as a food or as an orally administered pharmaceutical, but are preferably provided as a food. The granules according to the present invention may also be compressed into tablets. Furthermore, the granules according to the present invention may be contained in food or pharmaceutical containers or bags, such as paper, plastic, glass, or metal containers or bags. They may also be individually packaged for single oral intake. Among these, individually packaged portions (e.g., about 1-2 g) are preferred (stick packaging, individual packaging, etc.). The packaging material is not limited to those commonly used for food or pharmaceuticals, but for example, a combination of aluminum foil, synthetic resin (polyethylene terephthalate, etc.), laminated paper, etc., can be used. Nitrogen gas may be filled inside the container and packaging material from the viewpoint of maintaining quality.

[0051] <Usage> The granules according to the present invention are preferably taken orally with or without water or with a small amount of water. The amount of water is preferably 100 mL or less, more preferably 50 mL or less, and even more preferably 20 mL or less. [Examples]

[0052] The present invention will be described in more detail below with reference to examples and comparative examples, but these examples are not intended to limit the present invention.

[0053] 1. Analysis of Cellulose Derivatives The cellulose derivatives were analyzed by HPLC (High Performance Liquid Chromatography) according to the following method. The analytical instrument configuration is as follows: • Detector: Shodex RI • Column: Shodex OHpac SB-806M HQ (8.0mm ID x 300mm) x 2

[0054] The analysis conditions are as follows: Column temperature: 40°C ·Mobile phase: 0.1M NaCl aq. ·Flow rate: 1mL / min • Sample injection volume: 20 μL

[0055] 2. Analysis of organic acids (carboxylic acids) Add 5 mL of 5% perhydrochloric acid to 10 g of the sample and dilute to 50 mL with water. Dilute this with water as needed to bring it within the range of the calibration curves for each carboxylic acid to prepare the test solution. Inject the test solution into a high-performance liquid chromatograph, measure the electrical conductivity, and calculate the values ​​of each carboxylic acid from the calibration curve.

[0056] • Separation column: Shim-pack SCR-102H (manufactured by Shimadzu Corporation) Mobile phase: 5 mmol / L p-toluenesulfonic acid • Detection reagent: 5 mmol / L p-toluenesulfonic acid, 100 μmol / L EDTA, 20mmol / L Bis-Tris buffer ·Injection volume: 10μL ·Flow rate: 0.8mL / min • Electrical conductivity detector: CDD-10AVP (manufactured by Shimadzu Corporation) ·Temperature: 40℃

[0057] 3. Analysis of sugar alcohols The sugar alcohols were analyzed by HPLC (High Performance Liquid Chromatography) according to the following method. The analytical instrument configuration is as follows: • Detector: Differential refractometer RID-10A (manufactured by Shimadzu Corporation) • Column: Shodex Asahipak NH2P-50 4E φ4.6mm x 250mm (manufactured by Showa Denko Co., Ltd.)

[0058] The analysis conditions are as follows: Column temperature: Room temperature Mobile phase: A mixture of acetonitrile and water (81:19 volume ratio) ·Flow rate: 1mL / min • Sample injection volume: 20 μL

[0059] The analytical samples were prepared using the following procedure. 3 g of the sample was weighed out, dissolved in 10 mL of water, and neutralized. This solution was then subjected to ultrasonic extraction for 30 minutes using an ultrasonic cleaner. Water was added to the solution to bring it to a final volume of 20 mL. This solution was filtered through a membrane filter to obtain the sample solution. This sample solution was subjected to high-performance liquid chromatography analysis.

[0060] 4. Analysis of water-soluble dextrin To the sample and 1.5 mL of standard solutions of each concentration, add 250 μL of 1N-NaOH aqueous solution and 500 μL of 0.5 M PMP (3-methyl-1-phenyl-5-pyrazolone)-methanol solution, and heat at 70°C for 30 minutes. To the resulting solution, neutralize with 250 μL of 1N-HCl aqueous solution, add 5 mL of chloroform and partition, and the aqueous layer is used as the measurement sample. The measurement sample obtained by the above procedure is measured using high-performance liquid chromatography-mass spectrometry under the following conditions.

[0061] Analysis conditions • HPLC system: Model ACQUITY UPLC, manufactured by Waters. • MS unit: Model SYNAPT G2-S HDMS, manufactured by Waters. Ionization: ESI ·Mass range: m / z 100-2500 • Column: Model Unison UK-C18 UP (2.0 x 100 mm, 3 μm) , manufactured by Intact Corporation Mobile phase: Solution A: 0.05% aqueous solution of formic acid, Solution B: Acetonitrile (%B = 15 → 90) ·Flow rate: 0.6mL / min ·Injection volume: 1μL

[0062] 5. Analysis of plant extracts (1) Analysis of chlorogenic acids The sample solution was filtered through a filter (0.45 μm), and chromatography was performed using a high-performance liquid chromatograph (model LC-20 Prominence, Shimadzu Corporation) with a column [Cadenza CD-C18 (3 μm, 4.6 mmφ × 150 mm, Imtakt)] at a column temperature of 35 °C using the gradient method. The mobile phase C solution was a 5% acetonitrile solution containing 0.05 mol / L acetic acid, 0.01 mol / L sodium acetate, and 0.1 mmol / L HEDPO, and the mobile phase D solution was an acetonitrile solution. The flow rate was 1 mL / min, the sample injection volume was 10 μL, and the UV detector wavelength was 325 nm. The gradient conditions were as follows:

[0063] Concentration gradient conditions Time (minutes) | Solution C concentration (volume%) | Solution D concentration (volume%) 0 100% 0% 10 100% 0% 15 95% 5% 20 95% 5% 22 92% 8% 50 92% 8% 52 10% 90% 60 10% 90% 60.1 100% 0% 70 100% 0%

[0064] (2) Loss on drying One g of the sample was spread evenly in an aluminum dish with an inner diameter of 4 cm, heated in a 105°C oven for 3 hours, and then the weight of the sample was measured to calculate the loss of weight due to drying.

[0065] Loss on drying [%]=(PQ) / P×100

[0066] [In the formula, P represents the weight of the sample before drying, and Q represents the weight of the sample after drying.]

[0067] 5. Evaluation of granules (1) Yield Each granule obtained in the examples and comparative examples was left to dry in a 55°C constant temperature bath for 30 minutes, then sieved using a 30-mesh (500 μm opening) stainless steel sieve. The yield was calculated from the percentage of the mass of granules that did not pass through the 30-mesh sieve using the following formula.

[0068] Yield [%] = (Mass of granules in 30 mesh / Mass of all granules recovered) × 100

[0069] (2)90% dissolution time The change in electrical conductivity (mS / m) of 1.54 g of each granule obtained in the examples and comparative examples was measured every 2 seconds using an electrical conductivity clock (HORIBA ES-71) when added to a beaker filled with 200 g of deionized water. After the granules dissolved, the point at which the electrical conductivity value stopped fluctuating for 10 seconds or more was defined as the 100% dissolution point of the granules. The electrical conductivity value at the 100% dissolution point was multiplied by 0.9 to determine the 90% dissolution point of the granules, and the time at which the electrical conductivity of the 90% dissolution point was reached was defined as the 90% dissolution time. Note that the electrical conductivity values ​​are considered to be within the range of fractions.

[0070] (3) Median diameter Three g of each granule obtained in the examples and comparative examples was subjected to a Camsizer XT (manufactured by Verder Scientific), and the median diameter (D50) of the test granules was measured by digital image analysis under the following measurement conditions. The median diameter was the average value obtained when the granules were measured three times.

[0071] ·Dispersion Pressure [kPa]:30 Measurement range: 1 μm to 2000 μm ·Number of measured particles: Approximately 1 million particles • Measurement stopped: 150 images were taken without showing any particles (300 images were taken per second).

[0072] 6.Raw materials The raw materials used in this embodiment are shown below. • Cellulose derivative: Hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) (Part number SE-03) Methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., product code MCE-4) • Maltitol: Recis fine powder (manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.) (Contains 99.5% maltitol) • Water-soluble dextrin: Sandec #30 (manufactured by Sanwa Starch Industry Co., Ltd., DE=2~5) • Binding solution: 99.5% ethanol (Nippon Alcohol Sales)

[0073] Manufacturing Example 1 Coffee bean extract 400g of coffee beans (Vietnam) with an L value of 50 were placed in a drip brewer. 0.25L of hot water was added to the bottom of the drip brewer, and then 1.02L of hot water was supplied from the top of the drip brewer via a shower and maintained for 10 minutes. After this period, while supplying hot water via the shower, the beans were drawn from the bottom of the drip brewer at a rate of 12.5g / 10 seconds. When the amount of liquid collected reached 2.4L, the collection was stopped, and this collected liquid was used as the extract. The obtained extract was dried using a spray dryer to obtain a powdered coffee bean extract. The coffee bean extract had a chlorogenic acid content of 36.1% by mass and a loss on drying of 3.9% by mass.

[0074] Example 1 Hydroxypropyl methylcellulose, malic acid, maltitol, coffee bean extract (Production Example 1), and water-soluble dextrin were uniformly mixed in the proportions (mass%) shown in Table 1 to prepare a water-soluble powder raw material. 20% by mass of 99.5% ethanol was added to the water-soluble powder raw material as a binder and kneaded until uniformly distributed. The kneaded mixture was granulated using an extrusion granulator (Dalton Co., Ltd., Multi-Gran MG-55-1) with a pore size of 0.8 mm. The resulting granules were allowed to stand and dry in a 55°C constant temperature bath for 30 minutes to obtain granules. The obtained granules were then analyzed and evaluated. The results are shown in Table 1.

[0075] Example 2 Granules were obtained using the same procedure as in Example 1, except that tartaric acid was used instead of malic acid. The obtained granules were then analyzed and evaluated. The results are shown in Table 1.

[0076] Comparative Example 1 Granules were obtained using the same procedure as in Example 1, except that malic acid was not used. The obtained granules were then analyzed and evaluated. The results are shown in Table 1.

[0077] Comparative Example 2 Granules were obtained using the same procedure as in Example 1, except that hydroxypropyl methylcellulose was not used. The obtained granules were then analyzed and evaluated. The results are shown in Table 1.

[0078] [Table 1]

[0079] Comparative Example 3 Except for using water as the binding agent instead of 99.5% ethanol, granulation was performed using the same procedure as in Example 1. However, a highly viscous paste was formed, and granules could not be produced. Therefore, the evaluation of granules was abandoned. The composition of Comparative Example 3, along with the results of Example 1, is shown in Table 2.

[0080] [Table 2]

[0081] Example 3 Granules were obtained using the same procedure as in Example 1, except that coffee bean extract (Production Example 1) was not used. The obtained granules were then analyzed and evaluated. The results, along with those of Example 1, are shown in Table 3.

[0082] Example 4 Granules were obtained using the same procedure as in Example 1, except that coffee bean extract (Production Example 1) and water-soluble dextrin were not used. The obtained granules were then analyzed and evaluated. The results, along with those of Example 1, are shown in Table 3.

[0083] [Table 3]

[0084] Examples 5 and 6 Granules were obtained using the same procedure as in Example 3, except that the amount of hydroxypropyl methylcellulose was changed to the proportions shown in Table 4. The obtained granules were then analyzed and evaluated. The results, along with those from Example 3, are shown in Table 4.

[0085] Examples 7 and 8 Granules were obtained using the same procedure as in Example 3, except that methylcellulose was used in the proportions shown in Table 4 instead of hydroxypropyl methylcellulose. The obtained granules were then analyzed and evaluated. The results, along with those from Example 3, are shown in Table 4.

[0086] Example 9 and Comparative Example 4 Granules were obtained using the same procedure as in Example 3, except that the amount of malic acid was changed to the proportions shown in Table 4. The obtained granules were then analyzed and evaluated. The results, along with those of Example 3, are shown in Table 4.

[0087] [Table 4]

[0088] Examples 10 and 11 Granules were obtained using the same procedure as in Example 3, except that the amount of malic acid was changed to the proportions shown in Table 5. The obtained granules were then analyzed and evaluated. The results, along with those of Example 3, are shown in Table 5.

[0089] Examples 12 and 13 Granules were obtained using the same procedure as in Example 3, except that tartaric acid was used instead of malic acid in the proportions shown in Table 5. The obtained granules were then analyzed and evaluated. The results, along with those from Example 3, are shown in Table 5.

[0090] Examples 14 and 15 Granules were obtained using the same procedure as in Example 3, except that citric acid was used instead of malic acid in the proportions shown in Table 5. The obtained granules were then analyzed and evaluated. The results, along with those from Example 3, are shown in Table 5.

[0091] Example 16 Granules were obtained using the same procedure as in Example 3, except that acetic acid was used instead of malic acid in the proportions shown in Table 5. The obtained granules were then analyzed and evaluated. The results, along with those from Example 3, are shown in Table 5.

[0092] Comparative Example 5 Granules were obtained using the same procedure as in Example 3, except that ascorbic acid was used instead of malic acid in the proportions shown in Table 5. The obtained granules were then analyzed and evaluated. The results, along with those from Example 3, are shown in Table 5.

[0093] [Table 5]

[0094] Examples 17 and 18 Granules were obtained using the same procedure as in Example 3, except that the amount of binding solution used was changed to the proportion shown in Table 6. The obtained granules were then analyzed and evaluated. The results, along with those of Example 3, are shown in Table 6.

[0095] [Table 6]

[0096] Tables 1-6 show that when wet granulation of water-soluble powder raw materials, using (A) cellulose derivatives and (B) organic acids in a specific ratio while coexisting with the binding solution allows for the production of granules with excellent oral solubility in a high yield.

Claims

1. A method for producing granules, comprising the step of wet granulation using a water-soluble powder raw material and a binding solution which is ethanol with a purity of 99.5% or higher, by adding 20 to 30 parts by mass of the binding solution to 100 parts by mass of the water-soluble powder raw material, The following ingredients; (A) Cellulose derivatives, and (B) One or more organic acids selected from malic acid and tartaric acid (i) to (iii) below; (i) At least one of the water-soluble powder raw material and the binder solution comprises component (A) and component (B). (ii) The water-soluble powder raw material contains component (A), and the binding solution contains component (B). (iii) The water-soluble powder raw material contains component (B), and the binding solution contains component (A). In any one of the embodiments selected from the above, and used in a proportion such that the mass ratio of component (A) to component (B) [(B) / (A)] is 0.3 to 10 in the granules produced, A method for producing granules.

2. A method for producing granules according to claim 1, wherein the content of component (A) is 0.1 to 10% by mass.

3. A method for producing granules according to claim 1 or 2, wherein the content of component (B) is 0.1 to 10% by mass.

4. A method for producing granules according to any one of claims 1 to 3, wherein the component (A) is one or more selected from alkylcellulose, hydroxyalkylcellulose, and hydroxyalkylalkylcellulose.

5. A method for producing granules according to any one of claims 1 to 4, wherein the granules contain one or more plant extracts selected from coffee beans, tea, rosemary, asparagus, turmeric, zedoary, soybean, cocoa, long pepper, and ginkgo leaves.

6. A method for producing granules according to any one of claims 1 to 5, wherein the water-soluble powder raw material comprises component (A) and component (B).

7. A method for producing granules according to any one of claims 1 to 6, wherein the wet granulation is fluid bed granulation or extrusion granulation.

Images